Data_Sheet_1_The addition of genetic testing and cardiovascular magnetic resonance to routine clinical data for stratification of etiology in dilated cardiomyopathy.docx

BackgroundGuidelines recommend genetic testing and cardiovascular magnetic resonance (CMR) for the investigation of dilated cardiomyopathy (DCM). However, the incremental value is unclear. We assessed the impact of these investigations in determining etiology.MethodsSixty consecutive patients referred with DCM and recruited to our hospital biobank were selected. Six independent experts determined the etiology of each phenotype in a step-wise manner based on (1) routine clinical data, (2) clinical and genetic data and (3) clinical, genetic and CMR data. They indicated their confidence (1-3) in the classification and any changes to management at each step.ResultsSix physicians adjudicated 60 cases. The addition of genetics and CMR resulted in 57 (15.8%) and 26 (7.2%) changes in the classification of etiology, including an increased number of genetic diagnoses and a reduction in idiopathic diagnoses. Diagnostic confidence improved at each step (p ConclusionWe demonstrate that genetics and CMR, frequently changed the classification of etiology in DCM, improved confidence and interobserver variability in determining the diagnosis and had an impact on proposed management.</p

Phenotype, outcomes and natural history of early‐stage non‐ischaemic cardiomyopathy

AimsTo characterize the phenotype, clinical outcomes and rate of disease progression in patients with early‐stage non‐ischaemic cardiomyopathy (early‐NICM).Methods and resultsWe conducted a prospective observational cohort study of patients with early‐NICM assessed by late gadolinium enhancement cardiovascular magnetic resonance (CMR). Cases were classified into the following subgroups: isolated left ventricular dilatation (early‐NICM H−/D+), non‐dilated left ventricular cardiomyopathy (early‐NICM H+/D−), or early dilated cardiomyopathy (early‐NICM H+/D+). Clinical follow‐up for major adverse cardiovascular events (MACE) included non‐fatal life‐threatening arrhythmia, unplanned cardiovascular hospitalization or cardiovascular death. A subset of patients (n = 119) underwent a second CMR to assess changes in cardiac structure and function. Of 254 patients with early‐NICM (median age 46 years [interquartile range 36–58], 94 [37%] women, median left ventricular ejection fraction [LVEF] 55% [52–59]), myocardial fibrosis was present in 65 (26%). There was no difference in the prevalence of fibrosis between subgroups (p = 0.90), however fibrosis mass was lowest in early‐NICM H−/D+, higher in early‐NICM H+/D− and highest in early‐NICM H+/D+ (p = 0.03). Over a median follow‐up of 7.9 (5.5–10.0) years, 28 patients (11%) experienced MACE. Non‐sustained ventricular tachycardia (hazard ratio [HR] 5.1, 95% confidence interval [CI] 2.36–11.00, p < 0.001), myocardial fibrosis (HR 3.77, 95% CI 1.73–8.20, p < 0.001) and diabetes mellitus (HR 5.12, 95% CI 1.73–15.18, p = 0.003) were associated with MACE in a multivariable model. Only 8% of patients progressed from early‐NICM to dilated cardiomyopathy with LVEF <50% over a median of 16 (11–34) months.ConclusionEarly‐NICM is not benign. Fibrosis develops early in the phenotypic course. In‐depth characterization enhances risk stratification and might aid clinical management.</p

Assessing the association between genetic and phenotypic features of dilated cardiomyopathy and outcome in patients with coronary artery disease

AimsTo examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD).Methods and resultsThis study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated. Second, patients with CAD referred to a tertiary centre for evaluation with late gadolinium enhancement (LGE)‐CMR were recruited (London cohort); patients underwent genetic sequencing as part of the research protocol and long‐term follow‐up. From 31 154 individuals with CAD recruited to UKB, rare pathogenic variants in DCM genes were associated with increased risk of death or major adverse cardiac events (hazard ratio 1.57, 95% confidence interval [CI] 1.22–2.01, p < 0.001). Of 1619 individuals with CAD included from the UKB CMR substudy, participants with a rare variant in a DCM‐associated gene had lower left ventricular ejection fraction (LVEF) compared to genotype negative individuals (mean 47 ± 10% vs. 57 ± 8%, p < 0.001). Of 453 patients in the London cohort, 63 (14%) had non‐infarct pattern LGE (NI‐LGE) on CMR. Patients with NI‐LGE had lower LVEF (mean 38 ± 18% vs. 48 ± 16%, p < 0.001) compared to patients without NI‐LGE, with no significant difference in the burden of rare protein altering variants in DCM‐associated genes between groups (9.5% vs. 6.7%, odds ratio 1.5, 95% CI 0.4–4.3, p = 0.4). NI‐LGE was not independently associated with adverse clinical outcomes.ConclusionRare pathogenic variants in DCM‐associated genes impact left ventricular remodelling and outcomes in stable CAD. NI‐LGE is associated with adverse remodelling but is not an independent predictor of outcome and had no rare genetic basis in our study.</p