Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD.
Department of Anesthesiology, Columbia University, New York, NY.
Hepatology. 2020 Apr;71(4):1391-1407. doi: 10.1002/hep.30916. Epub 2020 Jan 24.
Hepatic cardiomyopathy, a special type of heart failure, develops in up to 50% of patients with cirrhosis and is a major determinant of survival. However, there is no reliable model of hepatic cardiomyopathy in mice. We aimed to characterize the detailed hemodynamics of mice with bile duct ligation (BDL)-induced liver fibrosis, by monitoring echocardiography and intracardiac pressure-volume relationships and myocardial structural alterations. Treatment of mice with a selective cannabinoid-2 receptor (CB -R) agonist, known to attenuate inflammation and fibrosis, was used to explore the impact of liver inflammation and fibrosis on cardiac function.
BDL induced massive inflammation (increased leukocyte infiltration, inflammatory cytokines, and chemokines), oxidative stress, microvascular dysfunction, and fibrosis in the liver. These pathological changes were accompanied by impaired diastolic, systolic, and macrovascular functions; cardiac inflammation (increased macrophage inflammatory protein 1, interleukin-1, P-selectin, cluster of differentiation 45-positive cells); and oxidative stress (increased malondialdehyde, 3-nitrotyrosine, and nicotinamide adenine dinucleotide phosphate oxidases). CB -R up-regulation was observed in both livers and hearts of mice exposed to BDL. CB -R activation markedly improved hepatic inflammation, impaired microcirculation, and fibrosis. CB -R activation also decreased serum tumor necrosis factor-alpha levels and improved cardiac dysfunction, myocardial inflammation, and oxidative stress, underlining the importance of inflammatory mediators in the pathology of hepatic cardiomyopathy.
We propose BDL-induced cardiomyopathy in mice as a model for hepatic/cirrhotic cardiomyopathy. This cardiomyopathy, similar to cirrhotic cardiomyopathy in humans, is characterized by systemic hypotension and impaired macrovascular and microvascular function accompanied by both systolic and diastolic dysfunction. Our results indicate that the liver-heart inflammatory axis has a pivotal pathophysiological role in the development of hepatic cardiomyopathy. Thus, controlling liver and/or myocardial inflammation (e.g., with selective CB -R agonists) may delay or prevent the development of cardiomyopathy in severe liver disease.
肝性心肌病是一种特殊类型的心力衰竭，在多达 50%的肝硬化患者中发展，是生存的主要决定因素。然而，在小鼠中没有可靠的肝性心肌病模型。我们旨在通过监测超声心动图和心内压-容积关系以及心肌结构改变，来描述胆管结扎（BDL）诱导的肝纤维化小鼠的详细血液动力学特征。使用一种已知可减轻炎症和纤维化的选择性大麻素-2 受体（CB -R）激动剂来治疗小鼠，以探讨肝脏炎症和纤维化对心脏功能的影响。
BDL 诱导肝脏发生大量炎症（白细胞浸润增加、炎症细胞因子和趋化因子增加）、氧化应激、微血管功能障碍和纤维化。这些病理变化伴随着舒张、收缩和大血管功能受损；心脏炎症（巨噬细胞炎性蛋白 1、白细胞介素-1、P 选择素、分化群 45 阳性细胞增加）；和氧化应激（丙二醛、3-硝基酪氨酸和烟酰胺腺嘌呤二核苷酸磷酸氧化酶增加）。在暴露于 BDL 的小鼠的肝脏和心脏中均观察到 CB -R 的上调。CB -R 激活显著改善了肝脏炎症、受损的微循环和纤维化。CB -R 激活还降低了血清肿瘤坏死因子-α水平并改善了心脏功能障碍、心肌炎症和氧化应激，这强调了炎症介质在肝性心肌病发病机制中的重要性。
我们提出 BDL 诱导的小鼠心肌病作为肝/肝硬化性心肌病的模型。这种心肌病类似于人类肝硬化性心肌病，其特征是全身低血压和大血管和微血管功能受损，同时伴有收缩和舒张功能障碍。我们的结果表明，肝-心炎症轴在心源性心肌病的发生发展中具有关键的病理生理学作用。因此，控制肝脏和/或心肌炎症（例如，使用选择性 CB -R 激动剂）可能会延迟或预防严重肝脏疾病中心肌病的发生。
