the heart of the matter. are omega-3 fatty acids …...the heart of the matter. are omega-3 fatty...

The heart of the matter. Are omega-3 fatty acids

beneficial in the prevention of cardiovascular disease?

Trevor A Mori

Medical School,

University of Western Australia

and

The Centre for Nutrition, Lifestyle

& Clinical Trials Research

Omega-3 Summit 2019, 20-22 February, Singapore

Pooled Relative Risk (95% CI) of CHD Mortality According to Fish Consumption

CHD and Fish Consumption in Population Studies

He K et al. Accumulated evidence on fish consumption and coronary heart disease mortality. Circulation 2004

11.8 years of follow-up

20 g /d increase in fish intake related to a 7% lower risk of CHD mortality (P=0.03)

Trevor A Mori, 2019

Cardiovascular Health Study

4,738 men & women > 65yrs

Heart Failure and Fish Consumption

Meta-analysis

7 prospective studies: 176,441 subjects & 5,480 incident cases of HF

RR = 0.85 fish intake (P=0.04)

RR = 0.86 w3 FA (P=0.05)

Djousse et al. Clin Nutr 2012Trevor A Mori, 2019

Fish Consumption and Stroke

16 studies (19 cohorts)

402,127 individuals

10,568 incident cases

12.8 yrs follow-up

9% total stroke (P=0.02) for 2-4 fish meals /wk vs < 1 fish meal /month

- only ischaemic stroke

Trevor A Mori, 2019

2,033 men who had survived an MI

2-3 serves of fatty fish weekly or fish oil supplements

total death by 29% over 2 yrs

DART Study (Lancet 1989)

Trevor A Mori, 2019

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

%

Decrease

Total deaths

CV death

Sudden deaths

GISSI-Prevenzione Trial (Lancet 1999)

11,323 patients who had survived an MI < 3 months supplemented with 1g daily fish oil

Marchioli R, et al. Circulation 2002

Trevor A Mori, 2019

7,000 patients with class II-IV HF randomised to 850mg n-3 fatty acids,

rosuvastatin (10mg), both or placebo

GISSI-HF Trial (Lancet 2008)

9% total mortality

8% total mortality or

hospitalisation for CVD

Trevor A Mori, 2019

18,645 men & women with hypercholesterolaemia, randomised to statin

or statin + EPA (1.8g/d)

JELIS Trial (Lancet 2007)

19% major CV events

Trevor A Mori, 2019

• Jan 1947-Nov 2015

• 18 RCTs (n=93,000) and 16 prospective cohort studies (n=732,000)

• Examined w3 FAs from foods or supplements and CHD (MI, SCD, coronary death, angina)

RCTs

Non-significant reduction (0.94; CI, 0.85-1.05)

Subgroup analyses significant CHD risk reduction

- elevated triglycerides (0.84; 0.72-0.98)

- elevated LDL-C (0.86; 0.76-0.98)

Prospective cohort studies

Significant reduction (0.82; 0.74-0.92) for risk of any CHD eventTrevor A Mori, 2019

Not all RCTs / Meta-analyses have shown benefit of w3 fatty acid

supplementation on CVD

• 64 yrs; trial duration mean 4.4 yrs

• w3 fatty acids (226-1800 mg/d)

• No significant association with coronary heart disease death (RR 0.93; P = 0.05)

Trevor A Mori, 2019

REDUCE-IT

• Multicenter, randomized, double-blind, placebo-controlled trial

• 8,179 patients with established CVD or diabetes and other risk factors

• On statin therapy

• Fasting triglycerides 1.52-5.63 mmol/L and LDL-C 1.06-2.59 mmol/L

• Received 4 g/day EPA or placebo

• Median follow-up 4.9 years

Trevor A Mori, 2019

REDUCE-IT

Composite of:

• cardiovascular death

• nonfatal myocardial infarction

• nonfatal stroke

• coronary revascularization or

• unstable angina

25%

Composite of:

• cardiovascular death

• nonfatal myocardial infarction or

• nonfatal stroke

26%

Trevor A Mori, 2019

VITAL

• Multicenter (USA), randomized, placebo-controlled, 2x2 factorial design

• Primary prevention of CVD and cancer in 25,871 participants: men >50 yrs and women >55 yrs

• Vitamin D3 and w3 fatty acids (840 mg/day)

• Median follow-up 5.3 years

Trevor A Mori, 2019

Composite of:

• myocardial infarction

• stroke

• death from cardiovascular causes

VITAL

Trevor A Mori, 2019

w3 Fatty Acids and Cardiovascular Disease

Data support benefit

• Coronary heart disease

• Stroke

• Antiarrhythmic Effects (Sudden Death)

• Heart failure

Trevor A Mori, 2019

w3 Fatty acids influence multiple mechanisms underlying atherosclerosis

and CVD, leading to improvements in:-

• Blood pressure

• Vascular function, arterial compliance

• Cardiac function (heart rate, anti-arrhythmic effects)

• Lipid metabolism

• Platelet and leukocyte function

• Inflammation & Resolution of Inflammation

• Oxidative stress

Biological Effects of n-3 Fatty Acids on Cardiovascular Risk Factors

Trevor A Mori, 2019

Effect on CV Risk Factors

Meta-Analyses

Morris MC, et al. Circulation 1993 (31 RCT, n=1356)

Average 4.8g w3 /d: Trial duration 3-24 wks

Overall -3.0 / -1.5 mmHg

Appel LJ, et al. Arch Inter Med 1993 (17 RCT, n=1019)

Average ~3g w3 /d: Trial duration < 3 months


Geleijnse JM, et al. J Hypertens 2002 (36 RCT, n=1019)

Median 3.7g w3 /d: Trial duration 11.7 wks


Miller PE, et al. Am J Hypertens 2014 (70 RCT)


Trevor A Mori, 2019

w3 Fatty acid BP-lowering effects are potentiated by concomitant:

Na+ restriction in healthy elderly volunteers

Cobiac L, et al. J Hypertens 1992

b-adrenergic receptor blockade in mild-to-moderate hypertensives

Singer P, et al. Hypertension 1990

b-blockers or diuretics in treated hypertensives

Lungershausen YK, et al. J Hypertens 1994

Trevor A Mori, 2019

w3 Fatty acid BP-lowering is potentiated by weight loss

Age (yrs) 54.1

BMI (kg/m2 ) 31.6

Supine SBP (mm Hg) 134.5DBP (mm Hg) 76.0

Anti H/T Drugs n =1 (65%)(ACE- inhibitors, b-Blockers, n =2 (27%)Diuretics, CEB) n >3 (8%)

Trevor A Mori, 2019

24hr ABPBaseline

Post- InterventionControl

Time (hrs)

BP

(

mm

Hg

)

0 6 12 18 2440

60

80

100

120

140

160

D Awake BP

(mm Hg)

Weight Reduction & Dietary w3 FAs in Overweight, Treated Hypertensives

24

Time (hrs)

0 6 12 1840

60

80

100

120

140

160Wt Loss

-5.5 / -2.2

-6.0 / -3.0

Time (hrs)

BP

(

mm

Hg

)

0 6 12 18 2440

60

80

100

120

140

160Fish

24

Time (hrs)

0 6 12 1840

60

80

100

120

140

160Fish + Wt Loss

-13.0 / -9.3

Bao D, et al. Hypertension 1998

Trevor A Mori, 2019

Baseline

Post-Intervention

OLIVE OIL

0 6 12 18 2450

60

70

80

90100

110

120

130

140

Time (hrs)

BP

(m

mH

g)

EPA

0 6 12 18 2450

60

70

80

90100

110

120

130

140

Time (hrs)

BP

(m

mH

g)

Mori TA, et al. Hypertension 1999

DHA

0 6 12 18 2450

60

70

80

90100

110

120

130

140

Time (hrs)B

P (

mm

Hg

)

-5.8 / -3.3

D 24hr BP

-3.5 / -2.0

D Awake BP

6 weeks of supplementation

Trevor A Mori, 2019

24hr ABP

Animal models and human studies have consistently shown:

w3 Endothelial-dependent vasodilation

Vasoconstriction

BP: Mechanisms

w3 Improve Vascular Function

Trevor A Mori, 2019

Enhanced production and/or release of NO

endothelial dysfunction (E-selectin, VCAM-1, ICAM-1)

plasma noradrenalin

membrane fluidity

vasoconstrictor prostanoids (TX)

20-HETE (Barden AE, et al. J Hypertension 2015)

Mechanisms Relevant to Vascular Function

0

500

1000

1500

pm

ol/L *

Control w3 FA

* P <0.001

Trevor A Mori, 2019

BP is strongly influenced by arterial compliance

BP: Mechanisms

w3 Improve Arterial compliance

10 trials

Trial duration: 6-105 weeks

Dosage: 640-3,000 mg/day Trevor A Mori, 2019

Heart Rate

HRV (Autonomic nerve function)

Myocyte electrophysiology

- inhibit Na+ & L-type Ca2+ channels - modulate K+ channels

BP: Mechanisms

w3 Improve Cardiac Function

Trevor A Mori, 2019

w3 Fatty Acids and Heart Rate

30 studies

Overall -1.6 bpm

Baseline HR > 69 bpm -2.5 bpm

Studies > 12 wks duration -2.5 bpm

5 bpm 14% Coronary events

Trevor A Mori, 2019

D Awake HR

(bpm)

He

art

Ra

te (

bp

m )l

l

l

lll

ll

l

l

ll

l

l

ll

l

l

lll

ll

l

nn

n

nn

n

nn

n

nnn

n

nn

n

n

n

n

nnn

nn

50

55

60

65

70

75

80

0 6 12 18 24Time (hrs)

Control

lll

ll

lll

l

l

l

ll

lll

l

l

l

l

ll

l

l

n

n

n

n

nn

n

n

n

nn

n

n

n

n

nn

n

nn

nn

nn

50

55

60

65

70

75

80

0 6 12 18 24Time (hrs)

Weight Loss

- 1.8

He

art

Ra

te (

bp

m )

Fish Diet

ll

l

ll

l

ll

l

l

ll

l

ll

ll

l

ll

ll

l

l

nn

nn

n

nn

nn

nn

n

n

n

n

n

n

n

n

nn

nn

n

50

55

60

65

70

75

80

0 6 12 18 24

Time (hrs)

- 4.3

- 6.1

Fish + Wt Loss

llll

lll

l

l

ll

lll

l

ll

l

ll

ll

l

l

n

n

nnn

n

n

nn

n

n

nn

n

n

n

n

n

nnn

n

n

n

50

55

60

65

70

75

80

85

90

0 6 12 18 24Time (hrs)

Bao D, Mori TA, et al. Hypertension 1998

Baseline Post-Intervention

w3 Fatty acid HR-lowering effects are potentiated by weight loss

Trevor A Mori, 2019

24hr HR

OLIVE OIL

0 6 12 18 2455

60

65

70

75

80

85

TIME (hrs)

HR

(b

pm

)

EPA

0 6 12 18 2455

60

65

70

75

80

85

TIME (hrs)

HR

(b

pm

)

Baseline Post-Intervention

Mori TA, et al. Hypertension 1999

DHA

0 6 12 18 2455

60

65

70

75

80

85

TIME (hrs)H

R (

bp

m)

D HR

(bpm)

-3.5 24 hr

-3.7 awake

-2.8 asleep

Trevor A Mori, 2019

24hr HR

• Blood Pressure

• Vascular Function / Cardiac Function / Arterial Compliance

• Lipids

Triglycerides (EPA ≈ DHA)

Total cholesterol

HDL-C

LDL-C LDL particle size

Harris WS. Am J Clin Nutr 1997

Mori TA and Beilin LJ. Cur Opin Lipidology 2001

Effect on Cardiovascular Risk Factors

Trevor A Mori, 2019

w3 Fatty Acids & Atorvastatin on Dyslipidaemia in the Metabolic Syndrome

Chan D, Watts GF, Mori TA, et al Eur J Clin Invest 2002

-60

-50

-40

-30

-20

-10

0

10

20

30

% C

han

ge

Placebo

Atorvastatin

Fish Oil

Atorvastatin + Fish Oil

TG LDL-C Non-HDL-C HDL-C

Trevor A Mori, 2019

• Blood Pressure


• Lipids

• Glucose & Insulin

Meta-analysis

16 studies including 540,184 individuals (25,670 cases of incident DM)

- no association between fish / seafood consumption / EPA+DHA

with risk of diabetes

Wu et al Br J Nutr 2012


Trevor A Mori, 2019

• Blood Pressure


• Lipids


• Platelet Function / Thrombosis

Platelet aggregation Platelet thromboxane


Trevor A Mori, 2019

• Blood Pressure


• Lipids



• Leukocyte Function / Inflammation

Calder PC. Biochim Biophys Acta-Molec Cell Biology Lipids 2015


CRP & Fibrinogen

Cytokines

VCAM-1, ICAM-1, E-selectin

Leukotrienes LTB4 LTB5

Trevor A Mori, 2019

• Blood Pressure


• Lipids




• Specialized Pro-resolving Lipid Mediators of Inflammation Resolution

SPM: Resolvins, Protectins, Maresins

(Serhan CN. FASEB J 2017)

Synthesized in epithelial or endothelial cells in airways, retinal pigment

epithelial cells, monocytes and macrophages

Blunt PMN infiltration

Block pro-inflammatory mediators (LTs, PGs)

Reduce cytokine release

Stimulate macrophage-dependent uptake of apoptotic PMNs


Trevor A Mori, 2019

• Blood Pressure


• Lipids




• Specialized Pro-resolving Lipid Mediators of Inflammation Resolution (SPM)

• Oxidative Stress

l w3 FAs oxidative stress (F2-Isoprostanes - markers of oxidative status)

Mori TA, et al. Free Radical Research 2010


Trevor A Mori, 2019

• Blood Pressure


• Lipids




• Specialized Pro-resolving Lipid Mediators of Inflammation Resolution (SPM)

• Oxidative Stress

• Atherosclerosis & Plaque Stability

l w3 fatty acids incorporated into plaque lipids following supplementation to patients

undergoing carotid endarterectomy

l Atherosclerotic plaques had thick fibrous caps and less inflammation, suggestive of

plaque stabilisation

Thies F, et al Lancet 2003


Trevor A Mori, 2019

Adapted from Mori TA. Curr Atherosclerosis Rep 2004

Review: Mori TA. Fitoterapia 2018

w3 FATTY ACIDS

Mononuclear cellsPMN

LTB4 LTB5

PGE2 PGE3

ROS

AggregabilityPlatelet-cell interactions

PGE2 PGE3

TNF-a, IFN-g

IL-1, IL-6, IL-13

ROS

Resolvins / Protectins

PGI2 PGI3 NO

PDGF, TGF-b

Adhesion molecules

Apoptosis

Cyclo-oxygenaseLipoxygenaseCytochrome P-450

Transcription / Translation

NFkB

TXA2 TXA3

PDGF

Platelets

Cell-cell interactionsImmunityOxidative stress

VasoconstrictionProliferation / Migration

Cell death

Vasodilation

Cell-endothelial cell interactionsCell death

Smooth Muscle Cells TXA2, PGE2 , TGF-b

PGI2, NO

Apoptosis

ox LDL

Foam CellEndothelial Cells

Trevor A Mori, 2019

Inverse relationship between w3 FA (particularly fish) and CVD risk

Benefits attributable to the integral effect of w3 FA on multiple physiological mechanisms

Sound evidence that w3 fatty acids (>2 g/day) BP

w3 fatty acids reduce triglycerides, antithrombotic, anti-inflammatory and anti-oxidative actions,

enhance the resolution of inflammation

2-4 serves/wk fish (150-200g serve) is likely to have CV benefits which may protect against coronary

disease, heart failure and ischaemic stroke

4,000-5,000 mg/day EPA + DHA for patients with hypertriglyceridaemia

w3 FA can compliment lifestyle changes (e.g. weight loss) and drug therapy (lipid-lowering,

antihypertensives) in at-risk populations

Magnitude benefits can be substantial when w3 fatty acids are incorporated into a broader dietary change

including increased fruits & vegetables, and moderation of salt intake

CONCLUSIONS

Trevor A Mori, 2019

the heart of the matter. are omega-3 fatty acids …...the heart of the matter. are omega-3 fatty...

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