Dos Santos Julia Matzenbacher, Joiakim Aby, Putt David A, Scherrer-Crosbie Marielle, Kim Hyesook
Detroit R&D, Inc., 2727 2nd Ave, Suite 4113, Detroit, MI, 48201, USA.
Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Cardiooncology. 2023 Dec 15;9(1):47. doi: 10.1186/s40959-023-00198-7.
Early identification of patients susceptible to chemotherapy-induced cardiotoxicity could lead to targeted treatment to reduce cardiac dysfunction. Rats treated with doxorubicin (DOX), a chemotherapeutic agent, have increased cardiac expression of 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), a bioactive lipid implicated in hypertension and coronary artery disease. However, the utility of 14,15-DHET as plasma biomarkers was not defined. The aim of this study is to investigate if levels of 14,15-DHET are an early blood biomarker to predict the subsequent occurrence of cardiotoxicity in cancer patients after chemotherapy.
H9c2 rat cardiomyocytes were treated with DOX (1 μM) for 2 h and levels of 14,15-DHET in cell media was quantified at 2, 6 or 24 h in media after DOX treatment. Similarly, female Sprague-Dawley rats were treated with DOX for two weeks and levels of 14,15-DHET was assessed in plasma at 48 h and 2 weeks after DOX treatment. Changes in brain natriuretic peptide (BNP) mRNA, an early cardiac hypertrophy process, were determined in the H9c2 cells and rat cardiac tissue. Results were confirmed in human subjects by assessment of levels of 14,15-DHET in plasma of breast cancer patients before and after DOX treatment and left ventricular ejection fraction (LVEF), a clinical marker of cardiotoxicity.
Levels of 14,15-DHET in cell media and rat plasma increased ~ 3-fold and was accompanied with increase in BNP mRNA in H9c2 cells and rat cardiac tissue after DOX treatment. In matched plasma samples from breast cancer patients, levels of 14,15-DHET were increased in patients that developed cardiotoxicity at 3 months before occurrence of LVEF decrease.
Together, these results indicate that levels of 14,15-DHET are elevated prior to major changes in cardiac structure and function after exposure to anthracyclines. Increased levels of 14,15-DHET in plasma may be an important clinical biomarker for early detection of anthracycline-induced cardiotoxicity in cancer patients.
早期识别易发生化疗所致心脏毒性的患者，有助于采取针对性治疗以减轻心脏功能障碍。用化疗药物阿霉素（DOX）处理的大鼠，其心脏中14,15 - 二羟基二十碳三烯酸（14,15 - DHET）的表达增加，14,15 - DHET是一种与高血压和冠状动脉疾病有关的生物活性脂质。然而，14,15 - DHET作为血浆生物标志物的效用尚未明确。本研究的目的是调查14,15 - DHET水平是否为预测癌症患者化疗后心脏毒性后续发生情况的早期血液生物标志物。
用DOX（1μM）处理H9c2大鼠心肌细胞2小时，并在DOX处理后的2、6或24小时对细胞培养基中14,15 - DHET的水平进行定量。同样，用DOX处理雌性Sprague - Dawley大鼠两周，并在DOX处理后的48小时和2周评估血浆中14,15 - DHET的水平。在H9c2细胞和大鼠心脏组织中测定早期心脏肥大过程中脑钠肽（BNP）mRNA的变化。通过评估DOX治疗前后乳腺癌患者血浆中14,15 - DHET的水平以及左心室射血分数（LVEF，心脏毒性的临床标志物），在人体受试者中证实了结果。
DOX处理后，细胞培养基和大鼠血浆中14,15 - DHET的水平增加了约3倍，并伴随着H9c2细胞和大鼠心脏组织中BNP mRNA的增加。在乳腺癌患者的配对血浆样本中，在出现LVEF降低前3个月发生心脏毒性的患者中，14,15 - DHET水平升高。
总之，这些结果表明，在接触蒽环类药物后心脏结构和功能发生重大变化之前，14,15 - DHET水平升高。血浆中14,15 - DHET水平升高可能是癌症患者早期检测蒽环类药物所致心脏毒性的重要临床生物标志物。
