J-point Elevation Research Articles

The association between body temperature and electrocardiographic parameters in normothermic healthy volunteers

Abstract Introduction Previous studies have observed that hypo- and hyperthermia are associated with several atrial and ventricular electrocardiographical parameters, including the corrected QT interval. Preclinical studies have shown that drugs that exert an effect on body temperature also exert an effect on the corrected QT interval. Therefore, increased characterization in healthy humans of the association between the corrected QT interval and body temperature within the normal body temperature range aids in understanding the mechanism behind drug induced corrected QT interval effects. The objective of this analysis was to evaluate the association between body temperature and electrocardiographical parameters in normothermic healthy volunteers. Methods Data from 3023 volunteers collected at our center were analyzed. Only subjects considered healthy after review of collected data by a physician, including a normal tympanic body temperature (35.5–37.5 °C) and in sinus rhythm, were included in the analysis. Subjects were divided into body temperature quartiles for analysis and a linear multivariate model with body temperature as a continuous was performed. Another multivariate analysis was performed with only the QT subintervals as independent variables and body temperature as dependent variable. Results Mean age was 33.8±17.5 years and mean body temperature was 36.6±0.4 °C. Body temperature was independently associated with age (standardized coefficient (SC)=−0.252, P<0.001), gender (SC=+0.208, P<0.001), heart rate (SC=+0.230, P<0.001), J-point elevation in lead V4 (SC=−0.118, P<0.001), and Fridericia corrected QT interval (SC=−0.061, P=0.002). Atrial and AV nodal parameters were not independently associated with body temperature. The effects of temperature on the surface ECG are displayed in figure 1. QT subinterval analysis revealed that only QRS duration (SC=−0.121, P<0.001) was independently associated with body temperature. Conclusion Body temperature in normothermic healthy volunteers was associated with heart rate, J-point amplitude in lead V4 and ventricular conductivity, primarily through a prolongation of the QRS duration. In contrast, atrial and AV nodal ECG parameters were not independently associated with body temperature. Funding Acknowledgement Type of funding source: None

Electrocardiographic interpretation in athletes

Participation in regular exercise of moderate intensity is associated with a plethora of systemic benefits, including a reduction in risk factors for coronary atherosclerosis; however, intensive exercise may paradoxically culminate in sudden cardiac arrest among individuals harboring arrhythmogenic substrates. The precise mechanism for arrhythmogenesis is likely multifactorial, however, surges in catecholamines, electrolyte shifts, acid-base disturbances, increased core temperature and demand myocardial ischemia are potential contributors. Although most deaths occur in middle aged and older males with atherosclerotic coronary artery disease, a significant proportion also affect young athletes with inherited or congenital cardiac abnormalities. The impact of such catastrophes on society, particularly when a young high-profile athlete is affected could be considered a justified reason for identifying individuals who may be at risk. Given the rarity of deaths in young athletes, only the simplest screening test, such as the 12-lead electrocardiography (ECG) may be considered to be cost effective. The ECG is effective for detecting serious electrical diseases in young athletes such as congenital electrical accessory pathways and ion channel diseases but can also identify athletes with potential life-threatening structural diseases such as hypertrophic and arrhythmogenic cardiomyopathy. One of the concerns about ECG screening is that regular intensive exercise results in several physiological alterations in cardiac structure and function that are reflected on the athlete's ECG. Sinus bradycardia, first-degree atrioventricular block, incomplete right bundle branch block, minor J-point elevation and large QRS voltages are common. Conversely, some repolarization anomalies affecting the ST segment, T waves and QT interval may overlap with patterns observed in patients with serious cardiac diseases. The situation is complicated further because age, sex and ethnicity of the athletes also influence the ECG and there is a risk that erroneous interpretation could have serious consequences. This review will describe the normal electrical patterns of the "athlete's heart" and provide insights into differentiation physiological electrical patterns from those observed in serious cardiac disease.

Regional repolarization shortening is more arrhythmogenic than regional conduction slowing in an ex vivo porcine experimental model

Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In patients without apparent structural heart disease, J-point elevation and J waves are often associated with an increased risk to VF. The mechanisms underlying these ECG patterns and the associated arrhythmogenesis are still debated. To investigate the respective role of conduction and repolarization heterogeneities in the emergence of J-waves and in the vulnerability to VF. Epi- and endocardial optical mapping experiments were performed in porcine right ventricular (RV) wedge preparations ( n = 26). Both right coronary and left anterior descending (LAD) arteries were perfused separately with Tyrode, followed by addition of either pinacidil (PINA; 20 μM, n = 14) or flecainide (FLECA; 2 μM, n = 12) in the LAD only. RV action potentials (AP) properties were assessed at 1 to 4 Hz stimulation frequencies, and a bath ECG was recorded to evaluate ST segment changes. Spontaneous or induced arrhythmias were quantified and analyzed to calculate dominant frequencies (DF) and regularity index (RI). Local perfusion of PINA induced strong AP duration and repolarization time (RT) heterogeneity on epi- and endocardial surfaces while regional FLECA perfusion significantly prolonged total activation time and increased RT heterogeneity. Both models were associated with changes in ST segment, but those of conduction heterogeneity were more subtle. They both decreased RI of arrhythmias compared to the baseline (0.53 vs. 0.84 P = 0.02 for PINA; 0.47 vs. 0.76 P = 0.06 for FLECA), and DF were significantly higher for PINA compared to FLECA (9.41 vs. 7.74 P = 0.03). Spontaneous VFs are more frequent with a local perfusion of PINA compared to FLECA (86 vs. 8% P = 0.0001). Regional repolarization shortening and conduction slowing result in specific ECG phenotypes and distinct VF dynamics. In our porcine model, repolarization heterogeneity is associated with a higher risk to VF.

The impact of testosterone levels on J-wave patterns observed in healthy Turkish males

Objectives: Early-repolarization (ER) and Brugada-type-ECG-patterns (BTEP) have recently been grouped under a common terminology called “J-wave patterns” (JWP) and have been associated with an increased risk of sudden-cardiac-death. Scarce data is present about the male dominance in JWP and the probable effects of gonadal hormones on cardiac ion-channel functions. We sought to evaluate the relationship of testosterone-levels and the presence of JWP in healthy Turkish-males. Methods: One hundred eighty-five healthy male volunteers between ≥18 to ≤50 years old without any cardiac disorders were evaluated. ECG, blood biochemistry and total testosterone levels were obtained together with thorough physical examination. Subjects with complete-bundle-branch-block, non-sinus-rhythms and any abnormality on cardiac examination were excluded from the study. BTEP was searched according to the EHRA/HRS 2016 Consensus Conference on V1-V3. ER on ECG was defined as J-point elevation of ≥ 0.1 mV in ≥ 2 leads in the inferior (II, III, aVF) (Inferior ER), lateral (DI, aVL, V4-6) (Lateral ER) or both (Inferolateral ER). Results: A total of 179 subjects (mean age 34.9 ± 7.9 years) were included in our analyses. Three BTEP (1.7%) and 45 ER (26%) were detected. 22 were lateral (49%), 13 inferior (29%) and 10 were (22%) inferolateral ER. JWP (+) subjects (n = 48, 27%) were demonstrating significantly lower basal heart rates (73.9 ± 11bpm vs 68.4 ± 10.3 bpm, p = 0.001) and longer PR intervals (153.9 ± 20.3 ms vs 163.3 ± 21.6 ms, p = 0.01). JWP (+) subjects had significantly higher testosterone levels compared with the ones without (485.5 ± 128.3 ng/dl vs 559.3 ± 167.7, p < 0.001). In the subgroup analyses, BTEP and inferior/inferolateral ER patterns were significantly associated with higher testosterone levels compared with the JWP (-) population, while testosterone levels of subjects with lateral ER was not significantly higher. Electrolytes and blood chemistry values were non-significant between JWP + and - subjects. In the ROC analysis, the cut-off value for predicting the presence of a JWP on ECG was 629 ng/dl with a sensitivity of 44% and specificity of 86% [AUC = 0.66 (95% CI: 0.56-0.75), p = 0.001]. In multivariate analysis, total testosterone level > 629 ng/dl was significantly predicting a JWP on ECG, even outperforming age and hs-CRP levels with an OR of 4.57 (95% CI 1.910-10.9, p = 0.001). Conclusions: Testosterone might be associated with the male predominance observed in the JWP. More malignant inferior/inferolateral ER seems to be mainly associated with the high testosterone levels in Turkish male population. This finding might be attributed to the previously demonstrated effects of testosterone on cardiac ion-channel functions, especially outward-K channels.

Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles

Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.

Protective effect of quercetin against myocardial ischemia as a Ca2+ channel inhibitor: involvement of inhibiting contractility and Ca2+ influx via L-type Ca2+ channels.

Many studies describe the stimulating effect of quercetin on Ca2+ channels and the treatment of cardiovascular diseases such as myocardial ischemia and hypertension. However, these studies are scattered and contradictory. The aim of this study is to elucidate the protective effects of quercetin against isoproterenol (ISO)-induced myocardial ischemia and verify the cellular mechanisms based on the L-type Ca2+ channel (LTCC), Ca2+ transients, and myocardial contractility. An animal model of myocardial ischemia was established by subcutaneous injection of ISO for 2days. Quercetin significantly reduced J-point elevation, heart rate, reactive oxygen species, serum levels of myocardial enzymes, superoxide dismutase, catalase, glutathione, glutathione peroxidase, glutathione S-transferase and improved heart pathologic morphology. L-type Ca2+ current (ICa-L) was tested in an experiment with isolated rat myocardial cells by using the whole-cell patch-clamp recording technique and IonOptix Myocam detection system. Quercetin reduced ICa-L in a concentration-dependent fashion with a half-maximal inhibitory concentration of 4.67 × 10-4M. Quercetin also shifted the current-voltage curve upwards, moved the activation and inactivation curves to the left and inhibited the amplitude of the cell shortening and Ca2+ transients. The results showed that quercetin acts as a LTCC inhibitor and exerts a cardioprotective effect by inhibiting Ca2+ influx and contractility in rats.

Identifying Electrocardiogram Pattern Changes and Their Association with Echocardiography among Malaysian Footballers Attending PreParticipation Evaluation

Introduction: Sudden cardiac death is the most common medical cause of death in athletes. The aim of this study was to identify the electrocardiogram (ECG) pattern changes and its association with echocardiography among Malaysian footballers during a pre-participation evaluation (PPE). Methods: A retrospective study was conducted on footballers attending a PPE at a primary care centre. Secondary data collection was conducted and the proforma included clinical history, physical examination, ECG, Echocardiogram and cardiovascular riskfactors assessment such as heart rate, blood pressure, lipid profile, fasting blood sugar and creatinine. Data were extracted from the medical records, echocardiogram report and the original ECG. The ECG patterns were analysed according to the International consensus for ECG interpretation in athletes to determine physiological versus pathological changes. The data was analysed using SPSS v24. Results: This study included 85 male Malaysian footballers with a mean age of 20.1 ± 3.0 years. The mean resting heart rate was 55.2 ± 9.3beats per minute. Abnormal ECG changes were found in 20% of the participants, which were higher compared to that reported in other studies (14% – 17.3%). The normal ECG findings in athletes were sinus bradycardia (76.5%), J-point elevation (68.2%), prolonged PR interval (3.5%) and incomplete right bundle branch block (4.7%). The abnormal ECG changes were multiple T wave inversions (5.9%), hypertrophy (2.4%), and deep Q-waves (8.2%). Four abnormal ECGs were consistent with abnormal echocardiography findings and out of these,two ECGs with hypertrophic changes were consistent with mild inter atrial septal bulging and apical hypertrophy. Conclusions: Malaysian footballers have ECG changes that are consistent with physiological changes in athlete’s heart. The positive association between ECG and Echocardiogram findings are useful in confirming pathological ECG changes. Physicians should be trained in PPE protocol and ECG interpretation in athletes in order to improve identification of those at risk of sudden cardiac death.

Autonomic Influences Related to Early Repolarization in Patients Without Structural Heart Disease

This cross-sectional study focused on the association between heart rate variability (HRV) and early repolarization pattern (ERP). It included 1236 patients categorized into three groups: ERP type 1: J-point elevation with notched/slurred QRS; ERP type 2: ST elevation without dominant J-wave; and non-ERP group. Analyzing time-domain indexes include standard deviation of NN (normal-to-normal) RR intervals (SDNN), root mean square of successive difference in NN RR intervals (RMSSD), and proportion of consecutive NN intervals that differ by more than 50ms (PNN50), there were significant differences between any two groups (all P < 0.01). All time-domain indexes showed: ERP type 2 > ERP type 1 > non-ERP. Multivariate logistic regression analysis revealed that SDNN at nighttime and gender were independently associated with the maximum magnitude of J-point elevation ≧0.2mV. The findings strongly suggested that based on electrocardiogram characteristics, parasympathetic tone denoted by HRV may be related to different types of ERP.

Crocin protects against cardiotoxicity induced by doxorubicin through TLR-2/NF-κB signal pathway in vivo and vitro

Doxorubicin (DOX) is widely used to treat multiple of tumors, but its clinical trials are allied with some serious adverse events mainly cardiac functional abnormalities. So the objective of our investigation is to identify the cardioprotective action of crocin (CRO), a natural compound derived from saffron, against DOX-induced cardiotoxicity. CRO was injected intraperitoneally (i.p.) to rats for sixconsecutive days and DOX (i.p.) was administered on the fourth day. H9c2 cells were treated with DOX for 24 h after being pre-treated by CRO for 2 h. CROreduced tachycardiaand J-point elevation,decreased the levelsof serum creatine kinase, lactate dehydrogenase,glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase.CRO exerted positive effect on DOX-induced ROS productionand changes of oxidative stress biomarkers. CRO significantlydecreased intracellular Ca2+ concentration andincreased mitochondria membrane potentialin H9c2 cells. CRO also resisted the DOX-induced high expressionof tumor necrosis factor-αand interleukin-6, inhibitedapoptosisand improved the abnormal expression levels of Bcl-2, Bax and Caspase-3 proteins.CRO obviously restrained DOX-mediatedhigh expression of toll-like receptor-2 (TLR-2) and nuclear factor kappa-B (NF-κB) in ventricular tissue. Inbrief,CRO distinctly restrained DOX-mediated cardiotoxicity by inhibiting oxidative stress, inflammation, apoptoticandredressingcardiomyocyte calcium dyshomeostasis and mitochondria damage.These cardioprotective effects may berelated closely with the TLR2/NF-κB pathway.

ECG-based Detection and Prediction Models of Sudden Cardiac Death: Current Performances and New Perspectives on Signal Processing Techniques

Heart disease remains the main leading cause of death globally and around 50% of the patients died due to sudden cardiac death (SCD). Early detection and prediction of SCD have become an important topic of research and it is crucial for cardiac patient’s survival. Electrocardiography (ECG) has always been the first screening method for patient with cardiac complaints and it is proven as an important predictor of SCD. ECG parameters such as RR interval, QT duration, QRS complex curve, J-point elevation and T-wave alternan are found effective in differentiating normal and SCD subjects. The objectives of this paper are to give an overview of SCD and to analyze multiple important ECG-based SCD detection and prediction models in terms of processing techniques and performance wise. Detail discussions are made in four major stages of the models developed including ECG data, signal pre-processing and processing techniques as well as classification methods. Heart rate variability (HRV) is found as an important SCD predictor as it is widely used in detecting or predicting SCD. Studies showed the possibility of SCD to be detected as early as one hour prior to the event using linear and non-linear features of HRV. Currently, up to 3 hours of analysis has been carried out. However, the best prediction models are only able to detect SCD at 6 minutes before the event with acceptable accuracy of 92.77%. A few arguments and recommendation in terms of data preparation, processing and classification techniques, as well as utilizing photoplethysmography with ECG are pointed out in this paper so that future analysis can be done with better accuracy of SCD detection accuracy.

Impact of age and sex on the long-term prognosis associated with early repolarization in the general population

Early repolarization (ER) has been linked to the risk of sudden cardiac death (SCD) in the general population, although controversy remains regarding risks across various subgroups. The purpose of this study was to investigate whether age and sex influence the prognostic significance of ER. We evaluated the 12-lead electrocardiograms of 6631 Finnish general population subjects age ≥30 years (mean age 50.1 ± 13.9 years; 44.5% men) for the presence of ER (J-point elevation ≥0.1 mV in ≥2 inferior/lateral leads) and followed them for 24.4 ± 10.3 years. We analyzed the association between ER and the risk of SCD, cardiac death, and all-cause mortality in subgroups according to age (<50 or ≥50 years) and sex. ER was present in 367 of the 3305 subjects age <50 years and in 426 of 3326 subjects ≥50 years. ER was not associated with any of the endpoints in the entire study population. After adjusting for clinical factors, ER was associated with SCD (hazard ratio [HR] 1.88; 95% confidence interval [CI] 1.16-3.07) in subjects <50 but not in older subjects (interaction between ER and age group, P = .048). In the younger subgroup, women with ER had a high risk of SCD (HR 4.11; 95% CI 1.41-12.03), whereas among men ER was not associated with SCD. Finally, ER was not associated with cardiac mortality or all-cause mortality in either age group. ER is associated with SCD in subjects younger than 50 years, particularly in women, but not in subjects 50 years and older.

P3827Low dose of quinidine is effective to normalize the slow inactivation in mutant Kv4.3 channel identified in an early repolarization syndrome patient

Abstract Background Early repolarization syndrome (ERS) is characterized by J-point elevation in the ECG and ventricular fibrillation (VF). Several mutations in genes encoding cardiac ion channels have been reported as the causes for ERS. For the treatment of ERS, clinical studies have shown that quinidine is effective for the suppression of electrical storm. However, the mechanism or the optimal concentration for quinidine to suppress the electrical storm has not been elucidated yet. Purpose The aim of the present study is to clarify pharmacological effect of quinidine on mutant Kv4.3 channel by electrophysiological analysis and to establish theoretically effective treatment for ERS. Methods A KCND3 mutation, p.G306A, identified heterozygously in a 12-year-old boy was examined by whole-cell patch-clamp methods using CHO cells. We performed functional analysis of the Kv4.3 channels encoded by KCND3 of wild-type (WT), heterozygous (WT/G306A), or homozygous (G306A) mutants. Pharmacological normalizing effects of quinidine to the WT and mutant channels were investigated by loading test in various concentration. The sensitivity of quinidine was evaluated in terms of the concentration of the clinical course and the loading test. Results The patient suffered VF while sleeping or under sedation. Significant J-point elevations in multiple leads were recorded and he was diagnosed as ERS. Quinidine administration in the serum concentration of 1.2 to 3.1 μM was effective to stop his VF storm. Mutant Kv4.3 currents showed significantly slow inactivation time course (Fig 1), which meant that the mutation caused the gain-of-function channel. Quinidine loading to the mutant Kv4.3 normalized the inactivation time course in concentration-dependent manner (Fig 2, 3). In the loading concentration of 1 μM, the peak currents were not changed regardless of the voltage (Fig 4). The optimal serum concentration of quinidine in clinical use as multi-ion-channels blocker is 6 to 15 μM and the concentration was higher than that of the patient to stop the VF storm. The electrophysiological analysis showed that the low dose loading of quinidine was effective to prevent the gain-of function change of mutant Kv4.3 channels. Electrophysiological analysis Conclusions We showed the pharmacological mechanism of quinidine against the mutant Kv4.3 channels identified in an ERS patient. Even the low concentration of quinidine was effective to normalize the slow inactivation, gain-of-function, in mutant Kv4.3 channels. Our data would be helpful to confirm the optimal concentration of quinidine for ERS patients to avoid adverse effect.

P6585Number of ECG leads and prognosis of spontaneous type 1 Brugada syndrome

Abstract Introduction Brugada syndrome (BrS) is an inherited arrhythmia syndrome with an increased risk of sudden cardiac death (SCD). The recent single lead-based diagnosis of Brugada syndrome recommended criterion may lead to overdiagnosis of Brugada syndrome and overestimation of the risk of SCD. Objective We aim to investigate the value of a single lead diagnosis in spontaneous type 1 ECG Brugada patient and to investigate the association between the number of ECG leads with a spontaneous type 1 ST elevation and the arrhythmic risk. Methods Consecutive patients affected with BrS were recruited in a multicentric prospective registry in France (15 centers) between 1994 and 2016. A total of 1613 patients affected by the Brugada syndrome were enrolled. For this specific study, only patient with a spontaneous type 1 BrS were enrolled (n=505). Data were prospectively collected with an average follow-up of 6.5±4.7 years. ECGs were reviewed by 2 physicians blinded to clinical status. Type 1 ST elevation was defined by ≥2 mm J-point elevation with coved ST segment and negative T wave. Results A total of 505 patients with a spontaneous type 1 BrS (mean age 46±15 years, 398 males, 79%) were enrolled. 117 patients (23%) were symptomatic at baseline (32 (6%) aborted SCD, 85 (17%) syncope). Implantable cardiac defibrillator (ICD) was implanted in 191 patients (38%). Brugada ECG pattern was found in 1 lead in 250 patients (50%, group 1), in 2 leads in 227 patients (45%, group 2) and in 3 leads in 28 patients (5%, group 3). Groups were comparable in term of clinical presentation except for group 3 who presented more frequently an early repolarization pattern (n=19 (8%) in group 1, n=15 in group 2 (6%) and n=7 (25%) in group 3, p=0.02) and more frequently QRS fragmentation (n=6 (2%) in group 1, n=3 in group 2 (1%) and n=3 (11%) in group 3, p=0.03). During follow-up, 46 (9%) patients presented an arrhythmic event: 22 (9%) in group 1 (4 SCD, 14 appropriate ICD therapy, 4 ventricular arrhythmias), 22 (10%) in group 2 (6 SCD, 11 appropriate ICD therapy, 5 ventricular arrhythmias) and 2 (7%) in group 3 (1 SCD, 1 appropriate ICD therapy). Patients with type 1 BrS pattern in 2 or 3 ECG leads had not a significantly higher rate of arrhythmic events than patients with type 1 BrS pattern in only 1 ECG lead (HR: 1.1; 95% CI: 0.6–1.9 for group 2 and HR: 0.7; 95% CI: 0.2–3 for group 2; p=0,087). Conclusion In the largest cohort of BrS patients ever described, the prognosis of Brugada syndrome with a spontaneous ECG pattern does not appear to be affected by the number of leads required for diagnostic.

P6588Impact of age and sex on the long-term prognosis associated with early repolarization in the general population

Abstract Background Early repolarization (ER) in the electrocardiogram (ECG) has been associated with increased sudden cardiac death (SCD) risk in the general population. However, controversy remains about the risk associated with ER in different population subgroups. Purpose We evaluated whether age and sex affect the prognostic significance of ER in general population subjects. Methods The study population consisted of Finnish general population subjects aged over 30 years participating in the Mini-Finland Health Survey in 1978–80. Subjects underwent extensive baseline health examinations including a resting 12-lead ECG and were followed for 24±10 years. After excluding ECGs with QRS duration &gt;110ms, the presence of ER (J-point elevation ≥0.1 mV in ≥2 inferior/lateral leads) was assessed from the remaining 6,631 subjects. The association between ER and SCD risk was analysed in subgroups according to age (&lt;50 years or ≥50 years) and sex by using the Cox proportional hazards model. Effect modification of ER by age group and by sex was tested using the Wald test. Results ER was present in 250 (15.7%) of the 1,592 male subjects aged &lt;50 years, 117 (6.8%) of the 1,713 female subjects aged &lt;50 years, 182 (13.4%) of the 1,362 male subjects aged ≥50 years, and 244 (12.4%) of the 1,964 female subjects aged ≥50 years. There was a significant interaction between age group and ER (p=0.011). Among subjects aged &lt;50 years, ER was associated with SCD risk after adjusting for age, sex, blood pressure, body mass index, serum cholesterol, coronary artery disease, diabetes, and active smoking (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.09–2.92; p=0.021), whereas in subjects aged ≥50 years ER was not associated with increased risk of SCD. Particularly female subjects aged &lt;50 years with ER had a high risk of SCD (HR 4.85; 95% CI 1.65–14.29; p=0.004) in the multivariate analysis, whereas among &lt;50-year-old male subjects ER was not associated with SCD (p=0.024 for interaction between sex and ER). Conclusion Our results suggest that among adults &lt;50 years old, and especially among &lt;50-year-old women, ER is associated with increased SCD risk, whereas among older subjects ER is not associated with SCD. Future research should focus on identifying the factors accounting for the difference between the age groups and to improve the risk stratification in the younger female patient populations with ER. Acknowledgement/Funding Aarne Koskelo foundation and Paavo Ilmari Ahvenainen Foundation

Impact of Ethnicity on the Prevalence of Early Repolarization Pattern in Children: Comparison Between Caucasian and African Populations

The patterns and prevalence of early repolarization pattern (ER) in pediatric populations from ethnic backgrounds other than Caucasian have not been determined. Black African children (ages 4-12) from north-west Madagascar were prospectively recruited and their ECGs compared with those of age- and sex-matched Caucasian ethnicity individuals. ER was defined by ≥ 0.1mV J-point elevation in at least two contiguous inferior and/or lateral ECG leads. A total of 616 children were included. There was a trend toward a higher frequency of ER in the Africans compared to the Caucasians (23.3% vs. 17.1%, respectively, p = 0.053). The subtype (slurred vs. notched) and location of ER (lateral, inferior, or inferior-lateral) were significantly different in the two groups (p < 0.001 and p = 0.020, respectively). There was no significant difference in the number of high-risk ECG features of ERP (i.e., horizontal/descendent pattern, inferior or inferior-lateral location or J-waves ≥ 2mm) between African and Caucasian children. On the multivariate analysis, African ethnicity was an independent predictive factor of ER (OR 3.57, 95% CI 2.04-6.25, p < 0.001). African children have an increased risk of ER compared to Caucasian counterparts. Future studies should clarify the clinical and prognostic significance of ER in the pediatric population, and whether ethnicity has an impact on the outcomes.

Crocin attenuates isoprenaline-induced myocardial fibrosis by targeting TLR4/NF-κB signaling: connecting oxidative stress, inflammation, and apoptosis.

Crocin is isolated from saffron and has multiple activities. There are many reports on its beneficial effects for cardiovascular disease, but crocin's effects on anti-myocardial fibrosis have not yet been reported. This study investigated crocin's effects and potential mechanisms on isoproterenol (ISO)-induced myocardial fibrosis (MF) in mice. Mice were infused intraperitoneally with crocin with concurrent ISO subcutaneous injections over 2weeks. Electrocardiography, cardiac weight index (CWI), hydroxyproline content, and heart morphology changes were observed. Administration of crocin markedly decreased heart rate, J-point elevation, QRS interval, CWI, and hydroxyproline content in the myocardial tissues, and improved heart pathologic morphology. Versus the control group, the ISO group showed an increase in lactate dehydrogenase and creatine kinase activities and malondialdehyde content. Meanwhile, superoxide dismutase, catalase, and glutathione contents decreased in the ISO group; crocin caused a significant reduction in oxidative stress levels in ISO-induced MF. ISO led to a significant increase in interleukin-1 and -6 and tumor necrosis factor-α in addition to nuclear factor kappa B (NF-κB) (p65) and toll-like receptor (TLR) 4 expressions. Crocin treatment suppressed these inflammatory cytokine expressions. Moreover, crocin treatment caused a significant decrease in connective tissue growth factor and transforming growth factor-β1 mRNA levels in addition to a decrease in B cell lymphoma-2, Bcl-2-associated X protein, caspase-3, and cleaved caspase-3 expressions. Crocin has a protective effect on ISO-induced MF, which may be associated with the TLR4/NF-κB (p65) signal transduction pathway.

Left ventricular geometry correlates with early repolarization pattern in adolescent athletes.

Some forms of early ECG repolarization QRS pattern (ERp) with J-point elevation of 0.1mV in two contiguous inferior and/or lateral leads with or without ST-elevation are potentially associated with a higher arrhythmic risk in adults. We assessed the prevalence of ERp among non-professional adolescent athletes and correlated it with age, sex, ethnicity, and structural and electric cardiac parameters. We retrospectively analyzed 414 ECGs obtained from young athletes referred to our center from 2006 to 2017. We found ERp in 22% of cases. In the ERp group, we found a greater percentage of black athletes, a higher systolic blood pressure, and lower heart rate (HR) compared with the group without ERp. This pattern was less frequent in female athletes. In athletes with ERp, the occurrence of ventricular ectopic beats was less frequent and QRS-duration was shorter. They also exhibited greater (a) ECG-based left ventricular hypertrophy (LVH), (b) left ventricular mass, and (c) relative wall thickness (RWT), suggesting a tendency to concentric geometry. At logistic regression analysis, we found that HR (OR 0.98 [0.96-0.99] P=.013), QRS-duration (OR 0.96 [0.94-0.99], P=.003), LVH (OR 1.09 [1.05-1.12], P<.001), and RWT (OR 1.08 [1.01-1.16] P=.032) were significant predictors of ERp incidence. ERp is quite common in adolescent athletes and correlates with concentric LV remodeling. Specific clinical and ECG-findings related to training such as lower HR, LVH, and QRS-duration are also predictors of ERp. In adolescent non-professional athletes, ERp is a benign finding associated with some structural and electric cardiac modifications induced by training.

A de novo gain-of-function KCND3 mutation in early repolarization syndrome

Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (Ito) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the Ito channel, is considered as one of target genes. The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis. We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-clamp methods. A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms. A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased Ito. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment.

The association of subclinical inflammation and early repolarization patterns observed in healthy Turkish males

Objective: Early repolarization pattern (ER) on surface ECG has recently been associated with an increased risk of sudden cardiac death (SCD) due to lethal ventricular arrhythmias. Inflammatory markers such as high-sensitive-C-reactive peptide (hs-CRP) have been linked with an increased risk of SCD and cardiac morbidity in numerous publications for various cardiovascular settings. However, data about the relationship between the inflammatory markers and ER is scarce. We sought to evaluate the relationship of subclinical inflammatory markers and the presence of ER on healthy Turkish males. Materials and Methods: 180 healthy male volunteers between ≥18 to ≤50 years old without any cardiac/systemic disorders were evaluated for our study. Supine surface ECG, complete blood count, hs-CRP, Erythrocyte sedimentation rate (ESR) and serum electrolytes were obtained. Subjects with complete-bundle-branch-blocks, non-sinus-rhythms and any abnormality on cardiac examination were excluded. ER was defined as J-point elevation of ≥0.1 mV in ≥2 leads in the inferior (II, III, aVF) (Inferior ER), lateral (DI, aVL, V4–6) (Lateral ER) or both (Inferolateral ER) leads. Results: 172 subjects (mean age 34,9±7,9 years) were included in our analyses. 45 ER (26%) was detected. 22 of them were lateral (49%), 13 was inferior (29%) and 10 of them were (22%) inferolateral ER. ER+ subjects had significantly higher hs-CRP levels (mg/dl, mean ±SD) (ER- 1.7±1.8 vs ER+ 3.1±2.9 , p<0.01). No significant association could be demonstrated with other inflammatory parameters. In the subgroup analyses, only inferior ER was significantly associated with higher hs-CRP levels compared with the ER - population, while hs-CRP levels of subjects with lateral and infero-lateral ER was not significantly higher (ER- 1.7±1.8 vs Inferior ER 4.5 ± 3.1 , p<0,01). In multivariate analyses, high hs-CRP levels were significantly predicting the presence of ER (Odds ratio: 1,24; %95 CI: 1,06 - 1,46; p = 0,008). Conclusions: Subclinical inflammation might influence the prevalence of ER on young healthy males. Suggestively more malignant Inferior ER seems to be mainly associated with the high hs-CRP levels in Turkish male population. This finding might be attributed to the experimentally demonstrated effects of inflammation on various cardiac ion channel functions taking part in the cardiac action potential.

Mechanisms underlying the cardio-protection of total ginsenosides against myocardial ischemia in rats in vivo and in vitro: Possible involvement of L-type Ca2+ channels, contractility and Ca2+ homeostasis

Here we aimed to observe the effects of total ginsenosides (TG) against isoproterenol (ISO) induced myocardial ischemia (MI) and to explore its underlying mechanisms based on L-type Ca2+ current (ICa-L), intracellular Ca2+ ([Ca2+]i) and contraction in isolated rat myocytes. Rat model of MI was induced by subcutaneously injection of ISO (85 mg/kg) for 2 consecutive days. J-point elevation, heart rate, serum levels of creatine kinase (CK) and lactated dehydrogenase (LDH), and heart morphology changes were observed. Influences of TG on ICa-L, [Ca2+]i and contraction in isolated rat myocytes were observed by the patch-clamp technique and IonOptix detection system. TG significantly reduced J-point elevation, heart rate, serum levels of CK and LDH, and improved heart pathologic morphology. TG decreased ICa-L in concentration-dependent manner with a half-maximal inhibitory concentration (IC50) of 31.65 μg/mL. TG (300 μg/mL) decreased ICa-L of normal and ischemic ventricular myocytes by 64.33 ± 1.28% and 61.29 ± 1.38% respectively. At 30 μg/mL, TG reduced Ca2+ transient by 21.67 ± 0.94% and cell shortening by 38.43 ± 6.49%. This study showed that TG displayed cardioprotective effects on ISO-induced MI rats and the underlying mechanisms may be related to inhibition of ICa-L, damping of [Ca2+]i and decrease of contractility.