The Limb Girdle Muscular Dystrophy Health Index (LGMD-HI).

Limb girdle muscular dystrophy (LGMD) is a debilitating disease and the fourth most common muscular dystrophy. This study describes the development of the LGMD-Health Index (LGMD-HI). Participants were aged >18 years and recruited from three LGMD registries and GRASP-LGMD consortium. The initial instrument, comprised of 16 thematic subscales and 161 items, underwent expert review resulting in item removal as well as confirmatory factor analysis followed by inter-rater reliability and internal consistency of the subscales. Following expert review, one subscale and 59 items were eliminated. Inter-rater reliability was assessed and five items were removed due to Cohen's kappa <0.5. The final subscales had high internal consistencies with an average Cronbach alpha of 0.92. Test re-test reliability of the final instrument was high (intraclass correlation coefficient=0.97). Known groups validity testing showed a statistically significant difference in LGMD-HI scores amongst subjects based on ambulation status (28.7 vs 50.0, p < 0.0001), but not sex, employment status, or genetic subtype. The final instrument is comprised of 15 subscales and 97 items. The LGMD-HI is a disease-specific, patient-reported outcome measure designed in compliance with published FDA guidelines. This instrument is capable of measuring burden of disease with no significant variation based on LGMD subtype.

Epigenetic Regulation of Cardiomyocyte Maturation by Arginine Methyltransferase CARM1.

BACKGROUND: During the neonatal stage, the cardiomyocyte undergoes a constellation of molecular, cytoarchitectural, and functional changes known collectively as cardiomyocyte maturation to increase myocardial contractility and cardiac output. Despite the importance of cardiomyocyte maturation, the molecular mechanisms governing this critical process remain largely unexplored. METHODS: We leveraged an in vivo mosaic knockout system to characterize the role of Carm1, the founding member of protein arginine methyltransferase, in cardiomyocyte maturation. Using a battery of assays, including immunohistochemistry, immuno-electron microscopy imaging, and action potential recording, we assessed the effect of loss of Carm1 function on cardiomyocyte cell growth, myofibril expansion, T-tubule formation, and electrophysiological maturation. Genome-wide transcriptome profiling, H3R17me2a chromatin immunoprecipitation followed by sequencing, and assay for transposase-accessible chromatin with high-throughput sequencing were used to investigate the mechanisms by which CARM1 (coactivator-associated arginine methyltransferase 1) regulates cardiomyocyte maturation. Finally, we interrogated the human syntenic region to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks for single-nucleotide polymorphisms associated with human heart diseases. RESULTS: We report that mosaic ablation of Carm1 disrupts multiple aspects of cardiomyocyte maturation cell autonomously, leading to reduced cardiomyocyte size and sarcomere thickness, severe loss and disorganization of T tubules, and compromised electrophysiological maturation. Genomics study demonstrates that CARM1 directly activates genes that underlie cardiomyocyte cytoarchitectural and electrophysiological maturation. Moreover, our study reveals significant enrichment of human heart disease-associated single-nucleotide polymorphisms in the human genomic region syntenic to the H3R17me2a chromatin immunoprecipitation followed by sequencing peaks. CONCLUSIONS: This study establishes a critical and multifaceted role for CARM1 in regulating cardiomyocyte maturation and demonstrates that deregulation of CARM1-dependent cardiomyocyte maturation gene expression may contribute to human heart diseases.

Contemporary Trends in Acute Myocardial Infarction in the American Indian/Alaska Native U.S. Population, 2000 to 2018.

Coronary heart disease is disproportionately prevalent in the American Indian/Alaska Native (AI/AN) population. As care for acute myocardial infarction (AMI) continues to advance, equitable distribution and access for the AI/AN population is essential. Primary AMI hospitalizations for adults ≥18 years of age were identified from the Healthcare Cost and Utilization Project National Inpatient Sample from 2000 to 2018. Related co-morbidities, procedures of interest, and in-hospital mortality were also identified. These rates were stratified by race then trended over years using Poisson regression. Overall, 9,904,714 weighted hospitalizations for primary AMI were identified. From 2000 to 2018, AI/AN adults had relatively high rates of primary AMI hospitalization, second only to non-Hispanic (NH) White adults. The AMI rate increased from 14.0/1,000 to 16.1/1,000 among AI/AN adults, remaining higher than NH Black adults (12.1/1,000 to 13.0/1,000) and Hispanic adults (10.3/1,000 and 12.7/1,000) and becoming increasingly closer to NH White adults (25.1/1,000 to 20.0/1,000) (p <0.001 for each). AI/AN adults presented 5 years earlier than their NH White counterparts (64 vs 69 years old; p <0.001). In-hospital mortality was approximately 5% for all race categories and decreased in all groups but decreased at a much greater rate for NH White, NH Black and Hispanic adults (0.2% per year) compared with AI/AN adults (0.08% per year; p <0.001 for each comparison). Rates of coronary angiography and percutaneous coronary intervention increased in all groups, but coronary artery bypass graft utilization increased only in AI/AN adults (from 7% to 10%, p <0.001). In conclusion, from 2000 to 2018, AI/AN adults had a high rate of AMI hospitalizations (second only to NH White adults) that increased significantly over time. AI/AN adults were 5 years younger than their NH White counterparts at index AMI hospitalization. Care during these hospitalizations was similar among all racial groups, and in-hospital mortality decreased for all groups, albeit to a lesser degree among AI/AN adults. This study highlights the need for improved access to outpatient primary AMI prevention in the AI/AN population.