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.
['Parbhudayal|Rahana Y|RY|', 'Harms|Hendrik J|HJ|', 'Michels|Michelle|M|', 'van Rossum|Albert C|AC|', 'Germans|Tjeerd|T|', 'van der Velden|Jolanda|J|']
D000328:Adult D002312:Cardiomyopathy, Hypertrophic D016022:Case-Control Studies D018450:Disease Progression D042241:Early Diagnosis D005260:Female D020022:Genetic Predisposition to Disease D014644:Genetic Variation D006801:Humans D019028:Magnetic Resonance Imaging, Cine D008297:Male D008875:Middle Aged D009200:Myocardial Contraction D009206:Myocardium D010101:Oxygen Consumption D010641:Phenotype D049268:Positron-Emission Tomography D011237:Predictive Value of Tests D011446:Prospective Studies D020107:Troponin T D018487:Ventricular Dysfunction, Left D016277:Ventricular Function, Left
oxygen consumption hypertrophic cardiomyopathy TNNT2 cardiac efficiency