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• W2014616632 abstract "HomeCirculationVol. 95, No. 1Atherogenic Lipids, Vascular Dysfunction, and Clinical Signs of Ischemic Heart Disease Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBAtherogenic Lipids, Vascular Dysfunction, and Clinical Signs of Ischemic Heart Disease Andrew P. Selwyn, Scott Kinlay, Peter Libby and Peter Ganz Andrew P. SelwynAndrew P. Selwyn Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass. Search for more papers by this author , Scott KinlayScott Kinlay Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass. Search for more papers by this author , Peter LibbyPeter Libby Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass. Search for more papers by this author and Peter GanzPeter Ganz Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, Boston, Mass. Search for more papers by this author Originally published7 Jan 1997https://doi.org/10.1161/01.CIR.95.1.5Circulation. 1997;95:5–7The report by Tamai and colleagues1 in this issue demonstrates that therapeutic lowering of serum cholesterol, LDL, and oxidized LDL results in improvement in endothelium-dependent dilation in the forearm vasculature of patients with hypercholesterolemia. These observations are novel and particularly interesting because they show that atherogenic lipids can interact with and adversely affect blood vessel function even more rapidly than previously suspected. It is important to consider that past research2 has focused on the effects of serum lipids on atherogenesis over decades. However, more recent trials in patients have shown that treatment of serum lipids can improve clinical outcomes in 18 months to 3 years,34 improve endothelial dysfunction in atherosclerotic arteries in 6 to 12 months,567 and affect endothelium-dependent vasomotor function in the forearm in 2 to 12 weeks.8 The article by Tamai et al1 now shows that the relationship between atherogenic lipids and vascular dysfunction is dynamic and subject to change within minutes. This finding has important implications regarding the pathogenesis of ischemic syndromes and the use of potent and rapidly acting lipid-lowering therapies in patients.Experimental Effects of LDL on Cell/Vessel Wall FunctionNative LDL has little direct effect on essential function(s) in cells within the arterial wall. However, when LDL is metabolized by endothelial cells, the normal component antioxidants (eg, α-tocopherols and β-carotene) are exhausted, the polyunsaturated phospholipids are converted to reactive hydroxyfatty acids, lysophosphotidylcholine is formed, and the proteins in the apolipoprotein-B 100 moiety undergo covalent modification and fragmentation so that the ligand can no longer bind to the classic LDL receptor. Eventually, this “oxidized” LDL molecule becomes more negatively charged, binds to alternative sites (eg, the scavenger receptor), and becomes capable of a wide range of toxic effects, leading to cell/vessel wall dysfunction(s).9 These characteristic cell dysfunctions are consistently associated with the development of atherosclerosis in large arteries in a variety of animal models.10A brief review of selected effects of oxidized LDL in experimental models is relevant to the dysfunctions found in the atherosclerotic arteries of patients. First, oxidized LDL can rapidly impair endothelium-dependent dilation. This probably occurs through a number of mechanisms, including direct inactivation of nitric oxide by excess production of oxygen-derived free radicals, reduced transcription of nitric oxide synthase mRNA, and posttranscriptional destabilization of mRNA.11 Activation of protein kinase C also occurs, and inflammatory processes are activated at the level of gene transcription by upregulation of nuclear factor κ-B. Finally, signal transduction by the G protein Gi is impaired by downregulation of the α-i2 Gi subunit transcription. Oxidized LDL triggers these processes in a time- and concentration-dependent manner, and many are reversible within hours during a single experiment.912 The decrease in the availability of nitric oxide is also accompanied by many other important vascular cell dysfunctions described below. For example, there is increased platelet adhesion, stimulation of plasminogen activator inhibitor, inhibition of plasminogen activator, induction of the procoagulant tissue factor mRNA, inhibition of mRNA transcription of thrombomodulin caused by degradation by lysosomes, and finally stereochemical alterations in heparan sulfate proteoglycans.9 These changes impair the antiplatelet and anticoagulant properties of the endothelium and initiate thrombus formation.13 Upregulated or newly expressed adhesion molecules also play a role in increased monocyte recruitment.14 Free radical production, activation of protein kinase C, upregulation of nuclear factor κ-B, and diminished available nitric oxide all likely play a role in the proinflammatory changes that lead to the accumulation of monocyte/macrophages and T lymphocytes. Oxidized LDL stimulates the early growth response gene-1 mRNA with increased DNA synthesis and proliferation, processes that are amplified by α-fibroblast growth factor. In health, these processes are usually contained by the continuous production of constitutive nitric oxide. Interestingly, low levels of oxidized LDL (1 to 10 μg/mL) appear to encourage cell integrity and many of these healthy and defensive functions listed above. However, physiological and pathological concentrations (10 to 100 μg/mL) can trigger all the above dysfunctions that are characteristic in experimental (and clinical) atherosclerosis.9 Moreover, well-known risk factors (eg, hypertension) increase uptake and amplify the toxic effects of oxidized LDL.Clinical Effects of LDL on Cell/Vessel Wall FunctionEpidemiological surveys have consistently described the relationships among serum cholesterol, LDL cholesterol, development of atherosclerosis, and adverse clinical outcomes (myocardial infarction and coronary death). There is evidence, albeit limited, that increased levels of oxidized LDL or greater susceptibility of LDL to oxidation is related to the severity of coronary atherosclerosis.15 In recent years, physiological investigations in patients have shown that increases in serum cholesterol and/or LDL or decreases in HDL are associated with a loss of endothelium-dependent dilation to acetylcholine, serotonin, and flow in coronary and brachial arteries.16 This evidence of endothelial dysfunction occurs before and throughout the appearance of angiographic evidence of atherosclerosis and results in abnormal constriction at stenoses that contributes to impaired coronary blood supply and transient ischemia. Resistance vessels also develop impaired endothelium-dependent nitric oxide–mediated dilation but do not develop atherosclerosis.9Recent clinical studies have further refined our understanding of the adverse interactions between serum lipids and essential functions of the arterial endothelium. Small, dense LDL particles and LDL particles that are more susceptible to oxidation are particularly prone to induce endothelial vasomotor dysfunction.1718 In patients, inhibition of oxygen free radicals can lead to significant improvement in endothelium-dependent vasomotion.18The loss of appropriate quantities of nitric oxide also likely contributes to inflammation in plaques because of increased adherence and migration of monocytes, formation of lipid-laden macrophages, and increased expression of plasminogen activator inhibitor and tissue factor, especially in areas surrounding a lipid core. All these dysfunctional processes in the arterial wall of patients during atherogenesis are remarkably similar to those produced in experimental models and described in detail above. Furthermore, these dysfunctions (of the endothelium and inflammatory infiltration) operate before and throughout the course of atherosclerosis, culminating when a fragile fibrous cap ruptures and releases the thrombogenic lipid core, thus triggering intravascular thrombus formation.19 Finally, the report by Tamai et al,1 along with prior studies,567 has demonstrated in the clinical setting that the adverse effects of LDL leading to loss of vasodilator function are dynamic and can fluctuate over months or weeks and can change from minute to minute.Experimental Effects of Lipid Therapies on Vascular DysfunctionExperimental studies have shown that elevation of serum LDL cholesterol inhibits endothelium-dependent nitric oxide–mediated vasodilation. Conversely, the cessation of cholesterol feeding and return of serum lipids to normal values in the monkey result in restoration of endothelial function and disappearance of intimal inflammation over a similar time period (months).20 In hypercholesterolemic rabbits, antioxidants can preserve endothelial vasomotor function, even though the induced atherosclerosis continues its progress. This apparent separation between the preservation of a characteristic cell dysfunction on one hand and continued development of atherosclerosis on the other should make us consider the rationale for antioxidants carefully.20 However, it is encouraging to find that therapeutic lowering of serum cholesterol and LDL leads to restoration of endothelium-dependent anticoagulant function(s) and a decrease in the adhesion and migration of macrophages, with slow but measurable regression of the intimal thickening that characterizes atherosclerosis.9Clinical Effects of Therapies on Vascular DysfunctionEvidence has accumulated that cholesterol-lowering therapy is associated with a modest but measurable reduction in new atherosclerotic lesions and less progression and very modest regression of coronary atherosclerosis over 2 to 10 years.2 Effective lowering of serum cholesterol and LDL in hypercholesteremic patients with angiographically smooth coronary arteries over 6 months has resulted in improved endothelium-dependent vasomotor response to acetylcholine. Additional studies have shown that cholesterol lowering by itself or cholesterol lowering plus an antioxidant (Probucol) leads to measurable improvement in endothelial dysfunction in patients with coronary atherosclerosis over 6 to 12 months.567These physiological observations of the treatment of vascular dysfunction in patients have occurred in parallel with large-scale therapeutic trials that demonstrated that cholesterol and LDL lowering results in very substantial reductions in the need for coronary revascularization procedures.34 Given the common indications for revascularization, this finding almost certainly means that therapy resulted in less angina. Therapeutic trials have also shown that effective lipid lowering results in improvement in measures of transient myocardial ischemia with positron emission tomography and ambulatory monitoring of ECGs in patients with obstructive coronary artery disease.22 Thus, evidence has accumulated of a reduction in these important signs of increased risk of adverse outcome, and this is supported directly by large trials that show major reductions in myocardial infarction and coronary death.34Summary and ConclusionsLDL is oxidized in vascular endothelial cells to a highly injurious product that results in characteristic cell dysfunction(s) in large arteries and resistance vessels. The characteristic dysfunctions (ie, loss of dilation, constriction, thrombosis, and inflammation) operate before and throughout the development of atherosclerosis and particularly during plaque rupture. Although oxidized LDL appears to induce these cell/vessel wall dysfunctions in a time- and concentration-dependent manner, Tamai and colleagues1 have shown that this interaction can be dynamic in that a reduction in lipids restores endothelium-dependent vasomotor function almost immediately. The same intervention (ie, lipid lowering) also appears to stabilize atheroma in the long term, improves endothelium-dependent vasomotion over months, and results in a reduction in clinical signs of risk in coronary heart disease (ie, ischemia and the need for revascularization).The above leads us to some important but unanswered questions. Can we rely on clinical measures of arterial vasomotor dysfunction to represent the other important cell dysfunctions (eg, inflammation, abnormal growth) while monitoring the response to therapeutic interventions? How can we effectively inhibit oxidation of LDL in the arterial wall, and is this useful in reversing the many cell dysfunctions and clinical sequelae of coronary atherosclerosis? What is the time course for restoration of endothelial dysfunction in the atherosclerotic epicardial coronary arteries in patients with effective lipid-lowering therapy? The intracellular responses to oxidized LDL are so numerous (loss of vasodilation, loss of anticoagulant mechanisms, abnormal inflammation, and growth) that targeting therapies to specific pathways may prove difficult.Parallel efforts in basic physiological and clinical research have resulted in remarkable progress that has improved outcomes in patients with coronary heart disease. We expect that many of the characteristic cell/vessel wall dysfunctions that result from adverse interactions with risk factors are dynamic and can be manipulated in a relatively short time frame. Treatment of atherogenic lipids with other risk factors must be further refined and may well become the cornerstone for effective management of angina, unstable syndromes, and ischemia in addition to the control of important outcomes such as myocardial infarction and coronary death.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.FootnotesCorrespondence to Andrew P. Selwyn, MD, Professor of Medicine, Harvard Medical School, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. References 1 Tamai O, Matsuoka H, Nishida H, Itabe H, Wada Y, Kohno K, Nomura G, Imaizumi T. Single LDL-apheresis improves endothelium-dependent vasodilation in hypercholesterolemic humans. Circulation..1997; 95:76-82.CrossrefMedlineGoogle Scholar2 Brown G, Albers JJ, Fisher LD. Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. N Engl J Med..1990; 323:1289-1298.CrossrefMedlineGoogle Scholar3 Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering therapy in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet..1994; 344:1383-1389.MedlineGoogle Scholar4 Shepherd J, Cobbe SM, Isles CG, Lorimer AR, MacFarlane PN, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia: West of Scotland Coronary Prevention Study Group. N Engl J Med..1995; 333:1301-1307.CrossrefMedlineGoogle Scholar5 Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med..1995; 332:488-493.CrossrefMedlineGoogle Scholar6 Leung WH, Lau CP, Wong CK. Beneficial effect of cholesterol-lowering therapy on coronary endothelium-dependent relaxation in hypercholesterolemic patients. Lancet..1993; 341:1496-1500.CrossrefMedlineGoogle Scholar7 Treasure CB, Klein JL, Weintraub WS, Alexander W. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med..1995; 332:481-487.CrossrefMedlineGoogle Scholar8 Stroes ES, Koomans HA, de Bruin TW, Rabelink TJ. Vascular function in the forearm of hypercholesterolaemic patients off and on lipid-lowering medication. Lancet..1995; 346:467-471.CrossrefMedlineGoogle Scholar9 Cox DA, Cohen ML. Effects of oxidized low-density lipoprotein on vascular contraction and relaxation: clinical and pharmacological implications in atherosclerosis. Pharmacol. Rev..1996; 48:3-19.MedlineGoogle Scholar10 Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL. Beyond cholesterol modification of low-density lipoprotein that increase its atherogenicity. N Engl J Med..1989; 320:915-924.CrossrefMedlineGoogle Scholar11 Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem..1995; 270:319-324.CrossrefMedlineGoogle Scholar12 Liao JK, Clark SL. Regulation of G-protein and 12 subunit expression by oxidized low-density lipoprotein. J Clin Invest..1995; 95:1457-1463.CrossrefMedlineGoogle Scholar13 Holvoel P, Collen D. Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J..1995; 8:1279-1284.Google Scholar14 Kume N, Cybulsky MI, Gimbrone M. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces mononuclear leucocyte adhesion molecules in cultured human and rabbit arterial endothelial cells. J Clin Invest..1993; 90:1138-1144.Google Scholar15 Regnstrom J, Nelsson J, Tomval P, Landou C, Hamsten A. Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet..1992; 339:1183-1186.CrossrefMedlineGoogle Scholar16 Harrison DG. Endothelial function in atherosclerosis. Basic Res Cardiol. 1994;89(suppl 1):87-102.Google Scholar17 Dyce MC, Anderson TJ, Yeung AC, Selwyn AP, Ganz P. Indices of LDL particle size closely relate to endothelial function. Circulation. 1993;88(suppl I):I-466-I-471.Google Scholar18 Anderson TJ, Meredith IT, Yeung AC, Charbonneau F, Selwyn AP, Ganz P. Endothelium-dependent coronary vasomotion relates to the susceptibility of LDL to oxidation in humans. Circulation..1996; 93:1647-1650.CrossrefMedlineGoogle Scholar19 Libby P. Molecular basis of the acute coronary syndromes. Circulation..1995; 91:2844-2850.CrossrefMedlineGoogle Scholar20 Harrison DG, Armstrong ML, Freiman PC, Heistad DD. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest..1987; 80:1808-1811.CrossrefMedlineGoogle Scholar21 Keaney JF, Xu A, Cunningham D, Jackson T, Frei B, Vita JA. Dietary probucol preserves endothelial function in cholesterol-fed rabbit by limiting vascular oxidative stress and superoxide generation. J Clin Invest..1995; 96:2520-2529.Google Scholar22 Andrews TC, Raby K, Barry J, Naimi C, Allred E, Ganz P, Selwyn AP. The effect of LDL cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation. In press.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zhang Z, Wang F, Zhang Y, Yao J, Bi J, He J, Zhang S, Wei Y, Guo H, Zhang X and He M (2022) Associations of serum PFOA and PFOS levels with incident hypertension risk and change of blood pressure levels, Environmental Research, 10.1016/j.envres.2022.113293, 212, (113293), Online publication date: 1-Sep-2022. 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