Sunday, November 4, 2012

Cardiovascular Disease

Cholesterol is essential for several functions in the body.  Lipoproteins, such as HDL and LDL, transport cholesterol through the bloodstream (like ships carrying cargo).  HDL and LDL aren’t different types of cholesterol they are different types of lipoproteins.  The cholesterol carried by them is exactly the same molecule
Atherosclerosis is a central part of many cardiovascular diseases, particularly coronary artery disease, which may develop into ischemic heart disease, but also ischemic strokes, peripheral artery disease and hypertension.  Regular LDL particles don’t cause atherosclerosis, whereas modified LDL particles do. Oxidation is one possible modification of LDL.  Particular oxidants such as peroxynitrite and hypochlorous acid seem to be the most likely to oxidise LDL
The lipid hypothesis is based off data showing the greater one’s cholesterol the greater their risk of CVD.  While total cholesterol is associated with CVD, the relationship between total cholesterol and all-cause mortality is a U-shaped curve.  It’s also important to remember that the lipid hypothesis is just a hypothesis.  Things that lower cholesterol needs shouldn’t be assumed to reduce the risk of cardiovascular disease, but to be tested as some things that reduce cholesterol don’t actually reduce cardiovascular disease
The total cholesterol to HDL cholesterol ratio (Total:HDL-C ratio) is probably the strongest blood lipid risk factor for cardiovascular disease (the higher the ratio the greater the risk).  However, once again we shouldn’t assume that things that lower the ratio reduce cardiovascular disease as drugs such as niacin and CETP inhibitors have failed to do so.
In addition to the exceptions with lowering total cholesterol and the Total:HDL-C ratio, almost half of people hospitalised for cardiovascular disease have LDL-C lower than 100 mg/dl.  One idea is small, dense LDL particles penetrate the endothelium, stick there and oxidise but the value of small, dense LDL and LDL-C as a risk factor is abolished when you adjust for LDL-P.  The reason why LDL-C is so variable and sdLDL depends on LDL-P is because the cholesterol in LDL doesn’t initiate CVD, the LDL particle does.  The proposed mechanism for LDL-P is the more LDL particles in the bloodstream the greater the chance of them penetrating the endothelium and oxidising (response-to-retention hypothesis).  The reason why LDL-C has value as a risk factor is because it correlates with LDL-P
The ability of HDL to remove cholesterol from macrophages is more strongly associated with lower risk of CVD than HDL-C and HDL-P and is independent of HDL-C and HDL-P.  HDL has many beneficial functions which can be impaired under conditions of oxidative stress, inflammation, infection and high triglycerides.  Regulatory T cells promote HDL function by increasing cholesterol efflux by HDL particles rather than have macrophages form atherosclerotic plaque
Nitric oxide is secreted by endothelial cells and protects against cardiovascular disease by inhibiting LDL oxidation, endothelial permeability, inflammation and monocyte adhesion.  Superoxide and combine with nitric oxide, which depletes nitric oxide, thereby impairing endothelial function and forms peroxynitrite.  Peroxynitrite can oxidise LDL and has other pro-atherogenic effects.  One of the main sources of superoxide is the mitochondria and in mitochondrial dysfunction more superoxide is generated and antioxidant defenses are overwhelmed.
Bacterial infections and LPS can promote cardiovascular disease through inflammation and oxidative stress.  In addition myeloperoxidase products (hypochlorous acid and chlorinated tyrosine) can oxidise LDL and HDL and are strongly associated with cardiovascular disease
The diet heart hypothesis suggests that: because high cholesterol/Total:HDL-C ratio is associated with CVD; and saturated fat raises cholesterol/Total:HDL-C ratio, therefore saturated fat increases CVD.  However, saturated fat doesn’t seem to raise cholesterol in the long term and SFA is not associated with CVD in meta-analysis of observational studies and clinical trials.  In the clinical trials when saturated fat and TFA are replaced with omega 6 polyunsaturated fat what happens is CVD mortality increases by 16%.  Seeing as TFA is bad, think what would happen if just saturated fat was replaced by omega 6 polyunsaturated fat.
One of the reasons omega 6 polyunsaturated fat increases CVD in clinical trials is because polyunsaturated fats are susceptible to oxidation.  The more polyunsaturated fat there is in LDL the more lipid peroxidation products there are.  Lag time is how long it takes for LDL to become oxidises and is related to the amount of polyunsaturated fat in the membrane and the amount of vitamin E
Some Strategies for Cardiovascular Disease
This is for informational purposes only and is not meant to diagnose or treat any medical condition.
Reduce LDL-P if Elevated
The higher your LDL-P the more LDL particles penetrate the endothelium, thereby potentially starting the events that lead to atherosclerosis.  See Troubleshooting High Cholesterol
Reduce Bacterial and LPS Translocation
Bacteria and LPS are inflammatory, but also increase myeloperoxidase.  See this post and for some ways to reduce LPS
Reduce Chronic Inflammation
Chronic inflammation impairs HDL, endothelial and mitochondrial function and is a major factor in insulin resistance.  See Causes of Inflammation
* Homocysteine (Hcy) is a risk factor for CVD but trials to lower Hcy with folic acid and sometimes B12 have been unsuccessful.  However, the trials may have been too short (only 2 years long) and folate may promote inflammation in an inflammatory environment [1].  Even if Hcy turns out to not be a factor in CVD, I’m only suggesting you get an adequate intake of several B vitamins
Improve Mitochondrial Function
Mitochondrial dysfunction can increase inflammation and insulin resistance, and mitochondrial superoxide can merge with nitric oxide, impairing endothelial function and forming peroxynitrite.  See Mitochondrial Dysfunction (mainly the second half)
Improve Immune Regulation
Having good immune regulation may reduce the likelihood of oxLDL forming atherosclerotic plaque and increase the likelihood of HDL doing reverse cholesterol transport.  Improving immune regulation also reduces the severity and duration of inflammation.  See Immune Dysfunction
Reduce Iron Levels if Elevated
Iron can modify LDL, ferritin (a marker of stored iron levels) is associated with CVD and the sex difference in CVD could be largely attributed to iron stores (see graph) [2].  See Chris Kresser’s AHS 2012 talk for information on the causes, problems, testing and treatment of iron overload

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