Increased interleukin-6 levels are associated with atrioventricular conduction delay in severe COVID-19 patients.

Background: Severely ill patients with coronavirus disease 2019 (COVID-19) show an increased risk of new-onset atrioventricular blocks (AVBs), associated with high rates of short-term mortality. Recent data suggest that the uncontrolled inflammatory activation observed in these patients, specifically interleukin (IL)-6 elevation, may play an important pathogenic role by directly affecting cardiac electrophysiology. The aim of our study was to assess the acute impact of IL-6 changes on electrocardiographic indices of atrioventricular conduction in severe COVID-19. Methods: We investigated (1) the behavior of PR-interval and PR-segment in patients with severe COVID-19 during active phase and recovery, and (2) their association with circulating IL-6 levels over time. Results: During active disease, COVID-19 patients showed a significant increase of PR-interval and PR-segment. Such atrioventricular delay was transient as these parameters rapidly normalized during recovery. PR-indices significantly correlated with circulating IL-6 levels over time. All these changes and correlations persisted also in the absence of laboratory signs of cardiac strain/injury or concomitant treatment with PR-prolonging drugs, repurposed or not. Conclusions: Our study provides evidence that in patients with severe COVID-19 and high-grade systemic inflammation, IL-6 elevation is associated with a significant delay of atrioventricular conduction, independent of concomitant confounding factors. While transient, such alterations may enhance the risk of severe AVB and associated short-term mortality. Our data provide further support to current anti-inflammatory strategies for severe COVID-19, including IL-6 antagonists.

Calcium handling abnormalities increase arrhythmia susceptibility in DMSXL myotonic dystrophy type 1 mice.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model. METHODS: ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively. RESULTS: DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins. CONCLUSIONS: The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment.

Differentiation of Sinoatrial-like Cardiomyocytes as a Biological Pacemaker Model.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are widely used for disease modeling and pharmacological screening. However, their application has mainly focused on inherited cardiopathies affecting ventricular cardiomyocytes, leading to extensive knowledge on generating ventricular-like hiPSC-CMs. Electronic pacemakers, despite their utility, have significant disadvantages, including lack of hormonal responsiveness, infection risk, limited battery life, and inability to adapt to changes in heart size. Therefore, developing an in vitro multiscale model of the human sinoatrial node (SAN) pacemaker using hiPSC-CM and SAN-like cardiomyocyte differentiation protocols is essential. This would enhance the understanding of SAN-related pathologies and support targeted therapies. Generating SAN-like cardiomyocytes offers the potential for biological pacemakers and specialized conduction tissues, promising significant benefits for patients with conduction system defects. This review focuses on arrythmias related to pacemaker dysfunction, examining protocols' advantages and drawbacks for generating SAN-like cardiomyocytes from hESCs/hiPSCs, and discussing therapeutic approaches involving their engraftment in animal models.

Chronic Illness Perceptions and Cardiovascular Disease Risk Behaviors in Black and Latinx Sexual Minority Men with HIV: A Cross-Sectional Analysis.

Ethnic and racial sexual minority men with HIV have a disproportionately higher risk of HIV-related cardiovascular disease (CVD). There is a lack of tailored and culturally salient behavioral interventions to address HIV-related chronic illness in ethnic and racial sexual minority men, and literature on their understanding and awareness of modifiable behavioral risks is limited. The purpose of this study was to assess illness perceptions about HIV and HTN, and describe physical activity, tobacco, and e-cigarette use in Black and Latinx sexual minority men living with HIV. We used the validated Illness Perception Questionnaire-Revised (IPQ-R) to assess perceptions about two interrelated chronic diseases, HIV and CVD. To assess CVD behavioral risk, we assessed physical activity using the International Physical Activity Questionnaire. Tobacco and e-cigarette use were assessed using items from the Behavioral Risk Factor Surveillance System. Sleep difficulties were the most prevalent symptom attributed to HIV, and were statistically associated with fatigue, upset stomach, and loss of strength. Anxiety was reported to be caused by HIV (57%) and HTN (39%). Half of the participants engaged in vigorous activity for 128 min (SD = 135) daily, and 63% engaged in moderate activity for 94 min (SD = 88) daily. Over a third reported current tobacco use and 20% reported current e-cigarette use. This study provides formative data to better understand how Black and Latinx sexual minority men with HIV perceive intersecting chronic illnesses and their engagement in modifiable CVD risk behaviors. Sleep, mental health disparities, and financial hardships were commonly reported. More research is needed to address intersecting chronic illnesses and mental health conditions that are influenced by social positioning over the life course, and impact CVD risk factors. This study was not registered.

Advanced Atrioventricular Block in Athletes: Prevalence and Role of Anti-Ro/Sjögren Syndrome-Related Antigen A Antibodies.

BACKGROUND: Advanced atrioventricular block (AVB), that is, higher than second-degree Mobitz-1, is an abnormal finding in athletes. Despite intensive investigation, in several cases the pathogenesis remains unknown, but frequently pacemaker implantation is still indicated. Increasing evidence points to circulating anti-Ro/Sjögren syndrome-related antigen A (SSA) antibodies cross-reacting with L-type calcium channel and inhibiting the related current as an epidemiologically relevant and potentially reversible cause of isolated AVB in adults. The aim of the study was to determine the prevalence of anti-Ro/SSA-associated advanced AVBs in a large sample of young athletes. METHODS AND RESULTS: A total of 2536 consecutive athletes aged <40 years without a history of cardiac diseases/interventions were enrolled in a cross-sectional study. Resting and exercise electrocardiography was performed, and those presenting any AVB were further evaluated by 24-hour Holter ECG. Athletes with second-degree AVBs and their mothers underwent anti-Ro/SSA testing. Moreover, purified immunoglobulin G from subjects with anti-Ro/SSA-positive and anti-Ro/SSA-negative advanced AVB were tested on L-type calcium current and L-type-calcium channel expression using tSA201 cells. The global prevalence of advanced AVB in the overall sample was ≈0.1%, but the risk considerably increased (2%) when intensely trained postpubertal male subjects were selectively considered. While none of the athletes with advanced AVB showed heart abnormalities, in 100% of cases anti-Ro/SSA antibodies were detected. Ex vivo experiments showed that immunoglobulin G from anti-Ro/SSA-positive but not -negative subjects with advanced AVB acutely inhibit L-type calcium current and chronically downregulate L-type-calcium channel expression. CONCLUSIONS: Our study provides evidence that advanced AVB occurs in young athletes, in most cases associated with anti-Ro/SSA antibodies blocking L-type calcium channels. These findings may open new avenues for immunomodulating therapies to reduce the risk of life-threatening events in athletes, avoiding or delaying pacemaker implantation.

Arrhythmias and ion channelopathies causing sudden cardiac death in Hispanic/Latino and Indigenous populations.

The limited literature and increasing interest in studies on cardiac electrophysiology, explicitly focusing on cardiac ion channelopathies and sudden cardiac death in diverse populations, has prompted a comprehensive examination of existing research. Our review specifically targets Hispanic/Latino and Indigenous populations, which are often underrepresented in healthcare studies. This review encompasses investigations into genetic variants, epidemiology, etiologies, and clinical risk factors associated with arrhythmias in these demographic groups. The review explores the Hispanic paradox, a phenomenon linking healthcare outcomes to socioeconomic factors within Hispanic communities in the United States. Furthermore, it discusses studies exemplifying this observation in the context of arrhythmias and ion channelopathies in Hispanic populations. Current research also sheds light on disparities in overall healthcare quality in Indigenous populations. The available yet limited literature underscores the pressing need for more extensive and comprehensive research on cardiac ion channelopathies in Hispanic/Latino and Indigenous populations. Specifically, additional studies are essential to fully characterize pathogenic genetic variants, identify population-specific risk factors, and address health disparities to enhance the detection, prevention, and management of arrhythmias and sudden cardiac death in these demographic groups.

Generation of three myotonic dystrophy type 1 patient iPSC lines (CBRCULi018-A, CBRCULi019-A, CBRCULi020-A) derived from lymphoblastoid cell lines for disease modelling and therapeutic research.

Myotonic dystrophy type 1 (DM1) is the most prevalent adult-onset muscular dystrophy affecting 1 in 8,000 individuals. It is characterized by multisystemic symptoms, primarily myopathy. The root cause of DM1 is a heterozygous CTG triplet expansion beyond the normal size threshold in the non-coding region of the DM1 protein kinase gene (DMPK). In our study, we generated and characterized three distinct DM1 induced pluripotent stem cell (iPSC) lines with CTG repeat expansions ranging from 900 to 2000 in the DMPK gene. These iPSC lines maintained normal karyotypes, exhibited distinctive colony morphology, robustly expressed pluripotency markers, differentiated into the three primary germ layers, and lacked residual viral vectors.

Ion channel trafficking implications in heart failure.

Heart failure (HF) is recognized as an epidemic in the contemporary world, impacting around 1%-2% of the adult population and affecting around 6 million Americans. HF remains a major cause of mortality, morbidity, and poor quality of life. Several therapies are used to treat HF and improve the survival of patients; however, despite these substantial improvements in treating HF, the incidence of HF is increasing rapidly, posing a significant burden to human health. The total cost of care for HF is USD 69.8 billion in 2023, warranting a better understanding of the mechanisms involved in HF. Among the most serious manifestations associated with HF is arrhythmia due to the electrophysiological changes within the cardiomyocyte. Among these electrophysiological changes, disruptions in sodium and potassium currents' function and trafficking, as well as calcium handling, all of which impact arrhythmia in HF. The mechanisms responsible for the trafficking, anchoring, organization, and recycling of ion channels at the plasma membrane seem to be significant contributors to ion channels dysfunction in HF. Variants, microtubule alterations, or disturbances of anchoring proteins lead to ion channel trafficking defects and the alteration of the cardiomyocyte's electrophysiology. Understanding the mechanisms of ion channels trafficking could provide new therapeutic approaches for the treatment of HF. This review provides an overview of the recent advances in ion channel trafficking in HF.

Elevated Interleukin-6 Levels Are Associated With an Increased Risk of QTc Interval Prolongation in a Large Cohort of US Veterans.

BACKGROUND: Although accumulating data indicate that IL-6 (interleukin-6) can promote heart rate-corrected QT interval (QTc) prolongation via direct and indirect effects on cardiac electrophysiology, current evidence comes from basic investigations and small clinical studies only. Therefore, IL-6 is still largely ignored in the clinical management of long-QT syndrome and related arrhythmias. The aim of this study was to estimate the risk of QTc prolongation associated with elevated IL-6 levels in a large population of unselected subjects. METHODS AND RESULTS: An observational study using the Veterans Affairs Informatics and Computing Infrastructure was performed. Participants were US veterans who had an ECG and were tested for IL-6. Descriptive statistics and univariate and multivariate regression analyses were performed to study the relationship between IL-6 and QTc prolongation risk. Study population comprised 1085 individuals, 306 showing normal (<5 pg/mL), 376 moderately high (5-25 pg/mL), and 403 high (>25 pg/mL) IL-6 levels. Subjects with elevated IL-6 showed a concentration-dependent increase in the prevalence of QTc prolongation, and those presenting with QTc prolongation exhibited higher circulating IL-6 levels. Stepwise multivariate regression analyses demonstrated that increased IL-6 level was significantly associated with a risk of QTc prolongation up to 2 times the odds of the reference category of QTc (e.g. QTc >470 ms men/480 ms women ms: odds ratio, 2.28 [95% CI, 1.12-4.50] for IL-6 >25 pg/mL) regardless of the underlying cause. Specifically, the mean QTc increase observed in the presence of elevated IL-6 was quantitatively comparable (IL-6 >25 pg/mL:+6.7 ms) to that of major recognized QT-prolonging risk factors, such as hypokalemia and history of myocardial infarction. CONCLUSIONS: Our data provide evidence that a high circulating IL-6 level is a robust risk factor for QTc prolongation in a large cohort of US veterans, supporting a potentially important arrhythmogenic role for this cytokine in the general population.

Urban and rural differences in needs, service use and satisfaction among caregivers of autistic children in Morocco.

LAY ABSTRACT: It is very important to understand the needs of caregivers to be able to empower caregivers and to develop or improve services around the world. Therefore, research in different regions is needed to understand differences in caregivers needs between countries, but also between areas within countries. This study investigated differences in needs and service use between caregivers of autistic children in Morocco, living in urban and rural areas. A total of 131 Moroccan caregivers of autistic children took part in the study and responded to an interview survey. The results showed both similarities and differences between urban and rural living caregivers' challenges and needs. Autistic children from urban communities were much more likely to receive intervention and attend school than children from rural communities, even though age and verbal skills of the two groups of children were comparable. Caregivers expressed similar needs for improved care and education, but different challenges in caring. Limited autonomy skills in children were more challenging to rural caregivers, while limited social-communicational skills were more challenging to urban caregivers. These differences may inform healthcare policy-makers and program developers. Adaptive interventions are important to respond to regional needs, resources, and practices. In addition, the results showed the importance of addressing challenges as experienced by caregivers such as costs related to care, barriers in access to information, or stigma. Addressing these issues may help reduce both global and within-country differences in autism care.

Electrophysiological basis of cardiac arrhythmia in a mouse model of myotonic dystrophy type 1.

Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patch-clamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics.

Cardiac involvement in patient-specific induced pluripotent stem cells of myotonic dystrophy type 1: unveiling the impact of voltage-gated sodium channels.

Myotonic dystrophy type 1 (DM1) is a genetic disorder that causes muscle weakness and myotonia. In DM1 patients, cardiac electrical manifestations include conduction defects and atrial fibrillation. DM1 results in the expansion of a CTG transcribed into CUG-containing transcripts that accumulate in the nucleus as RNA foci and alter the activity of several splicing regulators. The underlying pathological mechanism involves two key RNA-binding proteins (MBNL and CELF) with expanded CUG repeats that sequester MBNL and alter the activity of CELF resulting in spliceopathy and abnormal electrical activity. In the present study, we identified two DM1 patients with heart conduction abnormalities and characterized their hiPSC lines. Two differentiation protocols were used to investigate both the ventricular and the atrial electrophysiological aspects of DM1 and unveil the impact of the mutation on voltage-gated ion channels, electrical activity, and calcium homeostasis in DM1 cardiomyocytes derived from hiPSCs. Our analysis revealed the presence of molecular hallmarks of DM1, including the accumulation of RNA foci and sequestration of MBNL1 in DM1 hiPSC-CMs. We also observed mis-splicing of SCN5A and haploinsufficiency of DMPK. Furthermore, we conducted separate characterizations of atrial and ventricular electrical activity, conduction properties, and calcium homeostasis. Both DM1 cell lines exhibited reduced density of sodium and calcium currents, prolonged action potential duration, slower conduction velocity, and impaired calcium transient propagation in both ventricular and atrial cardiomyocytes. Notably, arrhythmogenic events were recorded, including both ventricular and atrial arrhythmias were observed in the two DM1 cell lines. These findings enhance our comprehension of the molecular mechanisms underlying DM1 and provide valuable insights into the pathophysiology of ventricular and atrial involvement.

Optical Mapping of Cardiomyocytes in Monolayer Derived from Induced Pluripotent Stem Cells.

Optical mapping is a powerful imaging technique widely adopted to measure membrane potential changes and intracellular Ca2+ variations in excitable tissues using voltage-sensitive dyes and Ca2+ indicators, respectively. This powerful tool has rapidly become indispensable in the field of cardiac electrophysiology for studying depolarization wave propagation, estimating the conduction velocity of electrical impulses, and measuring Ca2+ dynamics in cardiac cells and tissues. In addition, mapping these electrophysiological parameters is important for understanding cardiac arrhythmia mechanisms. In this review, we delve into the fundamentals of cardiac optical mapping technology and its applications when applied to hiPSC-derived cardiomyocytes and discuss related advantages and challenges. We also provide a detailed description of the processing and analysis of optical mapping data, which is a crucial step in the study of cardiac diseases and arrhythmia mechanisms for extracting and comparing relevant electrophysiological parameters.

Ethnic and racial differences in Asian populations with ion channelopathies associated with sudden cardiac death.

Cardiovascular diseases are associated with several morbidities and are the most common cause of worldwide disease-related fatalities. Studies show that treatment and outcome-related differences for cardiovascular diseases disproportionately affect minorities in the United States. The emergence of ethnic and racial differences in sudden cardiac death (SCD) and related ion channelopathies complicates cardiovascular disease prevention, diagnosis, management, prognosis, and treatment objectives for patients and physicians alike. This review compiles and synthesizes current research in cardiac ion channelopathies and genetic disorders in Asian populations, an underrepresented population in cardiovascular literature. We first present a brief introduction to SCD, noting relevant observations and statistics from around the world, including Asian populations. We then examined existing differences between Asian and White populations in research, treatment, and outcomes related to cardiac ion channelopathies and SCD, showing progression in thought and research over time for each ion channelopathy. The review also identifies research that explored phenotypic abnormalities, device usage, and risk of death in Asian patients. We touch upon the unique genetic risk factors in Asian populations that lead to cardiac ion channelopathies and SCD while comparing them to White and Western populations, particularly in the United States, where Asians comprise approximately 7% of the total population. We also propose potential solutions such as improving early genetic screening, addressing barriers affecting access to medical care and device utilization, physician training, and patient education on risks.

Fir(e)ing the Rhythm: Inflammatory Cytokines and Cardiac Arrhythmias.

Inflammatory activation is increasingly recognized as a nonconventional risk factor for arrhythmias, and experimental studies provided robust evidence that this association is mediated by direct arrhythmogenic effects of proinflammatory cytokines on cardiac cells. Additionally, inflammatory cytokines can favor arrhythmias indirectly through multiple systemic effects. Accumulating data confirm the clinical relevance of these mechanisms; the largest evidence being available for atrial fibrillation, acquired long-QT syndrome, and ventricular arrhythmias. However, clinical management of arrhythmias largely neglects inflammatory cytokines. This review integrates basic science and clinical research to present an updated overview of the topic and provides future directions for patient's management.

Lymphoblastoid cell lines derived from iPSCs of a myotonic dystrophy type 1 patient carrying 700 CTG repeats (CBRCULi007-A) and a control (CBRCULi006-A).

Myotonic dystrophy type 1 (DM1) is a genetic neuromuscular disorder that affects many organs, including the heart. DM1 is caused by a heterozygous CTG triplet expansion exceeding the normal size threshold in the non-coding region of the DM1 protein kinase gene (DMPK). We generated and characterized a DM1 iPSC line carrying a 700 CTG repeat expansion as well as a control iPSC line from a healthy individual. The two iPSC lines expressed several pluripotency markers, had the capacity to differentiate into the three primary germ layers, had no residual viral vectors, had normal karyotypes, and had a typical colony morphology.

Anti-Ro/SSA Antibodies Blocking Calcium Channels as a Potentially Reversible Cause of Atrioventricular Block in Adults.

BACKGROUND: In ∼50% of severe atrioventricular blocks (AVBs) occurring in adults <50 years, the underlying etiology remains unknown. Preliminary evidence from case reports suggests that autoimmunity, specifically the presence of circulating anti-Ro/SSA antibodies in the patient (acquired form), in the patient's mother (late-progressive congenital form), or in both (mixed form), could be involved in a fraction of idiopathic AVBs in adults by possibly targeting the L-type calcium channel (Cav1.2) and inhibiting the related current (ICaL). OBJECTIVES: The purpose of this study was to evaluate whether anti-Ro/SSA antibodies are causally implicated in the development of isolated AVBs in adults. METHODS: Thirty-four consecutive patients with isolated AVB of unknown origin and 17 available mothers were prospectively enrolled in a cross-sectional study. Anti-Ro/SSA antibodies were assessed by fluoroenzyme-immunoassay, immuno-Western blotting, and line-blot immunoassay. Purified immunoglobulin-G (IgG) from anti-Ro/SSA-positive and anti-Ro/SSA-negative subjects were tested on ICaL and Cav1.2 expression using tSA201 and HEK293 cells, respectively. Moreover, in 13 AVB patients, the impact of a short course of steroid therapy on AV conduction was evaluated. RESULTS: Anti-Ro/SSA antibodies, particularly anti-Ro/SSA-52kD, were found in 53% of AVB-patients and/or in their mothers, most commonly an acquired or mixed form (two-thirds of cases) without history of autoimmune diseases. Purified IgG from anti-Ro/SSA-positive but not anti-Ro/SSA-negative AVB patients acutely inhibited ICaL and chronically down-regulated Cav1.2 expression. Moreover, anti-Ro/SSA-positive sera showed high reactivity with peptides corresponding to the Cav1.2 channel pore-forming region. Finally, steroid therapy rapidly improved AV conduction in AVB-patients with circulating anti-Ro/SSA antibodies but not in those without. CONCLUSIONS: Our study points to anti-Ro/SSA antibodies as a novel, epidemiologically relevant and potentially reversible cause of isolated AVB in adults, via an autoimmune-mediated functional interference with the L-type calcium channels. These findings have significant impact on antiarrhythmic therapies by avoiding or delaying pacemaker implantation.

Pathophysiology of Cav1.3 L-type calcium channels in the heart.

Ca2+ plays a crucial role in excitation-contraction coupling in cardiac myocytes. Dysfunctional Ca2+ regulation alters the force of contraction and causes cardiac arrhythmias. Ca2+ entry into cardiomyocytes is mediated mainly through L-type Ca2+ channels, leading to the subsequent Ca2+ release from the sarcoplasmic reticulum. L-type Ca2+ channels are composed of the conventional Cav1.2, ubiquitously expressed in all heart chambers, and the developmentally regulated Cav1.3, exclusively expressed in the atria, sinoatrial node, and atrioventricular node in the adult heart. As such, Cav1.3 is implicated in the pathogenesis of sinoatrial and atrioventricular node dysfunction as well as atrial fibrillation. More recently, Cav1.3 de novo expression was suggested in heart failure. Here, we review the functional role, expression levels, and regulation of Cav1.3 in the heart, including in the context of cardiac diseases. We believe that the elucidation of the functional and molecular pathways regulating Cav1.3 in the heart will assist in developing novel targeted therapeutic interventions for the aforementioned arrhythmias.

Contribution of cytokine-mediated prolongation of QTc interval to the multi-hit theory of Torsade de Pointes.

BACKGROUND: Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). METHODS: Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate IKr inhibition at varying IL-6 and quetiapine concentrations. RESULTS: IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p = .0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD90:179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p = .0357). When hypokalemia was introduced, the APD90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p = .2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p = .2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate IKr inhibition. CONCLUSIONS: Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting.