Dr. Peter J.E. Verdegem Chief Scientific Officer

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

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

3. Calcium pump Glucose FFA and Calcium channel ATP ase sarcoplasmic reticulum glucose 6P glycogen ADP ATP ATP Ca2+ ase glycolyse CK myo actin/myosin Pyruvate filaments Ca2+ ATP mitochondrion Lactate ADP PCr ADP Krebs ATP NADH2 CK CK cycle ase myo mito FADH2 ATP ase Cr ATP ATP electron transport chain O 2 Cellular energy metabolism Heart function

4. Energy metabolism and Heart FunctionCellular abnormalities • 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

5. HomocysteineRole 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) Brouwer 1998: AJCN, Ward 1997: Q J M. Boushy 1995: J Am Med Ass.

6. CVD and elevated homocysteine 700 An increase in plasma tHcy of 1 micromol/L increases CVD risk with 10 % 600 NIR FIN SCO2 500 SCO1 GER2 400 GER1 CVD mortality per 100,000 DEN ICE 300 FAO ISR SPA 200 FRA JAP 100 0 6 7 8 9 10 11 12 Plasma total homocysteine (umol/L) Alfthan 1997

7. Homocysteine metabolism Folate Methionine THF Methylene-THF Vit.B12 Zn Homocysteine MethylTHF Vit.B6 Cystathionine Vit.B6 Cysteine

8. 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

9. 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)

10. 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

11. Heart FunctionRole 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 Soja 1997: Molec. Aspects Med, Kamikawa 1985: Am J Cardiol, Tanaka 1982: Ann Thorac Surg. Folkers 1985: Proc. Natl Acad. Sci.

12. 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

13. 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

14. Mitochondria

15. Mitochondria

16. Hawthorn (Crataegus Oxycantha)

17. Hawthorn (Crataegus Oxycantha) • 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

18. Heart functionrole 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

19. Hawthorn trials

20. 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

21. 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

22. Heart functionRole 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. Schaffer 1994, Adv. Exp. Med Biol, Suleiman 1993: Br Heart J Lake 1994: Adv. Exp. Med. Biol,

23. Taurine intervention trials

24. Taurine Hawthorn CoQ10 Anti-oxidants Cellular energy metabolism Calcium pump Glucose FFA and Calcium channel ATP ase sarcoplasmic reticulum glucose 6P glycogen ADP ATP ATP Ca2+ ase glycolyse CK myo actin/myosin Pyruvate filaments Ca2+ ATP mitochondrion Lactate ADP PCr ADP Krebs Heart function ATP NADH2 CK CK cycle ase myo mito FADH2 ATP ase Cr ATP ATP electron transport chain O 2

25. Oxidative Stressrole 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% Marangon 1999, Free Radic Biol Med, Stampfer 1993, NEJM (nurses health study), Stephans 1996, Lancet (CHAOS)

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

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

28. Clinical Trial with MyoVive

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

30. Clinical Trial with MyoVive • 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