The goal of this clinical trial is to evaluate a structured and personalized cardiac rehabilitation program for patients diagnosed with arrhythmogenic cardiomyopathy (ACM) who carry high-risk genetic mutations. Historically, physical exercise has been strictly restricted in these patients due to the potential risk of triggering life-threatening arrhythmias and accelerating structural heart disease. However, complete inactivity leads to severe physical deconditioning and reduced quality of life. This study aims to address this clinical dilemma by investigating a safe way to prescribe exercise.

The main question it aims to answer is: Is a supervised, moderate-intensity exercise program safe, and does it avoid increasing the risk of cardiac arrhythmias or worsening right ventricular function compared to standard physical restriction?

As secondary objectives, the study will thoroughly evaluate the impact of this tailored physical intervention on the participants' functional capacity, specifically measuring changes in physical fitness and peak oxygen consumption through cardiovascular testing. Additionally, the trial aims to assess the psychological benefits of the program, analyzing its effects on health-related quality of life, anxiety, and depression levels. Researchers will compare the experimental group undergoing cardiac rehabilitation to a control group receiving conventional physical restriction guidelines to determine if the program is both safe and comprehensive.

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 precisely 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 primarily 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. We will evaluate differences in safety and efficacy outcomes (such as changes in VO2 peak and left ventricular ejection fraction) 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.

Inclusion Criteria:

• Participant must be 18 years of age or older at the time of signing the informed consent.
• Definite diagnosis of arrhythmogenic cardiomyopathy (ACM) according to the 2024 European Task Force criteria.
• Documented left or right ventricular involvement confirmed via transthoracic echocardiography or cardiac magnetic resonance imaging (MRI), characterized by abnormalities in regional contractility, presence of aneurysms, reduced ejection fraction, and/or late gadolinium enhancement (LGE).
• Confirmed presence of a pathogenic or likely pathogenic genetic variant in the LMNA, DSP, FLNC, TMEM43, PLN, or DES genes.
• Clinical stability maintained for 3 months or longer prior to inclusion, defined as the absence of hospital admissions, sustained ventricular arrhythmic events, or implantable cardioverter-defibrillator (ICD) shocks.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form.

Exclusion Criteria:

• Inability or physical contraindication to perform physical exercise at the time of inclusion.
• Presence of overlapping phenotypes associated with other non-arrhythmogenic cardiomyopathies.
• Active pregnancy.
• Current engagement in competitive or high-intensity sports or exercise programs at the time of inclusion.