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Review Article
Adverse Cardiac Remodelling after Acute Myocardial Infarction:
Old and New Biomarkers
Alexander E. Berezin
1
and Alexander A. Berezin
2
1
Internal Medicine Department, State Medical University, Ministry of Health of Ukraine, Zaporozhye 69035, Ukraine
2
Internal Medicine Department, Medical Academy of Post-Graduate Education, Ministry of Health of Ukraine,
Zaporozhye 69096, Ukraine
Correspondence should be addressed to Alexander E. Berezin; aeberezin@gmail.com
Received 15 May 2019; Revised 6 January 2020; Accepted 22 May 2020; Published 12 June 2020
Academic Editor: Roberta Rizzo
Copyright © 2020 Alexander E. Berezin and Alexander A. Berezin. This is an open access article distributed under the Creative
Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited.
The prevalence of heart failure (HF) due to cardiac remodelling after acute myocardial infarction (AMI) does not decrease
regardless of implementation of new technologies supporting opening culprit coronary artery and solving of ischemia-relating
stenosis with primary percutaneous coronary intervention (PCI). Numerous studies have examined the diagnostic and
prognostic potencies of circulating cardiac biomarkers in acute coronary syndrome/AMI and heart failure after AMI, and even
fewer have depicted the utility of biomarkers in AMI patients undergoing primary PCI. Although complete revascularization at
early period of acute coronary syndrome/AMI is an established factor for improved short-term and long-term prognosis and
lowered risk of cardiovascular (CV) complications, late adverse cardiac remodelling may be a major risk factor for one-year
mortality and postponded heart failure manifestation after PCI with subsequent blood flow resolving in culprit coronary artery.
The aim of the review was to focus an attention on circulating biomarker as a promising tool to stratify AMI patients at high
risk of poor cardiac recovery and developing HF after successful PCI. The main consideration affects biomarkers of
inflammation, biomechanical myocardial stress, cardiac injury and necrosis, fibrosis, endothelial dysfunction, and vascular
reparation. Clinical utilities and predictive modalities of natriuretic peptides, cardiac troponins, galectin 3, soluble suppressor
tumorogenicity-2, high-sensitive C-reactive protein, growth differential factor-15, midregional proadrenomedullin, noncoding
RNAs, and other biomarkers for adverse cardiac remodelling are discussed in the review.
1. Introduction
Heart failure (HF) is a global health problem with serious
economic burden that has been considered as the dominant
cause of cardiovascular (CV) morbidity and mortality in
the developed and developing countries [1, 2]. HF affects
around 26 million people worldwide (including 5.7 million
and 3.4 million people in the US and in the EU, respectively),
and the estimated expenditures for HF care were around $31
billion [1]. It is expected that by 2030 more than 40 million
people will have this condition, and the HF diagnosis and
therapy will increase twice and even more [3]. The clinical
outcomes remain poor with a five-year survival rate of
approximately 50% regardless of phenotype of HF that
completely correspond to the expected survival rate in non-
metastatic cancer [3, 4]. Despite sufficient improvements in
diagnosis, prevention and treatment of HF new incidences
of HF with reduced ejection fraction (HFrEF) and midrange
ejection fraction (HFmrEF) in contrast to HF with preserved
ejection fraction (HFpEF) continue to occur as a need for
heart transplantation and mechanical support device use
[4]. Additionally, increased prevalence of HFpEF represents
the most frequent cause of CV and sudden death, primary
hospitalization, and readmission to the hospital due to acute
decompensation of HF [5].
The most common primary causes of HFrEF/HFmrEF
remain acute ST-segment elevation myocardial infarction
(STEMI) and hypertension, while incidences of HFpEF were
rather associated with hypertension, acute non-ST-segment
elevation myocardial infarction (non-STEMI), and
Hindawi
Disease Markers
Volume 2020, Article ID 1215802, 21 pages
https://doi.org/10.1155/2020/1215802
alternative causes (atrial fibrillation, cardiomyopathy, myo-
carditis, valvular heart disease, and diabetes mellitus) com-
pared with STEMI [6–8]. Contemporary strategy for the
prevention of HF after acute STEMI is based on early com-
plete cardiac revascularization and prevention of negative
impact of comorbidities, such as diabetes mellitus, abdomi-
nal obesity, hypertension, thyroid dysfunction, kidney fail-
ure, and conventional CV risk factors (smoking,
dyslipidaemia, insulin resistance, and hyperuricemia) [9,
10]. In fact, complete recovering of blood flow through cul-
prit coronary artery and other ischemia-related stenosis with
primary percutaneous coronary intervention (PCI) is not
warranted for full prevention of late adverse cardiac remod-
elling [11, 12]. Although improvement of prognosis, increase
in quality of life, and delay in progression or reversal of
ischemia-induced cardiac remodelling and chronic HF
remain prime targets for the treatment of AMI [13, 14], there
are no clear approaches for risk stratification in AMI patients
after successful PCI [15]. For instance, hyperemic microcir-
culatory resistance and no-reflow phenomenon were found
as strong predictors for the extent of infarct size and early
cardiac remodelling [16]. Additionally, optic coherent
tomography or intravascular ultrasound performed over 3
months after initial major cardiac event frequently allows
identifying several factors contributing advance in late car-
diac remodelling, such as silent restenosis, progression of
old stenotic lesions, late stent thrombosis, and several post-
PCI technical problems with incomplete stent branches’
expansion, stent malposition, and underpressed culprit pla-
que [17, 18]. Except for early revascularization, cardiac
remodelling could be prevented by pharmacotherapy includ-
ing complex neurohormonal blockade and device-based
therapies, which are addressed in the improvement of ven-
tricular dyssynchrony and prevention from fatal arrhythmias
[19]. In this context, new diagnostic and predictive options
are needed to prevent cardiac remodelling and HF. The aim
of the review was focused on the circulating biomarker as a
tool to stratify postmyocardial infarction patients at high risk
of poor cardiac recovery after reperfusion with primary PCI
and developing HF.
2. Adverse Cardiac Remodelling after Acute
Myocardial Infarction: Definitions and
Contributing Factors
2.1. Definition of Adverse Cardiac Remodelling. Adverse car-
diac remodelling after AMI is defined as complex interac-
tions between cellular and extracellular components of
myocardium, which are neurohumoral and epigenetic regu-
lations, leading to changes in the cardiac architectonics and
geometry frequently affecting both ventricles and atrials,
worsening diastolic filling and systolic function and associ-
ated with developing heart failure [17]. Additionally, there
is a large number of definitions of cardiac remodelling after
STEMI, which are based on multiple imaging modalities,
such as presentation of akinesia area, left ventricle enlarge-
ment, reduced LVEF, and early diastolic dysfunction (includ-
ing longitudinal strain increase, twist of LV apex, and
tethering effect). In fact, an impact of passive mechanical
constraint of surrounding myocardium on infarct zone
mediates infarct expansion and decline in both regional and
global systolic function [20].
Other criteria of cardiac remodelling affect shaping
stunned and hibernated myocardium after incomplete revas-
cularization or delay of PCI performing with inadequate per-
fusion recovery [21]. However, non-STEMI is also associated
with cardiac remodelling, rather mild-to-moderate than
severe, and frequently nondistinguished from STEMI-
induced cardiac disorders in prognostic aspects, but the
canonic model of pathogenesis of adverse cardiac remodel-
ling was based on STEMI impact on cardiac architectonic.
There is a sustainable option that STEMI-induced cardiac
remodelling frequently relates to HFrEF/HFmrEF, but non-
STEMI-induced cardiac remodelling is rather associated with
developing HFpEF than HFrEF.
2.2. Contributing Factors of Adverse Cardiac Remodelling. In
fact, there are at least two different variants of adverse car-
diac remodelling after acute MI, which distinguished each
other in pathogenesis, so called the early (at 2-3 weeks after
initial event) and late (at 3-6 months after AMI) remodel-
ling (see Figure 1).
Contemporary point of view is based on an idea that
early complete primary revascularization of culprit artery
and ischemia-induced stenosis/occlusions in other coronary
arteries at first hours of STEMI is independent and the
most powerful factor preventing early LV cavity dilation,
declining LV pump function and the developing of HF. It
has been postulated that preserved systolic function and
LV dimensions at early stage of various revascularization
procedures can accompany with myocardial biomechanical
and energetics stress, mitochondrial dysfunction, and oxi-
dative stress that lead to potent fatal arrhythmias even prior
to diastolic dysfunction developing [22]. Over the next
three months after restoring TIMI III blood flow through
culprit artery with PCI, the primary causes inducing
adverse cardiac remodelling can be different from the afore-
mentioned. Indeed, other factors that may contribute to
cardiac remodelling after successful primary PCI are arte-
rial healing, vessel remodelling, stent restenosis, thrombosis,
and incomplete expansion of stent branches (known as mal-
position), and stent fracture, which require ischemia-driven
target vessel revascularization further [23]. Performing of
optical coherence tomography (OCT) in STEMI patients
presenting with late and very late stent thrombosis has
yielded that stent malposition was determined in 55% cases,
quarter of which had been found evidence of positive vessel
remodelling [24]. Additionally, neoatherosclerosis and
uncovered stent struts were reported as the primary cause
of late thrombosis in 35% cases and 10% cases, respectively
[24]. Although coronary stent fracture is an underrecognized
event, it has been reported frequently in the drug-eluting
stent era [25]. However, investigators have shown that tech-
nical problems with first-generation eluting stent implanta-
tions in STEMI patients were associated with higher in-
hospital mortality and posthospital target vessel failure or
cardiac death [24].
2 Disease Markers
Endothelial shear stress, neointima formation, and late
thrombosis can appear beyond inadequate PCI and stent
positioning and are result of accelerating atherosclerosis
and inadequate drug support, i.e., nonoptimal care with
statins, refusal from dual antiplatelet therapy, effective antic-
oagulation if needed, and adenosine intracoronary for pre-
vention no-reflow/slow-flow phenomena. Even a novel
device (known as bioabsorbable cardiac matrix) was not able
to attenuate adverse cardiac remodelling after AMI [26],
while there were strong positive expectations regarding these
devices [27]. Despite implantation of second-generation
everolimus-eluting stent in STEMI appears to be better to
first-generation eluting stents, there is evidence that even a
small degree of chronic intrastent conditions may signifi-
cantly influence on healing persistence [28]. Frequencies of
uncovered and malapposed struts as well as percentage of
stents fully covered with neointima were 1.2%, 0.4%, and
60.9%, respectively, for over a one-year period after PCI with
second-generation everolimus-eluting stent implantation
[28]. In fact, they were not associated with the incidence of
clinical events and intrastent thrombus.
The next factor contributing to early and late cardiac
remodelling is the “no-reflow”phenomenon. Indeed, the
“no-reflow”phenomenon can be considered as a component
of early cardiac remodelling after STEMI that relates to
microvascular obstruction and dysfunction causing severe
disturbance in regional perfusion [29]. In fact, the “no-
reflow”phenomenon is a result in poor healing of the culprit
artery and adverse cardiac remodelling, increasing the risk
for major adverse cardiac events, such as recurrent MI, newly
diagnosed HF, and sudden death, but the “slow-flow”phe-
nomenon appears to be a serious factor contributing to both
types of adverse cardiac remodelling [30, 31].
Additional factor that is involved onto a development of
late adverse remodelling is epigenetically mediating distur-
bance of endogenous vascular repair system [32, 33]. It has
been found that altered vascular repair has maintained vaso-
constriction and vascular dysfunction that accelerated ath-
erosclerosis and supported hibernation in the grey zone
around myocardial infarction. Overall, the development of
adverse cardiac remodelling after AMI regardless of initial
cause (even in asymptomatic patients) was consistently asso-
ciated with poor clinical outcomes, and it could be predicted
and completely resolved [34, 35].
The factors preventing late adverse cardiac remodelling
after successful reperfusion with primary PCI in STEMI
patients are indicated in Figure 2. Recognition of the hetero-
geneous pathophysiology of adverse cardiac remodelling
after AMI can create a powerful risk stratification score based
on biomarkers reflecting various stages of pathogenesis of the
condition [36].
3. Pathogenetic Mechanisms of Adverse Cardiac
Remodelling after Acute
Myocardial Infarction
Advances in our understanding of the molecular mecha-
nisms of regulation toward late adverse cardiac remodelling
were associated with the breakthrough in the recognition of
Delaying revascularization
Incomplete rocovering
blood ow though culprit
coronary artery
Severe ischemia-related
stenosis
Advance hyperemic
microcirculatory resistance
“No-reow” phenomenon
“No-reow” phenomenon
Inadequate healing
Hibernation and stunning
Incomplete recovering
blood ow though culprit
coronary artery
Hibernation
Microvascular obstruction
Restenosis
Progression of old stenotic
lesions
Late stent thrombosis
Stent malapposition
Comorbidities
Dysfunction of endogenous
vascular repair system
Tri g ger s
Acute myocardial
infarction
Early adverse cardiac
remodelling
Infarct expansion
Early LV dilatation
Myocardial thinning
Akinesis area shaping
Diastolic dysfunction
Reducing LVEF
Presenting HF
Late adverse cardiac
remodelling
Late LV dilatation
LV diastolic dysfunction
Interventricular dissynchrony
Regional contractility
dysfunction
HFpEF/HFmrEF/HFrEF
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Figure 1: Adverse cardiac remodelling after AMI: the role of different triggers in development of cardiac architectonic disorders and heart
failure. LV: left ventricular; HF: heart failure; HFpEF: HF with preserved ejection fraction; HFmrEF: HF with midrange ejection fraction;
HFrEF: HF with reduced ejection fraction.
3Disease Markers
interplaying between various processes translating ische-
mia/reperfusion injury on myocardium, such as disrupting
nitric oxide (NO) and vascular endothelial growth factor
(VEGF) signalling systems, p38 MAPK pathway and redox
dysregulation, cytokine release, and activation of apoptotic
and necrotic death pathways with subsequent stimulation
of oxidative stress, mitochondrial dysfunction, altered
myocardial cell metabolism, excessive fibrosis, and cardiac
cell remodelling [37]. Therefore, preserved microvascular
inflammation, small vessel obstruction, endothelial dys-
function, and atherosclerotic lesions mediate a remote
effect on advance LV remodelling [38]. Additionally, there
are new explanations regarding individual susceptibility to
ischemia/reperfusion injury including early and remote
ischemic preconditioning [39]. Figure 3 yields main path-
ogenetic mechanisms that are involved in the pathogenesis
of late adverse cardiac remodelling.
In fact, restoration of adequate blood perfusion after a
critical period of ischemia and prevention of reperfusion
damage appear to be not the only protector over cardiac
damage. Early irreversible cardiac myocyte injury leading to
necrosis in the ischemic myocardium and expanding infarc-
tion zone are an attribute of susceptibility of cardiac cells to
impaired metabolism, loss of structural integrity and selec-
tive permeability of the cell membranes, altered ultrastruc-
ture of cell organoids, such as sarcolemma disruption,
deterioration of nucleus, ribosomes, mitochondria, and sar-
coplasmic reticulum, the presentation of mitochondrial
amorphous densities, and chromatin fragmentation [40].
During this early stage of AMI development, the mitochon-
drial dysfunction plays a pivotal role in cardiac myocyte apo-
ptosis in the ischemic/reperfused heart, cardiac necrosis, and
ischemia-induced preconditioning phenomenon [41, 42].
Numerous studies have shown that proapoptotic stim-
uli through involving cytokines, which belong to the B-cell
lymphoma 2 (Bcl-2) super family, mediate the permeabil-
ity of the mitochondrial membranes and stimulate the
release of a wide spectrum of the active apoptogenic mol-
ecules (cytochrome c, Bax) into the cytoplasm. They cause
the apoptotic response, peroxidation of membrane, and
disruption of mitochondrial chromatin materials, including
small interfering ribonucleic acid (RNA) and mitochon-
drial deoxyribonucleic acid (DNA) [43, 44]. Cytochrome
C is able to bind to the adaptor protein apoptotic protease
activating factor 1 (Apaf-1) and act as a trigger of its olig-
omerization that activates caspase cascade through initiat-
ing procaspase-9 recruitment. Caspases including caspase-
6 and caspase-9 cleave cellular proteins and DNAs/RNAs
emerging apoptosis [45]. This process is under the close
epigenetic regulation of long noncoding RNAs (LncRNA)
and microRNAs (miRNA-29b-1-5p, miRNA-195), which
negatively regulate Bcl2l2 gene expression and participate
in cardiac myocyte apoptosis, oxidative stress through
inducing hydrogen peroxide (H
2
O
2
), and inflammation
Preprocedural
Prevention of late adverse cardiac remodelling
Perprocedural Early postprocedural Late postprocedural
Optimal BP
Optimal
glycaemia
Statin initiation
Eective DAPT
Optimal time for
PCI
Radial vs femoral
access
TIMI III blood
ow recovery
Complete
revascularization
BES instead BMS
Optimal
anticoagulation
Nitrates
Anti-GPIIb/IIIa
inhibitors in
selected cases
romboectomy
in selected cases
Rotational
atheroectomy
protocol
Venous gra PCI
protocol
Reduce ischemic
time
IVUS-VH or OCT
enhancement
Hemodynamic
stabilization
Selective IC
calcium inhibitors
Adenosine
Anti-GPIIb/IIIa
inhibitors
Statins
Statins
Optimal DAPT
Optimal DAPT
IVUS-VH or OCT
control for
plaque necrotic
core component,
stent
implantation,
early stent
thrombosis/
restenosis
Beta-blockers,
ACE inhibitors or
ARBs in HF
Beta-blockers,
ACE inhibitors or
ARBs in HF
MCRA in
LVEF<35% MCRA in
LVEF<35%
Optimal
treatment
comorbidities
Preventing
transient
reversible
ischemia
Qualitative oine
analysis of IVUS-
VH or OCT
image for stent
implantation, late
stent thrombosis
/ restenosis,
neoatheroscleros
is, positive vessel
remodelling
•
•
•
•
•
•
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•
•
•
•
•
•
•
•
•
•
•
•
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•
•
•
•
•
•
Figure 2: The factors preventing late adverse cardiac remodelling in AMI patients after successful reperfusion with PCI. IVUS-VH:
intravascular ultrasound virtual-histology; BMS: bare metal stent; BES: biolimus eluting stent; OCT: optical coherence tomography;
DAPT: dual antiplatelet therapy; ACE: angiotensin-converting enzyme; ARBs: angiotensin-II receptor antagonists; MCRA:
mineralocorticoid receptor antagonists; IC: intracoronary.
4 Disease Markers
via triggering proinflammatory cytokine release [44, 46].
Therefore, downregulated miRNA-98 and miRNA-124 may
attenuate cell survival through diminished levels of STAT3
and p-STAT3 in response to ischemia and over production
of H
2
O
2
[47, 48]. During ischemia/reperfusion episodes, oxi-
dative stress, mitochondrial Ca
2+
overload, proinflammatory
cytokines (interleukin- (IL-) 2, IL-6, tumor necrosis factor-
alpha, and interferon-gamma) stimulate the activity of the
matrix metalloproteinases and suppress release of their tissue
inhibitors [49]. MMPs (MMP-2, MMP-6, and MMP-9)
directly contribute to global and local myocardial contractile
dysfunction and induce cell death [50]. Other matricellular
proteins, such as thrombospondin- (TSP-) 1 and TSP-2, as
well as bone-related proteins (osteopontin, osteonectin, and
osteoprotegerin), were found to regulate cardiac reparation
and remodelling via activation of VEGF and transforming
growth factor (TGF-β) by binding to the latency-associated
propeptide, inhibition of MMP activity, and exertion of potent
angiostatic actions of antigen-presenting cells and T-cells [51].
Moreover, they are triggers for accumulation, degradation and
remodelling of extracellular matrix (ECM), cleaving big
endothelin-1 and attenuating vasoconstriction, and modifica-
tion of architectonics of myocardium leading to cardiac
remodelling and HF development [51, 52].
Interestingly, susceptibility of myocardium to ischemia
and reperfusion may relate to various inhered causes, such
as mutations in genes encoding for angiotensin II,
angiotensin-converting enzyme, osteopontin, osteoproteg-
erin, CC chemokine receptor 2, the members of the family
of multidomain extracellular protease enzymes ADAMTS
(A Disintegrin and Metalloproteinase with Thrombospon-
din motifs), predominantly ADAMTS-2, ADAMTS-4,
ADAMTS-10, and ADAMTS-13, promoter region of endo-
thelial NO synthase, apelin, TGF-β, VEGF, galectin-3, fico-
lin-1, S100 calcium-binding protein A9, and mitochondrial
aldehyde dehydrogenase 2 (NDUFC2) [53–56]. Finally, sus-
ceptibility of cardiac cells to ischemia and reperfusion dam-
age may relate to the capability of endogenous redox
systems to protect cell membranes and cellular structures
(mitochondria, cytoskeletal proteins, growth factor receptors,
and microtubule-associated proteins) from the impaired effect
of the deteriorating energetic metabolism and detergenting
impact of oxidized lipids and proteins sustaining an effective
work of transmembrane ionic pumps [57]. This phenomenon
was called ischemic preconditioning, and now it is also recog-
nized as an early (before AMI or during acute phase of AMI)
and remote (overreparative period of AMI) phenomenon
depending on a period of onset of ischemia-reperfusion epi-
sodes. However, previous studies have revealed a reduction
of infarct size and peripheral area with hibernating/stunning
myocardium with both types of preconditioning due to intra-
cardiac protection that prevents cytosolic and mitochondrial
Ca
2+
overload, accumulation of reactive oxygen species
(ROS), lysosomal/nonlysosomal enzyme releasing, and
inflammatory reaction [58–60].
Recurrent episodes of ischemia/reperfusion induce cardi-
oprotective mechanisms in failed heart named postcondi-
tioning and remote conditioning [61, 62], which are
supported by various comorbidities (diabetes mellitus, insu-
lin resistance, obesity, and inflammatory conditions) [63,
64]. The cardiac protective mechanisms may include upregu-
lation of caveolin, resolvin D1/E1, ubiquinone, long pentra-
xin PTX3, apelin, glucocorticoids, and long noncoding
RNAs expression for IL-19, VEGF, eNO synthase, haem
Acute MI/ Acute
coronary syndrome
Early period aer
successful PCI
Remote period
aer PCI
First hours before
restoration of coronary
circulation
Over 3 months aer PCIWithin 3 months aer PCI
Myocardial necrosis Distal embolization Remote conditioning
Ischemia/reperfusion damage
Expanding necrosis
Preconditioning
Severity of coronary
atherosclerosis
Comorbidities
Comorbidities
Preexisting HF
Individual susceptibility
Stunning/hubernation
no-reow/slow-ow
Postconditioning
Transient ischemia/reperfusion
Post-PCI technical problems
Atherosclerosis progression
Atherosclerosis progression
Inammation and brosis
Inammation and brosis
Impaired cardiac and vascular
reparation
Hibernating myocardium
Remote ischemia/reperfusion
episodes
ECM and cell remodelling
Impaired cardia and vascular
reparation
Figure 3: The main pathogenetic mechanisms underlying the initiation and progression of late adverse cardiac remodelling in AMI patients
after successful reperfusion with PCI. HF: heart failure; ECM: extracellular matrix; PCI: percutaneous coronary intervention.
5Disease Markers
oxygenase-1 (HO-1), calcitonin gene-related peptide, and
peroxisome proliferator-activated receptor gamma, and
downregulation of β-adrenergic signalling, G protein-
coupled receptor kinase-2, and β-arrestin 1 and 2 in cardiac
myocytes, fibroblasts/myofibroblasts, tissue residence cells,
and circulating progenitor cells as well as mononuclears
[65–68]. These factors reduce inflammatory infiltrates, stabi-
lize cell membrane, support membrane ionic channels, and
suppress the formation of key proinflammatory cytokines,
such as tumor necrosis factor-alpha (TNF-α), IL-1β, and
IL-6. Additionally, IL-19 suppresses the polarization of pro-
inflammatory subtype M1 macrophages and triggers M2
macrophage polarization in infarct myocardium that leads
to inhibition of cardiac remodelling [68].
During AMI and recurrent episodes of micronecrosis in
myocardium after PCI due to remote ischemia/reperfusion
damage, the important role in the regulation of cardiac
remodelling belongs to alarmins, which are released by
necrotic myocardium and act as a powerful trigger of inflam-
matory cytokine synthesis [69]. Damaged and necrotic car-
diac myocytes secrete wide-spectrum factors called DAMPs
(Damage-Associated Molecular Patterns), such as high-
mobility group 1B protein (HMGB1), RNA, nucleotides, heat
shock proteins (HSP), members of the S100 family, and IL-
1a, which potentiate the inflammatory response, attenuate
oxidative stress, act as direct cytotoxic agents, and induce
thrombus formation and circulating blood cell aggregation
[70]. Numerous molecules, such as HMGB1, S100 family
members, are able to induce apoptosis of circulating endo-
thelial progenitor cells and tissue residence cells via a multi-
ligand receptor for advanced glycation end products-
(RAGE-) mediated activation of endoplasmic reticulum
stress pathway [71]. Therefore, the DAMPs and other che-
mokines, such as CXC and CC (predominantly CCL2,
CCR2, CCR5, and ELR+CXC chemokines), recruit various
subpopulations of peripheral blood cells including proin-
flammatory mononuclears, regulatory T-cells, nature killers,
and neutrophils in the infarcted myocardium and endothe-
lium supporting inflammatory response [72].
Inflammation is a crucial element for clearance of cellu-
lar and matrix debris, while suppression of proinflamma-
tory signalling is necessary to transform the inflammatory
phase to the proliferative phase [73]. Indeed, proinflamma-
tory mediators include uncoupling protein 2, superoxide
dismutase- (SOD-) 1 and SOD-2, ROS, through the activa-
tion of mTOR, hypoxia-induced factor- (HIF-) 1, Toll-like
receptor (TLR)/IL-1, and RAGE-dependent pathways in
surviving border-zone fibroblasts, cardiac myocytes, endo-
thelial cells, smooth muscle cells, mononuclears, and several
residence and progenitor cells mediating reparative pro-
cesses [74–76]. It relates to the modification of cardiac
fibroblasts into myofibroblasts that are enriched in α-
smooth muscle actin, accumulation of extracellular matrix,
neovascularization, and angiogenesis. However, the proin-
flammatory cytokines may have a detrimental impact on
cardiac remodelling and function directly maintaining
repetitive ischemia/reperfusion episodes, suppressing repa-
ration, supporting endothelial dysfunction, coagulation,
and thrombosis [77–79].
Over a 3-month period after PCI, the extracellular matrix
is continually being remodelled, and tissue fibroblasts, myo-
fibroblasts, and antigen-presenting cells become quiescent
and undergo apoptosis, and cell debris is cleared by macro-
phages [80–82]. The regulation of proliferative response
and changing of cellular phases of tissue inflammation are
mediated by the renin-angiotensin-aldosterone system
(RAAS) and simpatico adrenal system, which also are central
players in the endogenous repair system [83, 84]. Addition-
ally, the autonomic nervous system may play a crucial role
in the inflammatory and apoptotic remodelling following
AMI [85]. Thus, late adverse cardiac remodelling is a sophis-
ticated structural and functional response of failing heart to
numerous triggers (inflammation, fibrosis, cell survival sig-
nalling, and β-adrenergic signalling) and damaged factors
(ischemia, reperfusion, necrosis, and apoptosis) that appear
consequently and mutually activate each other.
4. Biomarkers of Adverse Cardiac Remodelling
Although there are well-developed current clinical recom-
mendations for HF provided by the experts of the European
Society of Cardiology (2016) [86] and American College of
Cardiology/American Heart Association (2017) [87], there
is a lack of statements for the use of biomarker strategies
for diagnosis, prediction, stratification, and prevention of
adverse cardiac remodelling. In fact, cardiac remodelling
after AMI regardless of PCI and other approaches for revas-
cularization is strongly associated with the development and
progress of HF. In this context, early biomarkers of myocar-
dial injury and necrosis, as well as biomarkers of biomechan-
ical stress, neurohumoral and inflammatory activation, and
fibrosis, having predictive and diagnostic evidence for acute
and chronic HF, are extrapolated over strategy regarding
diagnosis, outcomes, and stratification of adverse cardiac
remodelling (Table 1).
There is no complete agreement between experts from
the European Society of Cardiology and American College
of Cardiology/American Heart Association regarding the
utility of biomarkers in HF [88]. Natriuretic peptides (NPs)
are recommended by both guidelines for acute and chronic
HF diagnosis, prediction of HF-relating outcomes, including
death, and a risk stratification. In contrast, the European
Society of Cardiology (2016) HF clinical recommendation
does not consist the supporting evidence regarding other bio-
markers for multitask strategy in HF, and HF-guided therapy
is not routinely recommended, while the HF biomarker guid-
ance was previously approved by the American College of
Cardiology/American Heart Association. Additionally, there
was poor discrimination when NPs were used in patients
with HF at hospital discharge, which was inferior to its per-
formance in patients with ambulatory HF regardless of sever-
ity cardiac dysfunction and phenotypes.
However, there is a large body of evidence that other bio-
markers (growth/differential factor-15, MMP-2, MMP-6,
MMP-9, adipocytokines (apelin, chemerin, and visfatin),
circulating endothelial and mononuclear progenitor cells,
activated and apoptotic endothelial cell-derived microvesi-
cles, miRNAs, and bone-related proteins) reflecting different
6 Disease Markers
stages of the pathogenesis of adverse cardiac remodelling
after PCI can be considered as promising tools for further
strategies to improve prediction of clinical outcomes, attenu-
ate CV risk stratification, and develop personifying strategy
for treatment [89, 90]. For instance, miRNAs are speculated
to have crucial roles in the nature evolution of adverse car-
diac remodelling after AMI, and identification of key genes
associated with damaged heart response could improve pre-
diction models for the patients [91]. Moreover, miRNA pro-
filing and gene cards with information about a signature of
mutations involved in the regulation of the transcription fac-
tors, which mediate cardiac remodelling, appear to be prom-
ising for further precise medicine after PCI [92].
5. Biomarkers of Cardiac Injury and Necrosis
Elevated levels of high-specific cardiac troponins T (hs-TnT)
and I (hs-TnI) in peripheral blood are served as diagnostic
and predictive biomarkers for acute coronary syndromes
and AMI [93], as well as an independent prognosticator of
CV risk in the general population [94]. Cardiac troponins
are structure proteins of actin-myosin complex, which are
released from the cells due to necrosis or leakage from cytosol
through the permeable cell membrane [95]. High-sensitivity
cardiac troponin assay allows diagnosing patients with minor
myocardial injury and suggesting a size of infarction [96].
Cell-free pool of cardiac troponins was reported having a ten-
dency to decrease after AMI, while peak concentrations of
both hs-TnT and hs-TnI have strongly predicted major car-
diovascular events including death, recurrent MI, need of
PCI, and subsequent HF hospitalization [96, 97]. Moreover,
elevated concentrations of circulating cardiac troponins
remain useful independent predictive biomarkers of newly
post-AMI HF [98, 99]. Interestingly, elevated levels of hs-
TnI were associated with CV death, whereas hs-TnT has
more strongly predicted the risk of non-CV death [100]. In
fact, cardiac and noncardiac surgeries mediate the elevation
of troponins in the peripheral blood postprocedurally. It
requires specific approach to assay an impact of transient ele-
vation of these findings on a risk of poor prognosis. Obvi-
ously, the combined biomarkers’models are necessary.
After a prolonged period of hopes regarding improve-
ment of diagnostic and risk stratification in STEMI patients
with subsequent PCI using the combined biomarker models
(cardiac troponins, NPs, copeptin, choline, soluble ST2,
GDF-15, high-sensitivity C-reactive protein, galectin-3, and
lipoprotein-associated phospholipase A2) [101], it has clearly
become what large clinical trials need to evaluate diagnostic
and predictive values of various combinations of biomarkers,
because the evidence of previous studies in AMI patient
treated with PCI appeared to be controversial [102, 103].
Copeptin did not add diagnostic information to peak con-
centration of high-sensitive troponin T in STEMI patients
with subsequent PCI [104, 105]. Yet, hs-TnT/hs-TnI and
NT-probrain NP (NT-proBNP) were recognized to have
similar predictive values for all-cause mortality and first
readmission in HFpEF [106, 107], whereas NT-proBNP
was superior to cardiac troponins for the prognostication of
HFrEF clinical outcomes [108, 109]. It has been noted that
the predictive value of hs-TnI for HF-related clinical out-
come was strongest in men with HFpEF/HFrEF than in
women [108]. Other biomarkers, including soluble ST2,
Table 1: Clinical relevance of circulating biomarkers for late adverse cardiac remodelling: overlap with HF.
Biomarkers Heart failure Adverse cardiac remodelling
Diagnosis Outcomes Guided therapy Risk stratification Diagnosis Outcomes Risk stratification
Currently used or recommended biomarkers
hs-troponin T/I
҂
-++ –++++
NPs
#҂
++ +++ + ++ ++ +++ ++
MR-proADM + +++ - ++ + +++ ++
Galectin-3
҂
-+ - + -++ +
sST2
҂
–++ + - - +++ +
Promising biomarkers
Copeptin + ++ - + + ++ +
GDF15 –++ - + - ++ ++
hs-CRP –+- - –++
IL-1β–+- + –++
IL-6 –+- + –++
MMP-2 –+––++ +
MMP-9 –+––++ +
CTPpC-I –+–+-+++
APpC-III –+–+-+++
miRNAs –++ + -+ +
-
Mildly disagree;
–
moderately disagree;
+
mildly agree;
++
moderately agree;
+++
strongly agree;
#
approved by the European Society of Cardiology (2016);
҂
approved by the American College of Cardiology/American Heart Association (2017). hs: high sensitive; HF: heart failure; NPs: natriuretic peptides; sST2:
soluble suppression of tumorigenicity-2; MR-proADM: midregional proadrenomedullin; GDF: growth/differential factor; CRP: C-reactive protein; miRNAs:
microribonucleic acids; MMP: matrix metalloproteinase; CTPpC-I: carboxytelopeptides of procollagen type I; APpC-III: aminopeptide of procollagen type III.
7Disease Markers
high-sensitivity C-reactive protein, galectin-3, midregional
proadrenomedullin, and GDF-15, in combination with
hs-TnI/hs-TnT did not represent superiority in compari-
son with the isolated use of hs-TnI/hs-TnT in HFpEF,
whereas in patients with HFmrEF/HFrEF, multimarkers’
strategy was better in the prognostication of poor progno-
sis [110, 111].
Although previous clinical trials did not find significant
interactions between stable HFpEF and HFrEF when con-
sidering the prognostic value of the NT-proBNP, cystatin-
C, hs-TnT, and soluble ST2 [112–114], it can be otherwise
for HF that is associated with adverse cardiac remodelling
after AMI with subsequent PCI. Thus, clinical prediction
models for HF-related outcomes based on various biomarkers
of biomechanical stress (NT-proBNP, copeptin, midregional
proadrenomedullin (MR-proADM), and growth/differential
factor- (GDF-) 15), inflammation (high-sensitivity C-reactive
protein), and fibrosis (galectin-3, soluble ST2) were only
improved marginally by the addition of hs-TnT/hs-TnI.
Moreover, hs-TnT or hs-TnI added to NT-proBNP and
sST2 appears to be emerging biomarkers in the prediction of
adverse outcome of HF after AMI in a short-term period
[115], but whether this combination is most suitable for
remote prognostication in patients with known late adverse
cardiac remodelling and different phenotypes of ischemia-
induced HF is not fully clear.
6. Inflammatory Biomarkers
6.1. Interleukins. IL-1β, IL-6, and angiopoietin-like protein 2
(Angptl 2) are inflammatory cytokines that influence delete-
rious effects on myocardium structure and function unleash-
ing to cardiac remodelling [116]. There is strong evidence
clarifying that the myocardial expression levels of IL-1β, IL-
6, and Angptl 2 were significantly higher in the AMI patients
than in the healthy volunteers [117]. Moreover, the levels of
Angptl 2 and IL-6 rather correlated with the severity of
coronary atherosclerosis than the size of the infarct area
and HF presence. In contrast, IL-1βlevels were associated
with prior HF admissions, functional cardiac impairment,
and higher NT-proBNP, sST2, and hs-TnT concentrations
[115]. In fact, circulating IL-1βlevels had been clinically
meaningful in HF patients interfering with the predictive
ability of sST2. Indeed, regardless of LVEF, HF patients
with low sST2 (≥35.0 ng/ml) and also low IL-1β
(≥49.1 pg/ml) had significantly lower risk of CV death,
HF-related outcomes including readmission, than among
patients with high sST2 (>35.0 ng/ml) and also high IL-
1β(<49.1 pg/ml) levels [115].
6.2. Soluble Suppression of Tumorigenicity-2. Serum levels of
IL-33 and soluble suppression of tumorigenicity-2 (sST2),
which is the soluble form of IL-1 receptor-like 1 (IL-33), were
significantly higher in HF regardless of the presence HF phe-
notypes associated with HF symptom severity, LV hypertro-
phy, and the risk of CV death and hospitalization than in
healthy volunteers [118, 119]. It was found that IL-33
improved cell viability after ischemia injury through ST2 sig-
nalling and suppression nuclear factor kappa-B that
unleashed the upexpression of the antiapoptotic factors
(XIAP, cIAP1, surviving) and HIF-1, preventing apoptosis
[120]. In patients with AMI, serum levels of sST2 were found
to be increased, and after adjustment for comorbidities,
the Killip class and troponin T sST2 independently pre-
dicted the excess risk of death and HF [121]. Development
of adverse cardiac remodelling due to AMI was strongly
associated with the elevated levels of sST2 in the periph-
eral blood [122].
Serum sST2 served as a predictive biomarker in
patients at risk of HF and in individuals with established
chronic HF [123], but the prognostic value of the bio-
marker was diminished after adjusting for the clinical sta-
tus including comorbidity presence (abdominal obesity,
diabetes mellitus, and obstructive pulmonary disease) and
NT-proBNP [124–126]. Additionally, sST2 was able to be
helpful in short-term clinical outcome prognostication in
acute HF and actually decompensated HF patients regard-
less of worsening kidney function, whereas renal failure
was found to be a crucial factor for the NP predictive
value [127, 128]. In-patients survived after acute HF have
yielded the concentrations of sST2 at discharge which
were independently associated with sudden death, CV
death, HF-related death, and HF readmission during the
3-month period after discharge [127, 128]. Yet, sST2
yielded strong, independent predictive value for all-cause
and cardiovascular mortality, and HF hospitalization in
chronic HF, and deserves consideration to be part of a
multimarker panel together with NT-proBNP and hs-
TnT [129]. The PARADIGM-HF trial (Prospective Com-
parison of ARNI With ACEI to Determine Impact on
Global Mortality and Morbidity in Heart Failure) has
revealed the levels of sST2 increased at 1 month which
were associated with worse subsequent HF clinical out-
comes, and the decreased sST2 concentrations were related
to better prognosis particularly related to declined CV
death and HF admission [130].
6.3. C-Reactive Protein. High-sensitive C-reactive protein
(hs-CRP) has also markedly improved the risk stratification
of acute HF and acutely decompensated HF patients in mul-
tibiomarker models, which predominantly included MR-
proADM and NT-proBNP [131, 132]. However, circulating
levels of hs-CRP were associated with the New York Heart
Association functional class of HF, primary hospitalizations
and readmission predominantly in patients with HFrEF,
but not HFpEF [133]. Unfortunately, hs-CRP did not add
incremental value to NPs, sST2, and galectin-3 in patients
with HFpEF rather than HFpEF [133, 134]. The ASCEND-
HF trial has reported that the levels of hs-CRP at admission
in acute HF patients were not associated with acute dyspnea
improvement, in-hospital death, advancing HF, short-term
(30 days) and long-term (180 days) mortality, and HF read-
mission [135, 136]. On the contrary, at 30 days, elevated
levels of hs-CRP among survivors were associated with
higher 180-day mortality and readmission [135]. Although
hs-CRP is under ongoing investigations, potential treatment
options and goals of the therapy among HF individuals are
not fully determined.
8 Disease Markers
6.4. Growth Differential Factor-15. Growth differentiation
factor- (GDF-) 15 is determined as an inflammation and oxi-
dative stress biomarker, which belongs to the TGF-βcyto-
kine superfamily and is highly expressed in myocardium
and endothelial cells in CV disease including HF [137]. Pre-
vious studies have shown that GDF-15 protected the myocar-
dium from ischemia and reperfusion injury [138, 139].
Higher serum levels of GDF-15 were associated with poor
prognosis in acute HF independent from concentrations of
NPs [140] and chronic HF irrespective of LVEF [141, 142].
Moreover, the Valsartan Heart Failure Trial has shown that
serial measurements of GDF-15 had increased the incre-
mental predictive power to the only measure at baseline
for the severity of HF and prognosis [143]. Additionally,
the elevated serum level of GDF-15 was the most prognos-
tic biomarker in comparison to NT-proBNP, hs-CRP, and
hs-TnT, in predicting long-term mortality in advanced HF
[144]. Overall, a multimarker model based on NT-proBNP,
hs-CRP, GDF-15, and hs-TnT had more predictable HFrEF
and HFpEF than the isolating biomarker [145, 146]. Prob-
ably, inflammatory mediators, such as sST2 and GDF-15,
as it is expecting, can become molecular targets not only
for the diagnosis but also for the treatment of adverse car-
diac remodelling in the future.
7. Biomarkers of Cardiac Fibrosis
7.1. Galectin-3. Over the last decade, galectin-3 had been
widely investigated as a biomarker of fibrosis and inflamma-
tion with a promising predictive value for HF development
and CV events [147]. Galectin-3 is multifunction β-galacto-
side-binding protein, which belongs to lectin family and is
expressed in several tissues and circulating cells, such as
mononuclears, macrophages, progenitor cells, mast cells,
and neutrophils [148]. Galectin-3 plays a pivotal role in
inflammation, fibrosis, immunity, tissue repair, and cardiac
remodelling and acts as a mediator of the development and
progression of the diseases, for which these pathogenetic
stages are crucial [149, 150]. Indeed, galectin-3 is expressed
in myocardium releasing from activated macrophages and
contributes cardiac dysfunction through the remodelling of
ECM and accumulation of collagen [151]. Additionally,
galectin-3 is able to mediate cardiac and vascular fibrosis
induced by overexpressed aldosterone [152]. However, there
is evidence confirming the role of polymorphism of galectin-
3 gene in susceptibility to cardiac injury and fibrosis [153].
Being a mediator of both mutual relating processes—inflam-
mation and fibrosis—galectin-3 was approved by the Food
and Drugs Administration (USA) as a predictive biomarker
for HF development and progression [87, 154]. In fact, ele-
vated levels of galectin-3 were found in patients with adverse
cardiac remodelling regardless of HF phenotypes and it eth-
nologies [155, 156]. Therefore, galectin-3 having some
advantages to NPs (more stability and resistance against
hemodynamic overload and unloading state) predicted CV
mortality and rehospitalization in HFrEF and HFpEF [157,
158]. Moreover, the TRIUMPH (Translational Initiative on
Unique and Novel Strategies for Management of Patients
with Heart Failure) has shown that repeated measures of
serum levels of galectin-3 could be useful in routine clinical
practice for HF prognostication and treatment monitoring
[159]. However, head-to-head comparison of sST2 and
galectin3 has revealed the superiority of sST2 in long-term
risk stratification in an ambulatory stable HF [160]. For
future direction, these facts require to be investigated in detail
in large clinical trials with large sample size, because a meta-
analysis of a discriminative value of galectin-3 did not yield a
confirmation of previously received data [161].
7.2. Biomarkers of Collagen Turnover. It has been postulated
that biomarkers of collagen turnover, such as carboxy-
terminal telopeptide of collagen type I, amino-terminal pro-
peptide of type III procollagen, MMPs, and tissue inhibitors
of MMPs, may be useful for risk stratification of cardiac
remodelling associated with HFpEF and HFrEF [162, 163].
Indeed, myocardial fibrosis being a major cause of diastolic
dysfunction contributes predominantly to the HFpEF [164].
The ECM rearrangement corresponds to an intensity of the
inflammation in myocardium, and serum levels of bio-
markers of collagen turnover are mediated by a balance
between degradation of ECM components and synthesis.
Proliferative phase complimented to myocardial fibrosis is
considered a typical response during late adverse cardiac
remodelling, whereas increased degradation of ECM is suit-
able for AMI and early cardiac dilatation [165]. In fact,
MMP-2, MMP-9, carboxytelopeptides of procollagen type I,
and aminopeptide of procollagen type III had a predictive
value for HFpEF that was equal NT-proBNP [163], while dis-
criminative ability of elevated serum levels of MMP-2 was
superior to NT-proBNP for early HFpEF [162, 163, 166].
Whether emerging biomarkers of ECM rearrangement and
collagen turnover is essential to identify asymptomatic
patients with HFpEF after AMI with subsequent PCI is not
fully clear, while a loss of myocardial collagen scaffolding
plays a pivotal role in adverse cardiac remodelling with poor
prognosis. Interestingly, elevated levels of C-terminal telo-
peptide were associated with global LVEF, the risk of CV
death, and newly diagnosed or worsening HF due to various
causes [167–169]. In this context, integrity of ECM bio-
markers into personifying predictive strategy in AMI patients
appears to be promised, because multiple biomarkers’
approach with traditional biomarkers and indicators of
ECM turnover may have increased the sensitivity and speci-
ficity of clinical outcomes in patients with adverse cardiac
remodelling and isolated diastolic dysfunction.
8. Biomarkers of Biomechanical
Myocardial Stress
8.1. Natriuretic Peptides. The physiologically natriuretic pep-
tide (NP) system mediates water and sodium homeostasis
playing a pivotal role in blood pressure enhancement, fluid
retention, vascular function, structure remodelling of the
heart, kidney, and vessels, and maintaining differentiation
and repair tissue, and supports immunity, metabolic
response, and inflammation [170]. There are at least four
members of NP system, such as atrial NP (ANP), brain NP
(BNP), C-type of NP, and D-type of NP [171]. Biological
9Disease Markers
effects of NPs are provided through interacting with appro-
priate receptors: NPR-A, NPR-B, and NPR-C. Kidney effects
of NPs are diuresis and wateresis due to the decreasing tubu-
lar reabsorption of sodium and water, increasing glomerular
filtration rate (GFR) in result of inducing afferent arteriole
vasodilation, and protection of the kidney from metabolic
and ischemia injury [172]. Vascular effects of NPs corre-
spond to vasodilation, support, capillary permeability and
vascular reparation, and antiproliferative and hypocoagula-
tive effects [173]. NPs mediate cardiac protection with
respect to decreasing preload and afterload, diminishing bio-
mechanical stress, and maintaining anti-ischemic, antiprolif-
erative, and antiapoptotic abilities. Therefore, NPs have
direct inotropic and antiarrhythmic effects [174]. Overall,
the NP system is a physiological antagonist of RAAS and
the sympathoadrenal system. The main triggers for synthesis
and release of NPs are myocardial stretching, fluid retention,
increase of pre- and postload, BP elevation, decreasing GFR,
and ischemia of target organs (kidney, heart, and brain).
Therefore, adipocytes and glial cells can produce NPs as a
result of proinflammatory stimulation [175].
Increased activity of a circulating and local NP system
was determined in patients with CV disease including LV
hypertrophy, AMI, stable coronary artery disease, hyperten-
sion, and HF [176]. However, there are large numbers of
causes distinguishing from CV and accompanying elevation
of circulating levels of NPs (see Table 2). There is a large body
of evidence showing that NP production occurs in close rela-
tion to the severity of LV systolic dysfunction, and the circu-
lating levels of BNP and ANP strongly correspond to the
New York Heart Association functional class of HF [88].
However, the production of NPs in advanced HF became
blunt and irrespective of how high concentration of NPs
in peripheral blood fluid retention, vasoconstriction, and
cardiac dysfunction appears to progressed. In contrast,
adequate treatment of HF, which is associated with
improvement of clinical status and increase of tolerance
to physical exercise, corresponds to declining circulating
levels of BNP and ANP [177].
Therefore, patients with abdominal obesity frequently
present less levels of BNP that it is expected due to increased
circulating levels of neprilysin, which degradates BNP [178].
Although older age and female sex are the most common rea-
son association with increased levels of NPs in circulation
beyond relative causes, some structural abnormalities corre-
sponding to decreased mean e
′velocity and increased mitral
early flow velocity/early diastolic tissue velocity ratio can be
found [179–181].
Current clinical recommendations are considered NPs
predominantly BNP, NT-proBNP, and NT-proANP, as diag-
nostic and predictive biomarkers for HF regardless of LVEF,
as well as a tool for risk stratification in general population
[86, 87]. However, elevated levels of NPs (BNP ≥100 pg/ml
or NT −proBNP ≥300 pg/ml;orBNP ≥300 pg/ml or NT −
proBNP ≥900 pg/ml if in atrial fibrillation/flutter) in patients
with suspected HFmrEF/HFpEF were found to confirm the
diagnosis [182]. NPs are also excellent prognostic biomarkers
of adverse cardiac remodelling after AMI, whereas the clini-
cal value of such discriminative ability is less clear than estab-
lished acute and chronic HF [183]. Therefore, decreased
levels of NT −proBNP < 1000 pg/ml as a result of HF therapy
was associated with lower 180-day mortality and readmission
in comparison with NT −proBNP ≥1000 pg/ml, whereas
NT-proBNP reduction of >30% from initial levels did not
improve 6-month outcomes and was not more effective than
a traditional treatment [184–186]. Overall, elevated levels of
NPs including NT-proBNP and NT-proANP had higher
negative diagnostic value than the positive diagnostic value
for HF, while the positive predictive ability of NPs in elevat-
ing concentrations was superior to the negative predictive
value for asymptomatic cardiac remodelling, as well as HF
regardless of LVEF. In fact, high individual variability,
depending on the serum levels of NPs on comorbidities,
including GFR, abdominal obesity, and older age and
female sex, gives more opportunities to rule out major
structural cardiac abnormalities and HF, when NP levels
are normal or near normal. Confirmation of the HF and
cardiac remodelling with isolating diastolic dysfunction
requires more predictive information including clinical
conditions, diastolic characteristics, measure of LVEF, and
other biomarker assay.
8.2. Copeptin. Copeptin is a stable 39-aminoacid glycopep-
tide derived from C-terminal portion of the precursor of argi-
nine vasopressin, which is a key regulator of water
homeostasis and plasma osmolality [187]. Serum levels of
copeptin have exhibited close linear correlation with concen-
trations of arginine vasopressin and are use as surrogate bio-
marker of its secretion [188]. There is evidence that elevated
serum levels of copeptin are a diagnostic biomarker of
Table 2: CV and non-CV causes of elevating NPs in peripheral
blood.
CV causes Non-CV causes
Acute and chronic HF Sepsis/shock
LV hypertrophy Severe infections
Pulmonary hypertension Critical ill patients
ACS/AMI Acute and chronic kidney failure
Stable CAD Severe trauma/surgery
Multifocal atherosclerosis Chronic obstructive pulmonary
disease
Cardiomyopathies Severe bronchial asthma
Myocarditis Pneumonia
Atrial fibrillation and flutter Large burns and frostbite
Hypertension Stroke
Congenital and acquired
valvular heart disease Kidney amyloidosis
Pericardial disease Diabetes mellitus
Cardiac toxicity due to
tumoricidal therapy Thyroid dysfunction
Electrical
cardioversion/ablation Anemia
Successful resuscitation Pleural disease
HF: heart failure; LV: left ventricular; ACS: acute coronary syndrome; AMI:
acute myocardial infarction; CAD: coronary artery disease.
10 Disease Markers
asymptomatic cardiac remodelling, HF, sepsis, acute kidney
injury, insulin resistance, and metabolic syndrome [189].
Several trials have yielded that increased levels of copeptin
were strong predictor of mortality in patients with acute
and chronic HF [189, 190], stroke [191], end stage of renal
disease [192], stable CAD [193], and diabetes mellitus
[194]. However, there is a large number of confounding fac-
tors (hydration status, gender, blood pressure, GFR, and
body mass), which make it difficult to interpret data of
copeptin levels in patients with known CV disease, as well
as in healthy individuals [195]. Additionally, copeptin was
not better than the NPs in the diagnosis and prognosis of
HF as well as in prognostication of adverse cardiac remodel-
ling after AMI [196].
8.3. Midregional Proadrenomedullin. Midregional proadre-
nomedullin (MR-proADM) is stable peptide fragment
that is precursor for adrenomedullin (ADM) and gener-
ated through posttranslational processing from pre-
proadrenomedullin [197]. ADM is expressed in several
tissues (adrenal medulla, brain, kidney, lung, spleen, liver,
and vasculature) and cells (endothelial cells, cardiac myo-
cytes, vascular smooth muscle cells, and epithelial cells)
and mediates natriuresis, diuresis, vasodilation, positive
inotropic effect, and hypotension [198].
Early clinical trials have shown that circulating levels of
MR-proADM were significantly increased in patients with
acute HF and STEMI [199, 200], and a cut-offvalue of
0.79 nmol/l has been yielded to be asso ciated with adverse
outcomes including death [201, 202]. Additionally, serum
levels of MR-proADM >0.70 nmol/l were proposed to be
the rule-in criteria of AMI [203].
The MR-proADM has become a biomarker that was
specifically investigated as a possible prognosticator of
acute HF and early outcomes in STEMI patients under-
going PCI. The BACH (Biomarkers in Acute Heart Fail-
ure) study revealed that increased serum levels of MR-
proANP were a useful diagnostic biomarker as BNP for
acute HF in patients with acute dyspnoe [204]. The
results of the DANAMI-3 (The Danish Study of Optimal
Acute Treatment of Patients with ST-segment-elevation
myocardial infarction) study have shown that elevated
levels of MR-proADM were strong predictor of short-
and long-term mortality and hospital admission for HF
after AMI [205]. Unfortunately, MR-proADM has dem-
onstrated predictive ability with high similarity to BNP,
MR-proANP, and copeptin for one-year all-cause mortal-
ity in acute HF [206]. However, the measure of MR-
proADM may give additional diagnostic and prognostic
information for incident CV events associated with
advanced atherosclerosis that is useful for risk stratifica-
tion among patients with adverse cardiac remodelling
after AMI with subsequent PCI [207, 208]. Therefore,
MR-proADM was able to predict major adverse cardiac
events in patients suspecting AMI regardless of HF
[209]. Moreover, in contrast to NPs, MR-proADM did
not exhibit lowered concentration in obese patients with
known HF that may facilitate diagnosis and prognosis
of HF in this patient population [210].
9. Other Biomarkers of Cardiac Remodelling
9.1. Noncoding RNAs. Noncoding RNAs are powerful epige-
netic regulators of cardiac gene expression and mediators of
cardiac homeostasis and functions [211]. There are several
types of noncoding RNAs, such as microRNAs (miRNAs),
long noncoding RNAs, and circular RNAs, which play a cen-
tral role in the regulation of numerous pathogenetic mecha-
nisms and coordinate coupling of morbidity state with
susceptibility to inflammatory and proliferative response
[212]. Among these types of noncoding RNAs, various miR-
NAs are widely investigated (see Figure 4). Although there is
a large body of evidence regarding up- and downregulation
of genes for potassium channels, SERCA, subunits of recep-
tors, signal molecules, proinflammatory cytokines, apoptotic
mediators (Bax, caspase-9) in myocardium [213–216], and
miRNAs are considered rather targets for personifying inter-
vention and translational therapy, as well as prognosticators
than diagnostic biomarkers for adverse cardiac remodelling
and HF [217]. However, having signatures of miRNAs,
which correspond to adverse cardiac remodelling, HF, sud-
den death, and cardiac abnormalities with established poor
prognosis, such as concentric LV hypertrophy, fibrosis, and
inflammation, it has not completely understood whether
the “miRNA card”personally created for each patient will
have clinical significance in the prediction of HF [33, 218].
9.2. Circulating Mononuclear and Endothelial Progenitor
Cells. Mononuclears (MPCs) and endothelial progenitor cells
(EPCs) are essential components of endogenous vascular
repair system that is activated as a result of several triggers,
such as ischemia/hypoxia, inflammation, shear stress, throm-
bosis, infiltration of lipids, direct injury of vasculature, and
endothelium [32].
It has been hypothesized that mobilization of
MPCs/EPCs and increase in growth and differentiation into
mature cells in vasculature accompany acute events, includ-
ing AMI and acute HF, and are associated with vascular rep-
aration [219, 220]. However, previous acute CV events and
chronic metabolic and CV diseases, such as diabetes mellitus,
abdominal obesity, and hypertension, were reported to be
causes of an exhausting pool of circulating angiopoetic
MPCs/EPCs with immune phenotypes CD45+CD34+,
CD45+CD34+CD133+, and CD45+CD34+CD133+CD184+
[221]. Consequently, advanced HF and progression of
AMI-induced adverse cardiac remodelling were related to
impaired vascular repair, vascularization, and angiogenesis
due to a declined number of circulating precursors and
lowered their function and survival [222]. This phenome-
non is known as progenitor cell dysfunction and considered
a promising predictive biomarker for CV mortality and HF
progression and admission [223, 224], as well as in patient
population with AMI submitted to PCI [225]. Probably,
coronary circulating proangiogenic MPCs/EPCs collected
from coronary sinus in AMI patients with subsequent PCI
can become a powerful biomarker with increased accuracy
in the prediction of adverse cardiac remodelling. However,
the number and functionality of proangiogenic circulating
precursors appear as promising biomarkers for the
11Disease Markers
prediction of cardiac remodelling and HF development.
Large clinical trials are required to clearly understand the
role of new biomarkers in the diagnostic and predictive
strategies among AMI patients with PCI.
9.3. Future Perspectives. There are numerous biomarkers,
which were investigated as candidates for risk stratification
and prognosis in AMI patients with PCI, such as activated
and apoptotic endothelial cell-derived microvesicles,
bone-related proteins (osteopontin, osteoprotegerin, and
osteonectin), adipokines, gastrointestinal hormones, apelin,
cardiotrophin-1, defensin-1 and defensin-2, macrophage
inhibitory cytokine-1, circular RNAs, and gene card.
Although the data received appear to be promising, there
is no clear understanding whether diagnostic and predic-
tive abilities of these biomarkers will be better than the
conventional biomarkers of biomechanical stress, inflam-
mation, fibrosis, and cardiac injury.
10. Conclusions
Circulating biomarkers are a promising tool to stratify AMI
patients undergoing PCI at high risk of poor cardiac recovery
and HF development. NPs are traditionally recommended as
diagnostic and predictive biomarkers for acute HF and
chronic HF regardless of LVEF, whereas sST2, galectin-3,
and cardiac troponins can be used optionally. Previous clin-
ical studies have yielded that multimarker models, which
were based on the combination of biomarkers of several
pathological axes involved in the nature evolution of adverse
cardiac remodelling (biomechanical myocardial stress, necro-
sis and injury of cardiac myocytes, and inflammation), have
provided incremental prognostic information for prediction
of CV death or HF in AMI patients with subsequent PCI.
Future clinical trials with larger sample sizes are required to
elucidate the role of personifying biomarker-based strategy
for diagnostic, prediction, and treatment among patients sus-
pecting adverse cardiac remodelling and HF.
Abbreviations
ACE: Angiotensin-converting enzyme
ADAMTS: A Disintegrin and Metalloproteinase with
Thrombospondin motifs
ADM: adrenomedullin
AMI: Acute myocardial infarction
Apaf-1: Adaptor protein apoptotic protease activating
factor 1
ARBs: Angiotensin-II receptor antagonists
Bcl-2: B-cell lymphoma 2
BES: Biolimus eluting stent
BMS: Bare metal stent
CRP: C-reactive protein
CV: Cardiovascular
DAMPs: Damage-Associated Molecular Patterns
DAPT: Dual antiplatelet therapy
DNA: Deoxyribonucleic acid
ECM: Extracellular matrix
EF: Ejection fraction
GDF15: Growth/differential factor-15
Inammation
(regulation of
activity of
antigen-
presenting
cells,
macrophages
and 1-cells)
miRNA
146a
miRNA-155
miRNA-125a
Hypertension,
diabetes mellitus,
LVH, insulin
resistance,
metabolic
syndrome,
hypothyroid
dysfunction
Microvascular endothelial
dysfunction
miRNA-138 (eNOs)
miRNA-126 (VCAM-1)
miRNA-155 (antigen-
presenting cells)
miRNA-138 (eNOs)
miRNA-126 (VCAM-1)
miRNA-155 (cell-to-cell cooperation)
miRNA-26a (insulin resistance)
Late adverse cardiac
remodelling
Cell remodelling
miRNA-18
miRNA-19
miRNA-21
miRNA-22
miRNA-133
miRNA-30
miRNA-29
miRNA-195
miRNA-199
miRNA-210
miRNA-223
Fibrosis, extracellular
matrix accumulation
and angiogenesis
(regulation of cell
viability and apoptosis
of cardiac myocytes,
broblasts, smooth
muscle cells, regulation
of synthesis of MMPs,
growth factors {TGF-
beta, VEGF})
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Figure 4: The role of miRNAs in the pathogenesis of late adverse cardiac remodelling in AMI. VEGF: vascular endothelial growth factor;
TGF: transforming growth factor; NO: nitric oxide; eNOs: endothelial NO synthase; MMP: matrix metalloproteinase; VCAM: vascular
adhesive molecule.
12 Disease Markers
H
2
O
2
: Hydrogen peroxide
HF: Heart failure
HFmrEF: Heart failure with midrange ejection fraction
HFpEF: Heart failure with preserved ejection fraction
HFrEF: Heart failure with reduced ejection fraction
HIF: Hypoxia-induce factor
HMGB1: High-mobility group 1B protein
HO-1: Haem oxygenase-1
HSP: Heat shock proteins
IC: Intracoronary
IL: Interleukin
IVUS-VH: Intravascular ultrasound virtual-histology
LncRNA: Long noncoding RNA
LV: Left ventricle
MAPK: Mitogen-activated protein kinase
MCRA: Mineralocorticoid receptor antagonists
miRNA: MicroRNA
MMP: Matrix metalloproteinase
NO: Nitric oxide
NPs: Natriuretic peptides
OCT: Optical coherence tomography
PCI: Percutaneous coronary intervention
RAAS: Renin-angiotensin-aldosterone system
RNA: Ribonucleic acid
ROS: Reactive oxygen species
SOD: Superoxide dismutase
sST2: Soluble suppression of tumorigenicity-2
STEMI: ST-segment elevation myocardial infarction
TIMI score: Thrombolysis in Myocardial Infarction score
TGF: Transforming growth factor
TLR: Toll-like receptor
TNF: Tumor necrosis factor
TSP: Thrombospondin
VEGF: Vascular endothelial growth factor.
Data Availability
This is a narrative review, so dataset was not created.
Conflicts of Interest
The authors declare that there is no conflict of interest
regarding the publication of this paper.
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21Disease Markers
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