Determinants, Trajectories, and Consequences of Abnormal Cardiac Mechanics

心脏力学异常的决定因素、轨迹和后果

• 批准号: 9177301
• 负责人: Sanjiv J Shah
• 金额: $ 71.81万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-21 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177301
• 关键词: Albuminuria; Archives; Atherosclerosis; Body Composition; Calcium; Cardiac; Cardiac Myocytes; Clinical; Cross-Sectional Studies; Data; Development; Diastole; Diastolic heart failure; Disease; Dose; EFRAC; Echocardiography; Epidemiologic Studies; Event; Fibrosis; Functional disorder; Funding; Gene Expression Profiling; Genes; Genetic; Genetic Determinism; Genomic approach; Goals; Health; Heart; Heart failure; Homeostasis; Hypertension; Impairment; Inbred SHR Rats; Individual; Inflammation; Learning; Left atrial structure; Left ventricular structure; Link; Longitudinal Studies; Maps; Mechanics; Modeling; Muscle function; Myocardial; Myocardial dysfunction; Myocardium; Pathogenesis; Patients; Pattern; Population; Prevention; Public Health; Quantitative Trait Loci; Rattus; Right ventricular structure; Risk; Risk Factors; Staging; Syndrome; Systole; Time; Tissues; Ultrasonography; Variant; Visit; Work; base; cardiovascular health; coronary fibrosis; drug discovery; endothelial dysfunction; exome; exome sequencing; follow-up; genetic epidemiology; genetic risk factor; genome wide association study; improved; indexing; induced pluripotent stem cell; insight; novel; population based; precision medicine; response; tool; trait

Heart failure (HF), regardless of the underlying ejection fraction (EF), is a major public health problem. The study of the acquired and genetic risk factors for abnormal cardiac mechanics (indices such as Lagrangian strain and tissue velocities) can provide important insights into the pathogenesis of HF syndromes in patients with both preserved and reduced EF (HFpEF and HFrEF, respectively). Abnormalities in both systolic and diastolic cardiac mechanics are present in virtually all patients with HF, regardless of EF. Systole and diastole are closely intertwined, with continual calcium (Ca2+) cycling within cardiomyocytes. Improved understanding of the factors that disrupt normal cardiomyocyte Ca2+ cycling is therefore essential. Speckle-tracking echocardiography has revolutionized the quantitation of cardiac mechanics because it can detect subclinical abnormalities in myocardial function at the earliest stages of disease development, when cardiomyocyte Ca2+ homeostasis first becomes disrupted. Furthermore, indices of cardiac mechanics ascertained by speckle- tracking are heritable traits that appear to map to genetic loci. Thus, speckle-tracking echo provides a unique window into HF development. Despite considerable progress in the understanding of risk factors for abnormal cardiac mechanics, several unanswered questions related to cardiac mechanics and HF remain: (1) What are the risk factors for decline in cardiac mechanics over time? (2) Are abnormal cardiac mechanics independently associated with incident HF? (3) Can whole exome sequencing provide evidence for novel genetic loci that influence cardiac mechanics? and (4) Can induced pluripotent stem cell (iPS)-derived cardiomyocytes provide biologic insight into whole-heart mechanics? The overall goal of the proposed studies is to leverage a unique ability to digitize and speckle-track archived echos from epidemiologic studies with the goal of further understanding determinants, trajectories, and consequences of abnormal cardiac mechanics. Quantification of cardiac mechanics in (1) the Cardiovascular Health Study (CHS) (n=5,888), which has extensive baseline and longitudinal data, including serial echos and 1,962 incident HF events during follow-up; and (2) the HyperGEN Cardiomyocyte iPS (CiPS) study (n=250) will allow for the completion of the following aims: (1) Determine the association of risk factor patterns with decline in cardiac mechanics over time; (2) Determine the association of cardiac mechanics with incident HF (particularly HFpEF); (3) Examine the association between whole exome data and cardiac mechanics, and validate these findings with gene expression profiling in iPS-derived cardiomyocytes; and (4) Correlate abnormalities in whole-heart mechanics with Ca2+ transients in iPS-derived cardiomyocytes. The proposed studies will have a lasting impact on the field of HF by demonstrating the importance of cardiac mechanics in HF pathogenesis; elucidating novel mechanisms underlying abnormal cardiac mechanics; and providing a personalized window (iPS cardiomyocytes) into whole heart mechanics, which could accelerate drug discovery and result in precision medicine for the prevention of HF.

心力衰竭（HF），无论潜在的射血分数（EF），是一个主要的公共卫生问题。的 研究异常心脏力学的获得性和遗传性风险因素（如拉格朗日指数 应变和组织速度）可以为患者HF综合征的发病机制提供重要的见解 保留和降低EF（分别为HFpEF和HFrEF）。收缩压和舒张压 无论EF如何，几乎所有HF患者都存在舒张期心脏力学。收缩期和舒张期 与心肌细胞内持续的钙（Ca 2+）循环紧密交织在一起。更好地了解 因此，破坏正常心肌细胞Ca 2+循环的因素是必需的。斑点追踪 超声心动图已经彻底改变了心脏力学的定量，因为它可以检测亚临床 在疾病发展的最早阶段，当心肌细胞Ca 2 + 体内平衡首先被破坏。此外，还用散斑技术测定了心脏力学指标。 跟踪是可遗传的特征，似乎映射到遗传基因座。因此，散斑跟踪回波提供了一个独特的 HF发展的窗口。尽管在了解异常妊娠的风险因素方面取得了相当大的进展， 心脏力学，与心脏力学和HF相关的几个未回答的问题仍然存在：（1）什么是心脏力学？ 随着时间的推移，心脏力学下降的风险因素？(2)是独立的心脏力学异常 与HF事件有关？(3)全外显子组测序能否为新的遗传基因座提供证据， 影响心脏力学吗和（4）诱导多能干细胞（iPS）衍生的心肌细胞是否可以提供 对整个心脏机制的生物学洞察拟议研究的总体目标是利用一种独特的 能够对流行病学研究中存档的回波进行扫描和斑点跟踪，目的是进一步 了解异常心脏力学的决定因素、轨迹和后果。定量 （1）心血管健康研究（CHS）（n= 5，888）中的心脏力学，该研究具有广泛的基线， 纵向数据，包括随访期间的系列回波和1，962起事件HF事件;以及（2）HyperGEN 心肌细胞iPS（CiPS）研究（n=250）将允许完成以下目的： 风险因素模式与心脏力学随时间下降的相关性;（2）确定 心脏力学与事件HF（特别是HFpEF）;（3）检查整个外显子组之间的关联 数据和心脏力学，并验证这些发现与基因表达谱在iPS衍生的 （4）将全心脏力学异常与iPS衍生的心肌细胞中的Ca 2+瞬变相关联。 心肌细胞拟议的研究将对HF领域产生持久的影响， 心脏力学在HF发病机制中的重要性;阐明异常基础的新机制 心脏力学;以及提供进入整个心脏力学的个性化窗口（iPS心肌细胞）， 这可以加速药物发现并导致预防HF的精确医学。