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

PART I

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

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 settings^9-11 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 cardiomyopathy^14-15 and myocardial fibrosis associated with iron,^16-18 calcium¹⁹ and oxalate^20-21 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,^71,72 copper^73,74 and mercury^75,76 are risk factors for heart disease, while deficiencies of selenium^77,78 and chromium^79,80 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,^85,86 and coenzyme Q10,^87,88 as well as about synthetic antioxidants such as probucol^89,90 and EDTA.^91,92 The antiatherogenic roles of chronic alcohol intake—the so-called French paradox^93,94—and risk of IHD associated with hyperhomocysteinemia^95,96 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.

Article segments 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17

Index of Article Authors
Majid Ali, MD
Omar Ali, MD
Mary Ann Carroll, RN
Alfred Fayemi, MD
C.Grieder-Brandenburger, RN
Judy Juco, MD
Tsuneo Kobayashi MD
Jean A. Monro, MB, BS
(This index is incomplete and will be completed shortly)

Past and
Current Editors
Omar Ali, M.D.
Robert Atkins, M.D.
Robert Bradford, D.Sc
Paul Cheney, M.D., Ph.D.
Steven Davies, M.D.
Alfred O. Fayemi, M.D.
Claus Hanke, M.D.
Doug Hutto, N.D.
Judy Juco, M.D.
Paris Kidd, Ph.D.
Oscar Kruesi, M.D.
Derrick Lonsdale, M.D.
D. Vijen Poleszynski, B.S.
Christine Radulescu, Ph.D.
Ray Russamono, M.D.
Susan Test, Ph.D.
Lowell Weiner, D.D.S.
John C. Williams, M.D.

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The Journal of Integrative Medicine shall not be held responsible for statements of the contributing authors. The views and opinions expressed are those of the submitting authors and do not necessarily reflect those of The Journal of Integrative Medicine, The American Academy of Integrative Medicine, The American Academy of Preventive Medicine, any advertisers or staff members of The Journal of Integrative Medicine