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.

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.

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.

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.

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.

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).

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.

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.

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

Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of 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.

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.

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 Ca variations in excitable tissues using voltage-sensitive dyes and Ca 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 Ca dynamics in cardiac cells and tissues. In addition, mapping these electrophysiological parameters is important for understanding cardiac arrhythmia mechanisms.

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.

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.

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.

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 (Ca1.2) and inhibiting the related current (I).

Pathophysiology of Ca1.3 L-type calcium channels in the heart.

Ca plays a crucial role in excitation-contraction coupling in cardiac myocytes. Dysfunctional Ca regulation alters the force of contraction and causes cardiac arrhythmias. Ca entry into cardiomyocytes is mediated mainly through L-type Ca channels, leading to the subsequent Ca release from the sarcoplasmic reticulum.

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.

Generation of four myotonic dystrophy type 1 patient iPSC lines (CBRCULi002-A, CBRCULi003-A, CBRCULi004-A, CBRCULi005-A) and a control (CBRCULi001-A) derived from lymphoblastoids cell lines.

Myotonic dystrophy Type 1 (DM1) is a severe inherited neuromuscular disease and is the most prevalent form of muscular dystrophy in adults. DM1 involves not only the striated muscles including skeletal, and cardiac but also other organs such as the eye, brain and gonads. We have generated and characterized 4 adult heterozygous DM1 iPSC lines carrying between 1300 and 1600 CTG repeat expansion in the DM1 protein kinase gene, and a control from an apparently healthy individual.

Recent Progress and Challenges in the Development of Antisense Therapies for Myotonic Dystrophy Type 1.

Myotonic dystrophy type 1 (DM1) is a dominant genetic disease in which the expansion of long CTG trinucleotides in the 3' UTR of the myotonic dystrophy protein kinase () gene results in toxic RNA gain-of-function and gene mis-splicing affecting mainly the muscles, the heart, and the brain. The CUG-expanded transcripts are a suitable target for the development of antisense oligonucleotide (ASO) therapies. Various chemical modifications of the sugar-phosphate backbone have been reported to significantly enhance the affinity of ASOs for RNA and their resistance to nucleases, making it possible to reverse DM1-like symptoms following systemic administration in different transgenic mouse models.

Addressing challenges faced by underrepresented biomedical investigators and efforts to address them: An NHLBI-PRIDE perspective.

Junior investigators from groups underrepresented in the biomedical workforce confront challenges as they navigate the ranks of academic research careers. Biochemical research needs the participation of these researchers to adequately tackle critical research priorities such as cardiovascular health disparities and health inequities. We explore the inadequate representation of underrepresented minority investigators and the historical role of systemic racism in impacting their poor career progression.