Dr. Peter J.E. Verdegem Chief Scientific Officer
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Transcript of Dr. Peter J.E. Verdegem Chief Scientific Officer
Dr. Peter J.E. VerdegemChief Scientific Officer
Causes of Cardiovascular DiseaseCauses of Cardiovascular Disease
Atherosclerosis
Myocardial Ischemia
Arythmia, Angina, Heart Attacks
Heart Failure
Cholesterol Genetics SmokingAlcohol
Cellular energy metabolismCellular energy metabolism
GlucoseFFA
Pyruvate
glycogenglucose 6P
glycolyse
ATP
Ca2+
Krebscycle
NADH2
FADH2
electron transport chain
O2
PCrADP
ATPCr
ADP
ATP
CKmyo
ATP ase
ATP
CKmito
ATP ase
ATP ase
ATP ase
actin/myosin
filaments
sarcoplasmicreticulum
mitochondrion
Calcium pumpand
Calcium channel
CKmyo
ADP
Ca2+
Lactate
Heart function
Energy metabolism and Heart Function
Cellular abnormalities
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 CareSole 2000, Curr Opin Clin Nutr Metab Care
HomocysteineRole of folic acidHomocysteine
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.
CVD and elevated homocysteine
CVD and elevated homocysteine
NIR
SCO1SCO2 FIN
GER1
FAO
GER2
DENICEISR
SPAFRAJAP
0
100
200
300
400
500
600
700
6 7 8 9 10 11 12
Plasma total homocysteine (umol/L)
CV
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Alfthan 1997
An increase in plasma tHcy of 1 micromol/L increases CVD risk with 10 %
Homocysteine metabolismHomocysteine metabolism
Methionine
Homocysteine
Vit.B12
THF
Cystathionine
Cysteine
Vit.B6
Vit.B6
Methylene-THF
MethylTHF
Folate
Zn
Coenzyme Q10Coenzyme 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
Coenzyme Q10Coenzyme 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)
Coenzyme Q10Coenzyme 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
Heart FunctionRole of Co-enzyme Q10
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
• 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-CarnitineL-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
L-CarnitineL-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
MitochondriaMitochondria
MitochondriaMitochondria
Hawthorn (Crataegus Oxycantha)Hawthorn (Crataegus Oxycantha)
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
• 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 functionrole of HawthornHeart 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
Hawthorn trialsHawthorn 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 pectoris
100 mg 4 weeks
Reduction serum triglycerides and cholesterol
Schmidt 1994
DBPC
78 CHF NYHA II
600 mg 8 weeks
Improved exercise performance Reduction SBP, HR and pressure/rate
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 pectoris
100 mg 4 weeks
Reduction serum triglycerides and cholesterol
Schmidt 1994
DBPC
78 CHF NYHA II
600 mg 8 weeks
Improved exercise performance Reduction SBP, HR and pressure/rate
TaurineTaurine
• 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
TaurineTaurine
• 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
Heart functionRole of TaurineHeart 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.
• 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 trialsTaurine intervention trials
Study
Design
Subjects
Suppl.
Outcome
Azuma 1985
DBPC cross-over
14 CHF 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 4–8 weeks
Improved NYHA
Study
Design
Subjects
Suppl.
Outcome
Azuma 1985
DBPC cross-over
14 CHF 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 4–8 weeks
Improved NYHA
Cellular energy metabolismCellular energy metabolism
GlucoseFFA
Pyruvate
glycogenglucose 6P
glycolyse
ATP
Ca2+
Krebscycle
NADH2
FADH2
electron transport chain
O2
PCrADP
ATPCr
ADP
ATP
CKmyo
ATP ase
ATP
CKmito
ATP ase
ATP ase
ATP ase
actin/myosin
filaments
sarcoplasmicreticulum
mitochondrion
Calcium pumpand
Calcium channel
CKmyo
ADP
Ca2+
Lactate
Heart function
Taurine
CoQ10 Anti-oxidantsHawthorn
Oxidative Stressrole of Vitamin EOxidative 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%
• 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 MyoViveClinical 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
Clinical Trial with MyoViveClinical Trial with MyoVive
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week 0 week 4 week 12
MyoVivePlacebo
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Clinical Trial with MyoViveClinical Trial with MyoVive
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Baseline Post treatment
Clinical TrialClinical Trial
PlaceboMyoVive
End
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• 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 MyoViveClinical Trial with MyoVive