LDL (or low-density lipoprotein) is often referred to as "bad cholesterol." LDL, however, is not cholesterol. LDL is combination of a fat and a protein that acts as a carrier for cholesterol and fats in the blood stream. Cholesterol, on the other hand, is a fat-like steroid alcohol. Both LDL and cholesterol participate in the atherosclerosis process.
High LDL levels are considered more dangerous than high total cholesterol. Not only is the amount of LDL in the bloodstream important, so is its size. LDL comes in three sizes. The smallest size is the most troublesome. Small LDLs penetrate the artery wall easier than large LDLs; so they are more easily trapped in the artery wall and participate in plaque buildup. The small, dense LDLs are more vulnerable to oxidation than larger LDL particles. When LDL is oxidized, it is more dangerous. Oxidation of LDL renders it "sticky" and facilitates its deposition on the internal lining of blood vessels. Oxidized LDL initiates and contributes to the development of atherosclerosis through the following steps (Lau 2001):
- By direct cytotoxic actions on endothelial cells. (This induces endothelial injury and contributes to the pathogenesis of atherosclerosis).
- By increasing chemotactic stimulus for monocytes. (These monocytes are attracted to the arterial intima where atherogenesis begins. Monocytes then differentiate into macrophages.)
- By transforming macrophages into foam cells. (Production of foam cells is a starting point in atherogenesis but their presence is also typical for advanced atherosclerotic lesions, which are prone to rupture; producing clinical complications such as myocardial infarction and stroke) (Bobkova et al. 2003).
- By enhancing the proliferation of various cell types, e.g., endothelial cells, monocytes, and smooth muscle cells. (Proliferation and migration of cells leads to a thickening within the intima (innermost) layer and a marked occlusion of the vessel).
Homocysteine is a significant factor in the oxidation process that results in atherosclerosis. Homocysteine damages the artery and then oxidizes cholesterol before cholesterol infiltrates the vessel. Hemochromatosis (iron overload) can also contribute to the oxidation of cholesterol. (Free iron oxidizes LDL, increasing the damage imposed upon the heart and vascular system through promotion of free radicals.)
Although oxidized LDL plays an important role in the etiology of arterial disease, evidence shows that even if oxidation of LDL is prevented, it might still be dangerous. The binding of C-reactive protein to non-oxidized LDL enhances complement activation (complement plays a pathogenetic role in promoting lesion progression) (Bhakdi et al. 1999). Elevated LDL, whether it is oxidized or not, can alter the ability of endothelial cells to release nitric oxide. Nitric oxide allows the arteries of the cardiovascular system to properly dilate (Feron et al. 1999; Sheehan 2003).
Guidelines recommend getting LDL below 100, but many are uncertain that lower is still better. One study targeted a level of 80 and concluded that the more rigorous treatment aggressively stopped arterial clogging (CTV 2003). Other findings showed benefits to reducing LDL in individuals with average serum cholesterol levels and no evidence of coronary heart disease (Marais 1998).Abnormal Platelet Aggregation: An Important Player in Atherosclerosis
Platelets are small blood elements, but they play a major role in cardiovascular health. The primary role of platelets is to prevent bleeding by ‘clotting' leaks in the vessel wall. Blood vessels with smooth interior walls enable platelets to flow over their surface. When a blood vessel is damaged, exposing the underlying collagen, the platelets adhere to cover the gap. Activated platelets do more than form a plug. They release potent vasoconstrictors such as serotonin and the powerful platelet aggregator thromboxane A2. Though this action is desirable in response to injury, it can have deleterious effects. Abnormal platelet stickiness increases atherosclerosis and further narrows the internal diameter of the artery, factors that predispose one to strokes and heart attacks (Braly 1985).Fibrinogen
Fibrinogen is a blood protein that controls coagulation. In good health there are normal levels of fibrinogen and normal coagulation. When fibrinogen levels rise above normal there is an increased chance of abnormal blood clotting. If fibrinogen levels decrease below normal, a hemorrhage can result. Although the reference range used by most laboratories is 150-460 mg/dL, it is crucial to keep serum fibrinogen under 300 mg/dL, a level considered safe.
The coagulation of blood depends upon clotting factors that are activated following injury. A series of reactions produces a clot by converting fibrinogen to fibrin (a network of protein fibers that can trap blood cells and platelets), thus plugging the leak (Whiting 1989; Seeley et al. 1991; Kohler et al. 2000).
Fibrin provides a scaffold along which cells migrate and which can bind fibronectin. This stimulates cell migration, monocyte adhesion, and smooth muscle proliferation, further occluding the vessel. In advanced plaque, fibrin may also be involved in the tight binding of LDL-C and the accumulation of lipids (Smith 1986; Koenig 1999a).
Plaque is highly susceptible to breakage and clot formation. About 700,000 heart attacks and stroke deaths occur in the United States each year as a result of a blood clot obstructing the delivery of blood to the heart or brain. People with high levels of fibrinogen are more than twice as likely to die of a heart attack, but also from stroke (Wilhelmsen et al. 1984; Packard et al. 2000). Fibrinogen is a predictor of stroke, but the odds worsen with high blood pressure (Bots et al. 2002).
Fibrinogen promotes platelet aggregation (Koenig 1999b). Fibrinogen deposition at the vessel wall promotes platelet adhesion during ischemia (Massberg et al. 1999). Platelets are essential in sealing all vascular injuries. When the interior of the vessel is smooth, platelets are not activated; however, when traumatized, platelets are activated to plug the wound. Activated platelets release serotonin (a vasoconstrictor) and the platelet aggregator thromboxane A2, furthering clot formation (Braly 1985; Smith 1986; Ernst et al. 1993).
The Life Extension Foundation was the first research group to recognize the importance of assessing fibrinogen as an independent risk factor for cardiovascular disease, which was later corroborated (Ma et al. 1999). Individuals having heart attacks had significantly higher fibrinogen levels compared to healthy individuals. Several studies have shown a stronger association between cardiovascular deaths and fibrinogen levels than with cholesterol levels. Higher baseline levels of fibrinogen are predictive of a heart attack and the likelihood of sudden cardiac death. Coronary risk is low among patients with low fibrinogen concentrations despite increased serum cholesterol levels (Thompson 1995). Fibrinogen is directly associated with the risk of myocardial infarction (Acevedo et al. 2002; Bots et al. 2002; GSDL 2002).
High levels of homocysteine are toxic to the cardiovascular system. Part of this toxicity may result from the ability of homocysteine to block the natural breakdown of fibrinogen-derived fibrin by inhibiting the production of tissue plasminogen activator (t-PA) (Midorikawa et al. 2000). If fibrin cannot be digested by the enzymatic action of plasminogen, fibrin-containing clots accumulate, contributing to an increased incidence of heart attack and formation of larger plaques inside the arteries.
The Therapeutic section describes products with fibrinolytic and anti-platelet aggregating activity, such as aspirin, bromelain, curcumin, essential fatty acids, garlic, ginger, ginkgo biloba, green tea, gugulipid, niacin, pantethine, policosanol, proanthocyanidins, vitamin A, beta-carotene, vitamin C, and vitamin E. A novel drug approach to reduce excess fibrinogen is to take 400 mg of pentoxifylline twice daily. Vitamin C has been shown to break down excess fibrinogen (Bordia 1980).Inflammation
Typically, the risk of developing heart disease is assessed by monitoring plasma levels of cholesterol and by routinely checking for high blood pressure. Newer risk factors including C-reactive protein (CRP) and fibrinogen are markers of systemic inflammation.
Fibrinogen and CRP are produced in the liver by pro-inflammatory cytokines called interleukin-1b, interleukin-6, and tumor necrosis factor alpha (TNF-a) (Ridker et al. 2000). Injury to the inner lining of the arterial vessels, or arteriosclerosis, plays an important role in the development of atherosclerosis, which is characterized by the build up of fatty deposits in the lining of arteries (Ader et al. 2002).
Research indicates that the presence in blood of indicators of inflammation are strong predictors for who will develop CHD or have a cardiac-related death (Lindahl et al. 2000; Packard et al. 2000; Radar 2000). CRP levels increase during systemic inflammation and tests to determine the levels of this protein in the blood can help assess the risk of cardiovascular disease. Some evidence suggests that blood levels of CRP may be a stronger predictor of heart disease than levels of LDL-C (Ridker et al. 2002). High levels of CRP have predicted future coronary events in patients with stable CHD. Studies have shown that high CRP levels predict the risk of future heart attack, stroke, peripheral arterial disease and vascular death in people that have no other signs of cardiovascular disease (Ridker 2001; Ridker et al. 2000; Kuller et al. 1996; Mendall et al. 2000; Ridker et al. 1998). High CRP has also been associated with increased vascular events in people with acute ischemic heart disease, stable angina, and a history of heart attack (Ridker 2001).
If a person has an intermediate risk of cardiovascular disease, the American Heart Association recommends that a CRP test can be useful in predicting a future cardiovascular event or stroke. This information can help direct further evaluation and therapy. A person at high risk or who has established heart disease or stroke should be treated intensively regardless of CRP levels.
CRP rises several hundred-fold after tissue injury, but stays relatively stable in the absence of inflammation. Elevated CRP levels indicate a low-grade inflammation, including vascular disease (Pasceri et al. 2000). Responses to rising levels of CRP may include disruption of existing plaque resulting in a blood clot. There is significant improvement in predicting cardiac health when models include CRP testing. CRP levels can predict future coronary events in healthy individuals. Increased monocytes (white blood cells critical in early plaque development) and macrophages (mononuclear phagocytic cells capable of scavenging and ingesting dead tissue and degenerated cells) are present in atherosclerosis, particularly at points of plaque rupture. It appears that CRP and several other inflammatory markers may be elevated many years prior to a coronary event.
CRP acts upon blood vessels to activate adhesion molecules in endothelial cells: the intercellular adhesion molecule (ICAM-1) and the vascular cell adhesion molecule (VCAM-1). VCAM-1 is an early molecular marker of lesion-prone areas in response to experimental hypercholesterolemia. In humans, ICAM-1 and VCAM-I expression is increased in the endothelium of atherosclerotic plaque. CRP is involved in the inflammatory process and may be a target for the treatment of atherosclerosis (Pasceri et al. 2000; Biomedical Science 2001; Alvaro-Gonzalez et al. 2002).
CRP affects the activity of LDL, which contributes to the process of increasing atherogenesis. The cycle begins as stranded LDL is taken up by macrophages, becomes engorged with fats, and develops into foam cells, which explode and discharge their fats into the blood vessel walls. This recruits more macrophages to clean up the mess and the cycle repeats. CRP readies the LDL for uptake by the macrophages, initiating the sequence (Braley 1985; Zwaka et al. 2001). Higher levels of CRP increase the risk of stroke, heart attack, and peripheral vascular disease (Rifai et al. 2001a, b). Stroke patients with the highest CRP levels were 2-3 times more likely to die within a year than patients with low levels (DiNapoli et al. 2001).
Persistent CRP elevation following coronary stent implantation is predictive of restenosis (Gottsauner-Wolf et al. 2000). Patients requiring restenosis had increased CRP levels for over four days following the implant procedure, although their baseline CRP was normal at the time of restenosis.
Many of the newer risk factors are not standardized, yet some laboratories use a CRP reference range of 0.24-1.69 mg/L. Test results can be artificially high if there has been recent tissue injury, infection, or inflammation.
CRP levels decline following, DHEA, fish oil, pravastatin, vitamin C, vitamin E, and vitamin K supplementation (see the Therapeutic sections of this protocol and others in this book). Many nutrients and herbs with anti-inflammatory properties may maintain low CRP levels. Because CRP reduces vitamins A, C, E, carotenoids, zinc, and selenium, supplementation with these nutrients may contribution to better cardiovascular health when CRP levels are high.
Adding fish to your diet can help lower your risk of heart disease. Research indicates that fish oil supplements (1 gram per day) reduced the risk of cardiac deaths after 6-8 months in people who had a prior heart attack. Patients that took fish oil supplements had a 45% lower death rate than those who did not (Marchioli et al. 2002).
Supplements such as highly concentrated DHA derived from fish oil and the adrenal hormone, DHEA, suppress excess production of some of the dangerous cytokines. Interleukin-6 increases the risk of heart attack, even without the participation of CRP, which is otherwise released by interleukin-6 (Rader 2000).Low Testosterone = Increased Heart Attack Risk
The influence of sex hormones, especially testosterone, on coronary artery disease in men has been relatively ignored (Brewer Science Library 2003). Men with CHD have lower concentrations of testosterone than men with normal heart health (Wu et al. 1993; Channer et al. 2003). Hypogonadism, characterized by low testosterone levels, is twice as common in men with heart disease (Brewer Science Library 2003). Low testosterone is associated with high LDL, low HDL, high triglycerides, and high blood pressure. Administration of testosterone dilates blood vessels (Channer et al. 2003), improves exercise tolerance, and reduces angina in men with CHD (English et al. 2000). Low testosterone in older men may promote atherosclerosis and explain the higher incidence of CHD.
Although heart disease continues to be an epidemic, you can take a number of steps to lower your risk of developing the condition. Besides checking your cholesterol and blood pressure, have your blood assayed for CRP, homocysteine, fibrinogen, and free testosterone. Exercise naturally lowers the risk of stroke by lowering blood pressure, but also lowers levels of CRP that are an important measure of systemic inflammation (Szymanski et al. 1994; Ford 2002).
The most recent study showed that low free testosterone is an independent risk factor for developing aggressive coronary artery disease (Philips et al. 2004).Continued
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