Determinants, Trajectories, and Consequences of Abnormal Cardiac Mechanics

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。这个 心脏力学异常的获得性和遗传性危险因素研究(如拉格朗日指数 应变和组织速度)可以为患者的心力衰竭综合征的发病机制提供重要的见解 保留EF和降低EF(分别为HFpEF和HFrEF)。收缩期和舒张期异常 几乎所有的心衰患者都存在舒张期心脏力学，而与EF无关。收缩和舒张期 它们紧密地交织在一起，在心肌细胞内持续循环。更好地理解 因此，扰乱正常心肌细胞钙循环的因素是必不可少的。斑点跟踪 超声心动图使心脏力学的量化发生了革命性的变化，因为它可以发现亚临床 在疾病发展的早期阶段心肌功能异常，当心肌细胞钙离子 动态平衡首先会被破坏。此外，由散斑确定的心脏力学指数- 跟踪是似乎映射到遗传基因的可遗传特征。因此，斑点跟踪回波提供了独特的 了解高频发展的窗口。尽管对异常的风险因素的理解有了长足的进步 心脏力学，与心脏力学和心力衰竭有关的几个悬而未决的问题：(1)什么是 随着时间推移心脏力学下降的危险因素？(2)心脏力学异常是独立的。 (3)整个外显子组测序能否为新的遗传基因座提供证据 会影响心脏力学吗？和(4)诱导多能干细胞(IPS)来源的心肌细胞能否提供 对全心机制的生物学洞察？拟议研究的总体目标是利用一个独特的 能够数字化和斑点跟踪来自流行病学研究的存档回声，目标是进一步 了解心脏力学异常的决定因素、轨迹和后果。量化 (1)心血管健康研究(CHS)(n=5,888)中的心脏力学，该研究有广泛的基线和 纵向数据，包括后续行动中的连续回波和1,962个入射高频事件；以及(2)HyperGEN 心肌细胞iPS(CIPS)研究(n=250)将允许完成以下目标：(1)确定 危险因素模式与心脏力学随时间下降的关联性；(2)确定 心脏力学与入射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，并用iPS来源的基因表达谱验证这些发现 心肌细胞；以及(4)iPS来源的全心力学异常与钙瞬变的相关性 心肌细胞。拟议的研究将对高频领域产生持久的影响，因为它表明 心脏力学在心力衰竭发病机制中的重要性；阐明异常的新机制 心脏力学；以及提供了解整个心脏力学的个性化窗口(iPS心肌细胞)， 这将加速药物的发现，并产生预防心力衰竭的精准药物。

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.