鄧潮超 朱鵬立 黃峰 肖華貞
【摘要】 目的:研究急性心力衰竭患者胃促生長(zhǎng)素(Ghrelin)、氨基端B型利鈉肽原前體(NT-proBNP)水平的預(yù)后預(yù)測(cè)價(jià)值。方法:選擇241例急性心力衰竭患者,測(cè)定血漿Ghrelin和NT-proBNP水平,采用電話隨訪,記錄死亡時(shí)間。采用Kaplan-Meier曲線做生存分析,采用Cox比例風(fēng)險(xiǎn)回歸模型比較組間事件風(fēng)險(xiǎn)比(HR)。結(jié)果:所有患者,隨訪時(shí)間0~565 d,中位數(shù)時(shí)間為151 d。低Ghrelin組和高Ghrelin組年齡、舒張壓、鈉、肌酐、急性心肌梗死比較,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。高Ghrelin組(Ghrelin>9.19 ng/mL)全因死亡率低于低Ghrelin組(Ghrelin≤9.19 ng/mL)(P<0.05)。高NT-proBNP組(NT-proBNP>3 801.0 pg/mL)和低NT-proBNP(NT-proBNP≤3 801.0 pg/mL)心率、血紅蛋白、鈉、肌酐、左心室舒張末期容積、左心室射血分?jǐn)?shù)、冠心病、急性心肌梗死比較,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。高NT-proBNP組全因死亡率高于低NT-proBNP組(P<0.01)。Kaplan-Meier曲線顯示,高Ghrelin組的中位生存時(shí)間長(zhǎng)于低Ghrelin組(P<0.01),低NT-proBNP組的中位生存時(shí)間長(zhǎng)于高NT-proBNP組(P<0.05)。Cox比例風(fēng)險(xiǎn)模型分析顯示,低Ghrelin高NT-proBNP組發(fā)生死亡事件風(fēng)險(xiǎn)為高Ghrelin低NT-proBNP組5.346倍[95%CI(1.461,19.561),P<0.01]。結(jié)論:低Ghrelin、高NT-proBNP水平的急性心力衰竭患者預(yù)后差。
【關(guān)鍵詞】 急性心力衰竭 Ghrelin NT-proBNP 預(yù)后
Prognostic Value of Ghrelin and NT-proBNP in Patients with Acute Heart Failure/DENG Chaochao, ZHU Pengli, HUANG Feng, XIAO Huazhen. //Medical Innovation of China, 2021, 18(14): 0-080
[Abstract] Objective: To study prognostic value of Ghrelin and NT-proBNP in patients with acute heart failure. Method: Clinical data of 241 patients with acute heart failure were collected, plasma Ghrelin and NT-proBNP levels were determined, telephone follow-up was performed, and time of death was recorded. Kaplan-Meier curve was used for survival analysis, and Cox proportional risk regression model was used to compare the inter-group event risk ratio (HR). Result: All patients were followed up for 0-565 d, with a median of 151 d. There were statistically significant differences in age, diastolic blood pressure, sodium, creatinine and acute myocardial infarction between the low and high Ghrelin group (P<0.05). All-cause mortality rate of high Ghrelin group (Ghrelin>9.19 ng/mL) was lower than that of low Ghrelin group (Ghrelin≤9.19 ng/mL) (P<0.05). There were significant differences between the high NT-proBNP (NT-proBNP>3 801.0 pg/mL) group and the low NT-proBNP (NT-proBNP≤3 801.0 pg/mL)
in heart rate, hemoglobin, sodium, creatinine, left ventricular end-diastolic volume, left ventricular ejection fraction, coronary heart disease, and acute myocardial infarction (P<0.05). All-cause mortality rate of high NT-proBNP group was higher than that of low NT-proBNP group (P<0.01). Kaplan-Meier survival curve showed that the median survival time of high Ghrelin group was higher than that of low Ghrelin group (P<0.01). The median survival time of low NT-proBNP group was higher than that of high NT-proBNP group (P<0.05). Cox proportional hazards model analysis showed that, the death occurred HR of the low Ghrelin and high NT-proBNP group compared with the high Ghrelin and low NT-proBNP group was 5.346 [95%CI (1.461, 19.561), P<0.01]. Conclusion: The low Ghrelin level and high NT-proBNP level have poor outcome in patients with acute heart failure.
[Key words] Acute heart failure Ghrelin NT-proBNP Prognosis
First-authors address: Fujian Provincial Hospital South Branch, Fuzhou 350000, China
doi:10.3969/j.issn.1674-4985.2021.14.019
心力衰竭是常見(jiàn)危重病,住院死亡率3%~13%,半年內(nèi)再住院率達(dá)50%,5年死亡率高達(dá)60%,預(yù)后差[1-2]。氨基端B型利鈉肽原前體(NT-proBNP)在心力衰竭的診斷、預(yù)后預(yù)測(cè)都有重要價(jià)值,但是仍有局限性,在腎功能不全、高齡的患者中局限性尤其大。因此,在心力衰竭患者的診斷、療效判斷及預(yù)后預(yù)測(cè)等方面,各國(guó)指南均推薦聯(lián)合多種標(biāo)志物檢測(cè)。胃促生長(zhǎng)素(Ghrelin)是一種活性多肽,由28個(gè)氨基酸構(gòu)成[3]。研究表明,Ghrelin對(duì)心臟有多種益處,包括擴(kuò)張血管、抑制交感神經(jīng)活性、調(diào)節(jié)能量代謝、延緩心臟重構(gòu)和正性肌力等[4-6]。動(dòng)物實(shí)驗(yàn)表明,大鼠Ghrelin基因人為敲除后,心功能和生存率顯著降低[7],肌鈣蛋白T部分基因敲除的心力衰竭大鼠中,生理鹽水對(duì)照組死亡率高于Ghrelin治療組[8]。國(guó)內(nèi)一項(xiàng)隨訪研究顯示,在慢性心力衰竭患者中心血管事件組Ghrelin水平與非事件組有差異[9]。但在急性心力衰竭患者中,Ghrelin的預(yù)后價(jià)值尚無(wú)相關(guān)報(bào)道。本研究旨在探討急性心力衰竭患者中Ghrelin和NT-proBNP水平預(yù)后預(yù)測(cè)價(jià)值,現(xiàn)報(bào)道如下。
1 資料與方法
1.1 一般資料 選擇2014年6月-2015年1月就診于福建省立醫(yī)院的241例急性心力衰竭患者。納入標(biāo)準(zhǔn):(1)年齡≥18歲;(2)診斷為急性心力衰竭。排除標(biāo)準(zhǔn):(1)合并惡性腫瘤且預(yù)計(jì)壽命少于兩年;(2)合并消化性潰瘍;(3)胃切除病史。本研究通過(guò)醫(yī)院倫理委員會(huì)批準(zhǔn),患者均簽署知情同意書(shū)。
1.2 方法 (1)Ghrelin和NT-proBNP水平的測(cè)定:入院時(shí)即刻用EDTA抗凝管采集5 mL靜脈血2管,高速低溫離心(4 ℃,3 000 r/min)分離血漿,-80 ℃凍存。NT-proBNP由醫(yī)院免疫實(shí)驗(yàn)室統(tǒng)一測(cè)定。Ghrelin測(cè)定采用美國(guó)鳳凰城公司酶聯(lián)免疫吸附試劑盒,檢測(cè)濃度范圍0~100 ng/mL,線性范圍0.09~1.2 ng/mL,批間差異<15%,批內(nèi)差異<10%。(2)收集患者入院時(shí)臨床資料,以入院時(shí)間為隨訪開(kāi)始時(shí)間,記錄出院結(jié)局及時(shí)間。存活出院患者,通過(guò)電話隨訪獲取生存資料。隨訪的終點(diǎn)事件為全因死亡,最終截止時(shí)間為2016年2月1日。
1.3 觀察指標(biāo) (1)以Ghrelin中位數(shù)為界值,分為低Ghrelin組(Ghrelin≤9.19 ng/mL,n=121)和高Ghrelin組(Ghrelin>9.19 ng/mL,n=120)。比較兩組全因死亡率并采用Kaplan-Meier曲線做生存分析。(2)以NT-proBNP中位數(shù)為界值,分為低NT-proBNP組(NT-proBNP≤3 801.0 pg/mL,n=121)和高NT-proBNP組(NT-proBNP>3 801.0 pg/mL,n=120)。比較兩組全因死亡率并采用Kaplan-Meier曲線做生存分析。(3)采用Cox比例風(fēng)險(xiǎn)回歸模型比較組間事件風(fēng)險(xiǎn)比(HR)。
1.4 統(tǒng)計(jì)學(xué)處理 使用SPSS 19.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。正態(tài)分布計(jì)量資料用(x±s)表示,比較采用t檢驗(yàn);非正態(tài)分布計(jì)量資料用M(P25,P75)表示,比較用Mann-Whitney U檢驗(yàn);計(jì)數(shù)資料以率(%)表示,比較采用字2檢驗(yàn)。采用Kaplan-Meier法比較組間中位生存時(shí)間,多組間事件風(fēng)險(xiǎn)采用Cox比例風(fēng)險(xiǎn)回歸模型比較。雙側(cè)P<0.05為差異有統(tǒng)計(jì)學(xué)意義。
2 結(jié)果
2.1 失訪及全因死亡情況 241例患者中,失訪54例,失訪率22.4%,其中17例失訪是由手機(jī)號(hào)碼變更導(dǎo)致。隨訪時(shí)間0~565 d,151(14,449)d。全因死亡57例,占23.7%。
2.2 低Ghrelin組和高Ghrelin組全因死亡率及中位生存時(shí)間比較 兩組性別比例、體質(zhì)指數(shù)、收縮壓、心率、血紅蛋白、左心室舒張末期容積、左心室射血分?jǐn)?shù)、冠心病、高血壓、擴(kuò)張型心肌病比較,差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05);兩組年齡、舒張壓、鈉、肌酐、急性心肌梗死比較,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。見(jiàn)表1。高Ghrelin組全因死亡率為15.8%(19/120),低于低Ghrelin組的31.4%(38/121)(字2=8.090,P<0.05)。高Ghrelin組的中位生存時(shí)間為361 d長(zhǎng)于低Ghrelin組的65 d(字2=9.427,P<0.01)。見(jiàn)圖1。
2.3 低NT-proBNP組和高NT-proBNP組全因死亡率及中位生存時(shí)間比較 兩組年齡、性別比例、體質(zhì)指數(shù)、收縮壓、舒張壓、高血壓、擴(kuò)張型心肌病比較,差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05);兩組心率、血紅蛋白、鈉、肌酐、左心室舒張末期容積、左心室射血分?jǐn)?shù)、冠心病、急性心肌梗死比較,差異均有統(tǒng)計(jì)學(xué)意義(P<0.05)。見(jiàn)表2。高NT-proBNP組全因死亡率為35.8%(43/120),高于低NT-proBNP組11.6%(14/121)(字2=19.642,P<0.01)。Kaplan-Meier生存分析顯示,低NT-proBNP組的中位生存時(shí)間為398 d長(zhǎng)于高NT-proBNP組的52 d(字2=23.205,P<0.05)。見(jiàn)圖2。
2.4 NT-proBNP和Ghrelin水平聯(lián)合預(yù)測(cè)全因死亡事件風(fēng)險(xiǎn)比 研究對(duì)象以NT-proBNP及Ghrelin的中位數(shù)為界分為:高NT-proBNP低Ghrelin組(n=72)、高NT-proBNP高Ghrelin組(n=48)、低NT-proBNP低Ghrelin組(n=49)、低NT-proBNP高Ghrelin組(n=72)。Cox比例風(fēng)險(xiǎn)回歸模型分析顯示,校正年齡、性別比例、收縮壓、肌酐、左心室舒張末期容積、左心室射血分?jǐn)?shù)、冠心病和急性心肌梗死比例后,與低NT-proBNP高Ghrelin組比,高NT-proBNP低Ghrelin組死亡風(fēng)險(xiǎn)為5.346[95%CI(1.461,19.561),P<0.05]。
3 討論
急性心力衰竭是常見(jiàn)的急危重癥,預(yù)后差,心衰再入院率及死亡率高。研究隨訪結(jié)果表明,急性心力衰竭患者因心衰再入院率為11.9%~43.9%,1年全因死亡率高達(dá)17.4%~28.3%[10-12],本研究全因死亡率為23.7%。因此,急性心力衰竭患者需要有效的病情和預(yù)后預(yù)測(cè),以便盡早采取更佳的干預(yù)措施改善預(yù)后。
在急性心力衰竭中,NT-proBNP的診斷和預(yù)后預(yù)測(cè)價(jià)值無(wú)可厚非。但是,NT-proBNP并不是完美無(wú)缺的標(biāo)志物。大量研究著力于尋找其他指標(biāo)與NT-proBNP聯(lián)合使用。在急性心力衰竭患者中,有報(bào)道將HCT、CRP、血紅蛋白濃度、ST2、氧化三甲胺、細(xì)胞凋亡活性作為聯(lián)合指標(biāo),表明聯(lián)合檢測(cè)可提高預(yù)測(cè)價(jià)值[11,13-15]。但是,目前并無(wú)一致方案,仍不斷努力尋找新指標(biāo)。Ghrelin是Kojima最早在大鼠胃黏膜中發(fā)現(xiàn),血液中的大部分Ghrelin來(lái)源于胃腸道,少部分由心血管系統(tǒng)合成。心臟及血管內(nèi)皮細(xì)胞能夠檢測(cè)出Ghrelin配體,胃腸道來(lái)源的Ghrelin以及循環(huán)系統(tǒng)分泌的Ghrelin均可能作用對(duì)應(yīng)配體產(chǎn)生作用[16]。Ghrelin目前已被證實(shí)存在多種抗心衰機(jī)制,包括抑制交感神經(jīng)活性、改善心臟重塑、抑制凋亡、抗惡病質(zhì)、抗氧化、抗炎等[17-21]。一項(xiàng)Meta分析顯示,大鼠給予外源性Ghrelin治療后,死亡率明顯降低[22]。在慢性心力衰竭患者中,有項(xiàng)兩年隨訪研究報(bào)道,因心衰再入院、惡性心律失常及全因死亡事件組內(nèi)源性Ghrelin水平低于非事件組,生存分析表明,高Ghrelin組生存曲線高于低Ghrelin組[9]。在心力衰竭患者的診斷、治療及預(yù)后預(yù)測(cè)方面,Ghrelin有較大的潛在價(jià)值。Ghrelin在急性心力衰竭患者中的預(yù)后價(jià)值是否與慢性心力衰竭患者一致,尚無(wú)報(bào)道。本研究結(jié)果顯示,高NT-proBNP組全因死亡率高于低NT-proBNP組(P<0.05),低Ghrelin組全因死亡率高于高Ghrelin組(P<0.05)。生存分析顯示,高Ghrelin組的中位生存時(shí)間長(zhǎng)于低Ghrelin組(P<0.05),低NT-proBNP組的中位生存時(shí)間長(zhǎng)于高NT-proBNP組(P<0.05)。低Ghrelin高NT-proBNP組死亡風(fēng)險(xiǎn)為高Ghrelin低NT-proBNP組的5.346倍。
綜上所述,在急性心力衰竭中,低Ghrelin、高NT-proBNP水平的患者預(yù)后較差。但因本研究樣本量較少,且因手機(jī)號(hào)碼變更、患者不配合導(dǎo)致失訪率高,尚需大樣本、多中心、前瞻性研究進(jìn)一步論證。
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(收稿日期:2021-03-29) (本文編輯:張爽)