What to do for the Patient with Heart Failure and Preserved Ejection Fraction: HFpEF

What to do for the Patient with Heart Failure and Preserved Ejection Fraction: HFpEF Mariell Jessup MD, FAHA, FACC, FESC Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Disclosure: Mariell Jessup MD Speakers Bureau: Advisory Board: Honorarium: University of Pennsylvania NONE

Systolic Heart Failure HFrEF Normal Diastolic Heart Failure HFpEF Aurigemma, Zile, Gaasch Circulation 2005

Heart Failure with Preserved Ejection Fraction (HFpEF) HFpEF is defined by a normal or near-normal EF (>0.50 or 0.45). This cut point does not exclude systolic dysfunction, but is not usually associated with heart failure symptoms in the absence of other factors. Hence the term preserved systolic function. HFpEF is not a specific diagnosis or syndrome. It is a constellation of findings caused by diverse etiologies for which non-cardiac etiologies are excluded. HFpEF is often equated with diastolic heart failure.

prevalence % mean age 78-76 75-60 68 65 Prevalence of Heart Failure 10 9 8 7 USA (CHS) Finland (Helsinki) England (Poole) Sweden (Vasteras) Den. (Copen.) Spain (Asturias) Portugal (EPICA) Nether. (Rotter.) Proportion with decreased LV systolic function Proportion with preserved LV systolic function 6 5 8.8 8.2 7.5 6.7 6.4 4 3 4.9 4.2 age range 2 1 0 4.8 66-103 4.2 75-86 5.1 70-84 75 3.1 4.5 > 50 2.9 > 40 1.7 >25 2.1 1.5 55-95

HFpEF Epidemiology: Olmsted County, MN ~50% of all patients with HF have an LVEF 50% Average age 74±14 years 56% female, 44% male Relatively high rates of co-morbidities: Hypertension: 63% CAD: 53% AFib: 41% Obesity: 41% Diabetes: 33% Owan TE Redfield MM. N Engl J Med 355:251-9, 2006

Secular Trends in HFpEF Prevalence Associated with increasing prevalence of AFib (29 41%) and Diabetes (32 36%), but no change in CAD 59 59%) Owan TE Redfield MM. N Engl J Med 355:251-9, 2006

Prognosis of Patients with HFpEF After 1 st Hospitalization Overall Bhatia RS...Liu PP. N Engl J Med 355:260-9, 2006 Owan TE Redfield MM. N Engl J Med 355:251-9, 2006

Effect of LVEF on In-Hospital Outcomes for ADHF Data from >100,000 hospitalizations of the Acute Decompensated Heart Failure Registry (ADHERE) CHF-pEF present in 50.4% of patients Patients with CHF-pEF were older, women, and hypertensive; less likely to have prior MI In-hospital mortality was 2.8% for patients with CHF-pEF and 3.9% for patients with reduced EF Yancy CW et al. (ADHERE). J Am Coll Cardiol 47:76-84, 2006

Effect of LVEF on Post-Hospital Outcomes for ADHF The OPTIMIZE Registry examined 90-day follow up of 20,118 patients admitted with HF and LVEF<40% and 21,149 patients with HF-pEF There were similar rates of mortality (9.5% vs. 9.8%) and rehospitalization (29.2% vs. 29.9%) among patients with HF-pEF and HF with systolic dysfunction, respectively Fonarow G et al. J Am Coll Cardiol 50:768-77, 2007

Differences and Similarities Between HFpEF and HFrEF Differences More women Older patients More hypertension (past and current) Less CAD, especially MI More CKD Smaller, thicker LV Similarities Race Diabetes Tobacco Lipids Obesity Atrial fibrillation (?)

Pathophysiology of HFpEF: Cardiac Morphology & Hemodynamics LV Morphology (Normal: ) HF with LVEF HFpEF LVEDV Normal LV Mass or normal Relative Wall Thickness LVEF Normal Left Atrium Dilated Dilated LVEDP

Diagnosis of HF-pEF European Society of Cardiology Algorithm Symptoms/Signs of HF + LVEF>50% & LVEDVI>97 ml/m 2 Evidence of Abnormal LV relaxation, filling or stiffness Catheterization mpcw >12 mmhg LVEDP >15 mmhg Tau > 48 ms TD E/E >15 + or or or TD 8<E/E <15 + BNP>200 Paulus WJ et al. Eur Heart J 28:2539-50, 2007 TD 8<E/E <15 + Abnormal Blood flow Doppler

The unmet need of patients with heart failure and preserved ejection fraction, HFpEF. Co-morbidities in HFpEF

Pathophysiology of HF-pEF Focus on Arterial Stiffening

Vessel Composition Across the Circulatory System Relatively high elastic tissue content in large conduit arteries favors their ability to absorb and release energy

Effect of Normal Conduit Vessel Elasticity

Energy Storage in Elastic Materials The amount of energy stored in materials can be determined by calculating the area under the stress-strain curve, which is shown for the brittle material, stiff material, and compliant material. A compliant material will store more energy than a brittle material for a given value of applied stress, S. Saltzman WM. Biomedical Engineering: Bridging Medicine and Technology. (New York: Cambridge Univ Press, 2009)

Effect of Reduced Conduit Vessel Elasticity

Pathophysiology of HF-pEF: Arterial Stiffness and Wave Reflections 336 consecutive Pts hospitalized for LHC & EF>50% Invasive and noninvasive assessments of diastolic function Invasive and noninvasive assessments of arterial stiffness and wave reflection Arterial pulse wave velocity (an index of vascular stiffness) was the most powerful predictor of E and LVEDP In multivariate analysis, female gender & higher pulse wave velocity were independently associated with symptoms Weber T et al. Am J Hypertens 21:1194-1202, 2008

Augmentation Index Pulse Wave Velocity (m/s) LVEDP (mmhg) E septal (cm/s) NYHA: I II III. NYHA: I II III. NYHA: I II III. NYHA: I II III. Weber T et al. Am J Hypertens 21:1194-1202, 2008

Diastolic Function in HF-pEF vs. Hypertensive LVH (H-LVH) Control (56) H-LVH (40) HF-pEF (37) Age 65±11 67±10 65±10 LVEDV 111±24 112±32 115±33 E/A ratio 1.1±0.3 0.9±0.3 1.0±0.4 E-decel time 219±42 247±64 * 257±112 IVRT 78±11 96±17 85±22 E/E ratio 8.4±2.2 11±4.5 15±5.3* Dias Fxn Grade 0.6±0.9 1.1±0.9 1.4±0.9 Melenovsky V Kass DA. J Am Coll Cardiol 49:198-207, 2007

Exercise Responses in HF-pEF vs. Normal: Impairment in the Frank-Starling Mechanism Kitzman DW Sullivan MJ. J Am Coll Cardiol 17:1065-72, 1991

Exercise Responses in H-LVH vs. HF-pEF Differences at Peak Exercise - HTNsive LVH - HF-pEF Borlaug BA Kass DA. Circulation 114:2138-47, 2006

Decreased Contractile Reserve in HF-pEF Dobutamine Echo (max 16 g/kg/min) 10 Pts with HF-pEF & 9 controls (age, sex matched) Dynamic Strain Rate Reserve LVEF Reserve Lateral Longitudinal Velocity Reserve Norman HS Sweitzer NK. J Card Fail 17:301-8, 2011

Implications of increased LV & Arterial Stiffening Abnormality Consequence Clinical Relevance LV Stiffness Exaggerated LVEDP Increased sensitivity to volume shifts Reduced SV reserve Impaired Ex Tolerance Arterial Stiffness Impaired Coronary Reserve Exaggerated BP Increased afterload Reduced Capacitance Increased predilection to ischemia Increased predilection to ischemia Impaired Ex Tolerance Increased sensitivity to volume shifts

A new paradigm for HFPEF development: a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development.

Treatment: two phases Prevention Stage A Blood pressure control Coronary disease/ischemia prevention Obesity Diabetes Metabolic Syndrome Treatment Stage B, C and D

Incidence of Heart Failure (%) Prevention of Heart Failure in SHEP 8 RR=0.51 6 4 2 4.4% 95% CI 0.37-0.71 P<0.001 2.3% 0 Placebo Active Rx Kostis JB et al. JAMA. 1997;278:212-216. (Diuretic/BB)

CHARM-Preserved - Patient Disposition 3025 patients randomized NYHA class II-IV LVEF >40% 2 patients with no data Candesartan n=1514 Lost to follow-up n=2 Completed study n=1512 Placebo n=1509 Lost to follow-up n=1 Completed study n=1508 Median follow-up: 36.6 months NYHA, New York Heart Association; LVEF, left ventricular ejection fraction. Yusuf S et al. Lancet. 2003;362:777-781.

CHARM-Preserved: Primary outcome CV death or CHF hospitalization 30 25 20 15 10 5 0 % Placebo Candesartan HR 0.89 (95% CI 0.77-1.03), p=0.118 0 1 2 3 3.5years Number at risk Candesartan 1514 1458 1377 833 182 Placebo 1509 1441 1359 824 195 366 (24.3%) 333 (22.0%)

I-PRESERVE: Entry Criteria Age 60 years Current HF symptoms LVEF 0.45 NYHA class II - IV CHF hosp. 6 months NYHA Class III/IV CXR congestion ECG (LVH, LBBB) Echo (LVH, LAE) Key Exclusions: SBP >160 mm Hg; prior EF <40%; ACS or stroke 3m, hypertrophic or restrictive CM, pericardial or valvular disease, significant pulmonary disease, creatinine >2.5, Hb <11

Cumulative Incidence of Primary Events (%) I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization 40 - HR (95% CI) = 0.95 (0.86-1.05) Log-rank p=0.35 Placebo 30 - Irbesartan 20-10 - 0 - No. at Risk Irbesartan Placebo 0 6 12 18 24 30 36 42 48 54 60 Months from Randomization 2067 1929 1812 1730 1640 1569 1513 1291 1088 816 497 2061 1921 1808 1715 1618 1539 1466 1246 1051 776 446

Perindopril in elderly people with chronic heart failure (PEP-CHF) Cleland J G et al. Eur Heart J 2006;27:2338-2345

31% RRR in year 1 P=0.55

ACEI in HFpEF

*3445 patients with symptomatic heart failure a left ventricular ejection fraction of > 45 spironolactone (15 to 45 mg daily) or placebo. TOPCAT

NHLBI Heart Failure Network

In conclusion, receipt of isosorbide mononitrate, as compared with placebo, decreased daily activity levels did not improve submaximal exercise capacity, or quality-of-life scores, or NT-proBNP levels.

An exploratory study of patients enrolled in I-PRESERVE using latent class analysis (LCA) with validation using CHARM-Preserved study to identify HFpEF subgroups and results.

An exploratory study of patients enrolled in I-PRESERVE using latent class analysis (LCA) with validation using CHARM-Preserved study to identify HFpEF subgroups and results. In total, 4113 HFpEF patients randomized to irbesartan or placebo were characterized according to 11 clinical features. The HFpEF subgroups were identified using LCA. Event-free survival and effect of irbesartan on the composite of all-cause mortality and cardiovascular hospitalization were determined for each subgroup.

Kao et al. European Journal of Heart Failure (2015) 17, 925 935

Kao et al. European Journal of Heart Failure (2015) 17, 925 935 identified six subgroups of HFpEF patients with significant differences in event-free survival

The aim of this study was to characterize clinical features, exercise capacity, and outcomes in patients with HFpEF with or without diabetes and gain insight into contributing pathophysiological mechanisms.

Why Do HFPEF Patients Decompensate? (Potential targets ) Excess salt (or discontinuation of diuretic) Worsening hypertension Medications: NSAIDs, CCBs, thiazolidinediones Atrial fibrillation Iatrogenic volume overload Myocardial ischemia Worsening renal function Anemia

Summary HFpEF accounts for ~50 of HF, is increasingly prevalent, and carries a prognosis that is nearly as poor as for patients with systolic HF Patients with HFpEF usually have LV diastolic function abnormalities, however, these abnormalities are also present in elderly and hypertensive patients without heart failure Coexistant increases in arterial stiffness, impaired systolic reserve and co-morbid factors like atrial fibrillation, HTN and CAD contribute to HF-pEF Ang-II antagonists may reduce hospitalization in HFpEF, but do not affect mortality.

Conclusions Combined increases in LV and arterial stiffness likely account for the exaggerated volume sensitivity of patients with HFpEF Differences in pathophysiology and heterogeneity among patients with HFpEF may account for underwhelming responses to therapies that have been effective for patients with systolic HF Treatment strategies to achieve improved volume management and target ventricular and vascular abnormalities will be required to address the increasing prevalence of HFpEF

ESC 2005 Chronic HF Guidelines

Treatment of HFpEF Recommendations COR LOE Systolic and diastolic blood pressure should be controlled according to published clinical practice guidelines I B Diuretics should be used for relief of symptoms due to volume overload Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial ischemia is present despite GDMT Management of AF according to published clinical practice guidelines for HFpEF to improve symptomatic HF Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF ARBs might be considered to decrease hospitalizations in HFpEF Nutritional supplementation is not recommended in HFpEF I IIa IIa IIa IIb III: No Benefit C C C C B C

Thank You.