Physical Activity, Cardiorespiratory Fitness and Atherosclerotic Cardiovascular Disease: Part 1

Abstract

Background

The cardioprotective benefits and prognostic significance of regular moderate-to-vigorous physical activity (PA), increased cardiorespiratory fitness (CRF), or both are often underappreciated by the medical community and the patients they serve. Individuals with low CRF are two to three times more likely to die prematurely from atherosclerotic cardiovascular disease (CVD), than their fitter counterparts when matched for risk factor profile or coronary artery calcium (CAC) score. Accordingly, part 1 of this 2-part review examines these relations and the potential underlying mechanisms of benefit (e.g., exercise preconditioning) on atherosclerotic CVD, with specific reference to gait speed and mortality, CRF and PA as separate risk factors, and the relation between CRF and/or PA on attenuating the adverse impact of an elevated CAC score, as well as potentially favorably modifying CAC morphology, and on incident atrial fibrillation, all-cause and cardiovascular mortality, and on sudden cardiac death (SCD).

Summary

We explore the underappreciated cardioprotective effects of regular PA and CRF. Part 1 examines how CRF and PA reduce the risk of premature death from atherosclerotic CVD by investigating their roles as separate risk factors, the potential underlying mechanisms of benefit, and their impact on gait speed, mortality, and atrial fibrillation. The review also addresses how CRF and PA may mitigate the adverse impact of an elevated CAC score, potentially modifying CAC morphology, and reduce the risk of SCD.

Key Messages

Regular PA and high CRF are essential for reducing the risk of premature death from CVD and mitigating the negative impact of elevated CAC scores. Additionally, they provide significant protection against SCD and atrial fibrillation, emphasizing their broad cardioprotective effects.

Introduction

Coronary heart disease (CHD) is the leading cause of death in men and women worldwide. As the global burden of CHD rises, prevention of heart disease has gained heightened medical attention, and aggressive lifestyle modification and cardioprotective medications are increasingly being investigated, especially in combination. Several risk factors for the development of atherosclerotic cardiovascular disease (CVD) have been identified [1], including lack of regular physical activity (PA) and it is modulating impact on cardiorespiratory fitness (CRF). Chronic PA is an independent and additive risk factor associated with reduced cardiovascular morbidity and mortality (odds ratio [OR], 0.86 [0.76–0.97], p < 0.0001), conferring a population attributable risk of 12.2% for acute myocardial infarction [1].

Substantial epidemiologic, clinical, and basic science evidence suggests that regular PA, structured exercise training, and higher CRF delay the development of atherosclerotic CVD and reduce the incidence of CHD events. PA is defined as bodily movement resulting from the contraction of skeletal muscle that increases energy expenditure above the resting level, 1 metabolic equivalent (1 MET = 3.5 mLO₂/kg/min). PA may be quantified by using multiples of the resting energy expenditure, for example, 3 METs represents three times the resting oxygen consumption. Light, moderate, vigorous, and very-vigorous PA, correspond to absolute intensities of <3, ≥3–5.9, ≥6 to <9, and ≥9 METs, respectively [2]. Although an absolute exercise intensity ≥6 METs has been suggested as vigorous PA in some population-based applications, lower MET requirements can still place considerable stress on the cardiovascular system of unfit, older individuals and those with established CVD [3]. Accordingly, a more accepted standard is relative intensity which represents a percentage of the individual’s functional capacity or CRF. Vigorous PA is usually defined as ≥60% functional capacity, whereas moderate intensity PA approximates 40–59% functional capacity. Structured exercise training, which is considered a subcategory of PA, is defined as any planned intervention to improve or maintain CRF, health, athletic performance, or combinations thereof. The “gold standard” for CRF assessment involves the direct measurement of the highest attained oxygen consumption (VO₂) during progressive cardiopulmonary exercise testing to volitional fatigue, also referred to as aerobic capacity, and is commonly expressed as mLO₂/kg/min or as multiples of the resting oxygen consumption (METs). CRF is usually expressed as the maximal oxygen consumption (VO₂ max) or peak oxygen consumption (VO₂ peak) in apparently healthy and patient populations, respectively. Because direct measurement of oxygen consumption can be technically challenging and less accessible, CRF in many large-scale studies is commonly estimated from the attained workload during incremental cycle ergometry or treadmill testing.

In this two-part review, we summarize current evidence on the impact of PA and CRF on atherosclerotic CVD outcomes, drawing from large epidemiological studies, randomized controlled trials (RCTs), systemic reviews, and meta-analyses. We also examine the potential underlying mechanisms of the cardioprotective effects engaging regular PA/structured exercise, and explore their clinical implications. This review provides a comprehensive framework to inform clinical practice and shape future research in cardiovascular health.

Epidemiologic Studies

A seminal study that initially examined the relation between incident CHD and the strenuousness of work-related physical requirements reported that physically active bus conductors and mail delivery postmen had a 50% lower event rate from CHD compared with their sedentary counterparts, that is, bus drivers and clerical postal workers, respectively [4]. In an early meta-analysis of 43 studies of the relation between PA and CHD incidence, the relative risk of CHD in relation to physical inactivity ranged from 1.5 to 2.4, with a median value of 1.9 [5]. Furthermore, the relative risk of an inactive lifestyle appeared to be similar in magnitude to that associated with other major CHD risk factors. Another systematic review and meta-analysis of 33 PA studies (n = 883, 372 participants), reported pooled risk reductions of 35% and 33% for cardiovascular and all-cause mortality (ACM), respectively [6]. In a seminal meta-analysis, investigators examined the dose response between PA and the risk of CHD. Individuals who participated in 150 and 300 min per week (min/week) of moderate intensity PA demonstrated a 14% and 20% lower risk of CHD, respectively, as compared with their sedentary counterparts [7]. Nevertheless, people who were physically active at levels <150 min/week, also had a significantly lower risk of CHD. The associations were significantly (p = 0.03) stronger among women than men. On the other hand, the added benefits from PA doses >300 min/week, were only modest. More recently, researchers analyzed data from 2 major ongoing cohort studies, the Nurses’ Health Study (n = 78,865) and the Health Professionals Follow-up Study (n = 44,354) which, when combined with National Health and Nutrition Examination Survey data as well as mortality data from the Centers for Disease Control and Prevention, were used to estimate the impact of lifestyle on life expectancy in the US population [8]. Five low-risk lifestyle factors were considered: not smoking; body mass index 18.5–24.9 kg/m²; ≥30 min/day of moderate-to-vigorous PA; moderate alcohol intake; and, a healthy diet score. During up to 34 years of follow-up, the most physically active cohorts of men and women demonstrated 7–8-year gains in life expectancy. In aggregate, these epidemiologic data, and other analyses indicating that habitually sedentary individuals have an increased prevalence of 25 chronic diseases and/or risk factors, the phrase “sedentary death syndrome” has been put forth to describe the entity of hypokinetic-mediated unhealthy conditions that ultimately result in increased mortality [9].

Walking Distance, Speed, and Survival in Persons with and without CHD

Numerous studies and pooled analyses, in persons with and without CHD and/or heart failure (HF), have shown that walking distance and speed are powerful predictors of mortality in middle-aged and older adults [10–15]. Thomas Jefferson, the third US president, who lived to be 83 at a time when the average life expectancy was ∼40 years, firmly believed that physical exercise ensured not only bodily health, but mental health as well. Walking was his preferred activity, purportedly 4 miles/day. One of the first systemic studies on the impact of daily walking on mortality involved 707 nonsmoking retired men 61–81 years of age [10]. Over a 12-year follow-up, there were 208 deaths. The mortality rate among those men who walked <1 mile/day was nearly twice that among those who walked >2 miles/day. It was concluded that regular walking is associated with a lower overall mortality rate in older, physically capable men. For outpatients with stable CHD (n = 556), the 6-min walk test has been shown to provide independent and additive information beyond traditional risk factors and a discrimination ability similar to exercise capacity (peak METs) for predicting cardiovascular events over an 8-year follow-up, including HF, myocardial infarction, and death [14]. In adults ≥65 years with HF, impairment in gait speed (<0.8 vs. ≥ 0.8 m/s) was independently associated with heightened mortality (hazard ratio, 1.37), after adjusting for sociodemographic and potential clinical confounders [15].

Using data from the Concord Health and Ageing in Men Project, a cohort study of 1,705 healthy men ≥70 years of age living in several inner city suburbs in Sydney, Australia, researchers attempted to clarify the walking pace that may be associated with a heightened mortality [13]. At baseline, walking speed was carefully measured at the usual pace, documenting the fastest time from two trials. A natural walking speed of 2 miles per hour (mph) or 0.82 m/s was most predictive of early mortality, while older men who walked at speeds greater than this were less likely to die during the 6-year follow-up. In fact, no men who initially walked at speeds ≥3 mph or 1.36 m/s were among the 266 deaths reported [13]. Interestingly, the walking speed associated with the highest mortality was virtually identical to the gait speed (0.80 m/s) signifying the median life expectancy in a pooled analysis of 9 cohort studies using individual data from diverse populations (n = 34,485 community-dwelling older adults, ≥65 years; 59.6% women) with baseline gait speed data [12]. The pooled hazard ratio per each 0.1 m/s faster gait speed was 0.88 [12]. Collectively, these findings support the hypothesis that faster walking speeds are associated with increased survival, as has been previously reported in patients with stable CHD [14].

Why are walking speeds in older adults associated with mortality? A decreased walking speed may reflect greater underlying numbers and severity of unhealthy conditions linked to mortality, including CVD and cancer. A reduced walking speed may also serve as a surrogate marker for a high risk, inflammatory state in patients who may be less able to cope with the insults and metabolic derangements imposed by chronic and infectious diseases.

A reduced walking speed, as an index of gait ability, may partially reflect underlying vascular health parameters, such as arterial stiffness and intima media thickening. Arterial stiffness is primarily measured by carotid-femoral pulse wave velocity (cfPWV) or brachial-ankle pulse wave velocity, with higher PWV being a critical indicator of vascular aging and serving as an independent predictor of cardiovascular events and mortality [16]. Several studies have explored the association between walking speed and arterial stiffness in older adults. In the Whitehall II study of a large sample of adults aged 55–78 years (n = 5,392), lower walking speed was associated with higher cfPWV (coefficient: −0.67) after adjusting for confounding factors, including pulse pressure and mean arterial pressure [17]. Similarly, Gonzales et al. [18] demonstrated that poorer gait performance (distance and speed) using a 400-m walk test was associated with higher cfPWV, but not femoral artery stiffness index, in healthy older adults. Similarly, Ogawa et al. [19] also showed that among 492 older Japanese community dwellers (aged >65 years), poor walking speed was significantly associated with a higher brachial-ankle pulse wave velocity. These findings indicate that walking speed is closely associated with arterial stiffness in older adults, and understanding the link could insight into why gait ability serves as a predictor of CVD and mortality. However, a recent large, population-based study of community-dwelling older adults aged 75, 80, and 85 years did not find evidence for an association between PWV and walking capacity [20]. Therefore, longitudinal studies are needed to elucidate the association between arterial stiffness and walking performance.

Carotid plaques and higher common carotid artery-intima media thickness (IMT) values were associated with worse gait performance, with walking speed decreasing as common carotid artery-IMT and the number of plaques increased [21]. In the Whitehall II study, faster walking speed was linked to a reduced risk high coronary artery calcification (CAC) and lower IMT when compared to the slowest walkers, even after accounting for conventional risk factors in older adults without evident CVD [22]. There findings indicate that walking speed could be an indicator of underlying vascular disease.

On the other hand, the enhanced survival related to brisk walking (≥3 mph) may be attributed, at least in part, to the corresponding aerobic requirement (≥3.3 METs). It is highly likely that middle-aged and older adults who routinely walk at this pace have an aerobic capacity >5 METs, a CRF level that characterized men and women with reduced mortality [23, 24]. Nevertheless, clinical trials are needed before we can confidently state that increasing usual walking speed will improve survival outcomes in these population subsets [25].

Part 1 of this 2-part review summarizes the impact of structured exercise/PA interventions in individuals at risk for or with known atherosclerotic CVD, with specific reference to the cardiovascular and survival benefits of regular moderate-to-vigorous PA, improved CRF, and underlying mechanisms of benefit. In addition, we focus on relevant epidemiologic studies, gait speed and survival, and CRF and PA as separate risk factors. Additional sections examine the relations between CRF and PA on the impact or indices of CAC, incident atrial fibrillation (AF), and on mortality and sudden cardiac death (SCD).

Cardioprotective Benefits of Regular PA: Potential Underlying Mechanisms

Regular moderate-to-vigorous PA and/or structured exercise can decrease the risk of initial and recurrent cardiovascular events, presumably from multiple mechanisms, including anti-atherosclerotic, anti-ischemic, anti-arrhythmic, antithrombotic, and psychologic effects. Proposed mechanisms associated with the incremental and additive cardiovascular risk reduction benefits of vigorous-intensity exercise training (Fig. 1) [26].

Fig. 1.

Multiple mechanisms by which vigorous-intensity exercise training may be more effective than moderate-intensity exercise at reducing cardiovascular risk. Adapted from Franklin et al. [26].

Specific anti-ischemic effects include reducing myocardial oxygen demand by lowering the rate-pressure product at rest and during any given submaximal workload, as well as increasing the period of diastole, during which coronary perfusion predominates. Improved coronary blood flow and endothelial function have also been reported following exercise training [27]. Because >40% of the risk reduction associated with exercise cannot be explained by changes in coronary risk factors, a cardioprotective “vascular conditioning” effect, including enhanced nitric oxide vasodilator function, improved vascular reactivity, altered vascular structure, or combinations thereof, has been proposed [28]. Decreased vulnerability to threatening ventricular arrhythmias has also been postulated to reflect training-induced adaptations in autonomic control (i.e., decreased sympathetic drive and increased vagal tone) [29].

Beyond the long-term beneficial adaptions in vascular and structural remodeling among those who adopt a physically active lifestyle, exercise preconditioning provides immediate cardioprotective benefits and improved clinical outcomes following acute coronary events [30, 31]. This phenomenon offers a unique and undervalued non-pharmacologic approach to prevent and attenuate acute coronary syndromes. Specifically, acute bouts of aerobic exercise impose an isolated stress on the myocardium such that cellular biochemistry is favorably altered and an ischemic resistant phenotype is conferred, at least temporarily [30, 31]. These protective effects occur after just one to three bouts (e.g., 20–30 min) of moderate intensity exercise, and persist for several days to more than a week after the last exercise session. Researchers believe that the cardioprotective phenotype may be due to transiently altered biochemical pathways or enhanced cardiac electrical stability, and that higher intensity exercise does not bolster the magnitude of protection [30, 31]. Accordingly, it appears that regular increases in the rate-pressure product and somatic and cardiac metabolism evoked by moderate-to-vigorous PA can reduce subsequent infarct size and/or the potential for malignant ventricular arrhythmias triggered by acute myocardial ischemia [32]. This cardioprotective phenomenon represents an excellent “return on investment” in terms of the number of exercise days needed to evoke up to 9 or more days of robust protection following the most recent exercise bout [30].

CRF and PA as Separate Risk Factors: Comparative Benefits

Regular PA and increased levels of CRF, expressed as METs, are reported to be cardioprotective. However, an early meta-analysis concluded that these variables had significantly different relationships to CVD [33]. There was a 64% decline in the risk of heart disease from the least to the most fit, with a precipitous drop in risk comparing the lowest (0) to the next lowest fitness category (i.e., 25th percentile), but only a 30% decline from the least to the most physically active (Fig. 2). It was concluded that being unfit warrants consideration as an independent risk factor, and that a low level of CRF increases the risk of CVD to a greater extent than merely being physically inactive.

Fig. 2.

Risks of coronary heart disease and CVD decrease linearly in association with increasing percentiles of PA. In contrast, there is a precipitous drop in risk when the lowest is compared with the next lowest (25th%) category of CRF. Beyond this demarcation, the reductions in risk parallel those observed with increasing PA but are essentially twice as great for CRF. Adapted from Williams [33]. Reprinted with permission from the American Heart Association.

In a similarly study, Myers et al. [23] compared estimated CRF versus self-reported PA patterns in predicting ACM in 6,213 consecutive men (mean ± SD age = 59 ± 11 years) who were referred for exercise testing. Over an average follow-up of 5.5 ± 2 years, estimated CRF, based on the peak attained treadmill speed and grade, using age-specific quartiles, was a stronger predictor of mortality than was self-reported PA. Interestingly, a 1,000 kcal/week increase in PA was similar to a 1 MET increase in CRF; both conferred a mortality benefit of 20%.

However, others contend that with “self-reported” PA assessments, the magnitude of associations with health outcomes are significantly underestimated, especially when compared with accelerometry measured PA [34, 35]. Tikkanen et al. [36] evaluated the associations of CRF, PA, grip strength, and genetic risk with atherosclerotic CVD in a longitudinal analyses (median follow-up, 6.1 years) of 502,635 individuals from the UK Biobank. Although PA and CRF were inversely associated with atherosclerotic CVD, including individuals at high genetic risk for CVD, accelerometry-based PA showed the strongest inverse association for risk of premature death.

Recently, using wrist-worn accelerometry data from the UK Biobank, researchers evaluated the association of moderate-to-vigorous intermittent lifestyle PA bouts on major adverse cardiovascular events and mortality in people who reported no leisure-time exercise [37]. Over a mean follow-up of 7.9 ± 0.9 years, results showed that moderate-to-vigorous PA accrued through short bouts of activities of daily living was associated with a decrease in mortality and major cardiac event rates. Associations of 1 to <5 min bouts of moderate-to-vigorous incidental lifestyle PA with mortality and major cardiac events were comparable in magnitude to those of 5 to <10 min bouts, and more favorable than bouts of <1 min. Higher proportions of vigorous PA (>12–15%) strengthened the associations across all bout lengths in a dose-response manner. The authors concluded that intermittent lifestyle PA bouts as short as 1 to <5 min were associated with reductions in ACM and major adverse cardiovascular events among adults who do not exercise in their leisure time. These findings offer habitually sedentary individuals a viable alternative when structured exercise is not a feasible, appealing, or accessible option.

Collectively, these data and previous reports [38] suggest that brief bouts of intermittent lifestyle PA promote health and survival benefits. Moreover, because of the precision of accelerometry measurements, we now realize that the magnitude of association between PA and good health is larger than previously known from the self-report studies. In fact, it appears that no dose of PA is too small to mitigate declines in health and function with passing years [39].

CRF, PA and CAC: Implications regarding CVD Events and Mortality

CAC is closely associated with advanced atherosclerosis and a predictor of cardiovascular events [40]. The relationship between CRF and CAC has garnered significant interest in the field of cardiovascular health because both are crucial indicators of cardiovascular events and mortality, making it important to understand how these two factors are related. In an early study by Lee et al. [41], involving a 2,373 African-American and White young adults from the Coronary Artery Risk Development in Young Adults Study, high levels of CRF were associated with a lower risk of coronary calcification 15 years later. In another study involving a cohort of 5,341 women, higher CRF levels were modestly inversely associated with the presence and progression of CAC [42]. Furthermore, more recent studies have shown that being fit is associated with a reduced risk of significant CAC in individuals with metabolic syndrome [43]. Additionally, higher CRF was associated with lower Agatston and volume scores after adjusting for potential confounders [44].

Paradoxically, maximal CRF was associated with increased atherosclerosis, as established by CAC scores, with plaque burden significantly increased in patients with the highest exercise capacity level compared to the above-average group [45]. Nevertheless, higher CRF is consistently associated with a lower risk of CVD mortality, regardless of CAC scores. Researchers from the Cooper Center Longitudinal Study reported that among 8,245 asymptomatic men, over an average follow-up of 8.4 years, CVD events increased with increasing CAC and decreased with increasing CRF [46]. After adjusting for CAC level, each 1-MET increase in CRF was associated with an 11% decreased risk of CVD events (hazard ratio 0.89, 95% confidence interval [0.84–0.94]) irrespective of CAC score at baseline. Moreover, compared with the least-fit men, CVD events were progressively reduced with increasing CRF levels, and the effect was more prominent in men with the highest levels of CAC [46].

While PA is widely recognized for its cardioprotective effects, recent research has revealed a complex relationship between PA and CAC, particularly with varying exercise intensities and volumes. In a large study involving 25,485 participants, Sung et al. [47] found that higher PA, especially among those categorized as health-enhancing physically active, was associated with a faster progression of CAC, regardless of baseline scores. This paradoxical finding suggests that while PA is beneficial for cardiovascular health, it may also contribute to increased CAC over time, particularly at higher activity levels. Aengevaeren et al. [48] demonstrated mixed results, showing that vigorous-intensity exercise was associated with less CAC progression, whereas very-vigorous-intensity exercise was linked to an increase in both CAC and calcified plaque progression. Interestingly, exercise volume alone was not associated with changes in CAC, indicating that intensity, rather than volume, plays a role in modulating calcification. However, a contrasting result was provided by Pavlovic et al. [49], who examined the roles of exercise intensity versus duration in relation to CAC. Their study, involving 23,383 men, revealed that higher exercise intensity was associated with lower mean CAC, while longer durations of PA were linked to increased mean CAC. Adding further complexity, Shuval et al. [50] studied a large cohort of 8,771 healthy men and women aged 40 years and older who participated in multiple preventive medicine visits at the Cooper Clinic. With a mean follow-up time of 7.8 years between their first and last clinic visit, they observed no significant association between PA volume and CAC progression. Therefore, high-volume PA does not necessarily exacerbate CAC.

Why are high-volume PA/exercise linked to CAC? The potential mechanisms linking high-volume exercise to increased CAC remain unclear, but it has been hypothesized that exercise-induced hypertension, greater exposure to inflammatory factors, reactive oxygen species, elevated parathyroid hormone levels, and non-laminar blood flow in the coronary arteries may contribute to calcification, particularly in individuals with pre-existing atherosclerosis. These factors might be responsible through innumerable combinations [51].

On the other hand, Yoo et al. [52] explored the association between PA, CAC presence, and cardiovascular mortality (CVM). Their cohort study found that individuals with CAC had higher CVM rates, regardless of their PA levels. This finding emphasizes the importance of monitoring CAC in physically active individuals, as the presence of CAC may diminish some of the cardiovascular benefits typically associated with high levels of PA. In contrast, in a large cohort of asymptomatic men (n = 21,758) with more than a decade of follow-up in the Cooper Clinic Longitudinal Study, those with very high levels of PA (n = 432; ≥3,000 MET – min/week) had a higher prevalence of CAC score ≥100 as compared with those performing less PA [53]. However, the risk of all-cause and CVM among those with PA ≥3,000 MET – min/week and CAC score ≥100 was similar to those with PA <1,500 MET – min/week (hazard ratio 0.77, confidence interval 0.52–1.15), and it was lower than the least active cohort with similar CAC scores.

Collectively, these findings refute the notion that high-volume, high-intensity endurance training regimens increase mortality risk, regardless of the CAC level, and suggest that highly active individuals with an elevated CAC score or “hearts of stone” can generally continue their vigorous exercise programs, provided they remain asymptomatic [54]. Countering cardioprotective training adaptations may include a lower prevalence of vulnerable mixed plaques, increased coronary artery size and dilating capacity, and higher aerobic capacity, which may nullify the potentially deleterious impact of an elevated CAC score [55]. Accordingly, the risk for adverse cardiovascular outcomes, including nonfatal and fatal events, is lower in fit, physically active people than their unfit, inactive counterparts with the same CAC score.

Relation between CRF and Indices of CAC

Because the Agatston and volume scores for CAC are positively associated with an increased risk of atherosclerotic CVD, whereas the CAC density score, representing stabilized coronary plaques, is negatively associated with CVD risk [56], Jae et al. [57] evaluated whether higher levels of CRF, directly measured by expired gas analysis, expressed as VO₂ peak, correlated with varied CAC scoring indices. The study population involved a large cohort (n = 2,080) of middle-aged and older men (mean ± SD age, 53 ± 6 years; range, 40–78 years) who had no history of CHD, all of whom had measures of CAC and CRF. All were part of a comprehensive health screening program at Samsung Medical Center (Seoul, Republic of Korea). In a subgroup analysis (n = 1,179 participants [Agatston score, >0]), the highest CRF cohort had lower ORs for having advanced Agatston and volume CAC scores but greater ORs for having an advanced CAC density score than the lowest CRF quartile. With each 1 MET increment, higher VO₂ peak was associated with calculated ORs and 95% confidence intervals (CIs) of OR, 0.82; 95% CI, 0.72–0.93, OR, 0.79; 95% CI, 0.69–0.90, and OR, 1.44; 95% CI, 1.27–1.64, for advanced Agatston, volume, and advanced CAC density scores, respectively. Collectively, these data suggest that high CRF may attenuate coronary calcification and increase plaque stabilization, potentially reducing the risk of acute cardiac events in men. Similarly, other studies have shown that although endurance athletes >35 years of age have elevated CAC scores [58, 59], they also demonstrated predominately stable calcified plaques and fewer mixed vulnerable plaques, suggesting a plaque morphology more resistant to disruption. On the other hand, a recent study concluded that long-term endurance sports participation is not associated with a more cardioprotective coronary plaque composition [60]. Methodologic differences with the aforementioned reports may account for this discordant finding.

CRF and PA as Modulators of AF

AF is a cardiac arrhythmia characterized by chaotic electrical activity that replaces normal sinus rhythm during which the atria may contract very rapidly and irregularly. The incomplete contractions allow blood to pool and clots to form in the atria which can travel to the brain, lung, or periphery and cause a stroke, pulmonary embolism, or other life-threatening vascular event, respectively. Accordingly, AF is associated with increased morbidity and mortality [61, 62].

Today, AF is the most commonly treated cardiac arrhythmia in clinical practice, accounting for approximately one-third of US hospital admissions for cardiac rhythm disorders [63]. Conventional risk factors for AF include increasing age, structural heart disease, hypertension, overweight/obesity, diabetes mellitus, excessive alcohol intake, and obstructive sleep apnea. However, recent studies suggest that low levels of CRF and that high-volume, high-intensity endurance training regimens are associated with an increase in the incidence of AF independent of the aforementioned conventional contributing factors.

Individuals with low levels of estimated CRF (<6 METs) demonstrate a higher risk for AF, whereas their counterparts with higher levels of CRF (7.9 ± 1.0 and 9.3 ± 1.2 METs) exhibit a dose-dependent decrease in AF risk [64, 65]. Faselis et al. [65] evaluated the association between estimated CRF, derived from graded treadmill exercise using the Bruce protocol, and the incidence of AF in 5,962 Veterans (mean ± SD age, 56.8 ± 11.0 years). During a median follow-up period of 8.3 years, peak METs were inversely related to AF incidence. For every 1-MET increase in exercise capacity, the risk for developing AF was 21% lower. Fitness was further stratified into quartiles (least-fit, moderate-fit, fit, high-fit), with the least-fit group serving as the referent. The risk of developing AF progressively decreased, ranging from 20%, 45%, and 63% lower for the moderate-fit, fit and high-fit categories, respectively (Fig. 3). A similar inverse relationship between CRF and incident AF was reported in the FIT Project, but was even more pronounced in obese participants [64]. Although these data suggest that fitter individuals have the lowest AF risk, numerous epidemiologic and observational studies in middle-aged and older adults have reported a statistically significant association between chronic high-volume, high-intensity exercise training, and a heightened risk of developing AF [66, 67].

Fig. 3.

Risk of developing atrial fibrillation (AF) according to progressive levels of exercise capacity. The risk of developing AF decreased with increasing categories of CRF, ranging from 20% lower for individuals in the moderate fitness category (6.7 ± 1.0 METs) to 45% lower for fit individuals (7.9 ± 1.0 METs) and 63% lower for those in the highest-fit group (9.3 ± 1.2 METs). Adapted from Faselis et al. [65].

The Cardiovascular Health Study including 5,446 older men and women (≥65 years) examined associations of leisure-time PA and the incidence of AF [68]. Overall, 1 in 5 study subjects developed AF during the 12-year follow-up. As compared with no regular exercise, AF incidence was progressively lower with light- and moderate-intensity PA, but not with high-intensity exercise where AF began to increase, demonstrating the familiar J-shaped relationship.

In the US Physician’s Health Study, men who jogged 6 ± 1 times per week had a 50% higher risk of AF than men who did not exercise vigorously, even after adjustment for multiple cardiovascular risk factors [69]. Others, combining multiple reports through meta-analyses, found that regular endurance exercise increases the likelihood of developing AF by 2–10 fold as compared with control participants, even after adjusting for potential confounding variables and risk factors [70–72]. In other related studies [73, 74] investigators reported that the long-term volume of vigorous endurance exercise (i.e., ≥2,000 h of training or ≥20 years of training) was strongly associated with an increased risk for lone AF. Although the underlying mechanisms remain unclear, the combination of autonomic, structural, and hemodynamic effects of high-volume, high-intensity aerobic exercise, repeated over time, likely impart some of the increased risk for AF (Fig. 4) [66, 67]. Fortunately, much of the risk seems to resolve with detraining and/or exercising at more moderate intensities, presumably because of the normalization of atrial structure and neural tone [75].

Fig. 4.

Potential mechanisms and associated sequelae for AF induced by strenuous endurance exercise. The combination of autonomic, structural, and hemodynamic effects of high-volume, high-intensity aerobic exercise, repeated over time, likely impart some of the increased risk for AF. Adapted from Eijsvogels et al. [66] and Franklin et al. [67]. Reprinted with permission from the American Heart Association.

Collectively, these findings suggest that the relation between CRF, PA, and incident AF is complex. Higher levels of CRF, generally estimated from peak or symptom-limited exercise test time/workload, are associated with a reduced risk of developing AF. In contrast, lower levels of CRF (<6 METs) are associated with a higher risk for AF. Moreover, both low and very high volumes of exercise training are associated with an increased risk for AF, whereas light-to-moderate exercise volumes appear to reduce risk.

Modulating Impact of CRF on Mortality, SCD, and AF

Jae et al. [76] evaluated the dose-response relationship between CRF and selected cardiovascular outcomes, with specific reference to the “threshold of benefits” due to increasing levels of aerobic capacity. The study population included 2,368 middle-aged men (aged 42–61 years) from an ongoing population-based prospective cohort investigation in eastern Finland (the Kuopio Ischemic Heart Disease Study). CRF was directly measured during an electrically braked progressive cycle ergometer test to volitional fatigue/exhaustion, and expressed as peak metabolic equivalents or METs, where 1 MET = 3.5 mLO₂/kg/min. Cardiovascular outcomes included ACM, CVM, SCD, and AF obtained from hospital notes and varied creditable clinical/demographic sources. During a median follow-up of 25 years, and after adjusting for potential confounders, results indicated that there was no upper limit of ACM benefit associated with increasing levels of CRF. This finding is in line with other reports of no upper threshold for ACM benefit associated with increasing levels of estimated CRF [77–79]. In other words, the higher the CRF, the lower the subsequent ACM. The upper threshold of CVM, SCD, and AF benefits occurred at 9.9 METs, suggesting that this fitness level confers multiple cardioprotective effects in middle-aged men. Moreover, in view of the fact that CRF is highly reflective of habitual PA, these findings are also consistent with previous studies showing that high-volume, high-intensity levels of PA likely increase the risk of AF [80].

Implications for the Clinician

Regular moderate-to-vigorous-intensity exercise has been described as “a miracle drug that can benefit every part of the body and substantially extend lifespan” [81]. Part 1 of this 2-part review describes how regular PA and increased CRF have a profound and favorable impact on preventing and treating atherosclerotic CVD, with specific reference to relevant epidemiologic studies, walking metrics as prognostic indices in persons with and without CVD, the immediate (i.e., exercise preconditioning) and long-term cardiovascular benefits of moderate-to-vigorous PA, as well as their impact on CAC related cardiovascular events and morphology, AF, SCD, and mortality. Part 2 will expand on these topics and provide evidence-based exercise thresholds that the medical community can embrace and promote. If the salutary impact of regular exercise is to be applied and optimized, the prescription at present remains woefully underfilled. Thus, the medical community should embrace this clinically proven, readily accessible, and cost-effective strategy as a first-line therapy to prevent and treat the skyrocketing prevalence of atherosclerotic CVD.

Acknowledgment

Our thanks to Christie R. Radden for her invaluable help with the preparation, formatting, and serial revisions of this 2-part review, laboriously checking the accuracy of our citations.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

The authors received no financial for the authorship and/or publication of this article.

Author Contributions

Barry A. Franklin: concept, literature search, and write the manuscript; Sae Young Jae: critical review and final draft writing.

Funding Statement

The authors received no financial for the authorship and/or publication of this article.