Cardiotoxicity: Novel Biomarkers
Gerasimos Siasos MD, PhD
NATIONAL AND KAPODISTRIAN UNIVERSITY OF ATHENS
MEDICAL SCHOOL
1st Department of Cardiology, HIPPOKRATION Hospital
Director: Prof. Dimitris Tousoulis
Definition of cancer therapeutics–related cardiotoxicity
Cardiomyopathy characterized by a decrease in EF globally
Reduction of the EF ≥5% to <50% with symptoms or heart failure, or an asymptomatic reduction of the EF ≥10%
to <50%
Reversible: to within -5 % of baseline
Partially reversible: improved by ≥10 % from the nadir but remaining >-5 % below baseline
Irreversible: improved by <10 % from the nadir and remaining >-5 % below baseline
Relative percentage decrease in GLS >15% is indicative of subclinical LV dysfunction
Chemotherapy
Baseline risk factors for cardiotoxicity
AnthracyclinesMechanisms of cardiotoxicity
igure 1. Reyes J. Potential signaling pathways involved in anthracycline-induced cardiomyocyte injury. A.G Scientific, Inc.: Jannel Reyes; 2012.
❖ ROS/RNS overproduction oxidative stress and myocardial damage
❖ ROS and iron hypothesis redox cycling in mitochondria
❖ topoisomerase-IIb–anthracycline–deoxyribonucleic acid complex DNA double-strand breaks
AnthracyclinesMechanisms of cardiotoxicity
Rochette L. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends in Pharmacological Sciences, 2015 Jun;36(6):326-48.
TrastuzumabMechanisms of cardiotoxicity
Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nature reviews Cancer. 2007;7(5):332-44.
❖ ErbB2/4/PI3-K/Akt pathway cellular
proliferation, homeostasis and survival
❖ Neuregulin 1/ErbB inhibition
cardiomyocyte growth, angiogenesis, and
myofibrillar structure
Biomarkers for early detection of chemotherapy-induced cardiotoxicity
❖ Troponin Τ και Ι
❖ Controversial results
❖ Combination with Myeloperoxidase (MPO)
❖ BNP και ΝΤ-pro-BNP
❖ ΝΤ-pro-BNP >300 pg/ml less possible reversibility of cardiotoxicity
❖ Controversial results
❖ Immune response proteins
❖ miRNAs
❖ Imaging parameters + biomarkers
Troponins and Natriuretic peptides
Figure 2. Percentage of patient distribution for different threshold values with different degrees of LVEF reduction.
Daniela Cardinale et al. Circulation. 2004;109:2749-2754
Copyright © American Heart Association, Inc. All rights reserved.
Figure 3. Cumulative cardiac events rate in 3 study groups.
Daniela Cardinale et al. Circulation. 2004;109:2749-2754
Copyright © American Heart Association, Inc. All rights reserved.
p<0.001
Troponins
Tian S. Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol. 2014 Oct 9;4:277.
Natriuretic peptides
Tian S. Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol. 2014 Oct 9;4:277.
Natriuretic peptides
Tian S. Serum biomarkers for the detection of cardiac toxicity after chemotherapy and radiation therapy in breast cancer patients. Front Oncol. 2014 Oct 9;4:277.
Cardiac biomarkers for early detection and prediction oftrastuzumab and/or lapatinib-induced cardiotoxicity in patientswith HER2-positive early-stage breast cancer: a NeoALTTO sub-study (BIG 1-06)
Ponde N., Bradbury I., Lambertini M., Breast Cancer Res Treat. 2018 Apr;168(3):631-638
• Patients with HER2-positive early breast cancer received as neoadjuvant therapy oral lapatinib (1500mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg)plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by anadditional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80mg/m2)
• NT-proBNP and TnT were tested after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or theircombination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel
• Result: TnT and proBNP may not be useful as early predictors of cardiac toxicityin anthracycline-naïve patients receiving trastuzumab and/or lapatinib
Putt M., Shalkey Hahn V., Januzzi J., Clin Chem. 2015 Sep; 61(9): 1164–1172.
Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit .
Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy
TrI and MPO
Immune response proteins
Immune response proteins as predictive biomarkers of doxorubicin-induced cardiotoxicity in breast cancer patients
Li-Rong Yu , Zhijun Cao , Issam Makhou, Experimental Biology and Medicine 2018; 243: 248–255.
❖ Plasma samples were collected before (T0), and after the first (T1) and the second (T2) cycles of DOX-basedchemotherapy of 27 breast cancer patients, including 5 patients who presented with >10% decline of leftventricular ejection fraction (LVEF), 5 patients with LVEF decline of 5–10%, and 17 patients who maintainednormal LVEF at the end of chemotherapy.
T(0), (a) CXCL1 (pg/mL), (b) CCL3 (pg/mL), (c) GDF-15 (ng/mL), (d) haptoglobin (mg/mL), (e) CCL23 (pg/mL), (f) CCL27 (pg/mL), (g) CXCL6 (pg/mL), and (h) sICAM-1 (ng/mL )
These proteins could be potential predictive
biomarkers of cardiotoxicity
microRNAs
van Rooij E, Olson EN. MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nature reviews Drug discovery. 2012;11(11):860-72.
Early biomarkers of doxorubicin-induced heart injury in a mouse model
Varsha G. Desai, Joshua C. Kwekel, Vikrant Vijaya, Toxicology and Applied Pharmacology 281 (2014) 221–229.
• Male mice were injected intravenously with 3 mg/kg doxorubicin or saline once a week for 2, 3, 4, 6, and 8 weeks, resulting in cumulative DOX doses of 6, 9, 12, 18, and 24 mg/kg, respectively.
• A pro-apoptotic miR-34a was the only miRNA that was upregulated at all cumulative DOX doses and showed a significant dose-related response. Up-regulation of miR-34a at 6 mg/kg DOX may suggest apoptosis as an early molecular change in the hearts of DOX-treated mice.
• At 12 mg/kg DOX, up-regulation of miR-34a was associated with down-regulation of hypertrophy-related miR-150.
Int. J. Mol. Sci. 2015, 16, 14511-14525
• Over-expression of miR-21 attenuated DOX-induced apoptosis in cardiamyocyteswhereas knocking down its expression increased DOX-induced apoptosis.
(A) (The expression of miR-21 in myocardium. Note: C-DOX: Chronic DOX injury group; C-NS: Chronic normalsaline control group; A-DOX: Acute DOX injury group; A-NS: Acute normal saline control group; and(B) The expression of miR-21 in H9C2 cells treated withvarious doses (0–4 μM) of DOX for 24 h.
MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
Gustav Holmgren, Jane Synnergren, Christian X. Andersson, Toxicol In Vitro. 2016 Aug;34:26-34
▪ Expression of miRNAs in incubated cardiomyocytes with doxorubicin for 2 days with anadditional 12-day wash-out period without drug exposure
Upregulation of microRN-34a during and after doxorubicin exposure
MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity
Gustav Holmgren, Jane Synnergren, Christian X. Andersson, Toxicol In Vitro. 2016 Aug;34:26-34
Downregulation of microRNAs during and after doxorubicin exposure
(A) The expression levels of miR- 140-5p in H9C2 cells, rats andmice treated by DOX based on real-time PCR assay. (B) Theexpression levels of Sirt2 in H9C2 cells, rats and mice treated byDOX based on immunofluorescence staining assay
Validation of the eight differentially expressed miRNAs in rats caused by DOX based on real-time PCR assay.
(A) The serum levels of CK and LDH in DOX-treated mice afteradministered with agomir or antagomir of miR-140-5p. (B) Theserum level of SOD in DOX-treated mice after administered withagomir or antagomir of miR-140-5p
• miR-140-5p plays an important role in DOX-inducedcardiotoxicity by promoting myocardial oxidativestress via targeting Nrf2 and Sirt2.
• miR-140-5p may be considered as one potentialdrug target to treat DOX induced cardiotoxicity.
MiR-140-5p agomir or antagomir affects DOX-induced heart damage in vivo
Circulating miR-1 as a potential biomarker of doxorubicin-inducedcardiotoxicity in breast cancer patients
Vagner Oliveira-Carvalho Rigaud, Ludmila R.P. Ferreira, Silvia M. Ayub-Ferreira, Oncotarget, 2017, Vol. 8, (No. 4), pp: 6994-7002
➢ 56 female patients (49.9±3.3 years of age) treated with doxorubicin followed by taxanes
➢ cTnI, LVEF, and miRNAs were measured periodically
❑ An overall increase of the circulating levels of miR- 1, -133b, -146a, and -423-5p was observed during the DOX treatment
❑ No significant difference in the circulating levels of miR-133b, -146a, and -423-5p between cardiotoxicity and non-cardiotoxicity patients.
❑ miR-208a and miR-208b were considered undetected during the treatment
Circulating miR-1 as a potential biomarker of doxorubicin-inducedcardiotoxicity in breast cancer patients
Vagner Oliveira-Carvalho Rigaud, Ludmila R.P. Ferreira, Silvia M. Ayub-Ferreira, Oncotarget, 2017, Vol. 8, (No. 4), pp: 6994-7002
miR-1 was superior to cTnI for distinguishing between patients who did and did not develop cardiotoxicity
MicroRNA (miRNA) upregulation from baseline postanthracycline versus noncardiotoxic chemotherapy. Normalized miR-1, -29b, and -499 were significantly upregulated at multiple time points following the cycle anthracycline (AC; n=24), while unchanged in controls (n=9) receiving noncardiotoxic chemotherapy.
Micro-RNA 208
vs
Imaging
Peak systolic global longitudinal strain(GLS) with speckle trackingechocardiography (STE) appears to be thebest measure. A 10% to 15% earlyreduction in GLS by STE during therapyappears to be the most useful parameterfor the prediction of cardiotoxicity, definedas a drop in LVEF or heart failure.
Circ Cardiovasc Imaging. 2012;5:596–603
Circ Cardiovasc Imaging. 2012;5:596–603
Circ Cardiovasc Imaging. 2012;5:596–603
Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients
Sawaya Η., Sebag Ι., Plana J., Am J Cardiol. 2011 May 1; 107(9): 1375–1380.
❖ 43 patients with HER-2 positive breast cancer received anthracyclines and trastuzumab therapy, underwentechocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course ofchemotherapy).
❖ elevated hsTnI at 3 months (p <0.02) and a decrease inlongitudinal strain between baseline and 3 months (p <0.02)remained independent predictors of later cardiotoxicity.
Circulation Heart Fail. 2018 Mar;11(3):e004408
Longitudinal trends in vascular function, echocardiographic parameters, and cardiac biomarker BNP (B-type natriuretic peptide) to illustrate the mean trend in vascular function measures across visits. Figures grouped according to echocardiographic parameters and BNP (A), large artery stiffness (C), resistive load (D), and pulsatile load (E).
• 18% of participants receiving doxorubicin alone vs 42%receiving both therapies experienced CTRCD
• Decreased arginine and citrulline levels (both p < 0.001) andincreased ADMA and MMA levels (p < 0.001)
B.S. Finkelman, M. Putt, T. Wang, et al.
J Am Coll Cardiol, 70 (2017), pp. 152-162
▪Enrollment of 25 patients with breast cancer Her2 +, receiving chemotherapy with epirubicin and cyclophosphamide (2w x 4) followed by docetaxel (3w x 4) and Trastuzumab (Herceptin) (3w x 1 year).
Echocardiography, FMD και Trop Ι and NT pro-BNΡ every 3
months, 6 months Follow-up
first visit:
Baseline
U/S, PWV, FMD, Alx
Cardiac troponin I or NT-proBNP
Epirubicin & Cyclophosphamide
Second visit:
3 months
U/S, PWV, FMD, Alx
Cardiac troponin I or NT-proBNP
3 monthsBaseline 6 months
Trird visit:
6 months
U/S, PWV, FMD, AlxCardiac troponin I or NT-proBNP
TrastuzumabDocetaxel & Τrastuzumab
Anastasiou M, Oikonomou E, Zagouri F, Siasos G, Antonopoulos AS, Psaltopoulou T, Bamias A, Dimopoulos MA, Tousoulis D.J Am Coll Cardiol. 2017 Dec 19;70(24):3072.
Results
A reduction in LVEF >5% was observed in 5 and 9 patients at 3 and 6 months, respectively.
In the whole study population, LVEF was significantly reduced at 6 months
There was a stepwise decreased in LVEF at 3 and 6 months compared to BL in group of patients with impairedFMD<6.2% but not in the group of patients with FMD>6.2%
BL
6m
40
50
60
70
80
LV
EF
(%
)
BL
3m 6m
40
50
60
70
80
LV
EF
(%
)
FMD>6.2%FMD<6.2%
Anastasiou M, Oikonomou E, Zagouri F, Siasos G, Antonopoulos AS, Psaltopoulou T, Bamias A, Dimopoulos MA, Tousoulis D.J Am Coll Cardiol. 2017 Dec 19;70(24):3072.
p<0.01p<0.05
Results
There was a stepwise difference in GLS from BL to 3m and 6m (-20.23±2.45% vs. -19.54±2.35% vs. -18.56±2.65%, p=0.03)
Subjects with a significant difference in GLS>15% at 6 months had impaired FMD at baseline compared to subjects with no
significant change in GLS
BL 3m 6m
-25
-20
-15
-10
-5
0
Glo
bal L
on
git
ud
inal S
train
(%
)
GLSre
ductio
n>15%
No S
ignifi
cant G
LS c
hange
0
5
10
15
B/L
FM
D(%
)Anastasiou M, Oikonomou E, Zagouri F, Siasos G, Antonopoulos AS, Psaltopoulou T, Bamias A, Dimopoulos MA, Tousoulis D.J Am Coll Cardiol. 2017 Dec 19;70(24):3072.
p<0.01
p=0.03
Results
Brachial FMD had good discriminative value for the
nondevelopment of cardiotoxicity, defined as the nondrop
of LVEF at 6 months
Per 1 SD (2.7%) increase in FMD, there was a 37% less
likelihood for LVEF reduction at 6 months (odds ratio: 0.63)
The change in serum levels of cardiac troponin I and N-
terminal pro–B-type natriuretic peptide levels at 3 months
were not predictive of LVEF change at 6 months
Anastasiou M, Oikonomou E, Zagouri F, Siasos G, Antonopoulos AS, Psaltopoulou T, Bamias A, Dimopoulos MA, Tousoulis D. J Am Coll Cardiol. 2017 Dec 19;70(24):3072.
Conclusions
• Cancer patients treated with potentially cardiotoxic therapy are at high risk of developing HF and should therefore receive medical care aimed at obtaining strict control of cardiovascular risk factors.
• LVEF should be determined before and periodically during treatment for early detection of cardiac dysfunction in patients receiving potentially cardiotoxic chemotherapy
• Established biomarkers for CVD such as Troponins and Natriouretic peptides have shown controversial results for the early detection of cardiotoxicity
• The combination of biomarkers and imaging may increase the prognostic value
• Novel serum biomarkers (i.e. miRNAs) and markers of NO production may be useful predictive tools for cardiotoxicity
