High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality.

AIMS High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. METHODS AND RESULTS We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. CONCLUSION The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patients.

[1]  Christopher P Cannon,et al.  High-density lipoprotein and coronary heart disease: current and future therapies. , 2010, Journal of the American College of Cardiology.

[2]  J. Danesh,et al.  Major lipids, apolipoproteins, and risk of vascular disease. , 2009, JAMA.

[3]  Association of adiponectin with adverse outcome in coronary artery disease patients: results from the AtheroGene study , 2008 .

[4]  Robert L Wilensky,et al.  Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. , 2011, The New England journal of medicine.

[5]  F. Cambien,et al.  Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. , 2003, The New England journal of medicine.

[6]  M. H. Gault,et al.  Prediction of creatinine clearance from serum creatinine. , 1975, Nephron.

[7]  D. Carroll,et al.  Evidence of a synergistic association between heart rate, inflammation, and cardiovascular mortality in patients undergoing coronary angiography. , 2013, European heart journal.

[8]  Ahmed Tawakol,et al.  Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial , 2011, The Lancet.

[9]  Costantina Manes,et al.  Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy , 2010, Circulation.

[10]  J. Borén,et al.  Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management , 2011, European heart journal.

[11]  E. Benjamin,et al.  Multiple marker approach to risk stratification in patients with stable coronary artery disease. , 2010, European heart journal.

[12]  J. Kastelein,et al.  The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis? , 2010, Journal of Lipid Research.

[13]  J. Jukema,et al.  Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. , 2012, European heart journal.

[14]  H. Brenner,et al.  Changes of cardiovascular risk factors and their implications in subsequent birth cohorts of older adults in Germany: a life course approach , 2007, European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology.

[15]  P. Libby,et al.  HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: an analysis from the JUPITER trial , 2010, The Lancet.

[16]  H. Brenner,et al.  Proinflammatory Cytokines, Adiponectin, and Increased Risk of Primary Cardiovascular Events in Diabetic Patients With or Without Renal Dysfunction , 2013, Diabetes Care.

[17]  W. März,et al.  Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. , 2001, Pharmacogenomics.

[18]  D. Tousoulis,et al.  Vascular abnormalities, paraoxonase activity, and dysfunctional HDL in primary antiphospholipid syndrome. , 2009, JAMA.

[19]  Markus Abt,et al.  Effects of dalcetrapib in patients with a recent acute coronary syndrome. , 2012, The New England journal of medicine.

[20]  M. Caulfield,et al.  Effects of torcetrapib in patients at high risk for coronary events. , 2007, The New England journal of medicine.

[21]  P. Barter,et al.  Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database , 2010, Journal of Lipid Research.

[22]  Ming-Dauh Wang,et al.  Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. , 2011, JAMA.

[23]  D. Gordon,et al.  High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. , 1989, Circulation.

[24]  A. Khera,et al.  The anti-oxidative capacity of high-density lipoprotein is reduced in acute coronary syndrome but not in stable coronary artery disease. , 2011, Journal of the American College of Cardiology.

[25]  S. Reddy,et al.  HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms , 2011, Nature Reviews Cardiology.

[26]  H. Brenner,et al.  Clinical Utility of Creatinine- and Cystatin C–Based Definition of Renal Function for Risk Prediction of Primary Cardiovascular Events in Patients With Diabetes , 2012, Diabetes Care.

[27]  A. Kontush,et al.  Biological activities of HDL subpopulations and their relevance to cardiovascular disease. , 2011, Trends in molecular medicine.

[28]  A. Akhmedov,et al.  Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. , 2011, The Journal of clinical investigation.

[29]  A. Gotto,et al.  HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. , 2007, The New England journal of medicine.

[30]  A. von Eckardstein,et al.  High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. , 1996, Atherosclerosis.

[31]  S. Hazen,et al.  Paradoxical Association of Enhanced Cholesterol Efflux With Increased Incident Cardiovascular Risks , 2013, Arteriosclerosis, thrombosis, and vascular biology.