Faculty Bibliography

Progressive cardiac conduction defect often associated with variants in sodium voltage-gated channel SCN5A gene and variants in the L-type calcium voltage-gated channel CACNA1D gene are implicated in sinoatrial node dysfunction. We generated an induced pluripotent stem cell line (iPSC) from a 13-year-old patient with history of conduction system disease and ventricular tachycardia, carrying variants in SCN5A (c.2618C > G), CACNA1D (c.3786G > T), and DSP (c.1582C > G). The generated iPSC line exhibited pluripotency markers, differentiated into the three embryonic germ layers, and maintained a normal karyotype. This iPSC line offers insights into the pathophysiological mechanisms of cardiac arrhythmias and personalized therapies development.

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.

BACKGROUND/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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.

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.

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.

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/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.

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.

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.

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/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.

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.