ICPH 2013 Buenos Aires, Argentina October 19 th, 2013

Transcription

1 Flavonoids and Cardiovascular Health What Progress Has Been Made Towards Public Health Recommendations for Flavonoids? Carl L. Keen Department of Nutrition University of California, Davis ICPH 2013 Buenos Aires, Argentina October 19 th, 2013

2 Disclosures for: Carl L. Keen AFFILIATION/FINANCIAL INTERESTS CORPORATE ORGANIZATION Grants/Research Support: Scientific Advisory Board/Consultant: Speakers Bureau: Research Support From Mars Incorporated; California Walnut Board & California Strawberry Board Mars/Waltham Scientific Advisory Boards McCormick Spice Advisory Board None Stock Shareholder: None Other Financial or Material Support/Honorarium: None

3 Why address this issue?

4 Accepted Fact: Diets rich in plant foods are associated with an overall positive health status and a decreased risk for certain diseases (e.g. vascular disease, certain cancers)

5 Fruits, vegetables and CHD There are very few studies to date examining provision of, or advice to increase the consumption of, fruits and vegetables in the absence of additional dietary advice or other lifestyle interventions for the primary prevention of CVD. The limited evidence suggests advice to increase fruit and vegetables as a single has favorable effects on CVD risk factors but more trials are needed to confirm this. Hartley et al., The Cochrane Collaboration, (similar points made in Dauchet et al. Nat Rev Cardiol. 2009)

6 The inverse association seen between the consumption of plant food-rich diets and the risk for CVD is due to multiple nutritional variables: favourable sodium/potassium profile low in saturated fat high essential nutrient content high fibre content high in select non-essential phytochemicals

7 Flavonoid Intake and Risk of CHD Mortality Seven Countries Study Limited Analysis: Two Classes: Flavonol quercetin kaempferol myricetin Flavone luteolin apigenin Hertog et al. Arch Intern Med 1995; 155: 381-6

8 Flavanols & Vascular Health Speculation: The inverse association often reported between the consumption of plant food-rich diets and the risk for CVD is due to numerous factors including flavonoid-induced changes in: oxidant production and defence; the immune system; platelet reactivity, vascular reactivity, tissue repair and blood pressure.

9 Biomarkers are needed for the assessing an individuals status for the phytochemical(s) in question, as well as for following the acute, and chronic impact of these phytochemicals on select health parameters

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11 Evaluation of Biomarkers The Biomarker Evaluation Process Recommendations Recommendation 3: The FDA should use the same degree of scientific rigor for evaluation of biomarkers across regulatory areas, whether they are proposed for use in the arenas of drugs, medical devices, biologics, or foods and dietary supplements. Recommendation 4: The FDA should take into account a nutrient s or food s source as well as any modifying effects of the food or supplement that serves as the delivery vehicle and the dietary patterns associated with consumption of the nutrient or food when reviewing health related label claims and the safety of food and supplements. Recommendation 5b: Congress should grant the FDA authority to request studies and sufficient authority to act on the results of studies on consumer understanding of claims on foods and supplements. Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease; IOM, 2010

12 Evaluation of Biomarkers Case Studies Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease; IOM, 2010

13 Consumption of Flavanol-containing Beverage Products - Uptake of Flavanols into the Circulation hours 2 hours 1 hours 0 hours Epicatechin Response (na) Catechin 0

14 Blood Plasma Flavanols/Metabolites after eating a high-flavanol cocoa product Circulating Flavanols/Metabolites [nm] epicatechin catechin 4'MEC EC-7Gluc 4'MEC-Gluc Sum time [h] Schroeter et al. PNAS 103: ,2006

15 It is unlikely that the antioxidant properties of the flavanols being studied trigger the observed reduction in platelet reactivity Human Plasma [ORAC] Flavanol Metabolites Mixture Profile % of Total 2.5e+5 Flavanol Metabolites ( )-epicatechin (+)-catechin Procyanidin Dimer B2 O-methyl-epicatechin Epicatechin-glucuronide Trolox equivalent [µmol/l] 2.0e+5 1.5e+5 1.0e+5 5.0e+4 Range of Dietary Relevance * * O-methyl-epicatechin-glucuronide [µmol/l]

16 Acceptable Biomarkers Antioxidant activity?

17 Like Aspirin, CF (897 mg total flavonoids) can influence blood clotting (PFA-100) times in healthy adults Cocoa Aspirin Aspirin + Cocoa Closure Time (s) * * * * * Epi-collagen Cocoa Aspirin Aspirin + Cocoa Closure Time (s) * * * ADP-collagen Time (hr) Pearson et al. Thromb Res 2002; 106: 191-7

18 Effects of Flavanols and Flavanol-Rich Food Consumption on Platelet Function Reference Type Dose Duration Subjects n Platelet Test Pace-Asciak 96 Red wine White wine Purple grape juice 375 ml/day 375 ml/day 500 ml/day 4 wks Healthy adults 24 Aggregation -- Aggregation Aggregation Duffy 01 Black Tea 900 ml/day 4 wks CAD patients Aggregation Freedman 01 Purple grape juice 7 ml/kg/day 2 wks Healthy adults 20 Aggregation Rein 00 Cocoa beverage 300 ml 1 dose Healthy adults 10 Platelet Reactivity Heptinstall 06 Cocoa Beverage mg 1 dose Healthy adults 12 Flammmer 07 Chocolate 40 g 1 dose Heart transplant Collagen stimulated Platelet Aggregation Platelet adhesion Hamed 08 Chocolate 100 g / day 1 week Healthy adults 28 Platelet Reactivity Erlund 08 Berries 100 g 8 wks Health Adults 72 Platelet Reactivity Ostertag 10 Cocoa/Chocolate Moderate amount Acute Carnevale 12 Chocolate 40 g 1 dose Meta Analysis Healthy Adults Smokers 10 Studies Platelet Reactivity 40 Isoprostanes, NOX2 Ostertag 13 Chocolate 300 mg Acute Healthy Adults 42 Platelet Reactivity

19 Acceptable Biomarkers - Platelet Function? Water-soluble tomato concentrate (WSTC I and II) and platelet aggregation. Scientific substantiation of a health claim related to water-soluble tomato concentrate (WSTC I and II) and platelet aggregation pursuant to Article 13(5) of Regulation (EC) No 1924/2006. The EFSA Journal (2009) 1101, Scientific opinion on the modification of the authorization of a health claim related to water-soluble tomato concentrate and helps to maintain a healthy blood flow and benefits circulation pursuant to Article 13(5) of Regulation (EC) No 1924/2006 following a request in accordance with Article 19 of the Regulation (EC) No 1924/2006. The EFSA Journal (2010) 8(7), 1689.

20 Vascular Endpoints - FMD/PAT Ischemia (arterial occlusion) Shear Stress (arterial occlusion) Hyperemia (transient increase in organ blood flow) NO-Production (endothelial cells) Arterial Dilation (relaxation of smooth muscle)

21 FMD Nitric Oxide Flavanol/Metabolites a 12 Cocoa-mediated increases in FMD are inhibited by L-NMMA infusion and NOS inhibition b 4 c 3,500 hfcd lfcd Flow-mediated dilation (%) * # * # *# *# Increase RXNO (nm) * # * # * # * * Sum of plasma flavanols (nm) 3,000 2,500 2,000 1,500 1, * # * # * * * * # * # * # Time after cocoa drink (h) Schroeter et al. PNAS 2006

22 Epicatechin - FMD d PAT index *# *# * * * Water 1 mg/kg Epicatechin Time after Ingestion (h) Flow-mediated dilation (%) b *# *# Water 1 mg/kg Epicatechin Time after Ingestion (h) Schroeter et al. PNAS 103: ,2006

23 Effects of Flavanols and Flavanol-Rich Food Consumption on Vascular Function Reference Type Dose Duration Subjects n Vascular Response Heiss 2005 Cocoa mg 1-day Smokers 11 FMD, RXNO Schroeter 2006 Cocoa 917 mg 1-day Healthy Adults 16 FMD, RHI, RXNO Heiss 2007 Cocoa 918 mg 1-week Smokers 11 FMD Balzer 2008 Cocoa 963 mg 30-days Diabetics 41 FMD Heiss 2010 Cocoa 375 mg 30-days CAD patients 16 FMD, CAC, Nitrite Monohan 2011 Cocoa mg 1-day Older Healthy Adults 23 FMD Loffredo 2012 Chocolate 40 g 1-day Smokers Healthy Adults 40 FMD, NOX2 Nogueira 2012 Chocolate 50 g 4 wks Hypertensive 20 RHI Mellor 2013 Chocolate 13.5 g 1-day Diabetics 10 RHI

24 How Does FMD/PAT Compare to Blood Pressure as An Accepted Marker? Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events and restenosis in patients undergoing coronary stent implantation: a prospective study. Akcakoyun M, et. al. Coron Artery Dis, 2008; 19: Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. Kitta Y, et. al., J Am Coll Cardiol 2009;53:323-30

25 Rubinshtein, R et al. Eur Heart J 31:1142-8, 2010

26 Acceptable Biomarkers - FMD? Scientific Opinion on the substantiation of a health related to cocoa flavanols and maintenance of normal endothelium-dependent vasodilation pursuant to article 13(5) of regulation (EC) No 1924/2006. The EFSA Journal (2012) 10(7), Scientific opinion on the substantiation of a health claim related to vitamin K2 and contribution to the normal function of the heart and blood vessels (ID 125, further assessment) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. The EFSA Journal (2012) 10(6), 2714.

27 Effects of Flavanols and Flavanol-Rich Food Consumption on Blood Pressure Reference Type Dose Duration Subjects n Blood Pressure Grassi 2005 Chocolate ~ 500 mg 2 wks Healthy adults 15 Systolic Taubert 2007 Chocolate 30 mg /day 18 wks Pre Stage 1 hypertensive Davison 2008 Cocoa 902 mg 12 wks Overweight/ Obese Balzer 2008 Cocoa 960 mg 30 dys Medicated Diabetics 44 Systolic, Diastolic 49 Diastolic, MAP 41 No Change Manuiyappa 08 Cocoa ~ 900 mg 2 wk Hypertensive 20 No Change Shiina 2009 Chocolate 550 mg 2 wks Healthy Adults 39 No Change Davison 2010 Cocoa 33, 372, 712, 1052 mg /day 6 wks Hypertensive hr ambulatory SBP, DBP, MAP at high flavanol intake Desideri 2012 Cocoa 45, 520, 990 mg /day 8 wks Cognitively Impaired 90 Systolic, Diastolic (520 and 990 mg) Sarria 2013 Cocoa 416 mg 4 wks Healthy Adults 44 No Change

28 Fruit and Vegetable Intake in Childhood is Inversely Associated with Pulse Wave Velocity in Adulthood Vegetable consumption in childhood inversely associated with Adulthood PWV (p = 0.02) Persistently high consumption of both fruits and vegetables from childhood To adulthood was also associated with a lower PWV. PWV = Arterial Stiffness Aatola et al, Circulation 122:2521-8, 2010

29 Acceptable Biomarkers - Arterial Stiffness? Evolus and reduce arterial stiffness. Scientific substantiation of a health to Lacotbacillus helveticus fermented Evolus low-fat milk products and reduction of arterial stiffness pursuant to Article 14 of the Regulation (EC) No 1924/2006. The EFSA Journal (2009) 1101, Statement on the safety of the conjugated linoleic acid (CLA)-rich oils Clarinol and Tonalin TG 80 as Novel Food ingredients. The EFSA Journal (2012) 10(5), 2700.

30 New Biomarkers - circulating EPC levels? CAD patients (n=519) with Highest Medium Lowest numbers of EPCs. Werner et al., NEJM, 2005

31 Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk Hill, JM et al. NEJM 348: , 2003

32 CF effects in medicated CAD Patients n=16 medicated CAD patients Control 9 mg of flavanols twice a day Treatment 375 mg of flavanols twice a day Control 9 mg of flavanols twice a day Treatment 375 mg of flavanols twice a day Time (days) Wash-out Day 1 Day 30 Day 1 Day 30 Readouts FMD CAC BP NOx Heiss et al., JACC, 2010

33 CF Has Vascular Effects in CAD Patients a b FMD (%) Systolic BP (mmhg) pre post pre post C Heiss et al., JACC, 2010 * FI *# *# a CD34 + /KDR + (%MNC) b CD133 + /KDR + (%MNC) * C FI *# 1.0 *# 0.5 *# 0.0 pre post pre post

34 Contribution of 30 Biomarkers to 10-Year Cardiovascular Risk Estimation in 2 Population Cohorts: The MONICA, Risk, Genetics, Archiving, and Monograph (MORGAM) Biomarker Project Blackenberg, S et al. Circulation 121: , 2010

35 Conclusions/Summary: The results obtained from numerous intervention trials support the concept that the consumption of flavanol-rich foods can result in acute (1 30 days) improvements in vascular health parameters that are suggestive of a decreased risk for select chronic diseases.

36 Conclusions/Summary: With respect to dietary recommendations for flavonoids, the emphasis should be on defined members of the class, rather than the entire class

37 Conclusions/Summary: When considering the development of biomarkers for following the effects of a food or a non-essential nutrient on the risk for select diseases, there may be value in aiming for a model that takes into consideration the effects of the food/nutrient on multiple risk factors for the disease of interest.