AA OXIDOPATHY – PART 3

Majid Ali, M.D.

Coronary Artery Heart Disease Begins With AA Oxidopathy 


 

 

AA OXIDOPATHY HYPOTHESIS IS CONSISTENT WITH ALL KNOWN MOLECULAR DYNAMICS OF IHD

    Molecular dynamics that preserve the clotting-unclotting equilibrium (CUE) of life are marvels of biology. An elaborate system of coagulative proteins, fibrinolytic enzymes and inhibitors of fibrinolysis exists in the circulating blood that prevents clotting-unclotting disequilibrium (CUD) in health and causes prompt clotting of blood when the integrity of the vascular wall is breached. Our microscopic findings indicate that oxidative coagulopathy is the morphologic expression of initial oxidative disequilibrium of redox in the circulating blood (early changes of CUD). The broader range of changes of AA oxidopathy involving all circulating blood elements (erythrocytes, granulocytes, lymphocytes, platelets, and plasma components), as well as elements of the vascular wall, myocardial cell membrane, and conducting system are the later events (full expression of CUD). We regard atherosclerosis as the structural tissue response to chronic and insidious AA oxidopathy.
We have briefly reviewed the basic aspects of spontaneity of oxidation in nature and molecular duality of oxygen and have presented a host of morphologic patterns of oxidative coagulopathy and AA oxidopathy. Now we address the essential issue of how consistent our proposed AA oxidopathy hypothesis is to all known molecular dynamics of IHD. We follow that review with a discussion of the pathogenesis of cell and plasma membranes permeability dysfunctions (leaky cell membrane dysfunction) which is an integral part of AA oxidopathy. Finally, we present evidence for our view that dysregulations of cholesterol and related lipids are the consequence and not the cause of pathophysiologic derangements that result in AA oxidopathy and ischemic heart disease. The table on the following page gives a listing of the pro-oxidant factors that contribute to pathogenesis of AA oxidopathy and the antioxidant elements which normally arrest oxidopathy and have been—or may be—clinically employed to reverse ischemic heart disease.

In Part II of this article, we will address the issue of how well our hypothesis explains all known clinical risk factors of IHD.

AA OXIDOPATHY

Pro-oxidant Promoters of Oxidopathy Antioxidant Blockers of Oxidopathy
Lifestyle hyperadrenergic states Prayer, meditation and spiritual work
Physical inactivity Limbic exercise28
Hyperglycemic-hypoglycemic shifts/diabetes Optimal choices in the kitchen27
Hypertension Optimal hydration, rebounding exercise
Tobacco smoking Antioxidant vitamins (C, E and beta carotene). Food antioxidants: curcumin and others
Hyperhomocysteinemia Vitamins B6, B12, folic acid
Pro-oxidant minerals:iron, copper, mercury, lead Antioxidant minerals: selenium, chromium
Microbiologic agents: CMV, Chlamydia Coenzyme Q10, lipoic acid and others
Synthetic oxidants Synthetic antioxidants: EDTA, probucol
Oxidative dyslipidemias All of the above

    Unoxidized and “undenatured” cholesterol, like pure water, is essential for life. Oxidized and denatured cholesterol, like polluted water, causes disease. Cholesterol, a weak antioxidant, prevents AA oxidopathy. Hypercholesterolemia is a negative adaptive response to insidious oxidopathy. Excess cholesterol, when oxidized, fans its oxidative flames.

Lifestyle Stressors, AA Oxidopathy and IHD
Our clinical observations and autopsy findings convince us that lifestyle stress is by far the most important factor in the etiology of severe and fatal forms of IHD. In Part II of this article, we furnish excellent clinical outcome data obtained with an integrated heart disease reversal program in a series of patients with advanced IHD (poor outcome following angioplasty, coronary bypass surgery and multiple drug therapies) and demonstrate how valuable an effective program for stress control and meditation can be.
Clinically, we recognize lifestyle stress as the precipitating factor in severe ischemic events in a clear majority of our patients. Indeed, it would be hard to find a physician or a patient with IHD who would disagree with that statement. This common clinical observation is supported by firm pathologic data. One of us (MA) discovered early in his pathology training a fact of great significance that is rarely, if ever, given due consideration in discussions of the cause of IHD: A majority of victims of IHD who die within six hours of infarction or other acute ischemic events do not show coronary thrombotic occlusion, while those who die after 48 hours of such events almost always show thrombotic coronary occlusion (unpublished personal observation)—a fact that clearly establishes that thrombotic coronary occlusion in the majority of such patients is the consequence and not the cause of infarction or other acute ischemic events. The real cause, our experience shows, is lifestyle stress that triggers coronary vasospasm or cardiac rhythm disturbances. We hold that our view is fully validated by the angiographic and eventual autopsy studies in the survivors of out-of-the-hospital cardiac arrests. Angiographic coronary occlusion was observed in only 36 percent of such subjects in one study237 while coronary thrombotic occlusion was observed in 95 percent of subjects at autopsy.238

In 1959, individuals with type A behavior pattern (an emotional makeup that creates a continuing sense of urgency and easily aroused free-floating anxiety) were found to have a seven-fold greater prevalence of clinical coronary artery disease than persons without such pattern (type B behavior pattern).239 Significantly higher incidence of IHD was reported in type A than among type B persons.240 This association was further explored in many clinical,241pathologic,242 and epidemiologic studies.243-245 In 1981, a panel which reviewed the then existing studies linking IHD with type A pattern concluded that type A behavior pattern was an independent and important coronary risk factor.246 In 1986, reduction of cardiac morbidity and mortality in post infarction patients by altering type A behavior was documented within a controlled experimental design.247 Recently, Gullette and colleagues248 reported that in patients undergoing 48 hours of ambulatory electrocardiographic monitoring, feelings of tension, frustration, and sadness more than doubled the risk of myocardial ischemia in the subsequent hour. Surprisingly, the value of psychosocial approaches to reducing lifestyle stress has been questioned by some249. A study that is often cited to support the contrary view is Montreal Heart Attack Readjustment Trial250 which reportedly found a two-fold increase in the risk of death among women after a one-year follow-up and no change in the risk of death among men. We consider such conclusions so inconsistent with both common sense and common experience that no further comment seems necessary.
What was shown in the above-cited studies, however, has been recognized by common empirical experience for decades. At the institute, for over 11 years we have taught autoregulation to our patients with IHD to prevent and arrest acute life-threatening ischemic crises. We define autoregulation as the process by which a person enters a natural healing state.251 It comprises a host of simple methods intended to prevent and arrest adrenergic hypervigilence. We have shown that when autoregulation is learned well and practiced effectively, it can reduce blood lactate levels by up to 78 percent.252 Extensive clinical experience has convinced us that canceling adrenergic hypervigilence must be considered as the central clinical strategy in a holistic, integrated program for arresting and reversing IHD. We have clinically observed that myocardial ischemia shows considerable within-subject variation during ordinary daily activities that cannot be ascribed to any of the established risk factors. We have also repeatedly observed how expediently our patients can control ischemic symptoms with limbic breathing253—a method of slow breathing with prolonged breathe-out periods.
The biochemistry of lifestyle stressors is complex and may be considered as “Fourth-of-July chemistry.9,10 The most intensively studied (by Selye and others) component of such chemistry is the hyperadrenergic state.254-256Many nonradical compounds participate in this state and contribute to oxidative fires of stress response via different pathways. First, many such compounds undergo spontaneous oxidation (autoxidize) when exposed to diatomic oxygen to generate free radicals.257,258 Such compounds include catecholamines such as epinephrine, norepinephrine, 3,4-dihydroxyphenylalanine (dopa), 6-hydroxydopamine, 6-aminodopamine, and dialuric acid. These reactions may be enhanced by redox-active metals such as iron, copper, and manganese, as well as by pro-oxidant toxic metals such as mercury. Second, superoxides can react directly with catecholamines to produce semiquinone radicals and hydrogen peroxide; the former feeds into many other oxidant chain reactions while the latter can mediate tissue injury by alkylative adduct formation or by redox cycling to produce other toxic oxidizing species.259Third, catecholamines can be oxidized to organic free acids by superoxide produced by cytochrome P-450 activity.260 Removal of a single electron from such organic compounds can produce molecular species with unpaired electrons, which then enter cellular redox cycles, thus perpetuating free radical injury. Fourth, bursts of catecholamines potentiate many receptor-ligand functions during adrenergic hypervigilence, such as coronary vasoconstriction. The essential point here is that the core mechanism of such responses is non-lipid-related accelerated molecular injury is caused by a host of oxidant molecular species.

Physical Activity and AA Oxidopathy
Regular physical exercise of moderate degree reduces the risk of triggered cardiac events, including myocardial infarction and sudden cardiac death,261-272 while sedentary lifestyles and chronic inactivity increase the risk. Exercise requires expenditure of energy generated by oxidative metabolism of food, which cannot occur without bursts of free radical activity. Such activity should be expected to contribute to AA oxidopathy. Persistent inactivity, by contrast, may be expected to produce the opposite change in redox potential in the circulating blood. Kujala270 showed that oxidative modification is diminished in veteran endurance athletes. How may this apparent paradox in the context of AA oxidopathy hypothesis be explained? Human biology, as we described previously,5,9,27is an ever-changing kaleidoscope of energetic-molecular mosaics. It has many “buffering systems” in its redox pathways. Thus, each oxidant stress evokes an upregulatory antioxidant response. Regular and moderate exercise upregulates antioxidant enzyme systems and provides additional reserves against accelerated oxidative stress in the circulating blood. The converse obtains in chronic inactivity.
How does exercise precipitate acute ischemic myocardial events? Does it merely create myocardial anoxia when demands for myocardial work exceeds the ability of the coronary circulation to deliver sufficient oxygen? Does it induce coronary vasospasm? Does it lead to myocardial dysfunction by causing accumulation of intracellular oxidant metabolites? Is lactic acidosis the culprit? Clearly, all those mechanisms are operative in view of similar biochemical consequences for increased demand for work by the muscle tissue elsewhere. An analogy of leg soreness and cramps caused by a mother sprinting to save her toddler from a rushing car may be given to support this viewpoint. Are there other pathways by which physical exercise feeds the oxidative fires of AA oxidopathy? The answer again is yes. Exercise causes platelet activation and so favors the clotting arm of the CUE of the circulating blood.
Interestingly—and quite appropriately from a teleologic standpoint—exercise also enhances fibrinolytic activity of the blood, thus favoring the unclotting arm of the CUE and providing a counterbalance to its platelet activation effect.

Syndrome X, Insulin Resistance and AA Oxidopathy
Syndrome X is an association of hyperinsulinemia and electrocardiographically provable myocardial ischemia with angiographically normal coronary arteries. Insulin resistance is association of hyperglycemia with hyperinsulinemia. We propose that both phenomena result from oxidative cell membrane injury resulting in cell permeability and repolarization dysfunctions. In the case of syndrome X, such cell membrane derangements cause vasospastic insufficiency of coronary microvasculature as well as cardiac myocytic dysfunction. Insulin resistance results from functional and structural abnormalities of insulin receptors and mediators caused by oxidative cell membrane injury. We discuss the interrelationships between hyperglycemia, hyperinsulinemia, insulin resistance, IHD, and oxidopathy in Part II of this article, because we believe our proposed explanation of the nature of these relationships can be seen more clearly once the diverse factors feeding into oxidative coagulopathy and AA oxidopathy are fully understood.

Smoking and AA Oxidopathy 
Cigarette smoking is a well-established risk factor in the pathogenesis and progression of IHD, as well as myocardial infarction. 273-284 Smoking increases death from coronary artery disease by 70 percent.274 Furthermore, the excess risk of morbidity and mortality diminishes with cessation of smoking.275-276 Predictably, the benefits of cessation of smoking accrue even in advanced coronary artery disease following percutaneous coronary revascularization.277 Smoking causes norepinephrine and epinephrine release and results in other adrenergically mediated adverse hemodynamic and metabolic events.283 Even passive smoking impairs endothelium-dependent dilatation in healthy young adults.279
Cigarette smoke is a pro-oxidant in pregnant women regardless of antioxidant nutrient intake.280 In human subjects, cigarette smoking raises the pre-smoke nitric oxide-peroxynitrite ratio of 1:0.5 to a post-smoke ration as high 1:9.278 Rat alveolar macrophages challenged by cigarette smoke release nitric oxide and superoxides, which interact with each other to produce peroxynitrite. Following two to three puffs of smoke, activated phagocytes continue to release nitric oxide and peroxynitrite for up to 30 minutes277 (Deliconstantinos 1994.)
Ethane and pentane are volatile alkanes produced from peroxidation of omega-3 fatty acids, and the breath levels of those compounds are used as indicators of oxidant stress. The breath ethane levels are higher in smokers than in nonsmokers.280 The intake of antioxidants such as vitamin C and E in RDA amounts does not reduce breath ethane levels.
How can the recognized role of tobacco smoking in the pathogenesis of CAD be explained by the hypothesis of AA oxidopathy? Smoking has well-established procoagulant and coronary vasoconstrictive effects.281-284 As discussed earlier, factors directly fan the oxidative coagulative fires within the circulating blood. Cigarette smoke generates an enormous number of free radicals and markedly increases plasma oxidizability. As indicated earlier, both active and passive smoking impair endothelium-dependent arterial dilatation in healthy adults.279 There is a dose-related inverse relationship between the intensity of passive tobacco smoking and flow-mediated dilatation, indicating direct early arterial damage. Penn et at. reported a dose-dependent size increases of aortic lesions following exposure to 7,12 dimethylbenzene.278
We anticipated, and verified by direct microscopic observations, the ability of tobacco smoke to inflict direct plasma and cell membrane injury. To this purpose, we examined the immediate effects of free radical cascades generated by cigarette smoking on circulating blood in a volunteer who abstained from smoking for a period of 16 hours and then smoked three cigarettes in five minutes.

Hyperhomocysteinemia, IHD and AA Oxidopathy 
A characteristic feature of children with homocysteinuria, a rare inborn error of metabolism, is premature vascular disease. When left untreated, it has a high incidence of thromboembolic events (as high as 50%) and high mortality rate from vascular disease (20% before the age of 30).285-289 This association led McCully in 1969 to propose it as a pathogenetic mechanism for atherogenesis.95,96,290,291 Since then, most of over 75 epidemiologic and clinical studies have shown a relationship between plasma homocysteine levels and atherosclerosis, IHD, stroke, peripheral vascular disease and venous thrombosis.290-297 In an experimental model, Ueland et al.298 induced vascular atheromatous lesions in baboons by infusing homocysteine for three months. They also showed that homocysteine affects the expression of thrombomodulin and activates protein C, and so acts as a thrombogenic agent—a role which is also strongly suggested by the high frequency of thromboembolic phenomena in patients with homocysteinuria. Tsai et al.299 demonstrated the ability of homocysteine to promote smooth muscle cell growth. Stamler e al.300 described toxic effects of homocysteine on endothelium and showed that prolonged exposure of endothelial cells to homocysteine impairs their ability to produce endothelium-derived relaxing factor. Additional evidence for its procoagulant role is drawn from the observed incidence of thrombotic events in patients with systemic lupus erythematosus and raised plasma homocysteine levels.303 All such studies provide strong, albeit indirect, evidence that homocysteine acts as a procoagulant. Some other evidence suggests that homocysteine affects the coagulation pathways as well as the antithrombotic characteristics of endothelium.302 Furthermore, it seems to interfere with vasodilatory and antithrombotic functions of nitric acid.300 Evidently, all of the above associations are compatible with the AA oxidopathy hypothesis.
Epidemiologic studies have established hyperhomocysteinemia as a risk factor for atherogenesis, providing further validation of the homocysteine hypothesis. In Physician’s Health Study, myocardial infarction occurred in a significantly higher number of men who had higher mean base-line plasma homocysteine levels than in the matched controls.304 Among 14,916 male physicians without prior myocardial infarction followed for five years, the relative risk of heart attack in the subgroup with highest homocysteine levels was 3.1 as compared with the subgroup with the lowest homocysteine levels. Comparable data for Norwegian men were reported by the prospective Tromso Study.305 Among the elderly men followed in Framingham Heart Study, hyperhomocysteinemia was associated with a higher incidence of carotid stenosis.306
McCully explored the relationship between homocysteine metabolism, ascorbic acid deficiency, growth and atherosclerosis.95 He noted that homocysteine is present only in traces in a normal guinea pig liver, accumulates in the scorbutic liver because of diminished oxidation, and that this effect can be counteracted by physiologic amounts of ascorbic acid. He also observed that hyperhomocysteinemia results in increased production of homocysteic acid and phosphoadenosine phosphosulfate (PAPS). He recognized that homocysteinemia leads to increased synthesis of sulfated proteoglycans, which cause accelerated atherosclerosis, both in children with enzymatic disorders of sulfur amino acid metabolism and in experimental animals. From those observations, he concluded that “degeneration of elastic tissue, binding of lipoproteins, increased deposition of collagen, calcification and hyperplasia of myointimal cells observed in the vascular lesions associated with homocysteinemia are secondary to increased production and excessive sulfation of arterial wall proteoglycans.”95
To explain the molecular basis of the oxidant and procoagulant roles of homocysteine, we propose the following mechanism. Homocysteine is mainly cleared by the body by two biochemical pathways. In the first, trimethylglycine donates a methyl group for methylation and conversion into methionine, then into S-adenosylmethionine (SAMe). This reaction requires folic acid and vitamin B12. In the second pathway, homocysteine is converted into cystathionine, then into cysteine. This reaction requires vitamin B6. This pathway also explains why smokers and coffee drinkers have elevated homocysteine levels since both tobacco smoke and caffeine deplete vitamin B6.307,308Hyperhomocysteinemia in adults without inherited enzyme defects of sulfur amino acid metabolism develops when one or both of the above two mechanisms fail or are inadequate. The result is deficiency of cysteine (which contains a sulfhydryl group and serves as an antioxidant in redox reactions that involve sulfhydryl groups) and SAMe (a methyl donor and a powerful indirect antioxidant). While proposing these two mechanims, we recognize that there may be yet other ways by which hyperhomocysteinemia insidiously feeds into the myriad oxidative mechanisms underlying both oxidative coagulopathy and AA oxidopathy. We discuss the important therapeutic implications of these aspects of hyperhomocysteinemia in Part II of this article.

Coenzyme Q10, IHD and AA Oxidopathy
Coenzyme Q10, a lipid-soluble benzoquinone, is a naturally-occurring antioxidant which plays vitamin-like key roles in oxidative phosphorylation and cell membrane stabilization. It is a normal component of mitochondrial membranes and is an intermediate between NADH (reduced form of nicotinamide-adenine dinucleotide) or succinate dehydrogenase and cytochrome b in the human mitochondrial respiratory chain.309,310 Myocardial concentration of Q10 is diminished in diseased human hearts311-313 as well as in experimental heart disease.314 It protects cardiac myocytes from oxidative damage during episodes of ischemia and reperfusion. For these considerations, a biochemical rationale for its therapeutic use in cardiovascular disorders was first suggested by Folker and colleagues.87,88 These theoretical aspects have been clinically validated by a spate of recent studies.315-319Langsjoen et al.320 reported a statistically significant improvement in myocardial function with daily doses of Q10 ranging from 75 to 600 milligrams, obtaining an average blood level of 2.92 mcg/ml (n=297). Of 424 patients, 58% improved by one New York Heart Association (NYHA) class, 28% by two classes, and 1.2% by three classes. Mortensen observed clinical improvement with Q10 therapy in nearly two-thirds of his 45 patients with various cardiomyopathies, with benefits most pronounced in patients with dilated cardiomyopathy.321 Langsjoen et al.322reported an overall NYHA functional class improvement from a mean of 2.4 to 1.36 (P<0.001) in their series of 109 patients with essential hypertension managed with Q10. The use of antihypertensive drugs was discontinued in more than half of the patients in this study. Similar results in hypertensive patients were also reported by Digiesi et al.323
It may be pointed out here that coenzyme Q10 belongs to the family of antioxidant species that exert direct protective roles on the cells and plasma membranes of cardiac myocytes. Q10 inhibits AA oxidopathy, its effects are lipid-independent, and its cardioprotective roles add to several lines of evidence against the oxidative-modification-of-LDL hypothesis.

Minerals with Pro-oxidant Potential and AA Oxidopathy
High body stores of iron,71,72 copper,73,74 and mercury75,76 are established independent risk factors of IHD. However, it has been assumed that the atherogenic roles of these transitional metals are confined to oxidative modification of LDL cholesterol—an assumption that ignores the many non-lipid related roles played by oxidative stress created in the circulating blood by oxidative phenomena involving sugars, proteins and coagulative pathways, as well as by functional and structural alterations involving erythrocytes, granulocytes, and platelets in oxidative coagulopathy and AA oxidopathy that we discussed earlier in this article.
A pathophysiologic role of “normal” iron body stores in the development of IHD was first proposed by Sullivan.71as an explanation of the observed sex difference and international variations in the incidence of coronary artery disease. Subsequent reports attempted to link cardioprotective effects of aspirin, fish oils, and cholestyramine, as well as the atherogenic roles of oral contraceptives, to pro-oxidant potential of iron.324,326 In a cohort of 2,873 Framingham women, natural or surgical menopause was associated with an increase in the incidence of coronary artery disease as well as its clinical expression.327 In the Stockholm Prospective Study, the risk of myocardial infarction was higher among men aged <65 years in the highest quintile of hemoglobin levels.328 Salonen et al.71published the first empirical evidence that body iron stores, as assessed by the serum ferritin level, are a strong risk factor for acute myocardial infarction.
Several lines of experimental and epidemiologic evidence support the oxidizing role of iron. Hepatic iron stores correlate negatively with HDL cholesterol.329 In a study by Murray and colleagues,330 in iron- and copper-deficient nomads administration of 180 mg of iron daily reduced lipid peroxidation by 62% in 60 days. In a rat model, iron loading increased the susceptibility of rat heart to reperfusion oxidative damage.331,332 Furthermore, such oxidative reperfusion injury can be prevented by iron chelation therapy.333-337
Iron, as we write earlier, is a molecular Dr. Jekyll and Mr. Hyde. Bound to protective proteins, it plays several essential roles including oxygen transport and myriad enzyme functions. When free, it is a potent oxidizer.331,336Iron-induced free radical generation can be prevented by EDTA and desferroxamine. The essential point we wish to emphasize here again is that all iron-related free radical activities contribute to both oxidative coagulopathy and AA oxidopathy, and not merely oxidative modification of LDL.
Mercury, another transitional metal, is also a potent oxidizer. Salonen et al.75 studied the relationship between dietary fish and mercury intake and found that a high mercury intake is associated with an excess risk of myocardial infarction as well as death from coronary artery disease, cardiovascular disease and any cause in Eastern Finnish men. Mercury can add to human free radical pathology by any of the four following mechanisms:
First, it catalyzes Fenton-type reactions with free radical generation, a role first suggested by Ganther, who observed that vitamin E and antioxidant DPPD protects rats against methyl mercury toxicity.338 Jansson and Harms-Ringdhal followed Ganther by demonstrating the stimulating effects of mercuric and silver ions on the superoxide anion production in human polymorphonuclear leukocytes.339
Second, mercury binds avidly with, and inactivates, sulfhydryl groups in proteins,340 which have been estimated to contribute as much as 10% to 50% of the antioxidant defenses in the circulating blood.341 Notable among such thiolic antioxidants is glutathione which plays a central role in the regeneration of the tocopheroxyl radical to tocopherol and which is inactivated by mercury.342
Third, mercury inactivates superoxide dismutase and catalase, two of the cardinal free radical-quenching enzymes of human antioxidant defenses.343
Fourth, mercury inactivates antioxidant enzyme systems that depend on selenium by insolubly complexing with selenium to form mercury selenide.344
We end the above brief comments about the pro-oxidant roles of transitional metals by emphasizing that though the mechanism of action has been assumed to be oxidative modification of LDL cholesterol, we were not able to find any studies in the literature that proved this by systematically excluding the roles of non-lipid oxidative mechanisms that we discussed earlier in this article.

Minerals with Antioxidant Potential and AA Oxidopathy
Deficiency of selenium77,78 and chromium79,80 are established risk factors of IHD. Selenium-dependent antioxidant systems are important parts of human antioxidant enzyme systems, especially in the regeneration of glutathione and other thiol antioxidants.345 An association between low serum selenium levels and atherogenesis, lipid peroxidation in vivo, and progression of carotid atherosclerosis has been reported.77,78,346,347 Salonen et al.77 observed that selenium deficiency was associated with an excess risk of myocardial infarction as well as morbidity and mortality from other expressions of coronary artery disease and other variants of cardiovascular disease in Eastern Finland.77In this study, cardiovascular death and myocardial infarction were associated with low serum selenium levels in a matched-pair longitudinal study.
Aging and chromium deficiency share among them a cluster of metabolic alterations including elevated blood glucose and insulin levels, diminished insulin efficiency, elevated total cholesterol and triglycerides levels, decreased HDL cholesterol, decreased nerve conduction, and lower lean body mass.348 Serum chromium levels are lower in patients with angiographically documented coronary artery disease than in angiographically negative control subjects.349,350 Chromium supplementation in patients with type II diabetes results in improved glucose tolerance, lower total cholesterol and triglycerides levels and higher HDL cholesterol levels.351 The aorta in patients dying of coronary heart disease contains less chromium than the aorta in trauma victims.352 For all those reasons, a low plasma chromium level has been considered a risk factor for IHD.353 What is the molecular basis of the cardioprotective role of chromium? As reported by Glinsman and Abraham, this mineral has several normalizing influences on carbohydrate metabolism and lipid metabolism.354,355
Though we are not aware of any direct antioxidant effects of chromium, we believe—as we show in our discussion of the molecular basis of insulin resistance in Part II— the cardioprotective effects of chromium can be attributed to its indirect antioxidant roles.

Ascorbic Acid, IHD and AA Oxidopathy
Several studies show the protective roles of natural antioxidants such as vitamin C,81,82,83,84 and beta carotene.85,86 Ascorbic acid is an outstanding water-phase antioxidant in human plasma.356 It is the first antioxidant to be exhausted when progressive oxidative stress is imposed on human plasma, and lipid peroxidation is detected in such plasma only when all ascorbate has been used up.357 Indeed, it has been suggested that only this antioxidant can prevent initiation of lipid peroxidation.358 Though not lipid soluble, vitamin C also plays significant roles in lipid-phase antioxidant defenses due to its ability to enhance regeneration of the reduced form of vitamin E.359 Ascorbic acid inhibits oxidation of LDL cholesterol in vitro.356,358,360 We may add here that intake of larger doses of vitamin C (up to ten grams per day) has been shown by ultrafast computed tomography to drastically reduce dystrophic calcification in coronary artery disease.361
In epidemiological studies, significant international correlations exist between lower incidence of ischemic CAD and high intake of antioxidant nutrients81,362-369 Pauling and Ernstrom reported lower than expected mortality from ischemic CAD in 479 health-conscious elderly Californians366. A larger study of the relationship between vitamin C intake and mortality from ischemic CAD comprising 11,348 U.S. adults reported significantly reduced mortality rate from ischemic CAD in subjects taking vitamin C.81. Specifically, among those with highest intake of ascorbic acid, male subjects had the following standardized mortality ratios: 0.65 (0.52-0.80) for all causes; 0.78 (0.50-1.17) for all cancers; and 0.58 (0.41-0.78) for all cardiovascular diseases. The association between low plasma ascorbic acid levels and progression of atherosclerosis has been reported.369 In a Cox proportional hazards model adjusted for age, year of examination, and season of the year examined, Nyyssonen et al. observed a relative risk of 3.5 (ratio) among Finnish men with ascorbic acid deficiency as compared with those who were not deficient.364
Beyond the antioxidant roles of ascorbic acid given above—and its role in facilitating oxidation of homocysteine mentioned earlier—this vitamin plays many established roles in myriad enzyme functions involving hormone synthesis in the adrenal glands and other endocrine glands, functions which evidently affect the integrity of the cardiovascular system in diverse ways.
In previous reports we have documented the ability of intravenously administered ascorbic acid to restore damaged erythrocyte membranes in chronic fatigue syndrome and severe autoimmune disorders.13,16 We have also observed the same phenomenon in patients with congestive heart failure. This phenomenon could be predicted on theoretical grounds alone, given the established role of this vitamin as the principal aqueous-phase antioxidant (Frie).

Vitamin E, IHD and AA Oxidopathy
We have observed vitamin E to restore erythrocyte and leukocytic membrane deformities in states of accelerated oxidative injury.
Vitamin E plays a role in the prevention of coronary heart disease by several discrete mechanisms.370-374 It is the principal lipid-phase antioxidant in human plasma and prevents LDL oxidation.357 It stabilizes oxidatively damaged cell membranes (personal unpublished observation). It decreases platelet adhesiveness and aggregation, inhibits vitamin-K-dependent clotting factors, and suppresses nitric oxide synthesis. Vitamin E also lowers plasma triglycerides levels.372 All of those mechanisms may be expected to diminish the potential of oxidized LDL to cause coronary artery disease. Indeed, vitamin E has been proposed as the answer to the riddle of coronary arteriosclerosis.371 But do those theoretical benefits hold up in real life? From a teleologic standpoint, the answer is clearly affirmative. Free radicals are oxidative coals that curdle the blood, and initiate and perpetuate AA oxidopathy. All types of oxidative injury trigger coagulative pathways and result in the conversion of fibrinogen into fibrin that precedes morphologic changes observed in coagulopathy. The pathogenesis of this entity is further discussed in the section dealing with free radical pathology.

Beta Carotene, IHD and AA Oxidopathy
Beta carotene, a precursor of vitamin A, is generally regarded as a lipid-phase antioxidant. Shaish et al.85 showed that it modulates endothelial function, is thought to directly influence nuclear receptors, and inhibits atherosclerosis in rabbit. For those reasons, it has been empirically used by clinicians. Its value has been investigated for reversing degenerative disorders that are known to be caused by oxidative damage.90 Even though to-date, conclusive evidence for its efficacy as a cardioprotective agent has not been published, it seems likely that this will be shown to be the case with additional studies.

Synthetic Antioxidants and AA Oxidopathy
Probucol is a multifunctional agent that is a potent antioxidant. It has been investigated extensively for its clinical efficacy in IHD because of its antioxidant and cholesterol-lowering effects.89,90,375-379 Lee et al.377 and Setsuda et al.376 and others378-379 have shown efficacy of probucol in prevention of restenosis after coronary angioplasty. Tardif et al.90 demonstrated the ability of probucol to significantly reduce the incidence of restenosis after coronary angioplasty. They administered probucol in a daily dose of 500 mg for one month to patients before angioplasty and observed a restenosis rate of 20.7 per segment, while similar rates for a subgroup of patients who received a regimen of antioxidant vitamins and a control group were 40.3 and 38.9 percent respectively. An important observation in this context is the finding of Carew et al.380 that probucol reduces atherogenesis far out of proportion to its cholesterol-lowering effects. Anderson et al.381 demonstrated the ability of probucol, when used in conjunction with a cholesterol-lowering statin drug, to improve endothelium-dependent vasomotion in atherosclerotic arteries.
Ethylenediaminetetraacetic acid (EDTA) is an excellent cell membrane stabilizer. We demonstrated this characteristic of EDTA by its ability to restore abnormal erythrocyte morphology in freshly prepared, unstained peripheral blood smears.229 We also observed the capacity of EDTA to serve as a potent systemic antioxidant by microscopic studies of peripheral blood performed before and after EDTA infusion (one and one-half grams diluted in 300 ml of saline) in patients with peripheral arterial disease.34 EDTA is a potent vasodilator. In our patients with peripheral vascular disease, about one-half of the patients reported feelings of warmth and flushing in legs after EDTA infusions.
EDTA was first used as a chelating agent in a program to decalcify coronary arteries and reverse coronary artery disease in the 1960s.91,92 Since then a large number of studies have shown improved myocardial, carotid and limb perfusion with EDTA infusions.32-34,91,92,382-390 In an accompanying report in this issue of the Journal, we present details of our experience with EDTA infusion therapy for patients with advanced IHD.

Alcohol Consumption, Cirrhosis, IHD and AA Oxidopathy
The autopsy finding of absence of significant atherosclerosis in cirrhosis has been known to pathologists and is generally regarded as an enigma. The relationship between alcohol consumption, serum LDL and HDL levels, and IHD has drawn much interest in recent years. Recently Hein et al.391 reported a six-year follow-up of a group of 2,826 men, aged 53-74 years. Among men in the top 20% of elevated LDL levels (a minimum of 203 mg/dl), the first myocardial ischemic event occurred nearly four times as often (16.7%) among men abstained from alcohol completely than those who drank more than 3 servings of alcoholic beverages per day (4.4%). Alcohol did not protect subjects with the lowest cholesterol levels.
We suggest the following explanation for the molecular mechanisms that underlie what is widely believed to be an enigmatic relationship between alcohol and heart disease. Alcohol is metabolized by alcohol dehydrogenase. The enzyme uses NAD to extract hydrogen from alcohol and converts it into acetaldehyde, while NAD is reduced to NADH. Acetaldehyde is a potent hepatotoxin. It reacts strongly with proteins and peptides containing amino groups (Schiff’s reaction) and denatures them, thus setting the stage for insidious, ongoing hepatocyte injury. The continual release of NADH—the reducing equivalent released by the action of alcohol dehydrogenase on alcohol—provides support for the antioxidant arm of the redox equilibrium in blood, and thus arrests or diminishes AA oxidopathy.

MYCOTOXICOSIS AND AA OXIDOPATHY

    Historically, mycotoxicosis has been generally dismissed as an uncommon and sporadic problem.392-399 Poorly delineated clinical patterns of human illness occurring in clusters were associated with moldy rye in the seventeenth century,400 ergot alkaloids derived from fungus in the eighteenth century400, and moldy grain (alimentary toxic aleukia) and moldy rice (yellow rice disease in the early twentieth century.402,403 In recent decades, however, mycotoxicosis as the cause of clinical disease has drawn increasing attention.404,405 More than 12 percent of all Scottish houses were deemed affected by mold presence, and mold spores were considered as distinct health risks.”406 Matossian examined official vital statistics of Connecticut for 1848-1900407 and noted that mycotoxins in moldy grain strongly influenced the changing size of human populations.408 Specifically, increasing total mycotoxin load increased mortality during some periods and decreasing mycotoxin content of grain supplies seemed to cause the population explosion during others. The mycotoxins that appeared to have played important roles include ochratoxin A (derived from corn), aflatoxin (from corn, peanuts and wheat), dioxynivalenol (DON) from corn and wheat), ergot alkaloids (from rye) and zearalenone (from corn and wheat).
As discussed in Part II of this article, a growing body of experimental and clinical evidence suggests that inflammatory, infectious and autoimmune factors play atherogenic roles.63-69 In light of such evidence, our microscopic findings that fungal buds and mycelia are found with high frequency in the peripheral blood of patients with risk factors of IHD and cause congealing of blood under direct microscopic observation strongly suggest to us that mycotoxins have a strong atherogenic potential. Such roles would be especially expected of mycotoxins with recognized cardiovascular toxicity, such as patulin (associated with hemorrhages in lung and brain) and emodin (known to reduce cellular oxygen uptake).

Spontaneity of Structural and Functional Restoration, Stress Proteins (Mycotoxins, Endotoxins), AA Oxidopathy and IHD
A clear understanding of two essential aspects of protein structure and function is essential to recognizing the role of mycotoxins as well as bacterial, chlamydial, and viral products in the pathogenesis of oxidative coagulopathy, AA oxidopathy and IHD.
1. Enzymes are proteins that must maintain a precise atomic alignment within their structure to function. How does a protein molecule—a single strand of amino acids—continuously fold and unfold to assume and retain a specific globular structure to function as a highly specific and efficient catalyst?
2. Protein structure is highly sensitive to oxidative stress, slight changes in temperature, pH and concentration of substrates and end products. How do the protein molecules of enzymes withstand such stresses yet maintain the structural integrity upon which their functional stability depends?
The answer to the above two questions resides in the phenomenon of “spontaneity of structural restoration” in nature. Folding and unfolding of protein molecules that make up the highly specific structure of enzymes are spontaneous phenomena which are assisted (“chaperoned”) by other protein molecules that are designated heat-shock proteins (HSPs).410-425 Originally thought to be produced in response to stress of heat, this family of molecular chaperons are now known to be produced in response to almost all types of oxidative stress, including free radicals, toxic metals such as mercury and lead, and a miscellaneous group of molecules including alcohol. Thus, these molecular chaperons are now called stress proteins (SPs).416 Stress proteins are produced in response to stress for the specific purpose of protecting enzymes and other proteins from structural disfigurement—hence, functional impairment—and for preserving cellular health. For example, the oxidant stress of free radicals denatures enzymes by unfolding their amino acid strands. SPs, produced in response to that oxidant stress, then spring into action and “hold” the denatured enzymes in a “reversible” state of denaturation, thus preventing irreversible denaturation. As the oxidant stress abates, SPs gently fold the enzyme molecules back into their original structure and restore their lost function. Other chaperoning roles of SPs include molding enzyme molecules to facilitate their transport via cellular microtubules417 and preserving molecular structures during mRNA splicing, ribosome assembly and DNA replication and transcription.418,419

Molecular Duality of Shock Proteins
Stress proteins (SPs)—like oxygen, iron and hemoglobin—exhibit a molecular duality, playing Dr. Jekyll and Mr. Hyde roles under different conditions. When present in optimal concentrations, SPs chaperon and protect stress-folded and reversibly denatured enzyme molecules during periods of stress and restore their native structure when the stress has abated. However, when present in excess they also suppress the recovery process, thus pushing reversibly denatured enzymes into states of irreversibility and destruction.420
SPs—protein molecules in composition—are predictably vulnerable to oxidant stress. (The chaperons themselves need chaperoning!) When oxidatively denatured by accelerated oxidative injury, SPs are mutated and assume the destructive capacity of foreign antigens, thus triggering autoimmune injury.421

Four other aspects of chronic fungemia are pertinent to our discussion of the role of fungemia to the pathogenesis of IHD:

1. Close molecular homology between human SPs (molecular weight 70,000) and SPs of fungal and bacterial origin.406,422 Specifically, SPs of Candida albicans show an over 50% homology with human SPs.423 This, of course, creates a serious potential for clinical autoimmune injury caused by chronic Candida overload. Indeed, the ability of the T cells of patients infected with Histoplasma and malaria organisms to respond to peptides of human SPs has been documented.424

2. Ability of some Candida-derived SPs to block the production of plasminogen activator, and so diminish the fibrinolytic capacity of the plasma. One action of such Sps would be to oppose the unclotting side of the CUE equation and promote atherogenesis.425

3. Ability of some fungal SPs to block certain steroid synthetic pathways.426-428 Through such actions, fungal SPs may be expected to play a broad array of adverse roles in homeostasis of cellular membrane receptors and plasma components, damaging the ecology of circulating blood and triggering autoimmune responses.

4. There are sporadic reports of physicians treating IHD with griseofulvin and other antifungal agents.429 Higher blood levels of folic acid are associated with a lower incidence of IHD.430 It seems probable that at least some of the cardioprotective effects of griseofulvin and folic acid may be attributed to their antifungal properties. More importantly, many of the commonly used cholesterol-lowering drugs belong to the class of statin drugs with well-established, albeit very limited, cardioprotective actions.431-436 It seems likely that some, if not most, of the rather limited benefits of the statin group of lipid-lowering drugs are due to their ability to reduce the total mycotoxin burden and prevent or ameliorate oxidative coagulopathy and AA oxidopathy.
In summary, we hold that the high frequency and extent of fungemia in patients with active IHD and those with risk factors and the observed ability of fungal buds and mycelia to cause congealing of plasma (and so setting in motion oxidative coagulopathy) are strong reasons for attributing a pathogenetic role to fungal (and bacterial) toxins in atherogenesis. We return to this subject in Part II of this communication when we discuss inflammatory, infectious, and autoimmune theories of IHD.

Oxidative Cell and Plasma Membranes Permeability Dysfunction (Leaky Cell Membrane Dysfunction) in AA Oxidopathy
Why are calcium channel blockers used so often in mainstream clinical cardiology? Why is magnesium used so commonly in integrative medicine for cardiovascular disorders? These are important questions in any discussion of cell membrane permeability dysfunction.
The cell membrane separates an internal order from an external disorder. It protects cell innards from oxidant injury by employing a sophisticated arsenal of antioxidant defenses. It turns information derived from its microenvironment into physical change within the cell. It selectively admits what is needed within and vigorously excludes what is unneeded. An integral aspect of cell membrane function is gating the traffic of ions across it—in and out of cells—that is regulated by some ion-specific and some non-ion-specific cell membrane channels. Ion channels are tunnels composed of macromolecular proteins that span the lipid bilayer of the cell membrane. An amino acid strand of channel protein forms a lid that covers the mouth of the channel. The lid opens or closes by slight conformational changes in the protein molecular structure. Ions flow passively through such tunnels down chemical gradients at rates as high as 10 million ions per second.430 Defective ion channel proteins result in membrane permeability dysfunctions and are responsible for many cardiovascular entities such as the long-QT syndrome431that involve mutations of potassium and sodium channels, heritable hypertension (Liddle’s syndrome),432 and periodic paralysis,433 a variety of other myopathies.434,435 Although elucidation of the mechanisms of such channel protein-mutation-related disorders will undoubtedly shed light over many related gene-mutation disorders, it is unlikely to make significant contributions to the clinical care of the majority of patients with IHD in the foreseeable future. The issue that looms larger in this context, in our view, is the matter of insidious cell membrane injury—and resultant cell membrane permeability dysfunction—that may be expected to occur in oxidative coagulopathy and AA oxidopathy.
In 1987, we coined the term leaky cell membrane dysfunction to draw attention to the clinical evidence for significant cell and plasma membranes permeability dysfunctions that we encountered commonly in our clinical work with a host of clinicopathologic entities characterized by accelerated oxidative molecular injury.436, as evidenced by clinical functional improvement obtained with therapies directed to repairing oxidative membrane damage) We encountered symptom-complexes suggestive of such dysfunctions involving nearly all cellular ecosystems, causing a broad array of clinical symptom-complexes referable to various body organs.8 We speculated that when the permeability of cell and plasma membranes increases by oxidative injury—the membranes are shot full of holes, so to speak—they allow leakage from cells and intracelluar organelles elements that occurs predominantly within them (such as potassium, magnesium, taurine and glutathione) and influx into them of predominantly extracellular elements (such as calcium, as well as heavy metals such as lead, mercury and aluminum). We validated this simple model of membrane permeability dysfunction by effectively relieving the symptom-complexes with therapeutic use of magnesium, potassium, taurine and glutathione.8,229
Calcium channel blocking drugs are being used to relieve symptoms in several cardiovascular syndromes.437-440Beyond the approved indications of such drugs, many clinicians prescribe this group of drugs for a wide array of symptoms. The therapeutic effects of calcium channel blockers are believed to be due to their ability to inhibit influx of calcium ions during membrane depolarization of cardiac myocytes and arterial muscle cells. Other effects of these drugs are attributed to their negative inotropic influences on the sinoatrial and atrioventricular conduction tissue. An important question in this context is: Why is the preventing of entry of calcium into the cells so beneficial in so many clinical entities? We hold that pathophysiologic influx of calcium ions in ischemic heart disease occurs as a result of increased cell membrane permeability caused by accelerated oxidative injury in AA oxidopathy. It is noteworthy that calcium channel blockers protect the myocardium from free radical injury in reperfusion experiments.441-444 We regard this as strong, albeit indirect, evidence that calcium antagonists exert their beneficial effects by counteracting membrane-damaging effects of AA oxidopathy.
We and others have observed good clinical results obtained with oral, intramuscular, and intravenous magnesium therapies in as diverse a group of clinical disorders as the group benefited by calcium channel blockers,445-449though the benefits accrued at slower rates than observed with calcium antagonists. How may such clinical observation be explained? We hold that the efficacy of magnesium can be attributed to its ability to counterbalance the pathophysiologic influx of calcium ions across oxidatively injured cell membranes, and that this is another evidence, albeit indirect, to support our hypothesis. We also observed that the clinical benefits of magnesium supplementation are superior when oral and injectable taurine and glutathione are added to magnesium—two potent molecules of human cellular antioxidant systems.
The simple model of oxidative cell membrane dysfunction in the context of oxidative coagulopathy and AA oxidopathy hypotheses has an especially strong explanatory power when we focus on the function of cardiac myocytes and the conducting system of the heart. Our empirical experience strongly suggests that prevention of ongoing oxidative injury to myocyte cell membranes and repair of damage previously sustained by such membranes is of critical importance in the management of patients with advanced IHD. Cell membrane and intracellular dynamics of cardiac myocytes—as well as those of the interstitial fluid bathing myocytes—are more pertinent to optimal cardiac function than are the dynamics of myocytes and fibrocytes in atheroma plaque in peripheral arteries.
We address the issue of the clinical efficacy of EDTA chelation therapy for controlling AA oxidopathy and preventing IHD in Part II of this article. However, a passing reference to it seems warranted in the discussion of oxidative cell membrane dysfunction. In two companion reports in this issue of the Journal, we report excellent long-term clinical outcome in patients with advanced IHD32 and limited initial success in reversing renal failure with EDTA infusion therapy.33 How may those results be explained? Excess intracellular calcium impairs the function of certain mitochondrial enzymes,450 and EDTA blocks this adverse effect. EDTA is an excellent cell membrane stabilizer, as observed directly with high-resolution microscopy. It is a potent vasodilator. Indeed, it serves as a powerful systemic antioxidant when infused intravenously, and we attribute to it a major role in correction of oxidative cell membrane permeability dysfunction.

   The cell membrane separates an internal order from an external disorder. It protects cell innards from oxidant injury by employing a sophisticated arsenal of antioxidant defenses. It turns information derived from its microenvironment into physical change within the cell. It selectively admits what is needed within and vigorously excludes what is unneeded. An integral aspect of cell membrane function is gating the traffic of ions across it—in and out of cells—that is regulated by some ion-specific and some non-ion-specific cell membrane channels. Ion channels are tunnels composed of macromolecular proteins that span the lipid bilayer of the cell membrane. An amino acid strand of channel protein forms a lid that covers the mouth of the channel. The lid opens or closes by slight conformational changes in the protein molecular structure. Ions flow passively through such tunnels down chemical gradients at rates as high as 10 million ions per second.430 Defective ion channel proteins result in membrane permeability dysfunctions and are responsible for many cardiovascular entities such as the long-QT syndrome431that involve mutations of potassium and sodium channels, heritable hypertension (Liddle’s syndrome),432 and periodic paralysis,433 a variety of other myopathies.434,435 Although elucidation of the mechanisms of such channel protein-mutation-related disorders will undoubtedly shed light over many related gene-mutation disorders, it is unlikely to make significant contributions to the clinical care of the majority of patients with IHD in the foreseeable future. The issue that looms larger in this context, in our view, is the matter of insidious cell membrane injury—and resultant cell membrane permeability dysfunction—that may be expected to occur in oxidative coagulopathy and AA oxidopathy.
In 1987, we coined the term leaky cell membrane dysfunction to draw attention to the clinical evidence for significant cell and plasma membranes permeability dysfunctions that we encountered commonly in our clinical work with a host of clinicopathologic entities characterized by accelerated oxidative molecular injury.436, as evidenced by clinical functional improvement obtained with therapies directed to repairing oxidative membrane damage) We encountered symptom-complexes suggestive of such dysfunctions involving nearly all cellular ecosystems, causing a broad array of clinical symptom-complexes referable to various body organs.8 We speculated that when the permeability of cell and plasma membranes increases by oxidative injury—the membranes are shot full of holes, so to speak—they allow leakage from cells and intracelluar organelles elements that occurs predominantly within them (such as potassium, magnesium, taurine and glutathione) and influx into them of predominantly extracellular elements (such as calcium, as well as heavy metals such as lead, mercury and aluminum). We validated this simple model of membrane permeability dysfunction by effectively relieving the symptom-complexes with therapeutic use of magnesium, potassium, taurine and glutathione.8,229
Calcium channel blocking drugs are being used to relieve symptoms in several cardiovascular syndromes.437-440Beyond the approved indications of such drugs, many clinicians prescribe this group of drugs for a wide array of symptoms. The therapeutic effects of calcium channel blockers are believed to be due to their ability to inhibit influx of calcium ions during membrane depolarization of cardiac myocytes and arterial muscle cells. Other effects of these drugs are attributed to their negative inotropic influences on the sinoatrial and atrioventricular conduction tissue. An important question in this context is: Why is the preventing of entry of calcium into the cells so beneficial in so many clinical entities? We hold that pathophysiologic influx of calcium ions in ischemic heart disease occurs as a result of increased cell membrane permeability caused by accelerated oxidative injury in AA oxidopathy. It is noteworthy that calcium channel blockers protect the myocardium from free radical injury in reperfusion experiments.441-444 We regard this as strong, albeit indirect, evidence that calcium antagonists exert their beneficial effects by counteracting membrane-damaging effects of AA oxidopathy.
We and others have observed good clinical results obtained with oral, intramuscular, and intravenous magnesium therapies in as diverse a group of clinical disorders as the group benefited by calcium channel blockers,445-449though the benefits accrued at slower rates than observed with calcium antagonists. How may such clinical observation be explained? We hold that the efficacy of magnesium can be attributed to its ability to counterbalance the pathophysiologic influx of calcium ions across oxidatively injured cell membranes, and that this is another evidence, albeit indirect, to support our hypothesis. We also observed that the clinical benefits of magnesium supplementation are superior when oral and injectable taurine and glutathione are added to magnesium—two potent molecules of human cellular antioxidant systems.
The simple model of oxidative cell membrane dysfunction in the context of oxidative coagulopathy and AA oxidopathy hypotheses has an especially strong explanatory power when we focus on the function of cardiac myocytes and the conducting system of the heart. Our empirical experience strongly suggests that prevention of ongoing oxidative injury to myocyte cell membranes and repair of damage previously sustained by such membranes is of critical importance in the management of patients with advanced IHD. Cell membrane and intracellular dynamics of cardiac myocytes—as well as those of the interstitial fluid bathing myocytes—are more pertinent to optimal cardiac function than are the dynamics of myocytes and fibrocytes in atheroma plaque in peripheral arteries.
We address the issue of the clinical efficacy of EDTA chelation therapy for controlling AA oxidopathy and preventing IHD in Part II of this article. However, a passing reference to it seems warranted in the discussion of oxidative cell membrane dysfunction. In two companion reports in this issue of the Journal, we report excellent long-term clinical outcome in patients with advanced IHD32 and limited initial success in reversing renal failure with EDTA infusion therapy.33 How may those results be explained? Excess intracellular calcium impairs the function of certain mitochondrial enzymes,450 and EDTA blocks this adverse effect. EDTA is an excellent cell membrane stabilizer, as observed directly with high-resolution microscopy. It is a potent vasodilator. Indeed, it serves as a powerful systemic antioxidant when infused intravenously, and we attribute to it a major role in correction of oxidative cell membrane permeability dysfunction.

How Consistent is AA Oxidopathy with Known Molecular Dynamics of Dyslipidemias? 
Hypercholesterolemia has long been associated with atherosclerosis and has been extensively reviewed.451-455Several lipid research trials suggest that lowering of blood cholesterol levels can be expected to reduce the sequelae of atherosclerosis,127,128,136,456 though the benefits are extremely limited when the data are expressed in rates of incidence (generally in the range of less than one to two percent) rather than risk reduction (often reported as high as 30 to 45 percent).65,66 This critical issue is seldom addressed in discussions of the clinical implications of the cholesterol theory. We cite here one specific example by including the following quote from a recent issue of The New England Journal of Medicine:

    The West of Scotland study found an absolute reduction in cardiac mortality of 0.7 percent after five years of pravastatin therapy (40 mg per day, costing $100 per month). Therefore, 143 men with hypercholesterolemia must spend a total of $858,000 (drug cost only) to delay 1 such death…The problem is that outcome events in primary prevention are always rare, even in coronary disease, leading to the paradox that pravastatin is both highly effective and of very little benefit.457

    On issue of obvious importance here is the enormous monetary cost of therapies with cholesterol-lowering drugs. More importantly is the biologic cost of therapies that are designed to severely alter lipid metabolism and that have known carcinogenicity.134-145 The paramount issue here, in our view, is the administration of the drug to 99.3 percent of individuals who evidently do not need it to reach that 0.7 percent who do. We have discussed this critical issue in depth elsewhere458 and will return to it in Part II of this article.
It is generally believed that the risk of IHD rises when plasma cholesterol exceeds 4.1 mmol/l. While this general relationship between cholesterol and atherogenesis does hold for most populations, there is a wide range of the extent of atherogenesis and the degree of clinical disease at a given cholesterol level, so this relationship cannot be applied to individuals with impunity. Brown and Goldstein discovered that cells contain specific receptors for LDL, and that there is a correlation between LDL binding and control of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, a rate-limiting enzyme for cholesterol synthesis.459-466 They proposed this relationship as the molecular basis of maintenance of cholesterol homeostasis and held that the number of LDL receptors of a cell varies with its requirements for cholesterol. Specifically, cells protect themselves against excess cholesterol by reducing the number of LDL receptors and vice versa. A natural consequence of reduced numbers of LDL receptors is decreased cellular uptake of LDL cholesterol and, hence, a corresponding rise in blood cholesterol levels. As valuable as these insights into cholesterol homeostasis are, it is recognized that they do not explain how hypercholesterolemia causes atherosclerosis.57,99
In 1981, Henricksen and colleagues cultured LDL with endothelial cells and observed many physical and chemical changes in LDL and most notably described that modified LDL was taken up by cultured macrophages 3 to 10 times more rapidly than native LDL.467,468 These studies revealed that endothelium-modified LDL competed with acetyl LDL for uptake and degradation—and vice versa—thus establishing the fact that the two forms of LDL shared some common cell receptors. Henrickson et al. also demonstrated a similar ability of smooth muscle cells to modify LDL.468This was subsequently confirmed by others. Such studies were extended by Cathcart et al.37 who established that monocytes and neutrophils oxidize LDL, making it cytotoxic; by Parthasarathy et al.38 who reported the ability of macrophages to oxidize LDL and generate a modified form that is recognized by scavenger receptors; and by Hiramatsu et al.,39 who observed that superoxides initiate oxidation of LDL by human monocytes.

    Steinberg et al.37-45 and others35,36 have demonstrated that oxidative modification (denaturation) of LDL enhances its uptake by macrophages, and that the process of oxidative metabolism of LDL initiates many cascades of oxidative events, generating an array of oxidant and other molecules that profoundly influence the atherogenic process. Briefly, these include: 1) chemotactants for T-cells and monocytes; 2) endothelial cell adhesion molecules; 3) monocyte chemotactic protein 1; 4) macrophage colony stimulating hormone; 5) interleukin-1 which stimulates smooth muscle cell proliferation; 6) immunogenic epitomes that evoke immune responses; 7) cytokines released by CD4+ cells in atheroma plaques; 8) products that impair nitric oxide-mediated coronary vasorelaxation; 9) oxysterols that are highly toxic to endothelial cells; 10) tissue factors that initiate coagulation; and 11) insoluble toxic lipid-protein adducts. As valuable as these findings are to a clear understanding of atherogenesis, the precise nature of the mechanism by which cholesterol causes IHD is generally considered unclear.

    The cholesterol theory has other serious shortcomings. Specifically, it fails to explain the following important issues:

1. Cholesterol is an antioxidant, albeit a weak one, and cannot be expected to cause oxidative injury that clearly initiates atherogenesis.

2. A majority of patients who develop severe IHD, including episodes of myocardial infarction, do not have elevated blood cholesterol levels.64,469,470

3. When death occurs within six to eight hours of myocardial infarction, no acute coronary thrombotic occlusions are found at autopsy in more than 75 percent of cases; however, when death occurs after 48 hours, acute thrombotic occlusion is almost always found (personal unpublished data).

4. The range of frequency of acute thrombotic coronary occlusion in survivors of out-of-the-hospital cardiac arrest extends from 36 percent as determined by angiography237 to 95 percent in autopsy studies.238

5. There is a well-recognized paradox of IHD coexisting with normal angiograms.68-70

6. Reduction of atherosclerotic lesions does not follow when the death rate from myocardial infarction falls.59-61,471

7. Lowered blood cholesterol levels in women are not associated with the reduction in the rate of acute ischemic myocardial events to the same degree as is seen among men.67

8. Lifestyle stressors,239-247 tobacco smoking,269-273 and physical inactivity261-266 are recognized independent risk factors of IHD and exert potent pro-oxidant effects. We are not aware of any valid reason to believe that the oxidative stress of all those factors is confined to oxidative modification of LDL.

9. The cholesterol theory does not explain the recognized risk factors of IHD, such as hypertension and diabetes.

10. The cholesterol theory does not explain the cardioprotective role of coenzyme Q10,87,88,316-322 nor does it explain how hyperhomocysteinemia95,96,290-304 increases risk of IHD.

11. The cholesterol theory does not explain the recognized risk factors of increased body stores of iron71,72copper73 and mercury75,—transition metals with potent oxidizing potential.

12. The cholesterol theory does not explain the protective effects of selenium77,78,346,347 and chromium,79,80,472-475 minerals with recognized antioxidant effects.

13. The cholesterol theory does not explain the epidemiologic data showing reduced mortality from IHD in patients taking ascorbic acid81,82 and vitamin E.83,84

    In the face of the above evidence, how can the proponents of the cholesterol theory persist in their enthusiasm and continue to commit enormous financial resources to cholesterol research? An explanation was provided by Ravnskov who in 1992 evaluated 22 controlled cholesterol-lowering trials and concluded, “Lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. Claims of the opposite are based on preferential citation of supportive trials.”476 Specifically, he revealed that among the cholesterol trials published in major journals, supportive reports (n=8) were cited on average 61 times a year, while unsupportive trials (n=10) were cited eight times a year. In 14 cholesterol trials undertaken to establish a causal relationship between cholesterol changes and outcome, the data showed either an unsystematic effect or no effect at all. Ravnskov’s closing comment is especially pertinent to our discussion. It read: “Methods subject to bias, such as open trials or the use of drugs with characteristics side effects, or stratification instead of random allocation of participants, probably explain the overall 0.32% reduction recorded in non-fatal coronary heart disease.”

We hold, as we document in Part II, that all of the above thirteen aspects of IHD can be fully explained by the proposed AA oxidopathy hypothesis.

Lipid Redox Ecosystems
Lipids in plasma membranes are essential for membrane fluidity, surface potentials, surface ligand activity, and transport functions.477 To serve these diverse functions, lipids exist in blood and plasma membranes not as discrete molecular species—as it might seem from the conventional description of lipid chemistry—but as dynamic “lipid redox ecosystems” in which external pro-oxidant influences are vigorously counterbalanced by antioxidant defenses that exist within the lipid particles. For example, low density lipoprotein (LDL) particles are found as spherical particles with diameters ranging from 19-25 nm, molecular weight varying over a broad range from 1.8 to 2.8 million, and the density ranging from 1.019 to 1.063 g/ml. LDL is a large lipoprotein complex that includes the following: cholesterol moieties (estimated 1600 and 600 molecules of cholesterol esters and free cholesterol respectively), triglycerides (estimated 170 molecules), phospholipids (estimated 700 molecules), apolipoprotein B, neutral and polar lipids including polyunsaturated fatty acids, and lipophilic antioxidant species such as beta carotene and vitamin E. Predictably, the antioxidant content of LDL varies over a broad range and appears to be diet related. Lipoprotein (a) [Lp (a)] is structurally similar to LDL but is distinguished from it by the presence in it of a highly glycosylated protein designated apoliprotein(a).478 It binds to apolipoprotein B (apo B)-containing lipoproteins and proteoglycans.479 It has a complex relationship between fibrin, platelets, and atherogenesis. By its high affinity for and binding with fibrin, it activates plasminogen,480-482 while its binding to platelet receptors and leads to plasminogen binding and activation. Lp(a) is considered atherogenic because it is taken up by foam cells; however, elevated levels are associated with IHD in most, but not all, reports. We now return to the subject of spontaneity of oxidation in nature to put the notion of lipid redox ecosystems into perspective.

The LDL-Oxidative Modification Hypothesis of IHD Has Poor Explanatory Power   
In the preceding sections of this article, we have raised several essential issues that the LDL-oxidative modification hypothesis fails to address. First, this hypothesis assumes that oxidative modification of LDL occurs within sequestrated regions of the vascular wall. This assumption, as we stressed earlier in this article, is not warranted in view of our morphologic observations. Second, this hypothesis completely ignores the consequences of accelerated oxidative stress on erythrocytes in the bloodstream. The erythrocyte is the cell most vulnerable to high oxygen tension because it is the primary oxygen transport cell in the body. Third, this hypothesis fails to account for the contribution to atherogenesis of oxidative stress on platelets. Fourth, it ignores the atherogenic role of oxidative bursts of healthy and oxidatively damaged granulocytes, both insidiously during slowly progressive atherogenesis and acutely following intimal injury inflicted during angioplasty and coronary bypass surgery. Fifth, it ignores susceptibility of plasma proteins (including those of coagulation pathways) to redox dysregulation within the circulating blood. Sixth, the vulnerability of circulating plasma and cellular enzymes (and other functional proteins) is ignored by the LDL hypothesis. Seventh, this hypothesis assumes—again without justification—that oxidative injury to the vascular intima (and, hence, to subendothelial stroma and myocytes) is inflicted only by oxidatively modified LDL. Eighth, vitamin E significantly increases the resistance of LDL to oxidation without inhibiting atherogenesis in the same animals.85,483,484 Ninth, at least one antioxidant (beta carotene) decreases atherogenesis in cholesterol-fed rabbits without reducing susceptibility of LDL to oxidation.85 Tenth, in cholesterol-fed rabbits impaired nitric-oxide-mediated vasodilatation is due to increased endothelial generation of superoxide, which inactivates nitric oxide.485,486
There are yet other considerations of coronary vascular dynamics and clinical expressions of atherosclerosis that may not be explained by the LDL-modification hypothesis. The clinical course of IHD is determined not only by atherogenesis but also by diverse elements such as vasoconstriction, accretion of circulating microclots and microplaques on the intimal surface, thrombosis, plaque rupture, and release of proteolytic enzymes from ruptured and necrotic plaques, which further feed AA oxidopathy. The release of such proteolytic enzymes has been thought to contribute to lysis of fibrous caps of plaques with resulting plaque rupture and thrombotic occlusions.487-488Indeed, a large body of experimental evidence in atherogenesis point to etiologic roles of a multitude oxidant phenomena involving synthesis of connective tissue macromolecules,489 secretion of substances with PDGF-like activity by intimal smooth muscle cells,490,491, ozone induction of cytokine-induced neutrophil chemoattractants and nuclear factor kB,492 endothelial cell replication,493 cytokine-inducible nitric oxide synthesis,494 elaboration of circulating and tissue immunoreactivity,495 endothelial cell activity and its relationship with oxidation of LDL,496 and the role of oxidized LDL in recruitment of monocyte and macrophages.497 Evidently, all of the above biochemical and cellular responses can be accentuated by oxidized LDL. However, the essential point here is that none of them depends on oxidized LDL for its initiation and propagation.
The key unanswered questions in the context of the cholesterol hypothesis are: 1) Why does the blood cholesterol level go up in the first place? 2) What are the molecular events that lead to a decrease in the number of LDL receptors? 3) How do elevated levels of cholesterol cause vessel wall injury and initiate atheroma formation? Our morphologic studies of peripheral blood presented in this article, though not addressing the first two questions directly, strongly suggest that hypercholesterolemia develops as an antioxidant defense adaptation to accelerated, chronic, and persistent oxidative stress on the circulating blood—the events that create and perpetuate AA oxidopathy. Indirect evidence to support our view derives from the fact that raised blood cholesterol levels in many persons living highly stressed lives return to a normal range when lifestyle stressors are brought under control (unpublished personal data). Furthermore, it seems to us that a decrease in the number of LDL receptors is an adaptive response to hypercholesterolemia. We will return to this issue later in Part II of this article.
As regards the third question, several mechanisms by which hypercholesterolemia leads to atherosclerosis have been proposed. One such mechanism focuses on possible subtle endothelial injury caused by excess blood cholesterol that might increase endothelial cell membrane viscosity by altering its cholesterol-phospholipid ratio. Some other proposed mechanisms include the following: 1) the effect of hyperviscous, and hence less malleable, endothelial membrane on monocyte adhesion and chemotaxis; 2) the induction by excess cholesterol of growth factors in endothelial cells; and 3) the direct effects of cholesterol on platelets, monocyte/macrophage transformations, and accumulation of lipids in myocytes.490,493-497 Of greater interest to us in the context of the proposed AA oxidopathy hypothesis are the observations of Cathcart et al.37 and others that LDL exposed to all major cell types involved in atherogenesis (monocytes, macrophages, platelets, endothelial cells, and smooth muscle cells) is oxidized and triggers generation of a vast array of molecules that perpetuate oxidative chain reactions and inflict cellular injury in the vascular wall. This is consistent with the tenets of AA oxidopathy.
How may the association between elevated Lp(a) and IHD be explained in the context of oxidative coagulopathy? Lp(a) is structurally similar to plasminogen and is known to bind to fibrin.480-482 Thus, when present in the blood in elevated levels, it may be expected to exert a procoagulant effect and compound the procoagulant effects of oxidants in circulating blood, thus tipping the balance in favor of the clotting side of clotting-declotting equilibrium in health. In addition, Lp(a) can be expected to increase the thrombogenic character of blood in oxidative coagulopathy by its known antifibrinolytic actions.
In summary, what is the common denominator of all initial lipid-related factors that are involved with atherogenesis and clinical ischemic coronary heart disease? Evidently it is accelerated oxidative injury to all lipids, including lipoproteins and glycolipids. Hypercholesterolemia plays a role in atherogenesis to the degree that higher concentrations of cholesterol lead to generation of greater amounts of oxidized LDL, and hence greater oxidative stress on the circulating blood. We conclude that all of the known molecular dynamics of dyslipidemia are totally consistent with the proposed oxidative coagulopathy and AA oxidopathy hypotheses.

Dysregulation of HDL Cholesterol Metabolism and AA Oxidopathy
Low plasma level of HDL cholesterol is a recognized risk of IHD.498-500 Accelerated atherosclerosis is seen in most genetic HDL-deficiency syndromes. However, the mechanisms by which low HDL becomes a risk factor for IHD remain unelucidated.
Factors that lower HDL are also recognized risk factors for IHD and include obesity, lack of physical exercise, tobacco smoking, abstinence from alcohol, and male gender.501 Dietary sugars and starches lower plasma levels of HDL,502 and the levels stay low for as long as a low-fat diet is consumed.503 Physical exercise increases HDL levels.504
To our knowledge none of the commonly prescribed pharmacologic agents raise plasma HDL levels. Indeed, some drugs (such as probucol and EDTA) with potent antioxidant effects are antiatherogenic. For example, probucol, a powerful antioxidant, significantly reduces restenosis rate after coronary angioplasty.90,367-373 Yet, it reduced HDL levels by approximately 40% and thus may not be useful long term. By contrast, we have found EDTA chelation therapy to raise HDL cholesterol levels while it lowers the total cholesterol levels in many patients (personal unpublished observations).
What is the molecular basis of HDL dysregulation? We propose that reduction in plasma HDL levels observed in various clinicopathologic states is caused by oxidative dysregulation of lipid metabolism that occurs in AA oxidopathy. Such lipid dysregulation may involves one or more of the following: 1) accumulation in blood of oxidized and denatured lipids which lead to raised levels of LDL and VLDL (very low density lipoprotein particles); 2) accumulation of oxidized and denatured lipids in tissues; 3) down-regulation of lipoprotein lipase; 4) increased oxidizability of blood and tissue fats; and, as a result of all those factors, 5) expanding surface area of LDL and VLDL particles which “sucks” in yet more cholesterol. We hold that this view is consistent with all known aspects of HDL metabolism referred to above. Below, we elaborate our HDL hypothesis.
High-density lipoprotein by contrast to low-density lipoprotein, as the names implies, has a higher density as determined by ultracentrifugation. We hold that HDL has a higher density than LDL because it has a higher protein content. We propose any or all factors that cause AA oxidopathy and lead to lipid dysregulation result in accumulation of peroxidized lipids and, of necessity, reduced amounts of protein moieties in the lipid molecular species. This hypothesis—that the level of HDL is a function of the degree of oxidative lipid dysregulation associated with AA oxidopathy—is consistent with all known aspects of HDL dysregulation. Plasma HDL levels are reduced, as we indicate earlier, in obesity, tobacco smoking, physical inactivity, high intake of sugar and starches, abstinence from alcohol in males, and during periods of physical inactivity. The underlying mechanisms in all of those states is chronic lipid dysregulation which is caused, as we demonstrate in this article, by AA oxidopathy.
The effect of physical exercise on plasma HDL levels presents an apparent paradox as well as strong support for our proposed HDL hypothesis. Physical exercise required expenditure of energy which is derived from oxidative metabolism of sugars, fats and proteins, and, of course, is associated with increased free radical activity. Thus, exercise may be expected to feed AA oxidopathy. But exercise has other important counterbalancing metabolic functions. Specifically, during exercise myocytes are “hungry for fat” and their hunger is satisfied by upregulation of the activity of lipoprotein lipase which breaks up triglycerides contained within LDL and VLDL particles and makes them available to myocytes for utilization for energy generation. The LDL and VLDL particles depleted of their triglyceride contents shrink with loss of the particle surface. The reduced surface area of LDL and VLDL particles diminishes their capacity for carrying cholesterol molecules. Such lipid particles shed cholesterol which is avidly picked up by HDL particles for delivery to the liver for further metabolism. This explains how exercise simultaneously raises blood HDL and lowers blood LDL and VLDL levels. Beyond these effects, exercise, by increasing oxidant stress temporarily, brings about a compensatory upregulation of antioxidant defenses which seems to outlast the oxidant stress created by it. This view is supported by observations of Kujala who reported diminished oxidative modification of LDL in veteran endurance athletes.270
For decades, vigorous exercise has been prescribed for prevention of heart disease. Specifically, the emphasis has been on types of exercise—running, bicycling, speed-walking, etc.—to increase and sustain the heart rate far above the resting rate for at least 20 to 30 minutes at least three times a week. Such advice is tenable neither on teleologic grounds (in the context of AA oxidopathy) nor on the basis of empirical experience recorded by the practitioners of the ancient healing arts. We include below a quote from a recent issue of Science which has obvious relevance to our discussion:
A panel of exercise researchers convened by the Centers for Disease Control and prevention (CDC) and the American College of Sports Medicine (ACSM) reported that people needn’t exercise vigorously to improve their health. The panel concluded that moderate levels of moderate activity—walking, housework, gardening, or playing with children—broken up over the course of the day, provide the bulk of exercise-related health benefits.504
EDTA infusions are potent blockers of AA oxidopathy, and hence of oxidative lipid dysregulation. The reason why probucol, an antioxidant, lowers HDL levels remains unclear to us, though it is likely to be due to its other as yet undiscovered chemical effects.
In more than half of our patients with cardiovascular and metabolic disorders managed with integrated protocols including EDTA infusions, we have observed a pattern of changes in the lipid profile comprising reductions in blood total cholesterol and LDL cholesterol levels and an increase in HDL levels. A report of those data is in preparation. In the table given below, we illustrate the range of changes we observed with data for three patients.

LIPID PROFILES IN 3 PATIENTS
Effects of Control of AA Oxidopathy

Age/Diagnoses/Duration

Lipids Pre-Treatment Post-Treatment
Case 1: 32, male diabetic, managed for 18 months Total cholesterol

211

178

LDL

123

73

HDL

50

96

Case 2: 64, female hypertensive, managed for 14 months Total cholesterol

225

174

LDL

129

96

HDL

55

66

Case 3: 53 male, advanced coronary disease, managed for 8 months Total cholesterol

245

189

LDL

178

164

HDL

26

44

SUMMARY
Redox regulation in the circulating blood is a dynamic, elaborately integrated complex of diverse energetic-molecular events that involve all plasma and cellular oxidant-antioxidant systems. Changes of redox dysregulation in circulating blood comprise cell erythrocyte membrane damage and cell lysis, zones of plasma congealing, activation of polymorphonuclear leukocytes and monocytes, transformation of monocytes into macrophages, and formation of microclots and microplaques. We designate this broad spectrum of changes as AA oxidopathy. Derangements of the clotting-unclotting equilibrium (CUE), involving both established and as yet unrecognized coagulation pathways, are designated oxidative coagulopathy. Spontaneity of oxidation in the circulating blood assures that oxidative coagulopathy, and fibrinolytic response triggered by it, occurs in health at all times. Oxidatively triggered molecular responses to AA oxidopathy occurring in the endothelial cells, myocytes, and fibroblasts that constitute atherogenesis are regarded as consequences of unrelenting AA oxidopathy.
Plasma cholesterol, a weak antioxidant, initially prevents AA oxidopathy—albeit inadequately—and, once oxidized, feeds the oxidative fires set off by a host of oxidative stressors discussed above. Chronic use of HMG Co-reductase inhibitor statin drugs provides minimal short-term clinical benefits and, as yet undefined, long-term chemical consequences of disruption of lipid metabolism and carcinogenicity. The short-term benefits of statin drugs, in our view, may be largely attributed to their ability to address the single issue of mycotoxicity in the pathogenesis of oxidative coagulopathy.
The AA oxidopathy hypothesis provides a rational explanation of atherogenic mechanisms of risk factors of IHD as well as for the coronary vasospastic events that cause clinical ischemic heart disease without coronary occlusive disease. The proposed hypothesis also calls for a radically different clinical approach to prevention and reversal of ischemic heart disease. Specifically, it requires an integrative approach that addresses all of the following principal categories of chronic oxidant stressors: 1) adrenergic hypervigilence; 2) glucose-insulin dysregulation; 3) fungal and bacterial stress proteins, as well as other types of toxins; and 4) ecologic oxidants. The dominant prevailing approaches to ischemic coronary artery disease—such as angioplasty, coronary bypass and multiple drug therapies that focus on calcium channel and adrenergic blockade—evidently do not address any of the causes of AA oxidopathy, and thus cannot be regarded as optimal therapies.

 

 

 

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