Figure 3. Effect of propranolol in murine models of CCM disease.

Pdcd10^ECKO mice, treated with placebo (n = 5) or propranolol (n = 4), were challenged with increasing doses of isoproterenol (50–5000 pg) to determine whether the 50 mg/kg/day propranolol dose was sufficient to antagonize β-adrenergic receptors. Propranolol-treated mice showed a significant rightward shift in the dose response curve in (A) contractility (dP/dt max) and (B) heart rate (bpm) with increasing concentrations of isoproterenol. Data are expressed as the mean ± SEM. *P < 0.05 and **P < 0.01, by 2-way repeated-measures ANOVA with a post hoc independent samples t test. (C) Effect of propranolol on lesion burden in 2 Pdcd10 models. In the Pdcd10^ECKO model, propranolol (50 mg/kg/day) for 35 days (dose started on P21) significantly decreased lesion burden compared with placebo controls (P < 0.0001). One placebo-treated mouse was excluded as an outlier. In the Pdcd10^+/– Trp53^–/– model, propranolol (50 mg/kg/day) for 90 days (dose started on P21) significantly reduced lesion burden compared with placebo controls (P = 0.014). One placebo-treated mouse and 1 propranolol-treated mouse were excluded as outliers. Since the data were not normally distributed, the 2-sample Conover test was used. The mean (longer bars) and SEM (shorter lines above the mean bars) are indicated for each group. In both the Pdcd10^ECKO and Pdcd10^+/– Trp53^–/– models, the lesion burden was greater in the placebo-treated controls than in the propranolol-treated mice. (D) Representative micro-CT images of the brains of mice with a high lesion burden in the untreated groups and average mouse brains in the treated groups, showing the effect of propranolol primarily on animals with a high lesion burden. Propranolol did not affect survival in either the (E) Pdcd10^ECKO model (P = 0.59) or the (F) Pdcd10^+/– Trp53^–/– model (P = 0.76) compared with placebo controls. The log-rank (Mantel-Cox) test was used to determine significance.