Today´s research mainly focuses on the disturbance of working myocardium function and mechanisms of cardiac dysfunction have already been identified in several cases. Pathologic mutations, channelopathies or pathogens are known to induce dysfunctions in the working myocardium (ventricles and atria) leading to severe phenotypes, including death, in patients. Thereafter, excitation spreads from the AV node via His bundle and purkinje network to the ventricular apex, where the ventricular contraction is triggered. This electrical activity spreads via the atrial myocardium to the secondary pacemaker, the atrioventricular node (AV node). The SAN harbors so called pacemaker cells, which generate the hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4)-driven funny current I f, that leads to the controlled depolarization of pacemaker cells towards the action potential threshold. The sinoatrial node (SAN) is located at the right upper chamber of the heart and represents the primary pacemaker of the heart. Thereby, the cardiac pacemakers and conduction system is classified into several regions harboring different cell types with different tasks. These cells work together to generate an active blood flow, which can be adjusted to a multitude of external conditions. As cells of the working myocardium, ventricular and atrial cells, generate the actual muscle force for cardiac contractility, cells of the cardiac pacemakers and conduction system generate and propagate the electrical stimuli to activate the cells of the working myocardium.

The heart is a complex organ with a wide variety of different cells fulfilling their specific task to ensure correct generation of electrical signals and rhythmic contraction.

Summarizing, the enterovirus CVB3 inhibits human cardiac pacemaker function by reducing the pacemaker channel plasma membrane density, an effect that can be corrected by pharmacological intervention of endocytic vesicle trafficking. Treatment of cells with the Rab7 inhibitor CID 106770 or the CVB3-3A inhibitor GW5074 led to the recovery of the cytoplasmatic HCN4 accumulation into a healthy appearing phenotype, indicating that malfunctioning Rab7-directed autophagosome transport is involved in the disturbed, cytoplasmatic HCN4 accumulation in CVB3-expressing human pacemaker-like cells. Individual effects of single, non-structural CVB3 proteins were analyzed and demonstrated that CVB3 proteins 2C and 3A had the most robust effect on HCN4 activity. Increased autophagosome formation and autophagosomal HCN4 insertion was observed in hiPSC-derived pacemaker-like cells under CVB3 expression as well. In addition, using HCN4 cell expression systems, we found that HCN4 currents were decreased with altered voltage dependency of activation when CVB3 was expressed. We found that CVB3 drastically changed hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) distribution and function in hiPSC-derived pacemaker-like tissue. Here, we address this issue using the first human induced pluripotent stem cell (hiPSC)-derived pacemaker-like cells, in which the expression of a transgenic non-infectious variant of CVB3 can be controlled dose- and time-dependently. Besides clinical reports on bradycardia and sudden cardiac death, very little is known about the influence of CVB3 on the activity of human cardiac pacemaker cells. The enterovirus Coxsackievirus B3 (CVB3) is known to be a major source for the development of cardiac dysfunctions like viral myocarditis (VMC) and dilatative cardiomyopathy (DCM), but also results in bradycardia and fatal cardiac arrest.

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