Increased Vulnerability to Atrial Fibrillation Is Associated With Increased Susceptibility to Alternans in Old Sheep

Background-Atrial fibrillation (AF) is common in the elderly, but rare in the young; however, the changes that occur with age that promote AF are not fully understood. Action potential (AP) alternans may be involved in the initiation of AF. Using a translationally relevant model, we investigated whether age-associated atrial vulnerability to AF was associated with susceptibility to AP alternans. Methods and Results-AF was induced in conscious young and old sheep using 50 Hz burst pacing. Old sheep were more vulnerable to AF. Monophasic and cellular APs were recorded from the right atrium in vivo and from myocytes isolated from the left and right atrial appendages. AP alternans occurred at lower stimulation frequencies in old sheep than young in vivo (old, 3.0 +/- 0.1 Hz; young, 3.3 +/- 0.1 Hz; P<0.05) and in isolated myocytes (old, 1.6 +/- 0.1 Hz; young, 2.0 +/- 0.1 Hz; P<0.05). Simultaneous recordings of [Ca2+](i) and membrane potential in myocytes showed that alternans of APs and [Ca2+](i) often occurred together. However, at low stimulation rates [Ca2+](i) alternans could occur without AP alternans, whereas at high stimulation rates AP alternans could still be observed despite disabling Ca2+ cycling using thapsigargin. Conclusions-We have shown, for the first time in a large mammalian model, that aging is associated with increased duration of AF and susceptibility to AP alternans. We suggest that instabilities in Ca2+ handling initiate alternans at low stimulation rates, but that AP restitution alone can sustain alternans at higher rates.