Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts.

To investigate cardiac physiology at the onset of heart beating in embryonic mouse hearts, we performed optical imaging of membrane potential (Vm) and/or intracellular calcium (Ca(i)). Action potentials and Ca(i) transients were detected in approximately 50% of mouse embryo hearts at E8.5, but in all hearts at E9.0, indicating that beating typically starts between E8-E9. Beating was eliminated by Ca channel blocker nifedipine and the I(f) blocker ZD7288, unaffected by tetrodotoxin and only mildly depressed by disabling sarcoplasmic (SR) and endoplasmic (ER) reticulum Ca cycling. From E8.5 to E10, conduction velocity increased from 0.2-1 mm/s to >5 mm/s in first ventricular and then atrial tissue, while remaining slow in other areas. Arrhythmias included atrioventricular reentry induced by adenosine. In summary, at the onset of beating, I(f)-dependent pacemaking drives both AP propagation and Ca(i) transient generation through activation of voltage-dependent Ca channels. Na channels and intracellular Ca cycling have minor roles.

Ionic mechanism of electrical alternans.

Although alternans of action potential duration (APD) is a robust feature of the rapidly paced canine ventricle, currently available ionic models of cardiac myocytes do not recreate this phenomenon. To address this problem, we developed a new ionic model using formulations of currents based on previous models and recent experimental data. Compared with existing models, the inward rectifier K(+) current (I(K1)) was decreased at depolarized potentials, the maximum conductance and rectification of the rapid component of the delayed rectifier K(+) current (I(Kr)) were increased, and I(Kr) activation kinetics were slowed. The slow component of the delayed rectifier K(+) current (I(Ks)) was increased in magnitude and activation shifted to less positive voltages, and the L-type Ca(2+) current (I(Ca)) was modified to produce a smaller, more rapidly inactivating current. Finally, a simplified form of intracellular calcium dynamics was adopted. In this model, APD alternans occurred at cycle lengths = 150-210 ms, with a maximum alternans amplitude of 39 ms. APD alternans was suppressed by decreasing I(Ca) magnitude or calcium-induced inactivation and by increasing the magnitude of I(K1), I(Kr), or I(Ks). These results establish an ionic basis for APD alternans, which should facilitate the development of pharmacological approaches to eliminating alternans.