HFpEF: Pathophysiology & Treatment
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1 HFpEF: Pathophysiology & Treatment Barry A. Borlaug, MD Mayo Clinic, Rochester, MN
2 Disclosure Financial Relationships Research Support: Aires Pharmaceuticals, Medtronic, GSK Consulting/Advisory Board: Amgen, Merck, AstraZeneca Off-Label/Investigational Uses None
3 Outline Pathophysiology Treatment
4 Pathophysiology of HFpEF
5 LV Diastolic Dysfunction LV Pressure (mmhg) HFpEF n=47 Control n=1 PCWP (mmhg) p<.1 * * * * LV Volume (ml) Baseline Feet Up 1 min Exercise Peak Exercise 1 min Recovery Control HFpEF Zile New Eng J Med 24 Borlaug Circ Heart Fail 21
6 LVFP causes PH, linked to mortality PASP EX (mmhg) Control HFpEF 2 PASP EX = 1.21*PCWP EX + 2 R 2 =.76, p< PCWP EX (mmhg) Borlaug Circ Heart Fail 21 Survival p=.2 PASP<48 mmhg PASP 48 mmhg Years Number remaining PASP<48 mmhg PASP 48 mmhg Lam J Am Coll Cardiol 29
7 The RV: The first victim of PH p <.1 6 Controls r= -.1, p=.9 HFpEF Controls RV FAC% HFpEF r= -.4, p<.1 Group p = Right ventricular fractional area change (FAC) % PA mean pressure mmhg Melenovsky, Borlaug Eur Heart J 214
8 RVD predicts mortality in HFpEF, independent of PA pressures 1..8 HFpEF, no RVD Survival HFpEF with RVD p < Days of follow up Melenovsky, Borlaug Eur Heart J 214
9 Afib in HFpEF cm 2 RV diastolic area 3 * 25 2 * 15 Con HF SR HF AFib Zakeri Circulation 213 Zakeri Circ Heart Fail 214 RV FAC% Group p<.1 HFpEF atrial fib r = -.16, p=.3 HFpEF sinus rhythm r = -.4, p= PA mean pressure mmhg Melenovsky, Borlaug Eur Heart J 214
10 LVEF is normal in HFpEF but is contractility? PRSW (g/cm 2 ) 125 * 1 75 * Φ sc-mfs (%) * * Φ 5 CON HTN HFpEF 75 CON HTN HFpEF sc-efs (%) * * Φ Survival p<.7 sc-mfs>92.7% sc-mfs 92.7% 75 CON HTN HFpEF Years Borlaug J Am Coll Cardiol 29
11 Contractile Reserve in HFpEF Control Hypertension HFpEF PWR/EDV (mmhg/s) * ΔEes (mmhg/ml) 1..5 * Borlaug JACC 21 ΔPRSW (gm/cm 2 ) * Peak VO 2 (ml/min*kg) r=.7, p< Change in PWR/EDV Others showing Systolic reserve in HFpEF: Liu Circulation 1993, Borlaug Circulation 26, Ennezat JCF 28, Tan JACC 29, Phan JACC 29, Lee EHJ 21, Norman JCF 211, Ohara ijacc 212, Andersen Circ Heart Fail 215
12 Abnormal Vasodilatation in HFpEF? CON HTN HFpEF -.2 ΔEa (mmhg/ml) * CON HTN HFpEF ΔSVRI (DSC*m 2 )/ * Tartiere-Kesri J Am Coll Cardiol 212 Borlaug J Am Coll Cardiol 21
13 Why the Abnormal Vasodilation? PAT Ratio * * * * * Log RHI * % 1 5 p= Time After Occlusion Release (sec). CON HTN HFpEF CON HTN HFpEF Normal Endothelial Dysfunction Borlaug J Am Coll Cardiol 21
14 Endothelial Dysfunction associated with DOE in HFpEF 2W Borg Dyspnea p=.4 ED (-) ED (+) 2W Borg Dyspnea r= -.4, p= Framingham RHI Borlaug J Am Coll Cardiol 21
15 Chronotropic Incompetence in HFpEF Heart rate (bpm) Peak HFpEF Peak 53% of HFpEF patients Displayed abnormal HR recovery CONTROL Exercise Duration (sec) Borlaug Circulation 26
16 Combined CV dysfunction: Limited CO reserve 15 p<.1 Control 15 HFpEF ΔCO/ΔVO2 ΔCO (l/min) 1 5 Control HFpEF ΔCO (l/min) 1 5 *p<.1 p<.1 p= ΔVO 2 (l/min) +7.4±2.6 vs +5.9±2.5 p=.5 Abudiab Eur J Heart Fail 213
17 Pathophysiology of HFpEF Arterial stiffening Endothelial dysfunction LV diastolic reserve LV systolic reserve HR reserve LV filling pressures Pulmonary hypertension Atrial fibrillation RV dysfunction Cardiac output reserve Edema, ascites, and cachexia Activity avoidance Exertional dyspnea and fatigue Peripheral limitations Borlaug Nature Rev Cardiol 214
18 HFpEF Multiple diseases Multiple reserve limitations combine to cause HF # Abnormalities CON * * HTN HFpEF *p<.1; p<.5 Peak VO 2 (ml/min/kg) ANOVA p< # Abnormalities Borlaug J Am Coll Cardiol 21
19 Treatment of HFpEF
20 HFrEF HFpEF CHARM-Alternative s16 I-PRESERVE 16 CHARM-Preserved 15 OPTIMIZE-ACE 9 SOLVD s17 DIG 28 OPTIMIZE-BB 9 OPTIMIZE-BB 2 PEP-CHF 17 DIG-Preserved 27 OPTIMIZE-BB 9 OPTIMIZE-ACE 9 OPTIMIZE-BB Hazard Ratio for Death or HF Hospitalization Borlaug & Redfield Circulation 211
21 In the absence of convincing trial data, what should we do?
22 Finally, some evidence that Diuretics Work NNT = 2 over 18 months Adamson Circ Heart Fail 214
23 Need to be careful with vasodilators 25 End Systolic Arterial Pressure (mmhg) mmhg HFpEF Ees = ml Δ Ea = -.6 mmhg/ml - 18 mmhg HFrEF Ees = ml Estimated Left Ventricular Volume (ml) Δ Ea = -.8 mmhg/ml Schwartzenberg...Borlaug J Am Coll Cardiol 212
24 Stiffer LV: Greater Vulnerability to Preload 1 8 Cumulative % p<.1 HFrEF HFpEF ΔStroke Volume with SNP (ml) Schwartzenberg...Borlaug J Am Coll Cardiol 212
25 How about Aldosterone antagonists? Pitt, Pfeffer et al. New Engl J Med 214
26 Did all these patients really have HFpEF? Pfeffer Circulation 214
27 Therapeutic Advances in HFpEF over 25 years BP X X Diuretics X X Rx Ischemia X X Consider BB/ACE/Ca X X HR in AFib X X Consider CDV in AFib X X Chatterjee K: Western Journal of Medicine: 199 ACC/AHA HF Guidelines, Circulation, 213
28 What do we know about Ischemia in HFpEF? (n=15) (n=19) Kramer Am Heart J 2
29
30 Impact of CAD on Outcome in HFpEF 1. HFpEF without CAD Surviving.8.6 HFpEF with CAD p= Number remaining Years CAD (-) CAD (+) Hwang J Am Coll Cardiol 214
31 Does Revascularization improve survival? 1. HFpEF with CAD, Revascularized 1. HFpEF with CAD, Revascularized Surviving.8.6 HFpEF with CAD, Not revascularized Surviving.8.6 HFpEF, no CAD.4 Revasc (+) Revasc (-) p= Years Number remaining Revasc (+) CAD (-) p= Years Number remaining Hwang J Am Coll Cardiol 214
32 Exercise training works (but isn t paid for!) Kitzman Circ Heart Fail 21
33 What is on the horizon?
34 NO-cGMP-PKG candidate target Paulus & Tschope J Am Coll Cardiol 213
35 Redfield JAMA 213
36 Why didn t PDE5i work in HFpEF?.4 p= p=.54 Δ Ea (mmhg/ml) Δ RHI Placebo Sildenafil -1.5 Placebo Sildenafil Δ PWR/EDV (mmhg/s) Placebo p=.4 Sildenafil Δ SW/EDV (mmhg) 1 p= Placebo Sildenafil Borlaug Circ Heart Fail 215
37 Targeting cgmp via NP Solomon Lancet 212
38 Targeting cgmp w organic nitrates Zakeri Circ Heart Fail 215
39 Clinical Dilemma: The ephemeral nature of PCWP in HFpEF PCWP (mmhg) p<.1 * * * * Baseline Feet Up 1 min Exercise Peak Exercise 1 min Recovery Control HFpEF Borlaug Circ Heart Fail 21
40 Nitrite: An Alternative source of NO/cGMP Lundberg Nature Rev Cardiol 28
41 Beetroot Juice in HFpEF Aerobic Capacity Zamani et al. Circulation 215
42 NO 2- effects on Exercise Hemos & Cardiac Reserve Base NO 2 - Exercise 2W x 5 min, NO 2 - Base Hemos Exercise Hemos 2W x 5 min Re-base Hemos Base placebo Exercise 2W x 5 min, placebo Randomized: IV NO 2- or NS Borlaug, Koepp et al. J Am Coll Cardiol 215
43 Change in PCWP after study drug Rest Exercise Placebo Nitrite Placebo Nitrite ΔPCWP (mmhg) -5-1 ΔPCWP (mmhg) p<.1-15 p=.2 Borlaug, Koepp et al. J Am Coll Cardiol 215
44 Stroke volume (ml) p=.2 Stroke work (g/beat) p=.3 Placebo Nitrite Placebo Nitrite 2. p=.7 8 p=.5 Change in exercise Qp (L/min) ΔQp/ΔVO 2 (ml /ml) 6 4 p= Placebo Nitrite 2 Pre Post Pre Post Placebo Nitrite Borlaug, Koepp et al. J Am Coll Cardiol 215
45 Summary Pathophysiology is complex EF is preserved but systolic function is not Much more than diastolic dysfunction: LVSD, RVD, vascular, autonomic, peripheral Heterogeneity but also combined reserve dysfunction Treatment Nothing proven yet Exciting new studies coming soon
46 Thanks!
Diastolic Heart Failure Uri Elkayam, MD
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