MicroRNA-365 regulates human cardiac action potential duration

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.

Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current

The cardiac Mg2+-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg2+ concentration ([Mg2+]i) to activate the Mg2+-sensitive channels, raising extracellular [Mg2+] ([Mg2+]o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg2+]i. Under voltage clamp, in cells dialyzed with zero [Mg2+]i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg2+]o and was absent in cells dialyzed with physiological [Mg2+]i. In cells dialyzed with physiological [Mg2+]i, raising [Mg2+]o decreased the L-type Ca2+ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg2+-sensitive channels, and also suggest that the cardiac Mg2+-sensitive current shortens the APD, with potential implications in arrhythmogenesis.

Pharmacotherapy in arrhythmias: an overview of anti-arrhythmic drug therapy

The article provides an overview of the principles in anti-arrhythmic drug prescribing. The cardiac action potential is explained, followed by general principles involved in treating arrhythmias and prescribing decisions. An overview of the five classifications of anti-arrhythmic drugs is given, with examples of the main drugs in the classification and principles to consider within each. Finally, anticoagulation is reviewed, being a cornerstone prescribing decision-making in the most common arrhythmia, atrial fibrillation.

Hormonal Signaling Actions on Kv7.1 (KCNQ1) Channels

Kv7 channels (Kv7.1–7.5) are voltage-gated K+ channels that can be modulated by five β-subunits (KCNE1–5). Kv7.1-KCNE1 channels produce the slow-delayed rectifying K+ current, IKs, which is important during the repolarization phase of the cardiac action potential. Kv7.2–7.5 are predominantly neuronally expressed and constitute the muscarinic M-current and control the resting membrane potential in neurons. Kv7.1 produces drastically different currents as a result of modulation by KCNE subunits. This flexibility allows the Kv7.1 channel to have many roles depending on location and assembly partners. The pharmacological sensitivity of Kv7.1 channels differs from that of Kv7.2–7.5 and is largely dependent upon the number of β-subunits present in the channel complex. As a result, the development of pharmaceuticals targeting Kv7.1 is problematic. This review discusses the roles and the mechanisms by which different signaling pathways affect Kv7.1 and KCNE channels and could potentially provide different ways of targeting the channel.