Cardiogenetics

Somatic hematopoietic mutations, particularly clonal hematopoiesis of indeterminate potential (CHIP), represent an emerging link between aging, inflammation and cardiovascular disease beyond their established relevance in hematology. This narrative review examines how acquired mutations in hematopoietic stem and progenitor cells contribute to cardiovascular pathogenesis and how this knowledge may inform precision prevention and therapy. Evidence from experimental, clinical and population studies was synthesized with emphasis on clonal expansion, variant allele fraction, gene-specific mechanisms and cardiovascular phenotypes. The reviewed data indicate that driver mutations in DNMT3A, TET2, ASXL1, JAK2, TP53 and PPM1D can promote chronic myeloid inflammation, NLRP3/IL-1β and IL-6 signaling, endothelial dysfunction, atherosclerotic plaque instability, myocardial fibrosis, adverse remodeling, thrombosis, arrhythmias and cardio-oncology complications. The cardiovascular impact of CHIP appears heterogeneous and depends on the mutated gene, clone size, inflammatory phenotype, age, sex, treatment exposures and traditional risk factors. Anti-inflammatory, antithrombotic and mutation-oriented strategies, including IL-1β/NLRP3 blockade and pathway-specific approaches, are promising but remain incompletely validated. Somatic hematopoietic mutations should be considered cardiovascular risk modifiers rather than uniform disease entities. Future studies are needed to define screening thresholds, clinical utility and safety of CHIP-guided risk stratification and targeted therapy.

Non-dilated left ventricular cardiomyopathy (NDLVC) presents a unique clinical paradox: patients with nearly identical phenotypes can face radically different clinical outcomes. NDLVC has been recently recognized as a distinct dynamic phenotype within the spectrum of non-ischemic cardiomyopathies, linked by a high risk of life-threatening arrhythmias. Recent advances in genetics have overcome clinical phenotyping in prognostic accuracy. Specifically, gene-specific scores have been introduced to guide primary prevention ICD in high-risk gene carriers. On the other hand, while gene-elusive cases present a more favourable arrhythmic profile, their long-term clinical outcome is more challenging to predict. Despite advancements in therapeutic strategies, the heterogeneity of the disease represents an ongoing dilemma for risk stratification and long-term surveillance. This review offers a comprehensive analysis of NDLVC management in clinical practice, highlighting the profound prognostic divergence between genetic (both in actionable and VUS carriers) and gene-elusive cohorts. By synthesizing current evidence, we aim to clarify how genotype–phenotype correlations influence clinical outcomes and to provide a framework for more personalized approaches in the follow-up and treatment of these distinct patient populations. Furthermore, we address the current lack of standardized guidelines specifically tailored to gene-elusive phenotypes. In conclusion, NDLVC management requires a paradigm shift towards a multi-parametric, genotype-directed framework, where cardiac magnetic resonance tissue characterisation and personalized risk scores are essential to optimize sudden cardiac death prevention. Future research must leverage artificial intelligence and polygenic risk scores (PRSs) to integrate multi-parametric clinical-imaging data and refine risk stratification beyond traditional binary models. Concurrently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) will be pivotal as a translational platform to clarify VUS pathogenicity, unravel gene-specific arrhythmic mechanisms, and accelerate targeted therapeutic interventions.

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.