key: cord-0859343-prgnzd07
authors: Castelletti, Silvia; Gati, Sabiha
title: The Female Athlete’s Heart: Overview and Management of Cardiovascular Diseases
date: 2021-12-02
journal: Eur Cardiol
DOI: 10.15420/ecr.2021.29
sha: eb3dc005cc2749bea8b11067a5e28d18fa90eba4
doc_id: 859343
cord_uid: prgnzd07

The number of female athletes taking part in elite and amateur sport is ever increasing. In contrast with male athletes, few studies have focused on cardiovascular adaptations to exercise in women, the effects of lifelong exercise on heart muscle and electrical tissue, the risk of exerciserelated sudden cardiac death and the management of cardiovascular disease. Women have a lower prevalence of large QRS complexes, repolarisation changes including inferior and lateral T-wave inversion, and cardiac dimensions exceeding predicted limits compared with men. The risk of exercise-related sudden cardiac death is significantly lower in women than men. Also, women who have engaged in lifelong exercise do not have a higher prevalence of AF, coronary artery calcification or myocardial fibrosis than their sedentary counterparts. Apart from providing an overview of the existing literature relating to cardiac adaptations, this review explores possible reasons for the sex differences and focuses on the management of cardiovascular disorders that affect female athletes.

size). 10 Normal geometry is defined as a normal LV mass and relative wall thickness <0. 42 ; concentric remodelling is defined as a normal LV mass and increased relative wall thickness (>0.42); concentric LV hypertrophy is defined as an increased LV mass and a relative wall thickness; and eccentric LV hypertrophy is defined as an increased LV mass and normal relative wall thickness. 11 Finocchiaro et al. 10 studied LV geometry in 1,083 young adult athletes including 443 women competing in several sports. They identified that 22% of female athletes showed abnormal geometry with a higher prevalence of eccentric LV hypertrophy in those engaging in endurance sports. In contrast, male athletes are more likely to develop concentric hypertrophy (9% versus 3%; p<0.001). None of the women exhibited a relative LV wall thickness of >0. 48 , which suggests that female hearts adapt by increasing their LV cavity size. This parameter may be used to differentiate abnormal LV hypertrophy from physiological changes rather than absolute LV wall thickness measurements.

Furthermore, Rawlins et al. assessed how ethnic differences affect cardiac adaptations in 400 female athletes. 12 The authors demonstrated a greater LV wall thickness (9.2 ± 1.2 mm versus 8.6 ± 1.2 mm; p<0.001) and LV mass (187 ± 42 g versus 172 ± 42 g; p<0.008) in black compared with white female athletes. Eight black female athletes (3%) exhibited a LV wall thickness >11 mm (12-13 mm) , but none of the white female athletes did. All female athletes demonstrated normal indices of systolic and diastolic function. Therefore, a LV wall thickness of >13mm in a black female athlete is rare and warrants further evaluation.

Left atrial enlargement occurs in correlation with LV dilatation secondary to high preload imposed on all four chambers with intensive endurance exercise. 13 Female athletes have a greater absolute and indexed atrial volumes compared with controls. An indexed left atrial volume of 22-33 mm/m 2 has been suggested in women. 14 

The athlete's ECG reflects changes in vagal tone and cardiac dimensions. Women generally show smaller quantitative changes with a lower prevalence for voltage criteria for biventricular hypertrophy, and shorter PR interval and QRS duration. 10 Women have different patterns of T-wave inversion from male athletes. Minor anterior precordial T-wave inversion is more common in women, particularly when limited to leads V1-V3, and has not been associated with underlying structural heart disease. 10, 15, 16 The current international recommendations on ECG interpretations in athletes suggest T-wave inversion in leads V1-V2 in women does not warrant further evaluation in the absence of symptoms or a family history of cardiomyopathy. 17 In contrast, T-wave inversion in the lateral and inferior leads in female athletes is rare and should raise concerns of pathological LV hypertrophy. Women in general have a longer corrected QT interval than men. Based on international recommendations, a QTc >480 ms warrant further evaluation for long QT syndrome in female athletes. 17

Dilated cardiomyopathy (DCM) is defined as LV or biventricular systolic impairment with or without cavity enlargement that is not explained by coronary disease or abnormal loading conditions. 18 It has several causes including genetic predisposition, myocarditis, tachycardia-induced or ventricular premature beat-induced cardiomyopathy, drugs, toxins, peripartum cardiomyopathy and, occasionally, the cumulative effects of more than one aetiology. 18 The clinical spectrum of DCM may vary from a phenotype with the absence of symptoms, isolated LV dilatation and normal or low-normal systolic function to overt disease with significant systolic dysfunction. Some athletes engaging in endurance sport, such as long-distance running, swimming and rowing, may exhibit large cardiac dimensions that overlap with those observed in patients with DCM. The differentiation between cardiac pathology and physiological adaptation is fundamental to prevent a wrong diagnosis and fatal consequences. A dilated left ventricle of >60 mm consistent with a DCM is identified in only 1% of female athletes. 4 These women should be evaluated thoroughly with a detailed clinical history, including any relevant family history of cardiomyopathy. They should be investigated with cardiovascular MRI to exclude myocardial fibrosis, prolonged ECG analysis for significant arrhythmias and exercise echocardiography for their haemodynamic response to exercise, to assess for presence of exercise-induced symptoms or arrhythmias and to evaluate for a contractile reserve of >11% to exclude cardiac pathology.

In general, symptomatic women with DCM should abstain from most competitive and leisure sports associated with moderate or high-intensity exercise. 19 A select group of female athletes with DCM who have mildly impaired LV ejection fraction of 45-50% without high-risk markers or arrhythmias may participate in most competitive sport. 19 Annual follow-up is recommended for females with DCM who exercise regularly ( Figure 1 ).

Hypertrophic cardiomyopathy (HCM) is diagnosed in the presence of an unexplained increase in LV thickness to ≥15 mm in end-diastole in any myocardial segment. 20 HCM may also be considered in women with a LV wall thickness of ≥13 mm in the presence of a positive genetic test or family history of HCM. 20 Women and men should be equally affected given the autosomal dominance of this disease; however, this is not reflected in the literature. Although there may be a lack of awareness of cardiovascular disease (CVD) in women, it is possible that hormonal influences and genetics play a role. Oestrogens have a protective role as women usually have an older age of onset, a lower LV mass and a secondary hypertrophic response.

Female athletes rarely succumb to sudden cardiac death (SCD) from HCM. In the US National Registry, women accounted for only 3% of 302 individuals who died of HCM. 21 This observation is relevant to the prescription of competitive sports and intensive exercise in this cohort. White female athletes rarely exceed a LV wall thickness >11 mm and around 3% of black female athletes will have a LV wall thickness between 12 mm and 13 mm. 9, 12 Therefore, a LV wall thickness of 12 mm in a female athlete may fall into a grey zone depending on body size, sporting discipline and ethnicity, and may potentially raise concern for pathology, such as HCM.

A systematic approach is required when assessing women with HCM or the suspicion of pathological HCM who request exercise advice. The baseline evaluation should include a comprehensive personal and family history, assessment of the severity of the HCM phenotype and the presence of conventional risk factors for SCD. Evidence has been evolving over the past two decades that exercise is beneficial with low rates of adverse events in adults with mild phenotypes of HCM. 22 A more liberal approach to competitive sports participation and intensive exercise has been adopted in individuals with morphologically mild HCM and a low 5-year HCM risk of sudden cardiac death score of <4% ( Figure 1 ). 23 

Arrhythmogenic cardiomyopathy (AC) is defined by the presence of fibrofatty replacement and myocardial fibrosis of both or individual ventricles and life-threatening ventricular arrhythmias. It is also recognised that intensive exercise and endurance sport in individuals with AC accelerates the phenotype. 24 AC is an autosomal dominant disease with an equal number of men and women genetically affected. However, several large studies have shown women are less phenotypically affected than the men, possibly owing to different levels of participation in competitive sport and/or endocrine influences. [25] [26] [27] [28] [29] Studies in mice suggest androgen levels contribute to the advancement of the disease process. The androgen receptors in the heart are upregulated with exercise, which may be a contributory factor for the disease progression, and female athletes usually have a lower number of androgen receptors in their hearts than men. 30 One-third of athletes will exceed the cut-off values in RV dimensions for the minor criteria defining AC. Consequently, in female athletes with a disproportionate ratio of right to ventricular end-diastolic volume (RVEDV:LVEDV) of >1.3 should undergo a detailed evaluation in the presence of symptoms and/or relevant family history of cardiomyopathy. 6 It is also recognised that intensive exercise and endurance sport in individuals with AC exacerbates the phenotype. A cautious approach is therefore recommended in people with AC, including those who are genotype positive but phenotype negative. Participation in low to moderate intensity recreational exercise may be considered for individuals without a history of cardiac arrest, ventricular arrhythmias or unexplained syncope with minimal structural cardiac abnormalities or <500 premature ventricular complexes in 24 hours ( Figure 1 ). 19 

Myocarditis is a non-ischaemic inflammatory myocardial disease that may cause cardiac dysfunction and complex arrhythmias. In the developed world, viral myocarditis is the most common aetiology. 31, 32 The precise incidence and prevalence of myocarditis is unknown. It accounts for 5-15% of SCD in young athletic individuals. [33] [34] [35] [36] [37] Daily exercise in mice models infected with the coxsackie virus was associated with increased predisposition to fulminant myocarditis and sudden death. 38 Testosterone levels are associated with increase fibrosis and heart failure. 39 SCD during sports from myocarditis appears to be more prevalent in men than women, which may be linked to the testosterone-related inflammatory response. 33, 34 The clinical presentation of myocarditis is heterogenous and patients may initially present with coryzal symptoms. Athletic individuals may exhibit non-specific symptoms of general malaise, fatigue or diarrhoea. 40 At the other extreme, individuals can present with fatal arrhythmias and cardiogenic shock. Almost 50% of people with myocarditis will demonstrate full resolution of LV dysfunction within 30 days but 12-25% will progress to fulminant heart failure that is an adverse prognostic marker in the long term. 33 Currently, there is no single clinical or imaging marker to confirm the diagnosis of myocarditis with certainty. In the current era, cardiovascular MRI is the most useful diagnostic and prognostic test with an excellent sensitivity and specificity for detecting myocardial hyperaemia, inflammation, oedema and/or focal fibrosis. 42 The extent (>10% increase) and distribution (anteroseptal) of myocardial fibrosis are important predictors of cardiovascular events that should be assessed during clinical follow-up. [43] [44] [45] Intensive exercise should be avoided in individuals with myocarditis. Women with active myocarditis should not engage in sport for 3-6 months and should return to intensive exercise only when LV function is normal and no complex ventricular arrhythmias are seen on an exercise stress test (Figures 1 and 2) . 19 

Athletic individuals infected with severe acute respiratory syndrome coronavirus 2 may be at risk of a subclinical myocarditis and may remain asymptomatic or develop mild symptoms. 46 Women appear to be less severely affected by coronavirus disease 2019 (COVID-19) than men and have a lower prevalence of cardiovascular injury. 47, 48 It is likely that levels of ACE2 expression and sex hormones regulate these changes and control systemic inflammation. [49] [50] [51] Athletes who test positive for COVID-19 and exhibit isolated cardiac symptoms are required to refrain from high-intensity physical activity and sport for at least 7-14 days since they are symptom free. 52, 53 Following resolution of symptoms, athletes with a negative COVID-19 test should undertake cardiac testing including a high-sensitive troponin test, an ECG and echocardiogram to exclude cardiac involvement. 52, 53 Abnormalities specifically relating to myocarditis warrant a 3-6 month sports restriction.

More recently, rare cases of myocardial and pericardial inflammation following COVID-19 vaccination have been reported. 54, 55 The Centers for Disease Control and Prevention reported an incidence of 4.8 cases per 1 million between COVID-19 mRNA vaccines and myocarditis, particularly in young men within a few days of the second vaccination. 56 Pericarditis tended to affect older patients after the first or second dose. Women also experience post-vaccination cardiac inflammation but to a lesser degree. 54 The recommendations for the management of exercising after COVID-19 are likely to evolve over time as long-term data are acquired in this highly infectious virus.

Hypertension is common in the global population, affecting around onethird of people. Exercise is an effective treatment strategy for hypertension but conversely, exercise-induced hypertension may equally increase the risk of cardiovascular events. The precise prevalence of hypertension in female athletes is unknown as definitions in the literature vary but it is likely to be similar to that identified in the general population. 57 There is also a lack of consensus in the definition and threshold for abnormalities in exercise-induced hypertension, which carries an elevated cardiovascular risk as it is linked with subclinical hypertension. 58, 59 Determining factors for hypertension include older age, drugs (i.e. anabolic steroids and nonsteroidal anti-inflammatory drugs), sporting discipline and the intensity of sport.

Few studies in the literature have evaluated sex differences in hypertension. [60] [61] [62] [63] Female athletes appear to have a lower prevalence of hypertension and lower systolic and diastolic values compared to male athletes in both low and high bodyweight classes. 60, 61, 63 There are no significant differences between various sports although higher blood pressure (BP) readings have been detected in endurance (including swimming, triathlons and pentathlons) and artistic sports. 60 Only one study has reported higher BP values in female than male athletes (13% versus 7%) but this difference was likely due to a wide variation in age. 62 The study included athletes aged 13-77 years, but men were predominantly younger than 35 years. Of the hypertensive women, 92% were aged >35 years, while 73% of the hypertensive men were >35 years old. Out-of-office BP recordings should be performed in all athletes with BP >140/80 mmHg on physical examination as there is a high prevalence of white-coat syndrome. Hypertensive individuals should participate in at least 30 mins of moderate-intensive dynamic aerobic exercise 5-7 days per week to reduce systolic and diastolic BP of 7 and 5 mmHg, respectively.

Atherosclerotic coronary artery disease (CAD) is a potentially fatal condition affecting predominantly mature athletes. It is more common in men with a 9:1 ratio for SCD among competitive athletes and is even higher among recreational athletes with prevalence ratio of 20:1. 64 Although hormonal influences cannot be disregarded, the likely explanation for this sex difference is the engagement in lower-intensity sports and participation rates in sports among women. 65 The majority of studies evaluating CAD have been conducted in male runners. There are few data in female cohorts, demonstrating a low prevalence of CAD. [65] [66] [67] A study on 152 master athletes, 30% of them women, found no differences in the plaque prevalence and composition compared with sedentary women. 65 Similar results had been reported in the same year in a smaller study on 26 female marathon runners; athletes had coronary artery calcium (CAC) counts and calcified plaque volumes comparable to sedentary individuals. 66 Another large study on 9,501 women failed to demonstrate an association of high-intensity exercise and high coronary artery calcification scores. 67 In athletes with established CAD, there is a potentially increased risk of MI during vigorous physical activity. Therefore, the management of such individuals should focus on risk stratification for recurring events, arrhythmias and inducible ischaemia. Additional evaluation for symptoms of ischaemia, LV ejection fraction <50% and reduced exercise capacity is also warranted. Athletes with any of these high-risk features should be advised to confine themselves to low-and moderate-intensity exercise once symptoms have settled or following a period of 12 months after MI or coronary revascularisation (Figure 1 ).

Spontaneous coronary artery dissection (SCAD), although rare, is a frequent cause of acute coronary syndrome in low-cardiovascular risk, middle-aged women. 68, 69 SCAD is defined as non-iatrogenic separation of the coronary arterial wall with or without intimal tear by intramural haemorrhage and can be triggered by physical, emotional and hormonal stressors. 70 Spontaneous healing is recommended as the first-line therapy.

Data on the risk of exercise triggering coronary dissection are rare so a cautious approach to exercise is generally recommended. Individual assessment for symptoms and inducible myocardial ischaemia is advised before recommencing leisure sport or competitive exercise. 19 

Mitral valve prolapse (MVP) is characterised by fibromyxomatous changes of the mitral valve tissue with a >2 mm extension into the left atrial cavity.

MVP is more prevalent in women and the most common structural postmortem cardiac abnormality identified. [71] [72] Features of increased arrhythmic risk include: female sex; personal history of syncope; family history of SCD or MVP; T-wave inversion, ST-segment elevation, long QTc on ECG; bi-leaflet prolapse; the Pickelhaube sign (high velocity systolic signal with tissue Doppler imaging S-wave >16 cm/s, resembling the pickelhaube spiked helmet); mitral annulus disjunction; complex ventricular arrhythmias on ECG monitoring or exercising testing; and presence of fibrosis on CMR. [73] [74] The effect of high-intensity exercise on the risk of SCD remains uncertain.

In an 8 ± 2 years' follow-up study on 215 athletes with MVP, no cases of SCD were registered. 75 Other adverse events occurred at a rate of 0.5% per annum, mainly in older athletes, with none occurring in athletes with isolated MVP or mild mitral regurgitation. 75 Asymptomatic female athletes with MVP and mild or moderate mitral regurgitation can participate in all competitive and recreational sports in the absence of the aforementioned risk markers. In the presence of symptoms or high-risk features, the general advice is to restrict to lowintensity aerobic exercise. 22

Sex differences in electrophysiological changes are well known. Women have greater sinoatrial node automaticity, atrioventricular node function, infra-Hisian conduction and longer ventricular action potential duration, which may influence the prevalence of arrhythmias in female athletes. However, the vast majority of studies have focused mainly on male athletic populations and sub-data analyses are limited as they are largely underpowered.

Female athletes appear to be at lower risk of bradyarrhythmias and accessory pathways than male athletes, including a higher degree of atrioventricular block. [76] [77] [78] In contrast, atrioventricular nodal re-entry tachycardias appear to be more prevalent in women. 19, 76, 78 AF AF is the most common arrhythmia in the general population and is associated with a high risk of heart failure, stroke and mortality. Several studies have revealed a J-shaped relationship between exercise, the risk of developing AF and endurance exercise. The risk of AF is generally reduced at low to moderate intensity exercise (Figure 1) . [79] [80] [81] However, regular vigorous exercise may result in AF in some individuals. 78, [82] [83] [84] [85] [86] Mature endurance athletes generally have a fivefold increased risk of AF. 87 However, it remains controversial whether sex-specific differences exist in relation to the risk of AF and long-term endurance exercise. 88 The vast majority of data focus on male athletes and a number of studies have failed to prove any increased risk of AF in female athletes. [89] [90] [91] A meta-analysis that included 103,298 mature female athletes (aged 54-63 years) demonstrated an 8.7% lower risk of AF with moderate-intensity exercise with a further reduction to 28% in women exercising at a high intensity. 91 However, female endurance athletes who engaged in very high intensity exercise were underrepresented in this analysis.

In contrast the Norwegian Tromsø Study followed 20,484 subjects, half of them women, for an average of 20 years. 88 Healthcare records were intermittently reviewed prospectively to identify cases of AF. Intense endurance training was associated with a twofold increased risk of AF in women aged >40 years. However, moderate-intensity exercise was associated with a significantly lower risk of AF over the 20-year follow-up period.

A more recent study of 402,406 individuals (52.5% women) aged 40-69 years with 2.8 million person-years of follow-up reported a number of points pertaining to women. 79 Physical activity of >500 metabolic equivalent-minutes per week (MET-min/wk) was associated with reduced risk of AF, which was more pronounced in women than men. In women, incident AF declined with physical activity of up to 5,000 MET-min/wk compared with men who demonstrated a moderate decline.

Female athletes who develop AF without a substantial cumulative effect of exercise should be evaluated for typical causes of AF such as thyrotoxicosis, valvular heart disease, alcohol abuse, hypertension and ischaemic heart disease. AF ablation is recommended in exercising individuals with recurrent symptomatic AF and/or those who do not want drug therapy because of its impact on athletic performance. 19 The athlete should also be counselled on the effect of long-lasting intensive exercise on AF recurrence. Direct bodily contact sports are not recommended in athletes with AF who are anticoagulated. 19

Long QT syndrome (LQTS) is a genetic cardiac disorder characterised by a prolonged QT interval on the ECG and is associated with the increased risk of life-threatening arrhythmias, particularly stress-induced torsades de pointes. 92 Healthy women have longer QT intervals than men, which appears in the post-pubertal phase, owing to a longer ventricular action potential.

Recently published clinical observations demonstrated that exercise could induce repolarisation prolongation and suggest LQTS. 93 Differences in cardiac repolarisation in women and men have also been reported in LQTS. 94 Therefore, the upper limits of normal corrected QT are higher in female athletes than in men (480 ms versus 470 ms in female and male athletes, respectively). 77 Women are more likely to be affected by LQTS, despite the equal sex distribution of the disease genotype. They are also at a higher risk of arrhythmias in response to QT-prolonging drugs and electrolyte imbalances than men. Female sex also appears to be an independent risk marker for cardiac events in LQTS. 95 Although the data are scarce, given the sex differences, these finding supports the theory that sex hormones most likely regulate cardiac repolarisation.

In the setting of competitive sport, establishing arrhythmic risk can be difficult, particularly in individuals who are genotype positive and phenotype negative. Some studies have reported a lower incidence of arrhythmic events in affected individuals competing in sports but these studies were limited by younger age, participation in low-intensity sports inclusion and their retrospective nature. [96] [97] [98] In the general adult population, the major risk predictors include a history of cardiac events, QTc values, being a paediatric male or adult female individual as well as the pathogenic mutation in the QT genes. 98 It is recommended that all exercising individuals with LQTS with symptoms or prolonged QTc are treated with β-blocker therapy. Individuals should also be advised to avoid QT-prolonging drugs and electrolyte imbalance. Ventricular arrhythmias in LQTS are adrenergically driven; therefore, highintensity exercise is prohibited even while on beta-blockers in people with a QTc >500 ms or genetically confirmed LQTS with a QTc³ of 480 ms in women. In individuals who are genotype positive and phenotype negative, the European recommendations advise on shared decision making with the athlete in question (Figure 1) . 19 

The number of veteran athletes aged 40 years and above engaging in endurance sports including triathlon and marathons has continued to increase with time. There has been a surge in the number of recreational female athletes in this age category. In parallel, there is emergent evidence that chronic exposure to large amounts of endurance exercise may predispose athletes to AF, myocardial fibrosis and increased CAC. 65, [99] [100] [101] [102] Consequently, in some individuals, life-long exercise may be detrimental to an otherwise normal cardiac structure and function. Unfortunately, enrolment of women has been slow in studies evaluating the effects of long-term exercise on the heart to further our understanding of sex differences on cardiac maladaptation. Arrhythmias, myocardial fibrosis, high CAC and atherosclerotic plaque burden appear to be less prevalent in women suggesting oestrogen may play a role in preserving cardiac health. 65 A large meta-analysis including 149,000 women demonstrated that longterm vigorous exercise was associated with a 28% reduced risk of AF in female athletes. 79, 91 Studies investigating myocardial fibrosis have predominantly focussed on male athletes. In a study, otherwise healthy long-term triathletes of whom one-third were female were investigated with cardiovascular MRI. 103 None of the female athletes had myocardial fibrosis compared to 17% of male athletes correlating with a higher peak exercise BP and the number of hours of training. Female athletes generally have a lower peak exercise BP that may account for the difference.

A study by Merghani et al. 104 evaluated 170 veteran athletes aged 54 ± 8.5 years, of whom 29% were female, and 132 controls of a similar age, sex and low-risk coronary score for coronary disease. There was a higher prevalence of AF, coronary plaques, myocardial fibrosis and ventricular tachycardia limited to male athletes in comparison with healthy controls. None of the female veteran athletes exhibited adverse cardiac remodelling. Female athletes had a similar burden of coronary disease as sedentary women. The absence of coronary disease in female veteran athletes suggests their genetic and hormonal make-up may hold back adverse arrhythmogenic remodelling.

There is a significantly lower prevalence of exercise-related SCD in women with a ratio of 3:1-10:1, and this also holds true for older recreational athletes, where the men are 20-fold more likely to die of SCD than female athletes. 19 There also appear to be sex differences relating to diseases that predispose people to SCD. Female athletes rarely succumb to HCM according to the US National Registry, which is probably due to fewer ventricular arrhythmic events from a reduced volume and intensity of exercise in women. 21 However, hormonal and metabolic factors may also play a protective role in reducing the arrhythmic risk during intensive exercise.

In contrast, a different situation exists in women with MVP. In the Italian pathology registry of 650 SCDs, 7% of deaths were attributed to MVP and, of these, the majority (60%) were in women. 105 The vast majority of SCD in female athletes are associated with sudden arrhythmic death syndrome where structurally normal hearts are identified on post-mortem analysis. 33

In the last four decades, we have witnessed an increasing number of females participating in numerous sporting disciplines at elite levels.

Females show similar qualitative adaptations to exercise as men but they have a lower prevalence of concentric LVH and cardiac dimensions exceeding predicted upper limits.

In contrast with men, female endurance athletes do not show a higher prevalence of AF and raised CAC, according to current data. SCD during sport is significantly less common in women than men and is mainly secondary to electrical disease rather than structural abnormalities.

There are still major gaps in our knowledge relating to several CVDs beyond the scope of this review. Further large studies are required in female athletes with a variety of cardiovascular conditions to understand the disease process in our sex.

The upper limit of physiologic cardiac hypertrophy in highly trained elite athletes

Exercise and the heart: the good, the bad, and the ugly

Left ventricular morphology and function in female athletes: a metaanalysis

Physiologic left ventricular cavity dilatation in elite athletes

Clinical significance of electrocardiographic right ventricular hypertrophy in athletes: comparison with arrhythmogenic right ventricular cardiomyopathy and pulmonary hypertension

Clinical differentiation between physiological remodeling and arrhythmogenic right ventricular cardiomyopathy in athletes with marked electrocardiographic repolarization anomalies

Physiological right ventricular adaptation in elite athletes of African and Afro-Caribbean origin

RV remodeling in Olympic athletes

The upper limit of physiological cardiac hypertrophy in elite male and female athletes: the British experience

Effect of sex and sporting discipline on LV adaptation to exercise

Recommendations for chamber quantification

Ethnic differences in physiological cardiac adaptation to intense physical exercise in highly trained female athletes

Morphological and functional adaptation of left and right atria induced by training in highly trained female athletes

Left atrial volume index in highly trained athletes

Prevalence and significance of T-wave inversions in predominantly Caucasian adolescent athletes

Anterior T-wave inversion in young white athletes and nonathletes: prevalence and significance

International recommendations for electrocardiographic interpretation in athletes

Proposal for a revised definition of dilated cardiomyopathy, hypokinetic nondilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases

2020 ESC guidelines on sports cardiology and exercise in patients with cardiovascular disease: the Task Force on sports cardiology and exercise in patients with cardiovascular disease of the European Society of Cardiology (ESC)

ESC guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the diagnosis and management of hypertrophic cardiomyopathy of the European Society of Cardiology (ESC)

Demographics and epidemiology of sudden deaths in young competitive athletes: from the United States National Registry

Clinical outcomes in adult athletes with hypertrophic cardiomyopathy: a 7-year follow-up study

A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM risk-SCD)

Exercise and arrhythmogenic right ventricular cardiomyopathy

Comparison of clinical features of arrhythmogenic right ventricular cardiomyopathy in men versus women

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: pathogenic desmosome mutations in index-patients predict outcome of family screening: Dutch arrhythmogenic right ventricular dysplasia/cardiomyopathy genotype-phenotype follow-up study

Clinical presentation, long-term follow-up, and outcomes of 1001 arrhythmogenic right ventricular dysplasia/cardiomyopathy patients and family members

Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers

Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathyassociated desmosomal mutation carriers

Endocrinological roles for testosterone in resistance exercise responses and adaptations

Viral epidemiologic shift in inflammatory heart disease: the increasing involvement of parvovirus B19 in the myocardium of pediatric cardiac transplant patients

A geographical mystery: do cardiotropic viruses respect national borders?

Etiology of sudden death in sports: insights from a United Kingdom regional registry

Incidence, cause, and comparative frequency of sudden cardiac death in national collegiate athletic association athletes: a decade in review

Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States

Data from a nationwide registry on sports-related sudden cardiac deaths in Germany

Sudden cardiac death in Air Force recruits. A 20-year review

Coxsackievirus B3 myocarditis in C3H/HeJ mice: description of an inbred model and the effect of exercise on virulence

Testosterone and interleukin-1β increase cardiac remodeling during coxsackievirus B3 myocarditis via serpin A 3n

Management and treatment of myocarditis in athletes

Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathologic, clinical, and hemodynamic predictors

Cardiovascular magnetic resonance in myocarditis: a JACC white paper

Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY study

Comparison of myocardial fibrosis quantification methods by cardiovascular magnetic resonance imaging for risk stratification of patients with suspected myocarditis

Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

Sex differences underlying preexisting cardiovascular disease and cardiovascular injury in COVID-19

Gender difference is associated with severity of coronavirus disease 2019 infection: an insight from a meta-analysis

Suspected myocardial injury in patients with COVID-19: evidence from front-line clinical observation in Wuhan, China

Analysis of heart injury laboratory parameters in 273 COVID-19 patients in one hospital in Wuhan

Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19)

Exercise in the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) era: a question and answer session with the experts endorsed by the section of Sports Cardiology & Exercise of the European Association of Preventive Cardiology

A game plan for the resumption of sport and exercise after coronavirus disease 2019 (COVID-19) infection

Myocarditis and pericarditis after vaccination for COVID-19

Myocarditis and pericarditis following mRNA COVID-19 vaccination: what do we know so far?

COVID-19 mRNA vaccines in adolescents and young adults: benefit-risk discussion. Slide 28

Blood pressure and hypertension in athletes: a systematic review

Blood pressure response to exercise and cardiovascular disease

Exaggerated blood pressure reaction to exercise in subjects with and without systemic hypertension

Resting blood pressure values of adult athletes

Cardiovascular screening with electrocardiography and echocardiography in collegiate athletes

Cardiovascular risk and clinical factors in athletes: 10 years of evaluation

Prevalence of metabolic syndrome and its components among Chinese professional athletes of strength sports with different body weight categories

Sports-related sudden death in the general population

Prevalence of subclinical coronary artery disease in masters endurance athletes with a low atherosclerotic risk profile

Long-term marathon running is associated with low coronary plaque formation in women

Association of allcause and cardiovascular mortality with high levels of physical activity and concurrent coronary artery calcification

Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes

How and when to suspect spontaneous coronary artery dissection: novel insights from a single-centre series on prevalence and angiographic appearance

Spontaneous coronary artery dissection: angiographic follow-up and longterm clinical outcome in a predominantly medically treated population

Mitral valve prolapse: definition and implications in athletes

Mitral valve prolapse, ventricular arrhythmias, and sudden death

The pickelhaube sign: novel echocardiographic risk marker for malignant mitral valve prolapse syndrome

How to manage an athlete with mitral valve prolapse

Prevalence and clinical outcome of athletes with mitral valve prolapse

The effects of gender on electrical therapies for the heart: physiology, epidemiology, and access to therapies

International recommendations for electrocardiographic interpretation in athletes

Risk of arrhythmias in 52 755 long-distance cross-country skiers: a cohort study

Association between physical activity and risk of incident arrhythmias in 402 406 individuals: evidence from the UK Biobank cohort

Impact of CARDIOrespiratory FITness on arrhythmia recurrence in obese individuals with atrial fibrillation: the CARDIO-FIT Study

Physical activity and incidence of atrial fibrillation in older adults: the cardiovascular health study

Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists

Lone atrial fibrillation in vigorously exercising middle aged men: casecontrol study

Long-term endurance sport is a risk factor for development of lone atrial flutter

High prevalence of atrial fibrillation in long-term endurance cross-country skiers: echocardiographic findings and possible predictors -a 28-30 years follow-up study

Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: a follow-up study

Is the risk of atrial fibrillation higher in athletes than in the general population? A systematic review and meta-analysis

Physical activity, resting heart rate, and atrial fibrillation: the Tromsø Study

Gender differences of atrial and ventricular remodeling and autonomic tone in nonelite athletes

Physical activity and the risk of incident atrial fibrillation in women

Differential association of exercise intensity with risk of atrial fibrillation in men and women: evidence from a meta-analysis

Executive summary: HRS/ EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes

Exercise traininginduced repolarization abnormalities masquerading as congenital long QT syndrome

Age-and sex-related differences in clinical manifestations in patients with congenital long-QT syndrome: findings from the International LQTS Registry

Female gender as a risk factor for torsades de pointes associated with cardiovascular drugs

Return to play? Athletes with congenital long QT syndrome

Cardiac events during competitive, recreational, and daily activities in children and adolescents with long QT syndrome

Sports participation in genotype positive children with long QT syndrome

Management of mature athletes with cardiovascular conditions

Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study

Subclinical coronary artery disease in veteran athletes: is a new preparticipation methodology required?

Coronary atherosclerosis in middle-aged athletes: current insights, burning questions, and future perspectives

Myocardial fibrosis in competitive triathletes detected by contrast-enhanced CMR correlates with exercise-induced hypertension and competition history

Prevalence of subclinical coronary artery disease in masters endurance athletes with a low atherosclerotic risk profile

Arrhythmic mitral valve prolapse and sudden cardiac death