The control of cardiac ventricular excitability by autonomic pathways

Abstract

Central to the genesis of ventricular cardiac arrhythmia are variations in determinants of excitability. These involve individual ionic channels and transporters in cardiac myocytes but also tissue factors such as variable conduction of the excitation wave, fibrosis and source-sink mismatch. It is also known that in certain diseases and particularly the channelopathies critical events occur with specific stressors. For example, in hereditary long QT syndrome due to mutations in KCNQ1 arrhythmic episodes are provoked by exercise and in particular swimming. Thus not only is the static substrate important but also how this is modified by dynamic signalling events associated with common physiological responses. In this review, we examine the regulation of ventricular excitability by signalling pathways from a cellular and tissue perspective in an effort to identify key processes, effectors and potential therapeutic approaches. We specifically focus on the autonomic nervous system and related signalling pathways.

Ion Channel Expression and Characterization in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

“…Transcriptome analysis revealed the expression of adrenoceptors in iPS cell-derived cardiomyocytes [ 47 , 48 ]. In the normal human heart, beta 1 adrenoceptors predominate over beta 2 with the ratio being approximately 4 : 1 [ 49 , 50 ]. Our data showed the presence of alpha 1, alpha 2, beta 1, and beta 2, and the mRNA level of beta 2 is higher than that of beta 1 in hiPSC-CMs ( Figure 3 ), different from native human cardiomyocytes.…”

ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles

“…A variety of different arrhythmic mechanisms can be distinguished including re-entry, abnormal automaticity and abnormal electrical events such as early and delayed afterdepolarisations (146). In guinea pig ventricular myocytes action potential duration (APD) was reduced by as much as 50% when as little as 0.7% of the maximum K ATP conductance was active (387) and the opening of K ATP channels leads to foreshortened repolarisation and QT interval on the surface ECG (165; 294).…”

Autonomic modulation of the electrical substrate in mice haploinsufficient for cardiac sodium channels: a model of the Brugada syndrome

“…An interesting feature of Brugada Syndrome is that ventricular arrhythmia occurs at night when the patient is sleeping and this can be accompanied by accentuation of the characteristic ECG pattern (21; 23). The autonomic nervous system is well known to modulate ventricular excitability; however in many other channelopathies it is exercise or stress that precipitates ventricular tachycardia and/or fibrillation and thus this observation is intriguing (9). During rest, vagal activity is predominant in contrast to the situation in exercise where vagal activity is reduced and sympathetic drive predominates though the detailed picture may be more complex than this standard interpretation (18).…”