Oxygen Model of Coronary Heart Disease

A Clinical Outcome Study of Reversing Coronary Artery Disease

Majid Ali, M.D.

(originally published in Townsend Letter in 2006*) 

Coronary heart disease (CHD) is, first and foremost, an energetic lesion. Specifically, it begins with rupture of the initial step involving complex I in the chain of oxygen-driven events in mitochondrial ATP generation — and is perpetuated by disruptions of the later steps in that chain. That uncoupling of respiration from oxidative phosphorylation — including respiratory-to-fermentative shifts in ATP generation — is the core of the previously described dysox model of atherosclerosis.1 In this column, we summarize the essential aspects of the molecular pathobiology of the dysox model, and present long-term clinical outcome data obtained with integrated management plans that addresses all relevant issues for repairing the central energetic defects in atherogenesis.

Derangements of those primary oxystatic and energetic mechanisms set the stage for all subsequent autonomic, endothelial, inflammatory and atherogenic responses encountered in patients with chronic insidious as well as acute ischemic coronary artery syndromes.2-4 Of crucial significance to the dysox model of CHD are: (1) morphologic changes of oxidative coagulopathy5; (2) oxidative dysautonomia 6; (3) patterns of oxidative regression to primordial cellular ecology7; and (4) biochemical profiles of increased urinary excretion of metabolites of the Krebs cycle and glycolytic pathways indicating the presence of the dysox state.8,9 In 1998, those observations led to the hypotheses of the oxidative-dysoxygenative model of coronary artery disease (ODCAD)10 and subsequently to the dysox model of atherosclerosis,1 which has the following two core tenets:

First, the initial molecular lesions in atherogenesis are oxidative dysautonomia and oxidative coagulopathy involving oxidative injury to all plasma and cellular components of the circulating blood, resulting in the formation of microclots and microplaques in the circulating blood.

Second, the intimal and medial lesions of the vascular vessel essentially represent disturbed oxygen homeostasis with mitochondrial uncoupling of respiration and oxidative phosphorylation developing as consequences of oxidative dysautonomia and oxidative coagulopathy.

The dysox model of atherogenesis reaches far beyond the prevailing cholesterol and inflammatory theories of arteriosclerosis. In 1997, one of the authors (MA) with his colleague Omar Ali described the morpholgic features of oxidative coagulopathy, and marshalled thirteen lines of evidence for our view that cholesterol is not a major factor in the pathogenesis of atherosclerosis.11 In that article, we asserted that the inflammatory response in atheroma — the basis of the inflammatory theory of arteriosclerosis — occurs as a consequence of oxidosis in the circulating blood with subsequent regional intimal and medial injury. Since then, several lines of direct and incontrovertible experimental evidence for the dysox model of atherogenesis have been developed. For instance, in mice most atherosclerosis loci recognized so far have not been accompanied with systemic risk factors associated with atherosclerosis.12 For those reasons, in the clinical application of the dysox model of arteriosclerosis, we have emphasized the need for focusing on all relevant issues for restoring oxygen homeostasis in the vascular wall.

The vascular wall undergoes regional disturbances of molecular energetics.13-16 — including the uncoupling of respiration and oxidative phosphorylation — as components of physiologic inflammatory response discussed in a previous column.17 It has been shown that such uncoupling occurs to some extent in all cells, and to a greater degree in blood vessels that are predisposed to the development of atherosclerosis.18 Those earlier findings have been fully validated by recent studies with mice generated to exhibit doxycycline-inducible expression of uncoupling protein-1 (UCP1) in the artery wall.19 (Bernal-Mizrachi). In such mice, UCP1 expression in aortic smooth muscle cells causes hypertension and increases dietary atherosclerosis without affecting cholesterol levels. Furthermore, UCP1 expression regionally increases superoxide production and decreases the availability of nitric oxide — the two clear markers of local oxidosis. Some recent advances in our understanding of mitochondrial respiratory pathophysiology provide strong support for the dysox model of renal insufficiency. For readers with special interest in the subject, additional comments on this crucial subject are included in a later section.

The following five groups of factors that directly and/or indirectly uncouple respiration and oxidative phosphorylation, cause local and/or systemic dysoxygenosis, and play crucial roles in the pathogenesis of coronary artery disease are: 1) chronic adrenergic hypervigilence associated with lifestyle stressors; 2) rapid glucose-insulin shifts and hyperinsulinemia; 3) mycotoxins and, to lesser degrees, other microbial toxins; 4) dysequilibrium among nutrients with oxidant and antioxidant functions; and 5) ecologic oxidants.

Cholesterol is an antioxidant. CHD is an oxidative-dysoxygenative disorder. This native unoxidized cholesterol plays no direct role in the pathogenesis of CHD. Only oxidized cholesterol contributes to atherogenesis. This was clearly demonstrated in recent studies in which respiration was uncoupled from oxidative phosphorylation but cholesterol levels were kept unchanged in mice.19 All such animals developed atherosclerosis. This is a point of crucial significance since it requires that the focus must be on the nature of cholesterol — whether in a native unoxidized form or in an oxidized form — rather than on its level in the prevention and reversal of CHD.

The Prevailing Model of Cardiology

In the United States, advanced CHD is generally managed with one of the following four approaches: (1) pharmacologic regimens comprising multiple drugs; (2) mechanical approaches to segmental coronary arterial lesions, such as angioplasty and coronary bypass surgery; (3) holistic nutritional, herbal, and stress-reduction therapies; and (4) integrative programs that include EDTA chelation infusions in addition to therapies included in the third category. In mainstream cardiology, patients who fail to respond to multiple drug therapies, angioplasty, and bypass surgery generally continue to be managed with ineffective trials of drugs in various combinations. The efficacy of mechanical approaches to segmental coronary lesions in such patients is admittedly poor, even for the staunchest supporters of such therapies. The reason for failure of such therapies is that neither the pharmacologic nor the mechanical coronary approach addresses any of the pathogenetic mechanisms involved in CHD. Not unexpectedly, there is widespread disillusionment with such therapies.20,21

The Sun Soil Model for Reversing CHD

The integrated program for arresting and reversing advanced CHD used at the Institute comprises global strategies for restoring oxygen homeostasis, redox equilibrium, and acid-base balance. It is sharply focused on the following seven major components: (1) education; (2) self-regulation; (3) food choices; (4) limbic exercise; (5) nutritional therapies; (6) herbal protocols; and (7) EDTA infusions. The details of this program are furnished in Integrative cardiology, the sixth volume of The Principles and Practice of Integrative Medicine22

EDTA Chelation Therapy

The scientific basis and rationale for EDTA infusion therapy as an important component of an integrative management plan for acute and chronic coronary ischemic syndrome have been presented at length in Integrative Cardiology. (www,canary21. com). The other relevant issues of EDTA therapy, such as other metabolic benefits and potential adverse effects of such therapy were detailed in that volume.

The composition of ethylenediaminetetraacetic acid (EDTA) infusion protocol used in this study is shown in Table 1. At times, the composition was modified to address other concurrent nutritional and environmental, and autoimmune issues. EDTA has a greater affinity for magnesium than for sodium; hence, magnesium readily displaces sodium in the EDTA salt. The other components, heparin and sodium bicarbonate, are used as rheologic agents. The frequency of infusions was weekly except in cases of persistent symptomatology and a high risk of recurrent infarction, in which case EDTA was administered on a twice-weekly basis for the first two to three weeks. The issues of informed consent, clinical and laboratory evaluation, vein access, maintenance of the infusion, protocols for detection of adverse effects during EDTA infusion, and supplemental nutrition have been described previously.59

Table 1. Composition of EDTA Protocol

EDTA (sodium salt)

1.5 Gm

Magnesium sulfate

2,000 mg

Sodium bicarbonate

2.5 Meq

Multivitamin

*

Heparin

4,000 Units

Normal saline

150-400 ml

Vitamin C

5 gm

Pantothenic acid

500 mg

Pyridoxin

200 mg

Vitamin B12

1,500 mcg

* Multivitamin protocol includes the following: thiamine, 25 mg; riboflavin, 5 mg; niacin, 50 mg; niacinamide, 50 mg, pantothenic acid, 12.5; pyridoxin, 7.5 mg; ascorbic acid, 500 mg; vitamin A, 5,000 IU; vitamin D, 500 IU; vitamin E, 2.5 IU.

A Clinical Outcome Study

In this column, we present data for a clinical outcome data for 38 patients whose compliance to the integrative plans was jidged to be satisfactory (higher than 75 percent) over extended periods of time. Our primary purpose in this study is to report the incidence of serious adverse cardiac events that could not be prevented with our integrativeplans individualized for specific patients.

Table 2. Demographic Data of Patients with Coronary Heart Disease

Gender

Average age

Range of Age

Women

(n= 11 )

72.3

59-84

Men

(N= 27 )

73

53-82

Table 3. Clinical Presentation of Patients With Coronary Heart Disease

Bypass

Stent

MI

Advanced CHD

Women

(n=11)

0

0

2

0

Men

(n= 28 )

5

3

8

2

Table 4. Duration of Treatment of Patients with Coronary Heart Disease

1yr

>2 yrs

5> ys

> 7 ys

Women

(n=11)

0

1

2

8

Men

(n=27)

4

6

6

11

Table 5. Cardiac Events During Treatment

Gender

Bypass

Stent/

Angioplasty

MI

Women

(n=11)

3*

0

0

Men

(N=27)

2**

0

0

* Two of these three patients developed myocardial infarction, and one of the two had a coronary stent inserted as well. The third woman was hospitalized for pneumonia and was given a bypass (considered unnecessary by the authors) and developed a stroke after the byapss.

** Coronary bypass not recommended by the Institute physicians.

Selected Case Studies

In this section, we present some illustrative case studies to show the true potential of excellent long-term clinical outcomes achievable with comprehensive integrative managemnt plans for advanced stages CHD following failed coronary bypass operations.

Case #1: A 71-year-old executive presented at the Institute on January 23, 1997 with advanced coronary heart disease, hypertension, hypercholestrolemia, and early stages of renal insufficiency. In 1993, he suffered an acute myocardial infarction. In January of 1994, he underwent a quadruple coronary bypass. In 1995-6, he remained symptomatic and was repeatedly advised coronary stent and/or bypass procedures. Instead, he elected to proceed with an integrative program at the Institute which included EDTA infusion therapy. He was taking Acupril, Lopressor, Cardura, and Zocor. At the last follow-up on November 29, 2005, he was active, exercising, and symptom-free for over three years. His drug usage had been reduced to Zocor taken on alternate days (against our advice). He received a total of 45 EDTA infusions during his nine years of care at the Institute.

Case #2: A 54-year-old woman presented at the Institute in January 1996 with a history of coronary bypass procedure, persistent angina, insulin-dependent diabetes, diabetic neuropathy, hypertension, hypothyroidism, IgE-mediated allergy, recurrent yeast vaginitis, and incapacitating fatigue. Within three months, she responded well to the Institute’s integrative plan with marked reduction in angina and relief of fatigue symptoms and remained well until April 1997, when she discontinued the program for the reason of the non-reimbursement of her expense by her insurance carrier. Within several weeks, her angina returned. In July 1997, she underwent a quadruple coronary bypass. In March 1998, following a visit with her cardiologist, she reported “a sense of doom” because her cardiologist thought she had reached the end of the rope. In December 1998, a carotid Doppler showed a 75 percent narrowing on the left side and a 60 percent narrowing on the right side, and she was advised endarterectomy. She declined the procedure and decided to fully comply with the Institute’s program, including EDTA and hydrogen peroxide infusions. During a recent follow-up visit in August 2005, nearly ten years after her initial visit at the Institute, she reported only occasional episodes of chest symptoms which she cleared with self-regulatory methods and without any drug use. She received a total of 113 EDTA infusions over a period of ten years.

Case #3: A 51-year-old builder was advised immediate coronary bypass operation for rest angina. Instead he presented at the Institute on November 10, 1998 for an integrative management plan, including EDTA infusion therapy. In February 1999, he reported that he had not experienced any angina during the previous month. He discontinued therapy in 2001. Angina recurred and he was advised coronary bypass operation again in 2001. In 2005, he restarted his care at the Institute. During the last visit in February 2005, he reported total freedom from angina symptoms. He received a total of 107 infusions in seven years.

Comparison of Pre- and Postchelation Myocardial Perfusion Thallium Scans

Comparative studies of pre- and posttreatment thallium myocardial perfusion scans were conducted by radiologists. They reported objective evidence of improved myocardial perfusion in 5 of 6 patients. The essentials of the radiologist’s reports comparing the pre- and posttreatment thallium scans are included.

We quote below excerpts from the radiologists’ reports of the comparative study of pre- and posttreatment thallium myocardial perfusion scans for three patients:

Case 1: 67-year-old male with history of acute myocardial infarction. “Partial redistribution to the inferior wall seen on delayed images of pre-chelation scans not observed on post-chelation study…no inferior wall scarring seen. Triple bypass at 65; 36 chelation infusions. Today’s (post-chelation) images demonstrate that the intensity of activity in the inferior wall is greater than noted on the prior (pre-chelation) redistribution images.”

Case 2: 56-year-old woman. Coronary bypass recommended but declined. 29 chelations. Activity increased from walking less than a block to being able to walk three miles. Radiologist’s report: “Pre-chelation perfusion scans showed “diminished activity in the inferolateral segment which is fixed on the delayed films and most likely represents infarct.” Post-chelation showed “diminished activity without any fixed defects.”

Case 3: 71-year-old male; S/P angioplasty; 34 EDTA infusions. Radiologist’s report: “The degree of perfusion deficits in the thallium scans not quantified by the first radiologist. A pattern of increased perfusion in the post-chelation scans recognized by the reviewing radiologist.”

In closing, interative management protocols for coronary artery disease that address fundamental regulatory mechanisms — oxygen homeostasis, redox equilibrium, and acid-base balance — can be expected to yield good long-term results. This is also true for many cases with advanced coronary disease and failed vascularisation attempts, as illustrated by some case studies in this article.

References

1. Ali M. Darwin, oxidosis, dysoxygenosis, and integration. J Integrative Medicine 1999;3:11-17.

2. Ali M. Ali O. Fibromyalgia: An oxidative-dysoxygenative disorder (ODD). J Integrative Medicine 1999;3:17-37.

3. The Cause of Fibromyalgia: the respiratory-to-fermentative shift (the DysOx State) in ATP production. J Integrative Medicine. 2003;8:135-139.

4. Ali M, Ali O, Fayemi A, et al: Improved myocardial perfusion in patients with advanced ischemic heart disease with an integrative management program including EDTA chelation therapy. J Integrative Medicine 1997;1:113-145.

5. Ali M. Dysoxygenosis. J Integrative Medicine. 2002;6:1-34

6. Ali M. Ali A. Oxidative coagulopathy in fibromyalgia and chronic fatigue syndrome. Am J Clin Pathol 1999; 112:566-7.

7. Ali M. Oxidative coagulopathy. In: Syllabus of the Capital University of Integrative Medicine, Washington, D.C., 1997.

8. Ali M. Oxidative-dysoxygenative parasympathetic dystrophy: Frequency of diminished high-frequency parasympathetic outflow in subjects with chronic oxidosis and dysoxygenosis. J Integrative Medicine. 2002;6:101-107.

9. Ali M. Oxidative regression to primordial cellular ecology (ORPEC): evidence for the hypothesis and its clinical significance. J Integrative Medicine 1988;2:4-55.

10. Ali M. Beyond the cholesterol and inflammatory theories of coronary artery disease: The oxidative-dysoxygenative coronary disease (ODCAD) model. J Integrative Medicine. 2002; 7:1-19.

11. Ali M, Ali O: AA oxidopathy: the core pathogenic mechanism of ischemic heart disease. J Integrative Medicine 1997;1:6-112.

12. Allayee H, Gharalpour A, Lusis AJ. Using mice to dissect genetic factors in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2003;23:1501-1509.

13 Heuper, W. C. General reviews. Arch. Pathol. 1944;38:162-181.

14. Ali M. The primacy of the erythrocyte in vascular ecology. In:The Principles and Practice of Integrative Medicine Volume VI: Integrative Cardiology and Chelation Therapies: The Oxidative-Dysoxygenative Model and Chelation Therapies. 2003. Washington, D.C. Capital University Press (in collaboration with Canary 21 Press, New York).pgaes 121-142.

15. Boccaccio C, Sabatino G, Medico E, et al. The MET oncogene drives a genetic programme linking cancer to haemostasis. Nature 2005;434:396- 400.

16. Dröge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002;82:47-95.

17. Ali M. Respiratory-to-Fermentative (RTF) Shift in ATP Production in Chronic Energy Deficit States. Townsend Letter for Doctors and Patients. 2004. August/Sept. issue. 64-65.

18. Santerre, R. F., Nicolosi, R. J. & Smith, S. C. Respiratory control in preatherosclerotic susceptible and resistant pigeon aortas. Exp. Mol. Pathol. 1974.20:397-406.

19. Bernal-Mizrachi C, Gates AC, Weng, et al. Vascular respiratory uncoupling increases blood pressure and atherosclerosis. Nature. 2005;435:502-506.

20. Steinberg D, Parthasarathy S, Carew TE et al. Beyond cholesterol: Modification of low density lipoprotein that increases its atherogenecity. N Eng J Med 1989;320:915 24.

21. Witztum JL, Steinberg D. Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991;88:1785 92.”

22. Ali M. The Principles and Practice of Integrative Medicine Volume VI: Integrative Cardiology and Chelation Therapies: The Oxidative-Dysoxygenative Model and Chelation Therapies. 2003. Washington, D.C. Capital University Press (in collaboration with Canary 21 Press, New York). http://www.cuim.edu & http://www.Canary21press.com)

Coauthors: (Shara Fischer, B.A., Mahboob Baig, M.B;B.S; Judy Juco, M.D., Alfred Fayemi, M.D., Eli Bannahji, M.D.,Jenny Gutierrez, M.D., Claudia Jeannette Alvarado Estrada, M.D; Rosa Zapata, M.D; Sabitha Dasoju, M.B;B.S.

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