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18th World Congress on Heart Disease

 

CPT1b DEFICIENCY IS BAD FOR THE HYPERTROPHIED HEART


Qinglin Yang, M.D., University of Alabama at Birmingham, AL, USA

 

Objective: To investigate the effect of Carnitine palmitoyltransferase 1b (CPT1b) deficiency on pressure overload-induced cardiac hypertrophy.

Background: CPT1 is a rate-limiting step of mitochondrial -oxidation by controlling the mitochondrial uptake of long-chain acyl-CoAs. The muscle isoform, CPT1b, is the predominant isoform expressed in the heart. CPT-1 inhibitors have been shown to be protective against cardiac hypertrophy and heart failure. However, clinical and animal studies have shown mixed results, thereby posting concerns on the safety of this class of drugs. Preclinical studies using genetically modified animals should provide a better understanding of targeting CPT1 to evaluate it as a safe and effective therapeutic approach.

Methods: Heterozygous CPT1b knockout mice (CPT1b+/-) were subjected to transverse aorta constriction (TAC)-induced pressure-overload.

Results: These mice showed overtly normal cardiac structure/function under the basal condition. Under a severe pressure-overload condition induced by two weeks of transverse aorta constriction (TAC), CPT1b+/- mice were susceptible to premature death with congestive heart failure. Under a milder pressure-overload condition, CPT1b+/- mice exhibited exacerbated cardiac hypertrophy and remodeling compared with that in wild-type littermates. There were more pronounced impairments of cardiac contraction with greater eccentric cardiac hypertrophy in CPT1b+/- than in controlled mice. Moreover, the CPT1b+/- heart exhibited exacerbated mitochondrial abnormalities and myocardial lipid accumulation with elevated triglycerides and ceramide content, leading to greater cardiomyocytes apoptosis.

Conclusion: We conclude that CPT1b deficiency can cause lipotoxicity in the heart under pathological stress, leading to exacerbation of cardiac pathology. Therefore, caution should be applied in the clinical use of CPT-1 inhibitors.

 

 

 

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