LIFESTYLE CHOICES AND THE ORIGINS OF CHRONIC DISEASE

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Transcript of LIFESTYLE CHOICES AND THE ORIGINS OF CHRONIC DISEASE

LIFESTYLE CHOICES AND

INFLAMMATION:

THE ORIGINS OF

CHRONIC DISEASE

INFLAMMATION:

LIFESTYLE VS GENETICS

HIGH RISK TRIPLE THREAT

LIFESTYLE CHOICES IS MOST IMPORTANT

THANK YOU DR. OZ

WHAT IS INFLAMMATION?

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RUDOLF VIRCHOW

mid 19th century

Lamond, B. The American Journal of Pathology. 2008

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Concept Theory Disease

Dyslipidemia

Endothelial dysfunction

Free radicals

Immunologic

Atherosclerosis

/CAD

THEORY AND CONCEPT OF ATHEROSCLEROSIS

Inflamation

(Sargowo, 1996)

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LDL

CD40L=CD40 ligand; TNF-α=tumor necrosis factor-alpha; IL=interleukin; VCAM=vascular cell adhesion molecule;

ICAM=intercellular adhesion molecule.

Cockerill GW et al. Arterioscler Thromb Vasc Biol. 1995;15:1987-1994; Andre P et al. Circulation. 2002;106:896-899; Libby

P. Circulation. 2001;104:365-372; Libby P et al. Circulation. 2002;105:1135-1143; Ross R. N Engl J Med. 1999;340:115-126.

Vessel lumenMonocyte

Macrophage

Adhesion

molecules

(VCAM-1, ICAM-1)

Inflammatory mediators

(CRP, CD40/CD40L,

TNF-α, IL-1, IL-6)

IntimaFoam

cell

INFLAMMATION PROMOTES PROGRESSION OF

ATHEROSCLEROSIS

Endothelium

LDL

Ox-LDL

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Two theories gain more acceptance:

(a) the lipid theory

(b) inflammation theory

Endothelial dysfunction is now regarded as the

first abnormality leading to AS. More novel

cardiovascular risk factors are known

a. Fibrinogen

b. TMAO

c. Homocysteine

d. Lp(a)

e. small-dense LDL

f. infectious agents/periodontal

15Weissberg, 1999

Inflammation Repair

Stable plaqueUnstable plaque

- STATINS

- ACEI/CCB

- WFPB Diet

Paul M Ridker, MD, MPH

Eugene Braunwald Professor of Medicine Brigham and Women’s Hospital,

Harvard Medical School, Boston MA, USA

Ridker ACC 2017

Additional LDL Reduction

IMPROVE-IT : Ezetimibe 6% RRR FOURIER/SPIRE: PCSK9 Inhibition q2 weeks 15% RRR

Additional Inflammation Reduction

No Prior Proof of Concept

Known Cardiovascular Disease LDL 150 mg/dL (3.8 mmol/L)

hsCRP 4.5mg/L

High Intensity Statin

“Residual Cholesterol Risk”

LDL 110 mg/dL (2.8 mmol/L)hsCRP 1.8 mg/L

Ridker ESC 2017

“Residual Inflammatory Risk”

LDL 70 mg/dL (1.8 mmol/L)hsCRP 3.8 mg/L

RESIDUAL INFLAMMATORY RISK:Addressing the Obverse Side of the Atherosclerosis Prevention Coin

Ridker PM. Eur Heart J 2016;37:1720-22

CAN INFLAMMATION REDUCTION

REDUCE CARDIOVASCULAR EVENT

RATES?

Ridker ESC 2017

Ridker PM. Circ Res 2016;118:145-156.

FROM CRP TO IL-6 TO IL-1: MOVING UPSTREAM TO IDENTIFY NOVEL TARGETS FOR ATHEROPROTECTION

Ridker ESC 2017

CANAKINUMAB

• high-affinity human monoclonal anti-human

interleukin-1b (IL-1b) antibody designed to

bind to human IL-1b and functionally

neutralize the bioactivity of this pro-

inflammatory cytokine

• long half-life (4-8 weeks) with CRP and IL-6

reduction for up to 3 months

Ridker ESC 2017

150

-10

-20

-30

-40

-50

-60

0 150

CANAKINUMAB DOSE

Me

dia

nR

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uct

ion

Fibrinogen

Interleukin-6

C-reactive Protein

Ridker PM, et al; Circulation 2012; 126:2739-2748Ridker ESC 2017

Stable CAD (post MI)

On Statin, ACE/ARB, BB, ASA

Persistent Elevation

of hsCRP (> 2 mg/L)

Randomized

Canakinumab 150 mg

SC q 3 months

Randomized

Placebo

SC q 3 months

Randomized

Canakinumab 300 mg

SC q 3 months*

Randomized

Canakinumab 50 mg

SC q 3 months

N = 10,061

39 Countries

April 2011 - June 2017

1490 Primary Events

Primary CV Endpoint: Nonfatal MI,

Nonfatal Stroke, Cardiovascular

Death (MACE) Ridker ESC 2017

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-40

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Pe

rcentC

ha

nge

fro

mB

ase

line

(me

dia

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hsC

RP

LD

LC

HD

LC

TG

0 3 6 12 24 36 48

10

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10

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Placebo Canakinumab50 Canakinumab150 Canakinumab300

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MonthsRidker ESC 2017

CANTOS: Dose-Dependent Effects on Inflammatory Biomarkers and Lipids

Placebo SC q 3 mth

Canakinumab 50mg SC q 3 mth

Canakinumab 150mg SC q 3 mth Canakinumab 300mg SC q 3 mth

0.5 1.0Canakinumab

Superior

Canakinumab

Inferior

0.5 Canakinumab

Superior Canakinumab

Inferior

1.0

Group

Ridker ESC 2017

Women Men

Age < 60 yrs Age

> 60 yrs

Diabetes No

diabetes

Non Smoker

Smoker

BMI < 30 kg/m2

BMI > 30 kg/m2

LDLC < 80 mg/dL

LDLC > 80 mg/dL

hsCRP < 4 mg/L

hsCRP > 4 mg/L

HDLC > 45 mg/dL

HDLC < 45 mg/dL

TG < 150 mg/dL

TG > 150 mg/dL

Overall

MACE MACE +

CANTOS: CONSISTENCY OF EFFECT ACROSS ALL PATIENT GROUPS

CONCLUSIONS:

1. CANTOS was designed to directly test the inflammatory hypothesis of atherothrombosis.

2. As shown in these data, inhibition of IL-1 with SC canakinumab given once every three months among patients with a prior myocardial infarction substantially lowered the inflammatory biomarkers hsCRP and IL-6 while having no beneficial impact on atherogenic lipids.

3. The 150mg group met all pre-specified multiplicity adjusted thresholds for statistical significance for both the primary and secondary cardiovascular outcomes.

Ridker ESC 2017

CONCLUSIONS:THE CANAKINUMAB ANTI-INFLAMMATORY THROMBOSIS OUTCOMES STUDY (CANTOS)

In conclusion, these randomized placebo-controlled trial data demonstrate that targeting the IL-1 to IL-6 pathway of innate immunity with canakinumab reduces cardiovascular event rates. These data provide proof that inflammation inhibition, in the absence of lipid lowering, can improve atherothrombotic outcomes

Ridker ESC 2017

INFLAMMATION AND MEAT

Body weight

Visceral fat

Intracellular lipid

Iron

Nitrates

Inflammation

Diabetes

INFLAMMATION•MEAT-BASED DIETS POSITIVELY ASSOCIATED

WITH BIOMARKERS OF INFLAMMATION

• PLANT-BASED INVERSELY ASSOCIATED WITH

BIOMARKERS OF INFLAMMATION

Barbaresko J, et al. Dietary pattern analysis and biomarkers of low-grade inflammation: A systematic literature review. Nutr Rev. 2013;71:511–527.Lev SH, et al. Associations between red meat intake and biomarkers of inflammation and glucose metabolism in women. Am J Clin Nutr. 2010:99:352–360.

RED MEAT ALLERGY

AND HEART DISEASE

RED MEAT ALLERGY AND HEART DISEASE

RED MEAT ALLERGY AND HEART DISEASE

RED MEAT ALLERGY AND HEART DISEASE

Wilson JM et al. Arterioscler Thromb Vasc Biol. 2018 Jun 14. pii:

ATVBAHA.118.311222

IgE to the Mammalian Oligosaccharide Galactose-α-1,3-Galactose Is

Associated With Increased Atheroma Volume and Plaques With Unstable

Characteristics.

VISCERAL FAT

• ELIMINATING FAT FROM

ANIMAL SOURCES MAY

REDUCE VISCERAL FAT

AND IMPROVE INSULIN

SENSITIVITY, COMPARED

WITH CONVENTIONAL

DIABETES DIET.

• ↑ VISCERAL FAT → ↑

INSULIN RESISTANCE

Kahleova H, et al. Vegetarian diet improves insulin resistance and oxidative stress markers more than conventional diet in subjects with type 2 diabetes. Diabet Med. 2011;28:549-559.Hamdy O, et al. Metabolic obesity: The paradox between visceral and subcutaneous fat. Curr Diabetes Rev. 2006;2:367–373.

ORNISH LIFESTYLE PROGRAM: INFLAMMATION

ANTI-INFLAMMATORY EFFECT OF WHOLE-FOOD PLANT-

BASED VEGAN DIET VS THE AMERICAN HEART

ASSOCIATION - RECOMMENDED DIET IN PATIENTS WITH

CORONARY ARTERY DISEASE:

THE RANDOMIZED EVADE CAD TRIAL

Binita Shah et al

Originally published Jun 2018Circulation. 2018;136:A23081

METHODS

RESULTS

PERHAPS THE WORST SLIDE EVER

VALTER LONGO, PH.D: THE LONGEVITY

DIET & THE FASTING MIMICKING DIET

Wei et al., 2008; Cheng et al., 2014)

Eating Less, Living More

FMD in Humans:“The stomach receives food, while the metabolism fasts’

• Consists of soups, bars, teas, drinks, and snacks

• Five consecutive days/month, up to 12 times/year,

• Demonstrated to rejuvenate the body, induce fast fat loss

without decreasing muscle or bone mass, and prevent (and

potentially reverses) age-related metabolic changes

“The stomach receives food, while the metabolism fasts’

• Consists of soups, bars, teas, drinks, and snacks

• Five consecutive days/month, up to 12 times/year,

• Demonstrated to rejuvenate the body, induce fast fat loss

without decreasing muscle or bone mass, and prevent (and

potentially reverses) age-related metabolic changes

FMD: WFPB-ISH

FASTING MIMICKING DIET: RESULTS

Wei et al., Sci. Transl. Med. 9, 15 February 2017

SPICES

STEP 1: ELIMINATE ALL TYPES OF MEAT LIKE BEEF, PORK, LAMB, FISH,

CHICKEN, EGGS AND DAIRY PRODUCTS.

STEP 2: ELIMINATE ADDED OILS

STEP 3: ELIMINATE PROCESSED FOODS

STEP 4: ADDED IN LARGE AMOUNTS OF RAW FRUITS, VEGETABLES,

GREENS, SEEDS NUTS

STEP 5: ADD IN HYDRATION FROM PURE WATER

STEP 6: ADD IN OMEGA-3 WITH AT LEAST A ¼ CUP OF CHIA AND

FLAX SEEDS DAILY

STEPS TO LOWER INFLAMMATION

WITH PLANT BASED DIETS

WAKE UP! TIME FOR THE INFLAMMASONE!

THE INFLAMMASOME IS A MULTIPROTEIN INTRACELLULAR

COMPLEX THAT DETECTS PATHOGENIC MICROORGANISMS

AND STERILE STRESSORS, AND THAT ACTIVATES THE HIGHLY

PRO-INFLAMMATORY CYTOKINES INTERLEUKIN-1B (IL-1B)

AND IL-18.

DYSREGULATION OF INFLAMMASOMES IS ASSOCIATED WITH A

NUMBER OF AUTOINFLAMMATORY SYNDROMES AND

AUTOIMMUNE DISEASES.

NLRP3 INFLAMMASONE

•WHILE ALL INFLAMMASOMES RECOGNIZE

CERTAIN PATHOGENS, IT IS THE DISTINCTIVE

FEATURE OF NLRP3 INFLAMMASOME TO BE

ACTIVATED BY MANY AND DIVERSE STIMULI

MAKING NLRP3 THE MOST VERSATILE, AND

IMPORTANTLY ALSO THE MOST CLINICALLY

IMPLICATED INFLAMMASOME.

ANTI-INFLAMMATORY DIET LINKED TO

REDUCED RISK OF EARLY DEATH

• 68,273 SWEDISH MEN AND WOMEN AGED 45 TO 83 YEARS WHO

WERE FOLLOWED FOR 16 YEARS

• PARTICIPANTS WHO MOST CLOSELY FOLLOWED AN ANTI-INFLAMMATORY DIET HAD AN 18% LOWER RISK OF ALL-CAUSE

MORTALITY, A 20% LOWER RISK OF CARDIOVASCULAR MORTALITY, AND A 13% LOWER RISK OF CANCER MORTALITY

• SMOKERS WHO FOLLOWED THE DIET EXPERIENCED EVEN GREATER

BENEFITS WHEN COMPARED WITH SMOKERS WHO DID NOT FOLLOW THE

DIET.•

10.1111/JOIM.12823

ANTI-INFLAMMATORY DIET LINKED TO

REDUCED RISK OF EARLY DEATH

• ANTI-INFLAMMATORY FOODS CONSIST OF FRUITS

AND VEGETABLES, TEA, COFFEE, WHOLE GRAIN

BREAD, BREAKFAST CEREAL, OLIVE OIL AND CANOLA

OIL, NUTS, CHOCOLATE, AND MODERATE AMOUNTS

OF RED WINE AND BEER.

• PRO-INFLAMMATORY FOODS INCLUDE UNPROCESSED

AND PROCESSED RED MEAT, ORGAN MEATS, CHIPS,

AND SOFT-DRINK BEVERAGES.

REDUCE INFLAMMATION, REDUCE DISEASE