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

NCT07625488 | Enrolling By Invitation

• 3 other identifiers: MARC-3#01-001-2024-06214334294-1093118-PG
• Study Type: observational
• Target: 250
• Locations: 1 country
• Sites: 2

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

Conditions

Coronary Artery Disease; Atherosclerosis

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

Outcome Measures

Primary Outcomes (2)

• Coronary Artery Calcium (CAC) Score

  Total CACS (AU) AU: Agatston units

  Baseline

• Coronary stenosis and plaque characteristics

  Determine the characteristics (burden, composition, risk features)

  Baseline

Secondary Outcomes (5)

• Quantitative Plaque Phenotype and Burden

  Baseline

• Pericoronary Adipose Tissue Attenuation (PCATa)

  Baseline

• Peripheral Atherosclerosis

  Baseline

• Biomarker Profile

  Baseline

• Long-Term Clinical Outcomes

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

Study Arms (1)

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.

Eligibility Criteria

• Age: 45 Years+
• Sex: male
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

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

You may not qualify if:

• 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.
• 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).
• 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

Sponsors & Collaborators

• Radboud University Medical Center: lead
• Cleerly, Inc.: collaborator
• Caristo Ltd.: collaborator
• Collaborators within FIT-HEART consortium (e.g. UMC Utrecht, Amsterdam UMC): collaborator
• Philips Healthcare: collaborator

Study Sites (2)

Radboud University Medical Center

Nijmegen, 6525 GA, Netherlands

Location

University Medical Center Utrecht

Utrecht, 3584 CX, Netherlands

Location

Related Publications (10)

• 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.

  PMID: 25410576 RESULT

• 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.

  PMID: 26147752 RESULT

• 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.

  PMID: 27222386 RESULT

• 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.

  PMID: 28144819 RESULT

• 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.

  PMID: 28450347 RESULT

• 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.

  PMID: 30772217 RESULT

• 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.

  PMID: 36849122 RESULT

• 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.

  PMID: 38363583 RESULT

• 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.

  PMID: 39657626 RESULT

• 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.

  PMID: 39957063 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood, serum, plasma, and extracted DNA will be retained for biomarker analysis, lipid profiling, inflammatory markers, endocrine markers, and genomic analyses such as polygenic risk scoring. Additional biospecimens include hair samples for cortisol analysis and stored peripheral blood mononuclear cells (PBMCs) for immunophenotyping. All samples will be processed and stored according to institutional biobank SOPs in secured biorepository facilities.

MeSH Terms

Conditions

Coronary Artery Disease; Atherosclerosis; Motor Activity; Plaque, Atherosclerotic; Genetic Predisposition to Disease; Genetic Risk Score

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Behavior; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Disease Susceptibility; Disease Attributes; Pathologic Processes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 20, 2026
• First Posted: June 4, 2026
• Study Start: May 31, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: June 4, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share

Locations

NL (2)