Published online before print July 30, 2007, doi: 10.1161/HYPERTENSIONAHA.107.088609
(Hypertension. 2007;50:497.)
© 2007 American Heart Association, Inc.
Original Articles |
Pressure Overload-Induced Cardiomyopathy in Heterozygous Carrier Mice of Carnitine Transporter Gene Mutation
From the Department of Cardiology (R.T.), Chunichi Hospital, Nagoya, Japan; Department of Cardiology (T.A.), Aichi Cardiovascular and Respiratory Center, Ichinomiya, Japan; Department of Cardiology (H.M., R.M., M.T., H.M., T.M.), Nagoya University Graduate School of Medicine, Nagoya, Japan; and the Medical Science of Proteases (Y.N.) and Cardiovascular Research Medicine (K.O.), Nagoya University School of Medicine, Nagoya, Japan.
Correspondence Kenji Okumura, Cardiovascular Research Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. E-mail kenji{at}med.nagoya-u.ac.jp
Primary systemic carnitine deficiency is an autosomal recessive disorder caused by a decreased renal reabsorption of carnitine because of mutations of the carnitine transporter OCTN2 gene, and hypertrophic cardiomyopathy is a common clinical feature of homozygotes. Although heterozygotes for OCTN2 mutations are generally healthy with normal cardiac performance, heterozygotes may be at risk for cardiomyopathy in the presence of additional risk factors, such as hypertension. To test this hypothesis, we investigated the effects of surgically induced pressure overload on the hearts of heterozygous mutants of a murine model of OCTN2 mutation, juvenile visceral steatosis mouse (jvs/+). Eleven-week-old jvs/+ mice and age-matched wild-type mice were used. At baseline, there were no differences in physical characteristics between wild-type and jvs/+ mice. However, plasma and myocardial total carnitine levels in jvs/+ mice were lower than in wild-type mice. Both wild-type and jvs/+ mice were subjected to ascending aortic constriction with or without 1% L-carnitine supplementation for 4 weeks. At 4 weeks after ascending aortic constriction, jvs/+ mice showed an exaggeration of cardiac hypertrophy and pulmonary congestion, further increased gene expression of atrial natriuretic peptide in the left ventricles, further deterioration of left ventricular fractional shortening, reduced myocardial phosphocreatine:adenosine triphosphate ratio, and increased mortality compared with wild-type mice; L-carnitine supplementation prevented these changes in jvs/+ mice subjected to ascending aortic constriction. In conclusion, cardiomyopathy and heart failure with energy depletion may be induced by pressure overload in heterozygotes for OCTN2 mutations and could be prevented by L-carnitine supplementation.
Key Words: cardiomyopathy • genes • heart failure • hypertension • hypertrophy
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