Soluble form of the endothelial adhesion molecule CD146 binds preferentially CD16+ monocytes.

The cell adhesion molecule CD146 is normally located at the endothelial cell-to-cell junction and colocalizes with actin cytoskeleton. The soluble form of CD146 (sCD146) has been identified in the endothelial cell supernatant and in normal human plasma, and is increased in pathologic conditions with altered endothelial function. Soluble CD146 binding to monocytes promotes their transendothelial migration, which represents a central step in the development of atherosclerotic plaque. Since peripheral blood monocytes are characterized by a phenotypic and functional heterogeneity, with different transendothelial migration capacity, we hypothesized that monocyte subsets differently bind sCD146. Based on surface CD14 and CD16 expression monocytes were distinguished by flow cytometry (FACS) into three subsets: CD14++/CD16-, CD14++/CD16+ and CD14+/CD16+. CD16+ monocytes have been found to possess higher transendothelial migration ability. FACS analysis on blood monocytes from 30 healthy subjects revealed that higher percentages of CD14++/CD16+ (median, first and third quartile: 2.26, 1.62-3.87) and of CD14+/CD16+ (2.59, 1.28-4.80) were positive for CD146 (both p < 0.01), in comparison to CD14++/CD16- (0.66, 0.47-1.01). Moreover, in vitro treatment of ficoll separated monocytes with recombinant CD146 showed that both CD16+ subsets increased their percentage of CD146-positive events compared to CD16- monocytes (p < 0.01). Soluble CD146 levels were evaluated by ELISA in plasma samples of subjects from our study group and showed a correlation with percentage of CD146-positive CD14+/CD16+ monocyte subset. In this work we have demonstrated that monocyte subsets behave differently with regard to their sCD146 binding activity; because binding of CD146 influences transendothelial migration of monocytes, modulation of monocyte-CD146 interaction may represent a potential target to limit atherosclerotic plaque development.

A dangerous fruit juice.

We report the case of a female patient presenting to the emergency department with postprandial syncope and atrial fibrillation. After amiodarone administration, the electrocardiogram showed marked QT prolongation associated with ventricular arrhythmias, including an episode of torsade de pointes requiring immediate electrical cardioversion. During history taking, the patient reported that she had been drinking large amounts of grapefruit juice regularly. The inhibition of amiodarone metabolism induced by grapefruit juice was responsible for enhancing the proarrhythmic effects of the drug with development of electrical storm.

Sublethal doses of an anti-erbB2 antibody leads to death by apoptosis in cardiomyocytes sensitized by low prosenescent doses of epirubicin: the protective role of dexrazoxane.

The cardiotoxic synergism resulting from the sequential treatment with anthracyclines and trastuzumab has been attributed to the trastuzumab-induced loss of the erbB2-related functions that serve as a salvage pathway against the damaging effects of anthracyclines. Cellular senescence is a novel mechanism of cardiotoxicity induced by subapoptotic doses of anthracyclines. After having identified prosenescent and proapoptotic doses of epirubicin and rat MAb c-erbB2/Her-2/neu Ab-9 clone B10 (B10), an anti-erbB2 monoclonal antibody, we investigated the effects of the sequential treatment with prosenescent doses of both drugs on H9c2 cells and neonatal rat cardiomyocytes pretreated with or without the cardioprotective agent dexrazoxane. Cells were analyzed by senescence-associated beta-galactosidase, single-stranded DNA, annexin/propidium double staining, F-actin, and mitochondrial transmembrane potential. ErbB2 expression levels, AKT activation, and the effects of the inhibition of nicotinamide adenine dinucleotide phosphate oxidase [NAD(P)H oxidase] and phosphoinositide-3-OH kinase (PI3K) were also assessed. Data demonstrate that 1) the toxic effects of epirubicin mainly occur through NAD(P)H oxidase activation; 2) the erbB2 overexpression induced by epirubicin is a redox-sensitive mechanism largely dependent on NAD(P)H oxidase; 3) the loss of erbB2-related functions caused by B10 determines marginal cellular changes in untreated cells, but causes massive death by apoptosis in cells previously exposed to a prosenescent dose of epirubicin, 4) dexrazoxane promotes survival pathways, as demonstrated by the activation of Akt and the PI3K-dependent erbB2 overexpression; and 5) it also prevents epirubicin-induced senescence and renders epirubicin-treated cells more resistant to treatment with B10. Data underline the importance of NAD(P)H oxidase in epirubicin-induced cardiotoxicity and shed new light on the protective mechanisms of dexrazoxane.

Doxorubicin induces senescence or apoptosis in rat neonatal cardiomyocytes by regulating the expression levels of the telomere binding factors 1 and 2.

Low or high doses of doxorubicin induce either senescence or apoptosis, respectively, in cardiomyocytes. The mechanism by which different doses of doxorubicin may induce different stress-response cellular programs is not well understood. A recent study showed that the level of telomere dysfunction may induce senescence or apoptosis. We investigated the pathways to both apoptosis and senescence in neonatal rat cardiomyocytes and in H9c2 cells exposed to a single pulsed incubation with low or high doses of doxorubicin. High-dose doxorubicin strongly reduces TRF2 expression while enhancing TRF1 expression, and it determines early apoptosis. Low-dose doxorubicin induces downregulation of both TRF2 and TRF1, and it also increases the senescence-associated-beta-galactosidase activity, downregulates the checkpoint kinase Chk2, induces chromosomal abnormalities, and alters the cell cycle. The involvement of TRF1 and TRF2 with apoptosis and senescence was assessed by short interfering RNA interference. The cells maintain telomere dysfunction and a senescent phenotype over time and undergo late death. The increase in the phase>4N and the presence of micronuclei and anaphase bridges indicate that cells die by mitotic catastrophe. p38 modulates TRF2 expression, whereas JNK and cytoplasmic p53 regulate TRF1. Pretreatment with specific inhibitors of MAPKs and p53 may either attenuate the damage induced by doxorubicin or shift the cellular response to stress from senescence to apoptosis. In conclusion, various doses of doxorubicin induce differential regulation of TRF1 and TRF2 through p53 and MAPK, which is responsible for inducing either early apoptosis or senescence and late death due to mitotic catastrophe.

Increased neutrophil lifespan in patients with congestive heart failure.

AIMS: Congestive heart failure (CHF) can be thought of as a state of chronic immune activation. Polymorphonuclear neutrophil (PMN) apoptosis is one of the mechanisms responsible for the resolution of inflammation. A reduced PMN apoptotic rate in CHF patients may generate a persistent inflammatory response and hence mediate tissue damage in this group of patients. We aimed to measure levels of spontaneous apoptosis of circulating PMNs in CHF patients and in controls, and to examine whether NYHA class, left ventricular ejection fraction (LV-EF), and laboratory parameters of inflammation, endothelial damage, and of liver and renal function, could predict the rate of PMN apoptosis in CHF patients. METHODS AND RESULTS: A total of 29 CHF patients and 26 controls were studied. Propidium iodide and flow cytometry were used to assess PMN apoptosis. Delay in PMN apoptosis was expressed as percentage (expressed as median, first and third quartiles) of surviving PMNs in the study subjects. We found an increased percentage of surviving PMNs [38(27.1-47.1)] in CHF patients compared with controls [19.4 (15.8-25.2)] (P < 0.05). The PMN survival rate in the CHF group was correlated to NYHA class, and plasma levels of C-reactive protein and alkaline phosphatase, while it was inversely correlated to LV-EF and protein levels. A positive relationship between PMN survival and increased ex vivo endothelial apoptosis was found. CONCLUSION: Increased PMN lifespan in patients with worsening CHF could be used as a novel measurement of tissue and endothelial damage in this group of patients.

Percutaneous closure of patent foramen ovale in patients with presumed paradoxical embolism: periprocedural results and midterm risk of recurrent neurologic events.

OBJECTIVE: To report our data on selected patients with previous paradoxical embolism who underwent transcatheter patent foramen ovale (PFO) closure. METHODS: Between July 2001 and July 2007, percutaneous PFO closure was performed on 128 patients (65 women, mean age: 46 +/- 12.8 years). Patent foramen ovale closure was recommended for secondary prevention in patients with previous transient ischemic attacks (52.5%), stroke (46%), or peripheral embolism (1.5%). RESULTS: Implantation was successful in all patients, and at the end of intervention, complete PFO closure was achieved in 70.3% of them. There were no "major" complications (ie, deaths, device embolization or thrombosis, need for cardiac surgery). The overall incidence of complications (mostly hemorrhagic) was 7%. The mean follow-up period was 32 months. Complete closure had been achieved in 78.4% and in 82.5% of patients at the third month of transesophageal echocardiography examination and at the sixth month of transcranial Doppler examination, respectively. There were no recurrent thromboembolic events during the follow-up period. CONCLUSIONS: Percutaneous closure of PFO is a feasible procedure, but it is not a risk-free technique. However, in correctly selected patients (ie, large PFO and those at risk for neurologic relapse), nearly complete PFO closure seems to provide protection from future neurologic ischaemic events at midterm follow-up.

Beneficial effects of trimetazidine treatment on exercise tolerance and B-type natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy.

BACKGROUND: In patients with ischemic cardiomyopathy, mortality rate and quality of life are unsatisfactory. We investigated the effects of the metabolic agent trimetazidine (TMZ) on exercise tolerance and prognostic markers B-type natriuretic peptide (BNP) and cardiac troponin T (cTnT) plasma levels. METHODS: Fifty patients with ischemic cardiomyopathy were randomized either to receive TMZ (20 mg, TID) in addition to their conventional treatment (TMZ group, n = 25) or to continue their usual drug therapy (control group, n = 25) for 6 months. Patients were evaluated at baseline, at 1 month, and at 6 months (echocardiography and 6-minute walking test). At enrollment and at the end of follow-up, blood testing was performed for determination of BNP and cTnT plasma levels. RESULTS: After 6 months, no significant New York Heart Association class changes occurred in all patients (P = NS). In the TMZ group, a significant increase of exercise tolerance (P < .01) was detected, whereas left ventricular ejection fraction was unchanged (28% +/- 4%, 29% +/- 5%, and 32% +/- 5% at baseline, at 1 month, and at 6 months, respectively; P = NS). In the TMZ group, BNP was significantly reduced (6 months, 135 +/- 22 vs 252 +/- 44 pg/mL; P < .001), whereas it was significantly increased in controls (6 months, 288 +/- 46 vs 239 +/- 59 pg/mL; P < .02); cTnT significantly (P < .001) reduced during TMZ treatment, whereas it was unchanged in the control group. CONCLUSIONS: Six-month TMZ treatment improves exercise tolerance and reduces plasma levels of BNP and cTnT in patients with compensated ischemic cardiomyopathy.

An arrhythmic storm: a potential complication on opening the umbrella for percutaneous closure of interatrial communications.

Interatrial communications (ICs) have been linked to paradoxic embolism, which may be prevented using both surgical and percutaneous interventions. The case of a 61-year-old woman with a history of transient cerebral ischemic attack who developed repetitive ventricular arrhythmias and an intermittent left branch bundle block immediately after percutaneous closure of an IC is described. Transthoracic echocardiography showed that the device had migrated into the left ventricular outflow tract, and the patient consequently underwent emergency cardiac surgery to retrieve the device and repair the IC. In conclusion, percutaneous transcatheter closure of ICs is more rapid and less invasive compared with surgery, but nevertheless may be associated with significant short-term morbidity.

Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase.

OBJECTIVE: Dysregulation of myocardial metalloproteinases (MMPs) is now regarded as an early contributory mechanism for the initiation and progression of heart failure. Doxorubicin is a strongly cardiotoxic anticancer drug. This study investigates the effects of doxorubicin on myocardial MMP-2 and MMP-9 activation. METHODS: After pre-treatment with or without carvedilol or dexrazoxane, we exposed H9c2 cardiomyocytes to doxorubicin to evaluate reactive oxygen species (ROS) formation and MMP-2 and MMP-9 expression and activation. To investigate the signaling pathways leading to doxorubicin-induced MMP activation, we also examined the phosphorylation of three members of the MAPK family (ERK1/2, p38, and JNK), the effects of selective inhibitors of ERK1/2, p38, and JNK on MMP transcription and activity, the transcription of the NAD(P)H oxidase subunit Nox1, and the effects of the NAD(P)H oxidase inhibitor DPI on MMP activation. RESULTS: Doxorubicin induces a significant increase in ROS formation and a rapid increase of MMP expression and activation. Pre-treatment with carvedilol or dexrazoxane prevented these effects. We also found that p38 is the MAPK that is mainly responsible for MMP-9 activation through an NAD(P)H-independent mechanism. ERK and JNK modulate the transcription of the NAD(P)H oxidase subunit Nox1, while the JNK/ERK NAD(P)H oxidase cascade is an important pathway that mediates doxorubicin signaling to MMP-2. Inhibition of NAD(P)H oxidase attenuates the increase in MMP-2, but augments the doxorubicin-induced increase in MMP-9. CONCLUSIONS: Enhancement of MMP-2 and MMP-9 in cardiac myocytes in response to doxorubicin is mediated by the cooperation of ERK, JNK, and p38 kinase pathways, most of which are redox dependent.

C242T polymorphism in CYBA gene (p22phox) and risk of coronary artery disease in a population of Caucasian Italians.

BACKGROUND: specific polymorphisms of genes regulating intracellular redox balance and oxidative stress are related to atherogenesis. Some studies have identified a relationship between progression of atherosclerosis and C242T mutation in CYBA gene coding for p22phox, a subunit of the NADH/NADPH oxidase system. DESIGN: we investigated whether the C242T nucleotide transition is associated with the presence of coronary artery disease (CAD) in a population of 494 Caucasian Italians undergoing coronary angiography to diagnose the cause of chest pain. RESULTS: the frequency of the T mutant allele that we found in 276 patients with angiographically documented CAD was significantly higher compared to what we observed in 218 subjects with normal coronary arteries (Controls) (respectively: 0.400 and 0.332, p<0.01). The prevalence of the T allele was even stronger when we compared: 1) early onset (age < or =55) vs late onset (age > or =65) single-vessel CAD patients (respectively: 0.75 and 0.48, p<0.05), and 2) the subgroup of CAD patients with at least one > or =98% stenosis in a coronary vessel vs those with no > or =98% stenosis in a coronary vessel (respectively: 0.425 and 0.365, p<0.05). CONCLUSIONS: these results support the increased risk of developing early CAD and of having rapid progression of coronary stenosis in subjects carrying the C242T nucleotide transition among the Italian population.

Admission C-reactive protein serum levels and survival in patients with acute myocardial infarction with persistent ST elevation.

OBJECTIVE: To evaluate the prognostic value of a single and early determination of high sensitivity C-reactive protein levels at admittance in patients with acute myocardial infarction with persistent ST elevation. PATIENTS AND METHODS: We evaluated high-sensitivity C-reactive protein levels in 247 consecutive acute myocardial infarction with persistent ST elevation patients at admittance. Patients were monitored for the occurrence of major adverse cardiovascular events. RESULTS: Mean follow-up was 26 months. High C-reactive protein levels were principally associated with age > or = 65 years (P=0.01), diabetes (P=0.03) and reduced left ventricle ejection fraction (P=0.048). We observed a significant C-reactive protein level difference between the major adverse cardiovascular event-free group and the major adverse cardiovascular event group (28.2+/-21.9 vs. 47.7+/-31.9 mg/l, P=0.03), between deceased patients group (vs. 81.5+/-51.8 mg/l, P<0.001) and early deaths (vs. 129.5+/-71.9 mg/l, P<0.001). Kaplan-Meier plots for survival and major adverse cardiovascular event occurrence showed a significant separation (P=0.01 and 0.002 by log-rank test, respectively) between high and low C-reactive protein level groups. C-reactive protein levels were independent risk predictors of major adverse cardiovascular events (odds ratio 2.931, 95% confidence interval 1.512-5.893; P=0.046) and death (odds ratio 5.068, 95% confidence interval 2.056-20.195; P=0.04). Patients with high C-reactive protein levels and age > or = 65 years were at highest risk for major adverse cardiovascular event occurrence (odds ratio 5.658, 95% confidence interval 2.898-6.249; P=0.022) and death (odds ratio 8.120, 95% confidence interval 5.656-22.729; P=0.03). CONCLUSIONS: High C-reactive protein levels identify patients with a worse prognosis after acute myocardial infarction with persistent ST elevation. The evaluation of C-reactive protein and age may provide a tool to select high-risk patients.

Chronic treatment with rosuvastatin modulates nitric oxide synthase expression and reduces ischemia-reperfusion injury in rat hearts.

OBJECTIVE: Due to reported modulatory effects of statins on nitric oxide synthase (NOS) expression, we tested the hypothesis of protective effects of in vivo chronic treatment with rosuvastatin, a novel 3-hydroxy-3-methyl-glutaryl coenzyme A-reductase inhibitor, on ischemia-reperfusion injury, and investigated mechanisms involved. METHODS: After 3 weeks of in vivo treatment with rosuvastatin (0.2-20 mg/kg/day) or placebo, excised hearts from Wistar rats were subjected to 15 min global ischemia and 22-180 min reperfusion. We evaluated creatine-phosphokinase and nitrite levels in the coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and the expression of endothelial (e) and inducible (i) nitric oxide synthase (NOS) (by reverse-transcription polymerase chain reaction and Western blotting). RESULTS: Rosuvastatin 0.2 and 2 mg/kg/day significantly reduced myocardial damage and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions. At 2 mg/kg/day, rosuvastatin significantly increased eNOS mRNA and protein compared with untreated hearts, and conversely decreased iNOS mRNA and protein, as well as nitrite production after ischemia-reperfusion. The addition of the NOS inhibitor N(omega)-nitro-L-arginine methylester (L-NAME, 30 micromol/L) significantly reduced cardioprotection against ischemia-reperfusion. CONCLUSIONS: Chronic treatment with rosuvastatin before ischemia reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms.

Acute coronary syndromes do not promote prolonged in vivo FXII-dependent prothrombotic activity.

BACKGROUND: Coagulation FXII is activated on contact with lipoprotein particles. It has been suggested that contact with subendothelial tissue provides an alternative biological surface for FXII activation. Our aim was to investigate whether activated FXII (FXIIa) is elevated in patients with coronary atherosclerosis, and whether disease status (acute phase or stable state) affects circulating levels of FXIIa. METHODS: Circulating FXIIa levels were measured in the peripheral blood of 122 patients with coronary atherosclerosis (32, stable angina; 54, unstable angina; 36, nQ myocardial infarction) and in 45 age-matched subjects (Contr). RESULTS: FXIIa levels (median, first and third quartiles; ng/ml) were higher in patients than in Contr: 1.61 (1.26-2.02) vs. 1.34 (1.13-1.81) (p<0.01). FXIIa levels were similar among patients with stable angina [1.66 (1.23-1.91)], unstable angina [1.53 (1.21-2.04)], and nQ myocardial infarction [1.75 (1.34-2.03)]. The three groups of patients had similar prevalence for most atherothrombotic risk factors; patients with stable angina had an increased severity of coronary disease, which did not explain the different levels of FXIIa. Fasting levels of triglycerides were the best predictor of FXIIa levels in our patients. CONCLUSIONS: The finding of similar FXIIa levels among patients in either acute or chronic phases of coronary atherosclerosis suggests that the initial arterial denudation and the acute-phase response associated to acute coronary syndromes are not major determinants for prolonged FXII activation.

Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy.

BACKGROUND: Apoptosis has been implicated as a possible mechanism in the development of heart failure (HF), but the mechanisms involved remain unclear. In patients with severe dilated cardiomyopathy, we evaluated cardiomyocyte apoptosis in relation to the transmural distribution of Bax and Bcl-2 proteins (2 molecules inhibiting or promoting apoptosis, respectively) and left ventricular wall stresses. METHODS: We studied the presence and distribution of cardiomyocyte apoptosis in 90 tissue samples obtained from 8 patients who were undergoing left ventricular reduction with the Batista (ventricular remodeling) operation. Apoptosis was assessed in tissue samples taken from the entire left ventricular thickness (subdivided in subepicardial, midmyocardial, and subendocardial sections) with the terminal deoxynucleotidyl transferase mediated dUTP-biotin nick-end labeling (TUNEL) technique and DNA agarose gel electrophoresis. The expression of Bcl-2 and Bax proteins were determined with both Western analysis and immunohistochemistry. RESULTS: TUNEL-positive cells (apoptotic index) were 2.3% +/- 1.4%. Apoptotic cells were predominantly distributed in the subendocardium, where higher levels of Bax protein were detected. The ratio of Bax to Bcl-2 proteins (Bax/Bcl-2) was similar in the midmyocardium or subepicardium, but increased in the subendocardium, where it was directly related to systolic wall stress (y = 0.009x - 0.629; r2 = 0.85, P <.001). The apoptotic index was also directly related to systolic and end-diastolic stresses calculated from hemodynamic and echocardiographic data (r2 = 0.77, P <.001 and r2 = 0.40, P <.01, respectively). CONCLUSIONS: In patients with dilated cardiomyopathy, in whom cardiomyocyte apoptosis is an important cause of cell loss, apoptosis is more extensively localized in the subendocardium and strictly related to ventricular wall stresses and the Bax/Bcl-2 ratio.

[Trimetazidine and cardioprotection during ischemia-reperfusion]. / Trimetazidina e cardioprotezione durante ischemia-riperfusione.

Although early reperfusion of ischemic myocardium is now considered to be the only intervention able to restore the various cellular functions altered by ischemia and to prevent progression toward cell death of myocardial cells due to necrosis or apoptosis, reperfusion is accompanied by various manifestations grouped under the heading of reperfusion damage or reperfusion syndrome. Functional recovery is therefore not immediate, but usually appears after a certain delay following a period of contractile dysfunction (myocardial stunning) lasting for several hours or even days after the start of reperfusion. The cellular mechanisms underlying the reperfusion damage may involve cellular calcium overload, over-production of oxygen-derived free radicals, cellular acidosis, inflammatory reaction, and microcirculatory dysfunction. Numerous pharmacological studies have been conducted to limit such reperfusion injury and, consequently, prevent stunning and/or reperfusion-induced arrhythmias. A number of experimental and clinical studies have demonstrated the beneficial effects of trimetazidine, a drug that inhibits the long-chain mitochondrial 3-ketoacyl coenzyme A thiolase enzyme in the myocyte, resulting in a shift from fatty acid oxidation to glucose oxidation. This optimization of cardiac metabolism results in direct anti-ischemic effects, limiting calcium accumulation and acidosis, inflammation and oxygen free radical production, and improvement of coronary microcirculation following reperfusion. This agent appears to be particularly promising clinically in the treatment of reperfusion injury, for example in combination with reperfusion strategies during the acute phase of myocardial ischemia or infarction, or in the reduction of the pro-remodeling effects of ischemia in patients with chronic ischemic syndrome and left ventricular dysfunction.

Influence of device selection on angiographic outcomes for the treatment of in-stent restenosis. A sub analysis from the Washington Radiation for In-Stent restenosis Trial (WRIST).

BACKGROUND: Treatment of in-stent restenosis is still a challenge. Despite promising results obtained with intracoronary brachytherapy (ICB), the ideal strategy of device selection has not been identified. The aim of this study was to evaluate the influence of device selection on ICB for the treatment of instant restenosis. METHODS: The outcomes of 130 patients from the Washington Radiation for In-Stent restenosis Trial (WRIST) were studied. Patients were analyzed on the basis of device selection, prior to randomization to gamma-radiation (n = 65) or placebo (n = 65): balloon angioplasty (PTCA) (n = 15, 12%), rotational atherectomy (RA) (n = 40, 31%), excimer laser coronary angioplasty (ELCA) (n = 28, 22%) or additional stent implantation (n = 47, 36%). RESULTS: PTCA was less frequently used in lesions with prior in-stent restenosis (14.8%, p < 0.05); ELCA was less frequently used in saphenous vein grafts (57.1%, p < 0.05). The procedural outcomes and restenosis rates were similar among groups. In the RA group, patients assigned or Ir192 had a larger minimal lumen diameter (1.6 +/- 0.5 vs 0.9 +/- 0.4 mm, p < 0.05) and lower diameter stenosis (39 +/- 7 vs 65 +/- 16%, p < 0.05) at follow-up angiography and a reduced late loss (0.2 +/- 0.5 v 0.9 +/- 0.5 mm, P < 0.05) and loss index (0 +/- 0.4 vs 0.8 +/- 0.4, p < 0.05) when compared to placebo. The incidence of delayed thrombosis was 7.7% in the ICB and 4.6% in the placebo group (p = 0.71); additional stenting, either alone (relative risk 12.36, 95% confidence interval 1.56 divided by 94.43) or followed by ICB (relative risk 3.80, 95% confidence interval 1.02 divided by 14.27), was correlated with an increased risk of late thrombosis. CONCLUSIONS: ICB reduces the recurrence of in-stent restenosis through a reduction in late loss. In view of the higher risk of delayed thrombosis, additional stenting, either alone or followed by ICB, should be used with caution.

Diagnostic work-up of arrhythmogenic right ventricular cardiomyopathy by cardiovascular magnetic resonance.

Cardiovascular magnetic resonance (CMR) has become a widespread diagnostic tool. Since its introduction, CMR has been used to image patients with a known or suspected arrhythmogenic right ventricular cardiomyopathy (ARVC). Several abnormalities have been found and described by CMR and at present this diagnostic tool is considered very important for the diagnosis. However, the diagnosis of ARVC relies upon the fulfillment of both clinical and functional criteria and CMR can provide several but not all the information useful for the diagnosis. Furthermore, some findings such as evidence of right ventricular epicardial fat, once considered a peculiar marker of ARVC, have been shown to possess a low specificity. This document was prepared by representatives of the three Italian official Organizations involved in CMR. Its main scope is to highlight the problems encountered when studying patients with suspected ARVC at CMR, to indicate the basic technical equipment needed, to recommend a proper imaging protocol and to offer a consensus on the main features relevant for the diagnosis.

ACE inhibitors can induce circulating antibodies directed to antigens of the superficial epidermal cells.

Drug-induced pemphigus has been reported in patients receiving angiotensin-converting enzyme inhibitors. The aim of this work was to study a group of hypertensive patients without skin diseases treated with angiotensin-converting enzyme (ACE) Inhibitors (I), to verify the presence of serum circulating anti-antibodies. The indirect immunofluorescence showed that 33 sera (52.38%) presented autoantibodies directed to an antigen of the cytoplasm of the superficial epidermal keratinocytes. Two of the 33 positive sera had antibodies to Dsg1 and/or 3 in ELISA. Immunoblot analyses were negative. All the 48 control sera were found to have no circulating antibodies using the three assays. Our results would confirm that ACEI drugs may trigger the production of circulating autoantibodies also in patients without clinical manifestations of pemphigus.

Role of advanced oxidation protein products and Thiol ratio in patients with acute coronary syndromes.

OBJECTIVES: To identify systemically detectable vascular inflammation associated to redox system unbalance, advanced oxidation protein products (AOPP), formed by HClO reaction with proteins, Thiol levels, and their ratio (AOPP/Thiol ratio) were measured in patients with acute coronary syndromes (ACS). DESIGN AND METHODS: We evaluated AOPP/Thiol ratio together with CRP and IL-1ß in 18 acute myocardial infarction (AMI) and in 16 unstable angina (UA) patients at admission, and in 16 control subjects (CTR); the measurements were repeated at 1 and at 6 months. RESULTS: At admission, AMI and UA patients displayed higher AOPP/Thiol ratio and CRP and IL-1ß compared to CTR subjects. A correlation between AOPP/Thiols and IL-1ß in AMI was found. At follow-up, in UA only, AOPP/Thiol ratio and IL-1ß levels still remained high. CONCLUSIONS: The AOPP/Thiol ratio seems to affect the inflammatory process in ACS, and may represent a reliable marker of oxidative unbalance in this setting of patients.

Osteopontin plasma levels and accelerated atherosclerosis in patients with CAD undergoing PCI: a prospective clinical study.

OBJECTIVES: Growing evidence supports the role played by inflammation in atherosclerosis. Identifying sensitive biomarkers is useful in predicting accelerated atherosclerosis. We investigated prospectively the relationship between plasma levels of inflammatory biomarkers [osteopontin, C-reactive protein (CRP), interleukin-6 (IL-6)] and instent restenosis, and rapid coronary plaque progression in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI). METHODS: We studied 77 patients with CAD: 45 affected by unstable angina/non-ST elevation myocardial infarction [acute coronary syndrome (ACS)], and 32 by chronic coronary syndrome (CCS). Plasma osteopontin, IL-6, and CRP levels were measured before intervention in all patients; measurements were carried out on the basis of the following time course at 1,15, 30, 90, and 180 days follow-up in a subgroup of 39 consenting patients. Clinical and biohumoral data were correlated with baseline and 6-month PCI follow-up angiography. RESULTS: Osteopontin, IL-6, and CRP were higher in patients with ACS than in those with CCS (analysis of variance: P<0.001, 0.05, and 0.05, respectively). Baseline osteopontin levels proved to be associated with rapid coronary plaque progression (P=0.005) and instent restenosis (P=0.05). The highest osteopontin levels were found in patients with CAD with both rapid plaque progression and instent restenosis (P=0.003). PCI increased inflammatory markers acutely, and osteopontin remained elevated in patients with ACS. Patients with ACS showed a higher percentage (74%) of rapid plaque progression than those with CCS (26%) (P<0.05). CONCLUSION: The study prospectively shows the link between inflammatory status and accelerated atherosclerosis in patients with CAD undergoing PCI. The baseline and persistent rise of osteopontin is an expression of its contribution to the accelerated plaque progression, and therefore osteopontin may be a useful prognostic biomarker.