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Cardiovascular, Metabolic and Mental Health Benefits of Vasoactive Nutrients Professor Peter Howe Nutritional Physiology Research Centre University of.

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Presentation on theme: "Cardiovascular, Metabolic and Mental Health Benefits of Vasoactive Nutrients Professor Peter Howe Nutritional Physiology Research Centre University of."— Presentation transcript:

1 Cardiovascular, Metabolic and Mental Health Benefits of Vasoactive Nutrients Professor Peter Howe Nutritional Physiology Research Centre University of South Australia Newcastle, 11 th February, 2011

2 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)

3 Danaei G et al. PLoS Med 2009;6(4): e Preventable Causes of Death in the US in 2005

4 Obese Australians

5 Metabolic Syndrome Obesity high blood 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

6 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)

7 % change in diameter of artery Flow mediated dilatation G Born & C Schwartz Vascular Endothelium smoking high BP high blood sugar high blood fat obesity NO

8 Obese Lean P Impaired Endothelial Function in Obesity Davison K, Bircher S, Hill A, Coates A, Howe P, Buckley J. J Obes (accepted 29 Dec 2010)

9 physical incapacity reduced fat, glucose metabolism Cognitive decline depression neuro- degenerative disorders endothelium Endothelial dysfunction Obesity High blood pressure High blood sugar High blood fats (incl cholesterol) Smoking high BP coronary disease angina stroke impaired blood flow Can be improved/restored by regular aerobic exercise and supplementation with specific bioactive nutrients Circulatory effects of endothelial dysfunction

10 Bioactive nutrients from plants Erdman J et al. J Nutr 2007;137:718S Cocoa flavanols in dark chocolate

11 Effect of Cocoa Intake on Blood Pressure: meta-analysis Taubert D et al Arch Intern Med 2007;167: Cocoa flavanols attenuate Davison K, Berry N, Misan G, Coates AM, Buckley JD, Howe PRC 24hr Ambulatory BP Dose-related effects of flavanol-rich cocoa on blood pressure. J Hum Hypertens 2010

12 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 increase (mmHg) SBP MAP ( AUC) Time (sec) DBP ( AUC) LF 30mg flavanols HF 600mg flavanols (Berry NM et al, Br J Nutr 2010)

13 FMD responses to flavanol-rich cocoa supplementation * LF HF FMD (%) Before After * * 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:

14 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 flavanols Endothelial functions are dependent on NO production l-arginine l-arginase NO synthase free radical oxidation urea nitric oxide (NO)NO x reduce LDL oxidation inhibit platelet aggregation modulate inflammatory eicosanoids and cytokines

15 Meta-analysis: effects of flavonoids on FMD Hooper, L. et al. Am J Clin Nutr 2008;88:38-50 Acute Chronic

16 Large Artery Elasticity Index n=91) Small Artery Elasticity Index (n=91) ( ml/mmHg x100) Soy/Dairy + Iso Soy + Iso Dairy Flow mediated vasodilatation (n=55) % in dilatation from baseline diameter ** Normal dilatation % in dilatation from baseline diameter Nitroglycerine vasodilatation (n=55) * Sig difference in dilatation compared to Dairy (P<0.05) Effects of Soy on Arterial Function A Thorp et al. J Hypertens 2009;27(Suppl 4):S153

17 Letenneur L et al. Am J Epidemiol 2007;165:1364–1371 Flavonoid Intake and Cognitive Decline in men aged 65–70 years intake quartiles

18 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

19 Can soy isoflavones improve cognitive function? cerebellum hippocampus basal forebrain prefrontal cortex ER β ER α amygdalapituitary hypothalamus 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 ER β are localised in brain regions associated with learning and memory -- Resnick et al 2004 Estrogen acts on ER β to increase cerebral blood flow - Duckles & Krause 2007 ER α ER β Estradiol100 Genistein0.713 Daidzein 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)

20 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 Alzheimers 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

21 Hawkins & Davis, Pharmacol Rev 57:173–185, 2005 The Blood-Brain Barrier The Blood-Brain Barrier Neurovascular Unit in Health and Disease

22 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, Impaired Blood Brain Barrier in Alzheimer's Disease?

23 Cocoa flavanols and brain perfusion 18% increase in flow velocity in the MCA after eating flavanol-rich cocoa for 1 week Fisher N et al. J Cardiovasc Pharmacol 2006;47:S210 Transcranial Doppler ultrasound Vasodilator response to breathing 5% CO 2

24 *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)

25 1 Lekakis et al. 2005;Eur J Cardiov Prev Rehab:12: , 2 Davison et al. 2008;Int J Obes: 32: , 3 Widlansky et al. 2005; Free Rad Bio Med: 38: , 4 Widlansky et al. 2007; J Am Coll Nutr: 26: 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

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27 Health benefits of 3 PUFA Health benefits of 3 PUFA Inflammatory disorders psoriasis/dermatitis rheumatoid arthritis inflammatory bowel disease immune renal disease periodontal disease osteoporosis? asthma? Behavioural disorders depression, bipolar disorder cognitive impairment, ADHD schizophrenia, autism? Cancer? Cardiovascular disease lipids (TG, HDL-C) blood pressure arterial compliance endothelial dilatation platelet aggregation heart rate / variability arrhythmia cardiac hypertrophy heart failure kidney damage stroke Diabetes insulin resistance abdominal adiposity Health Benefits of Omega-3 PUFA Infant development & growth Promoting fitness (physical, mental, reproductive) Counteracting chronic disease (prevention, treatment)

28 Resolvins, Protectins Nucleus PPAR DNA a-Linolenic acid C18:3LNA Eicosapentaenoic acid C20:5EPA Linoleic acid C18:2LA EICOSANOIDS 2-series prostaglandins 3-series 4-series leukotrienes 5-series Arachidonic acid C20:4AA Thrombosis vasoconstriction inflammation Plants linseed, canola NUTS fish, fish oil plants safflower sunflower corn, soy inhibit animals promote inhibits thromboxane synthase Docosahexaenoic acid C22:6DHA Docosapentaenoic acid C22:5 DPA fish fish, fish oil excess may Omega 6Omega 3 cardiovascular and inflammatory disorders Modulates gene expression in regulatory pathways, e.g. metabolism, inflammation Physiological effects of PUFAs

29 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-P 2 : 9-10% CHS 3 : 8.8% DART 4 : 8-9% SCIMO 5 : 8.3% 5 epi. studies: 8% PHS 6 : 7.3% Seattle 7 : 6.5% 4% 8% PHS 6 : 3.9% Seattle 7 : 3.3% 6% 10% 1 Nilsen. AJCN. 74:50, 2001; 2 Marchioli. Circulation. 105:1897, 2002; 3 Mozaffarian. Circulation.107:1372, 2003; 4 Burr. Lancet. 2:757, 1989; 5 von Schacky Ann Intern Med 130:554, 1999; 6 Albert. NEJM. 346:1113, 2002; 7 Siscovick. JAMA. 274:1363, 1995 SCIMO 5 : 3.4% EPA + DHA % total fatty acids in red blood cells

30 Effects of Omega-3 and Exercise on CV risk factors * Change in HDL (mmol/L) * p < 0.05 Change in TG (mmol/L) FMD Change in artery diam. (mm) p = FOFOXSOSOX FOSO Hill A, Murphy K, Buckley J, Howe P, Am J Clin Nutr 2007;85:1267 * p < 0.05 *

31 Nutritional Physiology Research Group Effects on Energy intake, Weight & Body Composition Change in body weight kg p = 0.06 FOFOXSOSOX Change in energy intake kJ Change in fat mass kg Change in lean mass kg * * P < 0.05 for oil x time and exercise x time interactions Hill A, Murphy K, Buckley J, Howe P, Am J Clin Nutr 2007;85:1267

32 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 = 291BMIWC% Body Fat EPA *-0.17** DPA * DHA-0.28**-0.35**-0.33** Omega -3 Index-0.24**-0.32**-0.31** n = 185BMIWC% Body Fat EPA DPA *-0.23** DHA * Omega -3 Index *

33 women men Waist Circumference vs Omega-3 Index r= P> 0.05 r= P<0.0001

34 Omega-3 and mental health Omega-3 deficiency is associated with depression, schizophrenia, aggression, Alzheimers 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.

35 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

36 Reductions in inattention Baseline15 weeks30 weeks Parent ratings of DSM Inattention PUFA Placebo F = 11.24, p <.01 (Effect size.61) Reductions in hyperactivity-impulsivity Baseline15 weeks30 weeks Parent ratings of Hyperactive-Impulsive PUFA Placebo F = 7.68, p <.01 (Effect size.20)

37 Reductions in cognitive problems Baseline15 weeks30 weeks Parent ratings of Cognitive Problems PUFA Placebo F = 10.06, p <.01 (Effect size.52) Reductions in overall ADHD ratings Baseline15 weeks30 weeks Parent ratings of ADHD Index PUFA Placebo F = 9.09, p <.01 (Effect size.59)

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39 Current studies on omega-3 in mental health Current studies on omega-3 in mental health collaborative 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 MCI Emerging 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

40 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 = EPADPADHAEPA+DHAn-3 With learning difficulties Without learning difficulties *

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

42 lib.az.us p.005 Beta.421 Increase in cognitive measure indicates an improvement DHA predicts improvements in child cognition p.005 Beta.415 Word reading Switching attention

43 lib.az.us p.010 Beta.630 Switching attention p.018 Beta.611 Word reading DHA predicts improvements in child cognition Learning Difficulties Subgroup (N = 17) Divided attention p.013 Beta.682

44 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

45 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 controls CM Milte, N Sinn, AM Coates, J Buckley, PRC HoweISSFAL June, 2010

46 PUFAs in MCI compared with healthy controls *P <.05, **P <.01 Omega-6Omega-3 Higher omega-6 Lower omega-3 *

47 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=73 Age + gender + education R² = MCI Healthy Beta= P <.05

48 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=73 Age + gender + education MCI Healthy Beta = P <.01 R² = n-6 PUFA and impaired cognition

49 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=73 Age + gender + education MCI Healthy Beta = P <.05 R² = n-6 PUFA and impaired cognition

50 MCI Healthy Beta = P <.05 R² = 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=73 Age + gender + education n-6 PUFA and impaired cognition

51 Depressive scores in MCI * P < 0.01 * 8 MCI volunteers & no controls in possible depression range MCIHealthy 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

52 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 analysis EPA (p=.03) and DHA (p=.01) vs LA significant after controlling for basal EPA+DHA Correlated with change in EPA+DHA r=.039* AA r=-.031, AA/EPA r=-0.34* 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

53 Centre for Metabolic Fitness Centre for Metabolic Fitness Optimising 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

54 Investigating nutrition and exercise strategies to improve human health and performance


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