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AA Oxidopathy:
The Core Pathogenetic Mechanism of Ischemic Heart Disease

PART I

Majid Ali, M.D., Omar Ali, M.D.

Ali M, Ali O. AA Oxidopathy: the core pathogenetic mechanism of ischemic heart disease. 
J Integrative Medicine 1997;1:1-112.


From the Departments of Medicine, Capital University of Integrative Medicine, Washington, D.C., and Institute of Preventive Medicine, New York (MA and OA), and Department of Pathology, College of Physicians and Surgeons of Columbia University, New York (MA).

Outline of Part I
Abstract
Introduction
Spontaneity of Oxidation in Nature and Disease
Molecular Duality of Oxygen
Morphology of Atherosclerosis
Morphologic Patterns of AA Oxidopathy
AA Oxidopathy Is Consistent with All Known Molecular Dynamics of Ischemic Heart Disease (IHD)
Mycotoxicosis and AA Oxidopathy
Oxidative Cell and Plasma Membranes Dysfunction (Leaky Cell Membrane Dysfunction)
The Cholesterol Theory Has a Poor Explanatory Power for Atherogenesis and Related Clinical Phenomena

Outline of Part II
AA Oxidopathy Is the Common Denominator of IHD Risk Factors
AA Oxidopathy Hypothesis Versus and Other Proposed Theories of IHD
Why Therapies Based on the Cholesterol Theory Give Poor Results
Poor Long-Term Results of Mechanical Interventional Cardiology 
The New Evolving Integrative Molecular Cardiology
Clinical Outcome Studies
Summary and Future Directions

 

Related Pictures

* Blood Pictures Tell the Story - AA Oxidopathy

* AA Oxidopathy: The Core Pathogenetic Mechanism of Ischemic Heart Disease

* What Do Blood Platelet Tell About Diabetes

* What Do Blood Corpuscles Tell About Diabetes -The Taurine Story

 

 

ABSTRACT
    We propose that ischemic heart disease (IHD) is caused by "AA oxidopathy"—a state of accelerated oxidative molecular injury to blood corpuscles and plasma components. Although AA oxidopathy eventually results in the formation of "microclots" and "microplaques" in the circulating blood, it begins with oxidative permutations of plasma sugars, proteins, lipids and enzymes, and is not merely confined to oxidative activation of recognized coagulation pathways that we collectively designate as "oxidative coagulopathy." AA oxidopathy comprises localized areas of blood cell damage and congealing of plasma in its early stages, fibrin clots and thread formation with platelet entrapment in the intermediate stages, and "microclot" and "microplaque" formation in late stages. Such changes can be directly observed in peripheral blood smears with high-resolution phase-contrast and darkfield microscopy. As observed microscopically, the early changes of oxidative coagulopathy are reversible and constitute what we designate as "clotting-unclotting equilibrium (CUE)." The AA oxidopathy hypothesis seeks to establish oxidative "clotting-unclotting disequilibrium (CUD)" and related molecular and cellular events occurring in the circulating blood as the primary pathogenetic elements of IHD, and the patterns of tissue injuries taking place in the vessel wall (atheroma formation, scarring and rupture) as consequential events. Coronary vasospasm and membrane depolarization dysfunctions of myocytes as well as of the conducting system of myocardium are induced by AA oxidopathy and constitute nonatherogenic components of IHD. This hypothesis challenges two fundamental assumptions of the prevailing cholesterol, inflammatory, infectious, autoimmune and gene hypotheses: 1) that IHD is caused by initial tissue injury occurring in the arterial wall; and 2) that optimal therapeutic approaches must focus on lowering blood cholesterol levels and/or revascularization procedures such as angioplasty and coronary bypass surgery.
    AA oxidopathy is caused by oxidant stressors of all types; however, our morphologic observations lead us to recognize the following five groups of oxidants as the principal factors in its pathogenesis: 1) chronic adrenergic hypervigilence associated with lifestyle stressors; 2) rapid glucose-insulin shifts and hyperinsulinemia; 3) mycotoxins and, to lesser degrees, other microbial oxidants; 4) dysequilibrium among nutrients with oxidant and antioxidant functions; and 5) ecologic oxidants. Native, unoxidized cholesterol, a weak antioxidant, plays no direct role in the pathogenesis of IHD, which is an oxidative phenomenon. Clinical outcome data obtained with nondrug, nonsurgical therapies that arrest and reverse AA oxidopathy without addressing issues of blood lipid levels validate the theoretical tenets of the proposed hypothesis.

INTRODUCTION

    Why should any hypothesis be put forth? One reason is to seek a simpler concept that integrates new observations with established knowledge. A second reason is to merge the seemingly incongruous parts to facilitate comprehension of the whole. In clinical medicine, the compelling justification for a new hypothesis is to provide the scientific basis and/or rationale for therapies that are more logical, safer and clinically more effective than those based on preexisting theories. We believe the proposed AA oxidopathy hypothesis meets all of the above three criteria. (Letters AA stand for the names of the two authors and are added to the term oxidopathy to differentiate it from the myriad oxidative phenomena in human biology in health and disease.) We introduce the term oxidative coagulopathy for a state of accelerated oxidative intravascular clotting involving known coagulative pathways. The term AA oxidopathy represents a much broader range of oxidative injury to all the components of circulating blood, as well as coronary arteries, cardiac myocytes and the conducting system of the heart, that play various roles in pathogenesis of IHD. In the context of coronary artery disease, our high-resolution, phase-contrast observations are new and are not explained by the existing cholesterol, inflammatory, autoimmune and gene activation/mutation theories of pathogenesis of atherosclerosis. The concept of AA oxidopathy is simple and integrates the new observations with established knowledge. Finally, as we demonstrate later in this article, AA oxidopathy provides a sound scientific basis for therapies that are more logical, safer and clinically more effective than those based on existing cholesterol, inflammatory, infectious, autoimmune and gene theories of atherosclerosis.
    In introducing our hypothesis that AA oxidopathy is the core pathogenetic mechanism of IHD, we address the following five basic questions:

1. Since blood is the medium of the circulatory system, should inquiry into the pathogenesis of IHD be directed to the primary events occurring in the circulating blood rather than to secondary changes in the arterial wall that result in atheroma formation?

2. Since all the primary plasma and cell membrane events occurring in the circulating blood are oxidative in nature and since cholesterol is an antioxidant, is the prevailing focus on blood cholesterol as the centerpiece molecule under scrutiny in experimental and clinical research justified?

3. Do the cholesterol, inflammatory, infectious, autoimmune and gene hypotheses adequately explain the pathogenetic mechanisms of the established risk factors of IHD?

4. Does the proposed AA oxidopathy hypothesis completely explain the pathogenetic mechanisms of all of the established risk factors of IHD?

5. How effective are the long-term clinical outcomes of therapies for reversing IHD that are based on the cholesterol, inflammatory, infectious, autoimmune and gene mutation hypotheses? How effective are the therapies based on the AA oxidopathy hypothesis?

    In 1983, one of us (MA) published the hypothesis that the phenomenon of spontaneity of oxidation in nature is the core mechanism of molecular and cellular injury in all diseases.1 Since the publication of that hypothesis, we have surveyed a host of natural oxidative phenomena and drawn support for the hypothesis.2-8 The notion that a single mechanism can serve as the core pathogenetic mechanism of molecular injury in all disease processes appears too simplistic to be valid. Yet, diligent search of the literature of oxidative phenomena in nature and biology fails to uncover any evidence to the contrary.9 
    Specifically, we have investigated oxidative phenomena in peripheral blood in a variety of clinical settings9-11 and have described reversibility of oxidatively induced erythrocyte membrane deformities by ascorbic acid in patients with chronic fatigue syndrome12 and dissociation of aggregates caused in vitro by norepinephrine, collagen and ADP by ascorbic acid in healthy subjects.13 
    The evolution of the core concepts of AA oxidopathy and oxidative coagulopathy was preceded by our recognition of the many roles of oxidative phenomena in our microscopic findings in patients with IHD and a host of other disorders.14-31 Specifically, we observed microscopic evidence of cardiac myocytolysis in cardiomyopathy14-15and myocardial fibrosis associated with iron,16-18 calcium19 and oxalate20-21 deposits in hemodialysis patients. Some parallel morphologic observations concerned vascular intimal proliferative changes and other vascular alterations in hemodialysis patients.22-23 We also documented anatomic and enzymatic evidence of ischemic myocardial injury unaccompanied by occlusive coronary artery disease.25-26 We have also discussed many clinical implications of the hypothesis of spontaneity of oxidation in integrative medicine in areas of clinical nutrition,27 fitness,28 adrenergic hypervigilence,29 and meditative and self-regulatory methods for reducing stress associated with lifestyle elements.9,30,31
         During over a decade of our clinical work based on our concepts of oxidative injury, we examined freshly prepared and unstained smears of peripheral blood of several hundred patients with a host of degenerative, immune, nutritional, and ecologic disorders, as well as smears of healthy subjects, to establish a frame of reference for the range of high-resolution morphologic patterns in health and disease. For this report, we also examined 100 consecutive patients who presented with ischemic heart disease as assessed by clinical evaluation, electrocardiography, stress test, thallium perfusion scans and coronary angiography to define specifically the morphologic patterns of oxidative injury in IHD which we present here. In 1995, such experimental and clinical observations led us to define ischemic coronary artery disease as a specific example of disease processes that are initiated by oxidative injury.9 In a companion article in this issue of the Journal and two others appearing in the next issue, we present clinical outcome data obtained in patients with advanced IHD, periphery vascular and renal failure.32-34
   Several lines of chemical and clinical evidence for the oxidation hypothesis of ischemic heart disease have been developed during the last 15 years.35-50 There have also been dissenting voices.51 The proponents of the oxidation theory assumed "that the oxidative modification of LDL occurs primarily in the arterial intima, in microdomains sequestered from antioxidants in plasma."41 It has been further assumed that if oxidized LDL were to be generated in the circulating blood, it would be swept up within minutes by the liver.45 Hence, all research in atherogenesis has been exclusively directed to investigation of atherogenic changes in the vascular wall. It is important to note that these assumptions were made without benefit of direct microscopic observations of the oxidant phenomena in the circulating blood. Those assumptions are clearly not warranted in view of our morphologic observations of oxidative coagulopathy and AA oxidopathy documented in this report. Furthermore, the mechanisms of oxidation of LDL are deemed "unknown." Here again the fundamental phenomenon of spontaneity of oxidation in the blood ecosystem has been ignored. Our observations also challenge the cholesterol hypothesis of IHD, thus clearing the way for a wholly novel view of pathogenesis of atherogenesis and ischemic coronary artery disease. The clinical implications of this view, as we show in Part II of this article, are vastly different from those of the prevailing cholesterol, infectious and gene mutation theories of IHD. 
    We introduce the terms AA oxidopathy and oxidative coagulopathy in this article for specific reasons. Our morphologic observations of peripheral blood indicate to us that the molecular events involved in recognized intrinsic and extrinsic coagulative pathways are oxidative in nature, though the redox dynamics of such pathways have not been fully investigated. Limited published studies on this subject support our view.52-55 Recently, a third coagulative pathway, the Bradford-Allen Coagulation Pathway, has been proposed that involves activation of sialidase enzyme by reactive oxidative species.56 It seems likely that additional oxidatively triggered coagulative pathways will be discovered and characterized in the future. We introduce the term oxidative coagulopathy as an all-encompassing term for all such oxidative coagulative events that result in formation of microclots (microscopic clots formed in circulating blood and composed of loosely held blood elements within a matrix of congealed plasma and microplaques (microscopic plaques formed within the circulating blood and composed of compacted necrotic debris and blood elements. We introduce the term AA oxidopathy for a broader spectrum of energetic-molecular dysregulations of the redox phenomena. In advanced stages, the morphologic evidence of such injury may be observed in freshly prepared peripheral blood smears with high-resolution phase-contrast microscopy. AA oxidopathy includes patterns of blood cell and plasma component damage that involve oxidative injury to lipids, sugars and protein moieties as well as diverse enzymatic pathways of intracellular, extracellular and interstitial compartments. In the context of IHD, it also includes cell membrane depolarization dysfunction of cardiac myocytes and the conducting system of the heart. 
    While the concepts of oxidative coagulopathy and AA oxidopathy evolved from our extensive high-resolution, phase-contrast microscopic studies of unstained peripheral blood smears in diverse clinicopathologic states, the subject of this article—that AA oxidopathy is the core pathogenetic mechanism of IHD—developed from peripheral blood findings of patients with advanced coronary artery disease, congestive heart failure, cardiac arrhythmias, poorly controlled diabetes, and in smokers before and after smoking.
    We draw support for AA oxidopathy from many lines of evidence and recognize the oxidative nature of the involved processes as the common denominator. We also establish that the clinical implications of AA oxidopathy are radically different from those of other prevailing theories of IHD. Specifically, it requires that therapeutic strategies be directed to all aspects of blood ecology (initial redox phenomena occurring in the circulating blood) and not merely to aspects of vessel wall ecology (later atherogenic cellular and tissue changes taking place in the vascular wall).

A Need for A Unifying Concept of Atherogenesis
   The need for innovative research into the pathogenetic mechanisms of IHD was emphasized recently.57 The relationship between flow-limiting stenosis and ischemic coronary disease is weak.58 Reduction in the extent of atherosclerosis does not correlate with reduced mortality.59-63 Many persons with myocardial infarction have normal blood cholesterol levels.64-66 Treatment with lipid-lowering drugs does not reduce overall mortality in men in some studies,65 and decreases total and IHD mortality in women to a much lesser degree than in men.66,67 The paradox of IHD coexisting with normal coronary arteriogram is well recognized.68-70 Excess body stores of iron,71,72copper73,74 and mercury75,76 are risk factors for heart disease, while deficiencies of selenium77,78 and chromium79,80 increase risk of IHD. In the past, such associations between IHD and excess of pro-oxidants and deficiency of minerals with antioxidant roles have been assumed to contribute to oxidative modification of LDL cholesterol. We believe such assumptions are not warranted in view of our microscopic findings. Similar assumptions were made about the protective roles of natural antioxidants such as vitamins C,81,82 E,83,84 beta carotene,85,86and coenzyme Q10,87,88 as well as about synthetic antioxidants such as probucol89,90 and EDTA.91,92 The antiatherogenic roles of chronic alcohol intake—the so-called French paradox93,94—and risk of IHD associated with hyperhomocysteinemia95,96 are usually paid little attention by the proponents of the cholesterol hypothesis. A large body of experimental and epidemiological evidence points to a significant pathogenetic role of chronic inflammation.97-106 Among normal men, base line serum levels of C-reactive protein, an acute-phase reactant, correlate well with future myocardial infarction and stroke, and the increased risk is independent of lipid-related and non-lipid-related risk factors of atherosclerosis.107 Intriguingly, the benefits of aspirin in risk reduction diminish significantly with decreasing serum levels of C-reactive protein. Other evidence points to the roles of leukocyte activation and an autoimmune process.108-113 Several lines of evidence support the critical roles played by platelets, monocytes, macrophages, endothelial cells, myocytes and fibroblasts that are unequivocally independent of blood lipid levels.114-120 Recent investigations into the molecular basis of IHD have revealed activation of genes that encode for several mediator molecules such as platelet aggregation, vasoactive and chemotactic factors, as well as cytokines and interleukins.121-128
   The prevailing cholesterol theory of coronary artery disease ascribes the primary pathogenetic mechanism of coronary artery disease to a disturbance of cholesterol metabolism. This view holds up to careful scrutiny neither on theoretical grounds nor on the basis of known experimental and clinical observations. The clinical benefits of lipid-lowering drugs are limited,129-136 and their toxicity, including carcinogenicity, is increasingly recognized.137-145 The advocacy of some proponents of the cholesterol theory for use of such drugs for persons without raised blood cholesterol levels is disturbing.146.
   Below, we include a brief survey of pertinent literature as a frame of reference for presenting our AA oxidopathy hypothesis.

Ali M, Ali O. AA Oxidopathy: 
the core pathogenetic mechanism of ischemic heart disease. 
J Integrative Medicine 1997;1:1-112.


FIBRINOLYSIS

Historical Perspective
  In 1842, T.W. Jones, a British physician, asked the question: Why doesn't the blood circulating in the vessels coagulate?147 This question has intrigued blood coagulation researchers ever since. In 1845, Rudolph Virchow, the German physician and father of pathology, responded to the question raised by Jones by stating that under certain circumstances circulating blood does coagulate, and he speculated what those pathologic states might be.148Almost simultaneously, A. Trousseau, a French physician, observed that circulating blood does coagulate in the vessels in certain conditions and reported clinical observations to support Virchow's speculation.149 Trousseau's syndrome is the name still used when thrombophlebosis is associated with malignant diseases. 
    In 1893, Dastre first proposed the term "fibrinolyse" for his observations on the dissolution of blood clots.150However, his were not among the earliest observations on fibrinolysis. John Hunter, the eighteenth-century London surgeon, included his observation on clot dissolution in his famous treatise on blood.151 In 1887, Green's publication of his studies of the effect of sodium chloride on the dissolution of plasma clots also preceded those of Dastre.152 In 1903, Delezenne and Pozerski reported activation of serum proteolytic activity by chloroform,153 and four years later, Opie and Barker separated albumin from globulin and proteolytic activity was associated with the globulin fraction.154 In 1933, rapid lysis of plasma clots by extracts of beta-hemolytic streptococci was noted by Tillet and Garner,155 and in 1944 Kaplan demonstrated that the streptococcal factor was an activator for the proteolytic enzyme precursor in human plasma.156

Coagulative and Fibrinolytic Pathways
   The twin coagulative and fibrinolytic systems are similar in many ways and have been extensively investigated and reviewed.157-160 Both systems are activated, amplified and counterbalanced in biologic phenomena involving injury, inflammation, repair responses, metastatic cancer of spread and degenerative disorders. Both systems are composed of inactive precursors that are converted into active enzymes of serine protease type.161 Both systems involve intrinsic (plasma) and extrinsic (tissue) activation mechanisms which trigger a common pathway. In the coagulative system, the final common pathway involves polymerization of fibrinogen into fibrin, while that in the fibrinolytic system it involves activation of plasminogen. And, as we show later in this article, the primary mechanisms underlying both systems are related to oxidant phenomena in the circulating blood (which we designate as oxidative coagulopathy) as well as those which affect cell and plasma membranes and cytosol (which we collectively designate as AA oxidopathy). Even though the coagulative and fibrinolytic systems are generally regarded as two discrete enzymatic pathways, in reality the intrinsic pathways of the fibrinolytic system is coupled to the intrinsic pathways of the coagulative, so that clot formation and resolution are initiated concurrently and perpetuated in tandem. We introduce the term clotting-unclotting equilibrium (CUE) in this article to integrate the oxidative nature of events that lead to the concurrent phenomena of clot formation and clot resolution.
    Abnormal coagulative phenomena within the circulating blood occur in diverse clinicopathologic entities such as eclampsia, anaphylaxis, localized and generalized Shwartzman reactions, hemorrhagic diathesis in clinical and experimental acute viral infections, bacterial endotoxic shock and others.157 Some turn-of-the-century investigators mistook such coagulative phenomena within the vascular lumina—fibrin threads and amorphous deposits, as well as the classical thrombi—as postmortem events. However, this mistake was recognized by Ingerslev and Teilum, who in 1946 described fibrin thrombi in hepatic periportal sinusoids in the liver of women who survived eclampsia.162 Even though the concepts of pre-thrombotic and hypercoagulable states have drawn considerable interest158-161,163,164; however, the definitions of such states varies from author to author and discussions of the subjects have been confined to clinical thrombotic-hemorrhagic events. To our knowledge the central role of chronic, insidious clotting-unclotting disequilibrium in the pathogenesis of IHD has not been recognized. 
    The occurrence and patterns of free radical injury to the myocardium, the conducting system of the heart, and coronary arteries have been investigated extensively with ischemia-perfusion studies.165-170 Specifically, free radicals, particularly superoxide anion (O2._) and hydroxyl radical (OH*), are produced during and after ischemia and reperfusion, and cause oxidative functional and structural injury to the heart, including the loss of myocardial contractile function. Superoxide anion is a relatively weak oxidant and owes most of its destructive potential to its ability to generate hydrogen peroxide by reacting with molecular oxygen. Hydrogen peroxide, in turn, generates highly toxic OH* radicals in the presence of transition metals such as iron and copper.
    Fibrinolysis is generally assumed to occur only as a part of the spectrum of pathologic coagulative disorders. Our morphologic observations challenge this assumption. We sometimes observe congealed plasma and microclots in healthy subjects without history or demonstrable evidence of any coagulative disorders. We have also observed, as illustrated in this article, that such congealing of plasma and microclot formation is easily reversed by addition of antioxidants, proving that such coagulopathy is oxidative in nature. Our microscopic findings show that clotting and unclotting within circulating blood occurs with high frequency in a variety of cardiovascular disorders as well as in otherwise healthy subjects with established risk factors of IHD. In states of accelerated oxidative molecular injury, the rate of oxidative coagulation exceeds that of fibrinolysis, and the various patterns of oxidative coagulopathy and AA oxidopathy are readily observed. Clinicopathologic entities that are associated with disseminated intravascular coagulation, in our view, represent more advanced stages of the same process. While disseminated intravascular clotting in many acute and chronic disorders has been thoroughly studied, the occurrence and extent of such phenomena in the insidious development of molecular and cellular lesions that lead to IHD, to our knowledge, has not been previously recognized.

SPONTANEITY OF OXIDATION IN NATURE AND DISEASE
   We include below brief comments about some fundamental aspects of the phenomenon of oxidation as a framework for our discussion of oxidative coagulopathy. Oxidation is a spontaneous process—it requires neither an expenditure of energy nor any outside cues. A flower wilts spontaneously; a wilted flower does not "unwilt" spontaneously. Fish rot spontaneously; rotten fish do not "unrot" spontaneously. Cut grass decomposes spontaneously; decomposed grass does not "undecompose" spontaneously. Thus, spontaneity of oxidation in nature is the natural phenomenon that provides the core mechanism of molecular injury in biology. Stated in another way, spontaneity of oxidation is nature's grand scheme to assure that no oxygen-utilizing form of life remains immune to the immutable law of oxidative death. Oxidation plays a similar role in the decay of inanimate matter as well. Iron rusts spontaneously; rusted iron does not "unrust" spontaneously. Reduction, the other side of the redox equation of life, requires expenditure of energy. 
    What is the energetic basis of spontaneity of oxidation in nature? A simple analogy may be used to answer this question. A boy is playing with a ball attached to a string. He keeps the ball flying in an orbit around him by moving his extended arm in a circle above his head. In this circumstance, the kinetic energy of the ball seeks to move the ball away from the boy, but it is counterbalanced by the pull of the string on it so that the ball stays in a circular orbit. If the boy lets go of the string, the ball will spontaneously fly away. The same thing would happen if the boy were to spin the ball with a greater force than can be sustained by the string. The above analogy may be completed by imagining that the ball moves in elliptical orbits—the string has extreme elasticity and pulls the ball closer to the boy's head by shrinking at one time and allows the ball to move far away from the boy by stretching at another time. (Physicists believe that atoms exist in a simultaneous particle-wave state determined by a particle-wave probability distribution.) A similar set of conditions governs the motion of electrons as they spin around the nucleus of an atom. Thus, spontaneity of oxidation (electron loss) is in reality a function of the kinetic energy of electrons that favors their outward movement, hence their loss. Thus no external source of energy is required in oxidation. 
    Electrons within atoms and molecules do not orbit the nucleus of an atom in the sense that the earth orbits the sun. Rather, electrons occupy regions of space called orbitals, which can hold no more than two electrons. A characteristic of electrons in a given orbital is that they demonstrate opposite spins. Within a molecule, two electrons sharing the same orbital exist in a bond called a covalent bond. A lone electron within an orbital is considered unpaired. This leads us to the definition of a free radical: any atomic or molecular species capable of an independent ("free") existence that contains one or more unpaired electrons in one or more orbitals. We may point out that carbon- and sulfur-centered radicals generally react with oxygen with greater affinity than others included in the table given below.
    A partial list of common naturally occurring free radicals is shown in the following table adopted from Halliwell.171

Types of Radical Examples
Oxygen-centered Superoxide O2*-
Hydroxyl OH*
Lipid peroxyl lipid-O*
Hydrogen-centered Hydrogen atom H*
Carbon-centered Tichloromethyl Ccl3*
Sulfur-centered Glutathione GS*
Delocalized electrons Phenoxyl (delocalized into benzene ring) C6H5O*
Nitric oxide NO*

Ali M, Ali O. AA Oxidopathy: 
the core pathogenetic mechanism of ischemic heart disease. 
J Integrative Medicine 1997;1:1-112.


MOLECULAR DUALITY OF OXYGEN
Oxygen: A Molecular Dr. Jekyll and Mr. Hyde

   Oxygen ushers in life. Oxygen terminates life. We believe the comprehension of the molecular duality of oxygen is essential to understanding both oxidative coagulopathy and AA oxidopathy—and, hence, to an understanding of atherogenesis. At a fundamental level, life is stored energy of carbon in its various reduced forms. Life is sustained by release of that energy as carbon-containing compounds are oxidized by oxygen to produce water and carbon dioxide. This elemental aspect of living matter—and its profound implications in health and disease—is seldom given due attention in clinical medicine. 
    Diatomic oxygen in ambient air is considered a radical because it contains two unpaired electrons. This structural characteristic of oxygen, according to thermodynamics, should allow oxygen to cause immediate combustion of all organic molecules that come in contact with it. Why does that not happen? The explanation is that the two unpaired electrons of diatomic oxygen in two different orbitals have the same spin quantum number. If oxygen were to directly oxidize organic molecules, it would have to accept two electrons from a donor with spins that are opposite to its own two unpaired electrons so as to be properly accommodated into the vacant spaces in oxygen's two orbitals containing unpaired electrons. This, of course, cannot be achieved by electrons in covalent bonds, which spin in opposite directions. Such spin restriction explains oxygen's poor reactivity even though it is a good oxidizer.(Diatomic oxygen accepts electrons more efficiently than other electron acceptors such as NO3-, CO2 and SO42-, and to organic compounds such as NAD+ and quinones.) This explains why organic molecules do not spontaneously undergo combustion in oxygen. This also explains why glucose in oxygen, like ATP in water, is kinetically stable even though it is thermodynamically unstable. For oxygen to be reduced, it requires a paramagnetic catalyst such as heme iron or a copper chelate, which scrabble, so to speak, the electron spin in the donor. More than 90% of the oxygen used in the human body is utilized by mitochondrial cytochrome oxidase, which transfers four electrons into an oxygenmolecule to produce two molecules of water:

O2 + 4H+ + 4e- = 2H2O

    Under ordinary circumstances, reduction of oxygen by cytochrome oxidases in the above reaction does not release reactive oxygen radicals. This is assured by transitional metal ions such as iron, copper, vanadium and titanium, which are carried in the active sites of cytochrome oxidases. Such metal ions occur in variable states of oxidation, and changes in such states facilitate transfer of single electrons in an orderly fashion in which various partially reduced forms of oxygen are held bound to the metal ions. These ions also play essential roles in spontaneous oxidation (autoxidation) of several nonradical compounds including ascorbic acid; thiols such as cysteine, homocysteine and reduced glutathione; catecholamines such as epinephrine and norepinephrine; and a host of amines such as 3,4-dihydroxyphenylalanine (DOPA) and 6-hydroxydopamine. 
    Molecular oxygen has an interesting "love-hate" relationship with electrons. It avidly picks up free electrons in its vicinity, then just as avidly spins them out. In a vacuum, electrons travel at the speed of light. Even though the speed of an electron in tissues would be expected to be drastically reduced, the electron-oxygen transactions must still take place at amazingly fast speeds. During oxidative phosphorylation in the generation of ATP, molecular oxygen accepts an electron—is reduced—to become superoxide. Superoxide then loses its electrons spontaneously—is oxidized—in initiating the free radical chain reactions that result in the formation of peroxides, oxyacids, aldehydes and hydroxyl radicals. Such free radicals oxidize proteins of coagulation cascades, thus triggering oxidative coagulopathy, which further fans the fires of AA oxidopathy. However, our high-resolution microscopic observations described in this article lead us to conclude that accelerated oxidative stress on components of circulating blood is neither confined to oxidative injury of coagulation pathways nor, indeed, are the coagulative phenomena the initial events. We introduce the term AA oxidopathy to encompass a broad range of oxidative events that include: 1) peroxidation of plasma and cell membrane lipids; 2) oxidative permutations of plasma and cell membrane sugars and proteins; 3) accelerated autoxidation of nonenzymatic plasma antioxidants such as thiols and ascorbic acid; 4) inactivation or saturation of plasma enzymatic antioxidant mechanisms; 5) endothelial injury; and 6) later oxidative injury to subendothelial collagen and the muscularis of the arterial wall. Oxidative modification of LDL cholesterol—widely believed to be the critical event in atherogenesis—is, in our view, a relatively less significant event. We return to this essential issue later in this paper.

How Do Cells Autoregulate?
   Human cells regulate themselves, just as unicellular organisms do. In medical literature, the discussions of cellular growth and regulation are generally limited to how cells maintain their structure and function by affecting key transcription factors. One commonly used mechanism by which cells turn key proteins on and off is adding or removing phosphate groups. In the context of our discussion of spontaneity of oxidation in nature, molecular duality and human redox dynamics—as well as from a teleologic standpoint, oxygen may be expected to play central roles in cellular growth, differentiation and autoregulation. The prevailing notions of human cell biology hold that greater the oxygen supply to cells, the more efficient their growth and the better their structural integrity and functional stability. Such simplification, however, ignores the diverse roles oxygen plays under different conditions. We cite here the example of cytotrophoblastic growth and differentiation to illustrate this important point.
    During the first trimester, there is a discrepancy between the growth of the embryo and the placenta so that the placenta grows rapidly to prepare for the growth spurts in the embryo which are delayed well into the second trimester. The molecular basis of this phenomenon was unknown until recently when Genbacev et al.172 discovered that human placental development is regulated by the responsiveness of cytotrophoblast to changes in oxygen tension. They observed that cytotrophoblast in culture continue to proliferate and do not differentiate well under hypoxic conditions (2 percent oxygen), but stop proliferation and begin to differentiate when oxygen tension was raised with 20 percent oxygen—thus creating a paradox of a more rapid cellular growth occurring with lower oxygen tension. There are other lines of evidence that show that human cells may autoregulate by responding to oxygen and oxidant phenomena in other ways. For example, hypoxia induces the generation of vascular endothelial growth factor which stimulates endothelial proliferation. Hydrogen peroxide is involved in the signaling pathway of platelet-derived growth factor, which stimulates proliferation of vessel wall myocytes.173 Other examples of autoregulation of cells by employing their oxidants include activation of nuclear factor kB, which turns on genes for some mediators of inflammation, and inactivation of AP-1, which controls some genes involved with growth. Nature seems to have yet simpler and more elegant ways to allow individual cells to autoregulate via manipulation of oxygen and other oxidizing species. For example, it assigns important cell signaling functions to molecular oxygen by simply adding an electron to it. Recently, it has been shown that superoxides relay Ras protein's oncogenic message in transformed fibroblasts.174 We include the above brief comments about cellular autoregulation and oxygen in our discussion of IHD to suggest that there may yet be other mechanisms by which oxidant phenomena in the circulating blood contribute to (or abate) oxidative coagulopathy and AA oxidopathy.

MORPHOLOGY OF ATHEROSCLEROSIS
   By gross morphology, atherosclerosis is a simple process that progresses in three stages. In the first stage, a yellow-gray fatty streak appears on the inner surface of the vessel wall. Histologically, it comprises foamy, lipid-laden macrophages in the subendothelial space. The second stage is characterized by a fibrous plaque formation. The plaque is composed of a central necrotic, acellular area of fatty deposits covered by a fibrous cap, which in reality is made up of proliferating myocytes and fibroblasts in a matrix of collagen. In the third stage, hemorrhage occurs within the central necrotic area, resulting in a thrombus composed of fibrin threads with trapped platelets. The smooth fatty streak is often present in children and progresses to the two later stages with time.
    The common atheromatous plaque is a raised area of white-gray-yellow discoloration on the inside wall of a vessel. As plaque grows in size, it protrudes into the vascular lumen and begins to reduce the inner caliber of the vessel. Plaques may vary in size from 0.1 to 2 cm in diameter, but may grow to much larger sizes when they coalesce. In the aorta and larger arteries, plaques may extend for several centimeters. The luminal surfaces of plaques are usually irregular and indurated; small erosions covered with fibrin thrombi are commonly observed. On section, the center of large plaques often exudes viscous, yellow-gray-brown gummous material—hence, the name atheroma from the Greek word for gruel. Histologically, plaques are composed of necrotic tissue with cholesterol crystals and other lipid deposits, degeneration and necrosis of the collagen and the muscle in the vascular wall, smooth muscle proliferation, and fibrous scarring at the periphery of the plaque. In advanced stages, hemorrhage and dystrophic calcification frequently occur in necrotic tissues. 
    It is the presence of cholesterol crystals and other lipid deposits in the plaque that has misled generations of pathologists and cardiologists into thinking that cholesterol is the cause of atherosclerosis—just as a prior generation of pathologists made a similar error in mistaking deposits of dystrophic calcification in injured tissues as evidence for dysregulated calcium metabolism. In atherosclerosis, cholesterol deposits occur as a consequence of oxidative coagulopathy, just as calcium deposits are often seen in organized hematomas. As we mention briefly in the abstract of this paper and discuss at length below, cholesterol is an antioxidant and cannot cause the lesions of coronary artery disease that are produced as a result of oxidative injury.

MORPHOLOGIC PATTERNS OF AA OXIDOPATHY
    Below we describe our high-resolution, phase-contrast morphologic observations that comprise AA oxidopathy and oxidative coagulopathy. The degree and extent of oxidative changes, of course, varies over a broad range depending on the number and the nature of oxidative stressors. During the early months of our work with AA oxidopathy, we were concerned with the issue of whether the changes we observed involving the erythrocytes, granulocytes, platelets and plasma occurred in the circulating blood or were they artifacts caused by the process of preparing peripheral blood smears. We carefully examined fresh smears of several hundreds of apparently healthy individuals who sought our preventive medicine services—as well as those of many healthy volunteers—to assess the range of such morphologic changes in health. Thus, we were able to confidently differentiate semiquantitatively rather limited morphologic changes sometimes seen in healthy subjects from the frequently observed and pronounced abnormalities involving erythrocytes, platelets and plasma encountered in AA oxidopathy in a host of cardiovascular and noncardiovascular clinicopathologic entities.
    In the context of IHD, important oxidant stressors include hyperadrenergic state, smoking, hyperglycemia, excess oxidized plasma lipids, obesity and cardiac arrhythmias. We have microscopically microscopically coagulopathy within the circulating blood to generally progress in the following seven morphologic stages:

1. Erythrocyte and leukocyte membrane deformities
2. Diaphanous congealing of plasma
3. Platelet aggregation and lysis
4. Filamentous coagulum (fibrin needles)
5. Lumpy coagulum 
6. Microclots
7. Microplaques

    The patterns of oxidative coagulative injury described in this article were observed in extensive studies of blood morphology in a host of acute and chronic cardiovascular as well as non-cardiovascular disorders, including advanced IHD, unstable angina, congestive heart failure, cardiac arrhythmias, hypertensive crises, acute and chronic viral and bacterial infections, fungemia, acute and chronic atopic disorders, chemical sensitivity reactions, acute and chronic degenerative disorders and malignant diseases.

Erythrocyte Membrane Damage and Lysis in AA Oxidopathy
   Erythrocytes, when observed with an ordinary bright-light microscope in stained smears of peripheral blood, appear as rigid, biconcave, disc-shaped corpuscles. When examined with a high-resolution, phase-contrast microscope in freshly prepared unstained smears, these cells are seen as pliable, round cells that readily change their shape to ovoid, triangular, dumbbell, or irregular outlines to squeeze past other erythrocytes in densely populated fields. Such cells resume their regular rounded contour as soon as they find open space.
    Erythrocytes may be expected to show evidence of oxidative damage earlier than other blood corpuscles since these cells transport oxygen, the most important oxidizer in the body. Furthermore, unlike the leukocyte cell membrane which is sturdy and uniquely equipped with enzymatic antioxidant defenses against oxidative stresses of microbial invaders, the erythrocyte membrane is more permeable (to facilitate oxygen uptake and delivery) and, hence, may be deemed more vulnerable. Our microscopic findings provide some evidence for such theoretical considerations. The earliest and most common abnormalities we observed in AA oxidopathy are erythrocyte membrane irregularities and cell deformities. As oxidopathy progresses, an increasing number of red cells show morphologic abnormalities and some cells appear as ghost outlines. Many erythrocytes show surface wrinkling, teardrop deformity, sharp angulations and spike formations. Other changes include rouleaux formations and zones of plasma congealing around damaged erythrocytes.. Some zones of plasma congealing sometimes appear to form spontaneously (without a discernable cause) in close vicinity of damaged erythrocytes and leukocytes.
    We established the oxidative nature of plasma and cellular abnormalities described above by demonstrating their reversibility with antioxidants such as vitamin E, taurine, vitamin A, and vitamin C, reported previously12 but not shown here. Parenthetically, we add that we have observed similar evidence of erythrocyte membrane injury in diverse clinical entities associated with accelerated molecular injury such as disabling chronic fatigue, fibromyalgia and a host of severe nutritional, ecologic and autoimmune disorders.

Erythrocyte Homogenate, Free Iron and AA Oxidopathy
    In deliberations of atherogenesis, the issues of oxidative injury to erythrocytes and the presence in the plasma of free hemoglobin leached from damaged red cells—and the presence of excess iron in the plasma as a result of those factors—are seldom, if ever, addressed. Our morphologic findings lead us to propose that oxidative erythrocyte injury plays an important role in the genesis of AA oxidopathy and, hence, atherogenesis. We observed erythrocyte membrane damage and lysis with high frequency in many acute ischemic coronary syndromes and, less often, in patients with advanced IHD but without severe, acute coronary ischemia. 
    Iron, like oxygen, is a molecular Dr. Jekyll and Mr. Hyde. It is needed for molecular transport (in hemoglobin for oxygen), for storage (in myoglobin), for energy functions (in cytochrome oxidase and other cytochromes), for respiration (in non-heme-iron proteins), and for antioxidant defenses (in catalase). In its Mr. Hyde role, iron (in free form) is a potent oxidant and catalyzes the generation of many dangerous oxygen-derived radicals.175-182 In health, the Mr. Hyde roles of iron are minimized by transferrin, an iron-binding protein that rigidly limits the availability of free iron. In normal plasma, only 20 to 30 percent of transferrin occurs in a saturated state. 
    Free hemoglobin has been considered a dangerous protein—a biological Fenton catalyst.179 It rapidly quenches free radicals in a highly oxidizing environment and becomes oxidized, thus turning into a potent oxidant. It is readily degraded by H2O2 to release free iron, which initiates and propagates several free radical reactions.182-183Hemoglobin reacts with H2O2 to produce a protein-bound oxidizing species capable of causing lipid peroxidation.184Free hemoglobin also avidly binds with nitric oxide radicals and induces vasospasm, triggering yet other oxidizing events, which, in turn, feed the "oxidative fires" of AA oxidopathy. 
    Beyond ample evidence of the destructive oxidizing capacity of erythrocyte-derived factors discussed above, there is also direct evidence that red blood cells play a role in atherogenesis. Sambrano et al.185 and colleagues have shown that certain receptors on macrophages for oxidized LDL also bind to oxidatively-injured red cells prior to their internalization and lysis. Oxidatively-modified lipid, proteins, and carbohydrate moieties of erythrocyte membranes can be expected to play a host of roles in oxidative coagulopathy and AA oxidopathy, just as they do in attachment, endocytosis, membrane fusion, and viral hemagglutination in viral infections.186-189 We may point out in this context, as shown by Oda et al.189 that oxyradicals play the key pathogenetic roles in virus-induced illness. As we discuss in Part II of this article, a growing body of evidence points to the roles of strong inflammatory, infectious and autoimmune mechanisms in atherogenesis. It seems obvious to us that additional evidence for inflammatory and immunogenic roles of erythrocyte-derived factors in oxidative coagulopathy, AA oxidopathy, atherogenesis and IHD will be forthcoming as those areas are explored further in the future. Of considerable interest in this context is the matter of electrostatic interactions among oxidatively damaged erythrocyte membranes and other oxidized elements in the circulating blood ecosystem. Phospholipids and lipid components of LDL inhibit infectivity and hemagglutination of rhabdoviruses, probably because of structural similarity between such compounds and the receptors for viruses in cell membranes.190,191 In the case of vesicular stomatitis virus, phosphatidylinositol, phosphatidylserine and GM3 ganglioside show inhibitory activity.192 What are the mechanisms of action of such lipid moieties? Some light on this question is shed by studies of Mastromarino and colleagues193 in which removal of negatively charged molecules from membrane lipids by enzyme treatment significantly reduces their inhibitory activity, suggesting that electrostatic interactions play important roles in viral cell membrane dynamics. It seems highly likely that similar electrostatic roles involving platelets, monocytes and other elements in circulating blood ecology will also be discovered in the future.

Granulocyte Clumping, Membrane Damage, and Lysis in AA Oxidopathy
   The granulocyte is usually dismissed as inconsequential in discussions of atherogenesis. This surprises us for two reason: 1) we observe morphologic evidence of oxidative damage to granulocytes in AA oxidopathy with high frequency in patients with IHD; 2) it is known that granulocytes produce toxic oxidative species that degrade other intracellular and extracellular molecular species, inflict peroxidative injury to cytoplasmic and organelle membranes, enhance polymorphonuclear leukocyte-endothelial adhesion, and increase microvascular permeability.194-200Evidently, all of those factors can initiate, perpetuate and intensify oxidative phenomena that cause oxidative coagulopathy and AA oxidopathy and may result in IHD. Some oxidizing molecular species elaborated by granulocytes increase capillary permeability and enhance granulocyte-endothelial adhesiveness.202 It seems odd to us that the cell known to play initial and critical roles in oxidative tissue injury is ignored in conditions characterized by oxidative injury to the circulating blood that results in atherogenesis. We recognized that granulocytes would be found to play a central role in atherogenesis when the molecular dynamics of this cell in atherogenesis are eventually investigated. This, indeed, is beginning to happen.
    The granulocyte, like the erythrocyte, is a victim of the current infatuation of cholesterol enthusiasts with cholesterol. Our microscopic findings show that granulocytes play pivotal roles in initiating and perpetuating oxidative cascades in the circulating blood. In freshly prepared, unstained peripheral blood smears of healthy subjects, we observe granulocytes as hunter cells that move like crabs on the ocean floor, their locomotion provided by streaming of their granules into little protrusions of their cytoplasm. These cells continuously change their shapes as they explore their microenvironment. Not uncommonly, we visualize active phagocytosis of bacteria and cellular debris by such cells. In AA oxidopathy, the earliest change involving granulocytes is loss of locomotion—the cells lie limp in pools of plasma, with diminished or absent granular streaming. In later stages, granulocytes exhibit clumping. As in the case of erythrocytes, some granulocytes in more advanced cases of AA oxidopathy show blurring of membranes while others appear as ghost outlines of cells. Eventually, badly damaged granulocyte show disintegration of segments of their walls, degranulation and lysis.
    The cytoplasmic granules of human granulocytes are rich in many enzymes including proteases, such as elastase, which are capable of degrading proteins in intracellular as well extracellular fluids.202 Oxidative cell membrane injury may be expected to result in escape of proteases from granulocytes into the circulating blood. The destructive capacity of granulocytes represents an exaggerated physiologic response in which bursts of potent oxidative molecular species are produced during inflammatory and repair responses. Specifically, hydroxyl radical (OH.) derived from superoxide radical (O2-) produced by granulocytes are a major cause of cellular injury. Granulocytic myeloperoxidase generates hypochlorite radicals when exposed to H2O2 following phagocytic activation.203Hypochlorite, in turn, oxidizes protease inhibitors, thus leading to increased proteolytic tissue damage. 
    Granulocytes play a central role in the generation and function of oxidative species that control cellular signaling, regulate mediators of inflammatory and repair responses, and influence migration and replication of inflammatory cells.204-207 A spate of recent gene-activation studies show evidence of the involvement of granulocytes in atherogenesis. Transcription of many atheroscleroses-related genes is augmented by oxidant-sensitive regulatory pathways involving nuclear factor kB (NF-kB).207 Specifically, exposure to superoxide radicals produced in granulocytes—and to lesser degrees in other cells—activates the NF-kB regulatory complex,206,207 which, in turn, triggers transcription of genes that encode for a variety of proteins including leukocyte adhesion molecules, chemotactic cytokines and enzymes that regulate cellular and matrix metabolism.207 Indirect evidence of the relevance of granulocytic factors in coronary artery disease has been shown by Tanaka et al.204 who documented activation of vascular cells and leukocytes in the rabbit aorta after balloon injury. Direct evidence for activation of NF-kB in experimental injury has recently been shown by Lindner et al.209 Recent findings of Tardif et al.90 that probucol reduces the incidence of restenosis after coronary angioplasty is consistent with such considerations, since the drug is a potent antioxidant and would be expected to protect coronary arteries traumatized by the angioplasty procedure from granulocytic oxidative bursts.

Platelet Aggregation and Lysis in AA Oxidopathy
   The role of platelets in atherogenesis and coronary thrombosis has drawn much—and persistent—attention.210-222Yet, the atherogenic role of oxidatively damaged platelets in the circulating blood is ignored, just as the atherogenic consequences of oxidatively damaged circulating erythrocytes and granulocytes are neglected in deliberations of atherogenesis. In pathogenesis of atherosclerosis, the role of platelets is usually limited to the circumstances under which platelets adhere to endothelium or subendothelial stroma. This shifts the focus—to a great detriment to clear understanding of the pathogenesis of IHD—from initial molecular oxidative events taking place in the blood ecosystem to subsequent cellular oxidative events occurring in the vessel wall ecosystem. 
    In freshly prepared, unstained peripheral blood smears examined with a high-resolution, phase-contrast microscope, platelets appear as dark, round-to- ovoid, structureless bodies with poorly visualized granules, and without well-delineated plasma membranes. There is little or no tendency toward clumping and the plasma in their vicinity shows no evidence of congealing. Indeed even when smears are allowed to stand for 15 to 30 minutes, platelets remain discrete and do not cause congealing of fields of plasma that surround them in the central portions of the smears. (The peripheral portions of such smears often show early platelet clumping due to oxidative stress caused by exposure to the ambient oxygen.) Familiarity with the range of platelet morphology observed in health is essential before an observer can meaningfully interpret platelet changing seen in AA oxidopathy and oxidative coagulopathy.
    In subjects with known atherogenic risk factors—especially in smokers, uncontrolled diabetics and those with chronic inflammatory conditions—we observe evidence of variable damage to platelet membranes and degranulation. The platelets in AA oxidopathy aggregate, change shape, degranulate and release various thrombogenic and atherogenic factors. Not unexpectedly, most platelet aggregates and clumps are surrounded zones of plasma congealing of variable widths. In more advanced stages of AA oxidopathy, platelet membranes become indistinct and lysis occurs. Parenthetically, we might add that we also observe similar damage in patients with disabling chronic fatigue, fibromyalgia, chemical sensitivity and a host of acute autoimmune disorders. Such changes are only rarely seen in apparently healthy subjects.
    One of us (MA) established the oxidative redox nature of platelet aggregation and clot formation by addition of ascorbic acid and ethylenediaminetetraacetic acid (EDTA) to platelet aggregates induced by oxidizing agents such as collagen, epinephrine, ADP and ristocetin. We observed that both ascorbic acid and EDTA can readily break up platelet aggregates formed by addition of various aggregating agents.13 Those observations support our view that platelet aggregation and clot formation are oxidative phenomena and that antioxidants ascorbic acid and EDTA caused dispersal of platelet aggregates by protecting the platelet membranes from the oxidant stress. Interestingly, both ascorbic acid and EDTA failed to break up platelet aggregates caused by collagen, indicating a stronger—and perhaps irreversible—effect of collagen on platelet aggregation. From a teleologic perspective, it may be argued that collagen exerts a stronger aggregating influence than epinephrine because circulating platelets are exposed to collagen under more threatening conditions (bleeding from trauma to vessel walls) rather than to epinephrine (a common hyperadrenergic state created by lifestyle stressors).
    Endothelial cells and platelets repel each other by their nonthrombogenic character—by their surface charges as well as their ability to generate antithrombotic molecules such as heparin and prostacyclin.220 Thus, adhesion of platelets to endothelial cells is prevented under ordinary conditions. Such electromagnetic and molecular conditions, however, are threatened continuously by the normal oxidative stress in healthy circulating blood. In states associated with accelerated oxidative injury, the normal nonthrombogenic capacity of platelets and endothelial cells is exceeded and platelets begin to agglutinate and adhere to endothelial cells. Examples of conditions of accelerated oxidative stress include catecholamine surges that accompany lifestyle stresses, hypercholesterolemia, denuding endothelial injury caused by intra-arterial catheters, and anastomotic sites of bypass surgery. Under such conditions, injury to platelets triggers chain reactions of oxidative coagulopathy, first in the blood and subsequently in the vascular wall affecting all four lines of cells involved in atherogenesis—endothelial cells, monocytes/macrophages, myocytes, and yet more platelets.221-226 Platelet degranulation releases several growth factors, including platelet-derived growth factor (PDGF),215-217 epidermal growth factor,227 nitric oxide,228 and transforming growth factor-beta.228 Some of these growth factors are powerful mitogens. But generation of all such growth factors is initiated by direct oxidative stress on platelets. 
    What is the common denominator in all platelet factors that are associated with IHD? Evidently, it is accelerated oxidative injury to elements in the circulating blood that leads to oxidative coagulopathy and AA oxidopathy. Again, as for erythrocytes and granulocytes, the patterns of oxidative damage to the components of the vascular wall that lead to plaque formation—and which have claimed enormous sums of research funds without significant benefit to those who suffer from IHD—clearly are consequences of changes in the circulating blood.

Ali M, Ali O. AA Oxidopathy: 
the core pathogenetic mechanism of ischemic heart disease. 
J Integrative Medicine 1997;1:1-112.

Erythrocyte Morphology in Health
and Early Stages of AA Oxidopathy

Figure 1 (top): All erythrocytes and two lymphocytes shown in the photomicrograph keep their distance from each other (due to negative electrostatic surface charges) and show regular outlines. Note that none of the well-preserved erythrocytes are discoid in shape. Figure 2 (bottom) shows early changes of AA oxidopathy with many damaged erythrocytes.


Severe Erythrocyte Damage and Leukocyte
Clumping in AA Oxidopathy

Figure 3 (top) shows a more advanced stage of erythrocyte damage in a 66-year old hypertensive female than in figure 2. Only a few cells show well-preserved, completely regular outlines. Some cells appear as ghost outlines of leached cells. Figure 4 (bottom) shows clumped leukocytes surrounded by some faded cells.


Zones of Congealed Plasma Surrounding
Platelets and a Damaged Leukocyte

Figure 5 (top): A spreading zone of congealed plasma representing initial changes of oxidative coagulopathy in a smoker is seen near the center of the field. Note rouleaux formation of erythrocytes. Figure 6 (bottom) shows a similar zone of congealed plasma surrounding a damaged leukocyte. We confirmed the spreading nature of these zones of congealing by observing these zones over time.


Erythrocyte-Induced and "Spontaneous"
Plasma Congealing

Figure 7 (top) illustrates severely damaged erythrocytes in a 52-year-old man with persistent atrial fibrillation. Close examination shows some zones of congealing surrounding many damaged red blood cells. Figure 8 (bottom) illustrates a zone of plasma congealing unaccompanied by any cellular elements of the blood (seemingly a "spontaneous" phenomenon) in a diabetic with IHD. In our view, such congealing represents accelerated oxidative stress on plasma.

Needle-like and Amorphous Microclots 
And "Dirty" Field of AA Oxidopathy

Figure 9 (top) shows some needle-like and amorphous granular microclots in a patient with unstable angina. Figure 10 (bottom) shows a "dirty" blood smear of a man with severe peripheral vascular disease and extensive bilateral leg ulcerations, showing zones of plasma congealing and lumpiness, platelet clumping, and some other zones of plasma congealing unaccompanied by any blood corpuscular elements, representing diffuse changes of AA oxidopathy.


 A Large Platelet Clot And a Meshwork of Clots

Figure 11 (top) shows a microclot formed by a large aggregate of platelets and congealed plasma in a patient five days after angioplasty. Figure 12 (bottom) shows another field from the same smear and illustrates how microclots in oxidative coagulopathy grow in size when oxidative stress persists.


Microplaque Formation In AA Oxidopathy

Figure 13 (top) and figure 14 (bottom) show two microplaques in a patient who had received three unsuccessful angioplasties for advanced IHD. Photomicrographs were taken the day after a major nosebleed. Note the compaction of necrotic debris and blood elements in microplaques as contrasted with loose structure of microclots in figure 11.


Dissociation of Platelet Aggregates by Vitamin C

Figure 15 (top) shows patterns of aggregation of platelets induced by oxidative stress of epinephrine, collagen, ADP and ristocetin. Such aggregation is the in vitro counterpart of in-vivo platelet clumping seen in AA oxidopathy and shown in figure 11. Figure 16 (bottom) shows patterns of dissociation of platelet aggregates obtained with the four aggregating agents on addition (arrow) of a 0.5 percent solution of ascorbic acid. Note that ascorbic acid completely dissociates epinephrine-induced aggregates (top), while its effect on collagen-induced aggregation (bottom line) is minimal.13

Reversal of Early Changes of AA Oxidopathy

Figures 17 (top) and 18 (bottom) show abnormal erythrocyte morphology in a highly stressed 53-year-old man before and after addition of 1:50 dilution of mycelized vitamin E solution. Note how vitamin E normalizes red cell morphology and establishes the oxidative nature of erythrocyte injury.


Reversal of Early Changes of AA Oxidopathy with Taurine

Figures 19 (top) and 20 (bottom) illustrate AA oxidopathy changes involving erythrocytes before (top) and after (bottom) addition of taurine (1 mg/50 ml) in a 63-year-old man in congestive heart failure. Taurine is a powerful cell membrane stabilizer that is known for its cardio- and neuroprotective roles. This simple experiment establishes the oxidative nature of red cell abnormalities seen in congestive heart failure.

Diaphanous Congealing of Plasma
   We observed diaphanous zones of plasma congealing surrounding platelets, fragments of leukocytes, and fungal organisms. In many cases we observed areas of plasma congealing without any involvement of platelets, leukocytes and fungal organisms. That some free radical activity exists in plasma in health must be accepted on teleologic grounds alone. Such oxidative stress is generated by normal metabolic activity of red and white blood corpuscles as well as of platelets, oxidation of catecholamines, enzymatic glucose breakdown, nonenzymatic autoxidation of blood glucose in hyperglycemic states, and mechanical shearing stress on endothelial cells. Furthermore, zones of plasma congealing and microclots produced by physiologic redox dynamics may be expected to be dissolved as soon as they form by normal plasma fibrinolytic activity. Notwithstanding such physiologic fibrinolytic activity, some free radical damage to the endothelium and subendothelial matrix would be expected to ensue. Indeed, the presence of fatty-streak lesions in children attests to the existence of such insidious and clinically silent oxidative coagulopathy. 
    It is to be expected that normal oxidative stresses on blood plasma are markedly increased during a host of pathologic states of the cardiovascular system, as well as of other body organ ecosystems, accompanied by accelerated oxidative injury. This includes advanced IHD, unstable angina, congestive heart failure, cardiac arrhythmias, hypertensive crises, hyperglycemia, and during smoking.

Lumpy Coagulum and Fibrin Needles
   Intravascular coagulation has long been assumed to be an uncommon and potentially life-threatening state. Our high-resolution, phase-contrast microscopy observations of peripheral blood in a host of cardiovascular and non-cardiovascular entities challenge this assumption. In health, plasma in peripheral blood smears appears as clear liquid that bathes cells. In states of accelerated oxidative molecular injury, damaged plasma proteins begin to congeal, and such zones of clotted plasma spread as thin diaphanous films. As the oxidative process advances, cross-linked fibrin appears as filamentous and lumpy coagulum. Some platelets can usually be recognized trapped within filamentous and lumpy fibrin deposits, undoubtedly contributing oxidized phospholipids and glycolipids to the protein coagulum. Such needles and masses of oxidized, coagulated proteins and peroxidized lipids grow by triggering the chain reactions of plasma lipid peroxidation and protein coagulation. We have consistently documented the presence of fibrin needles and lumpy coagulum of protein in freshly prepared and unstained blood smears in states of accelerated oxidative damage. By comparing peripheral blood morphology before and after intravenous infusions of EDTA and ascorbic acid, both administered with magnesium, we have repeatedly observed dissolution of fibrin needles and lumpy protein after the infusions in cases in which such evidence of oxidative coagulopathy was clearly discerned.

Microclots
    The presence in circulating blood of microclots formed by oxidative stress of normal blood ecology, and an excess of such clots in states of accelerated oxidative stress, may be reasonably deduced from the foregoing discussion of redox dynamics of plasma components and blood corpuscles in health and disease. Congealing of plasma, erythrocyte and leukocyte membrane damage and platelet clumping may be expected to add to the oxidizing capacity of blood by triggering fibrinogenic and lipid peroxidation chain reactions. Furthermore, such changes may be expected to initiate oxidative chain reactions, thus increasing oxidative stress and enlarging zones of plasma congealing into microclots. We document such progressive changes of AA oxidopathy.

Microplaques
    A natural consequence of oxidant microclots—oxidative coals, in our terminology—circulating in blood would be for them to grow in size as the plasma at their periphery continues to congeal and as an increasing number of platelets and other blood corpuscles are entrapped into or stick to them. With ongoing oxidative stress, such microclots coalesce to make yet larger and lumpier microclots. With time, such loosely bound microclots are compacted in form layered structures with dead and dying cells and other necrotic debris trapped between layers of fibrin that we call microplaques. Such microclots and microplaques float in the bloodstream as simmering oxidative coals, lighting up oxidative fires and inflicting further oxidative damage to blood corpuscles, endothelial cells and subendothelial collagen matrix wherever the lining cells of the vascular lumen have been denuded by the shearing mechanical stress of circulating blood. We have observed microclots grow into microplaques that measure as much as several hundred microns.
    All oxidants in circulating blood trigger oxidative coagulative phenomena involving blood corpuscles and plasma contents. Our clinical and high-resolution microscopic observations lead us to consider the following groups of causes of accelerated oxidative stress on the circulating blood that lead to oxidative coagulopathy:

1. Adrenergic hypervigilence associated with lifestyle stressors
2. Rapid glucose-insulin and adrenergic shifts
3. Mycotoxicity and, to lesser degrees, toxins from other microbes
4. Increased oxidizability of blood associated with obesity 
5. Diminished dietary intake of natural antioxidants
6. Increased body burden of prooxidants such as iron, copper and mercury
7. Inflammatory factors
8. Infectious agents
9. Excess of oxidized and denatured lipids
10. Autoimmune factors
11. Oxidative stress of cigarette smoking
12. Hyperhomocysteinemia
13. Mechanical shearing stress associated with hypertension.

Ali M, Ali O. AA Oxidopathy: 
the core pathogenetic mechanism of ischemic heart disease. 
J Integrative Medicine 1997;1:1-112.

Smoking and AA Oxidopathy

Figure 21 (top) before smoking and Figure 22 (bottom) after smoking show changes of AA oxidopathy observed in a volunteer who abstained from smoking overnight and then smoked three cigarettes in three minutes.
 

AA Oxidopathy and Fungemia

There are four important questions here:

1. How often are fungal organisms seen in the circulating blood of nonfebrile ambulatory persons?

2. What roles do such organisms play in the pathogenesis of oxidative coagulopathy and AA oxidopathy?

3. What are the possible mechanisms of action of mycotoxins and other fungal proteins?

4. What roles do fungal organisms play in the inflammatory and autoimmune processes that are known to be atherogenic and involved in other aspects of IHD?

As to the first question of how frequently fungal organisms may be observed in afebrile ambulatory patients, there is wide divergence of opinion among those who routinely use high-resolution (15,000 x) phase-contrast microscopy and those who never use such technology. We have documented the presence of fungal organisms in peripheral blood of severely immunocompromised individuals with high frequency (over 95%).229 As a part of our study of the phenomena of oxidative coagulopathy and AA oxidopathy, we also examined the peripheral blood smears of 50 consecutive patients with advanced IHD (including those recovering from angioplasty and coronary bypass operations) and detected the presence of fungal organisms in many microscopic fields in 19. Identification of specific fungal species cannot be done with such microscopy. However, employing anticandida antibodies labeled with horseradish peroxidase, we have documented the presence of Candida species in peripheral smears in some cases.230,231 We have previously published the specificity characteristics of the anti-candida antibodies we employed in such studies.232,233 Such observations may be challenged by those unfamiliar with high-resolution microscopy on the ground that if true fungemia did exist in such patients, they would be critically ill. This requires further comment. 
    The clinical distinction between benign bacteremia and potentially life-threatening septicemia is well recognized; the former occurs after tooth brushing and is clinically insignificant. It is noteworthy that no such clinical distinction is made in the prevailing medical thinking between insidious and clinically silent fungemia and potentially life-threatening fungal invasion of the bloodstream. Fungemia, the presence of fungi in circulating blood, is always considered a serious pathologic entity. This is clearly erroneous in view of the direct evidence to the contrary that we present here. Regrettably, many physicians who have not taken the time to learn the use of high-resolution microscopy—and hence are uninformed about the prevalence of fungal organisms in the peripheral blood of immunocompromised individuals—make irresponsible and derogatory statements about those who use such technology. Indeed, some licensing boards controlled by such uninformed physicians have taken serious disciplinary actions, including suspension of medical licenses, against holistic practitioners who diagnosed fungemia with high-resolution phase-contrast microscopy and treated clinical yeast syndromes.234

Fungemia, Mycelia Formation and Fungal Budding
   In figures 27 through 30, we illustrate the replication, mycelia formation and fungal budding in peripheral blood smears observed over a period of five hours for two reasons: 1) to provide additional proof that the bodies we recognize as fungal organisms are indeed fungi (shown by their ability to form mycelia and the ability of the mycelia to show budding); and 2) to document the rapidity with which fungal organisms multiply as oxygen tension falls and acidity increases in their microenvironment—the two conditions under which fungi would be expected to grow luxuriantly. 
    As to the second question concerning the possible roles of fungal proteins and mycotoxins in the pathogenesis of oxidative coagulopathy and AA oxidopathy, we illustrate some of the observable phenomenon of zones of plasma congealing surrounding fungal organisms.. We observed this phenomenon to occur within ten to sixty minutes in almost all instances in which we studied the morphology of fungal organisms continuously in freshly prepared unstained peripheral blood smears. We also observed fungal spores to germinate within one to ten hours in most such cases. The zones of plasma congealing surrounding fungal organisms increase in area, trap platelets and cellular debris, and grow into microclots, and finally into micro-plaques. Such findings suggest that fungal organisms play a role in the pathogenesis of oxidative coagulopathy and AA oxidopathy. We return to this subject later in this article.
    If fungemia occurs frequently in chronic immune disorders, why can't the fungal organisms be cultured from blood in such cases? This is a valid question. We have addressed this issue at length elsewhere.235 It is noteworthy that negative blood cultures are frequently seen in patients with documented invasive tissue fungal infections. In one study of such patients, a Candida enzyme called enolase was detected in 42 percent of patients with proven tissue candidiasis.236
   The third and fourth questions concern the possible molecular mechanisms by which fungi cause AA oxidopathy and might play etiologic roles in the pathogenesis of IHD. We return to this subject after discussing AA oxidopathy in relationship to the known molecular dynamics of IHD.

Fungemia and AA Oxidopathy Phase-Contrast and Darkfield Views

Figure 23 (top) shows clusters of round-to-ovoid white fungal bodies that contrast with dark erythrocytes in a high-resolution (15,000X) phase-contrast photomicrograph. Figure 24 (bottom) shows the same microscopic field in darkfield. Note that unlike erythrocyte lipid membranes that reflect light, fungal membranes contain disaccharides that absorb light and do not appear as bright as red cell membranes.


Immunostaining of Candida Organisms
in Peripheral Smears

Figure 25 (top) and figure 26 (bottom) show unstained and immunostained Candida organisms in phase-contrast and darkfield fields. In this procedure, human anti-candida IgG antibodies labeled with horseradish peroxidase were used to specifically stain Candida organisms. For procedural details and antibody specificity characteristics, see references #230 through 233.

In Vitro Fungal Growth

Figure 27 (top) is a photomicrograph of a freshly prepared peripheral blood smear of a diabetic with leg ulcers and severe fatigue and shows several fungal organisms. Figure 28 (bottom) represents the same smear photographed 37 minutes later showing a luxuriant growth of fungal organisms as the oxygen tension of the smear under a coverslip falls and acidosis develops due to continued glycolysis(the two conditions that are known to support rapid fungal replication.


Mycelia Formation and Building


Figures 29 (top) and 30 (bottom) are photomicrographs of the smear shown in figures 27 and 28 taken 3 1/2 and 4 hours later respectively. Note how yeast grow mycelia with profusion and how some mycelia grow buds.

Fungemia and Oxidative Coagulopathy Earliest Changes


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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