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The Cholesterol Myth and the Role of Atherosclerosis 3/9/14

Note:  at the bottom of the page is a list of definitionsfor some printing will help

Generalizations have exceptions; but the purpose of this paper to teach, thus not bury you in details.

The purpose of this paper is to set right the spin generated by pharma as to the cause of cardiovascular disease (CVD).  CVD is caused by atherosclerosis (AS) which is an inflammatory response to oxidative damaged LDL which contains cholesterol.  The best treatment is to prevent AS or stop its progression by preventing oxidative damage to LDL.  Cholesterol/LDL is not the cause of CVD, thus lowering LDL has little if any affects upon the endpoint death.  At the end of this paper is a description of what works best.    

 

SUMMARY:  Hardening of the arteries (AS) causes high blood pressure and the thrombosis that result in ischemic heart attacks and strokes.  Acute ischemic events[1] are only weakly associated with high levels of LDL. Over 80% of ischemic events are caused by young unstable plaque leaking.  This plaque is the result of an inflammation response by white blood cells to oxidative damage of LDL in the lumen of arteries.  A second cause is infectious agents in the artery lumen.  For a variety of complex reasons lowering cholesterol by 30% with statins has at most a minimal effect upon the endpoint of acute ischemic events, and the same for drugs to lower blood pressure.  The process leading to atherosclerosis (AS) takes decades to become clinically evident.  For financial reasons pharma doesn’t want to intercede early with drugs that reduce the immune response and prevent oxidative damage to LDL and thus pharma promotes the cholesterol myth,&  marginalizes the chorus of critics.  The best choices are 325 mg aspirin for inflammation, 300 mg CoQ10 (Q10) to prevent oxidative damage, and for postmenopausal women estradiol (E2, the best of the estrogens).     

A cutting edge restatement of the above causes of cardiovascular disease (CVD) from a 2009 Journal article:  Atherosclerosis is now recognised as a chronic inflammatory disease occurring within the artery wall and ultimately responsible for myocardial infarction, stroke and peripheral vascular disease. A crucial step in atherogenesis is the infiltration of monocytes[2] into the sub-endothelial space of large arteries where they differentiate into macrophages and become functionally active. Macrophage[3] accumulation within plaques is an hallmark of all stages of atherosclerosis, indeed recent studies have shown their presence has the potential to act as a non-invasive marker of disease activity and plaque stability. Activated macrophages are major players in all stages of lesion development. They not only accumulate lipids but also express effector molecules that are pro-inflammatory, cytotoxic and chemotactic. Furthermore, they secrete enzymes that degrade extracellular matrix leading to plaque destabilisation and increased risk of rupture. However,  macrophages are heterogeneous and when appropriately activated they have the potential to drive tissue remodeling and ultimately vascular repair. Pharmacological modulation of macrophage activities therefore represents an important strategy for the prevention and treatment of atherosclerosis and other inflammatory diseases.   The aim of this review is to give a brief overview of our current understanding of macrophage activation, distribution and function within inflamed tissue. As just stated, the process of atherogenesis caused by oxidation of LDL and immune response conflicts with the pharma’s version of atherogenesis based on cholesterol like minerals in a water pipe coating the surface and eventually restricting the flow of water, and their statins like a water purifier that disposes the minerals.  Wrong causal model, bad cholesterol, entails poor results:  the early scientific clinical trials showed that lower cholesterol had no effect upon the endpoint of death[4].  (The later trials don’t meet scientific standards—more on that later).  There is something very wrong with pharma’s bad cholesterol/LDL theory and their treatments, but why does this persist? 

If you hear 20 times “Iraq has weapons of mass destruction” from our President and his cabinet, and it is patriotically carried by the corporate media, and just 1 time you hear from a marginalized critic; the vast majority of people will believe the President; the same with bad cholesterol as the cause of CVD.  But the early clinical trials were all negative.  “In effect, the clinical trial data overwhelmingly demonstrated no benefits of cholesterol-lowering for either coronary heart disease deaths, nonfatal coronary heart disease events, or all causes of deaths.4  The cholesterol myth gains momentum through acceptance by peers and the family doctor.  The logic is attractive:  those with cholesterol above 240 have over 70% of myocardial infarctions (MI, heart attacks).  But A occurring with B doesn’t mean that A causes B.  If so then old age causes heart attacks, because 95% of them occur past the age of 60.  Bad logic and downplaying the real cause atherogenesis made the high total cholesterol (TC) sale easy.   So when 2 top scientists, Edward Pinckney and Russell Smith, wrote in their book “The Cholesterol Conspiracy” most people dismissed it without reading.  People remember the marketing science that high TC causes CVD.  First pharma sells the condition, hypercholesterolemia as the cause of CVD, than pharma sells the drugs to lower cholesterol, plus drugs to ameliorate the affects of CVD.  And just like the war in Iraq, these drugs are winning the war on cholesterol and its children heart attacks and strokes.   Like news about a war, those with vested interest in clinical trials shouldn’t run them and use those results to educate their customers.  Are we in mass taking the products of pharma’s marketing (junk) science?

The short answer is the 800 lb gorilla[5] has a firm grasp upon the generation and dissemination of information.   As the author of "The Guide to the 4,000 Useful, Useless or Dangerous Medicines" (published in French) Dr. Philippe Even told The Guardian in Sept. 2012:  “The pharmaceutical industry is the most lucrative, the most cynical and the least ethical of all the industries. It is like an octopus with tentacles that has infiltrated all the decision-making bodies:  world health organizations, government agencies, parliaments, high administrations in health and hospitals and the medical profession."  Pharma is run by its marketing departments.  Positive bias in journal published trials is the norm, 32% the average.  Pharma funds and thus runs directly or indirectly clinical trials[6], from which they arm their thought leaders with marketing science to “educate” physicians in the mandated continuing education classes on their drugs.  Pharma with the same marketing science influences the content in medical textbooks, the requirements of clinical guidelines, Wikipedia’s medical articles, and media health articles.  As Dr. Ben Goldacre stated in Bad Pharma,We no longer have evidence based medicine; we now have expert-based medicine with pharma providing the experts.”  So where lays the truth about TC?

 

What follows exposes pharma’s  cholesterol myth by first examining the role played by oxidation of LDL, the subsequent immune response as the cause of atherogenesis, and thus of the minor role of high TC and hypertension (HT).  CVD is a result of atherosclerosis.  Though well supported by journal articles, this is not taught by the thought leaders, nor found in corporate media--but for rare exceptions.  The first premise in arriving at the best-reasoned health conclusions is to understand thoroughly the fact that pharma controls the practice of medicine, and that corporations, because of the corporate structure they apply marketing (tobacco) ethics.   With this knowledge of bad pharma, bad science, and bad drugs, the alternatives--all supported by significant evidence—become the prudent choice for avoiding cardiovascular disease.  

 

There are 4 classes of drugs that pharma hawks to treat cardiovascular disease based upon a claim that they dramatically reduce the devastating risks associated with cardiovascular disease (CVD).  The 4 classes are Statins to lower total cholesterol (TC), antihypertensive drugs to lower blood pressure, anticoagulant drugs to prevent the blood clots that cause acute ischemic events, and arrhythmic drugs to prevent irregular heart beat that cause sudden deaths—the links are to their critical reviews.  These drug families have been critical analyzed and found to be wanting; viz. their benefits are not worth their side effects (and there are better treatments).  Statins are supposed to prevent and slow the progression of CVD by lowering TC, its putative primary cause.   Hypertension (HT), the putative second major cause of CVD, is treated with antihypertensive drugs; but atherosclerosis (AS) is the primary cause of CVD; not high TC & HT.   A high level of LDL moderately accelerates atherogenesis because there is more material to be damaged by certain reactive chemicals, and only when the rate of damage overloads the cleanup process.  Hypertension (HT) does not cause AS nor ischemic events, but rather once the unstable plaque has leaked and formed a plug in an artery, a person with hypertension is moderately more likely to have a clot form at the point where the plug has limited the flow of blood.   HT contributes to the clotting process; but not significantly to atherogenesis.  That HT and hypercholesterolaemia are frequently present in patients with an acute ischemic events, this doesn’t entail that they are of the underlying cause of the event.  Keep this in mind that oxidative damage to LDL that produces an immune response that causes AS which is always present in CVD.  This is contra pharma’s spin concerning high cholesterol and HT as primary causes of CVD, while downplay the role of AS.   

So why isn’t pharma doing more to prevent AS and thereby prevent ischemic events than by treating TC and HT?   Pharma in their business model is against prevention of AS for 3 principle reasons:  1) there are no drugs that remove the plaque which is inside the lumen.[7]  2) To promote drugs that would prevent or slow atherogenesis by inhibiting the oxidative damage to LDL and the inflammatory response, these drugs would reduce the sales of drugs to treat/prevent HT, blood clots, arrhythmia and high TC[8].  The drugs that prevent AS would lower pharma’s profits by 50% within a generation. 3) For pharma to market drugs that prevent AS would stimulate the sales of 3 off-patent drugs of which two are over-the-counter, 325 mg aspirin and Q10.  Moreover, these drugs plus estradiol (an estrogen) as a group greatly reduce the risk of blood clots, cancer, osteoporosis, acute ischemic events, and other diseases; thereby justifying the above 50% estimate of profit reduction.   Pharma stresses as cause of CVD high levels of LDL, total cholesterol, triglycerides all which they treat with one of their 10 statins.  They also stress HT for which they treat with typically three from their over 120 drugs, which come in 7 categories based on method of action.   A patient who is in the high risk group for an ischemic event is also placed on an anticoagulant.  And if he has had a heart attack such person is likely to show on and EKG (electrocardiogram) an abnormal pattern, and is given an arrhythmia drug.  Typical treatment following a myocardial infarction (MI) results in subsequent medications that average over $70,000 per year.   Pharma is very good at marketing to maximizing profits. 


[1]  Ischemia:  an inadequate supply of blood to an organ or part, as from an obstructed blood flow. 

[2] Monocytes are a type of white blood cell.   They are the largest of allleucocytes. They are part of the innate immune system of vertebrates including all mammals (humans included), birds, reptiles, and fish. They are amoeboid in shape, having clear cytoplasm. Monocytes have bean-shaped nuclei and constitute 2-10% of all leucocytes in the human body. Monocytes play multiple roles in immune function. Such roles include: (1) replenishing resident macrophages under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8–12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. Half of them are stored in the spleenWiki.

[3] “Macrophages are cells produced by the differentiation of monocytes in tissues. Macrophages function in both non-specific defense (innate immunity) as well as help initiate specific defense mechanisms (adaptive immunity) of vertebrate animals. Macrophages have the unique ability to metabolize one aMIno acid, arginine, to either a "killer" molecule (Nitric Oxide) or a "repair" molecule (Ornithine). Macrophages predoMInantly expressing the killer or repair phenotype are now mainly called M1 or M2 macrophages because these 2 types of macrophages also stimulate T cell responses that further activate the killer macrophages or T cell phenotype (Th1), or stimulate antibody production (Th2).[4] Their role is to phagocytose, or engulf and then digest, cellular debris and pathogens, either as stationary or as mobile cells. They also stimulate lymphocytes and other immune cells to respond to pathogens. They are specialized phagocytic cells that attack foreign substances, infectious MIcrobes and cancer cells through destruction and ingestion. They are present in all living tissues, and have a function in regeneration.  Macrophages are highly specialized in removal of dying or dead cells and cellular debris. Macrophages are the predominant cells involved in creating the progressive plaque lesions of atherosclerosis Wiki. It is the role of dealing with oxidative damaged LDL that the series of events leading to atherosclerosis begins.  

[4]  Smith & Pickney in The Cholesterol Conspiracy:  “Drugs were used to lower blood cholesterol level in twelve trials…. Of the eight that met this standard (randomized and double blind), total deaths in six trials were the same or greater in the treatment group than in the control group.  For the remaining 4 trials there were no difference between the trial group and the control group;” taken from Bowden and Sinatra, The Great Cholesterol Myth, p. 98.  For trials using drugs and diet were the same for the endpoint death.   But pharma controls the production of information, and these results are ignored.   

[5] A phrase used by Marcia Angell to describe Big Pharma with its billions and lobbyists.  Her book The Truth About Drug Companies describes chapter by chapter the gorilla’s grip—link to a chapter.  Of all books, I recommend hers first. 

[6] They not only are involved in all aspects of the study from set to publish.  A contract with the researchers establishes pharma’s right to have final say as to what is publish.  This includes that pharma can withhold results including side effects, change the items measured, endpoint, withhold publication, etc.  Moreover the raw data, which is essential for a journal peer review panel, is always withheld.  The 32% average positive bias referred to above was uncovered by researchers who obtained under the federal Freedom of Information Act (FOIA) the raw data pharma had submitted to the FDA.  Other exposures reveal that positive bias is the norm.  The Jupiter trial on Statins is a classic of such deception.   Request for raw data made by the Cochrane Review for Tamiflu, a flu drug, and Roche’s response is an example of pharma’s resistance—for summary of these high profile examples with links.

[7] When atherogenesis stops the body will undergo a healing process that will reduce occlusion of arteries and improve through revascularization of the blood flow—a process that takes years for a significant improvement.  For example untreated angina pain will diminish gradually and physical endurance will increase following a MI. Pharma claims that statins remove plaque, the truth of which is doubted because of lack of in vitro evidence, bias in their marketing studies, and the lack of a suitable comparison cohort in carotid artery sonogram studies.  Moreover, it isn’t hard plaque, what is measured, but the soft plaque that causes MIs. Even if statins slow the process of atherogenesis and the bodily processes remove account for the reduction in plaque, what its affect on soft plaque?  Moreover, aspirin and Q10 perform better.  The topic is complex, see item #4, 6 & 2 under 10 negative effects in Statins.  

[8] Lipitor is all time leading drug world-wide based on dollar sales.  For statins a 2008 study found that 50% of men and 36%

 of women age 65 to 74 had taken a statin in the last 30 days

An understanding the role of atherosclerosis in the development of CVD is necessary for rational, evidence-based heart choices.  Atherosclerosis is caused by oxidative damage to the cholesterol contained within the LDL that is in the lumen of arteries.  [See LDL illustraton]  This causes an immune response by T-lymphocytes and macrophages (both types of white blood cells) that starts atherogenesis.  This response results in the formation of unstable young plaque within the lumen of arteries which over a period of several years will become harden (stable plaque).  The unstable plaque causes over 90% of MIs (myocardial infarctions, heart attacks) & 85% of strokes.  (Retain this essential relationship.)  This analysis has been accepted based upon a large body of experimental and epidemiological (population studies) evidence. 

Atheroma:  “The atheroma (accumulation & swelling in an artery wall) consists of LDL [see illustration], calcium, fibrous connective tissues, T-lymphocytes macrophages, and pathogens.  While in the early stages, based on gross appearance, have traditionally been  termed fatty streaks by pathologists, they are not composed of fat cells ( adipose cells), but are accumulations of  white blood cells, especially macrophages, that have taken up oxidized low-density lipoprotein (LDL).  After they accumulate large amounts of cytoplasmic membranes (with associated high cholesterol content) the macrophages are called foam cells. When foam cells die, their contents are released, which attracts more macrophages

Coronary artery disease (CAD), atherosclerotic heart disease, cardiovascular disease (CVD) are caused by atherosclerosis (AS) affects coronary arteries and thus the blood supply to the heart muscle. “Atherosclerosis is the most common type of heart disease and cause of heart attacks.[1] The disease is caused by plaque  building up along the inner walls of the arteries of the heart, which narrows the arteries and restricts blood flow to the heart. It is the leading cause of death worldwide.[1]  After decades of progression, some of the  atheromatous plaques may rupture and (along with the activation of the blood clotting system) start limiting blood flow to the heart muscle. The disease is the most common cause of sudden death,[2] and the leading cause of death over the age of 20 years.[3]   Most commonly, unstable young plaque ruptures and may lead to an acute myocardial infarction (AMI). Cholesterol is delivered into the vessel wall by cholesterol-containing low-density lipoprotein (LDL) particles. To attract and stimulate macrophages (a type of white cell), the cholesterol must be released from the LDL particles and oxidized, a key step in the ongoing inflammatory process” Wiki. “T-lymphocytes respond to the oxidized LDL by activating CXC chemokines which attracts macrophages” JCI.  “The process is worsened if there is insufficient high-density lipoprotein (HDL).  The lipoprotein particle [HDL] that removes cholesterol from tissues and carries it back to the liver.  When the macrophages [type of white blood cell] engulf a large amount of the oxidized cholesterol [as part of the disposal process] they are called foam cells because of appearance. In sufficient numbers they form the fatty streaks of the plaques of atheroma in the innermost layer of the artery wall.  A protective fibrous cap normally forms between the fatty deposits and the artery lining (the intima).  These capped fatty deposits (now called 'atheromas') produce enzymes that cause the artery to enlarge over time. Atheromas within the vessel wall are soft and fragile with little elasticity. Arteries constantly expand and contract with each heartbeat, i.e., the pulse. In addition, the calcification deposits between the outer portion of the atheroma and the muscular wall, as they progress, lead to a loss of elasticity and stiffening of the artery as a wholeWiki.  The heart responding to signals of insufficient oxygen pumps blood with more force in order to supply adequate oxygenated blood to the organs.  Hard, clogged arteries are the principle cause of high blood pressure.  The signal to pump harder is a response of organs to the lack of oxygen caused by AS.

 Hypertension thus is a trailing result not a cause of AS. The higher risk of ischemic events (MI and ischemic strokes) is a result of AS, not of the co-phenomena of HT [1]. To lower blood pressure does not significantly affect unstable plaque the cause of ischemic events.[2]  Macrophages during their cleanup function weaken the protein matrix and thereby increase the risk for the young plaque will leak out of the lumen. 

As stated above LDL plays a key role in AS only when it has been oxidized by reactive chemicals.  “The same data suggests that only small dense LDL (sdLDL) particles are able to get behind the cellular monolayer of endothelium [lumen].  LDL particles and their content are susceptible to oxidation by free radicals,[3] and the risk may be higher while in the bloodstream. However, LDL particles have a half-life of only a couple of days, and their content (LDL particles carry cholesterol, cholesteryl esters, and triglycerides from the liver to the tissues of the body) changes with time.  Once inside the vessel wall, LDL particles get stuck and their content becomes more prone to oxidation.  The damage caused by the oxidized LDL molecules triggers a cascade of immune responses which over time can produce an atheroma….   Atherosclerosis may be caused by an infection of the vascular smooth muscle cells.  For example, Cytomegalovirus  (CMV) infection is also associated with cardiovascular diseases.[13]  In time, as cells die, this leads to extracellular calcium deposits between the muscular wall and outer portion of the atheromatous plaques.  The accumulation of calcium leads to a loss of elasticity and stiffening of the artery as a whole [one cause of HT]Wiki.  A number of chronic conditions have been associated with CVD.  Thus women with rheumatoid arthritis have “double the risk of a heart attacks when compared to women without it… An infection that starts in the gums, for example, can easily lead bacteria into the blood-stream that may find fertile ground in a weakened arterial wall and fan the fires of inflammation there” (Bowden 45). Thus infection is a cause of AS.   

The infection vector in the causes of AS consists of a direct involvement through infection within the artery lumen, and an indirect through chronic infection.  Among chronic infections, the Helicobacter pylori (the cause for over 80% of ulcers) increase the risk of MI by 75%.  A number of acute and chronic infections including:  Chlamydophila pneumoniae,  lupus erythematosus, influenza, and Porphyromonas gingivalis [gingivitis] among others have been linked to atherosclerosis and myocardial infarction” Wiki.   “Women with rheumatoid arthritis, a highly inflammatory condition that primarily affects the joints, wind up having double the risk of a heart attack…” (Bowden 45).  Within the artery lumen Cytomegalovirus, herpes virus and several other pathogens have been found upon examination during autopsy examinations.  Thus there are two immune response involved in AS, one from oxidative damage to LDL, the other is caused by chronic bacteria and virus infections, of which some are in the lumen of the artery.  Epidemiological studies support their role as does examination of plaque.  Moreover the test for C-reactive protein (CPR) is a better predictor of ischemic events in men followed long-term than that of elevated LDL.  CPR is a marker for infection[4].  This is more evidence of the importance for reducing the process of oxidative damage to LDL and the inflammation response, rather than lowering LDL.  Thus on this model the current attempts to prevent the consequences of AS are not addressing its two major causal factors of immune response and oxidative damage to LDL. 

A review of the first 50 citation for “infection + atherosclerosis” found not one article published after 2003 on infection as a cause for atherosclerosis but for 3 on HIV.  A promising area of research is not being funded.  This follows the business model of pharma.  Pharma profits more from treating the results of CVD rather than preventing it:  profits come before people.  

Unstable plaque, the wild card:  unstable plaque is fresh, young plaque that forms within the lumen of an artery.  Unstable plaque is why a person, Al age 60, who has life-long a good lifestyle, has normal blood pressure and low TC is still at risk for an ischemic event.  Al has in a few sections of arteries with unstable plaque, and if it leaks he can have an acute ischemic event.  Suppose he has a twin brother, Herman, who has done life-long, all the risky things:  smokes, is obese, and has developed type II diabetes.   Herman has 10 times the risk compared to Al for an ischemic event because he has 10 times the amount of unstable plaque.   Al’s unstable plaque is caused by pathogens in his artery lumen.  If Al’s wife smokes cigarettes he would also be forming plaque from oxidative damage to LDL.  A third cause is from glycation of lipoproteins in the lumen.  These processes are silent, and why everyone past the age of 30 is at risk of an ischemic event.  However, women prior menopause, because of the protective effect of estradiol (best of estrogens), are at 1/10th the risk compared to men for an ischemic event.  (Contra-pharma, post-menopausal women should take estradiol to promote the cardiovascular protection, but so far past attempts to find an analog for men have failed.[5]) 

So what is the role of dietary fat?  Given the role of infection and oxidation of LDL and the lack of evidence that fat causes either of these, the logical conclusion is that dietary fat and cholesterol are not important.  Guidelines on diets recommend low fat and low cholesterol, as though fat is involved in the synthesis of cholesterol.  This fits in with pharma’s bad cholesterol model, but cholesterol is a sterol (a modified steroid) not a fat.  The structures of the two families of organic chemicals are miles apart.  So too is their production.  For cholesterol “Synthesis within the body starts with one molecule of acetyl CoA and one molecule of acetoacetyl-CoA, which are hydrated to form 3-hydroxy-3-methylglutaryl CoA (HMG-CoA).[34]Wiki.   “Fats are  triglycerides:   triesters of glycerol and any of several fatty acids,  Although the words "oils", "fats", and "lipids" are all used to refer to fats, in reality, fat is a subset of lipid distinguished from other lipids by structureWiki.  Triglycerides are three fatty acids bonded to glycerol. [stick graphs of structures]. 

  

Three fat (fatty acids) molecules joined at their COOH to 3-OH groups of a glycerol to form triglyceride.

Dietary cholesterol has little effect.  Most ingested cholesterol is esterified, and esterified cholesterol is poorly absorbed. Moreover nearly all of the cholesterol is synthesized in the body.[6]  “The body also compensates for any absorption of additional cholesterol by reducing cholesterol synthesis[9]  Cholesterol synthesis can also be turned off when cholesterol levels are high. HMG-CoA reductase [what statins block] contains both a cytosolic domain (responsible for its catalytic function) and a membrane domain.” Wiki.  In other words, dietary cholesterol does not affect blood cholesterol level.  Production is regulated through a homeostatic mechanism involving the SREBP protein which is activated when the cholesterol level is low and turned off when high.   “SREBP pathway regulates expression of many genes that control lipid formation and metabolism and body fuel allocation.”   SERBP regulation explains why most obese people have a high risk high TC.[7]  As for MI risk, obesity is associated with insulin resistance and thus a high level blood sugar, and this is associated with plaque formation through glycation of sugars--mainly fructose—that causes oxidative damage to LDL, thus their much higher MI rate.  But pharma misses the causes (prevention is not in their business plan) and treats cholesterol with statins, its second most profitable family of drugs (after psychiatric drugs).  Thus the official push for low-fat & cholesterol diets based on a wrong assumption, or do they work? 

 

“According to the [started in the 50s] Farmingham Heart Study, people who consumed the most cholesterol in their diet did not have any higher blood cholesterol levels than those who consumed the least amount…. For most people—though not all—the effect of dietary cholesterol on serum cholesterol is insignificant” (Bowden & Sinatra 31).[8]  So why are the high fat & high cholesterol diets touted as a major risk factor for CVD?  One reason is that plaque (atheroma) in part consists of cholesterol and looks fatty.[9]  Another reason is in the 50s rabbits fed a cholesterol rich diet developed AS.  (But these results were not repeated in animals su ch as rats and baboon that are not herbivores.)  Ancel Keys’ Seven-Country Study in the 50s led to the popular belief that high fat diet led to high level of TC and CVD.  Keys actively promoted the Mediterranean diet.  However, years later Keys reversed his position and stated in 1997:  “There’s no connection whatsoever between cholesterol in food and cholesterol in blood.  And we’ve known that all along.  Cholesterol in the diet doesn’t matter at all unless you happen to be a chicken or a rabbit” Bower supra 33.   This was confirmed in the diet component of the Women’s Health Initiative (WHI):  there was no significant reduction in the risk of CHD, stroke, or CVD,” Wiki.  Despite the common belief that high cholesterol is a significant risk factor for coronary artery disease, several independent population studies in healthy adults have shown that low total cholesterol is associated with cardiovascular and non-cardiac mortality, indicating that high total cholesterol is not a risk factor in a healthy population.16 17 18BMJ 10//22/13.  Following the pattern of marketing studies, researchers were selected to run clinical trials that had proved their usefulness to pharma in the past.   And the panel for clinical guidelines “were selected to include experts who would predictable say that … all level of blood cholesterol in the United States are too high and should be lowered” Bowden 41 quoting Dr. Michael Oliver on the new guidelines of the National Institute of Health Consensus Development Conference Statement, December 10-12, 1984.  This guidelines state:  “The evidence justifies… the reduction of calories from fat… to 30 percent, calories from saturated fat to 10 percent or less, and dietary cholesterol to no more than 250 or 300 mg daily.”  But in Lipids 2010 in a thorough review article on dietary intervention: “Diets appear to have beneficial lipoprotein effects in individuals with atherogenic dyslipidemia, compared to high-carbohydrate diets; whereas the content of total fat or saturated fat in the diet appears to have little effect.”  Given the diet-fat-cholesterol myth, doesn’t entail that all diet are junk.  So what diets are beneficial? 

The short answer is those that lower oxidative damage.  The main cause lies with carbohydrates that produce significant amounts of reactive chemicals that can oxidize small dense type-B LDL.  The process centers around glycation, ”which is the result of typically covalent bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without the controlling action of an enzyme.  All blood sugars  are reducing molecules.  Endogenous glycations occur mainly in the bloodstream to a small proportion of the absorbed simple sugars:  glucosefructose, and galactose.  It appears that fructose and galactose have approximately ten times the glycation activity of glucose, the primary body fuel.[6]  Some glycations are benign, but others are more reactive than the sugars they are derived from, and are implicated in many age-related chronic diseases such as cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged), Alzheimer's disease (amyloid proteins are side-products of the reactions progressing to AGEs),[7][8] cancer (acrylamide and other side-products are released), peripheral neuropathy  (the myelin is attacked), and other sensory losses such as deafness (due to demyelination).  This range of diseases is the result of the very basic level at which glycations interfere with molecular and cellular functioning throughout the body and the release of highly oxidizing side-products such as hydrogen peroxide.  Long-lived cells (such as nerves and different types of brain cell), long-lasting proteins (such as crystallins of the lens and cornea), and DNA may accumulate substantial damage over time.  Cells such as the retina cells in the eyes, and beta cells (insulin-producing) in the pancreas are also at high risk of damage. Damage by glycation results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure, especially in diabetes.[9]  Glycations also cause weakening of the collagen in the blood vessel walls which may lead to micro- or macro-aneurisms; this may cause strokes if in the brain” Wiki.  (Note that glycation is unrelated to glycemic index, insulin index and glycemic load.[10])  Pharma always makes marketing decisions and thus is not motivated to prevent AS, and will oppose prevention through their marketing science.  Thus pharma as teacher ignores the main culprit:  oxidative damage mostly through the process of glycation to type B (small hard) LDL[11].  Pharma followed its pattern of selling the disease and then selling the treatments.  Having sold us on cholesterol-CVD link, they sell us the fix.  So are their drugs effective for preventing acute ischemic events?



[1] It has been noted that with hypertension there is a response in the endothelium cells that accelerates the thickening of the artery wall in response to the increased blood pressure (see).  But that increase is blood pressure is initiated by AS in over 90% of cases.  A few cases of HT are associated with genetic s, drugs, and extreme prolonged emotional stress which produces an excess of certain neurotransmitters.  Supposedly in such cases there would be prolonged HT but a thickening of the wall but minimal plaque; however, I could not find definitive autopsy study of such patients.

[2]  There is an increased risk of blood clotting with hypertension that contributes to the occlusion of the coronary artery plugged by the leaked soft plaque.  HT is not essential for those with normal blood pressure who have an ischemic event also benefit, when administered early, from thrombolysis (clout busting drugs).   drugs used to ting this hypothesis of higher incidence of clotting is sketchy. 

[3]  The most significant free radicals are the products of metabolism and carbon monoxide which results from incomplete combustion such as from fires including cigarette smoke.  Pack-a-day smokers double their risk of death from MI. 

[4] Downplaying infective cause entails not promoting testing long-term CPR.   Since CPR is elevated during an infection, a short-term elevation is misleading, because AS develops over decades.  Women under the age of 55 are protected by estrogen, thus including them in a study is also misleading are doing short-term CPR testing are two ways for pharma to tweak results as desired. 

[5] In the 80s extensive research was done looking estrogen type protection from CVD for men.  None were marketed because these analogues blocked testosterone, and thus caused ED and loss of strength.  Today prevention doesn’t fit pharma’s business model. 

[6]   About 20–25% of total daily cholesterol production occurs in the liver; other sites of higher synthesis rates include the intestines, adrenal glands, and reproductive organs Wiki.

[7]   There are other causes, nothing is simple:  Resistin, a protein secreted by fat tissue, has been shown to increase the production of LDL in human liver cells and also degrades LDL receptors in the liver Wiki. 

[8] Jonny Bowden . Ph.D.  & Stephen  Sinatra, MD, The Great Cholesterol Myth:  Why Lowering Your Cholesterol Won’t Prevent Heart Disease—and the Statin-Free Plan That Will, Fair Winds Press, Nov.  2012; a national bestseller, has 23 experts who praised the book and are quoted on the cover & first page, and  at Amazon has a 4.8 star rating from 220 reviewers.   Getting a fair review of book is iffy because of heated nature of the topic and many the subscribers to pharma’s spin.  JK finds the book well supported in the critical portions on cholesterol’s role; but in spots questionable as to the alternative approaches to prevention of CVD.  A couple of years before reading this book, JK had arrived at those same conclusion as to risk of CVD and on some of their fixes. 

[9]  Atheroma is an accumulation and swelling in artery walls made up of (mostly) macrophage cells, or debris, and containing  lipids  (cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue… in the early stage an accumulation of mostly macrophages, that have taken up oxidized LKLWiki.

[10]   Glycemic Index (GI):  A measure of the blood-glucose level over 2 hour after 12 hours of fasting to a certain quantity of food, usually 50 grams based on the measurement of 10 subjects.  High GI is associated with an increase in glycation, the process of forming a covalent bond of a protein or lipid molecule with a sugar molecule, of which some of these molecules release highly oxidizing side-products such as hydrogen peroxide.  Thus glycation and GI are associated with an assortment of conditions including CVD, cancer Alzheimer’s diseases, peripheral neuropathy, sensory loss, diabetes and obesity.   A more accurate measurement than GI would be that of the amount of glycation or the insulin level (insulin index) which is determined by blood-sugar level.  Some of the GI figures do not accurately reflect the insulin response.  Even better would be a measurement of the amount of the glycation CVD, cancer Alzheimer’s diseases, peripheral neuropathy, sensory loss, diabetes and obesity.   A more accurate measurement than GI would be that of the amount of glycation or the insulin level (insulin index) which is determined by blood-sugar level.  Some of the GI figures do not accurately reflect the insulin response.  Even better would be a measurement of the amount of the glycation of protein and lipoproteins” Wiki and Wiki.

[11]  There are other ways glycation contributes to AS:  “Advanced glycation end products (RAGE)….  Soluble AGEs activate monocytes  [become macrophages after entering tissue], and AGEs in the basement membrane inhibit monocyte migration. AGE-bound RAGE increases endothelial permeability to macromolecules. AGEs block nitric oxide activity in the endothelium and cause the production of reactive oxygen species” Advanced Glycation End Products, 2006. 

Statins lower TC about 30%, but they have nearly no effect on ischemic events.   This is the conclusion I drew from Braunwald[1] on statin for the prevention of major events.  An article in Therapeutics letter came to the same conclusion doing a meta-analysis using some of the same major clinical trials:  This cardiovascular benefit is not reflected in 2 measures of overall health impact, total mortality and total serious adverse events.  Therefore, statins have not been shown to provide an overall health benefit in primary prevention trials.”  And repeated in JAMA in a meta-analysis of 11 studies that included the clearly cooked Jupiter and TNT Studies[2].   Assuming for good reason there was major positive bias, which is the industry norm; the actual results are significantly negative.  A reasonable conclusion is that there is moderate benefit for some of those in the highest risk group:  unstable angina, diabetes, previous heart attack, TC above 350, and current smoker.  No more than 5% of all those taking statins would have a net benefit.   And if they choice lifestyle changes, they all would benefit more than from a statin.  Given the affects of statins and hypertensive drugs on muscle strength and cognitive function, the probability of lifestyle changes is very significantly reduced.   Taking a statin has a significant negative effect upon quality of life, especially among those above the age of 60.   Sexual dysfunction, reduction in strength, and decline in cognitive functions has not been measured in pharma funded and government trials.  However in the vast body research and clinical trial on statins, the negative consequences are exposed.  In my article on statins fourteen of them were listed:

14 NEGATIVE EFFECTS:  One, ED, it lowers testosterone , and  nitrous oxide thus causes ED; a similar effect upon women for the sex steroids are synthesized from cholesterol.  Two, COX-2 inhibitor, just like Vioxx:    Vioxx given to elderly increased heart attacks (MIs) over 300%[3].  The American Heart Association warns: “accumulated evidence that non-steroidal,   anti-inflammatory drugs [NSAIDs are COX inhibitors], with the exception of aspirin, increase risk for heart attack and stroke.”  They promote atherogenesis.  Three, blocks production of Q10, which enters LDL and inhibits oxidative damage that causes atherogenesis, and.  Four, plaque instability:  “Vulnerability of plaques to rup­ture and thrombosis is of greater clinical relevance than the degree of stenosis they cause” (Corti et al., 2003).  Statins affect plaque stability in a variety of ways.  The meta-loproteinases degrade extra-cellular matrix components and thus “weaken the fibrous cap and destabilize the lesions” -- Goodman and Gilman pharmacology, 11th Ed, p 950.  Rupture of plaque causes over 80% of MIs.  Statins inhibit secretion MMP-1, 3, & 9 from SMC, and microphages make plaque less stable.   Five, reduction in ATP:  Q10 (CoQ10) is needed for the conversion of APD to ATP (adenosine-5-triphosphate), the source of energy for muscles contraction.  “ATP is often called the ‘molecular unit of currency of intracellular energy transfer including muscle contraction and for chemical reactions.  ATP transports chemical energy within cells for metabolism--Wikipedia.  A reduction of 40% in CoQ10 is accepted.[4]  Six, The heart muscle under stress needs more ATP, not less.  This is why pharma excludes the elderly and those with coronary heart failure (CHF) from trials.   This may explain previous reports that the mean age of ME/CFS patients dying from CHF are 2.5 years younger than the control group.”  In a summary of journal articles which concludes:  “As the potency of statin drugs increases and as the target LDL cholesterol level decreases, the severity of Q10 depletion increases and heart-muscle function declines. This tragic scenario may very well be prevented by using supplemental Q10 with all HMG CoA reductase inhibitors [statins]” and, and. Thus “Lower cholesterol, poorer outcome in CHF patients.”  Pharma ignores Q10 side effect.  Seven, All Statins inhibit the rate controlling enzyme HMGCR of the mevalonate pathway.  This pathway generates a range of other products in addition to cholesterol, including coenzyme Q10, heme-A, the production of dimethylallyl prophosphate (DMAP),  and  isopentenyl pyrophosphate(IPP), which serve as the basis for the biosynthesis of molecules used in processes as diverse  as terpenoid synthesis, protein prenylation and isoprenylated proteins10 which have pivotal roles in cell biology and human physiology and potential relevance to benefits as well as risks of statins.11-13  Drugs, such as the statins, stop the production of mevalonate by inhibiting HMG-CoA reductase.[1] Wiki  “The Mevalonate pathway is important for, cell membrane maintenance,  hormones,  protein anchoring, and N-glycosylation.  It is also a part of steroid biosynthesis” (Wiki).  Dolichols  are  isoprenoids synthesized from mevalonate. They are vital to the process of Glycoprotein formation in the endoplasmic reticulum of cells. In this capacity it is critical to the formation of the Glycoproteins involved in  neuro-peptides, cell identification, cell messaging and Immune defense.  Reduced bioavailability of dolichols can affect every cellular process in the bodyWiki.  And this is only a partial list.  Eight, Cholesterol is essential for life. “It is the precursor for the biosynthesis of steroid hormones, bile acids, vitamin D, and is an essential component of cell membranes for proper permeability and fluidity.  Effects include pancreatic and hepatic dysfunction, ED, diabetes[5], muscle weakness and myopathy (muscle disease). The myelin is a cholesterol base coating around nerve cells[6] (Wiki).  Nine, Cognitive:  the reduction Q10 & cholesterol for the myelin sheath causes cognitive decline--especially in the elderly where it often leads to an incorrect diagnosis of Alzheimer’s disease and to neuropathy.  Ten, Side effects account for the poor compliance in the elderly (25% use at 2 years).   Poor compliance also occurs with elite athletes.  Eleven, Fails to reduce ischemic events because atherosclerosis is caused by oxidative damage to LDL, not high levels of LDL; thus statins are ineffective.  Three out of 4 major studies of secondary prevention (ALL-HAT, ASCOT, & PROSPER) failed to find life extension from statins (Table 42-78, Braunwald’s Supra, p 1085).  This table stands in opposition to the “safe & effective” claim (p 2286), which is pharma’s mantra, a mantra supported by their marketing studies and guidelines. Junk science is the norm on TNT trial (p 3). Thirteen:  For high risk primary “no benefit on all-causes of mortality”. [7] Fourteen, women in those 4 major studies showed less benefits then men treated with statins; they have less AS because of estrogen.[8]  Thirteen, Drug interaction with serious side effects are common (and under reported).  The system for reporting barely functions. 

 

The results for statins are dismal:  A meta-analysis of predominantly industry sponsored data reported that in a low risk group of people aged 60-70 years taking statins the number needed to treat (NNT) to prevent one cardiovascular event in one year was 345.In this group [patients who had suffered an MI] the NNT is 415 for mortality over one years. This doesn’t mean that each patient benefits a little but rather that 414 will receive no prognostic benefit.  So, why do doctors have faith in statins?  As stated on page 2, the 800 pound gorilla has replaced evidence based medicine with expert based medicine, and the gorilla owns the clinical trials and provides the thought leaders.  These thought leaders repeat the mantra “safe and effective” which is also repeated in cardiology textbooks and guidelines. Secondly the thought leaders teach that plaque formation is strongly correlated with the TC and LDL blood levels, and thus the 30% average reduction in TC is assumed to entail a corresponding reduction in ischemic events, which is confirmed by their best marketing studies, which minimalizes side effects, of course.  All this is fed to physicians in continuing education classes given to promote drugs.  All patented drugs are improvement that are safe and effective.  Peer-pressure and the need to follow guidelines play an important role in marketing statins and promoting the cholesterol myth.   

So why does the FDA allow this to go on unchecked.  As stated on page 2, the FDA functions as an extension of pharma.  This failure to supervise in the public’s interest is not a topic for corporate media; but it is published elsewhere.  See for example the article Consumer Report article FDA:  From Watchdog to Lapdog?  Prof Marcia Angell in her book The Truth About the Drug Companies, chapter 12, gives a detailed history of how Congress was persuaded to pass pharma-friendly legislation.  Today it is the norm for pharma to find a select group who benefit from a drug and then expand its usage to a much larger population.  Merck tested Mevacor (the first statin) on a very select population of those with familial hypercholesterolemia (FH, about 1 in 1,500).  They have a genetic defect which causes their cholesterol to be several times above the norm.[9]  The surrogate end point lowering TC was used for FDA approval.  Moreover, “there are no interventional studies that directly show mortality benefit of cholesterol lowering in familial hypercholesterolemia patients” Wiki,   That is why Merck for Mevicor’s used the surrogate endpoint lower TC.  Once approved, their marketing department went to work.  Now pharma, based on AstraZeneca’s Jupiter Study, has lowered the guideline bar:   US recommendations for low density lipoprotein cholesterol concentrations could put most of the Western world's adult population on statins.  This is the message from the American National Cholesterol Education Program published last year.1  Recently, Getz et al calculated that in Norway, one of the healthiest nations in the world, about 85% of men and more than 20% of the women over age 40 would be classified as high risk using this criterion.”2  The BMJ article then listed the known side effects of statins, quite different than the safe sales mantra.  But our physicians won’t hear of side effects in pharma’s continuing education classes, nor will the public from our corporate media.  “The government’s obsession with levels of total cholesterol, which has led to the overmedication of hundreds of millions of people with statins, has diverted our attention from the more egregious risk factor of atherogenic dyslipidaemia” BMJ.

 

Since statins though they lower TC, they don’t prevent endpoint events, and diets doing the same also fail, what should be done to reduce risk?   There are life-style changes and drugs that reduce the causes for oxidative damage to LDL and others the inflammation response. It is rather a tricky proposition to long-term reduce the immune response with a drug can increase the risk for chronic and acute diseases. The immune system fights off pathogens and promotes the death of abnormal cells including in tumors. The other path is to lower oxidative damage, and this is a win-win situation in that there are other benefits including protection of the mitochondria.  Life style changes are equally important because they reduce oxidative damage.

Lifestyle makes a difference. The greatest gains are from weight control, low-carbohydrate diet, cessation of smoking, and vigorous exercise.  Rapping the heart in a layer of fat and making the heart pump harder through miles of blood vessels are consequences of obesity.  Moreover with obesity, fat adversely affects the feedback mechanism that regulates insulin; thus the risk of type-2 diabetes increases 30 fold.  Diabetes causes a higher level of blood borne sugars thus increases the amount of glycation.  Diabetes causes red blood cells to leak out of capillaries which cause an immune response by macrophages.  For these reasons diabetes doubles the rate of MI.  Diabetes shortens life an average of 5 years and with obesity more.  Carbon monoxide--a reactive chemical that damages LDL-- from tobacco doubles the rate MI.  A pack-a-day smoker shortens their life on an average 7-12 years.  Carbon monoxide promotes the production of unstable plaque, thus with cessation, the risk for MI dramatically drops over the next 5 years. Vigorous exercise strengthens the heart, improve vascularization, an anti-inflammatory, and healthful effects upon the epithelium cell (walls) of arties.  Controlling for lifestyle contravening variables, senior runners extended life 8.7 years, & it improves quality.   “Exercise capacity is a powerful predictor of mortality” NEJM.

Diet makes a difference, but not the diet that pharma & our government teach which promote the fat-cholesterol myth.  In 11 out of 12 studies reviewed in Wikipedia, results did not have a benefit from low fat, or increased ratio of polyunsaturated fats  A meta-analysis of 21 studies considered the effects of saturated fat intake and found that Intake of saturated fat was not associated with an increased risk of CHD (coronary heart disease), stroke, or CVD (cardiovascular disease)"[7] Wiki.  The main diet culprit in CVD is glycation of proteins and lipoproteins which produces reactive chemicals that cause oxidative damage to proteins and lipoproteins.  One source of reactive chemicals comes from the glycation of LDL.  A high sugar diet (especially fructose) is associated with insulin resistance, diabetes, and metabolic syndrome; all are causal factors for AS.  Fat as stated before is not the culprit:    Indeed, recent prospective cohort studies have not supported any significant association between saturated fat intake and cardiovascular risk.5 Instead, saturated fat has been found to be protective. The source of the saturated fat may be important. Dairy foods are exemplary providers of vitamins A and D. As well as a link between vitamin D deficiency and a significantly increased risk of cardiovascular mortality, calcium and phosphorus found commonly in dairy foods may have antihypertensive effects that may contribute to inverse associations with cardiovascular risk.6 7 8 One study showed that higher concentrations of plasma trans-palmitoleic acid, a fatty acid mainly found in dairy foods, was associated with higher concentrations of high density lipoprotein, lower concentrations of triglycerides and C reactive protein, reduced insulin resistance, and a lower incidence of diabetes in adults.9 Red meat is another major source of saturated fat. Consumption of processed meats, but not red meat, has been associated with coronary heart disease and diabetes mellitus, which may be explained by nitrates and sodium as preservatives.10Adopting a Mediterranean diet after a heart attack is almost three times as powerful in reducing mortality as taking a statin.  The recently published PREDIMED randomised controlled trial was stopped early after it showed that in high risk people the Mediterranean diet achieved a 30% improvement over a “low fat” diet in terms of cardiovascular events”22  BMJ.  A low-fat, high carbohydrate diet increases the intake of foods with sucrose and high fructose corn sweeteners, and fruits also a source of fructose.  The Mediterranean diet is also low sugar.  They promote glycation of fructose driven oxidative damage to LDL[10].

 

“Glucose is the primary food source of energy for the body cells—with a few exceptions.  Glucose is transported from the intestines or liver to body cells via the bloodstream, and is made available for cell absorption via the hormone insulin, produced by the body primarily in the pancreas.  The body's homeostatic mechanism keeps blood glucose levels within a narrow range.  It is composed of several interacting systems, of which hormone regulation is the most important.  Insulin decreases blood glucose.  If blood sugar levels remain too high the body suppresses appetite over the short term.  Long-term  hyperglycemia causes many health problems including heart disease, eye, kidney, and nerve damage” Wiki.  A second health consequence is from glycation (as prior discussed).  Glucose, a monosaccharide, has 1/10th the glycation potential of fructose; and glycation results in oxidative damage in the body including to LDL the main cause for AS.  Fructose is found in many plants, especially the fruits.  Sucrose (commercially from cane and beet sugar) is a disaccharide consisting of glucose and fructose.   Glucose has 1/10th the glycation rate of sucrose.  Note high fructose corn syrup (HFCS) is 24% water; the rest is glucose-fructose with a moderately elevated level of fructose (approximately 55% and glucose 42%).  Thus though 31% higher in fructose (13/42) than sucrose (50-50 of each) because it glycation rate is 10 fold that of glucose, there is 300% more glycation.  (Note glycemic index and glycemic load are not measurements of glycation, but measurements of blood serum glucose after eating a quantity of food.)  Though claims are made that HFCS is statistically linked to diabetes, obesity, and metabolic syndrome, the laboratory evidence is thin, and diverts attention from its link to oxidative damage of LDL and AS.   Carbohydrates are needed for the glucose that drives the ATP production (energy) and to be stored as a reserve as glycogen in animals. Fructose is also metabolized in a process leading to the synthesis of glycogen, and fructose at this point is also used for the production of fatty acids and triglycerides.  The best of carbohydrates are starches since they lack fructose and thus are less subject to glycation than sucrose and fructose.  Most starches are very long chain of glucose molecules most of which are in subunits, the water soluble amylose and insoluble amylopectin.  Starches are the best source of glucose, while sucrose and HFCS the worse.[11] The best are starches, the worse are foods high in fructose and galactose  (one half of the disaccharide lactose found in dairy products of which milk is by far the main source.)    

  

Since those living in Mediterranean countries have a significantly lower rate of CVD, and genetics is not the reason, it is assumed that diet is the reason.  Sorting out what works in a Mediterranean diet requires laboratory experiments.  First the fat-cholesterol myth entails that the praise of polyunsaturated fats misses the mark.  First “olive oil consumption is negligible…”moreover, Mediterranean countries tend to consume relatively high amounts of fat, they have far lower rates of cardiovascular disease than in countries like the United States, where similar levels of fat consumption are found. The inclusion of red wine is considered a factor contributing to health as it contains flavonoids with powerful antioxidant properties.  A healthy lifestyle (notably a physically active lifestyle or labour) is also beneficial… The proposed mechanism is solar UVB-induced synthesis [sun] of Vitamin D in the oils of the skin, which has been observed to reduce the incidence of coronary heart disease, and which rapidly diminishes with increasing latitude.  Mediterranean, low-sugar, low-glycemic index, and high-protein diets are effective in improving markers of risk for cardiovascular disease and diabetes. A recent randomized Spanish trial of diet pattern published in The New England Journal of Medicine in 2013 followed almost 7,500 individuals over around 5 years found that individuals on a Mediterranean diet supplemented with mixed nuts and olive oil had a 30 percent reduction in risk of having a major cardiovascular event and a 49 percent decrease in stroke risk” Wiki.  In summary antioxidants in red wine and dairy products with vitamin D and increased exposure to sun light, the low glycemic index of diet, & low fructose[12] all have positive effects.  The details from the lab uncovered what in their diet works.  In addition the lack of sedentary lifestyle, especially the elderly, and walking in hilly areas further significantly contribute.         

Three very effective drugs:  each has a proven track record; and they have additional health benefits besides significantly lowering the risk of CVD.  Pharma has done mountains of marketing studies to sell hypercholesterolemia and the use of statins.  Similarly pharma has done studies to dissuade doctors and public from the usage estrogen and aspirin by claiming their benefits aren’t worth the risks.  See Aspirin and Natural HRT for an exposure of the junk science on risks; and also for a list of their many benefits.   Since there are no side effects from Q10, pharma ignores Q10 and does junk science to deny its benefits.  These drugs effectiveness is more proof as to the role of oxidative damage to LDL and the immune response, and they significantly reduce the risk of other major conditions.

As stated above there are risk associated with immunosuppressant drugs.  The most popular are the NSAIDs (non-steroidal anti-inflammatory drugs) all increase very significantly the risk for ischemic events through their inhibition of the COX-2 (Cyclooxygenase) a prostaglandin hormone, but for aspirin[13].   In a news release:  Many doctors should change the way they prescribe pain relievers for chronic pain in patients with or at risk for heart disease based on accumulated evidence that nonsteroidal anti-inflammatory drugs (NSAIDs), with the exception of aspirin, increase risk for heart attack and stroke”, advice issued by the American Heart Association..  Vioxx and several others have been pulled from the market for this reason.  Long-term Vioxx use increased the risk of MI over 300%, and naproxen (Alive) by at least 50%.  This has been known for a decade, yet NSAIDs are taken long-term by millions for joint pain and arthritis. 

Aspirin:  In the 1950s, when I was growing up, aspirin was the dominant over-the-counter drug for mild pain, arthritis, anti-inflammatory, and colds.  It came in 500 mgs, and the initial dose was 2, followed by 1 every 3 hours, or as needed.  The standard daily usage for arthritic and joint pain, and chronic lower back pain was 2.5 grams per day, with 7.5 grams as the upper limit—this continued to be recommended by doctors until the 1990s.  Annual production reached a peak in the U.S. of 20,000 tons in 1958.  Nothing has changes since the 1960s as to its risk factors; and several major benefits were since discovered including those of prevention of blood clots, heart attacks, cancer, atherosclerosis, Alzheimer’s, and increased cancer survival, yet its sales have decline until now it is 8th.  Most sales are for the ineffective under 100 mg dose for those at risk of a heart attack—tolerance develops to the antiplatelet effect within 1 year.  Aspirin is the only safe NSAID.  The American Heart Association warns that all NSAIDs[14] increase significantly the risk of heart attack but for aspirin[15].  Being 8th is proof that pharma controls drug usage.  Among its significant benefits are prevention of hardening of the arteries, cancer, Alzheimer’s disease, and thrombosis which causes heart attacks, strokes, pulmonary embolism, and kidney damage.  Aspirin reduces significantly the top three killers.  Because of its anti-inflammatory action, “It is the standard against which all rheumatoid arthritis medication should be measured” Goodman & Gilman 11th Ed, 2006.  Aspirin is the drug of choice for osteoarthritis, Merck Manuel 15th Ed. p 973.  Aspirin’s anti-inflammatory action prevents hardening of the arteries, which is essentially an inflammatory process that oxidizes LDL.  Aspirin stimulates the body’s mechanism for destruction of abnormal cells (necrosis factor) including trauma damaged cells and precancerous and cancerous cells.  By doing so it both prevents most cancers and promotes survival.   For example, with breast cancer the rate is reduced over 40% and survival of stages I, II & III is increased over 60% (doesn’t affect metastatic cancers).  Yet the FDA gives it the lowest approval rating for cancer treatment.  Pharma attacks the usage aspirin because it would drastically reduce the sales of nearly half their blockbusters.  Besides ignoring aspirin’s benefits, pharma has blown out of proportion its health risks.   Doctors automatically blame aspirin for all major & minor bleeding episodes, though scientific studies shown an increases the risk of ulcer 4% over 5 years. This occurs because of pylori bacteria in their stomach that has penetrated the protective mucus membrane.  Goodman and Gilman supra, comment that “many clinicians favor the use of other NSAIDs perceived to have better gastrointestinal tolerability, even though this perception remains unproven by convincing clinical trial”.  And to prevent the next generation from taking aspirin, pharma and the FDA warn about Reyes Syndrome.  Once diagnosed based on symptom with 555 cases in 1980; now with the advent of genetic testing for the metabolic syndrome it dropped to two cases in 1994.   This drop in frequency is ignored by pharma and the FDA.  Finally on dosage:  pharma reduced aspirin from 500 to 325 mg, and initial dose from 1 gram to 325 mg, which is too low to be effective for pain and inflammation.   Effective dose for pain and arthritis is 2.5 g m daily.  For prevention of blood clot (thrombosis) cancer, atherosclerosis, and Alzheimer’s disease 325 mg once or twice daily, and twice that amount as chemotherapy for cancer.  For over 50 years 2.5 grams or more taken by millions for arthritis--the 1987 Merck Manual recommends 3.5 grams daily.  The increased ulcer risk was known for over a century, but it took pharma’s unwarranted assault to change doctor’s opinion.  Moreover the other NSAIDs increase the risk of ischemic heart attacks and strokes, and acetaminophen (Tylenol) causes triples the risk of asthma in children and is the leading cause of drug induced liver failure.  Tens of millions have died early from cancer, ischemic heart attacks & strokes, and Alzheimer’s disease because the marketplace has no conscience. 

Q10 (CoQ10):   recognized as the most effective antioxidant.[16]  A number of major health conditions are caused by oxidative damage including hardening of the arteries for which Q10 is protective.   Q10 is found in every cell in the body because it is used by the mitochondria in the production of ATP from glucose.  ATP accounts for 95% of the body’s energy.   The antioxidant effect of Q10 derives from its energy carrier function in the production of ATP.   As an energy carrier, the Q10 molecule is continually going through an oxidation-reduction cycle.  It is the best of anti-oxidants because it is distributed throughout the body, in every cell.  It is found in LDL and thus protects by preventing oxidative damage to LDL which is the initial step in the process that result in AS & CVD.  It protects other tissues from oxidative damage and thereby reduces the risk for a number of serious conditions including Alzheimer’s & Parkinson’s diseases, CVD, and macular degeneration.  The second important function is protection of the mitochondria from damage from the reactive chemicals produced in the metabolism of glucose.  Decline in endurance & peak performance with age is a result of oxidative damage to the mitochondria for which Q10 slows that process.  It is particular beneficial for those with heart disease, hypertensions, diabetics; and for those taking statins or beta blockers (for hypertension) for these drugs partially block the bodily production of Q10 (40% for statins) and the other products of the mevalonate pathway.  All these benefits from long-term Q10 add up to an increase in lifespan and greater endurance.  Q10 is not toxic:  a study found that daily dose of 3600 mg was well tolerated by both the healthy and unhealthy patients.  Recommendation:  100 mg for children, being gradually increased to 300 mg by the age of 40--and its yearly cost through Costco is under $70 for Kirkland brand Q10.   

Natural Estrogen (Estradiol) with progesterone HRT:  What every woman should be taking because of the numerous, major health benefits, benefits that would slash pharma’s profits.  As Dr. Ben Goldacre says, “the devil is in the details.”  Of the 4 natural estrogens, only estradiol (E2, 17β-estradiol) has major benefits.  Two (estriol (E3) and estetrol (E4)) are found in pregnant women.  They should not be used in HRT because they block estradiol’s action.  Big pharma being against hormone replacement therapy (HRT) markets ineffective products at too low a dose, and Prempro, the most popular HRT is the worse.  Based on marketing science, including the major WHI clinical trial by the FDA which knowingly used Prempro, a combination of estrogen derived from pregnant mare’s urine and the progestin MPA.  The biological effects of mare’s estrogens are different than human estrogen and MPA blocks most major of the benefits of estrogen.  Because of the use of Prempro the result of the WHI contradict other trials.  The finding for Prempro[17] cannot be validly applied to the natural estradiol and progesterone—though pharma and the FDA did.  The FDA warns that hormone replacement therapy has only one valid medical use, to manage hot flashes, and it should be used at the lowest dose for the shortest time.  Earlier trials and epidemiological studies found that HRT lowers  Alzheimer’s 83%, heart attacks 32%, coronary heart disease 50%, colorectal cancer 46%, breast cancer 73%, thrombosis 8%, osteoporosis fractures 90%, macular degeneration 65%, reduces & prevents arthritic join destruction, firmer breasts, healthier skin (less wrinkles, thicker, 48% more collagen), reduces hair loss, improved cognitive function, less depression and mental illness, and a general feeling of well-being with increased libido.  Estradiol is the most effective treatment to prevent osteoporosis—bisphosphonates the worse.  Estradiol’s methods of cardiovascular protection are well documented.  The lack of estradiol is the reason for the precipitous decline in health of women.  The brouhaha over estrogen receptors and breast cancer is based on marketing science.  Life extension with long-term natural HRT is at least 4 years.  Because of an  increase in a low incident cancer (uterine), a progestin (synthetic orally active hormone with some progesterone properties) is added to hormone replacement therapy rather than the natural progesterone which isn’t orally active—except when micronized and suspended in oil.  The best method of application is a lotion obtained from a compounding pharmacy in a dose of 4 mgs estradiol plus 100 mg of progesterone per application--absorption rate is about 15%.  Apply widely as possible over the torso, back, shoulders, underarms, and face using water and rubbing it in to promote better absorption. Recently progesterone has been micronized in oil and available as a pill.  Ideal free-serum estradiol level is 7-9 pg/mL.   A compounding pharmacy can prepare a pill consisting of 2 mg of estradiol with 50 mg of progesterone.  The lotion form is better for the skin.  Plant sources of estrogens are not very effective.  Doctors who follow the Wiley Protocol are other methods of hormone balancing for post-menopausal women are milking the insurance and patient, it lacks sound scientific evidence.  Keep it simple.      

Testosterone:   the male hormone that is almost identical in structure to estrogen and thus has many of the same benefits as estrogen.  Noticeable benefits for testosterone:  quality of life in 4 weeks, depressed mood in 30 weeks, bone mass in 26 weeks,  lipid profile in 52, inflammation in 12 weeks, sexual interest in 6 weeks, erection/ejaculation in 26 weeks,  red cells in  52 weeks, insulin sensitivity in 52 weeks , muscle strength in 16 weeks, fat mass in 16 weeks (Eur J Endocrinol. 2011, Nov. 675-85).  Other benefits include improved cognitive function, reduced risk for Alzheimer’s disease, metabolic syndrome, diabetes, cardiovascular disease and the fatal resultant heart attacks and strokes.  The brouhaha to CVD and prostate cancer are based on pharma’s marketing science.   Testosterone does not cause or produce deleterious effects on prostate cancer Wiki.  Recommended: once serum testosterone level drops below 350, to use 100 mg of testosterone in a topical cream.   Ideal level in the 850 to 1200 ng/dL or higher.   Increased to 150 mg at age 75 as effects diminish--bio-receptors and response decreases with age as does the level of free (available) testosterone.  Current assay methods are inaccurate as to measurement of free testosterone.  Best source for testosterone is from a compounding pharmacy.    Apply widely as possible over the torso, back, shoulders, underarms, and face using water and rubbing it in to promote better absorption.  Doctors who follow a program of hormone balance are milking the insurance and patient.  There is probably a value to taking also HGH, though how much lacks quality evidence. 





 


There is a large body of clinical trials and epidemiological studies that have shown that cholesterol and high fat diet have minimal effect upon promotion of CVD, and conversely that a low fat & low cholesterol diet is not cardiovascular protective (see Cholesterol Myth).  As stated prior oxidative damage to LDL and the immune response is the primary cause (infectious agents are second main cause), thus drugs listed below have modest effect while statins for an assortment of reasons are not worth taking (see statins).  Since so many believe in the cholesterol myth, the natural, safer method of lowering blood cholesterol of niacin and its inositol form are included below.







Niacin family and other natural cholesterol lowering drugs and cardiovascular disease (CVD):  Some of you will as a matter of insurance want to lower your TC a natural way or are taking a statin (a mistake).  Pharma recommends 1,500 to 3000 mgs of niacin (nicotinic acid) taken with meal; however insulin blocks its cholesterol lowering affect.  High dose causes the unpleasant flushing and thus low compliance.  The only long-term study (usage 6 years, followed 15 years) was of high dose niacin.  It produced a reduction in deaths from cardiovascular disease of 11%; this compares favorable to statins once the tobacco science trials are eliminated from consideration (see Statin, Braunwald table).   However, a study based on blood work showed that 200 mgs at bed is just as effective, and without flushing.  In the same experiment similar results were obtained with inositol hexanicotinate, a source of niacin.  Niacin also possesses anti-inflammatory and antioxidant benefits, and thus inhibits atherogenesis.  Phenolic substances found in red wine are of value, so too of value is nutritional yeast, red yeast extract, and omega-3 fatty acids (found in fish oil).  For lowering the bad cholesterol use 200 to 500 mgs at bedtime of either niacin or inositol hexanicotinate.  There is miniscule value of lowering cholesterol that is below 350 (though pharma promotes statins for those above 240).  Recall that pharma has turned cholesterol into a villain.  However, as explained the most important factor for CVD is the inflammatory response to damaged LDL, for which aspirin and Q10, along with estrogen for postmenopausal women offers a greater benefit than lowering cholesterol.  Testosterone once blood level is below 350 lowers risk of MI, heart failure, and metabolic syndrome.  Change in lifestyle is very effective. 

Following the advice of lifestyle change, Q10, aspirin, estradiol, and testosterone entails that statins and niacin are of no health value.  There are other drugs of value; however, doing more is not better, but for the sake of completeness several have shown to be of value.  D-ribose is a building block for ATP, L-carnitine aids in the production of Q10 and is an effective antioxidant, and vitamin C is an antioxidant lowers risk for AS (not recommended for those with hemochromatosis).  Magnesium 1 gm daily is recommended for those with the issue of high blood pressure and a significant load of arterial calcium. Coronary artery calcification is a major risk factor for heart disease and magnesium lowers that load (Bowden 136).  Berberine, a Chinese herbal product has a positive effect upon TC, reduces superoxide levels in LPS-stimulated macrophages, and is “useful for patients with congestive heart failure…suppresses the growth of a wide variety of tumor cells[18]Wiki, and it lowers blood sugars in treating diabetes. Improves TC, etc.  Glutathione is an organic chemical found in plants and animals.  “It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.[17] Wiki.  The issue as to what should be taken in addition to those listed in the recommended section.  One issue is the lack of long-term clinical trials, and the possibility that in combination there would be adverse consequences.   As preventative medications, those in the recommended section are totally adequate.  For those with severe CVD these additional drugs have value, depending on condition.  But asking your doctor is like asking his thought leaders.  I follow my  advice, and also consumes on his foods about 5 gm per day of nutritional yeast which I find a subtle feeling of wellness like that of drinking green tea with a meal.  The choices go back on you.  We have a long way to go  before the potential of medical science is unleashed from its corporate master. 



[1]  Braunwald, Heart Disease, 8th Ed. P 1085 table.  There of the 4 major clinical trials, 3 of them the placebo cohort had as many major ischemic events as those treated with statins. 

[2] For a detailed account of Pfizer’s TNT Study on how the evidence was worked to lower guidelines for statins (Lipitor).  The Jupiter study “a major discrepancy between significant reduction of nonfatal stroke and myocardial infarction, but no effect on mortality from stroke and myocardial infarction… raises troubling questions concerning the role of commercial sponsors “….  NIH, & Wiki.

[3] A reasonable assessment of total early deaths from the selective COX-2 inhibitors in the US would be over 200,000; and a much greater number for the non-selective COX inhibitors, the NSAIDs—but for aspirin.  Celebrex is still on the market, and though warnings about all COX inhibitors warning that they promote CVD, the oft-heard sales message prevails. 

[4] After 3 months treatment of healthy patients with a poor TC using pravastatin or simvastatin, the total cholesterol and CoQ10 (Q10) were lowered 40%, when compared to the placebo group.  “A diminution of Q10 availability may be the cause of membrane alteration with consequent cellular damage”Journal of clinical Pharmacology.  This finding is supported in other studies and widely accepted—summary article.  

[5] 9% increase in risk of developing diabetes over 4 years, meta study Lancet 2010 based on pharma trials--undoubtedly under-reported. 

[6]  The 2nd cause for neuropathy, the first low Q10.  The two are additive.

[7]  JAMA 2010:  In conclusion, based on aggregate data on 65 229 men and women from 11 studies, yielding approximately 244 000 person-years of follow-up and 2793 deaths, we observed that statin therapy for an average period of 3.7 years had no benefit on all-cause mortality in a high-risk primary prevention population.”  And this analysis included the low quality Jupiter Study. 

[8]  Jonny Bowden & Stephen Sinatra, The Great Cholesterol Myth, 2012, p. 124, Using several of the studies used in Braunwald’s table (supra 1085), they found only 28% in the trial were women, and they didn’t benefit from statins.  Pulling the 5 studies and including men, “total mortality is not reduced by statin therapy” (at 124). 

[9] At that abnormal level the rate of oxidative damage to LDL out-paces the cleanup process, and typically their first MI occurs in the 4 decades.  But this doesn’t prove that without other risk factors those with a TC near 350 are at significantly greater risk. 

[10]  This is an example of the need for laboratory experiments to provide the modus operandi for the results of a clinical trial.  In this case carbohydrates are bad only in the degree that they promote glycation, and for example glucose the rate is 1/10 that of fructose, Wiki.  The right carbohydrates are a healthful source of energy.  

[11] Common names create confusion:  corn starch contains fructose, and corn syrup is pure (35%) glucose with water.  Cellulose is a long chain of D-glucose for which we lack an enzyme to digest, though some bacteria can. 

[12] fructose:  sodas 29 gm/can, fruit juices 26-9, fruits; apple 25 , raisin 20, honeydew 16, strawberry 15, plum 13-10, banana 10, orange 9, pineapple 8, grapefruit 8, peach 8, nectarine 6, peach 7, apricot 4, ; vegetables tomato 14,  cucumber 13, pepper 11, lettuce 9-5, green bean 5-2 gm, gm, squash 9-4,  cabbage 8 celery 6,  peppers. Squash 13-11 gm, , carrot 2, broccoli 4-2, Sweet potato 1, potato 1, spinach 1.3, beet 1.3, pea 0.4,  corn 1-1/4;  grains 1/4th milk 0.04, cheese 0.07, bread 1.3, fish 0.2, nutritiondata.

[13]  Aspirin is unlike the other COX inhibitors (the NSAIDs); they increase the risk of CVD with prolonged usage as a result of blocking the mechanism by which atherogenesis process is shut down.  Thus with use of naproxen, Celebrex, and other NSAIDs, the rate of atherogenesis remains high once started.  These drugs in their suppression of COX-2 thereby suppress “dependent cardio-protective prostaglandins, prostacyclin in particularWiki. On the technical side, it seems that Pfizer in the promotion of Celebrex has offered a clotting mechanism for increased MI while ignoring its atherogenesis effect.   Namely, COX-2 inhibitors promote blood clots through blocking the mechanism for breaking up blood clots through blocking the production of prostacyclin. This explanation is contracted by the fact that incidents of MI goes up over time for those at high risk & not low risk, nor with short-term use.  Also contra clotting explanation is that the risk persists after stopping “in 1 year after Vioxx was stopped there was a 75% greater risk … at.      

[14]  NSAID are None Steroidal Anti-Inflammatory Drug, this includes naproxen in Aleve, ibuprofen, Celebrex, and over 30 others.  Naproxen, for example, has been shown when taken long-term to increase the risk of heart attacks at least 50% and Celebrex 200%, yet both are widely prescribed for arthritis.  Vioxx was removed by Merck (pending FDA actions) when it was shown to increase the death rate from heart attacks by 400% in a study on the prevention of Alzheimer’s disease.  

[15]   The mechanism is through an atypical effect of aspirin (but not other NSAIDs) through the stimulation of the production of 15-LO which is anti-inflammatory.  The other NSAIDs through promotion of 5-LO activity increase the risk of MI, as demonstrated in a study of an Icelandic population—at AHA and.   

[16]  Gluathione also highly rated antioxidant, Berberine a plant product with Lipid lowering properties, Vitamin D administered with calcium Inositol hexaphosphate (phytic acid) has promising claims.  All these at this point have not been sufficient reviewed for a claim to be made thereon. 

[17]   Prempro has been the leading selling HRT since the mid 40s in the US, and it still is.  The issues with MPA and mare’s urine estrogen have been know for decades by scientist including those in the FDA, as too the superiority of the natural HRT.  Because of birth control pills, HRT, and the possibility that an estrogen would protect men—as it does women—from cardiovascular disease, there has been thousands of published articles on the estrogen and progesterone family of hormones. 

[18] Berberine has drawn extensive attention towards its antineoplastic effects.[63][64] It seems to suppress the growth of a wide variety of tumor cells, including breast cancer,[65] leukemia, melanoma,[66] epidermoid carcinoma, hepatoma, pancreatic cancer,[67] oral carcinoma, tongue carcinoma,[68] glioblastoma, prostate carcinoma and gastric carcinoma.[69][70] Animal studies have shown that berberine can suppress chemical-induced carcinogenesis, clastogenesis,[71] tumor promotion, tumor invasion,[72][73][74][75][76] prostate cancer,[77][78][79][80] neuroblastoma,[81][82] and leukemia.[48][83]

It is a radiosensitizer of tumor cells, but not of normal cells. How berberine mediates these effects is not fully understood, but its ability to inhibit angiogenesis and to modulate Mcl-1, Bcl-xL, cyclooxygenase (COX)-2, MDR, tumor necrosis factor (TNF)- and IL-6, iNOS, IL-12, intercellular adhesion molecule-1 and ELAM-1 expression, MCP-1 and CINC-1, cyclin D1,[84]activator protein (AP-1), HIF-1, PPAR-, and topoisomerase II has been shown. By using yeast mutants, berberine was found to bind and inhibit stress-induced mitogen-activated protein kinase kinase activation. Because apoptotic, carcinogenic, and inflammatory effects and various gene products (such as TNF-α, IL-6, COX-2, adhesion molecules, cyclin D1, and MDR) modulated by berberine are regulated by the transcription factor nuclear factor- B (NF- B), it is postulated this pathway plays a major role in the action of berberine.[85] Berberine suppressed NF-κB activation induced by various inflammatory agents and carcinogens. This alkaloid also suppressed constitutive NF-κB activation found in certain tumor cells. It seems to protect against side effects of radiation therapy in lung cancer.[86] However, new studies suggest that while berberine decreases cell growth, it increases the side population (stem cell) fraction of H460 lung cancer cells.[87]

Berberine, 300 mg three times a day orally, also seems to inhibit complication of abdominal or pelvic radiation, called radiation-induced acute intestinal symptoms.[88] The studies suggest its use in clinical development may be more as a cytostatic agent than a cytotoxic compound.

Berberine reduces LDL cholesterol by upregulating LDLR mRNA expression posttranscriptionally while downregulating the transcription of proprotein convertase subtilisin/kexin type 9 (PCSK9), a natural inhibitor of LDL receptor (LDLR),[45] and increasing in the liver the expression of LDL receptors through extracellular signal-regulated kinase (ERK) signaling pathway,[46] while statins inhibit cholesterol synthesis in the liver by blocking HMG-CoA-reductase. This explains why berberine does not cause side effects typical to statins. Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters.[47]  Rave reviews on Amazon for controlling blood surgark Available at amazon.com, 60 500 mg capsules for $15.00

 

  • Heart, Vascular, Clinical, and Medical Science Terms---3/9/14

Acute Ischemic event (heart attack, myocardial infarction) occurs when a coronary artery or arteries are block by young, unstable plaque and sufficient to produce death or medical intervention

Arrhythmia (cardiac dysrhythmia, irregular heartbeat) is any of a group of conditions in which the electrical activity of the heart is irregular or is faster or slower than normal.  Arrhythmias can occur in the upper chambers of the heart, (atria), or in the lower chambers of the heart, (ventricles). Arrhythmias may occur at any age. Some are barely perceptible, whereas others can be more dramatic and can even lead to sudden cardiac death.  “Nearly every anti-arrhythmic drug has the potential to act as a pro-arrhythmic (promotes)” Wiki.   

Atheroma  is an accumulation and swelling in artery walls made up of (mostly) macrophage cells, or debris, and containing lipids(cholesterol and fatty acids), calcium and a variable amount of fibrous connective tissue. Atheroma occurs in atherosclerosis--Wiki.

Atherosclerosis

ATP

Bias: mainly a manipulation of the conditions of the clinical so as to promote marketing objectives; viz., a deviation from the goal of science to arrive at the best possible conclusion.  These results are then written up for journal articles with additional bias added to further marketing objectives.  Such works are commonly labeled tobacco (marketing) science.   

Cardiovascular Disease (CVD, heart disease) any disease, whether congenital or acquired, of the heart and blood vessels; any disease that affects the cardiovascular system, with atherosclerosis and HP being the most common.

Coronary artery disease  see ischemic heart disease

Total Cholesterol (TC) the amounts of High density, low density, and very low density lipoproteins, of triglycerides, and other blood borne compound that are indicators for angiogenesis.   

Chylomicrons (from the Greek chylo, meaning juice ormilky fluid, and micron, meaning small particle) arelipoprotein particles that consist of triglycerides (85-92%), phospholipids (6-12%), cholesterol (1-3%), andproteins (1-2%).[1] They transport dietary lipids from the intestines to other locations in the body. Chylomicrons are one of the five major groups of lipoproteins (chylomicrons, VLDLIDLLDLHDL) that enable fats and cholesterol to move within the water-based solution of the bloodstream.

Circulatory failure occurs when in the blood the concentration of oxygenated hemoglobin in the arterial blood, or the vascular bed is responsible for the inadequate cardiac output. 

Congestive Heart Failure (CHF, heart failure (HF), congestive cardiac failure (CCF)) occurs when the heart muscle is unable to maintain adequate circulation of blood in the tissues of the body or to pump out the venous blood returned to it by the venous circulation.

Coronary Artery Disease also known as atherosclerotic heart disease, coronary heart disease, and ischemic heart disease, is caused by plaque building up along the inner walls of the arteries of the heart, which narrows the coronary arteries, reduces blood flow to the heart muscle.

Coronary Failure (CF) heart failure in which the heart muscle is deprived of the blood necessary to meet its functional needs as a result of narrowing or blocking of one or more of the coronary arteries.

Coronary Heart Disease (CHD) a disease of the heart and coronary arteries that is characterized by atherosclerotic arterial deposits that block blood flow to the heart, causing myocardial infraction. 

Dyslipidaemia:  a disruption in the amount of lipids in the blood.  Prolonged elevation of insulin and also O-GlcNAc transferase (OGT) levels can also lead to dyslipidemia.

Endotoxin, the toxic protoplasm liberated when a microorganism dies and disintegrates.   Toxic substance bound to to the bacterial cell wall and releasedwhen the bacterium ruptures or disintegrates. Endotoxins consist of lipopoly- saccharide and lipoprotein complexes.  The protein component determines the antibody type that can react with the endotoxin molecule to produce an immune reaction.  Endotoxins are rarely fatal, although they often cause fever.   

End points, surrogate endpoints  

Epidemiological s

Heart Failure (HF) is a pathophysiological state in which the heart is unable to pump blood at a rate commensurate with the requirements of the metabolizing tissues or can do so only from an elevated filling pressure.   I t is usually, but not always caused by a defect in myocardial contraction, i.e., by myocardial failure

HMG-CoA reductase inhibitors (statins), the enzyme they inhibit, which is the method by which lower cholesterol.

Dyslipidemia is the presence of raised or abnormal levels of lipids and/or lipoproteins in the blood. The prolonged elevation of insulin levels can lead to dyslipidemia. Increased levels of O-GlcNAc transferase (OGT) are known to cause dylipidaemia. [Hyperlipidemia is elevated levels of lipids.] http://cache.lexico.com/r/g/link-extern.gif

Hypertension, high blood pressure HP

Ischemic heart disease ((ISH) coronary artery disease, atherosclerotic heart disease) causes about 70 of heart attacks.  It is caused by plaque building up along the inner walls of the arteries of the heart.  ischemic stroke, c

Immune response, inflammatory response:

Limpcocyte

Lipoproteins

Macrophage

Marketing Science (tobacco science)

Mediterranean Diet

Metastudy consists of grouping together studies according to a set of criteria and then calculating the summation of finding.  Cochrane Library consists of hundreds of such meta-studies without funding from PhARMA.  However, with few exceptions they underestimate/overestimate the results because it is not possible to eliminate pharma’s marketing clinical studies. 

Morbidity rate the relative incidence of a particular disease in a specific locality

Myocardial Infarction (MI): a heart attack that occurs when the blood that nourishes the heart muscle is cut off due to the leaking of unstable plaque which is often further occluded by a blood clot.  The resulting ischemia event damages the heart muscle. 

Plaque

Primary prevention: treatment for those with high total cholesterol, high C-reactive protein, and other causal factors, such as diabetes, hypertension, smoking, but not cardiovascular disease (CVD) (see secondary prevention below).

Raw data

Sarcopenia the loss of muscle mass causing weakness.  Statins contribute to this through lowering of CoQ10, and thereby affecting exercise and physical exertion, which are needed to maintain muscle mass and tone. 

Sepsis:  the poisoned condition resulting from the presence of pathogens or their toxins.   The severe infection caused by pathogenic organisms, especially bacteria, in the blood or tissues.  If untreated, a localized infection, as in the respiratory or urinary tracts, can lead to infection in the blood stream and widespread inflammation, characterized by fever, chills, and other symptoms and later septic shock.  Chronic infection is a causal factor for CVD.

Secondary prevention: treatment of those with pre-existing cardiovascular disease (CVD) including have had an MI, coronary heart failure, angina.

Statin

Thought Leader because of being PhARMA friendly a few administrators and researchers perform various well-paid services for PhARMA, such as a researcher, author of textbooks, head of clinic, and giving educationals.  They become known as an expert in their specialty.    

Thrombosis: “(Greek: θρόμβωσις) is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system.  It can be a response to injury, or the result of leaking plaque that can partially plug an artery and initiate the clotting process further occluding the artery.  In the brain it results in a stroke, the heart an myocardial infarction. 


Tibits

1)   Soft, young, unstable plaque is causes 80% of ischemic heart attacks (MI).  Because of the protective effect of estradiol (E2, 1 of 4 human estrogens women at the age of 65 have significantly less occlusion of their arteries then men.  Post menopause they are forming fresh young unstable plaque at a rate similar to men, and thus within 10 years of menopause their risk for a MI is close to the rate for men of the same age.   But since they don’t have major coronary arteries occluded to the extent of men, women’s heart attacks (MIs) on an average differ from men’s.  Four of these are: 1) symptoms of MI are less pronounced; 2) involves multiple small coronary arteries (men larger coronary arteries); 3) often doesn’t show up as occlusion on imaging; 4) thus cannot be treated with angioplasty which accounts for their somewhat higher rate of deaths from acute MIs. Moreover, the role of clotting is less pronounced in women.   

2)  High blood pressure (HBP) has become 6 fold more common since 1900, from 5-6% to 34% in 2008.  64% of men age 65-74 have high blood pressure and 69% of women, up from 54% and 53% respectively for that age 55-64.  About 7 in 10 U.S. adults (69.9%) with high blood pressure use medications to treat the condition2” Wiki  The genes pool has not shifted between 1900 and 2010 so as to explain the rise in HT.  Thus the argument from genetic factors as a major contributor fails, except in the sense that an environmental agent such as bisphenols A could initiate a greater response in those with certain genes and thereby cause obesity and thus CVD. 

3)  In the 1931, John Hay, Professor of Medicine at Liverpool University, wrote that "there is some truth in the saying that the greatest danger to a man with a high blood pressure lies in its discovery, because then some fool is certain to try and reduce it".[7][8]  This view was echoed by the eminent US cardiologist Paul Dudley White in 1937, who suggested that " HT may be an important compensatory mechanism which should not be tampered with, even when it’s certain that we could control it".[9] Charles Friedberg's 1949 classic textbook "Diseases of the Heart", [10] stated that "people with 'mild benign' HT ... [defined as blood pressures up to levels of 210/100 mm Hg] ... need not be treated"[8]  Wiki.   

4)  Six major causes of atherosclerosis (in order of importance):  carbon monoxide, infections in the artery walls, glycation (sugars, especially fructose), certain chronic infections, obesity, diabetes,  lack of strenuous exercise (exercise produces a response of the endothelial cells in the artery walls that diminishes the rate of plaque formation) and genetics (APOB, LDLRAP1, HCHOLA3 variant of PCSK9 genes).

5)   “It has been shown that physical injury to the endothelial lining of arteries sets off a process which probably is an attempt at healing the injury but which can lead to atherosclerosis. It has also been found that chemical agents such as homocystine can produce a similar series of events leading to atherosclerosis,  These events include focal loss of endothelium, exposure of subendothelial connective tissue, and adherence of platelets followed by release of factors that stimulate intimal smooth muscle proliferation. The present studies indicate that the effects of chronic hyperlipidemia are complex in that the condition results not only in the deposition of lipids in the atheromatous lesions but that it may produce the primary endothelial injury that initiates the process of atherosclerosis as well.” Science 17 September 1976.       

 

Health is essential for quality of life.  Given the proclivity for injurious behavior (the prime examples being obesity, tobacco, soldiering, and recreational drugs) I can only conclude that the rational function of the brain is primarily social, including the generation of reasons for what is inexcusable; and the rest of what we do is quite similar to the actions of our cats and dogs.  I wish that all people would develop a love of philosophy (the term in Greek means love of wisdom).  With such love there would be a commitment to hold beliefs in proportion to the evidence in support there of, and there would be a drive for to live a truly moral life. 

 

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