For years, the treatment of many cardiomyopathies has been solely focused on symptom management. However, cardiomyopathies have a genetic substrate, and directing therapy towards the pathophysiology rather than the epiphenomenon of the disease may be a winning strategy. Gene therapy involves the insertion of genes or the modification of existing ones and their regulatory elements through strategies like gene replacement and gene editing. Recently, gene therapy for cardiac amyloidosis and Duchenne muscular dystrophy has received approval, and important clinical trials are currently evaluating gene therapy methods for rare heart diseases like Friedreich’s Ataxia, Danon disease, Fabry disease, and Pompe Disease. Furthermore, favorable results have been noted in animal studies receiving gene therapy for hypertrophic, dilated, and arrhythmogenic cardiomyopathy. This review discusses gene therapy methods, ongoing clinical trials, and future goals in this area.

Background/Objectives: Cardiopulmonary exercise testing (CPET) is a well-established tool for risk stratification in patients with heart failure (HF); however, its utility is limited in routine clinical practice due to the associated cost and technical demands. The hemodynamic gain index (HGI), a non-metabolic parameter derived from systolic blood pressure and heart rate changes during exercise, has been demonstrated to play a promising role in HF populations. In this study, we aimed both to validate the prognostic value of the HGI and to evaluate a novel metric, heart hemodynamic reserve (HHR), in patients with HF and left ventricular ejection fraction (LVEF) below 50%. Methods: We retrospectively enrolled 479 consecutive patients with HF and reduced or mildly reduced LVEF who underwent maximal, symptom-limited CPET at three Italian university hospitals between 2012 and 2024. The HGI and HHR were computed using resting and peak exercise hemodynamic data. HHR is defined as the product of systolic blood pressure and heart rate reserve with exercise, normalized for the age-predicted maximum heart rate. The primary endpoint was a composite of cardiovascular death, urgent heart transplantation (HTx), or left ventricular assist device (LVAD) implantation. Prognostic associations were assessed using multivariable Cox regression and area under the receiver operating characteristic curves (AUCs). Results: During a median follow-up of 3.25 years, the composite outcome occurred in 56 patients (11.5%). Both the HGI and HHR were independently associated with the prespecified endpoint (HGI HR: 0.41, 95% CI: 0.20–0.83, p = 0.013; HHR HR: 0.89, 95% CI: 0.83–0.96, p = 0.004), with HHR showing a slightly higher prognostic accuracy than the HGI (AUC 0.78 vs. 0.74; p = 0.033). Conclusions: Both the HGI and HHR are independent prognostic markers in HF patients with LVEF < 50%. Their non-metabolic derivation makes them valuable tools for risk stratification in settings where CPET is unavailable.

Background and Objectives: Eccentric hypertrophy (EH) represents a common physiological cardiac adaptation in athletes, particularly in endurance disciplines. However, the biological correlates underlying EH and potential sex-specific differences remain poorly understood. This study aimed to investigate clinical, echocardiographic, and biochemical determinants of EH in a large cohort of elite athletes. Materials and Methods: We evaluated 2522 elite athletes undergoing pre-participation screening for Olympic competitions. Athletes were classified according to cardiac geometry into EH or normal geometry (NG) based on echocardiographic parameters. Clinical, anthropometric, echocardiographic, and biochemical variables were compared between groups. Univariate and multivariable logistic regression analyses were performed to identify independent predictors of EH. Results: EH was present in 601 athletes (23.8%) and was more prevalent in endurance sports (51.1% vs. 14.3%, p < 0.0001). Athletes with EH showed greater cardiac chamber dimensions and mass, with preserved systolic and diastolic function. Several biomarkers differed between groups, including higher AST, ALT, CPK, eosinophils, and HDL, and lower creatinine and TSH in EH (all p < 0.01). Following multivariable analysis, lower creatinine (OR 0.28, 95% CI 0.14–0.52, p < 0.0001), higher AST (OR 1.02, 95% CI 1.02–1.03, p < 0.0001), and higher eosinophil count (OR 1.12, 95% CI 1.06–1.20, p < 0.0001) independently predicted EH. The model showed moderate discrimination (AUC 0.72). Sex-stratified analyses showed different biomarker associations with EH in men (creatinine and AST) and women (eosinophils and HDL), with similar model performance (AUC 0.71 vs. 0.73). Conclusions: EH in elite athletes is associated with distinct biological signatures reflecting multiple physiological pathways. Notably, sex-specific patterns emerge, suggesting different mechanisms underlying cardiac adaptation in male and female athletes.

Background: The impact of cigarette smoking on cardiopulmonary function in elite athletes remains poorly characterised. This study aimed to evaluate the prevalence of smoking and its effects on pulmonary and exercise performance parameters among top-level competitors across different sport disciplines. Methods: 1005 Olympic-level athletes participating underwent comprehensive pre-participation screening, including spirometry and cardiopulmonary exercise testing (CPET). Smoking status was determined according to WHO definitions. Results: Among the 1005 athletes (53.4% males; mean age 26 ± 8.8 years), 117 (11.6%) were current smokers, predominantly males (70.9%). No smokers were identified among endurance athletes. Compared to non-smokers (n = 679), smokers were older (28 ± 5.8 vs. 25.5 ± 10.4 years, p = 0.026) and more frequently involved in mixed and skill disciplines (p = 0.043 and p = 0.006, respectively). In male smokers, spirometry revealed lower FVC (97.2 ± 10.3% vs. 101.1 ± 11.7%, p = 0.006), FEV₁ (97.3 ± 12.4% vs. 101.4 ± 10.3%, p = 0.002), and MVV (p = 0.010). CPET showed reduced functional capacity (W/kg, p < 0.0001), lower VO₂max (38.5 ± 7.8 vs. 42.2 ± 6.8 mL/min/kg, p < 0.0001), decreased O₂ pulse (p = 0.007) and lower first and second ventilatory thresholds (respectively p = 0.025; and p = 0.004), Similar but less pronounced reductions in VO₂max were found in female smokers (p = 0.003). Conclusions: Chronic smoking is associated with early spirometric and ventilatory impairments in elite athletes associated with lower aerobic capacity, despite their high levels of fitness. These effects are more marked in males, while females may exhibit partial protection. These findings highlight the importance of integrating smoking cessation and respiratory monitoring into athlete health programs.