Transcript Slide 1

Heart failure is
a progressive disease
The heart is unable
to maintain output sufficient
to meet metabolic demands
Ronald Ross Watson PhD
Professor University of Arizona
Mel and Enid Zuckerman College of Public Health,
and School of Medicine, Arizona.
OH
HO
Constituents
O
OH
OH
HO
O
Procyanidins:
OH
OH
OH
linked catechin
subunits
Composition defined in:
United States
Pharmacopoeia (28)
OH
OH
HO
OH
O
HO
OH
OH
endothelial cells of blood vessel wall
blood platelets
blood stream
NO
Pycnogenol®
arginine
+ O2
smooth muscle
NO
NO
NO
NO
NO
Fitzpatrick et al., J Cardiovasc Pharm 32: 509-515, 1998
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Enhanced
Platelet
Aggregration
Enhanced Platelet Aggregration in Smokers
in Smokers
Persistence
of Pycnogenol's Activity
Persistence of Pycnogenol's Activity
Single Dose
Pycnogenol
200mg
Platelet
Aggregation
0.1
3
Days Post Treatment
6
NO
1.20
NO
Platelet activity index
NO
NO
Pycnogenol
1.00
0.80
0
25
50
100
150
200
Single Pycnogenol dose [mg]
Pütter et al., Thromb Res 95: 155-161, 1999
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p<0.05
Hosseini et al., Nutrition Res 21: 1251-1260, 2001
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Devaraj et al., Lipids 37: 931-934, 2002
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Pycnogenol® is anti-inflammatory
Tissue damage
free radicals
cytokines &
oxidative stress
leukocyte
blood vessel
Development of Natural Products
for Health Promotion
Plant
Source
Extract
Characterization
Toxicity + Efficacy
In Vitro
Animals
Humans
Left = Control
Right = Heart Failure
Heart failure
A major and growing public health problem worldwide
More than 5 million people in the U.S.
Estimated 550,000 new cases per year
Anticipated increase in incidence and prevalence in the
aging population
Associated with considerable morbidity, mortality and
health care costs, estimated to be up to 29.6 billions in
2006
Slowing or reversing cardiac remodeling is considered
as a potential therapeutic target in heart failure
Hypertension escalates work-load of
the heart to meet metabolic demands
The heart compensates with increased
stroke volume and heart rate
Left ventricle
Hypertension escalates work-load of
the heart to meet metabolic demands
The heart compensates with increased
stroke volume and heart rate
Increased myocardial stretching stress
causes remodeling of ventricular wall
Hypertension escalates work-load of
the heart to meet metabolic demands
The heart compensates with increased
stroke volume and heart rate
Increased myocardial stretching stress
causes remodeling of ventricular wall
Heart muscle wears out and cell death
causes thinning of the ventricular wall
and sagging of the ventricle
Hypertension escalates work-load of
the heart to meet metabolic demands
The heart compensates with increased
stroke volume and heart rate
Increased myocardial stretching stress
causes remodeling of ventricular wall
Heart muscle wears out and cell death
causes thinning of the ventricular wall
and sagging of the ventricle
Significant ventricular dilation,
and incomplete ejection of
oxygenated blood to organs
Cardiac muscle fibers (myocytes)
Increased cell decay, elongation or hypertrophy
Cardiac fibroblast cells
Involved in collagen synthesis and degradation
Cardiac Collagen Network
Collagen synthesis
Collagen degradation
Induce cardiac remodeling in a mouse model
by blocking NO production, which leads to
hypertension and finally cardiomyopathy
Investigate the influence of Pycnogenol®
supplementation on cardiac remodeling
endothelial cells of blood vessel wall
blood platelets
blood stream
NO
NO
L-NAME
(arginine antagonist)
NO
NO
NO
NO
smooth muscle
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O
G
R
endothelial cells of blood vessel wall
Consequence in test animals:
blood platelets
blood stream
Arterial constriction
NO
Gradual blood pressure increase
NO
L-NAME
(arginine antagonist)
NO
Dilated cardiomyopathy
NO
NO
Induction of cardiac remodeling
NO
smooth muscle
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P
H
A
O
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Group I: Control
group
Group II: Pycnogenol®
group
• 60 female
• C57BL/6N
• 18 months old
Group III: L-NAME
group
Group IV: L-NAME –
Pycnogenol®
group
* Pycnogenol® was administrated in water, at 30 mg/kg
H2O
9 Weeks
H2O
+
5 Weeks
L-NAME +
5 Weeks
L-NAME +
5 Weeks
Pyc
4 Weeks
H2O
4 Weeks
Pyc
4 Weeks
Systolic Blood Pressure (mmHg)
160
Un-treated
L-NAME-treated
150
140
*
130
*
*
*
*
120
110
100
90
80
0
1
2
3
4
5
L-NAME Treatment period (week)
* P<0.001 compared with un-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
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
HR (beats/min)
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
7.0 ± 0.5
7.1 ± 0.5
6.8 ± 0.4
7.2 ± 0.6
80.2 ± 2.1
78.52 ± 1.2
τ Weiss (ms)
Vascular function
Pmax (mmHg)
78.4 ± 1.3
74.0 ± 1.6 a
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
↑ MMPs gene expression
and activity
Myocardial
hypertrophy
Hypertension
L-NAME
ECM Degradation
Cardiac Remodeling
Proinflammatory
cytokines
Oxidative
Stress
Ventricular Dilation
NF-B
Heart Failure
Stimulates vascular NO synthesis
Relaxes constricted arteries
Improves blood lipid profile
Lowers blood pressure in hypertension
Helps prevent thrombosis
Our new study suggests Pycnogenol®
can prevent adverse myocardial
remodeling
N
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Natural Health Science