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Medical Forum / General / Nutrition / March 2006(Oxydized) LDL not Mr. Bad Guy?
A new 8-year-long research says: "there was no relation between level of antibodies to oxidized LDL and the development of CHD or CVD." And a 2005 meta-analysis of 32 cohort studies in the Asia-Pacific region said: "Calculated LDL was a relatively poor predictor" of CHD and CVD... === http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=16476434&query_hl=20&itool=pubmed_docsum Atherosclerosis. 2006 Feb 11; [Epub ahead of print] Autoantibodies to oxidized LDL and cardiovascular risk: The Framingham Offspring Study. Wilson PW, Ben-Yehuda O, McNamara J, Massaro J, Witztum J, Reaven PD. Medical University of South Carolina, 96 Jonathan Lucas St, Suite 815, P.O. Box 250609, Charleston, SC 29425, United States; Framingham Heart Study, Framingham, MA 01702, United States. BACKGROUND: The relation between measures of oxidation of lipid particles and cardiovascular disease has not been extensively investigated prospectively on a population basis. METHODS: A community cohort of 1192 men and 1427 women with measures of IgG antibodies to oxidized LDL were followed 8 years for the development of initial coronary heart disease (CHD) and cardiovascular disease (CVD) events. RESULTS: Levels of IgG autoantibodies to a form of oxidized LDL were significantly associated with age in both sexes, positively with fibrinogen in men and negatively with HDL cholesterol in women. In sex-specific models that adjusted for age alone or those that adjusted for age, cholesterol, HDL cholesterol, smoking, and diabetes mellitus, there was no relation between level of antibodies to oxidized LDL and the development of CHD or CVD. CONCLUSION: Autoantibodies to oxidized LDL were strongly related to age and were not related to incident CHD or CVD over 8 years of follow up. PMID: 16476434 [PubMed - as supplied by publisher] === http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstra ct&list_uids=15840555&query_hl=23&itool=pubmed_docsum Ann Epidemiol. 2005 May;15(5):405-13. A comparison of lipid variables as predictors of cardiovascular disease in the Asia Pacific region. Barzi F, Patel A, Woodward M, Lawes CM, Ohkubo T, Gu D, Lam TH, Ueshima H; Asia Pacific Cohort Studies Collaboration. The George Institute for International Health, University of Sydney, Camperdown, NSW 2050, Australia. fbarzi@thegeorgeinstitute.org PURPOSE: Many guidelines advocate measurement of total or low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglycerides (TG) to determine treatment recommendations for preventing coronary heart disease (CHD) and cardiovascular disease (CVD). This analysis is a comparison of lipid variables as predictors of cardiovascular disease. METHODS: Hazard ratios for coronary and cardiovascular deaths by fourths of total cholesterol (TC), LDL, HDL, TG, non-HDL, TC/HDL, and TG/HDL values, and for a one standard deviation change in these variables, were derived in an individual participant data meta-analysis of 32 cohort studies conducted in the Asia-Pacific region. The predictive value of each lipid variable was assessed using the likelihood ratio statistic. RESULTS: Adjusting for confounders and regression dilution, each lipid variable had a positive (negative for HDL) log-linear association with fatal CHD and CVD. Individuals in the highest fourth of each lipid variable had approximately twice the risk of CHD compared with those with lowest levels. TG and HDL were each better predictors of CHD and CVD risk compared with TC alone, with test statistics similar to TC/HDL and TG/HDL ratios. Calculated LDL was a relatively poor predictor. CONCLUSIONS: While LDL reduction remains the main target of intervention for lipid-lowering, these data support the potential use of TG or lipid ratios for CHD risk prediction. PMID: 15840555 [PubMed - indexed for MEDLINE] === > A new 8-year-long research says: > "there was no relation between level of antibodies to oxidized LDL and > the development of CHD or CVD." In this case, the question is whether antibody formation is an accurate indicator, since it's not direct measure? > And a 2005 meta-analysis of 32 cohort studies in the Asia-Pacific > region said: > "Calculated LDL was a relatively poor predictor" of CHD and CVD... This is consistent with the research I've seen; TGL is a much more accurate predictor, and TGL/HDL ratios. The focus on LDL measurement without regard to particle size or other, better markers is the statin industry driving the public perception and research train to increase sales. Susan > > A new 8-year-long research says: > > "there was no relation between level of antibodies to oxidized LDL and > > the development of CHD or CVD." > > In this case, the question is whether antibody formation is an accurate > indicator, since it's not direct measure? Also oxidised LDL in circulation isn't the problem, it's oxidised LDL in the artery wall. Since the macrophages in the artery wall tend to get stuck there and then die (so never present to the rest of the immune system) it's possible that any antibodies are unrelated (or only weakly related) to actual plaque formation. MattLB Arachidonic is much more biochemically active than Mead acid, which is why some like Enig say that it is a "filler" and ineffective. Those who attack me want it both ways. If it is so much less biochemically active (as all agree with, including myself, except, apparently MattLB), then it will not cause the kinds of problems AA does. Moreover, I am suggesting that the body should produce Mead acid on its own, rather than getting it from the diet. In this way, you rely on the intelligence of cells to refrain from producing something dangerous to themselves. The only way you are going to get AA in your cells is if you eat a lot of PUFAs, which the evidence suggests is a terrible idea. I don't know how MattLB thinks the oxLDL is going to get to the artery wall if it is not in ciruculation first, though it's true that the antibodies could very well be a red herring here. What MattLB is talking about is not the first stage of "coronary heart disease" - inflammation will occur first, and the oxLDL is acting as an irritant that stresses cells, which then signal for the "immune system." Then the macrophages come in and are rendered dysfunctional, creating what one scientist called "death zones" in the artery walls. This is when plaque formation begins. It is important to point out that to have so much oxLDL as to cause this problem, your diet has to be really bad: full of PUFAs, meat cooked while exposed to air, and few antioxidant-rich foods. The "heart disease epidemic" began when more food items were refined to a point that destroyed much of the antioxidants. People were also eating food like fried meats in large amounts, without antioxidant-rich foods (meat and potatoes do not contain much in the way of antioxidants, for example). Such an "epidemic" happened in England in the late 1900s, when they began using powdered dairy, which is very rich in oxidized cholesterol. In the USA, it happened after WW II, for similar reasons. Refined oils, high in PUFAs, then became common by the 1960s, and the "epidemic" reached a peak, though it's very high now, considering how few people died of "heart disease" in the USA prior to 1940 or thereabouts. Since the "epidemic" killed many men in "middle age," this should have also happened prior to 1940, and thus the only explanation that makes sense in this dietary one. > Arachidonic is much more biochemically active than Mead acid, which is > why some like Enig say that it is a "filler" and ineffective. Those > who attack me want it both ways. If it is so much less biochemically > active (as all agree with, Unlikely since you've never said what you mean by biochemically active. > including myself, except, apparently > MattLB), then it will not cause the kinds of problems AA does. In an LDL particle it's irrelevant whether it's AA or Mead. They're both PUFA and both do nothing biochemical, because they have to be in cells to do that. > Moreover, I am suggesting that the body should produce Mead acid on its > own, rather than getting it from the diet. In this way, you rely on > the intelligence of cells to refrain from producing something dangerous > to themselves. What an impressive example of your ignorance. Ever hear of lactic acid? > I don't know how MattLB thinks the oxLDL is going to get to the artery > wall if it is not in ciruculation first, It's unlikely to be oxidized in circulation, but as soon as it gets lodged outside the bloodstream it's more prone to attack since there's less vitamin C to recycle the vitamin E in the particle. > though it's true that the > antibodies could very well be a red herring here. What MattLB is > talking about is not the first stage of "coronary heart disease" - Yes it is. The initial insult requires that LDL be accumulated at a specific point. There's a reason that plaques occur in particular places in particular arteries and not at random, you know. > inflammation will occur first, and the oxLDL is acting as an irritant > that stresses cells, which then signal for the "immune system." So inflammation is second, then. Or do you have your own definition of inflammation too in which the immune system isn't involved? >Then > the macrophages come in and are rendered dysfunctional, creating what > one scientist called "death zones" in the artery walls. This is when > plaque formation begins. This is when it becomes visually detectable. > It is important to point out that to have so much oxLDL as to cause > this problem, your diet has to be really bad: full of PUFAs, meat > cooked while exposed to air, and few antioxidant-rich foods. Not true. All the above makes it more likely, but you still have to recognise that it is a local phenomenon and that there are many contributing factors other than those you mention. MattLB >In an LDL particle it's irrelevant whether it's AA or Mead. They're >both PUFA and both do nothing biochemical, because they have to be in >cells to do that. Nah, not quite correct. Isoketals may still be formed and do harm even outside a cell, and chances are even increased that arachidonic acid will meet such a non-enzymatically fate outside the cell, where oxygen molecules may react with the cyclic form of it. Most probably, many physiological/biochemical effects of arachidonate not explainable by eicosanoids are due to the forming of isoketals and alike :-( (See isoketals, isoneurals and isofurans on PubMed, or do search for isolevuglandins and levuglandins. > >In an LDL particle it's irrelevant whether it's AA or Mead. They're > >both PUFA and both do nothing biochemical, because they have to be in > >cells to do that. > Nah, not quite correct. Isoketals may still be formed and do harm even > outside a cell, and chances are even increased that arachidonic acid > will meet such a non-enzymatically fate outside the cell, where oxygen > molecules may react with the cyclic form of it. Yes, but I'd call that chemistry rather than biochemistry. The biochemical function of AA is as a second messenger in cells. In lipoproteins it can't do that. Granted it's a slightly fuzzy use of biochemical, but montygram never defines what he means by it - presumably it's something different than "chemical". MattLB >Yes, but I'd call that chemistry rather than biochemistry. The >biochemical function of AA is as a second messenger in cells. In >lipoproteins it can't do that. Granted it's a slightly fuzzy use of >biochemical, but montygram never defines what he means by it - >presumably it's something different than "chemical". The detection of them in beginning was a chemistry thing, but, since it is proven to be a daily episode in many cells in body, it is biochemistry too. But, of course not only enzymologically. Check literature for the levuglandins (derived from PGH) and isolevuglanins (formed by oxygen attack and speeded up by myeloperoxidase) (See more in chapter of Laboratory examinations in http://focosi.immunesig.org/immunityinnate.html or do a search on either Pubmed or Google on the keywords isolevuglandins and levuglandins, evt. also isoprostanes. >A new 8-year-long research says: >"there was no relation between level of antibodies to oxidized LDL and >the development of CHD or CVD." Based on my readings of recent literature, isn't chronic inflammation the real culprit? Shouldn't people be paying attention to their C-reactive protein and fibrinogen levels, instead? >>A new 8-year-long research says: >>"there was no relation between level of antibodies to oxidized LDL and [quoted text clipped - 3 lines] > the real culprit? Shouldn't people be paying attention to their > C-reactive protein and fibrinogen levels, instead? Not *instead.* People should be paying attention to their TGLs, TGL/HDL ratios, blood glucose, too. Susan : x-no-archive: yes :: [quoted text clipped - 8 lines] : Not *instead.* People should be paying attention to their TGLs, : TGL/HDL ratios, blood glucose, too. The predictive value of certain markers depends on the metabolic type of the person. For those people who have insuline resistance/abdominal fat/ type 2 diabetes TGLs, TGL/HDL ratios and blood glucose have good predictive value, for others, less. In general the total cholesterol: HDL ratio has still the best predictive value. ApoB/ApoA1 ratio is an equally important ratio which is especially useful for diabetics as a test because no fasting is required.  SignatureJuhana > The predictive value of certain markers depends on the metabolic type of the > person. For those people who have insuline resistance/abdominal fat/ type 2 > diabetes TGLs, TGL/HDL ratios and blood glucose have good predictive value, > for others, less. I was slim when I was severely IR as are many other folks, and still had the dyslipidemia to show for it. I would guess that the vast majority of those with elevated risk are at risk due to being IR. Susan > > The predictive value of certain markers depends on the metabolic type of the > > person. For those people who have insuline resistance/abdominal fat/ type 2 [quoted text clipped - 6 lines] > > Susan Nobody gives a rats a.s, to quote TC. I agree with Just Cocky. Among "Asian Pacific" peoples, you will find big differences. For example, that guy who is always posting anti-iron studies here posted a study (I think it was less than a year ago) that said that Asians with high iron levels did not have the "diseases" that Western medicine "experts" would have predicted. I'd like to see oxidized LDL studied this way in a country like the USA. Also, they looked for antibodies for oxLDL, which again may not be the best idea, especially for this population, and they only let it go for 8 years. Also, was the difference between those with low oxLDL and high oxLDL similar to what it would be in the USA? And did these populations have the incidence of CHD that is common in Western nations? Thus, as usual, there is a need for better studies, and in the absence of them, there are foods you can eat that are not problematic in any of these contexts, so you can just avoid the ones that are most likely the "culprits," like refined oils with high unsaturated fatty acid contents, and cooking meat while exposed to air. To get a little technical about my "agreement" about the inflammation comment: Asians with no AA in their cells will not have the same "inflammatory" response as a "typcial" American, for example. oxLDL is still "bad" in such Asian peoples, but it would take a lot more than 8 years to see the "badness" in the form of CHD. The high omega 6 PUFA diet makes the body "hyper-responsive," and therefore speeds up the processes involved here in CHD. You want to get AA out of your cells, and let your body make the Mead acid PUFA as it sees fit. Then there should be little oxLDL problem, unless you are inhaling powerful toxins at work or something like that. Here are just a couple of studies that make the point: Oxidized LDL contains inflammatory PAF-like phospholipids. Trends Cardiovasc Med 2001 Apr-May;11(3-4):139-42 Marathe GK, Prescott SM, Zimmerman GA, McIntyre TM. Department of Pathology, University of Utah, Salt Lake City, Utah, USA. Atherosclerosis has an underlying inflammatory component. Oxidation of low-density lipoprotein (LDL) particles to modified forms promotes atherogenesis by supplying cholesterol and through the oxidative generation of agents that activate macrophages, smooth muscle and endothelial cells. A primary target of oxidizing compounds, derived from cigarette smoke, dietary sources, exuberant inflammatory cell responses and normal cellular metabolism among other sources, are the esterified polyunsaturated fatty acids in the phospholipid shell that surrounds the insoluble lipids of the lipoprotein core. One type of phospholipid oxidation product mimics the structure of the potent inflammatory mediator platelet-activating factor (PAF), and these oxidation products activate the PAF receptor found on platelets, monocytes and leukocytes. Production of such PAF mimetics is, in contrast to the physiologic generation of PAF, uncontrolled. PAF mimetics and other phospholipid oxidation products are found in atherosclerotic lesions or even in blood after exposure to cigarette smoke. Here we summarize our data describing the structure, activity and metabolism of the PAF-like lipids found in atherogenic LDL particles. Publication Types: · Review · Review, Tutorial PMID: 11686003 [PubMed - indexed for MEDLINE] Ital Heart J 2001 Dec;2(12):867-72 Low-density lipoprotein oxidation. Iuliano L, Micheletta F, Violi F. Istituto di I Clinica Medica Universita degli Studi La Sapienza Policlinico Umberto I Viale del Policlinico, 155 00161 Roma. Free radical mediated oxidation of low-density lipoproteins (LDL), which has been extensively studied in the last two decades, plays a central role in the development of the atherosclerotic plaque. Oxidation involves the lipid moiety of LDL in a chain reaction mechanism. In the initial phase, free radicals preferentially attack highly oxidizable polyunsaturated fatty acids. Subsequent recruitment of other molecules includes cholesterol and phospholipids. The process of oxidation is counteracted by antioxidants present in LDL. By-products formed during oxidation of LDL lipids, which may have biological activity, react with amino acid residues of the LDL protein backbone with the consequent modification of chemical and immunological properties responsible for cellular receptor shift. Oxidation-altered apolipoprotein B of oxidized LDL is, in fact, recognized by the macrophage scavenger receptor responsible for foam cell formation. The mechanism of LDL oxidation and the impact on atherogenesis are discussed. >You want to get AA out of your cells, > and let your body make the Mead acid PUFA as it sees fit. Then there > should be little oxLDL problem, You don't understand the mechanism of plaque formation, then. > unless you are inhaling powerful toxins > at work or something like that. Here are just a couple of studies that > make the point: The second one doesn't make the point it contradicts it. > Free radical mediated oxidation of low-density lipoproteins (LDL), > which has been extensively studied in the last two decades, plays a > central role in the development of the atherosclerotic plaque. > Oxidation involves the lipid moiety of LDL in a chain reaction > mechanism. In the initial phase, free radicals preferentially attack > highly oxidizable polyunsaturated fatty acids. This includes any Mead acid, ergo Mead acid is no protection in LDL. > Subsequent recruitment > of other molecules includes cholesterol and phospholipids. The process [quoted text clipped - 5 lines] > apolipoprotein B of oxidized LDL is, in fact, recognized by the > macrophage scavenger receptor responsible for foam cell formation. Oxidised LDL is taken up by scavenger macrophages which is the start of the plaque. whether it's Mead acid or arachidonic acid in the LDL makes no difference. OxLDL alone is enough to start a fatty streak in the artery through local effects. MattLB >I agree with Just Cocky. Among "Asian Pacific" peoples, you will find >big differences. For example, that guy who is always posting anti-iron >studies here posted a study (I think it was less than a year ago) that >said that Asians with high iron levels did not have the "diseases" that >Western medicine "experts" would have predicted. I'd like to see One difference is that people living in Asia and using either lot of fish in diet or using ertain berries like Chines Wolf Berry, has an enormouse intake of taurine compared to Western hemisphere. (A quick computation based on average food intakes in Norwegians a few years ago, based on knowledge about how much taurine is present in those nutrients, did show average intake would be around 30 mg taurine pr day, while in Japan it exceed by far 500 mg, possibly more than 1 g daily. Taurine has a structure that combined with phosphate groups of DNA form a mixed complex with iron completely locking it up from doing any harm at all. This is most probably lacking in Western hemisphere. >In general the total cholesterol: HDL ratio has still the best predictive >value. ApoB/ApoA1 ratio is an equally important ratio which is especially >useful for diabetics as a test because no fasting is required. Predictive value for what?? :: In general the total cholesterol: HDL ratio has still the best :: predictive value. ApoB/ApoA1 ratio is an equally important ratio :: which is especially useful for diabetics as a test because no :: fasting is required. : : Predictive value for what?? For cardiovascular disease in general. SignatureJuhana Rather than do a large study measuring a few variables, why not do a smaller study and measure all the plausible confounding variables? This study would have been a lot more enlightening if they'd measured C reactive protein HbA1c EPA and Arachidonic acid in the white blood cell membranes Lp(a) Those are my top 4. If they've got the inclination I'd also like to see fibrinogen, homocysteine, some measure of serum antioxidant status (ORAC, FRAP), white blood cell count, some measure of fitness. They could have done these tests as a nested case control study. That is, do an extra blood draw on everybody in the study, and freeze it. At the end of the study, pull the blood on those participants who've hit an endpoint (e.g. heart attack) and choose a matching set of incident-free participants. Only do the extra testing on those blood samples. Shouldn't run up the cost of an 8 year study very much. And it would have told us so much more! ========== Are there common lab tests for oxidized LDL, or is this just a test that research labs run? Are these tests standardized enough, or does one need a rich description of the "lab normal" outcomes in order to interpret the result? Is there one widespread test, or are there a bunch of different methods, with varying accuracies, to choose from? Is getting a reading after overnight fasting enough, or does one need multiple draws to get a meaningful measure? If I pressure my endo to test my oxidized LDL, am I asking for a $20 test or a $600 test? Anybody? >Based on my readings of recent literature, isn't chronic inflammation >the real culprit? Shouldn't people be paying attention to their >C-reactive protein and fibrinogen levels, instead? And active, accidently released myeloperoxidase and eosinophil peroxidase producing still HOCl in such inflammation areas. (C-reactive protein is most probably a marker of amount of PMN's and monocytes that has died an too quickly death by necrosis (or apoptosis) because HOCl has damaged far too much of the cell itself instead of the infectious agent. One report conclude that more than 85% material damaged by HOCl is the immune cells macromolecules, mostly inside the phagolysosomes where synthesis of HOCl mainly occure, except in eosinophils who release the enzyme into serum in order to kill bigger invaders, like Candida and other yeast cells etc. |
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