Cardiovascular & Fibrosis Discovery Biology, Lead Discovery & Optimization, Bristol Myers Squibb, NJ, USA.
J Pharmacol Toxicol Methods. 2020 Nov-Dec;106:106935. doi: 10.1016/j.vascn.2020.106935. Epub 2020 Oct 20.
Murine transverse aortic constriction (TAC) is a frequently used model of pressure overload-induced left ventricular (LV) remodeling. However, there is considerable variability in disease progression to overt heart failure (HF) development in the most commonly used strain of mice (i.e., C57BL/6J). Studies have shown that C57BL/6J mice are more resistant than BALB/c mice to congestive HF development following myocardial infarction or angiotensin II-induced hypertension. Therefore, we tested the hypothesis that BALB/c mice may be a better research model to study TAC-induced progressive HF.
Following sham or TAC surgery in both C57BL/6J (n = 29) and BALB/c (n = 32) mice, we evaluated cardiac dimensions and function by echocardiography at 2, 4, 8, and 12 weeks and monitored survival throughout the study. In a separate cohort of BALB/c mice, we repeated the study in the presence of the angiotensin converting enzyme inhibitor enalapril or a vehicle initiated 2 weeks post-TAC and administered for 6 weeks. At the end of the studies, we assessed the heart weight, lung weight, and plasma brain natriuretic peptide (BNP) concentration.
Following comparable TAC, both C57BL/6J and BALB/c mice showed significant LV remodeling compared with the sham control mice. BALB/c mice progressively developed systolic dysfunction, LV dilation, lung congestion, and significant mortality, whereas C57BL/6J mice did not. In the separate cohort of BALB/c TAC mice, enalapril significantly reduced the heart weight, lung weight, and plasma BNP concentration and improved survival compared with the vehicle control.
BALB/c mice uniformly developed congestive HF post-TAC. Enalapril was effective in improving survival and reducing lung congestion in this model. The data suggest that BALB/c mice may be a better research tool than C57BL/6J mice to study TAC-induced disease progression to HF and to evaluate novel therapies for the treatment of chronic HF with reduced ejection fraction.
小鼠主动脉缩窄（TAC）是一种常用于压力超负荷诱导左心室（LV）重构的模型。然而，在最常用的小鼠品系（即 C57BL/6J）中，向明显心力衰竭（HF）发展的疾病进展存在相当大的变异性。研究表明，与 BALB/c 小鼠相比，C57BL/6J 小鼠在心肌梗死或血管紧张素 II 诱导的高血压后对充血性 HF 发展的抵抗力更强。因此，我们测试了 BALB/c 小鼠可能是研究 TAC 诱导进行性 HF 的更好研究模型的假设。
在 C57BL/6J（n=29）和 BALB/c（n=32）小鼠进行假手术或 TAC 手术后，我们通过超声心动图在 2、4、8 和 12 周时评估心脏尺寸和功能，并在整个研究过程中监测生存情况。在 BALB/c 小鼠的另一队列中，我们在 TAC 后 2 周开始并持续 6 周给予血管紧张素转换酶抑制剂依那普利或载体的情况下重复该研究。在研究结束时，我们评估了心脏重量、肺重量和血浆脑钠肽（BNP）浓度。
在进行可比的 TAC 后，与假手术对照小鼠相比，C57BL/6J 和 BALB/c 小鼠的 LV 重构均显著。BALB/c 小鼠逐渐出现收缩功能障碍、LV 扩张、肺充血和显著的死亡率，而 C57BL/6J 小鼠则没有。在 BALB/c TAC 小鼠的另一个队列中，与载体对照相比，依那普利显著降低了心脏重量、肺重量和血浆 BNP 浓度，并提高了生存率。
BALB/c 小鼠在 TAC 后均发展为充血性 HF。依那普利在该模型中有效提高了生存率并减少了肺充血。数据表明，BALB/c 小鼠可能是研究 TAC 诱导疾病进展为 HF 以及评估新型疗法治疗射血分数降低的慢性 HF 的更好研究工具。
