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      Mitochondrial Dysfunction as an Initiating Event in Atherogenesis: A Plausible Hypothesis

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          Abstract

          It is now widely accepted that oxidant stress and the ensuing endothelial dysfunction play a key role in the pathogenesis of atherosclerosis and cardiovascular diseases. The mitochondrial respiratory chain is the major source of reactive oxygen species as byproducts of normal cell respiration. Mitochondria may also be important targets for reactive oxygen species, which may damage mitochondrial lipids, enzymes and DNA with following mitochondrial dysfunction. Free cholesterol, oxidized low-density lipoprotein and glycated high-density lipoprotein are further possible causes of mitochondrial dysfunction and/or apoptosis. Moreover, in patients with mitochondrial diseases, vascular complications are commonly observed at an early age, often in the absence of traditional risk factors for atherosclerosis. We propose that mitochondrial dysfunction, besides endothelial dysfunction, represents an important early step in the chain of events leading to atherosclerotic disease.

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          Most cited references42

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          Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.

          Observational and experimental studies suggest that the amount of vitamin E ingested in food and in supplements is associated with a lower risk of coronary heart disease and atherosclerosis. We enrolled a total of 2545 women and 6996 men 55 years of age or older who were at high risk for cardiovascular events because they had cardiovascular disease or diabetes in addition to one other risk factor. These patients were randomly assigned according to a two-by-two factorial design to receive either 400 IU of vitamin E daily from natural sources or matching placebo and either an angiotensin-converting-enzyme inhibitor (ramipril) or matching placebo for a mean of 4.5 years (the results of the comparison of ramipril and placebo are reported in a companion article). The primary outcome was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The secondary outcomes included unstable angina, congestive heart failure, revascularization or amputation, death from any cause, complications of diabetes, and cancer. A total of 772 of the 4761 patients assigned to vitamin E (16.2 percent) and 739 of the 4780 assigned to placebo (15.5 percent) had a primary outcome event (relative risk, 1.05; 95 percent confidence interval, 0.95 to 1.16; P=0.33). There were no significant differences in the numbers of deaths from cardiovascular causes (342 of those assigned to vitamin E vs. 328 of those assigned to placebo; relative risk, 1.05; 95 percent confidence interval, 0.90 to 1.22), myocardial infarction (532 vs. 524; relative risk, 1.02; 95 percent confidence interval, 0.90 to 1.15), or stroke (209 vs. 180; relative risk, 1.17; 95 percent confidence interval, 0.95 to 1.42). There were also no significant differences in the incidence of secondary cardiovascular outcomes or in death from any cause. There were no significant adverse effects of vitamin E. In patients at high risk for cardiovascular events, treatment with vitamin E for a mean of 4.5 years had no apparent effect on cardiovascular outcomes.
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            Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)

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              Apoptosis in myocytes in end-stage heart failure.

              Heart failure can result from a variety of causes, including ischemic, hypertensive, toxic, and inflammatory heart disease. However, the cellular mechanisms responsible for the progressive deterioration of myocardial function observed in heart failure remain unclear and may result from apoptosis (programmed cell death). We examined seven explanted hearts obtained during cardiac transplantation for evidence of apoptosis. All seven patients had severe chronic heart failure: four had idiopathic dilated cardiomyopathy, and three had ischemic cardiomyopathy. DNA fragmentation (an indicator of apoptosis) was identified histochemically by in situ end-labeling as well as by agarose-gel electrophoresis of end-labeled DNA. Myocardial tissues obtained from four patients who had had a myocardial infarction one to two days previously were used as positive controls, and heart tissues obtained from four persons who died in motor vehicle accidents were used as negative controls for the end-labeling studies. Hearts from all four patients with idiopathic dilated cardiomyopathy and from one of the three patients with ischemic cardiomyopathy had histochemical evidence of DNA fragmentation. All four myocardial samples from patients with dilated cardiomyopathy also demonstrated DNA laddering, a characteristic of apoptosis, whereas this was not seen in any of the samples from patients with ischemic cardiomyopathy. Histological evidence of apoptosis was also observed in the central necrotic zone of acute myocardial infarcts, but not in myocardium remote from the infarcted zone. Rare isolated apoptotic myocytes were seen in the myocardium from the four persons who died in motor vehicle accidents. Loss of myocytes due to apoptosis occurs in patients with end-stage cardiomyopathy and may contribute to progressive myocardial dysfunction.
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                Author and article information

                Journal
                CRD
                Cardiology
                10.1159/issn.0008-6312
                Cardiology
                S. Karger AG
                0008-6312
                1421-9751
                2005
                April 2005
                07 April 2005
                : 103
                : 3
                : 137-141
                Affiliations
                aDepartment of Internal Medicine, Cardioangiology, Hepatology, University of Bologna and bDepartment of Internal Medicine and Aging, S. Orsola-Malpighi Hospital, Bologna, Italy
                Article
                83440 Cardiology 2005;103:137–141
                10.1159/000083440
                15665536
                e8c73eb8-f70a-4b0a-95d2-ff91a5f490d8
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 06 July 2004
                : 03 August 2004
                Page count
                Figures: 1, References: 62, Pages: 5
                Categories
                Review

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Atherosclerosis,Mitochondrial dysfunction,Mitochondrial DNA,Oxidant stress

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