Transmural Dispersion Of Repolarization Research Articles

The effect of anabolic androgenic steroids on heart rate recovery index and electrocardiographic parameters in male bodybuilders

BackgroundThe control of the cardiovascular system depends on the autonomic nerve system. Chronic anabolic andorogenic steroids (AAS) use causes sympathovagal imbalance and increases sympathetic nerve activity. ObjectiveThe reduction in heart rate from the peak exercise rate following the end of the exercise stress test is known as the heart rate recovery index (HRRI). Several methods have been utilized to assess myocardial repolarization, such as QT interval (QT), corrected QT interval (QTc), and T-wave peak-to-end interval (Tp-e interval). Based on a growing number of data a higher Tp-e/QT ratio is linked to malignant ventricular arrhythmias, and an increased Tp-e interval may correlate with the transmural dispersion of repolarization. Our hypothesis is that the use of chronic AAS was decrease HRRI during maximal exercise and increased risk of cardiac arrhythmias and sudden cardiac death. MethodsThis study included 44 male bodybuilders, with an average age of 29.7 ± 8.14 years, divided into AAS abuse [AAS users (n = 21) and AAS nonuser (n = 23)]. ResultsThe first (p = 0.001) and second minute (p = 0.001) HRRI of the subjects with AAS users were significantly lower than those of the control group. Additionally, HRRI after the third (p = 0.004) and fifth minutes (p = 0.007) of the recovery period were significantly lower in AAS group compared with the control group. Who used AAS had significantly higher QT, QTc, Tp-e, Tp-e/QT, and Tp-e/QTc values than non-users (all p = 0.001). ConclusionsChronic AAS use has been shown to cause sympathetic dominance, which may be a pro arrhythmic state.

Repolarization abnormalities and outcomes following return of spontaneous circulation after cardiac arrest

Abstract Funding Acknowledgements Type of funding sources: Private hospital(s). Main funding source(s): Boston Medical Center Background Prolongation of ventricular repolarization, as measured by the corrected QT interval (QTc), is common in patients resuscitated from cardiac arrest and is exacerbated by targeted temperature management. In this population, QTc prolongation appears to be transient and may not be associated with risk for malignant arrhythmia. The T-peak to T-end interval (TpTe), which represents transmural dispersion of repolarization in the left ventricle, is an emerging marker of risk for sudden cardiac death. Purpose We sought to evaluate the association of prolonged QTc and TpTe with in-hospital mortality and favorable neurologic outcome at discharge in comatose survivors of cardiac arrest. Methods We conducted a retrospective analysis of patients enrolled in the Multimodal Outcome CHAracterization in cardiac arrest patients (MOCHA) study at a single academic center. Participants were comatose survivors of cardiac arrest aged 18-89 years who had an electrocardiogram (ECG) obtained after return of spontaneous circulation between 2011-2020. Prolonged QTc was defined as QTc >450 ms in males and QTc >460 ms in females as measured by automated algorithm. Prolonged TpTe was defined as TpTe >90 ms as measured by two trained assessors. The primary outcomes were in-hospital mortality and favorable neurologic outcome at hospital discharge (Cerebral Performance Category 1-2). Multivariable logistic regression, adjusted for age, medical comorbidities (diabetes, chronic kidney disease, heart failure, malignancy) and arrest characteristics (location, initial rhythm, witnessed status, bystander CPR) was used to test the association between QTc prolongation and TpTe prolongation and outcomes. Results 471 (89.0%) patients met inclusion criteria and were included in this analysis; 58 (11.0%) were excluded due to missing post-ROSC ECG. The median age was 62 years (Interquartile range (IQR): 51-73 years), and 284 (60.4%) were male. 297 (63.2%) presented with out-of-hospital cardiac arrest and 138 (29.4%) presented with a shockable rhythm. The median QTc was 479 ms (IQR: 445-517 ms) and the median TpTe was 82.5 ms (IQR: 66-102 ms). Patients with and without prolonged QTc had similar incidence of mortality (71.2% vs 65.5%, P=0.22) and favorable neurologic outcome (22.4% vs 26.9%, P=0.29). Mortality was higher among patients with prolonged TpTe (75.4% vs 65.8%, P=0.03), which persisted after multivariable adjustment (OR 1.91; 95% CI: 1.20-3.04, P<0.01). Patients with prolonged TpTe had lower incidence of favorable neurologic outcome (18.3% vs 27.1%, P=0.03), which persisted after multivariable adjustment (OR 0.47; 95% CI: 0.28-0.79, P<0.01). Conclusion TpTe prolongation, but not QTc prolongation, was independently associated with higher mortality and worse neurologic outcome in comatose survivors of cardiac arrest. Further research is needed to clarify the clinical significance of repolarization abnormalities in patients presenting with cardiac arrest.

PO-01-143 HYPOTHERMIA-INDUCED J-WAVES AND ARRHYTHMIAS ARE ASSOCIATED WITH AN EXACERBATION OF REPOLARIZATION RATHER THAN CONDUCTION HETEROGENEITY IN HUMAN HEARTS

The cardiac effects of hypothermia have been studied for many years since the initial discovery of the electrocardiographic J-wave in a case of accidental hypothermia. However, the precise mechanisms underlying the origin of the hypothermic J-wave and associated arrhythmias in man are still debated. A limited number of ex vivo animal studies have focused on the transmural repolarization dispersion, but do not provide global mapping of ventricular activation and repolarization heterogeneities. To map hypothermia-induced electrophysiological changes at a tissue level and study the mechanisms of initiation and maintenance of arrhythmias. Optical mapping experiments were performed on isolated right ventricles (RV) from pigs (N=7) and humans obtained through our organ donation program (N=3 control subjects; N=1 SCN5A BrS-associated mutant subject). Epi- and endocardial (EPI and ENDO) action potential conduction and repolarization properties were assessed at different pacing frequencies and arrhythmias were mapped and quantified at baseline (37°C), during severe hypothermia (29°C), and after a return to normothermia. Hypothermia induced a reversible prolongation of global action potential duration at 80% of repolarization (APD80) in pigs (EPI: +27%, ENDO: +21%; p<0.01) and humans (+45% in both EPI and ENDO), an increase in APD80 dispersion, and steepness of APD restitution curve. Repolarization time dispersion was increased in both species (pigs: +94%, p<0.001 in EPI and +79%, p<0.05 in ENDO; humans: +97% in EPI and +14% in ENDO). The total activation time was significantly prolonged in pigs (EPI: +58%, p<0.001; ENDO: +46%, p<0.01) but not in humans. Arrhythmogenicity was further increased in human ventricles (+43% of spontaneous arrhythmias in pigs versus +100% in humans), which always displayed defibrillation-resistant arrhythmias. In the carrier of a SCN5A mutant, hypothermia additionally potentiated epicardial localized conductive disorders already detected at baseline. Our results indicate that, in humans, and contrary to pigs, the hypothermic J-wave and associated arrhythmogenesis result more from an exacerbation of repolarization rather than conduction heterogeneity. Pre-existing localized conduction heterogeneities within pathological hearts can however contribute to the J-wave phenotype during hypothermia.

Impact of late sodium current inhibition on cardiac electrophysiology parameters and ventricular arrhythmias in isolated Langendorff perfused rabbit hearts with short QT interval

Objective: To determine the electrophysiological effects and related mechanisms of late sodium current inhibitors on hearts with short QT intervals. Methods: The electrophysiological study was performed on isolated Langendorff perfused rabbit hearts. A total of 80 New Zealand White rabbits were used and 34 hearts without drug treatment were defined as control group A, these hearts were then treated with IKATP opener pinacidil, defined as pinacidil group A. Then, 27 hearts from pinacidil group A were selected to receive combined perfusion with sodium channel inhibitors or quinidine, a traditional drug used to treat short QT syndrome, including ranolazine combined group (n=9), mexiletine combined group (n=9), and quinidine combined group (n=9). Nineteen out of the remaining 46 New Zealand rabbits were selected as control group B (no drug treatments, n=19), and then treated with pinacidil, defined as pinacidil group B (n=19). The remaining 27 rabbits were treated with sodium inhibitors or quinidine alone, including ranolazine alone group (n=9), mexiletine alone group (n=9), and quinidine alone group (n=9). Electrocardiogram (ECG) physiological parameters of control group A and pinacidil group A were collected. In control group B and pinacidil group B, programmed electrical stimulation was used to induce ventricular arrhythmias and ECG was collected. ECG physiological parameters and ventricular arrhythmia status of various groups were analyzed. The concentrations of pinacidil, ranolazine, mexiletine and quinidine used in this study were 30, 10, 30 and 1 μmol/L, respectively. Results: Compared with control group A, the QT interval, 90% of the repolarization in epicardial and endocardial monophasic action potential duration (MAPD90-Epi, MAPD90-Endo) was shortened, the transmural dispersion of repolarization (TDR) was increased, and the effective refractor period (ERP) and post-repolarization refractoriness (PRR) were reduced in pinacidil group A (all P<0.05). Compared with the pinacidil group A, MAPD90-Epi, MAPD90-Endo, QT interval changes were reversed in quinidine combined group and mexiletine combined group (all P<0.05), but not in ranolazine combined group. All these three drugs reversed the pinacidil-induced increases of TDR and the decreases of ERP and PRR. The induced ventricular arrhythmia rate was 0 in control group B, and increased to 10/19 (χ2=13.6, P<0.05) in pinacidil group B during programmed electrical stimulation. Compared with the pinacidil group B, incidences of ventricular arrhythmia decreased to 11% (1/9), 11% (1/9) and 0 (0/9) (χ2=4.5, 4.5, 7.4, P<0.05) respectively in ranolazine group, mexiletine group and quinidine group. Conclusions: Inhibition of late sodium current does not increase but even decreases the risk of malignant arrhythmia in hearts with a shortened QT interval. The antiarrhythmic mechanism might be associated with the reversal of the increase of TDR and the decrease of refractoriness (including both ERP and PRR) of hearts with shortened QT interval.

Kardiyak Resenkronizasyon Tedavisinin Ventriküler Repolarizasyon Parametreleri ve Ventriküler Aritmiler Üzerindeki Etkisi

Objective: Cardiac resynchronization therapy (CRT) is commonly used in patients with heart failure (HF) along with left ventricular mechanic and electrical dyssencrony. Left ventricular epicardial pacing in CRT patients changes the normal myocardial activation and increases the transmural dispersion of repolarization. We aimed to investigate the impact of CRT on repolarization parameters and reveal its consequences on arrhythmic events.&#x0D; Materials and Methods: The study consisted of 54 patients treated with CRT. Repolarization parameters; QT, T peak-to-T end and JT, Tpe/QT, QT dispersion and Tpe dispersion were measured. The patients were also investigated in two subgroups according to the presence of ventricular arrhythmias at the end of follow-up. Subgroups were compared in terms of repolarization parameters.&#x0D; Results The change in repolarization parameters according to baseline values were also compared in the whole group.In the whole study group, all of the repolarization parameters significantly increased in the acute phase. In the chronic phase, these abnormalities were significantly diminished. The comparison of the two subgroups did not show any significant difference in respect of repolarization parameters. &#x0D; Conclusion: Epicardial pacing prolongs myocardial repolarization time and increases transmural dispersion of repolarization. However, these abnormalities were transient and were not associated with ventricular arrhythmias.

Abstract P2091: Age-dependent Remodeling Of The Perinexus Modulates The Phenotype And Arrhythmic Risk Of Long Qt Syndrome Type 3

Background: The Long-QT Syndrome Type 3 (LQT3) is characterized by action potential duration (APD) prolongation due to cardiac voltage-gated sodium channel (Nav1.5) gain of function. Arrhythmia risk increases with age in LQT3 patients, but it is unknown whether this is due to progressive APD prolongation. Recent studies have shown that the LQT3 phenotype can be exacerbated by widening the perinexus, an intercalated disc nanodomain adjacent to gap junctions. However, it remains unclear if the perinexus mediates the LQT3 phenotype during aging. Objective: To investigate the role of the perinexus during aging in LQT3. Methods: Ventricular epicardial APD was obtained by optically mapping Langendorff-perfused adult (3-month) and aged (15-month) guinea pig hearts. LQT3 phenotype was induced with anemone toxin (ATXII), and the perinexus was widened with an intercalated disc adhesion inhibitor (βadp1). Perinexal width (Wp) was quantified by transmission electron microscopy. Susceptibility to arrhythmia was assessed with burst pacing in the absence and presence of βadp1 and evaluated from electrocardiograms (ECG). Results: APD was not different between adult and aged hearts at baseline, with ATXII, or ATXII+βadp1. Wp was significantly wider in adult LQT3 hearts either without or with βadp1 relative to aged hearts (without βadp1: 29.6±2.5 vs 22.9±3.8 nm; with βadp1: 38.3±1.7 vs 29.9±1.2 nm). These data suggest the perinexus narrows with aging and attenuates previously reported cellular APD prolongation such that there is no difference in whole-heart, epicardial APD between adult and aged LQT3 hearts. However, ECG Tpeak-Tend interval was not prolonged in adult, but significantly prolonged in aged hearts after treatment with ATXII+βadp1 (18.7±5.6 vs 35.5±11.5 ms), suggesting that βadp1 increases transmural dispersion of repolarization during aging in LQT3. Furthermore, ATXII+βadp1 did not induce arrhythmias in adult (0/6) but was arrhythmogenic in aged hearts (3/5). Conclusions: Perinexal narrowing associated with aging attenuates APD prolongation and reduces arrhythmic risk in aged LQT3 hearts. Loss of perinexal adhesion in aged LQT3 hearts results in significant and heterogeneous APD prolongation and increased risk of arrhythmia.

The Role of T Peak – T End Interval Reduction on Electrocardiogram as a Marker of Successful Reperfusion in Patients with ST Elevation Myocardial Infarction undergoing Fibrinolytic Therapy

Background: Immediate reperfusion is the key of ST Elevation Myocardial Infarction (STEMI) Management. Despite the superiority of primary percutaneous coronary intervention (PCI), fibrinolytic therapy is still the preferred choice in many settings because of their availability and easy resources. Assessment of successful fibrinolytic determines the next strategy, ST-segment resolution (STR) correlates well with TIMI flow, reflects myocardial perfusion, and has a better prognostic value. T Peak – T End (Tpe) interval is proposed to be a valuable tool for reperfusion marker as it measures the transmural dispersion of repolarization (TDR) which can be an additional myocardial perfusion assessment. This study aims to see whether the Tpe interval reduction can be a marker of the successful reperfusion in patients with STEMI treated with fibrinolytic. &#x0D; Methods : This cross-sectional study involved STEMI patients underwent fibrinolytic therapy. Tpe interval was measured at admission and 90 minutes after fibrinolytic, then the changes in the form of difference (ms) and resolution (%) were assessed and compared between successful and failed reperfusion groups according to STR.&#x0D; Results: Among total of 86 patients, there were 53 patients (61.2%) with successful reperfusion. Tpe interval reduction was greater in the successful reperfusion group. The value of Tpe difference in predicting STR ³ 50% had a sensitivity of 66% and specificity of 75.8% with an area under curve (AUC) of 0.726 and a cut-off point of 20 ms. While the AUC of Tpe resolution 0.726 with a cut-off point of 16.2%, had a sensitivity of 66% and a specificity of 72.7%.&#x0D; Conclusion: The Tpe interval reduction can be a valuable additional marker of successful reperfusion in patients with STEMI treated with fibrinolytic.&#x0D; &#x0D; &#x0D;

Sex-Specific Associations of Anxiety With Left Ventricular Hypertrophy and Transmural Dispersion of Repolarization in Hypertensive Patients.

BackgroundThe previous studies have shown that individuals with hypertension and anxiety have a higher mean left ventricular mass index (LVMI) and QTc dispersion. We explored the associations between anxiety and left ventricular hypertrophy (LVH) and between anxiety and transmural dispersion of repolarization (TDR) (as detected by T peak-T end interval/QT interval, Tp–Te/QT ratio) in patients with hypertension.MethodsA total of 353 patients with uncomplicated hypertension from the Shaanxi Provincial People’s Hospital were enrolled between 2017 and 2021. Anxiety was defined as a Hamilton Anxiety Scale (HAM-A) score ≥ 14. Logistic regression models were used to estimate the association between HAM-A and LVH. The association between HAM-A score and Tp–Te/QT was estimated using linear regression.ResultsParticipants were divided into two groups based on the presence of anxiety. LVMI was significantly higher in patients with hypertension and anxiety than in those with hypertension without anxiety (no anxiety: 84.36 ± 23.82, anxiety: 105.75 ± 25.45 g/m2, p < 0.001). HAM-A score was positively correlated with LVMI (r = 0.578, p < 0.001) and with Tp–Te/QT (r = 0.252, p < 0.001). Logistic regression models showed that patients with hypertension and anxiety were at higher risk of LVH than were patients with hypertension without anxiety (adjusted OR, 2.44, 95% CI, 1.35–4.43, p = 0.003). The linear regression analysis showed that the HAM-A score was associated with Tp–Te/QT ratio (adjusted β, 0.001, 95% CI, 0.001–0.002, p = 0.013). There was an interaction between sex and anxiety for LVH risk (p for interaction = 0.035) and for increased Tp–Te/QT (p for interaction = 0.014). After stratification by sex, anxiety was associated with increased risk for LVH in men with hypertension (adjusted OR, 5.56, 95% CI, 2.07–14.98, p = 0.001), but not in women (adjusted: OR, 1.44, 95% CI, 0.64–3.26, p = 0.377) with hypertension. The HAM-A score was also positively associated with Tp–Te/QT ratio in male (adjusted β, 0.002, 95% CI, 0.001–0.003, p < 0.001), but not in women (adjusted β, 0.001, 95% CI, –0.0002–0.002, p = 0.165).ConclusionOur results indicated that anxiety was associated with LVH and with increased TDR in men with hypertension, but not in women with hypertension.

Abstract EP29: Sex Differences In Anxiety Associated With Left Ventricular Hypertrophy And Transmural Dispersion Of Repolarization In Hypertensive Patients

Background: Previous studies showed that hypertensive with anxiety have a higher mean left ventricular mass index (LVMI) and QTc dispersion. This study explores the associations between anxiety and left ventricular hypertrophy (LVH) as well as transmural dispersion of repolarization (TDR) (as detected by T peak-T end interval/QT interval, Tp-Te/QT ratio) in hypertensive patients. Methods: A total of 353 uncomplicated hypertensive patients were enrolled at Shaanxi Provincial People’s Hospital from 2017 to 2021. All enrolled subjects completed the Hamilton Anxiety Scale (HAMA). HAM-A score ≥14 was defined as the presence of anxiety. The association between HAM-A and hypertensive LVH was estimated with logistic regression models. The association between HAM-A score and Tp-Te/QT was estimated with linear regression model (adjusted for age, sex, body mass index, smoking, creatinine, uric acid, triglyceride, total cholesterol, low density lipoprotein cholesterol, and high-density lipoprotein cholesterol). This study was approved by the Ethics Committee of Shaanxi Provincial People’s Hospital and performed in keeping with the requirements of the Declaration of Helsinki. Results: Participants were divided into two groups according to anxiety or not. The LVMI was significantly higher in hypertensive patients with anxiety than hypertensive patients without anxiety (no anxiety: 84.36±23.82, anxiety: 105.75±25.45, g/m 2 , P &lt;0.001). The HAM-A score was positive correlated with LVMI (r=0.578, P &lt;0.001) and Tp-Te/QT (r=0.252, P &lt;0.001). In logistic regression models, hypertensive patients with anxiety had a higher risk of hypertensive LVH than hypertensive patients without anxiety (unadjusted OR, 2.86, 95% CI, 1.65-4.93, P &lt;0.001; adjusted OR, 2.62, 95% CI, 1.49-4.64, P &lt;0.001). Linear regression analysis also showed that HAM-A score was associated with Tp-Te/QT ratio (unadjusted β, 0.002, 95% CI, 0.001-0.002, P &lt;0.001; adjusted β, 0.002, 95% CI, 0.001-0.002, P &lt;0.001). There was an interaction between sex and anxiety in regard to LVH risk ( P for interaction = 0.035) and increased Tp-Te/QT ( P for interaction = 0.014). After stratification by sex, the anxiety group had a higher risk of hypertensive LVH than no anxiety group in male (unadjusted OR, 5.73, 95% CI, 2.43-13.50, P &lt;0.001; adjusted OR, 5.39, 95% CI, 2.13-13.66, P &lt;0.001) but not in female (unadjusted OR, 1.70, 95% CI, 0.82-3.53, P =0.152; adjusted: OR, 1.62, 95% CI, 0.76-3.45, P =0.209) hypertensive patients. HAM-A score was also associated with Tp-Te/QT ratio in male (unadjusted β, 0.003, 95% CI, 0.002-0.004, P &lt;0.001; adjusted β, 0.003, 95% CI, 0.001-0.004, P &lt;0.001) but not in female (unadjusted β, 0.001, 95% CI, -0.0001-0.002, P =0.061; adjusted β, 0.001, 95% CI, -0.0001-0.002, P =0.086). Conclusion: Our data indicated that anxiety is associated with LVH and increased TDR in male but not female hypertensive patients.

Proarrhythmic effects of carbon monoxide in human ventricular tissue: insights from computational modeling

Epidemiological studies have demonstrated that ambient air pollution has been closely associated with cardiovascular diseases. Carbon monoxide (CO) is a common ambient air pollutant that can cause adverse effects on the heart. CO is known to cause tissue ischemia, resulting in ventricular arrhythmias. However, accumulating biological studies showed that CO could exert effects on multiple cardiac ionic channels under normoxic conditions, which might indicate new proarrhythmic mechanisms other than ischemia-mediated electrophysiology changes. In this work, we evaluated the functional impacts of CO on human ventricles using a multi-scale model of human ventricular tissue. Experimental data regarding the effects of CO on different ion channels were incorporated into the cell model to explore the alterations of ventricular electrophysiology. Simulation results suggested that CO significantly prolonged the duration of ventricular action potentials, enhanced the transmural dispersion of repolarization, and reduced the adaptability of ventricular tissue to fast heart rates. In addition, simulated pseudo-ECGs showed consistent manifestations with the clinical observation that CO caused an apparent QT interval prolongation and T-wave widening, indicating that CO affected the heart's abnormal ventricular repolarization.

Gender differences in ECG markers of increased risk for malignant arrhythmias, peripheral blood parameters, and adverse outcomes in patients with COVID-19 pneumonia

Background: The available data on gender differences in a) markers of cardiac involvement, b) peripheral blood parameters, and c) clinical adverse outcomes related to COVID-19 pneumonia severity are limited in the literature.: Objectives: To investigate gender differences in ECG markers of increased risk for malignant arrhythmias. This includes T from peak to end (Tp-e) interval, corrected QT (QTc), transmural dispersion of repolarization (TDR)(Tp-e/QTc), and index of cardiac electrophysiological balance (iCEB)(QTc/QRS), peripheral blood parameters, and in-hospital adverse outcomes in patients with COVID-19 pneumonia. Methods: A cross sectional study enrolled patients with COVID-19 pneumonia admitted to hospital from August 20th, to September 30th, 2020. Results: A total of 197 patients were included. Ninety-six (47%) were men and 101 women. There were no significant gender related differences concerning comorbidities. Men had higher QRS values, Tp-e interval and TDR, and lower values of iCEB. No significant gender differences were observed in the distribution of QTc interval. Men stayed longer in the hospital and had more extensive lung injury than women. In men, prolonged QTc interval, low lymphocytes %, high platelet distribution width (PDW), and low hemoglobin (Hb) were the main predictors of adverse in-hospital outcome, while prolonged QTc interval, high PDW, and low platelet count were the main predictors of adverse in-hospital outcome for women. Conclusions: Men had higher TDR values, lower iCEB, stayed longer in the hospital, and had more extensive lung injury than women, suggesting that, despite that there was no significant difference in mortality incidents between the two genders, the difference in surrogate markers may indicate that men are at a higher risk for adverse outcomes.

Abstract 12296: Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome

Introduction: Early repolarization syndrome (ERS) is an inherited sudden cardiac death syndrome. Hypothesis: In this study we test the role of genetic variants in cardiac calcium channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Methods: PCR-based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium channel variants were evaluated clinically and compared with matched healthy controls. Wild type (WT) and mutant CACNA1C genes were co-expressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp and confocal fluorescence microscope . Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium channel genes (32.2±14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (VT/VF, 62.5%), sudden cardiac death (SCD, 56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS susceptible genes. Compared with controls, the heart rate was slower (72.7±8.9 vs. 65.6±16.1 bpm), QTc interval was shorter (408.2±21.4 vs. 386.8±16.9 ms) and Tp-e/QT was longer (0.22±0.05 vs.0.28±0.04) in calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C -P817S revealed that the density of I Ca was reduced by approximately 84.6% compared to WT (-3.1±2.5 vs. -20.5±3.6 pA/pF, n=11 and 15, respectively). Heterozygous expression of mutant channels was associated with a 51.3% reduction of I Ca . Steady-state inactivation was shifted to more negative potentials and significantly accelerated. Confocal microscopy revealed trafficking impairment of CACNA1C -P817S (peripheral/central intensity: 0.94±0.1 in WT vs. 0.33±0.1 in P817S, n=10 and 9, respectively). Conclusions: ERS associated with loss of function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C -P817S impaired trafficking of the channel to the membrane contributes to the LOF.

Effect of age and sex on the incidence of ventricular arrhythmia in a rat model of acute ischemia

BackgroundThe impact of sex and age on the arrhythmic susceptibility within the setting of acute ischemia is masked by the fact that acute coronary events result from coronary artery disease appearing with age much earlier among men than among women. Methods and resultsLAD ligation or sham operations were performed in rats of both sexes at the age 3 and 24 months. An ECG was recorded continuously for 6 h after the operation. The number of early and late premature ventricular beats (PVBs), episodes of ventricular tachycardia (VT) and fibrillation (VF), heart rate, QRS, QT and Tpeak-Tend duration were analysed. Epicardial action potentials were recorded in vivo, Ca2+ signaling was evaluated in isolated cardiomyocytes, fibrosis and connexin-43 expression and localization were measured in the septum. PVBs, VT and VF episodes are much more common in older males than in young males and females independently from their age. Fibrosis with varying intensity in different muscle layers, hypertrophy of cardiomyocytes, reduced number of gap junctions and their appearance on the lateral myocyte membrane, QT prolongation, increase transmural dispersion of repolarisation and a decreased function of SERCA2a may increase the propensity to arrhythmia within the setting of acute ischemia. ConclusionWe show that the male sex, especially in case of older individuals is a strong predictor of increased arrhythmic susceptibility within the acute ischemia setting regardless of its impact on the occurrence of cardiovascular diseases. A personalized sex-dependent prevention treatment is needed to reduce the mortality in acute phases of myocardial infarction.

Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome.

Background: Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms.Methods: Polymerase chain reaction–based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium-channel variants were evaluated clinically and compared with matched healthy controls. Wild-type (WT) and mutant CACNA1C genes were coexpressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope.Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 ± 14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (62.5%), and SCD (56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS-susceptible genes. Compared with controls, the heart rate was slower (72.7 ± 8.9 vs. 65.6 ± 16.1 beats/min, *p < 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, **p < 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, ***p < 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C-P817S (c.2449C>T), revealed that the density of whole-cell calcium current (ICa) was reduced by ~84.61% compared to WT (−3.17 ± 2.53 vs. −20.59 ± 3.60 pA/pF, n = 11 and 15, respectively, **p < 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of ICa. Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of CACNA1C-P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, n = 10 and 9, respectively, **p < 0.01).Conclusions: ERS associated with loss-of-function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C-P817S, impaired trafficking of the channel to the membrane contributes to the LOF.

ECG markers of malignant arrhythmias and in-hospital outcome of COVID-19 pneumonia.

BackgroundECG abnormalities associated with COVID‐19 pneumonia and adverse outcome are undefined and poorly described in prior studies.ObjectivesTo assess the predictive role of baseline ECG markers of increased risk of malignant arrhythmias and cardiac death for adverse in‐hospital outcomes.Patients and methodsA retrospective study included 93 patients of newly diagnosed COVID‐19 with features consistent with pneumonia who were admitted to the hospital from August 20 to September 20, 2020. The main outcomes were defined as receiving mechanical ventilation, in‐hospital cardiac arrest, length of ICU stay, and degree of lung damage according to computed tomography (CT) score.ResultsIncreased QTc (QT corrected) interval, Tp‐e (T from peak to end) interval, and transmural dispersion of repolarization (TDR) were independent predictors of prolonged ICU stay (P < .0001) after adjustment for baseline clinical characteristics. Increasing age (P < .0001) followed by increased QTc interval (P = .02) and history of chronic lung disease (P = .04) were independent predictors of extensive lung damage. The independent predictors for in‐hospital cardiac arrest were increased QTc (P = .02) followed by increasing age (P = .04) and increased Tp‐e interval (P = .04).ConclusionRepolarization abnormalities on baseline ECG may be useful prognostic markers in patients with COVID‐19 pneumonia.

Electrocardiographic markers of increased risk of sudden cardiac death in patients with COVID-19 pneumonia.

BackgroundLittle is known about the role of ECG markers of increased risk of sudden cardiac death during the acute period of coronavirus disease 2019 ( COVID‐19) pneumonia.ObjectivesTo evaluate ECG markers of sudden cardiac death on admission, including the index of cardiac electrophysiological balance (iCEB) (QTc/QRS) and transmural dispersion of repolarization (TDR) (T from peak to end (Tp‐e) interval and Tp‐e/QTc), in patients with COVID‐19 pneumonia.Patients and methodsThis cross‐sectional study included 63 patients with newly diagnosed COVID‐19 pneumonia who presented to the outpatient clinic or admitted to the respiratory care unit between August 20 and September 15, 2020. Forty‐six persons matched for sex and age were selected from data collected before COVID‐19 pandemic.ResultsQRS and QTc showed a significant prolongation in patients with COVID‐19 pneumonia compared to the controls (87 vs. 78, p < .00, and 429 versus. 400, p < .00, respectively). After categorization of patients with COVID‐19 pneumonia into 3 groups according to the severity of pneumonia as mild‐moderate, severe, and critical groups, a decreased values of QRS were observed in the critical COVID‐19 pneumonia group compared to severe and mild‐moderate COVID‐19 pneumonia groups (p = .04) while increased values of QTc and iCEB(QTc/QRS) were noted in critical COVID‐19 pneumonia group compared to other 2 groups(p < .00).ConclusionsPatients with COVID‐19 pneumonia showed significant changes in repolarization and conduction parameters compared to controls. Patients with mild to severe COVID‐19 pneumonia may be at low risk for torsades de pointes development.

Acute effects of electronic cigarette smoking on ventricular repolarization in adults.

Electronic cigarette (e-cigarette) use is constantly increasing. However, the association between e-cigarette use and ventricular arrhythmia is unknown. Thus, in this study, we aimed to evaluate the markers of ventricular repolarization such as QT interval, corrected QT (QTc), QT dispersion (QTd), peak-to-end interval of the T wave (Tp-e), corrected Tp-e and Tp-e/QT ratios in e-cigarette users. The study population consisted 36 e-cigarette users and 40 healthy subjects. Ventricular repolarization parameters were obtained from 12-lead resting electrocardiogram. Ventricular repolarization parameters of the groups were compared. Basal demographic and laboratory data were similar in both groups. According to the electrocardiographic parameters, the Tp-e interval, corrected Tp-e, and Tp-e/QT ratio were significantly higher in individuals using e-cigarettes than in control subjects [74.9±6.4 milliseconds (ms) vs. 80.1±4.1ms, <0.001; 82.9±7.5 ms vs. 87.8±6.3 ms, p=0.003; 0.20±0.01 vs. 0.21±0.01, p=0.002; respectively]. This is the first study to show the disruption of ventricular repolarization properties in e-cigarette users. E-cigarette use in terms of public health leads to augmentation of transmural dispersion of repolarization, which may be potential indicator of ventricular arrhythmogenesis.

Transdermal Testosterone Attenuates Drug-Induced Lengthening of Both Early and Late Ventricular Repolarization in Older Men.

We have previously reported that transdermal testosterone attenuates drug-induced QT interval lengthening in older men. However, it is unknown whether this is due to modulation of early ventricular repolarization, late repolarization, or both. In a secondary analysis of a prospective, randomized, double-blind, placebo-controlled three-way crossover study, we determined if transdermal testosterone and oral progesterone attenuate drug-induced lengthening of early and late ventricular repolarization, represented by the electrocardiographic measurements J-Tpeak c and Tpeak -Tend , respectively, as well as Tpeak -Tend /QT, a measure of transmural dispersion of repolarization. Male volunteers ≥65years of age (n=14) were randomized to receive transdermal testosterone 100mg, oral progesterone 400mg, or matching transdermal/oral placebo daily for 7days. On the morning following the seventh day, subjects received intravenous ibutilide 0.003mg/kg, after which electrocardiograms were performed serially. One subject was excluded due to difficulty in T-wave interpretation. Pre-ibutilide J-Tpeak c was lower during the testosterone phase than during progesterone and placebo (216±23 vs. 227±28 vs. 227±21ms, P=0.002). Maximum post-ibutilide J-Tpeak c was also lower during the testosterone phase (233±22 vs. 246±29 vs. 248±23ms, P<0.0001). Pre-ibutilide Tpeak -Tend was not significantly different during the three phases, but maximum post-ibutilide Tpeak -Tend was lower during the testosterone phase (80±12 vs. 89±18 vs. 86±15ms, P=0.002). Maximum Tpeak -Tend /QT was also lower during the testosterone phase (0.199±0.023 vs. 0.216±0.035 vs. 0.209±0.031, P=0.005). Progesterone exerted minimal effect on drug-induced lengthening of J-Tpeak c, and no effect on Tpeak -Tend or Tpeak -Tend /QT. Transdermal testosterone attenuates drug-induced lengthening of both early and late ventricular repolarization in older men.

Different effects of amiodarone and dofetilide on the dispersion of repolarization between well-coupled ventricular and Purkinje fibers1.

Increased transmural dispersion of repolarization is an established contributing factor to ventricular tachyarrhythmias. In this study, we evaluated the effect of chronic amiodarone treatment and acute administration of dofetilide in canine cardiac preparations containing electrotonically coupled Purkinje fibers (PFs) and ventricular muscle (VM) and compared the effects to those in uncoupled PF and VM preparations using the conventional microelectrode technique. Dispersion between PFs and VM was inferred from the difference in the respective action potential durations (APDs). In coupled preparations, amiodarone decreased the difference in APDs between PFs and VM, thus decreasing dispersion. In the same preparations, dofetilide increased the dispersion by causing a more pronounced prolongation in PFs. This prolongation was even more emphasized in uncoupled PF preparations, while the effect in VM was the same. In uncoupled preparations, amiodarone elicited no change on the difference in APDs. In conclusion, amiodarone decreased the dispersion between PFs and VM, while dofetilide increased it. The measured difference in APD between cardiac regions may be the affected by electrotonic coupling; thus, studying PFs and VM separately may lead to an over- or underestimation of dispersion.

Targeting the β‐adrenergic receptor in the clinical management of congenital long QT syndrome

The long QT syndrome (LQTS) is largely treated pharmacologically with β-blockers, despite the role of sympathetic activity in LQTS being poorly understood. Using the trigger-substrate model of cardiac arrhythmias in this review, we amalgamate current experimental and clinical data from both animal and human studies to explain the mechanism of adrenergic stimulation and blockade on LQT arrhythmic risk and hence assess the efficacy of β-adrenoceptor blockade in the management of LQTS. In LQTS1 and LQTS2, sympathetic stimulation increases arrhythmic risk by enhancing early afterdepolarizations and transmural dispersion of repolarization. β-Blockers successfully reduce cardiac events by reducing these triggers and substrates; however, these effects are less marked in LQTS2 compared with LQTS1. In LQTS3, clinical and experimental investigations of the effects of sympathetic stimulation and β-blocker use have produced contradictory findings, resulting in significant clinical uncertainty. We offer explanations for these contradicting results relating to study sample size, the dose of the β-blocker administered associated with its off-target Na+ channel effects, as well as the type of β-blocker used. We conclude that the antiarrhythmic efficacy of β-blockers is a genotype-specific phenomenon, and hence the use of β-blockers in clinical practice should be genotype dependent.