Purkinje fibers (PFs) play a key role in cardiac conduction and arrhythmogenesis. Heart failure (HF) causes extensive electrical remodeling. HF-induced changes in atrial and ventricular ion channel subunit expression have been well characterized, but little is known about HF-induced ion channel subunit remodeling and functional consequences in PFs. This study assessed ion channel subunit expression, action potential (AP) properties and conduction in cardiac PF false tendons from control and HF dogs. HF was induced by 2 wk ventricular tachypacing (240 bpm). Control and HF PFs were fast-frozen for ion channel subunit mRNA (RT-qPCR) and protein (Western Blot, immunohistochemistry) assessment. APs were studied with standard micro-electrodes. HF significantly downregulated mRNA expression of subunits involved in AP propagation (Nav1.5, by 56%**, **P<0.01; Cx40, by 66%**, Cx43, by 56%**), automaticity (HCN2, by 75%**; HCN4, by 78%**) and repolarization (Kv4.3, by 43%*, *P<0.05; minK, by 31%*). No significant changes occurred in KChIP2, KvLQT1, ERG, Kir2.1 or Kir3.1/3.4 mRNA. At the protein level, significant downregulation was seen for Nav1.5 (by 38%**), Kv4.3 (by 42%**), HCN4 (by 74%*), Cx40 (by 53%**) and Cx43 (by 30%**). Immunohistochemistry revealed reduced Cx40 and Cx43 expression at PF intercalated disks. AP analysis showed changes consistent with observed decreases in I
to
and I
Na
subunits: HF decreased phase 1 slope (by 56%**), AP overshoot (by 32%*) and dV/dt
max
(by 35%*). AP properties associated with unchanged subunits (eg, resting potential, overall AP duration) were unaltered. Because of consistently significant changes in subunits governing impulse propagation (Nav1.5, Cx40, Cx43), we examined HF effects on AP propagation in PF false tendons with dual microelectrodes: conduction velocity decreased from 2.2±0.1 m/s (control) to 1.5±0.1 m/s* (HF). We have characterized for the first time HF effects on ion-channel subunit expression in cardiac PFs, finding prominent alterations in a variety of important subunits that control AP repolarization and propagation. These changes in PF ion-channel subunits likely contribute to conduction disturbances and arrhythmogenesis in the failing heart.
Ion Channel Subunit Expression Changes in Cardiac Purkinje Fibers
