current status and future expectation for management of diastolic heart failure
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Current status and future expectation for management of diastolic heart failure. Mehmet Birhan YILMAZ, MD, FESC. - PowerPoint PPT PresentationTRANSCRIPT
Current status and future expectation for management of
diastolic heart failure
Mehmet Birhan YILMAZ, MD, FESCMehmet Birhan YILMAZ, MD, FESC
Diastolic heart failure (Heart Failure with Heart Failure with Preserved Ejection FractionPreserved Ejection Fraction) refers to a clinical
syndrome in which patients have symptoms and signs of HF, normal or near normal left ventricular systolic function (?, near-normal EF), and evidence of diastolic dysfunction.
European Criteria for HFPEF (Diastolic HF)
1. Presence of signs and/or symptoms of chronic HF
2. Presence of Normal or only mildly abnormal LV systolic function (LVEF≥45-50%)
3. Evidence of diastolic dysfunction (abnormal LV relaxation or diastolic stiffness)
ESC Guideline 2008
Diagnostic Criteria of AHA/ACC
Symptoms and signs compatible with heart failure
Left ventricular ejection fraction >50% Exclusion of severe valvular disease and
pericardial disease
Hunt SA et al. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation 112: e154–e235
Concensus Statement HFA-EA of ESC
Paulus W et al. EHJ 2007;28:2539-50
Epidemiology 20% to 60% of patients with HF Increasing prevalence
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Owan T, et al. NEJM. 2006;355:251-9
Diastole
Viscoelastic properties
Coronary artery turgor
Pericardial restrant
Elastic recoil
Ventricular interaction
Ventricular and atrial non-uniformity
Relaxation rate
Eur J Echocardiogr. 2002;3(1):75-9 Eur J Heart Fail. 2002;4(4):419-30
In contrast to SHF, the diastolic pressure-volume curve is shifted up and left, indicating an increase in passive stiffness
of the ventricle .
Circulation 2006;113:296-304
Aurigemma GP, et al. Circulation 2006; 113: 296–304
Systolic HF
Normal heart
Diastolic HF
Pathophysiology
Structural abnormalities Chamber remodelling: Normal EDV Pathological wall thickening Increased ratio of myocardial mass/chamber
volume Increased ratio of wall thickness/chamber
diameter Increased cardiomyocyte diameter Increased extracellular matrix
Diastolic LV dysfunction does not seem to be the sole mechanism underlying DHF. Numerous other mechanisms:
reduced mitral annular shortening velocity Reduced radial deformation Impaired ventriculovascular coupling LA dilation pulmonary arterial hypertension
Non-diastolic mechanisms Volume overload Venoconstriction/volume redistribution Chronotropic incompetence: RESET trial
(Restoration of Chronotropic Competence in Heart Failure Patients with Normal Ejection Fraction) is ongoing to test rate-adaptive pacing
Endothelial dysfunction
Bench T, et al. Current Heart Failure Reports 2009, 6:57–64
Diastolic Heart Failure: MechanismsDiastolic Heart Failure: Mechanisms
Extramyocardial Hemodynamic load Heterogenity Pericardium
MyocardialCardiomyocyte
Myofilaments
Extracellular matrixFibrillar collagen Proteoglycans impaired MMP/TIMP ratio, AGE products (DM),
Neurohormonal activation: RAAS, SNS, NP, NO, Endothelin
Calcium homeostasis Modifying proteins (phospholamban, calmodulin, calsequestran)
Tn-C calcium bindingMyofilament calcium sensitivity/ß-myosin heavy chain ATPase ratioImpaired phosphorylation and structure of Titin (reduced Protein kinase G activity, related to decreased cGMP, N2B,isoform of titin, tends to predominate in stiffer ventricle, whereas N2BA occurs in more compliant hearts)
Circulation. 2002;105:1503-1508
Pathophysiology Signs and symptoms of fluid retention form the
clinical picture(secondary to abnormal renal sodium handling and arterial stiffness, in addition to myocardial stiffness reduced ventricular compliance)
The majority of patients have a history of hypertension
Most of the patients have evidence of LVH on echocardiography.
More frequent in elderly women
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-86
Single syndrome fans
Discrete syndromes fans
Myocardial disorders associated with HF and normal LVEF
Restrictive cardiomyopathy Obstructive hypertrophic cardiomyopathy Nonobstructive hypertrophic cardiomyopathy Infiltrative cardiomyopathies
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Diastolic CHF?
Understanding nondiastolic mechanisms of Heart Failure with Normal Ejection Fraction may provide further answers and, more importantly, lead to more therapeutic advances.
Myocardial systolic
VentricularVascular
Renal
Neurohumoral
Non-CV
Normal EF Heart Failure
Bench T, et al. Current Heart Failure Reports 2009, 6:57–64
Diagnosis Ventricular relaxation is slowed Elevated LV filling pressure in a patient with
normal LV volumes and contractility. Clinical diagnosis based on the finding of typical
symptoms and signs of HF in a patient who is shown to have a normal LVEF and no valvular abnormalities (aortic stenosis or mitral regurgitation, for example) on echocardiography.
Doppler echocardiography (TTE) BNP levels in addition to TTE improve
diagnostic accuracy.
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Echocardiography
Aurigemma GP. NEJM. 2004;351:1097-105.
E = early filling
A = atrial contration
Diastolic Dysfunction
LVLVpressurepressure
LVLVpressurepressure
Grade 1Grade 1Grade 1Grade 1 Grade 2Grade 2Grade 2Grade 2 Grade 3Grade 3Grade 3Grade 3 Grade 4Grade 4Grade 4Grade 4
Mitral flowMitral flowMitral flowMitral flow
TissueTissueDopplerDopplerTissueTissue
DopplerDoppler
PulmonaryPulmonaryveinvein
PulmonaryPulmonaryveinvein
CP1008785-63
E/e’E/e’
EE
e’e’
< 10< 10 10 -1510 -15 >15>15 >15>15
Nagueh et al: JACC, 1997Nagueh et al: JACC, 1997Ommen et al: Circ, 2000 Ommen et al: Circ, 2000
4545
4040
3535
3030
2525
2020
1515
1010
5500 101055 1515 2020 2525 3030 3535
E/e’
PCWP (mm Hg)
r = 0.87r = 0.87
n = 60n = 60
Annulus eAnnulus e
Mitral EMitral E
E/eE/e
As LV fillingAs LV fillingpressure pressure As LV fillingAs LV fillingpressure pressure
Impaired Impaired Active RelaxationActive Relaxation
Increased Increased Passive StiffnessPassive Stiffness
Impaired diastolic Impaired diastolic fillingfilling
Diastolic dysfunctionDiastolic dysfunction
Diastolic HFDiastolic HF
Impaired early filling
Normal exercise tolerance
Increasing LV filling pressure
Increasing pulmonary pressure during exercise
Exercise intolerance
Increasing LA pressure and size
Exercise intolerance and HF signs
&&
Systolic dysfunction with normal EF
New doppler echocardiography techniques reveals abnormal ventricular function particularly in the long axis.
Ejection is relatively preserved because of increased radial function.
Sanderson JE. Prog Cardiov Dis. 2006;49(3): 196-206
Prognosis
HR 1.13; 95%CI 0.94-1.36; P=0.18
Owan TE. NEJM. 2006;355:251-9.
Bhatia RS. NEJM. 2006;355:260-9.
The typical patient with HFPEF is an elderly woman with a history of hypertension often with diabetes whose heart failure is episodic often precipitated by an episode of AF, ischemia or infection.
Mottram, P. M et al. Heart 2005;91:681-695
Stepwise approach to clinical evaluation of the dyspnoeic patient with normal LV systolic function for the presence of diastolic heart failure.
Treatment Limited evidence. Use of same drugs as for systolic CHF justified
due to co-morbid conditions – Atrial fibrillation, hypertension, diabetes mellitus,
and coronary artery disease The management of these patients is based on
the control of physiological factors (blood pressure, heart rate, blood volume, and myocardial ischemia)
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Completed trials for HF with preserved EF
Lam CSP. Ann Acad Med. 2009;38(8): 663-666.
Large Outcome Trials in HFNEF
Paulus W et al. EHJ 2007;28:2539-50
HFNEF Registries
Paulus W et al. EHJ 2007;28:2539-50
Statins in diastolic HF
Fukuta H. Circulation. 2005;112:357-363RR death [95% CI] 0.20 [0.06 to 0.62]; P=0.005
Ongoing trials ALDO-DHF trial (Aldosterone Receptor Blockade in
Diastolic Heart Failure): results expected by the end of 2010
Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT)
Start Date: August 2006, Estimated Completion Date: July 2013, Spironolactone vs. Placebo, N = 4500
RELAX (Phosphodiesterase-5 Inhibition to Improve Quality of Life and Exercise Capacity in Diastolic Heart Failure Trial):
Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.
Reasons for Failure of Trials of HFNEF Expectation of similar pathophysiological mechanisms
though HFREF and HFNEF are very different Enrolment of heterogenous population with defective
criteria Overrepresentation of those with ischemia (CAD is
main cause of HFREF, but 1/3 in HFNEF) Lack of strict diastolic dysfnx criteria for enrolment In the presence of criteria for DD, enrolment of only
those with mild DD (lack of enrolment of those with severe disease)
Future Strategies Interference with specific myocardial signal
transduction pathways of cardiomyocyte hypertrophy
Upregulation of MMPs (or downregulation of TIMP) Treatment of stiff titin isoforms by
rephosphorylation (phosphodiesterase-5 inh) Substrate shifts from FA-glucose in order to avoid
toxic effects (especially in DM, eg: TZD) Use of specific AGE cross link breaker agents (for
DM DHF, eg: Alagebrium chloride)