heart failure is a progressive disease the heart is unable to maintain output sufficient to meet...

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



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


Significant ventricular dilation,and incomplete ejection ofoxygenated blood to organs

Significant ventricular dilation,and incomplete ejection ofoxygenated blood to organs






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


NO NO

NO

NO

NO

NO


H

P H A G

O R

L-NAME(arginine antagonist)


smooth muscle


NO NO

NO

NO

NO

NO


H

P H A G

O R



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

heart failure is a progressive disease the heart is unable to maintain output sufficient to meet...

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