Impaired myocardial energetics precede coronary microvascular dysfunction and ventricular hypertrophy in carriers of the hypertrophic cardiomyopathy MYBPC3 mutation

Objectives Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease characterized by an abnormal contractile apparatus, with subsequent increased energetic cost to force production. Insights into the causative factors of impaired energy metabolism and its relation to the onset of ventricular hypertrophy and microvascular dysfunction are of clinical importance. Therefore, the aim was to investigate myocardial energetics in asymptomatic HCM mutation carriers.

Methods Sixteen subjects with a MYBPC3 mutation underwent [11C]acetate positron emission tomography (PET) to obtain myocardial oxygen consumption (MVO2). By use of cardiovascular magnetic resonance (CMR) imaging, LV volumes and mass were defined to calculate myocardial external efficiency (MEE), i.e. the ratio between external work and MVO2 per gram of myocardial tissue. Resting myocardial blood flow (MBF) and hyperemic MBF (hMBF) were assessed by [15O]water PET. Eleven healthy family relatives, all non-carriers, underwent similar scanning protocols to serve as a control group.

Results MVO2 was comparable between the carriers and controls (0.16±0.05 vs. 0.15±0.04 mL/min/g, p=0.42), as was LVM (93±25 vs. 99±21 g, p=0.85). External work, however, was markedly reduced in the carriers (7398±1384 vs. 9196±2515 mmHg*mL, p=0.07). Hence, MEE was significantly decreased in the carriers compared to controls (26±10 vs. 36±8%, p=0.02). MBF and hMBF were comparable between the carriers and controls (1.22±0.34 vs. 1.18±0.31 mL/min/g, p=0.73 and 4.02±0.93 vs. 4.04±0.91 mL/min/g, p=0.94, respectively).

Conclusions Asymptomatic HCM mutation carriers already show reduced myocardial work generation in relation to oxygen consumption, in the absence of hypertrophy and flow abnormalities. Hence, impaired myocardial energetics precede the occurrence of microvascular dysfunction and ventricular hypertrophy, and may constitute a primary component of the pathological cascades in HCM