Increased Plasma Nitrite and von Willebrand Factor Indicates Early Diagnosis of Vascular Diseases in Chemotherapy Treated Cancer Patients
- 129 Downloads
Chemotherapy induced cardiotoxicity leads to development of hypertension, conduction abnormalities, and congestive heart failure. However, there is no simple test to detect and assess cardiovascular risk in a chemotherapy treated cancer patient. The aim of the present study on cancer patients treated with (n = 66) and without (n = 66) chemotherapy is to identify indicators from plasma for vascular injury. The levels of plasma nitrite, asymmetric dimethyl arginine (ADMA), von Willebrand factor (vWF), cardiac troponins, lipid peroxidation (MDA), and lactate dehydrogenase (LDH) were estimated. An R package, namely, Optimal Cutpoints, and a machine learning method—support vector machine (SVM) were applied for identifying the indicators for cardiovascular damage. We observed a significant increase in nitrite (p < 0.001) and vWF (p < 0.001) level in chemotherapy treated patients compared to untreated cancer patients and healthy controls. An increased MDA and LDH activity from plasma in chemotherapy treated cancer patients was found. The R package analysis and SVM model developed using three indicators, namely, nitrite, vWF, and MDA, can distinguish cancer patients before and after chemotherapy with an accuracy of 87.8% and AUC value of 0.915. Serum collected from chemotherapy treated patients attenuates angiogenesis in chick embryo angiogenesis (CEA) assay and inhibits migration of human endothelial cells. Our work suggests that measurement of nitrite along with traditional endothelial marker vWF could be used as a diagnostic strategy for identifying susceptible patients to develop cardiovascular dysfunctions. The results of the present study offer clues for early diagnosis of subclinical vascular toxicity with minimally invasive procedure.
Schematic representation of chemotherapy induced elevated plasma nitrite level in cancer patients.
KeywordsChemotherapy Nitrite von Willebrand factor Cardiotoxicity Vascular disease Support vector machine (SVM)
This work is financially supported by DBT (File No. 6242-P100/RGCB/PMD/DBT/GJLM/2015) Government of India. S.G. acknowledges financial support from DST, Govt. of India for INSPIRE fellowship. P.G. thanks UGC for post-doctoral fellowship to women. S.C. acknowledges a Grant from University Grants Commission - Faculty Recharge Programme, (UGC-FRP), Government of India.
Compliance with Ethical Standards
Conflict of interest
The authors declare that there is no conflict of interest.
All procedures carried out in the present study are in accordance with the 1964 Helsinki declaration. The study was also approved by the Institutional Ethics Committee, Rajiv Gandhi Government General Hospital (Ref no. 1482), and Institutional Biosafety & Ethical Committee of AU-KBC Research Centre, Chennai, India.
Patients were recruited after obtaining individual written informed consent.
- 8.Huang, H., Nijjar, P. S., Misialek, J. R., Blaes, A., Derrico, N. P., Kazmirczak, F., et al. (2017). Accuracy of left ventricular ejection fraction by contemporary multiple gated acquisition scanning in patients with cancer: Comparison with cardiovascular magnetic resonance. Journal of Cardiovascular Magnetic Resonance: Official Journal of the Society for Cardiovascular Magnetic Resonance, 19, 34.CrossRefGoogle Scholar
- 11.Horvath, B., Hegedus, D., Szapary, L., Marton, Z., Alexy, T., Koltai, K., et al. (2014). Measurement of von Willebrand factor as the marker of endothelial dysfunction in vascular diseases. Experimental and Clinical Cardiology, 9, 31–34.Google Scholar
- 13.Varin, R., Mulder, P., Richard, V., Tamion, F., Devaux, C., Henry, J. P., et al. (1999). Exercise improves flow-mediated vasodilatation of skeletal muscle arteries in rats with chronic heart failure: Role of nitric oxide, prostanoids, and oxidant stress. Circulation, 99, 2951–2957.CrossRefGoogle Scholar
- 15.Vejlstrup, N. G., Bouloumie, A., Boesgaard, S., Andersen, C. B., Nielsen-Kudsk, J. E., Mortensen, S. A., et al. (1998). Inducible nitric oxide synthase (iNOS) in the human heart: Expression and localization in congestive heart failure. Journal of Molecular and Cellular Cardiology, 30, 1215–1223.CrossRefGoogle Scholar
- 17.Falk, E. (2006). Pathogenesis of atherosclerosis. Journal of the American College of Cardiology. 47(8 Suppl):C7-12.Google Scholar
- 18.Reinstadler, S. J., Feistritzer, H. J., Klug, G., Mair, J., Tu, A. M., Kofler, M., et al. (2016). High-sensitivity troponin T for prediction of left ventricular function and infarct size one year following ST-elevation myocardial infarction. International Journal of Cardiology, 202, 188–193.CrossRefGoogle Scholar
- 20.Sobin, L. H., & Wittekind, C. H. (1997). Head and neck tumors: Lips and oral cavity. In C. H. Wittekind (Ed.), TNM classification of malignant tumours (5th ed., pp. 59–62). New York: Wiley-Liss.Google Scholar
- 21.Moncada, S., Palmer, R. M., & Higgs, E. A. (1991). Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacological Reviews, 43, 109–142.Google Scholar
- 25.Gill, J. H., Loadman, P. M., Shnyder, S. D., Cooper, P., Atkinson, J. M., Ribeiro Morais, G., et al. (2014). Tumor-targeted prodrug ICT2588 demonstrates therapeutic activity against solid tumors and reduced potential for cardiovascular toxicity. Molecular Pharmaceutics, 11, 1294–1300.CrossRefGoogle Scholar
- 33.Zhou, J., Zhu, Q., & Yao, H. (2000). Chemotherapy of non-small-cell lung cancer (NSCLC) and changes in serum sAPO-1/Fas and nitric oxide (NO) levels. Chinese Journal of Oncology [Zhonghua zhong liu za zhi], 22, 225–227.Google Scholar
- 34.Guerra, J., De Jesus, A., Santiago-Borrero, P., Roman-Franco, A., Rodriguez, E., & Crespo, M. J. (2005). Plasma nitric oxide levels used as an indicator of doxorubicin-induced cardiotoxicity in rats. The Hematology Journal: The Official Journal of the European Haematology Association, 5, 584–588.CrossRefGoogle Scholar
- 36.Rockenbach, G., Di Pietro, P. F., Ambrosi, C., Boaventura, B. C., Vieira, F. G., Crippa, C. G., et al. (2011). Dietary intake and oxidative stress in breast cancer: Before and after treatments. Nutricion Hospitalaria, 26, 737–744.Google Scholar
- 41.Burtis, A. C., Ashwood, E. R., Bruns, R. E.,D. E., D.E (2011). Tietz textbook of clinical chemistry and molecular diagnostics (5th edn.). Amsterdam: Elsevier.Google Scholar
- 44.Cardinale, D., Sandri, M. T., Martinoni, A., Borghini, E., Civelli, M., Lamantia, G., et al. (2002). Myocardial injury revealed by plasma troponin I in breast cancer treated with high-dose chemotherapy. Annals of Oncology: Official Journal of the European Society for Medical Oncology/ESMO, 13, 710–715.CrossRefGoogle Scholar