Although low-density lipoprotein cholesterol (LDL-C) lowering with statin therapy has been part of the National Cholesterol Education Program guidelines for 26 years, significant residual cardiovascular risk remains in both primary- and secondary-prevention patients. This residual risk is particularly prominent in patients following an acute coronary syndrome (ACS). Post ACS patients have two-year cardiovascular event rates of up to 22.4 percent despite high-dose statin therapy.1 In addition, nearly 50 percent of patients hospitalized with coronary artery disease(CAD) have LDL-C <100 mg/dl.2 Thus, there has been a search for markers that more completely reflect residual cardiovascular risk. One promising new marker is the recently described novel biomarker ratio: Apolipoprotein A1 (Apo A1) divided by the sum of the cholesterol components of very low-density lipoprotein 3 (VLDL3-C) and intermediate-density lipoprotein (IDL-C)-Apo A1/VLDL3-C +IDL-C. This is referred to as the Apo A1 Remnant Ratio (AARR).  

The utility of the AARR was first evaluated in 711 women > 50 years of age, referred for cardiac catheterization.3 The AARR was obtained utilizing Atherotech’s Vertical Auto Profile (VAP) method. Apo A1 was estimated by a derivative of high-density lipoprotein cholesterol (HDL-C) species and VLDL-C was measured by density- gradient ultracentrifugation.

The percent coefficient of variation is 2.9 percent; compared to directly measured Apo A1, VAP Apo A1 has a correlation coefficient of 0.92 and a standard error of estimate of 10.3mg/dl.4

The percent coefficient of variations for VLDL3-C and IDL-C as measured by density-gradient ultracentrifugation are, respectively, 4.9 percent, 8.2 percent.5 The lower limit of normal for Apo A1 is 118mg/dl and the upper limit of normal for VLDL3-C and IDL-C are, respectively, 10mg/d1 and 20mg/d1.  

In this study, the AARR was more predictive of death/MI at 3 years than any individual lipid, sublipid, or other well- known ratis (Tg/HDL-C, Apo B/Apo A1, TC/HDL-C).

The clinical importance of the AARR is potentially driven by both the numerator and denominator. Apo A1 is the protein component of HDL, which is a principle participant in reverse cholesterol transport. In review, it accepts cholesterol from the macrophage Adenosine triphosphate- binding membrane cassette transport protein A1 (ABCA1). Unlike HDL-C, Apo A1 has a consistent inverse relationship with coronary heart disease (CHD) events.6 In our study, low levels of Apo A1, not HDL-C, were associated with an 80 percent increase in one- and three-year death/MI rates.

The denominator of the AARR is VLDL3-C and IDL-C, these measures reflect remnant lipoprotein cholesterol (RLP-C) when elevated. RLPs in the non-fasting state include chylomicron remnants, VLDL remnants, and IDL remnants, and are the result of hydrolysis of triglyceride-rich lipoproteins (TGRL). Dr. John Gofman first showed that RLPs are associated with CHD more than 60 years ago.7 RLPs have been shown to predict future coronary events in patients with or without CAD or diabetes mellitus independent of elevated triglycerides, low HDL-C or elevated LDL- C.8,9 Multiple, serial angiographic studies have demonstrated that CAD progression has a greater association with IDL mass than LDL mass as measured by analytical ultracentrifugation.10,11 Recently, using a Mendelian randomization approach in a large study of 73,513 subjects, RLP-C was shown to be a causal factor for ischemic heart disease, independent of reduced HDL-C.12 It was found that, for every 39 mg/dL increase in RLP-C, there was a 2.8- fold greater risk for ischemic heart disease.  

Our study showed that the AARR was more predictive for death/MI than non HDL-C or Apo B. RLP-C has been reported to predict stroke in patients with mild carotid atherosclerosis and metabolic syndrome independent of non- HDL-C.13 In the Women’s Health Initiative Observational study, unlike HDL-C, LDL- C, baseline triglycerides, VLDL size, and IDL particle numbers were significantly associated with incident ischemic stroke in postmenopausal women.14 Is it possible that AARR is more predictive for future CHD events than LDL-C, non-HDL-C, or Apo B? All Apo B-containing lipoproteins are not equally atherogenic. It is not just the cholesterol content of the lipoproteins but also their triglyceride content that contributes to inflammation and atherosclerosis. The triglyceride content in VLDL and IDL is estimated to be 55 and 23 percent, respectively; however, the triglyceride content in LDL is only 6 percent.15

In a study involving human aortic endothelial cells exposed to the hydrolysis of human postprandial TRGL it was shown that it was the free fatty acids derived from the hydrolysis not the free cholesterol that was associated with endothelial production of tumor necrosis factor alpha (TNFa), intracellular adhesion molecule(ICAM), and reactive oxygen species.16 TGRL hydrolysis products also increase endothelial permeability. Exposure of cultured endothelial cells to fatty acids has been shown to result in increased transfer of LDL across the endothelium.17,18 Thus, the adverse effects of TGRL hydrolysis products allows increased subendothelial access, not just for LDL particles but also for RLP. Once becoming subendothelial, unlike LDL, RLPs do not require oxidation or modification for the development of foam cells. This is apparent in patients with Type III or Type IV hyperlipidemia whose oxidized beta-VLDL (B-VLDL) or VLDL remnants were found to cause greater macrophage cholesteryl ester formation than oxidized LDL.19,20 In addition, because of their increased diameter, RLPs carry more cholesteryl ester molecules than LDL. It has been estimated that chylomicron remnants — TGRL of 100 nanometers in diameter — contain 40 times more cholesteryl ester than LDL particles.21 Therefore, the AARR provides unique information compared to standard lipids and standard lipid ratios such as TC/ HDL-C, Tg/HDL-C, and LDL-C/HDL-C.  

In a recent preliminary report, the AARR in a primary prevention cohort of African Americans — 4,722 participants in the Jackson Heart Study — was found to better stratify risk for CHD incidence than standard lipids, non-HDL-C, Apo B or Apo A1.22

In summary, the novel biomarker AARR has been demonstrated in one study and in a preliminary report with a larger, second clinical cohort to be more predictive of CHD than standard lipids, non HDL-C, Apo B, and common lipid/lipoprotein ratios. This exciting, novel, new biomarker ratio is readily available. However, it needs to be evaluated in further populations. Of interest is whether targeting the AARR will be a better target than LDL-C for lowering the cardiovascular risk burden. 

Disclosure statement: Dr. May has no disclosures to report. Dr. Nelson has received speaker honoraria from Amarin, AstraZeneca, Atherotech Diagnostic Lab, and Kowa Pharmaceuticals America Inc. He’s been on the advisory board from Amarin, Atherotech Diagnostic Lab, and Kowa Pharmaceuticals American Inc. He’s received consulting fees and been a stockholder for Amarin.

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