Background
In heart failure (HF), ventricular arrhythmias are a key determinant of adverse outcomes and mortality. HF induces pathological remodeling of ion channels in ventricular myocytes, leading to electrophysiological alterations and prolonged action potential duration (APD). The mechanisms underlying these changes remain incompletely understood. This study investigated the contribution of inwardly rectifying potassium (Kir) channels to APD modulation in HF using animal models and myocardial samples from patients with dilated (DCM) and ischemic cardiomyopathy (ICM). We analyzed Kir channel expression and assessed their functional relevance under diverse cardiac stress conditions.
Methods
Left ventricular (LV) tissue from pigs with atrial burst pacing–induced HF was analyzed to determine Kir channel expression. To study etiology-specific effects, neonatal rat ventricular cardiomyocytes (NRVCMs) were subjected to hypoxia (HP), isoproterenol (IP), mechanical stretch (ST) and tachypacing (TP). Kir mRNA and protein levels were quantified by RT-qPCR and Western blot. APD at 90% repolarization (APD90) was determined via whole-cell patch-clamp technique with and without Tertiapin-Q (TTQ). TTQ is a selective inhibitor of IKACh, conducted by channels composed of Kir3.1 (KCNJ3) and Kir3.4 (KCNJ5) subunits. Kir expression in human LV tissue from patients with DCM and ICM was determined by RNA sequencing and validated by RT-qPCR.
Results
Kir channel remodeling was detected across experimental HF models and in human myocardium. Porcine LV tissue revealed an upregulation of Kir3.1 (+207%). In human LV tissue, both KCNJ3 and KCNJ5 were elevated in DCM (+541% and +259%, respectively), with KCNJ5 significantly upregulated in ICM (+160%). RT-qPCR analyses of NRVCM demonstrated stress-specific Kcnj3 upregulation under HP (+200%), ST (+104%), and TP (+61%) conditions. In contrast, Kcnj5 expression was reduced in ST (–30%) but increased in TP (+49%). Similar regulation was detected by Western blot analysis. Beyond these subunits, additional Kir isoforms showed stress-dependent regulation: Kcnj8 was altered across all conditions, Kcnj11 and Kcnj12 were modulated under HP and ST and Kcnj15 responded to HP, IP and TP stimulation. Electrophysiological recordings showed that TTQ led to a prolonged APD under ST (+10%) and TP (+31%) conditions, whereas the effect during HP (+16%) did not reach significance. Native NRVCMs displayed no TTQ-dependent APD changes.
Conclusion
Our data indicate an extensive remodeling of Kir channels, with prominent stress- and etiology-specific regulation of KCNJ3 and KCNJ5 in HF models and human ICM and DCM. In NRVCMs exposed to ST or TP, the upregulation of Kir3.1 and Kir3.4, together with the observed TTQ-sensitive APD prolongation, points to a significant stress-specific role of IKACh in ventricular repolarization during HF. These findings underscore the contribution of Kir channel alterations to HF pathophysiology. However, the precise mechanisms by which IKACh influences arrhythmogenesis remain to be elucidated. Further studies are warranted to define these mechanisms and to evaluate the potential antiarrhythmic and therapeutic implications of targeting IKACh.
