中性粒細(xì)胞與淋巴細(xì)胞比值對(duì)動(dòng)脈性肺動(dòng)脈高壓的預(yù)后價(jià)值

楊瑩瑩，鄭璐，楊海波，趙蔭濤

中性粒細(xì)胞與淋巴細(xì)胞比值對(duì)動(dòng)脈性肺動(dòng)脈高壓的預(yù)后價(jià)值

楊瑩瑩，鄭璐，楊海波，趙蔭濤

鄭州大學(xué)第一附屬醫(yī)院心血管內(nèi)科，河南鄭州 450000

研究中性粒細(xì)胞與淋巴細(xì)胞比值（neutrophil-to-lymphocyte ratio，NLR）與動(dòng)脈性肺動(dòng)脈高壓（pulmonary arterial hypertension，PAH）患者預(yù)后的關(guān)系?；仡櫺苑治?020年11月至2022年10月鄭州大學(xué)第一附屬醫(yī)院收治的58例PAH患者的臨床資料，中位隨訪時(shí)間10個(gè)月（1～22個(gè)月），定義心力衰竭加重再入院、全因死亡、心肺移植為終點(diǎn)事件。根據(jù)隨訪結(jié)果繪制受試者操作特征曲線（receiver operating characteristic curve，ROC曲線）評(píng)價(jià)NLR預(yù)測(cè)患者預(yù)后不良的敏感度和特異性，生存分析使用Kaplan-Meier法，采用多因素Cox回歸探討影響PAH患者預(yù)后的危險(xiǎn)因素。終點(diǎn)事件患者的男性占比、中性粒細(xì)胞、NLR、N末端腦鈉肽前體、尿酸、C反應(yīng)蛋白（C-reaction protein，CRP）均顯著高于無(wú)終點(diǎn)事件患者（<0.05）。相關(guān)性結(jié)果顯示NLR與CRP呈正相關(guān)（=0.490，<0.05）。ROC曲線結(jié)果顯示，NLR截?cái)嘀禐?.72時(shí)預(yù)測(cè)PAH患者預(yù)后不良的敏感度和特異性分別為75.0%和73.8%，曲線下面積為0.765。NLR<2.72患者的生存率顯著高于NLR≥2.72患者（<0.05）。多因素Cox回歸分析結(jié)果顯示，性別（=11.476，95%：3.26～40.4）、NLR（=3.657，95%：1.117～11.973）均是PAH患者預(yù)后不良的獨(dú)立危險(xiǎn)因素。高水平NLR提示PAH患者預(yù)后不良，是發(fā)生不良事件的獨(dú)立危險(xiǎn)因素。

動(dòng)脈性肺動(dòng)脈高壓；中性粒細(xì)胞；淋巴細(xì)胞；預(yù)后

動(dòng)脈性肺動(dòng)脈高壓（pulmonary arterial hypertension，PAH）是一種進(jìn)展性疾病，其平均肺動(dòng)脈壓（mean pulmonary arterial pressure，mPAP）≥25mmHg（1mmHg=0.133kPa），可導(dǎo)致肺血管阻力（pulmonary vascular resistance，PVR）慢性升高、右心室衰竭和早期死亡[1]；其病理表現(xiàn)為血管內(nèi)皮功能障礙、血管收縮、肺小動(dòng)脈閉塞性重塑及原位血栓形成。研究表明炎癥在PAH的發(fā)病機(jī)制中起重要作用，而中性粒細(xì)胞與淋巴細(xì)胞比值（neutrophil-to-lymphocyte ratio，NLR）是炎癥狀態(tài)的一個(gè)簡(jiǎn)單且易于評(píng)估的指標(biāo)[2-3]?；谌巳旱难芯勘砻?，NLR增加是心力衰竭和心血管死亡的獨(dú)立預(yù)測(cè)因素[4-5]。本文擬研究NLR與PAH嚴(yán)重程度及預(yù)后的關(guān)系，現(xiàn)將結(jié)果報(bào)道如下。

1 資料與方法

1.1 一般資料

回顧性選取2020年11月至2022年10月鄭州大學(xué)第一附屬醫(yī)院收治的PAH患者。納入標(biāo)準(zhǔn)：①年齡>18歲；②符合《中國(guó)肺動(dòng)脈高壓診斷與治療指南（2021版）》[6]中PAH的診斷標(biāo)準(zhǔn)；③臨床資料完整。排除標(biāo)準(zhǔn)：①其他類型的肺動(dòng)脈高壓，如左心疾病所致肺動(dòng)脈高壓、肺部疾病或低氧所致肺動(dòng)脈高壓、慢性血栓栓塞性肺動(dòng)脈高壓、其他肺動(dòng)脈阻塞性病變所致肺動(dòng)脈高壓等；②住院期間診斷感染性疾病并應(yīng)用抗生素；③既往痛風(fēng)病史；④臨床資料不完整或失訪。PAH是指海平面、靜息狀態(tài)下，經(jīng)右心導(dǎo)管檢查測(cè)定的肺動(dòng)脈平均壓≥25mmHg，肺小動(dòng)脈楔壓≤15mmHg及PVR>3WU（1WU=80dyn·s/cm5）[6]。研究共納入經(jīng)右心導(dǎo)管診斷的PAH患者58例，其中女52例，男6例；中位年齡35（31，51）歲；特發(fā)性肺動(dòng)脈高壓（idiopathic pulmonary arterial hypertension，IPAH）9例，先天性心臟病相關(guān)肺動(dòng)脈高壓（congenital heart disease associated with pulmonary arterial hypertension，CHD-PAH）12例，結(jié)締組織病相關(guān)肺動(dòng)脈高壓(connective tissue disease associated with pulmonary arterial hypertension，CTD-PAH）37例。所有患者均簽署右心導(dǎo)管檢查知情同意書(shū)，均經(jīng)肺血管?？漆t(yī)生行規(guī)范化肺動(dòng)脈高壓靶向治療，對(duì)CHD-PAH患者經(jīng)風(fēng)濕免疫科?？漆t(yī)生規(guī)范化診療并門(mén)診隨訪。PAH靶向治療中，單藥治療：內(nèi)皮素受體拮抗劑9例；磷酸二酯酶Ⅴ型抑制劑（phosphodiesterase type 5 inhibitor，PDE5抑制劑）3例。聯(lián)合治療：內(nèi)皮素受體拮抗劑+PDE5抑制劑30例；內(nèi)皮素受體拮抗劑+前列腺素受體激動(dòng)劑4例；內(nèi)皮素受體拮抗劑+可溶性鳥(niǎo)苷酸環(huán)化酶激動(dòng)劑4例；內(nèi)皮素受體拮抗劑+PDE5抑制劑+前列腺素受體激動(dòng)劑4例；內(nèi)皮素受體拮抗劑+可溶性鳥(niǎo)苷酸環(huán)化酶激動(dòng)劑+前列腺素受體激動(dòng)劑4例。

1.2 方法

1.3 統(tǒng)計(jì)學(xué)方法

2 結(jié)果

2.1 PAH患者的臨床基線數(shù)據(jù)

共16例患者到達(dá)隨訪終點(diǎn)，終點(diǎn)事件患者的男性占比、中性粒細(xì)胞、NLR、NT-proBNP、UA、CRP均顯著高于無(wú)終點(diǎn)事件患者（<0.05），見(jiàn)表1。

2.2 NLR與臨床指標(biāo)的相關(guān)性分析

表1 PAH患者的基線資料比較[M（Q1，Q3），，n（%）]

注：1mmHg=0.133kPa；1WU=80dyn·s/cm5

表2 NLR與臨床指標(biāo)的相關(guān)性

2.3 NLR對(duì)PAH患者預(yù)后不良的預(yù)測(cè)價(jià)值

ROC曲線結(jié)果顯示，NLR截?cái)嘀禐?.72時(shí)預(yù)測(cè)PAH患者預(yù)后不良的敏感度和特異性分別為75.0%和73.8%，曲線下面積為0.765。

2.4 不同NLR水平PAH患者的生存曲線

NLR<2.72患者的生存率顯著高于NLR≥2.72患者（<0.05），見(jiàn)圖1。

2.5 多因素Cox回歸分析

多因素Cox回歸分析結(jié)果顯示，性別（=11.476，95%：3.26～40.4）、NLR（=3.657，95%：1.117～11.973）均是PAH患者預(yù)后不良的獨(dú)立危險(xiǎn)因素（<0.05），見(jiàn)表3。

圖1 不同NLR水平PAH患者的生存曲線

3 討論

PAH患者全身炎癥反應(yīng)標(biāo)記物水平普遍升高。研究表明，PAH患者血管周圍炎癥細(xì)胞聚集，包括巨噬細(xì)胞、樹(shù)突狀細(xì)胞、T和B淋巴細(xì)胞及肥大細(xì)胞；其血液循環(huán)中炎癥細(xì)胞因子和趨化因子升高，如白細(xì)胞介素-1β、白細(xì)胞介素-6和腫瘤壞死因子-α[7]。NLR是一種基于炎癥的生物標(biāo)記物，它與心力衰竭、急性心肌梗死、冠心病、感染性心內(nèi)膜炎和急性肺栓塞等多種疾病的預(yù)后相關(guān)[8-12]。

表3 影響PAH患者預(yù)后的Cox回歸分析

本研究結(jié)果顯示，NLR與NT-proBNP、UA、RVD、LVEDD、LVEF及血流動(dòng)力學(xué)參數(shù)無(wú)顯著相關(guān)。Harbaum等[13]研究結(jié)果顯示，NLR與疾病嚴(yán)重程度可能相關(guān)，NLR與6min步行距離、RAP呈正相關(guān)，與NT-proBNP呈負(fù)相關(guān)。多因素Cox回歸分析結(jié)果顯示性別和NLR均是PAH患者不良預(yù)后的獨(dú)立預(yù)測(cè)因素，與既往研究相似[13-14]。NLR預(yù)測(cè)不良預(yù)后的最佳截?cái)嘀禐?.72，不同NLR水平患者的生存率差異顯著。Harbaum等[13]和Jutras-Beaudoin等[14]研究結(jié)果顯示NLR是此類患者預(yù)后不良的獨(dú)立預(yù)測(cè)因子，但截?cái)嘀稻?4，可能與其研究人群種族不同且年齡相對(duì)較大有關(guān)。研究表明NLR在不同年齡、性別、種族中有所差異[15-16]，因此NLR值的差異可能源于潛在的患者特征。

本研究結(jié)果顯示雖然女性的PAH患病率明顯高于男性，但男性發(fā)生終點(diǎn)事件的風(fēng)險(xiǎn)是女性的11.476倍，提示男性預(yù)后更差。隨訪期間不良預(yù)后患者的基線NLR顯著高于無(wú)終點(diǎn)事件患者。研究表明，與健康受試者相比，從IPAH患者中分離出的中性粒細(xì)胞釋放更多介質(zhì)，如彈性蛋白酶或白三烯B4[17]。中性粒細(xì)胞彈性蛋白酶由肺血管平滑肌細(xì)胞產(chǎn)生，抑制該酶可通過(guò)誘導(dǎo)平滑肌細(xì)胞凋亡預(yù)防和逆轉(zhuǎn)實(shí)驗(yàn)性PAH[18-19]。PAH患者的白三烯B4水平升高，降低其水平可逆轉(zhuǎn)實(shí)驗(yàn)性PAH[20]。缺氧嚴(yán)重抑制中性粒細(xì)胞凋亡[21]。PAH患者因氧彌散功能障礙而處于缺氧狀態(tài)。無(wú)胸腺大鼠T淋巴細(xì)胞的缺乏可導(dǎo)致PAH的發(fā)生，提示恢復(fù)缺失的淋巴細(xì)胞群可通過(guò)限制炎癥來(lái)預(yù)防PAH[22]。

綜上，NLR是PAH患者預(yù)后不良的獨(dú)立危險(xiǎn)因素，高水平NLR提示PAH患者預(yù)后不良，NLR有望成為PAH臨床管理的炎癥指標(biāo)。

[1] RUBIN L J. Pulmonary arterial hypertension[J]. Proc Am Thorac Soc, 2006, 3(1): 111–115.

[2] PRICE L C, WORT S J, PERROS F, et al. Inflammation in pulmonary arterial hypertension[J]. Chest, 2012, 141(1): 210–221.

[3] SHAH N, PARIKH V, PATEL N, et al. Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: Insights from the national health and nutrition examination survey-Ⅲ[J]. Int J Cardiol, 2014, 171(3): 390–397.

[4] FEST J, RUITER T R, KOERKAMP B G, et al. The neutrophil-to-lymphocyte ratio is associated with mortality in the general population: The rotterdam study[J]. Eur J Epidemiol, 2019, 34(5): 463–470.

[5] KIM S, ELIOT M, KOESTLER D C, et al. Association of neutrophil-to-lymphocyte ratio with mortality and cardiovascular disease in the Jackson heart study and modification by the Duffy antigen variant[J]. JAMA Cardiol, 2018, 3(6): 455–462.

[6] 中華醫(yī)學(xué)會(huì)呼吸病學(xué)分會(huì)肺栓塞與肺血管病學(xué)組, 中國(guó)醫(yī)師協(xié)會(huì)呼吸醫(yī)師分會(huì)肺栓塞與肺血管病工作委員會(huì), 全國(guó)肺栓塞與肺血管病防治協(xié)作組, 等. 中國(guó)肺動(dòng)脈高壓診斷與治療指南(2021版)[J]. 中華醫(yī)學(xué)雜志, 2021, 101(1): 11–51.

[7] RABINOVITCH M, GUIGNABERT C, HUMBERT M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension[J]. Circ Res, 2014, 115(1): 165–175.

[8] UTHAMALINGAM S, PATVARDHAN E A, SUBRAMANIAN S, et al. Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure[J]. Am J Cardiol, 2011, 107(3): 433–438.

[9] Nú?EZ J, Nú?EZ E, BODí V, et al. Usefulness of the neutrophil to lymphocyte ratio in predicting long-term mortality in ST segment elevation myocardial infarction[J]. Am J Cardiol, 2008, 101(6): 747–752.

[10] PAPA A, EMDIN M, PASSINO C, et al. Predictive value of elevated neutrophil-lymphocyte ratio on cardiac mortality in patients with stable coronary artery disease[J]. Clin Chim Acta, 2008, 395(1-2): 27–31.

[11] TURAK O, ?ZCAN F, I?LEYEN A, et al. Usefulness of neutrophil-to-lymphocyte ratio to predict in-hospital outcomes in infective endocarditis[J]. Can J Cardiol, 2013, 29(12): 1672–1678.

[12] KAYRAK M, ERDO?AN H I, SOLAK Y, et al. Prognostic value of neutrophil to lymphocyte ratio in patients with acute pulmonary embolism: A restrospective study[J]. Heart Lung Circ, 2014, 23(1): 56–62.

[13] HARBAUM L, BAASKE K M, SIMON M, et al. Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension[J]. BMC Pulm Med, 2017, 17(1): 72.

[14] JUTRAS-BEAUDOIN N, TORO V, LAJOIE A C, et al. Neutrophil-lymphocyte ratio as an independent predictor of survival in pulmonary arterial hypertension: An exploratory study[J]. CJC Open, 2021, 4(4): 357–363.

[15] HOWARD R, KANETSKY P A, EGAN K M. Exploring the prognostic value of the neutrophil-to-lymphocyte ratio in cancer[J]. Sci Rep, 2019, 9(1): 19673.

[16] AZAB B, CAMACHO-RIVERA M, TAIOLI E. Average values and racial differences of neutrophil lymphocyte ratio among a nationally representative sample of United States subjects[J]. PLoS One, 2014, 9(11): e112361.

[17] ROSE F, HATTAR K, GAKISCH S, et al. Increased neutrophil mediator release in patients with pulmonary hypertension--Suppression by inhaled iloprost[J]. Thromb Haemost, 2003, 90(6): 1141–1149.

[18] KIM Y M, HAGHIGHAT L, SPIEKERKOETTER E, et al. Neutrophil elastase is produced by pulmonary artery smooth muscle cells and is linked to neointimal lesions[J]. Am J Pathol, 2011, 179(3): 1560–1572.

[19] NICKEL N P, SPIEKERKOETTER E, GU M, et al. Elafin reverses pulmonary hypertension via caveolin-1- dependent bone morphogenetic protein signaling[J]. Am J Respir Crit Care Med, 2015, 191(11): 1273–1286.

[20] TIAN W, JIANG X, TAMOSIUNIENE R, et al. Blocking macrophage leukotriene B4 prevents endothelial injury and reverses pulmonary hypertension[J]. Sci Transl Med, 2013, 5(200): 200ra117.

[21] WALMSLEY S R, COWBURN A S, CLATWORTHY M R, et al. Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis[J]. Blood, 2006, 108(9): 3176–3178.

[22] TAMOSIUNIENE R, TIAN W, DHILLON G, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension[J]. Circ Res, 2011, 109(8): 867–879.

Prognostic value of neutrophil-to-lymphocyte ratio in pulmonary arterial hypertension

Department of Cardiovascular Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan, China

To study the relationship between neutrophil-to-lymphocyte ratio (NLR) and prognosis of patients with pulmonary arterial hypertension (PAH).The clinical data of 58 patients with PAH admitted to the First Affiliated Hospital of Zhengzhou University from November 2020 to October 2022 were retrospectively analyzed. The median follow-up time was 10 months (1-22 months), and the end events were defined as aggravated readmission of heart failure, all-cause death, and cardiopulmonary transplantation. According to the follow-up results, receiver operating characteristic (ROC) curve was drawn to evaluate the sensitivity and specificity of NLR in predicting poor prognosis of patients. Kaplan-Meier method was used for survival analysis. Multivariate Cox regression was used to investigate the risk factors affecting the prognosis of patients with PAH.The male proportion, neutrophils, NLR, N-terminal pro-brain natriuretic peptide, uric acid, and C-reaction protein (CRP) in patients with endpoint events were significantly higher than those without endpoint events (<0.05). The correlation results showed that NLR was positively correlated with CRP (=0.490,<0.05). ROC curve results showed that when the NLR truncation value was 2.72, the sensitivity and specificity of predicting poor prognosis in PAH patients were 75.0% and 73.8%, respectively, and the area under the curve was 0.765. The survival rate of patients with NLR<2.72 was significantly higher than that of patients with NLR≥2.72 (<0.05). Multivariate Cox regression analysis showed that gender (=11.476, 95%: 3.26-40.4) and NLR (=3.657, 95%: 1.117-11.973) were independent risk factors for poor prognosis in PAH patients.High NLR levels suggest poor prognosis and are an independent risk factor for adverse events.

Pulmonary arterial hypertension; Neutrophil; Lymphocyte; Prognosis

R563

A

10.3969/j.issn.1673-9701.2023.22.016

趙蔭濤，電子信箱：ytzhao@126.com

（2022–11–02）

（2023–07–17）