Prevalence and Phenotypic Burden of Monogenic Arrhythmias Using Integration of Electronic Health Records With Genetics.

BACKGROUND: Inherited primary arrhythmia syndromes and arrhythmogenic cardiomyopathies can lead to sudden cardiac arrest in otherwise healthy individuals. The burden and expression of these diseases in a real-world, well-phenotyped cardiovascular population is not well understood. METHODS: Whole exome sequencing was performed on 8574 individuals from the CATHGEN cohort (Catheterization Genetics). Variants in 55 arrhythmia-related genes (associated with 8 disorders) were identified and assessed for pathogenicity based on American College of Genetics and Genomics/Association for Molecular Pathology criteria. Individuals carrying pathogenic/likely pathogenic (P/LP) variants were grouped by arrhythmogenic disorder and matched 1:5 to noncarrier controls based on age, sex, and genetic ancestry. Long-term phenotypic data were annotated through deep electronic health record review. RESULTS: Fifty-eight P/LP variants were found in 79 individuals in 12 genes associated with 5 arrhythmogenic disorders (arrhythmogenic right ventricular cardiomyopathy, Brugada syndrome, hypertrophic cardiomyopathy, LMNA-related cardiomyopathy, and long QT syndrome). The penetrance of these P/LP variants in this cardiovascular cohort was 33%, 0%, 28%, 83%, and 4%, respectively. Carriers of P/LP variants associated with arrhythmogenic disorders showed significant differences in ECG, imaging, and clinical phenotypes compared with noncarriers, but displayed no difference in survival. Carriers of novel truncating variants in FLNC, MYBPC3, and MYH7 also developed relevant arrhythmogenic cardiomyopathy phenotypes. CONCLUSIONS: In a real-world cardiovascular cohort, P/LP variants in arrhythmia-related genes were relatively common (1:108 prevalence) and most penetrant in LMNA. While hypertrophic cardiomyopathy P/LP variant carriers showed significant differences in clinical outcomes compared with noncarriers, carriers of P/LP variants associated with other arrhythmogenic disorders displayed only ECG differences.

Novel plasma biomarkers improve discrimination of metabolic health independent of weight.

We sought to determine if novel plasma biomarkers improve traditionally defined metabolic health (MH) in predicting risk of cardiovascular disease (CVD) events irrespective of weight. Poor MH was defined in CATHGEN biorepository participants (n > 9300), a follow-up cohort (> 5600 days) comprising participants undergoing evaluation for possible ischemic heart disease. Lipoprotein subparticles, lipoprotein-insulin resistance (LP-IR), and GlycA were measured using NMR spectroscopy (n = 8385), while acylcarnitines and amino acids were measured using flow-injection, tandem mass spectrometry (n = 3592). Multivariable Cox proportional hazards models determined association of poor MH and plasma biomarkers with time-to-all-cause mortality or incident myocardial infarction. Low-density lipoprotein particle size and high-density lipoprotein, small and medium particle size (HMSP), GlycA, LP-IR, short-chain dicarboxylacylcarnitines (SCDA), and branched-chain amino acid plasma biomarkers were independently associated with CVD events after adjustment for traditionally defined MH in the overall cohort (p = 3.3 × 10-4-3.6 × 10-123), as well as within most of the individual BMI categories (p = 8.1 × 10-3-1.4 × 10-49). LP-IR, GlycA, HMSP, and SCDA improved metrics of model fit analyses beyond that of traditionally defined MH. We found that LP-IR, GlycA, HMSP, and SCDA improve traditionally defined MH models in prediction of adverse CVD events irrespective of BMI.

Identification of Undetected Monogenic Cardiovascular Disorders.

BACKGROUND: Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed. OBJECTIVES: The purpose of this study was to estimate the prevalence of monogenic cardiovascular diseases (MCVDs) and potentially missed diagnoses in a cardiovascular cohort. METHODS: Exomes from 8,574 individuals referred for cardiac catheterization were analyzed. Pathogenic/likely pathogenic (P/LP) variants associated with MCVD (cardiomyopathies, arrhythmias, connective tissue disorders, and familial hypercholesterolemia were identified. Electronic health records (EHRs) were reviewed for individuals harboring P/LP variants who were predicted to develop disease (G+). G+ individuals who did not have a documented relevant diagnosis were classified into groups of whether they may represent missed diagnoses (unknown, unlikely, possible, probable, or definite) based on relevant diagnostic criteria/features for that disease. RESULTS: In total, 159 P/LP variants were identified; 2,361 individuals harbored at least 1 P/LP variant, of whom 389 G+ individuals (4.5% of total cohort) were predicted to have at least 1 MCVD. EHR review of 342 G+ individuals predicted to have 1 MCVD with sufficient EHR data revealed that 52 had been given the relevant clinical diagnosis. The remaining 290 individuals were classified as potentially having an MCVD as follows: 193 unlikely (66.6%), 50 possible (17.2%), 30 probable (10.3%), and 17 definite (5.9%). Grouping possible, probable, definite, and known diagnoses, 149 were considered to have an MCVD. Novel MCVD pathogenic variants were identified in 16 individuals. CONCLUSIONS: Overall, 149 individuals (1.7% of cohort) had MCVDs, but only 35% were diagnosed. These patients represents a "missed opportunity," which could be addressed by greater use of genetic testing of patients seen by cardiologists.

Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1).

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome-wide association study (EWAS) for all-cause mortality with whole-transcriptome data in a cardiovascular cohort (CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow-up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δß). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated (P<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate-adjusted P<0.10: cg08215811 (SLC4A9; log2 fold change=-0.14); cg17845532 (MATK; fold change=-0.26); and cg17944110 (castor zinc finger 1 [CASZ1]; FC=0.26; P<0.0001; false discovery rate-adjusted P=0.046-0.080). Meta-analysis identified 6 probes (false discovery rate-adjusted P<0.05): the 3 above, cg20428720 (intergenic), cg17647904 (NCOR2), and cg23198793 (CAPN3). Messenger RNA expression of 2 MATK isoforms was lower in cases (fold change=-0.24 [P=0.007] and fold change=-0.61 [P=0.009]). The CASZ1, NCOR2, and CAPN3 transcripts did not show differential expression (P>0.05); the SLC4A9 transcript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element, UBIAD1 (P=0.01) and CLSTN1 (P=0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all-cause mortality. Methylation in CASZ1 may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.