Myocardial contractile and metabolic properties of familial hypertrophic cardiomyopathy caused by cardiac troponin I gene mutations: a simulation study

Authors

  • Bo Wu,

    1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics
    2. Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
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  • Longhui Wang,

    1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics
    2. Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
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  • Qian Liu,

    1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics
    2. Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
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  • Qingming Luo

    1. Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics
    2. Key Laboratory of Biomedical Photonics of Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, China
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Q. Liu: Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China. Email: qianliu@mail.hust.edu.cn

Abstract

Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is caused by sarcomeric protein gene mutations. The mechanism by which these mutant proteins cause disease is uncertain. Experimentally, cardiac troponin I (CTnI) gene mutations mainly alter myocardial performance via increases in the Ca2+ sensitivity of cardiac contractility. In this study, we used an integrated simulation that links electrophysiology, contractile activity and energy metabolism of the myocardium to investigate alterations in myocardial contractile function and energy metabolism regulation as a result of increased Ca2+ sensitivity in CTnI mutations. Simulation results reproduced the following typical features of FHC: (1) slower relaxation (diastolic dysfunction) caused by prolonged [Ca2+]i and force transients; (2) higher energy consumption with the increase in Ca2+ sensitivity; and (3) reduced fatty acid oxidation and enhanced glucose utilization in hypertrophied heart metabolism. Furthermore, the simulation indicated that in conditions of high energy consumption (that is, more than an 18.3% increase in total energy consumption), the myocardial energetic metabolic network switched from a net consumer to a net producer of lactate, resulting in a low coupling of glucose oxidation to glycolysis, which is a common feature of hypertrophied hearts. This study provides a novel systematic myocardial contractile and metabolic analysis to help elucidate the pathogenesis of FHC and suggests that the alterations in resting heart energy supply and demand could contribute to disease progression.

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