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NCT Number: NCT07625488

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.

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Key information

Conditions

Coronary Artery Disease Arterial Occlusive Diseases Arteriosclerosis Atherosclerosis Behavior Cardiovascular Diseases Coronary Disease Disease Attributes Disease Susceptibility Genetic Predisposition to Disease Genetic Risk Score Heart Diseases Motor Activity Myocardial Ischemia Pathologic Processes Pathological Conditions, Anatomical Pathological Conditions, Signs and Symptoms Plaque, Atherosclerotic Vascular Diseases

Age range

45 year and older

Sex eligibility

Male

Study type

Observational

Primary location

Radboud University Medical Center, Nijmegen, Netherlands

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About this study

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

Who can participate

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primary outcomes

  1. Coronary Artery Calcium (CAC) Score

    Time frame: Baseline

    Total CACS (AU)

    AU: Agatston units

  2. Coronary stenosis and plaque characteristics

    Time frame: Baseline

    Determine the characteristics (burden, composition, risk features)

Secondary outcomes

  1. Quantitative Plaque Phenotype and Burden

    Time frame: Baseline

    Total plaque volume (mm³); calcified, mixed, non-calcified and low-attenuation plaque (mm³); remodeling index.

  2. Pericoronary Adipose Tissue Attenuation (PCATa)

    Time frame: Baseline

    CCTA-derived PCAT attenuation around proximal coronary arteries (Hounsfield Units, HU).

  3. Peripheral Atherosclerosis and Vascular Function

    Time frame: Baseline

    Carotid artery intima-media thickness (IMT, mm)

  4. Long-Term Clinical Outcomes

    Time frame: Through current study baseline, approximately 13 years after initial cohort enrollment

    All-cause mortality and major adverse cardiac events (MACE)

Sponsors and collaborators

Lead sponsor

Radboud University Medical Center

Other

Collaborators

  • Caristo Ltd.
  • Cleerly, Inc.
  • Collaborators within FIT-HEART consortium (e.g. UMC Utrecht, Amsterdam UMC)
  • Philips Healthcare

Registry information

Acronym: MARC-3

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Jun 4, 2026
Registry last updated
Jun 30, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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