Abstract
Objectives
To search for biomarkers of RT-induced cardiotoxicity, we studied the behavior of ST2 during RT and three years after RT, and the associations with echocardiographic changes.
Materials and methods
We measured soluble ST2 (ng/ml) in serum samples from 63 patients receiving RT for early breast cancer. Sampling and echocardiography were performed at baseline, after RT and at the three-year follow-up. Patients were grouped by >15% (group 1) and ≤15% (group 2) relative worsening in global longitudinal strain (GLS).
Results
ST2 levels tended to increase during RT, from a median (interquartile range; IQR) of 17.9 (12.4–22.4) at baseline to 18.2 (14.1–23.5) after RT (p = 0.075). By the three-year follow up, ST2 levels increased to 18.7 (15.8–24.2), p = 0.018. The increase in ST2 level was associated with worsening cardiac systolic function at three-year follow-up, GLS (rho = 0.272, p = 0.034) and left ventricular ejection fraction (LVEF) (rho = ─0.343, p = 0.006). Group 1 (n = 14) had a significant increase in ST2 levels from 17.8 (12.3–22.5) at baseline to 18.4 (15.6–22.6) after RT, p = 0.035 and to 19.9 (16.0–25.1) three years after RT, p = 0.005. ST2 levels were stable in group 2 (n = 47): 17.8 (12.3–22.0) at baseline, 17.7 (12.6–23.5) after RT and 18.0 (15.5–22.4) at three years.
Conclusion
ST2 may be useful for determining which patients are at risk for long-term cardiovascular toxicity following adjuvant breast cancer RT, but prospective clinical studies are needed to confirm this hypothesis.
Keywords: ST2, Cardiotoxicity, Breast cancer, Radiotherapy, Echocardiography, Left ventricular systolic function
Highlights
-
•
ST2 levels increase 3 years from adjuvant radiotherapy for breast cancer.
-
•
The increase in ST2 levels is associated with a worsening in global longitudinal strain (GLS).
-
•
Increase in ST2 levels is seen during radiotherapy in patients with a >15% change in GLS over 3 years.
Abbreviations
- ACE
angiotensin converting enzyme inhibitor
- AI
aromatase inhibitor
- ARB
angiotensin II receptor blocker
- ASA
acetylsalicylic acid
- BCa
breast cancer
- BMI
body mass index
- CAD
coronary artery disease
- DCIS
ductal carcinoma in situ
- GLS
global longitudinal strain
- IQR
interquartile range
- LAD
left anterior descending coronary artery
- proBNP
N-terminal pro-brain natriuretic peptide
- Md
median
- RT
radiotherapy
- LV
left ventricle
- LVEF
left ventricular ejection fraction
- RV
right ventricle
1. Introduction
Adjuvant radiotherapy (RT) reduces breast cancer (BCa) recurrence and mortality [1,2], but the increase in long-term cardiac morbidity and mortality caused by RT is of concern [[3], [4], [5], [6], [7], [8], [9]]. ST2 is released by cardiomyocytes in response to myocardial stress [10]. In heart failure patients and in population-based studies, elevated levels were associated with increased mortality [[11], [12], [13], [14], [15], [16]]. No studies on the effect of RT alone exist, but radiation exposure was associated with increased ST2 levels in nuclear plant workers [17].
To identify predictive markers for the detection of adjuvant RT-induced changes in left ventricular (LV) function in BCa patients, we evaluated the behavior of ST2 and its association with LV systolic function before RT, after RT and at the three-year follow-up.
2. Materials and methods
This prospective, observational, single center study included 63 chemo-naïve patients with early-stage BCa or ductal carcinoma in situ (DCIS) who received postoperative RT ± concurrent endocrine therapy. Fifty patients had left-sided and 13 patients had right-sided BCa. The key inclusion and exclusion criteria, and the RT procedure were described in detail previously [18,19]. The local ethics committee (R10160) approved the study and informed consent was obtained from all participants.
Sampling and echocardiography were performed, as described previously [20,21], at the start of RT (bRT), at the end of RT (eRT) and at the three-year follow-up (3yRT). The concentrations of ST2 were measured by enzyme-linked immunosorbent assay with reagents from R&D Systems Europe Ltd. (Abingdon, UK). The detection limit and interassay coefficient of variation were 7.8 pg/ml and 6.2%, respectively. N-terminal pro-brain natriuretic peptide (proBNP) was measured at an accredited laboratory [22].
2.1. Statistical analysis
The basic statistical testing was done as described previously [23]. Multivariable linear regression analyses were performed to model the change in GLS and in left ventricular ejection fraction (LVEF) over three years, adjusting the models with the change in ST2 over three years, age, body mass index (BMI), laterality of BCa, aromatase inhibitor (AI) use and hypertension. Additionally, patients were divided into two groups: >15 and ≤ 15% relative change in global longitudinal strain (GLS) [24], a clinically meaningful change [24,25]. Differences between these groups were tested using multivariable logistic regression analysis, adjusting the model with the change in ST2 over three years, AI use, age and the mean dose to the left anterior descending coronary artery (LAD). Statistical testing was performed utilizing IBM SPSS Statistics software, version 25 for Windows (Armonk, NY, USA). P-values less than 0.05 were considered significant.
3. Results
3.1. Changes in ST2 levels and correlations with age, BMI and proBNP
ST2 levels increased slightly from bRT to eRT and increased significantly from bRT to 3yRT (Table 1).
Table 1.
ST2 levels at the different time points for the entire study population (n = 63).
| Baseline |
After RT |
3 years |
p1 | p2 | ||||
|---|---|---|---|---|---|---|---|---|
| Md | (IQR) | Md | (IQR) | Md | (IQR) | |||
| ST2 (ng/ml) | 17.9 | (12.4–22.4) | 18.2 | (14.1–23.5) | 18.7 | (15.8–24.2) | 0.075 | 0.018 |
RT, radiotherapy; Md, median; IQR, interquartile range; p1, change from baseline to after RT; p2, change from baseline to the three-year follow-up.
Statistical significance is shown in bold (p < 0.05).
Age and the change in ST2 level during RT (Spearman’s rho 0.281, p = 0.025), and BMI and the change in ST2 level during the follow-up (rho 0.309, p = 0.014) correlated. Furthermore, the change in ST2 and proBNP levels during the follow-up were correlated (rho 0.329, p = 0.009).
3.2. The change in ST2 level and baseline characteristics
The change in ST2 level was significantly greater patients with hypertension during RT, p = 0.008. Diabetic patients had higher median ST2 levels at bRT than non-diabetic patients, p = 0.025. There were no other significant differences according to other baseline characteristics.
3.3. ST2 levels and systolic echocardiographic measurements
A table of echocardiographic parameters at bRT, eRT and at 3yRT was published as a supplementary table in our previous publication [23]. The change in ST2 levels during RT correlated with GLS at 3yRT (rho = 0.287, p = 0.025). Furthermore, the change in ST2 level over the three years was correlated with GLS (rho = 0.272, p = 0.034) and LVEF (rho = ─0.343, p = 0.006) at 3yRT.
In multivariable linear regression analyses, no variables significantly explained the decrease in LVEF, but AI use and left-sided BCa were associated with the impairment in GLS over the follow-up, p = 0.042 and p = 0.013, respectively. The change in ST2 level did not quite reach significance in the model, p = 0.093. The variables explained 24.3% of the variance.
3.4. Grouping according to >15% and ≤15% relative change in GLS over three years
Patients were grouped according to a clinically meaningful GLS change: 14 patients with >15% (group 1) and 47 patients with ≤15% (group 2) relative worsening in GLS. Group 1 had a significant worsening in GLS during RT, p = 0.006, and during the follow-up, p < 0.001 (Table 2). Group 2 had a stable GLS during RT, p = 0.979, and the follow-up, p = 0.183.
Table 2.
Baseline characteristics, cardiac doses, GLS and ST2 levels compared according to the >15% (group 1) and ≤15% (group 2) relative change in GLS.
| Group 1 (n = 14) | Group 2 (n = 47) | p | |||
|---|---|---|---|---|---|
| Baseline characteristics | |||||
| Age, Md (IQR) | 67.0 | (59.0–73.5) | 64.0 | (58.0–66.0) | 0.049 |
| BMI, Md (IQR) | 28.8 | (24.8–30.7) | 25.8 | (23.9–27.7) | 0.081 |
| Left-sided BC, n (%) | 14 | (100.0) | 35 | (74.5) | 0.052 |
| AI, n (%) | 9 | (64.3) | 11 | (23.4) | 0.008 |
| Tam, n (%) | 0 | (0.0) | 6 | (12.8) | 0.321 |
| Hypertension, n (%) | 5 | (35.7) | 18 | (38.3) | 1.000 |
| ACE, n (%) | 3 | (21.4) | 13 | (27.7) | 0.742 |
| Beta-blockers, n (%) | 4 | (28.6) | 7 | (14.9) | 0.256 |
| ASA, n (%) | 1 | (7.1) | 4 | (8.5) | 1.000 |
| Statins, n (%) | 2 | (14.3) | 10 | (21.3) | 0.715 |
| CAD, n (%) | 1 | (7.1) | 2 | (4.3) | 0.549 |
| Diabetes, n (%), n = 14 and 44 | 1 | (7.1) | 3 | (6.8) | 1.000 |
| Smoking, n (%) | 1 | (7.1) | 5 | (10.6) | 1.000 |
| Hypothyreosis, n (%) | 4 | (28.6) | 6 | (12.8) | 0.245 |
| Radiation doses to the heart | |||||
| Dmean heart ≥2 Gy, n (%) | 11 | (78.6) | 23 | (48.9) | 0.068 |
| Dmean heart (Gy); Md (IQR) | 3.4 | (2.0–4.0) | 1.9 | (1.0–3.8) | 0.082 |
| V20 Gy to heart (%); Md (IQR) | 4.6 | (1.5–5.3) | 1.4 | (0–4.5) | 0.052 |
| Dmean LV (Gy); Md (IQR) | 4.6 | (3.0–5.6) | 2.7 | (1.1–5.9) | 0.148 |
| V20 Gy to LV (%), Md (IQR) | 6.8 | (1.9–8.0) | 1.8 | (0–8.4) | 0.150 |
| Dmean RV (Gy), Md (IQR) | 2.4 | (1.7–3.0) | 1.5 | (1.0–2.9) | 0.073 |
| Dmean LAD (Gy), Md (IQR) | 23.7 | (10.5–28.9) | 9.4 | (1.4–24.8) | 0.012 |
| V20 GY to LAD (%), Md (IQR) | 50.3 | (14.7–71.9) | 12.8 | (0–55.0) | 0.015 |
| GLS at different time points | |||||
| GLS baseline (%), Md (IQR) | ─20.0 | (─23.3-─17.0) | ─17.0 | (─19.0-─15.0) | 0.036 |
| GLS after RT (%), Md (IQR) | ─16.5 | (─19.3-─14.8) | ─17.0 | (─20.0-─15.0) | 0.704 |
| GLS at 3 years (%), Md (IQR) | ─14.0 | (─16.3-─11.0) | ─18.0 | (─20.0-─16.0) | < 0.001 |
| ST2 levels | |||||
| ST2 baseline (ng/ml), Md (IQR) | 17.8 | (12.3–22.5) | 17.8 | (12.3–22.0) | 0.803 |
| ST2 after RT (ng/ml), Md (IQR) | 18.4 | (15.6–22.6) | 17.7 | (12.6–23.5) | 0.561 |
| ST2 at 3 years (ng/ml), Md (IQR) | 19.9 | (16.0–25.1) | 18.0 | (15.5–22.4) | 0.383 |
GLS, global longitudinal strain; RT, radiotherapy; Md, median; IQR, interquartile range; BMI, body mass index; BC, breast cancer; AI, aromatase inhibitor; ACE, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ASA, low dose acetylsalicylic acid; CAD, coronary artery disease; Diabetes, use of diabetes medication; Dmean; mean dose to the structure; V20, the percentage of volume of the structure receiving 20 Gy; LV, left ventricle; RV, right ventricle; LAD, left anterior descending coronary artery; p, p-value from the Mann-Whitney U test.
Statistical significance is shown in bold (p < 0.05).
The baseline characteristics, cardiac doses, GLS measurements and ST2 levels are displayed in Table 2. The median ST2 level increased significantly only in group 1 during RT (p = 0.035) and the follow-up (p = 0.005). In group 2, the ST2 level remained stable, p = 0.220 during RT and p = 0.500 during the follow-up.
In multivariable binary logistic regression analysis, AI users (OR 5.61 [95% CI 1.25–25.10]) were more likely to be in group 1. Furthermore, increasing mean dose to LAD (OR 1.07 [95% CI 1.00–1.15]), greater increase in ST2 levels (OR 1.15 [95% CI 0.93–1.41]) and older age (OR 1.08 [95% CI 0.96–1.22]) nearly reached significance.
4. Discussion
We report a small, yet significant, increase in ST2, a possible marker of cardiotoxicity, three years after adjuvant RT for early BCa. One earlier study found no association between RT and ST2 levels, but the ST2 levels increased 6 months after chemotherapy, which could have masked the effect of RT [26].
Older age, BMI, hypertension and diabetes affected ST2 levels, possibly indicating that patients with underlying cardiac risk factors are at a greater risk for cardiotoxicity. These associations have been reported previously [16,27,28].
4.1. ST2 levels and changes in LV systolic function
The increase in the ST2 level during RT was associated with a higher, thus worse, GLS at the three-year follow-up. Additionally, the three-year change in the ST2 level correlated with a worsening in GLS and LVEF, both known prognostic factors for cardiovascular death [29]. The association between worsening GLS and increasing ST2 levels has been reported previously in patients with cardiac conditions [30,31]. In multivariable analysis, the worsening in GLS was predicted by AI use and left-sided BCa, an association we have reported previously [19,21]. The change in ST2 level was only suggestive in association with worsening GLS.
A significant increase in ST2 level was found in patients with a >15% relative worsening in GLS. In the multivariable analysis, only AI use significantly predicted the worsening of GLS. The associations between age, LAD radiation dose and the change in ST2 level during the follow-up and the change in GLS were hypothesis generating.
4.2. Limitations
The small sample size is a limitation of our study. Furthermore, the changes in LV systolic function and ST2 levels were subclinical and a longer follow-up is needed to determine whether these changes translate into clinically relevant cardiovascular risk.
5. Conclusion
We observed a small but significant increase in ST2 levels during adjuvant RT ± endocrine therapy for BCa and during the three-year follow-up. The increase was apparent in patients with a >15% worsening in GLS, which was also associated with AI use and higher radiation dose to the LAD. As it takes years for RT-induced heart disease to manifest, longer follow-up and larger prospective clinical studies are needed to confirm whether ST2 levels provide additional value in cardiotoxicity risk evaluation.
Ethical approval
The study was approved by the Tampere University Hospital ethics committee (R10160), Tampere, Finland, and informed consent was obtained from all participants.
Declarations of competing interest
None.
Acknowledgements
Ms. Salla Hietakangas is warmly acknowledged for her skillful technical assistance.
Financial support was provided by the Seppo Nieminen Fund (150620 and 150636), the Ida Montin Foundation (20180260), the Finnish Society for Oncology, the Finnish Cultural Foundation (Pirkanmaa Regional Fund 50181690), and the competitive state financing of the expert responsibility area of the Tampere University Hospital and the Paulo Foundation. The funding sources had no role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Contributor Information
Hanna Aula, Email: hanna.aula@tuni.fi.
Tanja Skyttä, Email: tanja.skytta@fimnet.fi.
Suvi Tuohinen, Email: suvi.tuohinen@fimnet.fi.
Tiina Luukkaala, Email: tiina.luukkaala@tuni.fi.
Mari Hämäläinen, Email: mari.hamalainen@tuni.fi.
Vesa Virtanen, Email: vesa.virtanen@sydansairaala.fi.
Pekka Raatikainen, Email: pekka.raatikainen@fimnet.fi.
Eeva Moilanen, Email: eeva.moilanen@tuni.fi.
Pirkko-Liisa Kellokumpu-Lehtinen, Email: pirkko-liisa.kellokumpu-lehtinen@tuni.fi.
References
- 1.EBCTCG (Early Breast Cancer Trialists’ Collaborative Group) McGale P., Taylor C., Correa C., Cutter D., Duane F. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383:2127–2135. doi: 10.1016/S0140-6736(14)60488-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Darby S., McGale P., Correa C., Taylor C., Arriagada R. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials. Lancet. 2011;378:1707–1716. doi: 10.1016/S0140-6736(11)61629-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Darby S.C., McGale P., Taylor C.W., Peto R. Long-term mortality from heart disease and lung cancer after radiotherapy for early breast cancer: prospective cohort study of about 300,000 women in US SEER cancer registries. Lancet Oncol. 2005;6:557–565. doi: 10.1016/S1470-2045(05)70251-5. [DOI] [PubMed] [Google Scholar]
- 4.Darby S.C., Ewertz M., McGale P., Bennet A.M., Blom-Goldman U., Brønnum D. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987–998. doi: 10.1056/NEJMoa1209825. [DOI] [PubMed] [Google Scholar]
- 5.Bouillon K., Haddy N., Delaloge S., Garbay J.-R., Garsi J.-P., Brindel P. Long-term cardiovascular mortality after radiotherapy for breast cancer. J Am Coll Cardiol. 2011;57:445–452. doi: 10.1016/j.jacc.2010.08.638. [DOI] [PubMed] [Google Scholar]
- 6.Hooning M.J., Botma A., Aleman B.M.P., Baaijens M.H.A., Bartelink H., Klijn J.G.M. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. JNCI J Natl Cancer Inst. 2007;99:365–375. doi: 10.1093/jnci/djk064. [DOI] [PubMed] [Google Scholar]
- 7.Harris E.E.R., Correa C., Hwang W.-T., Liao J., Litt H.I., Ferrari V.A. Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. J Clin Oncol. 2006;24:4100–4106. doi: 10.1200/JCO.2005.05.1037. [DOI] [PubMed] [Google Scholar]
- 8.Henson K.E., McGale P., Taylor C., Darby S.C. Radiation-related mortality from heart disease and lung cancer more than 20 years after radiotherapy for breast cancer. Br J Canc. 2013;108:179–182. doi: 10.1038/bjc.2012.575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Boekel N.B., Schaapveld M., Gietema J.A., Russell N.S., Poortmans P., Theuws J.C.M. Cardiovascular disease risk in a large, population-based cohort of breast cancer survivors. Int J Radiat Oncol. 2016;94:1061–1072. doi: 10.1016/j.ijrobp.2015.11.040. [DOI] [PubMed] [Google Scholar]
- 10.Weinberg E.O., Shimpo M., De Keulenaer G.W., MacGillivray C., Tominaga S., Solomon S.D. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation. 2002;106:2961–2966. doi: 10.1161/01.cir.0000038705.69871.d9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Manzano-Fernández S., Mueller T., Pascual-Figal D., Truong Q.A., Januzzi J.L. Usefulness of soluble concentrations of interleukin family member ST2 as predictor of mortality in patients with acutely decompensated heart failure relative to left ventricular ejection fraction. Am J Cardiol. 2011;107:259–267. doi: 10.1016/j.amjcard.2010.09.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Januzzi J.L., Peacock W.F., Maisel A.S., Chae C.U., Jesse R.L., Baggish A.L. Measurement of the interleukin family member ST2 in patients with acute dyspnea. J Am Coll Cardiol. 2007;50:607–613. doi: 10.1016/j.jacc.2007.05.014. [DOI] [PubMed] [Google Scholar]
- 13.Yancy C.W., Jessup M., Bozkurt B., Butler J., Casey D.E., Colvin M.M. ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American college of cardiology/American heart association task force on clinical practice guidelines and the heart failure society of amer. Circulation 2017. 2017;136:e137–e161. doi: 10.1161/CIR.0000000000000509. [DOI] [PubMed] [Google Scholar]
- 14.Wang T.J., Wollert K.C., Larson M.G., Coglianese E., McCabe E.L., Cheng S. Prognostic utility of novel biomarkers of cardiovascular stress: the Framingham Heart Study. Circulation. 2012;126:1596–1604. doi: 10.1161/CIRCULATIONAHA.112.129437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Cheng J.M., Akkerhuis K.M., Battes L.C., van Vark L.C., Hillege H.L., Paulus W.J. Biomarkers of heart failure with normal ejection fraction: a systematic review. Eur J Heart Fail. 2013;15:1350–1362. doi: 10.1093/eurjhf/hft106. [DOI] [PubMed] [Google Scholar]
- 16.Parikh R.H., Seliger S.L., Christenson R., Gottdiener J.S., Psaty B.M., DeFilippi C.R. Soluble ST2 for prediction of heart failure and cardiovascular death in an elderly, community-dwelling population. J Am Heart Assoc. 2016;5 doi: 10.1161/JAHA.115.003188. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Katsarska O., Zaharieva E., Aneva N., Savova G., Stankova K., Boteva R. The soluble receptor ST2 is positively associated with occupational exposure to radiation. Int J Radiat Biol. 2016;92:87–93. doi: 10.3109/09553002.2016.1115135. [DOI] [PubMed] [Google Scholar]
- 18.Tuohinen S.S., Skytta T., Virtanen V., Luukkaala T., Kellokumpu-Lehtinen P.-L., Raatikainen P. Early effects of adjuvant breast cancer radiotherapy on right ventricular systolic and diastolic function. Anticancer Res. 2015;35:2141–2147. [PubMed] [Google Scholar]
- 19.Skytta T., Tuohinen S., Virtanen V., Raatikainen P., Kellokumpu-Lehtinen P.-L. The concurrent use of aromatase inhibitors and radiotherapy induces echocardiographic changes in patients with breast cancer. Anticancer Res. 2015;35:1559–1566. [PubMed] [Google Scholar]
- 20.Tuohinen S.S., Skytta T., Virtanen V., Virtanen M., Luukkaala T., Kellokumpu-Lehtinen P.-L. Detection of radiotherapy-induced myocardial changes by ultrasound tissue characterisation in patients with breast cancer. Int J Cardiovasc Imaging. 2016;32:767–776. doi: 10.1007/s10554-016-0837-9. [DOI] [PubMed] [Google Scholar]
- 21.Tuohinen S.S., Skytta T., Poutanen T., Huhtala H., Virtanen V., Kellokumpu-Lehtinen P.-L. Radiotherapy-induced global and regional differences in early-stage left-sided versus right-sided breast cancer patients: speckle tracking echocardiography study. Int J Cardiovasc Imaging. 2017;33:463–472. doi: 10.1007/s10554-016-1021-y. [DOI] [PubMed] [Google Scholar]
- 22.Fimlab laboratories 2019. www.fimlab.fi
- 23.Aula H., Skyttä T., Tuohinen S., Luukkaala T., Hämäläinen M., Virtanen V. Transforming growth factor beta 1 levels predict echocardiographic changes at three years after adjuvant radiotherapy for breast cancer. Radiat Oncol. 2019;14:155. doi: 10.1186/s13014-019-1366-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Tuohinen S.S., Skyttä T., Huhtala H., Virtanen V., Kellokumpu-Lehtinen P.-L., Raatikainen P. Left ventricular speckle tracking echocardiography changes among early-stage breast cancer patients three years after radiotherapy. Anticancer Res. 2019;39:4227–4236. doi: 10.21873/anticanres.13584. [DOI] [PubMed] [Google Scholar]
- 25.Zamorano J.L., Lancellotti P., Rodriguez Muñoz D., Aboyans V., Asteggiano R., Galderisi M. ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur J Heart Fail 2017. 2016;19:9–42. doi: 10.1002/ejhf.654. [DOI] [PubMed] [Google Scholar]
- 26.Huang G., Zhai J., Huang X., Zheng D. Predictive value of soluble ST-2 for changes of cardiac function and structure in breast cancer patients receiving chemotherapy. Medicine (Baltim) 2018;97 doi: 10.1097/MD.0000000000012447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Chen L.Q., de Lemos J.A., Das S.R., Ayers C.R., Rohatgi A. Soluble ST2 is associated with all-cause and cardiovascular mortality in a population-based cohort: the dallas heart study. Clin Chem. 2013;59:536–546. doi: 10.1373/clinchem.2012.191106. [DOI] [PubMed] [Google Scholar]
- 28.Lin Y.-H., Zhang R.-C., Hou L.-B., Wang K.-J., Ye Z.-N., Huang T. Distribution and clinical association of plasma soluble ST2 during the development of type 2 diabetes. Diabetes Res Clin Pract. 2016;118:140–145. doi: 10.1016/j.diabres.2016.06.006. [DOI] [PubMed] [Google Scholar]
- 29.Kalam K., Otahal P., Marwick T.H. Prognostic implications of global LV dysfunction: a systematic review and meta-analysis of global longitudinal strain and ejection fraction. Heart. 2014;100:1673–1680. doi: 10.1136/heartjnl-2014-305538. [DOI] [PubMed] [Google Scholar]
- 30.Fabiani I., Conte L., Pugliese N.R., Calogero E., Barletta V., Di Stefano R. The integrated value of sST2 and global longitudinal strain in the early stratification of patients with severe aortic valve stenosis: a translational imaging approach. Int J Cardiovasc Imaging. 2017;33:1915–1920. doi: 10.1007/s10554-017-1203-2. [DOI] [PubMed] [Google Scholar]
- 31.Broch K., Leren I.S., Saberniak J., Ueland T., Edvardsen T., Gullestad L. Soluble ST2 is associated with disease severity in arrhythmogenic right ventricular cardiomyopathy. Biomarkers. 2017;22:367–371. doi: 10.1080/1354750X.2016.1278266. [DOI] [PubMed] [Google Scholar]