Regulatory T Cells in Severe Persistent Asthma in the Era of Monoclonal Antibodies Target Therapies.

Asthma is an immunoinflammatory disease characterized by bronchial hyper-reactivity to different external stimuli. New monoclonal target treatments have been developed, but few studies have investigated the role of regulatory T cells in severe asthma and the modulatory effect of biological therapy on regulatory T cell functions. Their dysfunction may contribute to the development and exacerbation of asthma. Here we review the recent literature on the potential immunological role of regulatory T cells in the pathogenesis of severe asthma. The analysis of the role of regulatory T cells was performed in terms of functions and their possible interactions with mechanisms of action of the novel treatment for severe asthma. In an era of biological therapies for severe asthma, little data is available on the potential effects of what could be a new therapy: monoclonal antibody targeting of regulatory T cell numbers and functions.

NK and NKT-like cells in granulomatous and fibrotic lung diseases.

ABTRACT: Background The pathogenetic and regulatory roles of natural killer (NK) and natural killer T-like cells in interstitial lung diseases (ILDs), fibrotic and granulomatous of unknown etiology are unclear. Objectives Here we investigated NK and NKT-like cells in peripheral blood (PB) and Bronchoalveolar lavage (BAL) from patients with ILDs. Method 190 patients (94 male mean age 61 ± 14.3 years) and 8 controls undergoing bronchoscopy for ILD diagnostic work-up were enrolled consecutively; 115 patients sarcoidosis, 24 chronic fibrotic hypersensitivity pneumonitis and 43 patients other ILDs [32 idiopathic pulmonary fibrosis (IPF) and 11 non-specific interstitial pneumonia (NSIP)]. PB and BAL were processed by flow cytometry using monoclonal antibodies to differentiate NK and NKT-like cells. Results NK% in BAL was significantly different among ILDs (p = 0.02). Lower NK% was observed in BAL from sarcoidosis than other ILDs (p < 0.05). Similar findings were observed for NKT-like, whereas no differences were found for PB NK%. Difference of NK% was observed between BAL and PB in all groups (p < 0.001). Sarcoidosis patients reported the best area under the curve for NKT-like (AUC = 0.678, p = 0.0015) and NK cells (AUC = 0.61, p = 0.001). In the IPF-NSIP subgroup, NK% cell was inversely correlated with FVC% (r = - 0.34, p = 0.03) and DLCO% (r = - 0.47, p = 0.0044). Conclusions NK and NKT-like were expressed differently in BAL from patients with different ILD and were significantly depleted in sarcoidosis respect to other ILDs. This suggests that these cells may play a protective role in the pathogenesis of sarcoidosis.

Exhaled nitric oxide in interstitial lung diseases.

Nitric oxide (NO) is a biomarker of nitrosative stress, which is involved in the pathogenesis of idiopathic interstitial pneumonias (IIP). This study evaluates exhaled NO levels in IIP patients and relates alveolar concentrations of NO (CalvNO) to pulmonary function test (PFT) and 6-minute walking test (6MWT) parameters. We measured fractional exhaled nitric oxide (FeNO), CalvNO and maximum conducting airway wall flux (J'awNO) in 30 healthy subjects and 30 patients with IIP (22 idiopathic pulmonary fibrosis and 8 idiopathic non-specific interstitial pneumonias). IIP patients had higher FeNO at flow rates of 50-100-150 ml/s and higher CalvNO levels than healthy controls (p<0.0001). CalvNO was significantly correlated with 6-minute walking distance (p<0.0001), recovery time (p<0.0005), TLC (p<0.001), FVC (p=0.01) and TLCO (p<0.01). IIP patients showed abnormal nitric oxide production, probably due to lung fibrosis and oxidative-mediated lung injury. CalvNO was correlated with PFT and 6MWT parameters and is proposed as a potential biomarker of lung fibrosis and exercise tolerance.

Correlation between clinical presentation and delayed-enhancement MRI pattern in myocarditis.

PURPOSE: The exact incidence of myocarditis is unknown, as the diagnosis is frequently delayed or missed. Clinical presentation and disease course are extremely variable, as there may be acute onset with acute coronary syndrome, or cardiogenic shock, or progressive heart failure or arrhythmias. The purpose of this study was to identify prognostic factors on magnetic resonance imaging (MRI) performed in patients with bioptically proven myocarditis at presentation and after 6 months. MATERIALS AND METHODS: Fifty-six consecutive patients with different presentations of myocarditis (20 with acute coronary syndrome, 20 with heart failure, 16 with arrhythmias) were enrolled. All patients underwent B-mode echocardiography (echo) and tissue Doppler imaging, coronarography, ventriculography, endomyocardial biopsy and contrast-enhanced MRI examination, as well as clinical and echo follow-up at 6 months. RESULTS: At 6-month follow-up, patients were divided in two groups according to values of end-systolic volume and ejection fraction: patients with negative remodelling and those with positive remodelling. Late enhancement was found to be an independent predictor of negative remodelling. CONCLUSIONS: Contrast-enhanced MRI is useful both in the diagnosis and as a prognostic indicator in the clinical suspicion of myocarditis.

A new scenario of bioprospecting of Hymenoptera venoms through proteomic approach

Venoms represent a huge and essentially unexplored reservoir of bioactive components that may cure diseases that do not respond to currently available therapies. This review select advances reported in the literature from 2000 to the present about the new scenario of Hymenoptera venom composition. On account of new technologies in the proteomic approach, which presents high resolution and sensitivity, the combination of developments in new instruments, fragmentation methods, strategic analysis, and mass spectrometry have become indispensable tools for interrogation of protein expression, molecule interaction, and post- translational modifications. Thus, the biochemical characterization of Hymenoptera venom has become a major subject of research in the area of allergy and immunology, in which proteomics has been an excellent alternative to assist the development of more specific extracts for diagnosis and treatment of hypersensitive patients to Hymenoptera venoms.

Impaired left ventricular energy metabolism in patients with hypertrophic cardiomyopathy is related to the extension of fibrosis at delayed gadolinium-enhanced magnetic resonance imaging.

OBJECTIVE: Areas of intramyocardial late enhancement (LE) at delayed enhanced magnetic resonance imaging (DE-MRI) and reduction of myocardial phosphocreatine (PCr)/ATP-ratio at phosphorus magnetic resonance spectroscopy ((31)P-MRS) are both reported in hypertrophic cardiomyopathy (HCM) and indicate areas of increased interstitial myocardial space with fibrosis and impairment of myocardial energy metabolism, respectively. We sought to ascertain whether in HCM patients the abnormal features of left ventricular (LV) interstitial space revealed by DE-MRI correlated with impaired LV energy metabolism shown at (31)P-MRS. METHODS: 19 patients with HCM proved by histological analysis of multiple endomyocardial biopsies and with normal coronary arteries, underwent cardiac MRI including DE-MRI and (31)P-MRS. DE-MRI for detection and quantification of late enhancement (LE) and (31)P-MRS to assess the myocardial PCr/ATP-ratio were performed by means of a 1.5-T magnet. 19 healthy subjects, matched for gender and age were studied by (31)P-MRS as control group. RESULTS: LE areas in the LV wall were found in 17 out of 19 patients with an extension ranging from 0.8% to 19.5% of the LV-mass (mean value 7.6% (SD 5.6%). The PCr/ATP-ratio was lower in HCM patients than in control subjects (2.18 (0.41) vs 2.41 (0.30); p<0.05). LE% and PCr/ATP-ratio were inversely related (R = -0.57; p<0.05) and LE% was the stronger predictor of PCr/ATP-ratio by multivariate analysis. CONCLUSIONS: This study demonstrated that the known alteration of the PCr/ATP-ratio observed in HCM patients is correlated with the presence of fibrotic areas in the myocardium of the left ventricle.

Exhaled carbon monoxide in sarcoidosis.

BACKGROUND: Exhaled Carbon monoxide has been proposed as a non-invasive marker in several inflammatory diseases of the lung, but no data are available in patients with sarcoidosis. METHODS: We evaluated the levels of exhaled CO in 78 nonsmoker patients with sarcoidosis and we compared the results with 25 healthy non smoker controls, of 25 patients with a variety of interstitial lung diseases, and 77 smokers. RESULTS: Mean value of exhaled CO in sarcoidosis was 3.3 (2.9-3.8) ppm (GM with 95% CI in parenthesis), resulting significantly higher than both normal controls, 1.4 (1.2-1.7) ppm (p<0.001), and clinical controls, 2.1 (1.7-2.7) ppm (p<0.02). All these levels, however, were markedly lower than those observed in smokers, 14.6 (12.7-16.9) ppm. No correlation was found with radiological stage, steroid therapy, respiratory function, or serum ACE activity. Using an upper normal value of 4 ppm, an increased level of exhaled CO was found in 50% of patients with sarcoidosis, in 24% of clinical controls, and in 97% of smokers. CONCLUSIONS: Our data indicate that significant release of endogenous CO occurs in sarcoidosis. It is unlikely that the measurement of exhaled CO could be of diagnostic usefulness, due to its low specificity and to the possible influence by occasional or passive smoke.

Immunosuppressive treatment of chronic non-viral myocarditis.

Inflammatory cardiomyopathy defined as myocarditis associated with cardiac dysfunction, represents a main cause of heart failure. Despite the improvement of diagnostic techniques, a specific standardized treatment of myocarditis is not yet available. The immunohistochemical detection of myocardial HLA up-regulation has been demonstrated useful in the identification of a sub-group of autoimmune inflammatory dilated cardiomyopathy (DCM) in part susceptible to immunosuppression. Recently, in a retrospective study, we defined the virologic and immunologic profile of responders and non-responders to immunosuppressive therapy of active lymphocytic myocarditis and chronic heart failure in patients who had failed to benefit from conventional supportive treatment. Non-responders were characterized by high prevalence (85%) of viral genomes in the myocardium and no detectable cardiac autoantibodies in the serum. Conversely, 90% of responders were positive for autoantibodies, while only 3 (15%) of them presented viral particles at PCR analysis on frozen endomyocardial tissue. With regard to the type of virus involved in non-responders, enterovirus, adenovirus, or their combination was associated with the worst clinical outcome. Hepatitis C virus (HCV) was the only viral agent of our series associated with detectable cardiac autoantibodies, suggesting a relevant immunomediated mechanism of damage by HCV and explaining the relief of myocardial inflammation after immunosuppressive treatment. The assessment of virologic and immunologic features of patients with biopsy-proven inflammatory cardiomyopathy may allow us to identify a specific treatment leading to recovery of cardiac function.

Inflammatory left ventricular microaneurysms as a cause of apparently idiopathic ventricular tachyarrhythmias.

BACKGROUND: We sought to investigate the arrhythmogenic role, incidence, treatment, and prognosis of inflammatory left ventricular (LV) microaneurysms in patients with apparently idiopathic ventricular tachyarrhythmias. Methods and Results-- We studied 156 consecutive patients (71 men, 85 women; mean age, 44.1+/-11.8 years) with severe ventricular arrhythmias and normal 2D echo cardiac parameters by coronary and ventricular angiography, biventricular endomyocardial biopsy, and electrophysiological study. Polymerase chain reaction was used to detect genomic sequences of enterovirus, adenovirus, Epstein Barr virus, cytomegalovirus, herpes simplex viruses, influenza A and B viruses, and hepatitis C virus in frozen endomyocardial samples. Of these patients, 15 (9.6%) showed angiographic evidence of single or multiple LV microaneurysms. All 15 patients had recurrent episodes of ventricular tachycardia with right bundle-branch block morphology, and the arrhythmias originated within or close to the aneurysms in those patients (n=6) undergoing ventricular mapping. A lymphocytic myocarditis was observed in LV biopsies of all patients and in the right ventricles of 3 patients. Polymerase chain reaction analysis was performed in 12 and viral genomes were found in 5 (42%): hepatitis C virus in 2, enterovirus in 2, and influenza virus A in 1. The patients were treated with antiarrhythmics, and cardiac function was preserved for the next 47+/-39.5 months of follow-up. No major clinical event was registered, and arrhythmias were successfully treated by antiarrhythmics. CONCLUSIONS: Inflammatory LV microaneurysms, often of viral origin, are a consistent cause of apparently idiopathic ventricular arrhythmias. Their prognosis so far has been benign, and aggressive therapeutic strategies have been unnecessary.

Prognostic significance of left ventricular aneurysms with normal global function caused by myocarditis.

OBJECTIVES: To evaluate the prognosis of left ventricular (LV) aneurysms with normal global function caused by myocarditis. BACKGROUND: LV aneurysms may result from idiopathic or viral myocarditis. The prognosis of inflammatory LV aneurysms when associated with a normal cardiac function is unknown. METHODS: Among 353 patients with a histologic diagnosis of myocarditis, 12 (3.3%) had single or multiple localized LV aneurysms (length, 10.6 +/- 3.1 mm; width, 7.4 +/- 4.2 mm) with normal cardiac function. Presenting symptoms were ventricular tachycardia (VT) in nine patients and unexplained chest pain in three. All patients underwent laboratory tests and noninvasive and invasive cardiac examinations, including biventricular endomyocardial biopsy. RESULTS: In all patients, LV endomyocardial biopsy specimen showed a lymphocytic myocarditis with focal intense myocytolysis or damage of intramural vessels, whereas right ventricular biopsy was diagnostic for myocarditis only in three. Serologic study suggested a viral infection in 3 patients and an immunologic disorder in 2, although it was negative in 7. Treatment included antiarrhythmics in 9 patients with VT, ss-blockers in 1 with chest pain, and immunosuppression (prednisone and azathioprine for 5 months) in 4 with active myocarditis (2 with chest pain and 2 with VT). At intermediate-term follow-up (mean, 53 months; range, 12 to 120 months), LV function was persistently normal in all patients, with an LV aneurysm occlusion being observed in two patients. All patients were asymptomatic, with no VT recurrence or major clinical events. None required implantable electrical devices or a surgical intervention. CONCLUSIONS: LV aneurysms with normal global function caused by myocarditis are an uncommon benign entity in which major therapeutic regimens are usually unnecessary.

Coronary angiodysplasia of epicardial and intramural vessels.

A case of coronary angiodysplasia combining large aneurysms of epicardial arteries with diffuse malformation of intramural vessels is reported. Clinical presentation may mimic a vascularized cardiac tumor. Although leaking of the aneurysms in the pericardial space may occur, this entity seems to have a benign prognosis not requiring surgical repair.

Giant cell myocarditis responding to immunosuppressive therapy.

An unusual case of giant cell myocarditis presenting with cardiogenic shock that dramatically responded to conventional dose of steroids and azathioprine is reported. Cardiac recovery was rapid, complete (left ventricular ejection fraction rose to 55% from 10%), and was accompanied by the disappearance of the inflammatory infiltrates including giant cells in the control endomyocardial biopsy. Maintenance of the recovery at 16 months of follow-up on a low dose of azathioprine suggests that giant cell myocarditis might be a heterogeneous disease having either a negative untreatable trend necessitating cardiac transplantation, or a curable substrate responding to immunosuppressive drugs.

[A clinical screening can predict coronary artery disease in women]. / Un cribado clínico puede pronosticar la enfermedad arterial coronaria en la mujer.

INTRODUCTION AND OBJECTIVE: Cardiovascular disease is the leading cause of death in women. Approximately one of every two women will die of some cardiovascular event, such as myocardial infarction. Thereby, the significance of discarding or confirming coronary artery disease in women presenting with chest pain. The objective of this trial was to demonstrate that on the bases of the Douglas and Ginsburg's clinic screening, it is possible to predict the existence of coronary artery disease in the angiography. MATERIAL AND METHODS: For this research only women with angina pectoris were included. These were 189 patients (cineangiographies) whose clinical determinants and angiographic findings were related. RESULTS: Taking in to account the estimated likelihood, there was a low-risk group A with 29 patients, a moderate-risk group B with 55 patients and a high-risk group C with 105 patients. There was no significant coronary artery disease in the first group, there was a significant coronary artery disease in 13 patients in the second group and 72 patients in the third group. Group A had 0%, 72%, 0% and 47%, group B 15.2%, 59.6%, 23.6% and 46.3%, and group C had 84.7%, 68.3%, 68.5% and 84.5%, of sensibility, specificity, positive and negative predictive value, respectively. CONCLUSION: The usage of the Douglas and Ginsburg's clinic Screening is very effective at the time of deciding whether to perform a coronary angiograpy or not, and it has very good correlation between the probability degree and the presence of coronary artery disease in the coronary angiography.

[Tachycardia-induced tachycardia: definitive treatment with radiofrequency ablation. Presentation of three cases]. / Taquicardia que induce taquicardia: tratamiento definitivo con ablación con radiofrecuencia. Presentación de tres casos.

Tachycardia-induced tachycardia is the phenomenon in which one tachycardia degenerates into another. Few data are available in patients suffering from AV nodal reentrant tachycardia an atrial fibrillation. For related to AV nodal reentrant triggered by tachycardia; there is a possible effective treatment by eliminating the slow nodal pathway, with radiofrequency ablation, as shown by other authors. In this study we present data on three patients with repeated episodes of documented atrial fibrillation and at least one episode of AV nodal reentrant tachycardia or regular palpitations. Radiofrequency ablation of the slow AV nodal pathway was successfully performed in both, and at a follow up of 6, 9 and 10 months, respectively, no new episode of AV nodal reentrant tachycardia or atrial fibrillation was documented.

Cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy.

A case of cardiac variant of Fabry's disease mimicking hypertrophic cardiomyopathy is reported. The diagnosis was obtained by biventricular endomyocardial biopsy showing severely hypertrophied myocardiocytes with large periodic acid-Schiff and Sudan black positive perinuclear vacuoles, shown at electromicroscopy to consist of lamellated cytoplasmic figures highly suggestive of Fabry's disease, and confirmed by diagnostic low activity of alpha-galactosidase A in the peripheral lymphocytes. Invasive approach was suggested by the occurrence of a long-standing atrial fibrillation that failed to determine deterioration of cardiac function. Differential diagnosis between hypertrophic cardiomyopathy and the cardiac variant of Fabry's disease is relevant for prognostic and therapeutic implications including the perspective of an enzyme replacement therapy.

Histologically proven myocarditis in patients with biventricular dysfunction and severe asymptomatic coronary artery disease.

The aim of our study was to investigate the pathogenesis of the global biventricular dysfunction observed in patients with critical coronary artery stenosis, but no evidence of myocardial ischemia or infarction. From January 1992 to January 1997, among consecutive patients undergoing invasive cardiac study including biventricular endomyocardial biopsy because of progressive heart failure (NYHA functional class III-IV) associated with biventricular dysfunction and no history of myocardial ischemic events, 7 patients had severe coronary artery disease (three vessel 4 patients; two vessel 1 patient, proximal occlusion of left anterior descending artery 2 patients). At two-dimensional echocardiography left and right ventricular end-diastolic diameter were 73 +/- 10.5 and 39 +/- 7 mm, respectively, left ventricular ejection fraction was 0.23 +/- 6.5 and right ventricular ejection fraction was 0.29 +/- 7.2. Histology showed extensive lymphocytic infiltrates with focal myocytolysis meeting the Dallas criteria for myocarditis in all patients. Two patients with active inflammation received prednisone and azathioprine in addition to conventional drug therapy for heart failure. At 6-month follow-up cardiac volume and function improved in immunosuppressed patients (left ventricular ejection fraction from 15 to 50% and from 20 to 38%, respectively) while they remained unchanged in conventionally treated patients. In conclusion, global biventricular dysfunction in patients with severe asymptomatic coronary artery disease and no evidence of previous myocardial infarction may be caused by myocarditis rather than by myocardial ischemia or hibernation.