Enhancer of Zeste 2 (EZH2) is up-regulated in malignant gliomas and in glioma stem-like cells.

AIMS: Proteins of the Polycomb repressive complex 2 (PRC2) are epigenetic gene silencers and are involved in tumour development. Their oncogenic function might be associated with their role in stem cell maintenance. The histone methyltransferase Enhancer of Zeste 2 (EZH2) is a key member of PRC2 function: we have investigated its expression and function in gliomas. METHODS: EZH2 expression was studied in grade II-IV gliomas and in glioma stem-like cells (GSC) by quantitative PCR and immunohistochemistry. Effects of EZH2 down-regulation were analysed by treating GSC with the histone deacetylase (HDAC) inhibitor suberoylanide hydroxamic acid (SAHA) and by shRNA. RESULTS: DNA microarray analysis showed that EZH2 is highly expressed in murine and human GSC. Real-time PCR on gliomas of different grade (n = 66) indicated that EZH2 is more expressed in glioblastoma multiforme (GBM) than in low-grade gliomas (P = 0.0013). This was confirmed by immunohistochemistry on an independent set of 106 gliomas. Treatment with SAHA caused significant up-regulation of PRC2 predicted target genes, GSC disruption and decreased expression of EZH2 and of the stem cell marker CD133. Inhibition of EZH2 expression by shRNA was associated with a significant decrease of glioma proliferation. CONCLUSION: The data suggest that EZH2 plays a role in glioma progression and encourage the therapeutic targeting of these malignancies by HDAC inhibitors.

Follow-up of residual shunt after patent foramen ovale closure.

OBJECTIVES: Transesophageal echocardiography (TEE) is usually recommended in the evaluation of the patent foramen ovale (PFO). Our goal is to confirm the efficacy of contrast-enhanced transcranial Doppler (ce-TCD) in detecting residual significant right-to-left shunts (RLS) after PFO percutaneous closure. MATERIALS AND METHODS: Sixty-eight patients with a previous transient ischemic attack, stroke and a large PFO were investigated for residual RLS after percutaneous closure. RESULTS: Assuming TEE as the gold standard, the sensitivity and negative predictive value of ce-TCD was 100%, whereas the specificity was 75.8% and the positive predictive value was 28%. CONCLUSIONS: ce-TCD appears to be the preferable technique to identify subjects with significant residual shunts after percutaneous closure of a PFO. In follow-up, if ce-TCD is negative, no further examination may be necessary; whereas if ce-TCD shows a residual shunt, it is advisable to perform a TEE investigation.

Recurrent cerebrovascular ischaemic events in patients with interatrial septal abnormalities: a follow-up study.

The aim of this study was to evaluate the risk of recurrent ischaemic cerebrovascular events (stroke or transient ischaemic attack (TIA)) in patients with patent foramen ovale (PFO) or atrial septal aneurysm (ASA) treated with different therapeutic regimens. We enrolled 86 patients aged 18-60 years with an unexplained ischaemic stroke or TIA referred to our inpatient department in the period May 1994-December 1999. Follow-up lasted until April 2003. Patients were excluded if the stroke or TIA was related to large-artery atherosclerosis, small artery occlusion, major cardiac sources of embolism or other uncommon causes. During a follow-up (mean+/-SD) of 64.1+/-28.8 months (range 8.1-105.6) a recurrent ischaemic cerebrovascular event occurred in 11/86 patients (12.8%) (5 TIA and 6 strokes). Eight events (4 TIA, 4 strokes) occurred in the 59 patients with PFO alone, three (1 TIA, 2 strokes) in the 21 with PFO plus ASA and none in the 6 patients with ASA alone. In the overall population the cumulative risk of recurrent stroke/TIA was 1.2% at 2 years, 5.5% at 4 years, 7.6% at 6 years and 23.6% at 8 years, and was similar in patients with PFO alone vs. patients with PFO plus ASA (9.0% vs. 6.1% at 6 years, 26.0% vs. 23.1% at 8 years; p>0.05). Nine cerebral ischaemic events (4 TIA, 5 strokes) occurred in the 48 patients treated with antiplatelet drugs (7 in patients with PFO, 2 in patients with PFO plus ASA), and two (1 TIA, 1 stroke) in the 17 patients treated with oral anticoagulants (1 with PFO, 1 with PFO plus ASA). No events occurred in patients submitted to transcatheteral closure.

Surgical revascularization in the ischemic heart disease. Long-term results in a series of consecutive patients selected according to the principles.

AIM: Ischemic heart disease can be treated with drugs, percutaneous coronary interventions (PCI) and surgical revascularization (CABG). In our institution the therapeutic decisions for non emergent cases have been regularly taken during a daily meeting attended by clinicians, interventionalists, and surgeons, who all adhere to the principles of Evidence Based Medicine. The purpose of the present report is to investigate the long-term results in a series of consecutive patients to whom surgical revascularization has been recommended following the abovementioned approach. METHODS: We selected 597 patients with no prior interventions, who were referred to our institution for coronary angiography between January 1991 and December 1997 and to whom surgical revascularization was recommended. The Kaplan-Meier method was adopted to evaluate survival and freedom from: non fatal acute myocardial infarction, PCI, repeat CABG. RESULTS: The results were compared to those of the randomized trials or of large follow-up reports. The mean observation period was 6.8 years. The results at 5 and 10 years were: overall survival 95.5% and 90.2%; freedom from acute myocardial infarction 95.5% and 90.2%; freedom from surgical reintervention 98.6% and 97.1%; freedom from PCI 91.2% and 79.8%; survival free from all events 79.3% and 58.1%. These rates were comparable to those reported by the most important clinical trials. CONCLUSIONS: If surgical treatment for patient with coronary artery disease is recommended according to the suggestions of the leading clinical trials and pertinent guidelines, the results in terms of mortality and morbidity are comparable to those of the trials themselves, even in the non selected patients of daily clinical practice.

[Functional assessment of mitral stenosis]. / La valutazione funzionale della stenosi mitralica.

The following parameters must be taken into account when assessing the severity of mitral stenosis: symptoms, objective examination, electrocardiogram, chest X-ray, a simple exercise test with or without cardiopulmonary test, echocardiography and lastly a hemodynamic test. Differences are often observed between the clinical and instrumental findings. In these cases a major contribution is made by the use of physical effort in response to both ECG and heart catheterization in order to quantify the patient's functional deficiency and valve response. The latter aspect must be validated using a simultaneous comparison between echocardiography and the hemodynamic test and longitudinal clinical studies.

Different patterns of atrial activation in idiopathic atrial fibrillation: simultaneous multisite atrial mapping in patients with paroxysmal and chronic atrial fibrillation.

OBJECTIVES: We aimed to evaluate: 1) the behavior of electrical activity simultaneously in different atrial regions during atrial fibrillation (AF); 2) the difference of atrial activation between paroxysmal and chronic AF; 3) the atrial refractoriness dispersion; and 4) the correlation between the effective refractory periods (ERPs) and the FF intervals. BACKGROUND: Little data exist on the electrophysiologic characteristics of the different atrial regions in patients with AF. A more detailed knowledge of the electrical activity during AF may provide further insights to improve treatment of AF. METHODS: Right and left atria were extensively mapped in 30 patients with idiopathic AF (18 paroxysmal and 12 chronic). In different atrial locations, we analyzed 1) the FF interval duration; and 2) the grade of organization and, in case of organized electrical activity, the direction of atrial activation. Furthermore, in patients with paroxysmal AF, we determined the atrial ERP, evaluated the ERP dispersion and assessed the presence of a correlation between the ERPs and the FF intervals. RESULTS: In patients with chronic AF, we observed a shortening of the FF intervals and a greater prevalence of disorganized activity in all the atrial sites examined. In patients with paroxysmal AF, a significant dispersion of refractoriness was observed. The right lateral wall showed longer FF intervals and more organized atrial activity and, unexpectedly, the shortest mean ERPs. In contrast, the septal area showed shorter FF intervals, greater disorganization and the longest mean ERPs. CONCLUSIONS: Electrical activity during AF showed a significant spatial inhomogeneity, which was more evident in patients with paroxysmal AF. The mean FF intervals did not correlate with the mean ERPs.

Atrial mapping by basket catheter in patients with atrial fibrillation submitted to linear ablation.

Recently non-pharmacological therapies for atrial fibrillation (AF) have been developed. The electrophysiological mechanisms of AF is thought to be the development of multiple reentrant wavelets circulating around anatomic barriers and variable regions of functional conduction block responsible of the perpetuation of the arrhythmia. Also the role of the triggering foci has been highlighted. To cure AF by means of non pharmacological therapy we may eliminate and/or modify the substrate. To better understand the mechanism underlying the AF and to choose the best ablation strategy is of fundamental importance to map the right and the left atrium during AF. Our experience shows that in chronic idiopathic AF disorganized atrial activity is observed at all atrial regions while in paroxysmal idiopathic AF the left septum and the right atrial posterior areas are highly disorganized while the lateral region shows more organized atrial electrical activity. Multipolar basket catheters are extremely useful in mapping right and left atrium in order to guide the best ablation strategy.

[Ischemic cardiovascular diseases. Correlation with Helicobacter pylori infection]. / Patologie cardiovascolari ischemiche. Correlazione con l'infezione da Helicobacter pylori.

Coronary heart disease is the primary cause of mortality in western countries. The well-established ("classical") risk factors cannot fully explain epidemiological variations of this disease. From several years infections have been linked to ischemic vascular events and recent studies pointed to the role of Helicobacter pylori (H. pylori), a spiral Gram negative bacterium, that chronically infects human stomach and is involved in the pathogenesis of gastritis and peptic ulceration. Systematic reviews of studies have suggested the existence of a possible weakly positive association between this bacterium and coronary heart disease, but this could be due to confounding bias and influenced by the degree of investigations heterogeneity. Experiments from animal studies demonstrated that H. pylori infection in mice induces the formation of platelet aggregates and in contrast to Chlamydia pneumoniae it has not been found in the plaque: therefore, the role of H. pylori, could be even more important in the acute phase of myocardial infarction. There is the need for extensive prospective studies to evaluate the incidence of these diseases in relation to the presence of H. pylori infection. Appropriately randomized studies employing an antibiotic treatment for patients affected by ischemic vascular disease will answer the question of whether H. pylori has a causal role in the pathogenesis of acute myocardial infarction and ischemic stroke.

Primary pulmonary hypertension.

Primary Pulmonary Hypertension (PPH) is a rare disease that progressively increases pulmonary arterial pressure and pulmonary vascular resistance to the point of right heart failure, in the absence of secondary causes of the disease. The following specific risk factors that can trigger PPH have been identified and examined: appetite depressant drugs, oral contraceptives and hyperuricaemia. Familial PPH transmitted by an incomplete penetrance dominant autosomic mechanism is responsible for about 6% of PPH cases. Recent research groups have identified the gene responsible for familial PPH. Since pulmonary vasoconstriction is the prime cause of PPH, vasodilation of the pulmonary arterial circulation system (using prostacyclin in the form of epoprostenol or iloprost) is the main aim of treatment.

Ischemic cardiovascular disease and Helicobacter pylori. Where is the link?

Coronary heart disease (CHD) is the leading cause of death in western countries. Although several major risk factors have been identified, they fail to account for all the epidemiological variants of the disease, thus warranting research into novel causal agents. Cardiovascular diseases have long been associated with chronic infections acting through the activation of inflammatory pathways, and antibiotic therapy has been shown to produce a dramatic decrease in the rate of disease recurrence in patients with a history of myocardial infarction or unstable angina. The link between Helicobacter pylori (H. pylori) infection and CHD, first described by Mendall et al. in 1994, has been the subject of a multitude of epidemiological and clinical studies; however, these have been so heterogeneous that not two of them are based on a comparable selection of patients and focused on the same kind of disease, e.g. stable coronary heart disease or acute myocardial infarction. Evidence from animal studies supports the thesis that H. pylori plays an extremely important role in the acute phase of myocardial infarction: the bacterium causes platelet aggregation and induces pro-coagulant activity in experimentally infected mice. H. pylori may also contribute to atherosclerosis through an auto-immune process against endothelial cells or an increased concentration of homocysteine in the blood due to decreased levels of folic acid and cobalamin. The exact role of H. pylori cannot yet be fully assessed: there is a clear and present need for further studies with appropriate epidemiological and clinical approaches to investigate through prospective and interventional trial the possible causal relationship between H. pylori and CHD.

Early and late risk factors in surgical treatment of acute type A aortic dissection.

BACKGROUND: Morbidity and mortality of emergency repair of type A dissecting aneurysms of the aorta are high. This is an attempt to investigate the risk determinants of early and late results. METHODS: A series of preoperative and operative variables were retrospectively collected from the clinical records of 291 patients operated on between January 1, 1979, and December 31, 1995. Risk factors for surgical death were investigated with univariate analysis and stepwise logistic regression. Follow-up was conducted between December 1995 and February 1996. Analysis of late results was conducted by means of actuarial survival curves (life method). After removing the surgical deaths, risk factors for late deaths were analyzed by a Cox model. RESULTS: The in-hospital mortality rate was 36.1%. Significant independent determinants of operative or early death were preoperative shock, preoperative neurologic impairment, operation before 1986, perioperative bleeding, and prolonged clamping time. The 10-year survival rate was 36.9% +/- 4.4%. Twenty-six patients required repeat operation. The long-term prognosis was significantly worse in patients who needed reoperation. CONCLUSIONS: Growing awareness of this disease and quicker diagnosis have increased the number of patients with acute dissection of the ascending aorta who are taken early to operation. This new challenge must be met by better preoperative support and intraoperative monitoring, and by surgical techniques that focus on lowering the rate of late complications, for which lifelong follow-up must be provided.

Ischemic chest pain and global T-wave inversion in women with normal coronary angiograms.

Patients presenting with ischemic chest pain and electrocardiographic evidence of global T-wave inversion are most frequently women with intact left ventricular function and no critical stenosis of major coronary vessels. Hence, this syndrome has a good immediate and long-term prognosis.

[Hypertrophic obstructive cardiomyopathy in a patient with Turner syndrome]. / Cardiomiopatia ipertrofica ostruttiva in una paziente con sindrome di Turner.

A case of hypertrophic obstructive cardiomyopathy in a patient with Turner syndrome is reported. The most frequently associated cardiac anomalies are coarctation of the aorta and bicuspid aortic valve. Hypertrophic cardiomyopathy has never been reported in this syndrome but is frequent in Noonan syndrome. In these two conditions the phenotype may be indistinguishable but the cariotype is different: normal in Noonan and 45X in Turner syndrome. Our patient had the typical somatic features, and the cariotype was 45X in all examined cells. A familial form of hypertrophic cardiomyopathy was excluded by the normal clinical examination of other members of the family. The presence of hypertrophic cardiomyopathy also in Turner syndrome and the recent localization on the long arm of the chromosome 12 of the gene for Noonan syndrome might postulate a common pathogenesis of the two syndromes.