Cardiovascular disease (CVD) in one of its various forms is the leading cause of morbidity (illness) and mortality (death) worldwide. It would be more accurate to say that atherosclerosis is the leading cause of morbidity and mortality. Arteriosclerosis or atherosclerosis, (the build up of plaque within the large and medium arteries of the body) is better known as coronary artery disease (CAD), carotid artery disease/ cerebrovascular disease (CVD), or peripheral artery disease (PAD). It is important to remember that atherosclerosis is one disease process that may manifest in different arteries and therefore puts different organs at risk. When the coronary arteries become narrowed with plaque build up, a person can develop ischemia (transient pain due to limited blood flow), a heart attack, chronic heart disease, or congestive heart failure. When the carotid arteries of the neck are plaque laden, a person may develop a stroke or vascular dementia because the arteries can no longer carry oxygen filled blood to the integral parts of the brain.
When the major arteries of the legs are compromised with plaque build up, a person develops pain when walking or peripheral neuropathy. When the arteries supplying the kidneys are compromised, renal function is impaired. Of course, at any time plaque from anywhere in the body can rupture and form a clot (thrombus). When a clot travels to the heart, it causes a myocardial infarction (heart attack). If a clot travels to the carotid arteries it can cause an acute stroke. If a clot travels to the lungs it is called a pulmonary embolism and can often lead to sudden death.
According to the World Health Organization (WHO), CVD accounted for 16.7 million deaths globally in 2003. The unfortunate reality is a significant percentage of these deaths could have been prevented by reducing the risk factors that contribute to the development of atherosclerosis. The focus of public health initiatives in the United States has been a strident campaign to reduce the major risk factors: high cholesterol, smoking, high blood pressure, and diabetes. There are additional modifiable risk factors that deserve our vigilance if we want to maintain our vitality throughout the aging process.
Novel risk factors
Homocysteine (a chemical that damages the vessel wall and increases the tendency to form a clot).
Fibrinogen (a marker of increased coagulation).
Lipoprotein (a) (a protein that inhibits fibrinolysis).
C – Reactive Protein (CRP) (a marker of inflammation).
Fifty years ago, atherosclerosis, often called hardening of the arteries, was considered a disease of older people. In 1953, fundamental theories about the pathogenesis of coronary artery disease were turned upside down with the publication of a paper in the Journal of American Medical Association describing the extent of coronary artery disease in otherwise healthy soldiers killed in combat in Korea. Similar findings were reported in 1971 when autopsies were performed on combat casualties in Vietnam. McNamara and his group reported that out of 105 soldiers examined (average age 22) 45% had some evidence of coronary atherosclerosis, and 5% had gross evidence of severe coronary atherosclerosis. It was obvious that atherosclerosis in susceptible individuals could begin very early in life. This new hypothesis has proven to be true in the last 50 years. The notion that atherosclerosis is a disease that takes root early in life and grows for decades before clinical symptoms appear has dramatic implications for all of us and our children.
Cholesterol belongs to a class of chemicals known as lipids. Cholesterol is necessary for life. It is the raw material from which the body makes steroid hormones, mineral corticoids, glucocorticoids, vitamin D and bile acids. It is present in every cell membrane and maintains cellular integrity. It is so important that if there is not enough cholesterol supplied by the diet, the body will synthesize cholesterol from fat, glucose and protein in the liver. Problems arise when there is an excess of cholesterol. Besides the cholesterol absorbed each day from the gastrointestinal tract, which is called exogenous cholesterol, a large quantity, called endogenous cholesterol, is formed in the cells of the body. Essentially all the endogenous cholesterol that circulates in the serum is formed by the liver, but all other cells of the body are able to form some cholesterol. Cholesterol travels through the bloodstream within spherical particles called lipoproteins. Each cholesterol fraction is made up of protein and lipid. Two lipoprotein fractions are involved in transport of lipid to peripheral tissues, very low density lipoproteins (VLDL) from the liver and chylomicrons from the intestinal tract. As the lipid portion is removed from the respective lipoproteins, the density of each fraction increases. VLDL becomes intermediate density lipoprotein (IDL) and eventually low density lipoprotein (LDL). The chylomicrons become chylomicron remnants. VLDL contains triglycerides which are now fractionated separately and can be an independent risk factor for atherosclerosis. High density lipoprotein (HDL) is involved in reverse cholesterol transport. The HDL particle is the smallest, heaviest, and least fatty particle. HDL cholesterol picks up the cholesterol from the periphery and returns it to the liver where it becomes bile acids and is innocuously excreted from the system.
The medical profession’s focus on hypercholesterolemia (high cholesterol) as the root cause of heart disease came from early theories about how hardening of the arteries began. The belief was when there is an excess of cholesterol in the blood stream, notably low density lipoprotein (LDL), some of that cholesterol would leave the bloodstream and penetrate the arterial wall, precipitating a series of cellular events that culminated in the formation of plaque. In the early 1990’s a new theory, first described by Russell Ross, posits that atherosclerosis is an inflammatory disease. Atherosclerosis or arteriosclerosis is a generic term for several diseases in which an arterial wall becomes thickened and loses elasticity. The endothelium becomes damaged by any number of the risk factors, i.e. homocysteine, smoke, oxidized LDL cholesterol, etc. The body makes an attempt to repair this damage by recruiting cholesterol, platelets, smooth muscle cells, cell adhesion molecules, cytokines, monocytes, and macrophages.
Other inflammatory molecules are called into action. This site becomes a weigh station where more oxidized LDL cholesterol can deposit. The deposition of platelets, cytokines, cell adhesion molecules, etc continues. Calcium in the blood stream also deposits and a complex lesion or plaque forms. This complex lesion is called an atheroma or plaque and it can interfere with blood flow by narrowing the lumen (the free space in the center of the artery through which the blood flows). In addition, it will continue to collect LDL cholesterol, particularly oxidized LDL, and other lipid particles until the artery becomes completely occluded. A complex plaque can be destabilized and rupture. That rupture appears to mediated by inflammation . At that point part of the atheroma will break off, recruit platelets and form a blood clot that can lodge in a critical artery.
As sclerotic plaques form, normal endothelial function is compromised. For years the endothelium was considered an inert barrier to elements contained in the blood. However, it is now apparent that the endothelium maintains the balance between vasodilation and vasoconstriction, inhibition and stimulation of smooth muscle cell proliferation and migration, and thrombogenesis and fibrinolysis. [Thrombogenesis is the creation of a thrombus or blood clot and fibrinolysis is the ‘lysis’ or dissolving of fibrin which is formed from fibrinogen.] The major vasodilating substance released by the endothelium is nitric oxide (NO). Other substances released such as prostacyclin contribute to the inhibition of platelet aggregation. Bradykinin also stimulates the release of NO and tissue plasminogen activator (t-PA) which plays a role in fibrinolysis. The endothelium also produces vasoconstrictor substances, most notably endothelin and angiotensin II. [One category of blood pressure lowering medication works by preveting vasoconstriction by targeting angiotensin II.] In addition to vasoconstriction, endothelin and angiotensin II promote proliferation of smooth muscle cells and in so doing contribute to plaque formation. The macrophages and vascular smooth muscle cells that constitute the atheroma also produce large amounts of endothelin so this unhealthy cycle can self perpetuate. This endothelial dysfunction upsets the vascular homeostasis and initiates a number of events that promote and exacerbate atherosclerosis. These processes include increased endothelial permeability, platelet aggregation, leukocyte adhesion, and production of inflammatory cytokines.
The very first event in the atherosclerotic process is a focal thickening of the intima, (the inner most layer of the artery) with an increase in smooth muscle cells which is called a fatty streak. This fatty streak also contains macrophages and a number of T lymphocytes, supporting the inflammatory theory. There is evidence that fatty streaks begin to appear in childhood. In fact, almost every North American child over the age of 3 years old has some degree of aortic fatty streaks. The role of oxidized LDL cholesterol cannot be minimized. Studies have shown that oxidized LDL (ox-LDL) promotes the pathogenesis and development of atherosclerosis. Obviously the process of atherosclerosis occurs over decades. Clinical symptoms may begin to appear in high risk individuals in the third or fourth decade. Symptoms in many individuals appear much later. In general women present with symptoms a decade later than men. Too often a person’s first symptom of atherosclerosis is death from a massive myocardial infarction (MI) or heart attack. Undoubtedly, it would be best to prevent the early lesions in the first place. Since that appears unlikely, strategies should focus on slowing or reversing this process that everyone seems vulnerable to.
How to delay the inevitable
If you are at all like me, by now you are thinking what hope is there for me? I’m a bit older than 3, and there is that chunk of time I consider as my misspent youth! Obviously one of the most effective ways of ensuring health and longevity is to address those risk factors that are modifiable from this point on. Certainly regular exercise is critical. There is probably nothing that will take the place of a healthy, low calorie, nutrient dense diet. It is also important to keep your weight as close to your ideal weight as possible. Obesity contributes dramatically to inflammation and other risk factors that promote atherosclerosis.
Everyone knows about the major risk factors – hypercholesterolemia (high cholesterol), hypertension (high blood pressure), smoking, and diabetes. It is time to address the ‘novel’ or emerging risk factors that may be equally as important if not more important than the risk factors we have focused on for the last 50 years. In general, each factor detailed below is considered ‘an independent risk factor’ for atherosclerosis. However, when one looks at the actual biochemistry and mechanism of action of the various factors discussed, it will be evident there is a tremendous inter-relationship and inter-dependency of these factors.
Homocysteine (Hcy) is an aminoacid produced by the body usually as a by-product of consuming meat. It is chemically related to the aminoacid cysteine. In the presence of adequate levels of vitamin B6, B12, and folic acid; Hcy is converted into the neutral aminoacids methionine and cysteine. In addition, any methyl donor such as s-andenosyl-l-methionine (SAMe) and betaine will aid in the conversion of this benign amino acid into the innocuous aminoacids. In 1969, Kilmer McCully suggested that high levels of Hcy in the blood contribute to atherosclerosis. He noticed that children with an inborn error of methionine metabolism developed homocysteinuria (high levels of Hcy in the urine) or homocysteinemia (high levels of Hcy in the serum). This error in metabolism can be caused a disruption of any of three interrelated pathways: 1) deficiency in cystathionine B- synthase enzyme, 2) defective methyl cobalamin synthesis, or 3) an abnormality in methylene tetrahydrofolate reductase (MTHFR). The pathway starts with methionine, progresses to homocysteine, and then to cysteine. This is a transsulfuration pathway. Conversion of Hcy back to methionine, catalyzed by methyl tetrahydrofolate and methlycobalamin is considered a methylation pathway. Children with homocysteinuria or homocysteinemia died in their 20’s with premature atherosclerosis. One does not have to have this inborn error of metabolism to develop high serum levels of Hcy. It is now thought that Hcy can cause direct damage to the endothelium prompting the atherogenic cascade described above. In addition, homocysteine promotes hypercoagulation of the blood leading to thrombosis. Hcy also promotes inflammation. Apparently Hcy can interfere with the release of nitric oxide by the endothelium thereby preventing vasodilation, the relaxation of the artery. There is also evidence that Hcy oxidizes LDL cholesterol which makes cholesterol even more dangerous. High Hcy may contribute to chronic disease in a more insidious way. People with elevated levels of Hcy may have a deficiency in the ability to perform methylating functions. Methylation of DNA plays a critical role in protecting DNA from damage. In fact, high Hcy has been implicated in such diverse conditions as Parkinson’s disease, Alzheimer’s disease, cognitive dysfunction, osteoporosis, and peripheral neuropathy. As mentioned above, high levels of homocysteine can be reduced easily and inexpensively with the B vitamins (vitamin B6, B12, and folic acid), betaine, and SAMe.
Fibrinogen is a protein that plays a critical role in clot formation. Fibrinogen is the direct precursor to fibrin, a coagulation protein that binds platelets together to form a blood clot. It is important to note that not all clot formation is bad. If we did not have the ability to clot, we could ‘bleed out’ with a minor cut. Clot formation is completely normal and necessary. It is when the atheroma or plaque that resides in the lining of an artery breaks or ruptures that the blood clot becomes deadly. A plaque ruptures, combines with fibrinogen which then releases fibrin. The fibrin forms scaffolding and releases peptides that draw blood platelets in the matrix. When this process occurs to stop a cut from bleeding it is a scab. When these blood clots form within the circulatory system they can become life threatening. A clot like this can cause a sudden and acute myocardial infarction (when it winds up in a coronary artery) or a devastating stroke (when the clot travels to the carotid arteries). The coagulation cascade is extremely complex and involves at least a dozen proteins, proteases, and enzymes. A defect in any one of those proteins leads to a disruption in healthy blood activity called hemostasis. Just as the body has the mechanisms to form blood clots, it also has the mechanisms to dissolve those clots. As we have seen, some of the blood clots or thrombi are pathogenic. It is important to prevent the clots from forming and when they do form, it is equally important that they be dissolved. The body dissolves blood clots with plasmin. Plasmin circulates in the blood in an inactive form. It binds to both fibrin and fibrinogen and becomes incorporated into the blood clot. Inactive tissue plasminogen activator (tPA) is released from vascular endothelial cells upon injury; it binds to fibrin and fibrinogen and is consequently activated. Inactive prourokinase is also released by the endothelium of the excretory ducts and its role (when converted to urokinase) is to dissolve clots that deposit in those ducts. Following the release of plasminogen and plasmin, they are rapidly inactivated by their respective inactivators. There have been at least four inactivators identified the two most important of which are plasminogen activator-inhibitors type I and type II (PAI-I) and (PAI-II).
The pharmaceutical industry has not really developed an effective treatment for elevated fibrinogen. It is a delicate balance. Too much fibrinogen and the risk is high blood viscosity, hypercoagulation and a predisposition to throw a clot. Too little fibrinogen and there is a risk of hemorrhage. Coumadin® (warfarin), the current medical therapy, is often not a viable choice since bleeding times must be monitored closely. There is always the risk the coagulation pathway tips in the wrong direction leading to too much ‘blood thinning’ which can lead to internal bleeding or hemorrhagic stroke. In addition, the anti-coagulant effects of Coumadin® can be negated by foods containing vitamin K. The drug company encourages patients taking the drug to stay away from dark, leafy, green vegetables. As a nutritionist, I object to this misrepresentation which can lead to nutrient deficiencies. People on Coumadin® can and should consume dark, leafy green vegetables on a consistent basis (not erratic) basis. The physician can and should adjust the dosage of the drug in accordance with patients’ dietary habits.
A recent study actually found that frequent consumption of nuts and seeds reduced inflammatory markers of inflammation and decreased fibrinogen levels. There are some novel proteolytic enzymes that seem to have the ability to digest fibrinogen and reduce the risk of clots. The interesting thing about these plant derived enzymes is they do not carry the risk of hemorrhage or hypercoagulation. One of the most interesting of these enzymes is called Nattokinase (Natto). It is an enzyme that is extracted from a traditional Japanese food, natto. Natto is a cheese like food made from fermented soybeans and has been part of the traditional Japanese diet for 1,000 years. Natto closely resembles plasmin and therefore it acts directly on the fibrin clot . In addition, it enhances the body’s ability to produce prourokinase, tPA, and PIA-1. In an animal model, Natto was shown to suppress initial thickening after vascular injury, as a result of its ability to inhibit thrombi formation. In summary, it replicates the action of the body’s natural fibrinolytic agent plasmin. There are a number of published studies demonstrating the efficacy of Natto. The beauty of Natto is it can be safely used long term without the risk of hemorrhage or excess bleeding. The plant proteolytic enzymes bromelain, papain, and rutin have a long history of use, particularly in Germany, as agents that effectively reduce the inflammation that accompanies inflammatory and osteoarthritis. The ability of these enzymes to ‘lyse’ or dissolve inflammatory proteins systemically account for their therapeutic properties. Bromelain in particular has also been shown to inhibit platelet aggregation. These very same novel plant enzymes literally dissolve the unwanted proteins that contribute to hypercoagulation.
The various cholesterol fractions can be confusing. With advances in molecular biochemistry, scientists are able to fractionate the various lipid fractions even further. The major protein component of HDL cholesterol is apolipoprotein A (apoA). LDL’s major protein component is apolipoprotein B (apoB). Lipoprotein (a) [Lp(a)] is a distinct serum lipoprotein composed of apoB and apolipoprotein ‘small’ a. Since apoB is part of LDL cholesterol, it is less confusing to think of lp(a) as LDL plus apolipoprotein (a). Lp(a) is an extremely atherogenic fraction that appears to be genetic and quite resistant to treatment. Lp(a) is prothrombotic. Its’ putative mechanism of action is that it interferes with blood protein factors that are involved in the dissolving of blood clots. There are still many people with normal cholesterol and normal CRP who have an acute event such as a heart attack or stroke. Often these individuals have high levels of lp(a) and therefore are at much higher risk of ‘throwing a clot’. They don’t know they are walking time bombs because lp(a) is not a risk factor that is routinely tested for. Perhaps it should be. Lp(a) also appears to be the factor that differentiates patients who experience rapid progression of atherosclerosis to occlusion from patients who do not progress so quickly . Linus Pauling had an interesting theory about lp(a) and based upon that theory, very high doses of vitamin C would neutralize the atherogenic properties of lp(a). When high doses of vitamin C are present in the bloodstream there is “an acceleration of wound healing and other cell-repair mechanisms, the strengthening of the extracellular matrix (e.g., in blood vessels), and the prevention of lipid peroxidation” . The problem has always been how can one take in high doses of vitamin C without incurring GI distress? Lp(a) is prothrombotic because it actually interferes with those factors in the clotting cascade that are responsible for lysing a thrombus or fibrin clot. Therefore NK would be beneficial for people with high levels of lp(a). The proteolytic enzymes bromelain, papain, and rutin would also be protective against high levels of lp(a).
C Reactive Protein (CRP)
In the late 1990’s, cardiologists were baffled by the fact that 50% of the patients entering the emergency room with an acute myocardial infarction (MI) had no identifiable risk factors. People with low and normal levels of cholesterol were developing atherosclerosis. There had to be something else going on. The theory that atherosclerosis is an inflammatory disease now seems old hat, but this theory was not published in peer review journals until 1999. A group of cardiologists working in the Boston area began to identify novel risk factors for systemic atherosclerosis. Paul Ridker, MD was the first to develop a ‘high sensitivity’ or ‘cardiac specific’ test for CRP. Numerous studies have now shown a strong correlation between high CRP scores as a predictor of future coronary events. Cardiovascular disease is the number one killer worldwide. And yet conventional algorithms that predict future cardiovascular events such as the one from the Framingham Heart Study fail to identify a large percentage of individuals at risk. Although further research is needed, it appears CRP is the leading candidate that will identify those at risk individuals.
The mainstay of treatment for high cholesterol, (particularly elevated LDL cholesterol) is a category of pharmaceutical drugs colloquially referred to as statin drugs. These include Zocor®, Mevacor®, Lipitor®, and Pravachol®. Most of the cholesterol in the bloodstream is synthesized in the liver. The production of cholesterol is regulated by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Actually, the rate limiting step in cholesterol production is that very enzyme (HMG CoA) reductase. In a healthy person with normal or low cholesterol levels, if the person eats a lot of cholesterol, the activity of this enzyme will slow down and less cholesterol will be synthesized in the liver. The reverse is also true. If a person eats little or no cholesterol, activity of HMG CoA reductase goes into overdrive and the liver becomes a cholesterol producing factory. Statin drugs are HMG CoA reductase inhibitors and lower LDL cholesterol by effectively shutting down the activity of the enzyme that tells the liver to produce cholesterol. In addition to lowering LDL cholesterol, statins have been shown to prevent the first incidence of acute heart attacks and strokes, as well as prolong the survival of patients who have already experienced an acute coronary event or who have had a vascular interventional procedure such as a stent, coronary bypass, or endarterectomy. Many cardiologists suggest these statins also reduce inflammation and lower CRP. However the clinical trials to confirm this hypothesis are only now getting underway. Researchers at Brigham and Women’s Hospital in Boston are recruiting patients with normal or low cholesterol and high CRP to see if the statins do in fact lower CRP. Ridker himself states, “CRP has been demonstrated to actively contribute to all stages of atherogenesis, participating in endothelial dysfunction, atherosclerotic-plaque formation, plaque maturation, plaque destabilization and eventual rupture”. He suggests the pharmaceutical industry might try to develop a drug that lowers CRP.
In the meantime, there are proactive steps people can take to lower systemic inflammation. Recurrent throughout the literature is the notion that obesity, (particularly central obesity) and insulin insensitivity contribute to inflammation and therefore elevate the risk of systemic atherosclerosis. The connection between insulin insensitivity and inflammation is supported by a recent report in the literature that Metformin reduces C-Reactive Protein in overweight patients with diabetes. Metformin is an oral diabetic agent that improves insulin sensitivity by making insulin receptors more sensitive to insulin. Therefore Metformin is important in the armamentarium against atherosclerosis.
Any lifestyle changes directed at glucose and insulin control would aid in reducing CRP. A whole foods diet rich in fruits, vegetables, whole grains, fiber, and omega 3 fatty acids is a diet that lowers inflammation. A diet that avoids saturated fats (fats from animal sources) and trans fatty acids (partially hydrogenated oils) is also important. Nut oils, olive oil, coconut oil are much better choices. A diet high in refined carbohydrates (highly processed, sugar laden foods) should be avoided. Some nutritionists speak in terms of a low carbohydrate diet or a diet rich in foods that have a low glycemic index. This is inaccurate advice in my opinion and leads to confusion and diet failure amongst the public. The glycemic index is an artificial tool food scientists use to calculate how quickly a food will raise blood glucose in a laboratory setting. The glycemic load is a much more important number to be aware of. The glycemic load represents a number that reflects how much blood sugar is raised when a person eats a particular food. It considers the fiber content of a specific food which affects how that food is metabolized. Raw carrots have a high glycemic index; however they have a reasonable glycemic load. I’ve never seen anyone become obese by consuming too many carrots. I’ve seen them turn orange, but not obese. [Ed.- For more information concerning the glycemic load of most foods go the website www.glycemicindex.com] Regular daily aerobic exercise can improve insulin sensitivity, raise HDL cholesterol, help maintain weight, which in turn will lower the risk of atherosclerosis.
The effectiveness of lifestyle changes in reducing inflammation and CRP can be enhanced by carefully selected nutritional supplements. Dehydroepiandrosterone (DHEA) has shown to be an excellent agent at reducing systemic inflammation which is “measurable via the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and the anti-inflammatory cytokine IL-10. DHEA has also proven to be an effective way to reduce central obesity. The omega 3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) contained in fish oil have been subject of countless clinical and epidemiological studies since the 1970’s. The interest in these omega 3 fatty acids is a direct result of the observation that Greenland Eskimos had noticeably low rates of coronary heart disease. Most of the early clinical trials however, focused on the ability of the omega 3 fatty acids to reduce inflammation, particularly the inflammation of rheumatoid arthritis . The omega 3 essential fatty acids proved to be extremely effective at reducing the systemic inflammation in both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) . In retrospect, it is logical that an agent that successfully reduces systemic inflammation would also be beneficial in atherosclerosis. After all, atherosclerosis is an inflammatory disease. The cardioprotective properties of the omega 3 fatty acids have many putative mechanisms of action. The essential fatty acids have antiarrhythmic properties, improve endothelial function, demonstrate anti-inflammatory action, and lower serum triglycerides . The omega 3 fatty acids may also play into the heart disease equation by controlling another risk factor that is expanded below – the metabolic syndrome . Researchers from the University of Virginia were able to demonstrate the low incidence of insulin resistance, metabolic syndrome, and diabetes in Alaskan Eskimos when compared to American Indians can be explained by the Eskimos high consumption of fish, particularly fish high in omega 3 fatty acids..
An anti-inflammatory diet
Diet is a contributor to chronic inflammation. It is not necessary to go on a low fat diet to reduce inflammation. It simply becomes very important to select the right type of fats. The inflammatory cascade begins with metabolic pathway controlled by the cyclo-oxygenase enzyme (COX). The products of the COX enzymes are a series of eicosanoids that consist of prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs). These eicosanoids are mediators of inflammation. The COX enzyme acts upon the fatty acids in the cell membrane. The primary dietary fatty acid that provides the substrate for the metabolic pathway is an omega-6 fatty, arachidonic acid (AA). If the AA is replaced by omega-3 fatty acids, the family of eicosanoids produced by the COX enzymes is far less inflammatory and has many health benefits. Foods high in AA include saturated fat, organ meats, and egg yolks. Foods that increase omega 3 fatty acids in the body are cold water, deep sea fish, nuts and seeds. As detailed above, fish oil supplementation is also extremely effective. Foods made with partially hydrogenated vegetable oils (trans fatty acids) are as atherogenic as saturated fat. Trans fatty acids do not exist in nature and are more pro inflammatory than AA. This increase in omega 3 fatty acids is proving far more important as research continues into obesity/overweight/ and insulin resistance. A group looking at overweight adolescents found that those with the highest plasma concentration of omega 3 fatty acids were less likely to develop insulin resistance and had lower levels of systemic inflammation.
Insulin resistance, inflammation, and atherosclerosis
Insulin resistance contributes to systemic inflammation and may be one of the most important factors in preventing accelerated atherosclerosis. One assumes everyone with insulin resistance is overweight or obese. This is not true. Normal weight individuals can be insulin resistant and overweight individuals can have normal insulin/glucose metabolism. Those individuals who are obese or overweight but remain insulin sensitive are not at increased risk of developing cardiovascular disease. It is more likely to find insulin resistance amongst overweight or obese individuals. I’m not sure if scientists know at this point which comes first. Does insulin resistance cause abdominal obesity or does abdominal obesity cause insulin resistance? Either way, dysregulation of insulin contributes to systemic inflammation, and that inflammation causes endothelial dysfunction, vascular injury, and atherosclerosis. Insulin resistance and inflammation contribute to atherosclerosis primarily by increasing oxidative stress throughout the body. Oxidized LDL (oxLDL) cholesterol is a more rapidly deposited in the endothelium and begins the process of vascular damage. Therefore the role of anti-oxidants is extremely important. It is also the production of advanced glycation end products (AGEs) that amplifies this process of vascular injury. Anything that limits the production of AGEs would be an extremely effective adjunct for preventing atherosclerosis. Aminoguanidine is the first pharmaceutical preparation to be approved for inhibiting AGEs. It has been shown to improve the exercise ability of people with peripheral vascular disease.
It seems obvious that anti-oxidants would also be beneficial. The problem is one cannot rely on the few published, peer review clinical or prospective trials. There is a published study that describes a beneficial effect of supplementation with vitamin C and E prior to the ingestion of a high fat meal. Taking the vitamin supplements prevented transient endothelial dysfunction. There is a fair amount of evidence about the benefits of resveratrol as an anti-oxidant and an anti-inflammatory. Resveratrol is the polyphenolic active ingredient in red wine and red grape skins. It is probably the single most beneficial and versatile phytochemicals that has yet to come to light. Resveratrol has anti-inflammatory, cardio protective, and cancer chemopreventive properties. It is not often that one plant compound has such protective qualities in so many areas.
I hope this treatise has given you a lot to chew on, literally! It is apparent that a healthy heart and a healthy vascular system can be achieved if only one can remain inspired and motivated to attend to the important risk factors. There are many agents that can play a critical role in heart health. Knowledge is power. We need to use these agents in addition to making healthy lifestyle choices. In my experience, making healthy food choices is the easy part. Now if I could only invent a pill that would take the place of exercise!
1 Enos WF, Holmes RH, Beyer J. Coronary disease among United States soldiers killed in action in Korea: preliminary report. JAMA. 1953;152:1090-1093.
2 McNamara JJ, Molot MA, Stremple JF, et al. Coronary artery disease in combat casualties in Vietnam. JAMA. 1971; 216:1185-1187.
3 Biggerstaff KD, Wooten JS. Understanding lipoproteins as transporters of cholesterol and other lipids. Adv Physiol Edu. 2004;28:105-6.
4 Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med. 1999; 340(2):115-126.
5 Liuzzo G, Giubilato G, Pinnelli M. T cells and cytokines in atherogensis. Lupus. 2005; 14(9):732-5.
6 Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109[suppl III]:III-27-III-32.
7 Luscher TF, Barton M. Biology of the endothelium. Clin Cardio. 1997;20(suppl II):II-3-II10.
8 Kinlay S, Libby P, Ganz P. Endothelial function and coronary artery disease. Curr Opin Lipidol. 2001;12:383-389.
9 Drexler H. Factors involved in the maintenance of endothelial function. Am J Cardiol. 1998;82:3S-4S
10 Kinlay S, Behrendt D, Wainstain M, et al. The role of endothelin-1 in the constriction of human atherosclerotic coronary arteries. Circulation. 2001;104:1114-1118.
11 Ross R. Athersclerosis: an inflammatory disease. N Engl J Med. 1999;340:115-126.
12 Holman RL, McGill HC Jr, Strong JP, Geer JC. The natural history of atherosclerosis. The early aortic lesions as seen in New Orleans in the middle of the 20th century. Am J Pathol 1958;2:209-35
13 Zhao GF, Seng JJ, Ahzng H, et al. Effects of oxidized low density lipoprotein on the growth of human artery smooth muscle cells. Chin Med J (Engl). 2005;118(23):1973-8.
14 Grassi M, Assanelli D, Mozzini, C, et al. Modeling premature occurrence of acute coronary syndrome with atherogenic and thrombogenic risk factors and gene markers in extended families. J Thromb Haemost. 2005;3(10):2238-44.
16 Gori AM, Corsi AM, Fedi S, et al. A proinflammatory state is associated with hyperhomocyteinemia in the elderly. Am J Clin Nutr. 2005;82(2):335-41.
17 Isobe C, Murata T, Sato C, et al. Increase of total homocysteine concentration in cerebrospinal fluid in patients with Alzheimer’s disease and Parkinson’s disease. Life Sci. 2005;77(15):1836-43.
18 Irizarry MC, Gurol ME, Raju S, et al. Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease. Neurology. 2005;65(9):1402-8.
19 Teunissen CE, van Boxtel MP, Jolles J, et al. Homocysteine in relation to cognitive performance in pathological and non-pathological conditions. Clin Chem Lab Med. 2005;43(10):1089-95.
20 Gjesdal CG, Vollset SE, Ueland PM, et al. Plasma total homocysteine level and bone mineral density: the hordaland homocysteine study. Arch Intern Med. 2006;166(1):88-94.
21 Cohen JA, Jeffers BW, Stabler S, et al. Auton Neurosci. 2001;87(2-3):268-73.
22 Cheuk BL, Cheung GC, Lau SS, et al. Plasma fibrinogen level: an independent risk factor for long-term survival in Chinese patients with peripheral artery disease? World J Surg. 2005;29(10):1263-7.
23 Jiang R, Jacobs DR Jr, Mayer-Davis, E, et al. Nut and Seed Consumption and Inflammatory Markers in the Multi-Ethnic Study of Atherosclerosis. Am J Epidemiol. 2005; [Epub ahead of print]
24 Fujita M, Nomura K, Hong K, et al. Purification and characterization of a strong fibrinolytic enzyme (nattakinase) in the vegetable cheese natta, a popular soybean fermented food in Japan. Biochem Biophys Res Commun. 1993; 197(3):1340-7.
25 Suzuki Y, Kondo K, Ichise H, et al. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition. 2003; 19(3):261-4.
26 Akhtar NM, Naseer R, Farooqi AZ, et al. Oral enzyme combination versus diclofenac in the treatment of osteoarthritis of the knee – a double-blind prospective randomized study. Clin Rheumatol. 2004; 23(5):410-5.
27 Glaser D, Hilberg T, The influence of bromelain on platelet count and platelet activity in vitro. Platelets. 2006; 17(1):37-41.
28 Caten C, Novello M, Lapenna R, et al. New risk factors for atherosclerosis in hypertension: focus on the prothromotic state and lipoprotein (a). J Hypertens. 2005;23(9):1617-31.
29 Nauk M, Marz W, Wielaud H. Is lipoprotein (a) cholesterol a significant indicator of cardiovascular risk? Clin Chem. 2000; 46:436-7.
30 Terres W, Tatsis E, Pfalzer B, et al. Rapid angiographic progression of coronary artery disease in patients with elevated lipoprotein (a). Circulation. 1995; 91(4):948-50.
31 Rath M, Pauling L. Hypothesis: lipoprotein (a) is a surrogate for ascorbate. Proc Natl Acad Sci USA. 1990; 87(16):6204-7.
32 Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein (a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA. 2001;285(19):2481-5.
33 Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med. 2005;2(1):29-36.
34 Verma S, Szmitko PE, Ridker PM. C-reactive protein comes of age. Nat Clin Pract Cardiovasc Med. 2005;2(1):29-36.
35 Carter AM, Bennett CE, Bostock JA, Grant PJ. Metformin reduces C-reactive protein but not complement factor C3 in overweight patients with Type 2 diabetes mellitus. Diabet Med. 2005’22(9):1282-4
36 Hillebrand F, Pape HC, Hoevel P, et al. The importance of systemic cytokines in the pathogenesis of polymicrobial sepsis and dehydroepiandrosterone treatment in a rodent model. Shock. 2003;20(4):338-46.
37 Villareal DT, Holloszy JO. Effect of DHEA on abdominal fat and insulin action in elderly women and men: a randomized controlled trial. JAMA. 2004;292(18):2243-8.
38 Das UN. Beneficial effect(s) of n-3 fatty acids in cardiovascular diseases: but, why and how? Prostaglandins Leukot Essent Fatty Acids. 2000; 63(6):351-62.
39 Skoldstam L, Borjesson O, Kjallman A, et al. Effect of six months of fish oil supplementation in stable rheumatoid arthritis – a double-blind controlled study. Scand J Rheumatol. 1992;21:178-85.
40 Geusens P, Wouters C, Nijs J, et al. Long-term effect of omega-3 supplementation in active rheumatoid arthritis – a 12 month, double-blind controlled study. Arthritis Rheum 1994;37:824-29.
41 Walton AJ, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis. 1991; 50:463-66.
42 Carroll DN, Roth MT. Evidence for the cardioprotective effects of omega-3 fatty acids. Ann Pharmacother. 2002; 36(12):1950-6.
43 Ebbesson SO, Risica PM, Ebbesson LO, et al. Omega-3 fatty acids improve glucose tolerance and components of the metabolic syndrome in Alaskan Eskimos: the Alaska Siberian project. Int J Circumpolar Health. 2005; 64(4):396-408.
44 Adam O, Beringer C, et al. Anti-inflammatory effects of a low arachidonic acid diet and fish oil in patients with rheumatoid arthritis. Rheumtol Int. 2003; 23(1):27-33.
45 Skoldstam L, Hagfors L, Johansson G. Mediterrean diet intervention in rheumatoid arthritis. Ann Rheum Dis. 2003; 62(3):193-5.
46 Mozaffarian D, Pischon T, Willett WC, et al. Dietary intake of trans fatty acids and systemic inflammation in women. Am J Clin Nutr. 2004; 79(4):606-12.
47 Baer DJ, Judd JT, Clevidence, BA, et al. Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. Am J Clin Nutr. 2004; 79(6):969-73.
48 Wu D. Modulation of immune and inflammatory responses by dietary lipids. Curr Opin Lipidol. 2004; 15(1):43-7.
49 Klein-Platat C, Drai J, Oujaa M, et al. Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. Am J Clin Nutr. 2005; 82(6):1151-2.
50 Haffner SM. Insulin resistance, inflammation, and the prediabetic state. Am J Cardiol. 2003; 18; 92(4A):18j-26J.
51 Reaven G. All obese individuals are not created equal: insulin resistance is the major determinant of cardiovascular disease in overweight/obese individuals. Diab Vasc Dis Res. 2005; 2(3):105-12.
52 Plotnick GD, Corretti MC, Vogel RA. Effect of antioxidant vitamins on the transient impairment of endothelium-dependent brachial artery vasoactivity following a single high fat meal. JAMA. 1997; 278(14):1069-70.
53 Biondi-Zoccai GG, Abbate S, Liuzzo G, et al. Atherothrobosis, Inflammation and Diabetes. JACCl. 2003; 41(7):1071-7.
54 Bucala R, Makita Z, Koschinsky T, et al. Lipid advanced glycosylation: pathway for lipid oxidation in vivo. Proc Nat’l Acad Sci USA. 1993; 90:6434-8.
55 Gotto AM Jr. Antioxidants, Statins and Atherosclerosis. JACC. 2003; 41(7):1205-10.
56 Srivastava R, Ratheesh A, Gude RK, et al. Resveratrol inhibits type II phosphatidylinositol 4-kinase: a key component in pathways of phosphoinositide turn over. Biochem Pharmacol. 2005;70(7):1048-55.