Arginine Cardio:

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

2. The Art of Staying Healthy 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. Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

3. The Scope of the Problem Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

4. What the CDC Promotes 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. Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

5. Mortality of acute heart attack drops, … but overall numbers of heart disease are constant Source: Centers for Disease Control 2014 www.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.

6. The Scope of the Problem: Hypertension Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

7. The Scope of the Problem: Heart Failure Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

8. What Can Be Done Source: Centers for Disease Control 2014 www.cdc.gov/heartdisease/facts.htm

9. The Miracles of Nitric Oxide 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. L-Citrulline O2 NO Synthase L-Arginine O N Dr. Louis J. Ignarro Nobel Laureate in 1998 for the discovery of nitric oxide NADP NADPH

10. vasodilation LDL oxidation platelet aggregation NO – O 2 superoxide radical elaboration monocyte adhesion smooth muscle cell proliferation The Potential of Nitric Oxide • NO – an endogenous anti-atherosclerotic molecule: • anti-atherosclerotic • anti-oxidant • vasodilator • anti-thrombotic • anti-proliferative • anti-inflammatory • anti-oxidant. Source: Böger et al., Atherosclerosis 1996; 127: 1-11

11. The Potential of L-Arginine Dr. John P. Cooke Pioneer of L-arginine research • 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 Cooke et al. 1991, 1992; Böger et al. 1995, 1997; Candipan et al. 1996 Böger et al. Atherosclerosis 1995 Cooke et al. Circulation 1991 Tsao et al. Circulation 1994 Böger et al. Atherosclerosis 1998 Böger et al. Atherosclerosis 1995

12. 60 55 50 45 A. carotis 40 * 35 30 25 20 Carotid intimal plaque area [% of total intima] # 15 Cholesterol 10 (0) 5 CONTROL CHOLESTEROL CHOL. 0 + L-ARGININE Cholesterol; treated with L-arginine The Potential of L-Arginine Study A: Prevention of Plaque Build-Up Design: Cholesterol + L-Arginine Cholesterol Control 0 weeks 8 Results: -80% Böger et al., Atherosclerosis 1995; 117: 273 – 284

13. The Potential of L-Arginine Study B: Stopping the Progression of Plaque Build-Up Cholesterol + L-Arginine Design: Cholesterol Cholesterol Cholesterol + Lovastatin Control Control 0 weeks 10 16 4 Results: 50 40 „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.“ 30 -92% Intimal plaque area (carotid artery) [%] 20 10 0 0 weeks 16 4 Böger et al., Circulation 1997; 96: 1282-1290

14. The Potential of L-Arginine Study C: Reversal of Pre-Existing Plaque Design: Cholesterol Cholesterol Cholesterol + L-Arginine Cholesterol 0 weeks 23 10 18 Results: 75 60 „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 “ 45 Intimal plaque area (carotid artery) [%] 30 15 0 0 weeks 16 10 18 14 Candipan et al., Arterioscler. Thromb. Vasc. Biol. 1996; 16: 44-50

15. The Promises of L-Arginine • 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.

16. The L-Arginine Paradox PRO L-Arginine caused improvements of coronary and systemic vascular endothelial function in human subjects in vivo. CONTRA 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.

17. The L-Arginine Paradox:Solution ADMA An endogenous inhibitor of NO synthase displaces L-arginine from the enzyme‘s catalytic site and blocks NO production. In vitro: without ADMA In patients with high ADMA 100 100 80 80 60 60 NO Synthesis Rate [%] NO Synthesis Rate [%] 50% 50% 40 40 20 20 K = m 2.9 µM 0 0 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000 L-Arginine [µmol/L] L-Arginine [µmol/L]

18. Total mortality HR = 1.21 (1.07-1.37) per SD increment (0.13 µmol/l) P = 0.003 ADMA Predicts Mortality 3,320 study participants from the general population; 10 years of follow-up Multivariate model adjusted for established CV risk factors included in the FRS plus BNP, renin, Hcys, CRP, urinary albumin excretion. The Framingham Offspring Study Böger et al. Circulation 2009

19. The L-Arginine / ADMA Balance NO Normal L-Arginine/ADMA Balance: > 100 : 1 ADMA L-Arginine 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 1998 Leong et al. ATVB 2008 …

20. Hazard Ratios for Mortality (Multivariable Model) 4 3,5 3 2,5 2 1,5 L-arginine L-arginine > 100 < 30 1 ADMA ADMA 0,5 Q4 Q3 0 Q2 Q1 ADMA Quartiles Q2 Q3 Q1 Q4 L-Arginine Quartiles The L-Arginine / ADMA Balance 4th 3rd 2nd 1st 2nd 1st 3rd 4th The Framingham Offspring Study Böger et al. Circulation 2009

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!

22. The Complexities of L-Arginine 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. Low (<0.2) Highly elevated (> 1.0) Normal (0.2 – 0.7) Elevated (0.7 – 1.0) Dr. Rainer H. Böger Inventor of Arginine Cardio Senior Medical and Scientific Advisor Source: Prof. Rainer H. Böger Data on file

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.“

24. 120 100 80 L-arginine [µmol/l] 60 40 20 6 months 0 baseline Placebo Arginine The Controversies of L-Arginine Controversy B: Some Clinical Studies with L-Arginine failed to show Benefit • 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. Schulman et al., J. Am. Med. Assoc. 2006; 295: 58-64

25. The Controversies of L-Arginine Controversy B: Some Clinical Studies with L-Arginine failed to show Benefit • 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. Wilson et al., Circulation 2007; 116: 188-195

26. The Wisdom of L-Arginine: Step 1 Prolong the Half-Life of L-Arginine L-Citrulline is converted into L-arginine after intestinal absorption. This results in prolonged elevation of L-arginine blood levels.

27. The Wisdom of L-Arginine: Step 1 Advantages of combined L-arginine plus L-citrulline Longer half-life of L-arginine blood levels Enables twice daily administration and results in build-up of L-arginine levels Improved bioavailability of L-citrulline over L-arginine

28. The Wisdom of L-Arginine: Step 2 Find the Right Dose in each Individual The individual dose of L-arginine is dependent on baseline L-arginine in plasma AND ADMA in plasma. Supplement with Arginine Cardio Assess L-arginine and ADMA

29. The Wisdom of L-Arginine: Step 3 Use the Complete Formula for the Heart and Arteries Arginine Cardio is more than just L-arginine plus L-citrulline. It combines other ingredients that strongly support the beneficial actions of nitric oxide. Resveratrol CoQ10 Vitamin D3 L-Taurine B vitamins Magnesium Curcumin Vitamin D3 Vitamin C Folic Acid