Understanding Diastole and Its Contribution to Heart Failure: State of the Art in 2016 James D. Thomas, MD, FACC, FASE Director, Center for Heart Valve Disease Bluhm Cardiovascular Institute Professor of Medicine, Feinberg School of Medicine, Northwestern University Chicago, Illinois Conflicts of interest: GE, Abbott, Edwards (honoraria)
Poor Outcome in HFpEF is Long Known Survival for EF 50% and <50% Survival 1.0.8.6.4.2.0 Expected EF = <50% EF = 50% p=0.279 0 1 2 3 4 5 6 Years EF = <50% 78 58 51 44 36 16 EF = 50% 59 44 35 32 29 15 Senni et al. Circulation 1998; 98: 2282-2289 031-304
Poor Outcome in HFpEF Survival for EF 50% and <50% Owan T et al. N Engl J Med 2006; 355: 251-259
Poor Outcome in HFpEF Survival for EF 50% and <50% As bad as advanced lung cancer! Owan T et al. N Engl J Med 2006; 355: 251-259
Increasing Frequency of HFpEF Prevalence for EF 50% and <50% Owan T et al. N Engl J Med 2006;355:251-259
Increasing Prevalence of HFpEF GWTG-HF: 110,621 HF Hospitalizations Steinberg et al. Circulation 2012; 126: 65-75
What s New in HFpEF? New ways of grading diastolic dysfunction New ways to categorize patients Novel approaches to treatment
It Used to Seem So Simple Patterns of Diastolic Function In the beginning (mid 80s) There was good and evil
It Used to Seem So Simple Patterns of Diastolic Function In the beginning (mid 80s) But some sick patients still looked like this
It Used to Seem So Simple Patterns of Diastolic Function In the beginning (mid 80s) And the sickest of all looked like this
And We Struggled to Understand Pseudonormaliztion In the beginning (mid 80s) Thomas et al. JACC 1990; 16: 644-55
Integrating Multiple New Parameters PV Flow, TDI, Color M-mode, LA volume D S S AR E A
Use of Additional Parameters PV Flow, Tissue Doppler, Color M-mode E A Mitral inflow Mitral Inflow S D PV flow PV flow S m TDE Tissue Doppler A m E m CMM - Vp Color M-mode v p Nl (young) NL (Young) Nl (adult) NL (Adult) Delayed relaxation Delayed Relaxation Pseudo normal Pseudo normal Restrictive Restrictive Garcia, Thomas & Klein JACC 1998; 32: 865-875
31 yo Man MV: E:A = 2 PV: S>D Lateral e = 15 cm/sec E/e = 7.5 CMM: V p = 65 cm/sec
What s the Diastolic Function? 1) Normal 2) Stage 1 3) Stage 2 4) Stage 3 5) Stage 4
What s the Diastolic Function? 1) Normal 2) Stage 1 3) Stage 2 4) Stage 3 5) Stage 4
31 yo Man Septic and cardiogenic shock 2d after appendectomy PE: BP 96/72, HR 86, RA 20, PA 41/28, PCW 26, CI 1.5 Meds: Dopa, dobut, nipride, NTG, IABP
Guidelines Approach to Grading Diastolic Dysfunction Septal e Lateral e LA volume Big Problem There are 8 combinations of these parameters, but only 3 fit the algorithm! Septal e 8 Lateral e 10 LA < 34 ml/m2 Septal e 8 Lateral e 10 LA 34 ml/m2 Septal e < 8 Lateral e < 10 LA 34 ml/m2 E/A < 0.8 DT > 200 ms Av. E/e 8 Ar-A < 0 ms Val E/A < 0.5 E/A 0.8-1.5 DT 160-200ms Av. E/e 9-12 Ar-A 30 ms Val E/A 0.5 E/A 2 DT < 160 ms Av. E/e 13 Ar-A 30 ms Val E/A 0.5 Normal. function Normal function, Athlete s heart, or constriction Grade I Grade II Grade III Nagueh et al. JASE 2009; 22: 108-33
A Room with Eight Ways Out But 5 of them are locked!
How Well Do These Work in Practice? 401 consecutive patients, age 59±16 years (60%M) Using only the 3 primary classifiers (LAVi, septal and lateral e ), diastolic function could be assigned in only 34% of cases For the 5 secondary indices (E/A ratio, E deceleration time, E/E, PV AR reversal duration, and E/A with Valsalva), concordance (3+/5 indices in agreement) occurred in only 64% of cases. Let s take another swing at the guidelines!
Nagueh et al. JASE 2016; 29: 277-314
Normal LV LVEF < 50% or other LV disease
Will the new guidelines be more applicable??? Time will tell, but clear there are many indeterminate cases
What s New in HFpEF? New ways of grading diastolic dysfunction New ways to categorize patients Novel approaches to treatment
The Many Faces of HFpEF Many thanks to Sanjiv Shah, MD, for some of these slides
The Many Faces of HFpEF
Clinical Categories of HFpEF Garden variety HFpEF (HTN, obesity, DM, CKD) CAD-HFpEF Right heart failure HFpEF AF predominante HfpEF HCM-like HFpEF High-output HFpEF Valvular HFpEF (multiple moderate lesions) Zebras: Constriction, amyloid (treatable) Oktay AA, Shah SJ. Curr Cardiol Rev 2014
397 HFpEF patients with detailed clinical, lab, ECG, and echo phenotyping (67 variables) Unbiased hierarchical clustering analysis 3 distinct groups identified 1: younger, lower BNP, less LVH and DD 2: most DM, obesity, OSA, lowest e, highest PCW and PVR 3: older, highest BNP, worst CKD, most electrical and echo changes, highest E/e, RV dysfunction Shah et al. Circulation 2015; 131; 269-79
Very Different Outcomes in the Three Groups Shah et al. Circulation 2015; 131; 269-79
What s New in HFpEF? New ways of grading diastolic dysfunction New ways to categorize patients Novel approaches to treatment
Key role of inflammation, altered signaling, fibrosis Circulation 2016; 134: 73-90
Matrix Approach to Therapy Matching Predisposing Factors and Clinical Presentation Bold: proven therapy; unbold: logical, promising, but unproven Shah et al. Circulation 2016; 134: 73-90
80+% of HFpEF patients Bold: proven therapy; unbold: logical, promising, but unproven Shah et al. Circulation 2016; 134: 73-90
Therapeutic Targets for HFpEF Diuresis Reduction in congestion/edema Improved RV afterload Lower PASP Better RV function Improved natriuresis/renal function Improved outcome with careful monitoring
80+% of HFpEF patients Almost universal Bold: proven therapy; unbold: logical, promising, but unproven Shah et al. Circulation 2016; 134: 73-90
Therapeutic Targets for HFpEF Weight Loss and Exercise Training Obesity and inactivity are risk factors for DM, HTN, HL Obesity also pro-inflammatory and impairs cardiac, renal, arterial, and skeletal muscle function Fat infiltration in muscle reduces O 2 diffusion and lowers A-V O 2 difference
23 HFpEF patients, 15 healthy controls (HC) Leg MRI to define skeletal muscle (SM) and intramuscular fat (IMF) Haykowsky et al. AJC 2014; 113: 1211-6
100 obese patients with HFpEF 2x2 design randomized for diet (D), exercise (E), both, or neither (control) Outcomes: exercise capacity and QOL, with a host of secondary ones 20 week trial, 84% adherence to exercise, 99% to diet Weight loss Control: 1 Kg Exercise: 4 Kg Diet: 7 Kg Diet + exercise: 11 Kg Kitzman et al. JAMA 2016; 315: 36-46
Diet and Exercise Work! AT = aerobic training; CR = calorie restriction Kitzman et al. JAMA 2016; 315: 36-46
Matrix Approach to Therapy Novel Approaches Bold: proven therapy; unbold: logical, promising, but unproven Shah et al. Circulation 2016; 134: 73-90
Rationale for Testing Nitrites in HFpEF Nitrites are very different from nitrates Endothelial dysfunction plays a central role in HFpEF Nitrites improve endothelial function Nitrates my actually worsen endothelial function via increased ROS There is strong preliminary preliminary data for nitrites in HFpEF (both oral and inhaled forms) Some evidence that nitrate (as beetroot juice) can improve exercise tolerance
Acute Infusion of Sodium Nitrite Improvement in LV and RV Hemodynamics Borlaug et al. JACC 2015; 66: 1211-6
Additional Targets for Therapy Novel Approaches Pleiotropic benefits of cgmp and protein kinase G cascade Importance of fibrosis and anti-fibrotic therapy Supporting trials of spironolactone (TOPCAT), and valsartan/sacubitril (PARAMOUNT)
1 Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) 351/1723 (20.4%) Placebo Spironolactone HR = 0.89 (0.77 1.04) p=0.138 320/1722 (18.6%) Pitt et al. NEJM 2014
Placebo Rates: Primary Outcome, by region US, Canada, Argentina, Brazil 12.6 per 100 pt-yr Placebo: 280/881 (31.8%) Russia, Rep Georgia 2.3 per 100 pt-yr Placebo: 71/842 (8.4%) Pfeffer et al. Circulation 2015
Exploratory (post-hoc): Placebo vs. Spiro by region US, Canada, Argentina, Brazil HR=0.82 (0.69-0.98) Placebo: 280/881 (31.8%) Interaction p=0.122 Placebo: 71/842 (8.4%) Russia, Rep Georgia HR=1.10 (0.79-1.51) Pfeffer et al. Circulation 2015
Lancet 2016; 387: 1290 Lancet 2016; 387: 1297
Lancet 2016; 387: 1290 Lancet 2016; 387: 1297
An Exciting Program to Come Thanks for your attention!
Hoping to Welcome You in Chicago Thanks for your attention!