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Study finds that long-term participation in marathon training/racing is paradoxically associated with increased coronary plaque volume

By Robert S. Schwartz, MD, Stacia Merkel Kraus, MPH, Jonathan G. Schwartz, MD, Kelly K. Wickstrom, BS, Gretchen Peichel, RN, Ross F. Garberich, MS, John R. Lesser, MD, Stephen N. Oesterle, MD, Thomas Knickelbine, MD, Kevin M. Harris, MD, Sue Duval, PhD, William O. Roberts, MD & James H. O’Keefe, MD

Published in Missouri Medicine, the Journal of the Missouri State Medical Association, March/April 2014 

Abstract

Background

Long-term marathon running improves many cardiovascular risk factors, and is presumed to protect against coronary artery plaque formation. This hypothesis, that long-term marathon running is protective against coronary atherosclerosis, was tested by quantitatively assessing coronary artery plaque using high resolution coronary computed tomographic angiography (CCTA) in veteran marathon runners compared to sedentary control subjects.

Methods

Men in the study completed at least one marathon yearly for 25 consecutive years. All study subjects underwent CCTA, 12-lead electrocardiogram, measurement of blood pressure, heart rate, and lipid panel. A sedentary matched group was derived from a contemporaneous CCTA database of asymptomatic healthy individuals. CCTAs were analyzed using validated plaque characterization software.

Results

Male marathon runners (n = 50) as compared with sedentary male controls (n = 23) had increased total plaque volume (200 vs. 126 mm3, p < 0.01), calcified plaque volume (84 vs. 44 mm3, p < 0.0001), and non-calcified plaque volume (116 vs. 82 mm3, p = 0.04). Lesion area and length, number of lesions per subject, and diameter stenosis did not reach statistical significance.

Conclusion

Long-term male marathon runners may have paradoxically increased coronary artery plaque volume.

Introduction

Regular physical activity is a key component of a healthy lifestyle. Vigorous aerobic exercise is considered protective against coronary artery plaque development based on its favorable effects on many cardiovascular (CV) risk factors including lower resting blood pressure and heart rate, improved lipid profile and glucose metabolism, reduced body mass index (BMI), and association with healthier lifestyles such as eating a nutritious diet and avoiding tobacco.^1-3 Daily physical activity and high levels of cardiorespiratory fitness are also associated with lower inflammatory markers and better life-expectancy.^4-8

Four decades ago, Thomas Bassler, MD, an American physician, notably hypothesized that marathon running confers immunity against coronary atherosclerosis.⁹ Exercise might be best understood as a drug with powerful benefits, especially for CV health. As with any potent drug, establishing the safe and effective dose range is critically important—an inadequately low dose may not confer full benefits, whereas an excessive dose may produce adverse effects that outweigh its benefits.

Two recently published long-term large observational studies independently showed that runners, as compared to non-runners, have increased life expectancy. However, these longevity benefits were most significant for those obtaining moderate doses of running; individuals chronically performing high-intensity long-distance running appeared to lose the mortality benefit.^{10, 11} Indeed, an emerging body of scientific data suggests that chronic, excessive, high-intensity exercise may induce oxidative stress and myocardial fibrosis, accelerate atherosclerosis, increase vascular wall thickness, and increase cardiac chamber stiffness.^{12, 13} Demand ischemia related to significant coronary narrowing may also occur in endurance running, and rarely this may even result in myocardial infarction and cardiac arrest.^{14, 15} Male marathon runners have also been shown to have paradoxically increased coronary artery calcified plaque as measured by computed tomography (CT) coronary calcium scoring.¹⁶ However, a study using high resolution coronary computed tomographic angiography (CCTA) for quantifying coronary artery plaque volume in marathoners has not been previously performed.

Recent advances in CCTA provide quantitative, noninvasive assessment of coronary artery plaque, and permit accurate measurement of plaque volume and location. In this study we used CCTA to examine whether long-term marathon running in men is associated with quantitative coronary artery plaque differences compared to a sedentary control group.

Methods

The study was approved by the Institutional Review Board of Abbott Northwestern Hospital (Minneapolis, MN). It was a single-center observational study of male long-term, very long-distance runners who participated in the Twin Cities’ Marathon (Minneapolis-St. Paul, MN). Eligible individuals were identified and invited to participate by reviewing marathon race records. After reviewing eligible subjects, participation thresholds were chosen as a minimum of 25 consecutive races for men.

A sedentary group of men was obtained from a coronary screening study of individuals who underwent CCTA scanning for clinical indications.^{17, 18} All subjects in this group were self-reported to lead sedentary lifestyles. Attempts were made to match the marathon runners to the sedentary controls for coronary disease risk factors.

Inclusion Criteria

All subjects signed informed consent. Exclusion criteria were those who declined to participate, were allergic to x-ray contrast, and had serum creatinine ≥ 2.0. Scans were not scheduled if a subject had run a marathon within the previous two weeks or intended to run a marathon within the following two weeks (to avoid potential nephrotoxic effects from intravenous contrast, since marathon running is associated with a transient creatinine rise).¹⁹

Procedures

CCTA was performed per standard clinical practice using Siemens Dual Source or FLASH CT in a minimum x-ray dose protocol. At or near the time of the CCTA, the following procedures were performed: 12-lead electrocardiogram, height, weight, blood pressure, resting heart rate, serum lipid panel, historical life-style and risk factor questionnaire, and serum creatinine.

Data Analysis

CCTA scans were evaluated for all measurable plaque, both calcified and non-calcified. Plaque was manually identified and characterized for volume and stenosis severity using validated, commercial software on a commercial CCTA 3-D workstation (Vitrea, Vital Images, Minnetonka, MN).

Descriptive statistics were calculated and included means and standard deviations or numerical counts and percentages. Chi-squared or Fisher’s exact tests were used to assess the statistical significance of categorical variables and t-tests or Wilcoxon tests were used for continuous variables where appropriate. The Shapiro-Wilk test was used to test for normality of continuous data. If normality assumptions failed, conclusions were based on non-parametric comparisons. A p value of ≤ 0.050 was considered statistically significant and all reported p values were two-sided. Statistical calculations were done with SAS software version 9.2 (SAS Institute Inc., Cary, NC).

Results

Fifty male marathon runners and 23 sedentary male control subjects were enrolled. All male runners reported no CV symptoms and had no CV or coronary history. The marathoners and controls were similar in age, resting blood pressure, height, smoking history, serum creatinine, total cholesterol, and low density lipoprotein (LDL) cholesterol (p = NS for all) (see Table 1). Marathoners had significantly lower resting heart rate, weight, BMI and triglyceride levels, but had higher high density lipoprotein (HDL) levels, and were less likely to have a history of diabetes and hypertension (see Table 1).

Tables 2 and 3 summarize coronary CT lesion analysis. There were 46 lesions in 12 of the 23 sedentary subjects and 95 lesions in 30 of the 50 marathon participants. There was no difference in lesion prevalence between groups. Male marathon runners however had paradoxically increased total plaque volume (200 vs. 126 mm³, p = 0.002), calcified plaque volume (84 vs. 44 mm³, p < 0.0001), and non-calcified plaque volume (116 vs. 82 mm³, p = 0.04) (see Figure 1). Lesion area, diameter stenosis, and length differences did not reach statistical significance between the two groups.

Table 1. Demographic Characteristics of Subjects

Values presented are mean ± SD or n (%), p values from Fisher’s Exact Test/T-test/Wilcoxon test for non-normal data, *Indicates failure of the normality assumptions based on Shapiro-Wilk test

†BMI-body mass index, ‡HDL-high-density lipoprotein, §LDL-low-density lipoprotein, ║CAD-coronary artery disease

Table 2. Lesion Prevalence Across Runners and Sedentary Subjects

Values presented are mean ± SD or n (%)

p values from Fisher’s Exact Test/T-test 

Table 3. CT-Derived Lesion Characteristics

p values from T-test/Wilcoxon test for non-normal data

^*Indicates failure of the normality assumptions based on Shapiro-Wilk test 

Discussion

The association of decades-long marathon training/racing with coronary artery plaque was examined in this study. Few prior studies have focused on this association, and none using plaque quantitation by CCTA. We found that long-term marathon running in men may not engender protection against coronary artery plaque development, despite conferring advantages in many traditional coronary risk factors including favorable changes in lipid levels, glucose metabolism, and blood pressure. To the contrary, this study found that long-term participation in marathon training/racing is paradoxically associated with increased coronary plaque volume (despite comparable plaque prevalence).

A recent study found the incidence of sudden death in marathon running is approximately 1 in 100,000 participants,¹⁵ with coronary artery disease (CAD) accounting for the majority of fatalities.¹⁴ Fortunately, these deaths, though tragic and disturbing, are rare. However, the bigger concern may be the fact that excessive exercise ultimately deprives the individual from reaping the significant longevity benefits conferred by moderate exercise.

The Copenhagen City Heart Study followed 1,878 runners and 10,158 non-runners for up to 35 years.¹⁰ The runners had an impressive 44% lower risk of mortality during follow-up, with an increase in life expectancy of about six years for both genders. Importantly though, U-shaped curves were apparent for mortality with respect to dose of running, whereby the benefits of running were most significant for those who jogged between 1 to 2.5 hours per week, at a slow to moderate pace, with a frequency of about three times per week.¹⁰ In those runners who were performing higher volume, higher intensity running, the long-term mortality rates were not significantly different from non-runners. In other words, excessive running may have abolished the remarkable improvements in longevity conferred by lower doses of running.

Strikingly concordant data were seen in a large decades-long observational study of 54,000 Americans.¹¹ Highly significant mortality reductions were seen in the runners compared to the non-runners, but U-shaped curves again showed that the lowest mortality rates were seen in those running 5 to 20 miles/week, and that the longevity benefits of running completely disappeared with distances greater than 25 to 30 miles/week. Still, the mortality rates in the high mileage runners were similar to but did not exceed those for sedentary individuals).¹¹

Cardiac over-use injury is a term that we have proposed for problems that arise with chronic excessive high intensity exercise. Reports have documented myocardial fibrosis and scarring, potentially dangerous rhythms, and accelerated coronary atherosclerosis (a constellation of pathology which has been labeled Pheidippides’ Cardiomyopathy by Peter McCullough, MD).^{12, 13, 19} The number of individuals running in marathons and other extreme endurance events has been rising dramatically during the past 40 years (see Figure 2).^{12, 13} We suspect some runners might choose shorter, less exhausting challenges if they were aware of the potential adverse cardiac effects of chronic extreme endurance efforts.

The metabolic and mechanical stresses produced by excessive running could constitute a causal role in accelerated atherosclerosis. Runners who train and race over very long-distances experience protracted elevations in heart rate, blood pressure, cardiac output, and atrial and ventricular volumes for up to several hours per day. Intense exercise generates large quantities of free-radicals that outstrip the buffering capacity of the system after approximately one hour of vigorous continuous exercise, leaving these individuals susceptible to oxidative stress, atherogenic modification of cholesterol particles, and endothelial dysfunction.²⁰ Ultra-endurance efforts also cause multiple other disturbances within the system including sustained elevations of catecholamines and resultant coronary vasoconstriction, protracted sinus tachycardia which reduces the diastolic filling time of the coronary arteries, changes in free fatty acid metabolism, lactic acidosis, and other metabolic derangements.^{12, 13, 19}

Figure 1. Marathoners had significantly more total coronary plaque volume, non-calcified plaque volume and calcified plaque volume compared to control subjects.

Figure 2. Marathon running trends in the United States, 1976-2011.

Limitations

The control group, although matched for age, gender and several CV risk factors, was unable to be matched to the marathoners for resting heart rate, weight and HDL levels, likely the result of chronic high intensity aerobic exercise. Still, these differences would be expected to protect against atherosclerosis, thereby favoring the marathoners. However, the sedentary controls had significantly less coronary plaque despite the marathoners’ more favorable CV risk factors.

This was a single-center observational study, based on recruitment from known runners who chose to participate. However, a study that randomly assigned individuals to either run marathons for 25 years or be sedentary for 25 years is practically impossible, and will never be done. Thus, a cause-and-effect relationship between marathon running and accelerated coronary plaque development cannot be established. Nonetheless, multicenter studies comparing coronary plaque volume in larger numbers of marathoners and matched sedentary control subjects would be of great interest.

Conclusion

Long-term training for and competing in marathons may in men be paradoxically associated with accelerated coronary artery plaque formation.

Acknowledgments

Presented in abstract at the American Heart Association Scientific Sessions, November 2011. This work was supported in part by the Ken Rome Foundation, Minneapolis, MN http://kenrome5k.wordpress.com/2008/08/01/ken-rome-foundation-information.

Disclosures

None reported. 

Published April TK, 2014

Robert S. Schwartz, MD, Kelly K. Wickstrom, BS, Gretchen Peichel, RN, Ross F. Garberich, MS, John R. Lesser, MD, Thomas Knickelbine, MD, Kevin M. Harris, MD, are with the Minneapolis Heart Institute and Foundation at Abbott Northwestern Hospital, Minneapolis, MN. Stacia Merkel Kraus, MPH, is with the Integra Group, Brooklyn Park, MN. Jonathan G. Schwartz, MD, is with the Department of Internal Medicine, University of Colorado Medical Center, Denver, CO. Stephen N. Oesterle, MD is with Medtronic Inc., Minneapolis, MN. Sue Duval, PhD, is with the School of Public Health, University of Minnesota, Minneapolis, MN. William O. Roberts, MD, MS, is with the Department of Family Medicine and Community Health, University of Minnesota, St. Paul, MN. James H. O’Keefe, MD, MSMA member since 2003, is with the Saint Luke's Mid America Heart Institute, Kansas City, MO, and the Missouri Medicine Preventive Medicine Editorial Board Member.

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