Flavonoids and Cardiovascular Health – What Flavonoids and Cardiovascular Health – What Progress Has Been Made Towards Public Health Progress Has Been Made Towards Public Health

Recommendations for Flavonoids?Recommendations for Flavonoids?

Carl L. KeenCarl L. KeenDepartment of NutritionDepartment of Nutrition

University of California, DavisUniversity of California, Davisclkeen@ucdavis.educlkeen@ucdavis.edu

ICPH 2013ICPH 2013

Buenos Aires, ArgentinaBuenos Aires, ArgentinaOctober 19October 19thth, 2013, 2013

Disclosures for: Carl L. KeenDisclosures for: Carl L. KeenAFFILIATION/FINANCIAL INTERESTS

CORPORATE ORGANIZATION

Grants/Research Support: Research Support From Mars Incorporated; California Walnut Board & California Strawberry Board

Scientific Advisory Board/Consultant:

Mars/Waltham Scientific Advisory Boards

McCormick Spice Advisory Board

Speakers Bureau: None

Stock Shareholder: None

Other Financial or Material Support/Honorarium:

None

Why address this issue?

Accepted Fact:Accepted Fact: Diets rich in plant foods are associated with Diets rich in plant foods are associated with

an overall positive health status and a decreased risk for an overall positive health status and a decreased risk for certain diseases (e.g. vascular disease, certain cancers) certain diseases (e.g. vascular disease, certain cancers)

Fruits, vegetables and CHDFruits, vegetables and CHD

“ “ There are very few studies to date examining There are very few studies to date examining provision of, or advice to increase the provision of, or advice to increase the consumption of, fruits and vegetables in the consumption of, fruits and vegetables in the absence of additional dietary advice or other absence of additional dietary advice or other lifestyle interventions for the primary prevention of lifestyle interventions for the primary prevention of CVD. The limited evidence suggests advice to CVD. The limited evidence suggests advice to increase fruit and vegetables as a single has increase fruit and vegetables as a single has favorable effects on CVD risk factors but more favorable effects on CVD risk factors but more trials are needed to confirm this.”trials are needed to confirm this.” Hartley et al., The Cochrane Collaboration, 2013.Hartley et al., The Cochrane Collaboration, 2013. (similar points made in Dauchet et al. Nat Rev Cardiol. 2009)(similar points made in Dauchet et al. Nat Rev Cardiol. 2009)

The inverse association seen between the The inverse association seen between the consumption of plant food-rich diets and the risk consumption of plant food-rich diets and the risk for CVD is due to multiple nutritional variables:for CVD is due to multiple nutritional variables:

favourable sodium/potassium profile favourable sodium/potassium profile low in saturated fatlow in saturated fat

high essential nutrient contenthigh essential nutrient contenthigh fibre content high fibre content

high in select “non-essential” phytochemicalshigh in select “non-essential” phytochemicals

Flavonoid Intake and Risk of CHD Mortality Flavonoid Intake and Risk of CHD Mortality – Seven Countries Study– Seven Countries Study

Hertog et al. Arch Intern Med 1995; 155: 381-6

Limited Analysis:Limited Analysis:

Two Classes:Two Classes:

•Flavonol Flavonol quercetinquercetin kaempferolkaempferol myricetinmyricetin

•FlavoneFlavone luteolinluteolin apigeninapigenin

Flavanols & Vascular HealthFlavanols & Vascular Health

Speculation:Speculation:The inverse association often reported between The inverse association often reported between the consumption of plant food-rich diets and the the consumption of plant food-rich diets and the

risk for CVD is due to numerous factors risk for CVD is due to numerous factors including flavonoid-induced changes in: oxidant including flavonoid-induced changes in: oxidant

production and defence; the immune system; production and defence; the immune system; platelet reactivity, vascular reactivity, tissue platelet reactivity, vascular reactivity, tissue

repair and blood pressure. repair and blood pressure.

Biomarkers are needed for the Biomarkers are needed for the assessing an individuals assessing an individuals

status for the phytochemical(s) status for the phytochemical(s) in question, as well as for in question, as well as for following the acute, and following the acute, and chronic impact of these chronic impact of these

phytochemicals on select phytochemicals on select health parameters health parameters

Recommendation 3:Recommendation 3:The FDA should use the same degree of scientific rigor for The FDA should use the same degree of scientific rigor for evaluation of biomarkers across regulatory areas, whether evaluation of biomarkers across regulatory areas, whether they are proposed for use in the arenas of drugs, medical they are proposed for use in the arenas of drugs, medical devices, biologics, or foods and dietary supplements.devices, biologics, or foods and dietary supplements.

Recommendation 4:Recommendation 4:The FDA should take into account a nutrient’s or food’s source as 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 well as any modifying effects of the food or supplement that serves as the delivery vehicle and the dietary patterns associated serves as the delivery vehicle and the dietary patterns associated with consumption of the nutrient or food when reviewing health with consumption of the nutrient or food when reviewing health related label claims and the safety of food and supplements.related label claims and the safety of food and supplements.

Recommendation 5b:Recommendation 5b:Congress should grant the FDA authority to request studies and Congress should grant the FDA authority to request studies and sufficient authority to act on the results of studies on consumer sufficient authority to act on the results of studies on consumer understanding of claims on foods and supplements.understanding of claims on foods and supplements.

Evaluation of Biomarkers 2010-Evaluation of Biomarkers 2010-The Biomarker Evaluation Process RecommendationsThe Biomarker Evaluation Process Recommendations

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

Evaluation of Biomarkers 2010-Evaluation of Biomarkers 2010-Case StudiesCase Studies

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

Consumption of Flavanol-containing Beverage ProductsConsumption of Flavanol-containing Beverage Products

- Uptake of Flavanols into the Circulation-- Uptake of Flavanols into the Circulation-

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Blood Plasma Flavanols/Metabolites after eating a Blood Plasma Flavanols/Metabolites after eating a high-flavanol cocoa producthigh-flavanol cocoa product

Schroeter et al. PNAS 103:1024-29,2006Schroeter et al. PNAS 103:1024-29,2006

Flavanol Metabolites Mixture ProfileFlavanol Metabolites Mixture Profile % of Total% of Total

(−)-epicatechin (−)-epicatechin

(+)-catechin(+)-catechin

Procyanidin Dimer B2Procyanidin Dimer B2

O-methyl-epicatechinO-methyl-epicatechin

Epicatechin-glucuronideEpicatechin-glucuronide

O-methyl-epicatechin-glucuronideO-methyl-epicatechin-glucuronide

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Range ofDietary Relevance

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It is unlikely that the antioxidant properties of the flavanols It is unlikely that the antioxidant properties of the flavanols being studied trigger the observed reduction in platelet being studied trigger the observed reduction in platelet reactivityreactivity

Acceptable Biomarkers – Antioxidant activity?

Pearson et al. Pearson et al. Thromb ResThromb Res 2002; 106: 191-7 2002; 106: 191-7Pearson et al. Pearson et al. Thromb ResThromb Res 2002; 106: 191-7 2002; 106: 191-7

Aspirin + CocoaAspirin + Cocoa

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Like Aspirin, CF (897 mg total flavonoids) can influence blood Like Aspirin, CF (897 mg total flavonoids) can influence blood clotting (PFA-100) times in healthy adultsclotting (PFA-100) times in healthy adults

ReferenceReference TypeType DoseDose DurationDuration SubjectsSubjects nn Platelet TestPlatelet Test

Pace-Asciak ‘96Pace-Asciak ‘96Red wineRed wineWhite wineWhite winePurple grape juicePurple grape juice

375 ml/day375 ml/day375 ml/day375 ml/day500 ml/day500 ml/day

4 wks4 wks Healthy adultsHealthy adults 2424

AggregationAggregation ---- Aggregation Aggregation

AggregationAggregation

Duffy ‘01Duffy ‘01 Black TeaBlack Tea 900 ml/day900 ml/day 4 wks4 wks CAD patientsCAD patients 4949 ---- Aggregation Aggregation

Freedman ‘01Freedman ‘01 Purple grape juicePurple grape juice 7 ml/kg/day7 ml/kg/day 2 wks2 wks Healthy adultsHealthy adults 2020 AggregationAggregation

Rein ‘00Rein ‘00 Cocoa beverageCocoa beverage 300 ml300 ml 1 dose1 dose Healthy adultsHealthy adults 1010 Platelet ReactivityPlatelet Reactivity

Heptinstall ‘06Heptinstall ‘06 Cocoa Beverage Cocoa Beverage 600-900 mg600-900 mg 1 dose1 dose Healthy adultsHealthy adults 1212 Collagen stimulated Collagen stimulated

Platelet AggregationPlatelet Aggregation

Flammmer ‘07Flammmer ‘07 ChocolateChocolate 40 g40 g 1 dose1 dose Heart Heart transplanttransplant

Platelet adhesionPlatelet adhesion

Hamed ‘08Hamed ‘08 ChocolateChocolate 100 g / day100 g / day 1 week1 week Healthy adultsHealthy adults 2828 Platelet ReactivityPlatelet Reactivity

Erlund ’08Erlund ’08 ““Berries”Berries” 100 g100 g 8 wks8 wks Health AdultsHealth Adults 7272 Platelet ReactivityPlatelet Reactivity

Ostertag ’10 Ostertag ’10 Cocoa/ChocolateCocoa/Chocolate ““Moderate Moderate amount”amount” AcuteAcute Meta AnalysisMeta Analysis

10 10

StudiesStudies Platelet ReactivityPlatelet Reactivity

Carnevale ’12Carnevale ’12 ChocolateChocolate 40 g40 g 1 dose1 doseHealthy AdultsHealthy Adults

SmokersSmokers4040 Isoprostanes, NOX2Isoprostanes, NOX2

Ostertag ‘13 Ostertag ‘13 ChocolateChocolate

300 mg300 mg AcuteAcute Healthy AdultsHealthy Adults 4242 Platelet ReactivityPlatelet Reactivity

Effects of Flavanols and Flavanol-Rich Food Effects of Flavanols and Flavanol-Rich Food Consumption on Platelet FunctionConsumption on Platelet Function

Water-soluble tomato concentrate (WSTC I and II) and platelet Water-soluble tomato concentrate (WSTC I and II) and platelet aggregation. aggregation.

Scientific substantiation of a health claim related to water-soluble Scientific substantiation of a health claim related to water-soluble tomato concentrate (WSTC I and II) and platelet aggregation tomato concentrate (WSTC I and II) and platelet aggregation pursuant to Article 13(5) of Regulation (EC) No 1924/2006.pursuant to Article 13(5) of Regulation (EC) No 1924/2006.The EFSA Journal (2009) 1101, 1-15.The EFSA Journal (2009) 1101, 1-15.

Acceptable Biomarkers - Platelet Function ?Acceptable Biomarkers - Platelet Function ?

Scientific opinion on the modification of the authorization of a Scientific opinion on the modification of the authorization of a health claim related to water-soluble tomato concentrate and helps health claim related to water-soluble tomato concentrate and helps to maintain a healthy blood flow and benefits circulation pursuant to maintain a healthy blood flow and benefits circulation pursuant to Article 13(5) of Regulation (EC) No 1924/2006 following a to Article 13(5) of Regulation (EC) No 1924/2006 following a request in accordance with Article 19 of the Regulation (EC) No request in accordance with Article 19 of the Regulation (EC) No 1924/2006.1924/2006.The EFSA Journal (2010) 8(7), 1689.The EFSA Journal (2010) 8(7), 1689.

Vascular Endpoints - FMD/PATVascular Endpoints - FMD/PAT

IschemiaIschemia(arterial occlusion)(arterial occlusion)

HyperemiaHyperemia(transient increase in(transient increase in

organ blood flow)organ blood flow)

Shear StressShear Stress(arterial occlusion)(arterial occlusion)

NO-ProductionNO-Production(endothelial cells)(endothelial cells)

Arterial DilationArterial Dilation(relaxation of smooth(relaxation of smooth

muscle)muscle)

FMD – Nitric Oxide – Flavanol/MetabolitesFMD – Nitric Oxide – Flavanol/Metabolites

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ReferenceReference TypeType DoseDose DurationDuration SubjectsSubjects nn Vascular ResponseVascular Response

Heiss 2005Heiss 2005 CocoaCocoa 88 -370 mg88 -370 mg 1-day1-day SmokersSmokers 1111 ↑↑FMD, RXNOFMD, RXNO

Schroeter 2006Schroeter 2006 CocoaCocoa 917 mg 917 mg 1-day1-day Healthy AdultsHealthy Adults 1616 ↑↑FMD, RHI, RXNOFMD, RHI, RXNO

Heiss 2007Heiss 2007 CocoaCocoa 918 mg 918 mg 1-week1-week SmokersSmokers 11 11 ↑↑FMDFMD

Balzer 2008Balzer 2008 CocoaCocoa 963 mg 963 mg 30-days30-days DiabeticsDiabetics 4141 ↑↑FMDFMD

Heiss 2010Heiss 2010 CocoaCocoa 375 mg375 mg 30-days30-days CAD patientsCAD patients 1616 ↑↑FMD, CAC, NitriteFMD, CAC, Nitrite

Monohan 2011Monohan 2011 CocoaCocoa 69 – 1095 mg69 – 1095 mg 1-day1-day Older HealthyOlder Healthy

AdultsAdults

2323 ↑↑FMDFMD

Loffredo 2012Loffredo 2012 ChocolateChocolate 40 g40 g 1-day1-day SmokersSmokers

Healthy AdultsHealthy Adults

4040 ↑↑FMDFMD, ↓NOX2, ↓NOX2

Nogueira 2012Nogueira 2012 ChocolateChocolate 50 g50 g 4 wks4 wks HypertensiveHypertensive 2020 ↑↑RHIRHI

Mellor 2013Mellor 2013 ChocolateChocolate 13.5 g13.5 g 1-day1-day DiabeticsDiabetics 1010 ↑↑RHIRHI

Effects of Flavanols and Flavanol-Rich Food Effects of Flavanols and Flavanol-Rich Food Consumption on Vascular FunctionConsumption on Vascular Function

How Does FMD/PAT Compare to Blood How Does FMD/PAT Compare to Blood Pressure as An Accepted Marker?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; 19:337-343

• 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

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

Scientific Opinion on the substantiation of a health related to cocoa Scientific Opinion on the substantiation of a health related to cocoa flavanols and maintenance of normal endothelium-dependent flavanols and maintenance of normal endothelium-dependent vasodilation pursuant to article 13(5) of regulation (EC) No vasodilation pursuant to article 13(5) of regulation (EC) No 1924/2006.1924/2006.The EFSA Journal (2012) 10(7), 2809.The EFSA Journal (2012) 10(7), 2809.

Acceptable Biomarkers - FMD?Acceptable Biomarkers - FMD?

Scientific opinion on the substantiation of a health claim related to Scientific opinion on the substantiation of a health claim related to vitamin K2 and contribution to the normal function of the heart and vitamin K2 and contribution to the normal function of the heart and blood vessels (ID 125, further assessment) pursuant to Article 13(1) blood vessels (ID 125, further assessment) pursuant to Article 13(1) of Regulation (EC) No 1924/2006.of Regulation (EC) No 1924/2006.The EFSA Journal (2012) 10(6), 2714.The EFSA Journal (2012) 10(6), 2714.

ReferenceReference TypeType DoseDose DurationDuration SubjectsSubjects nn Blood PressureBlood Pressure

Grassi 2005Grassi 2005 ChocolateChocolate ~ 500 mg~ 500 mg 2 wks2 wks Healthy adultsHealthy adults 1515 ↓↓ SystolicSystolic

Taubert 2007Taubert 2007 ChocolateChocolate 30 mg /day30 mg /day 18 wks18 wks Pre Pre Stage 1 Stage 1 hypertensivehypertensive

4444 ↓ ↓ Systolic, DiastolicSystolic, Diastolic

Davison 2008Davison 2008 CocoaCocoa 902 mg902 mg 12 wks12 wks Overweight/Overweight/

ObeseObese

4949 ↓ ↓ Diastolic, MAPDiastolic, MAP

Balzer 2008Balzer 2008 CocoaCocoa 960 mg960 mg 30 dys30 dys MedicatedMedicated

DiabeticsDiabetics

4141 No ChangeNo Change

Manuiyappa 08Manuiyappa 08 CocoaCocoa ~ 900 mg~ 900 mg 2 wk2 wk HypertensiveHypertensive 2020 No ChangeNo Change

Shiina 2009Shiina 2009 ChocolateChocolate 550 mg550 mg 2 wks2 wks Healthy AdultsHealthy Adults 3939 No ChangeNo Change

Davison 2010Davison 2010 CocoaCocoa 33, 372, 712, 33, 372, 712, 1052 mg /day1052 mg /day

6 wks6 wks HypertensiveHypertensive 5252 ↓↓ 24 hr ambulatory 24 hr ambulatory

SBP, DBP, MAP at SBP, DBP, MAP at

high flavanol intake high flavanol intake

Desideri 2012Desideri 2012 CocoaCocoa 45, 520, 990 45, 520, 990 mg /daymg /day

8 wks8 wks Cognitively Cognitively ImpairedImpaired

9090 ↓ ↓ Systolic, Diastolic (520 and Systolic, Diastolic (520 and 990 mg)990 mg)

Sarria 2013Sarria 2013 CocoaCocoa 416 mg416 mg 4 wks4 wks Healthy AdultsHealthy Adults 4444 No ChangeNo Change

Effects of Flavanols and Flavanol-Rich Food Effects of Flavanols and Flavanol-Rich Food Consumption on Blood PressureConsumption on Blood Pressure

Aatola et al, Circulation 122:2521-8, 2010Aatola et al, Circulation 122:2521-8, 2010

Fruit and Vegetable Intake in Childhood is Inversely Associated Fruit and Vegetable Intake in Childhood is Inversely Associated with Pulse Wave Velocity in Adulthoodwith Pulse Wave Velocity in Adulthood

↑ ↑ PWV = ↑ Arterial StiffnessPWV = ↑ Arterial Stiffness

Vegetable consumption in childhood inversely associated withVegetable consumption in childhood inversely associated withAdulthood PWV (p = 0.02)Adulthood PWV (p = 0.02)

Persistently high consumption of both fruits and vegetables from childhoodPersistently high consumption of both fruits and vegetables from childhoodTo adulthood was also associated with a lower PWV.To adulthood was also associated with a lower PWV.

Evolus® and reduce arterial stiffness. Scientific substantiation of Evolus® and reduce arterial stiffness. Scientific substantiation of a health to a health to Lacotbacillus helveticus Lacotbacillus helveticus fermented Evolus® low-fat fermented Evolus® low-fat milk products and reduction of arterial stiffness pursuant to milk products and reduction of arterial stiffness pursuant to Article 14 of the Regulation (EC) No 1924/2006.Article 14 of the Regulation (EC) No 1924/2006.The EFSA Journal (2009) 1101, 1-15.The EFSA Journal (2009) 1101, 1-15.

Acceptable Biomarkers - Arterial Stiffness?Acceptable Biomarkers - Arterial Stiffness?

Statement on the safety of the “conjugated linoleic acid (CLA)-rich Statement on the safety of the “conjugated linoleic acid (CLA)-rich oils” Clarinol® and Tonalin® TG 80 as Novel Food ingredients.oils” Clarinol® and Tonalin® TG 80 as Novel Food ingredients.The EFSA Journal (2012) 10(5), 2700.The EFSA Journal (2012) 10(5), 2700.

CAD patients (n=519) withHighest

Medium

Lowestnumbers of EPCs.

New Biomarkers - circulating EPC levels? New Biomarkers - circulating EPC levels?

Werner et al., NEJM, 2005

Hill, JM et al. NEJM 348:593-600, 2003Hill, JM et al. NEJM 348:593-600, 2003

Circulating Endothelial Progenitor Cells, Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular RiskVascular Function, and Cardiovascular Risk

Heiss et al., JACC, 2010

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twice a day

Treatment375 mg of flavanols

twice a day

Time (days)Time (days)

• n=16• medicated CAD patients

Day 1 Day 30Day 1

30 1

Control9 mg of flavanols

twice a day

Treatment375 mg of flavanols

twice a day

Wash-out

Day 30

FMD ++++

++++

++++

CF effects in medicated CAD PatientsCF effects in medicated CAD Patients

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Heiss et al., JACC, 2010Heiss et al., JACC, 2010

Blackenberg, S et al. Circulation 121:2388-97, 2010Blackenberg, S et al. Circulation 121:2388-97, 2010

Contribution of 30 Biomarkers to 10-Year Cardiovascular Risk Contribution of 30 Biomarkers to 10-Year Cardiovascular Risk Estimation in 2 Population Cohorts: The MONICA, Risk, Genetics, Estimation in 2 Population Cohorts: The MONICA, Risk, Genetics,

Archiving, and Monograph (MORGAM) Biomarker ProjectArchiving, and Monograph (MORGAM) Biomarker Project

Conclusions/Summary:Conclusions/Summary:

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

Conclusions/Summary:Conclusions/Summary:

With respect to dietary recommendations for With respect to dietary recommendations for “flavonoids”, the emphasis should be on “flavonoids”, the emphasis should be on defined members of the class, rather than the defined members of the class, rather than the entire classentire class

Conclusions/Summary:Conclusions/Summary:

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