A multiscale model of cardiac concentric hypertrophy incorporating both mechanical and hormonal drivers of growth.
A multiscale model of cardiac concentric hypertrophy incorporating both mechanical and hormonal drivers of growth.
复制标题
心脏向心性肥厚的多尺度模型，包含了机械和激素的生长驱动因素。
DOI：
10.1007/s10237-020-01385-6
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发表时间：
2021-03
影响因子：
3.5
通讯作者：
Holmes JW
中科院分区：
文献类型：
--
作者：
Estrada AC;Yoshida K;Saucerman JJ;Holmes JW
心脏的生长和重塑是由机械和激素信号的组合驱动的，这些信号会产生不同的生长模式，以响应运动，怀孕和各种病理。特别是，后负荷的增加导致向心性肥大，即增加心脏收缩能力同时减少壁应力的壁增厚。在目前的研究中，我们构建了一个多尺度的心脏肥大模型，该模型将代表左心室生长力学的有限元模型连接到肥大信号通路的细胞水平网络模型，该模型解释了力学和激素的变化。我们首先调整了我们的模型，以捕获已发表的异丙肾上腺素输注（刺激β-肾上腺素能信号通路而不改变力学）和横主动脉收缩（TAC）（涉及力学升高和激素水平改变）的体内生长趋势。然后，我们通过两种不同的遗传干预（转基因Gq偶联受体抑制剂过表达和去甲肾上腺素敲除）和两种药理学干预（血管紧张素受体阻滞剂氯沙坦和β-受体阻滞剂普萘洛尔）预测了TAC诱导的肥大的衰减，并将我们的预测与每种干预的体内数据进行了比较。我们的多尺度模型捕捉到的实验数据的趋势相当不错的所有条件下模拟。我们还发现，当处方与TAC相关的力学和激素的现实变化时，激素输入是多尺度模型预测的大部分生长的原因，并且是必要的，以便捕获TAC干预措施的效果。
Growth and remodeling in the heart is driven by a combination of mechanical and hormonal signals that produce different patterns of growth in response to exercise, pregnancy, and various pathologies. In particular, increases in afterload lead to concentric hypertrophy, a thickening of the walls that increases the contractile ability of the heart while reducing wall stress. In the current study, we constructed a multiscale model of cardiac hypertrophy that connects a finite-element model representing the mechanics of the growing left ventricle to a cell-level network model of hypertrophic signaling pathways that accounts for changes in both mechanics and hormones. We first tuned our model to capture published in vivo growth trends for isoproterenol infusion, which stimulates β-adrenergic signaling pathways without altering mechanics, and for transverse aortic constriction (TAC), which involves both elevated mechanics and altered hormone levels. We then predicted the attenuation of TAC-induced hypertrophy by two distinct genetic interventions (transgenic Gq-coupled receptor inhibitor overexpression and norepinephrine knock-out) and by two pharmacologic interventions (angiotensin receptor blocker losartan and β-blocker propranolol) and compared our predictions to published in vivo data for each intervention. Our multiscale model captured the experimental data trends reasonably well for all conditions simulated. We also found that when prescribing realistic changes in mechanics and hormones associated with TAC, the hormonal inputs were responsible for the majority of the growth predicted by the multiscale model and were necessary in order to capture the effect of the interventions for TAC.
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影响因子：
37.8
作者：
Iwanga, Y;Kihara, Y;Sasayama, S
通讯作者：
Sasayama, S
影响因子：
20.1
作者：
LINDPAINTNER, K;LUND, DD;SCHMID, PG
通讯作者：
SCHMID, PG
DOI：
10.1073/pnas.85.2.339
发表时间：
1988-01-01
影响因子：
11.1
作者：
IZUMO, S;NADALGINARD, B;MAHDAVI, V
通讯作者：
MAHDAVI, V
影响因子：
3.7
作者：
Allwood, Melissa A.;Kinobe, Robert T.;Simpson, Jeremy A.
通讯作者：
Simpson, Jeremy A.
影响因子：
2.4
作者：
Kerckhoffs RC;Omens J;McCulloch AD
通讯作者：
McCulloch AD