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.

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.

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.

Scintigraphic, electrocardiographic, and enzymatic diagnosis of perioperative myocardial infarction in patients undergoing myocardial revascularization.

To assess the incidence of perioperative myocardial infarction, 214 consecutive patients were evaluated 1-5 days after coronary bypass surgery, using Tc-99m pyrophosphate (TcPPi) myocardial imaging, serial electrocardiograms (ECG), and enzyme levels (SGOT, LDH, CPK). On the basis of the clinical course and scintigraphic, enzymatic, and ECG changes, the diagnosis of perioperative infarction was definite in 17 of 241 cases (7.9%) and probable in six of 241 (2.8%). In all of these 23 patients, TcPPi scans were abnormal; one additional patient had a false-positive scintigram. Only 13 of the 23 had ECG evidence of infarction, but there were no false positives. We set the threshold for abnormality of enzyme changes quite high, owing to experience in more than 900 postoperative patients (SGOT greater than 200, LDH greater than 500, CPK greater than 500 on the same day). Using these criteria, 22 of the 23 infarct patients had abnormal enzymes, and six others were falsely positive. These results indicate a relatively low sensitivity for the ECG in diagnosing perioperative infarction, but the lack of false positives suggests high specificity. The sensitivity and specificity of the enzymes and the TcPPi image were both excellent and quite similar; the main difference was a reduction of certainty of infarction with the enzyme criteria, caused by the six patients whose enzyme values were falsely positive. Considering its sensitivity, specificity, and ability to locate and to a certain extent quantitate necrosis. TcPPi imaging is probably the most valuable means of diagnosing perioperative myocardial infarction.

Is the treadmill exercise test useful for evaluating coronary artery disease in patients with complete left bundle branch block?

To aid in the study of coronary artery disease, 57 patients with complete left bundle branch block underwent clinical evaluation, treadmill exercise testing and cardiac catheterization. The patients were classified into two groups according to coronary angiographic findings: 30 patients with significant stenosis (70 percent or greater luminal narrowing) of at least one major vessel and 27 with no significant coronary artery disease. There was no difference in age, presenting symptoms or previous medical treatment between the two groups. There were more men in the group with coronary artery disease. Exercise-induced S-T changes were similar in the two groups; the sensitivity and specificity of these changes for the diagnosis of coronary artery disease were unacceptable irrespective of the criterion chosen. With additional S-T depression of either 1 or 2 mm below the baseline value, the predictive accuracy was only 53 percent. Combined exertional chest pain and 1 mm S-T depression increased the predictive accuracy of exercise testing to 71 percent. These data indicate that exercise-induced electrocardiographic changes do not facilitate detection of coronary artery disease in patients with complete left bundle branch block.

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.

Bedside evaluation of atrioventricular block with narrow QRS complexes: usefulness of carotid sinus massage and atropine administration.

Second-degree intra-His bundle block is frequently of type I (Wenckebach periods) or 2:1. In this situation, the surface electrocardiogram does not permit distinction between intranodal (atrioventricular [A-V] and subnodal (intra-His) block. This study examined the value of bedside carotid sinus massage and atropine administration in diagnosing the site of block from the standard electrocardiogram in subjects with chronic A-V block and narrow QRS complexes. Fifteen patients had intra-His bundle block and 10 had intranodal block. The combination of two tests correctly located the site of block in 22 subjects, and was noncontributory in 3. Thirteen of the 15 intra-His bundle blocks and 9 of the 10 intranodal blocks were properly identified; in three cases the results were nondiagnostic, but no wrong diagnoses were made. The noninvasive bedside method of carotid sinus massage and the use of atropine permit both the localization and the determination of the type of block in the majority of cases of second degree A-V block and narrow QRS complexes. In a proper clinical context they can obviate the need for invasive electrophysiologic studies.

Ultrasonic evaluation of thrombosis of Björk-Shiley aortic valve prosthesis.

Recognition of thrombosis of a Björk-Shiley aortic valve prosthesis 4 years after insertion in a patient was based upon sudden clinical deterioration, loss of prosthetic sounds, and development of new stenotic and regurgitant murmurs. Thrombotic fixation was confirmed by diagnostic alterations on the echocardiogram. All manifestations reverted to normal after successful surgical debridement of the prosthesis. Echocardiography is a valuable noninvasive adjunct in the differential diagnosis of prosthetic valve malfunction.

Ostial stenosis of the left main coronary artery in a young woman 10 years after radiation therapy.

A 26-year-old woman developed critical stenosis of the left main coronary artery 10 years after radiation treatment for Hodgkins disease. She was operated on but died in the immediate postoperative period. At autopsy the pathological findings were indistinguishable from those described in "typical" atherosclerotic plaques.

Results of total correction of tetralogy of Fallot performed in adults.

Today, total correction of tetralogy of Fallot is rarely performed in adults. In a 10-year period, 40 patients aged 20 to 67 years underwent intracardiac repair in our institution. Twenty-eight of them had had a palliative procedure 11 to 30 years earlier. Preoperatively, 23 patients were in New York Heart Association (NYHA) Functional Class II, 14 were in Class III, and 3 were in Class IV. Operative mortality was 2.5% (1/40). Follow-up ranged from 1 year to 11 years (average, 3 years). One patient died of a noncardiac cause 4 years after operation. Residual cardiac defects were observed in 4 patients. Postoperatively, 30 patients were in NYHA Functional Class I, 8 were in Class II, and 1 was in Class III. Major ventricular arrhythmias were recorded in 7 (35%) of 20 patients. Radionuclide angiography demonstrated impaired right ventricular function in 8 patients. Left ventricular impairment was present in 2. Total correction of tetralogy of Fallot can be performed safely in adults with low mortality and good functional improvement. The incidence of residual cardiac defects is low. The long-term importance of impaired ventricular function and arrhythmias remains to be ascertained.

Major sternal wound infection after open-heart surgery: a multivariate analysis of risk factors in 2,579 consecutive operative procedures.

From January, 1979, to December, 1984, at the Cardiac Surgery Department of the University of Torino Medical School, major sternal wound infections developed in 48 (1.86%) of 2,579 consecutive patients. These patients underwent open-heart procedures through a midline sternotomy and survived long enough for infection to appear. Possible risk factors were evaluated by means of a multivariate analysis. For the group of patients, we considered age, sex, hospital environment (different locations of our surgical facilities over the years), interval between hospital admission and operation, antibiotic prophylaxis, type of surgical procedure, elective or emergency surgical procedure, reoperation, duration of surgical procedures, duration of cardiopulmonary bypass, amount of blood transfused, postoperative blood loss, chest reexploration, rewiring of a sterile sternal dehiscence, duration of mechanical ventilation, and days of treatment in the intensive care unit. Univariate analysis indicated that age, sex, type and mode of surgical procedure, antibiotic prophylaxis, and duration of mechanical ventilation were not significantly associated with wound infection. For all other predisposing factors, a p value of less than .05 was demonstrated. These variables were entered in a multiple stepwise logistic regression. Six emerged as significant: hospital environment (p = .0001), interval between admission and surgery (p = .041), reoperation (p less than .0001), blood transfusions (p = .031), early chest reexploration (p less than .0001), and sternal rewiring (p less than .0001). Contamination of patients may occur before, during, and after operation, and any kind of reintervention may predispose to wound infection.

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.

Associated cardiac lesions in patients with radiation-induced complete heart block.

We investigated the clinical, electrophysiological, haemodynamic and angiographic aspects of four patients (two men and two women, aged 31-46 years) who developed complete heart block 13-20 years after therapeutic irradiation of the chest for Hodgkin's disease. The initial cardiac symptom was syncope in three, effort intolerance in one. The electrocardiogram recorded third-degree atrioventricular block in three patients, right bundle branch block and posterior fascicular block in one. The electrophysiological study, performed in three cases, showed that the block was infranodal in two. Three patients had significant coronary arterial stenoses, that involved the ostia in two. All patients had mild-to-moderate aortic and mitral regurgitation. One patient had haemodynamic signs of constriction. Another patient had recurrent pericardial effusions. All had echocardiographic evidence of a thickened pericardium. Cardiac involvement can be extensive in patient with radiation-induced heart block. Because coronary artery disease can be particularly severe, coronary angiography appears to be warranted in such patients.

Atypical chest pain: coronary or esophageal disease?

Retrosternal pain can be caused both by cardiac and esophageal disease. This work presents the results of cardiac and esophageal investigations in 55 patients, who had atypical chest pain. Isolated esophageal disease was found in 45% of the subjects while 14.5% had significant coronary arterial disease. Both diseases were found in 10.9% of the patients and neither disease in 29%. We conclude that esophageal disease is very frequent in patients with atypical chest pain but it does not always completely account for the symptoms. Such patients should, in our opinion, be submitted to an electrocardiographic stress test. If the result is positive or non-diagnostic, coronary cineangiography should be performed, irrespective of the results of esophageal investigations. If the electrocardiographic stress test is negative, coronary investigations can be deferred. Esophageal investigations can account for the symptoms in about half of such cases.

Absent pulmonary valve syndrome with associated anomalies of the pulmonary blood supply.

We report four cases of so-called absent pulmonary valve syndrome associated with absence or anomalous origin of the left pulmonary artery. The fate of the patients with this condition appears to be affected mainly by the occurrence of pulmonary complications (three of our patients died of pulmonary causes, two of them after surgery). The proper timing of corrective surgery is still uncertain. Preoperative investigations should strive to obtain a clear-cut identification of the pulmonary arteries, particularly the left one or, in its absence, of the anomalous vascular supply to the lung. Right ventriculography, as employed by us, is insufficient. Pulmonary angiography, aortography and pulmonary vein "wedge" angiography may be needed.

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.

Complicated removal of a hydatid cyst of the interventricular septum.

In a 27-year-old woman with a large hydatid cyst of the liver, an asymptomatic cardiac cyst located in the interventricular septum was discovered as well. The diagnosis was based upon echocardiography, computerized axial tomography and nuclear magnetic resonance. There was no evidence of damage to the atrioventricular conduction system or to the cardiac valves. At operation, however, the left posterior papillary muscle and chordae were firmly adherent to the cyst. Patch closure of the resulting ventricular septal defect, and mitral valve and chordae repair were necessary. The patient is alive and well 6 months after the operation, with mild residual mitral regurgitation. Precise anatomical delineation of the hydatid cyst localization within the heart, particularly in the interventricular septum, and its relations with the various cardiac structures is a difficult task, in spite of all the imaging techniques available. The surgical approach therefore has to be very careful and mindful of the potential complications.

Traumatic rupture of the thoracic aorta. (Report of two unusual cases).

Two unusual cases of traumatic aneurysm of the aorta are described. Both presented several days after thoracic trauma sustained in a car accident. The presenting features were progressing dysphagia and displacement of the oesophagus in the first case and a coarctation-like syndrome in the second. Diagnosis was confirmed in each case by aortography and emergency resection of the aneurysm with a dacron prosthesis was carried out. Aortic rupture should be considered in all cases of thoracic trauma, especially when severe, even several days after the trauma itself. Patients should be evaluated with serial chest roentgenograms and an aortography should be performed in any suspicious case. Treatment is surgical and the operative mortality and morbidity is acceptably low.