Pulmonary Arterial Hypertension (PAH) is a complex and progressive disease characterized by elevated pulmonary vascular resistance and right heart failure. Current therapies primarily focus on pulmonary vasodilation; however, novel approaches that target the underlying pathophysiological mechanisms-such as TGF-β signalling, epigenetic alterations, growth factors, inflammation, and extracellular matrix remodelling-are promising alternatives for improving treatment outcomes. This is a review of recent advances in the development of innovative therapeutic strategies for PAH. The first section of this paper explores approaches targeting TGF-β signalling, both acting directly on receptors through drugs like Sotatercept and exogenous BMP9, and indirectly, inhibiting the degradation of key receptors, such as BMPR2. Subsequent sections describe treatments that target epigenetic regulators, e.g. poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors and direct BRD4 antagonists, tyrosine kinase inhibitors (Seralutinib), and therapies aimed at inflammation, such as IL-6 inhibitors, CD-20 inhibitors, and monoclonal antibodies that prevent macrophage migration. Finally, strategies that target the serotonin pathway, and other metabolic and hormonal pathways are described. This review includes both preclinical and clinical trial data that support efficacy, safety and the future potential of such therapies. Collectively, these therapeutic approaches can be valuable in treating PAH by targeting multiple aspects of its pathogenesis, potentially resulting in improved clinical outcomes for patients affected by this debilitating, life-limiting condition.

Background: Transition from paediatric to adult care in congenital heart disease (CHD) represents a pivotal and vulnerable phase that critically influences long-term survival, morbidity, and quality of life. Advances in paediatric cardiology and surgery have generated a rapidly growing population of adults with congenital heart disease who exhibit complex, lifelong, and multidisciplinary needs. However, survival does not equate to cure, and discontinuity of care during adolescence remains a major predictor of adverse outcomes. Despite widespread recognition of their importance, transition programmes are heterogeneous worldwide, and standardised, evidence-based protocols are missing. Objective: This review calls for action acknowledging the urgent need for structured and standardised transition programmes in CHD care, integrating the key elements that should be addressed in any programme to optimise outcomes. Content: Transition should be understood as a multidisciplinary, longitudinal process integrating medical management, patient and family education, psychological preparation, and societal inclusion. Core domains include tailored physical activity, nutritional counselling, cardiovascular risk factor management, infective endocarditis prevention, reproductive health, psychosocial support, and engagement of primary care providers, educators, and employers. Evidence demonstrates that structured transition programmes enhance health literacy, adherence, and self-management, while reducing loss to follow-up. The active involvement of primary care providers, psychologists, educators, and employers is essential to sustain holistic and equitable care. Conclusions: Transition should be reframed as an essential, lifelong component of CHD care. The development and implementation of standardised, multidisciplinary, evidence-based transition protocols are urgently required to ensure continuity, empower patients, and optimise long-term clinical and psychosocial outcomes for adults with CHD.

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, classically characterized by right ventricular outflow tract obstruction, ventricular septal defect, overriding aorta, and right ventricular hypertrophy. Recent advances in molecular and genomic research indicate that TOF is part of a phenotypic continuum encompassing Trilogy, Tetralogy, and Pentalogy of Fallot, in which the variability of anatomical presentation reflects shared genetic and epigenetic mechanisms with highly variable penetrance and expressivity. Variants in NOTCH1, FLT4, KDR, GATA6, and TBX1 highlight key pathways in conotruncal development and endothelial–mesenchymal transition, yet these well-known genes explain only a fraction of the genetic landscape. Emerging studies have identified additional candidate genes and networks involved in cardiac morphogenesis, including transcriptional regulators, signaling mediators, chromatin-remodeling factors, and splicing-associated genes such as PUF60 and DVL3. Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNA expression, further modulate phenotypic expressivity and contribute to variability along the Trilogy–Tetralogy–Pentalogy spectrum. This review integrates current genomic and clinical evidence to provide a comprehensive overview of the molecular architecture of Fallot-type conotruncal malformations, emphasizing the interplay between genetic and epigenetic mechanisms, genotype–phenotype correlations, and implications for diagnosis, risk stratification, counseling, and personalized management in the era of precision cardiology.

Background: Cardiopulmonary exercise testing (CPET) is increasingly recognized as a key tool for evaluating patients with congenital heart disease (CHD). While traditional assessments focus on resting parameters, CPET provides dynamic, integrated insight into cardiovascular, respiratory, and muscular function during exertion. Objectives: This review explores the clinical value of CPET across the spectrum of CHD, with dedicated focus on its applications in both adult and paediatric populations. We analyse the prognostic significance of key CPET parameters—particularly peak oxygen consumption (peak VO₂), ventilatory efficiency (VE/VCO₂ slope), and heart rate dynamics—within distinct anatomical and physiological categories of CHD. Findings: CPET reliably detects exercise intolerance, guides intervention timing, informs exercise prescription, and stratifies risk. Peak VO₂ and heart rate reserve are consistently associated with adverse outcomes across most CHD types. However, the prognostic utility of other variables, such as the VE/VCO₂ slope, varies with pathophysiology—being less reliable in cyanotic lesions like Eisenmenger syndrome. In paediatric patients, CPET must be adapted to growth-related physiological variability and is increasingly used to assess quality of life, functional limitation, and response to therapy. Conclusions: CPET is a powerful, non-invasive tool that should be integrated into routine management of CHD patients across all ages. It enhances risk assessment, supports tailored care, and promotes safe physical activity, ultimately contributing to improved long-term outcomes and quality of life.

Cancer therapies have significantly improved survival but are frequently limited by cancer therapy-related cardiovascular toxicity (CTR-CVT). Cardiovascular imaging plays a central role in baseline risk stratification, surveillance during therapy and long-term follow-up. Transthoracic echocardiography (TTE) remains the first-line imaging modality; however, conventional parameters such as left ventricular ejection fraction (LVEF) often fail to detect early myocardial injury. Myocardial deformation imaging, particularly global longitudinal strain (GLS), has emerged as a sensitive marker of subclinical dysfunction across multiple cardiotoxic phenotypes. Cardiac magnetic resonance (CMR) further enhances diagnostic accuracy through tissue characterization techniques, enabling the detection of myocardial edema, inflammation, and fibrosis before overt functional decline. Different anticancer therapies induce distinct pathophysiological mechanisms of injury, each associated with characteristic imaging patterns. Emerging imaging biomarkers and multimodality approaches may improve early detection, the spatial characterization of myocardial injury and individualized surveillance strategies. Pediatric patients represent a uniquely vulnerable population due to their myocardial immaturity, altered pharmacokinetics and prolonged post-treatment life expectancy, resulting in a higher cumulative lifetime cardiovascular risk. In conclusion, a mechanism-based multimodality imaging approach integrating echocardiography, CMR and emerging data-driven technologies is essential to optimize early detection, risk stratification and long-term cardiovascular outcomes in both adult and pediatric cardio-oncology populations.

In 2014 a professional collaboration was established between IRCCS Policlinico San Donato, Milan, Italy (PSD) and the Institute for Cardiovascular Disease Dedinje, Belgrade, Serbia (ICDD) to support and improve the care of adult patients with congenital heart disease (ACHD) in the country. Since 2018, this collaboration has become more structured, with a specific focus on surgery for adults with complex congenital heart disease (CHD). Aim of the study was to evaluate the outcomes of this collaboration. We conducted a retrospective study on all consecutive adult patients (aged over 18 years) with CHD who underwent surgery at the Institute for Cardiovascular Disease Dedinje (ICDD) over a ten-year period, from January 2014 to December 2024. Collected data included number of cases, mean age at surgery, types of surgical procedures performed, number of previous operations, distribution of cases based on complexity, patient outcomes, and follow-up. Between 2014 and 2024, a total of 244 ACHD patients underwent surgery at ICDD. Eighty-eight of these patients (88/244 = 36%) required complex procedures and were referred to the visiting PSD cardiac surgeon. Mean age at surgery was 34.8 years (±14 years). The most common diagnosis was right ventricular outflow tract (RVOT) pathology, accounting for 89% of cases. Seventy patients (80%) underwent reoperations following previous procedures. In-hospital mortality was 4.5% (4 patients). No additional deaths or reoperations occurred during a mean follow-up of 58 months (2-122 months). This ten-year international partnership demonstrates that high-quality ACHD surgical care can be delivered sustainably in countries with limited case volumes and expertise. By combining local access with external specialist support, the model has achieved outcomes comparable to high-volume Western European centres. Increased access to ACHD surgery in their home country and reduced financial burden suggests that this model of care may potentially serve in other countries facing similar healthcare challenges.