High HDL prognosis and complications

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mugilan Poongkunran M.B.B.S [2]

Overview

The antiatherogenic actions of HDL-C through reverse cholesterol transport and the cardioprotective effect through endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects has been the basis trials to increase HDL and to determine prognosis. High-density lipoprotein (HDL) cholesterol levels are inversely related to risk for coronary artery disease (CAD), but because HDL particles are heterogeneous in size and composition, they may be differentially associated with other cardiovascular risk factors and with cardiovascular risk.

Prognosis and Complications

Coronary Heart Disease

Cardio Protective Effect

The mature spherical HDL particle is composed of enzymes, such as paraoxonase, platelet-activating factor acetylhydrolase (PAF-AH or Lp-PLA2), lecithin-cholesterol acyl transferase (LCAT), apolipoproteins (apoA-I and apoA-II), lipid molecules, such as triglyceride, cholesterol, phospholipids and bioactive lipid molecules, including sphingosine 1-phosphate (S1P) and related lysosphingolipids.[1] The antiatherogenic actions of HDL-C are complex and are mediated through the some of the aforementioned components. HDL-C plays a major role in reverse cholesterol transport, mobilizing cholesterol from the periphery to the liver. In addition, cardioprotective effects of HDL-C include endothelial protection, anti-inflammatory activity, as well as antioxidant and antithrombotic effects and maintenance of low blood viscosity through a permissive action on red cell deformability.

  • Apo A-I :
    • Several studies have shown that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. Macrophage cholesterol efflux is a process whereby excess cholesterol in cells and in atherosclerotic plaques is removed. Current data indicate that the plasma HDL associated apolipoprotein M (apoM) levels modulate the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.[2]
    • Animal models have shown that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis or its role in the anti-endotoxin function of HDL.[3][4][5][6]
    • Current data suggest that, ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in endothelial cells, and the scavenger receptor B type 1 mediate multiple intracellular signaling pathways as well as the efflux of cholesterol and/or oxysterols in response to apoA-I/HDL.[7]
  • ApoA-I/SR-BI :
    • HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling.[8] Recent studies have shown that SR-BI is also expressed in endothelial cells (ECs) and mediates HDL-associated apoA-I-induced stimulation of endothelial nitric oxide synthase (eNOS), inhibition of monocyte adhesion to endothelial cells, vasorelaxation, and re-endothelialization following perivascular electric injury.[9][10][11]
    • It is also proposed that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation, thus contributing to the atheroprotective functions.[12]
    • HDL promotes the production of signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). Studies have shown the ability of recombiant HDL (rHDL) or reconstituted apoA-I with phospholipids but without cholesterol to stimulate eNOS activation and to repair damaged endothelium and to enhance ischemia-induced angiogenesis through stimulation of endothelial progenitor cells (EPCs) in vivo.[13][14] The enhancement of SR-BI expression by simvastatin results in enhancement of HDL- and rHDL-induced eNOS activation and subsequent inhibition of adhesion molecule expression, which supports the role of SR-BI in HDL-induced anti-inflammatory actions.[15]
  • Sphingosine 1-phosphate (S1P) :
    • Fractionation by density gradient centrifugation has shown that sphingosine 1-phosphate (S1P) is concentrated in the lipoprotein fraction with a rank order of HDL > LDL > VLDL, and to a lesser extent, in the lipoprotein-deficient albumin fraction when expressed as pmol/mg protein. Thus, HDL-S1P has been proposed to mediate a variety of HDL-induced actions.[16]
    • S1P has been shown to improve ischemia/reperfusion-induced injury in vivo and in vitro with inhibition of inflammatory neutrophil recruitment and cardiomyocyte apoptosis in the infarcted area.[17][18][19]
    • The pro-atherogenic adhesion molecule expression elicited by S1P disappears in the presence of physiological concentrations of HDL in a manner sensitive to SR-BI.[20]
  • Paraoxonase 1 (PON1) :
    • Paraoxonase is an esterase enzyme that is synthesized by the liver and it is associated with HDL in the blood. There is considerable evidence to prove the fact that the antioxidant activity of HDL is largely due to the PON1 which is located on it.[21] A atorvastatin study demonstrating HDL-related antioxidant activity as well as lipid-lowering properties proves PON1 action of prevents LDL oxidation and inactivates LDL-derived oxidized phospholipids.[22]
    • Studies have suggested that serum antioxidant activity of PON1 was an important factor which provided protection from oxidative stress and lipid peroxidation in CAD.[23] Thus, evaluating the effects of PON 1 for CAD patients may be promising in the treatment and prognosis of CAD.
    • Studies have shown pomegranate to be a potent anti-atherogenic agent because of its antioxidants which have the ability to increase the activity of the HDL-associated paraoxonase 1 (PON1), which breaks down harmful oxidized lipids in lipoproteins, in macrophages, and in atherosclerotic plaques.[24]
  • Indirect cardioprotective actions :
    • It includes, HDL capacities to promote pancreatic β-cell insulin secretion, to protect pancreatic β cells from apoptosis, and to enhance glucose uptake by skeletal muscle myocytes. Studies have shown that inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with LDL was restored by co-treatment with HDL.[25]
    • In vascular smooth muscles, HDL tempers proinflammatory, promigratory, and degradative processes, and through actions on endothelium and platelets HDL is antithrombotic. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis.[26]
    • Furthermore, HDL decreases white adipose tissue mass, increases energy expenditure, and promotes the production of adipose-derived cytokine adiponectin that has its own vascular-protective properties.[27]

Many of these numerous actions of HDL have been observed not only in cell culture and animal models but also in human studies, and assessments of these functions are now being applied to patient populations to better-elucidate which actions of HDL may contribute to its cardioprotective potential and how they can be quantified and targeted. Further work on the many mechanisms of HDL action promises to reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health. Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risk.[28][29] This negative association that is strong, graded, and coherent across population studied, has led to the development of the “HDL-C hypothesis,” which proposes that pharmacological intervention to raise HDL-C will reduce cardiovascular risk.

Recently studies have found that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease. Some of the trials are :

  • VA-HIT trial : The VA-HIT trial on 2531 with CHD who had an LDL-cholesterol (≤140 mg/dL or 3.6 mmol/L), an HDL-cholesterol (≤40 mg/dL or 1.0 mmol/L), and triglycerides ≤300 mg/dL (3.4 mmol/L), showed that cardiac death and nonfatal myocardial infarction occurred less often in the gemfibrozil treated group and strongly correlated with the serum HDL-cholesterol concentration achieved with gemfibrozil therapy, but was independent of changes in LDL-cholesterol or triglycerides.[30]
  • Trial of simvastatin plus niacin : In this study patients receiving simvastatin plus niacin were significantly less likely to sustain a cardiovascular event such as cardiac death, myocardial infarction or revascularization and experienced angiographic regression of the most significant coronary stenosis.[31]
  • AIM-HIGH trial : A randomized trial comparing-extended release niacin (target dose 2000 mg per day) with placebo (100 to 200 mg of immediate release niacin) in 3414 patients with cardiovascular disease though increased levels of HDL-C and lowered levels of triglycerides and LDL-C was stopped early for futility after a mean follow-up of three years.[32]
  • ARBITER 2 study : A randomized trial that examined the effects of extended-release niacin 1000 mg daily in 167 patients with known CHD and an HDL-cholesterol concentration below 45 mg/dL who were already receiving a statin showed patients treated with niacin experienced a mean increase in HDL-cholesterol of 8 mg/dL (0.21 mmol/L) and had a trend toward decreased progression of carotid intima-media thickness.[33]
  • Infusion of apo A-I Milano : A pilot trial of intravenous therapy with recombinant apo A-1 Milano phospholipid complexes (ETC-216) was conducted in 57 patients who were within two weeks of onset of an acute coronary syndrome and showed a significant decrease in the mean percentage of coronary artery volume occupied by atheroma.[34]
  • Infusion of reconstituted HDL : The ERASE trial on 183 CHD patients with reconstituted human HDL estimating the coronary atheroma volume was associated with a high incidence of liver function test abnormalities, which led to early study discontinuation in this group.[35]
  • Theobromine study : Theobromine, as found in cocoa, has been associated with an increase in HDL-C and has been associated with a decreased risk of cardiovascular disease in observational studies.[36][37]
  • CETP inhibition : Torcetrapib, anacetrapib, evacetrapib, and dalcetrapib inhibit cholesteryl ester transfer protein (CETP) and raise HDL-cholesterol levels. Though investigation of torcetrapib and dalcetrapib has stopped due to the finding of an increased risk of cardiovascular events in the ILLUMINATE trial and dal-OUTCOMES, Anacetrapib in the DEFINE study has shown to increase HDL, but the overall safety in CHD is yet to be proved.[38]

Current Trends

HDL-P as an alternative to HDL-C
  • Few studies have evaluated HDL-P associations with CHD risk, and we know of none that evaluated it jointly with HDL-C and LDL-P.
    • Multi-Ethnic Study of Atherosclerosis (MESA) study on multi-ethnic men and women without clinical CVD or lipid-lowering medication use at baseline showed HDL-C (cholestrol content of HDL) associations with carotid intima-media thickness (cIMT) and its CHD incidence to be substantially attenuated by adjusting for atherogenic lipoproteins, particularly LDL-P. In contrast, HDL-P (particle concentrations) associations with cIMT and incident CHD were relatively unaffected by adjusting for atherogenic lipoproteins, HDL-C, and mean HDL particle size.[39]
    • Multiple Risk Factor Intervention Trial (MRFIT) : Low HDL-P levels predicted CHD death over 18 years of follow-up among men with metabolic syndrome in the MRFIT cohort. In the MRFIT, high levels of HDL-P and especially medium HDL-P were associated with a reduced risk of CHD[40]
    • EPIC-Norfolk Study : In this study lower HDL-P levels predicted incident events independent of age, sex, apoB, triglycerides, mean HDL particle size, smoking, myeloperoxidase, paraoxonase-1, and hsCRP.[41]
    • VA-HIT Study : In this study lower levels of baseline and on-trial HDL-P predicted CHD events among men with low HDL-C randomized to gemfibrozil vs. placebo.[42]
    • Women’s Health Study : This large study showed the inverse association of HDL-P with incident CVD over an 11 year follow-up was not significant.[43] However, HDL-P was inversely associated with incident CHD among postmenopausal women in the Women’s Health Initiative Hormone Trial, adjusted for treatment arm, and the inverse association of HDL-P with cIMT was statistically significant for women in the current study.[44]
Challenging HDL-C hypothesis
  • The theory of HDL-C levels to predict CVD risk has been challenged in clinical trials where LDL-C has reached a very low level. The recent failure of the large the following trials raised questions about the benefits of this therapeutic strategy to raise HDL.[45]
    • In the ILLUMINATE study adverse events caused by torcetrapib were likely to represent off-target effects of the drug but raised question about the value of raising HDL-C. Attempts to decrease cardiovascular risk in statin-treated patients with the CETP inhibitor torcetrapib have failed, despite an increase in HDL-C by 72%. The failure of torcetrapib and dalcetrapib may be explained by off-target adverse effects and weak CETP inhibition, respectively.[46]
    • The dal-OUTCOMES trial using dalcetrapib raised HDL-C by 31 to 40% but had no effects on cardiovascular events.[47]
    • Niacin, used at pharmacological doses (up to 2gm/day), led to a neutrality of results in terms of cardiovascular outcomes in the AIM-HIGM. This study was also criticized for having a relatively small sample size.[32]
    • The recent failure of the large (>25,000 subjects) HPS2-THRIVE trial with niacin raised questions about the benefits of this therapeutic strategy to raise HDL..[48]

Attention is focusing on specific HDL subfractions and on biomarkers of HDL function (reflecting its pleiotropic effects) as potential therapeutic targets for cardiovascular protection. Such studies have reinforced the need for validated assays of HDL function rather than static measurement of HDL-C. A variety of HDL/apoA-I-based therapies are currently under investigation. To better understand the relation between HDL and atherosclerosis, we should consider developing and measuring better markers of HDL function, rather than the cholesterol mass within HDL particles.

References

  1. ↑ Scanu AM, Edelstein C (2008). "HDL: bridging past and present with a look at the future". FASEB J. 22 (12): 4044–54. doi:10.1096/fj.08-117150. PMC 2614615. PMID 18716026.
  2. ↑ Elsøe S, Christoffersen C, Luchoomun J, Turner S, Nielsen LB (2013). "Apolipoprotein M promotes mobilization of cellular cholesterol in vivo". Biochim Biophys Acta. 1831 (7): 1287–92. PMID 24046869.
  3. ↑ Benoit P, Emmanuel F, Caillaud JM, Bassinet L, Castro G, Gallix P; et al. (1999). "Somatic gene transfer of human ApoA-I inhibits atherosclerosis progression in mouse models". Circulation. 99 (1): 105–10. PMID 9884386.
  4. ↑ 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.
  5. ↑ Navab M, Anantharamaiah GM, Hama S, Garber DW, Chaddha M, Hough G; et al. (2002). "Oral administration of an Apo A-I mimetic Peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol". Circulation. 105 (3): 290–2. PMID 11804981.
  6. ↑ Ma J, Liao XL, Lou B, Wu MP (2004). "Role of apolipoprotein A-I in protecting against endotoxin toxicity". Acta Biochim Biophys Sin (Shanghai). 36 (6): 419–24. PMID 15188057.
  7. ↑ Prosser HC, Ng MK, Bursill CA (2012). "The role of cholesterol efflux in mechanisms of endothelial protection by HDL". Curr Opin Lipidol. 23 (3): 182–9. doi:10.1097/MOL.0b013e328352c4dd. PMID 22488423.
  8. ↑ Saddar S, Mineo C, Shaul PW (2010). "Signaling by the high-affinity HDL receptor scavenger receptor B type I." Arterioscler Thromb Vasc Biol. 30 (2): 144–50. doi:10.1161/ATVBAHA.109.196170. PMID 20089950.
  9. ↑ Okajima F, Sato K, Kimura T (2009). "Anti-atherogenic actions of high-density lipoprotein through sphingosine 1-phosphate receptors and scavenger receptor class B type I." Endocr J. 56 (3): 317–34. PMID 18753704.
  10. ↑ Mineo C, Shaul PW (2007). "Role of high-density lipoprotein and scavenger receptor B type I in the promotion of endothelial repair". Trends Cardiovasc Med. 17 (5): 156–61. doi:10.1016/j.tcm.2007.03.005. PMID 17574123.
  11. ↑ Kimura T, Sato K, Tomura H, Okajima F (2010). "Cross-talk between exogenous statins and endogenous high-density lipoprotein in anti-inflammatory and anti-atherogenic actions". Endocr Metab Immune Disord Drug Targets. 10 (1): 8–15. PMID 20105136.
  12. ↑ Radojkovic C, Genoux A, Pons V, Combes G, de Jonge H, Champagne E; et al. (2009). "Stimulation of cell surface F1-ATPase activity by apolipoprotein A-I inhibits endothelial cell apoptosis and promotes proliferation". Arterioscler Thromb Vasc Biol. 29 (7): 1125–30. doi:10.1161/ATVBAHA.109.187997. PMID 19372457.
  13. ↑ Tso C, Martinic G, Fan WH, Rogers C, Rye KA, Barter PJ (2006). "High-density lipoproteins enhance progenitor-mediated endothelium repair in mice". Arterioscler Thromb Vasc Biol. 26 (5): 1144–9. doi:10.1161/01.ATV.0000216600.37436.cf. PMID 16528007.
  14. ↑ Sumi M, Sata M, Miura S, Rye KA, Toya N, Kanaoka Y; et al. (2007). "Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis". Arterioscler Thromb Vasc Biol. 27 (4): 813–8. doi:10.1161/01.ATV.0000259299.38843.64. PMID 17272742.
  15. ↑ Kimura T, Mogi C, Tomura H, Kuwabara A, Im DS, Sato K; et al. (2008). "Induction of scavenger receptor class B type I is critical for simvastatin enhancement of high-density lipoprotein-induced anti-inflammatory actions in endothelial cells". J Immunol. 181 (10): 7332–40. PMID 18981156.
  16. ↑ Murata N, Sato K, Kon J, Tomura H, Yanagita M, Kuwabara A; et al. (2000). "Interaction of sphingosine 1-phosphate with plasma components, including lipoproteins, regulates the lipid receptor-mediated actions". Biochem J. 352 Pt 3: 809–15. PMC 1221521. PMID 11104690.
  17. ↑ Jin ZQ, Zhou HZ, Zhu P, Honbo N, Mochly-Rosen D, Messing RO; et al. (2002). "Cardioprotection mediated by sphingosine-1-phosphate and ganglioside GM-1 in wild-type and PKC epsilon knockout mouse hearts". Am J Physiol Heart Circ Physiol. 282 (6): H1970–7. doi:10.1152/ajpheart.01029.2001. PMID 12003800.
  18. ↑ Karliner JS (2009). "Sphingosine kinase and sphingosine 1-phosphate in cardioprotection". J Cardiovasc Pharmacol. 53 (3): 189–97. doi:10.1097/FJC.0b013e3181926706. PMC 2835544. PMID 19247197.
  19. ↑ Theilmeier G, Schmidt C, Herrmann J, Keul P, Schäfers M, Herrgott I; et al. (2006). "High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor". Circulation. 114 (13): 1403–9. doi:10.1161/CIRCULATIONAHA.105.607135. PMID 16982942.
  20. ↑ Kimura T, Tomura H, Mogi C, Kuwabara A, Damirin A, Ishizuka T; et al. (2006). "Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells". J Biol Chem. 281 (49): 37457–67. doi:10.1074/jbc.M605823200. PMID 17046831.
  21. ↑ Huang Y, Wu Z, Riwanto M, Gao S, Levison BS, Gu X; et al. (2013). "Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex". J Clin Invest. 123 (9): 3815–28. doi:10.1172/JCI67478. PMC 3754253. PMID 23908111.
  22. ↑ Sozer V, Uzun H, Gelisgen R, Kaya M, Kalayci R, Tabak O; et al. (2013). "The effects of atorvastatin on oxidative stress in L-NAME-treated rats". Scand J Clin Lab Invest. doi:10.3109/00365513.2013.828241. PMID 24024670.
  23. ↑ Shekhanawar M, Shekhanawar SM, Krisnaswamy D, Indumati V, Satishkumar D, Vijay V; et al. (2013). "The role of 'paraoxonase-1 activity' as an antioxidant in coronary artery diseases". J Clin Diagn Res. 7 (7): 1284–7. doi:10.7860/JCDR/2013/5144.3118. PMC 3749616. PMID 23998046.
  24. ↑ Aviram M, Rosenblat M (2013). "Pomegranate for your cardiovascular health". Rambam Maimonides Med J. 4 (2): e0013. doi:10.5041/RMMJ.10113. PMC 3678830. PMID 23908863.
  25. ↑ Carey AL, Siebel AL, Reddy-Luthmoodoo M, Natoli AK, D'Souza W, Meikle PJ; et al. (2013). "Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein". PLoS One. 8 (2): e56601. doi:10.1371/journal.pone.0056601. PMC 3578940. PMID 23437184.
  26. ↑ Mineo C, Deguchi H, Griffin JH, Shaul PW (2006). "Endothelial and antithrombotic actions of HDL". Circ Res. 98 (11): 1352–64. doi:10.1161/01.RES.0000225982.01988.93. PMID 16763172.
  27. ↑ Mineo C, Shaul PW (2012). "Novel biological functions of high-density lipoprotein cholesterol". Circ Res. 111 (8): 1079–90. doi:10.1161/CIRCRESAHA.111.258673. PMC 3500606. PMID 23023510.
  28. ↑ 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.
  29. ↑ 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
  30. ↑ Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ; et al. (2001). "Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT: a randomized controlled trial". JAMA. 285 (12): 1585–91. PMID 11268266.
  31. ↑ Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS; et al. (2001). "Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease". N Engl J Med. 345 (22): 1583–92. doi:10.1056/NEJMoa011090. PMID 11757504.
  32. ↑ 32.0 32.1 AIM-HIGH Investigators. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P; et al. (2011). "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy". N Engl J Med. 365 (24): 2255–67. doi:10.1056/NEJMoa1107579. PMID 22085343. Review in: Ann Intern Med. 2012 Apr 17;156(8):JC4-08
  33. ↑ Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA (2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins". Circulation. 110 (23): 3512–7. doi:10.1161/01.CIR.0000148955.19792.8D. PMID 15537681.
  34. ↑ Ameli S, Hultgardh-Nilsson A, Cercek B, Shah PK, Forrester JS, Ageland H; et al. (1994). "Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits". Circulation. 90 (4): 1935–41. PMID 7923682.
  35. ↑ Tardif JC, Grégoire J, L'Allier PL, Ibrahim R, Lespérance J, Heinonen TM; et al. (2007). "Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial". JAMA. 297 (15): 1675–82. doi:10.1001/jama.297.15.jpc70004. PMID 17387133.
  36. ↑ Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, Kido T; et al. (2007). "Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans". Am J Clin Nutr. 85 (3): 709–17. PMID 17344491.
  37. ↑ Neufingerl N, Zebregs YE, Schuring EA, Trautwein EA (2013). "Effect of cocoa and theobromine consumption on serum HDL-cholesterol concentrations: a randomized controlled trial". Am J Clin Nutr. 97 (6): 1201–9. doi:10.3945/ajcn.112.047373. PMID 23595874.
  38. ↑ Cannon CP, Shah S, Dansky HM, Davidson M, Brinton EA, Gotto AM; et al. (2010). "Safety of anacetrapib in patients with or at high risk for coronary heart disease". N Engl J Med. 363 (25): 2406–15. doi:10.1056/NEJMoa1009744. PMID 21082868.
  39. ↑ 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. PMC 3411890. PMID 22796256.
  40. ↑ Kuller LH, Grandits G, Cohen JD, Neaton JD, Prineas R, Multiple Risk Factor Intervention Trial Research Group (2007). "Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome". Atherosclerosis. 195 (1): 122–8. doi:10.1016/j.atherosclerosis.2006.09.001. PMC 2098784. PMID 17011566.
  41. ↑ El Harchaoui K, Arsenault BJ, Franssen R, Després JP, Hovingh GK, Stroes ES; et al. (2009). "High-density lipoprotein particle size and concentration and coronary risk". Ann Intern Med. 150 (2): 84–93. PMID 19153411.
  42. ↑ Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ, McNamara JR; et al. (2006). "Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial". Circulation. 113 (12): 1556–63. doi:10.1161/CIRCULATIONAHA.105.565135. PMID 16534013.
  43. ↑ Mora S, Otvos JD, Rifai N, Rosenson RS, Buring JE, Ridker PM (2009). "Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women". Circulation. 119 (7): 931–9. doi:10.1161/CIRCULATIONAHA.108.816181. PMC 2663974. PMID 19204302.
  44. ↑ Hsia J, Otvos JD, Rossouw JE, Wu L, Wassertheil-Smoller S, Hendrix SL; et al. (2008). "Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials". Arterioscler Thromb Vasc Biol. 28 (9): 1666–71. doi:10.1161/ATVBAHA.108.170431. PMC 2701372. PMID 18599797.
  45. ↑ Cook C, Sheets C (2011). "Clinical equipoise and personal equipoise: two necessary ingredients for reducing bias in manual therapy trials". J Man Manip Ther. 19 (1): 55–7. doi:10.1179/106698111X12899036752014. PMC 3172958. PMID 22294855.
  46. ↑ Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M; et al. (2007). "Effects of torcetrapib in patients at high risk for coronary events". N Engl J Med. 357 (21): 2109–22. doi:10.1056/NEJMoa0706628. PMID 17984165.
  47. ↑ Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J; et al. (2012). "Effects of dalcetrapib in patients with a recent acute coronary syndrome". N Engl J Med. 367 (22): 2089–99. doi:10.1056/NEJMoa1206797. PMID 23126252.
  48. ↑ HPS2-THRIVE Collaborative Group (2013). "HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment". Eur Heart J. 34 (17): 1279–91. doi:10.1093/eurheartj/eht055. PMC 3640201. PMID 23444397.


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