~Cardiovascular Disease Comprehensive 5 - Newer Risk Factors

Newer Risk Factors, continued

Syndrome X

For the past 20 years, eclectic physicians have judged Syndrome X to be a powerful indicator of an eventual heart attack. For clarity, let it be understood that a syndrome represents clusters of symptoms. In Syndrome X, the symptoms are an inability to fully metabolize carbohydrates; hypertriglyceridemia; reduced HDL levels; smaller, denser LDL particles; increased blood pressure; visceral adiposity; disrupted coagulation factors; insulin resistance; hyperinsulinemia; and, often, increased levels of uric acid. Note: For years, high uric acid levels have been associated with cardiovascular disease, but the relationship was poorly understood. Dr. Gerald Reaven unraveled the link when he determined that elevations in uric acid are often prompted by Syndrome X, a forerunner to heart disease (Fang et al. 2000).

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

Syndrome X interferes with glucose delivery, a consequence initiated by insulin's nonresponsiveness at the receptor site on the cell. Normally, ordinary levels of insulin will escort glucose into the cell, leaving a bloodstream favoring neither hyper- or hypoglycemia. In Syndrome X, the receptor turns a cold shoulder to the hormone, and insulin is no longer able to deposit its cargo; as a result, glucose loads up in the bloodstream. The pancreas is aware of the problem and attempts to resolve it by discharging more and more insulin. The logic appears to be that since normal levels of insulin cannot get the job done, perhaps greater and greater amounts of circulating insulin will be able to drive glucose, the principal metabolic fuel, into our 100 trillion cells.

In most cases of Type II diabetes, the problem is insulin resistance and inadequate compensatory insulin; in Syndrome X, insulin resistance and excessive amounts of insulin are the hallmarks. The vast difference between the two conditions is that in Syndrome X, the pancreas does not falter in its effort to pump out insulin (Reaven 2000). It sounds as if the host has won, but the following reasons discredit this logic.
  • The pancreas can tire in its endless effort to supply compensatory insulin, and insulin-dependent diabetes will result.
  • Hormones are powerful substances with an equally meaningful purpose. When insulin is not used for its intended functions, insulin builds up in the bloodstream, and from various perspectives, the risk of heart disease increases.
For example, the Quebec Cardiovascular Study found that individuals with elevated levels of triglycerides and LDL cholesterol, plus low HDL cholesterol, had 4.4 times the risk of heart disease compared to men with none of the risk factors. But the risk soars to 20-fold for men with a triad of elevated fasting insulin, apolipoprotein B, and small, dense LDL particles. According to Dr. Benoit Lamarche (Laval University), hyperinsulinemia should not be overlooked as an independent risk factor for ischemic heart disease. His case-controlled study of 91 patients and 105 controls found fasting insulin levels 18% higher in cases than controls. For each 30% increase in insulin concentration, there was a 70% increase in the risk of ischemic heart disease over 5 years (Despres et al. 1996; Physician's Weekly 1998b).

Insulin growth factor-1 (IGF-1), a hormone that increases the body's sensitivity to insulin and promotes clearance of glucose and toxic metabolites, appears critical to surviving the crisis and aftermath of a heart attack (Conti et al. 2001). Lower levels of IGF-1 during the early phase of a myocardial infarction are associated with poorer clinical outcomes, arrhythmias, ischemia, and death.

Italian researchers measured IGF-1 levels in the blood of patients within 24 hours of the onset of heart attack symptoms. IGF-1 (a hormone that enhances the elasticity of blood vessels, strengthens heartbeat, and increases blood flow) was about 5 times lower compared to healthy controls (47 ng/mL versus 189 ng/mL). The transient reduction of IGF-1 during the early phase of infarction appears to cause an acute worsening of insulin resistance.

A decline in IGF-1 is also linked to poorer prognosis following a heart attack. Of the 23 patients evaluated regarding IGF-1 levels (postinfarction), 12 experienced adverse clinical events in the 90-day follow-up period. The two individuals with the lowest IGF-1 levels died from the heart attack or its complications. Negative end results were attributed to reduced insulin sensitivity, glucose clearance, fat metabolism, and cardiac function. Interestingly, infusing IGF-1 into rats (programmed to develop metabolic syndrome) alleviated hyperphagia (overeating), obesity, hyperinsulinemia, hyperleptinemia (excesses of a hormone frequently found in the bloodstream of overweight, cardiac-prone individuals), and hypertension (Vickers et al. 2001).

The IGF-1 system is regulated by various stimuli, including hormones, growth factors, and nutritional status (Fu et al. 2001). For example, IGF-1 increased when protein foods were emphasized in the diet, in combination with adequate levels of vitamin D and calcium (Rizzoli et al. 2001).

Unfortunately, many physicians fail to consider insulin resistance as a forerunner to Type II diabetes and cardiovascular disease. A fasting blood glucose level above 115 mg/dL, triglycerides above 160 mg/dL, low HDL cholesterol, blood pressure persistently over 140/90 mmHg, total cholesterol above 240 mg/dL, and 10-15 pounds of extra weight are important evaluations regarding the likelihood of insulin resistance (Challem et al. 2000). A normal 2-hour postprandial glucose is generally between 70-139 mg/dL. If fasting or 2-hour postprandial insulin levels are measured, a normal range is 6-35 mcIU/mL. The Life Extension Foundation believes that fasting insulin levels over 5 mcIU/mL may be a cause for concern, and respected physicians and scientists are aligning with this projection.

Even if these tests are run, physicians often err in properly assessing the cumulative values of multiple irregularities. The signs are all there, but a failure to connect the dots can lead to a treatment that never addresses the source of the ill health. Syndrome X is largely a nutritional disease that is manageable with dietary corrections, reducing carbohydrates such as sweets, pastas, and breads and instating good fats in carbohydrates' place (consult the section entitled Essential Fatty Acids in this protocol for a discussion regarding good and bad fats).

The Harvard University School of Public Health announced that women between the ages of 38-63 increased their risk of heart attack by about 40% if their diet contained quantities of carbohydrates, particularly refined carbohydrates (Liu et al. 2000). It has been determined that the type of food selected and the quantity consumed determine how much insulin must be supplied.

Dr. Gerald Reaven believes an appropriate breakdown of the food groups should be about 45% of calories from carbohydrates, 40% from fat, and 15% from protein. Substituting appropriate fats for carbohydrates quiets an insulin release from the pancreas, and a primary step in Syndrome X has been averted. Dr. Reaven cautions that current dietary recommendations, that is, replacing fats with carbohydrates, may be fine for some individuals, but it is a grievous, even fatal, suggestion for those who are insulin resistant (Reaven et al. 2000). Note: Nutritionists reviewing the concept of macronutrient fractions stress the importance of selecting healthy foods to supply requirements. Eating ad libitum from unwise food choices, but within acceptable percentages, could still render the diet unhealthy from many perspectives.

To read more about Syndrome X, consult the sections entitled Hypertension, Obesity, Sedentary Lifestyle, Fibrinolytic Activity, and Beta-Blockers. Also, the Therapeutic section has supplemental recommendations to assist in controlling Syndrome X, including alpha-lipoic acid, conjugated linoleic acid, DHEA, essential fatty acids, magnesium, vitamin A, and vitamin C.

C-Reactive Protein (CRP)

CRP is a marker for systemic inflammation that rises several hundredfold in response to acute tissue injury but stays relatively stable in the absence of inflammation. CRP appears in the serum before the erythrocyte sedimentation rate begins to rise, often within 24-48 hours of the onset of inflammation. Elevated CRP levels can indicate the presence of chronic low-grade inflammation, with linkage to blood vessel damage and vascular disease (Pasceri et al. 2000). High levels of CRP appear to alert inflammatory processes that have the potential to disrupt fatty plaque buildup inside blood vessels, causing a critical rupture; the end result is a blood clot.

When CRP levels are factored in as a cardiovascular risk, along with hypertension, diabetes, elevated cholesterol, family history, and BMI, there is significant improvement in predicting cardiac health compared with models that exclude CRP testing. Ten prospective studies (six in the United States and four in Europe) have consistently shown that hs-CRP is a powerful predictor of a future first coronary event in apparently healthy men and women. ("hs" refers to high sensitivity testing, the only method able to discriminate the subtle differences in CRP in a range that accurately predicts coronary risk.)

As new as CRP is to many as a risk factor in coronary artery disease, Rudolf Virchow, a German pathologist (1821-1902), hypothesized that inflammation was the causative factor in the atherogenic process. Decades later, scientists confirmed that increased monocytes (white blood cells critical in early plaque development) and macrophages (mononuclear phagocytic cells capable of scavenging and ingesting dead tissue and degenerated cells) are present, particularly at points of plaque rupture. It appears that CRP and several other inflammatory markers may be elevated many years prior to a coronary event.

However, data from the University of Texas Health Sciences Center indicate that CRP is more than a measurable antecedent preceding a cardiac problem. CRP, along with the cooperative efforts of an unidentified serum factor, acts directly upon the blood vessels to activate adhesion molecules in endothelial cells: the intercellular adhesion molecule (ICAM-1) and the vascular cell adhesion molecule (VCAM-1). VCAM-1 appears to be an early molecular marker of lesion-prone areas as a response to experimental hypercholesterolemia. In humans, ICAM-1 and VCAM-I expression is increased in the endothelium of atherosclerotic plaque. Researchers concluded that CRP appears intricately involved in the inflammatory process, thus proving to be a potential target for the treatment of atherosclerosis (Pasceri et al. 2000; Biomedical Science 2001; Alvaro et al. 2002).

The journal Circulation reports that CRP appears able to affect the activity of LDL cholesterol (increasing atherogenesis). The cycle begins as stranded LDL is taken up by macrophages; macrophages, gorged with fats contained in blood, become bloated and develop into foam cells. When foam cells have reached their maximum load, they explode, discharging their fatty contents into the blood vessel wall at the site of injury. The presence of added fat signals the need for more macrophages to clean up the mess. They stuff themselves, explode, and the cycle starts anew. Since native LDL does not induce foam cell formation, CRP appears to ready LDL for uptake by the macrophages, initiating the sequence (Braley 1985; Zwaka et al. 2001).

In the Physicians' Health Study, middle-aged men deemed healthy at baseline were evaluated over an 8-year period in regard to CRP levels and a cardiovascular event. This study showed that those in the highest quartile of hs-CRP had a twofold higher risk of (future) stroke, a threefold higher risk of (future) heart attack, and a fourfold higher risk of (future) peripheral vascular disease (Rifai et al. 2001a, 2001b). Stroke patients with the highest CRP levels were nearly 2.4 times more likely to die within the next year compared to patients with the lowest levels (DiNapoli et al. 2001). Another of hs-CRP's strengths is its ability to detect at-risk patients with normal cholesterol levels.

The risk of stroke, according to data reported in the New England Journal of Medicine, decreased among those using statin drugs (White et al. 2000). The Cholesterol and Recurrent Events Trial concluded that pravastatin (administered long term) appears to be doing more than reducing cholesterol, perhaps acting as an anti-inflammatory. Another study (also published in the New England Journal of Medicine) reported that pravastatin reduced CRP levels after both 12- and 24-weeks' administration, independent of LDL cholesterol levels. It appears statin therapy may prevent coronary events among individuals with relatively low lipid levels but with elevated levels of CRP (Ridker et al. 2001). Conversely, some drugs, including hormone replacement therapy, actually increase CRP levels and the inflammatory response.

Researchers hypothesized in the Journal of the American College of Cardiology that the cytomegalovirus (CMV) (herpes-type viruses) may stimulate an inflammatory response, reflected by elevated CRP levels. The journal Circulation reported that older people who have IgG antibodies to the herpes simplex-I virus experienced a twofold increase in the risk of a myocardial infarction or coronary heart disease death. Since the relationship between CMV and coronary heart disease is not observed in all people, researchers consider the ability of individuals to control CMV inflammatory activities, the variable in the progression to a myocardial infarction (Zhu et al. 1999; Siscovick et al. 2000).

The infectious process in heart disease is chronicled in numerous studies, but the microorganisms involved remain of interest. Subsequently, a group of researchers from Johannes Gutenberg University (in Mainz, Germany) evaluated 572 heart patients. They tested for antibodies in the bloodstream that would show that the immune system had at some stage been exposed to a variety of different viruses and bacteria. These included herpes simplex-1 and -2, which cause cold sores and genital herpes; Epstein-Barr virus, which causes mononucleosis, chlamydia, and flu virus; and Helicobacteria pylori, which causes stomach ulcers. Then they looked at the patients again 3 years later to see how many had survived. The death rate was 3.1% in patients who tested positive for only a few of the viruses or bacteria, 9.8% for those with four or five, and 15% in those positive for six to eight. Among those who had the most advanced artery hardening, 20% of those exposed to between six and eight infections had died, compared to 7% of those with three or fewer (BBC 2002b).

Japanese researchers concentrated upon finding a method to distinguish between bacterial and viral infection by measuring inflammatory markers, among them C-reactive protein (CRP). They found that during the acute stage of bacterial infections, CRP levels were moderately or highly increased, whereas in viral infections, CRP levels were normal or slightly increased. The researchers propose that the measurement of CRP (among various inflammatory markers) during the acute phase of illness, that is, within 5 days of onset, is of value to determine whether the infection is caused by a bacteria or virus (Sasaki et al. 2002). For an opposing view regarding the association between viruses and CRP levels, please consult the section entitled Link Between Infections and Inflammation in Heart Disease in this protocol.

The following shows the risk factors associated with CRP (data extracted from publications authored by Dr. Paul Ridker). It is important to note that risk factors vary according to individual publications and may change with future publications.

Risk Factors Associated with CRP
Future MI (heart attack)
Future Stroke
Future MI (heart attack)
Future Stroke
1Relative risk is the ratio of the chance of a disease developing among members of a population exposed to a factor compared to a similar population not exposed to the factor.

Ridker et. al. (1998); Ridker et. al. (1997).

Current research indicates that persistent CRP elevation, lasting longer than 96 hours following a successful coronary stent implantation, is predictive of prolonged inflammation leading to re-stenosis (Gottsauner-Wolf et al. 2000). Patients who developed restenosis within the first 6 months had increases in CRP levels for up to 96 hours following the procedure, although their baseline CRP had been normal. Patients without restenosis displayed an increased CRP level that was sustained for no longer than 48 hours and subsequently decreased. Higher CRP levels appear predictive of less satisfactory end results, following angioplasty and stent procedures.

Although many of the newer risk factors are not yet standardized, some laboratories are using a CRP reference range of 0.24-1.69 mg/L. Recent medical events resulting in tissue injury, infections, or inflammation may increase CRP levels and, if not factored into clinical interpretations, can distort results.

To read more about factors affecting CRP levels, consult the sections referring to Smoking, Obesity, Sedentary Lifestyle, Gender, Gum Disease, and The Link Between Infections and Inflammation in Heart Disease. Improved glycemic control and normalizing blood pressure may also assist in reducing inflammation and (subsequently) CRP levels.

CRP appears responsive to aspirin, DHEA, fish oil, pravastatin, vitamin C, vitamin E, and vitamin K supplementation (consult the Therapeutic Section to learn more about natural products). As research continues, it may be found that many other nutrients and herbs known for their anti-inflammatory properties are equally valuable in maintaining healthy CRP levels. Note: CRP appears to reduce levels of vitamins A, C, and E, as well as carotenoids, zinc, and selenium. Individuals with elevations in CRP may wish to emphasize these nutrients for their contribution to cardiac health.

Continued . . .

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