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.

BackgroundProne positioning has a beneficial role in COVID-19 patients receiving ventilation but lacks evidence in awake non-ventilated patients, with most studies being retrospective, lacking control populations and information on subjective tolerability.MethodsWe conducted a prospective, single-centre study of prone positioning in awake non-ventilated patients with COVID-19 and non-COVID-19 pneumonia. The primary outcome was change in peripheral oxygenation in prone versus supine position. Secondary outcomes assessed effects on end-tidal CO2, respiratory rate, heart rate, and subjective symptoms. We also recruited healthy volunteers to undergo proning during hypoxic challenge.Results238 hospitalised patients with pneumonia were screened; 55 were eligible with 25 COVID-19 patients and 3 non-COVID-19 patients agreeing to undergo proning – the latter insufficient for further analysis. 10 healthy control volunteers underwent hypoxic challenge. Patients with COVID-19 had a median age of 64 years (interquartile range [IQR] 53–75). Proning led to an increase in SpO2 compared to supine position (difference +1.62%; p=0.003) and occurred within 10 min of proning. There were no effects on end-tidal CO2, respiratory rate, or heart rate. There was an increase in subjective discomfort (p=0.003), with no difference in breathlessness. Among healthy controls undergoing hypoxic challenge, proning did not lead to a change in SpO2 or subjective symptom scores.ConclusionIdentification of suitable patients with COVID-19 requiring oxygen supplementation from general ward environments for awake proning is challenging. Prone positioning leads to a small increase in SpO2 within 10 min of proning though is associated with increased discomfort.

BackgroundThere 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.MethodsUK Biobank participants who had undergone whole exome sequencing (WES), ECG and cardiovascular magnetic resonance (CMR) imaging were selected for study. Three different variant calling strategies (one primary and two secondary) were used to identify subjects with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded to either 1) DCM (clinical or CMR diagnosis); 2) early DCM features, including arrhythmia and/or conduction disease, isolated ventricular dilation, and hypokinetic non-dilated cardiomyopathy; or 3) phenotype-negative.ResultsAmong 18,665 individuals included in the study, 1,463 (7.8%) subjects 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 CMR analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in 15.9% of individuals with putative pathogenic variants. Arrhythmias and/or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic non-dilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all three variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes, as compared to those with variants in moderate/limited evidence genes.ConclusionsIn the UK Biobank, approximately 1/6 of adults with putative pathogenic variants in DCM genes exhibited a subclinical phenotype based on ECG and/or CMR, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation/dysfunction.Clinical PerspectiveWhat is new?Among individuals with putative pathogenic DCM gene variants, subclinical DCM and early DCM features, detected by ECG and/or CMR, were nearly four times more common than clinically manifest DCM or early features (23.7% vs. 6.1%).Over 90% of subjects with a putative pathogenic variant in DCM-associated genes did not have a prior history of DCM.Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes (13.9% for clinical and subclinical), as compared to those with variants in moderate/limited evidence genes, but there was no significant difference in combined clinical/subclinical phenotype by cluster.The overall clinical/subclinical penetrance of DCM-associated single putative pathogenic variants was highly variable between genes, ranging from 0 to 66.7%.What are the clinical implications?Arrhythmias and cardiac conduction disease are the most common early manifestation of putative pathogenic variants implicated in DCM, mostly occurring prior to the development of structural/functional abnormalities.A genotype-first screening approach for DCM using a large genetic panel is currently not suitable in the general population due to incomplete understanding of DCM genetic architecture and reduced penetrance of DCM-associated putative pathogenic variants.Journal Subject TermsCardiomyopathy; Genetics; Sudden Cardiac Death

No abstract

No abstract