Biomedical subjects

Victoria N Parikh

Publications and source records attributed to Victoria N Parikh.

3 recordsLinked to original sources

PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P < .001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P < .001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P < .001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P = .046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P < .001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P = .01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗

PubMed2026

Social Determinants of Health and Clinical Outcomes in Hypertrophic Cardiomyopathy.

IMPORTANCE: Area-based indicators of social determinants of health (SDOH) are associated with higher risk for acquired heart disease, but their impact on conditions with a strong genetic etiology, such as hypertrophic cardiomyopathy (HCM), is not well understood. OBJECTIVE: To determine the association of area-based SDOH with clinical outcomes in patients with HCM. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, prospective cohort study was conducted among US adult patients with HCM from 5 sites in the Sarcomeric Human Cardiomyopathy Registry (a multicenter prospective registry of patients with HCM) who were followed up for a median (IQR) period of 2.15 (0.15-5.82) years. Data were entered from 2015 to March 2024, and data analysis was completed from March 2024 to June 2025. EXPOSURES: Patients' residential addresses were geocoded at the zip code level and linked to the American Communities Survey to estimate area-based (1) median household income and (2) social deprivation index (SDI), which ranges from 0 to 100, with higher scores indicating a more deprived area. MAIN OUTCOMES AND MEASURES: Multivariate models, adjusting for age at diagnosis, body mass index, hypertension, and sex, were used to estimate the independent association of area-based median household income and SDI with heart failure (HF), ventricular arrhythmias (VA), and an overall composite outcome (VA, HF, atrial fibrillation, stroke, and death). RESULTS: Among 4431 US adult patients with HCM, median (IQR) age at HCM diagnosis was 51.3 (38.9-61.6) years, and 1862 patients (42.0%) were female. Median (IQR) area-based household income was $80 000 ($60 000-$110 000), and median (IQR) SDI was 25 (10-55). Adjusted hazard ratios comparing the lowest income group to the highest income group were 2.07 (95% CI, 1.77-2.42; P < .001) for HF, 1.31 (95% CI, 0.97-1.78; P = .08) for VA, and 1.52 (95% CI, 1.36-1.69; P < .001) for the overall composite outcome. Adjusted hazard ratios comparing the highest SDI (ie, more deprived) group to the lowest SDI group were 1.48 (95% CI, 1.29-1.70; P < .001) for HF, 1.55 (95% CI, 1.15-2.09; P = .004) for VA, and 1.36 (95% CI, 1.22-1.50; P < .001) for the overall composite outcome. CONCLUSIONS AND RELEVANCE: In this multicenter cohort study, residing in an area with lower median household income or worse SDI were each independently associated with adverse clinical outcomes in patients with HCM. These findings suggest that despite the genetically determined nature of HCM, place of residence is associated with patient outcomes.

Humans↗

PubMed2025

Creating an atlas of variant effects to resolve variants of uncertain significance and guide cardiovascular medicine.

Cardiovascular diseases are leading global causes of death and disability, often presenting as interrelated phenotypes of atherosclerotic vascular disease, heart failure and arrhythmias. Cardiovascular diseases arise from interactions between environmental factors and predisposing genotypes and include common Mendelian lipid disorders, cardiomyopathies and arrhythmia syndromes. The identification of a pathogenic variant through genetic testing can inform disease diagnosis, risk prediction, treatment and family screening. However, a major roadblock in genomic medicine is that for many variants, especially missense variants, we lack sufficient evidence to enable a definitive classification, and therefore these variants are deemed as 'variants of uncertain significance'. In this Review, we describe how multiplexed assays of variant effects can enable the functional assessment of nearly all coding variants in a target sequence, potentially offering a proactive approach to identifying the functional significance of gene variants that are observed later in a patient. We discuss validation, including the role of in silico variant effect predictors, and how multiplexed experimental methods are informing cardiovascular disease biology and ultimately resolving the problem of variants of uncertain significance at scale.

Humans↗