Heart Failure With Preserved Ejection Fraction Akash Patel, M.D .

1. Heart Failure With Preserved Ejection Fraction Akash Patel, M.D.

2. Learning Objectives • Define heart failure with preserved ejection fraction • Discuss the burden of disease • Identify clinical features • Review diagnostic options • Discuss the evidence behind various therapies • Discuss the significance of associated conditions • Discuss prognosis

3. Defining The Problem • A Clinical Diagnosis • 1. Signs and symptoms of circulatory congestion • 2. Ejection fraction ≥50%

4. The Growing Scope • Proportion of heart failure with reduced ejection fraction (HFrEF) has been declining while that for heart failure with preserved ejection fraction (HFpEF) has increased. Currently estimated to be a 50/50 split1 • At least 2.5 million people in the United States are estimated to suffer from HFpEF • By 2020, an estimated 65% of HF-related hospitalizations will be HFpEF.2 In 2040, there will be.772,000 new cases of diagnosed HF in the United States.3

5. Clinical Features • Symptoms • Dyspnea +/− exertion • Exercise intolerance • Orthopnea/PND4 • Edema/weight gain • Chest Pain • Early satiety5

6. Clinical Features • Physical Exam • Elevated jugular venous pressure6 • Rales • Edema • Ascites

7. Diagnostic Tools: The Echo • Diastolic Dysfunction • Almost always present but not strictly necessary for the diagnosis • Assessment relies on Doppler and 2D assessment7: • Flow pattern and velocities across the mitral and tricuspid valves, and the pulmonary veins • Tissue Doppler assessment at the medial and lateral mitral annulus • Left atrial volume

9. Diastolic Function: Caveats • Patients with minimal symptoms and normal diastolic function at rest, but symptomatic with exertion • Patients with diastolic dysfunction and symptoms that are not clearly linked

10. Comparing Echo Parameters at Rest and With Exercise

11. Diagnostic Tools: Other Non-Invasive Data • Left atrial size (provides estimate of chronic left ventricular end-diastolic pressures)-measured via left atrial volume in apical acoustic windows • Serum brain natriuretic peptide levels • Cardiopulmonary exercise testing

12. Right Heart Catheterization • Due to the refinement of non-invasive methods of acquiring data, catheterization is usually not required to establish the diagnosis • Invasive measurement of filling pressures is the clinical gold standard • Can be augmented by provocative maneuvers (usually exercise)8

13. Other Modalities • Ischemic Evaluation • CAD present in 67% of patients with HFpEF9 • CAD isanunder-recognizedcause of diastolicdysfunction • 2013 ACCF/AHA guidelinessuggestanimagingstress test for patients with known CAD presenting with new-onsetHFpEF, evenwithout angina10 • Coronaryangiogramrecommended in patients with significant ischemia thatisfelt to be contributing to heartfailure • Specialized testing

14. Treatment: ACE-inhibitors • PEP-CHF trial compared perindopril to placebo in 850 patients with HFpEF11 • There was no significant difference with regard to primary endpoint (composite of mortality and HF-related hospitalization) due to insufficient powering • Improved functional class and 6-minute walk test in the treatment arm

15. Diuretics • Evidence from a CHAMPION trial ancillary study investigating the effect of CardioMEMS-guided assessment of pulmonary artery pressure on both HFpEF and HFrEF12 • Abnormal PA pressures most commonly resulted in a diuretic dose change • These device-guided changes in therapy resulted in a 50% decrease in hospitalizations at 1 year

16. Diuretics: A Gap in Knowledge • Diuretics are our first line treatment in reducing symptoms, but… • What provider would willingly enroll a patient into a trial in which they could potentially be assigned to a placebo in place of a diuretic for any significant length of time? • We inherently KNOW these medications provide benefit, this is not well-quantified

17. Beta Blockers • In HFrEF, a mainstay of therapy to prevent cardiac remodeling • In a meta-analysis of 11 RCTs, no benefit was found for beta blocker use in the subgroup of patients with LVEF≥50%13 • Not currently recommended unless there is another indication such as angina

18. Mineralocorticoid Antagonists • TOPCAT trial (2014) • ~3400 patients in this multinational study with LVEF≥45% treated with spirinolactone or placebo • Null for primary outcome (death, HF hospitalization, or aborted cardiac arrest) • Subgroup analyses: • Less HF hospitalizations in treatment arm • Significant reduction in primary outcome in America versus Eastern Europe • Decreased HF hospitalizations in those with elevated BNP at baseline14

19. Exercise Training • Underutilized but crucial aspect of HFpEF management • While exercise training does not impact mortality, it does improve exercise capacity and quality of life15 • Can be accomplished in outpatient cardiac rehabilitation programs • Barriers: cost to patients, resources required, frequent interruption with exacerbations

20. Ineffective Medications • Nitrates: reduced activity levels in patients at all doses (NEAT-HFpEF trial) without increase in exercise capacity or improvement in symptoms16 • PDE-5 inhibitors: did not improve exercise capacity or hemodynamics (cardiac output, maximum VO2, PCWP) in the RELAX trial17 • Digoxin: no effect on all-cause or cardiovascular mortality, or hospitalizations (DIG trial)18

21. Associated Conditions • HFpEF is associated with a number of other diseases that impact one another in bidirectional fashion • Hypertension: treatment reduces the incidence of HFpEF, but NOT the prognosis once heart failure is present • Atrial fibrillation: present in 67% of patients with HFpEF at some point in their clinical course; associated with increased morbidity and mortality19

22. Prognosis • Diastolic dysfunction increased mortality even without the development of heart failure (estimated to be up to 8-fold for mild dysfunction in the Mayo Clinic cross-sectional community survey)20 • For patients with HFpEF, there is conflicting data. Many large studies have reported similar longitudinal outcomes in HFrEF and HFpEF (up to 30% 1-year mortality) and other studies have noted a much better prognosis for HFpEF • Morbidity measures such as 6-minute walk testand peak VO2 are generally similar between HFrEF and HFpEF patients, suggesting a similar morbidity burden

23. Future Directions • Vascular and cellular involvement in inflammation and remodeling (nitric oxide, titin phosphorylation) • Cardiometabolic functional abnormalities (partial adenosine agonists, mitochondrial enhancers) • Mediators of cardiac stiffness (modification of titin, TGF-beta)

24. References 1. Epidemiology of Heart Failure With Preserved Ejection Fraction. Nat Rev Cardiol. 2017 Oct;14(10):591-602. doi: 10.1038/nrcardio.2017.65.Epub 2017 May 11. 2. The Emerging Epidemic of Heart Failure. Curr Heart Fail Rep. 2013 Dec; 10(4): 10.1007/s11897-013-0155-7. 3. Epidemiology of Diastolic Heart Failure. Prog Cardiovasc Dis. 2005;47(5):320. 4. Value of Orthopnea, Paroxysmal Nocturnal Dyspnea, and Medications in Prospective Population Studies of Incident Heart Failure. Ekundayo O et al. Am J Cardio. 2009 Jul 15; 104(2): 259-264. 5. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. Kitzman DW et al. JAMA. 2002;288(17):2144. 6. Butman SM et al. Bedside cardiovascular examination in patients with severe chronic heart failure: importance of rest or inducible jugular venous distention. J Am Coll Cardiol 1993; 22:968-974. 7. Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr; 2016;29:277-314). 8. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Circ Heart Fail. 2010 Sep;3(5):588-95. Epub 2010 Jun 11. 9. Implications of coronary artery disease in heart failure with preserved ejection fraction. Hwang SJ, Melenovsky V, Borlaug BA . J Am Coll Cardiol. 2014 Jul;63(25 Pt A):2817-27. Epub 2014 Apr 23. 10. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Yancy CW et al, American College of Cardiology Foundation, American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Oct;62(16):e147-239. Epub 2013 Jun 5. 11. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J, PEP-CHF Investigators. Eur Heart J. 2006;27(19):2338. Epub 2006 Sep 8. 12. Wireless pulmonary artery pressure monitoring guides management to reduce decompensation in heart failure with preserved ejection fraction. Adamson PB, Abraham WT, Bourge RC, Costanzo MR, Hasan A, Yadav C, Henderson J, Cowart P, Stevenson LW. Circ Heart Fail. 2014 Nov;7(6):935-44. Epub 2014 Oct 6. 13. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Cleland JGF, Bunting KV, Flather MD, Altman DG, Holmes J, Coats AJS, Manzano L, McMurray JJV, Ruschitzka F, van Veldhuisen DJ, von Lueder TG, Böhm M, Andersson B, Kjekshus J, Packer M, Rigby AS, Rosano G, Wedel H, HjalmarsonÅ, Wikstrand J, Kotecha D, Beta-blockers in Heart Failure Collaborative Group. Eur Heart J. 2018;39(1):26. 14. Spirinolactone for Heart Failure With Preserved Ejection Fraction. Pitt et al. for the TOPCAT investigators. N Engl J Med 2014; 370:1383-1392. 15. Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. Kitzman DW, Brubaker PH, Morgan TM, Stewart KP, Little WC. Circ Heart Fail. 2010 Nov;3(6):659-67. Epub 2010 Sep 17. 16. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ, Felker GM, Cole RT, Reeves GR, Tedford RJ, Tang WH, McNulty SE, Velazquez EJ, Shah MR, Braunwald E, NHLBI Heart Failure Clinical Research Network. N Engl J Med. 2015;373(24):2314. Epub 2015 Nov 8. 17. Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial. Hoendermis ES, Liu LC, Hummel YM, van der Meer P, de Boer RA, Berger RM, van Veldhuisen DJ, Voors AA. Eur Heart J. 2015;36(38):2565. 18. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF Jr, Gheorghiade M. Circulation. 2006;114(5):397. Epub 2006 Jul 24. 19. Temporal relationship and prognostic significance of atrial fibrillation in heart failure patients with preserved ejection fraction: a community-based study. Zakeri R, Chamberlain AM, Roger VL, Redfield MM. Circulation. 2013 Sep;128(10):1085-93. Epub 2013 Aug 1. 20. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. JAMA. 2003;289(2):194.