Arbeitsgruppe Cellular Electrophysiology
Leitung: Dr. med. Xiaobo Zhou, Prof. Dr. med. Ibrahim Akin
Cellular electrophysiology laboratory
The cellular electrophysiology laboratory consists of patch-clamp, calcium imaging and single-cell contraction measurement facilities. The lab facility provides useful platforms for studying ion channel functions including ion channel gating kinetics, intracellular calcium homeostasis and single cell contraction.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) provide an alternative to use human cardiomyocytes and human endothelial cells to model human cardiovascular diseases and perform mechanistic and therapeutic studies. Gene-editing using CRISPR/Cas 9-technique provides the opportunity to correct mutations in diseased cells, which is helpful for studying pathogenic roles of gene mutations or variants with unknown significance. In this lab, through the combination of these two techniques, cellular models of channelopathy and cardiomyopathy such as short QT syndrome, Brugada syndrome, Takotsubo cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, dilated cardiomyopathy have been established, which are useful for mechanistic study and drug-testing.
Short QT syndrome-mechanism and drug testing
Short QT syndrome (SQTS) is a rare, inheritable cardiac channelopathy associated with abbreviated corrected QT interval (QTc), tachyarrhythmias and sudden cardiac death (SCD). So far, hundreds of SQTS-patients with different gene mutations have been reported and different types of SQTS have been described. SQTS types 1-3 are linked to a gain of function of potassium channels caused by mutations in the KCNH2 (SQTS1), KCNQ1 (SQTS2) and KCNJ2 (SQTS3) gene. SQTS types 4-6 are linked to a loss of function of calcium channels resulting from mutations in CACNA1C (SQTS4), CACNB2 (SQTS5) and CACNA2D1 (SQTS6) gene. Recently, a mutation in the cardiac Cl/HCO3 exchanger AE3 was detected in SQTS-families. However, the pathogenic roles and mechanisms of most detected gene mutations or variants have not been clarified. The therapeutic approaches for SQTS are challenging for physicians because of the low prevalence and rare cases. Although an implantable cardioverter defibrillator (ICD) can be useful for terminating arrhythmias in SQTS-patients, ICD cannot be used for every patient. Therefore, pharmacotherapy is required at least for some SQTS-patients.
Human-induced stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with SQTS provide a useful platform for modeling cardiac disorders and testing drugs. Therefore, we have established cellular models of SQTS including SQTS1 and SQTS5 using hiPSC-CMs from SQTS-patients and are carrying out studies regarding arrhythmogenesis of SQTS and screening effective drugs for treatment of SQTS-patients. The studies may find out novel therapeutic targets or effective drugs for SQTS.
Brugada Syndrome-mechanism and drug testing
Brugada syndrome (BrS), a rare inherited channelopathy, is linked to sudden cardiac death (SCD). It is assumed that 5-10% of patients, who are dying at young age, may suffer from BrS. BrS type 1 ECG could be unmasked by fever, sodium channel blockers and increased parasympathetic state.
Mutations in different genes including Na+, Ca2+ and K+ channel genes have been associated with BrS, but nevertheless, 20-30% of BrS cases are related to mutations or variants in the SCN5A (encoding the ion channel Nav 1.5) gene. The pathogenic role of most identified variants in the SCN5A gene or other genes remains to be explored. Ideal strategy for BrS-treatment is still lacking.
Human cardiomyocytes from induced pluripotent stem cells (hiPSC-CMs) from BrS-patients have been successfully used to model BrS. Therefore, we used hiPS-CMs from BrS-patients carrying mutations or variants in Na+ and Ca2+ channel genes to perform mechanistic and drug-screening studies, in order to unveil pathogenic roles and underlying mechanisms of specific gene mutations or variants detected in BrS-patients and look for better effective drugs.
Takotsubo Syndrome-mechanistic studies
Takotsubo syndrome (TTS) is identified as an acute severe ventricular systolic dysfunction, which is usually characterized by a reversible and transient akinesia of walls of the ventricle in the absence of a significant obstructive coronary artery disease. TTS-patients present with chest pain, ST-segment elevation or ischemia signs on ECG and increased troponin, similar to myocardial infarction. In addition, TTS-patients can present severe complications including life-threatening ventricular arrhythmias, atrial fibrillation and/or long QT syndrome (LQTS). Currently, the known reasons for the development of TTS include elevated levels of circulating plasma catecholamines and their metabolites, coronary microvascular dysfunction, sympathetic hyperexcitability, inflammation, estrogen deficiency, genetic predisposition and thyroidal dysfunction. However, the real etiologic link remains unclear and seems to be multifactorial.
We use human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) and human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) for TTS studies including exploring the pathomechanism of the disease, mainly focusing on the mechanisms underlying the LQTS and coronary vascular endothelial dysfunction in TTS-patients.