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

Abstract

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 AP s 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 [Ca 2+ ] i and membrane potential in myocytes showed that alternans of AP s and [Ca 2+ ] i often occurred together. However, at low stimulation rates [Ca 2+ ] i alternans could occur without AP alternans, whereas at high stimulation rates AP alternans could still be observed despite disabling Ca 2+ 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 Ca 2+ handling initiate alternans at low stimulation rates, but that AP restitution alone can sustain alternans at higher rates.

Altered atrial cytosolic calcium handling contributes to the development of postoperative atrial fibrillation

“…Alternans of APs and Ca 2+ transients (CaTs) occurring at different stimulation frequencies were quantified with a discrete Fourier transform spectral method using modified custom-written software, as previously described. 16 …”

Chronic vagal nerve stimulation has no effect on tachycardia‐induced heart failure progression or excitation–contraction coupling

“…Data are presented as mean ± the standard error of the mean ( SEM ) for n observations in N animals. Where multiple observations ( n ) were made from the same animal (N), linear mixed‐model analysis (SPSS Statistics, IBM) was used to account for the nested design of the experiment, as described previously (Caldwell et al, ; Clarke et al, ; Lawless et al, ; Pearman et al, ). Survival curves were assessed using GraphPad Prism survival curve analysis (GraphPad Software Inc.).…”

Cellular and mitochondrial mechanisms of atrial fibrillation

“…Pathological beat-to-beat alterations (alternans) in SR Ca 2+ release can be translated into alterations of action potential duration (APD)—the aforementioned electrical alternans, as demonstrated in a sheep model by Pearman and colleagues [ 101 ]. This is presumably due to the close coupling of [Ca 2+ ] i with Ca 2+ -dependent ion channels and transporters such as L-type Ca 2+ channel and NCX1.…”