High density lipoprotein

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

High-density lipoproteins form a class of lipoproteins, varying somewhat in their size (8–11 nm in diameter), that carry cholesterol from the body’s tissues to the liver. About thirty percent of blood cholesterol is carried by HDL.^[1]

It is hypothesized that HDL can remove cholesterol from atheroma within arteries and transport it back to the liver for excretion or re-utilization— which is the main reason why HDL-bound cholesterol is sometimes called “good cholesterol”, or HDL-C. A high level of HDL-C seems to protect against cardiovascular diseases, and low HDL cholesterol levels (less than 40 mg/dL for males and less than 50 mg/dL for females) increase the risk for heart disease.^[2] When measuring cholesterol, any contained in HDL particles is considered as protection to the body’s cardiovascular health, in contrast to “bad” LDL cholesterol.

Most clinical trials on prevention of coronary artery disease focus on lowering the levels of LDL cholesterol in the blood using statins and other lipid lowering drugs. These have shown improved clinical outcomes and reduction in mortality.

However, a causal relationship between low HDL cholesterol levels and development of significant coronary artery disease has not been established. There is a lack of evidence for proving that raising HDL levels can reduce cardiovascular events in those with coronary artery disease. Statins are used in the treatment of patients with low HDL levels to reduce the levels of “bad” LDL cholesterol in the blood.^[3][4]

High density lipoprotein (HDL) is considered “good cholesterol” as its levels are inversely proportional to CAD. It is regarded as a positive cardiac risk factor if the levels are below 35 mg/dL or total cholesterol to HDL ratio in > 5.0 (in men) or total cholesterol to HDL ratio in > 4.5 (in women). When the levels are above 60 mg/dL it is considered a negative cardiac risk factor.

Epidemiological studies have shown that high concentrations of HDL (over 60 mg/dL) have protective value against cardiovascular diseases such as ischemic stroke and myocardial infarction. Low concentrations of HDL (below 40 mg/dL for men, below 50 mg/dL for women) are a positive risk factor for these atherosclerotic diseases.^[2]

Data from the landmark Framingham Heart Study showed that for a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low. Conversely, for a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.

The plasma levels of HDL are inversely proportional to the development of coronary artery disease (CAD) making HDL a negative cardiac risk factor.^[5] Low serum HDL-cholesterol can be an isolated abnormality or can be associated with hypercholesterolemia. Patients with premature coronary artery disease, defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age, have a primary reduction in HDL-cholesterol. Studies have shown that low HDL risk is independent of the risk attributed to elevated LDL-cholesterol (low density lipoprotein) in the serum. Findings from large scale prospective studies indicate that for every 1 mg/dL rise in serum HDL levels the risk of CAD reduces by 2% to 3% in men and women respectively.

Even though a causal relationship has not been established between low HDL-C levels in the serum and the incidence of coronary artery disease, low HDL-C is considered a significant risk factor for CAD. Numerous clinical trials, like VA-HIT, AIM-HIGH, 4S etc., were conducted to study the effects of various novel lipid lowering agents on the levels of HDL-C and the corresponding changes in cardiovascular morbidity and mortality.

Statins and fibrate appear to be effective in patients with low HDL levels compared to those in normal HDL levels in terms of risk reduction. Fibrates are more effective when low HDL levels coincide with low levels of LDL levels. Before a combination of statins and fibrates are considered, dietary modifications and lifestyle changes can be effective tools to raise HDL levels. However, a combination therapy of statins with fibrates can result in myopathy as a potential adverse effect.

There are promising future therapies that include CETP inhibitors, which are currently in the experimental phase. A combination therapy with statins and ACE inhibitors is also a safe option in patients with HDL levels who also share features with dysmetabolic syndrome. However, the preventive effects of these two drugs tend to be cumulative.^[6]

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

The discovery of HDL dates back to 1929 when Michel Macheboeuf isolated α-globulin from horse serum in the Pasteur Institute.^[1] This lipoprotein was identified as an alpha lipoprotein and was later referred to as HDL. The classification of lipoproteins into alpha and beta referring to HDL and LDL respectively led to a further understanding of lipoproteins.^[2] For a long time, LDL and its association with cardiovascular outcomes were the focus of research studies. However, the discovery that HDL is not as simple as it was thought in terms of structure and function fueled research with more studies about this complex lipoprotein. One of the earliest association between HDL level and cardiovascular risks was hypothesized in the mid 1970’s.^[3] The Framingham Heart Study and the Helsinki Heart Study were among the landmark studies that confirmed this association in the late 1980’s.^[4][5]

• In 1929, Michel Macheboeuf isolated the first lipoprotein from horse serum. A stable, water-soluble α-globulin was precipitated from a 50% neutral ammonium sulfate-treated horse serum and was later identified as HDL.^[1]

• Further understanding of the nature of lipoproteins was driven by the laboratories efforts to purify blood for transfusion during World War II. Lipoproteins were classified into “alpha-lipoprotein” and “beta-lipoprotein” referring to HDL and LDL respectively.^[2]

• HDL was initially thought to be as simple in structure as LDL. Insight about the complexity and heterogeneity of HDL began later on after the discovery that HDL has several constituent proteins.

• In an article published in The Lancet in 1975, scientists hypothesized the association between low HDL level and high cardiovascular risk based on the finding that body cholesterol pool increases as HDL decreases.^[3] The association between low HDL and cardiovascular risk factors was thoroughly investigated in The Framingham Heart Study and The Helsinki Heart Study in the late 1980’s.^[4][5]

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

High-density lipoprotein (HDL) does not represent one structure but rather a series of lipoproteins that are sequentially produced. HDL dynamically switches between different conformations. Fractionated HDL particles can be classified based on physiochemical properties, cholesterol component, apolipoprotein composition, electrophoretic mobility, density, and biological function.^[1][2] HDL concentration in the serum can be classified into either low and high when the serum HDL concentration ≥ 60mg/dL and < 40 mg/dL, respectively.^[3]

High HDL level is defined by the National Cholesterol Education Program (NCEP) as serum HDL concentration ≥ 60mg/dL.^[3]

Low HDL level is defined by the National Cholesterol Education Program (NCEP) as serum HDL concentration < 40 mg/dL.^[3]

HDLs are highly heterogenous in their physiochemical characteristics due to the differences in relative composition of intercalated apolipoproteins thus may be separated based upon buoyant density, size, charge, or apolipoprotein composition. Moreover, the amphiphatic helical structure of apoA-I possesses a hinge domain that allows it to switch between different conformations corresponding to HDLs of variable size.^[4] With density gradient ultracentrifugation, HDLs can be separated into HDL₂, HDL₃, and very-high-density lipoprotein (VHDL). Nondenaturing polyacrylamide gradient gel electrophoresis may also be used to fractionate HDLs into five distinct populations of descending size: HDL_2b, HDL_2a, HDL_3a, HDL_3b, and HDL_3c.^[5][6] Isopycnic density gradient ultracentrifugation has been used to analyze the fasting plasma to yield equivalent delineations as well.^[7][8] Yet another method of classifying HDL lipoprotein particles by size is nuclear magnetic resonance (NMR).^[9] Two-dimensional gel electrophoresis technique can be used to resolve HDL particles in the plasma into lipid-poor pre-β-HDLs and α-HDL that predominantly contains mature spherical cholesteryl esters.^[10]

HDLs may be ultracentrifugally fractionated into two major populations.^[11][12][13]

Type	Size	Density
HDL2	1.063-1.125 g/ml	8.8 to 13 nm
HDL3	1.125-1.21 g/ml	7.3 to 8.2 nm

HDL may be isolated on the basis of size by non-denaturing polyacrylamide gradient gel electrophoresis or by isopycnic density gradient ultracentrifugation.^[11]

In the order of decreasing size:^[13]

• HDL_2b
• HDL_2a
• HDL_3a
• HDL_3b
• HDL_3c

Another classification is:

• Very large HDL particles (VL-HDL)
• Large HDL particles (L-HDL)
• Medium HDL particles (M-HDL)
• Small HDL particles (S-HDL)
• Very-small HDL particles (VS-HDL)
• Pre-β-1 HDL (role in macrophage cholesterol efflux)^[1]

High density lipoproteins can be immunoseparated on the basis of apolipoprotein composition into particles containing different apolipoproteins. The two major apolipoproteins found within HDL particles are the apoA-I and apoA-II.^[14][15] Several other minor apolipoproteins associated with HDL include apoA-IV, apoA-V, apoC-I, apoC-II, apoC-III, and apoE.^[16] However, LpA-I and LpA-I:LpA-II constitute the major portions of ciculating HDLs.

• LpA-I (contains only apoA-I)
• LpA-I:LpA-II (contains both apoA-I and apoA-II)
• LpA-IV
• LpE^[11][13]

HDL can be separated according to charge by agarose gel electrophoresis.^[11]

Note that pre-beta < pre-alpha < alpha.

• Pre-beta (positive)
• Pre-alpha
• Alpha (negative)

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

The physiological role of HDL centers around the reverse cholesterol transport system. Nascent HDL secreted into the plasma by the liver or intestine pick up free cholesterol from peripheral tissues and the arterial wall, an action mediated mainly by the ATP-binding cassette A1 (ABCA1). The enzyme lecithin-cholesteryl acetyltransferase (LCAT) catalyzes the esterification of the free cholesterol, and also converts the nascent HDL into the mature form. The esterified cholesterol is transported to the liver where cholesterylester transfer protein (CETP), an enzyme produced in the liver, acts on it transferring the cholesterol to other apo B containing lipoproteins. The cholesterol-deplete HDL gets broken down by triglyceride lipases releasing apo A-I which either takes up free cholesterol to continue the cycle, or gets eliminated in the kidneys. In addition to its atheroprotective against cardiovascular diseases, HDL also exhibits anti-oxidant, anti-inflammatory, anti-apoptotic, anti-coagulant, vasodilatory, and metabolic properties.

Lipoprotein	Density	Size	% Protein	Cholesterol in Plasma	Triglyceride in Fasting Plasma	Major Apolipoprotein
HDL	1.063 – 1.210 g/mL	6 – 10 mm	40 – 55%	0.9 – 1.6 mmol/L	0.1 – 0.2 mmol/L	apoA-I, apoA-II

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

Shown below is a schematic image depicting the structure of the HDL. Note that the inner core is made of triglyceride and cholesterol esters whereas the surface is made of amphiphilic phospholipids along with apolipoproteins.

• HDL is the smallest of the lipoproteins. It is the densest because it contains the highest proportion of protein. It contains the A class of apolipoproteins. Apolipoprotein A-I is the main protein of HDL that removes excess cell cholesterol and protects against atherosclerosis.^[1]
• The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipids, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol from cells they interact with.
• A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol) which is then sequestered into the core of the lipoprotein particle eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol molecules into their structure.
• Thus it is the concentration of large HDL particles which more accurately reflects the HDL protective action, as opposed to the concentration of total HDL particles.^[2] This ratio of large HDL to total HDL particles varies widely and is only measured by more sophisticated lipoprotein assays using either electrophoresis, originally developed in the 1970s, or newer nuclear magnetic resonance (NMR) spectroscopy which was developed in the 1990s.
• HDL particles are not inherently protective. It is only the HDL particles which become the largest (actually picking up and carrying cholesterol) that are protective. There is no reliable relationship between total HDL and large HDL, and more sophisticated analyses which actually measure large HDL, and not just total HDL, correlate much better with clinical outcomes.^[3]
• Many studies have postulated an association between cholesterol efflux from peripheral tissue and Apo A-I HDL particles, whereas the HDL₃ containing both Apo A-I and A-II are less effective.^[4][5][6]

• ABCA1 transporter: it is expressed in the peripheral tissues, intestine, liver, and macrophages.^[7] An increase in intracellular cholesterol content upregulates ABCA1 transporter which is responsible for cholesterol efflux from the intracellular pool.^[8]

• ABCG1 transporter: it is expressed in the intestine and macrophages.^[7] ABCG1 is also responsible for cholesterol efflux. In addition, ABCG1 may facilitate the oxidation of plasma membrane cholesterol domains.^[9]

• Scavenger receptor class B type I (SR-BI): it is expressed in the liver, endothelial cells, and macrophages. It participates in reverse cholesterol transport in which extrahepatic cholesterol is delivered to the liver for excretion into the bile.^[10][11] In macrophages it blunts cytokine production.^[12] In endothelial cells it mediates HDL-induced endothelial nitric oxide synthase (eNOS) activation, proliferation, and migration.^[13]

• CETP mediates exchange of cholesterol between HDL particles, and triglyceride rich LDL and VLDL in both directions.
• CETP is normally present in both peripheral tissues and liver and functions to channel cholesterol to the liver for uptake and metabolism.

• LCAT is an enzyme that catalyzes the transfer of fatty acyl chain to free cholesterol which results in cholesteryl ester formation.^[14]
• Its role in extracellular cholesterol metabolism may facilitate the uptake of cholesterol from peripheral tissues to liver into HDL particles by maintaining a concentration gradient for the efflux of free cholesterol which may play a major role in reverse cholesterol transport (RCT).^[15]

HDL plays a pivotal role in cholesterol transport from peripheral tissues to the liver for excretion, a process known as reverse cholesterol transport. HDL’s protective atherosclerotic effect is related to its role in reverse cholesterol transport, where cholesterol efflux from macrophages to HDL is an important initial step.

Low concentration of HDL is one of the various risk factors of cardiovascular disease as demonstrated by preclinical and epidemiologic studies. Increasing HDL concentration by medical therapy, such as niacin and inhibition of cholesteryl ester transfer protein, was evaluated in many clinical trials. Studies such as ILLUMINATE,^[16] dal-OUTCOMES,^[17] and CHI-SQUARE, have failed to demonstrate an association between increasing HDL by therapy and improved cardiovascular outcomes. Higher cholesterol efflux capacity, however, is associated with a lower rate of cardiovascular disease, independently of HDL cholesterol concentration.^[18] These findings highlight the importance of HDL function in reverse cholesterol transport and cholesterol efflux.

Adapted from Nature Reviews Drug Discovery. ABCA1= ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; ABCG4: ATP-binding cassette transporter G4; ApoA-I= Apolipoprotein A-I; CETP: Cholesteryl transfer protein; LCAT: Lecithin cholesterol acyltransferase; SRBI: Scavenger receptor, class B, type I. ^[19]

• HDL consists of phospholipids and apolipoproteins, mainly apo A-I and/or apo A-II. Both the liver and the small intestine synthesize apo A-I while only the liver synthesizes apo A-II.
• Free apo A-I is released into the plasma as nascent HDLs. Nascent HDL readily takes up excess free cholesterol from the periphery such as fibroblasts, macrophages, and arterial wall, a process referred to as cholesterol efflux. This uptake of cholesterol is mediated by either ATP-binding cassette A1 (ABCA1), G1/G4, scavenger receptor class B type 1 (SR-B1), Cyp27A1, caveloin, and passive diffusion, leading to the formation of discoid HDL (a.k.a. pre-βHDL).
• Apo A-I is a cofactor of lecithin-cholesterol acetyltransferase (LCAT) which catalyzes the esterification of the free cholesterol bound to the discoid HDL. The apolipoprotein A1 acts as a signal protein in mobilizing cholesteryl esters from within the cells.

• The esterified cholesterol moves into the hydrophobic core of the HDL, changing the HDL particle from discoid to spherical (mature HDL). This process also prevents the re-uptake of cholesterol by cells. LCAT is responsible for the maturation of HDL particles.
• The esterified cholesterol can be delivered back to the liver through a number of routes:
  • CETP, secreted in the liver, transfers cholesterol from HDL to the apo B–containing lipoproteins e.g., very low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL) to be taken up by the liver. Mutations of this transport protein gene causes familial HDL deficiencies and Tangier disease.
  • HDL particles may be taken up directly by the liver.
  • Free cholesterol may be taken up directly by the liver.
  • HDL cholesterol esters may be selectively taken up via the scavenger receptor SR-B1, which is expressed in the liver.

• Triglyceride lipase degrades cholesterol-deplete HDL particles into small, dense HDL particles which release apo A-I (nascent HDL) after dissociation. The apo A-1 either rapidly re-uptakes free cholesterol again by ABCA1 to form discoid HDLs, or it is endocytosed into the kidney tubule, or cleared via glomerular filtration.

Shown below is an image summarizing the physiologic functions of HDL in an acute and chronic setting. Please refer to the text below for details about each one of functions of HDL.

It has been established that HDL-cholesterol has an inverse correlation with future atherosclerotic cardiovascular complications. HDL and apo A-I exhibit many atheroprotective functions which primarily aim at removing cholesterol from peripheral tissues and the arterial wall through various efflux mechanisms, mainly the reverse cholesterol transport system. HDL also plays a role in the attenuation of plaque progression and promotion of plaque stabilization. These functions are exhibited through its anti-oxidative, anti-platelet, anti-apoptotic, and anti-inflammatory properties. With all these properties in context, HDL potentially protects against reperfusion ischemic injuries and secondary plaque rupture observed in post-acute coronary syndrome patients.

• Plasma HDL associated apolipoprotein M (apoM) modulates the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.^[20]
• Animal models have demonstrated that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis.^{[21][22][23][24]}
• ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in endothelial cells and the scavenger receptor B type I mediate multiple intracellular signaling pathways as well as the efflux of cholesterol.^[25]

HDL has the ability to inhibit platelet activation and aggregation by directly inhibiting platelet activation,^[26][27] downregulating thromboxane A2 synthesis,^[28] increasing the synthesis of prostacyclin,^[29] and lowering the expression of the tissue factor which is required in the coagulation process.^[30]

The formation of free oxygen radicals contributes to the pathogenesis and progression of atherosclerotic plaques. Oxidized LDL is engulfed by macrophages, which leads to further oxidation and production of foam cells. Oxidized LDL acts as a chemotactic agent for circulating monocytes, converts macrophages into foam cells, induces cytotoxic effects on the endothelium, inhibits motility of tissue macrophages, and stimulates the migration and proliferation of vascular smooth muscle cells.^[31] HDL also inhibits the oxidative modification of oxidized LDLs,^[32] and prevents their infiltration into the vessel wall.^[33]

HDL has anti-inflammatory functions in both endothelial cells and leukocytes. During inflammation, several leukocyte adhesion molecules are activated, which promotes the binding of leukocytes and formation of atheroma. HDL inhibits the activation of vascular cell adhesion molecule (VCAM-1),^[34] interleukin-1-induced expresion of E-selectin,^[35] interleukin-8, intracellular adhesion molecule (ICAM)-1, neutrophils,^[36] monocytes,^[37] and also prevents the binding of T-lymphocytes to monocytes thereby preventing the formation of pro-inflammatory cytokines.^[38]

In a study on the effects and mechanisms of HDL on glucose metabolism, 13 type 2 diabetes patients were administered intravenous reconstituted HDL. There was a reduction in the plasma glucose of the patients due to an increase in plasma insulin in addition to the activation of AMP-activated protein kinase in the skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.^[39]

HDL might modulate glucose homeostasis through several mechanisms such as the stimulation of insulin secretion,^{[40][41][39][42]} enhancement of insulin sensitivity, and increased glucose uptake by skeletal muscle via activation of AMP-activated protein kinase (AMPK) signaling pathway.^[43][41] Preliminary evidence from genetic engineering studies that manipulate expression of related genes such as ABCA1,^{[44][45][46][47]} CETP,^[48][49] ABCG1,^[50] and apoA-I^[43] suggests associations between plasma HDL concentrations and glycemic control. Silencing of microRNA species was also been associated with upregulation of these target genes along with elevation of functional HDL levels,^{[51][52][53][54]} suggesting an extensively-linked yet fine-tuned state of homeostasis in energy metabolism.

Type 2 diabetes mellitus and impaired fasting glucose are both associated with decreased levels of HDL.^[55][56] In the Framingham Offspring Study, low levels of HDL cholesterol was reported as a significant predictor of incident type 2 diabetes mellitus.^[57]

Plasma HDL offers some cytoprotection against oxidized LDL-mediated apoptosis and generation of reactive oxygen species in-vitro .^[58] HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SRBI-initiated signaling.^[59] It is also suggested that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation.^[60]

HDL might play a role in the restoration of endothelial dysfunction implicated in the pathogenesis of type 2 diabetes. In one study, reconstituted HDL was infused in patients with type 2 diabetes and the vascular function (forearm blood flow) was assessed at 4 hours and 7 days post-infusion. HDL infusion was associated with an increase in the forearm blood flow in diabetic patients as compared to the controlled group, probably due to its effect on increasing the bioavailability of nitric oxide.^[61]

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

Insulin resistance contributes to a decrease in HDL number as well as functionality, which culminates in a decrease in the overall action of HDL in the body.^[1] Low HDL levels, exacerbates insulin resistance and consequently lead to a self perpetuating cycle of increment in insulin resistance and decrement in HDL action.^[2][3] Diabetes mellitus type II and visceral obesity, especially in genetically predisposed individuals, lead to low HDL through its contribution to insulin resistance.

• Insulin resistance, secondary to obesity and type II diabetes, contributes to dyslipidemia by increasing triglyceride and total cholesterol and decreasing HDL. And in return, dyslipidemia, including low HDL levels, further exacerbates insulin resistance leading to a self perpetuating cycle of increase insulin resistance and decrease HDL action.^[2][3]

• Insulin resistance contributes to a decrease in HDL’s number as well as functionality, which culminates in a decrease in the overall action of HDL in the body.^[1]

• There are several mechanisms by which insulin resistance contributes to low HDL action. In fact, insulin resistance downregulates ApoA-I transcription and increases HDL clearance which leads to decreased HDL levels.^[4][5] In addition to lowering HDL levels, insulin resistance lowers HDL functionality by glycation of HDL particles.^[1][6]

• Genetic predisposition also contributes to these mechanisms rendering some individuals more susceptible to having insulin resistance and dyslipidemia than other people.^[2][7]

Shown below is an image depicting the self perpetuating bidirectional relationship between insulin resistance and low HDL.

Adapted from Nature Reviews Endocrinology.^[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

High density lipoprotein (HDL) is considered “good cholesterol” as its levels are inversely proportional to CAD. It is regarded as a positive cardiac risk factor if the levels are below 35 mg/dL or total cholesterol to HDL ratio in > 5.0 (in men) or total cholesterol to HDL ratio in > 4.5 (in women). When the levels are above 60 mg/dL it is considered a negative cardiac risk factor.

• Apolipoprotein deficiency: Hypoalphalipoproteinemia can be of three types.

1. Impaired synthesis of apo A-I: Apo A-I deficiency, Apo A-I/C-III deficiency, Apo A-I structural variants
2. Increased catabolism: Familial HDL deficiency or Tangier disease
3. Enzymatic changes: genetic, reduced activity of lipoprotein lipase, elevated liver triglyceride lipase activity, LCAT (lecithin cholesterol acyltransferase) deficiency

• Insulin resistance^[1][2]
• Diabetes mellitus^[2]
• Metabolic syndrome^[3][4]
• Drugs

1. Beta-blockers^[5]
2. Benzodiazepines
3. Anabolic steroids
4. Diuretics
5. Progestins
6. Mifepristone^[6]

• Liver disease
• Menopause^[7]
• Obesity:High BMI is strongly associated with low serum HDl levels^[4]
• Puberty in males
• Uremia^{[8] [9]}
• Familial combined hypolipidemia^[10]
• Elevated CETP (cholesteryl ester transfer protein) activity: Polymorphism of the gene TaqIB (CETP gene) is known to be associated with variations in the plasma concentrations of CETP. A gene variant called TaqIB1 is associated with a higher CETP concentration and lower HDL-C levels in the plasma. Two other mutations that result in similar findings are A373P and R451Q.^{[11][12][13][14]}
• Smoking
• Lack of physical exercise^[4]
• High carbohydrate diet

• Drugs

1. Desogestrel and Ethinyl Estradiol
2. Niacin
3. Fibrates
4. Statins

• Chronic alcoholism: Alcohol consumption raises HDL cholesterol levels by possibly increasing the transport rate of apolipoproteins A-I and A-II. Alcohol consumption of 30-40 g/day (1-3 drinks/day) or more has been shown to increase HDL-C levels.^[15][16]
• Extensive aerobic exercise
• Alcoholic liver disease
• Weight loss: For every 1 kg weight loss serum HDL increases by 0.35 mg/dL^[17]
• Hyperalphalipoproteinemia
• Oral estrogen replacement therapy
• CETP deficiency (single gene defects in 16q21)^[18][19]
• Early stage primary biliary cirrhosis ^[20][21]

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

For 2009–2010, 21.3% of adults aged 20 and over had low HDL cholesterol (less than 40 mg/dL) in the United States. The percentage of adults with low HDL cholesterol was higher for men (31.4%) than for women (11.9%). Percentages among men were also higher than those among women of the same racial and ethnic group. For men, the percentage with low HDL cholesterol was lower among non-Hispanic black men than non-Hispanic white or Hispanic men. No racial or ethnic differences were found among women in the percentage with low HDL cholesterol.^[1]

• In 2009–2010, 21.3% of adults aged 20 years and over had low HDL cholesterol level (less than 40 mg/dL) in the United States.

• In Europe, the prevalence of low HDL-cholesterol was estimated to be approximately 33% among men and 40% among women, with very low HDL-cholesterol present in 14% (both genders combined). A higher prevalence was reported among diabetic patients compared to the general population.^[2]

• During 2009–2010, approximately 31% of men and 12% of women had low levels of HDL cholesterol. Percentages among men were also higher than those among women of the same racial and ethnic group.^[3]

Shown below are diagrams depicting the prevalence of low HDL cholesterol by age group and sex in the United States between 2009 and 2010 (Source:CDC.gov).

• In Europe, the prevalence of low HDL-cholesterol was estimated to be approximately 33% among men and 40% among women.^[4]

• For men, the prevalence of low HDL cholesterol was lower among non-Hispanic black men than non-Hispanic white or Hispanic men.^[3]

• No racial or ethnic differences were reported among women with low HDL cholesterol.^[3]

Shown below is a diagram depicting the prevalence of low HDL cholesterol by ethinicity in the United States between 2009 and 2010 (Source:CDC.gov).

The percentage of adults with low HDL cholesterol declines with age for men and women.

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According to the United States Preventive Services Task Force (USPSTF), screening for dyslipidemia, which includes low HDL-cholesterol (HDL-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 age 20 to 45 years 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 low HDL, 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, HDL, HDL, triglycerides)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]; Vendhan Ramanujam M.B.B.S [4]

Epidemiological studies have shown an inverse relationship between HDL-C levels and CVD risks,^[1][2][3] low circulating levels of HDL-cholesterol have been associated with the development of coronary artery disease, particularly when it is accompanied by other coronary risk factors.^[4][5][6] The protective role of high HDL levels against CVD can be explained by the antiatherogenic and cardioprotective actions of HDL through reverse cholesterol transport, endothelial protection, anti-inflammatory activity, antioxidant and antithrombotic effects; however, it should be noted that HDL particles are heterogeneous in size and composition and they may be differently associated with cardiovascular risks. Many case-control and prospective studies have demonstrated that the HDL2 sub fraction and the plasma apo A-I concentration are better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL3.^[7] The strong negative association between HDL level and CVD risks has lead to the development of the “HDL-C hypothesis” which suggests that raising HDL level with pharmacological intervention is likely to reduce cardiovascular risks. In fact, HDL based therapies are challenging and their efficacy in reducing cardiovascular risks has not been uniform among all studies. While some studies reported that raising HDL-cholesterol in patients with a low baseline serum concentration may be effective for secondary prevention of coronary heart disease, other studies failed to decrease cardiovascular risks by raising HDL.^[8] In addition to its prognotic role in CAD, low HDL levels have been associated with diseases and complications involving the neurological, renal, and liver systems as well as sepsis and carcinoma.

Low HDL has been evaluated as a possible prognostic factor in the following conditions:

• Acute ischemic stroke
• Atrial fibrillation
• Carcinoma
• Chronic kidney disease
• Cirrhosis
• Congestive heart failure
• Coronary artery disease
• Dementia
• Kawasaki disease
• Nonalcoholic fatty liver disease
• Post-cardiac procedures
• Sepsis

The inverse relation of HDL to either the presence or development of coronary artery disease (CAD) is well-established;^[9] in fact, for every 1% decrease in HDL concentration, there is a 2-3% increase in the risk of development of CHD.^[10] Studies on different populations supported low HDL as a significant cardiovascular risk factor as well as a prognostic factor, either independently or along with other physical and biochemical metrics. Low levels of HDL-cholesterol, which may reflect increased catabolism of triglyceride-enriched HDL particles, appear to interact with hypertriglyceridemia to increase the coronary risk.^[11][12] Plaque rupture, besides its correlation with high total cholesterol (TC), is also shown to be related to low HDL-cholesterol and an elevated TC/HDL-C ratio.^[13] Studies on the relationship between low HDL levels and CAD are as follows:

• Based on data from the Framingham Heart Study, the risk for myocardial infarction was found to increase by 25 percent for every 5 mg/dL (0.13 mmol/L) decrement in serum HDL-cholesterol, below the median values for both men and women.^[4] According to the study, the relative risk of death due to cardiovascular and coronary artery disease for men in the first HDL-cholesterol quintile (less than 35 mg/dL) as compared to the top quintile (greater than 54 mg/dL) is 3.6 and 4.1 respectively and for women the corresponding values were 1.6 and 3.1, comparing the bottom HDL-cholesterol quintile (less than 45 mg/dl) to the top quintile (greater than 69 mg/dl).
• The Lipoprotein and Coronary Atherosclerosis Study (LCAS) which studied patients with mild to moderate LDL-cholesterol elevation found that the patients who also had low HDL-cholesterol at baseline had more CAD progression than patients with higher HDL-cholesterol.^[14]
• Framingham Risk Assessment counts HDL values above 60 mg/dL (1.5 mmol/L) as a negative risk factor.^[5]
• Studies have shown that in patients with known coronary artery disease, HDL-cholesterol levels are predictive of coronary events over a broad range of LDL-cholesterol levels. The LIPID (Long-Term Intervention with Pravastatin in Ischemic Disease) trial^[15] and the CARE (Cholesterol and Recurrent Events) trial^[16] have shown that reduced serum HDL-cholesterol levels strongly predicted acute coronary events in patients with LDL-cholesterol less than 125 mg/dL compared to those with levels above 125 mg/dL. There was a significant reduction in the event rate in patients with LDL-cholesterol <125 mg/dL for every 10 mg/dL rise in HDL-cholesterol compared to those with LDL-cholesterol levels more than 125 mg/dL. A similar relationship between the levels of HDL-cholesterol and LDL-cholesterol was also shown in the Treating to New Targets (TNT) trial.^[17]
• The finding of very low HDL levels among one-fifth of patients with NSTEMI ACS added to a greater burden of atherosclerosis and a higher risk of mortality.^[18]
• A study conducted in a European population revealed that patients carrying at least one polymorphic allele of the paraoxonase2 (PON2) gene along with low HDL represent a category of subjects at a higher risk for the development of acute myocardial infarction with a worse prognosis.^[19]
• A 2011 population based study with individual-participant-data (over 200,000 individuals) meta-analysis of 23 studies in the Asia-Pacific region revealed that a low level of HDL cholesterol was seen significantly more often in Asians than non-Asians (33.1 versus 27.0%). Even the prevalence of isolated low HDL-cholesterol was significantly higher in Asians (22.4 versus 14.5 %). In all individuals, there was a significant correlation between low HDL cholesterol and cardiovascular events. Particularly in Asians, the isolated low levels of HDL cholesterol were strongly associated with CAD risk similar to low levels of HDL cholesterol combined with other lipid abnormalities. This study suggested that isolated low HDL cholesterol in Asians is a distinct phenotype, which is strongly associated with an increased risk of CAD.^[20]
• More recently low HDL-cholesterol was found to be the most powerful lipid parameter for predicting the risk and the clinical outcome of CAD in a Han Chinese population.^[21]

The Multi-ethnic Study of Atherosclerosis (MESA) adds to the concept that the inverse relationship between HDL and cardiovascular risks may be determined more by some structural or functional component of the HDL particle than by its cholesterol content.^[22] HDL₂ subfraction and apo A-I are reported to be better predictors of coronary atherosclerosis than total HDL-cholesterol or HDL₃ in some studies,^[7] while other reports have shown similar associations of total HDL and HDL₃ with coronary artery disease (CAD) as HDL2 and apo A-I.^[23] Polymorphisms in phospholipid transfer protein (PLTP) are also shown to be associated with increased concentrations of smaller, cholesterol-depleted HDL particles and a lower cardiovascular event rate.^[24] Despite the established crude association between HDL and cardiovascular risks, Mendelian randomization analyses, JUPITER trial, and studies in Tangier disease failed to demonstrate a cause-effect relationship.^{[25][26][27][28]}

Data is scarce about the contribution of HDL to CAD in the pediatric population due to the rarity of cases. A prospective follow-up study in pediatric cardiac transplant recipients showed that, although pravastatin improved the HDL2 concentrations in the treatment group, it failed to normalize serum triglyceride and prevent the progression of vasculopathy in some of the patients. It also suggested a predictive role of low HDL-C and high apoB-100/apoA-I ratio for the development of vasculopathy.^[29]

Premature CAD is usually defined as CAD in men less than 55 to 60 years of age and women less than 65 years of age. Numerous studies of the 20th century from both Middle East and US population have reported low HDL in over 19% to 52 % of premature CAD patients.^{[30][31][30][32][33][34]} In the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study that examined aortas and coronary arteries from autopsies of healthy 15 to 35 year old persons, a negative association of high HDL with both fatty streaks and raised lesions in the aorta and right coronary artery was seen, particularly after the age of 25. Post-hoc analyses of two randomized trials in the past 10 years have shown low HDL levels as predictors of coronary events in patients with known CAD. Analysis of 13,173 patients in the LIPID and CARE trials found that low serum HDL cholesterol was a significantly stronger predictor of CAD events in patients with an LDL-cholesterol <125 than ≥125 mg/dL (3.2 mmol/L).^[35] For a 10 mg/dL (0.26 mmol/L) increase in HDL-cholesterol the event rate decreased by 29 percent in those with LDL-cholesterol <125 mg/dL (3.2 mmol/L) compared to 10 percent in those with an LDL-cholesterol ≥125 mg/dL (3.2 mmol/L). Post hoc analysis of the Treating to New Targets trial (TNT) in which nearly 10,000 patients with established CAD was treated with either high or low dose statin therapy revealed that HDL cholesterol levels were predictive of major cardiovascular events. This relationship was also observed among patients with LDL cholesterol levels below 70 mg per deciliter.^[36]

An investigation of the effects of baseline HDL cholesterol on the outcomes of 1032 patients who underwent drug-eluting stent implantation for acute coronary syndrome showed a higher rate of incidences of mortality and major adverse cardiac events at 30 days in low HDL than the high HDL cholesterol group. At 1 year, more deaths and major adverse cardiac events occurred in the low HDL cholesterol group. Multivariate analysis finally showed that low HDL cholesterol is a key predictor of major adverse cardiac events and death at 1 year.^[37]

But not all disorders associated with low HDL cholesterol are accompanied by a predisposition to premature CAD.^[38] Examples in which there is not a strong association with atherosclerosis includes patients with LCAT deficiency,^[39] and patients with the apo A-I Milano variant.^[40]

Low HDL in elderly age group (above 60 and 65 years in men and women respectively) is a known high risk factor of CAD.^[41] Prevalence of around 70% of increased serum LDL cholesterol and 70% of decreased serum HDL cholesterol have been reported in elderly patients with atherosclerotic vascular disease.^[42] The Framingham Heart Study and the Systolic Hypertension in the Elderly Program (SHEP) also found that both high LDL and low HDL cholesterol levels were significant CAD risk factors in elderly subjects.^[43][44] Low HDL can also be a predictor of mortality in elderly CAD patients. In a prospective cohort study that included a total population of 2527 women and 1377 men, for each 1-unit increase in the total cholesterol/HDL-cholesterol ratio, a 17% increase in the risk of CAD death was reported.^[45]

Low HDL levels can be considered a prognostic factor of CAD in women. 40% to 50% of women classified as being at intermediate risk using the Framingham risk model were reclassified into either higher or lower risk categories, emphasizing the importance of HDL cholesterol level along with other factors in CAD development among women.

The Reynolds risk score was developed and validated using data available from nearly 25,000 healthy women followed up prospectively for incidence of CAD and stroke during a median of 10.2 years and it included HDL cholesterol levels along with other factors.^[46]

Weight cycling (repeated weight loss and weight gain) in women is known to carry an increased risk of death from CAD. This may be related to a significant reduction in HDL cholesterol concentration during each cycle.^[47]

In postmenopausal women, the degree of coronary atherosclerosis has been linked to dysregulation of the TG/HDL metabolism. Subpopulations of both triglyceride rich and HDL lipoproteins have been found to be better predictors of CAD than triglyceride and HDL cholesterol concentrations.^[48]

In women with polycystic ovarian syndrome (PCOS), most studies have demonstrated associated low HDL cholesterol.^[49][50] In one study , components of the metabolic syndrome including low HDL and insulin resistance appeared to mediate the association between PCOS and coronary artery calcification, independently of obesity.^[51]

An unfavorable lipid profile characterized by a low HDL level can occur in HIV positive patients. The lipid profile may further deteriorate after receiving protease inhibitor based treatment, leading to increased CAD risk.^[52]

According to a study conducted on 665 adults with growth hormone deficiency, increased total and LDL cholesterol or low HDL cholesterol were reported in 22 to 45% of patients prior to their treatment.^[53] More recently, increased mortality from cardiovascular causes was described in a large prospective trial involving 1014 hypopituitaric patients in the United Kingdom.^[54] Hence, it can be hypothesized that low HDL can possibly be associated with higher risk of CAD particularly in growth hormone deficient patients.

Lipids in general, received only modest attention in the prognosis of CAD in rheumatoid arthritis all these days. With the exception of a single study,^[55] most investigators agreed that total, LDL and HDL cholesterol and triglycerides are reduced in active rheumatoid arthritis compared to inactive disease, non-inflammatory arthritis or normal controls,^[56] with an inverse correlation between the lipid values and the acute phase response. The low lipid profile may appear to be advantageous, except for the low HDL, which carries an adverse prognostic effect on CAD development and progression in rheumatoid arthritis patients.^[23]

Residual cardiovascular disease risk, defined as risk of recurrent cardiovascular disease events after management of coronary artery disease, may remain after treatment with statins and it may stem, at least partially, from low HDL cholesterol and/or elevated triglycerides.^[57]

The association between low HDL level and CAD prognosis can further be understood from experimental models. Both atherosclerotic lesion prevention and low HDL level associated preexisting atherosclerotic lesion regression have been demonstrated in transgenic mice or rabbits following expressions of high levels of human apo A-I,^[58][59] by somatic gene transfer of apo A-I,^[60] by administration of oral apo A-1 mimetic peptides^[61] or by administration of apo A-I Milano, which is a natural variant of apo A-I.^[62] Furthermore, liver-directed gene transfer of human apo A-I results in significant regression of pre-existing atherosclerosis after four weeks.^[63]

Four and a half years follow-up of 4544 individuals who met the criteria for metabolic syndrome approved by the American Heart Association and the National Heart, Lung, and Blood Institute, revealed that 265 patients developed atrial fibrillation. The risk of developing atrial fibrillation was significantly greater in those individuals with metabolic syndrome. In the absence of elevated triglycerides, the risk of developing atrial fibrillation was found to be higher among patients with low HDL cholesterol, hypertension, obesity, and impaired glucose tolerance.^[64]

A prospective evaluation of the prognostic relationship of HDL levels in patients with severe heart failure was conducted by examining 132 consecutive patients. This study revealed that lower HDL levels correlate with worse prognosis and higher mortality independently of the etiology of the heart failure.^[65]

HDL cholesterol is an important predictor of survival in post-CABG patients. In a study involving more than 8500 patients with years of follow-up, HDL cholesterol was found to be the most important metabolic predictor of post-CABG survival. Approximately one third of the patients survived at 15 years when their HDL levels were ≦35 mg/dL at the time of CABG. Therefore, the measurement of HDL cholesterol provides a compelling strategy for the identification of high-risk subsets of patients who undergo CABG.^[66]

Low HDL cholesterol is also an independent predictor of the long-term outcome after coronary artery stenting. The combination of low HDL cholesterol and elevated inflammatory markers identified the high-risk patients.^[67]

Isolated low serum HDL-cholesterol is also a risk factor for the development of coronary artery disease and may contribute to the development of saphenous venous graft disease.^[68]

In a study involving a European population where 176 chronic kidney disease (CKD) patients were followed up for 84 months, low HDL cholesterol levels, diabetes and hypertension were found to be associated with reduced GFR. The HDL cholesterol level was the only lipid parameter that was found to affect the progression of CKD independently of the presence of diabetes. Hence, a low level of plasma HDL cholesterol can be considered as a poor prognostic sign in CKD patients.^[69]

High density lipoprotein cholesterol has recently received much attention as a possible risk marker of prostate cancer development and prognosis.^[70] In addition, preoperative low serum HDL cholesterol concentration or high TC/HDL cholesterol ratio might be a potential biomarker of advanced pN(2-3) stages in gastric cancer patients, especially those with the histologically differentiated type.^[71] Preoperative serum HDL-cholesterol levels retrospectively examined in 184 patients who had undergone gastrectomy revealed a positive correlation between low preoperative serum HDL-cholesterol levels and prognosis for gastric cancer.^[72] A major function attributed to HDL is to maintain normal cell cholesterol homeostasis by removing excess of cholesterol from intracellular pools. Because the use and storage of cholesterol are increased within the tumor tissues during growth, it can be hypothesized that the low HDL levels observed in patients with gastrointestinal cancer are associated with the increased cholesterol metabolism in proliferating tissues.^[73]

A Model for End-Stage Liver Disease (MELD) score ≥18 and TC ≤2.8 mmol/L are two important indexes to predict the prognosis of patients with decompensated cirrhosis. The serum triglycerides, total cholesterol, HDL and LDL levels were lowered with the increase of the MELD score. Their combination can effectively predict the long-term prognosis of patients with decompensated cirrhosis.^[74] In an Asian study, an inverse correlation of serum levels of HDL and APO A-I with the liver reserve and disease severity in cirrhotic patients with severe sepsis was found. Low level of HDL and APO A-I were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.^[75] In another study, HDL cholesterol in noncholestatic cirrhotic patients was found to be a liver function test as well as an indicator of prognosis.^[76]

A study involving academic nursing home patients revealed that the prevalence of increased serum LDL cholesterol and decreased serum HDL cholesterol were found to be significantly higher in elderly patients with atherosclerotic vascular disease plus dementia (72%) and also in dementia without atherosclerotic vascular disease (68%) than in patients with no dementia or atherosclerotic vascular disease.^[42] These results suggest a possible prognostic role of HDL levels in dementia with or without atherosclerotic vascular disease.

Children with Kawasaki disease are more likely to have low HDL than the general pediatric population. This finding suggests a possible association between low HDL levels and the vascular complications of Kawasaki disease.^[77]

The negative association between HDL-cholesterol and liver-fat content is a known phenomenon. Thus the prognosis of NAFLD, which is one of the commonest causes of chronic liver disease both in US and worldwide, is worsened by low HDL levels.^[78][79]

Low HDL level was found to be independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlated with increased platelet activation.^[80] Another study found that serum levels of HDL and apo-AI are inversely correlated with liver reserve and disease severity in cirrhotic patients with severe sepsis. Both were associated with a marked impairment of effective arterial volume, multiple organ dysfunction and a poor prognosis.^[75] A low HDL cholesterol level on day one of severe sepsis has been shown to be significantly associated with an increase in mortality and adverse clinical outcomes.^[81]

Low HDL has been established as one of the risk factors for acute ischemic stroke. Patients with acute ischemic stroke were found to have a significantly smaller HDL size, with more HDL_3a, HDL_3b and HDL_3c and less HDL_2b subclasses. Large artery atherosclerotic stroke and lacunar ischemic stroke had the strongest association with high total cholesterol levels and low HDL cholesterol levels in a case-control study.^[82]

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