Y 染色体丢失与慢性肾脏病中的心血管事件。

Loss of Y Chromosome and Cardiovascular Events in Chronic Kidney Disease.

机构信息

1Goethe University Frankfurt's University Hospital, Department of Internal Medicine 4, Nephrology (T.S., S.R.P., M.G., T.S., M.W.).

University Hospital, Department of Medicine, Cardiology (S.C., D.M.L.).

出版信息

Circulation. 2024 Sep 3;150(10):746-757. doi: 10.1161/CIRCULATIONAHA.124.069139. Epub 2024 Jul 15.

DOI:10.1161/CIRCULATIONAHA.124.069139

PMID:39005209

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11361358/

Abstract

BACKGROUND

Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease.

METHODS

LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study, n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed.

RESULTS

In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events.

CONCLUSIONS

LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.

摘要

背景

慢性肾脏病是心血管疾病的最强危险因素之一，尤其是心力衰竭。尽管药物治疗有所改善，但死亡率仍然很高。最近，实验研究表明，Y 染色体镶嵌缺失（LOY）与雄性小鼠的心脏纤维化有关。由于弥漫性心肌纤维化是所有心力衰竭形式进展的共同特征，我们确定了LOY 与慢性肾脏病患者的死亡率和心血管疾病结局之间的关系。

方法

在稳定的慢性肾脏病男性患者（CARE for HOMe 研究，n=279）和透析患者（4D 研究，n=544）中定量检测 LOY。评估 LOY 与死亡率、心血管和心力衰竭特定终点的联合以及超声心动图指标之间的关系。

结果

在 CARE for HOMe 中，LOY 的频率随年龄增长而增加。LOY >17%与死亡率增加相关（心率，2.58[95%CI，1.33-5.03]）和心脏失代偿或死亡风险增加（心率，2.30[95%CI，1.23-4.27]）。LOY >17%的患者在 5 年内射血分数显著下降，E/E'增加。一致地，在 4D 研究中，LOY >17%与死亡率增加显著相关（心率，2.76[95%CI，1.83-4.16]）、心力衰竭和心脏性猝死导致的死亡风险更高（心率，4.11[95%CI，2.09-8.08]），但与动脉粥样硬化事件无关。LOY >17%的患者可溶性白细胞介素 1 受体样 1 水平显著升高，这是心肌纤维化的生物标志物。在机制上，LOY >17%患者的中间单核细胞显示出 C-C 趋化因子受体 2 表达显著增加，以及 C-C 趋化因子受体 2 趋化因子（C 基序）配体 2 的血浆水平升高，这可能导致心力衰竭事件增加。