Nicolò Pasini

Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, leading to life-threatening ventricular arrhythmias and heart failure. Historically, management has focused on arrhythmia suppression and prevention of sudden cardiac death (SCD). However, recent advances in understanding disease mechanisms have redefined ACM as a structural–metabolic cardiomyopathy. Central to this evolving paradigm is the “adipogenic switch”, driven by desmosomal dysfunction, impaired Wnt/β-catenin signaling, and activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Emerging evidence highlights the critical role of metabolic dysregulation, specifically the oxidized low-density lipoprotein (oxLDL)/cluster of differentiation 36 (CD36)/PPARγ axis, in driving disease progression. Elevated oxLDL levels correlate with greater phenotypic severity, increased ventricular fat infiltration, and a higher arrhythmic risk. Translational models demonstrate that high-fat diets exacerbate the ACM phenotype, whereas lipid-lowering interventions, particularly statins, show potential to arrest fibro-fatty remodeling. In addition to the primary inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase associated with statins, these medications exert pleiotropic effects, including attenuation of systemic inflammation, stabilization of the intercalated disc via Rho GTPase modulation, and reduction of oxidative stress. Clinical data from non-ischemic dilated cardiomyopathy (NIDCM) suggest that lipophilic statins such as atorvastatin, may confer significant mortality and antiarrhythmic benefits by stabilizing the myocardial electrical substrate. The ongoing SEARCH trial (NCT06922994) represents a landmark effort to translate these insights into clinical practice. Using high-dose atorvastatin and sensitive primary endpoints, such as right ventricular free wall longitudinal strain, this study aimed to determine whether lipid-lowering therapy can function as a true disease-modifying intervention in ACM. The integration of lipid-lowering agents into the therapeutic armamentarium for ACM could enable a transition toward precision medicine, contingent upon successful clinical validation. If clinical trials confirm the efficacy of these agents in slowing myocardial substrate decay, this approach could redefine the management of ACM, including the use of targeted molecular strategies to preserve myocardial identity and electrical stability.

Chimeric antigen receptor T-cell therapy and bispecific T-cell engagers have transformed treatment of relapsed and refractory hematologic malignancies, achieving unprecedented response rates. However, their clinical adoption has revealed a complex spectrum of cardiovascular toxicities, differing in frequency and pattern between the two technologies. Manifestations range from common hemodynamic perturbations—hypotension and tachycardia—to severe events, including malignant arrhythmias, left ventricular dysfunction, myocardial infarction, and cardiogenic shock. These complications seem to have different pathophysiological pathways that are yet to be completely understood: on the one hand, they are frequently intertwined with cytokine release syndrome, the hallmark immune complication of T-cell-redirecting therapies, as seen with chimeric antigen receptor T-cell therapy; on the other, a substantial proportion of cardiovascular events—particularly with bispecific T-cell engagers—occur independently of cytokine release syndrome. Proposed cardiotoxic mechanisms include on-target, off-tumor antigen recognition and consequent damage; interleukin-6-driven systemic inflammation; and off-target, off-tumor antigen cross-reactivity. Effective management requires proactive baseline risk stratification, serial cardiac biomarker monitoring, and timely immunosuppressive intervention—primarily tocilizumab—to mitigate cytokine release syndrome-driven injury. Despite rapid clinical expansion, critical gaps remain: long-term cardiovascular outcomes are poorly characterized, validated surveillance protocols are lacking, and cardiovascular endpoints are rarely included in pivotal trials. This narrative review appraises the pathophysiology, clinical spectrum, and management of cardiovascular toxicities associated with these therapies, aiming to define this emerging cardio-oncology frontier, inform multidisciplinary care frameworks and propose a clinical management algorithm.

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of cardiac dysfunction in adults, resulting from extracellular deposition of misfolded transthyretin fibrils and progressive myocardial impairment. Clinical expression and diagnostic yield differ substantially between sexes, contributing to systematic underdiagnosis in women, who often present with subtler myocardial remodeling, heart failure with preserved ejection fraction (HFpEF)–dominant phenotypes, and nonspecific systemic manifestations that fall below conventional diagnostic thresholds, particularly in early disease stages. Female patients, particularly those with ATTRwt, tend to present at older ages and more frequently show HFpEF-dominant phenotypes and nonspecific extracardiac manifestations. Carpal tunnel syndrome (CTS) is an important extracardiac red flag for ATTR-CM, but its interpretation in women requires caution because of the high background prevalence of idiopathic CTS in the general population. Evidence also suggests sex-related differences in diastolic function, right ventricular involvement, and overall progression. Despite these biological and phenotypic distinctions, women are markedly underrepresented in trials of disease-modifying therapies, limiting conclusions about sex-specific treatment effects and leaving uncertainty about whether current pharmacologic interventions provide comparable benefit. Hormonal influences, genetic background, and age-related mechanisms, comorbidities, and diagnostic pathways may contribute to the distinctive female phenotype, but underlying mechanisms remain insufficiently defined. This narrative review examines sex-associated differences in ATTR-CA, focusing on mechanisms of underdiagnosis, principal clinical and imaging features, and implications for therapeutic response, with the goal of improving diagnostic accuracy, guiding individualized management, and ultimately enhancing outcomes for women and all affected patients worldwide in clinical practice.

Cardiac amyloidosis (CA) is an increasingly recognized cause of restrictive cardiomyopathy in which extracellular amyloid deposition leads to progressive structural and functional impairment. Beyond myocardial infiltration, growing evidence highlights the central role of autonomic nervous system dysfunction (ANS) —particularly the vagal nerve involvement—as a contributor to orthostatic intolerance, syncope, exercise limitation, arrhythmias, and reduced quality of life. Emerging data suggest that autonomic impairment may precede overt cardiac manifestations, offering a potential window for earlier recognition. This narrative review summarizes current knowledge on the mechanisms and clinical relevance of autonomic dysfunction in CA, emphasizing the novelty of the “vagal link” as a unifying framework connecting with a specific focus on the vagus nerve (VN) and its complex interplay with cardiac structure and function. We further discuss diagnostic approaches and the potential role of autonomic assessment in early detection, risk stratification, and personalized treatment strategies. A clearer understanding of vagal dysfunction may provide new insights into disease progression and identify opportunities for therapeutic innovation.

Arrhythmogenic cardiomyopathy (ACM; MIM #107970) is a primitive heart muscle disease characterized by progressive myocardial loss and fibrosis or fibrofatty replacement, predisposing patients to ventricular arrhythmias, sudden cardiac death, and heart failure. Despite advances in imaging and genetics, early diagnosis remains challenging due to incomplete penetrance, variable phenotypic expressivity, and the fact that fatal arrhythmic events may often occur in the early stages of the disease. In this context, the identification of reliable biomarkers could enhance diagnostic accuracy, support risk stratification, and guide clinical management. This narrative review examines the current landscape of potential and emerging biomarkers in ACM, including troponins, natriuretic peptides, inflammatory proteins, microRNAs, fibrosis-related markers, and other molecules. Several of these biomarkers have demonstrated associations with disease severity, arrhythmic burden, or structural progression, although their routine clinical utility remains limited. The increasing relevance of genetic testing and non-invasive tissue characterization—particularly through cardiac imaging techniques—should also be emphasized as part of a multimodal diagnostic strategy in which biomarkers may play a complementary role. Although no single biomarker currently meets the criteria for a standalone diagnostic application, ongoing research into multi-marker panels and novel molecular targets offers promising perspectives. In conclusion, the integration of circulating biomarkers with imaging findings, genetic data, and clinical parameters may open new avenues for improving early detection and supporting personalized therapeutic strategies in patients with suspected ACM.