Atherosclerosis

Chapter Atherosclerosis

Ronak Delewi, MD; Hayang Yang, MsC; John Kastelein, MD, PhD

A 53 years old man, without medical history or drug use, shows up in the family physician’s room and makes an anxious impression. His friend has recently suffered from myocardial infarction (MI) and he is worried that he might also face the same situation soon. As for family medical history, he has a father with hypertension and an uncle with diabetes mellitus. He doesn’t seem to have any symptoms or complaints at this moment, but he has been smoking for 25 years and is overweight. Due to these characteristics he is worried of having a high risk of getting a MI. During the physical examination, his BMI was 29, RR was 152/90 mmHg and heart rate was 75 bpm. The family physician orders a blood test for lipid profile and glucose. Both turn out to be in the normal range.

The family physician gives the patient several advices concerning primary prevention for atherosclerosis; quit smoking, try to achieve weight reduction, do regular physical activity, restrict alcohol consumption to <10-30g/day and follow a varied and balanced diet. Regarding the hypertension, the advice is to keep his RR under 140/90 mmHg. Antihypertensive medication is not indicated at this moment, because his 10-years risk of death due to cardiovascular diseases (Systematic COronary Risk Evaluation) is lower than 20%. He is advised for regular checkups of cardiovascular risk profile or report to the doctor’s office in case of chest pain.

Since the 20th century, cardiovascular diseases (CVD’s) have grown to be the leading cause of death and disability in the world, illustrated by 17.3 million deaths per year in 2008. Out of all cardiovascular diseases, coronary heart disease (46% among males, 38% among females) and cerebrovascular disease (34% among males, 37% among females) are accountable for the largest proportion of CVDs. In 2008, heart attack and stroke were responsible for 7.3 million deaths and 6.2 million deaths subsequently. Obstructive coronary and cerebrovascular disease are caused in most instances by atherosclerosis. It is a life-time illness that over time can eventually lead to obstructive disease. Once atherosclerotic lesions become clinically significant, serious acute complications such as ischemic heart disease, MI and stroke may occur. This chapter concerns the complex pathological process of atherosclerosis, possible consequences of atherosclerosis and the most recent treatment for atherosclerosis in order to prevent CVD’s.

1.1 Arterial vessel in homeostasis

The core of the pathogenesis of atherosclerosis is dysfunction of arterial vessels. In order to understand the pathogenesis of atherosclerosis, it is thus necessary to know about the functions and state of non-pathological arterial vessels.

Three layers of arterial vessel

The normal arterial vessel consists of 3 layers, namely intima, media and outer adventitia.

The intima is located closest to the arterial lumen and is therefore most ‘intimate’ with the blood. This layer is composed of a single layer of endothelial cells (endothelium), connective tissue, and several smooth muscle cells. The endothelium functions as an active metabolic barrier as well as a carrier between blood and the arterial wall. It plays a crucial role in atherosclerosis. Connective tissue consists of a matrix of collagen, proteoglycans and elastin. Lymphocytes, macrophages and other types of inflammatory cells may occasionally reside in the intima.

The media is the middle layer and is bounded by the internal and external elastic laminae. The media consists of layers of smooth muscle cells with contractile and synthetic function. As for the contractile function, smooth muscle cells enable vasoconstriction and vasodilatation. As for the synthetic function, they are responsible for the growth of the vascular extracellular matrix.

The most external vessel wall layer is called the adventitia and contains fibroblasts, connective tissue, nerves, lymphatics and vasa vasorum. Inflammatory cells may occasionally reside in the adventitia.

There is a constant dynamic interchange between the arterial wall and its cellular components and the surrounding extracellular matrix. By learning the physiology of this dynamic interchange and the functions of each cellular component, the dysfunction of these cellular components leading to atherogenesis can be understood.

Cellular components involved in atherosclerosis

Endothelial cells

The normal artery wall contains endothelial cells that manage the homeostasis of the wall by structural, metabolic, and signaling functions. The endothelium plays a role as a barrier to elements contained in the blood, but is also an active biologic interface between the blood and other tissues, regulating cellular and nutrient trafficking. It has several important functions such as keeping certain elements in blood separated from the vessel and maintaining a balance between pro-coagulant and anticoagulant activity, pro- and anti-inflammatory response, and contracted and relaxed vasomotor tone.

The endothelium produces antithrombotic molecules in order to prevent blood from clotting. Certain molecules such as heparin sulfate, thrombomodulin, and plasminogen rest on the endothelial surface whereas molecules such as prostacyclin and nitroic oxide (NO) enter the blood. Endothelium can produce prothrombotic molecules when it encounters stressors, however it normally maintains a balanced anticoagulant state, maintaining blood fluidity.

Endothelial cells also have an important function as a regulator of the immune response. In a normal situation without pathologic stimuli, endothelial cells are not capable to halt and bind patrolling leukocytes, thus maintaining an anti-inflammatory state. When local injury or infection initiates pathologic stimulation, endothelial cells respond by secreting chemokines that attract white blood cells to the injured area. Additionally, endothelium produces cell surface adhesion molecules, which recruit mononuclear cells to the endothelium and therefore promote their migration to the injury site. This response is important to the development of atherosclerosis.

Another function of endothelium is to modulate contraction of smooth muscle cells in the media by releasing substances such as vasodilators and vasoconstrictors. Vasodilators (e.g. NO, prostacyclin) and vasoconstrictors (e.g. endothelin) fine-tune the resistance of the vessel and subsequently alter the arterial blood flow. Endothelium normally maintains a state of net relaxed vasomotor tone with the predominance of vasodilators. Endothelium can also respond to various physical stimuli such as shear stress and can additionally dilate the blood vessel. The endothelium principally regulates such response through release of NO. This endothelial-dependent response is called flow-mediated vasodilation (FMD), which can be measured for clinical evaluation of endothelial function. For example, impairment of FMD is observed in the early stages of atherosclerosis. However, endothelial function tests are currently not recommended to be used for surrogate markers in clinical practice since the tests are technically challenging and the validation of clinical benefits in the evaluation of cardiovascular risk requires more evidence.

As mentioned earlier, endothelial cells can respond to or in other words get ‘activated’ due to changes in the local extracellular milieu. Examples of such changes are common stresses (e.g. shear stress and mild changes in temperature), transient infections and minor trauma. The term ‘endothelial cell activation’ (EC activation) refers to a change from the normal state, illustrated by loss of barrier function, pro-adhesive (leukocyte adhesion), vasoconstricting, and procoagulant properties. EC activation is not necessarily linked to disease and can be temporary and mild or permanent and severe.

In conclusion, the normal arterial endothelium consists of a dynamic interface with net anticoagulant properties, net relaxation of smooth muscle cells and anti-inflammatory characteristics. Endothelial cells may react to various changes in homeostasis and become ‘activated endothelial cells’.

Vascular smooth muscle cells

As mentioned earlier, smooth muscle cells have two functions, namely contractile and synthetic. Vasoconstriction and vasodilatation are regulated by various vasoactive substances such as angiotensin II, acetylcholine, NO and endothelin, which are released by endothelium. Another element of contractile function is the elasticity of the vessel, which is regulated by the lamina elastica. They are situated between the smooth muscle cells and are responsible for the stretching of the vessel during systole and diastole. This function is crucial in the pathogenesis of atherosclerosis, because it prevents the weakening of the vessel wall that can prevail as a complication of atherosclerosis. For example, aneurysm due to weakening of the vessel wall is a serious complication of atherosclerosis.

It is important to understand the synthetic function of smooth muscle cells since the dysfunction of it is thought to contribute to the pathogenesis of atherosclerosis. Normally the smooth muscle cells synthesize collagen, elastin and proteoglycans that form the connective tissue matrix of the vessel wall. Smooth muscle cells can also synthesize vasoactive and inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). These mediators stimulate leukocyte migration and induce the endothelial cells to express leukocyte adhesion molecules as mentioned earlier. This synthetic function is found to be more dominant in case of an atherosclerotic plaque, which is illustrated in the next section (1.2). Although smooth muscle cells rarely divide in normal circumstances, it can proliferate in response to injury, which is an important sign of atherosclerotic plaque formation.

Extracellular matrix

Vascular extracellular matrix in the media consists of elastin, proteoglycans and fibrillar collagen, which are principally synthesized by smooth muscle cells as mentioned earlier. With the provision of flexibility by elastin and biomechanical strength by fibrillar collagen, the arterial vessel is able to maintain the structural integrity despite high pressure within the lumen.

1.2 Arterial vessel with atherosclerosis

Three pathologic stages of atherogenesis

Atherogenesis can be divided into five key steps, which are 1) endothelial dysfunction, 2) formation of lipid layer within the intima, 3) migration of leukocytes and smooth muscle cells to the vessel wall, 4) foam cells formation and 5) degradation of extracellular matrix. Via these consecutive steps, an atherosclerotic plaque is formed. The formation of the plaque can also be divided into three major stages namely 1) the fatty streak, which represents the initiation 2) plaque progression, which represents adaption and 3) plaque disruption, which represents clinical complications of atherosclerosis.

Initiation and formation of atherosclerotic plaque

The earliest visible signs of atherogenesis are the fatty streak and pre-existing lesions of adaptive intimal thickening. Fatty streak is yellow discoloration on the surface of the artery lumen, which is flat or slightly elevated in the intima and contains accumulations of intracellular and extracellular lipid. At this stage of initiation, the fatty streak doesn’t protrude substantially into the artery wall nor impede blood flow. This process is already visible in most people by the age of 20. At this stage, there are no symptoms and this lesion may even diminish over time. Initiation of fatty streak development is most likely caused by endothelial dysfunction, since it involves entry and modification of lipids within the subintima. This modified layer of lipids creates a proinflammatory environment and initiates the migration of leukocytes and formation of foam cells (figure 8). Intimal thickening mainly contains smooth muscle cells and proteoglycan-collagen matrix with a few or no infiltrating inflammatory cells.

Endothelial dysfunction

Endothelial dysfunction is a primary event in atherogenesis, which can be caused by various agents, such as physical stress and chemical irritants. Endothelial dysfunction is also observed in other pathological conditions, which are often related to atherosclerosis such as hypercholesterolemia, diabetes, hypertension, heart failure, cigarette smoking and aging.