Is Arrhythmogenic Right Ventricular Dysplasia, Uhl's Anomaly and Right Ventricular Outflow Tract Tachycardia a Spectrum of the same Disease?

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

Running title: Right Ventricular Tachycardia and Uhl's anomaly: Differentiation

Keywords:

Right ventricular dyplasia Uhl's anomaly Right ventricular outflow tract tachycardia

Address Correspondence:
Frank I. Marcus, M.D.
University Medical Center
1501 N. Campbell Ave.
P.O. Box 24-5037
Tucson, AZ 85724
Telephone: 520-626-6358
Fax: 520-626-4333

Abstract

Whether arrhythmogenic right ventricular dysplasia (ARVD), Uhl's anomaly, and right ventricular outflow tract (RVOT) tachycardia are separate entities is undergoing reevaluation due to new information. Patients with Uhl's anomaly and ARVD have different clinical modes of presentation. The Uhl's anomaly patient frequently has congestive heart failure and presents at an earlier age, while a patient with ARVD manifests ventricular arrhythmias in adolescence or adulthood. Nevertheless, the pathogenesis of Uhl's may be due to the onset of apoptosis (cell death) of the right ventricle which starts in infancy or childhood and is a continuous process while the pathogenesis of ARVD may be similar, but the process of cell death starts in adolescence and can be intermittent. The patient with RVOT tachycardia may have structural disease of the right ventricle more commonly than previously appreciated. It is not clear if this condition represents a forme fruste of ARVD.

The three conditions, arrhythmogenic right ventricular dysplasia, Uhl's anomaly and right ventricular outflow tract tachycardia appear to be distinct separate entities. However, there is recent information that questions the view that these entities are different and readily distinguishable.

Arrhythmogenic right ventricular dysplasia (ARVD) is a disease in which the free wall of the right ventricle is partially or almost entirely replaced by fat. ARVD review (1,2). The remaining muscle fibers are interspersed with fatty tissue, providing a substrate for ventricular arrhythmias that may range from asymptomatic ventricular premature complexes to monomorphic ventricular tachycardia. Uncommonly, sudden cardiac death may be the first manifestation of the disease. The septum and left ventricle are not usually involved, but may be minimally or moderately affected. Since the right ventricular parietal wall is the usual site of origin of the ventricular arrhythmia, the QRS configuration of the arrhythmia is almost always that of left bundle branch block morphology. These arrhythmias may arise from the infundibulum resulting in an inferior QRS axis or from the apex or below the tricuspid valve resulting in a superior QRS axis. The ventricular tachycardia is due to a reentrant mechanism and sustained monomorphic ventricular tachycardia can usually be initiated by programmed electrical stimulation and terminated by burst pacing. This entity should be suspected in a young person, particularly male, who has ventricular tachyarrhythmias of left bundle branch block configuration, in the absence of other causes for the tachycardia. In patients who have sustained ventricular tachycardia due to ARVD, the T waves are usually inverted in one or more precordial leads. In addition, small notches may be seen just beyond the end of the QRS complex, called epsilon waves, representing delayed depolarization of the portion of the right ventricle due to parietal block (Fig 1). In patients with ARVD who have sustained ventricular tachycardia the signal average electrocardiogram is almost always positive (3,4) frequently with exceedingly long duration of the low amplitude signals. If ARVD is suspected, the diagnosis can be confirmed by finding areas of akinesia or diskinetic bulges in the right ventricle and the right ventricle may be globally enlarged. The left ventricle is normal or nearly normal both in size and function. An MRI can provide further evidence of this entity if there is a high signal intensity in the free wall of the right ventricle consistent with the presence of fatty tissue in this region. The cine MRI can demonstrate areas of hypokinesia or diskinesia in the right ventricle. Right and left ventricular radionuclide studies can document that the right ventricular ejection fraction is decreased while the left ventricle has nearly normal size and function. Negative results for the above tests do not necessarily exclude the diagnosis. If these non invasive tests are normal, a right ventricular angiogram should be considered and remains the gold standard. (5) Right ventricular myocardial biopsy is not particularly useful for diagnosis since the biopsy is generally obtained from the septum, a location that is not frequently involved in the pathological process.

Patients with ARVD may have other family members affected since it is inherited as a autosomal dominant trait with variable penetrance and clinical expression. (6)

Uhl's anomaly (7) appears to be different pathologically and clinically from ARVD. (Table 1) The pathology of Uhl's anomaly is usually but not always limited to the right ventricle. (8) The term, parchment heart, is appropriate since the parietal myocardium is paper thin and translucent since the endocardium is in apposition with the epicardium without intervening muscle. Some fine elastic fibers may be present. There is no apparent replacement of muscle by fatty tissue. Using these criteria, Gerlis et al. (9) reclassified 22 reports of Uhl's anomaly as ARVD. In contrast to ARVD where the classic presentation is usually with ventricular arrhythmias, patients with Uhl's anomaly generally present with cyanosis, dyspnea and right sided failure, usually in infancy or early childhood. Uhl's anomaly has not been documented to have a genetic basis. Thus a young adult who presents with ventricular arrhythmias of left bundle branch block configuration, particularly exercise induced and who has right ventricular disease and a family history of this condition has ARVD, not Uhl's anomaly.

If these two entities are so distinct why is there still controversy as to how to classify selected patients?

Patients with ARVD usually have a normal thickness of the right ventricular parietal wall due to fatty replacement. However, in some patients the free wall of the right ventricle range from 1-4 mm in thickness with the thinner areas devoid of muscle fibers and therefore parchment thin. However, adjacent areas have the typical histological picture of ARVD. According to Gerlis et al (9) and Fontaine et al (10) this pathological picture of some areas consistent with the Uhl's anomaly but others typical of ARVD should be classified as ARVD and not Uhl's. Since the pathogenesis of both ARVD and Uhl's are unknown, could there be a common denominator that links the two conditions? Recently, James suggested that both Uhl's and ARVD may share a common pathogenesis of apoptotic dysplasia. (11,12) In Uhl's anomaly the apoptotic process may be incessant and starts early in infancy or childhood with complete destruction of the right ventricular wall, whereas in ARVD there may be episodic apoptosis beginning at any time, possibly in the teens but also later in life. Thus what has previously appeared to be separate entities may in fact be different manifestations of the same disease process.

The other condition that needs to be differentiated from ARVD has been variously termed idiopathic ventricular tachycardia, benign ventricular arrhythmias, right ventricular tachycardia and more commonly, right ventricular outflow tract (RVOT) tachycardia. Prior to the report of Buxton et al. in 1983 (13), publications that described patients with ventricular arrhythmias in the absence of other obvious cardiac disease did not focus on tachycardias originating in the right ventricular outflow tract. The study of Buxton et al (13) described the clinical and electrophysiological characteristics of 30 patients without myocardial disease who had ventricular tachycardia with morphological characteristics of left bundle branch block and inferior axis. This type of ventricular tachycardia is now well characterized both clinically and electrophysiologically but the clinical presentation is not uniform. The tachycardia may consist of frequent uniform premature ventricular complexes, transient repetitive bursts of ventricular tachycardia, ventricular tachycardia induced during exercise or manifest only immediately after stopping exercise. In some patients the ventricular tachycardia may be sustained. Electrophysiological characteristics of this type of ventricular tachycardia include rate and catecholamine dependent initiation, suppression with beta blockers or calcium channel blockers and adenosine sensitivity. (14) The right ventricular outflow tract tachycardias are focal and the site can usually be localized by pace mapping and can be ablated with a high degree of success. However, ARVD may also present with ventricular tachycardia from the infundibulum without significant global abnormality of right ventricular contractility or increase in right ventricular size. How can one differentiate between these two conditions? (Table 2) If there are no clinical features of ARVD including lack of family history, normal 12 lead electrocardiogram, negative signal average ECG, (4) normal echo and right ventriculogram, the evidence is greatly in favor of the diagnosis of idiopathic right ventricular outflow tract tachycardia. In the electrophysiological laboratory, the finding of adenosine sensitivity adds to this diagnosis. Although not well established, it appears that most RVOT tachycardias originate in the intraventricular septum (13,15) where as the RVOT tachycardia in patients with RV dysplasia are more likely to originate from the right ventricular free wall. As previously mentioned, the ventricular septum is usually not involved in RV dsyplasia since the embryonic origin of the ventricular septum is similar to that of the left ventricle and not from the right. Nevertheless, Dr. James has pointed out that there is an area in the intraventricular septum - the septal band of the crista supraventricularis that is of right ventricular origin. (12) This tissue could be the focus of a right ventricular tachycardia in the septal area in patients with ARVD.

The pathological substrate of RVOT tachycardia is difficult to ascertain. In a few patients, there is apparent disappearance of the tachycardia suggesting an acute resolving process such as myocarditis (13). There is one report of surgical excision of the area of origin of the tachycardia in four patients (16). In three of the patients whose specimens were examined microscopically no abnormalities were detected, and in the other some interstitial fibrosis was seen. The absence of a pathological abnormality by myocardial biopsy in the region of the tachycardia in most patients have also been reported. (17,18,19) In view of the normal pathological findings it is surprising that the cine MRI has been reported to reveal structural and wall motion abnormalities in 75-95% of patients (20,21), although others have not confirmed the high incidence of abnormalities. (22,23). However, Kinoshita reported mild fibrosis and fatty infiltration in 8 of 12 patients with RVOT tachycardia (4). At present it is not possible to resolve these discrepant findings; that the majority of myocardial specimens or biopsies at or near the site of VT origin are normal yet there may be a high incidence of wall motion abnormalities in the RVOT. We must await further studies for resolution of this problem. Nevertheless, the possibility that many patients with RVOT tachycardia have structural abnormalities of the RVOT raises the question of whether some cases of RVOT tachycardia are forme fruste of ARVD that may be localized and not progress to other areas. Follow up of patients with RVOT tachycardia indicate that they do not appear to progress to ARVD and that their prognosis is excellent. Ritchie et al. followed 26 patients with non sustained RVOT tachycardia and did not observe any deaths in patients treated medically (24). Lerman stated that sudden death has not been documented in patients with RVOT tachycardia (14). Now that patients with RVOT tachycardia are being studied by sensitive techniques such as MRI, we should be able to learn about long term changes in the RVOT in patients with this problem.

In summary, ARVD, Uhl's anomaly and RVOT appear to be distinct clinical entities; although the pathogenesis of ARVD and Uhl's may be similar, Uhl's may be a more extreme and rapidly progressive form of ARVD presenting with congestive heart failure rather than with arrhythmias. RVOT tachycardia may be the initial manifestation of ARVD in a minority of patients. The localization of the origin of the VT in the RVOT may provide a clue to its etiology. If idiopathic, it most frequently will be located in the septum; If the tachycardia arises from the parietal wall it may be more likely to be due to ARVD. This hypothesis needs testing. More studies, especially MRI examinations, need to be done to clarify the frequency of progression of the RV outflow tract abnormalities using cine MRI in patients with RVOT tachycardia to determine which patients may have ARVD.

Table 1

Differentiation of Uhl's Anomaly from ARVD

Table 2

Differential features of RVOT Tachycardia and Right Ventricular Dysplasia

PVBs, Premature ventricular beats; AA drugs, antiarrhythmic drugs

Figure Legend
Figure 1. ECG of several left precordial leads from a patient with ARVD. The arrows point to the epsilon waves in V₁ and V₂.

Bibliography

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