2025 AHA科学声明：SARS-CoV2 急性后后遗症（长 COVID）患者运动不耐受及对训练的反应

Circulation

# AHA SCIENTIFIC STATEMENT

# Exercise Intolerance and Response to Training in Patients With Postacute Sequelae of SARS-CoV2(Long COVID): A Scientific Statement From the American Heart Association

William K.Cornwell III,MD,MSCS,Chair;Benjamin D.Levine,MD,FAHA,Vice Chair;Diane Baptiste,DNP;Nicole Bhave,MD,FAHA;Sarika Desai,MD;Elizabeth Dineen,DO;Matthew Durstenfeld,MD,MAS;Justin Edward,MD;Mu Huang,PhD,DPT;Roni Jacobsen,MD;Jonathan H.Kim,MD,FAHA;Erica Spatz,MD;on behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Secondary Prevention Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Lifestyle and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council

ABSTRACT: The postacute sequelae of SARS-CoV-2, also known as Long COVID, may affect 10% to 25% of individuals diagnosed with SARS-CoV-2. More than 100 symptoms have been reported among patients with Long COVID, but almost all patients report severe fatigue, orthostatic intolerance, shortness of breath, and reductions in exercise tolerance.Emerging data suggest that cardiovascular deconditioning plays a major role in the development of this syndrome and that reductions in functional capacity among patients with Long COVID are comparable to reductions seen among individuals with cardiovascular deconditioning resulting from bed rest. Concern has been raised about the use of exercise training as part of the management strategy for patients with Long COVID. However, exercise training appropriately tailored to the patient with cardiovascular deconditioning may be an effective strategy to facilitate improvement in symptoms. This American Heart Association scientific statement provides a concise yet comprehensive overview of mechanisms contributing to development of Long COVID and methods by which exercise training may be applied to this unique patient population to alleviate symptoms and improve quality of life. In addition, methods of reintroducing exercise and return to play among athletes affected by COVID-19 are discussed.

Key Words: AHA Scientific Statements cardiovascular deconditioning exercise post-acute COVID-19 syndrome return to sport■SARS-CoV-2■social determinants of health

s the SARS-CoV-2 pandemic has transitioned to A an endemic phase, attention has been focused on the emergence of the postacute sequelae of SARS-CoV-2(PASC), also known as Long COVID syndrome. Epidemiological data indicate that 10% to 25% of individuals diagnosed with SARS-CoV-2 may go on to develop Long COVID.1 However, it should be noted that in competitive athletes who are immediately placed on a graded return-to-play(RTP) rehabilita-tion program, the rate of persistent symptoms appears much lower at 0.02%.2 Long COVID is a heteroge-neous syndrome lacking a unifying definition but has

been broadly defined as any new symptom or condition persisting for>12 weeks after a SARS-CoV-2 infec-tion.3.4 Although efforts to characterize risk factors and prevention strategies are ongoing, treatment algorithms are warranted to promote symptom improvement/reso-lution of those already affected by this syndrome. The primary objective of this American Heart Association scientific statement is to provide a concise overview of the epidemiology and societal impact of Long COVID and emerging concepts of the physiological underpin-nings contributing to this syndrome that form a basis for exercise rehabilitation as a management strategy to

be incorporated into patient management and promote symptom improvement.

# LONG COVID: DEFINITION AND CLINICAL FEATURES

Long COVID is a heterogeneous syndrome character-ized by a myriad symptoms that develop after the index infection and last for an indefinite period of time. There-fore, definitions vary on the criteria required to definitively diagnose the syndrome. Accounting for these variations between major organizations, including the World Health Organization, the National Institutes of Health RECOV-ER Initiative(Researching COVID to Enhance Recovery),and the American College of Cardiology, Long COVID is broadly defined as any symptom or condition persisting for>12 weeks after a SARS-CoV-2 infection.3,4

A taxonomy has previously been proposed to dis-tinguish symptoms resulting from overt cardiovascular disease after COVID-19 infection from cardiovascular symptoms that cannot be explained from testing.4 In this regard, PASC with symptoms resulting from overt cardiovascular disease may refer to conditions such as myocarditis, pericarditis, new or worsening myocardial ischemia, arrhythmias, or an acquired cardiomyopa-thy; when possible, management of these conditions should follow standard guidelines.4 However, PASC with cardiovascular symptoms is a heterogeneous disorder and is recognized by symptoms(not present before COVID-19 infection) persisting beyond a time frame anticipated from severity of the infection and the individual's age and underlying comorbidities or health status.4 Although>100 symptoms have been ascribed to Long COVID,5 hallmark features as described in the RECOVER cohort(9764 participants, 89% with his-tory of SARS-CoV-2 infection)6 include postexertional malaise, brain fog/confusion, palpitations, dyspnea on exertion, and severe fatigue with exercise intolerance.Other symptoms may include gastrointestinal symp-toms, changes in sexual desire/capacity, abnormalities of smell/taste, thirst, and chronic cough.1,4 These symp-toms, particularly brain fog/confusion, lightheaded-ness, and dyspnea, may further impact the perception of illness and contribute to exercise intolerance. Long COVID has also been compared with myalgic enceph-alitis/chronic fatigue syndrome. Myalgic encephalitis/chronic fatigue syndrome is a heterogeneous condition characterized by cognitive and physical impairment and by a worsening of symptoms in response to physical,orthostatic, or cognitive stress.7

Exercise tolerance, as determined by peak oxygen uptake(peak $Vo_{2}$ ), is variably affected among patients with Long COVID. In a meta-analysis of 38 studies char-acterizing abnormalities on cardiopulmonary exercise testing(N=2160, 1228 with Long COVID), peak $Vo_{2}$ was lower in patients with, compared with those without

persistent symptoms by 4.9 mL·kg-1.min-1(95% CI,3.4-6.4).8 Factors hypothesized to contribute to this reduc-tion in peak Vo2 included cardiovascular deconditioning,chronotropic incompetence, impaired oxygen uptake in the periphery, and dysfunctional breathing.8 In an Italian study of 75 individuals(male sex, n=43; average age,≈57±12 years) with Long COVID, exercise testing per-formed 3 months after hospitalization demonstrated that peak Vo2 was 20.0 mL·kg-1.min-1(83% predicted).9 In a Norwegian cohort(N=156; male sex, 61%; average age,56±12.7 years) of patients with Long COVID, peak Vo2 was 28.7±8.4 mL·kg-1,min-1 and<80% predicted in almost half of the individuals.10 Exercise intolerance may also be related to an impairment in diffusion capac-ity.11 Among patients with Long COVID(N=367), the dif-fusion capacity of the lungs for carbon monoxide was lower among individuals with a more severe index infec-tion(diffusion capacity of the lungs for carbon monox-ide for asymptomatic infection, symptomatic infection,and infection requiring hospitalization: 95.2±14.3%,90.3±14.2%, and 79.6±19.3%, respectively).11 In this cohort, exercise tolerance, as determined by the 6-minute walk test, correlated with diffusion capacity of the lungs for carbon monoxide.11

# MECHANISMS CONTRIBUTING TO THE LONG COVID SYNDROME

The“oxygen cascade” describes the series of steps in-volved in the mobilization of atmospheric oxygen to exer-cising muscle for generation of adenosine triphosphate to sustain exercise.12 Organ systems involved include pulmonary, cardiovascular, and musculoskeletal. As de-scribed later, accumulating data indicate that abnormali-ties in function of these organ systems, cardiovascular and musculoskeletal in particular, contribute to the Long COVID syndrome.

# Cardiovascular Deconditioning

Cardiovascular deconditioning describes physiological adaptations occurring in response to physical inactivity and has been observed in a host of clinical scenarios,including bed rest,13-15 postural orthostatic tachycardia syndrome(POTS),16,17 and after viral illnesses,18 as well as in astronauts in flight or in simulated microgravity with head-down tilt(Figure 1).13,15,19 Specific alterations in left ventricular(LV) structure and function include cardiovascular atrophy with a smaller, less distensible ventricle leading to a steeper Frank-Starling curve(Fig-ure 2),20,21 The loss of a hydrostatic gradient(eg, during bed rest) results in a central fluid shift, leading to a neu-rohumorally mediated reduction in plasma/blood vol-ume.15,20 This reduction in plasma volume occurs early after bed rest as a result of this rapid onset of diuresis.21 The combination of cardiovascular deconditioning and

 Figure 1. Cardiovascular deconditioning in the setting of an acute illness can lead to development of many symptoms that are characteristic of Long COVID.

An exercise prescription specifically tailored to the patient with cardiac deconditioning increases ventricular compliance and mitochondrial function, facilitating improvements in orthostatic tolerance, exercise capacity, and overall quality of life.

reduced plasma/blood volume results in an excessive reduction in stroke volume(SV) with a compensatory rise in heart rate(HR), particularly in response to an orthostatic challenge(upright posture) in an effort to maintain cardiac output(Qc) and arterial perfusion.6,20

Multiple studies have demonstrated the physiologi-cal alterations characteristic of cardiovascular decon-ditioning. In the Dallas Bed Rest Study, 3 weeks of bed rest among healthy 20-year-old men led to a large reduction in functional capacity(baseline versus post-bed rest peak Vo2, 43.0±10.9 mL-kg-1.min-1 versus 31.8±11.1 mL·kg-1,min-1, respectively), along with a lower exertional SV(104 mL/beat versus 75 mL/beat)and Qc(20.0 L/min versus 14.8 L/min).14 A reduction in myocardial work after exposure to real or simulated microgravity contributes to cardiac atrophy,15 and bed

rest studies have demonstrated that cardiac mass gen-erally decreases by≈1%/wk.15 However, cardiovas-cular deconditioning may become evident with only a few days of microgravity22 or<24 hours of bed rest.23 For example, in 1 study, healthy men(41-48 years of age) were evaluated before and after 20 hours of bed rest in a head-down tilt(-5°).23 Bed rest reduced supine resting central venous pressure(-14%), SV(-19%), and Qc(-17%).23 Following bed rest, ortho-static stress produced a higher HR(90±18 bpm ver-sus 68±12 bpm), and on exercise testing, peak Vo2 was reduced(2.36±0.41 L/min versus 2.62±0.48 L/min).23 In an analysis of astronauts exposed to 16 days of microgravity, HR was increased(93±1 bpm ver-sus 74±4 bpm) and SV was reduced(46±5 mL/beat versus 76±3 mL/beat) during a postflight orthostatic

 Figure 2. Impact of cardiovascular deconditioning on ventricular hemodynamics.

Deconditioning leads to reductions in stroke volume for any given filling pressure and a leftward shift in pressure-volume curves. LVEDV indicates left ventricular end-diastolic volume; and PCWP,pulmonary capillary wedge pressure.

challenge compared with baseline preflight values.19 In that same analysis, sympathetic neural activity(deter-mined by microneurography) was augmented after flight compared with baseline preflight levels, indicat-ing that autonomic control of blood pressure(BP) was preserved. Said another way, there was no evidence of dysautonomia as a cause for orthostatic intolerance or positional tachycardia.19 The data suggest that tachy-cardia results from reductions in central filling pressures and is a compensatory response to a gravitational load placed on a deconditioned heart characterized by car-diac atrophy and a steepened Frank-Starling curve.This distinction is important to make because the underlying pathophysiology may guide treatment algorithms.

Along these lines, exercise protocols have been shown to mitigate/reverse the effects of bed rest and microgravity on cardiac structure and function.13,15 The aforementioned Dallas Bed Rest Study is particularly illustrative in this regard. In that study, after the 3 weeks of bed rest, 8 weeks of exercise training led to dra-matic improvements in peak Vo2(3.9 L/min), exertional SV(120 mL/beat), and Qc(22.8 L/min).14 In another analysis of healthy individuals undergoing 5 weeks of head-down(-6°) bed rest, those randomized to seden-tary bed rest experienced cardiac atrophy and increased ventricular stiffness, whereas cardiac mass and ventricu-lar compliance were preserved among those randomized to daily exercise by rowing ergometry.13 Among astro-nauts exposed to microgravity for 155±33 days aboard the International Space Station, daily exercise counter-measures preserved LV mass after flight(115±30 g before flight versus 118±29 g after flight), as well as SV, ejection fraction, and end-diastolic and end-systolic volumes.15 An overview of the hemodynamic and physi-ological responses to cardiovascular deconditioning is provided in the Supplemental Table.

Mitochondrial Dysfunction

Evidence suggests that alterations in fatty acid metabol-lism may contribute to exercise intolerance in patients with Long COVID.24,25 In an analysis of plasma metabolo-mics among patients with Long COVID(n=29) and con-trol subjects(n=30), the metabolic profile of patients with Long COVID revealed several abnormalities suggestive of mitochondrial dysfunction, including a reduced capac-ity for fatty acid oxidation.25 Specifically, compared with control subjects, patients with Long COVID had higher levels of plasma carnitine-conjugated and free fatty ac-ids, both polysaturated and highly unsaturated, as well as hydroxylated fatty acids.25 In a case-control analysis,limitations in exercise capacity were related to multiple abnormalities in the skeletal muscle, including impaired peripheral oxygen extraction and a shift in skeletal muscle fiber type to a less oxidative, more glycolytic phenotype. ${}^{26}$ Compared with control subjects, skeletal muscle biopsies

taken before an acute bout of exercise revealed a higher rate of skeletal myocytes, with centralized nuclei suggest-ing skeletal muscle regeneration.26 Biopsies taken after exercise demonstrated atrophic muscle fibers and focal necrosis suggestive of local tissue damage.26 Together,these data suggest that symptoms such as muscle pain,fatigue, and weakness among patients with Long COVID are related to exercise-induced muscle damage with sub-sequent regeneration in the postexertional period.26

Autonomic Regulation of BP and Dysautonomia

The arterial baroreceptor reflex pathway maintains BP on a beat-by-beat basis in response to alterations in body position and loading conditions.27 Stretching of the baro-receptors(as a result of an increase in static and pulsatile BP) increases vaginal nerve activity and inhibits sympathetic outflow, reducing HR and BP, whereas unloading of the baroreceptors(as a result of a reduction in BP) reduces parasympathetic activity and increases sympathetic output in order to increase BP. Upright posture leads to a gravita-tional displacement of blood toward the lower extremities and unloading of the baroreceptors. In response, sympa-thetic outflow increases among healthy individuals in order to maintain arterial perfusion.28 However, among individu-als with autonomic failure, autonomic reflexes in response to an orthostatic challenge are insufficient to maintain BP,limiting the ability to tolerate an orthostatic challenge.27

Long COVID has been attributed to and even equated with the vague and imprecise term dysautonomia.29 In an analysis of 24 patients with Long COVID, almost all indi-viduals had orthostatic intolerance, and increased HR was observed among participants after head-up tilt or nitro-glycerin administration, abnormalities that were attributed to dysautonomia.29 However, as previously described,increases in HR in response to orthostatic challenge indicate a preserved and appropriate arterial baroreflex29 in this regard, the term dysautonomia is nonspecific and may be misleading.30 Furthermore, hypotension resulting from a combination of tilt and pharmacological reduc-tions of cardiac filling pressures does not reflect ortho-static hypotension occurring among patients with true autonomic failure.2731,32 The integrity of the baroreflex and overall control of BP may be visualized by having patients perform a Valsalva maneuver.627 During Valsalva, healthy individuals demonstrate a normal phase IIB and hyperten-sive overshoot, whereas patients with autonomic failure have an absent phase IIB and absence of a hypertensive overshoot. An example Valsalva maneuver of a patient with Long COVID is displayed in Figure 3, demonstrating evidence of preserved autonomic control of BP6

Vascular Function in Long COVID

Emerging data suggest that Long COVID results, at least in part, from cytokine-mediated injury combined


Figure 3. Valsalva maneuver.

Example Valsalva maneuver from a 54-year-old female patient with Long COVID. The Valsalva maneuver demonstrates a normal phase llb response and a normal hypertensive overshoot during recovery of the Valsalva maneuver.These observations indicate preserved autonomic control of blood pressure as opposed to dysautonomia(see text for further discussion). Reproduced with permission from Edward et al.6 Copyright©2023 Wolters Kluwer Health, Inc.

with hypercoagulability leading to vascular endothelial damage.33,34 In an analysis of patients acutely infected with SARS-CoV-2(N=121), inflammatory biomarkers,including tumor necrosis factor-α and interferon-y-in-duced protein 10, were persistently elevated among individuals who developed Long COVID compared with those who did not35 In an analysis of retinal microcir-culation, individuals with Long COVID(N=41) had evidence of endothelial dysfunction demonstrated by im-paired venular flicker-induced dilation, narrower central retinal artery equivalent, and lower arteriolar-venueular ratio compared with age- and sex-matched control subjects.36 In that same study, there was an association between symptom severity and arteriolar-venular ratio.36 When re-active hyperemia is used as a metric of endothelial func-tion,≈40% of patients with Long COVID have evidence of frank endothelial dysfunction, and an additional≈20%have impaired endothelial function.34

Postural Orthostatic Tachycardia Syndrome

POTS is a common cause of orthostatic intolerance af-fecting≈500000 Americans.16 This syndrome is defined by orthostatic intolerance with a HR increase of≥30 bpm, frequently with HR≥120 bpm within 10 minutes of standing or during a head-up tilt, with an absence of or-thostatic hypotension(a reduction in systolic BP of≥20 mmHg or a decrease in diastolic BP of≥10 mmHg).16 It is important to emphasize that POTS is not defined by an HR that is higher than expected during exercise; it re-quires the quiet upright posture and symptoms of chronic orthostatic intolerance.

Although the mechanism of POTS is multifactorial,the syndrome typically results from an inciting event(eg,infection, surgery,enforced bed rest) in a susceptible indi-vidual, leading to a downward spiral of orthostatic intol-erance, increasing periods of bed rest, and worsening cardiovascular deconditioning, which in turn further exac-erbate symptoms. POTS may occur in isolation or coexist with other conditions such as fibromyalgia, autoimmune/inflammatory conditions, Ehlers-Danlos syndrome, or migraines.16 Although POTS and Long COVID should not be considered coequal, the 2 conditions have shared fea-

tures, namely cardiovascular deconditioning leading to a compensatory rise in HR in response to an orthostatic challenge and a positive response to exercise training.

EXERCISE TRAINING TAILORED TO THE PATIENT WITH LONG COVID

An overview of the hemodynamic and physiological re-sponses to exercise training is provided in the Supple-mental Table. Exercise training is increasingly recognized as a potential therapy for management of Long COV-ID.4,6,37 Indeed, data from NCAA athletes in the ORCCA Registry(Outcomes Registry for Cardiac Conditions in Athletes) provide a compelling background that rapid re-turn to regular physical activity, at least among competi-tive athletes, can markedly reduce the risk of developing Long COVID.2 That said, concern has been raised about the safety of exercise training for patients with Long COVID.38 This safety concern is centered around the potential exacerbation of postexertional malaise among individuals who are already deconditioned and are ex-periencing exercise intolerance.38 However, as has been previously demonstrated in other populations with similar symptoms,14,15,17 an exercise program modified appropri-ately to the patient with cardiovascular deconditioning may effectively and safely improve symptoms.The Levine protocol is an illustrative example of a protocol applied to patients with POTS, which over a 3-month period led to marked improvement in quality of life, orthostatic toler-ance, and functional capacity.17

However, several factors must be considered when an exercise prescription is implemented for patients with Long COVID(Figure 4). First, the exercise proto-col must incorporate low-duration, low-intensity exer-cise early to minimize or avoid the risk of postexertional malaise. These principles have been applied to exercise programs in other similar populations such as individu-als with POTS and enable affected patients to complete exercise protocols without exacerbating symptoms. ${}^{17,39}$ Overly aggressive protocols limit patient adherence and lead to discontinuation of exercise training.6 Second, it is important to consider the type of exercise prescribed;


Figure 4. Example exercise protocol.

Example exercise prescription for patients with Long COVID that is tailored to the patient with cardiac deconditioning.As discussed in the text, recumbent/semirecumbent exercises such as rowing or cycling are preferred. Exercise must be initiated at low duration/intensity, and as exercise tolerance increases over time,patients may gradually transition back to their preferred exercise modality. HR indicates heart rate.aPeak Heart Rate may be calculated as: 220-age(years).

cardiovascular remodeling in response to exercise varies in accordance with the type of exercise undertaken, and upright exercises such as walking or running introduce a gravitational load(orthostatic challenge), exacerbating symptoms in patients who already suffer from orthostatic intolerance. Thus, upright exercises are not likely to be tolerated early in exercise rehabilitation for patients with Long COVID.38 To accommodate orthostatic intolerance,exercises that are conducted in a recumbent/semirecum-bent position with the impact of gravity on the cardiovas-cular system minimized must be considered. Specifically,exercises such as rowing or recumbent/semirecumbent cycling may be advantageous in this setting.

These types of exercise may be particularly beneficial because the degree of physiological hypertrophy resulting from rowing or cycling may be greater than other types of exercise.40-43 For example, in an analysis of≈1300 Italian athletes,≈15% had an LV end-diastolic dimen-sion>60 mm, and exercise type, specifically participa-tion in cycling,rowing/canoeing, or cross-country skiing,was a major determinant of an enlarged LV cavity dimen-sion.42 In another imaging analysis of 947 athletes, those engaged in rowing/canoeing or cycling had greater lev-els of physiological hypertrophy than athletes engaged in other exercise types.41 These analyses of the athletic heart demonstrate the variable cardiac adaptations that occur in response to different exercise types. More specifically,certain exercises(in this case, rowing or semirecumbent cycling) may provide an additional benefit to patient popu-lations such as individuals with Long COVID with cardio-vascular deconditioning, for whom the goal is to promote physiological ventricular hypertrophy. An example exercise protocol is displayed in Figure 4, emphasizing the impor-tance of exercise type, duration, and intensity to minimize or avoid postexertional malaise and to promote recovery of function and symptomatic improvement.

A detailed review of the interaction of exercise and mitochondrial health is beyond the scope of this scientific statement, but a few critical points are worthy of merit.Generally, exercise is a powerful therapeutic intervention to improve mitochondrial health, ${}^{44}$ and there is an interac-tion among exercise duration, intensity, and mitochondrial

adaptation to exercise.45 Indeed, even patients with docu-mented mitochondrial myopathies are not harmed and derive much benefit from dedicated exercise training.46 Multiple proteins contribute to mitochondrial biogenesis,but the transcriptional coactivator peroxisome prolifera-tor-activated receptor coactivator 1a is referred to as the master regulator.44 Slow-twitch(type I) fibers contain the greatest percentage of mitochondria and are easily recruited at low-intensity workloads, as low as 40% peak Vo2 or lower.44 Workloads at higher intensities recruit fast-twitch red(type Ila) and white(type llx) fibers, which have lower mitochondrial content. Exercise training enhances mitochondrial content through upregulation of peroxi-some proliferator-activated receptor coactivator 1α in specific fiber types according to the level of exercise intensity undertaken as part of a training program.44 It is well recognized that routine exercise increases mitochon-drial content and the capacity for oxidative phosphoryla-tion and respiratory capacity per mitochondrion.44 Thus,an exercise program incorporating low-duration, low-intensity exercise, promoting mitochondrial biogenesis, is particularly advantageous to patients with Long COVID.

Emerging data indicate that exercise training pro-grams improve key outcomes in Long COVID, including peak Vo2,47-50 6-minute walk distance,47,49 and metrics of fatigue, dyspnea, or quality of life.47-49,51 For example, in a randomized crossover trial comparing exercise training for 6 weeks and usual care, patients with Long COVID(n=89) experienced improvements in peak Vo2 by≈2 mL-kg-1.min-1 and muscle strength on a 1-repetition maximum effort and reductions in depression and psy-chological distress.50 In another analysis, patients with Long COVID(n=39) randomized to exercise training for 8 weeks compared with control subjects experienced improvements in peak Vo2 and measures of fatigue,depression, and overall quality of life.48

SOCIETAL IMPACT AND DISPARITIES RESULTING FROM LONG COVID

Health disparities and inequities across health care are well documented and often driven by social and structural

factors. Health disparities are defined as differences in health outcomes resulting from social, economic, or envi-ronmental disadvantage. These differences in outcomes are determined by the conditions in which individuals live, learn, work, play, and pray, also referred to as social determinants of health.52,53 Health disparities are often described within the context of racial and ethnic dispari-ties, as well as health behaviors and exposure to risky behaviors.

Black people, Hispanic people, and Asian people were disproportionally affected by the COVID-19 pandemic,experiencing higher rates of infection, hospitalization,and death.54-56 Increased exposure and transmission of COVID-19 were also identified among individuals with lower socioeconomic status living in multigenera-tional homes and densely populated areas.54 Preexisting health disparities were exacerbated by the COVID-19 public health crisis, and these disproportionate health outcomes for ethnic minority groups have cascaded through COVID-19 infection to those experiencing Long COVID.54,57 Groups at higher risk for Long COVID include women, older adults, individuals with preexisting depres-sion and anxiety, and minority and socioeconomically disadvantaged groups, in part because of higher rates of infection and presence of comorbid conditions.54,57-59 However, a population-level analysis suggested that diagnosis codes associated with Long COVID are more likely to be used for individuals who are White and non-Hispanic and for those living in areas with low poverty and low unemployment.60 This discrepancy may suggest that Long COVID is underrecognized and undertreated in some populations who are most affected.

Multidisciplinary clinics have emerged to provide com-prehensive management strategies to patients with Long COVID. However, underinsured patients and those with limited financial means may have difficulty accessing cli-nicians with pertinent expertise, including but not limited to exercise therapists and sports cardiologists familiar-ized with exercise protocols tailored to the patient with cardiovascular deconditioning. Moreover, certain patient groups may be particularly disadvantaged in terms of access to care. For example, it has previously been demonstrated that Black individuals, Hispanic individu-als,Asian individuals, and women are less likely to attend cardiac rehabilitation.61,62 Specific factors limiting access or participation include referral inequities, financial and social stressors, and lack of transportation.

These factors underscore the need for additional research in this area. Specifically, further research is needed to understand how community resources, virtual care, and referral incentives can be leveraged to improve access to exercise therapy in disadvantaged populations.Evidence suggests that cardiovascular manifestations of Long COVID may be worse among members of ethnic minority and socially disadvantaged groups. ${}^{54,63}$ Aware-ness and recognition of these disparities are essential

to overcome these disparities, and treatment strategies need to address the social determinants of health that influence exposure to treatment centers.

RETURN TO PLAY FOR ATHLETES WITH LONG COVID

Because of the initial concerns of cardiac injury after COVID-19 infection,64-67 early consensus recommen-dations68,69 endorsed a conservative RTP screening ap-proach with 12-lead ECG, cardiac biomarker assessment(high-sensitivity troponin-l), and echocardiography(com-bined triad testing) for any athlete with COVID-19 symp-tomatology. Over time, however, robust data from large registries of previously infected US professional and col-legiate athletes confirmed a low prevalence of clinical cardiac pathology.70-72 Moreover, no COVID-19-associ-ated acute cardiac deaths or cardiac arrests have been reported from these registries.70,71 Only the presence of cardiopulmonary symptoms, including chest tight-ness/pain, dyspnea, palpitations, or lightheadedness/syncope, was predictive of myocardial involvement after COVID-19 infection.70 Therefore, current COVID-19 RTP recommendations advise cardiac evaluation only for athletes who present with these types of abnormalities.

Athletes With Long COVID and Consideration of Return to Exercise and Sport

Persistent cardiopulmonary symptoms6770 increase the probability of cardiovascular conditions(eg, myocarditis)that can be present during the early postacute or chron-ic periods of COVID-19 compared with cardiovascular symptoms that extend beyond the acute infection and are not fully explained by initial cardiac testing.4 For Mas-ters athletes who may harbor traditional cardiovascular risk factors,73,74 noncardiopulmonary COVID-19 symp-toms are still unlikely to be reflective of clinical myocar-ditis.70,71,75 Although data are limited for Long COVID,athletes with persistent noncardiopulmonary symptoms are unlikely to have myocardial involvement.70

Among athletes with Long COVID, persistent cardio-pulmonary symptoms warrant clinical evaluation and triad cardiac testing4 before RTP(Figure 5). If triad testing is normal but cardiopulmonary symptoms persist, cardiac magnetic resonance is then recommended to definitively exclude myocardial involvement. For all noncardiopul-monary Long COVID symptoms, cardiac testing is not recommended. In addition, if definitive cardiac imaging with cardiac magnetic resonance is normal but cardio-pulmonary symptoms persist, surveillance imaging is not recommended.

Determining whether borderline cardiac abnormalities(eg, isolated late gadolinium enhancement by cardiac magnetic resonance,72,76,77 mildly reduced LV ejection

 Figure 5. Return to play for individuals with Long COVID.

CMR indicates cardiac magnetic resonance imaging;cTn,cardiac troponin; and PFT,pulmonary function tests."Cardiopulmonary symptoms include chest pain/tightness, dyspnea, palpitations, and lightheadedness/syncope. tConsider individualized assessment/testing that could include cardiology consultation,ECG,cTn,and echocardiogram.

fraction,78 isolated troponin elevation) indicate frank car-diac involvement in athletes with Long COVID can be challenging and requires careful adjudication. Findings specific to each test such as the pattern of late gado-linium enhancement(right ventricular insertion-point late gadolinium enhancement is unlikely a finding of myocar-ditis)79-81 or the degree of troponin elevation and whether it was measured soon after exercise or after a period of at least 72 hours of rest(because postexercise tropo-nin elevations normalize within 72 hours after exercise,whereas persistent elevations in troponin are more indic-ative of cardiac injury)62 must be considered. Integration of the history and the compilation of all test findings is critical to determine the likelihood of cardiac involvement.Adjunctive tests such as stress echocardiography,83 ambulatory rhythm monitoring, or cardiopulmonary exer-cise testing may be useful as part of this determination.

In cases of clinical myocarditis, the 2015 American Heart Association/American College of Cardiology sports eligibility guidelines recommend 3 to 6 months of

exercise abstinence.84 However, because this duration is a non-evidence-based timeline, RTP can be consid-ered before 3 months with resolution of cardiopulmonary symptoms and biomarker evidence of cardiac inflamma-tion,normalization of LV systolic function, and absence of inducible cardiac arrhythmias.

Duration of Long COVID and Consideration of RTP Cardiac Evaluation

It is plausible that some athletes, more likely recreational,could delay presentation to the clinical setting after more extended time periods with Long COVID symptoms. If cardiopulmonary symptoms persist for≤3 months, we recommend proceeding with a complete cardiac evalua-tion. However, if cardiopulmonary symptoms persist for>3 months, it is reasonable to individualize cases in determin-ing the appropriate cardiac assessment. The rationale for this timeline stems from the minimum period of 3 months of exercise abstinence in cases of confirmed myocarditis.84

The presence and quality of other Long COVID symp-toms, specific cardiac symptoms disclosed, and trajectory of symptom severity are factors that may guide decision-making and level of cardiac testing deemed necessary.

KNOWLEDGE GAPS AND FUTURE DIRECTIONS

As COVID has transitioned from a worldwide pandemic to an endemic phase, a substantial minority of individuals acutely infected with COVID will go on to develop the Long COVID syndrome. Future research should focus on prevention through identifying risk factors predisposing to the development of Long COVID(eg, genetic, health related, socioeconomic), which will inform interventions to reduce the risk of developing this syndrome after the index infection. Further research is necessary to under-stand the mechanisms contributing to the multiple organ systems and symptoms characteristic of this syndrome,which will inform the development of additional treatment algorithms to alleviate symptom burden.

CONCLUSIONS

Long COVID is a devastating syndrome, affecting up to 25% of individuals previously infected with SARS-CoV-2. Although multiple factors contribute to develop-ment of this syndrome, there is accumulating evidence that cardiovascular deconditioning is a central compo-nent of the pathophysiology. This deconditioning results from a relative reduction in physical activity in the setting of the index infection and its quarantine/confinement and leads to cardiac atrophy, a reduction in ventricular distensibility, and steepening of the Frank-Starling curve.Clinically, this phenomenon results in symptoms such as lightheadedness and orthostatic intolerance, brain fog/confusion,tachycardia with minimal effort, palpitations,dyspnea on exertion, and severe fatigue/exhaustion.Re-ductions in Vo2 observed among individuals with Long

COVID are comparable to reductions observed among individuals with cardiovascular deconditioning as a result of bed rest. An exercise prescription specifically tailored to the patient with cardiovascular deconditioning may be an effective method of improving symptom severity. A shared decision-making process should be incorporated to determine the best methods for incorporating an exer-cise program into patient management and diagnostic/clinical evaluation for determining the optimal timing for RTP among affected athletes.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or poten-tial conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Spe-cifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Sci-ence Advisory and Coordinating Committee on May 9,2025, and the Ameri-can Heart Association Executive Committee on June 18,2025. A copy of the document is available at https://professional.heart.org/statements by using either“Search for Guidelines& Statements" or the“Browse by Topic” area.To purchase additional reprints, call 215-356-2721 or email Meredith.Edelman@wolterskluwer.com

The American Heart Association requests that this document be cited as follows: Cornwell WK 3rd, Levine BD, Baptiste D,Bhave N,Desai S,Dineen E,Durstenfeld M,Edward J,Huang M,Jacobsen R,Kim J,Spatz E;on behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Second-ary Prevention Committee of the Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Hypertension; Council on Life-style and Cardiometabolic Health; Council on Peripheral Vascular Disease; and Stroke Council. Exercise intolerance and response to training in patients with postacute sequelae of SARS-CoV2(long COVID): a scientific statement from the American Heart Association. Circulation.2025;151:e***-e***. doi: 10.1161/CIR.0000000000001348

The expert peer review of AHA-commissioned documents(eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the"Guide-lines& Statements" drop-down menu, then click"Publication Development."

Permissions: Multiple copies,modification,alteration,enhancement,and dis-tribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions.A link to the"Copyright Permissions Request Form" appears in the second paragraph(https://www.heart.org/en/about-us/statements-and-policies/copyright-request-form).

Disclosures

Writing Group Disclosures

|Writing group member|Employment|Research grant|Other research support|Speakers' bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |William K. Cornwell III|University of Colorado Anschutz Medical Campus Clinical Translational Research Center|None|None|None|None|None|None|None| |Benjamin D. Levine|University of Texas Southwestern Medical Center, Texas Health Presbyterian Hospital, Dallas Institute for Exercise and Environmental Medicine|None|None|None|None|None|None|None|

(Continued)

Writing Group Disclosures Continued

|Writing group member|Employment|Research grant|Other research support|Speakers' bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Diane Baptiste|Johns Hopkins University School of Nursing Center for Cardiovascular and Chronic Care|None|None|None|None|None|None|None| |Nicole Bhave|University of Michigan|None|None|None|None|None|None|None| |Sarika Desai|Arizona Heart 360|None|None|None|None|None|None|None| |Elizabeth Dineen|Mayo Clinic|None|None|None|None|None|None|None| |Matthew Durstenfeld|University of California, San Francisco and Zuckerberg San Francisco General|UCSF Resource Evaluation and Allocation Committee Grant(pilot study of Cardiac Rehabilitation for Long COVID)+; NHLBI(K12 and K23 Career Development Awards)t; National Institute on Aging (long COVID clinical trial of an immunomodulatory strategy [REVERSE-LC])+|None|None|None|None|Merck*|None| |Justin Edward|University of Colorado Anschutz Medical Campus|None|None|None|None|None|None|None| |Mu Huang|American Heart Association National Center|None|None|None|None|None|None|None| |Roni Jacobsen|Children's Hospital Colorado|None|None|None|None|None|None|None| |Jonathan Kim|Emory University School of Medicine,Emory Clinical Cardiovascular Research Institute|NIH/NHLBI(R01[PI])+|None|None|None|None|None|None| |Erica Spatz|Yale School of Medicine|Centers for Disease Control and Prevention*|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be"significant" if(a) the person receives$5000 or more during any 12-month period, or 5% or more of the person's gross income; or(b) the person owns 5% or more of the voting stock or share of the entity, or owns$5000 or more of the fair market value of the entity. A relationship is considered to be“modest” if it is less than“significant” under the preceding definition.

"Modest.

tSignificant.

Reviewer Disclosures

|Reviewer|Employment|Research grant|Other research support|Speakers' bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Eugene H. Chung|Massachusetts General Hospital|None|None|None|None|None|None|None| |Jerome Fleg|National Heart, Lung, and Blood Institute|None|None|None|None|None|None|None| |Ty J. Gluckman|Providence Heart Institute, Center for Cardiovascular Analytics, Research, and Data Science|None|None|None|None|None|None|None|

(Continued)

Reviewer Disclosures Continued

|Reviewer|Employment|Research grant|Other research support|Speakers' bureau/ honoraria|Expert witness|Ownership interest|Consultant/ advisory board|Other| |---|---|---|---|---|---|---|---|---| |Erin J. Howden|Baker Heart and Diabetes Institute (Australia)|NHMRC(research grant to support study of efficacy of exercise training for people with long COVID)t; NHMRC (research grant to support research project to understand the mechanisms of blood pressure regulation in people with long COVID)t; Mason Foundation (research grant to support study of autonomic function in people with long COVID and ME/CFS)+|None|None|None|None|None|None| |Richard Kovacs|Indiana University, Kranner Institute of Cardiology|None|None|None|None|None|None|None| |Justin Lawley|University of Innsbruck(Austria)|None|None|None|None|None|None|None| |Valentina O. Puntmann|University Hospital Frankfurt (Germany)|Bayer AG(support of IIR [Myoflame-19 RCT])+|DZHK (research program and infrastructure)t|None|None|Goethe CVI GmbHt|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Ques-tionaire, which all reviewers are required to complete and submit. A relationship is considered to be"significant" if(a) the person receives$5000 or more during any 12-month period, or 5% or more of the person's gross income; or(b) the person owns 5% or more of the voting stock or share of the entity, or owns$5000 or more of the fair market value of the entity. A relationship is considered to be“modest” if it is less than“significant” under the preceding definition.

tSignificant.

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