DECLARATION OF CONFLICT OF INTEREST

Transcription

1 DECLARATION OF CONFLICT OF INTEREST

2 ESC Congress 2011 Pathophysiology of HFPEF Vascular Remodeling & Pulmonary Hypertension Carolyn S.P. Lam MBBS, MRCP, MS

3 Case Presentation 81 yo woman with dyspnoea & oedema H/o systemic hypertension & AF BP 166/84, HR 74, JVD, bilat crepitations CXR: mild cardiomegaly, pulm congestion Hb, Creatinine normal; BNP 220 Echo: LVEDVI 94, LVEF 65%, mild RV enlargement with normal RV systolic function, flattening of IVS, biatrial enlargement, mod TR, mild MR, E/e 24, PASP 80 mmhg

4 Cardiac Catheterization 100 Baseline PA 80/31, mean 49mmHg CI 2.3 L/min*m 2, PVR 6.4 WU PCWP 22 mmhg RA 15 mmhg Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010

5 Is this A. Pure diastolic heart failure? B. Age-related vascular remodeling and diastolic dysfunction (DD)? C. Heart failure with preserved ejection fraction (HFPEF) with 2 pulmonary hypertension? D. Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence?

6 Paulus W J et al. Eur Heart J 2007

7 Diastolic Heart Failure HF cases: Referred N=47 34%F 59±12y Controls: Healthy Young Zile NEJM 2004

8 Diastolic Dysfunction in HFnlEF Population-based (Olmsted County) Lam, C. S.P. et al. Circulation 2007

9 LV Pressure (mmhg) Pressure-volume loop EDPVR LV Volume (ml)

10 LV Pressure (mmhg) Pressure-volume loop ESPVR Ea EDPVR LV Volume (ml)

11 LV Pressure (mmhg) Pressure-volume loop CON LV Volume (ml)

12 LV Pressure (mmhg) Pressure-volume loop HFpEF Beyond diastolic dysfunction, systolic vascular-ventricular stiffening are present in HFpEF CON LV Volume (ml) Lam C et al. Circulation 2007

13 Impact of Vascular-LV Stiffening Before & during isometric handgrip a patient with HFnlEF Kawaguchi M et al. Circulation 2003

14 Vascular-LV Coupling Kawaguchi, M. et al. Circulation 2003

15 Vascular-LV Coupling Kawaguchi, M. et al. Circulation 2003

16 Age-Related Systemic Arterial Stiffening Redfield MM et al Circulation 2006

17 Age-Related Systolic LV Stiffening Redfield MM et al Circulation 2006

18 Age-Related Diastolic Dysfunction Redfield MM et al Circulation 2006

19 Is this A. Pure diastolic heart failure? B. Age-related vascular remodeling and diastolic dysfunction (DD)? C. Heart failure with preserved ejection fraction (HFPEF) with 2 pumonary hypertension? D. Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence?

20 Age-Related Vascular Remodeling In the systemic circulation, age-related vascular stiffening contributes to isolated systolic hypertension & adverse outcome In the pulmonary circulation, less is known about age-related changes in pulmonary artery systolic pressure (PASP) and any prognostic impact of elevated PASP in the general community

21 Figure 2 Association of SBP & PASP with Age Olmsted County General Population A 200 Systemic circulation Overall: r=0.40; p<0.001 Women: r=0.45; p<0.001 B 60 Pulmonary circulation Overall: r=0.31; p<0.001 Women: r=0.34; p<0.001 SBP (mmhg) C Men: r=0.32; p< Age (years) PASP (mmhg) Men: r=0.26; p< Age (years) Lam C et al. Circulation 2009

22 Figure 2 Association of SBP & PASP with Age % Increase PASP SBP Age quartiles (years) Lam C et al. Circulation 2009

23 Figure 4A Entire population PASP & Survival in the General Cumulative Survival Population Overall Log Rank p<0.001 PASP Quintile 1: mmhg 2: mmhg 3: mmhg 4: mmhg 5: mmhg Time (Years) HR = 2.73 (unadjusted) or 1.46 per 10 mmhg (adjusted for age, PP, EF, E/e & FEV1) * * Lam C et al. Circulation 2009

24 Is this A. Pure diastolic heart failure? B. Age-related vascular remodeling and diastolic dysfunction (DD)? C. Heart failure with preserved ejection fraction (HFPEF) with 2 pulmonary hypertension? D. Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence?

25 PH & Left Heart Disease Left heart disease is a common cause of secondary PH Severe LV systolic dysfunction Mitral/ aortic valve disease Presence of PH portends poor prognosis in these patients Less is known about PH in HFPEF Oudiz RJ Clin Chest Med 2007

26 Pulmonary Hypertension Pulmonary hypertension (PH) is highly prevalent in HFpEF Lam C.S. et al J Am Coll Cardiol. 2009;53:

27 Pulmonary Hypertension Lam C.S. et al J Am Coll Cardiol. 2009;53:

28 Pulmonary Hypertension Pulmonary Venous HTN PASP Reactive PAH PASP Chronic PA Remodeling PASP PH: marker of the severity & chronicity of clinically significant pulmonary venous congestion in HFpEF?

29 Diagnostic Impact of PH in HFpEF Lam C.S. et al J Am Coll Cardiol. 2009;53:

30 Prognostic Impact of PH in HFpEF Lam C.S. et al J Am Coll Cardiol. 2009;53:

31 Invasive Data Dartmouth Dynamic Registry of pts with LVEDP>15 mmhg & LVEF 50% at cardiac cath (N=455): PH (mpap>25 mmhg) in 239 (52.5%) Leung CC et al. Am J Cardiol 2010

32 Invasive Data Dartmouth Dynamic Registry of pts with LVEDP>15 mmhg & LVEF 50% at cardiac cath (N=455): PH (mpap>25 mmhg) in 239 (52.5%) Risk factors for PH in HFPEF Leung CC et al. Am J Cardiol 2010

33 Is this A. Pure diastolic heart failure? B. Age-related vascular remodeling and diastolic dysfunction (DD)? C. Heart failure with preserved ejection fraction (HFPEF) with 2 pulmonary hypertension? D. Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence?

34 Unexplained PH in the Elderly Consecutive pts (N=197) from Mayo PH Clinic with suspected IPAH undergoing RHC 65y 24% < 65y 76% Shapiro BP et al. Chest 2007

35 Unexplained PH in the Elderly Consecutive pts (N=197) from Mayo PH Clinic with suspected IPAH undergoing RHC PCWP in 56% 65y 24% < 65y 76% PCWP in 19% Elderly pts with unexplained PH often have PCWP despite normal EF Shapiro BP et al. Chest 2007

36 High (>15) versus Low PCWP Similar PASP Similar RV size Similar RV function

37 High (>15) versus Low PCWP Similar PASP Similar RV size Similar RV function PCWP not attributable to ventricular interdependence

38 Back to the patient

39 Case Presentation 81 yo woman with dyspnoea & oedema H/o systemic hypertension & AF BP 166/84, HR 74, JVD, bilat crepitations CXR: mild cardiomegaly, pulm congestion Hb, Creatinine normal; BNP 220 Echo: LVEDVI 94, LVEF 65%, mild RV enlargement with normal RV systolic function, flattening of IVS, biatrial enlargement, mod TR, mild MR, E/e 24, PASP 80 mmhg

40 Is this A. Pure diastolic heart failure? B. Age-related vascular remodeling and diastolic dysfunction (DD)? C. Heart failure with preserved ejection fraction (HFPEF) with 2 pulmonary hypertension? D. Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence?

41 Is this Diastolic heart failure Age-related vascular remodeling and diastolic dysfunction (DD) Heart failure with preserved ejection fraction (HFPEF) with 2 pulmonary hypertension Idiopathic pulmonary arterial hypertension (IPAH) with DD from ventricular interdependence

42 Distinguishing HFPEF-PH from IPAH

43 Distinguishing HFPEF-PH from IPAH PH Connection Registry at University of Chicago: HFPEF-PH (PCWP>15 & PVR>2.5 and/or TPG>12) versus IPAH (mpap>25 & PCWP<15) Thenappan T et al Circ Heart Fail 2011

44 Distinguishing HFPEF-PH from IPAH Model 1 (age) Model 2 (+ clinical RF) Model 3 (+ echo) Model 4 (+ cath) Thenappan T et al Circ Heart Fail 2011

45 Symptoms HF Dx unclear Echo Doppler EF<40% or Valve Disease PH + Normal EF DHF Likely DHF Exclude Other Causes of PH DHF Uncertain Exclude Other Causes of PH DHF Unlikely RHC RHC PCWP 15 PVR < 3 PCWP 15 PVR 3 PCWP < 15 PVR 3 PCWP<15 PVR 3 PCWP 15 DHF Uncertain DHF Hypertensive? Nipride or NTG DHF Risk Factors PAH PCWP < 15 PVR 3 WU PCWP < 15 PVR < 3 WU Many Few Pre-capillary PH + Diastolic Dysfunction DHF Exercise or Volume PAH? Treat PH RCT Elevated PCWP DHF Normal PCWP PAH Hoeper et al JACC 2009

46 Symptoms HF Dx unclear Echo Doppler EF<40% or Valve Disease PH + Normal EF DHF Likely DHF Exclude Other Causes of PH DHF Uncertain Exclude Other Causes of PH DHF Unlikely RHC RHC PCWP 15 PVR < 3 PCWP 15 PVR 3 PCWP < 15 PVR 3 PCWP<15 PVR 3 PCWP 15 DHF Uncertain DHF Hypertensive? Nipride or NTG DHF Risk Factors PAH PCWP < 15 PVR 3 WU PCWP < 15 PVR < 3 WU Many Few Pre-capillary PH + Diastolic Dysfunction DHF Exercise or Volume PAH? Treat PH RCT Elevated PCWP DHF Normal PCWP PAH Hoeper et al JACC 2009

47 A Baseline PA 80/31, mean 49mmHg B C CI 2.3 L/min*m 2, PVR 6.4 WU Nitroprusside CI 2.6 L/min*m 2, PVR 3.6 WU Nitric Oxide CI 2.2 L/min*m 2, PVR 3.8 WU PCWP 22 mmhg RA 15 mmhg PA 61/19, mean 37 mmhg PCWP 20 mmhg RA 8 mmhg PA 77/27, mean 50 mmhg PCWP 35 mmhg RA 13 mmhg Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010

48 Boilson BA, Shirger JA, Borlaug BA. Eur J Heart Fail 2010 A HFpEF RA RV PA Increased PVR Stiff LA Stiff LV Elevated SVR RA Increased RV/PA pressures RV Afterload Elevated LV Afterload Elevated B HFpEF + IV Nitroprusside RA RV PA Reduced PVR Stiff LA Stiff LV Reduced SVR RA Reduced RV/PA pressures Reduced preload RV Afterload Reduced LV Afterload Reduced C HFpEF + inhaled NO RA RV PA Reduced PVR Stiff LA Stiff LV Elevated SVR RA Elevated RV/PA pressures Increased preload RV Afterload Reduced LV Afterload Unchanged

49 Clinical Implications When LVEF is normal in older pts with PH, evaluate LV diastolic function rigorously In elderly pts with multiple clinical risk factors for HFPEF, invasive cath may not be required When diagnostic uncertainty exists, or if pulmonary vasodilator therapy is contemplated, cardiac cath should be considered Pulmonary-specific vasodilators may worsen left heart filling pressures in PH-HFPEF The high prevalence and prognostic impact of PH in HFPEF suggests it may be a therapeutic target, but further study is needed

50 Phosphodiesterase-5 Inhibition RCT of sildenafil (50 mg tid) vs placebo in 44 pts with HFPEF and PASP>40 mmhg At 6 & 12 months, sildenafil mediated Reduction in mpap, RAP & PVR Improvement in RV & LV function Improvement spirometry & diffusing capacity Improvement in quality of life Guazzi M et al Circulation 2011

51 NIH-Sponsored, Chaired by Eugene Braunwald, 7 clinical centers (competitive application) including Duke, Baylor, Harvard, U of Utah, U of Vermont, U of M, Mayo.

52 Summary Diastolic dysfunction, vascular remodeling and pulmonary hypertension all contribute to the pathophysiology of HFPEF, and represent potential therapeutic targets Clinicians should recognize the typical clinical profile of patients with HFPEF, consider cardiac catheterization in cases of uncertainty and await results of ongoing clinical trials

53 Thank you