突破性發現：BNP和NT-proBNP在心臟功能評估中的雙重角色揭示

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近期研究發現，腦利鈉肽(BNP)和N端前腦利鈉肽(NT-proBNP)不僅在臨床醫學中作為心衰和心臟功能障礙的診斷生物標誌物，同時也在法醫學中作為評估死者死前心臟功能的重要指標。這項研究深入探討了它們的生物特徵、研究及應用狀態，並展望了未來研究前景。

BNP與NT-proBNP作為臨床與法醫學中心臟功能障礙的診斷生物標誌物

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515513/

Cao Z, Jia Y, Zhu B. BNP and NT-proBNP as Diagnostic Biomarkers for Cardiac Dysfunction in Both Clinical and Forensic Medicine. Int J Mol Sci. 2019 Apr 12;20(8):1820. doi: 10.3390/ijms20081820. PMID: 31013779; PMCID: PMC6515513.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6515513/

Abstract

Currently, brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are widely used as diagnostic biomarkers for heart failure (HF) and cardiac dysfunction in clinical medicine. They are also used as postmortem biomarkers reflecting cardiac function of the deceased before death in forensic medicine. Several previous studies have reviewed BNP and NT-proBNP in clinical medicine, however, few articles have reviewed their application in forensic medicine. The present article reviews the biological features, the research and application status, and the future research prospects of BNP and NT-proBNP in both clinical medicine and forensic medicine, thereby providing valuable assistance for clinicians and forensic pathologists.

Keywords: BNP, NT-proBNP, heart failure, cardiac dysfunction, forensic medicine, postmortem biochemistry

摘要

目前，腦利鈉肽（BNP）和N端前腦利鈉肽（NT-proBNP）廣泛用作心力衰竭（HF）和心臟功能障礙的診斷生物標誌物。它們在法醫學中也用作反映死者死前心臟功能的屍後生物標誌物。雖然之前有數篇研究回顧了BNP和NT-proBNP在臨床醫學中的應用，但很少有文章回顧它們在法醫學中的應用。本文回顧了BNP和NT-proBNP在臨床醫學和法醫學中的生物特徵、研究和應用現狀，以及未來的研究前景，為臨床醫師和法醫病理學家提供寶貴的幫助。

關鍵詞：BNP, NT-proBNP, 心力衰竭, 心臟功能障礙, 法醫學, 屍後生化

引言

全球超過2600萬人正遭受心力衰竭（HF）和心臟功能障礙的困擾，這已成為當前全球嚴重的公共衛生問題。隨著人口老齡化，HF和心臟功能障礙的全球負擔正在迅速而大幅增加[1,2,3,4,5,6]。由於患病率和死亡率高，HF和心臟功能障礙的診斷在臨床和法醫學中極為重要[7,8,9,10]。對於住院患者，HF和心臟功能障礙的診斷可以結合臨床輔助檢查，例如心電圖或超聲心動圖。然而，對於由法醫病理學家檢查的死者，由於缺乏死者的臨床醫療記錄和無法進行輔助檢查，死後診斷HF或評估心臟功能非常困難。尤其對於沒有典型可見形態改變的死者，其死後評估和診斷尤為具有挑戰性[10]。

腦利鈉肽（BNP）和N端前腦利鈉肽（NT-proBNP）廣泛用作臨床診斷HF和心臟功能障礙的重要指標[11,12,13,14,15,16,17]。近年來，許多法醫學研究通過大量動物實驗和屍體樣本證明，BNP和NT-proBNP可以用來反映死者死前的心臟功能，並可作為法醫學中診斷HF或心臟功能障礙的屍後生物標誌物[9,10,18,19,20]。然而，很少有文章回顧BNP和NT-proBNP在法醫學中的應用。為此，本文回顧了BNP和NT-proBNP的生物特徵、臨床與法醫研究，以及它們的應用現狀和未來研究前景，以期為臨床醫師和法醫病理學家提供寶貴的幫助。

2. BNP與NT-proBNP的生物特徵

利鈉肽家族主要包括心房利鈉肽（ANP），主要由心房肌細胞合成和分泌，以及腦利鈉肽（BNP）和C型利鈉肽（CNP）[21]。BNP最初於1988年從豬腦組織中分離出來，被命名為腦利鈉肽，但後續研究顯示其合成和分泌主要在心室肌細胞中[22]。

BNP主要由左心室（LV）的肌細胞合成和分泌，作為對心室壓力負荷或容積擴張所引起的肌細胞伸展的反應[12,23,24,25,26]。BNP的結構在不同物種之間高度保守，不同物種間的差異在於N端和C端尾鏈的長度和氨基酸組成[27]。人類的BNP是一種含有32個氨基酸的多肽，包含一個含有17個氨基酸的環狀結構，其中兩個半胱氨酸殘基通過二硫鍵連接[28,29]。編碼BNP的人類基因位於第1號染色體上，編碼BNP的mRNA包含一個不穩定的重複序列TATTTAT[28,30,31]。BNP mRNA的轉錄以及BNP蛋白質的合成和分泌並非在正常生理狀態下的心肌組織中儲存，而是以爆發性方式發生，並在心肌合成後迅速釋放到周圍組織中[30,32]。在病理條件下，不穩定的mRNA可以迅速合成134個氨基酸的BNP前體（pre-proBNP），並移除N端26個氨基酸信號肽形成108個氨基酸的BNP（proBNP），然後，proBNP被proNP轉化酶corin或furin分裂成不活躍的76個氨基酸NT-proBNP和活躍的32個氨基酸BNP[24,33]。在血漿中可以找到生物活性的BNP和NT-proBNP[34,35]。

利鈉肽具有三種膜結合型利鈉肽受體（NPR），分別為NPR-A、NPR-B和NPR-C。NPR-A在血管內皮系統以及其他一些器官如腎和腦中含量豐富[12,34]。NPR-A受體是ANP和BNP作用的主要效應器，而NPR-B受體則介導CNP的效應。環磷酸鳥苷單磷酸（cGMP）水平在NPR-A和NPR-B活化後會增加[33,36]。BNP與NPR-A結合後，通過抵制腎素-血管緊張素-醛固酮系統（RAAS）和交感神經系統，提高腎小球過濾率和過濾分數，並具有利尿、利鈉和血管擴張效應，從而介導其生物活性[37,38]。

大多數生理數據認為NPR-C是介導利鈉肽從細胞外環境清除的內吞和降解過程的受體[39]。除了參與BNP降解的NPR-C受體外，中性內肽酶（NEP）、二肽基肽酶-IV（DPPIV）和胰島素降解酶（IDE）也與生理條件下BNP的清除有關，這導致BNP的半衰期約為20分鐘，而NT-proBNP的半衰期為90-120分鐘[12,34,39,40]。2015年，美國食品和藥物管理局（FDA）批准了一種新類型藥物的首款產品；它是一種鈉超分子複合物，由血管緊張素受體拮抗劑瓦爾沙坦和尼普利辛抑制劑前藥沙固比利以等比例組成，已被證明能成功降低心臟功能降低射血分數（HFrEF）患者的死亡率[33,41,42]。

3. BNP基因表達的調控

BNP的合成和分泌可被機械應力、全身性缺血和缺氧、神經激素因素等誘導。然而，完整調控機制仍然不清楚。目前普遍認為，心肌中BNP水平的升高主要由機械伸展引起。在機械應力作用於心肌細胞後，BNP可能通過內皮素（ET）非依賴或ET依賴途徑被誘導[36,43]（圖1）。

圖1

機械伸展誘導腦利鈉肽（BNP）信號轉導事件、結構處理、受體結合、裂解處理和降解酶的示意圖（根據[36,43]修改，已獲許可）。

機械應力信號作用於機械感受器。隨後，從細胞外基質通過整合素啟動的信號激活了有絲分裂原活化蛋白激酶（MAPK）信號傳導途徑，從而激活BNP啟動子[43]。機械應力誘導的BNP產生主要依賴於p38 MAPK，它是MAPK的一個亞型。激活的p38 MAPK繼續激活其下游的核因子kappa B（NF-κB），NF-κB與BNP基因啟動子中的剪切應力反應元素（SSREs）結合，從而啟動BNP基因啟動子[43]。p38 MAPK有四種亞型：α、β、γ和δ。其中，p38α通過活化蛋白-1（AP-1）誘導BNP基因轉錄，而p38β通過ET-1誘導的轉錄因子GATA-4調節BNP基因表達[33,44]。GATA-4和許多其他轉錄調節因子，如活化T細胞的核因子、肌肉素、血清反應因子等，已被證明是調節BNP轉錄的轉錄效應因子[33]。

雖然應力受體激活細胞內激酶，機械應力則刺激血管緊張素II（Ang II）和內皮素-1（ET-1）複合體的形成，這些複合體通過p38 MAPK和細胞外信號調節激酶（ERK）信號傳導途徑激活BNP基因[45,46]。Ang II是通過血管緊張素酶作用於血管緊張素I（Ang I）產生的八肽物質，是腎素-血管緊張素系統的主要反應因子[47]。動物研究表明，注射Ang II 6小時後，大鼠左心室中BNP mRNA水平增加到對照組的4.5倍，兩週後增加到1.8倍。當給予Ang II 1型受體（AT1R）拮抗劑時，大鼠左心室中BNP mRNA水平顯著降低，這可能與醛固酮的降低有關。這表明Ang II通過與AT1R結合誘導BNP的產生[47]。Ang II還被證明能夠在心肌纖維化期間通過誘導ET-1基因表達促進BNP的合成[48]。ET是目前最強效的長效血管收縮劑。它由內皮細胞和心肌細胞產生，有三種異構肽，其中ET-1通過與ET-A受體結合進行非常有效的血管收縮和平滑肌收縮[49]。ET-1也是心血管疾病的主要原因之一，已有報告顯示它能夠通過p38 MAPK的磷酸化激活NF-κB轉錄因子，以及激活調節BNP表達的GATA-4轉錄因子[46]。

也有報告指出一些其他因素可調節BNP表達，但可能不是主導因素。在原發性醛固酮增多症患者中，利鈉肽經常增加。醛固酮已被廣泛證實能夠激活NF-κB，而血管緊張素II（Ang II）被報導可刺激醛固酮的合成，這也可以被BNP抑制[50,51,52]。Ang II和醛固酮在病理條件下經常合作誘導心肌纖維化、心肌細胞肥大和心臟重塑[53]。甲狀腺激素及其受體水平在心力衰竭和心肌梗塞動物模型的患者中降低，這表明BNP介導甲狀腺素在心力衰竭和心肌梗塞中的病理生理機制。甲狀腺激素可能觸發心肌細胞的肥大，而BNP基因作為甲狀腺激素作用的靶點，在甲狀腺激素作用下增加，包括BNP啟動子活性、BNP mRNA和BNP蛋白表達水平[54,55]。在心臟異體移植排斥反應中，活化的T淋巴細胞產生炎症因子如腫瘤壞死因子、IL-1和IL-6，這些也選擇性地上調BNP分泌[56]。

導致心肌肥大、缺血和缺氧損傷的各種刺激因素，如生長因子、腎上腺素能受體激動劑（儿茶酚胺）、甲狀腺激素、Ca2+等，可能通過多種信號傳導途徑作用於BNP啟動子元件，影響其啟動子的活性。這些信號傳導途徑的激活和傳遞不同，但可能相互協作[56]。

4. BNP和NT-proBNP作為心力衰竭診斷的臨床生物標誌物

心力衰竭是一種多因素系統性疾病，影響大約1至2%的成年人口。目前，心力衰竭的病例可根據射血分數（EF）分為心力衰竭降低射血分數（HFrEF）和“心力衰竭正常或保持射血分數”（HFnEF或HFpEF）[57,58]。根據美國心臟學院基金會/美國心臟協會（ACCF/AHA）和歐洲心臟學會（ESC）的指南，BNP和NT-proBNP被認為是診斷心力衰竭和心臟功能障礙最有價值和可靠的生物標誌物。它們還負責確定疾病的嚴重程度，指導相關治療策略，並評估心臟疾病的預後[59,60,61,62,63,64]。

ESC在2016年關於急性和慢性心力衰竭的診斷與治療指南建議，所有懷疑急性心力衰竭的患者應檢測其血漿利鈉肽水平（BNP和NT-proBNP），以幫助確定急性心力衰竭。非急性情況下BNP的正常上限為35 pg/mL，NT-proBNP為125 pg/mL，而在急性情況下，BNP的臨界值為100 pg/mL，NT-proBNP為300 pg/mL [59]。BNP水平可以幫助臨床醫生區分呼吸困難是由心力衰竭還是其他原因引起。如果BNP < 100 pg/mL，則認為心力衰竭不太可能，將追求呼吸困難的其他原因。如果BNP在100至500 pg/mL之間，應使用臨床判斷來診斷心力衰竭。如果BNP > 500 pg/mL，則認為心力衰竭或心臟功能障礙可能存在，建議迅速治療心力衰竭[65]。根據國際合作的NT-proBNP（ICON）研究，年齡依賴的NT-proBNP臨界值對診斷心力衰竭可能更有用。一般年齡無關的臨界值300 pg/mL可以排除急性心力衰竭。然而，對於50歲以下的患者，如果NT-proBNP水平 > 450 pg/mL，50至75歲之間的患者，NT-proBNP水平 > 900 pg/mL，以及75歲以上的患者，NT-proBNP水平 > 1800 pg/mL，則應診斷為心力衰竭[66]。

心力衰竭和心臟功能障礙——由各種原因引起，如缺血性心臟病、不同類型的心律失常和心肌病——可以導致BNP和NT-proBNP增加[29,65,67,68,69,70,71,72,73]。

急性缺血性心臟病與BNP水平升高有關，這可能反映左心室功能障礙的嚴重程度，研究建議使用利鈉肽水平指導對缺血性心臟病進行更積極的治療，以減少心室壁應力[29]。在穩定冠狀動脈心臟病患者中，BNP和NT-proBNP是不良心血管事件的強預測因子[67]。在急性心肌梗塞患者中，BNP和NT-proBNP與心肌損傷標誌物心肌肌鈣蛋白T（cTnT）、肌紅蛋白和肌酸激酶MB（CK-MB）一起進行了評估。NT-proBNP平均保持升高12周，可能是比BNP更好的診斷生物標誌物[32,70]。BNP和NT-proBNP是心肌梗塞大小的高靈敏度和特異性指標，它們還是預測急性冠狀動脈綜合徵患者中缺血性心臟病的預後和嚴重程度的有價值標誌物[68,69]。

除了缺血性心臟病，BNP和NT-proBNP也與心律失常和心肌病有關。在心房顫動患者中發現BNP和NT-proBNP增加[65]。動物實驗表明，在短暫致死性心室心律失常後10分鐘，BNP mRNA及其蛋白質就會增加[74]。BNP和NT-proBNP與擴張型心肌病和肥厚型心肌病患者的左心室舒張末期內徑（LVEDD）和左心室容積直接相關，與左心室射血分數（LVEF）成反比[71,72,73]。BNP水平在多發性心肌病中顯著升高，早期BNP/cTnT和BNP/CK-MB比率有助於比單獨BNP更準確地區分多發性心肌病與急性心肌梗塞（AMI）[75]。這表明，結合其他生物標誌物對BNP的檢測可用於某些心臟疾病的鑑別診斷。

BNP和NT-proBNP不僅在心力衰竭診斷中具有重要意義，還有助於評估心力衰竭的嚴重程度和預後。BNP和NT-proBNP是根據多普勒心超確定的心力衰竭保持射血分數（HFpEF）最強的獨立預測因子[76]。根據紐約心臟協會（NYHA）分類系統設計的試驗中，觀察到被認為屬於NYHA I-IV級的患者血漿BNP濃度逐漸增加，表明血漿BNP濃度隨著心力衰竭嚴重程度的增加而增加[77]。血漿BNP和NT-proBNP水平在心血管疾病患者中具有預後價值，BNP和NT-proBNP水平的降低預示著臨床症狀的改善。死亡風險與評估的BNP或NT-proBNP呈正相關[64]。對521名AMI患者的研究發現，BNP和NT-proBNP預測了猝死風險，即使在校正包括EF在內的臨床變量後，仍是最強的預測因子[78]。血漿BNP和NT-proBNP在臨床上也用於指導心力衰竭和心臟功能障礙患者的管理，同時也作為預後指標，有助於臨床醫生調整治療策略，確定治療效果，以改善患者的生存率[40,79]。

重組人腦利鈉肽（rhBNP）是一種合成的內源性激素，具有與BNP相同的氨基酸序列。它可以直接擴張血管，有效減少心臟前負荷和後負荷。2001年，FDA批准了Nesiritide用於急性失代償性心力衰竭的治療，它是一種成功的rhBNP，具有與內源性BNP類似的多種生物功能，包括促進利鈉作用、利尿作用、抑制RAAS、增加心輸出量、降低肺毛細血管楔壓以及改善心臟舒縮功能[80,81,82,83]。到目前為止，rhBNP已被廣泛用於治療各種原因引起的心力衰竭。

5. BNP和NT-proBNP作為法醫學評估心臟功能的屍後生物標誌物

不同於臨床醫生，法醫病理學家只關注BNP和NT-proBNP的診斷價值。在屍檢中診斷心力衰竭或評估心臟功能障礙主要基於形態學和病理學發現。這包括多個器官的靜脈充血，如肺和肝，或全身低輸出狀態下的缺血性動脈和毛細血管[84]。由於早期急性缺血性心臟病和致命性心律失常導致的急性心臟功能障礙發病率高，且缺乏典型的病理變化，這在法醫科學和病理學領域成為一個難題[7,85,86]。由急性心臟疾病，如急性心肌缺血性損傷引起的心肌結構的可見形態變化非常有限[87]。在法醫學中，極需對心力衰竭或心臟功能障礙的診斷提供客觀證據。與形態指標相比，功能指標或生物標誌物，如BNP和NT-proBNP，可以反映死亡時的心臟功能和病理生理過程，可能更好地闡明法醫學中的死亡機制[88]。功能性生物標誌物BNP和NT-proBNP在屍後生化中扮演了相當重要的角色，可以幫助解決許多常見自然死亡的法醫問題[88,89,90,91]。

心包液本質上是血漿的超濾液，是存在於心包腔內的淡黃色、清澈、透明液體，用以潤滑和防止粘連。在生理狀態下，正常的心包液體積為20-30毫升[92,93,94]。與血液和其他體液容易受到屍後變化（如自溶和腐敗）的影響不同，心包液存在於封閉的漿膜腔中，不易受到污染和屍後變化的影響[92,93]。在法醫屍檢過程中容易獲得，不僅是臨床重要的樣本，也在法醫鑑定中具有廣泛的應用前景。目前，它被用作屍後生化檢測中血清的替代物[95,96]。法醫研究還報導了心包液中的離子和蛋白質成分可用於法醫鑑定突發性心臟死亡、機械性窒息、低溫症、高溫症和死亡推斷[8,10,88,93,97,98,99,100]。幾項研究還報告了心包液中BNP和NT-proBNP的屍後生化調查，這些與不同的死亡原因相關[7,8,9,10]。

由於在許多急性疾病或創傷性死亡中可能發生急性或亞急性心力衰竭，因此客觀評估終末期心臟功能狀態對法醫診斷具有重要意義[101]。不同於其他心臟生物標誌物，如cTnT和cTnI存在於生理狀態下的心肌細胞中，BNP在生理條件下並不儲存於正常心肌組織中。然而，在病理條件下，BNP mRNA的轉錄和其蛋白質的合成可以在非常短的時間內敏感而迅速地發生和加速[30,32]。這意味著BNP和NT-proBNP在死後不會出現大幅波動，可能是更客觀的心臟功能生物標誌物[102,103]。在過去的十年裡，少數研究小組進行了屍後BNP和NT-proBNP的研究。調查BNP和NT-proBNP在體液和心肌組織中的濃度，以及心肌中BNP mRNA的表達，可能客觀反映死者死前終末期心臟功能狀態，主要描述如下[88]。

屍後個體的研究表明，死於急性缺血性心臟病（有或無心肌壞死）、慢性充血性心臟病、心律失常性右心室心肌病等疾病的死者的血液和心包液中BNP和NT-proBNP濃度顯著升高。患有這些疾病的個體的心肌中BNP mRNA也升高[7,8,90]。心包液中BNP濃度與死因密切相關，與非心臟性死亡相比，急性缺血性心臟病和復發性心肌梗塞等突發性心臟死亡案例中BNP水平顯著增加。這進一步證實BNP對評估缺血性心臟病死者的心臟功能很重要[9]。死後心包液中高水平的BNP和BNP/ANP比率是死前心臟功能障礙持續時間的標誌，可能是由於亞急性和慢性心室擴張所致[9]。患有心律失常性右心室心肌病的患者心包液中BNP水平升高，但有趣的是，右心室心肌中BNP mRNA水平高於左心室心肌[7,8]。在由急性心室心律失常引起的急性心臟功能障礙中，BNP蛋白和mRNA也顯示增加，表明BNP在沒有任何形態變化的急性心臟功能障礙診斷中可能具有重要的法醫意義[74]。在一些難以與突發性心臟死亡區分的法醫死亡案例中，如心包膜下出血和肺栓塞，心包液中BNP水平和心肌組織中BNP mRNA水平都沒有增加，表明BNP和BNP mRNA也可用於區分不同的診斷[8]。

此外，在法醫學中，由於NT-proBNP穩定性更高，半衰期長達90-120分鐘，如前所述，且不易受溫度、儲存時間和儲存條件的影響，NT-proBNP被期望成為比BNP更可靠的屍後生物標誌物[104,105,106,107,108]。幾項研究專注於不同體液中屍後NT-proBNP的調查。死後24小時內股血血清中的NT-proBNP濃度與生前血清中的NT-proBNP濃度無差異，且在48小時內保持穩定。發現死前進行心肺復蘇對NT-proBNP結果無影響[19]。屍後時間高達24小時的屍體中採集的血液和心包液中進行的NT-proBNP連續檢測顯示，NT-proBNP在24天內保持穩定，特別是心包液中的NT-proBNP濃度在-20°C儲存24天後降低不超過16%[18]。不同樣本，如血清和心包液中的NT-proBNP濃度呈現良好相關性，且在心包液中的NT-proBNP明顯高於其他體液，如血清，這表明在屍後生化檢測中調查心包液中的NT-proBNP可能是更好的選擇[18,19]。

雖然心包液中的BNP和NT-proBNP不易受到污染，但嚴重溶血和其他屍後變化（如屍體的保存條件等因素引起）可能影響BNP和NT-proBNP的屍後生物檢測。這應在屍後生化檢測中加以考慮，並且可以通過體液的物理過濾來減少溶血的影響[109,110]。此外，血液或心包液中BNP和NT-proBNP的進一步研究仍需要可靠的屍後臨界值[89]。目前，由於設備和人員的限制，並非世界各地的每個法醫實驗室都進行屍後生化檢測，這是缺乏基於大量數據的BNP和NT-proBNP屍後臨界值的原因之一。值得一提的是，所有利尿劑，包括腎素血管緊張素醛固酮和醛固酮受體的阻斷劑，都可能由於血漿容量和鈉的改善而降低BNP水平，在使用BNP或NT-proBNP進行法醫鑑定時，這也應予以考慮。

6. 臨床和法醫學中的研究和應用前景

BNP和NT-proBNP目前用於臨床和法醫實踐中評估心臟功能狀態。近年來，許多研究已經證實，一些非編碼RNA在心臟功能障礙患者中高度表達，並參與調節BNP表達[111,112,113,114,115]。因此，探索BNP相關特定非編碼RNA（如微RNA）在臨床和法醫樣本中的表達模式，以及探究它們如何調節BNP表達和在法醫樣本降解或損壞中的非編碼RNA表達，可能是這一領域未來的研究方向。

此外，外泌體——在血清和尿液等不同體液中的小囊泡——已被證明包含不同分子，如蛋白質、DNA和RNA（編碼RNA和非編碼RNA）。由於其特定的診斷價值和未知的潛在機制，外泌體被期望成為心血管疾病標誌物領域的一個新熱點問題[116,117,118]。已證實，外泌體RNA和蛋白質與心臟功能障礙有關，並介導心臟保護能力[119,120,121,122]。先前的研究發現，從心壓過載的小鼠中分離出含有AT1Rs的外泌體。然而，很少有研究報告體液中的外泌體與BNP是否相關。因此，將外泌體作為臨床和法醫學診斷心臟功能障礙的生物標誌物也可能是未來的研究前景[122]。正如前面所述，心包液是法醫病理學的理想生物樣本。臨床研究已證明，人類心包液中的外泌體是心臟疾病的診斷和治療分子。心包液中的外泌體是否可以用於法醫學診斷心臟疾病，仍需進一步研究[123,124,125,126]。

屍後生化檢測和分子生物學方法，如mRNA分析——應作為法醫學中的常規實驗室檢測——可能對調查死亡的病理生理學、過程和死因非常有用。它們還可以通過提供可見證據來支持包括心臟功能在內的病理診斷，提供有力支持[88]。因此，利用屍後化學和BNP及NT-proBNP的分子生物學結合檢測，以評估死亡過程中涉及的病理生理功能變化，可能更好地支持並加強法醫學中的形態學證據[90,127,128,129]。

7. 結論

超過30年的研究勾勒出BNP在心血管疾病中的重要貢獻，特別是在心力衰竭和心臟功能障礙方面。基於它們在診斷、治療和預後中的重要作用，BNP和NT-proBNP已被用作臨床和法醫學中的重要生物標誌物。隨著分子生物技術的快速發展，對BNP和NT-proBNP的準確調查將在未來更好地用於評估臨床和法醫心臟功能狀態。

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