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Abstract-Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET A and ET B receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET A and ET B receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (PϽ0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET A mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET B mRNA was almost exclusively localized on nonmyocyte cells. ET A -and ET B -specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (rϭ0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function. (Circ Res. 2000;86:377-385.)Key Words: endothelin Ⅲ heart failure Ⅲ myocytes Ⅲ receptors Ⅲ RNA E ndothelin (ET)-1 is a multifunctional peptide that exerts pleiotropic activities, including arterial and venous constriction, direct positive inotropic and chronotropic effects on isolated heart, and growth effects on vascular smooth muscle cells, fibroblasts, and isolated cardiomyocytes. 1 Prepro-ET-1 (ppET-1) mRNA is expressed by both rat and human cardiac myocytes and interstitial cells that synthesize and secrete mature ET-1. [2][3][4] The protease that catalyzes the conversion (ET-converting enzyme, ECE) from the 38-residue inactive intermediate big ET-1 to achieve ET-1 is expressed in the endocardium and myocardium. 5 The differing biological activities of ET-1 appear to be mediated through 2 receptor subtypes (ET A and ET B ), 6 which are both present in the human myocardium and that of other species. 7 Thus, a complete ET-1 system is represented in human myocardium.Cardiac ppET-1 mRNA expression and ET-1 synthesis have been found to be increased in experimental hypertrophy by pressure overload 8 -10 and in experimental models of congestive heart failure (CHF), [11][12][13] thus suggesting that the cardiac ET-1 system may be involved in cardiac diseases.There have been very f...

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In HTx recipients, measurement of pretransplant CXCL10 serum levels could be a clinically useful tool for predicting cardiac acute rejection, especially in the early posttransplant period.

Abstract-Angiotensin (Ang) II is now recognized to be a mediator of a wide variety of inflammatory processes. This study investigated renin-angiotensin system (RAS) components and a number of inflammatory mediators in left ventricular biopsies from 2-vessel disease unstable angina (UA) (nϭ43) and stable angina (SA) (nϭ15) patients undergoing coronary bypass surgery. Biopsy samples from 6 patients undergoing valve replacement for mitral stenosis served as controls. UA patients were randomly assigned to angiotensin-converting enzyme (ACE)-inhibitor (ramipril), AT1 antagonist (valsartan), or placebo and treated during the 5 days preceding coronary bypass surgery, performed from 6 to 9 days after coronary angiography. During coronary angiography coronary blood flow was measured and samples were obtained from aorta and coronary sinus for determination of Ang I and Ang II gradients. The hearts of UA patients produced Ang II in a greater amount than in SA patients (PϽ0.01). UA biopsy samples showed numerous DR ϩ cells, identified as lymphocytes, macrophages, and endothelial cells. Reverse-transcriptase polymerase chain reaction showed overexpression of AGTN, ACE, and AT1-R genes, as well as upregulation of TNF-␣, IL-6, IFN-␥, and iNOS genes (PϽ0.01), with no differences between nonischemic and potentially ischemic areas. AGTN, ACE, and cytokine genes were mainly localized on endothelial cells. Ramipril and valsartan markedly decreased the expression levels of TNF-␣, IL-6, and iNOS, and, to a lesser extent, of IFN-␥ genes, but did not affect the number of DR ϩ cells, with no significant difference between the 2 treatments. These results show that locally generated Ang II amplifies the immunomediated inflammatory process of coronary microvessels occurring in unstable angina. Key words: angiotensin II Ⅲ unstable angina Ⅲ myocardial inflammation U nstable angina (UA) classes IIB and IIIB of Braunwald classification 1 are an acute manifestation thought to be caused by recent inflammatory activation within coronary atherosclerotic plaque, often resulting in the plaque erosion or rupture with consequent nonocclusive thrombus development. 2 Unstable or vulnerable plaques are characterized by increased accumulation of inflammatory cells, particularly macrophages and T-lymphocytes, and by a large lipid core and a thin fibrous cap. 3 A high number of inflammatory cells express DR molecules and IL-2 receptors, 4,5 thus indicating that antigen presentation, as well as an immunological reaction, occurred. 6 However, the concept that UA is only an intraplaque event is strongly restrictive because recent studies have shown that Ͼ1 coronary plaque is activated in acute coronary syndromes. 7 Moreover, we showed that also coronary microvessels are involved in UA by an acute inflammatory process with cellular and molecular characteristics of an immunomediated reaction. 8 The complex pathophysiology of UA is also suggested by the link that seems to exist between renin-angiotensin system (RAS) and atherosclerosis. 9 Several immunohisto...

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