Faculty Bibliography

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.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by the replacement of myocardium by fibro-fatty infiltration and cardiomyocyte loss. ACM predisposes to a high risk for ventricular arrhythmias. ACM has initially been defined as a desmosomal disease because most of the known variants causing the disease concern genes encoding desmosomal proteins. Studying this pathology is complex, in particular because human samples are rare and, when available, reflect the most advanced stages of the disease. Usual cellular and animal models cannot reproduce all the hallmarks of human pathology. In the last decade, human-induced pluripotent stem cells (hiPSC) have been proposed as an innovative human cellular model. The differentiation of hiPSCs into cardiomyocytes (hiPSC-CM) is now well-controlled and widely used in many laboratories. This hiPSC-CM model recapitulates critical features of the pathology and enables a cardiomyocyte-centered comprehensive approach to the disease and the screening of anti-arrhythmic drugs (AAD) prescribed sometimes empirically to the patient. In this regard, this model provides unique opportunities to explore and develop new therapeutic approaches. The use of hiPSC-CMs will undoubtedly help the development of precision medicine to better cure patients suffering from ACM. This review aims to summarize the recent advances allowing the use of hiPSCs in the ACM context.

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.

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. We highlight challenges these investigators face, and opportunities to address these barriers are identified. Ensuring adequate recruitment and promotion of underrepresented biomedical researchers fosters inclusive excellence and augments efforts to address health inequities. The Programs to Increase Diversity among Individuals Engaged in Health-Related Research (PRIDE), funded by the National Heart, Lung, and Blood Institute (NHLBI), is a pilot program by the National Institutes of Health (NIH) that aims to address these challenges yet, only a limited number of URM can be accepted to PRIDE programs. Hence the need for additional funding for more PRIDE or PRIDE-like programs. Here we aim to examine the challenges underrepresented minority biomedical investigators face and describe ongoing initiatives to increase URM in biomedical research using the NHLBI-PRIDE program as a focus point.

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 (DMPK) 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. However, specific tissue delivery remains to be improved to achieve significant clinical outcomes in humans. Several strategies, including ASO conjugation to cell-penetrating peptides, fatty acids, or monoclonal antibodies, have recently been shown to improve potency in muscle and cardiac tissues in mice. Moreover, intrathecal administration of ASOs may be an advantageous complementary administration route to bypass the blood-brain barrier and correct defects of the central nervous system in DM1. This review describes the evolution of the chemical design of antisense oligonucleotides targeting CUG-expanded mRNAs and how recent advances in the field may be game-changing by forwarding laboratory findings into clinical research and treatments for DM1 and other microsatellite diseases.

BACKGROUND:Approximately every 36 seconds someone in the United States dies of cardiovascular disease (CVD). It has emerged as an important contributor to morbidity among persons with HIV. Black and Latinx sexual minority men are at higher risk of both HIV and CVD when compared to heterosexual, non-ethnic/minority men. Persons with HIV have a 1.5-to-2-time risk of CVD than HIV-negative persons. Data suggests that by the year 2030, an estimated 78% of persons with HIV will have cardiovascular disease. The relationship between HIV and CVD, in marginalized populations, is not well understood because overall awareness of HIV and CVD, as comorbid conditions, is low, which further heightens risk. This has created a critically pressing issue affecting underrepresented ethnic and racial populations with HIV and requires immediate efforts to mitigate risk. OBJECTIVE:The purpose of this formative, mixed methods study is to use a community-engaged approach to map a behavioral intervention for cardiovascular disease prevention in Black and Latinx sexual minority men with HIV in New York City. METHODS:Literature reviews focused on behavioral prevention studies using intervention mapping. In Aim 1, we will use qualitative interviews with HIV program managers and community members to understand facilitators and barriers to CVD prevention, chronic illnesses of concern, and early design elements needed for a web-based CVD prevention intervention. In Aim 2, we will conduct qualitative interviews and administer cross-sectional validated surveys with 30 Black and Latinx sexual minority men with HIV. We will assess illness perceptions of chronic conditions, such as HIV, hypertension, and diabetes. A total of 40 participants (program managers and community members) for Aims 1 and 2 will be enrolled to participate. To develop the protocol, we will follow steps 1 through 3 (needs assessment, change objectives, implementation strategy) of intervention mapping, using mixed methods. RESULTS:The study was approved by New York University Institutional Review Board in February 2021 (IRB-FY2021-4772) and also by the Yale University Institutional Review Board in June 2022 (2000031577). Data collection is ongoing. We anticipate completing data collection on or before December 2022. Early analyses suggested concerns about illnesses outside of HIV and associate comorbid conditions, such as COVID-19 and Monkeypox. Additionally, we noted a strong interest in using a web-based platform for CVD prevention education. CONCLUSIONS:Web-based, behavioral, CVD prevention interventions may be promising modalities to closing the cardiovascular health disparities gap in Black and Latinx sexual minority men with HIV by extending the reach of prevention interventions using community informed approaches and technological modalities that have been underutilized in this population. CLINICALTRIAL/BACKGROUND/:

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder that affects many organs. It is caused by the expansion of a cytosine-thymine-guanine triplet repeat in the 3' untranslated region of the human dystrophia myotonica protein kinase (hDMPK) gene, which results in a toxic gain of function of mutant hDMPK RNA transcripts. Antisense oligonucleotides (ASOs) have emerged in recent years as a potential gene therapy to treat DM1. However, the clinical efficacy of the systemic administration of ASOs is limited by a combination of insufficient potency and poor tissue distribution. In the present study, we assessed the potential of a new ligand-conjugated ASO (IONIS-877864; C16-HA-ASO) to target mutant hDMPK mRNA transcripts in the DMSXL mouse model of DM1 carrying over 1000 CTG pathogenic repeats. DMSXL mice were treated subcutaneously for 9 weeks with either IONIS-877864 (12.5 or 25 mg/kg) or IONIS-486178 (12.5 or 25 mg/kg), an unconjugated ASO with the same sequence. At 25 mg/kg, IONIS-877864 significantly enhanced ASO delivery into the striated muscles of DMSXL mice following systemic administration compared with the unconjugated control. IONIS-877864 was also more efficacious than IONIS-486178, reducing mutant hDMPK transcripts by up to 92% in the skeletal muscles and 78% in the hearts of DMSXL mice. The decrease in mutant hDMPK transcripts in skeletal muscles caused by IONIS-877864 was associated with a significant improvement in muscle strength. IONIS-877864 was nontoxic in the DMSXL mouse model. The present study showed that the C16-HA-conjugated ASO is a powerful tool for the development of gene therapy for DM1.