Printer Friendly

Comparison of Uhl's anomaly, right ventricular outflow tract ventricular tachycardia (RVOT VT) & arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) with an insight into genetics of ARVD/C.

Introduction

Uhl's anomaly, arrhythmogenic right ventricular dysplasia / cardiomyopathy (ARVD/C) and right ventricular outflow tract ventricular tachycardia (RVOT VT) involve pathogenic changes in the right ventricular (RV) myocardium. Though complete pathogenic mechanisms have not been discovered for the three disorders, there is a speculation that these may be milder or severe manifestations of the same condition.

In 1952, Uhl described a case in which the wall of the right ventricle was said to be paper thin and almost devoid of muscle fibres, an appearance akin to parchment heart (1). Fontaine et al (2) described an entity, called arrhythmogenic right ventricular dysplasia, which was characterized, by localized deficiency or fibrofatty tissue replacement of right ventricular myocardium. Since then, the term ARVD/C has been used increasingly and references to the Uhl's anomaly have decreased raising the question whether the two conditions are different entities or are variants of a single underlying disorder (3). Further cases with the morphology of ARVD/C have been inaccurately classified as Uhl's anomaly (4-24). Hence, it became necessary to differentiate between the two conditions.

Right ventricular tachycardia is commonly due to ARVD/C or idiopathic right ventricular ventricular outflow tract (RVOT) ventricular tachycardia (VT) (25,26). ARVD/C is an inherited cardiomyopathy with right ventricular dysfunction due to fibrofatty replacement of myocardium, predisposing to ventricular tachycardia and death. RVOT VT is a benign condition, considered as a primary electrical disorder in the absence of structural heart disease (27). Frequency of symptoms and history of syncope are similar in ARVD/C and RVOT VT (25,28). Detailed analyses using MRI, SAECG and endomyocardial biopsy have detected structural abnormalities in patients with RVOT VT were similar to those seen in the early stages of ARVD/C25, (29-33). Hence, to know whether the two conditions represent separate entities or together form a continuous spectrum of a disease is clinically important for better prognosis and management.

Uhl's anomaly and RVOT VT, severe and mild forms of ARVD/C?

ARVD/C and Uhl's anomaly are considered as different manifestations of the same disease (34). In Uhl's anomaly, there is virtually complete absence of the myocardium of the parietal wall of the right ventricle and the parietal wall is composed of the opposing endocardial and epicardial ventricular surfaces, with no fatty tissue interposed between these layers. These changes are congenital and diagnosed by foetal echocardiography (35). ARVD/C is characterized by patchy and localized replacement of the parietal wall of the right ventricle by fibrofatty tissue. This adipose replacement occurs primarily within the ventricular outflow tract, inlet or apical regions, sometimes progressing to the left ventricle. The clinical presentation of Uhl's anomaly includes cyanosis, dyspnoea and right-sided failure while patients with ARVD/C exhibit ventricular arrhythmias that may range from asymptomatic ventricular complexes to ventricular fibrillation. Uhl's malformation is usually diagnosed in neonatal or infant life, while ARVD/C patients manifest symptoms during adolescence. In a study, the male: female ratios for Uhl's anomaly was found to be 1.27:1, while for ARVD/C it was 2.28:1, this difference in the degree of male predominance was considered significant (3). Uhl's anomaly has been associated with other disorders like dysplasia of the tricuspid valve, pulmonary atresia and persistent ductus arteriosus, while ARVD/C has been seen as a part of a syndrome with hair and skin abnormalities inherited in an autosomal recessive form or as an isolated condition which is inherited in an autosomal dominant fashion.

James (36) suggested that both conditions share a common pathogenesis of apoptotic dysplasia. In Uhl's anomaly the apoptotic process may be incessant and starts early in infancy or childhood with complete destruction of RV wall, whereas in ARVD/C there may be episodic apoptosis beginning in adolescence (36). Though the pathogenic mechanism in ARVD/C is not completely understood, it is believed that defects in desmosomal components, which provide mechanical coupling between the intermediate filaments and the cytoplasmic membranes of adjacent cells, may compromise its adhesive function, predisposing to myocyte detachment and death. Further, as the regenerative capacity of myocardium is limited, fibrofatty substitution is observed as repair mechanism (37).

Gras et al (38) showed that the suppression of the signaling of canonical Wnt / [beta]-catenin pathway could be the pathogenic mechanism underlying ARVD/C. The probable molecular mechanism hypothesized was that by mutating desmosomal protein impairs desmosomal assembly releasing free plakoglobin from the desmosomes, which could translocate into the nucleus and through competition with [beta]-catenin suppress signaling through the canonical Wnt/ [beta]-catenin-Tcf/Lef pathway. Suppression of Wnt/ [beta]-catenin signaling provokes adipogenesis, fibrogenesis, and apoptosis, the characteristic hallmark of ARVD/C38. The mechanism involved in Uhl's anomaly would probably involve the factors that would either trigger apoptotic pathways or fail to protect from apoptosis leading to complete loss of right ventricular myocardium. Wnt pathway has not been implicated in Uhls anomaly till date but apoptosis can be triggered by many factors including the components of the Wnt pathway.

In the canonical Wnt pathway, frizzled receptors signal to the dishevelled (Dsh) protein, which causes accumulation of cytoplasmic [beta]-catenin. After translocation to the nucleus, [beta]-catenin activates T cell factor (TCF)-dependent target genes. Human frizzled receptor hFz5 induces apoptosis and the C-terminal region of the cytoplasmic tail of hFz5 shares significant similarity with the corresponding region of Xfz8a (frizzled receptor in Xenopus), required for JNK (a family of stress-activated serine/threonine kinases) activation and apoptosis. Wnt ligand Xwnt5a is a negative regulator of apoptosis induced by Xfz8. A similar process might be expected in Uhl's anomaly where the Wnt ligands fail to suppress the apoptosis leading to complete loss of RV myocardium. Studies in this regard are required to implicate or rule out this pathway in Uhl's anomaly (39).

Mallat et al (40) showed that apoptosis could be the primary process that precedes fibrofatty replacement of myocardial tissue in ARVD/C unlike in Uhl's anomaly where the only process of apoptosis is reported.

The mechanism operating in ARVD/C should be essentially different from the apoptosis triggered in Uhl's anomaly as in the later condition there is complete loss of RV myocardium unlike in ARVD/C where it is assumed that apoptosis process not being continued incessantly but being only episodic both spatially and temporally and result in the focal loss of myocardium in a few limited regions or may be more diffused. Further, there is no fibrofatty replacement of myocytes observed in Uhl's anomaly in contrast, which is the main pathological feature observed in ARVD/C. The difference in clinical expressions and the probable pathogenic mechanisms in these two conditions indicate that Uhl's anomaly and ARVD/C may be separate entities.

In right ventricular outflow tract (RVOT) ventricular tachycardia (VT), which occurs predominantly in young adults, the origin of VT in RVOT tachycardia is usually in the septum, while for ARVD/C it is in the parietal wall. Kinoshita et al (41) reported mild fibrosis and fatty infiltration in 8 of the 12 patients with RVOT VT. In the 12 lead ECG, the mean QRS duration is longer in ARVD/C patients compared to RVOT VT in all the leads (41). Late potentials on signal averaged electrocardiogram were not present in RVOT VT patients but were present in 78 per cent of the patients with ARVD/C. Unlike ARVD/C patients, none of the RVOT tachycardia patients had structural abnormalities on echocardiography or angiography, further no major structural abnormalities were observed in RVOT VT patients in MRI (27). Follow up of patients with RVOT VT has shown that they do not appear to progress to ARVD/C but RVOT VT was reported as a localized form of ARVD/C in 50 per cent of cases investigated (42). Table I shows differences in the clinical expressions of the RVOT VT and ARVD/C. These studies indicate that RVOT VT could be a different entity and not a milder form of ARVD/C and that RVOT VT does not progress into ARVD/C during a period of time. But to identify and distinguish between milder form of ARVD/C and RVOT VT is difficult as there is no technique to either establish or rule out these conditions. As the genetic basis of ARVD/C has been established, milder form of ARVD/C can be identified by screening the family members in the familial cases and the sporadic cases can be distinguished by molecular studies.

The molecular pathology of the disorders affecting the right ventricle has not been identified. The basis of preferential affection of right ventricle in the setting of the right ventricular disorders is the difference between the right and left ventricular wall thickness and their adaptation to the pressure of the blood flow against which the myocardium has to pump. Therefore, the left ventricle is thick-walled in order to counter the high pressure of the blood flow while the right ventricle also needs to adapt to the wide variations of the preload, i.e. the volume of blood it needs to accommodate, due to which the thin-walled right ventricle is highly distended. Among these three right ventricular disorders, ARVD/C is the only condition genetically well characterized. The molecular studies would aid in recognizing the condition in the early stages and the asymptomatic family members. It would also help in distinguishing the different types of RV disorders.

Genetics:

Eleven autosomal dominant forms of ARVD/C, all exhibiting incomplete penetrance have been identified. Naxos disease, associated with palmoplantar keratosis and wooly hair, has been identified as a recessive condition. Since, the identification of the first locus for ARVD/C in 1994, eight genes have been identified so far (43). The list of the genes identified for ARVD/Cs and their clinical manifestations is shown in Table II.

Non-desmosomal genes identified:

Transforming growth factor-beta 3 (TGF-/[beta]3): Mutations in untranslated 5' and 3' regions of TGF-/[beta]3 gene have been identified in the causation of ARVD/C-1. TGF-[beta]3 induces a fibrotic response in various tissues in vivo (44) and modulate expression of genes encoding desmosomal proteins in different cell types. Experiments have shown that incubation of cardiac fibroblasts in presence or absence of exogenous TGF[beta]3 revealed increased expression of plakoglobin gene (45) and overexpression of TGF[beta]3, caused by UTR mutations which might affect cell-to-cell junction stability leading to a final outcome as observed in ARVD/C which is caused by mutations in desmosomal genes.

Cardiac ryanodine receptor gene (RyR-2): RyR-2 is the first gene identified for the condition, which is characterized by the presence of peculiar effort-induced ventricular arrhythmias and high penetrance (46). This unique form of the condition was named ARVD/C-2. Mutations in RyR-2 gene decrease the binding strength between RyR2-FKBP12. (6) and increase the open probability of the channels enhancing Ca2+ leakage from the sarcoplasmic reticulum. In turn, the increased cytosolic [Ca.sup.2+] concentration would impair excitation contraction (E-C) coupling giving rise to arrhythmias and induce [Ca.sub.2+] activated apoptosis/necrosis processes, leading to myocardial damages (46) as reported in ARVD/C patients.

Transmembrane protein 43 (TMEM43): TMEM43 is the recently identified gene for ARVD/C-5 (47). Signaling pathways have been implicated in pathogenesis of ARVD/C. For example, plakoglobin, when freed from desmosomal complexes, translocates to the nucleus where it competes and opposes the action of [beta]-catenin and downregulates the canonical Wnt/-[beta]-catenin signaling pathway. Suppression of the canonical Wnt/ [beta]-catenin signaling upregulates two adipogenic transcription factors, CCAAT-enhancer-binding protein-a (C/EBP-[alpha]) and peroxisome proliferator response elements (PPAR[gamma]) (38). A genome-wide scan for PPREs identified 1085 potential target genes of PPAR[gamma], including TMEM43 (47). If TMEM (43) is a part of an adipogenic pathway regulated by PPAR[gamma], then perhaps dysregulation of this pathway may explain the fibrofatty replacement of the myocardium observed in ARVC patients (47).

Desmosomal genes identified:

Desmosomes are major intercellular adhesive junctions found in all epithelial and cardiac tissues. They provide anchorage of the plasma membrane to the cytoskeleton by interacting with intermediate filaments on their cytoplasmic side, thus contributing to tissue integrity. Desmosomes consist of three major protein families- Cadherins (desmogleins and desmocollins), Armadillo (Arm) repeat proteins (plakoglobin and plakophilins) and plakin (desmoplakin).

Desmoplakin: Mutations in the desmoplakin gene have been identified in the causation of ARVD/C-8 and arrhythmogenic left ventricular cardiomyopathy (ALVC) (48,49). Mutations at the inner dense plaque, particularly affecting the desmin-binding site of desmoplakin may result in ARVD/C with predominantly left ventricular involvement and clinical overlapping with dilated cardiomyopathy, while the mutations affecting the outer dense plaque of desmosome (desmoglein2, plakoglobin, plakophilin2 and the N-terminal of desmoplakin) result in ARVD/C with the ordinary described phenotype indicating that mutations in the same gene at different locations might lead to different phenotypes either ARVD/C or ALVC (50).

A variant of ARVD/C, where the condition is localized to left ventricle (LV), is called arrhythmogenic left ventricular cardiomyopathy (ALVC). The glaring departure from ARVD/C is apparent exclusive left sided nature of the disease51. Suzuki et al (52) reported a 43 year old man, who initially presented with left sided cardiomyopathy with preserved RV contraction, 10 years later developed biventricular progression. Table III gives the clinical findings of ARVD/C and ALVC. The clinical presentations of ALVC are similar to ARVD/C except that the disease is restricted to LV with a normal RV.

Plakophilin-2 (PKP-2): Highest number of mutations have been reported in PKP-2 gene causing ARVD/C9 thus suggesting the plakophillin may be a frequent cause of the disease. Plakophillin-2 is an essential armadillo-repeat protein of the cardiac desmosome. Plakophilins together with other desmosomal proteins, assemble to form cell adhesion complexes, which carry out important functions such as mechanically safeguarding cellular and organ architecture, and participating in signal transduction pathways (53).

Desmoglein-2 (DSG-2): DSG-2 is expressed in cardiac tissue and is an important component of desmosomal complex. Screening of this gene identified mutations accounting for ARVD/C and as this is the tenth loci for the condition was named ARVD/C-10 (54).

Desmosomes consist of 2 desmosomal-specific cadherin family members desmogleins (DSGs) and desmocollins (DSCs). All cadherins have tripartite functional domains--a calcium-inducible, extracellular amino terminal domain, important for homophilic intercellular associations, with 4 domains (EC1 to EC4), followed by an extracellular anchor domain (EA); a single transmembrane domain; and a cytoplasmic domain anchoring the cytoskeleton, an essential process for cell adhesion. So far all the mutations reported in this region have been observed in the highly conserved domains of DSG-2 and it is possible that even a single amino acid change could result in differences in molecular affinity and possibly in the abolition of the adhesive capacity of cadherins.

Desmocollin-2 (DSC-2): As desmocollin-2 (DSC-2) is also a component of demosomal complex, screening of this gene was initiated and mutations were identified causing ARVD/C-11. DSC-2 plays a crucial role in cell adhesion and tissue morphogenesis, it is speculated that absence of DSC-2 or incorporation of mutant DSC-2 in desmosomes would result in structurally and functionally impaired desmosomes. This corroborates with the widely accepted "desmosomal model" hypothesis (55), according to which under conditions of mechanical stress, impaired desmosome function due to desmsosmal gene mutations would lead to detachment and death of cardiac myocytes followed by inflammation and fibrofatty replacement (31).

Plakoglobin: Earlier mutations in plakoglobin were reported in a variant of ARVC called Naxos disease, which is characterized by signature features of ARVC accompanied by diffuse non-epidermolytic palmoplantar keratoderma (NEPPK) and wooly hair (WH) (56), a recently identified novel autosomal dominant plakoglobin mutation without any cutaneous and hair abnormalities. Plakoglobin is also known to participate in Wnt-signaling pathways, where it is associated with Tcf/Lef transcription factors (57) and regulates functions such as cell proliferation and apoptosis (58). Different mechanisms leading to altered turnover kinetics of plakoglobin might be responsible for the two variants --Naxos disease with skin and hair abnormalities and dominant ARVC form.

Clinical pathology:

ARVD/C may manifest in the following clinical phases: concealed, overt, right ventricular failure or biventricular failure pump phase. In the early concealed phase, individuals are often asymptomatic but may be at a risk of sudden cardiac death, notably during extreme exertion. Structural changes are absent or subtle and are frequently confined to one region of the triangle of dysplasia: the inflow, outflow, and apical portions of the RV. The second phase marks the onset of the overt electrical disorder, with symptomatic arrhythmia of RV origin and more prominent RV morphological abnormalities readily discernible by conventional imaging. In the third phase, diffuse RV disease results in an isolated right heart failure. LV involvement with biventricular pump failure occur in the final stage, leading to a phenotype that may resemble dilated cardiomyopathy (59).

Initial symptoms:

The first clinical presentation could be sustained ventricular tachycardia, palpitation, syncope, chest pain, recurrent ventricular tachycardia or cardiac arrest due to ventricular fibrillation. Clinically ARVD/C is responsible for approximately 5 per cent of unexplained sudden cardiac death (SCD) cases in young athletes in United States and 27 per cent of such cases in Italy (60-62). Cardiac deaths in ARVD/C are accounted by sudden death and heart failure. Hulot et al (63) reported heart failure as the cause of death in about two-thirds of the patients investigated.

Angiotensin converting enzyme (ACE) polymorphism was analyzed in ARVD/C patients and a high prevalence of DD genotype in patients with syncope was observed and might be useful in identifying high-risk patients for syncope (64).

The clinical manifestations of the probands harbouring desmoplakin gene mutations are similar to patients with other ARVCs except that probands with DSP mutations are characterized by a high occurrence of sudden death even in the concealed phase (49), while individuals harbouring plakophilin-2 genes mutations express the disease earlier in life, as determined by age at first clinical manifestation and age at first arrhythmias (65).

Structural progression of the condition:

Biventricular involvement is expected as the disease progresses. Involvement of the RV or LV is dependant on the site of the mutation in patients carrying desmoplakin gene mutation. Mutations in the plakophilin-2 genes cause the disease affecting predominantly the RV, while desmocollin-2 gene mutations may be more frequently associated with left ventricular phenotype without significant right ventricular involvement (55). LV involvement is not observed in patients with TGF gene mutation.

Diagnosis:

A Task Force of the European Society of Cardiology has proposed the criteria for the clinical diagnosis of ARVD/C categorized as the major and minor criteria, based on the identification of structural abnormalities, fatty or fibrofatty replacement of RV myocardium, electrocardiographic changes, arrhythmias of RV origin, and familial disease (66). The diagnosis is fulfilled in the presence of two major criteria or one major plus two minor criteria or four minor from different groups (66). Not all patients' family members fulfilled diagnostic criteria (67,68).

A modified diagnostic criteria has been proposed to screen and identify the family members of the probands, who were either asymptomatic or exhibited mild symptoms (69).

ECG: The ECG in ARVD/C patients usually show a regular sinus rhythm, with a QRS duration of greater than 110 milliseconds in lead V1 and an inversion of T waves in precordial leads V1-V3. The extent of T wave inversion in the precordial leads beyond lead V1 correlates with the extent of right ventricular involvement (70). Prolongation of QRS duration in the right precordial leads reflects late conduction in right ventricle (68). Small electrical potentials occurring at the end or immediately after the QRS complex in leads V1 or V2, called s (epsilon) waves are present in approximately 30 per cent of ARVD/C patients who have VT. s waves reflect delayed depolarization in the right ventricle (11).

All the patients showed repolarization abnormalities in 12 lead ECG and a T wave inversion in the leads V1 through V2, V3, V4 or V5 with complete or incomplete right bundle branch block (RBBB). Epsilon waves were observed in the probands carrying the mutation in the genes coding for the desmosomal proteins but not in the patients with TGF/3-3 gene mutation (12).

Signal averaged ECG (SAECG): Signal-averaged ECG has shown a significant correlation between presence of late potentials and occurrence of sustained VT (73,74). Ventricular late potentials appear to arise from the areas of structurally abnormal myocardium in which ventricular activation is delayed and asynchronous. Delayed fragmented electrical activity is probably related to re-entry of ventricular arrhythmias. Late potentials in SAECG are observed in all the probands irrespective of the type of ARVD/C.

Ventricular arrhythmias: The peculiar histopathology of the disease predisposes the patient to malignant ventricular arrhythmias (75,76). VT is generally believed to be re-entrant and is usually accompanied by abnormalities of ventricular activation (77). The presence of zones of altered myocardium, characterized by fibrofatty infiltration, can create re-entry circuits representing the substrate for repetitive ventricular arrhythmias. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are documented causes of sudden death in ARVD/C (78).

In all the ARVD/C patients irrespective of the type, left bundle branch block (LBBB) type VT is documented (either sustained or non sustained or both). Probands with TGF/3-3 gene mutation presented only non sustained ventricular tachycardia/ arrhythmias while probands carrying the mutation in the either desmoplakin or plakophilin-2 genes presented with all the four types--sustained ventricular tachycardia, non sustained VT (NVST), polymorphic ventricular complexes (PVCs) and ventricular fibrillation.

Echocardiographic studies:

Moderate to severe dilation of RV with RV wall motion abnormalities are observed in all ARVD/C patients. LV involvement with LV kinetic abnormalities of diffuse and localized forms were observed in all the probands except in the patients with TGF/[beta]-3 gene mutation, in whom there was no LV involvement (72).

Familial studies:

AllARVD/C patients carrying mutations in different genes (TGF/3-3, DSP, PKP-2, DSG 2 and DSC-2) had positive family history. Not all family members of the probands fulfilled the diagnostic criteria but fulfilled the modified diagnostic criteria (69) though they carried the mutation.

Histopathologicalfindings (autopsy/biopsy):

RV dilation was observed along with extensive replacement type fibrosis and fatty infiltration. Surviving myocytes entrapped within fibrous and fatty tissue showed degenerative changes and abnormal nuclei. ARVD/C is one of the major causes of sudden death and has variable penetrance and expressitivity. Although genotypically family members of the patient carry the mutant allele, phenotyically they might be asymptomatic. As the disease progresses, they might get symptomatic or may manifest sudden death. Hence genetic testing would aid in identifying the mutation carriers and help in treatment and prognosis.

Conclusions

Based on the symptoms, clinical investigations and the probable molecular mechanisms implicated, the three conditions, viz., Uhl's anomaly, ARVD/C and RVOT VT may be considered as separate clinical entities. Different ARVD/C types can be differentiated to an extent based on the clinical symptoms.

Mutations in the two non desmosomal genes, cardiac RYR-2 and TGF [beta-3] implicated in ARVD/C-2 and ARVD/C-1 exhibit different clinical presentations which are easily distinguishable from the symptoms and clinical manifestations exhibited by the desmosomal gene mutations. But in a study, two patients harbouring the same mutation in PKP-2 gene (almost same age, the only difference is the gender of the patients, unpublished data) exhibited different clinical phenotypes further complicating the condition to understand and differentiate. Can gender be another parameter that could affect the severity of the condition, has to be considered. The reports on monozygotic twins suggest the role of environmental factors on the expression of the disease (79). The identification of different types of ARVD/Cs based on specific symptoms would aid in genotype-phenotype correlations.

Received November 27, 2008

References

(1.) Uhl HS. A previously undescribed congenital malformation of the heart: almost total absence of the myocardium of the right ventricle. Bull Johns Hopkins Hosp 1952; 91 : 191-209.

(2.) Fontaine G, Guiraudon G, Frank R. Mechanism of ventricular tachycardia with and without associated chronic myocardial ischemia: surgical management based on epicardial mapping. In: Narula OS, editor. Cardiac arrhythmias. Baltimore: Williams and Wilkins; 1919. p. 516-23.

(3.) Gerlis LM, Schmidt-Ott SC, Ho SY, Anderson RH. Dysplastic conditions of the right ventricular myocardium: Uhl's anomaly vs. arrhythmogenic right ventricular dysplasia. Br Heart J 1993; 69 : 142-50.

(4.) Smeeton WM, Smith WM. Sudden death due to a cardiomyopathy predominantly affecting the right ventricle right ventricular dysplasia. MedSci Law 1981; 27 : 201-12.

(5.) Bharati S, Ciraulo DA, Bilitch M, Rosen KM, Lev M. Inexcitable right ventricle and bilateral bundle branch block in Uhl's disease. Circulation 1918; 57 : 636-44.

(6.) Vecht RJ, Carmichael JS, Gopal R, Philip G. Uhl's anomaly. Br Heart J 1919; 41 : 616-82.

(7.) Froment R, Perrin A, Loire R, Dalloz C. Papyraceous right ventricule in the young adult caused by congenital dystrophy. Apropos of 2 anatomo-clinical cases and 3 clinical cases. Arch Mal Coeur Vaiss 1968; 61 : 411-503.

(8.) Hoback J, Adicoff A, From AH, Smith M, Shafer R, Chesler E. A report of Uhl's disease in identical adult twins: evaluation of right ventricular dysfunction with echocardiography and nuclear angiography. Chest 1981; 79 : 306-10.

(9.) Child JS, Perloff JK, Francoz R, Yeatman LA, Henze E, Schelbert HR, et al. Uhl's anomaly (parchment right ventricle): clinical, echocardiographic, radionuclear, hemodynamic and angiocardiographic features in 2 patients. Am J Cardiol 1984; 53 : 635-1.

(10.) Diggelmann U, Baur HR. Familial Uhl's anomaly in the adult. Am J Cardiol 1984; 53 : 1402-3.

(11.) Fischer DR, Zuberbuhler JR. Familial Uhl's anomaly. Am J Cardiol 1984; 54 : 940.

(12.) Guiraudon GM, Klein GJ, Gulamhusein SS, Painvin GA, Del Campo C, Gonzales JC, et al. Total disconnection of the right ventricular free wall: surgical treatment of right ventricular tachycardia associated with right ventricular dysplasia. Circulation 1983; 67 : 463-10.

(13.) Fitchett DH, Sugrue DD, MacArthur CG, Oakley CM. Right ventricular dilated cardiomyopathy. Br Heart J 1984; 51 : 25-9.

(14.) Alcasena MS, Maqueda IG, Marti JS, Orbe IC, Gamallo C, Jadraque LM. Arrhythmogenic dysplasia of the right ventricle and trisomy X. Presentation of a case. Rev Esp Cardiol 1985; 38 : 351-60.

(15.) Ruder MA, Winston SA, Davis JC, Abbott JA, Eldar M, Scheinman MM. Arrhythmogenic right ventricular dysplasia in a family. Am J Cardiol 1985; 56 : 199-800.

(16.) Kawamura O, Ohaki Y, Nakatani Y, Miseigi K, Yoshimura H, Kobayashi H, et al. Idiopathic right ventricular dilatation. Special reference to "Arrhythmogenic right ventricular dysplasia" and analogous lesions. Acta Pathol Jpn 1986; 36 : 1693-105.

(17.) Moene RJ, Sobotka MA, Buis B, Bots GT, Elzenda NJ. Unclassified familial cardiomyopathy with ventricular dysrhythmia. Pediatr Cardiol 1981; 8 : 1H-880.

(18.) Rakovec P, Rossi L, Fontaine G, Sasel B, Markez J, Voncina D. Familial arrhythmogenic right ventricular disease. Am J Cardiol 1986; 58 : 311-8.

(19.) Laurent M, Descaves C, Biron Y, Deplace C, Almange C, Daubert JC. Familial form of arrhythmogenic right ventricular dysplasia. Am Heart J 1981; 113 : 821-9.

(20.) Blomstroem-Lundqvist C, Enestrom S, Edvardsson N, Olsson SB. Arrhythmogenic right ventricular dysplasia presenting with ventricular tachycardia in a father and son. Clin Cardiol 1981; 10 : 2H-83.

(21.) Nakanishi T, Shiroyama T, Inoue D, Uno M, Kitamura K, Kooda M, et al. A family study of the two cases of arrhythmogenic right ventricular dysplasia with reference to genetic aspects. Kokyu To Junkan 1986; 34 : 1009-14.

(22.) Nava A, Scognamiglio R, Thiene G, Canciani B, Daliento L, Buja G, et al. A polymorphic form of familial arrhythmogenic right ventricular dysplasia. Am J Cardiol 1981; 59 : 1405-9.

(23.) Nava A, Thiene G, Canciani B, Daliento L, Buja G, Martini B, et al. Familial occurrence of right ventricular dysplasia: a study involving nine families. J Am Coll Cardiol 1988; 12 : 1222-8.

(24.) Sabel KG, Blomstrom-Lundqvist C, Olsson SB, Enestrom S. Arrhythmogenic right ventricular dysplasia in brother and sister: Is it related to myocarditis? Pediatr Cardiol 1990; 11 : 113-6.

(25.) Kazmierczak J, De Sutter J, Tavernier R, Cuvelier C, Dimmer C, Jordaens L. Electrocardiographic and morphometric features in patients with ventricular tachycardia of right ventricular origin. Heart 1998; 79 : 388-93.

(26.) Hoch DH, Rosenfeld LE. Tachycardias of right ventricular origin. Cardiol Clin 1992; 10 : 151-64.

(27.) O'Donnell D, Cox D, Bourke J, Mitchell L, Furniss S. Clinical and electrophysiological differences between patients with arrhythmogenic right ventricular dysplasia and right ventricular outflow tract tachycardia. Eur Heart J 2003; 24 : 801-10.

(28.) Lerman BB, Stein KM, Markowitz SM. Idiopathic right ventricular outflow tract tachycardia: a clinical approach. Pacing Clin Electrophysiol 1996; 19 : 2120-3L

(29.) Grimm W, List-Hellwig E, Hoffmann J, Menz V, Hahn-Rinn R, Klose KJ, et al. Magnetic resonance imaging and signal averaged electrocardiography in patients with repetitive monomorphic ventricular tachycardia and otherwise normal electrocardiogram. Pacing Clin Electrophysiol 1991; 20 : 1826-33.

(30.) Carlson MD, White RD, Trohman RG, Alder LP, Biblo LA, Merkatz KA, et al. Right ventricular outflow tract ventricular tachycardia: detection of previously unrecognized anatomic abnormalities using cine magnetic resonance imaging. J Am Coll Cardiol 1994; 24 : 120-1.

(31.) Globits S, Kreiner G, Frank H, Heinz G, Klaar U, Frey B, et al. Significance of morphological abnormalities detected by MRI in patients undergoing successful ablation of right ventricular outflow tract tachycardia. Circulation 1991; 96 : 2633-40.

(32.) Markowitz SM, Litvak BL, Ramirez de Arellano EA, Marbisz JA, Stein KM, Lerman BB. Adenosine-sensitive ventricular tachycardia: right ventricular abnormalities delineated by magnetic resonance imaging. Circulation 1991; 96 : 1192-200.

(33.) Molinari G, Sardanelli F, Zandrino F, Parodi RC, Bertero G, Richiardi E, et al. Adipose replacement and wall motion abnormalities in right ventricle arrhythmias: evaluation by MR imaging. Retrospective evaluation on 124 patients. Int J Card Imaging 2000; 16 : 105-15.

(34.) Marcus FI. Is arrhythmogenic right ventricular dysplasia, Uhl's anomaly, and right ventricular outflow tract tachycardia a spectrum of the same disease. Cardiol Rev 1991; 5 : 25-9.

(35.) Wager GP, Couser RJ, Edwards OP, Gmach C, Bessinger B Jr. Antenatal ultrasound findings in a case of Uhl's anomaly. Am J Perinatol 1988; 5 : 164-L

(36.) James TN. Normal and abnormal consequences of apoptosis in the human heart. From postnatal morphogenesis to paroxysmal arrhythmias. Circulation 1994; 90 : 556-13.

(37.) Sen-Chowdhry S, Syrris P, McKenna WJ. Genetics of right ventricular cardiomyopathy. J Cardiovasc Electrophysiol 2005; 16 : 921-35.

(38.) Garcia Gras E, Lombardi R, Giocondo MJ, Willerson JT, Schneider MD, Khoury DS, et al. Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy. J Clin Invest 2006; 116 : 2012-21.

(39.) Lisovsky M, Itoh K, Sokol SY. Frizzled receptors activate a novel JNK-dependent pathway that may lead to apoptosis. Curr Biol 2002; 12 : 53-8.

(40.) Mallat Z, Tedgui A, Fontaliran F, Frank K, Durigon M, Fontaine G. Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 1996; 335 : 1190-6.

(41.) Kinoshita O, Kamakura S, Ohe T, Aihara N, Takaki H, Kurita T, et al. Frequency analysis of signal-averaged electrocardiogram in patients with right ventricular tachycardia. J Am Coll Cardiol 1992; 20 : 1230-1.

(42.) Lerman BB, Stein KM, Markowitz SM, Mittal S, Slotwiner DJ. Recent advances in right ventricular outflow tract tachycardia. Card Electrophysiol Rev 1999; 3 : 210-4.

(43.) Bauce B, Basso C, Rampazzo A, Beffagna G, Daliento L, Frigo GF, et al. Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations. Eur Heart J 2005; 26 : 1666-15.

(44.) Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004; 18 : 816-2L

(45.) Kapoun AM, Liang F, O'Young G, Damm DL, Quon D, White RT, et al. B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ Res 2004; 94 : 453-61.

(46.) Tiso N, Stephan DA, Nava A, BagattinA, Devaney JM, Stanchi F, et al. Identification of mutations in the cardiac ryanodin receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2). Hum Mol Genet 2001; 10 : 189-94.

(47.) Lemay DG, Hwang DH. Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics. J Lipid Res 2006; 47 : 1583-L

(48.) Rampazzo A, Nava A, Malacrida S, Beffagna G, Bauce B, Rossi V, et al. Mutation in human desmoplakin domain binding to plakoglobin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2002; 71 : 1200-6.

(49.) Norman M, Simpson M, Mogensen J, Shaw A, Hughes S, Syrris P, et al. Novel mutation in desmoplakin causes arrhythmogenic left ventricular cardiomyopathy. Circulation 2005; 112 : 636-42.

(50.) Tsatsopoulou AA, Protonotarios NI, McKenna WJ. Arrhythmogenic right ventricular dysplasia, a cell adhesion cardiomyopathy: insights into disease pathogenesis from preliminary genotype-phenotype assessment. Heart 2006; 92 : 1120-3.

(51.) De Pasquale CG, Heddle WF. Left sided arrhythmogenic ventricular dysplasia in siblings. Heart 2001; 86 : 128-30.

(52.) Suzuki H, Sumiyoshi M, Kawai S, Takagi A, WadaA, Nakazato Y, et al. Arrhythmogenic right ventricular cardiomyopathy with an initial manifestation of severe left ventricular impairment and normal contraction of the right ventricle. Jpn Circ J 2000; 64 : 209-13.

(53.) Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, et al. Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 2004; 36 : 1162-4.

(54.) Pilichou K, Nava A, Basso C, Beffagna G, Bauce B, Lorenzon A, et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006; 113 : 11H-9.

(55.) Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 2006; 79 : 918-84.

(56.) McKoy G, Protonotarios N, Crosby A, Tsatsopoulou A, Anastasakis A, Coonar A, et al. Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000; 355 : 2119-24.

(57.) Zhurinsky J, Shtutman M, Ben-Ze'ev A. Plakoglobin and [beta]-catenin: protein interactions, regulation and biological roles. J Cell Sci 2000; 113 : 3121-9.

(58.) Hakimelahi S, Parker HR, Gilchrist AJ, Barry M, Li Z, Bleackley RC, et al. Plakoglobin regulates the expression of the anti-apoptotic protein BCL-2. J Biol Chem; 275 : 10905-11.

(59.) 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 : 129-33.

(60.) Corrado D, Basso C, Thiene G, McKenna WJ, Davies MJ, Fontaliran F, et al. Spectrum ofclinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study. J Am Coll Cardiol 1991; 30 : 1512-20.

(61.) Maron BJ, Shirani J, Poliac LC, Mathenge R, Roberts WC, Mueller FO. Sudden death in young competitive athletes. Clinical, demographic, and pathological profiles. JAMA 1996; 276 : 199-204.

(62.) Tabib A, Loire R, Chalabreysse L, Meyronnet D, Miras A, Malicier D, et al. Circumstances of death and gross and microscopic observations in a series of 200 cases of sudden death associated with arrhythmogenic right ventricular cardiomyopathy and/or dysplasia. Circulation 2003; 108 : 3000-5.

(63.) Hulot JS, Jouven X, Empana JP, Frank R, Fontaine G. Natural history and risk stratification of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circulation 2004; 110 : 1819-84.

(64.) Ozben B, Altun I, Sabri Hancer V, Bilge AK, Tanrikulu AM, Diz-Kucukkaya R, et al. Angiotensin-converting enzyme gene polymorphism in arrhythmogenic right ventricular dysplasia: is DD genotype helpful in predicting syncope risk? J Renin Angiotensin Aldosterone Syst 2008; 9 : 215-20.

(65.) Dalal D, Molin LH, Piccini J, Tichnell C, James C, Bomma C, et al. Clinical features of arrhythmogenic right ventricular dysplasia/cardiomyopathy associated with mutations in plakophilin-2. Circulation 2006; 113 : 1641-9.

(66.) McKenna WJ, Thiene G, Nava A, Fontaliran F, Blomstrom-Lundqvist C, Fontaine G, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J 1994; 71 : 215-8.

(67.) Syrris P, Ward D, Evans A, Asimaki A, Gandjbakhch E, Sen-Chowdhry S, et al. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy associated with mutations in the desmosomal gene desmocollin-2. Am J Hum Genet 2006; 79 : 918-84.

(68.) Awad MM, Dalal D, Cho E, Amat-Alarcon N, James C, Tichnell C, et al. DSG2 mutations contribute to arrhythmogenic right ventricular dysplasia/cardiomyopathy. Am J Hum Genet 2006; 79 : 136-42.

(69.) Hamid MS, Norman M, Quraishi A, Firoozi S, Thaman R, Gimeno JR, et al. Prospective evaluation of relatives for familial arrhythmogenic right ventricular cardiomyopathy/dysplasia reveals a need to broaden diagnostic criteria. J Am Coll Cardiol 2002; 40 : 1455-50.

(70.) Peters S, Gotting B, Peters H. Localized right precordial QRS prolongation as the basic ECG finding in arrhythmogenic right ventricular dysplasia cardiomyopathy. Ann Noninvasive Electrocardiol 1999; 4 : 4-9.

(71.) Fontaine G, Fontaliran F, Hebert JL, Chemla D, Zenati O, Lecarpentier Y, et al. Arrhythmogenic right ventricular dysplasia. Annu Rev Med 1999; 50 : H-35.

(72.) Beffagna G, Occhi G, Nava A, Vitiello L, Ditadi A, Basso C, et al. Regulatory mutations in transforming growth factor beta3gene cause arrhythmogenic right ventricular cardiomyopathy type 1. Cardiovasc Res 2005; 65 : 366-13.

(73.) Turrini P, Angelini A, Thiene G, Buja G, Daliento L, Rizzoli G, et al. Late potentials and ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy. Am J Cardiol 1999; 83 : 1214-9.

(74.) Amlie JP. Increased dispersion of repolarization in patients with arrhythmogenic right ventricular dysplasia--a major electrophysiological factor responsible for malignant ventricular arrhythmias. Eur Heart J 1999; 20 : 103-5.

(75.) Fontaine G, Fontaliran F, Frank R, Lascault G, Tonet J, Tchoubrieva J, et al. Arrhythmogenic right ventricular dysplasia. A new clinical entity. Bull Acad Natl Med 1993; 177 : 501-12.

(76.) Fontaine G, Frank R, Tonet JL, Guiraudon G, Cabrol C, Chomette G, et al. Arrhythmogenic right ventricular dysplasia: a clinical model for the study of chronic ventricular tachycardia. Jpn Circ J 1984; 48 : 515-38.

(77.) Marcus FI, Fontaine GH, Guiraudon G, Frank R, Laurenceau JL, Malergue C, et al. Y. Right ventricular dysplasia: a report of 24 adult cases. Circulation 1982; 65 : 384-98.

(78.) Turrini P, Corrado D, Basso C, Nava A, Bauce B, Thiene G. Dispersion of ventricular depolarisation-repolarisation : A noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy. Circulation 2001; 103 : 3015-80.

(79.) Wlodarska EK, Konka M, Zaleska T, Ploski R, Cedro K, Pucilowska B, et al. Arrhythmogenic right ventricular cardiomyopathy in two pairs of monozygotic twins. Int J Cardiol 2005; 105 : 126-33.

Pranathi R. Pamuru, Maithili V.N. Dokuparthi, Sushant Remersu *, Narasimhan Calambur ** & Pratibha Nallari

Department of Genetics, Osmania University, Hyderabad, * Kakatiya Medical College, Warangal & ** Cardiology Care Hospital, The Institute of Medical Sciences, Hyderabad, India

Reprint requests: Dr Pratibha Nallari, Professor, Department of Genetics, Osmania University, Hyderabad 500 001, India e-mail: prathinallari@yahoo.com.
Table I. Clinical expressions of the RVOT VT and ARVD/C

 RVOT VT

Age at onset Third or fifth decade of life
Sex Females predominantly
Family history -
Reports of SCD -
12 lead ECG Normal

SAECG Normal
ECHO Normal

Arrhythmias PVCs, repetitive monomorphic
 VT, induced / sustained VT
Origin of arrhythmia Septum
Mechanism of arrhythmia cAMP mediated triggered activity
BNP levels Normal

 ARVD/C

Age at onset Third or fourth decade of life
Sex Males predominantly
Family history +
Reports of SCD +
12 lead ECG -T wave inversion in precodial
 leads from V1 - V5
 - Prolongation of QRS complex in
 leads V1 or V2
 - [epsilon] waves observed
SAECG Late potentials observed
ECHO Structural and wall motion
 abnormalities of RV
Arrhythmias PVCs, SVT, NSVT, VF

Origin of arrhythmia Parietal wall
Mechanism of arrhythmia Reentrant mechanism
BNP levels Increased

SCD, sudden cardiac death; ECG, electrocardiogram; SA ECG, signal
averaged ECG; ECHO, echocardiography; BNP, brain natriuretic
peptide; PVC, polymorphic ventricular complex; SVT, sustained
ventricular tachycardiac; NSVT, non sustained VT; VF, ventricular
fibrillation

Table II. Genes involved in different types of ARVD/Cs and their
clinical manifestations

Gene TGF[beta]-3 Desmoplakin

Ventricul NSVA SVT, NSVT, PVC and
Arrhythmias VF
ECG - T-wave inversion in - T wave inversion from
 precordial leads V1-V4 V1-V5
 - Prolongation of QRS in
 V1, V2 or V3
 - incomplete RBBB
 - ST elevation
 - QTS dispersion
 - [epsilon] waves
SAECG + +
ECHO - Trabecular - RV kinetic alteration
 disarrangement and RV - RV severely dilated
 dyskinesia at apex with trabecular
 - Moderate disarrangement
dilation of RV - LV involved with regional wall with
 localized motion kinetic abnormalities
 abnormality both diffuse and
 localized
RBBB not known +
Structural Only RV, no LV RV and LV
progression involvement reported
Family history + +
Biopsy/Autopsy - Extensive replacement - Myocardial atrophy
 type fibrous and fatty with transmural
 Infiltration fibrofatty tissue
 - Surviving myocytes replacement in the
 entrapped within fibrous walls of both RV and
 and fatty tissue LV
 - Myocytosis and
 lymphocytic
 inflammatory
 infiltrates
Diagnostic Not fulfilled Not fulfilled
criteria

Gene Plakophilin-2 Desmoglein-2

Ventricul SVT, NSVT, PVC and SVT, NSVT, PVC and
Arrhythmias VF VF
ECG - T wave inversion - T wave inversion from
 - Prolongation of QRS V1-V5
 - PQ Prolongation
 - Low voltages of QRS
 - Complete RBBB
 - [epsilon] waves

SAECG + +
ECHO - RV enlargement with - RV kinetic abnormality
 poor systolic function - LV involvement
 - Minor and localized with LV kinetic
 motion abnormalities abnormalities both
dilation of RV - Aneurismal segment in diffuse
 RVOT

RBBB + +
Structural RV and LV, RV and LV
progression predominantly RV
Family history + +
Biopsy/Autopsy - Infiltration of RV by - Myocardial atrophy
 fat with presence of with replacement type
 surviving strands of - Fibrosis and mild
 cardiomyocytes infiltration

Diagnostic Not fulfilled Not fulfilled
criteria

Gene Desmocollin-2 Plakoglobin

Ventricul NSVT with LBBB SVT
Arrhythmias morphology
ECG - T wave inversion - T wave inversion
 from V1 -V6 from V1-V3
 - [epsilon] waves - Prolonagtion of QRS
 - complete/ incomplete
 RBBB
 - [epsilon] waves

SAECG not known not known
ECHO - Severely dilated - Mild to severe RV
 hypokinetic RV with dilation
 diastolic bulging and - Regional/ diffuse
 disarrangement hypokinesia
dilation of RV - LV abnormalities

RBBB not known +
Structural RV and LV, Biventricular
progression predominantly LV involvement
Family history + -
Biopsy/Autopsy Extensive fibrofatty - Fibrofatty infiltration
 replacement of RV of RV and LV
 myocardium myocardium
 -Surviving myocytes
 surrounded by
 fibrosis embedded
 fatty tissue

Diagnostic Not fulfilled Fulfilled
criteria

Table III. Clinical findings of ARVD/C and ALVC

 ARVD/C

ECG -- Negative T-waves in precordial leads
 -- QRS prolongation in V1, V2 or V3
 -- Incomplete RBBB
 -- ST segment elevated
 -- Low QRS voltages in peripheral leads
 -- QRS dispersion (> 20 ms)
 -- Presence of e waves
SAECG Late potentials observed
Ventricular arrhythmias VF, SVT, NSVT, PVCs
ECHO --Mild to severe RVdilation with kinetic
 abnormality
 --LV involvement with kinetic
 Abnormality both diffuse and localized
Biopsy/Autopsy RV dilation with extensive replacement
 type fibrosis and fatty infiltration

 ALVC

ECG -- Inverted T waves in inferior and
 lateral leads
 -- Abnormal Q waves in the leads V5, V6,
 I and aVL, left axis deviation
 -- PVCs of LBBB pattern
SAECG Late potentials observed
Ventricular arrhythmias VF, SVT, NSVT, PVCs
ECHO -- LV dilation
 -- Diffuse and severe hypokinesis of the
 LV with no abnormalities of the RV
Biopsy/Autopsy LV dilation with focal areas of fibrosis
 and fatty infiltration

ECG, electrocardiography; LBBB, left bundle branch block; VF,
ventricular fibrillation; SVT, sustained ventricular tachycardia; NSVT,
non-sustained ventricular tachycardia; PVCs, poly ventricular complexes
COPYRIGHT 2010 Indian Council of Medical Research
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2010 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Pamuru, Pranathi R.; Dokuparthi, Maithili V.N.; Remersu, Sushant; Calambur, Narasimhan; Nallari, Pra
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Jan 1, 2010
Words:7060
Previous Article:Hepatitis C virus: molecular biology & current therapeutic options.
Next Article:Prevalence of metabolic syndrome in psychiatric inpatients in a tertiary care centre in north India.
Topics:

Terms of use | Privacy policy | Copyright © 2021 Farlex, Inc. | Feedback | For webmasters