Cardiac Rehabilitation in Patients With High-Genetic-Risk Arrhythmogenic Cardiomyopathy: The HGEN-CARE-AC Trial

Study Design:

This is an exploratory, randomized, parallel-group clinical trial designed to assess the safety and feasibility of a structured cardiac rehabilitation program for patients with high-genetic-risk arrhythmogenic cardiomyopathy (ACM). Participants will be randomized in a 1:1 ratio to either the experimental intervention group or a control group receiving standard-of-care physical restriction guidelines.

Interventions:

* Experimental Group: Participants will undergo a 12-week supervised cardiac rehabilitation program. This intervention involves individualized, moderate-intensity exercise sessions. The intensity of the exercise prescription will be titrated based on baseline cardiopulmonary exercise testing (CPET) and individual cardiovascular risk profiles, aiming to improve functional capacity while minimizing the risk of pro-arrhythmic events. * Control Group: Participants will follow conventional standard-of-care recommendations, which emphasize physical activity restriction as per current clinical practice guidelines for high-risk ACM.

Data Acquisition and Monitoring:

Safety and structural remodeling will be monitored throughout the study period. Safety assessments include continuous surveillance for adverse events (e.g., symptomatic arrhythmias, syncope, or hospitalizations). Structural and functional cardiac changes will be quantified through standardized advanced cardiac imaging techniques (echocardiography) and cardiopulmonary exercise testing at baseline and follow-up time points. Psychometric status will be evaluated using validated questionnaires to capture changes in health-related quality of life, anxiety, and depression.

Statistical Analysis Plan:

Continuous variables will be reported as mean ± standard deviation (or median and interquartile range for non-normal distributions), while categorical variables will be presented as frequencies and percentages. Longitudinal changes from baseline to follow-up will be evaluated using mixed-effects models for repeated measures, accounting for inter-individual variability.

An exploratory subgroup analysis will be conducted to assess the consistency of the intervention's effects across predefined patient strata. Differences in safety and efficacy outcomes (such as changes in VO2 peak and left ventricular ejection fraction) will be evaluated, stratified by:

* Biological Sex: Categorized as male or female. * Causal Genotype: Categorized by the identified pathogenic variant (LMNA, DSP, FLNC, TMEM43, PLN, or DES).

Statistical comparisons between subgroups will be performed using independent t-tests or ANOVA for normally distributed continuous data, and Mann-Whitney U or Kruskal-Wallis tests for non-normally distributed data. Categorical variables will be assessed using Chi-square or Fisher's exact tests. This exploratory analysis is intended to identify potential heterogeneous treatment effects; all tests will be two-tailed, with a p-value \< 0.05 considered statistically significant.

• Change from baseline in peak oxygen consumption (VO2 peak) [Срок оценки: Baseline and 12 weeks]
• Change from baseline in metabolic equivalents (METs) [Срок оценки: Baseline and 12 weeks]
• Change from baseline in 6-minute walk distance [Срок оценки: Baseline and 12 weeks.]
• Change from baseline in Hospital Anxiety and Depression Scale (HADS) score [Срок оценки: Baseline and 6 months.]
• Change from baseline in SF-36 health-related quality of life score [Срок оценки: Baseline and 6 months.]
• Change from baseline in EQ-5D-5L index score [Срок оценки: Baseline and 6 months.]
• Change in left ventricular ejection fraction (LVEF) [Срок оценки: Baseline and 6 months.]
• Change in right ventricular ejection fraction (RVEF) [Срок оценки: Time Frame: Baseline and 6 months.]
• Change in left ventricular internal diameter [Срок оценки: Baseline and 6 months.]
• Change from baseline in Body Mass Index (BMI) [Срок оценки: Baseline and 12 weeks.]
• Change from baseline in systolic blood pressure [Срок оценки: Baseline and 12 weeks.]
• Change from baseline in serum LDL cholesterol [Срок оценки: Baseline and 12 weeks.]