editorial use of has-bled score in an anticoagulation ... · pinheiro, ana luiza lima sousa, paulo...

Editorial

New Cholesterol Targets of SBC Guidelines on Dyslipidemia

Original Articles

NT-ProBNP at Admission Versus NT-ProBNP at Discharge as a Prognostic Predictor in Acute Decompensated Heart Failure

Safflower Oil (Carthamus tinctorius L.) Intake Increases Total Cholesterol and LDL-cholesterol Levels in an Experimental Model of Metabolic Syndrome

A Simpler and Shorter Neuromuscular Electrical Stimulation Protocol Improves Functional Status and Modulates Inflammatory Profile in Patients with End-Stage Congestive Heart Failure

Cirrhotic Patients with Child-Pugh C Have Longer QT Intervals

Predictors for Indication to Catheterization after Myocardial Perfusion Gated Spect

Assessment of Central Blood Pressure and Arterial Stiffness in Practicing Long-Distance Walking Race

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Use of HAS-BLED Score in an Anticoagulation Outpatient Clinic of a Tertiary Hospital

Review Articles

Performance of Diagnostic Tests for Intermediate Probabilities of Coronary Heart Disease: A Decision Making Analysis

The use of Cardiac 123I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize!

Viewpoint

Dance, Heart Failure and Erectile Function: Perspective of Better Clinical Management?

Case Reports

Tachycardiomyopathy and Extracorporeal Membrane Oxygenation: A Case Report

Familial Hypercholesterolemia: the Importance of Early Diagnosis and Management

SUMARY

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• Editorial

New Cholesterol Targets of SBC Guidelines on Dyslipidemia ....................................................................................... Maria Eliane Campos Magalhães

• Original Articles

NT-ProBNP at Admission Versus NT-ProBNP at Discharge as a Prognostic Predictor in Acute Decompensated Heart Failure ...............................................................................................................................................................................

Janine Magalhães, Fábio Soares, Márcia Noya, Gabriel Neimann, Lucas Andrade, Luiz Correia

Safflower Oil (Carthamus tinctorius L.) Intake Increases Total Cholesterol and LDL-cholesterol Levels in an Experimental Model of Metabolic Syndrome ......................................................................................................................

Lidiani Figueiredo Santana, Thaisa da Silva Dutra, Marcos Alexandre de Souza, Karine de Cássia Freitas, Silvia Aparecida Oesterreich, Cândida Aparecida Leite Kassuya, Fabíola Lacerda Pires Soares

A Simpler and Shorter Neuromuscular Electrical Stimulation Protocol Improves Functional Status and Modulates Inflammatory Profile in Patients with End-Stage Congestive Heart Failure ............................................

Maria Carolina Basso Sacilotto, Carlos Fernando Ramos Lavagnoli, Lindemberg Mota Silveira-Filho, Karlos Alexandre de Souza Vilarinho, Elaine Soraya Barbosa de Oliveira, Daniela Diógenes de Carvalho, Pedro Paulo Martins de Oliveira, Otávio Rizzi Coelho-Filho, Orlando Petrucci Junior

Cirrhotic Patients with Child-Pugh C Have Longer QT Intervals ................................................................................... Pedro Gemal Lanzieri, Ronaldo Altenburg Gismondi, Matheus de Castro Abi-Ramia Chimelli, Raíssa Pereira Cysne,

Thais Guaraná, Cláudio Tinoco Mesquita, Luís Otávio Mocarzel

Predictors for Indication to Catheterization after Myocardial Perfusion Gated Spect ............................................... Fernanda de Oliveira Mesquita, Larissa Andrade, Lívia Pitta, Andrea Rocha de Lorenzo, Ronaldo de Souza Leão Lima

Assessment of Central Blood Pressure and Arterial Stiffness in Practicing Long-Distance Walking Race ............ Edison Nunes Pereira, Priscila Valverde de Oliveira Vitorino, Weimar Kunz Sebba Barroso de Souza, Mariana Cardoso

Pinheiro, Ana Luiza Lima Sousa, Paulo Cesar Brandão Veiga Jardim, Jeeziane Marcelino Rezende, Antonio Coca

Use of HAS-BLED Score in an Anticoagulation Outpatient Clinic of a Tertiary Hospital ......................................... Rafael Coimbra Ferreira Beltrame, Franciele Taís Bandeira Giasson, André Luís Ferreira Azeredo da Silva, Bruna Sessim

Gomes, Luís Carlos Amon, Marina Bergamini Blaya, Rafael Selbach Scheffel, Fernando Pivatto Júnior

• Review Articles

Performance of Diagnostic Tests for Intermediate Probabilities of Coronary Heart Disease: A Decision Making Analysis ........................................................................................................................................................................

Clarissa Antunes Thiers, João Luis Barbosa, Bernardo Rangel Tura, Edilson Fernandes Arruda, Basilio de Bragança Pereira

The use of Cardiac 123I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize! .............................. Euclides Timóteo da Rocha, Wilson Eduardo Furlan Matos Alves, Derk O. Verschure and Hein J Verberne

• Viewpoint

Dance, Heart Failure and Erectile Function: Perspective of Better Clinical Management? ........................................ Tales de Carvalho, Ana Inês Gonzáles, Daiane Pereira Lima, Adair Roberto Soares dos Santos

• Case Reports

Tachycardiomyopathy and Extracorporeal Membrane Oxygenation: A Case Report .................................................. Joana Malheiro, João Almeida, Daniel Caeiro, Adelaide Dias, Marlene Fonseca, Vasco Gama

Familial Hypercholesterolemia: the Importance of Early Diagnosis and Management ............................................. Ana Flavia Cassini Cunha and Iliana Ribeiro

• News ...........................................................................................................................................................................................

• See in the Next Edition .......................................................................................................................................................

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ISSN 2359-4802 / IJCS ONLINE: ISSN 2359-5647

EditorCláudio Tinoco Mesquita – Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – Brazil

Associated EditorsClério Francisco Azevedo Filho (Cardiovascular Imaging Area) – Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ - Brazil

Gláucia Maria Moraes de Oliveira (Clinical Cardiology Area) – Departamento de Clínica Médica, Faculdade de Medicina (FM), Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ - Brazil

EDITORIAL BOARD

BrazilAndréia Biolo – Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS – BrazilAngelo Amato Vincenzo de Paola – Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP), São Paulo, SP – BrazilAntonio Cláudio Lucas da Nóbrega – Centro de Ciências Médicas, Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – BrazilAri Timerman – Unidades de Internação, Instituto Dante Pazzanese de Cardiologia (IDPC), São Paulo, SP - BrazilArmando da Rocha Nogueira – Departamento de Clínica Médica, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ - BrazilCarísi Anne Polanczyk – Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS – BrazilCarlos Eduardo Rochitte – Departamento de Cardiopneumologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP – BrazilCarlos Vicente Serrano Júnior – Faculdade de Medicina da Universidade de São Paulo, Instituto do Coração (InCor), São Paulo, SP – BrazilCláudio Gil Soares de Araújo – Instituto do Coração Edson Saad, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ - BrazilCláudio Pereira da Cunha – Departamento de Clínica Médica, Universidade Federal do Paraná (UFPR), Paraná, PR – BrazilCláudio Tinoco Mesquita – Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – BrazilDenílson Campos de Albuquerque – Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ – BrazilDenizar Vianna Araujo – Departamento de Clínica Médica, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ – BrazilEsmeralci Ferreira – Hospital Universitário Pedro Ernesto (HUPE), Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ - BrazilEvandro Tinoco Mesquita – Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – BrazilFernando Nobre – Faculdade de Medicina de Ribeirão Preto (FMRP), Universidade de São Paulo, São Paulo, SP – BrazilGabriel Blacher Grossman – Serviço de Medicina Nuclear, Hospital Moinhos de Vento, Porto Alegre, RS – BrazilHenrique César de Almeida Maia – Governo do Distrito Federal (GDF), Brasília, DF - BrazilHumberto Villacorta Júnior – Hospital Universitário Antônio Pedro (HUAP), Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – BrazilIran Castro – Fundação Universitária de Cardiologia (FUC), Instituto de Cardiologia do Rio Grande do Sul (IC), Porto Alegre, RS – BrazilJoão Vicente Vitola – Quanta Diagnóstico e Terapia (QDT), Curitiba, PR – BrazilJosé Geraldo de Castro Amino – Sessão Clínica, Instituto Nacional de Cardiologia (INC), Rio de Janeiro, RJ – BrazilJosé Márcio Ribeiro – Clínica Médica (Ambulatório), União Educacional Vale do Aço (UNIVAÇO), Ipatinga, MG - Brazil

Leonardo Silva Roever Borges – Departamento de Pesquisa Clínica, Universidade Federal de Uberlândia (UFU), MG – BrazilLeopoldo Soares Piegas – Fundação Adib Jatene, Instituto Dante Pazzanese de Cardiologia (IDPC/FAJ), São Paulo, SP - BrazilLuís Alberto Oliveira Dallan – Serviço Coronariopatias, Instituto do Coração (INCOR), São Paulo, SP - BrazilMarcelo Iorio Garcia – Clínica de Insuficiência Cardíaca, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ – BrazilMarcelo Westerlund Montera – Centro de Insuficiência Cardíaca, Hospital Pró Cardíaco (PROCARDIACO), Rio de Janeiro, RJ – BrazilMarcio Luiz Alves Fagundes – Divisão de Arritmia e Eletrofisiologia, Instituto Nacional de Cardiologia Laranjeiras (INCL), Rio de Janeiro, RJ – BrazilMarco Antonio Mota Gomes - Fundação Universitária de Ciências da Saúde Governador Lamenha Filho (UNCISAL), Maceió, AL - BrazilMarco Antonio Rodrigues Torres – Departamento de Medicina Interna, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS – BrazilMarcus Vinicius Bolivar Malachias – Instituto de Pesquisas e Pós-graduação (IPG), Faculdade de Ciências Médicas de Minas Gerais (FCMMG), Belo Horizonte, MG – BrazilMaria Eliane Campos Magalhães – Departamento de Especialidades Médicas, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ – BrazilMário de Seixas Rocha – Unidade Coronariana, Hospital Português, Salvador, BA – BrazilMaurício Ibrahim Scanavacca – Unidade Clínica de Arritmia, Instituto do Coração do Hospital das Clínicas da FMUSP, São Paulo, SP – BrazilNadine Oliveira Clausell – Faculdade de Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS – BrazilNazareth de Novaes Rocha – Centro de Ciências Médicas, Universidade Federal Fluminense, UFF - Rio de Janeiro, RJ – BrazilNelson Albuquerque de Souza e Silva – Departamento de Clínica Médica, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ – BrazilPaola Emanuela Poggio Smanio – Seção Médica de Medicina Nuclear, Instituto Dante Pazzanese de Cardiologia (IDPC) São Paulo, SP - BrazilPaulo Cesar Brandão Veiga Jardim – Liga de Hipertensão Arterial, Universidade Federal de Goiás (UFGO), Goiânia, GO – BrazilRonaldo de Souza Leão Lima – Pós-Graduação em Cardiologia, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro, RJ – BrazilSalvador Manoel Serra – Setor de Pesquisa Clínica, Instituto Estadual de Cardiologia Aloysio de Castro (IECAC), Rio de Janeiro, RJ – BrazilSandra Cristina Pereira Costa Fuchs – Departamento de Medicina Social, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS – BrazilTiago Augusto Magalhães – Ressonância Magnética e Tomografia Cardíaca, Hospital do Coração (HCor), São Paulo, SP – BrazilWalter José Gomes – Departamento de Cirurgia, Universidade Federal de São Paulo (UFESP), São Paulo, SP – BrazilWashington Andrade Maciel – Serviço de Arritmias Cardíacas, Instituto Estadual de Cardiologia Aloysio de Castro (IECAC), Rio de Janeiro, RJ – BrazilWolney de Andrade Martins – Centro de Ciências Médicas, Universidade Federal Fluminense (UFF), Niterói, Rio de Janeiro, RJ – Brazil

Guilherme Vianna e Silva (Interventionist Cardiology Area) – Texas Heart Institute, USAJoão Augusto Costa Lima (Integrative Imaging Area) – Johns Hopkins Hospital – Baltimore, USALauro Casqueiro Vianna (Multiprofessional Area) – Faculdade de Educação Física, Universidade de Brasília (UnB), Brasília, DF – BrazilMiguel Mendes (Ergometric and Cardiac Rehabilitation Area) – Sociedade Portuguesa de Cardiologia, PortugalRicardo Mourilhe-Rocha (Heart Failure and Myocardiopathy Area) – Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, RJ - Brazil

BIENNIUM BOARD 2016/2017

SOCIEDADE BRAZILEIRA DE CARDIOLOGIA/ BRAZILIAN SOCIETY OF CARDIOLOGY

PresidentMarcus Vinícius Bolívar Malachias

Vice-PresidentEduardo Nagib Gaui

President-ElectOscar Pereira Dutra

Scientific DirectorRaul Dias dos Santos Filho

Financial DirectorGláucia Maria Moraes Oliveira

Administrative DirectorDenilson Campos de Albuquerque

Government Liaison DirectorRenault Mattos Ribeiro Júnior

Information Technology DirectorOsni Moreira Filho

Communication DirectorCelso Amodeo

Research DirectorLeandro Ioshpe Zimerman

Assistance Quality DirectorWalter José Gomes

Specialized Departments DirectorJoão David de Sousa Neto

State and Regional Relations DirectorJosé Luis Aziz

Cardiovascular Health Promotion Director - SBC/FuncorWeimar Kunz Sebba Barroso de Souza

General OmbudsmanLázaro Fernandes de Miranda

Chief Editor of the Brazilian Archives of CardiologyLuiz Felipe Pinho Moreira

Governador - ACC Brazil ChapterRoberto Kalil Filho

ADJUNCT COORDINATION

International Relations CoordinatorDavid de Pádua Brazil

Universidade Corporativa CoordinatorGilson Soares Feitosa Filho

Standards and Guidelines CoordinatorJosé Francisco Kerr Saraiva

Cardiovascular Records CoordinatorOtávio Rizzi Coelho

Professional Valuation CoordinatorCarlos Japhet da Matta Albuquerque

New Projects CoordinatorFernando Augusto Alves da Costa

Continuing Education CoordinatorMarcelo Westerlund Montera e Rui Manuel dos Santos Póvoa

Strategic Planning ConcilAndrea Araújo Brandão, Ari Timeman, Dalton Bertolin Precoma, Fábio Biscegli Jatene

SBC Newsletter EditorCarlos Eduardo Suaide Silva

PRESIDENTS OF STATE AND REGIONAL BRAZILIAN SOCIETIES OF CARDIOLOGY

SBC/AL – Pedro Ferreira de AlbuquerqueSBC/BA – Nivaldo Menezes Filgueiras FilhoSBC/CE – Sandro Salgueiro RodriguesSBC/CO – Danilo Oliveira de ArrudaSBC/DF – José Roberto de Mello Barreto FilhoSBC/ES – Bruno Moulin MachadoSBC/GO – Aguinaldo Figueiredo Freitas Jr.

ExteriorAmalia Peix - Instituto de Cardiología y Cirugía Cardiovascular, Havana – Cuba Amelia Jiménez-Heffernan - Hospital Juan Ramón Jiménez, Huelva – SpainAna Isabel Venâncio Oliveira Galrinho - Hospital Santa Marta, Lisboa – PortugalAna Maria Ferreira Neves Abreu - Hospital Santa Marta, Lisboa – PortugalAna Teresa Timóteo - Hospital Santa Marta, Lisboa – PortugalCharalampos Tsoumpas - University of Leeds, Leeds – EnglandChetal Patel - All India Institute of Medical Sciences, Delhi – IndianEdgardo Escobar - Universidad de Chile, Santiago – Chile Enrique Estrada-Lobato - International Atomic Energy Agency, Vienna – Austria Erick Alexanderson - Instituto Nacional de Cardiología - Ignacio Chávez, Ciudad de México – México Fausto Pinto - Universidade de Lisboa, Lisboa - Portugal Ganesan Karthikeyan - All India Institute of Medical Sciences, Delhi – IndianGuilherme Vianna e Silva - Texas Heart Institute, Texas – USA Horacio José Faella - Hospital de Pediatría S.A.M.I.C. “Prof. Dr. Juan P. Garrahan”, Caba – Argentina

James A. Lang - Des Moines University, Des Moines – USA

James P. Fisher - University of Birmingham, Birmingham – England

João Augusto Costa Lima - Johns Hopkins Medicine, Baltimore – USA

Jorge Ferreira - Hospital de Santa Cruz, Carnaxide, Portugal

Manuel de Jesus Antunes - Centro Hospitalar de Coimbra, Coimbra – Portugal

Marco Alves da Costa - Centro Hospitalar de Coimbra, Coimbra – Portugal

Maria João Soares Vidigal Teixeira Ferreira - Universidade de Coimbra,

Coimbra – Portugal

Massimo Francesco Piepoli - Ospedale “Guglielmo da Saliceto”, Piacenza – Italy

Nuno Bettencourt - Universidade do Porto, Porto – Portugal

Raffaele Giubbini - Università degli Studi di Brescia, Brescia – Italy

Ravi Kashyap - International Atomic Energy Agency, Vienna – Austria

Roberto José Palma dos Reis - Hospital Polido Valente, Lisboa – Portugal

Shekhar H. Deo - University of Missouri, Columbia – USA

SBC/MA – Márcio Mesquita BarbosaSBC/MG – José Carlos da Costa ZanonSBC/MS – Delcio Gonçalves da Silva JuniorSBC/MT – Max Wagner de LimaSBC/NNE – Claudine Maria Alves FeioSBC/PA – Sônia Conde CristinoSBC/PE – Paulo Sérgio Rodrigues OliveiraSBC/PB – Miguel Pereira RibeiroSBC/PI – Wildson de Castro Gonçalves FilhoSBC/PR – Gerson Luiz Bredt JúniorSBC/RJ (SOCERJ) – Ricardo Mourilhe RochaSBC/RN – Maria de Fátima AzevedoSBC/RO (SOCERON) – João Roberto GemelliSBC/RS (SOCERGS) – Gustavo Glotz de LimaSBC/SC – Maria Emilia LuenebergSBC/SE – Sergio Costa Tavares FilhoSBC/SP (SOCESP) – Ibraim Masciarelli Francisco PintoSBC/TO – Andrés Gustavo Sánchez

DEPARTAMENTS AND STUDY GROUPS

SBC/DA – André Arpad FaludiSBC/DCC – José Carlos NicolauSBC/DCC/CP – Maria Angélica BinottoSBC/DCM – Elizabeth Regina Giunco AlexandreSBC/DECAGE – José Maria PeixotoSBC/DEIC – Luis Eduardo Paim RohdeSBC/DERC – Salvador Manoel SerraSBC/DFCVR – João Jackson DuarteSBC/DHA – Eduardo Costa Duarte BarbosaSBC/DIC – Samira Saady MorhySBCCV – Fabio Biscegli JateneSBHCI – Marcelo José de Carvalho CantarelliSOBRAC – Denise Tessariol HachulGAPO – Bruno CaramelliGECC – Mauricio WajngartenGECESP – Daniel Jogaib DaherGECETI – Gilson Soares Feitosa FilhoGECHOSP – Evandro Tinoco MesquitaGECIP – Gisela Martina Bohns MeyerGECN – Andréa Maria Gomes Marinho FalcãoGECO – Roberto Kalil FilhoGEECABE – José Antônio Marin NetoGEECG – Nelson SamesimaGEICPED – Estela AzekaGEMCA – Álvaro Avezum JuniorGEMIC – Felix Jose Alvarez RamiresGERCPM – Tales de CarvalhoGERTC – Marcello ZapparoliGETAC – João David de Souza NetoGEVAL – Luiz Francisco Cardoso

INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES

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International Journal of Cardiovascular Sciences (print ISSN 2359-4802 and online ISSN 2359-5647)

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This work is available per guidelines from the Creative Commons License. Attribution 4.0 International. Partial or total reproduction of this work is permitted upon citation.

DOI: 10.5935/2359-4802.20170090

466International Journal of Cardiovascular Sciences. 2017;30(6)466-468

EDITORIAL

Mailing Address: Maria Eliane Campos MagalhãesAv. N. Sra de Copacabana, 769/603. Postal Code: 22050-002, Copacabana, Rio de Janeiro – BrazilE-mail: [email protected]

New Cholesterol Targets of SBC Guidelines on DyslipidemiaMaria Eliane Campos MagalhãesHospital Universitário Pedro Ernesto (UERJ) e Hospital Pró-Cardíaco, Rio de Janeiro, RJ - Brazil

Atherosc leros is ; Cholesterol / s tandards ; Dyslipidemias; Risk Factor; Reference Standards.

Keywords

Evidence from clinical trials and meta-analysis have demonstrated that the most effective LDL (low-density lipoprotein) cholesterol–lowering treatment is associated with unequivocal benefits for reducing atherosclerotic cardiovascular disease (ASCVD) events.1 More recently, clinical trials concluded that the addition of ezetimibe and of a new class of drugs, inhibitors of proprotein convertase subtilisin/kexine type 9 (iPCSK9), to statins, were able to reduce LDL-C to levels not previously achieved with the available therapy so far.2-4

Is this context, the results of the IMPROVE-IT study - Improved Reduction of Outcomes: Vytorin Efficacy International Trial,2 with statins plus ezetimibe compared to statin monotherapy, achieved strict lipid control (LDL-c of 53.7 vs. 69.5 mg/dL, respectively) in patients with acute coronary syndrome, that is, individuals at high cardiovascular risk. In this study, patients achieving LDL-cholesterol levels less than 50 mg/dL had a significantly lower risk of major cardiovascular events compared to patients with LDL cholesterol levels above this value. The risk category was proportionally lower as the level of LDL-C decreased.2 Although at modest levels, there was an incremental cardiovascular event risk reduction, except mortality.

More recent clinical trials, also in subjects at high cardiovascular risk, on secondary prevention of atherosclerotic disease with PCSK9 inhibitors, notably with evolocumab (The Fourier study - Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk)3 and with bococizumab (Spire 1 and Spire 2 trials - Studies of PCSK9 Inhibition and the Reduction of Vascular Events,),4 in combination

with high-dose statin treatment regimens, have also shown major cardiovascular events reduction (except cardiovascular and general mortality). In the Fourier study,3 LDL cholesterol levels decreased to a median of 30 mg per deciliter (with LDL-C reduction of 59% from baseline in 48 weeks) and reduced by 15% the risk of the composite primary outcome (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina and coronary revascularization). However, only the Spire 2 study showed a significant benefit associated with the use of bococizumab.4 It is worth noting that, in the joint analysis of the SPIRE 1 and 2 trials, LDL-C had decreased by 56% by the 14th week of the study. The findings are in line with those observed with the evolocumab in the Global Assessment of Plaque Regression with a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV)5 trial, which evaluated the volume of atherosclerotic plaque, and showed that the cardiovascular benefits persisted even when LDL-C levels were reduced to 20-25 mg/dL. The study showed an average reduction of 1% in atheroma volume after 18 months of treatment and about two-thirds of patients showed plaque regression.5

On the other hand, Mendelian randomization studies involving more than 300,000 carriers of more than 50 genetic variants had already consistently demonstrated that lower LDL-C levels throughout life were associated with a decreased risk of ASCVD development. This not only demonstrated the causal relationship between LDL-C and ASCVD, but also a consistent dose-dependent log-linear association between the magnitude of LDL-C reduction and the risk of developing ASCVD.6

Due to these evidences, the Department of Atherosclerosis of the Brazilian Society of Cardiology (SBC-DA) released, in 2017, the Update of the Brazilian Dyslipidemias Directive and Prevention of Atherosclerosis,7 in accordance with the major international Guidelines on the subject,8

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Table 1 – Reference values and therapeutic target, according to the cardiovascular risk assessment estimated for adults aged 20 years and over

Lipids With fasting (mg/dL) Without fasting (mg/dL) Referential category

Total cholesterol† < 190 < 190 Desirable

HDL-c > 40 > 40 Desirable

Triglycerides < 150 < 175 ‡ Desirable

Risk category

LDL-c

< 130 < 130 Low

< 100 < 100 Intermediary

< 70 < 70 High

< 50 < 50 Very high

Non HDL-c

< 160 < 160 Low

< 130 < 130 Intermediary

< 100 < 100 High

< 80 < 80 Very high

*According to the cardiovascular risk assessment estimated by the prescribing physician; Total cholesterol > 310 mg/dL: consider the likelihood of familial hypercholesterolemia; When the triglyceride levels are above 440 mg/dL (without fasting), the prescribing physician must request a new triglycerides measurement after 12-hour fasting and the laboratory should consider this as a new triglycerides test.

Magalhães

New cholesterol targets of SBC Guidelines on Dyslipidemia

Int J Cardiovasc Sci. 2017;30(6)466-468

Editorial

and created the “very high cardiovascular risk category” for individuals with severe atherosclerotic coronary, cerebrovascular or peripheral vascular disease. For these subjects, targets for LDL-C were reduced to < 50 mg/dL (or a percentage reduction of at least 50% from baseline) and < 80 mg/dL for non-HDL (Non-high-density lipoprotein) cholesterol, maintaining the recommendation of achieving LDL-C goals as the primary target and non-HDL-C as a secondary treatment target.7

Table 1 shows the criteria for the analysis of lipid variables. The levels of TC, HDL-C and triglycerides remain interpreted as reference values, and only triglycerides are influenced by the metabolic state before collection (fasting and nonfasting), while LDL-C and non-HDL cholesterol must be interpreted according to individual health-risk category, estimated by the Global Risk Score (GRS)6. The Update of the Guidelines provided an application for calculating the GRS on the SBC-DA website (Risk Calculator 2017).6

Thus, aggressive reduction guidelines and, as a result, the inclusion of new LDL-C targets in the SBC-DA Update of the Guidelines of Dyslipidemia for high cardiovascular risk patients are based on the following rational:

– LDL-C plays an important role in the pathogenesis and perpetuation of ASCVD.

– Elevated levels of LDL-C are related to increased risk of ASCVD events and the reduction of LDL-C is associated with reduction of these events, continuously and incrementally. Therefore the higher the cardiovascular risk, the lower should be the level of LDL-C.

– Studies of Mendelian randomization have shown that individuals with low levels of LDL-C throughout life have a much lower risk of developing ASCVD.

– Randomized clinical trials with lipid-lowering drugs, notably statins, ezetimibe and PCSK9 inhibitors have shown a reduction of ASCVD events.

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1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al; Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomized trials. Lancet. 2010;376(9753):1670-81. doi: 10.1016/S0140-6736(10)61350-5.

2. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al; IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-97. doi: 10.1056/NEJMoa1410489.

3. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al; FOURIER Steering Comitee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-22. doi: 10.1056/NEJMoa1615664.

4. Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F; SPIRE Cardiovascular Outcome Investigators. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527-39. doi: 10.1056/NEJMoa1701488.

5. Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373-84. doi: 10.1001/jama.2016.16951.

6. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease. A Mendelian randomization analyses. J Am Coll Cardiol. 2012;60(25):2631-9. doi: 10.1016/j.jacc.2012.09.017.

7. Faludi AA, Izar MC, Saraiva JF, Chacra APM, Bianco HT, Afiune Neto A et al; Sociedade Brasileira de Cardiologia. Atualização da Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2017. Arq Bras Cardiol. 2017;109(2 supl 1):1-76. doi: 10.5935/abc.20170121.

8. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman J, Drexel H, et al; Authors/Task Force Members; Additional Contributor. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2016;37(39):2999-3058. doi:10.1093/eurheartj/ehw272.

References

Magalhães

New cholesterol targets of SBC Guidelines on Dyslipidemia


Editorial

DOI: 10.5935/2359-4802.20170082

Abstract

Background: Patients admitted for decompensated heart failure (HF) receive intensive diuretic and vasodilator therapy in the first days. Normally, this is a successful approach that leads to HF compensation and hospital discharge. However, recurrences within the first week of discharge are common.

Objective: to evaluate whether the main predictor of recurrent outcomes in patients with HF is the severity of decompensation at admission or patient’s blood volume after clinical management.

Methods: Prospective, cohort study of patients admitted between January 2013 and October 2014, with diagnosis of acute decompensated HF, who were followed-up for 60 days after discharge. Inclusion criterion was increased plasma NT-proBNP (> 450 pg/mL for patients younger than 50 years or > 900 pg/mL for patients older than 50 years). Primary outcome was the combination of cardiovascular death with rehospitalization for decompensated HF in 60 days.

Results: Ninety patients were studied, with median NT-proBNP at admission of 3,947pg/mL (IQR: 2,370 – 7,000 pg/mL), and median NT-proBNP at discharge of 1,946pg/mL (IQR: 1,000 – 3,781 pg/mL). The incidence of combined outcome was 30% (12.2% of deaths and 20% of rehospitalization). The area under the ROC curve for NT-proBNP at admission and 60-day cardiovascular events was 0.49 (p = 0.89; 95% CI = 0.36 – 0.62). The area under the curve of NT-proBNP absolute variation for 60 day-events was 0.65 (p = 0.04; 95%CI = 0.51 – 0.79), and the area under the curve for NT-BNP at discharge was 0.69 (p = 0.03; 95%CI = 0.58 – 0.80). In the multivariate analysis, pre-discharge NT-proBNP was a predictor of the primary outcome, independently of the NT-proBNP at admission and other risk factors.

Conclusion: Different from the severity of decompensation at hospitalization, blood volume after compensation of HF is associated with recurrent event. This finding suggests that, regardless of initial severity, therapy response during hospitalization is determinant of the risk of recurrent decompensation. (Int J Cardiovasc Sci. 2017;30(6)469-475)

Keywords: Heart Failure / therapy; Heart Failure / mortality; Ventricular Dysfunction; Natriuretic Peptide; Hospitalization.


ORIGINAL ARTICLE

Mailing Address: Luis C. L. Correia, MD, PhDAv. Princesa Leopoldina, 19/402. Postal Code: 40.150-080, Salvador, BA – BrazilE-mail: [email protected]

NT-ProBNP at Admission Versus NT-ProBNP at Discharge as a Prognostic Predictor in Acute Decompensated Heart FailureJanine Magalhães, Fábio Soares, Marcia Maria Noya-Rabelo, Gabriel Neimann, Lucas Andrade, Luis CorreiaEscola Bahiana de Medicina e Saúde Pública, Salvador, BA – Brazil

Manuscript received July 11, 2015, revised manuscript September 04, 2015, accepted June 05, 2017

Introduction

Acute decompensated heart failure (ADHF) is the

main cause of hospitalization in individuals older than

65 years.1 Usually, the use of intravenous diuretics and

vasodilators during hospitalization promotes a rapid

relief of congestive HF. Nevertheless, hospitalization rate

is high. Thus, it is important to identify mechanisms of

symptom recurrence after hospital discharge, in order

to determine whether the major triggering factor is the severity of initial decompensation or the capacity of patients to respond to the therapy.

Plasma concentration of NT-proBNP (N-terminal of the prohormone brain natriuretic peptide) reflects alteration of blood volume regulation in patients with ADHF, with a positive correlation with pulmonary capillary pressure.2-4

Besides, the reduction in NT-proBNP levels directly reflects blood volume response to diuretic therapy.5-7

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NT-proBNP in acute heart failure; hospital admission versus discharge


Original Article

With the aim of assessing the prognostic role of blood volume in both clinical decompensation at hospital admission and clinical compensation at discharge, plasma levels of NT-proBNP were measured in 90 consecutive patients admitted to a cardiac intensive care unit.

Methods

Sample selection

Patients with diagnosis of ADHF consecutively admitted to a cardiac unit of a tertiary hospital between January 2013 and October 2014 were included in the Heart Failure Registry. The inclusion criteria to this registry are the increase in plasma NT-proBNP (> 450 pg/mL in patients younger than 50 years or > 900 pg/mL for patients older than 50 years), and the presence of at least one of these characteristics: 1) dyspnea at rest or in the last 15 days; 2) signs of low cardiac output (hypotension – systolic blood pressure < 90 mHg; oliguria – urine output < 0.5 mL/kg/h; decreased level of consciousness); 3) signs of right heart failure (hepatomegaly, edema in lower limbs, jugular vein stasis). Exclusion criteria included age under 18 years, pregnancy, or refusal to participate in the study. The study was approved by the Ethics Committee of the institution, and all patients signed the informed consent form.

Determination of NT-proBNP plasma levels

NT-proBNP plasma levels were determined in blood samples collected as soon as the patient was admitted to the emergency, to obtain the shortest time between the onset of symptoms and blood collection. Another measurement was performed when the patient was clinically stable according to physician’s judgment and able to be discharged. NT-proBNP measurements were performed in serum by ELFA (Enzyme-Linked Fluorescent Assay).

Cardiovascular outcomes

Primary outcome was defined as 60-day cardiovascular death and/or rehospitalization by decompensated heart failure. Patients’ follow-up was performed during hospitalization and by telephone interview for assessment of combined symptoms at day 60 after discharge. Cardiovascular death was defined as sudden death or heart failure decompensation.

Statistical analysis

NT-proBNP values were expressed as median and interquartile range (IQR) and, as they were normally distributed, between-group comparisons were performed by the Mann-Whitney test. Analysis of NT-proBNP as a prognostic factor for cardiovascular outcomes in 60 days was performed by analysis of the area under the ROC (Receiver Operating Characteristics – ROC) curve. We also evaluated values of plasma NT-proBNP at hospital admission and discharge, as well as the absolute variation (difference between NT-proBNT at admission and NT-proBNT at discharge).

NT-proBNT was adjusted for clinical variables of death and rehospitalization for ADHF by logistic regression. First, an exploratory analysis of predicting variables was conducted, and then these variables were inserted into the model by the backward method. Kaplan Meier survival curves were plotted for patients with NT-proBNT levels above and below the median, and compared by the Log-rank test. Statistical significance was set at p < 0.05. Spearman correlation test (non-parametric test) was also conducted between NT-proBNT at admission and NT-proBNT absolute variation. Analyzes were performed by the SPSS software version 17.0 (SPSS Inc., Chicago, USA).

Sample size calculation

Sample size was estimated for adequate statistical power of pre-established analyzes, and to obtain a statistically significant ROC curve, with an area under the curve of 0.75 and event rates of 25%. A pilot study was conducted with the first 30 patients, and we found an event rate of 30%.

Results

Sample characteristics

A total of 90 patients (55% men) with diagnosis of ADHF, aged 69 ± 16 years were studied; 92% of them had dyspnea as a symptom of decompensation, and 95% were hospitalized with NYHA (New York Heart Association Functional Classification) class III/IV. Mean hospitalization period was 5 days. Ischemic heart disease was found in 50% of patients, and 49% of the sample had left ventricular ejection fraction (LVEF) lower than 40%. Among the causes of decompensation, low

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adherence to treatment was found in 41% of patients, and infection in 21% of patients. Median NT-proBNT at admission was 3,947 pg/mL (IQR: 2,370 – 7,000 pg/mL). Median absolute variation between admission and reversal of decompensation was –1533 pg/mL (IIQ = –3569 – 747 pg/mL), whereas NT-pro-BNP at discharge was 1,946 pg/mL (IIQ = 1000 – 3781 pg/mL).

During hospitalization, all patients received intravenous diuretics, 46% received angiotensin-converting-enzyme inhibitor, 36% received angiotensin receptor blockers, 71% received beta-blockers, 48% received intravenous nitroglycerin and 9% dobutamine. Other clinical features are described in Table 1.

During the first 60 days of admission, there was an incidence of 30% (n = 30) of combined cardiovascular events, 12.2% (n = 11) deaths in the first hospitalization (index hospitalization), and 20% (n = 18) of readmissions for heart failure.

Association between NT-proBNP and cardiovascular events

Median NT-proBNP at admission was similar between the patients free from events (3,341 pg/mL; IQR: 2,338 – 7,464 pg/mL) and those who had outcomes during the 60 days of follow-up (4,000 pg/mL; IQR = 2,376 – 6,927 pg/mL; p = 0.81). Also, the area under the ROC curve for NT-pro-BNP as an event predictor was 0.49 (95%IC: 0.36 – 0.62; p=0.89), suggesting the absence of predictive value (Figure 1A). Cardiovascular event-free survival was similar between the groups with NT-pro-BNP above the median and those with NT-pro-BNP below the median (67% vs 63%; p = 0.89; HR =1.07; 95%CI = 0.47 – 2.41; p = 0.86).

Regarding NT-proBNP variation, the absolute reduction was greater in the group free of cardiovascular events (- 2300 pg/mL; IQR: –4024 to –508 pg/mL) than in the group with outcomes after discharge (–1040 pg/mL; IQR = –2500 to – 832 pg/mL; p = 0.018). According to the area under the curve, the performance of NT-proBNP was 0.65 (95%CI: 0.53 – 0.77; p = 0.04) (Figure1B). Event-free survival was statistically different between the groups with absolute NT-proBNP variation above and below the median (52% vs 80%; p = 0.07; HR = 0.35; 95% CI = 0.16 – 0.78; p = 0.01).

NT-proBNP levels at discharge were higher among patients who required rehospitalization (2,300 pg/mL; IQR = 1,400 – 4,007 pg/mL), as compared with those free of events (1,489 pg/ml; IQR = 800 – 2,900 pg/ml;

p = 0.003). The performance of this variable according to the area under the ROC curve was 0.69 (95% CI: 0.58 – 0.81; p = 0.03) (Figure 1C). Event-free survival was statistically different between the groups with NT-proBNP above and below the median (53% vs 78%; p = 0.01; HR = 0.097; 95% CI = 0.013 – 0.71; p = 0.02) (Figure 1D).

There was a strong correlation between NT-proBNP at admission and the absolute variation during hospitalization (r= – 0.86; P=0.001), suggesting that these values may influence the medical approach to the negative water balance.

Multivariate analysis

In logistic regression analysis of both NT-proBNP at discharge (OR = 1.003; 95%CI = 1.0007 – 1.001; p = 0.009) and NT-proBNP absolute variation (OR = 1,001; IC 95% = 0,999 – 1,002; p = 0,17), NT-proBNP at discharge was an independent predictor, regardless of outcome occurrence, whereas the absolute variation lost its significance, which suggests that blood volume prior to hospital discharge is the strongest determinant.

In the second logistic regression model, we tested the predictive value of NT-proBNP at discharge, independently of the variables likely to have a causal effect on the outcome. Covariables included in the model were age, creatinine, and LVEF. After adjustment of the model, NT-proBNP at discharge (OR = 1.002; 95% CI = 1.001 – 1.003; p = 0.027) and creatinine (OR = 6.03; 95%CI = 2.63 – 13.8; P = 0.001) remained associated with the outcome, whereas age and LVEF lost its statistical significance (Table 2).

Discussion

The present study suggests that blood volume variation during hospitalization is more important than blood volume at admission for the prognosis of patients with ADHF. NT-proBNP at discharge, resulting from the clinical approach during hospitalization, was the strongest prognostic factor.

Different from studies with a blind design, in the present study in which the medical staff had access to the NT-proBNP values, the severity of decompensation at admission was not associated with any of the outcomes. The strong correlation between NT-proBNP at admission and its decrease suggests the possibility that the NT-proBNP levels were used as a base for therapy intensity, resulting in a greater reduction in blood

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Table 1 – General characteristics of the sample

Variables (n = 90)

Clinical data

Age (years) (mean and SD) 69 ± 16

Male sex 50 (55%)

Systolic blood pressure (mmHg)(mean and SD) 150 ± 35

Heart rate (bpm) (mean and SD) 92 ± 30

Creatinine (mg/dl)(mean and SD) 1.2 ± 0.6

Urea (mg/dl)(mean and SD) 60 ± 30

Prognostic score

ADHERE ( median and IQR) – 3 (IQ = – 3.6 a – 2.2)

OPTIMIZE (mean and SD) 35 ± 6

Heart failure etiology

Ischemic 45 (50%)

Hypertensive 18 (20%)

Chagasic 3 (3%)

Others 24 (27%)

Left ventricular ejection fraction

< 40% 43 (49%)

> 40% 42 (47%)

Therapy during hospitalization

ACEI 32 (46%)

ARB 25 (36%)

Beta-blockers 50 (71%)

Spironolactone 19 (27%)

Furosemide 90 (100%)

Digitalis 16 (23%)

Hydralazine 15 (21%)

Nitrate 30 (43%)

Dobutamine 6 (9%)

Nytroglicerin 34 (48%)

Nitroprusside 6 (9%)

Values of NT-proBNP

At admission 3,947 (IQ = 2,370 a 7,000)

Absolute variation –1,533 (IQ = – 3,569 a 747)

Discharge 1,946 (IQ = 1,000 a 3,781)

60-day cardiovascular outcomes

Combined (cardiovascular death and rehospitalization) 30 (34%)

Cardiovascular deaths after discharge 8 (9%)

Rehospitalization 22 (24%)

ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker

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NT-proBNP at discharge > medianNT-proBNP at discharge < median

Figure 1 – ROC curve of combined events – 60-day mortality and rehospitalization. NT-proBNP at admission (A); NT-proBNP absolute variation (B); NT-proBNP at discharge (C); Kaplan Meier curve of events or discharge b NT-proBNP at discharge (above or below the median)

Soares et al.



Original Article

volume. Besides, it is possible that hypervolemic patients are more responsive to diuretic therapy, regardless of the dose applied.

Our results are similar to those reported in an unblinded study by O’Brien et al.,8 which showed that NT-proBNP at discharge, rather than admission, acts as a predictor of adverse prognosis following acute left ventricular failure. A recent systematic review suggests that few studies with high methodological quality has been performed in this area, which emphasizes the importance of our study.9

In our analysis, another predictor factor of cardiovascular events was serum creatinine at admission, as demonstrated in previous studies.10 Changes in renal filtration are recognized as prognostic markers in heart failure patients. Multiple mechanisms, not fully elucidated, may explain this finding, since some of these patients already have pre-existing lesions. Another mechanism is cardiorenal syndrome type 1, which is the acute renal injury secondary to decompensated heart failure.

One limitation of this study is its single-center design which limits the generalization of the results. For a better

474

Table 2 – Logistic regression with NT-proBNP adjusted for the risk factors for combined events (death or rehospitalization)

Variables OR (95%CI) p-value

Age 2.69 (0.94-7.62) 0.85

Creatinine 6.03 (2.63-13.8) 0.001

Left ventricular ejection fraction 1.005 (0.956-1.056) 0.72

NT-proBNP at discharge 1.002 (1.001-1.003) 0.02

1. Rosamond W, Flegal K, Furie K, Go A, Greenlund K, Haase N, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-e146. doi: 10.1161/CIRCULATIONAHA.107.187998. Erratum in: Circulation. 2010;122(1):e10.

2. Forfia PR, Watkins SP, Rame JE, Stewart KJ, Shapiro EP. Relationship between B-type natriuretic peptides and pulmonary capillary wedge pressure in the intensive care unit. J Am Coll Cardiol. 2005;45(10):1667-71. doi: 10.1016/j.jacc.2005.01.046.

3. Maeder MT, Mariani JA, Kaye DM. Hemodynamic determinants of myocardial B-type natriuretic peptide release: relative contributions of

systolic and diastolic wall stress. Hypertension. 2010;56(4):682-9. doi: 10.1161/HYPERTENSIONAHA.110.156547.

4. Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA, et al. Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation. 2004;109(20):2432-9. doi: 10.1161/01.CIR.0000127882.58426.7A

5. Stienen S, Salah K, Moons AH, Bakx AL, Van Pol PE, Schroeder-Tanka JM, et al. Rationale and design of PRIMA II: a multicenter, randomized clinical trial to study the impact of in-hospital guidance for acute decompensated heart failure treatment by a predefined NT-PRoBNP target on the reduction of readmission and mortality rates. Am Heart J. 2014;168(1):30-6. doi: 10.1016/j.ahj.2014.04.008.

References

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Original Article

analysis, an interaction test should be performed between reduced LVEF and NT-proBNP, but such analysis was not possible due to small sample size. Besides, analyses of creatinine levels at discharge and its variation during hospitalization should also be performed for a better evaluation of this variable, similarly to what was performed with NT-proBNP.

From a clinical standpoint, the present study suggests that the therapy should focus on blood volume optimization before hospital discharge. This can be performed by assessment of cumulative water balance, change of body weight and radiologic data as well. On the other hand, due to its objectivity, NT-proBNP may be an important parameter of blood volume control before discharge, since there are limitations in the clinical examination for subclinical congestion.

Conclusion

Different from the severity of decompensation at hospitalization, blood volume after compensation of heart failure is associated with recurrent events, as evaluated by NT-proBNP plasma levels. This finding suggests that therapy response during hospitalization, rather than initial severity, was determinant of recurrent decompensation within 60 days of hospital discharge. This hypothesis

should be confirmed by randomized clinical trials that investigate the use of NT-proBNP during hospitalization.

Author contributions

Conception and design of the research: Magalhães J., Soares F., Correia L. Acquisition of data: Magalhães J. Analysis and interpretation of the data: Soares F. Statistical analysis: Soares F. Writing of the manuscript: Noya M. Critical revision of the manuscript for intellectual content: Noya M. Supervision / as the major investigador: Niemann G., Andrade L.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This study is not associated with any thesis or dissertation work.

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6. Singer AJ, Birkhahn RH, Guss D, Chandra A, Miller CD, Tiffany B, et al. Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management. Circ Heart Fail. 2009;2(4):287-93. doi: 10.1161/CIRCHEARTFAILURE.108.826685.

7. O’Brien RJ, Squire IB, Demme B, Davies JE, Ng LL. Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF. Eur J Heart Fail. 2003;5(4):499-506. PMID: 12921811.

8. Hayden JA, Côté P, Bombardier C. Evaluation of the quality of prognosis studies in systematic reviews. Ann Intern Med. 2006;144(6):427-37. PMID: 16549855.

9. Klein L, Massie BM, Leimberger JD, O'Connor CM, Piña IL, Adams KF

Jr, et al; OPTIME-CHF Investigators. Admission or changes in renal

function during hospitalization for worsening heart failure predict

postdischarge survival results from the outcomes of a prospective

trial of intravenous milrinone for exacerbations of chronic heart

failure (OPTIME-CHF). Circ Heart Fail. 2008;1(1):25-33. doi: 10.1161/

CIRCHEARTFAILURE.107.746933

10. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the

definition of a complex symbiosis gone wrong. Intensive Care Med.

2008;34(5):957-62. doi: 10.1007/s00134-008-1017-8.

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DOI: 10.5935/2359-4802.20170075


ORIGINAL ARTICLES

Mailing Address: Lidiani Figueiredo SantanaAv. Costa e Silva, s/n - Cidade Universitária, Postal Code: 79070-900. Campo Grande, MS – BrazilE-mail: [email protected]; [email protected]

Safflower Oil (Carthamus tinctorius L.) Intake Increases Total Cholesterol and LDL-cholesterol Levels in an Experimental Model of Metabolic SyndromeLidiani Figueiredo Santana,1 Thaisa da Silva Dutra,2 Marcos Alexandre de Souza,2 Karine de Cássia Freitas,1 Silvia Aparecida Oesterreich,2 Cândida Aparecida Leite Kassuya,2 Fabíola Lacerda Pires Soares3

Universidade Federal do Mato Grosso do Sul (UFMS),1 Campo Grande, MS; Faculdade de Ciências da Saúde, Universidade Federal da Grande Dourados (UFGD),2 Dourados, MS; Centro de Ciências da Saúde, Universidade Federal do Espírito Santo (UFES),3 Espírito Santo, ES – Brazil

Manuscript received October 11, 2016, revised manuscript November 01, 2016, accepted March 24, 2017

Abstract

Background: Overweight has been considered an important public health problem. To reverse this situation, various types of treatment are proposed. The safflower oil (Carthamus tinctorius L.) has been used in the prevention/treatment of obesity.

Objectives: The aim of this study was to evaluate the therapeutic effects of this oil in an experimental model of metabolic syndrome.

Methods: Male Wistar rats initially received a highly palatable (HP) diet for ten weeks for validation of a metabolic syndrome model. Following confirmation, the animals were treated with a HP diet and soybean oil (HPSO) or safflower oil (HPSA) supplementation (1.0 mL/1000 g of animal weight). At the end of the experiment, the body composition, lipid profile and blood glucose levels of the animals were assessed. Student t test was used for statistical analysis.

Results: In the first stage (induction of metabolic syndrome), the animals given the HP diet showed gain weight (p < 0.001), visceral adiposity (p = 0.001), and significantly higher levels of blood glucose (p = 0.001) and triglycerides (p = 0.03) than those of the control group. Also, there was a difference in liver weight (p = 0.01). These results demonstrate that the HP diet administration is an effective model for the experimental metabolic syndrome study. In the second stage, the animals of the HPSA group showed increased total cholesterol (p < 0.05) and LDL-cholesterol (p < 0.001) levels.

Conclusion: Under the referred experimental conditions, the use of safflower oil can cause possible deleterious effects on the lipid profile in a metabolic syndrome experimental model. (Int J Cardiovasc Sci. 2017;30(6)476-483)

Keywords: Oils; Carthamus; Cholesterol; Metabolic Syndrome; Dyslipidemias; Obesity / prevention & control.

Introduction

Obesity is a chronic, multifactorial disease defined as

abnormal or excessive fat accumulation, representing a

serious health risk. The prevalence of overweight and

obesity is increasing, and 12% of the world population

is considered obese.1 According to Brazilian studies,

52.5% of the adult population is over ideal healthy weight

and 17.9% are considered obese. The accumulation of

adipose tissue, particularly visceral fat, can contribute to changes in the body, triggering the metabolic syndrome. This syndrome can be defined as a complex disorder characterized by a set of cardiovascular risk factors related to central fat deposition and insulin resistance.2

In general, the pathophysiological basis for cardiovascular events is atherosclerosis, which is characterized by a chronic inflammatory process of the vascular wall and elevation of circulating serum

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Original Article

inflammatory markers, such as C-reactive protein (CRP). Regarding dyslipidemia, the primary goal in cardiovascular prevention is to achieve lower LDL-cholesterol (LDL-c) levels, and then reduce triglyceride levels and raise HDL-cholesterol (HDL-c) levels, and this latter goal is considered potentially beneficial for inhibiting the atherothrombotic process.3

To reduce these levels, dietary treatments that require changes in eating habits are proposed.4 In this context, the use of safflower oil (Carthamus tinctorius L.) is proposed to prevent or treat obesity. Safflower oil is extracted from saffron, a plant belonging to the Asteraceae family,5,6 contains high content of polyunsaturated (75% linoleic acid) and monounsaturated fatty acids.7 This composition stimulated further studies that demonstrated that dietary supplementation with safflower oil had a positive effect on lipid profile, with an antiatherogenic role.

Thus, given the lack of studies on the use of safflower oil on metabolic syndrome, and the existence of conflicting results in the literature, the present study aimed to assess the therapeutic effects of safflower oil on body composition, lipid profile and blood glucose in an experimental model of metabolic syndrome.

Methods

Animals and diet

The animals were provided by the central vivarium of the Health Sciences School of the Federal University of Grande Dourados (UFGD), city of Dourados, Mato Grosso do Sul state, Brazil. The procedures used in this study were approve by the Ethics Committee on Animal Use at UFGD (No 016/2013), according to the standards established by the Brazilian Committee for the protection of animals used for scientific purposes.8

A highly palatable (HP) diet was prepared based on the study by Naderali et al.,9 using 33% of ground Labina Purina® food preparation, 33% of condensed milk, 27% of water and 7% of sucrose (2.78 calories/g). The diet was kept under refrigeration until the moment of use, and the normal diet given to the control group was commercial food preparation of the Labina Purina® brand.

The experiment was divided into two stages. In the first stage, an animal model of metabolic syndrome was developed, and, in the second stage, intervention with safflower oil was performed in a disease model similar to the one observed in humans. Male Wistar rats aged 90 days (adult) were used in both experiments.

In the first stage, the animals were divided into two groups (n = 8): one group was fed a normal diet and water ad libitum, and the other group was fed a HP diet and water ad libitum, for ten weeks. In the second stage, the animals were also divided into two groups (n = 5-6), and both groups were fed a HP diet and water ad libitum, for ten weeks. The HP diet and soybean oil (HPSO) and HP diet and safflower oil (HPSA) were given by oral gavage to the animals. The daily administered dose was 1.0 mL/1000 g of animal weight.10,11

The safflower oil (Galena®) and soybean oil (Liza®) used in this study were purchased at a local store in the city of Dourados.

The same parameters were assessed in both stages. Therefore, food consumption and animal weight were daily measured. After ten weeks of treatment, the animals were fasted for 12 hours, anesthetized with xylazine and ketamine (10 mg/kg: 75 mg/kg) and euthanized by exsanguination via the inferior vena cava. The blood samples were centrifuged at 3000rpm for 15 minutes, and the serum was kept in freezer at –20°C until analysis. Adipose tissue samples from five sites was removed and weighed. The livers were subjected to histological analysis for the presence of hepatic steatosis.

Fasting blood glucose

For blood glucose assessment, the animals were fasted for 16 hours, and glucose was measured in blood collected from the tail artery, by using a glucometer (Testline Striptsl25), according to Formagio et al.11

Concentration of total cholesterol, HDL-c, LDL-c and triglycerides

The determination of total cholesterol, HDL-c and triglycerides in serum was based on the colorimetric enzymatic method, using commercial kit (Labtest®), according to the manufacturer’s instructions. The results were obtained with a spectrophotometer (Aaker/Bel - SF325NM - S05®). The concentration of LDL-c was obtained with a formula, according to the instructions of the manufacturer of the kit for quantification of HDL-c, using the Friedewald equation, where: VLDL-c = Triglycerides / 5 and LDL-c = Total Cholesterol - (HDL-c + VLDL-c).

Liver weight

The extracted liver was immediately immersed in saline solution to remove excess blood and then dried on paper and weighed.

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Table 1 – Total diatary intake, body composition, liver weight and biochemical parameters in rats fed with a normal diet and a highly palatable diet

Control Highly Palatable

Dietary intake (calories/group/week) 2606 ± 33.32 3084 ± 66.56 ***

Visceral Adiposity (%) 4.5 ± 0.3 6.401 ± 0.3 ***

Liver weight (g) 11.3 ± 0.4 12.8 ± 0.4 **

Total cholesterol (mg/dl) 82.8 ± 13.2 86.2 ± 7.1

Triglycerides (mg/dl) 96.6 ± 13.1 150.2 ± 19.0 *

Fasting blood glucose (mg/dl) 73.7 ± 1.4 85.6 ± 2.2 ***

Values expressed in man ± standard error of mean (SEN). Student t test. * p < 0.05; ** p < 0.01; ***p < 0.001; n = 8-9.

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Weight of adipose tissue

Adipose tissue samples from five sites (epididymal, retroperitoneal, perirenal, mesenteric and omental) were removed and weighed, and subsequently the animal fat (percentage of adipose tissue in each site to final body weight) was determined.

Liver histology

After euthanasia, the liver was removed for histological analysis and fixed in 10% formaldehyde solution unti l i t was embedded in paraff in. Then, microtome sections, 7 μm thick, were made and then mounted on glass slides. Each slide had a total of four sections removed from the paraffin block. The slides were then stained with hematoxylin and eosin, and analyzed under the microscope coupled to a digital camera with 200x magnification, for the classification of the presence of steatosis, according to Abbas et al.12 and Alves and Mello.13


The results were expressed in mean ± standard error of mean (SEM), and analyzed with Prisma 5.0 software (GraphPad Software, USA). Student t test was used to assess whether the means of the groups were statistically significant, and p < 0.05 values were considered statistically significant.

Results

The results of the first stage of the study where we attempted to develop an animal model of metabolic

syndrome can be seen in Table I. There was no statistically significant difference between the groups regarding water intake (unreported data).

In the second stage, the animals were fed a HP diet (that induces metabolic syndrome) supplemented with soybean oil (HPSO) or safflower oil (HPSA). Food and water intake of the animals was measured. However, there was no statistically significant difference between the groups for these parameters (unreported data).

Significant changes were observed in the lipid profile of the animals, and the HPSA group showed a higher concentration of total cholesterol and LDL-c than the control group (HPSO) (Figures 1A and 1B, p = 0.03 and p = 0.001, respectively). In contrast, HDL-c and triglycerides did not statistically differ between the groups (Figures 1C and 1D).

The HPSA group showed lower levels of fasting blood glucose as compared to the control group, but this difference was not statistically significant (Figure 2).

According to our results, there was no statistically significant difference regarding liver weight and weight gain between the control group and the HPSA group (Figures 3 and 4A, respectively). However, the HPSA group showed higher values of total adipose tissue, and epididymal and visceral adiposity, which were not statistically significant though (Figures 4B, 4C and 4D, respectively).

Regarding histological analysis of the liver, groups HPSO and HPSA showed mild microvesicular steatosis and moderate micro- and macrovesicular steatosis, respectively (Figure 5).

479

HPSO HPSA

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Figure 1 – Concentration of total cholesterol (A), LDL-cholesterol (B), HDL-cholesterol (C) and triglycerides (D) of rats fed with a highly palatable (HP) diet for 10 weeks, supplemented with soybean oil (HPSO) or safflower oil (HPSA). n = 5-6. Values expressed in mean ± standard error of mean (SEM). Student t test. * p < 0.05; ** p < 0.01.

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Figure 2 – Fasting blood glucose of rats fed with a highly palatable (HP) diet for 10 weeks, supplemented with soybean oil (HPSO) or safflower oil (HPSA). n = 5-6. Values expressed in mean ± standard error of mean (SEM). Student t test.

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Discussion

Several experimental models have been proposed

for the study of obesity and its metabolic disorders,

most of them based on genetic modifications.14,15

However, the animal model that most resembles the

etiology of human obesity is the one involving high

intake of dietary fat.16 However, the extrapolation

of many of these animal models to human obesity

is limited by the difficulty in reproducing disorders

that characterize metabolic syndrome, such as central

obesity and changes in the metabolism of lipids and

glucose. Also, they require long periods of time for the

induction of obesity.17,18 Thus, the model used in this

480

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16

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Figure 3 – Liver weight of rats fed with a highly palatable (HP) diet for 10 weeks, supplemented with soybean oil (HPSO) or safflower oil (HPSA). n = 5-6. Values expressed in mean ± standard error of mean (SEM). Student t test.

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Figure 4 – Body weight gain (A), weight of total adipose tissue (B), epididymal adipose tissue (C) and visceral adiposity (D) of rats fed with a highly palatable (HP) diet for 10 weeks, supplemented with soybean oil (HPSO) or safflower oil (HPSA). n = 5-6. Values expressed in mean ± standard error of mean (SEM). Student t test.

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study is the most suitable for the research of metabolic

syndrome interventions, because it effectively mimics

the disorder observed in humans, and requires a

relatively lower induction time compared to other

studies,19,20 which reduces research costs.

Such findings (visceral obesity, hyperglycemia and

hypertriglyceridemia) are consistent with the diagnosis

of metabolic syndrome, also including hepatic steatosis.

Several studies indicate an association between obesity

and metabolic disorders, particularly the intake of

hypercaloric and high carbohydrate diets, which is also

demonstrated in our study.16-21

According to the results obtained in the second

stage of the study, there was no statistically significant

difference between the groups regarding weight gain,

which is similar to the findings obtained in a study by

481

Figure 5 – Histological section of liver stained with Hematoxylin and Eosin (H&E) of rats fed with a highly palatable (HP) diet for 10 weeks, supplemented with soybean oil (HPSO) or safflower oil (HPSA) for 10 weeks n = 5-6. HPSO group: mild microgoticular steatosis. HPSA group: moderate micro and macrogoticular steatosis.

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Fernandes et al.,22 where no significant difference was found in the weight gain of animals in the groups given a diet supplemented with 1% of conjugated linoleic acid (CLA) compared to the groups that were not given the referred supplement. This finding is also corroborated by the study by Bhattachaya et al.,23 where BALB/C mice fed with a high-fat diet supplemented with 0.4% of CLA showed no change in body weight.

Nevertheless, different results were obtained by DeLany et al.19 and Park and Pariza.21 According to these studies, changes in body composition following the supplementation of CLA may be related to decreased proliferation and differentiation of preadipocytes, elevation of energy expenditure and changes in the concentration of leptin, a protein synthesized and secreted by adipocytes, involved in energy homeostasis. In contrast with the suggestions of these studies, in our study the group supplemented with safflower oil showed higher visceral adiposity, although this difference was not statistically significant. This fact indicates that there are conflicting reports in the literature regarding changes in body composition associated with the use of safflower or its main component, CLA.

Analysis of the lipid profile of the animals showed that the HPSA group had a higher concentration of total cholesterol and LDL-c compared to the control group (HPSO). Similar results were obtained by Fernandes et al.,22 who demonstrated increase in cholesterol levels following supplementation with 1% of CLA. This fact can be explained by changes in

hepatic lipid metabolism caused by CLA, which may affect metabolic interconversion of fatty acids in the liver, resulting in a modified composition of fatty acids, causing changes in lipoproteins.24

Still regarding cholesterol, in the above-mentioned study by Fernandes et al.22 with animals supplemented with CLA distributed into active and sedentary, there was improvement in HDL-c levels in the sedentary group supplemented with CLA. However, in our study, as well as in the study by Marques et al.,25 which used safflower oil other than CLA, there was no statistically significant difference between the groups regarding HDL-c and serum triglycerides.

In turn, analysis of fasting blood glucose showed that the HPSA group had higher values compared to the control group, though this difference was not statistically significant. Marques et al.25 concluded that exclusive supplementation with 2% CLA affected the metabolism of glucose in mice, and these animals had severe hyperglycemia compared to the control group. This difference may not have been observed in our study because we used safflower oil, not isolated CLA.

The study by Tanaka et al . 26 indicate that supplementation with CLA induces insulin resistance in animals and humans. However, other studies had controversial results, such as the study of Parra et al.,27 these authors demonstrated that the mixture of CLA isomers did not increase insulin resistance in rats given oral supplementation.

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1. World Health Organization. (WHO). Obesity and overweight. Geneva; 2012.

2. Mendes KG, Theodoro H, Rodrigues AD, Olinto MT. [Prevalence of metabolic syndrome and its components in the menopausal transition: a systematic review]. Cad Saúde Publica. 2012;28(8):1423-37.

3. Santos RD, Gagliardi AC, Xavier HT, Magnoni CD, Cassano R, Lottenberg AM, et al; Sociedade Brasileira de Cardiologia. [First guidelines on fat consumption and cardiovascular health]. Arq Bras Cardiol. 2013;100(1 Suppl 3):1-40.

4. Ministério da Saúde. Secretaria de Vigilância em Saúde. Vigilância e fatores de risco e proteção para doenças crônicas por inquérito telefônico (VIGITEL/MS). Brasília; 2014.

5. Alasnier C, Berdeaux O, Chardigny JM, Sebedio JL. Fatty acid composition and conjugated linoleic acid content of different tissues

in rats fed individual conjugated linoleic acid isomers given as triacylglycerols small star, filled. J Nutr Biochem. 2002;3(6):337-45.

6. Steck SE, Chalecki AM, Miller P, Conway J, Austin GL, Hardin JW. Conjugated linoleic acid supplementation for twelve weeks increases lean body mass in obese humans. J Nutr. 2007;137(5):1188-93.

7. Polunin O. Guia de campo de lãs Flores de Europa. (1088 fotografias a color). Omega; 1991.

8. Ministério da Ciência, Tecnologia e Inovação (MCTI). Conselho Nacional de Controle de Experimentação Animal (CONCEA). Lei nº 11.974, 08.10.2008. Regulamenta o inciso VII do § 1o do art. 225 da Constituição Federal, estabelecendo procedimentos para o uso científico de animais; revoga a Lei no 6.638, de 8 de maio de 1979, e dá outras providências. In: Diário Oficial da União, Brasília, 9 out. 2008.

References

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Therefore, there is no consensus on the relationship between CLA intake and insulin sensitivity. Further studies are needed to clarify such metabolic changes.

Also, there were no differences in the groups regarding the relative liver weight. The study by Gaiva et al.28 with rats fed diets rich in polyunsaturated fatty acids reported increased liver weight. It can be suggested that in our study there was no statistically significant difference in liver weight between the groups because soybean oil and safflower oil are both sources of polyunsaturated fatty acids, and, thus, have the same action on liver.

However, analysis of liver histological sections showed that supplementation with safflower oil interferes with hepatic steatosis, and the presence of micro- and macrovesicular steatosis is noticeable in this group. According to Reddy,29 fatty acid synthesis is stimulated to promote the storage of energy substrate in adipose tissue, a process that affects lipid metabolism, especially oxidation homeostasis and lipid synthesis, resulting in obesity, resistance to insulin, dyslipidemia and hepatic steatosis.

Conclusion

Our results showed that animals fed a HP diet constitute an effective model for the experimental study of metabolic syndrome, due to its similarity with the etiology of the syndrome observed in humans, and also because that model does not require the use of genetically modified animals, has shorter induction time and relatively low costs.

We concluded that the effect of safflower oil on the prevention of adverse impacts on body composition, lipid

profile and blood glucose was not confirmed under the conditions of the present study. Instead, supplementation with safflower oil resulted in the elevation of total serum cholesterol and its most atherogenic fraction, LDL-c, as well as in hepatic steatosis, indicating that the use of safflower oil may have deleterious effects on lipid profile and health.


Conception and design of the research: Santana LF, Dutra TS, Freitas CF, Soares FLP. Acquisition of data: Santana LF, Dutra TS, Souza MA, Freitas CF, Oesterriech AS, Kassuya CPL, Soares FLP. Analysis and interpretation of the data: Santana LF, Souza MA, Freitas CF, Oesterriech AS, Kassuya CPL, Soares FLP. Statistical analysis: Santana LF, Souza MA, Freitas CF, Oesterriech AS, Kassuya CPL, Soares FLP. Writing of the manuscript: Santana LF, Freitas CF, Kassuya CPL, Soares FLP. Critical revision of the manuscript for intellectual content: Santana LF, Freitas CF, Kassuya CPL, Soares FLP.



Sources of Funding

The present study had no external sources of funding.

Study Association

This article is part of the conclusion of the Bachelor's Degree in Nutrition from Lidiani Figueiredo Santana of the Federal University of Grande Dourados (UFGD).

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9. Naderali EK, Brown MJ, Pickavance LC, Wilding JP, Doyle PJ, Williams G. Dietary obesity in the rat induces endothelial dysfunction without causing insulin resistance: a possible role for triacylglycerols. Clin Sci (Lond). 2001;101(5):499-506.

10. Diisman E, Gonçalves LA, Reusing AF, Martin PG, Mariucci RG, Vicentini VE. Cytotoxic potential of waters of the streams Mandacaru, Maringá, Miosótis and Nazareth in the urban area of Maringá, Paraná State, Brazil. Acta Scientiarum Biological Sciences. 2012;34(3):311-8.

11. Formagio AS, Kassuya CA, Neto FF, Volobuff CR, Iriguchi EK, Vieira MdoC, et al. The flavonoid content ande antiproliferative, hypoglycaemic, anti-inflammatory and free radical scavenging activities of Annona dióica St. Hill. BMC Complement Altern Med. 2013;13:14.

12. Abbas AK, Kumar V, Fausto N, Robbins C. Patologia: bases patológicas das doenças. Rio de Janeiro: Elsevier; 2010.

13. Mello ES, Alves VA. Atlas de patologia hepática. São Paulo: Manole; 2010.

14. Duarte AC, Fonseca DF, Manzoni MS, Soave CF, Sene-Fiorese M, Damaso AR, et al. High-fat diet and secretory capacity of insulin in rats. Rev Nutr. 2006;19(3):341-8.

15. Kim CS, Lee SC, Kim YM, Kim BS, Choi HS, Kawada T, et al. Visceral fat accumulation induced by a high-fat diet causes the atrophy of mesenteric lymph nodes in obese mice. Obesity (Silver Spring). 2008;16(6):1261-9.

16. Cesaretti MLR, Kohlmann Jr O. Modelos experimentais de resistência à insulina e obesidade: lições aprendidas. Arq Bras Endocrinol Metab. 2006;50(2):190-7.

17. Coenen KR, Gruen ML, Chait A, Hasty AH. Diet-induced increases in adiposity, but not plasma lipids, promote macrophage infiltration into white adipose tissue. Diabetes. 2007;56(3):564-73.

18. Akagiri S, Naito Y, Ichikawa H, Mizushima K, Takagi T, Handa O, et al. A mouse model of metabolic syndrome: increase in visceral adipose tissue precedes the development of fatty liver and insulin resistance in high-fat diet-fed male KK/Ta mice. J Clin Biochem Nutr. 2008;42(2):150-7.

19. DeLany JP, Blohm F, Truett AA, Scimeca JA, West DB. Conjugated linoleic acid rapidly reduces body fat content in mice without affecting energy intake. Am J Physiol. 1999;276(4 Pt 2):R1172-9.

20. Hajer GR, van Haeften TW, Visserem FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J. 2008;29(24):2959-71.

21. Park Y, Pariza MW. The effects of dietary conjugated nonadecadienoic acid on body composition in mice. Biochim Biophys Acta. 2001;1533(3):171-4.

22. Fernandes SA, Natali AJ, Teodoro BG, Franco FS, Laterza MC, Peluzio M. Dieta hiperlipídica e ácido linoleico conjugado: efeitos nos lipídios séricos, peso e composição corporal de camundongos Apo E(-/-) exercitados. R Bras Ci e Mov. 2011;20(1):47-55.

23. Bhattacharya A, Banu J, Rahman M, Causey J, Fernandes G. Biological effects of conjugated linoleic acids in health and disease. J Clin Biochem Nutr. 2006;17(12):789-810.

24. Munday JS, Thompson KG, James KA. Dietary conjugated linoleic acids promote fatty streak formation in the C57BL/6 mouse atherosclerosis model. Br J Nutr. 1999;81(3):251-5.

25. Marques AC, Dragano NR, Naróstica Jr MR. Weight and blood glucose reduction resulting from conjugated linoleic acid and phytosterols supplementation on hiperlipidic diets of mice. Cienc Rural. 2012;42(2):374-80.

26. Tanaka N, Sano K, Horiuchi A, Tanaka E, Kiyosawa K, Aoyama T. Highly purified eico-sapentaenoic acid treatment improves nonalcoholic steato-hepatitis. J Clin Gastroenterol. 2008;42(10):413-8.

27. Parra P, Serra F, Poleu A. Moderate doses of conjugated linoleic acid isomers mix contribute to lowering body fat content maintaining insulin sensitivity and a noninflammatory pattern in adipose tissue in mice. J Nutr Biochem. 2010;21(2):107-15.

28. Gaiva MH, Couto RC, Oyama LM, Couto GE, Silveira VL, Ribeiro EB. Diets rich in polyunsaturated fatty acids: effect on hepatic metabolism in rats. Nutrition. 2000;19(2):144-9.

29. Reddy JK. Nonalcoholic steatosis and steatohepatitis. III. Peroxisomal beta-oxidation, PPAR alpha, and steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2001;281(6):1333-9.

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DOI: 10.5935/2359-4802.20170064


ORIGINAL ARTICLE

Mailing Address: Maria Carolina Basso SacilottoAvenida Arlindo Joaquim de Lemos, 865, Apto: 32. Postal Code: 13100450, Vila Lemos, Campinas, SP – BrazilE-mail: [email protected]; [email protected]

A Simpler and Shorter Neuromuscular Electrical Stimulation Protocol Improves Functional Status and Modulates Inflammatory Profile in Patients with End-Stage Congestive Heart FailureMaria Carolina Basso Sacilotto, Carlos Fernando Ramos Lavagnoli, Lindemberg Mota Silveira-Filho, Karlos Alexandre de Souza Vilarinho, Elaine Soraya Barbosa de Oliveira, Daniela Diógenes de Carvalho, Pedro Paulo Martins de Oliveira, Otávio Rizzi Coelho-Filho, Orlando Petrucci JuniorUniversidade Estadual de Campinas (UNICAMP), Campinas, SP – Brazil

Manuscript received September 04, 2016; revised manuscript November 21, 2016; accepted April 05, 2017.

Abstract

Background: Neuromuscular electrical stimulation (NMES) using a stimulation wave for 5 days/week over 8 weeks has been used as a treatment option for congestive heart failure (CHF) patients who are unable to tolerate aerobic exercise.

Objective: We assessed the impact of a shorter NMES protocol using a Russian stimulation wave on the functional status, quality of life (QoL) and inflammatory profile of end-stage CHF patients.

Methods: Twenty-eight patients with end-stage CHF (53 ± 11 years) were randomized to the NMES or control group. Treatment was an NMES training program with Russian stimulation wave, applied for 50 minutes to both quadriceps femoral muscles twice weekly over seven weeks. The stimulation intensity was chosen to elicit muscle contractions in the NMES group and current input up to sensory threshold in the control group. Distance in the 6-minute walk test (6MWT) and QoL score by the Minnesota Living with Heart Failure Questionnaire were evaluated before, immediately after and one month after NMES protocol completion. Peripheral leukocytes were obtained to measure the gene expression levels of inflammatory cytokines.

Results: The NMES group showed increases in the 6MWT (324 ± 117 vs. 445 ± 100 m; p = 0.02) and QoL score (64 ± 22 vs. 45 ± 17; p < 0.01) immediately but not 1 month after protocol completion, as well as increased gene expression levels of IL-1β, IL-6 and IL-8 after protocol completion.

Conclusion: Using a shorter and fewer sessions NMES protocol improved the QoL score and functional class of severe CHF patients, and modulated the gene expression levels of some cytokines. This protocol might be a good alternative for patients with severe CHF and limitations in protocol adherence. (Int J Cardiovasc Sci. 2017;30(6)484-495)

Keywords: Heart Failure; Exercise Tolerance; Electric Stimulation Therapy / adverse effects; Exercise; Rehabilitation; Heart Transplantation.

Introduction

Exercise intolerance is a challenging issue for patients with severe congestive heart failure (CHF)1,2, who commonly exhibit fatigue and dyspnea. Patients with stable CHF should perform aerobic exercise training protocols to decrease muscle weakness caused by lack of physical activity, as well as to improve functional status, exercise capacity and quality of life (QoL).3-5

However, some patients are unable to perform aerobic exercise training protocols due to exercise intolerance or an unwillingness to participate in such programs.2,6 As an alternative to muscular training therapy in patients with CHF or chronic obstructive pulmonary disease (COPD), neuromuscular electrical stimulation (NMES) may be used to improve functional status, exercise capacity, endothelial function and QoL.2,3,6-8 NMES has been demonstrated to modulate inflammatory mediators

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in patients with spinal cord lesions9 and athletes after a bout of running.10 However, the effects of NMES on the inflammatory profiles of CHF patients have not been well documented.

Common NMES training protocols involve treatments over 5 to 6 days/week for 6 to 8 weeks. These intensive therapy protocols may preclude some CHF patients from adhering to this treatment modality2,3 because, similarly to other exercise training protocols, patients may be unwilling to attend the outpatient clinic daily for treatment.2,3,7,8,11 Most studies of NMES-treated CHF patients have employed functional electrical stimulation,2,7,13,14 which causes muscle contractions. Another NMES electric waveform modality is the Russian current, which involves the application of a 2500-Hz current at a burst frequency of 50 Hz. This modality effectively produces muscular strength in normal individuals15-17 and may be more comfortable than other current modalities for patients during NMES sessions.15,18,19

The Russian current has a sine waveform, which has been reported as more comfortable for the patient during the electrical delivery to the muscle. Of note, the Russian current has an average frequency with a deeper stimulus effect and may be more tolerable by the patient.20-22

The unique characteristics of the Russian current might increase patient adherence to the NMES protocol. Therefore, the aim of this work was assess the effectiveness, compared to the literature, of a shorter NMES protocol consisting of twice-weekly training for 7 weeks using a Russian current, in terms of the functional status, QoL score, and inflammatory profile in patients with CHF.

Methods

Patient selection

Institutional Review Board approval was obtained for the study, and all patients provided written informed consent to participate. To be included in the study, patients must be on the awaiting heart transplant list, NYHA functional class III or IV, receiving optimal oral pharmacological treatment, and have stable CHF symptoms in the last 3 months. Exclusion criteria were neurologic or orthopedic disease that could limit the patient’s ability to accomplish the 6-minute walk test (6MWT). This study is registered at www.clinicaltrials.gov under the number NCT02313714.

Protocol for NMES

This study was carried out at an outpatient clinic of a university hospital with a room temperature maintained between 22 and 24 °C. NMES was applied by 2 adhesive electrodes on the skin over the upper lateral aspect of the quadriceps muscle, 5 cm below the inguinal fold and 3 cm above the upper patella border of both lower extremities (Figure 1).

In the NMES group, the stimulator (Neurodyn 2000, Ibramed, Amparo, SP, Brazil) was configured to deliver a direct electrical current with a 2500-Hz sinusoidal current at a burst frequency of 50 Hz (Russian current) for 3 seconds, followed by 9 seconds of rest. The intensity of stimulation was adjusted to achieve visible contraction. The stimulus intensity is adjusted according to patient tolerance. However, in order to be sure that muscle fiber contraction is occurring, the visual evaluation of at least one visible contraction is used. From this levels of contraction and patient´s comfort we adjusted higher levels of intensity and the highest level of intensity is adjusted according to patient´s tolerance.23

During electrical stimulation sessions, the legs were positioned in a light knee flexion position in both groups. In the control group, the same setup was used with 2 adhesive electrodes in the identical position as above, and the stimulator was configured to deliver a direct electrical current with the same specifications (Russian current). The intensity of stimulation was set low, to achieve a sensation of stimulus but with no visual muscular contraction.

Patients in both groups were evaluated weekly. The protocol was applied for 50 minutes twice a week, Wednesdays and Fridays, for 7 weeks.

Distance in the 6MWT

The 6MWT was performed in a 30-meter-long indoor hallway of the university hospital. Patients were trained and oriented to walk as fast as possible with encouragement. Only after the patient was considered trained was the walked distance recorded. All 6MWT sessions were carried out by the same observer (MCBS) in accordance with the American Thoracic Society (ATS) instructions.24 To ensure the patient’s safety and consistency in 6MWT application, the modified Borg scale was applied before, during and after the 6MWT to evaluate the patient’s self-perception of dyspnea and fatigue. The 6MWT was performed at 3 time points:

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Figure 1 – Placement of adhesive electrodes over the quadriceps femoral muscle. A single set of double adhesives was used as a simple way of applying neuromuscular electrical stimulation.

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immediately before the first NMES session, 1 day after the last NMES session and 1 month after termination of the NMES protocol.

QoL by the Minnesota Living with Heart Failure Questionnaire (LHFQ)

A Portuguese language version of the LHFQ25 was utilized to assess the QoL score 1 day before starting the NMES protocol, 1 day after completing the 7-week NMES protocol, and 1 month after protocol termination. The LHFQ is a questionnaire tool consisting of 21 questions, including physical and emotional variables. This questionnaire provides one score, with a scale from 0 to 105. Higher scores are associated with a worse QoL status. The LHFQ is a very frequently used score to assess QoL and is a reliable way to measure changes over time in the QoL of patients with CHF.13-26

Gene expression by peripheral leukocytes

Blood samples were drawn 1 day before NMES protocol initiation and 1 day after the last NMES session

(7 weeks). Peripheral leukocytes were isolated from

blood by centrifugation at 1100 rpm for 10 minutes in a

refrigerated centrifuge (4 oC). Total RNA was isolated

from the cellular pellet by using TRIzol ® LS reagent

(Ambion, Life Technologies, USA). Total RNA was

quantified by using the 260/280 nm absorbance ratio

data. The High-Capacity cDNA Reverse Transcription

kit (Applied Biosystems, Carlsbad, CA, USA) with 1 μg

of total RNA was used for reverse transcription reactions.

To assess different levels of gene expression, quantitative

real-time PCR was performed with the Taqman Fast

Advanced Master mix (Applied Biosystems) and

commercially available Taqman primers for IL-1α, IL-8,

TNF, IL-10 and IL-6 (Applied Biosystems). The GADPH

gene was used as an internal control.

Outcomes

The primary outcome of the study was the change in

6MWT after completion of the 7-week NMES protocol.

The secondary outcome was the QoL score after

completion of the 7-week NMES protocol.

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Statistical analyses

All continuous data with Gaussian distribution are reported as means ± standard deviations (SDs). All continuous data with no Gaussian distribution are reported as median and range. All variables were assessed for normality distribution using Shapiro-Wilk test.

Discrete variables are described as the frequency of the corresponding population. Analyses of the 6MWT and QoL score were performed by two-way analysis of variance and the Tukey post hoc test for detecting which time points were different. Correlations between the 6MWT and QoL score were calculated by linear regression analysis. Analyses of demographics were performed using t test or Mann-Whitney where was appropriated. Analyses of baseline characteristics and medication were performed using chi-square test.

A simple random sampling was used to allocate patients to the 2 groups. An online tool was employed for the group draw (www.graphpad.com). The sample size was based on previous studies12,13,26 and on the availability of inpatient/outpatient hospital facility. A P value smaller than 0.05 was considered statically significant.

All calculations were conducted and figures were constructed with GraphPad Prism software (version 6 for Mac OS X, GraphPad Software, La Jolla, CA, USA).

Results

Overall results

Of the 36 patients with severe CHF who were on the awaiting heart transplant list and initially assessed for the study, 8 patients refused to participate. The remaining 28 patients with end-stage CHF were randomly divided into 2 groups. Patients in the NMES group (n = 18) underwent treatment with the 7-week NMES protocol using the Russian current. Patients in the control group (n = 10) were tested with a similar protocol using an ineffective electric current. One month after termination of the treatment protocol, 9 patients in the NMES group and 5 patients in the control group were assessed. Figure 2 shows the flowchart of patient enrollment for the entire cohort. All patients were medicated for CHF, and the medication was not changed during the study period. The groups did not show differences regarding the distribution of

sex, age, demographics, medication, body mass index

or functional class (Table 1).

Safety of NMES application

During the 7-week protocol, no NMES-related

complications were observed in either group.

One month after protocol termination, 1 patient in

the NMES group had experienced cerebral vascular

stroke, 2 patients in the NMES group had died due to

CHF complications, and 2 patients in the NMES group

and 1 patient in the control group had undergone heart

transplant (Figure 2).

Improvement of the 6MWT with the 7-week NMES treatment

Compared to before treatment, 6MWT was increased

immediately after the 7-week treatment in the NMES

group (324 ± 117 vs. 445 ± 100 m; p = 0.02) but returned

to baseline values by 1 month after protocol termination

(324 ± 117 vs. 317 ± 194; p = 0.89). The control group

showed no differences in 6MWT values between before

and after treatment (Table 2).

Improvement of the QoL scores with the 7-week NMES treatment

Compared to pretreatment values, the NMES group

showed improvement in QoL scores after completion

of the 7-week NMES protocol (64 ± 22 vs. 45 ± 17;

p < 0.01), whereas the control group showed no

differences. However, the QoL scores in the NMES group

had returned to the baseline values by 1 month after

protocol termination (64 ± 22 vs. 51 ± 20; p = 0.07) (Table 2).

Association of QoL score with pretreatment 6MWT

Before commencement of the NMES protocol, the

6MWT was not associated with the QoL score in either

group (Figures 3A and B). In the control group, no

correlation was found between the pretreatment 6MWT

and the posttreatment QoL score (Figure 3C). However, the

pretreatment 6MWT was inversely correlated with the

QoL score obtained immediately after completion of the

treatment (Figure 3D). The pretreatment 6MWT was

directly correlated with the 6MWT obtained immediately

after treatment in both groups (Figure 3E and F).

488

Table 1 – Baseline characteristics, demographics and medication

Characteristic NMES group Control group p-Value(n = 18) (n = 10)

Gender

Male 15 (83) 9 (90)0.93**

Female 3 (17) 1 (10)

Age, years 54 ± 10 50 ± 12 0.39*

Height, cm 163 ± 28 172 ± 6 < 0.01*

Weight, kg 86 ± 22 80 ± 13 0.13*

BMI, kg/m2 27 ± 5 26 ± 5 0.85*

Ejection fraction, % 30 ± 10 34 ± 10 0.90*

CHF etiology

Idiopathic 6 (33) 4 (40)

0.51**

Ischemic 8 (44) 2 (20)

Valvar 2 (11) 2 (20)

Chagas’s disease 1 (6) 2 (20)

Viral 1 (6) 0 (0)

Functional class

III 13 (72) 9 (90)0.54**

IV 5 (28) 1 (10)

Medications

Diuretics 18 (100) 10 (100) 0.71**

Espironolactone 15 (83) 9 (90) 0.86**

Digoxin 11 (61) 5 (50) 0.68**

Beta-blocker 16 (89) 10(100) 0.79**

Antiarrhythmic 0 (0) 1 (10) 0.71**

Antiplatelet 11 (61) 60 (60) 0.89**

Statin 9 (50) 2 (20) 0.33**

Ca2+ channel blockers 3 (17) 0 (0) 0.52**

Nitrates 4 (22) 2 (20) 0.86

ACE inhibitors 13 (72) 9 (90) 0.22

Data are reported as n (%) or mean ± standard deviation. BMI: body mass index; diuretics include furosemide and bumetamide; ACE: angiotensin-converting enzyme. (*) P value using t test. (**) P value using Chi-square test.

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Modulation of gene expression with the 7-week NMES treatment

Compared to pretreatment values in the control group, the gene expression levels of IL-1β, IL-6, and IL-8

were increased immediately after protocol completion

in the NMES group (Figure 4A–C). No modulation of

IL-10 or TNF gene expression was observed in either

group (data not shown).

489

Figure 2 –– Flowchart of patient enrollment and reasons for patient drop-out from the study.

Table 2 – Hemodynamic values, functional capacity and quality of life

Parameter

Pretreatment Immediately posttreatment 1 month posttreatment

NMES Control NMES Control NMES Control(n = 18) (n = 10) (n = 15) (n = 9) (n = 9) (n = 5)

Resting HR, bpm 74 ± 14 74 ± 9 68 ± 16 72 ± 7 73 ± 11 73 ± 8

Resting SBP, mmHg 101 ± 11 110 ±10 115 ± 66 103 ± 16 101 ± 8 108 ± 13

Resting DBP, mmHg 66 ± 8 70 ± 8 67 ± 7 67 ± 8 69 ± 6 68 ± 8

LHFQ 64 ± 22 51± 25 45 ± 17† 52 ± 25 51 ± 20 48 ± 24

6MWT, m 324 ± 117 393 ± 151 445 ± 100† 353 ± 159 317 ± 194 366 ± 92

HR: heart rate; SBP: systolic blood pressure; DBP: diastolic blood pressure; 6MWT: distance in the 6-minute walk test; LHFQ: score on the Minnesota Living with Heart Failure Questionnaire; † Before treatment vs. immediately after treatment p < 0.05 (within NMES group).

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490

Figure 3 – Correlations among the pre- and/or post-treatment distance walked in the 6-minute walk test (6MWT) and quality of life (QoL) in the control group (A, C, E) and NMES group (B, D, F).

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491

Figure 4 – Fold differences in gene expression levels of cytokines before and after treatment in the control and NMES groups compared to the pretreatment levels in the control group. (A) IL-1β, (B) IL-6, (C) IL-8, (D) TNFα, and (E) IL-10.

Sacilotto et al.



Original Article

Discussion

We found that the application of a shorter NMES

protocol, exclusively to the quadriceps femoral

muscles improved the functional capacity and QoL

scores and modulated the inflammatory profiles of patients with severe CHF. This less-intense NMES protocol provided similar beneficial effects to those obtained with longer and more vigorous NMES protocols.2,3,6,7,27 Thus, this modified protocol could be

492Sacilotto et al.



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an alternative solution for greater patient adherence to a rehabilitation program.

NMES using a Russian current is a well-known and safe modality for treating patients and improving their comfort during NMES sessions.15,18,19 NMES has beneficial effects for functional capacity in patients with different diseases and conditions, including CHF, severe COPD, stroke, and osteoarthritis, as well as patients in intensive care units.3,28 The 6MWT was used to determine functional capacity in this study and has been commonly utilized for this purpose in previous reports.26,29 The 6MWT has a good correlation with peak oxygen consumption (VO2), and changes in the 6MWT can be used to predict mortality.6,27

The novelty of the present work lies in the less-frequent application of NMES through a simple pair of adhesive electrodes, which are placed on the skin over the quadriceps femoral muscle in each limb. All previous studies have used protocols with FES (Functional Electrical Stimulation) current ranging from 5 to 7 days per week.

All previous studies have enrolled patients with CHF of functional classes II and III, whereas the present study enrolled patients with functional classes III and IV on the awaiting heart transplant list.

Of note, we did not find in the literature studies that had evaluated a shorter protocol and using this specific type of current (Russian current) in a rehabilitation programs with patients in this specific clinical profile. Additionally, we did not find data reporting a longer training protocol that evaluated the functional capacity and quality of life following the discontinuation of electrical stimulus. We believe that a shorter protocol may improve patient adherence to the rehabilitation program, which is a day by day problem on those patients.

Previous studies of NMES protocols generally have utilized 8 adhesive electrodes in each limb.2,3 Using a more intense NMES protocol design of 8 adhesive electrodes applied for 30 minutes/day, 5 days/week for 6 weeks, Parissis et al.2 reported improvements in QoL, functional status, emotional status and endothelial function in patients with stable systolic CHF (NYHA class II or III).2 We demonstrated similar QoL and functional status results in sicker patients (NYHA functional class III or IV), using an less-demanding protocol with 1 pair of adhesive electrodes applied for 50 minutes/day, 2 days/week for 7 weeks. Banerjee et al.30 observed increases in the 6MWT and VO2 after 8 weeks of

NMES training in patients with CHF and low left-ventricular ejection fraction. They utilized a more complex stimulation apparatus, composed of adhesive electrodes applied at multiple muscles (quadriceps, hamstrings, calves and gluteal muscles) in each limb.30 Other authors have demonstrated similar results to the present manuscript regarding the functional capacity after training with more intense NMES protocols, such as 5 days/week for 30 to 60 minutes/day over 5 to 8 weeks.13,31,32

Several papers have demonstrated an improvement of QoL after NMES, as assessed by different questionnaires, such as the Beck Depression Inventory, Zung Self-Rating Depression Scale12 and Kansas City Cardiomyopathy Questionnaire.12 The LHFQ, which was used in the present study,26 is increasingly being applied for the assessment of QoL in patients with CHF.8,13,33 The QoL score was improved immediately after completion of the NMES protocol, consistent with several reports in the literature using different NMES protocols.2,7,8

The QoL score has consistently demonstrated to improve with NMES and low-intensity aerobic exercise programs; however, the durability of these effects has not been frequently reported. We found that the QoL scores had deteriorated to near-baseline levels by 1 month after protocol completion. Patients who walked longer distances during the 6MWT before NMES treatment were more likely to have better QoL scores immediately after completing the NMES protocol in the NMES group. However, the pretreatment 6MWT and QoL values were not correlated with each other in either group. These findings support the use of the 6MWT as a useful tool for assessing QoL after NMES treatment in this subset of patients. Several studies have reported improvements of the 6MWT and QoL score after NMES, but, to our knowledge, a relationship between both has not been reported.7,33

Some reports have demonstrated favorable effects of either aerobic and isometric exercises on inflammatory modulation in, for example, healthy individuals34 and patients with paraplegia or rheumatic disease.35 In CHF patients, data regarding the inflammatory profile after any physical exercise protocol have been inconsistent.36 Overall, it seems that physical activity may decrease serum TNF levels, with little to no effect on serum IL-6 and IL-10 levels.39 Additionally, very few papers have evaluated the effect of NMES on the inflammatory profile. In their study of severe COPD patients, Vivodtzev et al.37 described no changes in the serum levels of TNF,

493Sacilotto et al.



Original Article

IL-6, C-reactive protein (CRP) or insulin-like growth factor-1 (IGF-1) after 6 weeks of NMES application to the quadriceps and calf muscles. A single report studying CHF patients in functional class II or III assessed the endothelial function and immune response after NMES therapy for 5 days/week over 6 weeks.26 This study observed decreased levels of TNF, soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM-1) between before and after NMES treatment. Interestingly, no differences in the serum levels of IL-6 were observed in the control or NMES group.

The present work is the first to describe gene expression from peripheral leukocytes, which may resemble the inflammatory profile, before and after NMES treatment. Using a shorter NMES protocol, we observed increased gene expression levels of IL-6, IL-1β and IL-8. Measuring gene expression by peripheral leukocytes is a useful and reliable method for assessing diseases, such as asthma and seasonal diseases.38,39 The observed increased gene expression of these cytokines may represent a response to the local stress caused by NMES, which is similar to the stress caused by intense physical exercise.40,41 The chronic exercise may decrease the inflammatory response. However, in the present protocol is hard to tease out the chronic stimulation (the entirely protocol) from the acute phase. It is possible to say that the NMES modulates the inflammatory response, but we can not say whether or not increase or decrease it.

No previous study has followed patients for 1 month after completion of the NMES protocol. Surprisingly, we observed that the beneficial effects observed immediately after NMES termination were not permanent. The functional capacity and QoL scores returned to baseline values by 1 month after NMES protocol termination. These findings encourage the use of other strategies when implementing the shorter NMES protocol. Nevertheless, the most important aspect of our shorter protocol is that it could facilitate access to a different rehabilitation program. The protocol is composed of only a few sessions per week and does not cause fatigue or dyspnea comparable to conventional therapy (i.e. aerobic exercise training). These factors might stimulate treatment adherence and produce equivalent results to more intense NMES protocols or aerobic exercise training protocols.12,30,32,42-45

Although the present findings are motivating,

they must be considered in the context of the study

limitations. As a prospective study, we kept adherence

to the randomization draw before the study initiated.

The randomization generated blocks of studied groups

and not a single patient selection. This trial included a

relatively small number of patients with a different group

size, although most studies on the same subject have

enrolled similar numbers.6,12,13,26,31,32

We observed a more frequent negative events in the

treatment group compared to the control group after

termination of the training period. It is not possible

to exclude whether is related to the termination of the

protocol or random. It is important to highlight that there

are no data in the literature evaluating patients after

termination of the training period and this is the first work

that tries to show this information. However, it seems

important to keep special attention on the patients after

terminating the electrical stimulation protocol period.

Moreover, some patients discontinued treatment before

protocol completion due to cardiac transplant or death.

Conclusion

Using a shorter and simpler NMES protocol improved

the QoL score and functional status in patients with end-

stage CHF. The clinical improvement of these patients

was accompanied by a increase in gene expression of

some cytokines in peripheral leukocytes. This modified

treatment might be an interesting alternative for physical

rehabilitation in these very sick patients, and may

provide similar results compared to longer protocols

described in the literature.


Conception and design of the research: Sacilotto

MCB, Lavagnoli CFR, Petrucci Junior O. Acquisition

of data: Sacilotto MCB, Lavagnoli CFR, Vilarinho KAS,

Oliveira ESB, Carvalho DD, Oliveira PPM, Coelho-Filho

OR, Petrucci Junior O. Analysis and interpretation of

the data: Sacilotto MCB, Vilarinho KAS, Carvalho DD,

Petrucci Junior O. Statistical analysis: Sacilotto MCB,

Petrucci Junior O. Obtaining financing: Petrucci Junior

O. Writing of the manuscript: Sacilotto MCB, Carvalho

DD, Petrucci Junior O. Critical revision of the manuscript

for intellectual content: Sacilotto MCB, Silveira-Filho LM,

Vilarinho KAS, Carvalho DD, Oliveira PPM, Petrucci

Junior O.

494

1. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, Poole-Wilson PA, et al; ESC Committee for Practice Guidelines (CPG). Esc Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in Collaboration with the Heart Failure Association of the Esc (HFA) and Endorsed by the European Society of Intensive Care Medicine (ESICM).Eur Heart J. 2008;29(19):2388-442.

2. Parissis J, Karavidas A, Farmakis D, Papoutsidakis N, Matzaraki V, Arapi S, et al. Efficacy and safety of functional electrical stimulation of lower limb muscles in elderly patients with chronic heart failure: a pilot study. Eur J Prev Cardiol. 2015;22(7):831-6.

3. Sillen MJ, Franssen FM, Delbressine JM, Vaes AW, Wouters EF, Spruit MA. Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with copd and quadriceps muscle weakness: results from the Dices Trial. Thorax.2014;69(6):525-31.

4. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al; ESC Committee for Practice Guidelines. Esc Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in Collaboration with the Heart Failure Association (Hfa) of the Esc.Eur Heart J.2012;33(14):1787-847. Erratum in: Eur Heart J. 2013;34(2):158.

5. Downing J, Balady GJ. The role of exercise training in heart failure.J Am Coll Cardiol.2011;58(6):561-9.

6. Deboeck G, Muylem AV, Vachiery JL, Naeije R. Physiological response to the 6-minute walk test in chronic heart failure patients versus healthy control subjects. Eur J Prev Cardiol.2013;21(8):997-1003.

7. Smart NA, Dieberg G, Giallauria F. Functional electrical stimulation for chronic heart failure: a meta-analysis.Int J Cardiol.2013;167(1):80-6.

8. Giallauria F, Vigorito C, Piepoli MF, Stewart Coats AJ. Effects of cardiac contractility modulation by non-excitatory electrical stimulation on exercise capacity and quality of life: an individual patient's data meta-analysis of randomized controlled trials.Int J Cardiol.2014;175(2):352-7.

9. Paulson TA, Bishop NC, Smith BM, Goosey-Tolfrey VL. Inflammation-mediating cytokine response to acute handcycling exercise with/without functional electrical stimulation-evoked lower-limb cycling.J Rehabil Res Dev.2014;51(4):645-54.

10. ScottJP, Sale C, Greeves JP, Casey A, Dutton J, Fraser WD. Effect of exercise intensity on the cytokine response to an acute bout of running. Med Sci Sports Exerc.2011;43(12):2297-306.

11. Nuhr MJ. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. EurHeart J.2004;25(2):136-43.

12. Karavidas A, Parissis JT, Matzaraki V, Arapi S, Varounis C, Ikonomidis I, et al. Functional electrical stimulation is more effective in severe symptomatic heart failure patients and improves their adherence to rehabilitation programs. J Card Fail.2010;16(3):244-9.

13. Karavidas A, Driva M, Parissis JT, Farmakis D, Mantzaraki V, Varounis C, et al. Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction. Am Heart J.2013;166(4):760-7.

14. Sbruzzi G, Ribeiro RA, Schaan BD, Signori LU, Silva AM, Irigoyen MC, et al. Functional electrical stimulation in the treatment of patients with chronic heart failure: a meta-analysis of randomized controlled trials. Eur J Cardiovasc Prev Rehabil.2010;17(3):254-60.

15. WardAR, Oliver WG, Buccella D. Wrist extensor torque production and discomfort associated with low-frequency and burst-modulated kilohertz-frequency currents. Phys Ther.2006;86(10):1360-7.

16. Dantas LO, Vieira A, Siqueira Jr AL, Salvini TF, Durigan JL.Comparison between the effects of 4 different electrical stimulation current waveforms on isometric knee extension torque and perceived discomfort in healthy women. Muscle Nerve.2015;51(1):76-82.

17. Bellew JW, Beiswanger Z, Freeman E, Gaerte C, Trafton J. Interferential and burst-modulated biphasic pulsed currents yield greater muscular force than russian current. Physiother Theory Pract. 2012;28(5):384-90.

18. Broderick BJ, Kennedy C, Breen PP, Kearns SR, O. Laighin G. Patient tolerance of neuromuscular electrical stimulation (eenm) in the presence of orthopaedic implants. Med Eng Phys.2011;33(1):56-61.

19. Ward AR, Robertson VJ, Sensory, motor, and pain thresholds for stimulation with medium frequency alternating current. Arch Phys Med Rehabil. 1998;79(3):273-8.

20. Bennie SD, Petrofsky JS, Nisperos J, Tsurudome M, Laymon M. Toward the optimal waveform for electrical stimulation of human muscle. Eur J Appl Physiol.2002;88(1-2):13-9.

21. Baker LL, Bowman BR, McNeal DR. Effects of waveform on comfort during neuromuscular electrical stimulation. Clin Orthop Relat Res. 1988(233):75-85.

22. Bowman BR, Baker LL. Effects of waveform parameters on comfort during transcutaneous neuromuscular electrical stimulation. AnnBiomedEng.1985;13(1):59-74.

23. Maffiuletti NA. Physiological and methodological considerations for the use of neuromuscular electrical stimulation. Eur J Appl Physiol.20101;110(2):223-34.

24. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories.ATSstatement: guidelines for the six-minute walk test. Am J Respir Crit Care Med.2002;166(1):111-7.

25. Carvalho VO, Guimaraes GV, Carrara D, Bacal F, Bocchi EA. Validation of the Portuguese version of the Minnesota living with Heart Failure Questionnaire. Arq Bras Cardiol.2009;93(1):39-44.

26. Karavidas AI, Raisakis KG, Parissis JT, Tsekoura DK, Adamopoulos S, Korres DA, et al. Functional electrical stimulation improves endothelial function and reduces peripheral immune responses in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil.2006;13(4):592-7.

27. McDermott MM, Guralnik JM, Criqui MH, Liu K, Kibbe MR, Ferrucci L. Six-minute walk is a better outcome measure than treadmill walking tests in therapeutic trials of patients with peripheral artery disease. Circulation.2014;130(1):61-8.

28. Laufer Y, Shtraker H, Elboim Gabyzon M. The effects of exercise and neuromuscular electrical stimulation in subjects with knee osteoarthritis: a 3-month follow-up study. Clin Interv Aging.2014;9:1153-61.

29. Banerjee P. Electrical muscle stimulation for chronic heart failure: an alternative tool for exercise training?. Curr Heart Fail Rep.2010;7(2):52-8.

30. Banerjee P, Caulfield B, Crowe L, Clark AL. Prolonged electrical muscle stimulation exercise improves strength, peak VO2, and exercise capacity in patients with stable chronic heart failure. J Card Fail.2009;15(4):319-26.

References

Sacilotto et al.



Original Article



Sources of Funding

This study was funded by FAPESP.

Study Association

This article is part of the thesis of Doctoral submitted by Maria Carolina Basso Sacilotto, from Universidade Estadual de Campinas – Unicamp.

495

31. Deley G, Eicher JC, Verges B, Wolf JE, Casillas JM. Do low-frequency electrical myostimulation and aerobic training similarly improve performance in chronic heart failure patients with different exercise capacities?. J Rehabil Med.2008;40(3):219-24.

32. Deley G, Kervio G, Verges B, Hannequin A, Petitdant MF, Salmi-Belmihoub S, et al. Comparison of low-frequency electrical myostimulation and conventional aerobic exercise training in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil.200512;(3):226-33.

33. Smart NA, Giallauria F, Dieberg G. Efficacy of inspiratory muscle training in chronic heart failure patients: a systematic review and meta-analysis. Int J Cardiol.2013;167(4):1502-7.

34. Wethal T, Roysland R, Torbjorn O, Kjekshus J. Exercise induced vasodilatation in healthy males; a marker of reduced endothelial function. Scand Cardiovasc J.2015;49(3):123-9.

35. Benatti FB, Pedersen BK. Exercise as an anti-inflammatory therapy for rheumatic diseases-myokine regulation. Nat Rev Rheumatol.2015;11(2):86-97.

36. Smart NA, Steele M. The effect of physical training on systemic proinflammatory cytokyne expression in heart failure patients: a systematic review. Congest Heart Fail. 2011;17(3):110-4.

37. Vivodtzev I, DebigaréR, Gagnon P, Maingury V, Saey D, DubéA, et al. Functional and muscular effects of neuromuscular electrical stimulation in patients with severe COPD: a randomized clinical trial. Chest. 2012;141(3):716-25.

38. Kozmus CE, Potocnik U. Reference genes for real-time qPCR in leukocytes from asthmatic patients before and after anti-asthma treatment. Gene. 2015;570(1):71-7.

39. Goldinger A, Shakhbazov K, Henders AK, McRae AF, Montgomery

GW, Powell JE. Seasonal effects on gene expression. PLoS One.

2015;10(5):e0126995.

40. Wlec SS, Clanton TL. The regulation of interleukin-6 implicates skeletal

muscle as an integrative stress sensor and endocrine organ. Exp Physiol.

2013;98(2):359-71.

41. Peake J, Della Gatta P, Suzuki K, Nieman DC. Cytokine expression and

secretion by skeletal muscle cells: regulatory mechanisms and exercise

effects. Exerc Immunol Rev.2015;21:8-25.

42. Youssef MK. The impact of neuromuscular electric stimulation versus

aerobic exercise in rehabilitation of patients with chronic heart failure.

J Arab Soc Med Res. 2014:9(1):40-7.

43. Deftereos S,Giannopoulos G,Raisakis K,Kossyvakis C,Kaoukis A,

Driva M, et al. Comparison of muscle functional electrical stimulation

to conventional bicycle exercise on endothelium and functional status

indices in patients with heart failure.Am J Cardiol. 2010;106(11):1621-5.

44. Dobsak P, Novakova M, Fiser J, Siegelova J, Balcarkova O, Spinarova L,

et al. Electrical stimulation of skeletal muscles an alternative to aerobic

exercise training in patients with chronic heart failure? Int Heart J.

2006;47(3):441-53.

45. Harris S, LeMaitre JP, Mackenzie G, Fox KA, Denvir MA. A randomized

study of home-based electrical stimulation of the legs and conventional

bicycle exercise training for patients with chronic heart failure. Eur Heart

J. 2003;24(9):871-8.

Sacilotto et al.



Original Article

DOI: 10.5935/2359-4802.20170084

Introduction

Liver cirrhosis is a progressive pathological process characterized by fibrosis and nodular regeneration. A variety of well-known etiologies can cause cirrhosis, such as hepatitis virus infection (hepatitis B and C virus), drugs (including alcohol), autoimmune diseases, genetic diseases and nonalcoholic steatohepatitis. In addition to liver damage, cirrhotic patients have renal, pulmonary, hemodynamic and cardiac dysfunction that increase morbidity and mortality.1

Cirrhotic cardiomyopathy has been used to describe chronic cardiac dysfunction in cirrhotic patients with

no previous structural heart disease.1 It is defined by

the finding of one or more of the following changes:

normal or augmented systolic function at rest but poor

contractile response to stress; diastolic dysfunction;

structural abnormalities in cardiac chambers; and

electrophysiological changes.2 These abnormalities occur

to a varied degree in up to 50% of cirrhotic patients.3

Most patients with cirrhotic cardiomyopathy are

asymptomatic and, for this reason, complementary exams

are important to identify them.1 The electrocardiography

(ECG) is a low-cost and noninvasive method that may

help to identify patients with cirrhotic cardiomyopathy.


ORIGINAL ARTICLES

Mailing Address: Pedro Gemal LanzieriDepartamento de Clínica Médica (MMC), Hospital Universitário Antônio PedroRua Marquês do Paraná, 303, 6° andar, Postal Code: 24033-900 Centro, Niterói, RJ – BrazilE-mail: [email protected]

Cirrhotic Patients with Child-Pugh C Have Longer QT IntervalsPedro Gemal Lanzieri, Ronaldo Altenburg Gismondi, Matheus de Castro Abi-Ramia Chimelli, Raíssa Pereira Cysne, Thais Guaraná, Cláudio Tinoco Mesquita, Luís Otávio MocarzelPrograma de Pós-graduação em Ciências Cardiovasculares da Universidade Federal Fluminense (UFF), Niterói, RJ – Brazil

Manuscript received November 25, 2016, revised manuscript April 05, 2017, accepted May 10, 2017

Abstract

Background and aims: Cirrhotic cardiomyopathy has been used to describe chronic cardiac dysfunction in cirrhotic patients with no previous structural heart disease. Additionally, QT prolongation is one of the most important cardiac alterations related to cirrhosis. Previous studies suggest that QT prolongation is associated with a higher mortality rate among cirrhotic patients. The aim of this study was to analyze QT intervals according to cirrhosis severity as measured by the Child-Pugh classification.

Materials and methods: In a cross-sectional study, a total of 67 patients with nonalcoholic cirrhosis underwent clinical and electrocardiographic evaluation. Cirrhosis severity was classified according to the Child-Pugh score. The QT interval was measured by a 12-lead electrocardiogram.

Results: The QT intervals were longer in patients in the Child-Pugh C group than those in the Child-Pugh A and B groups (459 ± 33 vs 436 ± 25 and 428 ± 34 ms, respectively, p = 0.004). There was a positive correlation between the QT interval and the Child-Pugh score in individuals with Child-Pugh scores ≥ 7 (r = 0.50, p < 0.05) and QT intervals ≥ 440 ms (r = 0.46, p < 0.05).

Conclusion: The present study showed longer QT intervals in patients with Child-Pugh C cirrhosis, which reinforced the relationship between the severity of cirrhosis and electrocardiographic findings of cirrhotic cardiomyopathy. Moreover, this finding emerged in patients with no cardiac symptoms, which highlighted the importance of a simple and noninvasive method (ECG) to identify cirrhotic patients with cardiomyopathy. (Int J Cardiovasc Sci. 2017;30(6)496-503)

Keywords: Cardiomyopathies; Liver Cirrhosis / mortality; Long QT Syndrome; Electrocardiography / methods.

497

QT prolongation is one of the most important cardiac alterations related to cirrhosis and is easily determined by ECG. A prolonged QT interval is associated with a higher mortality rate among patients with chronic liver disease.4 In a study on QT prolongation in cirrhotic patients, when QT intervals were over 440 ms, the survival rate was significantly lower than in patients with shorter QT intervals. In the same study, during a median follow-up of 19 months, cirrhotic patients who died had longer QT intervals than those who survived (463 ± 7 versus 435 ± 3 ms, p < 0.001).5

Most previous studies have included patients with cirrhosis of alcoholic etiology.2,6,7 As alcohol may have direct cardiac toxicity, it is important to study QT intervals in nonalcoholic cirrhosis. The aim of this study was to analyze QT intervals in patients with nonalcoholic cirrhosis according to their cirrhosis severity estimated by the Child-Pugh classification.

Materials and Methods

Patient population

Patients were recruited from our outpatient cirrhosis clinics. The inclusion criterion was a previous diagnosis of cirrhosis confirmed by histopathology, clinical features and/or liver transient elastography. We excluded patients with alcoholic cirrhosis, electrolytic disorders in the last three months, angina, exertional dyspnea, palpitations, syncope and/or previous structural cardiac disease (including atrial fibrillation, myocardial infarction, valvar disease, heart failure, and/or complete left branch block). All of the patients agreed to participate by written informed consent. The hospital ethics committee approved the study (CAAE 3844813.5.0000.5243).

Study design

The present study had a cross-sectional design. At the same visit, patients underwent a clinical evaluation, ECG and Child-Pugh score calculation.8 The Child-Pugh score was used to divide patients in groups A, B and C. A post hoc analysis was done to compare cirrhosis etiologies between patients receiving and not receiving beta-blocker therapy. Laboratory data were collected from patient’s medical records, and those conducted more than three months before this study were excluded from the analysis. Patients underwent 12-lead ECGs using an Eletrotouch EP-3 (Philips Dixtal, São Paulo, Brazil) at a

paper speed of 25 mm/s. The QT interval was manually measured from the beginning of the Q wave (or R wave when Q was absent) until the end of the T wave in all 12 leads. The end of the T wave was defined as the point of return to the T-P baseline or the nadir of the curve between the T and the U wave when U waves were present. Leads in which the end of the T wave could not be determined, with a low-amplitude T wave, and isoelectric leads were eliminated. Three consecutive sinus beats were measured per lead, and a mean QT interval was calculated. The maximum average QT interval in any of the 12 leads was obtained for each patient. The measurements were made by a single observer blinded to the Child-Pugh classification. Additionally, QT was corrected according to heart rate (RR interval) using both the Bazett and Fridericia formulas (QTc = QT/2√RR and QTc = QT/3√RR, respectively).9,10 Both formulas have been previously used to study QT prolongation in cirrhotic patients with no significant difference between them.11


We used the Kolmogorov-Smirnov test to assess the normality of data. Parameters with normal distribution are presented as mean ± standard deviation (SD). The other parameters are presented as median ± interquartile range (25-75). An ANOVA (parametric) or Kruskal–Wallis (nonparametric) was used to compare the three groups, and the Tukey’s HSD test was used for the subgroup analysis. Correlations were evaluated using Pearson’s correlation coefficient and categorical variables were compared using chi-square test. We used previous studies on QT intervals in similar populations to estimate the sample size. Assuming an alpha error of 5% and a SD of 35 ms, we included 11 patients in each group with 80% power to detect a 45 ms difference in the QT intervals between the groups.12 Statistical significance was determined by α-level of 0.05. We used Statistica 12 (Statsoft, Tulsa, USA) for the database management and statistical analysis.

Results

In total, 67 patients were included by consecutive sampling and classified according to the Child-Pugh score (Table 1). Hepatitis virus infection was the most common etiology in all the groups, representing 71.6% of the entire study sample. Demographic, clinical and laboratorial data are shown in Table 1.

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Table 1 – Baseline demographic, clinical and laboratory characteristics of 67 patients with nonalcoholic cirrhosis by Child-Pugh classification

A (n = 36) B (n = 20) C (n = 11) p value

Age 58 ± 11 58 ± 13 61 ± 9 0.828

Men/women (n) 72% (26) / 28% (10) 50%(10) / 50% (10) 27% (3) / 63% (8) 0.255

Etiology (n)

Viral 78% (28) 70% (14) 55% (6) 0.408

Autoimmune 17% (6) 10% (2) 9% (1) 0.770

Drugs 3% (1) 0 0 0.675

Biliary 0 10% (2) 0 0.100

NASH 3% (1) 5% (1) 9% (1) 0.576

Criptogenic 0 5% (1) 27% (3) 0.016a

Beta blocker (n) 30% (11) 75% (15) 27% (3) 0.228

Spironolactone (n) 8% (3) 45% (9) 54% (6) 0.265

Diuretics (n) 33% (12) 55% (11) 27% (3) 0.237

eGFR (ml/min) 77 ± 24 78 ± 26 87 ± 33 0.590

Total Bilirrubin (μmol/l) 24.7 ± 11.6 41.5 ± 29.7 43.4 ± 7.8 0.002 a

INR 1.19 ± 0.14 1.33 ± 0.17 1.70 ± 0.18 <0.001 a

Serum K (mEq/L) 4.3 ± 0.5 4.1 ± 0.5 4.2 ± 0.3 0.551

Serum Mg (mEq/L) 1.8 ± 0.4 1.8 ± 0.6 1.8 ± 0.2 0.974

Serum Ca (mEq/L) 8.2 ± 0.4 8.4 ± 0.5 8.0 ± 0.3 0.606

Serum Na (mEq/L) 139 ± 2 139 ± 2 134 ± 6 0.001 a

Values are mean ± standard deviation or frequency distribution, unless otherwise specified. NASH, non-alcoholic steatohepatitis; eGFR, estimated glomerular filtration rate; INR, international normalized ratio. a p < 0.05, Student t test (continuous variables) or chi-square test (categorical variables).

The QT intervals were longer in patients of the Child-Pugh C group (Figure 1). There were no differences between the Bazett and Fridericia QT correction formulas (data not shown). Differences between the groups persisted when we analyzed the subgroups by viral etiology. Other etiologies had too few patients for a statistical analysis. In the subgroup of patients receiving beta-blockers, the QT intervals were also prolonged in the Child-Pugh C group (Figure 2). In addition, there was a positive correlation between the QT interval and the Child-Pugh score in individuals with Child-Pugh scores ≥ 7 (r = 0.50, p < 0.05) (Figure 3). In subjects with QT intervals ≥ 440 ms, the Child-Pugh score and QT interval were also correlated (r = 0.46, p < 0.05) (Figure 4).

Discussion

The present study showed a longer QT interval in Child-Pugh C cirrhotic patients, which reinforced the notion of a relationship between severity of cirrhosis and ECG findings of cirrhotic cardiomyopathy. Other studies have reported similar results, highlighting the importance of a simple and noninvasive method (ECG) to identify cirrhotic patients with cardiomyopathy.1,11,12

Even though the mechanism of the prolongation of QT intervals is not fully elucidated, it is attributed to autonomic changes caused by cirrhosis . 14 The QT interval extends from the earliest activation of ventricular myocardium to the end of the latest

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0.50

0.48

0.46

0.44

0.42

0.40

0.38A B C

Child Group

QT In

terv

al (S

)* *

* †

Figure 1 – QT intervals in the Child-Pugh A, Child-Pugh B and Child-Pugh C groups. QT intervals are presented as the means + standard deviation. *, p < 0.05 by ANOVA; †, p < 0.05 versus the Child-Pugh A group by Tukey’s HSD test.

0.50

0.48

0.46

0.44

0.42

0.40

0.38A B C

Child Group

QT In

terv

al (S

)

* *

* †

Figure 2 – QT interval in patients using beta-blockers divided into Child-Pugh A, Child-Pugh B and Child-Pugh C groups. QT interval as mean + standard deviation. *, p < 0.05 by ANOVA; †, p < 0.05 versus the Child-Pugh A group by Tukey’s HSD test.

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0.52

0.50

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0.46

0.44

0.42

0.40

0.38

0.36

0.344 5 6 7 8 9 10 11 12

r = 0.462p < 0.05

QT in

terv

al (S

)

Child Pugh Score

Figure 3 – Correlation between QT interval and Child-Pugh score in subjects with Child-Pugh scores ≥ 7.

0.52

0.50

0.48

0.46

0.44

0.42

0.40

0.38

0.36

0.346.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5

QT in

terv

al (S

)

Child-Pugh Score

r = 0.502p < 0.05

Figure 4 – Correlation between QT interval and Child-Pugh score in subjects with QT intervals ≥ 440 ms.

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ventricular repolarization. Therefore, QT intervals can be prolonged either because of a delay in the activation or because the complex process of repolarization is prolonged. Repolarization, per se, could be prolonged due to electrolytic abnormalities or previous cardiac disease.7 In our study, we chose to exclude patients with these conditions so that the QT prolongation could be attributed solely to autonomic dysfunction caused by cirrhosis. In addition, reductions in circulating blood volume and hyperdynamic circulation enhance sympathetic nervous system and renin-angiotensin-aldosterone system activities. The resulting increased cardiac output and reduced systemic vascular resistance may induce myocardial remodeling and left ventricular hypertrophy, causing systolic and diastolic dysfunction and, hence, cardiomyopathy. Sympathetic nervous system hyperactivity also contributes to myocardial dysfunction because of an increase in the levels of inflammatory cytokines such as interleukin-1b, interleukin-6 and tumor necrosis factor alpha.13

Other factors associated with prolonged QT intervals in cirrhosis are disease severity, serum uric acid levels and alcoholic etiology.12 The majority of our patients had hepatitis virus infection as the cause of cirrhosis, and this subgroup analysis also showed QT prolongation in cirrhotic Child-Pugh C patients. In addition, patients with more severe cirrhosis had a positive correlation between QT interval and Child-Pugh score. As alcohol is directly toxic to myocytes, we chose to exclude patients with alcoholic cirrhosis from this study.13 However, previous studies on alcoholic cirrhosis observed QT prolongation in patients with Child C cirrhosis.2,14 Regarding electrolytic alterations, serum potassium, calcium and magnesium levels were similar between the groups. Hyponatremia observed in the Child-Pugh C group was expected in these patients and was not severe.11 We believe that hyponatremia did not influence QT prolongation in the patients with Child-Pugh C cirrhosis.

In a study with 38 cirrhotic patients (50% male), Mozos et al. showed that corrected QT values were higher in Child-Pugh C cirrhotic patients (Child-Pugh A: 462 ± 25 ms, Child-Pugh B: 493 ± 62 ms and Child-Pugh C: 520 ± 45 ms, p < 0.001). Genovesi et al.12 also observed that Child-Pugh C patients had higher QT intervals.7 In a study of 409 cirrhotic patients, Bal et al.6 reported higher corrected QT in the Child-Pugh C group than the Child-Pugh B group (451±43 vs 434 ± 31 ms, p < 0.001).8 Despite similar ages and genders, mean corrected QT in our study was lower than the study by Mozos et al.12 and similar to the results by Genovesi et al.7 and Bal et al.8

The exclusion of alcoholic etiology and inclusion of patients receiving beta-blockers may explain the observed differences in corrected QT in absolute values. Most of all, these studies strengthened the notion that Child-Pugh C patients should be monitored for QT prolongation.

Beta-blocker use reduces QT intervals as well as portal pressure and hyperdynamic response in cirrhotic patients.13,14 Thus, this medication was indicated in most patients in the Child-Pugh B and C groups as variceal bleeding prophylaxis.15–17 Hypotension is the most common reason for beta-blocker withdrawal in Child-Pugh C patients.16,17 Most of our subjects in the Child-Pugh B and C groups were receiving beta-blockers. In a post hoc analysis of patients receiving beta-blockers, QT was longer in the Child-Pugh C group than in the A and B groups. Most of the previous studies on QT prolongation in cirrhosis have excluded the use of this medication.2,9,10,11,12 In our opinion, it is important to report this population because most real-world Child-Pugh B and Child-Pugh C cirrhotic patients are beta-blocker users.

A limitation of our study was the small sample size and the cross-sectional design. Thus, a study with a larger cohort is needed to confirm our results and better understand the prognosis of a prolonged QT interval. Such study could also clarify the relationship between cirrhotic cardiomyopathy and the severity of liver disease. In addition, the predominant etiology of cirrhosis in our patients was hepatitis C virus infection. Studies of other common etiologies of cirrhosis, such as nonalcoholic steatohepatitis , are highly desirable.

Conclusion

Patients with Child-Pugh C non-alcoholic cirrhosis show longer QT interval than Child-Pugh A or B patients. This difference persists despite beta-blocker use. Thus, an ECG should be considered in patient with more severe non-alcoholic cirrhosis.


Conception and design of the research: Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO. Acquisition of data: Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO. Analysis and interpretation of the data: Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO. Statistical analysis:

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1. Gassanov N, Caglayan E, Semmo N, Massenkeil G, Er F. Cirrhotic cardiomyopathy: a cardiologist’s perspective. World J Gastroenterol. 2014;20(42):15492-8. PMID: 25400434. doi: 10.3748/wjg.v20.i42.15492.

2. Zamirian M, Tavassoli M, Aghasadeghi K. Corrected QT interval and QT dispersion in cirrhotic patients before and after liver transplantation. Arch Iran Med. 2012;15(6):375-7. PMID: 22642249. doi: 012156/AIM.0012.

3. Rahman S, Mallett SV. Cirrhotic cardiomyopathy: implications for the perioperative management of liver transplant patients. World J Hepatol. 2015;7(3):507-20. PMID: 25848474. doi: 10.4254/wjh.v7.i3.507.

4. Kosar F, Ates F, Sahin I, Karincaoglu M, Yldirim B. QT interval analysis in patients with chronic liver disease: a prospective study. Angiology. 2007;58(2):218-24. PMID: 17495272. doi: 10.1177/0003319707300368.

5. Bernardi M, Calandra S, Colantoni A, Trevisani F, Raimondo ML, Sica G, et al. Q-T interval prolongation in cirrhosis: prevalence, relationship with severity, and etiology of the disease and possible pathogenetic factors. Hepatology. 1998;27(1):28-34. PMID: 9425913. doi: 10.1002/hep.510270106.

6. Genovesi S, Prata Pizzala DM, Pozzi M, Ratti L, Milanese M, Pieruzzi F, et al. QT interval prolongation and decreased heart rate variability in cirrhotic patients: relevance of hepatic venous pressure gradient and serum calcium. Clin Sci (Lond). 2009;116(12):851-9. PMID: 19076059. doi: 10.1042/CS20080325.

7. Bal JS, Thuluvath PJ. Prolongation of QTc interval: relationship with etiology and severity of liver disease, mortality and liver transplantation. Liver Int. 2003;23(4):243-8. PMID: 12895263. doi: 10.1111/j.1399-3046.2008.00909.

8. Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-9. PMID: 4541913. doi: 10.1002/bjs.1800600817.

9. Bazett H. An analysis of the time-relations of electrocardiograms. Heart. 1920;7:353-70. doi: 10.1111/j.1542-474X.1997.tb00325.

10. Fridericia L. Die Systolendauer im Elektrokardiogramm bei normalen Menshenund bei Herzkranken. Acta Med Scand. 1920;53:469-86. doi: 10.1111/j.0954-6820.1920.tb18266.

11. Zambruni A, Di Micoli A, Lubisco A, Domenicali M, Trevisani F, Bernardi M. QT interval correction in patients with cirrhosis. J Cardiovasc Electrophysiol. 2007;18(1):77-82. PMID: 17229304. doi: 10.1111/j.1540-8167.2006.00622.

12. Mozos I, Costea C, Serban C, Susan L. Factors associated with a prolonged QT interval in liver cirrhosis patients. J Electrocardiol. 2011;44(2):105-8. PMID: 21146831. doi: 10.1016/j.jelectrocard.2010.10.034.

13. Mozos I. Arrhythmia risk in liver cirrhosis. World J Hepatol. 2015;7(4):662-72. PMID: 25866603. doi: 10.4254/wjh.v7.i4.662.

14. Kim YK, Hwang GS, Shin WJ, Bang JY, Cho SK, Han SM. Effect of propranolol on the relationship between QT interval and vagal modulation of heart rate variability in cirrhotic patients awaiting liver transplantation. Transplant Proc. 2011;43(5):1654-9. PMID: 21693252. doi: 10.1016/j.transproceed.2011.02.017.

15. Bari K, Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol. 2012;18(11):1166-75. PMID: 22468079. doi: 10.3748/wjg.v18.i11.1166.

16. Mela M, Mancuso A, Burroughs A. Drug treatment for portal hypertension. Ann Hepatol. 2002;1(3):102-20. PMID: 15280809.

17. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey WD; Practice Guidelines Committee of American Association for Study of Liver Diseases, Practice Parameters Committee of American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Am J Gastroenterol. 2007;102(9):2086-102. PMID: 17879356. doi: 10.1002/hep.21907.

References

Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO. Writing of the manuscript: Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO. Critical revision of the manuscript for intellectual content: Lanzieri PG, Gismondi RA, Chimelli MCA, Cysne RP, Guaraná T, Mesquita CT, Mocarzel LO.



Sources of Funding


Study Association

This article is part of the thesis of master submitted by Pedro Gemal Lanzieri, from Universidade Federal Fluminense.

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

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Original Article

DOI: 10.5935/2359-4802.20170078

Introduction

Chronic arterial disease (CHD) is a cause of high morbidity and mortality. Studies have shown that patients with lower ejection fraction have an increased risk of annual mortality compared with those who maintain normal LVEF.1-3 Considering the increased risk of cardiac events in these patients, a careful analysis should be done (area of ischemia , LVEF, age, comorbidities, etc.) to assess risk vs. benefit that therapies4,5 - cardiac revascularization (surgical, percutaneous) and drug treatment - will bring

to the patients. The subgroup of patients with reduced

LVEF and extensive CAD are the major beneficiaries

of revascularization.4,6,7

Although physical capacity, age, presence of other

comorbidities are factors related to patient survival,

the most important prognostic factors are the extent

of ischemia and left ventricular ventricular function.

These are evaluated through myocardial perfusion

scintigraphy synchronized with the electrocardiogram

(Gated SPECT).


ORIGINAL ARTICLES

Mailing Address: Ronaldo de Souza Leão LimaRua Paissandu, 329 ap. 303 - Flamengo, Postal Code: 22210-085. Rio de Janeiro, RJ – BrazilEmail: [email protected]

Predictors for Indication to Catheterization after Myocardial Perfusion Gated SpectFernanda de Oliveira Mesquita,1 Larissa Andrade,1 Lívia Pitta,2 Andrea Rocha de Lorenzo,1,2 Ronaldo de Souza Leão Lima1,2

Universidade Federal do Rio de Janeiro(UFRJ),1 Centro de Diagnóstico por Imagem CDPI,2 Rio de Janeiro, RJ – Brazil

Manuscript received December 08, 2016; revised manuscript May 30, 2016; accepted July 07, 2017

Abstract

Background: Patients with coronary artery disease with left ventricular dysfunction present higher mortality and are the major beneficiaries of a myocardial revascularization procedure. A previous study showed that left ventricular ejection fraction (LVEF) is a negative determinant for cardiac catheterization (CAT) after myocardial perfusion scintigraphy (MPS).

Objective: To determine clinical and scintigraphic factors associated with cardiac catheterization (CAT) indication in patients undergoing myocardial perfusion SPECT (MPS).Population: Patients consecutively submitted to PMC in the period from March 2008 to December 2012.

Methods: All patients undergoing MPS during the study were recorded in a data bank, where epidemiological, clinical and scintigraphic data (perfusion scores and LVEF) were recorded. Patients or their attending physicians were contacted by phone semiannually for follow-up. For statistical analysis, univariate analyzes were performed and variables were selected for inclusion in a logistic regression model.

Results: 5536 patients were submitted to MPS, of which 643 performed CAT after the examination. This group presents a higher prevalence of males, hypertensive, dyslipidemic and previously revascularized. Patients undergoing CAT have angina more frequently, more extensive ischemia scores and lower LVEF. Only presence of angina (IC 95% 1.2 - 1.7, p < 0.001) and extent of ischemia (95% CI 1.2 - 1.3, p < 0.001) were independent variables for CAT indication.

Conclusion: The presence of angina and the extent of ischemia were the main predictors for CAT post-MPS indication while lower LVEF was not an independent predictor. (Int J Cardiovasc Sci. 2017;30(6)504-509)

Keywords: Coronary Diseases; Ventricular Dysfunction, Left/mortality; Cardiac Catheterization; Myocardial/diagnostic imaging.

505

The present study aims to determine the main clinical and scintigraphic factors associated with the indication of CAT in patients undergoing MPS.

Methodology

A total of 5536 adult patients who underwent MPS because of clinical indication from March 2008 to December 2012 were evaluated.

All data collected [among them, epidemiological, clinical and scintigraphic data (perfusion scores and LVEF)] were recorded in a database and patients or their physicians were contacted every six months by telephone for follow-up.

This study is in conformity with the ethical guidelines of the Declaration of Helsinki of 1975 and all the participants signed the Term of Free and Informed Consent.

Protocol of the study

A one-day protocol was performed, administering5-6 mCi (185-222 MBq) of Tc-99m Sestamibi in the resting phase and 18-20 mCi (666-740 MBq) in stress. Initially, 24 patients (13 men) were selected for a pilot study in which the total acquisition was made in 6 minutes in the listmode. The images were processed using 1 to 6 minutes of the total time of acquisition and then analyzed by 2 experienced observers who did not know the time interval used for the reconstruction, in turn their analyzes were evaluated resulting in satisfactory agreement. The study protocol, both for the stress phase and for rest in the MPS, was defined in a consensual way by the observers.

All patients underwent the 1-day rest/stress protocol with Tc-99m sestamibi. Ten minutes after intravenous injection of the radiotracer, the images were acquired supine. The second phase of the test was stress, performed with an ergometric or pharmacological test. Immediately after the stress phase the supine and prone images began to be acquired. The CZT camera (Discovery NM 530c, GE Healthcare, Haifa, Israel) was equipped with multiple pinhole collimators and 19 fixed cadmium and zinc telluride detectors and 19 cardiac images were simultaneously displayed. Each detector had 32 x 32 matrix and 5mm thick pixels (2.46 x 2.46 mm). The system structure allows high-definition images of volumes in 3D by all detectors (quality field-of-view), where the patient's heart has to be centered. Once the acquisition was started, there was no movement of the detector or the collimator.

Images Interpretation

All images were interpreted by consensus of two experienced observers. Processing was performed through Evolution for Cardiac® software. The images were reconstructed without attenuation or dispersion correction. The short and long, vertical and horizontal axes, as well as polar maps, were generated and interpreted in a video monitor.

The semiquantitative visual interpretation of perfusion defects was performed using a 17-segment model in accordance with the recommendations of the American Society of Nuclear Cardiology and the American Heart Association.8 Each segment of the myocardium was analyzed and scored by consensus of 2 observers, According to the level of radiopharmaceutical uptake on a scale of zero to five points (0 = normal perfusion, 1 = mild defect, 2 = moderate defect, 3 = severe defect, 4 = no uptake). The summed stress score (SSS) was obtained by summing the points of the 17 segments in the stress images. Summated rest score (SRS), obtained by summing the scores of the 17 segments in the resting images and the summed difference score (SDS), by the sum of the differences between the stress and rest scores (SSS - SRS).

Post-stress gated images on the short axis were processed using the gated SPECT software (Cedars-Sinai Medical Center, Los Angeles, California), left ventricular ejection fraction, final systolic and diastolic volume were automatically calculated.


Kolmogorov-Smirnov test was used to evaluate the presence of normal distribution of the studied variables. In the univariate analysis the continuous variables were expressed as means and standard deviations. They were compared by the independent Student's t test or ANOVA (those with normal distribution) or the Wilcoxon test (those with non-normal distribution). Categorical variables were expressed as proportions and compared using the chi-square test. Multivariate logistic regression was used to evaluate predictors of cardiac catheterization. The value of p < 0.05 was considered statistically significant. Statistical analysis was performed using statistical software SPSS 17.0, Chicago Illinois.

Results

Of the 5536 patients undergoing MPS between March 2008 and December 2012, 643 (11.6%) underwent CAT after myocardial scintigraphy.

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Table 1 – Demographic and scintigraphic characteristics of the groups that performed or did not perform post-MPS CAT

CharacteristicsPatients without post CAT

n = 4893

Patients with post CAT

n = 643p-value

Age 62.8 ± 12.3 63.8 ± 10.7 < 0.01

Male 2692 (55%) 403 (62.7%) < 0.05

Asymptomatic 3136 (64.1%) 355 (55.2%) < 0.05

Typical Pain 172 (3.5%) 68 (10.6%) < 0.001

Atypical Pain 1585 (32.4%) 220 (34.2%) = 0.124

Previous AMI 412 (8.4%) 106 (16.5%) < 0.01

SAH 2977 (60.9%) 442 (69 %) < 0.05

DM 1029 (21%) 196 (30.5%) < 0.001

Dyslipidemia 2371 (48.5%) 376 (58.5%) < 0.01

Previous PTCA 802 (16.4%) 204 (31.7%) < 0.001

Previous MRV 409 (8.4%) 75 (11.7%) < 0.01

SSS 2.7 ± 4.7 6.4 ± 6.3 < 0.001

SRS 2.0 ± 3.9 3.2 ± 4.2 < 0.001

SDS 0.6 ± 1.9 3.2 ± 4.2 < 0.001

LVEF 59.2 ± 10.9 54.9 ± 12.1 < 0.001

AMI: acute myocardial infarction; SAH: systemic arterial hypertension; DM: diabetes mellitus; Percutaneous transluminal coronary angioplasty; MRV: myocardial revascularization; SSS: added stress score; SRS: rest score; SDS: sum difference score; LVEF: left ventricular ejection fraction.

The baseline and scintigraphic characteristics of the two groups (without and with post-MPS CAT) are presented in Table 1.

Patients undergoing CAT were more frequently males with angina, hypertension, dyslipidemia, diabetes, previous MI and had been submitted to percutaneous transluminal coronary angioplasty or previous surgical myocardial revascularization.

The analysis of the continuous variables of the two groups reveals that the group that went to the post-MPS catheterization were older, with higher perfusion scores and lower LVEF when compared to group 1. In the multivariate analysis, the presence of typical pain (IC95% 1,2 – 1,7; p < 0,001), diabetes, past angioplasty and ischemia extension (95% CI 1.2 - 1.3; p < 0.001) were independent variables for CAT indication (Table 2).

Discussion

The studies showed the important role of MPS not only as a diagnostic test for CAD, but as an important role in

risk stratification and therapeutic decision-making.9-11 According to the latest guideline of the European Society of Cardiology, revascularization is recommended in cases in which the ischemic area of the left ventricle is greater than 10% (Class I, level of evidence B).12,13

Although the percentages of ischemia are more understandable for cardiologists, it should be noted that these are obtained automatically and with recognized limitations to obtain them. The scores obtained with the participation of the specialist express much more accurately the interpretation of the test. That is why we chose to use them.

Bateman et a l . 9 in their s tudy performed 4,162 myocardial scintigraphy in 3,374 patients during 26 consecutive months, 60% of the exams presented some degree of myocardial reversibility. The likelihood of catheterization was increased by eight fold in studies demonstrating reversibility, when it was associated with the high risk criteria (multi-vessel or left anterior descending reversal and abnormal radiotracer uptake in the lungs) the likelihood that these patients were referred

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Table 2 – Independent predictors of CAT post-MPS

Characteristics Wald p-value Risk Ratio (95% CI)

Age 1,970 0,258 0,9 (0,9 – 1,1)

Typical Pain 22,124 0,000 2,2 (1,2 – 1,7)

Previous AMI 0,479 0,489 0,9 (0,6– 1,1)

SAH 1,787 0,181 0,8 (0,7 – 1,0)

DM 11,907 0,001 1,4 (1,1 – 1,7)

Dyslipidemia 12,742 0,000 1,4 (1,1 – 1,6)

Previous PTCA 25,780 0,000 1,7 (1,4 – 2,2)

Previous MRV 3,649 0,056 1,3 (0,9 – 1,8)

SDS 272,341 0,000 1,3 (1,2 – 1,3)

LVEF 7,915 0,090 0,9 (0,9 – 1,1)

CI: confidence interval; AMI: acute myocardial infarction; SAH: systemic arterial hypertension; DM: diabetes mellitus; Percutaneous transluminal coronary angioplasty; MRV: myocardial revascularization; SDS: sum difference score; LVEF: left ventricular ejection fraction.

for angiography increased 20-fold. The scintigraphic findings were the most important factors at the time of the therapeutic decision, supplanting the clinical characteristics of the patients. In another study14 the determining factors for post-myocardial scintigraphy catheterization were the extent of ischemia and the significant drop in ejection fraction.

Hachamovitch et al.15 demonstrated in their study, with 3,369 patients, that the indication for CAT and MRV could be explained by the percentage of myocardial ischemia and the ejection fraction. CAT rates increased with LVEF decline and in the presence or absence of ischemia (mild to moderate). However, in patients with severe ischemia the number of CATs decreased proportionally with the drop of the ejection fraction. In our group, we evaluated 5,536 patients, of whom 643 were taken to CAT. These presented more angina and greater area of ischemia. The left ventricular ejection fraction did not significantly influence the catheterization indication.

Our study provides additional information to demonstrate that the LVEF of the MPS did not contribute significantly in our environment for the decision to indicate the catheterization. Determining the reason for this and the impact on patient survival needs to be established.

Study Limitations

The main limitation is due to the design of the study, since the patients come to perform the examination by medical indication and not by their real distribution in the population, and therefore we cannot extrapolate the results found. In addition, this is a study conducted in a single center, so more studies should be done to confirm their findings.

Conclusions

The presence of angina and the extent of ischemia were the main determinants for indication of catheterization in patients undergoing myocardial perfusion scintigraphy in our setting, while LVEF was not an independent predictor.


Conception and design of the research: Lima RSL. Acquisition of data: Andrade L, Pitta L. Analysis and interpretation of the data: Mesquita FO, Lorenzo AR, Lima RSL. Statistical analysis: Lima RSL. Writing of the manuscript: Mesquita FO. Critical revision of the manuscript for intellectual content: Lorenzo AR, Lima RSL. Supervision / as the major investigador: Lima RSL.

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1. Curtis JP, Sokol SI, Wang Y, Rathore SS, Ko DT, Jadbabaie F, et al. The association of left ventricular ejection fraction, mortality, and cause of death in stable outpatients with heart failure. J Am Coll Cardiol. 2003;42:736-42. PMID:2932612.

2. Muhlbaier L.H, Pryor D.B, Rankin J.S, Smith LR, Mark DB, Jones RH, et al.Observational comparison of event-free survival with medical and surgical therapy in patients with coronary artery disease: 20 years of follow-up. Circulation.1992; 86 (Suppl II):II198-204. pp. II198–204. PMID:1424000.

3. Emond M, Mock MB, Davis K.B, Fisher LD, Holmes DR Jr, Chaitman BR, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation. 1994;90(6):2645-57. PMID: 7994804.

4. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation. 2003;107923):2900–7. PMID:12771008.

5. Hachamovitch R, Rozanski A, Hayes SW, Thomson LE, Germano G, Friedman JD, et al. Predicting therapeutic benefit from myocardial revascularization procedures: Are measurements of both resting left ventricular ejection fraction and stress-induced myocardial ischemia necessary? J Nucl Cardiol. 2006;13(6):768–78. PMID: 17174808.

6. Yusuf S, Zucker D, Peduzzi P, Fisher LD, Takaro T, Kennedy JW, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomized trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet .1994;344(8922):563-70. PMID:7914958.

7. Hachamovitch R, Hayes S, Cohen I, Germano G, Berman DS. Inducible ischemia is superior to EF for identification of short-term survival benefit with revascularization vs. medical therapy (abstract). Circulation. 2002;106( Suppl:II):523.

8. Cerqueira MD, Weissman NJ, Dilsiziam V, Jacobs AK, Kaul S, Laskey WK, et al; American Heart Association Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare

professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association. Circulation. 2002;105(4):539-42. PMID:118151.

9. Bateman TM, O’Keefe JH Jr., Dong VM, Barnhart C, Ligon RW. Coronary angiographic rates after stress single-photon emission computed tomographic scintigraphy. J Nucl Cardiol. 1995;2(3):217–23. PMID:9420791.

10. Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging). J Am Coll Cardiol. 2003;42(7):1318–33. PMID:14522503.

11. Ward RP, Al-Mallah MH, Grossman GB, Hansen CL, Hendel RC, Kerwin TC, et al. American Society of Nuclear Cardiology review of the ACCF/ASNC appropriateness criteria for single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI). J NuclCardiol, 14 (2007), pp. e26–e38.

12. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A,t al. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949–3003. Doi: 10.1093/eurheartj/eht296.

13. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, et al. Guidelines on myocardial revascularization. Eur Heart J. 2010;31(20):2501–55. Doi:10.1093/eurheartj/ehq277.

14. Romero-Farina G, Candell-Riera J, Aguadé-Bruix S, Castell-Conesa J, García-Dorado D. Impact of myocardial perfusion gated-SPECT on the decision to perform coronary angiography in patients with left ventricular dysfunction of ischemic origin. Rev Esp Med Nucl. 2011;30(3):141-6. doi:10.1016/j.remn.2010.12.006.

15. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Kang X, Germano G, et al. Is there a referral bias against catheterization of patients with reduced left ventricular ejection fraction? Influence of ejection fraction and inducible ischemia on post-single-photon emission computed tomography management of patients without a history of coronary artery disease. J Am Coll Cardiol.2003;42(7):1286-94. PMID: 12796141.

References



Sources of Funding


Study Association

This article is part of the thesis of master submitted by Fernanda de Oliveira Mesquita, from Universidade Federal do Rio de Janeiro.

Mesquita et al.



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509Mesquita et al.



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DOI: 10.5935/2359-4802.20170076

Abstract

Background: An ecological hiking occurs yearly in Brazil. It is a unique event because of its distance (310 km) and dynamics (mean of 62 km/day for 5 days with mean pace of 7.6 km/h). Although beneficial effects of moderate-intensity exercises are well-known, the effects of intense and long-duration exercise still require study.

Objective: To evaluate the effects of mixed walking/running race on various blood pressure (BP) parameters 30 days before (A0), on the 2nd (A2), 3rd (A3), and 4th (A4) days after completing the day’s stage.

Methods: Central systolic (cSBP) and diastolic BP (cDBP), peripheral systolic (pSBP) and diastolic BP (pDBP), central pulse pressure (cPP), peripheral pulse pressure (pPP), amplified pulse pressure (aPP), corrected augmentation index (AIx75%) and pulse wave velocity (PWV) were measured using an oscillometric Mobil-O-Graph® (IEM, Stolberg, Germany) in 25 male athletes (mean age of 45.3 ± 9.1 years). A p value < 0.05 was considered a statistically-significant difference.

Results: cSBP decreased from A0 to A2 (109.5 to 118.1 mmHg) and from A0 to A3 (109.5 to 102.5 mmHg); pPP decrease from A0 to A2 (49.2 to 38.2 mmHg) and from A0 to A4 (49.2 to 41.2 mmHg); aPP decrease from A0 to A1 (15.6 to 9.5 mmHg), from A0 to A2 (15.6 to 8.0 mmHg) and from A0 to A3 (15.6 to 11.2 mmHg). PWV correlated with age.

Conclusions: Blood pressure dropped on the first days of the race and returned to close to baseline values at the end. PWV correlates strongly with age. This type of exercise promotes effects on BP and PWV similar to those seen in long-duration, high-intensity sports. These changes in trained healthy individuals do not seem to increase cardiovascular risks. This was the first study to assess the effects of this type of exercise on the cardiovascular system. (Int J Cardiovasc Sci. 2017;30(6)510-516)

Keywords: Hypertension; Blood Pressure; Vascular Stiffness; Exercise; Walking; Pulse Wave Analysis.


ORIGINAL ARTICLES

Mailing Address: Priscila Valverde de Oliveira VitorinoAvenida Carlos Elias, Qd. 21, Lt. 3. Postal Code: 75084-100, Bairro São Carlos, Anápolis, Goiás – BrazilE-mail: [email protected]; [email protected]

Assessment of Central Blood Pressure and Arterial Stiffness in Practicing Long-Distance Walking RaceEdison Nunes Pereira,1 Priscila Valverde de Oliveira Vitorino,1 Weimar Kunz Sebba Barroso de Souza,1,2 Mariana Cardoso Pinheiro,1 Ana Luiza Lima Sousa,2 Paulo Cesar Brandão Veiga Jardim,2 Jeeziane Marcelino Rezende,1 Antonio Coca3

Pontifícia Universidade Católica de Goiás,1 Liga de Hipertensão Arterial da Universidade Federal de Goiás,2 GO - Brazil; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona,3 Barcelona – Spain

Manuscript received February 16, 2017, revised manuscript May 07, 2017, accepted June11, 2017.

Introduction

Regular moderate exercise can reduce the risk of coronary heart disease through various mechanisms, including changes in cardiovascular risk factors,1 such as glucose, lipid metabolism and blood pressure (BP) values and weight control. The protective effects of moderate exercise on the cardiovascular system are well-established.2 The same is not true for long-distance

walking and vigorous exercise, whose effects on the

cardiovascular system remain unclear.3

A mixed walking/running race takes place every July in

Goiás state, in central western Brazil. Athletes cover 310 km

in 5 days (62 km/day, on average), with stops for lunch

and sleep. Women and men participate in the event and

enrol voluntarily. Those selected undergo physical fitness

tests and a cardiorespiratory evaluation. Men complete the

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entire course and women approximately 50%. The race ranges between fast walking and running, the average speed being 7.6km/h. No study has evaluated the effects of this type of exercise on the cardiovascular system.

The evaluation of parameters of central BP measurement and arterial stiffness, which assess aortic and peripheral pressure, vascular resistance and pressure variations throughout the arterial tree, may help improve understanding of changes in the cardiovascular system due to exercise.4 One parameter that should be emphasized is pulse wave velocity (PWV), which measures arterial stiffness, a factor highly predictive of cardiovascular events. In addition, arterial stiffness is associated with systolic BP (SBP) and pulse pressure (PP).5 The lower the PWV, the more elastic and complacent the arteries. Therefore, high PWV values reflect greater arterial stiffness.6 Age and physical activity can change the PWV.7,8

This study studied the effects of prolonged exercise on central BP measurement in athletes during this race in Goiás.

Methods

This longitudinal study evaluated men who participated in the race in Goiás, Brazil in July 2014. The race covered 310 km and lasted 5 days. The average distance covered was 62 km/day, and the average speed was 7.6 km/h. The mean temperature of the course was 30°C (range 18-42).

The initial assessment (A0) was carried out at a specialized medical centre, and other evaluations (A2, A3 and A4) were conducted at the end of each race day in the cities where the athletes slept. Assessments included measurements of central systolic and diastolic BP (cSBP and cDBP), peripheral systolic and diastolic BP (pSBP and pDBP), central PP (cPP), peripheral PP (pPP), amplified PP (aPP), corrected augmentation index (AIx75%), PWV and total vascular resistance (TVR) using a Mobil-OGraph® oscillometric device (IEM, Stolberg, Germany). Measurements were obtained from the right upper limb with the participant seated, arms at heart level, after resting for ≥ 5 minutes.

Measurements were carried out before dinner at the end of each day. For the initial assessment, a complete medical history was taken. Due to technical problems, no assessment was made at the end of the first day of walking. Women were excluded from the study because

they had a significant difference in all BP measurements and did not cover the entire course.

The medical history included the following variables: age (in years), body mass index (kg/m2), smoking (yes/no), physical activity (sufficiently active/ insufficiently active), diabetes mellitus (yes/no), dyslipidemia (yes/no) and hypertension (yes/no). Sufficiently active was defined as self-reported exercise of any type for ≥ 150 minutes weekly.9

This study was approved by the Ethics and Research Committee of Pontifícia Universidade Católica de Goiás (number 612.800, April 09, 2014). All participants gave written informed consent.


All participants in the ecological hiking were evaluated. Descriptive statistics are presented as means, standard deviation, confidence intervals (quantitative variables with normal distribution) and absolute and relative frequencies (qualitative variables). The statistical analysis was carried out using the Statistical Package for the Social Sciences® (SPSS), version 20.0. Shapiro-Wilk test was used to determinate the distributions of the quantitative variables data. Variables related to BP measurement were compared using repeated-measures analysis of variance (ANOVA), followed by a Bonferroni post hoc test. For correlations between BP variables and age, Pearson's correlation coefficient was used. A p value <0.05 was considered a statistically significant difference.

Results

We included 25 men with a mean age of 45.3 ± 9.1 years (range 27.8-60.8). All participants engaged in physical exercise regularly, and the mean body mass index was 23.1 ± 2.6 kg/m2. No participant was a smoker, and three had risk for cardiovascular disease (Table 1).

All parameters of central BP measurement and arterial stiffness were within normal levels in all assessments. cSBP decreased from A0 (113.8 ± 2.1 mmHg) to A2 (107.3 ± 1.7 mmHg) and to A3 (105.7 ± 1.6 mmHg). pPP decreased from A0 (49.2 ± 1.7 mmHg) to A2 (38.2 ± 1.8 mmHg) and to A4 (41.2 ± 1.2 mmHg). aPP increased from A0 (15.6±1.3 mmHg) to A2 (9.5 ± 0.7 mmHg) to A3 (11.2 ± 0.8 mmHg) and to A4 (8.2 ± 0.3 mmHg). There was no difference between the means of other variables (Table 2).

In all evaluations, PWV was strongly correlated with age (Figure 1).

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Table 1 – General health characteristics of participants in the race in Goiás, Brazil, 2014 (n = 25)

Sample characterization n (%)

Age

< 40 7 (2)

≥ 40 18 (72)

Exercise

Sufficiently active 23 (92)

Insufficiently active 2 (8)

Diabetes mellitus

Yes 1 (4)

No 24 (96)

Dyslipidemia

Yes 1 (4)

No 24 (96)

Systemic arterial hypertension

Yes 1 (4)

No 24 (96)

Discussion

This is the first study to evaluate effects of a mixed walking/running race on parameters of central BP measurement and arterial stiffness. Values of peripheral and aortic BP in the initial assessment were within the normal range. BP decreased at the beginning of walking and returned to initial values on the last days of the race. Therefore, between the start and finish of the event, it seems that no significant changes occurred in these parameters. These findings support the vasodilation potency of this type of moderate-intensity and long-duration exercise.

Endurance athletes may present arterial remodelling, which causes an accommodation of pressure during and after exercise. The ability of the arteries of the skeletal muscle to vasodilate, promoted by training, increases the cardiac deficit without relevant repercussions in BP. This elasticity of the arterial vessels in response to physical activity suggests arterial adaptation, which is indispensable to the performance of endurance athletes.10 Runners participating in marathons in Seoul11 and Athens12 showed a reduction in both DBP

and SBP at the event’s beginning and end. In our study, this behaviour was also identified regarding central BP measurement.

The PWV values of participants in our study were within the reference ranges for healthy individuals: 7.0 m/s for this age range.13 We found high values compared to controls performing moderate physical exercise.12 Therefore, because of the small amount of specific training, consisting of a few hours of training weekly, and the fact that the participants' cardiovascular parameters matched reference values, we believe that the group assessed in our study was composed of active individuals, but not professional athletes.

There was no significant change in PWV in different measurements throughout the walking event, but we observed a trend towards a reduction in the first 3 days. A study that analysed PWV in male athletes participating in a 75-km race found a reduction in PWV after 45 km; beyond that point, there was an increase until 75 km, after which values nearly returned to baseline. We found similar results.14 Other studies have found no change in PWV before and after exercise in marathon runners,11,12 walkers,15 and runners with high BP.16 In the latter two studies, the heart rate corresponded to that seen with moderate exercise.

Other studies found a significant reduction in PWV in hypertensive individuals who did running and/or walking17 and in normotensive individuals who engaged in various types of aerobic exercise (moderate to vigorous).18-20

A systematic review and meta-analysis that evaluated the effects of aerobic exercise on PWV found a reduction in PWV promoted by aerobic exercise. This reduction increased with long-duration exercises, which promote a higher oxygen consumption.21 However, reductions in cSBP and PWV have the potential to reduce the risk of additional cardiovascular events, then reinforcing the potential benefit of regular physical activity.5

Our study identified a strong positive correlation between PWV and age, as did studies that determined reference values,13,22 evaluated and compared competitive athletes and active individuals,23 and a study in men engaging in moderate exercise using a cycle ergometer.24 Other factors may be associated with PWV, such as BP and the intensity of exercise12 and body weight.25

Age influences both BP and PWV − the older the age, the higher the BP and PWV. This occurs, amongst other reasons, due to changes in arterial structure. This difference in values found between central BP

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Table 2 – Mean, standard deviation and confidence interval (95%) of central blood pressure measurements in participants in the race in Goiás, Brazil, 2014 (n = 25)

Parameter Mean ± SD 95% CIF

pPost hoc Parameter Mean ± SD 95% CI

F

pPost hoc

Central systolic blood pressure (mmHg) Central diastolic blood pressure (mmHg)

A0 113.8 ± 2.8 109.55-118.13 A0 80.2 ± 1.9 76.28-84.28

-A2 107.3 ± 1.7 103.74-110.97 4.42 A0-A2* A2 78.6 ± 1.0 76.48-80.80 2.68

A3 105.7 ± 1.6 102.46-109.06 0.006 A0-A3* A3 74.2 ± 1.5 71.27-77.29 0.051

A4 111.5 ± 1.6 108.22-114.89 A4 78.6 ± 1.7 75.13-82.15

Peripheral systolic blood pressure (mmHg) Peripheral diastolic blood pressure (mmHg)

A0 127.9 ± 1.3 123.07-132.85

-

A0 78.7 ± 1.8 74.90-82.62

-A2 115.6 ± 1.9 111.70-119.58 0.98 A2 77.4 ± 1.1 75.17-79.63 2.65

A3 115.6 ± 1.7 112.04-119.32 0.38 A3 73.0 ± 1.4 70.04-75.95 0.053

A4 118.6 ± 1.5 115.47-121.81 A4 77.4 ± 1.6 73.98-80.90

Central pulse pressure (mmHg) Peripheral pulse pressure (mmHg)

A0 33.5 ± 1.3 30.87-36.25

-

A0 49.2 ± 1.7 45.62-52.78

A2 28.7 ± 1.5 25.54-31.90 2.30 A2 38.2 ± 1.8 34.33-42.15 7.52 A0-A2*

A3 31.4 ± 1.5 28.27-34.69 0.082 A3 42.6 ± 1.8 38.91-46.45 < 0.001 A0-A4*

A4 32.9 ± 1.2 30.36-35.48 A4 41.2 ± 1.2 38.70-43.70

Amplified pulse pressure (mmHg) Corrected augmentation index (%)

A0 15.6 ± 1.3 1.95-18.33 A0-A1* A0 13.6 ± 2.0 9.35-17.93

-A2 9.5 ± 0.7 7.99-11.05 13.04 A0-A2* A2 17.0 ± 2.6 11.60-22.47 0.66

A3 11.2 ± 0.8 9.37-13.03 p < 0.001 A0-A3* A3 13.1 ± 2.1 8.69-17.55 0.580

A4 8.2 ± 0.3 7.48-9.07 A4 13.4 ± 2.0 9.26-17.70

Pulse wave velocity (m/s) Total vascular resistance

A0 6.9 ± 0.2 6.19-7.01

-

A0 1.0 ± 0.0 1.00-1.00

-A2 6.6 ± 0.2 6.19-7.01 1.06 A2 1.0 ± 0.0 1.00-1.00 0.77

A3 6.4 ± 0.1 6.14-6.82 0.369 A3 1.0 ± 0.0 1.00-1.00 0.515

A4 6.6 ± 0.2 6.24-7.12 A4 1.0 ± 0.0 1.00-1.00

* p < 0.05 (Repeated-measures ANOVA). SD: standard deviation; CI: confidence interval; A0: initial evaluation; A2: second evaluation; A3: third evaluation; A4: fourth evaluation.

and peripheral BP results from the reduction in arterial

gauge and compliance as central arteries become

peripheral.4 Elasticity depends especially on the

composition of the vascular media layer. In young and

healthy individuals, there is a predominance of elastin

over collagen in the central portion of the arterial bed.

However, an inversion of collagen proportion exists

in relation to elastin in muscle peripheral arteries. Therefore, the aorta presents greater elasticity compared with the arteries of the limbs, which are more rigid.26

Although this study did not evaluate the effects of inflammatory substances and endothelium adhesion, these factors must be also considered. Variations in PWV

514

m/s m/s9

8

7

6

5

4

9

8

7

6

5

4

9

8

7

6

5

4

9

8

7

6

5

420 30 40 50 60 70 20 30 40 50 60 70

20 30 40 50 60 7020 30 40 50 60 70

PWV

A0

PWV

A3

PWV

A2

PWV

A4

Age Ager = 0.831; p ≤ 0.001 r = 0.928; p ≤ 0.001

Age Ager = 0.831; p ≤ 0.001 r = 0.928; p ≤ 0.001

Figure 1 – Correlation between pulse wave velocity and age (in years) during the race at Goiás, Brazil, 2014 (n = 25). Pearson correlation coefficient. PVW: pulse wave velocity; A0: initial evaluation; A2: second evaluation; A3: third evaluation; A4: fourth evaluation.

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Original Article

may be related to many adaptations due to moderate aerobic activity that involve increased production of a number of substances with vasodilating and anti-inflammatory properties.27,28

A study that evaluated hypertensive and non-hypertensive ultra-marathon runners, collecting samples after 100 km, 200 km and 308 km (end of the race), identified an increase in vascular cell adhesion molecule 1 (at 100 and 200 km), E- selectin (at 100 km), and leukocytes (at 208 km), which were higher in hypertensive individuals than in normotensive individuals. In both groups, there was a gradual increase in creatine kinase and C-reactive protein. Therefore, vigorous exercise can stimulate more intense endothelial responses in hypertensive individuals, regardless of inflammatory markers.29

Likewise, PWV depends on the arterial structure and the relationship between resistance and elasticity, properties directly related to the amount of collagen and elastin. Therefore, PWV changes are identified over

time; to verify the effects of exercise on this parameter, further long-term, longitudinal studies would be needed to analyse the chronic effects of exercise.26

Our study also did not evaluate variations in mean central BP after the end of the event. However, the acute effect was well analysed and showed that this activity is fairly safe for well-evaluated participants, even without specific training.

Conclusion

Blood pressure dropped in the first days of the race and returned to close to baseline values at the end. PWV correlates strongly with age. Ecological hiking seems to promote effects on arterial pressure and PWV similar to those seen in marathons and other long-duration and high-intensity sports. Changes promoted by this type of exercise in active and healthy individuals do not seem to pose high risks for cardiovascular health.

515

1. Sesso HD, Paffenbarger RS Jr, Lee IM. Physical activity and coronary heart disease in men: The Harvard Alumni Health Study. Circulation. 2000;102(9):975-80. PMID: 10961960.

2. Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, et al; American Heart Association Council on Clinical Cardiology Subcommittee on Exercise, Rehabilitation, and Prevention; American Heart Association Council on Nutrition, Physical Activity, and Metabolism Subcommittee on Physical Activity. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation. 2003;107(24): 3109-16. doi: 10.1161/01.CIR.0000075572.40158.77.

3. O'Keefe JH, Schnohr P, Lavie CJ. The dose of running that best confers longevity. Heart. 2013;99(8): 588-90. doi: 10.1136/heartjnl-2013-303683.

4. McEniery CM, Cockcroft JR, Roman MJ, Franklin SS ,Wilkinson IB. Central blood pressure: current evidence and clinical importance. Eur Heart J. 2014;35(26):1719-25. doi: 10.1093/eurheartj/eht565.

5. Cecelja M ,Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54(6):1328-36. doi: 10.1161/HYPERTENSIONAHA.109.137653.

6. Rocha E. [Pulse wave velocity: a marker of arterial stiffness and its applicability in clinical practice]. Rev Port Cardiol. 2011;30(9):699-702. doi: 10.1016/S0870-2551(11)70012-9.

7. Townsend RR, Wilkinson IB, Schiffrin EL, Avolio AP, Chirinos JA, Cockcroft JR, et al; American Heart Association Council on Hypertension. Recommendations for improving and standardizing vascular research on arterial stiffness: a scientific statement from the American Heart Association. Hypertension. 2015;66(3):698-722. doi: 10.1161/HYP.0000000000000033.

8. Vlachopoulos C, Xaplanteris P, Aboyans V, Brodmann M, Cífková R, Cosentino F, et al. The role of vascular biomarkers for primary and secondary prevention. A position paper from the European Society of Cardiology Working Group on peripheral circulation: Endorsed by the Association for Research into Arterial Structure and Physiology (ARTERY) Society. Atherosclerosis. 2015;241(2):507-32. doi: 10.1016/j.atherosclerosis.2015.05.007

9. World Health Organization. (WHO). The world health report 2002: reducing risks, promoting healthy life. Geneva: 2002.

10. Green DJ, Spence A, Rowley N, Thijssen DH, Naylor LH. Vascular adaptation in athletes: is there an 'athlete's artery'? Exp Physiol. 2012;97(3):295-304. doi: 10.1113/expphysiol.2011.058826.

11. Jung SJ, Park JH, Lee S. Arterial stiffness is inversely associated with a better running record in a full course marathon race. J Exerc Nutrition Biochem. 2014;18(4):355-9. doi: 10.5717/jenb.2014.18.4.355.

12. Vlachopoulos C, Kardara D, Anastasakis A, Baou K, Terentes-Printzios D, Tousoulis D, et al. Arterial stiffness and wave reflections in marathon runners. Am J Hypertens. 2010;23(9):974-9. doi: 10.1038/ajh.2010.99.

13. Reference Values for Arterial Stiffness Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'establishing normal and reference values'. Eur Heart J. 2010;31(19):2338-50. doi: 10.1093/eurheartj/ehq165

14. Burr JF, Phillips AA, Drury TC, Ivey AC, Warburton DE. Temporal response of arterial stiffness to ultra-marathon. Int J Sports Med. 2014;35(8):658-63. doi: 10.1055/s-0033-1358478.

15. Choi KM, Han KA, Ahn HJ, Hwang SY, Hong HC, Choi HY, et al. Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial. J Clin Endocrinol Metab. 2012;97(10):3751-8. doi: 10.1210/jc.2012-1951.

16. Guimaraes GV, Ciolac EG, Carvalho VO, D'Avila VM, Bortolotto LA, Bocchi EA. Effects of continuous vs. interval exercise training on blood pressure and arterial stiffness in treated hypertension. Hypertens Res. 2010;33(6):627-32. doi: 10.1038/hr.2010.42.

17. Beck DT, Martin JS, Casey DP, Braith RW. Exercise training reduces peripheral arterial stiffness and myocardial oxygen demand in young prehypertensive subjects. Am J Hypertens. 2013;26(9):1093-102. doi: 10.1093/ajh/hpt080.

18. Rauramaa R, Halonen P, Vaisanen SB, Lakka TA, Schmidt-Trucksass A, Berg A, et al. Effects of aerobic physical exercise on inflammation and atherosclerosis in men: the DNASCO Study: a six-year randomized, controlled trial. Ann Intern Med. 2004;140(12):1007-14. PMID: 15197018.

19. Nordstrom CK, Dwyer KM, Merz CN, Shircore A, Dwyer JH. Leisure time physical activity and early atherosclerosis: the Los Angeles Atherosclerosis Study. Am J Med. 2003;115(1):19-25. PMID: 12867230.

20. Kozàkovà M, Palombo C, Morizzo C, Nolan JJ, Konrad T, Balkau B; RISC Investigators. Effect of sedentary behaviour and vigorous physical activity on segment-specific carotid wall thickness and its progression in a healthy population. Eur Heart J. 2010;31(12):1511-9. doi: 10.1093/eurheartj/ehq092.

21. Huang C, Wang J, Deng S, She Q, Wu L. The effects of aerobic endurance exercise on pulse wave velocity and intima media thickness in adults: a systematic review and meta-analysis. Scand J Med Sci Sports. 2016;26(5):478-87. doi: 10.1111/sms.12495.

References

Pereira et al.



Original Article


Conception and design of the research: Pereira EM, Vitorino PVO, Souza WKSB, Pinheiro MC, Sousa ALL, Jardim PCBV, Rezende JM. Acquisition of data: Pereira EM, Vitorino PVO, Souza WKSB, Pinheiro MC, Rezende JM. Analysis and interpretation of the data: Pereira EM, Vitorino PVO, Souza WKSB, Pinheiro MC, Rezende JM. Statistical analysis: Pereira EM, Vitorino PVO, Pinheiro MC, Rezende JM. Writing of the manuscript: Pereira EM, Vitorino PVO, Souza WKSB, Jardim PCBV, Rezende JM. Critical revision of the manuscript for intellectual content: Vitorino PVO, Souza WKSB, Sousa ALL, Jardim PCBV, Coca A.



Sources of Funding


Study Association

This article is part of the thesis of master submitted by Edison Nunes Pereira, from Universidade Católica de Goiás (PUC – GO).

516

22. Diaz A, Galli C, Tringler M, Ramirez A ,Cabrera Fischer EI. Reference values of pulse wave velocity in healthy people from an urban and rural argentinean population. Int J Hypertens. 2014; 2014: 653239. doi: 10.1155/2014/653239.

23. Maldonado J, Pereira T, Polonia J, Martins L. Modulation of arterial stiffness with intensive competitive training. Rev Port Cardiol. 2006;25(7-8):709-14. PMID: 17069436.

24. Roberts PA, Cowan BR, Liu Y, Lin AC, Nielsen PM, Taberner AJ, et al. Real-time aortic pulse wave velocity measurement during exercise stress testing. J Cardiovasc Magn Reson. 2015;17:86. doi: 10.1186/s12968-015-0191-4.

25. Petersen KS, Blanch N, Keogh JB, Clifton PM. Effect of weight loss on pulse wave velocity systematic review and meta-analysis. Arterioscler Thromb Vasc Biol. 2015;35(1):243-52. doi: 10.1161/ATVBAHA.

26. Safar ME, Frohlich ED. Atherosclerosis, large arteries, and cardiovascular risk. Basel (Switzerland): Karger; 2007.

27. Barroso WK, Jardim PC, Vitorino PV, Bittencourt A, Miquetichuc F. Influênca da atividade física programada na pressão arterial de idosos hipertensos sob tratamento não-farmacológico. Rev Assoc Med Bras. 2008;54(4):328-33.

28. Barroso WK. Benefícios da atividade física na hipertensão arterial e orientações práticas. Rev Bras Hipertens. 2004;11:115-6.

29. Jee H, Park J, Oh JG, Lee YH, Shin KA, Kim YJ. Effect of a prolonged endurance marathon on vascular endothelial and inflammation markers in runners with exercise-induced hypertension. Am J Phys Med Rehabil. 2013;92(6):513-22. doi: 10.1097/PHM.0b013e31829232db.

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Original Article

DOI: 10.5935/2359-4802.20170081


ORIGINAL ARTICLE

Mailing Address: Fernando Pivatto JúniorRua Ramiro Barcelos, 2.350, sala 700, Postal code 90.035-903. Porto Alegre, RS – Brazil.E-mail: [email protected]

Use of HAS-BLED Score in an Anticoagulation Outpatient Clinic of a Tertiary HospitalRafael Coimbra Ferreira Beltrame, Franciele Taís Bandeira Giasson, André Luís Ferreira Azeredo da Silva, Bruna Sessim Gomes, Luís Carlos Amon, Marina Bergamini Blaya, Rafael Selbach Scheffel, Fernando Pivatto JúniorHospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS – Brazil

Manuscript received February 11, 2017, revised manuscript April 06, 2017, accepted June 05, 2017

Abstract

Background: HAS-BLED score was developed to assess 1-year major bleeding risk in patients anticoagulated with vitamin K antagonists (VKA) due to atrial fibrillation (AF).

Objective: Of this study was to assess the ability of HAS-BLED score and its components to predict major bleeding in patients treated in an anticoagulation outpatient clinic of a tertiary hospital.

Methods: A retrospective cohort study on AF patients treated with VKA was conducted. Logistic regression analysis was performed to evaluate the ability of individual score components to predict major bleeding. The significance level adopted in all tests was 5%.

Results: We studied 263 patients with a mean age of 71.1 ± 10.5 years over a period of 237.6 patients-year. Median HAS-BLED score was 2 (1-3). The overall incidence of major bleeding was 5.7%, and it was higher among high-risk HAS-BLED score patients than in low risk patients (9.6 vs. 3.1%; p = 0.052). Area under the ROC curve was 0.70 (p = 0.01). Cut-off point ≥ 3 showed sensibility of 66.7%, specificity of 62.1%, positive predictive value of 9.6% and negative predictive value of 96.9%. Major bleeding-free survival was lower in high-risk group (p = 0.017). In multivariate analysis, concurrent antiplatelet use was the only independent predictor of major bleeding among score components (OR 5.13, 95%CI: 1.55-17.0; p = 0.007).

Conclusion: HAS-BLED score was able to predict major bleeding in this cohort of AF patients. Among score components, special attention should be given for concomitant antiplatelet use, which was independently associated to this outcome. Antiplatelets in AF patients under VKA anticoagulation should be used in selected patients with favorable risk-benefit assessment. (Int J Cardiovasc Sci. 2017;30(6)517-525)

Keywords: Atrial Fibrillation; Hemorrhage; Outpatient Clinics; Hospital.

Introduction

Atrial fibrillation (AF) is a common cardiac rhythm disturbance that increases in prevalence with advancing age: approximately 1% of patients with AF are under 60 years of age, whereas up to 12% of patients with AF are 75 to 84 years of age.1 AF is associated with a broad spectrum of negative outcomes, such as heart failure and major cardiovascular events, including ischemic stroke, with increased cardiovascular and all-cause mortality.2 Ischemic strokes related to AF usually result from cardioembolism of a large cerebral artery, and therefore

tend to be larger, more frequently fatal or associated with greater disability than strokes from other causes.3

Studies with oral anticoagulants (OAC) have shown reduction in all-cause mortality by 26% and in systemic thromboembolism by 64% with the use of vitamin K antagonists (VKA) compared with placebo or untreated controls.4 On the other hand, VKA are associated with increased risk of bleeding.5 Gomes et al6 demonstrated a 3.8% risk of hemorrhage per person-year with warfarin, especially within the first 30 days of therapy (11.8%), with almost 1% of all new users being admitted to hospital due to hemorrhagic complications during this period.

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HAS-BLED in an anticoagulation clinic


Original Article

There are several risk scores available to assess bleeding risk in patients in treatment with VKA.7-12 HAS-BLED score [Hypertension (uncontrolled), Abnormal renal/liver function, Stroke, Bleeding history or predisposition (anemia), Labile INR, Elderly (> 65 years), Drugs/alcohol concomitantly] offers a better prediction of bleeding compared with many other bleeding risk scores for AF patients, and has also been validated in several different cohorts, including large real-world and clinical trial populations.13 The score ranges from 0 to 9, with scores ≥ 3 indicating higher risk of bleeding. In this situation, thorough and regular patient follow-up is recommended.13 In addition, HAS-BLED score should be used to identify modifiable bleeding risk factors that might be addressed, but should not be used to exclude patients from OAC therapy, as suggested by CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, Stroke, Vascular disease, Age 65-74 years, Sex category (i.e., female gender)].3,14,15 The objective of this study was to assess the ability of HAS-BLED score and its components to predict major bleeding in patients treated at a anticoagulation outpatient clinic of a tertiary hospital.

Methods

A retrospective cohort study was conducted on patients on oral anticoagulation with VKA attending the outpatient anticoagulation clinic at Hospital de Clínicas de Porto Alegre (HCPA). This hospital is a tertiary care teaching hospital located in southern Brazil and most patients are low-income. All decisions regarding the management of anticoagulation are based on a protocol published by Kim et al.16 All patients who visited the clinic from January to March 2014 were screened for inclusion in the study. Non-valvular AF patients under VKA anticoagulation were included. Valvular AF was defined as AF associated to moderate to severe mitral stenosis or prosthetic heart valve.17 This study was approved by local Research Ethics Committee.

Ischemic stroke risk was estimated with the scores CHADS2 (Congestive heart failure, Hypertension, Age > 75, Diabetes, Stroke) and CHA2DS2-VASc.18,19 High-risk for ischemic stroke was defined as a score ≥ 2. As for the risk of major bleeding, patients were stratified into 2 groups according to individual HAS-BLED scores: (1) low-moderate risk group (score 0-2) and (2) high risk group (score ≥ 3).12 The acronym HAS-BLED represents each of the bleeding risk factors and assigns 1 point

for each of the following: uncontrolled hypertension, abnormal renal and/or liver function, previous stroke, bleeding history or predisposition, labile international normalized ratios, elderly, and concomitant drugs and/or alcohol abuse.13 Data were obtained by reviewing electronic health records during outpatient clinic visits, emergency visits and hospital admissions during the study period. Patients who were lost to follow-up, who died or whose anticoagulation therapy was discontinued were equally included in the analysis. Time in therapeutic range (TTR) was estimated though Rosendaal’s linear interpolation method.20

Laboratory test results and left ventricular ejection fraction (preferably assessed by echocardiogram) at the beginning of follow-up period were recorded. Anemia was defined by hemoglobin (Hb) below 13.0 g/L in men and 12.0 g/L in women.21 Uncontrolled hypertension was defined as systolic blood pressure > 160 mmHg.12 Major bleeding was defined as any bleeding requiring hospitalization and/or causing a decrease in hemoglobin level > 2 g/dL and/or requiring blood transfusion.12 Presence of chronic dialysis, renal transplantation or serum creatinine ≥ 200 μmol/L (2.26 mg/dL) was classified as abnormal renal function.12 Abnormal liver function was defined as previous clinical diagnosis of chronic hepatic disease (e.g., cirrhosis) or biochemical evidence of significant hepatic derangement (e.g., bilirubin > 2x upper limit of normal, in association with AST/ALT/ALP > 3 x upper limit of normal).12


Descriptive analyses were performed by absolute and relative frequency for qualitative variables, and mean ± standard deviation and median (interquartile range, 25-75th percentile) for quantitative variables with symmetric and asymmetric distribution, respectively. Normality of the distribution of each variable was evaluated using Shapiro-Wilk test. Comparison between the groups was performed by Chi-square test. Fisher exact test was used in situations of low frequency. Area under the Receiver Operating Characteristic (ROC) curve was calculated to evaluate the ability of HAS-BLED score to predict major bleeding. Major bleeding-free survival between HAS-BLED groups was analyzed by Kaplan-Meier curves and compared using log-rank test. Logistic regression was performed to detect the adjusted association of HAS-BLED score components with the outcome major bleeding. Relation between candidate

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Table 1 – Demographic characteristics of the patients

Variable n = 263

Female sex 113 (43.0)

Age 71.2 (64.1-78.5)

Warfarin use 256 (97.3)

Hypertension 231 (87.8)

Heart failure / LVEF < 40% 149 (56.7)

Labile INR (TTR < 60%) 124 (47.1)

Diabetes 108 (41.1)

Previous stroke / TIA 96 (36.5)

Coronary artery disease 76 (28.9)

Antiplatelet therapy 64 (24.3)

Anemia 67 (25.5)

Peripheral artery disease 25 (9.5)

Major bleeding history 24 (9.1)

Hypertension, uncontrolled 22 (8.4)

Alcohol 21 (8.0)

Abnormal renal function 7 (2.7)

Abnormal liver function 2 (0.8)

CHADS2 score 3 (2-4)

CHA2DS2-VASc score 4 (3-5)

HAS-BLED score 2 (1-3)

LVEF: left ventricle ejection fraction; TIA: transient ischemic attack; INR: international normalized ratio; TTR: time in therapeutic range. CHADS2: Congestive heart failure, Hypertension, Age > 75, Diabetes, Stroke; CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥ 75 years, Diabetes, Stroke, Vascular disease, Age 65-74 years, Sex category (i.e., female gender); HAS-BLED: Hypertension (uncontrolled), Abnormal renal/liver function, Stroke, Bleeding history or predisposition (anemia), Labile INR, Elderly (> 65 years), Drugs/alcohol concomitantly. Data presented as number (%) or median (interquartile range).

variables and the outcome was initially investigated in a series of bivariate analyses (p < 0.10 for selection of candidate variables). Next, we used stepwise forward selection for variable inclusion until all retained variables were statistically significant at a p < 0.05. The significance level adopted in all tests was 5%. Data were analyzed in Statistical Package for Social Sciences (SPSS) software, version 21.0 (IBM, Armonk, NY, USA).

Results

A total of 263 patients were included in the study, corresponding to 38.5% of individuals attending in outpatient anticoagulation clinic. Demographic characteristics are detailed in Table 1. There were no patients using nonsteroidal anti-inflammatory drug (NSAIDs). Indications for anticoagulation among patients not included in the current cohort were: mechanical cardiac prosthesis (21.2%), deep vein thrombosis / pulmonary thromboembolism (19.0%), valvular AF (8.6%) and thrombus in the left ventricle (2.0%).

Mean follow-up was 329.9 ± 81.9 days. Of the 263 patients, 205 (77.9%) completed the follow-up, 25 (9.5%) were lost to follow-up, 21 (8.0%) stopped the anticoagulation and 12 (4.6%) died. Overall, 2,754 INR tests were performed during the study period, with a median of 10 INR tests per patient (range 7-13). Of these, 1,270 (46.1%) presented values between 2.0 and 3.0 over a treatment time of 237.6 patients-year. Median TTR was 62.5% (44.2-79.5%). Patients were under-anticoagulated (i.e., INR < 2.0) during a median of 18.9% of time (6.1-36.6%) and over-anticoagulated (i.e., INR > 3.0) during a median 9.6% of time (1.6-23.3%).

The incidence of major bleeding in all patients was 5.7% (n = 15), which represents 6.3 major bleedings/100-patients-year. The major bleeding sites were mucocutaneous (n = 4; 26.7%), genitourinary (n = 4; 26.7%), gastrointestinal (n = 3; 20.0%), intracranial (n = 3; 20.0%) and retroperitoneal (n = 1; 6.7%).

“Elderly” was the most prevalent HAS-BLED score component (72.2%), followed by “Labile INR” (47.1%). When the patients were divided according the HAS-BLED score in high and low-moderate risk for major bleeding, we observed that 104 patients (39.5%) were classified as high risk (HAS-BLED ≥ 3). This group had a higher incidence of major bleeding compared with the low-moderate (9.6 versus 3.1%; p = 0.052).

The association of HAS-BLED score components with major bleeding incidence is described in Table 2. In multivariate logistic regression analysis, concurrent

antiplatelet use was the only independent predictor

of major bleeding among score components (OR 5.13,

95%CI: 1.55-17.0; p = 0.007).

The area under the ROC curve for HAS-BLED score

ability to predict major bleeding was 0.70 (95%CI:

0.53-0.86; p = 0.01). A score cut-off point ≥ 3 presented

sensibility of 66.7%, specificity of 62.1%, positive

predictive value of 9.6% and negative predictive value

of 96.9%. Major bleeding-free survival Kaplan-Meier

curves according HAS-BLED score categories are

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shown in Figure 1. High-risk patients, i.e. HAS-BLED score ≥ 3, had a significantly lower major bleeding-free survival (p = 0.017).

The magnitude of the risks associated to each score component is presented in Figures 2 and 3 in univariate and multivariate analysis, respectively. In multivariate analysis, only the concurrent use of antiplatelet agents independently predicted the occurrence of major bleeding among the score components. Antiplatelets used during follow-up and their indications are described in Figure 4 and Table 3.

Discussion

In this study, a significant association between high HAS-BLED scores (i.e, score ≥ 3) and major bleeding during

follow-up was observed. The only independent variable of HAS-BLED score associated with this adverse event was concomitant use of antiplatelet agents. Our findings corroborate the use of HAS-BLED score as a predictor of bleeding, and the importance of an adequate assessment of modifiable risk factors for bleeding.

Current literature suggest that increments in HAS-BLED score values are associated with progressively increased risk of bleeding, with little difference in hemorrhage rates between patients in use of OAC and controls. Because many risk factors for bleeding are also risk factors for stroke, the use of OACs is wrongly contraindicated for many patients with high risk of stroke (and consequently high risk of bleeding),3 thereby losing benefit of stroke prevention and maintaining a high risk of bleeding even without use of OAC.

Table 2 – HAS-BLED components and associated major bleeding incidence

Variable n (%) Bleeding, n (%) p

Hypertension, uncontrolledYes 22 (8.4) 3 (13.6)

.119*No 241 (91.6) 12 (5.0)

Abnormal renal functionYes 7 (2.7) 2 (28.6)

.054*No 256 (97.3) 13 (5.1)

Abnormal liver functionYes 2 (0.8) 1 (50.0)

.111*No 261 (99.2) 14 (5.4)

StrokeYes 96 (36.5) 5 (5.2)

1.0†

No 167 (63.5) 10 (6.0)

Bleeding historyYes 24 (9.1) 0 (0)

.374*No 239 (90.9) 15 (6.3)

Predisposition (anemia)Yes 67 (25.5) 7 (10.4) .067*

No 196 (74.5) 8 (4.1)

Labile INR (TTR < 60%)Yes 124 (47.1) 10 (8.1) .196†

No 139 (52.9) 5 (3.6)

Elderly (> 65 years)Yes 190 (72.2) 12 (6.3)

.767*No 73 (27.8) 3 (4.1)

Drugs (antiplatelets)‡Yes 64 (24.3) 9 (14.1)

.003*No 199 (75.7) 6 (3.0)

AlcoholYes 21 (8.0) 2 (9.5)

.341*No 242 (92.0) 13 (5.4)

INR: international normalized ratio; TTR: time in therapeutic range; *Fisher exact test; †Chi-square test; ‡There were no patients using nonsteroidal anti-inflammatory drug (NSAIDs). Data presented as number (%).

521

100

97

94

91

88

85Log rank p = 0.017

HAS-BLED < 3

HAS-BLED ≥ 3

HAS-BLED ≥ 3

Majo

r bled

ing-

free s

urviv

al (%

)

Patients at risk Follow-up (days)HAS-BLED < 3 159

10415596

15290

14986

14580

14174

13564

0 60 120 180 240 300 360

Figure 1 – Major bleeding-free survival according to HAS-BLED.

Variable OR 95% CI p

Hypertension, uncontrolled

Abnormal renal function

Abnormal liver function

Stroke

Bleeding history

Anemia

Labile INR

Elderly (> 65 years)

Drugs

Alcohol abuse

3.01

7.48

17.6

0.86

- - -

2.74

2.35

1.57

5.26

1.85

0.78 - 11.6

1.32 - 42.7

1.05 - 297

0.29 - 2.60

0.95 - 7.87

0.78 - 7.08

0.43 - 5.74

1.79 - 15.4

0.39 - 8.83

.109

.023

.046

.793

.061

.129

.493

.002

.438

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

Figure 2 – OR: odds ratio; CI: confidence interval; INR: international normalized ratio. HAS-BLED components and associated major bleeding risk in univariate analysis.

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The rate of major bleeding found in our study

(6.3/100 patients-year) was higher than previously

reported (1.4-2.4/100 patients-year).22 This may be

explained by the median TTR found in this cohort

(62.5%), which is in the lower limit of 60-65% of

currently accepted rate.23 Connolly et al.23 suggest

that this is the minimal threshold in which there

is significant benefit of using OAC as compared

with double antiplatelet therapy, with lower TTR

being associated with both stroke and hemorrhage rates that are comparable to those observed in AF patients treated with clopidogrel plus acetylsalicylic acid (ASA).

Another possible explanation for the high bleeding rate among our patients was the proportion of patients under concomitant use of antiplatelet drugs (24.3%). The majority of them had no clear indication to maintain antiplatelet use once OAC therapy has been initiated.

522

Variable OR 95% CI p

Hypertension, uncontrolled

Abnormal renal function

Abnormal liver function

Anemia

Labile INR

Drugs

1.91

4.72

18.3

1.28

2.09

5.13

0.41 - 8.82

0.60 - 36.9

0.76 - 444

0.35 - 4.73

0.65 - 6.79

1.55 - 17.0

.406

.139

.074

.707

.218

.007

0 1 2 3 4 5 6 7 8 9 10

Figure 3 – OR: odds ratio; CI: confidence interval; INR: international normalized ratio. HAS-BLED components and major bleeding risk associated in multivariate analysis.

CADStroke

PAD

Primary CVD prevention13 (20.3%)

8(12.5%)

29(45.3%)

4(6.3%)

2(3.1%)

3(4.7%)

5(7.8%)

n = 64

Figure 4 – Venn diagram of indication of concomitant use of drugs. CAD: coronary artery disease; PAD: peripheral artery disease; CVD: cardiovascular disease.

Beltrame et al.



Original Article

As shown in Figure 4, the reasons for concurrent use of

antiplatelets were coronary artery disease (CAD, 56.2%),

stroke (25.0%), primary cardiovascular disease (CVD)

prevention and peripheral artery disease (PAD, 14.1%).

Current guidelines recommend discontinuation of

antiplatelet therapy in most cases when OAC is indicated;

exceptions include acute coronary syndrome (ACS) and

stent implantation, though even in these cases antiplatelet

drugs should be discontinued as soon as possible.24 This is

based on low quality evidence that suggest that patients

with stable CAD have increased bleeding risk with OAC

plus antiplatelet agent without further decrease in major

adverse cardiovascular events in comparison with OAC

alone.15,25 According to the 2016 US Preventive Services

Task Force review,26 ASA for the primary prevention

of cardiovascular events has been shown to be safe

and effective in the very strict group of adults ranging

50-59 years old who have an estimated cardiovascular

risk > 10% and a low bleeding risk according to American

Heart Association (AHA) score. Regarding PAD and

stroke,27-29 current evidence indicates no benefit of adding

ASA to VKA.

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Table 3 – Antiplatelet agents used during follow-up and their indications

Drug(s) n = 64 Indication

ASA

13 (20.3) Cardiovascular disease primary prevention

12 (18.8) CAD with previous ACS > 1 year

11 (17.2) CAD without previous ACS

8 (12.5) Stroke

4 (6.3) CAD with previous ACS > 1 year + Stroke

3 (4.7) PAD

3 (4.7) Stroke + PAD

1 (1.6) CAD with previous ACS > 1 year + PAD

1 (1.6) CAD without previous ACS + Stroke

1 (1.6) CAD without previous ACS + PAD

ASA + Clopidogrel 4 (6.3) CAD with previous ACS < 1 year

Cilostazol 1 (1.6) PAD

Ticlopidine 1 (1.6) CAD without previous ACS

Clopidogrel 1 (1.6) CAD with previous ACS < 1 year

ASA: acetylsalicylic acid, CAD: coronary artery disease, ACS: acute coronary syndrome, PAD: peripheral artery disease. Data presented as number (%).

There are some limitations in our study that deserve to be mentioned. First, retrospective design may have influenced the quality and consistency of the data collected. Besides, review of the medical records could only identify events (cardiovascular and bleeding) that occurred at our hospital or that have been spontaneously reported by the patients during clinical care. This may underestimate adverse events occurrence. Second, the relative small sample size associated with the short follow-up period may have underestimated the occurrence of adverse events, especially events related to AF, which have a longer latency period. Yet, we believe that this may be a conservative bias, given the elevated event rates observed in this limited sample. Third, the higher rates of bleeding found in this study could have overestimated the prediction power of the score. Finally, the fact that the study was conducted at a single center can limit external validity of our findings.

Conclusion

HAS-BLED may be a useful and applicable tool to assess bleeding risk in our population, particularly to aid

the identification of potentially modifiable factors such as concomitant use of antiplatelet agents. We highlight that HAS-BLED should not be used as the single instrument to either initiate OAC or exclude patients from OAC therapy. Hospitals and clinical care facilities should implement protocols for regular assessment of patients using OAC, and HAS-BLED may have a major role helping to reduce complications associated with this therapy. Further research is needed to assess the impact of score-based protocols for modifying bleeding risk factors and rates in anticoagulation outpatient clinics.


Conception and design of the research: Pivatto Júnior F. Acquisition of data: Beltrame RCF, Giasson FTB, Gomes BS, Pivatto Júnior F. Analysis and interpretation of the data: Beltrame RCF, Giasson FTB, Amon LC, Scheffel RS, Pivatto Júnior F. Statistical analysis: Pivatto Júnior F. Writing of the manuscript: Beltrame RCF, Scheffel RS. Critical revision of the manuscript for intellectual content: Beltrame RCF, Giasson FTB, Silva ALFA, Gomes BS, Amon LC, Blaya MB, Scheffel RS, Pivatto Júnior F. Supervision / as the major investigador: Pivatto Júnior F.

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1. January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, et al; ACC/AHA Task Force Members. 2014 AHA/ACC/HRS Guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology / American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):e199-267. doi: 10.1161/CIR.0000000000000041. Erratum in: Circulation. 2014;130(23):e272-4.

2. Odutayo A, Wong CX, Hsiao AJ, Hopewell S, Altman DG, Emdin CA. Atrial fibrillation and risks of cardiovascular disease, renal disease, and death: systematic review and meta-analysis. BMJ. 2016;354:i4482. doi: 10.1136/bmj.i4482.

3. Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet. 2016;388(10046):806-17. doi: 10.1016/S0140-6736(16)31257-0.

4. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-67. PMID: 17577005.

5. Bengtson LG, Lutsey PL, Chen LY, MacLehose RF, Alonso A. Comparative effectiveness of dabigatran and rivaroxaban versus warfarin for the treatment of non-valvular atrial fibrillation. J Cardiol. 2017;69(6):868-876. doi: 10.1016/j.jjcc.2016.08.010.

6. Gomes T, Mamdani MM, Holbrook AM, Paterson JM, Hellings C, Juurlink DN. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013;185(2):E121-7. doi: 10.1503/cmaj.121218.

7. Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011;58(4):395-401. doi: 10.1016/j.jacc.2011.03.031.

8. Shireman TI, Mahnken JD, Howard PA, Kresowik TF, Hou Q, Ellerbeck EF. Development of a contemporary bleeding risk model for elderly warfarin recipients. Chest. 2006;130(5):1390-6. doi: 10.1378/chest.130.5.1390.

9. Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006;151(3):713-9. doi: 10.1016/j.ahj.2005.04.017.

10. Kuijer PM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med. 1999(5);159:457-60. PMID: 10074953.

11. Beyth RJ, Quinn LM, Landefeld CS. Prospective evaluation of an index for predicting the risk of major bleeding in outpatients treated with warfarin. Am J Med. 1998;105(2):91-9. PMID: 9727814.

12. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-100. doi: 10.1378/chest.10-0134.

13. Lane DA, Lip GY. Use of the CHA(2)DS(2)-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation. 2012;126(7):860-5. doi: 10.1161/CIRCULATIONAHA.111.060061.

14. Lip GY. Stroke and bleeding risk assessment in atrial fibrillation: when, how, and why? Eur Heart J. 2013;34(14):1041-9. doi: 10.1093/eurheartj/ehs435.

15. Olesen JB, Lip GY, Lindhardsen J, Lane DA, Ahlehoff O, Hansen ML, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial fibrillation: a net clinical benefit analysis using a 'real world' nationwide cohort study. Thromb Haemost. 2011;106(4):739-49. doi: 10.1160/TH11-05-0364.

16. Kim YK, Nieuwlaat R, Connolly SJ, Schulman S, Meijer K, Raju N, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost. 2010;8(1):101-6. doi: 10.1111/j.1538-7836.2009.03652.x

17. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Eur Heart J. 2012;33(21):2719-47. doi: 10.1093/eurheartj/ehs253. Erratum in: Eur Heart J. 2013;34(10):790. Eur Heart J. 2013;34(36):2850-1.

18. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-70. PMID: 11401607.

19. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72. doi: 10.1378/chest.09-1584.

20. Rosendaal FR, Cannegieter SC, van der Meer FJ, Briet E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost. 1993;69(3):236-9. PMID: 8470047.

21. World Health Organization. (WHO). Department of Nutrition for Health and Development. Iron deficiency anaemia: assessment, prevention and control: a guide for programme managers. Geneva; 2001.

22. Ogilvie IM, Welner SA, Cowell W, Lip GY. Ischaemic stroke and bleeding rates in ‘real-world’ atrial fibrillation patients. Thromb Haemost. 2011;106(1):34-44. doi: 10.1160/TH10-10-0674.

23. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al; ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118(20):2029-37. doi: 10.1161/CIRCULATIONAHA.107.750000.

24. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369-429. doi: 10.1093/eurheartj/ehq278. Erratum in: Eur Heart J. 2011;32(9):1172.

References

Beltrame et al.



Original Article



Sources of Funding


Study Association

This study is not associated with any thesis or

dissertation work.

525

25. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al.

Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy

and Prevention of Thrombosis, 9th ed: American College of Chest

Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2

Suppl):e531S-75S. doi: 10.1378/chest.11-2304.

26. Final Recommendation Statement: aspirin use to prevent cardiovascular

disease and colorectal cancer: preventive medication. U.S. Preventive

Services Task Force. [Access in 2016 Nov 10]. Available from: http://

www.uspreventiveservicestaskforce.org

27. Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, Budaj A, et al; Warfarin Antiplatelet Vascular Evaluation Trial Investigators. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007;357(3):217-27. doi: 10.1056/NEJMoa065959.

28. Fischer M. Does the combination of warfarin and aspirin have a place in secondary stroke prevention? No. Stroke. 2009;40(5):1944-5. doi: 10.1161/STROKEAHA.108.537670.

29. Furlan AJ. Does the combination of warfarin and aspirin have a place in secondary stroke prevention? Yes. Stroke. 2009;40(5):1942-3. doi: 10.1161/STROKEAHA.108.537662.

Beltrame et al.



Original Article

DOI: 10.5935/2359-4802.20170071


REVIEW ARTICLE

Mailing Address: Clarissa Antunes ThiersAvenida Embaixador Abelardo Bueno, n 3250, bl 2, apto. 603. Postal Code: 22775-040, Barra da Tijuca, Rio de Janeiro, RJ – Brazil.E-mail: [email protected]; [email protected]

Performance of Diagnostic Tests for Intermediate Probabilities of Coronary Heart Disease: A Decision Making AnalysisClarissa Antunes Thiers,1 João Luis Barbosa,1 Bernardo Rangel Tura,1,2 Edilson Fernandes Arruda,2,3 Basilio de Bragança Pereira2,3

Instituto Nacional de Cardiologia,1 Universidade Federal do Rio de Janeiro (UFRJ),2 Instituto Alberto Luiz Coimbra de Pós-Graduação e Pesquisa de Engenharia (COPPE),3 RJ – Brazil

Manuscript received on October 06, 2016; reviewed manuscript on May 11, 2017; accepted on July 07, 2017

Coronary Artery Disease; Probability; Clinical Decision-Making; Diagnosis; Meta-Analysis.

Keywords

Abstract

Patients with intermediate probability of coronary disease are a diagnostic challenge and it is precisely in this population where the degree of uncertainty is greater that the diagnostic tests have their greater applicability. However, according to the current definition, subjecting to tests a population with a disease probability between 10 and 90% can generate unnecessary tests and misleading results. Knowing the characteristics of each test, as well as risks and benefits of drug treatment for coronary disease and combining this information through diagnostic thresholds brings a new perspective to decision making. To review the origin of the currently recommended concepts of intermediate probability and to determine the thresholds for diagnosis and treatment of noninvasive tests and, based on them, propose a new concept of intermediate probability of coronary disease. Through the bibliographic review, meta-analyses were extracted in which data of sensitivity, specificity, positive and negative likelihood ratio, risks and benefits of the tests and treatment were provided. Using an algorithm developed by Pauker et al. it was possible to obtain the diagnostic and treatment thresholds adjusted for each tests in question. The concept of intermediate probability of coronary disease is quite broad, ranging, according to the authors, between 10 and 90%, 1 and 92%, 15 and 85%, with different rationale. Considering the discriminatory power of each test, risks and

treatment benefits, the diagnostic and treatment thresholds were defined for exercise testing (22-58%), eco-stress (10-72%), myocardial scintigraphy (12-80%), nuclear magnetic resonance (16-80%) and coronary angiotomography (6.7-81%). The decision to submit to diagnostic tests should be individualized, taking into account the diagnostic and treatment thresholds of each method in question.

Introduction

Estimation of the probability that a given event occurs is a constant challenge to decision making in virtually all areas of knowledge. Particularly in the medical field, the first step in the search for a specific diagnosis arises from a clinical suspicion, based on anamnesis and physical examination findings and on the prevalence of a given pathology in a population of interest. However, the determination of the patient's probability of presenting the pathology in question may still express a degree of uncertainty considered too large for decision-making - by both physicians and patients. Thus, often the investigation continues to increase the information pertinent to the case.

This knowledge assists in deciding on the best course of action: only observing a patient with a suspected pathology, submitting him to diagnostic tests or treating him without the need for further investigation. Few tests are able to completely determine whether a patient is healthy or sick, since we do not have diagnostic tests with sensitivity and specificity of 100%, but it is precisely in patients with intermediate probability that their greater applicability is found. Adequate knowledge of the characteristics

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and limitations of the test in question will allow us to determine the diagnostic and treatment thresholds that should guide the clinical decision. Bayesian analysis consists in adjusting a given initial probability given new information - whether it is a finding at the clinical examination or the result of a diagnostic test. It is possible to obtain the post-test probability by multiplying the likelihood ratio of a test by the a priori probability. In view of these values, it will be possible to evaluate the real usefulness in testing a patient and how much a particular result will be able to promote changes in the pre-test probability of disease obtained during the clinical evaluation.1

It is when the degree of uncertainty is larger that usually a given test is capable of promoting greater changes between the pre- and post-test probabilities. However, the definition of these limits is often arbitrary, reproducing in diagnostic studies ranges as wide as 10 and 90%.

Two thresholds are extremely important in the decision to observe, test, or treat without testing. When the pre-test probability of a particular disease is low, even if a particular test is accurate enough, little change will be observed in the post-test probability of the patient presenting the disease. This threshold, below which no diagnostic investigation or even specific treatment is justified is referred to as the diagnostic threshold. Certain patients are so likely to present a pathology that even a negative result from a diagnostic test will hardly reduce the patient's chance of developing disease (post-test probability). The value above which further investigation is dispensable and the patient should be conducted to the treatment in question is considered the therapeutic threshold. The establishment of such thresholds can be intuitively performed by the attending physician, considering the cost-benefit relationship of the treatment, using life expectancy data to calculate this relationship or even assigning value to the patient's preferences in relation to the possibilities of outcomes with the disease and its treatment.1

Determining the limits of the intermediate probability and its rationality is the focus of the present article, since the adequacy of these values is questionable in a scenario where the diagnostic tests present different performances.

Objectives

This review article looks for the origins of the concepts commonly used as an intermediate probability definition

and questions the adequacy of the values most frequently presented in relation to the variations in the diagnostic performance of the different tests used in clinical practice, as well as to determine the diagnostic and treatment thresholds for each test.

Methods

Through PUBMED/MEDLINE, a bibliographic research was conducted focusing on articles that considered the diagnostic performance and risks of the most frequently used tests for the diagnosis of coronary artery disease - ergometric test, myocardial perfusion scintigraphy, echo-stress, nuclear magnetic resonance and Angiotomography of Coronary Artery Disease; Risks and benefits of the treatment most frequently advocated in coronary artery disease - ASA, statin and beta-blocker; as well as references of intermediate probability of coronary disease and medical decision - more specifically the Bayesian analysis.

The search contained the following terms mesh: diagnostic test/ accuracy/ sensitivity/ specificity/ intermediate probability/ coronary disease/ exercise test/ myocardial perfusion imaging / magnetic resonance imaging/ coronary angiography/ medical decision/ Bayesian analysis/ pre-test probability/ post-test probability/adverse effects/ improvement.


For the calculation of the diagnostic and therapeutic thresholds, the formulas described below were used, based on the following data: sensitivity, specificity, risks and benefits of the test, risks and benefits of the treatment.2

Test Threshold or Diagnostic Threshold (Tt):

Tt = (Ppos/nd) x (Rrx) + Rt

(Ppos/nd) x (Rrx) + (Ppos/d) x (Brx)

Therapeutic Threshold (Ttx):

Ttrx = (Pneg/nd) x (Rrx) - Rt

(Pneg/nd) x (Rrx) + (Pneg/d) x (Brx)

Tt = Diagnostic threshold

Ttrx = Therapeutic threshold

Ppos/nd = Probability of a positive test, when the patient is healthy (False Positive or 1-Specificity)

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Table 1 – Characteristics of the diagnostic tests: sensitivity, specificity, positive and negative likelihood ratio

Diagnostic Tests Sensitivity (%) Specificity (%) LR+ LR-

Ergometric Testing4 67 71 2.31 0.46

Myocardial Scintigraphy7 87 81 4.57 0.16

Eco-stress8 79 87 6.07 0.24

NMR9 89 76 3.7 0.14

CCTA9 87 91 9.6 0.14

NMR: nuclear magnetic resonance; CCTA: Coronary computed tomography angiography; LR+: Positive likelihood ratio; LR: Negative likelihood ratio.

Ppos/d = Probability of a positive test, given that the patient is sick (True Positive or Sensitivity)

Pneg/nd = Probability of a negative test, given that the patient is not ill (True Negative or Specificity)

Pneg/d = Probability of a negative test, when the patient is sick (False Negative or 1-Sensitivity)

Rrx = Treatment risks

Rt = Test risks

Brx = Treatment benefit

Results

Among the studies that considered the delimitation of the intermediate probability, it is of particular importance the one realized by Diamond et al. that, in 1980, studied 43 patients submitted to Coronariography, later stratified with noninvasive tests. Of these, 8 out of 12 patients with normal coronary angiography had a posttest probability of less than 10%; While 26 of 31 patients with obstructive coronary artery disease had a posttest probability greater than 90%. This was the first work in which the limits of 10 and 90% were established for intermediate probability.3

In a study conducted by Goldman et al.4 in 1982, a pre-test probability of between 1 and 92% was considered intermediate, considering the probability on which the ergometric test was able to produce a post-test value above or below 50%. Also in this same article were calculated thresholds of pre-test probability on which non-invasive stratification would be able to generate a shift to a probability that would allow decision making.4

The Brazilian Guidelines for Stable Coronary Disease considers as intermediate probability values between 10% and 90%, and Montalescot et al.6 at the European Consensus of Stable Angina, admit as intermediate probability values between 15% and 85%, considering

that the majority of diagnostic tests show sensitivity and specificity around 85%.5-6 According to these data, when applied to a healthy population, 15 out of 100 tests will give false results and, therefore, it will be more appropriate not to submit patients with low disease prevalence (less than 15%) to the methods in question. In patients with high disease probability the test will also not bring benefits.

The characteristics of the following diagnostic tests were then analyzed: ergometric (or stress test), dipyridamole myocardial scintigraphy, myocardial scintigraphy with ET, dobutamine echo-stress, magnetic nuclear resonance and coronary angiotomography, where sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic and therapeutic threshold were considered and expressed in Table 1.7-9 A particularly noteworthy fact is the possibility of establishing thresholds for diagnosis and treatment for coronary angiography – until now considered a golben standard with which all the others are compared when comparing their performance with the data provided by the reserve flow fraction (RFF).10

To determine the risks related to the tests analysed only events with significant repercussion were considered as those capable of interrupting the test or generating clinical or hemodynamic repercussions - described in table 2,11-15 such as claustrophobia, hypotension, arrhythmias, infarction, stroke, cardiac arrest and death.

Considering ASA, statin - more specifically simvastatin and beta-blocker, the drugs most frequently used in the treatment of coronary artery disease, the risks and the benefit of the joint use of the 3 drugs were obtained for 1 year, considering the therapeutic adherence and the probability of each user benefitting from the use of the drugs in question, values are expressed in table 3.16,17

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Table 2 – Risks and adverse reactions in diagnostic tests

Diagnostic test Adverse reactions Incidence (%)

Ergometric Testing4 arrhythmia, AMI, death 0.11

Myocardial Scintigraphy11 Hypotension, arrhythmia, AMI, death 50

Dobutamine Eco-stress13 Hypotension, hypertension, arrhythmia, AMI, death 5.6

Magnetic Nuclear Resonance12 Claustrophobia 15

CCTA14 Serious reactions, Hypotension by Isordil 4.1

Coronary Cineangiography15 Dissection, Vessel occlusion, AMI, Bleeding, Stroke 11.5

Table 3 – Risks and benefits associated with treatment

Medicines Benefit (in 1 year) Risks (in 1 year)

ASA 2.47% 0.4 % (Bleeding)

Statin 6.85% 4.84% (Rhabdomyolysis, Elevation of transaminases)

Beta blocker 4.61% 4.2% (Atrioventricular block, syncope)

Set 13.34% 8.91%

Based on the information about the performance characteristics of the test, its associated risks, as well as the benefit of the joint treatment and the inherent risks, it was possible to establish the diagnostic and therapeutic thresholds of the five methods in question - ET, MPS Study, Eco-stress with dobutamine, MRI and coronary angiotomography, expressed in Table 4.

Discussion

The diagnostic process is configured in a complex procedure of association of ideas, with inclusion of positive and negative data. The estimation of the probability of coronary artery disease begins in a subjective way already in anamnesis and clinical examination, where today we search for information about the main known risk factors for coronary disease - hypertension, DM, dyslipidemia, smoking and family history - to know its characteristics and limitations is crucial. However, the physician often faces a level of certainty considered insufficient for decision making, especially when the patient has an "intermediate probability" of disease.

It is precisely in this larger range where researchers focus their efforts on a better risk stratification - using,

among other strategies, submission to diagnostic tests. Effective tests do not guarantee, by themselves, the best clinical outcome, but help find the best course of action, with patient benefits and savings for health services when used properly.

In 1980, Pauker et al.2 already advised how to quantitatively establish thresholds for diagnosis and treatment based on test performance data - sensitivity, specificity, risks and benefits, and risks and benefits of the treatment to be instituted if certain pathologies are confirmed.2

Thus, taking the ergometric test and its diagnostic and therapeutic thresholds of 22 and 58%, respectively, the adequacy of the "static" values from 10 to 90% can be questioned, since some patients within this range, should be submitted to the test in question. Thus, we would observe that patients between 10 and 22% pre-test probability of CAD would be unnecessarily submitted to the ergometric test, burdening the health system and without benefits to the patient. Still within this same perspective, patients with a probability of 58-90% of pre-test probability would also be submitted to the test, when the analysis of these thresholds suggests that rationality exists in treating these patients without testing them.

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This phenomenon can also be observed in relation to the other tests, enough to observe the discrepancy between the interval between the diagnostic and therapeutic thresholds of each test and the fixed values adopted in the literature, be them between 10-90% or 20-70%.

In all the studies analysed to obtain the data regarding the performance of the diagnostic tests, the methods were compared with the coronary angiography, considered gold standard. However, with the advent of the flow reserve fraction, the coronary angiography was questioned as the best parameter against which all the others could be compared, since the functional information showed a better correlation with adverse events, reflecting a pathological behavior that extrapolates the phenomenon of luminal obstruction when considering also the component of endothelial dysfunction in its evaluation.

Specifically analysing the coronary angiography when compared to the RFF in a study performed by Sant'Anna et al.,10 the results showed a 57% and 96% accuracy for moderate and severe lesions, respectively, with a sensitivity of 85.7% and a specificity of 36.7%. Extrapolating these data to the calculation of the thresholds, we highlight the narrow range of probability where its use would be justified, between 34% (diagnostic threshold) and 61% of pre-test probability (therapeutic threshold). This fact is of particular importance considering that the Brazilian Consensus of Stable Angina classifies as class II A, level of evidence C the stratification of high-risk patients with cineangiocoronariography. However, data in the Brazilian literature point to a rate of complications that cannot be neglected, capable of reaching values as expressive as 11.5% during catheterization followed by angioplasty.15

The submission to an invasive test in patients whose high probability of CAD would justify the start of treatment may add an unnecessary risk to the

Table 4 – Diagnostic and therapeutic thresholds of the different diagnostic methods

Diagnostic Tests Diagnostic Threshold (%) Therapeutic Threshold (%)

Ergometric Testing 22 58

Myocardial Scintigraphy 12 80

Dobutamine Eco-stress 10 72

Magnetic Nuclear Resonance 16 80

CCTA 6.7 81

propaedeutic of these patients. Emblematic works, such as that carried out by Patel et al.17 in 2010, point to a rate of 39.2% of negative tests for obstructive coronary disease (lesions lower than 20% of luminal obstruction) in 398,978 patients referred to coronary angiography in 663 hospitals, reinforcing the need for a better diagnostic stratification prior to the indication of invasive examination.18 Hence, it would be more appropriate to relocate the indication of the procedure to those in whom an intervention is planned, may be it angioplasty or surgery.

Data analysis shows that the risk of the test is the main determinant of the diagnostic threshold, while the risk of the treatment influences the therapeutic threshold. The greater the risk of the test, the greater the pre-test probability required to justify its use, with a higher diagnostic threshold and lower therapeutic threshold. Likewise, the greater the risk of the treatment, the greater the degree of certainty to start the treatment should be, raising the therapeutic threshold values.

Limitations

In the present study only the diagnostic role of the main tests was contemplated - which diverges from the current clinical practice, where the diagnosis of coronary artery disease can be obtained by clinical criteria and the tests play a prognostic role greater than the diagnostic one, and the catheterization is reserved to those patients in whom an intervention is planned. However, the methodology applied reinforces that clinical treatment can and should be offered and restricts the circumstances in which the tests are actually needed to obtain the diagnosis and institute treatment. Although changes in test performance are observed according to the source consulted, there is little impact on the observed outcome.

531

1. Fagan TJ. Letter: Nomogram for Bayes theorem. N Engl J Med. 1975;293(5):257. Doi 10.1056/NEJMi97507312930513.

2. Pauker SG, Kassirer JP. The threshold approach to clinical decision making. N Engl J Med. 1980;302(20):1109-17.doi:10.1056/NEJMi98005153022003.

3. Diamond GA, Forrester JS, Hirsch M, Staniloff HM, Vas R, Berman DS, et al. Application of conditional probability analysis to the clinical diagnosis of coronary artery disease. J Clin Invest. 1980;65(5):1210-21.PMID:6767741.

4. Goldman L, Cook EF, Mitchell N, Flatley M, Sherman H, Rosati R, et al. Incremental value of the exercise test for diagnosing the presence or absence of coronary artery disease. Circulation. 1982;66(5):945-53.PMID:7127706.

5. Cesar LA, Ferreira JF, Armaganijan D, Gowdak LH, Mansur AP, Bodanese LC, et al. Guideline for stable coronary artery disease. Arq Bras Cardiol. 2014;103(2 Suppl 2):1-56.PMID:254100816.

6. Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34(38):2949-3003.doi:10.1093/eurheartj/eht296.

7. Jaarsma C, Leiner T, Bekkers SC, Crijns HJ, Wildberger JE, Nagel E, et al. Diagnostic performance of noninvasive myocardial perfusion imaging using single-photon emission computed tomography, cardiac magnetic resonance, and positron emission tomography imaging for the detection of obstructive coronary artery disease: a meta-analysis. J Am Coll Cardiol. 2012;59(19):1719-28. doi:10.1016/j.jaac.2011.12.040.

8. Heijenbrok-Kal MH, Fleischmann KE, Hunink MG. Stress echocardiography, stress single-photon-emission computed tomography and electron beam computed tomography for the assessment of coronary artery disease: a meta-analysis of diagnostic performance. Am Heart J. 2007;154(3):415-23. PMID:17719283.

9. Budoff MJ, Achenbach S, Duerinckx A. Clinical utility of computed tomography and magnetic resonance techniques for noninvasive coronary angiography. J Am Coll Cardiol. 2003;42(11):1867-78. PMID:14662244.

10. Sant'Anna FM, da Silva ER, Batista LA, Brito MB, Ventura FM, Ferraz HA, et al. What is the angiography error when defining myocardial ischemia during percutaneous coronary interventions? Arq Bras Cardiol. 2008;91(3):162-7, 79-84.

11. Ranhosky A, Kempthorne-Rawson J. The safety of intravenous dipyridamole thallium myocardial perfusion imaging. Intravenous Dipyridamole Thallium Imaging Study Group. Circulation. 1990;81(4):1205-9. PMID:2107985.

12. Enders J, Zimmermann E, Rief M, Martus P, Klingebiel R, Asbach P, et al. Reduction of claustrophobia during magnetic resonance imaging: methods and design of the "CLAUSTRO" randomized controlled trial. BMC medical imaging. 2011;11:4. doi:10.1186/1471-2342-11-4.

13. Geleijnse ML, Krenning BJ, Nemes A, van Dalen BM, Soliman OI, Ten Cate FJ, et al. Incidence, pathophysiology, and treatment of complications during dobutamine-atropine stress echocardiography. Circulation. 2010;121(15):1756-67. doi:10,116/CIRCULATIONAHA.109.859264.

14. Heidenreich PA, McDonald KM, Hastie T, Fadel B, Hagan V, Lee BK, et al. Meta-analysis of trials comparing beta-blockers, calcium antagonists, and nitrates for stable angina. JAMA. 1999;281(20):1927-36. PMID:10349897

15. Mallet ALR, Oliveira GMMd, Klein CH, carvalho MRMd, Silva NASe. Letalidade e complicações de angioplastias em hospitais públicos no Rio de Janeiro, RJ. Rev Saúde Pública [online]. 2009;43(6):917-27.PMID:20027504.

16. Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Annals of internal medicine. 2002;136(2):161-72. PMID:11790072.

17. Deanfield JE, Sellier P, Thaulow E, Bultas J, Yunis C, Shi H, et al. Potent anti-ischaemic effects of statins in chronic stable angina: incremental benefit beyond lipid lowering? Eur Heart J. 2010;31(21):2650-9. doi:10.1093/eurheartj/eh9133.

18. Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, et al. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010;362(10):886-95. PMID:20220183.

References

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Review Article

Conclusion

Considering the performance of the majority of the diagnostic tests, with sensitivity and specificity around 80%, it is understood that values between 30 and 70% contemplate the great majority of the intervals between thresholds of the different diagnostic methods. However, there is still a significant portion that is inadequately evaluated, where the risk of being submitted to a diagnostic test is higher than the risk of non-treatment and another where the risk of treatment is lower than the risks related to the test. Thus, it is necessary that the intermediate probability be stipulated for each test, including updating it in the light of the recent advances that make possible a greater accuracy of the method in question, minimizing the uncertainties inherent in the decision-making process.


Conception and design of the research: Thiers CA, Barbosa JL, Tura BR, Arruda EF, Pereira BB. Acquisition

of data: Thiers CA. Analysis and interpretation of the data: Thiers CA, Tura BR, Arruda EF. Statistical analysis: Tura BR, Arruda EF, Pereira BB. Writing of the manuscript: Thiers CA. Critical revision of the manuscript for intellectual content: Thiers CA, Barbosa JL, Tura BR, Arruda EF.



Sources of Funding


Study Association

This article is part of the thesis of Doctoral submitted by Clarissa Antunes Thiers, Universidade Federal do Rio de Janeiro (UFRJ).

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DOI: 10.5935/2359-4802.20170070


REVIEW ARTICLE

Mailing Address: Euclides Timóteo da RochaRua Antenor Duarte Vilela, 1331. Postal Code: 14784-700 – Bairro Dr. Paulo Prata, Barretos, São Paulo, SP – Brazil.E-mail: [email protected]

The use of Cardiac 123I-mIBG Scintigraphy in Clinical Practice: The Necessity to Standardize!Euclides Timóteo da Rocha,1 Wilson Eduardo Furlan Matos Alves,1 Derk O. Verschure2 e Hein J Verberne2

Departamento de Medicina Nuclear, Hospital do Câncer de Barretos,1 Barretos, São Paulo, Brasil; Departamento de Radiologia e Medicina Nuclear, Academic Medical Center,2 Amsterdã - the Netherlands

Manuscript received April 20, 2017, revised manuscript April 23, 2017, accepted June 05, 2017

Heart Failure; Myocardium/diagnostic imaging; Radionuclide Imaging; 3-Iodobenzylguanidine; Sympathetic Nervous System.

Keywords

Abstract

Cardiac adrenergic imaging has a great potential in a wide variety of clinical applications. Cardiac 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy has a key role to assess chronic heart failure (CHF) by risk stratifying patients for cardiac events. The mIBG is a norepinephrine (NE) analogue that can evaluate cardiac sympathetic activity by assessing the down expression of β-adrenergic receptor (β-AR) in CHF. Furthermore, ¹²³I-mIBG scintigraphy in combination with other parameters of left ventricular function can be used to identify the best responder for implantable cardiac devices, as well as to assess oncological cardiotoxicity. Despite its usefulness, 123I-mIBG scintigraphy is not widely performed because of the lack of standardization between different institutions. Thus, standardization and validation may contribute to its acceptance in clinical setting.

Introduction

The cardiac sympathetic system is an important neurohormonal compensation mechanism in the pathogenesis of chronic heart failure (CHF). Patients with CHF have increased cardiac sympathetic activity with increased exocytosis of norepinephrine (NE) from the presynaptic vesicles and impaired NE re-uptake via the norepinephrine transporter (NET) in the sympathetic terminal nerve axons. This results in increased NE levels in the synaptic cleft. Initially, β-adrenergic receptor (AR) stimulation by increased synaptic NE levels

helps to compensate for impaired myocardial function. However, long-term NE excess has detrimental effects on myocardial structure and gives rise to a down regulation and availability of postsynaptic β-AR. This leads to left ventricular remodeling and is associated with increased mortality and morbidity in CHF.

Cardiac sympathetic activity can non-invasively be visualized by nuclear medicine techniques. The most clinically used tracer is the radiolabeled NE analogue 123I-meta-iodobenzylguanidine (123I-mIBG). From the planar 123I-mIBG images, semi-quantitative measurements of myocardial 123I-mIBG uptake can be derived: early heart-to-mediastinum (H/M) ratio (HMR), derived 15 min post injection (p.i.) of 123I-mIBG; late HMR, derived 4 h p.i. of 123I-mIBG; and 123I-mIBG washout, calculated as the difference between early and late HMR and expressed as a percentage of the early HMR. While HMR reflects the 123I-mIBG uptake in nerve terminals, washout rate indicates their integrity - neuronal retention.1

Although arrhythmia, lethal cardiac events and prognosis are multifactorial and have several determinants, cardiac 123I-mIBG scintigraphy alone and more likely in combination with other determinants may be able to better select CHF patients at increased risk for events. Indeed, a large number of studies on the prognostic value of 123I-mIBG-assessed cardiac sympathetic activity in CHF have been published. In addition, cardiac 123I-mIBG scintigraphy can be used in other pathophysiological conditions, for example to assess chemotherapy-induced cardiotoxicity. However, the lack of standardization between different institutions have hampered wide scale clinical implementation.

The purpose of this paper is to discuss how to further standardization of cardiac 123I-mIBG scintigraphy and to discuss the use of cardiac 123I-mIBG in different patient populations.

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Physiology of cardiac sympathetic innervation and 123I-mIBG uptake

The cardiac sympathetic nervous system is a complex agonist-receptor system with NE as neurotransmitter. Both β- and α-ARs belong to the G-protein family and have a transmembrane location. There are four types of β-AR that form the postsynaptic portion of sympathetic neurotransmission, the most abundant β-AR being β1, β2 and β3. β1- and β2-ARs determine positive inotropic response. Two types of α-ARs have been identified (i.e. α1 and α2), each with three known subtypes.2,3 The postsynaptic α1-ARs are important to modulate cardiac inotropy and arterial vasoconstriction. The α2A- and α2C-ARs subtypes have a postsynaptic localization and regulate myocardial catecholamine release. The presynaptic α2B-ARs seem to be associated with the pathogenesis of salt-induced hypertension. In addition, there are muscarine, angiotensin, adenosine, and cardiac opioid receptors.

Norepinephrine is synthesized from tyrosine and stored in high concentrations in vesicles in the presynaptic sympathetic nerve terminals. Upon stimulation, these vesicles release their content into the synaptic cleft. Most of the released NE is actively taken back up into the presynaptic sympathetic nerve terminals with a mechanism known as uptake-1 (i.e. the NET). This is a highly specific process, but with limited capacity. In addition, there is a less specific, but highly capable, postsynaptic re-uptake mechanism known as uptake-2.

Meta-iodobenzylguanidine is an analog of NE and can be radiolabeled with iodine. Radiolabeled mIBG follows the same re-uptake mechanism as NE (i.e. the NET). Once taken up in the presynaptic sympathetic nerve terminals, mIBG is not metabolized. 123I-mIBG is not only used in the cardiac sympathetic nervous activity assessment. Of note, the first clinical application of radio-labeled mIBG (i.e. 131I-mIBG) was the visualization of the adrenal medulla and different neural crest-derived tumors, such as pheochromocytomas and neuroblastomas. Radiolabeling with 131I also enables radionuclide therapy for these types of neoplasms. The striking myocardial uptake, however, made Wieland et al.4 suggest the potential use of radio-labeled mIBG for myocardial imaging.

Patient preparation for 123I-mIBG cardiac scintigraphy

In our department, patients referred for ¹²³I-mIBG myocardial scintigraphy undergo a medical interview to obtain clinical information relevant to the procedure

and to guide image interpretation, and to provide the patient with relevant explanation about the test. Special care should be taken regarding pregnant or breastfeeding women. Especially in these patients, it is necessary to discuss whether the procedure will bring real benefit, if the procedure could be rescheduled for later or if there are alternatives to evaluate the clinical question. Free iodine, either 123I or 131I, is excreted in breast milk. Therefore, it is recommended to interrupt breastfeeding for at least 36 hours when 123I-mIBG is used, and to discontinue breastfeeding completely when 131I-mIBG is used.5,6

Because of “free” iodine, the thyroid should be blocked with perchlorate, potassium iodide or Lugol's solution, at least 30 minutes before the administration of the 123I/131I-mIBG. Dose adjustment can be made taking into consideration the weight of the patient.

123I has a half-life of 13.22 hours, it decays by electron capture to 123Tellurium with gamma-ray emission of primarily 159 keV, which enables its use in obtaining images with a gamma camera. In addition, 123I decays with a small fraction of high energy photons. 123I is produced in a cyclotron by xenon irradiation.

Some food and drugs need to be discontinued before the administration of mIBG due to known or suspected interference with mIBG uptake. It is also recommended to discontinue the use of drugs, such as tricyclic antidepressants, antipsychotics, opioids, and sympathomimetics, at least for 5 biological half-lives prior to mIBG administration.7 In addition, beta-blockers and angiotensin-converting-enzyme (ACE) inhibitors are also known to influence the uptake of mIBG. Sometimes the discontinuation of these medications is considered unethical, such as in psychotic and heart failure (HF) patients. Therefore, the recommendation to discontinue these medications is not always possible and the decision to discontinue the medication should always be made after carefully considerations and on an individual patient basis.

Protocol for 123I-mIBG administration and planar image acquisition

We recommend administering the radiopharmaceutical via an intravenous catheter (e.g. in the antecubital vein), slowly, for about two minutes. This procedure prevents some side effects, such as dizziness, pruritus or blood pressure changes. Moreover, mIBG is considered contraindicated to patients with known hypersensitivity to iobenguane or iobenguane sulfate.1

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As previously mentioned and despite their lower abundance, 123I decay is accompanied with other higher-energy photons - 400 keV (2.87%) and 529 keV (1.28%). These high-energy photons may lead to the penetration of collimator septa. Therefore, some authors recommend acquiring images with a medium energy (ME) collimator for greater precision in the quantification of images.

The image acquisition protocols recommend an early acquisition 15 minutes after tracer injection and a late acquisition up to 4 hours after tracer injection. The planar images are recommended to be acquired in anterior projection for 10 minutes using a 128x128 or 256x256 matrix. Although a ME collimator seems to be preferred, these collimators are not widespread available. Because of their widespread availability, low-energy high-resolution (LEHR) collimators are very often used. Images can also be acquired using a count limit for the early acquisitions (e.g. 1 million counts), and then correct the duration of the late image acquisition for decay between the two acquisitions. It is important to exclude the liver as much as possible from the field of view, as this may deteriorate the myocardial image quality.1

Protocol for acquisition of SPECT images and quantification

For SPECT acquisition, a system similar to the acquisition of myocardial perfusion imaging is used, with 180-degree rotation, starting in 45-degree right anterior oblique rotating in counterclockwise direction to 45-degree left posterior oblique. It is recommended to acquire 64 projections (32 for each detector), going through 180 degrees. Reconstruction may be performed using established methods, such as filtered back-projection (FBP), or iterative methods, such as ordered subsets expectation maximization (OSEM).1

While various quantitation methods for measuring myocardial uptake have been used, the simplest and most practically used index has been HMR (Figure 1).1 However, there are inter-institutional variations in HMR, even for normal values. Especially the choice of collimator introduces considerable variations.8,9 Therefore, the need for standardization of 123I-mIBG myocardial uptake has been recognized. However, the availability of practical clinical standardization approaches is limited. To overcome this variation and to unify HMRs from various data acquisition systems, a cross-calibration phantom was developed.10,11 Using this cross-calibration phantom in Japan and

Europe has resulted in conversion coefficients for many different gamma-camera collimator combinations.11,12 There was a good agreement between Japanese and European LEHR, low-medium energy (LME) and medium-energy general purpose (MEGP) collimators. These findings are most likely a good basis for comparing the data from different camera collimator systems worldwide.

Use of 123I-mIBG scintigraphy in CHF

The action of NE in association with myocardial β-AR is the trigger responsible for muscle contraction, involving the sequential action of adenylate cyclase and cAMP and, subsequently, transmembrane calcium influx.13 In CHF, the initial beneficial adrenergic hyperstimulation has detrimental effects on the long term, and may result in cardiac remodeling.14 In addition, there is a reduction in the sensitivity and the expression of β-AR, which contributes to progressive worsening of cardiac function.15 Heart failure presents high mortality rates, and around 50% of deaths are related to sudden death.16 In 2014, only in Brazil, more than 26,000 deaths were related to HF, and approximately half of them occurred in the southeast of the country.17

Although arrhythmia, lethal cardiac events and prognosis are multifactorial and have several determinants, cardiac 123I-mIBG scintigraphy alone and more likely in combination with other determinants may be able to better select CHF patients with increased risk. Indeed, a large number of studies on the prognostic value of 123I-mIBG assessed cardiac sympathetic activity in CHF have been published.

In 1992, Merlet et al.18 demonstrated the prognostic value of ¹²³I-mIBG cardiac scintigraphy and its superiority over other diagnostic methods. In 90 patients with CHF (New York Heart Association - NYHA class II to IV) and left ventricular ejection fraction (LVEF) lower than 45% evaluated using radionuclide ventriculography (RV), late HMR was the best predictor of survival (p < 0.0001).18 From then on, new studies emerged confirming those results. A Japanese study evaluated 414 consecutive patients with known or suspected cardiac disease and showed that, apart from the non-heart-related deaths, a compromised sympathetic innervation evaluated by ¹²³I-mIBG scintigraphy was the best predictor of cardiac death.19

A retrospective European multicenter study used ¹²³I-mIBG scintigraphy to determine the risk of cardiac

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Figure 1 – Examples of normal cardiac 123I-mIBG images. Early planar image showing regions of interest (ROI) in the heart (red) and mediastinum (blue) for determination of heart-to-mediastinum ratio (A). Early SPECT images showing uniform distribution of 123I-mIBG on the walls of the left ventricle (B).

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events in patients with CHF. Cardiac events were defined as cardiac death from any cause, cardiac transplantation and potentially fatal arrhythmias. It was shown that patients with events had lower HMR than those without events (average HMR of 1.51 and 1.97, respectively, p < 0.0001). Patients with a HMR lower than 1.75 had a higher risk of events with an odds ratio of 7.6 (p < 0.0001). Furthermore, 2-year event-free survival using an optimum HMR threshold of 1.75 was 62% for HMR less than 1.75, and 95% for HMR greater than or equal to 1.75 (p < 0.0001).20 In a systematic review, Verberne et al. analyzed 18 studies including 1,755 patients, and observed a worse prognosis in patients with CHF and a reduced late HMR and increased cardiac washout.21

In 2010, the publication of ADMIRE-HF, a prospective multicenter study, confirmed the prognostic value of ¹²³I-mIBG cardiac scintigraphy in CHF. The late HMR was a prognostic predictor independent from other markers, such as brain natriuretic peptide (BNP) and LVEF. That study included 961 CHF patients with NYHA class II or III HF, LVEF ≤ 35% and optimized medical therapy. Progression of HF, potentially fatal arrhythmias and cardiac death were defined as cardiac events. The risk of event occurrence was significantly higher in patients who presented HMR < 1.6, with a 2-year event rate of 38% (p < 0.001). Moreover, the 2-year death rate, whether cardiac or all-cause, decreases linearly with increased HMR, dropping from 20% with HMR < 1.1 to 0% with HMR ≥ 1.8.22 Other studies confirmed the power of ¹²³I-mIBG scintigraphy in the evaluation of cardiac risk in patients with CHF.

Currently, there is an effort to better understand the relation between ¹²³I-mIBG scintigraphy findings and the occurrence of arrhythmic events. It appears that there is no linear relation between HMR and occurrence of arrhythmia, thus suggesting that the evaluation of the risk of arrhythmic events may be focused on SPECT,14,23 as similarly demonstrated in a PET study.24

Use of 123I-mIBG scintigraphy in the selection of patients for implantable cardiac devices

Another promising application of ¹²³I-mIBG myocardial scintigraphy is to better identify CHF patients who will benefit from implantable cardioverter-defibrillators (ICD) or cardiac resynchronization therapy (CRT). The implantation of these devices has contributed to significantly modify the survival of CHF patients,25,26 and it is indicated in several guidelines.27,28 Nevertheless, there still is a large number of patients that do not benefit from implantation (i.e. no therapeutic effects from CRT or no therapeutic discharge from ICD).29-31 In light of the increasing incidence of HF and the concomitantly increasing costs associated with HF, a better selection of patients for these expensive devices is mandatory. In this context, ¹²³I-mIBG scintigraphy could possibly be used to better discriminate between patients who most likely will benefit from these device implantations and patients who will not.

Publications on this subject are encouraging, but with a limited number of patients evaluated. With 30 patients, Nishioka et al.32 demonstrated that HMR was an independent predictor of CRT response (p = 0.01).

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A HMR > 1.36 had a sensitivity of 75% and specificity of 71% for the identification of potential CRT responders. Response to CRT with functional improvement of LVEF was also found in significantly higher frequency in patients with left ventricular dyssynchrony and late HMR ≥ 1.6 in a study performed by Tanaka et al.33 Moreover, the evolution of this group over 3 years was significantly more favorable than that of patients whose sympathetic function was more impaired. Moreover, CRT not only improves left ventricular function, but is also associated with an improved HMR.34 This supports the close relation between cardiac autonomic nervous activity and left ventricular function.

Regarding ICD, the ADMIRE-HF study already showed that possible fatal arrhythmias could be predicted by a HMR < 1.6.22 A better selection of patients for ICD is above all related to prevention (i.e. primary prevention) and not those patients referred for already proven (possible) lethal arrhythmias (i.e. secondary prevention). Nagahara et al.35 showed that late HMR was a predictor of the occurrence of ICD shock in patients with HF and LVEF < 50% and BNP > 187 pg/ml. When combined with high levels of BNP, HMR < 1.95 had a specificity of 94% and a positive predictive value of 82% for the appropriate use of ICD.35

In addition to global cardiac sympathetic activity assessed with 123I-mIBG scintigraphy, there is evidence that, in ischemic HF, regional innervation/perfusion mismatch with a larger defect size on 123I-mIBG SPECT than on myocardial perfusion imaging SPECT predisposes to ventricular arrhythmias.36-38 In a large prospective study in 116 CHF patients, eligible for ICD implantation for both primary and secondary prevention of sudden cardiac death (SCD), ¹²³I-mIBG SPECT was shown to be an independent predictor of appropriate ICD therapy and cardiac death.39 The cumulative incidence of appropriate ICD therapy during 3 years of follow-up was significantly higher when a relatively large ¹²³I-mIBG SPECT defect (median summed score ≥ 26) was present. Similar results have been shown in a prospective PET study using 11C-hydroxyephedrine for assessing sympathetic activity in ischemic heart disease (n=204), in which the innervation defect size predicted cause-specific mortality from SCD independently of LVEF and infarct volume.24

The screening ¹²³I-mIBG scintigraphy for a better selection of ICD candidates seems to be cost-effective. Screening is associated with a reduction in ICD utilization of 21%, resulting in a number needed to screen to prevent 1 ICD implantation of 5. Screening reduced

the costs per patient by US$5500 and US$13,431 (in 2013 dollars) over 2 and 10 years, respectively, in comparison with no screening, and resulted in losses of 0.001 and 0.040 life-years, respectively, over 2 and 10 years.40 These findings are encouraging in better discriminating responders from non-responders to ICD. However, larger studies are necessary to better define the role of ¹²³I-mIBG cardiac scintigraphy in identifying responders to ICD in HF. The results of a large randomized trial (i.e. ADMIRE-ICD) are therefore awaited with great anticipation.

Use of 123I-mIBG scintigraphy in the evaluation of cardiotoxicity

Anthracyclines have been used as antineoplastic agents in a wide variety of hematological and solid tumors. It is a powerful therapeutic agent, but with cardiotoxic effects.41 Cardiotoxicity may be acute or chronic, the latter could arise months or years later.41 Some risk factors are known, such as cumulative dose, female sex, age, previous irradiation, other concomitant chemotherapeutic drugs, and existing cardiac dysfunction.42 Mechanisms involved may include free radicals, myocyte death due to calcium overload and altered adrenergic function.42

Preventive measures have been adopted in experimental studies. Some studies have demonstrated that amifostine may be useful in the bleaching of hydroxyl and superoxide radicals.43 Other agents used are probucol, selenium and L-carnitine. Dexrazoxane has been very useful as a cardioprotector against the cardiotoxic effects of anthracyclines. Dexrazoxane is an iron chelator and results in the reduction of free radicals. However, its use in children has been questioned for possible interference with the antitumor effect of anthracyclines. Beta-blockers and ACE inhibitors, which are part of the arsenal in the treatment of HF, have also been employed, and have been useful to treat cardiotoxicity caused by anthracyclines. However, these drugs do not protect the myocardium from possible anthracycline cardiotoxicity. Monitoring cardiotoxicity is a challenge and involves a series of procedures such as endomyocardial biopsy that, despite providing a histopathological diagnosis, is an invasive procedure and requires evaluation by an experienced pathologist.44

Left ventricular dysfunction is the most common manifestation found in cardiotoxicity and may contribute to an increased mortality rate. Traditional non-invasive imaging methods, such as RV and echocardiography

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(ECHO), can be used to show changes, even if subtle, before the heart starts to fail. RV does not only provide a LVEF but also generates other information on left ventricular function that can be very useful, such as peak filling rate. All these parameters can be used to evaluate systolic and diastolic function, respectively. Ejection fraction and peak filling rate seem to correlate with the early stages of cardiotoxicity.45

Nousiainen et al. prospectively evaluated late impairment of cardiac function in 30 patients with non-Hodgkin lymphoma who were submitted to doxorubicin treatment in a low cumulative dose. The authors found that > 4% reduction after a 200-mg cumulative dose had a sensitivity of 90% and specificity of 72% to induce late cardiotoxicity.46 It should be taken into account that a certain cell mass should be damaged before the LVEF begins to fail due to myocardial compensatory reserve. In this way, the evaluation of ventricular (dys)function is the most appropriate approach.

Another study by Dos Santos et al.47 evaluated the late cardiotoxic effect of anthracyclines by assessing sympathetic activity with ¹²³I-mIBG. That study was performed in a sample of 89 young patients with mean age of 5.4 years and similar sex distribution. While patients receiving chemotherapy had a reduction in LVEF compared to controls, there was no difference in early or late HMR uptake ratios or washout rates of ¹²³I-mIBG.47 ¹²³I-mIBG has good reproducibility and seems sensitive enough to detect alterations in adrenergic innervation before ventricular dysfunction occurs.

A recent study looked at the interrelation between HMR and washout rate and parameters obtained through ECHO, such as GLS and GRS (global longitudinal and radial strain), and serum markers. The authors evaluated 59 women with breast cancer, 1 year after treatment with anthracycline. The parameters found as the most robust were those obtained with ¹²³I-mIBG scintigraphy - late HMR and washout rate. Nevertheless, it is important to emphasize that there was a significant correlation between HMR and GRS.48

In another smaller study (n=9), the use of ¹²³I-mIBG scintigraphy for the evaluation of trastuzumab-related cardiotoxicity and ventricular (dys)function was investigated. The data suggest that, in patients with a persistently decreased LVEF, 123I-mIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated.49

Taking all these preliminary data into account, it seems

feasible to assess cardiotoxicity with cardiac ¹²³I-mIBG scintigraphy. ¹²³I-mIBG scintigraphy in combination with parameters of left ventricular mechanical function seem to be promising for the routine clinical use in these oncology patients.

Use of 123I-mIBG scintigraphy in the evaluation of ischemia and diabetes mellitus

The potential use of ¹²³I-mIBG scintigraphy has also found its place in the evaluation of ischemia and in patients with diabetes mellitus (DM). It is important to highlight the association of DM with autonomic neuropathy. The evaluation of ischemia with ¹²³I-mIBG is of interest as sympathetic innervation is more susceptible to ischemia as compared to myocytes. This difference in ischemia susceptibility may be at the base of arrhythmogenicity.50

Simões et al. evaluated electrophysiological findings in denervated myocardium of 67 patients with acute myocardial infarction treated with early reperfusion. They correlated these electrophysiological findings with rest 201TI perfusion scintigraphy and sympathetic innervation with ¹²³I-mIBG. The data showed disagreement in size on perfusion imaging compared to ¹²³I-mIBG in 90% of the patients. In other words, ischemia-related adrenergic changes are more pronounced than perfusion defects alone. In addition, electrophysiological findings showed that these areas with perfusion innervation mismatch were correlated with prolonged repolarization.36

Diabetic autonomic neuropathy is the most common and troublesome complication of DM. Although involvement of the autonomic nervous system is generally diffuse, symptoms may be confined to a single target organ or organ system. The exact mechanism has not been elucidated yet. As with other diseases, cardiac ¹²³I-mIBG scintigraphy allows for the assessment of the sympathetic activity. Numerous reports have shown that in diabetic patients, uptake abnormalities of 123I-mIBG are correlated with a poor prognosis, even in the absence of clinical neuropathy.51,52 Impaired glucose tolerance (IGT) is associated with an increased risk of type 2 DM and cardiovascular disease. However, Asgahr et al.53 showed that global and regional measures of 123I-mIBG uptake and washout, as well as cardiac autonomic function, did not differ between subjects with IGT and healthy controls.

Another study looked at the impact of DM on cardiac sympathetic innervation in patients with HF. Diabetic patients with HF showed lower cardiac 123I-mIBG

539

1. Flotats A, Carrió I, Agostini D, Le Guludec D, Marcassa C, Schaffers M, et al; EANM Cardiovascular Committee; European Council of Nuclear Cardiology. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging. 2010;37(9):1802-12. doi: 10.1007/s00259-010-1491-4.

2. Brede M, Wiesmann F, Jahns R, Hadamek K, Arnolt C, Neubauer S, et al. Feedback inhibition of catecholamine release by two different α2-adrenoceptor subtypes prevents progression of heart failure. Circulation. 2002;106(19):2491-6. PMID: 12417548.

3. Chen GP, Tabibiazar R, Branch KR, Link JM, Caldwell JH. Cardiac receptor physiology and imaging: an update. J Nucl Cardiol. 2005;12(6):714-30. doi: 10.1016/j.nuclcard.2005.09.008.

4. Wieland DM, Wu JI, Brown LE, Mangner TJ, Swanson DP. Radiolabeled adrenergi neuron-blocking agents: adrenomedullary imaging with [131I] iodobenzylguanidine. J Nucl Med. 1980;21(4):349-53. PMID: 7381563.

5. Hedrick WR, Di Simone RN, Keen RL. Radiation dosimetry from breast milk excretion of radioiodine and pertechnetate. J Nucl Med. 1986;27(10):1569-71. PMID: 3020191.

6. Hsiao E, Huynh T, Mansberg R, Bautovich G, Roach P. Diagnostic I-123 scintigraphy to assess potential breast uptake of I-131 before radioiodine

therapy in a postpartum woman with thyroid cancer. Clin Nucl Med. 2004;29(8):498-501. PMID: 15249829.

7. Travin MI. Clinical applications of myocardial innervation imaging. Cardiol Clin. 2016;34(1):133-47. doi: 10.1016/j.ccl.2015.06.003.

8. Verberne HJ, Feenstra C, de Jong WM, Somsen GA, van Eck-Smit BL, Busemann Sokole E. Influence of collimator choice and simulated clinical conditions on 123I-MIBG heart/mediastinum ratios: a phantom study. Eur J Nucl Med Mol Imaging. 2005;32(9):1100-7. doi: 10.1007/s00259-005-1810-3.

9. Verschure DO, de Wit TC, Bongers V, Hagen PJ, Sonneck-Koenne C, D’Aron J, et al. 123I-MIBG heart-to-mediastinum ratio is influenced by high-energy photon penetration of collimator septa from liver and lung activity. Nucl Med Commun. 2015;36(3):279-85. doi: 10.1097/MNM.0000000000000238.

10. Nakajima K, Matsubara K, Ishikawa T, Motomura N, Maeda R, Akhter N, et al. Correction of iodine-123-labeled meta-iodobenzylguanidine uptake with multi-window methods for standardization of the heart-to-mediastinum ratio. J Nucl Cardiol. 2007;14(6):843-51. doi: 10.1016/j.nuclcard.2007.08.002.

11. Nakajima K, Okuda K, Yoshimura M, Matsuo S, Wakabayashi H, Imanishi Y, et al. Multicenter cross-calibration of I-123 metaiodobenzylguanidine heart-to-mediastinum ratios to overcome camera-collimator variations. J Nucl Cardiol. 2014;21(5):970-8. doi: 10.1007/s12350-014-9916-2.

References

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uptake than HF patients not having DM or than DM patients with a similar degree of autonomic dysfunction not having HF. HbA1c correlated with the degree of reduction in cardiac 123I-mIBG uptake.54 So it is important to realize that DM may have an impact on myocardial sympathetic activity and that these patients may be at an increased risk for events.

Conclusion

Cardiac sympathetic activity can be assessed non-invasively by cardiac 123I-mIBG scintigraphy. However, the lack of standardization of acquisition and post-acquisition analysis has hampered comparison between different institutions, and therefore wide scale clinical implementation. Cross-calibration of gamma-camera collimator combinations results in a good reproducibility with a small inter- and intra-observer variation. Moreover, the standardized cardiac 123I-mIBG scintigraphy outcomes seem to have good prognostic value. Therefore, major objections for clinical implementation seem to have been overcome. Furthermore, the use of standardized HMR allows for the development of universal prognostic cut-off values (high vs. low risk). These cut-off values can be calculated by re-analysis of the data of previous published multicenter studies. Finally, it should be stressed that standardization of the HMR is essential for the preparation of adequate risk models. In conclusion,

improving standardization and validation of cardiac 123I-mIBG scintigraphy will lead to a much more accepted application for individual HF management.


Conception and design of the research: Rocha ET, Alves WEFM, Verschure DO, Verberne HJ. Acquisition of data: Rocha ET, Alves WEFM, Verschure DO, Verberne HJ. Analysis and interpretation of the data: Rocha ET, Alves WEFM, Verschure DO, Verberne HJ. Writing of the manuscript: Rocha ET, Alves WEFM, Verschure DO, Verberne HJ. Critical revision of the manuscript for intellectual content: Rocha ET, Alves WEFM, Verschure DO, Verberne HJ.



Sources of Funding


Study Association


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12. Verschure DO, Poel E, Nakajima K, Okuda K, van Eck-Smit BL, Somsen GA, et al. A European myocardial 123I-mIBG cross-calibration phantom study. J Nucl Cardiol. 2017 Jan 24. doi: 10.1007/s12350-017-0782-6. [Epub ahead of print].

13. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, et al. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307(4):205-11. doi: 10.1056/NEJM198207223070401.

14. Verschure DO, Veltman CE, Manrique A, Somsen GA, Koutelou M, Katsikis A, et al. For what endpoint does myocardial 123I-MIBG scintigraphy have the greatest prognostic value in patients with chronic heart failure? Results of a pooled individual patient data meta-analysis. Eur Heart J Cardiovasc Imaging. 2014;15(9):996-1003. doi: 10.1093/ehjci/jeu044.

15. Chirumamilla A, Travin MI, editors. Cardiac applications of 123 I-mIBG imaging. Semin Nucl Med.2011;41(5):374-87. doi:10.1053/j.semnuclmed.2011.04.001

16. Hage FG, Aggarwal H, Patel K, Chen J, Jacobson AF, Heo J, et al. The relationship of left ventricular mechanical dyssynchrony and cardiac sympathetic denervation to potential sudden cardiac death events in systolic heart failure. J Nucl Cardiol. 2014;21(1):78-85. doi: 10.1007/s12350-013-9807-y.

17. Ministério da Saúde. Datasus. Óbitos infantís-Brasil [Internet]. Brasilia; 2015. [Citado em 2016 dez.10] Disponívem em: http://tabnet.datasus.gov.br/cgi/tabcgi.exe?sim/cnv/obt10uf.def.

18. Merlet P, Valette H, Dubois-Randé J, Moyse D, Duboc D, Dove P, et al. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. Journal of nuclear medicine: official publication, Society of Nuclear Medicine. 1992;33(4):471-7. PMID: 1552326.

19. Nakata T, Miyamoto K, Doi A, Sasao H, Wakabayashi T, Kobayashi H, et al. Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts. Journal of Nuclear Cardiology. 1998;5(6):579-90. PMID: 9869480.

20. Agostini D, Verberne HJ, Burchert W, Knuuti J, Povinec P, Sambuceti G, et al. I-123-mIBG myocardial imaging for assessment of risk for a major cardiac event in heart failure patients: insights from a retrospective European multicenter study. Eur J Nucl Med Mol Imaging. 2008;35(3):535-46. doi: 10.1007/s00259-007-0639-3

21. Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008;29(9):1147-59. doi: 10.1093/eurheartj/ehn113.

22. Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. J Am Coll Cardiol. 2010;55(20):2212-21. doi: 10.1016/j.jacc.2010.01.014.

23. Dimitriu-Leen AC, Scholte AJ, Jacobson AF. 123I-MIBG SPECT for evaluation of patients with heart failure. J Nucl Med. 2015;56 Suppl 4:25S-30S. doi: 10.2967/jnumed.115.157503.

24. Fallavollita JA, Heavey BM, Luisi AJ, Michalek SM, Baldwa S, Mashtare TL, et al. Regional myocardial sympathetic denervation predicts the risk of sudden cardiac arrest in ischemic cardiomyopathy. J Am Coll Cardiol. 2014;63(2):141-9. doi: 10.1016/j.jacc.2013.07.096.

25. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002;346(12):877-83. doi: 10.1056/NEJMoa013474.

26. Connolly S, Hallstrom A, Cappato R, Schron E, Kuck K-H, Zipes D, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. Eur Heart J. 2000;21(24):2071-8. doi: 10.1053/euhj.2000.2476.

27. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and

chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. doi: 10.1093/eurheartj/ehw128.

28. Tracy CM, Epstein AE, Darbar D, DiMarco JP, Dunbar SB, Estes NM, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update of the 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. [corrected]. Circulation. 2012;126(14):1784-800. doi: 10.1161/CIR.0b013e3182618569

29. Moss AJ, Greenberg H, Case RB, Zareba W, Hall WJ, Brown MW, et al; Multicenter Automatic Defibrillator Implantation Trial-II (MADIT-II) Research Group. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110(25):3760-5. doi: 10.1161/01.CIR.0000150390.04704.B7.

30. Daubert JP, Zareba W, Cannom DS, McNitt S, Rosero SZ, Wang P, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. Journal of the American College of Cardiology. 2008;51(14):1357-65. doi: 10.1016/j.jacc.2007.09.073.

31. Pires LA, Abraham WT, Young JB, Johnson KM; MIRACLE and MIRACLE ICD Investigators. Clinical predictors and timing of New York Heart Association class improvement with cardiac resynchronization therapy in patients with advanced chronic heart failure: results from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE-ICD) trials. Am Heart J. 2006;151(4):837-43. doi: 10.1016/j.ahj.2005.06.024.

32. Nishioka SA, Martinelli Filho M, Brandão SC, Giorgi MC, Vieira ML, Costa R, et al. Cardiac sympathetic activity pre and post resynchronization therapy evaluated by 123I-MIBG myocardial scintigraphy. J Nucl Cardiol. 2007;14(6):852-9. doi: 10.1016/j.nuclcard.2007.08.004.

33. Tanaka H, Tatsumi K, Fujiwara S, Tsuji T, Kaneko A, Ryo K, et al. Effect of left ventricular dyssynchrony on cardiac sympathetic activity in heart failure patients with wide QRS duration. Circ J. 2011;76(2):382-9. PMID: 22130315.

34. Scholtens A, Braat A, Tuinenburg A, Meine M, Verberne H. Cardiac sympathetic innervation and cardiac resynchronization therapy. Heart Fail Rev. 2014;19(5):567-73. doi: 10.1007/s10741-013-9400-0.

35. Nagahara D, Nakata T, Hashimoto A, Wakabayashi T, Kyuma M, Noda R, et al. Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function. J Nucl Med. 2008;49(2):225-33. doi: 10.2967/jnumed.107.042564.

36. Simões MV, Barthel P, Matsunari I, Nekolla SG, Schömig A, Schwaiger M, et al. Presence of sympathetically denervated but viable myocardium and its electrophysiologic correlates after early revascularised, acute myocardial infarction. European heart journal. 2004;25(7):551-7. doi: 10.1016/j.ehj.2004.02.016.

37. Sasano T, Abraham MR, Chang KC, Ashikaga H, Mills KJ, Holt DP, et al. Abnormal sympathetic innervation of viable myocardium and the substrate of ventricular tachycardia after myocardial infarction. J Am Coll Cardiol. 2008;51(23):2266-75. doi: 10.1016/j.jacc.2008.02.062.

38. Marshall A, Cheetham A, George RS, Mason M, Kelion AD. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts ventricular arrhythmia in heart failure patients receiving an implantable cardioverter-defibrillator for primary prevention. Heart. 2012;98(18):1359-65. doi: 10.1136/heartjnl-2012-302321.

39. Boogers MJ, Borleffs CJ, Henneman MM, van Bommel RJ, van Ramshorst J, Boersma E, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol. 2010;55(24):2769-77. doi: 10.1016/j.jacc.2009.12.066.

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541

40. O’Day K, Levy WC, Johnson M, Jacobson AF. Cost-Effectiveness Analysis of Iodine-123 Meta-Iodobenzylguanidine Imaging for Screening Heart Failure Patients Eligible for an Implantable Cardioverter Defibrillator in the USA. Appl Health Econ Health Policy. 2016;14(3):361-73. doi: 10.1007/s40258-016-0234-5.

41. O’Hare M, Sharma A, Murphy K, Mookadam F, Lee H. Cardio-oncology Part I: chemotherapy and cardiovascular toxicity. Expert Rev Cardiovasc Ther. 2015;13(5):511-8. doi: 10.1586/14779072.2015.1032940.

42. Smith TA, Phyu SM, Akabuogu EU. Effects of administered cardioprotective drugs on treatment response of breast cancer cells. Anticancer Res. 2016;36(1):87-93. PMID: 26722031.

43. Herman EH, Zhang J, Chadwick DP, Ferrans VJ. Comparison of the protective effects of amifostine and dexrazoxane against the toxicity of doxorubicin in spontaneously hypertensive rats. Cancer Chemother Pharmacol. 2000;45(4):329-34. doi: 10.1007/s002800050048.

44. Tashakori Beheshti A, Mostafavi Toroghi H, Hosseini G, Zarifian A, Homaei Shandiz F, Fazlinezhad A. Carvedilol administration can prevent doxorubicin-induced cardiotoxicity: a double-blind randomized trial. Cardiology. 2016;134(1):47-53. doi: 10.1159/000442722.

45. Skovgaard D, Hasbak P, Kjaer A. BNP predicts chemotherapy-related cardiotoxicity and death: comparison with gated equilibrium radionuclide ventriculography. PLoS One. 2014;9(5):e96736. doi: 10.1371/journal.pone.0096736.

46. Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. British journal of cancer. 2002;86(11):1697-700. doi: 10.1038/sj.bjc.6600346.

47. Dos Santos MJ, da Rocha ET, Verberne HJ, da Silva ET, Aragon DC, Junior JS. Assessment of late anthracycline-induced cardiotoxicity by 123I-mIBG cardiac scintigraphy in patients treated during childhood

and adolescence. J Nucl Cardiol. 2017;24(1):256-264. doi: 10.1007/s12350-015-0309-y.

48. Bulten BF, Verberne HJ, Bellersen L, Oyen WJ, Sabaté-Llobera A, Mavinkurve-Groothuis AM, et al. Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients. Cancer Chemother Pharmacol. 2015;76(5):957-67. doi: 10.1007/s00280-015-2874-9.

49. Stokkel MP, Boekhout A. I-123-MIBG myocardial imaging in trastuzumab-based cardiotoxicity: the first experience. Nucl Med Commun. 2013;34(1):19-24. doi: 10.1097/MNM.0b013e32835ae523.

50. Miyazaki T, Zipes DP. Presynaptic modulation of efferent sympathetic and vagal neurotransmission in the canine heart by hypoxia, high K+, low pH, and adenosine. Possible relevance to ischemia-induced denervation. Circ Res. 1990;66(2):289-301. PMID: 2153468.

51. L a n g e r A , F r e e m a n M R , J o s s e R G , A r m s t r o n g P W . Metaiodobenzylguanidine imaging in diabetes mellitus: assessment of cardiac sympathetic denervation and its relation to autonomic dysfunction and silent myocardial ischemia. J Am Coll Cardiol. 1995;25(3):610-8. doi: 10.1016/0735-1097(94)00459-4.

52. Hattori N, Tamaki N, Hayashi T, Masuda I, Kudoh T, Tateno M, et al. Regional abnormality of iodine-123-MIBG in diabetic hearts. J Nucl Med. 1996;37(12):1985. PMID: 8970519.

53. Asghar O, Arumugam P, Armstrong I, Ray S, Schmitt M, Malik R. Individuals with impaired glucose tolerance demonstrate normal cardiac sympathetic innervation using I-123 mIBG scintigraphy. J Nucl Cardiol. 2015;22(6):1262-8. doi: 10.1007/s12350-015-0070-2.

54. Paolillo S, Rengo G, Pagano G, Pellegrino T, Savarese G, Femminella GD, et al. Impact of diabetes on cardiac sympathetic innervation in patients with heart failure. Diabetes Care. 2013;36(8):2395-401. doi: 10.2337/dc12-2147.

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DOI: 10.5935/2359-4802.20170088


VIEWPOINT

Mailing Address: Ana Inês GonzálesRua Guerino Menegaro, N: 264. Postal Code: 88914-000, Areais Brancas, Balneário Arroio do Silva, SC – Brazil.E-mail: [email protected]

Dance, Heart Failure and Erectile Function: Perspective of Better Clinical Management?Tales de Carvalho, Ana Inês Gonzáles, Daiane Pereira Lima, Adair Roberto Soares dos SantosCentro da Ciência da Saúde e do Esporte, Universidade do Estado de Santa Catarina (UDESC), Florianópolis, SC – Brazil

Manuscript received May 28, 2017, revised manuscript July 03, 2017, accepted July 24, 2017.

Heart Failure / physiopathology; Exercise; Dance; Autonomic Nervous System; Inflammation.

Keywords

Abstract

In the pathophysiology of heart failure (HF), attention has been directed to sympathetic hyperactivity and low-intensity systemic inflammation, aspects also present in erectile dysfunction (ED). Physical exercise is a strategy that improves these parameters, which makes plausible the hypothesis that, when practiced through dance, exercise would provide better results. By combining physical activity and music, dance would be able to improve the functioning of central and peripheral neural networks additionally to other favorable mechanisms, contributing to the restoration of neurohormonal function and reduction of the inflammatory response, which would increase the efficacy of HF and ED treatment.

Introduction

Heart failure (HF) is a complex clinical syndrome of high morbidity and mortality rates, representing one of the major contemporary health problems. In the pathophysiology of HF, attention has been directed to sympathetic hyperactivity, ventricular remodeling and, more recently, inflammatory and prothrombotic factors. These physiopathological aspects have a close relationship to each other and have an influence on disease perpetuation, prognosis and severity.1

A high prevalence of sexual dysfunction, particularly erectile dysfunction (ED) has been reported among HF patients. ED has been considered a predictor of cardiovascular risk, and of cardiovascular and all-cause

mortality. For this reason, ED has a major role in public health, by negatively affecting health and quality of life of patients,2 with common characteristics of HF.

In this context, physical exercise, such as dancing and its own particularities, is an intervention with great potential to benefit both HF and ED conditions.

Development

In ED and HF physiopathology, high levels of pro-inflammatory cytokines, associated with impaired autonomic nervous system have been reported,3,4 which may be characterized as a phenomenon primarily inflammatory and neurovascular.

Sympathetic hyperactivity has an important compensatory role in the initial phase of HF. However, its maintenance contributes to further aggravation of cardiac dysfunction, which coexists with a significant increase in central and peripheral vasoconstriction,1 which in turn increases penile smooth muscle tone and vasoconstriction of penile blood vessels, characteristic of ED.3,4

Similar to sympathetic hyperactivity, the systemic, low-degree inflammatory process, characterized as ‘subclinical’ in ED patients, contributes to endothelial dysfunction3 and consequent reduction in penile arterial dilation capacity.2 Both abnormal autonomic modulation and subclinical inflammation are equally present in ED and HF.3

Recently, neuroscience studies have identified a neural basis, which combined with humoral and immune activities, is able to reflexively regulate and adjust the inflammatory response under physiological conditions, referred to as the “inflammatory reflex”.5 In this respect, the nervous system, which receives information from the immune system by means of soluble mediators and sensory neurons, is also able to inhibit inflammation,5 which is associated with both HF and ED.

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Dance, Heart Failure and Erectile Function


Viewpoint

Nevertheless, in sympathetic hyperactivity and/or vagal suppression conditions, as in HF, such inflammatory reflex is impaired. In this case, physical exercise may play an important role by contributing to anatomical modulation and control of inflammation. These exercise effects can be beneficial to erectile function in ED.6-8

Traditionally, aerobic exercise prescribed to HF patients is of moderate intensity and constant load, i.e., continuous training protocols that normally include conventional cyclic exercises. Such exercise programs may be monotonous, leading to low motivation and low adherence of patients to cardiac rehabilitation. In this regard, dancing is a playful, joyful activity that may be easily incorporated to social life, and a great potential alternative.9,10

Dance combines physical activity with music and thereby potentiates the physical, cognitive and emotional benefits, and promotes social integration.9 Thus, dance enables a true synergism of positive effects promoted by physical exercise and music.9,10 Similar to physical activity, music activates body functioning, particularly the nervous system. When music penetrates human ears, sound waves are converted into electrical activity that sends information to thalamic and subthalamic regions and to the limbic system, which is considered the unit responsible for emotions and social behaviors.9

The hypothalamus, which belongs to the limbic system and is considered the core of emotional expressions and sexual behavior, is also a central structure involved in the inflammatory reflex. This makes plausible the hypothesis that dancing can be an intervention capable to positively modulate inflammatory response by activation of cholinergic anti-inflammatory pathways, in a similar or even superior manner than conventional physical exercise, while promoting an increase in vagal activation.5

Considering similarities in the physiopathology that explain the high prevalence of ED in HF patients, a plausible hypothesis is that dancing may be effective

in the concomitant treatment of both conditions. However, so far only one observational, case-control study performed by our group showed that patients with cardiovascular diseases (coronary diseases and hypertension), who were ballroom dancing practitioners, had a lower risk to develop sexual dysfunction, and no other study on the effect of dance in HF patients was found.10 This represents a gap in the literature.

Conclusions

Considering the similarities in the physiopathology of HF and ED, particularly regarding autonomic modulation and inflammation, dance is shown as a promising therapy for both conditions. The lack of studies investigating the effects of dance in the concomitant treatment of both HF and ED is a gap in the literature to be filled.


Conception and design of the research: Carvalho T, Gonzáles AI, Lima DP, Santos ARS. Writing of the manuscript: Carvalho T, Gonzáles AI, Lima DP, Santos ARS. Critical revision of the manuscript for intellectual content: Carvalho T, Gonzáles AI, Lima DP, Santos ARS. Supervision / as the major investigador: Carvalho T, Gonzáles AI, Lima DP, Santos ARS.



Sources of Funding


Study Association


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1. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54(19):1747-62. doi: 10.1016/j.jacc.2009.05.015.

2. Alberti L, Torlasco C, Lauretta L, Loffi M, Salonia A, Margonato A, et al. Erectile dysfunction in heart failure patients: a critical reappraisal. Andrology. 2013;1(2):177-91. doi: 10.1111/j.2047-2927.2012.00048.x.

3. Rodrigues FL, Fais RS, Tostes RC, Carneiro FS. There is a link between erectile dysfunction and heart failure: it could be inflammation. Curr Drug Targets. 2015;16(5):442-50. PMID: 25892310.

4. Rodrigues FL, Lopes RA, Fais RS, de Oliveira L, Prado CM, Tostes RC, et al. Erectile dysfunction in heart Failure rats is associated with increased neurogenic contractions in cavernous tissue and internal pudendal artery. Life Sci. 2016;145:9-18. doi: 10.1016/j.lfs.2015.12.005.

5. Tracey KJ. The inflammatory reflex. Nature. 2002;420(6917):853-90. doi: 10.1038/nature01321.

6. Sties SW, Ulbrich AZ, Mara LS, Gonzáles AI, Netto AS, Carvalho T, et al. Influence of high intensity training on erectile function of patients with heart failure. Global Heart. 2013;1(9):270-1.

7. Hsu CY, Hsieh PL, Hsiao SF, Chien MY. Effects of exercise training on autonomic function in chronic heart failure: systematic review. Biomed Res Int. 2015;2015:591708. doi: 10.1155/2015/591708.

8. Guasch E, Benito B, Nattel S. Exercise training, inflammation and heart failure: working out to cool down. J Physiol. 2010;588(Pt 14):2525-6. doi: 10.1113/jphysiol.2010.194134.

9. Gomes Neto M, Menezes MA, Oliveira Carvalho V. Dance therapy in patients with chronic heart failure; a systematic review and a meta-analysis. Clin Rehabil. 2014;28(12):1172-9. doi: 10.1177/0269215514534089.

10. Gonzáles AI, Braga HO, Sties SW, Mara LS, Carvalho GD, Carvalho T, et al. Sexual function and cardiopulmonary capacity in coronary and hipertensive practitioners of dance. Rev Bras Ativ Fis Saúde. 2015;20(4):366-75. doi: http://dx.doi.org/10.12820/rbafs.v.20n4p366.

References

Carvalho et al.

Dance, Heart Failure and Erectile Function


Viewpoint

DOI: 10.5935/2359-4802.20170079


CASE REPORT

Mailing Address: Joana MalheiroRua de Grijo, 100, 4E. Postal Code: 4150. Lordelo do Ouro, Porto – PortugalE-mail: [email protected]; [email protected]

Tachycardiomyopathy and Extracorporeal Membrane Oxygenation: A Case ReportJoana Malheiro, João Almeida, Daniel Caeiro, Adelaide Dias, Marlene Fonseca, Vasco GamaCentro Hospitalar de Vila Nova de Gaia, Espinho – Portugal

Manuscript received October 06, 2016, revised manuscript February 08, 2017, accepted April 05, 2017.

Cardiomyopathies; Tachycardia; Shock, Cardiogenic; Extracorporeal Membrane Oxygenation; Atrial Fibrillation.

Keywords

Introduction

Tachycardiomyopathy (TCM) is a rare, but potentially reversible cause of cardiomyopathy and cardiogenic shock. It is defined by a global left ventricular systolic dysfunction secondary to persistent tachyarrhythmia, with partial (in patients with previous structural disease), or total recovery (in patients without previous structural disease) after cardiac rhythm normalization.1 The most commonly implicated arrhythmia is atrial fibrillation. The hemodynamic changes that characterize the patient with TCM include: increase in ventricular telediastolic and telesystolic volumes, global hypokinesis, increase in ventricular and pulmonary artery filling pressures, and, finally, decrease in ejection fraction (EF).1,2 It manifests clinically by congestive heart failure, and, in some cases, it may develop into cardiogenic shock. There are no specific methods to identify the presence of TCM. The diagnosis is usually attained retrospectively with normalization or improvement of left ventricular dysfunction, through tachyarrhythmia reversion or control. The most frequent complications of TCM are embolic events, complications due to the evolution of arrhythmia severity with degeneration to Ventricular Tachycardia (VT)/Ventricular Fibrillation (VF) and cardiogenic shock.3

The treatment includes measures of hemodynamic support, frequency control, and reversion to sinus rhythm, when possible.2 Extracorporeal Membrane Oxygenation (ECMO) is a mechanical device that ensures blood oxygenation and perfusion of the main organs for prolonged periods of time in patients with lung and/or

heart failure.4 The use of this device allows the patient to remain alive and hemodynamically stable, working as a bridge to eventual recovery, transplantation, decision-making or even as a “bridge to another bridge” (for instance, as a bridge to left ventricular assist device – LVAD – as target therapeutics).

In cardiogenic shock of potentially reversible etiology, this measure can be lifesaving, as it temporarily assumes cardiac function during the refractory, intrinsic, and reversible phase of cardiogenic shock until patient recovery, minimizing the myocardial effort, improving organ perfusion, and preserving renal function.4 The authors describe a case of a patient with cardiogenic shock secondary to TCM where the use of ECMO was very important in her evolution.

Clinical Case

The patient was a 54-year-old female patient with a history of hypertension, dyslipidemia, obesity, and rheumatic mitral stenosis. On May 5, 2015, she was submitted to a mitral mechanical valve implantation (St. Jude, n. 29) without complications and the echocardiogram at hospital discharge showed a normal-functioning prosthesis, in addition to preserved biventricular function. The patient came to the emergency department on July 6, 2015, due to history of approximately one month of palpitations and progressive worsening of the normal pattern of dyspnea, with complaints of dyspnea with minimal exertion (it usually was with moderate exertion), orthopnea and paroxysmal nocturnal dyspnea. She also reported antihypertensive drug discontinuation at the first postoperative month due to symptomatic hypotension (lipothymia). She denied chest pain and recent history of infection.

At admission to the emergency department, she showed signs of low output with compensated lactic acidosis (lactate levels of 6.5 mmol/L) in arterial blood gases.

546

Figure 1 – Transthoracic echocardiography performed at admission disclosed global hypokinesis of the left and right ventricles, with severe decrease in biventricular systolic function.

Malheiro et al.

Tachycardiomyopathy: A Case Report


Case Report

Analytically, she also showed normocytic/normochromic anemia (Hgb 11.6 g/dL), troponin-T elevation (1.96 ng/mL) and supra-therapeutic International Normalized Ratio (INR) (6.0). The electrocardiogram disclosed atrial fibrillation with Rapid Ventricular Response (RVR) and the echocardiogram showed a mechanical prosthesis with normal function without regurgitation, moderate tricuspid regurgitation and global hypokinesis of the left ventricle and right ventricle, with severe depression of biventricular systolic function (Figure 1).

Due to suspected worsening of the systolic function associated with atrial fibrillation with RVR, an attempt was made to carry out chemical cardioversion with amiodarone and, subsequently, electrical cardioversion (100 J), which was successful. After the electrical cardioversion, she had several episodes of VT, one of which required cardioversion due to loss of consciousness and, subsequently, an episode of VF, which was successfully defibrillated. Due to the electrical instability and possible need for ventricular support, she was transferred to the Coronary Intensive Care Unit.

On admission to the unit, she was started on dobutamine, with good hemodynamic and gasometric response, with subsequent recurrence of electrical instability, and cardiopulmonary arrest in FV, which was successfully defibrillated. As she did not tolerate dobutamine, and given the context of refractory cardiogenic shock, it was decided to initiate hemodynamic support with Venoarterial ECMO (CARDIOHELP System® of Maquet), as well as invasive mechanical ventilation.

Venous drainage cannulas were implanted using the Seldinger technique, through the right common femoral vein (25 F catheter) and an arterial cannula through the right femoral artery (19 F catheter). The initial blood flow was 3.6 L/minute, with gas flow (pure oxygen sweeper) of 3.5 L/minute. Initially, she persisted with electrical instability and several episodes of polymorphic VT and long QTc, the reason for which amiodarone was discontinued, and a temporary pacemaker (PM) was implanted to attain overdrive pacing. On the following days, she developed greater hemodynamic and electrical stability (maintaining atrial fibrillation rhythm), with progressive

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Figure 2 – Transthoracic echocardiogram performed on discharge showing moderate LVSF decrease with ejection fraction of 40% and preserved RVSF.

Malheiro et al.



Case Report

improvement of left ventricular systolic function in the echocardiographic control. Figure 3 summarizes the evolution of hemodynamic, and gasometric data, as well as the established parameters.

The venoarterial ECMO was removed on the 5th day, the temporary pacemaker on the 6th day, and she was extubated on the 8th day, maintaining clinical stability. Beta-blocker and digoxin were initiated on the 11th day of hospitalization, with good hemodynamic tolerance and good heart rate control. She underwent a coronary angiography, which excluded epicardial coronary disease, and a cardiac magnetic resonance, which showed no signs of myocardial edema or fibrosis. At discharge, with atrial fibrillation rhythm and controlled ventricular response, the transthoracic echocardiogram showed a normal-functioning mitral prosthesis, with mild prosthetic regurgitation, mild TI, moderate LVSF depression with 40% EF and preserved RVSF (Figure 2).

Discussion

TCM, being a rare and difficult-to-diagnose entity, may show an unfavorable evolution, if not diagnosed

early. Because there are no specific methods for its diagnosis, the latter is attained by a high index of clinical suspicion, based on clinical history and findings. Fenelon et al. proposed the following criteria for the diagnosis of TCM: dilated cardiomyopathy or heart failure; chronic or persistent cardiac arrhythmia, including incessant supraventricular tachycardia, atrial fibrillation, or flutter, and incessant VT.5

Generally, tachycardia that occurs in 10 to 15% of the day may result in cardiomyopathy.2 The ventricular rate that causes TCM has not been defined, but any heart rate above 100 beats per minute may be relevant.2

In the present case, the diagnostic suspicion of TCM was determined by the presence of de novo atrial fibrillation with symptom onset in the previous month, associated with clinical heart failure, a diagnosis that was confirmed after progressive recovery of the LVSF with frequency control, and after the exclusion of coronary disease and myocarditis. As differential diagnosis, the hypothesis of stress cardiomyopathy could be hypothesized; however, the slow progression and the absence of an "acute cause of stress" in addition to the echocardiographic data do not corroborate this pathology.

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Figure 3 – Hemodynamic and gasometric data, and parameters established in extracorporeal membrane oxygenation (ECMO). pO2: oxygen partial pressure; FiO2: fraction of inspired oxygen; MBP: mean blood pressure.

Malheiro et al.



Case Report

As TCM is characterized by being reversible, the

prognosis will be partially determined by the implemented

hemodynamic support measures. Hemodynamic support

with ECMO increasingly plays a key role in the approach

of patients with cardiogenic shock. This technique is

usually considered when hemodynamic instability

does not respond to conventional pharmacological

measures. There are few reports in the literature of

patients with TCM who developed cardiogenic shock3,6,7

and, to the best of our knowledge, this is the first case

of TCT with refractory shock in which ECMO was used

as a hemodynamic support measure. In the reported

case, given the context of electrical instability and the

consequent intolerance to aminergic support, we chose

the early onset with ECMO. The implementation of this

technique ensured tissue perfusion during the phase of greater electrical and hemodynamic instability, working as a bridge until heart rate control and recovery of left ventricular dysfunction were attained. After frequency control, progressive improvement of left ventricular systolic function was observed, which supported the diagnostic suspicion of TCM.


Conception and design of the research: Malheiro J, Caeiro D. Acquisition of data: Malheiro J, Almeida J, Dias A, Fonseca M. Analysis and interpretation of the data: Malheiro J, Caeiro D. Writing of the manuscript: Malheiro J. Critical revision of the manuscript for intellectual content: Almeida J, Caeiro D, Dias A, Fonseca M, Gama V.

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1. Araújo F, Ducla-Soares JL. Tachycardiomyopathies. Rev Port Cardiol. 2002;21(5):585-92.

2. Nam MC, Aravind A, Chan K, James S, Brown N. Tachycardia-induced cardiomyopathy- a fully reversible phenomenon. Am Heart Hosp J. 2010;8(2):E115-7.

3. Gariglio L, Larraburu A, Nicolini M, Crespo M, Arrinda Calzetta J, Perrone SV, et al. Shock cardiogénico por taquicardiomiopatía: propranolol endovenoso en la etapa aguda. Insuf Card. 2013;8(2):95-101.

4. Lawler PR, Silver DA, Scirica BM, Couper GS, Weinhouse GL, Camp PC Jr. Extracorporeal membrane oxygenation in adults with cardiogenic shock. Circulation. 2015;131(7):676-80.

5. Nakazato Y. Tachycardiomyopathy. Indian Pacing Electrophysiol J. 2002;2(4):104-13.

6. Walker NL, Cobbe SM, Birnie DH. Tachycardiomyopathy: a diagnosis not to be missed. Heart. 2004;90(2):e7.

7. Zwicker C, Becker M, Lepper W, Koch KC, Westenfeld R. Cardiogenic shock due to tachycardiomyopathy after heart transplantation: successful treatment with ivabradine. Cardiology. 2010;116(3):174-7.

References

Malheiro et al.



Case Report



Sources of Funding


Study Association

This study is not associated with any thesis or

dissertation work.

DOI: 10.5935/2359-4802.20170077


CASE REPORT

Mailing Address: Ana Flavia Cassini CunhaRua Senador Vergueiro 93 ap 1201. Postal Code: 22230-000. Flamengo, Rio de Janeiro, RJ – BrazilE-mail: [email protected]; [email protected]

Familial Hypercholesterolemia: the Importance of Early Diagnosis and ManagementAna Flavia Cassini Cunha1 and Iliana Ribeiro2

Departamento de Clínica Médica Hospital Geral de Nova Iguaçu;1 Residência médica de clínica médica do Hospital Geral de Nova Iguaçu,2 Rio de Janeiro, RJ – Brazil

Manuscript received November 27, 2016, revised manuscript July 05, 2017, accepted July 11, 2017

Peripheral Arterial Disease; Atherosclerosis; Ankle Brachial Index; Hyperlipoproteinemia Type II.

Keywords

Introduction

Familial Hypercholesterolemia (FH) is an autosomal dominant hereditary disease, a genetic disease of lipoprotein metabolism, mainly due to a defect in the LDLR gene encoding the LDL receptor.1-4 The diagnosis is established by clinical and laboratory criteria and should always be a diagnostic hypothesis in patients with low-density lipoprotein cholesterol (LDLc) levels greater than 190 mg/dL; and can be confirmed by genetic tests that determine the mutation.1,2 Some diagnostic criteria have been proposed in an attempt to standardize and formalize the diagnosis of FH, such as the Dutch Lipid Clinic Network (Dutch MEDPED).1 This calculates a patient score based on anamnesis data and physical and laboratory tests such as elevated rates of LDLc; characteristics such as tendinous xanthomas and corneal arch; family history of hypercholesterolemia and/or early coronary artery disease (man < 55 years and woman < 60 years) and identification of genetic mutations.1,3 The score determines the probability of an FH diagnosis as possible, probable or definitive FH.1 The most common mutation related to FH is in the gene encoding the LDL receptor, resulting in LDL receptors with functional reductions in their ability to remove LDLc from the circulation.3 There are two distinct phenotypes: the homozygous form, where two defective genes are inherited and LDL receptors have no functionality; a rare form,1 in 1 million individuals and in this case are observed LDL levels > 650 mg/dL; and the heterozygous form, where a gene defective to the LDL receptor is inherited from one parent and a normal gene from the other.1 The absence of a functional gene causes

an increase in the plasma level of LDLc; most frequently affects 1 in 500 individuals with LDL levels > 200 mg/dL.1 The homozygous form tends to present cardiovascular involvement already in childhood.1 The mutation may also be secondary to defects in the APOB gene encoding apolipoprotein B100, or by functional gain mutations in the pro-protein convertase subutilisin/kexin type 9 (PCSK) gene. -9).1,3,4 In patients with heterozygous FH the LDL particles circulate longer, being more subject to oxidation and chemical transformations that result in high uptake of LDL modified by macrophages, triggering pro-atherogenic mechanisms, causing atherosclerosis, coronary artery disease and arterial disease peripheral.1 The nutritional therapies, medication, and regular physical exercises help to control LDL levels and to prevent cardiovascular disease.1-3 It is recommended to reduce the intake of foods rich in cholesterol and saturated fatty acids.1-3 Pharmacological therapy is performed with high-potency statins, such as Atorvastatin (10-80 mg) and Rosuvastatin (10-40mg), in order to obtain a reduction of more than 50% of the baseline level.1 In patients with intolerant to statin therapy, other hypolipidemic agents, such as ezetimibe, niacin or cholestyramine may be used; and may be also combined with each others in patients who are poorly responding to single statin therapy.1,3 Drug therapy should be individually prescribed and maintained in the long term, with regular medical follow-up always evaluating liver (TGO/TGP) and muscular (CPK) enzymes.1,2 Lipid profile screening is recommended in all individuals over 10 years of age and in all first degree relatives of individuals diagnosed as having FH.1 In the presence of risk factors, clinical signs of FH or atherosclerotic disease, the lipid profile should be considered from 02 years old on.1

In this report, we describe the case of a patient in the fourth decade of life with Familial Hypercholesterolemia, who was successfully treated with high-potency statin.

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Figure 1 – Xanthoma in the calcaneus.

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Hipercolesterolemia Familiar: diagnóstico e tratamento precoce


Case Report

Case Report

A 31-year-old female patient from Rio de Janeiro sought outpatient care in March/ 2015 at the General Hospital of Nova Iguaçu with a history of hypercholesterolemia since the age of 16, but had never taken any medication and only had a diet without laboratory improvement. She used to do regular high-intensity physical activity 05 times/week since the was 18 years old. Family history of hypercholesterolemia (Total Cholesterol > 290 mg/dL) in two first-degree relatives (mother and sibling). Maternal grandfather died of AMI before 50 years. Patient presented a February/2015 laboratory test with lipidogram results: CT: 385 mg/dL; HDLc: 86 mg/dL; LDLc: 252 mg/dL and Triglycerides: 92 mg/dL.

Physical examination at the first consultation: Abdominal Waist: 72 cm, Weight: 66 kg, Height: 1.68 m, BMI: 23 kg/m2, BP: 110/70 mmHg, HR: 68 bpm. Presence of tendinous xanthoma (Figure 1). Corneal arch absent. No changes in cardiovascular, respiratory and abdominal examination. Electrocardiogram performed at the 1st consultation without alterations. Laboratory tests were requested to assess dyslipidemia and imaging tests.

According to the criteria of Dutch MEDPED the patient has 13 points (Relative of 1st degree TC > 290 mg/dL - 2 points, tendinous xanthoma - 6 points, LDLc 252 mg/dL - 5 points), being considered as definitive diagnosis of FH.

Atorvastatin 20mg was started at the first visit, but the patient irregularly used it and returned to the doctor's office after three months with the results of laboratory and imaging tests: Carotid echocardiography and abdominal USG. These tests didn't show significant alterations. Atorvastatin was prescribed at 40 mg and reassessment scheduled for three months. Patient returned in September/15 with laboratory tests, showing a decrease of Total Cholesterol and LDLc levels (Figure 2) and unchanged hepatic and muscular enzymes (TGP 19U/L, TGO 23U/L, CPK 117U/L); and exercise test without alterations.

Lipidogram was requested to first-degree relatives with the following results: Mother - TC: 205 mg/dL and LDLc 125 mg/dL and Brother - TC: 193 mg/dL and LDLc 89 mg/dL; Both on statin therapy for more than two years. Brother has tendinous xanthoma. Genetic testing without possibility of accomplishment in public health service until the moment.

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01st exam 2nd exam 3rd exam

Figure 2 – Evolution of total cholesterol and LDLc values.

1. Santos RD, Gagliardi ACM, Xavier HZ, Casella Fo A, Araujo DB, et al; Sociedade Brasileira de Cardiologia. I Diretriz brasileira de hipercoleterolemia familar (HF). Arq Bras Cardiol.2012;99(2 Supl 2):1-28. Doi:org/10.5935/1bc.20140097.

2. Xavier HT, Izar MC, Faria Neto JR, Assad MH, Rocha VZ, Sposito C, et al. Sociedade Brasileira de Cardiologia. V Diretriz brasileira de dislipidemias e prevenção da aterosclerose. Arq Bras Cardiol. 2013;101(2 Supl 1):1-20. Doi: org/10.5935/abc.20135010.

3. Genest J, Libby P. Distúrbios das lipoproteínas e doença cardiovascular.

In: Libby P, Bonow RO, Mann E, Braunwald E. Tratado de doenças

cardiovasculares. Rio de Janeiro: Elsevier; 2013. p.995-1116.

4. Pereira C, Miname M, Makdisse M, Kalil Fo R, Santos RD. Associação

da doença arterial periférica e cardiovascular na hipercolesterolmia

familiar (HF). Arq Bras Cardiol. 2014;103(2): . doi: org/10.5935/

abc.20140097.

References

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Case Report

Discussion

The findings described in literature show that FH is a worldwide health problem, with a high risk of early cardiovascular diseases. Early identification of disease carriers contributes to the reduction of morbimortality, through appropriate guidelines and necessary therapeutic measures. The heterozygous form affects one in 500 individuals, corresponding in Brazil to 400,000 people with HF. The described patient was classified as a definitive diagnosis of FH by the Dutch MEDPED criterion, although this has not yet been validated for the Brazilian population. The reported case showed the good result with the use of high-potency statin and the importance of regular medical follow-up. It should be noted that the homozygous form is severe and affects children as early as the first decade of life, so early diagnosis can ensure that these children have the same life expectancy as the general population.


Acquisition of data: Menezes IRR, Cunha AFC. Analysis and interpretation of the data: Menezes IRR, Cunha AFC. Writing of the manuscript: Menezes IRR, Cunha AFC. Critical revision of the manuscript for intellectual content: Menezes IRR, Cunha AFC.



Sources of Funding


Study Association


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Case Report

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