Cardiovascular Disease Protocol

SEDENTARY LIFESTYLE

Scientists believe that a properly planned exercise program may be the single greatest preventive measure against cardiovascular disease. However, it is extremely important that the individual and the activity be properly matched. Even among apparently fit persons, intense but sporadic exercise actually increases the risk of a fatal heart attack. A singles tennis match in an unprepared participant increases the risk of a heart attack sixfold.

The exercise level need not be unpleasantly aggressive to be beneficial. In the past, it was thought that an individual using exercise as a cardiovascular protective should select an activity that produced a state of breathlessness and participate in the action several times a week. It has now been determined that cardiovascular strengthening can be obtained from low intensity activity such as walking for 30 minutes a day. In fact, Dr. Shah Ebrahim, a British cardiologist, states that sexually active men, that is, those engaging in sex 3-4 times a week, reduce their risk of either a stroke or a heart attack by half. Some researchers question whether the mild to moderate energy expended during intercourse is the perk favoring a healthier cardiovascular system or if it is the mindset that drives the sexual act.

The New England Journal of Medicine reported findings relating to the impact of exercise upon 180 postmenopausal women (45-64 years) and 197 men (30-64 years) (Stefanick et al. 1998). The participants were divided into four groups: diet plus exercise, diet alone, exercise alone, and controls. LDL cholesterol levels in the diet-plus-exercise group were significantly reduced compared to the three remaining groups. It is also possible that exercise will alter the size of LDL particles. (Recall that abnormally small LDL particles are highly susceptible to oxidation and elude standard testing processes, misrepresenting the end results.)

Exercise reduces blood pressure and heart rate by influencing sympathetic neural and hormonal activity. As epinephrine (adrenaline) and norepinephrine levels are decreased, one's blood pressure and heart rate subsequently decrease (Katona et al. 1982; Duncan et al. 1985; Smith et al. 1989).

The statistics support that a regular exercise program reduces the risk of stroke, not only by lowering blood pressure, but also by increasing peripheral circulation and oxygen delivery. These findings were confirmed in a 10-year study, involving 14,101 Norwegian women (50-101 years of age). The results showed that the risk of dying from stroke declined as physical activity increased; the most active women had approximately 50% lower risk of death from stroke across all age groups (Ellekjaer et al. 2000).

Excessive fibrinogen, a risk factor for cardiovascular disease, is impacted by exercise. A study showed that exercise of moderate intensity increases fibrinolytic activity by increasing tissue plasminogen activators. (Tissue plasminogen activators break down fibrinogen, decreasing the risk of blood clot formation.) The substantiation of this process occurred when 14 sedentary men (average age 35) and 12 physically active men (average age 35) participated in exercise sessions in the morning and evening at 50% maximal oxygen consumption. The results of the study indicated that moderate-intensity exercise increased the activity of tissue plasminogen activators in both physically active and sedentary men, particularly during evening exercise. C-reactive protein, another of the newer risk factors for cardiovascular disease, also appears lowered by exercise (Szymanski et al. 1994; Ford 2002).

A sedentary lifestyle encourages weight gain and worsens Syndrome X, a condition of insulin resistance and compensatory hyperinsulinemia (insulin excess). Conversely, physical fitness increases cellular glucose responsiveness and decreases the amount of insulin secreted after a carbohydrate load (Challem et al. 2000). Exercise makes the vasculature less prone to damage when insulin levels are unstable. The vulnerabilities associated with Syndrome X, that is, diabetes, hypertension, hypertriglyceridemia, and suppressed HDL levels are often modifiable by exercise-induced weight loss.

If cardiovascular disease has manifested, a monitored exercise program can assist in recovery. Exercise helps in building a new network of blood vessels, naturally bypassing those impaired. The conclusion regarding exercise is that it is never too late to reap the benefits from a properly structured program. However, according to the Framingham Heart Study, only recent physical activity makes a significant difference (Sherman et al. 1999). Exercise undertaken earlier in life showed no sustained cardioprotection.

Beneficial as physical activity is, even low-intensity exercise can be a harbinger of free radicals; overexercising can generate enough free radicals to damage the DNA in white blood cells. The remedy is to provide the system with adequate amounts of antioxidants before engaging in physical activity. Also, sweating during exercise can drastically deplete minerals. This phenomenon likely contributes to the numbers of sudden deaths occurring among athletes and joggers. Lost body fluids and minerals should be replaced immediately.

GUM DISEASE

Researchers are examining the role of gum disease in the genesis and progression of heart disease. The inflammatory process, observed in the lining of atherosclerotic blood vessels, appears to be paralleling chronic inflammation observed in periodontal disease. The findings reported in the American Journal of Epidemiology showed that fibrinogen and C-reactive protein (coagulability and inflammatory markers) are increased in individuals with periodontal disease (Wu et al. 2000). Dr. Wu and colleagues at State University of New York reported that gum disease might also be related to hypercholesterolemia, although a weaker link is found between elevated cholesterol and gum disease than for the elevations in CRP and fibrinogen.

Bleeding, red, swollen gums are depictive of gingivitis, a condition of inflammation and bone deterioration promulgated by bacteria. The American Academy of Periodontology recently launched a media story showing that people with periodontal disease are 200-300% more likely to experience a heart attack than those with healthy gums. Allowing for multiple cardiac risk factors, the researchers concluded that gum disease was a greater risk for cardiovascular disease than hypertension (Genco 1997).

A pilot study (involving 38 heart attack patients matched to a comparable group of 38 people without known heart disease) showed a dramatic correlation between periodontal disease, CRP, and cardiac health: 85% of cardiac patients presented with gum disease compared to only 29% in the control group. Not only did the heart attack patients with periodontal disease have higher levels of CRP than those without gum disease, the CRP levels were directly related to the severity of the oral condition (Medscape Wire 2000) (to read about the risks imposed by high levels of CRP, please turn to the Newer Risk Factors section appearing in this protocol).

Should the gums be pulling away from the teeth and appear red, swollen, or tender, seek immediate dental care. Other red flags are gums that bleed while brushing, bad breath, or a discharge of pus. Turn to the Calcium, Coenzyme Q10, and Vitamin C subsections in the Therapeutic section to learn about maintaining healthy gum tissue and avoiding periodontal disease.

THYROID DISEASE (HYPO- AND HYPERTHYROIDISM)

Seldom considered but often the source of disease, the thyroid gland (a member of the endocrine system) should be evaluated in all cardiac patients. A healthy thyroid gland benefits the heart by modulating basal metabolic rate, improving one's mindset, lowering cholesterol and homocysteine levels, and regulating one's heartbeat and circulation. As the following dialog will exemplify, disease states are common when either over- or underperformance of an organ occurs.

Hypothyroidism
Researchers became keenly aware of the importance of a healthy thyroid gland after assessing the homocysteine and cholesterol levels in 7000 individuals from the general U.S. population (Morris et al. 2001). After subdividing test participants into two groups (those with hypothyroidism and those with normal thyroid function), researchers realized that about two-thirds of those diagnosed with hypothyroidism had cholesterol levels nearly 4 times higher than normal. Those who tested positive for hypothyroidism were more likely to be white, female, and "slightly older." Interestingly, an increase in plasma thyroxine concentrations (an iodine-containing hormone secreted by the thyroid gland with the chief function of increasing the rate of cell metabolism) typically precedes reductions in plasma cholesterol levels.

Approximately 50% of individuals thyroid-impaired also had high homocysteine levels compared to only 18% with a healthy gland. Researchers determined that about 90% of hypothyroid subjects in the U.S. population are either hyperhomocysteinemic or hypercholesterolemic; in contrast, only 31% of individuals with normal thyroid function have similar physical complaints (Morris et al. 2001).

The age groups affected by poor thyroid performance and cardiovascular disease are widespread. For example, clinicians examining a group of heart attack victims younger than 40 years of age found two common abnormalities: (1) elevations in serum cholesterol levels and (2) reductions in basal metabolic rate.

A 5-year study involving 347 patients (reported in the Journal of the American Geriatric Society) evaluated the effects of thyroid therapy upon atherosclerosis in a subset of the population 54.7-64.5 years old (Wren 1968): 132 of the individuals had experienced heart attacks, strokes, angina pectoris, or disruption in peripheral circulation; the remaining 215 participants were asymptomatic but were considered high risks because of the presence of electrocardiographic abnormalities, hypertension, diabetes, or hypercholesterolemia.

Only 9% of the patients (31 of the total 347) tested positive for hypothyroid conditions. Nonetheless, all were treated with thyroid extract, and substantial clinical improvements occurred in a number of the patients. Of the 132 symptomatic patients, 29 of 41 with angina reported benefits that included increased exercise tolerance, decreased frequency and severity of attacks, and less need for nitroglycerin. Mean cholesterol levels fell by about 22%. During the 5-year study, 11 patients died, less than half of the expected rate based on United States Life Tables (Barnes 1976).

How might poor thyroid function contribute to arteriosclerotic vascular disease, that is, the hardening of the arteries? Researchers speculate that hypothyroidism may slow or decrease the metabolic breakdown of fats such as cholesterol. In addition, a dysfunctional thyroid gland may also impair kidney function and interfere with the activity of a gene (methylenetetrahydrofolate reductase) that the body depends on to process (remethylate) homocysteine.

Also, if the body fails to convert thyroxine (T4) to triiodothyronine (T3), the body's most potent thyroid hormone, T3 becomes less available in the bloodstream, while levels of reverse T3 (rT3), an inactive metabolite of T3, tend to build up (Shanoudy et al. 2001). A low T3-rT3 ratio is associated with a lesser ability of the left ventricle to pump blood and is highly predictive of poorer short-term outcome in patients with severe chronic heart failure.

In 1998, the American College of Physicians established guidelines for maintaining thyroid health, recommending routine assessment of thyroid simulating hormone (TSH) levels in all women over 50 years of age; women ages 35 and older should be evaluated every 5 years.

In addition, a positive test for the thyroid peroxidase antibody (TPOAb) can be an important early warning sign of emerging dysfunction (Stockigt 2002). Having either high TSH or a positive TPOAb raises the risk of progressing to overt hypothyroidism eightfold; having both increases the risk 40-fold. Note: Hypothyroidism affects more women than men, but the risk increases with age for both men and women. In addition, women are about 5-10 times more prone to hyperthyroidism than men.

The attempts to improve cardiovascular performance without factoring in the possibility of a poorly functioning thyroid gland diminish the chances of success. Conversely, remarkable improvements can be expected if hypothyroidism exists and is treated as the primary condition provoking lipid or vascular derangements.

Hyperthyroidism
Hyperthyroidism (an overactive thyroid gland) is also an endangerment to cardiac health, forcing blood vessels into a chronic state of prolonged excitability. Italian researchers measured vascular function (before and after treatment for hyperthyroidism) and compared it to a control group with a healthy thyroid gland. Researchers found that excess levels of thyroid hormones had a strong negative impact on the function of the endothelium (the inner lining of blood vessel walls), resulting in upregulation of blood flow through the circulatory route (Napoli et al. 2001).

Compared to individuals with normal thyroid function, hyperthyroid patients produce significantly higher levels of nitric oxide, leading to increased blood flow and dilation of blood vessels in a resting state. Hyperthyroid patients, typically, show an exaggerated vascular reaction to the cardiac effects of acetylcholine (a neurotransmitter) and norepinephrine (a stress hormone synthesized by the adrenal medulla). Patients with overt hyperthyroidism as well as those with subclinical disease who were given echocardiograms showed that a supercharged thyroid gland caused the cardiovascular system to show clear signs of parasympathetic withdrawal (Petretta et al. 2001). Excitory instructions directed to the endothelium explain why even subclinical thyroid dysfunction is an independent risk factor for heart disease. Endo-thelium, stimulated by over-reactive thyroid messages, is implicated in both congestive heart failure as well as heart attacks.

In the early stages of hyperthyroidism (when TSH levels are high, but thyroid hormone levels are still normal), the heart may already be losing its ability to calm itself. Over time, chronic excitability (leading to increased blood circulation and heart rate) overworks the heart and literally wears it out. Interestingly, when following treatment to resolve hyperthyroidism, the vascular mechanics return to normal.

Illustrative of the value of a healthy thyroid gland, the National Health and Nutrition Examination Survey showed that once the thyroid falters in its performance, the heart may not be far behind (Rodriguez 2001). The need for a thyroid evaluation is thus impossible to overstate. Identifying and treating hypo- or hyperthyroidism can improve both the quality and duration of life.

IRON OVERLOAD (HEMOCHROMATOSIS)

The research to determine the effects of iron excess on cardiovascular health has had mixed findings. The Annals of Epidemiology reported that no association between iron levels and mortality from cardiovascular disease was found in data collected from NHANES II and the National Death Index (Sempos et al. 2000). Reports published in two respected journals (Journal of the American Heart Association and American Journal of Epidemiology) chronicled an opposing view, showing that free iron corresponds to a greater risk of fatal heart attacks and strokes by encouraging free-radical production (Kiechl et al. 1997; Klipstein-Grobusch et al. 1999).

Just as the iron in your car can rust, the iron in your body is susceptible to rust, or oxidation, a process that damages tissues and blood vessel walls. Several studies have found that iron is most damaging to the heart if LDL cholesterol levels are also high. This occurs as free iron oxidizes LDL cholesterol, increasing the damage imposed upon the heart and vascular system.

Hemochromatosis not only increases the oxidation process, but also reduces antioxidants, including glutathione (Young et al. 1994). As glutathione is depleted, free radicals (attacking in the cerebral region) can increase stroke progression. Stroke patients with high blood ferritin (a measurement of the total iron stored in the body) experienced greater poststroke trauma, that is, increased lethargy, aphasia, and unawareness (Davalos et al. 2000).

An iron overload further complicates a cardiovascular outcome by contributing to an irregular heartbeat, heart attacks, and heart failure. Every 1% rise in blood iron increases the risk of heart disease 4% (Whitney et al. 1998). Interestingly, iron-induced cardiac irregularities can affect both young and senior subjects, even anemic patients.

Dr. Hidehiro Matsuoka (Kurume Medical School in Japan) says iron somehow interferes with nitric oxide, a chemical that relaxes blood vessel walls, allowing the blood to flow more freely. As iron levels increase, malondialdehyde (a marker reflecting oxidation and impaired endothelial function) also increases. Individuals with hemochromatosis who were appropriately treated had lower levels of malon-dialdehyde, and their blood vessels performed with greater normalcy (Tzonou et al. 1998; Fox 2002).

Patients with an iron overload are frequently advised to avoid foods rich in vitamin C or vitamin C supplements because of the iron enhancing factors associated with ascorbic acid. Some (with hemochromatosis) can use 500 mg of buffered vitamin C, taken 3 times a day between meals, without difficulty. Cast-iron cookware and iron-fortified foodstuffs should be avoided, and meats and alcohol should be restricted. On the other hand, coffee or tea consumed with meals assists in blocking iron absorption from foods. Fruits (nonascorbic acid varieties) and vegetables are excellent dietary choices for individuals with an iron overload. Simply withdrawing iron-fortified foods from the diet can prompt dramatic changes in iron levels.

Dispersed throughout the Therapeutic section are supplemental suggestions to reduce iron overload, such as calcium, fiber, garlic, magnesium, vitamin E, and green tea, but individuals wishing to protect themselves from iron buildup may also want to consider a blood donation. Some individuals donate the blood to themselves to ensure a healthy future supply, but this course is only valuable if the individual is not anemic. Should anemia coexist with hemochromatosis, drugs in the form of iron chelators may be prescribed.

Optimal iron levels appear to be <100 mcg/dL, although the standard reference range is up to 180 mg/dL. Tests such as total iron binding capacity, serum iron, and a DNA test called HLA-H, along with family history, are other excellent screening tools for hemochromatosis.

Comment: Adequate amounts of iron are absolutely essential to good health, but using iron supplements or iron fortified foods is not recommended for men or postmenopausal women, unless diagnosed with an iron deficiency. It is judged that approximately one of every 200 people actually has iron overload disease. Read the sections devoted to Heredity and Chelation Therapy in this protocol to learn more about hemochromatosis.

NEWER RISK FACTORS

In the last 25 years, the incidence of coronary fatalities has decreased 33%. This is due largely to avoiding the traditional risk factors. Dr. Paul M. Ridker, M.D., M.P.H. (director of cardiovascular research at Brigham and Women's Hospital in Boston, MA), speculates that an auxiliary list of newer predictive factors may significantly increase the numbers benefiting from 21st century diagnostics and treatment (Ridker 1999a) (see Figure 3).

Fibrinogen
Fibrinogen is a blood protein that plays a critical role in normal and abnormal clot formation, a mechanism referred to as coagulation. A process of checks and balances, an interaction between clotting factors and naturally occurring anticoagulants, normally results in healthy levels of fibrinogen and normal coagulation. If fibrinogen levels increase above normal, however, a blood clot becomes a threat; 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 a number of proteins found in plasma, called clotting factors. Normally, clotting factors are inactive, but following injury, they become activated. Exposed collagen or chemicals released from injured tissues initiate a series of chemical reactions that result in the production of prothrombin activators. Prothrombin activators convert prothrombin to thrombin, which, in turn, converts fibrinogen to fibrin (a network of protein fibers that can trap blood cells, bloodstream infiltrates, and platelets). The risks multiply as materials become trapped in the tangle. An atheromatous tumor (capable of continued growth) can result in full occlusion (Whiting 1989; Seeley et al. 1991; Kohler et al. 2000).

Fibrin may stimulate cell proliferation by providing a scaffold along which cells migrate and by binding fibronectin, which stimulates cell migration and adhesion. Fibrinogen thus encourages monocyte adhesion and smooth muscle proliferation, further occluding the vessel. In advanced plaque, fibrin may also be involved in the tight binding of LDL and the accumulation of lipids (Smith 1986; Koenig 1999a).

Vascular closure represents only one facet of the risk: 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. Reports in the New England Journal of Medicine showed that those with high levels of fibrinogen were more than twice as likely to die of a heart attack, but the risk of a stroke increases as well (Wilhelmsen et al. 1984; Packard et al. 2000).

A cohort of the large scale EUROSTROKE project (215 cases and 521 controls) showed that fibrinogen was a powerful predictor of stroke, both fatal and nonfatal events. After dividing subjects into four quartiles based on fibrinogen levels, researchers found that the risk of stroke increased nearly 50% for each ascending quartile. Fibrinogen increased the risk of stroke independent of smoking status, but the odds ratio worsened with higher systolic blood pressure. For example, the fibrinogen risk increased from 1.21 among those with a systolic pressure below 120 mmHg to 1.99 among subjects with a systolic pressure of 160 mmHg or above (Bots 2002).

Fibrinogen also promotes the negative activity of platelets by encouraging platelet aggregation (Koenig 1999b). In addition, German researchers determined that fibrinogen deposition at the vessel wall promotes platelet adhesion during ischemia (Massberg et al. 1999). Platelets, the smallest of blood elements, are absolutely essential in sealing vascular injuries, whether caused by a knife wound or hypertension. According to Dr. James Braly, M.D., as long as the interior of the vessel is smooth, platelets are not summoned into service; however, if trauma is detected, platelets rush to the site, forming a plug to repair the wound. Once activated, platelets do more than provide the materials for vascular repair. They also release serotonin (a vasoconstrictor) and the powerful platelet aggregator thromboxane A2, further adding to the risk of a thrombus (Braly 1985; Smith 1986; Ernst et al. 1993).

Aortic stenosis is the abnormal narrowing of the valve between the left ventricle and the aorta. The narrowing, or stenosis, is often associated with calcification, a process that may involve fibrinogen (Levenson et al. 1997). Fibrinogen appears to have an attraction for calcium; as fibrinogen and calcium unite, the valvular diameter becomes smaller.

The Life Extension Foundation was the first research group to recognize the importance of assessing fibrinogen as an independent risk factor for cardiovascular disease. A study reported in the Journal of the American College of Cardiology corroborated the Foundation's position on fibrinogen, when nearly 400 male physicians participated in the Physicians' Health Study (Ma et al. 1999). The blood fibrinogen levels of 199 subjects, who experienced heart attacks during the study period, were compared with those of 199 control subjects who did not suffer heart attacks. Individuals having heart attacks had significantly higher fibrinogen levels compared to those physicians with healthy fibrinogen levels. Several studies have shown a stronger association between cardiovascular deaths and fibrinogen levels than for cholesterol.

For example, a study involving 3043 patients with angina pectoris (who underwent coronary angiography and were followed for 2 years) concluded that higher baseline levels of fibrinogen were predictive of a heart attack and likelihood of sudden cardiac death. In contrast, coronary risk was low among patients with low fibrinogen concentrations despite increased serum cholesterol levels (Thompson 1995). A similar study showed that fibrinogen was directly associated with the presence of myocardial infarction and an independent short-term predictor of mortality (Acevedo et al. 2002; Bots et al. 2002; GSDL 2002).

Various factors influence plasma fibrinogen levels:

Increased winter cardiovascular mortality is related to a cold weather increase in fibrinogen. The exposure to cold increased fibrinogen 23-38% over baseline (Woodhouse et al. 1997; Horan et al. 2001).
Smokers and depressed individuals have higher levels of fibrinogen (Mindell 1998; Castilla et al. 2002).
Estrogen replacement therapy appears to attenuate normal age-related increases in fibrinogen (Stefanick et al. 1995; el-Swefy et al. 2002).
Unfortunately, pharmaceutical drugs have not been of significant value in reducing fibrinogen levels. The initial data suggested that Bezafibrate (a European drug) reduced fibrinogen levels in patients with established coronary heart disease. However, the Bezafibrate Infarction Prevention Study yielded disappointing results, with no significant evidence of efficacy in lowering fibrinogen (Behar 1999).

Anticoagulant therapy usually becomes the treatment of choice to reduce fibrin. Warfarin (Coumadin) and heparin are often prescribed, but it is difficult to administer enough of an anticoagulant to lessen the risk of a blood clot without increasing the risk of a hemorrhage. Dispersed throughout the Therapeutic section are products with fibrinolytic and antiplatelet 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.

To read about other factors affecting fibrinogen, consult the Obesity, Sedentary Lifestyle, Gum Disease, Fibrinolytic Activity, and Link Between Infection and Inflammation in Heart Disease sections in this protocol.

Fibrinolytic Activity
Balance between tissue plasminogen activators (t-PA) and plasminogen inhibitors (PAI-1) controls activity in the fibrinolytic system. If the fibrinolytic process is faulty, individuals can be classed as either hemorrhage or thrombosis prone. Generally, increased PAI-1 concentrations reflect impairment of the fibrinolytic process, with a reduction in plasmin formation and an accumulation of fibrin, platelets, minerals, and lipids. This model can predispose recurrent thrombosis. Recent data from animal and human studies indicate that PAI-1 is preferentially produced in visceral adipose tissue, a finding that explains the hypercoagulability associated with obesity. In patients with PAI-1 deficiencies, a hemorrhage may be a concern (Reilly et al. 1991; Farrehi et al. 1998; Kohler et al. 2000; Ridker 2000).

The New England Journal of Medicine reported that anomalies occurring in t-PA and PAI-1 are likely to be critical factors underlying hyperinsulinemia in ischemic heart disease (Despres et al. 1996; Ridker 2000). Barry Sears, Ph.D., believes scientific evidence has rightly exposed hyperinsulinemia as an indicator of an eventual heart attack (Sears 1995). Hyperinsulinemia bestows some of its coronary damage by increasing the risk of hypertension (twofold), hypertriglyceridemia (three- to fourfold), Type II diabetes (five- to sixfold), and by diminishing HDL levels.

The research suggests that peripheral factors influence the clotting of blood. For example, The Lancet reported that air travel increases the risk of venous thrombosis by increasing prothrombin factors (Scurr et al. 2000). Note: Venous thrombosis is a condition characterized by a blood clot in a noninflamed vessel. Pain, swelling, and inflammation may follow if the vein is significantly occluded.

Although blood clots loom as one of the dominant factors in cardiovascular disease, the selection of supplements that favor fibrinolysis and discourage platelet aggregation should be done sensibly. It is possible that the cumulative value of nutrients that oppose blood clot formation could overcorrect a condition, particularly if used in concert with prescribed blood thinners. Note: For information regarding asymptomatic patients taking warfarin, please consult the Vitamin K subsection in the Therapeutic section of this protocol.

Lipoprotein(a) (Lp(a))
The peak time for the most damaging of heart attacks appears to be between 6 a.m. and noon. The reason why is of deep concern to the medical community. Some theorize that facing the challenges and urgencies of a new day could be activating the sympathetic nervous system. Was the "fight or flight" mentality too much stimulus for a cardiac prone individual? Note: UCLA researchers speculate that if the sympathetic nervous system is involved in the circadian pattern of sudden death, this involvement reflects exaggerated morning end organ responsiveness to norepinephrine (an adrenal medulla adrenergic hormone), not higher morning sympathetic outflow (Middlekauff et al. 1995).

Japanese researchers took the question further and measured serum lipids and clotting factors in two groups of men: those who suffered a heart attack during the 6-hour morning "peak period" and those who had a heart attack at other times during the day or night (Fujino et al. 2001). Morning heart attack victims were found to have significantly higher levels of Lp(a), the only distinguishable factor compared to the other group. There was also a tendency toward hypercoagulation, increasing the risk for developing a life-threatening thrombus or clot. The conclusion of the Japanese study was that increases in Lp(a) appear to be influencing coagulation factors involved in the occurrence of morning heart attacks.

The physical character of Lp(a) adds to its complexities. For example, Lp(a) is a distinctive serum lipoprotein composed of an apoB-containing lipoprotein structure (virtually identical to LDL cholesterol) attached by a single disulfide bond to a long carbohydrate-rich protein, apolipoprotein(a):

LDL + apo(a) = Lp(a).

Comment: apo(a) is remarkably similar to plasminogen, an inactive precursor of plasmin (also called fibrinolysin), an agent capable of dissolving fibrin (McClean et al. 1987; Hajar et al. 1989; Harpel et al.1989; Ridker 2000).

Because apo(a) is highly homogenous (having a likeness in form) with plasminogen, it has been hypothesized that Lp(a) competes for plasminogen that binds to fibrin and endothelial cell surfaces, thus inhibiting fibrinolysis. Experimental work indicates that Lp(a) modulates fibrinolysis, inhibits plasminogen binding to fibrin, and may also inhibit t-Pa, a clot-dissolving substance produced naturally by cells in the walls of blood vessels. The end result is a greater risk of blood clot formation, and thus heart attack and stroke (Loscalzo et al. 1990; Ridker 2000; Caplice et al. 2001).

Complicating the atherosclerotic-Lp(a) mechanism, apo(a) has a sticky "velcro" nature, causing it to easily tie up in blood vessels. As apo(a) participates in vascular repair, its adhesiveness provides an ideal trap for LDL, VLDL, and other bloodstream infiltrates, for example, calcium. In layered fashion, circulating materials mount the debris, promoting the growth of an atheromatous tumor. As plaque accumulates, greater amounts of Lp(a) are observed at the site of the occlusion.

It should be noted that plaque formation is an essential response to vascular injury. When a blood vessel has been damaged, repair is paramount. If benign materials, such as vitamin C, are available to protect the vessel from injury and to participate in vascular repair, the need for Lp(a) is moot. Without adequate amounts of vitamin C, Lp(a) becomes indispensable (Rath 1993).

There is a vast difference between the materials used to repair vascular injuries. For example, vitamin C repairs the wound, leaving the vessel wall smooth, but stronger; Lp(a) repairs the injury, leaving residual trappings, a sticky compress, capable of continued growth. Although Lp(a) has an important function in the body, Matthias Rath, M.D., considers Lp(a) 10 times more dangerous than LDL cholesterol.

The risk of a major cardiovascular event nearly tripled among middle-aged men (participating in a Lp(a)/heart study) whose Lp(a) levels fell within the highest 20% of the study group compared to those with lower levels (von Echardstein et al. 2001). The risks escalate even higher if Lp(a) coexists with high LDL cholesterol, low HDL cholesterol, and hypertension.

Elevated Lp(a), above 30 mg/dL, has been noted in 20% of all thromboembolism patients compared to 7% of healthy controls (von Depka et al. 2000). Lp(a) may prove to be one of the most predictive of the risk factors for strokes, restenosis (recurrent narrowing of a vessel), or heart attack following either coronary bypass surgery or angioplasty. Recent studies also incriminated Lp(a) in angina pectoris, citing accumulations of Lp(a) in the plaque of unstable angina patients. Comment: According to the American Heart Association, the lesions on artery walls contain substances that may interact with Lp(a), leading to the buildup of fatty deposits (American Heart Association 2002).

Aortic stenosis, the narrowing of the valve separating the left ventricle from the aorta, is often described as a calcification process. Lp(a) appears to play a role in this process; as Lp(a) is deposited on the aortic valve, it creates a binding site for calcium (Shavelle et al. 2002). Researchers at the University of Washington (Seattle) hypothesized that HMG CoA reductase inhibitors (statins) might slow aortic calcification: 28 patients receiving statin therapy for approximately 2.6 years had a 62-63% lower rate of aortic valve calcium accumulation; 44-49% fewer statin patients experienced definite progression of the disease process (Shavelle 2002) (please consult the section devoted to valvular disease for an in-depth discussion regarding aortic stenosis).

The reference interval for Lp(a) is 0-30 mg/dL. Reference ranges are valuable only as generic markers. Depending upon the test, risk may be significantly increased as values reach upper or lower limits of normal. Various reputable cardiologists strive for an Lp(a) less than 10 mg/dL among patients (Sinatra 2002). Read about essential fatty acids, L-lysine, L-proline, niacin, vitamin A, and vitamin C (nutrients that assist in maintaining healthy Lp(a) levels) in the Therapeutic section of this material.

Introduction to Homocysteine

Hazards of Hyperhomocysteinemia
For a discussion relating to detoxification mechanisms and nutrients to reduce homocysteine levels, consult the Homocysteine Lowering Nutrients and Elimination Pathways subsections in the Therapeutic Section of this protocol.

Although the dangers imposed by hyperhomocysteinemia are not a new discovery, most of the medical community has until recently ignored homocysteine as a cardiovascular risk. Decades ago, Kilmer McCully, M.D., pioneered the homocysteine/cardiovascular hypothesis; the Life Extension Foundation focused upon the dangers of homocysteine and outlined a vitamin protocol to reduce hyperhomocysteinemia in an article released in November 1981 (Anti-Aging News pp. 85-86). Eric Braverman, M.D., joined the crusade, describing homocysteine as a substance that is worse than cholesterol (Braverman 1987).

Homocysteine is regarded as more dangerous than cholesterol because homocysteine damages the artery and then oxidizes cholesterol before cholesterol infiltrates the vessel. Craig Cooney, Ph.D., says that homocysteine is now widely recognized by scientists as the single greatest biochemical risk factor for heart disease, estimating that homocysteine may be a participant in 90% of cardiovascular problems.

Although homocysteine's role in atherosclerosis and atherothrombosis is confirmed, it should be noted that most naturally occurring substances have purpose in physiology. The American Academy of Family Physicians explains that homocysteine is typically changed into other amino acids for use in the body's normal functions (American Family Physician 1997). For example, homocysteine is an intermediate product of methionine metabolism. Two pathways detoxify homocysteine, the remethylation pathway (which regenerates methionine) and the trans-sulfuration pathway (which degrades homocysteine into cysteine and then to taurine). The amino acids cysteine and taurine are important nutrients for cardiac health, hepatic detoxification, cholesterol excretion, bile salt formation, and glutathione production. Because homocysteine is located at a critical metabolic crossroad, it either directly or indirectly impacts the metabolism of all methyl- and sulfur groups occurring in the body (Miller et al. 1997).

In addition, a select group of researchers contend that the residuals (metabolites) of homocysteine appear to support adrenal gland function and contribute to neurotransmitter synthesis and the regeneration of bones and cartilage. If their undocumented speculations prove valid, it should be strongly emphasized that homocysteine must be detoxified in order for its byproducts to offer any biological advantage. If disposal systems (remethylation and trans-sulfuration) are nonfunctional, allowing homocysteine to accumulate, the results can be deadly. Remethylation and trans-sulfuration are discussed in detail in the Therapeutic section of this protocol, under the subsections Homocysteine Lowering Nutrients and Elimination Pathways.

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