Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals.

Importance: Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. Objective: To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. Design, Setting, and Participants: This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. Main Outcomes and Measures: The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. Results: The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. Conclusions and Relevance: In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

Very Late Pathological Responses to Cobalt-Chromium Everolimus-Eluting, Stainless Steel Sirolimus-Eluting, and Cobalt-Chromium Bare Metal Stents in Humans.

BACKGROUND: The "very late" clinical outcomes for durable polymer drug-eluting stents and bare metal stents (BMSs) have been shown to be dissimilar in clinical studies. Conceptually, the long-term vascular compatibility of BMSs is still regarded to be superior to drug-eluting stents; however, no pathologic study to date has specifically addressed this issue. We evaluated the very late (≥1 year) pathologic responses to durable polymer drug-eluting stents (cobalt-chromium [CoCr] everolimus-eluting stents [EESs] and stainless steel sirolimus-eluting stents [SS-SESs]) versus BMSs (CoCr-BMSs). METHODS AND RESULTS: From the CVPath stent registry, we studied a total of 119 lesions (40 CoCr-EESs, 44 SS-SESs, 35 CoCr-BMSs) from 92 autopsy cases with a duration ranging from 1 to 5 years. Sections of stented coronary segments were pathologically analyzed. Inflammation score and the percentage of struts with giant cells were lowest in CoCr-EESs (median inflammation score: 0.6; median percentage of struts with giant cells: 3.8%) followed by CoCr-BMSs (median inflammation score: 1.3 [P<0.01]; median percentage of struts with giant cells: 8.9% [P=0.02]) and SS-SESs (median inflammation score: 1.7 [P<0.01]; median percentage of struts with giant cells: 15.3% [P<0.01]). Polymer delamination was observed exclusively in SS-SESs and was associated with increased inflammatory and giant cell reactions. The prevalence of neoatherosclerosis with CoCr-EESs (50%) was significantly less than with SS-SESs (77%, P=0.02) but significantly greater than with CoCr-BMSs (20%, P<0.01). CONCLUSIONS: CoCr-EESs, SS-SESs, and BMSs each demonstrated distinct vascular responses. CoCr-EESs demonstrated the least inflammation, near-equivalent healing to BMSs, and lower neointimal formation. These results challenge the belief that BMSs have superior biocompatibility compared with some polymeric coated drug-eluting stents and may have implications for future stent design.