■阿霉素(DOX)的心脏毒性限制了其在癌症治疗中的使用。为了解决这个限制,我们开发了一种新的动物模型,该模型使用比格犬研究DOX引起的心脏疾病。不幸的是,缺乏针对DOX诱导的心脏毒性的有效心脏保护策略构成了重大挑战.建立低死亡率DOX致心功能不全的犬模型,探讨炎症重编程与DOX相关心脏毒性的关系。
■将20只2岁的雄性比格犬随机分为DOX(N=10)和对照组(CON)(N=10)。每两周输注DOX(1.5mg/kg)直至剂量累计达到12mg/kg。评估血清生物标志物和心肌病理学,而基于实时荧光的定量聚合酶链反应(RTFQ-PCR),二维和三维超声心动图(2DE和RT3DE),功能富集,并进行了矩阵相关性。
■在DOX组中,高敏心肌肌钙蛋白T(hscTnT)和N末端脑钠肽前体(NT-proBNP)显著升高.心肌病理学提示早期至中期心肌变性,心肌细胞横截面积(CSA)减小。炎症基因转录物(白细胞介素6(IL6),肿瘤坏死因子(TNF),转化生长因子β(TGFβ),细胞间粘附分子1(ICAM1),白细胞介素1(IL1),白细胞介素1β(IL1β),和白细胞介素8(IL8),胶原代谢和沉积调节基因(基质金属蛋白酶(MMP)家族和基质金属蛋白酶组织抑制剂(TIMP)家族),和利钠肽家族(NPS)(利钠肽A,B和C(NPPA,NPPB,和NPPC)。右室纵向间隔应变(RVLSS)的应变异常,右心室纵向自由壁应变(RVLFS),左心室整体纵向应变(LVGLS),在第28周检测到左心室整体周向应变(LVGCS)(vs.第0周或CON组,p分别<0.05)。RVLSS和RVLFS的显着下降发生在第16周,比相应的左心室区域更早。在第16周,右心室射血分数(RVEF)显着下降(vs.第0周,33.92±3.59%与38.58±3.58%,p<0.05),比左心室射血分数(LVEF)早12周,发生在第28周(与第0周,49.02±2.07%与54.26±4.38%,p<0.01)。右心室应变和功能损伤与炎症重编程(大多数R从0.60到0.90)的相关性强于左心室(大多数R从0.30到0.65),从而表明更明显的相关性。
■在新建立的DOX相关心肌病比格犬模型中,炎症重编程介导的应变能力和心脏功能紊乱主要发生在心脏右侧。
UNASSIGNED: The cardiotoxicity of doxorubicin (DOX) limits its use in cancer treatment. To address this limitation, we developed a novel animal model that uses beagle dogs to investigate DOX-induced cardiac disorders. Unfortunately, the lack of effective cardioprotection strategies against DOX-induced cardiotoxicity poses a significant challenge. To establish a canine model for low-mortality DOX-induced cardiac dysfunction and explore the relationship between inflammatory reprogramming and DOX-related cardiotoxicity.
UNASSIGNED: Twenty male beagle dogs aged two years were randomly assigned into the DOX (N = 10) and control (CON) (N = 10) groups. DOX was infused (1.5 mg/kg) every two weeks until doses cumulatively reached 12 mg/kg. Serum biomarkers and myocardial pathology were evaluated, while real-time fluorescence-based quantitative polymerase chain reaction (RTFQ-PCR), two- and three-dimensional echocardiography (2DE and RT3DE), functional enrichment, and matrix correlation were also performed.
UNASSIGNED: In the DOX group, high-sensitive cardiac troponin T (hs cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were significantly increased. Myocardial pathology indicated early to medium myocardial degeneration via a decreased cardiomyocyte cross-sectional area (CSA). Increased levels of inflammatory gene transcripts (interleukin 6 (IL6), tumor necrosis factor (TNF), transforming growth factor β (TGF β ), intercellular adhesion molecule 1 (ICAM1), interleukin 1 (IL1), interleukin 1 β (IL1 β ), and interleukin 8 (IL8)), of collagen metabolism and deposition regulatory genes (matrix metalloproteinase (MMP) family and tissue inhibitor of matrix metalloproteinase (TIMP) family), and the natriuretic peptide family (NPS) (natriuretic peptide A, B and C (NPPA, NPPB, and NPPC)) were observed. Strain abnormalities in the right ventricular longitudinal septal strain (RVLSS), right ventricular longitudinal free-wall strain (RVLFS), left ventricular global longitudinal strain (LVGLS), and left ventricular global circumferential strain (LVGCS) were detected at week 28 (vs. week 0 or CON group, p < 0.05, respectively). A significant decline in RVLSS and RVLFS occurred at week 16, which was earlier than in the corresponding left ventricular areas. A significant right ventricular ejection fraction (RVEF) decline was noted at week 16 (vs. week 0, 33.92 ± 3.59% vs. 38.58 ± 3.58%, p < 0.05), which was 12 weeks earlier than for the left ventricular ejection fraction (LVEF), which occurred at week 28 (vs. week 0, 49.02 ± 2.07% vs. 54.26 ± 4.38%, p < 0.01). The right ventricular strain and functional damages correlated stronger with inflammatory reprogramming (most R from 0.60 to 0.90) than the left ones (most R from 0.30 to 0.65), thereby indicating a more pronounced correlation.
UNASSIGNED: Inflammatory reprogramming mediated disorders of strain capacity and cardiac function predominantly in the right side of the heart in the newly established DOX-related cardiomyopathy beagle dog model.