Author + information
- Received August 3, 2004
- Revision received October 12, 2004
- Accepted October 18, 2004
- Published online March 15, 2005.
- Danita M. Yoerger, MD*,* (, )
- Frank Marcus, MD†,
- Duane Sherrill, PhD†,
- Hugh Calkins, MD‡,
- Jeffery A. Towbin, MD§,
- Wojciech Zareba, MD, PhD∥,
- Michael H. Picard, MD*,
- Multidisciplinary Study of Right Ventricular Dysplasia Investigators
- ↵*Reprint requests and correspondence to:
Dr. Danita M. Yoerger, Cardiac Ultrasound Laboratory, Massachusetts General Hospital, YAW 5, 55 Fruit Street, Boston, Massachusetts 02114
Objectives The purpose of this study was to quantify the echocardiographic abnormalities in probands who were newly diagnosed with arrhythmogenic right ventricular dysplasia (ARVD).
Background The diagnosis of ARVD remains challenging. The Multidisciplinary Study of Right Ventricular Dysplasia was initiated to characterize the cardiac structural, clinical, and genetic aspects of ARVD.
Methods Detailed echocardiograms were performed in 29 probands and compared with echoes from 29 normal control patients matched for age, gender, body size, and year of echo. Right atrial (RA) and right ventricular (RV) chamber dimensions, RV regional function, and the presence of morphologic abnormalities (hyper-reflective moderator band, trabecular derangement, and sacculations) were assessed. The RV systolic function was calculated as RV fractional area change (FAC).
Results The RV dimensions were significantly increased, and RV FAC was significantly decreased in probands versus control patients (27.2 ± 16 mm vs. 41.0 ± 7.1 mm, p = 0.0003). The right ventricular outflow tract (RVOT) was the most commonly enlarged dimension in ARVD probands (37.9 ± 6.6 mm) versus control patients (26.2 ± 4.9 mm, p < 0.00001). A RVOT long-axis diastolic dimension >30 mm occurred in 89% of probands and 14% of controls. The RV morphologic abnormalities were present in many probands (trabecular derangement in 54%, hyper-reflective moderator band in 34% and sacculations in 17%) but not in controls.
Conclusions Probands with ARVD have significant RA and RV enlargement and decreased RV function, which can be easily assessed on standard echocardiographic imaging. These parameters should be measured when ARVD is suspected and compared with normal values.
Arrhythmogenic right ventricular dysplasia (ARVD) is a cardiomyopathy characterized by fibrofatty infiltration of the right ventricular (RV) wall, which often leads to ventricular arrhythmias, RV dilation, and dysfunction, and ultimately may lead to RV failure (1,2). This condition often appears in young adulthood, appears to be more common in men, and affected individuals may be asymptomatic or minimally symptomatic. Arrhythmia or sudden cardiac death is often the first presentation of the condition (3). Arrhythmogenic right ventricular dysplasia has been implicated as a cause of sudden death in a significant proportion of young athletes. The disease appears to be inherited in an autosomal-dominant manner, thus making screening of first-degree relatives important (4).
In 1994, the Task Force of the Working Group on Cardiomyopathies proposed a set of major and minor criteria involving histologic, gross structural, and electrocardiographic (ECG) parameters to make the diagnosis of ARVD (5). Several major and minor criteria are evaluated using noninvasive testing and, when necessary, invasive testing (Table 1).Some form of cardiac imaging is coupled with clinical signs and symptoms, family history, and results of ECG and/or Holter monitoring to make the diagnosis.
Two-dimensional echocardiography, by virtue of its widespread availability, low cost, and ease of performance and interpretation, has been one of the tools for establishing the diagnosis of ARVD. Although several echocardiographic findings have been associated with ARVD, many of these studies involved a small number of definite cases of ARVD (6) and were undertaken before the Task Force Criteria were written, thereby causing concern regarding nonuniformity of the study populations (7,8). Although the goal of the Task Force Criteria was to improve the clinician's ability to make the diagnosis of ARVD, the criteria for echocardiographic abnormalities are subjective and qualitative. The lack of standardized or quantifiable echocardiographic criteria for ARVD has made the confirmation of this diagnosis challenging. In addition, recent developments in instrumentation have lead to improvement in RV imaging using cardiac ultrasonography.
In 2002, the Multidisciplinary Study of Right Ventricular Dysplasia was initiated to better characterize and quantify the cardiac structural, clinical, and genetic aspects of ARVD (9). Detailed echocardiography has been performed in individuals meeting Task Force Criteria and, thus, these can be used to better define the echocardiographic abnormalities associated with ARVD.
Twenty-two centers have participated in this ongoing study, and 11 centers have enrolled patients with ARVD. In brief, individuals with ventricular arrhythmias of left bundle branch block morphology and that have other major or minor Task Force Criteria (Table 1) undergo two-dimensional echocardiography according to a detailed protocol. This protocol is the standard imaging protocol from the Massachusetts General Hospital, with additional special emphasis on adequate visualization of the RV.
At a core laboratory, the echocardiograms from the participating patients were analyzed by an individual who was blinded to the clinical and other diagnostic information (D.M.Y.). The presence of RV morphologic abnormalities reported in ARVD, such as moderator band hyper-reflectivity, trabecular derangement, focal RV sacculations, and aneurysms, were recorded (Fig. 1)(8). Measurements of cardiac structure and function included end-diastolic and end-systolic right ventricular inflow tract dimensions and right ventricular outflow tract (RVOT) dimensions in long- and short-axis views, RV long-axis dimensions, RV medial lateral dimensions, and RV area from the apical transducer position (Fig. 1) (10). Right ventricular systolic function was calculated as RV fractional area change (FAC) from the apical four-chamber view. Two standard deviations greater than the published mean values for dimensions (10) and two standard deviations less than the published mean value for FAC (11) were used to discriminate normal from abnormal values. Given a reference value of 46.5 ± 7.1% for FAC (11), an RV FAC ≥26% and <32% was defined as mildly impaired and an FAC <26% was severely impaired. Right ventricular diastolic filling was assessed from peak tricuspid valve E and A velocities and tricuspid valve E-wave deceleration time. The segments of the RV myocardium were identified using anatomic criteria identical to those used in the angiographic analysis in this study (RVOT, anterior, anteroseptal, apical, septal, inferobasal, inferoapical) and assessed for mild hypokinesis, severe hypokinesis, akinesis and dyskinesis, thinning, and diastolic bulging. Left ventricular volume was measured by the single-plane Simpson's method, and ejection fraction was calculated from the volumes. The RV systolic pressure was estimated from the peak tricuspid regurgitant velocity on continuous wave Doppler using the modified Bernoulli equation and assuming an RA pressure of 10 mm Hg (12). The degrees of tricuspid and mitral regurgitation were assessed on color Doppler as none, trace, mild, moderate, and severe (13). The RA and left atrial volumes were calculated from linear dimensions by the ellipsoid method (14).
Echocardiograms matched for age, gender, body size, and year performed were selected from the Massachusetts General Hospital echocardiographic archive of normal studies. The protocol for image acquisition in the control population was similar to that used by the enrolling centers. Identical measurements were performed on these matched controls in a blinded fashion.
Data are presented as the mean ± one standard deviation. Data were tested for normality using the Shapiro-Wilk test for normality. Because all continuous variables were distributed normally, comparisons between the ARVD probands and controls were performed with paired ttests (Intercooled STATA 7, Chicago, Illinois). Chamber enlargement was defined as greater than two standard deviations outside of published mean values from reference populations (10,11). Significance levels were adjusted for multiple comparisons using the Bonferroni correction and, therefore, p < 0.003 was considered significant.
Echocardiograms from 29 subjects who met the Task Force Criteria for ARVD and were enrolled in this study as probands were analyzed. The baseline characteristics of these probands and the matched controls are listed in Table 2.The age ranged from 15 to 58 years. No significant differences in these characteristics were noted between the groups. In 28 of these 29 probands, the diagnosis of ARVD was made using Task Force Criteria exclusive of the echocardiographic components. All probands and control patients had normal left ventricular structure and systolic function.
RV morphologic abnormalities
At least one RV morphologic abnormality occurred in 62% of probands, whereas two or more RV morphologic abnormalities were present in 38% of probands (Table 3).The most frequent morphologic abnormality was trabecular derangement, occurring in 54%, whereas hyper-reflective moderator band was present in 34% and sacculations were present in 17% of probands. There were no RV morphologic abnormalities present in any control subject.
Right heart dimensions
The mean dimensions for the RA and RV are shown in Table 4.The systolic and diastolic RVOT and RV inflow tract dimensions were significantly increased in probands versus controls. In comparison with the published reference population data, the RVOT in diastole, whether measured on its long axis or short axis, was the most commonly enlarged dimension in these 29 affected individuals (Fig. 1). An RVOT diameter of >25 mm (>2 standard deviations than the mean value from the reference population) was present in 100% of probands. We examined receiver-operator characteristics to determine sensitivity and specificity of the RVOT dimension, comparing probands with our control population. An RVOT long-axis dimension of >30 mm had the highest sensitivity and specificity for the diagnosis of ARVD (89% and 86%, respectively). The diastolic dimensions of the RV taken from the apical four-chamber view were least commonly enlarged.
Subjectively, the global RV function was abnormal in 62% of probands (Table 3). Using the quantitative criteria, global RV function was impaired in 66% of the 29 probands (Table 5).Regional wall motion abnormalities (WMAs) were present in 79% of probands. The apex (72%) and the anterior wall (70%) were the most common sites of regional WMAs.
Normal global RV function (by quantitative assessment) was present in 35% of the probands. Six of these 10 patients (60%) with a normal RV FAC had either focal regional WMAs and/or a morphological abnormality. In only one of these probands did a morphologic abnormality occur in the absence of WMAs. A mild reduction in RV function, as represented by a FAC between 32% and 25%, was present in 24% of the total population. In these seven probands with mildly impaired RV function, there were morphologic abnormalities in 57% and focal regional WMA in 86%.
Arrhythmogenic right ventricular dysplasia is a significant cause of ventricular arrhythmias in the young. Its diagnosis is challenging because most patients are asymptomatic, and sudden death is often the first manifestation of the disease. A critical component of the screening for and diagnosis of this disease is noninvasive imaging of the right ventricle. Although there are echocardiographic criteria identified by the ARVD Task Force to support the diagnosis of ARVD, these criteria are subjective. In addition, although echocardiography commonly is used when ARVD is suspected, controversy exists regarding the relative importance of various morphologic findings for this diagnosis. In this study, we carefully characterized, using echocardiography, 29 patients who met Task Force Criteria for ARVD. These echoes were performed at enrolling centers by sonographers who were trained to use the standard imaging protocol, with special emphasis placed on complete visualization of the RV. Using quantitative techniques, none of these probands had a normal echocardiogram.
We found that RVOT dilation was the most common abnormality associated with the Task Force Criteria diagnosis of ARVD. An enlargement of the RVOT as defined in the literature was present in 100%, and an RVOT dimension >30 mm was present in 89% of probands. Additionally, global RV dysfunction was present in more than two thirds of our population. When those with segmental RV dysfunction with a normal RV FAC are added to those with global RV impairment, the presence of any RV dysfunction was noted in 82%. Thus, there is a strong association in this population between diagnosis using ARVD Task Force Criteria and RV enlargement and dysfunction on echocardiography.
From our study, specific recommendations can be made that RV enlargement on echocardiography for the diagnosis of ARVD should be defined as a diastolic RVOT dimension from the long axis view of >30 mm. Likewise, the use of RV dysfunction on echocardiography as the basis for diagnosing ARVD can be defined as a FAC of <32% or the presence of segmental RV WMAs. Enlargement of the RVOT should be the primary echocardiographic parameter quantified when this disease is suspected.
Another observation from our data is the regional nature of RV enlargement. In particular, we found that when assessing RV size from the apical four-chamber view, RV enlargement frequently was not observed. It is common for RV dimensions to be assessed from the apical four-chamber view; however, our data suggest that when screening for ARVD, it is important to assess the RVOT dimension, which can easily be obtained from the parasternal long-axis view.
The need to combine global and regional RV function assessment in this diagnosis may represent one of the challenges of this disorder, namely a varying natural history. Although all of our probands were enrolled as newly diagnosed with ARVD, these probands could have manifested signs and/or symptoms of ARVD at varying time points in the disease process. It is possible that those with normal global RV function or only mildly impaired global function are at an earlier time course in the disease process. By adding in the presence of regional wall motion and/or morphologic findings that may occur in the early phase of the disease, the strength of the echo as a diagnostic tool is enhanced. However, most importantly, regardless of where these probands fall on the natural history spectrum of ARVD, all had RVOT enlargement.
There are a limited number of reports using echocardiography to aid in the diagnosis of ARVD, with most performed before the diagnostic criteria were defined by the Task Force and before the widespread introduction of harmonic imaging, which improves RV visualization. Several small series demonstrated abnormal RV size and function in patients with suspected ARVD (defined with clinical and angiographic criteria) compared with groups without ARVD (6,7,15). These studies found that the presence of RV dysfunction by two-dimensional echocardiography had high specificity and predictive value for ARVD (6); however, a clear set of echocardiographic diagnostic criteria have not been decided. Scognamiglio et al. (8) reported echocardiographic findings in asymptomatic individuals who were family members of patients with ARVD. They described several features suggestive of ARVD, including an inferobasal localized diastolic bulge, an abnormal trabecular pattern, a highly reflective and irregularly shaped moderator band, or an isolated dilatation of the RVOT. However, none of these findings occurred frequently in their population and, again, this study was performed in the pre-Task Force era, which raises the question of diagnostic uncertainty in the population studied. In our well-defined group, these echo features were very common. For example, trabecular derangement occurred in 54% of our population versus 17% of their population. Lindstrom et al. (16) used the new quantitative Doppler tool of tricuspid annular motion to assess RV function. Although this is a promising technique to assess the RV, these parameters have been found to vary with age, and the normal range is still being defined.
Similar findings have been noted with magnetic resonance imaging (MRI). Tandri et al. (17) have found in a well-defined population of ARVD that trabecular disarray is the most common morphologic abnormality and that RV enlargement is common. Of note, an important value of the assessment via MRI was the ability to detect intramyocardial fibrofatty infiltration.
Several limitations can be raised from our study. Because RV enlargement can occur in a variety of conditions, including congenital heart disease and pulmonary hypertension, these conditions need to be excluded in patients suspected to have ARVD. These conditions are easily identifiable using standard echocardiography and were not found in any of our study subjects. Additionally, observations are based on what might appear to be a small number of probands. However, this is a rare disease, affecting approximately 1 in 5,000 (18), and our cases were collected from centers with specialized interest and expertise in ARVD during the course of a long period. In fact, to our knowledge, this population is larger than any of the previously published echocardiographic series of individuals meeting Task Force Criteria for the diagnosis of ARVD. As noted previously, another issue that confounds the interpretation of our findings is that various probands are at different time points in their natural history of the disease. A previous MRI study has shown that the duration of symptoms correlates with the extent of RV enlargement (17). Finally, because this trial is in progress, we are unable to correlate our findings with data from the other core laboratories and thus are unable to determine the strength of association of RV enlargement and dysfunction on echocardiography with RV biopsy, MRI, arrhythmia, and angiography.
In summary, echocardiography is a relatively sensitive tool for identifying structural and functional abnormalities when ARVD is suspected. In particular, the accuracy of the Task Force Criteria may be improved if RVOT enlargement and RV dysfunction are quantified.
For a list of the enrolling physicians, please see the March 15, 2005, issue of JACCat www.onlinejacc.org.
The Multidisciplinary Study of Right Ventricular Dysplasia is supported by grant HL65549 from the National Heart, Lung, and Blood Institute of the National Institutes of Health, Bethesda, Maryland.
- Abbreviations and acronyms
- arrhythmogenic right ventricular dysplasia
- fractional area change
- magnetic resonance imaging
- right atrial
- right ventricular
- right ventricular outflow tract
- wall motion abnormalities
- Received August 3, 2004.
- Revision received October 12, 2004.
- Accepted October 18, 2004.
- American College of Cardiology Foundation
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