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Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.

Kühnast S, Louwe MC, Heemskerk MM, Pieterman EJ, van Klinken JB, van den Berg SA, Smit JW, Havekes LM, Rensen PC, van der Hoorn JW, Princen HM, Jukema JW - PLoS ONE (2013)

Bottom Line: 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 decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects.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.

View Article: PubMed Central - PubMed

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.

ABSTRACT

Objective: 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).

Approach and results: 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).

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Effect of niacin, simvastatin and their combination on atherosclerosis development in aortic root area.After 18 weeks of treatment, number of lesions (A), lesion severity (B), percentage undiseased segments (C) and total lesion area (D) were determined per cross section. Lesion severity was classified as mild (type I–III) and severe (type IV–V) lesions. (Simva, simvastatin; values are means ± SD; n = 15 per group; **P<0.01 and ***P<0.001 as compared to control; ##P<0.01 as compared to niacin+simvastatin).
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pone-0066467-g004: Effect of niacin, simvastatin and their combination on atherosclerosis development in aortic root area.After 18 weeks of treatment, number of lesions (A), lesion severity (B), percentage undiseased segments (C) and total lesion area (D) were determined per cross section. Lesion severity was classified as mild (type I–III) and severe (type IV–V) lesions. (Simva, simvastatin; values are means ± SD; n = 15 per group; **P<0.01 and ***P<0.001 as compared to control; ##P<0.01 as compared to niacin+simvastatin).

Mentions: After 18 weeks of treatment, we measured the effect of niacin, with and without simvastatin on atherosclerosis development in the aortic root. Figure 3 illustrates representative images of atherosclerotic lesions for each group. We determined the number of lesions per cross section (Figure 4A), the lesion severity as a percentage of all lesions (Figure 4B), the percentage undiseased segments (Figure 4C) and the total lesion area per cross section (Figure 4D). To determine lesion severity as a percentage of all lesions, type I-III lesions were classified as mild lesions and type IV–V lesions were classified as severe lesions.


Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol.

Kühnast S, Louwe MC, Heemskerk MM, Pieterman EJ, van Klinken JB, van den Berg SA, Smit JW, Havekes LM, Rensen PC, van der Hoorn JW, Princen HM, Jukema JW - PLoS ONE (2013)

Effect of niacin, simvastatin and their combination on atherosclerosis development in aortic root area.After 18 weeks of treatment, number of lesions (A), lesion severity (B), percentage undiseased segments (C) and total lesion area (D) were determined per cross section. Lesion severity was classified as mild (type I–III) and severe (type IV–V) lesions. (Simva, simvastatin; values are means ± SD; n = 15 per group; **P<0.01 and ***P<0.001 as compared to control; ##P<0.01 as compared to niacin+simvastatin).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3686722&req=5

pone-0066467-g004: Effect of niacin, simvastatin and their combination on atherosclerosis development in aortic root area.After 18 weeks of treatment, number of lesions (A), lesion severity (B), percentage undiseased segments (C) and total lesion area (D) were determined per cross section. Lesion severity was classified as mild (type I–III) and severe (type IV–V) lesions. (Simva, simvastatin; values are means ± SD; n = 15 per group; **P<0.01 and ***P<0.001 as compared to control; ##P<0.01 as compared to niacin+simvastatin).
Mentions: After 18 weeks of treatment, we measured the effect of niacin, with and without simvastatin on atherosclerosis development in the aortic root. Figure 3 illustrates representative images of atherosclerotic lesions for each group. We determined the number of lesions per cross section (Figure 4A), the lesion severity as a percentage of all lesions (Figure 4B), the percentage undiseased segments (Figure 4C) and the total lesion area per cross section (Figure 4D). To determine lesion severity as a percentage of all lesions, type I-III lesions were classified as mild lesions and type IV–V lesions were classified as severe lesions.

Bottom Line: 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 decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects.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.

View Article: PubMed Central - PubMed

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.

ABSTRACT

Objective: 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).

Approach and results: 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).

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus