Cardiovascular, Metabolic and Mental

Health Benefits of Vasoactive Nutrients

Professor Peter Howe

Nutritional Physiology Research Centre

University of South Australia

Newcastle, 11th February, 2011

Goal: attain and maintain optimal health

Range of function in individuals

Age

Early Life Growth and

development

Adult Life Maintaining

highest level of function

Older Age Maintaining health and

independence

Disability threshold

• genes

• diet

• lifestyle

Functional capacity (physical & mental fitness)

Danaei G et al. PLoS Med 2009;6(4): e1000058

Preventable Causes of Death in the US in 2005

Obese Australians

Metabolic Syndrome

Obesity

highblood

pressure

high blood fats

high blood glucose, insulin

Heart disease

Mental disorders

Physical disability

obese individuals are 74% more likely to have dementia than normal weight individuals

Inflammation

$1.4B p.a.

$0.9B p.a.

Diabetes

Cancer$1.2B p.a.

AIHW, 2008

Is metabolic syndrome a circulatory disorder?

Endothelial cells• inhibit cell adhesion/aggregation• regulate vasomotor tone • maintain barrier function (selective permeability)

• maintain vascular integrity (inhibit smooth muscle cell

migration, proliferation)

% change in diameter of arteryFlow mediated dilatation

G Born & C Schwartz Vascular Endothelium

smoking high BP high blood sugar high blood fat obesity

NO

Obese

Lean

P

Impaired Endothelial Function in Obesity

Subjects 9 M, 18 F 8 M, 18 F

Age (yr) 49.6 ± 1.6 50.1 ± 1.3 0.80

Height (m) 1.69 ± 0.02 1.67 ± 0.02 0.54

Mass (kg) 100.9 ± 3.4 63.0 ± 1.5 <0.001

BMI (kg/ m2) 35.3 ± 0.9 22.5 ± 0.3 <0.001

DEXA Body f at (%) 43.5 ± 1.2 27.2 ± 1.6 < 0.001

SBP (mmHg) 127.0 ± 2.6 118.6 ± 3.1 < 0.05

DBP (mmHg) 72.4 ± 2.0 67.0 ± 1.8 < 0.05

Large artery elasticity 16.5 ± 0.9 15.5 ± 0.6 0.36

Small artery elasticity 7.0 ± 0.5 7.3 ± 0.5 0.67

FMD (%) 3.2 ± 0.4 5.7 ± 0.7 < 0.01

Davison K, Bircher S, Hill A, Coates A, Howe P, Buckley J. J Obes (accepted 29 Dec 2010)

physical incapacity

reduced fat, glucose metabolism

Cognitive decline

depression neuro-degenerative disorders

endothelium

Endothelial dysfunction

ObesityHigh blood pressure

High blood sugar

High blood fats(incl cholesterol)

Smoking

high BP coronary diseaseanginastroke

impaired blood flow

Can be improved/restored by

regular aerobic exercise and

supplementation with specific bioactive

nutrients

Circulatory effects of endothelial dysfunction

Bioactive nutrients from plantsErdman J et al. J Nutr 2007;137:718S

Cocoa flavanols in dark chocolate

Effect of Cocoa Intake on Blood Pressure: meta-analysis Taubert D et al Arch Intern Med 2007;167:626-634

Cocoa flavanols attenuate Davison K, Berry N, Misan G, Coates AM, Buckley JD, Howe PRC24hr Ambulatory BP Dose-related effects of flavanol-rich cocoa on blood pressure. J Hum Hypertens 2010

Flavanol-rich cocoa attenuates BP responses to exercise

Responses to exercise were tested in borderline hypertensives 2 hours after cocoa by continuously monitoring of beat to beat BP for 5 min at rest (Finapres) then for 10 min whilst cycling at 75% of age-predicted max HR.

BP increas

e(mmHg

)SBP

MAP( AUC)

Time (sec)

DBP( AUC)

LF 30mg flavanols

HF 600mg flavanols

(Berry NM et al, Br J Nutr 2010)

FMD responses to flavanol-rich cocoa supplementation

*

0

1

2

3

4

5

6

7

8

LF HF

FMD(%)

Before

After

* *

0

1

2

3

4

5

6

7

8

LF HF

FMD(%)

Week 0

Week 6

Week 12

Acute response 2hrs after single dose

Chronic response measured > 10hrs after previous dose

Davison K, Coates AM, Buckley JD, Howe PRC. Int J Obesity 2008;32:1289-96

• Cocoa flavanol supplementation can lower BP, attenuate BP responsiveness to stress and counteract hypertension

• not due to antioxidant activity • attributable to increased production of endothelial

NO and enhanced vasodilatation• probably mediated by epicatechin and related

flavanols

Cocoa flavanolsCocoa flavanols

Endothelial functions are dependent on NO production l-arginine

l-arginase NO synthase free radical oxidation

urea nitric oxide (NO) NOx

• reduce LDL oxidation• inhibit platelet aggregation• modulate inflammatory eicosanoids and

cytokines

Meta-analysis: effects of flavonoids on FMD

Hooper, L. et al. Am J Clin Nutr 2008;88:38-50Acute

Chronic

0.0

5.0

10.0

15.0

20.0

0.0

2.0

4.0

6.0

8.0

Large Artery Elasticity Index n=91)

Small Artery Elasticity Index (n=91)

( m

l/m

mH

g x

10

0)

( m

l/m

mH

g x

10

0)

Soy/Dairy + Iso Soy + IsoDairy

0

2

4

6

8

10

Flow mediated vasodilatation (n=55)

% ▲

in

dila

tati

on

fro

m b

ase

line

dia

mete

r

* *Normal

dilatation

0

6

12

18

24

% ▲

in

dila

tati

on

fro

m b

ase

line

dia

mete

r

Nitroglycerine vasodilatation (n=55)

* Sig difference in dilatation compared to Dairy (P<0.05)

Effects of Soy on Arterial FunctionA Thorp et al. J Hypertens 2009;27(Suppl 4):S153

Letenneur L et al. Am J Epidemiol 2007;165:1364–1371

Flavonoid Intake and Cognitive Decline in men aged 65–70 years

intake quartiles

Cognition is linked to endothelial function in older adults with cardiovascular disease

88 independent, community-dwelling older adults (average 70 years)

with mild to severe CVD but without neurological disease and dementia

Forman DE et al. Artery Research 2008;2:35-43

significant correlation with FMD

Can soy isoflavones improve cognitive function?

cerebellum

hippocampus

basal forebrain

prefrontal cortexER β

ER αamygdalapituitaryhypothalamus

ER β

ER α & ER β

ER β

Limbic System

ER α & ER β

ER α ER β

cerebral cortex

Important in visuospatial tasks &

memory recall

Important in spatial

working memory

• ERβ are localised in brain regions associated with learning and memory -- Resnick et al 2004

• Estrogen acts on ERβ to increase cerebral blood flow - Duckles & Krause 2007

ERα ERβ

Estradiol 100 100

Genistein 0.7 13

Daidzein 0.0

1

0.04

Relative binding affinities

We recently found that isoflavone supplementation enhances spatial working memory in men. (Thorp A, Sinn N, Buckley J, Coates A, Howe PR. Br J Nutr 2009)

Cerebral blood flow

• Local regulation of cerebral blood flow critical for brain function

• Ongoing supply required for delivery of glucose, oxygen & nutrients in response to requirements

• Evidence of reduced cerebral blood flow in psychopathologies

o mild cognitive impairment (Sun et al 2007)

o dementias including Alzheimer’s Disease (Crawford 1996, 1998; Warkentin et al 2004)

o ADHD (Bradley & Golden 2001)

o Depression (Yazici et al 1992)

o Schizophrenia (Mori et al 1999)

• High overlap between coronary heart disease and psychopathology

healthguide.howstuffworks.com/stroke-in-depth.htm

Hawkins & Davis, Pharmacol Rev 57:173–185, 2005

The Blood-Brain Barrier Neurovascular

Unit inHealth and Disease

A generalized mechanism for AD pathogenesis that includes breakdown of the blood-brain barrier, the leak of plasma components including soluble amyloid peptide (Aβ42) and autoantibodies into the brain tissue, the binding of both of these components to the surfaces of neurons, and their internalization and accumulation in neurons. Accumulation of Aβ42 causes loss of dendrites and synapses, impairment of neuronal function and eventual cell death.

Nagele RG, New Jersey Institute for Successful Aging, http://www.umdnj.edu/research/publications/fall06/4.htm

Impaired Blood Brain Barrier in Alzheimer's Disease?

Cocoa flavanols and brain perfusion

18% increase in flow velocity in the MCA after eating flavanol-rich cocoa for 1 weekFisher N et al. J Cardiovasc Pharmacol 2006;47:S210

Transcranial Doppler ultrasound

Vasodilator response to breathing 5% CO2

0 30 90 2700

1

2

3

4

5

6

7

8

9

Resveratrol dose (mg)

FM

D r

es

po

ns

e (

%)

* * *

*P<0.05 relative to placebo Mean ± SEM. N=18

Acute dose-related improvement of FMD

(Wong RHX, Howe PRC, Buckley JD, Coates AM, Kunz I, Berry NM. Nutr Metab Cardiovasc Dis 2010)

Resveratrol & cardiovascular health

Trans-resveratrol (3,4,5’-trihydroxystilbene)

0 30 90 2700

1

2

3

4

5

6

7

8

9

Resveratrol dose (mg)

FM

D r

es

po

ns

e (

%)

+1.9+2.4

+3.4

+1.5

1Lekakis et al. 2005;Eur J Cardiov Prev Rehab:12:596-600, 2Davison et al. 2008;Int J Obes: 32:1289-1296, 3Widlansky et al. 2005; Free Rad Bio Med: 38:499-506, 4Widlansky et al. 2007; J Am Coll Nutr: 26:95-102

+2.5 +2.4

+3.7

Red wine polyphenol

extract (600mg)1

Cocoa flavanols (902mg)2

Tea (450ml)3

EGCG (300mg)4

Acute dose-related improvement of FMD

Resveratrol & cardiovascular health

Health benefits of 3 PUFA

Inflammatory disorderspsoriasis/dermatitis rheumatoid arthritis inflammatory bowel disease immune renal disease periodontal diseaseosteoporosis?asthma?

Behavioural disordersdepression, bipolar disordercognitive impairment, ADHD schizophrenia, autism?

Cancer?

Cardiovascular diseaselipids (TG, HDL-C) blood pressurearterial complianceendothelial dilatationplatelet aggregation heart rate / variability arrhythmia cardiac hypertrophyheart failurekidney damage stroke

Diabetesinsulin resistanceabdominal adiposity

Health Benefits of Omega-3 PUFA Infant development & growth

Promoting fitness (physical, mental, reproductive) Counteracting chronic disease (prevention,

treatment)

Resolvins,Protec

tins

Nucleus

PPARDNA

a-Linolenic acidC18:3 LNA

Eicosapentaenoic acid

C20:5 EPA

Linoleic acidC18:2 LA

EICOSANOIDS2-series prostaglandins 3-

series4-series leukotrienes 5-

series

Arachidonic acid C20:4 AA

Thrombosisvasoconstriction

inflammation

Plantslinseed,canolaNUTS

fish,fish oil

plantssafflowersunflowercorn, soy

inhibit

animals

promote

inhibits thromboxane

synthase

Docosahexaenoic acidC22:6 DHA

Docosapentaenoic acid C22:5

DPA

fish

fish,fish oil

excess may

Omega 6

Omega 3

cardiovascular and inflammatory

disorders

Modulates gene expression in regulatory

pathways, e.g. metabolism, inflammation

Physiological effects of PUFAs

Current levels in Australians

~5%

Omega-3 Index - a new marker of health status

Harris and von Schacky, Preventive Medicine 2004

Least Protection

8.1%

Greatest cardiovascular protection

GISSI-P2: 9-10%

CHS3: 8.8%

DART4: 8-9%

SCIMO5: 8.3%

5 epi. studies: 8%

PHS6: 7.3%

Seattle7: 6.5%4%

8%

PHS6: 3.9%

Seattle7: 3.3%

6%

10%

1Nilsen. AJCN. 74:50, 2001; 2Marchioli. Circulation. 105:1897, 2002; 3Mozaffarian. Circulation.107:1372, 2003; 4Burr. Lancet. 2:757, 1989; 5von Schacky Ann Intern Med 130:554, 1999; 6Albert. NEJM. 346:1113, 2002; 7Siscovick. JAMA. 274:1363, 1995

SCIMO5: 3.4%

EPA + DHA % total fatty

acids in red blood cells

Effects of Omega-3 and Exercise on CV risk factors

*Change in HDL

(mmol/L)

-0.4

-0.2

0.0

FO SO

* p < 0.05

Change in TG(mmol/L)

-0.6

-0.4

-0.2

0.0

0.2

FO FOX SO SOX

FMDChange in

artery diam. (mm) p = 0.05

0.000

0.004

0.008

0.012

0.016

FO FOX SO SOX0.000

0.004

0.008

0.012

0.016

FO SO

Hill A, Murphy K, Buckley J, Howe P, Am J Clin Nutr 2007;85:1267

0.0

0.2

0.4

0.6

0.8

0.0

0.2

0.4

*p < 0.05

*

Nutritional Physiology Research Group

Effects on Energy intake, Weight & Body Composition

Change in body weight

kg

-3.0

-2.0

-1.0

0.0

1.0

2.0

FO FOX SO SOX

p = 0.06

-3000

-2000

-1000

0

1000

2000

FO FOX SO SOX

Change in energy intake

kJ

Change in fat mass

kg

Change in lean mass

kg

-3.0

-2.0

-1.0

0.0

1.0

2.0

FO FOX SO SOX

-3.0

-2.0

-1.0

0.0

1.0

2.0

*

* P < 0.05 for oil x time andexercise x time interactions

Hill A, Murphy K, Buckley J, Howe P, Am J Clin Nutr 2007;85:1267

Relationships between erythrocyte LC n-3 PUFA and

body composition• Cross sectional analysis

• BMI, waist circumference, DEXA (% body fat)

• GC analysis of erythrocyte fatty acids

n = 291 BMI WC % Body Fat

EPA -0.08 -0.16* -0.17**

DPA -0.05 -0.13 -0.14*

DHA -0.28** -0.35** -0.33**

Omega -3 Index -0.24** -0.32** -0.31**n = 185 BMI WC % Body

Fat

EPA 0.09 -0.06 -0.15

DPA -0.02 -0.20* -0.23**

DHA -0.08 -0.14 -0.19*

Omega -3 Index -0.04 -0.13 -0.19*

women

men

Waist Circumference vs Omega-3 Index

r= -0.18 P> 0.05

r= -0.36 P<0.0001

Omega-3 and mental health

• Omega-3 deficiency is associated with depression, schizophrenia, aggression, Alzheimer’s Disease, bipolar disorder and developmental disorders.

• Animal studies: omega-3 supplementation linked to improved learning and behaviour in rats.

• Humans trials: increasing evidence of beneficial impact (particularly EPA) on mental health outcomes, especially mood and cognition.

ADHD Intervention Trial

• ADHD is most commonly diagnosed childhood disorder

• Characterised by hyperactivity; poor impulse control; difficulty sustaining attention

• Randomised, placebo-controlled, double-blind 30 wk trial

• 132 children aged 7-12, 2/3rds boys, unmedicated and on upper end of Conners’ ADHD Index

• Evaluated effects of omega-3 supplementation on – inattention– hyperactivity– impulsivity– cognition

Sinn N & Bryan J. J Dev Behav Pediatr 2007

Reductions in inattention

12

13

14

15

16

17

18

19

20

21

Baseline 15 weeks 30 weeks

Pare

nt

rati

ngs

of

DSM

Inatt

enti

on PUFA

Placebo

F = 11.24, p < .01 (Effect size .61)

Reductions in hyperactivity-

impulsivity

10

11

12

13

14

15

16

17

18

Baseline 15 weeks 30 weeks

Pare

nt

rati

ng

s of

Hypera

ctiv

e-I

mpu

lsiv

e PUFA

Placebo

F = 7.68, p < .01 (Effect size .20)

Reductions in cognitive problems

16

17

18

19

20

21

22

23

24

25

26

Baseline 15 weeks 30 weeks

Pare

nt

rati

ng

s of

Cog

nit

ive P

rob

lem

s

PUFA

Placebo

F = 10.06, p < .01 (Effect size .52)

Reductions in overall ADHD

ratings

18

19

20

21

22

23

24

25

26

27

28

Baseline 15 weeks 30 weeks

Pare

nt

rati

ng

s of

AD

HD

In

dex

PUFA

Placebo

F = 9.09, p < .01 (Effect size .59)

Current studies on omega-3 in mental healthcollaborative studies at UniSA and QUT

Comparative effects of EPA and DHA in children with ADHD• 7-12 year old children with ADHD and learning difficulties• 12-month study: 3 x 4 mth crossover• EPA-rich oil, DHA-rich oil, placebo

Baseline red blood cell PUFA results:-• lower n-3 PUFA = poorer literacy • higher DHA = better word reading

Omega-3 and MCIEmerging evidence that n-3 supplementation slows the rate of cognitive decline in adults with MCI or early AD (Panza et al 2007, Kotani et al 2006, Freund-Levi et al 2006)

Comparative effects of EPA and DHA in adults with MCI• 6-month parallel comparison• EPA-rich oil, DHA-rich oil, placebo

lib.az.us

*p < .03

Controlling for age

ADHD Study: baseline RBC n-3 PUFA status CM Milte, N Sinn, AM Coates, J Buckley, PRC Howe. ISSFAL June, 2010

% of total fatty acids

N = 740

1

2

3

4

5

6

7

8

EPA DPA DHA EPA+DHA n-3

With learning difficulties

Without learning difficulties

*

-4

-3

-2

-1

0

1

2

3

4

5

6

EPA DHA Total n-3 AA Total n-6

EPA

DHA

LA

*

*

*

*

*

* *

*

*

Change in RBC PUFA status after 4 months% of total fas

lib.az.us

p .005 Beta .421

Increase in cognitive measureindicates an improvement

DHA predicts improvements in child cognition

p .005Beta .415

Word reading

Switching attention

lib.az.us

p .010 Beta .630

Switching attention

p .018Beta .611

Word reading

DHA predicts improvements in child cognitionLearning Difficulties Subgroup (N = 17)

Divided attention

p .013Beta .682

lib.az.us

DHA predicts improvements in parent ratings

Learning Difficulties Subgroup (N = 17)

P .005 Beta .658

Hyperactivity

P .003 Beta .676

Restless/impulsive

Study measures

• Memory and brain function– cognitive tests: RAVLT, Stroop, Boston naming

task, letter fluency, digits forward/backward, trail making, letter number sequencing

– delayed and immediate recall memory, executive function, attention, information processing speed, mental flexibility, naming

– Memory Functioning Questionnaire (MFQ)

• Quality of life/mood– Satisfaction with life scale (SWLS)

– Geriatric Depression Scale (GDS)

– Health Survey (SF-36)

• Blood samples– RBCs: PUFA content

Erythrocyte polyunsaturated fatty acid status, memory and cognition in older adults with mild cognitive impairment and healthy controlsCM Milte, N Sinn, AM Coates, J Buckley, PRC Howe ISSFAL June, 2010

PUFAs in MCI compared with healthy controls

*P < .05, **P < .01Omega-6 Omega-3

Higher omega-6 Lower omega-3

*

• ↓ verbal paired associates performance– ↑ DPA n-6

• ↓ excluded letter fluency– ↑ DPAn-6

• ↓ RAVLT delayed recall– ↑ LCn-6 PUFA– ↑ LCn-6 PUFA (20 min)

• ↓ digits backwards span performance– ↑ AA

n-6 PUFA and impaired cognition

n=73Age + gender + education

R² = 0.1206

MCI

HealthyBeta= -.272 P < .05

• ↓ verbal paired associates performance– ↑ DPA n-6

• ↓ excluded letter fluency– ↑ DPAn-6

• ↓ RAVLT delayed recall– ↑ LCn-6 PUFA– ↑ LCn-6 PUFA (20 min)

• ↓ digits backwards span performance– ↑ AA

n=73Age + gender + education

MCI

Healthy

Beta = -.276 P < .01 R² = 0.0662

n-6 PUFA and impaired cognition

• ↓ verbal paired associates performance– ↑ DPA n-6

• ↓ excluded letter fluency– ↑ DPAn-6

• ↓ RAVLT delayed recall– ↑ LCn-6 PUFA– ↑ LCn-6 PUFA (20 min)

• ↓ digits backwards span performance– ↑ AA

n=73Age + gender + education

MCI

Healthy

Beta = -.239 P < .05 R² = 0.0715

n-6 PUFA and impaired cognition

MCI

HealthyBeta = -.295 P < .05 R² = 0.1281

• ↓ verbal paired associates performance– ↑ DPA n-6

• ↓ excluded letter fluency– ↑ DPAn-6

• ↓ RAVLT delayed recall– ↑ LCn-6 PUFA– ↑ LCn-6 PUFA (20 min)

• ↓ digits backwards span performance– ↑ AA

n=73Age + gender + education

n-6 PUFA and impaired cognition

Depressive scores ↑ in MCI

* P < 0.01

*8 MCI volunteers & no controls in possible depression range

0

1

2

3

4

5

6

7

MCI Healthy Controls

GDS

Our data support previous work relating PUFA intake to dementia:

– high n-6 PUFA and low n-3 PUFA in erythrocytes may predict memory problems

– relationship of n-3 PUFA status to self-reported health may be due to depression

Effects of EPA and DHA vs LA on depressive symptoms (N=38; mixed model analysis N=50)

Sinn, Milte, Street, Buckley, Coates, Howe (in preparation)

Mixed model analysisEPA (p=.03) and DHA (p=.01) vs LAsignificant after controlling for basal EPA+DHA Correlated with change in ↑EPA+DHA r=.039* ↑AA r=-.031, ↓AA/EPA r=-0.34*

LA DHA EPA-0.8

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

Geriatric Depression Scale

• Both EPA and DHA improved depressive symptoms in elderly with MCI

• Improvements correlated with increases in erythrocyte EPA+DHA

• DHA was associated with improved health-related quality of life, and

to a small degree this explained improved mood

• Improved mood in elderly with MCI may reduce risk of dementia

Summary of key findings

 Centre for Metabolic FitnessOptimising Health Reducing Obesity Modifying Lifestyles

Conclusions• Increased intakes of bioactive nutrients such as

omega-3 PUFA, flavanols and other polyphenols offer multiple physical and mental health benefits

• These benefits may be partly attributable to improvements of circulatory function in chronic cardiometabolic and inflammatory disorders

• Functional foods enriched with bioactive nutrients have the potential to optimise health status, especially when combined with regular exercise

• They may also deliver therapeutic benefits, when used alone or as adjuncts to medication

Investigating nutrition and exercise strategies to improve human health and performance