本申請是申請日為2013年9月12日和名稱為“標(biāo)志物用于識別心臟毒性劑的用途”的201380058864.2號發(fā)明專利申請的分案申請。相關(guān)申請的交叉參考本申請要求2012年9月12日提交的61/700327號；2012年9月27日提交的61/706611號；2012年11月15日提交的61/727104號；2012年11月16日提交的61/727115號；和2012年11月30日提交的61/732105號美國臨時申請的優(yōu)先權(quán)。上述申請的全文通過引用在此引入。發(fā)明背景心血管疾病(也稱為心臟疾病)是一類涉及心臟、血管(動脈、毛細(xì)血管和靜脈)或這兩者的疾病。心血管疾病可以指影響心血管系統(tǒng)的任何疾病，主要是心臟疾病、腦和腎的血管疾病及外周動脈疾病。心血管疾病的原因是多種多樣的，但動脈粥樣硬化和/或高血壓是最常見的。此外，隨著年齡變老，出現(xiàn)了許多生理和形態(tài)學(xué)的變化，其改變心血管功能并隨后導(dǎo)致心血管疾病的風(fēng)險增加，甚至在健康無癥狀的個體中。心肌病是指心肌的疾病。這些疾病有很多的原因、征兆和癥狀及治療。在心肌病中，心肌變大、變厚或變硬。在少數(shù)情況下，心臟中的肌肉組織被疤痕組織所代替。當(dāng)心肌病惡化時，心臟變得更衰弱。它泵送血液通過身體并保持正常的電節(jié)律的能力降低。這可能會導(dǎo)致心力衰竭或不規(guī)則的心跳(稱為心律失常)。隨之，心力衰竭可以引起肺、踝、腳、腿或腹部中的液體積聚。心臟的衰弱也可能引起其他并發(fā)癥，如心臟瓣膜問題。心肌病的主要類型是擴(kuò)張型心肌病、肥厚性心肌病、限制型心肌病和致心律失常性右心室發(fā)育不良。其他類型的心肌病有時被稱為“未分類型心肌病”。心肌病可以是后天的或遺傳的，其中肥厚型心肌病和致心律失常性右心室發(fā)育不良基本上是遺傳性疾病。在某些受試者中，遺傳的心肌病不明顯直到出現(xiàn)災(zāi)難性的事件(例如，心臟病發(fā)作)。然而，在缺乏遺傳性心肌病的一些已知家族病史的情況下，普通人群篩查是不實際的，因為心肌病的診斷和監(jiān)測使用醫(yī)療和家族史、身體檢查、血液檢查及成像和功能分析(包括胸部x光檢查、ekg(心電圖)、動態(tài)心電圖和事件監(jiān)控器、超聲心動圖、壓力測試、心導(dǎo)管插入術(shù)、冠狀動脈造影、心肌活檢及遺傳學(xué)檢驗的組合進(jìn)行。心肌病可通過其它疾病或病癥或者通過各種毒素或藥物誘發(fā)。例如，冠狀動脈心臟病、心臟病發(fā)作、高血壓、糖尿病、甲狀腺疾病、病毒性肝炎和hiv可以導(dǎo)致擴(kuò)張型心肌?。桓腥?，特別是使心肌發(fā)炎的病毒感染可導(dǎo)致心肌??；酒精，特別是與不良的飲食習(xí)慣相結(jié)合；妊娠的最后一個月或出生5個月內(nèi)的并發(fā)癥；某些毒素，如鈷；和某些藥物(如可卡因和安非他明)和化療藥物(例如，蒽環(huán)類藥物如阿霉素和柔紅霉素)和用于治療糖尿病的藥物，其可能會導(dǎo)致突然性心肌病事件。限制型心肌病可由如血色素沉著癥、結(jié)節(jié)病、淀粉樣變性和結(jié)締組織疾病的病癥以及某些癌癥治療如放療和化療導(dǎo)致。心臟中毒是藥劑的發(fā)展和批準(zhǔn)中的重要障礙。目前制藥業(yè)進(jìn)入臨床開發(fā)的潛在化合物發(fā)生90％的損耗，其中的30％是由于差的臨床安全性(kola等(2004)natrevdrugdiscovery:3711-715)。在美國，致命的藥物不良反應(yīng)(adr)是導(dǎo)致死亡的第4至第6位的主要原因。在美國，直接歸因于adr的費用可能導(dǎo)致每年直接醫(yī)療費用增加15.6至40億美元(lazarouj等(1998)jama；279(15):1200-1225)。藥物發(fā)現(xiàn)和開發(fā)的成本已上升到約10億美元，部分是由于花費在化合物和后期臨床開發(fā)的nme的損耗增加(adamscp,brantnervv(2010)spendingonnewdrugdevelopment.healthecon.19:130–141)。缺乏可以在藥物研發(fā)早期幫助預(yù)測毒性的可靠工具部分地導(dǎo)致成本增加和投資回報率較低。此外，藥品安全性問題是在制藥行業(yè)中增長的訴訟和賠款的主要原因。在2009年1月和2011年5月之間，業(yè)界已經(jīng)對有關(guān)藥品安全性問題的訴訟案件花費了超過80億美元。為了強(qiáng)化在早期臨床試驗和藥物開發(fā)中化合物的“早期終止策略(killearlypolicy)”，fda當(dāng)前鼓勵制藥行業(yè)和社區(qū)采取高創(chuàng)新性的策略。fda白皮書創(chuàng)新或停滯：對新醫(yī)療項目的關(guān)鍵路徑面臨的挑戰(zhàn)與機(jī)遇(innovationorstagnation:challengesandopportunityonthecriticalpathtonewmedicalprojects)指出，“迫切需要包含功能強(qiáng)大的新的科學(xué)和技術(shù)方法如基于動物或計算機(jī)的預(yù)測模型、用于安全性和有效性的生物標(biāo)志物以及新的臨床評價技術(shù)的新產(chǎn)品開發(fā)工具包以提高沿著從實驗室概念至商業(yè)產(chǎn)品的關(guān)鍵路徑的預(yù)測性和效率”(fda，2005)。fda聲明中明確強(qiáng)調(diào)了缺乏能夠幫助藥物開發(fā)中的有效決策的創(chuàng)新技術(shù)的問題。心臟毒性指由包括治療性分子的藥劑誘導(dǎo)的對心臟功能產(chǎn)生的廣泛的不良影響。心臟毒性可能在臨床前研究的早期出現(xiàn)或在臨床環(huán)境中的后期變得明顯。這是藥物召回的主要原因，占1994年以來所有召回藥物的45％以上，這導(dǎo)致對于藥物開發(fā)的重大的財政負(fù)擔(dān)。心臟毒性導(dǎo)致包括延長的qt間期、心律失常、心肌缺血、高血壓和血栓栓塞性并發(fā)癥以及心肌功能障礙的狀況。目前由fda使用的心臟安全性生物標(biāo)志物包括qtc間期延長-神經(jīng)電生理性心律失常、循環(huán)肌鈣蛋白c、心率、血壓、脂質(zhì)、肌鈣蛋白、c-反應(yīng)蛋白(crp)、腦或b型利鈉肽(bnp)、離體血小板聚集和成像生物標(biāo)志物(心臟磁共振成像)。qtc間期延長是非常穩(wěn)定但復(fù)雜的標(biāo)志物。然而，僅僅基于qtc很難在早期開發(fā)中做出停止或維持藥物的決定。此外，qtc是主觀性的并取決于可導(dǎo)致心動過速(tachyarrythmias)的基礎(chǔ)病理。因此，迫切需要用于分析藥物和候選藥物的心臟安全性的新的生物標(biāo)志物，在受試者中存在或易發(fā)包括心肌病和心力衰竭的心血管疾病的生物標(biāo)志物。發(fā)明概述本發(fā)明至少部分地基于申請人的以下發(fā)現(xiàn)：在患心血管疾病(特別是心肌病，包括與心臟毒性劑暴露相關(guān)的心肌病)的受試者中，多種標(biāo)志物被差異調(diào)節(jié)。本發(fā)明還至少部分地基于發(fā)現(xiàn)對檢測心血管疾病(特別是心肌病，包括與心臟毒性劑暴露相關(guān)的心肌病)具有最強(qiáng)的預(yù)測能力的特定標(biāo)志物組合。本發(fā)明提供了使用本文中提供的標(biāo)志物或標(biāo)志物的組合在哺乳動物中診斷心血管疾病、監(jiān)測心血管疾病進(jìn)展或心血管疾病的治療、預(yù)后心血管疾病、治療心血管疾病、緩解心血管疾病的癥狀、抑制心血管疾病的進(jìn)展和預(yù)防心血管疾病的方法。本發(fā)明還提供了使用本文中提供的標(biāo)志物或標(biāo)志物的組合篩選調(diào)節(jié)心血管疾病的藥劑的方法。本發(fā)明還提供了用于篩選或鑒定心臟毒性劑，例如導(dǎo)致或引起心血管疾病的藥劑的方法。在本發(fā)明的優(yōu)選實施方式中，心血管疾病是心力衰竭或心肌病，包括與心臟毒性劑暴露相關(guān)的心肌病。本發(fā)明提供了用于診斷受試者中的心血管疾病的方法，包括：(1)檢測來自受試者的生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子(emmprin)、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；和(2)將來自受試者的生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照樣品中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中所述生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物相對于對照樣品的改變的水平是該受試者患有心血管疾病的指示。本發(fā)明用于識別具有患心血管疾病的提高的風(fēng)險的受試者，其中該方法包括：(1)檢測來自受試者的生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；和(2)將來自受試者的生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的水平相比較，其中所述生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物相對于對照樣品的改變的水平是該受試者具有患心肌病的提高的風(fēng)險的指示。本發(fā)明還用于監(jiān)測受試者中的心血管疾病，其中該方法包括：(1)檢測在第一時間從患有心血管疾病的受試者獲得的第一生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；(2)檢測在第二時間從受試者獲得的第二生物樣品中所述一種或多種cvd相關(guān)生物標(biāo)志物的水平，其中所述第二時間晚于所述第一時間；和(3)將所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與所述第一樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中與所述第一樣品相比，該第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的改變是受試者中cvd狀態(tài)改變的指示。本發(fā)明進(jìn)一步用于在受試者中監(jiān)測心血管疾病治療，其中該方法包括(1)檢測在第一時間從患心血管疾病的受試者獲得的第一生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，其中該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；(2)檢測在第二時間從受試者獲得的第二生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平，其中所述第二時間晚于所述第一時間；和(3)將所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與所述第一樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中與第一樣品相比，所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物水平的正?；窃撝委煼桨赣行е委熓茉囌咧械男难芗膊〉闹甘?。在某些實施方式中，所述心血管疾病包括心肌病。在某些實施方式中，心肌病是選自于擴(kuò)張型心肌病、肥厚性心肌病、限制型心肌病和致心律失常性右心室發(fā)育不良的至少一種病癥。在某些實施方式中，心肌病包括選自于延長的qt間期、心律失常、心肌缺血、高血壓和血栓栓塞性并發(fā)癥、心肌功能障礙、心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能障礙、心房撲動和顫動、心臟瓣膜損傷及心力衰竭中的至少一種病癥。在某些實施方式中，心肌病是遺傳性心肌病。在某些實施方式中，所述心肌病是后天性心肌病。在某些實施方式中，后天性心肌病是受試者中一種或多種另外的疾病或病癥的合并癥。在某些實施方式中，后天性心肌病不是受試者中一種或多種另外的疾病或病癥的合并癥。在某些實施方式中，受試者中一種或多種另外的疾病或病癥選自于冠狀動脈心臟病、心臟病發(fā)作、高血壓、糖尿病、甲狀腺疾病、病毒性肝炎、hivl、使心肌發(fā)炎的病毒感染、血色素沉著癥、結(jié)節(jié)病、淀粉樣變性和結(jié)締組織病癥。在某些實施方式中，后天性心肌病是受試者暴露于心臟毒素的結(jié)果。在某些實施方式中，所述心臟毒素是環(huán)境心臟毒素。在某些實施方式中，所述心臟毒素是心臟毒性藥物。在某些實施方式中，所述心臟毒性藥物選自于過量酒精、安非他明、抗癌藥物、化療藥物、糖尿病藥物、神經(jīng)藥物、抗炎藥、二膦酸鹽和tnf拮抗劑。在某些實施方式中，所述抗癌藥物選自于順鉑、阿霉素、柔紅霉素、蒽環(huán)類藥物、5-氟尿嘧啶、曲妥珠單抗或吉西他濱。在某些實施方式中，糖尿病藥物選自于羅格列酮、吡格列酮、曲格列酮和卡麥角林。在某些實施方式中，所述藥物是心臟毒性藥物培高利特或舒馬曲坦。在某些實施方式中，所述心血管疾病包括心力衰竭。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。在某些實施方式中，所述脂質(zhì)包括pc-li-183-d18:2-22:6。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。在某些實施方式中，與正常的受試者相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平降低是該受試者患有心血管疾病或具有發(fā)生心血管疾病的提高的風(fēng)險的指示。在某些實施方式中，與正常的受試者相比，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平的增加是該受試者患有心血管疾病或具有發(fā)生心血管疾病的增加的風(fēng)險的指示。在某些實施方式中，與正常的受試者相比，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平的降低是該受試者患有心血管疾病或具有發(fā)生心血管疾病的增加的風(fēng)險的指示。在某些實施方式中，與正常的受試者相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平的提高是該受試者未患心血管疾病或沒有發(fā)生心血管疾病的增加的風(fēng)險的指示。在某些實施方式中，與正常的受試者相比，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平的降低是該受試者未患心血管疾病或沒有發(fā)生心血管疾病的增加的風(fēng)險的指示。在某些實施方式中，與正常的受試者相比，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平的提高是該受試者未患心血管疾病或沒有發(fā)生心血管疾病的增加的風(fēng)險的指示。本發(fā)明提供了用于檢測一組心血管疾病(cvd)相關(guān)生物標(biāo)志物的方法，其中該方法包括：(1)分析來自受試者的生物樣品中一組cvd相關(guān)生物標(biāo)志物的兩種或更多種cvd相關(guān)生物標(biāo)志物的水平，其中該組cvd相關(guān)生物標(biāo)志物包括ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6；(2)檢測所述生物樣品中所述兩種或更多種cvd相關(guān)生物標(biāo)志物中的每一種，從而檢測該組cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的方法包括分離生物樣品的組分。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的方法包括標(biāo)記生物樣品的組分。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的方法包括處理所述生物樣品。在某些實施方式中，檢測或測定生物樣品中兩種或更多種cvd相關(guān)標(biāo)志物的水平的方法包括將待檢測的cvd相關(guān)標(biāo)志物與cvd相關(guān)標(biāo)志物結(jié)合劑相接觸。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平的方法包括形成待檢測的cvd相關(guān)標(biāo)志物與cvd相關(guān)標(biāo)志物結(jié)合劑之間的復(fù)合物。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平的方法包括將一種或多種cvd相關(guān)標(biāo)志物中的每一種與cvd相關(guān)標(biāo)志物結(jié)合劑相接觸。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平的方法包括形成一種或多種cvd相關(guān)標(biāo)志物中的每一種與cvd相關(guān)標(biāo)志物結(jié)合劑之間的復(fù)合物。在某些實施方式中，檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平的方法包括將待檢測的cvd相關(guān)標(biāo)志物連接到固體表面上。本發(fā)明提供了在檢測方法中使用的試劑組，該試劑組包含至少兩種檢測試劑，其中各檢測試劑對于一組心血管疾病(cvd)相關(guān)生物標(biāo)志物中的至少一種cvd相關(guān)標(biāo)志物的檢測是特異性的，其中該組cvd相關(guān)生物標(biāo)志物包括選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的兩種或更多種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6中的至少一種脂質(zhì)生物標(biāo)志物。在某些實施方式中，所述脂質(zhì)包括pc-li-183-d18:2-22:6。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。在某些實施方式中，所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。本發(fā)明提供了本發(fā)明的所述試劑組在本發(fā)明的任何方法中的用途。本發(fā)明提供了用于診斷、監(jiān)測或表征受試者中的心血管疾病的試劑盒，其包含：至少一種試劑，其對于選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種cvd相關(guān)標(biāo)志物的水平的檢測是特異性的。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。在某些實施方式中，所述脂質(zhì)包括pc-li-183-d18:2-22:6。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包含細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包含nucb1和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。本發(fā)明提供了識別用于治療心血管疾病的化合物的方法，其包括：(1)獲得受試細(xì)胞；(2)將受試細(xì)胞與受試化合物相接觸；(3)測定受試細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平；(4)將受試細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與未接觸受試化合物的對照細(xì)胞相比較；和(5)選擇調(diào)節(jié)受試細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的受試化合物，從而識別用于治療受試者中的cvd的化合物。本發(fā)明提供了識別引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的方法，其包括：(i)將第一細(xì)胞與受試藥劑相接觸；(ii)檢測與受試藥劑相接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物的水平；和(iii)將第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第二細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中該第二細(xì)胞是未接觸受試藥劑的對照細(xì)胞；其中，與所述第二細(xì)胞相比，該第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)是所述受試藥劑是引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的指示。本發(fā)明提供了識別用于預(yù)防、減輕或治療藥物誘導(dǎo)的心臟毒性的救援劑的方法，其包括：(i)將第一細(xì)胞與心臟毒性劑相接觸；(ii)將第二細(xì)胞與心臟毒性劑和候選救援劑相接觸；(iii)檢測與心臟毒性劑相接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物的水平；(iv)檢測與心臟毒性劑和候選救援劑相接觸的第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平；和(v)將第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第一細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中，與所述第一細(xì)胞相比，該第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)是候選救援劑是預(yù)防、減輕或治療藥物誘導(dǎo)的心臟毒性的救援劑的指示。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。在某些實施方式中，所述脂質(zhì)包括pc-li-183-d18:2-22:6。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包含細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。在某些實施方式中，所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。在某些實施方式中，與未處理的細(xì)胞相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平的降低是所述受試化合物用于治療心血管疾病無效的指示。在某些實施方式中，與未處理的細(xì)胞相比，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平的提高是所述受試化合物用于治療心血管疾病無效的指示。在某些實施方式中，與未處理的細(xì)胞相比，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平的降低是所述受試化合物用于治療心血管疾病無效的指示。在某些實施方式中，與未處理的細(xì)胞相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平的提高是所述受試化合物用于治療心血管疾病有效的指示。在某些實施方式中，與未處理的細(xì)胞相比，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平的降低是所述受試化合物用于治療心血管疾病有效的指示。在某些實施方式中，與未處理的細(xì)胞相比，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平的提高是所述受試化合物用于治療心血管疾病有效的指示。在本發(fā)明的某些篩選方法中，所述細(xì)胞是心肌細(xì)胞。在某些實施方式中，所述細(xì)胞是心肌細(xì)胞或糖尿病性心肌細(xì)胞。在本發(fā)明的某些篩選方法中，所述接觸在體外進(jìn)行。在本發(fā)明的某些篩選方法中，所述接觸是在體內(nèi)進(jìn)行。在某些實施方式中，所述至少一種cvd相關(guān)生物標(biāo)志物包括至少一種脂質(zhì)生物標(biāo)志物和至少一種蛋白質(zhì)生物標(biāo)志物。在某些實施方式中，所述至少一種cvd相關(guān)生物標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物和至少一種激酶標(biāo)志物。在某些實施方式中，獲得樣品包括從受試者采取血液和將血細(xì)胞與血清分離。在某些實施方式中，檢測標(biāo)志物的水平包括檢測所述標(biāo)志物的濃度。在某些實施方式中，檢測標(biāo)志物的水平包括檢測與對照樣品相比的相對濃度。在某些實施方式中，檢測標(biāo)志物的水平包括檢測所述標(biāo)志物的表達(dá)水平。在某些實施方式中，檢測標(biāo)志物的水平包括檢測所述標(biāo)志物的活性水平。本發(fā)明提供了用于診斷心肌病的方法，其包括：(1)測定從受試者獲得的生物樣品中選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；和(2)將從受試者獲得的生物樣品中一種或多種生物標(biāo)志物的表達(dá)水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中在所述生物樣品中一種或多種生物標(biāo)志物的表達(dá)水平的調(diào)節(jié)是所述受試者患有心肌病的指示。在一個實施方式中，edil3或nucb1的表達(dá)水平的降低是所述受試者患有心肌病的指示。本發(fā)明提供了預(yù)測受試者是否易于發(fā)生心肌病的方法，該方法包括：(1)測定從受試者獲得的生物樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；和(2)將從受試者獲得的生物樣品中存在的一種或多種生物標(biāo)志物的表達(dá)水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中，從受試者獲得的生物樣品中一種或多種生物標(biāo)志物的表達(dá)水平相對于對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平的調(diào)節(jié)是該受試者易于發(fā)生心肌病的指示。在一個實施方式中，edil3或nucb1的表達(dá)水平的降低是受試者易于發(fā)生心肌病的指示。本發(fā)明提供了用于監(jiān)測受試者中心肌病的治療的方法，其包括：(1)測定在向受試者施用至少一部分治療方案之前從受試者獲得的第一樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(2)測定在向受試者施用至少一部分治療方案之后從受試者獲得的第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平；及(3)將所述第一樣品中一種或多種生物標(biāo)志物的表達(dá)水平與所述第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中與第一樣品中的一種或多種生物標(biāo)志物相比，第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的正常化的表達(dá)水平是該治療用于治療受試者的心肌病有效的指示。在一個實施方式中，與第一樣品相比，第二樣品中edil3或nucb1的表達(dá)水平的提高是該治療用于治療受試者的心肌病有效的指示。本發(fā)明提供了表征受試者中的心肌病狀態(tài)的方法，所述方法包括：(1)測定從受試者獲得生物樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；和(2)將從受試者獲得的生物樣品中存在的一種或多種生物標(biāo)志物的表達(dá)水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中，從受試者獲得的生物樣品中一種或多種生物標(biāo)志物的表達(dá)水平相對于對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平是受試者中心肌病狀態(tài)的指示。在一個實施方式中，與對照樣品中相應(yīng)的生物標(biāo)志物的表達(dá)水平相比，從受試者獲得的生物樣品中edil3或nucb1的表達(dá)水平的提高是受試者的心肌病狀態(tài)改善的指示。在一個實施方式中，與對照樣品中相應(yīng)的生物標(biāo)志物的表達(dá)水平相比，從受試者獲得的生物樣品中edil3或nucb1的表達(dá)水平的降低是受試者的心肌病狀態(tài)惡化的指示。本發(fā)明提供了識別用于治療心肌病的化合物的方法，其包括：(1)獲得受試細(xì)胞；(2)將受試細(xì)胞與受試化合物相接觸；(3)測定受試細(xì)胞中選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(4)將受試細(xì)胞中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平與未接觸受試化合物的對照細(xì)胞相比較；和(5)選擇調(diào)節(jié)受試細(xì)胞中一種或多種生物標(biāo)志物的表達(dá)水平的受試化合物，從而識別用于治療受試者中的心肌病的化合物。在一個實施方式中，提高edil3或nucb1的表達(dá)水平的受試化合物被識別為治療受試者的心肌病的化合物。在某些實施方式中，心肌病選自于擴(kuò)張型心肌病、肥厚性心肌病、限制型心肌病和致心律失常性右心室發(fā)育不良。在某些實施方式中，心肌病是遺傳性心肌病。在某些實施方式中，心肌病是后天性心肌病。在一個實施方式中，后天性心肌病是受試者暴露于心臟毒素的結(jié)果。在一個實施方式中，所述毒素是一種環(huán)境毒素。在一個實施方式中，所述毒素是心臟毒性的藥物。在一個實施方式中，所述心臟毒性藥物選自于過量酒精、可卡因、安非他明、化療藥物、阿霉素、柔紅霉素、抗癌藥物、糖尿病藥物、神經(jīng)藥物、抗炎藥、蒽環(huán)類藥物、5-氟尿嘧啶、順鉑、曲妥珠單抗、吉西他濱、羅格列酮、吡格列酮、曲格列酮、卡麥角林、培高利特、舒馬曲坦、二膦酸鹽和tnf拮抗劑。在某些實施方式中，后天性心肌病是受試者中另一種疾病或病癥的合并癥。在一個實施方式中，受試者中的另一種疾病或病癥選自于冠狀動脈心臟病、心臟病發(fā)作、高血壓、糖尿病、甲狀腺疾病、病毒性肝炎、hivl、使心肌發(fā)炎的病毒性感染、血色素沉著癥、結(jié)節(jié)病、淀粉樣變性和結(jié)締組織病癥。本發(fā)明還提供了在受試者中治療其中心肌病是合并癥的疾病或病癥的方法，其包括：(1)測定從患有該疾病或病癥的受試者獲得的第一樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(2)測定在一段時間后從該受試者獲得的第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平；及(3)比較所述第一樣品中一種或多種生物標(biāo)志物的表達(dá)水平與第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平，其中第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相對于第一樣品中一種或多種生物標(biāo)志物的調(diào)節(jié)是該疾病或病癥在受試者中確實導(dǎo)致心肌病合并癥的指示。在一個實施方式中，第二樣品中edil3或nucb1的表達(dá)水平相對于第一樣品中相應(yīng)的生物標(biāo)志物的表達(dá)水平的降低是疾病或病癥在受試者中確實導(dǎo)致心肌病合并癥的指示。在某些實施方式中，當(dāng)檢測到在第二樣品中相應(yīng)的一種或多種生物標(biāo)志物水平的調(diào)節(jié)時，改變受試者的治療。在某些實施方式中，改變治療以保護(hù)心臟、治療心肌病，和該方法可以允許在心肌病的征兆或癥狀出現(xiàn)之前檢測合并癥。在另一個方面，本發(fā)明提供了用潛在心臟毒性劑治療受試者的方法，其包括(1)測定在向受試者施用至少一部分治療方案之前從受試者獲得的第一樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(2)測定在向受試者施用至少一部分治療方案之后從受試者獲得的第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平；和(3)將所述第一樣品中一種或多種生物標(biāo)志物的表達(dá)水平與所述第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中與第一樣品中一種或多種生物標(biāo)志物相比，第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的非調(diào)節(jié)的表達(dá)水平是受試者中的治療可以繼續(xù)且該藥劑對于該受試者不是心臟毒性的指示。在一個實施方式中，與所述相應(yīng)的生物標(biāo)志物的表達(dá)水平相比，第二樣品中edil3或nucb1的表達(dá)的水平的降低是該藥劑是心臟毒性的指示。在某些實施方式中，當(dāng)檢測到一種或多種生物標(biāo)志物的水平的調(diào)節(jié)(amodulation)時，改變受試者的治療。在一個實施方式中，當(dāng)所述第二樣品中一種或多種生物標(biāo)志物的表達(dá)水平相比gf第一樣品中的一種或多種生物標(biāo)志物調(diào)節(jié)時，減小潛在心臟毒性劑的劑量。在一個實施方式中，受試者共施用心臟保護(hù)劑以減輕心臟毒性劑的效應(yīng)。在另一個方面，本發(fā)明提供了用潛在心臟毒性劑治療受試者的方法，其包括(1)測定在向受試者施用至少一部分治療方案之前從受試者獲得的第一樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(2)測定在向受試者施用至少一部分治療方案之后從受試者獲得的第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平；和(3)將所述第一樣品中一種或多種生物標(biāo)志物的表達(dá)水平與所述第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中與第一樣品中的一種或多種生物標(biāo)志物相比，第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的非調(diào)節(jié)的或較低的表達(dá)水平是受試者中的治療可以繼續(xù)和該藥劑對于該受試者不是心臟毒性的指示；和其中與第一樣品中的一種或多種生物標(biāo)志物相比，第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的較高表達(dá)水平是藥劑對于受試者是心臟毒性的和受試者中的治療應(yīng)停止的指示。在另一個方面，本發(fā)明提供了用潛在心臟毒性劑治療受試者的方法，其包括(1)測定在向受試者施用至少一部分治療方案之前從受試者獲得的第一樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；(2)測定在向受試者施用至少一部分治療方案之后從受試者獲得的第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平；和(3)將所述第一樣品中一種或多種生物標(biāo)志物的表達(dá)水平與所述第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比較，其中與第一樣品中的生物標(biāo)志物相比，第二樣品中非調(diào)節(jié)的或提高的edil3或nucb1的表達(dá)水平是受試者的治療可以繼續(xù)和該藥劑對于該受試者不是心臟毒性的指示；和其中與第一樣品中的生物標(biāo)志物相比，第二樣品中edil3或nucb1的降低的表達(dá)水平是該藥劑對該受試者是心臟毒性的和受試者的治療應(yīng)停止的指示。在另一個方面，本發(fā)明提供了用潛在心臟毒性劑治療受試者的方法，其包括(1)測定在向受試者施用至少一部分包括潛在心臟毒性劑的治療方案后從受試者獲得的樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；和(2)比較所述樣品中一種或多種生物標(biāo)志物的表達(dá)水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平，其中第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中的一種或多種生物標(biāo)志物的非調(diào)節(jié)是受試者的治療可以繼續(xù)和該藥劑對該受試者不是心臟毒性的指示；和/或其中在樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中的一種或多種生物標(biāo)志物的調(diào)節(jié)是該藥劑對于該受試者是心臟毒性的和受試者的治療應(yīng)停止的指示。在另一個方面，本發(fā)明提供了用潛在心臟毒性劑治療受試者的方法，其包括(1)測定在向受試者施用至少一部分包括潛在心臟毒性劑的治療方案后從受試者獲得的樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平；和(2)比較所述樣品中一種或多種生物標(biāo)志物的表達(dá)水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平，其中所述樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中的一種或多種生物標(biāo)志物的非調(diào)節(jié)或降低是受試者的治療可以繼續(xù)和該藥劑對該受試者不是心臟毒性的指示；和/或其中所述樣品中相應(yīng)的一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中一種或多種生物標(biāo)志物的提高是該藥劑對受試者是心臟毒性的和受試者的治療應(yīng)停止的指示。在一個實施方式中，相比于對照樣品中相應(yīng)的生物標(biāo)志物所述樣品中edil3或nucb1的非調(diào)節(jié)的或提高的表達(dá)水平指示受試者的治療可以繼續(xù)且該藥劑對于該受試者不是心臟毒性的；和/或其中所述樣品中edil3或nucb1的表達(dá)水平相比于對照樣品中相應(yīng)的生物標(biāo)志物的降低指示該藥劑對于該受試者是心臟毒性的和受試者的治療應(yīng)停止。在一個實施方式中，上述方法進(jìn)一步包括停止?jié)撛谛呐K毒性劑的治療。在一個實施方式中，上述方法進(jìn)一步包括停止治療，并建議、指示或施用替代治療。在一個實施方式中，上述方法還包括繼續(xù)潛在心臟毒性劑的治療。在某些實施方式中，當(dāng)相對于對照樣品，檢測到所述樣品中一種或多種生物標(biāo)志物的水平的調(diào)節(jié)例如增加時，改變受試者的治療。在一個實施方式中，當(dāng)樣品中一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中的一種或多種生物標(biāo)志物調(diào)節(jié)(例如，提高)時，減小潛在心臟毒性劑的劑量。在一個實施方式中，當(dāng)所述第二樣品中一種或多種生物標(biāo)志物的表達(dá)水平相比于對照樣品中的一種或多種生物標(biāo)志物調(diào)節(jié)(例如，提高)時，受試者共同施用心臟保護(hù)劑以減輕心臟毒性劑的效應(yīng)。在一個實施方式中，當(dāng)檢測到樣品中一種或多種生物標(biāo)志物的水平相比于對照樣品調(diào)節(jié)(例如，提高)時，停止受試者的潛在心臟毒性劑的治療。在另一個方面，本發(fā)明提供了用于識別心臟毒性劑的方法，其包括：比較(i)在該藥劑治療前獲得的第一細(xì)胞樣品中存在的選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的水平，與(ii)在該藥劑治療后得到的第二細(xì)胞樣品中相應(yīng)的一種或多種生物標(biāo)志物的水平；其中，在所述第二樣品中相應(yīng)的一種或多種生物標(biāo)志物的水平與第一樣品相比的調(diào)節(jié)是該藥劑引起藥物誘導(dǎo)的毒性或具有引起藥物誘導(dǎo)的毒性的風(fēng)險的指示。在一個實施方式中，第二樣品中edil3或nucb1的表達(dá)水平相比于第一樣品的降低是該藥劑引起藥物誘導(dǎo)的毒性或具有導(dǎo)致藥物誘導(dǎo)的毒性的風(fēng)險的指示。在另一個方面，本發(fā)明提供了用于識別減輕或防止藥物誘導(dǎo)的毒性的救援劑的方法，其包括：(i)測定在毒性誘導(dǎo)藥物處理之前獲得的第一細(xì)胞樣品中選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的正常水平；(ii)測定在毒性誘導(dǎo)藥物處理后獲得的第二細(xì)胞樣品中存在的相應(yīng)一種或多種生物標(biāo)志物的處理水平以確定在處理的細(xì)胞樣品中具有水平變化的一種或多種生物標(biāo)志物；(iii)測定在毒性誘導(dǎo)藥物和救援劑處理后獲得的第三細(xì)胞樣品中存在的具有毒性誘導(dǎo)藥物處理的樣品中改變的水平的所述相應(yīng)的一種或多種生物標(biāo)志物的水平；及(iv)比較第三樣品中測定的相應(yīng)一種或多種生物標(biāo)志物的水平與第一樣品中存在的相應(yīng)一種或多種生物標(biāo)志物的水平；其中與第一樣品相比，所述第三樣品中相應(yīng)的一種或多種生物標(biāo)志物的正常化水平是救援劑可減輕或防止藥物誘導(dǎo)的毒性的指示。在一個實施方式中，與第一樣品中相應(yīng)的生物標(biāo)志物的表達(dá)水平相比，第三樣品中edil3或nucb1的非調(diào)節(jié)的或提高的水平是救援劑可減輕或防止藥物誘導(dǎo)的毒性的指示。在一個實施方式中，該一種或多種生物標(biāo)志物是edil3。在一個實施方式中，一種或多種生物標(biāo)志物是細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在一個實施方式中，一種或多種生物標(biāo)志物是hmox1。在一個實施方式中，一種或多種生物標(biāo)志物是nucb1。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由hmox1、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由edil3、nucb1、cfl2和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1、cfl2和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1和cfl2組成的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物包括edil3。在一個實施方式中，該一種或多種生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在一個實施方式中，該一種或多種生物標(biāo)志物包括hmox1。在一個實施方式中，該一種或多種生物標(biāo)志物包括nucb1。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括edil3、nucb1、cfl2和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1、cfl2和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1和cfl2的一組生物標(biāo)志物。在上述方法的某些實施方式中，在涉及igfbp7水平的檢測的方法中包括檢測hmox1的水平?jīng)]有顯著增加該方法的預(yù)測值。在某些實施方式中，在涉及hmox1水平的檢測的方法中包括檢測igfbp7的水平?jīng)]有顯著增加該方法的預(yù)測值。在另一個方面，本發(fā)明提供了用于診斷、監(jiān)測或表征心臟毒性或心肌病的試劑盒，包括：至少一種對于選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的表達(dá)水平的檢測特異性的試劑。在一個實施方式中，該試劑盒還包括基于一種或多種生物標(biāo)志物的表達(dá)水平診斷、監(jiān)測或表征心臟毒性或心肌病的說明書。在一個實施方式中，該一種或多種生物標(biāo)志物是edil3。在一個實施方式中，一種或多種生物標(biāo)志物是細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在一個實施方式中，一種或多種生物標(biāo)志物是hmox1。在一個實施方式中，一種或多種生物標(biāo)志物是nucb1。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由hmox1、igfbp7、ccdc47、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由edil3、nucb1、cfl2和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1、cfl2和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1和ptx3組成的一組生物標(biāo)志物。在一個實施方式中，一種或多種生物標(biāo)志物是由nucb1和cfl2組成的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物包括edil3。在一個實施方式中，該一種或多種生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在一個實施方式中，該一種或多種生物標(biāo)志物包括hmox1。在一個實施方式中，該一種或多種生物標(biāo)志物包括nucb1。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括edil3、nucb1、cfl2和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1、cfl2和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1和ptx3的一組生物標(biāo)志物。在一個實施方式中，該一種或多種生物標(biāo)志物是包括nucb1和cfl2的一組生物標(biāo)志物。在上述發(fā)明的一個實施方式中，一種或多種生物標(biāo)志物不包括ptx3。因此，本發(fā)明提供了用于識別引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的方法。在一個實施方式中，所述藥劑是藥物或藥物候選物。在一個實施方式中，所述藥劑是在環(huán)境中的藥劑(例如，污染物、建筑材料)。在一個實施方式中，所述毒性是藥物誘導(dǎo)的心臟毒性。在一個實施方式中，所述藥劑是用于治療糖尿病、肥胖癥、心血管疾病、癌癥、神經(jīng)障礙或炎性病癥的藥物或候選藥物。在一個方面，本發(fā)明提供了用于識別引起心臟毒性的藥劑的方法，包括：(i)將第一細(xì)胞與藥劑相接觸；(ii)檢測本文所提供的標(biāo)志物的水平，其中，檢測所述標(biāo)志物的水平包括：(a)形成標(biāo)志物和探針之間的復(fù)合物，并檢測標(biāo)志物和探針之間復(fù)合物的形成；和/或(b)從細(xì)胞分離標(biāo)志物以使得至少一種對于標(biāo)志物特有的特征可以被檢測；(iii)比較來自第一細(xì)胞的標(biāo)志物的水平與第二細(xì)胞中標(biāo)志物的水平，其中該第二細(xì)胞是未接觸所述藥劑的對照細(xì)胞；其中，所述第一細(xì)胞中標(biāo)志物的水平相比于第二細(xì)胞的調(diào)節(jié)是該制劑引起心臟毒性的指示。在另一個方面，本發(fā)明提供了用于識別預(yù)防或治療心肌病的救援劑的方法，包括：(i)將第一細(xì)胞與心臟毒性劑相接觸；(ii)將第二細(xì)胞與心臟毒性劑和候選救援劑相接觸；(iii)檢測本文所提供的標(biāo)志物的水平，其中檢測所述標(biāo)志物的水平包括：(a)形成標(biāo)志物和探針之間的復(fù)合物，并檢測標(biāo)志物和探針之間復(fù)合物的形成；和/或(b)從細(xì)胞分離標(biāo)志物以使得至少一種標(biāo)志物特有的特征可以被檢測；(iii)將來自所述第一細(xì)胞和第二細(xì)胞各自的標(biāo)志物的水平與對照細(xì)胞相比較，其中對照細(xì)胞沒有接觸心臟毒性劑或候選救援劑；其中，在所述第一細(xì)胞中標(biāo)志物的水平相比于對照細(xì)胞的調(diào)節(jié)以及在第二細(xì)胞中標(biāo)志物的水平相比于對照細(xì)胞的正常化是所述候選救援劑是預(yù)防或治療心臟毒性的救援劑的指示。在一個實施方式中，所述細(xì)胞是心肌細(xì)胞。在一個實施方式中，所述細(xì)胞是心肌細(xì)胞或糖尿病性心肌細(xì)胞。在一個實施方式中，所述接觸是在體外進(jìn)行在一個實施方式中，所述接觸是在體內(nèi)進(jìn)行。在一個實施方式中，心臟毒性包括心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能障礙、心房撲動和顫動、或心臟瓣膜損傷和心力衰竭的至少一種的征兆或癥狀。在一個實施方式中，藥物誘導(dǎo)心臟毒性包括心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能障礙、心房撲動和顫動、或心臟瓣膜損傷和心力衰竭的至少一種的征兆或癥狀。在一個實施方式中，心肌病是藥物誘導(dǎo)心臟毒性的結(jié)果。在一個實施方式中，所述藥物是抗癌藥、糖尿病藥物、神經(jīng)藥或抗炎藥。在一個實施方式中，所述藥物是蒽環(huán)類藥物、5-氟尿嘧啶、順鉑、曲妥珠單抗、吉西他濱、羅格列酮、吡格列酮、曲格列酮、卡麥角林、培高利特、舒馬曲坦、二膦酸鹽或tnf拮抗劑。在一個實施方式中，本文所提供的標(biāo)志物選自于附錄a中提供的標(biāo)志物的組。在一個實施方式中，本文所提供的標(biāo)志物選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、ptx3、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa。在一個實施方式中，本文所提供的標(biāo)志物選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4。在一個實施方式中，本文所提供的標(biāo)志物選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6；cacna2d1；ephx1；bax；prkar2a和mpa2k3。在一個實施方式中，本文所提供的標(biāo)志物選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6。在一個實施方式中，本文所提供的標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物。在一個實施方式中，本文所提供的標(biāo)志物包括至少一種激酶標(biāo)志物。在一個實施方式中，所述標(biāo)志物包括至少一種選自于ptx3、bpm-ctmb1、edil3和nuc1b的標(biāo)志物。在一個實施方式中，細(xì)胞中ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平響應(yīng)于藥劑治療的降低是該制劑引起心臟毒性的指示。在一個實施方式中，第一細(xì)胞中ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平相比于對照細(xì)胞的降低和第二細(xì)胞中所述標(biāo)志物的水平相比于對照細(xì)胞的正常化是該候選救援劑是防止或治療心臟毒性的救援劑的指示。在一個實施方式中，細(xì)胞中ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平響應(yīng)于藥劑處理的降低是該藥劑引起心臟毒性的指示。在一個實施方式中，第一細(xì)胞中ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平相比于對照細(xì)胞的降低和第二細(xì)胞中所述標(biāo)志物的水平相比于對照細(xì)胞的正?；撬龊蜻x救援劑是防止或治療心臟毒性的救援劑的指示。在另一個方面，本發(fā)明提供了用于預(yù)后或診斷受試者的心肌病的方法，包括：(i)獲得來自所述受試者的樣品；(ii)檢測所述樣品中本文所提供的標(biāo)志物的水平，其中檢測所述標(biāo)志物的水平包括：(a)形成標(biāo)志物和探針之間的復(fù)合物和檢測標(biāo)志物和探針之間復(fù)合物的形成；和/或(b)從細(xì)胞分離標(biāo)志物以使得至少一種標(biāo)志物特有的特征可被檢測；(iii)比較所述樣品中標(biāo)志物的水平與對照樣品中標(biāo)志物的水平，其中對照樣品來自未患心肌病的受試者；其中，所述樣品中標(biāo)志物的水平相比于對照樣品的調(diào)節(jié)是該受試者患有或易于發(fā)生心肌病的指示。在另一個方面，本發(fā)明提供了用于監(jiān)測受試者的心肌病的方法，包括：(i)在第一時間從受試者獲得第一樣品；(ii)檢測第一樣品中本文所提供的標(biāo)志物的水平，其中檢測標(biāo)志物的水平包括：(a)形成標(biāo)志物和探針之間的復(fù)合物和檢測標(biāo)志物和探針之間復(fù)合物的形成；和/或(b)從細(xì)胞分離標(biāo)志物以使得至少一個標(biāo)志物特有的特征可被檢測；(iii)將第一樣品中標(biāo)志物的水平與在隨后從受試者獲得的第二樣品相比較；其中第一樣品中標(biāo)志物的水平與第二樣品相比的調(diào)節(jié)是受試者中心肌病改變的指示。在另一個方面，本發(fā)明提供了識別用于治療心肌病的化合物的方法，包括：(i)獲得受試細(xì)胞；(ii)使受試細(xì)胞與受試化合物相接觸；(iii)檢測受試細(xì)胞中本文所提供的標(biāo)志物的水平，其中檢測標(biāo)志物的水平包括：(a)形成標(biāo)志物和探針之間的復(fù)合物和檢測標(biāo)志物和探針之間復(fù)合物的形成；和/或(b)從細(xì)胞分離標(biāo)志物以使得至少一個標(biāo)志物特有的特征可被檢測；(iv)將受試細(xì)胞中標(biāo)志物的水平與未接觸受試化合物的對照細(xì)胞相比較；和(v)選擇調(diào)節(jié)受試細(xì)胞中標(biāo)志物水平的受試化合物，從而識別用于治療受試者的心肌病的化合物。在一個實施方式中，心肌病包括選自于心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能障礙、心房撲動和顫動或者心臟瓣膜損傷和心力衰竭的至少一種征兆或癥狀。在一個實施方式中，心肌病是藥物治療的結(jié)果，如抗癌藥物、糖尿病藥物、神經(jīng)藥物或抗炎藥。在一個實施方式中，藥物是蒽環(huán)類藥物、5-氟尿嘧啶、順鉑、曲妥珠單抗、吉西他濱、羅格列酮、吡格列酮、曲格列酮、卡麥角林、培高利特、舒馬曲坦、二膦酸鹽或tnf拮抗劑。在一個實施方式中，本文所提供的標(biāo)志物選自于在附錄a中提供的標(biāo)志物。在一個實施方式中，本文所提供的標(biāo)志物選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、ptx3、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa。在一個實施方式中，本文所提供的標(biāo)志物選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4。在一個實施方式中，本文所提供的標(biāo)志物選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6；cacna2d1；ephx1；bax；prkar2a和mpa2k3。在一個實施方式中，本文所提供的標(biāo)志物選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6。在一個實施方式中，該標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物。在一個實施方式中，該標(biāo)志物包括至少一種激酶標(biāo)志物。在一個實施方式中，該標(biāo)志物包括至少一種選自于ptx3、bpm-ctmb1、edil3和nuc1b的標(biāo)志物。在一個實施方式中，樣品中ptx3、bpm-ctmb1、edil3和nuc1b的至少一種的表達(dá)水平相比于對照樣品的降低是該受試者患有或易于發(fā)生心肌病的指示。在一個實施方式中，第一樣品中ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平相比于第二樣品的降低是心肌病已經(jīng)惡化的指示。在一個實施方式中，與對照樣品相比，樣品中ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平的降低是該受試者患有或易于發(fā)生心肌病的指示。在一個實施方式中，與第二樣品相比，第一樣品中ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平的降低是心肌病已經(jīng)惡化的指示。在一個實施方式中，所述標(biāo)志物是多種標(biāo)志物。在一個實施方式中，檢測和比較多個標(biāo)志物的水平。在一個實施方式中，所述多個標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物和至少一種蛋白質(zhì)標(biāo)志物。在一個實施方式中，所述多個標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物和至少一種激酶標(biāo)志物。在一個實施方式中，心肌病是后天性心肌病。在一個實施方式中，心肌病是遺傳性心肌病。在一個實施方式中，心肌病由選自于心血管疾病、高血壓、高膽固醇血癥、心肌梗死、中風(fēng)和創(chuàng)傷的病癥引起。在一個實施方式中，獲得樣品包括從受試者采集血液和將血細(xì)胞與血清分離。在一個實施方式中，檢測標(biāo)志物的水平包括檢測標(biāo)志物的濃度。在一個實施方式中，檢測標(biāo)志物的水平包括檢測相比于對照樣品的相對濃度。在一個實施方式中，檢測標(biāo)志物的水平包括檢測所述標(biāo)志物的表達(dá)水平。在一個實施方式中，檢測標(biāo)志物的水平包含檢測所述標(biāo)志物的活性水平。在另一個方面，本發(fā)明提供用于實施本發(fā)明的方法的試劑盒。在一個實施方式中，該細(xì)胞是心血管系統(tǒng)的細(xì)胞，例如，心肌細(xì)胞。在一個實施方式中，該細(xì)胞是糖尿病性心肌細(xì)胞。在一個實施方式中，該藥物是用于治療糖尿病、肥胖癥、心血管疾病、癌癥、神經(jīng)障礙或炎性病癥的藥物或候選藥物。在一個實施方式中，該藥物是蒽環(huán)類藥物、5-氟尿嘧啶、順鉑、曲妥珠單抗、吉西他濱、羅格列酮、吡格列酮、曲格列酮、卡麥角林、培高利特、舒馬曲坦、二膦酸鹽和tnf拮抗劑中的任一種。在一個實施方式中，與第一樣品相比，第三樣品中選自于在表2中列出的標(biāo)志物中的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80、90、100、110、120、130、140、150、160種或更多種生物標(biāo)志物的大致相同的表達(dá)水平是救援劑可以降低或防止藥物誘導(dǎo)的心臟毒性的指示。本發(fā)明進(jìn)一步提供了在本文所提供的方法中有用的生物標(biāo)志物(例如，基因、蛋白質(zhì)、酶、脂類)。在某些實施方式中，該標(biāo)志物是選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、ptx3、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80或90種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4的一、二、三、四、五、六、七、八、九、十、十一、十二或十三種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6；cacna2d1；ephx1；bax；prkar2a和mpa2k3的一、二、三、四、五、六、七、八、九、十或十一種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的一、二、三、四、五、六或七種標(biāo)志物。在某些實施方式中，該標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物。在某些實施方式中，該標(biāo)志物包括至少一種激酶標(biāo)志物。在某些實施方式中，與正常受試者相比，ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平的降低是心肌病的指示。在某些實施方式中，ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平響應(yīng)于藥劑處理的降低指示該藥劑是心臟毒性的。在某些實施方式中，該方法包括檢測ptx3、bpm-ctmb1、edil3和nuc1b中至少一種的表達(dá)水平。在某些實施方式中，與正常受試者相比，ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平的降低是心肌病的指示。在某些實施方式中，脂質(zhì)水平被測量為正常脂質(zhì)水平的百分比。在某些實施方式中，脂質(zhì)水平降低至小于正常脂質(zhì)水平的95％、90％、80％、70％、60％、50％、40％、30％、20％、10％是心肌病的指示。在某些實施方式中，ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平響應(yīng)于藥劑處理的降低指示該藥劑是心臟毒性的。在某些實施方式中，脂質(zhì)水平被測量為正常脂質(zhì)水平的百分比。在某些實施方式中，在向受試者施用藥劑后，脂質(zhì)水平降低至小于正常脂質(zhì)水平的95％、90％、80％、70％、60％、50％、40％、30％、20％、10％指示該藥劑是心臟毒性的。在某些實施方式中，與正常的受試者相比，pe18:0-20:3水平的降低是心肌病的指示。在某些實施方式中，脂質(zhì)水平測量為正常脂質(zhì)水平的百分比。在某些實施方式中，脂質(zhì)水平降低至小于正常脂質(zhì)水平的95％、90％、80％、70％、60％、50％、40％、30％、20％、10％是心肌病的指示。在某些實施方式中，與正常受試者相比，pe18:0-20:3水平的降低是心臟中重建事件的指示。在某些實施方式中，脂質(zhì)水平測量為正常脂質(zhì)水平的百分比。在某些實施方式中，脂質(zhì)水平降低至小于正常脂質(zhì)水平的95％、90％、80％、70％、60％、50％、40％、30％、20％、10％是心臟中重建事件的指示。在某些實施方式中，pe18:0-20:3水平響應(yīng)于藥劑處理的降低指示該藥劑是心臟毒性的。在某些實施方式中，脂質(zhì)水平測量為正常脂質(zhì)水平的百分比。在某些實施方式中，在向受試者施用藥劑后，脂質(zhì)水平降低至小于正常脂質(zhì)水平的95％、90％、80％、70％、60％、50％、40％、30％、20％、10％指示該藥劑是心臟毒性的。特別地，本發(fā)明涉及以下各項：1、一種用于診斷受試者中的心血管疾病的方法，包括：(i)檢測來自所述受試者的生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，其中該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；和(ii)將來自所述受試者的生物樣品中所述一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照樣品中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中所述生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物相對于對照樣品的改變的水平是該受試者患有心血管疾病的指示。2、一種用于識別受試者為處于患心血管疾病的增加的風(fēng)險中的方法，該方法包括：(i)檢測來自所述受試者的生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，其中該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；和(ii)將來自所述受試者的生物樣品中的所述一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照樣品中相應(yīng)的一種或多種生物標(biāo)志物的水平相比較，其中所述生物樣品中一種或多種cvd相關(guān)的生物標(biāo)志物相對于對照樣品的改變的水平是該受試者處于患心肌病的增加的風(fēng)險中的指示。3、一種用于在受試者中監(jiān)測心血管疾病的方法，該方法包括：(i)檢測在第一時間從患有心血管疾病的受試者獲得的第一生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，其中該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；和(ii)檢測在第二時間從所述受試者獲得的第二生物樣品中所述一種或多種cvd相關(guān)生物標(biāo)志物的水平，其中所述第二時間晚于所述第一時間；和(iii)將所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與所述第一樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中與所述第一樣品相比，該第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的改變是受試者中cvd狀態(tài)的改變的指示。4、一種用于在受試者中監(jiān)測心血管疾病的治療的方法，該方法包括：(i)檢測在向所述受試者施用至少一部分治療方案前從受試者獲得的第一生物樣品中一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平，其中該生物標(biāo)志物選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6；(ii)檢測在向所述受試者施用至少一部分治療方案后從受試者獲得的第二生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平；和(iii)將所述第一樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中與所述第一樣品相比，所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的標(biāo)準(zhǔn)化水平指示該治療方案用于治療所述受試者中的心血管疾病是有效的。5、如第1-4項中任一項所述的方法，其中所述心血管疾病包括心肌病。6、如第5項所述的方法，其中心肌病為選自于擴(kuò)張型心肌病、肥厚性心肌病、限制型心肌病和致心律失常性右心室發(fā)育不良中的至少一種病癥。7、如第5或6項所述的方法，其中心肌病包括選自于延長的qt間期、心律失常、心肌缺血、高血壓和血栓栓塞性并發(fā)癥，心肌功能障礙、心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能障礙、心房撲動和顫動、心臟瓣膜損傷和心力衰竭中的至少一種病癥。8、如第5-7項中任一項所述的方法，其中所述心肌病是遺傳性心肌病。9、如第5-7項中任一項所述的方法，其中所述心肌病是后天性心肌病。10、如第9項所述的方法，其中所述后天性心肌病是在所述受試者中一種或多種另外的疾病或狀況的合并癥。11、如第10項的方法，其中所述受試者中一種或多種另外的疾病或病癥選自于冠狀動脈心臟病、心臟病發(fā)作、高血壓、糖尿病、甲狀腺疾病、病毒性肝炎、hivl、使心肌發(fā)炎的病毒感染、血色素沉著癥、結(jié)節(jié)病、淀粉樣變性和結(jié)締組織病癥。12、如第9項所述的方法，其中所述后天性心肌病是受試者暴露于心臟毒素的結(jié)果。13、如第12項所述的方法，其中所述心臟毒素是環(huán)境心臟毒素。14、如第12項所述的方法，其中所述心臟毒素是心臟毒性藥物。15、如第14項所述的方法，其中所述心臟毒性藥物選自于過量酒精、安非他明、抗癌藥物、化療藥物、糖尿病藥物、神經(jīng)藥物、抗炎藥、二膦酸鹽和tnf拮抗劑。16、如第15項所述的方法，其中所述抗癌藥物選自于順鉑、阿霉素、柔紅霉素、蒽環(huán)類藥物、5-氟尿嘧啶、曲妥珠單抗或吉西他濱。17、如第15項所述的方法，其中所述糖尿病藥物選自于由羅格列酮、吡格列酮、曲格列酮和卡麥角林。18、如第14項所述的方法，其中所述心臟毒性藥物是培高利特或舒馬曲坦。19、如第1-4項中任一項所述的方法，其中所述心血管疾病包括心力衰竭。20、如第1-19項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。21、如第1-19項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。22、如第1-19項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。23、如第21或22項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。24、如第21或22項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。25、如第1-24項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。26、如第25項所述的方法，其中所述脂質(zhì)包括pc-li-183-d18:2-22:6。27、如第1-26項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。28、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。29、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。30、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。31、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。32、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。33、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。34、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。35、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。36、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。37、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。38、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。39、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。40、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。41、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。42、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。43、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。44、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。45、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。46、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。47、如第1-27項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。48、如第1-2和5-47項中任一項所述的方法，其中與對照樣品中的水平相比，所述生物樣品中選自于ptx3、pai1、edil3和nuc1b的至少一種cvd相關(guān)標(biāo)志物的水平的降低是該受試者患有心血管疾病或處于患心血管疾病的增加的風(fēng)險中的指示。49、如第1-2和5-47項中任一項所述的方法，其中與正常的受試者相比，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種cvd相關(guān)標(biāo)志物的水平的提高是該受試者患有心血管疾病或處于患心血管疾病的增加的風(fēng)險中的指示。50、如第1-2和5-47項中任一項所述的方法，其中與對照樣品中的水平相比，所述生物樣品中選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種cvd相關(guān)標(biāo)志物的水平的降低是該受試者患有心血管疾病或處于患心血管疾病的增加的風(fēng)險中的指示。51、如第3-4和5-47項中任一項所述的方法，其中與所述第一樣品中的水平相比，所述第二樣品中選自于ptx3、pai1、edil3和nuc1b中的至少一種cvd相關(guān)標(biāo)志物的水平的提高是所述受試者的心血管疾病狀態(tài)改善或所述治療方案用于治療心血管疾病有效的指示。52、如第3-4和5-47項中任一項所述的方法，其中與所述第一樣品中的水平相比，所述第二樣品中選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種cvd相關(guān)標(biāo)志物的水平的降低是所述受試者的心血管疾病狀態(tài)改善或所述治療方案用于治療心血管疾病有效的指示。53、如第3-4和5-47項中任一項所述的方法，其中與所述第一樣品中的水平相比，所述第二樣品中選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種cvd相關(guān)標(biāo)志物的水平的提高是所述受試者的心血管疾病狀態(tài)改善或所述治療方案用于治療心血管疾病有效的指示。54、一種用于檢測一組心血管疾病(cvd)相關(guān)生物標(biāo)志物的方法，該方法包括：(i)分析來自受試者的生物樣品中一組cvd相關(guān)生物標(biāo)志物的兩種或更多種cvd相關(guān)生物標(biāo)志物的水平，其中該組cvd相關(guān)生物標(biāo)志物包括ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6；(ii)檢測所述生物樣品中所述兩種或更多種cvd相關(guān)生物標(biāo)志物中的每一種，從而檢測該組cvd相關(guān)生物標(biāo)志物。55、如第54項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。56、如第54項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。57、如第54項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。58、如第56或57項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括ptx3。59、如第56或57項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括pai1。60、如第54-59項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6中的至少兩種脂質(zhì)生物標(biāo)志物。61、如第60項所述的方法，其中所述脂質(zhì)包括pc-li-183-d18:2-22:6。62、如第54-60項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。63、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47。64、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3。65、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。66、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1。67、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1。68、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。69、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。70、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。71、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。72、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。73、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。74、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。75、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。76、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。77、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。78、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。79、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。80、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。81、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。82、如第54-62項中任一項所述的方法，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。83、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括分離所述生物樣品的組分。84、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括標(biāo)記所述生物樣品的組分。85、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括處理所述生物樣品。86、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括將待檢測的cvd相關(guān)標(biāo)志物與cvd相關(guān)標(biāo)志物結(jié)合劑相接觸。87、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平包括形成待檢測的cvd相關(guān)標(biāo)志物與cvd相關(guān)標(biāo)志物結(jié)合劑之間的復(fù)合物。88、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括將所述一種或多種cvd相關(guān)標(biāo)志物各自與cvd相關(guān)標(biāo)志物結(jié)合劑相接觸。89、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)標(biāo)志物的水平包括形成所述一種或多種cvd相關(guān)標(biāo)志物各自與cvd相關(guān)標(biāo)志物結(jié)合劑之間的復(fù)合物。90、如第1-82項中任一項所述的方法，其中檢測或測定生物樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平包括將待檢測的cvd相關(guān)標(biāo)志物連接到固體表面上。91、用于檢測方法中的一組試劑，該試劑組包含至少兩種檢測試劑，其中每種檢測試劑對于一組cvd相關(guān)生物標(biāo)志物的至少一種心血管疾病(cvd)相關(guān)標(biāo)志物的檢測是特異性的，其中該組cvd相關(guān)生物標(biāo)志物包括選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的兩種或更多種cvd相關(guān)生物標(biāo)志物。92、如第91項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。93、如第91項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。94、如第91項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。95、如第93或94項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括ptx3。96、如第93或94項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括pai1。97、如第91-96項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。98、如第97項所述的試劑組，其中所述脂質(zhì)包括pc-li-183-d18:2-22:6。99、如第91-98項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。100、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括ccdc47。101、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3。102、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。103、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1。104、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1。105、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。106、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。107、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。108、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。109、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。110、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。111、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。112、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。113、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。114、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。115、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。116、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。117、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。118、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。119、如第91-99項中任一項所述的試劑組，其中所述兩種或更多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。120、如第91-119項中任一項所述的試劑組在第1-90項中任一項所述的方法中的用途。121、一種用于診斷、監(jiān)測或表征受試者中的心血管疾病的試劑盒，其包含：至少一種對于選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種cvd相關(guān)標(biāo)志物的水平的檢測特異性的試劑。122、如第121項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。123、如第121項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。124、如第121項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。125、如第123或124項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。126、如第123或124項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。127、如第121-126項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包拓選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。128、如第127項所述的試劑盒，其中所述脂質(zhì)包括pc-li-183-d18:2-22:6。129、如第121-128項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。130、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。131、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。132、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。133、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。134、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。135、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。136、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。137、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。138、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。139、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。140、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。141、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。142、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。143、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。144、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。145、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。146、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。147、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。148、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。149、如第121-129項中任一項所述的試劑盒，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。150、一種識別用于治療心血管疾病的化合物的方法，包括：(i)獲得受試細(xì)胞；(ii)將受試細(xì)胞與受試化合物相接觸；(iii)測定所述受試細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種心血管疾病(cvd)相關(guān)生物標(biāo)志物的水平；(iv)將所述受試細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與未接觸受試化合物的對照細(xì)胞相比較；和(v)選擇調(diào)節(jié)受試細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的受試化合物，從而識別用于治療受試者中的cvd的化合物。151、一種識別引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的方法，包括：(i)將第一細(xì)胞與受試藥劑相接觸；(ii)檢測與所述受試藥劑相接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物的水平；和(iii)將所述第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第二細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中該第二細(xì)胞是未接觸所述受試藥劑的對照細(xì)胞；其中，與所述第二細(xì)胞相比，所述第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)是所述受試藥劑是引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的指示。152、一種用于識別用于預(yù)防、減輕或治療藥物誘導(dǎo)的心臟毒性的救援劑的方法，包括：(i)將第一細(xì)胞與心臟毒性劑相接觸；(ii)將第二細(xì)胞與所述心臟毒性劑和候選救援劑相接觸；(iii)檢測與所述心臟毒性劑相接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物的水平；(iv)檢測與所述心臟毒性劑和候選救援劑相接觸的第二細(xì)胞中的所述一種或多種cvd相關(guān)生物標(biāo)志物的水平；和(v)將所述第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與所述第一細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中，與所述第一細(xì)胞相比，所述第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)是所述候選救援劑是預(yù)防、減輕或治療藥物誘導(dǎo)的心臟毒性的救援劑的指示。153、如第152項所述的方法，還包括將所述第一和/或第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中所述對照細(xì)胞未接觸所述心臟毒性劑或候選救援劑。154、如第153項所述的方法，其中與對照細(xì)胞相比較，在所述第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的正?；窃摵蜻x救援劑是預(yù)防、減輕或治療藥物誘導(dǎo)的心臟毒性的救援劑的指示。155、如第150-154項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1。156、如第150-154項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47或hmox1。157、如第150-154項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47和hmox1。158、如第156或157項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括ptx3。159、如第156或157項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括pai1。160、如第150-159項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的至少一種脂質(zhì)生物標(biāo)志物。161、如第160項所述的方法，其中所述脂質(zhì)包括pc-li-183-d18:2-22:6。162、如第150-161項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物還包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的至少一種cvd相關(guān)生物標(biāo)志物。163、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括ccdc47。164、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3。165、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。166、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1。167、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1。168、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1。169、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1。170、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1。171、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括hmox1、igfbp7、ccdc47、ptx3、il27和pai1。172、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1。173、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1。174、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27。175、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3。176、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47。177、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7。178、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1。179、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括edil3、nucb1、cfl2和ptx3。180、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1、cfl2和ptx3。181、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和ptx3。182、如第150-162項中任一項所述的方法，其中所述一種或多種cvd相關(guān)生物標(biāo)志物包括nucb1和cfl2。183、如第150-182項中任一項所述的方法，其中所述細(xì)胞是心肌細(xì)胞。184、如第150-182項中任一項所述的方法，其中所述細(xì)胞是心肌細(xì)胞或糖尿病性心肌細(xì)胞。185、如第150-184項所述的方法，其中所述接觸在體外進(jìn)行。186、如第150-184項所述的方法，其中該接觸在體內(nèi)進(jìn)行。附圖簡述圖1示出了證明來自樣品集2的單個生物標(biāo)志物的性能的roc曲線。圖2示出了基于樣品集2通過邏輯回歸的各種標(biāo)志物組合模型的性能。前7個標(biāo)志物的組合顯示了區(qū)分正常和心肌病樣品的最高預(yù)測能力水平。圖3示出了后向消除模型以顯示根據(jù)特定標(biāo)志物組的分類器的差異性能。hmox1和igfbp7的消除不導(dǎo)致性能降低。圖4示出了證明來自asterand樣品集的單個生物標(biāo)志物的性能的roc曲線。圖5示出在asterand樣品集中進(jìn)行評估的4種生物標(biāo)志物的組合模型。如圖所示，edil3的性能未通過在心肌病預(yù)測中包括其他標(biāo)志物而提高。圖6a-b示出了人血清中(a)ptx3和(b)pai1的比較水平。圖7示出了人血清中edil3的比較水平。圖8示出了人血清中nucb1的比較水平。圖9a-b示出了從血清和體外細(xì)胞培養(yǎng)物模型得到的δ網(wǎng)絡(luò)的兩個重疊，其比較(a)心肌病與無心肌病和(b)羅格列酮治療與無羅格列酮治療。血清節(jié)點為矩形和細(xì)胞培養(yǎng)物節(jié)點是正方形。重疊的節(jié)點是在加黑方格中。圖10a-b示出了以(a)pmol脂質(zhì)/mg蛋白質(zhì)或(b)作為正常脂質(zhì)水平的百分比測定的血清脂質(zhì)網(wǎng)絡(luò)和顆粒脂質(zhì)網(wǎng)絡(luò)共同的脂質(zhì)的定量。與單獨的糖尿病和使用羅格列酮而沒有心肌病相比，ped18:0-20:3/d18:1-20:2/d16:0-22:3在具有心肌病臨床診斷的使用羅格列酮的糖尿病受試者中顯著降低。圖11示出了探詢式平臺技術(shù)的多組學(xué)輸出。菱形表示脂質(zhì)種類，正方形是蛋白質(zhì)和六邊形是激酶(其與活性中心具有因果相關(guān)性)。中心-cacna2d1，一種l型鈣通道，與map2k3和prkar2a(激酶)、bax(線粒體蛋白)、ephx1(微粒體蛋白)和pcli-183-d18:2-22:6(磷脂酰膽堿)相關(guān)。結(jié)果表明，δ多組學(xué)輸出提供了體外毒性模型中分子事件的非常有力的快照(snapshot)。圖12a-b示出了證明ccdc47區(qū)分(a)正常受試者與患有心血管疾病的受試者和(b)用或者沒有用羅格列酮治療的患有2型糖尿病和心肌病的受試者的預(yù)測值的roc曲線。圖13a-c示出了用(a)羅格列酮、(b)二甲雙胍或(c)阿托伐他汀治療的受試者中ccdc47水平的散點圖。圖14示出了比較ccdc47+igfbp7組合與ccdc47+igfbp7+pc-li-183-d18:2-22:6組合預(yù)測受試者的不良心臟事件的預(yù)測值的roc曲線。發(fā)明詳述定義如本文所使用的，下列術(shù)語中的每一個具有與其在本節(jié)相關(guān)的含義。如本文所用的，“心臟疾病相關(guān)標(biāo)志物”(其包括“心血管疾病相關(guān)生物標(biāo)志物”、“心肌病相關(guān)生物標(biāo)志物”和“心臟毒性相關(guān)生物標(biāo)志物”)包括一種或多種(例如，1、2、3、4、5、6、7、8、9、10或更多種)生物標(biāo)志物：細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的任何組合。心臟疾病相關(guān)生物標(biāo)志物還可以包括本文(例如，在序列表中)所提供的其他生物標(biāo)志物。將通過本發(fā)明的方法進(jìn)行治療的“患者”或“受試者”可以指人或非人動物，優(yōu)選哺乳動物。“受試者”是指任何動物，包括馬、狗、貓、豬、山羊、兔、倉鼠、猴、豚鼠、大鼠、小鼠、蜥蜴、蛇、綿羊、牛、魚和鳥。人類受試者可以被稱為患者。應(yīng)當(dāng)指出的是，本文所描述的臨床觀察是用人類受試者樣本進(jìn)行的，并且在至少一些實施方式中，該受試者是人類。如本文所使用的，“合并癥”是指在患者中引起同一患者中的另一病癥、被同一患者中的另一病癥引起或以其它方式與同一患者中的另一病癥相關(guān)的一種醫(yī)學(xué)病癥?！爸委熡行Я俊笔侵府?dāng)施用給患者用于治療疾病時足以實現(xiàn)治療這樣的疾病的效果的化合物的量，例如，以適用于任何治療的合理的利益/風(fēng)險比產(chǎn)生某些所希望的局部或全身效果的這種物質(zhì)的量。當(dāng)給藥用于預(yù)防疾病時，該量足以避免或延遲疾病的發(fā)作。所述“治療有效量”根據(jù)化合物、其治療指數(shù)、溶解度、疾病和其嚴(yán)重性及被治療的患者的年齡、體重等會有所不同。例如，可以以足夠的量施用通過本發(fā)明的方法發(fā)現(xiàn)的某些化合物以產(chǎn)生適用于這種治療的合理利益/風(fēng)險比。施用治療有效量的化合物可能需要施用超過一個劑量的該化合物?！邦A(yù)防”或“防止”是指降低獲得疾病或病癥的風(fēng)險(即，使得至少一種疾病的臨床癥狀不在可能接觸或易患該疾病但還沒有經(jīng)歷或顯示疾病的癥狀的患者中發(fā)生)。術(shù)語“預(yù)防性”或“治療性”治療是指向受試者施用一種或多種所述組合物。如果在不希望的病癥(例如，宿主動物的疾病或其它不希望的病癥)的臨床表現(xiàn)之前施用時，那么治療是預(yù)防性的，即它保護(hù)宿主以免于形成不想要的病癥，然而如果在表現(xiàn)不希望的病癥之后施用，該治療是治療性的(即，它意在減少、改善或維持現(xiàn)有的不希望病癥或其副作用)。術(shù)語“治療效果”是指由藥理活性物質(zhì)在動物，特別是哺乳動物中，以及更特別地是人類中所產(chǎn)生的局部或全身效果。因此該術(shù)語是指打算在動物或人中用于診斷、治愈、緩解、治療或預(yù)防疾病或者用于提高期望的身體或精神發(fā)育和狀態(tài)的任何物質(zhì)的效果。術(shù)語“病癥”和“疾病”被包含性地使用，且是指身體的任何部分、器官或系統(tǒng)(或它們的任意組合)的正常結(jié)構(gòu)或功能的任何偏離。具體的疾病表現(xiàn)為特征性的癥狀和體征，包括生物、化學(xué)和物理變化，并通常與各種其它因素相關(guān)，包括但不限于，人口統(tǒng)計學(xué)、環(huán)境、職業(yè)、遺傳性和醫(yī)學(xué)史因素?？梢酝ㄟ^各種方法來量化某些特征性體征、癥狀以及相關(guān)因素以得到重要的診斷信息。術(shù)語“藥物誘導(dǎo)的毒性”包括但不限于心臟毒性、肝毒性、腎毒性(hephrotoxicity)、神經(jīng)毒性、腎臟毒性或肌肉毒性。術(shù)語“心臟毒性”是由心臟毒性劑引起的，且指誘導(dǎo)對心臟功能的廣泛不良效應(yīng)的藥劑，包括治療性分子和毒素。心臟毒性的證據(jù)可以在臨床前研究的早期出現(xiàn)或隨后在臨床環(huán)境中變得明顯。心臟毒性劑可導(dǎo)致多種不良效應(yīng)，包括但不限于：延長的qt間期、心律失常、心肌缺血、高血壓和血栓栓塞性并發(fā)癥、心肌功能障礙、心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能不全、心房撲動和顫動，以及心臟瓣膜損傷和心力衰竭的任意一種或多種。本文使用的“心血管疾病”是一類涉及心臟、血管(動脈、毛細(xì)血管和靜脈)或這兩種的疾病。心血管疾病是指影響心血管系統(tǒng)的任何疾病，主要是心臟疾病，包括心肌病、腦和腎的血管疾病及外周動脈疾病。在某些實施方式中，心血管疾病是指主要影響心臟的疾病，且可以被稱為心臟疾病。在某些實施方式中，心血管疾病是指其中病理開始于心臟損傷、功能障礙或畸形的疾病，與其中心臟損傷、功能障礙或畸形是遠(yuǎn)離心臟部位處存在的主要病理的結(jié)果的疾病(例如，作為另一種疾病或病癥的合并癥的心血管疾病)相反。例如，心力衰竭、心臟節(jié)律紊亂(心臟節(jié)律的異常，包括延長的qt間期和心房撲動和/或顫動)、包括心內(nèi)膜炎(心臟內(nèi)層、心內(nèi)膜、最通常心臟瓣膜的炎癥)的炎性心臟病、炎性心臟肥大(心臟擴(kuò)大，心肌肥厚)、心肌炎(心肌的炎癥)、瓣膜心臟病、先天性心臟病和風(fēng)濕性心臟病(由于鏈球菌感染引起的風(fēng)濕熱導(dǎo)致的心肌和瓣膜損害)是心臟損傷、功能障礙或畸形的實例，其中主要病理可以或者是存在于心臟中，且隨后可導(dǎo)致血管或其他全身性疾病?？商娲?，冠狀動脈心臟病(還有缺血性心臟病或冠狀動脈病)、高血壓性心臟病(高血壓繼發(fā)的心臟疾病)、肺心病(牽連呼吸系統(tǒng)的右側(cè)心力衰竭)、腦血管疾病(腦供血到腦的血管的疾病，例如中風(fēng))、外周動脈疾病(供血至胳膊和腿的血管的疾病)和動脈粥樣硬化是最初存在于遠(yuǎn)離心臟位點的病理的結(jié)果。開始于心臟或遠(yuǎn)離心臟的位點的心血管疾病可導(dǎo)致心力衰竭。在本發(fā)明的某些實施方式中，心血管疾病包括其中初始病理在遠(yuǎn)離心臟的位點的疾病。在本發(fā)明的某些實施方式中，心血管疾病不包括其中初始病理在遠(yuǎn)離心臟的位點的疾病。在某些實施方式中，心血管疾病不包括心臟節(jié)律紊亂、包括心內(nèi)膜炎的炎癥性心臟病、炎癥性心臟肥大、心肌炎、瓣膜心臟病、先天性心臟病、風(fēng)濕性心臟病、冠狀動脈心臟病、高血壓性心臟病、肺心病、腦血管疾病、外周動脈疾病和動脈粥樣硬化的一種或多種。如本文所使用的，“心肌病”被理解為選自于延長的qt間期、心律失常、心肌缺血、高血壓和血栓栓塞性并發(fā)癥、心肌功能障礙、心肌病、心力衰竭、心房纖顫、心肌病和心力衰竭、心力衰竭和左心室功能不全、心房撲動和顫動以及心臟瓣膜損傷和心力衰竭的一種或多種病癥(例如，1、2、3、4、5、6、7、8、9、10或更多種)。在某些實施方式中，心肌病不包括作為另一種疾病或病癥的合并癥的心肌病。在某些實施方式中，心肌病是在本文中可互換使用的“誘發(fā)性心肌病”或“后天性心肌病”。在某些實施方式中，誘發(fā)性或后天性心肌病是暴露于心臟毒性的藥物或毒素的結(jié)果，例如，用于治療糖尿病的藥物，包括例如，羅格列酮和相關(guān)的噻唑烷二酮(tzd)；化療劑，例如阿霉素、5-氟尿嘧啶、環(huán)磷酰胺和類毒素；可卡因；安非他明；酒精，特別是與不良飲食習(xí)慣相結(jié)合；和毒素，例如重金屬、鈷。在某些實施方式中，誘發(fā)性心肌病不是藥物或毒素暴露的結(jié)果。在某些實施方式中，誘發(fā)性心肌病是感染的結(jié)果，例如病毒感染，包括心臟的細(xì)菌或病毒感染(如風(fēng)濕熱)、病毒性肝炎和hiv感染。例如，在某些實施方式中，誘發(fā)性心肌病不是感染的結(jié)果。在某些實施方式中，心肌病是內(nèi)分泌失調(diào)的結(jié)果，例如，糖尿病或甲狀腺疾病。在某些實施方式中，心肌病不是內(nèi)分泌失調(diào)的結(jié)果。在某些實施方式中，誘發(fā)性心肌病是高血壓或心臟病發(fā)作的結(jié)果。在某些實施方式中，誘發(fā)性心肌病不是高血壓或心臟病發(fā)作的結(jié)果。在某些實施方式中，誘發(fā)性心肌病是缺血的結(jié)果，例如，缺血造成的心絞痛、心肌梗死或心力衰竭。在某些實施方式中，誘發(fā)性心肌病不是缺血的結(jié)果。在某些實施方式中，心肌病是“遺傳性心肌病”，其中肥厚型心肌病和致心律失常性右心室發(fā)育不良基本上是遺傳性疾病。如本文所用的，“心力衰竭”(通常被稱為充血性心力衰竭(chf)或充血性心臟衰竭(ccf))應(yīng)被理解為當(dāng)心臟不能提供足夠的泵送作用以維持血流來滿足身體的需要時發(fā)生的狀況。心力衰竭可導(dǎo)致多種癥狀，包括氣促、下肢腫脹和運動不耐。該病癥一般由病人的身體檢查診斷和用超聲心動圖證實。心力衰竭的常見原因包括心肌梗塞和其它形式的缺血性心臟疾病、高血壓、心臟瓣膜病和心肌病。術(shù)語心力衰竭有時錯誤地用于其他心臟有關(guān)的疾病，如心肌梗死(心臟病發(fā)作)或心臟停搏(其可能會導(dǎo)致心臟的衰竭，但不等同于心力衰竭)。具有“發(fā)生心血管疾病(包括心肌病或心力衰竭)的增加的風(fēng)險”的受試者可能發(fā)生或不發(fā)生心血管疾病。應(yīng)當(dāng)監(jiān)測心血管疾病的另外的征兆或癥狀來識別有增加的發(fā)生心血管疾病的風(fēng)險的受試者。本文所提供的用于識別具有增加的發(fā)生心血管疾病的風(fēng)險的受試者的方法可以與心血管疾病的其他已知的風(fēng)險因子或征兆，包括但不限于，和年齡的評估組合使用。術(shù)語“表達(dá)”在本文中用來指由其從dna制備多肽的過程。該過程涉及基因轉(zhuǎn)錄為mrna及將該mrna翻譯成多肽。根據(jù)所用的上下文，“表達(dá)”可以指產(chǎn)生rna或蛋白質(zhì)或兩者。術(shù)語“基因的表達(dá)水平”或“基因表達(dá)水平”是指在細(xì)胞中由該基因編碼的mrna以及前mrna新生轉(zhuǎn)錄本、轉(zhuǎn)錄物加工中間體、成熟mrna和降解產(chǎn)物的水平，或蛋白質(zhì)的水平。術(shù)語“特異性識別”或“特異性檢測”理解為在足夠低的分析背景和所用試劑的交叉反應(yīng)性的情況下檢測目標(biāo)標(biāo)志物，使得該檢測方法可診斷應(yīng)用。在某些實施方式中，用于特異性識別標(biāo)志物的試劑只結(jié)合于標(biāo)志物的一個異形體。在某些實施方式中，用于特異性識別標(biāo)志物的試劑結(jié)合標(biāo)志物的超過一種異形體。在某些實施方式中，用于特異性識別標(biāo)志物的試劑結(jié)合標(biāo)志物的所有已知的異形體。在某些實施方式中，所述試劑僅結(jié)合于蛋白質(zhì)的磷酸化形式。在某些實施方式中，所述試劑僅結(jié)合該蛋白質(zhì)的非磷酸化形式。術(shù)語生物標(biāo)志物的“調(diào)節(jié)”是指生物標(biāo)志物或反應(yīng)的上調(diào)(即，激活或刺激)、下調(diào)(即，阻止或抑制)或者兩者的組合或分開?！罢{(diào)節(jié)劑”是調(diào)節(jié)的化合物或分子，和可以是，例如，激動劑、拮抗劑、活化劑、刺激劑、阻遏劑或抑制劑?！罢{(diào)節(jié)的水平”或“改變的水平”是指相對于對照水平或正常水平改變的值。正常是基于歷史的正常對照樣品或優(yōu)選在同一個實驗中測試的正常對照樣品。具體的“正?！敝祵⑷Q于，例如，分析的類型(例如，elisa、酶活性、免疫組織化學(xué)、pcr、光譜法)、待測試樣品(例如，細(xì)胞類型和培養(yǎng)條件、受試樣品)和本領(lǐng)域技術(shù)人員已知的其他考慮因素。對照樣品可以被用來定義正常和異常之間的截止值。與實驗室動物或組織培養(yǎng)物研究相關(guān)的術(shù)語“對照水平”是指標(biāo)志物的公認(rèn)的或預(yù)先確定的水平，或優(yōu)選地與測試樣品平行測試的對照樣品中測定的標(biāo)志物水平，其被用于與來自沒有用潛在毒性藥物或救援劑處理的細(xì)胞的樣品中標(biāo)志物的水平進(jìn)行比較?！皩φ账健笔菑脑谙嗤臈l件(例如，缺氧、高血糖、乳酸等)下培養(yǎng)的細(xì)胞獲得。術(shù)語“對照水平”指標(biāo)志物的公認(rèn)的或預(yù)先確定的水平，或優(yōu)選地與測試樣品平行測試的對照樣品中或合適的受試樣品中測定的標(biāo)志物的水平，其被用于與來自沒有用潛在毒性藥物或救援劑處理的細(xì)胞的樣品中標(biāo)志物的水平進(jìn)行比較。在某些實施方式中，“對照水平”是從在相同的條件(例如，缺氧、高血糖、乳酸等)下培養(yǎng)的細(xì)胞獲得。在某些實施方式中，對照水平從健康的受試者或用藥劑(包括，例如，用于治療心血管疾病，如心肌病的藥劑、用于預(yù)防和/或治療心肌病的藥劑)處理之前，或在用潛在心臟毒性劑處理之前的受試者獲得。如本文所用的術(shù)語“對照樣品”是指任何臨床相關(guān)對比樣品，包括，例如，來自未患心血管疾病和/或心肌病的健康受試者的樣品，或從較早的時間點，例如，在治療之前，或者在治療或疾病的早期階段來自受試者的樣品。對照樣品可以是純化的樣品，例如，用試劑盒提供的蛋白質(zhì)、核酸和/或脂質(zhì)。這樣的對照樣品可以被稀釋，例如，系列稀釋，以允許測試樣品中分析物的定量測定。對照樣品可以包括來自一個或多個受試者的樣品。對照樣品可以是在較早的時間點從待評估的受試者獲得的樣品，例如，在心肌病發(fā)病前、在疾病的較早期階段或在施用用于心肌病或其他病癥的治療或一部分治療(尤其用已知誘導(dǎo)心肌病的藥劑(例如，2型糖尿病藥物，化療劑)治療)之前，從待評估受試者獲得的樣品。對照樣品也可以是來自動物模型，或來自從心肌病的動物模型獲得的組織或細(xì)胞系的樣品?？梢?，例如，根據(jù)任何適當(dāng)?shù)慕y(tǒng)計度量，諸如，例如，集中趨勢的度量(包括平均值、中位數(shù)或模態(tài)值(modalvalue))來確定由一組測量值組成的對照樣品中生物標(biāo)志物的活性或表達(dá)水平。在一個實施方式中，對照是標(biāo)準(zhǔn)化的對照，如，例如，使用來自沒有心血管疾病或心臟疾病的受試者(尤其是沒有心肌病的受試者)群體的一種或多種標(biāo)志物的表達(dá)水平的平均值預(yù)先確定的對照。而在本發(fā)明的另外的實施方式中，標(biāo)志物的對照水平是來自具有心肌病的受試者的正常樣品中標(biāo)志物的水平。如本文所用，在“較早的時間點”獲得的樣品是在過去的足夠的時間獲得的樣品，以至可以從較早的時間點的樣品中獲得與稍后的時間點相比的臨床相關(guān)信息。在某些實施方式中，較早的時間點是至少四周前。在某些實施方式中，較早的時間點是至少6周前。在某些實施方式中，較早的時間點是至少兩個月前。在某些實施方式中，較早的時間點是至少三個月前。在某些實施方式中，較早的時間點是至少六個月前。在某些實施方式中，較早的時間點是至少九個月前。在某些實施方式中，較早的時間點是至少一年前。本領(lǐng)域技術(shù)人員可以根據(jù)正常的考慮測定對于特定受試者的適當(dāng)測試時間間隔。如本文所使用的，與對照樣品或受試者相比“變化的”、“改變的”或“調(diào)節(jié)的”被理解為水平與來自正常的、未處理的或?qū)φ諛悠返臉悠方y(tǒng)計差異的待檢測的分析物或者診斷或治療指示劑(例如，本發(fā)明的標(biāo)志物)的水平。統(tǒng)計顯著性的確定是在本領(lǐng)域的技術(shù)人員的能力范圍內(nèi)，例如，構(gòu)成正結(jié)果的距平均值的標(biāo)準(zhǔn)偏差數(shù)。如果細(xì)胞用藥物處理導(dǎo)致本文所提供的至少一種標(biāo)志物的水平相對于“正常的”或適當(dāng)?shù)膶φ盏乃浇y(tǒng)計學(xué)顯著的改變，該藥物被認(rèn)為是“心臟毒性”的。應(yīng)當(dāng)理解，并非藥物的所有濃度一定導(dǎo)致至少一種標(biāo)志物的水平的統(tǒng)計學(xué)顯著的變化。在一個優(yōu)選的實施方式中，如果藥物的治療相關(guān)的濃度導(dǎo)致至少一種或多種標(biāo)志物的水平統(tǒng)計學(xué)顯著的變化，該藥物被認(rèn)為潛在地具有心臟毒性。當(dāng)救援劑以治療相關(guān)的濃度存在，如果標(biāo)志物的水平以在統(tǒng)計學(xué)顯著的方式朝向“正常細(xì)胞”中的標(biāo)志物水平調(diào)節(jié)，“救援劑”被認(rèn)為有效地降低心臟毒性。在一個優(yōu)選的實施方式中，救援劑將標(biāo)志物恢復(fù)至與對照細(xì)胞中標(biāo)志物的水平非顯著差異的水平。如本文所用的，術(shù)語“獲得”在此應(yīng)理解為制造、購買或以其它方式占有?！吧飿悠贰被颉笆茉囌邩悠贰笔瞧渲心康臉?biāo)志物可能存在的體液或組織。在某些實施方式中，樣品是血液、嘔吐物、唾液、淋巴、囊液、尿液、通過支氣管肺泡灌洗收集的流體、通過腹膜漂洗收集的流體或婦科流體。在一個實施方式中，受試者樣品是血液樣品或它們的組分(例如，血清)。所述樣品可以是來自受試者的組織樣品，例如來自受試者的心臟組織樣品。在某些實施方式中，該組織選自于骨骼、結(jié)締組織、軟骨、肺、肝、腎、肌肉組織、心臟、胰腺和皮膚。細(xì)胞樣品或來自實驗室動物的樣品可以被用在本文所提供的許多相同的實驗方法中用于人的生物或受試者樣品中。如本文所使用的，“檢測”、“測定”等被理解為是指執(zhí)行用于識別樣品中的特定標(biāo)志物，例如，包括脂質(zhì)生物標(biāo)志物的任何本文提供的生物標(biāo)志物的試驗。樣品中檢測的標(biāo)志物表達(dá)、活性或水平的量可以是沒有或低于所述測定或方法的檢測水平。“本發(fā)明的蛋白質(zhì)”包括標(biāo)志物蛋白質(zhì)和它們的片段；變體標(biāo)志物蛋白質(zhì)和它們的片段；肽和多肽，其包含標(biāo)志物或變體標(biāo)志物蛋白質(zhì)的至少15個氨基酸的片段；和包含標(biāo)志物或變體標(biāo)志物蛋白質(zhì)或者標(biāo)志物或變體標(biāo)志物蛋白質(zhì)的至少15個氨基酸的片段的融合蛋白質(zhì)。在某些實施方式中，本發(fā)明的蛋白質(zhì)是足夠大以允許抗體與標(biāo)志物特異性結(jié)合的肽序列或表位。本發(fā)明進(jìn)一步提供了特異性結(jié)合于本發(fā)明的標(biāo)志物蛋白和標(biāo)志物蛋白片段的抗體、抗體衍生物和抗體片段。除非其中另有指南，術(shù)語“抗體”和“多種抗體”寬泛地包括天然存在的抗體的形式(例如，igg、iga、igm、ige)和重組抗體如單鏈抗體、嵌合的和人源化的抗體和多特異性抗體，以及所有前述的片段和衍生物，該片段和衍生物具有至少抗原結(jié)合位點。抗體衍生物可包含與抗體偶聯(lián)的蛋白質(zhì)或化學(xué)部分?！氨景l(fā)明的基因”包括標(biāo)志物基因和它們的片段；變體標(biāo)志物基因和它們的片段；核酸和互補(bǔ)序列、包含標(biāo)志物或變體標(biāo)志物基因的至少15個連續(xù)核苷酸的基因片段；和編碼包含標(biāo)志物或變體標(biāo)志物蛋白或者標(biāo)志物或變體標(biāo)志物蛋白的至少15氨基酸的片段的融合蛋白的核酸。在某些實施方式中，本發(fā)明的基因是核酸序列的足夠大的部分以允許互補(bǔ)核酸與標(biāo)志物特異性結(jié)合。如本文所用的，“更高的預(yù)測值”理解為比其所比較的測試具有顯著更高的靈敏度和/或特異性，優(yōu)選更高的靈敏度和特異性的分析?？梢允褂茫?，roc分析確定測試的預(yù)測值。在roc分析中，提供正常和疾病狀態(tài)之間完美區(qū)分或精度的測試的曲線下面積(auc)＝1.0，而不能提供比隨機(jī)更好的區(qū)分的很差的測試auc＝0.5。如本文所使用的，具有較高預(yù)測值的測試比另一試驗具有統(tǒng)計學(xué)改進(jìn)的auc。在某些實施方式中，提供正常和疾病狀態(tài)之間的區(qū)分或精確度的測試的roc分析具有至少0.65、至少0.7、至少0.75、至少0.8、至少0.85、至少0.9、至少0.91、至少0.92、至少0.93、至少0.94、至少0.95、至少0.96、至少0.97、至少0.98、至少0.99或更大的auc。在一個優(yōu)選的實施方式中，auc與0.5顯著不同。該試驗是在合適的受試者群體中進(jìn)行。如本文所用的，“形成復(fù)合物”應(yīng)理解為在允許標(biāo)志物和探針之間形成復(fù)合物的條件下將疑似含有標(biāo)志物(例如，肽、核酸標(biāo)志物、脂質(zhì)標(biāo)志物、酶標(biāo)志物)的樣品與疑似存在于樣品中的標(biāo)記物形成復(fù)合物的標(biāo)志物特異性結(jié)合劑或探針結(jié)合。在某些實施方式中，所形成的復(fù)合物的水平可以低于用來檢測所形成的復(fù)合物的分析的檢測水平。如本文所用的，“從細(xì)胞分離標(biāo)志物”應(yīng)理解為從來自目的受試者的細(xì)胞的環(huán)境中移除標(biāo)志物的任何方法，其可以包括獲得活檢樣本和處理細(xì)胞，獲得受試者樣品，例如血液或血清樣品，例如，從與心臟細(xì)胞的接觸移除。在體外，從細(xì)胞分離標(biāo)志物可以理解為處理細(xì)胞以使標(biāo)志物可被檢測。細(xì)胞提取的方法，例如，用有機(jī)溶劑來分離脂質(zhì)或無機(jī)溶劑以分離蛋白質(zhì)和核酸用于分析是本領(lǐng)域技術(shù)人員中已知的。應(yīng)該理解，從細(xì)胞移除的樣品中存在的標(biāo)志物的量可以低于試驗的檢測水平。術(shù)語“基因組”是指生物實體(細(xì)胞、組織、器官、系統(tǒng)、生物體)的遺傳信息的全部。它在dna或rna中(例如在某些病毒中)編碼?；蚪M包括基因和dna的非編碼序列。術(shù)語“蛋白質(zhì)組”是指在給定時間由基因組、細(xì)胞、組織或生物體表達(dá)的一整套蛋白質(zhì)。更具體地，它可以是指在限定的條件下在給定時間在給定類型的細(xì)胞或生物體中整套的表達(dá)蛋白質(zhì)。蛋白質(zhì)組可以包括由于，例如，基因的可變剪接和/或翻譯后修飾(如糖基化或磷酸化)導(dǎo)致的蛋白質(zhì)變體。術(shù)語“轉(zhuǎn)錄組”是指在給定時間在一個或一群細(xì)胞中產(chǎn)生的一整套轉(zhuǎn)錄的rna分子，包括mrna、rrna、trna、微rna和其它非編碼rna。該術(shù)語可應(yīng)用于給定生物體中的總轉(zhuǎn)錄物集合，或應(yīng)用于特定細(xì)胞類型中存在的轉(zhuǎn)錄物的特定子集。與對于給定的細(xì)胞系(不包括突變)大致固定的基因組不同，轉(zhuǎn)錄組可以根據(jù)外部環(huán)境條件的不同而不同。因為它包括細(xì)胞中的所有mrna轉(zhuǎn)錄物，轉(zhuǎn)錄組反映在任何特定時間活躍地表達(dá)的基因，例外是mrna降解現(xiàn)象，如轉(zhuǎn)錄衰減。轉(zhuǎn)錄組學(xué)(也稱作表達(dá)譜)的研究檢驗在給定的細(xì)胞群體中mrna的表達(dá)水平，通常采用基于dna微陣列技術(shù)的高通量技術(shù)。術(shù)語“代謝組”是指在給定的時間給定的條件下在生物樣品(如單一有機(jī)體)中發(fā)現(xiàn)的整個小分子代謝物(如代謝中間體、激素和其他信號傳導(dǎo)分子以及次級代謝產(chǎn)物)集合。代謝組是動態(tài)的，且可能隨時間變化。術(shù)語“脂質(zhì)組”是指在給定的時間給定的條件下在生物樣品(如單個有機(jī)體)中發(fā)現(xiàn)的整個脂質(zhì)集合。該脂質(zhì)組是動態(tài)的，且可能隨時間變化。術(shù)語“相互作用組”是指在被研究的生物系統(tǒng)(例如，細(xì)胞)中的整個分子間相互作用的集合。它可以被顯示為有向圖。分子間相互作用可以在屬于不同的生物化學(xué)家族的分子(蛋白質(zhì)、核酸、脂質(zhì)、碳水化合物等)之間和也可以在給定的家族內(nèi)發(fā)生。當(dāng)就蛋白質(zhì)組學(xué)方面而言，相互作用組指蛋白質(zhì)-蛋白質(zhì)相互作用網(wǎng)絡(luò)(ppi)或蛋白質(zhì)相互作用網(wǎng)絡(luò)(pin)。相互作用組的另一廣泛研究類型是蛋白質(zhì)-dna相互作用組(即通過轉(zhuǎn)錄因子和dna或染色質(zhì)調(diào)節(jié)蛋白形成的網(wǎng)絡(luò))以及它們的靶基因。術(shù)語“細(xì)胞輸出”包括與細(xì)胞的狀態(tài)有關(guān)的參數(shù)(優(yōu)選可測量的參數(shù))的集合，包括，但不限于，一種或多種基因的轉(zhuǎn)錄水平(例如，可通過rt-pcr、qpcr、微陣列等測量的)、一種或多種蛋白質(zhì)的表達(dá)水平(例如，可通過質(zhì)譜法或蛋白質(zhì)印跡測量的)、一種或多種酶或蛋白質(zhì)的絕對活性(例如，可測量為底物轉(zhuǎn)化率)或相對活性(例如，可測量為相對于最大活性的％值)、一種或多種代謝物或中間體的水平、氧化磷酸化的水平(例如，可由耗氧率或ocr測量)、糖酵解的水平(例如，可由細(xì)胞外酸化率或ecar測量)、配體-靶結(jié)合或相互作用程度、細(xì)胞外分泌分子的活性等。細(xì)胞輸出可以包括預(yù)定數(shù)目的靶基因或蛋白質(zhì)等的數(shù)據(jù)，或者可以包括用于所有可檢測的基因或蛋白質(zhì)的總體評估。例如，質(zhì)譜法可用于鑒定和/或定量在給定的樣品或細(xì)胞群體中表達(dá)的所有可檢測的蛋白質(zhì)而無需事先知道任何特定的蛋白質(zhì)是否可以在樣品或細(xì)胞群體中表達(dá)。如本文所使用的，“細(xì)胞系統(tǒng)”包括同質(zhì)或異質(zhì)細(xì)胞群體。系統(tǒng)內(nèi)的細(xì)胞可以在天然或生理環(huán)境中體內(nèi)生長，或可以在，例如，在受控的組織培養(yǎng)環(huán)境中體外生長。系統(tǒng)內(nèi)的細(xì)胞可以是相對均質(zhì)的(例如，不低于70％、80％、90％、95％、99％、99.5％、99.9％均質(zhì)的)，或者可以包含兩種或更多種細(xì)胞類型，如通常發(fā)現(xiàn)在體內(nèi)接近生長的細(xì)胞類型，或可以通過，例如，旁分泌或其他長距離細(xì)胞間通訊在體內(nèi)彼此相互作用的細(xì)胞類型。細(xì)胞系統(tǒng)內(nèi)的細(xì)胞可以源自已建立的細(xì)胞系，包括癌細(xì)胞系、永生細(xì)胞系或正常細(xì)胞系，或者可以是原代細(xì)胞或從活組織或器官新分離的細(xì)胞。細(xì)胞系統(tǒng)中的細(xì)胞通常與可以提供可以的營養(yǎng)物、氣體(氧氣或二氧化碳等)、化學(xué)物質(zhì)或蛋白質(zhì)性/非蛋白質(zhì)性刺激劑(其規(guī)定影響細(xì)胞行為的條件)的“細(xì)胞環(huán)境”相接觸。細(xì)胞環(huán)境可以是具有規(guī)定的化學(xué)成分和/或較少限定的組織提取物或血清組分的化學(xué)介質(zhì)，并且可以包括細(xì)胞生長的特定ph、co2含量、壓力和溫度?？商娲?，細(xì)胞環(huán)境可以是對于特定細(xì)胞系統(tǒng)在體內(nèi)發(fā)現(xiàn)的天然或生理環(huán)境。在某些實施方式中，細(xì)胞環(huán)境包含模擬生物系統(tǒng)或過程的方面的條件，例如，模擬疾病狀態(tài)、過程或環(huán)境。這樣的培養(yǎng)條件包括，例如，高血糖、缺氧或富乳酸條件。在本文中描述了許多其它的這類條件。在某些實施方式中，用于特定細(xì)胞系統(tǒng)的細(xì)胞環(huán)境還包括細(xì)胞系統(tǒng)的某些細(xì)胞表面特征，如在細(xì)胞表面上的受體或配體的類型和它們相應(yīng)的活性、碳水化合物或脂質(zhì)分子的結(jié)構(gòu)、膜極性或流動性、某些膜蛋白的簇集狀態(tài)等。這些細(xì)胞表面特征可以影響附近細(xì)胞的功能，如屬于不同細(xì)胞系統(tǒng)的細(xì)胞。然而，在某些其他實施方式中，細(xì)胞系統(tǒng)的細(xì)胞環(huán)境不包括細(xì)胞系統(tǒng)的細(xì)胞表面特征。細(xì)胞環(huán)境可以被改變?yōu)椤靶揎椀募?xì)胞環(huán)境”。改變可以包括在細(xì)胞環(huán)境中發(fā)現(xiàn)的任何一種或多種組分的變化(例如，增加或減少)，包括對細(xì)胞環(huán)境添加一種或多種“外部刺激成分”。環(huán)境擾動或外部刺激成分可以是細(xì)胞環(huán)境內(nèi)源的(例如，細(xì)胞環(huán)境包含某些水平的刺激物，和加入更多的相同刺激物以增加其水平)，或者可以是細(xì)胞環(huán)境外源的(如，改變之前細(xì)胞環(huán)境中大部分不存在的刺激物)。細(xì)胞環(huán)境可以通過加入外部刺激成分導(dǎo)致的次級變化而進(jìn)一步改變，因為外部刺激成分可以改變細(xì)胞系統(tǒng)的細(xì)胞輸出，包括由細(xì)胞系統(tǒng)分泌到細(xì)胞環(huán)境中的分子。如本文所使用的，“外部刺激成分”，在此也稱為“環(huán)境擾動”，包括可能會影響細(xì)胞功能的任何外部物理和/或化學(xué)刺激物。這可以包括任何大的或小的有機(jī)或無機(jī)分子、天然或合成的化學(xué)物質(zhì)、溫度偏移、ph變化、輻射、光(uva、uvb等)、微波、聲波、電流、調(diào)制的或未調(diào)制的磁場等。冠詞“一”和“一個”在本文中用于指一個或超過一個(即至少一個)所述冠詞的語法對象。以舉例的方式，“一個元素”意指一個元素或多于一個元素。術(shù)語“包括”在本文中用于指短語“包括但不限于”，并可與其互換使用。術(shù)語“或”在本文中包含地使用，并可與術(shù)語“和/或”互換使用，除非上下文另有明確說明。術(shù)語“例如”在本文中用于指短語“例如但不限于”，并可與其互換使用。除非特別說明或者從上下文中顯而易見的，本文所用的術(shù)語“約”被理解為在本領(lǐng)域中正常公差的范圍內(nèi)，例如在平均值的2個標(biāo)準(zhǔn)偏差內(nèi)。約可以被理解為在所述值的10％、9％、8％、7％、6％、5％、4％、3％、2％、1％、0.5％、0.1％、0.05％或0.01％內(nèi)。除非從上下文另外清楚的，本文所提供的所有數(shù)值可以通過術(shù)語約進(jìn)行修飾。本文的變量的任何定義中化學(xué)基團(tuán)列表的敘述中包括該變量作為所列舉基團(tuán)的任何單一基團(tuán)或組合的定義。本文的變量或方面的實施方式的敘述包括該實施方式作為任何單一實施方式或與任何其他實施方式或其部分組合。本文所提供的任何組合物或方法可與本文所提供的任何其他組合物和方法的一種或多種進(jìn)行組合。本文所提供的范圍被理解為范圍內(nèi)的所有值的簡寫。例如，1至50的范圍被理解為包括由1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49或50組成的組的任意數(shù)、數(shù)的組合或子范圍?，F(xiàn)在將對本發(fā)明的示例性實施方式進(jìn)行詳細(xì)地說明。盡管結(jié)合示例性實施方式對本發(fā)明進(jìn)行描述，但是應(yīng)該理解，其并不旨在將本發(fā)明限制于那些實施方式。與此相反，它旨在覆蓋可以被包括在通過所附權(quán)利要求書所限定的本發(fā)明的精神和范圍內(nèi)的替換、修改和等同物。本發(fā)明的標(biāo)志物及其用途本發(fā)明至少部分地基于識別與心血管疾病相關(guān)的生物標(biāo)志物，該心血管疾病包括心力衰竭、心肌病和誘導(dǎo)的毒性，例如，藥物誘導(dǎo)的心臟毒性，如藥物誘導(dǎo)心臟毒性，或藥物誘導(dǎo)毒性對擾動的反應(yīng)，例如治療或救援劑。標(biāo)志物也可用于檢測由于任何原因引起的心血管疾病和心肌病，例如遺傳或生理異?；驌p傷(例如，缺血性損傷、心血管病、創(chuàng)傷)。特別地，本發(fā)明涉及在實施例中描述的標(biāo)志物(以下稱為“標(biāo)志物”或“本發(fā)明的標(biāo)志物”)。本發(fā)明提供了由標(biāo)志物編碼或與標(biāo)志物對應(yīng)的核酸和蛋白質(zhì)(以下分別稱為“標(biāo)志物核酸”和“標(biāo)志物蛋白質(zhì)”)。本發(fā)明還提供了在實施例中描述的脂質(zhì)標(biāo)志物。本發(fā)明還提供了酶標(biāo)志物，例如，在實施例中描述的激酶標(biāo)志物。本發(fā)明的這些標(biāo)志物特別可用在診斷和預(yù)測誘導(dǎo)心臟毒性的狀態(tài)；開發(fā)用于各種藥物誘導(dǎo)心臟毒性狀態(tài)的藥物靶標(biāo)；篩選誘導(dǎo)心臟毒性的存在；識別引起或具有引起誘導(dǎo)心臟毒性的風(fēng)險的藥劑；識別可以減少或防止誘導(dǎo)心臟毒性(例如，毒素或藥物誘導(dǎo)心臟毒性)的救援劑；減輕、減少或預(yù)防誘導(dǎo)心臟毒性；和識別預(yù)測誘導(dǎo)心臟毒性的進(jìn)一步的標(biāo)志物。在優(yōu)選的實施方式中，誘導(dǎo)的毒性是藥物誘導(dǎo)毒性，優(yōu)選藥物誘導(dǎo)心臟毒性。還提供了用于預(yù)后、診斷和監(jiān)測心血管疾病(包括心肌病和心力衰竭)的方法?！皹?biāo)志物”是基因、蛋白質(zhì)、酶或脂質(zhì)，其在組織或細(xì)胞中的水平相對于它在正常或健康組織或細(xì)胞中水平的改變與心血管疾病(例如，心肌病)、藥物誘導(dǎo)的毒性(例如，心臟毒性)或心肌病的易感性(例如由于導(dǎo)致心臟疾病或心血管疾病(如心肌病或心力衰竭)的遺傳因素或狀態(tài)，例如，糖尿病、肥胖癥、高膽固醇血癥、高血壓等，產(chǎn)生的心血管疾病)相關(guān)。“標(biāo)志物核酸”是本發(fā)明的標(biāo)志物編碼的或與之相對應(yīng)的核酸(例如，mrna、cdna)。這樣的標(biāo)志物核酸包括dna(如cdna)，其包含作為本發(fā)明的標(biāo)志物的任何基因的整個或部分序列或這樣的序列的互補(bǔ)序列。在某些實施方式中，標(biāo)志物與由原發(fā)性心臟病理導(dǎo)致的心臟疾病相關(guān)。這樣的序列是本領(lǐng)域技術(shù)人員已知的，并可以在，例如，nih政府pubmed網(wǎng)站上找到。所述標(biāo)志物核酸也包括rna，其包含本發(fā)明的任何基因標(biāo)志物的整個或部分序列或這種序列的互補(bǔ)序列，其中所有的胸苷殘基被替換為尿嘧啶殘基?！皹?biāo)志物蛋白質(zhì)”是由本發(fā)明的標(biāo)志物編碼或與之對應(yīng)的蛋白質(zhì)。標(biāo)志物蛋白質(zhì)包含任何本發(fā)明的標(biāo)志物蛋白質(zhì)的整個或部分序列。這樣的序列是本領(lǐng)域的技術(shù)人員已知的，并可以在，例如，nih政府pubmed網(wǎng)站上找到。術(shù)語“蛋白質(zhì)”和“多肽”可互換使用?！皹?biāo)志物酶”，例如，激酶，是具有活性水平變化的酶，其中該變化是由于，例如，表達(dá)水平的變化、翻譯后修飾的改變(例如，酶的磷酸化、酶的裂解)、結(jié)合伴體的變化(例如，βγ亞基從α亞基釋放)中的一種或多種而導(dǎo)致，其導(dǎo)致與其在正?；蚪】到M織或細(xì)胞中的表達(dá)水平相比酶活性的變化，與包括心力衰竭或心肌病(包括藥物誘導(dǎo)性心肌病)的心血管疾病有關(guān)。檢測酶活性變化的方法是本領(lǐng)域公知的。“標(biāo)志物脂質(zhì)”是其與正?；蚪】到M織或細(xì)胞中的水平相比改變的水平與心血管疾病(例如藥物誘導(dǎo)的毒性，例如心臟毒性)相關(guān)或與心血管疾病或心肌病相關(guān)的脂質(zhì)。脂質(zhì)參與了細(xì)胞內(nèi)和細(xì)胞外信號傳導(dǎo)。此外，與大多數(shù)蛋白質(zhì)不同，脂質(zhì)在一系列規(guī)定的步驟中進(jìn)行加工，而不是被翻譯，使得存在于樣品中的脂質(zhì)的比率(而不是樣品中特定的脂質(zhì)水平)也可以被認(rèn)為是作為誘導(dǎo)的心臟毒性(例如，藥物誘導(dǎo)心臟毒性)、心血管疾病或心肌病引起的變化的“標(biāo)志物”?！皹?biāo)志物水平”或“生物標(biāo)志物水平”是存在于樣品中的標(biāo)志物的絕對或相對量。可以通過檢測樣品中標(biāo)志物的濃度來確定標(biāo)志物水平，例如，樣品中存在的蛋白質(zhì)、脂質(zhì)或核酸的量，或樣品中酶的活性單位的數(shù)量?？梢酝ㄟ^檢測樣品中標(biāo)志物的相對濃度來確定標(biāo)志物水平，例如，與另一個樣品(例如，對照的“正?！被颉拔唇?jīng)處理”的樣品、來自較早的時間點的樣品、受到不同處理的對照樣品等)相比存在于樣品中的蛋白質(zhì)、脂質(zhì)、核酸或酶活性的量。測定標(biāo)志物水平的具體方法取決于，例如，待測定的標(biāo)志物水平的類型。標(biāo)志物的“正?！彼交虮磉_(dá)水平是未有毒性狀態(tài)或心肌病的人類受試者或患者的細(xì)胞中標(biāo)志物的(表達(dá))水平。標(biāo)志物的“過表達(dá)”、“較高水平”或“較高表達(dá)水平”是指測試樣品中高于用來評估該標(biāo)志物水平的測定法的標(biāo)準(zhǔn)誤差的水平，并且優(yōu)選比對照樣品(例如，來自不具有心臟病，例如，心肌病的健康受試者的樣品)中標(biāo)志物水平和優(yōu)選地幾個對照樣品中所述標(biāo)志物(或多種標(biāo)志物)的平均水平高至少25％、高至少35％、高至少40％、高至少50％、高至少60％、高至少75％、高至少85％或是至少兩倍、至少三倍、至少四倍、至少五倍、至少六倍、至少七倍、至少八倍、至少九倍或至少十倍。為簡單起見，如本文所用的，較高的表達(dá)水平也可以指升高的脂質(zhì)水平，雖然可以理解脂質(zhì)不是被表達(dá)的。標(biāo)志物的“較低水平”或“較低表達(dá)水平”是指測試樣品中小于對照樣品(例如，來自不具有心臟病，例如，心肌病的健康受試者的樣品)中所述標(biāo)志物的水平和優(yōu)選地幾個對照樣品中所述標(biāo)志物的平均表達(dá)水平的90％、85％、80％、75％、70％、65％、60％、55％、50％、45％、40％、35％、30％、25％、20％、15％或10％的水平(例如，表達(dá)水平)。為簡單起見，如本文所用的，較低的表達(dá)水平也指降低的脂質(zhì)水平，盡管可以理解脂質(zhì)不是被表達(dá)的?！罢；健被颉罢；磉_(dá)”理解為將先前例如，由于心血管疾病、心肌病或心臟毒性劑的治療而失調(diào)的標(biāo)志物的水平恢復(fù)到更接近正常對照水平(例如，健康受試者中的標(biāo)志物水平，未處理的細(xì)胞中的標(biāo)志物水平)的水平。在一個實施方式中，標(biāo)志物的正?；絻?yōu)選是在標(biāo)志物的正常對照值的標(biāo)準(zhǔn)差內(nèi)。在一個實施方式中，標(biāo)志物的正常化水平是在標(biāo)志物的正常對照值的兩個標(biāo)準(zhǔn)差內(nèi)。在一個實施方式中，標(biāo)志物的正?；绞窃跇?biāo)志物的正常對照值的三個標(biāo)準(zhǔn)差內(nèi)。在一個實施方式中，標(biāo)志物的正?；绞窃跇?biāo)志物的正常對照值的10％內(nèi)。在一個實施方式中，標(biāo)志物的正常化水平是在標(biāo)志物的正常對照值的25％內(nèi)。在一個實施方式中，標(biāo)志物的正?；绞窃跇?biāo)志物的正常對照值的50％內(nèi)。在一個實施方式中，標(biāo)志物的正?；奖扰c疾病或心臟毒性狀態(tài)相關(guān)的標(biāo)志物異常水平更接近于標(biāo)志物正常對照值的值。在一個實施方式中，本發(fā)明的標(biāo)志物是與藥物誘導(dǎo)心臟毒性相關(guān)的或參與藥物誘導(dǎo)心臟毒性的基因、蛋白質(zhì)或脂質(zhì)。這類參與藥物誘導(dǎo)心臟毒性的基因或蛋白質(zhì)包括，例如，本文中(例如，在序列表)中提供的標(biāo)志物。在一些實施方式中，本發(fā)明的標(biāo)志物是本文所提供的至少二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80、90、100、110、120、130、140、150、160或更多種基因、蛋白質(zhì)或脂質(zhì)的組合；或它們的任何組合。在前述的列表中列出的所有值還可以是意在作為本發(fā)明的一部分的范圍的上限或下限，例如，前述基因、蛋白質(zhì)或脂質(zhì)的1至5、1至10、1至20、1至30、2至5、2至10、3至10、4至10、5至10、2至20、3至20、4至20、5至20、10至20、10至25、10至30種；或它們的任何組合。心血管疾病和心肌病相關(guān)標(biāo)志物本發(fā)明至少部分地基于識別與心血管疾病和心肌病(包括與誘導(dǎo)的心臟毒性如藥物誘導(dǎo)心臟毒性相關(guān)的心肌病)相關(guān)的生物標(biāo)志物。下面更詳細(xì)地描述一些特別優(yōu)選的本發(fā)明的標(biāo)志物。細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子也稱為m6、ok、5f7、tcsf、cd147和bsg。由該基因編碼的蛋白質(zhì)是質(zhì)膜蛋白，其在精子發(fā)生、胚胎著床、神經(jīng)網(wǎng)絡(luò)形成以及腫瘤發(fā)展中非常重要。所編碼的蛋白質(zhì)也是免疫球蛋白超家族的成員。已經(jīng)發(fā)現(xiàn)了這種基因的編碼不同異形體的多個轉(zhuǎn)錄物變體，具體地，genbanknm_001728.3，基礎(chǔ)免疫球蛋白(basigin)異形體1前體；genbanknm_198589.2，基礎(chǔ)免疫球蛋白異形體2；genbanknm_198590.2，基礎(chǔ)免疫球蛋白異形體3；和genbanknm_198591.2，基礎(chǔ)免疫球蛋白異形體4，其在seqidno:1-8中提供。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/682中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子的水平增加指示心血管疾病，例如，心力衰竭和心肌病。hmox1hmox1也被稱為血紅素加氧酶(脫環(huán))1、ho-1、hsp32和bk286b10。由該基因編碼的蛋白質(zhì)血紅素加氧酶(其為血紅素分解代謝中必不可少的酶)裂解血紅素以形成膽綠素，其隨后由膽綠素還原酶轉(zhuǎn)化為膽紅素和一氧化碳(推定的神經(jīng)遞質(zhì))。血紅素加氧酶活性是通過其底物血紅素和通過各種非血紅素物質(zhì)誘導(dǎo)的。血紅素加氧酶以2個同功酶存在，誘導(dǎo)型血紅素加氧酶1和組成型血紅素加氧酶2。hmox1和hmox2屬于血紅素加氧酶家族。hmox1的genbank登錄號是nm_002133且氨基酸和核酸序列在seqidno:9-10中提供。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/3162中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。hmox1水平的增加指示心血管疾病，例如，心力衰竭和心肌病。igfbp7胰島素樣生長因子結(jié)合蛋白7(igfbp7)也被稱為agm、psf、taf、fstl2、ibp-7、mac25、igfbp-7、ramsvps、igfbp-7v和igfbprp1。這個基因編碼胰島素樣生長因子(igf)結(jié)合蛋白(igfbp)家族的成員。igfbp以高親和力結(jié)合igf，并且在體液和組織中調(diào)節(jié)igf的可用性，并調(diào)節(jié)igf與其受體的結(jié)合。該蛋白質(zhì)以相對低的親和力結(jié)合igf-i和igf-ii，并屬于低親和力igfbp亞家族。它也刺激前列環(huán)素的產(chǎn)生和細(xì)胞粘附。已描述這種基因的編碼不同異形體的可變剪接轉(zhuǎn)錄物變體，且一個變體已與視網(wǎng)膜動脈大動脈瘤相關(guān)(pmid:21835307)。igfbp7異形體1和2的genbank登錄號分別是nm_001553和nm_001253835，其序列提供于seqidno:11-14中。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/3490中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。igfbp7水平的增加指示心血管疾病，例如，心力衰竭和心肌病。ccdc47含的卷曲螺旋結(jié)構(gòu)域47(ccdc47)也被稱為gk001、mstp041。genbank登錄號是nm_020198且氨基酸和核酸序列示于seqidno:15-16中。ccdc47水平的增加指示心血管疾病，例如，心力衰竭和心肌病。ptx3ptx3也被稱為穿透素(pentraxin)3，長；tnfaip5；tsg-14；tnfα誘導(dǎo)蛋白5；穿透素相關(guān)基因，il-1β快速誘導(dǎo)的，腫瘤壞死因子，α誘導(dǎo)蛋白5；穿透素相關(guān)蛋白ptx3；穿透素-3；穿透素相關(guān)基因，il-1β快速誘導(dǎo)的；穿透素相關(guān)蛋白ptx3；腫瘤壞死因子α誘導(dǎo)蛋白5；腫瘤壞死因子，α誘導(dǎo)蛋白5；腫瘤壞死因子誘導(dǎo)基因14蛋白；和腫瘤壞死因子誘導(dǎo)蛋白tsg-14。genbank登錄號是nm_002852且氨基酸和核酸序列示于seqidno:17-18中。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/5806中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。ptx3水平的下降指示心血管疾病，例如，心力衰竭和心肌病。il27白細(xì)胞介素27(il27)也被稱為il-27、il-27a、il27a、il27p28、il30、p28、il-27p28亞基；il-27α亞基；il-27-a；il27-a；白細(xì)胞介素30；和白介素27亞基α。由該基因編碼的蛋白質(zhì)是異二聚體細(xì)胞因子復(fù)合物的亞基之一。這種蛋白質(zhì)與白細(xì)胞介素12a(il12a)有關(guān)。它與epstein-barr病毒誘導(dǎo)基因3(ebi3)(類似于白細(xì)胞介素12b(il12b)的蛋白質(zhì))相互作用，并形成復(fù)合物(其已被證明驅(qū)動初始的但不是記憶cd4(+)t細(xì)胞的快速擴(kuò)增。該復(fù)合物也被發(fā)現(xiàn)與白細(xì)胞介素12強(qiáng)烈協(xié)同以觸發(fā)初始cd4(+)t細(xì)胞的干擾素γ(ifng)的產(chǎn)生。這種細(xì)胞因子的生物效應(yīng)是由i類細(xì)胞因子受體(wsx1/tcrr)介導(dǎo)的。genbank登錄號是1.nm_145659且氨基酸和核酸序列示于seqidno:19-20中。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/246778中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。il27水平的增加指示心血管疾病，例如，心力衰竭和心肌病。pai1pai1也被稱為serpine1，絲氨酸蛋白酶抑制蛋白肽酶抑制劑，進(jìn)化枝e(連接蛋白，纖溶酶原激活物抑制劑1型)，成員1；pai，pai-1，pai1，planh1；內(nèi)皮細(xì)胞纖溶酶原激活物抑制劑；纖溶酶原激活物抑制劑1；絲氨酸(或半胱氨酸)蛋白酶抑制劑，進(jìn)化枝e(連接蛋白，纖溶酶原激活物抑制劑1型)，成員1；和絲氨酸蛋白酶抑制蛋白e1。這個基因編碼絲氨酸蛋白酶抑制劑(serpin)超家族的成員。該成員是組織纖溶酶原激活劑(tpa)和尿激酶(upa)的主要抑制劑，并因此是纖維蛋白溶解的抑制劑。該基因的缺陷是纖維蛋白溶酶原激活物抑制劑-1缺陷(pai-1缺陷)的原因，且該基因產(chǎn)物的高濃度與血栓形成傾向有關(guān)。已經(jīng)發(fā)現(xiàn)這種基因的編碼不同異形體的可變剪接轉(zhuǎn)錄物變體。異形體1和2的genbank登錄號分別是nm_000602和nm_001165413，和提供在seqidno:21-24中。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/5054中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。pia1水平的下降指示心血管疾病，例如，心力衰竭和心肌病。cfl2cfl2也被稱為絲切蛋白(cofilin)2(肌肉)；nem7；絲切蛋白，肌肉異形體；和絲切蛋白-2。該基因編碼參與調(diào)節(jié)肌動蛋白絲動力學(xué)的細(xì)胞內(nèi)蛋白質(zhì)。這種蛋白是核內(nèi)和細(xì)胞質(zhì)肌動蛋白桿的主要成分。它可以以絲切蛋白與肌動蛋白1：1的比例結(jié)合g-以及f-肌動蛋白，并且它以ph依賴性的方式可逆地控制肌動蛋白的聚合和解聚。該基因的突變導(dǎo)致桿狀體肌病7型，先天性肌病的一種形式?？勺兗艚赢a(chǎn)生三個轉(zhuǎn)錄物變體，但是，兩個變體編碼相同的蛋白質(zhì)。該序列可在genbank登錄號nm_001243645(絲切蛋白-2異形體2)；nm_021914(絲切蛋白-2異形體1)；和nm_138638(轉(zhuǎn)錄物變體絲切蛋白-2異形體1)中獲得。氨基酸和核酸序列被提供在seqidno:25-30中。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/1073中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。cfl2水平的增加指示性心血管疾病，例如，心力衰竭和心肌病。edil3edil3也被稱為egf樣重復(fù)和盤狀結(jié)構(gòu)域(discoidin)i樣結(jié)構(gòu)域3；del1；內(nèi)皮發(fā)育位點(developmentalendotheliallocus)-1；發(fā)育調(diào)節(jié)內(nèi)皮細(xì)胞位點1蛋白；整聯(lián)蛋白結(jié)合蛋白del1。由該基因編碼的蛋白質(zhì)是整聯(lián)蛋白配體。它在介導(dǎo)血管發(fā)生中起重要作用，并可能在血管壁重建和發(fā)育中非常重要。它也影響內(nèi)皮細(xì)胞的行為。genbank登錄號是nm_005711且氨基酸和核酸序列可以在seqidno:31-32中找到。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/10085中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。edil3水平的下降指示心血管疾病，例如，心力衰竭和心肌病。nucb1nucb1也稱為核連蛋白(nucleobindin)1、calnuc和nuc。這個基因編碼小的鈣結(jié)合ef手蛋白(efhandprotein)家族的成員。所編碼的蛋白質(zhì)被認(rèn)為在高爾基器鈣穩(wěn)態(tài)和ca(2+)調(diào)控信號轉(zhuǎn)導(dǎo)事件中具有重要作用。genbank登錄號是1.nm_006184，且氨基酸和核酸序列可以在seqidno:33-34中找到。關(guān)于該基因的其他信息可以在www.ncbi.nlm.nih.gov/gene/4924中找到，其中的全部內(nèi)容以本申請的優(yōu)先權(quán)日可用的版本通過引用并入本文中。nucb1水平的下降指示心血管疾病，例如，心力衰竭和心肌病。脂質(zhì)脂質(zhì)標(biāo)志物ped18:0-20:3/d18:1-20:2/d16:0-22:3和lpc20:3在具有心肌病的臨床診斷的糖尿病受試者(其用已知心臟毒性藥物治療)中比沒有用已知心臟毒性藥物治療的糖尿病患者和比用已知心臟毒性藥物治療的無心肌病的糖尿病患者顯著降低。因此ped18:0-20:3/d18:1-20:2/d16:0-22:3和/或lpc20:3水平的降低指示心血管疾病，包括心肌病。pd18:0-20:3與正常受試者相比的水平降低指示代表心血管疾病的心臟重構(gòu)。根據(jù)標(biāo)志物的特性，標(biāo)志物的增加或減少可以指示包括心力衰竭或心肌病的心血管疾病，或指示藥劑很可能是心臟毒性的。例如，與正常受試者相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平的降低指示受試者患有心血管疾病或具有發(fā)生心血管疾病的增加的風(fēng)險或者指示藥劑是心臟毒性的。相反地，與正常受試者相比，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物的水平?jīng)]有變化或增加指示受試者未患心血管疾病或沒有發(fā)生心血管疾病的增加的風(fēng)險或者指示藥劑不是心臟毒性的。選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平相比于正常受試者的增加指示受試者患有心血管疾病或具有發(fā)生心血管疾病的增加的風(fēng)險或者指示藥劑是心臟毒性的。相反，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物的水平相比于正常受試者的降低指示受試者未患心血管疾病或沒有發(fā)生心血管疾病的增加的風(fēng)險或指示藥劑不是心臟毒性的。對于脂質(zhì)標(biāo)志物，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平相比于正常受試者的降低指示受試者患有心血管疾病或具有發(fā)生心血管疾病的增加的風(fēng)險或指示藥劑是心臟毒性的。選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物的水平相比于正常受試者的增加指示受試者未患心血管疾病或沒有增加的風(fēng)險發(fā)生心血管疾病的增加的風(fēng)險或指示藥劑不是心臟毒性的。當(dāng)分析化合物以識別用于治療心血管疾病的藥劑時，與未處理的細(xì)胞相比，用受試化合物處理的受試細(xì)胞中選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物水平的降低指示所述受試化合物用于治療心血管疾病是無效的。反之，選自于ptx3、pai1、edil3和nuc1b的至少一種心血管疾病標(biāo)志物水平的增加指示該受試藥劑在治療心血管疾病中是有效的。當(dāng)分析化合物以識別用于治療心血管疾病的藥劑時，與未處理的細(xì)胞相比，用受試化合物處理的受試細(xì)胞中選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc47的至少一種心血管疾病標(biāo)志物水平的升高指示所述受試化合物用于治療心血管疾病是無效的。相反，選自于hmox1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2和ccdc4的至少一種心血管疾病標(biāo)志物水平的降低指示該受試藥劑在治療心血管疾病中是有效的。當(dāng)分析化合物以識別用于治療心血管疾病的藥劑時，與未處理的細(xì)胞相比，用受試化合物處理的受試細(xì)胞中選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物水平的降低指示所述受試化合物用于治療心血管疾病是無效的。相反地，選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、lpc20:3和18:0-20:3的至少一種心血管疾病標(biāo)志物水平的增加指示該受試藥劑在治療心血管疾病中是有效的。在血清中檢測到的標(biāo)志物的量作為絕對值而不是相對值可被認(rèn)為是心血管疾病的指示，包括心力衰竭或心肌病。例如，不超過1000pg/ml、900pg/ml、800pg/ml、700pg/ml、600pg/ml或500pg/ml的ccdc47的血清水平可以指示不存在心血管疾病，包括心力衰竭或心肌病。至少1300pg/ml、1400pg/ml、1500pg/ml、1600pg/ml、1700pg/ml、1800pg/ml、1900pg/ml或2000pg/ml的ccdc47的血清水平可以指示沒有心血管疾病，包括心力衰竭或心肌病。不大于10pmole/mg蛋白質(zhì)、8pmole/mg蛋白質(zhì)、6pmole/mg蛋白質(zhì)或5pmole/mg蛋白質(zhì)的ped18:0-20:3/d18:1-20:2/d16:0-22:3的血清水平可被認(rèn)為指示包括心力衰竭或心肌病的心血管疾病。至少12pmole/mg蛋白質(zhì)、14pmole/mg蛋白質(zhì)、16pmole/mg蛋白質(zhì)或20pmole/mg蛋白質(zhì)的ped18:0-20:3/d18:1-20:2/d16:0-22:3的水平可被認(rèn)為指示沒有心血管疾病，包括心力衰竭或心肌病。對于標(biāo)志物lpc20:3，不大于25pmole/mg蛋白質(zhì)、22pmole/mg蛋白質(zhì)、20pmole/mg蛋白質(zhì)、18pmole/mg蛋白質(zhì)或15pmole/mg蛋白質(zhì)的水平指示包括心力衰竭和心肌病的心血管疾病。至少30pmole/mg蛋白質(zhì)、35pmole/mg蛋白質(zhì)、40pmole/mg蛋白質(zhì)或45pmole/mg蛋白質(zhì)的lpc20:3的水平可被認(rèn)為指示沒有心血管疾病，包括心力衰竭或心肌病。本發(fā)明的診斷/預(yù)后用途本發(fā)明提供了用于在受試者中診斷心血管疾病，尤其是心力衰竭和/或其中心肌病(包括與心臟毒性劑接觸而導(dǎo)致的心肌病)的方法。本發(fā)明進(jìn)一步提供了用于預(yù)后或監(jiān)測心血管疾病(尤其是心力衰竭和/或心肌病，包括與心臟毒性劑接觸而導(dǎo)致的心肌病)對于治療性處理的反應(yīng)的方法。本發(fā)明進(jìn)一步提供了用于選擇用于治療非心臟相關(guān)疾病或病癥的治療性處理中的變化的方法，例如，降低潛在心臟毒性劑的劑量。在一個實施方式中，本發(fā)明提供了用于診斷心血管疾病尤其是心力衰竭和/或心肌病(包括與心臟毒性劑接觸而導(dǎo)致的心肌病)的方法。本發(fā)明的方法可以與熟練技術(shù)人員所使用的任何其他方法結(jié)合實施來預(yù)后心血管疾病。本文所提供的診斷和預(yù)后方法可用于確定是否應(yīng)當(dāng)對受試者進(jìn)行附加的和/或更侵入性的測試或監(jiān)測?？梢岳斫?，如心血管疾病一樣復(fù)雜的疾病很少使用單一測試診斷。因此，可以理解，本文所提供的診斷、預(yù)后和監(jiān)測方法通常與本領(lǐng)域中已知的其它方法結(jié)合使用。例如，本發(fā)明的方法可以與包括遺傳測試和/或非基于標(biāo)志物的方法(例如，醫(yī)療和家族史分析、身體檢查、血液檢查及成像和功能分析，包括胸部x-射線檢查、ekg(心電圖)、動態(tài)心電圖和事件監(jiān)測器、超聲心動圖、壓力測試、心導(dǎo)管插入術(shù)、冠狀動脈造影及心肌活檢)的方法結(jié)合進(jìn)行。還提供了用于在受試者中評估治療方案(例如，血液稀釋劑、外科手術(shù)、β-阻滯劑)的功效或者改變潛在誘導(dǎo)或加重心肌病的藥劑(即，心臟毒性劑)的非心臟相關(guān)疾病治療的效力的方法。在這些方法中評估了一對樣品(在較早的時間點或治療方案之前的從受試者獲得的第一樣品，和在較晚的時間點例如在受試者已經(jīng)經(jīng)歷了至少一部分治療方案或已改變治療方案的較晚時間點從受試者獲得的第二樣品)中標(biāo)志物的量。也可以使用本發(fā)明的方法來選擇能夠調(diào)節(jié)(例如，減少)藥劑的心臟毒性的化合物。在該方法中，心肌細(xì)胞接觸受試化合物，和測定受試化合物調(diào)節(jié)心肌細(xì)胞中本發(fā)明的一種或多種標(biāo)志物的表達(dá)和/或活性的能力，其中在心肌細(xì)胞中調(diào)節(jié)本發(fā)明的一種或多種標(biāo)志物的表達(dá)和/或活性的受試化合物被選擇為能夠減少藥劑的心臟毒性的化合物。使用本文描述的方法，可以篩選多種分子以鑒定調(diào)節(jié)本發(fā)明的標(biāo)志物的表達(dá)和/或活性的分子?？梢韵蚴茉囌咛峁┻@樣鑒定的化合物以防止或治療受試者中的心肌病。在以下章節(jié)中進(jìn)一步詳細(xì)描述本發(fā)明的各個方面。篩選心臟毒性劑或救援劑的方法使用本文描述的方法，可以篩選多種分子(特別是包括足夠小以能夠穿過細(xì)胞膜的分子)以識別調(diào)節(jié)(例如，增加或減少)本發(fā)明的標(biāo)志物的表達(dá)和/或活性的分子。可以向受試者提供這樣識別的化合物以在受試者中減少、減輕或預(yù)防藥物誘導(dǎo)的心臟毒性。因此，在另一個方面，本發(fā)明提供了一種用于識別可以減少或預(yù)防藥物誘導(dǎo)心臟毒性或者預(yù)防或治療心肌病的藥劑的方法，包括：(i)測定用毒性誘導(dǎo)藥物處理之前獲得的第一細(xì)胞樣品中存在的一種或多種生物標(biāo)志物的正常水平；(ii)測定用毒性誘導(dǎo)藥物處理之后獲得的第二細(xì)胞樣品中存在的一種或多種生物標(biāo)志物的處理水平，以確定在處理的細(xì)胞樣品中具有表達(dá)變化的一種或多種生物標(biāo)志物；(iii)測定在用毒性誘導(dǎo)藥物和救援劑處理后獲得的第三細(xì)胞樣品中存在的毒性誘導(dǎo)藥物處理樣品中具有表達(dá)水平改變的一種或多種生物標(biāo)志物的水平；及(iv)比較第三樣品中測定的一種或多種生物標(biāo)志物的水平與在所述第一樣品中測定的一種或多種生物標(biāo)志物的水平；且與第一樣品相比，該第三樣品中一種或多種生物標(biāo)志物的正常化水平指示該藥劑可以減少或預(yù)防藥物誘導(dǎo)心臟毒性或可用于預(yù)防或治療心肌病。在一個實施方式中，該一種或多種生物標(biāo)志物選自于本文所提供的標(biāo)志物。在一個實施方式中，所述細(xì)胞是心血管系統(tǒng)的細(xì)胞，例如，心肌細(xì)胞。在一個實施方式中，該細(xì)胞是糖尿病性心肌細(xì)胞。在一個實施方式中，該藥物是用于治療糖尿病、肥胖癥或心血管疾病的藥物或候選藥物。在一個實施方式中，該藥物是蒽環(huán)類藥物、5-氟尿嘧啶、順鉑、曲妥珠單抗、吉西他濱、格列酮類(如羅格列酮、吡格列酮、曲格列酮)、卡麥角林、培高利特、舒馬曲坦、二膦酸鹽或tnf拮抗劑。在一個實施方式中，與第一樣品相比，所述第三樣品中選自于本文所提供的生物標(biāo)志物的一、二、三、四、五、六、七、八、九、十、十一、十二、十三、十四、十五、十六、十七、十八、十九、二十、二十五、三十、40、50、60、70、80、90、100、110、120、130、140、150、160或更多種生物標(biāo)志物的正?；磉_(dá)水平指示該救援劑可降低或預(yù)防藥物誘導(dǎo)心臟毒性。在某些實施方式中，該標(biāo)志物是選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80或90種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4的一、二、三、四、五、六、七、八、九、十、十一、十二或十三種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4、ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6、cacna2d1、ephx1、bax、prkar2a和mpa2k3的一、二、三、四、五、六、七、八、九、十或十一種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4、ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6的一、二、三、四、五、六或七種標(biāo)志物。在一個實施方式中，該受試者是人類。在一個實施方式中，生物樣品中的一種或多種標(biāo)志物的表達(dá)水平是通過分析樣品中轉(zhuǎn)錄的多核苷酸或一部分而測定的。在一個實施方式中，其中分析轉(zhuǎn)錄的多核苷酸包括擴(kuò)增所述轉(zhuǎn)錄的多聚核苷酸。在一個實施方式中，受試者樣品中標(biāo)志物的表達(dá)水平是通過分析樣品中的蛋白質(zhì)或其部分而測定的。在一個實施方式中，使用與蛋白質(zhì)特異性結(jié)合的試劑分析所述蛋白質(zhì)。在一個實施方式中，通過分析樣品中的脂質(zhì)水平或脂質(zhì)水平的比率(例如，一種特定脂質(zhì)與另一種的比率，或一種脂質(zhì)與總脂質(zhì)的比率)來測定受試者樣品中的標(biāo)志物水平。在一個實施方式中，使用選自于所述樣品的聚合酶鏈反應(yīng)(pcr)擴(kuò)增反應(yīng)、逆轉(zhuǎn)錄酶pcr分析、單鏈構(gòu)象多態(tài)性分析(sscp)、錯配切割檢測、異源雙鏈分析、southern印跡分析、northern印跡分析、western印跡分析、原位雜交、陣列分析、脫氧核糖核酸測序、限制性片段長度多態(tài)性分析以及它們的組合或子組合的技術(shù)測定樣品中一種或多種標(biāo)志物的表達(dá)水平。在一個實施方式中，使用選自于免疫組織化學(xué)、免疫細(xì)胞化學(xué)、流式細(xì)胞術(shù)、elisa和質(zhì)譜法的技術(shù)來測定樣品中標(biāo)志物的表達(dá)水平?？梢酝ㄟ^如本文所提供的多種光譜光度測量方法之一來完成脂質(zhì)檢測。在某些實施方式中，使用色譜法測定脂質(zhì)水平。在一個實施方式中，測定多種標(biāo)志物的水平。本發(fā)明進(jìn)一步提供了用于在有需要的受試者中減輕、減少、預(yù)防或治療心肌病(包括藥物誘導(dǎo)的心臟毒性)的方法，包括向受試者(例如，哺乳動物、人類或非人類動物)施用通過本文提供的篩選方法識別的藥劑，從而在受試者中減少或預(yù)防藥物誘導(dǎo)心臟毒性。在一個實施方式中，向已經(jīng)用心臟毒性誘導(dǎo)藥物治療的受試者施用所述藥劑。在一個實施方式中，在用心臟毒性誘導(dǎo)藥物治療受試者的同時向受試者施用所述藥劑。在一個實施方式中，在用心臟毒性誘導(dǎo)藥物治療受試者之前向受試者施用所述藥劑。在某些實施方式中，該標(biāo)志物是選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa中的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80或90種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4的一、二、三、四、五、六、七、八、九、十、十一、十二或十三種標(biāo)志物。在某些實施方式中，該標(biāo)志物是ccdc47和hmox1中的一種或兩種。在某些實施方式中，標(biāo)志物是ccdc47和hmox1。在某些實施方式中，該標(biāo)志物是ccdc47、hmox1和pai-1。在某些實施方式中，該標(biāo)志物是ccdc47、hmox1和ptx3。在某些實施方式中，該標(biāo)志物是ccdc47、hmox1、pai-1和ptx3。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4；ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6、cacna2d1、ephx1、bax、prkar2a和mpa2k3的一、二、三、四、五、六、七、八、九、十或十一種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4、ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6的一、二、三、四、五、六或七種標(biāo)志物。本發(fā)明進(jìn)一步提供了可用作藥物誘導(dǎo)心臟毒性的預(yù)測標(biāo)志物的生物標(biāo)志物(例如，基因和/或蛋白質(zhì))。這些生物標(biāo)志物包括在整個申請中所提供的標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80或90種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于timp1、ptx3、hsp76、finc、cyb5、pai1、ibp7(igfbp7)、1c17、edil3、hmox1、nucb1、cs010和hspa4的一、二、三、四、五、六、七、八、九、十、十一、十二或十三種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4、ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6、cacna2d1、ephx1、bax、prkar2a和mpa2k3的一、二、三、四、五、六、七、八、九、十或十一種標(biāo)志物。在某些實施方式中，該標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3、ped18:0-22:5/d18:1-22:4、ped16:1-22:6、pep18:1-18:1/p18:0-18:2/p16:0-20:2、lpc20:3、pc-li-183-d18:22-22:6的一、二、三、四、五、六或七種標(biāo)志物。在某些實施方式中，標(biāo)志物包括至少一種脂質(zhì)標(biāo)志物。在某些實施方式中，標(biāo)志物包括至少一種激酶的標(biāo)志物。但是，普通技術(shù)人員通過使用本文描述的方法，例如，通過實施本文描述的方法但使用已知誘導(dǎo)心臟毒性的不同藥物，能夠識別另外的預(yù)測藥物誘導(dǎo)心臟毒性的生物標(biāo)志物。下面進(jìn)一步描述本發(fā)明的示例性心肌病和藥物誘導(dǎo)心臟毒性的生物標(biāo)志物。本發(fā)明的目標(biāo)包括，但不限于，本文所提供的基因、蛋白質(zhì)、酶或脂質(zhì)?；谟缮暾埲嗽诖嗣枋龅膶嶒灥慕Y(jié)果，在心血管疾病中調(diào)節(jié)的關(guān)鍵標(biāo)志物與不同的途徑或分子組相關(guān)或者可以被劃分為不同的途徑或分子組，包括細(xì)胞骨架成分、轉(zhuǎn)錄因子、細(xì)胞凋亡反應(yīng)、戊糖磷酸途徑、生物合成途徑、氧化應(yīng)激(助氧化劑)、膜改變和氧化磷酸化代謝。因此，在本發(fā)明的一個實施方式中，標(biāo)志物可以包括選自于本文所提供的標(biāo)志物中的一種或多種基因(或蛋白質(zhì))。在一些實施方式中，該標(biāo)志物是本文所提供的標(biāo)志物中至少二、三、四、五、六、七、八、九、十、十一、十二、十三、十四、十五、十六、十七、十八、十九、二十、二十五、三十、40、50、60、70、80、90、100、110、120、130、140、150、160或更多種標(biāo)志物的組合。下面描述可用于識別所鑒定的標(biāo)志物的調(diào)節(jié)劑的篩選分析。本發(fā)明還提供了用于識別通過調(diào)節(jié)本發(fā)明的標(biāo)志物的表達(dá)和/或活性用于治療或預(yù)防心肌變或毒性狀態(tài)的調(diào)節(jié)劑，即候選或受試化合物或藥劑(例如，蛋白質(zhì)、肽、肽模擬物、類肽、小分子或其他藥物)，的方法(在此也稱為“篩選分析法”)。這類分析法一般包括本發(fā)明的標(biāo)志物和一種或多種分析組分之間的反應(yīng)。其它組分可以是受試驗化合物本身，或受試化合物與本發(fā)明標(biāo)志物的天然結(jié)合伴體的組合。通過如本文所述的那些分析法鑒定的化合物可被用于，例如，調(diào)節(jié)(例如，抑制、改善、治療或預(yù)防)疾病狀態(tài)或毒性狀態(tài)的侵襲性。在某些實施方式中，本發(fā)明提供了用于識別引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑的方法，其是通過將第一細(xì)胞與受試藥劑相接觸，并檢測與受試藥劑相接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)的生物標(biāo)志物或本文所提供的任何其它標(biāo)志物的水平。在某些實施方式中，檢測一種或多種生物標(biāo)志物的水平包括形成所述的一種或多種生物標(biāo)志物的每一種與相應(yīng)的生物標(biāo)志物特異性探針之間的復(fù)合物，并檢測各生物標(biāo)志物和相應(yīng)的生物標(biāo)志物特異性探針之間復(fù)合物的形成；和/或從細(xì)胞分離所述一種或多種生物標(biāo)志物，以使得一種或多種生物標(biāo)志物的每一種特有的至少一個特征能夠被檢測；和將第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第二細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中該第二細(xì)胞是尚未接觸受試藥劑的對照細(xì)胞；其中與第二細(xì)胞相比，在所述第一細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)指示所述受試藥劑是引起心臟毒性或具有引起心臟毒性的風(fēng)險的藥劑。在其他實施方式中，本發(fā)明提供了用于識別預(yù)防、減少或治療藥物誘導(dǎo)心臟毒性的救援劑的方法，其是通過將第一細(xì)胞與心臟毒性劑接觸；將第二細(xì)胞與心臟毒性劑和候選救援劑接觸；和檢測與心臟毒性劑接觸的第一細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物或本文所提供的任何其他標(biāo)志物的水平，并進(jìn)一步檢測接觸心臟毒性劑和候選救援劑的第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平。在某些實施方式中，檢測一種或多種生物標(biāo)志物的水平包括形成所述一種或多種生物標(biāo)志物的每一種與相應(yīng)的生物標(biāo)志物特異性探針之間的復(fù)合物，并檢測在各種生物標(biāo)志物和相應(yīng)的生物標(biāo)志物特異性探針之間復(fù)合物的形成；和/或從細(xì)胞分離所述一種或多種生物標(biāo)志物，以使得一種或多種生物標(biāo)志物的每一種特有的至少一個特征能夠被檢測；和將第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第一細(xì)胞中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平相比較，其中與第一細(xì)胞相比，在所述第二細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)指示該候選救援劑是用于預(yù)防、減少或治療藥物誘導(dǎo)心臟毒性的救援劑?？梢杂扇魏慰捎玫膩碓传@得在本發(fā)明的篩選分析法中使用的受試化合物，包括天然和/或合成化合物的系統(tǒng)文庫。受試化合物也可以通過本領(lǐng)域已知的組合文庫方法中的許多途徑中的任一種獲得，包括：生物學(xué)文庫；類肽文庫(具有肽的功能性但具有新型的非肽主鏈(其具有酶降解抗性而仍然保持生物活性)的分子的文庫；見，例如，zuckermann等，1994，j.med.chem.37:2678-85)；可空間尋址平行固相或溶液相文庫；需要去卷積的合成文庫方法；“一珠一化合物”文庫方法；和使用親和層析選擇的合成文庫法。生物學(xué)文庫和類肽文庫途徑限于肽文庫，而其它四種途徑適用于肽、非肽低聚物或化合物的小分子文庫(lam,1997,anticancerdrugdes.12:145)。用于分子文庫合成的方法的實例可以在本領(lǐng)域中找到，例如在：dewitt等(1993)proc.natl.acad.sci.u.s.a.90:6909；erb等(1994)proc.natl.acad.sci.usa91:11422；zuckermann等(1994).j.med.chem.37:2678；cho等(1993)science261:1303；carrell等(1994)angew.chem.int.ed.engl.33:2059；carell等(1994)angew.chem.int.ed.engl.33:2061；和gallop等(1994)j.med.chem.37:1233中。化合物文庫可存在于溶液中(例如，houghten，1992，biotechniques13:412-421)，或在珠(lam,1991,nature354:82-84)、芯片(fodor,1993,nature364:555-556)、細(xì)菌和/或孢子(ladner,usp5,223,409)、質(zhì)粒(cull等1992,procnatlacadsciusa89:1865-1869)或噬菌體(scott和smith，1990,science249:386-390；devlin,1990,science249:404-406；cwirla等,1990,proc.natl.acad.sci.87:6378-6382；felici,1991,j.mol.biol.222:301-310；ladner，同上)上。本發(fā)明的篩選方法包括將毒性狀態(tài)細(xì)胞與受試化合物接觸并測定受試化合物調(diào)節(jié)細(xì)胞中本發(fā)明的標(biāo)志物的表達(dá)和/或活性的能力?？梢匀绫疚乃龅臏y定本發(fā)明的標(biāo)志物的表達(dá)和/或活性。在另一個實施方式中，本發(fā)明提供了用于篩選作為本發(fā)明的標(biāo)志物或其生物活性部分的底物的候選或受試化合物的分析法。而在另一個實施方式中，本發(fā)明提供了用于篩選結(jié)合本發(fā)明的標(biāo)志物或其生物學(xué)活性部分的候選或受試化合物的分析法。例如，通過將化合物與放射性同位素或酶標(biāo)記綴合以使得可以通過檢測復(fù)合物中標(biāo)記的標(biāo)志物化合物來測定所述化合物與標(biāo)志物的結(jié)合，可以實現(xiàn)受試化合物直接結(jié)合標(biāo)志物的能力的測定。例如，可以直接或間接地用131i、125i、35s、14c或3h標(biāo)記化合物(如，標(biāo)志物底物)，和通過直接計數(shù)放射性輻射或通過閃爍計數(shù)檢測放射性同位素?？蛇x地，可以用例如，辣根過氧化物酶、堿性磷酸酶或螢光素酶酶學(xué)標(biāo)記分析成分，和通過測定合適的底物向產(chǎn)物的轉(zhuǎn)化檢測酶學(xué)標(biāo)記。本發(fā)明進(jìn)一步涉及通過上述篩選分析識別的新型藥劑。因此，在合適的動物模型中進(jìn)一步使用如本文所述識別的藥劑在本發(fā)明的范圍之內(nèi)。例如，可以在動物模型中使用如本文所述識別的能夠調(diào)節(jié)本發(fā)明標(biāo)志物的表達(dá)和/或活性的藥劑以測定用這樣的藥劑治療的功效、毒性或副作用?？蛇x代地，可以在動物模型中使用如本文所述識別的藥劑以測定這種藥劑的作用機(jī)制。此外，本發(fā)明涉及使用通過上述篩選分析識別的新藥劑用于如本文所述的治療。診斷分析和標(biāo)志物檢測分析對于蛋白質(zhì)和核酸標(biāo)志物的標(biāo)志物檢測分析通?；诎ㄔ跇?biāo)志物和探針之間形成特定的復(fù)合物并檢測包含該標(biāo)志物和探針的復(fù)合物的分析法。在某些實施方式中，通過從復(fù)合物移除未結(jié)合的標(biāo)志物或未結(jié)合的探針的至少一種而檢測該復(fù)合物。在某些實施方式中，復(fù)合物的形成導(dǎo)致產(chǎn)生可檢測的信號。在某些實施方式中，蛋白質(zhì)標(biāo)志物被抗體或受體結(jié)合以形成復(fù)合物?？蛇x地，核酸被互補(bǔ)核酸結(jié)合以形成復(fù)合物。在某些實施方式中，所述復(fù)合物一旦形成基本上在剩余的分析期間保持完整。例如，標(biāo)志物-抗體復(fù)合物在基于抗體的分析，例如elisa、western印跡、免疫沉淀、免疫組織化學(xué)、蛋白質(zhì)芯片、熒光激活細(xì)胞分選術(shù)中形成?；诳贵w的蛋白質(zhì)分離方法，例如那些在harlow和lane(harlow和lane，1988,antibodies:alaboratorymanual,coldspringharborlaboratorypress,coldspringharbor,newyork)中所描述的，可用于標(biāo)志物的檢測。標(biāo)志物核酸和核酸探針之間的復(fù)合物一旦形成，可以在整個分析中保持，例如基因芯片、熒光原位雜交(fish)、southern或northern印跡，或者在整個分析中瞬時地和可能反復(fù)地形成，例如，pcr和其他核酸擴(kuò)增方法。用于檢測生物樣品中標(biāo)志物蛋白質(zhì)或核酸的存在或不存在的示例性方法包括從測試受試者獲得生物樣品(例如，體液或組織樣品)和將生物樣品與能夠檢測多肽或核酸(例如，mrna、基因組dna或cdna)的化合物或藥劑接觸。因此本發(fā)明的檢測方法可用于檢測mrna、蛋白質(zhì)、cdna或基因組dna，例如，在體外以及在體內(nèi)生物樣品中。例如，用于檢測mrna的體外技術(shù)包括pcr、微陣列或基因芯片、northern雜交和原位雜交。用于檢測標(biāo)志物蛋白質(zhì)的體外技術(shù)包括酶聯(lián)免疫吸附測定(elisa)、western印跡、斑點或狹縫印跡、免疫沉淀和免疫熒光。用于檢測基因組dna的體外技術(shù)包括southern雜交。此外，用于檢測標(biāo)志物蛋白質(zhì)的體內(nèi)技術(shù)包括向受試者引入針對蛋白質(zhì)或其片段的標(biāo)記抗體。例如，可以用放射性標(biāo)志物標(biāo)記抗體，其在受試者中的存在和位置可通過標(biāo)準(zhǔn)成像技術(shù)來檢測。這樣的診斷和預(yù)后分析法的一般原理包括在適當(dāng)?shù)臈l件下在足以使標(biāo)志物和探針相互作用并結(jié)合的時間內(nèi)制備可以包含標(biāo)志物和探針的樣品或反應(yīng)混合物，從而形成可以在反應(yīng)混合物中被移除和/或檢測的復(fù)合物。在該方法中使用的特異性探針取決于許多因素。例如，如northern、southern、斑點或狹縫印跡和原位雜交的方法通常依賴于使用單一探針以檢測每種標(biāo)志物。應(yīng)當(dāng)理解，表達(dá)水平不通過southern印跡檢測。因此，為了提供與目的標(biāo)志物序列特異性雜交的探針，通常在高嚴(yán)格的條件下，至少約20個核苷酸長度，優(yōu)選至少約30個核苷酸長度，優(yōu)選至少50個核苷酸長度的探針。當(dāng)基因是短的，探針的長度可以通過該基因的長度限制。通常探針是約500個核苷酸或更少，通常約400個核苷酸或更少，通常約300個核苷酸或更少，和通常約200個核苷酸或更少。核酸探針可以是所提供的值所包含的任何長度范圍。在其中所述標(biāo)志物核酸結(jié)合單一探針序列的方法中，所述探針序列通常包括可檢測的標(biāo)記或連接于可檢測的標(biāo)記，例如，綠。在涉及擴(kuò)增步驟的方法中，如引物延伸或pcr(包括定量或?qū)崟rpcr和原位pcr)，使用相對較短的探針(例如，通常長度約15個核苷酸至約50個核苷酸)檢測標(biāo)志物。在pcr方法中，至少兩個探針，通常被稱為“引物”，被成對使用以擴(kuò)增目的靶序列。在定量pcr的某些形式中，第三引物被用于檢測，但不擴(kuò)增靶序列。在某些實施方式中，一個或多個引物包括可檢測的標(biāo)記。在某些實施方式中，擴(kuò)增產(chǎn)物能夠結(jié)合可檢測的標(biāo)記。應(yīng)當(dāng)理解，可以在探針中使用包括非天然的堿基、糖和骨架部分的核酸來調(diào)節(jié)探針對其靶序列的親和力和/或特異性。用于檢測蛋白質(zhì)標(biāo)志物的探針一般包括抗體，典型地對于蛋白質(zhì)特異性的單克隆抗體或重組抗體?？贵w寬泛地包括抗體的天然存在形式(例如，igg、iga、igm、ige)和重組抗體如單鏈抗體、嵌合和人源化抗體及多特異性抗體，以及所有上述形式的片段和衍生物，該片段和衍生物具有至少一個抗原結(jié)合位點?？贵w衍生物可包含與抗體綴合的蛋白質(zhì)或化學(xué)部分。elisa法通常依賴于使用在標(biāo)志物上的不同位點與目的標(biāo)志物結(jié)合的兩種抗體。western印跡、斑點和狹縫印跡、免疫組織化學(xué)方法且有時elisa和免疫沉淀法依賴于使用結(jié)合于與所述探針結(jié)合的抗體(即，第二抗體)的抗體。在某些實施方式中，第二抗體被可檢測地標(biāo)記?？梢酝ㄟ^多種方式進(jìn)行用于檢測標(biāo)志物的分析。下面提供示例性的方法。例如，進(jìn)行這種分析的一種方法涉及將標(biāo)志物或探針錨定在固相支持物(也被稱為基板)上，和在反應(yīng)結(jié)束時檢測錨定在固相上的目標(biāo)標(biāo)志物/探針復(fù)合物。在這樣的方法的一個實施方式中，待分析標(biāo)志物的存在和/或濃度的來自受試者的樣品可以被錨定到載體或固相支持物上。在另一個實施方式中，相反的情況是可能的，其中探針可以被錨定到固相上和來自受試者的樣品可以允許作為該分析的非錨定組分進(jìn)行反應(yīng)。其中至少兩個不同的探針(例如，用于檢測至少兩種標(biāo)志物，或用于檢測至少一種標(biāo)志物和適當(dāng)?shù)膶φ?連接的固體支持物被稱為一組(panel)。有許多用于將分析組分錨定到固相的已建立的方法。這些包括但不限于，通過生物素和鏈霉親和素的偶聯(lián)固定的標(biāo)志物或探針分子?？梢允褂帽绢I(lǐng)域中已知的技術(shù)(例如，生物素化試劑盒，piercechemicals,rockford,il)由生物素-nhs(n-羥基-琥珀酰亞胺)制備這樣的生物素化分析組分，并在鏈霉親和素涂布的96孔板(piercechemical)的孔中固定。在某些實施方式中，可以預(yù)先制備具有固定的分析組分的表面并存儲。用于此類分析的其它合適的載體或固相支持物包括能夠結(jié)合標(biāo)志物或探針?biāo)鶎俚姆肿臃N類的任何材料。公知的支持物或載體包括但不限于玻璃、聚苯乙烯、硝基纖維素、尼龍、聚丙烯、尼龍、聚乙烯、葡聚糖、淀粉酶、天然的和改性的纖維素、聚丙烯酰胺、輝長巖以及磁鐵礦。為在組中使用，優(yōu)選的固相支持物可以容易地手動操縱，例如，載玻片、多層板(multiwallplate)、膜等。為了用上述方法進(jìn)行分析，將非固定的組分加入到其上錨定第二成分的固相上。反應(yīng)完成后，可以在使得任何形成的復(fù)合物將保持固定在固相上的條件下移除(例如，通過洗滌)未復(fù)合的組分。本文中概述的許多方法可以完成錨定至固相的標(biāo)志物/探針復(fù)合物的檢測。在一個優(yōu)選的實施方式中，探針(當(dāng)它是未錨定的分析組分時)可以用可檢測標(biāo)記(例如，酶學(xué)標(biāo)記、熒光標(biāo)記、發(fā)光標(biāo)記)進(jìn)行標(biāo)記以為了無論是直接或間接的檢測和分析讀數(shù)的目的。也可能直接檢測標(biāo)志物/探針復(fù)合物的形成而無需任一組分(標(biāo)志物或探針)的進(jìn)一步處理或者標(biāo)記，例如通過利用熒光能量轉(zhuǎn)移的技術(shù)(參見，例如，lakowicz等，5,631,169號美國專利；stavrianopoulos等，4,868,103號美國專利)。選擇第一“供體”分子上的熒光團(tuán)標(biāo)記以使得當(dāng)用適當(dāng)波長的入射光激發(fā)時，其發(fā)射的熒光能量被第二“受體”分子上的熒光標(biāo)記吸收，其隨之由于吸收的能量而能夠發(fā)熒光?；蛘撸肮w”蛋白質(zhì)分子可以簡單地利用色氨酸殘基的天然熒光能量。選擇發(fā)射不同波長的光的標(biāo)記以使得“受體”分子標(biāo)記可以與“供體”的標(biāo)記區(qū)分開。由于標(biāo)記之間能量傳遞的效率與分子間隔的距離有關(guān)，可以評估分子之間的空間關(guān)系。在分子之間發(fā)生結(jié)合的情況下，分析中“受體”分子標(biāo)記的熒光發(fā)射應(yīng)是最大的。通過本領(lǐng)域中公知的標(biāo)準(zhǔn)熒光檢測方法(例如，使用熒光計)可以方便地測量fet結(jié)合事件。在另一個實施方式中，通過利用如實時生物分子相互作用分析(bia)(見，例如，sjolander,s.和urbaniczky,c.,1991,anal.chem.63:2338-2345，和szabo等,1995,curr.opin.struct.biol.5:699-705)的技術(shù)，可以完成探針識別標(biāo)志物的能力的測定而不標(biāo)記任一分子組分(探針或標(biāo)志物)。如本文所使用的，“bia”或“表面等離子體共振”是用于實時研究生物特異性相互作用而不標(biāo)記任何相互作用物的技術(shù)(例如，biacore)。結(jié)合表面處質(zhì)量變化(指示結(jié)合事件)導(dǎo)致表面附近光折射率的改變(表面等離子共振(spr)的光學(xué)現(xiàn)象)，從而產(chǎn)生可檢測的信號，其可以用作生物分子之間實時反應(yīng)的指示?；蛘?，在另一個實施方式中，可以用標(biāo)志物和探針作為在液相中的溶質(zhì)進(jìn)行類似的診斷和預(yù)后分析。在這樣的分析中，通過多種標(biāo)準(zhǔn)技術(shù)中的任何一種，包括但不限于：差速離心、色譜、電泳和免疫沉淀，從未復(fù)合的組分分離復(fù)合的標(biāo)志物和探針。在差速離心中，可以由于基于它們不同的尺寸和密度而導(dǎo)致的不同沉降平衡通過一系列離心步驟從未復(fù)合的分析組分分離標(biāo)志物/探針復(fù)合物(參見，例如，rivas,g.和minton,a.p.,1993,trendsbiochemsci.18(8):284-7)。標(biāo)準(zhǔn)層析技術(shù)也可用于將復(fù)合的分子與非復(fù)合物分子分離。例如，凝膠過濾色譜法基于大小和通過利用柱形式的適當(dāng)凝膠過濾樹脂分離分子，例如，相對較大的復(fù)合物可以與相對較小的未復(fù)合組分分離。類似地，可以利用標(biāo)志物/探針復(fù)合物與未復(fù)合的組分相比的相對不同的電荷性質(zhì)來區(qū)分復(fù)合物與未復(fù)合的組分，例如通過使用離子交換層析樹脂。這種樹脂和色譜技術(shù)是本領(lǐng)域技術(shù)人員公知的(參見，例如，heegaard,n.h.,1998,j.mol.recognit.winter11(1-6):141-8；hage,d.s.和tweed,s.a.jchromatogrbbiomedsciappl1997oct10；699(1-2):499-525)。也可使用凝膠電泳分離復(fù)合的分析組分與未結(jié)合的組分(見，例如，ausubel等ed.,currentprotocolsinmolecularbiology,johnwiley&sons,newyork,1987-1999)。在該技術(shù)中，例如根據(jù)大小或電荷分離蛋白質(zhì)或核酸復(fù)合物。為了在電泳過程中保持結(jié)合相互作用，非變性凝膠基質(zhì)材料和不存在還原劑的條件通常是優(yōu)選的。因此對于特定的分析和其組分適當(dāng)?shù)臈l件是本領(lǐng)域技術(shù)人員所公知的。在具體的實施方式中，使用本領(lǐng)域中已知的方法，可以通過原位和通過體外形式測定生物樣品中的標(biāo)志物mrna的水平。術(shù)語“生物樣品”旨在包括自受試者分離的組織、細(xì)胞、生物流體和其分隔物，以及受試者中存在的組織、細(xì)胞和體液。許多表達(dá)檢測方法使用分離的rna。對于體外方法，可以使用不針對mrna的分離選擇的任何rna分離技術(shù)以用于從細(xì)胞純化rna(見，例如，ausubel等,ed.,currentprotocolsinmolecularbiology,johnwiley&sons,newyork1987-1999)。此外，可以使用本領(lǐng)域的技術(shù)人員熟知的技術(shù)容易地處理大量的組織樣品，如，例如，chomczynski的單步rna分離方法(1989，4,843,155號美國專利)。可以在包括，但不限于，southern或northern分析、聚合酶鏈反應(yīng)分析和探針陣列的雜交或擴(kuò)增分析中使用分離的mrna。用于檢測mrna水平的一種優(yōu)選的診斷方法包括將分離的mrna與可以與被檢測到的基因編碼的mrna雜交的核酸分子(探針)相接觸。核酸探針可以是，例如，全長cdna或其部分，如長度至少7、15、20、25、30、50、100、250或500個核苷酸或者這些值所包括的任何長度范圍且在嚴(yán)格條件下足夠與編碼本發(fā)明標(biāo)志物的mrna或基因組dna特異性雜交的寡核苷酸。在本文中描述了在本發(fā)明的診斷分析中使用的其他合適的探針。mrna與探針的雜交表明所述的標(biāo)志物正被表達(dá)。在一種形式中，mrna被固定在固體表面上并接觸探針，例如通過在瓊脂糖凝膠上運行分離的mrna和將mrna從凝膠轉(zhuǎn)移至膜，如硝化纖維。在可選的形式中，探針被固定在固體表面上，且mrna與探針接觸，例如，在基因芯片陣列或其它的核酸探針陣列中。熟練的技術(shù)人員可容易地適應(yīng)于已知的mrna檢測方法而用于檢測由本發(fā)明的標(biāo)志物所編碼的mrna的水平?？芍苽浜辽賰蓚€探針的組，其中至少一個探針特異性結(jié)合一種核酸標(biāo)志物。在某些實施方式中，組包括至少兩個不同的探針以用于結(jié)合至少兩種不同的核酸標(biāo)志物。用于測定樣品中的mrna標(biāo)志物的水平的可選方法涉及核酸擴(kuò)增的過程，例如，通過rt-pcr(mullis，1987，4,683,202號美國專利中公開的實驗性實施方式)、連接酶鏈?zhǔn)椒磻?yīng)(barany,1991,proc.natl.acad.sci.usa,88:189-193)、自持續(xù)序列復(fù)制(guatelli等,1990,proc.natl.acad.sci.usa87:1874-1878)、轉(zhuǎn)錄擴(kuò)增系統(tǒng)(kwoh等,1989,proc.natl.acad.sci.usa86:1173-1177)、q-β復(fù)制酶(lizardi等,1988,bio/technology6:1197)、滾環(huán)復(fù)制(lizardi等5,854,033號美國專利)或任何其它核酸擴(kuò)增方法，隨后使用本領(lǐng)域的技術(shù)人員公知的技術(shù)檢測擴(kuò)增的分子。如果這樣的分子以非常低的量存在，則這些檢測方案對于核酸分子的檢測是特別有用的。如本文所使用的，擴(kuò)增引物被定義為是一對核酸分子，其可以與基因的5'或3'區(qū)域(分別正和負(fù)鏈，或反之亦然)退火，并包含之間的短區(qū)域。通常，擴(kuò)增引物長度是從約10至30或約15至50個核苷酸，并側(cè)鄰約50至200個核苷酸長度的區(qū)域。在適當(dāng)條件下和用適當(dāng)?shù)脑噭?，這類引物允許擴(kuò)增包含引物側(cè)鄰的核苷酸序列的核酸分子。對于原位方法，檢測之前不需要分離mrna。在這樣的方法中，使用已知的組織學(xué)方法制備/處理細(xì)胞或組織樣品。然后將樣品固定在支持物上，典型地玻璃載玻片，且然后與能夠與編碼標(biāo)志物的mrna雜交的探針接觸。在某些實施方式中，例如，用熒光標(biāo)記直接標(biāo)記探針用于檢測。在某些實施方式中，探針包括至少一個用于酶學(xué)標(biāo)記(例如，辣根過氧化物酶(hrp)或堿性磷酸酶)或熒光標(biāo)記的結(jié)合用于檢測結(jié)合的探針的結(jié)合位點，例如，生物素結(jié)合位點。可以通過分離檢測脂質(zhì)，典型地首先通過從樣品的大量非脂質(zhì)部分提取脂質(zhì)(通常通過使用有機(jī)溶劑，例如，氯仿/甲醇)，隨后分離脂質(zhì)組分，例如通過色譜法，例如，薄層色譜法、固相萃取(spe)色譜法、高效液相色譜法(hplc或lc)、正相(np)hplc或反相(rp)hplc、親水性相互作用液體色譜(hilic)和超高效液相色譜法(uplc)。檢測是基于色譜和/或光譜性質(zhì)，如通過質(zhì)譜(ms)(包括電噴霧電離(esi)和基質(zhì)輔助激光解吸/電離(maldi))、核磁共振(nmr)光譜法、熒光光譜和雙偏振干涉的一種或多種而測定的，典型地與已知的標(biāo)記對照脂質(zhì)相比較。本文所提供的用于分離和檢測標(biāo)志物脂質(zhì)的方法可用于與本文所提供的方法相關(guān)的脂質(zhì)的檢測。maldi方法還允許原位的直接脂質(zhì)檢測。當(dāng)在已經(jīng)涂布了maldi基質(zhì)的整個組織表面獲得連續(xù)光譜，從薄的組織切片的直接分析產(chǎn)生豐富的脂質(zhì)相關(guān)的離子。分子離子的碰撞激活可以被用來測定脂質(zhì)家族和通常從結(jié)構(gòu)上定義分子種類。這種技術(shù)使得能夠檢測組織如心臟、腎和腦中的磷脂、鞘脂和甘油脂類。此外許多不同的脂質(zhì)分子種類的分布常常定義這些組織內(nèi)的解剖區(qū)域。作為基于標(biāo)志物的絕對表達(dá)水平進(jìn)行測定的替代方式，測定可基于標(biāo)志物的標(biāo)準(zhǔn)化表達(dá)水平。通過校正標(biāo)志物的絕對表達(dá)水平來標(biāo)準(zhǔn)化表達(dá)水平，這是通過其表達(dá)與非標(biāo)志物的基因(例如組成型表達(dá)的管家基因)的表達(dá)相比較。用于標(biāo)準(zhǔn)化的合適基因包括管家基因如肌動蛋白基因或上皮細(xì)胞特異性基因。該標(biāo)準(zhǔn)化允許在一個樣品(例如，患者樣品)中的表達(dá)水平與另一樣品(例如，非疾病或非毒性樣品，或在不同來源的樣品之間)對比?？蛇x地，表達(dá)水平可以被提供為相對表達(dá)水平。為測定標(biāo)志物的相對表達(dá)水平，在測定研究中的樣品表達(dá)水平之前，例如，對于正常與疾病或治療的細(xì)胞物的10或更多個樣品，優(yōu)選50個或更多個樣品測定標(biāo)志物的表達(dá)水平。測定在較大量的樣品中分析的各基因的平均表達(dá)水平，并且這被用作標(biāo)志物的基線表達(dá)水平。然后對于受試樣品測定的標(biāo)志物表達(dá)水平(絕對表達(dá)水平)除以對于該標(biāo)志物所獲得的平均表達(dá)值。這提供了相對表達(dá)水平。優(yōu)選地，在基線測定中使用的樣品來自未經(jīng)毒性劑(特別是心臟毒性劑)處理的細(xì)胞，或從未患有心血管疾病和沒有用已知心臟毒性的藥劑治療的受試者獲得。細(xì)胞源的選擇取決于相對表達(dá)水平的使用。使用在正常組織中發(fā)現(xiàn)的表達(dá)作為平均表達(dá)評分來幫助驗證分析的標(biāo)志物是否為毒性特異性的(相對于正常細(xì)胞)。此外，隨著更多的數(shù)據(jù)被累積，平均表達(dá)值可以被修正，從而提供基于累積的數(shù)據(jù)改進(jìn)的相對表達(dá)值。來自疾病細(xì)胞或毒性細(xì)胞的表達(dá)數(shù)據(jù)提供了用于分級疾病或毒性狀態(tài)的嚴(yán)重程度的手段。在某些實施方式中，本發(fā)明提供了診斷和預(yù)后心血管疾病的方法，包括以下步驟。例如，本發(fā)明提供了用于在受試者中診斷或預(yù)后心血管疾病(cvd)，例如，心肌病的方法，其是通過從受試者獲得樣品和檢測樣品中一種或多種cvd-相關(guān)生物標(biāo)志物的水平，包括選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物或本文所提供的任何其它生物標(biāo)志物。在某些實施方式中，檢測所述一種或多種cvd相關(guān)生物標(biāo)志物的水平包括在所述一種或多種生物標(biāo)志物每一種和相應(yīng)的生物標(biāo)志物特異性探針之間形成復(fù)合物，和檢測每個生物標(biāo)志物和相應(yīng)的生物標(biāo)志物特異性探針之間復(fù)合物的形成；和/或從細(xì)胞分離所述一種或多種生物標(biāo)志物以使得一種或多種生物標(biāo)志物的每一種特有的至少一個特征能夠被檢測；和比較樣品中所述一種或多種cvd相關(guān)生物標(biāo)志物的水平與對照樣品中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平，其中所述對照樣品來自未患心肌病的受試者，其中與對照樣品相比，樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平的調(diào)節(jié)指示該受試者患有或易于發(fā)生心血管疾病(cvd)，例如心肌病。此外，本發(fā)明提供了用于在受試者中監(jiān)測心血管疾病(cvd)，例如，心肌病的方法，其是通過檢測在第一時間從受試者獲得的第一樣品中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物或任何本文所提供的其它生物標(biāo)志物的水平。在某些實施方式中，檢測一種或多種cvd相關(guān)生物標(biāo)志物的水平包括形成所述一種或多種生物標(biāo)志物每一種和相應(yīng)的生物標(biāo)志物特異性探針之間的復(fù)合物，和檢測每一種生物標(biāo)志物和相應(yīng)的生物標(biāo)志物特異性探針之間復(fù)合物的形成；和/或從細(xì)胞分離所述一種或多種生物標(biāo)志物以使得一種或多種生物標(biāo)志物的每一種特有的至少一個特征能夠被檢測；和比較第一樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與在較晚的時間從受試者獲得的第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平；其中，與所述第一樣品相比，第二樣品中標(biāo)志物的水平的調(diào)節(jié)指示受試者中心血管疾病，例如，心肌病狀態(tài)的變化。本發(fā)明進(jìn)一步提供了識別用于治療心血管疾病(cvd)，例如心肌病，的化合物的方法，其是通過獲得受試細(xì)胞；將受試細(xì)胞與受試化合物相接觸；檢測與受試化合物接觸的受試細(xì)胞中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3和pc-li-183-d18:22-22:6的一種或多種心血管疾病相關(guān)生物標(biāo)志物或任何本文所提供的其它生物標(biāo)志物的水平。在某些實施方式中，檢測一種或多種cvd相關(guān)生物標(biāo)志物的水平包括形成所述一種或多種生物標(biāo)志物的每一種和相應(yīng)的生物標(biāo)志物特異性探針之間的復(fù)合物，和檢測每一種生物標(biāo)志物和相應(yīng)的生物標(biāo)志物特異性探針之間復(fù)合物的形成；和/或從細(xì)胞中分離所述一種或多種生物標(biāo)志物以使得一種或多種生物標(biāo)志物的每一種特有的至少一個特征能夠被檢測；和比較受試細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平與未接觸受試化合物的對照細(xì)胞中一種或多種cvd相關(guān)生物標(biāo)志物的水平；并選擇在受試細(xì)胞中調(diào)節(jié)一種或多種cvd相關(guān)生物標(biāo)志物的水平的受試化合物，從而識別用于在受試者中治療心血管疾病(cvd)，例如心肌病的化合物。試劑盒本發(fā)明還提供了用于識別具有心血管疾病(包括心力衰竭和/或心肌病)的風(fēng)險或患心血管疾病的受試者；或監(jiān)測具有心血管疾病(包括心力衰竭和/或心肌病)的風(fēng)險或患有心血管疾病的受試者的組合物和試劑盒。本發(fā)明還提供了用于識別具有導(dǎo)致藥物誘導(dǎo)心臟毒性的風(fēng)險的藥劑或者可以減輕藥物誘導(dǎo)心臟毒性的藥劑的組合物和試劑盒。這些試劑盒可包括一種或多種(例如，1、2、3、4、5、6、7、8、9、10或更多種)對于一種或多種(例如，1、2、3、4、5、6、7、8、9、10或更多種)本發(fā)明的標(biāo)志物的檢測特異性的試劑，和使用說明書。對于基于抗體的試劑盒，該試劑盒可以包含，例如：(1)結(jié)合標(biāo)志物蛋白質(zhì)的第一抗體(例如，連接于固相載體)；和任選地，(2)不同的第二抗體，其結(jié)合于所述蛋白質(zhì)或第一抗體且與可檢測標(biāo)記偶聯(lián)。對于基于寡核苷酸的試劑盒，該試劑盒可以包含，例如：(1)與編碼標(biāo)志物蛋白質(zhì)的核酸序列雜交的寡核苷酸，例如，可檢測地標(biāo)記的寡核苷酸，或(2)可用于擴(kuò)增標(biāo)志物核酸分子的一對引物。該試劑盒還可以包含，例如，緩沖劑、防腐劑或蛋白質(zhì)穩(wěn)定劑。該試劑盒可以進(jìn)一步包含對于檢測可檢測標(biāo)記必需的組分(例如，酶或底物)。該試劑盒還可以含有可被分析并與受試樣品相比較的對照樣品或一系列對照樣品。試劑盒的各組分可以被封閉在單獨的容器內(nèi)，和各種不同的容器全部可以連同用于解釋使用該試劑盒進(jìn)行的分析的結(jié)果的說明在單一包裝內(nèi)。本發(fā)明的試劑盒可任選地包含用于執(zhí)行本發(fā)明的方法的其他組分。以舉例的方式，該試劑盒可以包含適合于退火互補(bǔ)核酸或適合于將抗體和與其特異性結(jié)合的蛋白質(zhì)相結(jié)合的流體(例如，洗滌緩沖液、封閉劑)、一個或多個樣品隔室、描述本發(fā)明方法的性能的指導(dǎo)材料和組織特異性對照/標(biāo)準(zhǔn)品。試劑盒可以包括用于特異性檢測本發(fā)明的一種或多種脂質(zhì)標(biāo)志物的組分(例如，對照樣品，對于本發(fā)明的脂質(zhì)特異性的提取緩沖液)。試劑盒可以包括用于檢測本發(fā)明的激酶標(biāo)志物的組分(例如，激酶特異性抗體)。本發(fā)明還包括用于檢測生物樣品中標(biāo)志物蛋白質(zhì)、核酸或脂質(zhì)的存在的試劑盒。這類試劑盒可以用來測定受試者是否具有心血管疾病(包括心力衰竭和/或心肌病)的風(fēng)險或患有心血管疾病；或用于監(jiān)測具有心血管疾病(包括心力衰竭和/或心肌病)的風(fēng)險或患有心血管疾病的受試者。這類試劑盒也可用于識別很可能導(dǎo)致更高藥物誘導(dǎo)心臟毒性的藥劑，或識別可以減輕藥物誘導(dǎo)心臟毒性的藥劑。例如，該試劑盒可以包含能夠檢測生物樣品中的標(biāo)志物蛋白質(zhì)或核酸的標(biāo)記的化合物或藥劑，以及用于測定樣品中的蛋白質(zhì)或mrna的量的手段(例如，結(jié)合蛋白質(zhì)或其片段的抗體，或結(jié)合編碼蛋白質(zhì)的dna或mrna的寡核苷酸探針)。試劑盒還可以包括用于特異性檢測本發(fā)明的一種或多種脂質(zhì)標(biāo)志物的試劑。試劑盒還可以包括使用該試劑盒用于實施任何本文所提供的方法或解釋基于本文所提供的教導(dǎo)使用試劑盒所獲得的結(jié)果的說明書。該試劑盒還可以包括用于檢測樣品中與心血管疾病不相關(guān)的對照蛋白質(zhì)(例如，對于組織樣品的肌動蛋白、對于樣品中存在的標(biāo)志物量標(biāo)準(zhǔn)化的血液或血液衍生的樣品中的白蛋白)。該試劑盒還可以包括用于檢測的純化標(biāo)志物，其用作對照或用于該試劑盒進(jìn)行的分析法的定量。試劑盒包括用于在受試者中診斷心血管疾病的方法中使用的試劑組，所述試劑組包含至少兩種檢測試劑，其中每種檢測試劑對于本文所提供的標(biāo)志物之一特異性的。對于基于抗體的試劑盒，該試劑盒可以包含，例如：(1)第一抗體(例如，連接于固相載體)，其結(jié)合第一標(biāo)志物蛋白；和任選地，(2)不同的第二抗體，其結(jié)合所述第一標(biāo)志物蛋白或所述第一抗體且與可檢測標(biāo)記偶聯(lián)。在某些實施方式中，試劑盒包括(1)第二抗體(例如，連接于固相載體)，其結(jié)合第二標(biāo)志物蛋白；和任選地，(2)不同的第二抗體，其結(jié)合第二標(biāo)志物蛋白或第二抗體且與可檢測標(biāo)記偶聯(lián)。在一個實施方式中，第一和第二標(biāo)志物是本發(fā)明的任何兩種標(biāo)志物。在一個實施方式中，第一和第二標(biāo)志物是ccdc47和hmox1。在某些實施方式中，該試劑盒包含第三抗體，其結(jié)合與第一和第二標(biāo)志物蛋白不同的第三標(biāo)志物蛋白，以及結(jié)合第三標(biāo)志物蛋白或與所述第三標(biāo)志物蛋白質(zhì)結(jié)合的抗體的不同的第二抗體，其中第三標(biāo)志物蛋白與第一和第二標(biāo)志物蛋質(zhì)不同。在某些實施方式中，第三標(biāo)志物是pai1或ptx3。對于基于寡核苷酸的試劑盒，該試劑盒可以包含，例如：(1)與編碼標(biāo)志物蛋白的核酸序列雜交的寡核苷酸，例如，可檢測地標(biāo)記的寡核苷酸，或(2)可用于擴(kuò)增標(biāo)志物核酸分子的一對引物。在某些實施方式中，該試劑盒可以進(jìn)一步包括，例如：(1)與編碼第二標(biāo)志物蛋白的核酸序列雜交的寡核苷酸，例如，第二可檢測地標(biāo)記的寡核苷酸，或(2)可用于擴(kuò)增所述第二標(biāo)志物核酸分子的一對引物。第一和第二標(biāo)志物是不同的。在一個實施方式中，第一和第二標(biāo)志物是本發(fā)明的任何兩種標(biāo)志物。在一個實施方式中，第一和第二標(biāo)志物是ccdc47和hmox1。在某些實施方式中，試劑盒還可以包括，例如：(1)與編碼第三標(biāo)志物蛋白的核酸序列雜交的寡核苷酸，例如，可檢測地標(biāo)記的第三寡核苷酸，或(2)可用于擴(kuò)增第三標(biāo)志物核酸分子的一對引物，其中所述第三標(biāo)志物與第一和第二標(biāo)志物不同。在某些實施方式中，試劑盒包括針對各核酸標(biāo)志物特異性的第三引物以允許用定量pcr方法檢測。對于色譜法，試劑盒可以包括標(biāo)志物(中包括標(biāo)記的標(biāo)志物)以允許通過色譜法檢測和識別本發(fā)明的一種或多種標(biāo)志物。在某些實施方式中，用于色譜方法的試劑盒包括用于發(fā)明的一種或多種標(biāo)志物衍生化的化合物。在某些實施方式中，用于色譜方法的試劑盒包括用于解析該方法的標(biāo)志物的柱。對于檢測本發(fā)明的標(biāo)志物特異性的試劑允許檢測和定量復(fù)雜混合物(例如，血液、血清或組織樣品)中的標(biāo)志物。在某些實施方式中，所述試劑是物種特異性的。在某些實施方式中，所述試劑不是物種特異性的。在某些實施方式中，所述試劑是異形體特異性。在某些實施方式中，所述試劑不是異形體特異性。在某些實施方式中，所述試劑檢測總細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、pai-1或cfl2。在某些實施方式中，所述試劑盒還可以包含，例如，緩沖劑、防腐劑、蛋白穩(wěn)定劑、反應(yīng)緩沖液。該試劑盒可以進(jìn)一步包含檢測可檢測標(biāo)記所必需的組分(例如，酶或底物)。該試劑盒還可以含有對照樣品或一系列對照樣品，其可被分析并與受試樣品相比較。該對照可以是對照血清樣品或者純化的蛋白質(zhì)、核酸或脂質(zhì)的對照樣品，適當(dāng)時，具有已知水平的目標(biāo)標(biāo)志物。試劑盒的各組分可以被封閉在單獨的容器內(nèi)，且各種不同的容器全部可以連同用于解釋使用該試劑盒進(jìn)行的分析的結(jié)果的說明在單一包裝內(nèi)。本發(fā)明的試劑盒可任選地包含用于執(zhí)行本發(fā)明的方法的其他組分。組(panel)本發(fā)明提供用于檢測受試者樣品中一種或多種心血管疾病、心肌病或心臟毒性標(biāo)志物的試劑的組和至少一種對照試劑。在某些實施方式中，對照試劑是為了檢測用于在生物樣品中進(jìn)行檢測的標(biāo)志物，其中所述組具有其中含有用作陽性對照的和任選地定量生物樣品中存在的標(biāo)志物量的標(biāo)志物的對照樣品。在某些實施方式中，該組包括用于已知存在或不存在于生物樣品中的與心血管疾病不相關(guān)的標(biāo)志物的檢測試劑以分別提供陽性或陰性對照。該組可具有用于檢測樣品中與心血管疾病不相關(guān)的對照蛋白質(zhì)(例如，用于組織樣品的肌動蛋白，血液或血液衍生樣品中用于標(biāo)準(zhǔn)化樣品中存在的標(biāo)志物量的白蛋白)的試劑。該組可以具有用于檢測的純化標(biāo)志物以用作對照或用于用該組進(jìn)行的分析的定量。在一個優(yōu)選的實施方式中，該組包括用于檢測本發(fā)明的兩種或更多種標(biāo)志物(例如，2、3、4、5、6、7、8、9種)的試劑，優(yōu)選與對照試劑結(jié)合。在該組中，每種標(biāo)志物是由對于該標(biāo)志物特異性的試劑進(jìn)行檢測的。在某些實施方式中，該組包括重復(fù)的孔、點或部分以允許分析生物樣品和對照樣品的各種稀釋物(例如，系列稀釋)。在一個優(yōu)選的實施方式中，該組允許定量檢測本發(fā)明的一種或多種標(biāo)志物。在某些實施方式中，該組是用于檢測一種或多種標(biāo)志物的蛋白質(zhì)芯片。在某些實施方式中，該組是用于檢測一種或多種標(biāo)志物的elisa板。在某些實施方式中，該組是用于檢測一種或多種標(biāo)志物的定量pcr的板。在某些實施方式中，該檢測試劑組被提供在包括用于本發(fā)明的一種或多種標(biāo)志物的檢測試劑和至少一個對照樣品的單一裝置上。在某些實施方式中，該檢測藥劑組被提供在包括用于本發(fā)明的兩種或更多種標(biāo)志物的檢測藥劑和至少一個對照樣品的單一裝置上。在某些實施方式中，用于檢測本發(fā)明的不同標(biāo)志物的多個組具有至少一個均勻的對照樣品以促進(jìn)組間結(jié)果的比較。陣列本發(fā)明還包括包含本發(fā)明的標(biāo)志物的陣列。該陣列可用于分析陣列中一種或多種標(biāo)志物的水平。在一個實施方式中，該陣列可用于分析組織中的基因表達(dá)以確定陣列中基因的組織特異性。以這種方式，可以同時分析最多達(dá)約7600個基因的表達(dá)。這允許開發(fā)顯示在一種或多種組織中特異性表達(dá)的一組基因的譜。除了這種定性測定，本發(fā)明允許基因表達(dá)的定量。因此，不僅可確定組織中基因的組織特異性，而且一組基因的表達(dá)水平可被確定。因此，可以基于其組織表達(dá)本身和該組織中的表達(dá)水平將基因分組。這可用于，例如，確定組織之間或之中基因表達(dá)的關(guān)系。因此，可以擾動一種組織和可測定第二組織中基因表達(dá)的影響。在這種情況下，可以測定一種細(xì)胞類型響應(yīng)于生物刺激對另一種細(xì)胞類型的影響。這樣的測定對于，例如，在基因表達(dá)水平了解細(xì)胞間相互作用的影響是有用的。如果治療性地施用治療一種細(xì)胞類型但對另一種細(xì)胞類型有不良的影響的藥劑，本發(fā)明提供了確定不良影響的分子基礎(chǔ)并因此提供共施用中和劑或以其他方式處理不良影響的機(jī)會的分析法。類似地，即使在單一細(xì)胞類型中，可以在分子水平測定不良生物影響。因此，藥劑對目標(biāo)基因以外的表達(dá)的影響可被確定并抵消。在另一個實施方式中，陣列可用于監(jiān)測陣列中一種或多種基因表達(dá)的時間過程。這可發(fā)生在各種生物學(xué)背景下，如本文所公開的，例如藥物誘導(dǎo)毒性的發(fā)生、藥物誘導(dǎo)毒性的發(fā)展和過程，如與藥物誘導(dǎo)的性相關(guān)的這樣的細(xì)胞轉(zhuǎn)化。該陣列也可用于確定一個基因的表達(dá)對于相同細(xì)胞或不同細(xì)胞中的其他基因的表達(dá)的影響。這提供了，例如，對于用于治療性干預(yù)的可選分子靶標(biāo)的選擇，如果最終或下游靶標(biāo)不能被調(diào)節(jié)。該陣列也可用于確定正常和異常細(xì)胞中一種或多種基因的差異表達(dá)模式。這提供了可以用作診斷或治療性干預(yù)的分子靶的一組基因。用于獲取和制備樣品的方法在本發(fā)明的方法中有用的樣品包括表達(dá)本發(fā)明的標(biāo)志物的任何組織、細(xì)胞、組織活檢或體液樣品。在一個實施方式中，樣品可以是組織、細(xì)胞、全血、血清、血漿、口腔刮屑、唾液、腦脊髓液、尿液、糞便或支氣管肺泡灌洗液。在優(yōu)選的實施方式中，組織樣品是毒性狀態(tài)樣品。在更優(yōu)選的實施方式中，組織樣品是心血管樣品或藥物誘導(dǎo)毒性樣品?？梢酝ㄟ^本領(lǐng)域已知的多種技術(shù)從受試者獲得身體樣品，包括例如，通過使用活檢或通過刮取或擦拭某區(qū)域或通過使用針抽吸體液。用于收集各種身體樣品的方法是本領(lǐng)域公知的。適合于檢測和定量本發(fā)明的標(biāo)志物的組織樣品可以是新鮮的、冷凍的或根據(jù)本領(lǐng)域技術(shù)人員公知的方法固定的。合適的組織樣品優(yōu)選被切片并放置在顯微鏡載玻片上用于進(jìn)一步分析。可選地，固體樣品，即組織樣品，可以被溶解和/或均質(zhì)化，并隨后作為可溶性提取物進(jìn)行分析。在一個實施方式中，使用例如，液氮或二氯二氟甲烷冷凍新獲得的活檢樣品。裝載冷凍樣品用于使用，例如oct切片，和在低溫恒溫器中連續(xù)切片。將連續(xù)切片收集在玻璃顯微鏡載片上。對于免疫組織化學(xué)染色，載玻片可被涂覆，例如，鉻明礬、明膠或聚l-賴氨酸，以確保該切片粘貼到載玻片上。在另一個實施方式中，切片前將樣品固定和包埋。例如，可以將組織樣品固定在，例如，福爾馬林中，連續(xù)脫水并包埋在例如石蠟中。一旦獲得了樣品，可以使用在本領(lǐng)域中已知適合于檢測和定量本發(fā)明的標(biāo)志物的任何方法(在核酸、蛋白質(zhì)和/或脂質(zhì)水平)。這些方法是本領(lǐng)域熟知的，且包括但不限于western印跡、northern印跡、southern印跡、免疫組織化學(xué)、elisa，例如，擴(kuò)增elisa、免疫沉淀、免疫熒光、流式細(xì)胞術(shù)、免疫細(xì)胞化學(xué)、質(zhì)譜分析，例如，maldi-tof和seldi-tof、核酸雜交技術(shù)、核酸反轉(zhuǎn)錄方法和核酸擴(kuò)增方法。在特定的實施方式中，使用例如，特異性結(jié)合這些蛋白質(zhì)的抗體在蛋白質(zhì)水平檢測本發(fā)明標(biāo)志物的表達(dá)。為了使得本發(fā)明的標(biāo)志物易達(dá)到抗體結(jié)合，可能需要修飾樣品。在免疫細(xì)胞化學(xué)或免疫組織化學(xué)方法的特定方面，載玻片可以被轉(zhuǎn)移到預(yù)處理緩沖液中和任選地被加熱以增加抗原可達(dá)性。在預(yù)處理緩沖液中加熱樣品迅速破壞細(xì)胞的脂質(zhì)雙層，并使抗原(可能是新鮮標(biāo)本的情況，但通常不發(fā)生在固定標(biāo)本中)更易達(dá)到與抗體的結(jié)合。術(shù)語“預(yù)處理緩沖器”和“制備緩沖液”在本文中可互換使用以指被用于制備用于免疫染色的細(xì)胞學(xué)或組織學(xué)樣品(特別是通過提高本發(fā)明的標(biāo)志物的對于抗體結(jié)合的可達(dá)性)的緩沖液。預(yù)處理緩沖液可包含ph特異性的鹽溶液、聚合物、洗滌劑或者非離子或陰離子表面活性劑如，例如，乙氧基化陰離子或非離子表面活性劑、鏈烷酸酯或烷氧基化物或甚至這些表面活性劑的混合物或甚至使用膽汁鹽。預(yù)處理緩沖液可以是，例如，0.1％至1％的脫氧膽酸、鈉鹽的溶液或月桂醇聚醚-13羧酸鈉(例如，sandopanls)的溶液或乙氧基化陰離子復(fù)合物。在一些實施方式中，預(yù)處理緩沖液也可以被用作載玻片存儲緩沖液。用于使得本發(fā)明的標(biāo)志物蛋白質(zhì)更易于抗體結(jié)合的任何方法可以用于本發(fā)明的實施中，包括在本領(lǐng)域中已知的抗原修復(fù)方法。見，例如，bibbo等(2002)acta.cytol.46:25-29；saqi等(2003)diagn.cytopathol.27:365-370；bibbo等(2003)anal.quant.cytol.histol.25:8-11，其各自的全部內(nèi)容在此通過引用并入本文。在預(yù)處理以增加標(biāo)志物蛋白質(zhì)可達(dá)后，可以使用適當(dāng)?shù)姆忾]劑，例如，過氧化物酶封閉劑如過氧化氫封閉樣品。在一些實施方式中，可使用蛋白質(zhì)封閉劑封閉樣品以防止抗體的非特異性結(jié)合。該蛋白質(zhì)封閉劑可以包含，例如，純化的酪蛋白。然后特異性結(jié)合本發(fā)明的標(biāo)志物的抗體，特別是單克隆抗體或多克隆抗體與樣品一起孵育。本領(lǐng)域的技術(shù)人員將理解，在某些情況下，可以通過檢測患者樣品中本發(fā)明的標(biāo)志物蛋白質(zhì)上的多個表位而得到更精確的預(yù)后或診斷。因此，在具體的實施方式中，使用至少兩種針對本發(fā)明標(biāo)志物的不同表位的抗體。當(dāng)使用一種以上的抗體時，這些抗體可以作為單獨的抗體試劑順序地或作為抗體的混合物同時地添加到單一樣品?？蛇x地，各單獨的抗體可以被添加到來自同一患者的單獨樣品，并將得到的數(shù)據(jù)匯總。用于檢測抗體結(jié)合的技術(shù)是本領(lǐng)域中公知的?？梢酝ㄟ^使用產(chǎn)生對應(yīng)于抗體結(jié)合水平并因此對應(yīng)于標(biāo)志物蛋白質(zhì)的表達(dá)水平的可檢測信號的化學(xué)試劑來檢測抗體與本發(fā)明標(biāo)志物的結(jié)合。在本發(fā)明的免疫組織化學(xué)或免疫細(xì)胞化學(xué)方法之一中，通過使用與標(biāo)記的聚合物偶聯(lián)的第二抗體檢測抗體結(jié)合。標(biāo)記的聚合物的實例包括但不限于聚合物-酶偶聯(lián)物。在這些復(fù)合物中的酶通常用于催化色原在抗原-抗體結(jié)合位點的沉積，從而導(dǎo)致對應(yīng)于目標(biāo)生物標(biāo)志物表達(dá)水平的細(xì)胞染色。特別感興趣的酶包括，但不限于，辣根過氧化物酶(hrp)和堿性磷酸酶(ap)。在本發(fā)明的一個特定的免疫組織化學(xué)或免疫細(xì)胞化學(xué)方法中，通過使用與二級抗體偶聯(lián)的hrp標(biāo)記聚合物檢測抗體與本發(fā)明標(biāo)志物的結(jié)合。也可以通過使用結(jié)合單克隆抗體或多克隆抗體的物種特異性探針試劑，和與所述物種特異性探針試劑結(jié)合的hrp相偶聯(lián)的聚合物檢測抗體與本發(fā)明標(biāo)志物的結(jié)合。載玻片使用任何色原，例如，色原3,3-二氨基聯(lián)苯胺(dab)進(jìn)行抗體結(jié)合的染色，然后用蘇木和任選的染藍(lán)劑例如氫氧化銨或tbs/吐溫20復(fù)染。其它合適的色原包括，例如，3-氨基-9-乙基咔唑(aec)。在本發(fā)明的一些方面中，由細(xì)胞學(xué)技師和/或病理學(xué)家對載片進(jìn)行顯微鏡檢查以評估細(xì)胞染色，例如，熒光染色(即，標(biāo)志物表達(dá))。或者，可以通過自動化顯微鏡或通過借助有利于識別陽性染色細(xì)胞的計算機(jī)軟件由人員對樣品進(jìn)行檢查?？赏ㄟ^將抗標(biāo)志物抗體與可檢測物質(zhì)偶聯(lián)來幫助抗體結(jié)合的檢測?？蓹z測物質(zhì)的實例包括各種酶、輔基、熒光材料、發(fā)光材料、生物發(fā)光材料和放射性材料。合適的酶的實例包括辣根過氧化物酶、堿性磷酸酶、β-半乳糖苷酶或乙酰膽堿酯酶；合適的輔基復(fù)合物的實例包括鏈霉親和素/生物素和抗生物素蛋白/生物素；合適的熒光材料的實例包括傘形酮、熒光素、熒光素異硫氰酸酯、若丹明、二氯三嗪基胺熒光素、丹磺酰氯或藻紅蛋白；發(fā)光材料的實例包括發(fā)光氨；生物發(fā)光材料的例子包括螢光素酶、螢光素和水母發(fā)光蛋白；合適的放射性物質(zhì)的例子包括125i、131i、35s、14c或3h。在本發(fā)明的一個實施方式中，如上所述地制備冷凍樣品，并隨后使用以例如tris緩沖鹽水(tbs)稀釋至適當(dāng)濃度的針對本發(fā)明標(biāo)志物的抗體染色?？梢酝ㄟ^將載玻片在生物素化抗免疫球蛋白中孵育來檢測初級抗體。這一信號可以任選地放大和利用抗原的二氨基聯(lián)苯胺沉淀來可視化。此外，載玻片可以任選地使用例如蘇木精復(fù)染以可視化細(xì)胞。在另一個實施方式中，被固定和包埋的樣品用針對本發(fā)明標(biāo)志物的抗體染色，并如上對于冷凍切片所述地復(fù)染。此外，可以任選地用藥劑處理樣品來放大信號，以可視化抗體的染色。例如，可以使用生物素-酪酰胺的過氧化物酶催化的沉積，其隨之與過氧化物酶偶聯(lián)的鏈霉親和素反應(yīng)(催化的信號擴(kuò)增(csa)系統(tǒng)，dako，carpinteria，ca)?；诮M織的分析(即，免疫組織化學(xué))是檢測和定量本發(fā)明標(biāo)志物的優(yōu)選的方法。在一個實施方式中，可通過免疫組織化學(xué)來測定本發(fā)明標(biāo)志物的存在或不存在。在一個實施方式中，免疫組織化學(xué)分析使用低濃度的抗標(biāo)志物抗體，使得缺乏該標(biāo)志物的細(xì)胞不被染色。在另一個實施方式中，使用采用高濃度的抗標(biāo)志物抗體以使得缺少標(biāo)志物蛋白質(zhì)的細(xì)胞重染色的免疫組織化學(xué)方法測定本發(fā)明的標(biāo)志物的存在或不存在。未染色的細(xì)胞包含突變的標(biāo)志物并且不能產(chǎn)生可抗原識別的標(biāo)志物蛋白，或者是其中調(diào)節(jié)標(biāo)志物水平的途徑失調(diào)而導(dǎo)致可忽略的標(biāo)志物蛋白質(zhì)的穩(wěn)態(tài)表達(dá)的細(xì)胞。本領(lǐng)域的技術(shù)人員將認(rèn)識到，用于實施本發(fā)明的方法的特定抗體的濃度將根據(jù)如用于結(jié)合的時間、抗體對于本發(fā)明標(biāo)志物的特異性水平以及樣品制備方法的這類因素而變化。此外，當(dāng)多種抗體被使用時，所需濃度可能受其中抗體被施加到樣品中的順序影響，例如，作為混合物同時地或作為單獨抗體試劑依次地。此外，用于可視化抗體與本發(fā)明標(biāo)志物的結(jié)合的檢測化學(xué)也必須被優(yōu)化以產(chǎn)生所需的信噪比。在本發(fā)明的一個實施方式中，蛋白質(zhì)組學(xué)方法，例如，質(zhì)譜法，被用于檢測和定量本發(fā)明的標(biāo)志物蛋白質(zhì)。例如，可以使用基質(zhì)輔助激光解吸電離飛行時間質(zhì)譜(maldi-tofms)或表面增強(qiáng)激光解吸電離飛行時間質(zhì)譜(seldi-tofms)(其涉及應(yīng)用生物樣品如血清至蛋白質(zhì)結(jié)合芯片)(wright,g.l.,jr.等.(2002)expertrevmoldiagn2:549；li,j.等(2002)clinchem48:1296；laronga,c.等(2003)dismarkers19:229；petricoin,e.f.等(2002)359:572；adam,b.l.等(2002)cancerres62:3609；tolson,j.等(2004)labinvest84:845；xiao,z.等(2001)cancerres61:6029)來檢測和定量py-shc和/或p66-shc蛋白質(zhì)。質(zhì)譜方法被描述于，例如，5,622,824、5,605,798和5,547,835號美國專利中，其各自的全部內(nèi)容通過引用并入本文。在其他的實施方式中，在核酸水平對本發(fā)明標(biāo)志物的表達(dá)進(jìn)行檢測。用于評估表達(dá)的基于核酸的技術(shù)是本領(lǐng)域眾所周知的，和包括，例如，測定來自受試者的樣品中標(biāo)志物mrna的水平。許多表達(dá)檢測方法使用分離的rna。不針對mrna的分離選擇的任何rna分離技術(shù)可以用于從表達(dá)本發(fā)明標(biāo)志物的細(xì)胞純化rna(見，例如，ausubel等人編,(1987-1999)currentprotocolsinmolecularbiology(johnwiley&sons,newyork))。另外，使用本領(lǐng)域的技術(shù)人員所熟知的技術(shù)，例如，如chomczynski的單步rna分離方法(1989，4,843,155號美國專利)可以容易地處理大量的組織樣品?？梢允褂媚び≯E(如在雜交分析如northern、southern、斑點印跡等中使用的)或者微孔、樣品管、凝膠、珠或纖維(或者任何包含結(jié)合的核酸的固體支持物)來監(jiān)測本發(fā)明標(biāo)志物的表達(dá)水平。見5,770,722、5,874,219、5,744,305、5,677,195和5,445,934號美國專利，其通過引用引入本文。標(biāo)志物表達(dá)的檢測還可以包括使用在溶液中的核酸探針。在本發(fā)明的一個實施方式中，微陣列被用于檢測本發(fā)明標(biāo)志物的表達(dá)。微陣列因為不同實驗之間的再現(xiàn)性而特別好地適用于此目的。dna微陣列提供了一種用于同時測量大量基因的表達(dá)水平的方法。每個陣列由被連接于固相載體的捕獲探針的可重現(xiàn)模式組成。標(biāo)記的rna或dna被雜交于陣列上的互補(bǔ)探針，且然后通過激光掃描檢測。測定陣列上各探針的雜交強(qiáng)度，并轉(zhuǎn)換為表示相對基因表達(dá)水平的定量值。見，6,040,138、5,800,992和6,020,135、6,033,860和6,344,316號美國專利，其通過引用引入本文。高密度寡核苷酸陣列特別可用于測定樣品中大量rna的基因表達(dá)譜。標(biāo)志物的量和/或本發(fā)明標(biāo)志物的量的數(shù)學(xué)關(guān)系可使用本發(fā)明的方法(其可以包括本領(lǐng)域技術(shù)人員已知的回歸分析的方法)被用來計算在用藥物治療的受試者中心血管疾病(包括心力衰竭和心肌病，包括藥物誘導(dǎo)的心肌病)的風(fēng)險，治療方案用于治療、預(yù)防或抵消毒性狀態(tài)的效果，等。例如，適合的回歸模型包括，但不限于cart(如，hill,t和lewicki,p.(2006)“statisticsmethodsandapplications”statsoft,tulsa,ok)、cox(例如，www.evidence-based-medicine.co.uk)、指數(shù)、常態(tài)和對數(shù)正態(tài)的(例如，www.obgyn.cam.ac.uk/mrg/statsbook/stsurvan.html)、邏輯(例如，www.en.wikipedia.org/wiki/logistic_regression)、參數(shù)、非參數(shù)、半?yún)?shù)的(例如，www.socserv.mcmaster.ca/jfox/books/companion)、線性的(例如，www.en.wikipedia.org/wiki/linear_regression)或加性的(例如，www.en.wikipedia.org/wiki/generalized_additive_model)。在一個實施方式中，回歸分析包括標(biāo)志物的量。在另一個實施方式中，回歸分析包括標(biāo)志物的數(shù)學(xué)關(guān)系。而在另一個實施方式中，標(biāo)志物的量和/或標(biāo)志物數(shù)學(xué)關(guān)系的回歸分析可以包括額外的臨床和/或分子共變量。使用的標(biāo)志物組合在整個申請中的方法、裝置以及試劑盒是指單獨或以任何組合使用本文所提供的任何標(biāo)志物。本發(fā)明還提供了可以在包括本文所提供的方法、裝置和試劑盒的任何本發(fā)明實施方式中使用的標(biāo)志物的組合。如下提供了示例性的非限制性的標(biāo)志物組合。如本文所用的，術(shù)語“一種或多種生物標(biāo)志物”意圖指細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的至少一種(或組合)用在本發(fā)明的方法、組或試劑盒中。在本發(fā)明的某些實施方式中，“一種或多種生物標(biāo)志物”包括ccdc47和hmox1中的一種或兩種。在某些實施方式中，該“一種或多種生物標(biāo)志物”除ccdc47和hmox1中的一種或兩種外還包括ptx3。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括pai1。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括ptx3和pai1。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括至少一種脂質(zhì)標(biāo)志物。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括至少一種脂質(zhì)標(biāo)志物和igfbp7。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了包括ccdc47和hmox1的一種或兩種的組合外還包括的至少一種脂質(zhì)標(biāo)志物，其是脂質(zhì)pc-li-183-d18:2-22:6。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括il-12。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括cfl2。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括還包括edil3。在某些實施方式中，該“一種或多種生物標(biāo)志物”除了ccdc47和hmox1的一種或兩種外還包括nuc1b。在某些實施方式中，組合或組至少包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，組合或組至少包括hmox1。在某些實施方式中，組合或組至少包括igfbp7。在某些實施方式中，組合或組至少包括ccdc47。在某些實施方式中，組合或組至少包括ptx3。在某些實施方式中，組合或組至少包括il27。在某些實施方式中，組合或組至少包括pai1。在某些實施方式中，組合或組至少包括cfl2。在某些實施方式中，組合或組至少包括edil3。在某些實施方式中，組合或組至少包括nucb1。在某些實施方式中，組合或組至少包括ped18:0-20:3/d18:1-20:2/d16:0-22:3。在某些實施方式中，組合或組至少包括ped18:0-22:5/d18:1-22:4。在某些實施方式中，組合或組至少包括ped16:1-22:6。在某些實施方式中，組合或組至少包括pep18:1-18:1/p18:0-18:2/p16:0-20:2。在某些實施方式中，組合或組至少包括lpc20:3。在某些實施方式中，組合或組至少包括pc-li-183-d18:22-22:6。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少兩種。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少三種。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少四種。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少五種。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少六種。在某些實施方式中，該組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少七種。在某些實施方式中，所述組包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1中的至少八種。在某些實施方式中，標(biāo)志物的組合或組包括選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27和pai1；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、igfbp7、ccdc47、ptx3、il27和pai1；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、ccdc47、ptx3、il27和pai1；hmox1、igfbp7、ccdc47、ptx3、il27和pai1；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ptx3、il27和pai1；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、il27和pai1；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3和il27；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47和ptx3；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7和ccdc47；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1和igfbp7；細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子和hmox1；edil3、nucb1、cfl2和ptx3；nucb1、cfl2和ptx3；nucb1和ptx3；nucb1和cfl2的組合或組。在某些實施方式中，任何上述組合或組進(jìn)一步包括至少一種脂質(zhì)標(biāo)志物。在某些實施方式中，所述至少一種脂質(zhì)標(biāo)志物包括ped18:0-20:3/d18:1-20:2/d16:0-22:3。在某些實施方式中，所述至少一種脂質(zhì)標(biāo)志物包括lpc20:3。在某些實施方式中，所述至少一種脂質(zhì)標(biāo)志物包括pe18:0-20:3。在一個優(yōu)選的實施方式中，該至少一種脂質(zhì)標(biāo)志物是選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的一、二、三、四、五、六或七種標(biāo)志物，優(yōu)選除了ccdc47和hmox1的一種或兩種之外，如那些上面所提供的。在某些實施方式中，該“一種或多種生物標(biāo)志物”進(jìn)一步包括選自于ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6；cacna2d1；ephx1；bax；prkar2a和mpa2k3的一、二、三、四、五、六、七、八、九、十或十一種標(biāo)志物，優(yōu)選除了ccdc47和hmox1的一種或兩種之外。在某些實施方式中，所述組包括ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的至少兩種。在某些實施方式中，所述組包括ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的至少三種。在某些實施方式中，所述組包括ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的至少四種。在某些實施方式中，所述組包括ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；pc-li-183-d18:22-22:6的至少五種。在任何前述的實施方式中，該“一種或多種生物標(biāo)志物”進(jìn)一步包括選自于1a69、1c17、acbd3、acly、actr2、anxa6、anxa7、ap2a1、arcn1、asna1、atad3a、atp5a、atp5b、atp5d、atp5f1、atp5h、atpif1、bsg、c14orf166、ca2d1、capn1、capza2、cars、ccdc22、ccdc47、cct7、clic4、cmpk1、cnn2、co1a2、co6a1、cotl1、cox6b1、crtap、cs010、ctsa、ctsb、cyb5、ddx1、ddx17、ddx18、dld、edil3、ehd2、eif4a3、eno2、ephx1、etfa、fermt2、finc、fkb10、fkbp2、flnc、g3bp2、golga3、gpat1、gpsn2、grp75、grp78、hmox1、hnrnpd、hnrnph1、hnrpg、hpx、hsp76、hsp90ab1、hspa1a、hspa4、hspa9、ibp7、idh1、iqgap1、itb1、itgb1、kars、kif5b、kpna3、kpnb1、lamc1、lgals1、lmo7、m6prbp1、macf1、map1b、mars、mdh1、mpr1、mthfd1、myh10、ncl、nhp2l1、nucb1、ola1、p08621、p3h1、p4ha2、p4hb、sec61a1(p61619)、pai1、papss2、pcbp2、pdcd6、pdia1、pdia3、pdia3、pdia4、pdlim7、pebp1、pfkm、ph4b、plin2、pofut1、prkdc、psma1、psma7、psmd12、psmd3、psmd4、psmd6、psme2、ptbp1、q9bqe5、q9y262、rab1b、rp515a、rpl32、rpl7a、rpl8、rps25、rps6、rras2、rrp1、sar1b、sdha、senp1、sept11、sept7、serph、serpine1、sfrs2、sh3bgrl、snrpb、snx12、sod1、sprc、st13、sub1、syncrip、tagln、taz、tgm2、timp1、tln1、tpm4、trap1、tsp1、ttll12、txndc12、uba1c、ugdh、ugp2、uqcrh、vamp3和vapa的一、二、三、四、五、六、七、八、九、10、11、12、13、14、15、16、17、18、19、20、25、30、35、40、50、60、70、80或90種標(biāo)志物，優(yōu)選除了ccdc47和hmox1的一種或兩種之外。在某些實施方式中，所述組合還包括至少一種脂質(zhì)。在整個申請中提供了其它的標(biāo)志物組合。如上所給出的標(biāo)志物組合不應(yīng)被理解為是限制性的。在本發(fā)明的某些實施方式中，該一種或多種標(biāo)志物可以被排除在本發(fā)明的實施方式(包括本文所提供的方法、裝置和試劑盒)之外。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括hmox1。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包含igfbp7。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括ccdc47。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括ptx3。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括il27。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括pai1。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括cfl2。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括edil3。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括nucb1。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括任何肌鈣蛋白標(biāo)志物。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括任何心肌肌鈣蛋白。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括肌鈣蛋白i、肌鈣蛋白c和/或肌鈣蛋白t中的一種或多種。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括c反應(yīng)蛋白(crp)。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括bnp。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括grp78。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括grp75。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括timp1。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括hsp76。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括pdai4。在某些實施方式中，心肌病或心臟相關(guān)生物標(biāo)志物不包括ca2d1。藥物基因組學(xué)本發(fā)明的標(biāo)志物也可用作藥物基因組學(xué)標(biāo)志物。如本文所使用的，“藥物基因組學(xué)標(biāo)志物”是客觀的生化標(biāo)志物，其表達(dá)水平與患者中的特定臨床藥物反應(yīng)或易感性相關(guān)(見，例如，mcleod等，(1999)eur.j.cancer35(12):1650-1652)。該藥物基因組學(xué)標(biāo)志物表達(dá)的存在或量與患者的預(yù)測反應(yīng)和更具體地患者對響應(yīng)于特定藥物或藥物種類的治療的不良事件的陽性反應(yīng)的可能性相關(guān)。通過評估患者中一種或多種藥物基因組學(xué)標(biāo)志物的存在或表達(dá)的量，可以選擇最適合于患者的或者被預(yù)測為具有較大的成功程度的藥物治療。例如，基于由特定的標(biāo)志物編碼的rna或蛋白質(zhì)在患者中的存在或量，可以選擇被優(yōu)化用于治療受試者以提高期望的治療效果和減少不良事件的藥物或治療過程。因此，使用藥物基因組學(xué)標(biāo)志物允許選擇或設(shè)計用于每個患者的最適當(dāng)治療而無需嘗試不同的藥物或方案。藥物基因組學(xué)的另一個方面涉及改變機(jī)體作用于藥物的方式的遺傳條件。這些藥物基因組學(xué)條件可以作為罕見的缺陷或以多態(tài)性發(fā)生。例如，葡萄糖-6-磷酸脫氫酶(g6pd)缺陷是常見的遺傳性酶病，其中主要的臨床并發(fā)癥是攝取氧化劑藥物(抗瘧疾藥物、磺胺類藥物、止痛藥、硝基呋喃)和食用蠶豆后的溶血。作為說明性的實施方式，藥物代謝酶的活性是藥物作用的強(qiáng)度和持續(xù)時間的主要決定因素。藥物代謝酶(例如，n-乙酰基轉(zhuǎn)移酶2(nat2)及細(xì)胞色素p450酶cyp2d6和cyp2c19)遺傳多態(tài)性的發(fā)現(xiàn)對于為什么有些病人在服用標(biāo)準(zhǔn)和安全劑量的藥物后沒有獲得預(yù)期的藥物作用或表現(xiàn)出過大的藥物反應(yīng)和嚴(yán)重毒性提供了解釋。這些多態(tài)性在人群中表現(xiàn)為兩個表型，強(qiáng)代謝者(em)和弱代謝者(pm)。pm的患病率在不同人群中是不同的。例如，編碼cyp2d6的基因是高度多態(tài)性的且一些突變已經(jīng)在pm中被確定，這都導(dǎo)致缺乏功能性的cyp2d6。當(dāng)cyp2d6和cyp2c19的弱代謝者接受標(biāo)準(zhǔn)劑量時，他們很經(jīng)常地發(fā)生過大的藥物反應(yīng)和副作用。如果代謝物為活性的治療部分，pm將不顯示治療效果，如由其形成的cyp2d6代謝產(chǎn)物嗎啡介導(dǎo)的可待因鎮(zhèn)痛作用所表現(xiàn)的。另一個極端是所謂的超快速代謝者，其不對標(biāo)準(zhǔn)劑量作為反應(yīng)。最近，超快速代謝的分子基礎(chǔ)已被確定為是由于cyp2d6基因的擴(kuò)增。因此，個體中的本發(fā)明標(biāo)志物的表達(dá)水平能夠被測定，從而選擇合適的藥劑用于個體的治療或預(yù)防性治療。此外，藥物遺傳學(xué)研究可被用于將編碼藥物代謝酶的多態(tài)性等位基因的基因分型應(yīng)用于鑒定個體的藥物反應(yīng)表型。這種知識當(dāng)被應(yīng)用于給藥或藥物選擇時，可以避免用本發(fā)明標(biāo)志物的表達(dá)的調(diào)節(jié)劑治療受試者時的不良反應(yīng)或治療失敗，從而增強(qiáng)治療或預(yù)防效率。監(jiān)控臨床試驗監(jiān)測藥劑(例如，藥物化合物)對本發(fā)明標(biāo)志物的水平的影響不僅可以應(yīng)用在基本的藥物篩選中而且可以應(yīng)用在臨床試驗中。例如，可以在接受心肌病(例如，心臟毒性)或藥物誘導(dǎo)毒性治療的受試者的臨床試驗中監(jiān)測藥劑影響標(biāo)志物表達(dá)的效力。在一個優(yōu)選的實施方式中，本發(fā)明提供了用于監(jiān)測藥劑(例如，激動劑、拮抗劑、擬肽、蛋白質(zhì)、肽、核酸、小分子或其他藥物候選物)治療受試者的有效性的方法，其包括步驟：(i)在施用藥劑之前從受試者獲得給藥前樣品；(ii)檢測給藥前樣品中本發(fā)明的一種或多種選擇的標(biāo)志物的水平；(iii)從所述受試者獲得一個或多個給藥后樣品；(iv)檢測所述給藥后樣品中所述標(biāo)志物的水平；(v)比較給藥前樣品中標(biāo)志物的水平與一個或多個給藥后樣品中標(biāo)志物的表達(dá)水平；和(vi)相應(yīng)地改變向受試者的藥劑施用。例如，在治療過程中增加的標(biāo)志物基因的表達(dá)可表明無效的劑量和增加劑量的需求。相反地，標(biāo)志物基因的減少的表達(dá)可以指示有效的治療和不需要改變劑量。例如，相比于正常受試者，ptx3、pai1、edil3和nuc1b中至少一種的表達(dá)水平的降低是心肌病的指示。類似地，響應(yīng)于藥劑治療的ptx3、pai1、edil3和nuc1b中至少一種的表達(dá)水平的降低指示該藥劑是心臟毒性的。相反地，響應(yīng)于藥劑治療的ptx3、pai1、edil3和nuc1b中至少一種的表達(dá)水平的增加或者表達(dá)水平?jīng)]有降低指示該藥劑是心臟保護(hù)性的。疾病狀態(tài)的治療本發(fā)明提供了用于使用一種或多種本文所提供的標(biāo)志物治療受試者，例如，哺乳動物，例如，人類中的疾病，例如，心血管疾病，尤其是心力衰竭和/或心肌病(包括與心臟毒性劑接觸導(dǎo)致的心肌病)的方法。本發(fā)明還提供了管理用潛在心臟毒性藥劑治療的受試者(例如，需要用潛在心臟毒性劑治療的受試者)的方法，包括：(i)檢測在向受試者施用至少一部分包含潛在心臟毒性劑的第一治療方案之前從受試者獲得的第一樣品中選自于ccdc47、hmox1、ptx3、pai1、il27、igfbp7、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、cfl2、edil3、nucb1、ped18:0-20:3/d18:1-20:2/d16:0-22:3；ped18:0-22:5/d18:1-22:4；ped16:1-22:6；pep18:1-18:1/p18:0-18:2/p16:0-20:2；lpc20:3；和pc-li-183-d18:22-22:6的一種或多種cvd相關(guān)生物標(biāo)志物的水平；(ii)檢測在向受試者施用至少一部分包含潛在心臟毒性劑的第一治療方案之后從受試者獲得的第二樣品中對應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平；(iii)將第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物的水平與第一樣品中相應(yīng)的一種或多種cvd相關(guān)生物標(biāo)志物的水平進(jìn)行比較，(iv)確定所述潛在心臟毒性劑是否對受試者是心臟毒性的，其中所述第二樣品中一種或多種cvd相關(guān)生物標(biāo)志物與第一樣品相比的非調(diào)節(jié)水平指示該藥劑對于受試者不是心臟毒性的，和所述第二樣品中一種或多種生物標(biāo)志物與第一樣品相比調(diào)節(jié)的水平指示該藥劑對于受試者是心臟毒性的；和(v)基于步驟(3)的比較選擇用于受試者的治療方案。在某些實施方式中，選擇用于受試者的治療方案包括當(dāng)藥劑確定為對受試者為心臟毒性時停止或改變第一治療方案，或藥劑確定為對受試者不具心臟毒性時繼續(xù)所述第一治療方案。在某些實施方式中，該方法包括改變第一治療方案，包括減少潛在心臟毒性劑的劑量、停止用潛在的臟毒性劑治療和/或選擇潛在心臟毒性劑的替代治療劑。本發(fā)明還提供了用調(diào)節(jié)一種或多種心肌病相關(guān)標(biāo)志物的表達(dá)或活性的治療劑(例如，基于核酸或抗體的治療劑)治療患有心血管疾病(尤其特別是心力衰竭和/或心肌病，包括與心臟毒性劑接觸而導(dǎo)致的心肌病)的受試者的方法。本發(fā)明還提供了用于根據(jù)檢測本文所提供的一種或多種標(biāo)志物的水平與對照相比的變化選擇已知的治療劑或治療性干預(yù)的方法。治療方案的選擇可以進(jìn)一步包括一種或多種非基于標(biāo)志物的方法以協(xié)助選擇治療劑和干預(yù)。本發(fā)明還提供了將本文所提供的標(biāo)志物用于非心臟相關(guān)疾病治療的選擇中，其中用于治療非心臟相關(guān)病癥的治療劑可以導(dǎo)致或加劇心肌病。分離的核酸分子本發(fā)明的一個方面涉及分離的核酸分子，包括編碼標(biāo)志物蛋白質(zhì)或其一部分的核酸。本發(fā)明的分離的核酸還包括足以用作雜交探針來鑒定標(biāo)志物核酸分子的核酸分子及標(biāo)志物核酸分子的片段，例如那些適合用作pcr引物用于擴(kuò)增標(biāo)志物核酸分子的特定產(chǎn)品或突變。如本文所用的，術(shù)語“核酸分子”旨在包括dna分子(例如，cdna或基因組dna)和rna分子(如，mrna)及使用核苷酸類似物產(chǎn)生的dna或rna的類似物。所述核酸分子可以是單鏈或雙鏈的，但優(yōu)選是雙鏈的dna。“分離的”核酸分子是與核酸分子的天然來源中存在的其它核酸分子分離的核酸分子。在一個實施方式中，“分離的”核酸分子沒有該核酸來源于其中的生物體的基因組dna中核酸天然側(cè)翼序列(即位于核酸的5'和3'端的序列)(優(yōu)選蛋白質(zhì)編碼序列)。例如，在各種實施方式中，分離的核酸分子可含有少于約5kb、4kb、3kb、2kb、1kb、0.5kb或0.1kb的該核酸來源于其中的細(xì)胞的基因組dna中核酸分子天然側(cè)翼的核苷酸序列。在另一個實施方式中，“分離的”核酸分子(如cdna分子)當(dāng)通過重組技術(shù)產(chǎn)生時可以基本上不含其它細(xì)胞物質(zhì)或培養(yǎng)基，或者當(dāng)被化學(xué)合成時可以基本上不含化學(xué)前體或其他化學(xué)品?；旧喜缓?xì)胞物質(zhì)的核酸分子包括具有少于約30％、20％、10％或5％的異源核酸(在此也稱為“污染核酸”)的制劑?？梢允褂脴?biāo)準(zhǔn)分子生物學(xué)技術(shù)和本文中所述的數(shù)據(jù)庫記錄中的序列信息來分離本發(fā)明的核酸分子。使用這樣的核酸序列的全部或一部分，本發(fā)明的核酸分子可以使用標(biāo)準(zhǔn)雜交和克隆技術(shù)(例如，如在sambrook等編輯,molecularcloning:alaboratorymanual,2nded.,coldspringharborlaboratorypress,coldspringharbor,ny,1989中所述的)分離?？梢允褂米鳛槟０宓腸dna、mrna或基因組dna和合適的寡核苷酸引物根據(jù)標(biāo)準(zhǔn)pcr擴(kuò)增技術(shù)來擴(kuò)增本發(fā)明的核酸分子。這樣擴(kuò)增的核酸可以被克隆到合適的載體中和通過dna序列分析表征。而且，可以通過標(biāo)準(zhǔn)合成技術(shù)，例如，使用自動的dna合成儀來制備對應(yīng)于本發(fā)明核酸分子的全部或一部分的核酸。在另一個優(yōu)選的實施方式中，本發(fā)明的分離的核酸分子包含具有與標(biāo)志物核酸的核苷酸序列或與編碼標(biāo)志物蛋白質(zhì)的核酸的核苷酸序列互補(bǔ)的核苷酸序列的核酸分子?；パa(bǔ)于給定的核苷酸序列的核酸分子是與給定的核苷酸充分地互補(bǔ)以至于其能夠與給定的核苷酸序列雜交從而形成穩(wěn)定的雙鏈體的核酸分子。“互補(bǔ)的”指在兩個核酸鏈的區(qū)域之間或同一核酸鏈的兩個區(qū)域之間的序列互補(bǔ)的廣義概念。已知第一核酸區(qū)域的腺嘌呤殘基能夠與反平行于所述第一區(qū)域的第二核酸區(qū)域的殘基(如果該殘基是胸腺嘧啶或尿嘧啶)形成特定的氫鍵(“堿基配對”)。類似地，已知第一核酸鏈的胞嘧啶殘基能夠與反平行于第一鏈的第二核酸鏈的殘基(如果該殘基是鳥嘌呤)堿基配對。如果當(dāng)兩個區(qū)域以反平行的方式排列時第一區(qū)域中的至少一個核苷酸殘基能夠與第二區(qū)域的殘基堿基配對，則核酸的第一區(qū)域與相同或不同核酸的第二區(qū)域互補(bǔ)。優(yōu)選地，所述第一區(qū)域包含第一部分和所述第二區(qū)域包含第二部分，由此當(dāng)?shù)谝缓偷诙糠忠苑雌叫械姆绞脚帕袝r，第一部分的至少約50％，和優(yōu)選至少約75％，至少約90％，或至少約95％的核苷酸殘基能夠與第二部分中的核苷酸殘基堿基配對。更優(yōu)選地，第一部分的所有核苷酸殘基能夠與第二部分中的核苷酸殘基堿基配對。如本文所使用的“相同的”或“同一性”是指相同核酸鏈的兩個區(qū)域之間或兩個不同核酸鏈的區(qū)域之間的核苷酸序列相似性。當(dāng)兩個區(qū)域中的核苷酸殘基由相同的核苷酸殘基占據(jù)時，則該區(qū)域在該位置處是相同的。如果各個區(qū)域的至少一個核苷酸殘基的位置由相同的殘基占據(jù)，則第一區(qū)域與第二區(qū)域相同。兩個區(qū)域之間的同一性是就由相同核苷酸殘基占據(jù)的兩個區(qū)域的核苷酸殘基位置的比例而言的。通過舉例的方式，具有核苷酸序列5'-attgcc-3'的區(qū)域和具有核苷酸序列5'-tatggc-3'的區(qū)域擁有50％的同一性。優(yōu)選地，第一區(qū)域包含第一部分和第二區(qū)域包含第二部分，由此所述部分各自的核苷酸殘基位置的至少約50％，和優(yōu)選至少約75％，至少約90％或至少約95％由相同的核苷酸殘基占據(jù)。更優(yōu)選地，所述部分各自的所有核苷酸殘基位置由相同的核苷酸殘基占據(jù)。此外，本發(fā)明的核酸分子可以包含僅一部分的核酸序列，其中全長核酸序列包含標(biāo)志物核酸或其編碼標(biāo)志物蛋白質(zhì)。這樣的核酸可用作，例如，探針或引物。所述探針/引物典型地被用作一種或多種基本上純化的寡核苷酸。寡核苷酸通常包含在嚴(yán)格條件下與本發(fā)明核酸的至少約15，更優(yōu)選至少約25、50、75、100、125、150、175、200、250、300、350或400個或更多個或者由這些值所包括的任何范圍的連續(xù)核苷酸雜交的核苷酸序列?；诒景l(fā)明核酸分子的序列的探針可以被用于檢測對應(yīng)于本發(fā)明的一種或多種標(biāo)志物的轉(zhuǎn)錄物或基因組序列。所述探針包含連接于其上的標(biāo)記基團(tuán)，例如，放射性同位素、熒光化合物、酶或酶輔因子。這樣的探針可以被用作診斷測試試劑盒的部分用于識別表達(dá)或誤表達(dá)蛋白質(zhì)的細(xì)胞或組織，例如通過測量來自受試者的細(xì)胞樣品中編碼蛋白質(zhì)的核酸分子的水平，例如檢測mrna水平或者測定編碼該蛋白質(zhì)的基因或它的翻譯控制序列是否已經(jīng)突變或刪除。本發(fā)明還包含由于遺傳密碼的簡并性而與編碼標(biāo)志物蛋白質(zhì)(例如，具有在圖中提供的序列的蛋白質(zhì))的核酸的核苷酸序列不同，且因此編碼相同的蛋白質(zhì)的核酸分子。那些本領(lǐng)域的技術(shù)人員可以理解的是，在群體(例如，人類群體)中可以存在導(dǎo)致氨基酸序列改變的dna序列的多態(tài)性。這些遺傳多態(tài)性可由于天然等位基因變異和已知例如在癌癥中發(fā)生的變化而存在于群體的個體之間。等位基因是可選擇地存在于給定基因座的一組基因中的一個。另外，可以理解的是，影響rna的表達(dá)水平的dna多態(tài)性也可以存在，其可影響該基因的總體表達(dá)水平(例如，通過影響調(diào)節(jié)或降解)。如本文所用的，短語“等位基因變體”是指存在于給定基因座的核苷酸序列或指由核苷酸序列編碼的多肽。如本文所用的，術(shù)語“基因”和“重組基因”是指包含編碼與本發(fā)明標(biāo)志物的多肽對應(yīng)的開放閱讀框的核酸分子。此類天然等位基因變異一般可導(dǎo)致給定基因的核苷酸序列中1-5％的差異度?？梢酝ㄟ^測序許多不同個體中的目的基因來鑒定可選的等位基因。這可以通過使用雜交探針來識別各種個體中的相同基因座而容易地進(jìn)行。作為天然等位基因變異的結(jié)果并且不改變功能活性的任何和所有此類核苷酸變異和所得的氨基酸多態(tài)性或變異都旨在屬于本發(fā)明的范圍。在另一個實施方式中，本發(fā)明的分離的核酸分子長度是至少15、20、25、30、40、60、80、100、150、200、250、300、350、400、450、550、650、700、800、900、1000、1200、1400、1600、1800、2000、2200、2400、2600、2800、3000、3500、4000、4500或更多個或由這些值所包括的任何范圍的核苷酸且在嚴(yán)格條件下與標(biāo)志物核酸或與編碼標(biāo)志物蛋白質(zhì)的核酸雜交。如本文所用的，術(shù)語“在嚴(yán)格條件下雜交”旨在描述用于雜交和洗滌的條件，在該條件下至少60％(65％、70％，優(yōu)選75％)彼此相同的核苷酸序列通常保持彼此雜交。此類嚴(yán)格條件是本領(lǐng)域技術(shù)人員已知的，并可以在currentprotocolsinmolecularbiology,johnwiley&sons,n.y.(1989)的6.3.1-6.3.6節(jié)中找到。嚴(yán)格雜交條件的優(yōu)選的非限制性例子是在6x氯化鈉/檸檬酸鈉(ssc)中在大約45℃下雜交，接著在0.2×ssc、0.1％sds中在50-65℃下洗滌一次或多次。核酸治療劑核酸治療劑是本領(lǐng)域中公知的。核酸治療劑包括與細(xì)胞中的靶序列互補(bǔ)的單鏈和雙鏈的(即，具有至少15個核苷酸長度的互補(bǔ)區(qū)的核酸治療劑，其可以是一個或兩個核酸鏈)核酸。核酸治療劑可以被遞送到培養(yǎng)中的細(xì)胞，例如，通過將核酸單獨添加到培養(yǎng)基中或者與促進(jìn)核酸攝取到細(xì)胞中的藥劑一起添加。核酸治療劑可以通過任何施用途徑被遞送到受試者中的細(xì)胞，即，在體內(nèi)。具體制劑取決于施用途徑。除非另外指出，如本文所用的術(shù)語“互補(bǔ)的”當(dāng)被用于與第二核苷酸序列有關(guān)描述第一核苷酸序列時，是指包含第一核苷酸序列的寡核苷酸或多核苷酸在特定條件下與包含第二核苷酸序列的寡核苷酸或多核苷酸雜交和形成雙鏈體結(jié)構(gòu)的能力，如本領(lǐng)域技術(shù)人員理解的。這樣的條件可以是，例如，嚴(yán)格條件，其中嚴(yán)格條件可包括：400mm的氯化鈉，40mmpipes，ph6.4，1mmedta，50℃或70℃下，12-16小時，隨后洗滌?？梢詰?yīng)用其它條件，如可能在生物體內(nèi)遇到的生理相關(guān)條件。技術(shù)人員將能夠根據(jù)雜交核苷酸的最終應(yīng)用來確定最適合于兩個序列互補(bǔ)性測試的條件組。當(dāng)?shù)谝缓塑账嵝蛄械暮塑账崤c第二核苷酸序列的核苷酸在第一和第二核苷酸序列的整個長度上存在堿基配對時，序列可以是彼此“完全互補(bǔ)的”。然而，當(dāng)本文中第一序列相對于第二序列被稱為“基本互補(bǔ)的”，該兩條序列可以是完全互補(bǔ)的，或者它們在雜交時可形成一個或多個，但一般不超過4、3或2個錯配的堿基對，而同時保留在與它們的最終應(yīng)用最相關(guān)的條件下雜交的能力。然而，當(dāng)如在雙鏈核酸治療劑中常見的，兩個寡核苷酸被設(shè)計成在雜交時形成一個或多個單鏈突出端時，這種突出端不應(yīng)視為對于確定互補(bǔ)性的錯配。例如，含有長度21個核苷酸的寡核苷酸和另一個長度23個核苷酸的寡核苷酸的dsrna(其中較長的寡核苷酸包含與較短的寡核苷酸完全互補(bǔ)的21個核苷酸的序列)還可以用于本文所描述的目的的被稱為“完全互補(bǔ)的”。如本文所使用的“互補(bǔ)”的序列也可以包括非watson-crick堿基對和/或由非天然的和修飾的核苷酸形成的堿基對，或者完全由其形成，只要滿足關(guān)于它們的雜交能力的上述要求。這樣的非watson-crick堿基對包括但不限于，g:u擺動或hoogstein堿基配對。術(shù)語“互補(bǔ)的”、“完全互補(bǔ)的”和“基本互補(bǔ)的”可以相對于dsrna的有義鏈和反義鏈之間，或者dsrna的反義核酸或反義鏈與靶序列之間的堿基匹配使用，如從其使用環(huán)境理解的。如本文所用的，“基本上互補(bǔ)于至少部分的”信使rna(mrna)的多核苷酸是指基本上互補(bǔ)于目的mrna的連續(xù)部分(包括5'utr、開放閱讀框(orf)或3'utr)的多核苷酸(例如，編碼心肌病相關(guān)標(biāo)志物的mrna)。例如，如果多核苷酸的序列基本上互補(bǔ)于編碼心肌病相關(guān)標(biāo)志物的mrna的非中斷部分，該多核苷酸互補(bǔ)于心肌病相關(guān)標(biāo)志物的mrna的至少一部分。核酸治療劑典型地包括化學(xué)修飾以改善其穩(wěn)定性和調(diào)節(jié)其藥代動力學(xué)和藥效學(xué)性質(zhì)。例如，核苷酸的修飾可以包括，但不限于，lna、hna、cena、2'-甲氧基乙基、2'-o-烷基、2'-o-烯丙基、2'-c-烯丙基、2'-氟、2'-脫氧、2'-羥基以及它們的組合。核酸治療劑可進(jìn)一步包含至少一個硫代磷酸酯或甲基膦酸酯核苷間鍵。硫代磷酸酯或甲基膦酸酯核苷間鍵修飾可以存在于鏈任何位置中的有義鏈或反義鏈或兩者(在包括有義鏈的核酸治療劑中)的任何核苷酸上。例如，核苷間鍵修飾可以存在于有義鏈或反義鏈的每個核苷酸上；每個核苷間鍵修飾可以以交替模式發(fā)生在有義鏈或反義鏈上；或者有義鏈或反義鏈可以交替的模式包含兩種核苷間鍵修飾。有義鏈上核苷間鍵修飾的交替模式與反義鏈可以是相同的或不同的，且有義鏈上核苷間鍵修飾的交替模式可以相對于反義鏈上核苷間鍵修飾的交替模式具有偏移。單鏈核酸治療劑反義核酸治療劑是單鏈核酸治療劑，通常為約16至30個核苷酸長度和互補(bǔ)于靶細(xì)胞(無論是在培養(yǎng)中或在生物體中)中的靶核酸序列。涉及反義核酸、化學(xué)修飾和治療用途的專利被提供于，例如，5,898,031號美國專利中(其涉及化學(xué)修飾的含rna治療性化合物)和6,107,094號美國專利中(其涉及使用這些化合物作為治療劑的方法)。7,432,250號美國專利涉及通過施用單鏈的化學(xué)修飾的rna樣化合物治療患者的方法；和7,432,249號美國專利涉及含有單鏈的化學(xué)修飾的rna樣化合物的藥物組合物。7,629,321號美國專利涉及使用具有多個核苷和至少一種化學(xué)修飾的單鏈寡核苷酸切割靶mrna的方法。在本段中列出的前述專利各自的全部內(nèi)容在此通過引用明確并入本文。雙鏈核酸治療劑在許多實施方式中，雙鏈體區(qū)的長度為15-30個核苷酸對。在一些實施方式中，雙鏈體區(qū)為17-23個核苷酸對長度、17-25個核苷酸對長度、23-27個核苷酸對長度、19-21個核苷酸對長度或21-23個核苷酸對長度。在某些實施方式中，每條鏈具有15-30個核苷酸。在本發(fā)明的方法中使用的rnai劑包括具有化學(xué)修飾的藥劑，如公開在例如公開wo2009/073809和wo/2012/037254中，其各自的全部內(nèi)容在此明確地通過引用引入。如本文中可互換使用的“rnai劑”、“雙鏈rnai劑”、雙鏈rna(dsrna)分子，也稱為“dsrna劑”、“dsrna”、“sirna”、“irna劑”是指核糖核酸分子的復(fù)合物，其具有包含兩個反平行的和基本上互補(bǔ)的(如下所定義)的核酸鏈的雙鏈體結(jié)構(gòu)。如本文所使用的，rnai劑還可以包括dsirna(見，例如，美國專利公開20070104688，其通過引用并入本文)。在一般情況下，每條鏈的大多數(shù)核苷酸是核糖核苷酸，但如本文中所描述的，每條鏈或兩條鏈也可以包括一種或多種非核糖核苷酸，例如，脫氧核糖核苷酸和/或修飾的核苷酸。此外，如在本說明書中所使用的，“rnai劑”可以包括具有化學(xué)修飾的核糖核苷酸；rnai劑可在多個核苷酸處包括實質(zhì)性的修飾。這樣的修飾可以包括所有類型的本文公開的或本領(lǐng)域已知的修飾。任何這樣的修飾，如在sirna型分子中使用的，用于本說明書和權(quán)利要求書的目的被涵蓋于“rnai劑”中。形成雙鏈體結(jié)構(gòu)的兩條鏈可以是一個較大rna分子的不同部分，或者它們可以是單獨的rna分子。在其中兩條鏈?zhǔn)且粋€較大分子的部分和因此在一條鏈的3'-端和形成雙鏈體結(jié)構(gòu)的相應(yīng)另一條鏈的5'端之間通過不間斷核苷酸鏈連接的情況中，連接rna鏈被稱為“發(fā)夾環(huán)”。在兩條鏈通過一條鏈的3'-端和形成雙鏈體結(jié)構(gòu)的相應(yīng)另一條鏈的5'端之間的不間斷核苷酸鏈之外的方式共價連接的情況中，該連接結(jié)構(gòu)被稱作“連接體”。該rna鏈可以具有相同或不同數(shù)目的核苷酸。堿基對的最大數(shù)目是dsrna中最短鏈的核苷酸數(shù)目減去存在于雙鏈體中的任何突出端。除了雙鏈體結(jié)構(gòu)外，rnai劑可包含一個或多個核苷酸突出端。術(shù)語“sirna”也用于本文中指如上所述的rnai劑。在另一個方面，所述藥劑是單鏈反義rna分子。反義rna分子互補(bǔ)于靶mrna內(nèi)的序列。反義rna可以通過與mrna堿基配對和物理上阻礙翻譯機(jī)制以化學(xué)計量方式抑制翻譯，參見，dias,n.等人，(2002)molcancerther1:347-355。反義rna分子可具有約15-30個互補(bǔ)于靶mrna的核苷酸。例如，反義rna分子可具有至少15、16、17、18、19、20或更多個連續(xù)核苷酸的序列，其互補(bǔ)于本文所提供的心肌病相關(guān)標(biāo)志物序列。術(shù)語“反義鏈”是指雙鏈rnai劑的包括與靶序列(例如，人ttrmrna)基本上互補(bǔ)的區(qū)域的鏈。如本文所用，術(shù)語“與編碼運甲狀腺素蛋白的mrna的部分互補(bǔ)的區(qū)域”是指反義鏈上與ttrmrna序列的部分基本上互補(bǔ)的區(qū)域。在互補(bǔ)性區(qū)域不與靶序列完全互補(bǔ)的情況中，錯配在末端區(qū)域中是最耐受的，且如果存在的話，通常是在一個或多個末端區(qū)域中，例如，在5'和/或3'末端的6、5、4、3或2個核苷酸內(nèi)。如本文使用的，術(shù)語“有義鏈”是指包括與反義鏈的區(qū)域基本互補(bǔ)的區(qū)域的dsrna鏈。本發(fā)明還包括具有至少一個與本發(fā)明的核酸的互補(bǔ)區(qū)域的分子信標(biāo)核酸，使得所述分子信標(biāo)可用于定量樣品中本發(fā)明的核酸的存在?！胺肿有艠?biāo)”核酸是包含一對互補(bǔ)的區(qū)域并且具有熒光團(tuán)和與其相關(guān)聯(lián)的熒光淬滅劑的核酸。熒光團(tuán)和淬滅劑與核酸的不同部分相關(guān)聯(lián)，其取向使得當(dāng)互補(bǔ)區(qū)域彼此退火時，熒光團(tuán)的熒光被淬滅劑淬滅。當(dāng)核酸的互補(bǔ)區(qū)域彼此不退火時，熒光團(tuán)的熒光被淬滅程度較輕。分子信標(biāo)核酸被描述于，例如，5,876,930號美國專利中。分離的蛋白質(zhì)和抗體本發(fā)明的一個方面涉及分離的標(biāo)志物蛋白質(zhì)及其生物活性部分，以及適合用作免疫原以產(chǎn)生針對標(biāo)志物蛋白質(zhì)或其片段的抗體的多肽片段。在一個實施方式中，通過適當(dāng)?shù)募兓桨甘褂脴?biāo)準(zhǔn)蛋白質(zhì)純化技術(shù)可從細(xì)胞或組織來源分離天然標(biāo)志物蛋白質(zhì)。在另一個實施方式中，通過重組dna技術(shù)生產(chǎn)包含標(biāo)志物蛋白的全部或片段的蛋白質(zhì)或肽。替代重組表達(dá)，這樣的蛋白質(zhì)或肽可使用標(biāo)準(zhǔn)肽合成技術(shù)來化學(xué)合成?！胺蛛x的”或“純化的”蛋白質(zhì)或其生物活性部分基本上不含細(xì)胞物質(zhì)或來自該蛋白質(zhì)所來源的細(xì)胞或組織來源的其他污染蛋白質(zhì)，或在化學(xué)合成時基本上不含化學(xué)前體或其他化學(xué)品。語言“基本上不含細(xì)胞物質(zhì)”包括其中蛋白質(zhì)是從它被分離或重組產(chǎn)生的細(xì)胞的細(xì)胞組分被分離的蛋白質(zhì)制劑。因此，基本上不含細(xì)胞物質(zhì)的蛋白質(zhì)包括具有少于約30％、20％、10％或5％(以干重計)的異源蛋白質(zhì)(在此也稱為為“污染蛋白質(zhì)”)的蛋白質(zhì)制劑。當(dāng)重組產(chǎn)生蛋白質(zhì)或其生物活性部分時，也優(yōu)選基本上不含培養(yǎng)基，即培養(yǎng)基占蛋白質(zhì)制劑體積的少于約20％、10％或5％。當(dāng)?shù)鞍踪|(zhì)通過化學(xué)合成產(chǎn)生時，優(yōu)選基本上不含化學(xué)前體或其它化學(xué)品，即它與蛋白質(zhì)的合成中所涉及的化學(xué)前體或其它化學(xué)品分離。因此這樣的蛋白質(zhì)制劑除了目的多肽外具有少于約30％、20％、10％、5％(以干重計)的化學(xué)前體或化合物?！氨景l(fā)明的蛋白質(zhì)”包括標(biāo)志物蛋白質(zhì)和它們的片段；變體標(biāo)志物蛋白質(zhì)和它們的片段；包含標(biāo)志物或變體標(biāo)志物蛋白質(zhì)的至少15個氨基酸的片段肽和多肽；和包含標(biāo)志物或變體標(biāo)志物蛋白質(zhì)或者標(biāo)志物或變體標(biāo)志物蛋白質(zhì)的至少15個氨基酸的片段的融合蛋白質(zhì)。在某些實施方式中，本發(fā)明的蛋白質(zhì)是足夠大以允許抗體與標(biāo)志物特異性結(jié)合的肽序列或表位。標(biāo)志物蛋白質(zhì)的生物活性部分包括多肽，其包含的氨基酸序列與標(biāo)志物蛋白質(zhì)的氨基酸序列充分相同或源自標(biāo)志物蛋白質(zhì)的氨基酸序列，其包括比全長蛋白質(zhì)較少的氨基酸，并表現(xiàn)出相應(yīng)的全長蛋白質(zhì)的至少一種活性。典型地，生物活性部分包含具有至少一種相應(yīng)的全長蛋白質(zhì)的活性的結(jié)構(gòu)域或基序。本發(fā)明標(biāo)志物蛋白質(zhì)的生物活性部分可以是為例如，10、25、50、100或更多個氨基酸的長度的多肽。此外，其中標(biāo)志物蛋白質(zhì)的其他區(qū)域被刪除的其他生物活性部分可通過重組技術(shù)制備和評估標(biāo)志物蛋白質(zhì)的天然形式的一種或多種功能活性。優(yōu)選的標(biāo)志物蛋白質(zhì)是由包含任何附圖的序列的核苷酸序列所編碼的。其他有用的蛋白質(zhì)與這些序列之一的是基本上相同的(例如，至少約40％，優(yōu)選50％、60％、70％、80％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％相同)，并保持相應(yīng)的天然存在的標(biāo)志物蛋白質(zhì)的功能活性而由于天然等位基因變異或誘變而在氨基酸序列上有所不同。為了測定兩個氨基酸序列或兩個核酸的百分同一性，將所述序列對準(zhǔn)用于最佳對比目的(例如，可以將空位引入第一氨基酸或核酸序列的序列中用于與第二氨基酸或核酸序列進(jìn)行最佳比對)。然后對在對應(yīng)的氨基酸位置或核苷酸位置處的氨基酸殘基或核苷酸進(jìn)行比較。當(dāng)?shù)谝恍蛄兄械奈恢帽慌c第二序列中相應(yīng)位置處相同的氨基酸殘基或核苷酸占據(jù)時，則所述分子在該位置上是相同的。優(yōu)選地，使用全局比對計算兩個序列之間的百分同一性?？蛇x地，使用局部比對計算兩個序列之間的百分同一性。兩個序列之間的百分同一性是序列共有的相同位置的數(shù)目的函數(shù)(即，％同一性＝相同位置#/總位置#(例如，重疊位置)×100)。在一個實施方式中，兩個序列具有相同的長度。在另一個實施方式中，兩個序列是不一樣的長度?？梢允褂脭?shù)學(xué)算法來完成兩個序列之間百分同一性的測定。用于兩個序列的比較的數(shù)學(xué)算法的優(yōu)選的非限制性實例是karlin和altschul(1990)proc.natl.acad.sci.usa87:2264-2268的算法，在karlin和altschul(1993)proc.natl.acad.sci.usa90:5873-5877中改進(jìn)。這樣的算法被整合到altschul等(1990)j.mol.biol.215:403-410的blastn和blastx程序中?？梢杂胋lastn程序，得分＝100，字長＝12進(jìn)行blast核苷酸檢索以獲得與本發(fā)明核酸分子同源的核苷酸序列。可以用blastp程序，得分＝50，字長＝3進(jìn)行blast蛋白質(zhì)檢索以獲得與本發(fā)明的蛋白質(zhì)分子同源的氨基酸序列。為了獲得用于比較目的的帶空位比對，可以利用被稱為帶空位blast的新版blast算法，如altschul等(1997)nucleicacidsres.25:3389-3402中所描述的，它能夠執(zhí)行程序blastn、blastp和blastx的帶空位局部比對。或者，psi-blast可以用于執(zhí)行迭代檢索，其檢測分子間的遠(yuǎn)源關(guān)系。當(dāng)利用blast、帶空位blast和psi-blast程序時，可使用相應(yīng)程序(例如，blastx和blastn)的默認(rèn)參數(shù)。參見http://www.ncbi.nlm.nih.gov。用于序列比較的數(shù)學(xué)算法的另一個優(yōu)選的非限制性實例是myers和miller，(1988)cabios4:11-17的算法。這樣的算法被整合到align程序(版本2.0)中，其是gcg序列比對軟件包的部分。當(dāng)使用align程序用于氨基酸序列比較時，可以使用pam120權(quán)重殘差表、12的空位長度罰分和4的空位罰分。而用于確定局部序列相似性的區(qū)域和比對的另一個有用的算法是fasta算法，如pearson和lipman(1988)proc.natl.acad.sci.usa85:2444-2448中所描述的。當(dāng)使用fasta算法用于比較核苷酸或氨基酸序列時，可以使用例如，pam120權(quán)重殘差表，具有k-元組值2?？梢允褂妙愃朴谏鲜龅哪切┘夹g(shù)來測定兩個序列之間的百分同一性，具有或不具有容許的空位。在百分同一性的計算中，只計數(shù)正確匹配。本發(fā)明的另一個方面涉及針對本發(fā)明蛋白質(zhì)的抗體。在優(yōu)選的實施方式中，抗體特異性地結(jié)合標(biāo)志物蛋白質(zhì)或其片段。在本文中可互換使用的術(shù)語“抗體”和“多種抗體”指免疫球蛋白分子以及其片段和其衍生物，其包含免疫球蛋白分子的免疫活性部分(即，這種部分包含與抗原特異性結(jié)合的抗原結(jié)合位點，如標(biāo)志物蛋白，例如標(biāo)志物蛋白的表位)。例如，除非文中另外指明，術(shù)語“抗體”和“多種抗體”寬泛地包括天然存在的抗體形式(例如，igg、iga、igm、ige)和重組抗體如單鏈抗體、嵌合和人源化抗體及多特異性抗體，以及所有前述形式的片段和衍生物，該片段和衍生物具有至少一個抗原結(jié)合位點?？贵w衍生物可包含與抗體偶聯(lián)的蛋白質(zhì)或化學(xué)部分。特異性結(jié)合于本發(fā)明蛋白質(zhì)的抗體是結(jié)合天然包含該蛋白質(zhì)的樣品(如生物樣品)中的蛋白質(zhì)但基本上不結(jié)合其它分子的抗體。免疫球蛋白分子的免疫活性部分的實例包括，但不限于，單鏈抗體(scab)、f(ab)和f(ab')2片段。本發(fā)明的分離的蛋白質(zhì)或其片段可以用作免疫原以產(chǎn)生抗體。可以使用全長蛋白質(zhì)，或者可選地本發(fā)明提供了用作免疫原的抗原性肽片段。本發(fā)明蛋白質(zhì)的抗原性肽包含本發(fā)明蛋白質(zhì)之一的氨基酸序列的至少8個(優(yōu)選10、15、20或30個或更多個)氨基酸殘基，且包括蛋白質(zhì)的至少一個表位以使得引起的針對該肽的抗體與該蛋白質(zhì)形成特異性免疫復(fù)合物?？乖噪乃膬?yōu)選的表位是位于該蛋白質(zhì)表面上的區(qū)域，例如親水性區(qū)域。疏水性序列分析、親水性序列分析或類似的分析可用于識別親水性區(qū)域。在優(yōu)選的實施方式中，分離的標(biāo)志物蛋白質(zhì)或其片段被用作免疫原。本發(fā)明提供了多克隆和單克隆抗體。如本文所用的術(shù)語“單克隆抗體”或“單克隆抗體組合物”是指只含有能夠與特定表位免疫反應(yīng)的一種類型的抗原結(jié)合位點的抗體分子群體。優(yōu)選的多克隆和單克隆抗體組合物是已經(jīng)選擇針對本發(fā)明蛋白質(zhì)的抗體的那些。特別優(yōu)選的多克隆和單克隆抗體制劑是僅包含針對標(biāo)志物蛋白質(zhì)或其片段的抗體的那些。制備多克隆、單克隆和重組抗體和抗體片段的方法是本領(lǐng)域公知的。用于識別本發(fā)明的標(biāo)志物的系統(tǒng)脂質(zhì)在細(xì)胞內(nèi)和細(xì)胞外信號傳導(dǎo)和代謝中發(fā)揮關(guān)鍵作用。蛋白質(zhì)、脂質(zhì)和核酸生物標(biāo)志物的相互作用及生物標(biāo)志物的蛋白質(zhì)、脂質(zhì)和核酸的失調(diào)可能會導(dǎo)致疾病和器官功能障礙。細(xì)胞模型被用于識別標(biāo)志物，包括毒性的標(biāo)志物(例如心臟毒性標(biāo)志物，包括蛋白質(zhì)/基因標(biāo)志物)、包括激酶標(biāo)志物的酶標(biāo)志物、脂質(zhì)標(biāo)志物和代謝產(chǎn)物標(biāo)志物。在國際申請?zhí)杙ct/us2012/027615、pct/us2012/054321和pct/us2012/054323中提供了用于樣品制備、收集和分析以識別這種標(biāo)志物的方法，其各自的全部內(nèi)容通過引用并入本文。下面進(jìn)一步討論用于識別本文所提供的脂質(zhì)標(biāo)志物的方法。血清中作為過氧化物酶體功能的整合標(biāo)志物的過氧化物酶體脂質(zhì)具有高氧化能力的組織需要碳水化合物和脂質(zhì)代謝產(chǎn)物的完整通道來建立動態(tài)的和可塑的代謝系統(tǒng)以適應(yīng)生理需求。需要整合充當(dāng)生化決策者的亞細(xì)胞器，如過氧化物酶體、微粒體和線粒體以實現(xiàn)高效的器官功能。因此，在疾病的病理進(jìn)展過程中或通過各種藥物干預(yù)的脫靶效應(yīng)，建立的生化動態(tài)平衡中細(xì)胞器功能的維持是生理功能所必需的。這個過程以糖尿病對心臟功能的效應(yīng)為例，這迫使心肌只能利用脂肪酸氧化來支持血液動力學(xué)功能，其然后促成心肌病。此外，經(jīng)由斷開過氧化物酶體-微粒體-線粒體軸改變脂肪酸代謝的藥物導(dǎo)致改變的代謝產(chǎn)物支持心血管或肌肉功能的輸送，這可能導(dǎo)致心力衰竭。該軸對于建立代謝流以及對于保持完整的膜功能和經(jīng)由嵌入結(jié)構(gòu)脂質(zhì)組中的氧化性代謝產(chǎn)物適應(yīng)環(huán)境壓力關(guān)鍵的脂質(zhì)組支架的產(chǎn)生是關(guān)鍵的。縮醛磷脂脂質(zhì)的獨特的一個亞類(縮醛磷脂)通過它們對膜曲率和融合、電生理學(xué)和抗氧化劑能力以及啟動調(diào)節(jié)血液動力學(xué)功能的高效信號傳導(dǎo)氧化分子的產(chǎn)生的調(diào)節(jié)作用而對于生物功能是關(guān)鍵的。縮醛磷脂只在過氧化物酶體中合成，并且可以是用于過氧化物酶體動態(tài)平衡的標(biāo)志物?？s醛磷脂與其他亞類的脂質(zhì)不同，因為它們是由在連接脂肪酸與甘油部分的磷脂的sn-1位置處的乙烯基醚鍵所組成。其他亞類在該位置具有醚或酯鍵。因此，通過在質(zhì)譜中使用結(jié)構(gòu)闡明的固有能力，可以采用可通過獨特的磷脂酶靶向的?；湹亩ㄎ晃恢毛@得不同脂質(zhì)亞類的定量來展現(xiàn)控制血管舒張/血管收縮、鈣動態(tài)平衡、炎癥以及消炎的機(jī)制的高效生物效應(yīng)。信號傳導(dǎo)脂質(zhì)氧化的脂質(zhì)代謝產(chǎn)物表示獨特種類的脂質(zhì)，其是形成導(dǎo)致在多樣的器官系統(tǒng)中差異生理的調(diào)節(jié)控制的生物過程的復(fù)雜通道的最終產(chǎn)物。信號傳導(dǎo)脂質(zhì)以高調(diào)控方式產(chǎn)生。信號傳導(dǎo)脂質(zhì)的前體在相對于細(xì)胞、組織或生物流體的代謝健康被控制和維持的脂質(zhì)種類的復(fù)雜網(wǎng)絡(luò)中自我平衡。一般地，信號傳導(dǎo)脂質(zhì)的前體被嵌入包括磷脂酰肌醇以及膽堿和乙醇胺甘油磷脂的磷脂上的sn-2位置。通過起到信號傳導(dǎo)脂質(zhì)產(chǎn)生的看門者作用的獨特磷脂酶的靶向作用，可釋放出酰基鏈的多樣集合，其可隨后被氧化。這些?；湴▉営退?18：2)、亞麻酸(18：3)、花生四烯酸(aa，20：4)、二十碳五烯酸(epa，20：5)、二十二碳五烯酸(dpa，22：5)和二十二碳六烯酸(dha，22：6)。靶向磷脂酶的?；溼尫藕?，脂肪酸被引導(dǎo)以被脂肪氧合酶、環(huán)氧合酶和細(xì)胞色素p450表氧化酶選擇性氧化，從而產(chǎn)生特定的氧化分子以適應(yīng)生理需求。因此，保持不同的功能性磷脂分子種類攜帶信號傳導(dǎo)脂質(zhì)前體的脂肪酸代謝以及指定的磷脂酶、脂肪氧合酶、環(huán)氧合酶和細(xì)胞色素p450表氧化酶的協(xié)調(diào)作用的動態(tài)平衡代表生物動態(tài)平衡的主軸?？墒斋@各前述的?；溡援a(chǎn)生在調(diào)節(jié)生理機(jī)能中具有多效作用的有力的氧化代謝產(chǎn)物。亞油酸(18：2)氧化代謝產(chǎn)物的功能重要性所知甚少，但是代表整體線粒體動態(tài)平衡以及用于控制膜的流動性的多不飽和脂肪酸(pufa)產(chǎn)生中的主要分支點。在心肌中，亞油酸高度富集在線粒體特異性脂質(zhì)心磷脂中。氧化的亞油酸代謝產(chǎn)物(hodes、dihomes、oxoodes和epomes)的信號傳導(dǎo)功能是調(diào)節(jié)離子通道和鈣動態(tài)平衡，這對于線粒體的功能是內(nèi)在重要的。另外，亞油酸起到前體的作用來合成花生四烯酸(20:4)，這是功能上最多研究的氧化代謝產(chǎn)物?；ㄉ南┧岽x產(chǎn)物(通常被稱為類花生酸類)主要形成hete’s、eets和前列腺素類。目前，數(shù)百種不同的氧化花生四烯酸代謝產(chǎn)物是已知的，然而，它們的獨特功能作用尚未在不同組織中被確定，盡管它們根據(jù)氧化產(chǎn)物的位置定位似乎是炎性/抗炎以及血管舒張/血管收縮功能的平衡。因此，控制氧化代謝產(chǎn)物的輸送調(diào)節(jié)炎性和血管調(diào)節(jié)軸。已經(jīng)進(jìn)行了許多嘗試來藥理學(xué)地調(diào)節(jié)該軸，但是缺乏對這些代謝物的平衡作用的認(rèn)識，這些代謝物的有利的和病理的作用已經(jīng)導(dǎo)致藥物從市場退出。特異性地抑制環(huán)氧合酶2(這被認(rèn)為產(chǎn)生促炎性代謝產(chǎn)物)的治療劑最突出，但是，缺乏對靶向炎癥和疼痛的下游代謝產(chǎn)物的生物效應(yīng)的理解導(dǎo)致了對心血管功能的最終有害作用，其在被治療的患者中促發(fā)心力衰竭。因為，這些炎癥途徑根據(jù)功能作用在不同組織中差異地調(diào)節(jié)，缺乏對這些過程的生物了解導(dǎo)致意外有害副作用，其限制靶向這些途徑的藥物干預(yù)的功效。二十二碳六烯酸(dha，22：6)主要由于對心血管和神經(jīng)系統(tǒng)功能的有益作用而已知，但是確切的機(jī)制遠(yuǎn)遠(yuǎn)超出在當(dāng)前的教導(dǎo)中所強(qiáng)調(diào)的其ω-3的化學(xué)結(jié)構(gòu)。實際上，dha的氧化代謝產(chǎn)物被喻為對炎癥的消退效應(yīng)超過十年的時間。dha氧化代謝物的種類包括d系列消退素(resolvin)、保護(hù)素/神經(jīng)保護(hù)素和maresins。一旦dha被釋放和氧化，代謝產(chǎn)物具有恢復(fù)炎癥級聯(lián)至動態(tài)平衡的關(guān)鍵調(diào)控能力。因此，通過磷脂酶以及特定氧化酶的協(xié)調(diào)作用，生理控制的動態(tài)平衡可被維持以及病理可通過復(fù)雜的生物學(xué)途徑的協(xié)調(diào)工作而改變。縮醛磷脂和信號傳導(dǎo)脂質(zhì)由spla2s、cpla2s或ipla2s的多樣集合對指定的磷脂靶向分子種類的調(diào)節(jié)控制在個別分子種類的混合的(amalgamated)化學(xué)組成的立體電子結(jié)構(gòu)?？s醛磷脂在sn-1位包含乙烯基醚鍵，它缺乏相鄰于頭基的羰基氧，從而使此亞類脂質(zhì)比酯或其它醚鍵脂質(zhì)亞類更親脂。這導(dǎo)致在頭基之間更強(qiáng)的分子間的氫鍵，從而導(dǎo)致形成逆六方相(hii)的更大傾向。這種固有的結(jié)構(gòu)特性允許被磷脂酶更高地識別，從而指定縮醛磷脂為用于氧化代謝產(chǎn)物前體的存儲的關(guān)鍵生物支架，其由于被磷脂酶容易地和特異性地識別。與縮醛磷脂的生物學(xué)作用一樣，起到心肌、神經(jīng)、免疫或血管組織中縮醛磷脂分子種類的信號傳導(dǎo)分析的支架的作用揭示了這些組織中縮醛磷脂的豐度以及亞油酸和花生四烯酸在sn-2位置的特異性定位，這是最容易被磷脂酶識別的。數(shù)據(jù)收集本發(fā)明的方法包括分析樣品，通常受試者樣品，以檢測標(biāo)志物，例如蛋白質(zhì)、核酸、脂質(zhì)。執(zhí)行定量聚合酶鏈反應(yīng)(qpcr)和蛋白質(zhì)組學(xué)來通過定量聚合酶鏈反應(yīng)(qpcr)和蛋白質(zhì)組學(xué)分析細(xì)胞mrna和蛋白質(zhì)表達(dá)的變化。可以使用市售的rna提取試劑盒來分離總rna。cdna合成后，可以按照制造商的說明采用對于疾病區(qū)域或細(xì)胞過程(如血管生成、細(xì)胞凋亡和糖尿病)的具體市售的qpcr陣列(例如，那些來自sabiosciences的)來分析預(yù)定組的基因。例如，cfx-384擴(kuò)增系統(tǒng)可用于所有轉(zhuǎn)錄譜實驗。數(shù)據(jù)采集(ct)后，按制造商的說明概述的δct法來測定相對于控制的最終倍數(shù)變化?？梢匀缭陔S后的章節(jié)中描述的進(jìn)行蛋白質(zhì)組學(xué)樣品分析。所述方法可以采用類似性質(zhì)的數(shù)百個樣品的大規(guī)模高通量定量蛋白質(zhì)組學(xué)分析，并提供識別細(xì)胞輸出差異所需的數(shù)據(jù)。有適用于這一目的的眾多本領(lǐng)域公認(rèn)的技術(shù)。示例性技術(shù)，與質(zhì)譜結(jié)合的分析，簡要描述如下。定量蛋白質(zhì)組學(xué)途徑是基于用8-重試劑和2d-lcmaldims/ms標(biāo)記的穩(wěn)定同位素而用于肽的識別和定量。用這一技術(shù)的定量是相對的：肽和蛋白質(zhì)被分配相對于參照樣品的豐度比率。在多重實驗中的共同參照料樣品促進(jìn)在多重實驗中的樣品比較。例如，為了實施這種分析方案，根據(jù)制造商的建議，6個初級樣品和兩個對照池樣品可以被組合成一個8-重混合物。然后可以通過二維液相色譜法對這一八樣品的混合物進(jìn)行分餾；然后可對第一維中的強(qiáng)陽離子交換(scx)和第二維中的反相hplc進(jìn)行質(zhì)譜分析。可以使用多種方法進(jìn)行脂質(zhì)檢測，其中包括但不限于，質(zhì)譜(ms)、核磁共振(nmr)譜、熒光光譜、雙偏振干涉和計算方法?？梢允褂眉傻目缮藤彽脑O(shè)備，如來自的tsqvantageemr三重四極桿質(zhì)譜，用于自動和/或高通量脂質(zhì)組學(xué)分析。本文中提供了可使用的示例性實驗室程序的簡要概述。蛋白質(zhì)提?。嚎梢杂?m尿素裂解緩沖液與蛋白酶抑制劑(thermoscientifichalt蛋白酶抑制劑，無edta)來裂解細(xì)胞并在冰上孵育30分鐘，每10分鐘渦旋5秒?？梢酝ㄟ^以5秒脈沖超聲完成裂解?？梢?4000×g將細(xì)胞裂解物離心15分鐘(4℃)以去除細(xì)胞碎片?？梢赃M(jìn)行bradford分析以測定蛋白質(zhì)濃度。來自每個樣品的100微克蛋白質(zhì)可被還原(10mm的二硫蘇糖醇(dtt)，55℃，1小時)、烷基化(25mm碘乙酰胺，室溫，30分鐘)和用胰蛋白酶消化(1:25w/w，200mm三乙基碳酸氫銨(teab)，37℃，16小時)。分泌組樣品制備：1)在一個實施方式中，可以在無血清培養(yǎng)基中培養(yǎng)細(xì)胞：條件培養(yǎng)基可通過冷凍干燥器將濃縮，還原(10mm的二硫蘇糖醇(dtt)，55℃，1小時)，烷基化(25mm碘乙酰胺，室溫下孵育30分鐘)，和然后通過丙酮(actone)沉淀脫鹽?？梢杂靡鹊鞍酌?1:25w/w，200mm三乙基碳酸氫銨(teab)，37℃，16小時)消化來自濃縮的條件培養(yǎng)基的等量蛋白質(zhì)。在一個實施方式中，可在含血清培養(yǎng)基中培養(yǎng)細(xì)胞：使用3kmwco的vivaspin柱(gehealthcarelifesciences)可以減少培養(yǎng)基的體積，然后可以用1xpbs重構(gòu)?？梢园凑罩圃焐痰恼f明及緩沖液交換的改進(jìn)使用albuvoid柱(biotechsupportgroup,llc)從所有樣品中耗減血清白蛋白以優(yōu)化用于條件培養(yǎng)基應(yīng)用。8重標(biāo)記：來自各實驗組中的各胰蛋白酶消化物的等分試樣可以匯集到一起來創(chuàng)建合并的對照樣品。根據(jù)制造商的說明(ab)，可以通過8重試劑標(biāo)記來自各樣品和合并的對照樣品的等份試樣。該反應(yīng)可以被結(jié)合，抽真空至干燥，通過加入0.1％的甲酸再懸浮，并通過lc-ms/ms進(jìn)行分析。2d-nanolc-ms/ms：可以通過在線2d-nanolc分離所有標(biāo)記的肽混合物并通過電噴霧串聯(lián)質(zhì)譜法進(jìn)行分析?？梢栽谂c配備有納米電噴霧離子源(thermoelectron,bremen,germany)的ltqorbitrap質(zhì)譜儀連接的2dnanolcultra系統(tǒng)上進(jìn)行實驗?？梢杂?微升/分鐘的流速將肽混合物注入到5cmscx柱(300μmid，5μm，polysulfoethylaspartamide柱，來自polylc,columbia,md)，和在10個離子交換洗脫片段中洗脫至c18捕捉柱(2.5cm，100μmid,5μm,proteopreptmii，來自newobjective,woburn,ma)中和用h2o/0.1％fa洗滌5分鐘。然后可使用2-45％b(h2o/0.1％fa(溶劑a)和acn/0.1％fa(溶劑b))的梯度，在15cm的熔融二氧化硅柱(75μmid，5μm，proteopeptmii，來自newobjective,woburn,ma)上以300nl/min進(jìn)一步進(jìn)行分離120分鐘。可以在orbitrap中用30000的分辨率來獲得全掃描ms譜(m/z300-2000)。最高強(qiáng)度的離子(高達(dá)10)可使用高能量c-阱解離(hcd)順序分離用于破碎，且動態(tài)排除30秒?？梢杂?.2da的分離寬度進(jìn)行hcd?？稍谲壍磊逯杏?500的分辨率掃描所得的碎片離子?？梢酝ㄟ^2.1基礎(chǔ)1.0.1對ltqorbitrapvelostm進(jìn)行控制。肽/蛋白質(zhì)識別和定量：可以使用具有針對swissprot數(shù)據(jù)庫的mascot搜索引擎的proteomediscoverer軟件(thermoelectron)通過自動化的數(shù)據(jù)庫檢索來識別肽和蛋白質(zhì)。檢索參數(shù)可以包括10ppm的ms容差，0.02da的ms2容差，和允許最多2個錯失切割的全胰蛋白酶消化。脲甲基化(c)可以被設(shè)置為固定的修飾。氧化(m)、tmt6和脫酰胺(nq)可被設(shè)置為動態(tài)的修飾?？梢杂胢ascot顯著性閾值(p<0.05)過濾肽和蛋白質(zhì)識別。該過濾器可以允許蛋白質(zhì)識別的99％的置信水平(1％fda)。proteomediscoverer軟件可以在報告離子上應(yīng)用校正因子，并可拒絕所有定量值，如果不是所有量化通道都存在。可通過在平均強(qiáng)度的標(biāo)準(zhǔn)化來實現(xiàn)相對蛋白質(zhì)定量。脂質(zhì)分離和檢測：從生物樣品中提取和分離脂質(zhì)的大多數(shù)方法利用烴鏈在有機(jī)溶劑中的高溶解度?？紤]到在脂質(zhì)類別的多樣性，不可能向所有類別提供共同的提取方法。傳統(tǒng)的bligh/dyer方法使用氯仿/甲醇為基礎(chǔ)的方案，其包括相分配到有機(jī)層中。這些方案對于各種各樣的生理相關(guān)脂質(zhì)效果相對較好，但它們必須適應(yīng)于復(fù)雜的脂質(zhì)化學(xué)及低豐度和不穩(wěn)定的脂質(zhì)代謝產(chǎn)物。這種考慮是本領(lǐng)域技術(shù)人員很好理解的。所使用的具體提取方法和檢測方法取決于，例如，待分離和檢測的脂質(zhì)的數(shù)量、待分離和檢測的脂質(zhì)的特定性能及待分離和檢測的其中脂質(zhì)的樣品的數(shù)量。固相萃取(spe)色譜可用于將粗脂質(zhì)混合物快速、制備性地分離成不同的脂質(zhì)種類。這涉及使用含有二氧化硅或其它固定相的預(yù)裝柱以從粗脂質(zhì)混合物分離甘油磷脂、脂肪酸、膽固醇酯、甘油脂質(zhì)和甾醇。高效液相色譜法(hplc或lc)被廣泛地使用在脂質(zhì)組學(xué)分析中以在質(zhì)量分析前分離脂質(zhì)?？梢酝ㄟ^正相hplc或反相hplc來實現(xiàn)分離。例如，正相hplc根據(jù)頭基極性有效地分離甘油磷脂，而反相hplc根據(jù)鏈長、不飽和度和取代度有效地分離脂肪酸如類花生酸。脂質(zhì)的hplc可以離線或在線執(zhí)行，其中洗脫液與質(zhì)譜儀的電離源整合。一般地可以通過光譜學(xué)方法和尤其用于質(zhì)譜的軟電離技術(shù)如電噴霧電離(esi)和基質(zhì)輔助激光解吸/電離(maldi)實現(xiàn)脂質(zhì)檢測?！败洝彪婋x不會引起廣泛的破碎，從而使在復(fù)雜的混合物中整個脂質(zhì)范圍的全面檢測可與實驗條件或疾病狀態(tài)相關(guān)聯(lián)。除了esi和maldi外，大氣壓化學(xué)電離(apci)的技術(shù)也可用于非極性脂質(zhì)的分析。esims可用于脂質(zhì)的分析，并包括來自極性的、熱不穩(wěn)定的和大多非揮發(fā)性分子的氣體離子的形成。軟電離方法通常不會在質(zhì)量分析前破壞分析物的化學(xué)性質(zhì)。已經(jīng)開發(fā)了各種esi-ms方法用于分析來自生物提取物的不同種類、亞類和個別脂質(zhì)種類且在本領(lǐng)域是已知的。esi-ms典型地是高度準(zhǔn)確的、靈敏的、可重復(fù)的，并且可以用于復(fù)雜的溶液而不需要事先衍生化。直接將粗脂質(zhì)提取物注入esi源(其基于其固有的電特性針對脂質(zhì)的內(nèi)源分離優(yōu)化)可用于復(fù)雜混合物的分析。maldi質(zhì)譜分析是通常用于大蛋白質(zhì)的分析的基于激光的軟電離方法，其已經(jīng)被成功地用于脂質(zhì)。脂質(zhì)與基質(zhì)如2,5-二羥基苯甲酸混合，并作為一個小斑點被施加到樣品支持物上。激光被射向該點，且基質(zhì)吸收能量，其然后被轉(zhuǎn)移到分析物，從而導(dǎo)致該分子的電離。maldi-飛行時間-(maldi-tof)ms已成為用于脂質(zhì)組學(xué)研究的非常有前途的途徑，特別是用于來自組織切片的脂質(zhì)的成像。apci類似于esi，除了離子通過被加熱的分析物溶劑與設(shè)定在高電勢的電暈放電針相互作用形成。在針周圍立即形成初級離子，且這些與溶劑相互作用以形成最終電離樣品的二級離子。apci對非極性脂質(zhì)如甘油三酯、甾醇和脂肪酸酯的分析特別有用。maldi方法的最近進(jìn)展已經(jīng)使得能夠原位直接檢測脂質(zhì)。當(dāng)在已涂覆有maldi基質(zhì)的組織表面上獲得連續(xù)譜時，從薄組織切片的直接分析產(chǎn)生豐富的脂質(zhì)相關(guān)離子。分子離子的碰撞活化可以被用來確定脂質(zhì)家族和通常結(jié)構(gòu)上定義分子種類。這種技術(shù)使得能夠檢測在組織如心臟、腎和腦中的磷脂、鞘脂和甘油脂質(zhì)。此外許多不同的脂質(zhì)分子種類的分布常常限定這些組織內(nèi)的解剖區(qū)域。利用細(xì)胞模型用于探詢式生物評估本文描述的，以及在國際申請?zhí)杗o.pct/us2012/027615和pct/us2012/054321(二者均通過引用并入本文)中所進(jìn)一步描述的方法和細(xì)胞模型可以用于或應(yīng)用于多種“探詢式生物評估”。用于識別心臟中毒相關(guān)標(biāo)志物的特定細(xì)胞模型被提供在，例如，pct/us2012/054323(通過引用并入本文)中。使用本發(fā)明的方法用于探詢式生物評估有利于識別藥物誘導(dǎo)毒性的“調(diào)節(jié)劑”或決定性細(xì)胞過程“驅(qū)動者”。如本文所使用的“探詢式生物評估”可包括識別生物系統(tǒng)的一種或多種調(diào)節(jié)劑，例如，與環(huán)境擾動或外部刺激成分相關(guān)的決定性細(xì)胞過程“驅(qū)動者”(例如，生物途徑或者該途徑的關(guān)鍵成員或者該途徑成員的關(guān)鍵調(diào)控者的活性的增加或減少)或者在生物系統(tǒng)或過程中特有的獨特因果關(guān)系。它可以進(jìn)一步包括被設(shè)計來測試或驗證所識別的決定性細(xì)胞過程驅(qū)動者對于與環(huán)境擾動或外部刺激成分(包括體內(nèi)動物模型和/或體外組織培養(yǎng)實驗)相關(guān)的下游事件是否必要和/或足夠的附加步驟。在一個優(yōu)選的實施方式中，探詢式生物評估是藥劑(例如，藥物)對細(xì)胞、組織、器官或生物體的藥物誘導(dǎo)毒理學(xué)特征的評估，其中識別的生物系統(tǒng)調(diào)節(jié)劑，例如，決定性的細(xì)胞過程驅(qū)動者(例如，在生物系統(tǒng)或過程中獨特的細(xì)胞交互差異或因果關(guān)系)可以是誘導(dǎo)的毒性(例如，藥物誘導(dǎo)毒性如心臟毒性)的指示劑，并且可以相應(yīng)地用來預(yù)測或識別藥物的毒理學(xué)特征。在一個實施方式中，識別的藥物誘導(dǎo)毒性調(diào)節(jié)劑，例如，決定性的細(xì)胞過程驅(qū)動者(例如，藥物誘導(dǎo)毒性特有的細(xì)胞交互差異或因果關(guān)系)是藥物或候選藥物的心臟毒性的指示劑，并且隨之可以用來預(yù)測或確定藥物或候選藥物的心臟毒性學(xué)特征。預(yù)測醫(yī)學(xué)本發(fā)明涉及預(yù)測醫(yī)學(xué)領(lǐng)域，其中診斷分析、預(yù)后分析、藥物基因組學(xué)和監(jiān)測臨床試驗被用于預(yù)后(預(yù)測)目的，從而預(yù)防性地治療個體。因此，本發(fā)明的一個方面涉及用于測定一種或多種標(biāo)志物蛋白或核酸的表達(dá)水平以確定個體是否具有發(fā)生疾病或病癥(例如但不限于，心肌病)的風(fēng)險的診斷分析法。此類分析可用于預(yù)后或預(yù)測目的，從而在發(fā)病前預(yù)防性地治療個體。本發(fā)明的再另一個方面涉及監(jiān)測藥劑(例如，施用用于抑制心肌病或用于治療或預(yù)防任何其他病癥(即，為了了解這種治療可能有的任何心臟毒性)藥物或其他化合物)對于臨床試驗中本發(fā)明標(biāo)志物的表達(dá)或活性的影響。在以下節(jié)中進(jìn)一步詳細(xì)描述這些和其它藥劑。隨同本文提交序列表以提供本文所提供的標(biāo)志物的序列?；蛎Q、相關(guān)聯(lián)的登錄號和相應(yīng)的核苷酸(偶數(shù))和氨基酸(奇數(shù))seqidno提供在下表中。所有相關(guān)的登錄號通過引用引入本文。本發(fā)明的示例說明：通過下列不應(yīng)被解釋為限制的實施例進(jìn)一步說明本發(fā)明。整個本申請中引用的所有參考文獻(xiàn)和公開的專利和專利申請的內(nèi)容通過引用并入本文。實施例1：心臟毒性與心肌病的生物標(biāo)志物的識別使用基于探詢式系統(tǒng)生物學(xué)的發(fā)現(xiàn)平臺獲得心臟毒性和心肌病生理知識的機(jī)制理解。該平臺技術(shù)涉及跨系統(tǒng)層級的發(fā)現(xiàn)，包括來自前列腺癌患者的基于人細(xì)胞的體外模型，及采用基于人工智能(ai)的信息學(xué)模塊的下游數(shù)據(jù)集成和數(shù)學(xué)建模。作為功能毒性組學(xué)(toxicomics)平臺的一部分，申請人開發(fā)了各種生理條件下探詢的原代心肌細(xì)胞的體外模型。另外，將來自七個患者的細(xì)胞培養(yǎng)物暴露于心臟毒性藥物和表觀代謝轉(zhuǎn)變劑(epimetabolicshifter)，輔酶q10。通過質(zhì)譜法分析信號傳導(dǎo)和代謝的變化。對高通量分子數(shù)據(jù)進(jìn)行預(yù)處理、標(biāo)準(zhǔn)化并通過貝葉斯網(wǎng)絡(luò)推理軟件進(jìn)行分析。所得的分子相互作用網(wǎng)絡(luò)對于與功能端點如耗氧率、atp產(chǎn)生以及活性氧物質(zhì)產(chǎn)生的變化直接關(guān)聯(lián)的因果關(guān)系進(jìn)行檢驗。產(chǎn)生潛在的毒性調(diào)節(jié)劑和標(biāo)志物的列舉用于進(jìn)一步在人血清中驗證。另外，由心臟毒性化合物的存在影響的分子變量也被分類為用于潛在生物標(biāo)志物進(jìn)一步驗證。本文所提供的結(jié)果表明，選自于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、hmox1、igfbp7、ccdc47、ptx3、il27、pai1、cfl2、edil3和nucb1的一種或多種生物標(biāo)志物的調(diào)節(jié)與心臟毒性和/或心肌病相關(guān)。通過使用平臺技術(shù)推斷這些生物標(biāo)志物的因果關(guān)系，其被詳細(xì)描述于2012年3月2日提交的wo2012119129和2012年9月7日提交的13/607630號美國申請中，其全部內(nèi)容在此通過引用明確并入本文。在本申請中，識別心肌病或心臟毒性病理生理學(xué)的新驅(qū)動者，和然后在患者血清樣品中進(jìn)行驗證。實施例2：候選標(biāo)志物的統(tǒng)計學(xué)性能：生物回收(bioreclamation)樣品集#2從商業(yè)來源獲得來自正常個體、患有心肌病、2型糖尿病的個體及用已知心臟毒性藥物治療的2型糖尿病個體的人血清樣品。用市售的elisa試劑盒測定正常和心肌病樣品中的標(biāo)志物組。圖1顯示了來自正常個體的16個血清樣品和來自心肌病患者的9個血清樣品的組中候選標(biāo)志物的性能。這些標(biāo)志物顯示各種預(yù)測能力。根據(jù)roc曲線度量(auc)的個體性能水平的組如下。生物標(biāo)志物auc細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子0.792hmox10.722igfbp70.660ccdc470.621ptx30.611il270.569pai1.b0.569pai1.a0.438在這一樣品集中細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子是表現(xiàn)最好的生物標(biāo)志物，而pai1運行1是表現(xiàn)最差的標(biāo)志物。由于運行之間的低相關(guān)性，對于pai1的兩種elisa運行被包括在分析中。因為運行之間的高度相關(guān)性，只有一個elisa運行被包括在對于hmox1的分析中。pai1.a數(shù)據(jù)被從后續(xù)研究排除。為了評估最高性能標(biāo)志物的子集是否能組合地實現(xiàn)最高性能水平，應(yīng)用逐步邏輯回歸。前七位的標(biāo)志物的邏輯回歸模型表現(xiàn)出在正常個體和心肌病患者之間進(jìn)行區(qū)分的優(yōu)越預(yù)測能力，達(dá)到0.961的auc。最優(yōu)標(biāo)志物的其它組合顯示低等的統(tǒng)計特征，如圖2所示。從向前的逐步邏輯回歸分析的結(jié)論是較低性能的標(biāo)志物如pai1.b、ptx3和il27可能潛在地有助于在較大臨床研究中分類器性能的統(tǒng)計學(xué)顯著的提高。向后消除逐步邏輯回歸被用來檢驗是否任何候選標(biāo)志物顯示冗余數(shù)據(jù)和可能不基于組合模型產(chǎn)生患者分層中的任何其他信息。圖3中示出了擇一模型(one-outmodel)的統(tǒng)計性能。值得注意的是，消除hmox1和igfbp7標(biāo)志物不導(dǎo)致在auc值的任何變化，表明該組的其余部分的兩個標(biāo)志物值中存在強(qiáng)冗余。此外，從該組消除hmox1導(dǎo)致了aic值的顯著減小，其表明6標(biāo)志物模型(不包括hmox1)可以是相比于包括整個生物標(biāo)志物組的7標(biāo)志物模型更優(yōu)的模型。同樣有趣地注意到，消除任何較低排名的生物標(biāo)志物導(dǎo)致了分類器性能的顯著降低。實施例3：候選標(biāo)志物的統(tǒng)計性能：asterand樣品集在來自asterand公司的單獨樣品集中評估其它的標(biāo)志物。由于該個體集合的變化，這些標(biāo)志物的性能不能直接與前面的集合相比且它們不能與前面的集合的標(biāo)志物組合來評估多變量的性能。圖4和下面的表展示了單個生物標(biāo)志物的性能。值得注意的是，ptx3蛋白質(zhì)在這兩個樣品集中都顯示出相當(dāng)?shù)男阅?，auc＝0.611和auc＝0.592。該edil3生物標(biāo)志物顯示出在asterand樣品集中的優(yōu)越性能。在正常個體和具有診斷的心肌病的患者之間區(qū)分的單獨edil3標(biāo)志物的預(yù)測能力是杰出的，auc＝0.947。還通過邏輯回歸對于四種生物標(biāo)志物檢驗了多變量分類。該四標(biāo)志物組邏輯回歸小幅提高了單獨edil3的預(yù)測能力，具有auc＝0.96。在無edil3的情況下，用剩下的三種生物標(biāo)志物的回歸模型顯示某種程度的臨床適當(dāng)?shù)男阅?，auc＝0.808。然而，大多數(shù)的變異性是由nucb1標(biāo)志物說明的，且添加cfl2和/或ptx3僅導(dǎo)致略有改善，其中auc＝0.788對auc＝0.808。根據(jù)單變量和多變量統(tǒng)計分析，所有分析的生物標(biāo)志物具有以不同水平的靈敏度和特異性在來自正常個體和心肌病患者的血清之間區(qū)分的預(yù)測能力。一些標(biāo)志物顯示出非常高的預(yù)測能力，例如，edil3、細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子、nucb1，而另一些表現(xiàn)出略微的預(yù)測能力，例如，ptx3、il27、cfl2。多變量分析評估了單個標(biāo)志物和它們的組合的測量中的信息含量。多變量分析表明，hmox1和igfbp7相比于細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子具有低的附加信息含量，且因此可能不是在生物標(biāo)志物組中與細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)因子組合的最佳標(biāo)志物。edil3單獨表現(xiàn)出顯著的預(yù)測性能，并且明確地是該組中最領(lǐng)先的生物標(biāo)志物。下表顯示了來自初步研究的生物標(biāo)志物的排名如下。實施例4：用生物標(biāo)志物監(jiān)測心肌病治療在診斷心肌病的時候，邀請受試者參與試驗。獲得受試者樣品，例如，對照樣品。定期地，在整個監(jiān)測和治療受試者期間，獲得新的受試者樣品。在研究結(jié)束時，對于上述的一種或多種生物標(biāo)志物的水平對所有的受試者樣品進(jìn)行測試。使受試者樣品與受試者的病歷相匹配以使相應(yīng)的一種或多種生物標(biāo)志物的水平與診斷時的心肌病狀態(tài)、疾病的進(jìn)展速率和/或受試者對于一種或多種干預(yù)的響應(yīng)相關(guān)聯(lián)。實施例5：人血清中心臟毒性生物標(biāo)志物的對比水平從商業(yè)來源獲得來自具有2型糖尿病(t2dm)(“組1”)個體和已經(jīng)用已知引起心臟毒性的糖尿病藥物治療的t2dm個體(“組2”)的人血清樣品。通過使用市售的elisa試劑盒測量來自t2dm個體和藥物治療的t2dm個體的血清樣品中心臟毒性生物標(biāo)志物ptx3和pai1的蛋白質(zhì)表達(dá)的水平。測定心臟毒性生物標(biāo)志物ptx3和pai1的表達(dá)水平和計算組1和組2的各生物標(biāo)志物的平均表達(dá)。然后將各樣品中ptx3與pai1的表達(dá)水平表示為對于該組(組1或組2)相應(yīng)的生物標(biāo)志物平均表達(dá)的百分比，如圖6a和6b所示。相比于其他六個藥物治療的t2dm個體(由上部的圓圈表示)，兩種藥物治療的t2dm個體表現(xiàn)出升高的ptx3和pai1表達(dá)水平。表現(xiàn)出ptx3和pai1兩者的較高表達(dá)水平的這兩個藥物治療t2dm個體被證實為患有心肌病。基于這些觀察，本文中鑒定的生物標(biāo)志物可以用來識別t2dm個體亞群，其當(dāng)用具有引起心臟毒性的風(fēng)險或已知引起心臟毒性的糖尿病藥物治療時很容易在治療期間發(fā)生心肌病。此外，本文中識別的生物標(biāo)志物可以被用于識別t2dm個體或t2dm個體亞群，其當(dāng)用具有引起心臟毒性的風(fēng)險或已知引起心臟毒性的糖尿病藥物治療時不易在治療期間發(fā)生心肌病和/或有可能從治療中獲益(例如，超越治療的心臟毒性副作用的治療益處)。實施例6：心臟毒性生物標(biāo)志物在人血清中的比較水平從商業(yè)來源獲得來自正常個體、沒有經(jīng)羅格列酮治療的2型糖尿病(t2dm)的個體、經(jīng)羅格列酮治療的t2dm個體以及具有心肌病的個體的人血清樣品。通過使用市售的elisa試劑盒測定來自這四組個體的血清樣品中心臟毒性生物標(biāo)志物edil3和nucb1的蛋白質(zhì)表達(dá)水平。測定心臟毒性生物標(biāo)志物edil3和nucb1的表達(dá)水平和計算每組個體的每個生物標(biāo)志物的平均表達(dá)。然后將各樣品中edil3和nucb1的表達(dá)水平表示為沒有用羅格列酮治療的t2dm個體中相應(yīng)生物標(biāo)志物的平均表達(dá)的百分比，如圖7和8中所示。一些經(jīng)羅格列酮治療的t2dm個體相比于其他羅格列酮治療的t2dm個體表現(xiàn)出降低的edil3和nucb1表達(dá)水平(由較低的圓圈表示)。如圖7和8所示，相比于所有其他三組的個體中edil3和nucb1的平均表達(dá)水平，心肌病的個體有降低的edil3和nucb1平均表達(dá)水平(由較低的圓圈表示)?；谶@些觀察，本文中識別的生物標(biāo)志物可用于識別t2dm個體的亞群，其當(dāng)用具有引起心臟毒性的風(fēng)險或已知引起心臟毒性的糖尿病藥物治療時很可能在治療期間發(fā)生心肌病。此外，本文中識別的生物標(biāo)志物可以被用于識別t2dm個體或t2dm個體的亞群，其當(dāng)用具有引起心臟毒性的風(fēng)險或已知引起心臟毒性的糖尿病藥物治療時不太可能在治療期間發(fā)生心肌病和/或有可能從治療中獲益(例如，超越治療的心臟毒性副作用的治療益處)。此外，基于這些觀察，本文中識別的生物標(biāo)志物可以被用于識別很可能發(fā)生心肌病的個體或個體亞群。此外，本文中識別的生物標(biāo)志物可以被用于識別個體或個體亞群，其當(dāng)用具有引起心臟毒性的風(fēng)險或已知引起心臟毒性的藥物治療時不太可能在治療期間發(fā)生心肌病和/或有可能從治療中獲益(例如，超越治療的心臟毒性副作用的治療益處)。實施例7：使用功能性toxicomicstm平臺來識別藥物誘導(dǎo)心臟毒性的生物標(biāo)志物。本文所提供的平臺方法使得能夠從人藥物誘導(dǎo)器官毒性模型整合多組學(xué)印記。此處考慮的該平臺性能的實際例子是人藥物誘導(dǎo)心臟毒性的情形。人類藥物誘導(dǎo)心臟毒性模型由以下組成：i)基于人心肌細(xì)胞的心臟毒性體外模型和ii)服用誘導(dǎo)心臟毒性的藥物的患者的血清樣品。體外模型包括用脂肪酸(亞油酸、油酸和l-肉堿)預(yù)處理，隨后用藥物處理的人心肌細(xì)胞。此處考慮的藥物是噻唑烷二酮。在體外模型上進(jìn)行特異性測定功能終點(即線粒體atp、ros、細(xì)胞存活力和線粒體生物能量學(xué))的基于細(xì)胞的分析法。如在以前的報告中提到的，使用來自thermoscientific的ltqorbitrap進(jìn)行蛋白質(zhì)組學(xué)。使用來自thermo的tsqvantageemr三quad質(zhì)譜進(jìn)行shortgun脂質(zhì)組學(xué)。使用bayesiannetworkinference算法進(jìn)行數(shù)據(jù)的整合來生成基于他們的聯(lián)合概率分布(jpd)的分子實體潛在關(guān)聯(lián)圖譜。生成以下類型的網(wǎng)絡(luò)。i)來自體外模型的單獨蛋白質(zhì)組學(xué)網(wǎng)絡(luò)ii)來自體外模型的蛋白質(zhì)組學(xué)+端點分析(線粒體atp、ros、細(xì)胞存活力和線粒體生物能量學(xué))iii)僅來自血清的脂質(zhì)組學(xué)和iv)血清脂質(zhì)網(wǎng)與顆粒脂質(zhì)網(wǎng)絡(luò)的交叉驗證模型v)來自體外模型的結(jié)合蛋白質(zhì)組學(xué)和脂質(zhì)組學(xué)輸出的多組學(xué)網(wǎng)絡(luò)從體外模型(顆粒)和血清脂質(zhì)分析產(chǎn)生脂質(zhì)網(wǎng)絡(luò)血清數(shù)據(jù)脂質(zhì)組學(xué)血清數(shù)據(jù)集的預(yù)bni產(chǎn)生244種脂質(zhì)和71個樣品。實驗的設(shè)計矩陣示于下表中。隨后是合并、標(biāo)準(zhǔn)化和歸因的標(biāo)準(zhǔn)程序。這些步驟的質(zhì)量控制圖包括在所附折頁(folder)中。表4：cm血清脂質(zhì)組學(xué)數(shù)據(jù)的設(shè)計矩陣心肌細(xì)胞數(shù)據(jù)脂質(zhì)組學(xué)血清數(shù)據(jù)集的預(yù)bni產(chǎn)生259種脂質(zhì)和41個樣品。實驗的設(shè)計矩陣示于表中。隨后是合并、標(biāo)準(zhǔn)化和歸因的標(biāo)準(zhǔn)程序。這些步驟的質(zhì)量控制圖包括在所附折頁中。表5：cm粒脂質(zhì)組學(xué)數(shù)據(jù)的設(shè)計矩陣bni和δ網(wǎng)絡(luò)血清網(wǎng)絡(luò)列舉產(chǎn)生469384個片段。在優(yōu)化過程中產(chǎn)生1000套網(wǎng)絡(luò)。待比較的條件是：糖尿病、無治療、cm和糖尿病、無治療和無cm。進(jìn)行模擬以：1.獲得基線表達(dá)的差異2.識別兩個條件的模擬網(wǎng)絡(luò)的δ圖9a中示出含有連接29種脂質(zhì)的20個邊緣的δ網(wǎng)絡(luò)(cm–無cm)。心肌細(xì)胞網(wǎng)絡(luò)列舉產(chǎn)生934782個片段。在優(yōu)化過程中產(chǎn)生1000套網(wǎng)絡(luò)。待比較的條件是：羅格列酮治療和對照。進(jìn)行模擬以識別兩個條件的模擬網(wǎng)絡(luò)的δ。δ網(wǎng)絡(luò)(羅格列酮-對照)包含連接64種脂質(zhì)的75個邊緣。δ網(wǎng)絡(luò)的概略顯示在圖9b中。血清脂質(zhì)網(wǎng)絡(luò)和顆粒脂質(zhì)網(wǎng)絡(luò)共有的脂質(zhì)的定量。如圖10a所示，與僅糖尿病和服用羅格列酮而無心肌病的糖尿病相比，ped18:0-20:3/d18:1-20:2/d16:0-22:3在服用羅格列酮的具有心肌病臨床診斷的糖尿病受試者中顯著降低。在圖10b中脂質(zhì)水平表示為正常脂質(zhì)水平的百分比。來自平臺的多組學(xué)輸出。藍(lán)色菱形代表脂質(zhì)種類，正方形是蛋白質(zhì)和六邊形是與活性中樞因果相關(guān)的激酶。中樞-cacna2d1是l型鈣通道，與map2k3和prkar2a(激酶)、bax(線粒體蛋白)、ephx1(微粒體蛋白)和pcli-183-d18:2-22:6(磷脂酰膽堿)相關(guān)。δ多組學(xué)輸出在體外毒性模型中提供非常強(qiáng)大的分子事件的概況，如圖11所示。通過脂質(zhì)組學(xué)分析對用羅格列酮治療的患者分層識別的標(biāo)志物對來自70個患者的血清樣品進(jìn)行總體脂質(zhì)組學(xué)的盲法分析用以產(chǎn)生基于治療策略的網(wǎng)絡(luò)，其相對于患者是否用羅格列酮治療進(jìn)行事后分析。采用探詢式生物學(xué)固有的計算能力，我們利用蛋白質(zhì)組學(xué)和脂質(zhì)組學(xué)數(shù)據(jù)來推斷條件之間的因果關(guān)系而生成多組學(xué)網(wǎng)絡(luò)。探詢式生物學(xué)識別的關(guān)鍵脂質(zhì)組學(xué)中樞的檢驗強(qiáng)調(diào)通用的共同生物關(guān)聯(lián)，其中65％以上的生物標(biāo)志物的分子種類存在于乙醇胺甘油磷脂中，這些標(biāo)志物的88％被鑒定為縮醛磷脂，幾乎所有那些含有用于氧化代謝產(chǎn)物的不同前體，其證明補(bǔ)償性生理作用效用的趨異平衡。識別乙醇胺甘油磷脂中關(guān)鍵脂質(zhì)組學(xué)中樞之后，在對照、對照心肌病、糖尿病、糖尿病性心肌病、糖尿病羅格列酮無心肌病、糖尿病羅格列酮心肌病之間進(jìn)行患者分層中不同病因?qū)W的進(jìn)一步剖析，其識別漿油烯基乙醇胺(plasmolenylethanolamine)分子種類內(nèi)的特定模式。在根據(jù)關(guān)于羅格列酮的臨床療效的患者組分層時，分離三種不同的病因用于比較，其包括糖尿病、糖尿病羅格列酮無心肌病和糖尿病羅格列酮心肌病。因為，羅格列酮治療的功效靶向糖尿病患者中過氧化物酶體代謝的調(diào)節(jié)，了解乙醇胺甘油縮醛磷脂含量的分層被用于評估與糖尿病患者中羅格列酮誘導(dǎo)心肌病相關(guān)的水平。因此，p16:0-20:4、d18:0-18:2、p16:0-22:6、p18:0-20:4和d18:0-20:4全部與羅格列酮治療一起分層且進(jìn)一步用心肌病分層。因為18:2、20:4和22:6氧化產(chǎn)物的產(chǎn)生在調(diào)節(jié)生理學(xué)中相互抵消，血清脂質(zhì)組中確定的這些固有變化表明起因于磷脂酶靶向的特定分子種類的信號傳導(dǎo)脂質(zhì)產(chǎn)生的前體的改變。用于羅格列酮治療的患者分層的治療策略或生物標(biāo)志物評估代表糖尿病誘導(dǎo)的過氧化物酶應(yīng)激、藥物治療的指示劑以及代表影響脈管血流動力學(xué)的脂質(zhì)誘導(dǎo)信號傳導(dǎo)的生理軸的脂質(zhì)分子種類的識別是至關(guān)重要的。在這里，我們證明功能性顯著分子種類的耗盡，其證明通過底物輸送治療的治療途徑或可選地用作生物標(biāo)志物以基于其幾種標(biāo)志物的水平確定是否病人應(yīng)該或不應(yīng)該用羅格列酮治療。此外，通過探詢式生物學(xué)識別的脂質(zhì)分子種類代表心肌中的主要種類。盡管在血清中天然不充裕，識別的分子種類反映功能失調(diào)的心肌過氧化物酶體代謝，因為血液代表其中組織與脈管系統(tǒng)連接的管道。這一信息的利用提供了理解羅格列酮誘導(dǎo)的或?qū)χ舅岽x的效應(yīng)引起的基礎(chǔ)心臟毒性機(jī)制的治療、生物標(biāo)志物以及功能性探索的幾種途徑。實施例8：如在病例對照研究中證明的血清中ccdc47是心肌病的預(yù)測生物標(biāo)志物從商業(yè)來源獲得來自用各種藥物治療的2型糖尿病(t2d)和/或心肌病的個體及適當(dāng)?shù)膶φ帐茉囌?總共n＝120)的人血清樣品。該組的特征如下：*顯著的使用市售的elisa試劑盒，在來自t2dm個體和藥物治療的t2dm個體的血清樣品中測量心肌病蛋白質(zhì)生物標(biāo)志物ccdc47的水平。使用制造商的說明書進(jìn)行分析。執(zhí)行roc分析以確定是否血清ccdc47水平與心肌病相關(guān)。該分析的結(jié)果示于圖12a和b中。圖12a示出升高的血清ccdc47的存在與患t2d的受試者中心肌病之間存在可測量的相關(guān)性(auc＝0.6770，t2d，無心肌病與t2d，心肌病)。然而，用羅格列酮治療的患t2d與心肌病的受試者與沒有用羅格列酮治療的患t2d與心肌病的受試者相比較升高的血清ccdc47之間有很強(qiáng)的相關(guān)性(auc＝0.9075，t2d，心肌病與用羅格列酮治療的t2d，心肌病)。這些結(jié)果表明，ccdc47是區(qū)分正常受試者(無2型糖尿病，無心肌病)與患有心肌病的受試者(無2型糖尿病)的良好預(yù)測子。此外，這些結(jié)果表明，ccdc47是區(qū)分用羅格列酮以外的藥劑(例如，二甲雙胍，阿托伐他汀)治療的患有心肌病的2型糖尿病受試者與用羅格列酮治療的患心肌病的2型糖尿病受試者的優(yōu)良預(yù)測子。這些結(jié)果表明，ccdc47在心肌病和在用已知誘導(dǎo)心肌病的藥劑治療的受試者中升高。圖13a-c示出受試者的血清中以pg/ml計的ccdc47濃度的散點圖，其中該受試者沒有用或用(a)二甲雙胍或阿托伐他汀相對羅格列酮，(b)羅格列酮或阿托伐他汀相對二甲雙胍；和(c)二甲雙胍或羅格列酮相對阿托伐他汀治療。a顯示，與用二甲雙胍或阿托伐他汀治療的受試者相比較，用羅格列酮治療的受試者的血清中ccdc47的水平顯著提高(p＝3.61×10-8)。在用羅格列酮或阿托伐他汀相對二甲雙胍；或用二甲雙胍或羅格列酮相對阿托伐他汀治療的受試者的ccdc47血清水平中沒有觀察到顯著的差異(分別為p值＝0.26和0.19)。實施例9：如在病例對照研究中證明的ccdc47、igfbp7和pc-li-183-d18:2-22:6作為血清中心肌病的預(yù)測生物標(biāo)志物從商業(yè)來源獲得來自具有2型糖尿病(t2d)的個體(n＝200)的人血清樣品。上面提供了該組的特征。使用市售的elisa試劑盒，在來自t2dm個體和藥物治療的t2dm個體的血清樣品中測定心肌病蛋白質(zhì)標(biāo)志物ccdc47和igfbp7的水平。使用制造商的說明書進(jìn)行該分析。使用tsqvantageemrtriplequadrapole與advionnanomate在相同血清樣品中測定脂質(zhì)pc-li-183-d18:2-22:6的水平。執(zhí)行roc分析以確定在用羅格列酮治療的患有2型糖尿病的受試者中，血清ccdc47和igfbp7水平或血清ccdc47、igfbp7和pc-li-183-d18:2-22:6水平是否與包括心力衰竭的不良心臟事件的增加的發(fā)生率相關(guān)。該分析的結(jié)果示于圖14中。圖14示出升高的血清ccdc47和igfbp7水平(auc＝0.67)的存在與包括心力衰竭的不良心臟事件的發(fā)生率之間有可測量的相關(guān)性，或和升高的血清ccdc47、igfbp7和pc-li-183-d18:2-22:6(auc＝0.78)的存在與包括心力衰竭的不良心臟事件之間的發(fā)生性存在更強(qiáng)的相關(guān)性。這些結(jié)果表明，在用羅格列酮治療的患有2型糖尿病的受試者中，ccdc47和igfbp7水平的組合是不良事件的良好的預(yù)測子，并表明進(jìn)一步包括pc-li-183-d18:2-22:6水平增加了該分析結(jié)果的可預(yù)測性。實施例10：識別在治療期間很可能發(fā)生藥物誘導(dǎo)心肌病的患者亞群當(dāng)指定用已知引起心肌病的藥物治療時，受試者被邀請參與試驗。獲得受試者樣品，例如，對照樣品。定期地，在監(jiān)測和治療受試者的整個過程中，獲得新的受試者樣品。在研究結(jié)束時，測試所有受試者樣品的上述一種或多種生物標(biāo)志物的水平。使受試者樣品與受試者的病歷相匹配以將相應(yīng)的一種或多種生物標(biāo)志物的水平(和/或其改變)與藥物誘導(dǎo)心肌病的發(fā)生和/或受試者對藥物治療的反應(yīng)關(guān)聯(lián)。可選地，分析在監(jiān)測和治療受試者的整個過程中獲得的受試者樣品中上述一種或多種生物標(biāo)志物的水平，并與對照群體(例如，具有類似的疾病和還沒有經(jīng)過任何治療或者具有類似的疾病和用不引起心臟毒性的不同藥物治療的受試者群體，或正常健康受試者群體)中一種或多種生物標(biāo)志物的平均水平相比較。進(jìn)一步驗證為與藥物誘導(dǎo)心臟毒性的發(fā)生相關(guān)的表達(dá)調(diào)節(jié)的標(biāo)志物可用于在心臟毒性的生理表現(xiàn)被檢測到之前很久，在用藥物(如，已知導(dǎo)致心臟毒性或已知具有引起心臟毒性的風(fēng)險的藥物)治療的早期識別受試者為具有發(fā)生心臟毒性的風(fēng)險。因此受試者的該藥物治療可以終止和/或可推薦、指定或施用替代療法。等同：本領(lǐng)域的技術(shù)人員可以認(rèn)識到或者能夠只使用常規(guī)實驗確定許多本文所述的具體的實施方式和方法的等同方式。這些等同方式意在被包含在以下的權(quán)利要求的范圍中。序列表<110>bergllc<120>標(biāo)志物用于識別心臟毒性劑的用途<130>119992-07820<140>pct/us2013/059559<141>2013-09-12<150>61/732,105<151>2012-11-30<150>61/727,115<151>2012-11-16<150>61/727,104<151>2012-11-15<150>61/706,611<151>2012-09-27<150>61/700,327<151>2012-09-12<160>461<170>patentinversion3.5<210>1<211>385<212>prt<213>智人<400>1metalaalaalaleuphevalleuleuglyphealaleuleuglythr151015hisglyalaserglyalaalaglyphevalglnalaproleusergln202530glnargtrpvalglyglyservalgluleuhiscysglualavalgly354045serprovalprogluileglntrptrpphegluglyglnglyproasn505560aspthrcysserglnleutrpaspglyalaargleuaspargvalhis65707580ilehisalathrtyrhisglnhisalaalaserthrileserileasp859095thrleuvalglugluaspthrglythrtyrglucysargalaserasn100105110aspproaspargasnhisleuthrargalaproargvallystrpval115120125argalaglnalavalvalleuvalleugluproglythrvalphethr130135140thrvalgluaspleuglyserlysileleuleuthrcysserleuasn145150155160aspseralathrgluvalthrglyhisargtrpleulysglyglyval165170175valleulysgluaspalaleuproglyglnlysthrgluphelysval180185190aspseraspaspglntrpglyglutyrsercysvalpheleuproglu195200205prometglythralaasnileglnleuhisglyproproargvallys210215220alavallyssersergluhisileasngluglygluthralametleu225230235240valcyslyssergluservalproprovalthrasptrpalatrptyr245250255lysilethraspsergluasplysalaleumetasnglysergluser260265270argphephevalserserserglnglyargsergluleuhisileglu275280285asnleuasnmetglualaaspproglyglntyrargcysasnglythr290295300serserlysglyseraspglnalaileilethrleuargvalargser305310315320hisleualaalaleutrppropheleuglyilevalalagluvalleu325330335valleuvalthrileilepheiletyrglulysargarglysproglu340345350aspvalleuaspaspaspaspalaglyseralaproleulysserser355360365glyglnhisglnasnasplysglylysasnvalargglnargasnser370375380ser385<210>2<211>2107<212>dna<213>智人<400>2gtacatgcgagcgtgtgcgcgcgtgcgcaggcggggcgaccggcgtccccggcgctcgcc60ccgcccccgagatgacgccgtgcgtgcgcgcgcccggtccgcgcctccgccgctttttat120agcggccgcgggcggcggcggcagcggttggaggttgtaggaccggcgaggaataggaat180catggcggctgcgctgttc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