The risk of coronary artery disease is increased in the presence of low high-density lipoprotein (HDL) cholesterol levels.^1,2 A similar but less reliable relationship has also been shown between carotid atherosclerosis and HDL cholesterol levels.^3-6 High-density lipoprotein cholesterol may exert its protective effects by shielding the vessel from injury directly, by impeding the oxidation of lipoprotein, and by returning low-density lipoprotein (LDL) back to the liver from the atheroma.⁷

Longitudinal data on HDL cholesterol levels and atherosclerotic plaque progression in humans are limited. Knowledge about how plaque morphology relates to plaque growth is also insufficient. Plaque echogenicity can be assessed by high-resolution ultrasound based on the amount of ultrasound energy reflected from the plaque to the transducer. Plaques that reflect much of the ultrasound energy will have a white appearance on the ultrasound monitor (echogenic, or hard, plaques), and the median of the gray-scale pixel distribution (gray-scale median, or GSM) will be high. Such plaques contain fewer cellular components, more connective tissue (collagen), and varying degrees of calcification.^8,9 Conversely, if most of the emitted ultrasound is refracted and transmitted through the plaque, the plaque will appear dark on ultrasound images (echolucent, or soft, plaques) and will have a low GSM. These plaques are morphologically characterized by a large lipid core and a high macrophage content.^8,9

Using computerized analysis of ultrasound images to examine the relation between HDL cholesterol and the change in carotid plaque area and echogenicity over a period of 7 years, we evaluated patients with at least 1 plaque in the right carotid artery in the population-based Tromsø Study.

Patients and methods
Participants in the Tromsø Study underwent multiple health evaluations. At baseline in 1994 to 1995, we scanned the right carotid artery of 6727 men and women between the ages of 25 and 80 years. Atherosclerotic plaques were present in 3345 (49.7%). In 2001, 4858 patients in the original cohort were reexamined. Plaque area and echogenicity measurements taken at baseline and follow-up were available for 1952 participants. Changes in plaque area (D plaque area) and plaque echogenicity (D plaque echo) were assessed in digitized images using Adobe Photoshop version 7.0 software. Plaque area was expressed in mm², and plaque echogenicity was expressed as the GSM. Each plaque was standardized against lumen and adventitia.¹⁰ At baseline, a medical history was taken, and HDL cholesterol levels were measured along with other traditional cardiovascular risk factors. Multiple linear regression analysis was used to evaluate the independent relationship between HDL cholesterol level and ¢ plaque area. Statistical tests were 2-sided (α = 0.05).

Results
Plaque growth was associated with age, systolic blood pressure, and current smoking, and there was an inverse relationship between plaque growth and HDL cholesterol level (Table 1). The plaque growth in the highest vs the lowest HDL cholesterol quintile was 6.0 mm² and 9.0 mm², respectively. Plaque growth was largely reduced in the upper quintile (HDL cholesterol > 1.80 mmol/L).

After adjusting for other potential confounding factors, HDL cholesterol was shown to be protective against plaque progression (a 1-SD greater HDL cholesterol level correlated with a 0.93-mm² decrease in plaque growth; Table 2, Model III). Repeating the analysis, taking into account the use of antihypertensive or lipid-lowering drugs as covariates, did not change the HDL estimate, nor did eliminating participants who had ever been treated with antihypertensive drugs. The HDL estimate was strengthened, however, when the 442 participants who used lipid-lowering drugs were eliminated from the model (β; = –1.46 mm²; P = .002). The HDL estimate was also strengthened when the analysis was adjusted for baseline plaque area.

Most of the plaques (60%) be­came more echogenic (increase in GSM value) during follow-up. The plaques that became more echogenic had a lower growth rate compared with the plaques that became more echolucent. The Figure shows the relationship between plaque growth and change in plaque echogenicity. The proportion with regressed lesions (Δ; plaque area < 0) accordingly was lower in the group that became more echolucent compared with the group that became more echogenic (26% vs 33%; P = .004).

Discussion
A high HDL cholesterol level protected against plaque growth, whereas older age, higher systolic blood pressure, and smoking increased plaque growth. An increase in plaque area was found in 70% of participants, and the majority of plaques became more echogenic during follow-up. The plaques that became more echolucent, however, had a higher growth rate compared with those that became more echogenic.

The findings of this study are consistent with results from previous animal experiments showing that high levels of the chief protein component of HDL cholesterol, apolipoprotein A1, and intravenous administration of HDL cholesterol resulted in a reduction in atherosclerotic plaques.¹¹ Le­sions that regressed were more fibrotic and contained fewer macro­phages and foam cells.¹² In our study, plaques that became more echogenic (fibrous) had a higher proportion of regressed lesions and a lower growth rate compared with plaques that became more echolucent. A main mechanism in plaque development is buildup and elimination of lipids from the arterial wall. Because the majority of plaques contain a mixture of echogenic (fibrous) and echolucent (lipid-rich) material, the echolucent proportion of the plaque is increased by the buildup of lipids within the plaque as it grows. On the other hand, the regressed plaque looks more echogenic because the echogenic proportion increases with the elimination of lipids from the plaque.

High density lipoprotein cholesterol particles may transform the plaques into more fib­rotic lesions and thereby thwart their growth by removing LDL cholesterol from the vessel wall. Besides the apolipoproteins, the enzyme para­ox­onase and the lipid-processing en­zymes cholesteryl ester transfer protein and lecithin-cholesterol acyl­transferase are contained in HDL particles. These proteins, in addition to promoting cholesterol efflux, may influence atherosclerosis by interfering with inflammatory, metabolic, and oxidative processes.⁷

Between the start of the study and follow-up, about 20% of patients received HMG-CoA reductase in­hibitor (statin) treatment. The high density lipoprotein effect was markedly increased when these patients were excluded from the analyses. HDL cholesterol level is increased slightly by statins, which also exert additional effects on the arterial wall (ie, anti-inflammatory, antioxidant, and plaque stabilization) that may counteract plaque growth.

A limitation of this study is the possible underrepresentation of disabled or severely ill individuals because of loss to follow-up, which probably diminished the association between HDL cholesterol and plaque growth. In addition, we evaluated only 1 arterial territory. We might have obtained a more complete measure of plaque burden by including the femoral and left carotid arteries.

Conclusions
The results of our study show that plaque growth is reduced in the presence of increased HDL cholesterol levels. By transforming plaques to more echogenic lesions, plaque growth is reduced. High density lipo­protein cholesterol may reduce plaque growth by decreasing the in­traplaque inflammation and lipid content, making plaques more stable.

References
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2. Gordon T, Castelli WP, Hjortland MC, et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707-714.

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8. Gray-Weale AC, Graham JC, Burnett JR, et al. Carotid artery atheroma: comparison of preoperative B-mode ultrasound ap­pearance with carotid endarterectomy specimen pathology. J Cardiovasc Surg. 1988;29(6):676-681.

9. Carotid artery plaque composition—relationship to clinical presentation and ultrasound B-mode imaging. European Carotid Plaque Study Group. Eur J Vasc Endovasc Surg. 1995;10(1):23-30.

10. Elatrozy T, Nicolaides A, Tegos T, et al. The effect of B-mode ultrasonic image standardisation on the echodensity of symptomatic and asymptomatic carotid bifurcation plaques. Int Angiol. 1998;17(3): 179-186.

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A more detailed discussion of this topic can be found in Johnsen, SH, Mathiesen, EB, Fosse E, et al. Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromsø Study. Circulation. 2005;112(4):498-504.