heart failure is a progressive disease the heart is unable to maintain output sufficient to meet...
TRANSCRIPT
Heart failure is a progressive disease
The heart is unableto maintain output sufficientto meet metabolic demands
Heart failure is a progressive disease
The heart is unableto maintain output sufficientto meet metabolic demands
Ronald Ross Watson PhDProfessor University of ArizonaMel and Enid Zuckerman College of Public Health, and School of Medicine, Arizona.
O
OH
OH
OHOH
OH
O
OH
OH
OHOH
OH
O
OH
OH
OHOH
OH
O
OH
OH
OHOH
OH
OHOH
O
OH
OH
OH
OHOH
O
OH
OH
OH
ConstituentsConstituents
Procyanidins:linked catechin
subunits
Procyanidins:linked catechin
subunits
Composition defined in:United States
Pharmacopoeia (28)
Composition defined in:United States
Pharmacopoeia (28)
Pycnogenol®Pycnogenol®
arginine+ O2
smooth muscle
blood plateletsblood platelets blood streamblood stream
NO NO
NO
NO
NO
NO
endothelial cells of blood vessel wall
H
P H A G
O RFitzpatrick et al., J Cardiovasc Pharm 32: 509-515, 1998
Enhanced Platelet Aggregration in Smokers
Enhanced Platelet Aggregration in Smokers
Persistence of Pycnogenol's ActivityPersistence of Pycnogenol's Activity
normal
stress
constriction
atherosclerotic plaque
artherosclerotic plaque + stress (constriction) thrombus
plateletaggregation
inducesplatelet
activation
thrombus formationvessel occlusion
heart infarctionstroke
adrenaline(fear, stress)
M. Pütter et al., Thromb. Res. (1999) 95: 155-161R. Watson, Cardiovascular Rev. & Rep. (1999) 20: 326-329
Pycnogenol® prevents blood platelets from getting stickyPycnogenol® prevents blood platelets from getting sticky
M. Pütter et al., Thrombosis Research 95: 155-161, 1999R. Watson, Cardiovascular Rev. & Rep. 1999, 20: 326-329
Pycnogenol prevents platelet aggregationPrevention of heart infarction, stroke and economy class syndrome
Pycnogenol prevents platelet aggregationPrevention of heart infarction, stroke and economy class syndrome
withoutmedication
withoutmedication
COX inhibitor(500 mg)
COX inhibitor(500 mg)
Pycnogenol®
(100 mg)
Pycnogenol®
(100 mg)
p<0.05p<0.05
1,2
1,3
1,4
1,5
1,6
1,2
1,3
1,4
1,5
1,6T
hro
mbo
cyte
rea
ctiv
ity
ind
exT
hro
mbo
cyte
rea
ctiv
ity
ind
ex smoking increases “stickiness“of platelets
smoking increases “stickiness“of platelets
Pycnogenol® prevents thisPycnogenol® prevents this
H
P H A G
O R
0.80
1.00
1.20
0 25 50 100 150 200
Pla
tele
t a
ctiv
ity in
de
x
Single Pycnogenol dose [mg]
0.80
1.00
1.20
0 25 50 100 150 200
Pla
tele
t a
ctiv
ity in
de
x
Single Pycnogenol dose [mg]
Pütter et al., Thromb Res 95: 155-161, 1999
NO
NO
NO
NO
PycnogenolPycnogenol
Hosseini et al., Nutrition Res 21: 1251-1260, 2001 H
P H A G
O R
p<0.05p<0.05
H
P H A G
O RDevaraj et al., Lipids 37: 931-934, 2002
Pycnogenol® is anti-inflammatoryPycnogenol® is anti-inflammatory
blood vesselblood vessel
Tissue damageTissue damage
cytokines & oxidative stresscytokines & oxidative stress
leukocyteleukocyte
free radicalsfree radicals
Development of Natural Products for Health Promotion
Development of Natural Products for Health Promotion
PlantSourcePlant
SourceExtractExtract CharacterizationCharacterization Toxicity + EfficacyToxicity + Efficacy
In VitroIn Vitro AnimalsAnimals HumansHumans
Left = ControlRight = Heart Failure
Heart failureA major and growing public health problem worldwide More than 5 million people in the U.S.Estimated 550,000 new cases per yearAnticipated increase in incidence and prevalence in the aging populationAssociated with considerable morbidity, mortality and health care costs, estimated to be up to 29.6 billions in 2006Slowing or reversing cardiac remodeling is considered as a potential therapeutic target in heart failure
Hypertension escalates work-load ofthe heart to meet metabolic demandsHypertension escalates work-load ofthe heart to meet metabolic demands
The heart compensates with increasedstroke volume and heart rateThe heart compensates with increasedstroke volume and heart rate
Left ventricleLeft ventricle
Hypertension escalates work-load ofthe heart to meet metabolic demandsHypertension escalates work-load ofthe heart to meet metabolic demands
The heart compensates with increasedstroke volume and heart rateThe heart compensates with increasedstroke volume and heart rate
Increased myocardial stretching stresscauses remodeling of ventricular wallIncreased myocardial stretching stresscauses remodeling of ventricular wall
Hypertension escalates work-load ofthe heart to meet metabolic demandsHypertension escalates work-load ofthe heart to meet metabolic demands
The heart compensates with increasedstroke volume and heart rateThe heart compensates with increasedstroke volume and heart rate
Increased myocardial stretching stresscauses remodeling of ventricular wallIncreased myocardial stretching stresscauses remodeling of ventricular wall
Heart muscle wears out and cell deathcauses thinning of the ventricular walland sagging of the ventricle
Heart muscle wears out and cell deathcauses thinning of the ventricular walland sagging of the ventricle
Significant ventricular dilation,and incomplete ejection ofoxygenated blood to organs
Significant ventricular dilation,and incomplete ejection ofoxygenated blood to organs
Hypertension escalates work-load ofthe heart to meet metabolic demandsHypertension escalates work-load ofthe heart to meet metabolic demands
The heart compensates with increasedstroke volume and heart rateThe heart compensates with increasedstroke volume and heart rate
Increased myocardial stretching stresscauses remodeling of ventricular wallIncreased myocardial stretching stresscauses remodeling of ventricular wall
Heart muscle wears out and cell deathcauses thinning of the ventricular walland sagging of the ventricle
Heart muscle wears out and cell deathcauses thinning of the ventricular walland sagging of the ventricle
Cardiac muscle fibers (myocytes)Increased cell decay, elongation or hypertrophy
Cardiac fibroblast cellsInvolved in collagen synthesis and degradation
Cardiac Collagen NetworkCollagen synthesis
Collagen degradation
Induce cardiac remodeling in a mouse modelby blocking NO production, which leads to hypertension and finally cardiomyopathy
Investigate the influence of Pycnogenol® supplementation on cardiac remodeling
Induce cardiac remodeling in a mouse modelby blocking NO production, which leads to hypertension and finally cardiomyopathy
Investigate the influence of Pycnogenol® supplementation on cardiac remodeling
smooth muscle
blood plateletsblood platelets blood streamblood stream
NO NO
NO
NO
NO
NO
endothelial cells of blood vessel wall
H
P H A G
O R
L-NAME(arginine antagonist)
L-NAME(arginine antagonist)
smooth muscle
blood plateletsblood platelets blood streamblood stream
NO NO
NO
NO
NO
NO
endothelial cells of blood vessel wall
H
P H A G
O R
L-NAME(arginine antagonist)
L-NAME(arginine antagonist)
Consequence in test animals:Consequence in test animals:
Arterial constriction
Gradual blood pressure increase
Dilated cardiomyopathy
Induction of cardiac remodeling
Group I: Control group
Group II: Pycnogenol®
group
Group III: L-NAME
group
Group IV: L-NAME – Pycnogenol®
group
H2O
9 Weeks
H2O
H2OL-NAME
+
5 Weeks 4 Weeks
Pyc
PycL-NAME
+
+
5 Weeks
5 Weeks
4 Weeks
4 Weeks
• 60 female
• C57BL/6N
• 18 months old
* Pycnogenol® was administrated in water, at 30 mg/kg
* P<0.001 compared with un-treated
80
90
100
110
120
130
140
150
160
0 1 2 3 4 5
L-NAME Treatment period (week)
Systo
lic B
loo
d P
ressu
re (
mm
Hg
)
Un-treated
L-NAME-treated
**
** *
Starting Pycnogenol®
supplementation
Parameter (unit) Control Pycnogenol L-NAME L-NAME-PYC
Hemodynamics
Body Weight (g) 34.0 ± 1.8 32.9 ± 1.8 28.0 ± 1.1 a 34.1 ± 2.2 c
Heart W/Body W (mg/g) 4.3 ± 0.2 4.2 ± 0.1 5.0 ± 0.1 a 4.1 ± 0.2 c
HR (beats/min) 541.0 ± 10.6 530.8 ± 10.0 518.4 ± 12.0 526.1 ± 9.0
Ved (µL) 31.6 ± 1.6 32.0 ± 0.9 38.4 ± 0.8 b 32.7 ± 1.8 c
Ves (µL) 14.5 ± 0.7 14.8 ± 1.4 18.3 ± 1.4 a 14.6 ± 0.9 c
SVI (µL/g) 0.53 ± 0.03 0.56 ± 0.05 0.76 ± 0.07 a 0.58 ± 0.06 c
EF (%) 58.8 ± 1.7 57.3 ± 2.9 54.8 ± 2.7 57.1 ± 2.3
CI (µL/min/g) 268 ± 21 301 ± 23 389 ± 36 a 297 ± 35 c
SWI (mmHg·µL/g) 33.1 ± 2.6 35.6 ± 2.7 50.1 ± 4.6 a 36.4 ± 4.1 c
Systolic function
dP/dtmax (mmHg/s) 7309 ± 266 7654 ± 385 8633 ± 422 a 7327 ± 256 c
PRSW (mmHg) 80.9 ± 1.9 78.5 ± 1.8 92.0 ± 4.5 a 85.0 ± 4.3
dP/dtmax-Ved (mmHg/s/µL) 771 ± 46 650 ± 54 852 ± 32 762 ± 33
Diastolic function
(mmHg/µL) 0.08 ± 0.01 0.14 ± 0.03 0.04 ± 0.01 a 0.12 ± 0.02 c
dP/dtmin (mmHg/s) -5490 ± 266 -5863 ± 343 -6303 ± 273 a -5520 ± 253 c
τ Weiss (ms) 7.0 ± 0.5 7.1 ± 0.5 6.8 ± 0.4 7.2 ± 0.6
Vascular function
Pmax (mmHg) 78.4 ± 1.3 74.0 ± 1.6 a 80.2 ± 2.1 78.52 ± 1.2
Ea (mmHg/µL) 5.4 ± 0.6 5.1 ± 0.5 4.4 ± 0.6 5.2 ± 0.5
Dilated cardiomyopathy at compensated state has been induced in L-NAME- treated mice
Pycnogenol® supplementation appeared to reduce Pmax (maximum arterial pressure) without affecting any other parameter
Most importantly, in the L-NAME-group treated with Pycnogenol®, all parameters resemble those of the healthy control group.
Therefore, Pycnogenol® is associated with reversal of L-NAME-induced alternations in hemodynamic parameters.
a P<0.01 compared with control;
b P<0.05 compared with L-NAME
Myocardial hypertrophy
↑ MMPs gene expression and activity
Proinflammatory cytokines
Hypertension
Oxidative Stress
NF-B
L-NAME
Cardiac Remodeling
Heart Failure
Ventricular Dilation
ECM Degradation
Stimulates vascular NO synthesisRelaxes constricted arteriesImproves blood lipid profileLowers blood pressure in hypertensionHelps prevent thrombosis
Our new study suggests Pycnogenol®
can prevent adverse myocardialremodeling
Stimulates vascular NO synthesisRelaxes constricted arteriesImproves blood lipid profileLowers blood pressure in hypertensionHelps prevent thrombosis
Our new study suggests Pycnogenol®
can prevent adverse myocardialremodeling
N H SNatural Health Science