Cardiogenetics

Takotsubo syndrome (TTS) is a temporary and reversible form of cardiomyopathy that clinically mimics acute coronary syndrome, typically triggered by intense physical or emotional stress. It mainly affects postmenopausal women and exhibits significant variation among individuals regarding its onset, progression, and outcomes. Although significant advances have been made since its initial description in 1990, the underlying pathophysiological mechanisms remain incompletely understood, limiting the development of effective prevention and targeted treatment strategies. A potential genetic predisposition has been suggested, supported by reports of familial clustering; however, a systematic and updated characterization of genetic and epigenetic factors associated with TTS is still lacking. This systematic and critical review aims to offer a comprehensive overview of current evidence on genetic susceptibility and epigenetic biomarkers potentially involved in the pathogenesis of TTS. Due to the heterogeneity and inconsistency of available findings, particular attention is also given to the methodological limitations of existing genetic studies. Finally, the review examines emerging multimodal approaches that may offer new perspectives for understanding the complex biological foundations of this syndrome.

Myocarditis is a complex inflammatory myocardial disease. Although traditionally regarded as exclusively immune-mediated, recent evidence highlights the significant role of underlying genetics on susceptibility, phenotypic variability, and long-term prognosis. This narrative review examines the evolving genetic architecture of myocarditis and its relationship to inherited cardiomyopathies, integrating mechanistic insights from molecular, imaging, and clinical studies. Variants in desmosomal genes such as desmoplakin (DSP) and plakophilin-2 (PKP2) are increasingly linked to recurrent myocarditis that may evolve into arrhythmogenic cardiomyopathy, supporting the concept of a genetically predisposed myocardium in which inflammatory stressors can act as triggers. Truncating variants in titin (TTN) and Filamin C (FLNC) are associated with fulminant or dilated phenotypes. Conversely, mutations in Lamin A/C (LMNA), Desmin (DES), and BCL2-Associated Athanogene 3 (BAG3) contribute to inflammatory myocardial remodeling and other forms of inherited cardiomyopathies. These findings collectively have the potential to redefine myocarditis as an inflammatory disorder influenced by genetic factors. Furthermore, advancements in genetic testing and multi-omics approaches show promise in enhancing diagnostic accuracy and informing management strategies.

Mitral annular disjunction (MAD) is associated with an increased risk of ventricular arrhythmias and sudden cardiac death, yet its genetic background remains poorly defined. We report the case of a 50-year-old man with MAD who survived cardiac arrest and carries three variants of unknown significance (VUS) in genes involved in cardiomyopathy pathogenesis. To explore the genetic basis of non-syndromic MAD, we performed a systematic review of the literature, identifying five case reports and one retrospective cohort study. The case reports described patients with MAD harboring four pathogenic variants and ten VUS. Two pathogenic variants were linked to cardiomyopathies, involving proteins of the nuclear envelope and cytoskeleton, while two were associated with channelopathies. The retrospective cohort study identified a recurrent variant in a gene involved in intercellular adhesion segregating within a family affected by MAD. Overall, available evidence suggests that genetic factors may hypothetically modulate susceptibility to MAD, not only in connective tissue disorders but also in isolated mitral valve disease. Variants associated with arrhythmogenic cardiomyopathies and channelopathies appear to cluster in families with non-syndromic MAD and arrhythmic phenotypes, suggesting a role in the arrhythmic substrate. However, in absence of definitive functional, segregation, or longitudinal data, the contribution of genetic variants to MAD should be interpreted with caution. Further genomic studies are needed to clarify their genetic contribution and prognostic implications.