We recently reported that mirabegron (a specific β-3 agonist) is antiarrhythmic in normal rabbit hearts. We hypothesized that mirabegron is also antiarrhythmic in heart failure with preserved ejection fraction (HFpEF). We previously reported a sex-specific HFpEF rabbit model affecting only females. Echocardiograms showed diastolic dysfunction (DD) with E/e’ rising from 8.00 ± 1.07 to 17.72 ± 1.33 after 8 weeks of a high cholesterol (HC) diet ( n = 4; p < 0.001). Left atrial diameter increased from 0.55 ± 0.13 to 0.96 ± 0.11 ( p = 0.026); NT-proBNP rose from 306.5 ± 201.8 to 3065.0 ± 630.1 ( p = 0.004); and serum cholesterol from 38.75 ± 6.24 to 980.3 ± 290.0 ( p = 0.008). In the present study, we fed six additional female rabbits an HC diet for 8 weeks. The hearts were Langendorff-perfused for optical mapping at baseline and after sequential administration of isoproterenol (ISO, 100 nM)—mirabegron (1 μM)—apamin (100 nM, a specific apamin-sensitive small conductance Ca 2+ activated K + (SK) current ( I KAS ) blocker). The action potential duration at 80% repolarization (APD 80 ) and at 25% repolarization (APD 25 ) were measured during right ventricular (RV) pacing at 200 ms pacing cycle length (PCL). Ventricular fibrillation (VF) was induced by ten RV burst pacing trials (50-ms PCL, 10 s), and VF inducibility, phase singularities (PSs), and dominant frequency (DF) were measured. ISO significantly increased the PSs/VF from 9.48 ± 1.22 to 12.42 ± 1.03 ( p = 0.006) and the dominant frequency (DF) from 7.75 ± 1.05 to 9.34 ± 1.09 ( p = 0.043). Subsequent addition of mirabegron significantly reduced the PSs/VF to 6.39 ± 1.42 ( p = 0.012) and DF to 7.44 ± 0.53 ( p = 0.002) with the presence of ISO. ISO shortened APD80, APD25, and APD80-25, which were not affected by mirabegron. Subsequent addition of apamin failed to prolong APD ( n = 6), as would be expected in HC-fed female rabbits. Mirabegron blocks I KAS and is antiarrhythmic in Langendorff-perfused HFpEF female rabbit ventricles.
Yang et al. (Sun,) studied this question.