"LDL poses a risk for cardiovascular disease when it invades the endothelium and becomes oxidized, since the oxidized form is more easily retained by the proteoglycans. A complex set of biochemical reactions regulates the oxidation of LDL, chiefly stimulated by presence of free-radicals in the endothelium.
Nitric oxide down-regulates this oxidation process catalyzed by L-arginine. In a corresponding manner, when there are high levels of asymmetric dimethylarginine in the endothelium, production of nitric oxide is inhibited and more LDL oxidation occurs.
Importance of antioxidants
Because LDL appears to be harmless until oxidized by free-radicals [2], it is postulated that ingesting antioxidants and minimizing free-radical exposure may reduce LDL's contribution to atherosclerosis, though results are not conclusive.
Level mg/dL Level mmol/L Interpretation
<100 <2.6 Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease
100 to 129 2.6 to 3.3 Near optimal LDL level
130 to 159 3.3 to 4.1 Borderline high LDL level
160 to 189 4.1 to 4.9 High LDL level
>190 >4.9 Very high LDL level, corresponding to highest increased risk of heart disease
These guidelines were based on a goal of presumably decreasing death rates from cardiovascular disease to less than 2% to 3% per year or less than 20% to 30% every 10 years. Note that 100 is not considered optimal; less than 100 is optimal, though it is unspecified how much less.
Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, has been the most effective strategy for reducing cardiovascular death rates in large double blind, randomized clinical trials; far more effective than coronary angioplasty/stenting or bypass surgery.
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. It has been estimated from the results of multiple human pharmacologic LDL lowering trials[citation needed] that LDL should be lowered to about 50 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[citation needed], it has been discovered that 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 LD-Lipoprotein concentrations, probably not the better approach.
LDL subtype patterns
LDL particles actually vary in size and density, and studies have shown that a pattern that has more small dense LDL particles—called "Pattern B"—equates to a higher risk factor for coronary heart disease (CHD) than does a pattern with more of the larger and less dense LDL particles ("Pattern A"). This is because the smaller particles are more easily able to penetrate the endothelium. "Pattern I," meaning "intermediate," indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm).
The correspondence between Pattern B and CHD has been suggested by some in the medical community to be stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test has been used more commonly.
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 LDL. [7] [5]
However, cholesterol and lipid assays, as outlined above were never promoted because they worked the best to identify those more likely to have problems, but simply because they used to be far less expensive, by about 50-fold, than measured lipoprotein particle concentrations and subclass analysis. 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 event and quantitatively-measured particle concentrations.
Lowering LDL
The mevalonate pathway serves as the basis for the biosynthesis of many molecules, including cholesterol. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA reductase) is an essential component in the pathway.
Pharmaceutical
The use of statins (HMG-CoA reductase inhibitors) is effective against high levels of LDL cholesterol. Statins inhibit the enzyme HMG-CoA reductase in the liver, which stimulates LDL receptors, resulting in an increased clearance of LDL.
Dietary
Insulin induces HMG-CoA reductase activity, whereas glucagon downregulates it. While glucagon production is stimulated by dietary protein ingestion, insulin production is stimulated by dietary carbohydrate. The rise of insulin is, in general, determined by the unfolding of carbohydrates into glucose during the process of digestion. Glucagon levels are very low when insulin levels are high.
(editor's note: This helps explain why carbohydrate ingestion and type II diabetes leads to heart disease. Generally reactive hypoglycemia leads to increase insulin production. It might also explain why sole protein eaters such as classical inuit have/had low heart disease, as the resulting glucagon levels act as an HMG-coA-reductase inhibition, reducing LDL.)
Lowering the blood lipid concentration of triglycerides, otherwise known as very low-density lipoprotein (VLDL), helps lower the amount of LDL, because VLDL gets converted in the bloodstream into LDL.
Fructose, a component of sucrose as well as high-fructose corn syrup, upregulates hepatic VLDL synthesis [9].
Niacin (B3), which blocks breakdown of fats, also lowers VLDL and, as a consequence, LDL. It comes with the added benefit of increasing hi-density lipoprotein, HDL, the so-called 'good' cholesterol.
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