Abstract 156: Enalapril prevents Development of Dilated Cardiomyopathy in Lamin A/C Mutant Mice
Dilated Cardiomyopathy (DCM) is one of the leading causes of heart failure due to systolic dysfunction. Mutations in the LMNA gene, which encodes the nuclear lamina proteins Lamin A and C, are the most common cause of familial DCM. Current treatment strategies to improve the prognosis are limited to implantable cardioverter-defibrillator and heart transplantation. Patients with LMNA-related DCM are treated in accordance with international guidelines for the management of heart failure with little consideration of the possible influence of the etiology on the response to treatment. Recent studies suggest that this might result in inappropriate therapy in some patients. The influence of genetic factors in determining the response (and timing) of drug therapy is largely unstudied in DCM. Therefore, our aim is to determine the efficacy of existing heart failure drugs in preventing or delaying LMNA-related DCM. We used a well-established mouse model of Lamin A/C mimicking human LMNA-related DCM. Mice heterozygous for the Lmna mutant gene (n=20 per group) were treated with Metoprolol (β-blocker) or Enalapril (ACE-inhibitor) before the onset of DCM and were functionally evaluated by serial echocardiography and ECG until 75 weeks of age. Hearts were harvested for histological analysis and molecular characterization. Interestingly, the experimental group treated with Enalapril had a preserved overall cardiac function comparable to wildtype mice. Mice treated with Metoprolol however, displayed progressive heart failure, and an aggravated cardiac function compared to untreated Lmna +/- mice. Both the beneficial effects of Enalapril in preventing development of systolic dysfunction as well as the detrimental effect of Metoprolol were confirmed by expression of molecular stress markers and degree of cardiac fibrosis. Our results suggest that Enalapril is effective in preventing Lmna+/- induced cardiomyopathy in mice. Strikingly, Metoprolol increases cardiac dysfunction and stress in Lmna+/- mice. Further studies will determine whether Enalapril is also effective in preventing LMNA-related DCM in patients, and whether omitting Metoprolol from the standard cocktail of prescribed heart failure medicine is beneficial for LMNA patients.
- © 2013 by American Heart Association, Inc.