COVID-19: Insights into long-term manifestations and lockdown impacts

Highlights

• •Non-respiratory symptoms are common in acute and post-acute coronavirus disease 2019 (COVID-19), including many aspects of cardiovascular diseases (CVDs).
• •CVDs are still the leading cause of deaths globally.
• •Sufficient levels of regular physical activity (PA) are crucial for cardiovascular health, healthy bodyweight, and good mental health.
• •Regular PA reduces the risk of severe COVID-19 outcomes.
• •New techniques such as fitness tracking apps and wearables, online sports classes, tele-rehabilitations or simple training at home according to special exercise plans are promising tools to achieve regular PA in difficult situations such as lockdowns.

Abstract

Coronaviruses are pathogens thought to primarily affect the respiratory tracts of humans. The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 was also marked mainly by its symptoms of respiratory illness, which were named coronavirus disease 2019 (COVID-19). Since its initial discovery, many other symptoms have been linked to acute SARS-CoV-2 infections as well as to the long-term outcomes of COVID-19 patients. Among these symptoms are different categories of cardiovascular diseases (CVDs), which continue to be the main cause of death worldwide. The World Health Organization estimates that 17.9 million people die from CVDs each year, accounting for ∼32% of all deaths globally. Physical inactivity is one of the most important behavioral risk factors for CVDs. The COVID-19 pandemic has affected CVDs as well as the physical activity in different ways. Here, we provide an overview of the current status as well as future challenges and possible solutions.

Graphical Abstract

1. Introduction

For almost 3 years now, the coronavirus disease 2019 (COVID-19) pandemic has remained an acute global emergency.¹ The drastic measures that were temporarily implemented since the start of the pandemic have affected most aspects of human activity, including physical activity (PA), social interaction, and the ability to maintain regular health checks.

In addition, massive efforts were undertaken by the scientific community during the pandemic to gain new insights into the disease's mechanisms. For example, angiotensin-converting enzyme 2 was identified as the primary severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry receptor,^2,3 and its common expression could explain the wide range of affected organs.^3,4 Nevertheless, COVID-19 is complex and still far from being completely understood. Many non-respiratory symptoms—a number of them related to cardiovascular diseases (CVDs)^5,6—have been found to be associated with acute SARS-CoV-2 infections as well as with long-term manifestations of COVID-19 (Fig. 1). Angiotensin-converting enzyme 2, for example, also plays an important role in the disease severity and long-term complications of heart failure (HF) patients.^4,7

Fig. 1.

Potential symptoms of acute and post-acute coronavirus disease 2019 (COVID-19). People suffering from COVID-19 show a diverse range of symptoms and signs affecting different organ systems. Potential cardiovascular symptoms of acute COVID-19 and long COVID are highlighted in red.

CVDs, a group of cardiac and vascular disorders, are the leading cause of death worldwide.⁸ The World Health Organization (WHO) estimates that 17.9 million people die from CVDs each year (∼32% of all deaths globally), primarily from heart attacks and strokes.⁸ CVDs are considered to be age-related pathological conditions, and since the world's elderly population is steadily increasing, they pose a growing health and socio-economic burden.9, 10, 11, 12

Aside from an unhealthy diet, smoking, and harmful use of alcohol, physical inactivity (PI) is one of the most important behavioral risk factors for heart disease and stroke.^8,13 Individuals are classified as physically inactive if they do not follow PA guidelines.14, 15, 16 There is a distinction, however, between PI and sedentary behavior (SB), which describes any waking behaviors characterized by an energy expenditure ≤1.5 metabolic equivalents that is done while in a sitting, reclining, or lying position.^15,16 However, PA, which is defined as any bodily movement produced by skeletal muscles that results in energy expenditure, has been shown to be beneficial for cardiovascular health and to reduce the risk of CVDs.^8,13,14,17, 18, 19, 20, 21, 22, 23

There are 5 types of PA: aerobic (e.g., running, bicycling), muscle strengthening (weight lifting or resistance training), bone strengthening, balance activity, and multicomponent PA.²⁴ Depending on age, different types and amounts/intensities of PA are recommended for substantial health benefits (e.g., for adults, at least 150–300 min of moderate-intensity aerobic PA per week, 75–150 min of vigorous-intensity aerobic PA per week, or an equivalent combination of both is generally recommended).²⁴ Additionally, muscle-strengthening activities should be performed 2 or more days per week.²⁴ The 2nd edition of “Physical Activity Guidelines for Americans” provides detailed recommendations,²⁵ and additional specifications for staying physically active during self-quarantine were released by the WHO and the American College of Sports Medicine (Table 1).^26,27 Noteworthy, “green exercise” (PA in nature) positively affects mental health and quality of life, reduces mental health problems, and offsets the negative effects of unhealthy eating habits.^28,29

Table 1.

Staying active during the COVID-19 pandemic (according to WHO and ACSM recommendations^26,27).

Type of activity	Place	Example
Aerobic	Indoors	Walking, climbing stairs, and dancing
	Outdoors	Running, cycling
Muscle-strengthening	Indoors/outdoors	Performing squats, sit-ups from the chair, push-ups, lunges, lunges/rises to 1 leg, plates, back extension quadrupeds with 2 supports, glute bridge, and triceps backgrounds
Flexibility-stretching	Indoors/outdoors	Yoga, chest opener, child's pose
Relaxation-meditation	Indoors/outdoors	Yoga, seated meditation, legs up to the wall, mindfulness and deep breathing

Abbreviations: ACSM = American College of Sports Medicine; COVID-19 = coronavirus disease 2019; WHO = World Health Organization.

In this review, we focus on cardiovascular complications from COVID-19 infections and the impact of the pandemic on PA and cardiovascular health. Additionally, we provide an outlook on future challenges and possible solutions in these areas.

For this purpose, original articles focusing on CVDs, COVID-19, and PA were researched in MEDLINE, PubMed, and PubMed Central. The search terms used were: “COVID-19”, “SARS-CoV-2”, “long COVID”, “cardiovascular disease”, “physical activity”, and “lockdown”, alone and in combination.

2. Cardiovascular injury—A symptom of COVID-19

2.1. Cardiovascular complications of acute COVID-19

Diverse abnormalities such as elevated cardiac biomarkers, electrocardiographic irregularities, and various cardiovascular complications (e.g., myocarditis, myocardial injury, thrombosis, and arrhythmias) were reported among hospitalized COVID-19 patients (Table 2).30, 31, 32, 33, 34, 35, 36 The underlying cause may be initially challenging to identify, as one or more of these abnormalities can coexist.³⁰ Myocardial injuries were additionally observed in both asymptomatic COVID-19 patients and COVID-19 mRNA vaccine recipients. ^30,37, 38, 39

Table 2.

Cardiovascular complications of acute COVID-19.

Reference	Number of patients	Age (year)	Patient characteristic	Conduction time	Main finding
Shi et al. (2020)31	416	Median = 64 (range: 21–95)	-50.7% females -Hospitalized (Renmin Hospital of Wuhan University, Wuhan, Hubei Province, China) -76.0% oxygen inhalation, 12.3% non-invasive mechanical ventilation, 7.7% invasive mechanical ventilation -Patients with cardiac injury: 46.3% non-invasive mechanical ventilation, 22.0% invasive mechanical ventilation -Chronic medical illness: 30.5% hypertension, 14.4% diabetes, 10.6% coronary heart disease, 4.1% chronic heart failure	January 20, 2020 to February 10, 2020	-Occurrence of cardiac injury in 19.7% of patients during hospitalization -Cardiac injury was an independent risk factor for in-hospital mortality -Cardiac injury was defined as blood levels of cardiac biomarkers (hs-TNI) above the 99th-percentile upper reference limit -28.1% shortness of breath, 13.2% fatigue, 3.4% chest pain -26.8% of patients with cardiovascular injury underwent ECG: 63.6% of ECGs showed abnormal findings compatible with myocardial ischemia (T-wave depression and inversion, ST-segment depression and Q-waves)
McCullough et al. (2020)33	756	Mean ± SD = 63.3 ± 16.0	-37% females -61% non-White -Hospitalized (Weill Cornell Medicine/New York-Presbyterian Hospital, New York, USA) -57% hypertension, 29.4% diabetes, 14.4% coronary artery disease, 7.3% heart failure -37.3% were obese	March 3, 2020 to April 9, 2020	-5.6% atrial fibrillation/flutter, 2.6% atrioventricular block -7.7% atrial premature contractions, 3.4% ventricular premature contractions -19.3% abnormal axis -11.8% abnormal intraventricular conduction -15.5% left and 4.0% right ventricular hypertrophy -40.2% repolarization abnormalities were common (0.7% localized ST elevation, 10.5% localized T-wave inversion, 29.0% nonspecific repolarization abnormalities) -13.9% previous Q-wave MI -Higher odds of death for patients with ECG findings of both left-sided heart disease (atrial premature contractions, intraventricular block, repolarization abnormalities) and right-sided disease (right bundle branch block)
Wang et al. (2020)217	138	Median = 56 (range: 22–92)	-45.7% females -Hospitalized (Zhongnan Hospital of Wuhan University, Wuhan, Hubei Province, China) -26.1% ICU (of those 11.1% high-flow oxygen therapy, 41.7% non-invasive ventilation, 47.2% invasive ventilation) -29% health professionals -Comorbidities: 31.2% hypertension, 14.5% cardiovascular disease, 10.1% diabetes	January 1, 2020 to January 28, 2020	-8.7% shock (30.6% of ICU patients) -7.2% acute cardiac injury (22.2% of ICU patients) -16.7% arrhythmia (44.4% of ICU patients)
Zhou et al. (2020)218	191	Median = 56 (range: 18–87)	-38% females -Hospitalized (135 from Jinyintan Hospital, 56 from Wuhan Pulmonary Hospital, Wuhan, Hubei Province, China) -26% ICU -Comorbidities: 30% hypertension, 29% diabetes, 8% coronary heart disease	December 29, 2019 to January 31, 2020 (discharged or dead)	-23% heart failure -59% sepsis, 20% septic shock -19% coagulopathy -17% acute cardiac injury -17% elevated troponin -Identified risk factors on admission: older age, high Sequential Organ Failure Assessment (SOFA) score, and D-dimer greater than 1 µg/mL
Guo et al. (2020)219	187	Mean ± SD = 58.50 ± 14.66	-51.3% females -Hospitalized (Seventh Hospital of Wuhan City, Wuhan, Hubei Province, China) -24.1% mechanical ventilation -Comorbidities: 32.6% hypertension, 11.2% coronary heart disease, 4.3% cardiomyopathy, 15% diabetes	January 23, 2020 to February 23, 2020	-27.8% myocardial injury indicated by elevated troponin T levels -In contrast to survivors, non-survivors showed a significant increase of plasma troponin T and NT-proBNP levels during hospitalization -Myocardial injury resulted in cardiac dysfunction and arrhythmia -Myocardial injury was significantly associated with a fatal outcome
Bilaloglu et al. (2020)35	3334	Median = 64 (interquartile range: 51–75)	-39.6% females -Hospitalized (NYU Langone Health, New York, USA) -24.9% ICU -43.31% non-Hispanic White, 7.14% Asian, 1.47% Hispanic, 15.27% non-Hispanic African American, 27.14% other/multiracial, 5.67% unknown	March 1, 2020 to April 17, 2020 (hospital admission)	-16% any thrombotic event (patients could have more than one) -6.2% venous thrombosis (3.2% PE, 3.9% DVT) -11.1% arterial thrombosis (1.6% ischemic shock, 8.9% MI, 1% systemic TE) -Hispanic ethnicity, male sex, coronary artery disease, prior MI, and higher D-dimer levels within 24 h of admission were associated with a thrombotic event
Giustino et al. (2020)36	305	Mean age = 63	-32.8% females -Hospitalized (7 hospitals in NYC and Milan, Italy) -43.9% ICU -34.5% mechanical ventilation -57% White, 14.1% Black, 8.9% Asian, 20% unknown -27.6% Hispanic ethnicity -BMI 24.5–32.8 kg/m2 -Comorbidities: 59.3% hypertension, 37.4% diabetes, 7.4% prior MI, 9.5% prior stroke, 7.9% history of heart failure	March 2020 to May 2020	-62.3% myocardial injury -60% shortness of breath, 17.4% chest pain -28.2% shock -72.7% acute coronary syndrome -almost 2/3 of patients who underwent TTE showed cardiac structural abnormalities (right ventricular dysfunction, left ventricular wall motion abnormalities, global left ventricular dysfunction, diastolic dysfunction, and pericardial effusions) -30.9% of patients with myocardial injury developed ECG ischemic changes

Abbreviations: BMI = body mass index; COVID-19 = coronavirus disease 2019; DVT = deep vein thrombosis; ECG = electrocardiography; hs-TNI = high-sensitivity troponin I; ICU = intensive care unit; MI = myocardial infarction; NT-proBNP = N-terminal pro–brain natriuretic peptide; NYC = New York City; PE = pulmonary embolism; TE = thromboembolism; TTE = transthoracic echocardiography.

Remarkably, although rather infrequently, both fulminant myocarditis with cardiogenic shock or distributive shock resulting from sepsis and/or a hyperinflammatory state can occur with COVID-19. Importantly, case numbers seem to exceed the ones associated with viral myocarditis unrelated to COVID-19.^30,40, 41, 42, 43, 44

Interestingly, in children (<18 years), most COVID-19 infections are asymptomatic or mild and hospitalizations are rare (though they did increase after the spread of the Delta variant).45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 However, multisystem inflammatory syndrome in children still occurred.^45,58 An assessment of multisystem inflammatory syndrome in children across the United States, most with no underlying conditions, revealed 80% with cardiovascular involvement, including elevated levels of B-type natriuretic peptide (73%) and troponin (50%), but with less severe or no respiratory problems.^45,59 However, a systematic review and meta-analysis reported a higher risk of severe COVID-19 and associated mortality for children with comorbidities, such as obese children, who had a 2.87 times higher risk of severe COVID-19.⁵⁴

As most data were gathered from hospitalized patients, more studies of asymptomatic and mild cases are required to better assess the percentage of cardiac involvement, particularly with respect to post-acute and long-term cardiovascular consequences, which are reported with increasing frequency.^5,60

2.2. Long-term cardiovascular outcomes of COVID-19

The term post-acute sequelae of SARS-CoV-2 infection (PASC) refers to a constellation of symptoms that emerge or persist after recovery from COVID-19, usually lasting for 4–12 weeks and beyond.^30,61,62 The terms: long COVID, post-acute COVID-19 syndrome, and long-haul COVID are also used to describe persisting symptoms after SARS-CoV-2 infection.^61,63,64 These patients suffer from diverse symptoms, such as fatigue, cognitive dysfunction, sleep disturbance, tachycardia, chest pain, and exercise intolerance.³⁰ Nearly all organ systems can be affected and, therefore, quality of life can be dramatically impacted. Importantly, even asymptomatic or minorly symptomatic individuals can experience long-term COVID-19 conditions.^30,65

It is difficult to estimate the prevalence of long COVID as it is influenced by various factors, including differences in cohort characteristics, age, and sex of subjects enrolled, timing of assessment, sociodemographic factors, vaccines and variants, pre-existing health problems, sample size, study design, and variability in questionnaires or tools used.⁶⁰ Consequently, the reported prevalence is highly variable both across and within countries (e.g., 49%–76% in China, 35%–77% in Germany, and 16%–53% in the United States^60,66, 67, 68, 69, 70, 71). However, risk factors (Fig. 2) for developing long COVID appear to be relatively consistent.⁶⁰ In particular, female sex, increased age, obesity, asthma, poor general health, poor pre-pandemic mental health, poor sociodemographic factors, and type of work place (social/health care or teaching and education) represent important determinants across several studies.^60,72, 73, 74, 75 Ironically, nationwide lockdowns and working remotely, which were measures meant to limit the spread of COVID-19, also restricted PA, increased obesity and poor dietary intake, and negatively affected mental health.^60,76, 77, 78

Fig. 2.

Long COVID risk factors. Important determinants for developing long-term symptoms after the acute illness across several studies include obesity, increasing age, female sex, poor sociodemographic factors, work place (social care, health care, teaching and education), poor general health, asthma, and poor pre-pandemic mental health. COVID = coronavirus disease.

With respect to cardiovascular manifestations, recent articles were published reporting persistent cardiovascular symptoms after the acute phase of COVID-19 infections. These studies can be divided into 2 categories: retrospective (Table 3), those that rely on electronic medical health records and labeled datasets; or prospective (Table 4), those that use innovative technologies such as telemedicine, symptom apps, or face–face reviews.^5,60,66,79, 80, 81, 82, 83

Table 3.

Retrospective cohort studies.

Reference	Number of patients	Age (year)	Patient characteristic	Follow-up time	Controls	Main finding
Ayoubkhani et al. (2021)81	47,780	Mean age = 65	55% men; hospitalized; UK citizens	140 days	About 50 million English people (electronic health records)	-Increased risk of multiorgan dysfunctions -127 (122–132) diagnoses of cardiovascular disease (p < 0.001) per 1000 person years -Increase in risk was not confined to the elderly and was not uniform across ethnicities
Al-Aly et al. (2021)79 (The first part)	73,435	Mean age = 61	88% men; non-hospitalized; US citizens	126 (81–203) days for patients; 130 (82–205) days for VHA users	4,990,835 VHA users (no COVID-19 infection, non-hospitalized)	-People with COVID-19 exhibit a higher risk of death (estimated excess death 8.39 per 1000 persons at 6 months) and use of health resources -Incident sequelae, among others, in the cardiovascular system (hypertension, cardiac dysrhythmias, circulatory signs + symptoms, chest pain, coronary atherosclerosis, heart failure)
Al-Aly et al. (2021)79 (The second part)	13,654	Mean age = 70	94% men; hospitalized; US citizens	150 (84–217) days for patients; 157 (87–220) days for VHA users	13,997 patients (hospitalized with seasonal influenza)	-Individuals with COVID-19 had a higher risk of death (estimated excess death 28.79 per 1000 persons at 6 months) -COVID-19 patients had a higher burden of different pulmonary and extra-pulmonary systemic manifestations, e.g., cardiovascular disorders (a burden of 17.92 (10.73–24.35) for circulatory signs and symptoms)
Daugherty et al. (2021)220	266,586	Mean age = 42(18–65)	43% men; hospitalized and non-hospitalized; US citizens	6 months, excess risk after 4 months	-266,586 matched pairs for the 2020 group without clinical diagnosis and for the historical group (2019) -244,276 matched pairs for the viral lower respiratory tract illness comparator group	-14% suffered from at least 1 new type of clinical sequelae that required medical care after the acute phase of the illness (4.95% higher than in the 2020 comparator group) -Increased risk of specific clinical sequelae after the acute infection in different organ systems, including cardiovascular complications -Rising risk for incident sequelae according to age, pre-existing conditions, and hospitalization -Still elevated risk for some clinical sequelae in adults aged ≤50, non-hospitalized patients, and those with no pre-existing conditions
Cohen et al. (2022)221	133,366 (total number); was matched to control groups	Mean age = 77 (>65)	44% men; hospitalized and non-hospitalized; US citizens	Excess risk after 120 days	-2020 control (n = 87,337) -Historical 2019 control (n = 88,070) -Historical control with viral lower respiratory tract illness (n = 73,490)	-32% suffered from at least 1 new type of clinical sequelae that required medical care after the acute phase of the illness (11% higher than in the 2020 comparison group) -Among others, hypertension (risk difference = 4.43, 95%CI: 2.27–6.37) and cardiac rhythm disorders (risk difference = 2.19, 95%CI: 1.76–2.57) had the greatest risk differences (compared to 2020 & 2019 controls) -Comparison with the historical viral lower respiratory tract illness control revealed no increased risk for cardiovascular disorders
Xie et al. (2022)5	153,760	Mean age = 62	89% men; hospitalized, non-hospitalized, and admitted to ICU; US citizens	347 (317–440) days for patients; 348 (318–441) days for VHA users (contemporary); 347 (317–440) days for VHA users (historical)	-5,637,647 (contemporary controls) -5,859,411 (historical controls)	-12 months risk of developing any of the 20 pre-specified cardiovascular outcomes was 63% higher in COVID-19 patients compared to the contemporary control group -12 months risk of MACE (a composite of myocardial infarction, stroke, and all-cause mortality) was 55% higher in COVID-19 patients vs. contemporary controls -As compared to the contemporary control group, the excess burden of a MACE was 23.48 while that of any cardiovascular outcome was 45.29 per 1000 COVID-19 patients at 12 months
aThe OpenSAFELY Collaborative, Tazare et al. (2022)222	77,347	Median age = 68 (adults aged ≥18)	51.5% men; hospitalized; UK citizens	One year total follow-up, then stratified into time windows: 0–29 days, 30–59 days, 60–89 days, 90–120 days, and 120+ days post discharge	-127,987 (patients discharged with pneumonia) -186,669 (matched general population control)	-Rates for the majority of the 7 measured outcomes (DVT, PE, ischemic stroke, MI, heart failure, AKI, and T2DM) peaked in the first month post-discharge, then declined over the following 4 months -COVID-19 patients had an increased risk of cardio-metabolic and pulmonary adverse outcomes compared to the general population -Excess risks were similar to those of patients discharged with pneumonia
Al-Aly et al. (2022)82	33,940 (3667 hospitalized with BTI vs. seasonal influenza)	Mean age = 67	91% men; hospitalized, non-hospitalized, and admitted to ICU; US citizens	6 months, divided in periods 30–90 days and 90–180 days	-4,983,491 (contemporary controls) -5,785,273 (historical controls) -2,566,369 (vaccinated controls) -113,474 (SARS-CoV-2 infection without prior vaccination) -14,337 (hospitalization with seasonal influenza)	-6 months risk of death and risk of incident post-acute sequelae were, respectively, 75% and 50% higher in patients with BTI as compared to the contemporary controls -Risks increased according to the severity of the acute illness (evident in non-hospitalized, higher in hospitalized, and highest in patients with admission to intensive care) -People with BTI had a 34% lower risk of death and a 15% lower risk of incident post-acute sequelae compared to patients with SARS-CoV-2 infection who were not previously vaccinated -Hospitalized patients with BTI had an increased risk of death (HR = 2.43) and of having at least 1 post-acute sequela (HR = 1.27) as compared to people hospitalized with seasonal flu

Abbreviations: 95%CI = 95% confidence interval; AKI = Acute kidney injury; BTI = break through infection; COVID-19 = coronavirus disease 2019; DVT = deep vein thrombosis; HR = Hazard ratio; ICU = intensive care unit; MACE = major adverse cardiovascular event; MI = myocardial infarction; PE = pulmonary embolism; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; T2DM = new type 2 diabetes mellitus; VHA = Veterans Health Administration.

^aPreprint.

Table 4.

Prospective cohort studies.

Reference	Number of patients	Mean age (year)	Patient characteristic	Follow-up time	Controls	Main finding
Puntmann et al. (2020)37	100	49	53% men; 67% non-hospitalized; 33% hospitalized; German citizens	Median 71 days (range: 64–92 days)	-50 healthy volunteers (age-/sex-matched) -57 risk factor-matched	-Lower LVEF, higher left ventricle volumes -78% abnormal CMR findings (73% raised myocardial native T1, 60% raised myocardial native T2, 32% LGE, and 22% pericardial enhancement) -60% myocardial inflammation -20% palpitations, 17% atypical chest pain, 36% dyspnea and fatigue
de Graaf et al. (2021)223	81	61 ± 13 (range: 27–88)	63% men; hospitalized; 41% ICU	6 weeks after discharge	-No control group	-62% NYHA Class II–III, 15% palpitations, 14% chest pain, 32% limited functional status -18% reduced left ventricular function, 10% reduced right ventricular function
Hall et al. (2021)224	200	54.8 ± 15.0	61.5% men; hospitalized; 38.5% ICU; 27.5% mechanical ventilation	4–6 weeks post discharge	-No control group	-40% dyspnea, 4% cardiac complications
Catena et al. (2021)225	105	57 ± 14	53% men; hospitalized	Median 41 days post COVID-19 diagnosis	-No control group	-No significant differences in left and right ventricular systolic and diastolic function between COVID-19 patients with or without prior serum troponin I increase
Lambert et al. (2022)226	5163	≤18 (77%: 35–64)	85.7% women; 89.3% non-hospitalized; 77.1% confirmed SARS-Cov-2 diagnosis by RT-PCR or clinician	Experience of symptoms for longer than 21 days	-Survey → no control	-Survey participants reported a mean of 21 symptoms -Fatigue (78.97%), shortness of breath (55.28%), inability to exercise or be active (49.56%), heart palpitations (39.47%), chest pain (33.37%), tachycardia (31.76%), arrhythmia (24.13%) -Longest lasting symptoms included the inability to exercise (106.5 days) and fatigue (101.7 days)
Havervall et al. (2021)227	323 (sero-positive)	Median age = 43 (adults aged 33–52)	83% women; health care professionals; no or mild prior symptoms; Swedish citizens	8 months	-1072 sero-negative participants; median age of 47 (36–56); 86% women	-26% sero-positive vs. 9% sero-negative participants reported at least 1 moderate to severe symptom lasting for at least 2 months, and 15% vs. 3% had at least 1 moderate to severe symptom lasting for at least 8 months -Sero-positive: 8.4% (≥2 months), 6.8% (≥4 months), 4.0% (≥8 months) fatigue; 4.3% (≥2 months), 3.4% (≥4 months), 1.9% (≥8 months) dyspnea; 2.5% (≥2 months), 1.9% (≥4 months), 0.6% (≥8 months) palpitations -Long-term symptoms impaired work, social, and home life of a considerable portion of low-risk individuals with mild COVID-19
Sonnweber et al. (2021)85	145	57 ± 14 (adults aged 19–87)	55% men; 61% overweight/obese; 75% hospitalized; 22% ICU; Austrian citizens	60- and 100-day post diagnosis	-No control group	-36% dyspnea after 100 days -60% diastolic dysfunction after 60 days, 55% after 100 days -4 participants (3%) showed a reduced LVEF after 60 and 100 days -10% pulmonary hypertension after 60 and 100 days -6% pericardial effusion after 60 days, 1% after 100 days
Moody et al. (2021)228	79	57 ± 11	74% men; hospitalized; 80% mechanical ventilation	3 months post discharge	-No control group	-14% right ventricular systolic dysfunction, 9% dilated right ventricle -9% left ventricular systolic dysfunction, 3% dilated left ventricle -72% low, 5% intermediate probability of pulmonary hypertension -4% pericardial effusion
Kotecha et al. (2021)84	148	64	70% men; hospitalized; elevated troponin levels; UK citizens	68 days	-40 patients matched historical control -40 healthy volunteers	-89% normal left ventricular function -54% cardiac abnormalities (26% myocarditis, 22% infarction and/or ischemia, 6% dual pathology)
Whitaker et al. (2022)73	606,434 (first analysis: 508,707 (survey) 76,155 (PSP); replication: 97,727)	≤18	57.3% women (PSP); community based; UK citizens	4 and 12 weeks	-Survey → no control group	-37.7% of 76,155 symptomatic people had at least 1 symptom, 17.5% had 3 or more symptoms lasting 12 weeks or longer (first analysis) -In the replication, 21.6% had at least 1 symptom and 11.9% had 3 or more symptoms at 12 weeks -Women had a higher risk (∼8 percentage points) of persistent symptoms than men at all ages -Risk of persistent symptoms increased linearly with age by 3.5 percentage points per decade of life -∼25% had predominantly respiratory symptoms (e.g., shortness of breath, tight chest, chest pain) 12 weeks post symptom onset -∼75% had predominantly less organ-specific symptoms, particularly fatigue -Female sex, increasing age, obesity, smoking, vaping, hospitalization with COVID-19, deprivation, and healthcare workers had a higher probability of long-term symptoms -Asian ethnicity had a lower probability of persistent symptoms
Sechi et al. (2021)89	105	57 ± 14	53% men; hospitalized; 26% mechanical ventilation	Median of 41 days post COVID-19 detection	-105 matched controls	-Male sex was more frequent in severe (74%) than mild-to-moderate (46%) COVID-19 -For mild-to-moderate vs. severe disease: 5%, 4% dyspnea; 4%, 7% chest pain; 8%, 11% abnormal sinus rhythm; 6%, 7% fatigue -Comparable echocardiographic findings between patients with mild-to-moderate and severe illness
Davis et al. (2021)229	3762 (1020 confirmed COVID-19)	86.9% between 30 and 60	78.9% women; 85.3% White; from 56 countries	Weeks 1–4 and Months 2–7	-Online survey → no control group	-The time to recovery exceeded 35 weeks in >91% -An average of 55.9 ± 25.5 (mean ± SD) symptoms were experienced during the illness -Mean prevalence of cardiovascular symptoms at any point of the disease: 86.04% -Palpitations, tachycardia, and chest pain are the most frequently reported cardiovascular symptoms
Peghin et al. (2021)230	599	53 ± 15.8	53.4% women; 73.8% non-hospitalized, 26.2% hospitalized, and 3.8% ICU	187 ± 22 days		-Post COVID-19 prevalence: 40.2% -13.1% fatigue, 6.0% dyspnea, 0.8% chest pain
Petek et al. (2022)231	3597	20 ± 1	66% men; collegiate athletes	3, 4, and 12 weeks	-No control group	-1.2% of athletes had persistent symptoms longer than 3 weeks post infection -0.02% had persistent symptoms for more than 12 weeks -4% had exertional cardiopulmonary symptoms -8.8% of cases of athletes with exertional symptoms (e.g., cardiac involvement, inappropriate sinus tachycardia) were related to SARS-CoV-2 sequelae -20.8% of athletes who developed chest pain on return to sports had probable or definite cardiac involvement assessed by CMR
Huang et al. (2021)66	1733	57	52% men; hospitalized; 4% ICU	Median of 186 days	-No control group	-63% fatigue or muscle weakness -9% palpitations, 5% chest pain
Huang et al. (2021)67	1276	59	53% men; hospitalized; 4% ICU	Median of 185 days and median of 349 days	-No control group	-68% at least 1 symptom (6 months), 49% (12 months) -52% fatigue or muscle pain (6 months), 20% (12 months) -26% dyspnea (6 months), 30% (12 months) -10% palpitations (6 months), 9% (12 months) -5% chest pain (6 months), 7% (12 months)
Dennis et al. (2021)90	201	45 (range: 21–71)	71% female; 88% White; 32% healthcare workers; 18.4% hospitalized	Median of 141 days	-Age-matched healthy control (n = 36)	-98% fatigue, 88% dyspnea, 76% chest pain -19.4% myocarditis, 9% systolic dysfunction
Raman et al. (2021)232	58	55 ± 13	59% men; hospitalized; 36.2% ICU; 20.7% mechanical ventilation	2–3 months	-Co-morbidity matched control (n = 30)	-64% dyspnea, 55% fatigue -26% cardiac abnormalities on MRI
Rajpal et al. (2021)105	26	19.5 ± 1.5	42% women; competitive college athletes	11–53 days after positive test	-No control group	-46% LGE (mean of 2 American Heart Association segments); of those, 30.8% had LGE without concomitant T2 elevation -15% myocarditis (7.5% had mild symptoms, such as shortness of breath; 7.5% were asymptomatic) -8% pericardial effusion
Joy et al. (2021)233	74	37 (range: 18–63)	58% women; healthcare workers; 85% mostly mild symptoms; 15% asymptomatic; 2.7% hospitalized	6 months	-75 age-, sex-, and ethnicity-matched sero-negative control subjects	-11% reported symptoms after 6 months -3% fatigue, 2% shortness of breath -4% myocarditis-like scare in both groups, the sero-positive and sero-negative; no significant differences
Myhre et al. (2021)234	58	Median age = 56 (range: 50–70)	56% men; hospitalized; 19% mechanical ventilation	Median 175 days	-32 healthy controls	-64% fatigue, 55% dyspnea, 4% chest pain -21% abnormal CMR; of those, 5% had a major pathology (scar and LVEF < 50% or LVEF < 40%) -17% had a myocardial scar
Hanneman et al. (2022)91	47	43	49% men; 85% non-hospitalized; 9% hospitalized, 6% ICU; Canadian	Mean ± SD = 52 ± 17 days	-No age-, sex-, and comorbidity-matched control group	-17% had focal FDG uptake on PET consistent with myocardial inflammation -FDG uptake patients showed higher regional T2, T1, and extracellular volume, higher prevalence of LGE (75% vs. 23%, p = 0.009), a reduced LVEF (55% ± 4% vs. 62% ± 5%, p < 0.001), and higher systemic inflammatory blood markers (e.g., IL-6, IL-8, high-sensitivity CRP) -40% had at least 1 cardiac symptom, including 23% palpitations, 19% chest pain, 21% dyspnea
Strahm et al. (2022)158	784 (556 positive NPS, 228 only seropositive)	Median age = 38.9 (positive NPS), 37.9 (seropositive)	80% women; healthcare workers	Median of 117 days	-Non-infected control group (n = 2550)	-73% (positive NPS) and 52% (only sero-positive) reported ≥1 symptom -Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores -Most commonly reported symptoms are fatigue, shortness of breath, chest pain, olfactory dysfunction, and neurocognitive impairment
O'Laughlin et al. (2022)235	2400	–	–	18 months	-Non-infected control group (n = 2400)	-Ongoing -Will characterize medium- and long-term sequelae of COVID-19 among a diverse population including predictors and relative risks

Abbreviations: CMR = cardiovascular magnetic resonance; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; FDG = fluorodeoxyglucose; IL= interleukin; ICU = intensive care unit; LGE = late gadolinium enhancement; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; NPS = nasopharyngeal swab; NYHA = New York Heart Association; PET = positron emission tomography; PSP = primary study population; RT-PCR = reverse transcription-polymerase chain reaction; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Within the scope of retrospective cohort studies, Xie and colleagues⁵ analyzed the national healthcare databases from the U.S. Veterans Health Administration system to estimate the risks and 1-year burdens of a set of pre-specified incident cardiovascular outcomes. Therefore, they set up a cohort of 153,760 individuals who survived the first 30 days of COVID-19 and subdivided it according to the care setting during the acute infection phase (non-hospitalized (n = 131,612), hospitalized (n = 16,760), and admitted to an intensive care unit (ICU) (n = 5388)).⁵ Comparing this cohort with either control group (a contemporary (n = 5,637,647) and a historical group from 2017 (n = 5,859,411), both without clinical evidence of COVID-19) revealed a higher risk of developing a pre-specified incident CVD (e.g., myocarditis, HF, or dysrhythmia) for persons suffering from COVID-19 beyond the first 30 days after SARS-CoV-2 infection.⁵ Interestingly, the risks and 1-year burdens of cardiovascular outcomes rose in accordance with severity of the acute illness.⁵ Importantly, the available data were obtained between March 1, 2020 and January 15, 2021,⁵ hence only the first variants (excluding Delta and Omicron) of SARS-CoV-2 were assessed and patients were almost exclusively unvaccinated. As variants differ in their characteristics (e.g., severity or symptoms) and vaccinations can often affect the severity of an illness, the risk of developing CVDs that they found might not be representative for the current stage of the pandemic. Furthermore, most study members were White males and, therefore, the groups are not representative of the whole population.⁵ Additionally, as the study is an electronic database analysis, misclassification bias and residual confounding cannot be excluded; and since the control group participants were not tested for SARS-CoV-2, it is possible that some of them were infected but asymptomatic.⁵ As asymptomatic persons can also suffer unnoticeably from myocardial injury and involvement,^30,37 these individuals could have been incorrectly categorized into a control group while potentially developing long-term cardiovascular injuries over time. Apart from that, information on causes of death were not included in the datasets.⁵ Nevertheless, a large sample size, the use of the U.S. Veterans Health Administration system, the evaluation across care settings, and multiple sensitivity analyses are strengths of this study.⁵

As a follow-up study, the same group investigated whether breakthrough SARS-CoV-2 infection (BTI) results in long COVID.⁸² Therefore, they again used the U.S. Veterans Health Administration system to set up a cohort with BTI patients (n = 33,940) and several controls of people without evidence of SARS-CoV-2 infection, including contemporary (n = 4,983,491), historical (n = 5,785,273), and vaccinated (n = 2,566,369) controls.⁸² The comparison to all control cohorts revealed a higher risk of death and incident PASC for people with BTIs 6 months after infection.⁸² However, compared to persons suffering from COVID-19 who were not previously vaccinated, individuals with BTIs had a lower risk of death and incident PASC.⁸²

Hence, the study has 2 key conclusions: (a) long COVID can also manifest in vaccinated individuals who experience a BTI, and (b) the range of organs affected by PASC, when it occurs, does not differ between BTIs and unvaccinated COVID-19 patients.⁸² Finally, Al-Aly and colleagues⁸² point out that vaccination prior to infection only provides partial protection in the post-acute phase of the disease and that measures to prevent BTIs are needed to reduce the risk of long-term health consequences from COVID-19. As the setup for this follow-up study mimics that of the first, the strengths and limitations are similar.

A retrospective cohort study of hospitalized COVID-19 patients quantified rates of organ specific dysfunction.⁸¹ It compared 47,780 individuals (mean age = 65 years; 55% men) hospitalized with a primary COVID-19 diagnosis between January 1 and August 31, 2020, to a matched control group of the general population (∼50 million).⁸¹ By doing so, this study revealed an increased risk of multiorgan dysfunction with a 3-fold higher chance of developing a major adverse cardiovascular event; this finding was not confined to the elderly and was more pronounced in ethnic minority groups.⁸¹ Aside from its large sample size and completeness, the following limitations of this study need to be considered: data were only obtained from hospitalized patients (55% men) with a mean age of 65; hypertension and diabetes were not diagnosed, and individuals were considered to be “healthy” regarding these conditions; and, again, the data were acquired before the Delta and Omicron variants were circulating and when no vaccines were readily available.

Regarding prospective studies, cardiac involvement in the post-acute stage was reported in many studies (Table 4). Echocardiography, cardiac/cardiovascular magnetic resonance (CMR), cardiopulmonary exercise tests, and 12-lead electrocardiogram are often used investigative tools.^60,84, 85, 86, 87, 88 Dependent on these tools and the study design, the prevalence of abnormalities is highly variable and includes fewer cardiopulmonary symptoms (e.g., 5% chest pain) and no cardiac abnormalities in echocardiography, no cardiopulmonary symptoms but myocardial injury (e.g., 26% myocarditis) as determined by CMR, and cardiopulmonary symptoms (e.g., 76% chest pain) with myocardial injury (e.g., 19% myocarditis) as assessed by CMR.^84,89,90

Recently, Hanneman and colleagues⁹¹ investigated whether myocardial inflammation is present in patients who have currently recovered from COVID-19 (85% at home, 9% hospitalized, 6% in ICU) and whether this is associated with abnormalities in tissue characterization and blood biomarkers. Using combined fluorodeoxyglucose-positron emission tomography/magnetic resonance imaging and blood biomarkers, they have demonstrated that myocardial inflammation is present in a small proportion of patients in association with cardiac magnetic resonance imaging abnormalities and systemic inflammation, and that all parameters improved after follow-up.⁹¹ These findings contrast with the higher rates reported by Kotecha et al.⁸⁴ and the much higher rates found by Puntmann and colleagues.³⁷ The first group examined severely ill COVID-19 patients (all hospitalized, 31% requiring ventilator support) with elevated troponin levels approximately 2 months after discharge by a standard CMR protocol. Although left ventricular function was found to be normal in 89% of patients, cardiac abnormalities were detected in 54%, including 26% with myocarditis-like scars, 22% with ischemic injury patterns, and 6% with both pathologies.⁸⁴ However, inflammatory injury was found to a limited extent (3 or fewer myocardial segments) with minimal functional consequence, discounting 12 patients (8%) with findings consistent with active myocarditis at this late timepoint.⁸⁴ Puntmann et al.³⁷ reported that German patients (67% at home, 33% hospitalized) had lower left ventricular ejection fraction and higher left ventricle volumes. Moreover, using CMR, cardiac involvement was found in 78% of patients, 60% of whom suffered from ongoing myocardial inflammation.³⁷ These findings were independent of preexisting conditions, severity and overall course of the acute illness, and time from original diagnosis.³⁷

Taken together, methodological and patient population variabilities (study size, severity characteristics, age, sex, varying definitions, co-morbidities, and medical history) make a direct comparison of these studies difficult. In this context, the different time periods of the studies should also be considered. Kotecha et al.⁸⁴ and Puntmann et al.³⁷ collected data during the first wave (until June 2020), whereas the data used by Hanneman et al.⁹¹ were generated between November 2020 and June 2021, when SARS-CoV-2 variants were already circulating and vaccinations had begun. Still, cardiac tissue abnormalities (as identified by magnetic resonance imaging) appear to be common in recovering COVID-19 patients. Further investigation is required to determine whether patients with mild infections have less inflammatory injury than severely ill patients, as a comparison of the results reported by Hanneman et al.⁹¹ and Kotecha et al.⁸⁴ could suggest. However, unlike the aforementioned retrospective studies, Puntmann and colleagues³⁷ did not find a relationship between these factors. In general, additional prospective studies with larger populations, defined parameters and controls, and mid- and long-term follow-up will be required to clearly identify cardiac long-term effects.

Regarding affected youth, fatigue (19%), headache (12%), insomnia (7.5%), muscle pain (6.9%), and confusion with concentration issues (6.8%) were the most common symptoms reported in a 12-month follow-up study.⁹² Chest pain (3.8%) was also observed, but specific cardiovascular symptoms were not reported as this data was often not recorded.92, 93, 94, 95, 96 Therefore, further studies are required to assess cardiovascular outcomes in youth, especially in severely ill pediatric patients (irrespective of multisystem inflammatory syndrome in children survivors, as those cardiovascular complications are known; see Section 2.1). Furthermore, the immune response to mild infections was similar in children and adults (reviewed by Chou et al.⁴⁵); thus, similar cardiovascular outcomes for children could be expected.

2.3. Returning to sports after COVID-19

Possible cardiovascular sequelae following mild COVID-19 infection and observed myocardial injury in hospitalized patients^5,30,37 have raised concerns about how to proceed in terms of returning to play after acute illness, especially since myocarditis is known to be a common cause of sudden cardiac death in athletes.⁹⁷

Several consensus recommendations were released, and they have changed over time according to increasing knowledge about the prevalence of cardiovascular events in collegiate and professional athletes, clinical manifestations, long-term complications, vaccine distributions, and features of new variants.98, 99, 100, 101

Examinations, including CMR, in collegiate athletes from the United States showed myocardial and pericardial involvement in some individuals recovering from COVID-19.102, 103, 104, 105 However, large registries revealed a low prevalence of clinical myocarditis and have not found an increasing number of reported acute adverse cardiac events.106, 107, 108 Additionally, a recent systemic cardiovascular screening in asymptomatic or mildly asymptomatic Olympic athletes before and after SARS-CoV-2 infections detected cardiac abnormalities (6% new ventricular arrhythmias, 2% evidence for acute myocarditis (symptoms and elevated biomarkers)).¹⁰⁹ Thus, the initially strict precautions regarding post-COVID exercise (e.g., resting for at least 7–14 days after being symptom free) were updated.^{30,101,110,111}

The WHO has published guidelines for adults recovering from COVID-19 to support their rehabilitation and self-management. They recommend athletes follow a graduated 5-phase training to return to their baseline exercise regime (Table 5).¹¹²

Table 5.

Graduated 5-phase training for adults recovering from COVID-19 (according to the WHO leaflet¹¹²).

Training phases	Recommendations
First phase (“preparation for return to exercise”)	Controlled breathing exercises, light walking, stretching (while sitting or standing, holding each stretch for 15–20 s), and balance exercises
Second phase (“low-intensity activity”)	Walking, light household/garden tasks for 10–15 min per day for at least 7 days
Third phase (“moderate-intensity activity”)	Brisk walking, going up and down stairs, jogging, introducing inclines, and resistance exercises
Fourth phase (“moderate-intensity exercises with coordination and functioning skills”)	Running, cycling, swimming, and dance classes
Fifth phase (“return to your baseline exercises”)	Ability to complete your usual pre COVID-19 regular exercise/sports/activity regime

Abbreviations: COVID-19 = coronavirus disease 2019; WHO = World Health Organization.

Moreover, the American College of Cardiology (ACC) has published an expert consensus decision pathway, summarizing the current literature and providing recommendations related to cardiovascular sequelae of COVID-19 in adults.³⁰

Here, it is important to evaluate cardiovascular symptoms suggestive of PASC and distinguish between a CVD (e.g., myocarditis, arrhythmia) and a cardiovascular syndrome (“a heterogeneous disorder that includes widely ranging cardiovascular symptoms, without objective evidence of CVD using standard diagnostic tests”).³⁰ Therefore, a multidisciplinary approach should be used, as provided by the ACC.³⁰ If patients have persistent symptoms without a CVD, additional evaluation for PASC cardiovascular syndrome is recommended and should be determined by (a) “the most prominent symptom(s)”, (b) “the patient's baseline characteristics”, and (c) “the pretest probability of CVD”.³⁰

Recommendations made by the ACC with respect to 3 common cardiovascular symptoms are summarized in Fig. 3. Regarding return to play (Fig. 4), ACC recommendations include the following: (a) asymptomatic athletes may resume exercise training after 3 days of exercise abstinence during self-isolation; (b) exercise training may be resumed after resolving of symptoms only if they were mild or moderate non-cardiopulmonary ones; (c) resumption of exercise training without the need for additional testing if athletes suffer from remote infections (≥3 months) without ongoing cardiopulmonary symptoms; (d) triad testing (electrocardiogram, cardiac troponin, and echocardiogram) should be performed in athletes with ongoing cardiopulmonary symptoms (chest pain/tightness, palpitations, or syncope) and/or hospitalized athletes with increased suspicion for cardiac involvement as well as in those who develop new cardiopulmonary symptoms after resumption of exercise training; (e) in case of abnormal triad testing or persistent cardiopulmonary symptoms, CMR is recommended; (f) with myocarditis, exercise should be completely paused for 3–6 months; (g) if athletes have persistent cardiopulmonary symptoms and either normal CMR or a CMR that demonstrates other forms of myocardial (or pericardial) involvement, maximal-effort exercise testing (myocarditis has to be excluded with CMR before performing) and/or an ambulatory rhythm monitor may be helpful; (h) in athletes with recurrent COVID-19 in the absence of cardiopulmonary symptoms, repeat cardiac testing is not warranted; and (i) screening asymptomatic athletes or those with non-cardiopulmonary symptoms by CMR is probably low yielding.³⁰ Additionally, individuals with PASC who are not able to readily resume their previous level of activity should perform a structured and individualized graded exercise regimen during their recovery.³⁰ Precise exercise guidelines according to interventions used for postural orthostatic tachycardia syndrome will be useful for patients with tachycardia, exercise/orthostatic intolerance, and/or deconditioning to increase cardiac mass and blood volume as well as stroke volume, and improve maximal oxygen uptake and functional capacity.³⁰ Detailed recommendations can be found in the ACC document.³⁰

Fig. 3.

Evaluation and management of post-acute sequelae of SARS-CoV-2 infection-cardiovascular syndrome. Summary of evaluation and management recommendations for the common post-COVID-19 syndromes tachycardia and exercise intolerance, chest pain, and dyspnea, according to the American College of Cardiology.³⁰ COVID-19 = coronavirus disease 2019; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Fig. 4.

Return to play. Simplified graphical summary of return to play guidance according to recommendations made by the American College of Cardiology.³⁰ SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

3. PA and COVID-19

3.1. PA—A severity predictor of COVID-19?

Since the beginning of the COVID-19 pandemic, the question has been, why are some patients asymptomatic or have only mild symptoms while others become severely ill, require hospitalization/intensive care, or die? As far as non-communicable disease outcomes are concerned, it is known that lifestyle risk factors are correlated to morbidity, mortality, and loss of disease-free years of life.113, 114, 115, 116 Moreover, low PA is a major risk factor for CVDs including coronary heart disease, stroke, peripheral artery disease, and HF.^13,117,118 Regardless of age, increased PA and reduced SB were found to be beneficial for health outcomes.^13,20,21,119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 For example, higher self-reported moderate-to-vigorous PA and less screen time were associated with lower cardio-metabolic risk in adolescents (12–17 years).¹²¹ In inactive healthy adults, the beneficial effects (p ≤ 0.05) of walking improved 7 cardiovascular risk factors (body mass, body mass index, body fat, systolic and diastolic blood pressure, fasting glucose, and maximal cardiorespiratory fitness).¹²⁴ Moreover, a 12-week aerobic exercise program significantly reduced ambulatory and office blood-pressure in patients with resistant hypertension.¹¹⁹ Furthermore, the effects of PA on mortality and CVDs in 130,000 people from 17 high-, middle-, and low-income countries were assessed.¹³⁰ Compared to low PA (<150 min/week of moderate intensity PA), moderate PA (150–750 min/week) and high PA (>750 min/week) were associated with a graded reduction of major cardiovascular events (hazard ratio for high vs. low, 0.75 (95% confidence interval (95%CI): 0.69–0.82); moderate vs. low, 0.86 (95%CI: 0.78–0.93); high vs. moderate, 0.88 (95%CI: 0.82–0.94) during a mean 6.9 years of follow-up.¹³⁰ Also for mobility-limited older adults (mean age = 78.9 years), higher levels of accelerometer-measured PA and increased step numbers were significantly associated with lower cardiovascular event rates.¹³⁹

In addition, PI was associated with a higher risk for systemic infections and pneumonia.140, 141, 142, 143, 144 In contrast, daily PA positively impacts the immune system.145, 146, 147 Several studies reported positive effects, such as higher levels of natural killer cells, neutrophils, lymphocytes, monocytes, and plasma interleukin-6, as well as an increased function of natural killer cells and a decrease in inflammation.^28,148, 149, 150, 151 Thus, several studies additionally focused on investigating whether PA is related to COVID-19 outcomes and severity.152, 153, 154, 155, 156, 157, 158, 159, 160, 161

Among the general population, there is a 32% higher relative risk for physically inactive persons and a 105% increased relative risk for obese people to experience a COVID-19-associated hospital admission.¹⁵⁶ This is in line with a cross-sectional study showing an association between low PA levels and more severe disease forms.¹⁶² In contrast, a UK Biobank study observed “suggestive evidence for lower odds (up to 20%) of severe COVID-19 per 30 min of daily moderate-to-vigorous PA (p = 0.06)”.^154,163 Another UK Biobank study found a significantly lower risk of dying from COVID-19 for persons with moderate (adjusted relative risk (aRR) = 0.43, 95%CI: 0.25–0.75) and high fitness (aRR = 0.37, 95%CI: 0.16–0.85).¹⁶⁴ Significantly reduced odds for hospital admission in physically active individuals were also reported using an online questionnaire.¹⁶⁵ Additionally, at least 150 min a week of moderate-intensity PA or 75 min a week of vigorous-intensity PA reduced the prevalence of hospital admission by 34.3%.¹⁵⁷ Furthermore, consistent PI was associated with a greater risk for severe COVID-19 outcomes requiring hospitalization (odds ratio (OR) = 2.26; 95%CI: 1.81–2.83), admission to the ICU (OR 1.73; 95%CI: 1.18–2.55), or leading to death (OR = 2.49; 95%CI: 1.33–4.67).¹⁶¹ Compared to physically inactive individuals, adults who followed the 2018 PA guidelines for both aerobic and muscle strengthening activities had a lower risk of SARS-CoV-2 infection (2.6% vs. 3.1%; aRR = 0.85; 95%CI: 0.72–0.96), severe COVID-19 illness (0.35% vs. 0.66%; aRR = 0.42; 95%CI: 0.19–0.91), and COVID-19-related death (0.02% vs. 0.08%; aRR = 0.24; 95%CI: 0.05–0.99).¹⁵³ One analysis of U.S. counties showed a negative association between PA rates and COVID-19 cases and deaths.¹⁶⁶

An accelerometer-based study supports these results by demonstrating that 30 min of daily moderate-to-vigorous PA reduced odds of severe COVID-19 by 37% in women and 16% in men.¹⁵⁴ Reinforcing these findings is a recent South African study, for which the PA of 65,361 adults was directly assessed by smart devices, clocked gym attendance, and mass participation using a healthy lifestyle behavioral change program called Vitality.¹⁵⁹ PA was found to be positively associated with protection against adverse outcomes from COVID-19.¹⁵⁹ Highly physically active adults had a 34% lower relative risk for hospitalization, 41% less relative risk of admission to the ICU, and a relative risk of death reduced by 42% compared to low activity participants.¹⁵⁹ Even moderate PA showed significantly better outcomes.¹⁵⁹ Regarding long-term symptoms, a negative association between PA and neurocognitive impairment and fatigue symptoms was detected in healthcare workers with initially asymptomatic, mild, and moderate infections.¹⁵⁸

Moreover, autonomic dysfunction, which can cause alterations in the cardiovascular and immune systems, was associated with an increased severity of COVID-19.^160,167,168 Even in mild-to-moderate COVID-19 infections, autonomic dysfunction (greater sympathetic activity, less parasympathetic activity, global heart rate variability) appeared in young adults.¹⁶⁰ As obesity and PI were correlated with worse indices of cardiac autonomic modulation,¹⁶⁰ this indicates a beneficial effect of PA.

In a study of hospitalized COVID-19 patients, sedentary lifestyle increased mortality risk by almost 6-fold.¹⁵² On the contrary, a separate study showed that PA was not independently associated with length of stay or any other clinically relevant outcomes of hospitalized patients with moderate-to-severe COVID-19.¹⁵⁵ Both studies had relatively small sample sizes and assessed PA levels using a questionnaire. Additionally, in the first study, the questionnaire was answered by relatives for patients who died. Thus, bias cannot be ruled out as self-reporting PA can lead to under- or overestimation.¹⁵⁹ It is likely that different underlying factors influenced the outcomes of hospitalized patients and that the benefit of PA may decrease with increasing severity of the disease. Further research with larger sample numbers and more defined methods will be required to determine whether PA levels are related to a better prognosis in already-hospitalized patients. However, these studies clearly emphasized the importance of regular PA for reducing the risk of severe COVID-19 outcomes in the general population. Hence, PA interventions are a valuable and cheap preventive tool to improve body composition along with cardiorespiratory, metabolic, and mental health, and to enhance antibody responses after vaccination.^28,169

3.2. Lockdown impact on PA and CVD

The COVID-19 pandemic has lasted almost 3 years and so, along with it, have the drastically restrictive measures that are temporarily affecting peoples’ daily lives. Occasionally, a complete or incomplete lockdown mandates remote school/work and orders all non-essential facilities closed, causing social isolation and loneliness as well as a relative decrease in PA and increase in SB for most of the global population.170, 171, 172, 173, 174

Social isolation (an objective state of absent social connections or interactions) and loneliness (the subjective experience of social isolation and feeling alone) are problems that co-occur in all ages, but they are particularly present in older adults.174, 175, 176, 177 Both were associated with mental health problems, cognitive decline, CVDs, and a higher risk of mortality.175, 176, 177, 178, 179, 180, 181, 182, 183, 184 Loneliness is a predictor of elevated systolic blood pressure and an independent risk factor for PI.185, 186, 187 Furthermore, unhealthy eating habits, such as overeating and snacking, might be developed as a consequence of social isolation and may lead to weight gain and nutritional imbalances that impair immune function.^28,188

Regarding PA, surveys of healthy adults in Spain compared a normal pre-pandemic week to the first 2 weeks of lockdown in 2020 and showed a reduction in vigorous PA and walking time of 16.8% and 58.2%, respectively, whereas sedentary time increased 23.8%.¹⁸⁹ Supporting this, an international online survey from April 2020 revealed a 24% reduction in the number of days/week for all PA and a decrease in the number of min/day of 33.5%, whereas the number of sitting hours per day increased by 28.6% in adults from Asia (36%), Africa (40%), Europe (21%), and others (3%) during home confinement.¹⁹⁰ Also, in young Chinese adults, a significant decrease in PA, along with an increase in SB and sleeping time, was reported during the COVID-19 pandemic.¹⁹¹ On the contrary, a recent study from the Republic of Korea has found no general decline of vigorous (adjusted OR (aOR) = 0.96, 95%CI: 0.79–1.18, p = 0.696) and moderate (aOR = 1.12, 95%CI: 0.94–1.32, p = 0.201) PA between the years 2019 and 2020.¹⁹² In fact, an increased moderate PA (aOR = 1.29, 95%CI: 1.01–1.65, p = 0.042) was seen in females in 2020 as compared to 2019.¹⁹² Moreover, the study found a lower sedentary time (aOR = 0.35, 95%CI: 0.17–0.72, p = 0.005) for adults from the Republic of Korea during the pandemic.¹⁹² Weekly PA (mean difference (MD) = –159.87; 95%CI: –100.44 to –219.31) and weekly sitting time (MD =  –106.76; 95%CI: –71.85 to –141.67) both increased in Spanish college students (age =  20.50 ± 4.56 years, mean ± SD).¹⁹³ Note that the weekly time of specific parameters was compared before and during the lockdown; hence, negative numbers indicate an increase in those behaviors during the lockdown. Interestingly, the female students increased their PA by 185.24 min/week during lockdown, whereas the rise was only 53.46 min/week in the male group.¹⁹³ In contrast, a Bavarian online survey based on step-count data from smartphones or wearables showed a 25% reduction in step counts/day during the lockdown.¹⁹⁴ Of the Bavarian students (age = 23.3 ± 4.0 years, mean ± SD), 44.5% decreased their amount of training and 32.8% increased their amount of PA.¹⁹⁴

Observed discrepancies in PA levels between the aforementioned studies might be caused by a number of factors, including the variety of lockdown regulations between countries. For example, during the first lockdown in Italy and Spain, people were only allowed to leave their houses for reasons related to work or health or to purchase food and drugstore items, whereas people could still perform outdoor activities in Germany. Moreover, personal characteristics could play a crucial role. It is conceivable that some people who, prior to the pandemic, would have liked to increase their PA but did not have enough time during the course of their normal working day would, as a result of the switch to remote or short-time work, suddenly have time to join an online sports class or go jogging. In contrast, people who used to cycle to work would likely see a decrease in PA if forced to work remotely due to the restrictions. Furthermore, among the Spanish university students, group-related alterations of PA levels and SB were found for groups “first year of study”, “overweight or obese”, and “smokers”. These individuals did not experience differences, which points toward a high baseline SB regardless of pandemic-related restrictions.¹⁹³

A Greek online survey showed an increase in sleep duration and screen time along with a decrease in PA, leading to an increase in bodyweight in children and adolescents.¹⁹⁵ Several studies have reported similar findings.196, 197, 198 Since lower levels of PA are associated with increased bodyweight and mental health problems (which can alter eating behavior), obesity is a clear potential risk factor for severe COVID-19 and for developing CVDs.^{13,28,54,188,195,199} The long-term consequences of safety/lockdown guidelines for today's youth strongly underline the importance of staying active. The elderly did not fare well in the lockdowns either, with decreased PA levels and a 5.8% increased prevalence of locomotive syndromes, according to one Japanese study.²⁰⁰

In another recently published Italian survey comparing pre- and post-lockdown time periods, sedentary time was still increased, especially during weekends, several months after the lockdown, with an overall 7% increase in PI.²⁰¹ Moreover, locations and types of activities have changed over time in the Italian population: PA at home increased by 13% but decreased by 17% indoors (e.g., gyms and swimming pools) and by 3% outdoors (e.g., outdoor playground and parks).²⁰¹ Fitness sports, jogging, and cycling increased, and participation in excursions, water sports, dance, and volleyball declined.²⁰¹

As exercise and PA are economic and successful methods for improving cardiovascular health and reducing CVDs,202, 203, 204 it is of special interest how the lockdown influenced patients suffering from CVDs. Similar to the majority of the findings in healthy individuals, a significant decline in PA and an increase in SB were reported in CVD patients during the lockdown (Table 6).^172,205, 206, 207, 208, 209, 210, 211 A large, accelerometer-based observational study was done on patients in New York City and Minneapolis/Saint Paul who had pacemakers and implantable cardioverter-defibrillators; it showed a 26% reduction in PA in New York City and a 15% reduction in Minneapolis/Saint Paul during the lockdown.²¹⁰ The decrease in PA was most pronounced within the first 2 weeks of the regional lockdown; it increased slowly but did not return to pre-restriction levels 5 months after the lockdown ended.²¹⁰ Additionally, a large registry has investigated the impact of the lockdown on PA and arrhythmia burden in patients who received cardiac resynchronization therapy (CRT) devices with daily, automatic remote monitoring functions.¹⁷² In these patients, PA abruptly decreased in the first 2 weeks of lockdown, then returned to pre-lockdown levels 3–7 weeks later, and surpassed these levels after 8–10 weeks.¹⁷² Thus, when PA was relatively decreased, by 6.5%, during the initial lockdown,¹⁷² the atrial high rate episode burden was increased by 17%, with no changes observed in ventricular arrhytmia.¹⁷² Moreover, a small single-center study in HF patients with CRT and implantable cardioverter-defibrillators analyzed the 3-month period immediately preceding the lockdown, the 69 days of lockdown, and the 3-month period following the first lockdown.²¹¹ It showed a decline in daily PA of 16.6% during the lockdown, with mean daily PA decreasing from 3.4 ± 1.9 to 2.9 ± 1.8 h per day (p < 0.001).²¹¹ No significant difference in the average daily PA was ascertained between the pre- and post-lockdown period (–0.0007 h/day; p = 0.99) or between the post-lockdown period and the same time period from the previous year (3.4 ± 2.0 h/day vs. 3.5 ± 2.0 h/day; p = 0.40).²¹¹ In contrast to the large registry,¹⁷² no significant difference was identified regarding the burden of atrial arrhythmias.²¹¹ However, lower PA during the lockdown correlated with more alarm episodes detected in HF patients, assuming a generally negative effect from reduced PA²¹¹ and a potentially underestimated arrhythmia burden due to the small study size.

Table 6.

Impact of COVID-19 restrictions on cardiovascular disease patients.

Reference	Number of patients	Study type	Time period	Patient characteristic	Main finding
Vetrovsky et al. (2020)205	26	Accelerometer-based	3 weeks preceding and first 3 weeks of lockdown	Heart failure	-Abrupt decline of daily step count by 16.2% during quarantine
Sassone et al. (2020)206	24	Based on ICD-embedded accelerometric sensors	Forced 40 days in home-confinement and 40 days confinement-free period	ICD	-25% decreased physical activity (1.2 ± 0.3 h/day during restrictions vs. 1.6 ± 0.5 h/day confinement-free period)
Chagué et al. (2020)207	124	Phone interview, questionnaire-based	Interview during 6th and 7th week of lockdown	Congestive heart failure	-Reduced physical activity in 41.9% of those surveyed; more frequent in women (p = 0.025) and urban dwellers (p = 0.009) -Increased screen time in 46.0% of respondents -Increase in common heart failure symptoms in 21.8% of the participants
Al Fagih et al. (2020)208	82	Based on accelerometer in CIEDs	∼1 month pre-lockdown; ∼1 month lockdown	Heart failure, implanted with CIEDs	-A 27.1% decrease in physical activity, -Median physical activity significantly declined from 2.4 to 1.8 h/day (p = 0.000010)
van Bakel et al. (2021)209	1565	Questionnaire-based	Baseline measure 2018; 5 weeks post lockdown onset	Chronic cardiovascular disease patients	-Increased moderate-to-vigorous physical activities (median: 1.6–2.0 h/day (p < 0.001)) mainly due to walking and doing odd jobs -Significantly decreased exercising time (1.0–0.0 h/week) -Increase in sedentary time (7.8–8.9 h/day (p < 0.001)) -Physical activity increased by 13 min/day -Sedentary behavior rose by 55 min/day
Lechner et al. (2022)212	474	CMR imaging	Periods with vs. without major public health restrictions in 2020; restriction timeframes 2020 vs. corresponding timeframes between 2015–2019	STEMI patients	-Data analysis from MARINA-STEMI cohort study (NCT04113356) -Increased infarct size during major public health restrictions in 2020 -Higher frequency and larger extent of microvascular obstruction -Higher rate of intramyocardial hemorrhage -These findings were consistent between patients admitted in 2020 vs. patients hospitalized prior to the pandemic (2015–2019) -Significantly longer total ischemia time (p < 0.01) and higher frequency of pre- primary percutaneous coronary intervention thrombolysis in myocardial infarction (p = 0.03) during major public health restrictions in 2020
Lu et al. (2022)210	11,102 (NYC: 7279 and MSP: 3823)	Accelerometer-based	January 1, 2019 to December 31, 2020	Pacemakers or ICDs	-Significant decline (p < 0.001) of physical activity, most pronounced in the first 2 weeks of lockdown -26% (NYC) and 15% (MSP) median reduction in physical activity -Walking distance decrease of 1 and 0.5 miles per day in NYC and MSP -No return to activity levels of 2019 within 5 months post lockdown (median daily activity levels were 14.5 min (NYC) and 9.6 min (MSP) lower)
Schmitt et al. (2022)172	405	Accelerometer-based	Lockdowns in early 2020	Heart failure with CRT pacemaker/ defibrillator implantation	-Data from BIO|STREAM.HF registry (NTC03366545) -Mean physical activity decreased by 6.5% (p < 0.001) -AHRE burden increased by 17% (p = 0.013) -Physical activity declined abruptly during the first 2 weeks of lockdown -Physical activity increased gradually during Weeks 3 to 7 -Pre-lockdown levels were exceeded during Weeks 8 to 12
Brasca et al. (2022)211	41	Accelerometer-based	3 months prior to lockdown onset, 69 days of lockdown 2020, 3 months post lockdown	Heart failure, implanted with CRT or ICD	-Significant reduction of the mean daily physical activity by 16.6% (p < 0.001) -Mean daily physical activity decreased from 3.4 ± 1.9 to 2.9 ± 1.8 h per day (p < 0.001) -No difference between the average daily physical activity before and after the lockdown period (–0.0007 h/day; p = 0.99) -No difference from the same period of the previous year (mean = 3.4 ± 2.0 vs. mean = 3.5 ± 2 h/day; p = 0.40) -No difference in the burden of atrial arrhythmias

Abbreviations: AHRE = atrial high rate episode; CIEDs = cardiac implantable electronic devices; CMR = cardiac magnetic resonance; COVID-19 = coronavirus disease 2019; CRT = cardiac resynchronization therapy; ICD = implantable cardioverter-defibrillators; MARINA-STEMI = magnetic resonance imaging in acute ST-elevation myocardial infarction; MSP = Minneapolis/Saint Paul; NCT = National Clinical Trial; NYC = New York City; STEMI = ST-elevation myocardial infarction.

Importantly, Lechner and colleagues²¹² explored how the major public health restrictions of the COVID-19 pandemic affected ST-elevation myocardial infarction with respect to severity and myocardial tissue damage. Using CMR, they found an increased infarct size (22% (interquartile range (IQR): 12%–29%) vs. 14% (IQR: 6%–23%), p < 0.01), more extensive micro-vascular obstruction (1.5% (IQR: 0.1%–11.4%) vs. 0.2% (IQR: 0.0%–2.6%), p < 0.01), and a higher rate of intramyocardial hemorrhage (56% vs. 34%, p = 0.02) in COVID-19 negative ST-elevation myocardial infarction patients during the lockdown period of 2020 as compared to phases without major COVID-19 restrictions.²¹² Different underlying causes are conceivable. For example, patients might have been afraid of getting infected with SARS-CoV-2 after visiting their physician or following a hospital admission and, therefore, might have delayed medical consultation. In support of this hypothesis, a reduction in hospital admissions was seen in Austria, Italy, and England during March 2020.213, 214, 215 Besides a decrease in hospital admissions, a significantly longer ischemia time and a door-to-balloon time beyond 30 min were observed by De Luca and colleagues,²¹⁶ which might be explained by organizational delay due to specific COVID-19 protocols (e.g., screening patients and preparing equipment).²¹⁶ Apart from that, an unhealthy lifestyle (PI, obesity) can also contribute to worsened ST-elevation myocardial infarction outcomes. Further research is required to investigate the impact of lockdown restrictions on CVDs and their underlying causes.

4. Conclusions and future perspectives

Almost 3 years in the COVID-19 pandemic has revealed that cardiovascular complications are common in severely ill patients, but also appear in mild and asymptomatic cases. PASC of COVID-19 evolved to become a major public health issue, in part due to the high burden of cardiovascular symptoms. The underlying pathomechanisms remain relatively ill-understood and could change to some degree with emerging variants. Hence, current priorities are, among others, (a) to establish the prevalence of long-term cardiovascular outcomes according to different circulating variants, vaccination status, and disease severity, (b) to further investigate underlying pathomechanisms, and (c) to ascertain the role of possible causal mechanisms, such as PA, obesity, social isolation, loneliness, immune function, and genetic predispositions. Adjusting vaccines to emerging variants and developing new therapies for acute and long COVID-19 are also high priority projects. With respect to long COVID, a wide range of clinical trials is listed on the WHO's International Clinical Trials Registry Platform, and Raman and colleagues have reviewed a selection of them.⁶⁰

Furthermore, maintaining sufficient levels of PA and staying active during the COVID-19 pandemic, despite potential quarantine restrictions, is crucial for health conditions.^26,27,170 There are new techniques and tools, such as fitness tracking apps and wearables, online sports classes, tele-rehabilitations or simple at-home training according to special exercise plans, that show promise for helping to achieve regular PA in difficult situations like in lockdowns. Further development and integration of these methods into daily life may be beneficial in case of another pandemic, as these things may be more easily implemented if patients are already familiar with them.