of each vary considerably.

[5]

The common clinical interpretation of blood lipid levels is that high LDL is associated with increased
risk of cardiovascular diseases.[6]

Biochemistry[edit]
Structure[edit]
Each native LDL particle enables emulsification, i.e. surrounding the fatty acids being carried,
enabling these fats to move around the body within the water outside cells. Each particle contains a
single apolipoprotein B-100 molecule (Apo B-100, a protein that has 4536 amino acid residues and a
mass of 514 kDa), along with 80 to 100 additional ancillary proteins. Each LDL has a highly
hydrophobic core consisting of polyunsaturated fatty acid known as linoleate and hundreds to
thousands (about 1500 commonly cited as an average) of esterified and unesterified cholesterol
molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded
by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100.
LDL particles are approximately 22 nm (0.00000087 in.) to 27.5 nm in diameter and have a mass of
about 3 million daltons.[7] Since LDL particles contain a variable and changing number of fatty acid
molecules, there is a distribution of LDL particle mass and size.[4] Determining the structure of LDL
has been a tough task because of its heterogeneous structure. However, the structure of LDL at
human body temperature in native condition, with a resolution of about
16 Angstroms using cryogenic electron microscopy, has been described in 2011.[8]

Physiology[edit]
LDL particles are formed when triglycerides are removed from VLDL by the lipoprotein
lipase enzyme (LPL) and they become smaller and denser (i.e. fewer fat molecules with same
protein transport shell), containing a higher proportion of cholesterol esters. [9][10]

Transport into the cell[edit]

When a cell requires additional cholesterol (beyond its current internal HMGCoA production
pathway), it synthesizes the necessary LDL receptors as well as PCSK9, a proprotein
convertase that marks the LDL receptor for degradation.[11] LDL receptors are inserted into the
plasma membrane and diffuse freely until they associate with clathrin-coated pits. When LDL
receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the
cell.

Vesicles containing LDL receptors bound to LDL are delivered to the endosome. In the presence of
low pH, such as that found in the endosome, LDL receptors undergo a conformation change,
releasing LDL. LDL is then shipped to the lysosome, where cholesterol esters in the LDL
are hydrolysed. LDL receptors are typically returned to the plasma membrane, where they repeat
this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the
lysosome, where they are degraded.[12]

Role in the innate immune system[edit]

LDL interfere with the quorum sensing system that upregulates genes required for
invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding
apolipoprotein B to a S. aureus autoinducer pheromone, preventing signaling through its receptor.
Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection. [13]
LDL size patterns[edit]
LDL can be grouped based on its size: large low density LDL particles are described as pattern A,
and small high density LDL particles are pattern B.[14] Pattern B has been associated by some with a
higher risk for coronary heart disease.[15]: 1–10 This is thought to be because the smaller particles are
more easily able to penetrate the endothelium of arterial walls. Pattern I, for intermediate, indicates
that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).
According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–
22 nm were designated as pattern A.[16] Other studies have shown no such correlation at all.[17]

Some evidence suggests the correlation between Pattern B and coronary heart disease is 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 is used more often.[15]

There has also been noted a correspondence between higher triglyceride levels and higher levels of
smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger,
less dense ("buoyant") LDL.[18][19]

With continued research, decreasing cost, greater availability and wider acceptance of
other lipoprotein subclass analysis assay methods, including NMR spectroscopy, research studies
have continued to show a stronger correlation between human clinically obvious cardiovascular
events and quantitatively measured particle concentrations.[20]

Oxidized LDL[edit]
Oxidized LDL is a general term for LDL particles with oxidatively modified structural components. As
a result, from free radical attack, both lipid and protein parts of LDL can be oxidized in the vascular
wall. Besides the oxidative reactions taking place in vascular wall, oxidized lipids in LDL can also be
derived from oxidized dietary lipids.[21][22] Oxidized LDL is known to associate with the development
of atherosclerosis, and it is therefore widely studied as a potential risk factor of cardiovascular
diseases.[23] Atherogenicity of oxidized LDL has been explained by lack of recognition of oxidation-
modified LDL structures by the LDL receptors, preventing the normal metabolism of LDL particles
and leading eventually to development of atherosclerotic plaques.[23] Of the lipid material contained in
LDL, various lipid oxidation products are known as the ultimate atherogenic species. [24] Acting as a
transporter of these injurious molecules is another mechanism by which LDL can increase the risk of
atherosclerosis.[22][25]

Testing[edit]
Blood tests commonly report LDL-C: the amount of cholesterol which is estimated to be contained
with LDL particles, on average, using a formula, the Friedewald equation. In clinical context,
mathematically calculated estimates of LDL-C are commonly used as an estimate of how much low
density lipoproteins are driving progression of atherosclerosis. The problem with this approach is
that LDL-C values are commonly discordant with both direct measurements of LDL particles and
actual rates of atherosclerosis progression.

Direct LDL measurements are also available and better reveal individual issues but are less often
promoted or done due to slightly higher costs and being available from only a couple of laboratories
in the United States. In 2008, the ADA and ACC recognized direct LDL particle measurement by
NMR as superior for assessing individual risk of cardiovascular events.[26]

Estimation of LDL particles via cholesterol content[edit]

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.

The lipid profile does not measure LDL particles. It only estimates them using the Friedewald
equation[19][27] by subtracting the amount of cholesterol associated with other particles, such
as HDL and VLDL, assuming a prolonged fasting state, etc.:

where H is HDL cholesterol, L is LDL cholesterol, C is total cholesterol, T are triglycerides,

and k is 0.20 if the quantities are measured in mg/dL and 0.45 if in mmol/L.
There are limitations to this method, most notably that samples must be obtained after a 12
to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L
(400 mg/dL). Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered
inaccurate.[28] If both total cholesterol and triglyceride levels are elevated then a modified
formula, with quantities in mg/dL, may be used

This formula provides an approximation with fair accuracy for most people, assuming
the blood was drawn after fasting for about 14 hours or longer, but does not reveal the
actual LDL particle concentration because the percentage of fat molecules within the
LDL particles which are cholesterol varies, as much as 8:1 variation. There are several
formulas published addressing the inaccuracy in LDL-C estimation.[29][30][31] The inaccuracy
is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is
always one-fifth of the triglyceride concentration. A new formulae published recently
addresses this issue by using an adjustable factor [32] or by using a regression equation.
[33]
There are few studies which have compared the LDL-C values derived form this
recently published formula and values obtained by direct enzymatic method.[34] Direct
enzymatic method are found to be accurate and it has to be the test of choice in clinical
situations. In the resource poor settings, the option of using the formula has to be
considered.[34]

However, the concentration of LDL particles, and to a lesser extent their size, has a
stronger and consistent correlation with individual clinical outcome than the amount of
cholesterol within LDL particles, even if the LDL-C estimation is approximately correct.
There is increasing evidence and recognition of the value of more targeted and accurate
measurements of LDL particles. Specifically, LDL particle number (concentration), and
to a lesser extent size, have shown slightly stronger correlations with atherosclerotic
progression and cardiovascular events than obtained using chemical measures of the
amount of cholesterol carried by the LDL particles.[35] It is possible that the LDL
cholesterol concentration can be low, yet LDL particle number high and cardiovascular
events rates are high. Correspondingly, it is possible that LDL cholesterol concentration
can be relatively high, yet LDL particle number low and cardiovascular events are also
low.

Normal ranges[edit]
In the US, the American Heart Association, NIH, and NCEP provide a set of guidelines
for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As
of about 2005, these guidelines were:[36][37][38]

Level mg/dL Level mmol/L Interpretation

 Optimal LDL cholesterol, levels in healthy young
25 to <50 <1.3 children before onset of atherosclerotic plaque in
heart artery walls

Optimal LDL cholesterol, corresponding to lower rates

of progression, promoted as a target option for those
<70 <1.8
known to clearly have advanced symptomatic
cardiovascular disease

Optimal LDL cholesterol, corresponding to lower, but

<100 <2.6 not zero, rates for symptomatic cardiovascular
disease events

Near optimal LDL level, corresponding to higher rates

100 to 129 2.6 to 3.3 for developing symptomatic cardiovascular disease
events

Borderline high LDL level, corresponding to even

130 to 159 3.3 to 4.1 higher rates for developing symptomatic
cardiovascular disease events

High LDL level, corresponding to much higher rates

160 to 199 4.1 to 4.9 for developing symptomatic cardiovascular disease
events

Very high LDL level, corresponding to highest

>200 >4.9 increased rates of symptomatic cardiovascular
disease events

Over time, with more clinical research, these recommended levels keep being reduced
because LDL reduction, including to abnormally low levels, was the most effective
strategy for reducing cardiovascular death rates in one large double blind, randomized
clinical trial of men with hypercholesterolemia;[39] far more effective than coronary
angioplasty/stenting or bypass surgery.[40]

For instance, for people with known atherosclerosis diseases, the 2004 updated
American Heart Association, NIH and NCEP recommendations are for LDL levels to be
lowered to less than 70 mg/dL, unspecified how much lower. This low level of less than
70 mg/dL (higher than Tim Russert's value shortly prior to his heart attack) was
recommended for primary prevention of 'very-high risk patients' and in secondary
prevention as a 'reasonable further reduction'. Lack of evidence for such a
recommendation is discussed in an article in the Annals of Internal Medicine.[41] Statin
drugs involved in such clinical trials have numerous physiological effects beyond simply
the reduction of LDL levels.

It has been estimated from the results of multiple human pharmacologic LDL lowering
trials[42] that LDL should be lowered to below 30 to reduce cardiovascular event rates to
near zero. For reference, from longitudinal population studies following progression of
atherosclerosis-related behaviors from early childhood into adulthood,[43] the usual LDL
in childhood, before the development of fatty streaks, is about 35 mg/dL. However, all
the above values refer to chemical measures of lipid/cholesterol concentration within
LDL, not measured low-density lipoprotein concentrations, the accurate approach. [citation
needed]

A study was conducted measuring the effects of guideline changes on LDL cholesterol
reporting and control for diabetes visits in the US from 1995 to 2004. It was found that
although LDL cholesterol reporting and control for diabetes and coronary heart disease
visits improved continuously between 1995 and 2004,[44][45] neither the 1998 ADA
guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for
diabetes relative to coronary heart disease.[46]

Direct measurement of LDL particle concentrations[edit]

There are several competing methods for measurement of lipoprotein particle
concentrations and size. The evidence is that the NMR methodology (developed,
automated & greatly reduced in costs while improving accuracy as pioneered by Jim
Otvos and associates) results in a 22-25% reduction in cardiovascular events within one
year,[47] contrary to the longstanding claims by many in the medical industry that the
superiority over existing methods was weak, even by statements of some proponents. [48]

Since the later 1990s, because of the development of NMR measurements, it has been
possible to clinically measure lipoprotein particles at lower cost [under $80 US (including
shipping) & is decreasing; versus the previous costs of >$400 to >$5,000] and higher
accuracy. There are two other assays for LDL particles, however, like LDL-C, most only
estimate LDL particle concentrations.

Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28
March 2008 joint consensus statement,[49] as having advantages for predicting individual
risk of atherosclerosis disease events, but the statement noted that the test is less
widely available, is more expensive [about $13.00 US (2015 without insurance
coverage) from some labs which use the Vantera Analyzer[50]]. Debate continues that it is
"...unclear whether LDL particle size measurements add value to measurement of LDL-
particle concentration", though outcomes have always tracked LDL particle, not LDL-C,
concentrations.

Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically
subdivided by percentiles referenced to the 5,382 men and women, not on any lipid
medications, who are participating in the MESA trial.[51]

Optimal ranges[edit]
The LDL particle concentrations are typically categorized by percentiles, <20%, 20–
50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being
tracked in the MESA trial, a medical research study sponsored by the United States
National Heart, Lung, and Blood Institute.
 MESA LDL particles
Interpretation
Percentile nmol/L

Those with lowest rate of cardiovascular disease

0–20% <1,000
events & low (optimal) LDL particle concentration

Those with moderate rate of cardiovascular disease

20–50% 1,000–1,299
events & moderate LDL particle concentration

Those with Borderline-High rate of cardiovascular

50–80% 1,300–1,599
disease events & higher LDL particle concentration

Those with High rate of cardiovascular disease

89–95% 1,600–2,000
events and even higher LDL particle concentration

Those with very high rate of cardiovascular disease

>95% >2,000
events and highest LDL particle concentration

The lowest incidence of atherosclerotic events over time occurs within the <20% group,
with increased rates for the higher groups. Multiple other measures, including particle
sizes, small LDL particle concentrations, large total and HDL particle concentrations,
along with estimations of insulin resistance pattern and standard cholesterol lipid
measurements (for comparison of the plasma data with the estimation methods
discussed above) are also routinely provided.

Lowering LDL-cholesterol[edit]
Markers indicating a need for LDL-C Reduction

(Per 2004 United States Government Minimum Guidelines [52][53])

then the patient should and LDL-C reduction is

If the patient's cardiac risk is... consider LDL-C reduction if indicated if the count in
the count in mg/dL is over... mg/dL is over...
High, meaning a 20% or greater risk of
heart attack within 10 years, or an 70[54] 100[54]
extreme risk factor
moderately high, meaning a 10-20%
risk of heart attack within 10 years and 100[54] 130[54]
more than 2 heart attack risk factors
moderate, meaning a 10% risk of heart 130[54] 160[54]
 attack within 10 years and more than 2
heart attack risk factors
low, meaning less than 10% risk of
heart attack within 10 years and 1 or 0 160[54] 190[54]
heart attack risk factors

The mevalonate pathway serves as the basis for the biosynthesis of many molecules,
including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase
(HMG CoA reductase) is an essential component and performs the first of 37 steps
within the cholesterol production pathway, and is present in every animal cell.

LDL-C is not a measurement of actual LDL particles. LDL-C is only an estimate (not
measured from the individual's blood sample) of how much cholesterol is being
transported by all LDL particles, which is either a smaller concentration of large particles
or a high concentration of small particles. LDL particles carry many fat molecules
(typically 3,000 to 6,000 fat molecules per LDL particle); this includes cholesterol,
triglycerides, phospholipids and others. Thus even if the hundreds to thousands of
cholesterol molecules within an average LDL particle were measured, this does not
reflect the other fat molecules or even the number of LDL particles.

Pharmaceutical[edit]
 PCSK9 inhibitors, in clinical trials, by several companies, are more effective
for LDL reduction than the statins, including statins alone at high dose
(though not necessarily the combination of statins plus ezetimibe).
 Statins reduce high levels of LDL particles by inhibiting the enzyme HMG-
CoA reductase in cells, the rate-limiting step of cholesterol synthesis. To
compensate for the decreased cholesterol availability, synthesis of LDL
receptors (including hepatic) is increased, resulting in an increased
clearance of LDL particles from the extracellular water, including of the
blood.
 Ezetimibe reduces intestinal absorption of cholesterol, thus can reduce LDL
particle concentrations when combined with statins.[55]
 Niacin (B3), lowers LDL by selectively inhibiting hepatic diacylglycerol
acyltransferase 2, reducing triglyceride synthesis and VLDL secretion
through a receptor HM74[56] and HM74A or GPR109A.[57]
 Several CETP inhibitors have been researched to improve HDL
concentrations, but so far, despite dramatically increasing HDL-C, have not
had a consistent track record in reducing atherosclerosis disease events.
Some have increased mortality rates compared with placebo.
 Clofibrate is effective at lowering cholesterol levels, but has been associated
with significantly increased cancer and stroke mortality, despite lowered
cholesterol levels.[58] Other, more recently developed and tested fibrates, e.g.
fenofibric acid[59] have had a better track record and are primarily promoted
for lowering VLDL particles (triglycerides), not LDL particles, yet can help
some in combination with other strategies.
 Some tocotrienols, especially delta- and gamma-tocotrienols, are being
promoted as statin alternative non-prescription agents to treat high
cholesterol, having been shown in vitro to have an effect. In particular,
gamma-tocotrienol appears to be another HMG-CoA reductase inhibitor,
and can reduce cholesterol production.[60] As with statins, this decrease in
 intra-hepatic (liver) LDL levels may induce hepatic LDL receptor up-
regulation, also decreasing plasma LDL levels. As always, a key issue is
how benefits and complications of such agents compare with statins—
molecular tools that have been analyzed in large numbers of human
research and clinical trials since the mid-1970s.
 Phytosterols are widely recognized as having a proven LDL cholesterol
lowering efficacy'[61] A 2018 review found a dose-response relationship for
phytosterols, with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%,
[62]
but reviews as of 2017 had found no data indicating that the consumption
of phytosterols may reduce the risk of CVD.[63] Current supplemental
guidelines for reducing LDL recommend doses of phytosterols in the 1.6-
3.0 grams per day range (Health Canada, EFSA, ATP III, FDA) with a 2009
meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a
mean dose of 2.15 gram per day.[64]