Diagnostic Differentiation Between Arrhythmogenic Cardiomyopathy and Athlete’s Heart by Using Imaging

JACC: CARDIOVASCULAR IMAGING

VOL. 11, NO. 9, 2018

ª 2018 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

STATE-OF-THE-ART PAPERS

Diagnostic Differentiation Between Arrhythmogenic Cardiomyopathy and Athlete’s Heart by Using Imaging Flavio D’Ascenzi, MD, PHD,a Marco Solari, MD,a Domenico Corrado, MD, PHD,b Alessandro Zorzi, MD, PHD,b Sergio Mondillo, MDa

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From the aDepartment of Medical Biotechnologies, Division of Cardiology, University of Siena, Siena, Italy; and the bDepartment of Cardiac, Thoracic, and Vascular Sciences, Division of Cardiology, University of Padova, Padova, Italy. All authors have reported that they have no industrial relationships relevant to the contents of this paper to disclose. Manuscript received March 19, 2018; revised manuscript received April 17, 2018, accepted April 19, 2018.

ISSN 1936-878X/$36.00

https://doi.org/10.1016/j.jcmg.2018.04.031

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JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 9, 2018 SEPTEMBER 2018:1327–39

Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

Diagnostic Differentiation Between Arrhythmogenic Cardiomyopathy and Athlete’s Heart by Using Imaging Flavio D’Ascenzi, MD, PHD,a Marco Solari, MD,a Domenico Corrado, MD, PHD,b Alessandro Zorzi, MD, PHD,b Sergio Mondillo, MDa

ABSTRACT Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death (SCD) in youth and athletes. In the last decade, several studies focused on right ventricular (RV) remodeling in athletes and revealed that features of the physiological adaptation of the right heart to training, such as RV dilation, may overlap with those of ARVC. Therefore, a careful multiparametric evaluation is required for differential diagnosis in order to avoid false diagnosis of ARVC or, in contrast, fail to identify the risk of causing SCD. This review summarizes physiological adaptation of the RV to exercise and describes features that could help distinguishing between athlete’s heart and ARVC. (J Am Coll Cardiol Img 2018;11:1327–39) © 2018 by the American College of Cardiology Foundation.

A

rrhythmogenic right ventricular cardiomyop-

found in young subjects; however, expertise and a

athy (ARVC) is a rare genetic disease histo-

focused examination are required (7).

logically characterized by replacement of

According to the Task Force Criteria, diagnosis of

myocardium with fibrous and fatty tissue, resulting

ARVC by echocardiography requires a combination of

in right ventricular (RV) dilation, dysfunction, and

regional RV wall motion abnormalities (WMAs) and

ventricular arrhythmia (1). ARVC is an important

global RV dilation and dysfunction. Cutoff values

cause of sudden cardiac death (SCD) in youth and ath-

were derived from studies in the general population.

letes (2). Life-threatening ventricular arrhythmias

Recently, a number of studies focused on training-

may occur in previously asymptomatic individuals

induced RV remodeling and revealed that some fea-

and are typically caused by physical exercise (3).

tures of the so-called “athlete’s heart” may overlap

Diagnosis of ARVC is based on International Task

with those of ARVC, especially at an early stage of the

Force Criteria, which combine family history and

disease. Therefore, a careful evaluation of the RV is

electrophysiological, morphological, functional, and

required for differential diagnosis in order to avoid

histological criteria (4). In 2010, Task Force Criteria

false diagnosis of ARVC (by interpreting physiological

were modified to improve sensitivity while main-

features as abnormal) or, on the contrary, to fail to

taining specificity, mostly for the clinical screening of

identify pathological features of a disease at risk of

family members, by incorporating the recent ad-

sports-related SCD (8).

vances in genetic testing and by providing quantita-

This paper provides a thorough discussion of the

tive imaging parameters, also by cardiac magnetic

echocardiographic characteristics of RV remodeling in

resonance (CMR) imaging (5). In clinical practice,

athletes, with a specific focus on the differential

CMR has become the preferred imaging technique for

diagnosis between athlete’s heart and ARVC.

evaluating the RV when ARVC is suspected because it is more sensitive than echocardiography for detecting

ATHLETE’S HEART

early ventricular dilation and dysfunction when clinical manifestations of early ARVC are subtle (6).

Intensive training results in morphological and

An additional advantage of CMR is its ability to

functional remodeling of cardiac chambers and in

characterize tissue types. Although CMR is a highly

peripheral cardiovascular adaptations.

accurate imaging modality, it is expensive, not widely

Cardiac enlargement was demonstrated by thoracic

available, and time consuming, and claustrophobic

percussion in cross-country skiers and confirmed by

patients may be unable to undergo the examination.

chest radiograms, pathology reports (9), and in the

Hence, echocardiography still has a crucial role in

1970s, by electrocardiography (ECG) and vectorcar-

detecting RV abnormalities and particularly valuable

diography (10). Two-dimensional echocardiography

for the high quality of acoustic windows usually

has led to important advances in our understanding

D’Ascenzi et al.

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

of cardiac adaptation to exercise conditioning (11–16).

population. Athletes engaged in combined

ABBREVIATION

Although athletic training results in remodeling of all

sports (such as rowing or canoeing), requiring

AND ACRONYMS

cardiac cavities, formal assessment of the RV has

a combination of static and dynamic exercise,

often been neglected primarily because of the lack of

exhibit the greatest RV dimensional remod-

simple and reliable methods to estimate RV function

eling, whereas athletes engaged in strength

(17) and its complex geometry (18). However, in the

sports, such as weight lifting, exhibited the

last decade, several studies have investigated RV

lowest degree of RV remodeling.

ARVC = arrhythmogenic right ventricular cardiomyopathy

CMR = cardiac magnetic resonance

LGE = late gadolinium

remodeling in athletes and have described the most

In addition to the type of sport practiced,

relevant characteristics of RV adaptation to training.

increasing age and years of training also have

LV = left ventricular

The most important findings are summarized in

been identified as predictors of right heart

RV = right ventricular

Table 1.

dimensions (26); thus, athletes with more

RVFAC = right ventricular

RV SIZE. Current evidence suggests that intensive

years of training show the greatest degree of

fractional area change

and prolonged physical exercise induces an increase

RV remodeling.

enhancement

RVOT = right ventricular outflow tract

in RV cavity size and RV mass (19–21) and that

Cardiovascular remodeling induced by ex-

competitive athletes exhibit a dimensional increase

ercise is associated not only with cardiac but

in the right chambers (7,21,22). RV size can be esti-

also with extracardiac modifications (27,28),

STE = speckle-tracking echocardiography

SCD = sudden cardiac death

mated by echocardiography through RV outflow tract

including dilation of the inferior vena cava

(RVOT) diameters, RV end-diastolic and end-systolic

that represents the consequence of physio-

areas, and RV basal and mid-cavity diameters, as

logical adaptation to the augmented venous

shown in Figure 1. Echocardiographic studies have

return, increased volume load, and cardiac output

demonstrated that the increase in RV size is more

(29,30). Therefore, a comprehensive evaluation of

evident in male endurance athletes, in whom dif-

athlete’s heart should include evaluation of extrac-

ferential diagnosis with pathological remodeling of

ardiac adaptations induced by hemodynamic changes

ARVC may be particularly challenging, although

imposed by training.

athletes usually maintain normal RV systolic and

WMA = wall motion abnormality

Exercise-induced RV remodeling is dynamic in

thickness,

nature. Indeed, when evaluating the athlete during

normal collapsibility of inferior vena cava, and

the competitive season, an increase in RV size can be

normal pulmonary artery systolic pressure (23). The

found in comparison with baseline data, confirming

extent of RV remodeling results in a relevant per-

that RV remodeling is a dynamic process and that the

centage of athletes fulfilling dimensional echocar-

RV rapidly adapts in response to the increased de-

diastolic

function,

end-diastolic

wall

diographic criteria for the diagnosis of ARVC. Zaidi

mand imposed by training (31). These findings also

et al. (23) found that 61% of male and 46% of female

were confirmed in children practicing competitive

athletes had RV dimensions above the cutoff value

sports (32) and suggest that, although RV dilation in

of the minor criteria, whereas 37% of male and 24%

ARVC patients is almost an irreversible process, the

of female athletes had RV dimensions above the

extent of training-induced RV enlargement in ath-

cutoff value of the major criteria. In a population of

lete’s heart can change according to load conditions

Olympic athletes, 23% exceeded the criteria of RV

imposed by training. Furthermore, the anatomic fea-

dilation proposed by the American Society of Echo-

tures of the RV, such as a thin wall and a propensity

cardiography, and in 16% and 41% of cases, respec-

for a volume-overload adaptation, could be respon-

tively, fulfilled major and minor criteria for the

sible for an earlier adaptation of this ventricle

diagnosis of ARVC (24). Endurance athletes demon-

compared to that of the left ventricle.

strated the greatest degree of RV remodeling and the

Therefore, taken together, these studies suggest

highest percentages of RV classified as “dilated”

that the RV is often dilated in competitive and top-

according to the American Society of Echocardiog-

level athletes. Male sex, sports discipline, age, and

raphy and Task Force Criteria for ARVC (24).

years of training should be taken into account in

Notably, RVOT dimensions indexed to body surface

order to properly interpret RV remodeling. The

area (BSA) were greater in female than in male ath-

greater the duration and intensity of exercise, the

letes (23,24).

higher the cardiac output and, ultimately, the he-

A recent meta-analysis of 46 echocardiographic

modynamic stimulus for the dimensional increase of

studies and a total of 6,806 competitive athletes (25)

the RV (24).

demonstrated that male competitive athletes exhibit

RV

a marked RV remodeling in which the upper limits of

characteristics of RV in athletes are not confined to a

normality are greater than those in the general

mere increase in cavity size. Indeed, elite athletes

MORPHOLOGIC

FEATURES. Echocardiographic

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

T A B L E 1 Summary of the Most Relevant Echocardiographic Findings of the Right Ventricle in Athlete’s Heart

Main Findings

Ref. #

Size Prolonged and intense training induces an increase in RV cavity size and mass

(6,18–21)

A relevant proportion of competitive athletes fulfills the minor and major echocardiographic dimensional criteria for the diagnosis of ARVC

(22,23)

RV size in athlete’s heart often exceeds the normative reference values proposed for the general population

(24)

Athletes engaged in combined disciplines (e.g., rowers, canoeists) have the highest degree of RV remodeling, whereas strength athletes have the lowest

(24)

Together with type of sport, age and years of training are predictors of RV size in athletes

(25)

RV remodeling in athlete’s heart is accompanied by extracardiac adaptations

(26,27)

RV remodeling is a dynamic process, and the RV rapidly adapts in response to training

(30)

RV enlargement in athletes is usually accompanied by remodeling of the LV

(23,40,41)

Function Despite marked RV dimensional remodeling, in athlete’s heart, systolic and diastolic function is usually normal

(22–24,31)

A lower reference value of RV FAC of 32% has been recently proposed in athletes (lower than the general population). Some authors reported normal or even supranormal value of RV strain, whereas others found a lower value than controls The reduction of RV strain is confined to the basal segment, particularly for endurance athletes. This functional adaptation is likely a physiological consequence of exercise-induced hemodynamic changes A potential detrimental effect of endurance and ultra-endurance training has been found. The clinical meaning of this transient reduction in RV function is currently unclear and under debate

(24) (21,30,35,36) (15,37) (35)

ARVC ¼ arrhythmogenic right ventricular cardiomyopathy; FAC ¼ fractional area change; LV ¼ left ventricular; RV ¼ right ventricular.

were found to have a characteristic remodeling of the

should be carefully taken into account when evalu-

RV in terms of qualitative features. Up to 81% of elite

ating the RV of competitive athletes and should be

athletes showed a round-shaped apex, 37% exhibited

interpreted as a benign and physiological adaptation

prominent RV trabeculations, and a hyper-reflective

of the RV induced by the high hemodynamic overload

moderator band was found in 0.5% of athletes (24).

during chronic intensive exercise.

Conversely, none of the athletes showed the RV

RV FUNCTION IN THE ATHLETE. Conventional indexes

WMAs that are required for imaging diagnosis of

of RV function. A comprehensive and appropriate

ARVC in addition to RV dilation. These peculiarities

assessment of the RV includes the most common

F I G U R E 1 Assessment of RV Size by Echocardiography

v

v

RV basal and mid-cavity diameters

RVOT PLAX 5

5

5

10

10

15

v

15

End-diastolic area

10

v

v

RVOT PSAX

5

5

10 10

15

End-systolic area

RV outflow tract diameters can be obtained by PLAX and PSAX views, whereas RV basal and mid-cavity diameters can be obtained from the 4-chamber view. PLAX ¼ parasternal long-axis; PSAX ¼ parasternal short-axis; RV ¼ right ventricular.

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

F I G U R E 2 Assessment of RV Function by 2D and Speckle-Tracking Echocardiography

LOCALE: Strain Longitudinal (%) =-23.50

s’ =0.14 m/s

T=338 msec

AVC

base

TAPSE

AVERAGE mid apex

Figure shows RV strain, s0 velocity, and TAPSE as measures of RV function. TAPSE ¼ tricuspid annular plane systolic excursion; other abbreviations as in Figure 1.

indexes of ventricular function, including tricuspid

the general population, suggesting that the novel

annular plane systolic excursion, tissue Doppler-

echocardiographic techniques seem to assess more

derived RV peak systolic velocity (RV s 0 ), and early

accurately RV function in competitive athletes.

myocardial relaxation velocity (RV e 0 ), RV fractional

Evaluation of RV function by speckle-tracking echocardiography.

area change (RVFAC), and RV strain (Figure 2). How-

Application of speckle-tracking echocardiography

ever, data currently available for RV function in ath-

(STE) has led to a more comprehensive knowledge of

letes are controversial, and these discrepancies are

exercise-induced cardiac remodeling (16,35). STE has

due mainly to differences among the studies in terms

recently been applied extensively to athlete’s heart.

of demographic and athletic characteristics of the

Application of STE to the RV provides global RV strain

study populations and in terms of indexes used for

and regional strain values of basal, mid, and apical

assessing RV function.

segments. Although some authors have focused on

Despite a marked RV dimensional remodeling,

differences between absolute values of RV and left

competitive athletes usually have almost normal

ventricular (LV) strain between athletes and controls

systolic and normal or supranormal diastolic func-

(36), others have analyzed predictors of RV size and

tions (23,24,33). A recent meta-analysis of 6,806

strain in athletes (37).

competitive athletes (25) showed that competitive

Conflicting results have been reported when

athletes had a lower reference value of RVFAC (i.e.,

applying

32%) than that recommended for the general pop-

although some authors reported normal or even

ulation by the American Society of Echocardiogra-

supranormal values of RV global strain in athletes,

phy

of

others found a reduction in athletes compared to

Cardiovascular Imaging (34) and significantly below

controls (22,31,37,38). However, the reduction of RV

(ASE)

and

the

European

Association

STE

to

the

RV

of

athletes.

Indeed,

the cutoff proposed by the Task Force for ARVC

strain was confined to the basal segment alone, and

diagnosis, which considers an RVFAC $40% to be

further studies demonstrated that resting parame-

normal (5). Conversely, normative reference values

ters of RV function were poorly suggestive of con-

for tricuspid annular plane systolic excursion, TDI-

tractile

derived parameters, and RV strain obtained in ath-

athletes, should not be interpreted as a sign of

letes were comparable with those recommended for

subclinical damage but rather as a physiological

reserve

and,

especially

in

endurance

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

exercise-induced modification (39). Particularly for

simple premature ventricular beats to ventricular

the basal segment, the hypothesis is that, given that

tachycardia and ventricular fibrillation leading to

volume is greatest at the RV base, a lesser degree of

cardiac arrest and SCD (41). The pathogenesis of

deformation may be required to generate the same

ventricular arrhythmias changes during the different

stroke volume, thereby explaining why RV defor-

disease phases: in young, often previously asymp-

mation may be reduced in this region (16,39). In

tomatic patients, SCD is mainly due to ventricular

subsets of endurance and ultraendurance (25) ath-

fibrillation, in the context of bouts of acute myocyte

letes, a possible detrimental effect of intensive

death and reactive inflammation (so-called hot

training on the RV systolic function has been hy-

phase). By contrast, older patients with a long-

pothesized

been

lasting disease more often experience scar-related

ultraendurance

hemodynamically stable ventricular tachycardia due

competition (37). This marked impact of a single

to a re-entry mechanism around a myocardial scar

endurance event on RV could represent a sort of

(42). Heart failure due to RV or biventricular

“fatigue” that is recovered in most well-trained

dysfunction (resembling a dilated cardiomyopathy)

subjects but that could have detrimental effects in

is rare and observed only in the late stage of the

other athletes who are not well adapted. Future

disease.

observed

as to

RV be

dysfunction reduced

and

after

has

studies with large samples of athletes observed over

Typical electrocardiographic abnormalities con-

a long-term period are needed to investigate the

sisting of T-wave inversion in the right precordial

cumulative effect of chronic exercise on RV func-

leads V 1 to V 4 with no J point and ST-segment

tion and to interpret the clinical meaning of a

elevation, and depolarization abnormalities (intra-

transient decrease in RV function.

ventricular conduction delay, epsilon waves) are

Taken together, the results of these studies suggest

observed in most patients (5).

that healthy athletes can show a slightly lower RVFAC at rest and question the applicability of the RVFAC

Imaging features and diagnostic criteria. The imaging

cutoff values included in the Task Force Criteria for

features of arrhythmogenic cardiomyopathy reflect

differential diagnosis between ARVC and athlete’s

the regional involvement of the disease process.

heart. On the other hand, the other indexes of RV

An essential element for the diagnosis of ARVC by

function are normal in competitive athletes, sug-

imaging modalities is the presence of a regional RV

gesting that evaluation of RV function should be

WMAs, consisting of akinesia and dyskinesia or

comprehensive and multiparametric.

aneurysm in combination with global RV dilation or

ARRHYTHMOGENIC RV CARDIOMYOPATHY. Pathogenesis

dysfunction. However, it must be emphasized that

and clinical presentation. ARVC is caused by a genetically determined defect of the intercellular junctions called “desmosomes.” The disease is characterized by incomplete

penetrance

and

variable

phenotypic

expression: it shows a male predominance and typically becomes overt after pubertal development. A family history of SCD or ARVC is reported by z50% of patients (40). The

pathophysiological

process

begins

with

rupture of the defective desmosomes and consequent necrosis or apoptosis of myocytes that are replaced by fibrofatty tissue. The disease initially affects the subepicardial layers of the ventricular wall and only later becomes transmural. Moreover, the fibrofatty replacement process does not homogenously affect the entire heart but, in the classic (right-dominant) variant, predominantly involves the angles of the so-

imaging abnormalities are not sufficient for the diagnosis of ARVC, which requires a combination of multiple criteria from different categories (imaging features, ECG abnormalities, ventricular arrhythmia, family history and genetic background, and endomyocardial biopsy) (Table 2) (5). Because the disease process spares the subendocardial layers, which mostly contribute to myocardial contraction, the left ventricle exhibits no dilation and no or mild regional dysfunction. However, in up to 70% of patients, contrast-enhanced CMR reveals areas of fibrofatty replacement in the form of late gadolinium enhancement (LGE), typically confined to the lateral LV wall (43). This observation suggests that the disease process is usually biventricular, although LV involvement often remains clinically concealed.

called triangle of dysplasia (RV inflow, apex, and

Link between ARVC and sports activity. Arrhythmogenic

RVOT). Other variants are characterized by a biven-

cardiomyopathy is one of the leading causes of SCD

tricular or left-dominant involvement (1).

in athletes (3,44). Competitive sports activity poses

The most common clinical presentation of ARVC

a 5-fold increase in the risk of SCD in adolescents

is ventricular arrhythmia, which can range from

and young adults with ARVC (45). Athletic activity

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

T A B L E 2 Criteria for the Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy According to the Task Force Criteria

Task Force Criteria Category*

Diagnostic Tool

Criteria

1. Histological changes

Endomyocardial biopsy

Reduction in residual myocytes with fibrous or fibrofatty replacement

2. Morphological and functional abnormalities

Echocardiography

RV wall motion abnormalities plus RV dilation (PLAX RVOT and/or PSAX RVOT) and/or RV dysfunction (estimated by FAC)

Cardiac magnetic resonance

RV wall motion abnormalities plus RV dilation (RV end-diastolic volume indexed to BSA) and/or RV dysfunction (estimated by EF)

Right ventricular angiography

RV wall motion abnormalities

3. Depolarization abnormalities

12-lead ECG

Epsilon wave, late potentials, increase in terminal activation duration

4. Repolarization abnormalities

12-lead ECG

Inverted T waves

5. Ventricular arrhythmias

History, ambulatory ECG monitoring or stress testing

>500 PVBs/day, nonsustained or sustained ventricular tachycardia

6. Familial and genetic background

Personal history

Family history of ARVC or SCD due to autopsy proven ARVC

Genetic testing

Gene mutation associated or probably associated with ARVC

*Only 1 major or 1 minor criterion per category can be considered. Diagnosis is considered definite with 2 major or 1 major plus 3 minor criteria, borderline with 1 major plus 2 minor or 3 minor, and possible with 1 major or 2 minor criteria. For precise definition of each criterion see Marcus et al. (5). BSA ¼ body surface area; ECG ¼ electrocardiogram; EF ¼ ejection fraction; PLAX ¼ parasternal long-axis view; PSAX ¼ parasternal short-axis view; PVBs ¼ premature ventricular beats; RV ¼ right ventricle; RVOT ¼ right ventricular outflow tract; SCD ¼ sudden cardiac death; other abbreviations as in Table 1.

also favors ARVC progression and worsening of the

disease lesion can be identified only by using

diseased arrhythmic substrate because of increased

contrast-enhanced CMR imaging (54). Not surpris-

mechanical wall stress and adrenergic stimulation

ingly

(3,46,47).

observed in athletes who have experienced cardiac

Clinical

studies

demonstrated

that

endurance sports and intense physical exercise in-

the

left-dominant

variant

is

increasingly

arrest (55–57).

crease age-related penetrance, risk of ventricular tachyarrhythmia, and occurrence of heart failure in

DIFFERENTIAL DIAGNOSIS BETWEEN

carriers of the ARVC desmosomal gene (48–50).

ATHLETE’S HEART AND ARVC

Indeed, Saberniak et al. (49) found that ARVC patients and mutation-positive family members who

Exercise-induced increase in RV dimension could

regularly practiced sports activity showed reduced

mimic the RV pathological remodeling in ARVC.

biventricular function compared with nonathletes.

Indeed, RV dilation is one of the most relevant

The amount and intensity of exercise activity were

phenotypic expression of ARVC (5). Therefore, the

associated with impaired LV and RV functions, and

differential diagnosis is sometimes challenging in the

the authors concluded that exercise may aggravate

athlete and could lead to an incorrect diagnosis of a

and accelerate myocardial dysfunction in ARVC.

rare and life-threatening disease in healthy subjects,

These findings are in agreement with those of the

with psychological, economic, and familiar conse-

study by James et al. (48) in which carriers of the

quences, or to miss a diagnosis in athletes, exposing

ARVC

that

them to the risk of SCD, particularly during competi-

endurance exercise increased the risk of major

tion. Furthermore, athletic activity may favor the

ventricular arrhythmias, heart failure, and ARVC

disease expression in carriers of the desmosomal

phenotypic expression in desmosomal mutation

gene mutation and worsen the disease severity in

carriers. For this reason, current recommendations

ARVC patients (48,49).

desmosomal

mutation

demonstrated

agree that patients with ARVC should be restricted

Many efforts have been made in the last decades to solve the controversial issue of the differential

from competitive sports activity (51,52). The left-dominant variant of ARVC is character-

diagnosis between athlete’s heart and ARVC and the

ized by an early and predominant LV involvement

Task Force Criteria were modified in 2010 to

(53). At variance with the classic right-dominant

improve the sensitivity while maintaining specificity

variant,

(5).

the

accuracy

of

conventional

in-

Despite

the

undisputed

usefulness

of

the

vestigations, including routine ECG and standard

Task Force 2010 criteria as a diagnostic tool for

echocardiography for the diagnosis of left-dominant

ARVC, concerns have been raised about their prac-

ARVC, is limited because repolarization abnormal-

tical applicability as a screening tool in low-risk

ities and LV systolic dysfunction, either regional or

populations

global, are observed in few affected patients, and the

modalities.

(25,58),

particularly

using

imaging

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Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

chambers, RV dilation is more pronounced in RV

T A B L E 3 Dimensional and Functional Parameters Obtained by Echocardiography in

inflow than in RVOT (58). Bauce et al. (7), investi-

Arrhythmogenic Right Ventricular Cardiomyopathy Versus Athlete’s Heart

gating 40 patients with ARVC, 40 athletes, and 40 Echocardiography and Differential Diagnosis Between ARVC and Athlete’s Heart ARVC

sedentary control subjects demonstrated that ARVC

Findings

Athlete’s Heart

þ

Marked dilation of RVOT





Moderate increase in RV main body with mild increase in RVOT

þ

þ

Disproportionate RV/LV ratio (<0.90)



parasternal long-axis diameter was greater in ARVC



Regression of RV dilation after detraining

þ

patients than in athletes, whereas the latter had

þ

RV wall motion abnormalities akinesia, dyskinesia, aneurysms, bulging



þ

Reduced RV function (FAC <32%)



parasternal long-axis diameter could be important

þ

Reduced RV longitudinal strain (<20%)



for the differential diagnosis. A longitudinal study

þ

Reduced RV s0 velocity <0.10 m/s



confirmed these findings, demonstrating that during

þ

Reduced RV function by CMR



the competitive season, RV areas and diameters

þ

RV and/or LV tissue abnormalities (fat infiltration and LGE) at CMR



Size

patients without severe RV dilation or dysfunction had both RV inflow and outflow tract dilation, whereas athletes showed a characteristic dilation of the RV inflow and subpulmonary diameter: RVOT

Function

greater RVOT parasternal long-axis diameter than control subjects. Accordingly, evaluation of RVOT

increased whereas RVOTs did not change significantly (31). However, despite the predominant in-

þ: more likely; -: less likely. CMR, cardiac magnetic resonance; LGE ¼ late gadolinium enhancement; other abbreviations as in Tables 1 and 2.

crease in RV body, physicians should be aware that competitive athletes have RVOT diameters beyond the cutoff values suggested by the ASE for the gen-

The imaging criteria proposed by the Task Force

eral population (26) and, in some cases, also beyond

rely on a combination of regional RV kinetic abnor-

the thresholds suggested as minor or major criteria

malities (i.e., akinesia, dyskinesia, aneurysms or

for the diagnosis of ARVC (23–25).

dyssynchronous contraction), and RV dilation or

RV enlargement in athletes is usually accompanied

reduced global RV function. Unfortunately, competi-

by a concomitant remodeling of the LV, reflecting a

tive athletes often exhibit training-induced RV dila-

global and symmetrical adaptation of the heart to the

tion and sometimes a slight reduction in RV function.

hemodynamic changes induced by training (58). This

However, despite similarities between athlete’s heart

balanced biventricular adaptation does not differ

and ARVC, in the last decades, some echocardio-

among athletes practicing different sports (24),

graphic features have been identified in order to help

whereas ARVC patients usually show no or mild LV

physicians distinguish between physiological and

dilation (7). Recently, the RV/LV ratio <0.9 has been

pathological RV remodeling. These features are

proposed to distinguish between RV physiological

summarized in Table 3. The first relevant echocardiographic difference

remodeling and ARVC (59). In a large population of highly trained athletes, the authors found an RV/LV

between ARVC patients and competitive athletes is

ratio of 0.74  0.08 (95% confidence interval: 0.73 to

the presence of RV WMAs: indeed, although RV

0.75), suggesting that this parameter could be used to

bulging, dyskinesia, akinesia, and aneurysms are

properly interpret RV enlargement in borderline cases

typical findings of ARVC, they are not found in

(24). A similar ratio between RV end-diastolic volume

healthy athletes (23,58) (Figures 3A and 3B, Online

and LV end-diastolic volume of >1.2 on CMR has been

Videos 1 and 2). Notably, hypokinesia is not consid-

reported (59).

ered among the criteria for the diagnosis of ARVC.

The analysis of global RV function is crucial for

Recognition of RV regional WMAs needs specific skills

the differential diagnosis between ARVC and ath-

in

of

lete’s heart. Among the Task Force Criteria for

misleading interpretations also in specialized centers.

echocardiography,

with

the

possibility

ARVC, only RVFAC is taken into account for esti-

Moreover, standard echocardiographic views do not

mating RV function (5). Although a marked decrease

explore the inferior (subtricuspid) RV wall, which

of RVFAC is uncommon in healthy athletes, a slight

requires a dedicated (inflow) echocardiographic view

reduction of RVFAC can be found (25). Therefore,

(Online Video 3). Accordingly, when the echocardio-

physicians should be aware that RVFAC is some-

graphic examination raises the suspicion of RV

times reduced also in healthy athletes. Further-

WMAs, CMR is needed to confirm the presence of

more, the calculation of RVFAC has some relevant

WMAs (Online Video 4).

limitations, such as reproducibility. Recently an

Notably, although RV remodeling in athletes is characterized by a global enlargement of the cardiac

expert consensus document from the European Association

of

Cardiovascular

Imaging

discussing

D’Ascenzi et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 9, 2018 SEPTEMBER 2018:1327–39

Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

F I G U R E 3 Typical Features of RV Size and Function in Athlete’s Heart and in ARVC

A

B V

V

RVOT

+1

Dilated RVOT

+1

5

5

+

+

10

10

15

V V

Dilated RV without WMAs

RV WMAs

5 5

10

10

15

15

Normal RV strain

Abnormal RV strain

(A) Typical features of athlete’s heart. (B) Typical features of ARVC. The arrows indicate wall motion abnormalities, typically found in ARVC. ARVC¼ arrhythmogenic right ventricular cardiomyopathy; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; WMA ¼ wall motion abnormalities; other abbreviations as in Figure 1. See Online Videos 1, 2, 3, and 4.

ARVC has recommended the inclusion of additional

global RV strain is typically reduced in ARVC pa-

quantitative echocardiographic data, suggesting that

tients, whereas it is normal in athletes (Figures 3A

a careful assessment of RV function will improve

and 3B). ARVC patients may show a subclinical RV

the accuracy of ARVC diagnosis (58) and support

dysfunction with reduced RV global longitudinal

the use of additional parameters for determining RV

strain, and a further decrease is observed in ARVC

function in these subjects (22,25,37,60). Indeed,

patients

who

are

regularly

engaged

in

sports

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D’Ascenzi et al. Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 9, 2018 SEPTEMBER 2018:1327–39

C E NT R AL IL L U STR AT IO N How to Distinguish Between Athlete’s Heart and Arrhythmogenic Cardiomyopathy

D’Ascenzi, F. et al. J Am Coll Cardiol Img. 2018;11(9):1327–39.

The differential diagnosis between athlete’s heart and arrhythmogenic right ventricular cardiomyopathy include imaging features and comprehensive clinical approaches including ECG, ambulatory ECG monitoring, stress testing, and evaluation of family members. CMR ¼ cardiac magnetic resonance; ECG ¼ electrocardiography; LGE ¼ late gadolinium enhancement; LV ¼ left ventricular; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; WMA ¼ wall motion abnormality.

activities (49). Additionally, mechanical dispersion

block configuration suggesting LV origin) (64). Due

of RV contraction detected by STE may represent an

to the high spatial resolution and unlimited imaging

early predictor of future arrhythmic events (61,62).

planes, CMR offers the potential to optimally evaluate dilation and dysfunction, regional WMAs, and

ADDITIONAL ROLE OF CMR

structural changes of the RV (64). It must be emphasized that areas of apparent dyskinesia and

CMR has emerged as a second-line technique for the

bulging are frequently encountered in normal in-

differential diagnosis between athlete’s heart and

dividuals and that a combination of WMAs and

ARVC and currently plays a relevant role in helping

global RV dilation and dysfunction is needed to

to establish an accurate diagnosis in athletes (63).

fulfill the CMR criteria for ARVC diagnosis (5,65).

Indications for the use of CMR include confirmation

The ability of CMR to allow noninvasive tissue

of abnormal or borderline echocardiographic find-

characterization by using dedicated sequences for

ings or when a left-dominant arrhythmogenic car-

evaluation of fat infiltration and post-contrast se-

diomyopathy is suspected (apparently unexplained

quences for LGE is another important advantage of

T-wave inversion in the inferolateral leads and/or

CMR. Although tissue characterization of the RV is

ventricular arrhythmia with a right bundle branch

not included among current diagnostic criteria, the

D’Ascenzi et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 11, NO. 9, 2018 SEPTEMBER 2018:1327–39

Arrhythmogenic Cardiomyopathy vs. Athlete’s Heart

presence of fat infiltration and/or LGE in an athlete

BEYOND CARDIAC IMAGING:

with RV morphological and functional abnormalities

A COMPREHENSIVE APPROACH

may be useful to confirm the diagnosis (58). However, there are some possible pitfalls that should be

The differential diagnosis between ARVC and ath-

taken into account. The first pitfall is that spin-echo

lete’s heart based only on cardiac imaging may be

sequences, which are used to detect the fatty tissue,

difficult, and second-line investigation such as CMR

may lead to ARVC misdiagnosis based on the low

can provide equivocal findings. However, it is

specificity of increased intramyocardial fat (66,67).

important to stress that ARVC is characterized by

The second pitfall is that it is conventionally

multiple abnormalities including not only ventricular

considered problematic to detect LGE at the level of

dilation and dysfunction but also ECG changes and

the thin RV wall (43). Availability of the newer

ventricular arrhythmia. Moreover, as the disease is

generation CMR machines with updated pulse se-

genetically determined, a large proportion of patients

quences enhance the ability to identify RV intra-

exhibit a positive family history for ARVC or SCD.

myocardial fibrofatty scar tissue and to discriminate

Accordingly, a comprehensive clinical approach that

pathologic fatty infiltration from normal epicardial

includes ECG, ambulatory ECG monitoring, stress

fat (64). Recent studies demonstrated the usefulness

testing, and evaluation of family members may be

of combined regional wall motion assessment and

useful to refine the diagnosis (Central Illustration).

tissue characterization by CE-CMR. The highest accuracy was found when WMAs and pre- and postcontrast

signal

abnormalities

were

CONCLUSIONS

considered The differential diagnosis between athlete’s heart

together (68). Left ventricular LGE with a nonischemic distri-

and ARVC is often challenging. Echocardiography is

bution is observed in most ARVC patients and is

the first imaging technique used in this setting, and a

more reproducible. In patients with left-dominant

comprehensive echocardiographic assessment of RV

ARVC, it can represent the only abnormality at

morphology and function could provide relevant in-

cardiac imaging. However, this finding is conven-

formation for the differential diagnosis between ath-

tionally believed to lack specificity in the setting of

lete’s heart and ARVC and to properly guide the

differential

heart

indication to CMR. Although imaging techniques

because of the high prevalence of LV LGE in trained

could help distinguish between physiological and

individuals (54). To overcome this possible limita-

pathological RV remodeling, integrating these find-

tion, it is crucial to evaluate the pattern and

ings with ECG, clinical signs and symptoms, family

regional distribution of LGE: in athletes, it is usu-

history, and occurrence of arrhythmia is crucial,

ally confined to the junction between the free wall

particularly in borderline cases.

diagnosis

with

the

athlete’s

and septum, probably as a result of increased pulmonary pressure during exercise, whereas in ARVC

ADDRESS FOR CORRESPONDENCE: Dr. Flavio D’As-

patients, a stria of LGE with a nonischemic (i.e.,

cenzi, Department of Medical Biotechnologies, Divi-

subepicardial/midmyocardial)

mostly

sion of Cardiology, University of Siena, Viale M.

involving the inferolateral LV wall is typically

Bracci, 16 53100 Siena, Italy. E-mail: flavio.dascenzi@

observed.

unisi.it. Twitter: @FlavioDascenzi.

distribution

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KEY WORDS arrhythmogenic right ventricular cardiomyopathy, athlete, cardiac magnetic resonance

A PPE NDI X For supplemental videos, please see the online version of this paper.

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