Cinnamaldehyde (CA), a major component of cinnamon, is known to have important actions in the cardiovascular system, including vasorelaxation and decrease in blood pressure. Although CA-induced activation of the chemosensory cation channel TRPA1 seems to be involved in these phenomena, it has been shown that genetic ablation of Trpa1 is insufficient to abolish CA effects. Here, we confirm that CA relaxes rat aortic rings and report that it has negative inotropic and chronotropic effects on isolated mouse hearts. Considering the major role of L-type Ca(2+) channels in the control of the vascular tone and cardiac contraction, we used whole-cell patch-clamp to test whether CA affects L-type Ca(2+) currents in mouse ventricular cardiomyocytes (VCM, with Ca(2+) as charge carrier) and in mesenteric artery smooth muscle cells (VSMC, with Ba(2+) as charge carrier). We found that CA inhibited L-type currents in both cell types in a concentration-dependent manner, with little voltage-dependent effects. However, CA was more potent in VCM than in VSMC and caused opposite effects on the rate of inactivation. We found these divergences to be at least in part due to the use of different charge carriers. We conclude that CA inhibits L-type Ca(2+) channels and that this effect may contribute to its vasorelaxing action. Importantly, our results demonstrate that TRPA1 is not a specific target of CA and indicate that the inhibition of voltage-gated Ca(2+) channels should be taken into account when using CA to probe the pathophysiological roles of TRPA1.

Zinc exists in biological systems as bound and histochemically reactive free Zn(2+) in the nanomolar range. Zinc is required as either structural or catalytic component for a large number of enzymes. It also modulates current passage through many ion channels. Here, we reinvestigated the effects of extracellular and intracellular Zn(2+) on the L-type Ca(2+) current (I (CaL)) and its modulation by β-adrenergic stimulation in rat ventricular cardiomyocytes. In the absence of Ca(2+) ions, Zn(2+) could permeate through the L-type channel at much lower concentrations and at a more positive voltage range, but with a lower permeability than Ca(2+). In the presence of Ca(2+), extracellular Zn(2+) demonstrated strong bimodal inhibitory effects on the I (CaL), with half-inhibition occurring around 30 nM, i.e., in the range of concentrations found in the plasma. Intracellular Zn(2+) also significantly inhibited the I (CaL) with a half-inhibitory effect at 12.7 nM. Moreover, β-adrenergic stimulation was markedly reduced by intracellular Zn(2+) at even lower concentrations (<1 nM) as a consequence of Zn(2+)-induced inhibition of the adenylyl cyclase. All these effects appeared independent of redox variations and were not affected by dithiothreitol. Thus, both basal intracellular and extracellular Zn(2+) modulate transmembrane Ca(2+) movements and their regulation by β-adrenergic stimulation. Considering that, in many pathological situations, including diabetes, the extracellular Zn(2+) concentration is reduced and the intracellular one is increased, our results help to explain both Ca(2+) overload and marked reduction in the β-adrenergic stimulation in these diseases.

To the Editor, We read with great interest the recent study by Maraj et al., 1 which showed an increased risk of QT prolongation with hydroxychloroquine and azithromycin for the treatment of COVID-19. The authors emphasized that "delineation of the determinants of significant QTc prolongation and proarrhythmic risk for hydroxychloroquine/azithromycin is very important." However, a major determinant is missing from this study: genetics. Genetics explains ∼30% of the variability in drug-induced QT prolongation. 2 Although Maraj et al. 1 stated that baseline QTc > 460 ms is considered a risk factor for QTc prolongation, several mutations in cardiac ion channels display low penetrance that results in clinically asymptomatic individuals with normal QT intervals at baseline. 3 In the presence of certain drugs, these individuals seem to be more susceptible to QTc prolongation than the rest of the population. Hydroxychloroquine and azithromycin are known to induce QT prolongation via a human Ether-à-go-go-related (HERG) gene potassium channel blockade. Indeed, multiple genetic variants in KCNH2-the gene encoding HERG-have been significantly associated with drug-induced QT prolongation and arrhythmias. 4 Other genetic variants in cardiac ion channels (and their subunits) have been repeatedly shown to be involved in drug-induced QT prolongation (e.g., rs1805128 in KCNE1 and rs79299226 in SCN5A). 4 Most genetic variants in cardiac ion channels are rare, but some of the high-risk variants are relatively common. For example, rs1805124 in SCN5A has a minor allele frequency of 22% in European, 31% in African, and 10% in East Asian ancestries. Genetic variants of other proteins and solute carrier transporters that are highly expressed in the heart have also been associated with drug-induced QT prolongation in genome-wide association studies (e.g., rs4959235 in SLC22A23, rs62624461 in ACN9, and rs7142881 in NUBPL). 4 In addition to these cardiac mechanisms, genetic variants can also significantly affect pharmacokinetic mechanisms, that is, the function of the metabolic enzymes and transporters responsible for the clearance of hydroxychloroquine and azithromycin. 5 Patients possessing variants in pharmacokinetic genes have significantly higher plasma concentrations of hydroxychloroquine and/or azithromycin than their counterparts, even at similar doses. Individuals with the C allele of rs1135840 in CYP2D6-encoding a defective metabolic enzyme-had ∼30% higher ratio of an active metabolite:parent hydroxychloroquine plasma concentrations (allele frequencies 30%-52%). 5 Individuals with the G allele of rs1045642 in ABCB1-encoding a drug transporter-had twofold higher peak plasma concentrations of azithromycin (allele frequencies 43%-85%). 5 These examples demonstrate the need for pharmacogenetics to be considered in studies of drug-induced QT prolongation. Since patients' genetic profiles can be obtained prior to the administration of QT-prolonging drugs, pharmacogenetics has tremendous potential to decrease the risk of drug-induced Q...

Drug-induced long QT syndrome (diLQTS) is an adverse effect of many commonly prescribed drugs, and it can increase the risk for lethal ventricular arrhythmias. Genetic variants in pharmacodynamic genes have been associated with diLQTS, but the strength of the evidence for each of those variants has not yet been evaluated. Therefore, the purpose of this review was to evaluate the strength of the evidence for pharmacodynamic genetic variants associated with diLQTS using a novel, semiquantitative scoring system modified from the approach used for congenital LQTS. KCNE1-D85N and KCNE2-T8A had definitive and strong evidence for diLQTS, respectively. The high level of evidence for these variants supports current consideration as risk factors for patients that will be prescribed a QT-prolonging drug.