Age-related changes in plaque composition

Abstract

Objective

The extent of atherosclerotic plaque burden and the incidence of atherosclerosis-related cardiovascular events accelerate with increasing age. The composition of the plaque is associated with plaque thrombosis and acute coronary occlusion. Surprisingly, however, the relation between advancing age and atherosclerotic plaque composition is still unclear. In the present study, we investigated the association between plaque characteristics and advancing age in a population of patients with haemodynamically significant carotid artery stenosis.

Methods

Patients (N=383), ages 39–89 years, underwent carotid endarterectomy (CEA). Morphometric analysis was performed on the dissected atherosclerotic plaques to study the prevalence of fibrous and atheromatous plaques. Picro sirius red, haematoxylin eosin, alfa actin and CD68 stainings were performed to investigate the extent of collagen, calcification, smooth muscle cells and macrophages in carotid plaques, respectively. The presence of metalloproteinases-2 and -9 was assessed by ELISA.

Results

With aging, a decrease in fibrous plaques and an increase in atheromatous plaques were observed. This was accompanied by an age-associated decrease in smooth muscle cell content in carotid plaques. Macrophage content slightly increased with age. In addition, total matrix metalloprotease (MMP)-2 was negatively and MMP-9 positively related with age. Differences in plaque phenotype were most prominent for the youngest age quartile compared with older age quartiles.

Conclusions

With increasing age, the morphology of atherosclerotic plaques from patients with carotid artery stenosis changes. Plaques become more atheromatous and contain less smooth muscle cells with increasing age. Local inflammation and MMP-9 levels slightly increased with age in plaques obtained from patients suffering from haemodynamically significant advanced atherosclerotic lesions.

Introduction

Atherosclerosis is an inflammatory disease starting early in adolescence. The incidence of atherosclerosis-related cardiovascular events accelerates with increasing age. Rupture or erosion of the plaque surface and subsequent luminal thrombus formation are the most important mechanisms underlying the acute coronary syndromes [1], [2]. It is well recognized that the risk of plaque rupture depends on atherosclerotic lesion composition rather than luminal stenosis [3], [4].

Pathology studies have determined several characteristics of plaques that are associated with plaque rupture and subsequent thrombosis. These rupture-prone lesions or “vulnerable plaques” consist of a large atheromatous core, which is separated from the lumen by a thin fibrous cap, hide inflammatory cells such as macrophages and T lymphocytes in the shoulder region of the fibrous cap [5], [6], [7] and lack smooth muscle cells and collagen [8]. These shoulder regions have increased matrix metalloprotease (MMP) activity, indicating that increased extracellular matrix degradation may occur, which can result in a more vulnerable plaque phenotype [9].

Epidemiological studies have clearly revealed that hypercholesterolemia, diabetes, smoking and hypertension are risk factors for coronary artery disease, congestive heart failure and stroke. Yet, the most predominant risk factor for symptomatic atherosclerotic disease is advancing age [10]. This is of particular importance, as the fastest growing population in our society is that of 60 years of age and older.

With aging, structural changes occur in the large elastic arteries such as the carotid artery and the aorta. Observed age-related changes include intimal wall thickening [11] and arterial dilation [12]. Age-associated intimal media thickening is accompanied by a reduction in arterial compliance [10], [13], increased arterial stiffening [13], [14] and endothelial dysfunction [15]. Although these vascular modifications may occur in healthy individuals independent of the presence of cardiovascular risk factors, they are considered to reflect early stages of atherosclerotic disease [16].

With age, the size and number of atherosclerotic lesions increase. However, the relation between advancing age and atherosclerotic plaque composition is still unclear. Insights into age-associated changes in plaque composition are important for the identification of factors that contribute significantly to the acceleration of cardiovascular disease, eventually leading to adverse cardiovascular events. The development of novel therapies that target age-associated vascular modifications may prove beneficial in stabilizing atherosclerotic lesions and preventing plaque rupture.

In a cross-sectional study, we investigated the relationship between the main components of atherosclerotic plaques and advancing age in a population of patients with haemodynamically significant carotid artery stenosis. We specifically addressed characteristics of the plaque that have been associated with a vulnerable plaque phenotype. We report that, with increasing age, plaque characteristics differ in clinically significant carotid stenotic plaques. In the higher age quartiles, plaques become more atheromatous and contain less smooth muscle cells. In addition, the macrophage content and MMP-9 levels slightly increase with age.