Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.

Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.

Cold pressor stress effects on cardiac repolarization.

The cold pressor test (CPT) elicits strong cardiovascular reactions via activation of the sympathetic nervous system (SNS), yielding subsequent increases in heart rate (HR) and blood pressure (BP). However, little is known on how exposure to the CPT affects cardiac ventricular repolarization. Twenty-eight healthy males underwent both a bilateral feet CPT and a warm water (WW) control condition on two separate days, one week apart. During pre-stress baseline and stress induction cardiovascular signals (ECG lead II, Finometer BP) were monitored continuously. Salivary cortisol and subjective stress ratings were assessed intermittently. Corrected QT (QTc) interval length and T-wave amplitude (TWA) were assessed for each heartbeat and subsequently aggregated individually over baseline and stress phases, respectively. CPT increases QTc interval length and elevates the TWA. Stress-induced changes in cardiac repolarization are only in part and weakly correlated with cardiovascular and cortisol stress-reactivity. Besides its already well-established effects on cardiovascular, endocrine, and subjective responses, CPT also impacts on cardiac repolarization by elongation of QTc interval length and elevation of TWA. CPT effects on cardiac repolarization share little variance with the other indices of stress reactivity, suggesting a potentially incremental value of this parameter for understanding psychobiological adaptation to acute CPT stress.

Caveolin-3 and Caveolae regulate ventricular repolarization.

RATIONALE: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. OBJECTIVE: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. METHODS AND RESULTS: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. CONCLUSION: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Pro-Arrhythmic Potential of Accumulated Uremic Toxins Is Mediated via Vulnerability of Action Potential Repolarization.

Chronic kidney disease (CKD) is represented by a diminished filtration capacity of the kidneys. End-stage renal disease patients need dialysis treatment to remove waste and toxins from the circulation. However, endogenously produced uremic toxins (UTs) cannot always be filtered during dialysis. UTs are among the CKD-related factors that have been linked to maladaptive and pathophysiological remodeling of the heart. Importantly, 50% of the deaths in dialysis patients are cardiovascular related, with sudden cardiac death predominating. However, the mechanisms responsible remain poorly understood. The current study aimed to assess the vulnerability of action potential repolarization caused by exposure to pre-identified UTs at clinically relevant concentrations. We exposed human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and HEK293 chronically (48 h) to the UTs indoxyl sulfate, kynurenine, or kynurenic acid. We used optical and manual electrophysiological techniques to assess action potential duration (APD) in the hiPSC-CMs and recorded IKr currents in stably transfected HEK293 cells (HEK-hERG). Molecular analysis of KV11.1, the ion channel responsible for IKr, was performed to further understand the potential mechanism underlying the effects of the UTs. Chronic exposure to the UTs resulted in significant APD prolongation. Subsequent assessment of the repolarization current IKr, often most sensitive and responsible for APD alterations, showed decreased current densities after chronic exposure to the UTs. This outcome was supported by lowered protein levels of KV11.1. Finally, treatment with an activator of the IKr current, LUF7244, could reverse the APD prolongation, indicating the potential modulation of electrophysiological effects caused by these UTs. This study highlights the pro-arrhythmogenic potential of UTs and reveals a mode of action by which they affect cardiac repolarization.

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

AIMS: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval. METHODS: In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS: After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION: OM does not have a clinically relevant effect on the studied ECG parameters.

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T-wave parameters.

BACKGROUND: The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T-wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T-wave markers to controlled drug-induced regional RT gradients in intact pig hearts. METHODS: Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff-perfused hearts placed inside a torso tank. From the 12-lead ECG on the torso tank, the mean, maximum, and dispersion (max-min) of QTtime , JTtime , Tpeak-end , Twidth , TQratio , dV/dtmax , Tarea , Tamp , and T-upslope duration were determined, as well as upslope end difference between leads V1 and V6 . RESULTS: Temporal T-wave parameters Tpeak-end , Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T-upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1 -V6 upslope end difference were not significantly correlated with RT gradient. CONCLUSION: Composite 12-lead ECG T-wave parameters Tpeak-end , Twidth , TQratio , upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T-wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.

Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia.

Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels.

Dasiglucagon Effects on QTc in Healthy Volunteers: A Randomized, Placebo-Controlled, Dose-Escalation, Double-Blind Study.

Background: Dasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes. Objective: The aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers. Methods: This double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model. Results: At the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting. Conclusions: Dasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Cardiac small-conductance calcium-activated potassium channels in health and disease.

Small-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.

Electrocardiogram-based index for the assessment of drug-induced hERG potassium channel block.

INTRODUCTION: Drug-induced block of the hERG potassium channel could predispose to torsade de pointes, depending on occurrence of concomitant blocks of the calcium and/or sodium channels. Since the hERG potassium channel block affects cardiac repolarization, the aim of this study was to propose a new reliable index for non-invasive assessment of drug-induced hERG potassium channel block based on electrocardiographic T-wave features. METHODS: ERD30% (early repolarization duration) and TS/A (down-going T-wave slope to T-wave amplitude ratio) features were measured in 22 healthy subjects who received, in different days, doses of dofetilide, ranolazine, verapamil and quinidine (all being hERG potassium channel blockers and the latter three being also blockers of calcium and/or sodium channels) while undergoing continuous electrocardiographic acquisition from which ERD30% and TS/A were evaluated in fifteen time points during the 24 h following drug administration ("ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects" database by Physionet). A total of 1320 pairs of ERD30% and TS/A measurements, divided in training (50%) and testing (50%) datasets, were obtained. Drug-induced hERG potassium channel block was modelled by the regression equation BECG(%) = a·ERD30% + b·TS/A+ c·ERD30%·TS/A + d; BECG(%) values were compared to plasma-based measurements, BREF(%). RESULTS: Regression coefficients values, obtained on the training dataset, were: a = -561.0 s-1, b = -9.7 s, c = 77.2 and d = 138.9. In the testing dataset, correlation coefficient between BECG(%) and BREF(%) was 0.67 (p < 10-81); estimation error was -11.5 ± 16.7%. CONCLUSION: BECG(%) is a reliable non-invasive index for the assessment of drug-induced hERG potassium channel block, independently from concomitant blocks of other ions.

How a concentration-effect analysis of data from the eliglustat thorough electrocardiographic study was used to support dosing recommendations.

Eliglustat is a first-line oral treatment for adults with Gaucher disease type 1 who have cytochrome P450 (CYP) 2D6 extensive, intermediate, or poor metabolizer phenotypes. Per International Conference on Harmonisation (ICH) E14 guidance, a Phase 1 thorough electrocardiographic (ECG) study was done during drug development to assess eliglustat's effects on cardiac repolarization by measuring ECG intervals in healthy adult subjects. Using data from the thorough ECG study, we performed pharmacokinetic/pharmacodynamic-ECG modeling to establish the relationship between eliglustat concentrations and their effects on ECG intervals. We then used that concentration-response relationship to predict the effects of eliglustat on each ECG interval for each CYP2D6 metabolizer phenotype (the main determinant of eliglustat exposure) and in different drug-drug interaction scenarios. These predictions, together with other exposure-related factors, contributed to the CYP2D6 phenotype-based dosing recommendations for eliglustat, including dose adjustments and contraindications when co-administered with drugs metabolized by the CYP2D6 and CYP3A pathways.

Toll-like receptor 3 controls QT interval on the electrocardiogram by targeting the degradation of Kv4.2/4.3 channels in the endoplasmic reticulum.

TLRs have been proven to be essential mediators for the early innate immune response. Overactivation of TLR-mediated immune signaling promotes deterioration of cardiovascular diseases; however, the role of TLRs in the heart under physiologic conditions remains neglected. Here, we show that Tlr3 deficiency induced the endoplasmic reticulum (ER) retention of Kv4.2/4.3 proteins and consequent degradation via the ubiquitin-proteasome pathway. Knockout of Tlr3 resulted in a prolonged QT interval (the space between the start of the Q wave and the end of the T wave) in mice with no significant signs of inflammation and tissue abnormality in cardiac muscles. Prolongation of action potential duration resulted from the depression of transient outward potassium channel (Ito) currents in Tlr3-deficient ventricular myocytes mirrored the change in QT interval. Mechanistically, we found that Tlr3 was exclusively localized in the ER of cardiomyocytes where it interacted with Kv4.2/4.3 subunits of Ito channel. Thus, our data indicated that TLR3 directly regulates Ito channel protein dynamics to maintain cardiac repolarization, which may implicate a new molecular surveillance system for cardiac electrophysiological homeostasis.-Gao, X., Gao, S., Guan, Y., Huang, L., Huang, J., Lin, L., Liu, Y., Zhao, H., Huang, B., Yuan, T., Liu, Y., Liang, D., Zhang, Y., Ma, X., Li, L., Li, J., Zhou, D., Shi, D., Xu, L., Chen, Y.-H. Toll-like receptor 3 controls QT interval on the electrocardiogram by targeting the degradation of Kv4.2/4.3 channels in the endoplasmic reticulum.

Transgenic short-QT syndrome 1 rabbits mimic the human disease phenotype with QT/action potential duration shortening in the atria and ventricles and increased ventricular tachycardia/ventricular fibrillation inducibility.

AIMS: Short-QT syndrome 1 (SQT1) is an inherited channelopathy with accelerated repolarization due to gain-of-function in HERG/IKr. Patients develop atrial fibrillation, ventricular tachycardia (VT), and sudden cardiac death with pronounced inter-individual variability in phenotype. We generated and characterized transgenic SQT1 rabbits and investigated electrical remodelling. METHODS AND RESULTS: Transgenic rabbits were generated by oocyte-microinjection of ß-myosin-heavy-chain-promoter-KCNH2/HERG-N588K constructs. Short-QT syndrome 1 and wild type (WT) littermates were subjected to in vivo ECG, electrophysiological studies, magnetic resonance imaging, and ex vivo action potential (AP) measurements. Electrical remodelling was assessed using patch clamp, real-time PCR, and western blot. We generated three SQT1 founders. QT interval was shorter and QT/RR slope was shallower in SQT1 than in WT (QT, 147.8 ± 2 ms vs. 166.4 ± 3, P < 0.0001). Atrial and ventricular refractoriness and AP duration were shortened in SQT1 (vAPD90, 118.6 ± 5 ms vs. 154.4 ± 2, P < 0.0001). Ventricular tachycardia/fibrillation (VT/VF) inducibility was increased in SQT1. Systolic function was unaltered but diastolic relaxation was enhanced in SQT1. IKr-steady was increased with impaired inactivation in SQT1, while IKr-tail was reduced. Quinidine prolonged/normalized QT and action potential duration (APD) in SQT1 rabbits by reducing IKr. Diverse electrical remodelling was observed: in SQT1, IK1 was decreased-partially reversing the phenotype-while a small increase in IKs may partly contribute to an accentuation of the phenotype. CONCLUSION: Short-QT syndrome 1 rabbits mimic the human disease phenotype on all levels with shortened QT/APD and increased VT/VF-inducibility and show similar beneficial responses to quinidine, indicating their value for elucidation of arrhythmogenic mechanisms and identification of novel anti-arrhythmic strategies.

Evaluation of Cardiac Repolarization Indices in Epilepsy Patients Treated with Carbamazepine and Valproic Acid.

BACKGROUND AND OBJECTIVES: Epilepsy patients have a higher risk of sudden unexplained death compared to the rest of the population. Cardiac repolarization abnormalities might be seen in epilepsy during interictal periods. We aimed to evaluate the changes in electrocardiography (ECG) parameters in generalized tonic-clonic seizure patients treated with carbamazepine or valproic acid (VPA) drug. MATERIALS AND METHODS: A totally of 129 subjects (66 epilepsy patients, 63 healthy subjects) were enrolled in the study. Of the patients, 36 were on carbamazepine and 30 were on VPA. There were 12-lead ECGs obtained from all participants. RR interval (time between consecutive R peaks), QT interval (defines the period of ventricular repolarization), corrected QT (QT interval corrected for heart rate; QTc), QTc-maximum (QTc-max), QTc-minimum (QTc-min), QTc dispersion (QTcd), P (atrial depolarization )-maximum (P-max), P-minimum (P-min) and P dispersion (Pd) were measured. RESULTS: QTd (QT dispersion), QTcd, and Pd values were significantly higher in the patients compared to the controls (p < 0.01). QTcd, Pd, and P-max values were statistically higher in male patients compared to healthy male controls. QTcd values were significantly higher in female patients using carbamazepine compared to the female patients on VPA and healthy controls (p = 0.01). Male patients using VPA had significantly higher QTcd values against the male population in carbamazepine and control groups. CONCLUSION: This study demonstrated that QTd, QTcd, and Pd values were significantly higher in epilepsy patients than in healthy controls. In addition, female patients using carbamazepine and male patients using VPA were prone to ventricular arrhythmia compared to the control group.

Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models.

AIMS: This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP. METHODS AND RESULTS: Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties. CONCLUSION: dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.

Ambient air pollution is associated with cardiac repolarization abnormalities in healthy adults.

BACKGROUND: Ambient air pollution has been associated with acute cardiovascular events; however, the underlying mechanisms remain incompletely understood. We aimed to examine the impacts of ambient air pollutants on cardiac ventricular repolarization in a highly polluted urban region. METHODS: Seventy-three healthy non-smoking young adults (66% female, mean age of 23.3 ±â€¯5.4 years) were followed with four repeated 24-h electrocardiogram recordings in 2014-2016 in Beijing, China. Continuous concentrations of ambient particulates in size fractions of 5-560 nm diameter, black carbon (BC), nitrogen dioxide (NO2), carbon monoxide (CO), sulfur dioxide (SO2), and ozone (O3) were measured at a fixed-location air pollution monitoring station. Generalized linear mixed models, with adjustment for individual risk factors, time-varying factors and meteorological parameters, were used to evaluate the effects of air pollution on 5-min segments of heart rate-corrected QT interval (QTc), an index of cardiac ventricular repolarization. RESULTS: During the study period, the mean levels of number concentrations of particulates in size range of 5-560 nm (PNC5-560) were 20,711 particles/cm3. Significant increases in QTc of 0.56% (95% CI: 0.27, 0.84) to 1.76% (95% CI: 0.73, 2.79) were associated with interquartile range increases in PNC50-560 at prior 1-5 moving average days. Significant increases in QTc were also associated with increases in exposures to traffic-related air pollutants (BC, NO2 and CO), a combustion pollutant SO2, and the secondary pollutant O3. The associations were stronger in participants who were male, overweight, with abdominal obesity, and with higher levels of high-sensitivity C-reactive protein. CONCLUSIONS: Our findings suggest that exposures to higher levels of ambient particulates in small size fractions and traffic pollutants were associated with cardiac repolarization abnormalities in healthy adults, and the cardio-metabolic risks may modify the adverse cardiac effects attributable to air pollution.

Classification of drug-induced hERG potassium-channel block from electrocardiographic T-wave features using artificial neural networks.

BACKGROUND: Human ether-à-go-go-related gene (hERG) potassium-channel block represents a harmful side effect of drug therapy that may cause torsade de pointes (TdP). Analysis of ventricular repolarization through electrocardiographic T-wave features represents a noninvasive way to accurately evaluate the TdP risk in drug-safety studies. This study proposes an artificial neural network (ANN) for noninvasive electrocardiography-based classification of the hERG potassium-channel block. METHODS: The data were taken from the "ECG Effects of Ranolazine, Dofetilide, Verapamil, and Quinidine in Healthy Subjects" Physionet database; they consisted of median vector magnitude (VM) beats of 22 healthy subjects receiving a single 500 µg dose of dofetilide. Fourteen VM beats were considered for each subject, relative to time-points ranging from 0.5 hr before to 14.0 hr after dofetilide administration. For each VM, changes in two indexes accounting for the early and the late phases of repolarization, ΔERD30% and ΔTS/A , respectively, were computed as difference between values at each postdose time-point and the predose time-point. Thus, the dataset contained 286 ΔERD30% -ΔTS/A pairs, partitioned into training, validation, and test sets (114, 29, and 143 pairs, respectively) and used as inputs of a two-layer feedforward ANN with two target classes: high block (HB) and low block (LB). Optimal ANN (OANN) was identified using the training and validation sets and tested on the test set. RESULTS: Test set area under the receiver operating characteristic was 0.91; sensitivity, specificity, accuracy, and precision were 0.93, 0.83, 0.92, and 0.96, respectively. CONCLUSION: OANN represents a reliable tool for noninvasive assessment of the hERG potassium-channel block.

Electrocardiographic parameters effectively predict ventricular tachycardia/fibrillation in acute phase and abnormal cardiac function in chronic phase of ST-segment elevation myocardial infarction.

BACKGROUND: Abnormal cardiac repolarization is closely associated with ventricular tachycardia/ventricular fibrillation (VT/VF). Myocardial ischemia and infarction aggravate cardiac repolarization dispersion, and VT/VF could be lethal in the early stage of ST-segment elevation myocardial infarction (STEMI). Unfortunately, VT/VF cannot be effectively predicted in current clinical practice. The present study aimed to assess electrocardiographic parameters of the sinus rhythmic complex in relation to cardiac repolarization, e.g., QT interval and T-peak to T-end interval (TpTe), to independently predict VT/VF in acute STEMI. Additionally, we hypothesized that QT and TpTe of PVC would be also valuable to predict VT/VF in STEMI. METHODS AND RESULTS: A total of 198 cases diagnosed as STEMI with PVC on admission by electrography were included. During hospitalization, VT/VF values were recorded. Logistic analysis was performed between patients with and without VT/VF to validate independent electrocardiographic predictors. QTcPVC interval > 520 ms (OR = 3.2; P = 0.027), TpTe interval > 100 ms (OR = 3.1; P = 0.04), TpTePVC  > 101 ms (OR = 3.6; P = 0.029), TpTe/QT > 0.258 (OR = 5.7; P = 0.003), and TpTe/QTPVC  > 0.253 (OR = 3; P = 0.048). However, QRS duration, QTc interval, coupling interval, and QRSPVC duration did not predict VT/VF. Besides, QRSPVC duration >140 ms (OR = 2.6; P = 0.001) independently predicted LVEF decrease after 1 year or more. CONCLUSIONS: QTcPVC interval, TpTe interval, TpTePVC interval, TpTe/QT ratio, and TpTe/QTPVC ratio are risk factors for ECG independent from other confounding factors in predicting VT/VF in the acute phase of STEMI. In addition, PVC characteristics as risk factors for VT/VF in acute phase and LVEF decrease in chronic phase were firstly reported.

Potassium currents in the heart: functional roles in repolarization, arrhythmia and therapeutics.

This is the second of the two White Papers from the fourth UC Davis Cardiovascular Symposium Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias (3-4 March 2016), a biennial event that brings together leading experts in different fields of cardiovascular research. The theme of the 2016 symposium was 'K+ channels and regulation', and the objectives of the conference were severalfold: (1) to identify current knowledge gaps; (2) to understand what may go wrong in the diseased heart and why; (3) to identify possible novel therapeutic targets; and (4) to further the development of systems biology approaches to decipher the molecular mechanisms and treatment of cardiac arrhythmias. The sessions of the Symposium focusing on the functional roles of the cardiac K+ channel in health and disease, as well as K+ channels as therapeutic targets, were contributed by Ye Chen-Izu, Gideon Koren, James Weiss, David Paterson, David Christini, Dobromir Dobrev, Jordi Heijman, Thomas O'Hara, Crystal Ripplinger, Zhilin Qu, Jamie Vandenberg, Colleen Clancy, Isabelle Deschenes, Leighton Izu, Tamas Banyasz, Andras Varro, Heike Wulff, Eleonora Grandi, Michael Sanguinetti, Donald Bers, Jeanne Nerbonne and Nipavan Chiamvimonvat as speakers and panel discussants. This article summarizes state-of-the-art knowledge and controversies on the functional roles of cardiac K+ channels in normal and diseased heart. We endeavour to integrate current knowledge at multiple scales, from the single cell to the whole organ levels, and from both experimental and computational studies.

Contribution of two-pore K+ channels to cardiac ventricular action potential revealed using human iPSC-derived cardiomyocytes.

Two-pore K+ (K2p) channels have been described in modulating background conductance as leak channels in different physiological systems. In the heart, the expression of K2p channels is heterogeneous with equivocation regarding their functional role. Our objective was to determine the K2p expression profile and their physiological and pathophysiological contribution to cardiac electrophysiology. Induced pluripotent stem cells (iPSCs) generated from humans were differentiated into cardiomyocytes (iPSC-CMs). mRNA was isolated from these cells, commercial iPSC-CM (iCells), control human heart ventricular tissue (cHVT), and ischemic (iHF) and nonischemic heart failure tissues (niHF). We detected 10 K2p channels in the heart. Comparing quantitative PCR expression of K2p channels between human heart tissue and iPSC-CMs revealed K2p1.1, K2p2.1, K2p5.1, and K2p17.1 to be higher expressed in cHVT, whereas K2p3.1 and K2p13.1 were higher in iPSC-CMs. Notably, K2p17.1 was significantly lower in niHF tissues compared with cHVT. Action potential recordings in iCells after K2p small interfering RNA knockdown revealed prolongations in action potential depolarization at 90% repolarization for K2p2.1, K2p3.1, K2p6.1, and K2p17.1. Here, we report the expression level of 10 human K2p channels in iPSC-CMs and how they compared with cHVT. Importantly, our functional electrophysiological data in human iPSC-CMs revealed a prominent role in cardiac ventricular repolarization for four of these channels. Finally, we also identified K2p17.1 as significantly reduced in niHF tissues and K2p4.1 as reduced in niHF compared with iHF. Thus, we advance the notion that K2p channels are emerging as novel players in cardiac ventricular electrophysiology that could also be remodeled in cardiac pathology and therefore contribute to arrhythmias.NEW & NOTEWORTHY Two-pore K+ (K2p) channels are traditionally regarded as merely background leak channels in myriad physiological systems. Here, we describe the expression profile of K2p channels in human-induced pluripotent stem cell-derived cardiomyocytes and outline a salient role in cardiac repolarization and pathology for multiple K2p channels.