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Lead Article
The association between dietary patterns and the novel
inflammatory markers platelet-activating factor and
lipoprotein-associated phospholipase A
2
: a systematic review
Carolyn J. English, Hannah L. Mayr, Anna E. Lohning, and Dianne P. Reidlinger
12
Context: Atherosclerosis is a disease of chronic inflammation. Recent research has
identified 2 novel inflammatory biomarkers: platelet-activating factor (PAF) and
lipoprotein-associated phospholipase A
2
(Lp-PLA
2
). Diet has been proposed as a
mediator of inflammation, but to date, the focus for these novel biomarkers has
been on individual foods and nutrients rather than overall dietary patterns.
Objective: To systematically review the literature on the association between die-
tary patterns and PAF and Lp-PLA
2
.Data Sources: The PubMed, Embase, CINAHL,
and Cochrane CENTRAL literature databases were searched. Data Analysis: Study
quality was evaluated using the Quality Criteria Checklist. Sixteen studies (n ¼4ob-
servational and n ¼12 interventional) were included and assessed for associations
between dietary patterns and PAF and Lp-PLA
2
.Conclusion: Study quality varied
from neutral (n ¼10) to positive (n ¼6). Mediterranean, heart healthy, and vege-
tarian dietary patterns were associated with improved levels of PAF and Lp-PLA
2
.
Conversely, Western dietary patterns were less favorable. A range of well-
established, healthier dietary patterns may lower inflammation and the risk of ath-
erosclerosis. More well-designed studies are needed to confirm these findings and
identify other dietary patterns that improve inflammation.
INTRODUCTION
Atherosclerosis, the main underlying cause of cardio-
vascular disease (CVD), is a chronic arterial disease
leading to fatty streaks and atheromas in the arterial
wall.
1,2
Once thought to be solely caused by dyslipide-
mia, atherosclerosis is now known to be a result of in-
flammatory responses.
3
Inflammation is involved in all
stages of atherosclerosis, from the initial injury of the
endothelium to plaque formation and eventual plaque
rupture and thrombosis.
4,5
Two novel inflammatory markers involved in CVD
that are receiving increasing attention are platelet-
activating factor (PAF) and lipoprotein-associated
phospholipase A
2
(Lp-PLA
2
).
6,7
PAF is the most potent
lipid inflammatory mediator and is produced upon
Affiliation: C.J. English,A.E. Lohning, and D.P. Reidlinger are with the Faculty of Health Sciences and Medicine, Bond University, Robina,
Queensland, Australia. H.L. Mayr is with the Faculty of Health Sciences and Medicine, Bond University, Robina, Queensland, Australia and
Department of Nutrition and Dietetics, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia.
Correspondence: D.P. Reidlinger, Faculty of Health Sciences and Medicine, Bond University, 14 University Dr, Robina, Queensland 4229,
Australia. E-mail: dreidlin@bond.edu.au.
Key words: cardiovascular disease, dietary patterns, inflammation, lipoprotein-associated phospholipase A
2
, Lp-PLA
2
, PAF, platelet-activating
factor.
V
CThe Author(s) 2021. Published by Oxford University Press on behalf of the International Life Sciences Institute.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://
creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium,
provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please
contact journals.permissions@oup.com
doi: 10.1093/nutrit/nuab051
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stimulation by numerous cells such as platelets, endo-
thelial cells, and leukocytes.
8,9
PAF is implicated in ev-
ery step of atherosclerosis (Figure 1).
4,6,10,11
PAF plays a
crucial role in the initiation of atherosclerosis and one
of its main pro-inflammatory actions is the mediation
of adhesion of monocytes to the endothelium and initi-
ation of gene transcription within monocytes to pro-
duce inflammatory cytokines such as monocyte
chemoattractant protein-1, interleukin (IL) 8, and tu-
mor necrosis factor a(TNF-a).
12,13
PAF also stimulates
the release of the proinflammatory cytokine IL-6 from
both endothelial cells and monocytes.
14
PAF induces an influx of Ca
2þ
, which results in in-
creased endothelial permeability as the endothelial cells
contract, allowing the migration of low-density lipopro-
tein (LDL) cholesterol and monocytes into the in-
tima.
15–18
PAF also stimulates reactive oxygen and
nitrogen species and contributes to the oxidation of
LDL.
6,19
PAF is further involved in the differentiation
of monocytes into pro-inflammatory macrophages that
engulf oxidized LDL, and is involved in the formation
of foam cells and the growth and rupture of plaques.
20,21
PAF, once produced, triggers an uncontrolled and pro-
longed inflammatory milieu, because it is responsible
for the production of new PAF molecules and addi-
tional free radicals.
21,22
Patients with diabetes, heart fail-
ure, acute myocardial infarction, and coronary heart
disease have elevated levels of PAF.
23–28
Lp-PLA
2
(alternatively known as platelet-activating
factor–acetylhydrolase) is an enzyme that catalyzes hy-
drolysis of PAF and belongs to the PLA
2
superfamily.
29
As Lp-PLA
2
hydrolyses PAF into the inactive form lyso-
PAF, Lp-PLA
2
levels are proposed to be determined by
in vivo levels of PAF and may serve as a reliable surro-
gate marker of PAF.
30
Because Lp-PLA
2
catabolizes
PAF, Lp-PLA
2
appears to play an anti-inflammatory
role. However, because of its nonspecificity for its li-
gand, the hydrolysis products of Lp-PLA
2
have been
linked to pathologies.
31
Lp-PLA
2
is primarily secreted by macrophages and
circulates in the blood bound to LDL and high-density
lipoprotein (HDL), with the majority attached to LDL,
and preferentially to small dense fractions.
32
It is pro-
posed that HDL bound to Lp-PLA
2
plays a protective
Figure 1 A simplified schematic of the role PAF plays in the initiation and progression of atherosclerotic plaques. After exposure to in-
jury, the endothelial cell is activated, triggering the production of PAF and expression of adhesion molecules. PAF acts as a strong chemoat-
tractant and mediates the firm adhesion of monocytes to the endothelium via adhesion molecules. PAF signals the transport of NF-jBinto
the nucleus of the monocytes, triggering gene transcription of pro-inflammatory cytokines such as MCP-1, IL-6, IL-8, and TNF-a.PAFstimu-
lates the production of ROS, which contributes to the oxidation of LDL. PAF reduces endothelial nitric oxide production and increases endo-
thelial permeability, allowing the transmigration of LDL and monocytes into the intima. PAF is responsible for the differentiation of
monocytes into macrophages that engulf oxLDL, which triggers the production of more PAF. Abbreviations: IL, interleukin; NF-jB, nuclear fac-
tor jB; LDL, low-density lipoprotein; MCP-1, monocyte chemoattractant protein-1; oxLDL, oxidized low-density lipoprotein; PAF, platelet-acti-
vating factor; ROS, reactive oxygen species; TNF-a, tumor necrosis factor a.
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role, whereas LDL-bound Lp-PLA
2
is atherogenic.
32
When associated with LDL, Lp-PLA
2
hydrolyzes oxidized
phospholipids on the surface of the LDL particles, creating
pro-inflammatory and pro-atherogenic by-products such
as lysophosphatidylcholine and oxidized, nonesterified
fatty acids.
33
Lysophosphatidylcholine and oxidized, non-
esterified fatty acids mimic PAF in mediating inflamma-
tion by upregulating adhesion molecules; acting as a
chemoattractant to monocytes; activating leukocytes; stim-
ulating cytokine production such as IL-6 and TNF-a;con-
tributing to necrosis and apoptosis of macrophages in the
plaque; and inducing smooth muscle migration into the
intima (Figure 2).
31,34–37
Lp-PLA
2
is an independent risk
marker for coronary heart disease events, stroke, calcific
aortic-valve stenosis, and plaque stability.
38–41
Previous research on diet and PAF and/or Lp-PLA
2
is limited. However, some research has demonstrated
that bioactive compounds found in foods regularly con-
sumed in the traditional Mediterranean diet contain
natural PAF inhibitors.
20
These compounds inhibit in-
flammation by preventing PAF from binding to its re-
ceptor, blocking the cascade of intracellular signaling
and inflammatory processes, and possibly by inhibiting
metabolic enzymes used in the remodeling pathway for
PAF synthesis.
42–44
This research provides some insight
into the potential mechanisms of components within
the Mediterranean diet and its established cardioprotec-
tive effects.
45
Research into specific Mediterranean foods that in-
hibit PAF have predominantly been in vitro studies us-
ing washed rabbit platelets and, more recently, human
platelets.
46
The foods include fish
47,48
; eggs
49
; honey
50
;
wild plants
51
; garden peas
52
; dairy (especially fermented
and of goat and sheep origin)
53–56
; goat and sheep
meat
57
; flaxseeds
58
; olive oil and olive pomace
59–61
;
wine
46
; grapes
62
;Origanum onites (Cretan oregano)
63
;
clove and cinnamon
64
; onion
65
; garlic
66
; and seeds oils,
such as corn, sunflower, and sesame.
59
Foods found
outside the Mediterranean region that inhibit PAF in-
clude soy sauce,
67
Camillea sinensis (tea),
68
and
curcumin.
69
Dietary effects on Lp-PLA
2
levels are largely unex-
plored, but some evidence from studies in humans has
shown that low-energy diets with concurrent weight
loss can reduce Lp-PLA
2
levels, whereas increased en-
ergy intake is associated with higher Lp-PLA
2
levels.
70,71
Figure 2 Lp-PLA
2
involvement in the progression of atherosclerosis. Lp-PLA
2
circulates primarily bound to LDL cholesterol, concentrating
in small dense LDL. After oxidation of LDL, Lp-PLA
2
hydrolyzes oxLDL, creating 2 inflammatory phospholipids, lyso-PC and oxNEFA, both of
which mimic PAF. Lyso-PC and oxNEFA upregulate inflammatory mediators such as adhesion molecules, MCP-1, IL-6, and TNF-a; contribute to
endothelial dysfunction; promote chemotaxis, drawing monocytes into the arterial intima; trigger smooth muscle cell migration; and induce
apoptosis and cytotoxic effects contributing to necrotic core growth. Abbreviations: LDL, low-density lipoprotein; Lp-PLA
2
, lipoprotein-associ-
ated phospholipase A
2
; Lyso-PC, lysophosphatidylcholine; MCP-1, monocyte chemoattractant protein-1; oxLDL, oxidized low-density lipopro-
tein; oxNEFA, oxidized nonesterified fatty acids; PAF, platelet-activating factor; ROS, reactive oxygen species; TNF-a, tumor necrosis factor
alpha.
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The replacement of 5% of energy from carbohydrates
with energy from protein is associated with a decrease
in Lp-PLA
2
activity.
72
An 8-week intervention with the
supplementation of omega-3 fatty acids did not influ-
ence Lp-PLA
2
activity in older adults,
73
whereas a simi-
lar 30-day intervention in people with stable coronary
artery disease resulted in decreased Lp-PLA
2
levels.
74
Studies have varied in terms of the assays used to
measure Lp-PLA
2
. Lp-PLA
2
assays can measure either
plasma concentrations or enzymatic activity. This
makes comparisons between studies and interpretation
of results difficult. Enzyme activity assays now predomi-
nate the recent literature, because mass assays have
been shown to be less accurate for risk stratification, be-
cause of their ability to only detect a smaller amount of
Lp-PLA
2
, particularly that associated with HDL.
75,76
In a recent review considering 17 studies of varying
designs that investigated the Mediterranean diet and its
components, the authors concluded that this dietary
pattern has the potential to lower PAF and Lp-PLA
2
lev-
els.
30
However, the scope of that review was limited to 1
database, and 12 of the 17 included studies examined
individual foods, alcohol, or supplements such as fish
oil and eicosapentaenoic acid, and not dietary patterns,
which are more translatable and relevant across popula-
tions. In the present review, we aimed to comprehen-
sively investigate the association between overall dietary
patterns and their effect on PAF and Lp-PLA
2
as novel
inflammatory biomarkers.
MATERIALS AND METHODS
For this systematic review, we followed the require-
ments of the Preferred Reporting of Systematic Reviews
and Meta-Analyses (PRISMA) statement (Supporting
Information online), and the review was registered in
July 2021 with the International Prospective Register of
Systematic Reviews (PROSPERO no. CRD42020169666;
available at http://www.crd.york.ac.uk/PROSPERO).
Search strategy
The databases PubMed, Embase, CINAHL, and
Cochrane CENTRAL were searched for relevant studies,
with backward citation checking of relevant reviews re-
trieved in the search. A search for trial protocols through
the ClinicalTrials.gov website (www.clinicaltrials.gov)
and World Health Organization International Clinical
Trials Registry Platform (https://apps.who.int/trialsearch/)
was also performed. Databases were searched from incep-
tion; the search date was February 21, 2020, with an up-
date to the search performed on February 7, 2021. Table 1
lists PICOS criteria (ie, participants, intervention, compa-
rators, outcomes, and study designs) used to identify stud-
ies for inclusion. Eligible studies in any language were
considered, provided they were full articles published in a
peer-reviewed journal.
A comprehensive search strategy was developed by
the research team in conjunction with an experienced
librarian. Terms used in the literature search included
PAF, platelet-activating factor, Lp-PLA
2
, lipoprotein-as-
sociated phospholipase A2, diet, and variations of these
terms. The complete search strategy is available in the
Supporting Information online.
Data management and extraction
Search results were imported into Endnote, version
X9.3.3,
77
for de-duplication, then uploaded to
Covidence
78
for removal of duplicates and screening.
Screening of titles and abstracts against the inclusion
criteria was undertaken independently and in duplicate
by 2 researchers. Full-text articles were then reviewed
independently and in duplicate by 2 researchers and
screened for inclusion criteria. Disagreements were re-
solved by discussion or by a third reviewer.
Data extraction was performed by populating data-
extraction tables for multiple study designs from the
Cochrane Handbook for Systematic Reviews of
Interventions,
79
which were further adapted to extract
Table 1 PICOS criteria for inclusion and exclusion of studies
Parameter Inclusion criteria Exclusion criteria
Participants Adults 18 y Aged <18 y
Intervention Studies examining diet assessed by dietary patterns,
dietary scores, dietary indices, and food patterns
Studies reporting animal or
cellular models, or that analyzed
consumption of single nutrients or
foods rather than a dietary pattern
Comparator Any/none Any/none
Outcome Any measurement of systemic inflammation using PAF and/or
Lp-PLA
2
. Secondary outcomes included other reported novel
markers of inflammation
Other cardiovascular
disease outcomes
Study design Observational (eg, prospective cohort, retrospective cohort, cross sectional,
longitudinal, case-control, case series), intervention and
randomized controlled trials
None
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additional information during this stage. Data extrac-
tion was piloted on included articles reporting 3 differ-
ent study designs, and then was amended to a final
format. Data extraction was undertaken by 1 researcher
and independently reviewed for accuracy by another
researcher.
Data extracted included author, date published,
study design, level of evidence, population, sex, country,
age, type of dietary pattern, control group, sample size,
and study duration. Primary outcomes extracted were
PAF levels, PAF-induced platelet aggregation in plate-
let-rich plasma, specific activities of plasma lyso-PAF
and PAF-AH, and LP-PLA
2
mass and activity.
Secondary outcomes extracted were any reported bio-
markers identified as novel (ie, not recognized as a
common inflammatory marker by the research team)
and related to CVD. Study authors were contacted by
email for additional information if required data had
not been published.
Outcomes
The primary outcomes included mean net change in
outcome measurements (ie, blood PAF, lyso-PAF, and
PAF-AH levels; Lp-PLA
2
mass and/or activity; or plate-
let aggregation induced by PAF) over the duration of
the trial for interventions. Mean net change is the
change from baseline to end point in the intervention
group minus the change from baseline in the control
group, or mean net change between baseline and end
point for single-arm studies. Outcomes extracted for
observational studies were a comparison of outcome
measurements between dietary patterns.
Quality assessment
The quality of included studies was assessed indepen-
dently and in duplicate using the Academy of Nutrition
and Dietetics Quality Criteria Checklist (Table 3).
80
Four relevance questions and 10 quality questions were
rated yes or no, ranging from clarity of research ques-
tion, selection bias, randomization, dropout, blinding,
clarity of intervention description, validity of measures,
appropriateness of statistical analyses, and conclusions
drawn and funding sources. A positive score was deter-
mined by “Yes” answers to questions 2, 3, 6, and 7, and
at least 1 additional “Yes” on the other questions. If a
“No” was the answer to 1 of questions 2, 3, 6, and 7
overall, and there were 8 “Yes” answers, the study was
rated positive. If answers to 2, 3, 6, and 7 were “No,” the
study was rated as neutral. The study received a nega-
tive score if 6 of the 10 questions were responded to
with “No.”
Data synthesis
A quantitative synthesis of the data was unable to be
performed because of substantial diversity in methodol-
ogy, dietary patterns, and measurements for outcomes
of interest. As such, a narrative review was performed.
Meta-bias(es)
To assess whether reporting bias was present in inter-
vention studies, an investigation of whether each study’s
protocol had been published before commencement of
the trial was undertaken. For all studies published after
July 1, 2005, the Clinical Trial Register of the
International Clinical Trials Registry Platform of the
World Health Organization was searched and outcome
reporting bias was assessed on the basis of whether se-
lective reporting of outcomes were present.
RESULTS
Figure 3 presents the process and PRISMA flowchart
for study selection. After deduplication, we identified
652 articles through the literature search. After review-
ing titles and abstracts, 56 articles were relevant for full-
text review. Exclusion of full-text articles was based
largely on the lack of examination of a dietary pattern.
Sixteen articles were eligible and included for narrative
synthesis.
Table 2
17,81–95
lists the characteristics of included
studies. The majority of studies were undertaken in
Greece (n ¼5) and the United States (n ¼3). Two stud-
ies were undertaken in South Korea and 1 each in
Taiwan, India, Sweden, Iran, Spain, and Canada.
Specific dietary patterns identified in the literature in-
cluded “Mediterranean” dietary patterns, “vegetarian”
dietary patterns, and “other heart healthy” dietary pat-
terns (which included the Dietary Approaches to Stop
Hypertension, or DASH, pattern; Living Heart dietary
pattern; National Cholesterol Education Program die-
tary pattern; and a dietary pattern that replaced refined
carbohydrates with whole grains and legumes and more
vegetables). A posteriori dietary patterns were also
reported and highlighted different patterns consumed
across different population groups (namely in Greece,
Sweden, and Iran). Data relating to primary and sec-
ondary outcomes were extracted from 7 randomized
controlled trials (RCTs), 2 non-RCTs, 2 pre-post or sin-
gle-arm studies, and 1 fixed-sequence intervention trial.
The remaining 4 studies were cross-sectional.
In the 4 intervention studies examining
Mediterranean dietary patterns, 2 showed significant
reductions in PAF-induced aggregation of platelets in
both healthy participants and people with type 2
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diabetes, with the latter showing a much greater re-
sponse.
17,88
A post hoc study of the Prevenci
on con
Dieta Mediterr
anea trial found a significant favorable
change in Lp-PLA
2
activity levels in HDL after a 1-year
Mediterranean dietary intervention supplemented with
extra-virgin olive oil, when compared with a low-fat
diet. However, no significant difference was seen in the
Mediterranean diet group supplemented with nuts,
when compared with a low-fat diet.
81
The other study
was a fixed-sequence study that presented Lp-PLA
2
as
percentage change only, which limited the usefulness of
the data.
91
In that study, the small number of people
whose HDL cholesterol was noted to have increased
(n ¼6 compared with n ¼6 with reduced HDL), and
there was a trend toward a favorable impact on Lp-
PLA
2
; however, the results were not significant.
91
Four studies examined vegetarian dietary patterns.
One study was an RCT and compared similar Indian
vegetarian diets that differed in the addition of either
coconut or peanuts.
83
Results showed PAF reduced
within the peanut group, but no between-group analysis
was conducted.
83
In the single cross-sectional study in
Taiwan,
95
Lp-PLA
2
activity was less favorable in omni-
vores. However, overall, both groups had low average
Lp-PLA
2
levels, which could be due to Asian ethnicity.
96
In the 2 papers that reported pre-post single-arm stud-
ies, 1 reported significantly lower Lp-PLA
2
levels after
4 weeks of a raw, vegan dietary intervention.
89
The
other reported a marginally significant increase in Lp-
PLA
2
after 21 days of a largely vegetarian Pritikin die-
tary pattern.
90
Heart-healthy dietary patterns were investigated in
5 studies, 4 of which were RCTs. Two of the RCTs fo-
cused on the replacement of refined grains with whole
grains, increased vegetables, and addition of legumes in
a South Korean population sample.
84,85
There were sig-
nificant reductions in Lp-PLA
2
levels after a 12-week
intervention. Another RCT evaluated a 3-week heart-
healthy dietary pattern (the Living Heart Diet) com-
bined with exercise and found significant reductions in
Lp-PLA
2
compared with participants receiving usual
care.
86
A pre-post study with a heart-healthy dietary in-
tervention that was broadly similar to the Living Heart
Diet found no significant difference in Lp-PLA
2
levels
Figure 3 PRISMA flowchart of article selection.
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Table 2 Summary of results
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
Shankar (2017)
India
83
RCT Healthy adults n ¼58 (31 M, 27 F) Age:
23.8 64.8 y Coconut group
weight: 59.8 610.2 kg
Peanut group BMI:
56.8 67.3 kg/m
2
90 d n ¼27 Vegetarian dietary pattern
with Coconut group: Balanced
vegetarian Yogic diet (based on
grains, pulses, fruits, and vege-
tables) þ100 g/d fresh coconut
n¼31 Vegetarian dietary pattern
with Peanut group: Balanced
vegetarian Yogic diet þ45 g
peanuts þ22 g/d peanut oil
PAF pg/mL (ELISA) Vegetarian
with coconut group: Pre:
186.88 6383.11 Post:
194.52 6174.40; P¼0.947
Vegetarian with peanut
group: Pre: 375.25 6705.03
Post: 139.45 6144.8;
P50.05 Between-group dif-
ference: P¼0.224 PON1 ng/
mL Vegetarian with Coconut
group: Pre: 2679.78 6878.8
Post: 2755.82 6918.3;
P¼0.67 Vegetarian with pea-
nut group: Pre:
2221.68 6647.7 Post:
2773.59 61145.7;
P50.001 Between-group dif-
ference: P¼0.95 MPO ng/mL
Vegetarian with Coconut
group: Pre: 657.92 6599.22
Post: 677.95 6551.65;
P¼0.84 Vegetarian with
Peanut group: Pre:
648.57 6529.38 Post:
924.26 6724.24; P50.006
Between-group difference: P
¼0.17
Kim et al
(2016)
South
Korea
84
RCT Nonobese adults with
impaired fasting
glucose or newly
diagnosed
diabetes
n¼80 (M:F ratio: not
reported) Age: 40–70 y
Weight: not reported BMI:
not reported
12 wk n¼40 Whole-grain dietary pattern
Whole-grain diet group: Refined
rice replaced with 33% legumes,
33% barley, 33% wild rice 3/d
þ6 servings of vegetables
(180–420 g)
n¼40 Usual diet (control) group:
Usual Korean diet with refined
rice
Plasma Lp-PLA
2
activity (nmol/
mL/min) (high-throughput ra-
diometric assay) Whole-grain
diet group: Pre: 28.0 61.2
Post: 25.7 61.11; P>0.05
Usual diet group: Pre:
30.1 61.64 Post: 30.3 61.61;
P>0.05 Between-group dif-
ference (change adjusted
for baseline): P<0.001
Unstimulated PBMC Lp-PLA
2
activity (nmol/mL/min) Whole-
grain diet group: Pre:
2.16 60.12 Post:
1.90 60.12; P<0.01 Usual
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
diet group: Pre: 2.00 60.12
Post: 2.28 60.13; P<0.01
Between-group difference
(change adjusted for base-
line): P<0.001 LDL particle
size (nm) Whole-grain diet
group: Pre: 24.4 60.15 Post:
24.6 60.17; P<0.001 Usual
diet group: Pre: 24.1 60.12
Post 24.1 60.13; P>0.05
Between-group difference
(change adjusted for base-
line): P50.001
Kim et al
(2014)
South
Korea
85
RCT Adults with impaired
fasting glucose,
impaired glucose
intolerance, or
newly diagnosed
T2DM
n¼99 (67 M, 32 F) Age, y:
Whole-grain group:
56.3 61.2 Usual diet (con-
trol) 55.4 61.5 y Weight:
not reported BMI (in lieu of
weight): Whole-grain diet
group: 24.0 60.38 kg/m
2
Usual diet (control):
24.1 60.44 kg/m
2
12 wk n¼50 Whole-grain dietary pattern
Whole-grain diet group: Refined
rice replaced with 33% legumes
(black soybeans), 33% barley,
33% wild rice 3/d þ6 servings
of vegetables (180–420 g)
n¼49 Usual diet (control) group:
Usual Korean diet with refined
rice
Plasma Lp-PLA
2
activity (nmol/
mL/min) (high-throughput ra-
diometric assay) Whole-grain
diet group: Pre: 30.2 61.32
Post: 27.8 61.08; P<0.01
Usual diet group: Pre:
29.16 61.29 Post:
29.84 61.28; P>0.05
Between-group difference
(change adjusted for base-
line): P<0.001 Unstimulated
PBMC Lp-PLA
2
activity (nmol/
mL/min) Whole-grain diet
group: Pre: 2.15 60.11 Post:
1.86 60.11; P<0.001 Usual
diet group: Pre: 1.99 60.11
Post: 2.27 60.13; P<0.01
Between-group difference
(change adjusted for base-
line): P<0.001 LDL particle
size (nm) Whole-grain diet
group: Pre: 24.3 60.12 Post:
24.5 60.14; P<0.01 Usual
diet group: Pre: 24.11 60.10
Post: 24.01 60.14; P>0.05
Between-group difference
(change adjusted for base-
line): P50.048
24 wk
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
Wooten et al
(2013)
United
States
86
RCT (5-arm drug trial) Data
extracted for 2 arms only: (1)
Living Heart Diet group (diet
and exercise, no medication)
and (2) usual care (control) only
Dyslipidemic, HIV-pos-
itive adults treated
with highly active
antiretroviral
therapy
n¼107 (98 M, 9 F) Age:
44.8 6. 9 y Weight: Living
Heart Diet 81.6 62.0 kg
Usual care (control)
78.4 61.9 kg
n¼22 Heart Healthy dietary pat-
tern, Living Heart Diet group:
Carbohydrate, 50% energy; fat,
30% energy (<7% SFA, 15%
MUFA, 8% PUFA, minimal TFA),
cholesterol <200 mg/d, fiber
20–30 g/d þ2 placebos. Aerobic
and resistance exercise: 75–
90 min 3/wk.
n¼19 Usual care (control) group:
General advice on heart-healthy
diet and exercise þ2 placebos.
Participants given booklet titled
Nutrition and Your Health
Lp-PLA
2
mass (ng/mL
1
)
mean 6SE (ELISA, PLAC test)
Living Heart Diet group: Pre:
387.2 617.9 Post:
323 627.2; P<0.05 Usual
care (control) group Pre:
415.1 631.7 Post:
402.2 625.3; P>0.05
Between-group difference
(adjusted for baseline): P
<0.05 RANTES (ng/mL
1
)
mean6SE Living Heart Diet
group: Pre: 40.0 63.2 Post:
55.0 611.3; P>0.05 Usual
care (control) group: Pre:
42.4 65.9 Post: 50.9 610.4;
P>0.05 Between-group dif-
ference (adjusted for base-
line): P>0.05
Rizos et al
(2011)
Greece
87
RCT: only cross-sectional data
extracted Results extracted for
baseline data only (all 3 arms),
after dietary intervention but
before randomization to drug
interventions
Adults with impaired
fasting plasma glu-
cose, mixed dysli-
pidemia, and stage
1 hypertension
n¼151 (73 M, 78 F) Age: 60
(46–70) y Weight: not
reported BMI (in lieu of
weight): Group 1: 29 64
kg/m
2
Group 2: 29 65 kg/
m
2
Group 3: 28 64 kg/m
2
12 wk n¼151 DASH dietary pattern: all
groups
N/A Cross-sectional data extracted
Plasma Lp-PLA
2
activity (nmol/
mL/min) (TCA precipitation)
Group 1 (RT): 57 617 Group 2
(RI): 53 611 Group 3 (RO):
58 614 Plasma Lp-PLA
2
mass
(ng/mL) (ELISA, PLAC test)
Group 1: 277 640 Group 2:
301 620 Group 3: 304 634
Small dense LDL cholesterol
(mg/dL) [mmol/L), median
(range)] Group 1: 17 (2–69)
[0.4 (0.1–1.8)] Group 2: 15 (7–
44) [0.4 (0.2–1.1)] Group 3: 17
(2–78) [0.4 (0.1–2)] LDL parti-
cle size (A
˚)Group 1: 261 67
Group 2: 262 64 Group 3:
262 66
Karantonis et al
(2005
Greece
88
Non-RCT T2DM: managed with
diet or OHAs.
Healthy age- and
weight-matched
adults
n¼67 (35 M, 32 F) Age: 56
(26–74) y Weight: 77 69kg
4 wk Total n ¼45 2 groups: Healthy:
n¼22; T2DM: n ¼23]
Mediterranean-type dietary pat-
tern: Based on fast-food meals
pretested for ability to reduce
Total n ¼22 (T2DM: all) Usual diet PAF EC
50
(PAF-induced platelet
aggregation in PRP) Healthy
group: Pre: 1.45 61.47 Post:
2.70 62.59; P50.023
T2DM group: Pre: 1.02 61.38
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
PAF-induced aggregation
in vitro (TPL)
Post: 2.40 64.65; P50.019
Usual/control (T2DM) group:
Pre: 0.774 60.522 Post:
0.831 60.5; P¼0.285
Roberts et al
(2006)
USA
90
Single-arm trial Overweight or obese
adult males
n¼22 (22 M) Age : 62.8 (46–
76) y Weight: 103.4 622.9
kg
21 d n ¼22 Vegetarian dietary pattern
Low-fat, Pritikin diet 5 serv-
ings/d whole grains, 4 serv-
ings/d vegetables 3 servings/d
fruit. Protein from plant sources,
nonfat dairy 2 servings/d;
fish/fowl 85–140 g/wk. Minimal
SFA and trans FA intake; no
added fats, sugars þ45–60 min
walking/d
N/A PAF-AH activity (nmol PAF/min/
mg protein) (solid-phase chro-
matography with liquid scintil-
lation) Pre: 23.4 60.6 Post:
24.6 60.6; P50.05 PON1
activity per mg/HDL Pre:
669.2 695.6 Post:
684.8 699.7; P>0.05
Observational studies
Hlebowicz et al
(2011)
Sweden
94
Prospective cohort study Adult men and
women No diagno-
sis of diabetes (IFG
eligible) or previ-
ous history of CVD
n¼4999 (2040 M; 2959 F)
Age: M (46–73) y F (45–73)
y Weight: not reported
N/A n ¼4999 A posteriori dietary pat-
terns identified by cluster analy-
sis Six dietary patterns 1. Many
foods and drinks 2. Fiber-rich
bread 15% of energy from fiber-
rich bread 3. Low-fat and high-
fiber foods 10.5% of total en-
ergy from fruit, 8% from low-fat
milk, both high-fat and low-fat
meats and sweets 4. White
bread 16% of total energy from
white bread, other major energy
sources were low-fat margarine,
both high-fat and low-fat meats
and sweets 5. Milk-fat pattern
12% of total energy from but-
ter/rapeseed oil spread, other
major energy sources included
cheese, whole milk, þsome
white bread and sweets 6.
Sweets and cakes pattern 18%
of total energy from sugar,
sweets, jam; other major energy
sources were cakes, biscuits, and
soft drinks
N/A General linear model (controlled
for age, total energy, season,
%body fat, WHR) Lp-PLA
2
mass (ng/mL
1
) (ELISA, PLAC
test) Many foods and drinks
pattern (n ¼1399): Male:
287.39 63.76 Female:
258.72 62.65 Fiber-rich
bread pattern (n ¼460):
Male: 286.51 65.48
Female: 257.15 65.17 Low-
fat and high-fiber foods pat-
tern (n ¼755): Male:
284.55 66.97* Female:
250.64 63.26* White-bread
pattern (n ¼713): Male:
291.74 64.22 Female:
263.62 64.40 Milk-fat pat-
tern (n ¼638): Male:
308.03 64.84** Female:
269.25 64.23** Sweets and
cakes pattern (n ¼1034):
Male: 296.33 64.17
Female: 265.42 63.19
Male: P5.009; Female:
P50.004 Lp-PLA
2
activity
(ng/mL
1
) (high-throughput
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
radiom etric assay) Many
foods and drinks pattern
(n ¼1399): Male: 49.17 60.61
Female: 41.59 60.42* Fiber-
rich bread pattern (n ¼460):
Male: 50.70 60.89 (lowest as-
sociation) Female:
42.98 60.82 Low-fat and
high-fiber foods pattern
(n ¼755): Male: 47.58 61.13
(highest association) Female:
42.01 60.52 White-bread
pattern (n ¼713): Male:
49.89 60.68 Female:
44.06 60.70 (highest associ-
ation) Milk-fat pattern
(n ¼638): Male: 50.09 60.78
Female: 43.27 60.67 Sweets
and cakes pattern (n ¼1034):
Male: 49.93 60.67 Female:
43.40 60.51 Male: P¼.291
Female: P50.007
Chen et al
(2011)
Taiwan
95
Cross-sectional Healthy, adult, non-
smoking women
n¼363 (363 F) Age:
51.9 69.9 y Weight: not
reported BMI (in lieu of
weight): Omnivores:
23.28 63.47 kg/m
2
Vegetarians: 22.87 62.94
kg/m
2
N/A n ¼173 Vegetarian dietary pattern
Lacto-ovo vegetarian
n¼190 Omnivore dietary pattern Lp-PLA
2
activity 10
3
lmol/min/
mL (PAF acetylhydrolase color-
imetric assay) Vegetarian:
18.32 67.19 Omnivore:
20.22 68.13 Between-group
difference: P<0.05
Univariate linear regression
Vegetarian: b520.19
(3.63, 0.016); P<0.05
Multivariate regression (age
and BMI) Vegetarian: b5
21.79 (3.58, 0.01);
P<0.05
Intervention studies
Hernaez et al
(2020)
Spain
81
RCT T2DM or 3 cardio-
vascular risk factors
(cholesterol, hyper-
tension, BMI,
smoking, family
history)
n¼358 (131 M, 227 F)
Age : 66.8 65.8 y
Weight: not reported
BMI: mean not reported
1 y Total n ¼239
2 groups:
Mediterranean diet supplemented
with EVOO: n ¼120;
Mediterranean diet supple-
mented with nuts: n ¼119
Total n ¼119
Low-fat diet
PAF-AH activity in HDLs (PAF
acetylhydrolase colorimetric
assay) (1-y change):
Mean change (95%CI)
Mediterranean diet with EVOO vs
control:
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
7.48%(0.17–14.8)
Mediterranean diet with nuts vs
control:
3.39% (3.64 to 10.4)
Makariou et al
(2019)
Greece
82
RCT
Results extracted for single-arm
control group only (diet þno
supplement)
Adults with metabolic
syndrome
n¼50 (25 M, 25 F)
Age: 53 (37–67) y
Weight: 89.0 613.4 kg
3mo n¼25
Heart Healthy Dietary Pattern
NCEP ATP III guidelines
Fat 25–35% energy (<7% SFA, re-
duced TFA), dietary cholesterol
<200 mg/d. Most dietary fat
unsaturated; simple sugars
limited
N/A Heart-healthy dietary pattern
Lp-PLA
2
activity (nmol/mL/min) (TCA
precipitation)
Pre: 57.4 613.3
Post: 52.7 612.4; P>0.05
sdLDL cholesterol mg/dL
Pre: 7 (0–22)
Post: 5 (2–25); P>0.05
sdLDL proportion, %
Pre: 3.8 62.8
Post: 3.3 62.3; P>0.05
Mean LDL size (nm)
Pre: 266.5 63.9
Post: 267 63.5; P>0.05
Antonopoulou
et al (2006)
Greece
17
Non-RCT Type 2 diabetes: man-
aged with diet or
OHAs.
Healthy age- and
weight-matched
adults
n¼69 (37 M, 32 F)
Age: 53 (26–70) y
Weight: 77 69kg
4 wk Total n ¼46
2 groups:
Healthy: n ¼22; T2DM: n ¼24]
Mediterranean-type dietary
pattern:
Based on catering company–sup-
plied meals pretested for ability
to reduce PAF aggregation
in vitro (TL)
Total n ¼23
(T2DM: all)
Usual diet
PAF EC
50
(PAF-induced platelet
aggregation in PRP)
Healthy group:
Pre: 1.4 61.4
Post: 2.70 62.6; P50.023
T2DM group:
Pre: 0.76 60.5
Post: 4.2 61.2; P<0.001
Baseline significantly different be-
tween groups
Usual/control (T2DM) group:
Pre: 0.77 60.52
Post: 0.83 60.5; P¼0.285
Najjar et al
(2018)
United
States
89
Single-arm trial Adults with hyperten-
sion and
dyslipidemia:
SBP 140 mmHg or
DBP 90 mmHg,
LDL-C 100 mg/dL
and BMI 25 kg/
m
2
.
n¼31 (10 M, 21 F)
Age: 53.4 (32–69) y
Weight: 108.1 65.1 kg
4wk n¼31
Vegetarian dietary pattern (vegan,
raw)
Vegan, raw plant-based diet: raw
fruits, vegetables, avocado, seeds,
and plant foods dehydrated to
temperatures 160F ad libitum.
Cooked foods, animal products,
free oils, soda, alcohol, and coffee
were excluded.
N/A Lp-PLA
2
mass (ng/mL) (not
reported)
Vegan raw plant–based diet:
Pre: 252.3 6136.3
Post: 210.7 6119.1; P50.001
MPO (pmol/L)
Pre: 124.1 658.1
Post: 104.5 653.6; P¼0.056
sdLDL cholesterol mg/dL
Pre: 33.7 611.5
Post: 23.7 68.7; P<0.0005
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
Richard et al
(2014)
Canada
91
Fixed-sequence intervention Nonsmoking male
adults with meta-
bolic syndrome
No CHD or diabetes;
not taking lipid-
lowering or antihy-
pertensive
medication
n¼26 (26 M)
Age: 49.4 (24–62) y
Weight: 98.3 617.6 kg
10 wk n¼26
Mediterranean dietary pattern
5-wk controlled feeding interven-
tion: high in whole grains,
legumes, fruits, vegetables, fish,
olive oil, nuts, and moderate
amount of red wine
n¼26
Standard North American diet—
the intervention diet followed a
5-wk run-in, which served as the
control
PAF-AH HDL protein (fold
change) (mass spectrometry
iTRAQ)
Med diet vs control ¼1.10;
P¼0.845
error factor ¼5.93 (an error factor
value >2 indicates the ratios
vary greatly from peptide to
peptide)
Seyedi et al
(2020) Iran
92
Cross-sectional Adult men and
women
5 of: TC >200 mg/
dL, LDL C
>100 mg/dL,
HDL C <40 mg/dL
(M), <50 mg/dL
(F), waist circ. ¼
>102 cm (M), >88 cm
(F), SBP
>140 mmHg, DBP
>90 mmHg, anti-
hypertensive medi-
cation, age 45 y
(M), 55 y (F),
smoker
n¼470 (114 M, 356 F)
Age: 40–70 y
Weight: not reported
N/A n ¼470
A posteriori dietary pattern identi-
fied by factor analysis. Three di-
etary patterns calculated:
1. Healthy (reference pattern):
high in fresh and dried fruits,
olives, high-and low-fat dairy
products, poultry and fish, liquid
oils, and canned products
2. Semi-Mediterranean:
characterized by legumes, pota-
toes, eggs, red meats, tea, and
coffee.
3. Western:
dominated by carbonated drinks,
fast foods, salty snacks, mayon-
naise, and organ meats
N/A Lp-PLA
2
mass ng/mL (ELISA)
Univariate linear regression
Western:
b50.35 (0.11, 0.78); P50.026
Semi-Mediterranean:
b50.12 (3.52, 0.16);
P50.043
Multivariate linear regression (age,
BMI, activity, EI, FBG, hormone
therapy, lipid-lowering drugs)
Western:
b51.32 (1.05, 1.64); P50.035
Semi-Mediterranean
b¼0.01 (0.16, 0.43); P¼0.75
Detopoulou et
al (2015
Greece
93
Cross-sectional Healthy adults
No history of CVD or
inflammatory dis-
ease, no current
respiratory infec-
tion, dental prob-
lems, renal/hepatic
abnormalities. Men
were age- and
BMI-matched to
women.
n¼106 (48 M, 58 F)
Age : 44 (31–57) y
Weight: not reported
BMI (in lieu of weight):
27.5 kg/m
2
N/A Mediterranean Dietary Pattern (and
2 miscellaneous other patterns):
1. A priori MedDietScore (as devel-
oped by Panagiotakos et al,
2006):
based on nonrefined cereal, fruits,
vegetables, potatoes, legumes,
olive oil, fish, red meat, poultry,
full-fat dairy products, and
alcohol).
2. Calculation of dietary antioxidant
capacity
3. Six a posteriori dietary patterns
identified by principal compo-
nent analysis
1: Fruits, nuts, and herbal drinks
None Total PAF (fmol/mL), median
(lower-upper quartile) (PAF-in-
duced platelet aggregation to-
ward washed rabbit platelets)
Male: 82 (29–372)
Female: 152 (43–944)
Total: 119 (34–578)
MedDietScore: Men only (n ¼48);
Adjusted for age, sex, EI/BMR
Bound PAF
r¼0.26; P¼0.08
Total PAF
r¼0.30, P>0.05
Dietary antioxidant capacity: ad-
justed for age, sex, EI/BMR
Total PAF (pmol/mL)
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
2: Legumes, vegetables, poultry
and fish
3: Low consumption of low-fat
dairy, high consumption of full-
fat dairy, cheeses, alcohol, and
red meat
4: Coffee and low intake of whole-
wheat products
5: Refined cereals and full-fat dairy,
cheeses
6: Whole-wheat products and olive
oil
DAC FRAP: r¼0.197; P¼0.06
DAC-TRAP: r50.211; P50.04
DAC TEAC: r50.200; P50.05
Lyso-PAF-AT (nmol/min/mg)
DAC FRAP: r50.200; P50.05
DAC-TRAP: r¼0.171; P¼0.1
DAC TEAC: r¼0.146; P¼0.1
Lp-PLA
2
(nmol/min/mL) (TCA
precipitation)
DAC FRAP r¼0.090; P¼0.30
DAC TRAP r¼0.119; P¼0.20
DAC TEAC r¼0.110; P¼0.30
Free PAF, bound PAF, PAF-CPT, and
PAF-AH: all results not significant.
A posteriori dietary patterns:
Linear regression adjusted for age,
sex, EI/BMR, and other dietary
patterns
Free PAF pmol/mL
Legumes, vegetables, poultry, and
fish dietary pattern:
0.157 60.087; P¼0.07
Total PAF pmol/mL
Coffee and low intake of whole-
wheat products dietary pattern:
0.147 60.08; P¼0.06
Lyso-PAF-AT (nmol/min/mg)
Fruits, nuts, herbal drinks:
1202 6652; P¼0.06
Whole-wheat products, olive oil di-
etary pattern:
1273 6571; P50.02
Cox proportional hazards regres-
sion (adjusted for age, total en-
ergy, season, %body fat, WHR,
and smoking)
Tertile 1: lowest adherence; tertile 3:
highest adherence
Lp-PLA
2
mass (ng/mL
1
)
Female:
Low-fat and high-fiber foods
pattern:
(continued)
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Table 2 Continued
Reference and
study location
Study design Inclusion criteria Population mean 6SD or
(range)
Duration Dietary pattern/intervention Control Outcomes (measurement method)
mean 6SD or (range)
a
Tertile 2: OR, 0.89 (0.71, 1.12)
Tertile 3: OR, 0.69 (0.54, 0.87)
P¼0.002
Sweets and cakes pattern:
Tertile 2: OR, 1.20 (0.96, 1.50)
Tertile 3: OR, 1.29 (1.02, 1.62)
P¼0.030
No significance when those with
past change in diet were ex-
cluded (P¼0.098 and P¼0.149,
respectively)
Data for other patterns not
reported
Lp-PLA
2
activity (ng/mL
1
)
Male:
Low-fat and high-fiber foods
pattern:
Tertile 2: OR, 0.92 (0.61, 1.38)
Tertile 3: OR, 0.62 (0.40, 0.96)
P¼0.036
No significance when those with
past change in diet were ex-
cluded: P¼0.352
Milk-fat pattern
Tertile 2: OR, 1.17 (0.85, 1.62)
Tertile 3: OR, 1.50 (1.10, 2.05)
P¼0.011
P50.009 when those with past
change in diet were excluded
Data for other patterns not
reported
Abbreviations: AH, acetylhydrolase; BMI, body mass index; BMR, basal metabolic rate; CHD, coronary heart disease; circ., circumference; CVD, cardiovascular disease; DAC, dietary antioxidant capacity; DASH, Dietary Approach to Stop Hypertension;
DBP, diastolic blood pressure; EC
50
, half-maximal effective concentration; ELISA, enzyme-linked immunosorbent assay; EVOO, extra virgin olive oil; F, female; FA, fatty acid; FBG, fasting blood glucose; FRAP, ferric-reducing antioxidant power; HDL,
high-density lipoprotein; IFG, impaired fasting glucose; iTRAQ, isobaric tags for relative and absolute quantitation; LDL-C, low-density lipoprotein cholesterol; Lp-PLA
2
, lipoprotein-associated phospholipase A2; M, male; MPO, myeloperoxidase;
MUFA, monounsaturated fatty acid; N/A, not applicable; OHA, oral hypoglycemic agent; OR, odds ratio; PAF, platelet activating factor; PBMC, peripheral blood mononuclear cells; PRP, platelet-rich plasma; PON1, serum paraoxonase and arylesterase
1; PUFA, polyunsaturated fatty acid; RCT, randomized controlled trial; SBP, systolic blood pressure; sdLDL, small dense low-density lipoprotein; SE, standard error; SF, saturated fat; SFA, saturated fatty acids; T2DM, type 2 diabetes mellitus; TC, total
cholesterol; TCA, trichloroacetic acid; TEAC, trolox-equivalent antioxidant power; TFA, trans fatty acids; TRAP, total radical-trapping antioxidant parameters; WHR, waist to hip ratio.
a
Bold indicates statistically significant results P0.05. For some observational studies, only statistically significant results (or results approaching significance) are included, for brevity.
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after 3 months.
82
In another RCT in which only cross-
sectional data were extracted, Lp-PLA
2
activity
was reported after a 12-week Dietary Approaches
to Stop Hypertension diet run-in period before
randomization.
87
Three cohort studies examined posteriori dietary
patterns. One study in Sweden used cluster analysis to
identify 6 novel dietary patterns, and the authors
reported somewhat inconsistent findings across male
and female participants.
94
However, across both sexes,
the low-fat and high-fiber dietary pattern (10.5% of total
energy derived from fruit, 8% energy from low-fat milk,
both high-fat and low-fat meats, and sweets) was associ-
ated with lower Lp-PLA
2
levels, whereas the milk-fat pat-
tern (12% of total energy derived from a butter/rapeseed
oil spread and other major energy sources that included
cheese, whole milk, and, to a lesser extent, white bread
and sweets) was associated with higher Lp-PLA
2
levels.
94
A second study in Greece also identified 6 unique dietary
patterns and found a pattern rich in whole-wheat prod-
ucts with olive oil was inversely correlated with levels of
lyso-PAF acetyltransferase (an enzyme related to PAF
metabolism).
93
In the same study, a high dietary antioxi-
dant capacity score (but not a Mediterranean diet score)
was inversely associated with total PAF after adjustment
for confounders.
93
The third study identified 3 unique
dietary patterns: (1)a healthy dietary pattern (ie, high in
fruits, dried fruit, olives, high- and low-fat dairy prod-
ucts, poultry and fish, liquid oils, and canned products),
(2) semi-Mediterranean dietary pattern (ie, legumes, po-
tatoes, eggs, red meats, tea, and coffee), and (3) a
Western dietary pattern (dominated by carbonated
drinks, fast foods, salty snacks, mayonnaise, and organ
meats).
92
Compared with the healthy dietary pattern, the
Western dietary pattern was associated with less favor-
able Lp-PLA
2
levels. After accounting for confounders,
the semi-Mediterranean dietary pattern showed no effect
on Lp-PLA
2
with the healthy dietary pattern as the
referent.
Four novel biomarkers were identified in the litera-
ture as secondary outcomes for this review: serum para-
oxonase and arylesterase 1 (PON1), myeloperoxidase
(MPO), RANTES (chemokine ligand 5; regulated on ac-
tivation, normal T-cell expressed and secreted), and
LDL particle size. PON1 is a cardioprotective enzyme
that prevents the accumulation of oxidized LDL and
promotes cholesterol efflux out of macrophages.
97
MPO
is an enzyme linked to inflammation and oxidative
stress and has been shown to be involved in all stages of
atherosclerosis.
98
RANTES is a pro-inflammatory cyto-
kine that induces leukocyte activation and migration
and is associated with a wide range of inflammatory dis-
orders.
99
LDL particle size can be a marker used in the
prediction of CVD. Small dense LDL particles are a
distinct LDL subclass that is more pro-atherogenic than
large LDL particles because they have a decreased affin-
ity for the LDL receptor, resulting in longer circulation
time; enter the arterial wall more easily; are more prone
to entrapment in the arterial wall; and are more suscep-
tible to oxidation.
100
A vegetarian diet supplemented with peanuts (but
not the same diet supplemented with coconut instead of
peanuts) resulted in a significant increase in PON1.
83
Similarly, MPO was significantly increased in the pea-
nuts-supplemented group but not the coconut group.
83
The largely vegetarian Pritikin dietary pattern showed
no effect on PON1 levels.
90
Similarly, a raw vegan dietary pattern intervention
significantly lowered small dense LDL particles and de-
creased levels of MPO (P¼0.056).
89
A heart-healthy in-
tervention resulted in no significant difference in
RANTES in either the usual-care or intervention
groups.
86
LDL particle size was significantly increased in
the whole-grain dietary pattern interventions compared
with a refined-grains dietary pattern.
84,85
Risk-of-bias assessment identified 6 positive, 10
neutral, and 0 negative articles (Table 3). Studies that
rated lower on the scale did so mostly because of inade-
quate description of follow-up methods and handling of
withdrawals and methods of blinding. There were no
discrepancies in outcome reporting when study reports
were checked against the Clinical Trial Register of the
International Clinical Trials Registry Platform of the
World Health Organization.
DISCUSSION
In this systematic review, we investigated the associa-
tion between overall dietary patterns and their effect on
PAF and Lp-PLA
2
as novel biomarkers of inflamma-
tion. There was a small number of published dietary
studies reporting these biomarkers. Thirteen of the 16
included studies reported Lp-PLA
2
and only 4 reported
PAF, with 1 study reporting on both markers. The pau-
city of research in this area is likely due to the novelty
of the markers, in addition to the difficulty in measur-
ing them and a lack of an established reference range
for PAF and Lp-PLA
2
activity in a normal, healthy
population.
However, a key finding from this review is that a
range of established dietary patterns broadly consistent
with country-specific dietary guidelines around the
world show promise in producing favorable changes in
these novel biomarkers. These included Mediterranean
dietary patterns, vegetarian dietary patterns, and other
heart-healthy dietary patterns. Conversely, dietary pat-
terns including foods that were more highly processed
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and reflective of Western diets were associated with un-
favorable outcomes.
The finding that Mediterranean dietary patterns
were associated with favorable changes in levels of both
PAF and Lp-PLA
2
post intervention is unsurprising.
The Mediterranean diet was associated with reduced
risk of CVD, including a reduction in events and deaths
in a recent systematic review, although the effect size
was small and the quality of evidence low to moder-
ate.
101
A previous systematic review that investigated
the Mediterranean diet or its components and PAF and
Lp-PLA
2
found a range of foods to have favorable
effects; the authors concluded that dietary patterns that
emphasize cereals, legumes, vegetables, fish, and wine
were worthy of additional investigation.
30
This study
also noted that research was lacking on olive oil (the
most characteristic component of Mediterranean diets).
Although not specific to these novel biomarkers, an-
other systematic review found that a Mediterranean die-
tary pattern was associated with lower levels of other
markers of inflammation and improved endothelial
function.
102
A Mediterranean diet intervention also sig-
nificantly improved dietary inflammatory index scores
(a measure of potential of diet to affect established in-
flammatory cytokines) compared with a low-fat diet in
people with coronary heart disease.
103
People with cardiometabolic conditions or risk fac-
tors may have greater responses to dietary intervention.
Results from 2 studies we included in the present review
suggested that Mediterranean dietary patterns may have
greater favorable effects on PAF-induced platelet activ-
ity in patients with type 2 diabetes who are treated with
both medication and diet, compared with healthy con-
trol study participants.
17,88
It is possible that this was
due to lower platelet resistance to PAF-induced platelet
aggregation in participants with type 2 diabetes at base-
line, compared with healthy participants, which pro-
vides greater scope for improvement because of their
naturally higher levels of platelet hyperactivity resulting
in increased activation and aggregation.
104
Furthermore, the results of the present study dem-
onstrated that vegetarian dietary patterns were associ-
ated with more favorable changes in levels of PAF and
Lp-PLA
2
. This is consistent with wider evidence sup-
porting cardiovascular benefits of minimally processed
plant-based diets, of which vegetarian dietary patterns
are a subset.
105
Vegetarian diets emphasizing foods low
in dietary fat may not confer the same benefits, because
they are lower in fats that contain anti-inflammatory
properties such as bioactive polar lipids (ie, phospholi-
pids, sphingolipids, glycolipids) found in olive and seed
oil, and higher-fat dairy products.
20
For example, in the
Roberts study,
90
participants consumed non-fat milk
that contained half the levels of PAF-inhibiting polar
lipids than did whole milk.
106
Other research has
highlighted potential benefits of full-fat dairy
Table 3 Risk-of-bias assessment
Reference Relevance questionsa Validity questionsbOverall
quality
rating
123412345678910
Karantonis et al (2005)
88
Neutral
Hernaez et al (2020)
81
Positive
Makariou et al (2019)
82
Positive
Shankar (2017)
83
Neutral
Kim et al (2016)
84
Neutral
Kim et al (2014)
8
5 Positive
Wooten et al (2013)
86
Positive
Rizos et al (2011)
87
Positive
Antonopoulou et al (2006)
1
7 Neutral
Najjar et al (2018)
89
Neutral
Roberts et al (2006)
90
Neutral
Richard et al (2014)
91
Positive
Seyedi et al (2020)
92
Neutral
Detopoulou et al (2013)
27
Neutral
Hlebowicz et al (2011)
94
Neutral
Chen et al (2011)
95
Neutral
Green = Yes; Yellow = Unclear; Grey = N/A; Red = No
a Relevance questions (n = 4):
1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group?
2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?
3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dietetics practice?
4. Is the intervention or procedure feasible?
b Validity questions (n = 10):
1. Was the research question clearly stated?
2. Was the selection of study subjects/patients free from bias?
3. Were study groups comparable?
4. Was method of handli ng withdrawals described?
5. Was blinding used to prevent introduction of bias?
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were intervening factors described?
7. Were outcomes clearly defined and the measurements valid and reliable?
8. Was the statistical analysis appropriate for the study design and type of outcome indicators?
9. Are conclusions supported by results with biases and limitations taken into consideration?
10. Is bias due to study’s funding or sponsorship unlikely?
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consumption, due to a greater bioavailability of high-
value nutrients such as vitamin D and other anti-
inflammatory microconstituents.
107,108
Within the current review, vegetarian diets with
and without dairy and/or eggs were associated with fa-
vorable outcomes. One observational study found lower
levels of Lp-PLA
2
in groups following a lacto-ovo vege-
tarian dietary pattern compared with groups who were
omnivores; however, the former group had higher levels
of high-sensitivity C-reactive protein than did the om-
nivore group.
95
These results are in contrast to those of
a recent systematic review and meta-analysis that found
vegetarian diets are associated with significantly lower
levels of high-sensitivity C-reactive protein compared
with nonvegetarian diets.
109
The researchers noted
Taiwanese vegetarians consume fewer fresh vegetables,
which they cook in oil, than do Western vegetarians,
and they consume many deep-fried and refined soybean
and grain products, which might contribute to higher
high-sensitivity C-reactive protein levels.
The other heart-healthy dietary patterns associated
with favorable effects on inflammation in this review
are broadly similar to country-specific dietary guide-
lines across the United States, the United Kingdom, and
Australia.
110–112
These guidelines advocate higher
intakes of vegetables and fruits, moderate dairy con-
sumption (albeit favoring reduced- or lower-fat
options), plant-based oils, and unprocessed protein
sources such as fish, lean meat, and legumes. A ran-
domized dietary intervention study in healthy men and
women compared a diet consistent with UK dietary
guidelines with a representative UK diet and demon-
strated a significant reduction in C-reactive protein lev-
els after 12 weeks. This suggests that inflammation is
positively affected when dietary guidelines are fol-
lowed,
113
possibly via increased food sources of poly-
phenols,
114
known to be PAF inhibitors.
63
Research has
shown an inverse association between Lp-PLA
2
and ret-
inol and carotene, markers for provitamin A fruit and
vegetable intake, in patients with incident CVD.
115
Higher intake of fruit and vegetables led to a reduction
in levels of inflammatory biomarkers in a recent sys-
tematic review and meta-analysis.
116
We found that a Western dietary pattern is associ-
ated with higher levels of inflammation. This is not unex-
pected, because Western dietary patterns are associated
with increased risk of coronary heart disease in both
men and women,
117,118
and given the known link be-
tween inflammation and heart disease. A recent review
found that Western dietary patterns are associated with
increased levels of the blood inflammatory biomarkers
high-sensitivity C-reactive protein, leptin, and IL-6.
119
Very few secondary outcomes were identified in
this review; however, key markers appear to be PON1,
MPO, and LDL particle size. Results for these outcomes
were mixed. LDL particle size appears to be an impor-
tant predictor of cardiovascular events and small dense
LDL particles are more pro-atherogenic than large LDL
particles.
100,120
Levels of Lp-PLA
2
in small dense LDL
have been reported to be 5 to 10 times higher than in
normal-size LDL.
121
Of the 3 secondary outcomes,
PON1 may be a useful addition to future studies investi-
gating PAF and Lp-PLA
2
, given its presence within
HDL and protective action against LDL oxidation.
Weight change may be a mediator of inflammatory
biomarkers. Authors of a recent review (which did not in-
clude the novel biomarkers investigated in the present re-
view) found no significant effect on markers of subclinical
inflammation when examining whole foods and dietary
patterns in weight-stable individuals with a high body
mass index.
122
The review authors concluded that weight
loss may be a key factor in dietary interventions that re-
duce inflammation. In the present review, there was no
change in mean weight from baseline in 7 of 10 interven-
tions, but there were improvements in inflammation after
the interventions. Three studies noted significant weight
loss, but inflammatory outcomes were inconsistent. One
study
89
showed a weight loss of >6% of body weight after
a 4-week intervention, with concomitant reductions in
levels of novel inflammatory biomarkers. In contrast, the
other 2 studies showed no or a worsening effect: one
study
87
reported a small reduction in weight with no
change in Lp-PLA
2
from baseline; the other study
90
reported a 3% reduction in body weight, but Lp-PLA
2
level actually increased after the intervention.
To our knowledge, this is the first systematic review
to explore the association between dietary patterns, be-
yond the Mediterranean Diet, and the novel biomarkers
PAF and Lp-PLA
2
. Strengths of our study include a
strong methodology and use of the PRISMA guidelines.
A comprehensive literature search was performed using
4 databases. Screening of title and abstracts and full-text
review for inclusion criteria were performed in dupli-
cate. Data extraction was independently reviewed for
accuracy and quality assessment was performed.
This review was comprehensive and systematic;
however, the analysis is limited by the small number of
studies adhering to the inclusion criteria assessing die-
tary patterns and these novel biomarkers. The sheer
novelty of the markers of interest are another limitation,
because measurement methods are varied and no con-
sensus of cutoff points have been derived for either PAF
or Lp-PLA
2
activity, making it difficult to interpret the
results reported in the studies. Other limitations of this
study include the wide diversity of groups reported in
the studies, which makes it difficult to draw compari-
sons, and the inclusion of cross-sectional studies that
encompass a high risk of bias and lower level of study
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quality when compared with RCTs. The number of
studies examining PAF was very limited, suggesting this
is a gap in the literature. Large-scale intervention stud-
ies are needed to gain a better understanding of how
diet affects this novel biomarker. Because little is known
about the normal concentrations of both biomarkers in
healthy populations, priority for research should be
placed on establishing reference values to determine the
clinical utility of these biomarkers.
CONCLUSION
There is limited evidence and considerable diversity in
existing studies investigating dietary patterns and the
novel inflammatory markers PAF and Lp-PLA
2
.A
range of well-established dietary patterns has potential
to improve these novel markers, including
Mediterranean, vegetarian, and other heart-healthy die-
tary patterns. Conversely, Western dietary patterns are
associated with higher levels of inflammation, as mea-
sured by these markers. More, well-designed studies are
needed to confirm these findings and identify other die-
tary patterns that could positively affect inflammation.
Acknowledgments
Author Contributions. C.J.E. and D.P.R. conceived the
study and extracted the data; CJE designed and per-
formed the literature search and wrote the initial draft
of the manuscript; C.J.E., D.P.R., and H.L.M. undertook
article screening. All authors analyzed and interpreted
the data and critically reviewed and approved the final
manuscript.
Funding. C.J.E. was supported by an Australian
Government Research Training Program Scholarship.
Declaration of interest. The authors declare no conflict
of interest.
Supporting Information
The following Supporting Information is available
through the online version of this article at the publish-
er’s website.
Table S1 Search terms used in the PubMed,
CINAHL, Embase, and Cochrane databases
Acknowledgement
The authors thank Sarah Bateup, Bond University
Faculty of Health Sciences and Medicine librarian, for
assistance with designing and refining the search terms.
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