Fulvio Bellocci

Histological substrate of atrial biopsies in patients with lone atrial fibrillation

BACKGROUND Lone atrial fibrillation (LAF) is a common clinical syndrome, but its origin remains unknown. METHODS AND RESULTS We performed endomyocardial biopsies of the right atrial septum (2 to 3 per patient; mean, 2.8) and of the two ventricles (6 per patient) in 12 patients (10 men, 2 women; mean age, 32 years) with paroxysmal LAF refractory to conventional antiarrhythmic treatment. As controls, we used endomyocardial biopsies (3 to 5 per patient; mean, 4.4) from the right atrial septum of 11 patients with Wolff-Parkinson-White syndrome (WPW) undergoing resection of the abnormal AV pathway. The weight of the biopsies ranged from 2.8 to 4.5 mg. Biopsy samples were processed for histology and electron microscopy and were read by a pathologist blinded to clinical data. All patients underwent two-dimensional Doppler echocardiography; cardiac catheterization; coronary angiography; and hormonal, virologic, and electrophysiological studies. All tests and WPW biopsies were normal, but all LAF atrial biopsy specimens (average, 2.8 per patient) showed abnormalities (P<.0001). The type of abnormalities varied: Two patients had a severe hypertrophy with vacuolar degeneration of the atrial myocytes and ultrastructural evidence of fibrillolysis occupying >50% of the areas assessed morphometrically (P=.50), 8 had lymphomononuclear infiltrates with necrosis of the adjacent myocytes (5 with fibrosis and 3 without; P<.003), and 2 had only nonspecific patchy fibrosis (P=.50). Biventricular biopsies were abnormal in only 3 patients and showed inflammatory infiltrates similar to those found in atrial biopsies. CONCLUSIONS Abnormal atrial histology was uniformly found in multiple biopsy specimens in all patients with LAF. It was compatible with a diagnosis of myocarditis in 66% of patients (active in 25%) and of noninflammatory localized cardiomyopathy in 17% and was represented by patchy fibrosis in 17%. The cause of the pathological changes, which were found only in atrial septal biopsies but not in biventricular biopsies, in 75% of patients remains unknown.

Cardiac histological substrate in patients with clinical phenotype of Brugada syndrome.

Background— The role of structural heart disease and sodium channel dysfunction in the induction of electrical instability in Brugada syndrome is still debated. Methods and Results— We studied 18 consecutive patients (15 males, 3 females; mean age 42.0±12.4 years) with clinical phenotype of Brugada syndrome and normal cardiac structure and function on noninvasive examinations. Clinical presentation was ventricular fibrillation in 7 patients, sustained polymorphic ventricular tachycardia in 7, and syncope in 4. All patients underwent cardiac catheterization, coronary and ventricular angiography, biventricular endomyocardial biopsy, and DNA screening of the SCN5A gene. Biopsy samples were processed for histology, electron microscopy, and molecular screening for viral genomes. Microaneurysms were detected in the right ventricle in 7 patients and also in the left ventricle in 4 of them. Histology showed a prevalent or localized right ventricular myocarditis in 14 patients, with detectable viral genomes in 4; right ventricular cardiomyopathy in 1 patient; and cardiomyopathic changes in 3. Genetic studies identified 4 carriers of SCN5A gene mutations that cause in vitro abnormal function of mutant proteins. In these patients, myocyte cytoplasm degeneration was present at histology, whereas terminal dUTP nick end-labeling assay showed a significant increase of apoptotic myocytes in right and left ventricle versus normal controls (P=0.014 and P=0.013, respectively). Conclusions— Despite an apparently normal heart at noninvasive evaluation, endomyocardial biopsy detected structural alterations in all 18 patients with Brugada syndrome. Mutations in the SCN5A gene, identified in 4 of the 18 patients, may have induced concealed structural abnormalities of myocardiocytes that accounted for paroxysmal arrhythmic manifestations.

High Prevalence of Myocarditis Mimicking Arrhythmogenic Right Ventricular Cardiomyopathy Differential Diagnosis by Electroanatomic Mapping-Guided Endomyocardial Biopsy

OBJECTIVES We evaluated the diagnostic contribution and the therapeutic and prognostic implications of 3-dimensional electroanatomic mapping (EAM)-guided endomyocardial biopsy (EMB) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). BACKGROUND ARVC is a frequent cause of life-threatening ventricular arrhythmias and sudden death in young people. The value of current diagnostic criteria and the role of imaging techniques and EMB are still debated. METHODS We studied 30 consecutive patients (17 male, mean age 43 +/- 17 years) with a noninvasive diagnosis of ARVC according to current criteria. All patients underwent 3-dimensional EAM-guided EMB. RESULTS Twenty-nine (97%) of 30 patients presented an abnormal voltage map. Histology and immunohistochemistry confirmed the diagnosis of ARVC in 15 patients, and showed active myocarditis according to Dallas criteria in the remaining 15 patients. Patients with ARVC were not distinguishable on the basis of clinical features, presence, and severity of structural and functional right ventricular abnormalities and 3-dimensional EAM findings. On the basis of clinical and histological features, a cardioverter-defibrillator was implanted in 13 patients with biopsy-proven ARVC and in 1 patient only with myocarditis. At a mean follow-up of 21 +/- 8 months, 7 (47%) patients with ARVC experienced a recurrence of symptomatic sustained ventricular arrhythmias with appropriate defibrillator intervention in all cases. All patients with myocarditis remained asymptomatic and free from arrhythmic events. CONCLUSIONS Right ventricular myocarditis frequently mimics ARVC. Three-dimensional EAM-guided EMB is a safe and effective tool in differential diagnosis and in the selection of the most appropriate therapeutic strategy.

Impact of Consistent Atrial Pacing Algorithm on Premature Atrial Complexe Number and Paroxysmal Atrial Fibrillation Recurrences in Brady-Tachy Syndrome: A Randomized Prospective Cross Over Study

AbstractAim of the study: The Consistent Atrial Pacing (CAP) algorithm has been designed to achieve a high percentage of atrial pacing to suppress paroxysmal atrial fibrillation. The aim of our study was to compare the impact of DDDR+CAP versus DDDR pacing on paroxysmal atrial fibrillation recurrences and triggers in patients with Brady-Tachy Syndrome. Methods: 61 patients, 23 M and 38 F, mean age 75±9 y, affected by Brady-Tachy Syndrome, implanted with a DDDR pacemaker, were randomized to DDDR or DDDR+CAP pacing with cross over of pacing modality after 1 month. Results: 78 % of patients in DDDR pacing and 73 % in DDDR+CAP pacing (p=n.s.) were free from symptomatic paroxysmal atrial fibrillation recurrences. During DDDR+CAP pacing, the atrial pacing percentage increased from 77±29 % to 96±7 % (p<0.0001). Automatic mode switch episodes/day were 0.73±1.09 in DDDR and 0.79±1.14 (p=n.s.) in DDDR+CAP. In patients with less than 50 % of atrial pacing during DDDR, automaticmode switch episodes/day decreased during DDDR+CAP from 1.13±1.59 to 0.23±0.32 (p<0.05) and in patients with less than 90 % from 1.23±1.27 to 0.75±1.10 (p<0.001). The number of premature atrial complexes per day decreased during DDDR+CAP from 2665±4468 to 556±704 (p<0.02). Conclusion: CAP algorithm allowed continuous overdrive atrial pacing without major side effects. Triggers of paroxysmal atrial fibrillation induction, such as premature atrial complexes, were critically decreased. Paroxysmal atrial fibrillation episodes were reduced in patients with atrial pacing percentage lower than 90 % during DDDR pacing.

Immediate and long-term clinical outcome after spinal cord stimulation for refractory stable angina pectoris*

The treatment of patients with angina pectoris refractory to medical therapy and unsuitable for revascularization procedures has yet not been well standardized. Previous retrospective studies and small prospective studies have suggested beneficial effects of spinal cord stimulation (SCS) in these patients. We created a Prospective Italian Registry of SCS to evaluate the short- and long-term clinical outcome of patients who underwent SCS device implantation because of severe refractory angina pectoris. Overall, 104 patients were enrolled in the registry (70 men, aged 68 +/- 17 years), most of whom (83%) had severe coronary artery disease. Average follow-up was 13.2 +/- 8 months. Overall, 17 patients (16%) died, 8 (8%) due to cardiac death. Among clinical variables, only age was found to be significantly associated both with total mortality (p = 0.04) and cardiac mortality (p = 0.02) on Cox regression analysis. A significant improvement of anginal symptoms (> or =50% reduction of weekly anginal episodes, compared with baseline) occurred in 73% of patients, and Canadian Cardiovascular Society angina class improved by > or =1 class in 80% and by > or =2 classes in 42% of patients, with a relevant reduction in the rate of hospital admission and days spent in the hospital because of angina (p <0.0001 for both). No life-threatening or clinically serious complications were observed. The most frequent side effect consisted of superficial infections, either at the site of puncture of electrode insertion or of the abdominal pocket, which occurred in 6 patients. In conclusion, our prospective data point out that SCS can be performed safely and is associated with a sustained improvement of anginal symptoms in a relevant number of patients with refractory stable angina pectoris.

Ventricular arrhythmia induced by programmed ventricular stimulation after acute myocardial infarction

The prevalence, characteristics and clinical significance of ventricular electrical instability with programmed ventricular stimulation was studied in 50 hemodynamically stable patients 17 to 40 days after acute myocardial infarction (AMI) using double extrastimuli at 2- and 10-mA intensity and from 2 right ventricular sites. Ventricular electrical instability was defined as induction of 10 or more consecutive intraventricular reentrant beats. Of 50 patients, 23 (46%) had ventricular electrical instability (10 of these had sustained ventricular tachycardia [VT] induced). No significant differences were observed between patients with and without ventricular electrical instability with respect to age, site of AMI, coronary prognostic index, maximal level of CK, number of narrowed coronary arteries and presence of severe wall motion abnormalities. During a mean follow-up of 11.2 months no patient died suddenly. During repeated Holter recordings patients with ventricular electrical instability had a higher incidence of nonsustained VT than did patients without ventricular electrical instability.

Recognizing and treating myocarditis in recent-onset systemic sclerosis heart disease: Potential utility of immunosuppressive therapy in cardiac damage progression

OBJECTIVES Scleroderma heart disease is a major risk of death in systemic sclerosis (SSc). Mechanisms underlying myocardial damage are still unclear. We performed an extensive study of SSc patients with recent-onset symptoms for heart disease and examined the efficacy of immunosuppressive therapy. METHODS A cohort of 181 SSc patients was enrolled. Of these, 7 patients newly developed clinical symptoms of heart disease (heart failure, chest pain, and palpitation); all of them showed mild but persistent increase in cardiac enzymes. These patients underwent Holter ECG, 2D-echocardiography, perfusional scintigraphy, delayed-enhancement-cardiac magnetic resonance (DE-CMR), coronary angiography, and endomyocardial biopsy. Patients were treated for at least 12 months and followed-up for 5 years. RESULTS Ventricular ectopic beats (VEBs) were found in 4 patients, wall motion abnormalities in 3, pericardial effusion in 6, and DE in CMR in 6 with T2-hyperintensity in 2. In all patients, histology showed upregulation of endothelium adhesion molecules and infiltration of activated T lymphocytes, with (acute/active myocarditis in 6) or without (chronic/borderline myocarditis in 1) myocyte necrosis. Parvovirus B19 genome was detected in 3. None showed occlusion of coronary arteries or microvessels. Compared with SSc controls, these patients more often had early disease, skeletal myositis, c-ANCA/anti-PR3 positivity, VEBs, pericardial effusion, and systolic and/or diastolic dysfunction. Immunosuppressive therapy improved symptoms and led to cardiac enzyme negativization; however, 2 patients died of sudden death during follow-up. CONCLUSIONS Myocarditis is a common finding in SSc patients with recent-onset cardiac involvement. Its early detection allowed to timely start an immunosuppressive treatment, preventing cardiac damage progression in most cases.

Electromagnetic interference of digital and analog cellular telephones with implantable cardioverter defibrillators: in vitro and in vivo studies.

The present study examines the potential electromagnetic interference effects induced by cellular telephones on ICDs. We developed ad hoc protocols to conduct both in vitro and in vivo trials on most of the implantable cardioverter defibrillators available on the international market. Trials were conducted with three cellular telephones: two GSM (Global System for Mobile Communication) and one TACS (Total Access Communication System). A human trunk simulator was used to carry out in vitro observations on six ICDs from five manufacturers. In vivo tests were conducted on 13 informed patients with eight different ICD models. During the trials in air, GSM telephones induced interference effects on 4 out of the 6 cardioverter defibrillators tested. Specifically, pulse inhibition, reprogramming, false ventricular fibrillation, and ventricular tachycardia detections occurred, which would have entailed inappropriate therapy delivery had this been activated. Effects were circumscribed to the area closely surrounding the connectors. When the ICD was immersed in saline solution, no effects were observed. Three cases of just ventricular triggering with the interfering signal were observed in vivo.

Long‐term follow‐up of patients with cardiac syndrome X treated by spinal cord stimulation

Objective: To assess the long-term effect of spinal cord stimulation (SCS) in patients with refractory cardiac syndrome X (CSX). Methods: A prospective, controlled, long-term follow-up was performed of 19 patients with CSX with refractory angina who underwent SCS (SCS group, 5 men, mean (SD) age 60.9 (8.5) years); 9 comparable patients with CSX who refused SCS treatment (3 men, mean (SD) age 60.9 (8.8) years) constituted the control group. Clinical and functional status were assessed at the time of screening for SCS indication (basal evaluation) and at a median (range) follow-up of 36 (15–82) months. Results: The two groups at baseline did not show any difference in clinical characteristics and angina status. All indicators of angina status (angina episode frequency, duration and short-acting nitrate use) improved significantly at follow-up in the SCS group (p<0.001) but not in controls. Functional status, as assessed by the Seattle Angina Questionnaire and a visual analogue scale for quality of life, improved at follow-up in the SCS group (p<0.001 for all scales) but not in controls. Exercise tolerance, exercise-induced angina and ST segment changes also significantly improved in the SCS group but not in controls. Conclusions: Data show that SCS can be a valid form of treatment for long-term control of angina episodes in patients with refractory CSX.

Risk of arrhythmia in type I Myotonic Dystrophy: the role of clinical and genetic variables

Objective: To examine the association between the presence of arrhythmia in type 1 myotonic dystrophy (DM1) and clinical–genetic variables, evaluating their role as predictors of the risk of arrhythmia. Methods: 245 patients with genetically proven DM1 underwent clinical and non-invasive cardiological evaluation. Severity of muscular involvement was assessed according to the 5 point Muscular Disability Rating Score (MDRS). Data were analysed by univariate and multivariate models. Results: 245 patients were examined and cardiac arrhythmias were found in 63 subjects, 40 of whom required a device implant. Statistical analyses revealed that men had more than double the risk of developing arrhythmias compared with women (p = 0.018). Addition of each year of age caused an increased risk of arrhythmia equal to 3% (p = 0.030). Subjects with MDRS 5 had a risk of arrhythmia 12 times higher than patients with MDRS 1–2 (p<0.001). Although all of these variables were significantly associated with cardiac rhythm dysfunction, they had a low sensitivity for the prediction of arrhythmic risk Conclusion: Male sex, age and muscular disability were strongly associated with the development of arrhythmia in DM1. However, all of these variables were weak predictors of arrhythmic risk. These results suggest that other factors may be involved in the development of cardiac conduction abnormalities in DM1.