High-density lipoprotein cholesterol (HDL-C)

Low concentration a major risk factor for coronary artery disease.

In a study of 200,000 peoples lipid profiles studying how the time since last meal affected levels found: HDL and total cholesterol values varied less than 2% with different durations of fasting, triglycerides values varied by 20%, and LDL, had a variation of about 10% (Sidhu D, Naugler C).

Carrier of excess cellular cholesterol in the reverse cholesterol transport pathway.

A low level of HDL is the most common lipid abnormality in patients with coronary artery disease.

Low levels of HDL is the primary lipid abnormality in half the patients with coronary artery disease.

Most patients with coronary heart disease who have a low HDL, also have a high production of LDL.

High density lipoprotein cholesterol levels have a strong inverse relation to incident major cardiac events, even among patients with very low levels of LDL-C with statin therapy

Each 1 mg/dL increase in HDL-C is associated with a 2% to 3% decrease in coronary artery disease risk, and predicts coronary risk regardless of LDL-C levels.

Levels less than 40 mg/dL are a risk factor for coronary artery disease.

HDL in young adulthood may play a role in cardiac remodeling impatiens who have hypertensive disease(Breslow).

Raising concentrations in persons with established CAD and both a low HDL-C and a low LDL-C significantly reduces the incidence of major coronary events.

Increasing levels of HDL associated with reduction in the development of atheroma progression as measured in carotid and coronary arteries.

Antiatherogenic influence includes reversing cholesterol transport pathway and antioxidant activity.

Promotes efflux of cholesterol from cells in the artery wall promotes endothelial repair and function, and inhibits thrombosis.

Stimulates endothelial nitric oxide production with antioxidant and antiinflammatory function.

Antioxidant properties related to associated enzymes.

Low levels increase the risk of nosocomial infection, especially surgical site infection.

Statins raise HDL levels by only 5-10%.

Niacin most effective medication to increase HDL levels.

In young adulthood may play a role in cardiac remodeling in patients who have hypertensive disease (Breslow).

Fibrates and niacin can increase HDL levels by levels less than 25%.

Decreased levels can be primary or secondary to other diseases or drugs.

Levels improved by exercise, weight loss and smoking cessation.

In genetic disorders associated with low HDL the level is approximately 5-10 mg/dL.

Secondary causes of low HDL include obesity, smoking, androgens, progesterone, low-fat diet, drugs beta blockers and probucol, and monoclonal gammopathy.

Cholesterol ester transfer protein (CTEP) inhibitors increase HDL-C levels and assist HDLs role of transporting excess cholesteril from the arterial wall to bile, liver, and fees for excretion.

Torcetrapib, a cholesterol ester transfer protein (CTEP) inhibitor, has been demonstrated to increase HDL levels by more than 60% but no effect on atherosclerosis was noted and there was an increased in major cardiovascular events and total mortality.

Evacetrapib, a cholesterol ester transfer protein (CTEP) inhibitor, when added to a statin improves lipid profiles by decreasing LDL levels and increases HDL levels (Nicholls SJ et al).

In a meta-analysis of a number of lipid trials increasing HDL levels did not reduce cardiovascular events (Briel).

Data from the Framingham Offspring Study from 1975-2003 to determine whether increases in HDL levels after the initiation of lipid therapy indcated that changes in such levels was an independent risk factor for cardiovascular events (Grover SA).

The Framingham Offspring Study indicated that changes in HDL levels with lipid therapy lowered risk of cardiovasular events over a wide range of clinical subgroups and was not associated with specific dtugs, and that lower pre-treatment LDL levels was associated with greater impact of increasing the HD (Grover SA).

HDL has the ability to promote cholesterol efflux from macrophages and this is strongly and inversely associated with subclinical atherosclerosis and obstructive coronary artery disease (Khera AV et al).

Cholesterol efflux from macrophages is only a small fraction of overall flux through the reverse-cholesterol-transport pathway, but it is one that is most relevant to atherosclerosis protection (Cuchel M, Rader DJ)

Cholesterol efflux capacity of macrophages is a measure of HDL function and has a strong inverse association with carotid intima-media thickness and the likelihood of coronary artery disease, independent of the HDL cholesterol level.

High-density lipoprotein

One of the five major groups of lipoproteins.

Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules around the body within water outside cells.

High-density lipoproteins are typically composed of 80-100 proteins/particle.

Larger lipoprotein particles which deliver fat molecules to cells,

HDL particles remove fat molecules from cells exporting fat molecules.

The fats carried include cholesterol, phospholipids, and triglycerides; amounts of each quite variable.

Lipoproteins, in order of molecular size, largest to smallest, are chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and HDL.

Lipoprotein molecules enable the transportation of all lipids, such as cholesterol, phospholipids, and triglycerides, within extracellular fluid, including the bloodstream.

HDL particles, unlike the larger particles, transfer fats away from cells, artery walls and tissues through the bloodstream, back to both (a) LDL particles and (b) back to the liver for other disposition.

Increasing concentrations of HDL particles are strongly associated with decreasing accumulation of atherosclerosis within the walls of arteries over weeks, years, decades.

HDL particles can reduce macrophage accumulation, and help prevent, even regress atherosclerosis and help prevent cardiovascular disease, stroke(s) and other vascular disease.

LDL particles deliver fat molecules to macrophages in the wall of arteries.

HDL-C is the cholesterol associated with ApoA-1/HDL particles.

About 30% of blood cholesterol, along with other fats, is carried by HDL.

HDL particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-utilization.

The cholesterol carried within HDL particles (HDL-C) is sometimes called good cholesterol.

Patients with higher levels of HDL-C tend to have fewer problems with cardiovascular diseases, while those with low HDL-C cholesterol levels, especially less than 40 mg/dL or about 1 mmol/L, have increased rates for heart disease.

Higher native HDL levels are correlated with better cardiovascular health.

Increasing HDL levels does not improve cardiovascular outcomes.

The serum cholesterol after subtracting the HDL is the non-HDL cholesterol, and the concentration of these other components may cause atheroma.

Non-HDL is now preferred to LDL-C as a secondary marker as it has been shown to be a better predictor and it is more easily calculated.

It is the smallest of the lipoprotein particles.

It is the densest because it contains the highest proportion of protein to lipids.

HDL’s most abundant apolipoproteins are apo A-I and apo A-II.

A rare genetic variant, ApoA-1 Milano, has been documented to be far more effecitive in both protecting against and regressing arterial disease.

The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles.

The complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the ATP-binding cassette transporter A1 (ABCA1).

Lecithin-cholesterol acyltransferase (LCAT), a plasma enzyme converts the free cholesterol into cholesteryl ester which is then sequestered into the core of the lipoprotein particle, causing the newly synthesized HDL to assume a spherical shape.

HDL particles increase in size as they circulate through the bloodstream and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins.

HDL increase particle size by the interaction with the ABCG1 transporter and the phospholipid transport protein (PLTP).

HDL transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by both direct and indirect pathways.

HDL is removed by HDL receptors such as scavenger receptor BI (SR-BI).

Cholesteryl ester transfer protein (CETP) exchanges triglycerides of VLDL against cholesteryl esters of HDL.

VLDLs are processed to LDL, which are removed from the circulation by the LDL receptor pathway.

The triglycerides are not stable in HDL, but are degraded by hepatic lipase so that small HDL particles are left, which restart the uptake of cholesterol from cells.

The cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids.

Delivery of HDL cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones.

HDL participate in the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile.

This pathway has been termed reverse cholesterol transport and is considered as the classical protective function of HDL toward atherosclerosis.

HDL carries many lipid and protein species, several of which have very low concentrations but are biologically very active.

HDL and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation, contributing protection from atherosclerosis.

Postulated that the concentration of large HDL particles more accurately reflects protective action, as opposed to the concentration of total HDL particles.

The ratio of large HDL to total HDL particles varies widely and is measured lipoprotein assays using advanced techniques.

Five subfractions of HDL have been identified.

The subfractions of HDL from largest to smallest are 2a, 2b, 3a, 3b, and 3c types.

The lipids are a group of compounds which are relatively insoluble in water and soluble in non-polar solvents.

Total cholesterol, triglycerides, and phospholipids are the major lipids in the body.

They are transported as complexes of lipid and proteins known as lipoproteins.

Triglycerides are formed by combining glycerol with three molecules of fatty acid.

Triglycerides as major components of VLDL and chylomicrons, play an important role in metabolism.

When the body requires fatty acids as an energy source, glucagon signals the breakdown of the triglycerides by lipase to release free fatty acids (FFA).

Triglycerides are water insoluble, non-polar neutral fats.

Triglycerides are synthesized and stored mostly in liver and adipose tissue.

Cholesterol: is an essential structural component of cell membrane, where it is required to establish proper membrane permeability and fluidity.

Cholesterol is an important component for the manufacture of bile acids, steroid hormones, and vitamin D.

High levels of serum cholesterol is an indicator for diseases such as heart disease.

High levels of HDL associated with dementia.

About 20-25% of total daily cholesterol production occurs in the liver.

Phospholipids are triglycerides that are covalently bonded to a phosphate group by an ester linkage.

Phospholipids perform important functions including regulating membrane permeability and in maintaining electron transport chain in mitochondria.

Phospholipids participate in the reverse cholesterol transport and thus help in the removal of cholesterol from the body.

Phospholipids are involved in signal transmission across membranes and they act as detergents and help to solubilization cholesterol.

Lipoproteins consist of a central core of a hydrophobic lipid encased in a hydrophilic coat of polar phospholipid, free cholesterol and apolipoprotein.

Men tend to have lower HDL levels, with smaller size and lower cholesterol content, than women.

Men also have an increased incidence of atherosclerotic heart disease.

Alcohol consumption tends to raise HDL levels, and moderate alcohol consumption is associated with lower cardiovascular and all-cause mortality.

HDL has a buffering role in the hypercoagulable state in type 2 diabetics and decreases the high risk of cardiovascular complications in these patients.

There is a significant negative correlation between HDL and activated partial thromboplastin time (APTT).

High concentrations of HDL of 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, increase the risk for atherosclerotic diseases.

For a given level of LDL, the risk of heart disease increases 10-fold as the HDL varies from high to low.

For a fixed level of HDL, the risk increases 3-fold as LDL varies from low to high.

Patients with very low LDL levels have increased risk of heart disease if their HDL levels are not high enough.

Patients with low HDL cholesterol, are at heightened risk for heart disease.

High HDL level, optimal condition protective against heart disease.

High LDL with low HDL level is an additional risk factor for cardiovascular disease.

Larger HDL particles carry more cholesterol.

Patients with highest large HDL particle concentrations have lowest rates of cardiovascular disease events.

Patients with moderately high large HDL particle concentrations have moderate rates of cardiovascular disease events.

Patients with lower large HDL particle concentrations have high rates of cardiovascular disease

Patients with lowest large HDL particle concentrations have the highest rates of cardiovascular disease events.

The lowest incidence of atherosclerotic events over time occurs within those with both the highest concentrations of total HDL particles and the highest concentrations of large HDL particles.

In a study of middle aged adults, low HDL cholesterol is associated with poor memory and decreasing levels over time is associated with decline in memory.

No medication used to increase HDL has been proven to improve health.

While high HDL levels correlate with better cardiovascular health, increasing one’s HDL may not increase cardiovascular health.

Certain changes in diet and exercise may raise HDL levels.

HDL levels may be increased by;

Decreasing intake of simple carbohydrates.

Aerobic exercise.

Weight loss.

Magnesium supplements.

Addition of soluble fiber to diet.

Consumption of omega-3 fatty acids such as fish oil or flax oil.

Increased intake of cis-unsaturated fats.

Consumption of medium-chain triglycerides (MCTs) such as caproic acid, caprylic acid, capric acid, and lauric acid.

Removal of trans fatty acids from the diet.

Most saturated fats increase HDL cholesterol to varying degrees and also raise total and LDL cholesterol.

HDL levels can be increased by smoking cessation, or mild to moderate alcohol intake.

Therapy to increase the level of HDL cholesterol includes use of fibrates and niacin.

Fibrates have not been proven to have an effect on overall deaths from all causes, despite their effects on lipids.

Niacin, vitamin B3, increases HDL by selectively inhibiting hepatic diacylglycerol acyltransferase.

Niacin reduces triglyceride synthesis and VLDL secretion.

Pharmacologic (1- to 3-gram/day) niacin doses increase HDL levels by 10–30%,[53] making it the most powerful agent to increase HDL-cholesterol.

Doses of niacin of 1- to 3-gram/day, increase HDL levels by 10–30%, making it the most powerful agent to increase HDL-cholesterol.

While niacin can significantly reduce atherosclerosis progression and cardiovascular events, niacin products sold as “no-flush”, do not contain free nicotinic acid and are therefore ineffective at raising HDL.

Niacin products sold as “sustained-release” may contain free nicotinic acid, but some brands may be hepatotoxic.

The recommended form of niacin for raising HDL is the immediate-release preparation.

The use of statins is effective against high levels of LDL cholesterol, but has little or no effect in raising HDL cholesterol.

However, several statins – rosuvastatin and pitavastatin – have been demonstrated to significantly raise HDL levels.

In the The CANHEART (Cardiovascular Health and Ambulatory Care Research Study of 631,762 participants lower HDL levels were associated with a higher risk of cardiovascular related mortality, cancer related mortality and other mortality.

Patients with lower HDL levels were more likely to have an unhealthy lifestyle, lower income, higher triglyceride levels, other cardiac risk factors, and other medical comorbidities.

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