Peripheral Contributions to HFpEF

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1 Peripheral Contributions to HFpEF Greg Lewis MD Heart Failure Section Head MGH Cardiology Division and Pulmonary Critical Care Unit Harvard Medical School March 12, 2018

2 Pathophysiology of HFpEF vs. HFrEF Endothelium HFpEF: a systemic disease Myocyte Paulus WJ et al, JACC, 2013

3 HFpEF as a Systemic Disease Relationship between cardiac abnormalities and incident HFrEF vs. HFpEF in the community (N>5,000) Relative degree of impairment in exercise capacity in agematched normals vs. HFrEF vs. HFpEF (N=119) Peak VO2 (ml/kg/min) P<0.001 Ho J, Eur J Cardiol 2012 Why? NO HFREF SD DD Healthy HFPEF Kitzman D, JAMA 2002

4 Importance of Understanding Exercise Intolerance in Heart Failure Exertional dyspnea and fatigue are the primary symptoms of HF, even when well-compensated and non-edematous Exertional intolerance Major contributor to reduced quality of life Measurements of exercise capacity (peak VO 2 ) are Standardized and objective Highly reproducible, even in elderly HFpEF Potently predict survival

5 Metabolic Machinery that Contributes to Impaired Functional Capacity in HFpEF Peripheral LV- S. Vasc Cardiac RV- P. Vasc Pulm Mechan Q CO2 Mitochondria MUSCLE HEART BLOOD LUNGS V CO2 Peak VO 2 Functional Capacity V O2 Q O2 Incr Ca-vO 2 Recruit Vasodilate Incr SV Incr HR Recruit Vasodilate Incr V T Wasserman K et al 1. Pulmonary: 1 abnormal PFT: 88-94% (Lopez-Giraldo ERJ 2012) 2. RV-Pvasc: PH: 83% (Lam JACC 2009), RV Dysfunction (TAPSE<16, qualitative) 33% 3. Cardiac: chronotropic incompetence (63% reach <80% HR reserve, Phan Circ HF 2010) stroke volume (Kitzman D, JACC 1991) 4. LV-Systemic Vasc: arterial stiffness and impaired LV-systemic vascular coupling (Borlaug Circulation 2006) 5. Peripheral: Ca-vO2 in >40% of patients with HFpEF (Dhakal B, Circ HF 2015)

6 How do we augment VO 2 with Exercise? VO2 (ml/kg/min) Heart Rate (bpm) VO 2 = HR VO2 x SV = HR x C(a-vO x SV x 2 ) C(a-v)O2 0 VO2 = HR x SV x C(a-v)O VO2 (ml/kg/min) X ~18X 10X Rest Peak Rest Peak Exercise Trained Exercise Peak The requisite in arteriovenous O 2 content difference C(a-v)O 2 during exercise is underappreciated. -Stroke volume +25%, C(a-v)O2 +180%, >7x O2 (ml O2/dL) 50 ~18X 140 Stroke Volume (ml/beat) Trained Peak Heart Rate (bpm) 200 3X 3X Rest P Rest 140 Peak Exe Traine Exercise 120 Peak 1.8X X 60 Stroke Volume (ml/beat) Rest P Exe Rest Peak Traine Arterial 25 Exercise Peak Venous Arterial 2.8 Venous 3.4X X O2 (ml O2/dL) D 5ml/dL 10 5 D 5ml/dL D 14ml/dL 0 Rest Rest Peak Exercise Ex Tra Pe Lewis, GD Up To Date 2017, Exercise Physiology

7 Oxygen content in ml/dl Impaired O 2 Extraction (C(a-v)O 2 ) in HFpEF 20 CaO2 CvO * HFpEF HFrEF Controls Haykowsky, Kitzman JACC 2014: Estimated C(a-v)O 2 Bhella, Levine Eur J HF 2011: Estimated C(a-v)O 2 Abudiab, Borlaug and Santos, Systrom: similar C(a-v)O2

8 What are the relative contributions of O 2 pathway deficits in HFpEF? VO 2 = CO x C(a-vO 2 ) V A : Alveolar ventilation D L : Lung diffusion capacity for O 2 Hb: Hemoglobin Q: Cardiac output D M : Skeletal muscle diffusion capacity V max : Mitochondrial respiration capacity

9 Comprehensive Characterization of the O 2 Pathway in HFpEF Radionuclide Ventriculography 9

10 O 2 Pathway Analysis in HFpEF: Hypothesis 1 A cardio-centric perspective on HFpEF Patients with HFpEF have impairment in exercise cardiac output alone Nothing to see here

11 Hypothesis 2: O 2 Pathway Analysis in HFpEF HFpEF is heterogeneous with single simple deficits in different clusters of individuals Single Heterogenous Deficits? Attractive paradigm for targeted interventions

12 O 2 pathway analysis in HFpEF n=60 HFpEF vs. n=60 controls -Rigorously defined HFpEF -S+Sx, EF + HD profile on day of evaluation Actual Patient Data n=60 HFpEF patients Multiple compound abnormalities are present In the O 2 pathway in HFpEF All 60 patients demonstrated abnormalities in >1 component of the O 2 pathway Houstis.Lewis, Circulation % -30% -27% -31% -5% -20%

13 What are the relative contributions of O 2 pathway deficits in HFpEF and are the evenly distributed across patients? VO 2 = CO x C(a-vO 2 ) -Fick variable reciprocity Dm is preferable to C(a-v)O 2 in determining Peripheral skeletal Muscle abnormalities In HF Dm is 30% in HFpEF Houstis et al. Circulation 2018

14 What is the relative significance of each O 2 pathway deficit and the impact of correcting it?

15 Skeletal Muscle Abnormalities in HFpEF: Lean Mass, Fat, PCr Recovery, Type I Fibers Bhella, et al. Eur J Heart Fail ; Haykowsky et al, J Gerontol A Biol Sci Med Sci. 2013; Haykowsky et al. Am J Cardiol. 2014;Kitzman et a. Am J Physiol.2014

16 Skeletal Muscle Plasticity and Interventional Studies of Exercise Training Study Inclusion Criteria Intervention Duration Results (Peak VO 2 ) Base f/u p Ex training Kitzman D Circ HF 2010 HF EF >50, hx pulm edema 1 of: DOE, PND, orthop, edema, ex fatigue Ex training n=26 Control=27 4 mos 13.8(2.5) 16.1(2.6) (2.6) 12.5(3.4) Ex DHF Pilot JACC 2011 NYHA 2-3, age>45, EF>50, echo DD>1, SR 1 of: obese, DM, HTN, chol, smoking Ex training n=46 Usual care n=21 3 mos 16.1(4.9) 18.7(5.4) (4.7) 16.6(6.0) Caloric restrict/ Exercise Training Kitzman D JAMA 2016 Age>60, BMI > 30 HF EF >50, Diet n=24 Ex n=26 Both n= 25 Control n= mos 14.7 (2.9) 1.3(0.8/1.8) (2.9) 1.2(0.7/1.7) No change in cardiac morphology

17 Heart R 125 Increased 120 A-V O 2 Accounts for Nearly 40 All the Training- Baseline Follow-Up Baseline Related Improvement in Exercise Capacity in HFpEF Strok 45 Follow-Up 7.5 C 22 D * Cardiac Output (L/min) A-VO 2 Difference (ml/dl) Baseline Follow-Up 14 Baseline Follow-Up Consistent findings by Levine et al AHJ 2012: No change in Cardiac Output (invasively measured) with Training in HFpEF Haykowsky, Kitzman, JACC 2012

18 Future Direction: Targeting the Periphery Facilitated exercise and weight loss programs Pharmacologic mitochondrial protection Targeting impaired endothelial and microcirculatory function -cgmp-augmenting therapies? Impaired muscle sympatholysis Iron deficiency related impairment in oxidative metabolism Borlaug BA,JACC 2010 Ferguon J Physiol 2013 Lewis G Circ HF 2016

19 Conclusions HFpEF is a total body (systemic) syndrome Likely triggered by inflammation The systemic trigger impacts striated muscle, both cardiac and skeletal Skeletal muscle has robust capacity for rapid regeneration and repair Improved skeletal muscle function may underlie the 2 interventions shown to date to improve exercise capacity in HFpEF exercise training and dietary weight loss The patient will be grateful for improved activity tolerance whether derived from improved skeletal muscle, vascular, or cardiac function

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21 Skeletal Muscle Mitochondrial Dysfunction in a Salt- Sensitive Rat Model of HFPEF Bowen et al; Eur J HF 2015 Exercise training prevented the development of mitochondrial dysfunction

22 How Did Diet Improve Exercise Function? Reduced Markers of Inflammation

23 Shift in Skeletal Muscle Fiber Type in HFpEF: Relationship to Exercise Capacity Kitzman et al, Am J Physiology 2014 Bhella, Levine, et al; EHJ 2011: Abnormal skeletal muscle metabolism by MR phosphorus spectroscopy