Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, United States.
Bioinfo, Plantagenet, Ontario, Canada.
Am J Physiol Heart Circ Physiol. 2023 Sep 1;325(3):H449-H467. doi: 10.1152/ajpheart.00130.2023. Epub 2023 Jul 7.
Detailed assessments of whole heart mechanics are crucial for understanding the consequences of sarcomere perturbations that lead to cardiomyopathy in mice. Echocardiography offers an accessible and cost-effective method of obtaining metrics of cardiac function, but the most routine imaging and analysis protocols might not identify subtle mechanical deficiencies. This study aims to use advanced echocardiography imaging and analysis techniques to identify previously unappreciated mechanical deficiencies in a mouse model of dilated cardiomyopathy (DCM) before the onset of overt systolic heart failure (HF). Mice lacking muscle LIM protein expression (MLP) were used to model DCM-linked HF pathogenesis. Left ventricular (LV) function of MLP and wild-type (WT) controls were studied at 3, 6, and 10 wk of age using conventional and four-dimensional (4-D) echocardiography, followed by speckle-tracking analysis to assess torsional and strain mechanics. Mice were also studied with RNA-seq. Although 3-wk-old MLP mice showed normal LV ejection fraction (LVEF), these mice displayed abnormal torsional and strain mechanics alongside reduced β-adrenergic reserve. Transcriptome analysis showed that these defects preceded most molecular markers of HF. However, these markers became upregulated as MLP mice aged and developed overt systolic dysfunction. These findings indicate that subtle deficiencies in LV mechanics, undetected by LVEF and conventional molecular markers, may act as pathogenic stimuli in DCM-linked HF. Using these analyses in future studies will further help connect in vitro measurements of the sarcomere function to whole heart function. A detailed study of how perturbations to sarcomere proteins impact whole heart mechanics in mouse models is a major yet challenging step in furthering our understanding of cardiovascular pathophysiology. This study uses advanced echocardiographic imaging and analysis techniques to reveal previously unappreciated subclinical whole heart mechanical defects in a mouse model of cardiomyopathy. In doing so, it offers an accessible set of measurements for future studies to use when connecting sarcomere and whole heart function.
详细评估整个心脏力学对于理解导致小鼠心肌病的肌节扰动的后果至关重要。超声心动图提供了一种易于获取且具有成本效益的方法来获得心脏功能的指标，但最常规的成像和分析方案可能无法识别微妙的机械缺陷。本研究旨在使用先进的超声心动图成像和分析技术，在扩张型心肌病（DCM）模型小鼠出现明显的收缩性心力衰竭（HF）之前，识别以前未被重视的机械缺陷。使用缺乏肌肉 LIM 蛋白表达（MLP）的小鼠来模拟与 DCM 相关的 HF 发病机制。在 3、6 和 10 周龄时，使用传统和四维（4-D）超声心动图研究 MLP 和野生型（WT）对照小鼠的左心室（LV）功能，然后进行斑点追踪分析以评估扭转和应变力学。还对小鼠进行了 RNA-seq 研究。尽管 3 周龄的 MLP 小鼠显示出正常的 LV 射血分数（LVEF），但这些小鼠显示出异常的扭转和应变力学，同时伴有β-肾上腺素能储备减少。转录组分析表明，这些缺陷先于大多数 HF 的分子标志物。然而，随着 MLP 小鼠年龄的增长并出现明显的收缩功能障碍，这些标志物的表达上调。这些发现表明，LV 力学的细微缺陷，无法通过 LVEF 和常规分子标志物检测到，可能是 DCM 相关 HF 的致病刺激因素。在未来的研究中使用这些分析将有助于进一步将肌节功能的体外测量与整个心脏功能联系起来。详细研究肌节蛋白的扰动如何影响小鼠模型中的整个心脏力学是进一步了解心血管病理生理学的一个重要但具有挑战性的步骤。本研究使用先进的超声心动图成像和分析技术，揭示了心肌病小鼠模型中以前未被重视的亚临床全心脏机械缺陷。通过这样做，它为未来的研究提供了一套易于获取的测量值，用于连接肌节和整个心脏功能。
