1. Heart failure is a progressive disease The heart is unable to maintain output sufficient to meet metabolic demands 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.

3. Constituents Procyanidins: linked catechin subunits Procyanidins: linked catechin subunits Composition defined in: United States Pharmacopoeia (28) Composition defined in: United States Pharmacopoeia (28)

4. Pycnogenol ® arginine + O 2 smooth muscle blood platelets blood stream NO endothelial cells of blood vessel wall H P HA G O R Fitzpatrick et al., J Cardiovasc Pharm 32: 509-515, 1998

5. Enhanced Platelet Aggregration in Smokers Persistence of Pycnogenol's Activity

10. H P HA G O R Pütter et al., Thromb Res 95: 155-161, 1999 NO Pycnogenol 

11. Hosseini et al., Nutrition Res 21: 1251-1260, 2001 H P HA G O R p<0.05

12. H P HA G O R Devaraj et al., Lipids 37: 931-934, 2002

13. Pycnogenol ® is anti-inflammatory blood vessel Tissue damage cytokines & oxidative stress cytokines & oxidative stress leukocyte free radicals

14. Development of Natural Products for Health Promotion Plant Source Extract Characterization Toxicity + Efficacy In Vitro Animals Humans

17. Left = Control Right = Heart Failure

18. 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

19. Hypertension escalates work-load of the heart to meet metabolic demands The heart compensates with increased stroke volume and heart rate Left ventricle

20. 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

21. 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 Heart muscle wears out and cell death causes thinning of the ventricular wall and sagging of the ventricle

22. Significant ventricular dilation, and incomplete ejection of oxygenated blood to organs Significant ventricular dilation, and incomplete ejection of oxygenated blood to organs 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 Heart muscle wears out and cell death causes thinning of the ventricular wall and sagging of the ventricle

23. 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

24. 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 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

25. smooth muscle blood platelets blood stream NO endothelial cells of blood vessel wall H P HA G O R L-NAME (arginine antagonist) L-NAME (arginine antagonist)

26. smooth muscle blood platelets blood stream NO endothelial cells of blood vessel wall H P HA G O R L-NAME (arginine antagonist) L-NAME (arginine antagonist) Consequence in test animals: Arterial constriction Gradual blood pressure increase Dilated cardiomyopathy Induction of cardiac remodeling

27. Group I: Control group Group II: Pycnogenol ® group Group III: L-NAME group Group IV: L-NAME – Pycnogenol ® group H2OH2O 9 Weeks H2OH2O H2OH2O L-NAME + 5 Weeks4 Weeks Pyc L-NAME + + 5 Weeks 4 Weeks 60 female C57BL/6N 18 months old * Pycnogenol ® was administrated in water, at 30 mg/kg

28. * P<0.001 compared with un-treated Starting Pycnogenol ® supplementation

30. Parameter (unit)ControlPycnogenolL-NAMEL-NAME-PYC Hemodynamics Body Weight (g)34.0 ± 1.832.9 ± 1.828.0 ± 1.1 a 34.1 ± 2.2 c Heart W/Body W (mg/g)4.3 ± 0.24.2 ± 0.15.0 ± 0.1 a 4.1 ± 0.2 c HR (beats/min)541.0 ± 10.6530.8 ± 10.0518.4 ± 12.0526.1 ± 9.0 V ed ( µ L) 31.6 ± 1.632.0 ± 0.938.4 ± 0.8 b 32.7 ± 1.8 c V es ( µ L) 14.5 ± 0.714.8 ± 1.418.3 ± 1.4 a 14.6 ± 0.9 c SVI ( µ L/g) 0.53 ± 0.030.56 ± 0.050.76 ± 0.07 a 0.58 ± 0.06 c EF (%)58.8 ± 1.757.3 ± 2.954.8 ± 2.757.1 ± 2.3 CI ( µ L/min/g) 268 ± 21301 ± 23389 ± 36 a 297 ± 35 c SWI (mmHg ·µ L/g) 33.1 ± 2.635.6 ± 2.750.1 ± 4.6 a 36.4 ± 4.1 c Systolic function dP/dt max (mmHg/s)7309 ± 2667654 ± 3858633 ± 422 a 7327 ± 256 c PRSW (mmHg)80.9 ± 1.978.5 ± 1.892.0 ± 4.5 a 85.0 ± 4.3 dP/dt max -V ed (mmHg/s/ µ L) 771 ± 46650 ± 54852 ± 32762 ± 33 Diastolic function  (mmHg/ µ L) 0.08 ± 0.010.14 ± 0.030.04 ± 0.01 a 0.12 ± 0.02 c dP/dt min (mmHg/s)-5490 ± 266-5863 ± 343-6303 ± 273 a -5520 ± 253 c τ Weiss (ms)7.0 ± 0.57.1 ± 0.56.8 ± 0.47.2 ± 0.6 Vascular function P max (mmHg)78.4 ± 1.374.0 ± 1.6 a 80.2 ± 2.178.52 ± 1.2 E a (mmHg/ µ L) 5.4 ± 0.65.1 ± 0.54.4 ± 0.65.2 ± 0.5

31. 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.

32. a P<0.01 compared with control; b P<0.05 compared with L-NAME

33. Myocardial hypertrophy ↑ MMPs gene expression and activity Proinflammatory cytokines Hypertension Oxidative Stress NF-  B L-NAME Cardiac Remodeling Heart Failure Ventricular Dilation ECM Degradation

34. 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 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 NHS Natural Health Science