EVIDENCE BASED MEDICINE (L. ROEVER, SECTION EDITOR)

The Role of Inflammation in Cardiovascular Outcome

Fabrizio Montecucco1,2,3 & Luca Liberale1 & Aldo Bonaventura1 & Alessandra Vecchiè1 &

Franco Dallegri1,2 & Federico Carbone1

# Springer Science+Business Media New York 2017

AbstractPurpose of Review The aim of this review is to update thepathophysiological role of innate immune response in the car-diovascular (CV) disease outcomes, particularly focusing oncoronary atherosclerosis and heart failure.Recent Findings Inflammatory processes comprised with theinnate immunity reaction are believed to actively trigger CVdisease development and final clinical events. For instance, byreleasing proteases and neutrophil extracellular traps, neutro-phil recruitment and activation might strongly influence ath-erosclerotic plaque stability. Similarly, neutrophils drive theearly inflammatory response following a myocardial infarc-tion. However, these cells contribute themselves to infarcthealing by orchestrating monocyte/macrophage recruitmentand polarization within the ischemic myocardium. Given theirheterogeneity and plasticity, the balance between recruitment,proliferation, and polarization of monocyte/macrophage is afurther leading determinant of advanced plaque maturation.Moreover, timely shift from a pro-inflammatory to a resolvingmacrophage phenotype may influence cardiac remodeling aswell as development of heart failure (HF). Alongside macro-phage recruitment and activation into the remote, non-

ischemic myocardium also contributes to cardiac remodelingand HF development.Summary Innate immune response is a tightly regulated pro-cess where a timely modulation of the balance between dam-aging and resolving properties critically impacts on CV out-come. Further progress may improve the determination of theprognostic relevance of inflammatory biomarkers on clinicalCVoutcome.

Keywords Atherosclerosis .Myocardial infarction . Heartfailure . Neutrophil . Macrophage . Inflammation

Introduction

The pathophysiological role of inflammation in atherogenesisand post-infarction cardiac remodeling was widely investigat-ed in both human domain and animal models. Recently, someanti-inflammatory treatments have been already tested in clin-ical trials. Two years ago, an interesting report by Riedker andLüscher highlighted pathophysiological and clinical relevancefor some cytokines (such as tumor necrosis factor [TNF]-α,interleukin [IL]-6, and IL-1) as well as acute phase proteins(such as C-reactive protein [CRP]) [1]. The preliminary resultsfrom human studies investigating selective treatmentstargeting these molecules were rather negative, suggesting thatthe modulation of additional inflammatory pathways might bealso involved, thus maintaining inflammation and CV diseaseprogression. Some inflammatory pathways recently emergedas more promising targets: lipoprotein-associated phospholi-pase (LpPL)A2, the axis osteoprotegerin/receptor activator ofnuclear factor kappa-B ligand (RANKL), osteopontin, andpro-protein convertase subtilisin/kexin type 9 [2–5]. As theinflammatory response is known to be redundant and compen-satory, it is hard to consider all these pathways as separate and

This article is part of the Topical Collection on Evidence Based Medicine

* Federico Carbonefederico.carbone@edu.unige.it

1 First Clinic of Internal Medicine, Department of Internal Medicineand Medical Specialties, University of Genoa, 6 viale Benedetto XV,16132 Genoa, Italy

2 IRCCS AOU San Martino-IST, Genova, 10 Largo Benzi,16132 Genoa, Italy

3 Centre of Excellence for Biomedical Research (CEBR), Universityof Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy

Curr Atheroscler Rep (2017) 19:11 DOI 10.1007/s11883-017-0646-1

independent when they all concur to plaque instability or ad-verse heart remodeling. In this context, both the innate andadaptive immune responses actively participate and sustainchronic CV inflammation. However, their modulation mayrepresent an additional therapeutic strategy in the potentialprevention of adverse CV events [6–12]. Based on basic re-search and clinical data, this narrative review aims at updatingthe pathophysiological role of innate immunity in coronaryatherogenesis and post-ischemic adverse cardiac remodeling.Particularly, clinical trials that have been conducted in thisarea will be summarized and discussed.

Inflammation in Coronary Atherogenesisand Plaque Vulnerability

The current pathophysiological paradigm considers myocar-dial infarction (MI) as the result of a “perfect storm” scenario,in which a coronary arterial stimulus for clinically relevantthrombosis overlaps a pro-thrombotic milieu at the site ofthe culprit plaque [13]. Chronic systemic inflammatory state,as observed in many pro-atherosclerotic conditions (includingoverweight/obesity, diabetes, hypertension, and dyslipid-emia), may directly promote clot generation, increasing thethrombotic risk as a consequence of increased bloodthrombogenicity or impaired fibrinolysis. Instead, localintraplaque inflammation contributes to the pro-thromboticstate indirectly, by fostering atherosclerosis and its complica-tions [14]. The transition to a symptomatic plaque rupture isthen a dynamic, non-linear, and unpredictable process whichinvolves only a small fraction of vulnerable plaques. In thisregard, studies also emphasized that the plaque correspondingto the culprit lesion might not be directly responsible for acritical stenosis, and even the coronary vascular bed inflam-mation may not co-localize with the culprit lesion [15, 16].Histopathological findings clearly identified local inflamma-tory activity as key feature of culprit lesions, andmuch interesthas recently focused on neutrophil-derived components(Fig. 1). Circulating neutrophils have been widely identifiedas a predictor of ACS, and their recruitment in the shoulderregion has been identified in both mouse and human plaques[8]. Once activated by micro-environmental stimuli, neutro-phils were shown to release a large amount of mediators in-cluding gelat inases, collagenases, elastases, andmyeloperoxidases involved in extracellular matrix degrada-tion and development of necrotic lipid core [6]. Beside thoseclassical effects, neutrophils also contribute to atheroscleroticplaque vulnerability by the release of nuclear chromatinforming a scaffold of granule protein and histones commonlynamed neutrophil extracellular traps (NETs) [17]. NETs re-leased by dying neutrophils (a process called NETosis) arenow under the spotlight as marker of CV risk and potentialtherapeutic target [18, 19].

Due to their heterogeneity and plasticity, monocytes/macrophages have a critical role in atherosclerotic plaque vul-nerability (Fig. 1). As reported in Table 1, various monocyte(Mon1, Mon2, and Mon3) and macrophage subsets with pro-(M1, M4) and anti-inflammatory (M2a, M2b, M2c, Mhb, andMhem) activity have been classically recognized in humanatherosclerotic plaques [12, 20]. However, bioinformatic anal-ysis of large transcriptomic dataset has recently clarified howenvironmental signals shape the functional program of mac-rophages by influencing their epigenetic landscape and tran-scriptional signature [21–23]. In the next future, a multi-dimensional approach integrating -omics data with mathemat-ical and bioinformatic modeling may better fit the extrememacrophage heterogeneity rather than the classical polariza-tion model [24]. As further expression of the extreme macro-phage plasticity, Robbins and colleagues recently showed thatmacrophage turnover within established atheroscleroticplaques is largely sustained by local proliferation, throughthe involvement of scavenger receptor (SR)-A [25••]. Fromthe histological examination of advanced atherosclerotic le-sions, the necrotic core formation and fibrous cap thinningwere associated with a defective efferocytosis. On the otherhand, an efficient efferocytosis prevents secondary necrosisand leakage of inflammatory and toxic molecules from dyingcells. An impaired engulfment of apoptotic cells leads to sec-ondary necrosis and unresolved inflammation and autoim-mune responses. An reduced efferocytosis may then occuras result of pro-inflammatory and oxidative stimuli whichwere shown to downregulate efferocytotic pathways, such asLDL receptor-related protein (LRP)1 and SR-BI [26–29].

Pathophysiology of Inflammation in Post-ischemicHeart Failure

The mechanical or pharmacological re-establishment of theblood flow (reperfusion) in a coronary artery is recommendedto salvage the ischemic myocardium from death and to pre-serve cardiac function. In the early phases, cardiac reperfusionitself is believed to induce injury via the activation of inflam-matory pathways [13]. After 30 min from the reperfusion on-set, neutrophils start to infiltrate the area at risk (Fig. 2). Thereactive oxygen species (ROS) generation and cytokine re-lease within ischemic myocardium further enhance neutrophilrecruitment through a positive feedback loop [6]. From 3 to7 days after myocardial infarction (MI), neutrophil infiltrationresolves via cell apoptosis [30]. Timely resolution of neutro-phil inflammation is a critical step for optimal healing of theinfarcted heart, and several inhibitory signals have evolved forthe negative regulation of the inflammatory cascade followingischemic injury [31–33]. However, neutrophil-mediated in-flammation directly contributes itself to infarct healing. Anaccurate clearance of dead cells is a prerequisite for favorable

11 Page 2 of 9 Curr Atheroscler Rep (2017) 19:11

MI healing, and this process is largely mediated by M2c-polarized macrophages (acting during 4 to 7 days after MI),a resolving phenotype which neutralizes M1 macrophages(acting during the first 1–3 days after MI) and is characterizedby the release of high levels of IL-10 and transforming growthfactor (TGF)-β [34•, 35] (Fig. 2). An inefficient removal ofdead cells, due to impaired macrophage phenotypic shift, hasbeen observed in absence of neutrophil secretome, especiallyneutrophil gelatine-associated lipocalin (NGAL).Accordingly, neutrophil-depleted mice subjected to MI devel-oped a dysregulated healing response with excessive fibrosis,loss of ventricular function, and progressive increase in bio-markers associated to heart failure (HF) [36••]. Those recentfindings were unexpected, given the detrimental role of neu-trophil count and secretion products (including NGAL) onventricular function and post-MI mortality [37, 38].However, a threshold level might identify where the acutetissue-damaging effects of neutrophils outweigh their resolv-ing properties during MI healing. Alongside macrophage

switch within the infarcted tissue, recent studies emphasizedthe role of macrophage recruitment and activation into theremote, non-ischemic myocardium [39]. In the steady state,the majority of resident macrophages does not derive fromcirculating monocytes, but rather proliferates from local pro-genitors. Those cells display an anti-inflammatory phenotypewith prevalence of M2-related genes and are likely to guardagainst infectious stimuli, regulate angiogenesis, and orches-trate matrix turnover, whereas potential interactions with car-diomyocyte metabolism, contraction, and survival remain tobe established [34•, 40]. When MI occurs, monocytes/macrophages are recruited in the non-ischemic myocardium,but more slowly as compared to the infarcted area, reachingthe peak around 10 days after ischemic injury [41, 42•].Although speculative, a substantial cross-talk between macro-phages and resident cells may then impact on post-MI myo-cardium remodeling and the consequent development of HF.A low-grade inflammation state may contribute to extracellu-lar matrix disruption through the proteolytic activity of matrix

Mon

foam cell

Ox-LDL

effective

efferocytosis

apoptotic

M

necrotic M

defective

efferocytosis

MMPs

blood flow

disturbance

Media

Intima

Blood lumen

activated

neutrophil

NETs

activated PLTT cells

BAFF

Natural Ab

B cells

erosion

rupture

RBC

fibrin

DCs

VSMCs

Fig. 1 Inflammatory cells are involved in the pathophysiology of acutecoronary syndrome. Macrophages (Mϕ) are the most represented cellsand their proliferation/activation accounts for the progression ofatherosclerotic process. Neutrophils have also shown to play a criticalrole, largely due to the release of neutrophil extracellular traps (NETs),which leads to the activation of platelets (PLT) and coagulation cascade.

More recently, T and B cells have been described as mediators ofatherosclerosis progression. Ab: antibody. BAFF: B cell-activatingfactor. DCs: dendritic cells. Mϕ: macrophage. Mon: monocyte. MMPs:metalloproteinases. NETs: neutrophil extracellular traps. Ox-LDL:oxidized low-density lipoprotein. PLT: platelet. RBC: red blood cell.VSMCs: vascular smooth muscle cells

Curr Atheroscler Rep (2017) 19:11 Page 3 of 9 11

metalloproteinases and cathepsin, whereas a direct role of in-flammatory macrophage activation in cardiomyocyte apopto-sis is an intriguing hypothesis but requires further validationstudies [43]. Therefore, once MI occurs, the ensuing inflam-matory response induced by the innate immune system mayupregulate a portfolio of cytokines useful in the short-termadaptation to the stress. This “cytokine hypothesis” suggeststhat HF progresses, at least in part, as a result of the deleteriouseffects exerted by endogenous cytokine cascade on the heartand the peripheral circulation [9]. Toll-like receptors,inflammasome, and the relative downstream cytokines

(TNF-α, IL-1β, and IL-18) have been demonstrated to pro-mote ventricular remodeling following MI and are then sug-gested as potential biomarkers or even potential therapeutictargets.

Clinical Evidence for Neutrophils and Monocytesto Predict CV Outcomes

In the last two decades, a direct correlation between innate im-mune activation and increased CV risk has been largely de-scribed in both experimental and epidemiological studies.Circulating neutrophils have been largely demonstrated to predictoccurrence of MI, risk of major adverse CV events (MACEs),and also negative post-ischemic ventricular remodeling (Table 2)[44–59]. Further supporting the detrimental role of neutrophilactivation on CVoutcome, serum levels of neutrophil productshave been identified as predictors of poor CVoutcome andworseventricular remodeling. Gelatinases (matrix metalloproteinase[MMP]-2 and -9), collagenases (MMP-1, -8, -7, -13), MPO,elastase, and NGAL have been shown to determine early clinicalpresentation of MI as well as the long-term occurrence ofMACEs [8, 60, 61]. Similarly, circulating monocytes (especiallythe Mon1 and Mon2 subsets) have been shown to predict therupture of coronary atherosclerotic plaques and then the occur-rence of acute coronary syndrome (ACS) (Table 1). Conversely,only a limited number of clinical studies have been designed toinvestigate the contribution of circulating monocyte subsets inthe pathophysiology of cardiac remodeling and development ofHF. As reported by Nahrendorf and colleagues, monocyte re-cruitment accounts for approximately 80% of all myocardialmacrophages duringMI healing inmice [34•]. Those experimen-tal observations were later confirmed in clinical studies showinga peak of Mon1 at day 3 after MI and a subsequent peak ofMon2 at day 5 post-MI. A negative association between Mon1and left ventricular ejection function recovery after MI was alsodemonstrated [55, 62–66]. On the other hand, the contribution ofmonocyte subsets in HF progression is still unclear, especially inthe setting of HF with preserved ejection fraction (HFpEF).Available data have associated the development of HFpEF withan increased amount of circulating Mon1 and a prevalent M2switch in the endomyocardium, which contributes to extracellu-lar matrix deposition and then diastolic dysfunction [67, 68].Further challenging the current knowledge on cardiac remodel-ing, a timely activation/inhibition of inflammatory processes isemerging as critical issue, which should be considered in design-ing future epidemiological (and interventional) studies [69, 70].

Therapeutic Strategies and Future Perspectives

Due to the impact of systemic and local inflammation on CVdisease, several anti-inflammatory approaches were tested in

Table 1 Comparative characteristics of monocyte/macrophage subsetsin humans

Phenotype Markers Function

Monocytes

Mon1 (classical) CD14++ CD16− Pro-inflammatory:phagocytosis,scavenging

Mon2(intermediate)

CD14++ CD16+ Anti-inflammatory:phagocytosis,angiogenesis

Mon3(non-classical)

CD14+ CD16++ Anti-inflammatory:collagen deposition

Macrophages

M1 CD68; CD11c, IL-1r;TLRs; MCH II;CD80/CD86; iNOS;SOCS1; MARCO

Pro-inflammatory:TNF-α; IL-1β; IL-6;IL-12; IL-23; CCL2,CCL3, CCL4, CCL5,CCL8, CCL9, CCL10,CCL11; MMP-1;MMP-3; MMP-9

M2a CD68; CD163; MHC II;SR; MR; CD200RIL-1r;

Anti-inflammatory: IL10;TGF-β; IL-1ra;CCL17; CCL18;CCL22; CCL24

M2b CD68; IL-10; CD86,MHC II; MR

Anti-inflammatory: IL-1β; IL-6; IL-10; TNF-α;CCL1

M2c CD68; MR; CD163;TLRs; Arg I

Anti-inflammatory:IL-10; TGF-β; PTX3

M4 CD68; MMP-7;S100-A8; MR

Pro-inflammatory:MMP12; IL-6; TNFα;MMP-7

Mhem CD68; CD163, MCH II Anti-inflammatory:HMOX-1

M(hb) CD68; CD163, MR Anti-inflammatory:LXRα, ABCA1,ABCG1

Monmonocyte, CD cluster of differentiation,Mmacrophage, IL-1r inter-leukin-1 receptor, TLRs toll-like receptors,MCHmajor histocompatibilitycomplex, inOS inducible nitric oxide synthase, SOCS1 suppressor ofcytokine signaling 1, MARCO macrophage receptor with collagenousstructure, TNF tumor necrosis factor,CCL chemokine (C-Cmotif) ligand,MMP matrix metalloprotease, SR scavenger receptor, MR mannose re-ceptor (CD206), TGF transforming growth factor, Arg1 arginase 1, PTX3pentraxin 3, HMOX heme oxygenase

11 Page 4 of 9 Curr Atheroscler Rep (2017) 19:11

the last decade, but none of these is currently approved forclinical use. Experimental studies have investigated the poten-tial role of adipocytokines as therapeutic target in animalmodels of ischemic/reperfusion injury. A reduction of myo-cardial infarcted area has been reported after infusion withC1q/TNF-related protein (CTRP) 9 before or at time of ische-mia [71], whereas the continuous infusion of CTRP 9 wasshown to improve survival, left ventricular function, and car-diac remodeling [72]. Even omentin-1 administration beforeor after ischemia has been demonstrated to reduced cardiacinjury [73]. Those molecules were also shown to reduce car-diomyocyte apoptosis in vitro [71, 73]. Similar improvementon cardiomyocyte apoptosis and reduction of ischemic areahave also been observed after treatment with chemerin, likelydue to the inhibition of neutrophil activity [74]. Due to theiranti-inflammatory and anti-oxidative activities, selective ago-nists of the cannabinoid receptor (CB)2 have widely demon-strated to be effective in ischemic injury by promoting cardio-myocyte regeneration and reducing myocardial fibrosis [75,76]. Moreover, activation of CB-2 receptor also showed aprotective role in balloon-induced neointima formation, sug-gesting a possible application in prevention of restenosis aftercoronary angioplasty [77]. Targeting inflammatory cell re-cruitment has been suggested as a further therapeutic strategyto reduce post-ischemic damage. Some interesting results oncardiac remodeling and cardiovascular mortality have beenreported in animal model of MI/reperfusion injury throughthe inhibition of chemotactic molecules, such as chemokineligand 5 [31], nicotinamide phosphoribosyltransferase [78],

and RANKL [33]. On the other hand, recent clinical trialshave mainly focused on the inhibition of the upstream inflam-matory pathway involving IL-1β, TNF-α, and IL-6. The se-lective IL-1β receptor antagonist anakinra has been demon-strated to reduce inflammatory markers in patients with non-ST elevation ACS, even if a reduction in infarct size was notobserved [79]. The Canakinumab Anti-inflammatoryThrombosis Outcomes Study (CANTOS) is currently ongoingto assess the effectiveness of canakinumab, a fully humanmonoclonal antibody characterized by selective inhibitory ac-tivity on IL-1β, in secondary CV prevention [80], whereastwo other IL-1β inhibitors (gevokizumab and LY2189102)are testing in phase II clinical trials. Concerning TNF-α inhi-bition, the Cardiovascular Inflammation Reduction Trial(CIRT) is ongoing to investigate the impact of low-dose meth-otrexate in secondary CV prevention after MI and in patientwith diabetes or metabolic syndrome [81]. A raising intereston the “cholesterol-related” target PCSK9 pushed phase IIIrandomized clinical trials for three monoclonal antibodies(i.e., alirocumab, evolocumab, and bococizumab). All thesePCSK9 inhibitors significantly reduced circulating levels oflow-density lipoprotein cholesterol, and they are currently ap-proved for clinical use in patients with familial hypercholes-terolemia, statin intolerance, and failure to achieve LDL-cholesterol goals. More recently, intriguing evidence linkingPCSK9 and inflammation has prompted to test the effective-ness of anti-PCSK9 drugs to reduce CVoutcomes in patientswith coronary atherogenesis [5]. Conversely, the stabilizationof atherosclerotic plaque through the administration of

MI

30’ day1 day3 day 4 day 7

PMN

M1

M2

Inflammatory Phase Healing PhaseFig. 2 Biphasic inflammatoryresponse after myocardialinfarction. Neutrophil (PMN)-mediated inflammation drivesearly stage of myocardial injuryfollowing an acute myocardialinfarction (AMI). Furthermore, atimely resolution of neutrophilinflammation also modulatesmonocyte recruitment andmacrophage polarization (M1 andM2), which orchestratemyocardial healing andsubsequent cardiac remodeling

Curr Atheroscler Rep (2017) 19:11 Page 5 of 9 11

Tab

le2

Recentstudies

investigatingneutrophilandmonocytecountsandcardiovascular

outcom

es

Author

Year

Studydesign

Outcome

Results

NeutrophilsandN/L

ratio

O’Hartaighetal.[44]

2012

Prospectiveobservational(3316

patientsundergoing

coronary

angiography)

CVmortality

Neutrophilcount

was

apositiveassociated

with

CVmortality(adjustedHR1.93

[95%

CI

1.39–2.67];p

<0.01).

Arbeletal.[45]

2012

Prospectiveobservational(3005

patientundergoing

PCA)

CAD

CVevents

N/L

ratio

predictedCADpresence

andseverity

(OR2.45

[95%

CI1.76–3.42];p

<0.001),as

wellasCVevents(H

R1.55

[95%

CI1.09–2.2];p=0.01).

Kalay

etal.[46]

2013

Case-ontrol

(196

progressiveCADand198not)

CADprogression

N/L

ratio

positivelycorrelatewith

progressivediseaseaftermultiv

ariateanalysis(RR2.27

[95%

CI1.07–4.82];p

=0.03).

Azabetal.[47]

2013

Prospectiveobservational(338T2D

M)

MACEs

After

4-year

follow-up,N/L

ratio

predictedMACEsoccurrence

(HR2.8[95%

CI

1.12–6.98];p

=0.027).

Ergelen

etal.[48]

2014

Case-control(2410

patientsundergoing

PCIforST

EMI)

CVmortality

N/L

ratio

was

positiv

elyassociated

with

ahigh

incidenceof

in-hospitaland

long-termCVmortality

(OR2.8[95%

CI1.37–5.74];p

=0.005).

Açaretal.[49]

2015

Prospectiveobservational(238patientsundergoing

CTA

)CAD

The

highesttertileof

N/L

ratio

predictedtherisk

ofCADpresence

(OR2.30

[95%

CI1.15–4.43];

p=0.023)

andseverity

(OR2.60;[95%

CI1.19–5.69;

p=0.017).N

/Lalso

positivelycorrelated

with

CADextension(p=0.001).

Zhang

etal.[50]

2015

Prospectiveobservational(1287

patientswith

STEMI)

MACEs

After

37monthsof

follow-up,neutrophilcountindependently

predictedMACEsoccurrence

(HR1.26

[95%

CI1.20–1.32];p

<0.001).F

urthermore,neutrophilcountimproves

predicted

ability

ofGRACEscore(A

UCfrom

0.698to

0.796;

p<0.001).

Verdoiaetal.[51]

2016

Prospectiveobservational(1542

patientsundergoing

PCI)

CADseverity

MI

HighN/L

ratio

was

associated

with

CADseverity

(p=0.009),tighter

stenosis(p<0.001),and

coronary

calcifications

(p=0.005).N

/Lratio

also

predictedperi-proceduralM

Ioccurrence

(OR1.33

[95%

CI1.02–2.3];p=0.02).

Karakas

etal.[52]

2016

Prospectiveobservational(106patientswith

STEMI)

LVdysfunction

N/L

ratio

was

positiveassociated

with

LVsystolicdysfunction(p=0.013).

Börekçietal.[53]

2016

Prospectiveobservational(274patientswith

STEMI)

LVremodeling

Onmultiv

ariatelogisticregression

analysis,N

/Lratio

was

associated

with

LVremodeling

(OR2.00

[95%

CI1.58–2.54];p

<0.001).A

cut-offvalueof

4.25

predictedventricular

remodelingwith

79%

sensitivity

and74%

specificity.

Bekleretal.[54]

2016

Prospectiveobservational(405patientswith

NST

EMI)

LVsystolicdysfunction

N/L

ratio

was

higher

inolder(p<0.001)

anddiabeticpatients(p=0.03).N/L

ratio

was

also

anindependentp

redictor

ofLV

dysfunction(H

R2.01

[95%

CI1.25–3.24];p

=0.004).

Monocytes

Tapp

etal.[55]

2012

Case-control(50

STEMI,40

stableCAD,and

40healthycontrols)

CADpresence

Mon1andespecially

Mon2subtypes

wereprevalentinpatientswith

STEMI(p<0.001forboth).

Mon2also

correlated

with

TnI

(r=0.310;

p=0.04)andindependently

predictedareduction

ofLV

EF(r=0.370;

p=0.013).

Rogacev

etal.[56]

2012

Prospectiveobservational(951subjectsundergoing

PCA)

CVevents

Duringamedianfollow-upof

2.6years,totalm

onocytecount,Mon1andMon2independently

predictedCVeventsin

univariateanalysis(p=0.010,p=0.024,andp<0.001,respectiv

ely).

OnlyMon2independently

predictedCVeventsin

adjusted

analysis(H

R3.02

[95%

CI1.32–6.93],p

=0.01).

Leersetal.[57]

2013

Prospectiveobservational(85

patientswith

chestp

ain)

UA/M

IMon2was

higher

inpatientswith

AUPandAMIas

comparedto

non-cardiacchestp

ain

(p<0.05

andp<0.001,respectiv

ely).

Gijsbertsetal.[58]

2015

Prospectiveobservational(1760

patientsunderw

entP

CA)

MACEs/MI

Monocytecountw

ashigher

intheMACEgroup(p=0.001).T

heoccurrence

ofMIwas

independently

predictedby

totalm

onocytecount(HR2.06

[95%

CI1.10–3.86];p

=0.024).

Gijsbertsetal.[59]

2016

Prospectiveobservational(1015

patientsunderw

ent

coronary

angiographyforsuspectedCAD)

CAD

MACEs

Monocytepercentage

show

edstrong

independentp

redictivevalueforall-causemortality(H

R1.44

[95%

CI1.19–1.74];p

<0.001),w

hereas

themonocyte-to-lym

phocyte

ratio

performed

bestforCVmortality(H

R1.42

[95%

CI1.11–1.81];p

=0.005).

N/L

neutrophilto

lymphocyte,CVcardiovascular,H

Rhazard

ratio

,CIconfidenceinterval,P

CApercutaneous

coronary

angiograph,C

ADcoronary

artery

disease,ORodds

ratio

,RRrelativ

erisk,T

2DM

type

2diabetes

mellitus,MACEsmajor

adverseCVevents,PCIpercutaneous

coronary

interventio

n,ST

EMIST

-elevatio

nmyocardialinfarctio

n,CTA

computerizedtomographyangiography,GRACE

globalregistry

ofacutecoronary

events,A

UCarea

underthecurve,MImyocardialinfarctio

n,LV

leftventricle,NST

EMInon-ST

-elevatio

nmyocardialinfarctio

n,Tn

Itroponin

I,LV

EFleftventricular

ejectio

nfractio

n,UAunstableangina

11 Page 6 of 9 Curr Atheroscler Rep (2017) 19:11

darapladib, a selective inhibitor of Lp-LpA2, failed to signifi-cantly improve CVoutcome in secondary prevention of coro-nary artery disease and ACS [82, 83]. Although no therapeutictargets have been so far explored, targeting cardiac macro-phages might be a further interesting opportunity.Nanoparticle may be suited to delivery drugs to, macrophageso that the injection of nanoparticle-loaded siRNA-targetingCCR2 has been demonstrated to resolve inflammation andinduce infarct healing in ApoE−/− mice.

Conclusions

This review updated and discussed how targeting the innateimmune response might impact on CV outcome in patientswith coronary atherosclerosis and post-ischemic heart remod-eling. Despite wide experimental advance in this field, thetranslation of the pathophysiological discoveries in the clinicalpractice still deserves additional investment. Further progressis expected by newer imaging tools, which allow us to dynam-ically investigate recruitment, death, and function of neutro-phils and monocytes/macrophages in atherosclerotic plaqueand ischemic myocardium [84, 85]. Emerging molecular im-aging probes that either target immune cells directly or followtheir specific functions might enable basic research and facil-itate clinical trials as well by adopting molecular imagingreadouts as end point. Implementation of imaging strategiesmight also help the drug testing, thus enabling faster and moreeconomical clinical trials. Finally, it should consider that theCV system is not isolated, but tightly interconnected with theentire organism. Therefore, we believe that innate immunityprocesses have to be investigated by taking into account thatsingle-target treatment approaches and high selective thera-pies might negatively impact on CVoutcomes due to compen-satory and redundant systems.

Acknowledgements This study was supported by a grant from theEuropean Commission 921 (FP7-INNOVATION I HEALTH-F2-2013-602114; Athero-B-Cell: Targeting and exploiting B cell function for922 treatment in cardiovascular disease) and a grant from the SwissNational Science Foundation Grant to Dr. F. 923 Montecucco(#310030_152639/1).

Compliance with Ethical Standards

Conflict of Interest Fabrizio Montecucco, Luca Liberale, AldoBonaventura, Alessandra Vecchiè, Franco Dallegri, and FedericoCarbone declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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