PHOENIX RISING

TREATING CHRONIC FATIGUE SYNDROME

Bringing Opportunity to ME/CFS Patients

A Laymen’s Guide to Cardiovascular Issues in CFS Part IVd: Free Radicals and the Heart: Antioxidants by Cort Johnson

This last section of this series of papers examines the outcomes of the antioxidant trials done on heart patients and gives an overview of two of the  antioxidants, CO2 and uric acid, Dr. Cheney recommends for battling peroxynitrite production in CFS patients.

Antioxidant Trials and Heart Disease – The notable free radical upregulation in cardiovascular disease suggests antioxidants may be an important treatment. Indeed antioxidant trials in laboratory animals have been most promising. Antioxidants have garnered enough interest in heart disease for public agencies to invest in many large (n= 4-20,000) and long (4-14 years) and undoubtedly very expensive observational or randomized studies. Observational studies appear to attempt to determine how much antioxidant intake occurs over time.  They then correlate that with indices of heart disease. The far more reliable randomized studies involve placebos and supplementation.

The results have been mostly negative and in one recent instance positively alarming. Once again we see a great divide between results in in vitro and in vivo tests involving antioxidants. In vitro tests indicate Vit. E blocks LDL oxidation, decreases LDL particle deposition into the arterial wall (beginning of plaque formation), and reduces monocytes adhesion to the arterial wall (reduces oxidative stress?), etc. Observational trials mostly do find benefit from increased Vit. E but rarely has benefit been found in the more rigorous placebo controlled randomized supplemental treatment trials (Duval 2005).

The most recent trial, the HOPE study, which followed almost 10,000 patients with coronary artery disease over 7 years found vitamin E supplementation (400 iu/day) not only did not significantly reduce the risk of heart attack, stroke, cardiovascular death, angina or mortality but significantly (p<.03) increased the risk of heart failure (!!). As none of the other randomized trials of vitamin E have examined the incidence of heart failure, the authors of the HOPE study strongly urged the investigators of those prior studies to re-analyze their findings. The mechanism linking Vit. E supplementation to heart failure was unclear but the authors suspected it was due to the potential for Vit. E to become a pro-oxidant in a oxidative rich milieu. (That’s a nice switch!). By displacing other fat soluble vitamins the authors also suggested high levels of Vit. E supplementation might have disrupted the natural balance of the antioxidant system and reduced HDL cholesterol levels. HDL cholesterol is the 'good' cholesterol.

Several observation trials have found benefit from taking Vit. C, while others have not. The one randomized study did not (Knekt et. al. 2004). While some studies have found benefits for taking carotenoids some of those that did had not been adjusted for confounding factors, most studies have found no benefit. (Knekt et. al. 2004).

Some smaller trials have examined the effects of combination therapy. A 3 year double-blinded trial involving Vit E, C, beta carotene and selenium found no benefit. Another involving high levels of Vit. E (800 mg) and Vit. C (1000 mg.) found a non-significant trend towards narrowed arteries. A large trial (n=30,000) involving Vit. E, Vit. C and beta carotene found no significant effect on mortality, cardiovascular death, stroke, etc. in patients with coronary artery disease and/or diabetes (Duval 2005). A trial employing beta carotene and Vit. E found an increased risk of lung cancer and ischemic heart disease.

The mostly poor results from antioxidant trials underscores the complexity of the cardiovascular disease process and our limited (though still very impressive) understanding of the processes governing the oxidant/antioxidant balance in the body. After several decades of large scale antioxidant trials employing well over 100,000 participants in total a recent review of the subject concluded there was no role for antioxidant therapy in cardiovascular disease (Duval 2005). It is interesting given this disappointing information that higher rates of fruit and vegetable intake were associated in a large study (n=6,000) with reduced death rates overall and reduced cancer and cardiovascular deaths, in particular.  Perhaps not surprisingly analysis of Vit E, C and A dietary intake found increased dietary intake of these antioxidants had no effect or mortality (Genkinger et. al. 2004). There's obviously more to fruits and vegetables than can be gotten in a pill.

Other antioxidants - Many substances other than Vit. C, E and beta carotene have antioxidant properties. Dr. Cheney's recommendation that CFS patients attempt to increase their CO2 and uric acid levels prompted a survey of the roles these antioxidants play in peroxynitrite scavenging and cardiovascular disease. 

Carbon Dioxide (CO2) –  C02 is probably the major sink for peroxynitrite in many physiological environments in the body. It was only in 1996 that peroxynitrite was found to interact with CO2.

The most startling facet of this reaction is its very high rate constant. Bicarbonate (HCO3-) in combination with CO2 reacts more rapidly with peroxynitrite in vitro than any other substance in plasma. The rate constant defines how rapidly one reactant interacts with another. It does not, however, take into account the diversity of reactants in a solution. A compound that is more common than another but has a lower rate constant may interact more frequently than one with a high rate constant and a low frequency (Vesala and Wilhelm 2002). This appears to be the case with thiols. Although the rate constant for glutathione and peroxynitrite is lower than that for carbon dioxide and peroxynitrite, because glutathione and other thiols are present in larger amounts in the cell, they interact more frequently with peroxynitrite than does CO2. The situation is reversed outside of the cell; carbon dioxide levels in the extracellular fluids are very high and peroxynitrite interacts most frequently with it (Vesala and Wilhelm 2002).

Through its ability to scavenge peroxynitrite CO2 is able to inhibit lipid oxidation and maintain vitamin E (a-tocopherol) levels (Rubbo and O’Donnell 2005). Studies indicating the HCO3/CO2 peroxynitrite interaction partially inhibits thiol (glutathione, cysteine, albumin) oxidation further suggest CO2 plays an important role in maintaining antioxidant levels (Bonini and Angusto 2001). Increased CO2 blood levels (hypercapnia) in the absence of superoxide are believed to be protective against the free radical damage induced by hypoxia probably because of CO2’s ability to stabilize the iron/transferrin complex and protect superoxide dismutase (Vesala and Wilhelm 2002). Certain iron ions are very potent free radical catalysts. Transferrin is the major iron binding ion in the blood. Its ability to bind iron appears to require certain levels of bicarbonate (HCO3-), the major buffering agent in the body. One study found CFS patients had reduced transferrin levels (Keenoy et. al. 2001). This suggests raising CO2 levels could reduced iron ion induced oxidation. Ironically this reaction also produces the carbonate radical which may cause further oxidative damage. The oxidatiion/antioxidant process is nothing if not complex!

Because the CO2/peroxynitrite interaction itself produces a free radical called a nitrosocarbonate (OONOCO2-) questions have arisen, however, regarding how beneficial the CO2/peroxynitrite is. Two scenarios have been produced surrounding the C02/peroxynitrite interaction (Lang et. al 2000).

CO2 is a ‘Good Guy’ - While the C02 peroxynitrite interaction produces a potent free radical, ONOOCO2-, this substance breaks down to an innocuous substance so much more quickly than peroxynitrite it reduces the exposure time of the cell to a highly oxidizing substance. Not only is the cell spared injury but it is spared reductions in the antioxidants, particularly the thiols such as glutathione used to subdue peroxynitrite.

CO2 is a ‘Bad Guy’– While OONOCO2- does degrade more quickly than peroxynitrite it can actually attack a wider number of substances. Furthermore the OONOC02- peroxynitrate interaction appears to enhance protein nitration, one of the most destructive aspects of peroxynitrite. Some researchers, in fact, believe many of peroxynitrites destructive effects are dependent upon CO2 and mediated by OONOCO2- (Lang et. al. 2000). Peroxynitrite appears to relatively inefficient at nitrating proteins when CO2 levels are low (Ronson et. al. 1999). Epithelial cells exposed to increased CO2 concentrations exhibited increased NO, tyrosine nitration, greater injury and increased risk of apoptosis (Lang et. al. 2000).

CO2 reacts with approximately 65% of peroxynitrite to form an innocuous substance, nitrate. The remaining products of the CO2/peroxynitrite interaction, C03- and NO2, however, are anything but benign. Because C03- reacts more efficiently with the tyrosine residues on protein than the hyrodxyl radical formed during a non-CO2 pathway of peroxynitrite degradation, the CO2 peroxynitrite interaction produces substantially more tyrosine nitration (e.g. nitrotyrosine production) and production of the tyrosyl radical. The fun doesn’t stop there.

While CO2 does appear to spare thiol oxidation a recent study indicated that two by-products of the CO2 peroxynitrite interaction, CO3- and NO2, create reactive species (RS) through their interactions with thiols (Bonini and Angusto 2000). RS species consequently react with each other and oxygen to produce more radicals (RSO, RSSR-). One of the radicals formed, oxidized glutathione (GSSG-)can interact with oxygen to produce superoxide. One author suggested ‘intracellular GSH oxidation by peroxynitrite derived radicals could trigger an oxygen dependent free radical chain reaction’. Also CO2 did not inhibit thiol oxidation in the more acidic environments found in ischemia or during phagocytosis nor did CO2 inhibit peroxynitrite induced cytochrome c oxidation in one study (Cassina et. al. 2000).

As often occurs with antioxidants the outcome of CO2’s interaction with peroxynitrite may depend upon the context in which it occurs. Vesala and Wilhelm posit that in the aqueous environment of the extracellular fluids CO2 plays a protective role. In the cell membranes, on the other hand, they suggest CO2 interactions with peroxynitrite results in protein nitration and increased oxidative damage (Vesala and Wilhelm 2002).

Uric Acid – After noting uric acids ability to scavenge peroxynitrite and the low levels of uric acid (1-2 mg/l) typically found in his patient population Dr. Cheney has made uric acid enhancement a part of his treatment protocol. Normal uric acid levels are between 3.8 and 4.1 (Fang and Alderman 2000).

It was rather startling to learn, therefore, that opposite is usually the case in heart failure; uric acid levels are typically high (>6 mg/l) and instead of being advantageous high uric acid levels (hyperuricemia) are considered a significant risk factor for cardiovascular disease (Alderman and Ayer 2004, Hoieggen et. al. 2004, Fang and Alderman 2000). Hyperuricemia has been linked to endothelial dysfunction, impaired oxidative metabolism and increased platelet adhesiveness (Hoieggen et. al. 2004). Many studies have found hyperurecemia is an independent risk factor for overall mortality, cardiovascular disease and ischemia related death. It is highly predictive of mortality in heart failure.

Hyperurecemia is often found in people with high blood pressure (hypertensives) where it is positively correlated with plasma renin activity. CFS patients appear to have low renin levels. Its cause is unclear but appears mostly to be due to an inability of the kidney to clear urate from the circulation. Gout and kidney stones are common complications. Gout occurs when urate crystals lodge in the connective tissues.

Uric acid is the final breakdown product of purine metabolism. Purines are found in their highest concentrations in organ meats such as kidney, liver and sweetbreads. Since some purine production in the body comes from food uric acid levels are somewhat susceptible to dietary modification. Since elevated uric acid levels can be lowered by inhibiting xanthine oxidase one wonders if this means that xanthine oxidase, an enzyme that is upregulated in heart failure, is also low in CFS.

Summary - the redox system is nothing if not bewildering in its complexity and the twists and turns it presents. The biggest scavenger of peroxynitrite in the body, CO2 may be protective or destructive depending on which author is read or where in the body it is found. Most of the papers concerning CO2's interactions with peroxynitrite suggested it had a negative effect. Vesala and Wilhelm, on the other hand, state it is protective in aqueous environments and that in vivo studies have shown mostly positive effects. Uric acid presents another twist; there is little doubt high uric acid levels are indicative of a poor prognosis in heart failure. Dr. Cheney states CFS patients, however, have low uric levels and given uric acid's potential as a peroxynitrite scavenger, suggests using dietary means to increase uric acid levels.  

Atypical Heart Failure in CFS? – It is too early to characterize the type of heart failure that may be present in CFS but preliminary indications indicate that if heart failure is prominent in CFS, it presents a most unusual picture. Besides low (not normal but low) uric acid levels, CFS patients appear to display a variety of factors that not often found in heart failure including normal or reduced levels of renin activation, low blood volume, blood pooling, normal Valsalva reading, atypical symptom presentation, possibly low xanthine oxidase activity and a non-progressive disease. That heart failure in CFS would not follow a familiar pattern will probably not surprise CFS patients who have long been accustomed to the signs of confusion wrought in the medical community by this complex and unusual disease. Dr. Cheney, Dr. Peckerman and Dr. Lerner suggest a subtle form of heart failure in CFS patients could still produce a profound disability.

Rampant Speculation - One wonders if the cause of the non-progression of heart failure lies not in the impaired GSH px levels, as Dr. Cheney suggests, but in the lack of several factors, such as increased RAA activation and high uric acid levels, that normally play a role in heart failu progression. If Dr. Cheney is correct in his assertion that many CFS patients are in 'heart failure' that is essentially non-progressive it stands to reasom they may be a kind of Rosetta stone for heart researchers. Could they hold the key to 'turning off' heart failure (?????).

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