在過去的30 年中，全球糖尿病（DM）的患病率顯著增加，從1990年的2億增加了一倍多，到2025年估計將超過5 億[1]。這對心肌梗死（MI）有重要的影響，而MI是DM患者最常見的死亡原因之一[2]。不僅DM患者的MI發病率增加，而且MI後的結果一直更差。DM患者的短期和長期死亡率較高，MI後再梗死，心力衰竭（HF），心源性休克和心律失常發生率高[3-8]。 MI治療進展大大降低了院內死亡率，從 1960 年代的30%[9]降至當代再灌注時代的< 7%[10]。然而，儘管治療和總體生存率有所改善，但DM患者的死亡率仍叫無DM患者增加 1.5~2 倍[11]。
重要的是，儘管在治療和總體生存方面取得了進展，但近幾十年來這種差異一直保持一致。出現了一些假設來解釋這種增加的風險，例如梗死麵積或冠狀動脈疾病嚴重程度的差異。本文回顧並重新評估MI後DM患者不良預後的證據，重點是如何針對炎症過程提供未探索的，但有價值的機會，以改善該脆弱患者群體的心血管預後。
在保守治療的時代，沒有再灌注治療相關嘗試，MI後DM患者的院內死亡率為 60.8% ，是非DM患者的兩倍[12]。在冠狀動脈監護病房（CCU）出現後，一項對832人的研究發現，在急性心肌梗死（AMI）後的第一個月，20.2% 的非DM患者和42.0%的DM患者死亡[13] 。在再灌注治療中，GUSTO-1 研究發現，在ST段抬高型心肌梗死（STEMI）患者中，DM患者 30 天的死亡率為 10.5%，而無DM患者為6.2%[14]。在GRACE 註冊試驗的患者中，DM 患者合併STEMI和非ST段抬高型心肌梗死 （NSTEMI）患者的院內死亡率較高（分別為11.7% vs 6.4%和6.3% vs 5.1%）[15]。
在當今常規侵入性冠脈造影和經皮冠狀動脈介入治療（PCI）時代，2005年至2013年對12270人（4388例DM患者）進行的一項單中心研究顯示，DM患者的30天和1年死亡率顯著增加（分別為13.5% vs 4.3%和25.7% vs 12.4%）[16]。PROSPECT II試驗的一個子研究顯示，DM患者的主要不良心血管事件（MACE） 增加了2倍[17]。同樣，HORIZONS-AMI 研究發現，在 30 天時，新診斷和確診的DM患者的死亡率較高（4.5% vs 1.8%）[18]。絕大多數DM患者患有2型糖尿病（T2DM），因此，大多數研究沒有足夠的效力來探究1型糖尿病（T1DM）對預後的影響。然而，Kerola 等[19]對芬蘭20家醫院的調查顯示，對於MI後患者，合併T1DM患者的30天和1年死亡率均較高 （分別為12.8% vs 8.5%和24.3% vs 16.8%），這一趨勢在不同亞組（有或無HF，有或無STEMI，有或無血運重建）中仍成立。因此，雖然潛在的病理生理學有所不同，但T1DM和T2DM似乎均對MI後患者的預後產生負面影響。
高血糖是T1DM和T2DM的主要特徵，AMI患者入院時血糖水平升高與患者預後不良有關[20]。在再灌注治療之前，溶栓劑使用[21]以及再灌注治療時代，這一點已被充分證實[22]。 一項薈萃分析納入了超過 20000名STEMI患者（23%為DM，但未指定型別)）接受直接PCI治療，顯示入院高血糖（AH）與30天和長期隨訪的死亡率較高有關。值得注意的是，AH在以前沒有發現DM的人群中很常見，特別是對於那些既往有MI、多支血管冠狀動脈疾病 （CAD）和左前降支梗死的人群[23]。儘管有這些長期的觀察結果，但在回答圍繞急性冠脈綜合徵（ACS）高血糖的關鍵問題方面進展甚微，其中最為重要的是高血糖是否為不良結果的介質或標誌物[24]。大多數關於MI預後的臨床研究沒有區分T1DM和 T2DM。從相對患病率推斷，大多數研究主要包括 T2DM患者。在本文中除另行說明外，其他均指T2DM患者。
在心血管風險評估中，通常考慮（以二元方式）給定患者是否患有DM。事實上，這種關注可能掩蓋了包括：①DM的持續時間，②血糖控制質量和 ③治療在內的重要因素的異質性。
在T2DM中，病程與死亡風險相關。在 2010 年1月至 2019 年12月期間，分析了義大利近14萬名STEMI或NSTEMI住院患者的區域資料[25]。研究者根據疾病持續時間將DM患者進一步分為三組：<5 年，5~10 年和 > 10年。在他們的分析（包括調整年齡）中，住院死亡率隨著DM的持續時間而增加，與沒有DM的人相比，受影響超過10年的人的風險最高（OR = 1.59）。這表明T2DM的不良結果可能不僅反映MI時的代謝狀態，而且反映了隨時間推移的病理特徵的累積。同樣，對糖化血紅蛋白（HbA1c）相關研究的薈萃分析 (n = 25 項研究和> 30萬名患者) 表明，即使並未確診T2MD，長期血糖高水平也與ACS後患者的預後較差相關[26]。
DM對MI後患者預後的影響也可透過特定的治療來改變。在GRACE登錄檔中，與接受其他DM治療的患者相比，需要胰島素治療的STEMI患者在急性住院期間死亡、HF、心源性休克和腎功能衰竭的風險增加[15]。同樣，對包括超過7000 名AMI和DM參與者在內的四項隨機對照試驗的彙總分析也顯示，在隨訪2年期間，與沒有DM的受試者相比，未接受胰島素治療的DM患者的心血管死亡風險增加 （HR=1.25），但進行胰島素治療的DM患者的心血管風險增加幅度更高 （HR=1.49）[27]。在 SWEDEHEART 登記處，與單獨飲食治療的 DM 患者相比，接受胰島素單藥治療的 DM 患者平均隨訪 3.4 年，死亡率、MI、卒中和HF綜合評分的風險增加（HR=1.32）[28]。然而，儘管這些研究顯示了一致的模式，但這可能不一定是由於胰島素治療，而是可能反映了混雜因素，例如長期或控制不佳的DM對口服降血糖藥物沒有反應。
二甲雙胍是T2D常用的一線口服降血糖藥。在MI的實驗模型中，有證據表明二甲雙胍改善心血管功能並減少梗死麵積[29]。一項觀察性研究顯示，二甲雙胍的使用與較低的肌酸激酶-肌鈣蛋白水平有關[30]，但這種相同的效果在其他地方沒有顯示出來[31]。在SWEDEHEART註冊研究中，與單獨進行飲食治療的DM患者相比，使用二甲雙胍單藥治療的患者有較低的MACE風險（HR=0.92）[28]。然而，由於迄今為止沒有大型隨機對照試驗，沒有明確的證據表明二甲雙胍在改善MI後的結局方面具有因果關係。同樣，沒有強效的證據表明磺脲類藥物的使用有效以及其對MI預後的可能影響。在對 188 名MI和DM患者的觀察性研究研究中，Garratt 等[32]發現，經過多變數調整後，磺脲類藥物的使用是早期死亡率的獨立預測因子 （HR=2.77）。然而，其他研究未能顯示這種關聯[33-36]。
雖然沒有明確的隨機對照試驗證實傳統降糖藥物對MI預後的影響，未來也不太可能進行相關試驗，但近年來對新型降糖藥物，特別是鈉葡萄糖協同轉運蛋白 2 （SGLT2）抑制劑對MI預後影響的興趣越來越大。SGLT2抑制劑對T2DM患者的心血管預後有益。在EMPA-REG OUTOUT試驗中，與安慰劑相比，每日一次恩格列淨（empagliflozin）的使用與心血管原因死亡（HR=0.62）和因HF住院率（HR=0.68）降低顯著相關，無論 HbA1c 降低如何[37]。
隨後，其他 SGLT2 抑制劑包括卡格列淨（canagliflozin）[38-39]，達格列淨（dapagliflozin）[40]和埃格列淨（ertugliflozin）[41] 的隨機臨床試驗都與T2DM患者HF住院風險降低有關，表現出一致的類效應。
此外，在 DAPA-HF試驗[42]中，對於左室射血分數（LVEF）≤40%的心衰患者，達格列淨與 HF惡化風險降低（HR=0.70）和心血管死亡風險降低（HR=0.82）相關。DELIVER-TRIAL試驗還表明，達格列淨的有益作用已經延伸到了射血分數輕度降低或保留的心衰患者[43]。重要的是，在兩項試驗中，這些益處均與是否合併DM無關。SGLT2 抑制劑發揮其心血管作用的機制尚不清楚，但其潛在機制已在相關文章中闡述[44-45]，SGLT2抑制劑可能影響炎症過程和動脈粥樣硬化斑塊。一項觀察性研究納入了接受PCI的T2DM和多支非阻塞性冠狀動脈病變患者，研究發現使用SGLT2 抑制劑與較高的最薄纖維帽厚度 （FCT）（斑塊易損性的測量）和較低的炎症臨床測量值[如白細胞計數、高敏感性C反應蛋白 （hs-CRP）、白細胞介素-6（IL-6）和腫瘤壞死因子-α（TNF-α）]相關[46]。
大量研究中一致的心血管獲益提示SGLT2抑制劑或可使MI後早期患者獲益[47]。在納入377名接受PCI的T2DM和AMI患者的觀察性研究中，無論患者的血糖狀況如何，SGLT2抑制劑使用均與改善預後相關[48]。也有證據表明，在 T2D 患者中，使用 SGLT2 抑制劑與 MI 後新發心律失常的風險較低有關。
最近的一項隨機對照試驗探究了SGLT2 抑制劑在 MI 後急性期的作用[49]。在該試驗中，476 名AMI患者（包括13%的 T2D 患者）被隨機分配到每日一次的恩格列淨或安慰劑中，在 PCI術後72小時內服用 26 周。研究顯示，恩格列淨使用與平均 N 末端 B 型利鈉肽前體（NT-proBNP）水平和LVEF顯著改善有關，且這些變化在幾周內就很明顯[50]。EMMY 試驗的事後分析顯示，與安慰劑相比，恩格列淨沒有顯著降低全身炎症標誌物，如IL-6、hs-CRP、嗜中性粒細胞計數、白細胞計數和嗜中性粒細胞/淋巴細胞比率[51]。在DAPA-MI試驗[52]探究了達格列淨對心血管死亡率或心衰發生的影響，但該研究的事件發生率較低、除外了高危人群，且隨訪時間較短，效力或不足。EMPACT-MI平均隨訪17.9個月顯示，與安慰劑相比，恩格列淨治療並沒有顯著降低首次住院或因任何原因死亡的風險[53]。
儘管總體死亡率已經下降，但與T2DM相關的風險仍持續增加[3]，提示對T2DM認識的必要性和緊迫性。首先，為什麼進行了當代T2DM治療，但AMI的預後更差預後；其次，該如何改變這些結局。
下文將重新分析相關風險的潛在機制，並評估最新資料，以探索針對這一人群風險的新機會。
在考慮早期死亡率增加的潛在原因時，探究造成DM患者MI後死亡的機制是有用的。據我們所知，還沒有研究專門調查DM患者MI後的死亡機制，也沒有研究詢問與沒有DM的人相比，是否存在不同分佈的特定致命表現。
雖然死亡率是一個明確的終點，但確定MI後人們死亡的確切機制是具有挑戰性的；且僅有少數人進行屍檢，因此死亡證明的資料是常常不準確[54] ，似乎不太可能對了解DM的不良風險有啟發作用。
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1.梗死麵積及LVEF
梗死麵積的大小與不良預後具有一定的相關性[55,56]。DM患者往往有不太嚴重或非典型的MI症狀[57] ，或導致尋求護理、診斷和治療的延遲，從而導致梗死麵積增大。梗死麵積與死亡率密切相關[58] ，限制心肌損傷已成為推動有效再灌注治療的關鍵臨床優先事項。
然而，對梗死麵積的量化並不能明確支援DM有助於梗死麵積的增大。心肌磁共振（CMR）是心肌組織非侵入性評估的金標準，包括MI後確定梗死麵積[59]。對92名MI患者（包括22名DM患者）進行的CMR研究表明，DM患者的晚期釓增強 （平均左室瘢痕百分比，25.6% vs 15.8%）測量的梗死麵積較大[55] ，然而本研究為觀察性，樣本量較小，效力或不足。
隨後的 CMR研究未能顯示類似的關聯[60-61]。Eitel 等[60]研究了 411 名接受直接PCI的 STEMI 患者的 DM 與梗死麵積之間的關係。研究顯示，DM患者的MACE風險增加了3倍，即使梗死麵積相似（左室瘢痕百分比 18.2 vs 18.2%)。有趣的是，預後不良與較大的梗死麵積有關，但在DM患者中這種關聯性較弱。Reinstadler等[61]的一項研究（792例STEMI患者）發現，有或無 DM 患者的梗死麵積或心肌挽救指數沒有顯著差異。
此外，除梗死麵積外，LVEF降低也是MI後死亡率的預測因子[62] ，但是LVEF在有/無DM患者之間是可比較的[55,56,61]。因此，似乎梗死麵積和LVEF的差異都不足以解釋T2D對MI後不良預後的影響。
2.動脈粥樣硬化負擔
ACS患者通常接受侵入性冠狀動脈造影，但冠狀動脈造影為腔內檢查，從而限制了動脈粥樣硬化的定量分析和斑塊組成的測定，這反過來影響斑塊的生物學特性，尤其是侵蝕或破裂的傾向。更詳細的斑塊成分可以使用血管內成像光學相干斷層掃描 （OCT）和血管內超聲（IVUS）獲得。
DM患者冠心病的患病率較高[63]，人們普遍認為DM與更嚴重和更廣泛的冠心病有關。Niccoli 等[64]的研究比較了伴或不伴DM的ACS患者的多支血管病變情況，提示合併DM組患者的多支血管疾病發生率更高（68% vs 42%）。
同樣，PROSPECT I 試驗的一項子研究（IVUS測量）顯示，合併DM的ACS患者具有更長的冠狀動脈病變（12.0 vs 10.7 mm）[65]。另一項主要納入穩定型冠心病患者的研究（CT測量）顯示，與不合並DM的患者相比，合併DM患者的混合冠脈斑塊數量更高（1.67 vs 1.23），但所有型別的斑塊（鈣化、非鈣化和混合）數量在兩組之間無顯著差異[66]。
然而，由於不同的研究採用的定量方法有所不同，因此不同研究中冠心病（CAD）患者的嚴重程度可能無法比較。此外，應用IVUS、OCT和/或其他侵入性冠脈測量方法的研究或包含對複雜和瀰漫性狹窄CAD患者的固有選擇偏倚。在 PROSPECT II試驗中，有/無DM患者的平均SYNTAX評分也沒有顯著差異[17]。因此，儘管CAD型別和嚴重程度或與DM患者的死亡率增加有關[67] ，但相關性或並不明顯。
PROSPECT II試驗[68]顯示，高脂質含量（OR=3.80）和高斑塊負荷（OR=5.37） 是非罪犯病變MACE（定義為心源性死亡、MI、不穩定型心絞痛或進行性心絞痛的複合事件）的獨立預測因子。PROSPECT II的一項亞組分析試驗顯示，與無DM患者相比，儘管DM患者進行了支架和/或藥物治療，但其MACE發生率仍增加了1倍（OR=1.94），這主要是由非罪犯病變中的自發性MI以及罪犯病變的再狹窄所致[68]。DM是非罪犯病變MACE的獨立預測因子（OR=2.47），但似乎不影響罪犯病變的MACE。此外，在有無DM的人群中[17]，罪犯和非罪犯病變的斑塊特徵（脂質含量和斑塊負荷）是相似的，基線和殘留SYNTAX評分沒有差異。
Sugiyama等[69]的報道（OCT檢測）提示，在ACS時，DM患者具有更廣泛的CAD和更 “脆弱”的斑塊。然而，正如Ali等[70]所強調的那樣，OCT對“脆弱”斑塊的確定受到觀察者間對於帽厚度和脂質弧測量的適度一致性的限制，再加上TCFA患者的每個病變事件發生率極低。雖然MI時冠心病的負擔在DM患者中可能更重，但這並無法說明DM對MI後患者預後的影響。
GUSTO血管造影試驗[71]比較了隨機接受四種不同溶栓方案的2431例STEMI患者的基線血管造影差異，發現DM患者的多支血管病變頻率更高，梗死相關動脈的參考直徑明顯更小，但在校正多支血管病變和90分鐘MI溶栓（TIMI）後，DM 仍然是30 天死亡率的獨立預測因子。然而，這項研究應用的衡量標準相對粗糙（有無多支血管病變），且未調查冠脈斑塊的組成。
總體而言，這些研究表明，透過侵入性血管造影、血管內成像或心臟CT等方法定量描述斑塊範圍、形態和病變複雜性差異無法充分解釋DM患者MACE風險增加的原因。
3.心肌灌注和冠狀動脈微血管功能障礙
有效、及時的再灌注治療是AMI預後的決定因素，主要與心外膜血管的通暢性和微血管系統的能力相關。即使進行PCI治療改善了心外膜血管的通暢性，冠狀動脈微血管功能障礙 （CMD）也可能延遲或阻止再灌注導致的持續性缺血和梗死。
冠狀動脈微迴圈由直徑 <500μm 的微小動脈和小動脈組成，是調節心肌灌注的主要部位。雖然這些血管在目前的成像模式（包括侵入性動脈造影）下是不可見的，但它們的功能可以透過生理測量來評估[72]。冠狀動脈血流儲備（CFR）異常或心肌血流儲備（MFR）等指標，可測量應激或最大充血時心肌血流量與靜息心肌血流量的比率，提供了在沒有心外膜狹窄的情況下 CMD 的定量定義。
重要的是，CMD影響MI後的預後，Kelshiker等[73]在他們的CFR和心血管預後系統綜述中表明，在急性和慢性冠狀動脈綜合徵中，CFR異常是MACE的預測因子。專門比較DM和非DM患者的研究很少，而且大多數是在症狀穩定而非AMI患者的情況下進行的。
在一項單中心研究顯示，與非DM患者相比，DM患者的MFR異常更為普遍，且DM和MFR均為MACE的獨立預測因子[74]。同樣，另一項研究顯示，CFR < 2是DM患者MACE風險的預測指標[75]。這些資料已經在侵入性血管造影測量中得到複製，以確定CFR以及微迴圈阻力特異性指標，如微迴圈阻力指數，充血性微血管阻力和微血管阻力儲備[76-79] ，表明DM患者（主要在穩定型心絞痛的情況下） 更可能具有較低的 CFR（<2），儘管不一致，但微迴圈阻力指數較高。
一項納入144名T2DM患者的研究[80]顯示， DM 患者的微血管阻塞（MVO）更為普遍，或導致死亡率過高。對7項納入直接PCI的STEMI患者的隨機對照試驗進行的彙總分析發現，在急性事件發生7天內測量的MVO與HF的死亡率和住院率密切相關[81]。介入治療後，糖尿病患者 ST 段抬高不完全，CMR 測量的心肌紅斑分級降低[82]，MVO 降低[83]。可以預期MVO透過增加梗死麵積影響預後，但 MVO 是不良結局的獨立預測因子，即使在調整梗死麵積後也是如此[81]。
總體而言，無論侵入性和非侵入性方法均表明，DM患者傾向於患有CMD，CFR是MACE的獨立預測因子，且STEMI後更易發生MVO。在MI後DM患者預後較差的情況下，這些發現可以反映：①損害再灌注或修復的冠脈微血管疾病和/或②加重AMI期間功能性微血管功能障礙或阻塞損害心肌再灌注。
4.糖尿病心肌病
DM 使HF[85-86]的風險增加 2 ~4 倍，這通常歸因於 “糖尿病心肌病”，這是指在沒有CAD，高血壓和DM個體中沒有顯著的瓣膜疾病的情況下心肌結構和功能異常。MI後HF的風險增加也很明顯，例如在 SWEDEHEART註冊研究中，DM使MI後HF的風險增加了30%[87-88] 。糖尿病患者的心臟結構改變包括心肌纖維化、心肌肥厚/重塑和微血管功能障礙[89]。 一項 CMR相關研究顯示，28%的既往無MI臨床證據的DM患者有心肌瘢痕，且研究中大多數患者或為T2DM[90]。在該佇列中，心肌瘢痕的高發生率提示T2DM患者有無症狀性梗死，或T2DM引起的纖維化。包括成纖維細胞增殖、神經體液啟用、促炎細胞因子產生、氧化應激、心肌轉化生長因子-β表達增加和晚期糖基化終產物（AGE）/AGE受體（RAGE）軸的啟用在內的多種機制或導致DM患者發生纖維化[91]。在DM患者中經常觀察到心臟重塑[92-93]，且由於僅少數患者進行CMR檢查，因此心臟重塑很可能未被檢測到。
總體而言，糖尿病心肌病的潛在不同表現或可解釋DM患者為什麼更容易受到MI的影響，如透過影響梗死區域或損傷遠端心肌等。
5.性別對預後的影響
多項研究表明，MI後，女性的預後往往比男性更差，包括住院率[94]、因HF住院[88,95]、短期[96-100]和長期死亡率[101-102]更高。然而，當校正年齡，風險因素和合並症等混雜因素時，這種預後差距往往會減少或消失[96,99,102-103]。此外，女性在MI後更不可能及時接受指南推薦的藥物治療[98-100]，提示這種預後差距並不完全由生物學性別差異解釋。
女性DM患者或為一個極其脆弱的群體。一項觀察性研究探究了17154名PCI後患者的1年死亡率和MI發生率，提示女性DM患者的死亡和MI風險最高[104]。值得注意的是，女性非DM患者與男性DM患者的不良事件風險相似[101,105]。對於短期死亡率，既往一項納入48878名AMI患者的研究提示，在校正混雜因素後，18 ~45歲之間的女性DM患者的住院死亡風險並不高於男性[106]。
儘管如此，女性在臨床研究中代表性不足，在瞭解性別對MI預後的影響，包括其與DM的相互作用方面仍然存在許多知識差距。
大量證據表明，在DM狀態下，細胞和分子反應發生改變。其中，氧化應激、血管生成和細胞能量改變已經被很好的描述了。
MI後，過量產生的活性氧類 （ROS）可透過直接損傷DNA、脂質、蛋白質和線粒體，導致心肌細胞死亡增加，在介導缺血/再灌注損傷中起著至關重要的作用[107]。ROS 也可以觸發炎症過程，例如啟用核苷酸結合寡聚化結構域，含有富亮氨酸重複結構域的蛋白 3 （NLRP3）炎性體[108]，Janus 激酶/訊號傳導和轉錄啟用因子（JAK-STAT）途徑[109]和核因子kappa B（NF-κB）途徑等。
DM患者表現出高NADPH氧化酶活性[110]和血管內皮一氧化氮合酶功能受損，導致活性氧的產生升高[111]。在DM患者的心肌中也觀察到活性氧水平升高[112]。透過提供氧氣和營養物質來限制缺血，血管生成在促進受損心肌的修復中也起著至關重要的作用[113]。白細胞的募集需要新的血管形成，白細胞是損傷和修復的重要介質[113]。缺氧誘導因子1-α（HIF1-α）是血管生成的關鍵調節因子，心肌細胞中HIF1-α的表達增加，可增強心臟功能並減少MI小鼠模型中的梗死麵積[114]。眾所周知，高血糖會損害內皮細胞中HIF1-α的穩定性[115]。既往研究也顯示，與無DM者相比，T2DM患者的HIF1-α和血管內皮生長因子表達下降[116]。此外，與新型血管生成蛋白相關的其他途徑[117]，缺陷內皮祖細胞[118]和血管一氧化氮抵抗[119]都可能損害T2DM後MI患者的血管生成[120,121]。
改變心肌能量學，可能影響MI後患者的預後。通常情況下，心臟使用多種底物，包括遊離脂肪酸、葡萄糖、氨基酸和酮來產生三磷酸腺苷。然而，在T2DM患者中，心臟代謝的靈活性降低。高胰島素血癥和胰島素抵抗降低了葡萄糖利用率，增加了心肌的遊離脂肪酸攝入量，導致毒性脂質代謝物和活性氧的積累，最終導致心肌功能障礙[122]。
然而，其他先前被忽視的與炎症過程有關的因素，似乎越來越相關和合理。迴圈炎症標誌物，特別是高敏C反應蛋白（hs-CRP），與各種臨床情況下的不良結果有關[123-126]。在CARE試驗中，透過升高的CRP和血清澱粉樣蛋白 A （SAA）[127]測量的全身炎症證據與MI後復發冠狀動脈事件的風險增加有關，但在T2DM患者中事件的比例較高。事實上，通常認為CRP和SAA在T2DM患者中更高。近期Ridker等[128]對三項隨機臨床試驗的薈萃分析顯示，hs-CRP 升高與未來事件的相關性較 “治療” LDL-C更強[129]。重要的是，該分析中的大多數人（76%）合併 T2DM。
總體而言，炎症過程或導致DM患者的預後惡化。然而，“炎症” 這個籠統的術語或無法提供足夠的資訊。由肝臟合成和釋放的CRP代表了幾種梗死後相關炎症過程的綜合下游作用，並且不足以描述複雜的分子和細胞炎症過程[130]。關於特定分子途徑啟用，互補（或競爭）細胞型別參與階段的功能相關資訊，急性炎症狀態與解析度，甚至炎症的精確位點目前在MI中沒有明確定義。因此，針對潛在易處理的炎症過程的干預措施的最佳時機和性質上是未知的。此外，針對炎症過程需要考慮對MI的免疫反應中的性別差異[131]。因此，我們將把重點放在機制上重要的，治療上易處理的炎症過程上，並受到DM患者潛在干擾。
MI引發區域性和全身炎症反應。在心肌中，梗死後的炎症反應可分為三個階段： 報警階段、白細胞動員階段和消退階段[122]。
在報警階段，死亡的心肌細胞和其他細胞釋放被稱為損傷相關分子模式 （DAMPs）的訊號，包括高遷移率組蛋白 B1[133]、熱休克蛋白[134]、S100A8/A9[135]和纖連蛋白[136]。DAMP與模式識別受體，如Toll 樣受體、核苷酸寡聚化結構域樣受體和RAGE結合，啟用先天性免疫通路[137]。可以在先天性免疫細胞內啟用的促炎訊號傳導途徑，包括但不限於 (NLRP3)/IL-1β[138]、NFκB[139]和 JAK-STAT 訊號傳導途徑[140]。
在白細胞動員階段，白細胞迅速浸潤缺血心肌。中性粒細胞是第一個有反應的細胞[141-142]，其次是促炎性單核細胞[143]（隨後分化成巨噬細胞） ，以清除死亡的心肌細胞和其他壞死組織。既往資料已表明內皮細胞衍生的細胞外囊泡如何將嗜中性粒細胞和單核細胞動員到梗死心肌[144-145]，以及這些細胞的轉錄組在募集到受損心肌之前如何在血液中改變。AMI也將白細胞動員到遠離缺血區域的心肌。
在消退階段，促炎症過程被抑制。在這個階段，巨噬細胞功能從吞噬作用，蛋白水解和細胞外間質降解轉變為血管生成和肉芽組織形成。系統地，MI 增加促炎細胞因子TNF-α[150] 和 IL-6[151] 的血漿濃度。值得注意的是，實驗性MI透過增加骨髓細胞向斑塊的募集來加速動脈粥樣硬化[152]。
炎症過程是潛在的治療靶點。在MI實驗模型中，抑制促炎性單核細胞向受損心肌的募集減少了梗死麵積 [153-155]。這導致了誇大或延長的促炎反應加劇損傷並使修復最小化，從而導致不良的心室重塑[149,156]。然而，MI後的非靶向抑制可能是有害的。既往已經顯示皮質類固醇和非甾體抗炎藥與MI後的心室壁破裂有關[157,158]。如前所述，巨噬細胞轉變成癒合劑，並且可以理解非靶向抑制損害癒合/修復。
近年來，針對性地抑制CAD中的炎症通路已經顯示出有希望的結果。2017 年的CANTOS試驗表明，針對炎症途徑的概念或有益，即使用單克隆抗體卡那單抗（canakinumab）的IL-1β可改善hs-CRP≥2 mg/L的已知CAD的預後，儘管效應大小是適度的[159]。
隨後，IL-6，一種更下游的細胞因子，目前正在作為一個潛在的治療靶點進行研究。在ASSAIL-MI 中，對199名個體進行的2期隨機臨床試驗中，用託珠單抗（tocilizumab）靶向 IL-6 顯著增加了胸痛6 h內進行直接PCI的STEMI患者的心肌挽救指數[160]。RESCUE 2 期隨機臨床試驗顯示，在腎功能受損的人群中，針對 IL-6 的單克隆抗體Ziltivekimab，可在不影響膽固醇水平的情況下，顯著降低CRP 水平[161]。ZEUS 3 期臨床試驗近期已完成患者招募。一項更相關的3期 ARTEMIS試驗將在侵入性操作後儘早探究Ziltivekimab的療效，STEMI患者在住院36小時內起始，NSTEMI患者在住院48小時內起始。
IL-1β和IL-6都是活性細胞因子，與冠心病及其併發症的因果途徑有關，因此是潛在的治療靶點。這與CRP相反，後者是一種在肝臟中產生的對 IL-6 有反應的急性期蛋白質，但其僅僅為一種生物標註物，對發病機制物影響。重要的是，對因果途徑的有針對性的抑制應該提供對驅動動脈粥樣硬化進展的炎症過程的更好的理解，並幫助描述和定義可能受益最大的患者組。
DM等代謝性疾病如何影響免疫細胞功能，人們對此越來越感興趣。還有很多東西有待理解，但是現有證據表明了DM病如何加重MI後的炎症過程，以及如何介導不良結局的潛在可能性。在動物模型中，高血糖驅動骨髓生成[162]，這似乎由於短暫間歇性高血糖的模式而加劇[163,164]。最近，發現了高血糖誘導的訓練免疫（HITI）的新現象，其中高血糖加劇經典炎症並抑制修復。高血糖導致造血幹細胞的表觀遺傳學改變，使其後代遠離M2修復表型，轉向M1促炎症表型。
儘管恢復了葡萄糖的生理水平，但這些修飾仍然存在[165]。雖然這種（M1/M2） 二分法是過於簡單化的，但研究結果表明，HITI 或影響 MI後的炎症過程，並導致不能透過降低葡萄糖來糾正的變化。DM或影響MI後巨噬細胞的炎症過程。與創面癒合相關，DM和HITI可能會損害MI。有效的傷口癒合需要炎症期的促炎性單核細胞的順序浸潤，然後是修復期的抗炎性單核細胞。然而，在DM小鼠的傷口中，Ly6Chi單核細胞可表現出 “第二次內流” 並浸潤，從而延遲其向 Ly6CLo單核細胞的轉變[166]。一種類似，但尚未探索的過程可能在心臟中發生。如前所述，高血糖導致偏離M2修復表型。促炎性單核細胞浸潤缺血心肌可損害炎症的消退，加重損傷程度。如果這些是病理學上重要的過程，人們可能預期 DM患者的梗死麵積會更大，但是在上述CMR研究中並不明顯（在急性期測量的梗死麵積沒有顯著差異）[60,61]，儘管已知梗死麵積僅在大約30天后達到其最終大小[167]。因此，研究者或過早測量梗死麵積，尤其是如果HITI可延遲梗死癒合和炎症消退時。此外，目前的成像技術無法檢測梗死癒合過程中潛在的重要組織學差異。
DM對造血和白細胞功能的影響似乎可能影響招募到遠端心肌的白細胞的性質。在人類心臟中，CCR2 +巨噬細胞 （來源於迴圈單核細胞）的存在與心室功能惡化和不良重塑有關[168]。偏向於促炎症過程的單核細胞可能不僅被招募到梗死區，而且被招募到遠端心肌，這可以部分解釋為什麼DM患者在MI後更可能發生 HF[169-170]。此外，最近的證據表明，炎症細胞可能是MI後心律失常的決定因素[171]。全身而言，高血糖增加炎性細胞因子（TNF-α，IL-6 和 IL-18）[172]和急性期蛋白的產生[173]。如前所述，hs-CRP 與心血管事件的殘餘風險密切相關，特別是在 DM 患者中[129]。CANTOS試驗的亞組分析顯示，對於T2DM患者進行抗炎治療沒有選擇性益處[175-176]。
綜上所述，DM的存在或不足以確定DM患者或受益於靶向活動性炎症。在細胞水平上，高血糖驅動糖酵解反過來導致特定組蛋白的翻譯後修飾。這些組蛋白修飾顯著的改變了IL-6 啟動子處的染色質可及性，這是 HITI 的主要特徵[165,177]。啟動子 “保持開放”，從而有效的啟動活性轉錄的 IL-6 基因。因此，T2D M導致HITI患者具有更高的IL-6 和 hs-CRP水平，且可能對IL-6抑制顯示出特殊的治療益處。
T2DM的全球流行正在迅速增加對心血管疾病的不利影響。儘管MI後預後總體上有所改善，但T2DM患者的預後持續惡化，併發症、再梗死和死亡率較高。影響因素是複雜和多重的，遠遠超出了血管造影表現的冠心病和/或MI大小的 “解剖學” 考慮範圍。特別是，新出現的一系列證據指出了炎症過程和炎症消退受損在 T2DM中的作用。流行病學研究表明，在T2DM患者中，hs-CRP是預測結局的優越指標（與LDL-C相比）；以及近期資料提示的高血糖對先天性免疫功能的影響。這些先天免疫功能的改變可能與動脈粥樣硬化的進展和AMI的反應有關，且所有名義上DM患者均會受到不同程度的影響。
另外，新出現強效證據表明，在未來，人們將受益於對疾病過程的描述，而不僅僅是名義上診斷的DM。特別是，對炎症過程和體內平衡紊亂結局的更好理解和角色塑造可能為針對併發症和改善DM患者的心血管預後開闢新的機會。
參考文獻
1. Lin X, Xu Y, Pan X, Xu J, Ding Y, Sun X, Song X, Ren Y, Shan P-F. Global, regional, and national burden and trend of diabetes in 195 countries and territories: an analysis from 1990 to 2025. Sci Rep 2020;10:14790.
2. Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N,Whincup PH, Mukamal KJ, Gillum RF, Holme I, Njølstad I, Fletcher A, Nilsson P, Lewington S, Collins R, Gudnason V, Thompson SG, Sattar N, Selvin E, Hu FB, Danesh J; Emerging risk factors collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med 2011;364:829–841.
3. Bauters C, Lemesle G, de Groote P, Lamblin N. A systematic review and meta-regression of temporal trends in the excess mortality associated with diabetes mellitus after myocardial infarction. Int J Cardiol 2016;217:109–121.
4. Simek S, Motovska Z, Hlinomaz O, Kala P, Hromadka M, Knot J, Varvarovsky I, Dusek J,Rokyta R, Tousek F, Svoboda M, Vodzinska A, Mrozek J, Jarkovsky J; On behalf of the prague-study group. The effect of diabetes on prognosis following myocardial infarction treated with primary angioplasty and potent antiplatelet therapy. J Clin Med 2020;9:2555.
5. Ritsinger V, Nyström T, Saleh N, Lagerqvist B, Norhammar A. Heart failure is a common complication after acute myocardial infarction in patients with diabetes: a nationwide study in the SWEDEHEART registry. Eur J Prev Cardiol 2020;27:1890–1901.
6. Echouffo-Tcheugui JB, Kolte D, Khera S, Aronow HD, Abbott JD, Bhatt DL, Fonarow GC. Diabetes mellitus and cardiogenic shock complicating acute myocardial infarction. Am J Med 2018;131:778–86.e1.
7. Faxén J, Jernberg T, Hollenberg J, Gadler F, Herlitz J, Szummer K. Incidence and predictors of out-of-hospital cardiac arrest within 90 days after myocardial infarction. J Am Coll Cardiol 2020;76:2926–2936.
8. Galasso G, De Angelis E, Silverio A, Di Maio M, Cancro FP, Esposito L, Bellino M, Scudiero F, Damato A, Parodi G, Vecchione C. Predictors of recurrent ischemic events in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2021;159:44–51.
9. de Vreede JJM, Gorgels APM, Verstraaten GMP, Vermeer F, Dassen WRM, Wellens HJJ. Did prognosis after acute myocardial infarction change during the past 30 years? A meta-analysis. J Am Coll Cardiol 1991;18:698–706.
10. McNamara RL, Kennedy KF, Cohen DJ, Diercks DB, Moscucci M, Ramee S, Wang TY, Connolly T, Spertus JA. Predicting in-hospital mortality in patients with acute myocardial infarction. J Am Coll Cardiol 2016;68:626–635.
11. Milazzo V, Cosentino N, Genovese S, Campodonico J, Mazza M, De Metrio M, Marenzi G. Diabetes mellitus and acute myocardial infarction: impact on short and long-term mortality. In: Islam MS (ed.), Diabetes: from research to clinical practice: volume 4. Cham: Springer International Publishing; 2021. p153–169.
12. Bradley RF, Bryfogle JW. Survival of diabetic patients after myocardial infarction. Am J Med 1956;20:207–216.
13. Rytter L, Troelsen S, Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 1985;8:230–234.
14. Mak KH, Moliterno DJ, Granger CB, Miller DP, White HD, Wilcox RG, Califf RM, Topol EJ. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. GUSTO-I Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. J Am Coll Cardiol 1997;30: 171–179.
15. Franklin K, Goldberg RJ, Spencer F, Klein W, Budaj A, Brieger D, Marre M, Steg PG, Gowda N, Gore JM; GRACE Investigators. Implications of diabetes in patients with acute coronary syndromes: the global registry of acute coronary events. Arch Intern Med 2004;164: 1457–1463.
16. Skoda R, Nemes A, Bárczi G, Vágó H, Ruzsa Z, Édes IF, Oláh A, Kosztin A, Dinya E, Merkely B, Becker D. Survival of myocardial infarction patients with diabetes mellitus at the invasiveera (results from the városmajor myocardial infarction registry). J Clin Med 2023;12:917.
17. Gyldenkerne C, Maeng M, Kjøller-Hansen L, Maehara A, Zhou Z, Ben-Yehuda O, Erik Bøtker H, Engstrøm T, Matsumura M, Mintz GS, Fröbert O, Persson J, Wiseth R, Larsen AI, Jensen LO, Nordrehaug JE, Bleie Ø, Omerovic E, Held C, James SK, Ali ZA, Rosen HC, Stone GW, Erlinge D. Coronary artery lesion lipid content and plaque burden in diabetic and nondiabetic patients: PROSPECT II. Circulation 2023;147:469–481.
18. Brener SJ, Mehran R, Dressler O, Cristea E, Stone GW. Diabetes mellitus, myocardial reperfusion, and outcome in patients with acute ST-elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI). Am J Cardiol 2012;109:1111–1116.
19. Kerola AM, Juonala M, Palomäki A, Semb AG, Rautava P, Kytö V. Case fatality of patients with type 1 diabetes after myocardial infarction. Diabetes Care 2022;45:1657–1665.
20. Ravid M, Berkowicz M, Sohar E. Hyperglycemia during acute myocardial infarction: a sixyear follow-up study. JAMA 1975;233:807–809.
21. Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL; ICONS Investigators. Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol 2002;40:1748–1754.
22. Singh K, Hibbert B, Singh B, Carson K, Premaratne M, Le May M, Chong A-Y, Arstall M, So Derek. Meta-analysis of admission hyperglycaemia in acute myocardial infarction patients treated with primary angioplasty: a cause or a marker of mortality? Eur Heart J Cardiovasc Pharmacother 2015;1:220–228.
23. Deedwania P, Kosiborod M, Barrett E, Ceriello A, Isley W, Mazzone T, Raskin P. Hyperglycemia and acute coronary syndrome: a scientific statement from the American Heart Association Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 2008;117:1610–1619.
24. Esdaile H, Hill N, Mayet J, Oliver N. Glycaemic control in people with diabetes following acute myocardial infarction. Diabetes Res Clin Pract 2023;199:110644.
25. Baviera M, Genovese S, Colacioppo P, Cosentino N, Foresta A, Tettamanti M, Fortino I, Roncaglioni MC, Marenzi G. Diabetes mellitus duration and mortality in patients hospitalized with acute myocardial infarction. Cardiovasc Diabetol 2022;21:223.
26. Pan W, Lu H, Lian B, Liao P, Guo L, Zhang M. Prognostic value of HbA1c for in-hospital and short-term mortality in patients with acute coronary syndrome: a systematic review and meta-analysis. Cardiovasc Diabetol 2019;18:169.
27. Rossello X, Ferreira JP, McMurray JJ, Aguilar D, Pfeffer MA, Pitt B, Dickstein K, Girerd N, Rossignol P, Zannad F; High-risk myocardial infarction database initiative. Editor’s choice-impact of insulin-treated diabetes on cardiovascular outcomes following high-risk myocardial infarction. Eur Heart J Acute Cardiovasc Care 2019;8:231–241.
28. Ritsinger V, Lagerqvist B, Lundman P, Hagström E, Norhammar A. Diabetes, metformin and glucose lowering therapies after myocardial infarction: insights from the SWEDEHEART registry. Diab Vasc Dis Res 2020;17:1479164120973676.
29. Hesen NA, Riksen NP, Aalders B, Brouwer MAE, Ritskes-Hoitinga M, El Messaoudi S, Wever KE. A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction. PLoS One 2017;12:e0183664.
30. Lexis CPH, Wieringa WG, Hiemstra B, van Deursen VM, Lipsic E, van der Harst P, van Veldhuisen DJ, van der Horst ICC. Chronic metformin treatment is associated with reduced myocardial infarct size in diabetic patients with ST-segment elevation myocardial infarction. Cardiovasc Drugs Ther 2014;28:163–171.
31. Basnet S, Kozikowski A, Makaryus AN, Pekmezaris R, Zeltser R, Akerman M, Lesser M, Wolf-Klein G. Metformin and myocardial injury in patients with diabetes and ST-segment elevation myocardial infarction: a propensity score matched analysis. J Am Heart Assoc 2015;4:e002314.
32. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr. Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 1999;33:119–124.
33. Halkin A, Roth A, Jonas M, Behar S. Sulfonylureas are not associated with increased mortality in diabetics treated with thrombolysis for acute myocardial infarction. J Thromb Thrombolysis 2001;12:177–184.
34. Klamann A, Sarfert P, Launhardt V, Schulte G, Schmiegel WH, Nauck MA. Myocardial infarction in diabetic vs non-diabetic subjects. Survival and infarct size following therapy with sulfonylureas (glibenclamide). Eur Heart J 2000;21:220–229.
35. Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, Berland J, Gueret P, Wyart P, Deturck R, Tabone X, Machecourt J, Leclercq F, Drouet E, Mulak G, Bataille V, Cambou J-P, Ferrieres J, Simon T; French registry of acute st-elevation and non-st-elevation myocardial infarction investigators. Impact of type of preadmission sulfonylureas on mortality and car
diovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;95:4993–5002.
36. Danchin N, Charpentier G, Ledru F, Vaur L, Guéret P, Hanania G, Blanchard D, Lablanche J-M, Genès N, Cambou J-P. Role of previous treatment with sulfonylureas in diabetic patients with acute myocardial infarction: results from a nationwide French registry. Diabetes Metab Res Rev 2005;21:143–149.
37. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128.
38. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657.
39. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu P-L, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295–2306.
40. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker A, Kuder JF, Murphy SA, Bhatt DL, Leiter LA., McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johansson PA, Langkilde A-M, Sabatine MS;
DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–357.
41. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, Shih WJ, Gantz I, Terra SG, Cherney DZI, McGuire DK; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425–1435.
42. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang C-E, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde A-M; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008.
43. Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CSP, Martinez F, Shah SJ, Desai AS, Jhund PS, Belohlavek J, Chiang C-E, Borleffs CJW, Comin-Colet J, Dobreanu D, Drozdz J, Fang JC, Alcocer-Gamba MA, Al Habeeb W, Han Y, Honorio JWC, Janssens SP, Katova T, Kitakaze M, Merkely B, O’Meara E, Saraiva JFK, Tereshchenko SN, Thierer J, Vaduganathan M, Vardeny O, Verma S, Pham VN, Wilderäng U, Zaozerska N, Bachus E, Lindholm D, Petersson M, Langkilde AM; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089–1098.
44. Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 2020;17:761–772.
45. Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors. JACC Basic Transl Sci 2020;5:632–644.
46. Sardu C, Trotta MC, Sasso FC, Sacra C, Carpinella G, Mauro C, Minicucci F, Calabrò P, D’Amico M, D’ Ascenzo F, De Filippo O, Iannaccone M, Pizzi C, Paolisso G, Marfella R. SGLT2-inhibitors effects on the coronary fibrous cap thickness and MACEs in diabetic patients with inducible myocardial ischemia and multi vessels non-obstructive coronary artery stenosis. Cardiovasc Diabetol 2023;22:80.
47. Udell JA, Jones WS, Petrie MC, Harrington J, Anker SD, Bhatt DL, Hernandez AF, Butler J. Sodium glucose cotransporter-2 inhibition for acute myocardial infarction. J Am Coll Cardiol 2022;79:2058–2068.
48. Marfella R, Sardu C, D’Onofrio N, Fumagalli C, Scisciola L, Sasso FC, Siniscalchi M, Marfella LV, D’Andrea D, Minicucci F, Signoriello G, Cesaro A, Trotta MC, Frigé C, Prattichizzo F, Balestrieri ML, Ceriello A, Calabrò P, Mauro C, Del Viscovo L, Paolisso G. SGLT-2 inhibitors and in-stent restenosis-related events after acute myocardial infarction: an observational study in patients with type 2 diabetes. BMC Med 2023;21:71.
49. Cesaro A, Gragnano F, Paolisso P, Bergamaschi L, Gallinoro E, Sardu C, Mileva N, Foà A, Armillotta M, Sansonetti A, Amicone S, Impellizzeri A, Esposito G, Morici N, Oreglia JA, Casella G, Mauro C, Vassilev D, Galie N, Santulli G, Pizzi C, Barbato E, Calabrò P, Marfella R. In-hospital arrhythmic burden reduction in diabetic patients with acute myocardial infarction treated with SGLT2-inhibitors: insights from the SGLT2-I AMI PROTECT study. Front Cardiovasc Med 2022;9:1012220.
50. von Lewinski D, Kolesnik E, Tripolt NJ, Pferschy PN, Benedikt M, Wallner M, Alber H, Berger R, Lichtenauer M, Saely CH, Moertl D, Auersperg P, Reiter C, Rieder T, Siller-Matula JM, Gager GM, Hasun M, Weidinger F, Pieber TR, Zechner PM, Herrmann M, Zirlik A, Holman RR, Oulhaj A, Sourij H. Empagliflozin in acute myocardial infarction: the EMMY trial. Eur Heart J. 2022;43:4421–4432.
51. Benedikt M, Mangge H, Aziz F, Curcic P, Pailer S, Herrmann M, Kolesnik E, Tripolt NJ, Pferschy PN, Wallner M, Zirlik A, Sourij H, von Lewinski D. Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction—a post-hoc analysis of the EMMY trial. Cardiovasc Diabetol 2023;22:166.
52. James S, Erlinge D, Storey RF, McGuire DK, Belder M, Eriksson N, Andersen K, Austin D, Arefalk G, Carrick D, Hofmann R, Hoole SP, Jones DA, Lee K, Tygesen H, Johansson PA, Langkilde AM, Ridderstråle W, Parvaresh Rizi E, Deanfield J, Oldgren J. Dapagliflozin in myocardial infarction without diabetes or heart failure. NEJM Evid 2024;3:EVIDoa2300286.
53. Butler J, Jones WS, Udell JA, Anker SD, Petrie MC, Harrington J, Mattheus M, Zwiener I, Amir O, Bahit MC, Bauersachs J, Bayes-Genis A, Chen Y, Chopra VK, Figtree G, Ge J, Goodman SG, Gotcheva N, Goto S, Gasior T, Jamal W, Januzzi JL, Jeong MH, Lopatin Y, Lopes RD, Merkely B, Parikh PB, Parkhomenko A, Ponikowski P, Rossello X, Schou M, Simic D, Steg PG, zachniewicz J, van der Meer P, Vinereanu D, Zieroth S, Brueckmann M, Sumin M, Bhatt DL, Hernandez AF. Empagliflozin after acute myocardial infarction. N Engl J Med 2024;390:1455–1466.
54. Lauer MS, Blackstone EH, Young JB, Topol EJ. Cause of death in clinical research: time for a reassessment? J Am Coll Cardiol 1999;34:618–620.
55. Mather AN, Crean A, Abidin N, Worthy G, Ball SG, Plein S, Greenwood JP. Relationship of dysglycemia to acute myocardial infarct size and cardiovascular outcome as determined by cardiovascular magnetic resonance. J Cardiovasc Magn Reson 2010;12:61.
56. Alegria JR, Miller TD, Gibbons RJ, Yi Q-L, Yusuf S; Collaborative organization of rheothrxevaluation (core) trial investigators. Infarct size, ejection fraction, and mortality in diabetic patients with acute myocardial infarction treated with thrombolytic therapy. Am Heart J 2007;154:743–750.
57. Berman N, Jones MM, De Coster DA. ’Just like a normal pain’, what do people with diabetes mellitus experience when having a myocardial infarction: a qualitative study recruited from UK hospitals. BMJ Open 2017;7:e015736.
58. Stone GW, Selker HP, Thiele H, Patel MR, Udelson JE, Ohman EM, Maehara A, Eitel I, Granger CB, Jenkins PL, Nichols M, Ben-Yehuda O. Relationship between infarct size and outcomes following primary PCI: patient-level analysis from 10 randomized trials. J
Am Coll Cardiol 2016;67:1674–1683.
59. Salerno M, Sharif B, Arheden H, Kumar A, Axel L, Li D, Neubauer S. Recent advances in cardiovascular magnetic resonance: techniques and applications. Circ Cardiovasc Imaging 2017;10:e003951.
60. Eitel I, Hintze S, Waha S, Fuernau G, Lurz P, Desch S, Schuler G, Thiele H. Prognostic impact of hyperglycemia in nondiabetic and diabetic patients with ST-elevation myocardial infarction: insights from contrast-enhanced magnetic resonance imaging. Circ Cardiovasc Imaging 2012;5:708–718.
61. Reinstadler SJ, Stiermaier T, Eitel C, Metzler B, de Waha S, Fuernau G, Desch S, Thiele H, Eitel I. Relationship between diabetes and ischaemic injury among patients with revascularized ST-elevation myocardial infarction. Diabetes Obes Metab 2017;19:1706–1713.
62. Sutton NR, Li S, Thomas L, Wang TY, de Lemos JA, Enriquez JR, Shah RU, Fonarow GC. The association of left ventricular ejection fraction with clinical outcomes after myocardial infarction: findings from the Acute Coronary Treatment and Intervention Outcomes Network (ACTION) Registry–Get with the Guidelines (GWTG) Medicare-linked database. Am Heart J 2016;178:65–73.
63. Goraya TY, Leibson CL, Palumbo PJ, Weston SA, Killian JM, Pfeifer EA, Jacobsen SJ, Frye RL, Roger VL. Coronary atherosclerosis in diabetes mellitus: a population-based autopsy study. J Am Coll Cardiol 2002;40:946–953.
64. Niccoli G, Giubilato S, Di Vito L, Leo A, Cosentino N, Pitocco D, Marco V, Ghirlanda G, Prati F, Crea F. Severity of coronary atherosclerosis in patients with a first acute coronary event: a diabetes paradox. Eur Heart J 2013;34:729–741.
65. Marso SP, Mercado N, Maehara A, Weisz G, Mintz GS, McPherson J, Schiele F, Dudek D, Fahy M, Xu K, Lansky A, Templin B, Zhang Z, de Bruyne B, Serruys PW, Stone GW. Plaque composition and clinical outcomes in acute coronary syndrome patients with metabolic syndrome or diabetes. JACC Cardiovasc Imaging 2012;5(Suppl.):S42–S52.
66. Ibebuogu UN, Nasir K, Gopal A, Ahmadi N, Mao SS, Young E, Honoris L, Nuguri VK, Lee RS, Usman N, Rostami B, Pal R, Flores F, Budoff MJ. Comparison of atherosclerotic plaque burden and composition between diabetic and non diabetic patients by non invasive CT angiography. Int J Cardiovasc Imaging 2009;25:717–723.
67. Morgan KP, Kapur A, Beatt KJ. Anatomy of coronary disease in diabetic patients: an explanation for poorer outcomes after percutaneous coronary intervention and potential target for intervention. Heart 2004;90:732–738.
68. Erlinge D, Maehara A, Ben-Yehuda O, Bøtker HE, Maeng M, Kjøller-Hansen L, Engstrøm T, Matsumura M, Crowley A, Dressler O, Mintz GS, Fröbert O, Persson J, Wiseth R, Larsen AI, Okkels JL, Nordrehaug JE, Bleie Ø, Omerovic E, Held C, James SK, Ali ZA, Muller JE, Stone GW; PROSPECT II Investigators. Identification of vulnerable plaques and patients by intracoronary near-infrared spectroscopy and ultrasound (PROSPECT II): a prospective natural history study. Lancet 2021;397:985–995.
69. Sugiyama T, Yamamoto E, Bryniarski K, Xing L, Fracassi F, Lee H, Jang I-K. Coronary plaque characteristics in patients with diabetes mellitus who presented with acute coronary syndromes. J Am Heart Assoc 2018;7:e009245.
70. Ali ZA, Karimi Galougahi K, Mintz GS, Maehara A, Shlofmitz RA, Mattesini A. Intracoronary optical coherence tomography: state of the art and future directions. EuroIntervention 2021; 17:e105–e123.
71. Woodfield SL, Lundergan CF, Reiner JS, Greenhouse SW, Thompson MA, Rohrbeck SC, Deychak Y, Simoons ML, Califf RM, Topol EJ, Ross AM. Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 1996;28:1661–1669.
72. Padro T, Manfrini O, Bugiardini R, Canty J, Cenko E, De Luca G, Duncker DJ, Eringa EC, Koller A, Tousoulis D, Trifunovic D, Vavlukis M, de Wit C, Badimon L. ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on ‘coronary microvascular dysfunction in cardiovascular disease’. Cardiovasc Res 2020;116:741–755.
73. Kelshiker MA, Seligman H, Howard JP, Rahman H, Foley M, Nowbar AN, Rajkumar CA, Shun-Shin MJ, Ahmad Y, Sen S, Al-Lamee R, Petraco R; Coronary Flow Outcomes Reviewing Committee. Coronary flow reserve and cardiovascular outcomes: a systematic review and meta-analysis. Eur Heart J 2022;43:1582–1593.
74. Aljizeeri A, Ahmed AI, Suliman I, Alfaris MA, Elneama A, Al-Mallah MH. Incremental prognostic value of positron emission tomography-derived myocardial flow reserve in patients with and without diabetes mellitus. Eur Heart J Cardiovasc Imaging 2023;24:563–571.
75. Kato S, Fukui K, Kodama S, Azuma M, Iwasawa T, Kimura K, Tamura K, Utsunomiya D. Incremental prognostic value of coronary flow reserve determined by phase-contrast cine cardiovascular magnetic resonance of the coronary sinus in patients with diabetes mellitus. J Cardiovasc Magn Reson 2020;22:73.
76. Gallinoro E, Paolisso P, Candreva A, Bermpeis K, Fabbricatore D, Esposito G, Bertolone D, Fernandez Peregrina E, Munhoz D, Mileva N, Penicka M, Bartunek J, Vanderheyden M, Wyffels E, Sonck J, Collet C, De Bruyne B, Barbato E. Microvascular dysfunction in patients with type II diabetes mellitus: invasive assessment of absolute coronary blood flow and
microvascular resistance reserve. Front Cardiovasc Med 2021;8:765071.
77. Hu X, Zhang J, Lee JM, Chen Z, Hwang D, Park J, Shin E-S, Nam C-W, Doh J-H, Chen S, Yang J, Tanaka N, Kuramitsu S, Matsuo H, Takashima H, Akasaka T, Koo B-K, Wang J. Prognostic impact of diabetes mellitus and index of microcirculatory resistance in patients undergoing fractional flow reserve-guided revascularization. Int J Cardiol 2020;307: 171–175.
78. Sara JD, Taher R, Kolluri N, Vella A, Lerman LO, Lerman A. Coronary microvascular dysfunction is associated with poor glycemic control amongst female diabetics with chest pain and non-obstructive coronary artery disease. Cardiovasc Diabetol 2019;18:22.
79. Zhang W, Singh S, Liu L, Mohammed AQ, Yin G, Xu S, Lv X, Shi T, Feng C, Jiang R, Mohammed AA, Mareai RM, Xu Y, Yu X, Abdu FA, Che W. Prognostic value of coronary microvascular dysfunction assessed by coronary angiography-derived index of microcirculatory resistance in diabetic patients with chronic coronary syndrome. Cardiovasc Diabetol 2022;21:222.
80. Cortigiani L, Rigo F, Gherardi S, Galderisi M, Bovenzi F, Sicari R. Prognostic meaning of coronary microvascular disease in type 2 diabetes mellitus: a transthoracic Doppler echocardiographic study. J Am Soc Echocardiogr 2014;27:742–748.
81. de Waha S, Patel MR, Granger CB, Ohman EM, Maehara A, Eitel I, Ben-Yehuda O, Jenkins P, Thiele H, Stone GW. Relationship between microvascular obstruction and adverse events following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: an individual patient data pooled analysis from seven randomized trials. Eur
Heart J 2017;38:3502–3510.
82. Fabris E, van ‘t Hof A, Hamm CW, Lapostolle F, Lassen JF, Goodman SG, ten Berg JM,Bolognese L, Cequier A, Chettibi M, Hammett CJ, Huber K, Janzon M, Merkely B, Storey RF, Zeymer U, Cantor WJ, Tsatsaris A, Kerneis M, Diallo A, Vicaut E, Montalescot G. Clinical impact and predictors of complete ST segment resolution after primary percutaneous coronary intervention: a subanalysis of the ATLANTIC trial. Eur Heart J Acute Cardiovasc Care 2019;8:208–217.
83. Timmer JR, van der Horst ICC, de Luca G, Ottervanger JP, Hoorntje JCA, de Boer M-J, Suryapranata H, Dambrink J-HE, Gosselink M, Zijlstra F, van ’t Hof AWJ; Myocardial Infarction Study Group. Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction with
versus without diabetes mellitus. Am J Cardiol 2005;95:1375–1377.
84. Timmer JR, Hoekstra M, Nijsten MWN, Horst I, Ottervanger JP, Slingerland RJ, Dambrink J-HE, Bilo HJG, Zijlstra F, van ’t Hof AWJ. Prognostic value of admission glycosylated hemoglobin and glucose in nondiabetic patients with ST-segment–elevation myocardial infarction treated with percutaneous coronary intervention. Circulation 2011;124:704–711.
85. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation 1979;59:8–13.
86. van Melle JP, Bot M, de Jonge P, de Boer RA, van Veldhuisen DJ, Whooley MA. Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease: data from the heart and soul study. Diabetes Care 2010;33:2084–2089.
87. Jia G, Hill MA, Sowers JR. Diabetic cardiomyopathy. Circ Res 2018;122:624–638.
88. Desta L, Jernberg T, Löfman I, Hofman-Bang C, Hagerman I, Spaak J, Persson H. Incidence, temporal trends, and prognostic impact of heart failure complicating acute myocardial infarction. The SWEDEHEART registry (Swedish web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended
therapies): a study of 199,851 patients admitted with index acute myocardial infarctions, 1996 to 2008. JACC Heart Fail 2015;3:234–242.
89. Ritchie RH, Abel ED. Basic mechanisms of diabetic heart disease. Circ Res 2020;126: 1501–1525.
90. Kwong RY, Sattar H, Wu H, Vorobiof G, Gandla V, Steel K, Siu S, Brown KA. Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction. Circulation 2008;118:1011–1020.
91. Russo I, Frangogiannis NG. Diabetes-associated cardiac fibrosis: cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol 2016;90:84–93.
92. Devereux RB, Roman MJ, Paranicas M, O’Grady MJ, Lee ET, Welty TK, Fabsitz RR, Robbins D, Rhoades ER, Howard BV. Impact of diabetes on cardiac structure and function. Circulation 2000;101:2271–2276.
93. Pararajasingam G, Løgstrup BB, Høfsten DE, Christophersen TB, Auscher S, Hangaard J, Egstrup K. Dysglycemia and increased left ventricle mass in normotensive patients admitted with a first myocardial infarction: prognostic implications of dysglycemia during 14 years of follow-up. BMC Cardiovasc Disord 2019;19:103.
94. Sawano M, Lu Y, Caraballo C, Mahajan S, Dreyer R, Lichtman JH, D’Onofrio G, Spatz E, Khera R, Onuma O, Murugiah K, Spertus JA, Krumholz HM. Sex difference in outcomes of acute myocardial infarction in young patients. J Am Coll Cardiol 2023;81:1797–1806.
95. Weaver WD, White HD, Wilcox RG, Aylward PE, Morris D, Guerci A, Ohman EM, Barbash GI, Betriu A, Sadowski ZZ, Topol EJ, Califf RM. Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I investigators. JAMA 1996;275:777–782.
96. Kuehnemund L, Koeppe J, Feld J, Wiederhold A, Illner J, Makowski L, Gerß J, Reinecke H, Freisinger E. Gender differences in acute myocardial infarction—a nationwide German real-life analysis from 2014 to 2017. Clin Cardiol 2021;44:890–898.
97. Milcent C, Dormont B, Durand-Zaleski I, Steg PG. Gender differences in hospital mortality and use of percutaneous coronary intervention in acute myocardial infarction. Circulation 2007;115:833–839.
98. Jneid H, Fonarow GC, Cannon CP, Hernandez AF, Palacios IF, Maree AO, Wells Q, Bozkurt B, LaBresh KA, Liang L, Hong Y, Newby LK, Fletcher G, Peterson E, Wexler L; Get With the Guidelines Steering Committee and Investigators. Sex differences in medical care and early death after acute myocardial infarction. Circulation 2008;118:2803–2810.
99. Radovanovic D, Erne P, Urban P, Bertel O, Rickli H, Gaspoz J-M; AMIS Plus Investigators. Gender differences in management and outcomes in patients with acute coronary syndromes: results on 20 290 patients from the AMIS Plus Registry. Heart 2007;93: 1369–1375.
100. Elgendy IY, Wegermann ZK, Li S, Mahtta D, Grau-Sepulveda M, Smilowitz NR, Gulati M, Garratt KN, Wang TY, Jneid H. Sex differences in management and outcomes of acute myocardial infarction patients presenting with cardiogenic shock. JACC Cardiovasc Interv 2022;15:642–652.
101. Plakht Y, Elkis Hirsch Y, Shiyovich A, Abu Tailakh M, Liberty IF, Gilutz H. Heterogenicity of diabetes as a risk factor for all-cause mortality after acute myocardial infarction: age and sex impact. Diabetes Res Clin Pract 2021;182:109117.
102. Bucholz EM, Butala NM, Rathore SS, Dreyer RP, Lansky AJ, Krumholz HM. Sex differences in long-term mortality after myocardial infarction: a systematic review. Circulation 2014; 130:757–767.
103. Valero-Masa MJ, Velásquez-Rodríguez J, Diez-Delhoyo F, Devesa C, Juárez M, Sousa-Casasnovas I, Angulo-Llanos R, Fernández-Avilés F, Martínez-Sellés M. Sex differences in acute myocardial infarction: is it only the age? Int J Cardiol 2017;231:36–41.
104. Farhan S, Baber U, Vogel B, Aquino M, Chandrasekhar J, Faggioni M, Giustino G, Kautzky-Willer A, Sweeny J, Shah S, Vijay P, Barman N, Moreno P, Kovacic J, Dangas G, Kini A, Mehran R, Sharma S. Impact of diabetes mellitus on ischemic events in men and women after percutaneous coronary intervention. Am J Cardiol 2017;119:1166–1172.
105. Norhammar A, Stenestrand U, Lindbäck J, Wallentin L; Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA). Women younger than 65 years with diabetes mellitus are a high-risk group after myocardial infarction: areport from the Swedish Register of Information and Knowledge about Swedish Heart
Intensive Care Admission (RIKS-HIA). Heart 2008;94:1565–1570.
106. Chakraborty S, Amgai B, Bandyopadhyay D, Patel N, Hajra A, Narasimhan B, Rai D, Aggarwal G, Ghosh RK, Yandrapalli S, Aronow WS, Fonarow GC, Naidu SS. Acute myocardial infarction in the young with diabetes mellitus- national inpatient sample study with sex-based difference in outcomes. Int J Cardiol 2021;326:35–41.
107. Hori M, Nishida K. Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc Res 2009;81:457–464.
108. Martinon F. Signaling by ROS drives inflammasome activation. Eur J Immunol 2010;40: 616–619.
109. Simon AR, Rai U, Fanburg BL, Cochran BH. Activation of the JAK-STAT pathway by reactive oxygen species. Am J Physiol 1998;275:C1640–C1652.
110. Morgan MJ, Liu Z-G. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res 2011;21:103–115.
111. Guzik TJ, Mussa S, Gastaldi D, Sadowski J, Ratnatunga C, Pillai R, Channon KM. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002;105:1656–1662.
112. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 2009;54:1891–1898.
113. Wu X, Reboll MR, Korf-Klingebiel M, Wollert KC. Angiogenesis after acute myocardial infarction. Cardiovasc Res 2021;117:1257–1273.
114. Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, Thistlethwaite PA. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol 2005;46:2116–2124.
115. Catrina S-B, Okamoto K, Pereira T, Brismar K, Poellinger L. Hyperglycemia regulates hypoxia-inducible factor-1α protein stability and function. Diabetes 2004;53:3226–3232.
116. Marfella R, Esposito K, Nappo F, Siniscalchi M, Sasso FC, Portoghese M, Pia Di Marino M, Baldi A, Cuzzocrea S, Di Filippo C, Barboso G, Baldi F, Rossi F, D’Amico M, Giugliano D. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes 2004;53:2383–2391.
117. Januszewski AS, Watson CJ, O’Neill V, McDonald K, Ledwidge M, Robson T, Jenkins AJ, Keech AC, McClements L. FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease. Sci Rep 2020;10:21655.
118. Ling L, Shen Y, Wang K, Jiang C, Fang C, Ferro A, Kang L, Xu B. Worse clinical outcomes in acute myocardial infarction patients with type 2 diabetes mellitus: relevance to impaired endothelial progenitor cells mobilization. PLoS One 2012;7:e50739.
119. Bahadoran Z, Mirmiran P, Kashfi K, Ghasemi A. Vascular nitric oxide resistance in type 2 diabetes. Cell Death Dis 2023;14:410.
120. Fadini GP, Albiero M, Bonora BM, Avogaro A. Angiogenic abnormalities in diabetes mellitus: mechanistic and clinical aspects. J Clin Endocrinol Metab 2019;104:5431–5444.
121. Kolluru GK, Bir SC, Kevil CG. Endothelial dysfunction and diabetes: effects on angiogenesis, vascular remodeling, and wound healing. Int J Vasc Med 2012;2012:918267.
122. An D, Rodrigues B. Role of changes in cardiac metabolism in development of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 2006;291:H1489–H1506.
123. Ferreirós ER, Boissonnet CP, Pizarro R, Merletti PFG, Corrado G, Cagide A, Bazzino OO. Independent prognostic value of elevated C-reactive protein in unstable angina. Circulation 1999;100:1958–1963.
124. Buffon A, Liuzzo G, Biasucci LM, Pasqualetti P, Ramazzotti V, Rebuzzi AG, Crea F, Maseri A. Preprocedural serum levels of C-reactive protein predict early complications and late restenosis after coronary angioplasty. J Am Coll Cardiol 1999;34:1512–1521.
125. Sakakura K, Kubo N, Ako J, Wada H, Fujiwara N, Funayama H, Ikeda N, Nakamura T, Sugawara Y, Yasu T, Kawakami M, Momomura S. Peak C-reactive protein level predicts long-term outcomes in type B acute aortic dissection. Hypertension 2010;55:422–429.
126. Chalmers JD, Singanayagam A, Hill AT. C-reactive protein is an independent predictor of severity in community-acquired pneumonia. Am J Med 2008;121:219–225.
127. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:839–844.
128. Choudhury RP, Leyva F. C-reactive protein, serum amyloid A protein, and coronary events. Circulation 1999;100:e65–e66.
129. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet 2023;401:1293–1301.
130. Ruparelia N, Chai JT, Fisher EA, Choudhury RP. Inflammatory processes in cardiovascular disease: a route to targeted therapies. Nat Rev Cardiol 2017;14:133–144.
131. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol 2016;16: 626–638.
132. Huang S, Frangogiannis NG. Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. Br J Pharmacol 2018;175:1377–1400.
133. Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, Buss S, Autschbach F, Pleger ST, Lukic IK, Bea F, Hardt SE, Humpert PM, Bianchi ME, Mairbaurl H, Nawroth PP, Remppis A, Katus HA, Bierhaus A. High-mobility group box-1 in ischemia-reperfusion injury of the heart. Circulation 2008;117:3216–3226.
134. Zou N, Ao L, Cleveland JC Jr, Yang X, Su X, Cai G-Y, Banerjee A, Fullerton DA, Meng X. Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global schemia-reperfusion. Am J Physiol Heart Circ Physiol 2008;294:H2805–H2813.
135. Volz HC, Laohachewin D, Seidel C, Lasitschka F, Keilbach K, Wienbrandt AR, Andrassy J, Bierhaus A, Kaya Z, Katus HA, Andrassy M. S100a8/A9 aggravates post-ischemic heart failure through activation of RAGE-dependent NF-κB signaling. Basic Res Cardiol 2012;107: 250.
136. Schoneveld A, Hoefer I, Sluijter J, Laman J, de Kleijn D, Pasterkamp G. Atherosclerotic lesion development and Toll like receptor 2 and 4 responsiveness. Atherosclerosis 2008;197: 95–104.
137. Prabhu SD, Frangogiannis NG. The biological basis for cardiac repair after myocardial infarction: from inflammation to fibrosis. Circ Res 2016;119:91–112.
138. Toldo S, Abbate A. The NLRP3 inflammasome in acute myocardial infarction. Nat Rev Cardiol 2018;15:203–214.
139. Riad A, Jager S, Sobirey M, Escher F, Yaulema-Riss A, Westermann D, Karatas A, Heimesaat MM, Bereswill S, Dragun D, Pauschinger M, Schultheiss HP, Tschope C. Toll-like receptor-4
modulates survival by induction of left ventricular remodeling after myocardial infarction in mice. J Immunol 2008;180:6954–6961.
140. Zhu J, Yao K, Guo J, Shi H, Ma L, Wang Q, Liu H, Gao W, Sun A, Zou Y, Ge J. Mir-181a and miR-150 regulate dendritic cell immune inflammatory responses and cardiomyocyte apoptosis via targeting JAK 1–STAT 1/c-Fos pathway. J Cell Mol Med 2017;21:2884–2895.
141. Frangogiannis NG. Cell biological mechanisms in regulation of the post-infarction inflammatory response. Curr Opin Physiol 2018;1:7–13.
142. Ma Y. Role of neutrophils in cardiac injury and repair following myocardial infarction. Cells 2021;10:1676.
143. van der Laan AM, ter Horst EN, Delewi R, Begieneman MPV, Krijnen PAJ, Hirsch A, Lavaei M, Nahrendorf M, Horrevoets AJ, Niessen HWM, Piek JJ. Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir. Eur Heart J 2013;35:376–385.
144. Akbar N, Braithwaite AT, Corr EM, Koelwyn GJ, van Solingen C, Cochain C, Saliba A-E, Corbin A, Pezzolla D, Møller Jørgensen M, Bæk R, Edgar L, De Villiers C, Gunadasa-Rohling M, Banerjee A, Paget D, Lee C, Hogg E, Costin A, Dhaliwal R,
Johnson E, Krausgruber T, Riepsaame J, Melling GE, Shanmuganathan M; Oxford Acute Myocardial Infarction Study (OxAMI); Bock C, Carter DRF, Channon KM, Riley PR, Udalova IA, Moore KJ, Anthony DC, Choudhury RP. Rapid neutrophil mobilization by VCAM-1+ endothelial cell-derived extracellular vesicles. Cardiovasc Res 2023;119: 236–251.
145. Akbar N, Digby JE, Cahill TJ, Tavare AN, Corbin AL, Saluja S, Dawkins S, Edgar L, Rawlings N, Ziberna K, McNeill E, Johnson E, Aljabali AA, Dragovic RA, Rohling M, Belgard TG, Udalova IA, Greaves DR, Channon KM, Riley PR, Anthony DC, Choudhury RP. Endothelium-derived extracellular vesicles promote splenic monocyte mobilization in myocardial infarction. JCI Insight 2017;2:e93344.
146. Ruparelia N, Godec J, Lee R, Chai JT, Dall’Armellina E, McAndrew D, Digby JE, Forfar JC, Prendergast BD, Kharbanda RK, Banning AP, Neubauer S, Lygate CA, Channon KM, Haining NW, Choudhury RP. Acute myocardial infarction activates distinct inflammation and proliferation pathways in circulating monocytes, prior to recruitment, and identified through conserved transcriptional responses in mice and humans. Eur Heart J 2015;36: 1923–1934.
147. Ruparelia N, Digby JE, Jefferson A, Medway DJ, Neubauer S, Lygate CA, Choudhury RP. Myocardial infarction causes inflammation and leukocyte recruitment at remote sites in the myocardium and in the renal glomerulus. Inflamm Res 2013;62:515–525.
148. Horckmans M, Ring L, Duchene J, Santovito D, Schloss MJ, Drechsler M, Weber C, Soehnlein O, Steffens S. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J 2017;38:187–197.
149. Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation 2010;121:2437–2445.
150. Valgimigli M, Ceconi C, Malagutti P, Merli E, Soukhomovskaia O, Francolini G, Cicchitelli G, Olivares A, Parrinello G, Percoco G, Guardigli G, Mele D, Pirani R, Ferrari R. Tumor necrosis factor-α receptor 1 is a major predictor of mortality and new-onset heart failure in patients with acute myocardial infarction: the cytokine-activation and long-term prognosis in
myocardial infarction (C-ALPHA) study. Circulation 2005;111:863–870.
151. Miyao Y, Yasue H, Ogawa H, Misumi I, Masuda T, Sakamoto T, Morita E. Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J 1993;126: 1299–1304.
152. Dutta P, Courties G, Wei Y, Leuschner F, Gorbatov R, Robbins CS, Iwamoto Y, Thompson B, Carlson AL, Heidt T, Majmudar MD, Lasitschka F, Etzrodt M, Waterman P, Waring MT, Chicoine AT, van der Laan AM, Niessen HWM, Piek JJ, Rubin BB, Butany J, Stone JR, Katus HA, Murphy SA, Morrow DA, Sabatine MS, Vinegoni C, Moskowitz MA, Pittet MJ, Libby P, Lin CP, Swirski FK, Weissleder R, Nahrendorf M. Myocardial infarction accelerates atherosclerosis. Nature 2012;487:325–329.
153. Leuschner F, Panizzi P, Chico-Calero I, Lee WW, Ueno T, Cortez-Retamozo V, Waterman P, Gorbatov R, Marinelli B, Iwamoto Y, Chudnovskiy A, Figueiredo J-L, Sosnovik DE, Pittet MJ, Swirski FK, Weissleder R, Nahrendorf M. Angiotensin-converting enzyme inhibition prevents the release of monocytes from their splenic reservoir in mice with myocardial infarction. Circ Res 2010;107:1364–1373.
154. Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo J-L, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science 2009;325:612–616.
155. Leuschner F, Dutta P, Gorbatov R, Novobrantseva TI, Donahoe JS, Courties G, Lee KM, Kim JI, Markmann JF, Marinelli B, Panizzi P, Lee WW, Iwamoto Y, Milstein S, Epstein-Barash H, Cantley W, Wong J, Cortez-Retamozo V, Newton A, Love K, Libby
P, Pittet MJ, Swirski FK, Koteliansky V, Langer R, Weissleder R, Anderson DG, Nahrendorf M. Therapeutic siRNA silencing in inflammatory monocytes in mice. Nat Biotechnol 2011;29:1005–1010.
156. Frangogiannis NG. The immune system and cardiac repair. Pharmacol Res 2008;58:88–111.
157. Silverman HS, Pfeifer MP. Relation between use of anti-inflammatory agents and left ventricular free wall rupture during acute myocardial infarction. Am J Cardiol 1987;59:363–364.
158. Roberts R, DeMello V, Sobel BE. Deleterious effects of methylprednisolone in patients with myocardial infarction. Circulation 1976;53(Suppl.):I204–I206.
159. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Kastelein JJP, Cornel JH, Pais P, Pella D, Genest J, Cifkova R, Lorenzatti A, Forster T, Kobalava Z, Vida-Simiti L, Flather M, Shimokawa H, Ogawa H, Dellborg M, Rossi PRF, Troquay RPT, Libby P, Glynn RJ; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119–1131.
160. Broch K, Anstensrud AK, Woxholt S, Sharma K, Tøllefsen IM, Bendz B, Aakhus S, Ueland T, Amundsen BH, Damås JK, Berg ES, Bjørkelund E, Bendz C, Hopp E, Kleveland O, Stensæth KH, Opdahl A, Kløw N-E, Seljeflot I, Andersen GØ, Wiseth R, Aukrust P, Gullestad L. Randomized trial of interleukin-6 receptor inhibition in patients with acute ST-segment elevation myocardial infarction. J Am Coll Cardiol 2021;77:1845–1855.
161. Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, Lo L, Kling D, Pergola P, Raj D, Libby P, Davidson M. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 2021;397:2060–2069.
162. Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, Ramkhelawon B, Distel E, Westerterp M, Huang L-S, Schmidt AM, Orchard TJ, Fisher EA, Tall AR, Goldberg IJ. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab 2013;17:695–708.
163. Flynn MC, Kraakman MJ, Tikellis C, Lee MKS, Hanssen NMJ, Kammoun HL, Pickering RJ, Dragoljevic D, Al-Sharea A, Barrett TJ, Hortle F, Byrne FL, Olzomer E, McCarthy DA, Schalkwijk CG, Forbes JM, Hoehn K, Makowski L, Lancaster GI, El-Osta A, Fisher EA, Goldberg IJ, Cooper ME, Nagareddy PR, Thomas MC, Murphy AJ. Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis. Circ Res 2020; 127:877–892.
164. Choudhury RP. Transient intermittent hyperglycemia-enhanced myelopoiesis and atherosclerosis. Circ Res 2020;127:893–895.
165. Edgar L, Akbar N, Braithwaite AT, Krausgruber T, Gallart-Ayala H, Bailey J, Corbin AL, Khoyratty TE, Chai JT, Alkhalil M, Rendeiro AF, Ziberna K, Arya R, Cahill TJ, Bock C, Laurencikiene J, Crabtree MJ, Lemieux ME, Riksen NP, Netea MG, Wheelock CE, Channon KM, Rydén M, Udalova IA, Carnicer R, Choudhury RP. Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis. Circulation 2021;144:961–982.
166. Kimball A, Schaller M, Joshi A, Davis FM, denDekker A, Boniakowski A, Bermick J, Obi A, Moore B, Henke PK, Kunkel SL, Gallagher KA. Ly6CHi blood monocyte/macrophage drive chronic inflammation and impair wound healing in diabetes mellitus. Arterioscler Thromb Vasc Biol 2018;38:1102–1114.
167. Ripa RS, Nilsson JC, Wang Y, Søndergaard L, Jørgensen E, Kastrup J. Short- and long-term changes in myocardial function, morphology, edema, and infarct mass after ST-segment elevation myocardial infarction evaluated by serial magnetic resonance imaging. Am Heart J 2007;154:929–936.
168. Bajpai G, Schneider C, Wong N, Bredemeyer A, Hulsmans M, Nahrendorf M, Epelman S, Kreisel D, Liu Y, Itoh A, Shankar TS, Selzman CH, Drakos SG, Lavine KJ. The human heart contains distinct macrophage subsets with divergent origins and functions. Nat Med 2018; 24:1234–1245.
169. Jenča D, Melenovský V, Stehlik J, Staněk V, Kettner J, Kautzner J, Adámková V, Wohlfahrt P. Heart failure after myocardial infarction: incidence and predictors. ESC Heart Fail 2021;8: 222–237.
170. Shanmuganathan M, Masi A, Burrage MK, Kotronias RA, Borlotti A, Scarsini R, Banerjee A, Terentes-Printzios D, Zhang Q, Hann E, OxAMI Study Investigators. Acute response in the noninfarcted myocardium predicts long-term major adverse cardiac events after STEMI. JACC Cardiovasc Imaging 2023;16:46–59.
171. Grune J, Lewis AJM, Yamazoe M, Hulsmans M, Rohde D, Xiao L, Zhang S, Ott C, Calcagno DM, Zhou Y, Timm K, Shanmuganathan M, Pulous FE, Schloss MJ, Foy BH, Capen D, Vinegoni C, Wojtkiewicz GR, Iwamoto Y, Grune T, Brown D, Higgins J, Ferreira VM, Herring N, Channon KM, Neubauer S, Sosnovik DE, Milan DJ, Swirski FK, King KR, Aguirre AD, Ellinor PT, Nahrendorf M. Neutrophils incite and macrophages avert electrical storm after myocardial infarction. Nat Cardiovasc Res 2022;1:649–664.
172. Esposito K, Nappo F, Marfella R, Giugliano G, Giugliano F, Ciotola M, Quagliaro L, Ceriello A, Giugliano D. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans. Circulation 2002;106:2067–2072.
173. Lin Y, Rajala MW, Berger JP, Moller DE, Barzilai N, Scherer PE. Hyperglycemia-induced production of acute phase reactants in adipose tissue. J Biol Chem 2001;276:42077–42083.
174. Ridker PM, Rane M. Interleukin-6 signaling and anti-interleukin-6 therapeutics in cardiovascular disease. Circ Res 2021;128:1728–1746.
175. Choudhury RP, Birks JS, Mani V, Biasiolli L, Robson MD, L’Allier PL, Gingras M-A, Alie N, McLaughlin MA, Basson CT, Schecter AD, Svensson EC, Zhang Y, Yates D, Tardif J-C, Fayad ZA. Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance. J Am Coll Cardiol 2016;68:1769–1780.
176. Everett BM, Donath MY, Pradhan AD, Thuren T, Pais P, Nicolau JC, Glynn RJ, Libby P, Ridker PM. Anti-Inflammatory therapy with canakinumab for the prevention and management of diabetes. J Am Coll Cardiol 2018;71:2392–2401.
177. Robinson KA, Akbar N, Baidžajevas K, Choudhury RP. Trained immunity in diabetes and hyperlipidemia: emerging opportunities to target cardiovascular complications and design new therapies. FASEB J 2023;37:e23231.
專家簡介
鄭剛 教授
•現任泰達國際心血管病醫院特聘專家
•中國高血壓聯盟理事，中國心力衰竭學會委員，中國老年醫學會高血壓分會天津工作組副組長、中國醫療保健國際交流促進會高血壓分會委員。天津醫學會心血管病專業委員會委員，天津醫學會老年病專業委員會常委。天津市醫師協會高血壓專業委員會常委，天津市醫師協會老年病專業委員會委員，天津市醫師協會心力衰竭專業委員，天津市醫師協會心血管內科醫師分會雙心專業委員會委員。天津市心臟學會理事、天津市心律學會第一屆委員會委員，天津市房顫中心聯盟常委。天津市醫藥學專家協會第一屆心血管專業委員會委員，天津市藥理學會臨床心血管藥理專業委員會常委。天津市中西醫結合學會心血管疾病專業委員會常委
•《中華老年心腦血管病雜誌》編委，《中華臨床 醫師雜誌》（電子版）特邀審稿專家，《中華診斷學電子雜誌》審稿專家，《華夏醫學》雜誌副主編，《中國心血管雜誌》常務編委，《中國心血管病研究》雜誌第四屆編委，《世界臨床藥物》雜誌編委、《醫學綜述》雜誌會編委、《中國醫藥導報》雜誌編委、《中國現代醫生》雜誌編委、《心血管外科雜誌（電子版）》審稿專家
•本人在專業期刊和心血管網發表文章948篇其中第一作者759篇，參加著書11部