Propensity and Severity of Cardiac Alternans is Enhanced in Heart Failure

Abstract

Cardiac alternans describes beat-to-beat alternations in contraction strength, action potential (AP) morphology or cytosolic Ca transient (CaT) amplitude a constant frequency that generates a pro-arrhythmic substrate leading to sustained arrhythmias, Alternans is observed under various pathological conditions including heart failure (HF), and in the atrium alternans has been identified as a precursor of atrial fibrillation. Under pathological conditions the heart attempts to compensate for injury through various cellular pathways that lead to altered electrophysiology, Ca handling properties and to and structural changes. We investigated cellular mechanisms that underlie enhanced susceptibility to alternans in remodeled atria from a chronic non-ischemic left-ventricular rabbit heart failure model. Experiments were carried out in single atrial myocytes isolated from normal and HF rabbit hearts. CaTs were monitored by fluorescence microscopy simultaneously with membrane currents or APs recorded with the patch clamp technique. From AP recordings during pacing induced simultaneous CaT and AP duration (APD) alternans two AP waveforms were selected that represented a typical short and long AP of APD alternans. These AP waveforms were used as command voltages in subsequent voltage clamp experiments (AP-clamp). Intracellular Ca handling and electrophysiological properties of the HF atrial cells were significantly altered. HF atrial myocytes 1) had a shorter APD, 2) were significantly more prone to develop alternans, 3) exhibit a higher degree of CaT alternans at a given pacing frequency, and 4) beat-to-beat alternation in APD during alternans was significantly increased. In additional experiments we tested the role of inositol 1,4,5-trisphosphate signaling, generation of reactive oxygen species, calmodulin kinase II activity and diastolic sarcoplasmic reticulum Ca leak for susceptibility and severity of CaT and APD alternans.