Low-density lipoprotein as the key factor in atherogenesis too high, too long, or both

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1 Low-density lipoprotein as the key factor in atherogenesis too high, too long, or both Lluís Masana Vascular Medicine and Metabolism Unit. Sant Joan University Hospital. IISPV. CIBERDEM Rovira i Virgili University REUS - SPAIN

2 HDL Residual risk Metaanalysis LDL Placebo n= 732 (29,3%) Rosuvastatin 25 n= 692 (27,5%) Negative assays Hazard ratio = 0.92 IC 95% 0,83 a 1,02 p= 0,12 Statins Diabetes Taylor AJ et al. N Engl J Med 2009;361: Kjekshus J. N Engl J Med 2007;357: Naveed Sattar et al. Lancet 2010, 375: Kausik K. Ray et al. Arch Intern Med. 2010;170:

3 A direct association between Cholesterol and CV Risk has been established by the main epidemiological studies Cholesterol appears as one of the main elements for CV Risk calculations LDL Major Lipids, Apolipoproteins, and Risk of Vascular Disease The Emerging Risk Factors Collaboration Individual records from 68 long-term prospective studies people without initial vascular disease 2.79 million person-years of follow-up 8857 nonfatal myocardial infarctions 3928 coronary heart disease [CHD] deaths 2534 ischemic strokes 513 hemorrhagic strokes 2536 unclassified strokes JAMA. 2009;302(18):

4 Cholesterol is a Major Component of the Atherosclerotic Plaque, in both Stable and Unstable Lesions William Insull, Jr. Am J Med (2009) 122, S3 S14

5 Animal Models With Lipid Metabolism Disturbances Develop Accelerated Aortic Arteriosclerosis Untreated FH patients develop accelerated CHD LDLR -/- ApoE -/-

6 Relation of Low-Density Lipoprotein Cholesterol Reduction to Risk of Coronary Artery Disease and Death Meta-Regression Analysis of Large-Scale Trials of Statin Therapy 20% 1 mmol/l Jorge R. Kizer et al. Am J Cardiol 2010;105:

7 Cardiovascular Residual Risk 4S LDL<100 TNT LDL<70?

8 * Atherogenic dyslipidemia Low HDL High Triglycerides Diabetes,Obesity, Metabolic Syndrome, FCHL, HIV, Lipodystrophy, Reumathoid Arthritis, Lupus, Inflammatory Chronic diseases * Cabre A et al. Atherosclerosis, 2007

9 LOW HDL HIGH TG Sd LDL HIGH APO B HIGH LDL P HIGH NON-HDL CHOL LARGE VLDL SMALL HDL DYSFUNCTIONING HDL INCREASED NEFA POSTPRANDIAL LIPEMIA

10 SMALL AND DENSE LDL More sd-ldl Particles Needed To Transport The Same Amount Of Cholesterol Normal Sd-LDL Cholesterol Apo B Apo B is a LDL Particle Number Subrogated Marker

11 The LDL Particle Number And Apo B Increase With The Number Of Metabolic Syndrome Components In Respect To LDL Cholesterol The Framingham Study in DIABETES AND VASCULAR DISEASE RESEARCH, Nov 2008

12 NMR LDL subclasses and IMT in SLE patients Total LDL Large LDL Small LDL Very Small LDL Gonzàlez et al. J Rheumat, 2010; 37:11; doi: /jrheum

13 Inflammation modified LDL LDL from Rheumatoid Arthritis patients are smaller and have a higher affinity for extracelular matrix glycosaminoglycanes. Hurt-Camejo E, Masana L et al Arthr Rheum, 2001; 44:

14 LDL in Rheumatoid Arthritis by TNFa genotype (-1031T>C) Vallvé et al. J Rheumatol 2008;35:

15 NMR LDL subclasses and IMT in DYSLIPIDEMIC patients total LDL p=0.009 large LDL p=0.031 small LDL very small LDL p=0.030 Guardiola et al. Manuscript in preparation adjusted for age, gender and BMI

16 Association of Low-Density Lipoprotein Subfractions With Cardiovascular Outcomes CV outcome and Measurement type Studies (n) Participants (n) Significant Result Nonsignificant Result CAD Incident Size Number Pattern CAD Progression Size Number Patern Stanley Ip et al. Ann Intern Med. 2009;150:

17 Mora S et al. Circulation 2009;119; NMR Lipoprotein Profiles and Incident CVD

18 Additional Clinical Objectives (mg/dl) LDL < 100 < 70 Non HDL Ch <100 <130 Apo B < 80 < 90 HDL > 40/50 Triglycerides < 150 ADA and ACC Joint Statement 2008

19 Proportion of Subjects Who Had an AMI or Revascularization, by LDL-C Reduction Category and Quartile of Age Age 0 LDL reduction < >75 < >70 Rahilly-Tierney CR et al. Circulation 2009;120;

20 Risk of MI or coronary death among patients with ACS or chronic CAD in 7 studies of statin therapy intensity Josan, K. et al. CMAJ 2008;178:

21 LDL plays a causal role in atherogenesis LDL cholesterol remains the main lipid target both in primary and secondary cardiovascular prevention LDL becomes modified and more atherogenic in proinflammatory conditions, including obesity, MS and diabetes. LDL cholesterol is a LDL particle subrogated marker. Other parameters, as particle number and size, could give a supplementary information about LDL metabolic status. Low HDL and high TG are associated to smaller and denser LDL Apo B and Non HDL cholesterol are clinical markers of LDL alterations A good lipid control includes low LDL, ApoB, Non-HDL Ch, TG and normal HDL, Apo A1

22 Many thanks for your attention from the REUS group!