Heart Failure Reviews (2021) 26:1195–1201

https://doi.org/10.1007/s10741-020-09948-6

Research progress of biomarkers in early detection

of chemotherapy-induced cardiotoxicity
Wanli Gai 1 & Jian An 1 & Zhixin Wang 1 & Xuebin Han 1 & Jianhui Geng 1 & Yunliang Liang 2 & Yanqing Guo 1

Published online: 11 May 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
With the advances of drug therapy, the prognosis of cancer patients has seen remarkable improvements, and cancer-related
mortality has decreased significantly. However, the followed drug-related cardiotoxicity becomes a serious threat to patients’
living quality and survival rate. Cardiovascular toxicity associated with some chemotherapy drugs is reversible and dose-
dependent. If early identification is possible, early cardiovascular protection measures or adjustment of chemotherapy regimens
can be taken to improve the prognosis of patients. Therefore, early prevention and monitoring of chemotherapy-related
cardiotoxicity are critical for cancer patients and survivors. Among them, biomarkers are an important method for the early
identification of myocardial injury.

Keywords Biomarker . Chemotherapy . Cardiotoxicity

Introduction disease in such patients are different from those in general

In the past few decades, with the progress of drug therapy, the
prognosis of patients with cancer has seen remarkable im-
provements, and the cancer-related mortality has decreased
significantly [1]. However, the consequent cardiotoxicity re-
lated to drug seriously threatens the quality of life and survival
rate of patients with cancer and survivors. A study by Mertens
AC et al. found that heart disease mortality among survivors
of childhood cancer was seven times higher than that of their
peers who had never received chemotherapy [2]. Therefore,
early prevention and monitoring of cardiotoxicity related to
chemotherapy are essential for patients with cancer and survi-
vors. Because of the unique potential mechanism and clinical
characteristics of heart disease in patients with tumor, it in-
volves the adjustment of the corresponding chemotherapy
program and other issues, and the diagnosis methods of heart
Wanli Gai and Jian An contributed equally to this work.
* Yanqing Guo
qingqing17bq@163.com
patients.
The current clinical work would evaluate the cardiotoxicity
of chemotherapy drugs by echocardiography. However, tradi-
tional conventional ultrasound indicators such as left ventric-
ular ejection fraction (LVEF), left ventricular fraction shorten-
ing, and tissue Doppler imaging cannot sensitively diagnose
the cardiovascular damage caused by early chemotherapy [3],
so it is impossible to take early measures to prevent the corre-
sponding cardiotoxicity. Researches showed that only 42% of
patients with cardiac insufficiency recovered completely [4]
despite the best drug treatment, and the evidence that cardiac
function was not affected does not exclude the possibility of
advanced cardiac deterioration [5, 6]. Therefore, it is impor-
tant to determine the early subclinical cardiotoxicity of che-
motherapy patients to improve the prognosis of patients. With
the development of related research, blood biomarkers of car-
diac injury have been increasingly considered as a rapid, non-
invasive, and more economical tool to identify early
cardiotoxicity. In this paper, the biomarkers studied are sum-
marized as follows (Table 1).

1
Department of Cardiology, Shanxi Cardiovascular Hospital,
Troponin
Taiyuan 030024, Shanxi, People’s Republic of China
2
Department of Cardiovascular Medicine, First Hospital of Shanxi
As a structural protein involved in the regulation of calcium-
Medical University, Taiyuan 030001, Shanxi, People’s Republic of mediated myocardial contraction, troponin (cTnI and cTnT)
China has been long used as a biomarker of myocardial necrosis in
1196
Table 1 Roles of biomarkers in the early detection of chemotherapy-induced cardiotoxicity
Biomarkers Sample
Troponin 78 patients with
HER2-positive breast can-
cer
452 patients with
HER2-positive breast can-
cer
A meta-analysis of
cardiotoxicity induced by
anthracyclines
455 patients with
HER2-positive breast can-
cer
Survivors of childhood cancer
patients
43 patients diagnosed with
breast cancer
40 breast cancer patients
BNP/NT-proBNP 69 leukemia survivors without [15]
any heart disease
symptoms
109 patients with sarcomas [16]
and lymphomas
455 patients with
HER2-positive breast can-
cer
MPO 78 breast cancer patients
treated with doxorubicin
and trastuzumab,
Micro-RNA 24 adolescents treated with
doxorubicin
A cell experiment
56 female patients treated
with anthracyclines
Toll-like 114 patients with cardiac
receptors insufficiency treated with
anthracycline drugs
sST2 45 breast cancer patients
treated with
cyclophosphamide and
epirubicin
81 patients with
HER2-positive breast can-
cer
Arginine-NO In a retrospective study of 170 [24]
metabolites breast cancer patients
EVs mice treated with doxorubicin [25]
Heart Fail Rev (2021) 26:1195–1201
References Main findings Conclusions
[7] Early troponin was significantly correlated with the Serve as diagnostic
occurrence of cardiotoxicity biomarkers
[8] The increase of troponin was uncorrelated with and the Serve as diagnostic
decrease of LVEF biomarkers
[9] Troponin has a good negative predictive value for the Serve as negative predictive
prognosis of patients biomarkers
[10] Troponin has a lower value in early monitoring of Controversial, diagnostic
cardiac toxicity value needs further study
[11, 12] No significant correlation between troponin and left Controversial, diagnostic
ventricular dysfunction and the survival rate value needs further study
[13] A decrease in longitudinal strain from baseline to Serve as negative predictive
3 months and detectable high-sensitivity cardiac biomarkers
troponin I at 3 months were independent predictors
of the development of cardiotoxicity at 6 months.
[14] Hs-TnT increment from baseline and hs-TnT integra- Serve as negative predictive
tion value above baseline were significantly greater biomarkers
in patients with cardiotoxicity
NT-proBNP level of the patients with anthracycline Serve as diagnostic
treatment history was significantly higher than that biomarkers
of the control group
The BNP level of the patients with heart event Serve as diagnostic
increased significantly before and after each biomarkers
anthracycline administration cycle, and the LVEF of
such patients was lower at the end of follow-up
[10] BNP and NT-proBNP have no correlation with Not recommended as a
cardiotoxicity induced by chemotherapy diagnostic biomarkers
[7, 17] The early increase of MPO level from baseline to Serve as diagnostic
3 months was related to the increased risk of the first biomarkers
cardiotoxicity event; the increase of MPO after
3 months could still predict the occurrence of
cardiotoxicity induced by chemotherapy
[18] The levels of miR-29b and miR-499 increased within Serve as diagnostic
6–24 h after treatment, showing a significant biomarkers
dose-dependent relationship, and their expressions
were higher in patients with myocardial injury
[19] The expression of miR-34a in cardiomyocytes treated Serve as diagnostic
with doxorubicin increased in a dose-dependent biomarkers
manner
[20] Serum miR-1 level increased significantly after Serve as diagnostic
anthracycline treatment, and was significantly cor- biomarkers
related with the decrease of troponin and LVEF
[21] TLR2 upregulation and TLR3 downregulation TLR2 and TLR3 could
predict the cardiac
insufficiency caused by
anthracyclines
[22] The level of sST2 increased after chemotherapy Serve as diagnostic
biomarkers
[23] sST2 had little predictive value in predicting Not recommended as a
cardiotoxicity caused by early chemotherapy diagnostic biomarkers
The decrease of arginine and citrulline and the increase Serve as diagnostic
of ADMA were found to be significantly correlated biomarkers
with the long-term cardiac dysfunction
Heart Fail Rev (2021) 26:1195–1201 1197

Table 1 (continued)

Biomarkers Sample References Main findings Conclusions

Concentration of extracellular vesicles containing Serve as diagnostic

Telomerase 94 breast cancer patients
activity
CRP 49 breast cancer patients
treated with trastuzumab
95 breast cancer patients
H-FABP 40 patients with
non-Hodgkin’s lymphoma
treated with adriamycin for
6 cycles
GPBB 24 patients with adult acute [30]
leukemia after
chemotherapy with
anthracycline drugs
brain/cardiac glycogen phosphorylase was increased biomarkers
in serum and the extracellular vesicles were released
before the increase of troponin
[26] Women who had prior exposure to chemotherapy were Diagnostic value needs
more likely to have higher levels of DNA damage further study
[27] Patients showed a high correlation between Serve as diagnostic
high-sensitivity CRP and subsequent cardiomyopa- biomarkers
thy development
[28] No correlation between CRP and LVEF decline Not recommended as a
diagnostic biomarkers
[29] H-FABP and BNP were increased in patients with EF Serve as diagnostic
less than 50%, both of which were positively biomarkers
correlated
GPBB was significantly higher than that before Serve as diagnostic
chemotherapy, echocardiography showed that the biomarkers
increase of GPBB was significantly related to left
ventricular diastolic dysfunction

BNP/NT-proBNP, B-brain natriuretic peptide/N-terminal brain natriuretic peptide; MPO, myeloperoxidase; sST2, soluble ST2; EVs, extracellular ves-
icles; CRP, C-reactive protein; H-FABP, heart-type fatty acid-binding protein; GPBB, glycogen phosphorylase BB

patients with chest pain [31]. It is also commonly used to
detect myocardial damage caused by some drugs (such as
anthracycline chemotherapy drugs) [32]. There is no random-
ized controlled trial to determine whether the use of troponin
measurement can improve clinical outcomes in patients with
tumor and heart disease. Currently, there is not enough data to
guide the use of troponin in the evaluation of cardiotoxicity
related to chemotherapy. However, the relationship between
troponin elevation and left ventricular dysfunction after treat-
ment has been determined in studies using biomarkers to early
assess the cardiotoxicity associated with cancer treatment.
Bonnie Ky et al. followed up 78 patients with HER2-
positive breast cancer treated with doxorubicin, taxane, and
trastuzumab combined with chemotherapy for 15 months and
found that the increase of early troponin was significantly
correlated with the occurrence of cardiotoxicity [7]. In another
observation study of 452 patients of HER2-positive breast
cancer treated with trastuzumab, it was found that cTnI in-
creased in 56 patients and cTnT increased in 101 patients,
and the increase of both had a significant correlation with
the decrease of LVEF [8], significantly correlated with the
increase of troponin and the decrease of LVEF [8]. A meta-
analysis of cardiotoxicity induced by anthracyclines showed
that troponin has a good negative predictive value for the
prognosis of patients [9]. However, Ponde N et al. found that
troponin has a lower value in the early monitoring of cardiac
toxicity caused by trastuzumab and/or lapatinib in patients
with HER2-positive breast cancer [10], and many studies
found that there was no significant correlation between tropo-
nin, left ventricular dysfunction, and the survival rate of the
survivors of childhood cancer [11, 12]. Such results may be
that the increase of troponin is not obvious in the patients with
cardiotoxicity caused by chemotherapy, so conventional de-
tection methods cannot get a positive result. However, high-
sensitivity troponin I (hs-TnI) overcomes this shortcoming.
Many studies have found that the combination of elevated
hs-TnI and myocardial strain can predict cardiotoxicity in
breast cancer patients receiving anthracyclines and
trastuzumab [13, 23, 33]. Bonnie Ky et al. confirmed that
the early increase of hs-TnI was correlated with the increased
risk of cardiotoxicity in breast cancer patients receiving
anthracycline drugs and trastuzumab [7], and the predictive
effect of hs-TnT increment was better than that of hs-TnT
absolute value [14].
B-brain natriuretic peptide (BNP)
and N-terminal brain natriuretic peptide
(NT-proBNP)
BNP and NT-proBNP are secreted by cardiomyocytes. When
the ventricular volume or pressure increases, cardiomyocytes
secrete a large amount of BNP (or NT-proBNP) into the blood
[34], which has been widely used in the prediction and prog-
nosis of heart failure and left ventricular systolic function.
Because of their value in predicting left ventricular dysfunc-
tion, researchers have done a lot of research on their value in
the early prediction of cardiotoxicity induced by chemothera-
py. Beata et al. studied 69 leukemia survivors without any
heart disease symptoms. It was found that the serum NT-
1198
proBNP level of the patients with anthracycline treatment his-
tory was significantly higher than that of the control group,
and there was no significant difference in heart color ultra-
sound between the two groups at the same time. It proved that
the increase of NT-proBNP can early predict the cardiotoxicity
caused by anthracyclines [15]. De Iuliis et al. found that NT-
proBNP increased significantly in multiple time points after
chemotherapy, and there was no significant difference in
LVEF during the period. A later follow-up found that NT-
proBNP could predict 1-year mortality [35]. In a prospective
study, continuous measurements of BNP levels before and
after anthracyclines were used to investigate whether
anthracyclines could predict cardiotoxicity in 109 patients
with sarcomas and lymphomas. The results showed that com-
pared with the patients without heart event, the BNP level of
the patients with heart event increased significantly before and
after each anthracycline administration cycle, and the LVEF of
such patients was lower at the end of follow-up [16].
However, some studies have found that BNP and NT-
proBNP have no correlation with cardiotoxicity induced by
chemotherapy [10, 14, 36]. The possible reasons for the above
results are that the concentrations of BNP and NT-proBNP are
also affected by gender, age, and renal function, and the ref-
erence values used in various studies are also different, so the
value of BNP and NT-proBNP in predicting early cardiac
toxicity remains still to be controversial.
Myeloperoxidase (MPO)
MPO is released into the blood by neutrophils when inflam-
mation and oxidative stress occur in cells. Cardiotoxicity
caused by anthracyclines may be related to the oxidative stress
effect of drugs [37, 38]. In 78 breast cancer patients treated
with doxorubicin and trastuzumab, the early increase of MPO
level from baseline to 3 months was related to the increased
risk of the first cardiotoxicity event during the treatment peri-
od [7]. In the later follow-up, the study also found that the
increase of MPO after 3 months could still predict the occur-
rence of cardiotoxicity induced by chemotherapy [17].
microRNA
Generally, RNA in gene transcription is divided into coding
RNA with protein-encoding function and non-coding RNAwith-
out protein-encoding function. Non-coding RNA plays an im-
portant regulatory role in cell activities, such as cell inflammatory
response, division, differentiation, proliferation, and metabolism
[39]. Based on the number of nucleotides, it can be divided into
short-chain RNA (including microRNA, siRNA, etc.) and long-
chain RNA (IncRNA and circRNA) [40]. miRNA has been
found to be involved in a variety of cardiac activities. More
Heart Fail Rev (2021) 26:1195–1201
and more evidences show that miRNA can monitor the
cardiotoxicity caused by chemotherapy in the early stage. In a
prospective cohort study, 24 miRNA expressions in sera of 24
adolescents at different time points before and after anthracycline
treatment were detected. Compared with the control group, the
levels of miR-29b and miR-499 increased within 6–24 h after
treatment, showing a significant dose-dependent relationship,
and their expressions were higher in patients with myocardial
injury [18]. A cell experiment by Gustav Holmgren et al. showed
that the expression of miR-34a in cardiomyocytes treated with
doxorubicin increased in a dose-dependent manner [19]. Rigaud
et al. studied 56 female patients treated with anthracyclines, and
found that the serum miR-1 level increased significantly after
anthracycline treatment, and was significantly correlated with
the decrease of troponin and LVEF, while the levels of miR-
133b, miR-146a, and miR-423-5p increased significantly, but
there was no significant correlation with the decrease of troponin
and LVEF [20].
Other new biomarkers
Toll-like receptors
Currently, it is believed that anthracyclines cause
cardiotoxicity through oxidative stress and self-inflammatory
response [41]. Toll-like receptors (such as TLR2 and TLR4)
play an important role in the natural immune process through
a variety of pathways. Early animal experiments showed that
toll-like receptors can improve the left ventricular function of
mice treated with anthracyclines, reduce oxidative and inflam-
matory stress reactions, and reduce cardiac apoptosis [42, 43].
Liang S et al. found that the patients with cardiac insufficiency
treated with anthracycline drugs showed TLR2 upregulation
and TLR3 downregulation by detecting the expression levels
of serum TLR2mRNA and TLR3mRNA, suggesting that
TLR2 and TLR3 could predict the cardiac insufficiency
caused by anthracyclines [21].
Soluble ST2 (sST2)
sST2 is one of the members of the interleukin receptor-1 fam-
ily. Frères P et al. found that the level of sST2 increased after
chemotherapy through comparing the changes of serum
markers in 45 breast cancer patients treated with cyclophos-
phamide and epirubicin before and after chemotherapy for
two cycles, suggesting that sST2 can predict the cardiotoxicity
caused by chemotherapy in early stage [22], but a registered
study from the Netherlands showed that sST2 had little pre-
dictive value in predicting cardiotoxicity caused by early che-
motherapy [44], and the study of Sawaya et al. also showed
that the value of predicting cardiotoxicity caused by early
chemotherapy of sST2 was not significant [44]. There was
Heart Fail Rev (2021) 26:1195–1201
no significant correlation between sST2 and cardiotoxicity
induced by anthracycline, taxane, and trastuzumab [23].
Arginine-NO metabolites
In a retrospective study of 170 breast cancer patients by compar-
ing the baseline level of patients and the concentration of serum
arginine-NO metabolites (arginine, citrulline, ornithine, asym-
metric dimethylarginine (ADMA), symmetric dimethylarginine
(SDMA), and N-monomethylarginine (MMA)) at 1 and
2 months after doxorubicin treatment, the results showed that
the decrease of arginine and citrulline and the increase of
ADMA were observed at 1 and 2 months, and the changes of
these three indicators were found to be significantly correlated
with the long-term cardiac dysfunction of the patients in later
follow-up [24], suggesting that the changes of serum arginine-
NO metabolites in the early stage can predict the cardiac dys-
function caused by doxorubicin in the early stage.
Extracellular vesicles (EVs)
Extracellular vesicles are membrane vesicles released into the
extracellular microenvironment by cells. When cells are dam-
aged, harmful substances will be released into the blood
through the extracellular vesicles [45]. In order to explore
whether the cellular vesicles can be used as early serological
markers of cardiotoxicity caused by anthracyclines, Yarana
et al. found increased concentration of extracellular vesicles
containing brain/cardiac glycogen phosphorylase by detecting
extracellular vesicles in serum of mice treated with doxorubi-
cin, and the extracellular vesicles were released before the
increase of troponin, suggesting that the extracellular vesicles
containing brain/cardiac glycogen phosphorylase can monitor
the cardiotoxicity caused by anthracyclines in early stage [25].
Telomerase activity and telomere length
Telomerase is a kind of ribonucleic acid protein. It can length-
en the telomere repeat sequence to prevent the shortening
caused by incomplete telomere replication. Telomerase is im-
portant in maintaining telomere length and function.
Researches show that the decreasing expression of telomerase
activity in atherosclerosis is directly relevant to cerebral stroke
and acute myocardial infarction [46]. Other researches show
that many classical cardiovascular risk factors, including hy-
percholesterolemia [47], are related to telomere length short-
ening, where oxidative stress and inflammatory response may
participate in this process. Therefore, indicators relating to
telomerase regulation can be regarded as a new marker for
predicting cardiovascular damage caused by chemotherapy
and other reasons [48]. In fact, studies have shown that, even
after several years of discontinuation, telomerase activity in
breast cancer survivors would decrease [26]. Although the
1199
study of telomerase in chemotherapy-related cardiotoxicity
is limited at present, with the deepening of researches on tel-
omerase regulation mechanism in oxidative stress-related dis-
eases, the detection of telomerase regulation mechanism relat-
ed indicators would fulfill its immense potential in the future.
C-reactive protein (CRP)
As one of the major indicators of inflammatory damage, CRP
plays a vital role in the formation of atherosclerosis.
Researches show that CRP cannot only predict cardiovascular
damages such as myocardial infarction and sudden cardiac
death [49] but also monitor cardiotoxicity caused by chemo-
therapy [50]. Elevation of CRP level can usually be detected
after severe cardiovascular injury. But there are researches
presenting totally opposite results. For example, a research
on 49 patients treated with trastuzumab showed a high corre-
lation between high-sensitivity CRP (hs CRP) and subsequent
cardiomyopathy development [27]. However, Morris et al.
found no correlation between hs CRP after anthracycline treat-
ment and echocardiographic results [28]. This may be related
to the susceptibility of CRP to other factors, and its diagnostic
value needs to be explored further.
Heart-type fatty acid-binding protein (H-FABP)
/glycogen phosphorylase BB (GPBB)
H-FABP is a cytoplasmic protein involved in fatty acid oxi-
dation and has strong specificity for myocardium. H-FABP
can be released into the blood and rise rapidly within 2–3 h
after myocardial injury. It will return to normal level within
18–30 h. H-FABP has been applied to the diagnosis of acute
myocardial infarction [51]. In cardiac toxicity test,
Elghandour et al. [29] found that H-FABP can be used as a
reliable early indicator for the prediction of amycin cardiomy-
opathy. They treated 40 patients with non-Hodgkin’s lympho-
ma with adriamycin for 6 cycles; H-FABP and BNP increased
in patients with EF lower than 50%, suggesting a positive
correlation between the two indicators.
GPBB is a glycogenolytic ferment which can provide glu-
cose for myocardial tissue. During glycogenolysis of ischemic
tissue, GPBB is released from sarcoplasmic reticulum to cy-
toplasm and then circulates through damaged cell membrane.
GPBB was released into circulation in 2–4 h after myocardial
injury and returned to normal level in 24–36 h. However, it is
still controversial as an early diagnostic index of AMI. In
2011, large-scale clinical trials [52] conducted by Keller
et al. did not support the diagnostic value of GPBB as an early
biomarker of AMI. Lillpopp et al. [53] measured the initial
GPBB level of patients with chest pain and found that GPBB
was valuable for improving the midterm prognosis of these
patients. There are limited researches on chemotherapy-
related cardiotoxicity of GPBB at present. Horacek et al.
1200
[30] found that the plasma GPBB concentration of 24 adult
patients with acute leukemia significantly increased after che-
motherapy with anthracycline drugs. Six months after the
treatment, patients’ echocardiography showed incomplete sig-
nificant correlation between the increase of GPBB and left
ventricular diastolic dysfunction. The reliability of GPBB as
a new marker still needs further verification through larger-
scale and long-term research.
Conclusion
In conclusion, we summarize the clinical research results of bio-
markers used to evaluate the cardiotoxicity and heart failure in-
duced by chemotherapy. Many studies have shown that troponin
and natriuretic peptides have a good predictive value for the
cardiotoxicity caused by early chemotherapy. In position paper
on cancer treatments and cardiovascular toxicity issued by the
European Society of Cardiology in 2016, it was suggested that
markers such as troponin (including high-sensitivity troponin)
and natriuretic peptides (BNP or NT-proBNP) were used to de-
tect cardiac injury related to chemotherapy. However, most of the
relevant studies focus on anthracyclines, lacking studies on the
cardiotoxicity caused by other types of chemotherapy drugs.
Moreover, there is still a lack of specific quantitative criteria for
predicting early cardiotoxicity by troponin and natriuretic peptide
in clinical practice. Therefore, a large sample randomized con-
trolled study is still needed for further determination. The study
of new biomarkers (such as extracellular vesicles) shows that the
new biomarkers can be detected before the increase of serum
troponin, suggesting that the new biomarkers have a great poten-
tial in the detection of early cardiotoxicity.
Funding information This study was funded by the basic applied re-
search projects in Shanxi Province (grant number 201601D021156) and
the Scientific Research Fund of Shanxi cardiovascular Hospital (grant
number 20170203) and the Scientific Research Topics of Shanxi Health
commission (grant number 2015070).
References
1. Truong J, Yan AT, Cramarossa G, Chan KK (2014) Chemotherapy-
induced cardiotoxicity: detection, prevention, and management.[J].
Can J Cardiol 30(8):869–878
2. Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W,
Armstrong GT, Robison LL, Yasui Y (2008) Cause-specific late
mortality among 5-year survivors of childhood cancer: the child-
hood cancer survivor study.[J]. J Natl Cancer Inst 100(19):1368–
1379
3. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie
M, Ganame J, Sebag IA, Agler DA, Badano LP, Banchs J,
Cardinale D, Carver J, Cerqueira M, DeCara J, Edvardsen T,
Flamm SD, Force T, Griffin BP, Jerusalem G, Liu JE, Magalhães
A, Marwick T, Sanchez LY, Sicari R, Villarraga HR, Lancellotti P
(2014) Expert consensus for multimodality imaging evaluation of
Heart Fail Rev (2021) 26:1195–1201
adult patients during and after cancer therapy: a report from the
American Society of Echocardiography and the European
Association of Cardiovascular Imaging[J]. Eur Heart J Cardiovasc
Imaging 15(10):1063–1093
4. Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, de
Giacomi G, Rubino M, Veglia F, Fiorentini C, Cipolla CM (2010)
Anthracycline-induced cardiomyopathy: clinical relevance and re-
sponse to pharmacologic therapy[J]. J Am Coll Cardiol 55(3):213–220
5. Bird BRJH, Swain SM (2008) Cardiac toxicity in breast cancer
survivors: review of potential cardiac problems[J]. Clin Cancer
Res 14(1):14–24
6. Jensen BV, Skovsgaard T, Nielsen SL (2002) Functional monitor-
ing of anthracycline cardiotoxicity: a prospective, blinded, long-
term observational study of outcome in 120 patients[J]. Ann
Oncol 13(5):699–709
7. Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr, Sebag IA, Plana
JC, Cohen V, Banchs J, Carver JR, Wiegers SE, Martin RP, Picard
MH, Gerszten RE, Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie
M (2014) Early increases in multiple biomarkers predict subsequent
cardiotoxicity in patients with breast cancer treated with doxorubi-
cin, taxanes, and trastuzumab[J]. J Am Coll Cardiol 63(8):809–816
8. Zardavas D, Suter TM, Van Veldhuisen DJ et al (2017) Role of
troponins I and T and N-terminal prohormone of brain natriuretic
peptide in monitoring cardiac safety of patients with early-stage
human epidermal growth factor receptor 2–positive breast cancer
receiving trastuzumab: a herceptin adjuvant study cardiac marker
substudy[J]. J Clin Oncol 35(8):878–884
9. Simões R, Silva LM, Cruz ALVM, Fraga VG, de Paula Sabino A,
Gomes KB (2018) Troponin as a cardiotoxicity marker in breast
cancer patients receiving anthracycline-based chemotherapy: a nar-
rative review[J]. Biomed Pharmacother 107:989–996
10. Ponde N, Bradbury I, Lambertini M et al (2017) Cardiac bio-
markers for early detection and prediction of trastuzumab and/or
lapatinib-induced cardiotoxicity in patients with HER2-positive
early-stage breast cancer: a NeoALTTO sub-study (BIG 1–06).[J].
Breast Cancer Res Treat:1–8
11. Armenian SH, Gelehrter SK, Vase T, Venkatramani R, Landier W,
Wilson KD, Herrera C, Reichman L, Menteer JD, Mascarenhas L,
Freyer DR, Venkataraman K, Bhatia S (2014) Screening for cardiac
dysfunction in anthracycline-exposed childhood cancer
survivors.[J]. Clin Cancer Res 20(24):6314–6323
12. Sherief LM, Kamal AG, Khalek EA et al (2012) Biomarkers and
early detection of late onset anthracycline-induced cardiotoxicity in
children[J]. Hematology 17(3):151–156
13. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, Gosavi
S, Carver JR, Wiegers SE, Martin RP, Picard MH, Gerszten RE,
Halpern EF, Passeri J, Kuter I, Scherrer-Crosbie M (2011) Early
detection and prediction of cardiotoxicity in chemotherapy-treated
patients.[J]. Am J Cardiol 107(9):1375–1380
14. Kitayama H, Kondo T, Sugiyama J, Kurimoto K, Nishino Y, Kawada
M, Hirayama M, Tsuji Y (2017) High-sensitive troponin T assay can
predict anthracycline- and trastuzumab-induced cardiotoxicity in
breast cancer patients.[J]. Breast Cancer 24(6):774–782
15. Mladosievicova B, Urbanova D, Radvanska E et al (2012) Role of
NT-proBNP in detection of myocardial damage in childhood leu-
kemia survivors treated with and without anthracyclines[J]. J Exp
Clin Cancer Res 31(1):86
16. Lenihan DJ, Stevens PL, Massey M, Plana JC, Araujo DM, Fanale
MA, Fayad LE, Fisch MJ, Yeh ET (2016) The utility of point-of-
care biomarkers to detect cardiotoxicity during anthracycline che-
motherapy: a feasibility study[J]. J Card Fail 22(6):433–438
17. Putt M, Hahn VS, Januzzi JL et al (2015) Longitudinal changes in
multiple biomarkers are associated with cardiotoxicity in breast
cancer patients treated with doxorubicin, taxanes, and
trastuzumab[J]. J Am Coll Cardiol 65(10):1164–1172
Heart Fail Rev (2021) 26:1195–1201
18. Leger KJ, Leonard D, Nielson D et al (2017) Circulating
microRNAs: potential markers of cardiotoxicity in children and
young adults treated with anthracycline chemotherapy[J]. J Am
Heart Assoc 6(4):e004653
19. Holmgren G, Synnergren J, Andersson CX et al (2016)
MicroRNAs as potential biomarkers for doxorubicin-induced
cardiotoxicity[J]. Toxicol In Vitro 34(1):26–34
20. Ruggeri C, Gioffré S, Achilli F, Colombo GI, D'Alessandra Y
(2018) Role of microRNAs in doxorubicin-induced cardiotoxicity:
an overview of preclinical models and cancer patients[J]. Heart Fail
Rev 23(1):109–122
21. Liang S, Xinyong C, Hongmin Z et al (2018) TLR2 and TLR3
expression as a biomarker for the risk of doxorubicin-induced heart
failure[J]. Toxicol Lett
22. Frères P, Bouznad N, Servais L, Josse C, Wenric S, Poncin A, Thiry
J, Moonen M, Oury C, Lancellotti P, Bours V, Jerusalem G (2018)
Variations of circulating cardiac biomarkers during and after
anthracycline-containing chemotherapy in breast cancer
patients[J]. BMC Cancer 18(1):102
23. Sawaya H, Sebag IA, Plana JC et al (2012) Assessment of echocar-
diography and biomarkers for the extended prediction of
cardiotoxicity in patients treated with anthracyclines, taxanes, and
trastuzumab.[J]. Circ Cardiovasc Imaging 5(5):596
24. Finkelman BS, Putt M, Wang T et al (2017) Arginine-nitric oxide
metabolites and cardiac dysfunction in patients with breast
cancer[J]. J Am Coll Cardiol 70(2):152
25. Yarana C, Carroll D, Chen J, et al (2017) Extracellular vesicles
released by cardiomyocytes in a doxorubicin-induced cardiac injury
mouse model contain protein biomarkers of early cardiac injury.[J].
Clin Cancer Res, 112:clincanres.2046.2017
26. Scuric Z, Carroll JE, Bower JE et al (2017) Biomarkers of aging
associated with past treatments in breast cancer survivors[J]. NPJ
Breast Cancer 3(1):50
27. Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja
L, D’Amico R (2014) Trastuzumab-containing regimens for meta-
static breast cancer. In: Moja L (ed) Cochrane Database of
Systematic Reviews. John Wiley & Sons, Ltd., Chichester
28. Morris PG, Chen C, Steingart R et al (2011) Troponin I and C-
reactive protein are commonly detected in patients with breast can-
cer treated with dose-dense chemotherapy incorporating
trastuzumab and lapatinib[J]. Clin Cancer Res 17(10):3490–3499
29. Elghandour AH, Sorady ME, Sahar A et al (2009) Human heart-
type fatty acid-binding protein as an early diagnostic marker of
doxorubicin cardiac toxicity[J]. Hematol Rev 1(1):543–543
30. Horacek JM, Jebavy L, Vasatova M, Pudil R, Tichy M, Jakl M,
Maly J (2013) Glycogen phosphorylase BB as a potential marker of
cardiac toxicity in patients treated with anthracyclines for acute
leukemia[J]. Bratisl Med J 114(12):708–710
31. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J,
Meinertz T (1997) Emergency room triage of patients with acute
chest pain by means of rapid testing for cardiac troponin T or tro-
ponin I.[J]. N Engl J Med 337(23):1648–1653
32. Adriana A, Giuseppina P, Francesco D et al (2010) Cardiotoxicity
of anticancer drugs: the need for cardio-oncology and cardio-
oncological prevention[J]. J Natl Cancer Inst 102(1):14–25
33. Kang Y, Xu X, Cheng L, Li L, Sun M, Chen H, Pan C, Shu X
(2014) Two-dimensional speckle tracking echocardiography com-
bined with high-sensitive cardiac troponin T in early detection and
prediction of cardiotoxicity during epirubicine-based
chemotherapy[J]. Eur J Heart Fail 16(3):300–308
34. Weber M, Hamm C (2006) Role of B-type natriuretic peptide
(BNP) and NT-proBNP in clinical routine[J]. Heart 92(6):843–849
35. De IF, Salerno G, Taglieri L et al (2016) Serum biomarkers evalu-
ation to predict chemotherapy-induced cardiotoxicity in breast can-
cer patients.[J]. Tumor Biol 37(3):3379–3387
1201
36. Ruggiero A, De Rosa G, Rizzo D et al (2013) Myocardial perfor-
mance index and biochemical markers for early detection of
doxorubicin-induced cardiotoxicity in children with acute lympho-
blastic leukaemia[J]. Int J Clin Oncol 18(5):927–933
37. Christenson ES, James T, Agrawal V, Park BH (2015) Use of bio-
markers for the assessment of chemotherapy-induced cardiac
toxicity[J]. Clin Biochem 48(4–5):223–235
38. Vejpongsa P, Yeh ET (2014) Prevention of anthracycline-induced
cardiotoxicity: challenges and opportunities[J]. J Am Coll Cardiol
64(9):938–945
39. Eulalio A, Huntzinger E, Izaurralde E (2008) Getting to the root of
miRNA-mediated gene silencing.[J]. Cell 132(1):9–14
40. Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham
AT, Stadler PF, Hertel J, Hackermüller J, Hofacker IL, Bell I,
Cheung E, Drenkow J, Dumais E, Patel S, Helt G, Ganesh M,
Ghosh S, Piccolboni A, Sementchenko V, Tammana H, Gingeras
TR (2007) RNA maps reveal new RNA classes and a possible
function for pervasive transcription.[J]. Science 316(5830):1484–
1488
41. Yi X, Bekeredjian R, DeFilippis NJ, Siddiquee Z, Fernandez E,
Shohet RV (2006) Transcriptional analysis of doxorubicin-
induced cardiotoxicity.[J]. Am J Physiol Heart Circ Physiol
290(3):1098–1102
42. Riad A, Bien S, Gratz M et al (2014) Toll-like receptor-4 deficiency
attenuates doxorubicin-induced cardiomyopathy in mice.[J]. Eur J
Heart Fail 10(3):233–243
43. Frantz S, Kelly RA, Bourcier T (2001) Role of TLR-2 in the acti-
vation of nuclear factor kappaB by oxidative stress in cardiac
myocytes.[J]. J Biol Chem 276(7):5197–5203
44. Boxtel WV, Bulten BF, Mavinkurve-Groothuis AMC et al (2015)
New biomarkers for early detection of cardiotoxicity after treatment
with docetaxel, doxorubicin and cyclophosphamide[J]. 20(2):143
45. Sharma A, Khatun Z, Shiras A (2016) Tumor exosomes: cellular
postmen of cancer diagnosis and personalized therapy[J].
Nanomedicine 11(4):421–437
46. Jih-Kai Y, Chao-Yung W (2016) Telomeres and telomerase in car-
diovascular diseases[J]. Genes 7(9):58
47. (2011) Telomere length in old age and cholesterol across the life
course[J]. J Am Geriatr Soc 59(10):1979–1981
48. Beyer AM, Freed JK, Durand MJ, Riedel M, Ait-Aissa K, Green P,
Hockenberry JC, Morgan RG, Donato AJ, Peleg R et al (2016)
Critical role for telomerase in the mechanism of flow-mediated
dilation in the human microcirculation. Circ Res 118:856–866
49. Shrivastava AK, Singh HV, Raizada A, Singh SK (2015) C-reactive
protein, inflammation and coronary heart disease. Egypt Heart J 67:
89–97
50. Christenson ES, James T, Agrawal Vet al (2014) Use of biomarkers
for the assessment of chemotherapy-induced cardiac toxicity[J].
Clin Biochem 48(4–5)
51. Xia Z (2018) Heart-type fatty acid binding protein (H-FABP) as a
biomarker for acute myocardial injury and long-term post-ischemic
prognosis[J]. Acta Pharmacol Sin 39(7)
52. Keller T, Zeller T, Ojeda F et al (2011) Serial changes in highly
sensitive troponin I assay and early diagnosis of myocardial
infarction[J]. JAMA 306(24):2684–2693
53. Lillpopp L , Tzikas S , Ojeda F et al (2012) Prognostic information
of glycogen phosphorylase isoenzyme BB in patients with
suspected acute coronary syndrome[J]. Am J Cardiol 110(9):
1225–1230
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