12
Concept Theory Disease
Dyslipidemia
Endothelial dysfunction
Free radicals
Immunologic
Atherosclerosis
/CAD
THEORY AND CONCEPT OF ATHEROSCLEROSIS
Inflamation
(Sargowo, 1996)
13
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
14
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
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
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
ed
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
10
0
-10
-20
-30
-40
-50
-60
-70
Pe
rcentC
ha
nge
fro
mB
ase
line
(me
dia
n)
hsC
RP
LD
LC
HD
LC
TG
0 3 6 12 24 36 48
10
0
-10
10
0
-10
10
0
-10
Placebo Canakinumab50 Canakinumab150 Canakinumab300
9
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
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.
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
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
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.