Myocardial energetic impairment differs in pre-hypertrophic carriers with mutations in MYH7 and MYBPC3 - a PET and MRI study

Abstract

Background: The majority of familial hypertrophic cardiomyopathy (HCM) (70%) is caused by mutations in the sarcomere genes, MYH7 and MYBPC3, which encode the thick filament proteins myosin heavy chain and myosin-binding protein C. Prognosis of patients with a MYH7 mutation is worse compared with MYBPC3 mutation patients, but no pathophysiological mechanism causing the difference in disease onset has been identified. It has been reported that HCM mutation carriers display reduced myocardial efficiency in the absence of hypertrophy. However, data regarding the myocardial energetic status in specific types of mutation carriers is lacking. Therefore, this study was conducted to study the energetic status in pre-hypertrophic MYH7 (MYH7mut) and MYBPC3 (MYBPC3mut) mutation carriers, using [11C] acetate-PET and cardiovascular magnetic resonance imaging (CMR). Methods: We included a total of 23 asymptomatic pre-hypertrophic carriers (9 MYH7mut and 14 MYBPC3mut; mean age 37±14 years, 6 males) and 14 healthy controls (mean age 48±11 years, 9 males). [11C]acetate-PET was performed to obtain myocardial oxygen consumption (MVO2). By use of CMR, left ventricular volumes and mass were defined to calculate myocardial external efficiency (MEE), i.e. the ratio between external work and MVO2. Results: Left ventricular mass index was comparable between controls, MYBPC3mut and MYH7mut (respectively, 48±8, 49±10 and 51±8 g/m2), as was stroke volume index (57±8, 53±9 and 52±7 ml/m2) and ejection fraction (62±6, 60±5 and 62±3 ml/m2). MVO2 was higher in carriers compared with controls (0.18±0.05 vs 0.15±0.04 ml·min-1·g-1), while cardiac work was significantly lower in carriers than in controls (7703±1501 vs 10162±2241 mmHg·ml, p<0.001). As a consequence, MEE was significantly lower in carriers (21.0±6.3%) compared with controls (33.6±6.4%, p<0.001). No significant difference was present in MVO2 between MYH7mut and MYBPC3mut (respectively 0.18±0.04 and 0.17±0.05 ml·min-1·g-1). However, cardiac work was lower in MYH7mut compared with MYBPC3mut (respectively 7170±1272 and 8045±1580 mmHg·ml). The higher MVO2 and lower cardiac work in MYH7mut resulted in a significantly lower MEE compared with MYBPC3mut (respectively 17.2±2.7 and 23.5±6.8%, p=0.02) Conclusion: MYH7 carriers are characterized by a more severe reduction in myocardial efficiency compared with MYBPC3 carriers before the development of hypertrophy. This apparent different mutation-effect on myocardial function and efficiency might partially explain the difference in disease onset between HCM caused by the thick filament mutations.