Sudden cardiac death (SCD) accounts for a substantial share of deaths in young individuals. Despite postmortem pathological, toxicological, and forensic examination and molecular autopsy, many cases remain unexplained, highlighting the need for complementary approaches to investigate the functional consequences of genetic variants identified after death. In this study, we describe a methodology for generating cardiomyocytes from human cadavers and demonstrate their functional viability. Achilles tendons were harvested from seven cadavers, all younger than 40 years of age, that had been preserved in a morgue and were subject to forensic autopsies. Fibroblasts were successfully cultured in six cases and reprogrammed into cadaver-derived induced pluripotent stem cells (CdiPSCs) in three cases. The CdiPSCs exhibited a stable pluripotent phenotype and were differentiated into cardiomyocytes (CdiPSC-CMs) positive for cardiac markers. Electrophysiological and optical characterization demonstrated functional cellular properties, including spontaneous and evoked action potentials, voltage-gated sodium currents, calcium wave propagation, and re-entrant rotor activity. CdiPSC-CMs also responded to β-adrenergic stimulation, demonstrating preservation of key excitable and signaling properties. Together, these findings establish the technical feasibility of recovering viable and functionally responsive cardiomyocytes from individuals post-death. This study provides a proof-of-concept platform for future functional studies of patient-specific genetic variants identified by molecular autopsy and, ultimately, for assessing their potential pathogenicity.
Background: Contemporary series report declining sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM), but whether this reflects fewer arrhythmic events or a greater proportion of deaths successfully prevented is unclear. We examined the proportion of arrhythmic events that were prevented rather than fatal over two decades, and its determinants. Methods: We conducted a systematic review of observational HCM cohorts published in 2000–2024 reporting SCD, resuscitated cardiac arrest (RCA) and appropriate ICD discharge (ICD-d). The primary outcome, the prevented fraction, was (RCA + ICD-d)/(SCD + RCA + ICD-d). Proportions were pooled using random-effects models (Freeman–Tukey transformation), compared between periods (2000–2013 vs. 2014–2024) and examined by meta-regression. Results: Fourteen cohorts (14,069 patients; 712 arrhythmic events) were included. The prevented fraction was 53.2% (95% CI 36.0–70.1) overall, and higher in 2014–2024 than in 2000–2013, (60.8% vs. 27.7%; p = 0.08), although this comparison relied on only three cohorts in the first period. This variation was strongly associated with cohort ICD penetration (β = 0.022, p < 0.0001), which explained 72% of the between-study heterogeneity, whereas calendar year was not independently associated (p = 0.45 when adjusted for ICD penetration). SCD fell from 72.3% to 39.2% of events while appropriate discharges rose from 9.8% to 40.5%; the share prevented by resuscitation did not increase. SCD incidence fell from 0.69 to 0.27 per 100 patient-years, while appropriate discharges rose from 0.10 to 0.27; the yield per implanted device did not improve (16.7% vs. 12.9%) and devices per prevented event rose from 5.8 to 8.1. Conclusions: Arrhythmic events in HCM have shifted from predominantly fatal to predominantly prevented, driven by ICD therapy rather than by the passage of time or by improved out-of-hospital resuscitation, but at the cost of broader implantation.
Background: Ischemic stroke (IS) is a major cause of global disability, with outcomes increasingly dictated by post-ischemic neuroinflammation. Despite advances in reperfusion, many patients experience neurological decline due to divergent inflammatory responses. Objectives: This review synthesizes current evidence on inflammatory signaling, stroke genetics, and genetically informed precision medicine relevant to the interplay between interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and ischemic stroke outcomes. Methods: We reviewed evidence from genome-wide association studies, Mendelian randomization analyses, experimental studies, observational biomarker cohorts, and relevant cardiovascular anti-inflammatory trials. Evidence from non-stroke populations is identified as indirect and is not interpreted as proof of efficacy in ischemic stroke. Results: IL-6 and TNF-α signaling involves receptor- and context-dependent mechanisms that may have both harmful and protective effects after cerebral ischemia. Multi-omic studies of the chromosome 9p21 locus and ANRIL suggest potential links among vascular-cell regulation, inflammation, and atherosclerotic risk, although stroke-specific mechanistic evidence remains limited. Elevated inflammatory-marker concentrations have been associated with greater stroke severity and unfavorable outcomes; however, their independent prognostic value and optimal sampling strategy require further validation. Selective anti-inflammatory approaches provide biologically plausible strategies for future study, but genotype-guided anti-cytokine treatment is not established for acute ischemic stroke or post-stroke recovery. Conclusions: Stroke genetics and multi-omic approaches may contribute to future precision-medicine strategies, but their clinical utility requires validation in prospective, stroke-specific studies. Current evidence does not support routine cytokine genotyping or genotype-guided anti-cytokine treatment in ischemic stroke.
Background: Heritable thoracic aortic disease (HTAD) accounts for approximately 20–25% of thoracic aortic aneurysm and dissection (TAAD) cases and is a major cause of premature death in young adults. Methods: This is a narrative, non-systematic review. We performed a selective synthesis of clinical practice guidelines (ACC/AHA 2022, EACTS/STS 2024), the revised Ghent nosology, large multicenter cohort studies (Montalcino Aortic Consortium), randomized pharmacotherapy trials, and molecular mechanism data published between 2010 and 2025; quantitative figures are reported as published in individual primary sources and were not pooled or re-analyzed. Results: The advent of next-generation sequencing (NGS) has driven a paradigm shift in HTAD management, from risk assessment based purely on phenotype (aortic diameter) to risk stratification based on genotype (molecular mutation). The 2022 ACC/AHA guideline identifies eleven genes with confirmed high-penetrance risk for HTAD; these, together with the established Loeys–Dietz gene TGFB3 (recognized through gene–disease validity assessment rather than the ACC/AHA list), can be grouped into three pathogenic mechanisms: extracellular matrix dysregulation, TGF-β signaling dysregulation, and vascular smooth muscle contractile dysfunction. Gene–disease association should be distinguished from guideline-defined classification and regarded as evolving, since additional candidate genes such as LTBP3 are already emerging in gene-negative families. Multigene panel testing identifies a pathogenic or likely pathogenic variant in roughly 8% of patients referred for suspected HTAD, a yield that rises substantially when applied to syndromic or strongly familial presentations. Prophylactic surgical thresholds are individualized by gene and are generally lower (around 4.0 cm) for high-risk TGFBR1/TGFBR2 and PRKG1 variants and higher (around 5.0 cm) for FBN1 and TGFB3, in contrast with the uniform 5.5 cm threshold historically applied to all patients. Randomized trials over the past decade—including the AIMS irbesartan trial, the Marfan Treatment Trialists’ individual patient data meta-analysis, and the celiprolol and irbesartan trials in vascular Ehlers–Danlos syndrome—now provide direct evidence that angiotensin receptor blockade slows the rate of aortic root dilation in Marfan syndrome, with more limited evidence in vascular Ehlers–Danlos syndrome and uncertain effects on dissection or mortality, while valve-sparing aortic root replacement provides durable long-term outcomes in reported single-center experience. These thresholds and pharmacotherapy recommendations rest predominantly on observational cohort, registry, and randomized trial data of varying maturity and should be interpreted as graded, evolving recommendations rather than fixed cut-points. Conclusions: This review synthesizes the molecular pathogenesis, diagnostic nosology, gene-specific epidemiologic and prognostic data, genetic testing yield, pharmacotherapy evidence, surgical outcomes, and updated prophylactic intervention algorithms per the ACC/AHA (2022) and EACTS/STS (2024) guidelines, providing a practical reference framework for individualizing surveillance and surgical decision-making in patients with HTAD.
Congenital heart defects (CHDs) are the most common congenital anomalies, with identifiable genetic etiologies in approximately 5-30% of affected infants, depending on the clinical presentation and comorbidities. This study included 216 children with CHD, predominantly syndromic, to explore the role of genetic variants in their morphological phenotypes. Chromosomal microarray (CMA) and whole-exome sequencing (WES) were performed, revealing clinically significant copy number variations (csCNVs) in 59 (27.3%) patients. The most frequent were 22q11.21 (8/59; 13.6%) and 7q11.23 (5/59; 8.5%) deletions. WES was conducted in 28.0% of cases, achieving a detection rate of 29.5%, primarily identifying variants related to Noonan syndrome. Genetic diagnoses were confirmed in 33.3% of patients, with clinically significant CNVs and SNV/INDELs found exclusively in those with syndromic CHD, leading to a 36.5% diagnosis rate in those patients. The identified variants most frequently affected genes encoding transcription factors (40.4%), followed by genes involved in the RAS signaling pathway and structural proteins (17.0%), and chromatin remodeling proteins (12.8%).
