Review Article

Atherosclerosis: a life changing phenomenon

Awani Kumar Rai, Suresh Chandra, Shashi Pratap Singh*, Asfa Parveen

Pranveer Singh Institute of Technology, Kanpur, U.P., India

*For correspondence

Shashi Pratap Singh,

Research Scholar

Pranveer Singh Institute of Technology, Kanpur, U.P., India.

Email: shashipratapsingh111 @gmail.com

 

 

 

 

Received: 20 March 2016

Revised: 28 March 2016

Accepted: 12 April 2016

ABSTRACT

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis, the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. The lesions of atherosclerosis occur principally in large and medium-sized elastic and muscular arteries and can lead to ischemia of the heart, brain, or extremities, resulting in infarction. They may be present throughout a person's lifetime. Among patients with established cardiovascular disease, mortality is lower among those who participate in an exercise program than among those who do not. Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many atherosclerotic process.

Keywords: Atherosclerosis, Dyslipidaemia, Antihyperlipidaemic, Cholesterol, Atherogenesis

Introduction

Atherosclerosis is a progressive disease with a multifactorial pathogenesis, which involves both large and mid-size arteries of different districts, causing stenosis of some vessels and ectasia in others. The clinical manifestations of the disease are different depending on the affected district (ischemic heart disease, ischemic stroke, peripheral artery diseases). Atherosclerosis represents the leading cause of death and disability in Europe and USA (about 52%)1 and it is predicted to become the main cause of mortality and disability worldwide.2,3 The simultaneous presence of atherosclerotic lesions in at least two major vascular territories is defined "multisite" artery disease.4 Atherosclerosis is implicated in 75% of all cardiovascular (CV) related deaths in the United States.5

Factors that influence the risk of developing atherosclerosis occur throughout one's lifetime; the disease or its precursors begin in childhood with asymptomatic but identifiable pathology and then progress slowly into adulthood.6 By the time young adults reach their 30s, some degree of atherosclerosis has developed in 80% to 90% of young men and women in the United States.7 In populations with LDL cholesterol levels 70 mg/dL, virtually no atherosclerosis occurs.8 Obesity, hypertension, diabetes mellitus, physical inactivity and smoking all are contributors to the development of atherosclerotic CVD.9

Atherosclerosis mainly affects large and medium-sized arteries, including the aorta, the carotid arteries, the coronary arteries and the arteries of the lower extremities. The earliest lesion of atherosclerosis is called the fatty streak, which is common even in infants and young children.10 In patients with hypercholesterolaemia, this influx of cells is preceded by lipid deposition.10,11 The fatty streak is a pure inflammatory lesion, consisting only of monocyte-derived macrophages and T lymphocytes.12-14 Hyperlipidemia plays an important role in the pathogenesis of atherosclerosis. Numerous studies have demonstrated that dyslipidemia, such as the increases in plasma concentrations of triglyceride, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), and a decrease in plasma concentration of high-density lipoprotein cholesterol (HDL-C), is an important risk factor for various cardiovascular diseases. Of these plasma lipids, LDL-C plays a crucial role in the development of atherosclerosis; however, the elevation of HDL-C prevents the initiation of atherosclerosis by blocking the atherogenic effects of LDL-C.15,16

Figure 1: Cardiovascular disease accounts for one third of deaths worldwide and half of deaths in the developed world. Data from World Health Organization (2002).17,18

These evidences indicate that improvement of blood lipid profile prevents blood vessel injury and the pathogenic development of atherosclerotic plaque formation leading to cardiovascular dysfunction. Atherosclerosis is also regarded as a chronic inflammatory disease that results from the production of various cytokines, such as tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b), as well as soluble mediators ,including inducible nitric oxide synthase (iNOS)-mediated NO production.17,18

Causes

Cardiovascular diseases have remained one of the leading causes of death all over the world.19 The development of these diseases has been linked to several factors such as high calorie diet intake, lack of exercise, smoking, age, alcohol consumption and genetic disposition.20 These factors ultimately result in disorders of lipid and lipoprotein metabolism including lipoprotein overproduction and deficiency.21

Causes of hyperlipidemia could be primary or secondary in nature. Primary (genetic) causes are single or multiple gene mutations that result in either overproduction or defective clearance of triglycerides and low density lipoprotein cholesterol, or underproduction and excessive clearance of high density lipoprotein cholesterol.22

Secondary causes include, among others diseases such as diabetes mellitus, chronic liver disease, hypothyroidism and primary biliary cirrhosis. Hyperlipidemia has also been associated with enhanced oxidative stress related to increased lipid peroxidation.23

Figure 2: Circle graph shows progression of plaque volumes in the 12-month period expressed as percent change (n=54).23

Importance of biomarkers in atherosclerosis

Biomarker

A biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes or pathogenic processes or as a physiologic response to a therapeutic intervention. In clinical medicine, biomarkers are routinely used in disease diagnosis, prognostication, ongoing clinical decision-making, and follow-up to assess effects of therapy. Commonly used biomarkers include the electrocardiogram, isotopic and ultrasound imaging studies applied in multiple areas of disease management, bone densitometry in the assessment of osteoporotic fracture risk, dynamic pulmonary function testing, and angiography in the management of coronary and peripheral arterial disease. Commonly used soluble biomarkers include C-reactive protein, low- and high-density lipoprotein cholesterol (LDL-C, HDL-C), triglycerides, serum creatinine, and hepatocellular enzymes, as well as a host of other routine clinical laboratory measurements. Cardiovascular disease (CVD), including myocardial infarction (MI), heart failure, and stroke, represents the leading cause of mortality worldwide, accounting for half of the total number of deaths in the developed world (World Health Organization, 2002). Furthermore, the increasing prevalence of diabetes and obesity, combined with poor adherence to clinical guidelines that address both therapeutic lifestyle changes and pharmacologic interventions (National Cholesterol Education Program Adult Treatment Panel III, 2002).24

Validation of new surrogate markers

Presently, there is no agreed-upon standard with respect to the body of evidence that must be developed for a biomarker to be considered a surrogate marker of clinical efficacy. A framework for the validation of biomarkers was proposed by24 and subsequently adapted by in a discussion of the usefulness of carotid ultrasound to measure the clinical efficacy of lipid-lowering medications in modifying the terminology of described clinical and statistical characteristics that a biomarker should have to be considered a surrogate marker of efficacy in atherosclerotic disease.27

Atherosclerosis is a systemic arterial disorder, as documented in numerous post-mortem studies, and because a patient who has developed atherosclerosis in one vascular bed will also have it in other vascular beds, such methods can be used to support a clinical diagnosis of systemic atherosclerosis and overall cardiovascular risk.26,28,30

A. Quantitative coronary angiography

B. Carotid B-mode ultrasound

C. Coronary intravascular ultrasound

Quantitative coronary angiography

Coronary angiography was first used and is still used in the clinical setting to confirm the presence or absence of symptom-limiting atherosclerotic arterial narrowing. Typically, patients at risk of coronary artery disease (CAD) present with symptoms of angina pectoris or a positive stress test and, if clinical suspicion and concern are high, undergo diagnostic cardiac catheterization. Cardiac catheterization is an "invasive procedure" in which a catheter is advanced through a large vessel, typically a femoral artery, over the aortic arch, and selectively engaged into each of the major coronary arteries. During the catheterization, angiography is performed by injection of radio-opaque contrast material into the vessels. By use of X-rays, images are acquired either on film or on a digital detector. The images are then analyzed for the presence of atherosclerotic narrowing that might require further intervention and "revascularization," either with an intravascular device or by arterial bypass grafting.

The current standard of care for patients with CAD is statin therapy titrated to an LDL-C target of 100 mg/dl (National Cholesterol Education Program Adult Treatment Panel III, 2002).25

Figure 3: Diagnostic coronary angiogram with subtotal occlusion of the left anterior descending coronary artery. Courtesy of Section of Cardiovascular Medicine, Yale University School of Medicine.25

Carotid B-mode ultrasound

With the development of medical ultrasound, it became possible to evaluate vessel wall structure in both clinical practice and research. Ultrasound in the clinical setting is used to detect pathologic conditions such as aortic aneurysms, peripheral vascular disease of the lower extremities, and carotid artery stenoses in patients with cerebrovascular disease (stroke or transient ischemic attacks) and as echocardiography to evaluate cardiac structure and function. By using high-resolution ultrasound, measurements of vessel wall intima-media thickness and lumen diameter along the axis of the ultrasound beam may be made. Another important advantage of ultrasound, compared with catheter guided angiography, is its noninvasive nature, permitting serial measures of vessel structure, without exposing patients to risks of vascular injury or ionizing radiation. In recent years, measurement of cIMT by B-mode ultrasound has come to the fore as a quantitative research tool in the study of atherosclerosis [29].

Coronary intravascular ultrasound

Coronary IVUS represents an emerging vascular imaging modality that is conceptually similar to extravascular ultrasound of the arterial wall. During IVUS, a miniaturized transducer is attached to the tip of a catheter, permitting the acquisition of intravascular images of the vessel wall. The transducer rotates at 1800 rpm, while the catheter is mechanically withdrawn at a fixed rate of 0.5 mm/s, acquiring serial images of vessel wall thickness throughout its 360° circumference. Approximately 30 images/s can be acquired. The data obtained are analyzed by trained readers who, either manually or using semi-automated systems, outline the intimal lining of the vessel lumen and the external elastic membrane that separates the media from the adventitia. The difference between the cross-sectional areas (CSA) bordered by the external elastic membrane and the CSA of the vessel lumen represents the vessel wall or atheroma cross-sectional area. The primary disadvantage of coronary IVUS is that it is an invasive procedure performed at the time of a cardiac catheterization. As such and as with any invasive procedure, there is a small risk of complications including, but not limited to, cardiac rhythm disturbances, vascular injury (such as spasm), thrombosis, dissection, or infection.29

Current treatment options available for atherosclerosis

It is useful to look at the past, before looking to the present and the future, to remind ourselves of what therapies were for severe heterozygous familial hypercholesterolemia (FH) and homozygous FH before the statin era. Partial ileal bypass, portocaval shunt, liver transplantation, gene therapy, and plasmapheresis—all of these options had considerable morbidity attached to them. The most acceptable one, plasmapheresis, has now been replaced with selective lowdensity lipoprotein (LDL) apheresis. Portocaval shunt reduced LDL by up to 40% in patients with homozygous FH, but there was the possibility of hepatic encephalopathy, and over the long term, pulmonary hypertension. Partial ileal bypass is like a super bile acid sequestrant, preventing reabsorption of bile salts. It was the intervention in a large, randomized, controlled angiographic study, the Program on the Surgical Control of the Hyperlipidemias (POSCH) trial.31

The statin era changed everything for FH. Now with a simple small pill with virtually no side effects, a 40% to 54% LDL reduction can be achieved in heterozygous FH patients [33-35]. Statins have also been tested extensively in children with FH. Lovastatin, Simvastatin, Atorvastatin, and Rosuvastatin have all been studied in adolescents.36-39 Another one of the older therapies, which is very much still a current therapy for FH, is the combination of niacin and bile acid sequestrants. This was the best therapy available before the statins.32

New approaches towards atherosclerosis

Hyperlipidemia as an investigator of inflammation: inaugurating new approaches to regulation of prevention. In this inaugural issue of Journal of the American Heart Association, Ammirati and colleagues in Milan add importantly to this body of work by presenting data indicating that our understanding of the complex interaction between lipid biology and inflammation may also require careful cellular sub-phenotyping, at least as we look toward novel T-cell targets for intervention. Previous work from several laboratories has suggested a role for CD4+ T cells in atherosclerotic lesion formation, but it has been uncertain as to whether specific CD4+ T cell subset might have greater or lesser relevance to disease progression. Activated T lymphocytes are functionally defined by the cytokines produced with IFNγ secreted from the Th1 cells and IL-4 from the Th2 cells.42 More recent reports describe the induction of macrophage proliferation by oxidized LDL. In early human lesions most proliferating cell nuclear antigen-positive cells were monocytes/ macrophages or lymphocytes.45

A substantial portion of CD4+ cells [which are generally thought to be T helper (Th) lymphocytes] isolated from atherosclerotic plaques recognize oxidized LDL as an antigen which induces them to proliferate and to secrete cytokines.41-44,47

The major classes of T lymphocytes present in atherosclerotic lesions are CD4+. In response to the local milieu of cytokines, CD4+ cells differentiate into the Th1 or Th2 lineage.46

Atherosclerois and inflammation

Atherosclerosis is an inflammatory disease. Because high plasma concentrations of cholesterol, in particular those of low-density lipoprotein (LDL) cholesterol, are one of the principal risk factors for atherosclerosis,48 the process of atherogenesis has been considered by many to consist largely of the accumulation of lipids within the artery wall; however, it is much more than that. Despite changes in lifestyle and the use of new pharmacologic approaches to lower plasma cholesterol concentrations,49,50 cardiovascular disease continues to be the principal cause of death in the United States, Europe, and much of Asia.51,52

In fact, the lesions of atherosclerosis represent a series of highly specific cellular and molecular responses that can best be described, in aggregate, as an inflammatory disease.53-57

The lesions of atherosclerosis occur principally in large and medium-sized elastic and muscular arteries and can lead to ischemia of the heart, brain, or extremities, resulting in infarction. They may be present throughout a person's lifetime. In fact, the earliest type of lesion, the so-called fatty streak, which is common in infants and young children,58 is a pure inflammatory lesion, consisting only of monocyte-derived macrophages and T lymphocytes.59 In persons with hypercholesterolemia, the influx of these cells is preceded by the extracellular deposition of amorphous and membranous lipids.58,60

Role of endothelial dysfunction in atherosclerosis

The response-to-injury hypothesis of atherosclerosis suggests that even before development of the fatty streak, damage to the endothelium lining the blood vessel sets the stage for lesion development. Originally, denudation of the endothelium was thought to be required61, but more recent work emphasizes the importance of endothelial dysfunction.62,63 In fact, some workers have gone so far as to suggest that the endothelial status may be regarded as 'an integrated index of all atherogenic and atheroprotective factors present in an individual', a sort of 'threshold switch' that only when activated translates an unfavourable risk factor profile into actual atherosclerotic disease [62].

The endothelium is a continuous layer of cells that separates blood from the vessel wall. An active, dynamic tissue, endothelium controls many important functions such as maintenance of blood circulation and fluidity as well as regulation of vascular tone, coagulation and inflammatory responses.64

The arterial endothelium responds to flow and to shear forces in the blood via a pathway that leads to phosphorylation of endothelial nitric oxide synthase (eNOS), which in turn produces the potent vasodilator nitric oxide (NO), thus leading to vasodilatation.65,66

This response allows arteries to accommodate increases in flow and control changes in shear stress.67 Regulation of eNOS occurs through its attachment to proteins such as caveolin68 and by means of phosphorylation reactions.69

In addition, the endothelium limits local thrombosis by producing tissue plasminogen activator, maintaining a negatively charged surface, and by secreting anticoagulant heparans and thrombomodulin.70 Endothelial dysfunction is characterized first by a reduction in the bioavailability of vasodilators, in particular NO, whereas endothelium-derived vasoconstrictors such as endothelin 1 are increased.62,71 This leads to impairment of endothelium-derived vasodilatation, the functional hallmark of endothelial dysfunction. Second, endothelial dysfunction is characterized by a specific state of endothelial activation, which is characterized by a pro-inflammatory, proliferative and procoagulatory state that favours all stages of atherogenesis.72

CD36 and macrophages in atherosclerosis

CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified. The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis. Unlike other cell types, macrophages express a number of scavenger receptors that are capable of taking up oxidized LDL, including scavenger receptor A, scavenger receptor B1 (SRB1), cluster of differentiation (CD) 36, CD68, and scavenger receptor for phosphatidylserine and oxidized lipoprotein.73

Of the receptors present, scavenger receptor A and CD36 appear to be the most important from a quantitative point of view in terms of uptake of modified lipoprotein. the specific role that these receptors play in the development of human atheroma remains to be determined.74

Uptake of oxidized LDL is mediated primarily by CD36, which recognizes the oxidized phospholipids within the particle. By contrast, scavenger receptor A recognizes the protein components of the particle. Exposure to oxidized LDL strongly induces expression of CD36 mRNA and protein via activation of the transcription factor peroxisome proliferator activated receptor γ (PPARγ).75,76

Physical activity in prevention of atherosclerosis

The link between physical activity and CHD was first established in the early 1950s and since this time population studies have consistently found high levels of physical activity to be associated with reduced risk of CHD morbidity and mortality.77,78

Among patients with established cardiovascular disease, mortality is lower among those who participate in an exercise program than among those who do not.79

Lemaitre et al. have shown that postmenopausal women in such a program had reduced the risk of myocardial infarction by 50% with modest leisure-time energy expenditures, equivalent to 30 to 45 minutes of walking for exercise three times a week.80

Table 1: Prevalence of renal artery stenosis at the time of cardiac catheterization.81

Study

Number of

patients (n)

Any RAs

(%)

RAs >50%

(%)

Bilateral

RAs (%)

Jean et al.

196

33

18

NR

Weber-Mzell et al.

177

25

11

8

Harding et al.

1,302

30

15

36

Rihal et al.

297

34

19

4

Vetrovec et al.

116

29

23

29

Aqel et al.

90

NR

28

10

Mean values

NA

30.2

19.0

17.4

NA: not applicable; NR: not reported; RAS: renal artery stenosis

Future prospects of atherosclerosis

Statins have reduced triglycerides, and gemfibrozil has been shown to increase high density lipoprotein (HDL) levels. Nicotinic acid has been made tolerable with sustained-release formulations, and is still considered an excellent choice in elevating HDL cholesterol and is potentially effective in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk factor for coronary heart disease (CHD). Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic. The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many atherosclerotic processes. More recently, the newer fibric acid derivatives have also reduced LDL to levels comparable to those achieved with patients.77

Funding: No funding sources

Conflict of interest: None declared

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