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Coronary Artery DiseaseMARC-3NCT07625488

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

An observational study of Coronary Artery Disease and Atherosclerosis, run by Radboud University Medical Center at 2 sites in Netherlands.

Enrolling by invitation

Enrolling by invitation. The study team selects and invites participants, usually from an existing group of patients.

Sites and contacts
Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 45 years and older, men only
Conditions the study is for
Coronary Artery Disease, Atherosclerosis
How many people
250 participants
Where
2 sitesNetherlands
Study dates
31 May 2026to 31 Dec 2027
Phase
Observational
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 45 years and older
  • Men only
  • Adult, Older adult

Study population: 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.

Who may be able to join

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

Who cannot join

  • 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.
Show all 25Show fewer
  • 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

Trial locations and contacts

2 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Netherlands2 sites
  • Radboud University Medical Center

    Nijmegen, 6525 GA

  • University Medical Center Utrecht

    Utrecht, 3584 CX

Other trials in Netherlands

About this study

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.

Read more

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.

Read the detailed description

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

Keywords
Exercise, Physical Activity, Coronary Artery Calcification, Plaque, Atherosclerotic, Coronary Computed Tomography Angiography, AI-based Quantitative Computed Tomography, Pericoronary Adipose Tissue Attenuation, Vascular Inflammation, Biomarkers, Genetic Predisposition to Disease, Polygenic Risk Score, Major Adverse Cardiovascular Events
Medical subject headings
Coronary Artery Disease, Atherosclerosis, Motor Activity, Plaque, Atherosclerotic, Genetic Predisposition to Disease, Genetic Risk Score

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT07625488
Study groupRoleWhat they receive
MARC-3 cohortParticipants in this cohort are the surviving and traceable members of the original MARC study, which enrolled 318 middle-aged male amateur endurance athletes between 2012 and 2014. In the first follow-up (MARC-2), 291 participants were successfully re-examined. All participants have a lifelong history of regular endurance exercise. In MARC-3, they undergo repeat evaluation of coronary atherosclerosis, cardiopulmonary fitness, exercise exposure, biomarkers, and genetic factors approximately 12.5 years after baseline.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Coronary Artery Calcium (CAC) Score

    Total CACS (AU)

    AU: Agatston units

    Measured: Baseline

  2. Coronary stenosis and plaque characteristics

    Determine the characteristics (burden, composition, risk features)

    Measured: Baseline

Secondary outcomes (4)
  1. Quantitative Plaque Phenotype and Burden

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

    Measured: Baseline

  2. Pericoronary Adipose Tissue Attenuation (PCATa)

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

    Measured: Baseline

  3. Peripheral Atherosclerosis and Vascular Function

    Carotid artery intima-media thickness (IMT, mm)

    Measured: Baseline

  4. Long-Term Clinical Outcomes

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

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Jun 2026
  2. Study start31 May 2026
  3. Primary completion31 Dec 2027 (estimated)
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Cross-sectional
Enrolment
250 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07625488
Sponsor's protocol ID
MARC-3
Other IDs
#01-001-2024-0621, 4334294-1093118-PG
Acronym
MARC-3
Status last verified
May 2026
First submitted
20 May 2026
Last updated
13 Aug 2026
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: 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.

Publications

  • Braber TL, Mosterd A, Prakken NH, Doevendans PA, Mali WP, Backx FJ, Grobbee DE, Rienks R, Nathoe HM, Bots ML, Velthuis BK. Rationale and design of the Measuring Athlete's Risk of Cardiovascular events (MARC) study : The role of coronary CT in the cardiovascular evaluation of middle-aged sportsmen. Neth Heart J. 2015 Feb;23(2):133-8. doi: 10.1007/s12471-014-0630-0.

    PubMed 25410576
  • Braber TL, Prakken NH, Mosterd A, Mali WP, Doevendans PA, Bots ML, Velthuis BK. Identifying Coronary Artery Disease in Asymptomatic Middle-Aged Sportsmen: The Additional Value of Pulse Wave Velocity. PLoS One. 2015 Jul 6;10(7):e0131895. doi: 10.1371/journal.pone.0131895. eCollection 2015.

    PubMed 26147752
  • Braber TL, Mosterd A, Prakken NH, Rienks R, Nathoe HM, Mali WP, Doevendans PA, Backx FJ, Bots ML, Grobbee DE, Velthuis BK. Occult coronary artery disease in middle-aged sportsmen with a low cardiovascular risk score: The Measuring Athlete's Risk of Cardiovascular Events (MARC) study. Eur J Prev Cardiol. 2016 Oct;23(15):1677-84. doi: 10.1177/2047487316651825. Epub 2016 May 24.

    PubMed 27222386
  • Schurink MM, Braber TL, Prakken NH, Doevendans PA, Backx FJ, Grobbee DE, Rienks R, Nathoe HM, Bots ML, Velthuis BK, Mosterd A. No psychological distress in sportsmen aged 45 years and older after cardiovascular screening, including cardiac CT: The Measuring Athlete's Risk of Cardiovascular events (MARC) study. Neth Heart J. 2017 Apr;25(4):271-277. doi: 10.1007/s12471-017-0948-5.

    PubMed 28144819
  • Aengevaeren VL, Mosterd A, Braber TL, Prakken NHJ, Doevendans PA, Grobbee DE, Thompson PD, Eijsvogels TMH, Velthuis BK. Relationship Between Lifelong Exercise Volume and Coronary Atherosclerosis in Athletes. Circulation. 2017 Jul 11;136(2):138-148. doi: 10.1161/CIRCULATIONAHA.117.027834. Epub 2017 Apr 27.

    PubMed 28450347
  • Aengevaeren VL, Mosterd A, Sharma S, Braber TL, Thompson PD, Velthuis BK, Eijsvogels TMH. Coronary Atherosclerosis in Athletes: Exploring the Role of Sporting Discipline. JACC Cardiovasc Imaging. 2019 Aug;12(8 Pt 1):1587-1589. doi: 10.1016/j.jcmg.2019.01.002. Epub 2019 Feb 13. No abstract available.

    PubMed 30772217
  • Berge K, Aengevaeren VL, Mosterd A, Velthuis BK, Lyngbakken MN, Omland T, Schalkwijk CG, Eijsvogels TMH. Plasma Advanced Glycation End Products and Dicarbonyl Compounds Are Not Associated with Coronary Atherosclerosis in Athletes. Med Sci Sports Exerc. 2023 Jul 1;55(7):1143-1150. doi: 10.1249/MSS.0000000000003152. Epub 2023 Apr 4.

    PubMed 36849122
  • Janssen SLJE, de Vries F, Mingels AMA, Kleinnibbelink G, Hopman MTE, Mosterd A, Velthuis BK, Aengevaeren VL, Eijsvogels TMH. Exercise-induced cardiac troponin release in athletes with versus without coronary atherosclerosis. Am J Physiol Heart Circ Physiol. 2024 Apr 1;326(4):H1045-H1052. doi: 10.1152/ajpheart.00021.2024. Epub 2024 Feb 16.

    PubMed 38363583
  • Berge K, Janssen SLJE, Velthuis BK, Myhre PL, Mosterd A, Omland T, Eijsvogels TMH, Aengevaeren VL. Predictors of coronary atherosclerosis in middle-aged and older athletes: the MARC-2 study. Eur Heart J Cardiovasc Imaging. 2025 Mar 3;26(3):461-470. doi: 10.1093/ehjci/jeae317.

    PubMed 39657626
  • Janssen SLJE, Aengevaeren VL, DE Vries F, Kleinnibbelink G, Mingels AMA, Hopman MTE, Mosterd A, Velthuis BK, Riksen NP, Eijsvogels TMH. Exercise-Induced Changes in Hemodynamics, Hormones, Electrolytes, and Inflammatory Markers in Veteran Athletes with and without Coronary Atherosclerosis. Med Sci Sports Exerc. 2025 Jul 1;57(7):1297-1308. doi: 10.1249/MSS.0000000000003674. Epub 2025 Feb 17.

    PubMed 39957063

Questions about this trial

What is this clinical trial studying?

An observational study of Coronary Artery Disease and Atherosclerosis, run by Radboud University Medical Center at 2 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: enrolling by invitation, as of the sponsor's last update on 13 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Coronary Artery Calcium (CAC) Score (time frame: Baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07625488, which also lists 10 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2026.

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