Differential diagnosis between ‘athlete’s heart’ and cardiomyopathies

Physiological adaptation to exercise results in a series of electrical, structural, and functional cardiac changes, broadly named ‘athlete’s heart’. Symmetrical enlargement of all cardiac chambers and mild increase in wall thickness are common findings in highly trained athletes. Typical electrocardiogram (ECG) features include sinus bradycardia, first-degree atrioventricular (AV) block, isolated voltage criteria for right and left ventricular hypertrophy and early repolarisation. Cardiac remodelling may be marked in some athletes, and it may be challenging to distinguish physiological adaptation from cardiac conditions at risk of sudden cardiac death (SCD), such as cardiomyopathies. Differential diagnosis often requires a comprehensive assessment starting from a detailed personal and family history to baseline tests, such as ECG and echocardiogram. In some cases, second-line tests, such as prolonged ambulatory ECG monitoring, exercise tolerance test and cardiovascular magnetic resonance are required.

In this narrative review, we will explore the key features of physiological cardiac adaptation to exercise, and we will focus on differential diagnosis between ‘athlete’s heart’ and cardiomyopathies.

Introduction

Regular intense exercise often results in a series of electrical, structural and functional changes, collectively named as the ‘athlete’s heart’.¹ These include mild harmonic increases in cardiac chamber size and in left ventricular wall thickness.² Athletes often exhibit sinus bradycardia, first-degree atrioventricular (AV) block, isolated QRS voltage criteria for right and left ventricular hypertrophy and early repolarisation.³ These physiological changes can closely mimic serious cardiac conditions, such as cardiomyopathies.⁴ The differentiation between ‘athlete’s heart’ and cardiomyopathies is crucial to prevent unnecessary restriction from competitive sports, and to ensure those with underlying pathological conditions receive appropriate management in order to avoid potentially fatal ventricular arrhythmias and sudden cardiac death (SCD).^5–10 In this narrative review, we will discuss the challenges in the differentiation between cardiac changes observed as part of physiological adaptation to exercise and cardiomyopathies. We will, therefore, focus on the strategies to accurately differentiate between benign and pathological entities.

The athlete’s heart: physiological adaptation to exercise

Cardiac adaptation to exercise in athletes is influenced by several factors, including the type and intensity of training, age, sex, ethnicity, and body size (figure 1). Knowledge of determinants of cardiac adaptation is crucial to ensure a learned and contextualised interpretation of cardiac investigations.

Electrocardiogram

Highly trained athletes display a plethora of electrocardiogram (ECG) changes, which typically result from physiological adaptation to exercise.^3,11,12 Sinus bradycardia, sinus arrhythmia, first-degree and Mobitz type I second-degree AV blocks are common in athletes, and are due to increased vagal activity and intrinsic AV node changes. Prominent QRS voltages are frequently observed, especially in male athletes.^3,13 Similarly, incomplete right bundle branch block (RBBB) and early repolarisation are common findings, which do not require any further investigation.^3,14–16 T-wave inversion (TWI) ≥1 mm in depth in the anterior leads is a marker of physiological adaptation to exercise in some athletes, especially when preceded by J-point/coved ST-segment elevation.^3,17 This pattern is more common in black athletes.¹⁸ The clinical significance of TWI varies according to its lead distribution on the ECG, namely anterior (leads V2–V4), lateral (V5 and/or V6, I and aVL) and inferior (II and aVF) leads. TWI may occasionally be more widespread, affecting the anterolateral and/or inferolateral leads.¹⁹ TWI is one of the most common ECG manifestations in individuals with cardiomyopathies and, therefore, differentiation between benign forms and pathological findings is crucial in this setting.³

Structural and functional adaptation

Elite athletes exhibit a series of structural and functional features, including increased left ventricular (LV) and right ventricular (RV) volumes, wall thickness and larger atrial dimensions.^2,20

Endurance athletes, particularly males with a large body surface area (BSA), tend to exhibit a significant increase in ventricular size. This is especially evident in those who participate in high-intensity dynamic exercise, for example competitive cyclists, who often display a combination of enlarged cavity dimensions, with a left ventricular end-diastolic diameter (LVEDD) commonly >60 mm, and mild reduction in left ventricular ejection fraction (LVEF).²¹ A study on Italian Olympic athletes across 38 sports, particularly in endurance disciplines, showed that 14% of male Olympic athletes exhibit a LVEDD greater than 60 mm.²² In contrast, in healthy female athletes, a significant increase in absolute values of LV dimensions is rarely observed.^22–26 Conversely, when indexed for BSA, LVEDD has been found to be significantly higher in female athletes compared with their male counterparts.²⁷

A large observational study that enrolled 2,723 athletes (1,819 white, 904 black) demonstrated that an increased left ventricular wall thickness (>12 mm) is rarely observed in white male athletes but is more common in black athletes of African and Afro-Caribbean descent (respectively 1.6% and 12.4%).¹⁸ In contrast, female athletes rarely exhibit a left ventricular wall thickness >12 mm, and this finding should be considered a red flag, raising the suspicion of cardiomyopathy.^23,25–27

Age is also a determinant of cardiac remodelling in athletes. Highly trained junior athletes typically exhibit only modest increase in LV cavity size and mass. In adolescent male athletes, for instance, LVEDD at echocardiography usually ranges between 40 and 60 mm, and less than 20% exceed 54 mm, with dimensions above 60 mm being uncommon.²⁴ Additionally, while trained adolescent athletes tend to show greater absolute left ventricular wall thickness compared with their non-athlete counterparts, only a small fraction exhibit a left ventricular wall thickness >12 mm. When this degree of increased wall thickness is observed, it is almost always associated with concurrent enlargement of the LV cavity in healthy athletes.²⁸

The RV is often dilated in endurance athletes, reflecting the high preload.^2,29,30 Physiological dilatation of the RV may be erroneously interpreted as a sign of arrhythmogenic cardiomyopathy (ACM).^31,32 Healthy athletes rarely show an RV end-diastolic volume/LV end-diastolic volume >1.2 and an RV ejection fraction (RVEF) <45% on cardiac magnetic resonance (CMR).^33,34

Differential diagnosis with cardiomyopathies

Cardiomyopathies are a heterogeneous group of conditions that affect the heart muscle, leading to structural and functional abnormalities.³⁵ Cardiomyopathies are common aetiologies of SCD in young athletes.¹⁰ The most common types include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic cardiomyopathy (ACM).³⁶ Each type presents distinct pathophysiological features that may overlap with physiological cardiac adaptation to exercise (figure 2).^37,38 Various diagnostic tools and criteria have been developed to aid clinicians in this process, including ECG, transthoracic echocardiography (TTE), CMR, and genetic testing.³⁹ In the absence of symptoms, the diagnosis may be triggered by the detection of ECG abnormalities, for example, in the context of pre-participation screening (figure 3). TTE should be the primary imaging modality for athletes with suspected cardiac pathology. CMR imaging may provide further insights into differential diagnosis. Beyond the very high spatial and temporal resolution, CMR allows tissue characterisation and may reveal myocardial oedema, tissue infiltration and myocardial fibrosis (figure 4).

Differential diagnosis with HCM

HCM is generally defined by the presence of left ventricular hypertrophy (LVH) with left ventricular wall thickness ≥15 mm in one or more myocardial segments, which is not explained by loading conditions.^35,40 One of the most feared complications of HCM is SCD, which can be the first manifestation of the disease in otherwise asymptomatic individuals.^41,42 Risk stratification in patients who are diagnosed with this condition is crucial for prevention and to instigate appropriate clinical management.⁴³

Electrocardiogram

The ECG is abnormal in about 95% of patients with HCM.³⁵ Pathological features that should raise suspicion of the disease include pathological Q-waves, ST-depression, and TWI, especially in the inferior and lateral leads.⁴⁴ In contrast, the ECG of highly trained athletes often reveals isolated voltage criteria for LVH, which is unusual in patients with HCM.³ Particular care should be taken when assessing Q-waves, and specifically pathological Q-waves (≥40 ms in duration and/or Q/R ratio ≥0.25 in two or more contiguous leads, excluding leads III and aVR), and ‘benign’ Q-waves, which can often be found in healthy athletes.^3,45,46 ST-segment depression ≥0.5 mm (relative to the isoelectric PR segment), in two or more leads, should be considered an abnormal finding and warrants further investigation to assess for underlying structural heart disease.^3,45,47 Lateral TWI should always be considered pathological until proven otherwise. A normal echocardiography may not be of full reassurance, and further assessment with CMR is indicated.³

Echocardiogram

TTE is the first-line imaging test in individuals with suspected HCM. Diagnosis of HCM relies on the demonstration of LVH (wall thickness ≥15 mm or ≥13 mm when combined with ECG abnormalities or family history of HCM).³⁵ A wall thickness of 16 mm or more is very rarely found in elite athletes, and this finding should always raise the suspicion of HCM.¹⁸ Therefore, the dilemma usually arises in asymptomatic athletes with mild asymmetric LVH of 13 to 15 mm, defined as ‘grey zone’. It is not just the absolute values of wall thickness that should be taken into consideration. Physiological LVH is often accompanied by enlargement of all four chambers and normal diastolic and longitudinal systolic functions.² A relative wall thickness (RWT) exceeding 0.5 should raise the suspicion of HCM, regardless of ethnicity.⁴⁸ The LVEDD has been proposed as a possible discriminator between physiological LVH and mild expression of HCM. Sheikh et al. compared 15 athletes with HCM in the ‘grey zone’ to 55 healthy athletes, both groups exhibiting concentric LVH with left ventricular wall thickness (LVWT) between 13 and 16 mm. A LVEDD ≤51 mm had good discriminating ability, but with a low sensitivity. Indeed, 13% of athletes with HCM in the ‘grey zone’ had a LVEDD >54 mm.⁴⁹ Other factors that favour pathology include impaired diastolic function, a bizarre pattern of LVH, asymmetric LVH, and dynamic LV outflow obstruction.⁵⁰

LV diastolic function is always normal, or even supranormal, in athletes, reflecting an enhanced ventricular filling pattern. Most diastolic function indicators have shown low sensitivity for detecting HCM in athletes. A retrospective analysis of LV diastolic function indices in 1,510 healthy young athletes, compared with 58 young patients with HCM, identified that the most sensitive diastolic markers for HCM include septal E wave <10 cm/s, lateral E wave <12 cm/s, average E/E’ >7.9, and E/A ratio <1.8.⁵¹

Finally, TTE may fail in the detection of apical HCM, due to poor visualisation of the LV apex.^52,53

Further investigations

Athletes in the ‘grey zone’ should be investigated with more detailed tests. CMR is crucial in this setting, providing an accurate assessment of LVWT, chamber volumes, and LV mass. Due to its excellent spatial resolution, this test enables the evaluation of apical hypertrophy and of subtle LVH that may not be adequately visualised by echocardiography. Notably, CMR detects hypertrophy in approximately 12% of HCM patients who were not diagnosed through TTE due to segmental LVH.⁵⁴ In addition, CMR allows a detailed assessment of possible architectural changes of the LV, including hypertrophic, accessory and anteriorly displaced papillary muscles and apical systolic obliteration.^53,55 The presence of myocardial crypts, which are defined as narrow, deep, blood-filled invaginations within the compacted myocardial wall, may suggest an underlying genotype positive status, even in the absence of other phenotypic signs of HCM.⁵⁶ Furthermore, CMR offers the possibility of tissue characterisation through late gadolinium enhancement (LGE) imaging. Patchy LGE suggests interstitial myocardial fibrosis, which is often present in HCM patients, especially within the hypertrophied segments.⁵⁷ Other techniques, such as T₁ mapping, allow quantification of the myocardial extracellular volume (ECV), which correlates with diffuse interstitial fibrosis.⁵⁸ A study on 50 HCM patients and 40 highly trained healthy athletes demonstrated that as LVH increases, extracellular compartment decreases in athletes but increases in HCM patients.⁵⁹ The negative correlation between ECV and wall thickness in athletes suggests that the increase in LV mass in healthy myocardium is driven by cellular hypertrophy, whereas in HCM, it is due to extracellular matrix expansion and myocardial disarray.⁶⁰

Other investigations can help in the differential diagnosis, such as cardiopulmonary exercise test (CPET) and ambulatory ECG monitoring. Athletes without pathological remodelling would be expected to have a high exercise tolerance (peak oxygen consumption [pVO₂] >50 ml/kg/min or >20% above the predicted maximum value) and absence of arrhythmias on ambulatory ECG monitoring.^49,61,62 Genetic testing should be reserved for those with high clinical suspicion or when the diagnosis remains uncertain.^63–65

Differential diagnosis with DCM

DCM is currently defined by the presence of LV or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment.^35,36 DCM may cause SCD in athletes, and, therefore, it is extremely important to differentiate physiological adaptation to exercise from DCM. It is not uncommon, especially for endurance athletes, to exhibit a markedly dilated LV and low LVEF, features that are typically observed in DCM.²¹

Electrocardiogram

Abnormal ECG features are reported in up to 80% of cases of DCM.⁶⁶ Various ECG abnormalities should raise the suspicion of DCM in an athlete with a dilated LV. Left bundle branch block (LBBB) is a common ECG feature, followed by left atrial enlargement, left axis deviation, low QRS voltages, TWI and pathological Q-waves.⁶⁷ Although sinus bradycardia and first-degree AV block are normal in athletes, extreme bradycardia (<30 bpm) and advanced AV blocks suggest a pathological process and require further investigation.³ Some ECG abnormalities in this context may even suggest the underlying genetic substrate. Examples are sinus node disease, AV blocks, and LBBB which, in the appropriate clinical context, may suggest a lamin A/C (LMNA) cardiomyopathy, or low QRS voltages, in combination with inferolateral TWI, which may suggest filamin C (FLNC) or desmosomal disease.⁶⁷

Echocardiogram

DCM is traditionally defined by the presence of LVEF <45% (>2 standard deviations [SD]) or fractional shortening <25% (>2 SD) and LVEDD >117% of predicted value corrected for age and BSA (>2 SD of the predicted normal limit +5%), in the absence of myocardial disease.⁶⁸ Endurance athletes often exhibit increased biventricular dimensions.²² In highly trained endurance athletes, the LV dilatation may be accompanied by a mildly reduced LVEF (45–54%).⁶⁹ An observational study of elite cyclists who participated in the Tour de France in 1995 and 1998, found that 51% of them exhibited LV dilatation (LVEDD >60 mm), and 18% a LVEF <55%.²¹

Further investigations

In athletes where the ECG and echocardiogram raise the suspicion of DCM, CMR may provide valuable insights, including an accurate assessment of LV volumes and the possible presence of mid-wall fibrosis, a feature that, if present, corroborates the diagnosis of DCM in the appropriate context.⁷⁰ Moreover, ambulatory ECG monitoring, exercise stress echocardiogram and CPET may be helpful in the differential diagnosis. For instance, failure to augment cardiac output during exercise in athletes falling in the ‘grey zone’ (mild impairment of LV systolic function and significant LV dilatation at baseline echocardiography) is a red flag for DCM.^71,72 Other features may suggest a pathological rather than physiological entity in this context, including high premature ventricular contractions (PVCs) burden (>2,000 per 24 hours) at ambulatory ECG monitoring, and propensity to develop frequent PVCs or non-sustained ventricular tachycardia (NSVT) during exercise tolerance test (ETT).^73–76

Differential diagnosis with ACM

Arrhythmogenic cardiomyopathy is an inherited condition, reportedly affecting one in 1,000 of the general population.³⁵ The disease is generally caused by mutations in genes encoding cardiac desmosomal proteins, with pathogenic or likely pathogenic variants identified in up to 60% of patients with a diagnosis of ACM.^63,77 Although the initial description of the disease suggested an exclusive involvement of the RV, recent studies showed that the LV is involved in the majority of patients.⁷⁸ The diagnosis of ACM is complex and traditionally based on the task force criteria (TFC), which include a series of clinical, ECG and structural/functional traits.⁷⁹ The more recently proposed Padua criteria and the revised European task force consensus criteria also take into account myocardial abnormalities within the LV, such as, for example, mid-wall and subepicardial fibrosis at CMR.^80,81 The disease hallmark is the replacement of healthy myocardium with fibrofatty tissue and a predilection for fatal arrhythmias, especially during exercise.^5,82 Intensive exercise is thought to result in myocyte detachment with subsequent inflammation and abnormal repair, resulting in progressive fibrofatty replacement of the ventricular myocardium in predisposed individuals.⁸³ SCD and progressive ventricular systolic dysfunction are the most feared complications.⁷⁸

Electrocardiogram

The ECG is abnormal in ACM in up to 80% of cases. The most common ECG abnormality is anterior TWI, which is present in up to 50% of patients.⁸¹ This feature may be physiological in healthy athletes, especially young and of African or Afro-Caribbean descent.¹⁸ Certain features may suggest a pathological substrate in athletes with anterior TWI. These include ‘isoelectric or downward shift’ of J-point and ST-segment in V1–V3, low voltages in the limb and/or precordial leads, QRS duration ratio V2:V5 >1.2, S-wave prolongation in V1–V2 (>55 ms), multiple PVCs, and combination with TWI in the inferior and lateral leads.⁸⁴ In contrast, in healthy athletes, anterior TWI is often accompanied by a J-point elevation of at least 1 mm.³ Patterns of PVCs may also be helpful in the differential diagnosis between ‘athlete’s heart’ and ACM. While PVCs originating from RV outflow tract are common in athletes and often disappear during exercise at the ETT, a RBBB pattern and superior axis with wide QRS may be a sign of ACM.^85,86 Another typical ECG finding in ACM is the presence of an epsilon wave, defined as a small positive deflection or notch between the end of the QRS complex and onset of the T-wave in leads V1–V3.⁸¹ An epsilon wave is found in 8–10% of patients with ACM, being highly specific and poorly sensitive.⁸⁷

Echocardiogram

During exercise, the RV is subjected to significant wall stress, adapting to an increased preload. Athletes, especially the ones engaged in endurance exercise, often exhibit RV dilatation.^29,30 Conventionally, echocardiography has a poor sensitivity for discriminating ACM from athlete’s heart due to the shortfall of a tri-dimensional view and lower spatial resolution in comparison to CMR.⁸⁸ RV systolic dysfunction (RV fractional area change [FAC] <32%) with or without regional wall motion abnormalities in an athlete favours a diagnosis of ACM.^32,89

Further investigations

When ACM is suspected, further investigations are warranted. CMR is the gold standard for the assessment of the RV and specifically to differentiate between normal and pathological findings.⁹⁰ RV enlargement in athletes is usually accompanied by concomitant LV remodelling, reflecting a symmetrical adaptation of the heart to the haemodynamic changes induced by training.³¹ Regional wall motion abnormalities, such as dyskinesia, akinesia and aneurysms, as well as an RV/LV end-diastolic volumes ratio >1.2 and an impaired RV systolic function (RVEF ≤45%), are features that support ACM.^33,34 Moreover, subepicardial and/or mid-wall LGE may corroborate the diagnosis.⁷⁰ Other tests, such as ambulatory ECG monitoring and ETT can be helpful in the differential diagnosis. The presence of ventricular arrhythmias, such as a high burden of PVCs (>500 per 24 hours) and NSVT at ambulatory ECG monitoring are features that may point toward a diagnosis of ACM in the appropriate clinical context.³³ In those with suspected ACM, ETT may reveal susceptibility to ventricular arrhythmias (either increased PVCs burden or NSVT) during exercise.^33,91

Conclusion

Differential diagnosis between physiological cardiac adaptation to exercise in athletes and cardiomyopathies is often challenging. A comprehensive approach, integrating family and personal history, ECG, advanced imaging, and, in some cases, genetic testing, is essential to ensure an appropriate management of possible dilemmas. A deep understanding of the determinants of cardiovascular adaptation in athletes, including type and intensity of exercise, age, sex, and ethnicity is a first step to distinguish between physiological and pathological findings. A learned interpretation of the ECG and knowledge of the value of second-line cardiac investigations, such as echocardiogram, CMR, ETT and ambulatory ECG monitoring, is crucial to identify red flags that may lead to the correct diagnosis.

Key messages

• Intense exercise may result in a series of physiological electrical, structural and functional cardiac changes, which may mimic serious cardiac conditions, such as cardiomyopathies
• Differentiation between physiological adaptation to exercise and pathological findings suggestive of a cardiomyopathy is often challenging
• Differential diagnosis is crucial in this setting and usually requires a systematic approach, which starts from an accurate collection of personal and family history and electrocardiogram (ECG), with further tests dictated by the results of these
• Knowledge of determinants of physiological cardiac adaptation and of normal findings in athletes is key to distinguish them from pathological signs that raise the suspicion of an underlying cardiac disease

Conflicts of interest

None declared.

Funding

None.

Editors’ note

This is the first article in a series on sports cardiology.

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