Current Cardiology Reports (2018) 20:52

https://doi.org/10.1007/s11886-018-1002-y

CARDIO-ONCOLOGY (SA FRANCIS AND RB MORGAN, SECTION EDITORS)

Biomarker Discovery in Cardio-Oncology

Anita Vohra 1,2 & Aarti Asnani 1,2

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review In this article, we review current and emerging approaches to biomarker discovery to facilitate early diagnosis
of cancer therapy-associated cardiovascular toxicity.
Recent Findings Although small studies have demonstrated an association between established biomarkers of cardiac injury
(troponins and brain natriuretic peptide) and acute or subacute cardiotoxicity, there is insufficient evidence to support their use in
routine clinical care. Preclinical studies to define the molecular mechanisms of cardiotoxicity, as well as the use of unbiased
“omics” techniques in small patient cohorts, have yielded promising candidate biomarkers that have the potential to enrich
current risk stratification algorithms.
Summary New biomarkers of cardiotoxicity have the potential to improve patient outcomes in cardio-oncology. Further studies
are needed to assess the clinical relevance of molecular mechanisms described in animal models. Similarly, findings from
“omics” platforms require validation in large patient cohorts before they can be incorporated into everyday practice.

Keywords Biomarker . Cardiotoxicity . Cardio-oncology . Genomics . Proteomics . Metabolomics

Introduction of therapy, and often results in irreversible cardiomyocyte inju-

The development of highly effective cancer therapies over the
past few decades has resulted in greatly improved survival rates
for many types of malignancies. However, recent improve-
ments in survivorship and quality of life following a diagnosis
of cancer have been accompanied by an increased awareness of
cancer therapy-related cardiotoxicity. Anthracyclines and anti-
HER2 monoclonal antibodies such as trastuzumab are the
agents most clearly associated with cardiac dysfunction, al-
though other newer agents (vascular endothelial growth factor
(VEGF) pathway inhibitors, proteasome inhibitors, and immu-
notherapies) have also been reported to cause cardiotoxicity.
Anthracycline-induced cardiomyopathy is dose-dependent, oc-
curs predominantly within the first year following completion
This article is part of the Topical Collection on Cardio-Oncology
* Aarti Asnani
aasnani@bidmc.harvard.edu
Anita Vohra
avohra@bidmc.harvard.edu
1
Beth Israel Deaconess Medical Center, 3 Blackfan Circle,
CLS-917H, Boston, MA 02115, USA
2
Harvard Medical School, Boston, MA 02115, USA
ry [1, 2]. In contrast, cardiotoxicity induced by the newer
targeted therapies is typically reversible with cessation of the
offending agent, but it can nonetheless prompt oncologists to
use suboptimal cancer treatment regimens and result in signif-
icant morbidity and mortality. Prospective identification of pa-
tients at high risk of cancer therapy-associated cardiotoxicity, as
well as prompt recognition of cardiotoxicity in the earliest
stages, would allow for more expedient and judicious use of
cardioprotective therapies.
At present, many clinical protocols to diagnose cardiotoxicity
rely on the use of transthoracic echocardiography, given the
widespread availability of this modality. However, use of echo-
cardiography to detect early cardiac dysfunction is limited by
large inter-observer variability in determining the left ventricular
ejection fraction (LVEF) [3], compounded by a lack of standard-
ization in defining cardiotoxicity across chemotherapeutic
agents and clinical trials. Efforts to incorporate the use of echo-
cardiographic contrast agents, three-dimensional echocardiogra-
phy, and LV strain imaging into screening algorithms seek to
address some of these limitations [4, 5], although the ability to
compare values between echocardiography laboratories remains
limited [6]. Cardiac magnetic resonance imaging (CMR) is the
gold standard for accurate quantification of LV function, but its
use in routine screening for cardiotoxicity has been limited by
cost and the requirement for expert interpretation.
52 Page 2 of 8
As a complementary approach to imaging modalities, blood
biomarkers of cardiac injury have become increasingly recog-
nized as rapid, non-invasive, and potentially more cost-effective
tools to identify early cardiotoxicity. The majority of published
literature to date has focused on the extrapolation of established
biomarkers of cardiovascular disease to patients undergoing can-
cer therapy. However, the specificity of these biomarker changes
remains a concern in this patient population, where comorbid
conditions such as infection, renal dysfunction, hypotension,
and other systemic illnesses may contribute to biomarker eleva-
tion. To address these limitations, new investigational biomarkers
have been proposed based on basic and translational experiments
highlighting the molecular mechanisms underlying
cardiotoxicity. Ultimately, these studies may identify pathways
specific to cardiotoxicity that can be assayed in human samples
and potentially modulated in patients receiving cancer therapy.
Another emerging approach to biomarker discovery takes advan-
tage of the “omics” technologies (genomics, proteomics, and
metabolomics) to identify early biomarkers of cardiotoxicity,
which can then lend insight into the underlying biology.
In this review, we summarize current approaches to bio-
marker discovery in the cardio-oncology patient population,
ranging from established markers of cardiac injury to investi-
gational biomarkers derived from basic and translational ob-
servations (Fig. 1).
Fig. 1 Approaches to biomarker discovery in cardio-oncology. Ongoing
efforts to identify biomarkers of cancer therapy-associated cardiotoxicity
include extrapolation from established markers of cardiac injury,
characterization of molecular pathways contributing to cardiotoxicity,
and unbiased “omics” technologies (genomics, proteomics, and
metabolomics). BNP, brain natriuretic peptide; NT-proBNP, N-terminal-
Curr Cardiol Rep (2018) 20:52
Established Biomarkers of Cardiovascular
Disease
Prior studies investigating biomarkers of cardiotoxicity have
largely focused on those that are well established in the diag-
nosis and prognostication of common cardiovascular condi-
tions, such as acute coronary syndromes (ACS) and conges-
tive heart failure (CHF). This approach is advantageous given
that the assays are readily available and yield robust, repro-
ducible results. For established biomarkers, sensitivity, speci-
ficity, and predictive value have already been well established
in other large patient populations, although extrapolation of
these test characteristics to patients at risk for cardiotoxicity
remains a challenge.
Troponins
As structural proteins involved in the regulation of calcium-
mediated myocardial contraction, the cardiac troponins (cTnI
and cTnT) have been long used as biomarkers of myocardial
necrosis in patients with presenting with chest pain [7]. With
the development of high-sensitivity cardiac troponin assays,
more recent studies have demonstrated troponin elevation in
conditions that have not been traditionally associated with
cardiomyocyte necrosis, such as prolonged exercise and
proBNP; CRP, C-reactive protein; ROS, reactive oxygen species; MPO,
myeloperoxidase; GDF, growth differentiation factor; MMA, N-
monomethylarginine; ADMA, asymmetric dimethylarginine; Top2β,
beta isoform of topoisomerase II; CYP1, cytochrome P450 family 1;
GWAS, genome-wide association study; IgE, immunoglobulin E; MB,
myoglobin; MMP-1, matrix metalloproteinase-1
Curr Cardiol Rep (2018) 20:52
brief periods of ischemia [8, 9]. In patients with stable coro-
nary artery disease, an elevated high-sensitivity troponin
confers an increased risk of cardiovascular death and heart
failure [10].
In the cardio-oncology population, the use of cardiac
troponins to diagnose cardiotoxicity has generally been
studied in small cohorts, and no randomized controlled
trials have investigated whether the use of troponin mea-
surement improves clinical outcomes. As a result, there is
currently insufficient data to guide the use of troponins in
the routine assessment of cancer therapy-associated
cardiotoxicity. The relationship between troponin elevation
and subsequent LV dysfunction has been most clearly
established in studies where biomarker assessment oc-
curred early following the administration of cancer therapy
and was compared to baseline values obtained prior to the
initiation of cancer therapy.
Several reports by Cardinale et al. have demonstrated an
association between elevated troponin levels and the develop-
ment of cardiotoxicity. In an initial study, cTnI levels were
measured within the first hours to days after chemotherapy
in 204 patients with refractory malignancies treated with a
broad range of high-dose chemotherapy regimens, many of
whom received prior treatment with anthracyclines [11]. The
majority of patients demonstrated a decline in LVEF during
the first 3 months after the initiation of therapy, but this decline
persisted and was more pronounced in patients with elevation
of cTnI to > 0.4 ng/ml. In a larger follow-up study of 703
patients with aggressive malignancies, cTnI was assessed at
two discrete time points, during the 3 days immediately fol-
lowing chemotherapy and at 1 month following chemothera-
py [12•]. Symptomatic CHF occurred in 7% of patients,
reflecting the sicker patient population enrolled for this study.
The number of elevated cTnI values (≥ 0.8 ng/ml) measured in
each patient correlated with the risk of developing
cardiotoxicity, and those patients with two elevated cTnI
values demonstrated the highest cardiac event rate. Troponin
elevation has similarly been associated with subsequent
cardiotoxicity, as defined by LV dysfunction on echocardiog-
raphy, in patients treated with trastuzumab [13].
Despite these observations, it has not been clearly
established that routine assessment of cardiac troponins im-
proves patient outcomes. Using an elevated troponin level to
identify patients at risk for cardiotoxicity, 114 patients treated
with high-dose chemotherapy with an early cTnI > 0.07 ng/ml
were randomized to receive the ACE inhibitor enalapril or no
treatment [14]. Those patients treated with enalapril demon-
strated preservation of LV function compared to those who
were not treated with enalapril. However, those patients with
normal cTnI levels were not included in the analysis, and it is
unclear whether these patients may have also benefited from
the initiation of an ACE inhibitor. Additional limitations in-
clude the small study size, the lack of a placebo control, and
Page 3 of 8 52
the open-label follow-up, reinforcing the need for additional
randomized, controlled studies to determine the incremental
value of troponin levels in this patient population. Notably,
other small studies have not found an association between
troponin levels and the development of cardiotoxicity [15,
16]. Potential explanations for these discrepancies include dif-
ferences in the assays or cutoff values used, the timing of
biomarker assessment, and the types of cancer therapy
administered.
Although much of the cardiotoxicity literature to date has
focused on the relationship between troponins and the devel-
opment of systolic dysfunction, a small study of 41 patients
with solid or hematological malignancies receiving
anthracycline therapy suggested that an elevation in troponin
may correlate with the development of diastolic dysfunction
[17]. In the pediatric population, increased cTnT within the
first 90 days of doxorubicin treatment was associated with
reduced LV mass and wall thickness 4 years later, suggesting
maladaptive LV remodeling [18]. However, troponin levels do
not appear to be as useful in predicting the development of late
LV dysfunction in survivors of childhood cancer [19, 20].
Elevation in troponin levels also correlates with the cardiac
radiation dose during radiotherapy for left-sided breast cancer,
although the clinical significance of this finding remains to be
determined [21]. Finally, the cardiac troponins have emerged
as important biomarkers for the development of autoimmune
myocarditis in patients treated with immune checkpoint inhib-
itors [22, 23]. As use of immunotherapies becomes more
widespread, further study will be needed to define the optimal
timing of troponin measurement, the sensitivity and specific-
ity of troponin in this context, and the potential impact of
troponin measurement on clinical outcomes. In general, pa-
tients with cancer are at risk for other systemic illnesses that
can affect biomarker levels, and tumor progression itself has
been associated with cardiac biomarker elevation [24]. As
such, clinical judgment and collaboration between the treating
oncologist and cardiologist are often necessary to interpret
abnormal troponin values in this patient population.
Brain Natriuretic Peptide (BNP)
and N-terminal-proBNP (NT-proBNP)
The cardiac peptide hormones BNP and its cleaved form, NT-
proBNP, are well-established biomarkers of LV wall stretch
that have been studied extensively as diagnostic and prognos-
tic markers in congestive heart failure. As with the troponins,
small studies have found BNP or NT-proBNP to be associated
with the subsequent development of cardiotoxicity [15, 16]. In
52 patients treated with high-dose chemotherapy for aggres-
sive malignancies, those who consistently demonstrated ele-
vated NT-proBNP levels shortly after a chemotherapy cycle
had evidence of decreased LV systolic and diastolic function
on echocardiography in the 6 to 12 months following
52 Page 4 of 8
treatment, as compared to patients with a transient or no in-
crease in NT-proBNP [25]. Elevated baseline NT-proBNP
levels of 900 pg/ml or more predicted a low overall survival
rate in patients with non-Hodgkin lymphoma treated with
CHOP and other anthracycline and non-anthracycline regi-
mens [26]. Elevation of NT-proBNP has also been observed
following radiotherapy for left-sided breast cancer [27].
However, other studies have not found BNP and NT-
proBNP to be of value in detecting cardiotoxicity [28], and
the clinical utility of following BNP levels during cancer ther-
apy remains debated.
C-Reactive Protein
Data supporting the measurement of C-reactive protein (CRP)
to detect cardiotoxicity in the setting of conventional chemo-
therapy have generally been lacking [29]. However, changes in
CRP may be of value specifically in patients treated with the
emerging adoptive T-cell therapies, such as CAR T-cells. In this
context, daily measurement of CRP has been shown to facili-
tate the early diagnosis of cytokine release syndrome (CRS)
[30, 31], where robust immune activation can cause severe
hypotension, LV dysfunction, arrhythmia, and cardiopulmo-
nary arrest.
Multimarker Approach
Given the limitations of currently available biomarkers
when measured individually, a multimarker approach has
been advocated in order to simultaneously assay two or
more unrelated pathways that may contribute to
cardiotoxicity. In 78 patients with breast cancer treated
with doxorubicin and trastuzumab, serial blood draws
were performed at baseline (pre-cancer therapy) and every
3 months to measure ultrasensitive TnI, NT-proBNP, and
high-sensitivity CRP in addition to the following markers:
growth differentiation factor (GDF)-15 and myeloperoxi-
dase (MPO) to assess oxidative stress; placental growth
factor (PIGF) to assess angiogenesis; soluble fms-like ty-
rosine kinase receptor (sFlt)-1 to assess vascular remod-
eling; and galectin (gal)-3 to assess fibrosis [32••]. Of
these, TnI and MPO were each associated with the sub-
sequent development of cardiotoxicity, and the combina-
tion of the two markers provided additive value.
I n cr e a s ed l e v el s of M P O w e r e a ss o c ia t e d w it h
cardiotoxicity throughout the 15 months of cancer thera-
py, and increased levels of PIGF and GDF-15 were asso-
ciated with cardiotoxicity at the same visit [33]. Although
promising, larger studies are needed to validate the
multimarker approach and to further explore the role of
PIGF and GDF-15 as biomarkers of cardiotoxicity.
Curr Cardiol Rep (2018) 20:52
Emerging Biomarkers of Cardiotoxicity
In light of the limitations associated with the use of established
biomarkers in cancer patients, a number of new biomarker
candidates have emerged over the past decade based on basic
and translational studies investigating mechanisms of cancer
therapy-induced cardiac injury. Of those discovered in pre-
clinical models, a subset has been validated in patients under-
going cardiotoxic cancer therapy, and the translational rele-
vance of others remains under investigation.
Biomarkers Derived from Molecular Mechanisms
of Cardiotoxicity
Oxidative stress has long been recognized as a key mediator of
anthracycline cardiotoxicity [2]. Doxorubicin forms a
semiquinone radical that reacts rapidly with oxygen to form
superoxide anion, leading to the production of hydroxyl rad-
icals in the presence of heavy metals such as iron [34]. Efforts
to interrogate this pathway in patients have included measure-
ment of MPO and GDF-15, as noted above [32••]. MPO is an
enzyme located in neutrophil granulocytes that catalyzes the
formation of hypochlorous acid, which can then react with
other reactive oxygen species to augment intracellular oxida-
tive stress [35]. GDF-15 is a member of the TGF-β superfam-
ily that is released from cardiomyocytes under conditions of
oxidative stress [36]. Similarly, nitric oxide metabolism lead-
ing to the production of peroxynitrite, a reactive oxygen spe-
cies, has been implicated in doxorubicin-induced mitochon-
drial dysfunction and cardiomyocyte apoptosis [37] as well as
endothelial dysfunction [38]. To further investigate the rele-
vance of this pathway as a biomarker of cardiotoxicity in
patients, plasma levels of several metabolites involved in ni-
tric oxide metabolism were assayed in 170 women with breast
cancer treated with anthracyclines and either paclitaxel or
trastuzumab [39]. Decreases in plasma levels of arginine after
two cycles of doxorubicin (1 month after initiation of chemo-
therapy) and increases in plasma asymmetric dimethylarginine
(ADMA) and N-monomethylarginine (MMA) at the completion
of doxorubicin treatment were associated with the development
of cardiotoxicity, defined as a decline in LVEF by ≥ 10 to < 50%
on serial echocardiography. Subsequent studies in validation
cohorts will be necessary to confirm these findings and to assess
for any potential confounders that could influence arginine me-
tabolism in this patient population.
Basic research in animal models has led to the identifica-
tion of several other pathways associated with anthracycline
cardiotoxicity. These include intracellular iron overload [40,
41], mitochondrial dysfunction [42, 43], autophagy [44],
doxorubicin’s interaction with the beta isoform of topoisom-
erase II (Top2β) [45], and the induction of Cytochrome P450
enzymes [46]. Cardiac injury may be further exacerbated by
inhibition of ErbB2 signaling by trastuzumab, and treatment
Curr Cardiol Rep (2018) 20:52
with the ErbB receptor family ligand neuregulin-1β is
cardioprotective in rodent models [47, 48].
Research is ongoing to support the clinical relevance of
many of these mechanistic pathways. With regard to intracel-
lular iron overload, a study of childhood cancer survivors
found that carriers of the C282Y hemochromatosis (HFE)
gene variant demonstrated increased evidence of late
cardiotoxicity compared to non-carriers, including elevated
cTnT, low LV mass, and decreased LV wall thickness [41].
Top2β levels are measurable in human peripheral blood cells
and have been found to correlate with the development of
doxorubicin-induced apoptosis [49], although the specificity
of these findings for the development of cardiotoxicity re-
mains to be determined. Human-induced pluripotent stem
cells (iPSCs) differentiated into cardiomyocytes have also
been shown to recapitulate many of the mechanisms that con-
tribute to doxorubicin cardiotoxicity in preclinical models
[50], such as ErbB-mediated signaling [51]. Further studies
in iPSCs, peripheral plasma, and peripheral blood mononucle-
ar cells (PBMCs) isolated from patients treated with
cardiotoxic cancer therapies will be critical to validating po-
tential biomarkers of cardiotoxicity in humans. Finally, few
mechanistic studies have focused on newer cancer treatments
associated with cardiovascular toxicity, such as the VEGF
pathway inhibitors [52]. Additional basic and translational
investigation is needed to facilitate risk stratification in the
expanding population of patients treated with these therapies.
Biomarkers Identified Using “Omics” Technologies
Unbiased genomic, proteomic, and metabolomic approaches
are being increasingly used to discover novel pathways asso-
ciated with cancer therapy-induced cardiovascular toxicity.
These techniques have the potential to uncover new biology
as well as to enable the development of new clinical bio-
markers of cardiotoxicity.
Genome-wide association studies (GWAS) have been used
to identify single nucleotide polymorphisms (SNPs) confer-
ring increased risk of cardiotoxicity following anthracycline
treatment. To date, the largest GWAS in this patient popula-
tion included 1191 patients with HER2-positive breast cancer
enrolled in the NCCTG N9831 trial and treated with
anthracyclines followed by paclitaxel, with or without
trastuzumab [53•]. In those patients who received
trastuzumab, SNPs in the following novel loci were associated
with the maximum observed decline in LVEF: LDB2 (limb
domain binding 2), BRINP1 (BMP/retinoic acid inducible
neural-specific protein 1, a suppressor of cell cycle progres-
sion), RAB22A (a member of the RAS oncogene family in-
volved in endocytic trafficking), TRPC6 (transient receptor
potential cation channel subfamily C member 6, which has
been previously implicated in cardiac remodeling and hyper-
trophic cardiomyopathy), LINC01060 (a long intergenic
Page 5 of 8 52
noncoding RNA), and chr6 intergenic region this analysis
was adjusted for age, baseline LVEF, antihypertensive medi-
cations, and the first two principle components. These find-
ings reached statistical significance in patients who received
trastuzumab (p = 7.8 × 10−6 to 8.9 × 10−8) but were not signif-
icant in patients who received taxanes alone. Another GWAS
used a derivation cohort of 385 patients treated with
anthracyclines to identify candidate variants that were then
validated in a replication cohort of 181 patients [54]. A SNP
near PR domain containing 2, with ZNF domain (PRDM2), a
gene associated with DNA double-strand break repair and
protection against oxidative stress, was associated with
LVEF decline with a combined P value of 6.5 × 10−7 in the
meta-analysis. Finally, in a GWAS consisting of three separate
cohorts of childhood cancer survivors treated with
anthracyclines (456 patients across the meta-analysis), a cod-
ing variant in RARG (retinoic acid receptor gamma), was as-
sociated with the development of cardiotoxicity [55]. Notably,
RARG has been previously reported to bind to Top2β, which
has been implicated in the pathogenesis of anthracycline
cardiotoxicity as described above. In summary, GWAS can
be used to identify novel loci associated with the risk of devel-
oping cardiotoxicity, potentially leading to the development of
new biomarkers within these pathways. Additional studies will
be needed to validate candidate SNPs in large patient cohorts.
Moreover, as causality cannot be inferred from these studies,
iPSCs or animal models expressing candidate SNPs could be
used to clarify the contributions of these gene variants to the
underlying mechanisms of cardiotoxicity.
Proteomic and metabolomic technologies hold similar ap-
peal for the discovery of new biomarkers of cardiotoxicity in
patients. Protein profiling has traditionally focused on liquid
chromatography-mass spectrometry (LC-MS)-based methods
in either targeted or discovery mode. In an initial proteomics
study of breast cancer patients receiving doxorubicin and
trastuzumab, longitudinal plasma samples from three patients
who developed cardiotoxicity (cases) were compared to those
from four age- and cancer-matched patients who did not de-
velop cardiotoxicity (controls) using LC-MS [56]. In this der-
ivation cohort, immunoglobulin E (IgE) levels were found to
be higher at baseline and throughout treatment in control pa-
tients compared to cases. In a validation cohort of 35 patients
treated with doxorubicin and trastuzumab, high baseline IgE
levels were associated with a lower risk of cardiotoxicity.
Compared to traditional mass spectrometry-based methods of
protein screening, newer platforms incorporating aptamers
(short single-stranded DNA sequences specific to a particular
protein, e.g., SOMAmers®) or proximity extension assays
(e.g., using Olink Proseek probes®) have enabled high-
throughput screening for biomarkers of cardiovascular disease
with high sensitivity and specificity [57, 58]. The Olink prote-
omics platform has been used in the context of carfilzomib
cardiotoxicity, where a small study of 25 patients identified
52 Page 6 of 8
several putative biomarkers with nominal but not false discov-
ery rate (FDR)-corrected significance, including myoglobin
(MB) and matrix metalloproteinase-1 (MMP-1) [59].
Similarly, both targeted and untargeted metabolomics tech-
niques based on LC-MS technologies have the potential to
identify circulating metabolites associated with cardiotoxicity
[60]. Ongoing discovery studies in larger derivation and vali-
dation cohorts will be important in identifying new biomarkers
to risk stratify patients receiving cardiotoxic cancer therapies.
Conclusion
Although advances are being made in biomarker discovery in
cardio-oncology, a number of questions remain regarding the
best way to incorporate circulating biomarkers into current
risk stratification algorithms. Access to large, well-
phenotyped patient populations treated with cardiotoxic can-
cer therapy remains a major limitation, and the development
of biorepositories will be important for the identification and
validation of potential biomarkers. Most biomarker studies to
date have focused on the cardiotoxic effects of anthracyclines
and trastuzumab, but similar efforts will be important to min-
imize the cardiac complications associated with radiotherapy,
newer targeted therapies, and immunotherapies. Finally, more
rigorous studies are needed to determine whether and how
new biomarker candidates should affect clinical management.
Ultimately, a multimarker approach and close collaboration
between treating cardiologists and oncologists will likely be
the most successful in improving outcomes in the cardio-
oncology population.
Compliance with Ethical Standards
Conflict of Interest Anita Vohra declares that she has no conflict of
interest.
Aarti Asnani reports a pending patent on Tricyclic Compounds as
CYP1 Inhibitors.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by the
author.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA,
Veglia F, et al. Early detection of anthracycline cardiotoxicity and
improvement with heart failure therapy. Circulation. 2015;131(22):
1981–8.
Curr Cardiol Rep (2018) 20:52
2. Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ,
Moens AL. Doxorubicin-induced cardiomyopathy: from molecular
mechanisms to therapeutic strategies. J Mol Cell Cardiol.
2012;52(6):1213–25.
3. Johri AM, Picard MH, Newell J, Marshall JE, King ME, Hung J.
Can a teaching intervention reduce interobserver variability in
LVEF assessment: a quality control exercise in the echocardiogra-
phy lab. JACC Cardiovasc Imaging. 2011;4(8):821–9.
4. Thavendiranathan P, Popovic ZB, Flamm SD, Dahiya A, Grimm
RA, Marwick TH. Improved interobserver variability and accuracy
of echocardiographic visual left ventricular ejection fraction assess-
ment through a self-directed learning program using cardiac mag-
netic resonance images. J Am Soc Echocardiogr. 2013;26(11):
1267–73.
5. Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick
TH. Use of myocardial strain imaging by echocardiography for the
early detection of cardiotoxicity in patients during and after cancer
chemotherapy: a systematic review. J Am Coll Cardiol. 2014;63(25
Pt A):2751–68.
6. Khouri MG, Ky B, Dunn G, Plappert T, Englefield V, Rabineau D,
et al. Echocardiography Core Laboratory Reproducibility of
Cardiac Safety Assessments in Cardio-Oncology. J Am Soc
Echocardiogr. 2018;31(3):361–371.e3.
7. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J,
Meinertz T. Emergency room triage of patients with acute chest
pain by means of rapid testing for cardiac troponin T or troponin
I. N Engl J Med. 1997;337(23):1648–53.
8. Shave R, Baggish A, George K, Wood M, Scharhag J, Whyte G,
et al. Exercise-induced cardiac troponin elevation: evidence, mech-
anisms, and implications. J Am Coll Cardiol. 2010;56(3):169–76.
9. Weil BR, Young RF, Shen X, Suzuki G, Qu J, Malhotra S, et al.
Brief myocardial ischemia produces cardiac troponin I release and
focal myocyte apoptosis in the absence of pathological infarction in
swine. JACC Basic Transl Sci. 2017;2(2):105–14.
10. Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM,
Jablonski KA, et al. A sensitive cardiac troponin T assay in stable
coronary artery disease. N Engl J Med. 2009;361(26):2538–47.
11. Cardinale D, Sandri MT, Martinoni A, Tricca A, Civelli M,
Lamantia G, et al. Left ventricular dysfunction predicted by early
troponin I release after high-dose chemotherapy. J Am Coll Cardiol.
2000;36(2):517–22.
12.• Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M,
Lamantia G, et al. Prognostic value of troponin I in cardiac risk
stratification of cancer patients undergoing high-dose chemother-
apy. Circulation. 2004;109(22):2749–54. This study of over 700
patients treated with high-dose chemotherapy demonstrated
that elevated troponin levels were associated with subsequent
LV dysfunction.
13. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici
M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognos-
tic implications of troponin I evaluation. J Clin Oncol: off J Am Soc
Clin Oncol. 2010;28(25):3910–6.
14. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N,
Civelli M, et al. Prevention of high-dose chemotherapy-induced
cardiotoxicity in high-risk patients by angiotensin-converting en-
zyme inhibition. Circulation. 2006;114(23):2474–81.
15. Romano S, Fratini S, Ricevuto E, Procaccini V, Stifano G, Mancini
M, et al. Serial measurements of NT-proBNP are predictive of not-
high-dose anthracycline cardiotoxicity in breast cancer patients. Br
J Cancer. 2011;105(11):1663–8.
16. Lenihan DJ, Stevens PL, Massey M, Plana JC, Araujo DM, Fanale
MA, et al. The utility of point-of-care biomarkers to detect
cardiotoxicity during anthracycline chemotherapy: a feasibility
study. J Card Fail. 2016;22(6):433–8.
Curr Cardiol Rep (2018) 20:52
17. Kilickap S, Barista I, Akgul E, Aytemir K, Aksoyek S, Aksoy S,
et al. cTnT can be a useful marker for early detection of
anthracycline cardiotoxicity. Ann Oncol. 2005;16(5):798–804.
18. Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, Silverman
LB, et al. Changes in cardiac biomarkers during doxorubicin treat-
ment of pediatric patients with high-risk acute lymphoblastic leu-
kemia: associations with long-term echocardiographic outcomes. J
Clin Oncol: Off J Am Soc Clin Oncol. 2012;30(10):1042–9.
19. Pourier MS, Kapusta L, van Gennip A, Bokkerink JP, Loonen J,
Bellersen L, et al. Values of high sensitive troponin T in long-term
survivors of childhood cancer treated with anthracyclines. Clin
Chim Acta; Int J Clin Chem. 2015;441:29–32.
20. Ylanen K, Poutanen T, Savukoski T, Eerola A, Vettenranta K.
Cardiac biomarkers indicate a need for sensitive cardiac imaging
among long-term childhood cancer survivors exposed to
anthracyclines. Acta Paediatr. 2015;104(3):313–9.
21. Skytta T, Tuohinen S, Boman E, Virtanen V, Raatikainen P,
Kellokumpu-Lehtinen PL. Troponin T-release associates with car-
diac radiation doses during adjuvant left-sided breast cancer radio-
therapy. Radiat Oncol. 2015;10:141.
22. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu
Y, et al. Fulminant myocarditis with cImmune checkpoint blockade.
N Engl J Med. 2016;375(18):1749–55.
23. Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, Pinto J,
et al. Clinical features, management, and outcomes of immune
checkpoint inhibitor-related cardiotoxicity. Circulation.
2017;136(21):2085–7.
24. Pavo N, Raderer M, Hulsmann M, Neuhold S, Adlbrecht C, Strunk
G, et al. Cardiovascular biomarkers in patients with cancer and their
association with all-cause mortality. Heart. 2015;101(23):1874–80.
25. Sandri MT, Salvatici M, Cardinale D, Zorzino L, Passerini R,
Lentati P, et al. N-terminal pro-B-type natriuretic peptide after
high-dose chemotherapy: a marker predictive of cardiac dysfunc-
tion? Clin Chem. 2005;51(8):1405–10.
26. Gimeno E, Gomez M, Gonzalez JR, Comin J, Alvarez-Larran A,
Sanchez-Gonzalez B, et al. NT-proBNP: a cardiac biomarker to
assess prognosis in non-Hodgkin lymphoma. Leuk Res.
2011;35(6):715–20.
27. D'Errico MP, Grimaldi L, Petruzzelli MF, Gianicolo EA, Tramacere
F, Monetti A, et al. N-terminal pro-B-type natriuretic peptide plas-
ma levels as a potential biomarker for cardiac damage after radio-
therapy in patients with left-sided breast cancer. Int J Radiat Oncol
Biol Phys. 2012;82(2):e239–46.
28. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al.
Assessment of echocardiography and biomarkers for the extended
prediction of cardiotoxicity in patients treated with anthracyclines,
taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5(5):
596–603.
29. Morris PG, Chen C, Steingart R, Fleisher M, Lin N, Moy B, et al.
Troponin I and C-reactive protein are commonly detected in pa-
tients with breast cancer treated with dose-dense chemotherapy in-
corporating trastuzumab and lapatinib. Clin Cancer Res: Off J Am
Assoc Cancer Res. 2011;17(10):3490–9.
30. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al.
Efficacy and toxicity management of 19-28z CAR T cell therapy in
B cell acute lymphoblastic leukemia. Sci Transl Med. 2014;6(224):
224ra25.
31. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M,
et al. Current concepts in the diagnosis and management of cytokine
release syndrome. Blood. 2014;124(2):188–95.
32.•• Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, et al.
Early increases in multiple biomarkers predict subsequent
cardiotoxicity in patients with breast cancer treated with doxoru-
bicin, taxanes, and trastuzumab. J Am Coll Cardiol. 2014;63(8):
809–16. This study in breast cancer patients treated with
anthracyclines and trastuzumab assessed the utility of a
Page 7 of 8 52
mul tima rker a pproa ch in predi cting s ubs equen t
cardiotoxicity.
33. Putt M, Hahn VS, Januzzi JL, Sawaya H, Sebag IA, Plana JC, et al.
Longitudinal changes in multiple biomarkers are associated with
cardiotoxicity in breast cancer patients treated with doxorubicin,
taxanes, and trastuzumab. Clin Chem. 2015;61(9):1164–72.
34. Myers C. The role of iron in doxorubicin-induced cardiomyopathy.
Semin Oncol. 1998;25(4 Suppl 10):10–4.
35. Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil
phagosome: oxidants, myeloperoxidase, and bacterial killing.
Blood. 1998;92(9):3007–17.
36. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J,
et al. The transforming growth factor-beta superfamily member
growth-differentiation factor-15 protects the heart from ischemia/
reperfusion injury. Circ Res. 2006;98(3):351–60.
37. Mukhopadhyay P, Rajesh M, Batkai S, Kashiwaya Y, Hasko G,
Liaudet L, et al. Role of superoxide, nitric oxide, and peroxynitrite
in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol
Heart Circ Physiol. 2009;296(5):H1466–83.
38. Duquaine D, Hirsch GA, Chakrabarti A, Han Z, Kehrer C, Brook R,
et al. Rapid-onset endothelial dysfunction with adriamycin: evi-
dence for a dysfunctional nitric oxide synthase. Vasc Med.
2003;8(2):101–7.
39. Finkelman BS, Putt M, Wang T, Wang L, Narayan H, Domchek S,
et al. Arginine-nitric oxide metabolites and cardiac dysfunction in
patients with breast cancer. J Am Coll Cardiol. 2017;70(2):152–62.
40. Ichikawa Y, Ghanefar M, Bayeva M, Wu R, Khechaduri A, Naga
Prasad SV, et al. Cardiotoxicity of doxorubicin is mediated through
mitochondrial iron accumulation. J Clin Invest. 2014;124(2):617–30.
41. Miranda CJ, Makui H, Soares RJ, Bilodeau M, Mui J, Vali H, et al.
Hfe deficiency increases susceptibility to cardiotoxicity and exac-
erbates changes in iron metabolism induced by doxorubicin. Blood.
2003 Oct 1;102(7):2574–80.
42. Berthiaume JM, Wallace KB. Adriamycin-induced oxidative mito-
chondrial cardiotoxicity. Cell Biol Toxicol. 2007;23(1):15–25.
43. Liu Y, Asnani A, Zou L, Bentley VL, Yu M, Wang Y, et al. Visnagin
protects against doxorubicin-induced cardiomyopathy through
modulation of mitochondrial malate dehydrogenase. Sci Transl
Med. 2014;6(266):266ra170.
44. Li DL, Wang ZV, Ding G, Tan W, Luo X, Criollo A, et al.
Doxorubicin Blocks Cardiomyocyte Autophagic Flux by
Inhibiting Lysosome Acidification. Circulation. 2016;133(17):
1668–87.
45. Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al.
Identification of the molecular basis of doxorubicin-induced
cardiotoxicity. Nat Med. 2012;18(11):1639–42.
46. Asnani A, Zheng B, Liu Y, Wang Y, Chen HH, Vohra A, et al.
Highly potent visnagin derivatives inhibit Cyp1 and prevent doxo-
rubicin cardiotoxicity. JCI Insight. 2018;3(1):e96753.
47. Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM.
Modulation of anthracycline-induced myofibrillar disarray in rat
ventricular myocytes by neuregulin-1beta and anti-erbB2: potential
mechanism for trastuzumab-induced cardiotoxicity. Circulation.
2002;105(13):1551–4.
48. Bian Y, Sun M, Silver M, Ho KK, Marchionni MA, Caggiano AO,
et al. Neuregulin-1 attenuated doxorubicin-induced decrease in car-
diac troponins. Am J Physiol Heart Circ Physiol. 2009;297(6):
H1974–83.
49. Kersting G, Tzvetkov MV, Huse K, Kulle B, Hafner V, Brockmoller
J, et al. Topoisomerase II beta expression level correlates with
doxorubicin-induced apoptosis in peripheral blood cells. Naunyn
Schmiedeberg’s Arch Pharmacol. 2006;374(1):21–30.
50. Burridge PW, Li YF, Matsa E, Wu H, Ong SG, Sharma A, et al.
Human induced pluripotent stem cell-derived cardiomyocytes reca-
pitulate the predilection of breast cancer patients to doxorubicin-
induced cardiotoxicity. Nat Med. 2016;22(5):547–56.
52 Page 8 of 8
51. Jay SM, Murthy AC, Hawkins JF, Wortzel JR, Steinhauser ML,
Alvarez LM, et al. An engineered bivalent neuregulin protects
against doxorubicin-induced cardiotoxicity with reduced
proneoplastic potential. Circulation. 2013;128(2):152–61.
52. Chintalgattu V, Rees ML, Culver JC, Goel A, Jiffar T, Zhang J, et al.
Coronary microvascular pericytes are the cellular target of sunitinib
malate-induced cardiotoxicity. Sci Transl Med. 2013;5(187):187ra69.
53.• Serie DJ, Crook JE, Necela BM, Dockter TJ, Wang X, Asmann
YW, et al. Genome-wide association study of cardiotoxicity in the
NCCTG N9831 (Alliance) adjuvant trastuzumab trial.
Pharmacogenet Genomics. 2017;27(10):378–85. This study rep-
resents the largest GWAS performed to date in patients treated
with cardiotoxic cancer therapy.
54. Wells QS, Veatch OJ, Fessel JP, Joon AY, Levinson RT, Mosley JD,
et al. Genome-wide association and pathway analysis of left ven-
tricular function after anthracycline exposure in adults.
Pharmacogenet Genomics. 2017;27(7):247–54.
55. Aminkeng F, Bhavsar AP, Visscher H, Rassekh SR, Li Y, Lee JW,
et al. A coding variant in RARG confers susceptibility to
anthracycline-induced cardiotoxicity in childhood cancer. Nat
Genet. 2015;47(9):1079–84.
Curr Cardiol Rep (2018) 20:52
56. Beer LA, Kossenkov AV, Liu Q, Luning Prak E, Domchek S,
Speicher DW, et al. Baseline Immunoglobulin E Levels as a
Marker of Doxorubicin- and Trastuzumab-Associated Cardiac
Dysfunction. Circ Res. 2016;119(10):1135–44.
57. Ngo D, Sinha S, Shen D, Kuhn EW, Keyes MJ, Shi X, et al.
Aptamer-Based Proteomic Profiling Reveals Novel Candidate
Biomarkers and Pathways in Cardiovascular Disease. Circulation.
2016;134(4):270–85.
58. Lind L, Arnlov J, Lindahl B, Siegbahn A, Sundstrom J, Ingelsson
E. Use of a proximity extension assay proteomics chip to discover
new biomarkers for human atherosclerosis. Atherosclerosis.
2015;242(1):205–10.
59. Lendvai N, Tsakos I, Devlin SM, Schaffer WL, Hassoun H,
Lesokhin AM, et al. Predictive biomarkers and practical consider-
ations in the management of carfilzomib-associated cardiotoxicity.
Leuk Lymphoma. 2018:1–5.
60. Asnani A, Shi X, Farrell L, Tainsh R, Vandenwijngaert S, Cheng K-
H, et al. Changes in citric acid metabolism are associated with the
development of anthracycline-induced cardiotoxicity in mice and in
patients. J Am Coll Cardiol. 2017;69(11 Supplement):669.