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

May 28, 2026 updated by: Radboud University Medical Center

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.

Study Overview

Status

Enrolling by invitation

Conditions

Detailed Description

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

Study Type

Observational

Enrollment (Estimated)

250

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Nijmegen, Netherlands, 6525 GA
        • Radboud University Medical Center
      • Utrecht, Netherlands, 3584 CX
        • University Medical Center Utrecht

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

N/A

Sampling Method

Non-Probability Sample

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.

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
MARC-3 cohort
Participants 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 the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Coronary Artery Calcium (CAC) Score
Time Frame: Baseline

Total CACS (AU)

AU: Agatston units
Baseline
Coronary stenosis and plaque characteristics
Time Frame: Baseline
Determine the characteristics (burden, composition, risk features)
Baseline

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quantitative Plaque Phenotype and Burden
Time Frame: Baseline
Total plaque volume (mm³); calcified, mixed, non-calcified and low-attenuation plaque (mm³); remodeling index.
Baseline
Pericoronary Adipose Tissue Attenuation (PCATa)
Time Frame: Baseline
CCTA-derived PCAT attenuation around proximal coronary arteries (Hounsfield Units, HU).
Baseline
Peripheral Atherosclerosis
Time Frame: Baseline
Carotid and femoral intima-media thickness (IMT, mm) and degree of stenosis (%).
Baseline
Biomarker Profile
Time Frame: Baseline
Lipid profile (mmol/L); HbA1c (%); inflammatory markers (e.g., hsCRP, mg/L); hair cortisol (pg/mg); immunophenotyping (cell subsets, % and absolute counts); polygenic risk score.
Baseline
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)
Through current study baseline, approximately 13 years after initial cohort enrollment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Collaborators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 31, 2026

Primary Completion (Estimated)

December 31, 2027

Study Completion (Estimated)

December 31, 2027

Study Registration Dates

First Submitted

May 20, 2026

First Submitted That Met QC Criteria

May 28, 2026

First Posted (Actual)

June 4, 2026

Study Record Updates

Last Update Posted (Actual)

June 4, 2026

Last Update Submitted That Met QC Criteria

May 28, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MARC-3
  • #01-001-2024-0621 (Other Grant/Funding Number: Dutch Heart Foundation (FIT-HEART consortium))
  • 4334294-1093118-PG (Other Identifier: Dutch Health Council)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

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.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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