No abstract

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...

In hypertension, an Ang II-driven activation of T-cell RAS, further amplified by low-grade inflammation, does occur and is associated to worse TOD. New therapeutic approaches aimed at this specific target might be proposed to control hypertension and hypertensive damage.

The premise of this study is that mitochondrial lesions caused by anthracyclines lead directly to cardiotoxicity. We compared several biochemical parameters, including endogenous cellular respiration, adenosine and guanosine triphosphate levels, and ¹⁴C-amino acid incorporation, of rat hearts treated with doxorubicin and some of its derivatives, recent products of pharmacological research aimed at selecting less toxic antiblastic agents. In rats treated in vivo, we further examined the ultrastructural changes induced by anthracycline antibiotics in order to elucidate which biochemical parameters were consistent with the morphological lesions. Our data indicate that mitochondria are the target of the anthracycline effects and that oxygen uptake and nucleotide levels may be regarded as markers of the toxicity when evaluating new drugs before their clinical use. The lack of cytoplasmatic or endoplasmatic reticulum alterations may account for the failure of anthracyclines to affect amino acid incorporation. In any event, the rate of protein synthesis cannot serve as a marker of cardiac toxicity. In this context, epidoxorubicin and iododoxorubicin are two derivatives characterized by less cardiotoxic potential than doxorubicin and thus appear to be promising antiblastic agents.