Myocardial Stiffness in Diastolic Heart Failure

舒张性心力衰竭的心肌僵硬

• 批准号: 8267690
• 负责人: Kenneth S Campbell
• 金额: $ 32.63万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8267690
• 关键词: Actins; Affect; 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(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脑室僵硬增加有关，在老年和/或肥胖人群中更为常见。目前还没有有效的临床治疗方法。这项研究的中心假设是，舒张期心肌硬度是“主动”硬度成分(由于肌球蛋白头部在舒张期持续循环)和“被动”硬度成分(归因于肌蛋白、胶原、弹性蛋白和中间丝)的总和。这项拟议的研究确定了这些成分在从单个心肌细胞到整个心脏的准备中的相对贡献，并利用这些结果创建了舒张期硬度的预测计算模型。具体目标1将确定导致老年大鼠心肌僵硬增加的分子成分。工作假说是，僵硬的增加反映了肌球蛋白动力学的减慢。实验将测量6个月、18个月、22个月和26个月大的Fischer 344大鼠的心肌的机械性能，方法是让化学渗透的单个肌细胞和多细胞制剂在不同水平的钙激活下重复拉伸。其他实验将通过快速充气放置在兰登多夫灌流心脏左心室内的气囊来测量不同年龄动物的心室硬度。肌球蛋白和肌球蛋白亚型的含量将通过凝胶电泳法进行测定。胶原蛋白和弹性蛋白的含量以及胶原蛋白的交联度将使用组织学和生化技术进行测定。特定目标2将使用相同的方法来确定在饮食诱导肥胖的大鼠模型中导致心肌僵硬明显增加的分子成分。这一目标的工作假设是，肥胖的Spraogue-Dawley大鼠观察到的心肌硬度增加反映了胶原含量的增加和/或胶原的交联性。特定目标3使用目标1和目标2的实验结果来创建舒张期硬度的预测计算模型。模型框架将由弹性和粘弹性元素(代表肌动蛋白、胶原、弹性蛋白和中间丝)平行排列，并对肌球蛋白相互作用进行空间显式模拟。通过多维优化确定模型参数。最终的模型将被用来测试关于心肌僵硬的跨桥成分的预测，并将被证明对评估舒张性心力衰竭潜在的新治疗方法的可能效果很有用。这项研究与公共健康相关，因为它试图找出为什么心脏在一种常见的心血管疾病-舒张性心力衰竭-中变得过于僵硬。实验结果应该有助于科学家为超重和老年患者开发更好的治疗方法。

项目成果

A Protocol for Collecting Human Cardiac Tissue for Research.

• DOI: 10.13023/vad.2016.12
• 发表时间: 2016
• 期刊: The VAD journal : the journal of mechanical assisted circulation and heart failure
• 作者: Blair CA;Haynes P;Campbell SG;Chung C;Mitov MI;Dennis D;Bonnell MR;Hoopes CW;Guglin M;Campbell KS
• 通讯作者: Campbell KS

Myocyte contractility can be maintained by storing cells with the myosin ATPase inhibitor 2,3 butanedione monoxime.

• DOI: 10.14814/phy2.12445
• 发表时间: 2015-06
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Chung CS;Mechas C;Campbell KS
• 通讯作者: Campbell KS

Distorting the sarcomere.

扭曲肌节。

• DOI: 10.1085/jgp.201010497
• 发表时间: 2010
• 期刊: The Journal of general physiology
• 作者: Campbell,KennethS

Myocardial hypertrophy reduces transmural variation in mitochondrial function.

• DOI: 10.3389/fphys.2014.00178
• 发表时间: 2014
• 期刊: Frontiers in physiology
• 影响因子: 4
• 作者: Haynes P;Campbell KS
• 通讯作者: Campbell KS

Temperature and transmural region influence functional measurements in unloaded left ventricular cardiomyocytes.

• DOI: 10.1002/phy2.158
• 发表时间: 2013-11
• 期刊: PHYSIOLOGICAL REPORTS
• 影响因子: 2.5
• 作者: Chung, Charles S;Campbell, Kenneth S
• 通讯作者: Campbell, Kenneth S