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Are Effective for CAD Prevention and Rehabilitation?

Joe Carlson, PhD, RD Associate Professor Director Div Sports & Cardiovascular , Dept of Radiology; College of Osteopathic Medicine Michigan State University, East Lansing, Michigan Are Phytochemicals Effective for CAD Prevention and Rehabilitation? I. Background – definitions; overview of evidence

II. classification with & beverage examples

III. Summary of evidence phytochemical rich food & supplements

IV. What is the best approach based on evidence to date? V. Summary-Applications and resource list. I. Background- What are Phytochemicals? Phyto = ; also called Phyto- A. Definitions: Many refer to non- plant food components with potential or known health benefits but do not have established intake recommendations like & .

• Biologically active but non-nutrient substances found in ; includes antioxidants and . Med Dictionary for the Health Profess & Nursing 2012 • The active chemical components, or constituents, present in a plant that account for its medicinal properties. Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier.

B. Are Phytochemicals Essential? Depends on definition -Most definitions do not classify as “nutrients” referring to essential vitamins & minerals that cause deficiency when not consumed. • FACT-selected phytochemicals are precursors or isomers; beta - Vit A precursor, & tocotrienols - Vit E isomers I. What is the best Approach for prevention and Management of CAD? • Evidenced Based Heart Healthy Phytochemical Rich Dietary pattern?

= ESTABLISHED BENEFITS

• OR Evidenced Based Heart Healthy Dietary pattern and added phytochemical supplements? + = = +-? II. Big Picture Phytochemical Classification Exs commonly studied with known or potential vascular benefits THIOLS (1 prim group) (6 prim groups) (4 prim groups) Flavanoids Tocopherols & Tocotrienols- -Alpha & Beta -Alpha, - - -Beta, -Luteolin - -Gamma -Rutin Allylic Phyto-estrogens -Limonoids - - -S-AllylCysteine - -Alpha Gluoslinates - Diterpenes -Dithiolthiones -Geneistein -Ginkolides - - -Carnosol -Sulforphane & -Anthocyanins -Xanthophylis - Phytosterols Epicatechins - Effects of HEART HEALTYH GUIDELINES and Nutrient and Phytochemical Rich , on CAD Risk Factors:

-Peterson et al Nutrition Rev 70(9) - M Bouchenek JourMed Food 2013 -RH LiuAm J Clin Nutr 2003;78;  - F Visioli et al Cardiov Res 47(2000) - RH Liu J Sci 46 (2007) -P Kris Ethertonet al J of Nutrit 2007 ;138 Ex) Carotenoids-Carotenes Sources- Key Forms

Forms- Lycopene

Functions & Health Implications: -carotene CAD Potential Benefits -Anti-oxidant roles -peroxyl radical & -carotene singlet O2 quenchers - Anti-thrombotic; Anti-inflammatory- Other Benefits • Eye Health- protect macula (lutein) • Reduce prostate risk (lycopene) Lutein Food vs. Supplements? • Optimal levels in blood, tissues unknown • Krinsky, NI, Johnson EJ. (2005) actions and their relation to health and disease. Molecular Aspects of Medicine, Elsevier 26 459-516 Phytochemical Rich Phytochemical(s) Examples THIOLS Allium -, , , Allylic sulfides--Allicin -S-AllylCysteine THIOLS – - , , -Dithiolthiones , Brussels sprouts, , , -Isothiocyanates , -Sulforphane Indoles

Compositae plants () Silymarin

Solanaceous vegetables -tomatoes, peppers TERPENES-

TERPENES- Umbelliferous vegetables (, , Carotenoids-Lycopene, cilantro, , ) Lutein Polyacetylenes Phytochemical Rich Foods & Beverage Phytochemicals Examples

Citrus TERPENES - (oranges, , ) Carotenoids- glucarates

Non citrus Fruits , , , - quercetin, , , Phenols- many

Legumes- () & Flavonoids (isoflavones) ()

PHENOLS, Flavonoids -lutein Whole Grains (, , , ,) zeaxanthin, b-cryptoxanthin

Herbs, spices , mint, rosemary, Flavonoids, thyme, oregano, sage, , tummeric, Terpenes , , ginger Coffee, Green tea, black tea, PHENOLS- Glycyrrhizin, wine, beer Catechins, Quercetin III. What is the evidence that phytochemicals protect against CAD?

STUDY TYPE Evidence Comments Epidemiological Studies: STRONG Well established relationship phyto-chemical rich foods, Limitations – no cause and effect food groups and patterns from cross-sectional. Does not isolate impact of individual phytochemicals Molecular & Nutri-genomic Promising mechanisms or pathways up or down- studies on selected But……. regulated by phytochemicals or drugs are phytochemical influenced by many factors. For ex) inflammatory pathways Experimental Studies: Phyto- STRONG •Can reduce CAD Risk factors chemical rich foods & food •Can reduce CAD progression patterns • Can reduce CAD morbidity & mortality * FOOD NUTRIENT SYNERGY IMPORTANT Experimental Studies: Mixed Examples – Soy; Garlic, Ginkgo biloba Isolated Phytochemical Some + , beet juice extracts supplements Some - ~ 25% US FDA approved drugs plant origins Many ?s •In US weak regulation, products &marketing lead to confusion The effect of a garlic preparation on plasma lipid levels in moderately hypercholesterolemic adults Christopher D. Gardner *, Lorraine M. Chatterjee, Joseph J. Carlson 154 (2001) 213–220 Food-Gene Interaction Examples Anti-inflammatory & Antioxidant Actions

Tart Cherries Exs) Phytochemical Rich Food & CAD Risk Factors

Ex 1) Lazarus et al JAMA 2004. Juice & Platelet Aggregation in Type II . Platelet Aggregation decreased sig in patients drinking for 3 wks vs tomato flavored beverage. Is this only due to Lycopene? ______

Ex 2) Ferrara et al Arch Internal Med 2000 “ Oil & Reduced Need for anti- hypertensive medications” By replacing PUFA with Virgin Olive Oil resulted in sig lowering of Systolic & Diastolic BP & need for Meds Is this only due to ? Lipid lowering with ~ 75 grams or 2.5 oz nuts/ day

Emilio Ros et al 2010

•Phytochemicals in nuts : carotenoids, β-Carotene, β-cryptoxanthin, lutein, zeaxanthin & flavonoids, henols, Chen C-Y O Asia Pac J Clin Nutr 2008; •What other components to nuts contain that may influence lipids? Summary of Nutrition & Vascular function         • Impair Vascular Function • Improve Vascular Function • Saturated fat (animal fat, • Unsaturated fats (veg based hydrogenated fat, oil) oils fats, nuts & fish oils) • Excess Animal PRO • Plant proteins () (L- & Isoflavones)

• Excess & low fiber • Vitamins C, E, & (sweets, low-nutrient density polyphenols CHOs) (fruits, veges & whole grains) * Dietary patterns high in sat fat, high in animal PRO & low in * Nutrient Dense Dietary patterns dietary fiber high in dietary fiber & low in sat. fat

Refs: Adapted from West Current Opinions in Lipidology 2003; I. What is the best Approach for prevention and Management of CAD? • Evidenced Based Heart Healthy Phytochemical Rich Dietary pattern?

= ESTABLISHED BENEFITS

• OR Evidenced Based Heart Healthy Dietary pattern and added phytochemical supplements? + = = +-? Summary of Evidenced based cardiovascular Nutrition guidelines/ Rxs 2000- present

. Nutrition effects multiple individual CAD Risk Factors

. Evidence for Atherosclerotic regression; Improved coronary blood flow

. ↓ CAD Morbidity ; ↓ CAD Mortality

Key References • Van Horn, et al. The evidence for dietary prevention & treatment of CVD. 2008 JADA 108(2) • Lichtenstein, A. H., L. J. Appel, et al. (2006). " & lifestyle recommendations revision 2006: a scientific statement from the AHA Nutrition Committee." Circulation 114(1): 82-96. • Krauss, R. M., R. H. Eckel, et al. "AHA Dietary Guidelines: revision 2000: A statement for healthcare professionals from the Nutrition Committee of the AHA." Circulation 102(18): 2284-99. • Executive Summary of The 3rd Report of The National Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). (2001) JAMA. 285: 2486-97. • DRIs, Nat Academies Press, 2002, 2005. SUMMARY of RISK FACTORS INFLUENCED BY NUTRITION ESTABLISHED / TRADITIONAL RISK FACTORS * EMERGING/ PUTATIVE RISK FACTORS † Dyslipidemia ( ie. elevated total cholesterol , LDL (ie, C-reactive protein) , low HDL) Thrombotic factors (ie, fibrinogen) Diabetes Mellitus Hyperhomocystienemia Impaired endothelial function Excess Alcohol intake Cardiac arrhythmias Metabolic syndrome Oxidative stress Inactivity ‡ Monocyte adhesiveness Smoking§ Elevated ADMA Poor hydration status Gene food interactions * Established/traditional cardiovascular disease (CVD) risk factors.Depression † Emerging/putative CVD risk factors. ‡ Inactivity: proper nutrition including adequate storage can influence ability to perform physical activity/exercise at an intensity and frequency that contributes to reduced CVD risk. § Smoking: nutritional factors can modulate oxidant stress in chronic smokers. ADMA= asymmetrical di-methyl arginine. Elevated levels of ADMA associated with less nitric oxide release & impaired vascular function. Refs. NCEP ATP III Executive summary (2001). Executive Summary of the 3rd Report o) JAMA. 285: 2486-97. Grundy, S. M. (2007). Am J Med 120(9 Suppl 1): S3-8; discussion S9. Hu, &Willett (2002). "Optimal diets for prevention of coronary heart disease." JAMA 288(20): 2569-78. -CACR Guidelines 2009; Ch 8- Carlson JJ, Monti V,) Evidenced informed Nutrition Applications for Preventing & Managing Atherosclerosis Secondary CVD Prevention Lifestyle Trials Emphasizing Plant Based Fiber Rich Nutrition Patterns (Early 1990s - 2001) • Trials Demonstrating Angiographic Improvements

• Lifestyle Heart Trial----10% Fat Vegetarian Diet +exercise & meditation • Heidelberg Trial ------26% Fat high fiber diet & exercise • STAR Trial------27% Fat high soluble fiber diet • *SCRIP------24% Fat + exercise, wt. mgt, relaxation, smoking cessation

• Trials Reducing CAD Morbidity & All Cause Mortality

• *Singh I------24% Fat Plant Based high fiber (52 gs) # • Lyon------30% Fat Modified Mediterranean • *Singh II------26% Fat Plant Based high fiber (48 gs) #

• All intervention diets were nutrient dense (~> 15 g dietary fiber/1000/Kcals), rich in plant foods and & low in saturated fat ( < 10% tot Kcals) • * indicates lipid reducing agents used as needed # Validity of study methods/results have been questioned following publication Summary of AHA & NCEP/ATP III Nutrition Rx 2000-present; With Evidence Grade INCLUSINARY Grade EXCLUSINARY  Grade Sat Fat < 7% tot cals I Lipids, CAD RR Soluble fiber 5-10 g/ d I Lipids Stanols /Sterols 2-3 g/d I-II Lipids Cholesterol<200 mg/d II-Lipids, CAD RR Dietary fiber(14g/1000 cals) II- CAD RR Trans-fat (<1% tot Cals) I-II Lipids,CAD RR Soy protein ~25g/d III- Lipids < 2.4 gm/d II Lipids, CAD RR Total Fat 25-35% I-II Lipids, CAD RR Simple CHO < 25% II Lipids, CAD RR MUFA < 20% kcals I-II Lipids Nuts II Lipids, CAD RR NEUTRAL Grade N-3 FAs~900mg/d/fish II-III CAD, M&M Kcals balance II-III CHD RR BMI Alcohol 0-2 drinks/d II- CHD RR Folate 400 ug/d II-III Hmcys & RCE PUFA 10% tot cals I-II Lipids,CHD RR ~4700 mg/d II-HTN, Stroke ~1200 mg/d II-HTN, Bone Antiox supplements not Rx KEY  Select nutrient dense FD CAD RR= Risk Reduct M &M = Morbidity & Mortality RCE= Repeat Coronary Event

Adapted from ;AHA 2000, 2006 Nutrition Rx; NCEP ATP III ; Van Horn et al 2008; Carlson, Monti,CACR Guidelines Ch 8, 2010 Evidenced based Nutrition guidelines summary for CAD prevention  Current Rxs increased emphasis on foods to include vs. what to exclude  List of recommendations can be overwhelming: Best Approach- a nutrient dense phytochemical rich dietary pattern incorporating as many Rxs as possible  Based on individual risk factor status and preference can fine tune  THERE IS NOT A SINGLE “Magic Bullet”  THE SUM OF THE PARTS OF FOOD ARE STRONGER THAN SINGLE COMPONENTS  FOOD is MEDICINE & can Prevent or Reduce the need for selected meds Dietary Patterns rich Plant based – Nutrient Dense food are rich in nutrients and Phyto-chemicals that promote vascular health (Fruits, Veges, whole grains, , nuts, seeds) Effects of HEART HEALTYH GUIDELINES Fiber and Nutrient and Phytochemical Rich Foods, on CAD Risk Factors:

 Evidenced-based dietary patterns rich in phytochemicals

1) DASH (Dietary Approaches to Stopping Hypertension) (Appel et al.1997) 2) NCEP Therapeutic Lifestyle Changes (TLC) diet 3) OMNI Heart Trial (Appel et al.2005) 4) Portfolio diet (Jenkins et al 2003)

Can Customize for cultural preferences See Reference list and additional slides for details SAD Two ex of dietary patterns consistent with AHA dietary Goals. Note based on 2000 kcal diet Table 4 adapted : AHA Nutrition and Lifestyle Guidelines; Circulation; 6/2006 Eating Pattern DASH NCEP Servings TLC Serving Size Examples Servings Grains 6-8 /d 7 /d 1 sl brd, 1 oz crl, ½ C, rice, , Vegetables 4-5 / d 5 /d ½ C veges, 1 C leafy v Fruits 4-5 /d 4 /d Med frt, ½ C, 4 oz jce Fat-free or low-fat milk & 2-3 /d 2-3 /d 1 C milk or prod 1 ½ oz of cheese Lean Meats Poultry & fish < 6 oz /d <5oz/d <2 decks of cards Nuts, seeds, & legumes 4-5 / wk Count as 1/3C 1.5 oz nuts or seeds, 2T veges butters, ½ C beans cked Fats & oils 2-3 /d Depends 1 tsp marg. Or veg oil, 1 T on Kcals mayonaise, 2 T salad dressing Sweets & added sugars <5/ wk No Rx 1 T sugar, 1 T jam.5 C sorbet; 6-8 oz frt. drink DASH I Trial/ Macro-Micro-nutrient Differences/day • Food Type DASH CONTROL (SAD) • & Veges 9 3.6 • Nuts & seeds .7 0 • “Grains” >Whole grains >Simple CHOS • Gm Fiber 31g 9g • Red Meat .5 serving 1.5 • Fish 1 serving 0 • Dairy > & Low fat 2% & whole

• Nutrients • NaCl 2300mg NS 2300 mg NS

• Total fat 26% 35% • Sat Fat 7% 14% • Ca+ 1265 mg 443 mg • K+ 4415 mg 1752 mg • Mg+ 480 mg 176 mg

UNKNOWNS - other nutrients & phyto chemicals that regulate BP & other RFs Matching the right dietary pattern for your patient Insights from The Omni Heart Trial Appel et al JAMA, 2005; 295

Title: Effects of Protein, Monounsaturated Fat, and CHO intake on Blood Pressure and Serum Lipids • Objective: To compare the effects of 3 healthful diets, each with reduced saturated fat (6%) on BP and serum lipids • Study design cross-over controlled feeding study- 6 wks on 3 different diets (isocaloric) • Subjects- 164 adults with pre-HTN to Stage 1 HTN; • Summary of the 3 healthful diets; all 3 were rich in fruits, veges, grains, dietary fiber, and low in Sat. Fat (6%)

• “CHO” (DASH) diet ------58% CHO, 27% Fat, 15% PRO • “Protein” diet ------48% CHO, 27% Fat, 25% PRO • “Monounsat.” fat diet------48% CHO, 37% Fat, 15% PRO Key results OMNI HEART STUDY Appel et al JAMA, 2005; 295 Adapted from table 5 and 6 Diet Pattern SBP ↓ DBP ↓ LDL ↓ Est 10 yr CHD mmHg mmHg Mg/dl risk % decrease CHO/DASH 8 4 12 16% 58% CHO, 27% fat, 15% PRO PROTEIN 10 5 14 21% 48% CHO, 27% fat, 25% PRO Monounsat 9 5 13 20% 48% CHO, 37% fat, 15% PRO

Note: Baseline mean BP 131 / 77; LDL 129; Are Phytochemicals Effective for CAD Prevention and Rehabilitation? Summary I. Background – definitions; overview of evidence

II. Phytochemical classification with food & beverage examples

III. Summary of evidence phytochemical rich food & supplements

IV. What is the best approach based on evidence to date? V. Summary-Applications and resource list. Selected Cardiovascular Health & Nutrition Resources Websites and Selected Refs for clinicians & clients  Heart and Stroke Foundation of Canada. www.heartandstroke.com  American Heart Association- http://www.americanheart.org/  of Canada official website – Education tools and resources for the nutrition professional. www.dietitians.ca  The American Dietetic Association (ADA) website: http://www.eatright.org/Public/ Includes position statements, resources and links; Nutrition and CVD; Vegetarian diets,  National Cholesterol Education Program Website; www.Nhlbi.nih.gov/chd  DASH (Dietary Approaches to Stopping Hypertension) eating pattern info & menus  NIH site: www.nhlbi.nih.gov/health/public/heart/hbp/dash/index.htm  “Portfolio diet” eating plans :Note: The recipes are based on a trial by Jenkins (see selected references) Go to- http://www.portfolioeatingplan.com/  Top 10 worst Fast Foods in Canada- keepcanadaslim.com.  Na+ Reduction efforts Canada http://www.healthhabits.ca/2010/06/01/the-war- against-salt/ Selected Texts for clinicians  Cardiovascular Nutrition; Disease Management and Prevention, Jo Ann Carson, Frances Burke, Lisa Hark, Copyright 2004; American Dietetic Association  Canadian Association for Cardiopulmonary Rehabilitation; Guidelines for Cardiac Rehabilitation and Cardiovascular Prevention Programs Chapter 8- Carlson JJ, Monti V. Evidence Informed Nutrition and Dietary Interventions for the Prevention and Management of Atherosclerosis. October 2009 Macro- & Selected Micro- Nutrient Summaries of Two Dietary Patterns Recommended in AHA Nutrition & LS Revision (2006) (fiber and micro nutrient levels based on 2000 Kcals /day) Nutrient DASH NCEP TLC Total Fat ~25% 20-35% Sat Fat <7-10% SAME Protein ~15% SAME Carbohydrate 55-60% 50-65% Fiber 30-35 g/d Same NaCl 2.3 g/d Similar Ca+ 1265 mg Similar K+ 4415 mg Similar Mg+ 480 mg Similar

Unknowns- potential benefits of phytochemicals and other nutrients in food patterns A Snapshot of the Omni Heart Diet Based on 2000 Kcals

Source: Nutrition Action Newsletter: Oct 2009 Issue Title: * WHAT SHOULD I EAT? Portfolio Diet Study Summary Jenkins et al JAMA 2003, 23; 290(4);502-510 • Title: Effects of a dietary portfolio of cholesterol lowering foods vs Lovastatin on Serum Lipids and C-reactive Protein

• Objective: to determine if the new dietary recommendations from NCEP ATP III leads to cholesterol reduction comparable to HMG Co A reductase inhibitor (20mg lovastatin)

• Setting/ Participants- 46 “healthy hyper-lipidemic adults (25 men 21 post -menopausal women). Ave age 59; BMI 27.6

• Design: Double blinded RCT (parallel design) 1 month 1. HH Control Diet 23% Fat (5% SFA); ~ 80 mg cholesterol 2. HH Control Diet 23% +Statin (5% SFA) ~ 80 mg cholesterol 3. Portfolio Diet 29% Fat (6% saturated) ~ 100 mg cholesterol H H Control Diet & “Dietary Portfolio” Jenkins et al JAMA2003, 23; 290(4);502-510 Portfolio diet- key unique components Vs control diet *1 g plant Sterols/1000 kcals plant sterol margarine * 10 g Viscous /1000Kcals (barley, oats, , , ) * 21 g soy Pro/ 1000 kcals ( & soy meat analogs)

#to balance Sat. Fat & cholesterol with control Added 1 egg/wk &1 pat butter/d Portfolio Diet Study Summary Jenkins et al JAMA 2003,23;290(4);502-510 • RESULTS LDL CRP • 1. HH Control Diet- 23% fat ↓ 8% ↓ 10%

• 2. HH Control Diet- 23% fat + statin ↓ 30% ↓ 33%

• 3. Portfolio Diet - 29% Fat ↓ 29% ↓ 28%

• CONCLUSIONS- no sig difference in the efficacy of the Portfolio Diet vs Control + Statin which were both superior to a Control Heart . Diversifying cholesterol lowering components in the same dietary portfolio increased the effectiveness of diet as a Treatment for hypercholesterolemia