REVIEW

CURRENT
OPINION Circulating biomarkers to assess cardiovascular
function in critically ill
Dirk van Lier and Peter Pickkers

Purpose of review
Circulatory shock is one of the most common reasons for ICU admission. Mortality rates in excess of 40%
necessitate the rapid identification of high-risk patients, as well as the early assessment of effects of initiated
treatments. There is an unmet medical need for circulating biomarkers that may improve patient
stratification, predict responses to treatment interventions and may even be a target for novel therapies,
enabling a better biological rationale to personalize therapy.
Recent findings
Apart from established biomarkers such as lactate, ScvO2 or NT-pro-BNP, novel biomarkers, including
adrenomedullin, angiopoietins, angiotensin I/II ratios, renin and DPP3 show promise, as they are all
associated with well defined, therapeutically addressable molecular pathways that are dysregulated during
circulatory shock. Although some of the therapies related to these biomarkers are still in preclinical stages
of development, they may represent personalized treatment opportunities for patients in circulatory shock.
Summary
From a molecular perspective, shock represents a highly heterologous syndrome, in which multiple unique
pathways are dysregulated. Assessment of the status of these pathways with circulating biomarkers may
provide a unique opportunity to detect specific phenotypes and implement personalized medicine in the
treatment of circulatory shock.
Keywords
biomarkers, circulatory shock, personalized medicine

INTRODUCTION and metabolomics have substantially improved the

Cardiovascular failure is a common reason for knowledge on molecular mechanisms involved in
&

admission to the ICU and observed in approxi-
mately one out of three patients while in the ICU
[1]. ICU patients display marked variability in the
severity of cardiovascular failure, associated with
different dysregulated molecular pathways. Shock,
defined as circulatory failure to an extent that sig-
nificantly impairs cellular oxygen utilization, repre-
sents the most severe end of the clinical spectrum
[1]. The development of circulatory shock is inde-
pendently associated with adverse outcomes, with
mortality rates in excess of 40% [2,3].
Traditionally, shock syndromes are classified
using four broad, nonexclusive categories based on
primary causative mechanisms; hypovolemic, cardio-
genic, obstructive or distributive [1]. Although these
categories provide a framework to enable basic treat-
ment decisions, they fail to address the complexity
and major heterogeneity of (patho)physiological
pathways involved in the development of different
&
shock syndromes [4 ]. In addition, recent develop-
ments of assays able to measure genomics, proteomics
the development of different shock syndromes [4 ].
Subsequently, multiple potential biomarkers are
being discovered [5], aimed to serve a wide range of
purposes as a diagnostic tool, to monitor treatment
effects, for prognostication or as an enrichment strat-
egy to increase the chances of a beneficial effect of a
specific intervention [6]. Despite these recent develop-
ments, it is acknowledged that treatment strategies
for circulatory shock have remained virtually
unchanged for decades. Up to now, treatment consists
of supportive therapies, including fluid resuscitation
and inotropic/vasopressor therapy, as well as organ-
Department of Intensive Care Medicine and Radboud Center for Infec-
tious Diseases (RCI), Radboud University Medical Center, Nijmegen, The
Netherlands
Correspondence to Peter Pickkers, MD, PhD, Radboud University Medi-
cal Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The
Netherlands. E-mail: peter.pickkers@radboudumc.nl
Curr Opin Crit Care 2021, 27:261–268
DOI:10.1097/MCC.0000000000000829

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Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Cardiopulmonary monitoring
KEY POINTS
 Biomarkers have the potential to improve risk
stratification, reduce patient heterogeneity and provide
an early prediction of treatment responses in circulatory
shock patients.
 An increasing amount of biomarker studies demonstrate
that multiple signalling pathways are altered during
circulatory shock, substantiating evidence that from a
(patho)physiological perspective, shock represents a
highly heterologous syndrome, rather than a single
disease entity.
 New biomarkers are emerging, some associated with
therapeutically addressable molecular pathways known
to be dysregulated during circulatory shock. These
biomarkers may represent a unique opportunity to
implement personalized medicine in the treatment of
circulatory shock.
support interventions such as mechanical ventilation
and renal replacement therapy [1]. Moreover,
although many novel biomarkers appear promising
in initial studies, a large proportion of these biomark-
ers may ultimately fail to impact clinical treatment
decisions [5]. These discrepancies imply that the gap
between the expanding fundamental knowledge on
circulating biomarkers and their clinical application is
only widening.
In this review, we discuss recent developments
in the use of circulating biomarkers to assess cardio-
vascular dysfunction in critically ill patients. We
also provide an in-depth review on the molecular
pathways associated with these biomarkers, as well
as the potential of targeted therapeutics aimed to
modulate dysregulations of these pathways. Lastly,
we discuss barriers complicating the use of biomark-
ers in (standard) clinical practice, and provide sug-
gestions to overcome them.
ESTABLISHED BIOMARKERS OF
CARDIOVASCULAR INSUFFICIENCY
Although many circulating biomarkers associated
with cardiovascular dysfunction in the critically ill
have only been developed recently, a few notable
examples have already been embedded in clinical
decision making. Below, we briefly discuss the ratio-
nale behind the use of these biomarkers, as well as
recent developments that have an implication on
their continued implementation in clinical care.
Lactate
Lactate represents the most extensively used and
studied goal-directed biomarker in clinical care
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practice [7]. Because of the strong relationship
between hyperlactatemia, lactate kinetics and circu-
latory failure in critically ill patients, hyperlactate-
mia is even included in the definition of circulatory
shock [1]. Ever since a lactate guided resuscitation
strategy was shown to improve treatment outcome
in septic shock patients, routine assessment of lac-
tate until normalization is advised by the surviving
sepsis campaign [8]. Although the potential of lac-
tate as an early-goal-directed-therapy (EGDT) bio-
marker is now broadly recognized, recently
performed randomized controlled trials that per-
formed a head-to-head comparison of the EGDT
potential of lactate to other measures of circulatory
function yielded conflicting results [7]. In early
sepsis patients, therapy aimed to decrease lactate
levels by at least 10% during the 6-hour study pro-
tocol, compared with a strategy aiming to normalize
central venous oxygenation (ScvO2), resulted in a
borderline significant lower mortality in the lactate
driven treatment group [9]. In another trial involv-
ing septic shock patients, a EGDT strategy aimed to
normalize peripheral capillary refill time (CRT)
resulted in a faster resolution of organ dysfunction
and lower mortality compared with a strategy aimed
&&
at a 20% 2-hourly reduction of lactate [10 ,11].
Although these studies thus effectively demonstrate
that EGDT strategies using biomarkers can improve
treatment outcome, they also show that lactate does
not necessarily outperform more readily available
treatment targets such as bedside clinical symptoms.
N-terminal pro B-type natriuretic peptide
Brain natriuretic peptide (BNP) and N-terminal (NT)-
pro-BNP are released from cardiomyocytes following
increases in ventricular wall stress due to pressure
overload [12]. Elevated plasma levels of BNP and NT-
pro-BNP are well established biomarkers in heart
failure patients, able to diagnose cardiac dysfunction
as the primary cause of pulmonary congestion [13].
Contrary, in critically ill patients in circulatory shock,
NT-pro-BNP levels appear to be elevated regardless of
the presence of cardiac dysfunction, as no clear asso-
ciations with new left or right ventricular dysfunc-
tion are observed [13,14]. Although these findings
suggest a limited potential of brain natriuretic pep-
tides as diagnostic biomarkers of new ventricular
dysfunction during circulatory shock, both BNP
and NT-pro-BNP may provide useful prognostic
information. In different noncardiogenic shock
causes, levels of both BNP and NT-pro-BNP were
predictive of short-term mortality, independent of
conventional risk scores like acute physiology and
chronic health evaluation (APACHE) II scores
[15,16].
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 Biomarkers to assess cardiovascular function van Lier and Pickkers

Cardiac troponins predictive capacity [18]. During septic shock, tro-

Troponins are well established as the criterion lab-
oratory diagnostic for acute coronary syndrome,
due to their high sensitivity and specificity for
myocardial injury [17]. During critical illness,
patients with preexisting atherosclerotic stenosis
may be unable to cope with increased cardiac oxy-
gen demands observed during circulatory shock,
leading to myocardial injury [13]. Patients also
often develop other causes of critical illness induced
myocardial injury, including stress cardiomyopa-
thy, septic cardiomyopathy, cardiac trauma, as well
as through the cardiotoxic side effects of different
implemented therapeutics [13,17]. Up to 15–30%
of noncardiac ICU patients develop elevated tropo-
nin levels during ICU admission [13]. In these
patients, admission troponin levels are indepen-
dently associated with short-term mortality
[13,18]. In contrast to the prognostic capacity of
admission troponin levels, serial measurements of
troponin in sepsis and septic shock do not improve
ponin levels correlate moderately with levels of left
ventricular diastolic dysfunction as well as right
ventricular systolic dysfunction, while the correla-
tion with left ventricular systolic dysfunction is
only minor [19]. High troponin levels in the criti-
cally ill should therefore prompt clinicians to per-
form a more detailed cardiac function assessment
than echocardiographic assessment of left ventric-
ular function alone.
NOVEL BIOMARKERS OF
CARDIOVASCULAR INSUFFICIENCY
The amount of available biomarkers associated with
cardiovascular failure in critically ill patients is
increasing. Below, we discuss notable examples of
recently developed biomarkers, the unique biologi-
cal pathways associated with them, as well as the
effect of potential therapeutics targeted at these
pathways. An overview is presented in Table 1.

Table 1. Overview on biomarker studies that were recently performed in circulatory shock patients, including the associated
dysregulated molecular mechanisms, as well as therapeutics able to correct them.
Investigated biomarker Predictive of Pathophysiological rationale Associated therapeutics

ADM
Angiopoietin II and the
Angiopoietin I/II ratio
Angiotensin I/II-ratio
Mortality [20,21] ADM release represents a compensatory ADM administration (66)
Vasopressor therapy [21] response aimed at restoring Nonneutralizing ADM
AKI [21,22] endothelial barrier function, that falls antibodies [25]
short during refractory shock [23,24]
Mortality [26,27] Angiopoietin II release is triggered by Angiopoietin II antibodies/
Microcirculatory dysfunction [28] inflammatory mediators, and inhibitors [30,31]
subsequently increases endothelial
permeability at the cell-cell junction
level [29,30]
Mortality [32 ] During circulatory shock, endothelial Angiotensin II [34,32 ]
&& &&

Vasopressor therapy [32 ] ACE function markedly decreases,

&&

leading to reduced Ang II formation.

The ratio of angiotensin I/II is thus a
measure of failing ACE function [33]
Renin Mortality [35 ] Renin is released to enhance angiotensin Angiotensin II [34,35 ]
&& &&

Vasopressor therapy [35 ] II production. High renin during

&&

Beneficial response to circulatory shock thus represents an

angiotensin-II therapy [35 ] angiotensin II response that is
&&

insufficient to maintain adequate

vascular tone [33]
DPP3 Mortality [36,37 ,38] High circulating DPP3 is caused by DPP3-neutralizing antibodies
&&

Ventricular dysfunction [37 ,38] uncontrolled release of cytosolic DPP3 [37 ,39]
&& &&

Vasopressor dependency [36,38] into the circulation following cell Angiotensin II [40]
AKI [38] death. This further deteriorates
vascular tone by inhibiting
compensatory angiotensin-II responses
[23]
Free cortisol Mortality [41 ] High cortisol during refractory shock Hydrocortisone [41 ]
& &

Shock resolution [41 ] represents relative adrenal

&

Shock recurrence [41 ] insufficiency, meaning rises in cortisol

&

concentrations are insufficient to

control for concurrent inflammatory
responses [42,43]

ACE, angiotensin-converting enzyme; ADM, adrenomedullin; AKI, acute kidney injury; DPP3, dipeptidyl peptidase 3.

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Cardiopulmonary monitoring
ENDOTHELIAL DYSFUNCTION
The vascular endothelium is increasingly recognized
as a full-fledged organ essential for the maintenance
of cardiovascular homeostasis, especially in criti-
&
cally ill patients [44 ]. The single cell layer of endo-
thelium marks the border between the intravascular
&
and interstitial space [44 ]. Endothelial signalling
function is essential to regulate the diffusion of
molecules through paracellular and transcellular
transport mechanisms [45,46]. Through different
signalling pathways, the endothelium also acts as
a key regulator of local vascular tone, local and
systemic inflammatory signalling, as well as haemo-
stasis and angiogenesis [46–48]. When tissue is
injured, release of danger-associated molecular pat-
terns (DAMPs) and subsequent inflammatory
responses lead to barrier compromise at the endo-
thelial cell-cell junction level, which allows for the
efflux of inflammatory signal molecules (e.g. cyto-
kines and prostaglandins), as well as leukocyte infil-
tration into tissues [47]. On one hand, local
endothelial barrier compromise may be viewed as
a physiological response, required to combat patho-
gens residing in the tissues, as well as for the repair of
damaged tissues. On the other hand, excessive sys-
temic damage to the endothelial barrier induced by
inflammatory responses can also cause large
amounts of intravascular fluids to leak into tissues,
leading to oedema formation, substantially contrib-
uting to tissue hypoxia and the development of
shock [49,50]. Biomarkers are widely recognized as
a tool to identify the presence of systemic endothe-
lial cell dysfunction [23].
Adrenomedullin
Adrenomedullin (ADM) is a key hormone involved
in the regulation of vascular tone and endothelial
barrier function [23]. The main effects of ADM
include endothelial barrier stabilization (through
regulation of the endothelial actin myosin cytoskel-
eton) and vasodilatation (through binding with its
target receptors on both endothelial cells and vas-
cular smooth muscle cells (VSMCs) [23,51]. Circu-
lating ADM levels are associated with clinical
outcome in a range of shock syndromes, including
acute heart failure, cardiogenic shock, as well as
septic shock [20,52,53,54,22]. In septic shock
patients, ADM levels are associated with disease
severity, vasopressor/inotrope dependency, the
necessity for renal replacement therapy and mortal-
ity [20,52,53,55]. Of interest, in patients with high
admission ADM levels, a decrease in ADM concen-
trations following the first 24 h of ICU treatment is
associated with a markedly reduced risk of organ
failure, as well as 28-day mortality [21]. Although
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these results might suggest that ADM plays a detri-
mental role during circulatory failure, high ADM
levels likely represent a failing compensatory
response, aimed at attenuating the endothelial bar-
rier compromise present during circulatory shock
[21]. A nonneutralizing antibody called Adrecizu-
mab, which enhances ADM’s endothelial barrier
stabilizing effects by trapping it into the circulation
[25], is currently under phase-2 investigation as a
treatment option for septic shock [56]. In this trial,
patients that may be more amendable to therapy
with Adrecizumab, were selected using predefined
ADM cutoff-values, implementing a bedside ADM-
biomarker assay [56].
Angiopoietins
The angiopoietin/Tie-2 signalling axis represents a
unique regulatory pathway involved in endothelial
inflammation, vascular haemostasis, vascular tone
and, most importantly, endothelial barrier function
[29,30]. Tie-2, the main effector receptor of this
system, is almost exclusively expressed on endothe-
lial cells. Activation of the Tie-2 receptor promotes
endothelial barrier stability at the cell-cell junction
level as well as strengthening of the actin cytoskele-
ton [30]. Angiopoietin 1 (Angpt-1) serves as the
main agonist of the Tie-2 receptor, while the effects
of Angiopoietin 2 (Angpt-2) are highly context
dependent [30]. Under noninflammatory condi-
tions, Angpt-2 acts a weak agonist of the Angpt-I/
Tie-2 axis [30]. During inflammation, Angpt-2 is
secreted by endothelial cells in response to inflam-
matory cytokines [29]. In this context, increased
Angpt-2 levels act as a Tie-2 antagonist, leading to
compromise of the endothelial barrier [30]. During
inflammation, Angpt-2, as well as Angpt-1/Angpt-2
ratios, thus serve as a measure of endothelial barrier
function. During septic shock, both Angpt-2 levels
and Angpt-1/Angpt-2 ratios are associated with dis-
ease severity and short-term mortality, with Angpt-
1/Angpt-2 ratios being the superior outcome predic-
tor in comparative studies [57,58,26]. High baseline
Angpt-2 levels are also independently associated
with short-term mortality in cardiogenic shock
patients [27]. During sepsis, Angpt-2 levels are
inversely related to nitric oxide dependent micro-
vascular reactivity [28]. Moreover, Angpt-2 levels
also strongly correlate with pro-inflammatory cyto-
kines, most notably TNF-a and IL-6 [26]. Angpt-2
inhibition has already demonstrated beneficial ther-
apeutic effects in murine models of acute inflamma-
tion, sepsis and acute lung injury [30]. In these
studies, treatment with Angpt-2 neutralizing anti-
bodies improved endothelial barrier function and
attenuated endothelial inflammation, leading to
Volume 27  Number 3  June 2021
 Biomarkers to assess cardiovascular function van Lier and Pickkers
increased survival [30]. Interestingly, in another
recently performed study, dual inhibition of
Angpt-2 and vascular endothelial growth factor
(VEGF) also improved outcome in a murine sepsis
model [31]. As inhibition of VEGF alone failed to
improve outcome in another preclinical sepsis
model [59], it remains to be determined whether
this dual inhibition strategy provides additional
outcome benefits compared to therapeutics that
only inhibit Angpt-2.
RENIN-ANGIOTENSIN-ALDOSTERONE-
SYSTEM DYSFUNCTION
The renin-angiotensin-aldosterone system (RAAS)
plays a vital role in the regulation of cardiovascular
system homeostasis [60]. Angiotensin II (Ang-II)
serves as the main effector molecule of this system,
by raising blood pressure through an increase in
sympathetic tone, endogenous catecholamine and
vasopressin release, as well as through direct stimu-
lation of VSMCs [60,61]. Moreover, Ang-II responses
are essential to maintain glomerular filtration during
periods of reduced renal perfusion, by causing selec-
tive vasoconstriction of efferent glomerular arterioles
[62]. During shock, upregulation of Ang-II is a physi-
ologic and potentially life-saving response aimed at
maintaining adequate tissue perfusion [61,63]. The
landmark ATHOS-3 trial has reinvigorated interest in
Ang-II as an alternative vasopressor therapy for cate-
cholamine-resistant vasodilatory shock (CRVS)
patients [51]. In this trial, CRVS patients who received
Ang-II as an additional vasopressor exhibited a sub-
sequently reduced risk of hypotension as well as
reduced catecholamine requirement, compared with
patients receiving placebo [34]. Two recently pub-
lished ancillary biomarker analyses of the ATHOS-3
trial investigated whether baseline measurements of
different RAAS-effector metabolites would be able to
identify patients with worse outcome, as well as
patients more amendable to Ang-II therapy. The
results of these studies as well as their biological
rationale are explained in detail in the next sections.
Angiotensin I/II ratios
Angiotensin I (Ang-I) is the first effector peptide of
the RAAS, which only becomes biologically active
after it is cleaved to Ang-II by angiotensin-converting
enzyme (ACE) [33]. The ratio of Ang I/II is thus a
measure of ACE function [33]. Circulatory shock is
associated with endothelial injury, with markedly
decreased endothelium-bound ACE activity, leading
to a decreased capacity to convert Ang-I to Ang-II
[64]. Thus, the Ang I/II ratio may be elevated in
circulatory shock and predict impaired clinical out-
come. In a sub-study of the ATHOS-3 trial, it was
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found that patients with higher admission Ang I/II
ratio’s received higher norepinephrine-equivalent
&&
doses [32 ]. In the placebo group, patients with
low Ang I/II ratios had markedly improved chances
of survival [hazard ratio 0.56 (95% confidence inter-
val, 95% CI 0.35–0.88] compared to patients with
&&
high Ang I/II ratios [32 ]. These results provide a
biological rationale for interventions aimed at cor-
rection of high Ang I/II ratios as a novel EGDT strat-
egy, including the use of angiotensin II as an
alternative vasopressor.
Renin
Renin is a key enzyme of the RAAS that facilitates the
conversion of biologically inactive angiotensinogen
to angiotensin I [60]. Renin is released by juxtaglo-
merular cells in the kidney in response to sympa-
thetic nerve activation or decreased sodium delivery
to the distal tubule [60]. Ang-II acts as a direct nega-
tive feedback on renin release through activation of
the Ang-II type 1 receptor. Contrary, when there is
insufficient activation of the Ang-II type 1 receptor,
renin concentrations are putatively increased [33]. A
different sub-study of the ATHOS-3 trial shows that
Ang-II therapy caused a marked reduction in renin
concentrations compared with placebo (54.3% vs.
&&
14.1%, P < 0.0001) [35 ]. Interestingly, while the
ATHOS-3 trial was underpowered to detect mortality
differences [34], in patients with high baseline renin
measurements, a clear survival benefit of Ang-II ther-
apy was found; hazard ratio 0.56 (95% CI 0.35–0.88)
&&
[35 ]. Renin measurements may thus serve as a novel
population enrichment strategy, identifying CRVS
patients for whom treatment with Ang-II is more
likely to improve clinical outcome.
Dipeptidyl peptidase 3
Dipeptidyl peptidase 3 (DPP3) is a ubiquitous, pri-
marily cytosolic enzyme involved in the degradation
of several important signal molecules relevant for the
regulation of vascular tone, most notably angioten-
sin II [23]. Whereas levels of circulating (c)DPP3 are
low in healthy volunteers [65], high cDPP3 concen-
trations are found in sepsis, septic shock, cardiogenic
shock as well as in burn victims exhibiting vasodila-
&&
tory shock syndrome [65,36,37 ,38]. High cDPP3
levels are associated with higher organ dysfunction
scores, the development of myocardial dysfunction,
refractory shock, acute kidney injury and increased
&&
short-term mortality [65,36,37 ,38]. Interestingly, a
decrease of cDPP3 following conventional treatment
was associated with less subsequent organ support
requirements and lower mortality in all of these
conditions [36]. On the basis of these clinical associ-
ations combined with the known short half-life and
www.co-criticalcare.com 265
Cardiopulmonary monitoring

primary cytosolic localization of DPP3 [65,66], high
levels of cDPP3 likely represent a state of ongoing cell
death (necrosis) [36] and release of cytosolic DPP3
into the circulation [23]. As the uncontrolled release
of DPP3 into the circulation is able to effectively
cleave Ang-II, DPP3 might represent a novel factor
contributing to the deterioration of vascular tone in
different shock conditions by incapacitating the
vasopressor effects of endogenous Ang-II [67].
Although limited, there are also studies investigating
DPP3-inhibition. Administration of a neutralizing
DPP3 antibody in a murine acute heart-failure model
normalized left ventricular function, an effect which
&&
was sustained after 24 h and 14 days [37 ]. Following
these findings, a DPP3 inhibiting antibody is cur-
rently being developed for clinical use [23,37 ].
&&
ADRENERGIC INSUFFICIENCY
Cortisol
Activation of the pituitary-adrenal axis and its most
important effector molecule cortisol is essential for
mounting an adequate stress-response during criti-
cal illness [68]. Despite the large increase in gluco-
corticoid secretion observed in different shock
syndromes, a significant number of critically ill
patients have relative adrenal insufficiency [68].
Despite numerous randomized controlled trials,
the use of corticosteroids as a therapeutic in circula-
tory shock remains a controversial issue [42,43]. In a
recently performed ancillary study of a randomized
controlled trial that investigated hydrocortisone
therapy in septic shock, baseline levels of free corti-
sol were associated with an increased risk for subse-
quent mortality; odds ratio (OR) 1.13 (95% CI 1.00–
1.27). However, after adjustment for disease sever-
ity, free cortisol levels were not related to efficacy of
hydrocortisone therapy, making it unlikely that
cortisol measurements have potential as a popula-
tion enrichment strategy for corticoid therapy in
&
septic shock [41 ].
CURRENT LIMITATIONS ON BIOMARKER
INTRODUCTION TO CLINICAL PRACTICE
A major limiting factor preventing the implementa-
tion of many novel biomarkers in clinical care is their
ultimate inability to meaningfully direct clinical
decision making. Some fail to improve outcome pre-
diction compared to other, already well established
risk-scores or conventional biomarkers. Of others, the
molecular mechanisms associated with high levels of
a biomarker are either to heterogenic, or not suffi-
ciently known. Even when these molecular pathways
have been fully elucidated, if no specific therapeutic
intervention putatively able to correct these path-
ways is available, the chance that measurement of a

Novel biomarker

Improves detecon of a
Potenal as a disease enty compared to
yes
diagnosc biomarker established diagnosc
opons?

no
Improves outcome predicon
Potenal as a
yes in addion to established
prognosc biomarker
risk-scores or biomarkers?
no
Potenal as a
Potenal as a
populaon enrichment
strafying biomarker
biomarker
yes yes
Idenficaon of
Specific therapeucs able to
dysregulaon of this pathway
yes no correct a dysregulated
reduces heterogeneity of a
pathway available?
clinical syndrome?

Associated with a specific no

molecular pathway?

This biomarker is unlikely to

no significantly impact
clinical decision making

FIGURE 1. Flowchart summarizing notable factors that are required for the successful implementation of novel biomarkers into
clinical practice for diagnosis, prognostication, stratification and/or population enrichment.

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 Biomarkers to assess cardiovascular function van Lier and Pickkers
biomarker will meaningfully impact clinical out-
come is greatly reduced. A graphic overview of these
limitations is presented in Fig. 1.
CONCLUSION AND FUTURE
IMPLICATIONS
In critical care, patients often present at the extremes
of disease, meaning they may not neatly fit one spe-
cific dysregulated physiological pathway or clinical
diagnosis. Although convenient, bedside clinical
symptoms such as blood pressure used in traditional
shock classifications fail to address the substantial
inter-patient heterogeneity as a result of differences
in causative molecular mechanisms, comorbidity and
genetic susceptibility. An increasing body of evidence
demonstrates that multiple signalling pathways are
altered during circulatory shock, substantiating evi-
dence that from a molecular perspective, shock rep-
resents a highly heterologous syndrome, instead of a
single disease entity. The biomarkers discussed in this
review all represent strong examples that are able to
overcome notable factors known to limit biomarker
implementation in clinical care, both by being associ-
ated with unique dysregulated molecular pathways
and by potentially having specific therapeutic inter-
ventions able to correct them. These circulating bio-
markers thus may provide a unique opportunity to
implement personalized medicine in the treatment of
circulatory shock. Nevertheless, this means that addi-
tional research on their application is highly war-
ranted to demonstrate if this will indeed result in
better clinical outcome for the patient.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
Peter Pickkers received travel and consultancy reimburse-
ment from Adrenomed and 4Teen4, the companies that
produced the ADM and DPP3 bioassays and antibodies
described. Dirk van Lier declares no financial conflicts of
interest.
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Volume 27  Number 3  June 2021