Transcript FY02 Business Strategy

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