Low density lipoprotein

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] Associate Editor(s)-in-Chief: Rim Halaby, M.D. [4]

Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. There is a direct association between high LDL and cardiovascular disease. Environmental and genetic factors are involved in the pathophysiology of high LDL. Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.^[1] Prior approaches to the management of LDL aimed towards the classification of LDL concentrations and the treatment of subjects with dyslipidemia to a target LDL concentration. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III classified LDL concentrations into optimal, near optimal, borderline high, high, and very high.^[2] However, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.^[1] There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c, which is driving ongoing and future investigational therapies.

From the early 1950s onward, Fredrickson specialized in the study of plasma lipoproteins, compounds of proteins and lipids which transport lipids in the blood. However, the study of lipids in the blood has started early in the 1900’s. In 1949, Faraday Society in Birmingham organized the first symposium on lipoproteins and separated for the first time lipoproteins into alpha and beta types. In 1950, LDL was first isolated.^[3] In 1973, Myant first hypothesized the role of LDL in the metabolism of cholesterol.^[4]

Prior approaches to the management of LDL aimed towards the classification of LDL concentrations and the treatment of subjects with dyslipidemia to a target LDL concentration. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III classified LDL concentrations into optimal, near optimal, borderline high, high, and very high.^[2] However, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.^[1]

Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. Its size is approximately 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that surrounds the fatty acids keeping them soluble in the aqueous environment.^[5] The average composition of LDL is approximately 20% protein, 20% phospholipids, 40% cholesteryl esters, 10% unesterified cholesterol, and 5% triglycerides.^[6]

Environmental and genetic factors are involved in the pathophysiology of high LDL. Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.^[1] Abnormally low LDL can occur, and they usually result from rare inherited conditions, such as familial hypobetalipoproteinemia and abetalipoproteinemia.

Low LDL levels can be caused by unusual inherited disorders of lipoprotein metabolism such as abetalipoproteinemia and hypobetalipoproteinemia.

High LDL can be primary or secondary to diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.^[1] High LDL can also be caused by inherited diseases that affect the lipid metabolism.

From 1976–1980 through 2007–2010, for U.S. adults aged 40–74, a decrease was observed in the prevalence of high LDL-cholesterol (LDL–C) from 59% to 28%, as well as an increase in adults using lipid-lowering medications and consuming a diet low in saturated fat. Despite recent advances in medical treatment, high LDL-C remains a significant public health problem in the United States, with more than one-quarter of adults aged 40–74 having high LDL–C.^[7]

Risk factors for high LDL include genetic predisposition, aging, and unhealthy life style choices.

According to the United States Preventive Services Task Force (USPSTF), screening for high LDL-cholesterol (LDL-c), is indicated among men 35 years and older (Grade: A Recommendation), men age 20 to 35 years in case of an elevated risk for coronary heart disease (Grade: B Recommendation), women age 45 years and older for in case of an elevated risk for coronary heart disease (Grade: A Recommendation), and women age 20 to 45 years in case of an elevated risk for coronary heart disease (Grade: B Recommendation).^[8] There is insufficient evidence to recommend for or against screening for dyslipidemia among infants, children, adolescents, or young adults less than 20 years of age (Grade: I statement).^[9]

The natural history and the prognosis of high LDL concentrations are directly associated with the complications of atherosclerosis, namely cardiovascular disease (CVD) which is the most common cause of mortality worldwide. Classically, elevated LDL concentration has been associated with significantly increased rates of coronary artery disease (CAD). However, emerging evidence has demonstrated that an elevated concentration of LDL is also strongly associated with insulin resistance as well as other forms of ischemic vascular diseases. The role of elevated levels of LDL in the development of ischemic complications, such as stroke, peripheral arterial disease, carotid atherosclerosis, and renovascular injury, has also been validated. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations.

Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available. However, there is increasing evidence and recognition of the value of more sophisticated measurements. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown much tighter correlation with atherosclerotic progression and cardiovascular events than is obtained using chemical measures of total LDL concentration contained within the particles. LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Alternatively, LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. If LDL particle concentration is tracked against event rates, many other statistical correlates of cardiovascular events, such as diabetes mellitus, obesity and smoking, lose much of their additive predictive power.

While prior approaches to the management of LDL plasma concentration aimed towards treating the subjects with dyslipidemia to a target LDL concentration,^[2] the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events. The 2013 ACC/AHA guidelines identifies the following statin benefit groups: subjects with atherosclerotic cardiovascular disease, subjects with LDL ≥ 190 mg/dL, subjects with diabetes mellitus PLUS age 40-75 years PLUS LDL 10-189 mg/dL, and subjects with LDL 70-189 mg/dL PLUS estimated 10 year risk of atherosclerotic cardiovascular disease ≥ 7.5%. The pooled cohort equation should be used to estimate the 10 year risk of atherosclerotic cardiovascular disease and guide the treatment among subjects with no diabetes mellitus or atherosclerotic cardiovascular disease. Lifestyle changes is a critical component of the management of patients with elevated LDL whether they are administered or not lipid lowering drugs.^[1]

There is an association between the concentration of circulating LDL cholesterol (LDL-c) and the risk of cardiovascular disease. There is an unmet need for more effective and tolerable therapies for the reduction of LDL-c. Ongoing studies are evaluating novel lipid-lowering therapeutic strategies, including anti-sense oligonucleotides (ASOs) to apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), microsomal triglyceride transfer protein (MTP), thyromimetics, squalene synthase, adenosine triphosphate-citrate lyase, AMP-activated protein kinase, and sterol regulatory element binding proteins.

Template:Vascular diseases

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]

From the early 1950s onward, Fredrickson specialized in the study of plasma lipoproteins, compounds of proteins and lipids which transport lipids in the blood. However, the study of lipids in the blood has started early in the 1900’s. In 1949, Faraday Society in Birmingham organized the first symposium on lipoproteins and separated for the first time lipoproteins into alpha and beta types. In 1950, LDL was first isolated.^[1] In 1973, Myant first hypothesized the role of LDL in the metabolism of cholesterol.^[2]

• In 1949, a new method for quantitative measurement of LDL and other lipoproteins using ultracentrifuge was developed.^[3]

• In 1950, LDL was first isolated.^[1]

• In 1963, another lipoprotein, Lp(a), was discovered as a complex particle in human plasma in an immunochemical study.^[4]

• In 1973, Myant first hypothesized the role of LDL in the metabolism of cholesterol.^[2]

• In 1979, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) demonstrated that reductions in total cholesterol and LDL were associated with reduction in coronary heart disease risk. It was reported that a 25% reduction in cholesterol or a 35% reduction in LDL cholesterol resulted in a 49% decrease in coronary heart disease risk.^[5][6]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

Prior approaches to the management of LDL aimed towards the classification of LDL concentrations and the treatment of subjects with dyslipidemia to a target LDL concentration. In 2001, the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III classified LDL concentrations into optimal, near optimal, borderline high, high, and very high.^[1] However, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events.^[2]

Shown below is the classification of the different concentrations of LDL according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III published in 2001.^[1]

The 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events. Shown below is the classification of the four statin benefit groups.^[2]

The estimated 10 year risk of atherosclerotic cardiovascular disease should be calculated every 4 to 6 years using the pooled cohort equation.^[2]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]

Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. Its size is approximately 22 nm but since LDL particles contain a changing number of fatty acids they actually have a mass and size distribution. Each native LDL particle contains a single apolipoprotein B-100 molecule (Apo B-100, a protein with 4536 amino acid residues) that surrounds the fatty acids keeping them soluble in the aqueous environment.^[1] The average composition of LDL is approximately 20% protein, 20% phospholipids, 40% cholesteryl esters, 10% unesterified cholesterol, and 5% triglycerides.^[2]

Low-density lipoprotein (LDL) belongs to the lipoprotein particle family. It has a discoid shape with an average diameter of approximately 20 nm.^[3] However, LDL is considered a heterogeneous molecule due to fluctuating density, size, and flotation rate.

The LDL particle can be structurally divided into 3 layers according to molecular orientational behavior:

• Outer surface layer with tangential orientation: It forms a shell composed of phospholipid monolayer to cover the core. The phospholipid monolayer is organized in a way that hydrophilic residues with polar head groups interact with the outer aqueous solvent; while the inner hydrophobic residues face the lipid interior.
• Interfacial layer with radial orientation
• A polar lipid core with random orientation: It contains cholesteryl esters and triglycerides.^[2][4]

Each native LDL particle contains a single apolipoprotein B-100 (Apo-100) molecule. Apo B-100 is a protein with 4536 amino acid residues. It encircles the fatty acids keeping them soluble in the aqueous environment.^[3]

ApoB-100 covers the surface layer of LDL in a heterogeneous fashion, covering one hemisphere of LDL, while keeping other surfaces uncovered with exposed lipids.^[2]

Shown below is a table depicting the biochemistry characteristics of LDL.

For more information about the biochemistry of all lipoproteins, click here.

LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles (“Pattern B”) equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles (“Pattern A”). This is because the smaller particles are more easily able to penetrate the endothelium. “Pattern I”, meaning “intermediate”, indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).

The correspondence between Pattern B and coronary heart disease has been suggested by some in the medical community to be stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test has been used more commonly.

LDL’s main role is mediating metabolism and transport of cholesterol. LDL transports cholesterol and triglycerides from the liver to peripheral tissues. LDL transports approximately 70% of circulating cholesterol.^[6] It is formed in the circulation from VLDL by the action of lipoprotein lipase (LPL). LDL receptors, located at specific coat pits on plasma membrane of specific target cells mediate the selective uptake of molecules into cells by endocytosis. The coat pits contain clathrin protein on the cytoplasmic end of the plasma membrane to promote endocytosis. LDL receptors are glycoproteins that have negatively charged domains capable of interacting with positively charged arginine and lysine residues of apo B-100. Inside the cell, LDL migrates within a vesicle and is targeted to be degraded within the lysosome that contains hydrolases capable of digesting components of LDL. LDL degradation produces cholesterol, amino acids, glycerol and fatty acids.^[7]

Not only does LDL transport cholesterol, but also this activity is key to control cholesterol homeostasis.^[8] Cholesterol derived from LDL following degradation within the lysosome contributes to the feedback inhibition of cholesterol synthesis by directly suppressing the rate-limiting step catalyzed by HMG-CoA reductase enzyme.^[7] LDL also has the ability to suppress the transcription of LDL receptor genes, preventing accumulation of cholesterol and keeping cholesterol amounts within membranes constant despite varying cholesterol supply and demand.^[9][10]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Environmental and genetic factors are involved in the pathophysiology of high LDL. Several conditions may contribute to the pathophysiology of high LDL, such as diet high in saturated fat, hypothyroidism, nephrotic syndrome, pregnancy, obesity, or medications such as amiodarone, cyclosporine, diuretics, and glucocorticoids.^[1] Abnormally low LDL can occur, and they usually result from rare inherited conditions, such as familial hypobetalipoproteinemia, abetalipoproteinemia, Anderson’s disease (chylomicron retention disease), familial combined hypolipidemia, and PCSK9 mutations.

• Contrary to other polygenic etiologies of elevated LDL, familial hypercholesterolemia (FH), also known as hyperlipidemia type II-A according to Fredrickson’s classification, is a monogenic hypercholesterolemia due to deficiency of LDL receptors caused by a mutation of LDLR gene on chromosome 19. The disorder follows an autosomal co-dominant segregation pattern.^[2]

• Homozygous FH is a rare disorder; where individuals have extremely high levels of LDL, often > 1000 mg/dl in the presence of family history and cardiac or cutaneous symptoms, irrespective of other environmental factors, like diet, medications, or exercise.^[3]

• Patients with homozygous FH are very susceptible to early-onset cardiovascular disease along with cutaneous manifestations of abnormal lipid metabolism, such as eruptive xanthomas.

• Goldstein and Brown described three cardinal features of FH:^[4]
  • Selective elevation of LDL
  • Selective deposition of LDL-derived cholesterol into macrophages throughout the body but not in parenchyma
  • Inheritance as autosomal dominant trait with gene dosage effect

• On the other hand, heterozygous FH, where only one mutated allele is present, has an incidence of 1 out of 500.^[5] It is defined as any of the following:
  • LDL-C levels > 200 mg/dL + coronary heart disease/risk equivalents
  • LDL-C levels > 300 mg/dL regardless of disease or risk equivalents

• Heterogeneous FH responds better to anti-lipidemics than the homogeneous counterpart.^[2]

• Although plasma LDL concentration may be normal in patients with type II diabetes mellitus, several qualitative modifications aid in promoting atherosclerosis in this particular population.^[6] The quantity of small dense triglyceride-rich LDL particles seem to be more abundant in patients with type II diabetes.^[7]

• Furthermore, patients with diabetes have increased LDL plasma residence time that contributes to increased arterial deposition of cholesterol and atherosclerosis.^[6] Altered residence time is attributed to reduced LDL catabolism and decreased turnover,^[6] probably due to decreased expression of LDL receptors.^[8] The modification in LDL receptor have been attributed to diabetes that causes increased glycation of Apo-B within LDL altering adequate LDL receptor affinity and even worsening LDL oxidation.^[9]

• However, it is notable that insulin therapy targeting diabetes and anti-lipidemic treatment with statins have profound beneficial effects on the unfavorable LDL modifications present in diabetics. By inhibiting HMG-CoA reductase, statin therapy indirectly increases the expression of LDL receptors thus improving the abnormal affinity.^[6]

• Renal disease causes a specific form of secondary dyslipidemia only when heavy proteinuria is present. Heavy proteinuria is required to exhibit decreased LDL receptor gene expression in hepatocytes, and alter gene expression of 2 key enzymes for LDL and cholesterol homeostasis: Increased activity of HMG-CoA reductase, the rate limiting enzyme for cholesterol synthesis, and reduced activity of 7α-hydroxylase, the rate limiting enzyme for cholesterol metabolism and bile acid synthesis.^[10]

• Similar to the pathogenesis observed in diabetic patients, nephrotic dyslipidemia also demonstrates changes in Apo-B that reduce LDL affinity to its receptor. The proportion of atherogenic small dense LDL particles is also increased.

• Individuals undergoing dialysis also have abnormal LDL profiles. Patients on hemodialysis generally have normal LDL cholesterol but more concentrated small dense particules.^[11] Specifically, patients on peritoneal dialysis generally have higher LDL and total cholesterol due to the considerable protein loss into the peritoneal dialysate that stimulates hepatic protein synthesis, including LDL and other lipoproteins.^[12]

• Non-alcoholic fatty liver disease (NAFLD) eventually contributes to the overproduction of LDL, among other lipoproteins. A two-hit hypothesis has been proposed by Day and James in 1998.^[13] Initially, lipid accumulates in hepatocytes following insulin resistance. Second, oxidative stress leads to non-alcoholic steatohepatitis (NASH). Irregular metabolism of fatty acids causes hypertriglyceridemia due to overproduction of VLDL that is eventually metabolized into LDL through CETP-mediated exchange of cholesteryl esters and triglycerides between the two lipoproteins.

• Similar to other disease entities, hepatocellular damage yields small dense triglyceride-rich lipoproteins that have low LDL receptor affinity, carry more residence time, and are more susceptible to oxidation and atherosclerosis.^[14]

• Cholestatic liver disease is associated with marked hyperlipidemia and elevated LDL. It is hypothesized that because HDL is also elevated in these patients and is believed to play a protective role, cardiovascular disease does not seem to be increased in patients with cholestatic liver disease. Such outcomes, however, remain controversial.^[15]

• Hypothyroidism is associated with marked elevations of LDL due to reduced LDL receptors that decrease LDL clearance. Since hypothyroidism also reduces oxygen consumption of cardiac myocytes, cardiac contractility is reduced and vascular resistance is increased.
• Both vascular changes and LDL accumulation seen in hypothyroidism promote atherosclerosis.^[16]

Oxidized LDL measured in patients with obstructive sleep apnea syndrome (OSAS) shows significant increase when compared to control groups.^[17] This was believed to be due to the hypoxemia experienced by these patients that cause lipid peroxidation and an imbalance between reactive oxygen species and counteracting antioxidant reserve.^[18] However, newer research findings have not entirely supported this theory; thus the exact mechanism that associates OSAS and elevated LDL remains controversial. Elevated LDL normalizes following appropriate continuous positive airway pressure (CPAP) therapy for patients with OSAS.

• The term atherosclerosis was first introduced by Marchand to describe the association between fatty degeneration and medium to large-sized arterial sub-intimal thickening. Since the early 1980s, it has been emphasized that LDL oxidation is important for the development of atherosclerosis and coronary heart disease (CHD).^[19] Atherosclerosis is considered the end-product and the most feared outcome of nearly all diseases that accompany an elevated LDL.

• LDL undergoes oxidative modification in vivo by mechanisms that are still poorly understood. In-vitro studies have hypothesized the role of several enzymes in LDL oxidation, including 15-lipoxygenase, myeloperoxidase, xanthine oxidase, among several others.^[20] It is believed that LDL oxidative modification accelerates accumulation of cholesterol within macrophages (foam cells) and initiate atherosclerotic lesions, called fatty streaks. Fatty streaks predispose to vascular disease and perturbation in endothelial function.

• As a result, adhesive proteins such as ICAM-1 are overactivated allowing leukocytic and monocytic accumulation.^[6] The latter plays a central role in the activation of inflammatory cascade and proliferation of smooth muscle cell and monocytes, further enhancing the inflammatory process and contributing to LDL oxidation and uptake by macrophages. Fatty streaks then evolve gradually into fibrous plaques, and subsequent lipid accumulation by LDL activity from the blood to the vessel wall leads to plaque instability and rupture resulting finally in thrombotic occlusion of the arterial bed. Oxidized LDL is considered significantly atherogenic and chemotactic for macrophages.

• Once LDL moves from the blood to the vessel media, one of three outcomes will occur:

1. LDL returns to blood causing regression of the lesion.
2. LDL undergoes oxidation due to leukocytes and free radicals.
3. LDL are taken up by scavenger receptors of macrophages that become foam cells. Scavenger receptors have particular recognition to LDL in oxidized form only.

• Rare inherited conditions, such as familial hypobetalipoproteinemia, abetalipoproteinemia, Anderson’s disease (chylomicron retention disease), familial combined hypolipidemia, and PCSK9 mutations might cause abnormally low LDL.

• Familial hypobetalipoproteinemia is a rare autosomal dominant genetic disorder caused by apolipoprotein B mutations leading to loss of the ability to form lipoproteins in the liver and intestine.^[21][22] Typically, plasma cholesterol levels will be in the range of 80-120 mg/dL, and LDL cholesterol will be in the range of 50-80 mg/dL.^[22]

• Abetalipoproteinemia is an autosomal recessive disorder that affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins containing apo-B: chylomicrons, VLDL, and LDL. Two genes have been identified in which mutations are associated with this disorder: microsomal triglyceride transfer protein (MTTP) and apolipoprotein B (ApoB).^[23]

• Anderson’s disease or chylomicron retention disease is an extremely rare disorder with approximately 50 cases reported. Patients with Anderson’s disease have a mutated SAR1B protein in enterocytes. Although they are able to synthesize chylomicrons they are unable to transport them out of the enterocytes leading to accumulation.^[24]

• Familial combined hypolipidemia (FCH) is an inherited disorder due to a mutation in angiopoietin-like 3 (ANGPTL3). FCH leads to very low levels of LDL, HDL, triglycerides, and apo-B.^[21]

• Protein convertase subtilin/kexin type 9 (PCSK9) mutations lead to a gain of function that increases available LDL-C receptors on the surface of hepatocytes. Patients with PCSK9 mutations have LDL-C levels usually below 20 mg/dL with no other comorbidities observed and a very dramatic reduction in the incidence of cardiovascular disease. These patients were the basis for the development of PSCK9 blocking agents such as evolocumab, alirocumab, and bococizumab.^[25]

Template:WikiDoc Sources

Are you looking for:

• Causes of low LDL, or

• Causes of high LDL

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

From 1976–1980 through 2007–2010, for U.S. adults aged 40–74, a decrease was observed in the prevalence of high LDL-cholesterol (LDL–C) from 59% to 28%, as well as an increase in adults using lipid-lowering medications and consuming a diet low in saturated fat. Despite recent advances in medical treatment, high LDL-C remains a significant public health problem in the United States, with more than one-quarter of adults aged 40–74 having high LDL–C.^[1]

In the United States, the prevalence of high LDL–C significantly decreased from 59% in 1976–1980 to 42% in 1988–1994, and to 33% in 2001–2004, reaching 27% in 2007–2010.^[1]

The decrease in the prevalence of high LDL is paralleled by an increase in the use of cholesterol-lowering medication that grew from 5% in 1988–1994 to 17% in 2001–2004, and reached 23% in 2007–2010. In addition, the percentage of adults meeting guidelines for low saturated-fat intake increased significantly from 1976–1980 to 1988–1994, from 25% to 41%, but no significant change occurred from 1988–1994 through 2007–2010.^[1]

Shown below is a diagram depicting the age-adjusted prevalence of high LDL cholesterol among adults aged 40–74, by sex and age in the United States between 1976–1980 and 2007–2010. (Source: CDC/NCHS, National Health and Nutrition Examination Survey.)

Shown below is a diagram depicting the age adjusted use of cholesterol-lowering medications among adults aged 40–74 in the United States between 1988–1994 and 2007–2010. (Source: CDC/NCHS, National Health and Nutrition Examination Survey.)

Shown below an image depicting the age-adjusted trends in prevalence of high LDL cholesterol, use of cholesterol-lowering medications, and low saturated-fat intake among adults aged 40–74 in the United States between 1976–1980 and 2007–2010.

¹ Significant decreasing linear trends from 1976–1980 to 2007–2010 (p < 0.05).
² Significant increase from 1976–1980 to 1988–1994 (p < 0.05); no significant change from 1988–1994 to 2007–2010.
³ Significant increasing trend from 1988–1994 to 2007–2010.

Between 1976–1980 and 2007–2010, the prevalence of high LDL–C significantly decreased among U.S. men from 65% to 31%.

The prevalence of high LDL–C also significantly decreased among U.S. women from 54% to 24% between 1976–1980 and 2007–2010.^[1]

Between 2007–2010, the prevalence of high LDL–C for U.S. adults aged 40–64 was between 6% to 27%. The prevalence of high LDL–C among subjects aged 65–74 was 72% to 30%.^[1]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vendhan Ramanujam M.B.B.S [2]

Risk factors for high LDL include genetic predisposition, aging, and unhealthy life style choices.

Common risk factors for elevated LDL concentration include:

• Genetic predisposition and family: The genetic predisposition to elevated LDL most probably involves a polygenic mechanism and a variable penetrance.^[1]

• Aging: Men who are 45 years or older and women who are 55 years or older are at increased risk of having high LDL levels.^[2][3]

• Menopause ^[4][5]

• Life style choices:^[6]
  • A diet high in trans fat and saturated fat
  • Physical inactivity
  • Smoking (especially in diabetics)
  • Excessive alcohol intake

• Overweight or obesity^[7]

• Type 2 diabetes^[8]

• Pregnancy^[9]

• Puberty: Puberty can predispose to both increase in LDL level and LDL particle size.^[10][11]

• Malnutrition^[12]

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [3]

According to the United States Preventive Services Task Force (USPSTF), screening for dyslipidemia, which includes high LDL-cholesterol (LDL-c), is indicated among men 35 years and older (Grade: A Recommendation), men 20 to 35 years old in case of an elevated risk for coronary heart disease (Grade: B Recommendation), women 45 years and older in case of an elevated risk for coronary heart disease (Grade: A Recommendation), and women 20 to 45 years old in case of an elevated risk for coronary heart disease (Grade: B Recommendation).^[1] There is insufficient evidence to recommend for or against screening for dyslipidemia among infants, children, adolescents, or young adults less than 20 years of age (Grade: I statement).^[1]

Screening for dyslipidemia, including high LDL, depends on the gender, age, and the risk for coronary heart disease. Screening for dyslipidemia is indicated among the following:^[1]

• Men 35 years and older (Grade: A Recommendation)
• Men 20 to 35 years old in case of an elevated risk for coronary heart disease (Grade: B Recommendation)
• Women 45 years and older in case of an elevated risk for coronary heart disease (Grade: A Recommendation)
• Women 20 to 45 years old in case of an elevated risk for coronary heart disease (Grade: B Recommendation)

There is insufficient evidence to recommend for or against screening for dyslipidemia among infants, children, adolescents, or young adults less than 20 years of age (Grade: I statement).^[1]

Screening for dyslipidemia includes:^[2]

• Identification of risk factors for coronary artery disease
• Estimation of the 10-year risk of cardiovascular disease
• Measurement of fasting lipid panel (total cholesterol, LDL, HDL, triglycerides)

Template:WikiDoc Sources

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]

The natural history and the prognosis of high LDL concentrations are directly associated with the complications of atherosclerosis, namely cardiovascular disease (CVD) which is the most common cause of mortality worldwide. Classically, elevated LDL concentration has been associated with significantly increased rates of coronary artery disease (CAD). However, emerging evidence has demonstrated that an elevated concentration of LDL is also strongly associated with insulin resistance as well as other forms of ischemic vascular diseases. The role of elevated levels of LDL in the development of ischemic complications, such as stroke, peripheral arterial disease, carotid atherosclerosis, and renovascular injury, has also been validated. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations.

The natural history and prognosis of patients with elevated LDL are directly related to the complications associated with dyslipidemia. The development of complications due to atherosclerosis are the major factors that determine the prognosis of patients with elevated LDL concentrations. The majority of patients with elevated plasma LDL and atherosclerosis who are left untreated often develop manifestations of cardiovascular disease (CVD), the most common cause of death worldwide. Elevated LDL is also frequently associated with other cardiovascular risk factors, such as diabetes mellitus, hypertension, and low HDL that lead more rapidly to the development of cardiovascular disease.^[1][2] Shown below is a list of complications associated with elevated concentrations of LDL and atherosclerosis:

• Dyslipidemia caused by elevated LDL is a major risk factor for coronary artery disease (CAD) and often regarded as a prerequisite.^[3]
• There is a direct association between cardiovascular death and duration of elevated plasma LDL levels.^[4]
• An increase of LDL by 10 mg/dL is associated with a 12% increase in CVD risk in both genders.
• Accumulating evidence has proved the role of elevated LDL in the development of atherosclerosis and has demonstrated that lowering LDL attributes to significant reductions (30-37%) in CAD.^[5]

• Elevated concentrations of small dense LDL is often observed among patients before development of insulin resistance.^[6]

• The majority of patients with elevated LDL have other components of the metabolic syndrome, such as hypertriglyceridemia, hypertension, and insulin resistance.^[6]

• The association between elevated LDL and stroke has been observed, but the association has not been as strongly established as in the case of coronary artery disease.^[7]
• Nonetheless, statin therapy is important in cerebrovascular events, especially among patients with other manifestations of atherosclerosis, namely coronary artery disease. Statin therapy may significantly reduce the rate of ischemic stroke by approximately 20-30%.^[7][8]

• The true relation between elevated LDL levels and ischemic stroke as a complication is yet to be delineated.

• Elevated LDL is the primary risk factor for the initiation and development of carotid artery atherosclerosis.
• A reduction of LDL concentrations by at least 25% is associated with a significant reduction in the radiographic progression of carotid atherosclerosis

• Elevations of LDL is hypothesized to be the major initiator of renovascular injury associated with renal artery stenosis.^[9]

• Oxidation of high concentrations of LDL, along with an increasein local and systemic oxidative stress, promotes the generation of reactive oxygen species (ROS) that cause vasoconstriction and worsen renal ischemia.^[10]
• Emerging evidence currently favors the pharmacologic management of dyslipidemia for the treatment of renal artery stenosis compared to angioplasty.^[9]

• Elevated LDL is a risk factor for the development of peripheral arterial disease (PAD) and contributes to its progression and other manifestations of CVD.
• The aggressive management of atherosclerosis is a primary goal in the management of PAD, given the abundance of data to suggest that LDL normalization improves femoral arterial atherosclerosis and alters the natural history of PAD.

• The Framingham study demonstrated that elevated LDL is associated with non-CAD-death among both genders.^[2]

Template:WikiDoc Sources