the correlation between biomarkers of inflammation …
TRANSCRIPT
i
THE CORRELATION BETWEEN BIOMARKERS OF INFLAMMATION AND LEFT
VENTRICULAR FUNCTION IN PATIENTS WITH HYPERTENSIVE HEART FAILURE
SEEN IN OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX.
A DISSERTATION SUBMITTED TO THE NATIONAL POSTGRADUATE MEDICAL
COLLEGE OF NIGERIA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE AWARD OF THE FELLOWSHIP OF THE COLLEGE IN INTERNAL MEDICINE.
SUBSPECIALITY: CARDIOLOGY
CANDITATE’S NAME: DR AGOKE ADEKUNLE KAYODE
MB,BS(UNILORIN) 2006
CANDITATE’S NUMBER: AF/009/14/098/040
NOVEMBER 2017
ii
DECLARATION
I hereby declare that this work is original unless otherwise acknowledged, and that it has
neither been presented to any other College for Fellowship award nor has it been submitted
elsewhere for publication.
-------------------------
DR A.K. AGOKE
iii
CERTIFICATION
This is to certify that this work was carried out by Dr. A.K. AGOKE in the Cardiac Care Unit
of the Department of Medicine, Obafemi Awolowo University Teaching Hospitals Complex,
Ile-Ife under our Supervision.
-----------------------------------------------
Prof M. O. Balogun (FMCP, FWACP)
Consultant Cardiologist
OAUTHC, Ile-Ife
--------------------------------------------
Dr O.E. Ajayi (FMCP)
Consultant Cardiologist
OAUTHC, Ile-Ife
------------------------------------
Dr T.R. Folorunso (FMCP)
Consultant Cardiologist
FMC, Owo
iv
ATTESTATION BY THE HEAD OF DEPARTMENT
I hereby certify that this work was carried out in the Cardiac Care Unit of the Department of
Medicine, Obafemi Awolowo University Teaching Hospitals Complex by Dr A.K. Agoke
under the supervision of Prof M. O. Balogun, Dr O.E. Ajayi, and Dr T.R. Folorunso.
----------------------------
Prof A. Sanusi (FWACP)
Head of Department
v
DEDICATION
To God Almighty, the author and finisher of our faith who gave me grace and strength from
the conception to the completion of this work.
vi
ACKNOWLEDGEMENTS
I am immensely grateful to my supervisors, Prof M. O. Balogun, Dr O.E. Ajayi and Dr T.R.
Folorunso for their highly cherished mentorship and painstaking supervision throughout the
execution of this work.
My sincere gratitude also goes to my other teachers and consultants in the cardiology unit, Dr
A. O. Akintomide, Prof R.A. Adebayo and Dr S. A. Ogunyemi for their guidance and support
during the execution of the work.
I also appreciate my esteemed trainers and consultants in the Department of Internal Medicine,
Federal Medical Centre, Owo for their support and encouragement especially to Dr Olatunde
L.O., Dr Ojo O.A., Dr Sumonu T.A., Dr Adeniyi B.O. and Dr Mrs Ojo O.A. for their selfless
input and corrections during the editing of the manuscript. I sincerely appreciate Dr Ilesanmi
in the Department of Community Medicine, Federal Medical Centre, Owo and Mr Opele J.K.
in Obafemi Awolowo University (OAU) for their advice on statistical analysis. My
appreciation cannot be completed until the contributions of Dr Adedeji, Dr Sola Jeje, Dr Busuyi
Sogo and the registrars in Chemical Pathology Department, OAUTHC are fully acknowledged
for their immense assistance in the storage, processing and analysis of samples of each
participant of this study.
I sincerely thank other senior registrars in the cardiology unit, OAUTHc namely, Drs Amjo,
Bamgboje, Olanipekun, Adebiyi and Oke. as well as the registrars and house officers who
assisted me during my data collection. I cannot but appreciate the senior registrars in the
Department of Medicine, Federal Medical Centre, Owo namely, Drs Ajiboye, Junaid,
Odeyemi, Akitikori, Adegboye, Owolabi, Akinwalere, Momoh and Bamiduro as well as the
medical officers and house officers who provided support and encouragement in the course of
this study. Special thanks go to other staff of the Cardiology unit, OAUTHC including Mrs
vii
Adebayo, Mr Jide Joraiah, and Miss Akinsete to mention a few, for their assistance during the
data collection.
My sincere appreciation go to all volunteers who freely gave their consent to participate in this
study without any inducement whatsoever.
I immensely appreciate the management of OAUTHC, Ile-Ife and that of Federal Medical
Centre, Owo for providing the much needed conducive environment and support for a
worthwhile residency training program.
My profound gratitude and appreciation go to my parents, Mr and Mrs Agoke who ensured that
I got all the necessary support throughout my education and career, and to my dear siblings
(Femi, Bolanle, Adedayo, and Olayiwola) for their unending love and support.
Last but not the least, I cannot stop appreciating my lovely wife, Omolola and my wonderful
children, Nifemi, Iremide and Timilehin for their reassuring smile all through the thick and thin
periods of residency training, and for their overwhelming love, support, encouragement and
prayers.
viii
TABLE OF CONTENTS
CONTENT PAGE
Title page i
Declaration ii
Certification iii
Attestation iv
Dedication v
Acknowledgements vi
Table of Contents viii
List of Tables and Figures ix
List of Abbreviations xi
Abstract xiii
CHAPTER ONE: INTRODUCTION 1
CHAPTER TWO: LITERATURE REVIEW 6
CHAPTER THREE: METHODOLOGY 33
CHAPTER FOUR: RESULTS 48
CHAPTER FIVE: DISCUSSION 76
CHAPTER SIX: CONCLUSION, RECOMMENDATIONS, LIMITATION 85
REFERENCES 86
APPENDICES 101
ix
ABBREVIATIONS
ACE = Angiotensin-Converting Enzyme
ACS = Acute Coronary Syndrome
AF= Atrial Fibrillation
ARB = Angiotensin-Receptor Blocker
BMI = Body Mass Index
BNP = B-type Natriuretic Peptide
CABG = Coronary Artery Bypass Graft
CAD = Coronary Artery Disease
CHARM = Candesartan in Heart Failure-Assessment of Reduction in Mortality and
Morbidity
CPAP = Continuous Positive Airway Pressure
CRT = Cardiac Resynchronization Therapy
CT= Computerised Tomography
DCM = Dilated Cardiomyopathy
DIG= Digoxin Investigation Group
ECG = Electrocardiogram
ESC= European Society of Cardiology
EF = Ejection Fraction
HF = Heart Failure
HHF = Hypertensive Heart Failure
HFpEF = Heart Failure with Preserved Ejection Fraction
HFrEF = Heart Failure with Reduced Ejection Fraction
x
HRQOL = Health-Related Quality of Life
HsCRP =Highly Sensitive C-reactive Protein
ICD = Implantable Cardioverter-Defibrillator
LBBB = Left Bundle-Branch Block
LV = Left Ventricular
LVDP= Left Ventricular Diastolic Pressure
LVEF = Left Ventricular Ejection Fraction
MI = Myocardial Infarction
Mmol/L= Millimole per Litre
NSAIDs = Nonsteroidal Anti-Inflammatory Drugs
NT-proBNP = N-terminal pro-B-type Natriuretic Peptide
OAUTHC= Obafemi Awolowo University Teaching Hospitals Complex
NYHA = New York Heart Association
RCT = Randomised Controlled Trial
RAAS=Renin-Angiotensin-Aldosterone System
SCD = Sudden Cardiac Death
SOLVD= Studies on Left Ventricular Dysfunction
SUA= Serum Uric Acid
TDI= Tissue Doppler Imaging
VAD = Ventricular Assist Devices
xi
Table Title Pages
Table 1 Classification of blood pressure according to JNC VII 39
Table 2 Classification of ejection fraction 46
Table 3 Demographics characteristics of the study population 49
Table 4 Summary of the medical history and treatment offered to HHF
subjects
51
Table 5
Table 6
Biomarkers result of the study population.
Laboratory findings of the study population.
53
57
Table 7 Two-dimensional and M-mode echocardiographic parameters of the
study population..
59
Table 8 Left ventricular systolic function parameters of the study population. 60
Table 9 Classification of the left ventricular ejection fraction. 61
Table 10
Table 11
Doppler echocardiographic findings of the study population.
Left ventricular geometry of the study population.
63
64
Table 12 12-lead ECG pattern of the study population. 66
Table 13 Summary of the Doppler echocardiography assessment of the left
ventricular diastolic function of the study population.
67
Table 14 Relationship between the biomarkers and the NYHA functional
classifications in HHF subjects.
69
Table 15 Relationship between the biomarkers and the left ventricular ejection
fraction in the HHF subjects.
71
xii
Figures Titles Pages
Figure 4.1 Bar chart showing frequency distribution of patients and controls. 50
Figure 4.2 Pie diagram illustrating frequency of patients in each NYHA class. 52
Figure 4.3 Bar showing the Hs-C reactive protein levels of the study
population.
54
Figure 4.4 Bar showing the serum uric acid levels of the study population. 55
Figure 4.5 Scatterplot showing a positive relationship between Hs-CRP and
NYHA functional class of the HHF patients.
72
Figure 4.6 Scatterplot showing a positive relationship between uric acid and
the NYHA functional class of the HHF patients.
73
Figure 4.7 Scatterplot showing a negative relationship between Hs-CRP and
the ejection fraction of the HHF patients.
74
Figure 4.8 Scatterplot showing a negative relationship between uric acid and
the ejection fraction of the HHF patients.
75
xiii
ABSTRACT
BACKGROUND
Heart failure is a common clinical syndrome associated with increased disease burden that
contributes greatly to enormous health cost, increased hospitalisation and mortality rates in
both the developed and the developing world. Hypertension is a major cause of heart failure in
the developing world. Inflammation plays an essential role in the pathogenesis and progression
of heart failure. Several studies on various biomarkers in relation to heart failure are being
carried out in the developed countries. In the developing world studies are still evolving and
for this reason, High sensitive C-reactive proteins (Hs-CRP) and serum uric acid (SUA) are
therefore used to determine the correlation between inflammation and disease severity of
patients in hypertensive heart failure (HHF).
Objective
This study set out to determine mean Hs-CRP and SUA in hypertensive heart failure patients
and compare same in control subjects. It was also set out to determine the relationship of Hs-
CRP and serum uric acid with the severity of HHF patients using New York Heart Association
(NYHA) functional classification and echocardiography parameter of left ventricular systolic
function based on the left ventricular ejection fraction.
METHODOLGY
One hundred and ten patients with hypertensive heart failure and One hundred and ten healthy
control subjects were recruited consecutively into the study. Hypertensive heart failure patients
in NYHA class II to IV were recruited. Baseline measurement of the biomarkers (Hs-CRP and
SUA) and transthoracic echocardiography were carried out.
xiv
RESULTS
The mean age of the hypertensive heart failure patients was 58.05±10.75 vs 56.46±10.01 years
for the control group. The median levels of Hs-CRP and mean SUA were significantly higher
in the hypertensive heart failure patients compared to the controls (Hs-CRP, patients 5(8.5) vs
controls 0.8(0.6) Mg/L p<0.001) (SUA, patients 485.54±114.95 vs controls 232.43±95.19
mmol/l p<0.001). The Hs-CRP and SUA levels were significantly higher in men than women.
There is a significant correlation between the two biomarkers and the NYHA functional
classification of the HHF patients. Also there is a significant correlation between the Hs-CRP,
SUA and patients with heart failure with reduce ejection fraction (HFrEF).
CONCLUSION
Heart failure affects the younger age group in this study more than the western countries. Levels
of Hs-CRP and serum uric acid are elevated in patients with hypertensive heart failure. There
is a proportionate increase in the biomarkers as the NYHA functional classifications worsened
and a significant relationship of the biomarkers with the left ventricular ejection fraction of the
HHF patients.
xv
CHAPTER ONE
1.0 INTRODUCTION
1.1 Definition
Heart failure is defined as an abnormality of cardiac structure or function leading to
failure of the heart to deliver oxygen at a rate commensurate with the requirements of the
metabolizing tissues despite normal filling pressures or only at the expense of increased filling
pressures1. It is a serious clinical condition which represents terminal stage of a myriad of other
cardiac diseases. Heart failure contributes largely to a major clinical problem worldwide. Heart
failure can simply be divided into two different types, though there are many other
classifications:
Heart failure with reduced ejection fraction (HFrEF), also known as heart failure due
to left ventricular systolic dysfunction or systolic heart failure. This is when the heart
muscle contracts poorly and blood is not adequately pumped out to the body. HFrEF
occurs when the ejection fraction is less than 40%2.
Heart failure with mid-range ejection fraction (HFmrEF) represent left ventricular
ejection fraction in the range of 40-49%2.
Heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart
failure3.The left ventricular ejection fraction is 50% and above2,3,4. The heart muscle
contracts well but the ventricles do not relax as adequately during ventricular filling
1.2 Epidemiology
More than 20 million people have heart failure worldwide5. The prevalence and
incidence of HF are on the increase, largely because of growing life span by modern therapeutic
xvi
advancements, increase in the number of risk factors (hypertension, diabetes, dyslipidaemia,
and obesity) and improved survival rates from other cardiovascular disease like myocardial
infarction and valvular heart disease6.
Few epidemiologic data are available on the prevalence of heart failure in sub-Saharan
Africa. Recent data from the sub-Saharan African Survey of Heart Failure (THESUS-HF)
which was a multicentre study carried out in 12 university hospitals in 9 countries revealed a
prevalence of 3-7%7. In the study hypertension was the predominant cause of HF followed by
rheumatic heart disease and ischaemic heart disease.
In Nigeria studies from different geographical areas have shown hypertension as the
commonest underlying cause of HF. In a study by Obasohan and Ajuyah hypertension was the
commonest cause of heart failure in their series8. Adedoyin and Adesoye also revealed that, of
the 1004 cardiovascular disease patients seen between 1997 and 2001, those with heart failure
from hypertension were 35%9. In another study in southern Nigeria hypertension was revealed
as the commonest aetiological factor, responsible for 78.5% of cases of HF10. In the savannah
part of Nigeria, hypertension accounted for the commonest cause of heart failure11.
Furthermore, a study in Aminu Kano Teaching Hospital recorded hypertension as the
commonest aetiological factor accounting for 57% of cases12.
In developed countries, the mean age of patients with heart failure is 75 years old5. In
the United State of America only two to three percent of the population have heart failure, but
in those 70 to 80 year old, it occurs in 20% to30%5.A Nigerian study carried out in the southern
part revealed mean age was 56.6 ± 15.3 years. The study revealed men had a higher incidence
of heart failure, but the overall prevalence rate is similar in both sexes, as women survived
longer after the onset of heart failure13. Women tend to be older when diagnosed with heart
xvii
failure after menopause, they are more likely than men to have diastolic dysfunction, and seem
to experience a lower overall quality of life than men after diagnosis13.
1.3 Burden of heart failure
According to a report by World Health Organisation (WHO) cardiovascular diseases
account as the leading cause of death and disability worldwide14. In Africa cardiovascular
disease is recognised as a contributor of disease burden for many years14. Across various health
services in Africa, heart failure has been described as the fifth to sixth cause of hospital
admission15.A study in Abuja, Nigeria had shown HHF as a major cause of morbidity and
mortality among urban Nigerians16.
Heart failure contributes to a high burden of health expenditure, mainly because of the
cost of hospitalizations; which has been estimated to amount to 2% of the total budget of the
National health insurance in the United Kingdom, and more than $35 billion in the United
States17. People above the age of 65 years in HF have a higher frequency of hospitalisation18.
The need for hospitalization is an important indicator for poor prognosis especially
among people of the old age who are frequently re-admitted after hospitalisation19.CHARMS
trials, a study carried out among 7572 patients in chronic HF with reduced EF and preserved
EF showed the association of hospitalization and subsequent increase in mortality rates20.
Despite increase in mortality rates from frequent hospitalisations, intra-hospital mortality rate
has been on the decrease21. According to Framingham study, long-term mortality rates for
patients with HF have shown decline over the years21.
1.4 BIOMARKERS IN HEART FAILURE
Inflammation plays an essential role in the pathogenesis and progression of heart
failure. Thus, the interest in biomarkers of inflammation seemed to have dated back to decades
ago. The interest in the presence of inflammatory mediators in patients with heart failure began
xviii
in 1954 when a crude assay for C- reactive protein became available. There are several other
biomarkers which have since been discovered with their varying roles in HF, namely:
Interleukins (Interleukin-1, 6 and 18), TNF-α, biopyrrins, isoprostane, uric acid,
norepinephrine, BNP, NT proBNP, troponins, adrenomodullins and endothelins-1. Newer ones
of growing interest are chromogranin A, galectin-3, osteoprotogerin and adiponectin22.
C - reactive protein is a pentameric protein, whose gene in humans is encoded in
chromosome 1. Elevated levels of CRP have been observed in patients with heart failure23, and
activation of the immune response may play a role in heart failure through modifications in the
renin–angiotensin–aldosterone and sympathetic systems.
Increased levels of serum uric acid have been found to contribute to increased
cardiovascular risk in cardiac diseases such as hypertension, however the level varies with age
and sex24.There is increasing evidence that xanthine oxidase, which catalyzes the production
of two oxidants, hypoxanthine and xanthine, plays a pathologic role in heart failure. Ofori and
Odia in a study among hypertensive Nigerians reported a significant elevation in SUA and was
correlated with the severity of hypertension25.
1.5 JUSTIFICATION OF STUDY
Heart failure is a common clinical syndrome associated with increased disease burden
that contributes greatly to enormous health cost, increased hospitalisation and mortality rates
in both the developed and the developing world. In the developing world hypertension accounts
for the commonest aetiology.
Several studies have been done in the developed world on the use of various biomarkers
to relate with severity among patients with heart failure. However, only few researchers in this
part of the world have studied the relationship of biomarkers in heart failure patients. A Sub-
Saharan study in 21 health centres has identified the value of measurement of biomarkers to
xix
heart failure diagnosis, risk stratification especially at admission and discharge as well as in
prognosis26. This is the reason the study aimed to determine hs-CRP and serum uric acid as
biomarkers to correlate with the severity of hypertensive heart failure.
1.6 AIM
To assess the serum levels of high sensitive C - reactive protein and uric acid and
correlate them with the severity of hypertensive heart failure.
1.7 OBJECTIVES
1. To determine mean hs-CRP and serum uric acid in patients with hypertensive heart failure
and compare same in apparently healthy age and sex matched controls.
2. To determine the relationship of hs-CRP and serum uric acid with the severity of HHF using
the NYHA functional classification.
3. To assess the relationship of hs-CRP and serum uric acid with the severity of HHF using the
echocardiography parameter of left ventricular systolic function based on the ejection fraction.
CHAPTER TWO
2.0 LITERATURE REVIEW
xx
2.1INTRODUCTION
Heart failure is a common clinical syndrome representing the end-stage of a number of
various cardiac diseases. By definition, HF is a complex clinical syndrome that results from
any structural or functional impairment of ventricular filling or ejection of blood leading to
failure of the heart to deliver oxygen at a rate commensurate with the requirements of the
metabolizing tissues 1,27.
Although HF is not a heart disease itself, it is a heart condition with a high social and
economic impact. Hypertension has been noted as the commonest cause of heart failure from
studies carried out in Nigeria9,10,12.
Elevated blood pressure as defined by the Seventh Joint National Committee Report
(JNC7)28include:
Stage 1: Hypertension defined as; systolic blood pressure (SBP) of 140 –
159mmHg and/or diastolic blood pressure between 90-99mmHg.
Stage 2: Hypertension defined as; systolic blood pressure greater or equal to
160mmHg and/or diastolic blood pressure greater or equal to 100mmHg.
2.2 Classification of heart failure
HF is a complex syndrome, clinically characterized by signs and symptoms which are due to
abnormal cardiac function. The presentation may be classified as follow:
Systolic dysfunction or diastolic dysfunction
Heart failure with mid-range ejection fraction
Functional classification (New York Heart Association)
Stages of heart failure (American Heart Association/ American College of Cardiology)
xxi
Acute (New onset First presentation) or Chronic (in which patient may be persistently
stable, worsen, or decompensated)
Forward and backward HF
Right and left HF
High and low output HF
Preload and afterload
2.2.1 Systolic heart failure (HFrEF)
This refers to a weakened ability of the heart to contract in systole, and remains the
most common type of HF2. This reflects the prevalence of coronary heart disease (CHD) in the
Western world, although hypertension is still a significant contributor to systolic heart failure29.
HFrEF is when the LVEF is less than 40%2. Apart from the reduced LVEF, systolic HF (SHF)
is characterized as abnormality in systolic function, which manifest with cardiac chamber
dilation and mainly with left ventricular eccentric remodelling.
2.2.2 Diastolic HF (HFpEF))
It is characterised by a normal LVEF, normal LV end-diastolic volume, and abnormal
diastolic function, usually with concentric remodelling or hypertrophy30.It is also called “HF
with preserved EF” 2,3, 4, defined as HF with LVEF greater than 50%. It presents as impaired
diastolic filling of the left ventricle because of slow early relaxation or increased myocardial
stiffness resulting in higher filling pressures, with or without impaired systolic contraction. It
is commoner in the elderly.
2.2.3 Heart failure with mid-range ejection fraction (HFmrEF)
This is a newer classification of HF and this area is still very grey in the areas of research2. The
LVEF is in the range of 40-49%2.
xxii
2.2.4 Functional classification:
There are different scales used to assess functional status in HF, namely: New York Heart
Association which is commonly used. Also, there is the Medical Research Council scale.
New York Heart Association (NYHA) functional classification is based on symptoms and
exercise capacity. This classification has proven to be clinically useful and is employed
routinely in assessment of patients in the hospital31.
NYHA functional classification
CLASS I-No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, or dyspnoea.
CLASS II-Slight limitation of physical activity. Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnoea.
CLASS III-Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity results in fatigue, palpitation, or dyspnoea.
CLASS IV-Unable to carry on any physical activity without discomfort. Symptoms occur at
rest. If any physical activity is undertaken, discomfort is worsened.
2.2.5 STAGING OF HF
American College of Cardiology/American Heart Association working group introduced four
stages of heart failure31:
Stage A: Patients at high risk for developing HF in the future but no functional or structural
heart disorder.
Stage B: a structural heart disorder but no symptoms at any stage.
xxiii
Stage C: previous or current symptoms of heart failure in the context of an underlying
structural heart problem, but managed with medical treatment.
Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative
care.
2.3 Epidemiology of Hypertensive Heart Failure
Congestive cardiac failure is an important cardiovascular event with increasing
incidence and prevalence worldwide7.The prevalence worldwide of HF has been rising during
the last few decades, which could be attributed to several factors: an increase in the incidence
of cardiovascular diseases; an aging population; better and more effective treatment of heart
disease, leading to a reduction in mortality and HF occurring over a longer time frame7.
The statistics of HF all over the world is of great significance. There are more than 20
million people diagnosed and being managed for HF worldwide6.In the United States of
America, HF affects 5.8 million people, and each year 550,000 new cases are diagnosed32. The
overall prevalence of HF in United States of America and Europe is between 2% and 3%6. The
prevalence in African-Americans is reported to be 25 percent higher than in the whites. The
incidence in men is higher than the women. However, there is similarity in the prevalence of
both the males and females13.
Although, notable differences in prevalence have been observed between studies in
different countries, HF is a common and severe condition in Africa, and remains the
commonest complication of hypertension33.A multicentre study across 9 countries in sub-
Saharan African region in a THESUS-HF study recorded prevalence of 3 to 7% of HF among
cardiovascular diseases7. In Nigeria, HF constitutes a huge burden of cardiovascular disease34.
In a study in southwest Nigeria, heart failure from hypertension represented 35% of
cardiovascular diseases that presented over a five-year period10. A study in the South-South
xxiv
region of Nigeria in University of Port-Harcourt Teaching hospital reported heart failure as the
commonest presentation among other cardiovascular diseases between the period of 1999 and
200535. Hypertension was regarded as the commonest cause of the HF 35. The mean age of
patients seen over the study period was 54.4 years. The study concluded with the observation
that heart failure from hypertension was the commonest cardiovascular disease presentation in
the region. This compared favourably with findings obtained in other parts of the country35.
2.4 Burden of heart failure
The burden of the disease is notably enormous on the patients mainly because of the
affectation of the aging population, frequent admissions and huge economic cost. In the United
States of America, HF accounts for 20% of all admissions among patients older than 65
years36.In various health services in Africa, HF is responsible for between the fifth to sixth
cause of hospital admission14. Patients older than 65years account for the highest age group of
HF admission18.
There are few data obtained on HF in the developing countries. Dokainish et al in a
study from Africa, Asia, the Middle East and South America showed different variations in age
group and severity of HF in these regions37. The study showed that participants from Africa,
closely followed by those from Asia heart failure affectation were of younger age group and
presentation in the hospitals were mostly in NYHA IV compared with participants from Middle
East and South America. The participants in South America and the Middle East were older
and hospital presentations were mostly in NYHA I37.
The health cost expended on HF on hospitalisation is estimated to amount to about 2%
of the total budget of the National Health Insurance in the United Kingdom, and more than $35
billion in the United States15,16.
2.5 AETIOLOGY
xxv
In the developed world, coronary artery disease and diabetes mellitus have become
increasingly responsible for HF while hypertension and valvular heart disease have become
less common due to improvements in detection and therapy38.Among the low to middle income
countries only few data are available on the causes of HF. In Africa untreated rheumatic
valvular disease, peripartum and idiopathic cardiomyopathy, and hypertension were the
predominant causes identified39. A study at the National Cardiothoracic Centre, Accra, Ghana,
over a four-year period with 572 patients with HF revealed hypertension (21.3%), rheumatic
heart disease (20.1%) and cardiomyopathy (16.8%) as main causes40.This observation is
consistent with results obtained from various parts of Nigeria. Hypertension is regarded as the
most common cause of HF in Nigeria9. Studies from the southern, northern and eastern Nigeria
showed hypertension as the commonest cause of HF accounting for 78.5%, 57% and 56.3%
respectively, of cases seen10,12,35. This is also in keeping with reports from several other centres
in Nigeria3,11,16.
The prevalence of coronary artery disease and other degenerative disorders in
developing countries remains low, but the situation is rapidly changing. However, the reason
for the reported low prevalence of CAD in sub-Saharan Africa may be due to a lack of
diagnostic facilities which limit its study14,41. Among the elderly several causes have been
identified as to why they are susceptible to the development of HF. Coronary heart disease and
hypertension are known to increase in incidence with age. There are also both structural and
functional changes that occur within the heart and vascular systems which may predispose to
this condition42.
2.6 PATHOPHYSIOLOGY
Heart failure is described as a progressive disorder that occurs following an index event
that either damages the cardiac muscle, with a consequent destruction of the cardiac myocytes,
xxvi
or, alternatively, affects the ability of the myocardium to generate force, thereby making the
heart unable to contract adequately. Overall, the changes associated with heart failure result in
a decrease in cardiac output. This results from a decline in stroke volume that is due to systolic
dysfunction, diastolic dysfunction, or a combination of the two28,29.
The index event that predisposes to HF may have a sudden onset, such as myocardial
infarction; it may have a gradual onset, as in the case of hemodynamic pressure or volume
overload; or it may be hereditary, as seen in genetic cardiomyopathies. The peculiar final
outcome that follows regardless of the initiating event is impaired the ability of the heart to
pump effectively27.
After this initial decline in pumping capacity, a variety of compensatory mechanisms
are activated. These compensatory mechanisms involve both the local cardiac and systemic
involvement. In a transient period, these systems are able to restore and sustain the
cardiovascular function to a normal homeostatic range with the aim of maintaining an
asymptomatic state in an affected individual. However, with continued progression of the
disease the sustained activation of these systems become overwhelmed and can lead to
secondary end-organ damage within the ventricle, with worsening left ventricular remodelling
and subsequent cardiac decompensation.
Adaptive mechanisms43 deployed by the body systems to sustain cardiovascular
functions overtime fail and then increase workload of the heart with consequent changes on the
heart:
Reduced force of contraction. In a healthy heart, increased ventricular filling results in
increased force of contraction by the Frank–Starling law of the heart and thus a rise in
cardiac output. There is failure of this mechanism in HF.
Reduced stroke volume.
xxvii
Increased in sympathetic activity
Myocardial hypertrophy
Myocardial remodelling
In addition, inflammatory changes occur with progression of HF whereby numerous
inflammatory markers play their varying roles in the pathogenesis. The inflammatory
mediators include the BNP, NT pro-BNP, C-reactive proteins and others24.
2.7 Clinical presentation
There are various algorithms for the diagnosis of heart failure, namely as follows:
Framingham Heart Study.
European Society of Cardiology (ESC)
For the purpose of this study clinical presentation of the patients will be interpreted
using the Framingham criteria.
Framingham criteria
Major criteria44 include the following:
Cardiomegaly on chest radiography
S3 gallop (a third heart sound)
Acute pulmonary oedema
Paroxysmal nocturnal dyspnoea
xxviii
Crackles on lung auscultation
Central venous pressure of more than 16 cm water at the right atrium
Jugular vein distension
Positive abdominojugular test
Weight loss of more than 4.5 kg in 5 days in response to treatment.
Minor criteria44 include the following:
Tachycardia of more than 120 beats per minute
Nocturnal cough
Dyspnoea on ordinary exertion
Pleural effusion
Decrease in vital capacity by one third from maximum recorded
Hepatomegaly
Bilateral ankle oedema
By the Framingham criteria, diagnosis of HF requires the presence of at least two major
criteria or one major criterion in conjunction with two minor criteria. The Framingham Heart
Study criteria are 100% sensitive and 78% specific for identifying persons with definite
congestive heart failure6.
2.8 Precipitating factors
Factors that may precipitate acute decompensation in patients with chronic heart failure
must be considered and include:
1. Dietary indiscretion-Excessive sodium and fluid intake may precipitate acute HF.
2. Myocardial ischemia/infarction
xxix
3. Arrhythmias (tachycardia or bradycardia)
4. Discontinuation/non-compliance with HF therapy
5. Infection (such as, pneumonia, viral illnesses)
6. Anaemia
7. Drugs
Calcium antagonists (verapamil, diltiazem)
Beta blockers
Non-steroidal anti-inflammatory drugs
Antiarrhythmic agents [all class I agents, sotalol (class III)]
8. Alcohol consumption
9. Pregnancy
10. Worsening hypertension.
11. Acute valvular insufficiency
12. Endocrine abnormalities (such as, diabetes mellitus, hyperthyroidism, hypothyroidism)
13. Pulmonary embolism
2.9 Investigative modalities
Investigation is imperative in any patient with suspected HF
The purpose of investigating CHF is to:
Confirm the clinical diagnosis
Determine the mechanism (LV systolic dysfunction, LV diastolic dysfunction, valvular
heart disease)
xxx
Identify a cause (CHD, hypertension)
Identify exacerbating and precipitating factors (arrhythmias, ischaemia, anaemia,
pulmonary embolism, infection)
Guide therapy
Determine prognosis.
2.9.1 Electrocardiogram
The electrocardiogram in HF is seldom normal, but abnormalities are frequently non-
specific. The most common are non- specific repolarisation abnormalities (ST–T wave
changes). A completely normal ECG makes a diagnosis of HF due to LV systolic dysfunction
unlikely45. However, it does not exclude other causes of CHF.
Conduction abnormalities may be seen, including:
Left bundle branch block
First-degree atrioventricular block
Left anterior hemiblock
Non-specific intraventricular conduction delays.
Other abnormal findings include:
LV hypertrophy
Evidence of pathological Q wave that denotes prior MI in patients with CHD
Sinus tachycardia (due to increased sympathetic activity)
Arrhythmia - Atrial fibrillation.
2.9.2 Chest x-ray
xxxi
A chest X-ray is important in making a diagnosis of CHF. Findings suggestive of HF
include cardiomegaly, cephalization of the pulmonary vessels, Kerley B-lines, bat wing
appearance and pleural effusions. The cardiac size and silhouette may also reveal features of
valvular disease (mitral stenosis or aortic stenosis).
2.9.3 Echocardiography
Transthoracic echocardiography (TTE) is a non-invasive imaging modality widely
available, rapidly performed, and safe which provide quantitative and qualitative evaluation of
cardiac anatomy (volumes, geometry46, and mass), wall motion, and valvular function.
Echocardiography is commonly used to assess the LV systolic and diastolic functions.
Measurement will be derived using the formulas proposed by the American Society of
Echocardiography.
Linear Measurements
Linear internal measurements of the LV and its walls by recommendation, is usually
performed in the parasternal long-axis view. Internal dimensions can be achieved with a two
dimensional (2D) echocardiography (2DE)–guided M-mode approach or directly from 2D
echocardiographic images.
Volumetric Measurements
LV volumes are measured using 2DE or 3DE. Volumetric measurements are usually based on
tracings of the interface between the compacted myocardium and the LV cavity from the apical
four- and two-chamber views.
Global LV function is commonly assessed by calculating the difference between the
end-diastolic and end-systolic value on M-mode, 2D, or 3D parameter divided by its end-
diastolic value. The end diastole is defined as the first frame after mitral valve closure or the
xxxii
frame in the cardiac cycle in which the respective LV dimension or volume measurement is
the largest. End systole is best defined as the frame after aortic valve closure or the frame in
which the cardiac dimension or volume is smallest.
LV systolic function
Ejection fraction (EF)
The EF is the volumetric decrease of the LV that occurs in diastole to systole. It
represents stroke volume as a percentage of end-diastolic volume. It can be estimated using the
Teichholz method47 and the modified Simpson’s rule. Teichholz method describes the left
ventricle as a simple ellipsoid with both orthogonal axes being equal. Modified Simpson’s rule
is based on summation of the smaller volumes in order to obtain the overall left ventricular
volume.
EF is calculated from end diastolic volume (EDV) and end systolic volume (ESV)
estimates, using the following formula:
Left Ventricular Ejection Fraction: (LVEDV-LVESV /LVEDV) x 100%
LV volume estimates may be derived from 2DE or 3DE. Reference for normal is >50%2.
Fractional shortening
Fractional shortening measures the percentage of the LV diameter change between
diastole to systole. Fractional shortening can be derived from 2D-guided M-mode imaging or
from linear measurements obtained from 2D images.
Left Ventricular Fractional Shortening: (LVIDd - LVIDs/LVIDd) X 100%
xxxiii
A study on HHF in Southern Nigeria showed majority of the patients presented with
LVEF <40%and FS <20%9. The predominance of those with depressed LV systolic function
was comparable to studies in other centres in Nigeria3,12,16.
Left ventricular diastolic function
Left ventricular diastolic function is evaluated by studying the filling dynamics of the
left ventricle. The mitral inflow velocities were determined from the apical four chamber view
with pulsed-wave Doppler and with the sample volume positioned at the tip of the mitral valve
leaflets. This inflow characteristics can be assessed by measuring the transmitral "E" wave
velocity (peak early mitral inflow velocity) and the "A" wave velocity (peak late atrial mitral
inflow velocity), the E/A ratio and the deceleration time (DT):(time interval of Peak E wave
velocity to its extrapolation to the baseline)48.
2.9.4Other important investigations that can be done include: Transoesophageal
echocardiography, stress echocardiography, cardiac magnetic resonance imaging, coronary
angiography, exercise testing and endomyocardial biopsy.
2.9.5 Blood tests
A complete blood count which may suggest concurrent or alternate conditions. Anaemia or
infection can exacerbate pre-existing HF.
Serum electrolytes, blood urea nitrogen, and creatinine may indicate associated conditions.
Renal impairment may be caused by and/or contribute to HF exacerbation.
Other Blood investigations that will be essential in HF are liver function test, fasting blood
glucose, fasting lipid profile and thyroid function test.
2.9.6 Biomarkers of heart failure
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There are several biomarkers of HF which are helpful in diagnosis and prognosticating.
These biomarkers play important roles in the progression of HF and include: Interleukins
(Interleukin-1, 6 and 18), TNF-α, biopyrrins, isoprostane, uric acid, norepinephrine, BNP,
troponins, adrenomodullins and endothelins-1. The role of BNP and NT-proBNP have also
largely been studied and are related to increased cardiovascular risk, mainly HF. BNP and NT-
pro BNP - Brain natriuretic peptide (BNP) is a natriuretic hormone released primarily from the
heart, particularly the ventricles. The active BNP hormone is cleaved from the C-terminal end
of its prohormone, pro-BNP. The N-terminal fragment (NT-proBNP) is also released into the
circulation49.Newer biomarkers of growing interest include: chromogranin A, galectin-3,
osteoprotogerin and adiponectin23.
Several studies on biomarkers in cardiovascular diseases have been carried out in the
developed countries24,25. More studies on biomarkers are now emerging in the developing
world. Few studies in Nigeria have worked on relationship of biomarkers, particularly Hs-
CRP and SUA and cardiovascular diseases 24,25. The studies have related the elevation of the
biomarkers to increased disease severity in patients with HF and these are greatly related to the
effect of inflammation24,25.
Role of Hs-CRP in heart failure
C - reactive protein is a pentameric protein comprised of 5 identical units whose gene
in humans is encoded in chromosome 1. Inflammation plays a role in the initiation and
progression of HF through atherosclerosis. CRP is a product of inflammation whose synthesis
by the liver is stimulated by cytokines in response to an inflammatory stimulus. CRP activates
xxxv
the classic complement pathway and participates in the opsonisation of ligands for
phagocytosis.
Elevated levels of CRP have been observed in patients with heart failure24 and the
increase is connected to Interleukin-6. Interleukin 6 is a determinant of the hepatic production
of CRP, and is produced in monocytes/macrophages, endothelial cells, vascular smooth muscle
cells, fibroblasts, and cardiac myocytes under hypoxic stress in response to a wide range of
acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections;
rheumatic and other inflammatory diseases, malignancy, and tissue injury and necrosis50. Left
ventricular dysfunction, liver or kidney damage caused by low cardiac output, hypoperfusion,
hypoxia, and venous congestion may all be sources of increased interleukin-6 and hence CRP
production50.
Several methods are used to measure CRP and these include ELISA,
immunoturbidimetry, rapid immunodiffusion, and visual agglutination. A high-sensitivity CRP
(Hs-CRP) test measures low levels of CRP using laser nephelometry.
Hs-CRP levels and risk of cardiovascular disease
High level of Hs-CRP has been related with increased risk of cardiovascular diseases51.
The cardiovascular diseases include hypertension, myocardial infarction, heart failure and
stroke. In a Framingham Heart study, the risk of heart failure was significantly elevated among
participants with CRP serum levels of ≥5 mg/L, even after adjustment for prevalent
cardiovascular disease and occurrence of myocardial infarction during follow-up were
considered51.Baba and colleagues in a study carried out in Obafemi Awolowo Teaching
Hospitals reported higher CRP levels among apparently healthy adult individuals who were at
increased risk of cardiovascular diseases52. CRP levels were elevated more in the females than
in the males. The increase was attributed to the gender difference of the body weight which
xxxvi
was higher in the females than in the males52. Another study in hypertensive patients reported
that elevated CRP levels were seen even among the normotensive subjects and were found to
correlate to increased risk of developing cardiovascular disease53.
Relationship between Hs-CRP and severity of heart failure
Hs-CRP have been used in several studies to relate with severity in patients with CCF51,
52. Clinical indexes that have been studied to determine severity had included relating the levels
of the elevated Hs-CRP with patient’s clinical and investigative parameters. The clinical
parameters had evaluated the functional class of the patients based on NYHA functional
classifications. Several investigative modalities had included 12 lead electrocardiography and
echocardiography. Some studies have evaluated roles of the biomarkers in predicting clinical
course, re-admission and mortality among CCF patients54, 55. Alonso-Martinez and colleagues
in a study reported a significant relationship between elevated Hs-CRP levels and NYHA
functional class III and IV. There was also significant relationship in HF patients with left
ventricular ejection fraction less than 35%. The limitation of the study was with the use of CRP
which had lesser sensitivity to identify cardiovascular diseases compared to Hs-CRP55.
Role of serum uric acid in heart failure
Patients with chronic heart failure exhibit elevations in serum uric acid56.UA is a
metabolic by-product of purine metabolism. Serum UA may increase in the failing heart
because of increased generation, decreased excretion, or a combination of the 2 factors. There
are several possible contributors to increased UA production in HF, including increased
abundance and activity of xanthine oxidase, increased conversion of xanthine dehydrogenase
to xanthine oxidase or increased xanthine oxidase substrate resulting from enhanced ATP
xxxvii
breakdown to adenosine and hypoxanthine. Xanthine oxidase is also known as one of the main
sources of free radicals and may contribute to oxidative damage in the myocardium55. A
chronic increase in myocardial oxidative stress is capable of causing subcellular abnormalities,
and may lead to cardiomyopathic changes, depressed contractile function and failure. Thus, an
elevated serum level of UA may relate to cardiac dysfunction and progression of heart failure
through oxidative stress by increased xanthine oxidase activity in patients with CHF56. The
roles of increased xanthine oxidase activity in inflammatory response are the focus of studies
in patients with chronic heart failure57,58.
SUA and risk of cardiovascular diseases
Several research works are emerging in recent years to study the contribution of UA in
cardiovascular diseases24, 25. Increased levels of UA have been found to contribute to increased
cardiovascular risk in cardiac diseases such as hypertension and heart failure24. Ofori and Odia
reported the significant contribution of elevated UA to the development of cardiovascular risk
in Nigerians with hypertension 25. In patients with heart failure SUA was shown to be elevated
and was strongly related to one of the circulating markers of inflammation which contribute to
increased cardiovascular risk57.
Relationship between SUA and severity of heart failure
Several research works have studied the relationship between SUA level and disease
severity in patients with HF using clinical and echocardiography parameters57,58. The clinical
parameters studied included the functional state of patients using the NYHA functional
classifications and echocardiography parameters of left ventricular systolic function. These
parameters have studied the contribution of SUA to prognostic outcome. In a study elevated
uric acid levels in patients with systolic heart failure was associated with impaired clinical and
xxxviii
hemodynamic profile. The study concluded that SUA levels might be used as a non-invasive
indicator of elevated left ventricular filling pressures57.In addition a study revealed that there
was a significant relationship between elevated SUA levels and HF patients with left
ventricular ejection fraction less than 40%. The study concluded that there was a negative
correlation between elevated SUA and HFrEF57.Also, some studies have shown significant
relationship between increased SUA levels and NYHA functional classifications of HF
patients57,58. These studies reported that the levels of SUA were increasing as the NYHA
functional class of the HF patients worsened from class I to class IV57,58.
2.10Treatment
Treatment focuses on improving the symptoms and preventing the progression of the
disease. Reversible causes and precipitants of heart failure also need to be addressed (for
example infection, alcohol ingestion, anaemia, thyrotoxicosis, arrhythmia, and
hypertension).There is a range of effective strategies available to support people with HF to
improve and prolong their lives and achieve a good quality of life.
These include:
1. Non-pharmacological interventions and management of co-morbidities
2. Pharmacotherapy
3. Surgical procedures and supportive devices (for example, coronary artery bypass graft
surgery and ICDs)
4. Post-discharge management programs (for example, home- based interventions).
2.10.1 Non-pharmacological management
1. Physical activity
2. Diet
xxxix
The adverse effect of being overweight or obese put increased demands upon the heart during
physical activity. Weight loss may improve physical activity tolerance and quality of life.
(I) Saturated fat
Saturated fat intake in all patients should be limited, especially in those who suffer from HF59.
(II) Fibre
Due to relative gastrointestinal hypoperfusion, constipation is common and a high-fibre diet is
recommended59.
(III) Undernutrition
Malnutrition, cardiac cachexia60 and anaemia are common problems that contribute to
debilitating weakness and fatigue. They are also associated with a much poorer prognosis.
(IV) Sodium
Reduced dietary sodium intake can result in beneficial clinical effects. For patients with
symptoms in HF (NYHA Class III/IV) requiring a diuretic regimen, a restricted intake of 2 g
per day should be applied.
(V) Caffeine
Excessive consumption of caffeine may exacerbate arrhythmia, increase heart rate and increase
blood pressure. The consumption should be reduced.
3. Alcohol
Alcohol is a direct myocardial toxin and may impair cardiac contractility59. It should be reduced
remarkably.
4. Smoking
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Cigarette smoking or chewing of tobacco is hazardous to health and must be stopped. Smoking
is atherogenic, reduces the oxygen content of blood, provokes vasoconstriction, impairs
endothelial functions and is arrhythmogenic.
5. Vaccination
Immunization with influenza and pneumococcal vaccines to prevent respiratory infections
should be given to patients especially the elderly.
2.10.2Pharmacological therapy
A systematic and expeditious approach to management of HF is required because many
patients will present in an acute state
Medical therapy for heart failure focuses on the following goals:
Preload reduction
Afterload reduction
Inhibition of deleterious neurohormonal activation
Improving myocardial contractility
Pharmacotherapeutic approach in management of chronic heart failure include the following:
(I) Diuretics
Diuretics remain an important part of standard therapy for acute heart failure. Examples are
furosemide, bumetanide, torsemide. Chronic diuretic therapy has not been shown to improve
survival. Diuretics are effective in preload reduction by increasing urinary sodium excretion
and decreasing fluid retention, with improvement in cardiac function, symptoms, and exercise
tolerance61.
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(II) Vasodilators
Vasodilators (for example, nitroprusside, nitroglycerin, or nesiritide) may be considered as an
addition to diuretics for patients with acute heart failure for relief of symptoms. Vasodilators
will decrease preload and/or afterload.
Sodium nitroprusside is a potent, primarily arterial, vasodilator resulting in a very efficient
afterload reduction and decrease of intracardiac filling pressures.
Nesiritide (human brain natriuretic peptide analogue) is a vasodilator and works by reducing
pulmonary capillary wedge pressure (PCWP), right atrial pressure, and systemic vascular
resistance but has no effect on heart contractility.
(III) ACEIs
ACE inhibitors have been proven useful in the treatment of symptomatic and asymptomatic
patients with a depressed EF (<40%)62. ACE inhibitors interfere with the renin-angiotensin
system by inhibiting the enzyme that is responsible for the conversion of angiotensin I to
angiotensin II.
ACEIs have been shown to:
Prolong survival in patients with NYHA Class II, III and IV symptoms62.
Improve symptom status, physical activity tolerance and reduce need for hospitalisation
in patients with worsening CHF62.
Increase ejection fraction.
(IV) Angiotensin II receptor antagonists
An overview of studies comparing the use of ACEIs and angiotensin II receptor antagonists in
heart failure shows similar outcomes63.
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(V) Aldosterone antagonists
Aldosterone receptors within the heart can mediate fibrosis, hypertrophy and
arrhythmogenesis. A study carried out on spironolactone revealed it causes reduction in
mortality and symptomatic improvement in patients with advanced CHF64.
(VI) Digoxin
The cardiac glycoside, digoxin, inhibits sodium–potassium ATPase. Digoxin has shown
improved inotropic effect especially in systolic HF65. Digoxin may also sensitise
cardiopulmonary baroreceptors, reduce central sympathetic outflow, increase vagal activity
and reduce renin secretion65. Digoxin can lead to a small increase in cardiac output,
improvement in heart failure symptoms, and decreased rate of heart failure hospitalizations65.
(VII) Beta-blockers
Beta-blockers inhibit the adverse effects of chronic activation of neurohormonal system acting
on the myocardium. Three beta-blockers—carvedilol (beta-1, beta-2 and alpha-1 antagonist),
bisoprolol (beta-1 selective antagonist) and metoprolol (beta-1 selective antagonist) provide
survival benefits in patients with HF by both causing reductions in sudden death, as well as
death due to progressive pump failure. Beta blockers can lessen the symptoms of HF, improve
the clinical status of patients and reduce hospital stay66.
(VIII) Positive inotropic agents
Inotropic therapy aims to improve pump function by acutely increasing contractility. Inotropic
drugs are generally indicated for acute, transient support of a patient with myocardial
dysfunction, reduced stroke volume, cardiac output, blood pressure and peripheral perfusion
with increased ventricular filling pressure. Dobutamine is generally used as a positive inotropic
drug with vasodilator activity, while dopamine is used as a vasopressor with positive inotropic
xliii
effects when given in medium to high doses67.Milrinone is less frequently used in CHF because
of concerns about arrhythmogenesis.
2.10.3 Emerging anti-HF regimens
1. Angiotensin receptor neprilysin inhibitor (ARNI)LCZ696 (Sacubitril/Valsartan) in HFrEF
and HFpEF. Study has shown beneficial effect of LCZ696 when compared with enalapril68.
2. Finerenone in HFrEF is a non-steroidal mineralocorticoid receptor antagonist (MRA). In
heart failure patients with diabetes and/or chronic kidney disease, finerenone was no more
effective than the currently approved MRA eplerenone in reducing the severity of heart
failure69.
3. Ferric carboxymaltose in iron-deficient HFrEF. The benefits of iron therapy in symptomatic,
iron-deficient HF patients includes over a 1-year period sustained improvement in functional
capacity, symptoms, and quality of life. It may also be associated with risk reduction of
hospitalization for worsening HF70.
4. Serelaxin in acute HF, recombinant human relaxin-2, is a vasoactive peptide hormone with
many biological and haemodynamic effects. In the RELAX-AHF trial, serelaxin was associated
with relief of dyspnoea, but had no effect on readmission rate to hospital71
2.10.4 Management of refractory heart failure
Ultrafiltration
Uses of devices
Types of devices proven safe in the effective treatment of systolic heart failure are as follow:
Atrial-synchronised biventricular pacing (also called cardiac resynchronisation
therapy);
xliv
Implantable cardioverter defibrillators;
In highly selected patients, left-ventricular assist devices
2.10.5 Surgical intervention
Various cardiac surgical interventions are being exploited to manage patients who are in
refractory CHF.
Cardiac transplantation
Coronary revascularisation (CABG)
Valve repair or replacement
Surgical ventricular reconstruction or restoration
2.11Co-morbidities
Diabetes mellitus
The likelihood of developing HF in patients without structural heart disease is further increased
in the presence of diabetes mellitus72 and may impact adversely on the outcomes of patients
with established HF.
Sleep apnoea
Two types are commonly seen in patients with HF. Obstructive sleep apnoea and central sleep
apnoea. Obstructive sleep apnoea occurs due to upper airway collapse and is likely to aggravate
but not necessarily cause CHF73. Obstructive sleep apnoea impacts adversely on the heart in
that it has been shown to cause a reduced LVEF, lower LV filling rates, and a higher incidence
of CHF74.
Anaemia
xlv
CHF may be associated with a normocytic normochromic anaemia. It is important to exclude
other causes of anaemia such as chronic renal impairment, toxic effects of pro-inflammatory
cytokines, haemodilution and the use of drugs like ACEIs that tend to lower haemoglobin
levels75.
Chronic renal failure
The assessment of renal dysfunction and or renovascular disease should be considered in all
patients with CHF who are elderly, have a history of hypertension or diabetes mellitus. The
presence of renal impairment is associated with a worse prognosis in patients with HF76.Renal
diseases often cause excessive salt and water retention in which patients will require higher
doses of loop diuretics.
Arthritis
Patients with severe systolic dysfunction and/or hyponatraemia should not be treated with large
doses of both selective and nonselective cyclooxygenase inhibitors for arthritis, as they will
increase the risk of worsening CHF77.
2.12 Prognostic factors
Determination of prognosis in HF is complex and patient survival is influenced by many
factors. Some include aetiology, age, co-morbidities and inter-individual variation in
progression.
DEMOGRAPHY
xlvi
Effect of Age-Studies have shown patients who are aged 65 years to 74 years and or greater
than 75 years had an independent increase in one-year mortality compared to patients aged 25
years to 49 years78.
Effect of gender-The prognosis has generally been better in women than men with HF12.Data
collated from the Framingham Heart Study suggest that the median survival time after
diagnosis was better in women than men79.
Effect of race-The effect of race on the prognosis of HF is unclear with different studies
revealing contrasting findings:
Higher mortality in blacks was noted in a post hoc analysis from the SOLVD trial of enalapril
in patients with asymptomatic LV dysfunction or overt HF80.
CHAPTER THREE
3.0 METHODOLOGY
3.1 Study Location
The study was conducted in the Cardiology Units of Department of Medicine, Obafemi
Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun state. Ile-Ife is an ancient
Yoruba city in Osun State, South-Western Nigeria. The town lies at the intersection of roads
from Ibadan, Ilesha, and Ondo. It is located at latitude 7˚ 28N and longitude 4˚ 34E.
Obafemi Awolowo University Teaching Hospitals Complex (OAUTHC), a 1600
bedded complex, is one of the first generation of teaching hospitals established by the Federal
xlvii
government in 1972 to provide qualitative health care delivery to her people. The hospital serves
patients from Osun, Ekiti, Ondo and Oyo states.
3.2 Study Population
The study population was made up of patients who were of the age 18 years and above with
hypertensive heart failure diagnosed by the Framingham criteria42, who presented at the
Cardiology Unit of Department of Medicine and Adult Accident/Emergency (A/E) unit of
OAUTHC who satisfied the inclusion criteria. Equal number of age and sex matched healthy
controls were also recruited.
3.3 Study design
It was a descriptive cross sectional study. /
3.4 Study period
This study was conducted between October 2016 and March 2017.
3.5 Sample Size
Fisher’s Statistical formula was used for accurate sample size determination81 using a HF
prevalence of 7%8:
N = (Z2) X P ( 1-P )/ d2
N =Minimum sample size
Z = Significant level of effort tolerable for this study at 0.05 confidence level of 95%
Z = 1.96 (from Z table)
P = Best estimation of prevalence
d = Absolute precision of 5%
xlviii
Prevalence rate of 7% for heart failure8
Where P = 0.07, Z = 1.96, d = 5
(1.96)2 X 0.07 (1.0 – 0.07)
(0.05)2
3.8416 X 0.07 X 0.93
0.05 X 0.05
N = 99 subjects.
Adjustment for loss to follow up assuming an estimate of 10% using the formula below,
Adjustment factor for X% loss = 100/(100-x).
Where x=10.
Therefore, the total sample size X adjustment factor is
= 100x100/89
= 112.3.
At the end of the study, a net total of 110 hypertensive heart failure patients and 110apparently
healthy age and sex matched control subjects without HHF were evaluated having excluded
patients and controls with incomplete data and those lost to follow up
3.5 Sampling methods
A non-probability sampling method by consecutive recruitment of volunteers until the desired
sample size was reached was employed. Certain inclusion and exclusion criteria were used as
a guide in selection.
xlix
3.6 Ethical Consideration and consent
1) Approval of the Ethics and Research Committee of the OAUTHC was sought and obtained
before the commencement of the study (APPENDIX II).
2) Informed consent of the individuals for the study were obtained verbally and in written
form (APPENDIX III).
3.7 Inclusion criteria for patients
1. Patients who gave an informed consent.
2. All male and female individuals with heart failure secondary to hypertension who are 18
years and above and were managed within the hospital were recruited into the study.
3.8 Exclusion criteria for patients
Patients with the following:
1. Unwillingness to participate in the study
2. Infection, specifically presence of fever, productive cough, diarrhoea and urinary
symptoms
3. Pregnancy, use of steroids, immunosuppressive drugs and oral contraceptive pills
because these conditions affect the level of hs-CRP.
4. Malignancy.
5. Use of hypouricaemic medications such as Non-steroidal anti-inflammatory agents,
uricosuric drugs like allopurinol.
6. Clinical evidence of gout.
7. Chronic kidney disease
l
3.9 Inclusion criteria for controls
1. Adults aged 18 years and above without hypertensive heart failure were recruited from
among members of the hospital community and patient’s relations.
2. Healthy adults free of any illness within the previous three weeks.
3.10Exclusion criteria for controls
Apparently healthy controls with the following:
1. Unwillingness to participate in the study
2. Individuals who are hypertensive
3. Infection, specifically presence of fever, productive cough, diarrhoea and urinary
symptoms
4. Pregnancy, use of steroids, immunosuppressive drugs and oral contraceptive pills
because these conditions affect the level of hs-CRP.
5. Malignancy.
6. Use of hypouricaemic medications such as Non-steroidal anti-inflammatory agents,
uricosuric drugs like allopurinol.
7. Clinical evidence of gout.
8. Chronic kidney disease.
3.11 Materials, Equipment and Reagents
Materials
Sample bottles – plain, lithium heparinised, ethylene diamine tetraacetic acid
Needles
Syringes (5ml, 10ml)
Disposable gloves
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Methylated spirit
Cotton wool
Equipment:
The equipment used for the study include:
- Littmann stethoscope
- Sphygmomanometer (Accuson) with blood pressure cuff 12X15cm
- Chest radiography machine
- 12 lead Electrocardiography (SCHILLER ECG machine)
- Transthoracic echocardiography GE medical system VIVID 7 dimension.
REAGENTS
- Enzyme immunoassay test kits for Hs-CRP and serum uric acid.
3.12 Data collection method
Protocol 1: History and examination
Data was obtained using a proforma (APPENDIX IV) that included demographic data, relevant
history and physical examination after an informed consent was given (APPENDIX III).
Clinical evaluation for diagnosis of HF was performed by the investigator. The following
information was obtained from each of the subjects; age, sex, residential address, telephone
numbers.
The patients were clerked and physically examined in detail by the investigator. Clinical
diagnosis of HF was based on the Framingham’s criteria of the concurrent presence of
two major or one major with two minor criteria44.
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The height was measured to the nearest 0.01 metre using a stadiometer. The weights of
the subjects were measured with light clothing on, using a secca scale to the nearest
0.5kgand the BMI calculated by the investigator using the formula: weight
(Kg)/[height(m)]2 . Classification of the weights was defined using the WHO criteria83.
The Pulse was determined at rest by palpating the radial artery with the tip of the fingers
compressing the vessel against the head of the radius, the forearm slightly pronated and
the wrist slightly flexed and counting the pulse for one minute. The rhythm and volume
of the pulse were also noted.
Protocol 2: Blood pressure and anthropometric measurements.
Blood pressure measurement
The blood pressure was measured sitting and standing with a Mercury column
sphygmomanometer after patients and controls were allowed to rest for an average of 5
minutes. Korotkoff phase 1 and 5 were used for systolic and diastolic blood pressure
respectively. Three consecutive measurements were taken at 5 minutes intervals and the
average values were recorded. Hypertension was defined as systolic BP ≥140mmHg and/or
diastolic BP ≥90mmHg or the current use of anti-hypertensive medications82.
The observed readings were classified according to 7th Report of the Joint National Committee
on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VII)28.
Table 1: Classification of blood pressure according to JNC VII
BP CLASSIFICATION SYSTOLIC BP( mmHg) DIASTOLIC BP (mmHg)
Normal < 120 and < 80
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Prehypertension 120-139 and/or 80-89
Stage 1 Hypertension 140-159 and/or 90-99
Stage 2 Hypertension > or = 160 and/or > or = 100
Protocol 3: Functional Classification and Follow-Up
The functional class of every participant was assessed clinically using the New York Heart
Association Classification31.
NYHA functional classification
CLASS I-No limitation of physical activity. Ordinary physical activity does not cause undue
fatigue, palpitation, or dyspnoea.
CLASS II-Slight limitation of physical activity. Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or dyspnoea.
CLASS III-Marked limitation of physical activity. Comfortable at rest, but less than ordinary
activity results in fatigue, palpitation, or dyspnoea.
CLASS IV-Unable to carry on any physical activity without discomfort. Symptoms at rest. If
any physical activity is undertaken, discomfort is increased.
Patients with NYHA classification II to IV were recruited into the study.
Protocol 4: Biomarkers and other test
Each participant had the following tests done: Hs-CRP and serum uric acid.
Biomarkers
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Hs-CRP – 5mls of venous blood samples were collected from both subjects and
controls and the samples were centrifuged to separate serum and stored at -40C.
PRINCIPLE: The Hs-CRP ELISA is based on the principle of a solid phase enzyme-
linked immunosorbent assay84. The assay system utilizes a unique monoclonal antibody
directed against a distinct antigenic determinant on the CRP molecule. This mouse
monoclonal anti-CRP antibody is used for solid phase immobilization (on the microtiter
wells).A goat anti-CRP antibody is in the antibody-enzyme (horseradish peroxidase)
conjugate solution. The test sample is allowed to react simultaneously with the two
antibodies, resulting in the CRP molecules being sandwiched between the solid phase
and enzyme-linked antibodies. After a 45-minute incubation at room temperature, the
wells are washed with water to remove unbound labelled antibodies. A
tetramethylbenzidine (TMB) reagent is added and incubated for 20 minutes, resulting
in the development of blue color. The color development is stopped with the addition
of 1N hydrochloric acid changing the color to yellow.
The concentration of CRP is directly proportional to the color intensity of the test
sample. Absorbance is measured spectrophotometrically at 450 nm (APPENDIX VII).
Procedure: Briefly, 10µl of appropriately diluted CRP standard, samples and controls
was dispensed into appropriately labelled microtitre wells shown in APPENDIX V (that
had been brought to room temperature i.e. 20-25oC) after which 100µl of enzyme
conjugate reagent was added, thoroughly mixed for 30 seconds and incubated at 20-
25oC for 45 minutes. The wells were later washed for 5 times with distilled water and
properly dried by striking sharply on absorbent paper. 100µl of tetremethylbenzidine
solution was added to each well, gently mixed for 5 seconds and then incubated at 20-
25oC for 20 minutes. Thereafter, 100µl of 1N hydrochloric acid (stop solution) was
added to each well, gently mixed for 30 seconds to stop the reaction and for the
lv
development of a yellow colour as shown in APPENDIX VI. The optical density of
each well was then determined with a microtitre well reader at 450 nm within
15minutes.
Calculation of results: The standard curve was created by plotting the optical density
values for stock, blank and for each standard on the x-axis against the concentration
(Mg/L) on the y-axis and a best fit curve was drawn through the points on the graph.
Results of subjects in this study were categorized into levels of Hs-CRP<1Mg/L, 1-
3Mg/L and Mg/L and were defined as low, intermediate and high risk according to the
American Heart Association and Center for Disease Control recommendations85,86.
Serum uric acid: This was determined by an enzymatic colorimetric method using an
auto-analyzer after 5mls of venous blood was collected. Mean value of uric acid in
cases was calculated and were compared with the controls. Reference value employed
as normal was 420umol/L for males and 360umol/L for females24. Values greater than
these levels were classified as having hyperuricaemia.
(i)Fasting blood glucose and 2-hour post prandial
After 10-12 hours of overnight fast without alcoholic drink and beverages, venous blood was
obtained from the subjects and analyzed for the fasting blood glucose. A second sample was
collected 2 hours post-prandial for blood sugar measurement. All samples were quickly sent to
Department of Chemical Pathology and analyzed immediately using the glucose oxidase
method. Diabetes mellitus and impaired fasting glucose were diagnosed according to the WHO
criteria87.
(ii) Fasting lipid profile
After 10-12 hours of overnight fast, venous blood was centrifuged and the serum immediately
separated and the concentrations of triglycerides (TG), total cholesterol (TC) and its fractions
lvi
[LDL-C, HDL-C] were analysed. The atherogenic Index of plasma (TC/HDL-C and
LDL/HDL-C) was calculated. The National Cholesterol Education Program Adult Treatment
Panel III (NCEP ATP III) cut off points were used to identify subjects with desirable,
borderline high and high levels of lipoprotein risk factors88.
(iii)Other laboratory tests that were done included packed cell volume for estimation of
anaemia, total white blood cells count and differentials to rule out evidence of infection.
Urinalysis to assess glucose and protein to rule out renal dysfunction. Also, chronic kidney
disease was ruled out with the calculation of the estimated glomerular filtration rate using the
National Kidney Foundation calculator.
Blood samples for serum sodium (Na), potassium (K), urea (U) and creatinine (Cr) were
collected in heparinized bottles and analysed in the Department of chemical pathology using
flame photometer (Na and K), diacetylmonoxime (U) and Jaffe (Picric) method (Cr).
Protocol 5: Imaging studies
12 lead ECG
A conventional resting 12 lead ECG (Schiller AG, Switzerland) with a long rhythm strip of
Lead II was performed in accordance with the American Heart Association (AHA)
recommendation for standardization of leads and specification for instrument89,90. The ECG
paper speed was adjusted to 25mm/mVs and amplitude of 10mm/Mv (APPENDIX X). All
ECGs were recorded in the supine position. The following parameters were analyzed from the
ECG strip;
Heart rate; with normal value considered to be 60 - 100 beats per minute. Values above 100bpm
were considered a tachycardia
lvii
Left ventricular hypertrophy (LVH); with changes in the QRS complex, the ST segment, and
the T wave. Voltage criteria using the Sokolow-Lyon criteria91SV1+ RV5 > 3.5 mV, Gubner
Ungerleider92(SIII + RI > 25 mm), Araoye code system93 (SV2 + RV6 > 35 mm in women or
> 40 mm in men or RI > 12 mm in both sexes), and Cornell’s criteria94 (SV3 + RaVL > 20 mm
in women or > 28 mm in men) were considered.
Echocardiography-
All subjects had 2 Dimensional (2D) derived M-Mode and Doppler (pulsed wave, continuous
wave and colour flow) transthoracic echocardiography with simultaneous ECG recordings
(APPENDIX VIII and APPENDIX IX). The echocardiography was performed according to
standard procedure95 by means of a standard ultrasound machine, GE medical system Vivid 7
dimension instrument with 5 MHz transducer.
Echocardiographic parameters
Left ventricular mass (LVM) was derived using the formula proposed by the American Society
of Echocardiography:
LVM (g)= 1.04[(LVIDd+PWTd+IVSd)3- (LVIDd)3] x0.8+0.6g
Where 1.04 = specific gravity of the myocardium
0.8 = correction factor
The normal LVMI is <100g/m for females and <125g/m for males²96.
LVIDd = left ventricular internal diameter in diastole [in centimeters (cm)]
PWTd = left ventricular posterior wall thickness in diastole (in cm)
lviii
IVSTd = interventricular septal thickness in diastole (in cm)
Relative wall thickness (RWT) was calculated using the formula:
RWT = (IVSTd+PWTd)/LVIDd.
RWT value <0.45 is indicative of normal left ventricular geometry or eccentric hypertrophy,
while a value of 0.45 or above indicates concentric left ventricular hypertrophy or
remodeling97.
Four left ventricular geometric pattern were described in this study: concentric hypertrophy
(elevated LVMI and RWT), concentric remodeling (normal LVMI and elevated RWT),
eccentric hypertrophy (increased LVMI and normal RWT) and normal geometry (normal
LVMI and RWT)96.
Where applicable, measurements were indexed for body surface area (BSA) which was
calculated with the Monsteller formula98:
Square root of [Weight (kg) x Height (cm)/3600]
Left ventricular systolic function
Left ventricular systolic function was determined with the following M-mode measurements
and parameters:
Left Ventricular Ejection Fraction: (LVEDV-LVESV /LVEDV) x 100%
Left Ventricular Fractional Shortening: (LVIDd-LVIDs/LVIDd) x100%
LVEDV-Left Ventricular end-diastolic volume
LVESV-Left Ventricular end-systolic volume
LVIDd-Left Ventricular internal diameter in diastole
lix
LVIDs-Left Ventricular internal diameter in systole
The software of the Teicholz formula was already factory-installed in the echocardiography
machine and automatically calculated the left ventricular volumes in end-diastole and end-
systole:
7/(LVID+2.4) x LVID3 100.
Where LVID = left ventricular internal dimension
The above formulae had been programmed by the automated facilities in the echocardiography
machine.
Stroke volume was gotten by calculating the difference between end diastolic volume (EDV)
and end systolic volume (ESV). Stroke Index(SI) is stroke volume divided by body surface
area, while cardiac output (CO) is stroke volume multiplied by heart rate. Cardiac index (CI)
is cardiac output indexed to body surface area.
Normal reference values for ejection fraction (EF) and fractional shortening (FS) are >50%2and
>20% respectively101.
Ejection fraction assessed for subjects recruited for this study were classified based on the table
below.4
Table 2: Classification of ejection fraction2
Ejection fraction (%) Interpretation
<40 HFrEF
40-49 HFmrEF
>50 HFpEF
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3.13 Statistical analysis
The data obtained were analyzed using the software Statistical Programme for Social Sciences
(SPSS) version 21. Data were tabulated in Microsoft excel worksheet and represented using
descriptive statistics such as tables, graphs, pie charts and bar charts. Discrete variables like
age and sex were represented in absolute numbers and percentages. Continuous variables were
presented as mean ± standard deviation or median ± interquartile range. Frequencies and simple
percentages of blood pressure were determined for both male and female subjects and controls.
Hs-CRP and serum uric acid levels were evaluated as dichotomous variables of elevated or not
elevated.
A statistical comparison was made with student t-test for quantitative variables, analysis of
variance for three or more variables and chi-square test for comparison of proportions.
Bivariate analysis was performed using Pearson Correlation Coefficient.
A p-value of less than 0.05 was taken as statistically significant and a confidence interval of
95%.
lxi
CHAPTER FOUR
RESULTS
4.00: Two hundred and twenty subjects participated in the study. Consecutive recruitment of
volunteers was carried out until a total of one hundred and ten (110) patients with HHF and
110apparently healthy age and sex matched controls were obtained to complete the study.
4.01.1: Sociodemographic characteristics of the Study population
The sociodemographic characteristics of the study population are summarised in table 3. The
hypertensive heart failure patients were matched for age and sex with their apparently healthy
controls counterparts. Each group comprised of 55 males and 55 females. The mean age of
both groups (HHF group, 58.05 ±10.75 vs control group 56.46±10.01, p =0.052) did not show
a significant statistical difference. Patients with HHF had no significantly lower mean body
weight compared to the controls (p = 0.003). There was also no significant difference in mean
height among the two groups (p =0.139).The mean BMI of the HHF patients compared with
the control group also did not show any statistically significant difference (p=0.369). Heart rate
at rest, systolic blood pressure and diastolic blood pressure were significantly higher in the
HHF group than the control groups (p < 0.001 in all cases).
lxii
Table 3: Demographic characteristics of the study population
Parameters HHF group
(mean±SD)
Control group
(mean±SD)
p value
Age (years) 58.05±10.75 56.46±10.01 0.052
Gender
Male
Female
55(50)
55(50)
55(50)
55(50)
1.000
Weight (Kg) 63.09±8.23 68.78±6.45 0.003
Height (m2) 1.65±0.05 1.68±0.67 0.139
BMI (Kg/m2) 23.12±2.96 24.20±2.92 0.369
BSA 1.73±0.15 1.78±0.11 0.256
PR (bpm) 96.65±12.54 80.74±10.48 <0.001
SBP (mmHg) 141.22±24.07 114.00±9.11 <0.001
DBP (mmHg) 88.85±14.81 75.65±7.54 <0.001
PP (mmHg)
50.87±15.12
37.65±9.39 <0.001
lxiii
KEY: BMI= Body mass Index; BSA= Body surface area, HR= Heart rate at rest; SBP=
Systolic blood pressure at rest; DBP= Diastolic blood pressure at rest. HTN=Hypertension
FIGURE. 4.1 BAR CHART SHOWING FREQUENCY DISTRIBUTION OF PATIENTS
AND CONTROLS
lxiv
This chart showed that the highest percentage of the HHF patients and the controls were in
the age group 50 – 59 years and the lowest percentage were those in the age group 30 -39
years.
4.01 Medical History and Treatment offered to HHF subjects
The table below shows the medical history and treatment offered to patients with hypertensive
heart failure. The percent of HHF patients on furosemide, spironolactone, digitalis, ACEi/ARB
and beta-blockers were 53.7%, 57.9%, 31.6%, 52.1% and 27.9% respectively. Twenty four
(21.8%) and 21(19.1%) gave a history of cigarette smoking and alcohol consumption
respectively.
Table 4: Summary of the medical history and treatment offered to HHF subjects.
Frequency Percent
Treatment
Furosemide 102 92.7
Spironolactone 110 100
Digitalis 60 54.5
ACEi/ARB 99 90
Beta-blockers 53 48.2
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Medical History
Cigarette smoking 24 21.8
Alcoholic intake 21 19.1
KEY: ACEi= Angiotensin Converting enzyme inhibitor; ARB= Angiotensinogen Receptor
Blocker
4.02 FREQUENCY OF PATIENTS ACROSS NYHA FUNCTIONAL CLASS
The NYHA functional classes of the HHF patients were as follow: 50 patients (45.5%) were in
NYHA class II, 43 patients (39.1%) were in NYHA class III and 17 patients (15.4%) were in
NYHA class IV. These were represented in the pie chart below.
lxvi
FIGURE 4.2 PIE DIAGRAM ILLUSTRATING FREQUENCY OF PATIENTS IN EACH
NYHA CLASS
4.03.01Result of the biomarkers of the study population
Table 5 shows the laboratory findings of the study population. The median of the serum
levels of high sensitive C-reactive protein (Hs-CRP) (5.3(8.8) vs 0.8(0.7) Mg/L, p<0.001)
and the mean serum uric acid(SUA)(485.54±114.95 vs 232.43±95.19 umol/l, p<0.001)in
the HHF patients were significantly elevated compared with that of controls (p <0.001).
lxvii
Table 5: Biomarkers result of the study population.
PARAMETERS Cases
(mean±SD)
Control
(mean±SD)
p value
Hs-CRP(Mg/L)
All* 5(8.4) 0.8(0.6) <0.001
Males* 5.3(8.8) 0.8(0.7) <0.001
Females* 5.0(7.8) 0.8(0.5) <0.001
SUA(umol/l)
All 485.54±114.95 232.43±95.19 <0.001
Males 501.72±116.56 231.19±87.93 <0.001
Females 467.50±111.53 234.12±105.57 <0.001
KEY:Hs-CRP= High sensitive C-reactive protein, SUA= Serum uric acid.
*= median ± interquartile range
lxviii
Figure 4.3: Bar chart showing the Hs-CRP levels of the study population.
This chart showed that a higher percentage of HHF patients had Hs-CRP levels greater than 3
Mg/L and a higher percentage of the control subjects had Hs-CRP levels lower than 1 Mg/L
while the percentage of HHF patients and the controls with Hs-CRP levels between 1 and 3
Mg/L was below 20%.
lxix
Figure 4.4: Bar chart showing the serum uric acid levels of the study population.
This chart showed that a high percentage of the HHF patients recorded elevation in their
serum uric acid levels while a high percentage of the control subjects showed no elevation in
the serum uric acid levels.
4.03.02 Other biochemical parameters
lxx
The mean total cholesterol (TC) and low density lipoproteins (LDL) were elevated in the
HHF group compared to the control group. The difference was statistically significant
(p<0.001). High density lipoproteins (HDL) and triglyceride (TG) were lower in the HHF
group and the difference was statistically significant (p<0.001).
PCV of the population was not statistically significantly lower in the HHF group when
compared to the control group (37.04±5.87 vs 37.96±2.89%, p=0.051). In addition, HHF
group had no statistically significant lower serum sodium compared with the controls
(134.71±4.82 vs 136.67±4.26mmol/l, p=0.020). The serum potassium, chloride,
bicarbonate, creatinine and urea were all significantly higher in the HHF group compared
with the controls (p< 0.001 respectively). These are as shown in table 6.
Table 6: Laboratory findings of the study population.
lxxi
PARAMETERS Cases
(mean±SD)
Control
(mean±SD)
p value
FBS(mmol/l) 4.96±2.32 4.84±0.75 <0.001
2HPP(mmol/l) 6.43±1.14 6.56±1.40 <0.001
TC(mmol/l) 5.09±1.49 4.84±0.75 <0.001
HDL(mmol/l) 0.92±0.67 1.13±0.39 <0.001
LDL(mmol/l) 3.13±0.10 1.81±0.14 <0.001
TG(mmol/l) 1.36±1.70 1.88±0.45 <0.001
PCV(%) 37.04±5.87 37.96±2.89 0.051
WBC(cm) 6031.13±1778.43 6542.22±1711.76 <0.001
Creatinine(mmol/l) 106.05±21.06 110.81±23.78 <0.001
Urea(mmol/l) 8.12±2.44 5.77±2.88 <0.001
Sodium(mmol/l) 134.71±4.82 136.67±4.26 0.020
Potassium(mmol/l)
eGFR(mi/min/1.76m2)
4.01±0.47
85.41±22.50
4.18±0.67
102.32±34.3
0.018
<0.001
KEY:Hs-CRP= TC=Total Cholesterol, HDL= High density lipoprotein, LDL= Low density
lipoprotein, TG= Triglyceride, PCV= Pack cell volume, WBC= White blood cell, %=
Percentage, eGFR=estimated glomerular filtration rate.
4.04 Echocardiographic findings of the Study population
lxxii
Table 7 shows the two dimensional and M-mode parameters of the study population. The
mean left atrial dimension (LAD), aortic root dimension (AOD), right ventricular diastolic
diameter (RVD), left ventricular internal diameter in systole and left ventricular internal
diameter in diastole (LVIDD) were statistically significantly elevated in the HHF patients
compared with their control counterparts(p<0.001).
The mean inter-ventricular septum thickness (IVST), left ventricular posterior wall
(LVPWT), relative wall thickness (RWT) and left ventricular mass (LVM) as well as its
index were all significantly higher in the HHF group compared to the control group.
Table 7: Two-dimensional and M-mode echocardiographic parameters of the study
population.
lxxiii
Parameters HHF group
(mean±SD)
Control group
(mean±SD)
p value
LAD (cm) 3.09±0.49 2.85±1.15 <0.001
LADi (cm/m2) 2.44±0.43 2.03±0.41 0.090
AOD (cm) 1.91±0.31 1.64±0.38 <0.001
AODi (cm/m2) 1.68±0.52 1.58±0.62 0.081
IVST (cm) 1.14±0.19 0.90±0.26 <0.001
LVPWT (cm) 1.19±0.15 0.95±0.14 <0.001
RVID (cm) 2.54±2.36 1.64±0.37 <0.001
RVIDi (cm/m2) 1.14±0.78 0.93±0.25 0.257
LVIDD (cm) 5.74±1.17 3.87±1.04 <0.001
LVIDDi (cm/m2) 3.22±5.29 2.17±0.61 0.051
LVIDS (cm) 4.53±1.29 3.02±0.51 <0.001
LVIDSi (cm/m2) 2.24±0.79 1.68±0.0.32 0.103
LVM (grams) 173.32±19.79 171.51±17.95 <0.001
LVMi (grams/m2) 102.42±42.03 96.46±13.18 0.034
RWT 0.42±0.11 0.39±0.05 0.009
KEY: LAD=left atrial diameter; AOD=Aortic root diameter; IVSD=interventricular septal
thickness in diastole; LVPWD=left ventricular posterior wall thickness in diastole;
LVPWT=left ventricular posterior wall thickness in systole; RVID=right ventricular internal
dimension ;LVIDD=left ventricular internal dimension in diastole; LVIDS=left ventricular
internal dimension in systole; LVM=left ventricular mass; RWT=relative wall thickness, [‘I’,
where seen as suffix, represents that parameter indexed for body surface area]
4.05: Left ventricular systolic function parameters of the study population.
lxxiv
Table 8 shows the left ventricular systolic parameters of the study population. The mean left
ventricular ejection fraction (39.48±16.46 vs 62.70±10.81%, p<0.001) and the fractional
shortening (19.25±8.64 vs 29.57±5.15%, p<0.001) were significantly lower in the HHF group
compared with the control group.
The stroke volume was statistically significant in the HHF group compared with the control
(p<0.001) while the in-between group difference in cardiac output was not statistically
significant.
Table 8: Left ventricular systolic function parameters of the study population.
Parameters HHF group
(mean±SD)
Controls
(mean±SD)
p value
SV (ml) 76.55±24.12 87.92±19.29 <0.001
SI (ml/m2) 44.49±13.73 49.40±11.84 0.426
CO (Litres) 6.60±1.8 6.97±1.39 0.145
CI (Litres/m2) 5.81±20.35 3.91±0.83 0.450
LVEF (%) 39.48±16.46 62.70±10.81 <0.001
LVFS (%) 19.25±8.64 29.57±5.15 <0.001
KEY: HTN= hypertension, SV= Stroke volume; CO= Cardiac output; LVEF= Left
ventricular ejection fraction;CI=Cardiac index;LVFS= Left ventricular fractional
shortening, SI= Stroke Index.
4.06 Classification of the left ventricular ejection fraction of the study population.
lxxv
Table 9 below summarized the categories of the ejection fraction of the study population.
66.4% of the HHF group recorded ejection fraction less than 40% and none among the control
group. 8.2% of the HHF group had ejection fraction between 40 to 49% and 25.5% had EF
greater than 50%. 5.5% of the control group recorded ejection fraction between 40 and 49%
while 94.5% of the controls had ejection fraction greater than 50%. The ejection fraction was
statistically significantly higher in the HHF group compared with their control group.
Table 9: Classification of the left ventricular ejection fraction.
Ejection fraction (%) HHF group Control group p value
<40 73(66.4) 0 <0.001
40-49 9(8.2) 6(5.5)
>50 28(25.5) 104(94.5)
Total 110 110
4.07 Doppler echocardiographic findings of the study population.
lxxvi
Table 10 shows the Doppler echocardiographic findings of the study population. There was a
statistically significant difference between the two groups in all the parameters recorded. Early
transmitral inflow velocity (MV E vel.) and Isovolumic relaxation time (IVRT) and early
transtricuspid inflow velocity (TV E vel.)were significantly lower in the HHF group than the
control group while the late transmitral inflow velocity (MV A vel.), the ratio of early to late
transmitral inflow velocity (MV E/A), deceleration time (DT), late transtricuspid inflow
velocity (TV A vel.) and the ratio of early to late transtricuspid inflow velocity were
significantly higher in the HHF group than the control group.
The difference in the percentage of subjects in the HHF group who had mitral regurgitation
(MR), tricuspid regurgitation (TR), aortic regurgitation(AR) and pulmonary regurgitation (PR)
compared with the control group was statistically significant (p<0.001).
Table 10: Doppler echocardiographic findings of the study population.
lxxvii
Parameters HHF group Controls p value
MV E vel.(m/s) 0.81±0.28 0.85±0.00 <0.001
MV A vel.(m/s) 0.87±3.58 0.62±0.00 <0.001
MV E/A 1.69±0.94 1.38±0.11 <0.001
Dec. T (ms) 193±18 174.63±15.38 <0.001
IVRT (ms) 79.32±33.52 80.76±12.16 <0.001
TV E vel.(m/s) 0.54±0.19 0.74±0.16 <0.001
TV A vel. (m/s) 0.45±0.16 0.38±0.78 0.008
TV E/A 1.34±0.66 1.25±0.21 <0.001
MR n(%) 75(68.2) 3(3.8) <0.001
TR n(%)
AR n(%)
59(53.6)
33(30.0)
0
0
<0.001
<0.001
PR n(%) 44(40.0) 8(10.0) <0.001
KEY:; MV E vel= early transmitral inflow velocity; MV A vel= late transmitral inflow
velocity; MVE/A= ratio of early to late transmitral inflow velocity; Dec Time= early
transmitral flow velocity; DT= deceleration time; IVRT= Isovolumic relaxation time.TV
Evel= early transtricuspid inflow velocity; TV Avel= late transtricuspid inflow velocity; TV
E/A=ratio of early to late transtricuspid inflow velocity: MR=Mitral regurgitation; TR=
Tricuspid regurgitation; AR= Aortic regurgitation; PR= Pulmonary regurgitation.
4.08 Left ventricular geometry of the study population.
lxxviii
There was a statistically significant difference in the left ventricular geometrical pattern
between the HHF group and the control group. The percentage in the HHF group presenting
with left ventricular eccentric hypertrophy, left ventricular concentric hypertrophy and left
ventricular concentric remodeling were 69.1%, 24.5% and 6.4% respectively. The control
group with normal geometry was 91.1% while 9.9% had left concentric hypertrophy.
Table 11: Left ventricular geometry of the study population.
HHF group Control group p value
Normal - 101(91.1)
LV conc. Hypert. 27(24.5) 9(9.9) <0.001
LV conc. Remodel. 7(6.4) -
LV eccent. Hypert. 76(69.1) -
KEY: LV conc. Hypertrophy=Left ventricular hypertrophy, LV conc. Remodel.= Left
ventricular remodeling, LV eccent. Hypert.=Left eccentric hypertrophy. HHF=Hypertensive
Heart Failure.
4.0912-lead ECG pattern of the study population.
lxxix
The table shows the ECG pattern of the study population. The heart rate was increased in the
HHF group compared to the control population (97.03±16.71 vs 83.88±11.57 bpm). The
difference was statistically significantly (p<0.001).
Sinus rhythm was recorded in 48(44.5%) of the HHF group compared to 68(85%) of the control
group. Sub analysis of the rhythm abnormalities shows sinus tachycardia was present in 38.2%
and 3.8% in the HHF group and control group respectively. Sinus bradycardia was present in
3.6% and 3.8% in the HHF and control groups respectively.
Sub analysis of the supraventricular arrhythmias showed that 7.3% of the supraventricular
arrhythmias in the HHF group due to atrial fibrillation while PACs were seen in 1.8%.
Premature ventricular complexes (PVC) were recorded in 11(10%) and 2(2.5%) in the HHF
and control groups respectively (p=0.043).
1st degree AV block was recorded in 6.4% of the HHF group and 1.3% of the control group.
Only the HHF group recorded 2nd degree AV block in 1.8%. Complete AV block was seen in
3.6% of the HHF group alone.
LBBB and RBBB pattern were recorded in 7.3% and 1.8% in the HHF group respectively.
None was present in the control group.
LVH by voltage criteria was observed in 85.5% of the HHF group and 2.5% of the control
group and this finding was statistically significant among the groups (P <0.001).
Table 12: 12-lead ECG pattern of the study population.
lxxx
Parameters HHF group Control group P value
HR(B/M) 97.03±16.71 83.88±11.57 <0.001
Heart rhythm(%)
Sinus rhythm 48(45.5) 68(85.0) <0.001
Sinus tachy 42(38.2) 3(3.8) <0.001
Sinus brady 4(3.6) 3(3.8) 0.967
Svent arrhyth n(%)
PAC 2(1.8) 1(1.3) 0.756
AF 8(7.3) 1(1.3) <0.001
Vent arrhythn(%)
PVC 11(10.0) 2(2.5) 0.043
AV Block(%)
1st degree 7(6.4) 1(1.3) 0.216
2nd degree 2(1.8) 0(0) 0.225
Complete AV Block 4(3.6) 0(0) 0.085
Conduction block
LBBB n(%) 8(7.3) 0(0) 0.014
RBBB n (%) 2(1.8) 0(0) 0.225
LVH n(%) 94(85.5) 2(2.5) <0.001
KEY: HR=Heart rate; Sinus Brady=Sinus bradycardia; Sinus Tachy=Sinus tachycardia;
Svent Arrhyt= Supraventricular arrhythmias; Vent Arrhyt=Ventricular arrhythmias;
PAC=Premature atrial complex; AF=Atrial fibrillation; PVC=Premature ventricular
complex; AV block= Atrioventricular block; RBBB=Right bundle branch block; LBBB=Left
bundle branch block; LVH=Left ventricular hypertrophy.
4.10 Left ventricular diastolic function of the study population.
lxxxi
As seen in table 13, normal diastolic function was observed only in the control group. Grade
1 diastolic dysfunction was present in 46(41.8%) and 5(6.3%) in the HHF and control groups
respectively. Grade 2 diastolic dysfunction 6(5.5%) was seen only in the HHF group.
Restrictive pattern was seen in 58(52.7%) of the HHF group alone.
Table 13: Summary of the Doppler echocardiography assessment of the left ventricular
diastolic function of the study population.
HHF group Controls group p value
Normal 0 105(93.7) <0.001
Grade 1 LV diast.
Fxn
46(41.8) 5(6.3) <0.001
Grade 2 LV diast.
Fxn
6(5.5) 0 0.137
Restrictive
Total
58(52.7)
110
0
110
<0.001
KEY:LV diast. Fxn=Left ventricular diastolic function.
4.11 Relationship between the biomarkers and the NYHA functional classification in
HHF subjects.
lxxxii
One way analysis of variance (ANOVA) in the relationship between the baseline measurements
of biomarkers (Hs-CRP and serum uric acid) and the NYHA functional classification in the
HHF patients.
The median levels of the Hs-CRP in the HHF patients in NYHA class II, NYHA class III and
NYHA class IV were 3.0(4.0) Mg/L, 8(7.3 Mg/L and 10(21.1) Mg/L respectively. The
difference was statistically significant (p<0.001).
The levels of the mean SUA in patients with HHF in NYHA class II, NYHA class III and
NYHA class IV were422.80±92.00umol/l, 526.74±97.46umol/l and 565.88±124.25mmol/l.
The difference was statistically significant (p<0.001).
There was a further in-between analysis of the HHF patients with elevated Hs-CRP and SUA
in NYHA class II, class III and class IV. The result showed there was a statistically significant
relationship among the three groups (p<0.001) of HHF patients with elevated Hs-CRP and
SUA. These are as shown in table 14.
Table 14: Relationship between the biomarkers and the NYHA functional classifications
in HHF subjects.
NYHA functional class p value
lxxxiii
Class II Class III Class IV
mean±SD mean±SD mean±SD
1Hs-
CRP(Mg/L)*
3(4.0)a 8(7.3)b 10(21.1)c <0.001
2SUA(umol/l) 422.80±92.00a 526.74±97.46b 565.88±124.25c <0.001
KEY: NYHA=New York Heart Association, EF=Ejection fraction, Hs-CRP= High sensitive C-reactive protein, SUA= serum uric acid.
*= median ± interquartile range
1. Post Hoc . Bonferroni significance across the NYHA functional classes are significant.
2. Post Hoc . Bonferroni significance across the NYHA functional classes are significant.
4.12 Relationship between the biomarkers and the LVEF in HHF subjects.
One-way analysis of variance (ANOVA) in the relationship between the left ventricular
ejection fraction and the biomarkers (HS-CRP and serum uric acid) of the HHF patients.
lxxxiv
The median levels of Hs-CRP in patients with HHF in HFrEF (<40%), HFmrEF (40-41%) and
HFpEF (>50%) were 8.0(7.8) Mg/L, 3.5(8.0) Mg/L and 3.0(4.0) Mg/L respectively. The
difference was statistically significant (p<0.001).
The levels of the mean SUA in HHF patients in HFrEF, HFmrEF and HFpEF were
520.13±107.7umol/l, 421.11±57.91umol/l and 416.07±108.40mmol/l. The difference between
the three groups showed a statistical significant (p<0.001).
Further in-between analysis of the three groups of HHF patients with elevated Hs-CRP and
SUA. The groups are HHF patients with HFrEF, HFmrEF and HFpEF. The result revealed that
there was a statistically significant relationship between the group of patients with HFrEF and
the other two groups with HFmrEF and HFpEF (p <0.001). There was no statistically
significant relationship between patients with HFmrEF and HFpEF (p=1.000). The result was
similar in both HHF patients with elevated Hs-CRP and SUA. This is as shown in table 15.
Table 15: Relationship between the biomarkers and the left ventricular ejection fraction
in the HHF subjects.
Ejection fraction p value
<40% 40-49% >50%
lxxxv
mean±SD mean±SD mean±SD
1Hs-
CRP(Mg/L)*
8.0(7.8)a 3.5(8.0)b 3.0(4.0)c <0.001
2SUA(umol/l) 520.13±107.77a421.11±57.91b 416.07±108.40c <0.001
KEY: NYHA=New York Heart Association, EF=Ejection fraction, Hs-CRP= High sensitive C-reactive protein, SUA= serum uric acid.
*= median ± interquartile range
1. Post Hoc Bonferroni significance in HFrEF shows significance when compared with HFmrEF and HFpEF while the relationship between HFmrEF and HFpEF were not significant.
2. Post Hoc Bonferroni significance in HFrEF shows significance when compared with
HFmrEF and HFpEF while the relationship between HFmrEF and HFpEF were not
significant.
4.13 Bivariate correlational analysis between the biomarkers and the New York Heart
Association functional class of the HHF patients.
Bivariate analysis showing relationship between the biomarkers and the New York Heart
Association functional class. As seen in Figure 4.5 and 4.6, there is a positive relationship
between Hs-CRP and serum uric acid levels and the New York Heart Association functional
lxxxvi
class. There is a worsening of the New York Heart Association functional class as the levels
of the biomarkers increases.
There is a positive correlation between the biomarkers (Hs-CRP r 0.339 and serum uric acid r
0.247 and the New York Heart Association functional class . The relationship between the
two biomarkers and the New York Heart Association functional class was statistically
significant, p <0.001.
lxxxvii
Figure 4.5 Scatterplot showing the relationship between Hs-CRP and NYHA functional
class of the HHF patients.
There was a positive relationship between Hs-CRP and NYHA functional class of the HHF
patients
lxxxviii
Figure 4.6 Scatterplot showing the relationship between uric acid and the NYHA functional
class of the HHF patients.
There was a positive relationship between uric acid and NYHA functional class of the HHF
patients.
4.14 Bivariate correlational analysis between the biomarkers and the left ventricular
ejection fraction of the HHF patient.
lxxxix
Pearson’s correlation showing the relationship between the biomarkers and the left
ventricular ejection fraction. There is an inverse relationship between the biomarkers of
inflammation and the left ventricular ejection fraction of the HHF patients.
There is a negative correlation between the biomarkers (Hs-CRP r -0.129 and serum uric acid
level r -0.124) and the left ejection fraction. The relationship between the two biomarkers was
statistically significant with the left ventricualar ejection (p <0.001). These are as shown in
figure 4.7 and 4.8.
xc
Figure 4.7 Scatterplot showing the relationship between Hs-CRP and the left ventricular
ejection fraction of the HHF patients.
There was an inverse relationship between Hs-CRP and the left ventricular ejection fraction
of the HHF patients.
xci
Figure 4.8 Scatterplot showing the relationship between uric acid and the left ventricular
ejection fraction of the HHF patients.
There was an inverse relationship between uric acid and the left ventricular ejection fraction
of the HHF patients.
CHAPTER FIVE
xcii
DISCUSSION
The study of correlation between Hs-CRP and serum uric acid levels in hypertensive heart
failure patients involved 110 subjects diagnosed HHF and 110 apparently healthy age and sex
matched controls.
5.01 DEMOGRAPHIC DATA OF THE STUDY POPULATION
AGE AND GENDER DISTRIBUTION
The mean age of the patients with HHF was 58.05±10.75 years which is similar to findings
obtained in other studies from centres within the country3,9,10,14. The mean age of the control
group was 56.46±10.01years. The mean age of HF patients in this study is comparable to the
mean age of HF patients in other African countries as reported by Damasceno and colleagues
(52.3±18.3 years)7. This however contrasts with the mean age of HF patients in some other
countries. The mean age in United States of America, Europe and Asia are 75 years, 69.9
years and 67.3 years respectively105-107.
Studies have shown that cardiovascular disease including HF occurs at an earlier age in the
developing countries than the developed world.This finding may be attributable to both the
earlier occurrence of cardiovascular events and inadequate facilities required for the care of
these patients in developing countries. Furthermore, hypertension as aetiology of HF occurs
earlier in the developing countries107.
The genders of the HHF and control groups were made up of 55 males and 55 females.
5.02 PHYSICAL CHARACTERISTICS OF THE STUDY POPULATION
xciii
5.02.01 BODY WEIGHT AND BODY MASS INDEX
The patients in the HHF group had a significantly lower body weight compared to the control
group. The lower body weight in the HHF group can probably be explained by the severity of
the CHF which contributes to cardiac cachexia. The underlying mechanisms are multi-
factorial and include an increased resting metabolic rate, release of cytokines such as Tumour
Necrosis Factor (TNF), Interleukin-1 (IL-1) Interleukin-6 (IL-6), and Interleukin-10 (IL-10),
early satiety from congestive hepatomegaly, abdominal fullness, reduced absorption of
nutrients due to congestion of the intestinal veins and anorexia108.
The height and body mass index were not statistically significant. The mean BMI in patients
in this study is in conformity with a finding obtained in an African study7. A study on obesity
paradox in Nigerians revealed HF patients with higher BMI had less severe presentation of
HF compared to patients with normal BMI109.
5.02.02 BIOCHEMICAL PARAMETERS:
The PCV was slightly lower in the patients with HHF compared with the control subjects,
although there was no statistically significant difference between the two groups (P =0.051).
This observation conforms with previous findings on the impact of anaemia on HF110,111.
Familoni and colleagues reported anaemia as one of the contributory factors to poor outcome
in Nigerian patients with advanced heart failure109. This was collaborated by Ogah and
colleagues who reported a low PCV in the registry obtained among HHF patients110. Anaemia
in Heart failure might be attributed to the effect of malnutrition as a result of chronic nature of
the illness110.
Serum creatinine was significantly elevated and eGFR lower in patients with HHF compared
with the control counterparts, the difference was statistically significant (P<0.001). Mild renal
impairment is a common finding in HF and also confers increased mortality risk112.Impairment
xciv
in renal function in HF occurs as a result of chronic hypoperfusion of the kidneys leading to
renal ischaemia and a reduction of GFR113. The concentration of serum sodium and potassium
were lower in the HHF group compared with the control counterparts. However, this difference
did not attain statistical significance at (P=0.020) and (p=0.018) respectively. The lower
sodium level has been shown to increase mortality in the heart failure population 114-116.
Hyponatremia in heart failure is due to inappropriate vasopressin activity despite
hypoosmolality and volume overload as well as use of diuretic treatment. Hyponatraemia has
been shown to be contributory to intra-hospital mortality among CHF patients117.
The total cholesterol and LDL were significantly higher among the HHF group compared with
the control group while the HDL and TG were lower in the HHF group. The difference was
statistically significant (P <0.001). The high cholesterol in this study is comparable to findings
obtained in other works among Nigerian patients with HHF16,110.111.
5.03 PULSE RATE, BLOOD PRESSURE, PULSE PRESSURE AND CARDIAC
OUTPUT: In the study, the pulse rate, systolic blood pressure, diastolic blood pressure and
pulse pressure were elevated more in the HHF group compared to the control group. This
increase was statistically significant (p<0.001). The significantly elevated pulse rate and BP
measurements in the HHF patients compares favourably to previous studies10,12,35,111. The
average heart rate among the HHF patients was 96.65±12.54 bpm, SBP was 141.22±24.07
mmHg and DBP was 88.35±14.81mmHg which is comparable with findings reported by Ogah
and colleagues. These findings also collaborated with the study by Ojji and colleagues in a
HHF registry16.
5.04 2-D AND 2-D DERIVED M-MODE ECHOCARDIOGRAPHIC PARAMETERS:
This study found a significantly higher LAD, LVIDD, LVIDS, IVSD and LVPWD among the
HHF patients compared with the controls. These findings compared favourably with reports
xcv
from the Heart Failure Registry in Abeokuta where 320 patients admitted with CHF were
consecutively studied110. The study revealed a significant difference in the 2-D and M-mode
echocardiographic parameters among HHF patients and their apparently healthy controls111. In
this study, LVM and LVMi were significantly increased in the HHF patients than their
apparently healthy controls.
The geometry of the HHF patients showed left ventricular eccentric hypertrophy was present
in 69.1% cases. Patients who had left ventricular concentric hypertrophy were 24.5% while
6.4% had left ventricular eccentric hypertrophy. This observation compares well with other
previous studies110,111,118.
5.05 SERUM Hs-CRP AND URIC ACID LEVELS OF THE STUDY POPULATION.
In this study the levels of both Hs-CRP and SUA in HHF patients were significantly elevated
compared with the control subjects. The increase in both Hs-CRP and uric acid levels can be
associated with increased degree of inflammation in CHF. This finding compares favourably
with previous studies 53,54,118. The increase in baseline measurement of Hs-CRP and serum uric
acid in this study showed that both biomarkers are associated with myocardial dysfunction in
patients with heart failure. In ASCEND-HF trial, elevation in baseline measurement of Hs-
CRP were associated with worsening progression of HF119. The Framingham Heart Study
demonstrated that participants with CRP serum levels of ≥5 mg/L experienced a significantly
increased risk of heart failure120. Limitation in that study was by the use of a low-sensitivity
CRP assay. Finally, in the Health ABC study, high levels of CRP independently predicted the
incidence of events of heart failure121. Leyva and colleagues reported in a study that increased
mean serum uric acid level was strongly related to severity of HF123. Elevated uric acid causes
increased xanthine oxidase activity in response to inflammation that contribute to the severity
of CHF56, 58.
xcvi
5.06 RELATIONSHIP BETWEEN BIOMARKERS AND THE NYHA FUNCTIONAL
CLASS
The study showed a significant relationship between the Hs-CRP and uric acid levels on the
one hand and the NYHC functional classification of the study population (p<0.001). In this
study, the levels of the biomarkers (Hs-CRP and uric acid) increased proportionately as the
NYHA functional classification worsened from class II to class IV. This can be due to the
higher degree of inflammation with the increased severity of CHF. The observation in this
study is comparable with similar studies on relationship between NYHA functional
classifications and each of the biomarkers (Hs-CRP 118,122,123and uric acid 56,57) done separately.
Hs-CRP has many pathophysiologic roles in the inflammatory process. It can amplify the
inflammatory response through complement activation, which may cause myocardial cell
apoptosis and thus ventricular damage or dysfunction. Also, at concentrations known to predict
adverse vascular events, it directly quenches the production of nitric oxide, which, in turn,
inhibits angiogenesis, an important compensatory mechanism in chronic ischemia. In doing so,
Hs-CRP may facilitate the development and worsening of CHF. Other proinflammatory effects
of Hs-CRP include the induction of inflammatory cytokines and tissue factor in monocytes and
a direct proinflammatory effect on human endothelial cells118. Karaye and colleagues reported
that increased morbidity and mortality in HF patients were observed more in those with higher
NYHA functional classifications12. This was similarly observed in the study by Ahmed and
colleagues where HF patients with NYHA class III and IV presented with increased disease
severity124.
Relationship in between the NYHA functional classes and the two biomarkers also showed
significant relationship (p<0.001). The biomarkers are significantly elevated in each of the
NYHA functional classification and tend to worsen as the class increases. The observation is
xcvii
similar to other previous works on biomarkers in HF 56, 124. The levels of the biomarkers are
more significantly elevated as the NYHA functional class increase. This increase is related to
increased inflammatory changes as the myocardial dysfunction worsened.
This study showed a positive correlation between Hs-CRP and uric acid and the NYHA
functional class among HHF patients. This finding compares favourably with previous studies
54,56,119. Anker and colleagues demonstrated that SUA positively correlated with HF and was
associated with increased myocardial dysfunction124. Alonso-Martinez and colleagues also
observed that Hs-CRP levels were significantly increased with the severity of CHF and were
correlating with NYHA functional class and that higher levels were associated with an
increased disease severity54.
5.07 RELATIONSHIP BETWEEN BIOMARKERS AND THE EJECTION FRACTION
In this study HHF patients with HFrEF were 66.4% at presentation. HHF patients who had
HFmrEF were 8.2% while those with HFpEF were 25.5%. The predominance of HFrEF in this
study is comparable to previous works obtained in other centers in Nigeria3,12,16,110. The
predominance of HFrEF may be related to hypertension as a cause of heart failure which the
study is centered upon. Also, the finding corroborates epidemiologically with research works
obtained in other centers within the country3,12,16.
This study also showed a progressive decrease in the ejection fraction with increasing
biomarkers values which relate to worsening disease severity. It reveals an inverse relationship
between the two biomarkers (Hs-CRP and uric acid) and LVEF. The levels of the biomarkers
were significantly elevated in patients with HFrEF when compared with HFmrEF and HFpEF.
This observation is in conformity with similar studies in the United States of America, Europe
and Asia where Hs-CRP and SUA were found to be significant in HF patients who had LVEF
less than 40% 54,123,125,126. HFrEF have been shown to contribute poorly to disease severity in
xcviii
HHF 12,16,111. The increase in the biomarkers at reduced LVEF in HF is associated with
worsening inflammatory process. Karaye and colleagues found that among factors which
contributed poorly to the outcome of CHF patients was the identification of low ejection less
than 40%12.
There was a negative correlation between the biomarkers and the ejection fraction of the
patients with the HHF in this study. This observation is comparable with similar research works
on Hs-CRP and SUA54,56,58,119. Alonso-Martinez and colleagues reported a significant
relationship between Hs-CRP and LVEF58. This was corroborated by Hirochi and colleagues
who showed a negative correlation between serum uric acid and LVEF58. The
pathophysiological process of serum uric acid to increase disease severity in HF is related to
the increase xanthine oxidase activity. This contributes to more oxidative stress and
inflammation58.
xcix
CHAPTER SIX
CONCLUSIONS
1. Hs-CRP and serum uric acid are elevated in patients with hypertensive heart failure.
2. There is a proportionate increase in the biomarkers as the NYHA functional
classifications of the HHF patients worsen.
3. There is a significant relationship between the biomarkers and left ventricular ejection
fraction of the HHF patients.
RECOMMENDATION
The recommendations are as follow.
1. Routine request of Hs-CRP and serum uric acid to provide further insight into the role
of inflammation among patients with HHF.
2. A larger prospective trial would be needed to assess the impact of elevated Hs-CRP
and serum uric acid in predicting the disease severity in HHF patients.
LIMITATIONS
A higher sample size of each study group may have brought out more statistically relevant
relationship among the parameters that were otherwise not significant.
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APPENDIX I
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INFORMATION SHEET
THE CORRELATION BETWEEN HIGH SENSITIVE C-REACTIVE PROTEINS AND
SERUM URIC ACID LEVELS IN HYPERTENSIVE HEART FAILURE PATIENTS IN
OBAFEMI AWOLOWO UNIVERSITY TEACHING HOSPITALS COMPLEX.
WHAT IS THE STUDY ABOUT?
The study is aimed at assessing the serum levels of high sensitive C - reactive protein and uric
acid and correlate them with the severity of hypertensive heart failure.
WHAT IS EXPECTED IF I AGREE TO PARTICIPATE?
You will be expected to provide answers to some questions like, your age, marital status,
occupation, address, telephone number as well as contact details of your next of kin.
Information about your health and your medications shall also be obtained.
You will undergo a thorough physical examination, which will include measurements of your
weight, height and blood pressure. You will also undergo an Echocardiography – a painless
test and have about 10mls of your blood collected for laboratory investigations.
CONFIDENTIALITY
The Information collected from you will be handled in absolute confidence. No information,
in part or whole shall be divulged to anybody except with your permission.
BENEFIT TO PARTICIPANTS
By enrolling into this study, you will have the benefit of knowing how well your heart is
functioning. If you have had an Echo done before, you will know if there is any improvement
in function as compared to the previous one.
RISKS
There is no risk except for the discomfort of a needle prick when the blood sample is collected.
REFUSAL
Refusal to participate in the study will not deny you access to continuity of care.
NAME OF RESEARCHER: DR AGOKE ADEKUNLE
PHONE NUMBERS OF RESEARCHER: 08033658146
ADDRESS OF RESEARCHER: DEPARTMENT OF MEDICINE, OBAFEMI AWOLOWO
UNIVERSITY TEACHING HOSPITAL COMPLEX, ILE-IFE.
EMAIL OF RESEARCHER: [email protected]
APPENDIX II
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APPENDIX III
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INFORMED CONSENT FORM Initials: ……………………………….......................
In order to participate in this research study, it is necessary that you give informed consent.
By signing this form, you are indicating that you understand the nature of the research study
and your role in the research, and that you agree to participate in the research.
Please consider the following points before signing:
• I understand that I am participating in a research;
• I understand that my participation will be anonymous (that is, my name will not be
linked with my data) and that all information I provide will remain confidential;
• I understand that I will be provided with an explanation of the research in which I am
participating
• I understand that my participation in this research is voluntary, and that I may refuse to
participate further at any time without having to offer an explanation.
By signing this form I am stating that I am 18 years or older, and that I understand the above
information and consent to participate in this study.
…………………………….. ……………………………..
Signature of participant/ Date Signature of Investigator/ Date
APPENDIX 1V
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PROFORMA
Tick (√ ) or circle as appropriate
DERMOGRAPHIC DATA
Serial No. …………… Date ......./ ……. / ……..
1. Initials ……………..
2. Age at last birthday (years)
3. Sex: 1. Male ( ) 2. Female ( )
4. Occupation: 1. Unemployed ( )
2. Civil servant ( )
3. Business ( )
4. Others ( )
(Specify)
5. Marital status: 1. Married ( )
2. Single ( )
3. Separated ( )
4. Divorced ( )
7. Religion: 1. Christianity ( )
2. Islam ( )
3. Traditional ( )
4. Others ( )
(Specify)
8. Ethnicity: 1. Hausa ( )
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2. Ibo ( )
3. Yoruba ( )
4. Others ( )
(Specify)
9. Educational status: 1. Primary ( )
2. Secondary ( )
3. Tertiary ( )
4. Others ( )
(Specify)
10. Phone number ……………………
HISTORY OF HEART DISEASE
1) Do you usually have difficulty in breathing ………
2) If yes, how often ………
3) Does it occur at rest ( ) or during moment of activity ( )
4) Do you usually have difficulty in breathing while lying down on bed unsupported by
pillow ………
5) If yes, how often ………
6) Do you usually have difficulty in breathing that may awake you at night ………
7) If yes, since when ……..
8) Do you usually cough ………
9) If yes, since when ……
10) Is the cough productive of sputum Yes ( ) No ( )
11) What is the colour of the sputum Whitish ( ), Reddish ( ), others ( )
12) Have you noticed leg swelling ………
13) If yes, since when ………
14) Do you usually have palpitation ………
15) If yes, how often ………
16) Do you usually have chest pain ………
17) If yes, how often ………
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18) Have you ever been told to have high blood pressure …………
19) If yes, when ………
20) Family history of hypertension/who ……………
CO-MORBID CONDITIONS
Diabetes Yes/No
Renal disease Yes/No
Height: Weight: BMI:
Waist circumference: Hip circumference:
SMOKING, ALCOHOL AND SALT CONSUMPTION
Do you smoke cigarettes? Yes/No
If yes, how many stick per day……………..
For how long
Do you take alcohol? Yes/No
If yes, what type, how much- how many bottles per day/week, how often?
Occasionally………………………
At least weekly……………………
Daily………………………………..
New York Heart Association Functional class…………………………..
Clinical outcome on follow-up
Re-admission Yes/No
Death Yes/No
CARDIOVASCULAR EXAMINATION
Pulse rate (beat/min): Volume: Rhythm:
Blood pressure (mmHg):
Jugular Venous Pulsation: Elevated/Not elevated
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Apex beat: Left parasternal heave:
Palpable sounds/Thrills: Heart sounds:
CHEST: Bilateral basal crepitations
ABDOMEN: Tender hepatomegaly Ascites
LABORATORY RESULTS
Urinalysis
Protein Yes/No
Glucose Yes/No
Ketones Yes/No
Urine microscopy findings:
Fasting Blood Glucose: ------------- (mmol/L)
2-Hour Post Prandial :------------------(mmol/L)
Fasting Serum Lipid.
• Total cholesterol :-------------( mmol/L)
• HDL cholesterol :--------------( mmol/L)
• LDL cholesterol :--------------( mmol/L)
• Triglycerides :-------------------( mmol/L)
PCV (Packed Cell Volume)… WBC (White blood cell)…
Electrolyte, Urea and Creatinine
• Sodium: ---------------(mmol/L) Potassium: -------------(mmol/L)
• Bicarbonate: ------------- (mmol/L) Urea: ----------------(mmol/L)
• Creatinine: --------------(Umol/L)
BIOMARKERS
Hs C-reactive protein …………… mg/L
Uric acid …………. Mg/dl
IMAGING
ELECTROCARDIOGRAPHY:
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HR: RHYTHM:
PR INTERVAL: QRS DURATION:
QT/QTC INTERVAL: P WAVE DURATION/MORPHOLOGY:
LVH/RVH: T AND S CHANGES:
ARRYTHMIAS:
ECHOCARDIOGRAPHY:
2D/M-MODE
LAD…………. (cm) AOD…………. (cm) ACS…………. (cm)
IVSD…………. (cm) IVSS…………. (cm) LVIDd…………. (cm)
LVIDs…………. (cm) LVPWd…………. (cm) LVPWs…………. (cm)
EDV…………. (ml) ESV…………. (ml) SV…………. (ml)
EF…………. (%) FS…………. (%) RVDd…………. (cm)
LAarea (apical 4 chamber) ..…. (cm2) LAlength (apical 4 chamber) …….(cm)
LAarea (apical 2 chamber) …….(cm2) LAlength (apical 2 chamber) …….(cm)
DOPPLER
PULMONARY VALVE
PVVmax………….(ms-1) PVVmean………….(ms-1)
PVPGmax………….(mmHg) PVPGmean………….(mmHg)
PVVTI………….(ms) PVET………….(ms)
PVPEP………….(ms) HR………….(min-1)
MITRAL VALVE
E VEL ………….(ms-1) A VEL………….(ms-1) E/A…………
Dec T………….(ms) IVRT………….(ms) IVCT………….(ms)
MVVmax………….(ms-1) MVVmean………….(ms-1)
MVPGmax…………. (mmHg) MVPGmean………….(mmHg)
MVVTI………….(ms) MVPHT………….(ms)
Aduration………….(ms) Eduration………….(ms)
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TDI
E1………….(ms-1) A1………….(ms-1) S1………….(ms-1)
AORTIC VALVE
AVVmax………….(ms-1) AVVmean………….(ms-1) AVPGmax………….(mmHg)
AVPGmean………….(mmHg) AVVTI………….(ms) HR………….(min-1)
LVET………….(ms) LVPEP………….(ms)
PULMONARY VEIN
PvS………….(ms-1) PvD………….(ms-1) S/D………….
Arev………….(ms-1) Adur………….(ms)
TRICUSPID VALVE
Evelocity………….(ms-1) Avelocity………….(ms-1)
E/A………….
FRAMINGHAM HEART FAILURE DIAGNOSTIC CRITERIA
Criteria: Major (Heart Failure diagnosis requires 1 or more criteria positive)
A. Acute pulmonary oedema Yes/No
B. Cardiomegaly Yes/No
C. Hepatojugular reflex Yes/No
D. Neck vein distention Yes/No
E. Paroxysmal nocturnal Dyspnoea or Orthopnoea Yes/No
F. Pulmonary rales Yes/No
G. Third Heart Sound (S3 Gallup Rhythm) Yes/No
Criteria: Minor (Heart Failure diagnosis requires 2 or more criteria positive)
A. Ankle oedema Yes/No
B. Dyspnoea on exertion Yes/No
C. Hepatomegaly Yes/No
D. Nocturnal cough Yes/No
E. Pleural Effusion Yes/No
F. Tachycardia (Heart Rate >120 beats per minute) Yes/No
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APPENDIX V
Immunoplate well before analysis
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APPENDIX VI
Immunoplate wells showing colour change
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APPENDIX VII
Data analysing on Hs-CRP
APPENDIX VIII
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Transthoracic M-mode echocardiography of a 57yr old hypertensive heart failure patient.
KEY: LAD=left atrial diameter; AOD=Aortic root diameter, AV Cusp= Aortic valve
cusp.
APPENDIX IX
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The investingator in an echo session.
APPENDIX X
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ECG tracing of a 59 year woman with low limb voltage and left ventricular hypertrophy
(Cornel’s criterion).