Lifetime Intensive Endurance Training May Increase the Overall Coronary Atherosclerotic Burden

Researchers have long been intrigued by the dose-response relationship between long-term intensive endurance exercise and coronary heart disease. Early research into this area demonstrated that regular endurance sport participation provides relative immunity from ischemic heart disease⁽¹⁾.

Recently, evidence indicates an increase in prevalence of coronary atherosclerotic plaques amongst highly trained athletes in comparison to healthy non-athletes⁽²⁾.

These recent studies emphasized a relative difference in plaque composition with a higher likelihood of more stable calcified plaques in athletes compared to non-athletes. However, there is very little research on the absolute prevalence of calcified and non-calcified coronary plaques in athletes compared to non-athletes. Therefore, it is possible that endurance athletes may have a similar or even greater amount of non-calcified and mixed plaques just because the overall number of plaques is higher.

Difference between calcified and non-calcified coronary plaques

A mature atherosclerotic plaque is composed of a lipid/macrophage-rich fatty material with an overlying fibrous cap. The potential danger is that this cap may rupture and – in the right context – may trigger an acute coronary syndrome. Plaque instability is associated with the degree of ongoing inflammation and plaque composition.

Coronary atherosclerotic plaques can be classified as calcified, noncalcified or mixed.

• Noncalcified atherosclerotic plaques are more metabolically active than heavily calcified plaques and are associated with increased risk of acute coronary syndromes. Noncalcified coronary plaque and the total plaque burden of the coronary arteries, even of only one segment of the artery, are related with an increased risk of cardiovascular events⁽³⁾.

It is important to gain a better understanding of the upper range of the dose–response relationship between exercise and coronary artery disease given the popularity of intensive endurance sports in modern society. It is well documented that regular exercise improves blood pressure control and lipid profiles, reduces the incidence of diabetes and myocardial infarction, and increases life expectancy⁽⁴⁾.

Enhanced cardiorespiratory fitness is associated with a progressive reduction of cardiovascular events, which would seem to be at odds with the link between lifelong exercise load and increased coronary atherosclerosis.

A very recent study (The Master@Heart study) investigated this apparent paradox of increased coronary atherosclerosis among highly trained endurance athletes despite having fewer cardiovascular events⁽⁵⁾.

Study population, inclusion/exclusion criteria and outcomes

The Master@Heart study compared the prevalence of calcified, mixed, and non-calcified coronary plaques by computed tomography between 176 controls, 191 late-onset endurance athletes, and 191 lifelong endurance athletes, in the absence of established risk factors for coronary artery disease.

The inclusion criteria for all participants were:

• Male sex and age between 45 and 70 years.
• Athletes were defined as follows: engagement in cycling ≥8 h or running ≥ 6 h per week, or triathlon (combination of swimming, cycling, and running) ≥ 8 h per week for at least 6 months prior to baseline. Lifelong and late-onset athletes started regular endurance exercise training at <30 years and >30 years of age, respectively.
• Non-athletes engaged ≤ 3 h per week in physical activity without prior exposure to regular endurance exercise.
• The metabolic equivalent of task (MET) minutes per week was calculated as a measure of exercise volumes obtained by multiplying the MET score for the specific sport by the reported exercise volume (minutes/week).

Exclusion criteria were:

• A medical history of cardiovascular disease
• History of established risk factors for coronary artery disease (diabetes mellitus, hypercholesterolaemia, or arterial hypertension)
• Current or history of smoking
• Body mass index >27.2 kg/m²

The Master@Heart study is the largest and most comprehensive study to assess the dose–response relationship between intensive endurance exercise and coronary atherosclerosis. The training load and cardiorespiratory fitness of athletic and non-athletic participants was higher than that of other similar studies. The three groups were free of any classical risk factors for atherosclerosis and carefully stratified for age and exercise exposure.

Study Outcomes

The primary endpoint was the prevalence of coronary plaques (calcified, mixed, and non-calcified plaques) on CTCA assessed cross-sectionally at baseline. The investigators hypothesized that more than late-onset training, lifelong endurance exercise would be associated with a lower prevalence of non-calcified plaques than non-athletes.

Major Findings of This Study

Lifelong endurance sports did not show to offer additional protection against coronary atherosclerosis compared to an active, healthy lifestyle. In contrast, lifelong middle-aged athletes had more coronary plaques, including more unstable non-calcified plaques in proximal segments.

Fig: Eur Heart J, Volume 44, Issue 26, 7 July 2023, Pages 2388–2399⁽⁵⁾

These findings do not support the hypothesis that highly trained endurance athletes have a more benign plaque composition to explain their lower risk of cardiovascular events compared to non-athletes. As studies on the impact of physical activity in the upper range are lacking, data from this study open the question on whether coronary events are indeed less prevalent in this high-end exercise cohort, and if that is the case, on what explains the paradox.

More longitudinal research at the higher end of the endurance exercise spectrum is needed.

Contrary to these previous studies, the Master@Heart study did investigate the absolute prevalence of different coronary plaque types. As a primary finding, results did not reveal a more benign plaque composition in endurance athletes, neither in lifelong nor in late-onset athletes, than in non-athletic controls.

There even seems to be a dose–response relationship, with late-onset athletes fitting in between lifelong athletes and non-athletes.

The most prevalent plaque type in both athletes and non-athletes was calcified plaques, followed by mixed and non-calcified plaques. Moreover, a greater proportion of lifelong athletes had proximal plaques and lesions with significant stenosis, as well as plaques of non-calcified and mixed morphology. The non-calcified/mixed characteristics, a stenosis grade of ≥50%, and the proximal location of coronary plaques are all established risk factors for ischemic heart disease⁽⁶⁾.

Surprisingly, the overall coronary plaque burden, which is associated with higher mortality risk, was greater in lifelong athletes.

It is very important to note that current evidence cannot relate an increased risk of ischemic heart disease events in endurance athletes. Some studies have shown that endurance exercise reduces the risk for ischemic events regardless of coronary artery calcium (CAC) score, and this reduction is greatest at the higher CAC scores⁽⁷⁾.

Potential explanation for this are:

• A first potential explanation for this apparent paradox can be found in the current study as vulnerable plaques, which carry the highest risk for events, were rare and not associated with an athletic lifestyle.
• Secondly, although this study observed an increase plaque burden in lifelong athletes; the overall plaque burden remains low in athletes.
• Thirdly, it is known that endurance athletes have larger coronary arteries and a greater vasodilatory potential, meaning that the plaque-to-vessel ratio in athletes could be lower and thus lead to less significant stenosis⁽⁸⁾. 

Another key area of discrepancy with previous studies is the participants’ training load and physical fitness. Lifelong and late-onset athletes from the Master@Heart study performed more training hours per week and had a higher METmin/week with a higher VO2peak than in other studies⁽²⁾.

Interestingly, also the non-athletes of Master@Heart had a higher aerobic capacity than controls in previous studies⁽²⁾.

Considering that a higher VO2peak is associated with a lower lipid volume, higher fibrous volume, and thicker fibrous cap in coronary plaques, the investigators speculate that the dose–response relationship between endurance exercise and coronary atherosclerosis might be reverse J-shaped rather than a descending logarithmic function⁽⁹⁾.

A sedentary and unhealthy lifestyle carries the highest risk of ischemic heart disease with a significant burden of high-risk plaques. The data from this study indicates that a healthy lifestyle and above-average cardiorespiratory training and fitness prevents coronary atherosclerosis with a more favorable pattern of more calcified and less mixed or non-calcified plaques. Additional increments of endurance sports training load and associated increases in fitness do not affect the distribution of plaque types.

However, lifetime intensive endurance training increases the overall coronary atherosclerotic burden with more plaques, including non-calcified and mixed plaques, plaques in proximal segments, and those with a significant degree of stenosis.

Potential mechanism of action

In support of the above findings, a recent study demonstrated that long-term intensive but not moderate training promoted adverse changes in the structural and functional properties of elastic and muscular arteries through a process mediated by the renin-angiotensin-aldosterone system, miR-212/132 and miR-146b, and matrix metalloproteinase 9⁽¹⁰⁾.  

This study utilized a rodent model and showed that intensive but not moderate training promoted aorta and carotid stiffening and elastic lamina ruptures, tunica media thickening of intramyocardial arteries, and an imbalance between vasoconstrictor and relaxation agents. An up-regulation of angiotensin-converter enzyme, miR-212, miR-132, and miR-146b might account for this deleterious remodeling. The results of this study suggest that intensive training blunts the benefits of moderate exercise⁽¹⁰⁾.

Summary

Lifelong endurance sport participation on top of a healthy lifestyle is not associated with a more favorable coronary plaque composition. Lifelong middle-aged athletes had more coronary plaques, including more non-calcified and mixed plaques and plaques in proximal segments with significant luminal stenosis, than fit and healthy individuals with a similarly low cardiovascular risk profile.

These findings may in part explain why moderate and vigorous physical activity beyond a specific amount of time does not offer additional reduction in mortality risk, thereby exhibiting a nadir in the dose–response relationship. More longitudinal research is needed to reconcile these findings with the risk of cardiovascular events at the higher end of the endurance exercise spectrum.

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