Multiscale characterization of heart failure
Multiscale characterization of heart failure
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DOI：
10.1016/j.actbio.2018.12.053
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发表时间：
2019-03-01
影响因子：
9.7
通讯作者：
Kuhl, E.
中科院分区：
文献类型：
--
作者：
Costabal, F. Sahli;Choy, J. S.;Kuhl, E.
扩张型心肌病是一种进行性不可逆疾病，与收缩功能障碍和心力衰竭有关。在扩张型心肌病期间，舒张期壁应变升高触发机械转导途径，启动连续增加肌节和肌细胞长度的总体增加。在整个器官水平，这导致心室慢性扩张，舒张末期和收缩末期容积增加，射血分数降低。然而，肌节数量的变化如何确切地转化为肌细胞形态的变化，以及这些细胞变化如何转化为心室扩张仍然不完全清楚。在这里，我们结合了慢性动物研究，连续生长模型和机器学习来量化肌节动力学，肌细胞形态和心室扩张之间的相关性。在对6头猪进行的为期8周的容量超负荷研究中，我们发现平均肌节数每周增加+3.8%，从47增加到62，导致肌细胞每周延长+3.3%，从85增加到108 μ m，而肌节长度和肌细胞宽度保持不变。同时，平均舒张末期容积增加+6.0%/周。使用连续生长模型和贝叶斯推断，我们将亚细胞、细胞和器官尺度上的改变相关联，发现连续肌节数解释了88%的肌细胞延长，这反过来解释了54%的心脏扩张。我们的研究结果表明，肌节数和肌细胞长度密切相关，并构成扩张性心力衰竭的主要决定因素。我们期望我们的研究成为更复杂的心力衰竭多尺度模型的起点。我们的研究表明，改变肌节的周转率--以及随之而来的肌细胞形态和心室尺寸--可能是一个潜在的治疗靶点，以减轻或逆转心力衰竭的进展。重要性声明心力衰竭是一个重要的全球性健康问题，影响全球超过2500万人，随着人口老龄化，患病率增加。心力衰竭已经在各种尺度上进行了大量的研究;然而，没有令人信服的概念来连接跨尺度的亚细胞，细胞和器官水平的知识。在这里，我们结合了慢性动物研究，连续生长模型和机器学习来量化肌节动力学，肌细胞形态和心室扩张之间的相关性。我们发现连续的肌节数解释了88%的肌细胞延长，这反过来又解释了54%的心脏扩张。我们的研究结果表明，肌节数和肌细胞长度密切相关，并构成扩张性心力衰竭的主要决定因素。这表明，改变肌节转换率--以及随之而来的肌细胞形态和心室尺寸--可能是减轻或逆转心力衰竭的潜在治疗靶点。(C)2019 Acta Materialia Inc.由爱思唯尔有限公司出版。保留所有权利。
Dilated cardiomyopathy is a progressive irreversible disease associated with contractile dysfunction and heart failure. During dilated cardiomyopathy, elevated diastolic wall strains trigger mechanotransduction pathways that initiate the addition of sarcomeres in series and an overall increase in myocyte length. At the whole organ level, this results in a chronic dilation of the ventricles, an increase in end diastolic and end systolic volumes, and a decrease in ejection fraction. However, how exactly changes in sarcomere number translate into changes in myocyte morphology, and how these cellular changes translate into ventricular dilation remains incompletely understood. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. In an eight-week long volume overload study of six pigs, we found that the average sarcomere number increased by +3.8%/week, from 47 to 62, resulting in a myocyte lengthening of +3.3%/week, from 85 to 108 mu m, while the sarcomere length and myocyte width remained unchanged. At the same time, the average end diastolic volume increased by +6.0%/week. Using continuum growth modeling and Bayesian inference, we correlated alterations on the subcellular, cellular, and organ scales and found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results demonstrate that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. We anticipate our study to be a starting point for more sophisticated multiscale models of heart failure. Our study suggests that altering sarcomere turnover-and with it myocyte morphology and ventricular dimensions-could be a potential therapeutic target to attenuate or reverse the progression of heart failure.Statement of SignificanceHeart failure is a significant global health problem that affects more than 25 million people worldwide and increases in prevalence as the population ages. Heart failure has been studied excessively at various scales; yet, there is no compelling concept to connect knowledge from the subcellular, cellular, and organ level across the scales. Here we combined a chronic animal study, continuum growth modeling, and machine learning to quantify correlations between sarcomere dynamics, myocyte morphology, and ventricular dilation. We found that the serial sarcomere number explained 88% of myocyte lengthening, which, in turn, explained 54% of cardiac dilation. Our results show that sarcomere number and myocyte length are closely correlated and constitute the major determinants of dilated heart failure. This suggests that altering the sarcomere turnover-and with it myocyte morphology and ventricular dimensions- could be a potential therapeutic target to attenuate or reverse heart failure. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.