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        代謝改變對(duì)圍術(shù)期心肌損傷影響的研究進(jìn)展

        2021-09-22 03:20:36余祺萬勇左友波文笛
        中國(guó)醫(yī)藥科學(xué) 2021年23期
        關(guān)鍵詞:代謝胰島素抵抗藥物

        余祺 萬勇 左友波 文笛

        [摘要]嚴(yán)重感染、創(chuàng)傷、大手術(shù)和麻醉后,患者往往會(huì)產(chǎn)生一系列的異常代謝,包括高代謝、高分解和營(yíng)養(yǎng)物、激素異常代謝,這些變化進(jìn)一步擾亂內(nèi)穩(wěn)態(tài),影響細(xì)胞能量代謝和功能,成為圍術(shù)期導(dǎo)致心肌損傷的重要原因。近年來,研究發(fā)現(xiàn)代謝改變與圍術(shù)期心肌損傷(PMI)密切相關(guān)。本文將從圍術(shù)期代謝改變及其對(duì) PMI 的影響、改善圍術(shù)期代謝變化的措施等方面進(jìn)行綜述,以期為 PMI 的深入研究和早期預(yù)防提供臨床參考。

        [關(guān)鍵詞]圍術(shù)期心肌損傷;代謝;胰島素抵抗;藥物;術(shù)前口服碳水化合物

        [中圖分類號(hào)] R619; R542.2? [文獻(xiàn)標(biāo)識(shí)碼] A?? [文章編號(hào)]2095-0616(2021)23-0057-04

        Advances in study on the effect of metabolic alterations on perioperative myocardial injury

        YU? Qi??? WAN? Yong??? ZUO? Youbo??? WEN? Di

        Department of Anesthesiology, Affiliated Hospital of North Sichuan Medical College, Sichuan, Nanchong 637000,China

        [Abstract] Patients undergoing severe infection, trauma, major surgery and anesthesia often develop a series of abnormal metabolism, including hypermetabolism, high decomposition and abnormal metabolism of nutrients and hormones. These alterations further disturb homeostasis and affect cellular energy metabolism and function, which become important cause of perioperative myocardial injury (PMI). In recent years, studies have found that metabolic alterations are closely associated to PMI. This paper reviews the perioperative metabolic alterations and their effects on PMI, and measures to improve perioperative metabolic alterations, with the aim of providing clinical reference for the in-depth study and early prevention of PMI.

        [Key words] Perioperative myocardial injury; Metabolism; Insulin resistance; Drugs; Preoperative oral carbohydrate

        全世界每年有超過兩億例非心臟手術(shù),其中約800萬患者在非心臟手術(shù)后發(fā)生心肌損傷[1]。圍術(shù)期心肌損傷(perioperative myocardial injury,PMI)以肌鈣蛋白升高為特征,無缺血特征[2]。PMI 是一種重要的非心臟手術(shù)后的并發(fā)癥,與30 d 死亡率密切相關(guān)[3-5]。與自發(fā)性心肌梗死相比,PMI 通常不表現(xiàn)出典型的心肌缺血癥狀,如胸痛、心絞痛或呼吸困難,因此在臨床中常被漏診。圍術(shù)期的代謝改變會(huì)擾亂機(jī)體內(nèi)環(huán)境穩(wěn)態(tài),影響細(xì)胞能量代謝和功能,成為 PMI 的重要原因之一。本文將從圍術(shù)期代謝改變及其對(duì) PMI 的影響、改善圍術(shù)期代謝變化的措施等方面進(jìn)行綜述,以期為 PMI 的深入研究和早期預(yù)防提供臨床參考。

        1圍術(shù)期代謝改變及其對(duì)PMI的影響

        1.1能量代謝改變及其對(duì)PMI的影響

        圍術(shù)期患者往往存在高代謝,能量消耗增加。正常的能量供應(yīng)對(duì)各個(gè)器官正常運(yùn)轉(zhuǎn)至關(guān)重要,尤其是大腦和心臟。大量證據(jù)表明,各種原因?qū)е碌暮哪茉黾雍彤a(chǎn)能減少與心臟損傷的發(fā)生密切相關(guān),包括 PIMT/NCOA6IP 基因缺失引起的遲發(fā)性心肌病、糖尿病性心肌病和全心肌缺血引起的心臟損傷,其機(jī)制可能與心肌細(xì)胞能量生成引起的過度凋亡有關(guān)[6-8]。線粒體是重要的能量供應(yīng)細(xì)胞器,與能量代謝有最直接的聯(lián)系。腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)是一種高度保守的絲氨酸/蘇氨酸蛋白激酶,是調(diào)節(jié)生物能量代謝的關(guān)鍵分子。激活 AMPK 能監(jiān)測(cè)線粒體功能和細(xì)胞能量狀態(tài),能調(diào)節(jié)沉默信息調(diào)節(jié)因子1(silencing information regulator 1,SIRT1)的活性,以及增加細(xì)胞內(nèi) NAD+。激活的 AMPK 和 SIRT1調(diào)節(jié)過氧化物酶體增殖物激活受體γ輔激活因子1α(peroxisome proliferator-activated receptor-γ coactivator-1α,PGC-1α)的活性,進(jìn)一步上調(diào)其表達(dá)。AMPK/SIRT1/PGC-1α信號(hào)通路作為能量感知網(wǎng)絡(luò),在線粒體生物合成、能量代謝和氧化應(yīng)激中發(fā)揮重要調(diào)控作用[9]。研究顯示激活的 AMPK/SIRT1/PGC-1α信號(hào)通路能改善氧化應(yīng)激損傷,改善能量代謝紊亂,并與心臟的保護(hù)作用有關(guān)[9-10]。

        1.2葡萄糖代謝改變及其對(duì)PMI的影響

        圍術(shù)期血漿胰島素水平增高,長(zhǎng)期增高的胰島素水平使激素質(zhì)膜受體數(shù)量的適應(yīng)性減少,需要更大劑量的胰島素才能達(dá)到同樣的生理效果,因此產(chǎn)生胰島素抵抗(insulin resistance,IR)[11]。IR 的特征是葡萄糖攝取和氧化缺陷,糖原合成減少,以及在較小程度抑制脂質(zhì)氧化的能力。大量研究提示 IR 是各種人群的心血管危險(xiǎn)因素,包括普通人群和糖尿病患者[12]。IR 通過以下機(jī)制導(dǎo)致心肌損傷:①促進(jìn)血脂異常,游離脂肪酸積累使活性氧產(chǎn)生增加,導(dǎo)致氧化應(yīng)激,進(jìn)而導(dǎo)致內(nèi)皮功能障礙和動(dòng)脈粥樣硬化疾病[13];② IR 發(fā)生時(shí),因胰島素作用而維持的血管內(nèi)穩(wěn)態(tài)被擾亂,導(dǎo)致一氧化氮的產(chǎn)生和消耗失衡以及內(nèi)皮功能障礙,而內(nèi)皮功能障礙被認(rèn)為是心源性死亡、心肌梗死獨(dú)立于其他危險(xiǎn)因素的預(yù)測(cè)因子[13-14];③促進(jìn)鈉重吸收以及使血管舒張受損導(dǎo)致高血壓,而高血壓也是心血管疾病的危險(xiǎn)因素之一[13,15-16];④使 PI3K/Akt 信號(hào)代謝通路受損,導(dǎo)致內(nèi)皮介導(dǎo)的血管擴(kuò)張減少,血管重塑和動(dòng)脈粥樣硬化增加[17]。

        1.3脂類代謝改變及其對(duì)PMI的影響

        圍術(shù)期患者兒茶酚胺分泌增多、炎癥免疫介質(zhì)及應(yīng)激激素釋放,導(dǎo)致體內(nèi)脂類物質(zhì)儲(chǔ)備消耗,使血漿游離脂肪酸和三酰甘油明顯增高。長(zhǎng)鏈脂肪酸和葡萄糖是維持心臟收縮功能所需的主要能量底物。長(zhǎng)期增加脂肪酸攝取會(huì)增加脂肪酸氧化和脂肪酸代謝產(chǎn)物的積累。增加脂肪酸氧化導(dǎo)致乙酰輔酶 A 和蛋白質(zhì)乙酰化水平增加。細(xì)胞內(nèi)惰性較低的脂類代謝產(chǎn)物如二?;视秃蜕窠?jīng)酰胺的濃度也有所增加。這些代謝物通過在不同的步驟[18]抑制胰島素信號(hào)來誘導(dǎo)胰島素抵抗。除了誘導(dǎo)胰島素抵抗外,脂質(zhì)積累還導(dǎo)致其他脂毒性作用,如脂質(zhì)誘導(dǎo)凋亡[19]。證據(jù)表明,過度脂質(zhì)積累與心肌收縮功能障礙相關(guān)[20]。因此過多的脂肪酸進(jìn)入心肌細(xì)胞,可能通過以下兩種方式對(duì)心臟功能產(chǎn)生負(fù)面影響:①增加脂肪酸氧化,誘導(dǎo)胰島素抵抗,降低心肌效率;②促進(jìn)心肌細(xì)胞內(nèi)脂質(zhì)過度積累。

        1.4蛋白質(zhì)代謝改變及其對(duì)PMI的影響

        圍術(shù)期患者骨骼肌分解,釋放大量氨基酸,肝糖異生,支鏈氨基酸氧化供能,肝臟合成尿素增加導(dǎo)致負(fù)氮平衡,肝臟白蛋白合成減少導(dǎo)致低蛋白血癥。低蛋白血癥能使心肌水腫,從而導(dǎo)致左心室舒張功能障礙。機(jī)體處于炎癥或損傷狀態(tài)時(shí),由于組織壞死及組織更新的增加,肝臟合成急性時(shí)相反應(yīng)蛋白明顯增加,包括 C 反應(yīng)蛋白(C-reactive protein,CRP)、α1-抗胰蛋白酶、α1-酸性糖蛋白銅藍(lán)蛋白等。研究顯示 CRP 水平的升高是心血管不良事件的獨(dú)立預(yù)測(cè)因子[21],也是冠狀動(dòng)脈或周圍血管成形術(shù)后心血管并發(fā)癥和不良預(yù)后的預(yù)測(cè)因子[21-22]。CRP 通過增加黏附分子(如人臍靜脈內(nèi)皮細(xì)胞中細(xì)胞間黏附分子-1和血管細(xì)胞黏附分子-1)表達(dá)、降低內(nèi)皮型一氧化氮合酶使內(nèi)皮功能障礙、觸發(fā)單核巨噬細(xì)胞的促動(dòng)脈粥樣硬化功能等方式促進(jìn)動(dòng)脈粥樣硬化[23]。通過低蛋白血癥引起心肌水腫,導(dǎo)致左心室舒張功能障礙,CRP 合成增加,促進(jìn)動(dòng)脈粥樣硬化等蛋白質(zhì)代謝改變對(duì)心臟產(chǎn)生負(fù)面影響。

        2改善圍術(shù)期代謝的措施

        2.1手術(shù)及麻醉技術(shù)

        腹腔鏡手術(shù)是目前普外科最重要的診療手段之一。腹腔鏡手術(shù)通過更小的腹部創(chuàng)傷組織操作,造成更少的創(chuàng)傷,應(yīng)激反應(yīng)也隨之減少[24]。研究顯示直腸癌根治術(shù)中腹腔鏡手術(shù)與開腹手術(shù)相比,對(duì)患者圍術(shù)期蛋白代謝及 Th1、Th2類炎性因子的影響相對(duì)較小[25]。隨著復(fù)合麻醉、聯(lián)合麻醉及超聲引導(dǎo)下神經(jīng)阻滯的應(yīng)用,麻醉后的應(yīng)激反應(yīng)及術(shù)后并發(fā)癥也隨之減少。研究顯示,老年患者行全膝關(guān)節(jié)置換術(shù),全身麻醉聯(lián)合股神經(jīng)坐骨神經(jīng)阻滯與全身麻醉相比,更具有良好的術(shù)后鎮(zhèn)痛效果,可以減少全身麻醉的劑量,降低術(shù)后惡心嘔吐發(fā)生率,增加患者的滿意度[26]。通過微創(chuàng)等技術(shù),大大減輕了手術(shù)刺激反應(yīng)。通過復(fù)合麻醉技術(shù),進(jìn)一步減輕圍術(shù)期的應(yīng)激反應(yīng)。

        2.2圍術(shù)期藥物的選擇

        研究表明揮發(fā)性麻醉藥(如七氟醚、異氟醚)具有心臟保護(hù)作用。七氟醚通過使血管內(nèi)皮生長(zhǎng)因子受體-1的表達(dá)增加,參與對(duì)心臟的保護(hù)。異氟醚通過 miR-21依賴機(jī)制及降低心肌細(xì)胞中 miR-23的表達(dá),從而增加對(duì)氧化應(yīng)激的抵抗,參與對(duì)心肌缺血再灌注損傷的保護(hù)[27]。右美托咪定是一種高選擇性的α2-受體激動(dòng)劑,具有心臟保護(hù)作用。右美托咪定可能通過以下方式對(duì)心臟起保護(hù)作用:①觸發(fā) PI3K/Akt/mTOR 級(jí)聯(lián)信號(hào)通路導(dǎo)致 GSK3β磷酸化和 mTOR 激活增加[28-29];②靶向 miRNA 減少凋亡,但尚未完全闡明 miRNA 在這一過程中是上調(diào)還是下調(diào)[30-33];③減少線粒體和線粒體中的氧化應(yīng)激反應(yīng)[34]。圍術(shù)期對(duì)心臟具有保護(hù)作用的藥物還有阿片類藥物、β-腎上腺素受體阻滯劑、硝酸鹽類藥物、正性肌力藥物等。

        2.3術(shù)前口服碳水化合物

        術(shù)前口服碳水化合物(preoperative oral carbohydrate, POC)是指臨床上擬實(shí)施擇期手術(shù)的患者在術(shù)前口服適量含碳水化合物的清飲料,讓患者由禁食狀態(tài)轉(zhuǎn)變?yōu)檫M(jìn)食狀態(tài),是快速康復(fù)外科的重要組成部分。越來越多的研究證實(shí) POC 可以改善術(shù)后胰島素抵抗,提高術(shù)后胰島素敏感性,通過抑制糖異生、促進(jìn)肝糖原合成,提供能量,減輕蛋白質(zhì)和脂肪分解,從而改善圍術(shù)期代謝改變[35]。但是,有關(guān)術(shù)前口服碳水化合物對(duì) PMI 的影響還未見研究。

        3總結(jié)

        綜上所述,圍術(shù)期能量代謝、營(yíng)養(yǎng)物質(zhì)(如葡萄糖、脂類、蛋白質(zhì))代謝改變與 PMI 密切相關(guān),可以通過手術(shù)及麻醉技術(shù)的提高、選擇保護(hù)心肌的藥物及術(shù)前口服碳水化合物等方式對(duì)圍術(shù)期的代謝變化進(jìn)行改善。因此,應(yīng)認(rèn)識(shí)并改善圍術(shù)期代謝變化以及盡早預(yù)防、識(shí)別 PMI,改善患者預(yù)后。

        [參考文獻(xiàn)]

        [1] SLOAN EN,MORLEY EE,DEVEREAUX PJ.Prevention, epidemiology, and prognosis of perioperative myocardial injury[J].The Journal of Cardiovascular Medicine,2016,19(4):103-109.

        [2]LEE H,PARULKAR S,SWEITZER BJ.Blood pressure management and perioperative myocardial injury[J].International Anesthesiology Clinics,2021,59(1):36-44.

        [3] WELTERS I.Association between postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery[J].Jama the Journal of the American Medical Association,2012,307(21):2295-2304.

        [4] DEVEREAUX PJ,BICCARD BM,SIGAMANI A,et al. Association of Postoperative High-Sensitivity Troponin Levels With Myocardial Injury and 30-Day Mortality Among Patients Undergoing Noncardiac Surgery[J]. JAMA,2017,317(16):1642-1651.

        [5] Ekeloef S,Alamili M,Devereaux PJ,et al.Troponin elevations after non-cardiac, non-vascular surgery are predictive of major adverse cardiac events and mortality: A systematic review and meta-analysis[J].Br J Anaesth,2016,117(5):559-568.

        [6] MAJD S,POWER J,CHATAWAY TK,et al.A comparison of LKB1/AMPK/mTOR metabolic axis response to global ischaemia in brain, heart, liver and kidney in a rat model of cardiac arrest[J].BMC Cell Biol,2018,19(1):7.

        [7] XU W, WANG Y, GUO Y, et al.Fibroblast growth factor19 improves cardiac function and mitochondrial energy homoeostasis in the diabetic heart[J].BiochemBiophys Res Commun,2018,505(1):242-248.

        [8] JIA Y,LIU N,VISWAKARMA N,et al.PIMT/ NCOA6IP Deletion in the Mouse Heart Causes Delayed Cardiomyopathy Attributable to Perturbation in Energy Metabolism[J].Int J Mol Sci,2018,19(5):7.

        [9] TIAN L,CAO W,YUE R,et al.Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/ reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway[J].J Pharmacol Sci,2019,139(4):352-360.

        [10]YU L,GONG B,DUAN W,et al.Melatonin ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic rats by preserving mitochondrial function: Role of AMPK-PGC-1alpha-SIRT3 signaling[J].Sci Rep,2017,7(1):41337.

        [11]WOLOSOWICZ M, LUKASZUK B,CHABOWSKI A.The Causes of Insulin Resistance in Type 1 Diabetes Mellitus: Is There a Place for Quaternary Prevention?[J].Int J Environ Res Public Health,2020,17(22):8651.

        [12]Adeva-Andany MM,Martínez-Rodríguez J,González- Lucán M,et al.Insulin resistance is a cardiovascular risk factor in humans[J].Diabetes MetabSyndr,2019,13(2):1449-1455.

        [13] KOSMAS CE,SILVERIO D,TSOMIDOU C,et al.The Impact of Insulin Resistance and Chronic Kidney Disease on Inflammation and Cardiovascular Disease[J].Clin Med Insights Endocrinol Diabetes,2018,11(1):1-6.

        [14] Janus A,Szahidewicz-Krupska E,Mazur G,et al. Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders[J].Mediators of Inflammation,2016(2016):3631948.

        [15] GILES TD,SANDER GE,NOSSAMAN BD,et al. Impaired vasodilation in the pathogenesis of hypertension: Focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins[J].Journal of Clinical Hypertension,2012,14(4):198-205.

        [16]LANDSBERG L,ARONNE LJ,LAWRENCE MB,et al. Obesity-related hypertension: Pathogenesis, cardiovascular risk, and treatment—A position paper of the The Obesity Society and the American Society of Hypertension[J].Obesity,2013,15(1):14-33.

        [17] VALESKA O,SOUMYALEKSHMI N,OMAR E,et al. Association between insulin resistance and the development of cardiovascular disease[J].Cardiovascular Diabetology,2018,17(1):122.

        [18]LIU Y,NEUMANN D,GLATZ J,et al.Molecular mechanism of lipid-induced cardiac insulin resistance and contractile dysfunction[J].Prostaglandins Leukotrienes and Essential Fatty Acids,2018,136(1):131-141.

        [19] LuikenJJFP,Nabben M,Neumann D,etal.Understanding the distinct subcellular trafficking of CD36 and GLUT4 during the development of myocardial insulin resistance[J].BiochimBiophys Acta Mol Basis Dis,2020,1866(7):165775.

        [20] KIM TT,DYCK J.The role of CD36 in the regulation of myocardial lipid metabolism[J].BiochimBiophys Acta,2016,1861(10):1450-1460.

        [21]SCHULZ S, L?DIKE H,LIERATH M, et al.C-reactive protein levels and genetic variants of CRP as prognostic markers for combined cardiovascular endpoint (cardiovascular death, death from stroke, myocardial infarction, and stroke/TIA)[J].Cytokine,2016,88(1):71-76.

        [22]STONE PA,SCHLARB H,CAMPBELL JE,et al.C- reactive protein and brain natriuretic peptide as predictors of adverse events after lower extremity endovascular revascularization[J].Journal of Vascular Surgery,2014,60(3):652-660.

        [23]MONTECUCCO F,MACH F.New evidences for C-reactive protein (CRP) deposits in the arterial intima as a cardiovascular risk factor[J].Clinical Interventions in Aging,2008,3(2):341.

        [24]YIANNAKOPOULOU EC,NIKITEAS N,PERREA D,et al. Effect of laparoscopic surgery on oxidative stress response: Systematic review[J].Surgical Laparoscopy Endoscopy & Percutaneous Techniques,2013,23(2):101-108.

        [25]韓樹坤,呂順.腹腔鏡結(jié)直腸癌根治術(shù)患者圍術(shù)期蛋白代謝及 Th1,Th2類炎性因子的變化觀察[J].中國(guó)醫(yī)學(xué)創(chuàng)新,2020,17(6):5-8.

        [26]GAO XG, ZHANG M, YUE XA, et al.Application of nerve block in total knee arthroplasty under general anesthesia[J].Zhongguogushang,2020,33(4):363-367.

        [27]BARTEKOVAM, JELEMENSKYM,DHALLANS.Emerging role of non-coding RNAs and extracellular vesicles in cardioprotection by remote ischemic conditioning of the heart[J].Reviews in Cardiovascular Medicine,2019,20(2):59-71.

        [28]ZHANG,JIANG,D-H,et al.Effectsofdexmedetomidine on myocardial ischemia-reperfusion injury through PI3K-Akt-mTOR signaling pathway[J].European Review for Medical and Pharmacological Sciences,2019,23(15):6736-6743.

        [29]CHENG X,HU J ,WANG Y,et al.Effects of Dexmedetomidine Postconditioning on Myocardial Ischemia/Reperfusion Injury in Diabetic Rats: Role of the PI3K/Akt-Dependent Signaling Pathway[J].Journal of Diabetes Research,2018,2018(1):1-10.

        [30]YANG X, CHEN H, CHEN Y, et al.Circulating miRNA Expression Profiling and Target Prediction in Patients Receiving Dexmedetomidine[J].Cellular Physiology and Biochemistry,2018,50(2):552-568.

        [31]YUSUKE,YOSHIKAWA,NAOYUKI,et al.Identification of Candidate Genes and Pathways in Dexmedetomidine- Induced Cardioprotection in the Rat Heart by Bioinformatics Analysis[J].International Journal of Molecular Sciences,2019,20(7):1614.

        [32]JUAN,YU,WEI,et al.Involvement of miR-665 in protection effect of dexmedetomidine against Oxidative Stress Injury in myocardial cells via CB2 and CK1[J].Biomedecine&Pharmacotherapie,2019,115(2019):108894.

        [33]LINGYAN,WANG,SHUMIAO,et al.The administration of dexmedetomidine changes microRNA expression profiling of rat hearts - ScienceDirect[J].Biomedicine & Pharmacotherapy,2019,120(1):109463.

        [34]LIU X, LI T,CAO L, et al.Dexmedetomidine attenuates H2O2-induced neonatal rat cardiomyocytes apoptosis through mitochondria- and ER-medicated oxidative stress pathways[J].Molecular Medicine Reports,2018,17(5):7258-7264.

        [35]余暢,閔蘇,呂碧霄.術(shù)前口服碳水化合物溶液研究進(jìn)展[J].國(guó)際麻醉學(xué)與復(fù)蘇雜志,2020,41(11):1100-1103.

        (收稿日期:2021-06-08)

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