Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.

Impact of intracardiac echocardiography on readmission morbidity and mortality following atrial fibrillation ablation.

INTRODUCTION: The use of intracardiac echocardiography (ICE) is beneficial during the ablation of atrial fibrillation (AF). Evidence is conflicting regarding the clinical impact of using ICE on arrhythmia recurrence and mortality. METHODS: Patients undergoing catheter ablation of AF during 2010-2017 were identified using the International Classification of Diseases-9th and 10th Revision-Clinical Modification (ICD-9-CM and ICD-10-CM) from the Nationwide Readmissions Database. Propensity matching was used to generate a control group. Patient demographics, Charlson comorbidity indexes, time from discharge to readmission, and the reason of readmission were extracted. RESULTS: From 2010 to 2017, 51 129 patients were included in the analysis out of which ICE was used in 8005 (15.7%) patients. The in-hospital mortality at readmission was significantly higher in the patients without ICE use (2.9% vs. 1.7%, p = .02). The length of stay (LOS) at readmission was significantly higher in non-ICE arm (median [interquartile range, IQR]: 3 [2-6] vs. 2 [3-5] days, p < .0001) with similar healthcare-associated cost (HAC) in both the groups (median [IQR]: US$7507.3 [4057.8-15 474.2] vs. 7339.4 [4024.8-15 191.6], p = .43). Freedom from readmission was 12% higher (hazard ratio [HR] [95% confidence interval, CI]: 0.88 [0.83-0.94], p < .0001) with the use of ICE at 90-day follow-up, which was driven by 24% reduction in heart failure (HF) at follow-up (HR [95% CI]: 0.76 [0.60-0.96], p = .02). CONCLUSIONS: ICE use during AF ablation procedure reduces readmissions at 90 days by 12%, driven by a 24% decrease in HF-related admissions. The non-ICE arm showed a significantly higher LOS which offsets marginally higher HAC in the ICE arm.

Metabolic dysfunction-associated fatty liver disease and implications for cardiovascular risk and disease prevention.

The newly proposed term "metabolic dysfunction-associated fatty liver disease" (MAFLD) is replacing the old term "non-alcoholic fatty liver disease" (NAFLD) in many global regions, because it better reflects the pathophysiology and cardiometabolic implications of this common liver disease. The proposed change in terminology from NAFLD to MAFLD is not simply a single-letter change in an acronym, since MAFLD is defined by a set of specific and positive diagnostic criteria. In particular, the MAFLD definition specifically incorporates within the classification recognized cardiovascular risk factors. Although convincing evidence supports a significant association between both NAFLD and MAFLD, with increased risk of CVD morbidity and mortality, neither NAFLD nor MAFLD have received sufficient attention from the Cardiology community. In fact, there is a paucity of scientific guidelines focusing on this common and burdensome liver disease from cardiovascular professional societies. This Perspective article discusses the rationale and clinical relevance for Cardiologists of the newly proposed MAFLD definition.

Clinical applications of heart rhythm monitoring tools in symptomatic patients and for screening in high-risk groups.

Recent technological advances have facilitated and diversified the options available for the diagnosis of cardiac arrhythmias. Ranging from simple resting or exercise electrocardiograms to more sophisticated and expensive smartphones and implantable cardiac monitors. These tests and devices may be used for varying periods of time depending on symptom frequency. The choice of the most appropriate heart rhythm test should be guided by clinical evaluation and optimized following accurate characterization of underlying symptoms, 'red flags', risk factors, and consideration of cost-effectiveness of the different tests. This review provides evidence-based guidance for assessing suspected arrhythmia in patients who present with symptoms or in the context of screening, such as atrial fibrillation or advanced conduction disturbances following transcatheter aortic valve implantation in high-risk groups. This is intended to help clinicians choose the most appropriate diagnostic tool to facilitate the management of patients with suspected arrhythmias.

Hypoxemia and pulmonary hypertension in patients with concomitant restrictive ventilatory defect and sleep apnea: the overlap syndrome.

BACKGROUND: To investigate the severity of hypoxemia and prevalence of pulmonary hypertension (PHTN) in patients with the overlap syndrome (OS) of restrictive ventilatory defect (RVD) and sleep apnea (SA). METHODS: Patients referred for both sleep test and spirometry for suspected SA and ventilatory disorders were recruited prospectively from January 2019 to January 2020. SA was determined by an apnea-hypopnea index ≥ 5/h; average oxygen saturation during sleep (meanSaO2) and percentage of total sleep time with saturation < 90% (T90) were calculated. RVD was diagnosed in the presence of forced expiratory volume in the first second/forced vital capacity (FVC) > 0.7 and FVC < 80% predicted value. PHTN was defined by tricuspid regurgitation peak velocity ≥ 3.4 m/s, documented by noninvasive transthoracic echocardiography. RESULTS: Patients with OS had significantly lower meanSaO2 but higher T90 than subjects with isolated SA and isolated RVD. Patients with OS vs. those with isolated SA had higher odds of PHTN in multivariable analysis with age, sex, and body mass index adjusted for (OR 2.96, 95%CI 1.05-8.91, p = 0.040). Patients with meanSaO2 < 92% vs. meanSaO2 ≥ 92% had significantly higher odds of being diagnosed with PHTN (OR 5.40, 95%CI 2.01-15.7, p < 0.001). Similarly, T90 (≥ 4.5% versus < 4.5%) was also independently associated with the prevalence of PHTN (OR 7.21, 95%CI 2.54-23.67, p < 0.001). CONCLUSION: Patients with OS of RVD and SA had severe hypoxemia, which is associated with the prevalence of PHTN. Further investigation is needed to discern whether therapeutic strategies toward OS might mitigate PHTN in this cohort. TRIAL REGISTRATION: Clinical Trial Registration No. ChiCTR1900027294 on 1 October 2019.

State of the Art Review on Genetics and Precision Medicine in Arrhythmogenic Cardiomyopathy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterised by ventricular arrhythmia and an increased risk of sudden cardiac death (SCD). Numerous genetic determinants and phenotypic manifestations have been discovered in ACM, posing a significant clinical challenge. Further to this, wider evaluation of family members has revealed incomplete penetrance and variable expressivity in ACM, suggesting a complex genotype-phenotype relationship. This review details the genetic basis of ACM with specific genotype-phenotype associations, providing the reader with a nuanced perspective of this condition; whilst also proposing a future roadmap to delivering precision medicine-based management in ACM.

Sex hormone therapy and progression of cardiovascular disease in menopausal women.

One of the most controversial health decisions facing women is deciding upon the use of hormonal treatments for symptoms of menopause. This brief review focuses on the historical context of use of menopausal hormone treatments (MHT), summarizes results of major observational, primary and secondary prevention studies of MHT and cardiovascular (CV) outcomes, provides evidence for how sex steroids modulate CV function and identifies challenges for future research. As medicine enters an era of personalization of treatment options, additional research into sex differences in the aetiology of CV diseases will lead to better risk identification for CV disease in women and identify whether a woman might receive CV benefit from specific formulations and doses of MHT.

Assessing heterogeneity on cardiovascular magnetic resonance imaging: a novel approach to diagnosis and risk stratification in cardiac diseases.

Cardiac disease affects the heart non-uniformly. Examples include focal septal or apical hypertrophy with reduced strain in hypertrophic cardiomyopathy, replacement fibrosis with akinesia in an infarct-related coronary artery territory, and a pattern of scarring in dilated cardiomyopathy. The detail and versatility of cardiovascular magnetic resonance (CMR) imaging mean it contains a wealth of information imperceptible to the naked eye and not captured by standard global measures. CMR-derived heterogeneity biomarkers could facilitate early diagnosis, better risk stratification, and a more comprehensive prediction of treatment response. Small cohort and case-control studies demonstrate the feasibility of proof-of-concept structural and functional heterogeneity measures. Detailed radiomic analyses of different CMR sequences using open-source software delineate unique voxel patterns as hallmarks of histopathological changes. Meanwhile, measures of dispersion applied to emerging CMR strain sequences describe variable longitudinal, circumferential, and radial function across the myocardium. Two of the most promising heterogeneity measures are the mean absolute deviation of regional standard deviations on native T1 and T2 and the standard deviation of time to maximum regional radial wall motion, termed the tissue synchronization index in a 16-segment left ventricle model. Real-world limitations include the non-standardization of CMR imaging protocols across different centres and the testing of large numbers of radiomic features in small, inadequately powered patient samples. We, therefore, propose a three-step roadmap to benchmark novel heterogeneity biomarkers, including defining normal reference ranges, statistical modelling against diagnosis and outcomes in large epidemiological studies, and finally, comprehensive internal and external validations.

Multimodal Imaging Findings Associated With Cardiac Oxalosis Cardiomyopathy.

We report the case of a 50-year-old woman with secondary oxalosis following bowel resection resulting in restrictive cardiomyopathy and a diagnosis of cardiac amyloidosis based on the initial workup. The case documented findings by cardiac magnetic resonance imaging and technetium Tc 99m-labeled pyrophosphate scan in patients with cardiac oxalosis, which can mimic findings in cardiac amyloidosis, expanding the differential diagnosis.

Health inequalities in cardiopulmonary resuscitation and use of automated electrical defibrillators in out-of-hospital cardiac arrest.

Out of hospital cardiac arrest (OHCA) outcomes can be improved by strengthening the chain of survival, namely prompt cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED). However, provision of bystander CPR and AED use remains low due to individual patient factors ranging from lack of education to socioeconomic barriers and due to lack of resources such as limited availability of AEDs in the community. Although the impact of health inequalities on survival from OHCA is documented, it is imperative that we identify and implement strategies to improve public health and outcomes from OHCA overall but with a simultaneous emphasis on making care more equitable. Disparities in CPR delivery and AED use in OHCA exist based on factors including sex, education level, socioeconomic status, race and ethnicity, all of which we discuss in this review. Most importantly, we discuss the barriers to AED use, and strategies on how these may be overcome.

Cardiovascular Disease Burden, Mortality, and Sudden Death Risk in Epilepsy: A UK Biobank Study.

BACKGROUND: Sudden death is the leading cause of mortality in medically refractory epilepsy. Middle-aged persons with epilepsy (PWE) are under investigated regarding their mortality risk and burden of cardiovascular disease (CVD). METHODS: Using UK Biobank, we identified 7786 (1.6%) participants with diagnoses of epilepsy and 6,171,803 person-years of follow-up (mean 12.30 years, standard deviation 1.74); 566 patients with previous histories of stroke were excluded. The 7220 PWE comprised the study cohort with the remaining 494,676 without epilepsy as the comparator group. Prevalence of CVD was determined using validated diagnostic codes. Cox proportional hazards regression was used to assess all-cause mortality and sudden death risk. RESULTS: Hypertension, coronary artery disease, heart failure, valvular heart disease, and congenital heart disease were more prevalent in PWE. Arrhythmias including atrial fibrillation/flutter (12.2% vs 6.9%; P < 0.01), bradyarrhythmias (7.7% vs 3.5%; P < 0.01), conduction defects (6.1% vs 2.6%; P < 0.01), and ventricular arrhythmias (2.3% vs 1.0%; P < 0.01), as well as cardiac implantable electric devices (4.6% vs 2.0%; P < 0.01) were more prevalent in PWE. PWE had higher adjusted all-cause mortality (hazard ratio [HR], 3.9; 95% confidence interval [CI], 3.01-3.39), and sudden death-specific mortality (HR, 6.65; 95% CI, 4.53-9.77); and were almost 2 years younger at death (68.1 vs 69.8; P < 0.001). CONCLUSIONS: Middle-aged PWE have increased all-cause and sudden death-specific mortality and higher burden of CVD including arrhythmias and heart failure. Further work is required to elucidate mechanisms underlying all-cause mortality and sudden death risk in PWE of middle age, to identify prognostic biomarkers and develop preventative therapies in PWE.

Characteristics and Outcomes of Hospitalized Patients with Heart Failure and Sarcoidosis: A Propensity-Matched Analysis of the Nationwide Readmissions Database 2010-2019.

BACKGROUND: Sarcoidosis is associated with a poor prognosis. There is a lack of data examining the outcomes and readmission rates of sarcoidosis patients with heart failure (SwHF) and without heart failure (SwoHF). We aimed to compare the impact of non-ischemic heart failure on outcomes and readmissions in these two groups. METHODS: The US Nationwide Readmission Database was queried from 2010 to 2019 for SwHF and SwoHF patients identified using the International Classification of Diseases, 9th and 10th Editions. Those with ischemic heart disease were excluded, and both cohorts were propensity matched for age, gender, and Charlson Comorbidity Index (CCI). Clinical characteristics, length of stay, adjusted healthcare-associated costs, 90-day readmission and mortality were analyzed. RESULTS: We identified 97,961 hospitalized patients (median age 63 years, 37.9% male) with a diagnosis of sarcoidosis (35.9% SwHF vs 64.1% SwoHF). On index admission, heart failure patients had higher prevalences of atrioventricular block (3.3% vs 1.4%, P < .0001), ventricular tachycardia (6.5% vs 1.3%, P < .0001), ventricular fibrillation (0.4% vs 0.1%, P < .0001) and atrial fibrillation (22.1% vs 7.5%, P < .0001). SwHF patients were more likely to be readmitted (hazard ratio 1.28, P < .0001), had higher length of hospital stay (5 vs 4 days, P < .0001), adjusted healthcare-associated costs ($9,667.0 vs $9,087.1, P < .0001) and mortality rates on readmission (5.1% vs 3.8%, P < .0001). Predictors of mortality included heart failure, increasing age, male sex, higher CCI, and liver disease. CONCLUSION: SwHF is associated with higher rates of arrhythmia at index admission, as well as greater hospital cost, readmission and mortality rates compared to those without heart failure.

Re-evaluating the Incidence and Prevalence of Clinical Hypertrophic Cardiomyopathy: An Epidemiological Study of Olmsted County, Minnesota.

OBJECTIVE: To contemporaneously reappraise the incidence-rate, prevalence, and natural history of hypertrophic cardiomyopathy (HCM) in Olmsted County, Minnesota, from 1984 to 2015. PATIENTS AND METHODS: A validated medical-record linkage system collecting information for residents of Olmsted County was used to identify all cases of HCM between January 1, 1984, and December 31, 2015. After adjudication of records from Mayo Clinic and Olmsted Medical Center, data relating to diagnoses and outcomes were abstracted. The calculated incidence rate and prevalence were standardized to the US 1980 White population (age- and sex-adjusted) and compared with a prior study examining the years 1975-1984. RESULTS: Two hundred seventy subjects with HCM were identified. The age- and sex-adjusted incidence rate was 6.6 per 100,000 person-years, and the point prevalence of HCM on January 1, 2016, was 89 per 100,000 population. The incidence rate and point prevalence of HCM on January 1, 2016, standardized to the US 1980 White population (age- and sex-adjusted), were 6.7 (95% CI, 7.1 to 8.8) per 100,000 person-years and 81.5 per 100,000 population, respectively. The incidence rate of HCM increased each decade since the index study. Individuals with HCM had a higher overall standardized mortality rate than the general population with an observed to expected HR of 1.44 (95% CI, 1.21 to 1.71; P<.001) which improved by each decade. CONCLUSION: The incidence and prevalence of HCM are higher than rates reported from a prior study in the same community examining the years 1975-1984, but lower than other study cohorts. The risk of mortality in HCM remains higher than expected, albeit with improvement in rates of mortality observed each decade during the study period.

DiscoVari: A Web-Based Precision Medicine Tool for Predicting Variant Pathogenicity in Cardiomyopathy- and Channelopathy-Associated Genes.

BACKGROUND: With genetic testing advancements, the burden of incidentally identified cardiac disease-associated gene variants is rising. These variants may carry a risk of sudden cardiac death, highlighting the need for accurate diagnostic interpretation. We sought to identify pathogenic hotspots in sudden cardiac death-associated genes using amino acid-level signal-to-noise (S:N) analysis and develop a web-based precision medicine tool, DiscoVari, to improve variant evaluation. METHODS: The minor allele frequency of putatively pathogenic variants was derived from cohort-based cardiomyopathy and channelopathy studies in the literature. We normalized disease-associated minor allele frequencies to rare variants in an ostensibly healthy population (Genome Aggregation Database) to calculate amino acid-level S:N. Amino acids with S:N above the gene-specific threshold were defined as hotspots. DiscoVari was built using JavaScript ES6 and using open-source JavaScript library ReactJS, web development framework Next.js, and JavaScript runtime NodeJS. We validated the ability of DiscoVari to identify pathogenic variants using variants from ClinVar and individuals clinically evaluated at the Duke University Hospitals with cardiac genetic testing. RESULTS: We developed DiscoVari as an internet-based tool for S:N-based variant hotspots. Upon validation, a higher proportion of ClinVar likely pathogenic/pathogenic variants localized to DiscoVari hotspots (43.1%) than likely benign/benign variants (17.8%; P<0.0001). Further, 75.3% of ClinVar variants reclassified to likely pathogenic/pathogenic were in hotspots, compared with 41.3% of those reclassified as variants of uncertain significance (P<0.0001) and 23.4% of those reclassified as likely benign/benign (P<0.0001). Of the clinical cohort variants, 73.1% of likely pathogenic/pathogenic were in hotspots, compared with 0.0% of likely benign/benign (P<0.01). CONCLUSIONS: DiscoVari reliably identifies disease-susceptible amino acid residues to evaluate variants by searching amino acid-specific S:N ratios.

Interchangeability in Left Ventricular Ejection Fraction Measured by Echocardiography and cardiovascular Magnetic Resonance: Not a Perfect Match in the Real World.

Comparisons of transthoracic echocardiography (TTE) and cardiovascular magnetic resonance (CMR) derived left ventricular ejection fraction (LVEF) have been reported in core-lab settings but are limited in the real-world setting. We retrospectively identified outpatients from 4 hospital sites who had clinically indicated quantitative assessment of LVEFTTE and LVEFCMR and evaluated their concordance. In 767 patients (mean age 47.6 years; 67.9% males) the median inter-modality interval was 35 days. There was significant positive correlation between the 2 modalities (r = 0.75; P < 0.001). Median LVEF was 54% (IQR 47%, 60%) for TTE and 59% (IQR 51%, 64%) for CMR, (P < 0.001). Normal LVEFTTE was confirmed by CMR in 90.6% of cases. Of patients with severely impaired LVEFTTE, 42.3% were upwardly reclassified by CMR as less severely impaired. The overall proportion of patients that had their LVEF category confirmed by both imaging modalities was 64.4%; Cohen's Kappa 0.41, indicating fair-to-moderate agreement. Overall, CMR upwardly reclassified 28% of patients using the British Society of Echocardiography LVEF grading, 18.6% using the European Society of Cardiology heart failure classification, and 29.6% using specific reference ranges for each modality. In a multi-site "real-worldˮ clinical setting, there was significant discrepancy between LVEFTTE and LVEFCMR measurement. Only 64.4% had their LVEF category confirmed by both imaging modalities. LVEFTTE was generally lower than LVEFCMR. LVEFCMR upwardly reclassified almost half of patients with severe LV dysfunction by LVEFTTE. Clinicians should consider the inter-modality variation before making therapeutic recommendations, particularly as clinical trial LVEF thresholds have historically been guided by echocardiography.

Genetic mechanisms underlying arrhythmogenic mitral valve prolapse: Current and future perspectives.

Mitral valve prolapse (MVP) is a heart valve disease that is often familial, affecting 2%-3% of the general population. MVP with or without mitral regurgitation can be associated with an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Research on familial MVP has specifically focused on genetic factors, which may explain the heritable component of the disease estimated to be present in 20%-35%. Furthermore, the structural and electrophysiological substrates underlying SCD/ventricular arrhythmia risk in MVP have been studied postmortem and in the electrophysiology laboratory, respectively. Understanding how familial MVP and rhythm disorders are related may help patients with MVP by individualizing risk and working to develop effective management strategies. This contemporary, state-of-the-art, expert review focuses on genetic factors and familial components that underlie MVP and arrhythmia and encapsulates clinical, genetic, and electrophysiological issues that should be the objectives of future research.

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in UK Biobank.

BACKGROUND: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general population. OBJECTIVES: The authors aimed to determine the risk of mortality and composite cardiomyopathy-related outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the UK Biobank. METHODS: Using whole exome sequencing data, variants in dilated, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy-associated genes with at least moderate evidence of disease causality according to ClinGen Expert Panel curations were annotated using REVEL (≥0.65) and ANNOVAR (predicted loss-of-function) considering gene-disease mechanisms. Genotype-positive and genotype-negative groups were compared using time-to-event analyses for the primary (all-cause mortality) and secondary outcomes (diagnosis of cardiomyopathy; composite outcome of diagnosis of cardiomyopathy, heart failure, arrhythmia, stroke, and death). RESULTS: Among 200,619 participants (age at recruitment 56.46 ± 8.1 years), 5,292 (2.64%) were found to host ≥1 predicted deleterious variants in cardiomyopathy-associated genes (CMP-G+). After adjusting for age and sex, CMP-G+ individuals had higher risk for all-cause mortality (HR: 1.13 [95% CI: 1.01-1.25]; P = 0.027), increased risk for being diagnosed with cardiomyopathy later in life (HR: 5.75 [95% CI: 4.58-7.23]; P < 0.0001), and elevated risk for composite outcome (HR: 1.29 [95% CI: 1.20-1.39]; P < 0.0001) than CMP-G- individuals. The higher risk for being diagnosed with cardiomyopathy and composite outcomes in the genotype-positive subjects remained consistent across all cardiomyopathy subgroups. CONCLUSIONS: Adults with predicted deleterious variants in cardiomyopathy-associated genes exhibited a slightly higher risk of mortality and a significantly increased risk of developing cardiomyopathy, and cardiomyopathy-related composite outcomes, in comparison with genotype-negative controls.

Beyond gene-disease validity: capturing structured data on inheritance, allelic-requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Background: As availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited cardiac condition (ICC) genes, including as secondary findings. Methods: We analyse evidence for inheritance patterns, allelic requirement, disease mechanism and disease-relevant variant classes for 65 ClinGen-curated ICC gene-disease pairs. We present this information for the first time in a structured dataset, CardiacG2P, and assess application in genomic variant filtering. Results: For 36/65 gene-disease pairs, loss-of-function is not an established disease mechanism, and protein truncating variants are not known to be pathogenic. Using CardiacG2P as an initial variant filter allows for efficient variant prioritisation whilst maintaining a high sensitivity for retaining pathogenic variants compared with two other variant filtering approaches. Conclusions: Access to evidence-based structured data representing disease mechanism and allelic requirement aids variant filtering and analysis and is pre-requisite for scalable genomic testing.