Risk Of Dilated Cardiomyopathy Research Articles

Association between dietary selenium and zinc intake and risk of dilated cardiomyopathy in children: a case-control study

BackgroundDilated cardiomyopathy (DCMP) is characterized by the enlargement and weakening of the heart and is a major cause of heart failure in children. Infection and nutritional deficiencies are culprits for DCMP. Zinc is an important nutrient for human health due to its anti-oxidant effect that protects cell against oxidative damage. This case-control study aimed to investigate the relationship between dietary intake of zinc and selenium and the risk of DCMP in pediatric patients.MethodsA total of 36 DCMP patients and 72 matched controls were recruited, and their dietary intakes were assessed via a validated food frequency questionnaire. We used chi-square and sample T-test for qualitative and quantitative variables, respectively. Logistic regression analysis was applied to assess the relationship between selenium and zinc intake with the risk of DCMP.ResultsAfter fully adjusting for confounding factors, analyses showed that selenium (OR = 0.19, CI = 0.057–0.069, P trend < 0.011) and zinc (OR = 0.12, CI = 0.035–0.046, P trend < 0.002) intake were strongly associated with 81% and 88% lower risk of pediatric DCMP, respectively.ConclusionsThis study highlights the protective role of adequate dietary intake of selenium and zinc in decreasing the risk of DCMP in children. Malnutrition may exacerbate the condition and addressing these micronutrient deficiencies may improve the cardiac function. Further studies are recommended to detect the underlying mechanisms and dietary recommendations for DCMP prevention.

Causal Relationship Between Immune Cells/Cytokines and Dilated Cardiomyopathy.

To date, whether there is any causal relationship between dilated cardiomyopathy (DCM) and the changes in the levels/expression of immune cells/cytokines is still unclear. This study aimed to investigate the causal relationship between the levels of various types of immune cells/cytokines and DCM. Herein, two-sample Mendelian randomization (MR) (TSMR) using R software was conducted. Single nucleotide polymorphisms (SNPs) related to the levels of various types of immune cells/cytokines and DCM were screened based on the genome-wide association studies (GWAS) obtained from open-source databases. The TSMR was conducted using inverse variance weighted (IVW), method, MR-Egger regression, weighted median method, and simple estimator based on mode to explore the causal association between the levels of each immune cell/cytokine and DCM. Sensitivity analysis was conducted using MR-Egger regression and a leave-one-out sensitivity test. A total of 1816 SNPs related to host immune status and DCM were identified. The IVW results showed a relationship between DCM and the circulating levels of basophils/eosinophils, total eosinophils-basophils, lymphocytes, and C-reactive protein (CRP). Increased lymphocytes levels (odds ratio (OR) = 0.91, 95% confidence interval (CI): 0.84-0.97, P = 0.005) were seen as protective against DCM, whereas increased basophil (OR = 1.18, 95% CI: 1.04-1.33, P = 0.022), eosinophil (OR = 1.1, 95% CI: 1.03-1.17, P = 0.007), eosinophil-basophil (OR = 1.09, 95% CI: 1.02-1.17, P = 0.014), and CRP (OR = 1.1, 95% CI: 1.03-1.18, P = 0.013) levels were associated with an increased risk of DCM. These analyses revealed that there may be a relationship between immune cells/select cytokine status and the onset of DCM. Future studies are required to further validate these outcomes in animal models and clinical trials.

M6A regulator-mediated RNA methylation modification remodels immune microenvironment in dilated cardiomyopathy.

The latest evidence suggested that the onset of dilated cardiomyopathy (DCM)is closely associated with immune microenvironment disturbance. Since N6 -methyladenosine (m6A) RNA methylation impacts on immunocyte function and antitumor immunity, it is predictable that m6A RNA methylation may result in immune microenvironment disorder. Here, we attempted to verify this hypothesis. We used single-sample gene set enrichment analysis (ssGSEA)to investigate the infiltration abundance of immunocytes, single-cell RNA-Seq to identify key m6A regulator, and a doxorubicin (Dox)-induced DCM mouse model to confirm our findings. ssGSEA revealed a higher infiltration abundance of CD8+ T lymphocytes, NK cells, monocytes, and B+ lymphocytes in DCM myocardium tissue. Single-cell RNA-Seq indicated a critical role of IGFBP2 in DCM. Cross-checking analysis hinted an interaction between IGFBP2 and NSUN5, ALYREF, RRP8, and ALKBH3. Mechanically, IGFBP2-mediated RNA methylation deteriorated the immune microenvironment and thus increased the risk of DCM by enhancing CD8+ T lymphocyte, NK cell, monocyte, B+ lymphocyte infiltration and activating check-point, MHC-I, and T cell co-stimulation signaling pathways. In the DCM mouse model, echocardiography indicated a significant reduction in ejection fraction (EF)and fractional shortening (FS)and an increase in left ventricular internal dimensions at systole (LVIDs)and diastole (LVIDd).MASSON staining indicated an increased fibrosis in myocardium tissue. qPCR and immunofluorescence staining indicated a significant increase in mRNA and protein levels of IGFBP2. The present study indicated that IGFBP2-mediated RNA methylation remodeled the immune microenvironment and increased the risk of DCM. IGFBP2 may serve as potential therapeutic target for DCM.

Association of rs35006907 Polymorphism with Risk of Dilated Cardiomyopathy in Han Chinese Population.

Several investigations have demonstrated the association of MTSS1 with left ventricular (LV) structure and function. A recently published study has even revealed that rs35006907 was associated with both MTSS1 expression and the risk of dilated cardiomyopathy (DCM). Our study intended to investigate the relationship between rs35006907 and the risk of DCM in the Han Chinese population. A total of 529 DCM and 600 healthy controls were recruited. We conducted genotyping for rs35006907 in all participants. Gene association studies were performed to assess the association between rs35006907 and the risk of DCM. A series of functional assays including western blot, realtime PCR and firefly luciferase reporter gene assays were conducted to illuminate the underlying mechanism. We found that rs35006907-A allele was significantly associated with reduced risk of DCM in additive (p= 0.004; OR=0.78; 95% CI=0.66-0.93) and recessive models (p= 0.0005; OR=0.56; 95%CI=0.41-0.78) when compared with the rs35006907-C allele. There were significant differences in the left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) between rs35006907-CC/AC and AA genotypes. Furthermore, the variant rs35006907-A allele presented lower reporter gene activity, reduced mRNA and protein expression levels when compared with the C allele. Our findings demonstrated that rs35006907-C allele increased the risk of DCM in Han Chinese population. Besides, rs35006907-C displayed higher reporter gene activity and increased MTSS1 expression in human samples.

Association of rs505080 Single Nucleotide Polymorphism in Lamin-A Gene with Familial Dilated Cardiomyopathy in Iranian Population; A Case-Control Study

Background: Dilated cardiomyopathy (DCM) is among the most prevalent causes of heart failure and sudden cardiac death worldwide. Nuclear lamin protein coding genes are believed to have a definitive role in the DCM phenotype. The rs505058 thymine (T) to cytosine (C) polymorphism in the lamin-A gene is one of the most common mutations reported in familial DCM in previous studies. Objectives: We aimed to demonstrate the possible role of this SNP in the lamin A and C (LMNA) gene in the incidence of DCM among the south of Iran population. Methods: This case-control study included 65 patients with familial DCM and 70 healthy participants in south Iran. DNA was extracted from nucleated blood cells, and polymerase chain reaction (PCR) was performed. First, the sequence of the LMNA gene was investigated. Then the frequency of alleles C (mutated allele) and T (normal) of the LMNA gene (rs505058) was compared between the case and controls. Results: No notable differences were seen in gender and age between the case and controls. The genotype frequencies of the LMNA rs505058 T/C polymorphism were 6% (CC), 31% (CT), and 63% (TT) amongst cases, and 1% (CC), 13% (CT) and 86% (TT) in controls. For allele level comparison, the LMNA rs505058 C allele has been shown to have a statistically significant association with an enhancement in the risk of dilated cardiomyopathy (OR = 2.92; 95% CI = 1.05 to 8.15, P-value = 0.034) Conclusions: The results indicated that the rs505058 T/C SNP of the LMNA gene is associated with familial DCM patients in the Iranian population.

Characterization of cardiac involvement in children with LMNA-related muscular dystrophy.

Introduction: LMNA-related muscular dystrophy is a rare entity that produce "laminopathies" such as Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy. Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR). Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis. Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death.

Fatty acids and risk of dilated cardiomyopathy: A two-sample Mendelian randomization study.

Previous observational studies have shown intimate associations between fatty acids (FAs) and dilated cardiomyopathy (DCM). However, due to the confounding factors and reverse causal association found in observational epidemiological studies, the etiological explanation is not credible. To exclude possible confounding factors and reverse causal associations found in observational epidemiological studies, we used the two-sample Mendelian randomization (MR) analysis to verify the causal relationship between FAs and DCM risk. All data of 54 FAs were downloaded from the genome-wide association studies (GWAS) catalog, and the summary statistics of DCM were extracted from the HF Molecular Epidemiology for Therapeutic Targets Consortium GWAS. Two-sample MR analysis was conducted to evaluate the causal effect of FAs on DCM risk through several analytical methods, including MR-Egger, inverse variance weighting (IVW), maximum likelihood, weighted median estimator (WME), and the MR pleiotropy residual sum and outlier test (MRPRESSO). Directionality tests using MR-Steiger to assess the possibility of reverse causation. Our analysis identified two FAs, oleic acid and fatty acid (18:1)-OH, that may have a significant causal effect on DCM. MR analyses indicated that oleic acid was suggestively associated with a heightened risk of DCM (OR = 1.291, 95%CI: 1.044-1.595, P = 0.018). As a probable metabolite of oleic acid, fatty acid (18:1)-OH has a suggestive association with a lower risk of DCM (OR = 0.402, 95%CI: 0.167-0.966, P = 0.041). The results of the directionality test suggested that there was no reverse causality between exposure and outcome (P < 0.001). In contrast, the other 52 available FAs were discovered to have no significant causal relationships with DCM (P > 0.05). Our findings propose that oleic acid and fatty acid (18:1)-OH may have causal relationships with DCM, indicating that the risk of DCM from oleic acid may be decreased by encouraging the conversion of oleic acid to fatty acid (18:1)-OH.

Exploring the Role of Obesity in Dilated Cardiomyopathy Based on Bio-informatics Analysis.

(1) Background: Obesity is a major risk factor for cardiovascular disease (CVD), contributing to increasing global disease burdens. Apart from heart failure, coronary artery disease, and arrhythmia, recent research has found that obesity also elevates the risk of dilated cardiomyopathy (DCM). The main purpose of this study was to investigate the underlying biological role of obesity in increasing the risk of DCM. (2) Methods: The datasets GSE120895, GSE19303, and GSE2508 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using GSE120895 for DCM and GSE2508 for obesity, and the findings were compiled to discover the common genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for the common genes in RStudio. In addition, CIBERSORT was used to obtain the immune cellular composition from DEGs. The key genes were identified in the set of common genes by the least absolute shrinkage and selection operator (LASSO) algorithm, the prognostic risk models of which were verified by receiver operator characteristic (ROC) curves in GSE19303. Finally, Spearman's correlation was used to explore the connections between key genes and immune cells. (3) Results: GO and KEGG pathway enrichment analyses showed that the main enriched terms of the common genes were transforming growth factor-beta (TGF-β), fibrillar collagen, NADPH oxidase activity, and multiple hormone-related signaling pathways. Both obesity and DCM had a disordered immune environment, especially obesity. The key genes NOX4, CCDC80, COL1A2, HTRA1, and KLHL29 may be primarily responsible for the changes. Spearman's correlation analysis performed for key genes and immune cells indicated that KLHL29 closely correlated to T cells and M2 macrophages, and HTRA1 very tightly correlated to plasma cells. (4) Conclusions: Bio-informatics analyses performed for DCM and obesity in our study suggested that obesity disturbed the immune micro-environment, promoted oxidative stress, and increased myocardial fibrosis, resulting in ventricular remodeling and an increased risk of DCM. The key genes KLHL29 and HTRA1 may play critical roles in obesity-related DCM.

Abstract 15670: Clinical Relevance of a Polygenic Susceptibility to Dilated Cardiomyopathy

Introduction: Both rare and common genetic variants have been associated with dilated cardiomyopathy (DCM), but their contributions to DCM risk in the context of clinical factors remains unexplored. Methods: In the UK Biobank, we identified carriers of rare, monogenic variants of relevance to DCM (ClinGenLOF), and also computed a genome-wide, common-variant (polygenic) score (GPS) based on imaging-derived measures of left ventricular structure and function. We evaluated the contributions of ClinGenLOF status, the GPS, and clinical factors to incident DCM through measures of relative risk, phenotypic variance explained (i.e. population attributable fraction, PAF), and discrimination. Results: In 160,485 UK Biobank participants, mean age was 56.5 (SD 8.1), 89,888 (56%) were female, and 226 developed DCM during a median of 10.9 years of follow-up. ClinGenLOF carriers had the highest hazards of disease (HR=14.5, 95%CI: 9.43 to 22.11), followed by atrial fibrillation (HR=3.25, 95%CI:1.94 to 5.48), and chronic kidney disease (2.56 95%CI:0.81 to 8.12). In contrast, hypertension accounted for the greatest proportion of DCM risk in the population (PAF=23.2%) followed by having a high (&gt;80th percentile) polygenic score (PAF= 17.9%). On top of a reference model, improvements in discrimination were individually greatest with addition of ClinGenLOF status (delta C-index = 0.049) or the GPS (delta C-index = 0.031), comparable to the addition of all clinical factors combined (delta C-index = 0.032; Figure ). When added sequentially to a model inclusive of clinical factors, ClinGenLOF status (delta C-index = 0.046) and GPS (additional delta C-index = 0.021) further improved discrimination. Conclusions: Rare, monogenic variants, a polygenic score, and clinical factors all contribute substantially to risk of DCM. Considering cumulative genetic (monogenic and polygenic) risk on top of clinical factors improves the prediction of incident DCM in the general population.

DILATED CARDIOMYOPATHY WITH CARDIOGENIC SHOCK SECONDARY TO COVID-19 INFECTION

DILATED CARDIOMYOPATHY WITH CARDIOGENIC SHOCK SECONDARY TO COVID-19 INFECTION

Risk Factors for Heart Disease in Pet Dogs Attended At a Veterinary Teaching Hospital in Malaysia

The distribution and risk factors of canine heart disease in Malaysia are still not widely studied. This retrospective study examined the distribution of common canine heart diseases and the role of gender, age group, and breed size as risk factors of the dogs in a teaching hospital in Malaysia. Medical records of all dogs presented between 2013 and 2020 with a heart disease diagnosed were reviewed and analyzed. Univariate and multivariate logistic regression was carried out to identify the risk factors for canine heart diseases in general and based on specific disease. In a duration of 7 years, a total of 9255 dog cases were presented and 7.9% (n=734, 95% CI: 0.07-0.09) of the dogs were diagnosed with heart disease. Majority of heart disease cases were valvular disease (n=528, 95% CI: 0.05-0.06), followed by heartworm disease (n=113. 95% CI: 0.01-0.01), dilated cardiomyopathy (DCM) (n=90, 95% CI: 0.01-0.01). Senior (OR 3.54, 95% CI: 2.32-5.37) and small breed (OR 6.74, 95% CI: 4.51-10.1) dogs had higher risk for valvular disease, while large breed (OR 7.18, 95% CI: 4.00-13.01) dogs were at risk for heartworm disease. Male (OR 1.83, 95% CI:1.11-3.04) and large breed dogs (OR 3.12, 95% CI: 1.80-5.39) had greater risk for DCM, respectively. Gender, age group and breed size play important role in predicting the likelihood of heart diseases in dogs and are best to be applied in the context of specific heart diseases. Information obtained would assist clinicians with their clinical diagnosis of the heart disease.

KARDIOMIOPATIA ROZSTRZENIOWA U PSA DOMOWEGO – ANALIZA IN SILICO WYBRANYCH GENÓW

Dilated cardiomyopathy (DCM) is a progressive loss of contractility of the heart muscle as the disease progresses. It causes a decrease in the heart’s minute capacity, i.e. the volume of blood pumped by the heart into the blood vessels in one minute. DCM leads to congestive heart failure and sudden death. The aim of this study was to identify in silico genes within which mutations have occurred that may cause DCM in the domestic dog (Canis lupus familiaris), to identify dog breeds at risk, and to propose breed-specific diagnostic molecular tests. For bioinformatic analyses of sequences retrieved from GenBank (NC_006587.3 – FGGY, NC_006583.3 – DCC and CM023383.1 – PDE3B) and from scientific publications (PDK4 – from patent publication number US 2011/0307965 A1 and STRN – Meurs et al. 2010), the following programs were used: Primer3 v. 0.4.0, NEBcutter v. 2.0 and BLAST. Based on literature data, domestic dog breeds such as Doberman Pinscher, Boxer, Portuguese Water Dog, Newfoundland, Irish Wolfhound and Great Dane were found to be among the breeds with the highest risk of DCM. In order to identify relevant mutations in the genes studied (FGGY, DCC, PDE3B, PDK4 and STRN) that may cause the occurrence of dilated cardiomyopathy, the use of specific restriction enzymes has been proposed in molecular diagnostic tests: BmiI for mutations in the PDK4 gene and Tth111I for SNPs in the FGGY gene (Doberman Pinscher) and TaqI for SNPs in the DCC gene and HinfI for SNPs in the PDE3B gene (Irish Wolfhound). This work, may serve as a prelude to analysis for targeted genetic testing to enable correct diagnosis of DCM in asymptomatic dogs

HF-566-01 INTERACTION OF ARRHYTHMIA AND CARDIOMYOPATHY WITH GENETIC VARIANT GROUPS IN THE UK BIOBANK POPULATION

Dilated cardiomyopathy (DCM) is a common cause of heart failure and rhythm disorders. It is estimated that a large proportion of DCM cases are familial and more than 250 genes of various functional groups have been suggested to be involved in the disease. However, there is a paucity of robust evidence regarding the majority of these genes’ role in the pathogenicity of DCM. Recently, an international group has curated a list of 51 DCM genes grouped by their level of evidence, graded as definitive, strong, moderate, limited, disputed and unknown. We evaluated the risk for DCM, arrhythmia and cardiovascular outcomes in individuals with rare variants in each of the curated gene groups using whole exome sequences (WES), cardiac MRI and clinical data from 200,630 UK Biobank participants. We annotated WES rare variants (MAF < 4×10-5) in four categories: nonsynonymous, nonsense, “ClinVar” pathogenic and likely pathogenic (P/LP), and SIFT predicted deleterious variants. We collected ICD codes for DCM, ventricular arrhythmias (VT, VF), supraventricular (SV) arrhythmias including SVT, AF, flutter, and AV block. Cardiac MRI was available for 21,222 of the WES individuals. We extracted the LV ejection fraction (LVEF), end-systolic (LVESV) and end-diastolic volumes (LVEDV). We removed outliers > 7 SD from the mean and normalized volumes (LVEDV, LVESV) by body surface area (BSA), age and sex. For each of the gene groups, we compared those with rare variants to the rest. We validated that nonsense variants in genes of the definitive and strong evidence group were associated with both adverse cardiovascular outcomes, LV dilation and ventricular/SV arrhythmia. Importantly, we found that genes in the “moderate” evidence group (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) with ClinVar annotations were associated with increased cardiac morbidity (OR 3.6, 95% CI 1.7-7.6), and variants with SIFT or nonsynonymous annotations were associated with increased LVESV (+3.94 ml vs control, p<0.001) and LVEDV (+4.45 ml vs control, p=0.03), and decreased LVEF (-0.65% vs control, p=0.03), as well as with SV arrhythmia (OR 5.1, 95% CI 2.2-11.6). We provide evidence to support the interaction of genes previously classified as “moderate” with DCM, arrhythmia and adverse cardiovascular outcomes.

Clinical Profile and Risk Factors for Cardiac Death in Pediatric Patients With Primary Dilated Cardiomyopathy at a Tertiary Medical Center in China.

AimWe sought to identify the clinical characteristics and risk factors for cardiac mortality in pediatric patients with primary dilated cardiomyopathy (DCM) in China.MethodsA total of 138 pediatric patients who were consecutively diagnosed with primary DCM from January 2011 to December 2020 were included. We assessed patients’ clinical symptoms and performed laboratory examinations, electrocardiography, and echocardiography.ResultsOf these patients, 79 (57%) had severe systolic dysfunction (left ventricular ejection fraction of < 30%), 79 (57.2%) developed DCM before 12 months of age, 62 (45%) were male, 121 (87.7%) presented with advanced heart failure (cardiac functional class III/IV), and 54 (39.1%) presented with arrhythmia. At a median follow-up of 12 months, the overall cardiac mortality rate was 33%, and 40 of 46 deaths occurred within 6 months following DCM diagnosis. A multivariate Cox regression analysis identified several independent cardiac death predictors, including an age of 12 months to 5 years [hazard ratio (HR) 2.799; 95% confidence interval (CI) 1.160–6.758; P = 0.022] or 10–15 years (HR 3.617; 95% CI 1.336–9.788; P = 0.011) at diagnosis, an elevated serum alanine aminotransferase (ALT) concentration (≥ 51.5 U/L) (HR 2.219; 95% CI 1.06–4.574; P = 0.031), and use of mechanical ventilation (HR 4.223; 95% CI 1.763–10.114; P = 0.001).ConclusionThe mortality rate of primary DCM without transplantation is high. Age, an elevated serum ALT concentration, and the need for mechanical ventilation predict mortality in patients with primary DCM, providing new insights into DCM risk stratification.

Clinical Utility and Validation of the Krakow DCM Risk Score-A Prognostic Model Dedicated to Dilated Cardiomyopathy.

Background: One of the most common causes of heart failure is dilated cardiomyopathy (DCM). In DCM, the mortality risk is high and reaches approximately 20% in 5 years. A patient’s prognosis should be established for appropriate HF management. However, so far, no validated tools have been available for the DCM population. Methods: The study population consisted of 735 DCM patients: 406 from the derivation cohort (previously described) and 329 from the validation cohort (from 2009 to 2020, with outcome data after a mean of 42 months). For each DCM patient, the individual mortality risk was calculated based on the Krakow DCM Risk Score. Results: During follow-up, 49 (15%) patients of the validation cohort died. They had shown significantly higher calculated 1-to-5-year mortality risks. The Krakow DCM Risk Score yielded good discrimination in terms of overall mortality risk, with an AUC of 0.704–0.765. Based on a 2-year mortality risk, patients were divided into non-high (≤6%) and high (>6%) mortality risk groups. The observed mortality rates were 8.3% (n = 44) vs. 42.6% (n = 75), respectively (HR 3.37; 95%CI 1.88–6.05; p < 0.0001). Conclusions: The Krakow DCM Risk Score was found to have good predictive accuracy. The 2-year mortality risk > 6% has good discrimination for the identification of high-risk patients and can be applied in everyday practice.

Prevalence and Cumulative Risk of Familial Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy (DCM) aggregates in families, and early detection in at-risk family members can provide opportunity to initiate treatment prior to late-phase disease. Most studies have included only White patients, yet Black patients with DCM have higher risk of heart failure-related hospitalization and death. To estimate the prevalence of familial DCM among DCM probands and the age-specific cumulative risk of DCM in first-degree relatives across race and ethnicity groups. A family-based, cross-sectional study conducted by a multisite consortium of 25 US heart failure programs. Participants included patients with DCM (probands), defined as left ventricular systolic dysfunction and left ventricular enlargement after excluding usual clinical causes, and their first-degree relatives. Enrollment commenced June 7, 2016; proband and family member enrollment concluded March 15, 2020, and April 1, 2021, respectively. The presence of DCM in a proband. Familial DCM defined by DCM in at least 1 first-degree relative; expanded familial DCM defined by the presence of DCM or either left ventricular enlargement or left ventricular systolic dysfunction without known cause in at least 1 first-degree relative. The study enrolled 1220 probands (median age, 52.8 years [IQR, 42.4-61.8]; 43.8% female; 43.1% Black and 8.3% Hispanic) and screened 1693 first-degree relatives for DCM. A median of 28% (IQR, 0%-60%) of living first-degree relatives were screened per family. The crude prevalence of familial DCM among probands was 11.6% overall. The model-based estimate of the prevalence of familial DCM among probands at a typical US advanced heart failure program if all living first-degree relatives were screened was 29.7% (95% CI, 23.5% to 36.0%) overall. The estimated prevalence of familial DCM was higher in Black probands than in White probands (difference, 11.3% [95% CI, 1.9% to 20.8%]) but did not differ significantly between Hispanic probands and non-Hispanic probands (difference, -1.4% [95% CI, -15.9% to 13.1%]). The estimated prevalence of expanded familial DCM was 56.9% (95% CI, 50.8% to 63.0%) overall. Based on age-specific disease status at enrollment, estimated cumulative risks in first-degree relatives at a typical US advanced heart failure program reached 19% (95% CI, 13% to 24%) by age 80 years for DCM and 33% (95% CI, 27% to 40%) for expanded DCM inclusive of partial phenotypes. The DCM hazard was higher in first-degree relatives of non-Hispanic Black probands than non-Hispanic White probands (hazard ratio, 1.89 [95% CI, 1.26 to 2.83]). In a US cross-sectional study, there was substantial estimated prevalence of familial DCM among probands and modeled cumulative risk of DCM among their first-degree relatives. ClinicalTrials.gov Identifier: NCT03037632.

Genetic variants in Chinese patients with sporadic dilated cardiomyopathy: a cross-sectional study.

BackgroundMultiple genes have been associated with familial dilated cardiomyopathy (DCM). However, the role of genetic factors in sporadic DCM (SDCM) remains unclear. Therefore, we studied the genetic variations in Chinese patients with SDCM.MethodsSixty-six unrelated Chinese patients (mean age 49.1±17.0 years; 71% male) diagnosed with SDCM were enrolled. The clinical history and genomic DNA of the cohort were collected and examined. The exons of 24 genes closely associated with familial DCM (ABCC9, ACTC1, ACTN2, DES, LAMA4, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYPN, PLN, PSEN1, PSEN2, RBM20, SCN5A, SGCD, TAZ, TCAP, TMPO, TNNI3, TNNT2, TPM1, and VCL) were sequenced using targeted next-generation sequencing method. All called nonsynonymous variants and their occurrence frequencies were compared against population data from public databases. And the nonsynonymous variants were also evaluated for pathogenicity by PolyPhen 2 (PP2) and Sorts Intolerant From Tolerant (SIFT) algorithms.ResultsEighty-five nonsynonymous variants were detected in 17 genes. The variants and their occurrence frequencies in the patients were compared against population data from the 1000 Genomes and NHLBI (National Heart, Lung, and Blood Institute) Go Exome Sequencing Project. Forty-nine nonsynonymous variants had occurrence frequencies that were significantly higher in the study patients than in the general population, indicating that they have the potential to increase the risk of DCM. The risk variants were distributed in 40 (61%) patients, among whom 25 carried a single variant, while the remaining patients carried multiple (2 to 4) variants. Risk variants occurred more frequently in MYBPC3 (14% of the patients), SCN5A (14%), MYH7 (12%), MYPN (9%), and LDB3 (8%), as verified by Poisson distribution analysis, which were considered “the five risky genes”.ConclusionsWe found that genetic variants with potential risk for DCM were commonly present in SDCM patients, indicating that genetic factors contribute to the pathogenesis, and (probably) the onset, of DCM in these patients.

Abstract 14154: Genome-Wide Association Study of Dilated Cardiomyopathy in the VA Million Veteran Program

Introduction: Rare, Mendelian drivers of dilated cardiomyopathy (DCM) are well-established, but the contribution of common genetic variation to DCM risk has emerged more recently. As common variant discovery has largely relied on genome wide association studies (GWAS) of prospectively recruited DCM cases, we sought to conduct a GWAS of retrospectively-defined DCM from a large biobank. Methods: We used electronic health record-based phenotyping to define DCM in the VA Million Veteran Program (MVP), performed ancestry-specific GWAS in MVP participants of European and African genetic ancestry, and then conducted a trans-ethnic meta-analysis. We pursued replication of sentinel DCM single nucleotide polymorphisms (SNPs) in the UK Biobank. We further assessed the association of sentinel DCM SNPs with subclinical cardiac magnetic resonance imaging measures of left ventricular (LV) structure and function in UK Biobank, and with hypertrophic cardiomyopathy (HCM) in MVP. Results: Among 459,937 MVP study participants, mean age was 61.5, 43,971 (9.6%) were female, and 5,597 had DCM (N=3,786 European ancestry, N=1,811 African ancestry). In trans-ethnic meta-analysis, we identified eight genomic regions associated with DCM at genome-wide significance (P &lt; 5x10 -8 ). These included three of four known DCM associations near HSPB7 , LSM3 , and BAG3 ; and five novel genomic regions near SLC39A8 , CDKN1A , CD36 , NEDD4L , and MAP3K7CL . Three of the novel regions (at CDKN1A , NEDD4L , and MAP3K7CL ) were replicated in UK Biobank (all p&lt;8.0E-4; N=899 DCM cases, 449,574 controls). SNPs associated with increased DCM risk also associated with increased LV end-diastolic and end-systolic volumes and lower LV ejection fraction in UK Biobank participants without clinical heart failure or cardiomyopathy (N &gt; 31,614; all p &lt; 0.01). Sentinel SNPs for DCM also showed a trend towards an opposite direction of association with HCM in MVP (N=1,533 HCM cases, 465,877 controls). Conclusions: We conducted the largest GWAS of DCM to date, and identified five novel, common genetic loci associated with DCM with replication of three novel loci in an external cohort. Our findings highlight the potential to leverage emerging biobank populations to scale common variant discovery for DCM.

Abstract 13271: Combined Assessments of Monogenic and Polygenic Risk for Dilated Cardiomyopathy

Introduction: Genetic testing for non-ischemic dilated cardiomyopathy (DCM) currently comprises assessment of rare (monogenic) mutations in DCM-relevant genes. The role of a common-variant (polygenic) predictor for DCM has yet to be evaluated. Methods: Leveraging genotyping array and exome-sequencing data from UK Biobank, we curated monogenic, predicted loss-of-function (LOF) mutations in 91 genes on clinical genetic testing panels for DCM, and tested their prevalence and penetrance. Next, we constructed and evaluated a polygenic score for DCM from measures of left ventricular structure and function by cardiac magnetic resonance imaging. Finally, we combined monogenic carrier status with the polygenic score to estimate aggregate genetic risk for DCM. Results: Among study participants (N= 166,690), mean age was 57 (SD, 8.1) years, 75,154 (41%) were male, and 336 (0.21%) had DCM. 14.4% of DCM cases harbored a disease-relevant LOF mutation, including 8.8% within cardiac exons of the sarcomeric gene TTN . LOF mutations in TTN (OR, 25.36), DSP (OR, 17.55), and RBM20 (OR, 12.85) were the most strongly associated with dilated cardiomyopathy (all P &lt; 0.001). 0.7% of all LOF carriers - and 4.0% of LOF carriers in TTN - developed DCM. A polygenic score comprising 2.3 million common genetic variants was strongly associated with DCM in all participants (OR per SD=1.62, p=8.61E-39), and in non-carriers (OR per SD=1.60, p=6.28E-15; N=159,811) and carriers (OR per SD=1.79, p=4.76E-05; N=6,879) of LOF mutations. Comparing the top and bottom 20% of the polygenic score, a &gt;3-fold risk difference was observed among non-carriers of TTN LOF, and a &gt;10-fold risk difference among TTN LOF carriers. TTN LOF carriers with high polygenic risk were at 46-fold odds of developing DCM as compared to non-carriers with intermediate polygenic risk (p=4.16E-29). Conclusions: Combining monogenic and polygenic risk expands the scope and improves the precision of clinical genetic testing for DCM.

Whole-exome sequencing reveals genetic risks of early-onset sporadic dilated cardiomyopathy in the Chinese Han population.

To reveal genetic risks of early-onset sporadic dilated cardiomyopathy (DCM) patients in the Chinese Han population, we enlisted 363 DCM cases and 414 healthy controls. Whole-exome sequencing and phenotypic characterization were conducted. In total, we identified 26 loss-of-function (LOF) candidates and 66 pathogenic variants from 33 genes, most of which were novel. The deleterious variants can account for 25.07% (91/363) of all patients. Furthermore, rare missense variants in 21 genes were found to be significantly associated with DCM in burden tests. Other than rare variants, twelve common SNPs were significantly associated with an increased risk of DCM in allele-based genetic model association analysis. Of note, in the cumulative risk model, high-risk subjects had a 3.113-fold higher risk of developing DCM than low-risk subjects. Also, DCM in the high-risk group had a younger age of onset than that in the low-risk group. In terms of cardiac function, the mean left ventricular ejection fraction of patients with the deleterious variants was lower than those without (27.73%±10.02% vs. 30.61%±10.85%, P=0.026). To conclude, we mapped a comprehensive atlas of genetic risks in Chinese patients with DCM that might lead to new insights into the mechanisms and risk stratification for DCM.