High density lipoprotein natural history, complications and prognosis: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
No edit summary
Line 4: Line 4:


==Overview==
==Overview==
The plasma levels of HDL are inversely proportional to the development of [[coronary artery disease]] ([[CAD]]) making HDL a negative cardiac risk factor.<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>  Low serum HDL-cholesterol can be an isolated abnormality or can be associated with [[hypercholesterolemia]]. Patients with premature coronary artery disease, defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age, have a primary reduction in HDL-cholesterol. Studies have shown that low HDL risk is independent of the risk attributed to elevated LDL-cholesterol ([[low density lipoprotein]]) in the serum.  Findings from large scale prospective studies indicate that for every 1 mg/dL rise in serum HDL levels the risk of CAD reduces by 2% to 3% in men and women respectively.
The protective high-density lipoprotein cholesterol (HDL), by a variety of mechanism protects blood vessels and organ systems.  The predominant mechanism is the macrophage cholesterol efflux by which it counteracts atherogenesis in blood vessels.<ref name="Rosenson-2012">{{Cite journal | last1 = Rosenson | first1 = RS. | last2 = Brewer | first2 = HB. | last3 = Davidson | first3 = WS. | last4 = Fayad | first4 = ZA. | last5 = Fuster | first5 = V. | last6 = Goldstein | first6 = J. | last7 = Hellerstein | first7 = M. | last8 = Jiang | first8 = XC. | last9 = Phillips | first9 = MC. | title = Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. | journal = Circulation | volume = 125 | issue = 15 | pages = 1905-19 | month = Apr | year = 2012 | doi = 10.1161/CIRCULATIONAHA.111.066589 | PMID = 22508840 }}</ref>  The other likely protective mechanisms are promotion of maintenance of endothelial function,<ref name="Kuhn-1991">{{Cite journal  | last1 = Kuhn | first1 = FE. | last2 = Mohler | first2 = ER. | last3 = Satler | first3 = LF. | last4 = Reagan | first4 = K. | last5 = Lu | first5 = DY. | last6 = Rackley | first6 = CE. | title = Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity. | journal = Am J Cardiol | volume = 68 | issue = 15 | pages = 1425-30 | month = Dec | year = 1991 | doi =  | PMID = 1746422 }}</ref> protection against oxidation of LDL,<ref name="Kontush-2003">{{Cite journal  | last1 = Kontush | first1 = A. | last2 = Chantepie | first2 = S. | last3 = Chapman | first3 = MJ. | title = Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. | journal = Arterioscler Thromb Vasc Biol | volume = 23 | issue = 10 | pages = 1881-8 | month = Oct | year = 2003 | doi = 10.1161/01.ATV.0000091338.93223.E8 | PMID = 12920049 }}</ref> protection against inflammation<ref name="Barter-2004">{{Cite journal | last1 = Barter | first1 = PJ. | last2 = Nicholls | first2 = S. | last3 = Rye | first3 = KA. | last4 = Anantharamaiah | first4 = GM. | last5 = Navab | first5 = M. | last6 = Fogelman | first6 = AM. | title = Antiinflammatory properties of HDL. | journal = Circ Res | volume = 95 | issue = 8 | pages = 764-72 | month = Oct | year = 2004 | doi = 10.1161/01.RES.0000146094.59640.13 | PMID = 15486323 }}</ref> and other mechanisms that may interfere with the thrombotic component of atherosclerosis.<ref name="Epand-1994">{{Cite journal  | last1 = Epand | first1 = RM. | last2 = Stafford | first2 = A. | last3 = Leon | first3 = B. | last4 = Lock | first4 = PE. | last5 = Tytler | first5 = EM. | last6 = Segrest | first6 = JP. | last7 = Anantharamaiah | first7 = GM. | title = HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity. | journal = Arterioscler Thromb | volume = 14 | issue = 11 | pages = 1775-83 | month = Nov | year = 1994 | doi = | PMID = 7947603 }}</ref>  Thus HDL levels tend to posses an inverse relation with diseases and complications involving the cardiovascular, neurological and renal systems.  Recent studies have further reported similar inverse relation with liver disease, sepsis and carcinoma.


==Cardiovascular Risk==
==Coronary Artery Disease==
The Framingham Heart Study has shown that the risk of [[myocardial infarction]] increases by about 25% for every 5 mg/dL decrement in serum HDL-cholesterol below median values for both men and women.<ref name="pmid3196218">{{cite journal |author=Wilson PW, Abbott RD, Castelli WP |title=High density lipoprotein cholesterol and mortality. The Framingham Heart Study |journal=Arteriosclerosis |volume=8 |issue=6 |pages=737–41 |year=1988 |pmid=3196218 |doi= |url=}}</ref>  According to the study the [[relative risk]] of death due to cardiovascular and [[coronary artery disease]] for men in the first HDL-C 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-C quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl).
HDL levels inverse relation with either the presence or development of coronary artery disease  (CAD) is a well-established phenomenon.<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>  A substantial number of body of evidences collected through different studies on different populations has accounted low HDL level as significant cardiovascular risk as well as a prognostic factor, either independently or along with other physical and biochemical parameters.  Low levels of HDL-cholesterol appear to interact with hypertriglyceridemia in particular 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>  The mechanism responsible for low HDL-cholesterol concentration results from increased catabolism of triglyceride-enriched HDL particles.<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, it is also related to low high-density lipoprotein cholesterol and an elevated TC/HDL-cholesterol 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 have shown that in patients with known coronary artery disease HDL-C levels are predictive of coronary events over a broad range of LDL-C levels. The LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial<ref name="pmid11889008">{{cite journal |author=Simes RJ, Marschner IC, Hunt D, ''et al.'' |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 |year=2002 |month=March |pmid=11889008 |doi= |url=}}</ref> and the CARE (Cholesterol and Recurrent Events) trial<ref name="pmid7572695">{{cite journal |author=Pfeffer MA, Sacks FM, Moyé LA, ''et al.'' |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 |year=1995 |month=September |pmid=7572695 |doi= |url=}}</ref> have shown that reduced serum HDL-C levels strongly predicted acute coronary events in patients with LDL-C 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-C <125 mg/dL for every 10 mg/dL rise in HDL-C compared to those with LDL-C levels more than 125 mg/dL. A similar relationship between the levels of HDL-C and LDL-C was also shown in the Treating to New Targets (TNT) trial.<ref name="pmid19410683">{{cite journal |author=Waters DD |title=Clinical insights from the Treating to New Targets trial |journal=Prog Cardiovasc Dis |volume=51 |issue=6 |pages=487–502 |year=2009 |pmid=19410683 |doi=10.1016/j.pcad.2009.01.001 |url=}}</ref>
Based upon 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).


Meta-analysis of 23 studies in the Asia-Pacific region showed that isolated low HDl-C, defined as <40 mg/dL in men and <50 mg/dL in women, is associated with an increased risk of cardiovascular events. But Mendelian randomization analyses failed to establish HDL-C as a causative factor for increased cardiovascular risk.
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>


Genetic studies have shown that two [[polymorphism]]s in phospholipid transfer protein are associated with a lower cardiovascular risk and elevate concentrations of cholesterol depleted HDL in the serum. MESA (Multi-ethnic Study of Atherosclerosis) cohort, a multi-ethnic study, evaluated nearly 6000 individuals without known coronary artery disease who were not taking lipid lowering drugs to evaluate independent associations of high-density lipoprotein cholesterol (HDL-C) and particle (HDL-P) concentrations with carotid intima-media thickness (cIMT) and incident coronary artery disease (CAD). The result of this study was a persistently significant inverse relationship between HDL-P but not HDL-C and CAD risk.<ref name="pmid22796256">{{cite journal |author=Mackey RH, Greenland P, Goff DC, Lloyd-Jones D, Sibley CT, Mora 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 |year=2012 |month=August |pmid=22796256 |pmc=3411890 |doi=10.1016/j.jacc.2012.03.060 |url=}}</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>


===Cholesterylester Transfer Protein===
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-C <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>
Cholesteryl ester transfer protein (CETP) (also called plasma lipid transfer protein) is a [[blood plasma|plasma]] [[protein]] that facilitates the transport of [[cholesteryl ester]]s and [[triglyceride]]s between the [[lipoprotein]]s. It collects triglycerides from [[Very low density lipoprotein|very low density]] or [[low density lipoprotein]]s (VLDL or LDL) and exchanges them for cholesteryl esters from [[high density lipoprotein]]s (and vice versa). Most of the time, however, CETP does a homoexchange- trading a triglyceride for a triglyceride or a cholesteryl ester for a cholesteryl ester. Numerous case control studies have shown that elevated CETP levels were associated with increased CAD risk in patients with elevated triglyceride (TG) levels and decreased risk in those with low TG levels. [[Mutation]] I405V ([[Isoleucine]] for [[Valine]] substitution at [[codon]] 405) has been shown to be associated with reduced activity of CETP of increased levels of HDL-C in the plasma, but the consistency of this finding has not been proved in all studies.<ref name="pmid19242900">{{cite journal |author=Darabi M, Abolfathi AA, Noori M, ''et al.'' |title=Cholesteryl ester transfer protein I405V polymorphism influences apolipoprotein A-I response to a change in dietary fatty acid composition |journal=Horm. Metab. Res. |volume=41 |issue=7 |pages=554–8 |year=2009 |month=July |pmid=19242900 |doi=10.1055/s-0029-1192034 |url=}}</ref><ref name="pmid22854712">{{cite journal |author=Rejeb J, Omezzine A, Boumaiza I, ''et al.'' |title=Four polymorphisms of cholesteryl ester transfer protein gene and coronary stenosis in a Tunisian population |journal=J Cardiovasc Med (Hagerstown) |volume=13 |issue=9 |pages=546–53 |year=2012 |month=September |pmid=22854712 |doi=10.2459/JCM.0b013e3283569b24 |url=}}</ref>
 
The finding of very low HDL levels among one-fifth of patients with NSTEMI ACS had 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 in European population revealed that patients with at least one C allele (C+ carriers) 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 CAD 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 clinical importance of the different HDL sub fractions has remained uncertain. 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>  In contrast, the Physicians' Health Study and some other reports have shown similar associations of total HDL and HDL3 with coronary heart disease (CHD) 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>  This may reflect the importance of both HDL2 and HDL3.<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>
 
Despite all these evidence regarding the inverse relationship between levels of HDL-cholesterol and cardiovascular risk presented above, low levels of HDL-cholesterol have not been established as causative of this relationship or with the development of atherosclerosis.<ref name="Di Angelantonio-2009">{{Cite journal  | last1 = Di Angelantonio | first1 = E. | last2 = Sarwar | first2 = N. | last3 = Perry | first3 = P. | last4 = Kaptoge | first4 = S. | last5 = Ray | first5 = KK. | last6 = Thompson | first6 = A. | last7 = Wood | first7 = AM. | last8 = Lewington | first8 = S. | last9 = Sattar | first9 = N. | title = Major lipids, apolipoproteins, and risk of vascular disease. | journal = JAMA | volume = 302 | issue = 18 | pages = 1993-2000 | month = Nov | year = 2009 | doi = 10.1001/jama.2009.1619 | PMID = 19903920 }}</ref>  This lack of causality relationship comes from Mendelian randomization analyses, and the difficulty in demonstrating improved outcomes with therapies to raise HDL- cholesterol.  The absence of premature CAD in individuals with rare disorders such as Tangier disease, who have very low levels of HDL-cholesterol but not the predicted increase in cardiovascular disease, provides some support for the lack of association.<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>  Early Mendelian randomized analyses found that genetically decreased HDL-cholesterol levels were not associated with an increased risk of CHD events and that genetically increased HDL-cholesterol levels were not associated with a decreased risk.<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>  JUPITER trial showed that low HDL did not remain as an important predictor of cardiovascular risk after correcting the elevated LDL levels.<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>  Studies published in 2012 in the field of HDL research have provided further evidence suggesting that a low HDL-cholesterol level, in the absence of related lipid or non lipid risk factors, is not associated with increased risk of coronary heart disease.<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>  Thus clinician’s are left with only weak evidence to support whether or not to target treatment of HDL-cholesterol with pharmacological therapy.<ref name="Rubenfire-2013">{{Cite journal  | last1 = Rubenfire | first1 = M. | last2 = Brook | first2 = RD. | title = HDL cholesterol and cardiovascular outcomes: what is the evidence? | journal = Curr Cardiol Rep | volume = 15 | issue = 4 | pages = 349 | month = Apr | year = 2013 | doi = 10.1007/s11886-013-0349-3 | PMID = 23420445 }}</ref> Additional evidence that may explain why HDL-cholesterol may not be causal comes from the Multi-ethnic Study of Atherosclerosis (MESA) cohort.<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>  In this study, the association between HDL-cholesterol and HDL particle number determined by NMR spectroscopy with carotid intimal medial thickness and coronary events were evaluated in a group of nearly 6000 individuals without known CAD who were not taking lipid-lowering medication.  After adjusting for the known predictors of CAD, a significant inverse relationship between HDL particle and CAD risk persisted, but not with HDL-cholesterol.  This study adds to the concept that the inverse relationship between HDL and cardiovascular risk may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.
 
Cholesterol component is only one of many structural or functional components of the HDL particle.  Thus, if low HDL-cholesterol level is found not to be causally associated with CAD, it is possible that other attributes of HDL could be causal.  For instance, it is possible that some component of the HDL particle or one of its functions may protect against CAD events or atherosclerosis.  The genetic determinants of this component or function may or may not be linked to the HDL-cholesterol composition of the HDL particle.  As an example, two polymorphisms in phospholipid transfer protein are 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>
 
Cholesteryl ester transfer protein (CETP) is integrally involved in high density lipoprotein (HDL) metabolism.<ref name="Niesor-2010">{{Cite journal  | last1 = Niesor | first1 = EJ. | last2 = Magg | first2 = C. | last3 = Ogawa | first3 = N. | last4 = Okamoto | first4 = H. | last5 = von der Mark | first5 = E. | last6 = Matile | first6 = H. | last7 = Schmid | first7 = G. | last8 = Clerc | first8 = RG. | last9 = Chaput | first9 = E. | title = Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport. | journal = J Lipid Res | volume = 51 | issue = 12 | pages = 3443-54 | month = Dec | year = 2010 | doi = 10.1194/jlr.M008706 | PMID = 20861162 }}</ref>  CETP is directly associated with low density lipoprotein cholesterol (LDL-C) concentrations and inversely associated with HDL-cholesterol concentrations.  This is a potentially important observation since some have suggested that the association between CETP and CAD is attenuated after adjusting for HDL and LDL-cholesterol concentrations.<ref name="Wolfe-2004">{{Cite journal  | last1 = Wolfe | first1 = ML. | last2 = Rader | first2 = DJ. | title = Cholesteryl ester transfer protein and coronary artery disease: an observation with therapeutic implications. | journal = Circulation | volume = 110 | issue = 11 | pages = 1338-40 | month = Sep | year = 2004 | doi = 10.1161/01.CIR.0000143047.52724.BB | PMID = 15364817 }}</ref>  Polymorphisms such as I405V that reduce the activity of CETP typically increase plasma HDL-cholesterol concentrations, although this has not been found consistently in all studies.<ref name="Barzilai-2003">{{Cite journal  | last1 = Barzilai | first1 = N. | last2 = Atzmon | first2 = G. | last3 = Schechter | first3 = C. | last4 = Schaefer | first4 = EJ. | last5 = Cupples | first5 = AL. | last6 = Lipton | first6 = R. | last7 = Cheng | first7 = S. | last8 = Shuldiner | first8 = AR. | title = Unique lipoprotein phenotype and genotype associated with exceptional longevity. | journal = JAMA | volume = 290 | issue = 15 | pages = 2030-40 | month = Oct | year = 2003 | doi = 10.1001/jama.290.15.2030 | PMID = 14559957 }}</ref>
 
In summary, HDL-cholesterol is a biomarker inversely associated with CAD risk, and it may still be considered in assessing patients’ CAD risk.  However, HDL-cholesterol is not likely causally responsible for that risk relationship.


===CAD in Pediatric Population===
===CAD in Pediatric Population===

Revision as of 23:41, 22 September 2013

High Density Lipoprotein Microchapters

Home

Patient information

Overview

Historical Perspective

Classification

Physiology

Pathophysiology

Causes

Low HDL
High HDL

Epidemiology and Demographics

Screening

Natural History, Complications and Prognosis

Diagnosis

HDL Laboratory Test

Treatment

Medical Therapy

Prevention

Future or Investigational Therapies

Clinical Trials

Landmark Trials

List of All Trials

Case Studies

Case #1

High density lipoprotein natural history, complications and prognosis On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of High density lipoprotein natural history, complications and prognosis

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on High density lipoprotein natural history, complications and prognosis

CDC on High density lipoprotein natural history, complications and prognosis

High density lipoprotein natural history, complications and prognosis in the news

Blogs on High density lipoprotein natural history, complications and prognosis

Directions to Hospitals Treating High density lipoprotein

Risk calculators and risk factors for High density lipoprotein natural history, complications and prognosis

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

The protective high-density lipoprotein cholesterol (HDL), by a variety of mechanism protects blood vessels and organ systems. The predominant mechanism is the macrophage cholesterol efflux by which it counteracts atherogenesis in blood vessels.[1] The other likely protective mechanisms are promotion of maintenance of endothelial function,[2] protection against oxidation of LDL,[3] protection against inflammation[4] and other mechanisms that may interfere with the thrombotic component of atherosclerosis.[5] Thus HDL levels tend to posses an inverse relation with diseases and complications involving the cardiovascular, neurological and renal systems. Recent studies have further reported similar inverse relation with liver disease, sepsis and carcinoma.

Coronary Artery Disease

HDL levels inverse relation with either the presence or development of coronary artery disease (CAD) is a well-established phenomenon.[6] A substantial number of body of evidences collected through different studies on different populations has accounted low HDL level as significant cardiovascular risk as well as a prognostic factor, either independently or along with other physical and biochemical parameters. Low levels of HDL-cholesterol appear to interact with hypertriglyceridemia in particular to increase the coronary risk.[7] The mechanism responsible for low HDL-cholesterol concentration results from increased catabolism of triglyceride-enriched HDL particles.[8] Plaque rupture, besides its correlation with high total cholesterol, it is also related to low high-density lipoprotein cholesterol and an elevated TC/HDL-cholesterol ratio.[9]

Based upon 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.[10] 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).

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.[11]

Framingham Risk Assessment counts HDL values above 60 mg/dL (1.5 mmol/L) as a negative risk factor.[12]

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[13] and the CARE (Cholesterol and Recurrent Events) trial[14] 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-C <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.[15]

The finding of very low HDL levels among one-fifth of patients with NSTEMI ACS had added to a greater burden of atherosclerosis and a higher risk of mortality.[16]

A study in European population revealed that patients with at least one C allele (C+ carriers) along with low HDL represent a category of subjects at a higher risk for the development of acute myocardial infarction with a worse prognosis.[17]

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 CAD 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.[18]

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.[19]

The clinical importance of the different HDL sub fractions has remained uncertain. 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.[20] In contrast, the Physicians' Health Study and some other reports have shown similar associations of total HDL and HDL3 with coronary heart disease (CHD) as HDL2 and apo A-I.[21] This may reflect the importance of both HDL2 and HDL3.[10]

Despite all these evidence regarding the inverse relationship between levels of HDL-cholesterol and cardiovascular risk presented above, low levels of HDL-cholesterol have not been established as causative of this relationship or with the development of atherosclerosis.[22] This lack of causality relationship comes from Mendelian randomization analyses, and the difficulty in demonstrating improved outcomes with therapies to raise HDL- cholesterol. The absence of premature CAD in individuals with rare disorders such as Tangier disease, who have very low levels of HDL-cholesterol but not the predicted increase in cardiovascular disease, provides some support for the lack of association.[23] Early Mendelian randomized analyses found that genetically decreased HDL-cholesterol levels were not associated with an increased risk of CHD events and that genetically increased HDL-cholesterol levels were not associated with a decreased risk.[24][25] JUPITER trial showed that low HDL did not remain as an important predictor of cardiovascular risk after correcting the elevated LDL levels.[26] Studies published in 2012 in the field of HDL research have provided further evidence suggesting that a low HDL-cholesterol level, in the absence of related lipid or non lipid risk factors, is not associated with increased risk of coronary heart disease.[27] Thus clinician’s are left with only weak evidence to support whether or not to target treatment of HDL-cholesterol with pharmacological therapy.[28] Additional evidence that may explain why HDL-cholesterol may not be causal comes from the Multi-ethnic Study of Atherosclerosis (MESA) cohort.[29] In this study, the association between HDL-cholesterol and HDL particle number determined by NMR spectroscopy with carotid intimal medial thickness and coronary events were evaluated in a group of nearly 6000 individuals without known CAD who were not taking lipid-lowering medication. After adjusting for the known predictors of CAD, a significant inverse relationship between HDL particle and CAD risk persisted, but not with HDL-cholesterol. This study adds to the concept that the inverse relationship between HDL and cardiovascular risk may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.

Cholesterol component is only one of many structural or functional components of the HDL particle. Thus, if low HDL-cholesterol level is found not to be causally associated with CAD, it is possible that other attributes of HDL could be causal. For instance, it is possible that some component of the HDL particle or one of its functions may protect against CAD events or atherosclerosis. The genetic determinants of this component or function may or may not be linked to the HDL-cholesterol composition of the HDL particle. As an example, two polymorphisms in phospholipid transfer protein are associated with increased concentrations of smaller, cholesterol-depleted HDL particles and a lower cardiovascular event rate.[30]

Cholesteryl ester transfer protein (CETP) is integrally involved in high density lipoprotein (HDL) metabolism.[31] CETP is directly associated with low density lipoprotein cholesterol (LDL-C) concentrations and inversely associated with HDL-cholesterol concentrations. This is a potentially important observation since some have suggested that the association between CETP and CAD is attenuated after adjusting for HDL and LDL-cholesterol concentrations.[32] Polymorphisms such as I405V that reduce the activity of CETP typically increase plasma HDL-cholesterol concentrations, although this has not been found consistently in all studies.[33]

In summary, HDL-cholesterol is a biomarker inversely associated with CAD risk, and it may still be considered in assessing patients’ CAD risk. However, HDL-cholesterol is not likely causally responsible for that risk relationship.

CAD in Pediatric Population

Premature CAD

CAD in Elderly

CAD in Women

CAD in AIDS

CAD in GH Deficiency

Post-CAD Treatment

CAD in Experimental Models

Post-Procedure

Congestive Heart Failure

Atrial Fibrillation

Chronic Kidney Disease

Carcinoma

Cirrhosis

Dementia

Kawasaki Disease

Sepsis

Stroke

References

  1. ↑ Rosenson, RS.; Brewer, HB.; Davidson, WS.; Fayad, ZA.; Fuster, V.; Goldstein, J.; Hellerstein, M.; Jiang, XC.; Phillips, MC. (2012). "Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport". Circulation. 125 (15): 1905–19. doi:10.1161/CIRCULATIONAHA.111.066589. PMID 22508840. Unknown parameter |month= ignored (help)
  2. ↑ Kuhn, FE.; Mohler, ER.; Satler, LF.; Reagan, K.; Lu, DY.; Rackley, CE. (1991). "Effects of high-density lipoprotein on acetylcholine-induced coronary vasoreactivity". Am J Cardiol. 68 (15): 1425–30. PMID 1746422. Unknown parameter |month= ignored (help)
  3. ↑ Kontush, A.; Chantepie, S.; Chapman, MJ. (2003). "Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress". Arterioscler Thromb Vasc Biol. 23 (10): 1881–8. doi:10.1161/01.ATV.0000091338.93223.E8. PMID 12920049. Unknown parameter |month= ignored (help)
  4. ↑ Barter, PJ.; Nicholls, S.; Rye, KA.; Anantharamaiah, GM.; Navab, M.; Fogelman, AM. (2004). "Antiinflammatory properties of HDL". Circ Res. 95 (8): 764–72. doi:10.1161/01.RES.0000146094.59640.13. PMID 15486323. Unknown parameter |month= ignored (help)
  5. ↑ Epand, RM.; Stafford, A.; Leon, B.; Lock, PE.; Tytler, EM.; Segrest, JP.; Anantharamaiah, GM. (1994). "HDL and apolipoprotein A-I protect erythrocytes against the generation of procoagulant activity". Arterioscler Thromb. 14 (11): 1775–83. PMID 7947603. Unknown parameter |month= ignored (help)
  6. ↑ 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 |month= ignored (help)
  7. ↑ 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 |month= ignored (help)
  8. ↑ 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 |month= ignored (help)
  9. ↑ 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)
  10. ↑ 10.0 10.1 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 |month= ignored (help)
  11. ↑ 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)
  12. ↑ "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 |month= ignored (help)
  13. ↑ 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)
  14. ↑ 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)
  15. ↑ 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.
  16. ↑ 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)
  17. ↑ 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)
  18. ↑ 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)
  19. ↑ 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)
  20. ↑ 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 |month= ignored (help)
  21. ↑ 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)
  22. ↑ Di Angelantonio, E.; Sarwar, N.; Perry, P.; Kaptoge, S.; Ray, KK.; Thompson, A.; Wood, AM.; Lewington, S.; Sattar, N. (2009). "Major lipids, apolipoproteins, and risk of vascular disease". JAMA. 302 (18): 1993–2000. doi:10.1001/jama.2009.1619. PMID 19903920. Unknown parameter |month= ignored (help)
  23. ↑ 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)
  24. ↑ 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)
  25. ↑ 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)
  26. ↑ 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)
  27. ↑ 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 |month= ignored (help)
  28. ↑ Rubenfire, M.; Brook, RD. (2013). "HDL cholesterol and cardiovascular outcomes: what is the evidence?". Curr Cardiol Rep. 15 (4): 349. doi:10.1007/s11886-013-0349-3. PMID 23420445. Unknown parameter |month= ignored (help)
  29. ↑ 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)
  30. ↑ 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)
  31. ↑ Niesor, EJ.; Magg, C.; Ogawa, N.; Okamoto, H.; von der Mark, E.; Matile, H.; Schmid, G.; Clerc, RG.; Chaput, E. (2010). "Modulating cholesteryl ester transfer protein activity maintains efficient pre-β-HDL formation and increases reverse cholesterol transport". J Lipid Res. 51 (12): 3443–54. doi:10.1194/jlr.M008706. PMID 20861162. Unknown parameter |month= ignored (help)
  32. ↑ Wolfe, ML.; Rader, DJ. (2004). "Cholesteryl ester transfer protein and coronary artery disease: an observation with therapeutic implications". Circulation. 110 (11): 1338–40. doi:10.1161/01.CIR.0000143047.52724.BB. PMID 15364817. Unknown parameter |month= ignored (help)
  33. ↑ Barzilai, N.; Atzmon, G.; Schechter, C.; Schaefer, EJ.; Cupples, AL.; Lipton, R.; Cheng, S.; Shuldiner, AR. (2003). "Unique lipoprotein phenotype and genotype associated with exceptional longevity". JAMA. 290 (15): 2030–40. doi:10.1001/jama.290.15.2030. PMID 14559957. Unknown parameter |month= ignored (help)


Template:WikiDoc Sources

Retrieved from "https://www.wikidoc.org/index.php?title=High_density_lipoprotein_natural_history,_complications_and_prognosis&oldid=906930"