Multiparametric CMR detects a higher burden of microstructural and metabolic abnormalities in sarcomeric HCM compared to non-sarcomeric HCM

Background Hypertrophic cardiomyopathy (HCM) patients with pathogenic sarcomeric gene variants (Sarc+ HCM) have a higher risk of ventricular arrhythmias and sudden cardiac death (SCD) compared to those without (Sarc- HCM). The reason for this increased risk is poorly understood. Using multiparametric cardiac magnetic resonance (CMR) imaging, we evaluated hypertrophy-matched Sarc+ and Sarc- HCM patients to identify key microstructural and metabolic differences and explore associations with arrhythmic risk. Methods 39 Sarc+ HCM, 41 Sarc- HCM and 20 age- and sex-matched controls underwent cine imaging, phosphorus magnetic resonance spectroscopy (31P-MRS), diffusion tensor CMR, blood oxygen level-dependent (BOLD) imaging, T1 mapping, and quantitative perfusion imaging. Quantitative ECG analysis was performed in all HCM patients, and extended ECG monitoring in those without prior non-sustained ventricular tachycardia (NSVT). Myocardial energetics were assessed using the phosphocreatine-to-ATP (PCr/ATP) ratio, oxygenation by ∆BOLD (%), disarray by diastolic fractional anisotropy (FA) adjusted for fibrosis, perfusion by myocardial perfusion reserve (MPR), and fibrosis by late gadolinium enhancement (LGE). Results Sarc+ HCM and Sarc- HCM patients had similar maximum wall thickness (20 mm vs. 18 mm, p=0.13). However, Sarc+ HCM patients were younger (51 vs. 57 years, p=0.005) and had a greater LGE burden (13% vs. 5%, p=0.007). PCr/ATP was reduced in HCM (1.64 ± 0.4 vs. 1.97 ± 0.3, p<0.001), but equally so between Sarc+ and Sarc- HCM (p=0.967). Mean diastolic FA was lower in HCM compared to controls (0.50 [0.45-0.52] vs. 0.57 [0.54-0.59], p<0.001), with Sarc+ HCM showing more pronounced FA reduction in hypertrophied segments compared to Sarc-HCM (0.46 [0.43-0.48] vs 0.49 [0.47-0.51], p=0.046), suggesting greater myocardial disarray. MPR was similarly reduced in both groups, but Sarc+ HCM patients exhibited more blunted myocardial oxygenation (∆BOLD 9% [7-11] vs. 12% [10-14], p=0.012). PCr/ATP, diastolic FA, and ∆BOLD independently associated with NSVT. Lower diastolic FA was associated with prolonged QTc intervals (r=-0.34, p=0.010) and greater QTc dispersion (r=-0.30, p=0.018). The presence of one of these CMR abnormalities in the most abnormal quartile associated with a nearly fourfold increased risk of NSVT (OR 3.8 [1.8-8.2], p<0.001), and two or more increased the risk almost fifteen times. Conclusion We show for the first time that Sarc+ HCM patients accumulate greater microstructural and metabolic abnormalities, including more fibrosis, myocardial disarray, and impaired oxygenation, at a younger age than Sarc- HCM. This increased cumulative burden of abnormalities may underlie the heightened arrhythmic and SCD risk in Sarc+ HCM. Key novel markers including PCr/ATP, diastolic FA, and ∆BOLD were independently associated with NSVT and repolarization abnormalities, highlighting their potential future role in arrhythmic risk stratification.