Commentary: Increased Beat-to-Beat Variability of T-Wave Heterogeneity Measured From Standard 12-Lead Electrocardiogram Is Associated With Sudden Cardiac Death: A Case-Control Study

The electrocardiogram (ECG) reflects the electrical activity within the heart. Following the discovery of the small electrical signals in the human heart, the Dutch scientist Willem Einthoven developed sensitive methods for detecting them and recognized their clinical implications (Kligfield, 2002). For his contributions Willem Einthoven, whose scientific roots originated from the Utrecht physiology department (Einthoven, 1885), was awarded the Nobel Prize in 1924. Since then, many enigmas of the ECG have been solved and its intricate information carries valuable clues for clinical decision making. In vivo mapping studies have established that spatial heterogeneity in repolarization is a requisite for re-entrant ventricular arrhythmias by effecting unidirectional conduction block. Important modulators of spatial heterogeneity of repolarization include autonomic tone, ischemia, heart rate and premature or ectopic beats, which can produce temporal heterogeneity in the order of seconds, minutes, or hours depending on their time-constants. In the contemporary era of dynamic surface electrocardiography, a formidable challenge is quantifying spatiotemporal repolarization heterogeneity with sufficient fidelity to image the arrhythmogenic myocardial substrate and thereby provide indices for a patient’s risk of arrhythmic death (Laguna et al., 2016). Hekkanen et al. (2020) performed a large case-control study of 200 victims..

Structure-affinity relationships (SARs) and structure-kinetics relationships (SKRs) of Kv11.1 blockers

Medicinal Chemistr

Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue

Medicinal Chemistr

LUF7244 plus Dofetilide Rescues Aberrant Kv11.1 Trafficking and Produces Functional IKv11.1

Kv11.1 (hERG) channels play a critical role in repolarization of cardiomyocytes during the cardiac action potential (AP). Drug mediated Kv11.1 blockade results in AP prolongation, which poses an increased risk of sudden cardiac death. Many drugs, like pentamidine, interfere with normal Kv11.1 forward trafficking and thus reduce functional Kv11.1 channel densities. Although class III antiarrhythmics, e.g. dofetilide, rescue congenital and acquired forward trafficking defects, this is of little use due to their simultaneous acute channel blocking effect. We aimed to test the ability of a combination of dofetilide plus LUF7244, a Kv11.1 allosteric modulator/activator, to rescue Kv11.1 trafficking and produce functional Kv11.1 current. LUF7244 treatment by itself did not disturb or rescue WT or G601S Kv11.1 trafficking as shown by western blot and immunofluorescence microcopy analysis. Pentamidine-decreased maturation of WT Kv11.1 levels was rescued by 10 μM dofetilide or 10 μM dofetilide + 5 μM LUF7244. In trafficking defective G601S Kv11.1 cells, dofetilide (10 μM) or dofetilide+LUF7244 (10+5 μM) restored Kv11.1 trafficking also, as demonstrated by western blot and immunofluorescence microscopy. LUF7244 (10 μM) increased IKv11.1 despite the presence of dofetilide (1 μM) in WT Kv11.1 cells. In G601S expressing cells, long-term treatment (24-48 h) with LUF7244 (10 μM) and dofetilide (1 μM) increased IKv11.1 compared to non-treated, or acutely treated cells. We conclude that dofetilide plus LUF7244 rescues Kv11.1 trafficking and produces functional IKv11.1. Thus, combined administration of LUF7244 and an IKV11.1 trafficking corrector could serve as a new pharmacological therapy of both congenital and drug-induced Kv11.1 trafficking defects.Toxicolog

Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels.

L-type Ca(2+) channels are predominantly regulated by beta-adrenergic stimulation, enhancing L-type Ca(2+) current by increasing the mean channel open time and/or the opening probability of functional Ca(2+) channels. Stimulation of beta-adrenergic receptors (ARs) results in an increased cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and consequently activation of protein kinase (PK) A and phosphorylation of L-type Ca(2+) channels by this enzyme. Beta(1)-Adrenergic receptors couple exclusively to the G protein Gs, producing a widespread increase in cAMP levels in the cell, whereas beta(2)-adrenergic receptors couple to both Gs and Gi, producing a more localized activation of L-type Ca(2+) channels. Other signaling intermediates (protein kinase C, protein kinase G or protein tyrosine kinase (PTK)) either have negative effects on L-type Ca(2+) current, or they interact with the stimulatory effect of the protein kinase A pathway

Adrenergic regulation of conduction velocity in cultures of immature cardiomyocytes

During cardiac maturation, increased exposure of the heart to circulating catecholamines correlates with increased conduction velocity and growth of the heart. We used an in vitro approach to study the underlying mechanisms of adrenergic stimulation induced changes in conduction velocity. By combining functional measurements and molecular techniques, we were able to demonstrate that the increased conduction velocity after β-adrenergic stimulation is probably not caused by changes in intercellular coupling. Instead, RT-PCR experiments and action potential measurements have shown an increased excitability that may well explain the observed increase in conduction velocity. Apart from being relevant to cardiac maturation, our findings are relevant in the context of stem cells and cardiac repair. Preconditioning of stem cell derived cardiomyocytes may help to enhance electrical maturation of de novo generated cardiomyocytes and consequently reduce their proarrhythmogenic potential. (Neth Heart J 2008;16:106-9.