In myocarditis, biventricular dysfunction at diagnosis was the main predictor of death/transplantation. AHA identified immune-mediated myocarditis in the majority of cases. Viral genome was a univariate predictor of adverse prognosis. Our approach of using AHA and positive PCR as aetiopathogenetic markers should help patient selection and recruitment in future studies on aetiological therapy.

Dilated cardiomyopathy (DCM) is a relevant cause of heart failure and a common indication for heart transplantation. It may be idiopathic, familialygenetic, viral, autoimmune or immune-mediated associated with a viral infection. Myocarditis is an inflammatory disease of the myocardium; it may be idiopathic, infectious or autoimmune and may heal or lead to DCM. Thus, in a patient subset, myocarditis and DCM are thought to represent the acute and chronic stages of an organ-specific autoimmune disease of the myocardium. In keeping with this hypothesis, autoimmune features in patients with myocarditisyDCM include: familial aggregation; a weak association with HLA-DR4; abnormal expression of HLA class II on cardiac endothelium on endomyocardial biopsy; and detection of organ-and disease-specific cardiac autoantibodies of the IgG class in the sera of affected patients and symptom-free relatives. The cardiac autoantibodies detected by immunofluorescence are directed against multiple antigens. Two of these, first identified using immunoblotting and confirmed by ELISA, are the atrial-specific a-and the ventricular and skeletal muscle b-heavy chain isoform. The a-myosin isoform fulfils the expected criteria for organ-specific autoimmunity, in that immunization with cardiac, but not skeletal myosin reproduces, in susceptible mouse strains, the human disease phenotype of myocarditisyDCM; in addition, a-myosin is entirely cardiac-specific. Additional antigenic targets of heart-reactive autoantibodies include unknown sarcolemmal proteins, mitochondrial enzymes, b-adrenergic and muscarinic receptors. For some of these antibodies, there is in vitro evidence for a functional role. The organ-specific cardiac autoantibodies detected by immunofluorescence in symptom-free relatives were associated with echocardiographic features suggestive of early disease. Mid-term follow-up suggests that these antibodies are predictive markers of progression to DCM among symptom-free relatives with or without abnormal echocardiographic findings.

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In women diagnosed as having category I primary obstetric antiphospholipid syndrome, clinical characteristics and the risk of subsequent thromboembolic events and further unsuccessful pregnancy has not been clearly documented. Women with unexplained obstetric complications and no definite autoimmune systemic diseases were tested for lupus anticoagulant (LA), IgG/IgM anticardiolipin (aCL) and IgG/IgM anti-human beta2-Glycoprotein I (abeta2GPI) antibodies and diagnosed as having primary antiphospholipid syndrome (APS) in classification category I on the basis of more than one laboratory criteria present in any combination. Characteristics at the time of diagnosis and risk factors for subsequent clinical events during a mean follow-up of 6.3 years were evaluated. Fifty-three of 600 women studied were found to fulfil obstetric criteria and had more than one positive laboratory test at the time of diagnosis. All the women were aCL and abeta2GPI positive, and 16 were also LA positive. This latter group (triple positivity) had distinct features and had more frequently experienced previous thromboembolism (OR = 122.5, 95% CI 16-957, p < 0.001). They also had an increased rate of late pregnancy loss (OR = 16.2, 95%CI 0.9-292, p = 0.01), and a higher IgG abeta2GPI titer at diagnosis (median, 25(th) and 75(th) percentile were 118, 37-962, vs. 23, 18-32, respectively, p< 0.0001). During follow-up, the rate of thromboembolic events was significantly higher in the group of women with triple positivity and/ or previous thromboembolism (OR = 57.5, 95% CI 2.7-1160, p = 0.0004) which were the only independent predictors of TE in the multivariate model. Recurrent pregnancy loss took place in seven out of 47 women who had a new pregnancy. Triple positivity and/or previous thromboembolism were again the only independent markers (OR = 34.4, 95% CI 3.5-335.1, p = 0.003) of an unsuccessful new pregnancy. In conclusion, in primary APS with pregnancy morbidity in classification category I, quite different groups of patients may be identified on the basis of laboratory tests. Triple positivity and/or a history of thromboembolism predict new TE events and new unsuccessful pregnancies.

The detection of AHA and of AIDA supports the involvement of autoimmunity in the majority of patients with IRAP.

O besity is a worldwide health problem because of the associated increased morbidity and cardiovascular mortality. Accompanying metabolic disorders such as insulin resistance and type 2 diabetes mellitus and risk factors such as dyslipidemia increase the disease risk linked to obesity. In particular, obesity induces endothelial dysfunction, which precedes atherosclerosis, but also contributes to insulin resistance in tissues Background-Roux-en-Y gastric bypass (RYGB) reduces body weight and cardiovascular mortality in morbidly obese patients. Glucagon-like peptide-1 (GLP-1) seems to mediate the metabolic benefits of RYGB partly in a weight lossindependent manner. The present study investigated in rats and patients whether obesity-induced endothelial and highdensity lipoprotein (HDL) dysfunction is rapidly improved after RYGB via a GLP-1-dependent mechanism. Methods and Results-Eight days after RYGB in diet-induced obese rats, higher plasma levels of bile acids and GLP-1 were associated with improved endothelium-dependent relaxation compared with sham-operated controls fed ad libitum and sham-operated rats that were weight matched to those undergoing RYGB. Compared with the sham-operated rats, RYGB improved nitric oxide (NO) bioavailability resulting from higher endothelial Akt/NO synthase activation, reduced c-Jun amino terminal kinase phosphorylation, and decreased oxidative stress. The protective effects of RYGB were prevented by the GLP-1 receptor antagonist exendin 9-39 (10 μg·kg). Furthermore, in patients and rats, RYGB rapidly reversed HDL dysfunction and restored the endothelium-protective properties of the lipoprotein, including endothelial NO synthase activation, NO production, and anti-inflammatory, antiapoptotic, and antioxidant effects. Finally, RYGB restored HDLmediated cholesterol efflux capacity. To demonstrate the role of increased GLP-1 signaling, sham-operated control rats were treated for 8 days with the GLP-1 analog liraglutide (0.2 mg/kg twice daily), which restored NO bioavailability and improved endothelium-dependent relaxations and HDL endothelium-protective properties, mimicking the effects of RYGB. Conclusions-RYGB rapidly reverses obesity-induced endothelial dysfunction and restores the endothelium-protective properties of HDL via a GLP-1-mediated mechanism. The present translational findings in rats and patients unmask novel, weight-independent mechanisms of cardiovascular protection in morbid obesity. Furthermore, obesity and insulin resistance result in proatherogenic dyslipidemia, 4 characterized by high low-density lipoprotein and triglyceride and low high-density lipoprotein (HDL) cholesterol plasma levels.1,5 Abnormal HDL remodeling and maturation have been reported in obese subjects with an HDL profile similar to that of subjects with established cardiovascular disease. 5 In addition, pathological situations associated with obesity, in particular type 2 diabetes mellitus 6 and coronary artery disease, 7 impair the physiological protective properties of HDL, which preserves en...

We studied 361 patients, to evaluate risk factors for cardiac allograft vasculopathy (CAV) onset and severity/diffusion in heart transplantation (HT). Rejection scores (RS) on endomyocardial biopsy were calculated (first year and whole follow-up). CAV onset was defined as any lesion seen at yearly angiography. A CAV severity/diffusion index was calculated for each patient summing up the scores of all lesions. Cox multivariate analysis included: donor age, sex, and weight; recipient sex, age, pre-HT diagnosis, hypertension, diabetes and hyperlipidemia post-HT; number of treated rejections and RS; and immunosuppressive dosage at 3, 6, and 12 months. CAV frequency was 2% at 1 year, 22% at 5 and 39% at 10 years. Risk factors for CAV onset were older donor age [p < 0.0001, relative risk (RR) = = 9.9], male donor (p < 0.001, RR = = 3.2), high RS for severe (≥ 3A) grades (p < 0.02, RR = = 2.01), high cyclosporine at 3 months (p < 0.02, RR = = 1.9). Risk factors for CAV severity/diffusion were higher donor weight (p < 0.01, RR = = 7.5), high prednisone dosage at 1 year (p < 0.0001, RR = = 21.1), and coronary disease pre-HT (p < 0.002, RR = = 9.7). High RS was an independent predictor for CAV onset, not severity/diffusion. This suggests an immune basis for CAV onset and nonimmune modulation for progression. High RS for severe grades may provide a predictor for patients at risk.

Background-We assessed coronary flow velocity pattern and coronary flow reserve (CFR) by contrast-enhanced transthoracic echocardiography (CE-TTE) as markers of major adverse cardiac events (MACE) related to cardiac allograft vasculopathy (CAV) after heart transplantation (HT). Methods and Results-Deceleration time of diastolic flow velocity (DDT) and CFR were measured in the left anterior descending coronary artery (LAD) by CE-TTE in 66 consecutive HT patients (follow-up 19Ϯ5 months). CFR was calculated as the ratio of hyperemic to basal diastolic flow velocity. Angiographies were analyzed by a qualitative grading system; CAV was defined as changes grade II or higher. MACE were cardiac death, stent implantation, and heart failure. Patients with MACE had higher CAV incidence (Pϭ0.004) and grade (Pϭ0.008), shorter DDT (Pϭ0.006), and lower CFR (Pϭ0.008).A receiver-operating characteristic-derived DDT cutpoint Յ840 ms (area under the curve 0.793; Pϭ0.01) was 75% specific and 86% sensitive for predicting MACE, with positive predictive value (PPV) and negative predictive value (NPV) of 33% and 97%, respectively (Pϭ0.002). A CFR cutpoint of Յ2.6 (area under the curve 0.746; Pϭ0.01) was 62% specific and 91% sensitive for predicting MACE (PPV ϭ32%, NPV ϭ97%) (Pϭ0.001). Patients with CFR Յ2.6 and patients with DDT Յ840 ms had a lower survival free from MACE (Pϭ0.006 and Pϭ0.009, respectively). By Cox regression, only a lower CFR predicted the risk of MACE (relative risk 3.1; 95% CI, 1.26 to 7.9; Pϭ0.01). Conclusions-In