Search Results (35)

Kv11.1 (hERG1) channels, encoded by KCNH2, mediate the rapid delayed rectifier potassium current (I_Kr) crucial for cardiac repolarization. Disruptions, via mutations or antiarrhythmic drugs like dofetilide cause severe arrhythmogenic disorders, including Long QT Syndrome Type 2 (LQT2), Brugada Syndrome (BrS), and Torsades de Pointes (TdP). While Kv11.1’s role in channelopathies and drug-induced arrhythmias is established, understanding its complex regulation and therapeutic targeting remains a challenge. This review synthesizes the structural, functional, and regulatory aspects of Kv11.1 channels and their clinical implications. Recent studies using iPSC-derived cardiomyocytes highlight regulation by PI3K/Akt, PKC, and PKA signaling via phosphorylation (Ser283, Ser890) and interactions with proteins like 14-3-3. Beyond electrophysiology, Kv11.1 influences pathological hypertrophy and non-cardiac functions including insulin secretion. Pharmacological efforts focus on activators to shorten action potential duration and suppress TdP, and blockers with overdose risks. Mutation heterogeneity, exemplified by trafficking impairment (G785D) in LQT2 and gain-of-function (R397C) in BrS, complicates precision therapy. Clinically, systematic risk stratification using electrocardiographic parameters and genotype-specific approaches enables personalized management. Beta-blockers remain first-line therapy for LQTS2, while rigorous avoidance of QT-prolonging medications and electrolyte monitoring form the cornerstones of preventive care. Advancing Kv11.1-targeted therapies with approaches like CRISPR-Cas9 and pharmacological chaperones (e.g., lumacaftor) holds promise for personalized treatments, ultimately reducing arrhythmic events and sudden cardiac death. Full article

The objective of this paper was to review the possibility that the QT interval may be a marker of adult human longevity or life expectancy. Following a literature review, data supporting this possibility was assembled and consists of the following. First, in adults, QT interval increases with increasing age. This is analogous to aging-induced hypertension and diabetes mellitus, both of which are associated with shorter longevity. Second, older persons frequently die suddenly regardless of whether or not they have chronic illnesses for which death is expected. Third, longer QTintervals are associated with increased probability of sudden death. Fourth, patients with two conditions associated with accelerated brain aging, namely dementia and Parkinson’s disease, show longer QTcs than age-matched controls. Both of these conditions are associated with sudden cardiac death. Fifth, aging processes may affect the molecular determinants of the QT interval, alter heart composition with increased myocardial fibrosis, or alter the amount of sympathetic and parasympathetic tone, any or all of which can alter myocardial repolarization and the duration of the QTc. Sixth, considering the molecular determinants of the QT interval in the aging heart, which has longer transmembrane action potentials, several factors can account for this change, including changes in late inward Na⁺ current (I_NaL), I_Kr, I_ca, I_to, and K_ATP channels. Transgenic mice overexpressing the Kir6.1 subunit of a K_ATP channel show a prolonged QT interval and reduced longevity, with animals appearing to die suddenly. Seventh, chronic kidney disease, which is associated with a reduced lifespan, is associated with reduced expression of the anti-aging factor Klotho and Klotho-deficient mice have a prolonged QTc and a reduced lifespan. Taken together, there is a cogent case for factors that increase action potential duration in the aging heart, as recognized by increased QTc, to act in concert with other factors to produce fatal arrhythmias leading to sudden cardiac death and shortened longevity. Full article

The macrolide class of antibiotics are widely utilized in clinical settings for a broad range of bacterial infections and have additional roles as immunomodulatory agents. Although efficacious with a good safety profile overall, they have been associated with prolongation of the QT interval and development of the polymorphic ventricular tachycardia, Torsades de pointes (TdP). In a 2020 scientific statement, the American Heart Association (AHA) classified azithromycin, clarithromycin and erythromycin as QT-prolonging drugs known to cause TdP and the online database, CredibleMeds, that maintains a list of drugs known to cause QT prolongation classifies these drugs as having an increased risk of QT prolongation. The mechanism of this risk has been delineated to involve macrolide binding to and a blockade of delayed rectifier potassium channels that conduct rapid potassium current, I_kr, during repolarization, leading to prolonged repolarization and subsequent QT prolongation. Studies investigating this association have revealed variable results, with several suggesting that the risk of QT prolongation and TdP with macrolide use may be highly dependent on underlying patient risk factors and comorbidities. In the present investigation, we summarize current evidence on association of macrolide antibiotics, azithromycin, clarithromycin and erythromycin, with the development of QT prolongation and TdP, pathophysiology of and risk factors predisposing to development of these events, the role of implementation of strategies to reduce this risk and highlight emerging research. Full article

Under chronic stress, the pro-arrhythmic effect and mechanism of circulating humoral factors in human cardiomyocytes remain unknown. In the present study, we observed the effect of serum from chronic-stress mice on the electrical activity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Male C57/BL6J mice were subjected to 35 days of chronic unpredictable mild stress (CUMS). The serum from CUMS mice induced arrhythmia-like events (cell arrhythmias) in hiPSC-CMs in a time- and concentration-dependent manner. Patch clamp recordings in the heterologous expression system demonstrated that the serum derived from CUMS mice exerted an inhibitory effect on the cloned human potassium currents (I_to, I_Kr, I_Ks) that mediate action potential repolarization. In addition, serum from CUMS reduced the expression of relevant channel proteins. Moreover, both heat-inactivated serum and deproteinized serum evoked similar severity of cell arrhythmias in hiPSC-CMs as the untreated serum, indicating that circulating substances with small molecules were mainly involved in the occurrence of arrhythmias. Furthermore, metabolomics analysis showed that 90 small-molecule metabolites increased and 390 decreased in CUMS serum. We concluded that circulating humoral substances under chronic stress conditions have direct arrhythmogenic effects by inducing ion channel dysfunction in myocardial cells. Full article

Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD₉₀), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the I_Kr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD₉₀ and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD₉₀, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation. Full article

Cenobamate is a novel third-generation antiepileptic drug used for the treatment of focal onset seizures and particularly for multi-drug-resistant epilepsy; it acts on multiple targets: GABA_A receptors (EC₅₀ 42–194 µM) and persistent neuronal Na⁺ currents (IC₅₀ 59 µM). Side effects include QT_c interval shortening with >20 ms, but not <300 ms. Our in vitro cardiac safety pharmacology study was performed via whole-cell patch-clamp on HEK293T cells with persistent/inducible expression of human cardiac ion channel isoforms hNav1.5 (I_Na), hCav1.2 (α1c + β2 + α2δ1) (I_CaL), hKv7.1 + minK (I_Ks), and hKv11.1 (hERG) (I_Kr). We found IC50 of 87.6 µM (peak I_Na), 46.5 µM (late I_Na), and 509.75 µM (I_CaL). In experiments on Ncyte^® ventricular cardiomyocytes, APD90 was reduced with 28.6 ± 13.5% (mean ± SD) by cenobamate 200 µM. Cenobamate’s marked inhibition of I_Na raises the theoretical possibility of cardiac arrhythmia induction at therapeutic concentrations in the context of preexisting myocardial pathology, in the presence of action potential conduction and repolarization heterogeneity. This hypothetical mechanism is consistent with the known effects of class Ib antiarrhythmics. In simulations with a linear strand of 50 cardiomyocytes with variable inter-myocyte conductance based on a modified O’Hara–Rudy model, we found a negligible cenobamate-induced conduction delay in normal tissue, but a marked delay and also a block when gap junction conduction was already depressed. Full article

Several ion currents in the mammalian ventricular myocardium are substantially regulated by the sympathetic nervous system via β-adrenergic receptor activation, including the slow delayed rectifier K⁺ current and the L-type calcium current. This study investigated the downstream mechanisms of β-adrenergic receptor stimulation by isoproterenol (ISO) on the inward rectifier (I_K1) and the rapid delayed rectifier (I_Kr) K⁺ currents using action potential voltage clamp (APVC) and conventional voltage clamp techniques in isolated canine left ventricular cardiomyocytes. I_K1 and I_Kr were dissected by 50 µM BaCl₂ and 1 µM E-4031, respectively. Acute application of 10 nM ISO significantly increased I_K1 under the plateau phase of the action potential (0–+20 mV) using APVC, and similar results were obtained with conventional voltage clamp. However, β-adrenergic receptor stimulation did not affect the peak current density flowing during terminal repolarization or the overall I_K1 integral. The ISO-induced enhancement of I_K1 was blocked by the calcium/calmodulin kinase II (CaMKII) inhibitor KN-93 (1 µM) but not by the protein kinase A inhibitor H-89 (3 µM). Neither KN-93 nor H-89 affected the I_K1 density under baseline conditions (in the absence of ISO). In contrast, parameters of the I_Kr current were not affected by β-adrenergic receptor stimulation with ISO. These findings suggest that sympathetic activation enhances I_K1 in canine left ventricular cells through the CaMKII pathway, while I_Kr remains unaffected under the experimental conditions used. Full article

The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP₃ (inositol 1,4,5 trisphosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP₃ receptor (IP₃-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP₃ on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP₃-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt₃-(1,4,5)IP₃-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on I_Ca,L, I_Kr, I_f or I_NCX. By contrast, application via the patch pipette of 5 µM of the IP₃-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt₃-(1,4,5)IP₃-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP₃ led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP₃-R activity; however, it was also found to inhibit I_Ca,L and I_Kr, confounding its use for studying IP₃-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP₃ activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP₃ can modulate AVN cell pacemaking rate. Full article

To understand the large inter-species variations in drug effects on repolarization, the properties of the rapid (I_Kr) and the slow (I_Ks) components of the delayed rectifier potassium currents were compared in myocytes isolated from undiseased human donor (HM), dog (DM), rabbit (RM) and guinea pig (GM) ventricles by applying the patch clamp and conventional microelectrode techniques at 37 °C. The amplitude of the E-4031-sensitive I_Kr tail current measured at −40 mV after a 1 s long test pulse of 20 mV, which was very similar in HM and DM but significant larger in RM and GM. The L-735,821-sensitive I_Ks tail current was considerably larger in GM than in RM. In HM, the I_Ks tail was even smaller than in DM. At 30 mV, the I_Kr component was activated extremely rapidly and monoexponentially in each studied species. The deactivation of the I_Kr component in HM, DM, and RM measured at −40 mV. After a 30 mV pulse, it was slow and biexponential, while in GM, the I_Kr tail current was best fitted triexponentially. At 30 mV, the I_Ks component activated slowly and had an apparent monoxponential time course in HM, DM, and RM. In contrast, in GM, the activation was clearly biexponential. In HM, DM, and RM, I_Ks component deactivation measured at −40 mV was fast and monoexponential, while in GM, in addition to the fast component, another slower component was also revealed. These results suggest that the I_K in HM resembles that measured in DM and RM and considerably differs from that observed in GM. These findings suggest that the dog and rabbit are more appropriate species than the guinea pig for preclinical evaluation of new potential drugs expected to affect cardiac repolarization. Full article

The sodium-glucose co-transporter-2 (SGLT2) inhibitor dapagliflozin is increasingly used in the treatment of diabetes and heart failure. Dapagliflozin has been associated with reduced incidence of atrial fibrillation (AF) in clinical trials. We hypothesized that the favorable antiarrhythmic outcome of dapagliflozin use may be caused in part by previously unrecognized effects on atrial repolarizing potassium (K⁺) channels. This study was designed to assess direct pharmacological effects of dapagliflozin on cloned ion channels K_v11.1, K_v1.5, K_v4.3, K_ir2.1, K_2P2.1, K_2P3.1, and K_2P17.1, contributing to I_Kur, I_to, I_Kr, I_K1, and I_K2P K⁺ currents. Human channels coded by KCNH2, KCNA5, KCND3, KCNJ2, KCNK2, KCNK3, and KCNK17 were heterologously expressed in Xenopus laevis oocytes, and currents were recorded using the voltage clamp technique. Dapagliflozin (100 µM) reduced K_v11.1 and K_v1.5 currents, whereas K_ir2.1, K_2P2.1, and K_2P17.1 currents were enhanced. The drug did not significantly affect peak current amplitudes of K_v4.3 or K_2P3.1 K⁺ channels. Biophysical characterization did not reveal significant effects of dapagliflozin on current–voltage relationships of study channels. In conclusion, dapagliflozin exhibits direct functional interactions with human atrial K⁺ channels underlying I_Kur, I_Kr, I_K1, and I_K2P currents. Substantial activation of K_2P2.1 and K_2P17.1 currents could contribute to the beneficial antiarrhythmic outcome associated with the drug. Indirect or chronic effects remain to be investigated in vivo. Full article

Although repolarization has been suggested to propagate in cardiac tissue both theoretically and experimentally, it has been challenging to estimate how and to what extent the propagation of repolarization contributes to relaxation because repolarization only occurs in the course of membrane excitation in normal hearts. We established a mathematical model of a 1D strand of 600 myocytes stabilized at an equilibrium potential near the plateau potential level by introducing a sustained component of the late sodium current (I_NaL). By applying a hyperpolarizing stimulus to a small part of the strand, we succeeded in inducing repolarization which propagated along the strand at a velocity of 1~2 cm/s. The ionic mechanisms responsible for repolarization at the myocyte level, i.e., the deactivation of both the I_NaL and the L-type calcium current (I_CaL), and the activation of the rapid component of delayed rectifier potassium current (I_Kr) and the inward rectifier potassium channel (I_K1), were found to be important for the propagation of repolarization in the myocyte strand. Using an analogy with progressive activation of the sodium current (I_Na) in the propagation of excitation, regenerative activation of the predominant magnitude of I_K1 makes the myocytes at the wave front start repolarization in succession through the electrical coupling via gap junction channels. Full article

Loperamide has been a safe and effective treatment for diarrhea for many years. However, many cases of cardiotoxicity with intentional abuse of loperamide ingestion have recently been reported. We evaluated loperamide in in vitro and in vivo cardiac safety models to understand the mechanisms for this cardiotoxicity. Loperamide slowed conduction (QRS-duration) starting at 0.3 µM [~1200-fold (×) its human Free Therapeutic Plasma Concentration; FTPC] and reduced the QT-interval and caused cardiac arrhythmias starting at 3 µM (~12,000× FTPC) in an isolated rabbit ventricular-wedge model. Loperamide also slowed conduction and elicited Type II/III A-V block in anesthetized guinea pigs at overdose exposures of 879× and 3802× FTPC. In ion-channel studies, loperamide inhibited hERG (I_Kr)_, I_Na, and I_Ca currents with IC₅₀ values of 0.390 µM, 0.526 µM, and 4.091 µM, respectively (i.e., >1560× FTPC). Additionally, in silico trials in human ventricular action potential models based on these IC50s confirmed that loperamide has large safety margins at therapeutic exposures (≤600× FTPC) and confirmed repolarization abnormalities in the case of extreme doses of loperamide. The studies confirmed the large safety margin for the therapeutic use of loperamide but revealed that at the extreme exposure levels observed in human overdose, loperamide can cause a combination of conduction slowing and alterations in repolarization time, resulting in cardiac proarrhythmia. Loperamide’s inhibition of the I_Na channel and hERG-mediated IKr are the most likely basis for this cardiac electrophysiological toxicity at overdose exposures. The cardiac toxic effects of loperamide at the overdoses could be aggravated by co-medication with other drug(s) causing ion channel inhibition. Full article

hERG (human Ether-à-go-go Related Gene)-encoded potassium channels underlie the cardiac rapid delayed rectifier (I_Kr) potassium current, which is a major target for antiarrhythmic agents and diverse non-cardiac drugs linked to the drug-induced form of long QT syndrome. E-4031 is a high potency hERG channel inhibitor from the methanesulphonanilide drug family. This study utilized a methanesulphonate-lacking E-4031 analogue, “E-4031-17”, to evaluate the role of the methanesulphonamide group in E-4031 inhibition of hERG. Whole-cell patch-clamp measurements of the hERG current (I_hERG) were made at physiological temperature from HEK 293 cells expressing wild-type (WT) and mutant hERG constructs. For E-4031, WT I_hERG was inhibited by a half-maximal inhibitory concentration (IC₅₀) of 15.8 nM, whilst the comparable value for E-4031-17 was 40.3 nM. Both compounds exhibited voltage- and time-dependent inhibition, but they differed in their response to successive applications of a long (10 s) depolarisation protocol, consistent with greater dissociation of E-4031-17 than the parent compound between applied commands. Voltage-dependent inactivation was left-ward voltage shifted for E-4031 but not for E-4031-17; however, inhibition by both compounds was strongly reduced by attenuated-inactivation mutations. Mutations of S6 and S5 aromatic residues (F656V, Y652A, F557L) greatly attenuated actions of both drugs. The S624A mutation also reduced I_hERG inhibition by both molecules. Overall, these results demonstrate that the lack of a methanesulphonate in E-4031-17 is not an impediment to high potency inhibition of I_hERG. Full article

N′-(5-bromofuran-2-carbonyl)isonicotinohydrazide (1) was obtained in the form of a colorless solid from the 2-methyl-6-nitrobenzoic anhydride (MNBA)/4-dimethylaminopyridine (DMAP)-catalyzed reaction of 5-bromofuran-2-carboxylic acid and isoniazid in dichloromethane at room temperature with a yield of 83%. The structure of N′-(5-bromofuran-2-carbonyl)isonicotinohydrazide (1) was elucidated using ¹H NMR, ¹³C NMR, FTIR, and high-resolution mass spectrometry. Molecular docking screening of the title compound (1) on cyclooxygenase-2 (COX-2) protein (PDB ID: 5IKR) indicated that compound (1) has a good binding affinity, suggesting that further structure optimization and in-depth research can be carried out on compound (1) as a potential COX-2 inhibitor. Full article