Increased Myocardial Oxygen Consumption Precedes Contractile Dysfunction in Hypertrophic Cardiomyopathy Caused by Pathogenic TNNT2 Gene Variants

BACKGROUND: Hypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin-filament variant present with milder hypertrophy than carriers of thick-filament variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in TNNT2 (troponin T gene) variant carriers. METHODS AND RESULTS: Fourteen individuals with TNNT2 variants (genotype positive), without left ventricular hypertrophy (G+/LVH−; n=6) and with LVH (G+/LVH+; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and [11C]-acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/LVH− and G+/LVH+. Lower myocardial external efficiency in G+/LVH− is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/LVH+ is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/LVH+ compared with G+/LVH−. Although LV ejection fraction was higher in G+/LVH+, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall. CONCLUSIONS: Using cardiac magnetic resonance and [11C]-acetate positron emission tomography imaging, we show that G+/LVH− have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/LVH+. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant–mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.

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