Measuring Athlete's Risk of Cardiovascular Events 3 (MARC-3)

Measuring Athlete's Risk of Cardiovascular Events 3 (MARC-3)

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