Purpose: To study myocardial perfusion reserve and myocellular metabolic alterations indicated by triglyceride content as possible causes of diastolic dysfunction in patients with type 2 diabetes mellitus, preserved systolic function, and without clinically evident coronary artery disease. Materials and Methods:Patients with type 2 diabetes mellitus (n ¼ 42) underwent cardiac magnetic resonance (CMR) for quantification of 1) myocardial contractility by strain-encoded MR (SENC); 2) myocardial triglyceride content by proton magnetic resonance spectroscopy ( 1 H-MRS); and 3) myocardial perfusion reserve during pharmacologic hyperemia. Age-matched healthy volunteers (n ¼ 16) also underwent CMR to acquire normal values for myocardial strain and perfusion reserve.Results: Stress CMR procedures were successfully performed in all subjects, and no regional inducible perfusion defects were observed in type 2 diabetes mellitus patients. Diastolic strain rate and myocardial perfusion reserve were significantly impaired in patients with type 2 diabetes mellitus compared to control subjects (P < 0.001 for both). Interestingly, impaired diastolic function in type 2 diabetes mellitus was not associated with impaired myocardial perfusion reserve (r ¼ 0.12, P ¼ NS). Conversely a significant association was observed between diastolic dysfunction and myocardial triglyceride content (r ¼ À0.71, P < 0.001), which proved to be independent of age, gender, diabetes duration, blood pressure, and fasting blood glucose. Conclusion:Myocardial steatosis may represent an early marker of diabetic heart disease, triggering subclinical myocardial dysfunction irrespective of myocardial perfusion reserve.

Purpose: To elicit a long-lasting antitumor immune response, CD8+ and CD4 + Tcells should be activated. We attempted to isolate HLA-DR^presented peptides directly from dissected solid tumors, in particular from renal cell carcinoma, to identify MHC class II ligands from tumorassociated antigens (TAA) for their use in peptide-based immunotherapy. Experimental Design: Tumor specimens were analyzed by immunohistochemical staining for their HLA class II expression. HLA class II peptides were subsequently isolated and identified by mass spectrometry. Gene expression analysis was done to detect genes overexpressed in tumor tissue. Peptides from identifiedTAAs were used to induce peptide-specific CD4 + T-cell responses in healthy donors and in tumor patients. Results: In the absence of inflammation, expression of MHC class II molecules is mainly restricted to cells of the immune system. To our surprise, we were able to isolate and characterize hundreds of class II peptides directly from primary dissected solid tumors, especially from renal cell carcinomas, and from colorectal carcinomas and transitional cell carcinomas. Infiltrating leukocytes expressed MHC class II molecules and tumor cells, very likely under the influence of IFNg. Our list of identified peptides contains ligands from several TAAs, including insulin-like growth factor binding protein 3 and matrix metalloproteinase 7. The latter bound promiscuously to HLA-DR molecules and were able to elicit CD4 + T-cell responses. Conclusions: Thus, our direct approach will rapidly expand the limited number of T-helper epitopes fromTAAs for their use in clinical vaccination protocols. CD4+ helper T cells play an important role in orchestrating the effector function of antitumor T-cell responses (1), and for this reason, the identification of CD4 + T-cell epitopes derived from tumor-associated antigens (TAA) has recently been a major focus of attention (2, 3). Even in the absence of CTL effector cells, helper T cells in the mouse can inhibit tumor angiogenesis via IFNg (4) and counteract tumor progression via the induction of an antibody response (5). In contrast to HLA class I ligands, only a small number of class II ligands of TAA has been described. Because HLA class II molecules are constitutively presented on cells of the immune system alone (6), the possibility of isolating class II peptides directly from primary tumors as opposed to class I ligands (7) has not been considered viable. Therefore, numerous strategies to target antigens into the class II processing pathway of antigenpresenting cells have been described (e.g., the incubation of antigen-presenting cells with the antigen of interest to enable it to be taken up, processed, and presented; ref. 8).To identify HLA class II ligands from TAA for their use in peptide-based immunotherapy, we attempted to isolate HLA-DR -presented peptides directly from dissected solid tumors, in particular from renal cell carcinoma (RCC). Even if the majority of tumor cells were class II negative, with state-of-the-ar...

Abstract. Andrassy M, Volz HC, Riedle N, Gitsioudis G, Seidel C, Laohachewin D, Zankl AR, Kaya Z, Bierhaus A, Giannitsis E, Katus HA, Korosoglou G (University of Heidelberg, Heidelberg, Germany). HMGB1 as a predictor of infarct transmurality and functional recovery in patients with myocardial infarction. J Intern Med 2011; 270: 245-253.Objectives. High-mobility group box 1 (HMGB1) protein is an innate danger signal for the initiation of host defence and tissue repair. The aim of this study was to analyse serum HMGB1 concentration and its correlation with infarct transmurality and functional recovery in patients with ST-elevation (STEMI) and non-ST-elevation myocardial infarction (NSTEMI).Design. We prospectively examined patients with firsttime STEMI (n = 46) or NSTEMI (n = 49), treated according to current guidelines. Contrast-enhanced cardiac magnetic resonance imaging was performed 2-4 days after infarction for the estimation of infarct transmurality and was repeated after 6 months for the estimation of residual left ventricular function. HMGB1 was measured 2-4 days after infarction.Results. High-mobility group box 1 concentration was related to infarct size and to residual ejection fraction in patients with STEMI (r 2 = 0.81 and r 2 = 0.40, respectively, P < 0.001 for both) and NSTEMI (r 2 = 0.74 and r 2 = 0.25, respectively, P < 0.001 for both). Receiver operating characteristic (ROC) curvederived cut-off values of 6.2 and 5.9 ng mL )1 for patients with STEMI and NSTEMI, respectively, were predictive of infarct transmurality greater than 75% (STEMI: area under the curve (AUC) = 0. Conclusion. High-mobility group box 1 serum levels represent a highly valuable surrogate marker for infarct transmurality and for the prediction of residual left ventricular function after MI.

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ObjectivesThe role of inflammation in atherosclerosis is widely appreciated. High mobility group box 1 (HMGB1), an injury-associated molecular pattern molecule acting as a mediator of inflammation, has recently been implicated in the development of atherosclerosis. In this study, we sought to investigate the association of plasma HMGB1 with coronary plaque composition in patients with suspected or known coronary artery disease (CAD).DesignHMGB1, high sensitive troponin T (hsTnT) and high sensitive C-reactive protein (hsCRP) were determined in 152 consecutive patients with suspected or known stable CAD who underwent clinically indicated 256-slice coronary computed tomography angiography (CCTA). Using CCTA, we assessed 1) coronary calcification, 2) non-calcified plaque burden and 3) the presence of vascular remodeling in areas of non-calcified plaques.ResultsUsing univariate analysis, hsCRP, hsTnT and HMGB1 as well as age, and atherogenic risk factors were associated with non-calcified plaque burden (r = 0.21, p = 0.009; r = 0.48, p<0.001 and r = 0.34, p<0.001, respectively). By multivariate analysis, hsTnT and HMGB1 remained independent predictors of the non-calcified plaque burden (r = 0.48, p<0.01 and r = 0.34, p<0.001, respectively), whereas a non-significant trend was noticed for hs-CRP (r = 0.21, p = 0.07). By combining hsTnT and HMGB1, a high positive predictive value for the presence of non-calcified and remodeled plaque (96% and 77%, respectively) was noted in patients within the upper tertiles for both biomarkers, which surpassed the positive predictive value of each marker separately.ConclusionsIn addition to hs-TnT, a well-established cardiovascular risk marker, HMGB1 is independently associated with non-calcified plaque burden in patients with stable CAD, while the predictive value of hs-CRP is lower. Complementary value was observed for hs-TnT and HMGB1 for the prediction of complex coronary plaque.

ObjectivesWe sought to investigate the association of epicardial adipose tissue (eCAT) volume with plaque burden, circulating biomarkers and cardiac outcomes in patients with intermediate risk for coronary artery disease (CAD).Methods and Results177 consecutive outpatients at intermediate risk for CAD and completed biomarker analysis including high-sensitive Troponin T (hs-TnT) and hs-CRP underwent 256-slice cardiac computed tomography angiography (CCTA) between June 2008 and October 2011. Patients with lumen narrowing ≥50% exhibited significantly higher eCAT volume than patients without any CAD or lumen narrowing <50% (median (interquartile range, IQR): 108 (73–167) cm3 vs. 119 (82–196) cm3, p = 0.04). Multivariate regression analysis demonstrated an independent association eCAT volume with plaque burden by number of lesions (R2 = 0.22, rpartial = 0.29, p = 0.026) and CAD severity by lumen narrowing (R2 = 0.22, rpartial = 0.23, p = 0.038) after adjustment for age, diabetes mellitus, hyperlidipemia, body-mass-index (BMI), hs-CRP and hs-TnT. Univariate Cox proportional hazards regression analysis identified a significant association for both increased eCAT volume and maximal lumen narrowing with all cardiac events. Multivariate Cox proportional hazards regression analysis revealed an independent association of increased eCAT volume with all cardiac events after adjustment for age, >3 risk factors, presence of CAD, hs-CRP and hs-TnT.ConclusionEpicardial adipose tissue volume is independently associated with plaque burden and maximum luminal narrowing by CCTA and may serve as an independent predictor for cardiac outcomes in patients at intermediate risk for CAD.

Use of hsTnT as a marker of myocardial microinjury and cardiac CT angiography as a marker of the total atherosclerotic burden improves the prediction of cardiac outcome in patients with presumably stable CAD and may aid in personalized risk stratification in patients at intermediate risk.

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