Concealed cardiomyopathies in competitive athletes with ventricular arrhythmias and an apparently normal heart: role of cardiac electroanatomical mapping and biopsy Antonio Dello Russo, MD, PhD,* Maurizio Pieroni, MD, PhD,† Pasquale Santangeli, MD,§ Stefano Bartoletti, MD,*储 Michela Casella, MD, PhD,* Gemma Pelargonio, MD, PhD,† Costantino Smaldone, MD,† Massimiliano Bianco, MD,‡ Luigi Di Biase, MD PhD,§¶ Fulvio Bellocci, MD,† Paolo Zeppilli, MD,‡ Cesare Fiorentini, MD,*储 Andrea Natale, MD, FACC, FHRS,§ Claudio Tondo, MD, PhD* From the *Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Milan, †Institute of Cardiology and ‡Institute of Sports Medicine, Catholic University of the Sacred Heart, Rome, Italy, §Texas Cardiac Arrhythmia Institute at St David’s Medical Center, Austin, Texas and ¶Department of Cardiology, University of Foggia, Foggia, and 储 Department of Cardiovascular Sciences, University of Milan, Milan, Italy. BACKGROUND The diagnosis of subtle structural heart disease in competitive athletes with ventricular arrhythmias (VAs) and an apparently normal heart is challenging. Three-dimensional electroanatomic mapping (EAM) has been demonstrated to reliably identify low-voltage areas that correspond to different cardiomyopathic substrates.
which corresponded at EAM-guided endomyocardial biopsy to the histological diagnosis of active myocarditis in seven patients and of arrhythmogenic right ventricular cardiomyopathy in five. In one patient the histological evidence of contraction band necrosis allowed the unmasking of caffeine and ephedrine abuse.
OBJECTIVE The purpose of this study was to test whether EAM may help in the diagnosis of concealed cardiomyopathies in athletes with VAs and an apparently normal heart.
CONCLUSIONS Electroanatomical substrate mapping may help diagnose concealed myocardial diseases in competitive athletes presenting with recent-onset VAs and an apparently normal heart. Further studies are warranted to assess the prognostic implications of such subtle myocardial abnormalities.
METHODS We studied 13 consecutive competitive athletes (12 males, age 30 ⫾ 13 years) who had documentation of VAs within the previous 6 months on 12-lead electrocardiogram (ECG), 24-hour Holter ECG, or ECG exercise testing and who were judged as having a structurally normal heart after a thorough noninvasive evaluation, including signal-averaged ECG, transthoracic echocardiogram, and cardiac magnetic resonance imaging. Depending on the presumed site of VA origin according to 12-lead ECG criteria, patients underwent right or left ventricular EAM and EAM-guided endomyocardial biopsy. RESULTS Presenting arrhythmias included sustained ventricular tachycardia (n ⫽ 3), multiple episodes of nonsustained ventricular tachycardia (n ⫽ 7), and frequent ventricular ectopic beats (⬎1,000 during 24 hours; n ⫽ 3). Three patients had a history of syncope. Twelve (92%) patients had at least one low-voltage region at EAM,
KEYWORDS Ventricular arrhythmias; Athletes; Normal heart; Arrhythmogenic right ventricular cardiomyopathy; Myocarditis ABBREVIATIONS ARVC ⫽ arrhythmogenic right ventricular cardiomyopathy; cMRI ⫽ cardiac magnetic resonance imaging; EAM ⫽ electroanatomic mapping; ECG ⫽ electrocardiogram; LV ⫽ left ventricle, ventricular; RFCA ⫽ radiofrequency catheter ablation; RV ⫽ right ventricle, ventricular; VA ⫽ ventricular arrhythmias; VPB ⫽ ventricular premature beat; VT ⫽ ventricular tachycardia (Heart Rhythm 2011;8:1915–1922) © 2011 Heart Rhythm Society. All rights reserved.
Introduction The first two authors contributed equally to this work and should be both considered as first authors. C.T. has served as a member of the advisory board of Biosense Webster and has been a consultant for and received lecture fees from St. Jude Medical. A.N. has received consultant fees or honoraria from Biosense Webster, Boston Scientific, Medtronic, Biotronik, and LifeWatch. The other authors declare no significant relationships with industry. Address for reprints and correspondence: Antonio Dello Russo, M.D., Ph.D., Cardiac Arrhythmia Research Centre, Centro Cardiologico Monzino IRCCS, Via Carlo Parea 4, 20138 Milan, Italy. E-mail address:
[email protected]. (Received February 13, 2011; accepted July 14, 2011.)
The clinical assessment of ventricular arrhythmias (VAs) in the setting of an apparently normal heart is a challenging issue,1 particularly in competitive athletes, in whom a clear association between some forms of structural heart disease and sudden cardiac death has been consistently reported,2 thus representing a clinical dilemma regarding their eligibility for sports.3 Distinguishing truly idiopathic VAs from those related to undetected subclinical cardiomyopathies may be difficult4 – 6 but is critically important because it implies different prognosis and management strategies.7,8
1547-5271/$ -see front matter © 2011 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2011.07.021
1916
Heart Rhythm, Vol 8, No 12, December 2011
The clinically subtle abnormalities of early-stage cardiomyopathies, however, may remain undetected by currently available noninvasive diagnostic techniques, including echocardiography and even cardiac magnetic resonance imaging (cMRI).4,9,10 Three-dimensional electroanatomical mapping (EAM) has been demonstrated to reliably identify the pathological substrate underlying VAs in different clinical settings by the detection of myocardial areas with abnormally low voltages,11 which reflect the presence of different cardiomyopathic substrates at endomyocardial biopsy.9 –11 In this study on a consecutive series of competitive athletes with recent-onset VAs and an apparently normal heart, we tested the hypothesis that EAM may help in the differential diagnosis between truly idiopathic and cardiomyopathy-related VAs by the identification of otherwise concealed cardiomyopathic substrates.
Methods From January 2008 to February 2009 we examined 1,644 athletes at our institution, a national-level referral center for Sports Cardiology. Repetitive VAs (nonsustained and sustained ventricular tachycardia [VT]) were present in 27 (1.6%) subjects, while frequent ventricular premature beats (VPBs) (⬎1,000/24 hours) were found in 30 (2.1%) subjects. All these subjects underwent a full noninvasive evaluation as reported below, and 17 were judged normal and were considered eligible for invasive study with EAM and EAM-guided endomyocardial biopsy. Four of these patients had a normal EAM and biopsy (all presenting with frequent VPBs from the right ventricular [RV] outflow tract). The remaining 13 athletes (12 males, mean age 30 ⫾ 13 years) formed the study population. A flow diagram showing the patient selection process is shown in Figure 1.
Figure 1
Selection process of patients included in the study.
Noninvasive evaluation and definition of structurally normal heart The noninvasive evaluation included clinical history, physical examination, laboratory tests, chest X-rays, 12-lead electrocardiogram (ECG), signal-averaged ECG (unfeasible in one patient for excessive signal noise), two-dimensional echocardiography, and gadolinium-enhanced cMRI. The latter was performed with a 1.5-T Signa Excite 2 scanner (General Electric Medical Systems, Milwaukee, WI) using a cardiac eightchannel phased-array coil, as described elsewhere.12 In this study, a structurally normal heart was defined on the basis of normal resting ECG, absence of late potentials on signalaveraged ECG, normal dimension and function (global and regional) of the left ventricular (LV) and RV chambers as determined by echocardiography and cMRI, and absence of late gadolinium enhancement on cMRI. Findings from all noninvasive tests were reviewed by two blinded experts.
Invasive evaluation The invasive study was approved by the Institutional Review Board, and all patients gave their written informed consent. All patients underwent three-dimensional EAM with EAM-guided endomyocardial biopsy10,13 and a standard electrophysiology study with programmed electrical stimulation from both the apex and outflow tract and isoprenaline challenge.14
Three-dimensional EAM Three-dimensional ventricular EAM was performed in all patients using the CARTO system15 (Biosense Webster, Diamond Bar, CA); in three patients the CARTOSOUND technology16 (Biosense Webster) was also used to obtain intracardiac echocardiographic fans superimposed on CARTO maps. The decision on whether to map the RV or LV was settled on the basis of the presumed origin of the VAs, as assessed by surface ECG criteria.17 Mapping points were sampled with a 7-Fr 3.5-mm irrigated tip Navi-Star Thermocool catheter (Biosense Webster) to generate an accurate three-dimensional EAM of the ventricle. High-density mapping was performed in sinus rhythm (reference channel: QRS complex) by sampling at least 300 uniformly distributed points. The voltage maps were edited by setting the point density (fill threshold) to 15 mm and manually eliminating intracavitary points, as described elsewhere.15 We considered as satisfying evidence of adequate catheter contact the concordant motion of the catheter tip with the cardiac silhouettes on fluoroscopy and the reproducibility of voltage measurements on repeated catheter navigation to the same site with different electrode orientations.13 In the three patients in whom CARTOSOUND was used, adequate catheter contact was also confirmed by intracardiac echocardiography. In accordance with previous studies, electroanatomical scar was defined as an area ⱖ1 cm2 including at least three adjacent points with bipolar signal amplitude ⬍0.5 mV; the reference value for normal ventricular endocardium was set at 1.5 mV, and any value in between was defined as a low-voltage area.13,15 The CARTO-incorporated surface
Dello Russo et al Table 1
Ventricular Arrhythmias in Normal Hearts
Clinical characteristics
Age/sex
Type of sport
Family history of SCD
Baseline ECG
1
45/M
Kickboxing
No
Normal
2
51/M
Cycling
No
Normal
3a
36/M
Volley
Yes
4
19/M
Skiing
No
Incomplete RBBB Normal
5b
29/M
Soccer
Yes
6
25/M
Cycling
No
Incomplete RBBB Normal
7
19/M
Soccer
No
Normal
8
16/M
Soccer
No
Normal
9
16/M
Soccer
No
Normal
10 11 12
42/M 44/M 31/M
Cycling Marathon Skating
No No No
Normal Normal Normal
13
15/F
Skiing
No
Normal
Patient no.
1917
Index VA
ECG features of VA
Nonsustained VT Nonsustained VT Frequent VPBs Frequent VPBs Nonsustained VT Sustained VT
LBBB; inferior axis
Nonsustained VT Nonsustained VT Frequent VPBs Sustained VT Sustained VT Nonsustained VT Nonsustained VT
RBBB; superior axis LBBB; inferior axis LBBB; inferior axis LBBB; superior axis LBBB; inferior axis RBBB; intermediate axis RBBB; superior axis LBBB; axis LBBB; LBBB; LBBB;
intermediate inferior axis inferior axis inferior axis
LBBB; intermediate axis
Diagnosis of VA
Symptoms
24-hour Holter ECG ECG stress testing 24-hour Holter ECG 24-hour Holter ECG 12-lead ECG
Syncope
ECG stress testing ECG stress testing ECG stress testing 24-hour Holter ECG 12-lead ECG 12-lead ECG 24-hour Holter ECG 12-lead ECG
Dizziness
Syncope Palpitations Palpitations Dizziness
Palpitations Dizziness Palpitations Dizziness Dizziness Palpitations Syncope
Note: SCD: sudden cardiac death; LBBB: left bundle branch block; RBBB: right bundle branch block. Signal-averaged ECG not feasible for excessive noise, rSr’ in lead V1 at 12-lead ECG with QRS duration of 104 ms. b rSr’ in lead V1 at 12-lead ECG with QRS duration of 102 ms. a
area calculation tool was used to measure the extension of ventricular electroanatomical scars and their size in percentage compared with the total ventricular area.
EAM– guided endomyocardial biopsy
probability values reported are two-sided, and P⬍.05 was considered statistically significant. Statistical analysis was performed with the STATA 11.1 statistical package (Stata Corporation, College Station, TX).
We obtained four to five endomyocardial bioptic samples from each patient with the use of a preformed long sheath and a disposable bioptome (Cordis, Johnson and Johnson, Bridgewater, NJ). These were withdrawn from ventricular wall segments with abnormal voltages, as described elsewhere10,13; in case of a normal EAM, samples were withdrawn from the right side of the interventricular septum. Bioptic samples were then processed for histology and immunohistochemistry, as described elsewhere.6,10,18,19 The diagnosis of myocarditis was based on the Dallas criteria and immunohistochemistry, as reported elsewhere.14,20 The diagnosis of arrhythmogenic RV cardiomyopathy (ARVC) was established on the basis of extensive fibrofatty myocardial atrophy with a percentage of fat ⬎3% and fibrous tissue ⬎40%, which is associated with residual myocytes amounting to ⬍45% of the specimen on morphometric analysis.21
Results
Statistical analysis
Noninvasive evaluation
Continuous variables are expressed as mean ⫾ standard deviation, whereas categorical variables are expressed as number and percentages. Percentage comparisons between groups were evaluated by two-tailed Fisher’s exact text. All
All patients were judged as having a structurally normal heart after noninvasive evaluation. In particular, resting ECG was deemed normal in all patients, without evidence of depolarization/repolarization abnormalities suspect for
Clinical characteristics Clinical characteristics and electrophysiological data are summarized in Tables 1 and 2. All patients were actively involved in competitive sports (see Table 1). Two patients (15%) had a family history of premature sudden death (age ⬍40 years) due to ARVC. Spontaneous VAs were documented in all patients, on 12-lead ECG (n ⫽ 4), or on 24-hour Holter monitoring (n ⫽ 5), or on ECG exercise testing (n ⫽ 4). Sustained VT was documented in three (23%) patients, nonsustained VT in seven (54%) patients, and frequent VPBs in three (23%) patients. The presumed site of origin of VAs according to ECG criteria was the RV in 10 (77%) and the LV in three (23%) patients (Table 1). All patients had arrhythmia-related symptoms: three had syncope, five had dizziness, and five had palpitations.
1918 Table 2
Heart Rhythm, Vol 8, No 12, December 2011 Invasive findings
Patient no.
Mapping system
Ventricle mapped
Electroanatomical scar localization
Endomyocardial biopsy
1a 2 3 4 5a 6b 7 8 9 10b 11b 12 13
CARTO CARTO CARTO CARTO CARTOSOUND CARTO CARTOSOUND CARTO CARTO CARTO CARTOSOUND CARTO CARTO
Right Left Right Right Right Right Left Left Right Right Right Right Right
Outflow tract; inferior-posterior wall; free wall Apex Outflow tract; apex Outflow tract; free wall Inferior-posterior wall; apex Outflow tract — Inferior wall Free wall; inferior-posterior wall Outflow tract; inferior-posterior wall; free wall Outflow tract Outflow tract; inferior-posterior wall Outflow tract; inferior-posterior wall; free wall
ARVC Myocarditis ARVC ARVC ARVC Contraction band necrosisc Myocarditis Myocarditis Myocarditis Myocarditis Myocarditis ARVC Myocarditis
Note: According to the 2010 Task Force criteria for ARVC diagnosis, two patients had a definite diagnosis of ARVC (patient nos. 3 and 5). Patient no. 3 had two additional minor criteria (arrhythmia ⫹ family history of SCD), while patient no. 5 had one major (arrhythmia) and one minor criterion (family history of SCD). The remaining three patients (nos. 1, 4, and 12) had one additional minor criterion (arrhythmia) and therefore satisfied current Task Force requirements for a borderline diagnosis of ARVC. a Patients implanted with an implantable cardioverter-defibrillator. b Patients underwent radiofrequency ablation. c Due to previous caffeine and ephedrine abuse.
underlying cardiomyopathies.22 Two-dimensional echocardiography was normal, and signal-averaged ECG found no late potentials in all cases. With regard to cMRI findings, late gadolinium enhancement was absent in all patients, and only two patients showed mild RV apical bulging, which was deemed a normal variant by the reading radiologist. Global RV and LV systolic functions were normal in all patients (mean ejection fraction 57% ⫾ 3% and 55% ⫾ 2%, respectively).
EAM results EAM was performed during sinus rhythm in all patients without complications. According to the presumed site of origin of VAs, the RV was mapped in 10 patients and the LV in three (Table 2). The mean number of sites sampled in EAM was 355 ⫾ 34, with an average mapping duration of 36 ⫾ 8 minutes. Electroanatomical voltage mapping was abnormal in 12 (92%) patients, showing ⱖ1 area (mean 1.8 ⫾ 0.9) with bipolar electrogram voltage ⬍0.5 mV (i.e., electroanatomical scar tissue), sharply demarcated by a border zone with low voltages (0.5–1.5 mV). The mean ventricular area showing electroanatomical scar was 18.5 ⫾ 8.7 cm2, corresponding to an average 11.1% ⫾ 5.1% of the total ventricular area. All 10 patients with VAs of RV origin showed abnormal RV EAM. Activation mapping was performed in four of these patients, and the origin of VAs was consistent with the localization of electroanatomic scars. The RV areas most frequently presenting low voltages were the outflow tract (80%; Figure 2), followed by the inferior-posterior wall (60%), the free wall (50%), and the apex (20%). Of the three patients presenting with VAs of LV origin, only two showed low-voltage areas on LV EAM, which were localized in the inferior wall and in the apex.
Endomyocardial biopsy results Endomyocardial biopsy was obtained from all patients, with no procedural complications. In five (38%) patients the presence of myocardial atrophy and fibrofatty replacement led to a histological diagnosis of ARVC. All of these patients had low-voltage areas on EAM: in four, the electroanatomical scar areas included the RV outflow tract, while in the remaining one the RV outflow tract was not involved and scar could only be detected in the inferior wall and apex. According to the 2010 Task Force criteria for ARVC diagnosis,23 two of these patients satisfied the criteria for a definite diagnosis of ARVC. The remaining three patients satisfied Task Force requirements for a borderline diagnosis of ARVC (Table 2). In seven (54%) patients, histological examination showed inflammatory infiltrates associated with necrosis of adjacent myocytes, consistent with the diagnosis of active myocarditis according to the Dallas criteria. Of these seven patients, four had VAs of RV origin and an abnormal RV EAM, whereas three had VAs of LV origin but only two showed low-voltage areas at LV EAM (Table 2). Finally, in one patient who showed low voltages in the RV outflow tract on EAM, endomyocardial biopsy revealed contraction band necrosis and allowed the unmasking of doping with stimulant drugs (caffeine and ephedrine; Figure 3A).
Radiofrequency catheter ablation (RFCA) and defibrillator implantation Of the 13 enrolled patients, three (23%) underwent (RFCA): all had sustained monomorphic VT, which could be induced on electrophysiological study. These three were the cyclist with contraction band necrosis, in whom noncontact mapping was used for the RFCA procedure (Figure 3B); a marathon runner with myocarditis, in whom CARTOSOUND technol-
Dello Russo et al
Ventricular Arrhythmias in Normal Hearts
1919
Figure 2 ARVC. A: A 31-year-old male skater (patient no. 12) with a 3-month history of nonsustained VT with left bundle branch morphology and inferior axis. B: RV EAM showed scars in the outflow tract and in the inferior-posterior wall. C: Endomyocardial biopsy guided by EAM demonstrated ARVC.
ogy was preferred; and a cyclist with myocarditis (Figure 4) ablated using the CARTO system. Two other patients (15%) were equipped with an implantable cardioverter-defibrillator; in both cases a ventricular flutter associated with syncope was reproducibly induced on electrophysiological study and biopsy revealed ARVC.
Discussion The granting of sports eligibility in athletes with VAs with no visible cardiac structural anomalies is a challenging problem, since even subtle structural heart disease in these patients increases the risk of sudden cardiac death by a factor of 2.5 compared with nonathletes.24 Therefore, an early diagnosis of concealed cardiomyopathy in athletes is crucial to promptly ban these subjects from competitive sports.2,3,7 In this study, we demonstrate that EAM allows the early recognition of concealed forms of cardiomyopathies diagnosed by endomyocardial biopsy in athletes presenting with VAs in the absence of overt structural cardiac anomalies on a thorough noninvasive evaluation, including cMRI.
Significant findings and clinical implications Our study may have important implications for the management of competitive athletes. In fact, VAs in athletes without evidence of structural heart disease after noninvasive evaluation have been suggested not to convey adverse clinical significance and not to represent an indication of disqualification from competitive sports.17 However, we found that concealed cardiomyopathic substrates may still remain undetected by conventional noninvasive diagnostic techniques. Notably, five (38%) patients had histological diagnosis of ARVC, a condition that permanently prevents eligibility in sports activity.2,7,24 In these patients, mechanical
stress such as that which occurs during training and sports competition has been linked to adverse effects by worsening myocyte death and triggering VAs.25,26 On the other hand, there is no clear consensus on how to manage athletes with VAs due to active myocarditis, who constituted 54% of our study population, as reasonable doubt exists on whether these may regress spontaneously with time. However, at least a temporary sports disqualification is warranted also in patients with myocarditis. Moreover, the transient and self-limiting nature of myocardial inflammation in the majority of these patients may account for the apparently spontaneous reduction in frequency and complexity of VAs after physical detraining, which has been reported in large cohorts of competitive athletes.18 Interestingly, in that study, structural myocardial abnormalities were found in 38% of patients who experienced a significant reduction of VAs after detraining, suggesting that a favorable decrease in arrhythmia frequency does not exclude the possibility of underlying heart disease and that a careful cardiac evaluation and case-by-case assessment are recommended. With regard to the type of VAs, we found evidence of underlying subtle cardiomyopathies independent of the type of presenting VAs (i.e., sustained VAs vs. nonsustained VAs vs. frequent VPBs). It is important to emphasize, however, that only 2/6 (34%) athletes with apparently normal hearts and frequent VPBs from the RV outflow tract were eventually diagnosed with structural heart disease by EAM with EAM-guided biopsy.
Diagnostic contribution of EAM with EAM-guided endomyocardial biopsy At the present time, there is no full agreement on exactly how far investigations should go to reliably exclude struc-
1920
Heart Rhythm, Vol 8, No 12, December 2011
Figure 3 A: Contraction band necrosis, diagnostic studies. A 25-year-old male cyclist (patient no. 6) with recent episodes of dizziness found to be associated with rapid sustained VT on ECG exercise testing (panel A). CARTO EAM of the RV outflow tract showed discrete low-voltage areas (panel B). Endomyocardial biopsy showed signs of contraction band necrosis (panel C). Figure B: Same patient with contract band necrosis (patient no. 6), VT ablation supported by noncontact EAM using the EnSite NavX system (St. Jude Medical, St. Paul, MN). A spontanous nonsustained VT was observed during mapping (panel A). Activation mapping showed the origin of the patient’s VT in the RV outflow tract (panel B), where radiofrequency ablation lesions were then delivered (panel C).
tural heart disease in athletes with VAs. In this regard, previous studies on athletes with VAs reported a lower prevalence of cardiomyopathic substrates as compared with
the present study.17,18 Notably, the diagnostic approach adopted in previous studies was quite limited and essentially consisted of two-dimensional echocardiography, reserving
Dello Russo et al
Ventricular Arrhythmias in Normal Hearts
1921
Figure 4 Myocarditis. A 42-year-old male cyclist (patient no. 10) presenting with dizziness. A: Twelve-lead ECG demonstrated sustained VT with left bundle branch morphology and inferior axis. B: RV EAM showed scars in the outflow tract, in the free wall, and in the inferior-posterior wall. C: Endomyocardial biopsy guided by EAM demonstrated myocarditis. The patient underwent successful ablation.
cMRI only for selected subgroups of patients.17,18 On the other hand, we adopted an extensive noninvasive evaluation, including gadolinium-enhanced cMRI in all patients, which may explain the higher prevalence of cardiac structural abnormalities found in our study. Thus far, gadolinium-enhanced cMRI is considered by many to be the noninvasive imaging modality of choice, owing to its multiplanar capability and unique ability to provide tissue characterization.27,28 We reported that EAM may provide additional diagnostic value even to cMRI, by the detection of otherwise unrecognized myocardial substrate anomalies associated with concealed cardiomyopathies. The value of EAM in the diagnosis of subtly abnormal cardiomyopathic substrates has been recently evaluated by Corrado et al9 in a cohort of 27 patients with RV outflow tract VT. All enrolled patients had no evidence of RV dilatation or dysfunction on echocardiography, and none satisfied current criteria for ARVC diagnosis. EAM was shown to reliably distinguish between ARVC and idiopathic RV outflow tract VT by detecting electroanatomical scars that corresponded to the histological finding of fibrofatty infiltration.9 Our study confirms and expands such results in patients with VAs of both RV and LV origin, in the apparent absence of structural heart disease even on cMRI. Of note, in the study by Corrado et al,9 cardiac MRI was performed in 7/27 (26%) patients and was normal only in three. Furthermore, unlike Corrado et al, we performed endomyocardial biopsies directly from areas displaying low voltages at EAM. Such a bioptic technique provides additional diagnostic yield even compared with EAM alone, as we recently reported in a consecutive series of patients with noninvasive diagnosis of ARVC.10,13
The striking additional diagnostic yield of EAM in identifying scars as compared with gadolinium-enhanced cMRI may have several potential explanations. First, more than 70% of our patients had VAs of RV origin. In this setting, cMRI has been reported to significantly underestimate the presence of scar as compared with EAM.9,29 The small extension of scar detected by EAM (mean 11.1% of the RV area) may further explain the inability of cMRI to identify such subtle cardiomyopathic substrates. Of the three patients with VAs of LV origin, only two had scars at EAM (Table 2). Electroanatomical scars in these two patients corresponded to the histological diagnosis of active myocarditis. Although late gadolinium enhancement on cMRI has been consistently shown to reflect the presence of tissue necrosis, its diagnostic value has been questioned in the setting of active myocarditis, in which myocardial necrosis and tissue edema may be patchy.30 In accordance with this concept, in a previous study, we found evidence of late gadolinium enhancement only in 46% of patients with myocarditis confirmed by EAM-guided endomyocardial biopsy.10
Potential limitations Our institution is a tertiary referral center for the study of complex arrhythmias in athletes, and many athletes with clinical suspicion of structural heart disease are frequently sent from other institutions or referring physicians. As such, our study population should be viewed as affected by an unavoidable degree of referral bias. This may explain the high prevalence of structural heart disease detected in our patients and suggests caution in generalizing our results to the general population of patients with VAs and an apparently normal heart; further studies in this setting are certainly warranted.
1922 The limited sample size and the relatively short-term follow-up (2 years on average) do not allow us to draw conclusions on the long-term prognostic impact of concealed cardiomyopathic substrates in athletes with VAs. To this regard, it is entirely plausible that a focal area of cardiomyopathic involvement might not confer the same risk of an overt cardiomyopathy evident at noninvasive evaluation (e.g., abnormal ECG, echocardiography, and/or cMRI). Further studies with long follow-up periods are warranted to assess the long-term prognostic implications of our findings. Finally, only endocardial voltage maps were obtained. While we recognize this may underdiagnose pathologic processes typically starting from the epicardial side (such as ARVC),31 we should remark that in all patients with an eventual histological diagnosis of ARVC, abnormalities had indeed been observed on endocardial mapping and used to guide biopsy. Epicardial mapping may be of particular value in detecting underlying cardiomyopathic substrates in the subset of athletes (7.8% in our institution) presenting frequent VPBs from the RV outflow tract, a structurally normal heart at noninvasive evaluation, and normal endocardial EAM with EAM-guided biopsy. The diagnostic value of epicardial mapping in this setting warrants further evaluation.
Conclusions Our results demonstrate that EAM allows the unmasking of subtle structural heart disease in athletes with VAs and an apparently normal heart, despite a thorough noninvasive evaluation, including cMRI. Further studies are warranted to explore the prognostic implications of such subtle myocardial abnormalities and to assess the optimal management strategies for these patients.
Acknowledgments The authors thank Gianluca Cionci, MD, for his help in data collection.
References 1. Latif S, Dixit S, Callans DJ. Ventricular arrhythmias in normal hearts. Cardiol Clin 2008;26:367–380, vi. 2. Corrado D, Basso C, Schiavon M, Pelliccia A, Thiene G. Preparticipation screening of young competitive athletes for prevention of sudden cardiac death. J Am Coll Cardiol 2008;52:1981–1989. 3. Douglas PS. Saving athletes’ lives a reason to find common ground? J Am Coll Cardiol 2008;52:1997–1999. 4. Frustaci A, Bellocci F, Olsen EG. Results of biventricular endomyocardial biopsy in survivors of cardiac arrest with apparently normal hearts. Am J Cardiol 1994;74:890 – 895. 5. Heidbuchel H, Hoogsteen J, Fagard R, et al. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Role of an electrophysiologic study in risk stratification. Eur Heart J 2003;24:1473–1480. 6. Di Biase M, Chiddo A, Caruso G, et al. Ventricular premature beats in young subjects without evidence of cardiac disease: histological findings. Eur Heart J 1992;13:732–737. 7. Zipes DP, Ackerman MJ, Estes NA, 3d, et al. Task Force 7: arrhythmias. J Am Coll Cardiol 2005;45:1354 –1363. 8. Estes NA, 3d, Link MS, Cannom D, et al. Report of the NASPE policy conference on arrhythmias and the athlete. J Cardiovasc Electrophysiol 2001; 12:1208 –1219.
Heart Rhythm, Vol 8, No 12, December 2011 9. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomical voltage mapping and histologic evaluation of myocardial substrate in right ventricular outflow tract tachycardia. J Am Coll Cardiol 2008;51:731–739. 10. Pieroni M, Dello Russo A, Marzo F, et al. High prevalence of myocarditis mimicking arrhythmogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic mapping-guided endomyocardial biopsy. J Am Coll Cardiol 2009;53:681– 689. 11. Corrado D, Basso C, Leoni L, et al. Three-dimensional electroanatomic voltage mapping increases accuracy of diagnosing arrhythmogenic right ventricular cardiomyopathy/dysplasia. Circulation 2005;111:3042–3050. 12. Casella M, Perna F, Dello Russo A, et al. Right ventricular substrate mapping using the Ensite Navx system: accuracy of high-density voltage map obtained by automatic point acquisition during geometry reconstruction. Heart Rhythm 2009;6:1598 –1605. 13. Avella A, d’Amati G, Pappalardo A, et al. Diagnostic value of endomyocardial biopsy guided by electroanatomic voltage mapping in arrhythmogenic right ventricular cardiomyopathy/dysplasia. J Cardiovasc Electrophysiol 2008;19:1127–1134. 14. Zipes DP, DiMarco JP, Gillette PC, et al. Guidelines for clinical intracardiac electrophysiological and catheter ablation procedures. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Clinical Intracardiac Electrophysiologic and Catheter Ablation Procedures), developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol 1995;26:555–573. 15. Dello Russo A, Pelargonio G, Parisi Q, et al. Widespread electroanatomic alterations of right cardiac chambers in patients with myotonic dystrophy type 1. J Cardiovasc Electrophysiol 2006;17:34 – 40. 16. Khaykin Y, Skanes A, Whaley B, et al. Real-time integration of 2D intracardiac echocardiography and 3D electroanatomical mapping to guide ventricular tachycardia ablation. Heart Rhythm 2008;5:1396 –1402. 17. Biffi A, Pelliccia A, Verdile L, et al. Long-term clinical significance of frequent and complex ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2002;40:446 – 452. 18. Biffi A, Maron BJ, Verdile L, et al. Impact of physical deconditioning on ventricular tachyarrhythmias in trained athletes. J Am Coll Cardiol 2004;44:1053–1058. 19. Chimenti C, Calabrese F, Thiene G, et al. Inflammatory left ventricular microaneurysms as a cause of apparently idiopathic ventricular tachyarrhythmias. Circulation 2001;104:168 –173. 20. Noutsias M, Fechner H, de Jonge H, et al. Human coxsackie-adenovirus receptor is colocalized with integrins alpha(v)beta(3) and alpha(v)beta(5) on the cardiomyocyte sarcolemma and upregulated in dilated cardiomyopathy: implications for cardiotropic viral infections. Circulation 2001;104:275–280. 21. Angelini A, Basso C, Nava A, Thiene G. Endomyocardial biopsy in arrhythmogenic right ventricular cardiomyopathy. Am Heart J 1996;132:203–206. 22. Jain R, Dalal D, Daly A, et al. Electrocardiographic features of arrhythmogenic right ventricular dysplasia. Circulation 2009;120:477– 487. 23. Marcus FI, McKenna WJ, Sherrill D, et al. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the task force criteria. Circulation 2010;121:1533–1541. 24. Corrado D, Basso C, Rizzoli G, Schiavon M, Thiene G. Does sports activity enhance the risk of sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959 –1963. 25. Thiene G, Nava A, Corrado D, Rossi L, Pennelli N. Right ventricular cardiomyopathy and sudden death in young people. N Engl J Med 1988;318:129 –133. 26. Corrado D, Thiene G, Nava A, Rossi L, Pennelli N. Sudden death in young competitive athletes: clinicopathologic correlations in 22 cases. Am J Med 1990;89:588 –596. 27. Tandri H, Calkins H, Nasir K, et al. Magnetic resonance imaging findings in patients meeting task force criteria for arrhythmogenic right ventricular dysplasia. J Cardiovasc Electrophysiol 2003;14:476 – 482. 28. Tandri H, Macedo R, Calkins H, et al. Role of magnetic resonance imaging in arrhythmogenic right ventricular dysplasia: insights from the North American arrhythmogenic right ventricular dysplasia (ARVD/C) study. Am Heart J 2008;155: 147–153. 29. Perazzolo Marra M, Bauce B, Cacciavillani L, et al. Imaging study of fibrofatty scar in arrhythmogenic right ventricular cardiomyopathy/dysplasia: contrastenhanced magnetic resonance imaging versus electroanatomic voltage mapping. Circulation 2009;120:S338. 30. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: a JACC White Paper. J Am Coll Cardiol 2009;53: 1475–1487. 31. Avella A, d’Amati G, Zachara E, Musumeci F, Tondo C. Comparison between electroanatomic and pathologic findings in a patient with arrhythmogenic right ventricular cardiomyopathy/dysplasia treated with orthotopic cardiac transplant. Heart Rhythm 2010;7:828 – 831.
