title: Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.
abstract: Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).
  
  
  
  Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by -50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (-30%; -55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (-36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (-46%; -47%, P<0.01; -53%, P<0.001), atherosclerotic lesion area (-78%; -49%, P<0.01; -87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (-71%, P<0.01; -81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R(2) = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R(2) = 0.20, P<0.001).
  
  
  
  Niacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.
authors.affiliation: TNO - Metabolic Health Research, Leiden, The Netherlands ; Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands ; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Susan
authors.initials: S
authors.lastname: Kühnast
authors.forename: Mieke C
authors.initials: MC
authors.lastname: Louwe
authors.forename: Mattijs M
authors.initials: MM
authors.lastname: Heemskerk
authors.forename: Elsbet J
authors.initials: EJ
authors.lastname: Pieterman
authors.forename: Jan B
authors.initials: JB
authors.lastname: van Klinken
authors.forename: Sjoerd A A
authors.initials: SA
authors.lastname: van den Berg
authors.forename: Johannes W A
authors.initials: JW
authors.lastname: Smit
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: José W A
authors.initials: JW
authors.lastname: van der Hoorn
authors.forename: Hans M G
authors.initials: HM
authors.lastname: Princen
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
mesh_terms: D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics*; D050197:Atherosclerosis / Q000517:prevention & control*; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood*; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009525:Niacin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D053318:Apolipoprotein E3; D053480:Cholesterol Ester Transfer Proteins; D012333:RNA, Messenger; D014280:Triglycerides; C052720:apolipoprotein E3 (Leidein); D009525:Niacin; D002784:Cholesterol; D019821:Simvastatin