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International Atherosclerosis |
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Featured IAS Commentaries These Commentaries, including all information, text, graphics, images, and other material are for general educational purposes only and are not intended to be used for the purposes of providing medical treatment or attention or making medical or health-related decisions. These Commentaries are not a substitute or replacement for medical advice. If you are seeking medical advice, we encourage you to consult a physician or other medical professional. The views expressed in these Commentaries are those of the authors and are not necessarily those of IAS. COMMENTARIES POSTED IN FEBRUARY 2010 The following commentary is based on and summarizes my paper “The mainstream hypothesis that LDL cholesterol drives atherosclerosis may have been falsified by non-invasive imaging of the coronary plaque burden and progression” [1]. Progress in science depends not only on hypothesis generation but also on hypothesis falsification. Cholesterol, and in particular LDL, has been called the driving force of atherosclerosis [2]. But this widely held view is based almost entirely on studies with cardiac event endpoints rather than a direct measure of coronary plaque burden and progression. Extensive data continues to accumulate indicating that, contrary to the conventional wisdom, total cholesterol (TC) and LDL cholesterol in asymptomatic individuals are not associated with either the extent or progression of coronary plaque, as quantified either by electron beam tomography (EBT) or coronary CT angiography. Since conventional lipid risk factors fail to identify significant numbers of individuals with extensive plaque burden and also fail to identify many with zero or low plaque burden, non-invasive imaging can lead to reassignment of risk categories and can identify individuals who by traditional assessment qualify for therapy when none is in fact indicated [3]. When enhanced risk is identified by high coronary calcium scores, it appears to be almost universally an indication for lipid lowering. If the hypothesis is false, this brings into question the proposed approach, in the context of primary prevention, that calls for LDL targets as the central and in many cases the only therapeutic response to the enhanced risk [4,5].
Kynurenine and Its Metabolites as Biomarkers of Atherosclerosis
in Chronic Kidney Disease Patients Cardiovascular disease (CVD) is a significant cause of morbidity and mortality for patients with chronic kidney disease (CKD). These subjects have a much higher prevalence of atherosclerosis than the general population with no renal function impairment [1]. CKD is associated with a higher prevalence of several traditional and uremia-related risk factors for atherogenesis, such as hypertension, hyperlipidemia, diabetes mellitus, inflammation, anemia, and increased oxidative stress. However, the combination of the known risk factors accounts only partly for the particularly increased burden of atherosclerotic disease in uremic patients, indicating that other factors yet to be defined are also probably triggered in this patients population [1-2]. The Kynurenine Pathway In addition to the process of protein synthesis, in mammals, tryptophan (TRP) is metabolized in several pathways. The most commonly known is the serotonergic pathway, which is active in platelets and neurons. TRP is also the precursor of a pineal hormone, melatonin. The less well-known, but actually the main alternative route for the TRP metabolism, is through the kynurenine (KYN) pathway. In the first step of this metabolic way, TRP is transformed into KYN in reaction catalyzed by dioxygenases: indoleamine 2.3-dioxygenase (IDO) and tryptophan 2.3-dioxygenase (TDO). KYN can be metabolized in three separate ways: to kynurenic acid (KYNA) by kynurenine aminotransferase, to 3-hydroxykynurenine (3-HKYN) by kynurenine-3-hydroxylase, and to anthranilic acid (AA) by kynureninase. Both AA and 3-HKYN can be converted to 3-hydroxyanthranilic acid (3-HAA), and subsequently to quinolinic acid (QA), the precursor of NAD [3].
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