ABC | Volume 114, Nº6, June 2020

Original Article Yang et al Chemotherapy-related coronary-artery disease Arq Bras Cardiol. 2020; 114(6):1004-1012 chemotherapy. 5-7 Acute coronary-artery events that occurred shortly after administration of chemotherapeutic agents were reported. 3,8 Haugnes et al. 26 showed a 5.7-fold higher risk of CAD and a 3.1-fold higher risk of myocardial infarction with cisplatin-based regimens compared with surgery alone, in a median observation time of 19 years. 26 The present study investigated the association between chemotherapy and anatomical abnormalities of coronary arteries among lung cancer patients. Lung cancer is the most common incident cancer and the leading cause of cancer death. 9 The study assessed anatomical abnormalities of coronary arteries by the SXscore and investigated the relationship between chemotherapy and anatomical complexity of CAD among lung cancer patients. Results showed that both SXscore and SXhigh rates were significantly greater in patients who underwent chemotherapy compared with patients who did not. Multivariate stepwise logistic-regression analysis showed that the risk of more severe anatomical CAD is increased by chemotherapy as a whole by 5.323 times, and by platinum-based regimens by 5.850 times. The results indicate that chemotherapy is associated with the anatomical complexity and severity of CAD, which may at least partly explain the long-term higher morbidity of chemotherapy-related CAD, including myocardial infarction. 26 To our knowledge, no similar large study has quantitatively detected the association between chemotherapy and anatomical complexity and severity of CAD among lung cancer patients. Although chemotherapy-related CAD is becoming an emerging issue, the underlying mechanism of chemotherapy- related CAD remains unclea. Acute coronary-artery events that occurred shortly after administration of chemotherapeutic agents were possibly due to acute thrombosis or vasospasm. 3,8 Our study indicated that long-term chemotherapy-related coronary events may be due to more severe anatomical abnormalities induced by chemotherapeutic agents. In the present study, about 90% of the study patients are non-small cell lung cancer patients, and the others are small cell lung cancer patients. Most of chemotherapy regimens for the study patients involved more than one chemotherapeutic agent, most of which contained platinum. In fact, platinum was the base of chemotherapy for most of the patients. In the study, five patients received gefitinib and one patient received anthracycline, which is known to have cardiac toxicity. It is reasonable to determine that endothelial cells play an important role during the pathogenesis of chronic anatomical CAD. Besides, chemotherapeutic agents-induced endothelial injuries might be the core cause of chemotherapy-related CAD. Each study patient took various chemotherapeutic agents. Thus, it was difficult to infer which played the most important role in the progress of chemotherapy-related CAD. Since platinum is the most used agent, it may be one of the most important agents to be further studied for illustrating the underlying mechanisms of chemotherapy-related CAD. Radiotherapy plays a major role in the management of lung cancer. 27 Previous studies have shown the effect of radiation on heart diseases. 20,28-30 In the present study, both the SXscore and the SXhigh percentage were greater in the radiotherapy group in relation to the non-radiotherapy group. Nevertheless, no significant differences were observed between the two groups. In logistic-regression analysis, the OR of radiotherapy for the SXhigh was 2.112 (95% CI: 0.790–5.646), which means that radiotherapy is likely to increase the anatomical complexity of coronary arteries. However, the results could not show significant differences. The ambiguous results may be due to the smaller sample of patients receiving radiotherapy in the study population. Based on the results mentioned, we could say that chemotherapy may play a more important role than is currently thought in terms of CAD. However, it was not possible to determine that chemotherapy is worse than radiotherapy in terms of CAD, particularly due to the small sample and the lack of enough individual data for each chemotherapeutic agent. Still, we believe the results are interesting and deserve further study. Heart disease manifesting after cancer may be due to several mechanisms: shared cardiovascular risks between cancer and cardiovascular disease, inflammatory states associated with malignancies and/or cardiotoxic effects of cancer therapy. Age, gender, tobacco use, family history of CAD, hypertension, type II diabetes and hyperlipidemia are the well-known risk factors for CAD. 31-35 Smoking is a well- known common risk factor for both CAD and lung cancer. In Table 2 – SXscore and SXscore grades in lung cancer patients stratified by chemotherapy or radiotherapy Variables Statistical variable Chemotherapy stratification Radiotherapy stratification Chemotherapy group Non-chemotherapy group (n = 58) p value Radiotherapy group (n = 21) Non-radiotherapy group (n = 73) p value SXscore 0.3045 Mean ± SD 20.00 ± 12.70 14.96 ± 10.47 0.0195 18.67 ± 12.58 16.38 ± 11.31 Median 25.25 16.50 22.00 19.00 Q1–Q3 4.50–30.00 5.00–22.00 5.00–30.00 5.00–25.00 Min–max 0.00–38.00 0.00–38.00 1.00–35.50 0.00–38.00 SXscore grade 0.0016 0.1319 SXlow (<22) N (%) 15 (41.67%) 43 (74.14%) 10 (47.62%) 48 (65.75%) SXhigh (≥22) N (%) 21 (58.33%) 15 (25.86%) 11 (52.38%) 25 (34.25%) 1008