The Effect of Cardiac Rehabilitation on Ferroptosis in Patients With Coronary Artery Disease

Coronary artery disease (CAD) remains a major global public health challenge and is the leading cause of cardiovascular mortality worldwide. In recent years, ferroptosis, an iron-dependent form of regulated cell death, has emerged as a major focus of biomedical research. Characterized by excessive lipid peroxidation and the accumulation of reactive oxygen species (ROS), ferroptosis has provided new insights into the pathophysiology of CAD and represents a promising therapeutic target.

The pathophysiological significance of ferroptosis in cardiovascular diseases stems from its central role in dysregulated iron metabolism, lipid peroxidation, and excessive ROS accumulation. These mechanisms contribute substantially to the initiation and progression of CAD. Under pathological conditions such as ischemia and hypoxia, cardiomyocytes exhibit increased susceptibility to ferroptosis, leading to cellular dysfunction, myocardial injury, and impaired cardiac function.

Cardiac rehabilitation (CR) is a comprehensive, multidisciplinary intervention that integrates exercise training, cardiovascular risk factor management, lifestyle modification, and psychosocial support, and constitutes a cornerstone of contemporary CAD management. CR has been shown to slow or delay disease progression by targeting modifiable cardiovascular risk factors while improving quality of life, cardiac performance, exercise capacity, and cardiovascular symptoms. Furthermore, CR reduces anxiety, depression, and psychological stress, facilitates return to work, and promotes independence in activities of daily living.

Exercise-based cardiac rehabilitation is among the interventions supported by the strongest evidence for reducing mortality and morbidity in patients with CAD. Experimental studies in animal models have demonstrated that aerobic exercise suppresses ferroptosis, thereby reducing cardiomyocyte death, protecting the ischemic myocardium, and improving cardiac function. Conversely, induction of ferroptosis in cardiomyocytes has been shown to exacerbate ischemia-reperfusion injury. However, no clinical study has comprehensively investigated ferroptosis-related molecular alterations in patients with CAD or evaluated the effects of cardiac rehabilitation on these pathways in humans.

Therefore, the present study aims to compare ferroptosis-related molecular and biochemical biomarkers among patients with CAD undergoing cardiac rehabilitation, patients with CAD who voluntarily decline participation in cardiac rehabilitation, and healthy controls. In addition, changes in ferroptosis-related biomarkers before and after completion of the cardiac rehabilitation program will be evaluated in patients undergoing cardiac rehabilitation.

Inclusion criteria

Patients With Coronary Artery Disease (CAD):

• Age between 18 and 75 years.
• Diagnosis of coronary artery disease within the previous 3 months.
• Eligible to participate in a cardiac rehabilitation program or voluntarily decline participation in the cardiac rehabilitation program.
• Peak exercise capacity of ≥5 metabolic equivalents (METs).
• Able to undergo cardiopulmonary exercise testing (CPET).
• Able to understand the study procedures and provide written informed consent.

Healthy Controls:

• Age between 18 and 75 years.
• No history of coronary artery disease or other cardiovascular diseases.
• No history of chronic systemic diseases, including diabetes mellitus, hypertension, chronic kidney disease, chronic liver disease, inflammatory or autoimmune diseases, or malignancy.
• Not receiving regular medication.
• Able to provide written informed consent.

Exclusion criteria

Patients With Coronary Artery Disease (CAD):

• Decompensated heart failure.
• Unstable angina pectoris.
• Uncontrolled or complex ventricular arrhythmias.
• Severe pulmonary hypertension.
• Neurological, orthopedic, or musculoskeletal disorders limiting exercise performance.
• Absolute contraindications to cardiopulmonary exercise testing or cardiac rehabilitation according to current clinical guidelines.
• Chronic kidney failure or chronic liver disease.
• Active infection.
• Active inflammatory or autoimmune disease.
• Active malignancy or history of malignancy.
• Pregnancy.
• Cognitive or psychiatric disorders that would interfere with study participation or protocol compliance.

Healthy Controls:

• History of coronary artery disease or other cardiovascular diseases.
• History of chronic systemic diseases, including diabetes mellitus, hypertension, chronic kidney disease, chronic liver disease, inflammatory or autoimmune diseases, or malignancy.
• Regular medication use within the previous 6 months.
• Active infection.
• Pregnancy.
• Age younger than 18 years or older than 75 years.