Department of Cardiovascular Medicine, Nara Medical University, Kashihara, Nara, Japan.
Department of Internal Medicine, Yamato-Takada Municipal Hospital, Yamato-Takada, Nara, Japan.
ESC Heart Fail. 2021 Aug;8(4):3156-3167. doi: 10.1002/ehf2.13423. Epub 2021 May 14.
Patients undergoing dialysis, even those without coronary artery disease or valvular abnormalities, sometimes present with reduced heart function, which resembles dilated cardiomyopathy (DCM). This condition is known as uraemic cardiomyopathy (UCM). The mechanisms of UCM development are not fully understood. Previous studies demonstrated that the balance between placental growth factor (PlGF) and fms-like tyrosine kinase-1 (Flt-1) is correlated with renal function, and PlGF/Flt-1 signalling is involved in the development of cardiovascular diseases in patients with chronic kidney disease. This study was conducted to evaluate the pathogenesis of UCM and clarify the differences in the mechanisms of UCM and DCM by using human endomyocardial biopsy and blood samples.
The clinical and pathological features of 30 patients on dialysis with reduced cardiac function [left ventricular ejection fraction (LVEF) ≤50%] (UCM group; mean age: 58.5 ± 9.4 years and LVEF: 39.1 ± 7.2%), 196 DCM patients (DCM group; mean age: 62.7 ± 14.0 years and LVEF: 33.5 ± 8.8%) as controls with reduced cardiac function (LVEF ≤ 45%), and 21 patients as controls with normal cardiac function (control group; mean age: 56.2 ± 19.3 years and LVEF: 67.5 ± 6.7%) were analysed. The percentage of the interstitial fibrosis area in the UCM group was greater than that in the DCM group (P = 0.045). In UCM patients, the percentage of the interstitial fibrosis area was positively correlated with the duration of renal replacement therapy (P < 0.001). The number of infiltrated CD68-positive macrophages in the myocardium and expression of monocyte chemoattractant protein-1 (MCP-1) in cardiomyocytes were significantly greater in the UCM group than in the other groups (P < 0.001, respectively). Furthermore, while the serum level of soluble form of Flt-1, an endogenous inhibitor of PlGF, in the UCM group was lower compared with that in the DCM group (P < 0.001), the serum levels of PlGF and PlGF/soluble form of Flt-1 ratio and plasma level of MCP-1 in the UCM group were higher than those in the DCM group (P < 0.001, respectively).
These results suggest that activated PlGF/Flt-1 signalling and subsequent macrophage-mediated chronic non-infectious inflammation via MCP-1 in the myocardium are involved in the pathogenesis of UCM.
即使没有冠状动脉疾病或瓣膜异常，接受透析的患者有时也会出现心脏功能降低，类似于扩张型心肌病（DCM）。这种情况被称为尿毒症性心肌病（UCM）。UCM 发展的机制尚不完全清楚。先前的研究表明，胎盘生长因子（PlGF）和 fms 样酪氨酸激酶-1（Flt-1）之间的平衡与肾功能有关，PlGF/Flt-1 信号通路参与了慢性肾脏病患者心血管疾病的发展。本研究旨在通过使用人类心内膜活检和血液样本评估 UCM 的发病机制，并阐明 UCM 和 DCM 机制的差异。
对 30 名接受透析且心脏功能降低（左心室射血分数（LVEF）≤50%）的患者（UCM 组；平均年龄：58.5±9.4 岁，LVEF：39.1±7.2%）、196 名 DCM 患者（DCM 组；平均年龄：62.7±14.0 岁，LVEF：33.5±8.8%）作为对照组（LVEF≤45%）和 21 名对照组（对照组；平均年龄：56.2±19.3 岁，LVEF：67.5±6.7%）的心脏功能正常）进行分析。UCM 组的间质纤维化面积百分比大于 DCM 组（P=0.045）。在 UCM 患者中，间质纤维化面积百分比与肾脏替代治疗的持续时间呈正相关（P<0.001）。UCM 组心肌浸润的 CD68 阳性巨噬细胞数量和心肌细胞中单核细胞趋化蛋白-1（MCP-1）的表达均明显高于其他组（P<0.001）。此外，与 DCM 组相比，UCM 组血清可溶性 Flt-1（PlGF 的内源性抑制剂）水平较低（P<0.001），而 UCM 组血清 PlGF、PlGF/可溶性 Flt-1 比值和 MCP-1 血浆水平均高于 DCM 组（P<0.001）。
这些结果表明，激活的 PlGF/Flt-1 信号通路以及随后通过 MCP-1 介导的心肌中的巨噬细胞慢性非传染性炎症参与了 UCM 的发病机制。
