A4M IV TRAINING 10/12/19

HISTORY Lecture 2
Cases and Calculations EDTA
Atherosclerosis: Mechanisms
TACT
Metal: Mechanisms
TRIAL

EDTA Dorothy Merritt, MD

ATHERO‐ • ACAM CAP Co-CHAIR
SCLEROSIS
• TACT PI
• 30+ years IM experience

VASCULO 
TOXIC 
CASES METALS
EDTA 
 I HAVE NO CONFLICTS OF INTEREST OR
Treatment
FINANCIAL CONFLICTS - DFM MD
 Disclosure of Financial Relationships:
 None

 Off-Label Usage
 Yes, The nature of the unapproved or investigative
use is:
 EDTA and heart disease
1) Review ideal set up of infusion suite
2) Recall use of hood
3) Explain
new laws and regulations
coming/enforcement varies state to state
COCKCROFT-GAULT FORMULA

 EDTA dose = (50 mg/Kg) x (LBW) x (CrCl)/100 Max 3gms

 Adjust for females x 0.85
 Lean Body Weight Calculation:
 For males: 50.0 kg plus 2.3 kg for every inch over 5’
 For females: 45.5 kg plus 2.3 kg for every inch over 5’
 If actual weight is less than LBW? Use actual weight
Case 1:
 85 year old male
 Hx CABG x 2, T2DM
 Weight 218
 Height 6’5”
 Serum creatinine 2.1 mg/dL
Case 1: Calculation
 LBW: 50 kg + (2.3) x 17 = 50kg + 39 kg = 89 kg
 Actual weight 99 kg
 CrCl= (140 - 85) x (89)÷ (72 X 2.1)
 CrCl= 4895 ÷ 151.2 = 32.4 mg/min
 Dosage = 50mg/kg x 89 kg x 32.4/100 = 1440 mg. EDTA = 1.4 gms

Comment: His age would make me cut it by 50% until I saw stable creatinine after
5-6 treatments and I would check creatinine every other time and I would make
treatments every other week initially
What if Case 1 was a female
 LBW formula would use 45.5 instead of 50 mg/kg= 84.5kg
 Creatinine Clearance formula would be reduced by .85

 Dose would be 1.1 gm instead of 1.4 gm EDTA

 Creatinine Clearance would be 27 instead of 33 mg/min
Case 2:
 Age 59 female
 Hx mild renal disease, T2DM
 Weight 205
 Height 5’ 2”
 Serum creatinine 1.7 mg/dL
 Hypertensive, controlled with meds
Case 2: Calculation
 LBW 5’2” = 45.5 kg + (2.3 x 2) = 50.1 kg
 Actual Weight = 93kg
 CrCl= (140 - 59 ) x (50)÷ (72 X = 1.7) = 33 mg/min
 Dosing: (50 mg/kg x 50.1) x 33/100 = 826 mg. EDTA dose
over 3 hours
 .85(826mg) = 702 mg FEMALE CORRECTION

Comment: Don’t forget to take .85 x dose for females

Case 3
 75 year old female
 Non-alcoholic fatty liver stage 2-3 biopsy
 Hx CVD, whole blood lead 14.0
 Weight 130 lbs (59kg)
 Height 5’9” (BMI 19.0)
 Serum creatinine .8 mg/dL
 Case 3: Calculation
 LBW = 45.5 x 2.3 (9) = 45.5 + 20.7 = 66.2kg
 Actual weight: 59kg
 CrCl= (140-75) x (59)÷ (72 X .8 mg/dL) = 67 mg/min
 Dosing: (50 mg/kg x 59) x 67 CrCl/100 x .85 = 1680mg total
dose over 3 hours

Comment: LBW calculation is more than her actual weight: Use actual Kg
Pts with liver disease have renal insufficiency starting at .8 creatinine
.85 dose reduction in dose due to being female and I would suggest
further reduction in dose due to hepatic status and creatinine until
stable creatinine status proven
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• Healthy: NO adjustment
• Stage‐1: Multiply full dose by 0.75
• Stage‐2: Multiply full dose by 0.66
• Stage‐3: Multiply full dose by 0.50
• Stage‐4: Multiply full dose by 0.25

IF Chelation benefits outweigh risks
• Stage 5: Chelation contraindicated
 Calculation Example:
65 Kg 35 YO Male, healthy and “normal” eGFR
• EDTA Dose: 50 mg X 65 Kg = 3250 mg
• Max dose adjustment: 3000 mg  
• eGFR adjustment: NONE  
• Form of EDTA: Na2EDTA
• DMPS Dose: 2 mg X 65 Kg = 130 mg
• Max dose adjustment: NONE  
• eGFR adjustment: NONE
• Other adjustment considerations:
• NONE
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency:
EDTA Dose: 3000mg DMPS Dose: 130mg Admin Rate: Na2EDTA 1000mg/hr – DMPS  
25 mg/min. Test / First Dose: Na2EDTA 2000 mg / DMPS 75 mg Remin. Freq.: 1:3

© PS Anderson – www.ConsultDrA.com 2018

1
4

Calculation Example:
75 Kg 65 YO Female (frail appearing) with Stage‐3 CKD
• EDTA Dose: 50 mg X 75 Kg = 3750 mg
• Max dose adjustment: 3000 mg
• eGFR adjustment: (X 0.50) 1500 mg Merritt’s comments
• Form of EDTA: CaNa2EDTA EDTA 1000/hr max for Ca or
• DMPS Dose: 2 mg X Kg = 150 mg Na EDTA by published
• Max dose adjustment: NONE standards. However, faster
• eGFR adjustment: (x 0.50) 75 mg rates appear to be tolerated
• Other adjustment considerations:
• Frail:
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency:  EDTA 
Dose: 1500mg DMPS Dose: 75 mg Admin Rate: EDTA 2000 mg/hr
Test / First Dose: EDTA 500 mg / DMPS 50 mg Remin. Freq.: 1:2

© PS Anderson – www.ConsultDrA.com 2018

 Calculation Example:
100 Kg 70 YO Male with Stage 2 CHF and Stage 1 CKD
• EDTA Dose: 50 mg X 100 Kg = 5000 mg Merritt’s comments:
• Max dose adjustment: 3000 mg Max rate for EDTA Ca or Na
• eGFR adjustment: (X 0.75) 2250 mg
• Form of EDTA: CaNa2EDTA should be 1000mg/hour based
• DMPS Dose: 2 mg X 100 Kg = 200 mg on original studies. However,
• Max dose adjustment: NONE faster rates are tolerated but
• eGFR adjustment: (X 0.75) 150 mg space them out and check Cr
• Other adjustment considerations:
• Elderly / CHF:
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency:
EDTA Dose: 2250 mg DMPS Dose: 150 mg Admin Rate: 2000 mg/hr Test / First Dose:  
EDTA 1000 mg / DMPS 100 mg Remin. Freq.: 2 Nutrient IV’s PRIOR to first chelation,  
then 1:2 [remin:chelation] until tolerance is known

© PS Anderson – www.ConsultDrA.com 2018 130

1
6

Calculation Example:
Healthy 90 Kg 32 YO Male, excellent health (In addition to Pb, Cd, Hg  
elevations he has very high Al).
• EDTA Dose: 50 mg X 90 Kg = 4500 mg
• Max dose adjustment: 3000 mg  
• eGFR adjustment: NONE  
• Form of EDTA: CaNa2EDTA
• DMPS Dose: 2 mg X 90 Kg 180 mg  
• Max dose adjustment: NONE  
• eGFR adjustment: NONE
• Other adjustment considerations: ALUMINUM
Final Dose, Admin. Rate, Test / First Dose, Remin. Frequency: 
EDTA Dose: 3000 mg DMPS Dose: 200 mg Admin Rate: EDTA 2000 mg/hr First
Dose: both at 50% Remin. 1:3 AND: add Magnesium Malate 850 mg PO BID

© PS Anderson – www.ConsultDrA.com 2018

IV EDTA FOR PROFESSIONALS 

A Workbook For The 
Administration Of IV EDTA In An 
Outpatient Setting 

Mixing alternatives, osmolarity, 
dose calculations, example cases
 OSMOLARITY WORKSHEET FOR EDTA CHELATION AND VARIOUS IVS

KEEP mOsm/l less than 1000 and greater than 330 for best results
Medication mOSM/cc Amount(cc) Total mOsm

EDTA 150mg/cc‐DOSE BY CC = 1.34 20 26.8

Vit C (500mg/cc) 7gm 5.8 14 92.8 36.70%
Vit B12 (1000mcg/cc) 0.31 1 0.31
B‐comp (100mg/cc) 2.14 2 4.28
Sodium Bicarb (8.4%) 1.79 20 35.8
*Hep(5000u/cc) optional 0.46 0.5 0.23
*Lidocaine 2% optional 0.15 10 1.5
Mgcl(200mg/cc) 2.95 10 29.5
Pantothene( 250mg/cc) 0.85 1 0.85
Pyridoxine (100mg/cc) 1.11 1 1.11
KCL ( 2meq/cc) 4 1 4

additives cc 65.5
mOsm additives with 7gms Vit C 188.05
mOsm additives with 2gms Vit C 118.45
 Total IV mOsm/l
IV Sizes  Tot IVcc mOsm/l 7gm C 2 gm C
1 Sterile water 500cc 0 500 565.5 0 332 209
2 NS 250cc 0.602 250 315.5 150.5 1072 852
3 NS 500cc 0.602 500 565.5 301 978 741
4 1/2NS 250cc 0.465 250 315.5 116.25 964 743
5 1/2 NS 500cc 0.465 500 565.5 232.5 744 621
6 RL 500cc 0.569 500 565.5 284.5 945 712
7 D5W 250cc 0.569 250 315.5 142.25 1047 826
8 D5W 500cc 0.569 500 565.5 284.5 835 712

Other Meds

EDTA Calcium  300mg/cc x 10cc 2.39 10 23.9

Glutathione 200mg/cc 2.16 1 2.16

Keep mOsm under 1000 and above 330
Remove all but 2gms  Vit C if needing to reduce osmolarity due to IV shortages 
NUTRITIONAL SUPPORT TO SUPPORT LEAD TOXICITY
MY OFFICE SET UP
 MY OFFICE SET UP

To‐Go balls          Trochar for Vit C
W.A. Shrader, Jr., MD
Santa Fe Center for Allergy
& Environmental Medicine
EQUIPMENT NEEDED
Safety Catheter Needle
Tourniquet
Alcohol Swab
Gloves
Gauze
IV Tubing
Paper Tape
IV Bag and IV Pole
AirClean Hood
 Laminate and use one of the tact trial slides that compares 
EDTA to usual medical treatment and put on your exam room 
walls or display areas
 Use the lead slides to show 18% of people who die per year 
die of lead (NHANES 2018) or 412K people in US; Emphasize 
the fact that US CV death rate dropped 32% in the decade 
after lead taken out of cars but its still in their bones
 Draw BLL in all people yearly after age 50 
 Prevent bone turnover now
 Set up an account with a national lab such as Genova, Doctors 
Data or similar lab for urine metal testing
 Set up an account a 501B compounding lab for iv materials
 Set up account to get your IV s and to go balls
 Buy a hood 
 Find out your state requirements for compounding and 
enforcement
 Find out your labs lower limit of lead: quest 3, Lab corp 1
 Print off the HnP and consent forms‐very important
 HISTORY
Atherosclerosis

TACT
TRIAL

EDTA
ATHEROSCLEROSIS

VASCULO 
TOXIC 
METALS

CASES
EDTA 
 I HAVE NO CONFLICTS OF INTEREST OR
Treatment
FINANCIAL CONFLICTS - DFM MD
 Atherosclerosis Learning Objectives
 #1 cause of mortality in world is CV
 low level lead exposure in 1988 causes 
412,000 deaths/year now (NHANES 2018) 

ATHERO‐  Reduction of exposure to Pb and Cd has 
reduced CV mortality by 32% from late 80’s 
SCLEROSIS to late 90’s. Total reduced CV mortality  was 
43% from reduction of exposures to metals
 EDTA reverses many pathways in the 
formation of atherogenic plaque and 
removes lead and other heavy metal ions 
 ATHEROSCLEROSIS 2018

 CV is the leading cause of death worldwide

 Kills 3x more people than cancer
 In US, 2400 deaths per day from CV disease - one
every 37 seconds, 800,000 deaths per year (1/3)
 In US, someone has a MI every 25 sec and every
minute someone dies of one.
 In 2010, cost of heart disease was 316.4 BILLION $
 In 2018, Lead Exposure proven to be major
causative agent
 DIRECT COSTS OF THE 10 LEADING DIAGNOSTIC GROUPS
(United States: 2010)

Cardiovascular 390-459 324.1

Digestive System 520-579 225.2

Mental 290-319 177.7

Nervous System 320-389 175.4

Injury and Poisoning 800-999 172.9

Respiratory System 460-519 159.1

Musculoskeletal system 710-739 126.1

Neoplasms 140-239 102.7

Genitourinary System 580-629 93.8

Endocrine System 240-279 87.4

(Billions of dollars)
0.0 50.0 100.0 150.0 200.0 250.0 300.0 350.0

Source: NHLBI.
 AT WHAT AGE SHOULD WE SCREEN AND TREAT TO 
PREVENT MORBIDITY AND MORTALITY?

40 36.7
Percent of Population
35
30 25.1
25 22.7
20 16.6
15
10 7.0 7.0
5 0.7 0.7
0
20-39 40-59 60-79 80+

Men Women

Prevalence of CHD is 7x  Prevalence of CHD by age and sex Prevalence of CHD is 3x 

more at 40‐60 than at  (NHANES :2003-2006). Source:  more at 60‐70 than 50‐
20‐39 years of age NCHS and NHLBI. 60 years of age
NOV 2014 EDTA STUDY ON PHYSIOLOGICAL MARKERS
Physiological Markers For Vascular Disease Are Important In Determining Who May Need To Be 
Treated Rather Than Just Blood Lead Levels
Results: 25 treatments  Pulse Wave Velocity 6.8 HR in top
Group A:
tertile for all cause mortality
 PWV improved: went from iv to iii risk  Aortic PWV increases by 1 SD
group
increases mortality by 47%
 Central BP improved from 146.3 to 133.9
 Aix improved from 31.2 to 12.2  PWV > 12 correlates with 50%
Group B: blockage
 PWV improved; went from 11.2 to 8.4  Central pressure relates more
(normalized)
strongly than BP
 Central BP improved from 148.3 to 129.8
 Aix improved from 21.6 to 4.4% (iv to iii  Augmented aortic index (Aix)-
risk category) assessment of endothelial function
ENVIRONMENTAL CARDIOLOGY
ENVIRONMENTAL TOXICANTS ASSOCIATED WITH CARDIOVASCULAR DISEASE

 Lead  Ozone
 Arsenic  Aldehydes
 Mercury  Carbon Monoxide 
 Cadmium  Particulate matter

Environ Health Perspect. 2004 Nov; 112 (15):A880-7. Environmental

Cardiology: Getting to the Heart of the Matter. Wenhold B.

150,000 CV deaths in US yearly from air pollution

7 million deaths globally from air pollution
 ENVIRONMENTAL CARDIOLOGY

 Metals: lead, cadmium, mercury, arsenic,   Long‐term exposure to fine particulate matter 
cobalt, thallium, tungsten. less than 2∙5 μm in diameter (PM2∙5) and traffic‐
related air pollutant concentrations are 
 Air pollutants: DEP (diesel exhaust particles), 
associated with CV risk
ozone, particulate matter (PM <2.5), solvents
 For each 5 μg PM 2∙5/m(3) increase, coronary 
 Women’s Health Initiative: 76% increase in risk 
calcium progressed by 4∙1 Agatston units per 
with each increase of 10 μg per cubic meter in 
year (95% CI 1∙4‐6∙8) and for each 40 ppb NOX 
long‐term PM 2.5 exposure — accounting for 
coronary calcium progressed by 4∙8 Agatston
subjects in approximately the 10th to 90th 
units per year (0∙9‐8∙7) 
percentiles for exposure. 
 Pollutant exposures were not associated with 
intima‐media thickness change
J Med Toxicol. 2012 Jun;8(2):166‐75./J Thorac Dis. 2016 
Jan; 8(1): E8–E19./N Engl J Med 2007; 356:447‐458
Kaufman JD, et al. Lancet. 2016.
Lead in soil
 The review identified 37 unique studies comprising 348 259 
non‐overlapping participants, with 13 033 coronary heart 
disease, 4205 stroke, and 15 274 cardiovascular disease 
outcomes in aggregate

Exposure to arsenic, lead, cadmium, and copper is associated 
with an increased risk of cardiovascular disease and coronary 
heart disease. Mercury is not associated with cardiovascular 
risk.

NHANES surveys document a marked reduction in population 
exposure to lead and cadmium largely reflecting large scale 
public health policies on the control of tobacco, reduction of 
air pollution, remediation of hazardous waste, renovation of 
drinking water infrastructures, and banning of lead in gasoline

Concomitant with these reductions, cardiovascular mortality 
rates in the US decreased by 43% from 1988‐94 to 1999‐
2004. An analysis that accounted for traditional 
cardiovascular disease risk factors, showed that 32% of this 
reduction in cardiovascular mortality could be explained by 
the decline in lead and cadmium exposures.
BMJ 2018;362:k3310
Int J Epidemiol. 2017 Dec 1;46(6):1903-1912
 CORONARY RISK FACTORS

Non-modifiable risks Modifiable metabolic risks Metabolic toxins

Male sex High LDL(ox) Homocysteine
Advancing age Low HDL Smoking
High Trigs. Trans-Fats
Inflammation Iron & Heavy Metals
Th1/Th17 Dysregulation Elevated Lipoprotein(a) Oxidative Stress
Sleep Apnea Organic Pollutants
Chronic infection Endothelial Dysfunction Air Pollution
Insulin Insensitivity
Deficiency states
Spiritual risk factors Autonomic Dysfunction Anti-oxidant vitamins
Chronic Stress Anti-oxidant minerals
Lack of Social Connectedness Elevated Viscosity EFAs  3 & 6
Lack of Belief Bioflavonoids
Hormone Deficiency Vitamin K2 and D
Bioenergetic deficiency Methyl Donors
Co-Enzyme Q10 Hypertension
Carnitine Overweight Genomic Defects
Magnesium Diabetes Methyl Cycle
www.heartfixer.com
 ALLOPATHIC TREATMENT

Statins (high dose)

 Co-Q depletion → ATP deficiency → Diastolic dysfunction
 Testosterone deficiency → Th1/Th17 Immune dysregualtion Plaque regression proven
 Erectile dysfunction
ACEI/ARB
 Hyperkalemia (manageable)
-Blockers
 Co-Q depletion
 Impaired conditioning
 Weight gain
 Depression
 Erectile dysfunction
ASA and Platelet inhibitors
Healthful diet and adequate sleep and exercise
No role for nutritional supplements
 RELATIVE RISK REDUCTION OF CURRENT THERAPIES

 Aspirin: 25%  (Anti‐platelet Trialists’ Collaboration. BMJ 1994;308:81‐106 Level A)   (NNT 25‐50 2 years)
 Beta‐Blocker: 23%  (Capricorn Investigators Lancet 2001 Level A)    (NNT 42 2 years)
 Statin: 21%  4S Trial Level A  (NNT 33‐65  2 years)
 ACE‐ Inhibitor: 19% SAVE trial Level A  (NNT 28 ‐> 200)
 Chelation/Vitamins: 26% trial level A

 EDTA in Diabetics‐ 41% (ALL), 51% (MI), 43% (Death)  Level A 
Number RR Death p value
IV EDTA+ Vits in Post MI
Beta blocker during MI 28,970 .87 (.77-.98) 0.02
• 26% reduction in endpoints NNT 12
Beta blocker post MI 24,298 .77 (.70-.84) <0.001
ACEI during MI 100,963 .94 (.89-.98) 0.006
ACEI post MI if LV dysfxn 5,986 .78 (.70-.86) <0.001 IV EDTA IN DIABETICS POST MI
Nitrates during MI 81,908 .94 (.90-.99) 0.03 • 43% reduction in death NNT 7
Ca++ blockers 20,342 1.04 (.95-1.14) 0.41 • 41% reduction in cv endpoint NNT 12
Magnesium 61,860 1.02 (.96-1.08) >0.05
Lidocaine 9,155 1.38 (.98-1.95) >0.05 IV EDTA IN DIABETICS POST MI with high dose vitamins
Class I Antiarrhythmics 6,300 1.21 (1.01-1.44) 0.04 • Primary endpoint reduction NNT 6
 PLAQUE RUPTURE  AUTONOMOUS IMMUNE TSUNAMI
“Tsunami” of Inflammation, thrombosis,
and vasoconstriction effects after the
“Earthquake”(rupture)
 Endothelial lining thins, retracts, allows migration 
of LDL, foam cells exposed
 Macrophage foam cells interact with platelets
 Fibrous lesion results
 Grows to mature atherosclerotic lesion
 Plaque with fibrous cap
 “Vulnerable” plaque ruptures leading to 
thrombosis
 68% of MI: < 50% Stenosis
 14% of MI: < Significant Stenosis
 62% of men – 1st symptom of CHD is MI
 46% of women – 1st symptom of CHD is MI
 STATIN REGRESSION DATA

Banach et al, BMC Med, (2015) 13: 229

CALCIUM AND REMODELING
 “KETO DIET” AND COACHING   
Cardiovascular disease risk factor responses to a 
type 2 diabetes care model including nutritional 
ketosis induced by sustained carbohydrate 
restriction at 1 year: an open label, non‐
randomized, controlled study

22 of 26 cardiometabolic risk biomarkers 
showed statistical improvement in the 
“treatment” group compared to 0/26 in the 
usual care group at one year

Cardiovascular Diabetology2018 17:56  Bhanpuri et al
INTEREST IN THE KETOGENIC DIET GROWS FOR 
WEIGHT LOSS AND TYPE 2 DIABETES

First of 5 Studies over the next few years will start

Summer of 2018 in Framingham, Mass to study
cardiometabolic changes and weight loss
associated with Keto diet.

The ketogenic diet was introduced in 19241 after two years of 
clinical trial. Wilder,2 in 1921, on the basis of Geyelin's3 results 
with starvation, suggested that diets in which the proportion of 
carbohydrate and protein was sufficiently restricted might offer a 
method of treatment of epilepsy.   JAMA 1928;90(18):1427‐29

JAMA. 2018;319(3):215‐217. doi:10.1001/jama.2017.20639
 ROBERT FURCHGOTT, LOUIS IGNARRO AND FERID MURAD

SHARED NOBEL PRIZE IN MEDICINE IN 1998 FOR DISCOVERIES PROVING 
NITRIC OXIDE AS A SIGNALING MOLECULE IN THE CV SYSTEMS 

Robert Furchgott Louis Ignarro Ferid Murad

 REDUCED NO AVAILABILITY IS A HALLMARK OF 
MANY  CARDIOVASCULAR DISORDERS
Endothelial NO function loss associated with 
atherosclerosis
(Davignon & Ganz 2004)

Defects in endothelial NO function associated with all 
major CV risk factors & has predictive value for disease 
progression
(Schachinger, Britten et al. 2000; Halcox, Schenke et al. 2002; Bugiardini,
Manfrini et al. 2004; Lerman and Zeiher 2005 )
 NITRIC OXIDE MECHANISMS AND LEAD

Human NO and Lead Levels in Blood

We found a negative correlation 
between plasma nitrite and B‐Pb
concentrations  suggesting increased 
inhibition of NO formation with 
increasing B‐Pb or P‐Pb
concentrations. 
Clinical evidence for lead‐induced inhibition of nitric oxide 
formation, Fernando Barbosa, Jonas T. C. Sertorio, Raquel 
F. Gerlach and Jose E. Tanus‐Santos, Arch Toxicol (2006) 
80:811‐816
CA EDTA PROTECTS VIA NO PATHWAY

Foglieni et al BMC Nephrol 2006 Mar 15;7:5

 HYPERTENSION DUE TO LEAD EXPOSURE

 Oxidative stress
 Nitric Oxide inactivation
 Changes in B receptor
density
 Endocrine Disruption
 Renal impairment-Prox
Tubular dysfx
 Lipid Peroxidation

Anna Skoczynska1 and Marta Skoczynska1

[1] Wroclaw Medical University, Poland

 METAL‐INDUCED ATHEROGENIC MECHANISM
Redox‐active metals

↑ produc on of ROS

NF‐B activation  Inflammation  Decreased NO, ↑ ONOO‐

Endothelial injury
Chemokines Vascular remodeling Vasoconstriction
Monocyte adhesion Platelet activation      Na retention
LDL oxidation ↓ TPAI  Adrenergic activity
Foam cell formation
Hypertension
Atherosclerosis
Thrombosis
Am J Physiol Hrt Circ Physiol(2008)295:H454‐H465
 NITRIC OXIDE‐SUMMARY

 Lead and other heavy metals reduce NO

 EDTA independent of removing lead, increased NO, 
and eNOS and has other anti‐inflammatory, anti‐
atherogenic properties
 DMSA increases GFR in high via NO and low dose lead 
exposed rats, but does not fix pathological lesions in 
kidney
 Farhad Khalil‐Manesh, Harvey C. Gonick, Arthur Cohen, Enrico Bergamaschi, Antonio Mutti Experimental model of lead nephropathy: II. Effect of removal from 
lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA)  Environmental Research  Volume 58, Issues 1–2, Pages 35‐54 (June–August 1992)
 NITRIC OXIDE
NOS III

NO
Inhibition of
- -
- -
Oxidation of Smooth muscle Expression of Endothelin
LDL-cholesterol proliferation adhesion molecules production

Platelet Smooth muscle Monocyte and

aggregation contraction platelet adhesion

Anti-atherosclerotic properties of nitric oxide produced by the vascular endothelium

Vascular Biology in Clinical Practice, Oct. 2000; Mark C. Houston, MD

 GLUTATHIONE PEROXIDASE AND CHD

 Increased Glutathione Peroxidase (GSH-Px) lowers BP, reduces MI, LVH and CHF.

 GSH-Px confers more cell, tissue and organ protection than SOD or catalase, or the
combination of both.

 5 GSH-Px (#1-#4 are selenium-dependent, #5 is not) is located in mitochondria and

cytosol, which neutralize lipid peroxides and hydrogen peroxide, preventing formation of
hydroxyl radical and other ROS. GSH-Px has greater affinity for hydrogen peroxide than
catalase.

 Highest quartile of RBC GSH-Px had 71% lower risk of MI compared

to lowest quartile (p<.001). GSH-Px is major CHD risk factor.

Circulation 2004; 109:544-549/ NEJM 2003; 349:1605-13./Coronary Artery Disease 2003; 14:149-153).
GSH STATUS AND OXIDATIVE STRESS
59 YO WM, heavy smoker‐ hypertension, and elevated 
levels of blood lead and cadmium

1,000 - 2,000 µmoles/L

RBC GSH

8‐OH‐dG*

Oxidized LDL < 45 U/L

*(8‐hydroxy‐2’‐deoxyguanosine)
* First AM urine collection
 Dorothy Merritt, MD
LEAD
Vasculotoxic Metals 1

ARSENIC

GADOLINIUM
VASCULO
TOXIC 
MERCURY

IRON
METALS
CADMIUM
PLATINUM

CHROMIUM THALLIUM  I HAVE NO CONFLICTS OF INTEREST OR

FINANCIAL CONFLICTS - DFM MD
 Learning Objectives for Vasculotoxic Metals
 Know the sources of common vasculotoxic metals such as lead, cadmium, arsenic,
mercury, cobalt, iron and gadolinium and how to avoid them
 Know the metabolic factors involved in excreting metals, including genetic, and
methylation factors
 Be able to identify clinical patients in your practice that have heavy exposures to
metals due to work, or hobby related activities
 Be able to recommend other interventions for metal exposure
 SCOPE OF THE PROBLEM

84,000 chemicals unleashed on environment over the past 70 years

Pesticides doubled between 1964-1982 (USDA)
2000-3000 new chemicals per year

Environ Health Perspect; DOI:10.1289/ehp.0800404

CONSEQUENCES OF CHEMICAL EXPOSURE

Cancers 2013, 5(1), 184-204; doi:10.3390/cancers5010184

90% REDUCTION IN CANCER MORTALITY
AFTER CHELATION THERAPY WITH EDTA

• 231 adults living in a small industrial Swiss town near a major highway were
followed for 18 years (1959-1976)
• 59 adults received 10+ IV Calcium EDTA in starting in late1958
• 1/59 EDTA patients 1.7% died of cancer during the 18 years
• 30/172 control patients(17.4%) died of cancer during the 18 years

The two groups did not differ in smokers, age, exposure to highway, male/female
ratio or income

Blumer, Walter MD, Cranton, Elmer, MD J Adv Med, 1989

 TOXICOLOGY OF METALS
BASIC TOXICOLOGY

ATSDR/CDC Tox Profile for Lead (2007 update)

Mutation Res(2003) 544:235
Am J Clin Nutr (2009)89:425-30
 Net Retention of Metals

• “Low‐level exposures are associated with long‐term effects
not previously recognized” (NIEHS)
• Knowledge of adverse effects are based primarily on  independent studies 
of a single toxicant (C.D.C)
• Metals can elicit independent, additive or synergistic toxic
effects (C.D.C.)
• MRLs for exposures have not considered that humans  bioaccumulate 
metals (C.D.C.)
 Lead and Cadmium are Synergistic
1+1>2

• Environmental cadmium and lead exposures are widespread, and both metals are
nephrotoxic at high exposure levels
• 14,778 adults with mean blood Cd levels of 0.41 microg/L and lead levels of 1.58
microg/dL in study

• RESULTS : the odds ratios for albuminuria, reduced GFR, and both albuminuria and reduced eGFR were
1.92 , 1.32 and 2.91 respectively, comparing the highest with the lowest blood cadmium quartiles.
• The odds ratios comparing participants in the highest with the lowest quartiles of both cadmium and lead were
2.34, 1.98 and 4.10 for both outcomes.

These findings support consideration of cadmium and lead as

chronic kidney disease risk factors in the general population and
provide novel evidence of risk with environmental exposure to
both metals.
PMID: 19700501 PMCID: PMC2781739

National Health and Nutrition Survey 1999-2006

 METABOLIC INHIBITING EFFECTS OF METALS AND
GENETIC SNPS THAT PREDISPOSE TO TOXICITY
Metals act like the “hairball” in the drain by inhibiting many initial reactions, many of which may already be 
compromised by genetic snps

Inhibition of Phase I and Phase II  PHASE II GLUTATHIONE GENE SNPS

Pb,Hg,As,Cd,Co,Cr6 glyphosate, 0 antigen on P aero and K pneu  GSTP1 33% have SNP Extracellular: Eczema, asthma, sinusitis IBS
inhibit metabolism and increase toxicity of xenobiotic or drug
 GSTM1 9% have SNP Intracellular: Cancer

 GSTM3 16% have SNP Brain: Dementia

 PHASE II METHYLATION GENE SNPS

 MTR (Methionine Synthase)- 15% have SNP mutation

 Regenerates methionine from homocysteine; Requires MTHF* and MB12

 MTRR (Methionine Synthase Reductase)

PHASE II NAT 2 Enzyme inhibition  Regenerates MB12 for MTR-50% have SNP mutation MTHF, MB12, MET

Cd, As, Pb, Hg inhibit NAT2 (cancer risk)  ACHY (Adenosylhomocysteinase)

NAT2 SNP 53% of population, Homozygotes typically
Chemically avoidant  Converts AH into adenosine and homocysteine Glutathione, NAC
 METHYLATION AND LEAD

23&Me ($199 on line) provides the Methylation SNPS and Phase I

and II genes (Plus 1000 total) that can be downloaded into reports
SNPS TESTING FOR PHASE I AND II METABOLISM
 PHASE III DETOX AND GENOMICS
ATP DEPENDENT TRANSPORTERS CROSS LIPID MEMBRANES FOR EXPORT 
INTO URINE AND BILE VIA MERCAPTURIC ACIDS

Detoxification of Reactive Molecules

Free Radicals: SOD2, SOD3 (Needs Cu, Zn, Mn)
Peroxides: GPX3 5% SNP, Support with glutathione, Se
Take caution with ozone and IV Vit C
Proinflammatory Immune: STAT4,TNF, CTLA4
These SNPS increase autoimmunity and oxidative burden
Treatment includes low dose naltrexone(LDN), bioidentical
hormones, cannabidiol oil(CBD), cryotherapy, alkalinization

Bottomline: Metals further inhibit metabolic enzymes that are already at risk due to SNPs in the population
7+ 7+ 7+ 
Heavy metal pollution still represents a primary concern regarding human health.
Recently, it become evident that the contribution of heavy metals extends far
beyond their accepted role in allergic diseases, and that they may play a more
extensive role in a variety of other diseases. Several lines of evidence indicate that
heavy metals have a key role in the induction or exacerbation of several
autoimmune diseases (AD).

Moreover, the association between exposure to heavy metals and the signs of
autoimmunity are supported by some studies. The mechanisms by which heavy
metals induce the development of AD are not yet fully understood. Our objective
here is to highlight the association of exposure to some heavy metals and AD. In
addition, we present recent results showing the possible alterations in Th1/Th2
reactivity by some heavy metals, which may constitute the trigger for the
incidence of autoimmunity in susceptible individuals.

Ann. N.Y. Acad. Sci. 1109: 129–137 (2007). C 2007 New

York Academy of Sciences. doi: 10.1196/annals.1398.015
WALK AWAY POINTS FOR METALS AND CV DISEASE
 Excess metals act like a “hairball” in the drain: They block phase I, 
II and III metabolism, CYP metabolism, inflammatory pathways, 
cause oxidized LDL, AGES and ALES,  and reduce Glutathione, 
Nitric Oxide, and cause DNA damage
 Metals are major blockers in the methylation cycles
 Bioaccumulation of metals adds to the toxicity as well
 Synergistic effects such as cadmium and lead on renal disease
 34% reduction in cardiac mortality in the last decade due to 
reduction of exposure to lead and cadmium
 High risk for lead due to age, family hx and exposure: 
Construction work history, Family hx, born before 1980
 Vascular disease functionally disappeared as lead burden 
went down 
 His disease would not have been discovered if he had not 
been looking for asymptomatic vascular disease and 
persistent in his request for a stress test 
 50 year old asymptomatic man 
 Extremely positive family hx CAD
 Stress test positive, cath showed 50% LAD lesion and 
narrow distal vessel
 Presented to me wanting NaEDTA
 Presented to his cardiologist for a repeat stress test 
after doing 50 treatments of Na EDTA in a year.
 8.6ug, 5.98 ug, and .285 ug lead in serial, post treatment  6 
hour collections at the beginning, and after 15 and 50 
NaEDTA txs.
 Cardiologist put him on 20mg statin, asa, ace inhibitor

 Initial Nuclear stress test POSITIVE

 Final Nuclear stress test NEGATIVE

PERSONAL CASE FROM MY PRACTICE
Results of Serial Urine Lead
(result x urine concentration of cr x volume and move
decimal point back 5 spaces)

10 x 46 x 1300 = 598000 = 5.98 ug total lead in collection

 57 yo obese WF, nonsmoker, APO ¾, Neg 23&Me for CV genes, Chol 160, 
Double MTHFR heterozygous, extreme stress x 1 years, low risk by 
Framingham, Fhx in smoking males , cath 20 yrs ago‐neg lesions but early 
diasolic dysfx
 Last 30 years lives in extremely polluted petrochem area: high particulate 
matter, lead exposure in childhood, solvent exposure but low on testing due to 
high NAC usage
 Noncompliant with HTN Rx and diet ,had 15 chelations 8 years ago for BLL 2,  
born in 1958 in high lead risk exposure period, extreme work stress ; 
Case 2: Predicted CAD with Multiple Environmental Exposures: Lead, AQI, Stress
2010  SVR 1400  AI  1.34 DDI  .17 ESI  low
2011 SVR 1337 AI  1.30 DDI  .25 ESI  high
2012 SVR 1383   AI  1.30 DDI  .30 ESI  high
2013 SVR  1010  AI     .9   DDI  .25 ESI  low
2014 SVR  1210  AI  1.28  DDI .25  ESI  low
2015 SVR  990    AI     .9   DDI .25 ESI VERY HIGH
2016 STEMI  Jan 6th  2 inch clot in LAD
2016  SVR 1053  AI     .9   DDI  .25  ESI  Borderline

Jan 6, 2016 AMI EKG
Post STEMI‐ 100% compliant with lifestyle and Rxs
s/p 2 EDTA per week post MI, BLL <1
In 1 month, essentially normal parameters.EKG
almost back to normal, BLL<1
What Environmental Factors Could be Involved
• Lives in one of the top 10 cities for poor AQI : aldehydes, ozone, PM<2.5 high 
• Extreme emotional stress due to employment changes; hostile work environment for 
over a year prior to change
• Grew up in a high lead period and has high lead bone by exposure hx

What Environmental Factors Increase Viscosity
Abnormal Plasma Volume Without Compensation
There are at least four conditions in which hyperviscosity is caused by hemoconcentration: primary 
hypertension, secondary hypertension caused by alcoholism, cigarette smoking,4 and dehydration. In these 
conditions, hematocrit is elevated because of normal or increased red cell mass and decreased plasma 
volume. In primary hypertension, plasma volume is appropriately decreased, but red cell mass is not 
proportionately decreased for unknown reasons. Hence, hematocrit and blood viscosity are increased, resulting 
in hypertension. Ethanol reduces secretion of antidiuretic hormone, resulting in water loss and contraction of 
plasma volume. Conditions which are associated with hypertension, such as cigarette smoking, obesity, 
diabetes mellitus, and metabolic syndrome are also associated with hyperviscosity and activate the 
homeostatic pathway to control blood viscosity. In those who are predisposed to partial failure of this 
pathway, the result is hypertension.
 8/9/13   right carotid bulb stenosis 55%  left carotic bulb 75% stenosis
 3/28/17  right carotid bulb stenosis 40% , left 50‐60% stenosis
 3/22/18  right carotid bulb <15%,  left carotid bulb  <15% stenosis
 7/26/18 Calcium scoring heart:  LAD 65.57 

4/19/17  Came in for EDTA consult. BLL 4 hx cataracts, osteopenia  Had been using 
RRY, Nattokinase and homeopathic treatments  A1c 5.8  Chol 211, ldl 116, ldl
particle 1500, hdl 73, crp 2, T3 elevated(on armour) 13/30 pos on lead HnP ROS , 
43ug/lead on 24 hour challenged urine, and elevated Cadmium too.  
 Changed to Levothyroid and Cytomel to avoid high T3 
associated with Pork thyroid
 Started on weekly IV Ca EDTA
 BLL < 1 after 20 treatments
 3/22/18  right carotid bulb <15%,  left carotid bulb  <15% 
stenosis
 7/26/18 Calcium scoring heart:  LAD 65.57 
 Patient electing to continue monthly treatments for 
maintenence