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Presented by: Karin Klingel, Dept. of Molecular Pathology, University Hospital Tübingen, Germany
Authors: Zürn CS, Walker B, Sauter M, Schaub M, Chatterjee M, Müller K, Rath D, Vogel S, Tegtmeyer R, Seizer P, Geisler T, Kandolf R, Lang F, Klingel K, Gawaz M, Borst O. Clin Res Cardiol. 2015 May 26. [Epub ahead of print]
Myocarditis represents a significant subgroup of primary cardiomyopathies which critically contributes to the global burden of chronic heart failure. Various risk predictors were identified in patients with suspected myocarditis and heart failure, such as advanced NYHA class, impaired left ventricular ejection fraction (LVEF), cardiac biomarkers including brain natriuretic peptides, troponins, Galectin-3 or immunohistological markers of inflammation (Kindermann, 2008). However, due to the diverse presentation of myocarditis and the widely varying individual course of progression of the disease, early and accurate diagnosis of myocarditis and identification of novel reliable risk factors that help to confirm the diagnosis of myocarditis and identify high-risk patients are still warranted.
In this paper, the cardiac expression of the inflammatory CXC- chemokine SDF-1 (CXCL12), which is transiently expressed in the myocardium upon cardiomyocyte damage, was investigated in order to evaluate whether SDF-1 may serve as a predictor of mortality in a cohort of patients suspected for myocarditis. SDF-1 binds to its receptors CXCR4 and CXCR7 regulating adhesion and migration of inflammatory cells including platelets, monocytes and lymphocytes (Rath, 2014). SDF-1 further increases homing of circulating CXCR4- positive progenitor cells to ischemic tissue and plays a major role in cell proliferation and ventricular remodeling in ischemic cardiomyopathy.
174 patients with non-ischemic heart failure who underwent endomyocardial biopsy for suspected (viral) myocarditis were enrolled in this study. Biopsies were analyzed using established histopathological and immunohistological criteria and SDF-1 staining.
73 % of the patients (n = 127) showed histopathologically chronic myocarditis. 36.8 % of the patients were virus-positive (19.5 % for parvovirus B19, 10.9 % for Epstein Barr virus, 9.8 % for human herpesvirus 6 and 0.6 % for coxsackievirus B3).
53 % of the patients revealed a cardiac expression for SDF-1. SDF-1-positive patients had a higher prevalence of myocardial inflammation (90 vs. 54 %, p<0.0001) with higher amounts of CD3+ T cells (58 vs. 16 %, p<0.0001), CD68+ macrophages (76 vs. 18 %, p<0.0001) and enhanced expression of MHCII (76 vs. 18 %, p<0.0001), when compared to SDF-1 negative patients. Furthermore, patients with SDF-1 positive EMB were significantly more often virus-positive (45 vs. 28 %, p = 0.024) and TnI-positive (37 vs. 20 %, p = 0.011). In EMB of patients with myocardial inflammation, SDF-1 was predominantly present in endothelial cells and interstitial cells, most likely representing fibroblasts and immune cells, e.g. macrophages and dendritic cells. All patients with acute myocarditis (100 %) and 75/119 (63.0 %) of patients with chronic myocarditis were SDF-1 positive (p = 0.033). Levels of myocardial SDF-1 expression correlated significantly with the degree of myocardial fibrosis (correlation coefficient r = 0.196; p = 0.010) since patients with high SDF-1 expression showed severe fibrosis. 83/174 patients showed moderate fibrosis. In this group, 46/83 (55.1 %) were SDF-1 positive. 61.1 % of patients with severe fibrosis were SDF-1 positive.
During a mean follow-up of 27.5 months, 20 patients (11.5 %) died. The 4-year mortality rate was 26.0 % among the 92 SDF-1-positive patients vs. 9.5 % among the 82 SDF-1-negative patients (p = 0.001). On multivariable analysis which considered clinical (NYHA functional class, left ventricular ejection fraction), laboratory (brain natriuretic peptide, troponin I) and biopsy staining, SDF-1 was the strongest independent predictor of mortality (hazard ratio 6.1; 95 %confidence interval 1.4–27.5; p = 0.018).
Cardiac expression of SDF-1 is enhanced in inflammatory cardiomyopathy, positively correlates with myocardial fibrosis and identifies high-risk patients with suspected myocarditis.
Here, it was shown that cardiac SDF-1 expression is significantly correlated with cardiac inflammation revealing enhanced numbers of CD68 and CD3 positive cells and cardiac virus infection.
SDF-1 is strongly chemotactic and triggers inflammation by recruiting monocytes, macrophages and T-lymphocytes. Migration of these inflammatory cells into the myocardial tissue is one of the key events in myocarditis. Interestingly, most of the studies in patients after acute myocardial infarction indicate a beneficial role of SDF-1 in ischemic cardiomyopathy. However, there is growing evidence of both beneficial and detrimental effects of the myocardial CXCR4 axis by SDF-1 (Frangogiannis NG, 2011). A recent study by Chu et al. displayed that expression and secretion of SDF-1 in the failing myocardium is significantly upregulated by angiotensin II, a hormone critically involved in the pathogenesis of progressive heart failure (Chu, 2010). According to a recent study with Framingham Heart Study, participants increased plasma SDF-1 levels were further associated with development of heart failure and all-cause mortality (Subramanian, 2014).
In the present study it was also demonstrated that the extent of SDF-1 expression in EMB significantly correlates with the degree of myocardial fibrosis, supporting the hypothesis that high myocardial SDF-1 expression is linked to the development of myocardial fibrosis in non-ischemic cardiomyopathies. Previously it was shown that the SDF-1/CXCR4 interaction may mediate the migration of BMSCs toward areas of myocardial infarction through activation of PI3K/Akt (Yu, 2010). Also, in other studies it was demonstrated that SDF-1 can induce migration of CD133+ cells. Interestingly, there is firm evidence that prominin-1+/CD133+ progenitor cells mediate cardiac fibrosis via TGF-ß in experimental autoimmune myocarditis (Kania, 2009). In this context it will be important to determine the role of SDF-1 and the involved (CXCR4- and CXCR7-dependent) intracellular signaling pathways in myocardial inflammation and fibrosis in autoimmune or viral-triggered myocarditis.
Kindermann I, Kindermann M, Kandolf R, Klingel K, Bültmann B, Müller T, Lindinger A, Böhm M (2008) Predictors of outcomein patients with suspected myocarditis. Circulation 118:639–648.
Rath D, Chatterjee M, Borst O, Muller K, Stellos K, Mack AF, Bongartz A, Bigalke B, Langer H, Schwab M, Gawaz M, Geisler T (2014) Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J 35:386–394.
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Chu PY, Mariani J, Finch S, McMullen JR, Sadoshima J, Marshall T, Kaye DM (2010) Bone marrow-derived cells contribute to fibrosis in the chronically failing heart. Am J Pathol 176:1735–1742.
Subramanian S, Liu C, Aviv A, Ho JE, Courchesne P, Muntendam P, Larson MG, Cheng S, Wang TJ, Mehta NN, Levy D (2014) Stromal cell-derived factor 1 as a biomarker of heart failure and mortality risk. Arterioscler Thromb Vasc Biol 34:2100–2105.
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Kania G, Blyszczuk P, Stein S, Valaperti A, Germano D, Dirnhofer S, Hunziker L, Matter CM, Eriksson U. Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of transforming growth factor beta-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res. 2009 Aug 28;105(5):462-70.
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