High density lipoprotein natural history, complications and prognosis: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{High density lipoprotein}} | {{High density lipoprotein}} | ||
{{CMG}}; {{AE}} {{AN}}; {{RT}} | {{CMG}}; {{AE}} {{AN}}; {{RT}}; {{VR}} | ||
==Overview== | ==Overview== | ||
The | Epidemiological studies have shown an inverse relationship between HDL-C levels and [[CVD]] risks,<ref name="pmid193398">{{cite journal| author=Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR| title=High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. | journal=Am J Med | year= 1977 | volume= 62 | issue= 5 | pages= 707-14 | pmid=193398 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=193398 }} </ref><ref name="pmid19903920">{{cite journal| author=Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK et al.| title=Major lipids, apolipoproteins, and risk of vascular disease. | journal=JAMA | year= 2009 | volume= 302 | issue= 18 | pages= 1993-2000 | pmid=19903920 | doi=10.1001/jama.2009.1619 | pmc=PMC3284229 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19903920 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20157124 Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212] </ref><ref name="pmid2642759">{{cite journal| author=Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD et al.| title=High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. | journal=Circulation | year= 1989 | volume= 79 | issue= 1 | pages= 8-15 | pmid=2642759 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2642759 }} </ref> low circulating levels of HDL-cholesterol have been associated with the development of [[coronary artery disease]], particularly when it is accompanied by other coronary risk factors.<ref name="Oram-1987">{{Cite journal | last1 = Oram | first1 = JF. | last2 = Johnson | first2 = CJ. | last3 = Brown | first3 = TA. | title = Interaction of high density lipoprotein with its receptor on cultured fibroblasts and macrophages. Evidence for reversible binding at the cell surface without internalization. | journal = J Biol Chem | volume = 262 | issue = 5 | pages = 2405-10 | month = Feb | year = 1987 | doi = | PMID = 3029079 }}</ref><ref name="-2002">{{Cite journal | title = Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. | journal = Circulation | volume = 106 | issue = 25 | pages = 3143-421 | month = Dec | year = 2002 | doi = | PMID = 12485966 }}</ref><ref name="Després-2013">{{Cite journal | last1 = Després | first1 = JP. | title = HDL cholesterol studies--more of the same? | journal = Nat Rev Cardiol | volume = 10 | issue = 2 | pages = 70-2 | month = Feb | year = 2013 | doi = 10.1038/nrcardio.2012.182 | PMID = 23319099 }}</ref> The protective role of high HDL levels against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differently associated with cardiovascular risks. Many case-control and prospective studies have demonstrated that the HDL2 sub fraction and the plasma [[apo A-I]] concentration are better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3.<ref name="Salonen-1991">{{Cite journal | last1 = Salonen | first1 = JT. | last2 = Salonen | first2 = R. | last3 = Seppänen | first3 = K. | last4 = Rauramaa | first4 = R. | last5 = Tuomilehto | first5 = J. | title = HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. | journal = Circulation | volume = 84 | issue = 1 | pages = 129-39 | month = Jul | year = 1991 | doi = | PMID = 2060089 }}</ref> The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.<ref name="pmid20425274">{{cite journal| author=Khera AV, Rader DJ| title=Future therapeutic directions in reverse cholesterol transport. | journal=Curr Atheroscler Rep | year= 2010 | volume= 12 | issue= 1 | pages= 73-81 | pmid=20425274 | doi=10.1007/s11883-009-0080-0 | pmc=PMC3315100 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20425274 }} </ref> In addition to its prognotic role in [[CAD]], low HDL levels have been associated with diseases and complications involving the neurological, renal, and liver systems as well as sepsis and carcinoma. | ||
==Low | ==Low High-Density Lipoprotein as a Prognostic Factor== | ||
Low HDL has been evaluated as a possible prognostic factor in the following conditions: | |||
* [[Acute ischemic stroke]] | |||
* [[Atrial fibrillation]] | |||
* [[Carcinoma]] | |||
* [[Chronic kidney disease]] | |||
* [[Cirrhosis]] | |||
* [[Congestive heart failure]] | |||
* [[Coronary artery disease]] | |||
* [[Dementia]] | |||
* [[Kawasaki disease]] | |||
* [[Nonalcoholic fatty liver disease]] | |||
* Post-cardiac procedures | |||
* [[Sepsis]] | |||
==Coronary Artery Disease== | |||
The inverse relation of HDL to either the presence or development of [[coronary artery disease|coronary artery disease (CAD)]] is well-established;<ref name="pmid23565387">{{cite journal |author=Rajagopal G, Suresh V, Sachan A |title=High-density lipoprotein cholesterol: How High |journal=Indian J Endocrinol Metab |volume=16 |issue=Suppl 2 |pages=S236–8 |year=2012 |month=December |pmid=23565387 |pmc=3603035 |doi=10.4103/2230-8210.104048 |url=}}</ref> in fact, for every 1% decrease in HDL concentration, there is a 2-3% increase in the risk of development of [[CHD]].<ref name="pmid12485966">{{cite journal| author=National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)| title=Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. | journal=Circulation | year= 2002 | volume= 106 | issue= 25 | pages= 3143-421 | pmid=12485966 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12485966 }} </ref> Studies on different populations supported low HDL as a significant cardiovascular risk factor as well as a prognostic factor, either independently or along with other physical and biochemical metrics. Low levels of HDL-cholesterol, which may reflect increased catabolism of triglyceride-enriched HDL particles, appear to interact with [[hypertriglyceridemia]] to increase the coronary risk.<ref name="Wittrup-1999">{{Cite journal | last1 = Wittrup | first1 = HH. | last2 = Tybjaerg-Hansen | first2 = A. | last3 = Nordestgaard | first3 = BG. | title = Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. | journal = Circulation | volume = 99 | issue = 22 | pages = 2901-7 | month = Jun | year = 1999 | doi = | PMID = 10359734 }}</ref><ref name="Manninen-1992">{{Cite journal | last1 = Manninen | first1 = V. | last2 = Tenkanen | first2 = L. | last3 = Koskinen | first3 = P. | last4 = Huttunen | first4 = JK. | last5 = Mänttäri | first5 = M. | last6 = Heinonen | first6 = OP. | last7 = Frick | first7 = MH. | title = Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment. | journal = Circulation | volume = 85 | issue = 1 | pages = 37-45 | month = Jan | year = 1992 | doi = | PMID = 1728471 }}</ref> Plaque rupture, besides its correlation with high total cholesterol (TC), is also shown to be related to low HDL-cholesterol and an elevated TC/HDL-C ratio.<ref name="Burke-1997">{{Cite journal | last1 = Burke | first1 = AP. | last2 = Farb | first2 = A. | last3 = Malcom | first3 = GT. | last4 = Liang | first4 = YH. | last5 = Smialek | first5 = J. | last6 = Virmani | first6 = R. | title = Coronary risk factors and plaque morphology in men with coronary disease who died suddenly. | journal = N Engl J Med | volume = 336 | issue = 18 | pages = 1276-82 | month = May | year = 1997 | doi = 10.1056/NEJM199705013361802 | PMID = 9113930 }}</ref> Studies on the relationship between low HDL levels and CAD are as follows: | |||
* Based on data from the [[Framingham Heart Study]], the risk for [[myocardial infarction]] was found to increase by 25 percent for every 5 mg/dL (0.13 mmol/L) decrement in serum HDL-cholesterol, below the median values for both men and women.<ref name="Oram-1987">{{Cite journal | last1 = Oram | first1 = JF. | last2 = Johnson | first2 = CJ. | last3 = Brown | first3 = TA. | title = Interaction of high density lipoprotein with its receptor on cultured fibroblasts and macrophages. Evidence for reversible binding at the cell surface without internalization. | journal = J Biol Chem | volume = 262 | issue = 5 | pages = 2405-10 | month = Feb | year = 1987 | doi = | PMID = 3029079 }}</ref> According to the study, the [[relative risk]] of death due to cardiovascular and [[coronary artery disease]] for men in the first HDL-cholesterol quintile (less than 35 mg/dL) as compared to the top quintile (greater than 54 mg/dL) is 3.6 and 4.1 respectively and for women the corresponding values were 1.6 and 3.1, comparing the bottom HDL-cholesterol quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl). | |||
* The Lipoprotein and Coronary Atherosclerosis Study (LCAS) which studied patients with mild to moderate LDL-cholesterol elevation found that the patients who also had low HDL-cholesterol at baseline had more CAD progression than patients with higher HDL-cholesterol.<ref name="Ballantyne-1999">{{Cite journal | last1 = Ballantyne | first1 = CM. | last2 = Herd | first2 = JA. | last3 = Ferlic | first3 = LL. | last4 = Dunn | first4 = JK. | last5 = Farmer | first5 = JA. | last6 = Jones | first6 = PH. | last7 = Schein | first7 = JR. | last8 = Gotto | first8 = AM. | title = Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy. | journal = Circulation | volume = 99 | issue = 6 | pages = 736-43 | month = Feb | year = 1999 | doi = | PMID = 9989957 }}</ref> | |||
* Framingham Risk Assessment counts HDL values above 60 mg/dL (1.5 mmol/L) as a negative risk factor.<ref name="-2002">{{Cite journal | title = Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. | journal = Circulation | volume = 106 | issue = 25 | pages = 3143-421 | month = Dec | year = 2002 | doi = | PMID = 12485966 }}</ref> | |||
* Studies have shown that in patients with known coronary artery disease, HDL-cholesterol levels are predictive of coronary events over a broad range of LDL-cholesterol levels. The LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial<ref name="Simes-2002">{{Cite journal | last1 = Simes | first1 = RJ. | last2 = Marschner | first2 = IC. | last3 = Hunt | first3 = D. | last4 = Colquhoun | first4 = D. | last5 = Sullivan | first5 = D. | last6 = Stewart | first6 = RA. | last7 = Hague | first7 = W. | last8 = Keech | first8 = A. | last9 = Thompson | first9 = P. | title = Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels? | journal = Circulation | volume = 105 | issue = 10 | pages = 1162-9 | month = Mar | year = 2002 | doi = | PMID = 11889008 }}</ref> and the CARE (Cholesterol and Recurrent Events) trial<ref name="Pfeffer-1995">{{Cite journal | last1 = Pfeffer | first1 = MA. | last2 = Sacks | first2 = FM. | last3 = Moyé | first3 = LA. | last4 = Brown | first4 = L. | last5 = Rouleau | first5 = JL. | last6 = Hartley | first6 = LH. | last7 = Rouleau | first7 = J. | last8 = Grimm | first8 = R. | last9 = Sestier | first9 = F. | title = Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators. | journal = Am J Cardiol | volume = 76 | issue = 9 | pages = 98C-106C | month = Sep | year = 1995 | doi = | PMID = 7572695 }}</ref> have shown that reduced serum HDL-cholesterol levels strongly predicted acute coronary events in patients with LDL-cholesterol less than 125 mg/dL compared to those with levels above 125 mg/dL. There was a significant reduction in the event rate in patients with LDL-cholesterol <125 mg/dL for every 10 mg/dL rise in HDL-cholesterol compared to those with LDL-cholesterol levels more than 125 mg/dL. A similar relationship between the levels of HDL-cholesterol and LDL-cholesterol was also shown in the Treating to New Targets (TNT) trial.<ref name="Waters-">{{Cite journal | last1 = Waters | first1 = DD. | title = Clinical insights from the Treating to New Targets trial. | journal = Prog Cardiovasc Dis | volume = 51 | issue = 6 | pages = 487-502 | month = | year = | doi = 10.1016/j.pcad.2009.01.001 | PMID = 19410683 }}</ref> | |||
*The finding of very low HDL levels among one-fifth of patients with [[Unstable angina / non ST elevation myocardial infarction|NSTEMI ACS]] added to a greater burden of atherosclerosis and a higher risk of mortality.<ref name="Roe-2008">{{Cite journal | last1 = Roe | first1 = MT. | last2 = Ou | first2 = FS. | last3 = Alexander | first3 = KP. | last4 = Newby | first4 = LK. | last5 = Foody | first5 = JM. | last6 = Gibler | first6 = WB. | last7 = Boden | first7 = WE. | last8 = Ohman | first8 = EM. | last9 = Smith | first9 = SC. | title = Patterns and prognostic implications of low high-density lipoprotein levels in patients with non-ST-segment elevation acute coronary syndromes. | journal = Eur Heart J | volume = 29 | issue = 20 | pages = 2480-8 | month = Oct | year = 2008 | doi = 10.1093/eurheartj/ehn364 | PMID = 18716006 }}</ref> | |||
* A study conducted in a European population revealed that patients carrying at least one polymorphic allele of the paraoxonase2 (PON2) gene along with low HDL represent a category of subjects at a higher risk for the development of acute myocardial infarction with a worse prognosis.<ref name="Marchegiani-2009">{{Cite journal | last1 = Marchegiani | first1 = F. | last2 = Spazzafumo | first2 = L. | last3 = Provinciali | first3 = M. | last4 = Cardelli | first4 = M. | last5 = Olivieri | first5 = F. | last6 = Franceschi | first6 = C. | last7 = Lattanzio | first7 = F. | last8 = Antonicelli | first8 = R. | title = Paraoxonase2 C311S polymorphism and low levels of HDL contribute to a higher mortality risk after acute myocardial infarction in elderly patients. | journal = Mol Genet Metab | volume = 98 | issue = 3 | pages = 314-8 | month = Nov | year = 2009 | doi = 10.1016/j.ymgme.2009.05.008 | PMID = 19540141 }}</ref> | |||
* A 2011 population based study with individual-participant-data (over 200,000 individuals) [[meta-analysis]] of 23 studies in the Asia-Pacific region revealed that a low level of HDL cholesterol was seen significantly more often in Asians than non-Asians (33.1 versus 27.0%). Even the prevalence of isolated low HDL-cholesterol was significantly higher in Asians (22.4 versus 14.5 %). In all individuals, there was a significant correlation between low HDL cholesterol and cardiovascular events. Particularly in Asians, the isolated low levels of HDL cholesterol were strongly associated with CAD risk similar to low levels of HDL cholesterol combined with other lipid abnormalities. This study suggested that isolated low HDL cholesterol in Asians is a distinct phenotype, which is strongly associated with an increased risk of CAD.<ref name="Huxley-2011">{{Cite journal | last1 = Huxley | first1 = RR. | last2 = Barzi | first2 = F. | last3 = Lam | first3 = TH. | last4 = Czernichow | first4 = S. | last5 = Fang | first5 = X. | last6 = Welborn | first6 = T. | last7 = Shaw | first7 = J. | last8 = Ueshima | first8 = H. | last9 = Zimmet | first9 = P. | title = Isolated low levels of high-density lipoprotein cholesterol are associated with an increased risk of coronary heart disease: an individual participant data meta-analysis of 23 studies in the Asia-Pacific region. | journal = Circulation | volume = 124 | issue = 19 | pages = 2056-64 | month = Nov | year = 2011 | doi = 10.1161/CIRCULATIONAHA.111.028373 | PMID = 21986289 }}</ref> | |||
* More recently low HDL-cholesterol was found to be the most powerful lipid parameter for predicting the risk and the clinical outcome of CAD in a Han Chinese population.<ref name="Lu-2013">{{Cite journal | last1 = Lu | first1 = Q. | last2 = Tian | first2 = G. | last3 = Zhang | first3 = Y. | last4 = Lu | first4 = M. | last5 = Lin | first5 = X. | last6 = Ma | first6 = A. | title = Low HDL-C predicts risk and PCI outcomes in the Han Chinese population. | journal = Atherosclerosis | volume = 226 | issue = 1 | pages = 193-7 | month = Jan | year = 2013 | doi = 10.1016/j.atherosclerosis.2012.09.011 | PMID = 23107044 }}</ref> | |||
The Multi-ethnic Study of Atherosclerosis (MESA) adds to the concept that the inverse relationship between HDL and cardiovascular risks may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.<ref name="Mackey-2012">{{Cite journal | last1 = Mackey | first1 = RH. | last2 = Greenland | first2 = P. | last3 = Goff | first3 = DC. | last4 = Lloyd-Jones | first4 = D. | last5 = Sibley | first5 = CT. | last6 = Mora | first6 = S. | title = High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis). | journal = J Am Coll Cardiol |volume = 60 | issue = 6 | pages = 508-16 | month = Aug | year = 2012 | doi = 10.1016/j.jacc.2012.03.060 | PMID = 22796256 }}</ref> HDL<sub>2</sub> subfraction and [[apo A-I]] are reported to be better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL<sub>3</sub> in some studies,<ref name="Salonen-1991">{{Cite journal | last1 = Salonen | first1 = JT. | last2 = Salonen | first2 = R. | last3 = Seppänen | first3 = K. | last4 = Rauramaa | first4 = R. | last5 = Tuomilehto | first5 = J. | title = HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men. | journal = Circulation | volume = 84 | issue = 1 | pages = 129-39 | month = Jul | year = 1991 | doi = | PMID = 2060089 }}</ref> while other reports have shown similar associations of total HDL and HDL<sub>3</sub> with [[coronary artery disease]] ([[CAD]]) as HDL2 and apo A-I.<ref name="Stampfer-1991">{{Cite journal | last1 = Stampfer | first1 = MJ. | last2 = Sacks | first2 = FM. | last3 = Salvini | first3 = S. | last4 = Willett | first4 = WC. | last5 = Hennekens | first5 = CH. | title = A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. | journal = N Engl J Med | volume = 325 | issue = 6 | pages = 373-81 | month = Aug | year = 1991 | doi = 10.1056/NEJM199108083250601 | PMID = 2062328 }}</ref> Polymorphisms in phospholipid transfer protein (PLTP) are also shown to be associated with increased concentrations of smaller, cholesterol-depleted HDL particles and a lower cardiovascular event rate.<ref name="Vergeer-2010">{{Cite journal | last1 = Vergeer | first1 = M. | last2 = Boekholdt | first2 = SM. | last3 = Sandhu | first3 = MS. | last4 = Ricketts | first4 = SL. | last5 = Wareham | first5 = NJ. | last6 = Brown | first6 = MJ. | last7 = de Faire | first7 = U. | last8 = Leander | first8 = K. | last9 = Gigante | first9 = B. | title = Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. | journal = Circulation | volume = 122 | issue = 5 | pages = 470-7 | month = Aug | year = 2010 | doi = 10.1161/CIRCULATIONAHA.109.912519 | PMID = 20644014 }}</ref> Despite the established crude association between HDL and cardiovascular risks, Mendelian randomization analyses, [[The JUPITER Trial|JUPITER trial]], and studies in [[Tangier disease]] failed to demonstrate a cause-effect relationship.<ref name="Haase-2010">{{Cite journal | last1 = Haase | first1 = CL. | last2 = Tybjærg-Hansen | first2 = A. | last3 = Grande | first3 = P. |last4 = Frikke-Schmidt | first4 = R. | title = Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. | journal = J Clin Endocrinol Metab | volume = 95 | issue = 12 | pages = E500-10 | month = Dec | year = 2010 | doi = 10.1210/jc.2010-0450 | PMID = 20826588 }}</ref><ref name="Haase-2012">{{Cite journal | last1 = Haase | first1 = CL. | last2 = Tybjærg-Hansen | first2 = A. | last3 = Qayyum | first3 = AA. | last4 = Schou | first4 = J. | last5 = Nordestgaard | first5 = BG. |last6 = Frikke-Schmidt | first6 = R. | title = LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals.| journal = J Clin Endocrinol Metab | volume = 97 | issue = 2 | pages = E248-56 | month = Feb | year = 2012 | doi = 10.1210/jc.2011-1846 | PMID = 22090275 }}</ref><ref name="Frikke-Schmidt-2010">{{Cite journal | last1 = Frikke-Schmidt | first1 = R. | title = Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population. | journal = Atherosclerosis | volume = 208 | issue = 2 | pages = 305-16 | month = Feb | year = 2010 | doi = 10.1016/j.atherosclerosis.2009.06.005 | PMID = 19596329 }}</ref><ref name="Ridker-2010">{{Cite journal | last1 = Ridker | first1 = PM. | last2 = Genest | first2 = J. | last3 = Boekholdt | first3 = SM. | last4 = Libby |first4 = P. | last5 = Gotto | first5 = AM. | last6 = Nordestgaard | first6 = BG. | last7 = Mora | first7 = S. | last8 = MacFadyen | first8 = JG. | last9 = Glynn | first9 = RJ. |title = HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial. | journal = Lancet | volume = 376 |issue = 9738 | pages = 333-9 | month = Jul | year = 2010 | doi = 10.1016/S0140-6736(10)60713-1 | PMID = 20655105 }}</ref> | |||
===CAD in Pediatric Populations=== | |||
Data is scarce about the contribution of HDL to CAD in the pediatric population due to the rarity of cases. A prospective follow-up study in pediatric [[cardiac transplant]] recipients showed that, although pravastatin improved the HDL2 concentrations in the treatment group, it failed to normalize serum [[triglyceride]] and prevent the progression of vasculopathy in some of the patients. It also suggested a predictive role of low HDL-C and high apoB-100/apoA-I ratio for the development of vasculopathy.<ref name="Hedman-2007">{{Cite journal | last1 = Hedman | first1 = M. | last2 = Pahlman | first2 = R. | last3 = Sundvall | first3 = J. | last4 = Ehnholm | first4 = C. | last5 = Syvänne | first5 = M. | last6 = Jokinen | first6 = E. | last7 = Jauhiainen | first7 = M. | last8 = Holmberg | first8 = C. | last9 = Antikainen | first9 = M. | title = Low HDL-C predicts the onset of transplant vasculopathy in pediatric cardiac recipients on pravastatin therapy. | journal = Pediatr Transplant | volume = 11 | issue = 5 | pages = 481-90 | month = Aug | year = 2007 | doi = 10.1111/j.1399-3046.2007.00690.x | PMID = 17631015 }}</ref> | |||
===Premature CAD=== | |||
Premature CAD is usually defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age. Numerous studies of the 20th century from both Middle East and US population have reported low HDL in over 19% to 52 % of premature CAD patients.<ref name="Genest-1992">{{Cite journal | last1 = Genest | first1 = JJ. | last2 = Martin-Munley | first2 = SS. | last3 = McNamara | first3 = JR. | last4 = Ordovas | first4 = JM. | last5 = Jenner | first5 = J. | last6 = Myers | first6 = RH. | last7 = Silberman | first7 = SR. | last8 = Wilson | first8 = PW. | last9 = Salem | first9 = DN. | title = Familial lipoprotein disorders in patients with premature coronary artery disease. | journal = Circulation | volume = 85 | issue = 6 | pages = 2025-33 | month = Jun | year = 1992 | doi = | PMID = 1534286 }}</ref><ref name="Buring-1992">{{Cite journal | last1 = Buring | first1 = JE. | last2 = O'Connor | first2 = GT. | last3 = Goldhaber | first3 = SZ. | last4 = Rosner | first4 = B. | last5 = Herbert | first5 = PN. | last6 = Blum | first6 = CB. | last7 = Breslow | first7 = JL. | last8 = Hennekens | first8 = CH. | title = Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction. | journal = Circulation | volume = 85 | issue = 1 | pages = 22-9 | month = Jan | year = 1992 | doi = | PMID = 1728453 }}</ref><ref name="Genest-1992">{{Cite journal | last1 = Genest | first1 = J. | last2 = McNamara | first2 = JR. | last3 = Ordovas | first3 = JM. | last4 = Jenner | first4 = JL. | last5 = Silberman | first5 = SR. | last6 = Anderson | first6 = KM. | last7 = Wilson | first7 = PW. | last8 = Salem | first8 = DN. | last9 = Schaefer | first9 = EJ. | title = Lipoprotein cholesterol, apolipoprotein A-I and B and lipoprotein (a) abnormalities in men with premature coronary artery disease. | journal = J Am Coll Cardiol | volume = 19 | issue = 4 | pages = 792-802 | month = Mar | year = 1992 | doi = | PMID = 1531990 }}</ref><ref name="Kwiterovich-1993">{{Cite journal | last1 = Kwiterovich | first1 = PO. | last2 = Coresh | first2 = J. | last3 = Bachorik | first3 = PS. | title = Prevalence of hyperapobetalipoproteinemia and other lipoprotein phenotypes in men (aged or = 50 years) and women ( or = 60 years) with coronary artery disease. | journal = Am J Cardiol | volume = 71 | issue = 8 | pages = 631-9 | month = Mar | year = 1993 | doi = | PMID = 8447257 }}</ref><ref name="Genest-1993">{{Cite journal | last1 = Genest | first1 = J. | last2 = Bard | first2 = JM. | last3 = Fruchart | first3 = JC. | last4 = Ordovas | first4 = JM. | last5 = Schaefer | first5 = EJ. | title = Familial hypoalphalipoproteinemia in premature coronary artery disease. | journal = Arterioscler Thromb | volume = 13 | issue = 12 | pages = 1728-37 | month = Dec | year = 1993 | doi = | PMID = 8241092 }}</ref><ref name="-1992">{{Cite journal | title = Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel. | journal = Circulation | volume = 86 | issue = 3 | pages = 839-48 | month = Sep | year = 1992 | doi = | PMID = 1516196 }}</ref> In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study that examined [[aortas]] and [[coronary arteries]] from autopsies of healthy 15 to 35 year old persons, a negative association of high HDL with both [[fatty streaks]] and raised lesions in the [[aorta]] and right [[coronary artery]] was seen, particularly after the age of 25. Post-hoc analyses of two randomized trials in the past 10 years have shown low HDL levels as predictors of coronary events in patients with known [[CAD]]. Analysis of 13,173 patients in the LIPID and [[CARE trial]]s found that low serum HDL cholesterol was a significantly stronger predictor of CAD events in patients with an LDL-cholesterol <125 than ≥125 mg/dL (3.2 mmol/L).<ref name="Sacks-2002">{{Cite journal | last1 = Sacks | first1 = FM. | last2 = Tonkin | first2 = AM. | last3 = Craven | first3 = T. | last4 = Pfeffer | first4 = MA. | last5 = Shepherd | first5 = J. | last6 = Keech | first6 = A. | last7 = Furberg | first7 = CD. | last8 = Braunwald | first8 = E. | title = Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors. | journal = Circulation | volume = 105 | issue = 12 | pages = 1424-8 | month = Mar | year = 2002 | doi = | PMID = 11914249 }}</ref> For a 10 mg/dL (0.26 mmol/L) increase in HDL-cholesterol the event rate decreased by 29 percent in those with LDL-cholesterol <125 mg/dL (3.2 mmol/L) compared to 10 percent in those with an LDL-cholesterol ≥125 mg/dL (3.2 mmol/L). Post hoc analysis of the [[TNT Trial|Treating to New Targets trial]] (TNT) in which nearly 10,000 patients with established CAD was treated with either high or low dose statin therapy revealed that HDL cholesterol levels were predictive of major cardiovascular events. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter.<ref name="Barter-2007">{{Cite journal | last1 = Barter | first1 = P. | last2 = Gotto | first2 = AM. | last3 = LaRosa | first3 = JC. | last4 = Maroni | first4 = J. | last5 = Szarek | first5 = M. | last6 = Grundy | first6 = SM. | last7 = Kastelein | first7 = JJ. | last8 = Bittner | first8 = V. | last9 = Fruchart | first9 = JC. | title = HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. | journal = N Engl J Med | volume = 357 | issue = 13 | pages = 1301-10 | month = Sep | year = 2007 | doi = 10.1056/NEJMoa064278 | PMID = 17898099 }}</ref> | |||
An investigation of the effects of baseline HDL cholesterol on the outcomes of 1032 patients who underwent drug-eluting stent implantation for [[acute coronary syndrome]] showed a higher rate of incidences of mortality and major adverse cardiac events at 30 days in low HDL than the high HDL cholesterol group. At 1 year, more deaths and major adverse cardiac events occurred in the low HDL cholesterol group. Multivariate analysis finally showed that low HDL cholesterol is a key predictor of major adverse cardiac events and death at 1 year.<ref name="Wolfram-2006">{{Cite journal | last1 = Wolfram | first1 = RM. | last2 = Brewer | first2 = HB. | last3 = Xue | first3 = Z. | last4 = Satler | first4 = LF. | last5 = Pichard | first5 = AD. | last6 = Kent | first6 = KM. | last7 = Waksman | first7 = R. | title = Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation. | journal = Am J Cardiol | volume = 98 | issue = 6 | pages = 711-7 | month = Sep | year = 2006 | doi = 10.1016/j.amjcard.2006.04.006 | PMID = 16950168 }}</ref> | |||
But not all disorders associated with low HDL cholesterol are accompanied by a predisposition to premature CAD.<ref name="Rader-1993">{{Cite journal | last1 = Rader | first1 = DJ. | last2 = Ikewaki | first2 = K. | last3 = Duverger | first3 = N. | last4 = Feuerstein | first4 = I. | last5 = Zech | first5 = L. | last6 = Connor | first6 = W. | last7 = Brewer | first7 = HB. | title = Very low high-density lipoproteins without coronary atherosclerosis. | journal = Lancet | volume = 342 | issue = 8885 | pages = 1455-8 | month = Dec | year = 1993 | doi = | PMID = 7902482 }}</ref> Examples in which there is not a strong association with atherosclerosis includes patients with [[LCAT deficiency]],<ref name="Klein-1992">{{Cite journal | last1 = Klein | first1 = HG. | last2 = Lohse | first2 = P. | last3 = Pritchard | first3 = PH. | last4 = Bojanovski | first4 = D. | last5 = Schmidt | first5 = H. | last6 = Brewer | first6 = HB. | title = Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met). | journal = J Clin Invest | volume = 89 | issue = 2 | pages = 499-506 | month = Feb | year = 1992 | doi = 10.1172/JCI115612 | PMID = 1737840 }}</ref> and patients with the apo A-I Milano variant.<ref name="Sirtori-2001">{{Cite journal | last1 = Sirtori | first1 = CR. | last2 = Calabresi | first2 = L. | last3 = Franceschini | first3 = G. | last4 = Baldassarre | first4 = D. | last5 = Amato | first5 = M. | last6 = Johansson | first6 = J. | last7 = Salvetti | first7 = M. | last8 = Monteduro | first8 = C. | last9 = Zulli | first9 = R. | title = Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study. | journal = Circulation | volume = 103 | issue = 15 | pages = 1949-54 | month = Apr | year = 2001 | doi = | PMID = 11306522 }}</ref> | |||
===CAD in Elderly=== | |||
Low HDL in elderly age group (above 60 and 65 years in men and women respectively) is a known high risk factor of CAD.<ref name="Windler-2007">{{Cite journal | last1 = Windler | first1 = E. | last2 = Schöffauer | first2 = M. | last3 = Zyriax | first3 = BC. | title = The significance of low HDL-cholesterol levels in an ageing society at increased risk for cardiovascular disease. | journal = Diab Vasc Dis Res | volume = 4 | issue = 2 | pages = 136-42 | month = Jun | year = 2007 | doi = 10.3132/dvdr.2007.032 | PMID = 17654448 }}</ref> Prevalence of around 70% of increased serum LDL cholesterol and 70% of decreased serum HDL cholesterol have been reported in elderly patients with atherosclerotic vascular disease.<ref name="Suryadevara-2003">{{Cite journal | last1 = Suryadevara | first1 = V. | last2 = Storey | first2 = SG. | last3 = Aronow | first3 = WS. | last4 = Ahn | first4 = C. | title = Association of abnormal serum lipids in elderly persons with atherosclerotic vascular disease and dementia, atherosclerotic vascular disease without dementia, dementia without atherosclerotic vascular disease, and no dementia or atherosclerotic vascular disease. | journal = J Gerontol A Biol Sci Med Sci | volume = 58 | issue = 9 | pages = M859-61 | month = Sep | year = 2003 | doi = | PMID = 14528045 }}</ref> The Framingham Heart Study and the Systolic Hypertension in the Elderly Program (SHEP) also found that both high LDL and low HDL cholesterol levels were significant CAD risk factors in elderly subjects.<ref name="Castelli-1989">{{Cite journal | last1 = Castelli | first1 = WP. | last2 = Wilson | first2 = PW. | last3 = Levy | first3 = D. | last4 = Anderson | first4 = K. | title = Cardiovascular risk factors in the elderly. | journal = Am J Cardiol | volume = 63 | issue = 16 | pages = 12H-19H | month = May | year = 1989 | doi = | PMID = 2523187 }}</ref><ref name="Frost-1996">{{Cite journal | last1 = Frost | first1 = PH. | last2 = Davis | first2 = BR. | last3 = Burlando | first3 = AJ. | last4 = Curb | first4 = JD. | last5 = Guthrie | first5 = GP. | last6 = Isaacsohn | first6 = JL. | last7 = Wassertheil-Smoller | first7 = S. | last8 = Wilson | first8 = AC. | last9 = Stamler | first9 = J. | title = Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP). | journal = Circulation | volume = 94 | issue = 10 | pages = 2381-8 | month = Nov | year = 1996 | doi = | PMID = 8921777 }}</ref> Low HDL can also be a predictor of mortality in elderly CAD patients. In a prospective cohort study that included a total population of 2527 women and 1377 men, for each 1-unit increase in the total cholesterol/HDL-cholesterol ratio, a 17% increase in the risk of CAD death was reported.<ref name="Corti-1995">{{Cite journal | last1 = Corti | first1 = MC. | last2 = Guralnik | first2 = JM. | last3 = Salive | first3 = ME. | last4 = Harris | first4 = T. | last5 = Field | first5 = TS. | last6 = Wallace | first6 = RB. | last7 = Berkman | first7 = LF. | last8 = Seeman | first8 = TE. | last9 = Glynn | first9 = RJ. | title = HDL cholesterol predicts coronary heart disease mortality in older persons. | journal = JAMA | volume = 274 | issue = 7 | pages = 539-44 | month = Aug | year = 1995 | doi = | PMID = 7629981 }}</ref> | |||
===CAD in Women=== | |||
Low HDL levels can be considered a prognostic factor of CAD in women. 40% to 50% of women classified as being at intermediate risk using the Framingham risk model were reclassified into either higher or lower risk categories, emphasizing the importance of HDL cholesterol level along with other factors in CAD development among women. | |||
The Reynolds risk score was developed and validated using data available from nearly 25,000 healthy women followed up prospectively for incidence of CAD and stroke during a median of 10.2 years and it included HDL cholesterol levels along with other factors.<ref name="Ridker-2007">{{Cite journal | last1 = Ridker | first1 = PM. | last2 = Buring | first2 = JE. | last3 = Rifai | first3 = N. | last4 = Cook | first4 = NR. | title = Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. | journal = JAMA | volume = 297 | issue = 6 | pages = 611-9 | month = Feb | year = 2007 | doi = 10.1001/jama.297.6.611 | PMID = 17299196 }}</ref> | |||
[[Weight cycling]] (repeated weight loss and weight gain) in women is known to carry an increased risk of death from CAD. This may be related to a significant reduction in HDL cholesterol concentration during each cycle.<ref name="Olson-2000">{{Cite journal | last1 = Olson | first1 = MB. | last2 = Kelsey | first2 = SF. | last3 = Bittner | first3 = V. | last4 = Reis | first4 = SE. | last5 = Reichek | first5 = N. | last6 = Handberg | first6 = EM. | last7 = Merz | first7 = CN. | title = Weight cycling and high-density lipoprotein cholesterol in women: evidence of an adverse effect: a report from the NHLBI-sponsored WISE study. Women's Ischemia Syndrome Evaluation Study Group. | journal = J Am Coll Cardiol | volume = 36 | issue = 5 | pages = 1565-71 | month = Nov | year = 2000 | doi = | PMID = 11079659 }}</ref> | |||
In postmenopausal women, the degree of coronary atherosclerosis has been linked to dysregulation of the TG/HDL metabolism. Subpopulations of both [[triglyceride]] rich and HDL lipoproteins have been found to be better predictors of CAD than [[triglyceride]] and HDL cholesterol concentrations.<ref name="Lamon-Fava-2008">{{Cite journal | last1 = Lamon-Fava | first1 = S. | last2 = Herrington | first2 = DM. | last3 = Reboussin | first3 = DM. | last4 = Sherman | first4 = M. | last5 = Horvath | first5 = KV. | last6 = Cupples | first6 = LA. | last7 = White | first7 = C. | last8 = Demissie | first8 = S. | last9 = Schaefer | first9 = EJ. | title = Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women. | journal = Arterioscler Thromb Vasc Biol | volume = 28 | issue = 3 | pages = 575-9 | month = Mar | year = 2008 | doi = 10.1161/ATVBAHA.107.157123 | PMID = 18174456 }}</ref> | |||
In women with [[polycystic ovarian syndrome]] ([[PCOS]]), most studies have demonstrated associated low HDL cholesterol.<ref name="Conway-1992">{{Cite journal | last1 = Conway | first1 = GS. | last2 = Agrawal | first2 = R. | last3 = Betteridge | first3 = DJ. | last4 = Jacobs | first4 = HS. | title = Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. | journal = Clin Endocrinol (Oxf) | volume = 37 | issue = 2 | pages = 119-25 | month = Aug | year = 1992 | doi = | PMID = 1395062 }}</ref><ref name="Birdsall-1997">{{Cite journal | last1 = Birdsall | first1 = MA. | last2 = Farquhar | first2 = CM. | last3 = White | first3 = HD. | title = Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization. | journal = Ann Intern Med | volume = 126 | issue = 1 | pages = 32-5 | month = Jan | year = 1997 | doi = | PMID = 8992921 }}</ref> In one study , components of the [[metabolic syndrome]] including low HDL and insulin resistance appeared to mediate the association between PCOS and coronary artery calcification, independently of obesity.<ref name="Talbott-2004">{{Cite journal | last1 = Talbott | first1 = EO. | last2 = Zborowski | first2 = JV. | last3 = Rager | first3 = JR. | last4 = Boudreaux | first4 = MY. | last5 = Edmundowicz | first5 = DA. | last6 = Guzick | first6 = DS. | title = Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. | journal = J Clin Endocrinol Metab | volume = 89 | issue = 11 | pages = 5454-61 | month = Nov | year = 2004 | doi = 10.1210/jc.2003-032237 | PMID = 15531497 }}</ref> | |||
===CAD in AIDS=== | |||
An unfavorable lipid profile characterized by a low HDL level can occur in [[HIV]] positive patients. The lipid profile may further deteriorate after receiving protease inhibitor based treatment, leading to increased CAD risk.<ref name="Asztalos-2006">{{Cite journal | last1 = Asztalos | first1 = BF. | last2 = Schaefer | first2 = EJ. | last3 = Horvath | first3 = KV. | last4 = Cox | first4 = CE. | last5 = Skinner | first5 = S. | last6 = Gerrior | first6 = J. | last7 = Gorbach | first7 = SL. | last8 = Wanke | first8 = C. | title = Protease inhibitor-based HAART, HDL, and CHD-risk in HIV-infected patients. | journal = Atherosclerosis | volume = 184 | issue = 1 | pages = 72-7 | month = Jan | year = 2006 | doi = 10.1016/j.atherosclerosis.2005.04.013 | PMID = 15935358 }}</ref> | |||
===CAD and GH Deficiency=== | |||
According to a study conducted on 665 adults with [[growth hormone deficiency]], increased total and LDL cholesterol or low HDL cholesterol were reported in 22 to 45% of patients prior to their treatment.<ref name="Bengtsson-1999">{{Cite journal | last1 = Bengtsson | first1 = BA. | last2 = Abs | first2 = R. | last3 = Bennmarker | first3 = H. | last4 = Monson | first4 = JP. | last5 = Feldt-Rasmussen | first5 = U. | last6 = Hernberg-Stahl | first6 = E. | last7 = Westberg | first7 = B. | last8 = Wilton | first8 = P. | last9 = Wüster | first9 = C. | title = The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board. | journal = J Clin Endocrinol Metab | volume = 84 | issue = 11 | pages = 3929-35 | month = Nov | year = 1999 | doi = | PMID = 10566630 }}</ref> More recently, increased mortality from cardiovascular causes was described in a large prospective trial involving 1014 hypopituitaric patients in the United Kingdom.<ref name="Tomlinson-2001">{{Cite journal | last1 = Tomlinson | first1 = JW. | last2 = Holden | first2 = N. | last3 = Hills | first3 = RK. | last4 = Wheatley | first4 = K. | last5 = Clayton | first5 = RN. | last6 = Bates | first6 = AS. | last7 = Sheppard | first7 = MC. | last8 = Stewart | first8 = PM. | title = Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. | journal = Lancet | volume = 357 | issue = 9254 | pages = 425-31 | month = Feb | year = 2001 | doi = | PMID = 11273062 }}</ref> Hence, it can be hypothesized that low HDL can possibly be associated with higher risk of [[CAD]] particularly in [[growth hormone]] deficient patients. | |||
===CAD in Rheumatoid arthritis=== | |||
Lipids in general, received only modest attention in the prognosis of CAD in [[rheumatoid arthritis]] all these days. With the exception of a single study,<ref name="Lakatos-1988">{{Cite journal | last1 = Lakatos | first1 = J. | last2 = Hárságyi | first2 = A. | title = Serum total, HDL, LDL cholesterol, and triglyceride levels in patients with rheumatoid arthritis. | journal = Clin Biochem | volume = 21 | issue = 2 | pages = 93-6 | month = Apr | year = 1988 | doi = | PMID = 3390902 }}</ref> most investigators agreed that total, LDL and HDL cholesterol and triglycerides are reduced in active rheumatoid arthritis compared to inactive disease, non-inflammatory arthritis or normal controls,<ref name="Lazarevic-1992">{{Cite journal | last1 = Lazarevic | first1 = MB. | last2 = Vitic | first2 = J. | last3 = Mladenovic | first3 = V. | last4 = Myones | first4 = BL. | last5 = Skosey | first5 = JL. | last6 = Swedler | first6 = WI. | title = Dyslipoproteinemia in the course of active rheumatoid arthritis. | journal = Semin Arthritis Rheum | volume = 22 | issue = 3 | pages = 172-8 | month = Dec | year = 1992 | doi = | PMID = 1295090 }}</ref> with an inverse correlation between the lipid values and the acute phase response. The low lipid profile may appear to be advantageous, except for the low HDL, which carries an adverse prognostic effect on CAD development and progression in rheumatoid arthritis patients.<ref name="Stampfer-1991">{{Cite journal | last1 = Stampfer | first1 = MJ. | last2 = Sacks | first2 = FM. | last3 = Salvini | first3 = S. | last4 = Willett | first4 = WC. | last5 = Hennekens | first5 = CH. | title = A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. | journal = N Engl J Med | volume = 325 | issue = 6 | pages = 373-81 | month = Aug | year = 1991 | doi = 10.1056/NEJM199108083250601 | PMID = 2062328 }}</ref> | |||
===Post-CAD Treatment=== | |||
Residual cardiovascular disease risk, defined as risk of recurrent cardiovascular disease events after management of coronary artery disease, may remain after treatment with statins and it may stem, at least partially, from low HDL cholesterol and/or elevated triglycerides.<ref name="Alagona-2009">{{Cite journal | last1 = Alagona | first1 = P. | title = Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy. | journal = Am J Manag Care | volume = 15 | issue = 3 Suppl | pages = S65-73 | month = Mar | year = 2009 | doi = | PMID = 19355805 }}</ref> | |||
===CAD in Experimental Models=== | |||
The association between low HDL level and CAD prognosis can further be understood from experimental models. Both atherosclerotic lesion prevention and low HDL level associated preexisting atherosclerotic lesion regression have been demonstrated in transgenic mice or rabbits following expressions of high levels of human apo A-I,<ref name="Rubin-1991">{{Cite journal | last1 = Rubin | first1 = EM. | last2 = Krauss | first2 = RM. | last3 = Spangler | first3 = EA. | last4 = Verstuyft | first4 = JG. | last5 = Clift | first5 = SM. | title = Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI. | journal = Nature | volume = 353 | issue = 6341 | pages = 265-7 | month = Sep | year = 1991 | doi = 10.1038/353265a0 | PMID = 1910153 }}</ref><ref name="Duverger-1996">{{Cite journal | last1 = Duverger | first1 = N. | last2 = Kruth | first2 = H. | last3 = Emmanuel | first3 = F. | last4 = Caillaud | first4 = JM. | last5 = Viglietta | first5 = C. | last6 = Castro | first6 = G. | last7 = Tailleux | first7 = A. | last8 = Fievet | first8 = C. | last9 = Fruchart | first9 = JC. | title = Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits. | journal = Circulation | volume = 94 | issue = 4 | pages = 713-7 | month = Aug | year = 1996 | doi = | PMID = 8772693 }}</ref> by somatic gene transfer of apo A-I,<ref name="Benoit-">{{Cite journal | last1 = Benoit | first1 = P. | last2 = Emmanuel | first2 = F. | last3 = Caillaud | first3 = JM. | last4 = Bassinet | first4 = L. | last5 = Castro | first5 = G. | last6 = Gallix | first6 = P. | last7 = Fruchart | first7 = JC. | last8 = Branellec | first8 = D. | last9 = Denèfle | first9 = P. | title = Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models. | journal = Circulation | volume = 99 | issue = 1 | pages = 105-10 | month = | year = | doi = | PMID = 9884386 }}</ref> by administration of oral apo A-1 mimetic peptides<ref name="Navab-2002">{{Cite journal | last1 = Navab | first1 = M. | last2 = Anantharamaiah | first2 = GM. | last3 = Hama | first3 = S. | last4 = Garber | first4 = DW. | last5 = Chaddha | first5 = M. | last6 = Hough | first6 = G. | last7 = Lallone | first7 = R. | last8 = Fogelman | first8 = AM. | title = Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. | journal = Circulation | volume = 105 | issue = 3 | pages = 290-2 | month = Jan | year = 2002 | doi = | PMID = 11804981 }}</ref> or by administration of apo A-I Milano, which is a natural variant of apo A-I.<ref name="Ameli-1994">{{Cite journal | last1 = Ameli | first1 = S. | last2 = Hultgardh-Nilsson | first2 = A. | last3 = Cercek | first3 = B. | last4 = Shah | first4 = PK. | last5 = Forrester | first5 = JS. | last6 = Ageland | first6 = H. | last7 = Nilsson | first7 = J. | title = Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits. | journal = Circulation | volume = 90 | issue = 4 | pages = 1935-41 | month = Oct | year = 1994 | doi = | PMID = 7923682 }}</ref> Furthermore, liver-directed gene transfer of human apo A-I results in significant regression of pre-existing atherosclerosis after four weeks.<ref name="Tangirala-1999">{{Cite journal | last1 = Tangirala | first1 = RK. | last2 = Tsukamoto | first2 = K. | last3 = Chun | first3 = SH. | last4 = Usher | first4 = D. | last5 = Puré | first5 = E. | last6 = Rader | first6 = DJ. | title = Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice. | journal = Circulation | volume = 100 | issue = 17 | pages = 1816-22 | month = Oct | year = 1999 | doi = | PMID = 10534470 }}</ref> | |||
==Atrial Fibrillation== | |||
Four and a half years follow-up of 4544 individuals who met the criteria for metabolic syndrome approved by the [[American Heart Association]] and the [[National Heart, Lung, and Blood Institute]], revealed that 265 patients developed [[atrial fibrillation]]. The risk of developing atrial fibrillation was significantly greater in those individuals with [[metabolic syndrome]]. In the absence of elevated [[triglyceride]]s, the risk of developing [[atrial fibrillation]] was found to be higher among patients with low HDL cholesterol, [[hypertension]], [[obesity]], and [[impaired glucose tolerance]].<ref name="Grundy-2005">{{Cite journal | last1 = Grundy | first1 = SM. | last2 = Cleeman | first2 = JI. | last3 = Daniels | first3 = SR. | last4 = Donato | first4 = KA. | last5 = Eckel | first5 = RH. | last6 = Franklin | first6 = BA. | last7 = Gordon | first7 = DJ. | last8 = Krauss | first8 = RM. | last9 = Savage | first9 = PJ. | title = Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. | journal = Circulation | volume = 112 | issue = 17 | pages = 2735-52 | month = Oct | year = 2005 | doi = 10.1161/CIRCULATIONAHA.105.169404 | PMID = 16157765 }}</ref> | |||
==Congestive Heart Failure== | |||
A prospective evaluation of the prognostic relationship of HDL levels in patients with severe [[heart failure]] was conducted by examining 132 consecutive patients. This study revealed that lower HDL levels correlate with worse prognosis and higher mortality independently of the etiology of the [[heart failure]].<ref name="Mehra-2009">{{Cite journal | last1 = Mehra | first1 = MR. | last2 = Uber | first2 = PA. | last3 = Lavie | first3 = CJ. | last4 = Milani | first4 = RV. | last5 = Park | first5 = MH. | last6 = Ventura | first6 = HO. | title = High-density lipoprotein cholesterol levels and prognosis in advanced heart failure. | journal = J Heart Lung Transplant | volume = 28 | issue = 9 | pages = 876-80 | month = Sep | year = 2009 | doi = 10.1016/j.healun.2009.04.026 | PMID = 19716038 }}</ref> | |||
==Post Cardiac Procedures== | |||
HDL cholesterol is an important predictor of survival in post-[[CABG]] patients. In a study involving more than 8500 patients with years of follow-up, HDL cholesterol was found to be the most important metabolic predictor of post-CABG survival. Approximately one third of the patients survived at 15 years when their HDL levels were ≦35 mg/dL at the time of CABG. Therefore, the measurement of HDL cholesterol provides a compelling strategy for the identification of high-risk subsets of patients who undergo CABG.<ref name="Foody-2000">{{Cite journal | last1 = Foody | first1 = JM. | last2 = Ferdinand | first2 = FD. | last3 = Pearce | first3 = GL. | last4 = Lytle | first4 = BW. | last5 = Cosgrove | first5 = DM. | last6 = Sprecher | first6 = DL. | title = HDL cholesterol level predicts survival in men after coronary artery bypass graft surgery: 20-year experience from The Cleveland Clinic Foundation. | journal = Circulation | volume = 102 | issue = 19 Suppl 3 | pages = III90-4 | month = Nov | year = 2000 | doi = | PMID = 11082369 }}</ref> | |||
Low HDL cholesterol is also an independent predictor of the long-term outcome after coronary artery stenting. The combination of low HDL cholesterol and elevated inflammatory markers identified the high-risk patients.<ref name="Niessner-2007">{{Cite journal | last1 = Niessner | first1 = A. | last2 = Hofmann | first2 = R. | last3 = Kypta | first3 = A. | last4 = Steinwender | first4 = C. | last5 = Kerschner | first5 = K. | last6 = Kammler | first6 = J. | last7 = Leisch | first7 = F. | last8 = Huber | first8 = K. | title = Low high-density lipoprotein cholesterol predicts cardiovascular events after carotid stenting: a long-term survey. | journal = J Thromb Haemost | volume = 5 | issue = 5 | pages = 950-4 | month = May | year = 2007 | doi = 10.1111/j.1538-7836.2007.02451.x | PMID = 17367491 }}</ref> | |||
Isolated low serum HDL-cholesterol is also a risk factor for the development of [[coronary artery disease]] and may contribute to the development of [[Vein graft disease|saphenous venous graft disease]].<ref name="Chen-1996">{{Cite journal | last1 = Chen | first1 = L. | last2 = Théroux | first2 = P. | last3 = Lespérance | first3 = J. | last4 = Shabani | first4 = F. | last5 = Thibault | first5 = B. | last6 = De Guise | first6 = P. | title = Angiographic features of vein grafts versus ungrafted coronary arteries in patients with unstable angina and previous bypass surgery. | journal = J Am Coll Cardiol | volume = 28 | issue = 6 | pages = 1493-9 | month = Nov | year = 1996 | doi = | PMID = 8917263 }}</ref> | |||
==Chronic Kidney Disease== | |||
In a study involving a European population where 176 [[chronic kidney disease]] ([[CKD]]) patients were followed up for 84 months, low HDL cholesterol levels, [[diabetes]] and [[hypertension]] were found to be associated with reduced [[GFR]]. The HDL cholesterol level was the only lipid parameter that was found to affect the progression of CKD independently of the presence of [[diabetes]]. Hence, a low level of plasma HDL cholesterol can be considered as a poor prognostic sign in CKD patients.<ref name="Baragetti-2013">{{Cite journal | last1 = Baragetti | first1 = A. | last2 = Norata | first2 = GD. | last3 = Sarcina | first3 = C. | last4 = Rastelli | first4 = F. | last5 = Grigore | first5 = L. | last6 = Garlaschelli | first6 = K. | last7 = Uboldi | first7 = P. | last8 = Baragetti | first8 = I. | last9 = Pozzi | first9 = C. | title = High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease. | journal = J Intern Med | volume = 274 | issue = 3 | pages = 252-62 | month = Sep | year = 2013 | doi = 10.1111/joim.12081 | PMID = 23607805 }}</ref> | |||
==Carcinoma== | |||
High density lipoprotein cholesterol has recently received much attention as a possible risk marker of [[prostate cancer]] development and prognosis.<ref name="Kotani-2013">{{Cite journal | last1 = Kotani | first1 = K. | last2 = Sekine | first2 = Y. | last3 = Ishikawa | first3 = S. | last4 = Ikpot | first4 = IZ. | last5 = Suzuki | first5 = K. | last6 = Remaley | first6 = AT. | title = High-density lipoprotein and prostate cancer: an overview. | journal = J Epidemiol | volume = 23 | issue = 5 | pages = 313-9 | month = Sep | year = 2013 | doi = | PMID = 23985823 }}</ref> In addition, preoperative low serum HDL cholesterol concentration or high TC/HDL cholesterol ratio might be a potential biomarker of advanced pN(2-3) stages in [[gastric cancer]] patients, especially those with the histologically differentiated type.<ref name="Guo-2007">{{Cite journal | last1 = Guo | first1 = E. | last2 = Chen | first2 = L. | last3 = Xie | first3 = Q. | last4 = Chen | first4 = J. | last5 = Tang | first5 = Z. | last6 = Wu | first6 = Y. | title = Serum HDL-C as a potential biomarker for nodal stages in gastric cancer. | journal = Ann Surg Oncol | volume = 14 | issue = 9 | pages = 2528-34 | month = Sep | year = 2007 | doi = 10.1245/s10434-007-9401-0 | PMID = 17597347 }}</ref> Preoperative serum HDL-cholesterol levels retrospectively examined in 184 patients who had undergone gastrectomy revealed a positive correlation between low preoperative serum HDL-cholesterol levels and prognosis for gastric cancer.<ref name="Tamura-2012">{{Cite journal | last1 = Tamura | first1 = T. | last2 = Inagawa | first2 = S. | last3 = Hisakura | first3 = K. | last4 = Enomoto | first4 = T. | last5 = Ohkohchi | first5 = N. | title = Evaluation of serum high-density lipoprotein cholesterol levels as a prognostic factor in gastric cancer patients. | journal = J Gastroenterol Hepatol | volume = 27 | issue = 10 | pages = 1635-40 | month = Oct | year = 2012 | doi = 10.1111/j.1440-1746.2012.07189.x | PMID = 22647147 }}</ref> A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of [[cholesterol]] are increased within the tumor tissues during growth, it can be hypothesized that the low HDL levels observed in patients with gastrointestinal [[cancer]] are associated with the increased cholesterol metabolism in proliferating tissues.<ref name="Dessì-1994">{{Cite journal | last1 = Dessì | first1 = S. | last2 = Batetta | first2 = B. | last3 = Pulisci | first3 = D. | last4 = Spano | first4 = O. | last5 = Anchisi | first5 = C. | last6 = Tessitore | first6 = L. | last7 = Costelli | first7 = P. | last8 = Baccino | first8 = FM. | last9 = Aroasio | first9 = E. | title = Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer. | journal = Cancer | volume = 73 | issue = 2 | pages = 253-8 | month = Jan | year = 1994 | doi = | PMID = 8293385 }}</ref> | |||
==Cirrhosis== | |||
A Model for End-Stage Liver Disease (MELD) score ≥18 and [[Cholesterol|TC]] ≤2.8 mmol/L are two important indexes to predict the prognosis of patients with decompensated [[cirrhosis]]. The serum [[triglyceride]]s, total [[cholesterol]], HDL and [[LDL]] levels were lowered with the increase of the MELD score. Their combination can effectively predict the long-term prognosis of patients with decompensated cirrhosis.<ref name="Jiang-2010">{{Cite journal | last1 = Jiang | first1 = M. | last2 = Liu | first2 = F. | last3 = Xiong | first3 = WJ. | last4 = Zhong | first4 = L. | last5 = Xu | first5 = W. | last6 = Xu | first6 = F. | last7 = Liu | first7 = YB. | title = Combined MELD and blood lipid level in evaluating the prognosis of decompensated cirrhosis. | journal = World J Gastroenterol | volume = 16 | issue = 11 | pages = 1397-401 | month = Mar | year = 2010 | doi = | PMID = 20238407 }}</ref> In an Asian study, an inverse correlation of serum levels of HDL and APO A-I with the liver reserve and disease severity in cirrhotic patients with severe sepsis was found. Low level of HDL and APO A-I were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.<ref name="Tsai-2009">{{Cite journal | last1 = Tsai | first1 = MH. | last2 = Peng | first2 = YS. | last3 = Chen | first3 = YC. | last4 = Lien | first4 = JM. | last5 = Tian | first5 = YC. | last6 = Fang | first6 = JT. | last7 = Weng | first7 = HH. | last8 = Chen | first8 = PC. | last9 = Yang | first9 = CW. | title = Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. | journal = J Hepatol | volume = 50 | issue = 5 | pages = 906-15 | month = May | year = 2009 | doi = 10.1016/j.jhep.2008.12.024 | PMID = 19304335 }}</ref> In another study, HDL cholesterol in noncholestatic cirrhotic patients was found to be a liver function test as well as an indicator of prognosis.<ref name="Habib-2005">{{Cite journal | last1 = Habib | first1 = A. | last2 = Mihas | first2 = AA. | last3 = Abou-Assi | first3 = SG. | last4 = Williams | first4 = LM. | last5 = Gavis | first5 = E. | last6 = Pandak | first6 = WM. | last7 = Heuman | first7 = DM. | title = High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics. | journal = Clin Gastroenterol Hepatol | volume = 3 | issue = 3 | pages = 286-91 | month = Mar | year = 2005 | doi = | PMID = 15765449 }}</ref> | |||
==Dementia== | |||
A study involving academic nursing home patients revealed that the prevalence of increased serum [[LDL]] cholesterol and decreased serum HDL cholesterol were found to be significantly higher in elderly patients with atherosclerotic vascular disease plus [[dementia]] (72%) and also in dementia without atherosclerotic vascular disease (68%) than in patients with no dementia or atherosclerotic vascular disease.<ref name="Suryadevara-2003">{{Cite journal | last1 = Suryadevara | first1 = V. | last2 = Storey | first2 = SG. | last3 = Aronow | first3 = WS. | last4 = Ahn | first4 = C. | title = Association of abnormal serum lipids in elderly persons with atherosclerotic vascular disease and dementia, atherosclerotic vascular disease without dementia, dementia without atherosclerotic vascular disease, and no dementia or atherosclerotic vascular disease. | journal = J Gerontol A Biol Sci Med Sci | volume = 58 | issue = 9 | pages = M859-61 | month = Sep | year = 2003 | doi = | PMID = 14528045 }}</ref> These results suggest a possible prognostic role of HDL levels in [[dementia]] with or without atherosclerotic vascular disease. | |||
==Kawasaki Disease== | |||
Children with [[Kawasaki disease]] are more likely to have low HDL than the general pediatric population. This finding suggests a possible association between low HDL levels and the vascular complications of [[Kawasaki disease]].<ref name="Newburger-2004">{{Cite journal | last1 = Newburger | first1 = JW. | last2 = Takahashi | first2 = M. | last3 = Gerber | first3 = MA. | last4 = Gewitz | first4 = MH. | last5 = Tani | first5 = LY. | last6 = Burns | first6 = JC. | last7 = Shulman | first7 = ST. | last8 = Bolger | first8 = AF. | last9 = Ferrieri | first9 = P. | title = Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. | journal = Pediatrics | volume = 114 | issue = 6 | pages = 1708-33 | month = Dec | year = 2004 | doi = 10.1542/peds.2004-2182 | PMID = 15574639 }}</ref> | |||
==Nonalcoholic Fatty Liver Disease== | |||
The negative association between HDL-cholesterol and liver-fat content is a known phenomenon. Thus the prognosis of [[NAFLD]], which is one of the commonest causes of chronic liver disease both in US and worldwide, is worsened by low HDL levels.<ref name="Seppälä-Lindroos-2002">{{Cite journal | last1 = Seppälä-Lindroos | first1 = A. | last2 = Vehkavaara | first2 = S. | last3 = Häkkinen | first3 = AM. | last4 = Goto | first4 = T. | last5 = Westerbacka | first5 = J. | last6 = Sovijärvi | first6 = A. | last7 = Halavaara | first7 = J. | last8 = Yki-Järvinen | first8 = H. | title = Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. | journal = J Clin Endocrinol Metab | volume = 87 | issue = 7 | pages = 3023-8 | month = Jul | year = 2002 | doi = | PMID = 12107194 }}</ref><ref name="Adiels-2006">{{Cite journal | last1 = Adiels | first1 = M. | last2 = Taskinen | first2 = MR. | last3 = Packard | first3 = C. | last4 = Caslake | first4 = MJ. | last5 = Soro-Paavonen | first5 = A. | last6 = Westerbacka | first6 = J. | last7 = Vehkavaara | first7 = S. | last8 = Häkkinen | first8 = A. | last9 = Olofsson | first9 = SO. | title = Overproduction of large VLDL particles is driven by increased liver fat content in man. | journal = Diabetologia | volume = 49 | issue = 4 | pages = 755-65 | month = Apr | year = 2006 | doi = 10.1007/s00125-005-0125-z | PMID = 16463046 }}</ref> | |||
==Sepsis== | |||
Low HDL level was found to be independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlated with increased platelet activation.<ref name="Barlage-2009">{{Cite journal | last1 = Barlage | first1 = S. | last2 = Gnewuch | first2 = C. | last3 = Liebisch | first3 = G. | last4 = Wolf | first4 = Z. | last5 = Audebert | first5 = FX. | last6 = Glück | first6 = T. | last7 = Fröhlich | first7 = D. | last8 = Krämer | first8 = BK. | last9 = Rothe | first9 = G. | title = Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation. | journal = Intensive Care Med | volume = 35 | issue = 11 | pages = 1877-85 | month = Nov | year = 2009 | doi = 10.1007/s00134-009-1609-y | PMID = 19669126 }}</ref> Another study found that serum levels of HDL and apo-AI are inversely correlated with liver reserve and disease severity in cirrhotic patients with severe sepsis. Both were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.<ref name="Tsai-2009">{{Cite journal | last1 = Tsai | first1 = MH. | last2 = Peng | first2 = YS. | last3 = Chen | first3 = YC. | last4 = Lien | first4 = JM. | last5 = Tian | first5 = YC. | last6 = Fang | first6 = JT. | last7 = Weng | first7 = HH. | last8 = Chen | first8 = PC. | last9 = Yang | first9 = CW. | title = Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis. | journal = J Hepatol | volume = 50 | issue = 5 | pages = 906-15 | month = May | year = 2009 | doi = 10.1016/j.jhep.2008.12.024 | PMID = 19304335 }}</ref> A low HDL cholesterol level on day one of severe sepsis has been shown to be significantly associated with an increase in mortality and adverse clinical outcomes.<ref name="Chien-2005">{{Cite journal | last1 = Chien | first1 = JY. | last2 = Jerng | first2 = JS. | last3 = Yu | first3 = CJ. | last4 = Yang | first4 = PC. | title = Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis. | journal = Crit Care Med | volume = 33 | issue = 8 | pages = 1688-93 | month = Aug | year = 2005 | doi = | PMID = 16096442 }}</ref> | |||
==Acute Ischemic Stroke== | |||
Low HDL has been established as one of the risk factors for acute ischemic stroke. Patients with acute ischemic stroke were found to have a significantly smaller HDL size, with more HDL<sub>3a</sub>, HDL<sub>3b</sub> and HDL<sub>3c</sub> and less HDL<sub>2b</sub> subclasses. Large artery atherosclerotic stroke and lacunar ischemic stroke had the strongest association with high total cholesterol levels and low HDL cholesterol levels in a case-control study.<ref name="Tirschwell-2004">{{Cite journal | last1 = Tirschwell | first1 = DL. | last2 = Smith | first2 = NL. | last3 = Heckbert | first3 = SR. | last4 = Lemaitre | first4 = RN. | last5 = Longstreth | first5 = WT. | last6 = Psaty | first6 = BM. | title = Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. | journal = Neurology | volume = 63 | issue = 10 | pages = 1868-75 | month = Nov | year = 2004 | doi = | PMID = 15557504 }}</ref> | |||
==References== | ==References== | ||
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Latest revision as of 02:31, 15 October 2014
High Density Lipoprotein Microchapters |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]; Vendhan Ramanujam M.B.B.S [4]
Overview
Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risks,[1][2][3] low circulating levels of HDL-cholesterol have been associated with the development of coronary artery disease, particularly when it is accompanied by other coronary risk factors.[4][5][6] The protective role of high HDL levels against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differently associated with cardiovascular risks. Many case-control and prospective studies have demonstrated that the HDL2 sub fraction and the plasma apo A-I concentration are better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3.[7] The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.[8] In addition to its prognotic role in CAD, low HDL levels have been associated with diseases and complications involving the neurological, renal, and liver systems as well as sepsis and carcinoma.
Low High-Density Lipoprotein as a Prognostic Factor
Low HDL has been evaluated as a possible prognostic factor in the following conditions:
- Acute ischemic stroke
- Atrial fibrillation
- Carcinoma
- Chronic kidney disease
- Cirrhosis
- Congestive heart failure
- Coronary artery disease
- Dementia
- Kawasaki disease
- Nonalcoholic fatty liver disease
- Post-cardiac procedures
- Sepsis
Coronary Artery Disease
The inverse relation of HDL to either the presence or development of coronary artery disease (CAD) is well-established;[9] in fact, for every 1% decrease in HDL concentration, there is a 2-3% increase in the risk of development of CHD.[10] Studies on different populations supported low HDL as a significant cardiovascular risk factor as well as a prognostic factor, either independently or along with other physical and biochemical metrics. Low levels of HDL-cholesterol, which may reflect increased catabolism of triglyceride-enriched HDL particles, appear to interact with hypertriglyceridemia to increase the coronary risk.[11][12] Plaque rupture, besides its correlation with high total cholesterol (TC), is also shown to be related to low HDL-cholesterol and an elevated TC/HDL-C ratio.[13] Studies on the relationship between low HDL levels and CAD are as follows:
- Based on data from the Framingham Heart Study, the risk for myocardial infarction was found to increase by 25 percent for every 5 mg/dL (0.13 mmol/L) decrement in serum HDL-cholesterol, below the median values for both men and women.[4] According to the study, the relative risk of death due to cardiovascular and coronary artery disease for men in the first HDL-cholesterol quintile (less than 35 mg/dL) as compared to the top quintile (greater than 54 mg/dL) is 3.6 and 4.1 respectively and for women the corresponding values were 1.6 and 3.1, comparing the bottom HDL-cholesterol quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl).
- The Lipoprotein and Coronary Atherosclerosis Study (LCAS) which studied patients with mild to moderate LDL-cholesterol elevation found that the patients who also had low HDL-cholesterol at baseline had more CAD progression than patients with higher HDL-cholesterol.[14]
- Framingham Risk Assessment counts HDL values above 60 mg/dL (1.5 mmol/L) as a negative risk factor.[5]
- Studies have shown that in patients with known coronary artery disease, HDL-cholesterol levels are predictive of coronary events over a broad range of LDL-cholesterol levels. The LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial[15] and the CARE (Cholesterol and Recurrent Events) trial[16] have shown that reduced serum HDL-cholesterol levels strongly predicted acute coronary events in patients with LDL-cholesterol less than 125 mg/dL compared to those with levels above 125 mg/dL. There was a significant reduction in the event rate in patients with LDL-cholesterol <125 mg/dL for every 10 mg/dL rise in HDL-cholesterol compared to those with LDL-cholesterol levels more than 125 mg/dL. A similar relationship between the levels of HDL-cholesterol and LDL-cholesterol was also shown in the Treating to New Targets (TNT) trial.[17]
- The finding of very low HDL levels among one-fifth of patients with NSTEMI ACS added to a greater burden of atherosclerosis and a higher risk of mortality.[18]
- A study conducted in a European population revealed that patients carrying at least one polymorphic allele of the paraoxonase2 (PON2) gene along with low HDL represent a category of subjects at a higher risk for the development of acute myocardial infarction with a worse prognosis.[19]
- A 2011 population based study with individual-participant-data (over 200,000 individuals) meta-analysis of 23 studies in the Asia-Pacific region revealed that a low level of HDL cholesterol was seen significantly more often in Asians than non-Asians (33.1 versus 27.0%). Even the prevalence of isolated low HDL-cholesterol was significantly higher in Asians (22.4 versus 14.5 %). In all individuals, there was a significant correlation between low HDL cholesterol and cardiovascular events. Particularly in Asians, the isolated low levels of HDL cholesterol were strongly associated with CAD risk similar to low levels of HDL cholesterol combined with other lipid abnormalities. This study suggested that isolated low HDL cholesterol in Asians is a distinct phenotype, which is strongly associated with an increased risk of CAD.[20]
- More recently low HDL-cholesterol was found to be the most powerful lipid parameter for predicting the risk and the clinical outcome of CAD in a Han Chinese population.[21]
The Multi-ethnic Study of Atherosclerosis (MESA) adds to the concept that the inverse relationship between HDL and cardiovascular risks may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.[22] HDL2 subfraction and apo A-I are reported to be better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3 in some studies,[7] while other reports have shown similar associations of total HDL and HDL3 with coronary artery disease (CAD) as HDL2 and apo A-I.[23] Polymorphisms in phospholipid transfer protein (PLTP) are also shown to be associated with increased concentrations of smaller, cholesterol-depleted HDL particles and a lower cardiovascular event rate.[24] Despite the established crude association between HDL and cardiovascular risks, Mendelian randomization analyses, JUPITER trial, and studies in Tangier disease failed to demonstrate a cause-effect relationship.[25][26][27][28]
CAD in Pediatric Populations
Data is scarce about the contribution of HDL to CAD in the pediatric population due to the rarity of cases. A prospective follow-up study in pediatric cardiac transplant recipients showed that, although pravastatin improved the HDL2 concentrations in the treatment group, it failed to normalize serum triglyceride and prevent the progression of vasculopathy in some of the patients. It also suggested a predictive role of low HDL-C and high apoB-100/apoA-I ratio for the development of vasculopathy.[29]
Premature CAD
Premature CAD is usually defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age. Numerous studies of the 20th century from both Middle East and US population have reported low HDL in over 19% to 52 % of premature CAD patients.[30][31][30][32][33][34] In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study that examined aortas and coronary arteries from autopsies of healthy 15 to 35 year old persons, a negative association of high HDL with both fatty streaks and raised lesions in the aorta and right coronary artery was seen, particularly after the age of 25. Post-hoc analyses of two randomized trials in the past 10 years have shown low HDL levels as predictors of coronary events in patients with known CAD. Analysis of 13,173 patients in the LIPID and CARE trials found that low serum HDL cholesterol was a significantly stronger predictor of CAD events in patients with an LDL-cholesterol <125 than ≥125 mg/dL (3.2 mmol/L).[35] For a 10 mg/dL (0.26 mmol/L) increase in HDL-cholesterol the event rate decreased by 29 percent in those with LDL-cholesterol <125 mg/dL (3.2 mmol/L) compared to 10 percent in those with an LDL-cholesterol ≥125 mg/dL (3.2 mmol/L). Post hoc analysis of the Treating to New Targets trial (TNT) in which nearly 10,000 patients with established CAD was treated with either high or low dose statin therapy revealed that HDL cholesterol levels were predictive of major cardiovascular events. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter.[36]
An investigation of the effects of baseline HDL cholesterol on the outcomes of 1032 patients who underwent drug-eluting stent implantation for acute coronary syndrome showed a higher rate of incidences of mortality and major adverse cardiac events at 30 days in low HDL than the high HDL cholesterol group. At 1 year, more deaths and major adverse cardiac events occurred in the low HDL cholesterol group. Multivariate analysis finally showed that low HDL cholesterol is a key predictor of major adverse cardiac events and death at 1 year.[37]
But not all disorders associated with low HDL cholesterol are accompanied by a predisposition to premature CAD.[38] Examples in which there is not a strong association with atherosclerosis includes patients with LCAT deficiency,[39] and patients with the apo A-I Milano variant.[40]
CAD in Elderly
Low HDL in elderly age group (above 60 and 65 years in men and women respectively) is a known high risk factor of CAD.[41] Prevalence of around 70% of increased serum LDL cholesterol and 70% of decreased serum HDL cholesterol have been reported in elderly patients with atherosclerotic vascular disease.[42] The Framingham Heart Study and the Systolic Hypertension in the Elderly Program (SHEP) also found that both high LDL and low HDL cholesterol levels were significant CAD risk factors in elderly subjects.[43][44] Low HDL can also be a predictor of mortality in elderly CAD patients. In a prospective cohort study that included a total population of 2527 women and 1377 men, for each 1-unit increase in the total cholesterol/HDL-cholesterol ratio, a 17% increase in the risk of CAD death was reported.[45]
CAD in Women
Low HDL levels can be considered a prognostic factor of CAD in women. 40% to 50% of women classified as being at intermediate risk using the Framingham risk model were reclassified into either higher or lower risk categories, emphasizing the importance of HDL cholesterol level along with other factors in CAD development among women.
The Reynolds risk score was developed and validated using data available from nearly 25,000 healthy women followed up prospectively for incidence of CAD and stroke during a median of 10.2 years and it included HDL cholesterol levels along with other factors.[46]
Weight cycling (repeated weight loss and weight gain) in women is known to carry an increased risk of death from CAD. This may be related to a significant reduction in HDL cholesterol concentration during each cycle.[47]
In postmenopausal women, the degree of coronary atherosclerosis has been linked to dysregulation of the TG/HDL metabolism. Subpopulations of both triglyceride rich and HDL lipoproteins have been found to be better predictors of CAD than triglyceride and HDL cholesterol concentrations.[48]
In women with polycystic ovarian syndrome (PCOS), most studies have demonstrated associated low HDL cholesterol.[49][50] In one study , components of the metabolic syndrome including low HDL and insulin resistance appeared to mediate the association between PCOS and coronary artery calcification, independently of obesity.[51]
CAD in AIDS
An unfavorable lipid profile characterized by a low HDL level can occur in HIV positive patients. The lipid profile may further deteriorate after receiving protease inhibitor based treatment, leading to increased CAD risk.[52]
CAD and GH Deficiency
According to a study conducted on 665 adults with growth hormone deficiency, increased total and LDL cholesterol or low HDL cholesterol were reported in 22 to 45% of patients prior to their treatment.[53] More recently, increased mortality from cardiovascular causes was described in a large prospective trial involving 1014 hypopituitaric patients in the United Kingdom.[54] Hence, it can be hypothesized that low HDL can possibly be associated with higher risk of CAD particularly in growth hormone deficient patients.
CAD in Rheumatoid arthritis
Lipids in general, received only modest attention in the prognosis of CAD in rheumatoid arthritis all these days. With the exception of a single study,[55] most investigators agreed that total, LDL and HDL cholesterol and triglycerides are reduced in active rheumatoid arthritis compared to inactive disease, non-inflammatory arthritis or normal controls,[56] with an inverse correlation between the lipid values and the acute phase response. The low lipid profile may appear to be advantageous, except for the low HDL, which carries an adverse prognostic effect on CAD development and progression in rheumatoid arthritis patients.[23]
Post-CAD Treatment
Residual cardiovascular disease risk, defined as risk of recurrent cardiovascular disease events after management of coronary artery disease, may remain after treatment with statins and it may stem, at least partially, from low HDL cholesterol and/or elevated triglycerides.[57]
CAD in Experimental Models
The association between low HDL level and CAD prognosis can further be understood from experimental models. Both atherosclerotic lesion prevention and low HDL level associated preexisting atherosclerotic lesion regression have been demonstrated in transgenic mice or rabbits following expressions of high levels of human apo A-I,[58][59] by somatic gene transfer of apo A-I,[60] by administration of oral apo A-1 mimetic peptides[61] or by administration of apo A-I Milano, which is a natural variant of apo A-I.[62] Furthermore, liver-directed gene transfer of human apo A-I results in significant regression of pre-existing atherosclerosis after four weeks.[63]
Atrial Fibrillation
Four and a half years follow-up of 4544 individuals who met the criteria for metabolic syndrome approved by the American Heart Association and the National Heart, Lung, and Blood Institute, revealed that 265 patients developed atrial fibrillation. The risk of developing atrial fibrillation was significantly greater in those individuals with metabolic syndrome. In the absence of elevated triglycerides, the risk of developing atrial fibrillation was found to be higher among patients with low HDL cholesterol, hypertension, obesity, and impaired glucose tolerance.[64]
Congestive Heart Failure
A prospective evaluation of the prognostic relationship of HDL levels in patients with severe heart failure was conducted by examining 132 consecutive patients. This study revealed that lower HDL levels correlate with worse prognosis and higher mortality independently of the etiology of the heart failure.[65]
Post Cardiac Procedures
HDL cholesterol is an important predictor of survival in post-CABG patients. In a study involving more than 8500 patients with years of follow-up, HDL cholesterol was found to be the most important metabolic predictor of post-CABG survival. Approximately one third of the patients survived at 15 years when their HDL levels were ≦35 mg/dL at the time of CABG. Therefore, the measurement of HDL cholesterol provides a compelling strategy for the identification of high-risk subsets of patients who undergo CABG.[66]
Low HDL cholesterol is also an independent predictor of the long-term outcome after coronary artery stenting. The combination of low HDL cholesterol and elevated inflammatory markers identified the high-risk patients.[67]
Isolated low serum HDL-cholesterol is also a risk factor for the development of coronary artery disease and may contribute to the development of saphenous venous graft disease.[68]
Chronic Kidney Disease
In a study involving a European population where 176 chronic kidney disease (CKD) patients were followed up for 84 months, low HDL cholesterol levels, diabetes and hypertension were found to be associated with reduced GFR. The HDL cholesterol level was the only lipid parameter that was found to affect the progression of CKD independently of the presence of diabetes. Hence, a low level of plasma HDL cholesterol can be considered as a poor prognostic sign in CKD patients.[69]
Carcinoma
High density lipoprotein cholesterol has recently received much attention as a possible risk marker of prostate cancer development and prognosis.[70] In addition, preoperative low serum HDL cholesterol concentration or high TC/HDL cholesterol ratio might be a potential biomarker of advanced pN(2-3) stages in gastric cancer patients, especially those with the histologically differentiated type.[71] Preoperative serum HDL-cholesterol levels retrospectively examined in 184 patients who had undergone gastrectomy revealed a positive correlation between low preoperative serum HDL-cholesterol levels and prognosis for gastric cancer.[72] A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it can be hypothesized that the low HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in proliferating tissues.[73]
Cirrhosis
A Model for End-Stage Liver Disease (MELD) score ≥18 and TC ≤2.8 mmol/L are two important indexes to predict the prognosis of patients with decompensated cirrhosis. The serum triglycerides, total cholesterol, HDL and LDL levels were lowered with the increase of the MELD score. Their combination can effectively predict the long-term prognosis of patients with decompensated cirrhosis.[74] In an Asian study, an inverse correlation of serum levels of HDL and APO A-I with the liver reserve and disease severity in cirrhotic patients with severe sepsis was found. Low level of HDL and APO A-I were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.[75] In another study, HDL cholesterol in noncholestatic cirrhotic patients was found to be a liver function test as well as an indicator of prognosis.[76]
Dementia
A study involving academic nursing home patients revealed that the prevalence of increased serum LDL cholesterol and decreased serum HDL cholesterol were found to be significantly higher in elderly patients with atherosclerotic vascular disease plus dementia (72%) and also in dementia without atherosclerotic vascular disease (68%) than in patients with no dementia or atherosclerotic vascular disease.[42] These results suggest a possible prognostic role of HDL levels in dementia with or without atherosclerotic vascular disease.
Kawasaki Disease
Children with Kawasaki disease are more likely to have low HDL than the general pediatric population. This finding suggests a possible association between low HDL levels and the vascular complications of Kawasaki disease.[77]
Nonalcoholic Fatty Liver Disease
The negative association between HDL-cholesterol and liver-fat content is a known phenomenon. Thus the prognosis of NAFLD, which is one of the commonest causes of chronic liver disease both in US and worldwide, is worsened by low HDL levels.[78][79]
Sepsis
Low HDL level was found to be independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlated with increased platelet activation.[80] Another study found that serum levels of HDL and apo-AI are inversely correlated with liver reserve and disease severity in cirrhotic patients with severe sepsis. Both were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.[75] A low HDL cholesterol level on day one of severe sepsis has been shown to be significantly associated with an increase in mortality and adverse clinical outcomes.[81]
Acute Ischemic Stroke
Low HDL has been established as one of the risk factors for acute ischemic stroke. Patients with acute ischemic stroke were found to have a significantly smaller HDL size, with more HDL3a, HDL3b and HDL3c and less HDL2b subclasses. Large artery atherosclerotic stroke and lacunar ischemic stroke had the strongest association with high total cholesterol levels and low HDL cholesterol levels in a case-control study.[82]
References
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- ↑ Emerging Risk Factors Collaboration. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK; et al. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMC 3284229. PMID 19903920. Review in: Ann Intern Med. 2010 Feb 16;152(4):JC-212
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- ↑ 4.0 4.1 Oram, JF.; Johnson, CJ.; Brown, TA. (1987). "Interaction of high density lipoprotein with its receptor on cultured fibroblasts and macrophages. Evidence for reversible binding at the cell surface without internalization". J Biol Chem. 262 (5): 2405–10. PMID 3029079. Unknown parameter
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ignored (help) - ↑ 5.0 5.1 "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report". Circulation. 106 (25): 3143–421. 2002. PMID 12485966. Unknown parameter
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ignored (help) - ↑ Després, JP. (2013). "HDL cholesterol studies--more of the same?". Nat Rev Cardiol. 10 (2): 70–2. doi:10.1038/nrcardio.2012.182. PMID 23319099. Unknown parameter
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ignored (help) - ↑ 7.0 7.1 Salonen, JT.; Salonen, R.; Seppänen, K.; Rauramaa, R.; Tuomilehto, J. (1991). "HDL, HDL2, and HDL3 subfractions, and the risk of acute myocardial infarction. A prospective population study in eastern Finnish men". Circulation. 84 (1): 129–39. PMID 2060089. Unknown parameter
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ignored (help) - ↑ Khera AV, Rader DJ (2010). "Future therapeutic directions in reverse cholesterol transport". Curr Atheroscler Rep. 12 (1): 73–81. doi:10.1007/s11883-009-0080-0. PMC 3315100. PMID 20425274.
- ↑ Rajagopal G, Suresh V, Sachan A (2012). "High-density lipoprotein cholesterol: How High". Indian J Endocrinol Metab. 16 (Suppl 2): S236–8. doi:10.4103/2230-8210.104048. PMC 3603035. PMID 23565387. Unknown parameter
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ignored (help) - ↑ National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2002). "Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report". Circulation. 106 (25): 3143–421. PMID 12485966.
- ↑ Wittrup, HH.; Tybjaerg-Hansen, A.; Nordestgaard, BG. (1999). "Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis". Circulation. 99 (22): 2901–7. PMID 10359734. Unknown parameter
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ignored (help) - ↑ Manninen, V.; Tenkanen, L.; Koskinen, P.; Huttunen, JK.; Mänttäri, M.; Heinonen, OP.; Frick, MH. (1992). "Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study. Implications for treatment". Circulation. 85 (1): 37–45. PMID 1728471. Unknown parameter
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ignored (help) - ↑ Burke, AP.; Farb, A.; Malcom, GT.; Liang, YH.; Smialek, J.; Virmani, R. (1997). "Coronary risk factors and plaque morphology in men with coronary disease who died suddenly". N Engl J Med. 336 (18): 1276–82. doi:10.1056/NEJM199705013361802. PMID 9113930. Unknown parameter
|month=
ignored (help) - ↑ Ballantyne, CM.; Herd, JA.; Ferlic, LL.; Dunn, JK.; Farmer, JA.; Jones, PH.; Schein, JR.; Gotto, AM. (1999). "Influence of low HDL on progression of coronary artery disease and response to fluvastatin therapy". Circulation. 99 (6): 736–43. PMID 9989957. Unknown parameter
|month=
ignored (help) - ↑ Simes, RJ.; Marschner, IC.; Hunt, D.; Colquhoun, D.; Sullivan, D.; Stewart, RA.; Hague, W.; Keech, A.; Thompson, P. (2002). "Relationship between lipid levels and clinical outcomes in the Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Trial: to what extent is the reduction in coronary events with pravastatin explained by on-study lipid levels?". Circulation. 105 (10): 1162–9. PMID 11889008. Unknown parameter
|month=
ignored (help) - ↑ Pfeffer, MA.; Sacks, FM.; Moyé, LA.; Brown, L.; Rouleau, JL.; Hartley, LH.; Rouleau, J.; Grimm, R.; Sestier, F. (1995). "Cholesterol and Recurrent Events: a secondary prevention trial for normolipidemic patients. CARE Investigators". Am J Cardiol. 76 (9): 98C–106C. PMID 7572695. Unknown parameter
|month=
ignored (help) - ↑ Waters, DD. "Clinical insights from the Treating to New Targets trial". Prog Cardiovasc Dis. 51 (6): 487–502. doi:10.1016/j.pcad.2009.01.001. PMID 19410683.
- ↑ Roe, MT.; Ou, FS.; Alexander, KP.; Newby, LK.; Foody, JM.; Gibler, WB.; Boden, WE.; Ohman, EM.; Smith, SC. (2008). "Patterns and prognostic implications of low high-density lipoprotein levels in patients with non-ST-segment elevation acute coronary syndromes". Eur Heart J. 29 (20): 2480–8. doi:10.1093/eurheartj/ehn364. PMID 18716006. Unknown parameter
|month=
ignored (help) - ↑ Marchegiani, F.; Spazzafumo, L.; Provinciali, M.; Cardelli, M.; Olivieri, F.; Franceschi, C.; Lattanzio, F.; Antonicelli, R. (2009). "Paraoxonase2 C311S polymorphism and low levels of HDL contribute to a higher mortality risk after acute myocardial infarction in elderly patients". Mol Genet Metab. 98 (3): 314–8. doi:10.1016/j.ymgme.2009.05.008. PMID 19540141. Unknown parameter
|month=
ignored (help) - ↑ Huxley, RR.; Barzi, F.; Lam, TH.; Czernichow, S.; Fang, X.; Welborn, T.; Shaw, J.; Ueshima, H.; Zimmet, P. (2011). "Isolated low levels of high-density lipoprotein cholesterol are associated with an increased risk of coronary heart disease: an individual participant data meta-analysis of 23 studies in the Asia-Pacific region". Circulation. 124 (19): 2056–64. doi:10.1161/CIRCULATIONAHA.111.028373. PMID 21986289. Unknown parameter
|month=
ignored (help) - ↑ Lu, Q.; Tian, G.; Zhang, Y.; Lu, M.; Lin, X.; Ma, A. (2013). "Low HDL-C predicts risk and PCI outcomes in the Han Chinese population". Atherosclerosis. 226 (1): 193–7. doi:10.1016/j.atherosclerosis.2012.09.011. PMID 23107044. Unknown parameter
|month=
ignored (help) - ↑ Mackey, RH.; Greenland, P.; Goff, DC.; Lloyd-Jones, D.; Sibley, CT.; Mora, S. (2012). "High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis)". J Am Coll Cardiol. 60 (6): 508–16. doi:10.1016/j.jacc.2012.03.060. PMID 22796256. Unknown parameter
|month=
ignored (help) - ↑ 23.0 23.1 Stampfer, MJ.; Sacks, FM.; Salvini, S.; Willett, WC.; Hennekens, CH. (1991). "A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction". N Engl J Med. 325 (6): 373–81. doi:10.1056/NEJM199108083250601. PMID 2062328. Unknown parameter
|month=
ignored (help) - ↑ Vergeer, M.; Boekholdt, SM.; Sandhu, MS.; Ricketts, SL.; Wareham, NJ.; Brown, MJ.; de Faire, U.; Leander, K.; Gigante, B. (2010). "Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility". Circulation. 122 (5): 470–7. doi:10.1161/CIRCULATIONAHA.109.912519. PMID 20644014. Unknown parameter
|month=
ignored (help) - ↑ Haase, CL.; Tybjærg-Hansen, A.; Grande, P.; Frikke-Schmidt, R. (2010). "Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease". J Clin Endocrinol Metab. 95 (12): E500–10. doi:10.1210/jc.2010-0450. PMID 20826588. Unknown parameter
|month=
ignored (help) - ↑ Haase, CL.; Tybjærg-Hansen, A.; Qayyum, AA.; Schou, J.; Nordestgaard, BG.; Frikke-Schmidt, R. (2012). "LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals". J Clin Endocrinol Metab. 97 (2): E248–56. doi:10.1210/jc.2011-1846. PMID 22090275. Unknown parameter
|month=
ignored (help) - ↑ Frikke-Schmidt, R. (2010). "Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population". Atherosclerosis. 208 (2): 305–16. doi:10.1016/j.atherosclerosis.2009.06.005. PMID 19596329. Unknown parameter
|month=
ignored (help) - ↑ Ridker, PM.; Genest, J.; Boekholdt, SM.; Libby, P.; Gotto, AM.; Nordestgaard, BG.; Mora, S.; MacFadyen, JG.; Glynn, RJ. (2010). "HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial". Lancet. 376 (9738): 333–9. doi:10.1016/S0140-6736(10)60713-1. PMID 20655105. Unknown parameter
|month=
ignored (help) - ↑ Hedman, M.; Pahlman, R.; Sundvall, J.; Ehnholm, C.; Syvänne, M.; Jokinen, E.; Jauhiainen, M.; Holmberg, C.; Antikainen, M. (2007). "Low HDL-C predicts the onset of transplant vasculopathy in pediatric cardiac recipients on pravastatin therapy". Pediatr Transplant. 11 (5): 481–90. doi:10.1111/j.1399-3046.2007.00690.x. PMID 17631015. Unknown parameter
|month=
ignored (help) - ↑ 30.0 30.1 Genest, JJ.; Martin-Munley, SS.; McNamara, JR.; Ordovas, JM.; Jenner, J.; Myers, RH.; Silberman, SR.; Wilson, PW.; Salem, DN. (1992). "Familial lipoprotein disorders in patients with premature coronary artery disease". Circulation. 85 (6): 2025–33. PMID 1534286. Unknown parameter
|month=
ignored (help) - ↑ Buring, JE.; O'Connor, GT.; Goldhaber, SZ.; Rosner, B.; Herbert, PN.; Blum, CB.; Breslow, JL.; Hennekens, CH. (1992). "Decreased HDL2 and HDL3 cholesterol, Apo A-I and Apo A-II, and increased risk of myocardial infarction". Circulation. 85 (1): 22–9. PMID 1728453. Unknown parameter
|month=
ignored (help) - ↑ Kwiterovich, PO.; Coresh, J.; Bachorik, PS. (1993). "Prevalence of hyperapobetalipoproteinemia and other lipoprotein phenotypes in men (aged or = 50 years) and women ( or = 60 years) with coronary artery disease". Am J Cardiol. 71 (8): 631–9. PMID 8447257. Unknown parameter
|month=
ignored (help) - ↑ Genest, J.; Bard, JM.; Fruchart, JC.; Ordovas, JM.; Schaefer, EJ. (1993). "Familial hypoalphalipoproteinemia in premature coronary artery disease". Arterioscler Thromb. 13 (12): 1728–37. PMID 8241092. Unknown parameter
|month=
ignored (help) - ↑ "Lipids and lipoproteins in symptomatic coronary heart disease. Distribution, intercorrelations, and significance for risk classification in 6,700 men and 1,500 women. The Bezafibrate Infarction Prevention (BIP) Study Group, Israel". Circulation. 86 (3): 839–48. 1992. PMID 1516196. Unknown parameter
|month=
ignored (help) - ↑ Sacks, FM.; Tonkin, AM.; Craven, T.; Pfeffer, MA.; Shepherd, J.; Keech, A.; Furberg, CD.; Braunwald, E. (2002). "Coronary heart disease in patients with low LDL-cholesterol: benefit of pravastatin in diabetics and enhanced role for HDL-cholesterol and triglycerides as risk factors". Circulation. 105 (12): 1424–8. PMID 11914249. Unknown parameter
|month=
ignored (help) - ↑ Barter, P.; Gotto, AM.; LaRosa, JC.; Maroni, J.; Szarek, M.; Grundy, SM.; Kastelein, JJ.; Bittner, V.; Fruchart, JC. (2007). "HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events". N Engl J Med. 357 (13): 1301–10. doi:10.1056/NEJMoa064278. PMID 17898099. Unknown parameter
|month=
ignored (help) - ↑ Wolfram, RM.; Brewer, HB.; Xue, Z.; Satler, LF.; Pichard, AD.; Kent, KM.; Waksman, R. (2006). "Impact of low high-density lipoproteins on in-hospital events and one-year clinical outcomes in patients with non-ST-elevation myocardial infarction acute coronary syndrome treated with drug-eluting stent implantation". Am J Cardiol. 98 (6): 711–7. doi:10.1016/j.amjcard.2006.04.006. PMID 16950168. Unknown parameter
|month=
ignored (help) - ↑ Rader, DJ.; Ikewaki, K.; Duverger, N.; Feuerstein, I.; Zech, L.; Connor, W.; Brewer, HB. (1993). "Very low high-density lipoproteins without coronary atherosclerosis". Lancet. 342 (8885): 1455–8. PMID 7902482. Unknown parameter
|month=
ignored (help) - ↑ Klein, HG.; Lohse, P.; Pritchard, PH.; Bojanovski, D.; Schmidt, H.; Brewer, HB. (1992). "Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met)". J Clin Invest. 89 (2): 499–506. doi:10.1172/JCI115612. PMID 1737840. Unknown parameter
|month=
ignored (help) - ↑ Sirtori, CR.; Calabresi, L.; Franceschini, G.; Baldassarre, D.; Amato, M.; Johansson, J.; Salvetti, M.; Monteduro, C.; Zulli, R. (2001). "Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study". Circulation. 103 (15): 1949–54. PMID 11306522. Unknown parameter
|month=
ignored (help) - ↑ Windler, E.; Schöffauer, M.; Zyriax, BC. (2007). "The significance of low HDL-cholesterol levels in an ageing society at increased risk for cardiovascular disease". Diab Vasc Dis Res. 4 (2): 136–42. doi:10.3132/dvdr.2007.032. PMID 17654448. Unknown parameter
|month=
ignored (help) - ↑ 42.0 42.1 Suryadevara, V.; Storey, SG.; Aronow, WS.; Ahn, C. (2003). "Association of abnormal serum lipids in elderly persons with atherosclerotic vascular disease and dementia, atherosclerotic vascular disease without dementia, dementia without atherosclerotic vascular disease, and no dementia or atherosclerotic vascular disease". J Gerontol A Biol Sci Med Sci. 58 (9): M859–61. PMID 14528045. Unknown parameter
|month=
ignored (help) - ↑ Castelli, WP.; Wilson, PW.; Levy, D.; Anderson, K. (1989). "Cardiovascular risk factors in the elderly". Am J Cardiol. 63 (16): 12H–19H. PMID 2523187. Unknown parameter
|month=
ignored (help) - ↑ Frost, PH.; Davis, BR.; Burlando, AJ.; Curb, JD.; Guthrie, GP.; Isaacsohn, JL.; Wassertheil-Smoller, S.; Wilson, AC.; Stamler, J. (1996). "Serum lipids and incidence of coronary heart disease. Findings from the Systolic Hypertension in the Elderly Program (SHEP)". Circulation. 94 (10): 2381–8. PMID 8921777. Unknown parameter
|month=
ignored (help) - ↑ Corti, MC.; Guralnik, JM.; Salive, ME.; Harris, T.; Field, TS.; Wallace, RB.; Berkman, LF.; Seeman, TE.; Glynn, RJ. (1995). "HDL cholesterol predicts coronary heart disease mortality in older persons". JAMA. 274 (7): 539–44. PMID 7629981. Unknown parameter
|month=
ignored (help) - ↑ Ridker, PM.; Buring, JE.; Rifai, N.; Cook, NR. (2007). "Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score". JAMA. 297 (6): 611–9. doi:10.1001/jama.297.6.611. PMID 17299196. Unknown parameter
|month=
ignored (help) - ↑ Olson, MB.; Kelsey, SF.; Bittner, V.; Reis, SE.; Reichek, N.; Handberg, EM.; Merz, CN. (2000). "Weight cycling and high-density lipoprotein cholesterol in women: evidence of an adverse effect: a report from the NHLBI-sponsored WISE study. Women's Ischemia Syndrome Evaluation Study Group". J Am Coll Cardiol. 36 (5): 1565–71. PMID 11079659. Unknown parameter
|month=
ignored (help) - ↑ Lamon-Fava, S.; Herrington, DM.; Reboussin, DM.; Sherman, M.; Horvath, KV.; Cupples, LA.; White, C.; Demissie, S.; Schaefer, EJ. (2008). "Plasma levels of HDL subpopulations and remnant lipoproteins predict the extent of angiographically-defined coronary artery disease in postmenopausal women". Arterioscler Thromb Vasc Biol. 28 (3): 575–9. doi:10.1161/ATVBAHA.107.157123. PMID 18174456. Unknown parameter
|month=
ignored (help) - ↑ Conway, GS.; Agrawal, R.; Betteridge, DJ.; Jacobs, HS. (1992). "Risk factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome". Clin Endocrinol (Oxf). 37 (2): 119–25. PMID 1395062. Unknown parameter
|month=
ignored (help) - ↑ Birdsall, MA.; Farquhar, CM.; White, HD. (1997). "Association between polycystic ovaries and extent of coronary artery disease in women having cardiac catheterization". Ann Intern Med. 126 (1): 32–5. PMID 8992921. Unknown parameter
|month=
ignored (help) - ↑ Talbott, EO.; Zborowski, JV.; Rager, JR.; Boudreaux, MY.; Edmundowicz, DA.; Guzick, DS. (2004). "Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome". J Clin Endocrinol Metab. 89 (11): 5454–61. doi:10.1210/jc.2003-032237. PMID 15531497. Unknown parameter
|month=
ignored (help) - ↑ Asztalos, BF.; Schaefer, EJ.; Horvath, KV.; Cox, CE.; Skinner, S.; Gerrior, J.; Gorbach, SL.; Wanke, C. (2006). "Protease inhibitor-based HAART, HDL, and CHD-risk in HIV-infected patients". Atherosclerosis. 184 (1): 72–7. doi:10.1016/j.atherosclerosis.2005.04.013. PMID 15935358. Unknown parameter
|month=
ignored (help) - ↑ Bengtsson, BA.; Abs, R.; Bennmarker, H.; Monson, JP.; Feldt-Rasmussen, U.; Hernberg-Stahl, E.; Westberg, B.; Wilton, P.; Wüster, C. (1999). "The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board". J Clin Endocrinol Metab. 84 (11): 3929–35. PMID 10566630. Unknown parameter
|month=
ignored (help) - ↑ Tomlinson, JW.; Holden, N.; Hills, RK.; Wheatley, K.; Clayton, RN.; Bates, AS.; Sheppard, MC.; Stewart, PM. (2001). "Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group". Lancet. 357 (9254): 425–31. PMID 11273062. Unknown parameter
|month=
ignored (help) - ↑ Lakatos, J.; Hárságyi, A. (1988). "Serum total, HDL, LDL cholesterol, and triglyceride levels in patients with rheumatoid arthritis". Clin Biochem. 21 (2): 93–6. PMID 3390902. Unknown parameter
|month=
ignored (help) - ↑ Lazarevic, MB.; Vitic, J.; Mladenovic, V.; Myones, BL.; Skosey, JL.; Swedler, WI. (1992). "Dyslipoproteinemia in the course of active rheumatoid arthritis". Semin Arthritis Rheum. 22 (3): 172–8. PMID 1295090. Unknown parameter
|month=
ignored (help) - ↑ Alagona, P. (2009). "Beyond LDL cholesterol: the role of elevated triglycerides and low HDL cholesterol in residual CVD risk remaining after statin therapy". Am J Manag Care. 15 (3 Suppl): S65–73. PMID 19355805. Unknown parameter
|month=
ignored (help) - ↑ Rubin, EM.; Krauss, RM.; Spangler, EA.; Verstuyft, JG.; Clift, SM. (1991). "Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI". Nature. 353 (6341): 265–7. doi:10.1038/353265a0. PMID 1910153. Unknown parameter
|month=
ignored (help) - ↑ Duverger, N.; Kruth, H.; Emmanuel, F.; Caillaud, JM.; Viglietta, C.; Castro, G.; Tailleux, A.; Fievet, C.; Fruchart, JC. (1996). "Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits". Circulation. 94 (4): 713–7. PMID 8772693. Unknown parameter
|month=
ignored (help) - ↑ Benoit, P.; Emmanuel, F.; Caillaud, JM.; Bassinet, L.; Castro, G.; Gallix, P.; Fruchart, JC.; Branellec, D.; Denèfle, P. "Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models". Circulation. 99 (1): 105–10. PMID 9884386.
- ↑ Ameli, S.; Hultgardh-Nilsson, A.; Cercek, B.; Shah, PK.; Forrester, JS.; Ageland, H.; Nilsson, J. (1994). "Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits". Circulation. 90 (4): 1935–41. PMID 7923682. Unknown parameter
|month=
ignored (help) - ↑ Tangirala, RK.; Tsukamoto, K.; Chun, SH.; Usher, D.; Puré, E.; Rader, DJ. (1999). "Regression of atherosclerosis induced by liver-directed gene transfer of apolipoprotein A-I in mice". Circulation. 100 (17): 1816–22. PMID 10534470. Unknown parameter
|month=
ignored (help) - ↑ Grundy, SM.; Cleeman, JI.; Daniels, SR.; Donato, KA.; Eckel, RH.; Franklin, BA.; Gordon, DJ.; Krauss, RM.; Savage, PJ. (2005). "Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement". Circulation. 112 (17): 2735–52. doi:10.1161/CIRCULATIONAHA.105.169404. PMID 16157765. Unknown parameter
|month=
ignored (help) - ↑ Mehra, MR.; Uber, PA.; Lavie, CJ.; Milani, RV.; Park, MH.; Ventura, HO. (2009). "High-density lipoprotein cholesterol levels and prognosis in advanced heart failure". J Heart Lung Transplant. 28 (9): 876–80. doi:10.1016/j.healun.2009.04.026. PMID 19716038. Unknown parameter
|month=
ignored (help) - ↑ Foody, JM.; Ferdinand, FD.; Pearce, GL.; Lytle, BW.; Cosgrove, DM.; Sprecher, DL. (2000). "HDL cholesterol level predicts survival in men after coronary artery bypass graft surgery: 20-year experience from The Cleveland Clinic Foundation". Circulation. 102 (19 Suppl 3): III90–4. PMID 11082369. Unknown parameter
|month=
ignored (help) - ↑ Niessner, A.; Hofmann, R.; Kypta, A.; Steinwender, C.; Kerschner, K.; Kammler, J.; Leisch, F.; Huber, K. (2007). "Low high-density lipoprotein cholesterol predicts cardiovascular events after carotid stenting: a long-term survey". J Thromb Haemost. 5 (5): 950–4. doi:10.1111/j.1538-7836.2007.02451.x. PMID 17367491. Unknown parameter
|month=
ignored (help) - ↑ Chen, L.; Théroux, P.; Lespérance, J.; Shabani, F.; Thibault, B.; De Guise, P. (1996). "Angiographic features of vein grafts versus ungrafted coronary arteries in patients with unstable angina and previous bypass surgery". J Am Coll Cardiol. 28 (6): 1493–9. PMID 8917263. Unknown parameter
|month=
ignored (help) - ↑ Baragetti, A.; Norata, GD.; Sarcina, C.; Rastelli, F.; Grigore, L.; Garlaschelli, K.; Uboldi, P.; Baragetti, I.; Pozzi, C. (2013). "High density lipoprotein cholesterol levels are an independent predictor of the progression of chronic kidney disease". J Intern Med. 274 (3): 252–62. doi:10.1111/joim.12081. PMID 23607805. Unknown parameter
|month=
ignored (help) - ↑ Kotani, K.; Sekine, Y.; Ishikawa, S.; Ikpot, IZ.; Suzuki, K.; Remaley, AT. (2013). "High-density lipoprotein and prostate cancer: an overview". J Epidemiol. 23 (5): 313–9. PMID 23985823. Unknown parameter
|month=
ignored (help) - ↑ Guo, E.; Chen, L.; Xie, Q.; Chen, J.; Tang, Z.; Wu, Y. (2007). "Serum HDL-C as a potential biomarker for nodal stages in gastric cancer". Ann Surg Oncol. 14 (9): 2528–34. doi:10.1245/s10434-007-9401-0. PMID 17597347. Unknown parameter
|month=
ignored (help) - ↑ Tamura, T.; Inagawa, S.; Hisakura, K.; Enomoto, T.; Ohkohchi, N. (2012). "Evaluation of serum high-density lipoprotein cholesterol levels as a prognostic factor in gastric cancer patients". J Gastroenterol Hepatol. 27 (10): 1635–40. doi:10.1111/j.1440-1746.2012.07189.x. PMID 22647147. Unknown parameter
|month=
ignored (help) - ↑ Dessì, S.; Batetta, B.; Pulisci, D.; Spano, O.; Anchisi, C.; Tessitore, L.; Costelli, P.; Baccino, FM.; Aroasio, E. (1994). "Cholesterol content in tumor tissues is inversely associated with high-density lipoprotein cholesterol in serum in patients with gastrointestinal cancer". Cancer. 73 (2): 253–8. PMID 8293385. Unknown parameter
|month=
ignored (help) - ↑ Jiang, M.; Liu, F.; Xiong, WJ.; Zhong, L.; Xu, W.; Xu, F.; Liu, YB. (2010). "Combined MELD and blood lipid level in evaluating the prognosis of decompensated cirrhosis". World J Gastroenterol. 16 (11): 1397–401. PMID 20238407. Unknown parameter
|month=
ignored (help) - ↑ 75.0 75.1 Tsai, MH.; Peng, YS.; Chen, YC.; Lien, JM.; Tian, YC.; Fang, JT.; Weng, HH.; Chen, PC.; Yang, CW. (2009). "Low serum concentration of apolipoprotein A-I is an indicator of poor prognosis in cirrhotic patients with severe sepsis". J Hepatol. 50 (5): 906–15. doi:10.1016/j.jhep.2008.12.024. PMID 19304335. Unknown parameter
|month=
ignored (help) - ↑ Habib, A.; Mihas, AA.; Abou-Assi, SG.; Williams, LM.; Gavis, E.; Pandak, WM.; Heuman, DM. (2005). "High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics". Clin Gastroenterol Hepatol. 3 (3): 286–91. PMID 15765449. Unknown parameter
|month=
ignored (help) - ↑ Newburger, JW.; Takahashi, M.; Gerber, MA.; Gewitz, MH.; Tani, LY.; Burns, JC.; Shulman, ST.; Bolger, AF.; Ferrieri, P. (2004). "Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association". Pediatrics. 114 (6): 1708–33. doi:10.1542/peds.2004-2182. PMID 15574639. Unknown parameter
|month=
ignored (help) - ↑ Seppälä-Lindroos, A.; Vehkavaara, S.; Häkkinen, AM.; Goto, T.; Westerbacka, J.; Sovijärvi, A.; Halavaara, J.; Yki-Järvinen, H. (2002). "Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men". J Clin Endocrinol Metab. 87 (7): 3023–8. PMID 12107194. Unknown parameter
|month=
ignored (help) - ↑ Adiels, M.; Taskinen, MR.; Packard, C.; Caslake, MJ.; Soro-Paavonen, A.; Westerbacka, J.; Vehkavaara, S.; Häkkinen, A.; Olofsson, SO. (2006). "Overproduction of large VLDL particles is driven by increased liver fat content in man". Diabetologia. 49 (4): 755–65. doi:10.1007/s00125-005-0125-z. PMID 16463046. Unknown parameter
|month=
ignored (help) - ↑ Barlage, S.; Gnewuch, C.; Liebisch, G.; Wolf, Z.; Audebert, FX.; Glück, T.; Fröhlich, D.; Krämer, BK.; Rothe, G. (2009). "Changes in HDL-associated apolipoproteins relate to mortality in human sepsis and correlate to monocyte and platelet activation". Intensive Care Med. 35 (11): 1877–85. doi:10.1007/s00134-009-1609-y. PMID 19669126. Unknown parameter
|month=
ignored (help) - ↑ Chien, JY.; Jerng, JS.; Yu, CJ.; Yang, PC. (2005). "Low serum level of high-density lipoprotein cholesterol is a poor prognostic factor for severe sepsis". Crit Care Med. 33 (8): 1688–93. PMID 16096442. Unknown parameter
|month=
ignored (help) - ↑ Tirschwell, DL.; Smith, NL.; Heckbert, SR.; Lemaitre, RN.; Longstreth, WT.; Psaty, BM. (2004). "Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups". Neurology. 63 (10): 1868–75. PMID 15557504. Unknown parameter
|month=
ignored (help)