Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis: Multicenter Lombardy Registry.

BACKGROUND: There is controversy about the outcome of patients with acute myocarditis (AM), and data are lacking on how patients admitted with suspected AM are managed. We report characteristics, in-hospital management, and long-term outcome of patients with AM based on a retrospective multicenter registry from 19 Italian hospitals. METHODS: A total of 684 patients with suspected AM and recent onset of symptoms (<30 days) were screened between May 2001 and February 2017. Patients >70 years of age and those >50 years of age without coronary angiography were excluded. The final study population comprised 443 patients (median age, 34 years; 19.4% female) with AM diagnosed by either endomyocardial biopsy or increased troponin plus edema and late gadolinium enhancement at cardiac magnetic resonance. RESULTS: At presentation, 118 patients (26.6%) had left ventricular ejection fraction <50%, sustained ventricular arrhythmias, or a low cardiac output syndrome, whereas 325 (73.4%) had no such complications. Endomyocardial biopsy was performed in 56 of 443 (12.6%), and a baseline cardiac magnetic resonance was performed in 415 of 443 (93.7%). Cardiac mortality plus heart transplantation rates at 1 and 5 years were 3.0% and 4.1%. Cardiac mortality plus heart transplantation rates were 11.3% and 14.7% in patients with complicated presentation and 0% in uncomplicated cases (log-rank P<0.0001). Major AM-related cardiac events after the acute phase (postdischarge death and heart transplantation, sustained ventricular arrhythmias treated with electric shock or ablation, symptomatic heart failure needing device implantation) occurred in 2.8% at the 5-year follow-up, with a higher incidence in patients with complicated forms (10.8% versus 0% in uncomplicated AM; log-rank P<0.0001). ß-Adrenoceptor blockers were the most frequently used medications both in complicated (61.9%) and in uncomplicated forms (53.8%; P=0.18). After a median time of 196 days, 200 patients had follow-up cardiac magnetic resonance, and 8 of 55 (14.5%) with complications at presentation had left ventricular ejection fraction <50% compared with 1 of 145 (0.7%) of those with uncomplicated presentation. CONCLUSIONS: In this contemporary study, overall serious adverse events after AM were lower than previously reported. However, patients with left ventricular ejection fraction <50%, ventricular arrhythmias, or low cardiac output syndrome at presentation were at higher risk compared with uncomplicated cases that had a benign prognosis and low risk of subsequent left ventricular systolic dysfunction.

Applications of Three-Dimensional Printing in the Management of Complex Aortic Diseases.

The use of three-dimensional (3D) printing is gaining considerable success in many medical fields, including surgery; however, the spread of this innovation in cardiac and vascular surgery is still limited. This article reports our pilot experience with this technology, applied as an additional tool for 20 patients treated for complex vascular or cardiac surgical diseases. We have analyzed the feasibility of a "3D printing and aortic diseases project," which helps to obtain a more complete approach to these conditions. 3D models have been used as a resource to improve preoperative planning and simulation, both for open and endovascular procedures; furthermore, real 3D aortic models were used to develop doctor-patients communication, allowing better knowledge and awareness of their disease and of the planned surgical procedure. A 3D printing project seems feasible and applicable as an adjunctive tool in the diagnostic-therapeutic path of complex aortic diseases, with the need for future studies to verify the results.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).

BACKGROUND: Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. RESULTS: MINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57-1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08-0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52-1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87-3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43-1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15-0.47;p < 0.001). CONCLUSIONS: MINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure. Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1-22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52-0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up. Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes. Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Sacubitril/Valsartan to Treat Heart Failure in a Patient with Relapsing Hairy Cell Leukaemia: Case Report.

Experience with angiotensin-receptor neprilysin inhibitors (ARNI) in oncologic patients with heart failure (HF) is limited. We report a case of ARNI started as first-choice therapy in a patient with relapsing hairy cell leukaemia (HCL) and HF with depressed left ventricular ejection fraction (LVEF). A middle-aged male, previously treated with rituximab for HCL, was scheduled for cardiologic screening before starting a new antineoplastic therapy for cancer relapse. The patient had symptomatic HF with reduced LVEF and high NT-proBNP levels. In this patient, early ARNI treatment was well tolerated and produced a rapid and durable improvement of symptoms, LVEF and NT-proBNP levels. Consequently, the oncologic team could start an experimental treatment with obinutuzumab, with complete HCL remission. In conclusion, in this patient with HCL and HF, ARNI therapy was safe and effective, contributing to undelayed cancer treatment.

In-hospital Heart Rate Reduction With Beta Blockers and Ivabradine Early After Recovery in Patients With Acute Decompensated Heart Failure Reduces Short-Term Mortality and Rehospitalization.

Objective: In the past years, heart rate (HR) has emerged as a highly relevant modifiable risk factor for heart failure (HF) patients. However, most of the clinical trials so far evaluated the role of HR in stable chronic HF cohorts. The aim of this multi-center, prospective observational study was to assess the association between HR and therapy with HR modulators (beta blockers, ivabradine, or a combination of ivabradine and beta blockers) at hospital discharge with patients' cardiovascular mortality and re-hospitalization at 6 months in acutely decompensated HF patients. Materials and Methods: We recruited 289 HF patients discharged alive after admission for HF decompensation from 10 centers in northern Italy over 9 months (from April 2017 to January 2018). The primary endpoint was the combination of cardiovascular mortality or re-hospitalizations for HF at 6 months. Results: At 6 months after discharge, 64 patients were readmitted (32%), and 39 patients died (16%). Multivariate analysis showed that HR at discharge ≥ 90 bpm (OR = 8.47; p = 0.016) independently predicted cardiovascular mortality, while therapy with beta blockers at discharge was found to reduce the risk of the composite endpoint. In patients receiving HR modulators the event rates for the composite endpoint, all-cause mortality, and cardiovascular mortality were lower than in patients not receiving HR modulators. Conclusions: Heart rate at discharge ≥90 bpm predicts cardiovascular mortality, while therapy with beta blockers is negatively associated with the composite endpoint of cardiovascular mortality and hospitalization at 6 months in acutely decompensated HF patients. Patients receiving a HR modulation therapy at hospital discharge showed the lowest rate of cardiovascular mortality and re-hospitalization.

A Random Shuffle Method to Expand a Narrow Dataset and Overcome the Associated Challenges in a Clinical Study: A Heart Failure Cohort Example.

Heart failure (HF) affects at least 26 million people worldwide, so predicting adverse events in HF patients represents a major target of clinical data science. However, achieving large sample sizes sometimes represents a challenge due to difficulties in patient recruiting and long follow-up times, increasing the problem of missing data. To overcome the issue of a narrow dataset cardinality (in a clinical dataset, the cardinality is the number of patients in that dataset), population-enhancing algorithms are therefore crucial. The aim of this study was to design a random shuffle method to enhance the cardinality of an HF dataset while it is statistically legitimate, without the need of specific hypotheses and regression models. The cardinality enhancement was validated against an established random repeated-measures method with regard to the correctness in predicting clinical conditions and endpoints. In particular, machine learning and regression models were employed to highlight the benefits of the enhanced datasets. The proposed random shuffle method was able to enhance the HF dataset cardinality (711 patients before dataset preprocessing) circa 10 times and circa 21 times when followed by a random repeated-measures approach. We believe that the random shuffle method could be used in the cardiovascular field and in other data science problems when missing data and the narrow dataset cardinality represent an issue.

Levels of circulating pro-angiogenic cells predict cardiovascular outcomes in patients with chronic heart failure.

BACKGROUND: Circulating pro-angiogenic cells (PACs) contribute to vascular and myocardial regeneration. A low level of PACs is associated with worse outcome in patients with coronary heart disease. However, little is known about PACs in heart failure (HF). METHODS AND RESULTS: Blood was sampled at baseline in 111 patients with HF, 67 from 5 Italian Centers and 44 from Frankfurt, Germany. In cultured mononuclear cells from peripheral blood, PACs were counted as double-stained by tetramethylindocarbocyanine-labeled acetylated LDL and fluorescein-5-isothiocyanate-labeled lectin. Mean age of the patients was 62 years, 12 were females, 66 had ischemic etiology, 26 were in New York Heart Association Class >II. Cutoffs for PACs were assessed by receiver operating characteristic curves, to identify the optimal cutoffs for PAC level in predicting outcomes. Mean level of PACs was 35+/-29 (mean+/-SD) cells/mm(2), 2- to 3-fold lower than in age-matched healthy volunteers, but unrelated to severity of HF, age, or sex. Over 2.5 years, 12 cardiovascular deaths and 47 first hospitalizations for cardiovascular reasons were recorded. After adjustment for demographic and clinical variables, elevated creatinine and natriuretic peptides, and PACs

Relevance of echocardiographic evaluation of right ventricular function in patients undergoing cardiac resynchronization therapy.

AIMS: Right ventricular (RV) dysfunction is a marker of poor prognosis in heart failure (HF) patients. It is still unclear whether RV function might influence response to cardiac resynchronization therapy (CRT). METHODS: Forty-four consecutive patients with HF, large QRS, and either intraventricular or interventricular dyssynchrony underwent echocardiographic evaluation before, 1 month after, and 6 months after CRT. Response to CRT was considered in case of significant LV reverse remodeling, defined as the occurrence of LV end-systolic volume (LVESV) reduction > or =15% at 6 months. RESULTS: All echocardiographic indexes of baseline RV function and dimensions were significantly more impaired in nonresponders versus responders to CRT: tricuspid annular plane systolic excursion (TAPSE 15 +/- 4 mm vs 20 +/- 5 mm, P = 0.001), RV systolic pulmonary artery pressure (RVSP 39 +/- 14 mmHg vs 27 +/- 8 mmHg, P = 0.02), RV end-diastolic area (RVEDA 23 +/- 6 cm(2) vs 16 +/- 3 cm(2) P < 0.001), RV end-systolic area (RVESA 16 +/- 6 cm(2) vs 8 +/- 2 cm(2), P = 0.001), and RV fractional area change (30 +/- 12% vs 48 +/- 8%, P < 0.001). All the indexes of RV function significantly correlated with the percentage of LVESV reduction after CRT. Severe RV dysfunction was defined as TAPSE < or =14 mm and the population was stratified into two groups based on baseline TAPSE < or = or > 14 mm. As compared to those with high TAPSE (n = 30), patients with low TAPSE (n = 14) were less likely to show LV reverse remodeling after CRT (76% vs 14%, P < 0.001). CONCLUSIONS: Our study suggests that RV function significantly affects response to CRT. Poor LV reverse remodeling occurs after CRT in patients with HF having severe RV dysfunction at baseline.

Patent Foramen Ovale Closure Versus Medical Therapy in Cryptogenic Strokes and Transient Ischemic Attacks: A Meta-Analysis of Randomized Trials.

Cryptogenic strokes account for about 25% to 40% of total ischemic strokes, and 1 of the 3 of these have a patent foramen ovale (PFO). A meta-analysis concerning the effectiveness and safety of PFO closure in cryptogenic strokes or transient ischemic attacks (TIAs) was performed. We systematically searched Medline, Embase, and the Cochrane Library through April 2018. Eligible studies were randomized clinical trials. Primary and secondary end points were, respectively, stroke or TIA and stroke recurrences. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) for all end points using fixed- and random-effects meta-analyses. Data were included from 6 trials involving 3560 patients. In the pooled analysis, PFO closure was superior to medical treatment for both primary (RR: 0.39; 95% CI: 0.18-0.82; P < .02) and secondary end points (RR: 0.58; 95% CI: 0.44-0.76; P < .001). Transcatheter closure significantly increased the risk of new-onset atrial fibrillation (AF; RR: 5.74; P < .001). Percutaneous closure is superior to medical treatment in reducing stroke and TIA recurrence, even if with a significant risk increasing for new-onset AF. These findings suggest that transcatheter closure is indicated in patients with cryptogenic strokes and large PFO.

Favourable effects of heart rate reduction with intravenous administration of ivabradine in patients with advanced heart failure.

BACKGROUND: Heart rate (HR) reduction may be useful in treatment of patients with heart failure (HF). There are no data on the haemodynamic effects of ivabradine (a selective I(f) current inhibitor) in advanced HF patients. AIMS: To assess the haemodynamic effects of ivabradine in patients with advanced HF and markedly depressed left ventricular (LV) function. METHODS AND RESULTS: Ten NYHA class III patients (50+/-12 years, LV ejection fraction 21+/-7%) underwent 24-h haemodynamic monitoring. Ivabradine 0.1 mg/kg was infused over 90', followed by 0.05-0.075 mg/kg in the subsequent 90'. Baseline HR was 93+/-8 bpm, cardiac index (CI) 2.2+/-0.6 l/min*m2; LV stroke volume 44+/-11 ml and systolic work 39+/-13 g. Ivabradine significantly reduced HR, by a maximum of 27% (to 68+/-9 bpm) at 4 h, without decreasing CI. Ivabradine increased stroke volume and LV systolic work by a maximum of 51% (to 66+/-17 ml) and 53% (to 58+/-20 g) at 4 h. No serious adverse events occurred. CONCLUSION: In patients with advanced HF and markedly depressed LV function, the acute administration of ivabradine is well tolerated, effectively reduces HR, markedly increases stroke volume and preserves cardiac output. Ivabradine appears a promising approach for the treatment of patients with moderate and advanced heart failure.

Long term vagal stimulation in patients with advanced heart failure: first experience in man.

BACKGROUND: Experimentally, vagal stimulation (VS) is protective in chronic heart failure (HF). In man, VS is used in refractory epilepsy but has never been used in cardiovascular diseases. Increased sympathetic and reduced vagal activity predict increased mortality in HF. AIMS: This pilot study assessed feasibility and safety and tested possible efficacy of chronic VS in HF patients. METHODS: We studied 8 patients (mean age 54 years). CardioFit (BioControl Medical), a VS implantable system delivering pulses synchronous with heart beats through a multiple contact bipolar cuff electrode, was used. VS was started 2-4 weeks after implant, slowly raising intensity; patients were followed 1, 3 and 6 months thereafter. RESULTS: All procedures were successful: as sole surgical side effect, one patient had transient hoarseness. VS was well tolerated, with only mild side effects (cough and sensation of electrical stimulation). There was a significant improvement in NYHA class, Minnesota quality of life (from 52+/-14 to 31+/-18, p < 0.001), left ventricular end-systolic volume (from 208+/-71 to 190+/-83 ml, p = 0.03), and a favourable trend toward reduction in end-diastolic volume. CONCLUSIONS: This novel approach to the treatment of patients with HF is feasible, and appears safe and tolerable. The preliminary efficacy results appear promising. These findings suggest the opportunity to proceed with a larger multicentre study.

Ambient air pollution and cardiovascular diseases: From bench to bedside.

Air pollution has a great impact on health, representing one of the leading causes of death worldwide. Previous experimental and epidemiological studies suggested the role of pollutants as risk factors for cardiovascular diseases. For this reason, international guidelines included specific statements regarding the contribution of particulate matter exposure to increase the risk of these events. In this review, we summarise the main evidence concerning the mechanisms involved in the processes linking air pollutants to the development of cardiovascular diseases.

Heart rate as a prognostic marker and therapeutic target in acute and chronic heart failure.

Since increased heart rate (HR) is associated with higher mortality in several cardiac disorders, HR is considered not only a physiological indicator but also a prognostic and biological marker. In heart failure (HF), it represents a therapeutic target in chronic phase. The use or up-titration of beta-blockers, a milestone in HF with reduced left ventricular ejection fraction (LVEF) treatment, is at times limited by patients' hemodynamic profile or intolerance. Ivabradine, a HR-lowering drug inhibiting the f-current in pacemaker cells, has been shown to improve outcome in patients with chronic HF, in sinus rhythm with increased HR beyond beta-blocker therapy. The rationale for this review is to update the role of HR as a prognostic biomarker and a potential therapeutic target in other scenarios than chronic HF; namely, in patients with coexisting atrial fibrillation (AF), in HF with preserved LVEF (HFpEF), in acute HF, and in patients discharged after an episode of acute HF. Preliminary studies and case reports that evaluated the use of ivabradine in the setting of acute HF will be summarized. Recent results of HR reduction in the setting of HFpEF with ivabradine will be presented. Finally, data from large registries and trials that evaluated the prognostic impact of HR in patients with acute HF and sinus rhythm or AF will be reviewed, showing that only patients in sinus rhythm may benefit from HR reduction.

Importance of the echocardiographic evaluation of right ventricular function in patients with AL amyloidosis.

BACKGROUND: Patients with AL amyloidosis often present with signs of congestive heart failure. AIM: This study was prospectively designed to assess the significance of RV dysfunction in AL amyloidosis. METHODS AND RESULTS: Seventy-four patients with biopsy proven AL amyloidosis underwent a thorough echocardiographic evaluation. A tricuspid annular plane systolic excursion (TAPSE)<17 mm was taken as marker of RV dysfunction. Plasma NT-proBNP determinations were performed in all cases. RV function was normal in 60 patients and reduced in 14 patients. Patients with RV dysfunction had thicker left ventricular (LV) walls (p<0.01), lower LV end-diastolic volumes (p<0.01), lower LV ejection fraction (p<0.01) and more frequently a restrictive LV filling pattern (p<0.01). RV dimensions and RV free wall thickness were not significantly different in the two groups. A thick interventricular septum and a reduced TAPSE were associated with high NT-proBNP levels (both p<0.01). Seven patients died during a median follow-up period of 19 months; TAPSE<17 mm was the only echocardiographic parameter associated with poor survival. CONCLUSION: In patients with AL amyloidosis, RV dysfunction is associated with more severe involvement of the left ventricle, higher plasma levels of NT-proBNP and with poor prognosis.

Return to work after thoracic organ transplantation in a clinically-stable population.

PURPOSE: To evaluate the rate of return to work after transplantation and its determinants in a clinically-stable population of patients transplanted and followed-up at a single institution in Italy. METHODS: 151 thoracic organ transplant recipients (72 lung, 79 heart) were examined. Patients were asked about daily activities, level of education, employment and clinical condition. A six-minute walking test was performed with measurement of dyspnoea using the Borg scale. Quality of Life was evaluated with the SF-36 and GHQ questionnaires. RESULTS: Before transplantation 131 patients (87%), (70 heart and 61 lung) worked. After transplantation, 51 patients (39%) went back to work and 3 more started working. We found that younger age, a better quality of life (mainly in the mental domain), having had an occupation previously (particularly as an entrepreneur/freelancer), and having been off work for less than 24 months, were independent predictors of return to work. CONCLUSIONS: Considering their good, objective and subjective, functional status, some patients who could have returned to work, chose not to. Identifying factors which affect return to work might help health professionals to adopt the best course of treatment and psychological support in order to fulfil this goal; however, return to work should not be considered as the only expression of a patient's real psychophysical condition.

Short-term air pollution exposure and cardiovascular events: A 10-year study in the urban area of Como, Italy.

BACKGROUND: In the last years several studies have investigated the effects of some air pollutants on cardiovascular diseases (CVD), but the results are not conclusive. Aim of this study was to investigate the association between short-term exposure to ambient air pollution and CVD events in a long-term observational period. METHODS: All CVD events (myocardial infarction - MI and ischemic stroke - IS) which occurred in residents of Como between January 2005 and December 2014 were included. Demographics and main vascular risk factors were registered for each patient. Principal meteorological variables and four ambient particles (O3, SO2, NO2, PM10) were recorded. Statistical analysis was performed using linear regression (GLM) and a generalized additive model (GAM) estimating Poisson distribution and adjusted for the main risk factors and ambient meteorological variables. RESULTS: A total of 4110 events were registered with a mild prevalence of MI (51.6%). In GLM analysis we observed a continuative association between CVD events and SO2 (p<0.05), while PM10 was associated with CVD occurrences at two-day lag time (p<0.05). Using GAM we observed a positive association between CVD and PM10 at the same day and at three- and four-day lag time with HRs ranging between 1.025 and 1.039 (p<0.001). These results were observed for both MI and IS, with an earlier effect for MI than for IS. CONCLUSIONS: These data confirm a possible association between some ambient air pollutants and CVD events, precisely MI and IS, with different temporal and cumulative effect.

B-cell posttransplant lymphoproliferative disorders in heart and/or lungs recipients: clinical and molecular-histogenetic study of 17 cases from a single institution.

BACKGROUND: Posttransplantation lymphoproliferative disorders (PTLDs) are heterogeneous lymphoid proliferations representing a major complication of solid organ transplant. This study details the clinicopathological and molecular features of 17 B-cell PTLDs observed in a single center series of 988 heart and/or lung transplant recipients. METHODS: Cases were classified according to World Health Organization lymphoma classification and tested for Epstein-Barr Virus (EBV), clonality, histogenetic phenotypic (CD10, Bcl-6, MUM1, CD138), and genotypic (immunoglobulin and BCL-6 genes somatic hypermutation) markers. RESULTS: This series of 17 PTLDs included: two B-cell monoclonal polymorphic PTLDs and 15 B-cell monomorphic PTLDs (13 diffuse large B-cell lymphomas [DLBCL] and 2 Burkitt lymphomas [BL]). EBV was detected in 9/17 cases. A monoclonal immunoglobulin variable (IGV) genes rearrangement was documented in 17/17 cases; IGV somatic hypermutation was found in 88% of cases, indicating a prevalent origin from germinal center (GC)-experienced B cells. Using immunophenotypic markers, three histogenetic profiles were identified: a) CD10/bcl-6/MUM1/CD138, mimicking GC B-cells; b) CD10-/bcl-6+/MUM1+/CD138-, reminiscent of B-cells at the latest phases of GC reaction; and c) CD10-/bcl-6-/MUM1+/CD138+/-, consistent with preterminally differentiated B-cells. CONCLUSIONS: Correlation between morphology, histogenesis, and EBV status demonstrated a high degree of homogeneity in the two GC-related groups, mostly including EBV-negative cases with BL and DLBCL-centroblastic features; the third group, consisting of post GC EBV-positive cases, was histologically less homogeneous, as it included polymorphic PTLDs and DLBCL with immunoblastic and anaplastic features. The EBV-negative cases with GC histogenetic phenotype showed a slightly better outcome; however, such less aggressive prognostic trend was not confirmed by statistical analysis.

Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects.

BACKGROUND: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. AIMS: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. METHODS AND RESULTS: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and alphaB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon-intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. CONCLUSIONS: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical.