Cardiovascular disease rarely is caused by a single frailty. Rather, it is a multifaceted failure that includes physical, psychological, and genetic weaknesses. Since cardiovascular disease remains the number one killer in Western societies, there is more published scientific information about prevention and treatment than exists for other diseases. This Cardiovascular Disease protocol is the longest chapter in this book, but we urge those concerned with the disease to study it carefully. Overlooking just one risk factor, such as elevated levels of C-reactive protein, fibrinogen or homocysteine, could lead to the development or worsening of heart and/or vascular disease.

At least 68 million people in this country suffer from some form of heart disease, with an estimated 1.1 million Americans, annually, experiencing an acute myocardial infarction (heart attack). According to statistics released from the National Heart, Lung, and Blood Institute's Atherosclerotic Risk in Communities (ARIC) Study, of those numbers over 40% die. Dr. Kenneth Chien, a cardiologist and molecular biologist, states that improved post-infarction care has resulted in greater numbers surviving a heart attack, but the long-term prognosis may still be bleak. Dr. Chien warns that as primary mortality decreases, the incidence of morbidity, i.e., an increase in the incidence of heart failure is increasing among heart attack survivors.

Reports appearing in the American Journal of Critical Care further unsettled the scientific community when they declared that 50% of the patients with coronary artery disease do not have any of the traditional risk factors. (Futterman et al.,1998) In fact, 50% of all individuals 50 years or younger, who die from heart disease, succumb without any established risk factors. Does this mean that traditional risk factors are no longer valid? The intent of this material is to answer that question, by providing a comprehensive view of contemporary and novel risk factors that contribute to cardiovascular disease and a complete dialogue regarding treatment options available to patients.

BALDNESS

Male pattern baldness is a subject of interest, in regard to the incidence of coronary heart disease (CHD). The Department of Medicine at Harvard Medical School and Brigham and Women's Hospital conducted an 11-year study involving 22,071 male physicians, to determine the relationship between baldness and CHD. The study evaluated the following patterns of hair growth: (1) no hair loss, (2) frontal baldness only, and (3) frontal baldness with mild, moderate or severe vertex balding (vertex refers to the top of the head). The Harvard study concluded that the risk of CHD increased progressively throughout the different groups, with vertex balding showing the greatest association. Vertex baldness appears a valid marker for an increased risk of coronary heart disease, particularly when clustered with other factors, such as hypertension or hypercholesterolemia (high cholesterol).

EARLOBE CREASES

Around 1973, the association between diagonal earlobe creases and the threat of an eventual heart attack was made. Chronic circulatory problems allow the vascular bed in the earlobe to collapse and the telltale earlobe crease to appear. More than 30 studies have been recorded in the medical literature, with the largest study, to date, involving 1,000 randomly selected patients. Diagonal earlobe creases, appearing at a 45-degree downward angle toward the shoulder, appear a better predictor of sudden death from a heart attack than age, smoking, obesity, elevated cholesterol levels, or a sedentary lifestyle.

It appears that individuals with an earlobe crease have a 55% greater risk of dying from heart disease than those without the marking, with the risk becoming even more prognostic if diagonal creases appear on both ears. The predictive value, of the diagonal earlobe crease, does not apply to Orientals, Native Americans, or children with Beckwith's syndrome, a heredity disorder associated with neonatal hypoglycemia and hyperinsulinism.

While earlobe creases do not prove heart disease, the Mayo Clinic announced that out of 121 patients, the earlobe crease plus symptoms of heart attack (i.e., chest pain) meant a heart attack about 90% of the time. Similar symptoms but without the earlobe crease terminated in a non-coronary diagnosis 90% of the time.

SMOKING

Kentucky and Tennessee have the highest rates of heart disease deaths, but also the highest rates of cigarette smoking. Prolonged exposure to cigarette smoke, either direct or second hand, increases the risk of dying from a heart attack or complications arising from atherosclerosis, by three to fivefold. Much of the ill-omened health effects related to smoking occur due to an increase in free radical activity. Unfortunately, as the population of free radicals increases, vitamin C, a powerful antioxidant, decreases in the smoker.

Many explanations have been documented, explaining the hardship that cigarette smoking imposes upon the cardiovascular system. Increased heart rate (one cigarette can increase the heart rate 20 to 25 beats per minute), disrupted circulation to the legs and feet (it takes 6 hours for the circulation to return to normal after just one cigarette), lowered skin temperature, increased need for oxygen, insulin resistance, hypertension, and increased levels of adrenaline are some of the hazards associated with smoking. Note: Smoking doubles blood levels of adrenaline; the results are vaso-constriction and platelet aggregation, increasing the risk for both heart attacks and strokes.

Earl Mindell, R.Ph., Ph.D., warns that smokers have higher levels of fibrinogen. Fibrinogen is necessary for proper clotting of blood, but abnormally high levels of fibrinogen can cause blood clots to form spontaneously. It is judged that smoking accounts for half of the vascular risks attributable to fibrinogen.

Cigarettes contain toxic substances (there are 4,000 poisons contained in tobacco) some of which inactivate vitamin B6, a nutrient extremely important in homocysteine control. Homocysteine management is, typically, difficult in smokers. (Consult the Newer Risk Factors section of this protocol for a complete discussion regarding homocysteine and to the Therapeutic Section for a supplemental regime to maintain healthy homocysteine levels.)

The Lancet added to the concerns surrounding smokers when they reported that men with the lowest serum albumin levels have the highest rate of death from various causes, including heart disease. (Schatz et al., 2001) Smoking lowers this predictive protein.

Data published in the Journal of the American Medical Association (JAMA), indicates that the critical phase of cardiovascular disease is, significantly, accelerated in the smoker. (Grundy, 1986) The critical phase is marked by 60% coverage of arterial surfaces with atheromatous materials. Though the ages were hypothetically assigned, a smoker with normal blood pressure and cholesterol levels reaches the critical phase 10 years earlier than the non-smoker and 20 years earlier if the smoker is, also, hypertensive.

It is estimated that each cigarette steals 8 minutes of life from the smoker. This means that an individual smoking one pack a day loses a month of life each year. Two packs clip 12 to 16 years off of life expectancy for lifetime smokers. It is important, however, for the smoker to realize that the body has immense capacity for restoration. Within 24 hours of being tobacco free, the chance of heart attack decreases. Within 48 hours nerve endings start to regroup and breathing becomes noticeably improved. Within two to three months, circulation improves and walking becomes easier. Lung capacity increases up to 30%, and energy levels rebound. After one year, the risk of a heart attack is 50% less than the individual still smoking; within two years, the risk of heart attack drops to ranges closely rivaling an individual who has never smoked. Another bonus occurs as inflammation (a newer of the risks associated with heart disease) is reduced and subsequently C-reactive protein (CRP), an inflammatory marker also decreases. (Turn to Newer Risk Factors to read more concerning CRP and the role of inflammation in the onset of heart disease.)

Though the body is resilient, it is extremely important that the smoker not wait too long to embark upon recovery. For information pertaining to nutrients that offer protection to the smoker, turn to bromelain, coenzyme Q10, curcumin, proanthocyanidins, vitamin C, and vitamin E in the Therapeutic Section of this protocol.

HYPERTENSION

Hypertension (high blood pressure), observed more in men and blacks, is a disorder characterized by blood pressure persistently exceeding 140/90 mmHg. Current research indicates that optimal blood pressure is <120/80 mmHg and normal is 120-129 over 80-85. It is important to note that damage to the vasculature can occur when the blood pressure is moderately but chronically elevated. Some individuals may not realize they are hypertensive since symptoms as epistaxis (nosebleed), tinnitus, dizziness, headache, blurred vision, and arrhythmias are not always present.

Dr. Charles DeCarli, of the University of Kansas, found that men who had even mildly elevated blood pressure 25 years earlier now have abnormal brain signals and more vascular disease and strokes than men who had normal blood pressure in midlife. "Take care of risk factors when you're young or they'll come back to haunt you," warns DeCarli.

The Archives of Internal Medicine reported results of the most comprehensive study to date, evaluating 10,874 Chicago men (ages 18 to 39) from 1967-1973 concerning the long-term effects of high blood pressure. (Katsuyuki et al., 2001) About 62% of those studied had either high-normal blood pressure (systolic pressure 130-139 and diastolic pressure 85-89) or stage 1 hypertension (systolic pressure 140-159 and diastolic pressure 90-99).

Life expectancy was shortened by 2.2 years for men with high normal blood pressure and by 4.1 years for those with stage 1 hypertension. This means an individual with a high-normal blood pressure has a 34% higher risk of dying from coronary heart disease; those with stage 1 hypertension have a 50% higher risk of dying of coronary heart disease. After 25 years, 197 of the men had died of coronary heart disease, 257 of cardiovascular disease, and 759 from other causes, some of which might, also, be attributed to high blood pressure, as kidney disease. Dr. David A Meyerson, a Johns Hopkins cardiologist and spokesman for the American Heart Association, said the study affirms the need for disease prevention through lifestyle modification. The commitment should be begun early in life and continued lifelong.

Findings published in the New England Journal of Medicine (exploring the role of moderately elevated blood pressure as a forerunner of heart disease) concurred with results gathered from the Chicago/ hypertension trial. (Vasan, 2001) The parameters describing moderately elevated blood pressure were identical in both trials, i.e., a systolic pressure of 130 to 139 mmHg and a diastolic blood pressure of 85 to 89 mmHg, or both.

Researchers, tracking the 6859 participants, noted a stepwise increase in cardiovascular events among persons with higher base line blood pressure. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age with high-normal blood pressure was 4% for women and 8% for men. In older subjects (those 65 to 90 years of age), the incidence was 18% (women) and 25% (men). As compared with optimal blood pressure, high-normal blood pressure was associated with a risk factor-adjusted hazard ratio for cardiovascular disease of 2.5% in women and 1.6% in men. Thus, the results of various credible studies demonstrate that high-normal blood pressure should not be taken lightly; a regime to counter even a slight rise in blood pressure (exceeding optimal/normal levels) should be regarded as essential to reducing cardiovascular risk.

For decades it was thought that the diastolic (the lower blood pressure) was the most critical measurement when diagnosing hypertension and assessing blood pressure-induced vascular damage. The journal Hypertension renounced this theory, reporting that systolic pressure is the crucial assessment, not the diastolic as previously considered. (Izzo et al., 2000) (Systolic pressure represents the maximum force exerted by the heart against the blood vessels during the heart's pumping phase.) The difference between the systolic and diastolic blood pressure is referred to as pulse pressure; if the number chronically exceeds 60, advanced atherosclerosis is, usually, evidenced.

While most cases of high blood pressure are classed as essential or primary hypertension (meaning no known cause can be found for the elevation), it is a misnomer to imply that unfounded hypertension is innocent. Any sustained elevation of blood pressure can affect the intima (innermost structure) of small vessels, brain, retina, kidneys, and heart.

Secondary hypertension is, frequently, linked to primary diseases, such as renal, pulmonary, endocrine, and vascular disease. Malignant hypertension, the most lethal form, is characterized by severely elevated blood pressure that commonly damages small vessels, brain, retina, heart, and kidneys. Many patients with this condition exhibit signs of hypokalemia (inadequate levels of potassium in the bloodstream), alkalosis (blood pH >7.44), and excessive aldosterone secretion (a hormone that conserves water and sodium and increases potassium excretion).

Hypertension increases the risk of cardiovascular disease by affecting the performance of arteries. Normally, arteries expand and contract effortlessly with each heartbeat. With sustained hypertension, arterial walls become thickened, inelastic, and resistant to blood flow. This process injures arterial linings and accelerates plaque formation. Non-functional, blocked vessels are unable to expand to accommodate the flow of blood and the left ventricle is forced to pick up the slack. The endless exertion proves too much and the ventricle may become distended and hypertrophied. In exhaustion, the pump eventually fails. The health of the left ventricle is an extremely important assessment when evaluating the worthiness of the heart.

Arterial damage is invitational to spasms occurring in the walls of the arteries. The spasm further impedes the flow of blood, adding additional challenge to the ailing heart as it works to move the blood against the backpressure. Lack of egress and the heart's aggressive action can cause a weakened area in the arterial wall to balloon, forming an aneurysm. Rupture of the artery can result in massive internal bleeding and death. An aneurysm or stroke, angina pectoris, and myocardial infarction are even more likely to occur if hypercholesterolemia and hypertension coexist.

Serum creatinine levels in hypertensive patients are an extremely important marker, and, unfortunately, one frequently ignored. Creatinine is proving highly reliable in predicting cardiac outcome in individuals with high blood pressure. Researchers analyzed data from a massive study involving 14 U.S. medical schools and 10,940 participants. It was determined that 50% of hypertensive individuals with creatinine levels of 2.5 mg/dL (or greater) will die within 8 years, according to Dr. Neil B. Shulman, principal investigator (Emory University). Cardiac deaths begin to spiral when creatinine levels reach 1.2 mg dL, with fatalities mounting as creatinine increases. Though high levels of creatinine frequently reflect kidney impairment, most individuals with high creatinine die of heart attacks and stroke, not renal disease.

Patients are searching for alternatives to hypertension medications in light of information gathered from an 8-year study involving 117,534 people. Half of the individuals were given anti-hypertensive drugs and the other half a placebo. The number of deaths at the end of the 8-year study was about the same in each group; the side effects of the drugs, however, eroded the equality of the results. Note: Additional information regarding the ineffectiveness of drug therapy among many hypertensive patients may, also, be read in the British Medical Journal, Nuesch et al, 2001.

Syndrome X, one of the newer cardiac risk factors, may best explain why some individuals are not protected from heart disease when hypertension is treated independently. Excesses of insulin, a hallmark of Syndrome X, make dominant the sympathetic nervous system and the release of catecholamines, i.e., dopamine, epinephrine, and norepinephrine, which contribute to hypertension by diminishing blood vessel diameter. Hyperinsulinemia, also, encourages retention of salt and water, a process that increases blood volume and blood pressure. About 50% of hypertensive patients are insulin resistant and should be treated for this condition primarily, rather than focusing on a symptom of the syndrome, i.e., high blood pressure. Gerald Reaven, Professor Emeritus (Active) of Medicine at Stanford University, states that it is vital that every healthy-heart program address the hypertension/ Syndrome X association or little success in shielding hypertensive patients from heart attack can be expected.

If anti-hypertensive drug therapy is used, Cozaar or Hyzaar (angiotensin II antagonists), appear safer and more effective than short-acting calcium channel blockers. It should be noted that beta-blockers and diuretics (anti-hypertensive treatments) have been associated with an increased risk of developing diabetes by impairing insulin sensitivity. (Lithell, 1996) New generation calcium channel blockers are, generally, neutral in regard to advancing diabetes, but exceptions occur. Striking benefits have been obtained with alpha 1-blockers in hypertensive populations at high risk for developing diabetes mellitus. Since credible options are available, the patient is strongly advised to opt for anti-hypertensive drugs that actually improve insulin sensitivity, avoiding drugs with the potential of causing diabetes.

RESULTS OF THE HOPE PROJECT

On March 11, 2000, a satellite symposium of the American College of Cardiology Scientific Session (Anaheim, CA) was held during which several speakers discussed the results of the Heart Outcomes Prevention Evaluation (HOPE) study, a 6-year trial assessing the value of ramipril, an angiotensin-converting enzyme (ACE) inhibitor in the prevention and management of cardiovascular disease. (Ramipril, a generic of the drug Altace, is principally used in the treatment of high blood pressure but its cardiovascular benefits appear far-reaching.) During the study, researchers also sought to determine whether vitamin E was more effective than a placebo in preventing major cardiovascular outcomes.

A brief explanation of the renin-angiotensin system follows:

The juxtaglomerular cells in the kidneys stimulate renin secretion when either blood volume or serum sodium decreases. Renin, an enzyme, participates in the conversion of angiotensinogen to angiotensin I, which is rapidly hydrolyzed to form the active compound, angiotensin II. The vasoconstrictive action of angiotensin II decreases the glomerular filtration rate; the concomitant action of aldosterone, a mineralocorticoid hormone produced by the adrenal cortex, promotes sodium retention, causing blood volume and sodium reabsorption to increase. Agents that inhibit the angiotensin-converting enzyme decrease sodium and water retention, reduce blood pressure, improve cardiac output, and, typically, decease heart size.

Some 9500 people from 270 hospitals in 19 countries participated in the HOPE study. Included in the trial were those with evidence of vascular disease, i.e., coronary artery disease, stroke or peripheral vascular disease, and high-risk patients with diabetes. Subjects were randomized to one of four treatments: ramipril alone, vitamin E alone, ramipril and vitamin E, or neither.

Dr. Salim Yusuf, Ph.D., (Professor of Medicine and Director of the Division of Cardiology, McMaster University (Ontario, Canada) reported the HOPE study showed that ramipril reduced the risk of new heart attacks, strokes, and mortality by 20% to 25%. (Lancet, 1993) Incidences of coronary revascularization, heart failure, and complications related to diabetes were significantly reduced as well. Dr. Yusuf reported on another phase of the HOPE study (the effectiveness of vitamin E as a cardio-protector) announcing that no beneficial effects were evidenced with vitamin E supplementation.

As frequently occurs when trial results are overwhelmingly in favor of one treatment over others, the study was halted. The ramipril treated group received such obvious benefit, it was deemed unethical to withhold the drug from the control group. (The SECURE study, a subset of the HOPE project, also found that ramipril was effective at impeding the progression of atherosclerosis, but found no positive effects attributable to vitamin E therapy.) So effective was ramipril, Dr. Victor Dzau, M.D., Professor of Theory and Practice of Medicine at Harvard Medical School, suggests that it might be helpful (in certain cases) to use ACE inhibitors to reduce risks of potentially costly problems even in the absence of hypertension.

Of tremendous interest was the finding that patients with diabetes experienced a reduction in diabetic neuropathy and the progression of the diabetic process while using ramipril. Over the four and one-half years of the HOPE study, the number of patients who developed new diabetes in the ramipril group was one-third that of the placebo group. If the ramipril/diabetes advantage can be confirmed, it would indicate that the renin-angiotensin system is, also, involved in the pathogenesis of diabetes. Bolstering the hypothesis, Captopril, another ACE inhibitor, also results in an improvement in insulin sensitivity.

According to Dr. Bertram Pitt, Professor of Internal Medicine at the University of Michigan (Ann Arbor) the HOPE study confirms that activation of the renin angiotensin system is an important risk factor for a heart attack. When angiotensin II is elevated in the vascular wall, it affects the transport of cholesterol into the wall and its oxidation, as well as increasing cytokine numbers. This begins a cycle, i.e., high levels of low-density lipoproteins (LDLs) leads to an increase in angiotensin II, which in turn increases oxidation of LDL cholesterol. The power of ACE inhibitors (such as ramipril) to prevent cardiovascular events is partially explained by their ability to interrupt this cycle.

An interesting finding was that the benefit derived from ramipril was independent of blood pressure modulation. A reduction of only 3 systolic points and 1.8 diastolic points from a mean baseline of 138/76 mmHg was observed. Nonetheless, a clear reduction in unwanted outcomes, i.e., cardiovascular death, myocardial infarction, and stroke, occurred in all blood pressure categories. Dr. Yusuf speculates that two million people (per year) could be spared a major cardiovascular event if ramipril were widely used.

Dr. Dzau explains that within unstable atherosclerotic plaque, a great deal of inflammation has been observed, and inflammatory cells produce angiotensin II. This situation is complicated by the fact that angiotensin also leads to inflammation. The result is the creation of a sequence that leads to constantly increasing levels of angiotensin production and inflammation, a cycle invitational to the progression of atherosclerosis and ischemic events.

Researchers were impressed with the absence of side effects during the course of the trial. If a patient has hypercholemia (an excess of chloride in the blood) or renal dysfunction, the physician should, however, be very careful about administering any ACE inhibitor. If ramipril is to be used, 10 mg per day appears the optimal dosage. (The SECURE study found lesser dosages ineffective.) Hypotensive patients should start at a lower dose, such as 2.5 mg and gradually increase. It is uncertain whether all ACE inhibitors are equal to ramipril in delivering cardioprotection; the ACE inhibitor quinapril failed in reducing ischemic events, but researchers question whether the dosage was more in error than the drug.

Comments regarding the unfavorable review of vitamin E: Dr. Richard Passwater, a long-time vitamin E devotee, explains that the length of time vitamin E is used determines its cardiovascular defense. The trend is especially apparent beyond nine years. Passwater showed that taking 400 IU of vitamin E daily for 10 years or more, dramatically, reduced the occurrence of heart disease prior to 80 years of age. (Turn to vitamin E, in the Therapeutic Section of this protocol, to read about Dr. Passwater's study, as well as current documentation supporting supplementation to protect against cardiovascular disease.) Also, the type and blend of vitamin E selected can alter outcome. The Life Extension Foundation has long advocated a complex of alpha-tocopherol (80%) with gamma-tocopherol (20%) for optimal protection when supplementing with vitamin E.

In contrast to the HOPE study, the Lancet reported the benefit of administering 800 IU/day of vitamin E to individuals with pre-existing cardiovascular disease and on haemodialysis. (Boaz et al., 2000) Increased oxidative stress, imposed through dialysis, appears to increase cardiovascular mortality. Supplementing with vitamin E reduced composite cardiovascular disease endpoints and myocardial infarction by about 50% compared to the placebo group. While bewildering to the consumer, varying dosages applied to diverse populations, often, results in unlike endpoints and dissimilar conclusions.

The Therapeutic Section highlights numerous suggestions to treat hypertension, as alpha lipoic acid, angelica, L-arginine, calcium, coenzyme Q10, essential fatty acids, garlic, hawthorn, magnesium, olive leaf extract, 3-n-butyl-phthalide, policosanol, potassium, taurine, and vitamin C. Natural ACE inhibitors are green tea, garlic, hawthorn, olive leaf, taurine, proanthocyanidins (mild ACE inhibition), angelica, and ginkgo biloba.

To read about the influence other conditions has upon hypertension, consult the following sections within this protocol: Smoking, Obesity, Stress, Genetics, Fibrinolytic Activity, Homocysteine, Syndrome X, Chelation Therapy, and Does Sodium Restriction Lower Blood Pressure.

OBESITY

Excessive body weight is a risk factor in so many diseases, that obesity, itself, is now regarded as a disease. In America 104.4 million adults are overweight and 42.5 million are obese. Considering these alarming numbers, it is prudent to wonder when a troublesome weight problem is no longer just an annoyance but a significant risk to heart disease? Measuring body mass index (BMI) has helped physicians and patients answer this question. BMI may be figured as follows:

	Convert weight into kilograms by dividing total weight by 2.2.
	Determine height and convert to inches.
	Convert height in inches to meters. (One meter equals 39.37 inches.) Divide the height in inches by 39.37.
	Square the height in meters by multiplying it by itself.
	Divide the weight in kilograms by the height in meters squared.

During the American Heart Association's 71st Scientific Session in 1998, guidelines for assessing the risks imposed by obesity (as measured by BMI) were reported. This study was based on data from the Framingham Heart Study and the Third National Health and Nutrition Examination Survey. The results follow in figure 2.

The pattern of the fat distribution is another important prognosticator of host vulnerability. For example, android obesity or male pattern obesity is characterized by central abdominal obesity. Android obesity, i.e., apple-shaped bodies, is, historically, associated with an increased risk of hypertension, diabetes, hyperinsulinism, cardiovascular disease, and premature death. Conversely, fat distribution confined primarily to the hips and thighs, i.e., gynoid or pear shaped obesity, is more likely to be regarded as benign and is common in females.

Research has clarified the reasons fatness increases cardiovascular risks. Obesity forces the heart into intensive labor, since the useless pounds must be serviced in the same fashion, as valuable tissues and organs. The risk of diabetes and hypertension increases almost three times in obese individuals. In fact, losing as little as 2 pounds can result in a 1-2 point reduction in blood pressure. Blood cholesterol levels increase by about 2 mg/dL for each kilogram (2.2 pounds) of excess body weight; fasting blood glucose levels increase about 2 mg/dL for every 10% over ideal body weight. (It has been confirmed that a diabetic can reduce their cardiovascular risk by losing as little as 5 to 10 pounds.) Other factors increasing cardiovascular risk as excessive fibrinogen, elevated C-reactive protein, and insulin resistance, often, share a common denominator, i.e., obesity.

A 10-15 pound weight loss can, also, lessen the risk and progression of Syndrome X, a condition of insulin resistance and hyperinsulinemia. As weight drops, tissues become more insulin sensitive, amending a primary identifiable trait in Syndrome X. Though not all obese individuals develop Syndrome X, the more overweight one is, the greater the risk of developing the syndrome and the clusters of disease factors surrounding it. (A discussion of Syndrome X as an antecedent to cardiovascular disease may be found in the section devoted to newer cardiovascular risk factors.)

Overeating in the absence of obesity poses a cardiac risk, as well. Reports from patients indicated that unusually heavy meals were, often, consumed during a 26-hour period preceding the myocardial infarction (heart attack).

It is apparent that individuals need to establish a sensible approach to eating, i.e., a program that can be comfortably maintained long-term, void of either binges or periods of starvation. To lose weight only to regain it poses many health risks. For example, a decrease in HDL cholesterol is, often, reported in women who chronically cycle their weight from highs to lows. (Merz, 2000) Weight cycling is defined as intentionally losing at least 10 pounds three or more times during one's life. Weight cyclers, typically, have a 7% lower HDL cholesterol than non-cyclers. (Olson et al., 2000)

For dietary supplements that may assist in weight loss, read about L-carnitine, chromium, CLA, coenzyme Q10, fiber, hawthorn, and zinc in the Therapeutic Section of this protocol.

DIABETES

The degenerative process that accompanies diabetes, significantly affects the heart. Atherosclerosis tends to develop early, progress rapidly, and be more virulent in the diabetic. Data released from the Framingham Study showed a fourfold increase in heart failure in diabetic men under age 65 and an eightfold increase in young diabetic women.

Diabetics are particularly susceptible to silent myocardial infarctions, i.e., an asymptomatic attack that interrupts blood flow to the coronary arteries. Understanding Normal and Clinical Nutrition reported that more than 80% of people with diabetes die as a consequence of cardiovascular diseases, especially heart attacks. (Whitney et al., 1998) High homocysteine levels, also, play a significant role in diabetes-induced cardiovascular disease. In fact, hyperhomocysteinemia is considered a reliable predictor of mortality among diabetic patients.

Much of the stress of diabetes is due to a constant state of flux, i.e., moving from hyperglycemia to hypoglycemia in a relatively short period of time. Non-diabetics are spared glycemic-induced stress. For example, most healthy individuals maintain post-absorptive blood glucose levels of 90-100 mg/dL. Even after fasting or overeating, blood glucose levels seldom fluctuate lower than 60 or over 160 mg/dL. It has been suggested that evolutionary success requires staunch defense of the range of blood sugar, since exceeding the limits at either end produces dire circumstances. An unstable diabetic lacks the homeostatic mechanisms that provide for intricate glucose balance and, as a result, the heart and circulatory system suffer.

Typically, type 2-diabetes develops because of a lack of insulin sensitivity at the cellular level. As a result, the bloodstream becomes overloaded with non-functional insulin and a glut of glucose. The reason for this is that as glucose is increasingly unable to be used for energy metabolism and accumulates in the blood, the pancreas secretes more insulin in a futile attempt to restore normal glycemic control. After an extended period of excess insulin secretion, the pancreas may lose its ability to produce insulin and the Type II diabetic may then become insulin dependent.

When insulin loses its sensitivity or receptivity, its metabolic disposition changes, becoming more an adversary than an advocate. Cholesterol and other lipids are more likely to be deposited on arterial walls; hypertension, impaired coagulation, and obesity are common problems. Of all the hormones, insulin (in excess) has the greatest influence upon weight gain.

Chronic hyperglycemia causes monocytes and adhesion molecules to bind to vessel walls. Lipids become disorganized, with more of the LDL cholesterol and less of the beneficial HDL appearing in the bloodstream. The volume of urine produced increases and dehydration may result. Life-saving minerals are often excreted with the urine and electrolyte imbalances can occur. As vital minerals are pulled from the system, the heart can be forced into fatal arrhythmias.

During hypoglycemia (a condition of low blood glucose levels that can occur in less stable diabetic patients), the ability of the nervous system to function decreases, but the breakdown of fats increases. In this guise, the fat assumes the role of a glucose surrogate. Necessary as this mechanism is, it is not without disadvantage. Substitute pathways are not always well regulated, and excess fats, not used as an energy source, may accumulate, contributing to the atherogenic process.

Symptoms of hypoglycemia can mimic a heart attack, i.e., dizziness, fatigue, sweating, shakiness, lightheadedness, palpitations, and in some cases, unconsciousness. Normal brain function requires 6 gm of glucose per hour, which can be delivered only if arterial blood contains over 50 mg/dL of glucose. Though hypoglycemia is not a heart attack, the stress imposed upon the heart can be extreme.

To learn more about the impact obesity, stress, gender, sedentary lifestyle, fibrinolytic activity, and syndrome X has upon diabetes, consult the Traditional and Newer Risk Factors section of this protocol. For natural suggestions to benefit the diabetic, read about alpha lipoic acid, L-carnitine, chromium, DHEA, essential fatty acids, fiber, garlic, magnesium, olive leaf extract, selenium, vitamin A, vitamin E, vitamin K, and zinc in the Therapeutic Section (appearing later in this protocol).

HYPERCHOLESTEROLEMIA AND DERANGED LIPID PROFILES

Too much cholesterol is not good, but too little may not be either. The American Heart Association announced in 1999 (at the annual stroke conference) that people with cholesterol levels less than 180 mg/dL doubled their risk of hemorrhagic stroke compared to those with cholesterol levels of 230 mg/dL. Studies indicate that low serum cholesterol levels may, also, increase the risk of death due to cancer, particularly lung cancer. Canadian investigators reporting in Epidemiology reported that after adjusting for age and sex, they found that those in the lowest quarter of total cholesterol concentrations had more than six times the risk of committing suicide, as did those in the highest quarter. (Ellison et al., 2001)

The New England Journal of Medicine reported that though there has been concern for hemorrhagic stroke in hypocholesterolemic patients, a current study did not support this fear. (White et al., 2000) Until the quandary has been resolved, there are reasons to be cautious about severely reducing dietary fat and serum cholesterol. Recall that triglycerides, the largest of the fat molecules in the body, carry the fat-soluble vitamins (including vitamin K, an extremely important nutrient in normal blood coagulation). Also, platelets (cells essential to blood coagulation) are, in part, made from cholesterol, which, if in short supply could influence platelet numbers. Other researchers believe that hypocholesterolemia weakens arterial walls in the brain, making them susceptible to breakage under pressure. (About 20% of all strokes result from cerebral hemorrhages.)

Cholesterol is so important that the body produces from 800 to 1500 mg each day to provide for the following metabolic processes:

	Cholesterol is present in every cell in the body, strengthening cell walls and assisting in the exchange of nutrients and waste materials across the membranes.
	The central nervous system, composed of the brain and spinal cord, contains nearly one-fourth of the body's store of cholesterol. As much as 50% of myelin, surrounding nerves is cholesterol. Cholesterol is essential for the conduction of nerve impulses.
	Bile acids, formed from cholesterol, are vital for proper fat digestion.
	Cholesterol is the precursor of adrenal and reproductive steroid hormones.
	Surface cholesterol makes the skin resistant to chemicals and disease organisms, hindering entry through pores. Cholesterol stored in the skin assists in converting sunlight to vitamin D.

Though high concentrations of total serum cholesterol are related to mortality in individuals younger than 65 years, clinical trials have failed (until recently) to look at large numbers of individuals (>70 years of age) to assess their response to higher cholesterol levels. According to data published in the Lancet, the risk imposed by hypercholesterolemia decreases with age. (Weverling et al., 1997) (Schatz et al., 2001) In fact, low cholesterol may be associated with higher death rates among elderly people, due to mortality from cancer and infection. Cholesterol can assume the role of modulator, controlling cell signaling, reducing inflammation, and assisting in cellular repair. Therefore, administering a hypocholesterolemic drug to a senior subject may, actually, increase their risk of succumbing with other forms of degenerative disease.

Dr. Steven Whiting, Dean of the Institute of Nutritional Science, explains how cholesterol can change from an essential sterol to an atheromatous material. Free radicals and hypertension can damage the inside of an artery, causing a small rupture or tear to occur. The body recognizes the problem and attempts to handle it, with the materials available. Fibrin, a stringy, insoluble protein, is the first material laid down at a wound sight. Fibrin has done what it must, seal or coat the damaged area in the artery. Unfortunately, fibrin can grasp other bloodstream infiltrates in its web-like structure, i.e., collagen proteins and minerals that have precipitated out of solution. A significant bump in the arterial pathway has developed, when along comes cholesterol. Cholesterol appears to add the final coat to the plaque, building up in the artery.

An inverse relationship exists between high-density lipoproteins (good cholesterol) and cardiovascular disease. The HDL2 subfraction is even more correlated with cardiac protection and longevity than total HDL cholesterol.

(Sardesai, 1998) Typically, low triglyceride/LDL levels and high HDL levels, place an individual in a better posture cardiovascularly.
HDL levels are considered desirable in a range of 55-70 mg dL. Total cholesterol, for most individuals, appears best managed between 180-200 mg/dL. The "how low can you go" logic is not wise when setting relevant cholesterol goals, considering the many functions assigned to cholesterol and the unsettled questions surrounding the safety of very low cholesterol levels.

Risk factors for heart disease are often calculated by dividing the total cholesterol by the HDL. Assessment of HDL/total cholesterol ratios is not standardized but, according to Health and Wellness (sixth edition), a value of 4.5 places the individual at an average risk, ratios above 4.5 indicate an increased risk, and ratios below 4.5 mean a decreased likelihood of developing heart disease. (Edlin et al., 1999)

Most laboratories use a reference range of 90-130 mg/dL for LDL cholesterol, but LDL appears optimal at 100 mg/dL or lower. It is purported that a 1% reduction in LDL cholesterol lessens the risk of heart attack by 2%. (LDL cholesterol is not measured directly; levels are calculated using the following formula: LDL = Total Cholesterol - HDL - (Triglycerides/5.)

Cholesterol tests, indicating acceptable levels, may convey a false sense of security. Current research indicates that standard tests miss 50% of people at risk for heart attack, due to the inability to detect abnormally small cholesterol particles. (Excessive insulin production, a hallmark of Syndrome X, is a factor that causes LDL cholesterol to assume a smaller, denser configuration.)

LDL pattern B is the smallest and most susceptible to oxidation of all forms of cholesterol. Both LDL pattern B and lipoprotein(a) increase the risk of heart attack by threefold, and cannot be detected by standard cholesterol tests. Without detection of the smaller cholesterol subsets and appropriate treatment, plaque buildup progresses twice as fast. Trapped LDL or lipoprotein(a), over time, forms plaque with a fibrous cap. Unstable plaque can rupture which causes the blood to clot, increasing the risk of sudden heart attacks or strokes. Laboratories providing total screening, i.e., testing for normal and abnormal sized lipoproteins should be used for evaluations.

Triglyceride levels are, usually, regarded within a normal range at 30-199 mg/dL, but Clin Rev Spring reported that patients with clinical coronary heart disease were less likely to experience new events if triglyceride levels were <101 mg/dL. (Kreisberg et al., 2000) Most researcher/physicians agree that triglyceride levels are best maintained below 100 mg/dL. According to information obtained from The Anti-Aging Zone, the ideal ratio of triglycerides to HDLs is less than 1. A ratio of 1.5 is acceptable, but a ratio of 2 and above should be reason to take action. (Sears, 1999)

Individuals with high triglycerides and low HDL cholesterol are 16 times more likely to have a heart attack than a person with normal levels. Triglyceride levels rarely rise unless one is suffering from insulin resistance or hyperinsulinemia, conditions often modifiable by controlling carbohydrate in the diet. According to data reported in Atherosclerosis, elevated triglyceride levels usually modulate when less food is consumed, particularly foods causing a rise in blood sugar levels, i.e., bakery products, pastas, and foods with added sugar. (Stavenow et al., 1999)

Other areas relating to hyperlipidemia are: heredity, sedentary, lifestyle, gum disease, hypothyroidism, hemochromatosis, fibrinogen, Lp(a), homocysteine, Syndrome X, and C-reactive protein. Read about natural lipid-reducing agents as, alpha lipoic acid, artichoke extract, L-carnitine, chromium, conjugated linoleic acid, curcumin, DHEA, essential fatty acids, fiber, garlic, ginger, grapefruit pectin, gugulipid, hawthorn, niacin, pantethine, policosanol, polyenylphosphatidylcholine, soy protein, and tocotrienols in the Therapeutic Section of this protocol.

STRESS

More than a quarter-million heart episodes occur annually, i.e., palpitations, angina, arrhythmias, heart attacks, and strokes as a result of a stressful experience. This is particularly evidenced when an ailing heart, struggling to keep pace with circulatory demands, is forced to deal with emotional provocation. The journal Circulation reported that an individual who is prone to anger is about three times more likely to have a heart attack or sudden cardiac death than someone who is the least anger-prone. (Williams et al., 2000)

The journal Life Sciences offers an explanation for unfortunate end events. Higher levels of homocysteine are associated with feelings of aggression and rage, in both men and women. (Stoney et al., 2001) Individuals may be spurred into erratic behavior by metabolic processes gone awry. Modulation of homocysteine levels may allow a more docile individual to emerge, less cardiac risk prone from two perspectives. (Less homocysteine = less violent behavior = less cardiac disease.) An extensive review of homocysteine appears in the section devoted to Newer Risk Factors. Vitamins/minerals to maintain healthy levels are presented in the Therapeutic Section.

Type A individuals are, also, at a greater cardiovascular risk because their lives are dominated by self-imposed stress. Work expectations are driven by an unrelenting desire to achieve. An exaggerated sense of time urgency prompts accelerated locomotion and faster decision-making. Cynicism, hostility, and impatience, snuff out many personal relationships, denying the heart a much-needed rest from disharmony.

Under stress, the sympathetic nervous system is alerted and the release of adrenaline increases; ultimately, breathing, heartbeat, and blood pressure, also, increase. Cardiac patients are, often, prescribed beta-adrenergic blocking agents that calm the sympathetic nervous system, a gesture that asks a drug to succeed where attempts at lifestyle change may have failed.

Type D behavior, another variant having heart disease linkage, was recently described in the Lancet. (Denollet et al., 1996) Withheld and denied emotions, i.e., refusing to cry even when weeping is justified, and a lack of social connectedness (traits common to a type D personality) appear contributory to heart disease and stroke.

During periods of mental or emotional arousal, a silent ischemic attack (decreased supply of oxygenated blood) can occur. Though asymptomatic, severe heart damage may result. Unlike an angina attack, which is usually prompted by physical exertion, more than three fourths of silent ischemic attacks are caused by mental arousal. There is, also, a definite link between hardening of the carotid artery and higher levels of stress.

A recent study of 2800 men and women over 55 years of age showed that even minor depression can increase cardiac mortality by 60%, while major depression may actually triple the rate of cardiac-related death. (Penninx et al, 2001) There is, also, convincing evidence (published in ANZ J Surg) suggesting depression significantly increases the risk of mortality following myocardial infarctions and coronary bypass surgery. (Baker et al., 2001) Researchers explain the relationship between mind-set and mortality, pointing out the stress response to depression appears to trigger chronically high cortisol levels. Hormonal imbalances, in turn, can alter insulin resistance and increase blood pressure, magnifying the risks of a heart attack or surgery.

Stress protracts to so many traditional risk factors that emotions may be the dominant issue in coronary health. Note the following risk factors that share as their common bond, stress.

	Stress can destroy sound eating habits by the uncaring selection of inappropriate foodstuffs, eating hurriedly, or eating, not because of hunger, but as a respite from a dismal situation. Stress is a strong contributor to obesity, a factor in cardiovascular disease.
	Stress increases blood pressure. Studies involving 3000 Caucasians, suffering from depression and anxiety (ages 23 to 64) were found to have twice the risk of developing hypertension. The odds worsened for African-Americans, with the risk factor for hypertension increasing more than three times, during periods of unresolved stress. Even the companionship of a pet has been shown to reduce stress and the subsequent rise in blood pressure. (Relationship between psychological stress and coronary disease confirmed in journal Hypertension, (Hunyor, et al., 1997.)
	Stress makes blood glucose levels more difficult to control. Diabetes, a long-established risk to heart health, has been termed a disease fueled by emotions.
	Alternative Medical News reports that stress increases blood cholesterol levels. Students preparing for exams, Indianapolis 500 drivers (following the race), and accountants after the April 15th deadline show higher cholesterol levels. (Staff of Alternative Medical News, 1995)

HEREDITY

Scientific testing has advanced genetic screening far beyond compiling an oral history of ancestral successes and failures. Instead, geneticists are looking for mutated genes that may be expressing themselves, as contributors to coronary/artery disease. For example, 50% of suppressed HDL levels can be linked to genetic factors. A gene, ABC1, when mutated, appears responsible for increasing the risk of heart disease, by lowering levels of HDL cholesterol. Michael Hayden, professor of medical genetics at the University of British Columbia, reports that people with defects in ABC1 have just as much risk for heart disease because of too little HDL as individuals with high levels of LDL cholesterol.

The apoE4 variant of apoprotein E is the most well-defined genetic trait affecting poor LDL levels. A double allele, i.e., one apoE4 from each parent referred to as a double E4 genotype, reflects an increased prevalence of cardiovascular disease. Ronald Krauss, M.D., states that people with apoE4 have a tendency toward high blood cholesterol levels and increased heart disease risk. The apoE4 allele is very saturated fat sensitive, suggesting dietary manipulation may be of advantage to those with this genetic fault. In most cases, i.e., 90% or more of the population, modest dietary cholesterol has very little impact upon LDL cholesterol levels. (Bland, 2001) Moderate dietary cholesterol intake in apoE4 individuals can, however, lead to significant increases in plasma LDL levels. Bland challenges that public health recommendations do not address genotypes that alter dietary guidelines. Recommendations to universally avoid cholesterol-rich foods prevent some, who are not cholesterol sensitive, from eating a dietary that is a "pretty good food," as an egg.

Framingham researchers have found that a variation in the ACE (angiotensin converting enzyme) gene, apparently a sex-specific gene, may be an important contributor to high blood pressure in men. Men with the ACE variant have a 59% increased risk for developing hypertension.

Cardiac researchers at the University of California, San Diego School of Medicine have demonstrated that, in animal studies, the progression of heart failure can be completely arrested by inhibiting a single gene called phospholamban (PLB). This gene is a calcium-cycling gene, i.e., a gene that regulates the movement of calcium within heart muscle cells, promoting cardiac contractions. PLB acts as a brake on the calcium pump, increasing calcium storage so that it can be released on each heartbeat. The brake on the calcium pump is released by adrenaline, a sympathetic nervous system hormone; but, with a PLB failure, the balance between the accelerator and brake is disrupted. Either a heart attack or a genetic defect can cause the brake on the pump to be on too hard, thus restricting calcium and further weakening heart function. Cross breeding a mouse that is genetically engineered to develop heart failure with a mouse that lacks PLB produced an offspring with no signs of heart failure.

Dr. Paul Hopkins and researchers at the Cardiovascular Geriatrics Research Clinic in Salt Lake City, Utah, studied 266 patients with early coronary artery disease, all having a family history of early onset heart disease. They found high levels of homocysteine in this group, showing a connection between homocysteine and an inherited tendency to develop atherosclerosis.

Epidemiological evidence has shown homocysteine levels to be 45% lower in westernized adult black South Africans than in age-matched white adults, revealing racial genetic differences in homocysteine metabolism. (Vermaak et al., 1991) In fact, scientists at the Oregon Regional Primate Research Center theorize that refractory hyperhomocysteinemia may best be explained by disrupted gene expression. For example, about one half of individuals with hyperhomocysteinemia respond favorably to higher doses of vitamin B6, due to an inborn cystathionine synthase deficiency; others have a genetic deficiency of methylenetetrahydrofolate reductase (MTHFR). (Mudd et al., 1972)

A study reported in Nature Structural Biology showed that folates, derivatives of folic acid, work by activating MTHFR. (Guenther et al., 1999) MTHFR participates in homocysteine control by producing methyltetrahydrofolate, a compound that plays an important role in regulating blood homocysteine levels. Individuals with a mutation in the MTHFR gene lack the ability to convert folic acid into 5-methyltetrahydrofolate, an active contributor in the methyl donation pathway of the folate cycle. (James et al., 1999) Disruption of this cycle represents the domino effect (when one system fails to perform, others downstream suffer as well). In this case, homocysteine clearance is disrupted and hyperhomocysteinemia, a powerful endangerment to cardiac health, results. The genetic flaw is correctable by administering 5-methyltetrahydrofolate supplements, the principal circulating folate, to unlock the metabolic block. (Sagar et al., 2001) (Folinic acid (5-formylTHF) is available as calcium folinate (also know as leucovorin calcium) an immediate precursor to 5,10 methylenetetrahydrofolate.)

According to researchers reporting in the American Journal of Physiology, about 50% of individuals who are insulin resistant have the condition because of an inherited propensity. (Bogardus, et al., 1985) The other 50% fall victim because of lifestyle demerits, i.e., a lack of physical fitness, poor dietary selections, and obesity.

Approximately 32 million Americans are carriers for hemochromatosis, or iron overload. Hemochromatosis is predominantly a genetic disease reflecting abnormal iron metabolism. The gene responsible for hemochromatosis was identified in 1991 and contributes to excessive iron retention despite eating an ordinary diet. Small numbers of individuals with hemochromatosis acquire the condition through massive doses of iron supplements or blood transfusions, but the genetic form is most common. To learn more about hemochromatosis, consult Iron Overload, appearing in this section (Traditional Risk Factors).

Arteriosclerosis, Thrombosis and Vascular Biology reported that carotid plaque was significantly more common in both men and women whose parents died prematurely of coronary heart disease (CHD) than in subjects with no familial history of premature death from CHD. (Zureik et al., 1999)

Genetic factors can influence obesity and blood lipids. Laval University in Quebec, Canada determined that pairs of identical twins, overfed by the same amount of calories, showed nearly identical weight gain, body fat, and lipid levels. Comparisons of nonrelatives, participating in the study, showed little similarity.

GENDER

Cardiovascular disease, at one time, was considered to be, predominantly, a disease affecting men, not women. Statistics do not support this logic, for studies have demonstrated that heart disease is the number one killer for both men and women. Of the 1.1 million heart attacks reported annually, about 500,000 occur among women.

The Framingham Study reported findings involving 5,209 participants, 2,873 of whom were women. Results of the study follow:

	In both men and women, coronary heart disease has exceeded that of other cardiovascular illnesses, such as stroke or congestive heart failure.
	While coronary events occurred twice as often in men, with advancing age, the incidence of heart disease in women approaches that seen in men. Menopause appears the interval associated with a significant rise in coronary events, as well as a shift to more serious manifestations of the disease.
	The New England Journal of Medicine reported that hormone replacement therapy (HRT) in menopausal women with angiographic-determined heart disease did not lower the progression of the disease. (Nabulsi, 1993) New guidelines, issued by the American Heart Association, agreed that women with cardiovascular disease should not be given HRT for the sole purpose of preventing future heart attacks. HRT, in fact, raised the risk of recurrent attack and death during the first year of usage, and thereafter lowered it only slightly. (Mosca et al., 2001) Though estrogen replacement therapy may be helpful in lowering refractory lipoprotein(a) and high fibrinogen levels, it increases C-reactive protein levels, making its benefit an apparent stand off.
	Coronary heart disease manifests itself differently in men and women. In women, angina was the most common initial symptom, whereas in men, myocardial infarction was the most frequent first coronary symptom.
	High triglycerides were more predictive of eventual heart disease in women than in men. Elevations in C-reactive protein are, however, the single strongest predictor of future vascular risk, according to the Women's Health Study. Women with the highest levels of C-reactive protein in their blood had a five-fold increased risk of future cardiovascular disease and a sevenfold increase in heart attack, compared to those with low levels.
	When heart attack was the first coronary event, nearly half were unrecognized in women, compared to only 1/3 undetected in men.
	Only 56% of women suffering a heart attack can expect to live another year, compared to 73% of male victims. Twenty-seven percent of men who have a heart attack will likely have a second attack within six years, compared to 31% of women.
	Diabetes was a particularly potent coronary risk factor in women.
	While many studies have demonstrated that men who are active tend to live longer, it has never been clear that the same is true for women. Men had a clear exercise-response curve, with greater activity more effective than moderate. The women in the most active group had a higher rate of heart disease and mortality than did those in the moderately active group. An increased risk of sudden cardiac death in the more active women, demonstrates that the level of the exercise must match the strength and metabolic type of the participant.

SEDENTARY LIFESTYLE

Scientists believe that a properly planned exercise program may be the single greatest preventive against cardiovascular disease (CVD). It is extremely important, however, that the individual and the activity be properly matched. Even among young athletes, 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 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, either daily or every other day. In fact, Dr. Shah Ebrahim, a British cardiologist, states that sexually active men, i.e., those engaging in sex three or four times a week halve their risk of either a stroke or a heart attack. 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 mind-set that drives the sexual act.

The New England Journal of Medicine reported findings involving 180 postmenopausal women (45 to 64 years) and 197 men (30 to 64 years). (Stefanick et al., 1998) The participants were divided into 4 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, making them larger and less dense. (Recall that abnormally small LDL particles are highly susceptible to oxidation and elude standard testing processes, misrepresenting end results.)

Exercise reduces blood pressure and heart rate by quieting the sympathetic nervous system. As epinephrine (adrenaline) secretion decreases, blood pressure and heart rate also decrease. Consequently, 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 114,000 deaths occurring among Norwegian women. All of the women entered the study stroke free, but only the middle-aged to elderly women, who were physically active, retained their stroke-free status. (Ellekjaer et al., 2000)

Excessive fibrinogen, a risk factor for cardiovascular disease, is impacted by exercise. A study has shown 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.) Substantiation of this process occurred when 14 sedentary men (average age 35) and 12 men who were regularly active (average age 35) participated in exercise sessions, 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.

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 by as much as 25% and decreases the amount of insulin secreted after a carbohydrate load. Exercise makes the vasculature less prone to damage when insulin levels are unstable. Vulnerabilities associated with Syndrome X, i.e., diabetes, hypertension, hypertriglyceridemia, and suppressed HDL levels are, often, modifiable by exercise-induced weight loss.

If CVD has already 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. According to the Framingham Heart Study, only recent exercise, however, makes a significant difference. Exercise undertaken earlier in life showed no sustained cardio-protection.

Even low-intensity exercise can be a harbinger of free radicals; over exercising can generate enough free radials 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.

Having extolled the virtues of a properly planned exercise program, it is quite all right to enjoy an afternoon nap, as well. A recent Greek study found that men who regularly took a half-hour nap had a 30% lower risk of having a heart attack; men who rested for an hour reduced their risk by 50%.

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. 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. Tiejian Wu and colleagues at State University of New York reported that gum disease might, also, be related to hypercholesterolemia, though a weaker link is found between elevated cholesterol and gum disease than for elevations in C-reactive protein and fibrinogen.

Bleeding, red, swollen gums are depictive of gingivitis, a condition of inflammation and bone deterioration, promulgated by bacteria. Researchers at the University of Buffalo, New York School of Dental Medicine have determined that the bacteria, B. forsythus, P. gingivalus, and C. recta (oral pathogens) can inflict cardiac damage. Dr. Robert Genco found that the increased risk of heart problems in individuals with one or more of these bacteria was from 200-300%. Infection and Immunity, also, incriminated Eikenella corrodens and Prevotella intermedia as strains of bacteria capable of invading coronary artery cells. (Dorn et al, 1999) A study, involving 10,000 adults, concluded that periodontal disease should be regarded as a valid marker, for either frank or eventual heart disease.

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, a bad breath, or a discharge of pus. Turn to calcium, coenzyme Q10, and vitamin C in the Therapeutic Section to read about maintaining healthy gum tissue and avoiding periodontal disease.

HYPOTHYROIDISM (Low Thyroid Function)

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 influencing weight, reducing depression, and modulating cholesterol and homocysteine levels. Hypothyroidism impairs methionine metabolism, a key process in homocysteine control.

Researchers measured levels of homocysteine and cholesterol in 7000 individuals from a general U.S. population. (Morris et al., 2001) The 7000 were then subdivided into two groups: those with hypothyroidism and those with normal thyroid function. Those who tested positive for hypothyroidism (reference range for high sensitivity TSH testing is 0.34-5.00mIU/mL) were more likely to be white, female, and slightly older.

About two-thirds of those diagnosed with hypothyroidism had cholesterol levels nearly four times greater than normal. Approximately 50% of those thyroid impaired had high homocysteine levels, compared to 18% of people in the general population. It is estimated that about 90% of hypothyroid subjects in the U.S. population are either hypercholesterolemic or hyperhomocysteinemic as compared with only 31% of individuals with normal thyroid function.

A 5-year study involving 347 patients (reported in the Journal American Geriatric Society) evaluated the effects of thyroid therapy upon atherosclerosis. (Wren, 1968) One hundred thirty two individuals suffering from heart attack, stroke, angina pectoris or disruption in peripheral circulation (mean age 64.5 years) were among the patients enrolled in the study. Two hundred and fifteen of the 347 participants (mean age 54.7 years) were asymptomatic but 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 out 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 22%. Eleven patients died during the 5-year study, less than half of the expected rate based on U.S. Life Tables.

How might poor thyroid function contribute to arteriosclerotic vascular disease, i.e., hardening of the arteries? Researchers speculate that hypothyroidism may slow or decrease the metabolic breakdown of fats like cholesterol. It may also impair kidney function and interfere with the activity of an enzyme, methylenetetrahydrofolate reductase that the body depends upon to process (remethylate) homocysteine.

In addition, the Journal Card Fail reported that 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, tends to build up. (Shanoudy et al., 2001) A low T3/rT3 ratio is associated with a weakened ability of the left ventricle to pump blood and is highly predictive of poorer short-term outcome in patients with severe chronic heart failure.

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. (Valuable information regarding the thyroid gland is contained in the Therapeutic Section under soy protein.)

IRON OVERLOAD (Hemochromatosis)

Research to determine the effects of dietary iron on cardiovascular disease (CVD) have had mixed findings. Annals of Epidemiology reported that no association between iron levels and mortality from CVD was found in data collected from NHANES II and the National Death Index. (Sempos et al., 2000) The Journal of the American Heart Association chronicled an opposing view, reporting that free iron corresponds to a greater risk of heart disease by encouraging free radical production. (Stefan et al., 1997) The warning extended to exclude supplemental iron and foodstuffs containing high concentrations of iron. Data published in the American Journal of Epidemiology confirmed that excessive amounts of heme iron increased the risk of fatal myocardial infarctions. (Klipstein-Grobusch et al., 1999)

Hemochromatosis causes severe depletion of liver glutathione, an extremely important antioxidant. As glutathione is depleted, free radical damage becomes even more aggressive. The increase in free radical activity in brain cells can increase stroke progression. Stroke patients with high blood ferritin (a measurement of the total iron stored in the body), showed greater post stroke trauma, i.e., increased lethargy, aphasia, and unawareness.

Several studies have found that iron overload is most damaging to the heart if LDL cholesterol levels are, also, high. Free iron oxidizes LDL cholesterol; oxidized LDL cholesterol, markedly, increases the damage imposed upon the cardiovascular system. Understanding Normal and Clinical Nutrition reported that every 1% rise in blood iron increases the risk of heart disease by 4%. (Whitney et al., 1998)

High iron levels affect endothelial function by interfering with nitric oxide activity, a vasodilating, lipid lowering, and anti-platelet aggregating factor. When 10 healthy volunteers were injected with high doses of iron (0.7 mg/kg body weight), malondialdehyde (a marker for peroxidized polyunsaturated lipids) increased and the functionality of the endothelium was altered.

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. Dr. Hidehiro Matsuoka, of Kurume Medical School in Japan, says that people should watch their intake of iron with the same commitment that they watch cholesterol levels. This means being checked regularly for high iron levels, if over 40 years of age and displaying other risk factors for heart disease. Optimal iron levels appear to be <100 mcg/dL, though 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. Determining iron status is extremely important, for if untreated, iron overload becomes a strong contributor to atherosclerosis, irregular heartbeat, heart attack, or heart failure. Iron-induced cardiac irregularities can affect both young and senior subjects, even anemic individuals.

An individual with iron overload is frequently advised to avoid foods rich in vitamin C or vitamin C supplements because of the iron enhancing factors associated with the nutrient. (Many individuals with hemochromatosis can, however, use 500 mg of buffered vitamin C 3 times per day between meals.) Cast-iron cookware and iron-fortified foodstuffs should be avoided, and meats and alcohol restricted. On the other hand, coffee and tea consumed with meals assist in blocking iron absorption from foods. Fruits (non-ascorbic acid varieties) and vegetables are excellent dietary choices. 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, 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 denote 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.

It is important to note that adequate amounts of iron are absolutely essential to good health, but using iron supplements or iron fortified foods are not recommended for men or postmenopausal women, unless diagnosed with an iron deficiency. It is judged that approximately one out of every 200 people actually have 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 by 33%. This is due largely to adherence to traditional risk factors. Dr. Paul M. Ridker, M.D., M.P.H., Director of Cardiovascular Research, at Brigham and Women's Hospital, Boston, Massachusetts speculates that an auxiliary list of newer predictive factors may increase the numbers benefiting from 21st Century diagnostics and treatment. (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, i.e., an interaction between clotting factors and naturally occurring anticoagulants, normally results in healthy levels of fibrinogen and normal coagulation. If, however, fibrinogen levels increase above normal, a blood clot becomes a threat; if fibrinogen levels decrease below normal, a hemorrhage can result. Though 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 initiates a series of chemical reactions that results in the production of prothrombin activators. Prothrombin activators convert prothrombin to thrombin, which in turn converts fibrinogen into fibrin. This network of protein fibers traps blood cells, bloodstream infiltrates, and platelets producing a clot.

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; but 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. Abnormal platelet stickiness increases atherosclerosis and further narrows the arteries, preliminaries to most strokes and heart attacks. Fibrinogen promotes the negative activity of platelets by encouraging their binding together, a sequence common to a deadly blood clot.

About 700,000 heart attack and stroke deaths occur each year in the U.S., as a result of a blood clot obstructing the delivery of blood to the heart or the brain. This occurs, in part, because fibrinogen combines well with LDL cholesterol, initiating plaque formation. If fibrinogen is then converted to fibrin (a protein having the nature of barbed wire), other bloodstream infiltrates can become entrapped in the tangle. From this mesh, emerges an atheromatous tumor, capable of continued growth until full occlusion occurs. Closure represents only part of the risk, for plaque is highly susceptible to breakage and clot formation.

Fibrinogen, also, plays a role in monocyte adhesion and smooth muscle proliferation, adding to the likelihood of vascular closure. Reports published 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. (Wilhelmsen et al., 1984)

The Life Extension Foundation (LEF) was the first research group to recognize the importance of assessing fibrinogen as an independent risk factor for cardiovascular disease. A study in the Journal of the American College of Cardiology corroborated LEF's position on fibrinogen, when nearly 400 male physicians participated in the Physicians' Health Study. (Jing et al., 1999) 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 with those physicians with healthy fibrinogen levels. Several studies have shown a stronger association between cardiovascular deaths and fibrinogen levels than for cholesterol.

A study, involving 3043 patients with angina pectoris who underwent coronary angiography and were followed for 2 years thereafter, concluded that higher base-line levels of fibrinogen was an independent predictor of an increased incidence of myocardial infarction or sudden death. In contrast, coronary risk was low among patients with low fibrinogen concentrations despite increased serum cholesterol levels. (Thompson et al., 1995)

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. Fibrinogen appears to have an attraction for calcium; as fibrinogen and calcium unite, the valvular diameter becomes smaller.

Various factors influence plasma fibrinogen levels. For example:

	Homocysteine, by inhibiting the production of tissue plasminogen activators, a substance that breaks down fibrinogen, contributes to fibrinogen excesses.
	Fibrinolysis and Proteolysis reported that increased winter cardiovascular mortality is related to a cold weather increase in fibrinogen concentrations. (Exposure to cold increases fibrinogen levels by about 23%.) (Khaw et al., 1997)
	Smokers and sedentary people have higher levels of fibrinogen.
	Nutrient depletion can retard fibrinolysis and increase fibrinogen levels.
	Infections tend to increase fibrinogen levels.
	Estrogen replacement therapy appears to attenuate normal age-related increases in fibrinogen, while Lopid (gemfibrozil) increases fibrinogen by 9% to 21%.

Unfortunately, pharmaceutical drugs have not been of significant value in reducing fibrinogen levels. Initial data suggested that Bezafibrate, a European drug, reduced fibrinogen levels in patients with established coronary heart disease. The Bezafibrate Infarction Prevention Study yielded disappointing results, however, with no significant evidence of efficacy in lowering fibrinogen.

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 natural products with either fibrinolytic or platelet aggregation inhibiting activity as, aspirin, bromelain, curcumin, essential fatty acids, garlic, ginger, ginkgo biloba, green tea, gugulipid, niacin, pantethine, policosanol, proanthocyanidins, vitamin A and beta-carotene, vitamin C, vitamin E, and homocysteine-lowering nutrients. (Recall that homocysteine, by inhibiting the production of tissue plasminogen activators, contributes to fibrinogen excesses.)

To read more about fibrinogen, consult the sections entitled Obesity, Sedentary Lifestyle, Gum Disease, and Fibrinolytic Activity, Introduction to Homocysteine, and Link Between Infection and Inflammation In Heart Disease contained in this protocol.

FIBRINOLYTIC ACTIVITY

Balance between tissue plasminogen activators (t-PA) and plasminogen inhibitors (PAI-1) controls activity of the fibrinolytic system in healthy individuals. If the fibrinolytic process is impaired, individuals can be classed as either hemorrhage or thrombosis prone. Generally, an increased PAI-1 concentration reflects 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 studies of both animals and humans 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.

The N Engl J Med 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) Barry Sears, Ph.D., believes scientific evidence has, rightly, exposed hyperinsulinemia as an indicator of an eventual heart attack. Hyperinsulinemia bestows some of its coronary damage by increasing the risk of hypertension (twofold), hypertriglyceridemia (three to fourfold), type 2-diabetes (five to six fold), and diminishing HDL levels. Impaired fibrinolytic activity appears to be a contributor in this sequence.

Though blood clots loom as one of the dominant factors in cardiovascular disease, the selection of supplements that favors fibrinolysis and discourages platelet aggregation should be done sensibly. It is possible that the cumulative value of nutrients with similar intent, i.e., blood thinners and anti-fibrinogens, could, significantly, overcorrect a condition, particularly if used in concert with prescribed blood thinners.

The Lancet reported that asymptomatic patients on warfarin, a blood thinning therapy, should consider low-dose vitamin K if blood-clotting time, as measured by the international normalized ratio (INR), is between 4.5 and 10.0. (Crowther et al., 2000) Follow-up studies to determine the success of vitamin K therapy (1 mg/day) showed that 4% of the patients who received vitamin K therapy had bleeding episodes, compared with 17% of those in the placebo group. The conclusion of the study was that low dose Vitamin K, an inexpensive intervention without known toxicity, might prevent a hemorrhage in patients on warfarin therapy.

Research suggests that many 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 non-inflamed vessel. Pain, swelling, and inflammation may follow if the vein is significantly occluded. Prothrombin is an intermediate factor in the coagulation process.

LIPOPROTEIN(a)…Lp(a)

Peak time for a heart attack appears to be between 6:00 AM and 12:00 noon. Heart attacks occurring during these hours are thought to cause more heart damage than those occurring at other times of the day. The "why" is deeply concerning 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?

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. It has a lipoprotein structure, nearly identical to LDL cholesterol. A variation occurs when a disulfide bond attaches Apo(a), a protein having the nature of plasminogen, to the lipoprotein. LDL + Apo(a) = Lp(a). Plasminogen is an inactive plasma protein that is converted to its active form, plasmin (also called fibrinolysin), an agent capable of dissolving fibrin.

Because of similar structure, it is theorized that Lp(a) competes for plasminogen that binds to fibrin and the surface of endothelial cells, inhibiting the break down of fibrin. Thus it appears that Lp(a) alters fibrinolysis (the breakdown of fibrin) occurring at the cell surface and inhibits plasminogen binding to fibrin. The end result is a greater risk of blood clot formation. (Loscalzo et al., 1990)

Complicating the atherosclerotic/Lp(a) mechanism, Apo(a) has a sticky, Velcro nature, causing it to easily tie up in blood vessels. Apo(a)'s adhesiveness provides an ideal trap for LDL, VLDL, and other bloodstream infiltrates, as 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. Recent studies also incriminated lipoprotein(a) in angina pectoris, sighting accumulations of Lp(a) in the plaque of unstable angina patients.

The risk of a major coronary 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. (VonEchardstein et al., 2001) The risks escalate even higher if Lp(a) coexists with high LDL cholesterol, low HDL cholesterol, and hypertension. Investigators, also, noted elevated Lp(a), i.e., above 30 mg/dL in 20% of all thromboembolism patients, compared to 7% of healthy controls. 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.

Plaque formation is an essential response to vascular injury. When a blood vessel has been damaged, repair is paramount. If benign materials are available, as vitamin C, 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.

There is a vast difference between 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, i.e., 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.

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 deposition of Lp(a) on the aortic valve creates a binding site for calcium. Please consult the section devoted to valvular disease, for an in-depth discussion, relating to aortic stenosis.

The reference interval for Lp(a) is 0-30 mg/dL. Reference ranges are only valuable as generic markers. Depending upon the test, risk may be, significantly, increased as values reach upper or lower limits of normal.

Read about essential fatty acids, niacin, vitamin A, and vitamin C (nutrients that assist in maintaining healthy levels of lipoprotein(a)) in the Therapeutic Section of this material. Introduction to Homocysteine (below) provides additional information relating to Lp(a).

Introduction to HOMOCYSTEINE

(Consult Homocysteine Lowering Nutrients and Elimination Pathways in the Therapeutic Section for a discussion relating to detoxification mechanisms and nutrients to reduce homocysteine levels.)

Homocysteine, a sulfur containing amino acid, is in the forefront as a cardiovascular risk factor. Though its role in atherosclerosis and atherothrombosis is confirmed, it should be noted that most naturally occurring substances have purpose in physiology; homocysteine is not the exception.

The American Academy of Family Physicians explains that homocysteine is normally changed into other amino acids for use in the body's normal functions. For example, homocysteine is an intermediate in the biosynthesis of L-cysteine, a non-essential amino acid and metabolic precursor to cystine. Cysteine is important in fatty acid synthesis and energy metabolism, but its most important role takes place in the liver where it assists glutathione in the detoxification of carcinogens and dangerous chemicals. (Braverman, 1987) Once cysteine is generated, it can be directed into several pathways, including synthesis of glutathione and taurine. Amino acids play strategic roles in cardiac function, cholesterol excretion, and bile salt formation. (Lehninger et al., 1993) Because the intermediate metabolite, homocysteine, is located in a critical metabolic crossroad, it either directly or indirectly impacts all methyl and sulfur group metabolism occurring in the body. (Miller, et al., 1997)

Some researchers believe that the residuals of homocysteine may support the adrenal glands, contribute to neurotransmitter synthesis and the regeneration of bones and cartilage. It should be strongly emphasized that homocysteine must be detoxified in order for its by-products to offer bio-chemical advantage. If disposal systems (remethylation and transsulfuration) are nonfunctional, allowing homocysteine to accumulate, the results can be deadly. Remethylation and transsulfuration are discussed in detail in the Therapeutic Section of this protocol under Homocysteine Lowering Nutrients and Elimination Pathways.

Experiments have demonstrated if high levels of homocysteine accumulate in the cell, all methylation reactions are completely inhibited. (Duerre et al., 1981) Because methylation is used for so many body processes apart from homocysteine metabolism, if this system becomes less functional, multiple negatives can occur. For example, methylation is fundamental to maintaining healthy DNA; without DNA repair, mutations and strand breaks occur. Also, the liver depends upon methylation to perform the rites of detoxification. Nutrients considered methylation enhancers are vitamin B12, folic acid, zinc, trimethylglycine, choline, and vitamin B6. (Vitamin B6 is of particular importance if the diet emphasizes methionine-rich foods, i.e., animal products.)

If homocysteine is not detoxified and begins to accumulate, plaque builds up in the endothelial cells lining the arteries. This occurs as homocysteine reacts with LDL to form small, dense particles. Macrophages use these particles to form foam cells, that historically like to "swell," protruding into the space of the artery, obstructing blood flow. Elevated levels of homocysteine, also, block production of nitric oxide in the cells of the blood vessel walls, making the vessels less pliable and even more susceptible to plaque buildup. Dr. Kilmer McCully, crusader for the homocysteine theory of heart disease, says that homocysteine plays a key role in every pathophysiological process that leads to arteriosclerotic plaque. (McCully, 1996)

The Journal Clin Invest reported that homocysteine facilitates the generation of hydrogen peroxide. By creating oxidative damage to LDL cholesterol and endothelial cell membranes, hydrogen peroxide can then catalyze injury to vascular endothelium. (Starkebaum G et al., 1986) Stamler et al., 1993) Nitric oxide, released by endothelial cells (also known as endothelium-derived relaxing factor), protects endothelial cells from damage by reacting with homocysteine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation. However, as homocysteine levels increase, this protective mechanism can become overloaded, allowing damage to endothelial cells to occur. (Stamler et al., 1992) (Stamler et al., 1996)

A heart attack or stroke is more likely to occur as homocysteine inhibits the production of tissue plasminogen activators (a substance produced naturally by cells in the walls of blood vessels that breaks down fibrinogen). Thromboxane A2, a pro-platelet aggregating compound, increases, as well as the binding of Lp(a) to atheromatous materials. Blood flow, as demonstrated by numerous studies, is significantly impaired, particularly among middle aged and senior subjects with high levels of homocysteine.

The European Journal of Clinical Investigation reported that 40% of all stroke victims have elevated homocysteine levels compared to only 6% of controls. (Brattstrom et al., 1992) Other studies chronicled similar findings, i.e., elevations in homocysteine in 16 out of 38 patients with cerebrovascular disease (42%), 7 of 25 with peripheral vascular disease (28%), and 18 of 60 with coronary vascular disease (30%), but in none of the 27 normal subjects. (Clarke et al., 1991) A team from Massachusetts General reported even more incriminating data, announcing that mild-moderate hyperhomocysteinemia independently increased the risk of stroke by 86%. (Results collected through meta-analysis of 15 studies and reported by Kelly, 2001) High concentrations of homocysteine and low levels of folate and vitamin B6 are, also, associated with an increased risk of extracranial carotid-artery stenosis in the elderly. (Selhub et al., 1995) Higher levels of homocysteine predispose deep venous thrombosis, as well. (den Heijer et al., 1996)

Because homocysteine encourages free radical activity, genes are also involved in the homocysteine attack. This has significant impact upon the cardiovascular system, as homocysteine activates genes in blood vessels, encouraging the coagulation process and the proliferation of smooth muscles. Since homocysteine wields such a powerful cardiovascular blow from so many different directions, it is estimated that a 3-unit increase in homocysteine equates to a 35% increase in heart attack risk. (Verhoef et al., 1996) The risk becomes even greater if hyperhomocysteinemia occurs with other risk factors. For example, a hypertensive woman with elevated homocysteine levels has a 25-fold increased risk of vascular disease.

Though the dangers imposed by hyperhomocysteinemia are not a new find, most of the medical community has (until recently) ignored homocysteine, as a cardiovascular risk. Decades ago, Dr. 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 Nov. 1981 (Anti-Aging News pp 85-86). Eric Braverman, M.D., joined the crusade, describing homocysteine as a substance worse then cholesterol. 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 excessive 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. While cholesterol does not, normally, pose a cardiac risk until levels exceed 240 mg/dL, some researchers consider homocysteine so capricious that even so called "normal" levels may contribute to heart disease.

Homocysteine levels should be kept as low as possible, i.e., below 7 micromolar per liter of blood plasma. Laboratories usually regard levels up to 15 micro mol/L as normal, but epidemiological data reveal that homocysteine levels above 6.3 reflect a steep, progressive increase in the risk of a heart attack. (Robinson et al., 1995) Though the incidence of hypertension, thrombotic stroke, peripheral vascular disease (gangrene), blood vessel toxicity, and the risk of heart attack escalate as homocysteine levels increase, tests to measure homocysteine are not routinely ordered in a cardiovascular workup.

The incrimination of homocysteine in the disease process continues:

	While the focus of this protocol is upon cardiovascular disease, it should be noted that individuals suffering with Alzheimer's disease, depression, eye problems, liver damage, several types of malignancies, i.e., acute lymphoblastic leukemia, breast, pancreatic, and ovarian cancer, Crohn's disease, ulcerative colitis, and irritable bowel disease, often, present with elevated homocysteine levels. (Clarke et al., 1998) (Cattaneo et al., 1998) (Mayer et al., 1997) (Refsum et al., 1991) (Romagnuolo et al., 2001)
	Plasma homocysteine levels predictably increase with elevations in creatinine. Chronic renal failure can cause homocysteine levels to skyrocket up to 4 times normal value. (Wilcken et al., 1979) (Chauveau et al., 1993)
	The link between hyperhomocysteinemia and hypothyroidism is clearly drawn in the sections devoted to Hypothyroidism and Soy Protein appearing in this protocol.
	Patients with pernicious anemia (PA) are frequently hyperhomocysteinemic; elevated homocysteine levels are, in fact, helpful in diagnosing PA. (Savage et al., 1994)
	Homocysteine metabolism is impaired in patients with type II diabetes. Intramuscular injections of 1000 mcg of methylcobalamin daily for 3 weeks reduced elevations of plasma homocysteine in diabetic test subjects. (Araki et al., 1993)

To read about the impact smoking, diabetes, stress, genetics, and hypothyroidism has upon homocysteine levels, please consult the section in this protocol devoted to Traditional Risk Factors. In the Therapetuic Secion, essential fatty acids, magnesium, and homocysteine-lowering nutrients (vitamin B6, vitamin B12, folic acid, and trimethylglycine) detail a program to assist in managing hyperhomocysteinemia. Because of homocysteine's role in sulfur and methyl group metabolism, elevated levels of homocysteine would be expected to negatively impact the biosynthesis of SAMe, carnitine, chondroitin sulfate, coenzymeQ10, creatine, cysteine, dimethylglycine, epinephrine, glucosamine sulfate, glutathione, melatonin, pantethine, phosphatidylcholine, and taurine. Many of these substances are profiled in the Therapeutic Section for their cardio-protection/restorative qualities. Short supply of these nutrients could severely disable cardiac performance.

SYNDROME X (Metabolic Syndrome, i.e., insulin resistance and hyperinsulinemia)

Eclectic physicians have, for the past 20 years, judged hyperinsulinism, or Syndrome X, a powerful indicator of an eventual heart attack. For clarity, let it be understood that a syndrome represents clusters of symptoms; in Syndrome X the symptoms are an inability to fully metabolize carbohydrates, hypertriglyceridemia, reduced HDL, smaller, denser LDL particles, increased blood pressure, visceral adiposity, disrupted coagulation factors, insulin resistance, hyperinsulinemia, and, often, increased levels of uric acid.

For years, high uric acid levels have been associated with cardiovascular disease, but the relationship was poorly understood. Dr. Gerald Reaven unraveled the link when he determined that elevations in uric acid are, often, promulgated by Syndrome X; Syndrome X, in turn, is a forerunner to heart disease. (Fang et al., 2000)

Until hyperinsulinemia is diagnosed and a therapeutic course charted, the arteries are under severe attack and the risk of a blood clot increases. Lesions, i.e., wounds and injuries, damage the arteries; attempts at vascular repair corrode the vasculature with atheromatous material, blockading and closing off vital circulatory routes. The population of sticky platelets increases, as well as the production of free radicals. Lipogenesis (the production and accumulation of fat in arterial tissue) encourages smooth muscles in the vasculature to proliferate. Along with excessive amounts of fibrinogen (a plasma protein that encourages the clotting of blood), PAI-1 (an inhibitor of the fibrinolytic process) becomes more active, further increasing the likelihood of a blood clot. HMG-CoA reductase, the rate-limiting enzyme involved in hepatic cholesterol production, appears simulated in both diabetic and non-diabetic animal studies amidst high levels of insulin. (Dietsschy et al., 1974)