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Effects of mechanical stress and carvedilol in lamin A/C-deficient dilated cardiomyopathy


RATIONALE: Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. OBJECTIVE: Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice. METHODS AND RESULTS: Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. CONCLUSIONS: These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts.

Type Journal
ISBN 1524-4571 (Electronic) 0009-7330 (Linking)
Authors Chandar, S.; Yeo, L. S.; Leimena, C.; Tan, J. C.; Xiao, X. H.; Nikolova-Krstevski, V.; Yasuoka, Y.; Gardiner-Garden, M.; Wu, J.; Kesteven, S.; Karlsdotter, L.; Natarajan, S.; Carlton, A.; Rainer, S.; Feneley, M. P.; Fatkin, D.;
Published Date 2010-11-01
Published Volume 106
Published Issue 3
Published Pages 573-82
Status Published in-print
URL link to publisher's version
OpenAccess link to author's accepted manuscript version