Current status and future expectation for management of diastolic heart failure

1. Current status and future expectation for management of diastolic heart failure Mehmet Birhan YILMAZ, MD, FESC

2. Diastolic heart failure (Heart Failure with Preserved 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.

3. European Criteria for HFPEF (Diastolic HF) • Presence of signs and/or symptoms of chronic HF • Presence of Normal or only mildly abnormal LV systolic function (LVEF≥45-50%) • Evidence of diastolic dysfunction (abnormal LV relaxation or diastolic stiffness) ESC Guideline 2008

4. 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

5. Concensus Statement HFA-EA of ESC Paulus W et al. EHJ 2007;28:2539-50

6. 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

7. Diastole Viscoelastic properties Relaxation rate Elastic recoil Pericardial restrant Coronary artery turgor Ventricular interaction Ventricular and atrial non-uniformity Eur J Echocardiogr. 2002;3(1):75-9 Eur J Heart Fail. 2002;4(4):419-30

8. 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

9. Pathophysiology Systolic HF Normal heart Diastolic HF Aurigemma GP, et al. Circulation 2006; 113: 296–304

10. 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

11. DiastolicLV dysfunction does not seem to be the sole mechanism underlying DHF. Numerous other mechanisms: • reduced mitral annularshortening velocity • Reduced radial deformation • Impaired ventriculovascular coupling • LA dilation • pulmonary arterial hypertension

12. 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

13. Diastolic Heart Failure: Mechanisms Myocardial Cardiomyocyte Myofilaments Extracellular matrix Fibrillar collagen      Proteoglycans  impaired MMP/TIMP ratio, AGE products (DM), Extramyocardial Hemodynamic load Heterogenity     Pericardium Calcium homeostasis                       Modifying proteins (phospholamban, calmodulin, calsequestran)             Tn-C calcium binding Myofilament calcium sensitivity /ß-myosin heavy chain ATPase ratio Impaired 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) Neurohormonal activation: RAAS, SNS, NP, NO, Endothelin         Circulation. 2002;105:1503-1508

14. 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.

15. Ouzounian M. Nature Clin Pract Cardiovasc Med. 2008; 5(7): 375-86

16. Single syndrome fans Discrete syndromes fans

17. 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.

18. Diastolic CHF? Ventricular Understanding nondiastolic mechanisms of Heart Failure with Normal Ejection Fraction may provide further answers and, more importantly, lead to more therapeutic advances. Myocardial systolic Vascular Normal EF Heart Failure Renal Non-CV Neurohumoral Bench T, et al. Current Heart Failure Reports 2009, 6:57–64

19. 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.

20. Echocardiography E = early filling A = atrial contration Aurigemma GP. NEJM. 2004;351:1097-105.

21. Grade 1 Grade 2 Grade 3 Grade 4 Diastolic Dysfunction LVpressure E Mitral flow TissueDoppler e’ Pulmonaryvein E/e’ < 10 10 -15 >15 >15 CP1008785-63

22. PCWP (mm Hg) 45 40 r = 0.87 35 n = 60 30 Mitral E 25 20 Annulus e 15 10 E/e 5 0 5 10 15 20 25 30 35 E/e’ As LV fillingpressure  Nagueh et al: JACC, 1997 Ommen et al: Circ, 2000

23. Increasing LV filling pressure Increasing pulmonary pressure during exercise Exercise intolerance Impaired Active Relaxation Increased Passive Stiffness & Impaired early filling Increasing LA pressure and size Normal exercise tolerance Exercise intolerance and HF signs Impaired diastolic filling Diastolic dysfunction Diastolic HF

24. 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

25. 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.

26. 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.

27. Stepwise approach to clinical evaluation of the dyspnoeic patient with normal LV systolic function for the presence of diastolic heart failure. Mottram, P. M et al. Heart 2005;91:681-695

28. 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.

29. Completed trials for HF with preserved EF Lam CSP. Ann Acad Med. 2009;38(8): 663-666.

30. Large Outcome Trials in HFNEF Paulus W et al. EHJ 2007;28:2539-50

31. HFNEF Registries Paulus W et al. EHJ 2007;28:2539-50

32. Statins in diastolic HF RR death [95% CI] 0.20 [0.06 to 0.62]; P=0.005 Fukuta H. Circulation. 2005;112:357-363

33. 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):

34. Hunt, et al. 2009 ACCF/AHA Heart Failure Guidelines. (Circulation. 2009;119:e391-e479.

35. 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)

36. 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)