Cardiovascular Disease: Comprehensive Analysis

Cardiovascular disease is rarely 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 its prevention and treatment than exists for other diseases. Overlooking just one risk factor, such as elevated levels of C-reactive protein, fibrinogen, or homocysteine, could lead to the development or worsening of the heart and/or vascular disease. The Cardiovascular Disease protocol is the most comprehensive chapter in this book; we urge persons concerned with the disease to study the chapter carefully. This comprehensive analysis of cardiovascular disease could be a book in and of itself. If you prefer to review a more succinct version, refer to the protocol entitled Cardiovascular Disease: Overview.

At least 68 million people in the United States suffer from some form of heart disease, with an estimated 1.1 million Americans annually experiencing an acute myocardial infarction (MI or heart attack). According to current statistics released from the American Heart Association, cardiovascular disease accounts for about 950,000 deaths annually (about 41% of total mortality from all causes); coronary heart disease accounts for 460,000 of those deaths. In fact, one person dies every 33 seconds from heart disease, culminating in about 2600 deaths every single day. Additionally, the scope of this insidious health problem is worldwide. Globally, cardiovascular disease accounts for almost 50% of all deaths (GSDL 2002).

Researchers reporting in the American Journal of Critical Care further unsettled the scientific community when they declared that 50% of 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 signs of heart disease. Does this mean that traditional risk factors are no longer valid?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 review 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 (Lotufo et al. 2000). The study evaluated the following patterns of hair growth: no hair loss, frontal baldness only, and 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 to be 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

About 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 medical literature, with one involving 264 patients from a university-based coronary care unit or a catheterization laboratory who were followed for 10 years. Researchers concluded that after adjusting for other risk factors, the presence of a unilateral earlobe crease was associated with a 33% increase in the risk of a heart attack; the risk increased to 77% when the earlobe crease appeared bilaterally (Elliott et al. 1996).

Diagonal earlobe creases, appearing at a 45° downward angle toward the shoulder, are a better predictor of sudden death from a heart attack than age, smoking, obesity, elevated cholesterol levels, or a sedentary lifestyle, particularly before the age of 80. The predictive value of the diagonal earlobe crease does not apply to Asians, Native Americans, or children with Beckwith's syndrome (a heredity disorder associated with neonatal hypoglycemia and hyperinsulinism) (Elliott 1983). 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 noncoronary diagnosis 90% of the time (Pearson et al. 1982).

SMOKING

Kentucky and Tennessee have not only the highest rates of heart disease deaths, but also the highest rates of cigarette smoking. Prolonged exposure to cigarette smoke, either direct or secondhand, 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.

The following reactions define the hardship cigarette smoking imposes upon the cardiovascular system: increased heart rate (one cigarette can increase the heart rate 20-25 beats a minute); disrupted circulation to the legs and feet (it takes 6 hours for the circulation to return to normal after just one cigarette); an increased need for oxygen; insulin resistance; hypertension; and higher levels of adrenaline. Note: Smoking doubles the blood levels of adrenaline. This results in vasoconstriction and platelet aggregation, increasing the risk of both heart attacks and strokes.

Earl Mindell, R.Ph., Ph.D., warns that smokers have higher levels of fibrinogen (Mindell 1998). Fibrinogen is necessary for the 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 4000 poisons in tobacco), some of which inactivate vitamin B6, a nutrient extremely important in homocysteine control. Homocysteine management is typically difficult in smokers (consult Newer Risk Factors in this protocol for a complete discussion regarding homocysteine; the Therapeutic Section of this protocol outlines a detailed strategy to reduce homocysteine levels).

The Lancet added to the concerns surrounding smokers when it 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 (Mindell 1998).

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

It is estimated that each cigarette steals 8 minutes of life from a smoker. This means that an individual smoking one pack a day loses a month of life each year. Two packs clip 12-16 years off the life expectancy of a lifetime smoker (Goldberg 1999).

However, it is important for a smoker to realize that the body has an 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 2-3 months, circulation improves and walking becomes easier. Lung capacity increases up to 30% and energy levels rebound. After 1 year, the risk of a heart attack is 50% less than the individual still smoking; within 2 years, the risk of heart attack drops to ranges closely rivaling an individual who has never smoked. Another bonus occurs as inflammation is reduced and subsequently C-reactive protein (CRP), a newer cardiovascular risk factor (discussed later in this protocol), decreases.

Although 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 a smoker, turn to the Bromelain, Coenzyme Q10, Curcumin, Proanthocyanidins, Vitamin C, and Vitamin E subsections in the Therapeutic section of this protocol.

HYPERTENSION

Hypertension, observed more in men and African Americans, is a disorder characterized by blood pressure persistently exceeding 140/90 mmHg. Current research indicates that an optimal blood pressure is below 120/80 mmHg. 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 because symptoms such as epistaxis (nosebleed), tinnitus, dizziness, headache, blurred vision, and arrhythmias are not always present.

Dr. Charles DeCarli (University of Kansas) found that men who had even mildly elevated blood pressure 25 years earlier now have abnormal brain signals and suffer from vascular disease and strokes more often 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 the results of the most comprehensive study to date, evaluating 10,874 Chicago men (ages 18-39 from 1967-1973) concerning the long-term effects of high blood pressure. About 62% of those studied had either high-normal blood pressure (systolic pressure 130-139 and diastolic pressure 85-89) or Stage I hypertension (systolic pressure 140-159 and diastolic pressure 90-99).

Individuals with a high-normal blood pressure had a 34% increased risk of dying from coronary heart disease and those with Stage I hypertension a 50% higher risk. Life expectancy was shortened by 2.2 years for men with high-normal blood pressure and by 4.1 years for those with Stage I hypertension. Dr. David A. Meyerson (Johns Hopkins cardiologist and spokesman for the American Heart Association) said the Chicago study affirms the need for a population-wide effort for health promotion by lifestyle modification; the commitment should begin early in life and continue lifelong. Since the lifetime risk for hypertension among middle-aged and elderly individuals is 90%, corrective intervention (at an earlier age) could relieve a huge public health burden (Miura et al. 2001; Vasan et al. 2002).

Findings in the New England Journal of Medicine (exploring the role of moderately elevated blood pressure as a forerunner of heart disease) concurred with the results gathered from the Chicago hypertension trial (Vasan 2001). The parameters describing moderately elevated blood pressure were identical in both trials, that is, a systolic pressure of 130-139, a diastolic blood pressure of 85-89, or both. The researchers tracked 6859 participants, noting a stepwise increase in cardiovascular events among persons with higher base line blood pressure. 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.

Diastolic or Systolic: Which Poses the
Greater 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 present.

Types of Hypertension
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 blood vessels, the brain, the retina, the kidneys, and the heart.

Secondary hypertension is frequently linked to primary diseases, such as renal, pulmonary, endocrine, and vascular diseases. Malignant hypertension, the most lethal form, is characterized by severely elevated blood pressure that commonly damages major organs and the vascular system. Many patients with this condition exhibit signs of hypokalemia (inadequate levels of potassium in the bloodstream), alkalosis (blood pH >7.45), and excessive aldosterone secretion (a hormone that conserves water and sodium and increases potassium excretion).

How Does Hypertension Inflict Damage?
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, the arterial walls become thickened, inelastic, and resistant to blood flow. This process injures arterial linings and accelerates plaque formation. Nonfunctional 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 backflow. A lack of egress and the heart's aggressive action can cause a weakened area in the arterial wall to balloon, forming an aneurysm. The 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 the individual has high cholesterol and/or elevated blood pressure.

Watch Serum Creatinine Levels
Serum creatinine levels in hypertensive patients are an extremely important marker, and unfortunately one frequently ignored. Creatinine is 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 subjects. It was determined that 50% of hypertensive individuals with creatinine levels of 2.5 mg/dL (or greater) die within 8 years. According to Dr. Neil B. Shulman (principal investigator) cardiac deaths begin to spiral when creatinine levels reach 1.7 mg/dL, with fatalities mounting as creatinine increases. Although high levels of creatinine frequently reflect kidney impairment, most individuals with high creatinine die as a result of a heart attack or stroke, not renal disease (Shulman 1989).

Syndrome X and Hypertension
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, makes the sympathetic nervous system dominant and results in the release of catecholamines, that is, dopamine, epinephrine, and norepinephrine, which contribute to hypertension by diminishing blood vessel diameter. Hyperinsulinemia also encourages the 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 hyperinsulinemia (excess blood insulin) primarily rather than focusing on a symptom of the syndrome, that is, 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 a heart attack can be expected (Reaven 2000).

Blood Pressure Medication:
Often Disappointing
Patients are searching for alternatives to hypertension medications in light of the information gathered from an 8-year study involving 117,534 people. Half of the individuals were given antihypertensive 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; however, the side effects of the drugs eroded the equality of the results. Additional information regarding compliance/response rates among hypertensive patients using drugs to reduce blood pressure may be found in the British Medical Journal (Nuesch et al. 2001).

If an antihypertensive drug therapy is used, Cozaar or Hyzaar (angiotensin II antagonists) appear to be safer and more effective than short-acting calcium channel blockers. It should be noted that beta-blockers and diuretics (antihypertensive treatments) have been associated with an increased risk of developing diabetes by impairing insulin sensitivity. However, benefits have been obtained using alpha-1-blockers (antihypertensive vasorelaxants) in regard to increasing insulin sensitivity (Lithell 1996). Unfortunately, the National Heart, Lung, and Blood Institute stopped one phase of a large hypertension study because alpha-blockers were found less effective (even dangerous) compared to more traditional drugs in reducing the incidence of cardiovascular events. The troublesome results surfaced after gathering statistics from the ALLHAT (Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial) study (ALLHAT 2000).

During the course of the ALLHAT study, it was found that subjects taking doxazosin (Cardoxan, Carduran, and Dosan) had a 25% higher risk of death from coronary heart disease, as well as nonfatal myocardial infarction, peripheral artery disease, stroke, angina, and congestive heart failure. The high numbers of cardiovascular events could chiefly be explained by a doubled risk for congestive heart failure. The other significant finding was that doxazosin was less effective (by an average of 3 mmHg) in controlling systolic blood pressure compared to other drugs evaluated. The researchers surmised that while this discovery may explain the higher risk for angina (16%) and stroke (19%), it could not fully account for the doubling of congestive heart failure (IHP Information for Health Professionals 2000).

The HOPE Project
On March 11, 2000 , a satellite symposium of the American College of Cardiology Scientific Session was held during which several speakers discussed the results of the Heart Outcomes Prevention Evaluation (HOPE) study. The study represented a 6-year undertaking, assessing the value of ramipril (an angiotensin-converting enzyme, or ACE inhibitor) in the prevention and management of cardiovascular disease (Anon. 1993; Hall et al. 1997; Doctors' Guide 1999). Ramipril, a generic of the drug Altace, is principally used in the treatment of high blood pressure, but its 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 (see the comments regarding the unfavorable review of vitamin E).

Some 9500 people from 270 hospitals in 19 countries participated in the HOPE study. Included in the trial were those with evidence of 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 ), reported that ramipril reduced the risk of new heart attacks, strokes, and mortality by 20-25%. Diabetic complications, heart failures, and the need for coronary revascularization (reestablishing blood flow through surgical means) were significantly reduced as well. Dr. Yusuf reported on another phase of the HOPE study, that is, documenting the worth of vitamin E as a cardioprotector, announcing that no advantage was observed with 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 an obvious benefit it was deemed unethical to withhold the drug from the control group. In fact, 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 medical problems even in the absence of hypertension.

According to Dr. Bertram Pitt (professor of internal medicine at the University of Michigan ) the HOPE study confirms that the activation of the renin-angiotensin system impacts the risk of a heart attack through various pathways. For example, when angiotensin II is elevated, it affects the transport of cholesterol into the vessel wall and its oxidation, as well as increasing cytokines, inflammatory proteins. This begins a cycle that involves high levels of low density lipoproteins (LDLs), increasing angiotensin II, which, in turn, increases the oxidation of LDL cholesterol.

In addition, 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 II also leads to inflammation. The result is a sequence that constantly increases angiotensin production and inflammation, events invitational to atherosclerosis and ischemic events. The power of ACE inhibitors (such as ramipril) to prevent cardiovascular disease is partially explained by their ability to interrupt these cycles.

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 4.5 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 resulted in improved insulin sensitivity.

A remarkable 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 was observed. Nonetheless, a clear reduction in unwanted outcomes, that is, cardiovascular deaths, myocardial infarctions, and strokes occurred in all blood pressure categories. Dr. Yusuf speculates that 2 million people a year could be spared a major cardiovascular event if ramipril were widely used.

Researchers were impressed with the absence of side effects during the course of the trial. However, if a patient has hyperch lo r lemia (an excess of chloride in the blood) or renal dysfunction, the physician should be very careful about administering any ACE inhibitor. If ramipril is to be used, 10 mg a day appears to be the optimal dosage. Hypertensive 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 in which vitamin E is used determines its cardiovascular defense. Dr. Passwater showed (1977) 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. Also, the type and blend of vitamin E administered can alter outcome. The Life Extension Foundation has long advocated a complex of alpha-tocopherol (80%) with gamma-tocopherol (20%) for optimal protection.

In contrast to the HOPE study, The Lancet reported the benefit of administering 800 IU a day of alpha-tocopherol (vitamin E) to individuals with preexisting cardiovascular disease and on hemodialysis (Boaz et al. 2000). Increased oxidative stress (imposed through dialysis) appears to increase cardiovascular mortality. A total of 15 (16%) of the 97 patients assigned to vitamin E and 33 (33%) of the 99 patients assigned to placebo had a primary endpoint. Five (5.1%) patients assigned to vitamin E and 17 (17.2%) patients assigned to placebo had myocardial infarctions.

A new Israeli study showed the incidence of a fatal heart attack was 43% lower in a vitamin E supplemented group compared to a placebo group. Despite the reduced death rate from heart disease in the vitamin E group, both vitamin E and placebo groups had approximately the same overall risk of dying during the course of the trial. The increase in noncardiac deaths (which included deaths from a car accident, surgery, and complications following kidney transplantation) appears to be a distortion of statistics (Austin 2002).

While bewildering to the consumer, varying dosages and blends of vitamin E applied to diverse populations often result in dissimilar conclusions. Turn to the Vitamin E subsection in the Therapeutic section to read about Dr. Passwater's study, as well as current documentation supporting supplementation to protect against cardiovascular disease.

The Therapeutic section also highlights numerous suggestions to treat hypertension, including alpha-lipoic acid, L-arginine, calcium, coenzyme Q10, essential fatty acids, garlic, hawthorn, magnesium, olive leaf extract, policosanol, potassium, taurine, and vitamin C. Natural ACE inhibitors are green tea, garlic, hawthorn, olive leaf, taurine, proanthocyanidins, angelica, and ginkgo biloba. To read about the influence other conditions have on hypertension, consult the following sections in 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 the United States , 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 for heart disease. Measuring body mass index (BMI) has helped physicians and patients answer this question.

During the American Heart Association's 71st Scientific Session (in 1998), the 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 (Edelsberg et al. 1998). 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, that is, apple-shaped bodies, are 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--that is, gynoid or pear-shaped obesity--is more likely to be regarded as benign and is common in females (Sardesai 1998).

The Risks of Obesity: The Benefits of Weight Loss
Research has clarified the reasons that fatness increases cardiovascular risks. Obesity forces the heart into intensive labor because useless pounds must be serviced in the same fashion as valuable tissues and organs. The risk of diabetes and hypertension increases almost 3 times in obese individuals. For example, a weight gain of 10% can increase systolic blood pressure by 6.5 mmHg and fasting blood glucose by 2 mg/dL. Blood cholesterol levels typically increase by about 12 mg/dL for each 10% of weight gained and HDL levels decrease (Family Practice Notebook 2000). Even a 5- to 10-pound weight loss can provide significant health benefits such as lowered blood pressure or improved blood glucose control in the diabetic (Chandler 2002). Other factors increasing cardiovascular risk, such as excessive fibrinogen, elevated C-reactive protein, and insulin resistance, often share a common denominator, that is, obesity.

A 10- to 15-pound weight loss can also lessen the risk and progression of Syndrome X. As weight drops, tissues become more insulin sensitive, amending a primary identifiable trait in Syndrome X. Although 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 a myocardial infarction (Lopez-Jimenez et al. 2000).

Leptin in Obesity and Heart Disease
Leptin, a hormone produced by fat cells, increases with obesity and appears to play a role in the vascular complications associated with overweight conditions. The discovery of leptin (in the last decade) raised hopes that it could be used as a drug to treat obesity. However, most obese people were later found to have elevated levels of the hormone, making leptin injections inappropriate. However, assessing leptin levels has emerged as a means of screening for heart disease.

The journal Circulation showed that men with established heart disease had blood leptin levels 16% higher than men considered heart healthy. Every 30% increase in leptin increased the risk of a heart attack or a vascular event 25% (Wallace et al. 2001). The association between leptin and heart disease was observed regardless of BMI, suggesting that leptin is a reliable marker for the amount of fat in the body. Body composition (the comparative proportions of protein, fat, water, and mineral components in the body) may thus be a better indicator of risk for heart disease than overall obesity.

The levels of leptin, structurally a cytokine, rise in tandem with C-reactive protein (CRP), a marker of blood vessel inflammation and itself a significant heart risk. These findings imply that body fat influences CRP levels (Mercola 2002a) in addition to a myriad of other health problems.

JAMA recently reported that leptin has a stimulatory effect on platelet aggregation (Nakata et al. 1999; Bodary et al. 2002). The identification of a functional leptin receptor (OB-Rb) on platelets suggests a signaling mechanism between fat cells and platelets. To test the hypothesis, researchers examined mice deficient in leptin or the leptin receptor after a laboratory-induced vascular injury. Leptin-deficient mice had a prolonged time to occlusion, whereas leptin-deficient mice administered the hormone demonstrated a significant reduction in the time to occlusive thrombosis. Since leptin levels correlate well with adiposity, strategies aimed at weight reduction should remain the first line of defense. Lastly, exercise training in Type II diabetic subjects also reduced serum leptin levels independent of changes in body fat mass, insulin, or glucocorticoids (Ishii et al. 2001).

It is apparent that individuals need to establish a sensible approach to eating, that is, 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 (Olson 2000). Weight cyclers typically have 7% lower HDL cholesterol than noncyclers (Olson et al. 2000). To read about dietary supplements that may assist in weight loss, see the subsections relating to L-Carnitine, Chromium, CLA, and nutrients that lower serum insulin levels 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 2.4-fold increase in congestive heart failure in diabetic men and a 5.1-fold increase in diabetic women over the course of the 18-year study (Fein et al. 1994).

Diabetics are particularly susceptible to silent myocardial infarctions, that is, an asymptomatic attack that interrupts the blood flow to coronary arteries. 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.

Typically, Type II diabetes develops because of a lack of insulin sensitivity at the cellular level. As a result, the bloodstream becomes overloaded with nonfunctional 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, and insulin becomes more of an adversary than an advocate within the host.

Much of the stress of diabetes is due to a constant state of flux, that is, moving from hyperglycemia to hypoglycemia in a relatively short period of time. Nondiabetics are spared glycemic-induced stress. For example, most healthy individuals maintain postabsorptive blood glucose levels of 90-100 mg/dL. Even after fasting or overeating, blood glucose levels seldom fluctuate lower than 60 mg/dL or over 160 mg/dL (Pike et al. 1984). It has been suggested that evolutionary success requires a 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.

Chronic hyperglycemia causes monocytes and adhesion molecules to bind to vessel walls. In turn, cholesterol and other lipids are more easily deposited. Lipids become disorganized, with more of the LDL cholesterol and less of the beneficial HDL cholesterol appearing in the bloodstream (Reaven 2000). As the volume of urine produced increases, life-saving minerals are often excreted with urine. Without adequate mineral representation, the heart can be forced into fatal arrhythmias. Hypertension, abnormal coagulation, and obesity multiply the health concerns that frequently plague diabetic patients.

During hypoglycemia, the ability of the nervous system to function decreases, but the breakdown of fats increases. In this situation, fat assumes the role of a glucose surrogate. Necessary as this mechanism is, it is not without a disadvantage. Substitute pathways are not always well regulated, and excess fats not used as an energy source may accumulate, contributing to the atherogenic process.

The symptoms of hypoglycemia can mimic a heart attack, that is, dizziness, fatigue, sweating, shakiness, lightheadedness, palpitations, and in some cases, unconsciousness. Normal brain function requires 6 grams of glucose an hour, which can be delivered only if arterial blood contains over 50 mg/dL of glucose (Pike et al. 1984). Although hypoglycemia is not a heart attack, the stress imposed upon the heart can be significant.

To learn more about the impact that Obesity, Stress, Gender, and a Sedentary Lifestyle have upon diabetes, consult those subsections in the Traditional Risk Factors section of this protocol; other relative information may be found in the Fibrinolytic Activity and Syndrome X subsections of Newer Risk Factors (also in this protocol). For natural suggestions to benefit a diabetic, read about Alpha-Lipoic Acid, L-Carnitine, Chromium, DHEA, Essential Fatty Acids, Fiber, Garlic, Magnesium, Olive Leaf Extract, Selenium, Vitamin A, Gamma-Tocopherol, Vitamin K, and Zinc in the Therapeutic section of this protocol. The Diabetes protocol in this book should be thoroughly studied by individuals with unstable blood glucose levels.

HYPERCHOLESTEROLEMIA AND DERANGED LIPID PROFILES

Too much cholesterol is not good, but too little may not be good 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; however, the risk of a stroke escalated as cholesterol levels exceeded 230 mg/dL. It is estimated that high cholesterol levels account for about 10-15% of ischemic strokes; low cholesterol may be a contributing factor in nearly 7% of hemorrhagic strokes. The National Cholesterol Education Program announced that cholesterol levels of approximately 200 mg/dL appear ideal for stroke prevention (CNN 1999; Mercola 1999).

Nonetheless, opinions are still divided as to the magnitude of the hypocholesterolemic risk. Until the quandary has been fully resolved, there are reasons to be cautious about severely reducing dietary fat and serum cholesterol. Recall that in foods, triglycerides carry the fat-soluble vitamins (including vitamin K, an extremely important nutrient in normal blood coagulation) (Whitney et al. 1998). In addition, some researchers believe that hypocholesterolemia weakens cerebral arterial walls, making breakage under pressure more likely (Hama 2001). (About 20% of all strokes result from cerebral hemorrhages.) Various studies indicate that very low levels of cholesterol may also increase the risk of death due to cancer, particularly leukemia and lung cancer (Zyada et al. 1990; Telega et al. 2000).

Cholesterol is so important that the body produces from 800-1500 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 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 (the insulating sheath on many nerve fibers) 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.

Although 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-Rijnsburger et al. 1997; Schatz et al. 2001). In fact, hypocholesterolemia (low cholesterol levels) appears associated with higher death rates among elderly people, due to mortality from cancer and infection. Therefore, administering a hypocholesterolemic drug to senior subjects may actually increase their risk of succumbing through 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 does what it must: seal or coat the damaged area in the artery. Unfortunately, fibrin can grasp other bloodstream infiltrates in its web-like structure, that is, collagen proteins and minerals that have precipitated out of solution. According to Dr. Whiting, a significant bump in the arterial pathway may have developed and then along comes cholesterol. Cholesterol appears to add the final coat to the plaque, building up in the artery (Whiting 1989).

Optimal Ranges of Blood Lipids
When levels of HDL (high density lipoproteins, also known as good cholesterol) are elevated, cardiovascular disease is reduced. 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 position cardiovascularly. HDL levels are considered desirable in a range of 50-70 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.

The risk factors for heart disease are often calculated by dividing total cholesterol by HDL. Assessment of the HDL-total cholesterol ratio is not standardized, but according to Health and Wellness (Sixth Edition), a value of 4.5 places the individual at an average risk; a ratio above 4.5 indicates an increased risk; and a ratio below 4.5 means 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. Dr. Henry Ginsberg ( Columbia University ) estimates that reducing LDL cholesterol 7% may translate into a 15-20% reduction in risk of coronary heart disease (Ginsberg et al. 1998). Note: LDL cholesterol is not measured directly; levels are calculated using the following formula:

LDL = total cholesterol - HDL - (triglycerides 4 5).

Cholesterol tests indicating acceptable levels may convey a false sense of security. Current research indicates that standard cholesterol tests miss 50% of people at risk for heart attacks, due to the inability to detect abnormally small cholesterol particles. Note: Syndrome X is characterized by abnormal lipoprotein metabolism, showing smaller, denser LDL particles. To read more about Syndrome X, please consult the Newer Risk Factors section in this protocol.

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 threefold; neither can be detected by standard cholesterol tests. Without the detection of the smaller cholesterol subsets and the 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, that is, 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 researchers have found that patients with clinical coronary heart disease were less likely to experience new events if tri-glyceride levels were below 101 mg/dL (Kreisberg et al. 2000). Most clinicians believe that triglycerides are best maintained below 101 mg/dL in all subsets of the population. Perhaps J.M. Gaziano ( Harvard Medical School ) led the most startling study in regard to the risks imposed by deranged blood lipids. The subjects with the highest ratio of triglycerides to HDL had a 16-fold greater incidence of coronary events compared to those with the lowest ratio (Gazinao et al. 1997).

Triglyceride levels rarely rise unless one has insulin resistance or hyperinsulinemia, conditions often modifiable by controlling carbohydrates in the diet. According to the data reported in Atherosclerosis, elevated triglyceride levels usually modulate when less food is consumed, particularly foods causing a rise in blood sugar levels, that is, bakery products, pastas, and foods with added sugar (Stavenow et al. 1999; Atkins 2002). Note: Other areas in this protocol 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 such as artichoke extract, L-carnitine, chromium, conjugated linoleic acid, curcumin, DHEA, essential fatty acids, fiber, garlic, ginger, grapefruit pectin, gugulipid, hawthorn, niacin, pantethine, policosanol, poly-enylphosphatidylcholine, and tocotrienols in the Therapeutic section of this protocol.

STRESS

More than one-quarter of a million heart episodes occur annually--that is, palpitations, angina, arrhythmias, and heart attack--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 an emotional provocation. The journal Circulation reported that an individual who is prone to anger is about 3 times more likely to have a heart attack or sudden cardiac death than someone who is the least prone to anger (Williams et al. 2000).

The journal Life Sciences offers an explanation for stress-related cardiovascular events. Higher levels of homocysteine are associated with feelings of aggression and rage in both men and women (Stoney et al. 2000). Individuals may be spurred into erratic behavior by metabolic processes gone awry. The modulation of homocysteine levels may allow a more docile individual to emerge, less cardiac risk prone from two perspectives (less homocysteine = less violent behavior and less cardiac disease). A comprehensive review of homocysteine appears in the section devoted to Newer Risk Factors. Vitamins and minerals to maintain healthy homocysteine 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 and deny the heart a much needed rest from disharmony.

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

Type D behavior, another variant having heart disease linkage, was described in The Lancet (Denollet et al. 1996). Withheld and denied emotions, that is, 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 (a decreased supply of oxygenated blood) can occur. Although 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 the hardening of the carotid artery and higher levels of stress (Barnett 1997).

A recent study of 2800 men and women over 55 years of age showed that even minor depression can increase cardiac mortality 60%, while major depression may actually triple the rate of cardiac-related deaths (Pennix et al. 2001). There is also convincing evidence that depression significantly increases the risk of mortality following a heart attack or coronary bypass surgery (Baker et al. 2001).

Researchers explain the relationship between mindset and mortality, pointing out that stress response to depression appears to trigger chronically high cortisol levels, a hormone secreted by the adrenal glands (Pennix et al. 1999a). Hormonal imbalances, in turn, can alter insulin resistance and increase blood pressure, magnifying the risks imposed by a heart attack or bypass surgery.

A study conducted at Duke University ( Durham , NC ) showed that men with established heart disease who underwent 4 months of stress management (1.5 hours weekly) experienced a significant reduction in clinical cardiovascular events. The advantage was observed at the conclusion of counseling and throughout 5 years of assessment, suggesting both economic as well as clinical benefit (Blumenthal et al. 2002).

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 stress as their common bond.

• 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. In studies involving 3000 Caucasians with depression and anxiety (ages 23-64), these individuals 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 3 times during periods of unresolved stress. Even the companionship of a pet has been shown to reduce stress and subsequently blood pressure (Alexander et al. 1996; Beck et al. 1996).
• Stress makes blood glucose levels more difficult to control (Challem et al. 2000). 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 15 deadline show higher cholesterol levels (Alternative Medical News staff 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 cholesterol 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 (Cosgrove 1999).

Assessing Apo-E Status
The apoE4 variant of apoprotein E is the most well-defined genetic trait affecting poor LDL levels. According to Ronald Krauss, M.D., a double allele (referred to as a double E4 genotype) is associated with high blood cholesterol and an increased prevalence of cardiovascular disease (American Heart Association 1998).

The apoE4 allele is very saturated fat sensitive, suggesting dietary manipulation may be an advantage to those with this genetic fault. In 90% or more of the population, modest dietary cholesterol has very little impact upon LDL cholesterol levels (Bland 2001). However, moderate dietary cholesterol intake in apoE4 individuals can lead to significant increases in plasma LDL levels. Jeff Bland, Ph.D., 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 food that is a "pretty good food," such as an egg.

There are three main alleles or variants of the apoE gene: E2, E3, and E4. Every individual inherits two of these alleles: one from each parent. Research has shown that each allele affects cholesterol metabolism differently. Smoking appears to increase the risk of coronary heart disease in men of all genotypes but particularly in men carrying the E4 allele. Researchers hypothesize that the genetic-coronary link may be due to increased oxidation of LDL cholesterol among smokers with this genotype. Compared to individuals who carry two neutral E3 alleles, those who carry at least one E4 allele tend to produce significantly more LDL cholesterol as well as more total cholesterol; those who have at least one E2 allele typically produce less LDL cholesterol (Humphries et al. 2001; Wang et al. 2001).

Establishing an apoE genotype in menopausal women sheds light on the complex issues of estrogen replacement therapy (ERT) as a cardioprotector. For example, women with the apoE-2 genotype (and using ERT) appeared to benefit the most from the lipid-altering effects of hormones compared to other genotypes. Menopausal women with the apoE-2 genotype (and not using ERT) have the lowest levels of protective HDL cholesterol. If on ERT, apoE-2 carriers have the highest HDL levels of all genotypes. This study suggests that the apoE-2 genotype may predispose a woman's body to produce more protective HDL cholesterol in response to ERT than those of other types (Heikkinen et al. 1999).

The study also showed that women with the apoE-3 genotype (and using ERT) had the highest levels of triglycerides. It appears women with the apoE-3 genotype are more sensitive to the triglyceride-raising effects of hormone therapy. A previous placebo-controlled study of over 150 postmenopausal Finnish women found that LDL cholesterol levels in women with the apoE-4 genotype respond less favorably to ERT (Heikkinen et al. 1999).

Studies that fail to consider genotype may explain the wide disparity in results regarding lipid levels and cardiovascular risk in postmenopausal women receiving HRT. With recent advances in genetic testing, another important piece of the puzzle is now available to help physicians predict how hormone replacement therapy will impact each woman's cardiovascular health (Kardia et al. 1999; von Muhlen et al. 2002).

Homocysteine: The Genetic Link
Compiling a family history of cardiovascular health is a common medical assessment, looking particularly at the early onset of disease. Because of an increasing awareness of the risks imposed by newer risk factors, homocysteine is being factored into the genetic equation. With a gene frequency between one in 70 and one in 200, elevated blood levels of homocysteine may be more common than previously thought (Berwanger et al. 1995). Canadian researchers estimate the inherited amino acid disorder (homocysteinemia) is present in approximately 20% of coronary artery disease patients (Superko et al. 1995).

There are multiple mechanisms involved in the pathogenesis of hyperhomocysteinemia, including not only heterozygosity, but dietary factors as well (Kardaras et al. 1995). Note: Heterozygous refers to inheriting a gene for a characteristic from one parent and the alternative gene from the other parent. The offspring of a heterozygous carrier (of a genetic disorder) has a 50% chance of inheriting the gene associated with the trait. In support of the genetic theory of hyperhomocysteinemia, 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).

About one-half of individuals with hyperhomocysteinemia respond favorably to higher doses of vitamin B6 due to an inborn cystathionine-B-synthase deficiency; others have a mutation in the methylenetetrahydrofolate reductase gene (MTHFR), which controls the ability to convert folic acid into 5-methyl tetra-hydrofolate, an active contributor in the methyl donation pathway of the folate cycle (James et al. 1999). The disruption of this cycle represents the domino effect, that is, when one system fails to perform, others downstream are affected as well. In this case, homocysteine clearance is disrupted and hyperhomo-cysteinemia, a powerful endangerment to cardiac health, results. The genetic flaw is correctable by administering 5-methyltetrahydrofolate supplements (the active form of folate) to bypass the metabolic block (Bland 2000a).

Additional Inheritable Risks for Degenerative Disease

• In 1991, researchers identified the gene responsible for hemochromatosis, a predominantly genetic disease reflecting abnormal iron retention despite eating an ordinary diet. Small numbers of individuals with hemochromatosis acquire the condition through chronic iron supplementation or blood transfusions, but the genetic form is most common. To learn more about hemochromatosis (a significant threat to heart health), consult the Iron Overload section.
• The journal 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 early cardiac death (Zureik et al. 1999).
• Lp(a) is frequently cited in medical literature as an important inheritable cardiac risk factor for individuals without other apparent signs of heart disease. Approximately 50% of children whose parents have elevated Lp(a) will also have similar Lp(a) derangements (Superko 1996). Although Lp(a) levels are influenced by heredity, this marker is often modifiable by targeted nutritional intervention.
• Genetic factors can influence obesity and fat distribution. Laval University (Quebec, Canada) determined that pairs of identical twins, overfed by the same amount of calories, showed a similarity with respect to body weight and percentage of fat, with about 3 times more variance among pairs than within pairs. After adjustment for the gains in fat mass, the within-pair similarity was particularly evident with respect to the changes in regional fat distribution and amount of abdominal visceral fat, with about 6 times as much variance among pairs as within pairs. Researchers concluded that the tendency to store energy as either fat or lean tissue is influenced by genetic factors (Bouchard et al. 1990).
• A condition known as Dunnigan-type familial partial lipodystrophy (FPLD) bears striking similarities to Syndrome X. The gene mutation responsible for FPLD causes weight gain in the abdomen as well as the face and chest. Affected individuals have high insulin levels, high blood pressure, high triglycerides, and low levels of HDL cholesterol. A recent study confirmed that individuals with FPLD have 6 times the risk of coronary heart disease compared to noncarrier relatives in a control group, that is, 34.8% versus 5.9% at any age and 26.1% versus 0% before the age of 55. The average age of developing heart disease was 46.5 years in individuals with FPLD, with the risk being greater among women than in men. Four of 14 women (about 28%) with FPLD underwent bypass surgery before the age of 55. In contrast, hospitalization data from the general Canadian population in 1996 indicated that one woman in 7350 had been hospitalized between the ages of 35-54 for coronary bypass artery surgery (Canadian Institute for Health Information, http://www.cihi.ca; Hegele 2001; Today's News 2001).

GENDER

At one time, cardiovascular disease was considered to be predominantly a disease affecting men, not women. Statistics do not support this logic. 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 5209 participants, 2873 of whom were women (Framingham Heart Study 1998). 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 to be 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; Herrington et al. 2000). 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. In fact, HRT raised the risk of recurrent attack and death during the first year of usage and thereafter lowered it only slightly (Mosca et al. 2001). Although estrogen replacement therapy may be helpful in lowering refractory lipoprotein(a) and high fibrinogen levels, it increases C-reactive protein levels, making its benefit uncertain (please read the previous section on Heredity and Assessing ApoE Status for extremely valuable information regarding HRT in postmenopausal women).
• 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. In fact, high triglycerides threaten the outcome in diabetic women undergoing bypass surgery (Sprecher et al. 2000). Elevations in C-reactive protein (CRP) are the single strongest predictor of future vascular risk, according to the Women's Health Study. Women with the highest levels of CRP in their blood had a fivefold increased risk of future cardiovascular disease and a sevenfold increase in the likelihood of a heart attack compared to those with low levels.
• When a heart attack was the first coronary event, nearly half were unrecognized in women, compared to only a third undetected in men.
• Only 56% of women experiencing a heart attack can expect to live another year, compared to 73% of male victims. Women under 50 years of age are twice as likely to succumb following the attack compared to similarly afflicted men. Statistics change with age, with men and women between the ages of 60-69 showing similar survival patterns (Mukamal et al. 2001): 27% of men who have a heart attack will likely have a second attack within 6 years compared to 31% of women.
• Diabetes is a particularly strong coronary risk factor in women.
• The New England Journal of Medicine reported that the risk of myocardial infarction increased among women who used second generation oral contraception, that is, levonorgestrel. Although inconclusive, early trials indicate third generation oral contraceptives, that is, desogestrel or gestodene, may carry a lesser risk (Tanis et al. 2001).
• Many studies have demonstrated that men who are physically active tend to live longer, illustrating a clear exercise-response curve, with greater activity more effective than moderate. The New England Journal of Medicine recently reported similar findings for women. Both walking and vigorous exercise are associated with substantial reductions in the incidence of cardiovascular events among postmenopausal women; prolonged sitting is predictive of increased cardiovascular risk (Manson et al. 2002).

SEDENTARY LIFESTYLE

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

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

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

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

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

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

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

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

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

GUM DISEASE

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

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

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

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

THYROID DISEASE
(HYPO- AND HYPERTHYROIDISM)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IRON OVERLOAD (HEMOCHROMATOSIS)

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

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

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

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

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

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

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

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

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

NEWER RISK FACTORS

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

Fibrinogen
Fibrinogen is a blood protein that plays a critical role in normal and abnormal clot formation, a mechanism referred to as coagulation. A process of checks and balances, an interaction between clotting factors and naturally occurring anticoagulants, normally results in healthy levels of fibrinogen and normal coagulation. If fibrinogen levels increase above normal, however, a blood clot becomes a threat; if fibrinogen levels decrease below normal, a hemorrhage can result. Although the reference range used by most laboratories is 150-460 mg/dL, it is crucial to keep serum fibrinogen under 300 mg/dL, a level considered safe.

The coagulation of blood depends upon a number of proteins found in plasma, called clotting factors. Normally, clotting factors are inactive, but following injury, they become activated. Exposed collagen or chemicals released from injured tissues initiate a series of chemical reactions that result in the production of prothrombin activators. Prothrombin activators convert prothrombin to thrombin, which, in turn, converts fibrinogen to fibrin (a network of protein fibers that can trap blood cells, bloodstream infiltrates, and platelets). The risks multiply as materials become trapped in the tangle. An atheromatous tumor (capable of continued growth) can result in full occlusion (Whiting 1989; Seeley et al. 1991; Kohler et al. 2000).

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

Vascular closure represents only one facet of the risk: plaque is highly susceptible to breakage and clot formation. About 700,000 heart attacks and stroke deaths occur in the United States each year as a result of a blood clot obstructing the delivery of blood to the heart or brain. Reports in the New England Journal of Medicine showed that those with high levels of fibrinogen were more than twice as likely to die of a heart attack, but the risk of a stroke increases as well (Wilhelmsen et al. 1984; Packard et al. 2000).

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

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

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

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

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

Various factors influence plasma fibrinogen levels:

• Increased winter cardiovascular mortality is related to a cold weather increase in fibrinogen. The exposure to cold increased fibrinogen 23-38% over baseline (Woodhouse et al. 1997; Horan et al. 2001).
• Smokers and depressed individuals have higher levels of fibrinogen (Mindell 1998; Castilla et al. 2002).
• Estrogen replacement therapy appears to attenuate normal age-related increases in fibrinogen (Stefanick et al. 1995; el-Swefy et al. 2002).

Unfortunately, pharmaceutical drugs have not been of significant value in reducing fibrinogen levels. The initial data suggested that Bezafibrate (a European drug) reduced fibrinogen levels in patients with established coronary heart disease. However, the Bezafibrate Infarction Prevention Study yielded disappointing results, with no significant evidence of efficacy in lowering fibrinogen (Behar 1999).

Anticoagulant therapy usually becomes the treatment of choice to reduce fibrin. Warfarin (Coumadin) and heparin are often prescribed, but it is difficult to administer enough of an anticoagulant to lessen the risk of a blood clot without increasing the risk of a hemorrhage. Dispersed throughout the Therapeutic section are products with fibrinolytic and antiplatelet aggregating activity, such as aspirin, bromelain, curcumin, essential fatty acids, garlic, ginger, ginkgo biloba, green tea, gugulipid, niacin, pantethine, policosanol, proanthocyanidins, vitamin A, beta-carotene, vitamin C, and vitamin E. A novel drug approach to reduce excess fibrinogen is to take 400 mg of pentoxifylline twice daily.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The Hazards of Hyperhomocysteinemia
Experiments show that if homocysteine accumulates in the cell, all methylation reactions are inhibited. Because methylation is used for so many body processes (apart from homocysteine metabolism), if this system becomes dysfunctional, essential pathways are foiled. For example, methylation is fundamental to maintaining healthy DNA, lessening the possibility of mutations and strand breaks. Since DNA strand breaks have been detected in the biopsies of diseased cardiac tissue, it is suspected that strand breaks fuel the progression of heart disease. In addition, DNA strand breaks are associated with accelerated aging and a greater cancer risk (Domagala et al. 1998; Seki et al. 1998).

If homocysteine is not detoxified and begins to accumulate, plaque builds up in the endothelial cells lining the arteries through various mechanisms. For example, homocysteine speeds the oxidation of cholesterol, which then becomes bound to small, dense LDL particles. Macrophages then take up the particles to become foam cells in plaque. The earliest detectable lesion of atherosclerosis is the fatty streak (consisting of lipid-laden foam cells that are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima) that later become fibrous plaque (Naruszewicz et al. 1994; Cranton et al. 2001). Dr. Kilmer McCully, a 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).

A heart attack or stroke is more likely to occur as homocysteine promotes coagulation factors, favoring clot formation (Magott 1998). 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: the elevations in homocysteine in 16 of 38 patients with cerebrovascular disease (42%), seven 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).

In addition to causing cardiovascular disease by increasing the incidence of blood clots, hyperhomocysteinemia triggers atherosclerosis by encouraging smooth muscle cell proliferation, intimal-medial wall thickness, thromboxane A2 activity, lipid abnormalities, and the binding of Lp(a) to fibrin (Magott 1998; Sandrick 2000).

Vascular integrity is compromised as homocysteine blocks production of nitric oxide in the cells of blood vessel walls, causing vessels to become less pliable and even more susceptible to plaque buildup (Boger et al. 2000; Holton 2001). Scientists explain that vessels lose their expansion capacities as homocysteine reduces nitric oxide's availability (Tawakol et al. 2002). Homocysteine significantly hampers coronary microvascular circulation by impairing dilation functions.

Drs. Allen Miller and Gregory Kelly explain that homocysteine facilitates the generation of hydrogen peroxide. By creating oxidative damage to LDL cholesterol and endothelial cell membranes, hydrogen peroxide can then promote injury to vascular endothelium (Starkebaum et al. 1986; Stamler et al. 1993; Miller et al. 1997). Nitric oxide (also known as endothelium-derived relaxing factor) normally protects endothelial cells from damage by reacting with homocyst eine, forming S-nitrosohomocysteine, which inhibits hydrogen peroxide formation. However, as homocysteine levels increase, this protective mechanism can become overloaded, allowing damage to the endothelial cells to occur (Stamler et al. 1992, 1993, 1996).

Genes are also involved in homocysteine attack. This has a significant impact upon the cardiovascular system, as homocysteine activates genes in blood vessels, encouraging the coagulation process and the proliferation of smooth muscles (Outinen et al. 1999).

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.

Other homocysteine/disease associations are:

• High concentrations of homocysteine and low levels of folate and vitamin B6 are associated with an increased risk of extracranial carotid-artery stenosis, particularly in the elderly (Selhub et al. 1995).
• Higher levels of homocysteine predispose deep venous thrombosis (den Heijer et al. 1996).
• The link between hyperhomocysteinemia-hypercholesterolemia and hypothyroidism is clearly drawn in the section devoted to Thyroid Disease appearing in this protocol.
• Plasma homocysteine levels predictably increase with elevations in creatinine. As chronic renal failure occurs, hyperhomocysteinemia is frequently observed (Wilcken et al. 1979; Chauveau et al. 1993).
• Homocysteine metabolism is impaired in patients with Type II diabetes. Intramuscular injections of 1000 mcg of methylcobalamin (a homocysteine-lowering nutrient) once a day for 3 weeks reduced elevations of plasma homocysteine in diabetic test subjects (Araki et al. 1993).
• 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 dama