[Cardiac arrhythmias-Cellular mechanisms, consequences and challenges in the diagnostics using human models]

Cardiac arrhythmias significantly contribute to morbidity and mortality in cardiovascular diseases. Hereditary ion channel disorders, including Brugada syndrome, long/short QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT), represent critical entities with elevated risk of malignant ventricular arrhythmias. Although beta-blockers, ion channel modulators and implantable cardioverter defibrillators (ICD) are available and the indications for them are increasingly based on genetic analyses, variants of uncertain significance (VUS) substantially impair the risk stratification. Atrial tachyarrhythmias, particular atrial fibrillation, can cause an often-reversible arrhythmia-induced cardiomyopathy (AIC). Pathophysiologically, the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) plays an important role in atrial and ventricular arrhythmias. It can be activated by various pathological triggers, such as high heart rate, neuroendocrine activation and oxidative stress, the latter often resulting from mechano-energetic uncoupling. The development of effective treatment options for arrhythmia-associated cardiovascular diseases requires the use of human model systems in addition to animal experimental approaches, due to the genetic heterogeneity and systemic comorbidities. Patient-specific cardiac stem cell-models enable the classification of VUS and personalised drug testing. The integration of new methodological approaches into existing animal experimental approaches thus paves the way for functionally validated precision medicine and could fundamentally transform the treatment of both disease patterns.