Novel Morphological Features on CMR for the Prediction of Pathogenic Sarcomere Gene Variants in Subjects Without Hypertrophic Cardiomyopathy

Background: Carriers of pathogenic DNA variants (G+) causing hypertrophic cardiomyopathy (HCM) can be identified by genetic testing. Several abnormalities have been brought forth as pre-clinical expressions of HCM, some of which can be identified by cardiovascular magnetic resonance (CMR). In this study, we assessed morphological differences between G+/left ventricular hypertrophy-negative (LVH-) subjects and healthy controls and examined whether CMR-derived variables are useful for the prediction of sarcomere gene variants. Methods: We studied 57 G+ subjects with a maximal wall thickness (MWT) < 13 mm, and compared them to 40 healthy controls matched for age and sex on a group level. Subjects underwent CMR including morphological, volumetric and function assessment. Logistic regression analysis was performed for the determination of predictive CMR characteristics, by which a scoring system for G+ status was constructed. Results: G+/LVH- subjects were subject to alterations in the myocardial architecture, resulting in a thinner posterior wall thickness (PWT), higher interventricular septal wall/PWT ratio and MWT/PWT ratio. Prominent hook-shaped configurations of the anterobasal segment were only observed in this group. A model consisting of the anterobasal hook, multiple myocardial crypts, right ventricular/left ventricular ratio, MWT/PWT ratio, and MWT/left ventricular mass ratio predicted G+ status with an area under the curve of 0.92 [0.87–0.97]. A score of ≥3 was present only in G+ subjects, identifying 56% of the G+/LVH- population. Conclusion: A score system incorporating CMR-derived variables correctly identified 56% of G+ subjects. Our results provide further insights into the wide phenotypic spectrum of G+/LVH- subjects and demonstrate the utility of several novel morphological features. If genetic testing for some reason cannot be performed, CMR and our purposed score system can be used to detect possible G+ carriers and to aid planning of the control intervals.