Atrial fibrillation (AF) is increased in heart failure (HF), increasing mortality. Alternans, a beat-to-beat oscillation in the atrial action potential (AP) and/or Ca2+ transient, has been implicated in AF initiation as both a trigger and a substrate. However, alternans aetiology in neither health nor disease is fully understood. HF sheep, induced by rapid pacing of the right ventricle, were more vulnerable to both AF and alternans, quantified through conscious in vivo electrophysiology. Thus a cellular mechanism for alternans was investigated further. Atrial contraction is driven by intracellular Ca2+ cycling in response to membrane depolarisation. The relationship between the AP and the Ca2+ transient is symbiotic in that alteration to one shall directly affect the other. The proportional response of the AP to Ca2+ transient and vice-versa results in alternans being an alternation in both AP and Ca2+ transient irrespective of causality. This work investigated whether alternans could be induced more easily in HF and how remodelling in HF exacerbated mechanisms driving alternans in health. Left atrial myocytes were isolated from control and HF models. Fluo-5F loaded myocytes were incrementally paced at physiological rates under current clamp control. The lowest frequency at which alternans was detectable was deemed the threshold. In HF vs. control a greater proportion of cells exhibited alternans and both Ca2+ alternans and AP alternans thresholds were decreased. Increased alternans susceptibility in HF was directly attributable to the longer AP in HF compared to control, which is also unable to adapt to rate increases as effectively as control cells. The longer AP is unable to fully repolarise resulting in an alternating INa. Hyperpolarisation of the membrane potential, through injected current, increasing repolarisation speed, terminated alternans in every HF cell. Our data shows that alternans occurs more readily in HF atrial cells, potentially providing a mechanism for increased prevalence of AF in HF. Further work shall determine the physiological relevance of electrical alternans in AF initiation in HF.
Understanding the mechanisms of atrial alternans in disease and its relationship to cellular remodelling
Madders, G. (Author). 1 Aug 2020
Student thesis: Phd