Ware, James S.

Background: Myocarditis may predispose to dilated cardiomyopathy (DCM) and sudden cardiac death (SCD). Familial data indicate a potential genetic susceptibility shared with arrhythmogenic cardiomyopathy (ACM). We present the first large-scale genotype-phenotype study of adults with acute myocarditis. Methods: A cohort comprising 336 consecutive patients with acute myocarditis was enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterised cardiomyopathy-associated genes. The burden of rare protein altering variants (PAV) in ACM genes, DCM genes, and TTN specifically, were compared with local healthy controls sequenced on the same platform (n=1053). Case ascertainment was assessed against national hospital admission data. Results: We identified rare protein-altering variants in 23% of cases compared to 16% in controls (Δ+6.8%; p=0.021), with rare truncating variants (tv) in 6% of cases compared to <1% of controls ((Δ+5%; p=0.0097). In London (n=230; median left ventricular ejection fraction (LVEF) 63%), which was representative of national myocarditis admissions, 4.8% of cases carried rare tv, particularly within ACM genes (3% cases vs 0% controls; odds ratio 8.2; p=0.001). This was predominantly driven by desmoplakin (DSP)-tv in patients with normal LVEF. In Maastricht (n=106; median LVEF 30%), rare tv in DCM genes were enriched, particularly TTN-tv found in 7% (all with LVEF<50%) compared to 1% in controls (OR 3.6; p=0.0116). During a median follow-up of 1.9 years, all-cause mortality was greatest in those with a DCM variant (18% vs 4% with no variant; OR 5.0; p=0.004). Conclusion: We identified enrichment of cardiomyopathy gene variants in acute myocarditis patients, dominated by DSP-tv in those with normal LVEF and TTN-tv in those with reduced LVEF. Incorporation of genetic testing may be beneficial to identify such high-risk individuals and guide family screening in acute myocarditis patients.

Introduction: Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant which remains unexplained after comprehensive clinical and pathological assessment. Prior studies have implicated inherited cardiac conditions (ICC). Hypothesis: Whole exome sequencing will identify a significant burden of putative pathogenic (PP) and rare functionally significant (RFS) cardiac genetic variants in SIDS. Methods: 96 SIDS cases with complete phenotypic data were selected from 434 cases. Prone sleeping position was excluded to enrich for genetic risk. Genomic DNA underwent target enrichment using Agilent SureSelect Human All Exon v5 kit and sequencing on Illumina HiSeq. Reads were aligned to GRCh37 reference genome with Novoalign and variants called with SAMtools. Principal component analysis identified 82 cases of North European (NE) ancestry. Variants were annotated with Annovar and compared to control data from a local exome database, 1000 Genomes and ESP. Analysis focused on 83 known ICC susceptibility genes (27 channelopathy-associated [CH]; 56 cardiomyopathy-associated [CM]). PP was defined as ultra rare nonsense or frameshift mutations or other variants previously reported as disease-associated and absent in controls. RFS was defined as variants with abnormal functional characterization and <0.5% prevalence in controls. Results: 20/82 cases (24%) carried at least 1 PP/RFS variant: 12 CH variants in 9 genes (AKAP9, ANK2, CACNB2, CAV3, KCNE2, RYR2, SCN5A, SNTA1, TRDN) in 13 cases; 7 CM variants in 5 genes (ABCC9, ACTN2, CSRP3, TCAP, TTN) in 8 cases. Variants were most commonly identified in the 3-6 months age group (p=0.009). There were no other significant phenotypic differences between variant-positive and negative cases (Table 1). Conclusions: There was an 11% yield of PP variants in non-prone sleeping SIDS cases of NE ancestry, with an additional 13% hosting RFS variants. These may provide a potential substrate in the pathophysiology of SIDS.

Introduction: The safety of vigorous exercise for individuals with appropriately-treated LQTS remains unproven, and physical activity practices in this population have not been described. Methods: LIVE-LQTS prospectively enrolled individuals age 8-60 years with overt LQTS or gene mutation carriers. Participants (or parents, for children) answered surveys describing activity patterns. Vigorous exercise was defined as > 6 METS for > 60 hours per year. Clinical and demographic data were derived from medical record review. Results: Among 1554 participants, 804 (52%) reported exercising vigorously, 473 of these competitively, 577 (37%) exercising at moderate, and 173 (11%) at low levels. Seven percent of those working describe jobs more active than walking, including 10 in protective services and 19 in sports/coaching. Over 90% are genotype positive, 57% are phenotype positive at rest and an additional 16% have exercise-induced QT prolongation. Forty four percent have had documented ventricular arrhythmias or syncope. Eighty-four percent are appropriately treated with either beta-blockers, ICD, and/or sympathectomy, although among beta-blocked patients, only 60% are on the most effective agents. Among adults, BMI was significantly lower among the vigorous exercisers. Conclusion: While the high percentage of vigorous exercisers seen in this study may not represent all patients with LQTS due to self-selection for study participation, many patients with LQTS are engaged in vigorous exercise or competitive athletics. Prospective follow up of this cohort is ongoing and will determine safety of vigorous exercise through comparison of arrhythmic outcomes in vigorous exercisers vs moderate/low level exercisers.