Impaired myocardial energetics in both sarcomere positive and negative HCM are linked to arrhythmic risk

Background Impaired myocardial energetics play a pivotal role in the complex pathophysiology of hypertrophic cardiomyopathy (HCM), and are thought to be mediated by energy-costly sarcomeric mutations and mitochondrial dysfunction (1). Two thirds of HCM patients, however, do not possess pathogenic sarcomeric mutations (2) and instead develop the condition due to a combination of increased polygenic susceptibility and comorbidities. Whether energetic impairment, a target of novel HCM treatments (e.g., myosin modulators such as Mavacamten), similarly affects sarcomere mutation positive (Sarc+) and negative (Sarc-) HCM remains unclear, as does the association between impaired energetics and markers of arrhythmic risk such as hypertrophy severity, cardiac function and non-sustained ventricular tachycardia (NSVT). This study aimed to investigate differences in resting myocardial energetics between Sarc+ and Sarc- HCM by measuring the phosphocreatine-to-adenosine triphosphate (PCr/ATP) ratio using phosphorus magnetic resonance spectroscopy (31P-MRS) and explore the association between impaired energetics and markers of arrhythmic risk in HCM. Methods We recruited one hundred (100) participants (80 non-obstructive HCM patients and 20 age- and sex-matched controls). Myocardial energetics were assessed using 31P-MRS to measure the PCr/ATP ratio. Cardiac magnetic resonance (CMR) imaging including cine, T1 (ShMOLLI), quantitative pixel-wise perfusion mapping (3) and late gadolinium enhancement (LGE) imaging was also performed. In addition, HCM patients underwent 7-day ECG monitoring to document NSVT episodes (3 beats ≥120 bpm). Results HCM patients had impaired myocardial energetics (PCr/ATP ratio) relative to controls (HCM 1.64±0.36 vs controls 1.97±0.32 p<0.001). PCr/ATP ratios did not differ between Sarc+ and Sarc- HCM even after adjustment for confounders including age, hypertrophy and fibrosis burden (Sarc+ 1.64 [1.50-1.78] vs Sarc- 1.64 [1.52-1.77], p=0.993). PCr/ATP ratio showed no correlation with maximum wall thickness (p=0.257), left ventricular ejection fraction (p=0.727) or myocardial perfusion reserve (p=0.851), but did inversely correlate with global longitudinal strain (r=-0.3, p=0.025). Reduced PCr/ATP was associated with presence of fibrosis (LGE+ 1.58±0.35 vs LGE- 1.79±0.37 p=0.025) and with NSVT, independent of age or fibrosis burden (NSVT+ 1.54 [1.40-1.67] vs NSVT- 1.73 [1.62-1.86], p=0.046). Conclusion Myocardial energetics are similarly impaired in Sarc+ and Sarc- HCM, and are independently associated with impaired contractility, greater fibrosis severity and heightened arrhythmic risk. Our findings provide novel mechanistic insights into the potentially favourable response of HCM patients to energy-sparing myosin modulator therapies irrespective of genotype and highlight the potential for cardiac energetics to serve as a marker of arrhythmic risk.