chondroitin-sulfates and Cardiomyopathy--Dilated

Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening prothrombotic complication following heparin administration. We describe a patient, known with idiopathic dilating cardiomyopathy, presenting nine days after a biventricular ICD implantation with dyspnoea and thrombocytopenia. Thirteen days after administration of a single heparin flush during ICD implantation, the patient developed venous thrombosis in two extremities and pulmonary embolism caused by HIT. HIT is the development of thrombocytopenia, caused by IgG antibodies against complexes of platelet factor 4 and heparin, leading to platelet aggregation. HIT may be accompanied by thrombosis in 20-50% of patients and untreated mortality rates are high. Once HIT is suspected, heparin should be replaced by an alternative anti-factor Xa or anti-factor II therapy. Regardless of the low incidence of HIT, because of the widespread use of heparin and the potentially life-threatening course of HIT, all physicians should be aware of it.

Topics: Antibodies; Anticoagulants; Cardiomyopathy, Dilated; Chondroitin Sulfates; Defibrillators, Implantable; Dermatan Sulfate; Female; Follow-Up Studies; Heparin; Heparitin Sulfate; Humans; Immunoglobulin G; Middle Aged; Platelet Aggregation; Platelet Factor 4; Postoperative Complications; Pulmonary Embolism; Thrombocytopenia; Treatment Outcome; Venous Thromboembolism

In cardiac fibrosis remodeling of the failing myocardium is associated with a complex reorganization of the extracellular matrix (ECM). Xylosyltransferase I and Xylosyltransferase II (XT-I and XT-II) are the key enzymes in proteoglycan biosynthesis, which are an important fraction of the ECM. XT-I was shown to be a measure for the proteoglycan biosynthesis rate and a biochemical fibrosis marker. Here, we investigated the XT-I and XT-II expression in cardiac fibroblasts and in patients with dilated cardiomyopathy and compared our findings with nonfailing donor hearts. We analyzed XT-I and XT-II expression and the glycosaminoglycan (GAG) content in human cardiac fibroblasts incubated with transforming growth factor (TGF)-beta(1) or exposed to cyclic mechanical stretch. In vitro and in vivo no significant changes in the XT-II expression were detected. For XT-I we found an increased expression in parallel with an elevated chondroitin sulfate-GAG content after incubation with TGF-beta(1) and after mechanical stretch. XT-I expression and subsequently increased levels of GAGs could be reduced with neutralizing anti-TGF-beta(1) antibodies or by specific inhibition of the activin receptor-like kinase 5 or the p38 mitogen-activated protein kinase pathway. Usage of XT-I small interfering RNA could specifically block the increased XT-I expression under mechanical stress and resulted in a significantly reduced chondroitin sulfate-GAG content. In the left and right ventricular samples of dilated cardiomyopathy patients, our data show increased amounts of XT-I mRNA compared with nonfailing controls. Patients had raised levels of XT-I enzyme activity and an elevated proteoglycan content. Myocardial remodeling is characterized by increased XT-I expression and enhanced proteoglycan deposition. TGF-beta(1) and mechanical stress induce XT-I expression in cardiac fibroblasts and have impact for ECM remodeling in the dilated heart. Specific blocking of XT-I expression confirmed that XT-I catalyzes a rate-limiting step during fibrotic GAG biosynthesis.

Topics: Activin Receptors; Antibodies; Cardiomyopathy, Dilated; Cells, Cultured; Chondroitin Sulfates; Extracellular Matrix; Fibroblasts; Fibrosis; Gene Expression Regulation, Enzymologic; Heart Ventricles; Humans; Myocardium; p38 Mitogen-Activated Protein Kinases; Pentosyltransferases; Protein Kinase Inhibitors; RNA, Small Interfering; Stress, Mechanical; Transforming Growth Factor beta1; UDP Xylose-Protein Xylosyltransferase