Nut consumption and incidence of cardiovascular diseases ... · 3/19/2019 · Special Article Nut...

Special Article

Nut consumption and incidence of cardiovascular diseases andcardiovascular disease mortality a meta-analysis of prospectivecohort studies

Nerea Becerra-Tomas Indira Paz-Graniel Cyril WC Kendall Hana Kahleova Dario RahelicJohn L Sievenpiper and Jordi Salas-Salvado

Context Previous meta-analyses evaluating the association between nut consump-tion and the risk of cardiovascular disease (CVD) had substantial methodological lim-itations and lacked recently published large prospective studies hence making anupdated meta-analysis highly desirable Objective To update the clinical guidelinesfor nutrition therapy in relation to the European Association for the Study ofDiabetes (EASD) a systematic review and meta-analysis of prospective studies wasconducted using the Grading of Recommendations Assessment Development andEvaluation (GRADE) system to summarize the evidence of the association betweentotal nuts specific types of nuts and the incidence of and mortality from CVD out-comes Data sources Relevant articles were identified by searching the PubMedand Cochrane databases Data extraction Two independent researchers screenedthe articles to identify those that met the inclusion criteria Data analysis The in-verse variance method with fixed-effect or random-effects models was used to pooldata across studies (expressed as risk ratio [RR] and 95 confidence interval [CI])Heterogeneity was tested and quantified using the Cochrane Q test and I2-statisticrespectively The GRADE system was used to assess the quality of the evidenceResults Nineteen studies were included in the analyses The results revealed an in-verse association between total nut consumption (comparing highest vs lowest cat-egories) and CVD incidence (RR 085 95CI 080091 I2 0) CVD mortality (RR077 95CI 072ndash082 I2 3) coronary heart disease (CHD) incidence (RR 08295CI 069ndash096 I2 74) CHD mortality (RR 076 95CI 067ndash086 I2 46)stroke mortality (RR 083 95CI 075ndash093 I2 0) and atrial fibrillation (RR 08595CI 073ndash099 I2 0) No association was observed with stroke incidence and

Affiliation Nerea Becerra-Tomas Indira Paz-Graniel and Jordi Salas-Salvado are with the Human Nutrition Unit Department of Biochemistryand Biotechnology Universitat Rovira i Virgili Reus Spain the Nutrition Unit University Hospital of Sant Joan de Reus Reus Spain and theInstitut drsquoInvestigacio Sanitaria Pere Virgili (IISPV) Reus Spain Nerea Becerra-Tomas and Jordi Salas-Salvado are with the Centro deInvestigacion Biomedica en Red Fisiopatologıa de la Obesidad y la Nutricion (CIBEROBN) Institute of Health Carlos III Madrid Spain Cyril WCKendall and John L Sievenpiper are with the Department of Nutritional Sciences Faculty of Medicine University of Toronto Toronto OntarioCanada and the Toronto 3D Knowledge Synthesis and Clinical Trials Unit Clinical Nutrition and Risk Factor Modification Centre St MichaelrsquosHospital Toronto Ontario Canada Cyril WC Kendall is with the College of Pharmacy and Nutrition University of Saskatchewan SaskatoonSaskatchewan Canada Hana Kahleova is with the Institute for Clinical and Experimental Medicine Prague Czech Republic and the PhysiciansCommittee for Responsible Medicine Washington District of Columbia USA Dario Rahelic is with Vuk Vrhovac University Clinic for DiabetesEndocrinology and Metabolic Diseases Merkur University Hospital Zagreb Croatia and the School of Medicine University of Zagreb ZagrebCroatia John L Sievenpiper is with the Li Ka Shing Knowledge Institute St Michaelrsquos Hospital Toronto Ontario Canada John L Sievenpiper iswith the Division of Endocrinology and Metabolism Department of Medicine St Michaelrsquos Hospital Toronto Ontario Canada

Correspondence Jordi Salas-Salvado and Nerea Becerra-Tomas Human Nutrition Unit Faculty of Medicine and Health Sciences UniversitatRovira i Virgili CSant Llorenc 21 43201 Reus Spain E-mails jordisalasurvcat and nereabecerraurvcat

Key words cardiovascular disease meta-analysis nuts peanut butter peanuts tree nuts walnuts

VC The Author(s) 2019 Published by Oxford University Press on behalf of the International Life Sciences InstituteAll rights reserved For permissions please e-mail journalspermissionsoupcom

doi 101093nutritnuz042Nutrition ReviewsVR Vol 77(10)691ndash709 691

Dow

nloaded from httpsacadem

icoupcomnutritionreview

sarticle-abstract77106915540978 by guest on 25 September 2019

heart failure The certainty of the evidence ranged from moderate to very lowConclusions This systematic review and meta-analysis revealed a beneficial roleof nut consumption in reducing the incidence of and mortality from different CVDoutcomes

INTRODUCTION

Cardiovascular disease (CVD) is an important publichealth issue According to the World HealthOrganization (WHO) it is the leading cause of death

worldwide affecting approximately 177 million peoplein 20151 Importantly CVDs are susceptible to behavior

modifications In this sense a healthy diet is one of thelifestyle components that could be promoted to help ad-

dress this global health concern2 Different healthy die-tary patterns such as the Mediterranean diet

(MedDiet)3 the DASH diet4 or a vegetarian diet5 havenuts as a key food component Nuts despite their high

fat content (mainly unsaturated fatty acids)6 are alsorich in minerals vitamins fiber and bioactive com-

pounds7 Given this exceptional nutritional profile fre-quent nut consumption has been inversely associated

with a lower risk of CVD in large prospective cohortstudies which have been summarized in several meta-

analyses8ndash20 Nonetheless some of the previous meta-analyses had methodological limitations such as the in-

clusion of studies with nuts plus seeds or legumes as ex-posure the inclusion of studies combining different

outcomes across analyses (eg inclusion of studies withonly fatal CHD [coronary heart disease] outcome in the

CVD mortality analysis) and the inclusion of studieswithout the first category of exposure as reference

Moreover since publication of the last meta-analysesthe results of two new large prospective cohort studies

evaluating the association between nut consumptionand CVD outcomes have been published2122 One study

reported updated results from the Nursesrsquo Health StudyI (NHSI) Nursesrsquo Health Study II (NSHII) and Health

Professionals Follow-up Study (HPFS) comprising upto 32 years of follow-up and a large number of cases21

Another reported the association between nut con-sumption and the incidence of 7 CVD outcomes in apopulation of 32 911 males22 Importantly most of the

previous meta-analyses have focused on total nut in-take and only a few have taken into account the poten-

tial associations between specific types of nutconsumption and the risk of CVD outcomes which

may vary considerablyTherefore taking into consideration the aforemen-

tioned issues and in order to develop evidence-basedrecommendations the Diabetes and Nutrition Study

group (DNSG) of the EASD (European Association forthe Study of Diabetes) commissioned a systematic re-

view and meta-analysis (SRMA) of prospective cohortstudies using the Grading of Recommendations

Assessment Development and Evaluation (GRADE)system to summarize the evidence of the association be-

tween the consumption of total nuts or specific types ofnuts and the incidence of and mortality from certain

CVD outcomes The shape of the associations with lin-ear and non-linear dose-response analysis was also

evaluated

METHODS

The current systematic review and meta-analysis fol-

lowed the methodological guidelines of the CochraneHandbook for Systematic Reviews of Interventions23

Results are reported according to Meta-analysis ofObservational Studies in Epidemiology (MOOSE)

guidelines24 The protocol is available at httpwwwcrdyorkacukPROSPERO (identifier PROSPERO

2018 CRD42018103360)

Search strategy

A systematic search limited to human studies with no lan-

guage restrictions was conducted of the MEDLINE(PubMed) and Cochrane Library databases through 5

June 2018 An updated search was then performed onMarch 19 2019 Table 1 shows the PICOS (participants

interventionsexposures comparators outcomes andstudy design) criteria used to identify studies eligible for

inclusion The electronic search was supplemented with amanual review of the reference lists of the retrieved

articles Figure 1 and Table S1 in the SupportingInformation online summarize the search and selection

process

Study selection

An initial screening of all titles and abstracts of the re-

trieved articles was performed to evaluate compliancewith the eligibility criteria Inclusion criteria were

prospective cohort studies with at least 1 year of follow-up conducted in an adult population with total nuts or

specific types of nuts as exposure with the incidence of

692 Nutrition ReviewsVR Vol 77(10)691ndash709

Dow




or mortality from CVD CHD stroke heart failure(HF) or atrial fibrillation (AF) as the outcome and

reporting effect estimators as odds ratios (ORs) riskratios (RRs) or hazard ratios (HRs) and their corre-

sponding 95 confidence intervals (CIs) When morethan 1 article from the same study was revealed both

papers were included if the end points were different(ie AF in one article and stroke in the other) When

multiple publications from the same study reported thesame outcome the study with the longest follow-up was

selected for inclusion Proceedings or publishedabstracts were not included in the present systematic re-

view and meta-analysisTwo publications were identified for the Nursesrsquo

Health Study I and Health Professionals Follow-up

Study which evaluated the association between nutconsumption and CVD outcomes in a whole population

cohort study21 and in individuals with diabetes only25

Therefore for the present meta-analysis the study con-

ducted in the whole cohort where participants with dia-betes where also included was selected Similarly for

The Netherlands Cohort Study two different articleswere also identified one published in 201526 and an-

other one in 201927 However in both cases the totalsample size and the period of follow-up were the same

Therefore the 2015 publication26 was included becauseits main aim fitted better with the objective of the pre-

sent systematic review and meta-analysis

Data extraction

Two independent reviewers (NB-T and IP-G) reviewed

the full text of the articles that were selected in the firstphase of the screening process Using a standardized pro-

forma the following relevant information was extractedfrom those studies that met all of the inclusion criteria

authors journal and year of publication study design co-hort name country or study location total sample size

characteristics of subjects follow-up duration sources offindings type of exposure and method used for its assess-

ment outcome and method assessment effect estimators

(OR RR or HR and 95 confidence intervals) and statis-tical analyses When necessary authors were contacted by

email to obtain additional information relevant to theanalyses Any disagreement was resolved by discussion or

if necessary by a third author (JS-S)

Quality of the included studies

The Newcastle-Ottawa scale (NOS) was utilized to as-

sess the quality of the included studies28 It is a ratingscale from 0 to 9 where points are allocated according

to 3 different domains population selection outcomeassessment and comparability of the groups A maxi-

mum of 4 3 and 2 points were allotted to each study af-ter evaluation of the aforementioned domains High-

quality studies were considered those studies with a to-tal score of at least 7 points Disagreements in grading

the quality of the studies were resolved through consen-sus between the reviewers

Outcomes

The primary outcomes were CVD incidence (including

only nonfatal or a combination of nonfatal and fataloutcomes of a composite of different CVD outcomes)and CVD mortality which only included a composite

of different fatal CVD end points Secondary outcomesincluded incidence of nonfatal or a combination of

nonfatal and fatal outcomes and mortality from fataloutcomes ie CHD stroke AF and HF

Studies that reported fatal CHD and nonfatal myo-cardial infarction separately were combined using a

fixed-effects model to generate an overall estimate forCHD incidence2930 In the same way following the

same procedure ischemic stroke and intracerebralhemorrhage outcomes22 and fatal ischemic stroke and

fatal hemorrhagic stroke31 end points were combinedto obtain an overall estimate for stroke incidence and

stroke mortality respectively

Table 1 PICOS criteria for inclusion and exclusion of studiesParameter Inclusion criteria Exclusion criteria

Participants General population of adults Aged lt18 yearsInterventionexposure Nut consumption (including total nuts or

subtypes of nuts eg walnuts almondspeanuts peanut butter hazelnuts)

Dietary intakes do not include total nut consumptionor different subtypes of nut consumption

Comparison Extreme quantiles Risk estimate on continuous scaleOutcome Incidence of or mortality from cardiovas-

cular disease coronary heart diseasestroke heart failure atrial fibrillation

Other cardiovascular disease outcomes

Study design Prospective cohort studies Cross-sectional case-control ecological retrospectiveobservational studies clinical trials and non-hu-man studies

Nutrition ReviewsVR Vol 77(10)691ndash709 693

Dow




Statistical analyses

The generic inverse variance method with a random-

effects model (5 comparisons) or fixed-effects model(lt5 comparisons) was used to pool the natural log-

transformed RRs for CVD incidence and mortality out-comes to compare highest vs lowest categories of nut

consumption For one study32 that reported results us-ing the second category of nut consumption rather

than the lowest one as the reference the RR and its cor-responding 95CI were recalculated following the

Hamling et al33 method using the first category as thereference

Heterogeneity among studies was estimated usingCochranrsquos Q test and quantified by the I2 statistic

Statistical significance was set at Plt 010 and an I2

value 50 was considered to reflect substantial

heterogeneityMeta-regression analysis was performed in order

to assess whether a priori specified study characteris-tics (ie sex follow-up geographical area NOS scale

and its individual domains) may have affected theoverall effect estimates This subgroup analysis was

only conducted if at least 10 study comparisons wereavailable23

Sensitivity analysis excluding 1 study at a time and

recalculating the summary estimates was performed toascertain the influence of individual studies on the sum-

mary estimates If the removal of a study yielded achange in the level of significance magnitude (by

gt10) or direction of the pooled risk estimates orchanged the evidence of heterogeneity then it was con-

sidered as influentialLinear dose-response analysis for total nut con-

sumption and different CVD outcomes was conductedfollowing the 2-stage generalized least-squares trend

(GLST) estimation method developed by Greenlandand Longnecker34 and Orsini et al35 In the first stage

the method fits the dose-response model within eachstudy and in the second stage it combines study-

specific trends Data on RRs and the corresponding95CIs total number of participants cases and doses

for at least 3 categories of nut consumption wereneeded to carry out this method The mean or median

of nut consumption from each exposure category wasused if it was directly reported For those studies that

did not report this information the midpoint betweenthe upper and lower boundaries was assigned when

ranges of nut consumption were available For studiesthat reported open-ended extreme categories a width

equal to the adjacent category was assumed in order toestimate the upper or lower cutoff value Some studies

reported the information on nut consumption in gramsand others in servings Therefore servings were

converted to grams where 1 serving equated to 28 g

unless authors specified other serving sizesPotential nonlinear association between nut con-

sumption and CVD outcomes was assessed using re-stricted cubic splines (MKSPLINE procedure) which

were combined using multivariate meta-analysis Thedeparture from linearity was assessed by the Wald testconstraining the regression coefficient for the second

spline equal to zero36

Publication bias was tested by the visual inspection

of the funnel plots for asymmetry and statisticallyBeggrsquos test and Eggerrsquos test When few studies are in-

cluded in the analysis the power of the tests is too lowtherefore publication bias was only examined if more

than 10 study comparisons were included in the analy-sis23 Statistical significance was set at Plt 005

Data analysis was performed using ReviewManager (RevMan) software version 53 Copenhagen

The Nordic Cochrane Centre The CochraneCollaboration 2014 and STATA version 15 software

(StataCorp LP College Station Texas)

Grading the evidence

The GRADE system was used to rate the overall qualityand the strength of the evidence The quality of evi-

dence for each outcome was categorized as high mod-erate low or very low This system regards

observational studies as low-quality evidence37 Thelevel of evidence can be upgraded or downgraded

according to different specified criteria Determinantsto downgrade included study design and execution lim-

itations38 inconsistency39 indirectness40 impreci-sion41 and publication bias42 Determinants to upgradeincluded large magnitude effect dose-response gradi-

ent and attenuation by plausible confounding effects43

Discrepancies in ratings of the evidence quality were

resolved by consensus between NB-T and IP-G

RESULTS

Study selection process

The present systematic review and meta-analysis in-cluded 19 prospective studies from the 2992 identified

articles (Figure 1) Three study comparisons (1 report)were included in the meta-analysis for total CVD21 14

study comparisons (9 reports) for CVD mortal-ity21263144ndash49 7 study comparisons (5 reports) for

CHD2122293050 12 study comparisons (8 reports) forCHD mortality2122263031444851 7 study comparisons

(5 reports) for stroke2122325253 11 study comparisons(7 reports) for stroke mortality21263132474851 5 study

comparisons (4 reports) for hemorrhagic stroke2252ndash54


Dow




7 study comparisons (5 reports) for ischemic

stroke2122325253 2 study comparisons for AF2255 and2 study comparisons for HF2256

Four studies57ndash60 that reported the risk estimate oncontinuous scale instead of categories of nut consump-

tion were identified and therefore were not included inthe high vs low categories of consumption analyses and

the dose-response analyses

Study characteristics

The characteristics of the included studies are presentedin Table 221222629ndash324446ndash60 Publication date ranged

from 1992 to 2018 Six of the studies originated fromEurope 13 from America 1 from Asia 1 from

Australia 1 from both China and the USA and 1 fromboth China and Germany The duration of follow-up

ranged from 43 to 287 years All the studies assessed

nut intake via a food frequency questionnaire The vast

majority of studies (709) were of high quality accord-ing to the NOS scale Tables S1ndashS5 in the Supporting

Information online describe the characteristics of theincluded studies by type of nut consumption

High vs low categories of consumption analyses

Nuts and cardiovascular disease incidence Three cohort

comparisons involving 210 836 participants and 14 136cases analyzed the association between nut consump-

tion and the risk of CVD incidence The summary RR(95CI) for high vs low categories of nut consumption

was 085 (080ndash091) with no evidence of interstudy het-erogeneity (I2frac14 0 Pheterogeneity 081) (Figure 2 and

Figure S1 in the Supporting Information online)Regarding specific types of nuts consumption of tree

nuts ([RR 085 95CI 079ndash091] I2 0

Figure 1 Flow diagram of the literature search and selection process


Dow




Tabl

e2

Char

acte

rist

ics

ofth

ein

clud

edst

udie

sev

alua

ting

the

asso

ciat

ion

betw

een

nuts

and

risk

ofca

rdio

vasc

ular

dise

ase

outc

omes

Stud

yCo

untr

ySt

udy

nam

ePo

pula

tion

Nut

cons

umpt

ion

asse

ssm

ent

met

hod

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Fras

eret

al(1

992)

29U

SASe

vent

h-da

yAd

vent

ists

2647

3M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

51

serv

ings

wk

vslt

1se

rvin

gw

k

25

6N

onfa

talM

I13

4Ag

ency

7CH

Dm

orta

lity

463

Albe

rtet

al(2

002)

30U

SAPh

ysic

ians

rsquoH

ealth

Stud

y21

454

MSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gm

o

40ndash8

417

CHD

mor

talit

y56

6Ag

ency

7N

onfa

talM

I10

37

Blom

hoff

etal

(200

6)44

USA

Iow

aW

omen

rsquosH

ealth

Stud

y31

778

FSe

lf-ad

min

is-

tere

dFF

QN

uts

plus

pean

utbu

tter

7se

rvin

gsw

kvs 0

5se

rvin

gsw

k

55ndash6

915

CVD

mor

talit

y16

75Ag

ency

6CH

Dm

orta

lity

948

Djo

uss e

etal

(200

8)56

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2097

6M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gw

k

40ndash8

419

6H

eart

failu

re10

93N

R6

Net

tleto

net

al(2

008)

57U

SAAt

hero

scle

rosi

sRi

skin

Com

mun

ities

Stud

y

1415

3M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

erCo

ntin

uous

1se

rvin

gd

45ndash6

413

Hea

rtfa

ilure

1140

Agen

cy8

Djo

uss e

etal

(201

0)52

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2107

8M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

7se

rvin

gsw

kvs lt

1se

rvin

gw

k

40ndash8

421

1St

roke

1424

Agen

cy6

Isch

emic

stro

ke11

89H

emor

rhag

icst

roke

219

Bern

stei

net

al(2

012)

54U

SAN

urse

srsquoH

ealth

Stud

yI

8001

0F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

034

serv

ings

dvs

0se

rvin

gsd

30ndash5

526

Hem

orrh

agic

stro

ke13

83Ag

ency

6

Hea

lthPr

ofes

sion

als

Follo

w-U

pSt

udy

4315

0M

060

serv

ings

dvs

0se

rvin

gsd

40ndash7

522

Hem

orrh

agic

stro

ke82

9

Khaw

aja

etal

(201

2)55

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2105

4M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

6

serv

ings

wk

vs0

serv

ings

wk

40ndash8

424

Atria

lfib

rilla

tion

3317

Agen

cy7

Yaem

siri

etal

(201

2)58

USA

Wom

enrsquos

Hea

lthIn

itiat

ive

Obs

erva

tiona

lSt

udy

8702

5F

Self-

adm

inis

-te

red

FFQ

Not

spec

ified

Cont

inuo

us1

serv

ing

d50

ndash79

76

Isch

emic

stro

ke10

49Ag

ency

8

von

Rues

ten

etal

(201

3)59

Ger

man

yEP

IC-P

otsd

amst

udy

2353

1M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Pean

uts

wal

nuts

br

azil

nuts

Cont

inuo

us1

serv

ing

d35

ndash65

8CV

D36

3Ag

ency

8

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Gua

sch-

Ferr

eet

al(2

013)

46Sp

ain

PRED

IMED

stud

y72

16M

FIn

terv

iew

-adm

in-

iste

red

vali-

date

dse

mi-

quan

titat

ive

FFQ

Alm

onds

pea

-nu

tsh

azel

-nu

tsp

ista

-ch

ios

pine

nuts

gt3

serv

ings

wk

vs neve

r

55ndash8

04

8CV

Dm

orta

lity

81Ag

ency

-In

dust

ry9

Bona

ccio

etal

(201

5)48

Italy

Mol

i-san

istu

dy10

509

F88

77M

Valid

ated

sel

f-ad

min

iste

red

FFQ

Wal

nuts

haz

el-

nuts

alm

onds

pe

anut

s

Inta

kevs no

inta

ke

gt35

43

CVD

mor

talit

y10

4Ag

ency

6CH

Dm

orta

lity

39St

roke

mor

talit

y19

diG

iuse

ppe

etal

(201

5)32

Ger

man

yEP

IC-P

otsd

amst

udy

2599

7M

FVa

lidat

eds

elf-

adm

inis

tere

dFF

Q

Pean

uts

wal

nuts

br

azil

nuts

142

gd

vs 0g

d

F49

2M

52

58

3St

roke

288

Agen

cy8

Isch

emic

stro

ke23

5St

roke

mor

talit

y36

Gop

inat

het

al(2

015)

51Au

stra

liaBl

ueM

ount

ains

Eye

Stud

y13

12F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

490

to10

0g

dvs 0

to0

50g

d

49

15CV

Dm

orta

lity

258

Agen

cy7

IHD

mor

talit

y18

8St

roke

mor

talit

y10

1

1581

MCV

Dm

orta

lity

288

IHD

mor

talit

y24

2St

roke

mor

talit

y75

Har

ing

etal

(201

4)50

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1206

6M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Not

spec

ified

06

serv

ings

dvs

01

serv

ings

d45

ndash64

22CH

D11

47Ag

ency

9

Har

ing

etal

(201

5)53

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1160

1M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

er1

serv

ings

dvs 0

serv

ings

d

45ndash6

422

7St

roke

699

Agen

cy8

Hem

orrh

agic

stro

ke11

4

Isch

emic

stro

ke59

8H

shie

het

al(2

015)

47U

SAPh

ysic

ians

rsquoH

ealth

Stud

y20

742

MU

nval

idat

eds

elf-

adm

inis

tere

dFF

Q

Not

spec

ified

5

serv

ings

wk

vs lt1

serv

ing

wk

40ndash8

49

6CV

Dm

orta

lity

760

Agen

cy6

Stro

kem

orta

lity

143

Luu

etal

(201

5)31

USA

Sout

hern

Com

mun

ityCo

hort

Stud

y

7176

4M

FSe

mi-q

uant

ita-

tive

FFQ

Tota

lnut

san

dpe

anut

butt

er

184

5g

dvs lt

095

gd

40ndash7

95

4CV

Dm

orta

lity

1857

Agen

cy8

IHD

mor

talit

y79

3Is

chem

icst

roke

mor

talit

y12

1

Hem

orrh

agic

stro

kem

orta

lity

96

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Chin

aSh

angh

aiW

omen

rsquosH

ealth

Stud

yan

dSh

angh

aiM

enrsquos

Hea

lthSt

udy

134

265

MF

Pean

ut

254

gd

vs lt0

14gr

amd

ay

40ndash7

0an

d40

ndash74

122

and

65

CVD

mor

talit

y25

87IH

Dm

orta

lity

631

Isch

emic

stro

kem

orta

lity

588

Hem

orrh

agic

stro

kem

orta

lity

597

van

den

Bran

dtan

dSc

hout

en(2

015)

26

Net

herla

nds

Net

herla

nds

Coho

rtSt

udy

3202

MF

(sub

coho

rt)

Self-

adm

inis

-te

red

valid

ated

FFQ

Tree

nuts

pe

anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

IHD

mor

talit

y14

88St

roke

mor

talit

y56

5

Wan

get

al(2

016)

60Ch

ina

Linx

ian

NIT

coho

rt24

45M

FFF

QPe

anut

sch

est-

nuts

wal

nuts

Cont

inuo

us3

serv

ings

mo

40ndash6

926

Hea

rtdi

seas

em

orta

lity

355

Agen

cy6

Ger

man

ySt

roke

mor

talit

y45

2

Esla

mpa

rast

etal

(201

7)49

Iran

Gol

esta

nCo

hort

Stud

y28

257

FVa

lidat

eds

elf-

adm

inis

tere

dse

miq

uant

ita-

tive

FFQ

Pean

uts

tree

nuts

3

serv

ings

wk

vs neve

r

40ndash8

77

CVD

mor

talit

y91

1Ag

ency

720

855

M11

05

Gua

sch-

Ferr

eet

al(2

017)

21U

SAN

urse

srsquoH

ealth

Stud

yI

7636

4F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Pean

uts

othe

rnu

tsa

ndw

al-

nuts

(ifav

aila

ble)

5

serv

ings

wk

vs neve

rora

lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

7CV

Dm

orta

lity

1770

CHD

3552

CHD

mor

talit

y99

6St

roke

3322

Stro

kem

orta

lity

773

Isch

emic

stro

ke16

35N

urse

srsquoH

ealth

Stud

yII

9294

6F

25ndash4

221

5CV

D19

15CV

Dm

orta

lity

82CH

D67

0CH

Dm

orta

lity

46St

roke

1262

Stro

kem

orta

lity

36

Isch

emic

stro

ke22

0H

ealth

Prof

essi

onal

sFo

llow

-Up

Stud

y

4152

6M

40ndash7

522

5CV

D54

94CV

Dm

orta

lity

2599

CHD

4168

CHD

mor

talit

y19

21St

roke

1326

Stro

kem

orta

lity

367

Isch

emic

stro

ke74

2

(con

tinue

d)


Dow




Pheterogeneity 070) peanuts ([RR 087 95CI

081ndash093] I2 0 Pheterogeneity 067) and walnuts ([RR081 95CI 071ndash092] I2 73 Pheterogeneity 003) was

associated with a lower risk of CVD incidence aftercomparing highest vs lowest categories of consumption

(Table 3 and Figures S2ndashS4 in the SupportingInformation online) No association was reported be-tween peanut butter consumption and the risk of CVD

incidence ([RR 098 95CI 093ndash103] I2 89Pheterogeneitylt001) (Table 3 and Figure S5 in the

Supporting Information online)

Nuts and cardiovascular disease mortality Fifteen co-hort comparisons analyzed the association between

nut consumption and CVD mortality including413 727 participants and 14 475 cases The summary

RR (95CI) for high vs low categories of nut con-sumption was 077 (072ndash082) with no evidence of

interstudy heterogeneity (I2 3 Pheterogeneity 042)(Figure 2 and Figure S6 in the Supporting Information

online) Regarding specific types of nuts only peanutshave been studied in relation to CVD mortality show-

ing a summary RR of 077 (95CI 070ndash085) for highvs low categories of consumption with no evidence of

interstudy heterogeneity (I2 0 Pheterogeneity 081)(Table 3 and Figure S7 in the Supporting Information

online)

Nuts and coronary heart disease incidence Seven cohortcomparisons analyzed the association between nut con-

sumption and CHD incidence including 275 812 par-ticipants and 12 654 cases The summary RR (95CI)

for high vs low categories of nut consumption was 082(069ndash096) with evidence of substantial interstudy het-

erogeneity (I2 74 Pheterogeneitylt001) (Figure 2 andFigure S8 in the Supporting Information online)

Regarding specific types of nuts consumption of treenuts ([RR 077 95CI 070ndash084] I2 61

Pheterogeneity 008) peanuts ([RR 085 95CI 079ndash092] I2 0 Pheterogeneity 055) and walnuts ([RR0791 95CI 066ndash094] I2 69 Pheterogeneity 004) was

associated with a lower risk of CHD incidence aftercomparing highest vs lowest categories of consumption

(Table 3 and Figures S9ndashS11 in the SupportingInformation online) No association was reported be-

tween peanut butter consumption and the risk of CHDincidence ([RR 100 95CI 094ndash107] I2 43

Pheterogeneity 017) (Table 3 and Figure S12 in theSupporting Information online)

Nuts and coronary heart disease mortality Thirteen co-

hort comparisons analyzed the association between nutconsumption and CHD mortality including 396 041

participants and 7877 cases The summary RR (95CI)Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Lars

son

etal

(201

8)22

Swed

enCo

hort

ofSw

edis

hM

en32

911

MFF

QN

uts

(not

incl

ud-

ing

coco

nuto

rch

estn

uts)

3

serv

ings

wk

vs neve

r

45ndash8

317

MI

4983

Agen

cy8

MIm

orta

lity

917

Hea

rtfa

ilure

3160

Atria

lfib

rilla

tion

7550

Isch

emic

stro

ke37

82In

trac

ereb

ral

hem

orrh

age

543

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CVD

car

diov

ascu

lard

isea

seE

PIC

Euro

pean

Pros

pect

ive

Inve

stig

atio

nin

toCa

ncer

and

Nut

ritio

nF

fem

ales

FFQ

foo

dfr

eque

ncy

ques

tionn

aire

IH

Di

sche

mic

hear

tdis

ease

Mm

ales

MI

myo

card

iali

nfar

ctio

nN

ITN

utrit

ion

Inte

rven

tion

Tria

lsN

OS

New

cast

le-O

ttaw

asc

ale

NR

Not

repo

rted

PRE

DIM

EDP

reve

nci o

nco

nD

ieta

MED

iterr

anea


Dow




for high vs low categories of nut consumption was 076(067ndash086) with evidence of moderate interstudy het-

erogeneity (I2 46 Pheterogeneity 004) (Figure 2 andFigure S13 in the Supporting Information online)

Regarding specific types of nuts peanut consumption

was inversely associated with the risk of CHD mortalityafter comparing high vs low categories of consumption

([RR 075 95CI 064ndash088] I2 0 Pheterogeneity 046)(Table 3 and Figure S14 in the Supporting Information

online)

Table 3 Summary RR of cardiovascular disease outcomes by different types of nut consumption (comparing highest vslowest categories)

No of cohorts No of participants No of cases RR (95CI) P for heterogeneity I2 ()

Tree nutsCVD 3 210 836 14 136 085 (079 091) 070 0CVD mortality ndash ndash ndash ndash ndash ndashStroke 3 210 836 5910 100 (089 111) 093 0Stroke mortality 3 118 962 1851 093 (077 113) 044 0CHD 3 210 836 8390 077 (070 084) 008 61CHD mortality ndash ndash ndash ndash ndash ndash

PeanutsCVD 3 210 836 14 136 087 (081 093) 067 0CVD mortality 2 134 265 5572 077 (070 085) 081 0Stroke 3 210 836 5910 090 (081 099) 032 13Stroke mortality 4 253 227 3036 083 (073 095) 007 57CHD 3 210 836 8390 085 (079 092) 055 0CHD mortality 2 134 265 2119 075 (064 088) 046 0

WalnutsCVD 3 144 021 5255 081 (071 092) 003 73CVD mortality ndash ndash ndash ndash ndash ndashStroke 3 144 021 5910 085 (071 102) 019 39Stroke mortality ndash ndash ndash ndash ndash ndashCHD 3 144 021 2685 079 (066 094) 004 69CHD mortality ndash ndash ndash ndash ndash ndash

Peanut butterCVD 3 210 836 14 136 098 (093 103) lt001 89CVD mortality ndash ndash ndash ndash ndash ndashStroke 3 210 836 5910 094 (087 102) lt001 86Stroke mortality ndash ndash ndash ndash ndash ndashCHD 3 210 836 8390 100 (094 107) 017 43CHD mortality ndash ndash ndash ndash ndash ndash

Abbreviations CHD coronary heart disease CI confidence interval CVD cardiovascular disease RR risk ratio

Figure 2 Summary plots of effect estimates from prospective cohort studies evaluating the association between nut consumptionand the risk of different cardiovascular outcomes Abbreviations CHD coronary heart disease CI confidence interval CVD cardiovasculardisease RR risk ratio


Dow




Nuts and stroke incidence Seven cohort comparisonsanalyzed the association between nut consumption and

stroke incidence including 302 888 participants and12 646 cases The summary RR (95CI) for high vs low

categories of nut consumption was 100 (092ndash109)with no evidence of interstudy heterogeneity (I2 0

Pheterogeneity 097) (Figure 2 and Figure S15 in theSupporting Information online) Regarding specific

types of nuts peanut consumption was associated witha lower risk of stroke incidence after comparing highest

vs lowest categories of consumption ([RR 090 95CI081ndash099] I2 13 Pheterogeneity 032) (Table 3 andFigure S16 in the Supporting Information online) No

association was observed between tree nut walnut andpeanut butter consumption and the risk of stroke inci-

dence (Table 3 and Figures S17ndashS19 in the SupportingInformation online)

Nuts and stroke mortality Twelve cohort comparisons

analyzed the association between nut consumption andstroke mortality including 351 618 participants and

2332 cases The summary RR (95CI) for high vs lowcategories of nut consumption was 083 (075ndash093)

with no evidence of interstudy heterogeneity (I2 0Pheterogeneity 045) (Figure 2 and Figure S20 in the

Supporting Information online) Regarding specifictypes of nuts peanut consumption was associated with

a lower risk of stroke mortality after comparing highestvs lowest categories of consumption ([RR 085 95CI

079ndash092] I2 0 Pheterogeneity 055) (Table 3 andFigure S21 in the Supporting Information online) No

association was reported between tree nut consumptionand the risk of stroke death (Table 3 and Figure S22 in

the Supporting Information online)

Nuts and hemorrhagic stroke Five cohort comparisonsanalyzed the association between nut consumption and

hemorrhagic stroke incidence involving 188 750 partic-ipants and 3088 cases The summary RR (95CI) for

high vs low categories of nut consumption was 102(077ndash134) with no evidence of interstudy heterogene-ity (I2 15 Pheterogeneity 032) (Figure 2 and Figure S23

in the Supporting Information online) No studyanalyzed the association between different types of nuts

and the risk of hemorrhagic stroke

Nuts and ischemic stroke Seven cohort comparisonsanalyzed the association between nut consumption and

ischemic stroke incidence involving 302 423 partici-pants and 8401 cases The summary RR (95CI) for

high vs low categories of nut consumption was 099(089ndash110) with no evidence of interstudy heterogene-

ity (I2 0 Pheterogeneity 062) (Figure 2 and Figure S24 in

the Supporting Information online) No study analyzed

the association between different types of nuts and therisk of hemorrhagic stroke

Nuts and atrial fibrillation Two cohort comparisonsanalyzed the association between nut consumption and

AF involving 53 965 participants and 10 867 cases Thesummary RR (95CI) for high vs low categories of nut

consumption was 085 (073ndash099) with no evidence ofinterstudy heterogeneity (I2 0 Pheterogeneity 052)

(Figure 2 and Figure S25 in the Supporting Informationonline) No study analyzed the association between dif-

ferent types of nuts and the risk of AF

Nuts and heart failure Two cohort comparisonsanalyzed the association between nut consumption and

HF involving 53 887 participants and 4253 cases Thesummary RR (95CI) for high vs low categories of nut



ferent types of nuts and the risk of HF

Dose-response analyses

Figures S27ndashS34 in the Supporting Information onlineshow the linear and non-linear dose-response analyses

between total nut consumption and CVD outcomesThe summary RR (95CI) for a 28-gd increment was

087 (081ndash093) for CVD incidence 071 (061ndash084)for CVD mortality 075 (064ndash088) for CHD incidence

067 (052ndash087) for CHD mortality 106 (097ndash115) forstroke incidence 101 (088ndash118) for stroke mortality

105 (077ndash143) for hemorrhagic stroke and 106(086ndash131) for ischemic stroke

Total nut consumption and the risk of CVD inci-dence (Figure S27 in the Supporting Information on-

line) CVD mortality (Figure S28 in the SupportingInformation online) stroke mortality (Figure S32 in theSupporting Information online) and hemorrhagic

stroke (Figure S33 in the Supporting Information on-line) showed a non-linear association (Pnon-line-

aritylt001) The reduction in the risk of CVD incidencewas observed up to a consumption of 10 gd with no

further reduction with higher consumptions (Table S6in the Supporting Information online) For CVD mor-

tality and CHD mortality there was a steeper reductionin the risk at approximately 15ndash20 gd with no further

reduction with a higher consumption (Table S6 in theSupporting Information online) The reduction in the

risk of stroke mortality was observed up to a consump-tion of 5 gd with no significant reductions above this

amount (Table S6 in the Supporting Information


Dow




online) The association between total nuts and

hemorrhagic stroke appeared to be J-shaped with a riskreduction up to 5 gd but there was a slight non-

significant positive association at intakes of 25 gd(Table S6)

There was no evidence of non-linear associationfor the other outcomes

Sensitivity analyses

Table S7 in the Supporting Information online showsthe sensitivity analysis by the removal of one study at a

time Regarding total nut consumption no trial modi-fied the magnitude direction or significance of the

pooled estimates or the evidence for heterogeneity fortotal CVD incidence and mortality stroke incidence

and mortality HF or AF Removal of the Guasch-Ferreet al study (NHSI)21 changed the pooled estimates of to-

tal CHD incidence from significant to nonsignificantRemoval of the Larsson et al22 study explained the het-

erogeneity for CHD death (I2 16 Pheterogeneity 028)With regard to different types of nuts removal of the

Guasch-Ferre et al study (HPFS) and Guasch-Ferrestudy (NHSII)21 modified the significance of the pooled

RR for peanut consumption and total stroke from sig-nificant to nonsignificant and removal of the Bao

et al45 study explained the heterogeneity (I2 0Pheterogeneity 077) In the case of peanut butter removal

of the Guasch-Ferre et al study (NHSII)21 explained theheterogeneity for total CVD (I2 0 Pheterogeneity 060)

and for total stroke (I2 0 Pheterogeneity 053)Furthermore removal of the Guasch-Ferre et al study

(NHSI)21 changed the significance of the pooled esti-mates for total stroke from nonsignificant to significant

Regarding walnuts removal of the Guasch-Ferre et alstudy (HPFS)21 changed the magnitude of the RR for

total CVD and CHD and the pooled estimates becamesignificant for total stroke Removal of the Guasch-

Ferre et al study (NHSI)21 changed the significance ofthe pooled estimates for total CVD and CHD from sig-nificant to nonsignificant Finally removal of the

Guasch-Ferre et al study (NHSII)21 explained the het-erogeneity (I2 0 Pheterogeneity 053) for CHD and

changed the significance of the pooled estimates fromsignificant to nonsignificant

Subgroup analyses

Subgroup analyses could only be conducted for CVD

CHD and stroke death Figures S35ndashS40 in theSupporting Information online show the a priori sub-

group analyses for the aforementioned outcomes Themeta-regression analysis revealed no evidence of effect

modification by sex duration of follow-up or NOS

quality score and its individual domains However the

risk of CVD death was modified by geographical area(Pfrac14 003) In studies conducted in America nut con-

sumption was inversely associated with the risk of CVDmortality (RR 068 95CI 061ndash077) whereas no as-

sociation was observed in those studies conducted inEurope (RR 091 95CI 072ndash114) or Oceania (RR095 95CI 071ndash128) Geographical area explained

389 of the total heterogeneity (I2 47Pheterogeneity 004) No effect modification by geographi-

cal area was observed for CHD mortality and strokemortality

Publication bias

Figures S41ndashS43 in the Supporting Information onlineshow the funnel plots used to assess publication bias for

death from CVD CHD and stroke (the only outcomeswith more than 10 study comparisons in the analyses)

There was no statistical evidence of small study effectsbased on visual inspection of the funnel plots with ei-

ther Eggerrsquos test or Beggrsquos test (all Pgt 005)

Grading of the evidence

Table 4 shows the GRADE assessment for the certainty

of the evidence for the association between total nutconsumption and the risk of CVD outcomes The evi-dence was rated as moderate for CVD mortality and

CHD mortality low for CVD incidence and strokemortality and very low for CHD incidence stroke inci-

dence hemorrhagic stroke ischemic stroke AF andHF Tables S8ndashS11 in the Supporting Information on-

line show the GRADE assessment for the associationbetween subtypes of nut consumption and the risk of

CVD outcomes The overall certainty of the evidencewas graded as very low for all subtypes of nut consump-

tion and CVD outcomes

DISCUSSION

The results of the present systematic review and meta-analysis of prospective cohort studies showed a signifi-

cant inverse association between total nut consumptionand the risk of CVD incidence and mortality CHD in-

cidence and mortality and AF There was no associa-tion between total nut consumption and stroke

incidence or mortality hemorrhagic stroke ischemicstroke and HF Regarding specific types of nuts tree

nut consumption was associated with a lower risk ofCVD and CHD incidence while peanut consumption

was associated with a lower incidence of and mortalityfrom CVD stroke and CHD and walnut consumption

with a lower incidence of CVD stroke and CHD No


Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

fort

hese

outc

omes

no

dow

ngra

des

wer

em

ade

forp

ublic

atio

nbi

as

bSe

rious

indi

rect

ness

forC

VDin

cide

nce

asth

ein

clud

edst

udie

sw

ere

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(69

30

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

mal

es

c Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CVD

inci

denc

e(Plt

001

)se

eFi

gure

S27

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ed

Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

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Dow




association was observed between peanut butter con-

sumption and CVD outcomesSeveral previous meta-analyses have focused on

summarizing data regarding nut consumption and dif-ferent CVD outcomes8ndash20 It is important to highlight

that some limitations in terms of methodology werepresent such as the inclusion of studies with nuts plusseeds or fruits as exposure9101617 or the arbitrary com-

bination of different end points across the analyses (egthe inclusion of studies with a cause-specific CVD out-

come in CVD)91418ndash20 The present meta-analysisattempted to deal with these methodological issues by

including exclusively those studies that reported onlynut consumption as exposure Additionally in the anal-

yses of CVD incidence only those studies evaluating acomposite of non-fatal or a combination of nonfatal

and fatal CVD events were included Similarly forCVD mortality only studies that evaluated a composite

of fatal CVD events were considered For secondaryoutcomes the same definition criteria as in the primary

outcomes were appliedThe results of the present study regarding total nut

consumption are highly consistent with one of themost recent meta-analyses in this field15 which showed

an inverse association between nut consumption anddifferent CVD outcomes and which also took into ac-

count the aforementioned methodological issues at thetime of performing their analyses Recently one study

conducted only among individuals with diabetes ob-served similar results Those individuals consuming 5

servings of total nuts per week presented a lower risk ofCVD incidence (HR 083 95CI 071ndash098) CHD in-

cidence (HR 080 95CI 067ndash096) and CVD mortal-ity (HR 066 95CI 052ndash084) than those consuming

less than 1 serving per month25

Results regarding specific types of nuts are in line

with those of previous meta-analyses which alsoshowed an inverse association between tree nut con-

sumption and peanut consumption and the risk ofCVD incidence CVD mortality CHD incidence andCHD mortality91115 and no association with stroke in-

cidence915 In a recent analysis conducted only amongindividuals with diabetes the results were similar for

tree nut consumption which was also associated with alower risk of CVD incidence and mortality and CHD

incidence However the findings revealed no associa-tion between peanut consumption and CVD out-

comes25 Although the present meta-analysis alsoevaluated the association between walnut consumption

and peanut butter consumption and the risk of CVDCHD and stroke incidence the data was sourced from

only one report which included information from threedifferent cohorts the NHSI NHSII and HPFS21 The

lack of association between peanut butter consumption

and the risk of CVD outcomes may be due to the addi-

tion of salt and hydrogenated fats which could counter-act the beneficial effect of other nutrients present in raw

peanuts At present owing to the limited number ofstudies included in previous meta-analyses and in the

present analyses and considering the high degree ofinterstudy heterogeneity it is unclear whether differenttypes of nuts are associated with CVD outcomes

Different potential mechanisms have been pro-posed to explain the beneficial association observed be-

tween nut consumption and different CVD outcomesNuts are rich in unsaturated fatty acids proteins differ-

ent minerals (including potassium and magnesium)vitamins (including vitamin C and E) and phenolic

compounds This unique nutritional profile means thatnuts possess different properties that beneficially mod-

ify CVD risk factors and therefore reduce the risk ofCVD In fact the ability to lower total cholesterol and

low-density lipoprotein (LDL)-cholesterol levels isprobably one of the best-known properties of nuts as

was demonstrated by a pooled analysis of 25 interven-tion trials61 and more recently in one meta-analysis of

61 randomized controlled trials62 Other possible mech-anisms include a reduction in circulating levels of in-

flammatory cytokines (especially C-reactive protein)the modulation of nitric oxide production an improve-

ment in endothelial function and a reduction in oxida-tive stress6364

The present analysis has some strengths that shouldbe elucidated First a comprehensive systematic search

strategy was used to identify all available prospective co-hort studies Second studies reporting only nut con-

sumption as exposure were included Third the certaintyof the evidence was assessed using the GRADE

approachHowever the present systematic review and meta-

analysis also has some limitations Subgroup analyses formost of the outcomes could not be performed because

less than 10 study comparisons were availableMeasurement error in the evaluation of nut consumptioncould not be ruled out because all included studies used

food frequency questionnaires for this purpose Becauseof this limitation along with the possibility of residual

confounding because of the observational nature of theincluded studies GRADE-assessed prospective cohort

studies tend to be of lower quality than other types ofprospective studies Another important limitation is that

the certainty of the evidence in the effect estimates re-garding total nut consumption was moderate only for

two outcomes (CVD mortality and CHD mortality) andit was considered as low and very low for the others

mainly owing to downgrading for indirectness and im-precision Therefore future research is very likely to

change the confidence in the effect estimates


Dow




CONCLUSION

The present systematic review and meta-analysis pro-vides the most updated and comprehensive summary

estimates of the association between total nut consump-tion different subtypes and CVD outcomes The results

suggest a beneficial role of total nut consumption in re-ducing the incidence of and mortality from different

CVD outcomes Future research should focus on spe-cific types of nuts in order to better clarify their effect

on CVD outcomes

Acknowledgments

Author contributions NB-T and JS-S designed thestudy NB-T JS-S and IP-G contributed to data

acquisition NB-T JS-S and IP-G analyzed andinterpreted data NB-T JS-S IP-G CWCK

HK DR and JLS drafted and critically revised themanuscript for important intellectual content NB-Tand JS-S are the guarantors of this work have full ac-

cess to the data of the study and take responsibility forthe accuracy of the data analysis and the integrity of the

data

Funding The Diabetes and Nutrition Study Group(DNSG) of the European Association for the Study of

Diabetes (EASD) commissioned this systematic reviewand meta-analysis and provided funding and logistical

support for meetings as part of their development ofclinical practice guidelines for nutrition therapy JS-S

was funded by a PSI Graham Farquharson KnowledgeTranslation Fellowship Canadian Diabetes Association

Clinician Scientist award CIHR INMDCNS NewInvestigator Partnership Prize and Banting amp Best

Diabetes Centre Sun Life Financial New InvestigatorAward With the exception of the Clinical Practice

Guidelines Committee of the DNSG of the EASD noneof the sponsors had a role in any aspect of the present

study including design and conduct of the study col-lection management analysis and interpretation of the

data and preparation review approval of the manu-script or decision to publish IP-G has received grants

from the Spanish Ministry of Education Culture andSports (FPU 1701925)

Declaration of interest JS-S reports serving on the

board of the International Nut and Dried Fruit Counciland the Eroski Foundation and receiving grant support

from these entities through his institution He alsoreports serving on the Executive Committee of the

Instituto Danone Spain He has received research fund-ing from the Instituto de Salud Carlos III Spain

Ministerio de Educacion y Ciencia Spain Departamentde Salut Publica de la Generalitat de Catalunya

Catalonia Spain and the European Commission Hehas also received research funding from the California

Walnut Commission Sacramento CA USAPatrimonio Comunal Olivarero Spain La Morella

Nuts Spain and Borges SA Spain He reports receiv-ing consulting fees or travel expenses from Danone the

California Walnut Commission the Eroski Foundationthe Instituto Danone - Spain Nuts for Life the

Australian Nut Industry Council Nestle AbbottLaboratories and Font Vella Lanjaron He is on the

Clinical Practice Guidelines Expert Committee of theEuropean Association for the study of Diabetes

(EASD) and has served on the Scientific Committee ofthe Spanish Food and Safety Agency and the Spanish

Federation of Food Nutrition and Dietetic SocietiesHe is a member of the International Carbohydrate

Quality Consortium (ICQC) and Executive BoardMember of the Diabetes and Nutrition Study Group

(DNSG) of the EASD JLS has received research sup-port from the Canadian Foundation for Innovation

Ontario Research Fund Province of Ontario Ministryof Research and Innovation and Science Canadian

Institutes of health Research (CIHR) Diabetes CanadaPSI Foundation Banting and Best Diabetes Centre(BBDC) American Society for Nutrition (ASN) INC

International Nut and Dried Fruit Council FoundationNational Dried Fruit Trade Association The Tate and

Lyle Nutritional Research Fund at the University ofToronto The Glycemic Control and Cardiovascular

Disease in Type 2 Diabetes Fund at the University ofToronto (a fund established by the Alberta Pulse

Growers) and the Nutrition Trialists Fund at theUniversity of Toronto (a fund established by an inaugu-

ral donation from the Calorie Control Council) He hasreceived in-kind food donations to support a random-

ized controlled trial from the Almond Board ofCalifornia California Walnut Commission American

Peanut Council Barilla Unilever UnicoPrimo LoblawCompanies Quaker Kellogg Canada and WhiteWave

Foods He has received travel support speaker feesandor honoraria from Diabetes Canada Mottrsquos LLP

Dairy Farmers of Canada FoodMinds LLCInternational Sweeteners Association Nestlu Pulse

Canada Canadian Society for Endocrinology andMetabolism (CSEM) GI Foundation Abbott Biofortis

ASN Northern Ontario School of Medicine INCNutrition Research amp Education Foundation European

Food Safety Authority (EFSA) and PhysiciansCommittee for Responsible Medicine He has or has

had ad hoc consulting arrangements with Perkins CoieLLP Tate amp Lyle and Wirtschaftliche Vereinigung


Dow




Zucker eV He is a member of the European Fruit JuiceAssociation Scientific Expert Panel He is on the

Clinical Practice Guidelines Expert Committees ofDiabetes Canada European Association for the study of

Diabetes (EASD) Canadian Cardiovascular Society(CCS) and Obesity Canada He serves or has served as

an unpaid scientific advisor for the Food Nutritionand Safety Program (FNSP) and the Technical

Committee on Carbohydrates of the International LifeScience Institute (ILSI) North America He is a member

of the International Carbohydrate Quality Consortium(ICQC) Executive Board Member of the Diabetes and

Nutrition Study Group (DNSG) of the EASD andDirector of the Toronto 3D Knowledge Synthesis and

Clinical Trials foundation His wife is an employee ofSobeys Inc CWCK has received grants or research

support from the Advanced Food Materials NetworkAgriculture and Agri-Foods Canada (AAFC) Almond

Board of California American Pistachio GrowersBarilla Calorie Control Council Canadian Institutes of

Health Research (CIHR) Canola Council of CanadaInternational Nut and Dried Fruit Council

International Tree Nut Council Research andEducation Foundation Loblaw Brands Ltd Pulse

Canada Saskatchewan Pulse Growers and Unilever Hehas received in-kind research support from the AlmondBoard of California American Peanut Council Barilla

California Walnut Commission Kellogg CanadaLoblaw Companies Quaker (PepsiCo) Primo Unico

Unilever and WhiteWave Foods He has received travelsupport andor honoraria from the American Peanut

Council American Pistachio Growers BarillaCalifornia Walnut Commission Canola Council of

Canada General Mills International Nut and DriedFruit Council International Pasta Organization Loblaw

Brands Ltd Nutrition Foundation of Italy OldwaysPreservation Trust Paramount Farms Peanut Institute

Pulse Canada Sabra Dipping Co Saskatchewan PulseGrowers Sun-Maid Tate amp Lyle Unilever and

WhiteWave Foods He has served on the scientific advi-sory board for the International Tree Nut Council

International Pasta Organization McCormick ScienceInstitute Oldways Preservation Trust Paramount

Farms and Pulse Canada He is a member of theInternational Carbohydrate Quality Consortium

(ICQC) Executive Board Member of the Diabetes andNutrition Study Group (DNSG) of the European

Association for the Study of Diabetes (EASD) is on theClinical Practice Guidelines Expert Committee for

Nutrition Therapy of the EASD and is a director of theToronto 3 D Knowledge Synthesis and Clinical Trials

foundation DR is the president of the Croatian

Society for Diabetes and Metabolic Disorders of theCroatian Medical Association He serves as an

Executive Committee member of the CroatianEndocrine Society Croatian Society for Obesity and

Croatian Society for Endocrine Oncology He was aboard member and secretary of IDF Europe and cur-

rently he is the chair of the IDF YLD Program He hasserved as an Executive Committee member of the

Diabetes and Nutrition Study Group of the EASD andcurrently he serves as a Executive Committee member

of Diabetes and Cardiovascular Disease Study Group ofthe EASD He has served as principal investigator or

coinvestigator in clinical trials of AstraZeneca Eli LillyMSD Novo Nordisk Sanofi Aventis Solvay and

Trophos He has received honoraria for speaking or ad-visory board engagements and consulting fees from

Abbott Amgen AstraZeneca Bayer BoehringerIngelheim Eli Lilly Lifescan ndash Johnson amp Johnson

Novartis Novo Nordisk MSD Merck Sharp amp DohmePfizer Pliva Roche Salvus Sanofi Aventis and Takeda

No competing interests were declared by NB-T IP-G and HK

Supporting Information

The following Supporting Information is available

through the online version of this article at the publish-errsquos website

Table S1 Search strategy

Table S2 Characteristics of the included studies

evaluating the association between tree nut consump-

tion and the risk of cardiovascular disease outcomes

comparing highest vs lowest categories


evaluating the association between peanut consump-




evaluating the association between walnut consump-




evaluating the association between peanut butter con-

sumption and the risk of cardiovascular disease out-

comes comparing highest vs lowest categories

Table S6 Risk ratio and 95CI from non-linear

dose-response analysis of total nuts and cardiovascu-

lar disease coronary heart disease and stroke

Table S7 Sensitivity analysis by systematic exclu-

sion of one study at a timea

Table S8 GRADE assessment of the systematic re-

view and meta-analysis of prospective cohort studies


Dow




assessing the association between tree nut consump-

tion and cardiovascular disease outcomes



assessing the association between peanut consump-


Table S10 GRADE assessment of the systematic

review and meta-analysis of prospective cohort stud-

ies assessing the association between walnut con-

sumption and cardiovascular disease outcomes

Table S11 GRADE assessment of the

systematic review and meta-analysis of prospective

cohort studies assessing the association between pea-

nut butter consumption and cardiovascular disease

outcomes

Figure S1 Association between nut consumption

(highest vs lowest categories) and the risk of cardio-

vascular disease

Figure S2 Association between tree nut consump-

tion (highest vs lowest categories) and the risk of car-

diovascular disease

Figure S3 Association between peanut consump-


diovascular disease

Figure S4 Association between walnut consump-


diovascular disease

Figure S5 Association between peanut butter con-

sumption (highest vs lowest categories) and the risk

of cardiovascular disease



vascular disease mortality



diovascular disease mortality


(highest vs lowest categories) and the risk of coronary

heart disease


tion (highest vs lowest categories) and the risk of cor-

onary heart disease



onary heart disease



onary heart disease

Figure S12 Association between peanut butter

consumption (highest vs lowest categories) and the

risk of coronary heart disease



heart disease mortality



onary heart disease mortality


(highest vs lowest categories) and the risk of stroke


tion (highest vs lowest categories) and the risk of stroke

Figure S17 Association between tree nut con-


of stroke


tion (highest vs lowest categories) and the risk of

stroke



risk of stroke



mortality



stroke death



of stroke mortality


(highest vs lowest categories) and the risk of hemor-

rhagic stroke


(highest vs lowest categories) and the risk of ischemic

stroke


(highest vs lowest categories) and the risk of atrial

fibrillation


(highest vs lowest categories) and the risk of heart

failure

Figure S27 Linear and non-linear dose-response

relation between increasing total nut intake by 28-g

increments and the risk of cardiovascular disease

incidence




mortality



increments and the risk of coronary disease incidence



increments and the risk of coronary disease mortality


relation between increasing total nut intak by 28-g

increments and the risk of stroke incidence


Dow






increments and the risk of stroke mortality



increments and the risk of hemorrhagic stroke



increments and the risk of ischemic stroke

Figure S35 Subgroup analyses of total nut con-

sumption and the risk of cardiovascular disease

mortality

Figure S36 Risk of bias (Newcastle-Ottawa Scale

[NOS]) subgroup analysis of total nut consumption

and the risk of cardiovascular disease mortality


sumption and the risk of coronary heart disease

mortality



and the risk of coronary heart disease mortality


sumption and the risk of stroke mortality



and the risk of stroke mortality

Figure S41 Funnel plot of the natural logarithm

risk ratio for cardiovascular disease mortality


risk ratio for coronary heart disease mortality


risk ratio for stroke mortality

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2 Yu E Malik VS Hu FB Cardiovascular disease prevention by diet modification JAm Coll Cardiol 201872914ndash926

3 Willett WC Sacks F Trichopoulou A et al Mediterranean diet pyramid a culturalmodel for healthy eating Am J Clin Nutr 1995611402Sndash1406S

4 Sacks FM Obarzanek E Windhauser MM et al Rationale and design of theDietary Approaches to Stop Hypertension trial (DASH) A multicenter controlled-feeding study of dietary patterns to lower blood pressure Ann Epidemiol19955108ndash118

5 Craig WJ Mangels AR American Dietetic Association Position of the AmericanDietetic Association vegetarian diets J Am Diet Assoc 20091091266ndash1282

6 Ros E Mataix J Fatty acid composition of nutsndashimplications for cardiovascularhealth Br J Nutr 200696S29ndashS35

7 Segura R Javierre C Lizarraga MA et al Other relevant components of nuts phy-tosterols folate and minerals Br J Nutr 200696S36ndashS44

8 Afshin A Micha R Khatibzadeh S et al Consumption of nuts and legumes andrisk of incident ischemic heart disease stroke and diabetes a systematic reviewand meta-analysis Am J Clin Nutr 2014100278ndash288

9 Aune D Keum N Giovannucci E et al Nut consumption and risk of cardiovas-cular disease total cancer all-cause and cause-specific mortality a system-atic review and dose-response meta-analysis of prospective studies BMCMed 201614207

10 Bechthold A Boeing H Schwedhelm C et al Food groups and risk of coro-nary heart disease stroke and heart failure a systematic review and dose-response meta-analysis of prospective studies Crit Rev Food Sci Nutr 2017591071ndash1090

11 Chen G-C Zhang R Martınez-Gonzalez MA et al Nut consumption in relation toall-cause and cause-specific mortality a meta-analysis 18 prospective studiesFood Funct 201783893ndash3905

12 Grosso G Yang J Marventano S et al Nut consumption on all-cause cardiovascu-lar and cancer mortality risk a systematic review and meta-analysis of epidemio-logic studies Am J Clin Nutr 2015101783ndash793

13 Luo C Zhang Y Ding Y et al Nut consumption and risk of type 2 diabetes cardio-vascular disease and all-cause mortality a systematic review and meta-analysisAm J Clin Nutr 2014100256ndash269

14 Ma L Wang F Guo W et al Nut consumption and the risk of coronary artery dis-ease a dose-response meta-analysis of 13 prospective studies Thromb Res2014134790ndash794

15 Mayhew AJ de Souza RJ Meyre D et al A systematic review and meta-analysis ofnut consumption and incident risk of CVD and all-cause mortality Br J Nutr2016115212ndash225

16 Shao C Tang H Zhao W et al Nut intake and stroke risk a dose-response meta-analysis of prospective cohort studies Sci Rep 2016630394

17 Shi ZQ Tang JJ Wu H et al Consumption of nuts and legumes and risk of strokea meta-analysis of prospective cohort studies Nutr Metab Cardiovasc Dis2014241262ndash1271

18 Weng Y-Q Yao J Guo M-L et al Association between nut consumption and coro-nary heart disease Coron Artery Dis 201627227ndash232

19 Zhang Z Xu G Wei Y et al Nut consumption and risk of stroke Eur J Epidemiol201530189ndash196

20 Zhou D Yu H He F et al Nut consumption in relation to cardiovascular diseaserisk and type 2 diabetes a systematic review and meta-analysis of prospectivestudies Am J Clin Nutr 2014100270ndash277

21 Guasch-Ferre M Liu X Malik VS et al Nut consumption and risk of cardiovasculardisease J Am Coll Cardiol 2017702519ndash2532

22 Larsson SC Drca N Bjorck M et al Nut consumption and incidence of seven car-diovascular diseases Heart 20181041615ndash1620

23 Higgins JP Green S eds Cochrane Handbook for Systematic Reviews ofInterventions Version 510 United Kingdom The Cochrane Collaboration 2011

24 Stroup DF Berlin JA Morton SC et al Meta-analysis of observational studies in ep-idemiology a proposal for reporting Meta-analysis Of Observational Studies inEpidemiology (MOOSE) group JAMA 20002832008ndash2012

25 Liu G Guasch-Ferre M Hu Y et al Nut consumption in relation to cardiovasculardisease incidence and mortality among patients with diabetes mellitus Circ Res2019124920ndash929

26 van den Brandt PA Schouten LJ Relationship of tree nut peanut and peanut but-ter intake with total and cause-specific mortality a cohort study and meta-analy-sis Int J Epidemiol 2015441038ndash1049

27 van den Brandt PA Red meat processed meat and other dietary protein sourcesand risk of overall and cause-specific mortality in The Netherlands Cohort StudyEur J Epidemiol 201934351ndash369 doi101007s10654-019-00483-9

28 Wells G Shea B OrsquoConnell D et al The NewcastlendashOttawa Scale (NOS) for assess-ing the quality of nonrandomised studies in meta-analyses Ottawa OttawaHospital Research Institute 2014 Available at wwwohricaprogramsclinical_epi-demiologyoxfordasp Accessed April 11 2018

29 Fraser GE Sabate J Beeson WL et al A possible protective effect of nut consump-tion on risk of coronary heart disease The Adventist Health Study Arch InternMed 19921521416ndash1424

30 Albert CM Gaziano JM Willett WC et al Nut consumption and decreased risk ofsudden cardiac death in the Physiciansrsquo Health Study Arch Intern Med20021621382ndash1387

31 Luu HN Blot WJ Xiang Y-B et al Prospective evaluation of the association of nutpeanut consumption with total and cause-specific mortality JAMA Intern Med2015175755ndash766

32 di Giuseppe R Fjeld MK Dierkes J et al The association between nut consump-tion and the risk of total and ischemic stroke in a German cohort study Eur J ClinNutr 201569431ndash435

33 Hamling J Lee P Weitkunat R et al Facilitating meta-analyses by deriving relativeeffect and precision estimates for alternative comparisons from a set of estimatespresented by exposure level or disease category Stat Med 200827954ndash970

34 Greenland S Longnecker MP Methods for trend estimation from summarizeddose-response data with applications to meta-analysis Am J Epidemiol19921351301ndash1309

35 Orsini N Bellocco R Greenland S Generalized least squares for trend estimationof summarized dosendashresponse data Stata J 2006640ndash57

36 Desquilbet L Mariotti F Dose-response analyses using restricted cubic spline func-tions in public health research Stat Med 2010291037ndash1057

37 Guyatt G Oxman AD Akl EA et al GRADE guidelines 1 Introduction-GRADE evi-dence profiles and summary of findings tables J Clin Epidemiol 201164383ndash394

38 Guyatt GH Oxman AD Vist G et al GRADE guidelines 4 Rating the quality ofevidencendashstudy limitations (risk of bias) J Clin Epidemiol 201164407ndash415

39 Guyatt GH Oxman AD Kunz R et al GRADE guidelines 7 Rating the quality of ev-idencemdashinconsistency J Clin Epidemiol 2011641294ndash1302

40 Guyatt GH Oxman AD Kunz R et al GRADE guidelines 8 Rating the quality of ev-idencemdashindirectness J Clin Epidemiol 2011641303ndash1310


Dow




41 Guyatt GH Oxman AD Kunz R et al GRADE guidelines 6 Rating the quality of ev-idencemdashimprecision J Clin Epidemiol 2011641283ndash1293

42 Guyatt GH Oxman AD Montori V et al GRADE guidelines 5 Rating the quality ofevidencemdashpublication bias J Clin Epidemiol 2011641277ndash1282

43 Guyatt GH Oxman AD Sultan S et al GRADE guidelines 9 Rating up the qualityof evidence J Clin Epidemiol 2011641311ndash1316

44 Blomhoff R Carlsen MH Andersen LF et al Health benefits of nuts potential roleof antioxidants Br J Nutr 200696S52ndashS60

45 Bao Y Han J Hu FB et al Association of nut consumption with total and cause-specific mortality N Engl J Med 20133692001ndash2011

46 Guasch-Ferre M Bullo M Martınez-Gonzalez MA et al Frequency of nut con-sumption and mortality risk in the PREDIMED nutrition intervention trial BMCMed 201311164 doi1011861741-7015-11-164

47 Hshieh TT Petrone AB Gaziano JM et al Nut consumption and risk of mortality inthe Physiciansrsquo Health Study Am J Clin Nutr 2015101407ndash412

48 Bonaccio M Di Castelnuovo A De Curtis A et al Nut consumption is in-versely associated with both cancer and total mortality in a Mediterraneanpopulation prospective results from the Moli-sani study Br J Nutr2015114804ndash811

49 Eslamparast T Sharafkhah M Poustchi H et al Nut consumption and total andcause-specific mortality results from the Golestan Cohort Study Int J Epidemiol20174675ndash85

50 Haring B Gronroos N Nettleton JA et al Dietary protein intake and coronaryheart disease in a large community based cohort results from the AtherosclerosisRisk in Communities (ARIC) study PLoS One 20149e109552

51 Gopinath B Flood VM Burlutksy G et al Consumption of nuts and risk of totaland cause-specific mortality over 15 years Nutr Metab Cardiovasc Dis2015251125ndash1131

52 Djousse L Gaziano JM Kase CS et al Nut consumption and risk of stroke in USmale physicians Clin Nutr 201029605ndash609

53 Haring B Misialek JR Rebholz CM et al Association of dietary protein consump-tion with incident silent cerebral infarcts and stroke the Atherosclerosis Risk inCommunities (ARIC) Study Stroke 2015463443ndash3450

54 Bernstein AM Pan A Rexrode KM et al Dietary protein sources and the risk ofstroke in men and women Stroke 201243637ndash644

55 Khawaja O Gaziano JM Djousse L Nut consumption and risk of atrial fibrillationin the Physiciansrsquo Health Study Nutr J 20121117

56 Djousse L Rudich T Gaziano JM Nut consumption and risk of heart failure in thePhysiciansrsquo Health Study I Am J Clin Nutr 200888930ndash933

57 Nettleton JA Steffen LM Loehr LR et al Incident heart failure is associated withlower whole-grain intake and greater high-fat dairy and egg intake in theAtherosclerosis Risk in Communities (ARIC) study J Am Diet Assoc20081081881ndash1887

58 Yaemsiri S Sen S Tinker L et al Trans fat aspirin and ischemic stroke in postmen-opausal women Ann Neurol 201272704ndash715

59 von Ruesten A Feller S Bergmann MM et al Diet and risk of chronic diseasesresults from the first 8 years of follow-up in the EPIC-Potsdam study Eur J ClinNutr 201367412ndash419

60 Wang J-B Fan J-H Dawsey SM et al Dietary components and risk of total cancerand cardiovascular disease mortality in the Linxian Nutrition Intervention Trials co-hort in China Sci Rep 2016622619

61 Sabate J Oda K Ros E Nut consumption and blood lipid levels Arch Intern Med2010170821ndash827

62 Del Gobbo LC Falk MC Feldman R et al Effects of tree nuts on blood lipids apoli-poproteins and blood pressure systematic review meta-analysis and dose-response of 61 controlled intervention trials Am J Clin Nutr 20151021347ndash1356

63 Coates A Hill A Tan S Nuts and cardiovascular disease prevention CurrAtheroscler Rep 20182048

64 Bitok E Sabate J Nuts and cardiovascular disease Prog Cardiovasc Dis20186133ndash37


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nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

heart failure The certainty of the evidence ranged from moderate to very lowConclusions This systematic review and meta-analysis revealed a beneficial roleof nut consumption in reducing the incidence of and mortality from different CVDoutcomes

INTRODUCTION

Cardiovascular disease (CVD) is an important publichealth issue According to the World HealthOrganization (WHO) it is the leading cause of death

worldwide affecting approximately 177 million peoplein 20151 Importantly CVDs are susceptible to behavior

modifications In this sense a healthy diet is one of thelifestyle components that could be promoted to help ad-

dress this global health concern2 Different healthy die-tary patterns such as the Mediterranean diet

(MedDiet)3 the DASH diet4 or a vegetarian diet5 havenuts as a key food component Nuts despite their high

fat content (mainly unsaturated fatty acids)6 are alsorich in minerals vitamins fiber and bioactive com-

pounds7 Given this exceptional nutritional profile fre-quent nut consumption has been inversely associated

with a lower risk of CVD in large prospective cohortstudies which have been summarized in several meta-

analyses8ndash20 Nonetheless some of the previous meta-analyses had methodological limitations such as the in-

clusion of studies with nuts plus seeds or legumes as ex-posure the inclusion of studies combining different

outcomes across analyses (eg inclusion of studies withonly fatal CHD [coronary heart disease] outcome in the

CVD mortality analysis) and the inclusion of studieswithout the first category of exposure as reference

Moreover since publication of the last meta-analysesthe results of two new large prospective cohort studies

evaluating the association between nut consumptionand CVD outcomes have been published2122 One study

reported updated results from the Nursesrsquo Health StudyI (NHSI) Nursesrsquo Health Study II (NSHII) and Health

Professionals Follow-up Study (HPFS) comprising upto 32 years of follow-up and a large number of cases21

Another reported the association between nut con-sumption and the incidence of 7 CVD outcomes in apopulation of 32 911 males22 Importantly most of the

previous meta-analyses have focused on total nut in-take and only a few have taken into account the poten-

tial associations between specific types of nutconsumption and the risk of CVD outcomes which

may vary considerablyTherefore taking into consideration the aforemen-

tioned issues and in order to develop evidence-basedrecommendations the Diabetes and Nutrition Study

group (DNSG) of the EASD (European Association forthe Study of Diabetes) commissioned a systematic re-

view and meta-analysis (SRMA) of prospective cohortstudies using the Grading of Recommendations

Assessment Development and Evaluation (GRADE)system to summarize the evidence of the association be-

tween the consumption of total nuts or specific types ofnuts and the incidence of and mortality from certain

CVD outcomes The shape of the associations with lin-ear and non-linear dose-response analysis was also

evaluated

METHODS

The current systematic review and meta-analysis fol-

lowed the methodological guidelines of the CochraneHandbook for Systematic Reviews of Interventions23

Results are reported according to Meta-analysis ofObservational Studies in Epidemiology (MOOSE)

guidelines24 The protocol is available at httpwwwcrdyorkacukPROSPERO (identifier PROSPERO

2018 CRD42018103360)

Search strategy

A systematic search limited to human studies with no lan-

guage restrictions was conducted of the MEDLINE(PubMed) and Cochrane Library databases through 5

June 2018 An updated search was then performed onMarch 19 2019 Table 1 shows the PICOS (participants

interventionsexposures comparators outcomes andstudy design) criteria used to identify studies eligible for

inclusion The electronic search was supplemented with amanual review of the reference lists of the retrieved

articles Figure 1 and Table S1 in the SupportingInformation online summarize the search and selection

process

Study selection

An initial screening of all titles and abstracts of the re-

trieved articles was performed to evaluate compliancewith the eligibility criteria Inclusion criteria were

prospective cohort studies with at least 1 year of follow-up conducted in an adult population with total nuts or

specific types of nuts as exposure with the incidence of


Dow




















Data extraction

















Outcomes



















Dow






















































RESULTS









Dow























nuts ([RR 085 95CI 079ndash091] I2 0



Dow




Tabl

e2

Char

acte

rist

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ting

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tion

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cons

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ing

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ceN

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Not

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51

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ings

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vslt

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lity

463

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002)

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Stud

y21

454

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417

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37

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hoff

etal

(200

6)44

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omen

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Stud

y31

778

FSe

lf-ad

min

is-

tere

dFF

QN

uts

plus

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7se

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kvs 0

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k

55ndash6

915

CVD

mor

talit

y16

75Ag

ency

6CH

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lity

948

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uss e

etal

(200

8)56

USA

Phys

icia

nsrsquo

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lthSt

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2097

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40ndash8

419

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008)

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y

1415

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terv

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Nut

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uous

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413

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1140

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cy8

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(201

0)52

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7se

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421

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1424

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cy6

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stro

ke11

89H

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rhag

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219

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012)

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Stud

yI

8001

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sel

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Not

spec

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034

serv

ings

dvs

0se

rvin

gsd

30ndash5

526

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agic

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ke13

83Ag

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6

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lthPr

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sion

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ings

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rvin

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40ndash7

522

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agic

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ke82

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2)55

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3317

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3)59

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azil

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d)


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Tabl

e2

Cont

inue

dSt

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Coun

try

Stud

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latio

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e

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sch-

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013)

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IMED

stud

y72

16M

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ings

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vs neve

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55ndash8

04

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orta

lity

81Ag

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dust

ry9

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ccio

etal

(201

5)48

Italy

Mol

i-san

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509

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sel

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iste

red

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nuts

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pe

anut

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kevs no

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mor

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y10

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mor

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y19

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5)32

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142

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288

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cy8

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490

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lthSt

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265

MF

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254

gd

vs lt0

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amd

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40ndash7

0an

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122

and

65

CVD

mor

talit

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87IH

Dm

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rtSt

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(sub

coho

rt)

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adm

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-te

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Tree

nuts

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anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

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y14

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5

Wan

get

al(2

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rt24

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40ndash6

926

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orta

lity

355

Agen

cy6

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man

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talit

y45

2

Esla

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rast

etal

(201

7)49

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Gol

esta

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hort

Stud

y28

257

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tive

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tree

nuts

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serv

ings

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vs neve

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40ndash8

77

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mor

talit

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720

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sch-

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tsa

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nuts

(ifav

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vs neve

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lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

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Dm

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1770

CHD

3552

CHD

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talit

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3322

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Isch

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Subgroup analyses











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DISCUSSION









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Tabl

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GRA

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

















Data extraction

















Outcomes



















Dow






















































RESULTS









Dow























nuts ([RR 085 95CI 079ndash091] I2 0



Dow




Tabl

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Char

acte

rist

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clud

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Stud

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060

serv

ings

dvs

0se

rvin

gsd

40ndash7

522

Hem

orrh

agic

stro

ke82

9

Khaw

aja

etal

(201

2)55

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2105

4M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

6

serv

ings

wk

vs0

serv

ings

wk

40ndash8

424

Atria

lfib

rilla

tion

3317

Agen

cy7

Yaem

siri

etal

(201

2)58

USA

Wom

enrsquos

Hea

lthIn

itiat

ive

Obs

erva

tiona

lSt

udy

8702

5F

Self-

adm

inis

-te

red

FFQ

Not

spec

ified

Cont

inuo

us1

serv

ing

d50

ndash79

76

Isch

emic

stro

ke10

49Ag

ency

8

von

Rues

ten

etal

(201

3)59

Ger

man

yEP

IC-P

otsd

amst

udy

2353

1M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Pean

uts

wal

nuts

br

azil

nuts

Cont

inuo

us1

serv

ing

d35

ndash65

8CV

D36

3Ag

ency

8

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Gua

sch-

Ferr

eet

al(2

013)

46Sp

ain

PRED

IMED

stud

y72

16M

FIn

terv

iew

-adm

in-

iste

red

vali-

date

dse

mi-

quan

titat

ive

FFQ

Alm

onds

pea

-nu

tsh

azel

-nu

tsp

ista

-ch

ios

pine

nuts

gt3

serv

ings

wk

vs neve

r

55ndash8

04

8CV

Dm

orta

lity

81Ag

ency

-In

dust

ry9

Bona

ccio

etal

(201

5)48

Italy

Mol

i-san

istu

dy10

509

F88

77M

Valid

ated

sel

f-ad

min

iste

red

FFQ

Wal

nuts

haz

el-

nuts

alm

onds

pe

anut

s

Inta

kevs no

inta

ke

gt35

43

CVD

mor

talit

y10

4Ag

ency

6CH

Dm

orta

lity

39St

roke

mor

talit

y19

diG

iuse

ppe

etal

(201

5)32

Ger

man

yEP

IC-P

otsd

amst

udy

2599

7M

FVa

lidat

eds

elf-

adm

inis

tere

dFF

Q

Pean

uts

wal

nuts

br

azil

nuts

142

gd

vs 0g

d

F49

2M

52

58

3St

roke

288

Agen

cy8

Isch

emic

stro

ke23

5St

roke

mor

talit

y36

Gop

inat

het

al(2

015)

51Au

stra

liaBl

ueM

ount

ains

Eye

Stud

y13

12F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

490

to10

0g

dvs 0

to0

50g

d

49

15CV

Dm

orta

lity

258

Agen

cy7

IHD

mor

talit

y18

8St

roke

mor

talit

y10

1

1581

MCV

Dm

orta

lity

288

IHD

mor

talit

y24

2St

roke

mor

talit

y75

Har

ing

etal

(201

4)50

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1206

6M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Not

spec

ified

06

serv

ings

dvs

01

serv

ings

d45

ndash64

22CH

D11

47Ag

ency

9

Har

ing

etal

(201

5)53

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1160

1M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

er1

serv

ings

dvs 0

serv

ings

d

45ndash6

422

7St

roke

699

Agen

cy8

Hem

orrh

agic

stro

ke11

4

Isch

emic

stro

ke59

8H

shie

het

al(2

015)

47U

SAPh

ysic

ians

rsquoH

ealth

Stud

y20

742

MU

nval

idat

eds

elf-

adm

inis

tere

dFF

Q

Not

spec

ified

5

serv

ings

wk

vs lt1

serv

ing

wk

40ndash8

49

6CV

Dm

orta

lity

760

Agen

cy6

Stro

kem

orta

lity

143

Luu

etal

(201

5)31

USA

Sout

hern

Com

mun

ityCo

hort

Stud

y

7176

4M

FSe

mi-q

uant

ita-

tive

FFQ

Tota

lnut

san

dpe

anut

butt

er

184

5g

dvs lt

095

gd

40ndash7

95

4CV

Dm

orta

lity

1857

Agen

cy8

IHD

mor

talit

y79

3Is

chem

icst

roke

mor

talit

y12

1

Hem

orrh

agic

stro

kem

orta

lity

96

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Chin

aSh

angh

aiW

omen

rsquosH

ealth

Stud

yan

dSh

angh

aiM

enrsquos

Hea

lthSt

udy

134

265

MF

Pean

ut

254

gd

vs lt0

14gr

amd

ay

40ndash7

0an

d40

ndash74

122

and

65

CVD

mor

talit

y25

87IH

Dm

orta

lity

631

Isch

emic

stro

kem

orta

lity

588

Hem

orrh

agic

stro

kem

orta

lity

597

van

den

Bran

dtan

dSc

hout

en(2

015)

26

Net

herla

nds

Net

herla

nds

Coho

rtSt

udy

3202

MF

(sub

coho

rt)

Self-

adm

inis

-te

red

valid

ated

FFQ

Tree

nuts

pe

anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

IHD

mor

talit

y14

88St

roke

mor

talit

y56

5

Wan

get

al(2

016)

60Ch

ina

Linx

ian

NIT

coho

rt24

45M

FFF

QPe

anut

sch

est-

nuts

wal

nuts

Cont

inuo

us3

serv

ings

mo

40ndash6

926

Hea

rtdi

seas

em

orta

lity

355

Agen

cy6

Ger

man

ySt

roke

mor

talit

y45

2

Esla

mpa

rast

etal

(201

7)49

Iran

Gol

esta

nCo

hort

Stud

y28

257

FVa

lidat

eds

elf-

adm

inis

tere

dse

miq

uant

ita-

tive

FFQ

Pean

uts

tree

nuts

3

serv

ings

wk

vs neve

r

40ndash8

77

CVD

mor

talit

y91

1Ag

ency

720

855

M11

05

Gua

sch-

Ferr

eet

al(2

017)

21U

SAN

urse

srsquoH

ealth

Stud

yI

7636

4F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Pean

uts

othe

rnu

tsa

ndw

al-

nuts

(ifav

aila

ble)

5

serv

ings

wk

vs neve

rora

lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

7CV

Dm

orta

lity

1770

CHD

3552

CHD

mor

talit

y99

6St

roke

3322

Stro

kem

orta

lity

773

Isch

emic

stro

ke16

35N

urse

srsquoH

ealth

Stud

yII

9294

6F

25ndash4

221

5CV

D19

15CV

Dm

orta

lity

82CH

D67

0CH

Dm

orta

lity

46St

roke

1262

Stro

kem

orta

lity

36

Isch

emic

stro

ke22

0H

ealth

Prof

essi

onal

sFo

llow

-Up

Stud

y

4152

6M

40ndash7

522

5CV

D54

94CV

Dm

orta

lity

2599

CHD

4168

CHD

mor

talit

y19

21St

roke

1326

Stro

kem

orta

lity

367

Isch

emic

stro

ke74

2

(con

tinue

d)


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online)














e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Lars

son

etal

(201

8)22

Swed

enCo

hort

ofSw

edis

hM

en32

911

MFF

QN

uts

(not

incl

ud-

ing

coco

nuto

rch

estn

uts)

3

serv

ings

wk

vs neve

r

45ndash8

317

MI

4983

Agen

cy8

MIm

orta

lity

917

Hea

rtfa

ilure

3160

Atria

lfib

rilla

tion

7550

Isch

emic

stro

ke37

82In

trac

ereb

ral

hem

orrh

age

543

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CVD

car

diov

ascu

lard

isea

seE

PIC

Euro

pean

Pros

pect

ive

Inve

stig

atio

nin

toCa

ncer

and

Nut

ritio

nF

fem

ales

FFQ

foo

dfr

eque

ncy

ques

tionn

aire

IH

Di

sche

mic

hear

tdis

ease

Mm

ales

MI

myo

card

iali

nfar

ctio

nN

ITN

utrit

ion

Inte

rven

tion

Tria

lsN

OS

New

cast

le-O

ttaw

asc

ale

NR

Not

repo

rted

PRE

DIM

EDP

reve

nci o

nco

nD

ieta

MED

iterr

anea


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Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

fort

hese

outc

omes

no

dow

ngra

des

wer

em

ade

forp

ublic

atio

nbi

as

bSe

rious

indi

rect

ness

forC

VDin

cide

nce

asth

ein

clud

edst

udie

sw

ere

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(69

30

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

mal

es

c Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CVD

inci

denc

e(Plt

001

)se

eFi

gure

S27

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ed

Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CVD

mor

talit

y(Plt

001

)se

eFi

gure

S28

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ee Se

rious

inco

nsis

tenc

yfo

rCH

Din

cide

nce

due

tohi

ghde

gree

ofun

expl

aine

dhe

tero

gene

ity(I2frac14

74

Pfrac14

000

1)

f Serio

usin

dire

ctne

ssfo

rCH

Din

cide

nce

asgt

50

ofth

ew

eigh

t(55

4

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

gSe

rious

impr

ecis

ion

forC

HD

inci

denc

eas

the

95

CI(0

69ndash

096

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

hU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

GLS

Tdo

se-r

espo

nse

anal

yses

reve

aled

asi

gnifi

cant

linea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CHD

inci

denc

e(Plt

001

)se

eFi

gure

S29

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ei U

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dCH

Dm

orta

lity

(Plt

001

)se

eFi

gure

S30

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ej Se

rious

indi

rect

ness

fors

trok

ein

cide

nce

asgt

50

ofth

ew

eigh

t(72

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

k Serio

usim

prec

isio

nfo

rstr

oke

inci

denc

eas

the

95

CI(0

92ndash

109

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

l Serio

usim

prec

isio

nfo

rstr

oke

mor

talit

yas

the

95

CI(0

76ndash

100

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

mU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dst

roke

mor

talit

y(Pfrac14

002

9)s

eeFi

gure

S32

inth

eSu

ppor

ting

Info

rmat

ion

onlin

en

Serio

usris

kof

bias

forh

emor

rhag

icst

roke

asgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

o Serio

usin

dire

ctne

ssfo

rhem

orrh

agic

stro

kea

sgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(55

7

)was

cont

rib-

uted

byst

udie

sco

nduc

ted

amon

gm

ales

p

Serio

usim

prec

isio

nfo

rhem

orrh

agic

stro

keas

the

95

CI(0

77ndash

134

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

qU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dhe

mor

rhag

icst

roke

(Pfrac14

001

)se

eFi

gure

S33

inth

eSu

ppor

ting

Info

rmat

ion

onlin

er Se

rious

indi

rect

ness

fori

sche

mic

stro

kea

sgt

50

ofth

ew

eigh

t(66

1

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

s Serio

usim

prec

isio

nfo

risc

hem

icst

roke

as

the

95

CI(0

89ndash

110

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

t Serio

usin

dire

ctne

ssfo

ratr

ialf

ibril

latio

nas

only

2av

aila

ble

stud

ies

wer

eco

nduc

ted

amon

gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27



















































RESULTS









Dow























nuts ([RR 085 95CI 079ndash091] I2 0



Dow




Tabl

e2

Char

acte

rist

ics

ofth

ein

clud

edst

udie

sev

alua

ting

the

asso

ciat

ion

betw

een

nuts

and

risk

ofca

rdio

vasc

ular

dise

ase

outc

omes

Stud

yCo

untr

ySt

udy

nam

ePo

pula

tion

Nut

cons

umpt

ion

asse

ssm

ent

met

hod

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Fras

eret

al(1

992)

29U

SASe

vent

h-da

yAd

vent

ists

2647

3M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

51

serv

ings

wk

vslt

1se

rvin

gw

k

25

6N

onfa

talM

I13

4Ag

ency

7CH

Dm

orta

lity

463

Albe

rtet

al(2

002)

30U

SAPh

ysic

ians

rsquoH

ealth

Stud

y21

454

MSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gm

o

40ndash8

417

CHD

mor

talit

y56

6Ag

ency

7N

onfa

talM

I10

37

Blom

hoff

etal

(200

6)44

USA

Iow

aW

omen

rsquosH

ealth

Stud

y31

778

FSe

lf-ad

min

is-

tere

dFF

QN

uts

plus

pean

utbu

tter

7se

rvin

gsw

kvs 0

5se

rvin

gsw

k

55ndash6

915

CVD

mor

talit

y16

75Ag

ency

6CH

Dm

orta

lity

948

Djo

uss e

etal

(200

8)56

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2097

6M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gw

k

40ndash8

419

6H

eart

failu

re10

93N

R6

Net

tleto

net

al(2

008)

57U

SAAt

hero

scle

rosi

sRi

skin

Com

mun

ities

Stud

y

1415

3M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

erCo

ntin

uous

1se

rvin

gd

45ndash6

413

Hea

rtfa

ilure

1140

Agen

cy8

Djo

uss e

etal

(201

0)52

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2107

8M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

7se

rvin

gsw

kvs lt

1se

rvin

gw

k

40ndash8

421

1St

roke

1424

Agen

cy6

Isch

emic

stro

ke11

89H

emor

rhag

icst

roke

219

Bern

stei

net

al(2

012)

54U

SAN

urse

srsquoH

ealth

Stud

yI

8001

0F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

034

serv

ings

dvs

0se

rvin

gsd

30ndash5

526

Hem

orrh

agic

stro

ke13

83Ag

ency

6

Hea

lthPr

ofes

sion

als

Follo

w-U

pSt

udy

4315

0M

060

serv

ings

dvs

0se

rvin

gsd

40ndash7

522

Hem

orrh

agic

stro

ke82

9

Khaw

aja

etal

(201

2)55

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2105

4M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

6

serv

ings

wk

vs0

serv

ings

wk

40ndash8

424

Atria

lfib

rilla

tion

3317

Agen

cy7

Yaem

siri

etal

(201

2)58

USA

Wom

enrsquos

Hea

lthIn

itiat

ive

Obs

erva

tiona

lSt

udy

8702

5F

Self-

adm

inis

-te

red

FFQ

Not

spec

ified

Cont

inuo

us1

serv

ing

d50

ndash79

76

Isch

emic

stro

ke10

49Ag

ency

8

von

Rues

ten

etal

(201

3)59

Ger

man

yEP

IC-P

otsd

amst

udy

2353

1M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Pean

uts

wal

nuts

br

azil

nuts

Cont

inuo

us1

serv

ing

d35

ndash65

8CV

D36

3Ag

ency

8

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Gua

sch-

Ferr

eet

al(2

013)

46Sp

ain

PRED

IMED

stud

y72

16M

FIn

terv

iew

-adm

in-

iste

red

vali-

date

dse

mi-

quan

titat

ive

FFQ

Alm

onds

pea

-nu

tsh

azel

-nu

tsp

ista

-ch

ios

pine

nuts

gt3

serv

ings

wk

vs neve

r

55ndash8

04

8CV

Dm

orta

lity

81Ag

ency

-In

dust

ry9

Bona

ccio

etal

(201

5)48

Italy

Mol

i-san

istu

dy10

509

F88

77M

Valid

ated

sel

f-ad

min

iste

red

FFQ

Wal

nuts

haz

el-

nuts

alm

onds

pe

anut

s

Inta

kevs no

inta

ke

gt35

43

CVD

mor

talit

y10

4Ag

ency

6CH

Dm

orta

lity

39St

roke

mor

talit

y19

diG

iuse

ppe

etal

(201

5)32

Ger

man

yEP

IC-P

otsd

amst

udy

2599

7M

FVa

lidat

eds

elf-

adm

inis

tere

dFF

Q

Pean

uts

wal

nuts

br

azil

nuts

142

gd

vs 0g

d

F49

2M

52

58

3St

roke

288

Agen

cy8

Isch

emic

stro

ke23

5St

roke

mor

talit

y36

Gop

inat

het

al(2

015)

51Au

stra

liaBl

ueM

ount

ains

Eye

Stud

y13

12F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

490

to10

0g

dvs 0

to0

50g

d

49

15CV

Dm

orta

lity

258

Agen

cy7

IHD

mor

talit

y18

8St

roke

mor

talit

y10

1

1581

MCV

Dm

orta

lity

288

IHD

mor

talit

y24

2St

roke

mor

talit

y75

Har

ing

etal

(201

4)50

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1206

6M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Not

spec

ified

06

serv

ings

dvs

01

serv

ings

d45

ndash64

22CH

D11

47Ag

ency

9

Har

ing

etal

(201

5)53

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1160

1M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

er1

serv

ings

dvs 0

serv

ings

d

45ndash6

422

7St

roke

699

Agen

cy8

Hem

orrh

agic

stro

ke11

4

Isch

emic

stro

ke59

8H

shie

het

al(2

015)

47U

SAPh

ysic

ians

rsquoH

ealth

Stud

y20

742

MU

nval

idat

eds

elf-

adm

inis

tere

dFF

Q

Not

spec

ified

5

serv

ings

wk

vs lt1

serv

ing

wk

40ndash8

49

6CV

Dm

orta

lity

760

Agen

cy6

Stro

kem

orta

lity

143

Luu

etal

(201

5)31

USA

Sout

hern

Com

mun

ityCo

hort

Stud

y

7176

4M

FSe

mi-q

uant

ita-

tive

FFQ

Tota

lnut

san

dpe

anut

butt

er

184

5g

dvs lt

095

gd

40ndash7

95

4CV

Dm

orta

lity

1857

Agen

cy8

IHD

mor

talit

y79

3Is

chem

icst

roke

mor

talit

y12

1

Hem

orrh

agic

stro

kem

orta

lity

96

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Chin

aSh

angh

aiW

omen

rsquosH

ealth

Stud

yan

dSh

angh

aiM

enrsquos

Hea

lthSt

udy

134

265

MF

Pean

ut

254

gd

vs lt0

14gr

amd

ay

40ndash7

0an

d40

ndash74

122

and

65

CVD

mor

talit

y25

87IH

Dm

orta

lity

631

Isch

emic

stro

kem

orta

lity

588

Hem

orrh

agic

stro

kem

orta

lity

597

van

den

Bran

dtan

dSc

hout

en(2

015)

26

Net

herla

nds

Net

herla

nds

Coho

rtSt

udy

3202

MF

(sub

coho

rt)

Self-

adm

inis

-te

red

valid

ated

FFQ

Tree

nuts

pe

anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

IHD

mor

talit

y14

88St

roke

mor

talit

y56

5

Wan

get

al(2

016)

60Ch

ina

Linx

ian

NIT

coho

rt24

45M

FFF

QPe

anut

sch

est-

nuts

wal

nuts

Cont

inuo

us3

serv

ings

mo

40ndash6

926

Hea

rtdi

seas

em

orta

lity

355

Agen

cy6

Ger

man

ySt

roke

mor

talit

y45

2

Esla

mpa

rast

etal

(201

7)49

Iran

Gol

esta

nCo

hort

Stud

y28

257

FVa

lidat

eds

elf-

adm

inis

tere

dse

miq

uant

ita-

tive

FFQ

Pean

uts

tree

nuts

3

serv

ings

wk

vs neve

r

40ndash8

77

CVD

mor

talit

y91

1Ag

ency

720

855

M11

05

Gua

sch-

Ferr

eet

al(2

017)

21U

SAN

urse

srsquoH

ealth

Stud

yI

7636

4F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Pean

uts

othe

rnu

tsa

ndw

al-

nuts

(ifav

aila

ble)

5

serv

ings

wk

vs neve

rora

lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

7CV

Dm

orta

lity

1770

CHD

3552

CHD

mor

talit

y99

6St

roke

3322

Stro

kem

orta

lity

773

Isch

emic

stro

ke16

35N

urse

srsquoH

ealth

Stud

yII

9294

6F

25ndash4

221

5CV

D19

15CV

Dm

orta

lity

82CH

D67

0CH

Dm

orta

lity

46St

roke

1262

Stro

kem

orta

lity

36

Isch

emic

stro

ke22

0H

ealth

Prof

essi

onal

sFo

llow

-Up

Stud

y

4152

6M

40ndash7

522

5CV

D54

94CV

Dm

orta

lity

2599

CHD

4168

CHD

mor

talit

y19

21St

roke

1326

Stro

kem

orta

lity

367

Isch

emic

stro

ke74

2

(con

tinue

d)


Dow

















online)














e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Lars

son

etal

(201

8)22

Swed

enCo

hort

ofSw

edis

hM

en32

911

MFF

QN

uts

(not

incl

ud-

ing

coco

nuto

rch

estn

uts)

3

serv

ings

wk

vs neve

r

45ndash8

317

MI

4983

Agen

cy8

MIm

orta

lity

917

Hea

rtfa

ilure

3160

Atria

lfib

rilla

tion

7550

Isch

emic

stro

ke37

82In

trac

ereb

ral

hem

orrh

age

543

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CVD

car

diov

ascu

lard

isea

seE

PIC

Euro

pean

Pros

pect

ive

Inve

stig

atio

nin

toCa

ncer

and

Nut

ritio

nF

fem

ales

FFQ

foo

dfr

eque

ncy

ques

tionn

aire

IH

Di

sche

mic

hear

tdis

ease

Mm

ales

MI

myo

card

iali

nfar

ctio

nN

ITN

utrit

ion

Inte

rven

tion

Tria

lsN

OS

New

cast

le-O

ttaw

asc

ale

NR

Not

repo

rted

PRE

DIM

EDP

reve

nci o

nco

nD

ieta

MED

iterr

anea


Dow









online)










Dow


























































Dow


























Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

fort

hese

outc

omes

no

dow

ngra

des

wer

em

ade

forp

ublic

atio

nbi

as

bSe

rious

indi

rect

ness

forC

VDin

cide

nce

asth

ein

clud

edst

udie

sw

ere

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(69

30

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

mal

es

c Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CVD

inci

denc

e(Plt

001

)se

eFi

gure

S27

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ed

Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

KSPL

INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CVD

mor

talit

y(Plt

001

)se

eFi

gure

S28

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ee Se

rious

inco

nsis

tenc

yfo

rCH

Din

cide

nce

due

tohi

ghde

gree

ofun

expl

aine

dhe

tero

gene

ity(I2frac14

74

Pfrac14

000

1)

f Serio

usin

dire

ctne

ssfo

rCH

Din

cide

nce

asgt

50

ofth

ew

eigh

t(55

4

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

gSe

rious

impr

ecis

ion

forC

HD

inci

denc

eas

the

95

CI(0

69ndash

096

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

hU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

GLS

Tdo

se-r

espo

nse

anal

yses

reve

aled

asi

gnifi

cant

linea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CHD

inci

denc

e(Plt

001

)se

eFi

gure

S29

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ei U

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dCH

Dm

orta

lity

(Plt

001

)se

eFi

gure

S30

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ej Se

rious

indi

rect

ness

fors

trok

ein

cide

nce

asgt

50

ofth

ew

eigh

t(72

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

k Serio

usim

prec

isio

nfo

rstr

oke

inci

denc

eas

the

95

CI(0

92ndash

109

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

l Serio

usim

prec

isio

nfo

rstr

oke

mor

talit

yas

the

95

CI(0

76ndash

100

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

mU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dst

roke

mor

talit

y(Pfrac14

002

9)s

eeFi

gure

S32

inth

eSu

ppor

ting

Info

rmat

ion

onlin

en

Serio

usris

kof

bias

forh

emor

rhag

icst

roke

asgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

o Serio

usin

dire

ctne

ssfo

rhem

orrh

agic

stro

kea

sgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(55

7

)was

cont

rib-

uted

byst

udie

sco

nduc

ted

amon

gm

ales

p

Serio

usim

prec

isio

nfo

rhem

orrh

agic

stro

keas

the

95

CI(0

77ndash

134

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

qU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

taln

utco

nsum

ptio

nan

dhe

mor

rhag

icst

roke

(Pfrac14

001

)se

eFi

gure

S33

inth

eSu

ppor

ting

Info

rmat

ion

onlin

er Se

rious

indi

rect

ness

fori

sche

mic

stro

kea

sgt

50

ofth

ew

eigh

t(66

1

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

s Serio

usim

prec

isio

nfo

risc

hem

icst

roke

as

the

95

CI(0

89ndash

110

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

t Serio

usin

dire

ctne

ssfo

ratr

ialf

ibril

latio

nas

only

2av

aila

ble

stud

ies

wer

eco

nduc

ted

amon

gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27




















nuts ([RR 085 95CI 079ndash091] I2 0



Dow




Tabl

e2

Char

acte

rist

ics

ofth

ein

clud

edst

udie

sev

alua

ting

the

asso

ciat

ion

betw

een

nuts

and

risk

ofca

rdio

vasc

ular

dise

ase

outc

omes

Stud

yCo

untr

ySt

udy

nam

ePo

pula

tion

Nut

cons

umpt

ion

asse

ssm

ent

met

hod

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Fras

eret

al(1

992)

29U

SASe

vent

h-da

yAd

vent

ists

2647

3M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

51

serv

ings

wk

vslt

1se

rvin

gw

k

25

6N

onfa

talM

I13

4Ag

ency

7CH

Dm

orta

lity

463

Albe

rtet

al(2

002)

30U

SAPh

ysic

ians

rsquoH

ealth

Stud

y21

454

MSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gm

o

40ndash8

417

CHD

mor

talit

y56

6Ag

ency

7N

onfa

talM

I10

37

Blom

hoff

etal

(200

6)44

USA

Iow

aW

omen

rsquosH

ealth

Stud

y31

778

FSe

lf-ad

min

is-

tere

dFF

QN

uts

plus

pean

utbu

tter

7se

rvin

gsw

kvs 0

5se

rvin

gsw

k

55ndash6

915

CVD

mor

talit

y16

75Ag

ency

6CH

Dm

orta

lity

948

Djo

uss e

etal

(200

8)56

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2097

6M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gw

k

40ndash8

419

6H

eart

failu

re10

93N

R6

Net

tleto

net

al(2

008)

57U

SAAt

hero

scle

rosi

sRi

skin

Com

mun

ities

Stud

y

1415

3M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

erCo

ntin

uous

1se

rvin

gd

45ndash6

413

Hea

rtfa

ilure

1140

Agen

cy8

Djo

uss e

etal

(201

0)52

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2107

8M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

7se

rvin

gsw

kvs lt

1se

rvin

gw

k

40ndash8

421

1St

roke

1424

Agen

cy6

Isch

emic

stro

ke11

89H

emor

rhag

icst

roke

219

Bern

stei

net

al(2

012)

54U

SAN

urse

srsquoH

ealth

Stud

yI

8001

0F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

034

serv

ings

dvs

0se

rvin

gsd

30ndash5

526

Hem

orrh

agic

stro

ke13

83Ag

ency

6

Hea

lthPr

ofes

sion

als

Follo

w-U

pSt

udy

4315

0M

060

serv

ings

dvs

0se

rvin

gsd

40ndash7

522

Hem

orrh

agic

stro

ke82

9

Khaw

aja

etal

(201

2)55

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2105

4M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

6

serv

ings

wk

vs0

serv

ings

wk

40ndash8

424

Atria

lfib

rilla

tion

3317

Agen

cy7

Yaem

siri

etal

(201

2)58

USA

Wom

enrsquos

Hea

lthIn

itiat

ive

Obs

erva

tiona

lSt

udy

8702

5F

Self-

adm

inis

-te

red

FFQ

Not

spec

ified

Cont

inuo

us1

serv

ing

d50

ndash79

76

Isch

emic

stro

ke10

49Ag

ency

8

von

Rues

ten

etal

(201

3)59

Ger

man

yEP

IC-P

otsd

amst

udy

2353

1M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Pean

uts

wal

nuts

br

azil

nuts

Cont

inuo

us1

serv

ing

d35

ndash65

8CV

D36

3Ag

ency

8

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Gua

sch-

Ferr

eet

al(2

013)

46Sp

ain

PRED

IMED

stud

y72

16M

FIn

terv

iew

-adm

in-

iste

red

vali-

date

dse

mi-

quan

titat

ive

FFQ

Alm

onds

pea

-nu

tsh

azel

-nu

tsp

ista

-ch

ios

pine

nuts

gt3

serv

ings

wk

vs neve

r

55ndash8

04

8CV

Dm

orta

lity

81Ag

ency

-In

dust

ry9

Bona

ccio

etal

(201

5)48

Italy

Mol

i-san

istu

dy10

509

F88

77M

Valid

ated

sel

f-ad

min

iste

red

FFQ

Wal

nuts

haz

el-

nuts

alm

onds

pe

anut

s

Inta

kevs no

inta

ke

gt35

43

CVD

mor

talit

y10

4Ag

ency

6CH

Dm

orta

lity

39St

roke

mor

talit

y19

diG

iuse

ppe

etal

(201

5)32

Ger

man

yEP

IC-P

otsd

amst

udy

2599

7M

FVa

lidat

eds

elf-

adm

inis

tere

dFF

Q

Pean

uts

wal

nuts

br

azil

nuts

142

gd

vs 0g

d

F49

2M

52

58

3St

roke

288

Agen

cy8

Isch

emic

stro

ke23

5St

roke

mor

talit

y36

Gop

inat

het

al(2

015)

51Au

stra

liaBl

ueM

ount

ains

Eye

Stud

y13

12F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

490

to10

0g

dvs 0

to0

50g

d

49

15CV

Dm

orta

lity

258

Agen

cy7

IHD

mor

talit

y18

8St

roke

mor

talit

y10

1

1581

MCV

Dm

orta

lity

288

IHD

mor

talit

y24

2St

roke

mor

talit

y75

Har

ing

etal

(201

4)50

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1206

6M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Not

spec

ified

06

serv

ings

dvs

01

serv

ings

d45

ndash64

22CH

D11

47Ag

ency

9

Har

ing

etal

(201

5)53

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1160

1M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

er1

serv

ings

dvs 0

serv

ings

d

45ndash6

422

7St

roke

699

Agen

cy8

Hem

orrh

agic

stro

ke11

4

Isch

emic

stro

ke59

8H

shie

het

al(2

015)

47U

SAPh

ysic

ians

rsquoH

ealth

Stud

y20

742

MU

nval

idat

eds

elf-

adm

inis

tere

dFF

Q

Not

spec

ified

5

serv

ings

wk

vs lt1

serv

ing

wk

40ndash8

49

6CV

Dm

orta

lity

760

Agen

cy6

Stro

kem

orta

lity

143

Luu

etal

(201

5)31

USA

Sout

hern

Com

mun

ityCo

hort

Stud

y

7176

4M

FSe

mi-q

uant

ita-

tive

FFQ

Tota

lnut

san

dpe

anut

butt

er

184

5g

dvs lt

095

gd

40ndash7

95

4CV

Dm

orta

lity

1857

Agen

cy8

IHD

mor

talit

y79

3Is

chem

icst

roke

mor

talit

y12

1

Hem

orrh

agic

stro

kem

orta

lity

96

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Chin

aSh

angh

aiW

omen

rsquosH

ealth

Stud

yan

dSh

angh

aiM

enrsquos

Hea

lthSt

udy

134

265

MF

Pean

ut

254

gd

vs lt0

14gr

amd

ay

40ndash7

0an

d40

ndash74

122

and

65

CVD

mor

talit

y25

87IH

Dm

orta

lity

631

Isch

emic

stro

kem

orta

lity

588

Hem

orrh

agic

stro

kem

orta

lity

597

van

den

Bran

dtan

dSc

hout

en(2

015)

26

Net

herla

nds

Net

herla

nds

Coho

rtSt

udy

3202

MF

(sub

coho

rt)

Self-

adm

inis

-te

red

valid

ated

FFQ

Tree

nuts

pe

anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

IHD

mor

talit

y14

88St

roke

mor

talit

y56

5

Wan

get

al(2

016)

60Ch

ina

Linx

ian

NIT

coho

rt24

45M

FFF

QPe

anut

sch

est-

nuts

wal

nuts

Cont

inuo

us3

serv

ings

mo

40ndash6

926

Hea

rtdi

seas

em

orta

lity

355

Agen

cy6

Ger

man

ySt

roke

mor

talit

y45

2

Esla

mpa

rast

etal

(201

7)49

Iran

Gol

esta

nCo

hort

Stud

y28

257

FVa

lidat

eds

elf-

adm

inis

tere

dse

miq

uant

ita-

tive

FFQ

Pean

uts

tree

nuts

3

serv

ings

wk

vs neve

r

40ndash8

77

CVD

mor

talit

y91

1Ag

ency

720

855

M11

05

Gua

sch-

Ferr

eet

al(2

017)

21U

SAN

urse

srsquoH

ealth

Stud

yI

7636

4F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Pean

uts

othe

rnu

tsa

ndw

al-

nuts

(ifav

aila

ble)

5

serv

ings

wk

vs neve

rora

lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

7CV

Dm

orta

lity

1770

CHD

3552

CHD

mor

talit

y99

6St

roke

3322

Stro

kem

orta

lity

773

Isch

emic

stro

ke16

35N

urse

srsquoH

ealth

Stud

yII

9294

6F

25ndash4

221

5CV

D19

15CV

Dm

orta

lity

82CH

D67

0CH

Dm

orta

lity

46St

roke

1262

Stro

kem

orta

lity

36

Isch

emic

stro

ke22

0H

ealth

Prof

essi

onal

sFo

llow

-Up

Stud

y

4152

6M

40ndash7

522

5CV

D54

94CV

Dm

orta

lity

2599

CHD

4168

CHD

mor

talit

y19

21St

roke

1326

Stro

kem

orta

lity

367

Isch

emic

stro

ke74

2

(con

tinue

d)


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e2

Cont

inue

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udy

Coun

try

Stud

yna

me

Popu

latio

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utco

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ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Lars

son

etal

(201

8)22

Swed

enCo

hort

ofSw

edis

hM

en32

911

MFF

QN

uts

(not

incl

ud-

ing

coco

nuto

rch

estn

uts)

3

serv

ings

wk

vs neve

r

45ndash8

317

MI

4983

Agen

cy8

MIm

orta

lity

917

Hea

rtfa

ilure

3160

Atria

lfib

rilla

tion

7550

Isch

emic

stro

ke37

82In

trac

ereb

ral

hem

orrh

age

543

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CVD

car

diov

ascu

lard

isea

seE

PIC

Euro

pean

Pros

pect

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stig

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ncer

and

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Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

fort

hese

outc

omes

no

dow

ngra

des

wer

em

ade

forp

ublic

atio

nbi

as

bSe

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indi

rect

ness

forC

VDin

cide

nce

asth

ein

clud

edst

udie

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ere

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(69

30

)was

cont

ribut

edby

stud

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cond

ucte

dam

ong

mal

es

c Upg

rade

fora

dose

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pons

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dose

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alys

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asi

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cant

nonl

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tions

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betw

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tota

lnut

cons

umpt

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and

CVD

inci

denc

e(Plt

001

)se

eFi

gure

S27

inth

eSu

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ting

Info

rmat

ion

onlin

ed

Upg

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fora

dose

-res

pons

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dose

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alys

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gnifi

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eSu

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rmat

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due

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ity(I2frac14

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Pfrac14

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f Serio

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asgt

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ong

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impr

ecis

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denc

eas

the

95

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69ndash

096

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ally

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pgra

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se-r

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nse

grad

ient

as

the

GLS

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se-r

espo

nse

anal

yses

reve

aled

asi

gnifi

cant

linea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CHD

inci

denc

e(Plt

001

)se

eFi

gure

S29

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ei U

pgra

defo

rado

se-r

espo

nse

grad

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as

the

MKS

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se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

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utco

nsum

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dCH

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(Plt

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)se

eFi

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ej Se

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indi

rect

ness

fors

trok

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7

)was

cont

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edby

stud

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cond

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dam

ong

heal

thpr

ofes

sion

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k Serio

usim

prec

isio

nfo

rstr

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eas

the

95

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em

inim

ally

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cefo

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ndha

rm(R

R1

05)

l Serio

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nfo

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the

95

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76ndash

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em

inim

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cefo

rclin

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bene

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grad

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as

the

MKS

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nse

anal

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eda

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ifica

ntno

nlin

eari

nver

sere

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pbe

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dst

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mor

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y(Pfrac14

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9)s

eeFi

gure

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eSu

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ting

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rmat

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onlin

en

Serio

usris

kof

bias

forh

emor

rhag

icst

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asgt

50

ofth

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eigh

t(68

7

)was

cont

ribut

edby

stud

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cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

o Serio

usin

dire

ctne

ssfo

rhem

orrh

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stro

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sgt

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ofth

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eigh

t(68

7

)was

cont

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stud

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cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(55

7

)was

cont

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udie

sco

nduc

ted

amon

gm

ales

p

Serio

usim

prec

isio

nfo

rhem

orrh

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stro

keas

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95

CI(0

77ndash

134

)ove

rlapp

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em

inim

ally

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eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

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qU

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eda

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eari

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sere

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mor

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(Pfrac14

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eFi

gure

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ting

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rmat

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onlin

er Se

rious

indi

rect

ness

fori

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mic

stro

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50

ofth

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eigh

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1

)was

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edby

stud

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cond

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dam

ong

heal

thpr

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s Serio

usim

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hem

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cefo

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ble

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ted

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gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

Tabl

e2

Char

acte

rist

ics

ofth

ein

clud

edst

udie

sev

alua

ting

the

asso

ciat

ion

betw

een

nuts

and

risk

ofca

rdio

vasc

ular

dise

ase

outc

omes

Stud

yCo

untr

ySt

udy

nam

ePo

pula

tion

Nut

cons

umpt

ion

asse

ssm

ent

met

hod

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Fras

eret

al(1

992)

29U

SASe

vent

h-da

yAd

vent

ists

2647

3M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

51

serv

ings

wk

vslt

1se

rvin

gw

k

25

6N

onfa

talM

I13

4Ag

ency

7CH

Dm

orta

lity

463

Albe

rtet

al(2

002)

30U

SAPh

ysic

ians

rsquoH

ealth

Stud

y21

454

MSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gm

o

40ndash8

417

CHD

mor

talit

y56

6Ag

ency

7N

onfa

talM

I10

37

Blom

hoff

etal

(200

6)44

USA

Iow

aW

omen

rsquosH

ealth

Stud

y31

778

FSe

lf-ad

min

is-

tere

dFF

QN

uts

plus

pean

utbu

tter

7se

rvin

gsw

kvs 0

5se

rvin

gsw

k

55ndash6

915

CVD

mor

talit

y16

75Ag

ency

6CH

Dm

orta

lity

948

Djo

uss e

etal

(200

8)56

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2097

6M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

2

serv

ings

wk

vslt

1se

rvin

gw

k

40ndash8

419

6H

eart

failu

re10

93N

R6

Net

tleto

net

al(2

008)

57U

SAAt

hero

scle

rosi

sRi

skin

Com

mun

ities

Stud

y

1415

3M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

erCo

ntin

uous

1se

rvin

gd

45ndash6

413

Hea

rtfa

ilure

1140

Agen

cy8

Djo

uss e

etal

(201

0)52

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2107

8M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

7se

rvin

gsw

kvs lt

1se

rvin

gw

k

40ndash8

421

1St

roke

1424

Agen

cy6

Isch

emic

stro

ke11

89H

emor

rhag

icst

roke

219

Bern

stei

net

al(2

012)

54U

SAN

urse

srsquoH

ealth

Stud

yI

8001

0F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

034

serv

ings

dvs

0se

rvin

gsd

30ndash5

526

Hem

orrh

agic

stro

ke13

83Ag

ency

6

Hea

lthPr

ofes

sion

als

Follo

w-U

pSt

udy

4315

0M

060

serv

ings

dvs

0se

rvin

gsd

40ndash7

522

Hem

orrh

agic

stro

ke82

9

Khaw

aja

etal

(201

2)55

USA

Phys

icia

nsrsquo

Hea

lthSt

udy

2105

4M

Unv

alid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

6

serv

ings

wk

vs0

serv

ings

wk

40ndash8

424

Atria

lfib

rilla

tion

3317

Agen

cy7

Yaem

siri

etal

(201

2)58

USA

Wom

enrsquos

Hea

lthIn

itiat

ive

Obs

erva

tiona

lSt

udy

8702

5F

Self-

adm

inis

-te

red

FFQ

Not

spec

ified

Cont

inuo

us1

serv

ing

d50

ndash79

76

Isch

emic

stro

ke10

49Ag

ency

8

von

Rues

ten

etal

(201

3)59

Ger

man

yEP

IC-P

otsd

amst

udy

2353

1M

FSe

lf-ad

min

is-

tere

dse

mi-

quan

titat

ive

FFQ

Pean

uts

wal

nuts

br

azil

nuts

Cont

inuo

us1

serv

ing

d35

ndash65

8CV

D36

3Ag

ency

8

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Gua

sch-

Ferr

eet

al(2

013)

46Sp

ain

PRED

IMED

stud

y72

16M

FIn

terv

iew

-adm

in-

iste

red

vali-

date

dse

mi-

quan

titat

ive

FFQ

Alm

onds

pea

-nu

tsh

azel

-nu

tsp

ista

-ch

ios

pine

nuts

gt3

serv

ings

wk

vs neve

r

55ndash8

04

8CV

Dm

orta

lity

81Ag

ency

-In

dust

ry9

Bona

ccio

etal

(201

5)48

Italy

Mol

i-san

istu

dy10

509

F88

77M

Valid

ated

sel

f-ad

min

iste

red

FFQ

Wal

nuts

haz

el-

nuts

alm

onds

pe

anut

s

Inta

kevs no

inta

ke

gt35

43

CVD

mor

talit

y10

4Ag

ency

6CH

Dm

orta

lity

39St

roke

mor

talit

y19

diG

iuse

ppe

etal

(201

5)32

Ger

man

yEP

IC-P

otsd

amst

udy

2599

7M

FVa

lidat

eds

elf-

adm

inis

tere

dFF

Q

Pean

uts

wal

nuts

br

azil

nuts

142

gd

vs 0g

d

F49

2M

52

58

3St

roke

288

Agen

cy8

Isch

emic

stro

ke23

5St

roke

mor

talit

y36

Gop

inat

het

al(2

015)

51Au

stra

liaBl

ueM

ount

ains

Eye

Stud

y13

12F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Not

spec

ified

490

to10

0g

dvs 0

to0

50g

d

49

15CV

Dm

orta

lity

258

Agen

cy7

IHD

mor

talit

y18

8St

roke

mor

talit

y10

1

1581

MCV

Dm

orta

lity

288

IHD

mor

talit

y24

2St

roke

mor

talit

y75

Har

ing

etal

(201

4)50

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1206

6M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Not

spec

ified

06

serv

ings

dvs

01

serv

ings

d45

ndash64

22CH

D11

47Ag

ency

9

Har

ing

etal

(201

5)53

USA

Athe

rosc

lero

sis

Risk

inCo

mm

uniti

esSt

udy

1160

1M

FIn

terv

iew

-adm

in-

iste

red

FFQ

Nut

spl

uspe

anut

butt

er1

serv

ings

dvs 0

serv

ings

d

45ndash6

422

7St

roke

699

Agen

cy8

Hem

orrh

agic

stro

ke11

4

Isch

emic

stro

ke59

8H

shie

het

al(2

015)

47U

SAPh

ysic

ians

rsquoH

ealth

Stud

y20

742

MU

nval

idat

eds

elf-

adm

inis

tere

dFF

Q

Not

spec

ified

5

serv

ings

wk

vs lt1

serv

ing

wk

40ndash8

49

6CV

Dm

orta

lity

760

Agen

cy6

Stro

kem

orta

lity

143

Luu

etal

(201

5)31

USA

Sout

hern

Com

mun

ityCo

hort

Stud

y

7176

4M

FSe

mi-q

uant

ita-

tive

FFQ

Tota

lnut

san

dpe

anut

butt

er

184

5g

dvs lt

095

gd

40ndash7

95

4CV

Dm

orta

lity

1857

Agen

cy8

IHD

mor

talit

y79

3Is

chem

icst

roke

mor

talit

y12

1

Hem

orrh

agic

stro

kem

orta

lity

96

(con

tinue

d)


Dow




Tabl

e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Chin

aSh

angh

aiW

omen

rsquosH

ealth

Stud

yan

dSh

angh

aiM

enrsquos

Hea

lthSt

udy

134

265

MF

Pean

ut

254

gd

vs lt0

14gr

amd

ay

40ndash7

0an

d40

ndash74

122

and

65

CVD

mor

talit

y25

87IH

Dm

orta

lity

631

Isch

emic

stro

kem

orta

lity

588

Hem

orrh

agic

stro

kem

orta

lity

597

van

den

Bran

dtan

dSc

hout

en(2

015)

26

Net

herla

nds

Net

herla

nds

Coho

rtSt

udy

3202

MF

(sub

coho

rt)

Self-

adm

inis

-te

red

valid

ated

FFQ

Tree

nuts

pe

anut

s19

6g

dvs 0

gd

55ndash6

99

CVD

mor

talit

y29

85N

R7

IHD

mor

talit

y14

88St

roke

mor

talit

y56

5

Wan

get

al(2

016)

60Ch

ina

Linx

ian

NIT

coho

rt24

45M

FFF

QPe

anut

sch

est-

nuts

wal

nuts

Cont

inuo

us3

serv

ings

mo

40ndash6

926

Hea

rtdi

seas

em

orta

lity

355

Agen

cy6

Ger

man

ySt

roke

mor

talit

y45

2

Esla

mpa

rast

etal

(201

7)49

Iran

Gol

esta

nCo

hort

Stud

y28

257

FVa

lidat

eds

elf-

adm

inis

tere

dse

miq

uant

ita-

tive

FFQ

Pean

uts

tree

nuts

3

serv

ings

wk

vs neve

r

40ndash8

77

CVD

mor

talit

y91

1Ag

ency

720

855

M11

05

Gua

sch-

Ferr

eet

al(2

017)

21U

SAN

urse

srsquoH

ealth

Stud

yI

7636

4F

Valid

ated

sel

f-ad

min

iste

red

FFQ

Pean

uts

othe

rnu

tsa

ndw

al-

nuts

(ifav

aila

ble)

5

serv

ings

wk

vs neve

rora

lmos

tne

ver

30ndash5

528

7CV

D67

27Ag

ency

7CV

Dm

orta

lity

1770

CHD

3552

CHD

mor

talit

y99

6St

roke

3322

Stro

kem

orta

lity

773

Isch

emic

stro

ke16

35N

urse

srsquoH

ealth

Stud

yII

9294

6F

25ndash4

221

5CV

D19

15CV

Dm

orta

lity

82CH

D67

0CH

Dm

orta

lity

46St

roke

1262

Stro

kem

orta

lity

36

Isch

emic

stro

ke22

0H

ealth

Prof

essi

onal

sFo

llow

-Up

Stud

y

4152

6M

40ndash7

522

5CV

D54

94CV

Dm

orta

lity

2599

CHD

4168

CHD

mor

talit

y19

21St

roke

1326

Stro

kem

orta

lity

367

Isch

emic

stro

ke74

2

(con

tinue

d)


Dow

















online)














e2

Cont

inue

dSt

udy

Coun

try

Stud

yna

me

Popu

latio

nN

utco

nsum

ptio

nas

sess

men

tm

etho

d

Type

ofnu

tsN

utin

take

Age

yFo

llow

-up

(mea

nm

edia

nor

rang

e)y

Out

com

eIn

cide

ntca

ses

Fund

ing

sour

ceN

OS

scor

e

Lars

son

etal

(201

8)22

Swed

enCo

hort

ofSw

edis

hM

en32

911

MFF

QN

uts

(not

incl

ud-

ing

coco

nuto

rch

estn

uts)

3

serv

ings

wk

vs neve

r

45ndash8

317

MI

4983

Agen

cy8

MIm

orta

lity

917

Hea

rtfa

ilure

3160

Atria

lfib

rilla

tion

7550

Isch

emic

stro

ke37

82In

trac

ereb

ral

hem

orrh

age

543

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CVD

car

diov

ascu

lard

isea

seE

PIC

Euro

pean

Pros

pect

ive

Inve

stig

atio

nin

toCa

ncer

and

Nut

ritio

nF

fem

ales

FFQ

foo

dfr

eque

ncy

ques

tionn

aire

IH

Di

sche

mic

hear

tdis

ease

Mm

ales

MI

myo

card

iali

nfar

ctio

nN

ITN

utrit

ion

Inte

rven

tion

Tria

lsN

OS

New

cast

le-O

ttaw

asc

ale

NR

Not

repo

rted

PRE

DIM

EDP

reve

nci o

nco

nD

ieta

MED

iterr

anea


Dow









online)










Dow


























































Dow


























Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

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heal

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stud

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7

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ally

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ucte

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

Tabl

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Har

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7176

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Stud

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online)










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Subgroup analyses











Publication bias













DISCUSSION









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Tabl

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

Tabl

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online)














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online)










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Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

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asse

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ewan

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anal

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27














online)














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Tabl

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ade

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ublic

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clud

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ong

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30

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ribut

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ucte

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mal

es

c Upg

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KSPL

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27






online)










Dow


























































Dow


























Subgroup analyses











Publication bias













DISCUSSION









Dow




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latio

nas

only

2av

aila

ble

stud

ies

wer

eco

nduc

ted

amon

gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27























































Dow


























Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

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ctne

ssIm

prec

isio

nO

ther

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ider

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nsa

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(95

CI)

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lity

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denc

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rious

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usb

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serio

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onse

grad

ient

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085

(08

0to

091

)

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mor

talit

y14

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erva

tiona

lstu

dies

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serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

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77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

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erva

tiona

lstu

dies

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serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

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serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

fort

hese

outc

omes

no

dow

ngra

des

wer

em

ade

forp

ublic

atio

nbi

as

bSe

rious

indi

rect

ness

forC

VDin

cide

nce

asth

ein

clud

edst

udie

sw

ere

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(69

30

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

mal

es

c Upg

rade

fora

dose

-res

pons

egr

adie

nta

sth

eM

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INE

dose

-res

pons

ean

alys

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owed

asi

gnifi

cant

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inea

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erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

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CVD

inci

denc

e(Plt

001

)se

eFi

gure

S27

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ed

Upg

rade

fora

dose

-res

pons

egr

adie

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eM

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INE

dose

-res

pons

ean

alys

essh

owed

asi

gnifi

cant

nonl

inea

rinv

erse

rela

tions

hip

betw

een

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lnut

cons

umpt

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mor

talit

y(Plt

001

)se

eFi

gure

S28

inth

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ppor

ting

Info

rmat

ion

onlin

ee Se

rious

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tenc

yfo

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Din

cide

nce

due

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ghde

gree

ofun

expl

aine

dhe

tero

gene

ity(I2frac14

74

Pfrac14

000

1)

f Serio

usin

dire

ctne

ssfo

rCH

Din

cide

nce

asgt

50

ofth

ew

eigh

t(55

4

)was

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ribut

edby

stud

ies

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ucte

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ong

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ofes

sion

als

gSe

rious

impr

ecis

ion

forC

HD

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denc

eas

the

95

CI(0

69ndash

096

)ove

rlapp

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ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

hU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

GLS

Tdo

se-r

espo

nse

anal

yses

reve

aled

asi

gnifi

cant

linea

rinv

erse

rela

tions

hip

betw

een

tota

lnut

cons

umpt

ion

and

CHD

inci

denc

e(Plt

001

)se

eFi

gure

S29

inth

eSu

ppor

ting

Info

rmat

ion

onlin

ei U

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

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utco

nsum

ptio

nan

dCH

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lity

(Plt

001

)se

eFi

gure

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ting

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rmat

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onlin

ej Se

rious

indi

rect

ness

fors

trok

ein

cide

nce

asgt

50

ofth

ew

eigh

t(72

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

k Serio

usim

prec

isio

nfo

rstr

oke

inci

denc

eas

the

95

CI(0

92ndash

109

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

l Serio

usim

prec

isio

nfo

rstr

oke

mor

talit

yas

the

95

CI(0

76ndash

100

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

mU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

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utco

nsum

ptio

nan

dst

roke

mor

talit

y(Pfrac14

002

9)s

eeFi

gure

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inth

eSu

ppor

ting

Info

rmat

ion

onlin

en

Serio

usris

kof

bias

forh

emor

rhag

icst

roke

asgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

o Serio

usin

dire

ctne

ssfo

rhem

orrh

agic

stro

kea

sgt

50

ofth

ew

eigh

t(68

7

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

andgt

50

ofth

ew

eigh

t(55

7

)was

cont

rib-

uted

byst

udie

sco

nduc

ted

amon

gm

ales

p

Serio

usim

prec

isio

nfo

rhem

orrh

agic

stro

keas

the

95

CI(0

77ndash

134

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

qU

pgra

defo

rado

se-r

espo

nse

grad

ient

as

the

MKS

PLIN

Edo

se-r

espo

nse

anal

yses

show

eda

sign

ifica

ntno

nlin

eari

nver

sere

latio

nshi

pbe

twee

nto

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utco

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ptio

nan

dhe

mor

rhag

icst

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(Pfrac14

001

)se

eFi

gure

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ting

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rious

indi

rect

ness

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sche

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stro

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ofth

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eigh

t(66

1

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

s Serio

usim

prec

isio

nfo

risc

hem

icst

roke

as

the

95

CI(0

89ndash

110

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

t Serio

usin

dire

ctne

ssfo

ratr

ialf

ibril

latio

nas

only

2av

aila

ble

stud

ies

wer

eco

nduc

ted

amon

gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27























Subgroup analyses











Publication bias













DISCUSSION









Dow




Tabl

e4

GRA

DE

asse

ssm

ent

ofth

esy

stem

atic

revi

ewan

dm

eta-

anal

ysis

ofpr

ospe

ctiv

eco

hort

stud

ies

asse

ssin

gth

eas

soci

atio

nbe

twee

nto

taln

utco

nsum

ptio

nan

dca

rdio

vasc

u-la

rdi

seas

eou

tcom

esO

utco

me

No

ofst

udie

sSt

udy

desi

gnRi

skof

bias

Inco

nsis

tenc

yIn

dire

ctne

ssIm

prec

isio

nO

ther

cons

ider

atio

nsa

Rela

tive

(95

CI)

Qua

lity

CVD

inci

denc

e3

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usb

Not

serio

usD

ose-

resp

onse

grad

ient

cRR

085

(08

0to

091

)

LOW

CVD

mor

talit

y14

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

ntd

RR0

77(0

72

to0

82)

MO

DER

ATE

CHD

inci

denc

e7

Obs

erva

tiona

lstu

dies

Not

serio

usSe

rious

eSe

rious

fSe

rious

gD

ose-

resp

onse

grad

ient

hRR

082

(06

9to

096

)

VERY

LOW

CHD

mor

talit

y12

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Not

serio

usN

otse

rious

Dos

e-re

spon

segr

adie

nti

RR0

76(0

67

to0

86)

MO

DER

ATE

Stro

kein

cide

nce

7O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

jSe

rious

kN

one

RR1

00(0

92

to1

09)

VERY

LOW

Stro

kem

orta

lity

11O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usN

otse

rious

Serio

usl

Dos

e-re

spon

segr

adie

ntm

RR0

87(0

76

to1

00)

LOW

Hem

orrh

agic

stro

ke5

Obs

erva

tiona

lstu

dies

Serio

usn

Not

serio

usSe

rious

oSe

rious

pD

ose-

resp

onse

grad

ient

qRR

102

(07

7to

134

)

VERY

LOW

Isch

emic

stro

ke7

Obs

erva

tiona

lstu

dies

Not

serio

usN

otse

rious

Serio

usr

Serio

uss

Non

eRR

099

(08

9to

110

)

VERY

LOW

Atria

lfib

rilla

tion

2O

bser

vatio

nals

tudi

esN

otse

rious

Not

serio

usSe

rious

tSe

rious

uN

one

RR0

85(0

73

to0

99)

VERY

LOW

Hea

rtfa

ilure

2O

bser

vatio

nals

tudi

esSe

rious

vN

otse

rious

Serio

usw

Serio

usx

Non

eRR

100

(08

6to

116

)

VERY

LOW

Abbr

evia

tions

CH

Dc

oron

ary

hear

tdis

ease

CI

conf

iden

cein

terv

alC

VDc

ardi

ovas

cula

rdis

ease

GLS

Tge

nera

lized

leas

tsqu

ares

tren

dG

RAD

EG

radi

ngof

Reco

mm

enda

tions

Ass

essm

ent

Dev

elop

men

tan

dEv

alua

tion

NO

SN

ewca

stle

-Ott

awa

scal

eRR

ris

kra

tio

a Publ

icat

ion

bias

coul

dno

tbe

asse

ssed

inm

eta-

anal

yses

that

incl

udedlt

10tr

ialc

ompa

rison

sTh

eref

ore

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Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

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eigh

t(66

1

)was

cont

ribut

edby

stud

ies

cond

ucte

dam

ong

heal

thpr

ofes

sion

als

s Serio

usim

prec

isio

nfo

risc

hem

icst

roke

as

the

95

CI(0

89ndash

110

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)

t Serio

usin

dire

ctne

ssfo

ratr

ialf

ibril

latio

nas

only

2av

aila

ble

stud

ies

wer

eco

nduc

ted

amon

gm

ales

u

Serio

usim

prec

isio

nfo

ratr

ialf

ibril

latio

nas

the

95

CI(0

73ndash

099

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)

v Serio

usris

kof

bias

forh

eart

failu

rea

sgt

50

ofth

ew

eigh

t(65

40

)was

cont

ribut

edby

ast

udy

cons

ider

edto

beat

high

risk

ofbi

as(N

OSlt

7)

wSe

rious

indi

rect

ness

forh

eart

failu

rea

son

ly2

avai

labl

est

udie

sw

ere

cond

ucte

dam

ong

mal

es

x Serio

usim

prec

isio

nfo

rhea

rtfa

ilure

as

the

95

CI(0

86ndash

116

)ove

rlapp

edw

ithth

em

inim

ally

impo

rtan

tdiff

eren

cefo

rclin

ical

bene

fit(R

R0

95)a

ndha

rm(R

R1

05)


Dow




























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

























































Dow




CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

CONCLUSION





on CVD outcomes

Acknowledgments





data










































Dow





































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27


































































Dow


















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27















outcomes



vascular disease



diovascular disease



diovascular disease



diovascular disease












heart disease



onary heart disease



onary heart disease



onary heart disease
















of stroke



stroke



risk of stroke



mortality



stroke death



of stroke mortality



rhagic stroke



stroke



fibrillation



failure




incidence




mortality











Dow















mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27












mortality






mortality















REFERENCES










































Dow





























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27


























Dow




nuz042-TF1

nuz042-TF2

nuz042-TF3

nuz042-TF4

nuz042-TF5

nuz042-TF6

nuz042-TF7

nuz042-TF8

nuz042-TF9

nuz042-TF10

nuz042-TF11

nuz042-TF12

nuz042-TF13

nuz042-TF14

nuz042-TF15

nuz042-TF16

nuz042-TF17

nuz042-TF18

nuz042-TF19

nuz042-TF20

nuz042-TF21

nuz042-TF22

nuz042-TF23

nuz042-TF24

nuz042-TF25

nuz042-TF26

nuz042-TF27

Nut consumption and incidence of cardiovascular diseases ... · 3/19/2019 · Special Article Nut...

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