NEWS & VIEWS CORONARY ARTERY DISEASE
HDL and coronary heart disease —novel insights Ulf Landmesser
The association between HDL cholesterol and cardiovascular events, and the potential antiatherogenic effects of HDL particles, are altered in patients with established coronary heart disease. HDL particle composition has, therefore, gained attention after trials of therapies to increase HDLcholesterol levels did not reduce the risk of an adverse cardiovascular event. Landmesser, U. Nat. Rev. Cardiol. 11, 559–560 (2014); published online 2 September 2014; doi:10.1038/nrcardio.2014.128
Investigators analysing data from two different trials, and publishing their results in the European Heart Journal, suggest that, in patients with an acute myocardial infarction or undergoing coronary angiography for myocardial infarction, unstable angina, or stable coronary heart disease (CHD), HDL-cholesterol levels are not related to long-term adverse cardiovascular events.1 However, when separating HDL2 choles terol and HDL3 cholesterol in these patients by single vertical spin density ultra centrifug ation, the investigators report that a low HDL3-cholesterol level, but not a low HDL2-cholesterol level, was associated with an increased risk of myocardial infarction or death, which was consistently seen in both studies they analysed.1 Notably, HDL3 cholesterol, which is denser than HDL2 cholesterol, accounted for 78% of all HDL cholesterol, and was more closely correlated with levels of apolipoprotein A‑I.1 These data further support the hypothesis that the association between HDL c holesterol and cardiovascular risk is altered in the setting of secondary prevention, that is, in patients with established CHD. These observations are interesting in light of findings from several large-scale clinical outcome trials, in which therapies to increase the HDL-cholesterol level were assessed in patients after acute coronary syndrome or with atherosclerotic vascular disease. For example, in the ILLUMINATE2 and dal-OUTCOMES3 trials using cholest eryl ester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, and the HPS2THRIVE study 4 using niacin–laropiprant, patients with established CHD derived
no benefit from these lipid-modifying therapies, despite significant increases in HDL-cholesterol levels. The findings in the new article by Martin and colleagues1 provide a potential explanation for these observations. The original hypothesis that an increase in total HDL-cholesterol level might reduce cardiovascular events in patients with CHD was largely based on observational primary prevention studies. In these studies, increasing HDL-cholesterol levels were associated with a reduced risk of CHD.5,6 However, in the study by Martin and colleagues, elevated HDL-cholesterol levels were not associated with a reduced risk of adverse events in patients with established CHD.1 In atherosclerotic CHD, inflammatory pathways are considered drivers of plaque
rupture or erosion, and subsequent thrombosis, leading to acute coronary syndromes. Notably, in experimental or translational studies, HDL that has been reconstituted or obtained from healthy individuals can exert potentially antiatherogenic and antiinflammatory effects.7–9 For example, HDL can stimulate macrophage cholesterol efflux (and thereby reduce their inflammatory activation) or promote endothelial cell atheroprotective properties, such as increasing endothelial cell nitric oxide production, reducing endothelial cell inflammatory activation, or apoptosis.7–9 However, these antiatherogenic properties are altered in patients with established CHD in whom HDL loses the capacity to exert endothelial anti-inflammatory or anti apoptotic effects.8,9 Interestingly, in prote omics studies, HDL3 subfractions have a higher content of antioxidant proteins (such as serum paraoxonase/arylesterase 1 and serum paraoxonase/lactonase 3), which are associated with a more potent capacity than that of HDL2 to protect LDL from oxidation (Figure 1).10 Notably, HDL-associated paraoxonase activity was also identified as a regulator of endothelial atheroprotective properties of HDL particles.8 Martin et al. suggest that the measurement of the dense HDL 3 cholesterol might be better associated with cardiovascular outcomes in patients with CHD than measurement of total HDL cholesterol.1
Apo-AI CLI Remodelling of HDL proteome in CHD CLI/PON1
Apo-CIII
PON1 Apo-CIII HDL3
HDL2
Figure 1 | HDL particles are highly heterogeneous. Different protein composition result in differences in HDL particle function, which is altered in patients with CHD. HDL 2 particles are larger than dense HDL3 particles. Both HDL2 and HDL3 contain Apo-AI, but HDL2 has more Apo‑CIII, and HDL3 more PON1, which might help to preserve the antiatherogenic properties of these HDL particles. HDL3 particles also have more CLI than HDL2. In patients with CHD, Apo‑CIII is likely to be enriched in HDL2 particles compared with healthy individuals. Abbreviations: Apo‑AI, apolipoprotein A‑I; ApoC‑III, apolipoprotein C‑III; CHD, coronary heart disease; CLI, clusterin; PON1, serum paraoxonase/arylesterase 1.
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | OCTOBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS In conclusion, the findings of Martin et al. further suggest that the association between HDL cholesterol and adverse cardiovascular events is markedly altered in patients with established CHD, compared with findings from primary prevention studies. 1 Total HDL-cholesterol levels might, therefore, not aid risk stratification in such patients, and increasing HDL-cholesterol levels cannot currently be regarded as a reliable therapeutic target. Measurements of HDL3cholesterol subfractions might provide better risk stratification in these patients. However, a causal relationship between HDL3 cholesterol and the risk of cardiovascular events remains to be determined.
Acknowledgements U.L. is supported by a grant from the Fondation Leducq, the Swiss National Science Foundation (grant no 310030-149990) and from European-FP7 “Risky CAD”.
University Heart Center, University Hospital Zurich, Raemistrassse 100, 8091 Zurich, Switzerland. [email protected]
4.
OCTOBER 2014 | VOLUME 11
Competing interests U.L. has received research support, honoraria, or consultant fees from Amgen, Astra Zeneca, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi-Aventis. 1.
2.
3.
Martin, S. S. et al. HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the lipoprotein investigators collaborative. Eur. Heart J. http:// dx.doi.org/10.1093/eurheartj/ehu264. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007). Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012). HPS2-THRIVE Collaborative Group et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).
5.
Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber. T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977). 6. Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009). 7. Westerterp, M. et al. ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ. Res. 114, 157–170 (2014). 8. Besler, C. et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J. Clin. Invest. 121, 2693–2708 (2011). 9. Riwanto, M. et al. Altered activation of endothelial anti‑and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation 127, 891–904 (2013). 10. Davidson, W. S. et al. Proteomic analysis of defined HDL subpopulations reveals particlespecific protein clusters: relevance to antioxidative function. Arterioscler. Thromb. Vasc. Biol. 29, 870–876 (2009).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
HDL and coronary heart disease —novel insights Ulf Landmesser
The association between HDL cholesterol and cardiovascular events, and the potential antiatherogenic effects of HDL particles, are altered in patients with established coronary heart disease. HDL particle composition has, therefore, gained attention after trials of therapies to increase HDLcholesterol levels did not reduce the risk of an adverse cardiovascular event. Landmesser, U. Nat. Rev. Cardiol. 11, 559–560 (2014); published online 2 September 2014; doi:10.1038/nrcardio.2014.128
Investigators analysing data from two different trials, and publishing their results in the European Heart Journal, suggest that, in patients with an acute myocardial infarction or undergoing coronary angiography for myocardial infarction, unstable angina, or stable coronary heart disease (CHD), HDL-cholesterol levels are not related to long-term adverse cardiovascular events.1 However, when separating HDL2 choles terol and HDL3 cholesterol in these patients by single vertical spin density ultra centrifug ation, the investigators report that a low HDL3-cholesterol level, but not a low HDL2-cholesterol level, was associated with an increased risk of myocardial infarction or death, which was consistently seen in both studies they analysed.1 Notably, HDL3 cholesterol, which is denser than HDL2 cholesterol, accounted for 78% of all HDL cholesterol, and was more closely correlated with levels of apolipoprotein A‑I.1 These data further support the hypothesis that the association between HDL c holesterol and cardiovascular risk is altered in the setting of secondary prevention, that is, in patients with established CHD. These observations are interesting in light of findings from several large-scale clinical outcome trials, in which therapies to increase the HDL-cholesterol level were assessed in patients after acute coronary syndrome or with atherosclerotic vascular disease. For example, in the ILLUMINATE2 and dal-OUTCOMES3 trials using cholest eryl ester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib, and the HPS2THRIVE study 4 using niacin–laropiprant, patients with established CHD derived
no benefit from these lipid-modifying therapies, despite significant increases in HDL-cholesterol levels. The findings in the new article by Martin and colleagues1 provide a potential explanation for these observations. The original hypothesis that an increase in total HDL-cholesterol level might reduce cardiovascular events in patients with CHD was largely based on observational primary prevention studies. In these studies, increasing HDL-cholesterol levels were associated with a reduced risk of CHD.5,6 However, in the study by Martin and colleagues, elevated HDL-cholesterol levels were not associated with a reduced risk of adverse events in patients with established CHD.1 In atherosclerotic CHD, inflammatory pathways are considered drivers of plaque
rupture or erosion, and subsequent thrombosis, leading to acute coronary syndromes. Notably, in experimental or translational studies, HDL that has been reconstituted or obtained from healthy individuals can exert potentially antiatherogenic and antiinflammatory effects.7–9 For example, HDL can stimulate macrophage cholesterol efflux (and thereby reduce their inflammatory activation) or promote endothelial cell atheroprotective properties, such as increasing endothelial cell nitric oxide production, reducing endothelial cell inflammatory activation, or apoptosis.7–9 However, these antiatherogenic properties are altered in patients with established CHD in whom HDL loses the capacity to exert endothelial anti-inflammatory or anti apoptotic effects.8,9 Interestingly, in prote omics studies, HDL3 subfractions have a higher content of antioxidant proteins (such as serum paraoxonase/arylesterase 1 and serum paraoxonase/lactonase 3), which are associated with a more potent capacity than that of HDL2 to protect LDL from oxidation (Figure 1).10 Notably, HDL-associated paraoxonase activity was also identified as a regulator of endothelial atheroprotective properties of HDL particles.8 Martin et al. suggest that the measurement of the dense HDL 3 cholesterol might be better associated with cardiovascular outcomes in patients with CHD than measurement of total HDL cholesterol.1
Apo-AI CLI Remodelling of HDL proteome in CHD CLI/PON1
Apo-CIII
PON1 Apo-CIII HDL3
HDL2
Figure 1 | HDL particles are highly heterogeneous. Different protein composition result in differences in HDL particle function, which is altered in patients with CHD. HDL 2 particles are larger than dense HDL3 particles. Both HDL2 and HDL3 contain Apo-AI, but HDL2 has more Apo‑CIII, and HDL3 more PON1, which might help to preserve the antiatherogenic properties of these HDL particles. HDL3 particles also have more CLI than HDL2. In patients with CHD, Apo‑CIII is likely to be enriched in HDL2 particles compared with healthy individuals. Abbreviations: Apo‑AI, apolipoprotein A‑I; ApoC‑III, apolipoprotein C‑III; CHD, coronary heart disease; CLI, clusterin; PON1, serum paraoxonase/arylesterase 1.
NATURE REVIEWS | CARDIOLOGY
VOLUME 11 | OCTOBER 2014 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS In conclusion, the findings of Martin et al. further suggest that the association between HDL cholesterol and adverse cardiovascular events is markedly altered in patients with established CHD, compared with findings from primary prevention studies. 1 Total HDL-cholesterol levels might, therefore, not aid risk stratification in such patients, and increasing HDL-cholesterol levels cannot currently be regarded as a reliable therapeutic target. Measurements of HDL3cholesterol subfractions might provide better risk stratification in these patients. However, a causal relationship between HDL3 cholesterol and the risk of cardiovascular events remains to be determined.
Acknowledgements U.L. is supported by a grant from the Fondation Leducq, the Swiss National Science Foundation (grant no 310030-149990) and from European-FP7 “Risky CAD”.
University Heart Center, University Hospital Zurich, Raemistrassse 100, 8091 Zurich, Switzerland. [email protected]
4.
OCTOBER 2014 | VOLUME 11
Competing interests U.L. has received research support, honoraria, or consultant fees from Amgen, Astra Zeneca, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi-Aventis. 1.
2.
3.
Martin, S. S. et al. HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the lipoprotein investigators collaborative. Eur. Heart J. http:// dx.doi.org/10.1093/eurheartj/ehu264. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007). Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012). HPS2-THRIVE Collaborative Group et al. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371, 203–212 (2014).
5.
Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber. T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977). 6. Emerging Risk Factors Collaboration et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009). 7. Westerterp, M. et al. ATP-binding cassette transporters, atherosclerosis, and inflammation. Circ. Res. 114, 157–170 (2014). 8. Besler, C. et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J. Clin. Invest. 121, 2693–2708 (2011). 9. Riwanto, M. et al. Altered activation of endothelial anti‑and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation 127, 891–904 (2013). 10. Davidson, W. S. et al. Proteomic analysis of defined HDL subpopulations reveals particlespecific protein clusters: relevance to antioxidative function. Arterioscler. Thromb. Vasc. Biol. 29, 870–876 (2009).
www.nature.com/nrcardio © 2014 Macmillan Publishers Limited. All rights reserved
