Abstract 1247: Beta3-Adrenoceptor Agonist BRL 37344 and Ventricular Arrhythmia in a Canine Model of Sudden Death
Background: Beta3-adrenoceptor (AR) mediated pathways may function as a buffer against excessive beta1-AR and beta2-AR stimulation. We hypothesize that beta3-AR agonist BRL37344 infusion can suppress spontaneous ventricular tachycardia (VT) in a canine model of sudden cardiac death (SCD) created by myocardial infarction, atrioventricular block and nerve growth factor infusion to left stellate ganglion.
Methods: We used an implanted radiotransmitter to continuously monitor the heart rhythm 24 hr/d, 7 d/wk in 18 SCD model dogs. Among them, 10 received subcutaneous BRL37344 infusion (1.5μg/kg/hr) by an osmotic pump, which continuously delivered its content over one month (Experimental Group) from the first surgery. The remaining 8 dogs were used as Control Group. The dogs were followed up for 48 ± 17 d in the Experimental Group and 55 ± 40 d in the Control Group.
Results: The size of infarct in the Experimental Group was not different from the Control Group (14.0 ± 2.4% vs. 14.3 ± 2.4%). We manually reviewed all ECG recordings and quantified VT episodes. All dogs had frequent phase-1 VT (i.e., VT induced by acute ischemia) immediately after surgery. From postoperative day (POD) 5, paroxysmal VT episodes (phase-2 VT) began. From POD 7 to 30, the average VT episodes in the Experimental Group was significantly lower compared to the Control Group (0.5 ± 0.95 episode/d vs. 2.6 ± 2.3 episode/d, p<0.05); and SCD occurred in 1 dog in the Experimental Group and in 2 dogs in the Control Group. From POD 31 to POD 60, 3/9 dogs in the Experimental Group died suddenly at POD 30, 38 and 50, respectively and 1/7 dogs died suddenly at day 60 in the Control Group. The VT episodes of survival dogs in the Experimental Group were also lower than the Control Group (0.2 ± 0.2 episode/d vs. 1.2 ± 1.1 episode/d, p<0.05) during this time period.
Conclusion: Beta3-AR agonist infusion significantly decreased the number of VT episodes in a canine SCD model. This finding is consistent with the hypothesis that beta3-AR mediated pathways function as a buffer against excessive beta1-AR and beta2-AR stimulation. In spite of a significant reduction of VT episodes, the beta3-AR agonist failed to prevent SCD.