CN1787850A - 用于传送电信号以修改心脏组织中基因表达的装置与方法 - Google Patents

用于传送电信号以修改心脏组织中基因表达的装置与方法 Download PDF

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CN1787850A
CN1787850A CNA2004800126875A CN200480012687A CN1787850A CN 1787850 A CN1787850 A CN 1787850A CN A2004800126875 A CNA2004800126875 A CN A2004800126875A CN 200480012687 A CN200480012687 A CN 200480012687A CN 1787850 A CN1787850 A CN 1787850A
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gene expression
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CN1787850B (zh
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尤瓦尔·米卡
哈尼·萨巴
瓦利德·哈达德
本尼·鲁索
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Impulse Dynamics NV
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/02Details
    • A61N1/04Electrodes
    • A61N1/05Electrodes for implantation or insertion into the body, e.g. heart electrode
    • A61N1/0587Epicardial electrode systems; Endocardial electrodes piercing the pericardium
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/326Applying electric currents by contact electrodes alternating or intermittent currents for promoting growth of cells, e.g. bone cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362Heart stimulators
    • A61N1/3627Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00Electrotherapy; Circuits therefor
    • A61N1/18Applying electric currents by contact electrodes
    • A61N1/32Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362Heart stimulators
    • A61N1/365Heart stimulators controlled by a physiological parameter, e.g. heart potential
    • A61N1/36514Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure
    • A61N1/36557Heart stimulators controlled by a physiological parameter, e.g. heart potential controlled by a physiological quantity other than heart potential, e.g. blood pressure controlled by chemical substances in blood

Abstract

通过施加电场修改心肌细胞(110)中基因表达的方法与装置(120)。

Description

用于传送电信号以修改心脏组织中基因表达的装置与方法
对相关申请的交叉参照
本申请基于2003年3月10日提出的美国临时专利申请60/453,349以及2003年9月10日提出的美国临时专利申请60/503,075,并且本申请要求它们根据35USC 119(e)享有的权益,在此通过引用将它们所公开的全部内容并入本申请。
发明领域
本发明涉及心肌控制领域。在某些实施例中,本发明涉及通过修改(modify)基因表达,使用电信号来治疗心力衰竭和/或其它疾病。
发明背景
心力衰竭影响心脏功能中所涉及的多种机制(和/或可能由这些机制所导致)。在这些机制中,某些基因的表达可能会受到影响,致使它们处于抑制或过度表达状态,这影响了细胞以及肌肉作为一个整体的功能。多个基因的表达也被用作疾病发展的临床标记。
在涉及心力衰竭的基因表达和蛋白质改变的文献中,可以发现脑和心房钠尿肽(brain and atrial natriuatic peptides)(BNP,ANP)的mRNA基因表达、碱性成纤维细胞生长因子(bFGF)、α肌球蛋白重链αMHC的mRNA基因表达、以及间隙连接(gap junction)蛋白质连接蛋白43(connexin43)方面的变化。在心力衰竭(HF)过程中,脑(B型)和心房(A型)的钠尿肽的血浆水平增高,而且预示着不良后果。碱性成纤维细胞生长因子(bFGF)的增高水平与所增加的血管生成、增加的毛细血管密度、以及改进的左室(LV)射血分数相关(如在患心力衰竭的狗身上所显示的)。肌球蛋白重链(MHC)是心脏收缩机制的一个关键成份。最近的研究表明,从αMHC向βMHC同种型的转换出现在心力衰竭的病人身上。这一转换可能部分地导致了心力衰竭所特有的左心室功能的逐渐恶化。
间隙连接的丧失和受损的细胞间联络是心力衰竭过程中改型的特征,并且起因于间隙连接蛋白质连接蛋白43的迅速丧失。另据称在患心力衰竭的病人中连接蛋白43的丧失导致了恶性室性心律失常。
先前,已显示:在患心力衰竭的狗中,在绝对难治(absolute refractory)期,向左心室肌肉传送非刺激性(excitatory)心脏收缩性调制(CCM)(cardiaccontractility modulation)电信号,导致左心室功能的慢性改善和再造。在患心力衰竭的病人和狗中,还把慢性CCM疗法与抑制室性心律不齐相联系。
可兴奋的组织控制(ETC)(excitable tissue control)设备是通过把非刺激性心脏收缩性调制(CCM)电场信号通过与组织相接触的适当的电极施加于可兴奋的组织来调控可兴奋的组织的活性的设备。例如,除其它用途之外,可以在体外、体内以及在原位把ETC设备用于增大或减小心肌的收缩性,如Ben-Haim等人的序号为PCT/IL97/00012、名称为“电肌肉控制器”的PCT申请(国际申请号WO97/25098),以及美国专利号6,317,631中所详细公布的,特将这两者所公开的全部内容并入此处,以作参考。
发明目的
本发明的某些实施例的目的是,提供一种心肌控制的方法与设备。
本发明的某些实施例的目的是,提供非刺激性或者非刺激性与刺激性心脏收缩性调制信号以影响心脏例如治疗心律不齐。
本发明的某些实施例的目的是,提供非刺激性或者非刺激性与刺激性心脏收缩性调制信号以影响心脏例如改善心肌收缩。
本发明的某些实施例的目的是,提供传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号的方法与装置,以修改与心脏功能相关的基因表达和蛋白质水平,从而改善心脏功能。
本发明的某些实施例的目的是,提供一种通过修改与可刺激的心脏组织相关的基因的表达来治疗心力衰竭的方法与装置。
在以下的讨论中,本发明的实施例的这些及其它目的将变得更加明显。
发明概述
根据本发明的某些实施例,传送给衰竭心脏的心脏组织长达数小时或更长或更短时间的非刺激性信号,例如心脏收缩性调制信号或非刺激性和刺激性信号改变了影响心血管系统功能的多个基因的表达。表达的改变改善了心脏功能,并可能导致心力衰竭疾病发展的逆转,甚至可以使心脏返回到更正常的功能。
如以下所讨论的实验证据中所反映的,CCM信号的传送导致细胞和肌肉活性的改进,如mRNA表达所显示的。更具体地讲,CCM信号减少了脑和心房钠尿肽(BNP,ANP)的mRNA基因表达,增加了碱性成纤维细胞生长因子(bFGF)的水平,正常化了α肌球蛋白重链αMHC的mRNA基因表达。
在心力衰竭过程中,脑(B型)和心房(A型)钠尿肽的血浆水平增高,而且预示着不良后果。根据本发明的某些实施例,CCM疗法降低B型和A型钠尿肽的mRNA基因表达。
碱性成纤维细胞生长因子(bFGF)的水平增高与血管生成增加相关。先前已显示,在患慢性心力衰竭的狗身上,bFGF的mRNA基因表达增加与毛细血管密度增加相关。还显示,例如在患心力衰竭的狗身上,毛细血管密度增加与左心室射血分数改善相关。根据本发明的某些实施例,CCM疗法使bFGF的mRNA基因表达恢复到正常水平之上,或患病水平之上。CCM疗法似乎增强了bFGF的表达,因而,可以成为一种增强血管生成的治疗方法,血管生成是很可能在慢性心力衰竭和可能的心绞痛的治疗中十分重要的状况。
肌球蛋白重链(MHC)是心脏收缩机制的关键成份。最近的研究表明,从αMHC的βMHC同种型的转换出现在心力衰竭的病人身上。这一转换可能部分地导致了作为心力衰竭特性的LV功能的逐渐恶化。根据本发明的某些实施例,CCM疗法改善了αMHC的mRNA基因表达,并且可以使其达到可被视为基本上正常的水平。由于与慢收缩βMHC相比,αMHC与心肌较快的缩短速度相关,所以在CCM疗法之后,这一正常化可能是导致所观察到的左室射血分散(LV EF)的改进的部分原因,并且可将其用于病人心力衰竭的治疗。
由于可以将CCM信号用于降低B型和A型钠尿肽的mRNA基因表达,以及用于将bFGF的mRNA基因表达恢复到正常水平之上和/或正常化αMHC的mRNA基因表达,所以可以将这一疗法用于改进心脏功能,并且可以将其用作一种增强血管生成的治疗方法,血管生成是在慢性心力衰竭和可能的心绞痛的治疗中可能十分重要的状况。
而且,由于与慢收缩βMHC相比,αMHC与心肌较快的缩短速度相关,通过CCM传送对衰竭心脏进行治疗可被用于获得较好的收缩,所述CCM传送旨在改善、或正常化ANP和BNP水平,从而可以是CCM疗法之后所观察到的LV EF的改善的部分原因。
根据本发明的某些实施例,非刺激性心脏收缩性信号被用于心律不齐的治疗和/或心脏内细胞之间连接的改善,所述治疗和/或改善通过促进相关基因,特别是作为细胞之间间隙连接形成的成因之一的连接蛋白43蛋白质的表达而实现的。这可被用于改进心室的收缩和/或同步化。左室收缩的改善可改善收缩的同步化,增加心脏收缩性,并也可减轻病人患心衰的痛苦。
尽管某些特殊的基因的例子已被显示修改了其表达,仍期望其它基因的表达也能被修改。在本发明的示范性实施例中,施加CCM信号的效果在于改善某些心脏细胞的表达谱,使其更健康和/或更适合于它们的功能。
在本发明的某些实施例中,施加了不具有临床上显著的心脏收缩性修改效果的非刺激性电场。
在本发明的示范性实施例中,把一种设备用于施加CCM信号,并且监视对基因表达的影响,从而可以修改CCM或其它非刺激性信号的施加。作为选择,当达到了所希望的基因表达效果时,可以停止CCM的施加。作为选择,还可以针对某一具体的病人或疾病状态,优化CCM参数。作为选择,还可以令该设备包括一个闭合回路,该闭合回路感应CCM信号的基因表达效果,并相应地修改这一基因表达效果。
因此,根据本发明的示范性实施例,提供了能够向心脏组织传送非刺激性或者非刺激性与刺激性信号的设备,其中所述信号将以改善心脏功能的方式修改心脏组织中细胞的基因表达。
根据本发明的示范性实施例,还提供了能够向心脏组织传送非刺激性心脏收缩性或者非刺激性与刺激性调制信号的设备,其中所述信号将修改心脏组织中BNP和ANP的表达以治疗心力衰竭。
根据本发明的示范性实施例,还提供了能够向心脏组织传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号的设备,其中所述信号将正常化或改善心脏组织中α肌球蛋白重链αMHC的表达以治疗心力衰竭。
根据本发明的示范性实施例,还提供了能够传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号的设备,其中所述信号将修改心脏组织中碱性成纤维细胞生长因子(bFGF)的表达以治疗心力衰竭。
根据本发明的示范性实施例,还提供了用于改善心脏功能的方法,该方法通过修改影响心血管系统功能的基因在心脏组织中的表达改善心脏功能。
根据本发明的一个示范性实施例,还提供了通过修改影响心血管系统功能的基因在心脏组织中的表达治疗心力衰竭的方法。作为选择,心力衰竭为充血性心力衰竭。作为选择或者额外地,向心脏组织传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号以修改心脏组织中基因表达。作为选择,这一信号或这些信号降低BNP、ANP或BNP与ANP二者的mRNA基因表达。作为选择,这一信号或这些信号使bFGF mRNA基因表达恢复到正常水平之上。作为选择,根据本发明的示范性实施例,这一信号或这些信号正常化或改善αMHC mRNA基因表达。
根据本发明的示范性实施例,还提供了治疗患有与心脏相关的疾病的病人的方法,包括:
确定心脏组织中所需的基因表达谱;以及
将非刺激性信号施加于心脏组织以获得所需的基因表达谱。
根据本发明的示范性实施例,还提供了适合于将非刺激性电场施加于心脏的设备,其特征在于,该设备适合于把对基因表达的影响考虑于其功能活动中。作为选择,所述设备是可植入的。作为选择或者额外地,所述设备包括反馈控制回路(loop),所述回路响应一个指示先前施加的非刺激性电场的基因表达影响的指示,修改非刺激性电场的施加。作为选择,所述设备包括监控设备,该监控设备响应对心脏中基因表达施加电信号所产生的影响,停止或修改向心脏施加电信号。
附图简述
图1示意地性说明了用于根据本发明的示范性实施例传送电信号的装置;
图2是用于根据本发明的示范性实施例传送电信号的装置的更详细的示意图;
图3是流程图,说明了用于根据本发明的示范性实施例治疗病人心力衰竭的方法;以及
图4说明了在琼脂糖-乙啡啶凝胶上不同基因的条带。
发明详述
根据本发明的某些实施例,将非刺激性或者非刺激性与刺激性CCM信号施加于病人心脏中的心脏组织。所施加的信号可以是完全的非刺激性信号,也可以是非刺激性与刺激性信号的混合。这些信号可以是叠加的,也可以根据相应的电压按诸如从大约20∶1到大约1∶10的比率,或者按从大约10∶1到大约1∶11的比率断续地施加。这些信号均可具有诸如从大约0.1Hz到大约1000H的频率。在另一个例子中,可以使用从大约10到大约80Hz范围的信号频率。信号均可具有从大约10mV到大约50V的电压。在另一个例子中,可以把电压限制在从大约1到大约15V的范围,或者进一步限制在使用从大约3到大约10V范围内的电压。在另一个例子中,信号可以可配置的延迟(delay)和局部肌肉活动的持续时间(duration)与心脏活动同步传送。例如,有可能以距局部电活动检测最多150毫秒的延迟施加信号。可以把延迟进一步限制在最多100毫秒。在另一个例子中,可以按最多150毫秒的持续时间施加信号。把这一范围更进一步限制在使用最多50毫秒的持续时间也是可能的,例如大约10毫秒、大约20毫秒、大约30毫秒或大约40毫秒。在另一个例子中,可以使用多于3倍时值,或者超过5毫秒的信号持续时间。在另一个例子中,可以使用超过8毫秒的信号持续时间,例如20毫秒或40毫秒。
作为选择,信号还可具有平衡的波形,例如,呈双相脉冲的形状。
使用CCM疗法的时间长短可能明显不同。例如,可以为10分钟、1小时、2小时、6小时、1天、1星期、或者1个月。可以提供一个或多个休息期和/或间歇期,以测试信号的长期效果,例如,测试即使在一个星期没有施加CCM之后基因表达是否仍不发生变化。应该认识到,基因表达水平可能随时间变化。例如,丢失了连接蛋白43的细胞可以通过连接蛋白43mRNA片段的显著表达响应CCM信号,而一旦满足其需求,则减少其表达。细胞功能的改进可以为即时的,也可以为延迟的和/或渐进的和/或依赖于其它因素的。在任何情况下,作为选择,当测量CCM信号的积极影响时,任选考虑因细胞需求的缺乏所导致的基因表达的这样的变化。作为选择,还可以周期性地令细胞休息,以驱动它们更多地产生所需的分泌物和/或蛋白质。
在本发明的示范性实施例中,把CCM信号设置为3~7.5伏的电压,每一节拍传送1~5个双相脉冲的串,总共具有10~80毫秒的持续时间,以及距局部电活动最多100毫秒的延迟。预计其它脉冲参数也将能够产生所希望的基因表达效果。
在优选实施例中,在局部组织的绝对难治期传送信号,其中对参数加以调整,以产生所希望的基因表达效果。在又一个实施例中,信号包括起搏,后接非刺激性信号,其中所述参数提供了所希望的基因表达效果。在又一个实施例中,信号是具有第一刺激性边缘(edge)的延长的起博信号,接续一个长于5毫秒的信号,其中,对参数加以调整,以产生所希望的基因表达效果。
在本发明的示范性实施例中,将由信号生成器单元生成非刺激性信号和/或刺激性信号,所述单元是植入的或是外部的。该设备可以包括心脏活动的传感器,而且还可以包括附加的传感器和/或来自其它传感器的输入,所述其它传感器直接或间接与有关基因表达的水平相关,以能够调整信号的传送,以实现所测参数的所希望的变化。
示范性实施例
图1描述了本发明的示范性实施例。使用导线130和一个或多个电极142~148,把CCM信号生成器单元120连接于心脏110。例如,可以把电极142、144、146、148无论是通过心内通路、心外通路还是静脉内通路分别定位在诸如右心室112、左心室114、心房116或者隔膜118的不同位置上。电极和导线可选择地被用于从一个或多个位置感应心脏活动,并且可用于向一个或多个位置传送CCM信号。CCM信号生成器单元120可以接收从不同传感器所测量的输入。例如,可以把一个或多个这样的传感器150附接于心脏(无论内部还是外部)。在额外的例子中,可以把一个或多个传感器154定位在血管中,或者定位在另一个身体器官中。可以经由连接器152直接连接这样的传感器,以把所测信号传送于CCM信号生成器单元120。在额外的例子中,单元120可以接收非直接连接于单元120的传感器158所测量的输入,例如接收具有诸如无线连接的外部传感器所测量的输入。可以把这样的传感器用于测量各种生物化学化合物的水平,例如,mRNA、蛋白质、肽等的水平。这些传感器可以由商业上可得的用于分析生物样品中化合物的生物芯片(例如,Affymetrix公司用于DNA分析的生物芯片)技术加以制造。CCM信号生成器可以从传感器接收信号,或者可以根据这样的读数进行调节,并且可以接收与心脏活动有关的信号,以确定参数和传送CCM信号,以影响相关基因表达和相关蛋白质的水平。作为选择,生成器(设备120)包括有限数量的生物化学测试细胞,当要确定基因表达的状态时,可有选择地和激活这些细胞中的每一个细胞。在这一技术领域中,这样的微型化的基因组和生物化学系统是人们所熟悉的。例如,可以提供用于测试血液的具有10个小室的血液插入物。在另一个例子中,提供配有一个内螺旋元件的管子。该元件用于切除组织样本,并且将其传送于设备内的测试室中。作为选择,也可以提供外部控制单元,例如,将测试结果或组织的活体检查提供给这一外部控制单元。这一外部控制单元对变化进行决断,和/或从人用户接收输入。
图2描述了一种可用于生成控制蛋白质和基因表达水平的CCM信号的系统的实例。该系统可以由传感器222构成,并且可以从远程传感器220接收信息。该系统可以包括处理输入信号的传感器分析单元230。该系统可进一步由心脏活动分析单元250构成,心脏活动分析单元250可用于处理从附接于心脏的一个或多个电极270所接收的信息。该系统可以包括控制单元240,控制单元240根据所希望的治疗确定将加以传送的CCM信号的参数,并且可以考虑来自传感器和心脏活动单元(分别为单元230和250)的所分析的信息。该系统包括CCM传送单元260,CCM传送单元260中并入了必要的电路,以产生所希望的CCM信号。把这些信号传送于一个或多个电极270和280,以影响相关基因表达和相关蛋白质的水平。
在一个示范性的应用中,在植入期间(或者接下来的期间)对设备120加以调整,以达到如基因表达所测量的最好的效果。在另一个示范性的应用中,设备120可以响应所测基因表达变化,修改其CCM信号的生成。应该加以注意的是,可以把此处所描述的某些传感器用于设备120的闭回路控制。作为选择,也可以接受或请求人交互。例如,也可以使用标准类型的遥测单元。例如,可以把这样的遥测用于数据登录、编程和/或实时或脱机参数控制。应该认识到,实现最佳CCM信号参数,并不总是可能、可行、或必要的。例如,出于安全、功率极限、生理极限、电极设置、优化时间等等起见,具有次优化参数的脉冲足以实现有用的治疗信号。
在本发明的一个示范性的实施例中,设备120是用于相对较长时间治疗的植入设备,例如一个星期以上、一个月以上、几个月或者永久。在本发明的一个可选的实施例中,设备120是外部设备,例如带有植入的导线。作为选择,从体外施加CCM的电场。外部设备可以用于例如,在短期(例如,1小时或1小时以下、1天)治疗或者急性应用(例如,暂时心力衰竭)之后显示基因表达响应的病人。根据病人的情况,可以按不同的周期,例如一分钟一次、一小时一次、一天一次、一个星期一次或其或多或少的频度施加CCM,以实现所希望的或适当的基因表达修改。如以下所描述的,可以根据CCM的效果,按需求提供CCM,例如当基因表达谱达到某一极限时。在某些情况下,例如,在外科手术或作为独立的治疗期间,例如,使用导管,可以精确地施加CCM。
尽管作用机制尚待开发并无意限制实际的应用,人们可以推断电流调节细胞器的离子可得性(availability),这一可得性调节影响生物化学反应和/或直接影响基因转录。另一种可能的解释是,信号诱导组织机械的和电的功能,这缓解了对细胞的压力,从而消除了不规则基因的触发因素(trigger)。作为选择,这种所诱导的功能其自身可导致、触发或者调节某些基因转录。可能的是,任何改进细胞的功能活动和/或减少细胞上的压力和/或增加(或降低)平台期时间和/或细胞或其细胞器内钙可得性的信号,均可以具有可利用的基因转录和/或表达效果。
本发明的又一个优选实施例是,在设备中包括来自生物化学传感器的输入,所述感受器无论是并入在设备中还是连接于设备均可,用于报告所希望的分析水平。在又一个优选实施例中,从间接测量,包括与分析活动相关的电或机械传感器(例如,心律不齐的变化或收缩性),间接推导表达水平的变化。作为选择,还可以把收缩性的长期变化与基因表达的变化相关联。于是,可以从心脏或其它身体系统的电和机械行为的变化(例如,测量液体的潴留)推导(一个病人中或一组病人中)各种基因的基因表达的变化。在某些实施方案中,把此处所描述的基因之一作为标记物检测,用于指示其它基因已修改了其表达;和/或作为特定基因表达谱的指示物。作为选择,对于此处所描述的基因或者其它基因,可以把不同的基因用作标记物或指示物。
可以把不同的设计方法用于停止、启动或者修改CCM信号的施加以及参数。在一个例子中,设备120根据所测量的水平、根据预编程的决策规则,改变CCM的传送。作为选择或者额外地,凡是在分析水平跨越极限时,设备120均施加CCM信号或信号组。作为选择或者额外地,在结合多个参数的计算跨越极限时,设备120施加信号。作为选择或者额外地,信号参数(延迟持续时间、频率、电压、极性、脉冲链、信号形状)被改变,以实现被测参数所希望的水平。作为选择或者额外地,施加否定规则,例如,不施加对基因表达具有负面影响的刺激性或非刺激性信号。
在以上所提到的序号为WO 97/25098的PCT出版物和序号为6,317,631的美国专利中给出了导线的实际传送和/或植入以传送信号的步骤,特将其全部内容并入此处,以作参考。以下是描述了可以结合本发明一起使用的装置与方法的专利和出版物的列表,特将所有这些的全部内容并入此处,以作参考。
心脏输出增强起搏器,序号为6,463,324的美国专利;用于控制肌肉收缩性的装置与方法,序号为6,233,484的美国专利;使用非刺激性电场控制心脏性能,序号为6,371,631的美国专利;肌肉收缩辅助设备,序号为6,285,906的美国专利;使用施加于组织的非刺激性电信号调节细胞内钙浓度,PCTWO01/24871和PCT WO00/12525;电肌肉控制器,序号为6,363,279的美国专利;使用非刺激性电场的电肌肉控制器,序号为6,330,476的美国专利;心脏输出控制器,序号为6,298,268的美国专利;心脏输出增强起搏器,序号为6,463,324的美国专利;基于传感器的心脏可刺激性组织控制调节,WO 00/27475;基于生理输入的心脏可刺激性组织控制的调节,WO 00/27476;基于心脏可刺激性组织控制的调节的触发器,序号为6,587,721的美国专利;血液动力改进的起搏过程,PCTIL99/00392;经由RV隔膜的ETC传送,PCTWO0182771A3;具有心脏收缩性调节能力的抗心律不齐设备,PCTWO01/30445;以及抗心律不齐设备与用于传送抗心律不齐心脏疗法的方法,PCT WO01/30139。
示范性治疗方法
图3是一个示范性流程图,说明了一种用于治疗病人的方法。从测量基因表达和/或蛋白质水平的各种传感器收集(300)数据。还可以使用信号调节、统计工具、分类、或者能够产生可提供信息的结果的其它数学方法进一步分析(310)输入数据。可以把所收集的数据和/或分析的结果进一步与极限的第一集合进行比较(320),以判断是否应根据参数的第一集合施加(322)CCM。如果不满足这些准则,可以进一步与第二极限进行比较,以判断是否应根据参数的第二集合施加(332)CCM。也可以使用极限和参数的更多的集合。如果这些准则均不满足,则可以使用默认的CCM参数集合,或者根本不传送CCM。不同的CCM集合可代表例如不同的功率水平或者对心脏的不同的压力水平(出于这一原因,可能会希望对其使用进行限制)。
治疗
从以下的例子将可以看出,基因表达修改的效果可能是短期的,也可能是长期的。例如,连接蛋白蛋白质停留在细胞中,并且修改其行为。BFGF是离开细胞的物质的实例。然而,其通过促进血管生成可产生长期的效果。
在本发明的一个示范性实施例中,施加CCM信号,以达到特别有利的效果,该效果作为选择,可以由设备120加以监视和/或管理。
在促进血管生成的一个示范性实施例中,任选定位设备120,以在需要血管生成的区域的上游使心脏细胞带电。
在本发明的一个示范性实施例中,为了产生血管生成,施加CCM,直至分泌了足够量的血管生成促进物质。作为选择,同时提供了可望促进血管生成的额外的治疗,例如锻炼或药物治疗。
作为选择,可以根据疾病的严重性确定治疗的持续时间(例如,数分钟、数小时、数天、数月),其中,疾病的严重性由相关基因表达和/或其它生理的或生物化学的指示,如这一技术领域中已知的加以指示。作为选择或额外地还可以根据疾病参数设置其它参数,例如强度。
在治疗或辅助心律不齐的例子中,作为选择把CCM信号施加于(例如,连续地或周期性地)心肌部分,直至实现了传导速度方面的所希望的改进。例如,在心房纤颤中,可以把CCM信号施加于整个或部分心房。作为选择,可以例如通过减少某些肌肉部分的活动模拟(model)传导速度,从而可能防止CCM信号的影响。作为选择或者额外地,还可以发现某些信号对基因表达具有负面影响。然而,可以利用这样的负面影响模拟心脏中肌肉的质量和/或传导速度。除了心房纤颤外,典型的心律不齐还包括PVC、VT、传导阻滞以及心室去同步化。可以认为,通过对心脏的某些部分中的基因表达进行选择性的或非选择性的增强,能够改进这些病症中的某些或所有病症。
也可以治疗其它病症。应该加以注意的是,可以在心脏之外找出心脏基因表达的结果。直接效果例如防止液体潴留(例如,通过分泌物对肾的直接作用)中,间接效果(例如,逆转CHF的症状,或减少心绞痛的痛苦)。
可以发现某些药物和CCM对基因表达的影响之间的相互作用。在本发明的示范性实施例中,因CCM对基因表达的影响使药物的剂量加以改变和/或停止了药物的使用。作为选择或者额外地,还可以停止某些药物,例如,如果发现它们阻止了CCM对心脏组织的影响(例如,可能是钙通道阻断剂),或者如果其组合倾向于心律不齐。也可以发现其它药物具有协合效应。作为选择,通常也可以把这样的药物施用于心脏的某些部分,以选择性地阻止或增强CCM的影响。作为选择,也可以把CCM基因表达的修改用于增强药物的活性或者克服其副作用(例如,对于某些抗心律不齐药物而言传导速度降低)。
治疗的变异
现在,描述为实现基因表达而施加CCM信号的某些变异。在一个变异中,施加(例如,连续地或周期性地)CCM信号,直至基因表达的改善稳定。或许,可能需要周期性连续的测试和/或CCM的施加。
在本发明的示范性实施例中,在一个具体病人身上,使用设备120确定基因表达修改的参数。例如,使用设备120确定具有所希望的基因表达效果的CCM信号施加系列的最小或最佳长度。在降低功率需求方面,这可能是有用的。可以由此确定的其它示例性参数是CCM的重复频率和CCM的功率水平。应该加以注意的是,即使直接从一拍一拍的CCM的施加中找到很少或找不到临床收缩性的改进,CCM信号也会对基因表达产生影响。
作为选择,可以使用设备120对病人进行试验,以确定对该病人最佳的参数。作为选择或者额外地还可以找到对基因表达具有不利影响的参数。
应该加以注意的是,可以存在多个适当的/健全的/可允许的基因表达谱。例如,设备120可以针对这些谱中的一个,和/或旨在避免一个或多个已知的不佳表达谱和/或具体基因的某些低或高的基因表达值。作为选择,可以通过对大量样本进行取样,和/或通过对同一病人中的健康细胞进行取样,找出各种基因的目标基因表达谱或极限。还应该加以注意的是,最佳基因表达谱依不同年龄、种族、基因组图谱、疾病、细胞的功能活动(例如,包括工作负荷)、以及在心脏中的位置,可能不尽相同。
在某些情况下,基因表达值自然波动。设备120(或其它反馈机制,例如人)任选例如,通过平均,考虑这些波动。任选或额外地通过周期性地刺激和不刺激细胞,特意针对这些波动,以致基因表达谱可以更像健康细胞那样波动。
在本发明的示范性实施例中,使用设备120把病人(或者考察一组病人)的基因表达的响应绘制到各种CCM序列和/或参数上。
在本发明的示范性实施例中,设备120或用户监视对某些起博序列和步骤和/或某些非刺激性序列,例如,“栅栏(fencing)”序列的负面影响。可将这用于限制这样的序列的使用,和/或通过基因表达促进信号抵消它们的影响。或许,可能会发现某一起博体系对某一病人、疾病状态和/或一组病人具有有益的效果,因此认为是所希望的。
任选地,也可以把基因表达监视作为标准类型起博器中的安全特征,以指示是否导致了对心脏的负面影响。任选地,也可以通过周期性地测量心脏组织对CCM信号的敏感度,确定基因表达效果。敏感度的变化预期在某些病人中和在某些情况下与基因表达方面的变化相关联。例如,可以在传导速度未被损害的组织中,传导速度可显著地改变。在另一个例子中,液体潴留将不改善,或不基于组织是否能生成额外的适当的分泌物。任选在这样使用之前,收集病人的基线。
另一个可选的安全特征是对心脏进行跟踪,以观察异常的ECC信号或诸如ST可变性的各种危险信号的增加。这样的变化可能表示基因表达的变化是无益的,应该停止、减慢或用保护心脏和/或抵消这样的负面效果的刺激性或非刺激性信号补偿。
作为选择或者额外地,为了停止或修改CCM施加,可以生成对用户、医生或看护者的警告。
在本发明的示范性实施例中,对标准CCM或其它非刺激性信号的施加加以修改,以考虑CCM信号短期影响的组合和基因表达的变化所造成的长期影响。例如,可以改变收缩性增强的程度和/或时机选择以考虑到传导方面的变化。任选,可以生成数据库,其中存储了所希望的效果和/或CCM信号对基因表达的影响的进展情况,以及所导致的CCM施加的变化。
在本发明的示范性实施例中,在植入所植入的设备或者对该设备进行编程之前,对病人进行测试,以观察某些已知的CCM序列是否具有所希望的基因表达影响和/或影响的程度。如果这一影响很小或者为负面的,则指示该病人可能不适于植入。作为选择,可以把这样的测试结果用于对病人进行分类,即把病人分为已知病人类型的组,所述类型具有对CCM信号的已知(例如,先前收集的)基因组或者其它响应。任选也可以把非基因组指示信息,例如收缩性修改,与基因表达效果相关联。于是,可以把一种效果用于预测其它效果的一个或多个特性。
在本发明的示范性实施例中,施加CCM,以实现基因表达统计的数值变化。例如,可能希望把基因的表达增加10%、30%、70%、100%、300%或者任何较小的、介于中间的或较大的百分比。任选,所希望的是,把基因表达降低,例如20%、50%、80%、90%或者介于中间的或较大的百分比。在某些情况下,希望在通路中加以连接的一组基因中的任何一个得以降低(或升高),例如使用上面的百分比。在某些实施例中,所希望的是,随时间增加分泌物的体积、或者绝对分泌物数量、或者分泌速率。例如,目标可为增加20%、50%、200%、1000%或者较小的、介于中间的或较大的数量。在某些实施例中,目标是接近正常值,例如为当前表达水平差异的一半。在某些实施例中,所希望的是,在1、3、5、10或其它数目的基因或mRNA片段上,使表达谱类似于基线,例如与基线表达谱相差不到50%、30%或者20%。
应该认识到,此处,按一般意义使用术语“基因”。然而,可以按以上可测量的量的数目表达靶目标,例如,其中可测量的量为mRNA片段、肽以及血清分析物。
实施例
以下,介绍了三项研究的结果,按非限制方式展示非刺激性信号用于改变三种不同类型基因的表达水平的基本原则,并据此提供心力衰竭的疗法。
实施例1
在一项研究中,我们考察了使用来自OPTIMIZER-II ETC设备(可得于Impulse Dynamics)的心脏收缩性调制(CCM)信号进行4小时连续治疗,是否可以使患有冠状微栓塞所导致的HF的狗的LV心肌中A型和B型钠尿肽的基因表达正常化。在开胸准备过程中,把CCM导线植于LV的前表面。
所使用的信号参数为:3~7.5V的CCM电压、每拍所传送的2~4个双相脉冲串、总共20~35毫秒的持续时间、距局部电活动最多100毫秒的延迟。尽管这些参数设置足以产生所希望的效果,但我们认为其它脉冲参数也能达到这样的效果。
总共考察了3只狗。把来自3只正常(NL)狗和3只未治疗的HF狗的LV组织用于比较。把被宰杀时所获得的LV组织用于提取全部RNA。通过使用逆转录酶-聚合酶链反应(RT-PCT)中的特定引物,鉴定琼脂糖-乙啡啶凝胶上的B型和A型钠尿肽,以光密度单位定量相应的荧光带。以下的表中显示了结果。
                         表1
  NL   未治疗的HF   HF+CCM
  B型NP   2590±1399   5181±293*   2008±796
  A型NP   1553±306   4976±1025*   3636±1669
  *=p<0.05相对于NL;=p<0.05相对于未治疗的HF
与NL相比在未治疗的HF狗中B型和A型钠尿肽的基因表达增加。与未治疗的HF狗相比CCM疗法降低B型和A型钠尿肽的mRNA表达。
结论:结果表明,在患有HF的狗中,4小时连续的CCM治疗降低了B型和A型钠尿肽的mRNA基因表达。这些结果与CCM疗法后的狗中所观察到的心房与心室大小方面所观察到的减少一致。
实施例2
在另一个例子中,我们考察了使用来自OPTIMIZER-II ETC设备的心脏收缩性调制(CCM)信号进行4小时连续治疗,是否可以恢复患有冠状微栓塞所导致的HF的狗中bFGF的基因表达。CCM疗法以前曾显示可改进患有HF的狗中LV射血分数(EF)。在开胸准备过程中,把CCM导线植于LV的前表面。把CCM信号参数设置为与以上实施例1中所描述的相同的值。总共考察了3只狗。把来自3只正常(NL)狗和3只未治疗的HF狗的LV组织用于比较。把宰杀时所获得的LV组织用于提取全部RNA。通过使用逆转录酶-聚合酶链反应(RT-PCT)中的特定引物和RT-PCR产物的限制酶分析,测量bFGF,以光密度单位定量带。以下的表中显示了结果。
                            表2
  NL   未治疗的HF  HF+CCM
  bFGF(光密度单位)   6099±1486   4798±223*  7600±145
  *=p<0.05相对于NL;=p<0.05相对于未治疗的HF
与NL相比,在未治疗的HF狗中,bFGF的mRNA表达明显减少。CCM疗法与bFGF的mRNA表达恢复到正常水平以上相关联。
结论:在患有HF的狗中,与NL狗相比,LV bFGF的mRNA基因表达降低。4小时连续的CCM治疗使bFGF的mRNA基因表达恢复到正常水平以上。CCM疗法似乎增强bFGF的表达,并因此可以成为增加血管生成的治疗方法,血管生成在慢性心力衰竭和可能的心绞痛的治疗中可能是十分重要的状况。
实施例3
在又一个实验中,我们考察了使用来自一个OPTIMIZER-II ETC设备的心脏收缩性调制(CCM)信号进行4小时连续治疗,是否可以恢复患有冠状微栓塞所导致的HF的狗中αMHC的基因表达。CCM疗法以前曾显示改善患有HF的狗中LV射血分数(EF)。在开胸准备过程中,CCM导线被植于LV的前表面。CCM信号参数被设置为与以上实施例1中所描述的相同的值。总共考察了3只狗。把来自3只正常(NL)狗和3只未治疗的HF狗的LV组织用于比较。把宰杀时所获得的LV组织用于提取全部RNA。通过使用逆转录酶-聚合酶链反应(RT-PCT)中的特定引物,和RT-PCR产物的限制酶分析测量αMHC,以及以光密度单位定量带。以下的表中显示了结果。
                          表3
  NL   未治疗的HF  HF+CCM
  αMHC(光密度单位)   3486±351   978±63*  3090±142
  *=p<0.05相对于NL;=p<0.05相对于未治疗的HF
与NL相比,在未治疗的HF狗中,αMHC mRNA表达明显减少。CCM疗法与αMHC的mRNA表达恢复至接近正常水平相关联。
结论:在患有HF的狗中,与NL狗相比,LVαMHCmRNA基因表达降低。4小时连续的CCM治疗使αMHC mRNA基因表达正常化。由于与慢收缩的βMHC相比αMHC与心肌的较快的缩短速度相关联,这一正常化可能是导致在CCM疗法之后所观察到的LV EF的改善的部分原因。
图4中给出了以上所讨论的结果,该图描述了琼脂糖-乙啡啶凝胶上的不同基因的带。该凝胶显示了GAPDH的表达水平,GAPDH是用于测试这一过程的精度的持家基因,以及4种以上所讨论的不同的基因(ANP、BNP、αMHC、以及bFGF)。
在每一个条中,存在3组带:
NL-代表正常组织中的表达。
HF-代表心力衰竭组织中的表达。
HF+CCM-代表使用CCM信号治疗了4个小时的HF组织中的表达。
每一组包含来自3个不同组织的3个不同的带。
实施例4
用6只患有冠状微栓塞所导致的HF的狗进行研究。通过经由左开胸术放置在LV前壁的心外膜导线,连续4小时传送CCM信号。CCM信号参数被设置为与以上所描述的实施例1中相同的值。在治疗结束时,来自前壁的组织样本用于提取RNA。从6只正常(NL)狗和6只未治疗的HF狗得到类似的组织样本。使用逆转录酶-聚合酶链反应(RT-PCT)测量连接蛋白43的基因表达。通过基因测序,证实RT-PCR产物为连接蛋白43。带以光密度单位定量,并且标准化为持家基因GAPDH。
结果:在所有3个研究组中,GAPDH mRNA表达是类似的。与NL相比,在未治疗的HF狗中,明显减少了连接蛋白43mRNA表达(0.05±0.002相对于±0.62±0.03,P<0.001)。CCM疗法部分地恢复了连接蛋白43mRNA表达(0.13±0.01,P<0.001)。
结论:在患有HF的狗中,CCM治疗增加了连接蛋白43mRNA表达。这些观察结果可以部分地解释了在HF中长期CCM疗法后LV功能的改进和电机械机能障碍的稳定。
尽管以上所描述的装置集中在硬件方面,但应该认识到,本发明包括可编程的硬件、针对可编程设备的软件、用于对这样的硬件进行编程的软件以及包括用于对这样的设备进行编程的软件的计算机。例如,可以提供一个外部的编程站,这一外部的编程站任选使用遥测技术与可植入设备进行通信。也可以实行使用遥测技术的数据收集。另外,还可包括含有这样的程序的计算机可读媒体。并且包括微代码和其它类型的编程、硬连线的电路与ASIC。此处给出的仅仅是实例的列表,不应当将其视为一种限制。示范性的设备软件包括决策制订模块、计时模块、电源模块和/或信号分析模块。
不应该把以上的描述解释为:本发明的范围局限于所描述的这些具体的实施例,提供这些实施例仅仅是为了举例,或者是为了便于说明。本发明的范围包括这一领域中的熟练技术人员已知的或所意识到的可互换的替代物。许多其它的变化形式也是可能的。因此,本发明的范围应该由所附权利要求以及它们的合法的等价物加以确定,而不是仅由以上所给出的实施例加以确定。

Claims (16)

1.一种能够向心脏组织传送非刺激性或者非刺激性与刺激性信号的设备,其中所述信号将以改善心能功能的方式修改心脏组织中细胞的基因表达。
2.一种能够向心脏组织传送非刺激性心脏收缩性或者非刺激性与刺激性调制信号的设备,其中所述信号将修改心脏组织中BNP和ANP的表达以治疗心力衰竭。
3.一种能够向心脏组织传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号的设备,其中所述信号将使心脏组织中α肌球蛋白重链αMHC的表达正常化。
4.一种能够传送非刺激性或者非刺激性与刺激性心脏收缩性调制信号的设备,其中所述信号将修改心脏组织中碱性成纤维细胞生长因子(bFGF)的表达以治疗心力衰竭。
5.一种改善心脏功能的方法,通过修改影响心血管系统功能的基因在心脏组织中的表达改善心脏功能。
6.一种治疗心力衰竭的方法,通过修改影响心血管系统功能的基因在心脏组织中的表达治疗心力衰竭。
7.根据权利要求6所述的方法,其中心力衰竭为充血性心力衰竭。
8.根据权利要求5或6所述的方法,其中,向心脏组织传送修改心脏组织中基因表达的非刺激性或者非刺激性与刺激性心脏收缩性调制信号。
9.根据权利要求8所述的方法,其中这一信号或这些信号降低BNP、ANP或BNP与ANP的mRNA基因表达。
10.根据权利要求8所述的方法,其中这一信号或这些信号将bFGF的mRNA基因表达恢复到正常水平之上。
11.根据权利要求8所述的方法,其中这一信号或这些信号使αMHC的mRNA基因表达正常化。
12.一种治疗患有心脏相关疾病的病人的方法,包括:
确定心脏组织中所希望的基因表达谱;以及
将非刺激性信号施加于心脏组织以实现所希望的基因表达谱。
13.一种适合于将非刺激性电场施加于心脏的设备,其特征在于,该设备适合于把对基因表达的影响考虑于其功能活动中。
14.根据权利要求13所述的设备,其中所述设备是可植入的。
15.根据权利要求13所述的设备,其中所述设备包括反馈控制回路,所述回路响应于先前施加的非刺激性电场对基因表达影响的指示,修改非刺激性电场的施加。
16.根据权利要求15所述的设备,包括监控设备,该监控设备响应这样的施加对心脏中基因表达的影响,停止或修改电信号向心脏的施加。
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US8326416B2 (en) 2012-12-04
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EP1606011B1 (en) 2015-08-19
WO2004080533A8 (en) 2004-10-28
US20070027487A1 (en) 2007-02-01
WO2004080533A1 (en) 2004-09-23
US20110093028A1 (en) 2011-04-21
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EP1606011A1 (en) 2005-12-21
US7840262B2 (en) 2010-11-23

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