Involvement of chronic inflammation via monocyte chemoattractant protein‐1 in uraemic cardiomyopathy: a human biopsy study

• Main Authors: Tomoya Nakano, Kenji Onoue, Ayako Seno, Satomi Ishihara, Yasuki Nakada, Hitoshi Nakagawa, Tomoya Ueda, Taku Nishida, Tsunenari Soeda, Makoto Watanabe, Rika Kawakami, Kinta Hatakeyama, Yasuhiro Sakaguchi, Chiho Ohbayashi, Yoshihiko Saito
• Format: Article
• Language: English
• Published: Wiley 2021-08-01
• Series: ESC Heart Failure
• Subjects: Human heart tissue; Immunohistochemistry; Monocyte chemoattractant protein‐1; Placental growth factor; Uraemic cardiomyopathy
• Online Access: https://doi.org/10.1002/ehf2.13423

Abstract Aims 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. Methods and results 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). Conclusions 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.