Spectrum of clinicopathologic manifestations of arrhythmogenic right ventricular cardiomyopathy/dysplasia: a multicenter study

OBJECTIVES: The aim of the present investigation was to redefine the clinicopathologic profile of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), with special reference to disease progression and left ventricular (LV) involvement. BACKGROUND: Long-term follow-up data from clinical studies indicate that ARVC is a progressive heart muscle disease that with time may lead to more diffuse right ventricular (RV) involvement and LV abnormalities and culminate in heart failure. METHODS: Forty-two patients (27 male, 15 female; 9 to 65 years old, mean [+/-SD] age 29.6 +/- 18) from six collaborative medical centers, with a pathologic diagnosis of ARVC at autopsy or heart transplantation, and with the whole heart available, were studied according to a specific clinicomorphologic protocol. RESULTS: Thirty-four patients died suddenly (16 during effort); 4 underwent heart transplantation; 2 died as a result of advanced heart failure; and 2 died of other causes. Sudden death was the first sign of disease in 12 patients; the other 30 had palpitations, with syncope in 11, heart failure in 8 and stroke in 3. Twenty-seven patients experienced ventricular arrhythmias (ventricular tachycardia in 17), and 5 received a pacemaker. Ten patients had isolated RV involvement (group A); the remaining 32 (76%) also had fibrofatty LV involvement that was observed histologically only in 15 (group B) and histologically and macroscopically in 17 (group C). Patients in group C were significantly older than those in groups A and B (39 +/- 15 years vs. 20 +/- 8.8 and 25 +/- 9.7 years, respectively), had significantly longer clinical follow-up (9.3 +/- 7.3 years vs. 1.2 +/- 2.1 and 3.4 +/- 2.2 years, respectively) and developed heart failure significantly more often (47% vs. 0 and 0, respectively). Patients in groups B and C had warning symptoms (80% and 87%, respectively, vs. 30%) and clinical ventricular arrhythmias (73% and 82%, respectively, vs. 20%) significantly more often than patients in group A. Hearts from patients in group C weighed significantly more than those from patients in groups A and B (500 +/- 150 g vs. 328 +/- 40 and 380 +/- 95 g, respectively), whereas hearts from both group B and C patients had severe RV thinning (87% and 71%, respectively, vs. 20%) and inflammatory infiltrates (73% and 88%, respectively, vs. 30%) significantly more often than those from group A patients. CONCLUSIONS: LV involvement was found in 76% of hearts with ARVC, was age dependent and was associated with clinical arrhythmic events, more severe cardiomegaly, inflammatory infiltrates and heart failure. ARVC can no longer be regarded as an isolated disease of the right ventricle.     

Value of tomoscintigraphy with Fourier analysis in the diagnosis of arrhythmogenic right ventricular cardiomyopathy

ECG gated blood pool tomography has been performed in sixteen patients with right ventricular arrhythmias in whom the diagnosis of arrhythmogenic right ventricular cardiomyopathy was made based on the finding of abnormalities on contrast angiography. They were compared both to control subjects and to patients with primary dilated cardiomyopathy. Thick slices of ventricles were obtained throughout the cardiac cycle in three orthogonal planes: horizontal long axis and short axis thick slices for analysis of right and left ventricular regional wall motion abnormalities and analysis of the spread of the contraction by means of Fourier phase imaging, vertical long axis slices (one for each ventricle) for ejection fractions, because of easy and reproducible determination of valvular planes and analysis of all right ventricular segments, especially the pulmonary infundibulum. Five typical right ventricular abnormalities were seen: decreased ejection fraction (32 +/- 15% vs 55 +/- 3% in control; p < 0.001), increased diameter (ratio of right to left diameters = 1.2 +/- 0.3 vs 0.9 +/- 0.1; p < 0.01), global delayed contraction versus that of the left ventricle (22 +/- 20 degrees vs -2 +/- 6%; p < 0.01), increased dispersion of contraction (32 +/- 16 degrees vs 13 +/- 4 degrees; p < 0.01) and presence of segments with decreased and/or delayed contraction. Right ventricular disease was observed in all the patients: localized form (56%), diffused form (44%). This method provides accurate functional data for diagnosis and follow-up of patients. In future, this wall motion evaluation method may replace planar nuclear angiography as myocardial SPECT have replaced myocardial planar scintigraphy.     

Diagnosis of arrhythmogenic right ventricular cardiomyopathy by fourier analysis of gated blood pool single-photon emission tomography

OBJECTIVES: To investigate the effect of frequency of alternating current on electrically induced torque in healthy subjects, and to establish an optimum frequency for motor stimulation. DESIGN: A repeated-measures design using 12 subjects (part 1) and 3 subjects (part 2). SETTING: A laboratory setting was used. PARTICIPANTS: Participants were volunteers who met the inclusion criteria. INTERVENTIONS: Alternating current with carrier frequencies between 1 and 15kHz, modulated at 50Hz, was applied to each subject on two separate occasions. The frequencies were applied in a different random order on each occasion and different random orders were used between subjects. For part 1 of this study, six frequencies were used: 1, 2, 4, 7, 10, and 15kHz. For part 2, three frequencies were used: 1, 4, and 10kHz. MAIN OUTCOME MEASURES: Part 1: The maximum electrically induced torque, defined as the torque induced at the pain threshold, was recorded for each applied frequency. Part 2: The variation of torque with increasing stimulus intensity was recorded for each applied frequency. RESULTS: Highest electrically induced torque was produced at the lowest frequency examined (1kHz). Torque decreased systematically with increasing frequency over the frequency range examined. The rate of increase in torque with applied stimulus intensity was also found to decrease systematically with increasing frequency in a way that depended strongly on the skinfold thickness of the subject. CONCLUSIONS: Electrical stimulators using an alternating current waveform typically use a carrier frequency in the range of 2kHz to 4kHz for motor stimulation. This study shows that carrier frequencies in this range, modulated at 50Hz, are a compromise between comfort and maximum torque production. For maximum comfort with a low torque, a frequency close to 10kHz is indicated. For maximum torque, a lower frequency of alternating current (1kHz or less) is preferable.     

Arrhythmogenic right ventricular dysplasia/cardiomyopathy: review for the clinician

The objectives of this study were to measure the proliferation indices in canine mammary tumors using immunohistochemical detection of Ki-67 and proliferating cell nuclear antigen (PCNA), to determine the relationship of these antigens to clinical and pathologic variables, and to investigate the usefulness of these antigens as prognostic indicators. Ninety-six female dogs with 115 primary nonmetastasized spontaneous mammary tumors and dysplasias were included in the study. Immunostaining was performed using MIB-1 and PC10 monoclonal antibodies against Ki-67 and PCNA, respectively. Ki-67 and PCNA proliferation indices were determined. Dogs were followed for 18 months, with clinical examinations every 3-4 months. There was a significant correlation between Ki-67 and PCNA indices in the dogs with dysplasias and benign tumors but not in the dogs with malignant tumors. The clinical stage at first presentation was related to the proliferative index measured with Ki-67 but not to that measured with PCNA. Proliferation indices were significantly lower in the nonmalignant tumors and dysplasias than in the malignant tumors. In malignant tumors, the PCNA index had a positive correlation with the histologic malignant grade and the nuclear grade. High index values of Ki-67 were positively correlated with metastasis, death from neoplasia, low disease-free survival rates, and low overall survival rates. PCNA displayed no significant association with these variables. Multivariate analyses concerning metastasis, disease-free survival, and overall survival revealed that the Ki-67 index had prognostic value.     

Left ventricular lesions in arrhythmogenic right ventricular dysplasia and 12-lead electrocardiographic findings

Left ventricular lesions in arrhythmogenic right ventricular dysplasia have not been well described, and the relationship between the left ventricular lesions and the 12-lead electrocardiographic findings has not been analyzed. This study examined whether the presence of left ventricular lesions and the extent of right ventricular lesions due to arrhythmogenic right ventricular dysplasia are predictable by 12-lead electrocardiographic findings. The 12-lead electrocardiograms during sinus rhythm and left and right ventriculography were studied in 29 patients (27 males and 2 females, mean age 42.6 +/- 15.5 years) diagnosed by the current criteria for this disease. After evaluation, patients were divided into two groups: those with normal left ventricles (normal group) and those with left ventricular wall motion abnormalities (abnormal group). Seventeen of the 29 patients (59%) were classified into the abnormal group. Left ventricular wall motion abnormalities were located in the posterolateral (4 patients), apical (1), and posterolateral and apical regions (12). QS patterns of abnormal Q waves in lead I, aVL or V5, V6 rS patterns (R/S ratio < 1) in leads I and V6, and/or R or Rs patterns (R/S ratio > 1) in lead V1 were observed in all patients in the abnormal group, but in none in the normal group. There was a positive correlation between the right ventricular end-diastolic volume index and the number of precordial negative T waves (r = 0.746, p < 0.0001), and the time from onset of the QRS to the terminal portion of the epsilon wave in lead V1 (r = 0.627, p < 0.001). The correlation coefficients showed no significant differences between the groups. A left ventricular lesion associated with arrhythmogenic right ventricular dysplasia was not unusual (59%), and our study suggests that the posterolateral and apical regions are the most frequent sites. The presence of these lesions were predictable by the QRS abnormalities. Moreover, regardless of the presence of such a lesion, the extent of the right ventricular lesion is also predictable by the 12-lead electrocardiographic findings.     

Arrhythmogenic right ventricular cardiomyopathy associated with multiple right atrial thrombi

The authors report the case of an arrhythmogen right ventricular cardiomyopathy. The disease is characterised by the partial or total loss and the fibro-fatty replacement of right ventricular musculature and by the higher familiar incidence. The clinical importance of the disease is the malignant ventricular arrhythmia generated in the right ventricular wall, that is often fatal. Right heart failure is less frequent and develops mainly preterminally. The curiosity of this case is right atrial and ventricular thrombi diagnostized concomitantly with progressive heart failure. This combination is a rarity in medical literature, in contrast with the disease itself, as it was previously supposed. Early diagnosis, pharmacological and non-pharmacological treatment can reduce the fatal outcome.     

Gene for arrhythmogenic right ventricular cardiomyopathy with diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart muscle disease of unknown etiology that causes arrhythmias, heart failure, and sudden death. Diagnosis can be difficult, and this hampers investigation of its molecular basis. Forms of ARVC in which gene penetrance and disease expression are greater should facilitate genetic study. We undertook a clinical and genetic investigation of Naxos disease, originally described by Protonotarios in 1986. This disease constitutes the triad of ARVC, diffuse nonepidermolytic palmoplantar keratoderma, and woolly hair. METHODS AND RESULTS: We evaluated the population of Naxos, Greece, to identify probands, which was followed by family screening. Twenty-one affected persons from 9 families of 150 persons were identified. Linkage analysis was performed with microsatellite markers. The disease locus mapped to 17q21. A peak 2-point LOD score of 3.62 at theta=0.0 was found with a marker within intron 4 of the keratin 9 gene, a member of the type I (acidic) keratin family. A preserved homozygous disease haplotype was identified. Haplotype analysis delimited the disease interval. CONCLUSIONS: Hair and skin abnormalities were found to be reliable markers of subsequent heart disease. This suggests the presence of a single mutant gene with novel cardiac, skin, and hair function or two or more tightly linked disease genes. Recessive inheritance of Naxos disease and a founder effect were demonstrated. Identification of a fully informative genetic marker linked to the disease and uncommon in the background population may be of use as a test to identify disease gene carriers.     

Right precordial leads and sudden death. Relation with arrhythmogenic right ventricular dysplasia

Non-coronary ST-segment elevation during right sided chest pain has been described in subjects with episodes of ventricular fibrillation at rest. This syndrome has been attributed to functional phenomena or to structural myocardial changes. A personal case has features belonging to two categories: ST-segment elevation observed before, during and after episodes of arrhythmia was compared to 11 previously recorded ECG recordings. Right ventricular dysplasia was shown by electrocardiography, electrophysiology and echocardiography. In addition, ST-segment elevation is classified in 3 categories: triangular and dome-shaped are the most commonly observed forms during the arrhythmias: the third form with "saddle"-shaped appearances has not been previously described and would seem to be a minor equivalent observed during intercritical periods. This form is found in 30% of clinically documented cases of arrhythmogenic right ventricular dysplasia.     

Arrhythmogenic right ventricular cardiomyopathy. Etiology, diagnosis and therapy

In the fungus Neurospora crassa, the chol-1 mutation blocks the synthesis of the lipid phosphatidylcholine and also lengthens the period of the circadian rhythm of conidiation under conditions of choline depletion. The frq mutations, which have no known metabolic defect, affect both the period of the rhythm and temperature compensation. In this article, the chol-1 mutant strain has been further characterized with respect to its temperature compensation and its interactions with frq. Choline depletion of chol-1 abolishes good temperature compensation: Low temperatures lengthen the period under choline-depleted conditions, and low choline lengthens the period at any one temperature. Double-mutant strains carrying both chol-1 and one of a series of frq alleles demonstrate interactions between chol-1 and frq: On high choline, the periods of the double mutants are identical to the corresponding chol+ strains, whereas on low choline all double mutants display very long periods (greater than 50 h). Short-period frq mutations shorten the long period on low choline, whereas long-period frq mutations frq mutations have no effect. A null frq mutation in the chol-1 background is arrhythmic on high choline but is robustly rhythmic on low choline and has no effect on the long period. The interactions between frq and chol-1 are similar to the interactions between frq and cel, another lipid-deficient mutant. These results provide support for the hypothesis that membrane lipids may be involved in temperature compensation of the circadian rhythm. The possibility is discussed that the frq gene may not be required for circadian rhythmicity under some conditions and therefore may not be a central component of the circadian oscillator but rather a component of an input pathway.     

Localization of a gene responsible for arrhythmogenic right ventricular dysplasia to chromosome 3p23

BACKGROUND: Arrhythmogenic right ventricular dysplasia (ARVD), a familial cardiomyopathy occurring with a prevalence of 1 in 5000, is characterized by replacement of myocytes with fatty and fibrous tissue. Clinical manifestations include structural and functional abnormalities of the right ventricle and arrhythmias, leading to a sudden death rate of 2.5% per year. Four loci have been mapped, but no gene has been identified as yet. METHODS AND RESULTS: We identified a large family of >200 members with ARVD segregating as an autosomal dominant trait affecting 10 living individuals. The diagnosis of ARVD was based on international diagnostic criteria including history, physical examination, ECG, echocardiogram, right ventricular angiogram, endomyocardial biopsy, and 24-hour ambulatory ECG. Blood was collected for DNA from 149 family members. Analysis of 257 polymorphic microsatellite markers by genetic linkage excluded previously known loci for ARVD and identified a novel locus at 3p23. Analysis of an additional 20 markers further defined the region. A peak logarithm of the odds score of 6.91 was obtained with marker D3S3613 at theta=0% recombination. Haplotype analysis identified a shared region between markers D3S3610 and D3S3659 of 9. 3 cM. CONCLUSIONS: A novel locus for ARVD has been mapped to 3p23 and the region narrowed to 9.3 cM. Identification of the gene will allow genetic screening and a specific diagnosis for a disease with protean nonspecific findings. It should also provide insight fundamental to understanding cardiac chamber-specific gene expression and/or the mechanism of myocyte apoptosis observed in this disease.     

Polypoid ulcerating endocarditis aortalis caused by Streptococcus viridans with perforation of the right atrium. Pathology and clinical aspects of 2 autopsy cases

We report two cases of patients (one 65 and one 43 years of age, respectively) who died of Streptococcus-viridans induced endocarditis of the aortic valve with perforation into the right atrium. Whereas perforation in Staphylococcus-induced endocarditis is a common complication, it occurs rarely in Streptococcus-induced endocarditis. Because of its uncharacteristic symptoms, the endocarditis was clinically unknown in both cases and was recognized to be the cause of death only at autopsy. To reduce the large number of complications in patients suffering from endocarditis, it is necessary to confirm the diagnosis as soon as possible if endocarditis might be suspected.     

Radiofrequency current caused slowing of non-reentrant idiopathic right ventricular tachycardia originating from a wide arrhythmogenic area

Radiofrequency catheter ablation was attempted in a patient with non-reentrant idiopathic right ventricular tachycardia (VT). Endocardial mapping indicated that the VT originated in the outflow tract of the right ventricle; however, an electrogram with an almost the identical activation time was recorded from an area extending to 1.0 x 2.0 cm. Each application of radiofrequency current within the area terminated VT, but a progressively slower VT with the same QRS configuration was induced until the area was covered by separate radiofrequency lesions. A progressive prolongation of VT cycle length might be related to a residual arrhythmogenic myocardium. Termination and slowing of the VT rate can be a hallmark of efficacy of each radiofrequency lesion.     

Arrhythmogenic right ventricular cardiomyopathy underlies syndrome of right bundle branch block, ST-segment elevation, and sudden death

In all experimental mammals tested (rats, dogs, primates), intramuscular injections of the oil-soluble antimalarial artemisinin derivatives artemether and arteether have produced an unusual pattern of selective damage to brain stem centers predominantly involved in auditory processing and vestibular reflexes. Artesunate, the most widely used of these compounds, is a water soluble hemisuccinate derivative given parenterally either by intravenous or intramuscular injection. The neurotoxic potential of parenteral artesunate and artemether was compared in a murine model. Adult Swiss albino mice were assigned randomly to 28-day regimens of intramuscular artemether or artesunate in doses ranging from 30 to 100 mg/kg/day. At 30 mg/kg/day, no abnormalities were detected with either drug. At 50 mg/kg/day, abnormalities were observed in six of 12 artemether recipients and two of 12 artesunate recipients. These were reversible in all but one (artemether) mouse. At 100 mg/kg/day, eight of 36 artemether recipients, two of 36 artesunate recipients, and one of 18 control mice died. All but four surviving mice in the artemether group (86%) showed obvious and usually irreversible abnormalities of balance and equilibrium, whereas only four artesunate recipients (11%) exhibited abnormalities, and these were reversible in each case (P < 0.001). At this dose the relative risk (95% confidence interval) for death or disability was 5.3 (2.6-11.2) for artemether recipients. Intramuscular artemether is significantly more neurotoxic than intramuscular artesunate in this murine model.     

A morphological study of human epipharyngeal mucosa: 10 autopsy cases

The epipharynx lies between the nasal cavity and the mesopharynx, which is behind the oral cavity. It is a conduit for respired air, contributes to the equalization of pressure within the middle ear space via the eustachian tube and is closed by the soft palate during swallowing of food and fluid. It acts as a drainage channel for the mucous secreted by the nose and the glands within the epipharynx area. Various exchanges of the epipharyngeal mucosa occur because of the function of the epipharynx. In this study, distribution of the 3 types of epithelium in the epipharynx, which are ciliated, transitional and squamous epithelium, was investigated. The specimens of the mucosa with the bony wall of the epipharynx were collected from 10 autopsy cadavers at, (6 males and 4 females, aged from 37 to 83 years). Distribution of the 3 types of epithelium differed with the type, but there was no marked difference between the right and left halves of the epipharynx. Therefore, the distribution pattern was investigated by drawing superimposed geographical schemata of the epithelia, which were confirmed histologically in all 10 cases. The results obtained were as follows. On the superior-posterior wall, the squamous epithelium was invaginated into an area of the ciliated epithelium just like islands or bands in the nasal side and the epithelia of all 3 types were mixed in the mesopharyngeal side. The lateral wall was covered with a mixture of ciliated and transitional epithelia on the nasal side from the posterior lip of the eustachian tube and with a mixture of transitional and squamous epithelia on its mesopharyngeal side. The inferior wall was covered mostly with ciliated epithelium on the nasal side and with squamous epithelium on the mesopharyngeal side from Passavant's ridge. The transitional epithelium was distributed like an island between the areas of the ciliated and squamous epithelia in the lateral wall. The clearly definite schema of the 3 types of epithelium in the epipharynx, reported by Ali, has been generally accepted. However, the 3 types appeared as a mosaic or an island in the epipharyngeal wall and their distribution pattern was different in each individual.