Prolongation Of Cardiac Repolarization Research Articles

Effects of Anesthetics on Cardiac Repolarization in Adults: A Network Meta-Analysis of Randomized Clinical Trials.

Prolongation of cardiac repolarization, especially the heart rate-corrected QT (QTc) interval, is associated with life-threatening dysrhythmias. This study aimed to identify the anesthetic with the lowest risk of prolonging cardiac repolarization and provide guidance for anesthesia management in patients with cardiac diseases or long QT syndrome. Randomized controlled trials (RCTs) comparing the effects of anesthetics on cardiac repolarization indices were searched for in multiple databases. The primary outcome was QTc; and the secondary outcomes were other repolarization indices. A network meta-analysis was conducted using a frequentist approach and registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022304970). Thirteen RCTs investigating 953 adults with normal QTc interval and without cardiovascular diseases were included. Direct meta-analyses found that propofol had less influence than sevoflurane (95% confidence interval (CI): 16.10, 33.54) and desflurane (95% CI: 4.85, 35.36), and sevoflurane had less influence than desflurane (95% CI: 6.96, 19.39) on QTc prolongation. Network analysis found that propofol had less influence than sevoflurane (95% CI: 17.78, 29.63), halothane (95% CI: 11.29, 41.24), desflurane (95% CI: 23.79, 39.88), and isoflurane (95% CI: 20.11, 46.10), and sevoflurane had less influence than desflurane (95% CI: 0.43, 15.82) on QTc prolongation. The rank order of cumulative ranking curve analysis was propofol (100%), sevoflurane (63.8%), halothane (49.5%), desflurane (21.1%), and isoflurane (15.6%). The direct meta-analysis found that propofol had less influence than sevoflurane on QT prolongation (95% CI: 23.12, 57.86). Other secondary outcomes showed no conclusive findings. This meta-analysis found that propofol had a minimal effect on QTc prolongation, followed by sevoflurane and desflurane in adults with normal QTc interval and without cardiovascular diseases. Propofol is the best anesthetic for adult patients with long QT syndrome or cardiac diseases, but still needs more robust evidence.

Determining the role of the unique N-terminal 1b domain in the gating of heterotetrameric hERG1a/hERG1b potassium channels.

Two isoforms of hERG (human Ether-a-go-go-Related Gene) potassium channel, hERG1a and hERG1b, associate in the heart to form the rapid delayed rectifier current (IKr), which is primarily responsible for repolarizing cardiac action potentials. Inherited mutations in both hERG1a and hERG1b cause Long QT Syndrome type 2 (LQT2), marked by prolonged cardiac repolarization and sudden death arrhythmia. The assembly of hERG1a subunits with hERG1b subunits increases the number of hERG1b subunits at the plasma membrane, but the mechanism by which hERG1a enhances hERG1b is not completely understood. Recently, it was reported that when expressed in trans, the hERG1a N-terminal region markedly increased hERG1b currents and increased biotin-labelled hERG1b protein at the plasma membrane surface. A direct structural interaction between the hERG1a N-terminal residues 216-220 and the hERG1b N-terminal region was characterized and proposed to be necessary for the upregulation of hERG1b (Johnson, Crawford, and Trudeau, 2022). However, hERG1b channels with a deletion of the unique N-terminal 1b domain did not have a measurable increase in current density or in biotinylated protein when co-expressed with hERG1a N-terminal region pieces. This indicates that the 1b domain is required for the increase in hERG1b by hERG1a. Interestingly, the 1b domain-deleted hERG1b channels displayed a large leftward shift in the voltage dependence of activation when co-expressed with the full hERG1a N-terminal region. This is unexpected, as the 1b domain was not previously considered as a determinant of hERG gating. Here, we will investigate the mechanism of this large leftward shift and determine the role of the 1b domain in the gating properties of hERG1a/hERG1b heterotetrameric channels.

Increasing Daily Physical Activity and Its Effects on QTc Time in Severe to Very Severe COPD: A Secondary Analysis of a Randomised Controlled Trial

Approximately, half of COPD patients die from cardiovascular diseases. A prolongation of cardiac repolarization (measured as QTc interval) is associated with cardiovascular events or cardiovascular deaths in populations of older adults and COPD. One way to reduce the QTc could be to increase physical activity (PA). We investigated whether QTc can be reduced by an increase in PA in patients with severe COPD. This is a secondary outcome analysis from a randomized controlled trial investigating the effects of a 3 months pedometer based program to improve PA. 12-lead ECG was assessed at baseline and after 3 months. We measured PA using a validated triaxial accelerometer. Data were analyzed from 59 participants. Multiple regression modeling, including adjustment for baseline QTc, sex, QT prolonging medications, BMI, smoking status and FEV1%, showed no evidence for an association between an improvement of ≥15% PA and QTc reduction. A 15% improvement in PA according to step counts over 3 months seems not to reduce QTc interval by its MCID of 20 ms in patients with severe to very severe COPD.

The N-linker region of hERG1a upregulates hERG1b potassium channels

A major physiological role of hERG1 (human Ether-á-go-go-Related Gene 1) potassium channels is to repolarize cardiac action potentials. Two isoforms, hERG1a and hERG1b, associate to form the potassium current IKr in cardiomyocytes. Inherited mutations in hERG1a or hERG1b cause prolonged cardiac repolarization, long QT syndrome, and sudden death arrhythmia. hERG1a subunits assemble with and enhance the number of hERG1b subunits at the plasma membrane, but the mechanism for the increase in hERG1b by hERG1a is not well understood. Here, we report that the hERG1a N-terminal region expressed in trans with hERG1b markedly increased hERG1b currents and increased biotin-labeled hERG1b protein at the membrane surface. hERG1b channels with a deletion of the N-terminal 1b domain did not have a measurable increase in current or biotinylated protein when coexpressed with hERG1a N-terminal regions, indicating that the 1b domain was required for the increase in hERG1b. Using a biochemical pull-down interaction assay and a FRET hybridization experiment, we detected a direct interaction between the hERG1a N-terminal region and the hERG1b N-terminal region. Using engineered deletions and alanine mutagenesis, we identified a short span of amino acids at positions 216 to 220 within the hERG1a “N-linker” region that were necessary for the upregulation of hERG1b. We propose that direct structural interactions between the hERG1a N-linker region and the hERG1b 1b domain increase hERG1b at the plasma membrane. Mechanisms regulating hERG1a and hERG1b are likely critical for cardiac function, may be disrupted by long QT syndrome mutants, and serve as potential targets for therapeutics.

Comparison of Tp-e Interval Between Obese and Healthy Children in Adolescence and its Correlation with Insulin Resistance in Obese Children

Background: Prolonged cardiac repolarization may increase cardiovascular susceptibility to ventricular arrhythmias, leading to sudden cardiac death. This condition in obese children is not clearly demonstrated in childhood. Objectives: This study aimed to investigate the effect of obesity on cardiac electrical activity in children by comparing Tp-e intervals between obese and healthy children and evaluating the correlation between Tp-e intervals and insulin resistance in obese children. Methods: The study enrolled 50 obese and 50 healthy children. A pediatric cardiologist assessed electrocardiograms and echocardiographs. Electrocardiographic, demographic, and laboratory parameters were analyzed statistically. Results: There was no statistically significant difference between the two groups in age and gender (P > 0.05). The Tp-e intervals were statistically higher in the obese group than in the control group (P = 0.001). A statistically significant difference was found between the obese group with or without insulin resistance and the control group in Tp-e intervals (P = 0.001 for all). All other ECG parameters were similar in the patient and control groups. Conclusions: It is essential to recognize the early symptoms of future cardiovascular events in childhood obesity cases. Repolarization differences in obese children, when compared with the normal population, may reflect obesity-related early-stage subclinical findings. Prospective broad-based studies are needed to recognize these early changes.

Metformin Reduces Potassium Currents and Prolongs Repolarization in Non-Diabetic Heart.

Metformin is the first choice drug for the treatment of type 2 diabetes due to positive results in reducing hyperglycaemia and insulin resistance. However, diabetic patients have higher risk of ventricular arrhythmia and sudden cardiac death, and metformin failed to reduce ventricular arrhythmia in clinical trials. In order to explore the mechanisms responsible for the lack of protective effect, we investigated in vivo the effect of metformin on cardiac electrical activity in non-diabetic rats; and in vitro in isolated ventricular myocytes, HEK293 cells expressing the hERG channel and human induced pluripotent stem cells derived cardiomyocytes (hIPS-CMs). Surface electrocardiograms showed that long-term metformin treatment (7 weeks) at therapeutic doses prolonged cardiac repolarization, reflected as QT and QTc interval duration, and increased ventricular arrhythmia during the caffeine/dobutamine challenge. Patch-clamp recordings in ventricular myocytes isolated from treated animals showed that the cellular mechanism is a reduction in the cardiac transient outward potassium current (Ito). In vitro, incubation with metformin for 24 h also reduced Ito, prolonged action potential duration, and increased spontaneous contractions in ventricular myocytes isolated from control rats. Metformin incubation also reduced IhERG in HEK293 cells. Finally, metformin incubation prolonged action potential duration at 30% and 90% of repolarization in hIPS-CMs, which is compatible with the reduction of Ito and IhERG. Our results show that metformin directly modifies the electrical behavior of the normal heart. The mechanism consists in the inhibition of repolarizing currents and the subsequent decrease in repolarization capacity, which prolongs AP and QTc duration.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Postmarketing pharmacovigilance: Remdesivir and cardiovascular events.

Thyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes

Prolongation of cardiac repolarization (QT interval) represents a dangerous and potentially life-threatening electrical event affecting the heart. Thyroid hormones (THs) are critical for cardiac development and heart function. However, little is known about THs influence on ventricular repolarization and controversial effects on QT prolongation are reported. Human iPSC-derived cardiomyocytes (hiPSC-CMs) and multielectrode array (MEA) systems were used to investigate the influence of 3,3′,5-triiodo-l-Thyronine (T3) and 3,3′,5,5′-tetraiodo-l-Thyronine (T4) on corrected Field Potential Duration (FPDc), the in vitro analog of QT interval, and on local extracellular Action Potential Duration (APD). Treatment with high THs doses induces a significant prolongation of both FPDc and APD, with the strongest increase reached after 24 h exposure. Preincubation with reverse T3 (rT3), a specific antagonist for nuclear TH receptor binding, significantly reduces T3 effects on FPDc, suggesting a TRs-mediated transcriptional mechanism. RNA-seq analysis showed significant deregulation in genes involved in cardiac repolarization pathways, including several QT-interval related genes. In conclusion, long-time administration of high THs doses induces FPDc prolongation in hiPSC-CMs probably through the modulation of genes linked to QT-interval regulation. These results open the way to investigate new potential diagnostic biomarkers and specific targeted therapies for cardiac repolarization dysfunctions.

Molecular and Electrophysiological Role of Diabetes-Associated Circulating Inflammatory Factors in Cardiac Arrhythmia Remodeling in a Metabolic-Induced Model of Type 2 Diabetic Rat.

Background: Diabetic patients have prolonged cardiac repolarization and higher risk of arrhythmia. Besides, diabetes activates the innate immune system, resulting in higher levels of plasmatic cytokines, which are described to prolong ventricular repolarization. Methods: We characterize a metabolic model of type 2 diabetes (T2D) with prolonged cardiac repolarization. Sprague-Dawley rats were fed on a high-fat diet (45% Kcal from fat) for 6 weeks, and a low dose of streptozotozin intraperitoneally injected at week 2. Body weight and fasting blood glucose were measured and electrocardiograms of conscious animals were recorded weekly. Plasmatic lipid profile, insulin, cytokines, and arrhythmia susceptibility were determined at the end of the experimental period. Outward K+ currents and action potentials were recorded in isolated ventricular myocytes by patch-clamp. Results: T2D animals showed insulin resistance, hyperglycemia, and elevated levels of plasma cholesterol, triglycerides, TNFα, and IL-1b. They also developed bradycardia and prolonged QTc-interval duration that resulted in increased susceptibility to severe ventricular tachycardia under cardiac challenge. Action potential duration (APD) was prolonged in control cardiomyocytes incubated 24 h with plasma isolated from diabetic rats. However, adding TNFα and IL-1b receptor blockers to the serum of diabetic animals prevented the increased APD. Conclusions: The elevation of the circulating levels of TNFα and IL-1b are responsible for impaired ventricular repolarization and higher susceptibility to cardiac arrhythmia in our metabolic model of T2D.

The short-chain fatty acid propionate improved ventricular electrical remodeling in a rat model with myocardial infarction.

The short-chain fatty acid (SCFA) propionate (C3), a microorganism metabolite produced by gut microbial fermentation, has parasympathetic-activation effects. The cardiac autonomic rebalancing strategy is considered as an important therapeutic approach to myocardial infarction (MI)-produced ventricular arrhythmias (VAs). Thus, our research was designed to clarify the potential functions of the SCFA propionate in VAs and cardiac electrophysiology in MI rats. A hundred adult Sprague-Dawley rats were allocated to four groups: the sham group (200 mM sodium chloride), the sham + C3 group (200 mM propionate), the MI group (200 mM sodium chloride) and the MI + C3 group (200 mM propionate). In comparison with the sham group, propionate significantly increased the parasympathetic components heart rate variability (HRV) and acetylcholine levels, prolonged cardiac repolarization, induced STAT3 phosphorylation and up-regulated the c-fos expression in nodose ganglia and solitary nucleus. Propionate intake reduced the susceptibility to VAs. MI induced by coronary ligation caused a significant increase in the sympathetic components HRV, abnormal repolarization, global repolarization dispersion, norepinephrine and inflammatory cytokines, reduction and redistribution of Connexin 43 in the infarcted border zone, and activation of NFκB, which were attenuated in the MI + C3 group. Oral propionate supplementation, as a nutritional intervention, protected the heart against MI-induced VAs and cardiac electrophysiology instability partly by parasympathetic activation based on the gut-brain axis.

Propofol abolishes torsade de pointes in different models of acquired long QT syndrome

There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to elucidate the risk of propofol-induced TdP and to investigate the impact of propofol in drug-induced long QT syndrome. 35 rabbit hearts were perfused employing a Langendorff-setup. 10 hearts were perfused with increasing concentrations of propofol (50, 75, 100 µM). Propofol abbreviated action potential duration (APD90) in a concentration-dependent manner without altering spatial dispersion of repolarization (SDR). Consequently, no proarrhythmic effects of propofol were observed. In 12 further hearts, erythromycin was employed to induce prolongation of cardiac repolarization. Erythromycin led to an amplification of SDR and triggered 36 episodes of TdP. Additional infusion of propofol abbreviated repolarization and reduced SDR. No episodes of TdP were observed with propofol. Similarly, ondansetron prolonged cardiac repolarization in another 13 hearts. SDR was increased and 36 episodes of TdP occurred. With additional propofol infusion, repolarization was abbreviated, SDR reduced and triggered activity abolished. In this experimental whole-heart study, propofol abbreviated repolarization without triggering TdP. On the contrary, propofol reversed prolongation of repolarization caused by erythromycin or ondansetron, reduced SDR and thereby eliminated drug-induced TdP.

KCNQ1 Antibodies for Immunotherapy of Long QT Syndrome Type 2

BackgroundPatients with long QT syndrome (LQTS) are predisposed to life-threatening arrhythmias. A delay in cardiac repolarization is characteristic of the disease. Pharmacotherapy, implantable cardioverter-defibrillators, and left cardiac sympathetic denervation are part of the current treatment options, but no targeted therapy for LQTS exists to date. Previous studies indicate that induced autoimmunity against the voltage-gated KCNQ1 K+ channels accelerates cardiac repolarization. ObjectivesHowever, a causative relationship between KCNQ1 antibodies and the observed electrophysiological effects has never been demonstrated, and thus presents the aim of this study. MethodsThe authors purified KCNQ1 antibodies and performed whole-cell patch clamp experiments as well as single-channel recordings on Chinese hamster ovary cells overexpressing IKs channels. The effect of purified KCNQ1 antibodies on human cardiomyocytes derived from induced pluripotent stem cells was then studied. ResultsThe study demonstrated that KCNQ1 antibodies underlie the previously observed increase in repolarizing IKs current. The antibodies shift the voltage dependence of activation and slow the deactivation of IKs. At the single-channel level, KCNQ1 antibodies increase the open time and probability of the channel. In models of LQTS type 2 (LQTS2) using human induced pluripotent stem cell-derived cardiomyocytes, KCNQ1 antibodies reverse the prolonged cardiac repolarization and abolish arrhythmic activities. ConclusionsHere, the authors provide the first direct evidence that KCNQ1 antibodies act as agonists on IKs channels. Moreover, KCNQ1 antibodies were able to restore alterations in cardiac repolarization and most importantly to suppress arrhythmias in LQTS2. KCNQ1 antibody therapy may thus present a novel promising therapeutic approach for LQTS2.

THE SCN5A VARIANT C683R RESULTS IN A GAIN-OF-FUNCTION OF THE CARDIAC SODIUM CURRENT (NAV1.5) WITH ADRENERGIC MODULATION

Congenital Long QT syndrome (LQTS) is an inherited arrhythmia characterized by prolonged cardiac repolarization that may result in torsades de pointes and sudden cardiac death. Gain-of-function variants of the SCN5A gene, encoding the cardiac sodium channel Nav1.5; INa, underlie nearly 10% of LQTS and cause LQT3. In LQT3 patients, bradycardia and low sympathetic tone (associated with sleep and rest) have been considered to trigger the arrhythmias. Recently, a novel SCN5A variant (C683R) was identified in two unrelated patients with personal/family history of prolonged QT and sudden cardiac arrest. Paradoxically, C683R-associated arrhythmias in these two patients have only been observed during hyperadrenergic states. We therefore conducted a functional study to characterize the electrophysiological effects of the SCN5A C683R variant on Nav1.5 current in a cellular model. The C683R SCN5A variant was engineered into the pcDNA1 vector by using site-directed mutagenesis. Wild-Type (WT) or C683R SCN5A cDNA was transfected into tsA201 cells, along with the human Nav1.5 channel ß1-subunit. Electrophysiological characterization of the C683R variant was performed using the whole cell patch-clamp technique. The selective protein kinase A (PKA) activator 8-CPT-cAMP 50 μM was used in the pipette solution to mimic the effect of epinephrine on either WT or C683R Nav1.5 currents. The C683R variant did not generate any persistent (late) Nav1.5 current when compared to WT. It did not cause any significant change on recovery from inactivation vs WT nor on both steady-state and slow inactivation. However, the C683R variant increased maximal Nav1.5 current density from 341±64 to 766±103 pA/pF when compared to WT (p < 0.05, n≥9) and the midpoint of activation voltage (V½) was negatively shifted from -57.18±1.24 to -63.63±1.40 mV (p < 0.001 vs WT). Moreover, when exposed to the PKA activator 8-CPT-cAMP 50 μM, the C683R variant showed a greater maximal Nav1.5 current density than WT; 993±100 vs 645±137 pA/pF (p < 0.05, n≥6). Our observations suggest a gain-of-function of the Nav1.5 current in the C683R variant compared to the WT protein. This gain of function may be further enhanced upon stimulation with catecholamines. The C683R variant of SCN5A results in a significant gain of function of the Nav1.5 current with increased responsiveness to adrenergic stimulation. Our observations provide a likely explanation for the unusual phenotype in carriers of the C683R variant that is characterized by epinephrine-triggered ventricular arrhythmias. The electrophysiological properties are different from conventional LQT3 and may represent a distinct inherited arrhythmia syndrome.

Comment: postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2-Authors' reply.

Comment: postpartum hormones oxytocin and prolactin cause pro-arrhythmic prolongation of cardiac repolarization in long QT syndrome type 2-Authors' reply.

Cardiac repolarization evolves differently during the course of benign and disabling multiple sclerosis

BackgroundCardiac repolarization is modulated by the autonomic nervous system. Even though multiple sclerosis associates with prolonged cardiac repolarization the physiology responsible for the phenomenon remains unknown. ObjectiveTo study in longitudinal setting whether the patients with confirmed benign and disabling outcome of relapsing-remitting multiple sclerosis (RRMS) differ in regard to changes of cardiac repolarization. MethodsTotal of 43 patients, 26% with benign (EDSS ≤2 at least 10y after onset symptom) and 74% with disabling (EDSS >2 at least 10y after onset symptom) RRMS, having 12-lead electrocardiogram (ECG) recorded at the time of onset symptom (ECG1) and for follow-up (ECG2), were studied. Heart rate (HR) corrected QT intervals (QTc) reflecting cardiac repolarization were assessed. ResultsThe time interval between ECG1 and ECG2 showed no statistical difference between benign (7.8 ± 4.8y) and disabling (10.2 ± 5.6y; p = .211) RRMS. Patients with benign and disabling RRMS showed similar values of HR (66±9 bpm vs 73 ± 15 bpm; p=.146) and QTc (403 ± 13 ms vs 408 ± 19 ms; p = .450) at the time of ECG1. However, at the time of ECG2, HR was higher (79 ± 14 bpm vs 65 ± 10 bpm; p = .004) and QTc was longer (420 ± 24 ms vs 400 ± 15 ms; p = .012) in patients with disabling than benign RRMS. Correspondingly, HR increased (p = .063) and QTc prolonged (p = .014) during the disease course only in patients with disabling RRMS. ConclusionsDeterioration of cardiac autonomic regulation during the disease course associates with disabling but not with benign RRMS. Our findings suggest that assessment of cardiac autonomic regulation should be included in the evaluation of RRMS disease course. In addition, patients with disabling RRMS might be prone to unfavorable cardiovascular outcome also due to deterioration of autonomic nervous system.

Sleep-disordered breathing is associated with disturbed cardiac repolarization in patients with a coronary artery bypass graft surgery

BackgroundThe development of malignant ventricular arrhythmias due to abnormal cardiac repolarization is a major complication after coronary artery bypass graft surgery (CABG). Sleep-disordered breathing (SDB) is linked to prolonged cardiac repolarization in non-surgical patients. This study evaluates cardiac repolarization in patients with and without SDB who underwent CABG. Methods100 patients who had received CABG (84% men, age 68 ± 10 years, body-mass-index [BMI] 28.7 ± 4.2 kg/m2) were retrospectively evaluated. Polygraphy was recorded the night before CABG. SDB was defined as an apnea-hypopnea index (AHI) of ≥15/h and differentiated into central (CSA) and obstructive (OSA) sleep apnea. Cardiac repolarization was assessed by means of T-peak-to-end (TpTe) and QTc-intervals and TpTe/QT-ratios derived from 12-lead electrocardiography (ECG). Results37% of patients had SDB, 14% CSA and 23% OSA. Before CABG, patients with CSA and OSA had longer TpTe intervals than those without SDB (TpTe: CSA 100 ± 26 vs. OSA 97 ± 19 vs. no SDB 85 ± 14 ms, p = 0.013). QTc intervals and TpTe/QT ratios differed between the two groups (QTc: 444 ± 54 vs. 462 ± 36 vs. 421 ± 32 ms, p < 0.001; TpTe/QT ratio: 0.24 ± 0.04 vs. 0.23 ± 0.05 vs. 0.21 ± 0.03, p = 0.045). SDB was associated with abnormal cardiac repolarization independent of known risk factors for cardiac arrhythmias, such as age, sex, BMI, N-terminal-pro-brain-natriuretic-peptide (NT-proBNP), and heart failure (TpTe: B-coefficient [95%CI]: 16.0, [7.6–24.3], p < 0.001; QTc: 27.2 [9.3–45.1], p = 0.003; TpTe/QT ratio: 2.9 [1.2–4.6], p < 0.001). ConclusionIndependent of known risk factors for cardiac arrhythmias, SDB was significantly associated with abnormal cardiac repolarization before CABG. Data suggest that SDB may contribute to an increased risk of ventricular arrhythmias after CABG.

Electromechanical heterogeneity in the heart : Akey to long QT syndrome?

In the healthy heart, physiological heterogeneities in structure and in electrical and mechanical activity are crucial for normal, efficient excitation and pumping. Alterations of heterogeneity have been linked to arrhythmogenesis in various cardiac disorders such as long QT syndrome (LQTS). This inherited arrhythmia disorder is caused by mutations in different ion channel genes and is characterized by (heterogeneously) prolonged cardiac repolarization and increased risk for ventricular tachycardia, syncope and sudden cardiac death. Cardiac electrical and mechanical function are not independent of each other but interact in abidirectional manner by electromechanical and mechano-electrical coupling. Therefore, changes in either process will affect the other. Recent experimental and clinical evidence suggests that LQTS, which is primarily considered an "electrical" disorder, also exhibits features of disturbed mechanical function and heterogeneity, which in turn appears to correlate with the risk of arrhythmia in the individual patient. In this review, we give ashort overview of the current knowledge about physiological and pathological, long QT-related electrical and mechanical heterogeneity in the heart. Also, their respective roles for future risk prediction approaches in LQTS are discussed.

Relative QT interval prolongation and electrical inhomogeneity of cardiac repolarization in childhood obesity

ObjectiveStudies in adults demonstrated an association of obesity with prolongation of cardiac repolarization and an increased risk of ventricular arrhythmia and sudden cardiac death. The aim of this study was to evaluate potential alterations in cardiac repolarization in obese children. Methods83 lean and 132 obese consecutive healthy pediatric volunteers from the LIFE Child Study cohort were prospectively enrolled and their ECGs were analyzed. ResultsThere was a significant prolongation of corrected QT interval (p=0.001), T peak-to-end (p=0.001) and QT dispersion (p=0.001) in obese compared to lean children. The QT interval prolongation was more pronounced in girls than in boys (p=0.002), whereas there were no significant sex dependent differences in QT dispersion (p=0.18) or T peak-to-end (p=0.39). ConclusionChildhood obesity seems to be associated with a cardiac electrical inhomogeneity with the hypothetical potential for an increased arrhythmogenic risk. Furthermore, it causes a relative prolongation of the QTc interval compared to lean children with a more evident effect in females, yet without prolongation beyond the upper limits of normal.

Late INa Inhibition as an Antiarrhythmic Strategy.

Late sodium channel current (late INa) is considered to be an antiarrhythmic target. The prime antiarrhythmic mechanisms of late INa inhibition have been suggested to be (1) suppression of intracellular calcium [Cai]-mediated rhythmic activity (through reduction in Cai secondary to the decrease in intracellular sodium [Nai]) and (2) normalization of repolarization. Endogenous late INa is a small current and acceleration of the heart rate decreases late INa density. Late INa influx may significantly contribute to Nai loading, but it seems to largely occur under the combined conditions of augmented late INa density, bradycardia, and prolonged repolarization. At the same time, the relative contribution of late INa (including endogenous) in any type of prolonged cardiac repolarization is critical. Sodium channel blockers inhibit both late INa and peak INa, and a specific block of late INa might be achieved at slow and normal but seems not at rapid activation rates, at which peak INa, a much greater current, is also likely to be inhibited. The antiarrhythmic potential of a specific inhibition of late INa seems to best fit for, or may be limited to, the prevention of arrhythmias associated with prolonged repolarization, but it seems to be applicable to all types of arrhythmic abnormalities with elongated cardiac repolarization.

The impact of multiple sclerosis onset symptom on cardiac repolarization.

IntroductionMultiple sclerosis is associated with prolonged cardiac repolarization but the underlying physiology has remained unknown. In this study, we compared cardiac repolarization during the relapsing‐remitting multiple sclerosis (RRMS) disease course in patients with motor and sensory onset symptom.MethodsTwenty‐five RRMS patients with motor and 33 RRMS patients with sensory onset symptom having 12‐lead electrocardiogram (ECG) recorded at the time of the first demyelinating event (ECG1) as well as at the later disease course (ECG2) were identified from the patient records. The average time interval between ECG1 and ECG2 was 8.6 ± 5.9 y. Heart rate‐corrected QT intervals reflecting cardiac repolarization were calculated by Bazett (QTcBaz), Fridericia (QTcFri), and Karjalainen (QTcKar) formulas.ResultsHeart rate‐corrected QT intervals as well as heart rate were similar in patients with motor and sensory onset symptom in ECG1. However, QTcBaz (p = .002), QTcFri (p = .019), and QTcKar (p = .026) were longer and heart rate was higher (p = .035) in patients with motor than sensory onset symptom in ECG2. Correspondingly, QTcBaz (p = .002), QTcFri (p = .033), and QTcKar (p = .043) prolonged and heart rate tended to increase (p = .060) during the disease course only in the patients with motor onset symptom.ConclusionsCardiac repolarization prolonged and heart rate increased during the disease course in RRMS patients with motor but not with sensory onset symptom. This suggests different traits in RRMS according to its initial manifestation and also association of motor onset symptom with more unfavorable cardiovascular prognostic determinants.