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occlusion, while those who die after 48 hours of such events almost always show thrombotic coronary occlusion (unpublished personal observation)—a fact that clearly establishes that thrombotic coronary occlusion in the majority of such patients is the consequence and not the cause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,²⁴¹ pathologic,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.^254-256 Many 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.²⁵⁹ Third, 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,^5,9,27 is 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.

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 (SAM). 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.^307,308 Hyperhomocysteinemia 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 SAM (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.