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Dr. Peter J.E. Verdegem Chief Scientific Officer Causes of Cardiovascular Disease Genetics Smoking Atherosclerosis Myocardial Ischemia Arythmia, Angina, Heart Attacks Heart Failure Cellular energy metabolism Calcium pump and Calcium channel Glucose FFA ATP ase glucose 6P glycogen ADP ATP glycolyse sarcoplasmic reticulum ATP ase CK myo Pyruvate ATP Lactate mitochondrion PCr ADP NADH2 CK mito FADH2 ATP ase electron transport chain 2 actin/myosin filaments Ca2+ ADP Krebs cycle O Ca2+ ATP ase CK myo Cr ATP ATP Heart function 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 Sole 2000, Curr Opin Clin Nutr Metab Care 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 metaanalysis) Brouwer 1998: AJCN, Ward 1997: Q J M. Boushy 1995: J Am Med Ass. CVD and elevated homocysteine CVD mortality per 100,000 700 An increase in plasma tHcy of 1 micromol/L increases CVD risk with 10 % 600 NIR 500 SCO2 FIN SCO1 GER1 400 300 FAO ICE ISR SPA FRA JAP 7 8 200 GER2 DEN 100 0 6 9 10 11 Plasma total homocysteine (umol/L) Alfthan 1997 12 Homocysteine metabolism Folate Methionine THF Methylene-THF Vit.B12 Homocysteine Vit.B6 Cystathionine Vit.B6 Cysteine Zn MethylTHF 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 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) 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, enddiastolic volume (Soja, 1997) • Although statin drugs are used to reduce cardiovascular morbidity and mortality, they consequently lower Co Q10 levels 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 Soja 1997: Molec. Aspects Med, Kamikawa 1985: Am J Cardiol, Tanaka 1982: Ann Thorac Surg. Folkers 1985: Proc. Natl Acad. Sci. 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 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 Mitochondria Mitochondria Hawthorn (Crataegus Oxycantha) 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 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 Hawthorn trials Study Design Subjects Suppl. Outcome Weikl 1996 DB 136 CHF NYHA II 160 mg 8 weeks Improved pressure heart rate and QOL Reduction Dyspnea Weng 1984 DBPC 46 angina 100 mg pectoris 4 weeks Reduction serum triglycerides and cholesterol 78 CHF NYHA II Improved exercise performance Reduction SBP, HR and pressure/rate Schmidt DBPC 1994 600 mg 8 weeks 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 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 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. Schaffer 1994, Adv. Exp. Med Biol, Suleiman 1993: Br Heart J Lake 1994: Adv. Exp. Med. Biol, Taurine intervention trials Study Design Azuma 1985 Subjects Suppl. Outcome DBPC 14 CHF cross-over patients 6 g/d 4 weeks Improved NYHA Decrease pre-ejection period Reduced chest film abnormalities Azuma 1992 DBPC 17 HF patients 3 g/d 6 weeks Improved left ventricular function Azuma 1983 Open study 24 CHF patients 2 g/d Improved NYHA 4–8 weeks Cellular energy metabolism Calcium pump and Calcium channel FFA Glucose ATP ase glucose 6P glycogen ATP glycolyse Pyruvate Lactate Krebs cycle sarcoplasmic reticulum ADP ATP ase CK myo ATP Taurine Ca2+ actin/myosin filaments Ca2+ mitochondrion ADP NADH2 FADH2 ADP ATP ase electron transport chain ATP PCr CK mito ATP ase CK myo Heart function Cr ATP O2 Hawthorn CoQ10 Anti-oxidants 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% Marangon 1999, Free Radic Biol Med, Stampfer 1993, NEJM (nurses health study), Stephans 1996, Lancet (CHAOS) Clinical Trial with MyoVive • Performed in Toronto Canada with MyoVive • Double blind placebo controlled trial • 41 Congestive Heart Failure patients Clinical Trial with MyoVive MyoVive Placebo 130 120 110 100 90 80 70 week 0 week 4 week 12 Clinical Trial with MyoVive Clinical Trial Placebo MyoVive 200 190 180 170 160 150 140 130 120 110 100 Baseline Post treatment Clinical Trial with MyoVive • Conclusions: – Supplementation with carnitine, taurine and CoQ10 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