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 Ca(2+) 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 Ca(2+) sensitivity in CTnI mutations. Simulation results reproduced the following typical features of FHC: (1) slower relaxation (diastolic dysfunction) caused by prolonged [Ca(2+)](i) and force transients; (2) higher energy consumption with the increase in Ca(2+) 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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Authors | Bo Wu, Longhui Wang, Qian Liu, Qingming Luo |
Journal | Experimental physiology
(Exp Physiol)
Vol. 97
Issue 1
Pg. 155-69
(Jan 2012)
ISSN: 1469-445X [Electronic] England |
PMID | 21967901
(Publication Type: Journal Article)
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Chemical References |
- Fatty Acids
- Troponin I
- Lactic Acid
- Adenosine Triphosphate
- Glucose
- Calcium
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Topics |
- Adenosine Triphosphate
(metabolism)
- Animals
- Calcium
(metabolism)
- Cardiomyopathy, Hypertrophic, Familial
(genetics, metabolism, physiopathology)
- Computer Simulation
- Energy Metabolism
- Fatty Acids
(metabolism)
- Glucose
(metabolism)
- Glycolysis
- Guinea Pigs
- Lactic Acid
(metabolism)
- Mutation
- Myocardial Contraction
(genetics)
- Myocardium
(metabolism, pathology)
- Myofibrils
(metabolism, physiology)
- Oxidation-Reduction
- Rats
- Troponin I
(genetics, metabolism)
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