Problems in the Clinical Recognition and Documentation of Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy

Frank I. Marcus, M.D.
University of Arizona College of Medicine
Tucson, AZ

Short running title: Clinical recognition of ARVD

Keywords: Right ventricular dysplasia, cardiomyopathy, right ventricular outflow tract tachycardia

Correspondence:
Frank I. Marcus, M.D.
P.O. Box 24-5037
Tucson, AZ 85724
Phone: 520-626-6358
Fax: 520-626-4333
E-mail: fmarcus@ccit.arizona.edu

INTRODUCTION
Arrhythmogenic right ventricular dysplasia (ARVD) is a disease entity that has been well described (1). Recognition of this disease is hampered by the fact that it is an unusual condition and not well known to most physicians or pathologists. Therefore, it may not be considered in the differential diagnosis of ventricular arrhythmias of left bundle branch block configuration or at necropsy in patients who die suddenly. Once the entity is considered as a diagnostic possibility, several non-invasive as well as invasive tests can readily confirm the presence of the overt form of the disease by finding marked dilatation and/or aneurysmal bulges of the right ventricle in the absence of significant left ventricular involvement. However, in patients who have minimal anatomic changes such as mild right ventricular dilatation or localized hypokinesia of the right ventricle, confirmation of ARVD can be a challenge (2). Difficulties in the diagnosis of patients with minimal anatomic abnormalities of the right ventricle using various non-invasive as well as invasive tests is the subject of this presentation. The problems of correctly diagnosing ARVD in patients who have minimal involvement of the right ventricle is becoming increasingly important since the condition has a genetic basis and family members are being evaluated with increasing frequency to determine the presence of the disease as well as the associated risks. Criteria for the diagnosis of ARVD is shown in Table I (3).

CLINICAL PRESENTATION
The most common clinical manifestation of ARVD is the presence of ventricular arrhythmias, ranging from symptomatic ventricular premature beats (VPBs) to non-sustained ventricular tachycardia or sustained ventricular tachycardia. Uncommonly, the first manifestation of ARVD may be sudden cardiac death. The physician should consider ARVD in the differential diagnosis if the ventricular arrhythmias have a left bundle branch block configuration with an inferior, horizontal or superior QRS axis. The probability that the ventricular arrhythmias are due to ARVD is enhanced if there are inverted T waves in the right precordial leads beyond V₁ in individuals over the age of 12. Recently, additional diagnostic findings on the 12 lead ECG have been described that can further help to implicate this condition as responsible for the ventricular arrhythmias. They are based on the presence of right ventricular parietal block in ARVD. This causes an intraventricular conduction delay localized to the anterior precordial leads that is seen as a prolongation of the QRS duration in leads V₁- V₃ as compared to the lateral precordial leads, V₄-V₆. Fontaine et al., 1994 (4), reported that a QRS duration of > 110 msec in V₁, V₂, or V₃ in association with a negative T wave in lead V₂, had an 84% sensitivity and 100% specificity for the diagnosis of patients with ARVD who had sustained ventricular tachycardia. Peters, et al. reported a 93% sensitivity, 96% specificity and 98% positive predictive value for the diagnosis of ARVD if the QRS duration in V₂ + V₃/V₄ or V₅ was >1.2. They stated that there was an even greater sensitivity if there is a QRS prolongation of > 100 msec in addition to the above criteria (5). The patients studied by Peters had non-sustained (n=26), sustained ventricular tachycardia (VT) (n=14) or cardiac arrest (n=2). Recently, Fontaine et al. showed that selective prolongation of the QRS duration in V₁, V₂, or V₃ in comparison with V₆ in the presence of right bundle branch block was also a diagnostic marker of the disease (6) (Fig 1). Corrado et al., observed that the QRS duration in the precordial leads correlated with the severity of the clinical manifestations (7). For example, both the maximum QRS duration (usual V₁-V₃ of the 12 lead ECG) as well as the difference in the maximum minus the minimum QRS duration increased from controls to patients with ARVD whose condition was stable. Those patients who had sudden cardiac death had more pronounced ECG abnormalities (7). These ECG measurements, if confirmed, could be included as part of a screening evaluation for competitive athletes since ARVD accounts for about 3% of sudden deaths related to sports (8,9). The utility of these ECG measurements for diagnosing asymptomatic patients or family members with ARVD is not known.

SIGNAL AVERAGED ELECTROCARDIOGRAM
The Signal Averaged Electrocardiogram (SAECG) is usually markedly abnormal in patients with ARVD who have sustained ventricular tachycardia, particularly if the tachycardia has a superior QRS axis (10). An abnormal SAECG (based on two positive criteria) was present in 71% (5 of 7) of ARVD patients with ventricular fibrillation, in 71% (36 of 50) of patients with sustained ventricular tachycardia, in 40% (13 of 32) of patients with non-sustained ventricular tachycardia and in 51% (25 of 29) of patients with premature ventricular beats (10). The incidence of abnormal SAECG findings were found to be directly proportional to the extent of anatomic right ventricular involvement, being abnormal in only 32% (21 of 66) with a localized form of the disease (10). Thus, a positive SAECG can be confirmatory in establishing the diagnosis, but it's lack of sensitivity precludes its use as a diagnostic aid for those patients with minimal right ventricular involvement. In addition, the presence of late potentials does not give precise information as to electrical instability in these patients (11).

ECHOCARDIOGRAM
The echocardiogram is extremely useful to detect right ventricular enlargement or wall motion abnormalities that would confirm the diagnosis of ARVD. The left ventricle is normal or not severely involved with regard to increased size or functional abnormalities except in the advanced stages of this disease. The major problems with the echocardiogram for diagnostic purposes are lack of attention to a systematic examination specifically directed towards assessing right ventricular size and function as suggested by Foale et al. (12). Manyari et al. assessed the sensitivity and specificity of 2D echocardiography to detect right ventricular dysplasia in 44 patients suspected of having this condition. ARVD was present in 14 patients and absent in 30 patients as determined by cardiac catheterization including right ventricular angiography. A ratio of > 0.5 for the RV/LV end diastolic diameter had a sensitivity of 86%, specificity of 93% and positive predictive value of 86% for the diagnosis of ARVD (13). The negative predictive value was 93%.

The value of 2D echocardiography to detect ARVD in asymptomatic patients was studied by Scognamiglio et al. (14) in 77 patients who were either family members of patients who died suddenly or in whom the diagnosis of right ventricular dysplasia was confirmed in a family member at autopsy. They also performed echocardiograms in 38 control subjects, none of whom had any wall motion abnormalities detected. Of the 77 subjects who had a family history of heart disease as described above or who had premature ventricular beats 34 (44%) had an echocardiogram suggestive of right ventricular cardiomyopathy even though the right ventricular ejection fraction was normal in all 34 patients. They concluded that 2 dimensional echocardiogram is useful for the early diagnosis of right ventricular dysplasia, even in asymptomatic patients. Nevertheless, since other confirmatory tests such as right ventricular angiography or MRI were not done routinely in all of these asymptomatic family members the sensitivity of the examination could not be determined.

Most patients who have an echocardiographic examination for possible ARVD, probably do not have a systematic, quantitative evaluation of the inflow as well as the outflow tract of the right ventricle in systole and diastole. There are technical problems that present difficulties in excluding the diagnosis of ARVD in patients who have minimal disease of this chamber. For example, there may be localized disease in the absence of the right ventricular enlargement (15) or difficulties in measuring the absolute diameter of the right ventricle. Contrast echocardiography using injections of saline may help to evaluate right ventricular regional or global function (16). Contrast echocardiography may better outline the right ventricle to permit measurement of right ventricular volume analysis as proposed by Levine et al. (17) and utilized by Scognamiglio et al. (14). According to the latter authors, right and left ventricular end diastolic volume in control subjects was 48+-6ml/M² and 64+-6 ml/M² (mean +-50) respectively. The right ventricular volume was calculated by the area length method derived from orthogonal planes, (apical 4-chamber and right ventricular subcostal long axis views). A modified Simpson rule was used to calculate left ventricular volumes from the parasternal short axis and apical 2 chamber views. Each ventricular volume was calculated as the mean of three different frames. In the individuals suspected of having ARVD, the right ventricular end diastolic volume was 54+-8 ml/M², which was statistically greater than controls (p=<0.01). There was no difference in the left ventricular end diastolic volume compared to controls.

The transesophageal echocardiography may be more sensitive than a transthoracic approach in detecting wall motion abnormalities (18,19). Three-dimensional echocardiography, particularly combined with the transesophageal approach is being investigated to enhance the diagnostic accuracy of echocardiography (20,21).

RIGHT VENTRICULAR ANGIOGRAPHY
The difficulty in utilizing the right ventricular angiogram for the diagnosis of ARVD relate to the technical performance of the study as well as to the problems in interpretation of the angiogram. The study is usually performed in both the 30° right anterior oblique as well as the 60° left anterior oblique views. It is important to avoid frequent premature ventricular beats during contrast injection in order to properly interpret wall motion as well as right ventricular volumes. In order to accomplish this it is suggested that a Berman balloon catheter be placed near the middle of the right ventricular inferior wall in order to give a uniform distribution of dye throughout the chamber (22). Before injection of contrast material, a 10 ml saline solution is injected manually. If ventricular arrhythmias are induced, the catheter tip is moved to a position that does not cause ventricular arrhythmias (22). Right ventricular volumes can be measured by means of a surface length method in the biplane mode. Daubert et al. found that maximum normal RV end-diastolic volume was 82+-13 ml/M² and end-systolic volume was 35+-8 ml/M² (mean +- 2 SD). In another study using the anterior, posterior and lateral projections and analyzing right ventricular volumes from digitized ventriculograms by a modification of Simpson's rule, the end-diastolic volume index in normals was 62+-13 ml/M² (23). The major problem in interpretation of right ventricular contraction abnormalities is that the segments of the right ventricle do not contract equally (24). Also, the reproducibility of assessment of right ventricular dimensions, contractility and regional wall motion scores varied unexpectedly both within and between two observers (24). It is clear that an objective approach is needed for evaluating angiographic changes in ARVD.

MAGNETIC RESONANCE IMAGING
This technique has the advantage of not only being able to show right ventricular anatomy but also can show tissue characterization. In ARVD, the right ventricular wall is infiltrated with fatty tissue. The excessive fat is displayed as a white area as compared with a gray color that is characteristic of normal ventricular muscle. In addition, there may be myocardial thinning. The cine MRI can be used to define localized dyskinetic regions of the myocardium (25). Technical considerations that have not been adequately addressed include the precise views needed to optimize the diagnostic accuracy of this technique for ARVD, the slice thickness as well as other considerations. It is difficult to interpret the data from the literature since the sensitivity and specificity of the MRI in one center to another may be quite different. A common protocol is in the process of being developed.

The interpretation of the MRI also poses a problem, due to the fact that the right ventricular free wall is thin and that epicardial fat which is normally present merges with the thin right ventricular musculature. Fat is normally present in the AV groove. Since there is a quantitative rather than qualitative difference between the fat in the right ventricular free wall in normals and patients with ARVD, the assessment of excessive fat is subject to individual interpretation as well as the quality of the images obtained. The cine MRI can assess wall motion of the right ventricle. Despite these limitations, the MRI is a valuable technique for diagnostic evaluation of right ventricular dysplasia as well as the extent of involvement of the right and left ventricles in this condition (26,27).

MYOCARDIAL BIOPSY
The confirmation of the diagnosis of ARVD by endocardial biopsy lacks sensitivity because the typical pathological changes are not consistently seen in the septum, the usual site of biopsy. The right ventricular free wall is not usually biopsied because of possible myocardial perforation. Biopsy performed at the junction of the septum and the free wall may increase the sensitivity. However, this requires experience to be certain that the bioptome is in this location. Using this latter site and performing a quantitative analysis of fat in the biopsy specimen Angellini et al.. found a 67% sensitivity and 92% specificity for this diagnosis (28). On a practical basis however, myocardial biopsy can not be routinely recommended to confirm the diagnosis of ARVD.

DIFFERENTIAL DIAGNOSIS
The two major conditions from which ARVD must be differentiated are other cardiomyopathies including myocarditis and right ventricular outflow tract tachycardia. Generally other cardiomyopathies show a more diffuse pattern involving both left as well as right ventricular muscle. In particular, left ventricular function is frequently decreased as much if not more than the right. However, in rare cases of cardiomyopathy due to myocarditis there can be selective early involvement of the right ventricular muscle. (29).

The differentiation of ARVD from ventricular tachycardias originating in the right ventricular outflow tract, usually termed RVOT tachycardias, can present considerable difficulty (30, 31). The differential diagnosis is listed in Table 2. It is important to differentiate these two conditions for several reasons. The first is that ARVD is known to have a genetic etiology whereas RVOT tachycardia does not. Therefore, it has implications with regards to screening of family members. The prognosis of RVOT tachycardia is uniformly excellent with sudden death occurring extremely rarely. Finally, ablation is usually curative in RVOT tachycardia where radiofrequency ablation is only palliative in patients with ARVD, since ventricular arrhythmias usually of a morphology other than that ablated, frequently recur (32).

CONCLUSION
In summary, the recognition of patients with ARVD who have the typical clinical presentation of ventricular tachycardia originating from the right ventricle associated with selective right ventricular enlargement and/or wall motion abnormalities is not difficult. However, patients who have ARVD with minimal right ventricular enlargement and/or wall motion abnormalities may present a challenging problem with regard to diagnosis even after performing echocardiography, right ventricular angiography and MRI. Recent findings on the 12 lead electrocardiogram may help to detect overt forms of ARVD but its role in the diagnosis of the early forms of this disease has not been well studied. ARVD must be differentiated from other cardiomyopathies and RVOT tachycardia. There is a need to enhance the accuracy of non-invasive as well as invasive tests to confirm the diagnosis of patients suspected with this condition.

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FIGURE LEGEND

Figure 1: Electrocardiogram with right bundle branch block pattern is shown from a patient with ARVD (left) and from a patient with hypertension (right). In the patient with ARVD the difference in the duration of the QRS complex in V₁-V₆ = 60 msec while in the other patient it is 10 msec.