Arrhythmogenic right ventricular cardiomyopathy. Contribution of cardiac magnetic resonance imaging to the diagnosis.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease of the heart muscle, mostly due to genetically defective desmosomal proteins. The disease is characterized by fibrofatty replacement leading to ventricular arrhythmias and sudden death in young people and athletes. There is no single clinical gold standard examination for making a definitive diagnosis. The diagnosis is based on multiple parameters, including: (1) global or regional dysfunction and structural alteration of the right ventricle demonstrated on imaging; (2) tissue characterization by endomyocardial biopsy; (3) repolarization and (4) depolarization electrocardiographic abnormalities; (5) arrhythmias; and (6) family history. The so-called phenocopies must be included in the differential diagnosis, always taking into account that there is no single criterion sufficiently specific for a reliable diagnosis of ARVC. Contrast-enhanced cardiac magnetic resonance imaging (CE-CMR) is not yet included in the revised diagnostic criteria, although this is the only imaging modality able to depict fibrosis as late gadolinium enhancement (LGE) deposition. This review analyzes the role of CMR imaging in the diagnostic work-up of ARVC. The lack of specific diagnostic criteria contributes to the under-recognition of the nonclassic variants of ARVC, i.e., dominant or isolated left ventricular disease.

Differences and similarities between arrhythmogenic right ventricular cardiomyopathy and athlete's heart adaptations.

BACKGROUND: Regular intensive physical activity is associated with non-pathological changes in cardiac morphology. Differential diagnosis with arrhythmogenic right ventricular cardiomyopathy (ARVC) constitutes a frequent problem, especially in athletes showing ventricular arrhythmias with left bundle branch block morphology. AIM OF THE STUDY: To assess the different clinical and non-invasive instrumental features of the subjects affected by ARVC and by athletes. METHODS: Three groups of subjects (40 ARVC patients, 40 athletes and 40 controls, mean age 27 (9) years) were examined with family and personal history, physical examination, 12-lead ECG, 24-h ECG, signal-averaged ECG and 2-D and Doppler echocardiography. RESULTS: 12-Lead ECG was abnormal in 62% of ARVC patients versus 7.5% of athletes and 2.5% of controls (p<0.0001). Ventricular arrhythmias and late potentials were present in 70% and 55% of ARVC subjects, respectively (vs 5% of athletes and 7.5% of controls, p<0.0001). Left ventricular parietal wall thickness and left ventricular end-diastolic diameters were significantly higher in athletes. Both athletes and ARVC patients presented a right ventricular (RV) enlargement compared with controls. Moreover, RV outflow tract, measured on parasternal long axis and at the level of aortic root, was significantly larger in ARVC patients (33.6 (4.7) mm vs 29.1 (3.4) mm and 35.6 (6.8) mm vs 30.1 (2.9) mm; p<0.0001), and RV fractional shortening and ejection fraction were significantly lower in ARVC patients compared with athletes (40 (7.9)% vs 44 (10)%; p=0.05 and 52.9 (8)% vs 59.9 (4.5)%; p<0.0001). A thickened moderator band was found to be present in similar percentage in ARVC patients and athletes. CONCLUSIONS: An accurate clinical and instrumental non-invasive evaluation including echocardiography as imaging technique allows to distinguish RV alterations typical of ARVC from those detected in athletes as a consequence of intensive physical activity.

Dispersion of ventricular depolarization-repolarization: a noninvasive marker for risk stratification in arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: We retrospectively investigated the value of clinical and ECG findings as well as QT-QRS dispersion in predicting the risk of sudden death in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: Duration and interlead variability of the QT interval and QRS complex were measured manually from standard ECGs in 20 sudden death victims with ARVC diagnosed at autopsy (group I), in 20 living ARVC patients with sustained ventricular tachycardia (group II), in 20 living ARVC patients with /=40 ms had a sensitivity and specificity of 90% and 77%, respectively; QT dispersion >65 ms, 85% and 75%, respectively; negative T wave beyond V(1), 85% and 42%, respectively; and syncope, 40% and 90%, respectively. CONCLUSIONS: QRS dispersion (>/=40 ms) was the strongest independent predictor of sudden death in ARVC. Syncope, QT dispersion >65 ms, and negative T wave beyond V(1) refined arrhythmic risk stratification in these patients.

Clinical profile and long-term follow-up of 37 families with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: We sought to define the clinical picture and natural history of familial arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy is a myocardial disease, often familial, clinically characterized by the impending risk of ventricular arrhythmias and sudden death. METHODS: Thirty-seven ARVC families of northeast Italy were studied. Probands had a histologic diagnosis of ARVC, either at autopsy (19 families) or endomyocardial biopsy (18 families). Protocol of the investigation included basal electrocardiogram (ECG), 24-hour ECG, signal-averaged ECG, stress test and two-dimensional Doppler echocardiography. Invasive evaluation was performed when deemed necessary. RESULTS: Of the 365 subjects, 151 (41%) were affected, 157 (43%) were unaffected, 17 (5%) were healthy carriers, and 40 (11%) were uncertain. Mean age at diagnosis was 31+/-13 years. By echocardiography, 64% had mild, 30% had moderate, and 6% had severe form. Forty percent had ventricular arrhythmias, 49 were treated with antiarrhythmic drugs, and two were treated with implantable cardioverter defibrillators. Sport activity was restricted in all. Of the 28 families who underwent linkage analysis, 6 mapped to chromosome 14q23-q24, 4 to 1q42-q43, and 4 to 2q32.1-q32.3. No linkage with known loci was found in four families and 10 had uninformative results. During a follow-up of 8.5+/-4.6 years, one patient died (0.08 patient/year mortality), and 15 developed an overt form of ARVC. CONCLUSIONS: Arrhythmogenic right ventricular cardiomyopathy is a progressive disease appearing during adolescence and early adulthood. Systematic evaluation of family members leads to early identification of ARVC, characterized by a broad clinical spectrum with a favorable outcome. In the setting of positive family history, even minor ECG and echocardiographic abnormalities are diagnostic.

Familial effort polymorphic ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy map to chromosome 1q42-43.

In the present study we report on another cause of an arrhythmia associated with familial arrhythmogenic right ventricular cardiomyopathy (ARVC), which is linked to chromosome 1q42-43. Two families with 48 subjects were studied with 12-lead electrocardiography, 24-hour ambulatory electrocardiography, chest x-ray, M-mode and 2-dimensional echocardiography, signal-averaging electrocardiography, and exercise stress testing. Six subjects also underwent right and left ventricular angiography and electrophysiologic study. An endomyocardial biopsy was performed in 1 subject. The genetic study included pedigree reconstruction and linkage analysis with polymorphic DNA markers. Five young subjects died suddenly during exercise; autopsy was performed in 3 and showed segmental fibro-fatty replacement of the right ventricle, mostly at the apex. Two of them experienced syncopal attacks during effort. Sixteen living subjects, without arrhythmias at rest had polymorphic ventricular arrhythmias during effort; ARVC was diagnosed in 15, whereas 1 did not have any demonstrable cardiac abnormality. The remaining family members were healthy and did not have arrhythmias. The linkage study assigned the disease locus to chromosome 1q42-q43, in close proximity to the alpha-actinin 2 locus (maximal lod score was 5.754 at theta = 0) with a 95% penetrance. Thus, these data suggest that effort-induced polymorphic ventricular arrhythmias and juvenile sudden death can be due to adrenergic stimulation in a particular genetic group of ARVC patients. In these cases the pathology was segmental, mostly localized to the right ventricular apex. Ventricular arrhythmias that are present in these families differ from the monomorphic ones that are usually seen in patients with ARVC.

Evolution of focal moderate (International Society for Heart and Lung Transplantation grade 2) rejection of the cardiac allograft.

BACKGROUND: In the absence of clinical evidence of cardiac allograft rejection, it is still poorly defined whether the International Society for Heart and Lung Transplantation biopsy grade 2 (e.g., focal moderate rejection) should be treated. Aim of the present study was to retrospectively investigate the evolution of focal moderate rejection, diagnosed during the first postoperative year in patients who had undergone orthotopic heart transplantation. METHODS: A retrospective analysis was conducted on 256 International Society for Heart and Lung Transplantation grade 2 biopsies from 110 orthotopic heart transplantations; 125 episodes occurred within the first 3 months (group 1), 131 later (group 2). For each grade 2 diagnosis, two biopsies, one immediately before and one after, were analyzed and classified as follows: lower (grade 0 or 1), equal (grade 2), or higher (grade 3 or 4). RESULTS: Evolution of grade 2 rejection was to a lower grade in 66% of cases, an equal grade in 16.8%, and a higher grade in 17.2%, with differences between group 1 and 2 (higher: 25% versus 10%, respectively, p = 0.005). Episodes which progressed into higher grades occurred earlier compared with those which persisted or resolved (9.2 +/- 8.6 weeks versus 20.0 +/- 15.6, p < 0.001). Five-year actuarial survival and incidence of graft coronary disease were similar in patients whose conditions progressed and those whose conditions did not. However, left ventricular ejection fraction at 1 and 2 years was lower in patients whose conditions progressed compared with those whose conditions persisted or resolved (56% +/- 4% versus 66% +/- 2%, p = 0.004; 56% +/- 10% versus 64% +/- 8%, p = 0.02, respectively). CONCLUSIONS: Progression of grade 2 rejection occurred in a minority of cases and did not affect 5-year survival or incidence of coronary disease, but its relationship with long-term cardiac allograft dysfunction warrants further investigation.

Factores que influyen en la prevalencia de patologías bucales de tejidos blandos y duros de niños y adolescentes: revisión de la literatura / Factors affecting the prevalence of oral soft tissue pathology and hard of children and teens: literature review

El objetivo de este trabajo es hacer una revisión bibliográfica del tema, con el fin de actualizar los conocimientos relativos al mismo, considerando las variables involucradas y presentar una propuesta de línea de investigación, ya que como señalan algunos autores la edad pediátrica es una etapa de crecimiento rápido, desarrollo, de múltiples aptitudes en los campos de las áreas motoras, de la inteligencia, del lenguaje, de la personalidad y de la emocionalidad, por lo que constituye una edad crucial que requiere ser atendida eficazmente en la prevención de sus múltiples aspectos. La Organización Mundial de la Salud, (OMS), ha incrementado las recomendaciones epidemiológicas en los últimos años a este grupo poblacional, además los signos y síntomas de la mucosa bucal de los infantes pueden cambiar con la edad y son a menudo diferentes a las del adulto. Metodología: Se revisaron 34 publicaciones en revistas especializadas, todas referidas a escolares con edades comprendidas entre 6 y 14 años, aunque algunos se refieren a edades puntuales. Resultados: las patologías de los adolescentes difieren de la de los adultos, aunque existen pocas referencias; no hay acción definida en los planes y proyectos nacionales ni regionales para esta población; la mayoría de las patologías que ocurren en la cavidad bucal de esta población, son relativamente inocuas, no necesitan tratamiento, presentándose de forma asintomática y limitándose al desarrollo cronológico del niño. Conclusión: definir una línea de investigación, e incorporar la población de niños, niñas y adolescentes, por cuanto en Venezuela y América Latina, la investigación en esta área es limitada

The goal is to make a literature review of the subject, in order to update the knowledge relating to the subject, considering the variables involved and submit a proposal for a line of research, as some authors point out the Pediatric is rapid growth, development of multiple skills in the fields of motor areas, intelligence, language, personality and emotionality, for what constitutes a crucial age requiring to be dealt with effectively in the prevention of its multiple aspects. The World Health Organization, (who), the epidemiological recommendations has increased in recent years to this population group, also the signs and symptoms of the buccal mucosa of infants can change with age and are often different from the adult. Methodology: We reviewed 34 publications in specialized magazines, all relating to school children aged between 6 and 14 years old, although some refer to specific ages. Results: pathologies of adolescents differ from that of adults, although there are few references; There is no action defined in the plans and national and regional projects for this population; the majority of diseases that occur in the oral cavity of this population, are relatively harmless, do not need treatment, presenting of asymptomatic form and limited to the chronological development of the child. Conclusion: define a line of research, and to incorporate the population of children and adolescents, as in Venezuela and Latin America, research in this area is limited

Signal-averaged electrocardiogram in patients with arrhythmogenic right ventricular cardiomyopathy and ventricular arrhythmias.

OBJECTIVE: The aim of the study was to assess the prevalence, sensitivity, specificity and predictive value of the signal-averaged ECG in patients with arrhythmogenic right ventricular cardiomyopathy and different forms of ventricular arrhythmias. METHODS: The signal averaged ECG in 138 patients and 146 healthy subjects (control group), using a three bandpass filter system (25-250, 40-250, 80-250 Hz), was considered abnormal when at least two parameters were abnormal at each filter setting. Patients were divided into three groups according to the extent of the right ventricular enlargement (mild, moderate, extensive), and into five groups according to the type of ventricular arrhythmia. RESULTS: The signal averaged ECG was abnormal in 57% of the patients and in 4% of the healthy subjects. The sensitivity was 57%, specificity 95% and positive predictive value 92%. The signal averaged ECG was abnormal in 94.4% of patients with the extensive form of the disease, in 77.7% of patients with the moderate form and in 31.8% of patients with the minor form, demonstrating good correlation with the extent of the disease. According to the type of ventricular arrhythmia, a higher correlation was found between signal averaged ECG abnormality and sustained ventricular tachycardia with superior axis (94.4%, P<0. 02); the correlation for the other arrhythmias varied from 16.6% to 55.8%. CONCLUSION: There is a closer correlation between the signal averaged ECG and extent of disease than with the presence of ventricular arrhythmias. The signal averaged ECG is not helpful in diagnosing minor forms of the disease, but since it is a non-invasive method, it may be useful in evaluating progression of the disease.

[Improvement of short-term prognosis in patients with refractory heart failure]. / Miglioramento della prognosi a breve termine dei pazienti con scompenso cardiaco refrattario.

BACKGROUND: Prognosis of patients with severe heart failure is poor, despite improved results in medical therapy. Heart transplantation is the only treatment possible in end-stage heart failure. The aim of this study was to evaluate the variation in prognosis over the past six years in the patients admitted to Intensive Care Unit for heart failure in spite of optimal oral therapy. STUDY POPULATION AND METHOD: Between January 1990 and December 1995, 133 patients with heart failure were admitted to the Intensive Care Unit, despite the fact that they were on optimal oral therapy. All patients were in New York Heart Association (NYHA) functional class III to IV and required intravenous administration of sympathomimetic amines, in addition to standard heart failure treatment procedures. Cumulative survival at six months of patients observed between 1990-1992 (group A) was compared with the survival rate of patients observed from 1993 to 1995 (group B). RESULTS: Clinical and haemodynamic parameters were similar in groups A and B, but ACE-inhibitors were used more frequently in group B (75 vs 31% respectively, p < 0.05). During the follow-up period, heart transplantation was indicated in a similar percentage of patients (A 53% vs B 58%). However, mortality on the waiting list (58% group A vs 21% group B; p < 0.05) and the percentage of patients who underwent heart transplantation (41% group A vs 78% group B; p < 0.05) differed. Moreover, all patients in group A and 50% of group B were operated on as "status one" patients. The total six-month mortality rate decreased from 69% before 1992 to 48% thereafter (p < 0.05). CONCLUSION: The short-term prognosis of patients with refractory heart failure improved over time. In the latter period, ACE-inhibitors were used more frequently and the number of heart transplantations was greater. Nevertheless, our results do not allow us to identify the causes of the improved survival rate.

Identification of mutations in the cardiac ryanodine receptor gene in families affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2).

Arrhythmogenic right ventricular dysplasia type 2 (ARVD2, OMIM 600996) is an autosomal dominant cardiomyopathy, characterized by partial degeneration of the myocardium of the right ventricle, electrical instability and sudden death. The disease locus was mapped to chromosome 1q42--q43. We report here on the physical mapping of the critical ARVD2 region, exclusion of two candidate genes (actinin 2 and nidogen), elucidation of the genomic structure of the cardiac ryanodine receptor gene (RYR2) and identification of RYR2 mutations in four independent families. In myocardial cells, the RyR2 protein, activated by Ca(2+), induces the release of calcium from the sarcoplasmic reticulum into the cytosol. RyR2 is the cardiac counterpart of RyR1, the skeletal muscle ryanodine receptor, involved in malignant hyperthermia (MH) susceptibility and in central core disease (CCD). The RyR2 mutations detected in the present study occurred in two highly conserved regions, strictly corresponding to those where mutations causing MH or CCD are clustered in the RYR1 gene. The detection of RyR2 mutations causing ARVD2, reported in this paper, opens the way to pre-symptomatic detection of carriers of the disease in childhood, thus enabling early monitoring and treatment.

Autoimmunity in myocarditis and dilated cardiomyopathy: cardiac autoantibody frequency and clinical correlates in a patient series from Italy.

BACKGROUND: Organ- and disease-specific cardiac autoantibodies, detected by indirect immunofluorescence, represent markers of autoimmunity in a subgroup (25-35%) of patients with dilated cardiomyopathy or myocarditis from Northern Europe and the United States of America. Autoantibody frequencies, as well as associations between clinical and immunological features, may vary in patients from different countries, due to ethnically related differences in genetic susceptibility to autoimmune disease. METHODS: We assessed the frequency of cardiac autoantibodies in a series from Italy, including 91 subjects with idiopathic dilated cardiomyopathy (61 male, aged 49 +/- 11 years) and 11 with biopsy-proven (Dallas criteria) myocarditis (7 male, aged 23 +/- 16), including 2 cases of giant cell myocarditis. Controls were 160 patients with other cardiac disease, 141 with ischemic heart failure and 270 normals Cardiac antibody test was performed blindly by indirect immunofluorescence on normal human myocardium and skeletal muscle. RESULTS: The frequency of organ-specific cardiac autoantibodies was higher (p = 0.0001) in myocarditis (45%) and in dilated cardiomyopathy (20%) than in other cardiac disease (1%), in ischemic heart failure (1%), or in normals (2.5%). Cross-reactive antibodies were detected in similar proportions of study patients and controls. Both patients with giant cell myocarditis were antibody positive. Myocarditis patients with cardiac antibodies had shorter duration of symptoms compared to those who were antibody negative (0.4 +/- 0.3 vs 4 +/- 1 months, p = 0.004). In dilated cardiomyopathy, antibody status was not associated with any clinical or diagnostic feature. CONCLUSIONS: Autoimmunity is involved in a subset of patients with myocarditis and with dilated cardiomyopathy, regardless of their geographical origin or immunogenetic background. The antibody frequency in our dilated cardiomyopathy series from Italy tended to be lower than in other countries. This may reflect reduced antibody levels with disease progression and/or the recognised feature that Mediterranean populations are often less susceptible to autoimmune disease.