https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Heidelberg Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie Heidelberg, Deutschland; 2Universität Heidelberg Institut für Physiologie und Pathophysiologie Heidelberg, Deutschland; 3Universitätsklinikum Heidelberg Klinik für Herzchirurgie Heidelberg, Deutschland; 4Universitätsklinikum Heidelberg Innere Medizin III, Inst. für Molekulare und Translationale Kardiologie Heidelberg, Deutschland; 5Universität Heidelberg Herz- und Kreislaufphysiologie Heidelberg, Deutschland
Background
Ventricular arrhythmia is a major contributor to the high morbidity and mortality observed in heart failure (HF) patients. In HF, pathological remodeling at the cellular level involves significant alterations in the expression of various ion channels, resulting in electrical adaptation that prolongs the ventricular action potential duration (APD). However, the precise mechanisms underlying this APD modulation remain poorly understood. We hypothesized that the remodeling of Kir channels may contribute to the proarrhythmogenic APD prolongation observed in HF. This study aimed to characterize Kir channel expression across various animal models of heart failure and in patients with dilated cardiomyopathy (DCM) and ischemic cardiomyopathy (ICM), as well as to evaluate the functional impact of Kir channels on APD under diverse cardiac stress conditions.
Methods
Kir channel expression was analyzed in left ventricular (LV) tissue of pigs with HF induced by atrial burst pacing. For etiology-specific analyses, neonatal rat ventricular cardiomyocytes (NRVCMs) were exposed to different stressors: ischemic stress through hypoxia (HP), catecholaminergic stress with isoproterenol (IP), mechanical stress due to stretching (ST) and electrical stress through tachypacing (TP). In both models, Kir channel mRNA expression was analyzed by RT-qPCR and protein expression by western blot. Whole-cell patch-clamp measurements to analyze APD at 90% repolarization (APD90) were carried out with and without application of Tertiapin-Q (TTQ). TTQ is a specific blocker of IKACh, a current conducted by an ion channel composed of Kir3.1 and Kir3.4 (encoded by KCNJ3 and KCNJ5, respectively). The expression of Kir channels in human LV tissue was measured by RNA sequencing and specific findings were validated using RT-qPCR.
Results
Kir channel remodeling was observed across HF animal models and in human samples. Western blot analysis of LV tissue of pigs showed KCNJ3 upregulation (+207%). Upregulation of Kcnj3 was also observed in RT-qPCR of stressed NRVCM after HP (+200%), ST (+104%) and TP (+61%), with downregulation of Kcnj5 in ST (-30%) and upregulation in TP (+49%). %). APD prolongation was detected for these stressors upon blocking the IKACh with TTQ (+10% for ST, +31% for TP) and was nonsignificant for HP (+16%). There was no APD effect in native NRVCM. In DCM, KCNJ3 and KCNJ5 were significantly upregulated, showing increases of +541% and +259%, respectively, with KCNJ5 also upregulated in ICM by +160%. Alongside known Kcnj2 remodeling, we observed notable regulation of other Kir channels: Kcnj8 was significantly altered following all stress treatments, Kcnj11 showed regulation under HP and ST conditions, Kcnj12 was impacted by HP and ST, and Kcnj15 displayed regulation following HP, IP and TP stressors.
Conclusion
Kir channels, including Kir3.1 and Kir3.4, show altered expression across HF models and in human ICM and DCM. In HF caused by mechanical stress or tachypacing, ventricular Kir3.1 and Kir3.4 expression in NRVCMs increases, which, together with the observed reduction in APD, suggests a significant role of IKACh in modulating the APD. Our results highlight the importance of Kir remodeling in HF, although the exact mechanisms linking IKACh to arrythmias in HF remain unclear. Further studies are necessary to clarify this mechanism and to explore the possible antiarrhythmic properties and therapeutic potential of IKACh modulation.