Heart rate control with bioengineered pacemakers

项目摘要/摘要 对于有症状的缓慢性心律失常患者，目前也是唯一的治疗方法是植入电子节律。 起搏器。目前几乎所有关于节奏管理的研究，包括无铅起搏器， 在留置装置小型化方面投入了渐进的进展。虽然这些设备可以提供稳定的 和长期起搏，该技术远不理想，起搏技术固有的问题和 异物问题，由于留置硬件。对于患有以下疾病的儿童患者来说，这些问题可能会很严重 先天性心脏传导阻滞，因为需要进行多次侵入性手术来替换或翻修植入的心脏 在患者的一生中使用电子设备。与设备相关的急性问题也在增加，包括感染 发电机和/或引线，需要手术取出整个植入的装置。 相比之下，生物工程起搏器通过创造无硬件的心脏，超越了所有当前的模式 快步走。我们之前已经证明，以微创方式传递自然转录因子基因 在完全性心脏传导阻滞的小动物和大动物模型中都能起到心室起搏的作用。使能技术 是以再生组织工程为基础的，在再生组织工程中，普通的心肌转化为专门的 起搏器组织用局部传递的基因构建物原位构建。将这一概念推广到临床 在实践中，需要回答两个问题：1)生物工程起搏器的功能能保留多久， 2)生物工程起搏器在病变心肌中的功能有多好 使用起搏器的患者也会出现潜在的心肌疾病。在这项提案中，我们将 通过使用已知可引起心脏特征的慢性心脏传导阻滞模型，直接回答这些问题 失败，并在一项纵向研究中检查基因治疗的有效性和持久性。

Project Summary/Abstract For patients with symptomatic bradyarrhythmias, the current and only treatment is to implant an electronic pacemaker. Nearly all of the current research regarding rhythm management, including the leadless pacemakers, are invested in incremental progress in miniaturizing the indwelling devices. While the devices can provide stable and long-term pacing, the technology is far from ideal with problems inherent to the pacing technology and to foreign body issues due to the indwelling hardware. The problems can be severe for pediatric patients with congenital heart block as multiple and invasive surgeries are needed for replacement or revision of the implanted devices over the patients’ lifetime. Device-related acute problems are rising as well, include infections with the generator and/or leads wire, which require surgical removal of the entire implanted device. Bioengineered pacemakers, in contrast, transcend all current modalities by creating hardware-free cardiac pacing. We have previously demonstrated that minimally-invasive delivery of a natural transcription factor gene could pace the ventricles in both small and large animal models of complete heart block. The enabling technology is based on regenerative tissue engineering in which ordinary heart muscle is converted to specialized pacemaker tissue construct in situ with a focally delivered genetic construct. To advance this concept to clinical practice, two questions need to be answered: 1) how long can the bioengineered pacemaker retain its function, and 2) how well the bioengineered pacemaker be able to function in diseased myocardium since most patients with a pacemaker are also presented with underlying diseases in the myocardium. In this proposal, we will directly answer these questions by employing chronic heart block models that are known to elicit traits of heart failure, and examining the efficacy and durability of the gene therapy in a longitudinal study.