Krishnan: Is the available evidence sufficient to establish a cause-and-effect relationship?

La Gerche: The way you prove causation is through intervention studies, comparing calcium levels in exercising versus nonexercising groups. However, conducting such studies is ethically complex. Instead, we often look at associations to uncover potential underlying factors. While some argue that factors unrelated to exercise such as sugary drink consumption causing insulin fluctuations could be a cause, I find this unlikely. Also, whatever behavior is associated with exercise still contributes to coronary calcium levels and is still part of the picture. So, I think that, although we should remember that we don't have any clear evidence that it is causative, the associations are sufficiently strong to suggest a meaningful link.

Krishnan: From the studies on lifelong athletes you co-authored,¹ and the MARC-2 (Measuring Athlete's Risk of Cardiovascular Events 2) study you mentioned,² it appears athletes differ from the general population. Notably, the lifelong athletes' study showed mixed plaques, not just calcified ones. Was that surprising?

La Gerche: Part of the reason for our study was the "Jim Fixx" phenomenon. Jim Fixx took up running to combat his history of heavy smoking and strong familial health risks; he then wrote the complete book of running but then died in his 50s. The lesson here is that starting a sport later doesn't erase past health issues.

Studies such as those by Aengevaeren et al. and Merghani et al. showed a notable proportion of ex-smokers.^2,3 I wondered whether there was a bias toward those addressing personal health risks leading people toward exercise and participation in studies. Our aim was to contrast lifelong athletes with those who embraced sports later. I hypothesized that coronary disease would be prevalent among the latter. Unexpectedly, the results contradicted this, suggesting a deeper causative link.

Krishnan: I guess you as a scientist have to accept the findings despite your preconceived notion. What insights can we glean about the nuances of plaque composition?

La Gerche: Proving yourself wrong is one of the joys of science. I just wish it was a different topic. Plaque composition seems more complex than we previously thought. The three main studies before ours indicated increased coronary calcification predominantly from calcified plaque, and less from mixed or soft plaques, especially in nonathletes. Yet, our research on lifelong athletes observed a broader spectrum of plaque types, including soft, mixed, and proximal, often with multiple lesions. This was unexpected, and such findings challenge the dogma that while there's more coronary disease, it's mostly just calcium. Our study's findings contradict that, but it doesn't necessarily override previous research. Further research is needed to better understand plaque composition in athletes.

Krishnan: Turning to the management side, what are the primary considerations for handling athletes with CAC? Do you rely on any specific diagnostic tools for risk stratification?

La Gerche: I often assess coronary calcification in asymptomatic athletes to work out preventive strategies. While I consider their clinical profiles before routine assessments, I discuss the potential benefits and risks, especially for those at low risk, letting individuals decide on proceeding. For those with coronary calcification, the first step is assurance. There's a graph I show my patients on a weekly basis from a study by Radford et al.,⁴ which shows that despite coronary calcium being a significant risk indicator, enhanced fitness can reduce this risk substantially—up to 60% for those with high calcium scores. In essence, exercise remains one of the best preventive measures against heart attacks in individuals with coronary calcium. Therefore, my primary advice is never to stop exercising. I've seen instances when athletes halted their regimes because of a high CAC score, which is actually the very worst advice because staying fit is number one on the list of preventive strategies.

Krishnan: It's a paradox. A scan reveals mixed plaque, suggesting potential risk years before an event might occur. Yet, exercise appears protective even with plaque presence. Given this, how do you recommend exercise for such individuals?

La Gerche: The "exercise paradox" is interesting because there's a heightened risk when unfit individuals suddenly start intense exercise. Although exercise can trigger coronary events, regular exercise minimizes this risk. Also, you are more likely to have events during exercise, but if you're fit then the risk is very small. So, I tell people the best way to deal with that paradox is to gradually increase workout intensity and duration. I always say when you're young you can do whatever you like. Your mates say, "Let's go mountain biking," and you haven't done it for ages, but you just go. Whereas from middle age onwards, you've got to be a bit sensible about these things. For athletes with coronary disease, I tell them to be alert but not alarmed. If they feel chest pain, they need to get checked out really fast. They need to be aware that they're not invulnerable.

Krishnan: When evaluating athletes with known CAC, how do you interpret these data and decide on further action? Do you also incorporate tests such as cardiopulmonary exercise testing (CPET) or computed tomography (CT) angiography?

La Gerche: In our research, we observed profound ST depressions on some Olympic rowers' electrocardiograms during CPETs. Yet, further evaluation such as CT scans showed no issues, raising questions about potential microvascular or perfusion–demand mismatches. If athletes with high CAC scores are asymptomatic, I don't push for further tests. If they're symptom free during their regular daily "stress testing," why investigate further? The exception would be if there's a lot of undetected ischemia, especially with significant conditions such as left main or proximal left anterior descending artery disease. Most asymptomatic local competitors are unlikely to have large territory ischemia. An elevated calcium score does inform us about risk and I'd discuss preventive measures, such as statin therapy, but wouldn't change after revascularization unless there's suspicion of undetected ischemia, in which case I'd do a functional test such as a stress echocardiogram.