COMMENTARIES

ApoB/ApoA1 ratio and Subclinical Atherosclerosis in a Cypriot population

Andrie Panayiotou, Ph.D.1, Maura Griffin, M.Sc., DIC, Ph.D. 2,3, Niki Georgiou R.N. 3, Dawn Bond, S.R.N. 2,3, Theodosis Tyllis, M.D., M.Sc., DIC3, Chrysa Chakouri, M.D. 4, Charis Fessas, M.D. 5, and Andrew Nicolaides, M.S., FRCS1,2,3,6, 1Department of Biomedical Sciences, University of Cyprus, Nicosia Cyprus; 2Vascular screening and Diagnostic Centre, London, U.K.; 3Vascular Screening and Diagnostic Centre, Nicosia, Cyprus; 4Department of Radiology, Nicosia General Hospital, Nicosia, Cyprus; 5The Cyprus Heart Foundation, Nicosia, Cyprus; 6Department of Vascular Surgery, Imperial College, London, U.K.
Please address correspondence to:
Andrie Panayiotou, Ph.D.
Department of Biological Sciences
University of Cyprus
P.O. Box 20537
1678, Nicosia, Cyprus
Email: andriepanayiotou@cytanet.com.cy

Introduction

High concentrations of LDL cholesterol represent a risk factor for atherosclerotic cardiovascular disease and mortality [1]. However, they provide no information on other lipoprotein particles or the atherogenetic ability of the LDL particles. Apolipoprotein B (apoB) serum concentration is a measure of the number of LDL, intermediate density lipoprotein, and VLDL atherosclerotic particles [2] and studies have shown that apoB is a better candidate risk parameter than non-HDL cholesterol for identifying subgroups of individuals with elevated cardiovascular risk [3] as well as predicting carotid intima-media thickness (IMT) [4]. Apolipoprotein A-1 (apoA1) serum concentration is a measure of HDL particle number [5]. Epidemiological studies have shown that serum levels of HDL cholesterol and apoA-1 are inversely correlated with risk of CVD.

Recent findings indicate that a high apoB/apoA-1 ratio is associated with both the metabolic syndrome and rapid progression of atherosclerosis as shown by IMT measurements in the common carotid artery and carotid bulb [6]. However, the association between apoB/apoA-1 ratio and measures of subclinical atherosclerosis such as presence, number, size, and echolucency of plaques has not been investigated.

 

Methods

We sought to determine the relationship of the apoB/apoA1 ratio to early atherosclerosis as measured by ultrasound in terms of IMT, plaque size, and plaque echolucency in a Cypriot population cohort of 767 people (men and women) over 40. In all of the participants fasting total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides (TG), glucose, apolipoprotein B (apoB), and apolipoproteinA-1 (apoA1) were determined with automated methods. A full medical history and physical examination was taken recording cardiovascular symptoms as well as past and current medication. The physical examination included height and weight measurements, a sitting blood pressure, and a resting 12-lead ECG.

Ultrasonic scans of each carotid and femoral bifurcation were taken first transversely and then longitudinally and the intima-media complex of the far wall of the common carotid artery or common femoral artery 1.5 to 2.0 cm proximal to the bifurcation was measured at its thickest part (mean of three readings) on both transverse and longitudinal sections. The mean of the measurements from both carotid arteries was used in the analysis (IMTcc). An arterial bifurcation (internal carotid or common femoral bifurcation) was classified as being affected by plaque if there was a localised thickening of greater than 1.2 mm that did not uniformly involve the whole arterial wall. Careful transverse scanning in addition to longitudinal scanning and the use of colour flow allowed for a better appreciation of the geometry and borders of the plaque, thereby allowing a more accurate assessment and measurement of plaque thickness (IMTmax). In the absence of plaques the IMTcc measurement was used. The mean of the measurements from both carotid arteries was used in the analysis. Total plaque thickness (TPT) was defined as the sum of the maximum plaque measurements made in each of the four bifurcations scanned. Plaques were also classified as 1 to 5 according to Widder et al. [7] classification (with type 1 being the most echogenic and type 5 the most echolucent). The ultrasonic features of plaques were defined as follows: total plaque thickness (TPT) was the sum of the thickest plaques in each of the four arteries and mean plaque type (MPT), the Widder mean plaque type in the four arteries. Black plaque burden (BPB) is the product of TPT * MPT.

 

Results

In a univariate linear regression analysis, the ratio of apoB/apoA1 was significantly associated with IMTcc (P = 0.002). After adjustment for age, sex, smoking in pack-years, diabetes mellitus, and hypertension, the apoB/apoA1 ratio remained significantly associated with IMTcc (P < 0.0001).

In a univariate linear regression analysis, the ratio of apoB/apoA1 was significantly associated with IMTmax (P = 0.004). After adjustment for age, sex, smoking in pack-years, diabetes mellitus, and hypertension, the apoB/apoA1 ratio remained significantly associated with IMTmax (P < 0.0001).

In a univariate linear regression analysis, the ratio of apoB/apoA1 was significantly associated with TPT (P = 0.003). After adjustment for age, sex, smoking in pack-years, diabetes mellitus, and hypertension, the apoB/apoA1 ratio remained significantly associated with TPT (P < 0.0001).

Finally, in a univariate linear regression analysis, the ratio of apoB/apoA1 was significantly associated with BPB (P < 0.0001). After adjustments for age, sex, smoking in pack-years, diabetes mellitus, and hypertension, the apoB/apoA1 ratio remained significantly associated with BPB (P < 0.0001).

The ratio of total cholesterol/HDL was also associated with IMTcc, IMTmax, TPT, and BPB but the association was not as strong as with the apoB/apoA1 ratio (data not shown).

 

Discussion

Our data support the hypothesis that the apoB/apoA1 ratio is associated with subclinical atherosclerosis as indicated by measurements not only of IMT but also of total plaque thickness and black plaque burden, a measure of plaque instability. The association between ultrasonic measurements of plaque echolucency and the risk of stroke has been shown previously [8-10].

          Recent findings by the Tromso Study group [11] that the change in plaque area was inversely correlated with change in echogenicity, suggest that it is the change in echogenicity that it is associated with plaque growth; therefore, plaques that remain echolucent may have a higher growth potential than plaques that remain echogenic. The same group has already shown that presence of echolucent plaques was associated with higher degree of stenosis, which suggests that echolucent plaques are more likely to develop into advanced stenosis compared to fibrous and calcified plaques [9].

          The high percentage of people on cholesterol lowering therapy (19%) might pose some questions concerning our findings. However, statins may lower LDL cholesterol but have little effect on HDL and consequently apoA1. Moreover, higher levels of LDL in our subjects (as a result of not receiving cholesterol lowering therapy) would accentuate even more the relationship between ultrasonic features and the apoB/apoA1 ratio.

          Evidence is now accumulating that the apoB/apoA1 ratio is superior to the total cholesterol/HDL cholesterol ratio for prediction of CV risk in both sexes and in all ages as shown by Walldius et al. [12]. Even more recently, it was shown in the AMORIS study population that the diagnostic accuracy of the apoB/apoA1 ratio was significantly greater than any cholesterol ratio and that the difference between the apoB/apoA1 OR compared with the TChol/HDL progressively widened as risk increased. This would suggest that the advantage of the apoB/apoA1 ratio is greatest in populations at highest risk [13].

          Given that the apoB/apoA1 ratio is a measurement of the number of apoB atherogenic particles over the number of apoA1 anti-atherogenic particles there is also a biological plausibility that it is a more important factor than the amount of lipids carried per particle. In addition, as demonstrated by Marcovina and Packard [14] standardization of apolipoproteins A1 and B is easier to achieve because of the availability of suitable reference materials and uniformity of methodological approaches. Furthermore, unlike lipid and lipoprotein measurements, measurements of apolipoproteins can be performed in nonfasting samples; high triglyceride values can interfere with direct measures of HDL and LDL cholesterol, but do not appear to have a significant effect on the accuracy of apoAI and apoB measurements [14].

So far, studies have correlated apoB/apoA1 ratio with late atherosclerosis, mainly clinical events. Our data suggest that the apoB/apoA1 ratio is associated with early atherosclerosis and may be a key-factor in the early formation of stable and unstable plaques. However, prospective studies are required in order to determine causality.

References

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