In a mouse model of severe cardiomyopathy, βARK1 inhibition significantly increased mean survival age from 9 to 15 weeks (P<0.0001), an effect further potentiated by metoprolol to 25 weeks.
Absolute Event Rate: 15% vs 9%
p-value: p=< 0.0001
Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of βARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of βARK1 (βARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca 2+ -binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 ± 1 weeks). In contrast, CSQ/βARKct mice exhibited a significant increase in mean survival age (15 ± 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/βARKct, left ventricular end diastolic dimension 5.60 ± 0.17 mm vs. 4.19 ± 0.09 mm, P < 0.005; % fractional shortening, 15 ± 2 vs. 36 ± 2, P < 0.005). The enhancement of the survival rate in CSQ/βARKct mice was substantially potentiated by chronic treatment with the βAR antagonist metoprolol (CSQ/βARKct nontreated vs. CSQ/βARKct metoprolol treated, 15 ± 1 weeks vs. 25 ± 2 weeks, P < 0.0001). Thus, overexpression of the βARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with β-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of βARK1 inhibition.
Harding et al. (Tue,) conducted a other in Severe heart failure / cardiomyopathy. βARK1 inhibition (βARKct overexpression) vs. CSQ mice (no βARKct) was evaluated on Mean survival age (p=< 0.0001). In a mouse model of severe cardiomyopathy, βARK1 inhibition significantly increased mean survival age from 9 to 15 weeks (P<0.0001), an effect further potentiated by metoprolol to 25 weeks.