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HDL function as a predictor of coronary heart disease events: time to re-assess the HDL hypothesis?
Comment
HDL function as a predictor of coronary heart disease events: time to re-assess the HDL hypothesis? The association of high HDL cholesterol concentrations with decreased risk of coronary heart disease was first reported more than 40 years ago, and has since been confirmed in numerous population studies. The strength of this association led to the hypothesis that interventions that increase plasma HDL cholesterol concentrations would reduce risk of coronary heart disease. Although interventions that increase HDL cholesterol concentrations reduce atherosclerosis in animals,1 trials of niacin2 and the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib3 have shown no benefit compared with placebo for clinical outcomes in human beings. Furthermore, treatment with the CETP inhibitor torcetrapib caused harm, possibly as a result of off-target effects of the drug.4 Genetics studies have suggested that polymorphisms that affect HDL cholesterol concentration are associated with risk of coronary heart disease only when accompanied by a concomitant reduction in LDL cholesterol or triglyceride concentrations.5 These negative outcomes have shifted the focus of HDL research to strategies that improve the cardioprotective functions of HDLs, rather than increasing HDL cholesterol concentration as a means of reducing cardiovascular risk. HDLs have several cardioprotective functions. They inhibit inflammation in multiple cell types and prevent LDL oxidation.7 HDLs are also antithrombotic and anti-diabetic.6 The most studied function of HDLs and their main apolipoprotein, apoA-I, is as acceptors of the excess cholesterol that effluxes from macrophages in the artery wall in the first step of the potentially anti-atherogenic reverse cholesterol transport pathway. The first evidence of a relation between cholesterol efflux capacity and risk of coronary heart disease came from a cross-sectional study7 of people with and without coronary heart disease. Serum samples from these participants were depleted of apoB-containing lipoproteins, leaving HDLs as the sole lipoproteins. When the capacity of these samples to efflux radiolabelled cholesterol from mouse macrophages was assessed, cholesterol efflux capacity correlated inversely with carotid intima media thickness and angiographically
determined coronary artery disease. This relation was still apparent after adjusting for HDL cholesterol and apoA-I concentrations. This result was confirmed in an outpatient cohort by other investigators.8 However, investigation of an angiography case-control cohort as part of the same study showed a paradoxical positive association of cholesterol efflux capacity with the risk of a major cardiovascular event.8 These contradictory findings suggested that the relation of cholesterol efflux capacity to cardiovascular events might be population-specific. They also indicate that interpretation of results that depict the cholesterol efflux capacity of apoB-depleted serum is complex and could depend on multiple factors, including the relative concentrations of mature, spherical HDL and lipid-free apoA-I in the apoBdepleted serum, the nature of the donor macrophages, and the assay conditions. Despite these caveats, most studies support the idea that HDL function, at least in the context of cholesterol efflux capacity, is inversely associated with risk of coronary heart disease. The first evidence that serum cholesterol efflux capacity predicts cardiovascular events was reported in 2014,9 when the cholesterol efflux capacity of baseline plasma samples from disease-free participants in the Dallas Heart Study was assessed and related to incident cardiovascular events. This study showed an inverse association of cholesterol efflux capacity and HDL particle concentration, but not HDL cholesterol concentration, with incident cardiovascular events. However, this study was done with fluorescently labelled cholesterol in an assay that had not been rigorously validated. Furthermore, because there were few events in the Dallas Heart Study, it was important that the findings were confirmed in an independent cohort, using radiolabelled cholesterol to assess cholesterol efflux capacity. Such a study is reported in The Lancet Diabetes & Endocrinology, in which radiolabelled cholesterol was used to measure the cholesterol efflux capacity of apoB-depleted serum in a prospective investigation of 1745 patients with incident coronary heart disease and 1749 healthy controls from the EPIC-Norfolk study.10 The results show a significant and inverse correlation of
www.thelancet.com/diabetes-endocrinology Published online May 27, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00205-3
Lancet Diabetes Endocrinol 2015 Published Online May 27, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00205-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00126-6
1
Comment
cholesterol efflux capacity with incident coronary heart disease events, thus confirming the findings from the Dallas Heart Study. Additionally, the results from the EPIC-Norfolk substudy show that the relation between cholesterol efflux capacity and incident coronary heart disease events was independent of multiple cardiovascular risk factors and remained significant after adjustment for HDL cholesterol and apoA-I concentrations. This conclusion strengthens the case that at least one of the cardioprotective functions of HDLs is a predictor of cardiovascular events. It also raises the possibility that perhaps it is time to redefine the HDL hypothesis. The results of ongoing outcome trials with CETP inhibitors should provide further insight into whether HDL function is key to cardioprotection.
We declare no competing interests.
*Kerry-Anne Rye, Kwok Leung Ong
10
Centre for Vascular Research, Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia (K-AR, KLO) [email protected]
2
Copyright © Rye et al. Open Access article distributed under the terms of CC BY-NC-ND. 1
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6 7
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Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000; 406: 203–07. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371: 203–12. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089–99. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109–22. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Rye KA, Barter PJ. Cardioprotective functions of HDLs. J Lipid Res 2014; 55: 168–79. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364: 127–35. Li XM, Tang WH, Mosior MK, et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol 2013; 33: 1696–705. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371: 2383–93. Saleheen D, Scott R, Javad S, et al. Association of HDL cholesterol efflux capacity with incident CHD events: a prospective case control study. Lancet Diabetes Endocrinol 2015; published online May 27. http://dx.doi. org/10.1016/S2213-8587(15)00126-6.
www.thelancet.com/diabetes-endocrinology Published online May 27, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00205-3
HDL function as a predictor of coronary heart disease events: time to re-assess the HDL hypothesis? The association of high HDL cholesterol concentrations with decreased risk of coronary heart disease was first reported more than 40 years ago, and has since been confirmed in numerous population studies. The strength of this association led to the hypothesis that interventions that increase plasma HDL cholesterol concentrations would reduce risk of coronary heart disease. Although interventions that increase HDL cholesterol concentrations reduce atherosclerosis in animals,1 trials of niacin2 and the cholesteryl ester transfer protein (CETP) inhibitor dalcetrapib3 have shown no benefit compared with placebo for clinical outcomes in human beings. Furthermore, treatment with the CETP inhibitor torcetrapib caused harm, possibly as a result of off-target effects of the drug.4 Genetics studies have suggested that polymorphisms that affect HDL cholesterol concentration are associated with risk of coronary heart disease only when accompanied by a concomitant reduction in LDL cholesterol or triglyceride concentrations.5 These negative outcomes have shifted the focus of HDL research to strategies that improve the cardioprotective functions of HDLs, rather than increasing HDL cholesterol concentration as a means of reducing cardiovascular risk. HDLs have several cardioprotective functions. They inhibit inflammation in multiple cell types and prevent LDL oxidation.7 HDLs are also antithrombotic and anti-diabetic.6 The most studied function of HDLs and their main apolipoprotein, apoA-I, is as acceptors of the excess cholesterol that effluxes from macrophages in the artery wall in the first step of the potentially anti-atherogenic reverse cholesterol transport pathway. The first evidence of a relation between cholesterol efflux capacity and risk of coronary heart disease came from a cross-sectional study7 of people with and without coronary heart disease. Serum samples from these participants were depleted of apoB-containing lipoproteins, leaving HDLs as the sole lipoproteins. When the capacity of these samples to efflux radiolabelled cholesterol from mouse macrophages was assessed, cholesterol efflux capacity correlated inversely with carotid intima media thickness and angiographically
determined coronary artery disease. This relation was still apparent after adjusting for HDL cholesterol and apoA-I concentrations. This result was confirmed in an outpatient cohort by other investigators.8 However, investigation of an angiography case-control cohort as part of the same study showed a paradoxical positive association of cholesterol efflux capacity with the risk of a major cardiovascular event.8 These contradictory findings suggested that the relation of cholesterol efflux capacity to cardiovascular events might be population-specific. They also indicate that interpretation of results that depict the cholesterol efflux capacity of apoB-depleted serum is complex and could depend on multiple factors, including the relative concentrations of mature, spherical HDL and lipid-free apoA-I in the apoBdepleted serum, the nature of the donor macrophages, and the assay conditions. Despite these caveats, most studies support the idea that HDL function, at least in the context of cholesterol efflux capacity, is inversely associated with risk of coronary heart disease. The first evidence that serum cholesterol efflux capacity predicts cardiovascular events was reported in 2014,9 when the cholesterol efflux capacity of baseline plasma samples from disease-free participants in the Dallas Heart Study was assessed and related to incident cardiovascular events. This study showed an inverse association of cholesterol efflux capacity and HDL particle concentration, but not HDL cholesterol concentration, with incident cardiovascular events. However, this study was done with fluorescently labelled cholesterol in an assay that had not been rigorously validated. Furthermore, because there were few events in the Dallas Heart Study, it was important that the findings were confirmed in an independent cohort, using radiolabelled cholesterol to assess cholesterol efflux capacity. Such a study is reported in The Lancet Diabetes & Endocrinology, in which radiolabelled cholesterol was used to measure the cholesterol efflux capacity of apoB-depleted serum in a prospective investigation of 1745 patients with incident coronary heart disease and 1749 healthy controls from the EPIC-Norfolk study.10 The results show a significant and inverse correlation of
www.thelancet.com/diabetes-endocrinology Published online May 27, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00205-3
Lancet Diabetes Endocrinol 2015 Published Online May 27, 2015 http://dx.doi.org/10.1016/ S2213-8587(15)00205-3 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(15)00126-6
1
Comment
cholesterol efflux capacity with incident coronary heart disease events, thus confirming the findings from the Dallas Heart Study. Additionally, the results from the EPIC-Norfolk substudy show that the relation between cholesterol efflux capacity and incident coronary heart disease events was independent of multiple cardiovascular risk factors and remained significant after adjustment for HDL cholesterol and apoA-I concentrations. This conclusion strengthens the case that at least one of the cardioprotective functions of HDLs is a predictor of cardiovascular events. It also raises the possibility that perhaps it is time to redefine the HDL hypothesis. The results of ongoing outcome trials with CETP inhibitors should provide further insight into whether HDL function is key to cardioprotection.
We declare no competing interests.
*Kerry-Anne Rye, Kwok Leung Ong
10
Centre for Vascular Research, Faculty of Medicine, The University of New South Wales, Sydney, NSW 2052, Australia (K-AR, KLO) [email protected]
2
Copyright © Rye et al. Open Access article distributed under the terms of CC BY-NC-ND. 1
2 3 4 5
6 7
8
9
Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature 2000; 406: 203–07. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371: 203–12. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; 367: 2089–99. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357: 2109–22. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Rye KA, Barter PJ. Cardioprotective functions of HDLs. J Lipid Res 2014; 55: 168–79. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011; 364: 127–35. Li XM, Tang WH, Mosior MK, et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol 2013; 33: 1696–705. Rohatgi A, Khera A, Berry JD, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014; 371: 2383–93. Saleheen D, Scott R, Javad S, et al. Association of HDL cholesterol efflux capacity with incident CHD events: a prospective case control study. Lancet Diabetes Endocrinol 2015; published online May 27. http://dx.doi. org/10.1016/S2213-8587(15)00126-6.
www.thelancet.com/diabetes-endocrinology Published online May 27, 2015 http://dx.doi.org/10.1016/S2213-8587(15)00205-3