Editor's Note: Commentary based on Mandsager K, Harb S, Cremer P, Phelan D, Nissen SE, Jaber W. Association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing. JAMA Netw Open 2018;1:e183605.

Introduction

The inverse association between physical activity and incidence of chronic diseases and life expectancy has long been established;¹ however, many large studies linking physical activity with long-term health outcomes have relied on self-reported data and questionnaires which limit robust associations by recall bias.^2,3 Additionally, some studies of exercise habits and mortality have suggested the possible existence of a "U-shaped curve," in which extremely active individuals may have increased cardiovascular morbidity and overall mortality compared to those who engage in some, but not extreme, amounts of activity.^4,5 Such findings invite questions about just how much physical activity is safe. A recent original investigation by Mandsager et al. aimed to address some of these issues by examining the association between cardiorespiratory fitness (CRF) in participants undergoing routine exercise treadmill testing (ETT) and long-term mortality.

Study Summary

This was a large, retrospective analysis of 122,007 consecutive patients who underwent ETT during a 24-year period at a tertiary care center with a median follow-up of 8.4 years. The most common reasons for referral for testing including evaluation for coronary artery disease (CAD) and symptom assessment. CRF was assessed by performance during symptom-limited exercise stress testing, and was quantified as peak estimated metabolic equivalents (METs) using well-established formulas for each sex. The normal distribution of achieved METs was separated by decade of age for each sex. Performance on ETT by age group was stratified as elite (≥97.7th percentile), high (75th-97.6th percentile), above average (50th-74th percentile), below average (25th-49th percentile) and low (<25th percentile). The primary outcome was all-cause mortality as determined from the Social Security Death Index and supplemented by the institutional death index. The authors used a multivariable regression model to adjust for differences in baseline characteristics between groups. The model included the following variables: age, sex, body mass index, history of CAD, hyperlipidemia, hypertension, diabetes, smoking, end-stage renal disease (ESRD) and current medication use of aspirin, beta-blockers or statins.

Among the 122,007 patients included in the study, the mean age was 53.4 years, and 59.2% were male. The prevalence of associated comorbidities decreased significantly with increasing performance except for hyperlipidemia, which was present in more elite performers than low performers. In this study, the authors found that risk-adjusted all-cause mortality was inversely associated with increasing CRF in a dose-effect manner. This finding was also observed when the cohort was separated by sex. The increase in mortality associated with incremental reductions in CRF was comparable to or greater than the risks observed with traditional clinical risk factors, including CAD, smoking, diabetes and ESRD. Risk-adjusted all-cause mortality was lowest in elite performers as a cohort. When analyzed by age group, the difference in survival seen between the elite and high performers was seen only among those 70 years or older. In younger age groups, and when stratified by sex, there was no significant difference in survival between the elite and high performing groups.

Multivariate regression was also performed amongst clinical subgroups with known CAD, diabetes, hypertension and hyperlipidemia. In each subgroup, all-cause mortality was inversely associated with CRF when compared to the low performers (p < .0001 for all), and mortality was lowest among elite performers. Among those with hypertension, the difference in survival between elite and high performers was statistically significant.

Discussion

This study represents a well-executed analysis of the association between aerobic fitness and mortality in present-day American society and is an important contribution to the body of literature regarding the importance of physical activity. By virtue of the large-scale nature of this study, the observed risks associated with low cardiorespiratory fitness regardless of major cardiovascular comorbidities are notable. That they are comparable to or greater than the risks associated with traditionally cited cardiovascular risk factors including hypertension, diabetes, known CAD and ESRD further underlines the importance of physical fitness as a cornerstone of a healthy lifestyle. A major limitation of this study is its retrospective nature, which prohibits drawing conclusions about CRF and causation of mortality. However, the multivariate population-based assessment of CRF in association with survival is consistent with robust methodology used to study association between major chronic diseases and mortality.

A notable strength of this study is the direct assessment of CRF rather than reliance on patient-reported behaviors. However, CRF assessment was based on performance on ETT at a single point in time, so these findings do not speak to the association between long-term levels of fitness or physical activity and mortality. Nonetheless, it does highlight the utility of the ETT in capturing physical fitness at a given point in time and prognostication with these results. The performance on ETT and its association with survival, as assessed in this study, corroborate other long-standing evidence of the association between fitness and mortality.

In this study, the increases in CRF were associated with reduction in all-cause mortality at all levels of fitness, without evidence of a "U-shaped curve," as has been described in prior population-based studies. The authors state that they believe this difference may reflect the objective measurement of fitness used in this study as opposed to self-reported activity levels. They also note that this could also be reflective of non-activity-related determinants of aerobic fitness, including genetics and unmeasured other health habits.

Prior published data have suggested a potential risk of extreme levels of exercise including an increased risk of atrial fibrillation, myocardial fibrosis and coronary artery calcification when compared to more sedentary controls.⁵ While relative incidences of these co-morbidities in different performance groups were not specifically addressed, this paper contextualizes these potential risks but showing no increased mortality in the elite performance group and, indeed, a mortality benefit when one moves from a high to elite level of CRF.

Importantly, while the rates of cardiac and non-cardiac conditions (except hyperlipidemia) were significantly lower in the elite performance group compared with all other performance groups, the association between increasing fitness and mortality risk-reduction remained even amongst those with common chronic risk factors for cardiovascular disease.

Conclusions

• The health and mortality benefits of exercise are too important to ignore.
• Elite levels of cardiorespiratory fitness are associated with a reduction in all-cause mortality when compared to any other performance levels, including high levels of fitness.
• Low levels of cardiorespiratory fitness are associated with the highest risk of long-term mortality. In this study, the risk of low cardiorespiratory fitness exceeded the mortality risks of smoking, diabetes and hypertension.
• As the study authors note, "cardiorespiratory fitness is a modifiable indicator of long-term mortality." Consequently, we ought to counsel patients to engage in physical activity with the same emphasis we place on the importance of smoking cessation and good glucose control for overall health improvement.

References

1. Blair SN, Kohl HW, Paffenbarger RS, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA 1989;262:2395-401.
2. Prince SA, Adamo KB, Hamel ME, et al. A comparison of direct versus self-report measures for assessing physical activity in adults: a systematic review. Int J Behav Nutr Phys Act 2008;5:56.
3. Clausen JSR, Marott JL, Holtermann A, Gyntelberg F, Jensen MT. Midlife cardiorespiratory fitness and the long-term risk of mortality: 46 years of follow-up. J Am Coll Cardiol 2018;72:987-95.
4. Schnohr P, O'Keefe JH, Marott LJ, Lange P, Jensen GB. Dose of jogging and long-term mortality: the Copenhagan City Heart Study. J Am Coll Cardiol 2015;65:411-9.
5. Merghani A, Malhotra A, Sharma S. The U-shaped relationship between exercise and cardiac morbidity. Trends Cardiovasc Med 2016;26:232-40.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Sports and Exercise Cardiology, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Nonstatins, Novel Agents, Statins, Exercise, Hypertension

Keywords: Sports, Athletes, Metabolic Equivalent, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Artery Disease, Retrospective Studies, Body Mass Index, Risk Factors, Cardiovascular Diseases, Smoking Cessation, Aspirin, Life Expectancy, Atrial Fibrillation, Symptom Assessment, Tertiary Care Centers, Physical Fitness, Longitudinal Studies, Exercise, Diabetes Mellitus, Comorbidity, Hyperlipidemias, Hypertension, Risk Reduction Behavior, Chronic Disease, Kidney Failure, Chronic, Glucose, Cohort Studies

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