Multi-Scale Laws of Myocardial Growth and Remodeling

描述（由申请人提供）：心力衰竭 (HF) 是一种世界范围内的流行病，在发达国家的医疗保健总体成本中占很大比例。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 并将持续很多年。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分叉到不稳定的心力衰竭状态的机械罪魁祸首，并确定生理/代偿性和病理生理性/非代偿性生长和重塑 (G&R) 之间的界限。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大型动物心力衰竭制剂，通过实验了解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) 患者发生心力衰竭的倾向。我们的具体目标 1 是阐明与心脏扩张相关的偏心肥大中心肌 G&R 的预测验证多尺度规律。我们假设基于纤维应变的生长定律可以预测心脏 G&R 对容量超负荷的反应，即，升高的肌纤维应变刺激同心生长。将测试基于应力、应变率和应变能的竞争假设。目标 2 是验证与壁增厚相关的向心肥大中心肌 G&R 的预测多尺度规律。我们假设基于统一的跨纤维应变的生长定律可以预测心脏 G&R 对压力过载的反应。将测试与目标 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，根据心肌功能的特定机械指标来预测缺血性心脏病中心力衰竭的倾向。我们假设存在一个相对于肌节长度的最大应变变化率阈值，超过该阈值，补偿性 G&R 是不可能的，并且维持稳态的生理负反馈回路让位于正反馈回路，导致心肌的进展重塑和最终死亡。这项工作的成功完成将使人们对心肌对机械刺激的反应有一个基本的了解，这具有重大的临床意义。从科学角度来看，这种方法将提供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，这对于心脏病学、组织工程、心脏康复和心脏手术至关重要。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心力衰竭的倾向，这可能具有重大的医疗保健意义。

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.