Faculty Bibliography

Myotonic Dystrophy Type 1 (DM1) is a complex multisystemic genetic disorder caused by CTG repeat expansions in the DMPK gene, leading to RNA toxicity and widespread splicing defects. These splicing abnormalities affect multiple systems, including the respiratory, skeletal, cardiac, nervous, and endocrine systems, resulting in aggressive symptoms that significantly impact quality of life and survival. Cardiac complications are the second leading cause of deaths in DM1, after respiratory insufficiency. Current research is largely focused on understanding cardiac pathology in DM1. This review highlights recent advancements in the clinical and pathological characterization of DM1 cardiac involvement, preclinical models used to study cardiac dysfunction, and emerging therapeutic strategies that target the molecular basis of DM1. Promising approaches include RNA-targeting strategies such as antisense oligonucleotides (ASOs), gene-editing tools like CRISPR-Cas9, and small molecules that modulate RNA splicing. ASOs aim to reduce toxic RNA accumulation, CRISPR-based approaches aim to excise or correct the expanded CTG repeats, and repurposed small-molecule drugs, such as vorinostat, tideglusib, and metformin, could serve as potential therapeutic agents for DM1 patients with cardiac complications. Despite this progress, several challenges remain: the heterogeneity of cardiac manifestations, unpredictable and often silent progression of arrhythmias, limited therapeutic options beyond implantable cardioverter-defibrillator (ICD)/pacemaker implantations, and complex interplay with the multisystemic nature of DM1. More research and well-designed clinical trials are urgently needed to translate these promising strategies into effective treatments for DM1-associated cardiac disease. Here, we discuss the current knowledge in DM1 cardiac pathology and preclinical models as well as the benefits and pitfalls of the available therapeutic approaches.

BACKGROUND:Female sex is a well-recognized risk factor for long QT syndrome and torsades de pointes (TdP), likely reflecting the influence of sex hormones on ventricular repolarization. Overall, estradiol prolongs, whereas progesterone and testosterone shorten, heart rate-corrected QT interval. However, no studies have comprehensively evaluated sex hormone levels in male and female long QT syndrome patients developing TdP, nor their implications in terms of clinical outcomes and electrophysiological changes. OBJECTIVES/OBJECTIVE:This study was aimed at determining the sex hormones profiles in male and female TdP patients, and defining their role in this clinical setting. METHODS:The authors investigated: 1) the levels of sex hormones in a prospective cohort of male and female patients who developed TdP; 2) the relationship between sex hormones and arrhythmia outcome in TdP men and women; 3) the in vitro impact of sex-specific TdP hormone profiles on guinea pig ventricular myocyte and human-induced pluripotent stem cell-derived cardiomyocyte action potential duration, and their modulation by sex-specific hormonal interventions. RESULTS:Over 13 years, 68 TdP patients (42 female) were consecutively enrolled. Compared to control subjects, a differential sex hormone profile was observed in TdP men and women, primarily reduced testosterone in male patients and increased 17β-estradiol in female patients. Within the TdP cohort, lower testosterone in men and higher 17β-estradiol in women were associated with a worse short-term arrhythmia outcome. In vitro reproduction of sex-specific TdP hormone profiles prolonged action potential duration in sex-matched cardiomyocytes, an effect reversed by the addition of testosterone in male patients and progesterone in female patients, respectively. CONCLUSIONS:Different sex hormone profiles, primarily low testosterone in male patients and high 17β-estradiol in female patients, are associated with TdP occurrence and outcome in men and women. These endocrine milieus act, at least in part, via direct and reversible effects on cardiac electrophysiology, thereby supporting the antiarrhythmic potential of sex-specific hormonal-modulating therapies.

INTRODUCTION/BACKGROUND:Heart failure (HF) affects approximately 6.7 million Americans and rising. Despite multi-modality therapy, patient outcomes remain suboptimal. It has been recently shown that Cav1.3 L-type calcium channels are re-expressed in ischemic failing human ventricles, and the Cav1.3-C-terminus is cleaved and acts as a transcription factor. Here, we leveraged the Cav1.3-C-terminus's auto-enhancer properties as a novel therapy to restore ejection fraction (EF) in HF. METHODS:) mice 15-days post-ligation of the left-anterior-descending coronary artery (LAD). Treatment groups received adeno-associated-virus-serotype-9(AAV9)-Cav1.3-C-terminus or vehicle. Echocardiography, histology, biochemistry, patch-clamp, optical mapping, and RNA-seq were performed. RESULTS:HF mice post-AAV9-Cav1.3-C-terminus-treatment. CACN1D, encoding Cav1.3, was upregulated 1.9-Log2-fold in the AAV9-Cav1.3-C-terminus-treated group vs. vehicle. CONCLUSIONS:AAV9-Cav1.3-C-terminus-treatment of mice with HF resulted in resistance to inducible arrhythmia and normalization of left ventricular EF, likely via a transcriptional upregulation of Cav1.3 and the resulting optimal increase in L-type calcium current. Therefore, AAV9-Cav1.3-C-terminus may be leveraged as a novel therapeutic approach to improve cardiac function.

Cardiac arrhythmias still represent a major health problem worldwide, at least in part because the fundamental pathogenic mechanisms are not fully understood, thus affecting the efficacy of therapeutic measures. In fact, whereas cardiac arrhythmias are in most cases due to structural heart diseases, the underlying cause remains elusive in a significant number of patients despite intensive investigations even including postmortem examination and molecular autopsy. A large body of data progressively accumulated during the last decade provides strong evidence that autoimmune mechanisms may be involved in a significant number of such unexplained or poorly explained cardiac arrhythmias. Several proarrhythmic anti-cardiac ion channel autoantibodies have been discovered, in all cases able to directly interfere with the electrophysiologic properties of the heart but leading to different arrhythmic phenotypes, including long QT syndrome, short QT syndrome, and atrioventricular block. These autoantibodies, which may develop independent of a history of autoimmune diseases, could help explain a percentage of arrhythmic events of unknown origin, thereby opening new frontiers for diagnosis and treatment of heart rhythm disorders. Based on this evidence, the novel term autoimmune cardiac channelopathies was coined in 2017. Since then, the interest in the field of cardioimmunology has shown a tumultuous growth, so much so that the number of arrhythmogenic anti-ion channel autoantibodies reported has significantly increased, also in association with not previously described arrhythmic phenotypes, such as atrial fibrillation, Brugada syndrome, and ventricular fibrillation/cardiac arrest. Thus, an updated reassessment of this topic, also highlighting perspectives and unmet needs, has become necessary and represents the main objective of this review.

INTRODUCTION/UNASSIGNED:Cardiovascular disease (CVD) is a leading cause of mortality in the United States, disproportionately affecting marginalized populations such as Black and Latinx sexual minority men with HIV. These individuals face heightened CVD risk due to chronic inflammation related to HIV, side effects from treatment, and intersecting social disadvantages, including stigma and discrimination. Behavioral interventions specifically targeting these populations have been limited, with insufficient uptake in marginalized communities. METHODS/UNASSIGNED:This study used Intervention Mapping (IM) to develop a culturally tailored CVD prevention intervention for Black and Latinx sexual minority men with HIV. IM is a systematic, theory- and evidence-based framework for health promotion program planning. We focused on the first three of six steps in the IM process: (1) assessing community needs through literature review, framework development, and community-engaged research; (2) identifying program outcomes to develop a logic model of change; and (3) selecting theory-based methods and practical strategies for program design. RESULTS/UNASSIGNED:The needs assessment revealed significant barriers to cardiovascular health, including medical distrust, stigma, and lack of access to culturally appropriate healthcare. The logic model of change highlighted behavioral and environmental determinants influencing cardiovascular health, leading to specific performance objectives and change objectives. Strategies included leveraging eHealth technologies, such as avatar-led interactive videos, to provide private, culturally relevant health education and reduce barriers like medical distrust. Community-based participatory methods were integral to ensure the intervention was culturally resonant and acceptable. DISCUSSION/UNASSIGNED:This study demonstrated the use of IM to systematically develop a culturally tailored CVD prevention intervention for Black and Latinx sexual minority men with HIV. The findings highlight the importance of community-engaged and culturally appropriate approaches in developing interventions for historically marginalized populations. These strategies aimed to address health disparities and empower them to engage in cardiovascular health-promoting behaviors, ultimately improving cardiovascular health outcomes. Leveraging technology to foster engagement and providing culturally relevant support were crucial elements of the intervention. The insights gained may inform future cardiovascular health promotion efforts targeting similar populations.

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.