Arrhythmogenic effects of ultra-long and bistable cardiac action potentials

Contemporary accounts of the initiation of cardiac arrhythmias typically rely on after-depolarizations as the trigger for reentrant activity. The after-depolarizations are usually triggered by calcium entry or spontaneous release within the cells of the myocardium or the conduction system. Here we propose an alternative mechanism whereby arrhythmias are triggered autonomously by cardiac cells that fail to repolarize after a normal heartbeat. We investigated the proposal by representing the heart as an excitable medium of FitzHugh-Nagumo cells where a proportion of cells were capable of remaining depolarized indefinitely. As such, those cells exhibit bistable membrane dynamics. We found that heterogeneous media can tolerate a surprisingly large number of bistable cells and still support normal rhythmic activity. Yet there is a critical limit beyond which the medium is persistently arrhythmogenic. Numerical analysis revealed that the critical threshold for arrhythmogenesis depends on both the strength of the coupling between cells and the extent to which the abnormal cells resist repolarization. Moreover, arrhythmogenesis was found to emerge preferentially at tissue boundaries where cells naturally have fewer neighbors to influence their behavior. These findings may explain why atrial fibrillation typically originates from tissue boundaries such as the cuff of the pulmonary vein.

Arrhythmogenic effects of doxorubicin

The article discusses the adverse arrhythmogenic effects of an antitumor drug – doxorubicin.Doxorubicin has a significant effect on the action potentials and ion currents of cardiomyocytes, the dynamics of intracellular calcium concentration.Oncological diseases are the leading causes of death and disability of the population, causing extremely high socio-economic damage. Among the many currently available drugs for the treatment of cancer, an important place is taken by the anthracycline antibiotic – doxorubicin. However, adverse concomitant effects on several organs and systems of the human body, in particular on the cardiovascular system, do not allow the full use of the high potential of doxorubicin`s antitumor effectiveness. Cardiotoxicity of doxorubicin is manifested in the form of electrocardiographic abnormalities and arrhythmias, degenerative cardiomyopathy and chronic heart failure. The authors consider the following arrhythmogenic effects of doxorubicin: the mechanisms of influence of doxorubicin on electrocardiographic parameters, the action potential of cardiomyocytes, cardiac ion currents and the dynamics of intracellular calcium concentration. The study and assessment of specific pathophysiological mechanisms of arrhythmogenic effects of doxorubicin is necessary for the development and justified use of cardioprotective measures.

Inotropic and lusitropic, but not arrhythmogenic, effects of adipocytokine resistin on human atrial myocardium

The adipocytokine resistin is released from epicardial adipose tissue (EAT). Plasma resistin and EAT deposition are independently associated with atrial fibrillation. The EAT secretome enhances arrhythmia susceptibility and inotropy of human myocardium. Therefore, we aimed to determine the effect of resistin on the function of human myocardium and how resistin contributes to the proarrhythmic effect of EAT. EAT biopsies were obtained from 25 cardiac surgery patients. Resistin levels were measured by ELISA in 24-h EAT culture media ( n = 8). The secretome resistin concentrations increased over the culture period to a maximal level of 5.9 ± 1.2 ng/mL. Coculture with β-adrenergic agonists isoproterenol ( n = 4) and BRL37344 ( n = 13) had no effect on EAT resistin release. Addition of resistin (7, 12, 20 ng/mL) did not significantly increase the spontaneous contraction propensity of human atrial trabeculae ( n = 10) when given alone or in combination with isoproterenol. Resistin dose-dependently increased trabecula-developed force (maximal 2.9-fold increase, P < 0.0001), as well as the maximal rates of contraction (2.6-fold increase, P = 0.002) and relaxation (1.8-fold increase, P = 0.007). Additionally, the postrest potentiation capacity of human trabeculae was reduced at all resistin doses, suggesting that the inotropic effect induced by resistin might be due to altered sarcoplasmic reticulum Ca2+ handling. EAT resistin release is not modulated by common arrhythmia triggers. Furthermore, exogenous resistin does not promote arrhythmic behavior in human atrial trabeculae. Resistin does, however, induce an acute dose-dependent positive inotropic and lusitropic effect.