Myocardial Stiffness in Diastolic Heart Failure

舒张性心力衰竭的心肌僵硬

• 批准号: 7899934
• 负责人: Kenneth S Campbell
• 金额: $ 32.96万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899934
• 关键词: Actins; Affect; Age; Aging; American; Animal Model; Animals; Biochemical; Calcium; Cardiac; Cardiovascular Diseases; Categories; Catheters; Cessation of life; Characteristics; Clinical; Clinical Treatment; Collagen; Computer Simulation; Control Animal; Control Groups; Data; Diagnosis; Diastole; Diastolic heart failure; Diet; Disease; EFRAC; Elastin; Elderly; Elements; Etiology; Extracellular Matrix; Failure; Fat-Restricted Diet; Fatty acid glycerol esters; Figs - dietary; Filament; Functional disorder; Future; Gene Expression; Head; Health Care Costs; Heart; Heart failure; Histological Techniques; Inbred F344 Rats; Individual; Intermediate Filaments; Kinetics; Left ventricular structure; Measurement; Measures; Mechanics; Methods; Modeling; Molecular; Molecular Profiling; Muscle Cells; Myocardial; Myocardium; Myosin ATPase; Myosin Heavy Chains; Obesity; Overweight; Patients; Physiological; Preparation; Principal Investigator; Property; Protein Isoforms; Proteins; Public Health; Rat-1; Rattus; Relative (related person); Research; Research Project Grants; Resistance; Sampling; Scientist; Simulate; Sprague-Dawley Rats; Stretching; Sum; Symptoms; Takeda brand of pioglitazone hydrochloride; Techniques; Testing; Therapeutic; Tissues; Ventricular; Ventricular Function; Weight; Work; age related; aged; connectin; crosslink; feeding; gel electrophoresis; in vivo; mathematical model; older patient; particle; pressure; research study; sensor; simulation

DESCRIPTION (provided by applicant): Diastolic heart failure is a major cause of illness and death. The condition is nearly always associated with increased ventricular stiffness and is more common in elderly and/or obese populations. There are no effective clinical treatments. The central hypothesis underlying this research is that diastolic myocardial stiffness is the sum of an 'active' stiffness component (due to myosin heads that continue to cycle during diastole) and a 'passive' stiffness component (attributed to titin, collagen, elastin and intermediate filaments). The proposed research determines the relative contributions from these components in preparations ranging from single myocytes to whole hearts and uses these results to create a predictive computational model of diastolic stiffness. Specific Aim 1 will identify the molecular components responsible for the increased stiffness of myocardium from aged rats. The working hypothesis is that the increased stiffness reflects slowed acto-myosin kinetics. Experiments will measure the mechanical properties of myocardium from 6, 18, 22 and 26-month-old Fischer 344 rats by subjecting chemically permeabilized single myocytes and multicellular preparations to repeated stretches at different levels of calcium activation. Additional experiments will measure ventricular stiffness in the different aged animals by rapidly inflating balloons placed inside the left ventricles of Langendorff-perfused hearts. Titin and myosin isoform content will be measured by gel electrophoresis. Collagen and elastin content and collagen cross-linking will be determined using histological and biochemical techniques. Specific Aim 2 will use identical methods to identify the molecular components responsible for the increased myocardial stiffness evident in a rat model of diet-induced obesity. The working hypothesis for this aim is that the elevated myocardial stiffness observed in obese Sprague-Dawley rats reflects increased collagen content and/or collagen cross-linking. Specific Aim 3 uses the experimental results from Aims 1 and 2 to create a predictive computational model of diastolic stiffness. The model framework will consist of elastic and visco-elastic elements (representing titin, collagen, elastin and intermediate filaments) arranged in parallel with a spatially-explicit simulation of acto-myosin interactions. Model parameters will be determined by multi-dimensional optimization. The final model will be used to test predictions about the cross-bridge component of myocardial stiffness and should prove useful for assessing the likely effects of potential new treatments for diastolic heart failure. NARRATIVE This research is relevant to public health because it seeks to identify why hearts become excessively stiff in a common cardiovascular disease called Diastolic Heart Failure. The experimental results should help scientists to develop better treatments for the disease in overweight and elderly patients.

描述（由申请人提供）：舒张性心力衰竭是疾病和死亡的主要原因。这种情况几乎总是与心室僵硬度增加有关，在老年人和/或肥胖人群中更常见。没有有效的临床治疗方法。本研究的核心假设是舒张期心肌硬度是“主动”硬度成分（由于肌球蛋白头在舒张期继续循环）和“被动”硬度成分（归因于肌联蛋白、胶原蛋白、弹性蛋白和中间丝）的总和。拟议的研究确定了从单个肌细胞到整个心脏的制剂中这些组分的相对贡献，并使用这些结果创建舒张刚度的预测计算模型。具体目标1将确定负责从老年大鼠心肌僵硬度增加的分子成分。工作假设是刚度增加反映了肌动蛋白-肌球蛋白动力学减慢。实验将测量心肌的机械性能从6，18，22和26个月大的Fischer 344大鼠通过进行化学渗透的单肌细胞和多细胞制剂在不同水平的钙激活重复拉伸。另外的实验将通过快速膨胀放置在Langendorff灌注心脏的左心室内的球囊来测量不同年龄动物的心室硬度。将通过凝胶电泳测定肌联蛋白和肌球蛋白亚型含量。将使用组织学和生物化学技术测定胶原蛋白和弹性蛋白含量以及胶原蛋白交联。具体目标2将使用相同的方法来鉴定导致饮食诱导的肥胖大鼠模型中明显的心肌硬度增加的分子组分。该目的的工作假设是，在肥胖Sprague-Dawley大鼠中观察到的心肌硬度升高反映了胶原蛋白含量和/或胶原蛋白交联增加。具体目标3使用目标1和2的实验结果创建舒张期刚度的预测计算模型。该模型框架将由弹性和粘弹性元素（代表肌联蛋白，胶原蛋白，弹性蛋白和中间丝）平行排列的空间显式模拟肌动蛋白-肌球蛋白的相互作用。模型参数将通过多维优化确定。最终的模型将用于测试心肌僵硬度的跨桥成分的预测，并应被证明有助于评估舒张性心力衰竭潜在新治疗方法的可能影响。叙述这项研究与公共卫生相关，因为它试图确定为什么心脏在一种称为舒张性心力衰竭的常见心血管疾病中变得过度僵硬。实验结果应该有助于科学家开发更好的治疗超重和老年患者的疾病的方法。