Immunoglobulin Super Family, Cellular adhesion molecules and Integrins

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Epidemiology of cardiovascular diseases

CVD are considered complex non-communicable diseases (NCD), as they are caused by a combination of multiple genes, behavior, physiological and environmental factors. CVD account for most NCD-related deaths annually (17.7 million people), followed by cancers (8.8 million), respiratory diseases (3.9 million), and diabetes (1.6 million) according to the WHO. All together, these diseases are responsible for 40 million deaths each year, representing 70% of all deaths globally, up from 60% in 2000 (Figure 1).
To put things in perspective, the number of people dying from these complex diseases is more than the double of the number of people dying from nutritional deficiencies and all infectious diseases (including malaria, tuberculosis and HIV/AIDS).
During the last two decades, there has been a global epidemiologic shift, affecting all countries regardless of their economic development (Figure 2).
Thus, it is not exaggerated to say that these complex diseases are actually dominating the global human health landscape, being the major challenge of our generation and the coming ones.
CVD are the leading cause of death and disability in the world and as said previously, cause an estimated 17.7 million deaths per year. Of these deaths, 7.4 million were caused by CHD and 6.7 million were due to strokes. Worldwide, the number of fatalities caused by CVD increased the past few decades. Indeed, in 1990, 25.9% of all deaths were caused by CVD, while in 2013, this percentage raised to 31%, and up to 48% of all NCD deaths, being more than the double caused by cancer (4) (Figures 3 and 4).
Most of the CVD deaths can be prevented by an early detection of the disease, prevention, detection and reduction of risk factors as well as by a continuous surveillance and monitoring of the patients affected.

Pathophysiology of cardiovascular diseases

CVD are the group of disorders of the heart, vascular diseases of the brain and diseases of blood vessels. Among those diseases, the ischemic heart disease (e.g. heart attack), cerebrovascular disease (e.g. stroke) and diseases of the arteries, including hypertension and peripheral vascular disease, are caused by the underlying disease process known as atherosclerosis (Figure 5). It is the major precursor of CVD, and is a complex pathological process that needs many years to develop until the pathological symptoms appear.
An initial lesion of the intima-media, occurring in the early stages will produce some macrophage lipid infiltration to the blood vessel walls. With time, more cholesterol and fatty material are deposited in the lumen of arteries, and there is an invasion and accumulation of white blood cells (known also as foam cells). The excessive accumulation of white blood cells will produce a chronic inflammatory response and will also reduce the elasticity of the artery walls (due to the calcium and other crystallized remnants present in the foam cells). However, the process will need many years until the first pathological symptoms appear.
The stiffening of the arteries due to a progressive inflammatory state and lipid and foam cells accumulation will eventually produce high blood pressure (hypertension). If the removal of fats and cholesterol from the intima-media of the artery doesn’t exceed their accumulation, a hardening will occur and multiple atheromatous plaques will grow, causing irregularities and thickness in the inner surface of the arteries, making it harder for blood to flow through. Ultimately, the rupture of the plaque can happen. The rupture of the fibrous cap will expose thrombogenic material to the circulation and eventually induce thrombus formation in the lumen, stopping blood flow, and leading to death of the tissues fed by the artery in question. This event will cause a heart attack if the thrombus formation develops in a coronary artery and a stroke if it develops in the brain.
The atherosclerosis process is multifactorial and complex, which is a result of a synergy between many risk factors (1, 2, 28). The individual contribution of each risk factor varies widely between different communities, ethnic groups and individuals. However, the overall contribution of these risk factors is very consistent (3). They can be congenital or acquired and modifiable or not, and are divided as classical and non-classical risk factors.

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Classical cardiovascular disease risk factors

The early stages of the atherosclerosis process begin in childhood and adolescence due to different factors (1, 2). Among the classical risk factors is included hyperlipidemia, high blood pressure, age and gender, tobacco use, physical inactivity, harmful use of alcohol, genetic predisposition, diabetes and obesity.

Dyslipidemia

Dyslipidemia is an abnormal amount of lipids in the blood. The most common form of dyslipidemia is hyperlipidemia, when there are abnormally elevated levels of lipids in the blood, and is a major cause of atherosclerosis. Although it can be caused by a genetic predisposition (familial or primary hyperlipidemia), the principal cause of hyperlipidemia is the high dietary intakes of saturated fat (acquired or secondary hyperlipidemia).

 Total cholesterol and LDL-cholesterol

High levels of total cholesterol and specially LDL-cholesterol have shown a close relationship with CVD and atherosclerosis (29). The LDL is the major transporter of both cholesterol and fatty acids. LDL are important in maintaining cholesterol homeostasis, and the direct relation with lower levels of LDL and lower atherosclerosis is been known for a long time now (30). It has been demonstrated that the size of the LDL particles are as important as the total amount of LDL in the blood. Early atherosclerosis is associated with larger LDL particles, rather than small dense LDL (31, 32). One of the possible reasons for this explanation is that LDL particles with higher surfaces are more prone to oxidation, resulting in antibody formation and a subsequent macrophage migration and uptake of LDL particles.

Table of contents :

CHAPTER I
HYPOTHESIS AND OBJECTIVES 
CHAPTER II
INTRODUCTION 
1. Epidemiology of cardiovascular diseases
2. Pathophysiology of cardiovascular diseases
2.1 Classical cardiovascular disease risk factors
2.1.1 Dyslipidemia
2.1.1.1 Total cholesterol and LDL-cholesterol
2.1.1.2 HDL-cholesterol
2.1.1.3 Triglycerides
2.1.2 Hypertension
2.1.3 Age and Gender
2.1.4 Tobacco use
2.1.5 Physical inactivity
2.1.6 Obesity
2.1.7 Diabetes
2.2 Novel cardiovascular disease risk factors
2.2.1 Thrombogenic factors
2.2.2 Cell Adhesion molecules
2.2.2.1 Selectins
2.2.2.1.1 L-Selectin
2.2.2.1.2 P-Selectin
2.2.2.1.3 E-Selectin
2.2.2.2 Immunoglobulin Super Family, Cellular adhesion molecules and Integrins
2.2.2.2.1 ICAM-1 and ββ integrins
2.2.2.2.2 VCAM-1 and α4β1 Integrins
2.2.2.2.3 PECAM-1
2.2.3 Inflammatory molecules
2.2.3.1 CRP
2.2.3.2 Cytokines
2.2.3.2.1 TNF-α
2.2.3.2.2 INF-
2.2.3.2.3 IL-6
2.2.3.3 TREMs (TREM-1 and TREM-2)
2.2.4 Hyperhomocysteinemia
2.2.5 VEGF-A
2.2.6 Oxidative stress (free radicals)
2.3 Genetics of Cardiovascular diseases
2.3.1 Approaches to discover genes for cardiovascular diseases
2.3.1.1 Linkage analysis
2.3.1.2 Association studies
2.3.1.2.1 Genome-wide Association Studies
2.3.1.2.2 Phenome-wide Association Studies
2.3.1.2.3 Candidate gene .
2.3.2 Missing heritability problem
2.3.3 Genetic pleiotropy
CHAPTER III 
RESULTS AND DISCUSSION

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