ORCID Profile
0000-0002-8935-5304
Current Organisation
University Medical Center Hamburg-Eppendorf
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Publisher: Springer Science and Business Media LLC
Date: 10-10-2018
DOI: 10.1007/S00392-018-1377-1
Abstract: Cardiac arrhythmias remain a common challenge and are associated with significant morbidity and mortality. Effective and safe rhythm control strategies are a primary, yet unmet need in everyday clinical practice. Despite significant pharmacological and technological advances, including catheter ablation and device-based therapies, the development of more effective alternatives is of significant interest to increase quality of life and to reduce symptom burden, hospitalizations and mortality. The mechanistic understanding of pathophysiological pathways underlying cardiac arrhythmias has advanced profoundly, opening up novel avenues for mechanism-based therapeutic approaches. Current management of arrhythmias, however, is primarily guided by clinical and demographic characteristics of patient groups as opposed to in idual, patient-specific mechanisms and pheno-/genotyping. With this state-of-the-art paper, the Working Group on Cellular Electrophysiology of the German Cardiac Society aims to close the gap between advanced molecular understanding and clinical decision-making in cardiac electrophysiology. The significance of cellular electrophysiological findings for clinical arrhythmia management constitutes the main focus of this document. Clinically relevant knowledge of pathophysiological pathways of arrhythmias and cellular mechanisms of antiarrhythmic interventions are summarized. Furthermore, the specific molecular background for the initiation and perpetuation of atrial and ventricular arrhythmias and mechanism-based strategies for therapeutic interventions are highlighted. Current "hot topics" in atrial fibrillation are critically appraised. Finally, the establishment and support of cellular and translational electrophysiology programs in clinical rhythmology departments is called for to improve basic-science-guided patient management.
Publisher: EMBO
Date: 03-11-2019
Publisher: Elsevier BV
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 26-03-2014
DOI: 10.1007/S00210-014-0974-4
Abstract: The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β1-adrenoceptors (β2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β2-adrenoceptors (β1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.
Publisher: Oxford University Press (OUP)
Date: 22-08-2023
Abstract: Cardiac arrhythmia originating from the papillary muscle (PM) can trigger ventricular fibrillation (VF) and cause sudden cardiac death even in the absence of structural heart disease. Most premature ventricular contractions, however, are benign and hitherto difficult to distinguish from a potentially fatal arrhythmia. Altered repolarization characteristics are associated with electrical instability, but electrophysiological changes which precede degeneration into VF are still not fully understood. Ventricular arrhythmia (VA) was induced by aconitine injection into PMs of healthy sheep. To investigate mechanisms of degeneration of stable VA into VF in structurally healthy hearts, endocardial high-density and epicardial mapping was performed during sinus rhythm (SR) and VA. The electrical restitution curve, modelling the relation of diastolic interval and activation recovery interval (a surrogate parameter for action potential duration), is steeper in VA than in non-arrhythmia (ventricular pacing and SR). Steeper restitution curves reflect electrical instability and propensity to degenerate into VF. Importantly, we find the parameter repolarization time in relation to cycle length (RT/CL) to differentiate self-limiting from degenerating arrhythmia with high specificity and sensitivity. RT/CL may serve as a simple index to aid differentiation between self-limiting and electrically instable arrhythmia with the propensity to degenerate to VF. RT/CL is independent of cycle length and could easily be measured to identify electrical instability in patients.
Publisher: Wiley
Date: 16-05-2013
DOI: 10.1111/BPH.12167
Publisher: MDPI AG
Date: 20-01-2020
DOI: 10.3390/CELLS9010253
Abstract: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) represent an unlimited source of human CMs that could be a standard tool in drug research. However, there is concern whether hiPSC-CMs express all cardiac ion channels at physiological level and whether they might express non-cardiac ion channels. In a control hiPSC line, we found large, “noisy” outward K+ currents, when we measured outward potassium currents in isolated hiPSC-CMs. Currents were sensitive to iberiotoxin, the selective blocker of big conductance Ca2+-activated K+ current (IBK,Ca). Seven of 16 in idual differentiation batches showed a strong initial repolarization in the action potentials (AP) recorded from engineered heart tissue (EHT) followed by very early afterdepolarizations, sometimes even with consecutive oscillations. Iberiotoxin stopped oscillations and normalized AP shape, but had no effect in other EHTs without oscillations or in human left ventricular tissue (LV). Expression levels of the alpha-subunit (KCa1.1) of the BKCa correlated with the presence of oscillations in hiPSC-CMs and was not detectable in LV. Taken together, in idual batches of hiPSC-CMs can express sarcolemmal ion channels that are otherwise not found in the human heart, resulting in oscillating afterdepolarizations in the AP. HiPSC-CMs should be screened for expression of non-cardiac ion channels before being applied to drug research.
Publisher: Elsevier BV
Date: 07-2016
No related grants have been discovered for Torsten Christ.