**2. Pathophysiology of atherosclerosis**

The coronary arteries are composed of three layers: tunica intima, tunica media, and tunica adventitia. The tunica intima is the innermost lining inside these vessels, which is further composed of three layers of the endothelium. Simple squamous cells make up the innermost layer, which functions as a barrier that allows blood to flow smoothly. Any break in any part of the endothelial lining exposes blood to the subendothelial layer, starting the clotting mechanism. The tunica media is the middle layer of the vessels, composed of layers of smooth muscle cells. The tunica adventitia is the outer connective tissue layer supporting the vessel itself formed of loose connective tissue, vessels, and nerves [1]. When the initial fatty streaks or plaque precursors grow, it is usually outward, meaning there is not an initial direct effect on the blood flow or size of the lumen [5]. Lesions progress when the intima's smooth muscle cells begin to divide and secrete extracellular matrix molecules, such as collagen [6]. Other smooth muscle cells will penetrate the intima from the media, where they will join the other muscle cells in forming a fibrous cap overlying the lipid core. When there is a persistence of risk factors such as high LDL levels, the lipid core continues to grow in this manner.

The major lipoprotein classes include chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Larger in size and more triglyceride-rich lipoproteins are the less dense. Protein molecules, known as apolipoproteins (apo) on these particles' surface, guide the lipoproteins' interaction with tissues, cells, and different organs. LDL receptors bind to apo-B, the predominant apoprotein in LDL, and apo-E found on VLDL and some HDL particles. This receptor-mediated uptake delivers circulating cholesterol to the liver and other tissues. Apo-B may contribute to LDL's atherogenicity by promoting Apo-B particle entrapment within the arterial wall. Apo A-I, the predominant apoprotein in HDL, aids antiatherogenic efflux of cholesterol from peripheral tissues [6].

The different type of plaque morphology includes foam cell-rich matrix (obtained from fatty streaks), collagen-rich matrix (from sclerotic plaques), collagen-poor matrix without cholesterol crystals (from fibrolipid plaques), atheromatous core with abundant cholesterol crystals (from atheromatous plaques), and segments of normal intima derived from human aortas at necropsy. Atheromatous cores are associated with the most significant platelet deposition and largest thrombus formation than other components of atherosclerotic lesions. Therefore, we are led to believe that atherosclerotic plaques with larger atheromatous cores are more prone to cause acute coronary events because of their greater thrombogenicity after rupture [7].

Studies have also shown that aggressively lowering LDL cholesterol alters the composition of coronary atheromas. Lowering LDL cholesterol decreases the size of the lipid core, stabilizing the plaque by decreasing the lipid core and increasing the ratio of fibrous tissue to atheroma. This stabilizes the plaque by increasing the calcification of the plaque, reducing likelihood of plaque rupture [6]. There is an increase in fibrous tissue and calcified tissue within the atheroma replacing the lipid core. Therefore, calcification increases with aggressive lipid-lowering therapies like statins.

**133**

*Changes in Atherosclerotic Plaque Composition with Anti-Lipid Therapy as Detected…*

**3. Plaque characterization by noninvasive imaging**

Noninvasive imaging modalities such optical coherence tomography (OCT), intravascular ultrasound (IVUS), and coronary computed tomography angiography (CCTA) have the ability to characterize plaque based on the above pathophysiology and define high risk features that in turn increase risk of cardiovascular events [8].

Coronary artery calcium scoring and coronary artery calcification assessment are among the most emerging noninvasive coronary artery imaging applications. Initially, calcifications on chest radiography and ex vivo histology were used to discuss the relationship between coronary calcification and obstructive coronary artery diseases. The coronary artery calcium (CAC) scan consists of a non-contrast, electrocardiogram gated computed tomography of the heart. It is obtained during a short period of held inspiration. Once the image is obtained, the arterial calcium is defined using Hounsfield units. A density of greater than 130 Hounsfield units across an area of at least 1 mm is considered significant. Atherosclerotic calcification is reported either by volume or mass in Agatston units (AU), a semiquantitative measure that further incorporates aspects of calcium density and

Progression of coronary calcium scores have a direct impact on clinical coronary events. One of the largest cohorts, the Multi-Ethnic Study of Atherosclerosis (MESA), followed over 5,600 patients. Participants received initial CAC scans and were followed for a median duration of 7.6 years, and then received follow up CAC. The change in calcium score was measured between initial and follow up was correlated with coronary artery events. Endpoints included myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, and cardiac death. Patients with non-zero CAC score at baseline were more likely to be older, male, diabetic, previous smoker and be on lipid lowering medication or hypertensive medication. Eighty-four percent of patients with a zero CAC score at baseline remained at zero on follow up. Patients with calcium score increases greater than 100 had a two to three-fold greater risk for the cardiac endpoints. Patients with 15–29% annual increase in CAC had an increased risk (hazard ratio: 1.6) for cardiac events compared to those with less than five percent progression annually. The study concluded that CAC scores correlate with clinical events including MI and

Computed tomography can characterize plaque morphology based upon Hounsfield Units, identifying high risk plaque. Plaque morphology on CCTA is characterized as low-attenuating plaque, fibrofatty, fibrocalcified and densely calcified. High risk or vulnerable plaque features include low-attenuating, spotty calcification and positive remodeling. Compared with intravascular ultrasound,, CCTA has shown high sensitivity and specificity in evaluating plaque morphology [4]. A large study published in the Journal of American College of Cardiology by Motoyama et al. established CCTA characterization of plaque morphology and the clinical implications. The study stratified patients into different morphological groups. Low attenuated plaque was defined as less than 30 Hounsfield Units. This was correlated with previous studies using intravascular ultrasound showing a sensitivity of 91% and specificity of 100%. %. Intermediate attenuated plaque was defined 30 HU to 150 HU and calcified plaque was defined as greater than 150 HU. Remodeling was the other factor in this study (positive, negative, or none). Coronary artery positive remodeling was defined as when the size of the lumen is increased by 10% more in the region of the plaque than in a reference segment

*DOI: http://dx.doi.org/10.5772/intechopen.96673*

distribution [9].

cardiac death [10].

*Changes in Atherosclerotic Plaque Composition with Anti-Lipid Therapy as Detected… DOI: http://dx.doi.org/10.5772/intechopen.96673*

Noninvasive imaging modalities such optical coherence tomography (OCT), intravascular ultrasound (IVUS), and coronary computed tomography angiography (CCTA) have the ability to characterize plaque based on the above pathophysiology and define high risk features that in turn increase risk of cardiovascular events [8].

### **3. Plaque characterization by noninvasive imaging**

Coronary artery calcium scoring and coronary artery calcification assessment are among the most emerging noninvasive coronary artery imaging applications. Initially, calcifications on chest radiography and ex vivo histology were used to discuss the relationship between coronary calcification and obstructive coronary artery diseases. The coronary artery calcium (CAC) scan consists of a non-contrast, electrocardiogram gated computed tomography of the heart. It is obtained during a short period of held inspiration. Once the image is obtained, the arterial calcium is defined using Hounsfield units. A density of greater than 130 Hounsfield units across an area of at least 1 mm is considered significant. Atherosclerotic calcification is reported either by volume or mass in Agatston units (AU), a semiquantitative measure that further incorporates aspects of calcium density and distribution [9].

Progression of coronary calcium scores have a direct impact on clinical coronary events. One of the largest cohorts, the Multi-Ethnic Study of Atherosclerosis (MESA), followed over 5,600 patients. Participants received initial CAC scans and were followed for a median duration of 7.6 years, and then received follow up CAC. The change in calcium score was measured between initial and follow up was correlated with coronary artery events. Endpoints included myocardial infarction, angina followed by revascularization, resuscitated cardiac arrest, and cardiac death. Patients with non-zero CAC score at baseline were more likely to be older, male, diabetic, previous smoker and be on lipid lowering medication or hypertensive medication. Eighty-four percent of patients with a zero CAC score at baseline remained at zero on follow up. Patients with calcium score increases greater than 100 had a two to three-fold greater risk for the cardiac endpoints. Patients with 15–29% annual increase in CAC had an increased risk (hazard ratio: 1.6) for cardiac events compared to those with less than five percent progression annually. The study concluded that CAC scores correlate with clinical events including MI and cardiac death [10].

Computed tomography can characterize plaque morphology based upon Hounsfield Units, identifying high risk plaque. Plaque morphology on CCTA is characterized as low-attenuating plaque, fibrofatty, fibrocalcified and densely calcified. High risk or vulnerable plaque features include low-attenuating, spotty calcification and positive remodeling. Compared with intravascular ultrasound,, CCTA has shown high sensitivity and specificity in evaluating plaque morphology [4].

A large study published in the Journal of American College of Cardiology by Motoyama et al. established CCTA characterization of plaque morphology and the clinical implications. The study stratified patients into different morphological groups. Low attenuated plaque was defined as less than 30 Hounsfield Units. This was correlated with previous studies using intravascular ultrasound showing a sensitivity of 91% and specificity of 100%. %. Intermediate attenuated plaque was defined 30 HU to 150 HU and calcified plaque was defined as greater than 150 HU. Remodeling was the other factor in this study (positive, negative, or none). Coronary artery positive remodeling was defined as when the size of the lumen is increased by 10% more in the region of the plaque than in a reference segment

*Management of Dyslipidemia*

densely calcified plaque [4].

**2. Pathophysiology of atherosclerosis**

lipid core continues to grow in this manner.

cholesterol from peripheral tissues [6].

thrombogenicity after rupture [7].

This development has made plaque characterization possible. Categories of plaque are placed into 4 broad categories: low-attenuating, fibrofatty, fibrocalcified, and

The coronary arteries are composed of three layers: tunica intima, tunica media, and tunica adventitia. The tunica intima is the innermost lining inside these vessels, which is further composed of three layers of the endothelium. Simple squamous cells make up the innermost layer, which functions as a barrier that allows blood to flow smoothly. Any break in any part of the endothelial lining exposes blood to the subendothelial layer, starting the clotting mechanism. The tunica media is the middle layer of the vessels, composed of layers of smooth muscle cells. The tunica adventitia is the outer connective tissue layer supporting the vessel itself formed of loose connective tissue, vessels, and nerves [1]. When the initial fatty streaks or plaque precursors grow, it is usually outward, meaning there is not an initial direct effect on the blood flow or size of the lumen [5]. Lesions progress when the intima's smooth muscle cells begin to divide and secrete extracellular matrix molecules, such as collagen [6]. Other smooth muscle cells will penetrate the intima from the media, where they will join the other muscle cells in forming a fibrous cap overlying the lipid core. When there is a persistence of risk factors such as high LDL levels, the

The major lipoprotein classes include chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins, low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Larger in size and more triglyceride-rich lipoproteins are the less dense. Protein molecules, known as apolipoproteins (apo) on these particles' surface, guide the lipoproteins' interaction with tissues, cells, and different organs. LDL receptors bind to apo-B, the predominant apoprotein in LDL, and apo-E found on VLDL and some HDL particles. This receptor-mediated uptake delivers circulating cholesterol to the liver and other tissues. Apo-B may contribute to LDL's atherogenicity by promoting Apo-B particle entrapment within the arterial wall. Apo A-I, the predominant apoprotein in HDL, aids antiatherogenic efflux of

The different type of plaque morphology includes foam cell-rich matrix (obtained from fatty streaks), collagen-rich matrix (from sclerotic plaques), collagen-poor matrix without cholesterol crystals (from fibrolipid plaques), atheromatous core with abundant cholesterol crystals (from atheromatous plaques), and segments of normal intima derived from human aortas at necropsy. Atheromatous cores are associated with the most significant platelet deposition and largest thrombus formation than other components of atherosclerotic lesions. Therefore, we are led to believe that atherosclerotic plaques with larger atheromatous cores are more prone to cause acute coronary events because of their greater

Studies have also shown that aggressively lowering LDL cholesterol alters the composition of coronary atheromas. Lowering LDL cholesterol decreases the size of the lipid core, stabilizing the plaque by decreasing the lipid core and increasing the ratio of fibrous tissue to atheroma. This stabilizes the plaque by increasing the calcification of the plaque, reducing likelihood of plaque rupture [6]. There is an increase in fibrous tissue and calcified tissue within the atheroma replacing the lipid core. Therefore, calcification increases with aggressive lipid-lowering therapies like

**132**

statins.

proximal to the plaque. This large study showed that when a subject has both positive remodeling and low attenuated plaque they are at high risk for having an acute coronary syndrome in the next two years. Twenty two percent of subjects with both low attenuated plaque and positive remodeling had acute coronary syndrome within the next two years compared to less than one half of one percent of the subjects with neither positive remodeling nor low attenuated plaque [11].

Several trials have demonstrated that use of statin therapy has shown benefit in primary prevention of coronary artery disease and secondary prevention of coronary artery disease. Statins have become the standard of care in coronary artery disease and are in all major anti lipid and coronary artery disease guidelines. Statins offer several benefits. Directly, they reduce hepatic cholesterol synthesis but several pleiotropic effects have been defined, including reduction in inflammation, cholesterol egress from the vasculature and plaque stabilization as described. There are many different areas of research being performed on various potential beneficial effects of statin therapy including beneficial effect on vascular tone by the upregulation of nitric oxide, reducing platelet aggregation and having antithrombotic properties, and anti-inflammatory properties including reduction in oxidative stress [4].
