Chandar S.,Molecular Cardiology Division |
Yeo L.S.,Molecular Cardiology Division |
Leimena C.,Molecular Cardiology Division |
Tan J.-C.,Victor Chang Cardiac Research Institute |
And 15 more authors.
Circulation Research | Year: 2010
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 β-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. © 2010 American Heart Association, Inc.