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.
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 Does this mean that traditional risk factors are no longer valid?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.Traditional Risk and Predictive FactorsBALDNESS
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 isimportant 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).
A brief explanation of the renin-angiotensin system:
The juxtaglomerular cells in the kidneys stimulate renin secretion when either blood volume or serum sodium decreases. Renin (an enzyme) participates in the conversion of angiotensinogen to angiotensin I, which is rapidly hydrolyzed to form the active compound angiotensin II. The vasoconstrictive action of angiotensin II decreases the glomerular filtration rate; the concomitant action of aldosterone, a mineralocorticoid hormone produced by the adrenal cortex, promotes sodium retention, causing blood volume and sodium reabsorption to increase. Agents that inhibit the angiotensin-converting enzyme decrease sodium and water retention, reduce blood pressure, improve cardiac output, and typically decrease heart size.
Some 9500 people from 270 hospitals in 19 countries participated in the HOPE study. Included in the trial were those with evidence of 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 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 hypercholemia (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 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?Continued . . .