Exercise, Physical Activity, and Cardiometabolic Health: Insights into the Prevention and Treatment of Cardiometabolic Diseases

Abstract

Physical activity (PA) and exercise are widely recognized as essential components of primary and secondary cardiovascular disease (CVD) prevention efforts and are emphasized in the health promotion guidelines of numerous professional societies and committees. The protean benefits of PA and exercise extend across the spectrum of CVD, and include the improvement and reduction of risk factors and events for atherosclerotic CVD (ASCVD), cardiometabolic disease, heart failure, and atrial fibrillation, respectively. Here, we highlight recent insights into the salutary effects of PA and exercise on the primary and secondary prevention of ASCVD, including their beneficial effects on both traditional and non-traditional risk mediators; exercise “prescriptions” for ASCVD; the role of PA regular exercise in the prevention and treatment of heart failure; and the relationships between, PA, exercise and atrial fibrillation. While our understanding of the relationship between exercise and CVD has evolved considerably, several key questions remain including the association between extreme volumes of exercise and subclinical ASCVD and its risk; high-intensity exercise and resistance (strength) training as complementary modalities to continuous aerobic exercise; and dose- and intensity-dependent associations between exercise and atrial fibrillation. Recent advances in molecular profiling technologies (i.e., genomics, transcriptomics, proteomics, and metabolomics) have begun to shed light on inter-individual variation in cardiometabolic responses to PA and exercise and may provide new opportunities for clinical prediction in addition to mechanistic insights.

Introduction

While cardiovascular disease (CVD) remains the leading cause of death globally and in the United States,^1,2 a majority of CVD mortality can be attributed to a small number of modifiable risk factors.³ Among these, physical inactivity and sedentary behavior independently contribute to adverse CVD outcomes and are also closely linked with several metabolic risk factors, including obesity, diabetes, dyslipidemia, and hypertension.⁴ Physical activity (PA) and exercise are inversely associated with CVD in a manner that does not appear to have a threshold of effect, with benefits continuing to accrue as PA levels increase.^5,6 Beyond the health benefits associated with PA and exercise, there are substantial costs associated with physical inactivity, which places an enormous burden on the healthcare system. In the United States, physical inactivity is estimated to cost $117 billion yearly, representing more than 11% of total health care expenditures.⁷

Despite the abundance of evidence supporting the salutary effects of regular PA on cardiometabolic health and the emphasis placed on PA and exercise in health promotion guidelines,^6,8,9 a significant portion of the population engages in PA levels far below the recommended amounts.¹⁰ Only 1 out of 4 adults in the United States report participating in the minimum amount of aerobic activity and resistance training recommended by the latest Physical Activity Guidelines for Americans.² While some concerns about the risks of high levels of vigorous activity have been raised,^11,12 the evidence overwhelmingly supports that regular PA and exercise training (ET) in both health and disease states is safe and should form one of the cornerstones of a healthy lifestyle. In this review, we first focus on PA and exercise in the primary and secondary prevention of atherosclerotic CVD (ASCVD). We also explore the effects of PA and ET on traditional and non-traditional mediators of CVD, concerns regarding extreme volumes of exercise and the development of subclinical atherosclerosis, and the exercise prescription for patients with ASCVD. Next, we discuss the emerging body of evidence that supports regular exercise for the prevention and treatment of heart failure (HF), including its role in individuals with HF with reduced and preserved ejection fractions (HFrEF and HFpEF, respectively). Finally, we discuss recent advances that have enhanced our understanding of the complex relationship between exercise and atrial fibrillation.

Primary Prevention of ASCVD

Effects of physical activity and exercise on mediators of ASCVD

Hypertension

The ability of PA and regular exercise to lower the risk of incident hypertension and to reduce blood pressure among adults with hypertension is well-established.^13–16 In particular, numerous efforts have investigated the efficacy of either aerobic exercise or dynamic resistance training on blood pressure reduction among adults with hypertension.^13,17,18 Recent systematic reviews and meta-analyses suggest that aerobic exercise and dynamic resistance training reduce blood pressure in adults with hypertension by 5–7 mm Hg and 2–3 mm Hg, respectively.¹⁹ The magnitude of blood pressure reduction achievable through ET in adults with hypertension may be comparable to that of anti-hypertensive medications²⁰ and can translate into significant ASCVD risk reduction.^13,19

While areas of debate remain, including the comparative effectiveness of different intensities and modalities of ET on blood pressure,^21–24 the effects of PA and ET on blood pressure are supported by a convincing body of evidence. A recent umbrella systematic review and meta-analysis by Pescatello et al.²⁴ synthesized observational data examining the effects of PA on both incident hypertension and health outcomes in adults with hypertension, as well as randomized controlled trials (RCTs) examining the effects of various ET interventions on blood pressure reduction, and reached several conclusions regarding PA and ET (grouped together as PA in this meta-analysis). First, PA reduces blood pressure in adults regardless of one’s baseline blood pressure. Second, the magnitude of blood pressure reduction from PA depends on baseline blood pressure status: 5–8 mm Hg, 2–4 mm Hg, and 1–2 mm Hg for adults with hypertension, prehypertension, and normotension, respectively. Among adults with normotension, PA is inversely associated with incident hypertension in a dose-response manner with no observed cutoff of benefit. Finally, PA reduces the risk of CVD progression among adults with hypertension.

Dyslipidemia

Regular exercise has significant effects on lipids, including fasting triglycerides and HDL-C.²⁵ Regular exercise increases HDL-C,²⁶ with additional studies demonstrating increases in HDL₂-C and HDL particle size.^27,28 Few studies have demonstrated beneficial changes in LDL-C concentration in response to exercise, however some evidence suggests a favorable shift toward larger, less atherogenic LDL-C subfractions.^28–30

Exercise-induced improvements in lipids occur in a dose-response manner,²⁸ however, different intensities and modalities may have variable effects on lipoprotein classes.^31–33 For example, moderate-intensity exercise may have a greater impact on serum triglycerides, while high-intensity exercise may impart greater effects on HDL-C, although additional investigation is needed to confirm these findings.²⁵ Further, the impact of weight changes in response to ET must also be considered when interpreting exercise-induced lipid responses. ET that results in at least modest weight loss in overweight or obese individuals results in greater improvements in lipids, including reduced triglycerides and larger HDL- and LDL-particle size.³⁴ While high-intensity interval training (HIIT) has been shown to benefit several cardiometabolic disease risk factors its effects on lipids have not been established.^35,36

Diabetes and metabolic syndrome

Both aerobic exercise and resistance training confer improvements in metabolic parameters in people with type 2 diabetes (T2DM), including fasting glucose, insulin resistance, and HbA1c.^37–41 Moreover, aerobic exercise and resistance training appear to have additive effects on glycemic control,^42–47 forming the basis for the recommendation from the American Diabetes Association that all patients with T2DM incorporate both endurance and resistance modalities in a regular exercise program to optimize metabolic health.³⁹ Indeed, in a randomized trial of 606 adults with T2DM, improvements in CRF from combined aerobic and resistance training were associated with significant improvements in HbA1c, insulin resistance, HDL-C, and waist circumference.⁴⁸ The benefits of PA and ET also extend to prevention, with numerous prospective cohort and cross-sectional studies suggesting an inverse relationship between PA and incident diabetes.^49,50 However, while PA in conjunction with dietary modification clearly reduces the risk of progression to T2DM in individuals with impaired glucose tolerance, additional randomized trials are needed to assess whether PA alone may produce the same benefits.⁵¹

Recent efforts have focused on whether more vigorous exercise interventions may induce greater cardiometabolic benefits in patients with diabetes or metabolic syndrome.⁵² A meta-analysis of 50 studies including a total of 2,033 participants, found that HIIT improved insulin resistance to a greater extent compared with continuous training interventions, with more pronounced benefits in individuals with T2DM.⁵³ A subsequent meta-analysis found that HIIT improved CRF to a greater capacity compared with moderate-intensity continuous training in adults with prediabetes or T2DM but did not provide additional benefits in HbA1c or fasting glucose.⁵⁴ In contrast, a meta-analysis of 24 studies including 962 participants with T2DM found that high-intensity resistance training (defined as one-repetition maximum between 75–100%) led to a larger reduction in HbA1c and insulin concentrations compared to low- to moderate-intensity resistance training.⁵⁵ Given the challenges of sustained adherence to any ET modality, there is great interest in further understanding the relative effectiveness of more time-efficient interventions - such as HIIT - to cardiometabolic health.⁵⁶

Obesity

Numerous observational studies have shown an inverse association between PA and weight gain over the lifecourse.⁵⁷ A notable prospective cohort study of 34,000 healthy women in the United States followed for 13 years found that 60 minutes of daily moderate-intensity exercise was needed to maintain a normal weight (defined as a BMI < 25).⁵⁸ Another prospective cohort study of more than 12,000 active male and female runners postulated that in order to compensate for age-related weight gain, an individual’s average weekly mileage may need to increase annually by 2.8 miles/week for men and 3.8 miles/week for women.⁵⁹ While there appears to be a dose-response, inverse relationship between PA and weight gain, the amount of PA needed to prevent adverse weight changes remains unclear.⁶⁰ The 2018 Physical Activity Guidelines Advisory Committee Scientific Report evaluated the totality of data and concluded that there is strong evidence to support an inverse relationship between PA and weight gain in adults, with the greatest effects most likely to be observed at doses > 150 minutes/week.⁵⁷

The cornerstone of obesity treatment involves lifestyle interventions that increase energy expenditure through PA and ET and decrease energy intake through adherence to caloric restriction and a healthful diet.⁶¹ Total daily energy expenditure is comprised of three components: resting metabolic rate, diet-induced thermogenesis, and PA/exercise. PA and ET interventions in isolation - although resulting in increased energy expenditure - are often ineffective at inducing weight loss due to intrinsic homeostatic mechanisms that drive compensatory increases in energy intake.⁶² The majority of evidence demonstrates that adherence to a daily exercise program resulting in > 2000 kcal/week of energy expenditure is required to result in clinically significant weight loss (defined as 5–10% of total body weight) in the absence of other lifestyle changes, however several individual factors influence outcomes.^63–65

Still, ET interventions resulting in modest weight loss (i.e., 3–5% of total body weight) as well as those independent of weight loss have demonstrated significant improvements in several cardiometabolic health markers in adults with overweight or obesity.^34,64,66 Nonetheless, the 5–10% threshold target for weight loss may confer more significant improvements in cardiometabolic risk factors and CVD outcomes.⁶⁶ For example, a secondary analysis of the Look AHEAD trial, in which 5,145 overweight or obese adults with T2DM were assigned to an intensive lifestyle intervention that included dietary modifications and exercise, demonstrated that individuals who lost 10% of their total body weight in the first year of the trial had an approximately 20% CVD risk reduction over roughly 10 years of follow-up.⁶⁷

Non-traditional risk factors

The mechanistic underpinnings of several cardiometabolic adaptations to PA and ET outside of traditionally recognized biological pathways of CVD are explored in Part I of this review, including the reversal of cardiac and vascular stiffness, improved endothelial function, myokine signaling, and attenuation of systemic inflammation. Fiuza-Luces et al.⁶⁸ also recently explored the effects of PA and ET on non-traditional mediators of cardiometabolic disease, including atherosclerotic plaque morphology, circulating angiogenic cells, sarcopenia, autonomic balance, and the microbiome which are beyond of the scope of this review.

The relationship between heart rate variability (HRV) and exercise highlights the potential beneficial effects of PA and ET on non-traditional risk factors. Diminished HRV is associated with adverse cardiovascular outcomes and increased all-cause mortality.^69,70 In an analysis of roughly 2,500 Framingham Heart Study participants without clinically apparent CVD, reduced HRV was associated with an increased risk of CVD events after multivariate adjustment.⁶⁹ A subsequent meta-analysis of 8 studies involving more than 20,000 participants without known CVD concluded that low HRV is associated with a roughly 40% increased risk of an adverse cardiovascular event.⁷¹ Physical activity and aerobic exercise are associated with increased HRV,^72,73 including in high-risk groups, such as adults with T2DM.⁷⁴ While there is strong evidence that ET modulates HRV, the precise mechanisms through which this occurs - including its effects on vagal tone - remain incompletely understood.⁷⁵ Furthermore, the impact that exercise-induced HRV improvements have on long-term CVD outcomes requires further study.⁷⁶

Recently, the ability to classify an individual’s risk of ASCVD using genetic risk scores derived from genome-wide association studies (GWAS) has garnered attention.⁷⁷ ASCVD polygenic risk scores have been applied to large observational cohorts in which genotyping information is available to evaluate the efficacy of lifestyle interventions to attenuate genetic CVD risk. One such study analyzed data from over 500,000 UK BioBank Study participants and found that individuals in the highest tertile of coronary heart disease (CHD) risk based on a polygenic risk score had a significantly increased risk of incident CHD compared with those in the lowest tertile (HR 1.77; 95% CI, 1.67–1.87).⁷⁸ However, among individuals within the highest genetic risk group, high CRF conferred a nearly 50% decreased risk of CHD compared with low CRF. This study adds to the emerging body of evidence that suggests the inherited risk of ASCVD may be significantly attenuated by lifestyle and behavioral factors, including habitual PA, ET, and improving CRF.

Regular exercise training and ASCVD outcomes

The advent of molecular profiling has brought renewed attention to understanding inter-individual cardiometabolic responses to ET,^79–81 yet the cardiovascular health benefits at the population level are indisputable. The landmark INTERHEART case-control study evaluated the relationship between several common risk factors and cardiovascular health, including PA and ET, in participants across 52 countries spanning all 7 continents.⁸² In this study, individuals that reported regular exercise led to a significantly reduced risk of CVD compared to those who did not exercise (adjusted OR 0.86; 99% CI, 0.76–0.97). The value of regular exercise across the lifespan for CVD risk reduction was further underscored in a cross-sectional study of 12,440 participants that characterized an individual’s exercise pattern over a period of 32 years.⁸³ The investigators found that CVD prevalence was lower across all quantities of exercise compared with non-exercise in a curvilinear pattern. While the greatest CVD risk reduction was observed in the third quintile of estimated exercise dose (adjusted OR 0.36; 95% CI, 0.28–0.47), even the lowest active quintile of exercise conferred a significant reduction in CVD compared with non-exercisers. Indeed, a previous study demonstrated that as little as 15 minutes of daily, moderate-intensity exercise reduced the risk of all-cause mortality by 14% and was associated with a 3 year longer life expectancy than sedentary individuals.⁸⁴ Importantly, these findings remained significant in individuals with CVD risk factors, including diabetes, hypercholesterolemia, hypertension, metabolic syndrome, and chronic kidney disease.

High-volume exercise and subclinical atherosclerosis

While PA and exercise are unlikely to increase the risk of coronary artery calcification (CAC) at the general population level, extreme endurance ET (such as long-term marathon running) may confer an increased risk of higher CAC in a small percentage of athletes.⁸⁵ In a cross-sectional analysis of 108 healthy marathon runners ≥50 years who had completed 5 or more marathons in the preceding three years, the percentage of marathon runners with a CAC score $\ge$100 Agatston units (AU) was significantly greater than age- and risk factor-matched controls (36.1% vs 21.8%, P = 0.01).⁸⁶ Another small cross-sectional study of 152 masters athletes (77% runners, median 13 lifetime marathons per athlete) with a low 10-year ASCVD risk profile found that masters athletes were more likely to have a CAC score ≥300 AU compared with age- and risk-factor matched sedentary controls (11.3% vs 0%, P =0.009).⁸⁷ These findings were supported by Aengevaeren et al.⁸⁸, who categorized 284 amateur athletes by lifelong exercise volume and found a greater prevalence of CAC scores $\ge$100 AU among those in the highest tertile of exercise volume (>2000 MET-min/week) compared with athletes in both the middle (1000–2000 MET-min/week) and lowest tertiles (<1000 MET-min/week). Most recently, Defina et al.⁸⁹ performed a large prospective cohort study including more than 20,000 men and found that a CAC score $\ge$100 AU was more prevalent among men engaged in at least 3000 MET-min/week of endurance exercise compared with those reporting lower amounts of PA, although the risk increase was relatively small (RR 1.11; 95% CI, 1.03–1.20).

It is important to note that the prognostic significance of increased CAC among masters endurance athletes with increased CAC remains uncertain. Several findings suggest that the implications of CAC in high-volume exercisers may be fundamentally different than CAC in sedentary individuals.⁹⁰ In the study by Defina and colleagues, men in the highest exercise tertile (3000 MET-min/week) with a CAC score of ≥100 AU did not have higher all-cause or CVD mortality over more than 10 years of follow-up.⁸⁹ Instead, there was a trend towards lower risk compared to individuals with CAC scores <100 AU performing fewer than 1500 MET-min/week of PA.⁸⁹ Notably, the mean PA level in the highest-volume exercise group was more than 4600 MET-min/week (equivalent to running 6 miles/day at a pace of 10 min/mile), which provides support that volumes of endurance exercise that exceed current health promotion guidelines do not confer an increased risk of mortality. Furthermore, Aengevaeren et al.⁸⁸ demonstrated that the plaque composition of adults with very high levels of PA are more likely to be densely calcified and indicative of a more benign plaque profile. Taken together, these findings raise the possibility that high-level aerobic endurance training may promote plaque stability, offering a possible mechanism contributing to lower levels of CVD morbidity and mortality in this population.⁹¹ Routine assessment of CAC in asymptomatic athletes with low ASCVD risk is not recommended, and specific guidelines for additional testing in asymptomatic athletes with established high CAC scores are based largely on expert opinion due to insufficient data but are an ongoing area of investigation.^12,92

Secondary Prevention of ASCVD

Physical activity and ET are safe and highly effective components of ASCVD secondary prevention. In a landmark study of 15,486 adults with stable CHD from different countries, habitual exercise was associated with a graded decrease in all-cause and CVD mortality.⁹³ Furthermore, a doubling of exercise volume and duration were each associated with lower adjusted all-cause mortality (HR: 0.90; 95% CI, 0.87–0.93 and HR: 0.92; 95% CI, 0.88–0.96, respectively).⁹³ A recent population-based study of over 400,000 Korean adults with and without CVD demonstrated an inverse relationship between PA level and all-cause mortality in both groups.⁹⁴ Notably, the survival benefit from higher PA levels (i.e., above 500 MET-min/week) was greater for the secondary prevention group than for those without CVD. Interestingly, the mortality risk of participants with CVD who performed high PA levels was lower than that of sedentary participants without CVD.

Role of cardiac rehab

After an acute cardiovascular event, enrollment in a cardiac rehabilitation (CR) program is an essential component of secondary prevention. Supervised ET is one of the foundational components of CR, in addition to comprehensive education, counseling, and support services to address modifiable CVD risk factors.⁹⁵ CR has been demonstrated to improve survival, decrease the incidence of recurrent CVD-related events and hospitalizations, and improve well-being and quality of life.⁹⁶ A meta-analysis of 63 studies (n=14,486) demonstrated that exercise-based CR for CHD resulted in reduced cardiovascular mortality (RR 0.74; 95% CI, 0.64–0.86) and hospital admissions (RR 0.82; 95% CI, 0.70–0.96) compared with control subjects.⁹⁷

There is a dose-response relationship between number of CR sessions attended and improved health outcomes,⁹⁸ and the greatest benefits occur in patients that are adherent to a full program⁹⁹ (typically 3 sessions/week for 12 weeks in the United States). However, recent evidence suggests that assessment of CRF progression may provide additional prognostic information beyond attendance and program completion. For example, a retrospective cohort study of 1,171 patients with CHD found significant variation in the degree of improvement in CRF after CR, and further demonstrated that high CRF response was associated with reduced mortality compared with low- or non-response.¹⁰⁰ Additionally, a retrospective cohort study of more than 5,600 patients with CHD who completed a 12-week CR program demonstrated a 25% reduction in mortality at 1 year for each MET increase in CRF (HR 0.75; 95% CI, 0.67–0.83).¹⁰¹ Further studies are needed to evaluate the clinical utility of measuring CRF as a response metric to identify patients that are at greater risk of adverse outcomes after completion of a CR program.

Despite the established efficacy of CR on health outcomes, a significant proportion of eligible individuals are not enrolled. Overall participation rates in the United States for patients that merit referral to CR is estimated to be between 20–30%, which has prompted large-scale initiatives to increase the number of individuals that utilize these services.¹⁰² Moreover, significant disparities in CR utilization rates have been observed based on race, gender, age, and socioeconomic status.^103–105 Numerous strategies have been explored to improve enrollment and adherence rates, including systems-based approaches (e.g., automatic referral for hospitalized patients meeting eligibility requirements)¹⁰² and individual-level approaches (e.g., financial incentives programs to improve adherence rates).¹⁰⁶

Moreover, traditional center-based CR (CBCR) programs may pose logistical barriers to participation for some individuals. An emerging body of evidence has highlighted the potential efficacy of home-based CR (HBCR) - used either alone or as a hybrid model with CBCR- to mitigate roadblocks to participation.¹⁰⁷ Several other countries, including Australia, Canada, and the United Kingdom have already begun to integrate a home-based model into their healthcare systems. A joint 2019 Scientific Statement reviewed the available evidence on the comparable efficacy of HBCR and CBCR, recognizing HBCR as a plausible alternative delivery system for low- to moderate-risk patients with barriers to attending CBCR.¹⁰⁷ However, further research is needed to evaluate the appropriateness of HBCR in specific populations and high-risk groups.

Exercise prescription for ASCVD

The optimal frequency, intensity, duration, and modality of PA and ET for the primary prevention of CVD continues to be studied and is an area of controversy.⁴ Several major professional societies advise that adults perform a minimum of 75 minutes of vigorous-intensity aerobic activity or 150 minutes of moderate-intensity aerobic activity (or an equivalent combination of the two) each week along with at least two resistance training sessions (Table 1).^6,8,9 Recent guidelines also highlight that shorter bouts of aerobic exercise in increments of 10 minutes or more are likely as effective as longer durations when performed in equivalent total weekly volumes.^8,9 PA accumulated in even shorter bouts (i.e., <10 minutes) may also be associated with improved health outcomes but needs further study.¹⁰⁸ Most evidence points to a curvilinear relationship between exercise volume and CVD risk, in which the greatest incremental reduction in risk occurs from no exercise to low-moderate levels, with proportionally less additional benefit increasing from moderate to high levels of exercise. An increase in exercise beyond moderate levels results in a progressively smaller reduction in cardiovascular events.^84,109,110 These data inform current guidelines that recognize small but tangible additional health benefits - including a greater reduction in ASCVD risk - from doses of moderate-intensity aerobic activity more than 300 minutes per week.⁸

Table 1.

Exercise recommendations from professional societies and committees

Primary prevention of ASCVD and general health promotion
Professional society/committee	Exercise prescription	Class *	Evidence rating *
ACC/AHA Clinical Practice Guideline (2019) 1	Aerobic • ≥150 min/week of accumulated moderate-intensity or 75 minutes/week of vigorous-intensity PA (or an equivalent combination of moderate- and vigorous-intensity) • Additional reduction in ASCVD risk achieved with >300 minutes per week of moderate-intensity aerobic PA or >150 minutes per week of vigorous intensity aerobic PA Resistance • Resistance exercise should also be encouraged	I - -	B-NR** - -
Joint ESC Guidelines (2016) 2	Aerobic • ≥150 min/week of moderate-intensity or 75 minutes/week of vigorous-intensity PA (or an equivalent combination of moderate- and vigorous-intensity) • For additional benefits in healthy adults, a gradual increase in aerobic PA to 300 minutes a week of moderate-intensity or 150 minutes a week of vigorous intensity aerobic PA • Multiple sessions of PA should be considered, each lasting >10 minutes and evenly spread throughout the week (i.e., 4–5 days a week and preferably 7 days of the week) Resistance • At least 2 days per week, performed in two to three sets of 8–12 repetitions at 60–80% 1-RM	I I IIa -	A A B -
Physical Activity Guidelines for Americans, 2nd edition (2018)3	Aerobic • ≥150 minutes to 300 minutes of moderate-intensity or 75 minutes to 150 minutes of vigorous-intensity aerobic PA each week (or an equivalent combination of moderate- and vigorous-intensity) • Aerobic activity should be spread through the week • Additional benefits by engaging in PA beyond the equivalent of 300 minutes of moderate-intensity PA each week Resistance • Muscle-strengthening activities of moderate or greater intensity and that involve all major muscle groups on 2 or more days a week	- - -	“Evidence graded as strong or moderate was used to as the basis for the Guidelines”
Secondary prevention of ASCVD
Professional society/committee	Exercise prescription	Class	Evidence rating
ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Practice Guideline (2012) 4	Aerobic/Resistance • 30 to 60 minutes of moderate-intensity aerobic activity (such as brisk walking) at least 5 days and preferably 7 days per week • It is reasonable to recommend two days per week of complementary resistance training Risk assessment • A physical activity history and/or exercise test is recommended to guide prognosis and prescription Cardiac rehabilitation • Cardiac rehabilitation and physician-directed, home based programs are recommended for at-risk patients at first diagnosis	I IIa I I	B C B A
ESC Guidelines (2020) 5	Aerobic/resistance • Individuals with established chronic coronary syndrome should perform the minimal PA recommendations for general and CV health Risk assessment • Risk stratification for exercise-induced adverse events is recommended in individuals with established chronic coronary syndrome prior to engaging in exercise Cardiac rehabilitation • After an acute coronary syndrome, exercise-based CR is recommended in all individuals to reduce cardiac mortality and rehospitalization	- I I	- C A

AATS: American Association for Thoracic Surgery; ACC: American College of Cardiology; ACCF: American College of Cardiology Foundation; ACP: American College of Physicians; AHA: American Heart Association; CVD: cardiovascular disease; CR: cardiac rehabilitation; CV: cardiovascular; ESC: European Society of Cardiology; PA: physical activity; PCNA: Preventive Cardiovascular Nurses Association; 1-RM: one-repetition maximum; SCAI: Society for Cardiovascular Angiography and Interventions: STS: Society of Thoracic Surgeons

^*Classification of recommendation and level of evidence as per each professional organization’s criteria

^**Level B-NR: Moderate-quality evidence from 1 or more well-designed, well executed nonrandomized studies, observational studies, or registry studies or meta-analyses of such studies

^1.Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;140(11):e596–e646.

^2.Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–2381.

^3.US Department of Health and Human Services. Physical Activity Guidelines for Americans. 2nd ed. Wasington, DC: US Dept of Health and Human Services; 2018.

^4.Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):2564–2603.

^5.Pelliccia A, Sharma S, Gati S, et al. 2020 ESC Guidelines on sports cardiology and exercise in patients with cardiovascular disease. Eur Heart J. 2020.

The relative benefits of vigorous- vs. moderate-intensity aerobic exercise also require further study. A large (n=44,452) prospective cohort study from 2002 showed an inverse association between higher intensities of exercise and CHD incidence.¹¹¹ A more recent prospective cohort study (n=403,681) found that for the same volume of exercise, a greater proportion of vigorous exercise was associated with lower adjusted all-cause mortality but not with CVD mortality.¹¹² Moreover, HIIT has been recognized as a time-efficient alternative to moderate-intensity exercise with possible additional cardiometabolic health benefits, but long-term clinical outcomes data is lacking in this area and many of the studies to date have been of short duration (<12 weeks).⁵⁷

While much of the research connecting PA with improved CVD outcomes has focused on aerobic exercise, resistance training is associated with lower CVD and all-cause mortality,^113,114 and has emerged as a promising therapeutic modality.¹¹⁵ Meta-analyses of resistance training interventions have demonstrated significant improvements in lipids¹¹⁶ and blood pressure.¹¹⁷ Moreover, resistance training may offer distinct benefits in contrast with aerobic exercise for specific cardiometabolic risk factors. For example, one recent study found that while both aerobic and resistance training reduced epicardial adipose tissue in adults with obesity, only resistance training reduced pericardial adipose tissue.¹¹⁸ An RCT comparing the effects of aerobic exercise, resistance training, and combined exercise is currently underway to examine the effects of each approach on CVD risk factors.¹¹⁹

Individuals with ASCVD should engage in PA amounts that are similar to those recommended for primary prevention, but should undergo risk stratification with a history, physical examination and, on occasion, an exercise stress test beforehand (Table 1).^92,120 Current guidelines from the United States specifically recommend 30 to 60 minutes of moderate-intensity aerobic activity all days of the week (at least 5) with resistance training two days per week.¹²⁰ The safety of strenuous ET in cardiac patients (such as HIIT) has also been evaluated in several studies but there is insufficient safety and long-term outcomes data to support its use in patients with CAD, especially outside of supervised CR programs.⁹⁰

Exercise, physical function and heart failure

Heart failure (HF) is a complex clinical syndrome characterized by structural and/or functional impairment(s) of ventricular filling or ejection of blood.¹²¹ This results in the inability of the heart to meet the cellular demands of tissue, or its ability to do so only with elevated filling pressures. Approximately half of HF patients have a reduced left ventricular systolic function (HFrEF), while the remainder have preserved systolic function (HFpEF).¹²² Exercise intolerance is one of the defining features of HF, and often its first manifestation. Multiple studies demonstrate that patients with HF have reduced aerobic capacity which, in turn, portends a poor prognosis.^123–129 While there are marked differences in pathophysiology between HFrEF and HFpEF, exercise capacity is similarly impaired in both diseases.¹²⁴

Aerobic exercise capacity can be objectively measured by maximal oxygen consumption (V̇o₂max) or more often peak oxygen consumption (V̇o₂peak). According to the Fick principle, V̇o₂max is determined by the product of cardiac output (i.e. heart rate × stroke volume) and arterio-venous oxygen content difference (i.e. C[a-v]O₂).¹³⁰ The pathophysiology of exercise intolerance is complex, and depends in part on the etiology and degree of HF. In both HFrEF and HFpEF, there is an impaired ability to augment cardiac output, resulting in poor convective O2 delivery to meet the metabolic demands of exercising skeletal muscle.^131–135 Several factors may influence the cardiac output response in patients with HF, including an inability to i) increase left ventricular preload (due to decreased left ventricular compliance)^132,136; ii) increase left ventricular systolic emptying (due to poor contractile reserve)¹³⁷; iii) decrease afterload (due to a blunted peripheral arterial vasodilator response to exercise)^134,138; iv) increase heart rate (due to chronotropic incompetence),^134,139 Finally, comorbid disease such as the presence of concomitant valvular disease or arrhythmias may also contribute to an inability to increase cardiac output in patients with HF.

In addition to a central cardiopulmonary limitation to exercise, HF patients demonstrate abnormal skeletal muscle morphology, including a lower proportion of type I (oxidative fibers), reduced number of mitochondria, and decreased capillary-fiber ratio.^140–143 These pathological HF adaptations result in poor diffusive transport from red blood cells to myocyte mitochondria culminating in impaired oxygen utilization by active skeletal muscle.^136,144 The relative contributions of central (convective O2 delivery) and peripheral (diffusive O2 transport from red blood cells to mitochondria) factors to exercise limitation varies among HF phenotypes, and is beyond the scope of this review.

Regular exercise and risk of future HF

Since the 1980s, there is a substantial body of work to show that exercise is important, both as a preventive as well as therapeutic intervention in HF. Several studies have demonstrated an inverse relationship between physical activity and future risk of HF across various demographics using large prospective cohorts.^145–149 A meta-analysis of twelve prospective cohort studies with 20,203 HF events among 370,460 participants (median follow-up = 13 years) showed a dose-dependent relationship between PA and HF risk. Compared with those not engaging in any leisure-time PA, individuals performing 500 MET-min/wk had a 10% reduction in HF risk (HR 0.90; 95% CI, 0.87–0.92). By contrast, those achieving 2000 MET-min/wk had a 35% lower risk of HF (95% CI, 0.58–0.73).¹⁵⁰ Interestingly, when assessing HF subtype, PA is more consistently associated with a lower risk of HFpEF compared with HFrEF.¹⁵¹

Similarly, prospective cohort studies demonstrate a strong and consistent inverse relationship between CRF and risk of incident HF.^152–156 A meta-analysis of ten studies showed a relative risk reduction of 18% for each increase in 1 MET (RR 0.82; 95% CI, 0.80–0.84) with similar benefits observed in men and women.¹⁵⁷ At a structural level, even low CRF in young adulthood is associated with subclinical left ventricular remodeling in middle-age.¹⁵⁸

Regular exercise in patients with established HF

Exercise training now holds a Class I recommendation as safe and effective for patients with established HF in order to improve functional status.^121,159 Despite initial concern for hemodynamic compromise and risk of sudden cardiac death, early data from the 1990s consistently demonstrated the efficacy and safety of exercise in patients with established HF.^160–164 A meta-analysis of the ExTraMATCH Collaborative also showed that ET for at least 8 weeks reduces mortality by 45% in patients with HFrEF (HR 0.65; 95% CI, 0.46–0.92),¹⁶⁵ although this has not been consistently replicated in subsequent studies. The landmark HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial is the largest trial of ET in patients with HFrEF. More than 2,300 stable patients with HFrEF (LVEF ≤35%) with New York Heart Association class II to IV were randomized to 36 supervised sessions of aerobic ET in addition to standard of care or to standard of care alone.¹⁶⁶ The results of this study were consistent with previous observations that regular aerobic ET is well-tolerated, safe, and improves quality of life measures. However, after a median follow-up of ∼30 months, there was only a modest increase (~4%) in VO2peak and reductions in mortality and hospitalization rates did not reach significance in the primary analysis. Following pre-specified adjustment for highly prognostic baseline characteristics, exercise training was associated with reductions in cardiovascular mortality or HF hospitalizations (HR 0.85; 95% CI, 0.74–0.99). Furthermore, adherence was challenging in this population (only 30% of patients achieved the targeted level of ET in terms of recommended minutes/wk), which may have diluted the effects of the ET regimen. In post-hoc analyses, moderate exercise volumes of at least 3 MET-hours per week were associated with >30% relative risk reduction in cardiovascular mortality or HF hospitalization, and the benefits and safety of ET were consistent regardless of age, race, or sex, as well as HF etiology and severity.^166–168 Subsequent meta-analyses have also demonstrated the beneficial effects of ET in HF, largely driven by an improved quality of life and lower HF hospitalizations.^169–173 Consistent with the primary analysis of HF-ACTION, most studies have not shown significant reductions in mortality,^166,169,171 however, this may be due to low adherence and highlights the challenge and importance of maintenance exercise.¹⁷⁴

The improvements in CRF following ET are mediated by a variety of mechanisms and likely influence different HF phenotypes in different ways. In patients with HFrEF, ET can increase contractility, reduce left ventricular end-diastolic volume and end-systolic volume, culminating in improved maximal cardiac output.^175,176 In addition, a variety of peripheral adaptations occur with regular ET in patients with HF, causing increased muscle blood flow, oxygen delivery to myocytes, and increased oxygen extraction leading to an increased systemic arteriovenous oxygen difference.¹⁷⁵ By contrast, in HFpEF, a meta-analysis of ET RCTs failed to show any changes in LV systolic or diastolic function with regular exercise, despite an increase in VO2peak and improved quality of life metrics.¹⁷¹ These data suggest that peripheral factors may be a predominant modifiable feature of exercise intolerance in HFpEF - as acute exercise physiological testing has demonstrated - and may mediate the beneficial effects of exercise in these patients.¹⁷⁷ Given the lack of effective therapies in this population, ET remains a key intervention to alter disease burden and improve functional capacity. Most recently, a European RCT of ET in HFpEF sought to determine the optimal ET regimen in these patients.¹⁷⁸ The authors randomized stable but sedentary patients with HFpEF and New York Heart Association Class II-III to either moderate continuous training, HIIT, or guideline-based PA counseling (control group). The exercise intervention took place over 12 months, with 3 months of supervised training, followed by 9 months of home-based exercise. Impressively, the investigators achieved a > 80% retention at 12 months, far higher than the HF-ACTION albeit over a shorter follow-up period. At 3 months, there was a greater improvement in VO2peak in both the HIIT arm and moderate continuous training arm when compared to the control arm. However, the magnitude of this improvement did not meet the pre-specified threshold of 2.5 ml/kg/min and there was no significant difference in VO2 improvement between the high-intensity and moderate continuous exercise arms. Finally, any differences between the intervention and control arms at 3 months were not sustained at 12 months, which may be in part due to lower adherence after transition to home-based training.¹⁷⁹ Although this study was well designed and the patients enrolled were well phenotyped, it should be noted that HFpEF is a highly heterogenous population, which makes understanding mechanisms of disease and treatment effects among these patients highly challenging. Moreover, it remains unclear whether absolute or relative improvements in VO2 should be used to assess efficacy of ET on functional aerobic capacity.

The relationship between exercise and atrial fibrillation

Atrial fibrillation (AF) is the most common, clinically significant arrhythmia and has a growing burden worldwide.¹⁸⁰ AF is characterized by irregular atrial activity that replaces normal sinus rhythm leading to loss of the regular atrial contraction during left ventricular diastolic filling, and is associated with increased risk of stroke, HF, and mortality.^181,182 It has been well established that risk promoters of AF include several cardiometabolic traits that are modifiable by increased PA and ET, including obesity, hypertension, and T2DM.^183–185 Thus, there has been great interest in understanding the role that increased PA and exercise play in the prevention and management of AF.

Primary prevention of AF

Even low to moderate volumes of exercise are associated with a decreased risk of incident AF. Among 5,446 adults ≥ 65 years followed for 47,280 person years, moderate-intensity exercise (categorized as activities estimated to require <6 METs or an average walking pace >2mph) reduced the relative risk of incident AF by 28% (HR 0.72; 95% CI, 0.58–0.89). In fact, more than a quarter of new cases of AF were deemed to be attributable to the absence of even moderate levels of exercise.¹⁸⁶ These data have been replicated by other large cohorts, including the UK Biobank cohort and the Korean National Health Insurance Service database, which included >400,000 and >500,000 individuals, respectively.^187–189 In the UK Biobank, women appeared to derive slightly greater protection from incident AF with exercise than men (women: HR 0.85; 95% CI, 0.74–0.98; men: HR 0.90; 95% CI, 0.82–1.0). In addition, there appears to be a graded, inverse relationship between CRF and incident AF with every MET increase achieved during treadmill testing associated with a 7% lower risk of AF (HR; 0.93; 95% CI, 0.92–0.94).¹⁹⁰ However, the relationship between exercise and incident AF becomes more complex at the upper end of the exercise dose spectrum. Rather than demonstrating a linear benefit from increasing levels of exercise, there may be a threshold effect beyond which increasing exposure attenuates the benefit, or is associated with an increased risk of AF,^{186,191–198} although conflicting evidence exists.^188,189

The most compelling evidence for a dose- and intensity-dependent associations between regular exercise and AF comes from elite endurance athletes, Among > 50,000 skiers competing in the Vasaloppet skiing event in Sweden,¹⁹⁸ the strongest predictors of AF were the number of races completed and race times (HR for ≥ 5 vs. 1 completed race 1.29; 95% CI, 1.04–1.61; HR for 100–160% vs. > 240% of winning time 1.20; 95% CI, 0.93–1.55, respectively). While a subsequent analysis of these skiers demonstrated either a lower or a similar incidence of AF compared to the general population,¹⁹⁹ multiple meta-analyses suggest that the risk of AF is higher in athletes than in the general population.^200,201 Importantly, the thromboembolic risk of AF in athletes appears to be lower than that of the general population. When Vasaloppet skiers were compared to the general population, both males and females had a lower incidence of stroke compared to non-skiers, independent of races completed and race times (HR 0.64; 95% CI, 0.60–0.67).¹⁹⁹ However, skiers with AF had a higher risk of stroke compared to non-skiers without AF. Taken together, while exercise at the highest end of the exercise dose spectrum may attenuate the benefit or even increase the risk of AF, the thromboembolic risk is lower, and the additional cardiometabolic benefits derived should be considered in a holistic manner when viewing the risks and benefits of such exercise.

Further, the mechanisms driving a possible increase in risk of atrial fibrillation at high levels of exercise are unclear and likely multifactorial. First, atrial chamber enlargement is commonly observed in an athlete’s heart, caused by increased volume overload through regular, intense aerobic exercise.²⁰² Atrial dilatation may act as an arrhythmogenic substrate, although the relationship between left atrial size and AF in athletes is more complex than in sedentary individuals.²⁰² Other mechanisms may include induction of profibrotic pathways (as has been shown in murine exercise models), pulmonary vein stretch, alterations in vagal tone, and intrinsic conduction adaptations mediated by ion channel remodeling.^203–206 Additional research aimed at identifying the molecular mechanisms for AF risk is needed.

Secondary prevention of AF

In patients with established AF, several studies demonstrate that exercise interventions, often as part of wider risk factor management, may improve AF-specific outcomes, CVD- and all-cause mortality. Data from the ARREST-AF (Aggressive Risk Factor Reduction Study for Atrial Fibrillation) cohort show that aggressive management of risk factors, modifiable by exercise, alters AF burden in patients.²⁰⁷ Those who attended a specific risk factor management clinic had decreased frequency, duration, symptoms, and symptom severity compared to controls, and aggressive risk factor management was an independent predictor of arrhythmia-free survival (HR 4.8; 95% CI, 2.04–11.4).²⁰⁷ With regards to ET in particular, a small study (N = 49) of participants with permanent AF randomized to 12 weeks of training showed an increase in both exercise capacity and quality of life in the exercise arm compared to the control arm.²⁰⁸ Along these lines, observational data show that those with greater baseline CRF have decreased burden of AF with and without rhythm control strategies. In addition, AF burden and symptom severity decreased in those who gain ≥ 2 METs through participation in a tailored exercise program,²⁰⁹ highlighting a ubiquitous and cheap adjunctive therapy for AF management.

Further, patients with AF engaging in regular exercise (defined as exercise ≥ 3 hrs/wk for ≥ 2 years) had a lower risk of thromboembolic events, regardless of age, sex, or risk of stroke in the EURObservational Research Programme on AF (EORP-AF) Pilot Survey.²¹⁰ This study also demonstrated lower rates of CVD- and all-cause mortality in patients who engaged in regular or intense PA, although several factors may contribute to these findings. Other observational data also show that patients with AF who meet the PA guidelines (≥150 min of moderate-intensity or ≥75 min of vigorous-intensity per week) have a lower risk of all-cause and CVD mortality, as well as cardiovascular morbidity and stroke, compared with inactive patients (HR for all-cause mortality: 0.55; 95% CI, 0.41–0.75; HR for cardiovascular mortality: 0.54, 95% CI, 0.34–0.86; HR for cardiovascular morbidity: 0.78; 95% CI, 0.58–1.04; HR for stroke: 0.70; 95% CI, 0.42–1.15).²¹¹ Furthermore, each 1-MET increase in estimated CRF (derived from a prediction model using sex, age, waist, resting heart rate, and PA) is associated with a lower risk of all-cause mortality (HR 0.88; 95% CI, 0.81–0.95), CVD mortality (HR 0.85; 95% CI, 0.76–0.95), and morbidity (HR 0.88; 95% CI, 0.82–0.95). In sum, low to moderate levels of regular PA and exercise, in combination with aggressive risk factor modification, is important in not only reducing the risk of incident AF but emerging as a potential treatment strategy in patients with established disease.

Conclusion

Regular PA and exercise lead to numerous cardiovascular health benefits, including a reduction in ASCVD risk factors and events, cardiometabolic disease, HF, and AF. While the beneficial effects of aerobic exercise are well established, there is a growing interest in the use of other exercise modalities, including low-volume, high-intensity exercise, and resistance (strength) training. As our understanding of different exercise modalities develops, it is plausible that the impact of these modalities on the cardiovascular system may be complementary to one another. This notion, in conjunction with recent efforts in molecular profiling to assess inter-individual responses to ET, may allow us to understand and even predict an individual’s response to a given exercise modality. While this would have profound implications for individualized exercise prescriptions, at present, regular dynamic exercise should remain an important focus in the management of CVD.