current status and future expectation for management of diastolic heart failure

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)