Regular physical exercise is recommended for both symptomatic and healthy individuals to improve morbidity and mortality from atherosclerosis (28). Several mechanisms have been identified to contribute to a reduced cardiovascular event rate associated with regular exercise, which are in part mediated via an improved cardiovascular risk factor profile (13). At the same time, coronary atherosclerosis accounts for the majority of exercise-related sudden deaths in individuals above the age of 35 yr (15,16,27,29), but identification of runners at increased cardiovascular risk remains challenging. We recently observed a high prevalence of coronary atherosclerosis in presumably healthy marathon runners, which contrasted with their favorable risk factor profile (17,18). The extent of coronary atherosclerosis was associated with a higher rate of late enhancement imaged by magnetic resonance imaging evidencing myocardial damage. However, routine coronary artery calcium (CAC) scoring in presumably healthy marathon runners has not yet been accepted for risk assessment.
In contrast, carotid and peripheral arteries are readily accessible to duplex ultrasound. Subclinical atherosclerosis in these vessels is associated with the presence and severity of CAD (1,11,12,19,20,28) and with an increased 10-yr risk of cardiovascular events (4). The prevalence of noncoronary atherosclerosis in marathon runners has not yet been reported. Of note, in long-distance runners, noncoronary alterations in arterial wall morphology may be different from typical atherosclerosis because regular physical activity can increase peripheral arterial diameters (7,23). However, lifetime risk factor exposure has to be taken into account too.
The purpose of the present study was to determine the prevalence of noncoronary atherosclerotic plaque burden and to explore its association with cardiovascular risk factors and coronary atherosclerosis in marathon runners. We hypothesized that noncoronary atherosclerotic plaque burden can be used to define marathon runners with a high CAC.
Participants and methods.
Participants for the marathon study were recruited by an advertisement in a German marathon journal (Runner's World), a press conference at the inauguration of the study, and by referral from participants. All participants answered a questionnaire to specify inclusion criteria and provided written informed consent including evaluation of death certificates. The study was approved by the local ethics committee and by the German board of radiation safety.
Inclusion and exclusion criteria.
Male runners were eligible if they were >50 yr and had completed at least five full-distance marathon races (42.195 km) during the preceding 3 yr. Exclusion criteria included a history of heart disease, diabetes mellitus, severe renal failure predisposing to nonatherosclerotic coronary calcification, musculoskeletal disease at entry preventing future regular marathon running, psychiatric disease, and unwillingness to give informed consent.
Cardiovascular risk factors.
Blood pressure was measured with an automated oscillometric blood pressure device (OMRON 705CP; OMRON, Mannheim, Germany). The mean value of the second and third of three measurements taken at least 3 min apart was used for analysis. Blood pressure was classified according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure threshold values. Body mass index (BMI (kg·m−2)) was calculated from standardized measurements of height and weight. Current smoking was defined as a history of cigarette smoking during the past year. Standard enzymatic methods were used to measure total, LDL, and HDL cholesterol and triglycerides. Diabetes was defined by physician diagnosis, the use of antidiabetic medications, or a fasting glucose level >126 mg·dL−1. Angina pectoris was defined as a positive response in the physician-based interview or as definite angina pectoris in the Rose angina questionnaire. Subjects were queried about current routine cardiovascular medications.
Extracoronary atherosclerosis was determined by B-mode ultrasound (7.5-MHz transducer, Elegra; Siemens, Erlangen, Germany) in the internal, external, and common carotid arteries, bilaterally, as well as in the infrarenal aorta, and iliac, common femoral, and proximal (within the first 10 cm from origin) and distal superficial femoral arteries (SFA) (adductor channel) of both legs. Patients were studied in the supine position in an acclimatized room after 15 min of rest. The presence of plaque and maximal wall thickening were measured.
The presence of plaque was defined as detectable circumscript echogenic or echolucent intima lesions. Plaque was not visually classified into hypoechoic, isoechoic, or hyperechoic plaque (23) because such a classification is possible for the carotid arteries with local plaque only but not for extended atherosclerosis in peripheral arteries. Thus, the presence of plaque was documented categorically as "yes" or "no" for each single arterial segment. To approximate the atherosclerotic burden, the maximal thickness of the most prominent plaque (maximal plaque thickness = MPT) was measured in each arterial segment. If there was now plaque, intima-media thickness (IMT) was determined at the far wall of each arterial segment as recommended in the literature (19,31). Thus, in nonatherosclerotic arteries, MPT represents IMT. In participants with atherosclerotic plaque, MPT represents maximal thickness of the most prominent plaque that is not necessarily at the far wall. In these cases, MPT was measured in the most suitable image knowing that near or lateral wall measurements suffer from a lower measurement precision (31). Because we did not focus on longitudinal observations requiring the measurement of small changes in IMT or plaque thickness, this compromise was chosen to have a simple and easily repeatable method. Focusing just on the far wall would have missed the plaque in Figure 1. Vascular diameters, defined as distance from media to media, were strictly measured from the near to the far wall. To estimate segmental plaque burden, we calculated local vascular lumina, defined as (vessel diameter − plaque)/vessel diameter (%).
Electron beam computed tomography.
Nonenhanced electron beam computed tomography (EBCT) scans were performed with a C-150 scanner (GE Imatron, South San Francisco, CA). EBCT scans were obtained in the Alfried Krupp Krankenhaus, Essen, Germany. The protocol was identical at all scanner sites as previously described (14,25): the scanners were operated in the single-slice mode with an image acquisition time of 100 ms and a section thickness of 3 mm. Prospective ECG triggering was done at 80% of the R-R interval. Contiguous slices to the apex of the heart were obtained in both studies. The total CAC Agatston score was computed by summing the CAC scores of all foci in the epicardial coronary system. The CAC score was not reported to runners or their general practitioners.
Subject characteristics for all runners and in relation to the presence of plaque are given as mean ± SD, median (25th-75th percentile), or count (%). Differences in location measures were statistically evaluated using Mann-Whitney U statistics, and differences in proportions, using the χ2 test. Bonferroni-Holm testing was used to prove differences of plaque frequency in the different arterial segments. The relations of vessel diameters and lumina versus coronary calcification were also evaluated using the Mann-Whitney test. Positive and negative predictive values (PPV and NPV) of plaque presence and a Framingham risk score >10% for a CAC > 0 or a CAC ≥ 100 are given as percentage. Correlations of demographics or plaque thicknesses with CAC were computed as Spearman rank correlation.
Cardiovascular risk factor profile.
The risk factor profile of the runners is given in Table 1. Only 10 participants were free of plaque in the carotids and peripheral arteries. Runners with plaque were slightly older and had a higher Framingham score. Individual risk factors were mostly higher and more prevalent in runners with plaque. Of note, none of the runners without peripheral plaque had a history of arterial hypertension. The odds ratios for the presence of plaque (95% confidence interval) per 1% increase in the Framingham risk score and per year of age were 1.36 (1.00-1.85), P = 0.049 and 1.15 (0.98-1.34), P = 0.094, respectively. When age was set at 56 yr (median age), the odds ratio for the Framingham risk score was 1.30 (0.91-1.86), P = 0.15.
Prevalence of carotid, peripheral, and coronary artery plaque.
Plaque was visualized most frequently in the distal SFA followed by the carotids (P < 0.02 for distal SFA vs each of carotid, aorta, and iliac, common femoral, and proximal femoral arteries). All participants with carotid plaque also presented with peripheral artery plaque. Runners with any peripheral artery plaque tended to have a higher prevalence and extent of calcified coronary plaque burden, but this was not statistically significant (Table 1). Even in the absence of peripheral plaque, however, CAC was detectable in 50% of runners (Table 1). In the presence of any peripheral artery plaque, at least 78.4% of runners had a CAC > 0 (see Table 2 for common femoral artery).
Peripheral arterial diameters, lumen, and CAC.
Runners with CAC > 100 had larger diameters and smaller lumen of the proximal peripheral arteries, including the aorta and the iliac and the common femoral arteries, than those with lower CAC burden (Table 3). This was not consistently observed in the distal peripheral arteries (Table 3). We specifically tested for laterality to exclude an influence of data sampling. Only the difference in lumen of the proximal SFA reached significance (P = 0.04), whereas all other arteries did not.
PPV and NPV of carotid and peripheral plaque to identify coronary atherosclerosis.
Different arterial segments seem not to have specific associations with CAC. The PPV for plaque in the carotid or peripheral arteries ranged from 76.7 to 87.5 for any CAC and from 40.0 to 57.5 for a CAC > 100. The NPV ranged from 30.0 to 50.0 and from 71.0 to 80.0, respectively. The PPV for a Framingham risk score >10% were 100 and 54.6, respectively, with lower NPV (Table 4). Test characteristics were in a similar range for other thresholds of CAC burden, i.e., CAC ≥ 400 or CAC ≥ 75th percentile (data not shown).
There are several new findings in this study: 1) marathon runners have almost a 90% prevalence of carotid or peripheral artery atherosclerotic plaque; 2) despite the very low overall risk factor burden in male marathon runners, their atherosclerotic risk factor profile is related to the presence of carotid and peripheral artery plaque; 3) peripheral arteries seem to undergo the same remodeling process in response to atherosclerosis as the coronary arteries, and this remodeling cannot be solely attributed to exercise-induced adaptations; and 4) the presence of carotid and peripheral artery plaque in runners is associated with the extent of coronary atherosclerosis measured by CAC, but the ability of carotid or peripheral artery plaque to predict coronary atherosclerosis is limited.
The high prevalence of atherosclerotic lesions in the carotid and peripheral arteries is surprising because regular exercise training exerts many antiatherosclerotic effects (13), and habitual physical activity is inversely associated with coronary atherosclerosis burden even after adjustment for established risk factors (5). A small study in 20 older runners aged 66 ± 6 yr still practicing endurance sports and 20 clinically healthy sedentary controls showed significantly less extracoronary atherosclerosis and generally smaller atherosclerotic plaque in the peripheral arteries of the runners. Specifically, atherosclerotic plaque was present in 35% of the runners versus 90% of controls (9). Physical activity also alters peripheral arterial structure and function. Among 55 endurance-trained men (47 ± 2 yr), the common femoral artery diameter was 7% greater than that in sedentary controls, and femoral IMT and IMT/diameter ratio were 16%-21% smaller (7). Vice versa, femoral artery diameter and femoral artery maximal blood flow are lower in spinal cord-injured subjects compared with able-bodied individuals (22). In three other studies, femoral artery diameters and cross-sectional compliance were also greater than those in healthy sedentary males matched for age, height, and weight in one study (30), in sedentary and paraplegic subjects in another (26), and in able-bodied elite road-cyclist athletes compared with 26 athletes with paraplegia (11). Thus, it is not clear whether the larger peripheral artery size noted in the present study is due to atherosclerotic remodeling or to extensive endurance exercise.
We hypothesize that the peripheral arterial changes in the present study are primarily due to atherosclerotic remodeling. Runners with peripheral plaque had a higher Framingham risk score and, more frequently, arterial hypertension. They also tended to have a higher coronary atherosclerosis burden, and runners with CAC ≥ 100 had larger diameters but smaller perfused lumina in proximal large peripheral arteries, suggesting a more extensive arterial remodeling than that in runners with lower coronary plaque burden. This difference in arterial diameters associated with CAC is not in contrast to the finding that the size and blood flow volume of the proximal limb arteries are adjusted to the metabolic needs of the corresponding extremity musculature (11,26,30) because both effects can develop parallel. Our study does not have the power to determine the degree to which traditional risk factors have a dominant causal role and to which degree the observed changes are attributable to age and hence frequent stress and strain on the arteries. Runners with plaque were older, but this association was of only borderline significance, whereas the association of plaque with the Framingham risk score was statistically significant. Of note, no runners without plaque had a history of arterial hypertension, which suggests that hypertension is an important contributor to carotid and peripheral plaque formation in marathon runners as it is also in patients.
Our data suggest that the effect of risk factors may differ among the different vascular territories. Atherosclerotic plaque prevalence in our study was highest in the distal superficial artery, but the association of peripheral artery plaque with coronary plaque burden was highest in the proximal peripheral arteries, such as the aorta and the iliac and the common femoral arteries. We speculate that the alterations in the more distal lower limb arteries may predominantly result from repetitive mechanical shear forces producing injury-induced atherosclerosis (26), whereas changes in the carotid and proximal large arteries may be more responsive to cardiovascular risk. Previous studies have identified differences among arterial territories in their response to cardiovascular risk factors and their association with coronary atherosclerosis (2,10,14). Specifically, atherosclerosis in the femoral artery and carotid bulb have been reported to be independent predictors of the extent of CAD, but the common femoral artery might be more specific in predicting coronary calcification (14). Such observations may not just represent effects of risk factor burden in different vascular territories, but atherosclerosis and remodeling of the proximal peripheral arteries may cause an increase in aortic stiffness and may thereby add to the increase in CAC burden by raising central aortic pressure. This hypothesis must be verified using tests such as pulse wave analysis and calculation of an augmentation index (3).
The presence of carotid or peripheral atherosclerosis could not be used to reliably predict the presence and extent of CAC, which agrees with previous studies. In the Rancho Bernardo Study (1), the sensitivity of the internal or common carotid artery IMT for severe CAC was 50%-60%. In 414 older adults without clinical cardiovascular disease (CVD) from the community-based cardiovascular health study, carotid artery IMT was closely related to CAC, but the rate of misclassification of advanced CAC was substantial, either with the use of the ankle-brachial index, the resting ECG, or carotid ultrasound (21). The weak although significant association of carotid IMT with CAC is also consistent with data from the Heinz Nixdorf RECALL Study, where a high intraindividual variability of the association with IMT and CAC was observed.
The clinical relevance of our findings emanates from the increase in cardiovascular risk in the presence of increased subclinical carotid and peripheral atherosclerosis (10). Compared with a normal wall or wall thickening of the carotid or femoral bifurcation defined by B-mode ultrasound, nonstenosing plaque increased the 10-yr risk of cardiovascular events or deaths (8.6% vs 39.3%, P < 0.02) in the population of the Italian CAFES-CAVE study (4). An increased IMT was an independent predictor of cardiovascular events in the MESA study (8), and the German Epidemiological Trial on Ankle Brachial Index study (6) demonstrated a high predictive value of peripheral atherosclerosis for cardiovascular events. However, whether this association also holds in marathon runners is unclear. Our data indicate at least an association of both carotid and peripheral atherosclerosis with coronary plaque burden, which supports the concept that good cardiovascular risk factor control is important to prevent atherosclerotic disease manifestation in marathon runners.
The strength of the article would importantly improve if a healthy, moderately trained/nontrained control group could be included. Our findings are even not necessarily representative for all older marathon runners because this cohort was self-referred in response to an advertising campaign for this study with a high rate of former smokers. Equally, these findings cannot be translated to younger runners, women, or non-Caucasian runners. Yet, we believe that our findings apply to a large number of active marathon runners, whose increased atherosclerotic risk might be overlooked on the basis of traditional risk factors alone.
We have no data on the functional implications of carotid or peripheral artery plaque burden. Furthermore, we have no histology to prove that the observed changes truly represent atherosclerosis. Yet, the evidence supports an increased awareness of the fact that atherosclerosis is highly prevalent in marathon runners, and it seems prudent to recommend aggressive risk factor modification in runners with plaque who intend to undergo exhaustive competitive exercise.
The prevalence of carotid and peripheral atherosclerosis in marathon runners is high and is related to cardiovascular risk factors and the coronary atherosclerotic burden. Remodeling of peripheral arteries seems to occur in response to exercise and atherosclerosis. These data support an increased awareness of atherosclerosis prevalence and good cardiovascular risk factor control in marathon runners.
The authors thank the Ruhrkohle AG, Essen, Germany, and the "Hans und Gertie Fischer Stiftung," Essen, Germany, for their generous grants for the marathon study.
The authors also thank the help of David Kiefer and Martin Hensel in acquiring data for the marathon study and the help of the dedicated personnel in the electron beam tomography (EBT) scanner facility.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
1. Barrett-Connor E, Laughlin GA, Connor C. Coronary artery calcium versus intima-media thickness as a measure of cardiovascular disease among asymptomatic adults (from the Rancho Bernardo Study). Am J Cardiol
2. Bauer M, Möhlenkamp S, Lehmann N, et al. The effect of age and risk factors on coronary and carotid artery atherosclerotic burden in males: results of the Heinz Nixdorf RECALL Study. Atherosclerosis
3. Baulmann J, Nürnberger J, Slany J, et al. Arterial stiffness and pulse wave analysis [in German]. Dtsch Med Wochenschr
. 2010;135(1 suppl):S4-14.
4. Belcaro G, Nicolaides AN, Ramaswami G. Carotid and femoral ultrasound morphology screening and cardiovascular events in low risk subjects: a 10-year follow-up study (the CAFES-CAVE study (1)). Atherosclerosis
5. Desai MY, Nasir K, Rumberger JA, et al. Relation of degree of physical activity to CAC score in asymptomatic individuals with multiple metabolic risk factors. Am J Cardiol
6. Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation
7. Dinenno FA, Tanaka H, Monahan KD, et al. Regular endurance exercise induces expansive arterial remodelling in the trained limbs of healthy men. J Physiol
. 2001;534(Pt 1):287-95.
8. Folsom AR, Kronmal RA, Detrano RC, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med
9. Galetta F, Rossi M, Franzoni F, Credidio L, Vagheggini G. Atherosclerosis vascular damage in elderly athletes and sedentary people. Angiology
10. Held C, Hjemdahl P, Eriksson SV, Bjorkander I, Forslund L, Rehnqvist N. Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris. Eur Heart J
11. Huonker M, Schmid A, Schmidt-Trucksass A, Grathwohl D, Keul J. Size and blood flow of central and peripheral arteries in highly trained able-bodied and disabled athletes. J Appl Physiol
12. Kafetzakis A, Kochiadakis G, Laliotis A, et al. Association of subclinical wall changes of carotid, femoral, and popliteal arteries with obstructive coronary artery disease in patients undergoing coronary angiography. Chest
13. Kojda G, Hambrecht R. Molecular mechanisms of vascular adaptations to exercise: physical activity as an effective antioxidant therapy? Cardiovasc Res
14. Lekakis JP, Papamichael CM, Cimponeriu AT, et al. Atherosclerotic changes of extracoronary arteries are associated with the extent of coronary atherosclerosis. Am J Cardiol
15. Maron BJ, Gohman TE, Aeppli D. Prevalence of sudden cardiac death during competitive sports activities in Minnesota high school athletes. J Am Coll Cardiol
16. Maron BJ, Poliac LC, Roberts WO. Risk for sudden cardiac death associated with marathon
running. J Am Coll Cardiol
17. Möhlenkamp S, Lehmann N, Breuckmann F, et al. Running: the risk of coronary events: prevalence and prognostic relevance of coronary atherosclerosis in marathon
runners. Eur Heart J
18. Möhlenkamp S, Schmermund A, Kröger K, et al. Coronary atherosclerosis and cardiovascular risk in masters male marathon
runners. Rationale and design of the "marathon
19. Montauban van Swijndregt AD, The SH, Gussenhoven EJ, et al. An in vitro
evaluation of the line pattern of the near and far walls of carotid arteries using B-mode ultrasound. Ultrasound Med Biol
20. Newman AB, Naydeck B, Sutton-Tyrrell K, Edmundowicz D, Gottdiener J, Kuller LH. Coronary artery calcification in older adults with minimal clinical or subclinical cardiovascular disease. J Am Geriatr Soc
21. Newman AB, Naydeck BL, Sutton-Tyrrell K, et al. Relationship between coronary artery calcification and other measures of subclinical cardiovascular disease in older adults. Arterioscler Thromb Vasc Biol
22. Olive JL, Dudley GA, McCully KK. Vascular remodeling after spinal cord injury. Med Sci Sports Exerc
23. Polak JF, Shemanski L, O'Leary DH, et al. Hypoechoic plaque at ultrasound of the carotid artery: an independent risk factor for incident stroke in adults 65 years or older. Radiology
24. Schmermund A, Möhlenkamp S, Berenbein S, et al. Population-based assessment of subclinical coronary atherosclerosis using electron-beam computed tomography. Atherosclerosis
25. Schmermund A, Möhlenkamp S, Stang A, et al. Assessment of clinically silent atherosclerotic disease and established and novel risk factors for predicting myocardial infarction and cardiac death in healthy middle-aged subjects: rationale and design of the Heinz Nixdorf RECALL Study. Risk Factors, Evaluation of Coronary Calcium and Lifestyle. Am Heart J
26. Schmidt-Trucksäss A, Schmid A, Brunner C, et al. Arterial properties of the carotid and femoral artery in endurance-trained and paraplegic subjects. J Appl Physiol
27. Siscovick DS, Weiss NS, Fletcher RH, et al. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med
28. The National Physical Activity Plan [Internet]. [cited 2010 Dec 2]. Available from: http://www.physicalactivityplan.org/NationalPhysicalActivityPlan.pdf
29. Van Camp SP, Bloor CM, Müller FO, et al. Non-traumatic sports death in high school and college athletes. Med Sci Sports Exerc
30. Wijnen JA, Kuipers H, Kool MJ, et al. Vessel wall properties of large arteries in trained and sedentary subjects. Basic Res Cardiol
. 1991;86(1 suppl):25-9.
31. Wikstrand J. Methodological considerations of ultrasound measurement of carotid artery intima-media thickness and lumen diameter. Clin Physiol Funct Imaging