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Doi:10.1016/j.pathophys.2004.06.00

Pathophysiology 11 (2004) 95–101 Calcification in coronary artery disease can be reversed by EDTA–tetracycline long-term chemotherapy Benedict S. Maniscalco , Karen A. Taylor a 4730 N. Habana Avenue, Suite 201, Tampa, FL 33614, USA b PA-C 2727 W. Martin Luther King Blvd., Suite 850, Tampa, FL 33607, USA Received 7 May 2004; accepted 3 June 2004 Atherosclerosis is a complex process with multiple mechanisms and factors contributing to its initiation and progression. Detection and quantification of coronary artery calcium (CAC) scores with electron beam tomography has been shown to correlate with obstructive andnonobstructive coronary artery disease (CAD). Pathogen-triggered calcification could play a role in CAD. Recent reports suggest that infectiousblood nanobacteria (NB) emerge to be such a trigger. So far, minimal or no reversal of atherosclerosis has been claimed by therapies with ivethylenediaminetetraacetic acid disodium salt (EDTA), antibiotics, or other regimens, and therapies for atherosclerosis remain non-curative.
We have now combined EDTA with antibiotic tetracycline (comET), an in vitro proven nanobacteriocidal treatment, and tested comET therapyin patients with documented CAD. Three hypotheses were probed: (1) Are NB present in patients with CAD?; (2) Does treatment with comETaffect blood NB antigen and serology?; (3) Does a comET decrease CAC scores? One hundred patients with stable CAD and positive CAC scores were enrolled into a 4 month study of comET therapy. ComET therapy is composed of (1) Nutraceutical Powder (Vitamin C, Vitamin B6, Niacin, Folic Acid, Selenium, EDTA, l-Arginine, l-Lysine, l-Ornithine,Bromelain, Trypsin, CoQ10, Grapeseed Extract, Hawthorn Berry, Papain) 5 cm3 taken orally every evening; (2) Tetracycline HCl 500 mgtaken orally every evening; (3) EDTA 1500 mg taken in a rectal suppository base every evening. CAC scoring was repeated at 4 months andserum samples were analyzed for NB antigen and serology at baseline, 2 and 4 months. Complete blood count, metabolic panel, liver function,C-reactive protein (hs-CRP) and lipids were analyzed at baseline and 4 months.
Seventy-seven patients completed the study and all patients were positive for NB serology, antigen or both. Responders (n = 44; 57%) had significant decreases in total CAC scores (P = 0.001), the average decrease being 14%. Non-responders (n = 33; 44%) had no change or hadincreases in CAC scores. Angina was decreased or ablated in 16 of 19 patients (84%). Lipid profiles improved to non-atherogenic directionsignificantly (P = 0.001), a remarkable finding in a patient group where 86% were on continuous statin medication already before the trial.
No adverse physiologic effects were seen in renal, hepatic, or hematopoetic systems.
In conclusion, CAC scores decreased during ComET therapy trial in most CAD patients inferring regression of calcified coronary artery plaque volume. The patients tolerated the therapy well and their angina and lipid profiles improved. Further treatment trials for long termtherapy with matched controls are warranted.
2004 Elsevier Ireland Ltd. All rights reserved.
Keywords: Coronary artery disease; Infection; Nanobacteria; Calcification individual atheromas as the immune system attempts to"wall off" or isolate the area of injury The hall- mark of this process is fibro-lipid matrix synthesis and atherosclerosis is an inflammatory disease with injury degradation–absorption processes in soft plaque. O'Brien or infection in the vascular endothelium predisposing to et al. Tenaglia et al. neovascular- atheromas Inflammatory cascades wax and wane within ization of the atheroma at this stage of healing and plaqueregression. These processes occur on a dynamic contin-uum within the atheromatous plaque. The rate of plaque ∗ Corresponding author. Tel.: +1 813 264 2241; fax: +1 813 265 5512.
synthesis–resorption is dependent upon the degree and/or E-mail address: [email protected] (K.A. Taylor).
stage of inflammatory activity within atheroma 0928-4680/$ – see front matter 2004 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pathophys.2004.06.001 B.S. Maniscalco, K.A. Taylor / Pathophysiology 11 (2004) 95–101 Mature atheromas contain pathological calcification de- positive CAC scores using Helical Computerized Tomogra- posits that increase at an annual rate of 24–82% phy or Electron Beam Computerized Tomography®. All pa- Quantification of coronary artery calcium (CAC) by com- tients provided written, informed consent and were enrolled puter tomography appears to be a better predictor of future in this prospective, open-label observational study, and were events than conventional risk factors Although calcific treated with comET. Study inclusion criteria included: medi- deposits are a hallmark of atherosclerosis, the mechanism cally co-operative stable patients with documented CAD and of calcium precipitation has remained enigmatic. Some re- positive CAC scores. Exclusion criteria included: (1) known searchers have suggested a relationship to the inflammatory tetracycline allergy; (2) zero CAC score; (3) recent (less than cascade Infectious burden theory has linked many bac- 30 days) major adverse cardiac event; (4) women of child- teria and virus to atherosclerosis but not with agents causing bearing age; (5) recent diagnosis of thyroid or parathyroid calcification in the host. Intriguingly, association of serum disease; (6) clinically significant renal insufficiency or liver antibodies to mycobacterial heat-shock protein 65 with CAC function abnormalities and (7) recent (less than 30 days) scores suggests a role for pathogen-triggered calcification acute congestive heart failure. The clinical protocol for this Although Mycobacteria are known inducers of calcifi- study was reviewed and approved by the Western Institu- cation in the host, they have not been found in the plaques, tional Review Board (WIRB-Seattle, WA) on 6 December and autoimmune reaction has been proposed as the cause for antibody formation. It remains to be elucidated what agent One patient withdrew secondary to a presumed sensitivity could trigger such antibodies in atherosclerotic patients.
to Tetracycline HCL. Twenty-two patients were withdrawn Infection by unconventional apatite-forming bacteria-like due to noncompliance.
nano-organisms, NB, is a novel theory for pathological calci- All patients in the study were maintained on their normal fication in general especially in CAD The medical regimen, but they were instructed to discontinue all latter role is supported by detection of nanobacteria (NB) or herbal or vitamin preparations. Baseline history and physical similar structures in atherosclerotic plaques n calcified examination were performed.
carotid arteries, aortic aneurysms and cardiac valves Furthermore, NB particles morphologically and functionally 2.1. Nanobiotic therapy resemble the calcifiable vesicles, capable of active calciumphosphate precipitation under suitable nutrient conditions, ComET is a proprietary prescription compound formu- previously isolated from atherosclerotic aorta lated to treat atherosclerotic plaque forming processes po- NB are nanometer-sized, ubiquitous, pleomorphic agents tentially related to nanobacterial infection. ComET is com- that adapt to extremes of environment. They have a novel posed of: (1) Nutraceutical Powder (Vitamin C, Vitamin B6, cell-wall structure and produce lipopolysaccharide (LPS) en- Niacin, Folic Acid, Selenium, EDTA, l-Arginine, l-Lysine, dotoxin biofilm The NB biofilm contains calcium ap- l-Ornithine, Bromelain, Trypsin, CoQ10, Grapeseed Ex- atite and prothrombin complex NB can be clinically tract, Hawthorn Berry, Papain) 5 cm3 taken orally every detected with specific culture and electron microscopy tech- evening; (2) tetracycline HCl 500 mg taken orally every niques and there exists a commercial ELISA test for evening; (3) ethylenediaminetetraacetic acid disodium salt nanobacteria antigen and serology (Nanobac Life Sciences, (EDTA-sequestrant) 1500 mg taken in a rectal suppository Inc., USA). Nanobacteria are sensitive in vitro to tetracycline base every evening. Study patients were instructed to com- and its action is increased by ethylenediaminetetraacetic acid ply with the following nightly dosing schedule: (1) mix the disodium salt (EDTA) dissolving NB apatitic protective coat nanobiotic powder into water or apple juice and consume Thus, combination of these drugs might offer a novel orally; (2) take the tetracycline HCl 500 mg capsule orally; treatment for calcific atherosclerotic disease. The present (3) insert 1 suppository rectally and (4) lie down flat and go trial treatment regimen also included oral powder contain- ing EDTA plus amino acids, vitamins and proteins to sup-port the EDTA–tetracycline therapy and to elicit beneficial 2.2. CAC scoring effects on known risk factors for heart disease.
The purposes of this investigation were: (1) to identify the The same CAC scoring machine was used for each indi- serological presence of NB in a cohort of patients with CAD; vidual patient to assess initial and final CAC scores. CAC (2) to evaluate possible changes in NB antigen and serology scoring radiologists were experienced in CAC scoring and during antinanobacterial (nanobiotic) comET therapy; and were blinded to patient identity. CAC scoring was repeated (3) to determine CAC score changes during the therapy.
after 4 months of comET therapy.
2.3. Laboratory analysis 2. Materials and methods
Study-patient blood specimen tubes were bar-coded and The treatment was applied on 100 patients presenting with laboratory analysis were performed at a core independent stable coronary atherosclerotic heart disease who showed clinical laboratory. The pathologist was blinded to patient B.S. Maniscalco, K.A. Taylor / Pathophysiology 11 (2004) 95–101 identity. The analysis included C-Reactive Protein (hs-CRP), Complete Blood Count (CBC), Metabolic Panel (CMP), Characteristics of the CAD study population Liver Functions Tests (LFT), Lipid Profile (LP), and NB Study participants ELISA antigen and NB IgG antibody serology (Nanobac Life Sciences, Inc., USA). NB serology was assessed atbaseline, 2 and 4 months.
2.4. Statistical analysis Data are presented as frequency and percentage distribu- tions. Values of continuous variables are expressed as mean± Age groups (years) standard deviation. Within group comparison of means for initial and ending CAC scores and laboratory values were conducted using a paired t-test. Between groups com- parison of continuous variables was accomplished with the Student's t-test. Univariate analysis of selected discrete vari- ables was accomplished by X2, the continuity X2 analysis or Coronary risk factors a two-tailed Fischer Exact test with the appropriate degrees of freedom. Statistical procedures were performed using the Diabetes mellitus Number Cruncher Statistical Systems® (NCSS, Kaysville, Peripheral vascular disease UT). A p-value of less than or equal to 0.05 was designated History of congestive heart failure as statistically significant in the present study.
Renal insufficiency (Creatinine >2.0 mg/dl) Previous myocardial infarction 3. Results
Previous cardiovascular intervention Prior coronary artery bypass grafting Prior percutaneous coronary intervention 3.1. CAC scores Current medications The clinical characteristics of the final sample (n = 77) are described in were 44 (57%) patients who responded to therapy as evidenced by a decrease in total CAC score. The remaining 33 patients (43%) were consid- ered non-responders only with reference to the CAC score parameter. Clinical variables for both groups are presented in These data reveal that both groups were com- parable with respect to pre-treatment clinical variables and a Numbers in parentheses are percentages.
risk factors. In a comparison of initial and endingCAC scores for responders is presented. Total CAC scoresdecreased significantly (P = 0.001). Significant reduction 3.3. Lipid profiles in left anterior descending and right coronary artery CACscores were also documented (P = 0.002). There was no Beneficial changes were noted in the patients' lipid pro- significant difference found in the left main (P = 0.972) or files as evidence by reduced total cholesterol levels (P circumflex coronary artery scores (P = 0.106).
= 0.001), reduced triglycerides (P = 0.006), decreased LDL(P = 0.001) and increased HDL (P = 0.001), see 3.2. NB antigen and antibodies 3.4. Angina pectoris All patients were found to be positive for the presence of anti-NB IgG antibodies prior to the commencement of ther- Prior to trial, 19 patients (25%) had stable angina pectoris.
apy During the course of therapy, NB antigen and At the conclusion of 4 months of therapy, angina symptoms serology titers tended to fluctuate, although changes were had been either substantially ameliorated or eliminated in not statistically significant, in all patients without regard to 16 of 19 patients (84%: P = 0.013). Two patients (3%) with changes in CAC scores or time-point of therapy, see severe claudication and faint pedal pulses reported near res- Initial and ending hs-CRP values were obtained in 19 pa- olution of symptoms with peripheral pulses returning to nor- tients. The values were relatively low, and they did not differ in the beginning and ending of therapy (0.54 ± 0.76 mg/l One patient (1%) was hospitalized with progressive versus 0.45 ± 0.71 mg/l, P = 0.674).
angina secondary to an in-stent restenosis. All patients with B.S. Maniscalco, K.A. Taylor / Pathophysiology 11 (2004) 95–101 Table 2Comparison of pre-treatment clinical variables and risk factors of study population in comET responder and nonresponder CAD patients Age groups (years) Coronary risk factors Diabetes mellitus Peripheral vascular disease History of congestive heart failure Renal insufficiency (Creatinine >2.0 mg/dL) Previous myocardial infarction) Previous cardiovascular intervention Prior coronary artery bypass grafting Prior percutaneous coronary intervention Current medications a Numbers in parentheses are percentages.
were minor side effects reported by the patients, such as Comparison of initial and ending scan CAC scores for comET responder gas and short-time diarrhea, and stomach pain during the Left main coronary artery This is the first study to combine antibiotic therapy with Left anterior descending EDTA administration for a long-term therapeutic interven- tion in CAD patients undergoing optimal current therapy.
Circumflex coronary artery The results were promising as every second CAD patient Right coronary artery showed an objective improvement in their cardiac vascu- a Numbers in parentheses are percentages.
lature. CAC scores reduced by an average of 14% in a 4months therapy trial. This is striking, because CAC scores compliance to treatment completed the protocol without are known to increase by more than 20% annually. There serious adverse complications. Moreover, there were no are no previous reports showing a significant decrease in other complications observed, e.g., non fatal myocardial CAC scores with any regimen found in literature. Thus, the infarction, cerebral vascular accident, in patient hospital- novel therapy brought a unique, dramatic drop in hallmark ization or death during the course of the study. There for coronary events.
B.S. Maniscalco, K.A. Taylor / Pathophysiology 11 (2004) 95–101 Table 4Comparison of nanobacteria antibody levels (units) and antigen levels (units) for comET responder CAD patients responders Beginning value mean ± S.D.
Two month value mean ± S.D.
Ending value mean ± S.D.
Nanobacteria antibody Beginning vs. 2 months Beginning vs. ending 2 months vs. ending Nanobacteria antigen Beginning vs. 2 months Beginning vs. ending 2 months vs. ending Since the two study groups, responders and non-res- during 4 month comET therapy. The therapy was reducing ponders, were comparable, it may be inferred that the vari- CAC scores in 44 patients (57%, P = 0.001). As the respon- ables of time, plaque density/volume, tissue penetration and ders had 14% reduction in their CAC scores it meant that blood supply may be critical factors that influence overall the therapy was not curing the calcifications in the 4 months outcomes. Based on these findings, CAC scores should period. Thus, it was unlikely that nanobacterial markers or continue to decrease in this cohort with a longer duration hs-CRP could have markedly changed. Longer curative treat- of therapy. This was documented by substantial decreases ments would be needed to evaluate the marker responses.
in CAC scores in both responders and non-responders who ComET therapy may influence atherosclerosis in several elected to continue comET therapy following the conclusion ways that are independent from its actions on NB. EDTA of the study (data not shown).
is chelating calcium, copper and iron, high blood and tissue Research with the pathogen NB, suggests that it can concentrations of which are suspected to promote atheroge- "trigger" atherogenesis, inflammation and thrombus forma- nesis through oxidative stress. EDTA chelates and removes tion The unique property of NB to utilize calcium via urine other poisonous heavy metals which may promote (Ca2+) and phosphate (PO4−) to fix a calcium apatite layer atherogenesis Interestingly, very high-dose (3 g per upon its cell membrane at physiologic pH and concentration day) oral EDTA or subcutaneous EDTA-magnesium therapy provides a viable explanation of the process of patholog- have been reported to reduce cholesterol content in hyperc- ical calcification within the atheroma. NB gain entry into holesterolemic rabbits Lipid modulating effects of cells by molecular mimicry and endocytosis to establish EDTA are also supported by the present findings: comET a life-long parasitic relationship NB endotoxin therapy improved blood lipid patterns in CAD patients even can cause acute inflammation and sustain chronic inflam- under statin therapy. Increased activity of matrix metallo- matory cascades. Through these processes it is suggested proteinases has been implicated in atherosclerosis in several that NB triggers inflammation resulting in deposition of ways. Metalloproteinase activity is dependent on zinc and fibro-lipid soft plaque and fibrous cap in addition to forming calcium ions Both tetracycline and EDTA inhibit ma- trix metalloproteinases. EDTA and tetracycline also inhibit In vitro studies have shown that EDTA decalcifies NB, oxidative enzymes and act as antioxidants, even reducing but only at a sustained concentration. Further, tetracycline experimental ischemic and reperfusion lesion sizes. EDTA HCl is cidal to NB at pharmacologically acceptable and ther- has strong inhibitory action on blood clotting. EDTA may apeutically achievable concentrations Based on these inhibit many calcium-mediated signaling pathways directly tenets, comET was formulated to be nanobacteriocidal.
or indirectly via changes in the concentration of extracellu- If NB is present in patients with CAD, one would expect lar ionized calcium affecting function of calcium channels to document serologic evidence of their presence. This study in cell membrane. One such target is immunological acti- documents the presence of NB in all patients. This study vation, another is smooth muscle contraction, both of im- could not, however, detect significant variation in serology portance, e.g., in coronary angina. All these action mecha-nisms could be pharmacologically important in atheroscle- rosis. Novel rectal administration of EDTA has been shown Comparison of beginning and ending cholesterol levels (mmol/l) for to result in high blood EDTA levels sustained for a long comET responder CAD patients time (Kajander et al., manuscript in preparation). Further- more, the contributory effects of the oral powder component mean ± S.D.
mean ± S.D.
should be evaluated. It contained several antioxidants, vita- Total cholesterol mins, amino acids among other agents. Thus, comET ther- apy is a multitargeted therapy focused on various aspects in atherogenesis. Further studies are needed to delineate its actions and targets.
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Comparison of Beginning and Ending Cholesterol Levels (mg/dl) for Responders Total Cholesterol

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