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

D m

orta

lity

per

100

,000

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

70

80

90

100

110

120

130

week 0 week 4 week 12

MyoVivePlacebo

Tim

e til

l exh

aust

ion

Clinical Trial with MyoViveClinical Trial with MyoVive

100110120130140150160170180190200

Baseline Post treatment

Clinical TrialClinical Trial

PlaceboMyoVive

End

dia

stol

ic v

olum

e

• 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