Multi-Scale Laws of Myocardial Growth and Remodeling

描述（由申请人提供）：心力衰竭（HF）是一种世界性流行病，在发达国家的医疗保健总成本中占相当大的比例。患有这种复杂疾病的人数正在以惊人的速度增加-这一趋势很可能 在未来的许多年里继续下去。我们提出的研究的总体目标是确定机械罪犯，支配系统从稳定的健康状态到HF的不稳定状态的分叉，并确定生理/代偿性和病理生理/非代偿性生长和重塑（G&R）之间的边界。为了实现这些目标，我们的研究方法是使用三种不同的临床相关的大型动物HF制剂，以预测心肌梗死（MI）患者发生HF的倾向，通过实验告知和验证心肌生长和重塑（G&R）的多尺度定律。我们的具体目标1是阐明一个预测性验证的多尺度法律的心肌G&R的离心性肥大与心脏扩张。我们假设基于纤维应变的生长规律可以预测心脏G&R对容量超负荷的反应，即，升高的肌纤维张力刺激向心性生长。将测试基于应力、应变率和应变能的竞争假设。目的二是验证心肌G&R在向心性肥厚伴室壁增厚中的多尺度预测规律。我们假设，一个统一的跨纤维应变为基础的增长规律可以预测心脏G&R的压力负荷。将检验目标1中类似的竞争假设。在目标3中，我们将应用这些G&R定律来预测基于心肌功能的特定机械指标的缺血性心脏病的HF倾向。我们假设，存在一个阈值的最大应变率的变化，参照肌节长度，在此之上的补偿G&R是不可能的，生理负反馈回路，以保持体内平衡让位于一个正反馈回路，导致进展重塑和最终死亡的心肌。这项工作的成功完成将为心肌对机械刺激的反应提供基本的了解，这具有重大的临床意义。从科学上讲，这种方法将提供有史以来第一个经过验证和校准的心肌生长和重塑的预测微观结构模型，这是心脏病学，组织工程，心脏康复和心脏手术的基础。在临床上，我们将提供一个特定的机械指标来预测缺血性心脏病中HF的倾向，这可能具有重大的医疗意义。

DESCRIPTION (provided by applicant): 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. The overall goals of our proposed research are to identify the mechanical culprits that dictate the bifurcation of the system from the stable healthy state into the instable state of HF and to determine the borderline between physiological/compensatory and pathophysiological/non-compensatory growth and remodeling (G&R). To address these goals, our research approach is to experimentally inform and validate multiscale laws of myocardial growth and remodeling (G&R) using three different clinically relevant large animal HF preparations in order to predict the propensity of patients with a myocardial infarction (MI) developing HF. Our specific Aim 1 is to elucidate a predictive validated multiscale law of myocardial G&R in eccentric hypertrophy associated with cardiac dilation. We hypothesize that a fiber-strain-based growth law can predict cardiac G&R in response to volume-overload, i.e., elevated myofiber strains stimulate concentric growth. Competing hypotheses based on stress-, strain rate-, and strain energy will be tested. Aim 2 is to validate a predictive multi-scale law of myocardial G&R in concentric hypertrophy associated with wall thickening. We hypothesize that a unified cross-fiber strain based growth law can predict cardiac G&R in response to pressure-overload. Similar competing hypotheses as in Aim 1 will be tested. In Aim 3, we will apply these G&R laws to predict the propensity for HF in ischemic heart disease based on specific mechanical indices of myocardial function. We hypothesize that there exists a threshold of a maximal rate of change of strain in reference to sarcomere length, above which compensatory G&R is not possible and the physiological negative feedback loop to maintain homeostasis gives way to a positive feedback loop that leads to progress remodeling and ultimate demise of the myocardium. Successful completion of this work will provide a fundamental understanding of the response of myocardium to mechanical stimuli that has substantial clinical relevance. Scientifically, this approach will provide the first ever validated and calibrated predictive micro-structural model of myocardial growth and remodeling that is fundamental to cardiology, tissue engineering, cardiac rehabilitation, and cardiac surgery. Clinically, we will provide a specific mechanical index to predict the propensity of HF in ischemic heart disease that may have a significant healthcare implication.