- Email: [email protected]
HDL: Quality or quantity?
Atherosclerosis 243 (2015) 121e123
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Discussion
HDL: Quality or quantity? Carlos G. Santos-Gallego AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, 1428 Madison Avenue, Atran Building, 6th Floor, Room 6.20, USA
a r t i c l e i n f o Article history: Received 18 August 2015 Accepted 19 August 2015 Available online 29 August 2015 Keywords: High density lipoprotein Atherosclerosis Coronary artery disease Cardiovascular risk Prognostic factor
In the last six decades, high density lipoproteins (HDL) have been extensively considered to reduce the risk for coronary artery disease (CAD); in fact, the cholesterol carried by HDL (HDL-C) has earned the moniker of “good cholesterol” [1]. This fact is of critical significance because the first cause of death in Western countries is CAD caused by atherosclerosis, a chronic inflammatory disease of the arterial wall, arising from an imbalance in lipid metabolism and a maladaptive inflammatory response [2]. However, several recent lines of evidence cast a shadow on the role of HDL-C as a relevant therapeutic target (see later). The conclusion remains that there are critical gaps in knowledge in the area of HDL. In this issue of Atherosclerosis, Izuhara et al. [3] add another piece to the puzzle of this relationship. The proposition that HDL protects against CAD is based on several robust and consistent observations: i) numerous human population studies have shown that the HDL-C concentrations are independent, inverse predictors of the risk of suffering future CAD events (for a detailed summary, see [1]); ii) mechanistically, HDL have several well-documented functions with the potential to protect against CAD [1,4] (cholesterol efflux contributing to reverse cholesterol transport is the best characterized effect, but HDL also exerts anti-inflammatory, antiapoptotic, vasorelaxant, and endothelial-protective properties); iii) interventions increasing HDL abrogate the development and progression of atherosclerosis
E-mail addresses: [email protected], [email protected]. http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.027 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
in several animal models [5,6]; and iv) in proof-of-concept studies in humans, intravenous infusions of reconstituted HDL promote regression of coronary atheroma [7]. Nevertheless, the hypothesis that raising HDL-C levels will result in reduced CAD risk has never been factually proven. In fact, four modern observations have questioned HDL-C as relevant therapeutic target: i) some genetic variants that raise plasma HDL-C concentrations are not associated with a proportionally lower risk of CAD events [8]; ii) a sub-analysis of JUPITER trial revealed that high HDL-C levels were associated with reduced risk of CAD events only among patients in the placebo arm, but that this association was lost among people on rosuvastatin 20 mg achieving very low LDL-C [9]; iii) population studies [10] and a meta-analysis [11] have suggested that changes in HDL-C levels after initiation of lipidmodifying therapy are not independently associated with CAD risk; and iv) recent clinical trials have shown that HDL-C-raising pharmacological therapies such as niacin (in the AIM-HIGH [12] and HPS2-THRIVE [13] clinical trials) do not reduce CAD events. We have previously formulated a comprehensive hypothesis that explains this paradox [1]. We want the reader to consider the following three specific facts. First, there is a crucial distinction between HDL-C (ie. the amount of cholesterol carried by the HDL) and the HDL particle (HDL-P, the individual molecule containing proteins and lipidsenot only cholesterol esters but also other types of lipids such as sphingosine-1-phosphate or S1P-). The levels of HDL-C do not necessarily reflect the concentration of HDL-P because HDL-P can be fully or only partially loaded with cholesterol. Second, only 5% of the total HDL-C is derived from actual macrophage cholesterol efflux, thus the amount of HDL-C is a poor surrogate of reverse cholesterol transport, the postulated main antiatherogenic effect of HDL. Third, the cholesterol content of HDL does not represent many important antiatherogenic HDL properties (eg. anti-inflammatory or vasorelaxant). Therefore, we conclude that HDL-C is an insensitive method to quantify the beneficial antiatherosclerotic properties of HDL. In fact, HDL-C (a static massbased measurement) cannot represent a dynamic functional process such as reverse cholesterol transport (or the antiinflammatory, anti-apoptotic, and anti-oxidant effects of HDL). As a corollary, we should focus on validated HDL functions (HDL “quality”) that truly reflect and are responsible for the actual beneficial effects of HDL [1] rather than on HDL-C levels (HDL-C “quantitity”).
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C.G. Santos-Gallego / Atherosclerosis 243 (2015) 121e123
Methods for assessment of HDL functions are available [14] (although they may not be readily applicable in the everyday clinical practice). For instance, a new method for quantifying cholesterol efflux from macrophages has been recently discovered [15]. The recent report that cholesterol efflux assessed by this method predicts both CAD severity [15] and CAD events [16] while HDL-C did not [16] confirms our hypothesis that HDL function (quality) is more important than HDL-C levels (quantity). However, HDL loses its beneficial properties in certain pathological situations, specifically in acute situations such as acute infections [17] or chronic conditions such as CAD [18], which has been termed “dysfunctional HDL” [1]. Oxidation of the HDL particle has been demonstrated as one of the main causes of HDL dysfunction. Circulating HDL swiftly diffuses into the artery wall and into the atherosclerotic lesions, where leukocyte myeloperoxidase oxidizes the residue Trp72 of the apoA-I helix [19]; this oxidation causes a cross-linking of apoA-I molecules and a subsequent conformational change of the HDL particle, which becomes both pro-inflammatory and with reduced ability to promote cholesterol efflux or vasodilatation [19]. A second mechanism of HDL dysfunction involving S1P has been recently described [20,21]; in fact, S1P has been recently discovered to be both a mechanistic cause and a therapeutic target for HDL dysfunction. CAD patients exhibited lower HDL-bound S1P than healthy volunteers, while CAD-HDL was found dysfunctional as demonstrated by lower activation of endothelial signaling and inducing less vasodilatation. HDL could be S1P-loaded both in vivo and in vitro with a novel method, coincubation with S1P-loaded erythrocytes. This S1P loading greatly improved both HDL-induced endothelial molecular signaling and HDL-triggered vasodilatory potential. The important feature is that CAD-HDL could be loaded with S1P equally effective as healthy HDL, which completely corrected the defects inherent to dysfunctional HDL [20]. The fact that the measurement of HDL-C neglects the quantification of S1P (and the central role of S1P in HDL functionality) confirms our hypothesis that HDL function is not properly assessed by HDL-C concentrations. As most of the beneficial effects of HDL (both cholesterol efflux and the pleiotropic actions) are carried out by the HDL particles (independently of the cholesterol content of HDL), we want to highlight that the concentration of HDL-P is a better surrogate of HDL function than HDL-C. In the MESA trial HDL-C was not associated with atherosclerosis burden after adjusting for HDL-P, but low HDL-P predicted atherosclerosis burden regardless of HDL-C level [22]. Also, in the VA-HIT trial, the concentration of small HDL-P (the functionally more active HDL particles, also not surprisingly carrying the higher concentration of S1P) predicted risk of future CAD events independently of HDL-C levels [23]. This novel postulated theory allows to explain the four recent lines of evidence questioning the relevance of HDL-C as a relevant therapeutic target that we previously explained; 1) Problem: Genetic variants in the endothelial lipase gene that raise plasma HDL-C concentrations are not associated with a proportionally lower risk of myocardial infarction [8]. Possible explanation: Mutations resulting in reduced endothelial lipase activity only increase HDL-C without actually increasing HDL-P or HDL function, which does not translate into reduced CAD risk [8]. On the contrary, the mutations resulting in reduced phospholipid transfer protein activity translate into reduced CAD risk [24] because they result in increased number of HDL-P and enhanced HDL functionality. 2) Problem: A sub-analysis of JUPITER trial revealed that high HDL-C levels were associated with reduced risk of CAD events only among patients in the placebo arm. This beneficial
association was lost among people on rosuvastatin 20 mg achieving very low LDL-C [9]. Possible explanation: HDL-C is not a sensitive enough surrogate of HDL function. A recent analysis of the JUPITER trial has shown that, even though HDL-C did not predict CAD risk in statin-treated patients, HDL-P (a more accurate surrogate of HDL functionality) did predict CAD risk in all patients (both placebo and statin-treated) and even after adjusting for HDL-C levels [25]. 3) Problem: A recent meta-analysis and population studies suggest that changes in HDL-C levels after initiation of lipidmodifying therapy are not independently associated with CAD risk [10,11]. Possible explanation: As previously discussed, HDL-C levels (or the change in them) may not be the proper parameter to assess adequately the contribution of HDL to CAD risk. Unfortunately, neither the meta-analysis [11] nor the population studies [10] measured HDL functionality or HDL-P concentrations. 4) Problem: Recent clinical trials have shown that HDL-C-raising pharmacological therapies such as niacin (in the AIM-HIGH [12] and HPS2-THRIVE [13] clinical trials) do not reduce CAD events. Possible explanation: Strategies that increase HDL-C without enhancing HDL function or expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. Despite increasing HDL-C levels, niacin does not increase neither HDL functionality (cholesterol efflux or anti-inflammatory properties) [26] nor the HDL-P concentrations [27]. Therefore the HDL-C levels increased by niacin seem not to be functionally ideal for the treatment of CAD. It is in this context where we should place the very interesting study of Izuhara et al. [3]. The authors should be praised for shedding more light into this interesting but yet obscure topic of HDL and CAD risk, and also for their extensive study, large sample size achieved and the use of rigorous and solid methodology. The authors retrospectively evaluate 10,391 CAD patients undergoing PCI in 2005e2007. Those patients with low HDL-C had a higher unadjusted 5-year incidence of CAD events than patients with normal HDL-C; however, low HDL-C patients also exhibited more comorbidities (they were older and more obese, with higher incidence of smokers, diabetes, renal failure, heart failure, atrial fibrillation, multivessel CAD, previous MI or previous stroke). Thus, after adjusting for confounders, low HDL-C was not associated with a higher risk of CAD events. This interesting study by Izuhara et al., [3] actually confirms the previously explained hypothesis of HDL functionality being more relevant regarding prediction and therapy than HDL-C concentration, or briefly the hypothesis that HDL function is more relevant than HDL-C quantity. Higher HDL-C levels were not associated in this article [3] with lower CAD events in patients who underwent PCI; however, as CAD induces HDL dysfunction, it is safe to assume that all those PCI patients displayed dysfunctional HDL, and thus HDL function (not assessed by the authors) would be a much more sensitive predictor of future CAD risk than HDL-C levels. Therefore, we should focus on the evaluation (at the clinical level) and therapeutic improvement (at the research level) of HDL quality (HDL functionality) while not paying so much attention to HDL-C quantity (HDL-C concentrations). References [1] C.G. Santos-Gallego, J.J. Badimon, R.S. Rosenson, Beginning to understand high-density lipoproteins, Endocrinol. Metab. Clin. North Am. 43 (4) (2014) 913e947.
C.G. Santos-Gallego / Atherosclerosis 243 (2015) 121e123 [2] C.G. Santos-Gallego, B. Picatoste, J.J. Badimon, Pathophysiology of acute coronary syndrome, Curr. Atheroscler. Rep. 16 (4) (2014) 401. [3] M. Izuhara, K. Ono, H. Shiomi, T. Morimoto, Y. Furukawa, Y. Nakagawa, S. Shizuta, T. Tada, J. Tazaki, T. Horie, Y. Kuwabara, O. Baba, T. Nishino, T. Kita, T. Kimura, High-density lipoprotein cholesterol levels and cardiovascular outcomes in Japanese patients after percutaneous coronary intervention: a report from the CREDO-Kyoto registry cohort-2, Atherosclerosis (19 May 2015) pii: S0021-9150(15)01311-8, http://dx.doi.org/10.1016/j. atherosclerosis.2015.05.010 [Epub ahead of print]. [4] C.G. Santos-Gallego, B. Ibanez, J.J. Badimon, HDL-cholesterol: is it really good? Differences between apoA-I and HDL, Biochem. Pharmacol. 76 (4) (2008) 443e452. [5] J.J. Badimon, L. Badimon, V. Fuster, Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit, J. Clin. Invest. 85 (4) (1990) 1234e1241. [6] E.M. Rubin, R.M. Krauss, E.A. Spangler, J.G. Verstuyft, S.M. Clift, Inhibition of early atherogenesis in transgenic mice by human apolipoprotein AI, Nature 353 (6341) (1991) 265e267. [7] S.E. Nissen, T. Tsunoda, E.M. Tuzcu, P. Schoenhagen, C.J. Cooper, M. Yasin, G.M. Eaton, M.A. Lauer, W.S. Sheldon, C.L. Grines, S. Halpern, T. Crowe, J.C. Blankenship, R. Kerensky, Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial, JAMA 290 (17) (2003) 2292e2300. [8] B.F. Voight, G.M. Peloso, M. Orho-Melander, R. Frikke-Schmidt, M. Barbalic, M.K. Jensen, G. Hindy, H. Holm, E.L. Ding, T. Johnson, H. Schunkert, N.J. Samani, R. Clarke, J.C. Hopewell, J.F. Thompson, M. Li, G. Thorleifsson, C. Newton-Cheh, K. Musunuru, J.P. Pirruccello, D. Saleheen, L. Chen, A. Stewart, A. Schillert, U. Thorsteinsdottir, G. Thorgeirsson, S. Anand, J.C. Engert, T. Morgan, J. Spertus, M. Stoll, K. Berger, N. Martinelli, D. Girelli, P.P. McKeown, C.C. Patterson, S.E. Epstein, J. Devaney, M.S. Burnett, V. Mooser, S. Ripatti, I. Surakka, M.S. Nieminen, J. Sinisalo, M.L. Lokki, M. Perola, A. Havulinna, U. de Faire, B. Gigante, E. Ingelsson, T. Zeller, P. Wild, P.I. de Bakker, O.H. Klungel, A.H. Maitland-van der Zee, B.J. Peters, A. de Boer, D.E. Grobbee, P.W. Kamphuisen, V.H. Deneer, C.C. Elbers, N.C. Onland-Moret, M.H. Hofker, C. Wijmenga, W.M. Verschuren, J.M. Boer, Y.T. van der Schouw, A. Rasheed, P. Frossard, S. Demissie, C. Willer, J.M. Do R, Ordovas, G.R. Abecasis, M. Boehnke, K.L. Mohlke, M.J. Daly, C. Guiducci, N.P. Burtt, A. Surti, E. Gonzalez, S. Purcell, S. Gabriel, J. Marrugat, J. Peden, J. Erdmann, P. Diemert, C. Willenborg, I.R. Konig, M. Fischer, C. Hengstenberg, A. Ziegler, I. Buysschaert, D. Lambrechts, F. Van de Werf, K.A. Fox, N.E. El Mokhtari, D. Rubin, J. Schrezenmeir, S. Schreiber, A. Schafer, J. Danesh, S. Blankenberg, R. Roberts, R. McPherson, H. Watkins, A.S. Hall, K. Overvad, E. Rimm, E. Boerwinkle, A. Tybjaerg-Hansen, L.A. Cupples, M.P. Reilly, O. Melander, P.M. Mannucci, D. Ardissino, D. Siscovick, R. Elosua, K. Stefansson, C.J. O'Donnell, V. Salomaa, D.J. Rader, L. Peltonen, S.M. Schwartz, D. Altshuler, S. Kathiresan, Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study, Lancet 380 (9841) (2012) 572e580. [9] P.M. Ridker, J. Genest, S.M. Boekholdt, P. Libby, A.M. Gotto, B.G. Nordestgaard, S. Mora, J.G. MacFadyen, R.J. Glynn, J.J. Kastelein, HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial, Lancet 376 (9738) (2010) 333e339. [10] K. Ray, N.W. Wainwright, L. Visser, J. Witteman, M. Breteler, B. Ambegaonkar, A. Hofman, B. Stricker, N. Wareham, K.T. Khaw, M. Sandhu, Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy, Heart 98 (10) (2012) 780e785. [11] M. Briel, I. Ferreira-Gonzalez, J.J. You, P.J. Karanicolas, E.A. Akl, P. Wu, B. Blechacz, D. Bassler, X. Wei, A. Sharman, I. Whitt, S. Alves da Silva, Z. Khalid, A.J. Nordmann, Q. Zhou, S.D. Walter, N. Vale, N. Bhatnagar, C. O'Regan, E.J. Mills, H.C. Bucher, V.M. Montori, G.H. Guyatt, Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis, BMJ 338 (2009) b92. [12] W.E. Boden, J.L. Probstfield, T. Anderson, B.R. Chaitman, P. Desvignes-Nickens, K. Koprowicz, R. McBride, K. Teo, W. Weintraub, Niacin in patients with low
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HDL cholesterol levels receiving intensive statin therapy, N. Engl. J. Med. 365 (24) (2011) 2255e2267. M.J. Landray, R. Haynes, J.C. Hopewell, S. Parish, T. Aung, J. Tomson, K. Wallendszus, M. Craig, L. Jiang, R. Collins, J. Armitage, Effects of extendedrelease niacin with laropiprant in high-risk patients, N. Engl. J. Med. 371 (3) (2014) 203e212. C.G. Santos-Gallego, C. Giannarelli, J.J. Badimon, Experimental models for the investigation of high-density lipoprotein-mediated cholesterol efflux, Curr. Atheroscler. Rep. 13 (3) (2011) 266e276. A.V. Khera, M. Cuchel, M. de la Llera-Moya, A. Rodrigues, M.F. Burke, K. Jafri, B.C. French, J.A. Phillips, M.L. Mucksavage, R.L. Wilensky, E.R. Mohler, G.H. Rothblat, D.J. Rader, Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis, N. Engl. J. Med. 364 (2) (2011) 127e135. A. Rohatgi, A. Khera, J.D. Berry, E.G. Givens, C.R. Ayers, K.E. Wedin, I.J. Neeland, I.S. Yuhanna, D.R. Rader, J.A. de Lemos, P.W. Shaul, HDL cholesterol efflux capacity and incident cardiovascular events, N. Engl. J. Med. 371 (25) (2014) 2383e2393. B.J. Van Lenten, A.C. Wagner, D.P. Nayak, S. Hama, M. Navab, A.M. Fogelman, High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection, Circulation 103 (18) (2001) 2283e2288. C.G. Santos-Gallego, R.S. Rosenson, Role of HDL in those with diabetes, Curr. Cardiol. Rep. 16 (8) (2014) 512. Y. Huang, J.A. Didonato, B.S. Levison, D. Schmitt, L. Li, Y. Wu, J. Buffa, T. Kim, G.S. Gerstenecker, X. Gu, C.S. Kadiyala, Z. Wang, M.K. Culley, J.E. Hazen, A.J. Didonato, X. Fu, S.Z. Berisha, D. Peng, T.T. Nguyen, S. Liang, C.C. Chuang, L. Cho, E.F. Plow, P.L. Fox, V. Gogonea, W.H. Tang, J.S. Parks, E.A. Fisher, J.D. Smith, S.L. Hazen, An abundant dysfunctional apolipoprotein A1 in human atheroma, Nat. Med. 20 (2) (Feb 2014) 193e203, http://dx.doi.org/10.1038/ nm.3459 [Epub 26 Jan 2014]. €ler, P. Keul, S. Weske, C.M. Reimann, H. Jindrov K. Sattler, M. Gra a, €cker-Preuss, R. Erbel, G. Heusch, P. Kleinbongard, R. Sabbadini, M. Bro B. Levkau, Signaling and functional defects of high-density lipoproteins (HDL) in coronary artery disease (CAD) are caused by low sphingosine-1-phosphate (S1P) content and can be efficiently corrected by HDL loading with S1P, J. Am. Coll. Cardiol. 66 (13) (2015). In press. J. Badimon, C.G. Santos-Gallego, HDL dysfunction: is the answer in the sphinx's riddle? J. Am. Coll. Cardiol. 66 (13) (2015). In press. R.H. Mackey, P. Greenland, D.C. Goff Jr., D. Lloyd-Jones, C.T. Sibley, S. Mora, High-density lipoprotein cholesterol and particle concentrations, carotid atherosclerosis, and coronary events: MESA (multi-ethnic study of atherosclerosis), J. Am. Coll. Cardiol. 60 (6) (2012) 508e516. J.D. Otvos, D. Collins, D.S. Freedman, I. Shalaurova, E.J. Schaefer, J.R. McNamara, H.E. Bloomfield, S.J. Robins, Low-density lipoprotein and highdensity 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) (2006) 1556e1563. M. Vergeer, S.M. Boekholdt, M.S. Sandhu, S.L. Ricketts, N.J. Wareham, M.J. Brown, U. de Faire, K. Leander, B. Gigante, M. Kavousi, A. Hofman, A.G. Uitterlinden, C.M. van Duijn, J.C. Witteman, J.W. Jukema, E.E. Schadt, E. van der Schoot, J.J. Kastelein, K.T. Khaw, R.P. Dullaart, A. van Tol, M.D. Trip, G.M. Dallinga-Thie, 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) (2010) 470e477. S. Mora, R.J. Glynn, P.M. Ridker, High-density lipoprotein cholesterol, size, particle number, and residual vascular risk after potent statin therapy, Circulation 128 (11) (2013) 1189e1197. A.V. Khera, P.J. Patel, M.P. Reilly, D.J. Rader, The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality, J. Am. Coll. Cardiol. 62 (20) (2013) 1909e1910. S.L. Airan-Javia, R.L. Wolf, M.L. Wolfe, M. Tadesse, E. Mohler, M.P. Reilly, Atheroprotective lipoprotein effects of a niacin-simvastatin combination compared to low- and high-dose simvastatin monotherapy, Am. Heart J. 157 (4) (2009) 687 e681e688.
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Discussion
HDL: Quality or quantity? Carlos G. Santos-Gallego AtheroThrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, 1428 Madison Avenue, Atran Building, 6th Floor, Room 6.20, USA
a r t i c l e i n f o Article history: Received 18 August 2015 Accepted 19 August 2015 Available online 29 August 2015 Keywords: High density lipoprotein Atherosclerosis Coronary artery disease Cardiovascular risk Prognostic factor
In the last six decades, high density lipoproteins (HDL) have been extensively considered to reduce the risk for coronary artery disease (CAD); in fact, the cholesterol carried by HDL (HDL-C) has earned the moniker of “good cholesterol” [1]. This fact is of critical significance because the first cause of death in Western countries is CAD caused by atherosclerosis, a chronic inflammatory disease of the arterial wall, arising from an imbalance in lipid metabolism and a maladaptive inflammatory response [2]. However, several recent lines of evidence cast a shadow on the role of HDL-C as a relevant therapeutic target (see later). The conclusion remains that there are critical gaps in knowledge in the area of HDL. In this issue of Atherosclerosis, Izuhara et al. [3] add another piece to the puzzle of this relationship. The proposition that HDL protects against CAD is based on several robust and consistent observations: i) numerous human population studies have shown that the HDL-C concentrations are independent, inverse predictors of the risk of suffering future CAD events (for a detailed summary, see [1]); ii) mechanistically, HDL have several well-documented functions with the potential to protect against CAD [1,4] (cholesterol efflux contributing to reverse cholesterol transport is the best characterized effect, but HDL also exerts anti-inflammatory, antiapoptotic, vasorelaxant, and endothelial-protective properties); iii) interventions increasing HDL abrogate the development and progression of atherosclerosis
E-mail addresses: [email protected], [email protected]. http://dx.doi.org/10.1016/j.atherosclerosis.2015.08.027 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
in several animal models [5,6]; and iv) in proof-of-concept studies in humans, intravenous infusions of reconstituted HDL promote regression of coronary atheroma [7]. Nevertheless, the hypothesis that raising HDL-C levels will result in reduced CAD risk has never been factually proven. In fact, four modern observations have questioned HDL-C as relevant therapeutic target: i) some genetic variants that raise plasma HDL-C concentrations are not associated with a proportionally lower risk of CAD events [8]; ii) a sub-analysis of JUPITER trial revealed that high HDL-C levels were associated with reduced risk of CAD events only among patients in the placebo arm, but that this association was lost among people on rosuvastatin 20 mg achieving very low LDL-C [9]; iii) population studies [10] and a meta-analysis [11] have suggested that changes in HDL-C levels after initiation of lipidmodifying therapy are not independently associated with CAD risk; and iv) recent clinical trials have shown that HDL-C-raising pharmacological therapies such as niacin (in the AIM-HIGH [12] and HPS2-THRIVE [13] clinical trials) do not reduce CAD events. We have previously formulated a comprehensive hypothesis that explains this paradox [1]. We want the reader to consider the following three specific facts. First, there is a crucial distinction between HDL-C (ie. the amount of cholesterol carried by the HDL) and the HDL particle (HDL-P, the individual molecule containing proteins and lipidsenot only cholesterol esters but also other types of lipids such as sphingosine-1-phosphate or S1P-). The levels of HDL-C do not necessarily reflect the concentration of HDL-P because HDL-P can be fully or only partially loaded with cholesterol. Second, only 5% of the total HDL-C is derived from actual macrophage cholesterol efflux, thus the amount of HDL-C is a poor surrogate of reverse cholesterol transport, the postulated main antiatherogenic effect of HDL. Third, the cholesterol content of HDL does not represent many important antiatherogenic HDL properties (eg. anti-inflammatory or vasorelaxant). Therefore, we conclude that HDL-C is an insensitive method to quantify the beneficial antiatherosclerotic properties of HDL. In fact, HDL-C (a static massbased measurement) cannot represent a dynamic functional process such as reverse cholesterol transport (or the antiinflammatory, anti-apoptotic, and anti-oxidant effects of HDL). As a corollary, we should focus on validated HDL functions (HDL “quality”) that truly reflect and are responsible for the actual beneficial effects of HDL [1] rather than on HDL-C levels (HDL-C “quantitity”).
122
C.G. Santos-Gallego / Atherosclerosis 243 (2015) 121e123
Methods for assessment of HDL functions are available [14] (although they may not be readily applicable in the everyday clinical practice). For instance, a new method for quantifying cholesterol efflux from macrophages has been recently discovered [15]. The recent report that cholesterol efflux assessed by this method predicts both CAD severity [15] and CAD events [16] while HDL-C did not [16] confirms our hypothesis that HDL function (quality) is more important than HDL-C levels (quantity). However, HDL loses its beneficial properties in certain pathological situations, specifically in acute situations such as acute infections [17] or chronic conditions such as CAD [18], which has been termed “dysfunctional HDL” [1]. Oxidation of the HDL particle has been demonstrated as one of the main causes of HDL dysfunction. Circulating HDL swiftly diffuses into the artery wall and into the atherosclerotic lesions, where leukocyte myeloperoxidase oxidizes the residue Trp72 of the apoA-I helix [19]; this oxidation causes a cross-linking of apoA-I molecules and a subsequent conformational change of the HDL particle, which becomes both pro-inflammatory and with reduced ability to promote cholesterol efflux or vasodilatation [19]. A second mechanism of HDL dysfunction involving S1P has been recently described [20,21]; in fact, S1P has been recently discovered to be both a mechanistic cause and a therapeutic target for HDL dysfunction. CAD patients exhibited lower HDL-bound S1P than healthy volunteers, while CAD-HDL was found dysfunctional as demonstrated by lower activation of endothelial signaling and inducing less vasodilatation. HDL could be S1P-loaded both in vivo and in vitro with a novel method, coincubation with S1P-loaded erythrocytes. This S1P loading greatly improved both HDL-induced endothelial molecular signaling and HDL-triggered vasodilatory potential. The important feature is that CAD-HDL could be loaded with S1P equally effective as healthy HDL, which completely corrected the defects inherent to dysfunctional HDL [20]. The fact that the measurement of HDL-C neglects the quantification of S1P (and the central role of S1P in HDL functionality) confirms our hypothesis that HDL function is not properly assessed by HDL-C concentrations. As most of the beneficial effects of HDL (both cholesterol efflux and the pleiotropic actions) are carried out by the HDL particles (independently of the cholesterol content of HDL), we want to highlight that the concentration of HDL-P is a better surrogate of HDL function than HDL-C. In the MESA trial HDL-C was not associated with atherosclerosis burden after adjusting for HDL-P, but low HDL-P predicted atherosclerosis burden regardless of HDL-C level [22]. Also, in the VA-HIT trial, the concentration of small HDL-P (the functionally more active HDL particles, also not surprisingly carrying the higher concentration of S1P) predicted risk of future CAD events independently of HDL-C levels [23]. This novel postulated theory allows to explain the four recent lines of evidence questioning the relevance of HDL-C as a relevant therapeutic target that we previously explained; 1) Problem: Genetic variants in the endothelial lipase gene that raise plasma HDL-C concentrations are not associated with a proportionally lower risk of myocardial infarction [8]. Possible explanation: Mutations resulting in reduced endothelial lipase activity only increase HDL-C without actually increasing HDL-P or HDL function, which does not translate into reduced CAD risk [8]. On the contrary, the mutations resulting in reduced phospholipid transfer protein activity translate into reduced CAD risk [24] because they result in increased number of HDL-P and enhanced HDL functionality. 2) Problem: A sub-analysis of JUPITER trial revealed that high HDL-C levels were associated with reduced risk of CAD events only among patients in the placebo arm. This beneficial
association was lost among people on rosuvastatin 20 mg achieving very low LDL-C [9]. Possible explanation: HDL-C is not a sensitive enough surrogate of HDL function. A recent analysis of the JUPITER trial has shown that, even though HDL-C did not predict CAD risk in statin-treated patients, HDL-P (a more accurate surrogate of HDL functionality) did predict CAD risk in all patients (both placebo and statin-treated) and even after adjusting for HDL-C levels [25]. 3) Problem: A recent meta-analysis and population studies suggest that changes in HDL-C levels after initiation of lipidmodifying therapy are not independently associated with CAD risk [10,11]. Possible explanation: As previously discussed, HDL-C levels (or the change in them) may not be the proper parameter to assess adequately the contribution of HDL to CAD risk. Unfortunately, neither the meta-analysis [11] nor the population studies [10] measured HDL functionality or HDL-P concentrations. 4) Problem: Recent clinical trials have shown that HDL-C-raising pharmacological therapies such as niacin (in the AIM-HIGH [12] and HPS2-THRIVE [13] clinical trials) do not reduce CAD events. Possible explanation: Strategies that increase HDL-C without enhancing HDL function or expanding the pool of HDL-P with its rich proteome/lipidome do not seem to be an effective strategy. Despite increasing HDL-C levels, niacin does not increase neither HDL functionality (cholesterol efflux or anti-inflammatory properties) [26] nor the HDL-P concentrations [27]. Therefore the HDL-C levels increased by niacin seem not to be functionally ideal for the treatment of CAD. It is in this context where we should place the very interesting study of Izuhara et al. [3]. The authors should be praised for shedding more light into this interesting but yet obscure topic of HDL and CAD risk, and also for their extensive study, large sample size achieved and the use of rigorous and solid methodology. The authors retrospectively evaluate 10,391 CAD patients undergoing PCI in 2005e2007. Those patients with low HDL-C had a higher unadjusted 5-year incidence of CAD events than patients with normal HDL-C; however, low HDL-C patients also exhibited more comorbidities (they were older and more obese, with higher incidence of smokers, diabetes, renal failure, heart failure, atrial fibrillation, multivessel CAD, previous MI or previous stroke). Thus, after adjusting for confounders, low HDL-C was not associated with a higher risk of CAD events. This interesting study by Izuhara et al., [3] actually confirms the previously explained hypothesis of HDL functionality being more relevant regarding prediction and therapy than HDL-C concentration, or briefly the hypothesis that HDL function is more relevant than HDL-C quantity. Higher HDL-C levels were not associated in this article [3] with lower CAD events in patients who underwent PCI; however, as CAD induces HDL dysfunction, it is safe to assume that all those PCI patients displayed dysfunctional HDL, and thus HDL function (not assessed by the authors) would be a much more sensitive predictor of future CAD risk than HDL-C levels. Therefore, we should focus on the evaluation (at the clinical level) and therapeutic improvement (at the research level) of HDL quality (HDL functionality) while not paying so much attention to HDL-C quantity (HDL-C concentrations). References [1] C.G. Santos-Gallego, J.J. Badimon, R.S. Rosenson, Beginning to understand high-density lipoproteins, Endocrinol. Metab. Clin. North Am. 43 (4) (2014) 913e947.
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