Gene transfer during LVAD support

继发于收缩功能障碍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，减轻症状，但这种疾病是进行性的，许多患者最终表现为暴发性和/或持续的症状。在这组患者中，左心室辅助装置（LVAD）已被用作左心室辅助装置植入和心脏移植之间的“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，这使得研究人员假设LVAD支持可能使患者成为“恢复的桥梁”。事实上，研究已经证明，慢性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，针对抑制基质重塑的治疗干预可能会提高患者脱离LVAD支持的能力。在过去的5年中，我们已经证明了促炎细胞因子肿瘤坏死因子（TNF）在终末期心力衰竭表型的发展中起着重要作用。在动物模型中输注TNF或过度表达TNF可诱导心脏舒张、收缩力减弱、纤维化和细胞外基质重塑：这些变化可通过TNF可溶性受体（sTNFR）治疗逆转。事实上，sTNFR的全身管理已被证明对有症状的心力衰竭患者有益。由于TNF在LVAD支持的心脏中高水平表达，我们假设sTNFR治疗将大大提高患者恢复和LVAD脱机的能力。不幸的是，在LVAD支持的心脏中，由于这些患者固有的感染风险和TNF在免疫反应中的重要作用，全身给药是有问题的。因此，我们假设直接注射驱动sTNFR表达的腺相关病毒（AAV）会产生有益的效果。我们自己实验室的研究表明，AAV载体：1)非免疫原性；2)在肌肉中持续表达；3)可以用心脏特异性和四环素反应启动子构建。因此，本研究将验证这样一个假设，即在LVAD植入时直接在心内注射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.