Review ArticleRunning away from cardiovascular disease at the right speed: The impact of aerobic physical activity and cardiorespiratory fitness on cardiovascular disease risk and associated subclinical phenotypes
Introduction
Physical activity (PA) and cardiorespiratory fitness (CRF) are important modifiable cardiovascular (CV) risk factors. Individuals who are sedentary have a higher risk of all-cause and CV disease (CVD)-related mortality as compared with their physically active counterparts.1,2 Several studies have additionally demonstrated an inverse dose-response relationship between aerobic PA and incident CVD events, including atherosclerotic coronary artery disease (CAD) and heart failure (HF).3., 4., 5. The favorable association between higher PA levels and CVD risk is thought to be mediated by traditional CVD risk factor modification, vascular conditioning, cardiac remodeling, and cardiomyocyte molecular adaptations.6 Regular endurance exercise also protects against CVD through biochemical preconditioning against ischemic damage.7,8 PA intensity is typically expressed as metabolic equivalents (METs) with 1 MET defined as the amount of energy expended while sitting at rest.9 A number of modalities are utilized to gauge patient aerobic PA levels and information obtained from questionnaires,10 accelerometers,11 or pedometers12 and is commonly stratified into light, moderate, vigorous, and very-vigorous PA, which correspond to absolute intensities of <3, ≥3 to <6, ≥6 to <9, and ≥ 9 METs, respectively.13 However, a more accepted standard is relative intensity which represents a percentage of the individual's exercise or functional capacity, since a given MET load may correspond to highly varied relative intensities in younger versus older adults. Consequently, lower MET requirements may still place considerable stress on the CV system of unfit, older individuals and those with established CVD. Accordingly, vigorous PA is usually defined as ≥60% functional capacity, whereas moderate intensity PA approximates 40% to 59% functional capacity.14
Possibly more important than aerobic PA, CRF is a separate measure of physical wellness that captures the capacity of CV and respiratory systems to supply oxygen to skeletal muscles during progressive PA or incremental exercise to volitional fatigue.15 Similar to PA levels, low levels of CRF are associated with higher overall mortality16 and CVD, including both atherosclerotic CAD and HF.17., 18., 19. These consistent findings prompted the American Heart Association (AHA) to release a scientific statement that builds the case for considering CRF, in addition to PA, as a clinical vital sign.15,20 It is also important to note that low CRF is a distinct risk factor from low PA level as the relationship of CRF with CVD risk is different from the relationship of PA with CVD risk as demonstrated in the seminal meta-analysis by Williams.21 The gold standard for CRF assessment is direct measurement of the highest attained oxygen consumption (VO2) during cardiopulmonary exercise testing, and CRF is usually expressed as maximal oxygen consumption (VO2max) in apparently healthy populations or peak oxygen consumption (VO2peak) in patient populations.22 Absolute VO2 is generally expressed as liters of oxygen consumed per minute (l/min) or, in relative terms, as milliliters of oxygen consumed per kilogram of body weight per minute (ml/kg/min).15,23 However, direct measurement of VO2max or VO2peak can be technically challenging, and predicted CRF derived from the highest attained work rate during graded, maximal or submaximal exercise protocols, is commonly used in large scale studies.15
A careful assessment of several epidemiologic studies reporting the consistent inverse association of PA and CRF with CVD risk reveals that the relationships with atherosclerotic CAD and HF risk are distinct. While the association with CAD risk is curvilinear, a more linear inverse relationship is observed with HF risk.3,4 This observation is further substantiated by recent studies highlighting the association of extreme PA levels with accelerated subclinical coronary atherosclerosis and incident atrial fibrillation (AF) among endurance athletes. Therefore, personalizing exercise prescriptions with the goal of optimally augmenting PA and CRF levels in asymptomatic individuals is important. In this review, we discuss the associations of PA and CRF levels with CAD and HF risk along with the preceding subclinical cardiac phenotypes to better characterize the optimal exercise dose needed to optimize an individual's health trajectory.
Section snippets
Aerobic PA, CRF and CAD Risk
Substantial evidence accumulated primarily through comprehensive epidemiologic studies supports the inverse relationship of PA and CRF with CAD risk. In 1953, Morris and colleagues reported that CAD rates were ~ 50% lower among physically active British bus conductors (collecting tickets) as compared with British bus drivers who were habitually sedentary.24 Subsequent observational studies over the past six decades have consistently shown that higher PA levels are independently associated with
Aerobic PA, CRF, and Coronary Artery Calcification
Coronary artery calcium (CAC), a marker of subclinical coronary atherosclerosis, is a phenotype proximal to the development of atherosclerotic CAD.40 Multiple studies have evaluated the predictive value of CAC score for incident CAD and have consistently reported a significant improvement in risk-discrimination and risk-reclassification indices beyond established risk assessment tools.41., 42., 43., 44., 45. As per the American College of Cardiology (ACC)/AHA primary prevention guidelines, CAC
CAC in the General Population
Several cross-sectional studies over the past two decades have evaluated the association of PA with prevalent CAC in the general population (Table 1A). These studies have reported heterogenous observations with some reporting an inverse association with PA and CAC,48,49 while others demonstrating no association between the two after adjustment for prevalent cardiovascular risk factors.50., 51., 52., 53.
Studies evaluating the association of CRF with CAC in the general population are summarized
CAC in Endurance Athletes
Atherosclerotic CAD is the most common cause of death during exercise among athletes older than 35 years.60,61 There is a paucity of studies evaluating the association of PA and CRF with CAC among strength athletes. Two small studies have reported that the prevalence of CAC among retired American football players is similar to the general population,62 and players in linemen positions tend to have higher CAC than non-linemen.63
The relationship of high-volume vigorous PA and high CRF with CAC
Aerobic PA, CRF, and HF Risk
The association of PA and CRF with HF risk appears to be distinct and perhaps stronger as compared to the relation with atherosclerotic CAD. Similar to CAD, PA has an inverse, graded relationship with HF risk, that is consistent across age, race, sex, and geographical subgroups. However, in contrast to the curvilinear association with CAD, the relationship between PA and HF is more linear, and substantial reduction in HF risk can be observed with PA levels beyond the guideline recommended doses
Aerobic PA, CRF, and Left Ventricular Structure and Function
Parameters of left ventricular (LV) structure and function provide meaningful prognostic information in asymptomatic individuals. Impaired LV systolic and diastolic dysfunction, LV mass, and LV concentricity are epidemiologically associated with higher risk of mortality and incident HF.81., 82., 83., 84., 85., 86. Importantly, these phenotypes represent intermediate stages in the progression to clinical HF and changes in these parameters provide insight into the mechanisms by which regular PA
Cardiac Remodeling in the General Population
Several cross-sectional studies have linked PA and CRF to abnormalities in cardiac structure and function in the general population (Table 3). In an analysis from the Cooper Clinic, we showed that low CRF was strongly associated with higher LV filling pressure and impairment in diastolic filling.87 On the other hand, CRF was not associated with reduced systolic function quantified by EF. However, in a cross-sectional analysis using the Dallas Heart Study, we observed an inverse, independent
Cardiac Remodeling in Endurance Athletes
Athletes undergo regular exposure to extreme exercise training and competition compared to individuals in the general population, and therefore have distinct remodeling patterns that warrant exploration. Among Italian cohorts of elite athletes, Pellicia et al. reported that in contrast to healthy individuals, athletes may have greater LV wall thickness (≥13 mm), larger LV end diastolic diameters, and marked LV hypertrophy, findings that would be considered pathological in the general population.
Role of Aerobic PA and CRF in Modifying CAD and HF Risk
The association of PA and CRF with future CAD and HF risk among asymptomatic individuals sparked the hypothesis that increases in these variables may decrease the risk of subsequent adverse CV events. Indeed, a prospective observational study of older men in Britain showed that increases in PA were associated with lower risk of non-fatal CAD events.106 In a sub-analysis of the Cooper Clinic cohort, we showed that temporal increases in CRF were associated with lower risk of HF in older age.
Aerobic PA, CRF and Atrial Fibrillation Risk
Atrial fibrillation (AF) comprises a substantial portion of CVD worldwide110 and unlike CAD and HF, the associations between PA, exercise patterns, and risk of AF are complex and vary by nature of the study population, intensity of PA, and overall levels of PA.
Association between PA and Risk of AF in the General Population and Athletes
Several cohort investigations have evaluated the association between self-reported PA and risk of AF in community-dwelling, non-athlete populations with inconsistent patterns of association reported across studies, with some showing no association and others demonstrating a reverse J or U-shaped relation.111., 112., 113., 114., 115., 116., 117., 118., 119., 120., 121. In a recent dose-response meta-analysis that pooled 19 cohort studies with over 30,000 incident AF events, Ricci et al. reported
Association Between CRF and Risk of AF
Similar to self-reported PA, studies evaluating the association between CRF and AF have yielded varied results. In a cohort of Finnish middle-aged men, Khan et al. reported a nonlinear association between CRF as determined by cycle ergometer testing and AF. In the adjusted analysis, fitness levels between 6 and 9 METs afforded the greatest benefit in AF risk reduction; however, at 10 to 12 METs, there was an increased risk of AF.140 A similar pattern was observed in a cohort of 1.1 million
Aerobic PA, CRF and Cardiovascular Disease Phenotypes
The association of PA and CRF with multiple CVD outcomes (CAD, HF, and AF) within the same cohort has been evaluated in a few studies. We have shown that CRF had a stronger association with HF risk than CAD risk among healthy, middle-aged adults of the Cooper Clinic cohort.19 Similar observations were reported by Khan and colleagues who studied Finnish participants of the Kuopio Ischemic Heart Disease study.145 In the same cohort, Khan et al. have demonstrated a J-shaped association between CRF
Current Guidelines for Aerobic PA and their Implications in Prevention of CVD
The PA guidelines for Americans were updated by the US Department of Health and Human Services in 2018.147 These guidelines recommend that all healthy adults should engage in at least 150 to 300 min of moderate-intensity aerobic exercise (40% to 59% functional capacity or 3 to 5.9 METs) each week, or 75 to 150 min of vigorous-intensity aerobic PA (≥60% functional capacity or ≥ 6 METs), or an equivalent combination thereof.147 The minimal weekly PA dose of 150 min of moderate-intensity or 75 min of
Conclusion
In summary, regular endurance exercise and maintaining higher CRF and aerobic PA levels represent an important potential strategy to reduce risk of CVD, but maximal effectiveness will require far more proactive, comprehensive lifestyle-based preventive interventions for CVD. During the past 50 years, our understanding of how aerobic PA and CRF modify risk of CVD has grown substantially. The benefits of endurance exercise as a preventative strategy have robust epidemiological support; however,
Funding
Dr. Pandey is supported by the Texas Health Resources Clinical Scholarship. Dr. Mehta is supported by American Heart Association postdoctoral fellowship award 19POST34400057. The funding sources had no involvement in the manuscript.
Declaration of Competing Interest
The authors declare that there is no conflict of interest.
Acknowledgements
None.
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