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 O
OH

Constituents OH
OH
OH

HO O
OH

Procyanidins: OH
OH

linked catechin HO OH

subunits
O
HO
Composition defined in:
United States
OH
Pharmacopoeia (28)
OH
 endothelial cells of blood vessel wall
blood platelets
blood stream
NO

Pycnogenol NO

arginine NO NO

+ O2 NO

smooth muscle
NO

Fitzpatrick et al., J Cardiovasc Pharm 32: 509-515, 1998 H O R

P H A G
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 6
Days Post Treatment
 NO

1.20 NO
NO
NO
Platelet activity index

Pycnogenol
1.00

0.80
0 25 50 100 150 200
Single Pycnogenol dose [mg]

Ptter et al., Thromb Res 95: 155-161, 1999 H O R

P H A G
 p<0.05

Hosseini et al., Nutrition Res 21: 1251-1260, 2001 H O R

P H A G
Devaraj et al., Lipids 37: 931-934, 2002 H O R
P H A G
 Pycnogenol is anti-inflammatory

Tissue damage
free radicals
cytokines &
oxidative stress

blood vessel
leukocyte
Development of Natural Products
for Health Promotion

Plant Extract Characterization Toxicity + Efficacy

Source
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 NO NO

(arginine antagonist) NO

NO

smooth muscle

H O R
P H A G
 endothelial cells of blood vessel wall
Consequence in test animals:
blood platelets
blood stream
Arterial constriction
NO

Gradual blood pressure increase

NO

L-NAME NO
Dilated cardiomyopathy
NO

(arginine antagonist) NO

Induction of cardiac remodeling

NO

smooth muscle

H O R
P H A G
 Group I: Control H2O
group
9 Weeks

Group II: Pycnogenol H2O + Pyc

group 5 Weeks 4 Weeks

Group III: L-NAME L-NAME + H2O

60 female
group 5 Weeks 4 Weeks
C57BL/6N
18 months old Group IV: L-NAME
L-NAME + Pyc
Pycnogenol 5 Weeks 4 Weeks
group

* Pycnogenol was administrated in water, at 30 mg/kg

 160
Systolic Blood Pressure (mmHg)

Un-treated
150 L-NAME-treated
140 * *
*
130
*
120
*

110

100

90

80
0 1 2 3 4 5
L-NAME Treatment period (week)
Starting
Pycnogenol
* P<0.001 compared with un-treated 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 (L) 31.6 1.6 32.0 0.9 38.4 0.8 b 32.7 1.8 c
Ves (L) 14.5 0.7 14.8 1.4 18.3 1.4 a 14.6 0.9 c
SVI (L/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 (L/min/g) 268 21 301 23 389 36 a 297 35 c
SWI (mmHgL/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/L) 771 46 650 54 852 32 762 33
Diastolic function
(mmHg/L) 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
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
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
ECM Degradation
and activity

Myocardial
hypertrophy Cardiac Remodeling
Proinflammatory
Oxidative cytokines
Stress Ventricular Dilation
Hypertension
NF-B

Heart Failure
L-NAME
 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 H S
Natural Health Science