Regular endurance exercise is widely known to improve cardiovascular health and reduce the risk of heart disease. Yet several imaging studies have shown that male endurance athletes have a higher prevalence of coronary artery calcification (CAC) and calcified plaque than less active individuals. It remains unclear whether this represents harmful progression of coronary artery disease or a more benign, stable form of atherosclerosis. Understanding this distinction is essential, because coronary atherosclerosis is the leading cause of exercise-related cardiac events in athletes >35 years.

The MARC-3 study is the second long-term follow-up of the original Measuring Athlete's Risk of Cardiovascular Events (MARC) cohort and aims to clarify how lifelong exercise training influences coronary artery health.

The study will:

1. examine how long-term exercise patterns relate to the progression of coronary atherosclerosis;
2. assess plaque characteristics using artificial-intelligence based quantitative coronary CT angiography (AI-QCT);
3. identify biological markers that may link exercise to plaque development; and
4. evaluate long-term clinical outcomes, including all-cause mortality and major adverse cardiovascular events (MACE).

Our working hypothesis is that endurance exercise predominantly leads to more stable, calcified plaque, and that mechanisms such as exercise-induced hypertension, inflammation, lipid regulation, and genetic background may provide an explanation for the unexpected results observed in previous studies.

For a detailed description, please see the attached study protocol under 'Documents'.

Inclusion Criteria:

- Previous participation in the original MARC study (enrolled between 2012-2014).

Exclusion Criteria:

• Inability to provide written informed consent.
• Not willing to receive information about potential incidental CT findings.
• Concurrent participation in an interventional study targeting cardiovascular health.

Additional exclusion criteria for CCTA:

• Not willing to undergo CCTA with intravenous contrast.
• History of severe allergic reaction to iodinated contrast agents.
• Renal dysfunction (eGFR < 30 mL/min/1.73 m²).

Additional exclusion criteria for maximal exercise testing:

• Absolute contraindications to maximal exercise testing as defined by institutional SOPs, including but not limited to:
• Recent acute myocardial infarction (3-5 days)
• Unstable angina
• Uncontrolled arrhythmias with symptoms or hemodynamic compromise
• Syncope
• Active endocarditis
• Acute myocarditis or pericarditis
• Uncontrolled heart failure
• Acute pulmonary embolus or pulmonary infarction
• Lower extremity thrombosis
• Suspected aortic dissection
• Uncontrolled asthma
• Pulmonary edema
• Resting room-air oxygen saturation ≤ 85 percent
• Respiratory failure
• Acute non-cardiopulmonary disorders that impair or are aggravated by exercise (e.g., infection, renal failure, thyrotoxicosis)
• Mental impairment preventing cooperation

Participants are invited from the established MARC cohort, which originally included 318 Caucasian, middle-aged (≥45 years) male amateur athletes recruited between 2012 and 2014. At baseline, athletes were eligible if they engaged in regular endurance exercise and were free of known cardiovascular disease. All participants underwent a comprehensive sports medical evaluation without abnormalities prior to enrollment. The initial exclusion criteria included inability to provide informed consent and medical conditions precluding participation in exercise testing or CT imaging.

Pseudonymised individual participant data underlying published results may be made available to qualified researchers upon reasonable request. Data access will be subject to approval by the study group leaders, compatibility with participant consent, institutional privacy/legal review, and execution of a data sharing agreement. Only data necessary for the approved research question will be shared.