| | Arrhythmogenic right ventricular cardiomyopathy/dysplasia clinical presentation and diagnostic evaluation: Results from the North American Multidisciplinary StudyReceived 3 November 2008; accepted 6 March 2009. published online 12 March 2009. BackgroundPrior reports on patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) focused on individuals with advanced forms of the disease. Data on the diagnostic performance of various testing modalities in newly identified individuals suspected of having ARVC/D are limited. ObjectiveThe purpose of the Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia was to study the clinical characteristics and diagnostic evaluation of a large group of patients newly identified with ARVC/D. MethodsA total of 108 newly diagnosed patients with suspected ARVC/D were prospectively enrolled in the United States and Canada. The patients underwent noninvasive and invasive tests using standardized protocols that initially were interpreted by the enrolling center and adjudicated by blind analysis in six core laboratories. Patients were followed for a mean of 27 ± 16 months (range 0.2–63 months). ResultsThe clinical profile of these newly diagnosed patients differs from the profile of reported patients with more advanced disease. There was considerable difference in the initial and final classification of the presence of ARVC/D after the diagnostic tests were evaluated by the core laboratories. Final clinical diagnosis was 73 affected, 28 borderline, and 7 unaffected. Individual tests agreed with the final diagnosis in 50% to 70% of the 73 patients with a final classification of affected. ConclusionThe clinical profile of 108 newly diagnosed probands with suspected ARVC/D indicates that a combination of diagnostic tests is needed to evaluate the presence of right ventricular structural, functional, and electrical abnormalities. Echocardiography, right ventricular angiography, signal-averaged ECG, and Holter monitoring provide optimal clinical evaluation of patients suspected of ARVC/D. Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited cardiomyopathy characterized by fibrofatty replacement primarily of right ventricular (RV) muscle. The resultant heterogeneous structure of the RV myocardium results in ventricular arrhythmias, including premature ventricular complexes (PVCs) and nonsustained or sustained ventricular tachycardia (VT). Ventricular and structural or functional alterations of the RV and left ventricle (LV) may lead to congestive heart failure.1, 2, 3 ARVC/D is uncommon but may account for up to 20% of cases of sudden death among young individuals.4, 5, 6, 7 The first clinical profile of ARVC/D was published in 1982.8 In that report, 24 cases of ARVC/D were described, almost all of whom had advanced disease and were referred to a tertiary medical center for treatment of recurrent VT. The structural and functional changes of the RV were readily apparent. Since then, it has become evident that the disease can be exceedingly difficult to diagnose, particularly when minimal structural and/or functional alterations of the RV are present.9 Recognition of the problems in diagnosing ARVC/D and the fact that there is no “gold standard” or single test that is diagnostic of ARVC/D led to the formation of a task force that put forth major and minor criteria in 1994 to aid in the diagnosis.10 Despite these standardized diagnostic guidelines, there remains uncertainty, primarily due to lack of quantification of many of these task force criteria. In addition, the clinical profile of a large number of newly diagnosed patients with ARVC/D, who were systematically evaluated using standardized protocols to determine the presence of task force criteria, has not been reported previously. The Multidisciplinary Study of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia was initiated in 2001 with the following goals: (1) to study a large group of newly diagnosed patients with this uncommon disorder, (2) to elucidate the genetic etiology of the disease, and (3) to evaluate treatment of ARVC/D in these patients. This report focuses on the diagnostic and clinical features of the first 108 unrelated probands who were enrolled in the study. Comparison and relative contribution of different testing modalities are emphasized. Methods  Organizational structure The Multidisciplinary Study of Right Ventricular Cardiomyopathy/Dysplasia established the North American ARVC/D Registry, which consisted of 18 enrolling centers in the United States and Canada (see Appendix), a clinical center at the University of Arizona, a data coordinating center at the University of Rochester, a genetic center at Baylor College of Medicine, six core laboratories in the United States and Europe, and a National Institutes of Health (NIH)-appointed Data and Safety Monitoring Board (see Appendix). The design of the study has been published previously.11 Patient population Patients 12 years or older and newly diagnosed with ARVC/D were evaluated for enrollment in the study. The sequence of evaluation is shown in Figure 1. Initially patients were excluded if they had undergone implantable cardioverter-defibrillator (ICD) placement prior to enrollment. However, because patients and their personal physicians often became aware of this study after ICD placement, this criterion severely hampered referral for enrollment. During the second year of the study, the Data Safety Monitoring Board agreed to allow enrollment of patients whose ICDs had been placed within 6 months. In the last 2 years of the study, patients were permitted to be enrolled in the study if they had an ICD in place for fewer than 2 years. All subjects provided institutional review board–approved signed informed consent. Evaluation and clinical testing Standardized tests included 12-lead ECG, signal-averaged ECG (SAECG), 24-hour Holter monitor, and electrophysiologic study with programmed stimulation for induction of ventricular arrhythmias. SAECG was classified as positive if two of the three parameters were abnormal.12 The electrophysiologic study protocol was based on that used in the Multicenter Unsustained Tachycardia Trial (MUSTT).13 Imaging of the RV was performed by echocardiography,14 magnetic resonance imaging (MRI),15 and RV angiography. RV free-wall biopsy samples were obtained and sent to the core laboratory for pathologic examination, including histomorphometric analysis.16, 17 Septal biopsy samples were separated from the free-wall biopsy samples and sent to the genetic laboratory for viral studies. Blood was obtained for genetic analysis. Standardized protocols for the performance of these diagnostic tests were developed and distributed to the enrolling centers. The ECG, SAECG, echocardiogram, and MRI protocols are available at the website www.arvd.org. At the time of screening for enrollment, copies of the ECG, SAECG, and reports of the imaging test results from the referring and enrolling centers were sent to the principal investigator (F.M.) for evaluation for enrollment based on the task force criteria (Figure 1). In order to enhance accuracy as well as uniformity of interpretation of the diagnostic studies, core laboratories were established. The diagnostic tests were evaluated blindly by the core laboratories. The internal consistency of the intraobserver variability of the imaging studies was excellent, with intraclass correlation of 89% for echocardiogram and 93% for MRI. Rating reliability was assessed by comparing the variability of different ratings of the same subject to the total variation across all ratings and all subjects. Diagnostic test results were sent to the data coordination center and entered into a secure web-based data management system. Based on the core laboratory interpretation of each test as affected, borderline, or unnaffected, the principal investigator (F.M.) performed final classification of the phenotype. Affected probands met task force criteria of 2 major, 1 major and 2 minor, or 4 minor criteria; borderline probands had either 1 major criterion and 1 minor or 3 minor criteria. Blood for DNA extraction and lymphoblastoid cell line immortalization was obtained from all but eight of the probands. Statistical analysis Descriptive characteristics of the probands are presented as mean and SD. Proportions were stratified by phenotypic classification. P values were obtained by the Pearson Chi-square test. To determine the relative contribution of each diagnostic procedure, we used the C statistic, which is a standard measure of discriminative power for logistic regression models. Each diagnostic measure phenotype was dichotomized as 1 for affected and 0 otherwise. The seven different core laboratory test results (ECG, SAECG, Holter, echocardiogram, angiogram, MRI, biopsy) were entered into a multivariate logistic regression model to capture the overall prediction. The model was run seven times, each time leaving out a different diagnostic measure. The differences in C statistic between the “full” model and each model that withheld a different diagnostic test were plotted to show the relative contribution to model fit that each made. In addition, a comparison was made between models containing all seven tests and models containing a decreasing number of tests starting with 6, 5, 4 using the likelihood scores. Results Demographic and clinical characteristics (Table 1) The database was evaluated as of October 4, 2007, at which time final classification was available for 112 probands. Of these patients, four diagnosed as having ARVC/D subsequently were documented to have cardiac sarcoidosis by pathologic examination of myocardial or cervical lymph node biopsy, even though they fulfilled task force criteria. Therefore, for descriptive purposes of the ARVC/D population, these four patients were excluded, and analysis was performed on the remaining 108 probands. The final classification was 73 affected, 28 borderline, and 7 unaffected.  | Age at onset of symptoms (years) | 36 ± 15 | | | Age at diagnosis (years) | 38 ± 13 | | | Age at enrollment (years) | 39 ± 14 | | | Sex ratio (M/F) | 62/46 | | |  Symptoms | N = 108 | % | | | Palpitations | 61 | 56 | | | Dizziness | 29 | 27 | | | Syncope | 23 | 21 | | | Chest pain | 15 | 14 | | | Twelve-lead ECG | N = 95⁎ | | | | No TWI [11A, 8B, 5U] | 24 | 25 | | | TWI only V1 [11A, 5B, 1U] | 17 | 18 | | | TWI only V1–V2 [3A, 3B] | 6 | 6 | | | TWI only V1–V3 [11A, 4B] | 15 | 16 | | | TWI extending beyond V3 [29A, 1B] | 30 | 32 | | | TWI not in V2 and V3 but beyond | 3 | 3 | | | QRS prolongation >110 ms in V1, V2, V3 [4A, 1U] | 5 | 5 | | | QRS prolongation in V1–V3/V4–V6 >1.2 [12A, 3B, 1U] | 16 | 17 | | | S-wave duration ≥55 ms [18A, 11B, 2U] | 31 | 32 | | | Signal-averaged ECG | N = 86 | | | | Late potentials (2/3 criteria abnormal) | 50⁎ | 58 | | | Holter monitor | N = 86 | | | | PVCs >1,000 in 24 hours | 49 | 57 | | | Sustained VT clinical | N = 38† | 35 | | | LBBB superior-axis VT | 14 | | | | LBBB inferior-axis VT | 10 | | | | LBBB indeterminate axis | 8 | | | | VT of indeterminate morphology | 5 | | | | RBBB | 1 | | | | Electrophysiology study performed | N = 75 | | | | Sustained VT at electrophysiologic study | N = 36† | 49 | | | LBBB superior-axis VT | 15 | | | | LBBB inferior-axis VT | 15 | | | | LBBB indeterminate axis | 3 | | | | RBBB | 3 | | | | Histopathology of endomyocardial biopsy | N = 64 | | | | Meet histomorphometric criteria | 20 | 31 | | | Familial history | | | | Familial history of ARVC/D | 23 | 21 | | | Family disease confirmed at autopsy | 6 | 6 | | | Sudden death in family member age <35 years | 8 | 7 | | | | |
| ⁎ Excluding 11 right bundle branch block (RBBB), 1 left bundle branch block (LBBB), 1 uninterpretable (ventricular paced). †Report or documented by ECG. |
Of the 108 probands, 57% (62/108) were male. The ethnic distribution was as follows: 95 Caucasian, 4 Hispanic, 7 Asian, and 2 African-American. The age of probands at diagnosis ranged from 12 to 63 years. Mean age at onset of symptoms was 36 ± 15 years. Mean age at diagnosis was 38 ± 13 years; nine patients were diagnosed between the ages of 12 to 18 years. Mean age at enrollment was 39 ± 14 years (range 15–78 years). Four probands had New York Heart Association class II and one had class IV right heart failure. Palpitation was the most common symptom and was present in 56% (61/108) of enrolled probands, followed in frequency by dizziness in 27% (29/108) and syncope in 21% (23/108). The most frequent reason for clinical suspicion of ARVC/D was a history of ventricular arrhythmias reported in 70% (76/108). One proband had cardiac arrest as the first symptom. Of particular interest is that 34% of the probands participated in competitive or professional sports prior to diagnosis. Of these, 68% were male. An additional 36% of patients were active in recreational sports. ECG findings One of 108 ECGs was uninterpretable due to atrial fibrillation with a ventricular paced rhythm; 11 had complete right bundle branch block (RBBB); and 1 had left bundle branch block (LBBB). Therefore, 95 ECGs were analyzed. Thirty (32%) of the 95 probands had T-wave inversion beyond V3; their final phenotype was 29 affected and 1 borderline. Three probands had T-wave inversion limited to leads V4, V5, or V6. In addition, T-wave inversion was present in two or three of the inferior leads II, III, and aVF in 20 probands, 14 of whom had T-wave inversion beyond V3in the precordial leads. Therefore, this finding correlated with the extent of precordial T-wave inversion. Five (5%) of the 95 probands met the task force criterion of QRS >110 ms in leads V1, V2, and V3. Eighteen had QRS >110 ms in one, two, or all of the precordial leads V1–V6. Of the 86 patients who had 24-hour Holter recordings, 57% (49/86) had >1,000 PVCs in 24 hours; of these patients, 6% (5/86) had >10,000 PVCs in 24 hours. Sixteen percent had <200 PVCs in 24 hours, and 20% had between 200 and 1,000 PVCs in 24 hours. The morphology and axis of the QRS complex during clinical VT could be determined in 63% (24/38) of the probands who presented with clinical sustained VT. Ten had reports or tracings of LBBB inferior axis and 14 of LBBB superior axis. Eight reported LBBB VT, axis undetermined and one had sustained RBBB VT. Five had inadequate documentation to determine VT morphology. The mean rate of the clinical VT was documented at 215 ± 21 bpm in 14 patients. Of the 38 patients with clinical sustained VT, 59% (19/32) were inducible at electrophysiologic study. In 9 of these 19 patients, the induced VT had the same morphology as the clinical VT. Cardiac imaging The imaging test interpreted by the core laboratory that reported the most severe abnormality was used for classification of structural and functional abnormalities. Severely reduced RV wall motion or global function was detected in 36% by MRI, in 15% by echocardiography, and in 21% by RV angiogram (Table 2). | ⁎ No. of imaging studies including views adequate for right ventricular ejection fraction (RVEF) or fractional area change (FAC) measurements †Major task force criteria. ‡Minor task force criteria. |
Thirty-eight probands phenotyped as affected had both echocardiograms and MRI studies that were suitable for analysis of RV and LV function by the core laboratories. The echocardiograms were interpreted as showing normal RV function (fractional area change [FAC] ≥32%) in 58%, whereas MRI showed fewer probands with normal right ventricular ejection fraction (RVEF; ≥52%) in 34%. Conversely, MRI showed more probands with moderately or severely reduced RV function (RVEF ≤45%) in 32% than did the echocardiogram (FAC ≤26%) in 16%. All but 2 of 75 probands had normal or mildly decreased LV function by echocardiography. Of 38 probands phenotyped as affected and who had all three imaging tests, the agreement among all three interpretable imaging tests classified as affected was 45% (17/38) and 32% (12/38) for those with two imaging tests in agreement. Ten of 108 probands had only one interpretable imaging test. Table 3 lists the frequency of diagnostic tests by core laboratory analysis as affected, borderline, or unaffected in the 73 probands with final classification of affected and in the 28 probands with final classification of borderline based on the task force criteria. This provides an estimate of the percentage of each test that can be expected to be positive (affected), borderline, or unnaffected (negative or normal). | ⁎ Includes data on seven probands classified as unaffected. |
Relation of initial classification versus final classification after core laboratory analysis of data The design of this study provided a unique opportunity to compare the extent of agreement in the interpretation of imaging studies (echocardiogram, RV angiogram, and MRI) by the referring centers with that of the core laboratories where the studies were interpreted blindly. The following criteria were used. When the referring center described only a minor task force imaging abnormality (e.g., mild hypokinesis), the imaging study classification was determined to be borderline. When a major task force imaging criterion was selected (e.g., severe global dysfunction), the imaging study was classified as affected. This information was compared with the blinded analysis reported by the core laboratory as to whether the imaging study was normal, borderline, or unaffected. The frequency of a positive test for ARVC/D by MRI was considerably greater at the referral center than at the core laboratory. Of the 41 MRIs thought to have a major imaging abnormality by the referring center, 29% were not confirmed by the MRI core laboratory. Interpretation of abnormalities on two-dimensional echocardiograms showed the reverse trend: a smaller percentage of studies was thought to be affected by the referring center than by core laboratory analysis. Twenty-six echocardiograms were categorized as affected by the referring center compared with 45 by core laboratory analysis. RV angiography interpretation was similar between the referring center and the core laboratory. The relation of the initial classification at enrollment based on data from the referring center and the final classification after core laboratory analysis is of interest. Of the 108 probands, 86 probands were classified as affected on enrollment. After blind interpretation of diagnostic testing by core laboratories, 78% (67/86) had the final classification of affected, 17 borderline, and 2 unaffected (Figure 2A). Nineteen probands met some but not all of the task force criteria and were enrolled as borderline. Only 26% (5/19) of those classified as borderline at enrollment met task force criteria after final classification (P = .001; Figure 2B) Thus, if the task force criteria were present at enrollment, there is a reasonable certainty that the patient would have a final classification of affected, whereas there was a lower chance that the suspected probands who were “borderline” at enrollment would meet the established task force criteria. Diagnostic performance of individual tests and their combination in the final diagnosis We performed comprehensive analyses to evaluate the diagnostic performance of the following core laboratory tests performed in this study: ECG, SAECG, Holter, echocardiogram, RV angiogram, MRI, and RV biopsy. Table 3 and Figure 3 show the frequency of diagnostic tests by core laboratory analysis as affected, borderline, or unaffected in the 73 probands with final classification of affected and in the 28 probands with final classification of borderline based on the task force criteria. This provides an estimate of the percentage of each test that can be expected to be positive (affected), borderline, or unaffected (negative or normal). Figure 4 shows the diagnostic performance of individual tests evaluated separately without taking into account other tests. Echocardiogram, RV angiogram, and ECG show a better diagnostic performance than do other evaluated tests. We also performed analyses of the diagnostic performance of the same tests evaluated simultaneously, reflecting clinical practice when physicians obtain results of several tests at the same time (Table 4). We used all seven tests to determine optimal categorization of patients and then removed each test one at a time from this seven-test model to determine the decline in the C statistic reflecting the diagnostic performance of a given test. Figure 4 shows that the biggest decline in diagnostic performance of the model occurred when the echocardiogram was removed. Removing RV angiogram and SAECG one at a time also caused a decline in testing performance. On the other hand, removing MRI, ECG, and RV biopsy, one at a time, caused less decline in the predictive model. | | | | No. of variables in the model | Variables included in predictive model | Variable removed | Score (Chi-square) | |
|---|
| Seven-variable model | Echo, Angio, SAECG, Holter, Biopsy, ECG, MRI | None | 61.44 | | | Best six-variable model | Echo, Angio, SAECG, Holter, Biopsy, ECG | MRI | 61.24 | | | Best five-variable model | Echo, Angio, SAECG, Holter, ECG | Biopsy, MRI | 59.34⁎ | | | Best four-variable model | Echo, Angio, SAECG, Holter | ECG, Biopsy, MRI | 57.11⁎ | | | Best three-variable model | Echo, Angio, SAECG | Holter, Biopsy, ECG, MRI | 52.26⁎ | | | | |
| ⁎ Models with diagnostic performance inferior to full seven-variable model at P <.05. |
Additional analyses were performed to evaluate how the models with fewer than the full set of seven tests would perform in diagnosing affected ARVC/D probands. The best six-variable model that performed as well as the full seven-variable model consisted of all tests except the MRI. When a five-variable model was considered, the best performance was achieved when echocardiogram, RV angiogram, ECG, SAECG, and Holter were used and MRI and RV biopsy were removed. This model was only marginally inferior to the seven-variable model. When four- and three-variable models were used, the diagnostic performance of testing was significantly compromised. Based on the analyses of the models, we concluded that evaluating RV echocardiogram, RV angiogram, and SAECG is optimal for all successful models. Routinely used ECG and Holter tests complement these tests, providing best diagnostic performance. Genetic data Single or digenic mutations were found in 33 of 100 probands (8 probands did not provide blood for genetic analysis). Plakophilin-2 (PKP-2) was the most commonly found gene variant, present in 22% (22/100). Six of the 22 probands with PKP-2 mutations had compound heterozygosity with mutations in other desmosomal proteins, one with three variants. Of the remaining 11, 2 had heterozygous mutations in desmosomal genes other than PKP-2, 7 had homozygous mutations in other desmosomal proteins, and 2 had a polymorphism variant. There was a similar frequency of desmosomal abnormalities in approximately one third of patients phenotyped as borderline and of those phenotyped as affected. This observation supports the hypothesis that most, if not all, of the probands phenotyped as borderline do have this disease. This illustrates the relative insensitivity of the task force criteria for the diagnosis of early disease. Discussion This is the first study of a large number of newly diagnosed patients suspected of having ARVC/D, who were studied systematically with a variety of standardized diagnostic tests. The clinical characteristics of this large group of newly diagnosed probands provide a unique profile of these patients. In addition, this design allows, for the first time, a comparison of the interpretation of the three imaging tests by the referring center with blinded interpretation of the tests by the core laboratories. It also permits comparison of the interpretation of the imaging tests with one another. The initial classification of whether the patient met the task force criteria was compared with final classification based on the interpretation of the diagnostic tests by the core laboratories (ECG, echocardiogram, MRI, RV angiogram, pathology). These study results complement the clinical profile of 69 living patients with ARVC/D reported by Dalal et al.18 The clinical characteristics of the 108 probands indicate a slight preponderance of men (57% [62/108]). The major reason for the clinical suspicion of ARVC/D was a recent history of ventricular arrhythmias, of which 35% were reported as sustained VT. The finding that 34% of the probands were competitive or professional athletes lends support to the hypothesis that vigorous and/or sustained athletic activity facilitates the phenotypic expression of the disease due to repetitive stretch of the vulnerable thin-walled RV with a genetic desmosomal protein abnormality that is the underlying myocardial defect responsible for this disease.19, 20, 21 Of interest, 29 of 30 probands with T-wave inversion beyond V3 had a final phenotype of affected. Only 17% (12 affected, 3 borderline, 1 unaffected) of the ECGs in probands met the criteria proposed by Peters et al22 of QRS duration of V1+ V2 + V3/V4 + V5 + V6 ≥1.2. We also analyzed digitized ECGs using the ratio of QRS duration of V2/V5. We observed that 27% had a ratio ≥1.2. Another manifestation of localized prolongation of the QRS in right precordial leads is that of S-wave duration ≥55 ms, which was found in 95% by Nasir et al,23 who defined S-wave duration as the interval from the nadir of the S wave to the end of the QRS complex, excluding any R prime wave. We observed this finding in V1, V2, or V3 in only 32% when R prime was included. Cox et al24 measured the time from the nadir of the S wave to the end of all depolarization, including R prime and any epsilon wave, and found S wave >55 ms in 71%. In our series, the one patient with an epsilon wave also had RBBB. Two probands with sarcoidosis, not included in this analysis, also had epsilon waves. SAECG was positive (2/3 criteria) in 58% of probands. The lower incidence of several of the ECG findings in our study compared with the values reported in the literature may reflect the fact that the population in this study is relatively newly diagnosed and therefore likely to have earlier manifestations of this disease. Evidence indicates that patients with desmosomal genetic abnormalities may have a major or predominant decrease in LV function that is greater than the decrease in RV function.25, 26, 27 The fact that only two patients had a moderate decrease in LVEF (35% and 40%) may be due to selectively not enrolling patients with ARVC/D with severe LV impairment because the task force criteria indicate that only patients with no or mild LV impairment should be considered to have this diagnosis. Of particular importance are the data indicating that diagnostic classification based on referral center interpretation of test results may not be confirmed after independent review of the tests, particularly the imaging studies. For example, of the 86 probands who met task force criteria based on initial interpretation of diagnostic tests at the referring center, reclassification after core laboratory analysis indicated that 19 (23%) did not meet the established task force criteria and received a final classification of borderline and two patients were classified as unaffected. Also, five of the 19 probands initially classified as borderline had a final classification of affected. This brings into question the reliability of diagnostic tests as currently performed and interpreted for the diagnosis of ARVC/D. The observation that the frequency of a positive test for ARVC/D by MRI is considerably greater at the referral center than that of the core laboratory is particularly striking. Of the 41 MRIs thought to have a major imaging abnormality by the referring center, only 63% of these were confirmed by the MRI core laboratory. This finding is consistent with a previous report that documented the apparent high false-positive rate of the interpretation of the MRI for the diagnosis of ARVC/D by referring centers.9 There are several possible reasons for the discrepancy in interpretation of the imaging studies. ARVC/D is a rare disease that requires specific protocols for optimum evaluation. The imaging core laboratories used a consistent definition that, whenever possible, incorporated quantitative criteria. The MRIs from the referring centers did not always contain short-axis images, which were required in the standardized protocol, and quantitative measurements of RV dimensions could not be made in 20%. Physicians who interpret MRIs may have limited experience in differentiating normal structure and function of the highly irregular contour of the RV from that of ARVC/D, especially in the early stages of the disease. A high rate of error in differentiating normal from abnormal RV wall motion by MRI, particularly near the insertion of the moderator band, has been documented.28 In addition, substantial error in the interpretation of fatty infiltration as well as thinning of the RV wall has been reported.29 It is not well appreciated that, in the normal heart, a certain amount of fatty tissue usually is present within the myocardium of the RV wall, particularly in the anterolateral and apical regions.30, 31 These findings should be taken into account when interpreting structural abnormalities in patients suspected of ARVC/D. This study emphasizes the importance of expert interpretation of the complex-shaped RV and the need for quantitation of RV structure and function.32, 33 As a result of this study, this area is beginning to be addressed.34 Viral analysis of endomyocardial biopsies was performed because of uncertainty regarding the role of viral myocarditis as a cause of ARVC/D in some cases and/or ARVC/D possibly predisposing to viral myocarditis, which could lead to a decrease in RV function and accelerate the progression of the disease.35, 36, 37, 38 Evidence of viral infection was found in 15% of endomyocardial biopsies. Parvovirus was detected in four probands. Interestingly, enterovirus, which was present in 5 of 12 patients with ARVC/D in a previous study, was not identified in this population. This could be due to a change in the epidemiology of viral diseases. The relatively small percentage of positive viral identifications does not support a primary role for viral myocarditis as an etiology of ARVC/D. However, it does not exclude the possibility that ARVC/D may predispose to secondary viral myocarditis in a subset of patients or that a viral infection could unmask the disease. This could lead to more rapid progression of the disease and possibly precipitate ventricular arrhythmias in ARVC/D. Endomyocardial biopsy was performed in 59%, which is the lowest percentage of any of the diagnostic tests (Table 1). An average of three biopsy samples (range 1–7) was obtained per person. Nine of the biopsies were obtained from the septum, possibly because of concern among the investigators of the risk of the procedure, although the protocol indicated that the biopsy be obtained from the RV free wall. The reason for not targeting the septum is that the septum is seldom involved in the disease process.17 Other series reported the safety of RV free-wall biopsy, demonstrating no instances of cardiac tamponade.39, 40 In our experience, one patient had a small pericardial effusion after biopsy that resolved spontaneously. Of note, at the onset of the study, interventionalists in each enrolling center were taught how to safely perform the endomyocardial biopsy by video and by written instructions from the director of the angiography core laboratory. An unexpected finding was the presence of sarcoidosis identified by myocardial biopsy in three probands. In a fourth patient, sarcoidosis was suspected based on pulmonary infiltrates, and the diagnosis was confirmed by cervical biopsy. This finding indicates that patients with sarcoidosis can have signs and symptoms that mimic ARVC/D. This finding of sarcoidosis masquerading as ARVC/D has been reported previously.41 Analysis of the diagnostic performance of individual tests favors echocardiogram, RV angiogram, SAECG, and ECG. When evaluating these tests in combination, obtaining a minimum of the following five tests is recommended: echocardiogram, RV angiogram, SAECG, ECG, and Holter. In our cohort of newly identified patients, the diagnostic performance of MRI and RV biopsy seems to be inferior in comparison to the five tests recommended. However, the number of patients with MRI and RV biopsy was less than with the other tests, which might have contributed to the underperformance of these studies. Further comparative analyses in a homogeneous patient population using standardized core laboratory evaluated tests are needed to confirm these findings. The question arises as to whether the probands with a final phenotype of borderline do indeed have ARVC/D. Probands with final classification of affected had slightly more symptoms of dizziness, nausea, fatigue, palpitations, and chest pain than did patients classified as borderline. Borderline probands had nearly the same incidence of syncope (25%) and history of no VT (25%) as affected probands (21% and 19%). At electrophysiologic study, 53% of affected probands had sustained VT induced versus 27% of borderline probands. The phenotype for ARVC/D develops over time, and there is a potential for variation in the diagnostic accuracy of various tests that might change over time.42 The finding of similar frequencies of desmosomal abnormalities in those phenotyped as borderline and as affected illustrates the relative insensitivity of the task force criteria for the diagnosis of early disease. Study limitations The study has several limitations. Not all diagnostic tests were done in every enrolled proband. Also, in some patients the diagnostic studies were done before the patients were seen at the enrolling center. It was not feasible or practical to repeat these studies using the standardized protocols. Patients who had a cardioverter defibrillator implanted prior to referral to the enrolling center could not have a repeat MRI. Patients with probable desmosomal cardiomyopathy involving primarily the LV were not referred for enrollment because the task force criteria exclude patients with moderate LV impairment. Conclusion The clinical profile of 108 newly diagnosed patients with suspected ARVC/D indicates that a combination of diagnostic imaging tests is needed to evaluate the presence of RV structural, functional, and electrical abnormalities. Echocardiography, RV angiography, SAECG, and Holter monitoring provide optimal clinical evaluation of patients suspected of having ARVC/D. In the early stages of ARVC/D, overall RV function may be normal, with local or regional wall-motion abnormalities that are difficult to quantify. Supplementary data References 1. 1Marcus FI, Fontaine G. Arrhythmogenic right ventricular dysplasia/cardiomyopathy, a review. Pacing Clin Electrophysiol. 1995;18:1298–1314. MEDLINE |
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 Address reprint requests and correspondence: Dr. Frank I. Marcus, Section of Cardiology, Cardiology Room 6304, University of Arizona, 1501 N. Campbell Avenue, Tucson, Arizona 85724-0001
This study was supported by Grant NIH UO1-HL65594. Author affiliations are listed in the Appendix. PII: S1547-5271(09)00288-4 doi:10.1016/j.hrthm.2009.03.013 © 2009 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved. | |
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