1. Heart Failure With Preserved Ejection Fraction Prof.M.Khalilullah New Delhi, India Former Prof. & Head of Cardiology, Director, G.B.Pant Hospital, New Delhi Director, The Heart Centre, New Delhi

2. Ist Pulmonary Balloon Valvuloplasty 23 rd March, 1985 Percutaneous Catheter Commissurotomy in Rheumatic Mitral Stenosis. N Engl J Med 1985; 313:1515-1518 27 th March 1985 28 th March 1985 July 1985

3. 1987 1 st Balloon Renal Angioplasty 1986 Before After Double-balloon valvuloplasty of tricuspid stenosis.Am Heart J. 1987 Nov;114(5):1232–1233 Balloon dilatation of valv. AS, 1986

4. PDA Closure 1988 ASD Closure 1991 VSD Closure,1995 PTCA 1987

5. What is the difference between HFpEF, diastolic dysfunction, and diastolic HF? Heart failure with preserved ejection fraction (HFpEF)  Preferred term (ACC/AHA)  Most often have abnormalities in diastolic function (non-diastolic abnormalities in CV function also) Diastolic heart failure / Diastolic dysfunction  Other common terms for HFpEF but less specific

6. HFpEF is not “benign” Similar functional decline, hospital readmission rates, economic costs as HFrEF

7. What are the risk factors for HFpEF?  For HF in general  Age  Hypertension  Obesity  Dyslipidemia  Insulin resistance  For HFpEF  Older, more hypertensive, and higher prevalence of AF (than in HFrEF)  CAD prevalence comparatively lower  More common in women (by 2:1)

8. Are any interventions effective for primary prevention of HFpEF?  Control hypertension  Main factor in development and progression  Lower systolic & diastolic according to guidelines  Treat hyperlipidemia and hyperglycemia  Reduces risk for HFpEF and HFrEF  Encourage smoking cessation, exercise, healthy diet  Weight reduction can prevent diabetes, AF, obstructive sleep apnea, hypertension

9. Diagnosis  Signs and symptoms  Impaired exercise tolerance, orthopnea, dyspnea, and signs suggestive of HF  History may include hypertension and atrial fibrillation  Diagnosed based on H&P exam, x-rays, BNP levels, & ECHO  Criteria for diagnosing HFpEF  Signs / sxs of HF  Preserved systolic LV function (EF ≥45%–50%)  Evidence of: diastolic LV dysfunction, elevated LV filling pressures or surrogate markers of diastolic LV dysfunction

10. Which diagnostic tests should the clinician order for patients with suspected HF?  Electrocardiography  Radiography  Echocardiography  Laboratory tests  Plasma BNP or NT-proBNP  CBC: ? anemia, serum electrolytes, creatinine, glucose, liver function, urinalysis  Renal function and electrolytes

11. What additional tests should clinicians consider for patients with suspected HFpEF?  Cardiac catheterization (for new-onset HF)  Left heart: measure LVEDP + coronary angiography  Right heart: if needed to evaluate valvular heart disease suggested by echo, or if pulmonary hypertension not explained by left heart disease  When abnormal myocardial function present (? Infiltrative processes, constriction, others), consider:  Myocardial or fat pad tissue CT or MRI

12. What is the role of BNP in diagnosis and management?  Levels usually lower in HFpEF than HFrEF  When elevated: strong independent predictors of clinical events in HFpEF  No consensus on use to guide medical therapy  NT-proBNP  Superior for evaluating suspected acute HFpEF  Sensitive & specific for Dx acute HF in emergency dept: >450 pg/mL ( 900 pg/mL (≥50y)  BNP  Falsely negative in up to 20% with HFpEF  Doesn’t correlate with symptoms

13. How should HFpEF be treated?  Reduce preload  Use diuretics and vasodilators  BUT NOTE: Assess Volume Status carefully as aggressive reduction may cause hypotension if hypertensive & normovolemic  Consider control of hypertension with vasodilators alone  Treat acute HFpEF  First-line therapy: Vasodilators  I.V. nitrates + furosemide (improve cardiac output and reduce the symptoms)  Nitroglycerin to relieve acute pulmonary edema  Avoid aggressive diuresis (may cause hypotension)  Heart rate control, with particular attention in rapid AF

14.  Provide long-term treatment of hypertension  Improves diastolic tissue velocity in hypertension w/o HF  If no comorbid conditions: thiazide diuretics  If coronary atherosclerosis or AF: beta-blocker  Reduce / reverse adverse remodeling: ARBs  Manage Atrial Fibrillation  In HFpEF + AF: restore normal HR and NSR to improve symptoms (maybe not outcomes)  Rate control first: AV nodal blocking agents + β-blockers  Rhythm control: when rate control not achieved or when symptoms persist despite rate control  Immediate electrical cardioversion: new-onset AF and myocardial ischemia, symptomatic hypotension, or pulmonary congestion or rapid ventricular response uncontrolled by appropriate pharmacologic measures  Anticoagulation: to reduce thromboembolism risk

15. When should inotropic agents be considered?  Not indicated  Increase inotropy and heart rate  Have no lusitropic/diastolic relaxation effects  Studies on digoxin showed no significantly positive result

16. How does drug therapy for HFpEF differ from that of HFrEF?  Many of the same drugs are used but evidence differs  HFrEF: Improved mortality and morbidity with ACE inhibitors, ARBs, β- blockers, and aldosterone antagonists  HFpEF: No similar improvements found from the therapies  HFpEF focus: symptom relief, BP and heart rate control

17. Are any novel drug therapies being investigated for HFpEF?  Spirinolactone  Proven therapy for HFrEF  Under investigation for HFpEF (TOPCAT study)  Sildenafil (phosophodiesterase-5 inhibition)  In small study: Reduced pulmonary arterial pressure, improved right ventricular systolic function, reduced right atrial pressure, improved QOL  Efficacy being studied in larger RELAX trial

18. What are potential triggers of decompensation?  Dietary indiscretion  Use of NSAIDs  Medication nonadherence  Dysrhythmias (particularly AF)  Ischemia or infarction  Hypertension  Worsening renal function  Valvular cardiac disease  Alcohol abuse  Infection

19. What is the role of diet and monitoring weight?  Advise patients to weigh themselves daily  Unexpected weight gain may warrant prompt action  If weight gain, increased edema, other HF symptoms occur, patient should promptly call health care provider  Sodium restriction recommended in symptomatic HF  To prevent fluid retention  Fluid restriction (≤1.5-2 L/day)  For severe symptoms of HF, especially hyponatremia

20. What should clinicians advise patients with HFpEF about exercise?  Advise regular, moderate daily activity  Aerobic exercise especially beneficial  Improve CV performance  Lowers blood pressure  Prevents or reverses deconditioning  Increases energy levels  Reduces symptoms of HF

21. What is the prognosis of HFpEF?  Annual death rate ≈5%  ≈50% die of noncardiovascular diseases  Risk factors for mortality in HFpEF  Increasing age, male gender  Higher natriuretic peptide levels, higher NYHA class  Coronary artery or peripheral vascular disease  Diabetes mellitus, chronic renal insufficiency  Lower EF, restrictive filling pattern on Doppler ECHO  Low and very high BMI (in HFpEF)

22. How should patients with HFpEF be followed?  Educate patients on signs of fluid retention  Provide guidelines for using a flexible diuretic regimen  Provide telephone access to health care providers  Emphasize low-salt diet + medical regimen compliance  Frequency of follow-up visits depends stability of patient  See w/in 7d of hospital discharge for decompensated HF  See well-compensated patient every 4 to 6 months

23. When should patients with HFpEF be hospitalized?  Respiratory failure secondary to pulmonary edema  Moderate to severe volume overload  Atrial fibrillation with rapid ventricular response  Severe hypotension or hypertension  Need for close monitoring during therapy (e.g., of renal function, electrolytes)

24. When should clinicians consider consulting a cardiologist?  Diagnosis of HFpEF uncertain  Cause of HFpEF unclear  Patient symptomatic despite treatment  Frequent hospitalizations for decompensation  Comorbid cardiac conditions complicate management (CAD or dysrhythmia)

25. Ivabradine  Ivabradine is a highly selective blocker of inward “funny” channels, which are central regulators of spontaneous depolarization in pacemaker cells.  Thus ivabradine selectively decreases heart rate without having negative inotropic or lusitropic effects, as can occur with beta-blockers.  Furthermore, animal and human studies have shown that ivabradine can decrease heart rate while simultaneously improving stroke volume and cardiac output.

26. Ivabradine –If channel inhibition  Heart rate reduction by If-inhibition improves vascular stiffness and left ventricular systolic and diastolic function in a mouse model of heart failure with preserved ejection fraction.  Genetic mouse model of HFpEF (db/db)  Invasive hemodynamics with Ivabradine  Ivabradine improved diastolic function (Reil et al, Eur Heart J, 2012:1-11)

27.  An elegant study, which used a novel HFpEF animal model, the db/db (leptin-receptor deficient) mouse, found that heart rate lowering with ivabradine had several beneficial effects, including reduced effective arterial elastance (Ea), increased aortic distensibility and decreased LV end-systolic elastance (Ees).  In addition, ivabradine accelerated myocardial relaxation by increased phosphorylation of phospholamban, reversing the SERCA2a inhibition that was present in the db/db mouse.

28. Ivabradine phase II study in HFpEF Primary objective Ivabradine vs placebo on diastolic function, exercise capacity and neuroendocrine activation over an 8-month treatment period in patients with chronic HF-PEF. Primary endpoint Co-primary endpoint based on echocardiography (E/e'), neuroendocrine activation (NT-proBNP) and six-minute walk test evaluated at 8 months. Secondary objectives - To evaluate the effects of ivabradine compared to placebo on cardiac function and structural parameters, quality of life (KCCQ), NYHA classification and other biomarkers. - To evaluate the safety and tolerance profile of ivabradine compared to placebo. (Start: May 2013 !)

29. Ivabradine - conclusion In conclusion, Kosmala, Marwick and colleagues should be congratulated for carrying out a carefully conduced and detailed exercise hemodynamic study in HFpEF patients, By taking ivabradine, a blocker of the inward “funny” current and matching it with the right type of HFpEF patient, coupled with appropriate endpoints (peak VO2 and exercise E/e), the authors were successful matchmakers and may have found a novel therapy for an otherwise difficult-to-manage patient population.

30. SUMMARY HFpEF constitute about 50% of all Pts of HF. More common in females, with elderly age, HTN, DM,COPD, AF. Comorbidities contribute to progress of disease. Accurate diagnosis & proper Rx may prolong life, reduce hospital re admissions and improve QOL. Newer drugs like ivabradine, sidnofil, neprilysin inhibitions, MR antagonist are under trial. New devices & interventions to be developed. - Renal denervation, interatrial shunting, vagus / baroreceptor stimulation