Abstract
Introduction: Abnormal cardiac mitochondrial function and energetics may be a unifying feature in the pathogenesis of heart failure with preserved ejection fraction (HFpEF), while transient pulmonary congestion during exercise is an important determinant of reduced exercise capacity and symptoms. Hypothesis: We hypothesized that a gradient of myocardial energetic impairment exists across the spectrum of HFpEF and limits cardiac reserve during exercise, leading to transient pulmonary congestion. Methods: 43 patients across the spectrum of diastolic dysfunction and HFpEF (age-matched controls n=11; type 2 diabetes (T2DM) n=9; HFpEF n=14; severe diastolic dysfunction due to cardiac amyloid n=9) underwent assessment of cardiac energetics (myocardial phosphocreatine to ATP ratio, PCr/ATP) and function using CMR, and lung water using a novel MR proton density mapping sequence. Studies were performed at rest and during exercise (20 W for 6 minutes). Results: Paralleling the stepwise decline in diastolic function across the groups (E/e’ ratio p<0.001) was an increase in NT-pro BNP (p<0.001) and a reduction in PCr/ATP (p<0.001). During exercise, lower left ventricular (LV) diastolic filling rates (r 0.58, p<0.001), left atrial (LA) dilatation (r -0.52, p<0.001), lower right ventricular (RV) contractile reserve (ΔRVEF; r 0.57, p<0.001), and right atrial (RA) dilatation (r -0.71, p<0.001) were strongly linked with impaired energetics. The pulmonary proton density sequence provided images that scaled linearly with water content, validated using a water-doped sponge phantom (r 0.98, p<0.0001), and revealed transient pulmonary congestion in patients with HFpEF (+4.4% [0.5, 6.4], p=0.002) and amyloid (+6.4% [3.3, 10.0], p=0.004), which was not seen in controls (-0.1% [-1.9, 2.1], p=0.89) or T2DM (+0.8% [-1.7, 1.9], p=0.82). Exercise-induced pulmonary congestion was associated with reduced LV diastolic filling (r -0.33, p=0.03), RVEF augmentation (r-0.50, p<0.001), RA dilatation (r 0.44, p=0.004), and impaired myocardial energetics (r -0.43, p=0.004). Conclusion: A gradient of myocardial energetic deficit exists across the spectrum of HFpEF, leading to impaired cardiac functional reserve and transient exercise-induced pulmonary congestion.
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