SK4 K+ channels are therapeutic targets for the treatment of cardiac arrhythmias.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a stress-provoked ventricular arrhythmia, which also manifests sinoatrial node (SAN) dysfunction. We recently showed that SK4 calcium-activated potassium channels are important for automaticity of cardiomyocytes derived from human embryonic stem cells. Here SK4 channels were identified in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from healthy and CPVT2 patients bearing a mutation in calsequestrin 2 (CASQ2-D307H) and in SAN cells from WT and CASQ2-D307H knock-in (KI) mice. TRAM-34, a selective blocker of SK4 channels, prominently reduced delayed afterdepolarizations and arrhythmic Ca2+ transients observed following application of the ß-adrenergic agonist isoproterenol in CPVT2-derived hiPSC-CMs and in SAN cells from KI mice. Strikingly, in vivo ECG recording showed that intraperitoneal injection of the SK4 channel blockers, TRAM-34 or clotrimazole, greatly reduced the arrhythmic features of CASQ2-D307H KI and CASQ2 knockout mice at rest and following exercise. This work demonstrates the critical role of SK4 Ca2+-activated K+ channels in adult pacemaker function, making them promising therapeutic targets for the treatment of cardiac ventricular arrhythmias such as CPVT.

Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels.

The proper expression and function of the cardiac pacemaker is a critical feature of heart physiology. The sinoatrial node (SAN) in human right atrium generates an electrical stimulation approximately 70 times per minute, which propagates from a conductive network to the myocardium leading to chamber contractions during the systoles. Although the SAN and other nodal conductive structures were identified more than a century ago, the mechanisms involved in the generation of cardiac automaticity remain highly debated. In this short review, we survey the current data related to the development of the human cardiac conduction system and the various mechanisms that have been proposed to underlie the pacemaker activity. We also present the human embryonic stem cell-derived cardiomyocyte system, which is used as a model for studying the pacemaker. Finally, we describe our latest characterization of the previously unrecognized role of the SK4 Ca(2+)-activated K(+) channel conductance in pacemaker cells. By exquisitely balancing the inward currents during the diastolic depolarization, the SK4 channels appear to play a crucial role in human cardiac automaticity.

Influence of the observer's level of experience on systolic and diastolic arterial blood pressure measurements using Doppler ultrasonography in healthy conscious cats.

The objective of this study was to determine the influence of the observer's level of experience on within- and between-day variability, and the percentage of successful systolic (SAP) and diastolic arterial blood pressure (DAP) measurements obtained by Doppler ultrasonography (DU) in awake cats. For this purpose, six healthy conscious cats were used and four observers with different levels of training performed 144 SAP and DAP measurements on 4 days using DU. Measurements were recorded five consecutive times, and mean values were used for statistical analysis. Only the two most skilled observers - a PhD student in cardiology and a Dipl ECVIM-CA (cardiology) - had within- and between-day coefficients of variation (CVs) for SAP ⩽16% (13-16%). Conversely, the two less experienced observers - a fifth-year student and an assistant - had high between-day CVs (61% and 73%). For DAP, only the most experienced observer (Dipl ECVIM-CA) succeeded in 100% of the attempts, with within- and between-day CVs of 11% and 4%, respectively. Conversely, DAP could not be measured by the other three observers in 8%, 19% and 56% of attempts (from the highest to the lowest level of experience); therefore, the corresponding CV values could not be calculated. In conclusion, SAP may be assessed using DU in healthy awake cats with good repeatability and reproducibility by a well-trained observer. Measurement of DAP is more difficult than of SAP, and needs a longer training period, which represents one of the limitations of DU in cats.