Abstract 1702: Cardiac Alternans in Embryonic Mouse Hearts
BACKGROUND: Cardiac alternans can arise from unstable dynamics of either voltage (electrical restitution) or sarcoplasmic reticulum (SR) calcium (Cai) cycling, and is highly arrhythmogenic. In the adult, β-adrenergic stimulation suppresses alternans driven by SR Cai cycling. We assessed the effects of autonomic stimulation on the inducibility of alternans in embryonic hearts, known to lack a functional SR.
METHODS: We studied isolated embryonic mouse hearts (age E11–E12 days) superfused at 37° under three conditions: control (n=16), isoproterenol (ISO, 1μM, n=14) and ISO (1μM) =carbachol (CCh, 10μM, n=6). Simultaneous optical mapping of voltage (V) and Cai was performed with RH237 and Rhod-2-AM respectively, using CCD cameras at 5 ms/frame. Hearts were paced at 340 ms cycle length (CL), decremented by 20 ms every 8 beats to 140 ms and then back to 340 ms. SERCA immunostaining was performed at E10, E11, E12, and in neonatal and adult mouse hearts.
RESULTS: In the control group, action potential duration (APD) and Cai alternans were induced in 50% of the specimens (n=8/16). The shorter APD was associated with a smaller Cai transient (V-Ca concordance). β-adrenergic stimulation with ISO significantly increased incidence of alternans (n=14/14, p<0.01) and decreased the pacing frequency at the onset of alternans (3.9±0.6 vs. 4.9±1.4 Hz, p<0.05). With ISO + CCh, the incidence and pacing frequency at the onset of alternans were similar to control (n=4/6 vs. 8/16 specimens, 4.7±0.7 vs. 4.9±1.4 Hz, p=NS). Hysteresis between the onset and offset of alternans was uncommon (n=3/36 specimens, 1 in each group). Immunostaining revealed poor SERCA staining at E10–12 compared to older hearts.
CONCLUSIONS: In embryonic mouse hearts, APD and Cai transient alternans can be evoked by rapid pacing. Unlike the adult heart, ISO potentiated alternans in embryonic mouse hearts. This is consistent with functional SR Cai cycling being poorly developed at this stage, and suggests that alternans is driven primarily by voltage factors associated with L-type Ca current potentiation (e.g. steep APD restitution).