Pathogenesis of Atherogenic Dyslipidemia

Scott M. Grundy, MD, PhD.

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In This Article

Atherogenic Dyslipidemia

It is well established that elevation of serum LDL is a major cause of atherosclerosis and coronary heart disease (CHD).[1,2,3,4,5,6,7,8] However, it is also known that other serum lipoproteins-ie, triglyceride-rich lipoproteins (TGRLP), very low-density lipoproteins (VLDL), chylomicrons, and HDL-are involved.

In atherogenic dyslipidemia, the pattern of lipoprotein abnormalities-or atherogenic lipoprotein phenotype-includes elevations of VLDL levels, increased small LDL particles, and low HDL-cholesterol (HDL-C).[9,10,11] The abnormalities usually occur together because they have a common metabolic basis (Figure 1). The term "atherogenic" is applied to this form of dyslipidemia because it frequently occurs in patients with premature CHD.[11,12] Moreover, the pattern frequently is observed in patients with type 2 diabetes, and in patients with diabetes, it has been called diabetic dyslipidemia.[13,14]

Insulin resistance, leading to hyperinsulinemia, plays a central role in increasing the synthesis of very low-density lipoprotein (VLDL), small dense low-density lipoprotein (LDL), and triglyceride-rich lipoproteins (TGRLP), as well as depleting the level and cholesterol content of high-density lipoprotein (HDL). This cascade of lipid abnormalities accelerates the development of atherosclerosis.

Patients with elevated TGRLP have high serum triglyceride levels. The serum triglyceride concentrations almost always exceed 150 mg/dL and often are greater than 200 mg/dL.[15] The major form of TGRLP in atherogenic dyslipidemia consists of VLDL remnants, ie, smaller, partially catabolized VLDL. VLDL remnants tend to be enriched in cholesterol esters. Many studies indicate that VLDL remnants, like LDL, are atherogenic,[16,17,18,19,20] perhaps even more atherogenic than LDL.[20] Particle size of VLDL remnants is somewhat greater than that of LDL; but even so, these remnants almost certainly enter the artery wall similarly to LDL. It is here that they exert their atherogenic action.

When triglyceride levels are raised, LDL particles typically are reduced in size. The reduction in particle size is somehow related to high triglyceride concentrations; LDL seemingly become depleted of cholesterol esters by their transfer to TGRLP. Several studies[11,12,21,22] show a positive association between small LDL particles and risk for CHD. Small LDL particles may have increased atherogenicity because of at least two factors: they probably are filtered more readily into the arterial wall than are normal-sized LDL; and small LDL are prone to oxidation, which may enhance their atherogenicity.[21]

It is important that primary care providers be aware that the presence of small LDL particles can mask an elevated level of LDL particles.[21,22] Thus, the LDL-C level underestimates the atherogenic potential of LDL.[23,24] An increased number of LDL particles undoubtedly is one factor contributing to the increased risk of CHD in many patients with atherogenic dyslipidemia.

The third component of atherogenic dyslipidemia is a low concentration of HDL-C. In this condition, HDL particles tend to be partially depleted of cholesterol; this accounts for some of the reduction of HDL-C levels. The number of HDL particles is reduced in addition. HDL appears to play a protective role against the development of atherosclerosis.[1] Several mechanisms have been implicated.[25,26,27,28,29,30,31]

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