Multi-Scale Laws of Myocardial Growth and Remodeling

描述(由申请人提供)：心力衰竭(HF)是一种世界性的流行病，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长--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导致系统从稳定的健康状态进入不稳定状态的力学元凶，并确定生理性/代偿性和病理生理学/非代偿性生长和重构(G&R)之间的界限。为了达到这些目标，我们的研究方法是使用三种不同的临床相关大动物心力衰竭制剂，通过实验揭示和验证心肌生长和重塑(G&R)的多尺度规律，以预测心肌梗死(MI)患者发展为心力衰竭的倾向。我们的具体目标1是阐明与心脏扩张相关的离心性肥厚的心肌G&R的预测性验证的多尺度规律。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，即提高肌纤维张力刺激同心性生长。基于应力、应变率和应变能的相互竞争的假设将得到检验。目的2是验证与室壁增厚相关的向心性肥厚心肌G&R的多尺度预测性规律。我们假设，基于跨纤维应变的统一生长规律可以预测心脏G&R对压力超负荷的反应。与目标1中类似的相互竞争的假设将得到检验。在目标3中，我们将应用这些G&R定律，基于特定的心肌功能机械指标来预测缺血性心脏病患者发生心衰的倾向。我们假设存在一个关于肌节长度的最大应变变化率的阈值，超过这个阈值，代偿性G&R是不可能的，维持动态平衡的生理负反馈环让位于正反馈环，从而导致心肌的进展重塑和最终死亡。这项工作的成功完成将从根本上了解心肌对机械刺激的反应，这具有重要的临床意义。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结构模型，这是心脏病学、组织工程、心脏康复和心脏外科的基础。临床上，我们将提供一个特殊的机械指数来预测缺血性心脏病的心衰倾向，这可能具有重要的医疗意义。

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.