| To: LindyBill who wrote (1248) | 9/23/2008 9:33:36 PM | | From: LindyBill | of 24947 | | | DR DAVIS: Not that it matters much, but I was told that she had pericarditis, an inflammatory condition of the sac surrounding the heart that is relatively harmless, induced by viral infections.
Nonetheless, microvascular angina is an important issue. The whole microvascular dysfunction conversation has great overlap with that of endothelial dysfunction. In fact, it's hard to separate these in practical life.
Microvascular angina tends to occur more so in perimenopausal women in their 40s and 50s. It responds well to l-arginine but is a harbinger of standard coronary disease over the long-run.
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The Injured Endothelium:
How it lays the groundwork for plaque growth—
And how to put a stop to it!
TYP FORUM
The endothelium is the single-celled layer lining the arteries of the body. In fact, it's the most extensive organ system in the human body. It's also a recipient of the abuse our bodies receive, a fragile organ that injury transforms into a plaque-lined landmine.
Endothelial injury precedes real trouble by years. Here's how to recognize when you have it and nutritional supplements and health strategies to help correct it.
Vascular health from the inside-out
The paper-thin, barely visible endothelium is a marvelously complex organ that lines the body's entire network of arteries and veins from the heart to the smallest capillary in your fingertips. This single-celled layer maintains the fluid nature of flowing blood, triggers blood clotting when needed, cell adhesion, and transmits inflammatory signals.
The endothelium is also the traffic cop of the vascular system, regulating arterial tone and maintaining a balance between constriction and dilation, thereby controlling the ebb and flow of blood to various organs. To do this, endothelial cells manufacture regulatory proteins such as selectins, vascular cell adhesion molecule-1 (VCAM-1), von Willebrand factor (vWF), and thrombomodulin.
Any disruption in the delicate balance triggers endothelial cells to transform into an active state. Oxidized LDL particles, for instance, or even a greasy cheeseburger, spark an increase in protein production and arterial tone. Activation is transient, with a return to basal conditions within hours to days. But if triggers of endothelial activation are persistent or repetitive, the endothelium can develop signs of permanent dysfunction. A cascade of events ensues: inflammatory white blood cells bind to the endothelial surface, migrate into the arterial wall, and, in turn, lay the groundwork for growth of atherosclerotic plaque. If activation continues, ultimately heart attack and stroke result.
Awareness of the endothelium as a vulnerable organ system has unlocked a panorama of new preventive approaches. Because dysfunction of the endothelium precedes overt coronary or other vascular disease by years, correction of endothelial dysfunction potentially permits you to engage the process before it unravels.
"A healthy endothelium is like Teflon, a nonstick surface that enhances the flow of blood. By contrast, an unhealthy endothelium is like Velcro, with white blood cells and platelets sticking to it. When the lining of the blood vessel in healthy cells don't stick, clots don't form, arteries don't harden, and you won't die of a heart attack or stroke."
Dr. John Cooke
Stanford University
Endothelial dysfunction—an everyday phenomenon
Conventional notions of arterial health received a jolt when it was recognized that endothelial dysfunction is an everyday phenomenon shared by common disorders like hypertension and high cholesterol. Even something like eating a high-fat, processed fast food restaurant meal can yield transient evidence of dysfunction.1
Restoration of normal endothelial capacity can reverse the earliest phases of arterial disease. Correction of endothelial dysfunction can also be a strategy for health in advanced phases of disease once atherosclerotic plaque has been detected (heart scan, carotid scan, a stent has been implanted, a heart attack or stroke has occurred, etc.).
Endothelial dysfunction is also a phenomenon of aging, a result of "wear and tear", affecting everyone after age 60.2 Righting the phenomena gone awry in endothelial health may provide interesting strategies for maintenance of both health and youth.
Nitric oxide—a prizewinning molecule
In 1980, Dr. Robert Furchgott of the State University of New York was conducting experiments using rabbit arteries. He inadvertently stumbled on the observation that arteries constricted when their inner lining—the endothelium—was removed, but dilated when the lining was left intact. Dr. Furchgott theorized that the endothelium was necessary to permit normal arterial dilatation, and that damaged endothelium prevented it.
This sparked a furious effort to identify the factor produced by the endothelium governing relaxation. Originally dubbed "endothelium-derived relaxation factor," or EDRF, identification of EDRF proved elusive, as it was present for mere seconds. Nonetheless, in 1986 EDRF was discovered to be nitric oxide. This discovery resulted in the Nobel Prize for Medicine awarded to Drs. Furchgott, Louis Ignarro, and Ferid Murad in 1998. Nitric oxide is now recognized to be a signaling molecule for many processes and the single most powerful artery dilating agent known.3,4
Because endothelial tissue is just a single cell-layer thick, you might be tempted to believe there is not much margin for error when it comes to keeping it healthy. Although the endothelium is a razor-thin line of demarcation between blood and tissues, it is without doubt one of the body's most tireless workhorses. Industrious, and if anything overachieving, endothelial tissue is responsible for keeping our bodies supplied with nitric oxide. With the help of an enzyme called endothelial NO synthase, endothelial cells function as the power plant where NO—a renewable resource essential to good health—is manufactured and mobilized.
Dr. Louis J. Ignarro
Nobel Laureate in Medicine, 1998
The identification of nitric oxide as the pivotal molecule for arterial control has launched a worldwide scramble to develop strategies to increase the body's capacity for its production.
Endothelial injury—the first step
The combination of coronary heart disease and stroke is responsible for 38% of all deaths in the U.S. with costs approaching $400 billion dollars. (American Heart Association, Heart Disease and Stroke Statistics Update, 2005.) You might say that diseases of the endothelium are therefore the number one killer of Americans.
Injury to the delicate endothelium can assume many faces. The endothelium is acutely sensitive to foods you eat, blood pressure, and toxic substances in the blood like LDL cholesterol particles and homocysteine.
Endothelial injury is measurable as a dysfunctional response to a variety of dilating substances. Just as in Dr. Furchgott's groundbreaking experiments, administration of specific agents triggers an artery to dilate when the endothelium is healthy. When the endothelium is dysfunctional, the artery constricts.
In the heart, the coronary arteries normally dilate with exercise, allowing a deluge of blood to nourish heart muscle and satisfy the surge in oxygen demand. But in the presence of dysfunctional endothelium, coronary arteries surrender the normal capacity to dilate. Instead, they constrict. Repetitive, sustained constriction results in damage to the endothelium, laying the foundation for plaque formation.
Endothelial dysfunction can be assessed in living persons. A common technique is to examine the easily accessible forearm (brachial) artery with ultrasound. Maneuvers such as occlusion of the brachial artery with a blood pressure cuff inflated to maximum pressure for several minutes can be used to uncover endothelial dysfunction. After the period of (painful!) occlusion and release of the cuff, normal endothelium allows enlargement of the artery (often 10% or more). No increase or outright constriction is seen when unhealthy endothelium is present.5
Endothelial dysfunction is one of the fundamental phenomena behind high blood pressure. (If you have high blood pressure, you definitely have dysfunctional endothelium. If you don't have high blood pressure, you may still have dysfunctional endothelium.) It is also behind diverse processes like stroke, eclampsia (of pregnancy), headaches, aneurysm formation, and erectile dysfunction.
An injured and dysfunctional endothelium is the initial step in creating the atherosclerotic plaque of coronary, carotid, and other arteries. Endothelial dysfunction can precede the appearance of visible atherosclerosis by decades.5
9 ways to correct endothelial dysfunction
L-Arginine
The amino acid, L-arginine, is the body's source of nitric oxide. L-arginine is metabolized by the enzyme nitric oxide synthase in endothelial cells to yield a continuous supply of nitric oxide. Nitric oxide relaxes muscle cells that control the "tone" of the body's arteries. It's not unusual, for instance, for vessels like the heart's coronary arteries to enlarge up to 50% in diameter when nitric oxide is readily available. Because of its extremely short life, a constant supply of nitric oxide is required to maintain relaxed arteries. Any drop in nitric oxide production and arteries constrict. Left unchecked, chronic constriction damages the artery lining, which then promotes plaque growth. Plaque-filled arteries are less and less able to produce nitric oxide, yielding even more injury. Thus, a vicious cycle ensues.
Furnishing sufficient l-arginine to fuel nitric oxide synthase can increase nitric oxide. One major discovery of the last few years is a specific inhibitor of l-arginine called asymmetric dimethylarginine, ASDM. This l-arginine look-alike is elevated in hypertension, high cholesterol, high triglycerides, small LDL particles, low HDL, and high homocysteine, and with aging. ASDM may, in fact, represent the final pathway shared by many, if not all, of these abnormal conditions. Increased levels of ASDM blocks nitric oxide production, leading to dysfunction of the endothelium. L-arginine, in effect, overpowers ASDM and restores nitric oxide availablility.6,7
The pharmaceutical industry is keenly aware of the power of nitric oxide and l-arginine for protection against endothelial dysfunction. The popular prescription medicine for male erectile dysfunction, Viagra®, boosts nitric oxide. Originally intended to be a heart drug, it proved to target the penile circulation. Another nitric oxide enhancing prescription agent called nebivolol is also nearing completion of clinical trials. However, a powerful nitric oxide source is already available to us: l-arginine. L-arginine remains among the most incredible and effective supplements available. (L-arginine also enhances erections, though full benefit is slow to develop and may require 3 months.)
The average American ingests about 3000–5000 mg of l-arginine per day, since it is an amino acid naturally contained in many foods. Meats of all varieties, nuts, and dairy products are rich in l-arginine, so your body is already accustomed to several-thousand milligram quantities each and every day.
Evidence shows that endothelial function is restored by administration of l-arginine. L-arginine restores arterial dilating capacity when studied in people with hypertension9, high cholesterol10,11 , increased free fatty acids (as in pre-diabetes and diabetes) and triglycerides12,13, pre-diabetes14 and diabetes15. In other words, l-arginine corrects the inappropriate arterial constriction of endothelial dysfunction regardless of the initiating cause.
Besides l-arginine, there are several other nutritional strategies that can augment endothelial health:
Citrulline
Citrulline is an amino acid that participates in a two-way conversion: some is converted by the kidney to l-arginine, which is then in turn metabolized back to citrulline. Some have therefore speculated that supplemental citrulline can act as a repository for l-arginine.21 The dose of citrulline is not well worked out but, anecdotally, 500–1,000 mg per day have been used successfully.
Flavonoids
Flavonoids provide a means to magnify the endothelial-health benefits of l-arginine. Flavonoids are naturally-occurring food substances believed to possess anti-cancer, anti-hypertensive, anti-oxidant, and anti-inflammatory properties. They are likely a major part of the reason that the Mediterranean diet (rich in vegetables, fruits, olive oil, and red wine) slashes heart attack risk by a remarkable 70%.22 Over 4000 different flavonoids in six sub-groups have been identified: flavonols, flavones, flavonones, catechins, anthocyanidins, and isoflavonoids.
Oxidative molecules, like superoxide, can inactivate nitric oxide and form peroxynitrite, a potent constrictor of arteries. Flavonoids serve a protective role by scavenging peroxynitrite.23
Chocolate, green tea, blueberries, pomegranate, beets, red wine resveratrol, and soy isoflavones are the most potent food sources of flavonoids that have been shown to normalize endothelial function.24–28. Most flavonoids are also available as nutritional supplements, either singly or in various combinations, e.g., quercetin, grapeseed extract, pine bark extract.
Magnesium
Magnesium is a potent modulator of endothelial function. Animal studies have shown markedly impaired function with magnesium deficiency, corrected with magnesium supplementation. Human investigations have confirmed that magnesium-deficiency impairs normal arterial dilation; artery diameter increases 25% after magnesium replacement.29,30 Magnesium replacement also reduces blood pressure through endothelium-normalizing effects.31,32
Magnesium deficiency is growing to epidemic levels and has become a societal issue as municipal water treatment intensifies and people turn to bottled water with nearly zero magnesium content. In cities with the highest magnesium water content, only 30% of the RDA can be obtained by drinking two liters of tap water per day. A study of people with heart disease showed that tissue magnesium levels (superior to blood levels usually obtained) were deficient in 53% of participants.33
A confident dose for supplementation is 500 mg per day of "elemental" magnesium. This is the quantity of magnesium regardless of the form you take (e.g., magnesium citrate, magnesium lactate, magnesium oxide, etc.), usually listed on the bottle as "elemental magnesium." Doses are best taken distributed throughout the day in order to avoid diarrhea. (Our preferred form is magnesium citrate, 200 mg two or three times per day.)
Homocysteine
Increased levels of this toxic amino acid are associated with endothelial dysfunction.34 A Harvard study showed that people with homocysteine levels >16 µmol/l had half the arterial dilating endothelial function of people with normal homocysteine blood levels.35 Homocysteine encourages blood coagulation, increases levels of oxidative by-products, attracts inflammatory white blood cells, and triggers plaque growth in the arterial wall.36 It has recently been discovered that high homocysteine levels increase levels of asymmetric dimethylarginine (ADMA), the blocker of l-arginine and nitric oxide production.37
A folic acid dose of 0.8 mg (800 mcg), the highest dose available over the counter, reduces homocysteine around 25%. Higher doses up to 5 mg yield greater effects. Vitamin B12 and folic acid should be replaced together to maximize homocysteine-reducing effects. Vitamin B6 is effective for blocking the after-eating surge of homocysteine, particularly when methionine-rich meats are part of a meal. The vast majority of people obtain substantial homocysteine-lowering benefits with B6 50–100 mg per day and vitamin B12 100–250 mcg per day, provided folic acid is at optimal levels.
Recent data confirm that therapies to reduce homocysteine also reduce levels of ADMA and improve endothelial function.38 Interestingly, one study showed that reducing homocysteine from the "normal" range of 9.0 µmol/l to 7.9 µmol/l with folic acid supplementation resulted in 20% improvement in endothelial function after one year of treatment.39
Two recent studies have called into question whether reducing homocysteine with B vitamins reduces risk of heart attack. This will be the topic of a future in-depth report.
Vitamin D
The exploration of vitamin D's role as an agent for health is in its infancy. Once regarded only as a means to prevent rickets, it is now recognized as among the most crucial of nutrients for a sweeping array of health issues.
Among its diverse physiologic roles, vitamin D is a regulator of blood volume, electrolytes, and blood pressure. A recent University of Chicago study showed that vitamin D achieves this through suppression of the blood pressure hormone, renin.40 This effect is similar to that of the prescription angiotensin converting enzyme inhibitors (lisinopril, captopril, etc.). Other data have shown that vitamin D modulates endothelial function and reduces blood pressure around 20 mmHg (on average) in hypertensive individuals.41–43 The dose of vitamin D that achieves maximum health benefits is being debated (the Recommended Daily Allowance has been rescinded by the Institute of Medicine) but is probably in the range of 2000 units per day in the absence of substantial sun exposure.44 We find that most women require 3000-4000 units per day to bring blood levels into the desirable range of around 50 ng/dl. Men generally require 4000–6000 units per day. The best vitamin D to take are oil-based capsules, not tablets, as the blood levels rise more assuredly with the capsules. Try to find preparations with just vitamin D without calcium, vitamin A, etc. Higher doses of D are too hard to get when combined with other ingredients, or your could get toxic quantities of the other ingredient.
Fish oil
The omega-3 fatty acids of fish oil exert endothelium-protecting benefits through a number of routes. Fish oil reduces blood levels of adhesive molecules like VCAM-1 and E-selectin, and shuts down markers of endothelial activation like vWF and plasminogen activator antigen-1. Suppression of endothelial activation is more dramatic in people with diabetes, high triglycerides, and metabolic syndrome.36 High triglycerides, low HDL cholesterol, and small LDL particles all provoke endothelial dysfunction; fish oil improves endothelial function by contributing to correction of all three patterns.45
Fish oil increases endothelial dilating capacity of arteries. Omega-3 fatty acids are incorporated into cell walls of the endothelium and thereby substantially improve dilating capacity in persons with high cholesterol. These effects may require several months of supplementation to develop.46,47
Endothelial health-preserving effects of fish oil are consistent with the substantial reduction in death from heart disease seen in fish-eating cultures and in clinical trials like the 11,000-participant GISSI Prevenzione Trial (45% reduction in cardiac death).48 The GISSI study used a EPA + DHA dose of 882 mg, equivalent to approximately three capsules of a standard fish oil preparation (300 mg EPA + DHA per capsule). It is unclear whether higher doses than that used in GISSI provide greater benefits from a mortality viewpoint, but higher doses can be used to correct high triglycerides and related lipoprotein abnormalities. For these purposes, doses of 4,000–10,000 mg per day are used effectively, providing 1,200–3,000 mg EPA + DHA.
Lipoproteins
Lipoproteins also modulate endothelial function. High-density lipoprotein particles (HDL), in particular, exert powerful endothelial health-preserving effects. People with high HDL levels experience less heart attack, stroke, cancer, and are more likely to live longer, with HDL's in the >90 mg range predicting extreme longevity. A Dutch study in people with an inherited defect of HDL cholesterol (familial hypoalphalipoproteinemia) demonstrated severe endothelial dysfunction that was dramatically reversed with infusion of a synthetic HDL.49
Conversely, high low-density lipoprotein (LDL), small LDL particles, and increased triglycerides trigger endothelial dysfunction. All of these undesirable patterns are also important causes of heart disease and stroke.5,50 Small LDL particles, in particular, are potent instigators of endothelial dysfunction. A Helsinki University study showed that small LDL particles were responsible for a 39% reduction in arterial dilation compared to men with healthy large LDL particles, even when the LDL cholesterol levels were the same.51
The after-eating flood of fat that develops after a high-fat meal is being increasingly recognized as a cause of endothelial dysfunction. These "lipoprotein remnants" can provoke as much as a 50% reduction in artery diameter.52 Fish oil has proven to be an effective tool for suppressing the after-eating flood of remnant particles. Fish oil exerts its benefits through stimulation of the enzyme, lipoprotein lipase, that metabolizes lipoprotein particles, and by decreasing very low-density lipoprotein synthesis, a major component of after-meal lipoproteins.53
Niacin is the number one supplement for raising HDL, beginning at doses of 250 mg per day. (Doses exceeding 500 mg per day should be taken with the help of your doctor.) Niacin also effectively reduces small LDL particles. Fish oil, beginning at doses of 4000 mg per day (to provide 1200 mg of EPA + DHA), raises HDL a few points and is very effective for reducing, often eliminating, lipoprotein remnants. The combination of niacin and fish oil can dramatically reduce abnormal lipoproteins.
Antioxidants
Oxidative radicals are destructive by-products of metabolism that damage arteries and generate endothelial dysfunction. An Italian study demonstrated that people before age 60 respond most vigorously to l-arginine supplementation to restore nitric oxide, while after age 60 the antioxidant, vitamin C, was required with l-arginine to restore endothelial dilating capacity.2 This suggests that oxidant injury to the endothelium assumes a more important role as we age.
Oxidant injury may also be a major factor disabling endothelial health in high blood sugar states like pre-diabetes and diabetes. Normal endothelial dilating responsiveness is restored by vitamin C during both diabetes and experimental hyperglycemia and has been theorized to heighten the effects of nitric oxide.54 In fact, a Greek study showed a near doubling of the coronary artery dilating effect of l-arginine when vitamin C was added.55 Vitamin C can also reverse abnormal endothelial responses when homocysteine is elevated, in people who smoke, and in the presence of kidney disease.36
Whether vitamin C and other antioxidant nutrients can actually affect outcome, such as reducing heart attack and cancer, is still an open question. Particularly interesting would be outcome studies on the combined use of l-arginine and antioxidant preparations. No studies have yet been conducted.
The Track Your Plaque approach to maximization of endothelial health
* Lipoproteins—Have you achieved the Track Your Plaque goals of 60/60/60 for LDL/HDL/Triglycerides? This is the easiest way to ensure that your lipoproteins are fully corrected. Also, any hidden patterns, like Lp(a) and small LDL need to be corrected.
* Magnesium—Our preferred form is magnesium citrate, 200 mg two or three times a day.
* Fish oil—If fish oil is not part of your program yet, it should be! 4000 mg per day (providing 1200 mg EPA + DHA) is the minimum.
* Vitamin D—Ideally, your blood level of 25-OH-D3 is corrected to 50 ng. We find that 2000 units per day for women, 3000 units for men bring most people who lack sun exposure into the desirable range.
* Antioxidants—Vitamin C is the one anti-oxidant worth adding. 1000 mg per day works well, allowing other constituents of your program, like flavonoids and l-arginine, to exert full effect.
* Flavonoids—Colorful vegetables and fruits are key, here. Also, red wine, dark chocolate, green and black teas.
* Homocysteine—Despite the controversy, our bias is to continue reducing homocysteine levels to <10 for endothelial health. Most people can easily accomplish this with a high-potency B-complex vitamin.
Conclusion
The appreciation of endothelial health as the earliest manifestation of vascular disease may allow us to intervene earlier and more effectively in preventing heart and vascular diseases like stroke and heart attack. Dysfunction of the endothelium is triggered by hypertension, cholesterol and lipoprotein abnormalities, increased homocysteine, vitamin D deficiency, oxidative injury, and other abnormal—yet common— states. Endothelial dysfunction can be partially or completely corrected through an applied nutritional effort that includes use of l-arginine, fish oil, omega-3 fatty acids, flavonoid sources, magnesium replacement, vitamin D, correction of abnormal lipoprotein patterns and antioxidants.
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Copyright 2007, Track Your Plaque.
Focus on l-arginine
L-arginine is a powerhouse supplement that can restore normal endothelial function. But it packs many other benefits:
L-arginine magnifies benefits of cholesterol-lowering treatment when used with statin agents
Blood levels of asymmetric dimethylarginine can reach 10 times normal once coronary plaque is established. When l-arginine is added to a statin (cholesterol-lowering) medication, the artery-relaxing benefits are compounded. The combination is safe and requires no modification in dosage of either the l-arginine or the statin drug.8
L-arginine re-sensitizes your body to insulin
30% or more of all adults in the U.S. are insulin-resistant, i.e., unresponsive to their own insulin, a condition called metabolic syndrome or pre-diabetes. L-arginine can re-sensitize your body to insulin and scale back insulin-resistance.8,13
L-arginine is anti-inflammatory
Inflammatory cells emigrate from the bloodstream and into plaque, causing plaque to grow and eventually rupture, resulting in heart attack. L-arginine acts as kind of a Teflon-coating on the artery lining, preventing their entry.16
L-arginine shrinks plaque
Few things truly shrink atherosclerotic plaque. After all, a complex mix of genetic and lifestyle factors interact over decades to create the fatty gruel that lines arteries and can erupt without warning. L-arginine is one of the few agents that has been shown to be capable of shrinking plaque size.17–20
How to use l-arginine
Effective doses range from 3000–6000 mg twice a day on an empty stomach. For this dose, capsules are generally too cumbersome to use, since most capsules contain 500 mg. Powdered preparations are therefore recommended.
Adverse effects of l-arginine are few.
Loose stools occasionally occur with the 6000 mg dose (usually a single loose bowel movement, not repeated diarrhea). Cut back the dose and build up gradually over several months if you experience this effect. (If you have any active gastrointestinal diseases, particularly those associated with diarrhea or frequent loose stools, like ulcerative colitis, Crohn's disease, and malabsorption, discuss with your doctor first. L-arginine can also reactivate latent oral or genital herpes or shingles, though we've had many patients successfully use l-arginine with no increase in the frequency of viral eruptions. If you have a history of cold sores, genital herpes, or shingles, speak with your doctor about l-arginine.)
L-arginine: A cornucopia of health effects
L-arginine is a fascinating, multi-faceted nutritional component of an endothelial health program. Though found in foods, supplemental l-arginine provides a powerful boost. L-arginine relaxes coronary and muscle arteries, protects the arterial wall from inflammation, prevents blood clots by blocking platelets, facilitates plaque regression, lowers blood pressure, increases exercise capacity, increases the vigor of erections in men, and enhances feelings of well-being.
Is l-arginine dangerous after heart attack?
Among nitric oxide's many beneficial effects, it is believed to help improve heart muscle (left ventricular) function when impaired by injury. Prescription medications that increase nitric oxide have been shown to reduce mortality in heart failure. Most recently, the combination of hydralazine and nitroglycerin has yielded substantial benefits through its nitric oxide increasing effects.56
The VINTAGE MI Study recently attempted to study whether l-arginine had a similar effect. In this study of 153 participants, all of whom suffered a recent heart attack, three grams three times per day of l-arginine was compared to placebo. To the surprise of the University of Maryland researchers, six deaths occurred in the group receiving l-arginine, none in the placebo group.57 The media seized hold of this, declaring l-arginine a deadly supplement.
Should we panic and stop l-arginine based on this report? We think not. First of all, two of the deaths occurred months after l-arginine treatment was stopped. Two other deaths were due to infections and likely unrelated to heart disease or l-arginine use. This leaves two deaths attributable to heart disease. Numbers this small are likely to represent chance statistical effects, especially in view of the small size of the overall trial.
We should also view this one study in the context of all preceding studies examining l-arginine use. No such excess dangers have been observed in thousands of participants with coronary disease, angina, peripheral vascular disease, and heart failure over the last decade of investigation.58 Need we also remind everyone that l-arginine is a food substance. Do fish, chicken, eggs, and nuts also pose danger? Of course not.
As always, each study should be viewed within the broader context of the available scientific and clinical experience. The overwhelming experience, as well as common sense, suggests that the VINTAGE MI Trial is a statistical fluke.
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