**4. The role of lipids and lipoproteins in atherogenesis**

Consistent evidence from epidemiologic and clinical studies, supports the key role of the apoB containing lipoproteins in atherogenesis. All ApoB-containing lipoproteins with size less than 70 nm can cross the endothelial barrier, particularly in the presence of endothelial dysfunction [16]. Uptake and accumulation of apoBcontaining lipoproteins in the arterial wall is a critical initiating event in the development of atherosclerosis. Upon entry, apoB-containing lipoproteins are modified and oxidized into proinflammatory particles, which provoke the activation of the innate immune system within the arterial intima. The endothelial cells secrete adhesion molecules, and the smooth muscle cells (SMCs) secrete chemokines, which together attract monocytes and other immune cells into the arterial wall. When monocytes enter the subendothelial space, they transform into macrophages.

#### *Management of Dyslipidemia*

Macrophage inflammation leads to enhanced oxidative stress and cytokine secretion, further promoting apoB-containing lipoproteins oxidation, endothelial cell activation, proliferation of SMCs and monocyte recruitment [17]. Uptake of the apoB containing particles by macrophages promotes foam cell formation which accumulate in early atherosclerotic lesions known as fatty streaks [18]. Fatty streaks are not clinically significant, but they are the precursors of more advanced lesions characterized by the accumulation of lipid-rich necrotic debris and SMCs. With the secretion of fibrous elements by the SMCs, forming a fibrous cap over the lipid-rich necrotic cores, atherosclerotic fibrous plaques develop. Continued exposure to apoB-containing lipoproteins results in additional particles being retained over time in the arterial wall, and to the growth and progression of atherosclerotic plaques [19]. A person's total atherosclerotic plaque burden is determined by the concentration of circulating LDL and other apoB-containing lipoproteins, and by the cumulative exposure to these particles. In general, people with higher concentrations of plasma apoB-containing lipoproteins will retain more particles and accumulate lipids faster, resulting in more rapid growth and the progression of atherosclerotic plaques ultimately leading to the reduced vascular lumen and clinically significant ischemia. Plaques can become increasingly complex, with calcification, ulceration at the luminal surface, and hemorrhage within the arterial wall from small fragile vessels growing into the lesion from the media. Eventually, changes in the composition of the plaque reach a critical point at which disruption of a plaque can result, with the formation of an overlying thrombus that acutely obstructs blood flow. Atherosclerotic plaque formation is greatest at the branching points of major vessels and in areas of turbulent flow [17]. Depending on the location, atherosclerosis may lead to a variety of conditions, such as coronary heart disease, cerebrovascular and peripheral artery disease.

Epidemiological studies have consistently shown that HDL-C levels are inversely related to atherosclerotic cardiovascular events [20, 21]. HDL-C has been traditionally considered as "good "cholesterol having a protective role against atherosclerosis. The proposed mechanism underlying its protective effect is the role in the removal of excess cholesterol from peripheral tissues. Besides, it has been considered that HDL prevents lipoprotein oxidation and removes oxidized lipids from LDL due to its anti-inflammatory and anti-oxidant properties. However, the protective role has been seriously challenged by the evidence from recent clinical trials aimed at raising HDL-C that failed to reduce cardiovascular events. Modern genome-wide and Mendelian randomization studies have failed to show a causal link between total HDL-C concentration and CAD, which might be related to the fact that HDL comprise a range of particles differing in size and density [22, 23]. It has been shown that the concentration of large HDL particles is inversely associated with CVD while that of small HDL particles is positively associated with CVD.

#### **5. Clinical classification of dyslipidemias**

Dyslipidemia may present as a single disorder affecting only one specific type of lipid, such as pure or isolated hypertriglyceridemia or hypercholesterolemia or may represent as a combination of lipid abnormalities, such as mixed or combined dyslipidemias. Lipid disorders were traditionally categorized by patterns of elevation in lipids and lipoproteins into six phenotypes according to the Fredrickson classification (**Table 3**). A more practical approach is to classify dyslipidemias as primary or secondary. Primary dyslipidemias are genetic disorders caused by single or multiple gene mutations that result in either overproduction or defective clearance of LDL and TG or excessive clearance of HDL. The understanding of the

**9**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

I Chylomicrons TG IIa LDL Cholesterol IIb LDL and VLDL TG and cholesterol III VLDL and chylomicron remnants TG and cholesterol

IV VLDL TG

*LDL - low-density lipoprotein; TG - triglycerides; VLDL - very-low-density lipoprotein.*

**Phenotype Elevated Lipoprotein(s) Elevated Lipids**

genetic and biochemical basis of these disorders has revealed a large and diverse group of diseases, many of which have similar clinical expressions (**Table 4**) [24]. The names of many primary dyslipidemias reflect an old nomenclature in which lipoproteins were differentiated by how they separated into alpha (HDL) and beta (LDL) bands on electrophoretic gels. Individuals with primary dyslipidemias are at higher risk of developing complications, such as atherosclerotic cardiovascular disease, at a younger age. Patients may also present with acute pancreatitis and deposition of cholesterol in the skin and tendons (xanthomas), eyelids (xanthe-

V Chylomicrons and VLDL TG and cholesterol

Familial hypercholesterolemia (FH) is one of the most common monogenic lipid disorders associated with premature CVD due to significantly elevated plasma levels of LDL-C. FH is caused by loss-of-function mutations in the LDL receptor or apoB genes, or a gain-of-function mutation in the PCSK9 gene [25]. There are two main types of FH; homozygous (HoFH) and heterozygous (HeFH). The prevalence of HeFH in the population is estimated to be 1/200-250, making it the most common genetically transmitted disease [26, 27]. If left untreated, men and women with HeFH typically develop early coronary artery disease (CAD) before the ages of 55 and 60 years respectively. However, early diagnosis and appropriate treatment can dramatically reduce the risk for CAD. HoFH is a rare and life-threatening disease with a prevalence estimated to be 1/160,000-320,000. Patients present with extensive xanthomas, premature and progressive CVD, and total cholesterol level

exceeds 13 mmol/L. Most patients die before 30 years of age [28].

nephrotic syndrome, hypothyroidism and obesity [31, 32].

Secondary dyslipidemias are caused by lifestyle factors or medical conditions that interfere with blood lipid levels [29, 30]. The most important cause is a sedentary lifestyle with excessive dietary intake of total calories, saturated fats, cholesterol and trans fats. Some diseases that are associated with a higher risk of dyslipidemia are diabetes mellitus, cholestatic liver disease, chronic kidney disease,

Diabetes is an especially important secondary cause of dyslipidemia characterized by an atherogenic combination of high TGs, high sdLDL particles and low HDL [33]. Patients with type 2 diabetes are particularly at risk [34]. It has been shown that the lipoprotein abnormalities are related to the severity of the insulin resistance and the degree of visceral adiposity. Poor glycemic control and inflammation of visceral adipose tissue increase the concentration of circulating free fatty acids (FFAs), leading to increased VLDL production in the liver. TG-rich VLDL then transfers TG and cholesterol to LDL and HDL, promoting formation of TG-rich, sdLDL and clearance of TG-rich HDL. Diabetic dyslipidemia is additionally promoted by unhealthy diet and physical inactivity. Other factors that increase the risk of dyslipidemias are smoking, alcohol overuse and certain medications such as thiazide

*DOI: http://dx.doi.org/10.5772/intechopen.98386*

lasma), and corneas (arcus corneae).

*Fredrickson classification of dyslipidemias.*

**Table 3.**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*


#### **Table 3.**

*Management of Dyslipidemia*

peripheral artery disease.

Macrophage inflammation leads to enhanced oxidative stress and cytokine secretion, further promoting apoB-containing lipoproteins oxidation, endothelial cell activation, proliferation of SMCs and monocyte recruitment [17]. Uptake of the apoB containing particles by macrophages promotes foam cell formation which accumulate in early atherosclerotic lesions known as fatty streaks [18]. Fatty streaks are not clinically significant, but they are the precursors of more advanced lesions characterized by the accumulation of lipid-rich necrotic debris and SMCs. With the secretion of fibrous elements by the SMCs, forming a fibrous cap over the lipid-rich necrotic cores, atherosclerotic fibrous plaques develop. Continued exposure to apoB-containing lipoproteins results in additional particles being retained over time in the arterial wall, and to the growth and progression of atherosclerotic plaques [19]. A person's total atherosclerotic plaque burden is determined by the concentration of circulating LDL and other apoB-containing lipoproteins, and by the cumulative exposure to these particles. In general, people with higher concentrations of plasma apoB-containing lipoproteins will retain more particles and accumulate lipids faster, resulting in more rapid growth and the progression of atherosclerotic plaques ultimately leading to the reduced vascular lumen and clinically significant ischemia. Plaques can become increasingly complex, with calcification, ulceration at the luminal surface, and hemorrhage within the arterial wall from small fragile vessels growing into the lesion from the media. Eventually, changes in the composition of the plaque reach a critical point at which disruption of a plaque can result, with the formation of an overlying thrombus that acutely obstructs blood flow. Atherosclerotic plaque formation is greatest at the branching points of major vessels and in areas of turbulent flow [17]. Depending on the location, atherosclerosis may lead to a variety of conditions, such as coronary heart disease, cerebrovascular and

Epidemiological studies have consistently shown that HDL-C levels are inversely related to atherosclerotic cardiovascular events [20, 21]. HDL-C has been traditionally considered as "good "cholesterol having a protective role against atherosclerosis. The proposed mechanism underlying its protective effect is the role in the removal of excess cholesterol from peripheral tissues. Besides, it has been considered that HDL prevents lipoprotein oxidation and removes oxidized lipids from LDL due to its anti-inflammatory and anti-oxidant properties. However, the protective role has been seriously challenged by the evidence from recent clinical trials aimed at raising HDL-C that failed to reduce cardiovascular events. Modern genome-wide and Mendelian randomization studies have failed to show a causal link between total HDL-C concentration and CAD, which might be related to the fact that HDL comprise a range of particles differing in size and density [22, 23]. It has been shown that the concentration of large HDL particles is inversely associated with CVD while

Dyslipidemia may present as a single disorder affecting only one specific type of lipid, such as pure or isolated hypertriglyceridemia or hypercholesterolemia or may represent as a combination of lipid abnormalities, such as mixed or combined dyslipidemias. Lipid disorders were traditionally categorized by patterns of elevation in lipids and lipoproteins into six phenotypes according to the Fredrickson classification (**Table 3**). A more practical approach is to classify dyslipidemias as primary or secondary. Primary dyslipidemias are genetic disorders caused by single or multiple gene mutations that result in either overproduction or defective clearance of LDL and TG or excessive clearance of HDL. The understanding of the

that of small HDL particles is positively associated with CVD.

**5. Clinical classification of dyslipidemias**

**8**

*Fredrickson classification of dyslipidemias.*

genetic and biochemical basis of these disorders has revealed a large and diverse group of diseases, many of which have similar clinical expressions (**Table 4**) [24]. The names of many primary dyslipidemias reflect an old nomenclature in which lipoproteins were differentiated by how they separated into alpha (HDL) and beta (LDL) bands on electrophoretic gels. Individuals with primary dyslipidemias are at higher risk of developing complications, such as atherosclerotic cardiovascular disease, at a younger age. Patients may also present with acute pancreatitis and deposition of cholesterol in the skin and tendons (xanthomas), eyelids (xanthelasma), and corneas (arcus corneae).

Familial hypercholesterolemia (FH) is one of the most common monogenic lipid disorders associated with premature CVD due to significantly elevated plasma levels of LDL-C. FH is caused by loss-of-function mutations in the LDL receptor or apoB genes, or a gain-of-function mutation in the PCSK9 gene [25]. There are two main types of FH; homozygous (HoFH) and heterozygous (HeFH). The prevalence of HeFH in the population is estimated to be 1/200-250, making it the most common genetically transmitted disease [26, 27]. If left untreated, men and women with HeFH typically develop early coronary artery disease (CAD) before the ages of 55 and 60 years respectively. However, early diagnosis and appropriate treatment can dramatically reduce the risk for CAD. HoFH is a rare and life-threatening disease with a prevalence estimated to be 1/160,000-320,000. Patients present with extensive xanthomas, premature and progressive CVD, and total cholesterol level exceeds 13 mmol/L. Most patients die before 30 years of age [28].

Secondary dyslipidemias are caused by lifestyle factors or medical conditions that interfere with blood lipid levels [29, 30]. The most important cause is a sedentary lifestyle with excessive dietary intake of total calories, saturated fats, cholesterol and trans fats. Some diseases that are associated with a higher risk of dyslipidemia are diabetes mellitus, cholestatic liver disease, chronic kidney disease, nephrotic syndrome, hypothyroidism and obesity [31, 32].

Diabetes is an especially important secondary cause of dyslipidemia characterized by an atherogenic combination of high TGs, high sdLDL particles and low HDL [33]. Patients with type 2 diabetes are particularly at risk [34]. It has been shown that the lipoprotein abnormalities are related to the severity of the insulin resistance and the degree of visceral adiposity. Poor glycemic control and inflammation of visceral adipose tissue increase the concentration of circulating free fatty acids (FFAs), leading to increased VLDL production in the liver. TG-rich VLDL then transfers TG and cholesterol to LDL and HDL, promoting formation of TG-rich, sdLDL and clearance of TG-rich HDL. Diabetic dyslipidemia is additionally promoted by unhealthy diet and physical inactivity. Other factors that increase the risk of dyslipidemias are smoking, alcohol overuse and certain medications such as thiazide


**11**

**Disorder** Familial HDL deficiency

Familial hypercholesterolemia

Loss-of-function mutations in the LDL receptor or apoB genes, or a gain-of-function mutation in the PCSK9

Diminished LDL clearance

**Genetic Defect**

ABCA1 gene

**Inheritance**

Dominant Codominant

•

premature CAD

Heterozygotes:

• •

TC: 6.5–13 mmol/L

Homozygotes:

• •

Familial hypertriglyceridemia

Familial LCAT deficiency

Fisheye disease (partial LCAT deficiency)

Hepatic lipase deficiency

Hepatic lipase

LCAT gene

LCAT gene

Unknown, possibly multiple defects and mechanisms

Dominant

•

Usually no symptoms or findings; occa-

sionally hyperuricemia, sometimes early atherosclerosis

•

TG: 2.3–5.6 mmol/L, possibly higher depend-

ing on diet and alcohol use

Recessive

• disease

• • • • • • •

HDL: variable

TG: 4.5–93 mmol/L

TC: 6.5–39 mmol/L

premature CAD

HDL: < 0.26 mmol/L

Corneal opacities

Recessive Recessive

HDL: < 0.26 mmol/L

Corneal opacities, anemia, chronic kidney

TC > 13 mmol/L

planar and tendon xanthomas and tuberous xanthomas, premature CAD (before age 18)

tendon xanthomas, arcus corneae, premature CAD (ages 30–50), responsible for about 5% of MIs in people < 60 years

**Clinical Features**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

*DOI: http://dx.doi.org/10.5772/intechopen.98386*


#### *Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*

*Management of Dyslipidemia*

**10**

**Disorder** Apo C-II deficiency

Cerebrotendinous xanthomatosis

Cholesteryl ester storage disease and

Lysosomal acid lipase deficiency

Wolman disease

Familial apo AI deficiency/mutations

Familial combined hyperlipidemia

Familial defective apo B-100

Familial dysbetalipoproteinemia

Apo B (LDL receptor–binding region defect)

Diminished LDL clearance

Apo E (usually e2/e2 homozygotes)

Diminished chylomicron and VLDL clearance

Unknown, possibly multiple defects and mechanisms

Dominant

•

premature CAD, responsible for about 15% of

MIs in people < 60 years

• • •

> Dominant

• •

Recessive or dominant

• • •

TG: 2.8–5.6 mmol/L

TC: 6.5–13.0 mmol/L

xanthomas (especially tuberous and palmar),

yellow palmar creases, premature CAD

TC: 6.5–13 mmol/L

xanthomas, arcus corneae, premature CAD

TG: 2.8–8.5 mmol/L

TC: 6.5–13.0 mmol/L

Apo B: Disproportionately elevated

Apo AI

Hepatic mitochondrial 27-hydroxylase defect accumulation

Recessive

of cholestanol due to the blockage of bile acid synthesis and

conversion of cholesterol to cholestanol

**Genetic Defect**

Apo C-II (causing functional LPL deficiency)

**Inheritance**

Recessive

• • • • • •

• ataxia

• • • • (in some people)

•

HDL: 0.39–0.78 mmol/L

corneal opacities, xanthomas, premature CAD

Unknown

cirrhosis

accumulation of cholesteryl esters and TG in

lysosomes in the liver, spleen, and lymph nodes

premature CAD

Recessive

neuropathy

premature CAD

cataracts

TG: > 8.5 mmol/L

pancreatitis (in some adults)

metabolic syndrome (often present)

**Clinical Features**


*- lecithin-cholesterol acyltransferase; LDL - low-density lipoprotein; LPL - lipoprotein lipase; MI - myocardial infarction; PCSK9 - proprotein convertase subtilisin-like/kexin type 9; TC - total cholesterol; TG - triglyceride; VLDL - very-low-density lipoprotein. Adapted from Ref. [23].*

**Table 4.**

*Primary dyslipidemias.*

**13**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

**Medical conditions Lipid abnormalities**

diuretics, beta blockers, oral contraceptives, atypical antipsychotics, antiretroviral agents, corticosteroids, tacrolimus, and cyclosporine. Secondary causes of dyslipid

*HDL-C - high density lipoprotein cholesterol; LDL-C - low density lipoprotein cholesterol; sdLDL-C -small dense* 

Consistent evidence from epidemiological studies indicates that saturated fatty

Statin treatment, targeting LDL cholesterol reduction, remains the cornerstone of dyslipidemia management. There is a clear linear relationship between the degree of LDL-cholesterol lowering achieved with statins and CV benefits, pointing out

acids (SFAs) and trans unsaturated fatty acids are the dietary factors with the greatest elevating impact on LDL-C levels [5]. Therefore, current dietary guidelines uniformly recommend reducing intakes of saturated and trans fatty acids with replacement by increasing intake of mono- and polyunsaturated fatty acids [35]. Moreover, recommended food choices to lower LDL-C and improve the overall lipoprotein profile include higher consumption of non-starchy vegetables, fruit, legumes, nuts, fish, vegetable oils, yoghurt, and wholegrains, along with a lower intake of red and processed meats, foods higher in refined carbohydrates, and salt [36, 37]. Dietary patterns that may have a role in the prevention and management of dyslipidemia are the Mediterranean diet and the DASH diet [38, 39]. Excessive body weight loss exhibits the LDL-C decreasing effect, but the magnitude of the effect is small. In people with obesity, a decrease in LDL-C concentration of 0.2 mmol/L is observed for every 10 kg of weight reduction [40, 41]. Regular physical exercise results in even smaller reduction of LDL-C levels [42, 43]. Overall, through dietary changes and weight loss, LDL-C can be lowered by approximately 10–15% [44].

emia and their major lipid abnormalities are shown in **Table 5**

**6.1 Impact of diet and lifestyle modifications on lipid levels**

**6. Treatment strategies**

*Secondary causes of dyslipidemia.*

**6.2 Drugs for treatment of dyslipidemias**


.

↑ sdLDL-C,

↑ LDL-C

↑ LDL-C

↑ TC

↑ TC,

↑ TC,

↑ TG

↑ LDL-C,

↑ LDL-C,

↓ HDL-C

↑ LDL-C

↑ TG

↓ HDL-C,

↓ HDL-C,

↑ TG

↑ LDL-C,

↑ TG

↑ TG

↓ HDL-C,

↑ TG

*DOI: http://dx.doi.org/10.5772/intechopen.98386*

Diabetes mellitus, metabolic syndrome

Cholestatic liver disease

Nephrotic syndrome

Hypothyroidism

Cigarette smoking

**Medications**

**Table 5.**

Excessive alcohol consumption

blockers, thiazides, anabolic steroids

Diuretics, cyclosporine, glucocorticoids, amiodarone

Oral estrogens, glucocorticoids, protease inhibitors, sirolimus, beta

*low density lipoprotein cholesterol; TC-total cholesterol; TG - triglycerides.*

Obesity

Chronic kidney disease

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*


*HDL-C - high density lipoprotein cholesterol; LDL-C - low density lipoprotein cholesterol; sdLDL-C -small dense low density lipoprotein cholesterol; TC-total cholesterol; TG - triglycerides.*

#### **Table 5.**

*Management of Dyslipidemia*

**12**

**Disorder** LPL deficiency PCSK9 gain of function mutations

Polygenic hypercholesterolemia

Primary hypoalphalipoproteine-mia

Unknown, possibly apo A-I, C-III, or A-IV

ABCG5 and ABCG8 genes

Dominat Recessive Recessive

• • *ABCA1 - ATP-binding cassette transporter A1; ABCG5 and 8 - ATP-binding cassette subfamily G members 5 and 8; apo - apoprotein; CAD - coronary artery disease; HDL - high-density lipoprotein; LCAT* 

*- lecithin-cholesterol acyltransferase; LDL - low-density lipoprotein; LPL - lipoprotein lipase; MI - myocardial infarction; PCSK9 - proprotein convertase subtilisin-like/kexin type 9; TC - total cholesterol;* 

*TG - triglyceride; VLDL - very-low-density lipoprotein.*

*Adapted from Ref. [23].*

**Table 4.**

*Primary dyslipidemias.*

HDL: < 0.13 mmol/L

premature CAD (in some people), peripheral

neuropathy, hemolytic anemia, corneal opacities, hepatosplenomegaly, orange tonsils

(familial or nonfamilial)

Sitosterolemia Tangier disease

ABCA1 gene

Increased degradation of LDL receptors

Unknown, possibly multiple defects and mechanisms

Dominat

Variable

**Genetic Defect**

Endothelial LPL defect

Diminished chylomicron clearance

**Inheritance**

Recessive

• • • • • • • •

tendon xanthomas, premature CAD

HDL: 0.39–0.91 mmol/L

premature CAD

TC: 6.5–9.0 mmol/L

premature CAD

similar to familial hypercholesterolemia

TG: > 8.5 mmol/L

failure to thrive (in infants), eruptive xanthomas, hepatosplenomegaly, pancreatitis

**Clinical Features**

*Secondary causes of dyslipidemia.*

diuretics, beta blockers, oral contraceptives, atypical antipsychotics, antiretroviral agents, corticosteroids, tacrolimus, and cyclosporine. Secondary causes of dyslipidemia and their major lipid abnormalities are shown in **Table 5**.
