Current and future management of HFpEF. C. Tschöpe Charite Campus Benjamin Franklin Berlin

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1 Current and future management of HFpEF C. Tschöpe Charite Campus Benjamin Franklin Berlin

2 Outcome HFREF vs. HFpEF Owan T et al. N Engl J Med 2006

3 Differences in the causes of death between HPpEF and HFREF? Zile et al. Circulation 2010

4 Therapy of HFpEF today Focusing: neurohumoral activation ACE-Inhibitor PEP-Studie neutral AT1-Blocker CHARM neutral I-PRESREVE news Digitalis DIG negative Beta-Blocker ELLAND news Aldo-Antagonists RAAM-PEF news

5 Cumulative Incidence of Primary Events (%) I-PRESERVE: Primary Endpoint HR (95% CI) = 0.95 ( ) Log-rank p=0.35 Placebo Irbesartan Months from Randomization

6 I-Preserve: Irbesartan was effective only in patients with low BNP levels Anand I S et al. Circ Heart Fail 2011;4:

7 Therapy of HFpEF today Focusing: neurohumoral activation ACE-Inhibitor PEP-Study neutral AT1-Blocker CHARM neutral I-PRESREVE neutral Digitalis DIG negative Beta-Blocker ELLAND news Aldo-Antagonists RAAM-PEF news

8 Eplerenone in HFpEF RAAM-PEF-Study 6 min Walking Test : pos BNP-levels : pos Quality of live : pos E/E` : pos 50 mg Eplerenone; n= 44 Deswal et al, J Card Fail 2011

9 PIIIPs as discriminators of survival in I-PRESERVE PIIIP Krum et al. Circ HF 2011 B. López et al., J Am Coll Cardiol, 2004

10 Targeting PIP: DROP-PIP DHF-Study A multicenter, Double-blind, RandOmized, Placebocontrolled, three arm parallel-group trial to determine the effects of torasemide versus furosemide on one marker (PIP) of cardiac fibrosis in patients with Diastolic Heart Failure and diabetes mellitus type II FP7 Tschöpe et al for the Media Consortium

11 Therapy of HFpEF today Focusing: neurohumoral activation ACE-Inhibitor PEP-Studie neutral AT1-Blocker CHARM neutral I-PRESREVE neutral Digitalis DIG negative Beta-Blocker ELLAND news Aldo-Antagonists RAAM-PEF promising ALDO-DHF, TOP-CAT?

12 Nebivolol in HFpEF ELANDD-Study 6 min Walking Test : neg BNP-levels : neg Quality of live : neg E/E : neg Moderate improvement in pv02 and Peak HF during stress Conraads V M et al. Eur J Heart Fail 2012

13 OPTIMIZE-HF Study Beta-Blocker treatment start after HF hospitalisation Mortality HFREF (EF<40%, N=3001) HFpEF (EF>40%, N=4153) 12Mo Mortality 34% 12Mo Rehospit. 63% 12Mo Mortality 31% 12Mo Rehospit. 65% 23% Hernandez et al. JACC 2009 N=25901, Age >65

14 Therapy of HFpEF: New options ACE-Inhibitor PEP-Study neutral AT1-Blocker CHARM neutral I-PRESREVE neutral Digitalis DIG negative Beta-Blocker Nebivolol neutral Aldo-Antagonists Eplerenone promising late Na- Inhibitoren Ranolazine! PDE-Inhibitor Sildenafil! Exercise training!

15 Late I Na Inhibition reduces LVEDP in vivo human: in patients with CAD Hayashida et al., Cardiovasc Drugs & Therapy, 1994

16 Ranolazine in HFpEF preliminary results of the RALI-DHF-Study D LVEDP-fall : ca. 5mmHg, p < 0.05 D Wedge-fall : ca. 5mmHg, p < 0.05 Tau Contractility : no Effect : no Effect Prof. L Maier, Univ. Göttingen, ESC 2011

17 PDE5-Inhibition and diastolic function Improvement in measures of structure and function with Sildenafil Phosphorylation of Titin in dogs with DHF Baseline 6 months 1 Year Bishu K et al. Circulation 2011 E/E Placebo n=22 E/E Sildenafil n= ± ± ± 5 P < ± ± ± 5 Guazzi et al. Circ HF 2011

18 Exercise training in HFpEF Ex-DHF-P study Edelmann at al JACC 2011

19 Prevalence of abnormal diastolic dysfunction according to treatment Hare J L et al. Circ Heart Fail 2011;4:

20 Therapy of HFpEF: New options - role of devices Renale Denervation CRT, pace maker Ventile Shunts CCM

21 Renale denervation in hypertension and HFpEF Brandt et al. JACC 2012

22 Role of dyssynchrony in HFpEF CRT 350 RV AS S Inf LV Ant Lat Post

23 Dyssynchrony in HFpEF 350 RV AS S Inf Ant LV Lat Post * QRSd (ms) High EF 92 ±13 Control 85± * Control High EF Basal Mid Basal Mid Basal Mid Basal Mid Basal Mid Basal Mid Septal Anteroseptal Anterior Lateral Posterior Inferior Kasner, Tschöpe, Curr Pharm Biotechnol 2012

24 Speckle tracking: Delay of contraction leads to a high energy lost Pan et al. 2010

25 Shunt induction between LA and RA in patients with HFpEF Ventile Patients admitted had an average LAp of 23 mm Hg Rule of thumb: LAp<18 = good LAp = b line Lap > 24 = trouble

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27 Shunt induction between LA and RA in patients with HFpEF Before Implant After Implant

28 Shunt induction between LA and RA in patients with HFpEF One-way LA/RA flow through the transplant no RA/LA shunt during valsalva LA pressure RA pressure

29 Shunt induction between LA and RA in patients with HFpEF DCD barrel size is 4mm radius computer calculation Derived by Dan Burkhoff with data from Professor David M Kaye

30 Future for HFpEF therapy? New drugs and Targets: Ivabradine FT011 LCZ696 Fasudil ALT-711 DPP-IV inhibitors, targeting Endoglin,IGF-1, TGF-Beta, Antagomirs (microrna21) Cell therapeutic options?

31 Immunomodulatory properties of Mesenchymal stem cells Abdi et al., 2008

32 % AF cells / mm2 cells / mm2 Cardiac inflammatory resposne in biopsies of patients with HFpEF Adhäsions Moleküle (VCAM) * T-Lymphozyten (CD3 + ) * Makrophagen (CD68 + ) * 0.00 controle HEpEF 0 control HFpEF 0 control HFpef Colocalization of TNF- a / CD 68 cells CD 68 TNF Colocalication of TGF-b / CD 3 cells CD 3 TGFß Westermann & Tschöpe, Circulation HF 2011 n = 65/ Gruppe * p < 0.05

33 Anti-inflammatory effects of mesenchymal stem cells in diabetes-induced diastolic heart failure VCAM-1 mrna expression IL-10 mrna expression CD$CD25FoxP3 (% of CD4) Annexin V + cells (%CD4) day 0-5: STZ 50 mg/kg KG, i.p. day 7: i.v. injection of 10 6 PLX day 21: Hemodynamics+ sacrifice mice * * LV VCAM-1 LV IL-10 Blood Treg * * * * * * Blood apoptotic CD4+ T cells * * * *=p<0.05; ns= not significant

34 Mesenchymal stem cells (PLX) restore diabetesinduced hypophosphorylation of titin N2BA and N2B N2BA phosphorylation % N2B phosphorylation % Pro-Q Diamond (Phospho-proteins) SYPRO Ruby (Total proteins) N2BA 3.3 MDa N2B 3.0 MDa N2BA 3.3 MDa N2B 3.0 MDa * * * * * * Control STZ STZ+PLX1 STZ+PLX2 Control STZ STZ+PLX1 STZ+PLX2 Tschöpe / Linke unpublished 2012 * p<0.05; n=3/group

35 Model of extracardiac immunomodulation of MSCs in diabetes-mellitus induced diastolic dysfunction Diabetes mellitus Heart cytokines Inflammation (IL1ß, TNF) Ox. stress inflammatory Apoptosis cells (CD4, Fibrosis CD8, CD68) systemic MSC/PLX application anti-inflammatory inflammatory Tregs cells (CD4, CD8, CD68) spleen / lymph nodes Apoptosis cytokines inflammatory (IL1ß, TNF) cells (CD4, CD8, CD68) inflammatory cells Stimulation (CD4, CD8, of CD68) Tregs (Tregs CD4/CD25/FoxP3)

36 Conclusions upstream strategy / reducing of risk factors RAAS Blockade effective in the early phase no general recomendation for Beta Blockade High dose aldosterone antagonism? Ranolazine (role of ischemia)? Sildenafil - promising Sport - promising Devices: renal Denervation! new drugs, cell therapeutic options

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