Exercise intolerance, measured as peak oxygen consumption (VO₂peak) during exercise in patients with heart failure with reduced ejection fraction (HFrEF). Change in VO₂peak (ΔVO₂peak), which serves as a prognostic marker for HFrEF engaged in exercise based cardiac rehabilitation program (ExCR). Responders to ExCR generally show improved cardiac function but some patients with HFrEF do not respond to ExCR. VO₂peak depends on three major components of oxygen transport: Pulmonary (lungs), circulatory (heart and vessels) and skeletal muscle (oxygen utilization) functions. These physiological responses to ExCR may be influenced by epigenetic regulation, specifically the expression of circulating microRNAs (c-miRNAs).

Linking non-invasive measurements and epigenetic markers could 1) identify which component of the oxygen transport chain is most impaired and 2) allow personalized interventions to maximize VO₂peak improvements.

The primary objective of this stidy is to assess the association between changes in VO₂peak during exercise training and circulating microRNA expression (miR-146a, miR-191, miR-23a, miR-140, miR-1, miR-21, miR-133a, miR-17-5p, miR-3200-3p).

The secondary objective is to examine the relationship between pulmonary, cardiovascular, and neuromuscular adaptations to exercise and circulating microRNA expression.

Key Takeaways VO₂peak is a clinically relevant, prognostic measure in HFrEF. .ExCR benefits are heterogeneous, partly due to variable cardiac and muscular adaptations. c-miRNAs may mediate or indicate the molecular response to ExCR. c-miRNAs may Enhance pulmonary, cardiac, or muscular adaptations → improved VO₂peak, or, if maladaptive, contribute to fatigue → explaining non-response.

Goal Connect ΔVO₂peak with cellular precursors of adaptation, providing a mechanistic understanding of CR responses.

Method 62 patients with HFrEF will be engaged in a this prospective, single-center cohort follow-up study with a prognostic aim and minimal risk to human participants.

Peak values of oxygen uptake, cardiac hemodynamics, cerebral and muscle oxygenation, non-coding RNA will be measured before and after Exercise based cardiac rehabilitation during a cardiopulmonary exercise testing. All the patients will perform a force - velocity test in order to prescribe an individualized resistance training program.

Originality of study: Combines non-invasive physiological measurements during exercise and biomarker (c-miRNA) analysis before and after ExCR.

Scientific and Clinical Significance

Linking non-invasive measurements and epigenetic markers could:

1. Identify which component of the oxygen transport chain is most impaired.
2. Combining physiological and molecular assessments could guide tailored rehabilitation strategies.

Inclusion Criteria:

• Heart failure with reduced ejection fraction < 40%
• NYHA functional class ≥ II
• Clinically stable for at least 6 weeks
• On optimized medical therapy for at least 6 weeks
• Prescription for phase II cardiac rehabilitation
• BMI between 20-30 kg·m-²
• Physical activity level: sedentary or physically active but untrained
• Signed informed consent to participate in the study
• Affiliation to the French national health insurance system

Exclusion Criteria:

• Contraindication to regular adapted physical activity
• Uncontrolled arterial hypertension
• Secondary respiratory disease such as emphysema or chronic obstructive pulmonary disease (COPD)
• Secondary cardiovascular disease
• Individuals under legal protection or deprived of liberty
• Pregnant or breastfeeding women

Heart failure patient with altered left ventricular ejection fraction