Lipoproteins/Particles ApoA1 ApoB TG Rich Chylomicron VLDL 0.95 Chylomicron Remnants VLDL Remnants 1.006 IDL Density (g/ml) LDL-R 1.019 By reporting single values for lipoprotein cholesterol levels, the traditional lipid panel implies that lipoproteins such as HDL, LDL,… are single entities. This slide illustrates that all lipid sub-fractions are present in a continuum of size and density, with an especially large gradient for the triglyceride-rich lipoproteins IDL, VLDL, and chylomicrons. Technologies that sort by particle size (NMR and GGE) cannot separate IDL and Lp(a) from LDL-R, as these particles have overlapping size. They do differ by density so ultracentrifugation is the best way to separate total LDL into its 3 components. Total LDL is made up of Lp(a), IDL and real LDL or R-LDL-R. We define R-LDL as total LDL-C minus Lp(a)-C minus IDL-C. Each requires different therapies, confers different risk and has different inheritance. Both Lp(a) and IDL are more atherogenic than LDL itself. They do not respond to statins and both are highly inherited and implicated in premature CAD. Lp(a), “the widowmaker” doubles risk but when another lipid risk factor, such as dense LDL, is also present the risk leaps to 25x. It may be useful to point out that Lp(a) cannot be accurately measured in most commercial laboratories because the immunoassay kits are sensitive to the size heterogeneity of the apoprotein(a) due to variation in the # of kringle repeats. Lp(a) rises in renal failure and is probably partly responsible for the terrible CAD in ESRD patients. High IDL requires combination therapy with a statin plus niacin. Density 1.006-1.019 g/ml. Lp(a) and R-LDL are density range 1.019-1.063 g/ml. Lp(a) and small/dense LDL overlap in the density range 1.050-1.063 g/ml. Note that Lp(a) has overlaps with IDL and large R-LDL when GGE is used because of its different electrophoretic mobility – while the actual Lp(a) size is 21nm-25nm. Dense, small LDL is called Pattern B and increases risk 4x. Intermediately dense LDL is called Pattern A/B and doubles risk. HDL2 is the most protective HDL sub-fraction. HDL3 may be mildly protective to inert. You may have normal HDL but still have low HDL2 and not know it. Exercise and wine raise HDL2, as does niacin, fenofibrate and simvastatin. Atherogenic remnant lipoproteins include IDL and VLDL3 (small/dense). These are elevated in Metabolic Syndrome and NIDDM, and respond to low carbohydrate diets. If Lp(a), IDL or small/dense LDL pattern B are found, then first degree relatives should be tested. Note that large LDL may be confused with Lp(a) and IDL with size-based (vs. density based) separation methods as Lp(a) and IDL overlap with large R-LDL in size. 1.050 1.063 HDL2 Lp(a) Only these lipoprotein particles found in plaque at biopsy. 1.100 HDL3 1.20 1000 5 10 20 40 60 80 Lipoprotein/Particle Size (nm)

What is Total Cholesterol…Really VLDL3: Most dense VLDL subclass. Atherogenic B Total VLDL: Main carrier of triglycerides. Elevated levels shown to contribute to increased risk for CAD. VLDL-C Buoyant LDL Pattern A: Large, buoyant LDL B B IDL Remnants IDL: An intermediate in VLDL catabolism. Atherogenic B Dense LDL Pattern B: Small, dense LDL. “Highest Risk” Total LDL: The end product of VLDL catabolism. LDL-C TG-RICH LIPOPROTEINS HDL2 HDL2:Large, buoyant HDL. A B Lp(a): Consists of LDL plus a protein called apo(a). “Heart attack” cholesterol. Total HDL HDL-C HDL3 HDL3: Small, Less mature A ApoA lipoproteins ApoB lipoproteins (Bad – NHDLc = VLDL, IDL, LDL, Lpa-c)

Lipoprotein Particles by Density and Size Segrest et al. Atlas of Atherosclerosis. 2nd Edition; Philadephia