27th December 2023, A/Prof Chee L Khoo
When we think about extreme physical activity (EPA) such as marathon running, apart from the perceived issue of wearing out knee and hip joints (that’s another issue, another day), we think about the cardiovascular risks or benefits that comes with this intense physical activity. We explored the issue of marathon running and cardiovascular risks 9 months ago here. EPA is associated with the risk of a number of cardiac events – sudden cardiac deaths (SCD), atrial fibrillation, myocardial fibrosis and atherosclerotic cardiovascular disease (ASCVD). We will re-look at ASCVD in this. We are not talking about acute coronary syndrome (ACS) or SCD that can occur during a marathon but coronary artery disease (CAD) that manifest itself during the life of a marathon runner.
Coronary artery calcium scores (CAC scores)
The data on whether marathon runners are at higher risk of atherosclerotic cardiovascular events (CVE) is not that straightforward. Traditionally, it is recognised that endurance athletes are at lower mortality risks than the general population (1). However, endurance athletes have higher CAC scores than the general population. How does that translate into lower mortality rates?
Möhlenkamp et al and Aengevaeren et al reported an increased CAC prevalence across progressive tertiles of physical activity (PA) volumes among German and Dutch male amateur athletes respectively (2,3). In the general population, any CAC or plaque presence represents a higher cardiovascular risk. Does that mean elite endurance athletes are at higher risk of CVE?
Atherosclerotic plaques have 2 common phenotypes: stable versus unstable plaques. Stable (calcified) plaques are characterised by a small lipid pool, low concentrations of inflammatory cells, and a thick fibrous cap that reduces vulnerability to plaque rupture and subsequent ACS, including AMI. Unstable (mixed) plaques are characterised by a large lipid pool, high inflammatory activity, and a thin fibrous cap, which makes them more vulnerable to rupture and trigger an acute coronary syndrome (ACS).
Merghani et al reported that British male master endurance athletes had a higher prevalence of atherosclerotic stable plaques with any degree of luminal stenosis compared with control participants (4). Athletes demonstrated predominantly stable calcified plaques (73% versus 31%, P<0.001) and fewer vulnerable mixed plaques (23% versus 62%). These observations demonstrated an increased prevalence of stable plaques among highly active middle-aged endurance athletes.
When we explored this issue last time, we cited the Master@Heart study which was the largest and most comprehensive study to assess the dose-response relationship between intensive endurance exercise and coronary atherosclerosis (5) by looking at 191 lifelong master endurance athletes, 191 late-onset athletes (endurance sports started after 30 yo), and 176 healthy non-athletes. They found ~1.5-3.0 X higher plaque burden (calcified and non-calcified) compared to a healthy non-athletic lifestyle. While the study reported that endurance athletes had less vulnerable plaques, less coronary stenosis, larger coronary arteries and a greater vasodilatory potential, they speculated that the dose-response relationship between endurance exercise and coronary atherosclerosis might be reverse J-shaped rather than a descending logarithmic function.
The reverse J-shaped curve phenomena is consistently shown in multiple observational studies but after more than a decade of follow-up of a large cohort of men (n=21 758), data from the Cooper Clinic Longitudinal study, the risk for all-cause and cardiovascular mortality in men whose CAC score was > 100 AU, was not higher than that even for those exercising at more moderate levels. It was lower than the least active cohort with similar CAC scores. These findings refute the notion that high-volume endurance activity (>1 h/d) increases mortality risk, regardless of CAC level (6). The reverse J-shaped curve did not occur here.
Why more atherosclerosis?
A number of theoretical reasons why endurance athletes have more atherosclerotic plaques albeit most of them are of the stable type. Atherosclerosis develops most frequently at branch points in the arterial system where laminar blood flow is disrupted creating turbulence. Such turbulence occurs in the coronary arteries where the beat-by-beat twisting and flexing of the coronaries creates turbulence. This may explain why coronary atherosclerosis and symptomatic narrowing occurs in the coronaries before atherosclerosis occurs in straighter, less turbulent non-coronary arterial segments. The increased cardiac output and contractility during EPA could increase this coronary flexing.
The coronary artery flexing during exercise is also a possible explanation for the increased risk of ACE during exercise. Such flexing and bending may increase the risk of atherosclerotic plaque rupture in atherosclerotic, and thereby stiffened, coronary arteries. Healing of these clinically silent ruptures could contribute to high CAC scores in athletes, since some have proposed that coronary calcification represents healed rupture plaque [7].
Increase in systolic blood pressure during exercise may also exacerbate the development of atherosclerotic plaques. Another contribution to the atherosclerotic plaques may be the increased inflammation associated with the abnormally prolonged physical activity (>5-6 hours). These repetitive bouts of inflammation may accelerate atherosclerotic process and add to the plaque volume. Exercise also increases parathyroid hormone release and the increase in PTH could facilitate the calcification in CAC.
Does EPA improve or worsen existing atherosclerosis?
So far, the data is a rather mixed. Moderate physical activity is protective against ASCVD but EPA may accelerate or cause ASCVD. In many studies, the drop-off in risk reduction noted with very high dose exercise did not reach statistical significance due to the small number of individuals in the upper extreme cohort. This reverse-J pattern is recurring theme in those studies and indeed, in very large studies, the attenuation of health benefits noted with extremely high doses of exercise does meet statistical significance (8).
On the other hand, a meta-analysis of 10 cohort studies consisting of 42,807 elite athletes found that all-cause mortality was 33% lower in athletes compared with the general population (9). ASCVD mortality and cancer mortality were 27% and 40% lower in athletes, respectively.
Does the benefit or harm dependent on whether there is co-existing CAD?
A very elegant longitudinal, prospective repeated-measures study was conducted by Lin et al back in 2017 when they looked at 8 marathon runners who completed the Race Across the USA, a 140-day foot race from California to Maryland (10). The runners ran 25 miles per day 6 days a week during the 140-day race. CT coronary angiograms (CTCA) were performed within 24 hours prior to the race and after the race. Half the runners had pre-existing CAD and the other half were free of CAD as demonstrated on CTCA. All those with CAD had at least one risk factor (3 former smoker, 1 had hypertension). One was on a statin throughout the study period.
Post race, in all participants, systolic BP was reduced while diastolic BP, LDL-C and BMI remained unchanged. On the other hand, HS-CRP and HDL-C were elevated.
The 4 runners who were free of CAD remained free of CAD after the race. The remaining 4 runners, each with 1 pre-existing cardiovascular risk factor, had CAD at baseline with luminal stenosis of 1% to 29% and 30% to 49% confined to the proximal or mid left anterior descending artery. Post-race, 1 runner demonstrated appreciable increase in coronary stenosis (from 1% to 29% to 30% to 49%). However, coronary plaque volume increased in each runner with baseline CAD driven by increases in noncalcified plaque and a minimal increase in calcified plaque in 1 runner who took a statin throughout the race. All plaque progression occurred at sites of pre-existing disease. Importantly, none of the runners who began the race without any atherosclerosis developed new plaques during the event.
It would appear that extreme physical activity is NOT universally protective against atherosclerosis. In patients who already have pre-existing ASCVD, EPA progressed their atherosclerosis which primarily comes from increases in non-calcified plaques which is the less favourable type. EPA also appears to increase inflammation as demonstrated by the increase in HS-CRP without any effect on the LDL-C.
To reinforce the importance of considering pre-existing CAD when considering the harms or benefits of EPA, one should look further at data from the Cooper Clinic (11). They found:
- Even among fit individuals, higher CAC scores were associated with a worse prognosis. In individuals performing 15 METs, CAC scores > 400 AU resulted in an approximately 2X increase in annual total ASCVD incidence rates when compared with CAC scores of 0
- In the lowest fit (5 METs) participants, the effect of CAC was even more noticeable, with close to a 5X increase in annual total ASCVD incidence rates in participants with CAC scores ≥400 compared with those with CAC scores ≥ 400 compared with those with CAC score of 0
- Men with CAC of < 100 AU and reported physical activity of ≥ 3000 MET-min/week were close to 50% less likely to die compared with men with < 1500 MET-min/week
In summary, the above studies suggest that physical activity is still beneficial in reducing CVE and mortality but one needs to be cautious in those who has known pre-existing CVD or may have good reason to have subclinical ASCVD as extreme PA can increase plaque burden – some stable calcified ones as well some less stable plaques. They also remind us that patients with CV risk factors and significant coronary artery plaques (whether on CAC or CTCA) need aggressive risk factor management including consideration of statins +/- anti-platelet therapy if appropriate, irrespective of how cardiorespiratory fit they may be. If they have high plaque burden, they need to be treated as such. As many of these patients engaged in EPA have high CAC scores, their LDL-C target should be < 1.8 mmol/L and often necessitate medications like statins or the newer PCSK9 inhibitors especially if muscular side effects become an issue with training. Aggressive reduction of LDL-C has been shown to reduce lipid content in the lipid filled plaques, reduce plaque volume and increase the fibrous cap all of which suggest plaque regression as well improve plaque stability.
References:
- P.D. Thompson, D. Buchner, I.L. Pina, et al. Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology and the Council on Nutrition, Physical Activity, and Metabolism Circulation, 107 (2003), pp. 3109-3116
- Mohlenkamp S, Lehmann N, Breuckmann F, Brocker-Preuss M, Nassenstein K, Halle M, et al. Running: the risk of coronary events : prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur Heart J. 2008;29(15):1903–10.
- Aengevaeren VL, Mosterd A, Braber TL, Prakken NHJ, Doevendans PA, Grobbee DE, et al. Relationship between lifelong exercise volume and coronary atherosclerosis in athletes. Circulation. 2017 Jul 11;136(2):138–48.
- Merghani A,Maestrini V, Rosmini S, Cox AT, Dhutia H, Bastiaenan R, et al. Prevalence of subclinical coronary artery disease in masters endurance athletes with a low atherosclerotic risk profile. Circulation. 2017;136(2):126–37.
- De Bosscher R, Dausin C, Claus P, Bogaert J, Dymarkowski S, Goetschalckx K, Ghekiere O, Van De Heyning CM, Van Herck P, Paelinck B, El Addouli H, La Gerche A, Herbots L, Willems R, Heidbuchel H, Claessen G; Master@Heart Consortium. Lifelong endurance exercise and its relation with coronary atherosclerosis. Eur Heart J. 2023 Mar 6:ehad152. doi: 10.1093/eurheartj/ehad152.
- DeFina LF, Radford NB, Barlow CE, Willis BL, Leonard D, Haskell WL, Farrell SW, Pavlovic A, Abel K, Berry JD, et al. Association of all-cause and cardiovascular mortality with high levels of physical activity and concurrent coronary artery calcification. JAMA Cardiol. 2019;4:174–181. doi:10.1001/jamacardio.2018.4628
- Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed? Arterioscler Thromb Vasc Biol. 2014;34(4):724–36.
- Armstrong ME, Green J, Reeves GK, Beral V, Cairns BJ, Million Women Study C. Frequent physical activity may not reduce vascular disease risk as much as moderate activity: large prospective study of women in the United Kingdom. Circulation. Feb 24 2015;131(8):721-729.
- Garatachea N, Santos-Lozano A, Sanchis-Gomar F, Fiuza-Luces C, Pareja-Galeano H, Emanuele E, et al. Elite athletes live longer than the general population: a meta-analysis. Mayo Clin Proc. 2014;89(9):1195–200.
- Jeffrey Lin MD, James R. DeLuca BA, Michael T. Lu MD, et al. Extreme Endurance Exercise and Progressive Coronary Artery Disease. Journal of the American College of Cardiology Volume 70, Issue 2, 11 July 2017, Pages 293-295. https://doi.org/10.1016/j.jacc.2017.05.016