~Cardiovascular Disease Comprehensive 4 - 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 is a blood protein that plays a critical role in normal and abnormal clot formation, a mechanism referred to as coagulation. A process of checks and balances, an interaction between clotting factors and naturally occurring anticoagulants, normally results in healthy levels of fibrinogen and normal coagulation. If fibrinogen levels increase above normal, however, a blood clot becomes a threat; if fibrinogen levels decrease below normal, a hemorrhage can result. Although the reference range used by most laboratories is 150-460 mg/dL, it is crucial to keep serum fibrinogen under 300 mg/dL, a level considered safe.

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

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

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

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

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

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

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

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

Various factors influence plasma fibrinogen levels:

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

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

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

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

Fibrinolytic Activity

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

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

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

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

Lipoprotein(a) (Lp(a))

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

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

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

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

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

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

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

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

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

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

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

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

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

Introduction to Homocysteine

Hazards of Hyperhomocysteinemia

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

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

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

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

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

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 homocystine, 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 damage, Crohn's disease, ulcerative colitis, irritable bowel disease, pernicious anemia, and Parkinson's disease often present with elevated homocysteine levels (Refsum et al. 1991; Savage et al. 1994; Mayer et al. 1996; Cattaneo et al. 1998; Clarke et al. 1998; Romagnuolo et al. 2001; Duan et al. 2002).

  • A large-scale prospective study of 4700 Norwegian men and women (65-67 years of age) showed that for each 5-millimol/L increase in plasma homocysteine levels, the number of deaths from all causes jumped 49%. This included a 50% increase in cardiovascular deaths, a 26% increase in cancer mortality, and a 104% increase in noncancer and noncardiovascular fatalities (Vollset et al. 2001).

Chronically high levels of homocysteine normally affect 30-40% of healthy elderly people. But in older individuals with severe illnesses, the prevalence of hyperhomocysteinemia may almost double. Based on a random testing of 600 hospitalized elderly patients (ages 65-102 years), researchers found evidence of hyperhomocysteinemia in over 60% of those with serious chronic conditions): 70% presented with vascular disease and 63% presented with cognitive impairment (Ventura et al. 2001). Impaired kidney function, the use of drugs (particularly diuretics), and malnutrition were suspected as causes of age-related hyperhomocysteinemia. Of the senior population in the United States, 67% have one or more vitamin levels within 15% of the lower recommended range, suggesting the need for review of reference values in elderly people.

While cholesterol does not normally pose a cardiac risk until levels exceed 240 mg/dL, some researchers consider homocysteine so capricious that even so-called normal levels may contribute to heart disease. Homocysteine levels should be kept as low as possible, below 7 micromol/L of blood plasma. Laboratories usually regard levels up to 15 micromol/L as normal, but epidemiological data reveal that homocysteine levels above 6.3 reflect a steep, progressive increase in the risk of a heart attack (Robinson et al. 1995). Although the incidence of hypertension, thrombotic stroke, peripheral vascular disease (gangrene), blood vessel toxicity, and the risk of heart attack escalate as homocysteine levels increase, homocysteine levels are not routinely evaluated in a cardiovascular work-up.

The Therapeutic section and the sections Homocysteine Lowering Nutrients and Elimination Pathways detail a program to assist in managing hyperhomocysteinemia. Note: Because of homocysteine's role in the metabolism of sulfur and methyl groups, elevated levels of homocysteine would be expected to negatively impact the biosynthesis of SAMe, carnitine, chondroitin sulfate, coenzyme Q10, creatine, cysteine, dimethylglycine, glucosamine sulfate, glutathione, melatonin, pantethine, phosphatidylcholine, and taurine. Many of these substances are profiled in the Therapeutic section for their cardioprotection and restorative qualities. The short supply of these agents could severely disable cardiac performance (Miller 1997).

Continued . . .

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