1. Dr. Peter J.E. Verdegem Chief Scientific Officer

2. Respiratory Digestion Cardiovascular Infections Cancer Stroke Homicide Suicide MVA External Liver Causes of Death in South East Asia

3. Cardiovascular Disease Cardiovascular disease - the single leading cause of death in the USA Millions of individuals in USA have angina, have had a heart attack or other forms of cardiovascular disease. Most women have a fear of breast cancer, yet are actually ten times more likely to die from cardiovascular disease. Cardiovascular disease - the single leading cause of death in the USA Millions of individuals in USA have angina, have had a heart attack or other forms of cardiovascular disease. Most women have a fear of breast cancer, yet are actually ten times more likely to die from cardiovascular disease.

4. Causes of Cardiovascular Disease Atherosclerosis Myocardial Ischemia Arythmia, Angina, Heart Attacks Heart Failure Cholesterol Genetics Smoking Alcohol

5. Cellular energy metabolism Heart function

6. Energy metabolism and Heart Function Cellular abnormalities Gradual accumulation of calcium in myocytes Mitochondrial calcium overload Decreased myocyte energy production Increased oxidative damage and protease activation Myocyte dysfunction and death Gradual accumulation of calcium in myocytes Mitochondrial calcium overload Decreased myocyte energy production Increased oxidative damage and protease activation Myocyte dysfunction and death Sole 2000, Curr Opin Clin Nutr Metab Care

8. High Cholesterol is a Major Culprit for Cardiovascular Risk

9. Homocysteine Role of folic acid Folic acid supplementation (0.2 - 1.0 mg/d) reduces plasma homocysteine levels up to 50 % (various studies) Folic acid enriched cereals in US Folic acid supplementation (0.4 mg/d) might prevent 8% of CVD deaths in US (estimation from meta- analysis) Folic acid supplementation (0.2 - 1.0 mg/d) reduces plasma homocysteine levels up to 50 % (various studies) Folic acid enriched cereals in US Folic acid supplementation (0.4 mg/d) might prevent 8% of CVD deaths in US (estimation from meta- analysis) Brouwer 1998: AJCN, Ward 1997: Q J M. Boushy 1995: J Am Med Ass.

10. CVD and elevated homocysteine NIR SCO1 SCO2 FIN GER1 FAO GER2 DEN ICE ISR SPA FRA JAP 0 100 200 300 400 500 600 700 6789101112 Plasma total homocysteine (umol/L) CVD mortality per 100,000 Alfthan 1997 An increase in plasma tHcy of 1 micromol/L increases CVD risk with 10 %

11. Homocysteine metabolism Methionine Homocysteine Vit.B12 THF Cystathionine Cysteine Vit.B6 Methylene-THF M ethylTHF Folate Zn

12. Coenzyme Q10 Small fat soluble molecule with distinct functions: Transport of electrons to mitochondria, essential for energy production Fat soluble antioxidant protecting a.o. LDL particles A high concentration of Co Q10 is found in the heart muscle Small fat soluble molecule with distinct functions: Transport of electrons to mitochondria, essential for energy production Fat soluble antioxidant protecting a.o. LDL particles A high concentration of Co Q10 is found in the heart muscle

13. Coenzyme Q10 Functions in energy production within the mitochondria Deficiency states have been demonstrated in the research to be associated with many diseases, primarily cardiovascular (Bliznakow EG, et al. Adv in Ther. 1998;15(4):218 ‑ 228) Functions in energy production within the mitochondria Deficiency states have been demonstrated in the research to be associated with many diseases, primarily cardiovascular (Bliznakow EG, et al. Adv in Ther. 1998;15(4):218 ‑ 228)

14. Coenzyme Q10 Over 40 human clinical trials have been conducted in relation to cardiac parameters Meta-analysis on 8 studies showed significant effects for ejection fraction, cardiac output, stroke volume, end- diastolic volume (Soja, 1997) Although statin drugs are used to reduce cardiovascular morbidity and mortality, they consequently lower Co Q10 levels Over 40 human clinical trials have been conducted in relation to cardiac parameters Meta-analysis on 8 studies showed significant effects for ejection fraction, cardiac output, stroke volume, end- diastolic volume (Soja, 1997) Although statin drugs are used to reduce cardiovascular morbidity and mortality, they consequently lower Co Q10 levels

15. Heart Function Role of Co-enzyme Q10 Limiting factor in electron transport chain Reduced concentration in myocyte A meta-analysis of 8 DBPC Q10 (60-200 mg/d) intervention trials in patients with NYHA class I-IV showed improved: –Ejection fraction: 1.37 SD –Stroke volume: 0.71 SD –Cardiac output: 0.61 SD –End diastolic volume: 1.23 SD Pre-operative Q10 supplementation (30-60 mg) in CABG patients improves post-operative cardiac output Limiting factor in electron transport chain Reduced concentration in myocyte A meta-analysis of 8 DBPC Q10 (60-200 mg/d) intervention trials in patients with NYHA class I-IV showed improved: –Ejection fraction: 1.37 SD –Stroke volume: 0.71 SD –Cardiac output: 0.61 SD –End diastolic volume: 1.23 SD Pre-operative Q10 supplementation (30-60 mg) in CABG patients improves post-operative cardiac output Soja 1997: Molec. Aspects Med, Kamikawa 1985: Am J Cardiol, Tanaka 1982: Ann Thorac Surg. Folkers 1985: Proc. Natl Acad. Sci.

16. L-Carnitine Amino acid, although strictly speaking not Belongs more to the B vitamins Body can synthesize if enough iron, vitamin B1, vitamin B6, lysine, and methionine are present Dietary source is meat Amino acid, although strictly speaking not Belongs more to the B vitamins Body can synthesize if enough iron, vitamin B1, vitamin B6, lysine, and methionine are present Dietary source is meat

17. L-Carnitine Transfers long-chain fatty acids into the mitochondria Fuels the energy factories of the heart 70% of the heart energy comes from fatty acid breakdown In 1978, the first cardiovascular anti-ischemic effect was demonstrated and improvements in Electrocardiogram measurements Transfers long-chain fatty acids into the mitochondria Fuels the energy factories of the heart 70% of the heart energy comes from fatty acid breakdown In 1978, the first cardiovascular anti-ischemic effect was demonstrated and improvements in Electrocardiogram measurements

18. Mitochondria

20. Heart Sonogram

21. Hawthorn (Crataegus Oxycantha)

22. Small shrubby tree with with bark Rich in flavonoids, vitamins, minerals and cardiotonic amines Exerts antioxidant effect on radicals inhibiting Angiotensin Converting Enzymes (ACEs) Vasodilation, blood flow to the heart Supports muscle contraction, cardiac rhythm Hawthorn is included in Germany’s Commission E Monograph for cardiovascular health Small shrubby tree with with bark Rich in flavonoids, vitamins, minerals and cardiotonic amines Exerts antioxidant effect on radicals inhibiting Angiotensin Converting Enzymes (ACEs) Vasodilation, blood flow to the heart Supports muscle contraction, cardiac rhythm Hawthorn is included in Germany’s Commission E Monograph for cardiovascular health

23. Heart function role of Hawthorn Active ingredients –flavonoids, polyphenols, triterpenic acids, vitamins, minerals and cardiotonic amines Mechanistic action –inhibiting cellular phosphodiesterase, enhance intracellular cAMP and improve contractile force –inhibiting the angiotensin converting enzyme activity, resulting in vasodilatation –capturing free radicals Active ingredients –flavonoids, polyphenols, triterpenic acids, vitamins, minerals and cardiotonic amines Mechanistic action –inhibiting cellular phosphodiesterase, enhance intracellular cAMP and improve contractile force –inhibiting the angiotensin converting enzyme activity, resulting in vasodilatation –capturing free radicals

24. Hawthorn (Crataegus Oxycantha) Most recent multi centre placebo-controlled study performed in 136 patients with cardiac insufficiency Double blind placebo controlled 8 Weeks of Hawthorn or placebo Significant improvement in pumping pressure, heart rate product, and heart performance Weikl A.v., Assmuss K.D., Neukum-Schmidt A., Schmitz J., Zapfe jun. G., Noh H.S., et al. (1996) Crataegus special extract WS1442. Assessment of objective effectiveness in patients with heart failure. Fortschr Med, 114, 291-6 Most recent multi centre placebo-controlled study performed in 136 patients with cardiac insufficiency Double blind placebo controlled 8 Weeks of Hawthorn or placebo Significant improvement in pumping pressure, heart rate product, and heart performance Weikl A.v., Assmuss K.D., Neukum-Schmidt A., Schmitz J., Zapfe jun. G., Noh H.S., et al. (1996) Crataegus special extract WS1442. Assessment of objective effectiveness in patients with heart failure. Fortschr Med, 114, 291-6

25. Hawthorn trials

26. Taurine Amino acid Found in eggs, meat, fish and milk Can be synthesized by the body, but is often too low Vegetarians rely on body synthesis Amino acid Found in eggs, meat, fish and milk Can be synthesized by the body, but is often too low Vegetarians rely on body synthesis

27. Taurine High concentrations are found in heart muscle Plays a role in electrolyte balance within the cells (Calcium balance) and has an effect on cardiac muscle tissue cell membrane Prevents potassium leak from the heart muscle. This leak can result in dangerous cardiac arrhythmias Has antioxidant properties, protecting membrane lipids from peroxidation High concentrations are found in heart muscle Plays a role in electrolyte balance within the cells (Calcium balance) and has an effect on cardiac muscle tissue cell membrane Prevents potassium leak from the heart muscle. This leak can result in dangerous cardiac arrhythmias Has antioxidant properties, protecting membrane lipids from peroxidation

28. Heart function Role of Taurine Modulation of calcium transport Elevated taurine levels prevent calcium overload and are cardioprotective, Taurine deficiency reduces ventricular contractile force Ischaemic and CABG heart patients have reduced intracellular taurine levels. Modulation of calcium transport Elevated taurine levels prevent calcium overload and are cardioprotective, Taurine deficiency reduces ventricular contractile force Ischaemic and CABG heart patients have reduced intracellular taurine levels. Schaffer 1994, Adv. Exp. Med Biol, Suleiman 1993: Br Heart J Lake 1994: Adv. Exp. Med. Biol,

29. Taurine intervention trials

30. Cellular energy metabolism Glucose FFA Pyruvate glycogen glucose 6P glycolyse ATP Ca 2+ Krebs cycle NADH2 FADH2 electron transport chain O 2 PCr ADP ATP Cr ADP ATP CK myo ATP ase ATP CK mito ATP ase ATP ase ATP ase actin/myosin filaments sarcoplasmic reticulum mitochondrion Calcium pump and Calcium channel CK myo ADP Ca 2+ Lactate Heart function Taurine CoQ10Anti-oxidants Hawthorn

31. Oxidative Stress role of Vitamin E Vitamin E reduces susceptibility of LDL to oxidize. Long term use (> 2 years) of vitamin E supplements is associated with reduced risk of coronary heart disease: –RR of 0.59 (95% confidence interval 0.38 - 0.91) DBPC Vitamin E (400 - 800 IU) intervention trial in 2002 CVD patients resulted in significant reduction of non fatal Myocard Infarcts with 77% Vitamin E reduces susceptibility of LDL to oxidize. Long term use (> 2 years) of vitamin E supplements is associated with reduced risk of coronary heart disease: –RR of 0.59 (95% confidence interval 0.38 - 0.91) DBPC Vitamin E (400 - 800 IU) intervention trial in 2002 CVD patients resulted in significant reduction of non fatal Myocard Infarcts with 77% Marangon 1999, Free Radic Biol Med, Stampfer 1993, NEJM (nurses health study), Stephans 1996, Lancet (CHAOS)

32. Oxidative stress Role of other nutrients Q10: prevents LDL-oxidation Lipoic acid:prevents LDL-oxidation, recycling Vit E Selenium: GSH-peroxidase Magnesium:Serum and dietary intake related to CVD, hypertension, artherosclerosis Hawthorn:anti-oxidative capacity of flavonoids, polyphenols, Garlic:anti-oxidative capacities of allicine and alliine Q10: prevents LDL-oxidation Lipoic acid:prevents LDL-oxidation, recycling Vit E Selenium: GSH-peroxidase Magnesium:Serum and dietary intake related to CVD, hypertension, artherosclerosis Hawthorn:anti-oxidative capacity of flavonoids, polyphenols, Garlic:anti-oxidative capacities of allicine and alliine

33. Clinical Trial with MyoVive Performed in Toronto Canada with MyoVive Double blind placebo controlled trial 41 Congestive Heart Failure patients Performed in Toronto Canada with MyoVive Double blind placebo controlled trial 41 Congestive Heart Failure patients

34. Clinical Trial with MyoVive 70 80 90 100 110 120 130 week 0week 4week 12 MyoVive Placebo Time till exhaustion

35. Clinical Trial with MyoVive

36. 100 110 120 130 140 150 160 170 180 190 200 Baseline Post treatment Clinical Trial Placebo MyoVive End diastolic volume

37. Conclusions: –Supplementation with carnitine, taurine and Co- Q10 resulted in higher myocardial levels of the ingredients –These higher levels improve myocardial function –After supplementation the time to exhaustion is larger –Supplementation leads to a reduction of end diastolic volume –This reduction improves prognosis for cardiac diseases Conclusions: –Supplementation with carnitine, taurine and Co- Q10 resulted in higher myocardial levels of the ingredients –These higher levels improve myocardial function –After supplementation the time to exhaustion is larger –Supplementation leads to a reduction of end diastolic volume –This reduction improves prognosis for cardiac diseases Clinical Trial with MyoVive