THE RESPONSE TO INJURY HYPOTHESIS
Finally I’ll expand on the last and most accepted theory on atherosclerosis which nicely ties in the above concepts. This very concise article was taken from the emedicine website. I have paraphrased much of it for simplicity.
ENDOTHELIAL INJURY AS THE MECHANISM OF ATHEROSCLEROSIS
Response to (vascular/endothelial) injury theory.
According to the response-to–vascular injury theory, injury to the endothelium by local disturbances of blood flow at angulated or branch points, along with systemic risk factors, perpetuates a series of events that culminate in the development of atherosclerotic plaque.
As discussed below, endothelial damage occurs in many clinical settings and can be demonstrated in individuals with dyslipidemia, hypertension, diabetes, advanced age, nicotine exposure, and products of infective organisms (i.e., Chlamydia pneumoniae).
Endothelial dysfunction is the initial step that allows diffusion of lipids [LDL] and inflammatory cells (i.e., monocytes, T lymphocytes) into the endothelial and subendothelial spaces. LDL can latch on to the damaged endothelium by connecting to an LDL receptor like a key in a lock. Once this occurs LDL is taken under the endothelial surface to the subendothelial level. Here it becomes oxidized [low level, or it was oxidized on the surface?]. With a damaged endothelium LDL keeps accruing under the endothelial surface. Once subendothelial, the oxLDL stimulates the immune system for recruiting monocytes [mono’s become macrophages] which further oxidizes the LDL particle as previously described.
Oxidized LDL inhibits nitric oxide synthase activity [resulting in greater injury to the endothelium because it cannot make enough beneficial nitric oxide a powerful anti-oxidant and vasodilator] and increases reactive oxygen species generation [fancy word for free radical formation e.g., superoxide, hydrogen peroxide].
Substantial evidence suggests that oxLDL is the prominent component of atheromas. [This statement lacks a citation and it contradicts my research which shows atheromas to be made up of smooth muscle cells, fibroblasts, oxidized omega 6 PUFA, dead immune cells, oxLDL, and an assortment of other toxic materials. See the Toxic Atheroma above]
Oxidative stress has therefore been recognized as the most significant contributor to atherosclerosis by causing LDL oxidation and increasing nitric oxide breakdown.
Note the above comment. It is telling us that CVD is caused not by cholesterol but by your body’s level of free radicals and oxidative stress.
Risk factors for coronary artery atherosclerosis
- Hyperlipidemia and dyslipidemia
- Cigarette habituation
- Air pollution
- Diabetes mellitus
- Age [male 45 or older, female 55 or older]
- Sex [male greater risk than female]
The presence of risk factors accelerates the rate of development of atherosclerosis. Diabetes causes endothelial dysfunction, decreases endothelial thromboresistance [ability to prevent clot formation], and increases platelet activity, thus accelerating atherosclerosis.
Established risk factors successfully predict future cardiac events in about 50-60% of patients, [the odds are no better than a coin toss at predicting who has a heart attack using conventional risk factors such as LDL level].
Other risk factors for coronary artery atherosclerosis include the following:
- Family history of premature CAD
- Physical inactivity
- Syndromes of accelerated atherosclerosis – Graft atherosclerosis, CAD after cardiac transplantation
- Chronic kidney disease
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Metabolic syndrome
- Chronic inflammation [any inflammatory disease like gum disease for example]
- Infectious agents
- Increased fibrinogen levels
- Increased lipoprotein(a) levels
- Familial hypercholesterolemia
Note that many of the risks in the list directly above are inflammatory diseases. A very curious condition often occurs when patients have one or more of these conditions. They become hypothyroid. Low thyroid is a cause of atherosclerosis. I elaborate on this point more in my section on the use of bioidentical hormones. I would add to this list these inflammation generating candidates:
ü Consumption of omega 6 PUFA
ü Sugar and high glycemic load foods
ü [in relation to the above high AGE’s consumption from Industrial Dinners and elevated insulin level]
ü Inflammatory metals (lead, Al, mercury, and cadmium)
ü Radiation exposure
ü Exposure to excitotoxic food additives (aspartame, MSG, others).
ü Low testosterone
ü Low thyroid
ü High estrogen (in men)
ü High homocysteine
OOPS WE MISSED A FEW
It’s interesting that four of the most powerful contributors to atherosclerosis were not listed including consumption of Ω6PUFA, sugar, high GI cereal grains and starches, and hyperhomocysteinemia (high blood levels of homocysteine), a highly inflammatory byproduct of methionine metabolism. Most Americans have higher than normal levels and are therefore at higher risk for heart disease, bone fractures, and dementia. Search Kilmer McCully MD, and read my section on homocysteine in the lab tests chapter for more information.
ENDOTHELIAL DYSFUNCTION AT THE ROOT OF ATHEROSCLEROSIS
This theory establishes an injured endothelium as the primary root cause of atherosclerosis, and where oxLDL also plays a major role. Once damage occurs to the endothelium from any one of the risk factors listed previously, like hypertension which damages the endothelium through mechanical stress, then sdLDL can enter the subendothelial space as if it had its own house key. It’s like removing a few paving stones from the Appian Way of your endothelium. Once those holes expose the foundation or basement membrane it’s much easier for sdLDL to dig under and stick to the subendothelial surface. Somewhere along the way sdLDL becomes partially oxidized either in the bloodstream, on the endothelial surface or under the endothelium, only to be further oxidized once it encounters monocytes which become macrophages and gobble them up forming foam cells. Macrophages and foam cells provide the cytokine stimulus for initiating a full blown immune response. The rest of the story is the same.
Either way if the endothelium is damaged first, or oxLDL damages the endothelium first, or some other process injures the endothelium like smoking, it’s obvious that oxidation and free radical production are there from the very beginning. Nearly all of the classic risk factors and the emerging ones generate free radicals which can damage the endothelium and oxidize LDL.
TREAT ENDOTHELIAL DYSFUNCTION AND YOU TREAT EVERYTHING
The treatment is the same either way and no Tammy we don’t use statins to treat this. You will want to decrease inflammatory stimulation directly, mop up free radicals and prevent oxidation. If you follow my suggestions you will prevent the formation of oxLDL and prevent your endothelium from becoming sick and dysfunctional at the same time. These are the foremost tasks that must be addressed if you wish to cure your heart disease.
In summary this hypothesis states that a large and diverse group of cardiac risk factors initiate endothelial injury. This provides the fertile background for sdLDL to penetrate the subendothelial space into the intima where it then becomes partially oxidized (low level oxidation) at or under the endothelium where the body’s first line of defense is to eat them up with macrophages forming foam cells. Foam cells initiate the inflammatory response recruiting more macrophages, T-lymphocytes and smooth muscle cells. This process furthers LDL oxidation to a fully oxidized form which is itself highly inflammatory since it interferes with the endothelial production of nitric oxide (NO) by inhibiting nitric oxide synthase, while stimulating more macrophages and T-lymphocytes (and other cells such as platelets) to the injury site. It also states (in the original article) that your oxidation status plays a key role in the initiation of disease by oxidizing LDL while in circulation or at any other time.
A perfect example of how these processes fuel each other is the uncomfortable fact that oxLDL inhibits nitric oxide synthase the enzyme responsible for the formation of NO within the endothelium which is vital for endothelial function and proper vascular integrity. Low NO promotes the generation of reactive oxygen species (ROS) and free radical cascades thus further stimulating a viscous inflammatory cycle ultimately leading to atheroma formation.
I believe Masterjohn put it best by reminding us that LDL can be dangerous if oxidized while your endothelium can be sickened by this same oxidation process. In the end whichever came first matters little. You will need to keep your endothelium healthy and your LDL unoxidized. My suggestions on diet and lifestyle effortlessly do both.
Note that the last list of risk factors above from the author and myself introduces some new components to the mix. Overall there are at least 20-30 risk factors to consider since any one of them can cause endothelial injury or oxidation of LDL. Nearly every factor listed above is inflammatory (free radical generating) even physical inactivity. In short when I refer to an anti-inflammatory lifestyle I am really saying that your body needs to be in a low oxidation state where minimal damage to either the endothelium or the LDL particle occurs. The easiest way to achieve this state is to eat according to my Super Mediterranean Diet, the use of antioxidant supplements, and exercise.
The response to injury theory demonstrates that injury to vascular endothelium kick starts the entire inflammatory/immune, atherosclerotic process.
All stages of atherosclerosis-from initiation and growth to complication of the plaque-are considered an inflammatory response to injury. Endothelial injury is thought to have a primary role.
However, note that oxLDL may be considered as an equal. The current opinion is that atherosclerosis is an immune/inflammatory response of the intima to endothelial injury. It is also well known that the injury is mainly initiated by lipid accumulation.
The lipid accumulation we refer to is sdLDL which can accumulate and cause damage only when it in the oxidized form, oxsdLDL or oxLDL for short. It is known to be an initiator of endothelial dysfunction, not just a participator once endothelial injury occurs.
Numerous factors may initiate endothelial injury, including mechanical factors (hypertension and high shear stress in the artery), homocysteine, oxidized low-density lipoprotein (LDL) [actually they mean to say sdLDL which is denser than LDL], possibly infectious agents such as Chlamydia, viruses, and toxins such as nicotine. These factors lead to endothelial cells’ increasing expression of receptors for LDL [allowing sdLDL to stick to the endothelial surface] and increased adherence of monocytes and macrophages and T cells. Progression of atherosclerosis can lead to the development of a plaque that is vulnerable to rupture and that would then produce an acute coronary syndrome [heart attack]. [Emphasis mine].
OXIDIZED LDL SUMMARY
To clarify the point on endothelial injury we can view oxLDL as an initiator of damage as well as a promoter. The entire process of atherosclerosis cannot occur without oxidized LDL. However, you also need a damaged, dysfunctional endothelium. Normal “native” LDL is non-atherogenic and will not cause atherosclerosis by itself regardless of how much is present in the blood. In other words the whole process could be seen as driven by oxidized LDL. It is oxLDL that causes monocytes to penetrate the subendothelial space where fatty streaks are then formed. OxLDL also provides the stimulus to convert monocytes into macrophages which then gobble up endless quantities of oxLDL to become foam cells in a never ending cycle. Furthermore it is oxLDL that stimulates a greater immune/inflammatory response, it inhibits nitric oxide synthase thus crippling the endothelium causing dysfunction and leading to the formation of ROS. OxLDL also forms the highly dangerous necrotic core of the atheroma.
There is enticing evidence that small dense LDL may already be “pre-oxidized” before it becomes grossly oxidized in the intima (as oxLDL). If so then oxidation is driving the entire process and oxidation, not endothelial activation [dysfunction], is at the root of atherosclerosis.
Chris Masterjohn phrases it succinctly in his well-referenced paper.
Oxidized LDL initiates the inflammatory process by causing foam cells to secrete molecules that attract T cells and other inflammatory cells. Oxidized LDL enhances the process whereby T cells, foam cells, smooth muscle cells and endothelial cells decrease collagen production and increase collagen degradation, which leads to the rupture of the fibrous plaque. Endothelial cells produce nitric oxide, a gas that protects LDL from oxidation, increases blood flow, decreases the adhesion of monocytes to the endothelium, and decreases blood clotting. Oxidized LDL impairs the endothelial cell’s ability to produce nitric oxide. In short, oxidized LDL contributes to the entire atherosclerotic process from start to finish. Writers who argue that atherosclerosis has nothing to do with lipids but is all about inflammation and response to injury must contend with the fact that oxidized LDL injures endothelial cells and causes inflammation!
Therefore, if we can prevent LDL from being oxidized we can prevent atherosclerosis. It’s that simple-in theory. We just need to know what herbs, supplements, vitamins and foods reduce oxLDL or prevent oxidation of LDL. Things like cacao powder powerfully reduce oxLDL. We must also learn what we do or consume-our lifestyle choices-which oxidize LDL. We already have a huge head start. Simply look over the lists of emerging risk factors and the classic risk factors for starters. After that you’ll need to read the entire section on diet for an in depth look at inflammatory foods and then the remaining chapters. Every chapter sheds light on other sources of inflammation and helps prevent further inflammatory damage. Finally, after some lifestyle changes, you can order your initial cardio-metabolic profile by following my instructions in the laboratory section. This will tell you where you stand in the sphere of wellness, silent inflammation or overt dis-ease. From there the healing can begin with important changes in diet and lifestyle as laid out for you in this book.
Lastly, any of the suggestions that I provide to prevent the formation of oxLDL will simultaneously heal you endothelium and help regenerate NO. Therefore, even if we are mistaken regarding the role of oxLDL in initiating atherosclerosis we have our six covered by keeping our endothelial cells vibrant, happy and impregnable to LDL, while simultaneously reducing oxLDL into harmless concentrations with the use of powerful antioxidants from FAV and select supplements.
Let’s now look at an interesting article from Barry Sears that came out in 2012. He showed us a study that compared the rate of CAD with LDL verses CAD plotted against oxLDL as shown below:
A BIG SCAM. From Dr Sear’s website and article entitled A New Wrinkle in the Cholesterol Story.
These graphs also appear in the chapter on statins.
Figure 7 Plot of serum LDL vs % CAD
Figure 8 Plot of serum oxLDL vs % CAD
Here you can clearly see the role oxLDL plays in the promotion of CAD. In the first graph no correlation exists when you plot increasing serum LDL against % of patients with CAD. I think it’s prudent to provide an important quote from Anthony Colpo in his book The Great Cholesterol Con:
..it is most disingenuous to claim that elevated cholesterol causes fatty streaks or promotes the transformation of fatty streaks into advanced atherosclerosis when careful investigations repeatedly show no relationship between serum cholesterol levels and extent of atherosclerosis. The extensive involvement of white blood cells merely reinforces the contention that atherosclerosis is not the product of simple blood cholesterol elevations, but an inflammatory immune response to arterial injury. [Emphasis mine]
But when the oxidized LDL particle is plotted against % CAD in figure 8 we see an interesting correlation. There is a perfect linear relationship: the higher the serum oxLDL the greater percentage of CAD in that population. This provides exquisite proof that it is oxLDL (the amount of inflammation in your body), not LDL that causes or contributes to CAD.
 Coronary Artery Atherosclerosis Author: John A McPherson, MD, FACC, FAHA, FSCAI; Chief Editor: Yasmine Subhi Ali, MD, MSCI, FACC, FACP (http://emedicine.medscape.com/article/153647-overview#aw2aab6b2b4aa) 12/14/2011
 Blaylock Wellness Report May 2013 p. 5
 Merck Manual Chapter 72 Arteriosclerosis. (Whitehouse Station, NJ: Merck Research Laboratories a Division of Merck & Co., Inc. 18th Ed. 2006) 621.
 Platelet lipoprotein interplay: trigger of foam cell formation and driver of atherosclerosis Cardiovasc Res (2008) 78 (1): 8-17. doi: 10.1093/cvr/cvn015 First published online: January 24, 2008 (http://cardiovascres.oxfordjournals.org/content/78/1/8.full) 12/13/2011
(From the originalde Rijke YB, Bredie SJH, Demacker PNM, Vogelaar JM, Hak-Lemmers HLM, Stalenhoef AFH. The Redox Status of Coenzyme Q10 in Total LDL as an Indicator of In Vivo Oxidative Modification. Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:127-133).
 Chris Masterjohn High Cholesterol And Heart Disease — Myth or Truth? The Response-to-Injury Rabbit Never Developed Atherosclerosis — Why Not? August 23, 2008