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Diastolic Heart Failure: The Other Heart Failure (Heart Failure with Preserved EF, or HFpEF) • Mariell Jessup MD, FAHA, FACC • Professor of Medicine • University of Pennsylvania • Philadelphia, Pennsylvania Mariell Jessup MD • No conflicts to report • I will discuss some off-label uses of drugs Outline • Semantics/Definitions • Epidemiology • Pathophysiology/Mechanisms – Diastolic Dysfunction (types) – Ventriculo-Vascular Coupling – Impaired systolic reserve • Evaluation • Treatment (current and emerging) A case of “old lady legs” • 71 year old woman with well controlled hypertension, chronic atrial fibrillation, and diabetes was seen for her yearly check-up. • She denied angina, palpitations or dizziness. • Her only complaint was progressive swelling of her legs during the day-reminding her of her mother’s legs as she aged. • When prompted, she did admit she was more breathless while walking her small dog. A case of “old lady legs” • • • • • BP: 150/95mmHg, HR: 95 bpm, irreg No JVD, no carotid bruits Lungs clear, abdomen mildly obese Heart: soft systolic murmur, no S3+ 1+ edema of both lower legs, pulses intact • EKG: atrial fibrillation, LVH, non-specific STTW • Echo: LVEF normal, RV normal, LA enlarged • Labs: mild elevation of BUN, BNP elevated x 2 Semantics and Related Questions • If not systolic HF, must it be diastolic HF? • Is LVEF the best determinant of systolic HF? • What is a “reduced” LVEF? 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. HF-pEF 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 Prevalence of Heart Failure USA 10 Finland England (CHS) (Helsinki) (Poole) Sweden Den. prevalence % Portugal Nether. (Vasteras) (Copen.) (Asturias) (EPICA) 9 (Rotter.) Proportion with decreased LV systolic function Proportion with preserved LV systolic function 8 7 6 Spain 8.8 8.2 7.5 6.7 6.4 5 4 4.9 3 4.2 2 1 2.1 4.8 4.2 5.1 3.1 4.5 2.9 1.7 1.5 0 age range 66-103 75-86 70-84 75 > 50 > 40 >25 55-95 mean age 78 76 75 - 60 68 65 - Secular Trends in HF-pEF Prevalence Associated with increasing prevalence of AFib (2941%) and Diabetes (3236%), but no change in CAD 5959%) Owan TE…Redfield MM. N Engl J Med 355:251-9, 2006 Audience Question #1 The prognosis for patients with diastolic heart failure is significantly better than for patients with systolic heart failure. 1. True 2. False 41% 59% Prognosis of Patients with HF-pEF After 1st Hospitalization Overall Bhatia RS...Liu PP. Owan TE…Redfield MM. N Engl J Med 355:260-9, 2006 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 Preserved EF and Reduced EF Heart Failure 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 HF-pEF: Cardiac Morphology & Hemodynamics HF with ↓ LVEF HF-pEF ↑ ↑ Normal ↑ or normal ↑ LV Morphology (Normal: ) LVEDV LV Mass Relative Wall Thickness LVEF Left Atrium LVEDP ↓ ↓ Dilated ↑ Normal Dilated ↑ Audience Question #2 The primary pathophysiological mechanism driving the syndrome of HF-pEF is impaired diastolic filling of the left ventricle 1. True 2. False 62% 38% 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 Pathophysiology of HF-pEF I. Focus on Diastolic Dysfunction Pathophysiology of HF-pEF: Diastolic Dysfunction HF-PEF (N=47) Controls (N=10) 71±11 73±13 103±22 115±9 LVEDP, mmHg 25±6 8±2 Tau, msec 59±14 35±10 PSR, mmHg 7±5 0 Heart Rate, bpm LVEDV, ml Zile MR…Gaasch WH. N Engl J Med 350:1953-9, 2004 Diastolic Function in HF-pEF vs. Hypertensive LVH (H-LVH) Age Control (56) 65±11 H-LVH (40) 67±10 HF-pEF (37) 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 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 IVRT Melenovsky V…Kass DA. J Am Coll Cardiol 49:198-207, 2007 NT-proBNP levels in diastolic dysfunction are elevated and correlate with the severity of disease Tschope C et al. Eur Heart J 26:2277-2284, 2005 Diagnosis of HF-pEF European Society of Cardiology Algorithm Symptoms/Signs of HF + LVEF>50% & LVEDVI>97 mL/m2 + Evidence of Abnormal LV relaxation, filling or stiffness or Catheterization mPCW >12 mmHg LVEDP >15 mmHg Tau > 48 ms or TD E/E’>15 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 Pathophysiology of HF-pEF I. Focus on Arterial Stiffening 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) Vessel Composition Across the Circulatory System • Relatively high elastic tissue content in large conduit arteries favors their ability to absorb and release energy 15-2 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 E’ septal (cm/s) LVEDP (mmHg) I II III . NYHA: I II III . NYHA: I II III . I II III . Augmentation Index Pulse Wave Velocity (m/s) NYHA: NYHA: Weber T et al. Am J Hypertens 21:1194-1202, 2008 Central Aortic Stiffness and HF-pEF Desai AS…Creager MA. J Cardiac Failure 15:658-64, 2009 Pathophysiology of HF-pEF I. Focus Impaired Contractile Reserve 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) LVEF Reserve Dynamic Strain Rate 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 Reduced SV reserve Increased sensitivity to volume shifts Impaired Ex Tolerance Impaired Coronary Reserve Increased predilection to ischemia Exaggerated ↑ BP Increased predilection to ischemia Impaired Ex Tolerance ↑ Arterial Stiffness Increased afterload Reduced Capacitance Increased sensitivity to volume shifts Audience Question #3 Which of the following reduces mortality among patients with HFpEF? 1. Beta-blockers 2. ACE-inhibitors 3. Angiotensin receptor blockers 4. Cardiac resynchronization therapy 5. None of the above 22% 26% 8% 10% 32% Treating Diastolic Heart Failure The Theory hundreds of papers! The Evidence virtually none!! HF Due to Diastolic Dysfunction Potential Treatment Targets LV volume & edema: diuretics, salt, avoid NSAIDS Rx systolic HTN: diuretics, others Reverse LVH: ACEI, ARB, most anti-HTN Prevent fibrosis: ACEI, ARB, aldo blockers Prevent ischemia: BB, CA, nitrates HR, prevent AF: BB, some CA, ACEI, ARB Enhance relaxation: no drugs currently available vascular compliance: product ?RAAS I, glycation endcrosslink breakers 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 95% CI 0.37-0.71 6 4.4% P<0.001 4 2.3% 2 0 Placebo Active Rx (Diuretic/BB) Kostis JB et al. JAMA. 1997;278:212-216. 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 Baseline Characteristics Alternative n=2028 Mean age (yrs) Women (%) NYHA class (%) II III IV Mean LVEF (%) Medical history (%) Myocardial infarction Diabetes Hypertension Atrial fibrillation Added n=2548 Preserved n=3023 Overall n=7599 67 32 64 21 67 40 66 32 48 49 4 30 24 73 3 28 61 38 2 54 45 52 3 39 62 27 50 25 56 30 48 26 44 28 64 29 53 28 55 27 NYHA, New York Heart Association; LVEF, left ventricular ejection fraction. McMurray J et al. Eur J Heart Fail. 2003;5:261-270. CHARM-Preserved Baseline Medications Alternative n=2028 Added n=2548 Preserved n=3023 Overall n=7599 ACE inhibitor 0 100 19 41 Beta-blocker 55 55 56 55 Diuretic 86 90 75 83 Spironolactone 24 17 12 17 Digitalis 46 58 28 43 Aspirin 58 52 58 56 Lipid-lowering 42 41 42 42 Baseline therapy (%) McMurray J et al. Eur J Heart Fail. 2003;5:261-270. CHARM-Preserved: Primary outcome CV death or CHF hospitalization 30 25 20 15 10 5 0 % Placebo 366 (24.3%) 333 (22.0%) Candesartan HR 0.89 (95% CI 0.77-1.03), p=0.118 0 Number at risk Candesartan 1514 Placebo 1509 1 2 1458 1441 1377 1359 3 3.5years 833 824 182 195 CHARM – Preserved Conclusions • Among patients with symptomatic heart failure and an ejection fraction >40%, treatment with the ARB candesartan was associated with a non-significant reduction in the primary endpoint of cardiovascular death or heart failure hospitalizations • Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%. 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 One-year outcomes in PEP-CHF perindopril vs. placebo End point Perindopril, n=424 (%) Placebo, n=426 (%) p All-cause mortality or unplanned HF hospitalization 10.8 15.3 0.055 Unplanned HF hospitalization 8.0 12.4 0.033 All-cause mortality 4.0 4.5 NS Cleland JGF. World Congress of Cardiology 2006; September 3, 2006; Barcelona, Spain. PEP-CHF Conclusions • The ACE-Inhibitor perindopril improved symptoms and exercise capacity and led to fewer hospitalizations for heart failure in the first year • There was no improvement in total mortality 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 I-PRESERVE: Outcomes • Primary endpoint: All cause mortality and protocolspecified CV hospitalizations (for heart failure, MI, unstable angina, stroke, ventricular or atrial arrhythmia). • Secondary endpoints: – All cause mortality – – – – – CV death HF death or HF hospitalization CV death, MI or stroke QoL (Minnesota) Change in BNP levels I-PRESERVE: Patient Characteristics Cohort & Epidemiological Studies I-PRESERVE (n=4,128) Age, yr 75 72 Women 65-70% 60% 60% 59% 80-90% 88% <20% 23% Atrial fibrillation 20-30% 29% Diabetes 20-30% 27% EF Hypertension Prior MI I-PRESERVE: Primary Endpoint Death or protocol specified CV hospitalization HR (95% CI) = 0.95 (0.86-1.05) Placebo Log-rank p=0.35 Primary Events (%) Cumulative Incidence of 40 - 30 - Irbesartan 20 - 10 - 00 No. at Risk Irbesartan Placebo 6 12 18 24 30 36 42 48 Months from Randomization 2067 1929 1812 1730 1640 1569 1513 1291 1088 2061 1921 1808 1715 1618 1539 1466 1246 1051 54 60 816 776 497 446 I-PRESERVE: Conclusions • In I-PRESERVE, HF-PEF patients experienced substantial mortality and cardiovascular morbidity. • Irbesartan did not reduce the primary endpoint of death and protocol-specified CV hospitalizations, nor did it significantly benefit prespecified secondary endpoints. • The results are consistent with the two previous trials in patients with HF-PEF that did not demonstrate a positive effect. • For this large group of patients constituting half of all heart failure patients, there continues to be no specific evidencebased therapy. • In order for this field to move forward, a better understanding of the mechanisms underlying this syndrome and additional potential targets for treatment are required. Randomized Trials in HF-pEF Trial Name CHARMPreserved1 Drug (Class) Outcome [# Pts] Candesartan (ARB) No Δ Mortality [3,023] ↓ Hospitalization I-Preserved2 Irbesartan (ARB) [4,128] PEP-CHF Perindopril (ACE-I) [384] 1 Yusef No Δ Mortality No Δ Hospitalization No Δ Mortality ↓ Hospitalization (1 yr) S et al. Lancet 362:777–81, 2003 2 Massie B et al. N Engl J Med 359:2456-2467 3 Cleland JG et al. Eur Heart J 27:2338-45, 2006 TOPCAT • TOPCAT is a multi-center, international, randomized, double blind placebo-controlled trial of the aldosterone antagonist, spironolactone, in 4500 adults with heart failure and left ventricular ejection fraction of at least 45%, recruited internationally from over 200 clinical centers in the US, Canada, Russia, Republic of Georgia, Argentina, and Brazil. TOPCAT - Endpoints • The primary endpoint is a composite of cardiovascular mortality, aborted cardiac arrest or hospitalization for the management of heart failure. • Secondary endpoints include all-cause mortality, new onset of diabetes mellitus or atrial fibrillation, and quality of life. DIG ancillary Trial • Randomized 988 patients with chronic heart failure who were in sinus rhythm and had LVEFs greater than 45%. • No differences between mortality in the digitalis and placebo groups • Secondary endpoint of death or hospitalization for worsening heart failure, trend toward benefit when sinus rhythm is present driven by decreased hospitalizations. Digoxin • Trend toward more hospitalizations for nonheart failure causes, resulting in no significant difference in all-cause hospitalizations • Therefore, digoxin has at most a very limited role in the management of patients in normal sinus rhythm N. Engl. J. Med. 336 (1997), pp. 525–533. SENIORS Trial • Evaluated nebivilol (vasodilating Betablocker) in patients > 70 years with heart failure • About 20% had EF > 35% • Appeared to be beneficial but need more data about the subgroup with preserved EF • Will need another trial specific to HFpEF Eur. Heart J. 26 (2005), pp. 215–225 COHERE - Hospitalizations before and after Carvedilol, by EF HF Hosp. prior yr 40 HF Hosp. 1 yr f/u * 35 P = 0.001 vs. prior year 30 % of Patients 25 20 * 15 * 10 * * 5 0 <21 21-30 Ejection Fraction Massie BM et al. AJC 2007; 99: 1263-8 31-40 >40 Common Sense HF-pEF Management • Address underlying diseases (CAD, HTN, renal dysfunction, DM, obesity & sleep apnea) • Avoidance of excessive tachycardia – especially Afib with rapid ventricular response • Careful volume status management (education, weights, BNP tracking, implanted monitoring devices) Patients With Heart Failure and Normal Left Ventricular Ejection Fraction Normal Left Ventricular Ejection Fraction I IIa IIb III Physicians should control systolic and diastolic hypertension in patients with HF and normal LVEF, in accordance with published guidelines. NO CHANGE I IIa IIb III Physicians should control ventricular rate in patients with HF and normal LVEF and atrial fibrillation. NO CHANGE I IIa IIb III Physicians should use diuretics to control pulmonary congestion and peripheral edema in patients with HF and normal LVEF. NO CHANGE ESC 2005 Chronic HF Guidelines Emerging Strategies for Pathophysiological Targeting for HF-pEF Mechanism Approach Possible Agents Abnormal LV Relaxation Increase myocyte Ca2+ uptake rates SERCA agonists Ranolazine PDE-5 inhibitors Ivabradine Slow heart rate Increased LV Stiffness ↓ Collagen X-links ↓ AGEs ↓ fibrosis TGFβ inhibitors Aminoguanidine Alagebrium Aldosterone Antag. ↑ Vascular Stiffness ↓ Atherosclerosis ↓ Aortic Stiffness Statins Nitrates Aminoguanidine Alagebrium ↓ Vascular Capacitance Improved volume management Implantable monitors (± interventions) Summary • HF-pEF 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 HF-pEF 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 HF-pEF, but do not affect mortality. Conclusions • Combined increases in LV and arterial stiffness likely account for the exaggerated volume sensitivity of patients with HF-pEF • Differences in pathophysiology and heterogeneity among patients with HF-pEF 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 HF-pEF