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© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 1
Arginine Cardio:
The intelligent way of combining the best that nature offers for the protection of your heart and blood vessels.
The complete formula to
Enhance nitric oxide
Reduce inflammation
Fight oxidative stress
Strengthen the heart‘s contractile force
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 2
About 600,000 people die of heart disease in the United States every year – that’s 1 in every 4 deaths.
Heart disease is the leading cause of death for both men and women.
More than half of the deaths due to heart disease in 2009 were in men.
Coronary heart disease is the most common type of heart disease, killing nearly 380,000 people annually.
Every year about 720,000 Americans have a heart attack. Of these, 515,000 are a first heart attack and 205,000 happen in people who have already had a heart attack.
Coronary heart disease alone costs the United States $108.9 billion each year.
The Art of Staying Healthy
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 3
The Scope of the Problem
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 4
Early Action is Key
About 47% of sudden cardiac deaths occur outside a hospital. This suggests that many people with heart disease don't act on early warning signs.
Americans at Risk
High blood pressure, high LDL cholesterol, and smoking are key risk factors for heart disease. About half of Americans (49%) have at least one of these three risk factors.
Protect Your Heart
Lowering you blood pressure and cholesterol will reduce your risk of dying of heart disease. Eat a healthy diet. Take a brisk 10-minute walk, 3 times a day, 5 days a week. Don’t smoke. If you smoke, quit as soon as possible.
What the CDC Promotes
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 5
Mortality of acute heart attack drops, … butoverall numbers of heart disease are constant
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm Source: CDC/NCHS, Health, United States, 2012
http://www.cdc.gov/nchs/data/hus/hus12.pdf
Heart disease death rates fall - but the number of diseased people is stable
or
Cardiology is good at treatment - but falls short in prevention.
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 6
The Scope of the Problem: Hypertension
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 7
The Scope of the Problem: Heart Failure
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 8
What Can Be Done
Source: Centers for Disease Control 2014www.cdc.gov/heartdisease/facts.htm
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 9
Nitric Oxide (NO) is the most important protective mediator of the arterial wall.
It is generated from the amino acid precursor,
L-arginine.
NO promotes vasodilation and arterial elasticity.
Dr. Louis J. IgnarroNobel Laureate in 1998
for the discovery of nitric oxide
The Miracles of Nitric Oxide
NO SynthaseL-Arginine
N O
L-CitrullineO2
NADPH NADP
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 10
NO – an endogenous anti-atherosclerotic molecule:
anti-atherosclerotic anti-oxidant vasodilator anti-thrombotic anti-proliferative anti-inflammatory anti-oxidant.
The Potential of Nitric Oxide
NO
vasodilation
platelet aggregation
monocyte adhesionsmooth muscle cell
proliferation
superoxide radicalelaboration
LDL oxidation
O2–
Source: Böger et al., Atherosclerosis 1996; 127: 1-11
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 11
L-arginine maintains vascular elasticity (endothelium-dependent vascular relaxation) and reverses build-up of soft plaque even in pre-existing atherosclerosis – this effect is lost after withdrawal of L-arginine.
In experimental studies, L-arginine Increases NO formation Improves vasodilation Inhibits platelet aggregation Reduces leukocyte infiltration Diminishes superoxide radical formation
The Potential of L-Arginine
Dr. John P. CookePioneer of L-arginine research
Cooke et al. Circulation 1991
Tsao et al. Circulation 1994
Böger et al.Atherosclerosis 1995
Böger et al. Atherosclerosis 1995
Böger et al. Atherosclerosis 1998
Cooke et al. 1991, 1992; Böger et al. 1995, 1997; Candipan et al. 1996
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 12
The Potential of L-Arginine
Böger et al., Atherosclerosis 1995; 117: 273 – 284
Study A: Prevention of Plaque Build-Up
Design:
0 8 weeks
Control
Cholesterol
Cholesterol + L-Arginine
Results:
Cholesterol
Cholesterol; treated with L-arginineCONTROL CHOLESTEROL
051015202530354045505560
Car
otid
intim
al p
laqu
e ar
ea
[%
of t
otal
intim
a]
*
CHOL.+ L-ARGININE
#
(0)
A. carotis
-80%
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 13
The Potential of L-Arginine
Böger et al., Circulation 1997; 96: 1282-1290
Study B: Stopping the Progression of Plaque Build-Up
Design:
0 10 weeks
Control
Cholesterol
Results:
164
Cholesterol + L-Arginine
Cholesterol
Cholesterol + Lovastatin
Control
0 weeks164
Intim
al p
laqu
e ar
ea(c
arot
id a
rter
y) [%
]
0
50
40
30
20
10
-92%
„Dietary L-arginine completely suppressed the aggravation of intimal plaque formation during the second part of the study Lovastatin treatment significantly reduced the progression of plaque formation but did not completely block it.“
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 14
The Potential of L-Arginine
Candipan et al., Arterioscler. Thromb. Vasc. Biol. 1996; 16: 44-50
Study C: Reversal of Pre-Existing Plaque
Design:
0 18 weeks
Cholesterol
Results:
2310
Cholesterol
Cholesterol + L-Arginine
0 weeks1610
Intim
al p
laqu
e ar
ea(c
arot
id a
rter
y) [%
]
0
75
60
45
30
15
„This is the first demonstration that restoration of NO activity can induce regression of preexisting intimal lesions and provides evidence that L-arginine therapy may be of potential clinical benefit “
Cholesterol
1814
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 15
In clinical studies with human subjects, L-arginine was shown to:
Restore arterial elasticity
Improve blood flow
Enhance memory function
Accelerate recovery from exercise
Lower blood pressure
Reduce the symptoms of chronic heart failure coronary artery disease peripheral arterial disease erectile dysfunction.
The Promises of L-Arginine
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 16
CONTRACONTRA
PROPROL-Arginine caused improvements of coronary and systemic vascular endothelial function in human subjects in vivo.
The L-Arginine Paradox
Not all patients with vascular disease have low plasma L-arginine levels.
In vitro, NO synthase is saturated with substrate at concentrations corresponding to usual plasma levels.
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 17
ADMAADMAAn endogenous inhibitor of NO synthase displaces L-arginine from the enzyme‘s catalytic site and blocks NO production.
The L-Arginine Paradox:Solution
1000100101.1.010
20
40
60
100
80
L-Arginine [µmol/L]
NO
Syn
thes
is R
ate
[%]
2.9 µMKm =
50%
1000100101.1.010
20
40
60
100
80
L-Arginine [µmol/L]
NO
Syn
thes
is R
ate
[%]
50%
In vitro:without ADMA
In patientswith high ADMA
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 18
ADMA Predicts Mortality
Total mortality
HR = 1.21 (1.07-1.37) per SD increment (0.13 µmol/l)P = 0.003
3,320 study participants from the general population;10 years of follow-up
Multivariate model adjustedfor established CV riskfactors included in the FRSplus BNP, renin, Hcys, CRP,urinary albumin excretion.
The Framingham Offspring StudyBöger et al. Circulation 2009
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 19
The L-Arginine / ADMA Balance
ADMAL-Arginine
NO
Normal L-Arginine/ADMA Balance:> 100 : 1
The physiological model was constructed based upon data from the prospective Framingham Offspring Study, the Gutenberg Health Study, the Gotenberg Women‘s Study, the SHIP Study, and others, totalling over 20,000 study participants.
Böger et al. Circulation 1998Leong et al. ATVB 2008…
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 20
The L-Arginine / ADMA Balance
0
0,5
1
1,5
2
2,5
3
3,5
4
Q1Q2
Q3Q4
ADMA QuartilesQ1 Q2 Q3 Q4L-ArginineQuartiles
Hazard Ratios for Mortality (Multivariable Model)
The Framingham Offspring StudyBöger et al. Circulation 2009
4th
L-arginineADMA > 100
L-arginineADMA < 30
3rd2nd1st
4th
3rd
2nd
1st
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 21
The ADMA Card test
The ultimate tool for assessing risk and controlling L-arginine treatment
► measure ADMA and arginine blood levels in just a few drops of blood!► send sample by surface mail from any place to the specialized lab!► Know who really is in need of arginine supplementation!► Check whether your status has improved during L-arginine intake!
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 22
In our recent epidemiological survey (2012/2013) 2 out of 3 subjects had high ADMA levels, justifying dietary L-arginine supplementation.
Normal range for ADMA: 0.2 – 0.7 µmol/l.
The Complexities of L-Arginine
Dr. Rainer H. BögerInventor of Arginine Cardio
Senior Medical and Scientific Advisor
Low (<0.2)
Normal(0.2 – 0.7)
Elevated (0.7 – 1.0)
Highly elevated (> 1.0)
Source: Prof. Rainer H. BögerData on file
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 23
The Controversies of L-Arginine
Controversy A: L-Arginine has a short half-life
„The vascular effects of L-arginine are closely correlated with its plasma concentrations. […] Terminal elimination half-life for L-arginine was calculated as 59.6. ± 9.1 min and
79.5 ± 9.3 min after intravenous and oral administration, respectively.“
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 24
The Controversies of L-Arginine
Controversy B: Some Clinical Studies with L-Arginine failed to show Benefit
Schulman et al., J. Am. Med. Assoc. 2006; 295: 58-64
• 153 patients recruited within 3-21 days after ST elevation MI
• L-Arginine 3x3 g/d versus placebo,6 months• Primary endpoint: Composite of total mortality
and change in ejection fraction
Study was ended early due to excess mortality in patients in the L-arginine group. However, none of the deaths could be causally related to arginine.Only 56 patients total ended the study and were included in the analysis.Further, arginine did not succeed to increase the arginine blood level.
PlaceboArginine
baseline
6 months0
20
40
60
80
100
120
L-ar
gini
ne [µ
mol
/l]
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 25
The Controversies of L-Arginine
Controversy B: Some Clinical Studies with L-Arginine failed to show Benefit
Wilson et al., Circulation 2007; 116: 188-195
• 133 patients with peripheral arterial disease• L-Arginine 3x1 g/d versus placebo during 6 months• Primary endpoint: Change in absolute claudication distance at 6 mo.
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 26
L-Citrulline is converted into L-arginine after intestinal absorption.This results in prolonged elevation of L-arginine blood levels.
The Wisdom of L-Arginine: Step 1
Prolong the Half-Life of L-Arginine
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 27
Longer half-life of L-arginine blood levelsEnables twice daily administration and results in build-up of L-arginine levelsImproved bioavailability of L-citrulline over L-arginine
The Wisdom of L-Arginine: Step 1
Advantages of combined L-arginine plus L-citrulline
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 28
The individual dose of L-arginine is dependent on
baseline L-arginine in plasma
AND
ADMA in plasma.
The Wisdom of L-Arginine: Step 2
Find the Right Dose in each Individual
Assess L-arginine and ADMA Supplement with Arginine Cardio
© Arginine Benefits LLC, 2013Author: Dr. Rainer Böger Page 29
Arginine Cardio is more than just L-arginine plus L-citrulline.
It combines other ingredients that strongly support the beneficial actions of nitric oxide.
The Wisdom of L-Arginine: Step 3
Use the Complete Formula for the Heart and Arteries
ResveratrolCoQ10Vitamin D3L-TaurineB vitaminsMagnesiumCurcuminVitamin D3Vitamin CFolic Acid