Abstract 4371255: The Role of Myocardial Histological Remodeling in Exercise Intolerance Among Patients with Heart Failure with Preserved Ejection Fraction

Introduction: Exercise intolerance is a hallmark of heart failure with preserved ejection fraction (HFpEF), and while myocardial histopathologic findings have been reported, they have not been correlated with exercise intolerance and hemodynamic assessment. Methods: We analyzed data from 91 HFpEF patients who underwent right heart catheterization (RHC) with supine bicycle exercise and research endomyocardial biopsy (EMB) from the Johns Hopkins HFpEF Registry. EMB samples were assessed for hypertrophy and fibrosis, categorized as: (1) absent, (2) mild/patchy, (3) moderate, or (4) severe. For analysis, patients were categorized as none/mild versus moderate/severe. Groups were compared by clinical characteristics, echocardiography, and hemodynamic measures. Results: EMB revealed cardiomyocyte hypertrophy as absent in 6 (7%), mild in 60 (66%), moderate in 24 (26%), and severe in 1 (1%) of patients. Fibrosis was absent in 1 (1%), mild in 80 (88%), and moderate in 10 (11%); none exhibited severe fibrosis. Patients with moderate/severe hypertrophy were older and had larger left atrial diameters, elevated E/e’ ratios, higher NT-proBNP and increased hepatic congestion markers compared to those with no/mild hypertrophy. No significant differences were observed regarding fibrosis extent. Maximal exercise capacity did not differ between hypertrophy groups (37±16 W vs. 40±16 W, P=0.48) or fibrosis groups (41±18 W vs. 39±16 W, P=0.72). ( Figure A, D ) However, patients with moderate/severe hypertrophy exhibited higher pulmonary capillary wedge pressures at rest (19.2±7.4 mmHg vs. 14.0±6.7 mmHg, P=0.002), intermediate (31.9±9.2 mmHg vs. 25.4±8.2 mmHg, P=0.002), and peak exercise (36.6±9.4 mmHg vs. 28.6±7.4 mmHg, P<0.001). They also had lower cardiac index at peak exercise (3.69±0.71 L/min/m2 vs. 4.41±1.12 L/min/m2, P=0.019). ( Figure B, C ) Fibrosis extent did not correlate with hemodynamics, except for higher systemic vascular resistance at peak exercise in the moderate fibrosis group (32±12 Wood Units vs. 28±8 Wood Units, P=0.010). Conclusion: Moderate to severe myocyte hypertrophy is associated with elevated pulmonary capillary wedge pressure at rest and with exercise, and reduced cardiac index during exercise, while moderate myocardial fibrosis is associated with increased pulmonary vascular resistance – all negative prognostic markers in HFpEF. Our findings highlight potential mechanistic underpinnings of exercise intolerance in HFpEF and warrant further investigation.