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.

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、怀孕和各种疾病。特别是，后负荷的增加会导致向心性肥大，即心脏壁增厚，从而增加心脏的收缩能力，同时减少壁应力。在当前的研究中，我们构建了一个多尺度心脏肥大模型，该模型将表示左心室生长机制的有限元模型与肥大信号通路的细胞水平网络模型连接起来，该模型说明了机制和激素的变化。我们首先调整我们的模型以捕捉已发表的异丙肾上腺素输注体内生长趋势，它在不改变机制的情况下刺激 β-肾上腺素能信号通路，和横向主动脉缩窄（TAC），这涉及升高的力学和改变的激素水平。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）和两种药物干预（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 诱导的肥大的减弱，并将我们的预测与公布了每种干预措施的体内数据。我们的多尺度模型相当好地捕捉了所有模拟条件下的实验数据趋势。我们还发现，在对与 TAC 相关的力学和激素进行现实的改变时，