Effect of Algisyl Injection on Porcine Heart Failure Models

Heart failure (HF) is a worldwide epidemic that contributes considerably to the overall cost of health care in developed nations. The number of people afflicted with this complex disease is increasing at an alarming pace—a trend that is likely to continue for many years to come. Over 1 million Americans suffer a myocardial infarction (MI) each year and many experience post-MI left ventricular (LV) remodeling, which manifests as progressive changes in LV structure and function. Post-MI LV remodeling is responsible for nearly 70% of all HF cases. Reduction of LV wall stress is considered a cornerstone in the treatment of HF. There are currently no reliable means to directly measure wall stresses in the intact LV. Thus, we rely on FE models, using LS-DYNA, to predict these stresses, knowing that the predictions cannot be validated directly, albeit we can validate deformations. To make our work more accessible to other researchers we are willing to help convert our models to freely available FE software like Continuity (http://www.continuity.ucsd.edu/) and FEBio (https://febio.org/).A novel promising therapy for HF using intramyocardial injections of alginate to de-stress the heart based on a “micro-LVAD” (LV assist device) mechanism of action was designed computationally, validated pre-clinically, and then validated clinically in the AUGMENT-HF international prospective multi-center trial. The overall goal of our proposed research is to optimize a therapy for HF that involves percutaneous injection of an alginate hydrogel (Algisyl) in the failing myocardium.We developed a novel percutaneous large animal (swine) model of ischemic HF. By preconditioning coronary arteries using balloon inflation prior to placing embolism coils two weeks apart, we reduced swine mortality to 10% and generated a realistic model of ischemic cardiomyopathy in large coronary arteries similar to those in patients. Treatment of HF with Algisyl, even without coronary artery bypass grafting (CABG), resulted in sustained improvement of LV contractile function with reduced LV volume. Our method for automatically optimizing intramyocardial injections for treating HF strongly suggests LV contractile function will be further improved if stiffer implants are placed in chronically infarcted LV regions. Additionally, our method for simulating the progression of HF8 strongly suggests that delivering Algisyl in the borderzone of acutely infarcted LV regions can prevent HF progression. Our studies support the exciting concept that the injection of inert material into the LV free-wall (with or without CABG) is an effective strategy for inducing LV reverse remodeling that improves LV function and results in decreased myofiber stress. Moreover, if this therapy can be delivered percutaneously rather than via the currently used open-heart procedure, this therapy may become revolutionary for HF treatment. A minimally invasive procedure would be in the best interest of this patient population (i.e., one that cannot tolerate general anesthesia and surgery) and it would be significantly more cost effective than surgery. We have developed a novel suction-based catheter device that accurately and precisely delivers the material into the LV subendocardium and prevents any potential embolization of the Algisyl in the ventricle. Our catheter device latches onto the endocardium using a suction cup to ensure injections at the needed sites. This innovation makes it possible to inject material endocardially into the heart wall percutaneously (including the interventricular septum) through a femoral artery access. Furthermore, this approach allows us to test a pre-emptive or preventative strategy for treating acute MI so that ischemic HF does not develop. <br/><br/>This project includes the following software/data packages: <br/> <ul> <li> <a href="https://simtk.org/frs?group_id=1177#pack_1888">LS-DYNA model of Pig LV </a> : LS-DYNA keyword files of 3 different model types: 1) Pig with an induced infarct then treated with alginate injection. Infarct location was based on high resolution ex-vivo MRI and mapped onto the mesh. Pressure curves were based on in-vivo measurements and fiber angles at each element were based on ex-vivo diffusion tensor MRI. 2) Pressure overload via aortic banding. Models based on 4 different imaging acquisitions over the course of study. 3) Volume overload model, created by creating mitral regurgitation in pig. </li> </ul>

心力衰竭（HF）已成为全球性的流行病，对发达国家医疗保健的整体成本贡献颇大。患有这种复杂疾病的人数正以惊人的速度增加，这一趋势可能在未来许多年里持续下去。每年有超过一百万美国人遭受心肌梗死（MI），许多人经历MI后的左心室（LV）重塑，这表现为LV结构和功能的渐进性变化。MI后的LV重塑是几乎所有HF病例的近70%的成因。降低LV壁应力被认为是HF治疗的基础。目前尚无可靠的直接测量完整LV壁应力的方法。因此，我们依赖有限元模型（FE模型），使用LS-DYNA来预测这些应力，尽管预测无法直接验证，但我们能够验证变形。为了使我们的工作更易于其他研究人员理解，我们愿意帮助将我们的模型转换为免费可用的FE软件，如Continuity（http://www.continuity.ucsd.edu/）和FEBio（https://febio.org/）。我们设计了一种基于“微型-LVAD”（LV辅助装置）作用机制的 alginate 内心肌注射治疗HF的新型有希望的治疗方法，该方法在临床前进行了验证，然后在AUGMENT-HF国际多中心前瞻性临床试验中进行了临床验证。我们提出的研究的总体目标是优化一种涉及在衰竭心肌中经皮注射 alginate 水凝胶（Algisyl）的HF治疗方法。我们开发了一种新颖的经皮大型动物（猪）缺血性HF模型。通过使用球囊扩张预先准备冠状动脉，并在放置栓塞线圈两周后进行，我们降低了猪的死亡率至10%，并产生了一种在大冠状动脉中类似于患者的大冠状动脉缺血性心肌病的真实模型。使用Algisyl治疗HF，即使没有冠状动脉旁路移植术（CABG），也导致LV收缩功能的持续改善和LV体积的减少。我们自动优化心肌内注射以治疗HF的方法强烈表明，如果在慢性梗死LV区域放置更硬的植入物，LV收缩功能将进一步改善。此外，我们模拟HF8进展的方法强烈表明，在急性梗死LV区域的边缘区域输送Algisyl可以防止HF进展。我们的研究支持这样一个令人兴奋的概念：将惰性材料注入LV自由壁（无论是否进行CABG）是一种有效的策略，可以诱导LV逆向重塑，从而改善LV功能并降低肌纤维应力。此外，如果这种治疗可以通过经皮途径而不是目前使用的开胸手术进行，那么这种治疗可能会对HF治疗产生革命性的影响。对这一患者群体（即无法耐受全身麻醉和手术的患者）来说，微创手术将是最有益的，并且与手术相比，这将显著更具成本效益。我们开发了一种基于吸力的新型导管装置，该装置可以精确地将材料输送到LV下内膜，并防止Algisyl在心室中的任何潜在栓塞。我们的导管装置使用吸盘固定在心内膜上，以确保在所需部位进行注射。这一创新使得可以通过股动脉途径经皮将材料注射到心壁的内膜（包括心室间隔）中。此外，这种方法使我们能够测试治疗急性MI的预防或预防性策略，以防止缺血性HF的发生。该项目包括以下软件/数据包：

<ul>
<li><a href="https://simtk.org/frs?group_id=1177#pack_1888">猪LV的LS-DYNA模型</a>：3种不同模型类型的LS-DYNA关键字文件：1）通过 alginate 注射治疗的诱导梗死猪。梗死位置基于高分辨率离体MRI，并将其映射到网格上。压力曲线基于体内测量，每个单元的纤维角度基于离体扩散张量MRI。2）通过主动脉结扎引起的压力过载。模型基于研究过程中4种不同的成像采集。3）通过在猪中创建二尖瓣反流来创建容量过载模型。</li>
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