Gene transfer during LVAD support

心脏收缩功能障碍继发的心力衰竭在美国是一种流行的疾病。虽然药物治疗可以延长生存期、减少住院时间并缓解症状，但这种疾病是进行性的，许多患者最终会出现暴发性和/或持续性的症状。在这组患者中，左心室辅助装置(LVAD)被用来在LVAD植入和心脏移植之间架起桥梁。有趣的是，在一部分患者中，LVAD可以随着时间的推移而断奶，这导致研究人员假设LVAD支持可能使患者成为恢复的桥梁。事实上，研究表明，长期LVAD支持后心肌细胞功能发生了有益的变化。然而，LVAD支持的心脏也表现出纤维化、细胞凋亡和细胞外基质重塑的增加。这些报道使我们推测，旨在抑制基质重塑的治疗干预可能会提高患者摆脱左冠状动脉前降支支持的能力。在过去的5年中，我们证明了促炎性细胞因子肿瘤坏死因子在终末期心力衰竭表型的发生发展中起着重要作用。在动物模型中，注射肿瘤坏死因子或过表达肿瘤坏死因子会导致心脏扩张、心脏收缩能力减弱、纤维化和细胞外基质重构：这些变化可以通过使用肿瘤坏死因子可溶性受体(STNFR)来逆转。事实上，全身应用sTNFR已证明对有症状的心力衰竭患者有好处。由于肿瘤坏死因子在LVAD支持的心脏中高水平表达，我们假设使用sTNFR治疗将显著提高患者过渡到康复和LVAD撤机的能力。不幸的是，在LVAD支持的心脏中，全身应用TNFR是有问题的，因为这些患者存在固有的感染风险，以及肿瘤坏死因子在免疫反应中的重要作用。因此，我们假设直接在心肌中注射驱动sTNFR表达的腺相关病毒(AAV)会有有益的效果。我们实验室的研究表明，AAV载体：1)非免疫原性；2)在肌肉中持续表达；3)可以由心脏特异性启动子和四环素反应启动子构建。因此，这项应用将检验这样的假设，即在LVAD植入时直接心肌内注射AAV-sTNFR可以影响心脏的适应性变化，从而促进衰竭心脏脱离LVAD支持的能力。

Heart failure secondary to systolic dysfunction is a disease of epidemic proportions in the U.S. Although medical therapy can prolong survival, decrease hospitalization, and alleviate symptoms, the disease is progressive and many patients eventually present with fulminant and/or unremitting symptoms. In this group of patients, left ventricular assist devices (LVADs) have been utilized to "bridge" patients between LVAD implantation and cardiac transplantation. Interestingly, in a subset of patients, the LVAD can be weaned over time, leading investigators to hypothesize that LVAD support might enable patients to be "bridge to recovery" Indeed, studies have demonstrated salutory changes in myocyte function after chronic LVAD support. However, LVAD supported hearts also demonstrate increased fibrosis, apoptosis, and extracellular matrix remodeling. These reports led us to speculate that therapeutic interventions directed at inhibiting matrix remodeling might improve the ability to wean patients from LVAD support. During the past 5 years, we have demonstrated that the pro-inflammatory cytokine tumor necrosis factor (TNF) plays an important role in the development of the end-stage heart failure phenotype. Infusions of TNF or over-expression of TNF in animal models induces cardiac dilitation, diminished cardiac contractility, fibrosis, and extracellular matrix remodeling: changes that can be reversed by treatment with TNF soluble receptor (sTNFR). Indeed, systemic administration of sTNFR has demonstrated benefits in patients with symptomatic heart failure. As TNF is expressed at high levels in the LVAD supported heart, we hypothesized that treatment with sTNFR would substantially improve the ability to bridge patients to recovery and LVAD weaning. Unfortunately, systemic administration of TNFR is problematic in LVAD supported hearts because of the inherent risk of infection in these patients and the important role of TNF in the immune response. Thus, we hypothesized that direct injection of the heart muscle with an adeno- associated virus (AAV) driving sTNFR expression would have salutory effects. Studies in our own laboratory have demonstrated that AAV vectors: 1) are non-immunogenic; 2) provide persistent expression in muscle; and 3) can be constructed with cardiac specific and tetracycline- responsive promoters. Accordingly, this application will test the hypothesis that direct intramyocardial injection of AAV-sTNFR at the time of LVAD implantation could effect adaptive changes in the heart that could facilitate the ability to wean failing hearts from LVAD support.