Hallow K Melissa, Van Brackle Charles H, Anjum Sommer, Ermakov Sergey
School of Chemical, Materials, and Biomedical Engineering, University of Georgia, Athens, GA, United States.
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., South San Francisco, CA, United States.
Front Physiol. 2021 Jun 16;12:679930. doi: 10.3389/fphys.2021.679930. eCollection 2021.
Cardiac and renal function are inextricably connected through both hemodynamic and neurohormonal mechanisms, and the interaction between these organ systems plays an important role in adaptive and pathophysiologic remodeling of the heart, as well as in the response to renally acting therapies. Insufficient understanding of the integrative function or dysfunction of these physiological systems has led to many examples of unexpected or incompletely understood clinical trial results. Mathematical models of heart and kidney physiology have long been used to better understand the function of these organs, but an integrated model of renal function and cardiac function and cardiac remodeling has not yet been published. Here we describe an integrated cardiorenal model that couples existing cardiac and renal models, and expands them to simulate cardiac remodeling in response to pressure and volume overload, as well as hypertrophy regression in response to angiotensin receptor blockers and beta-blockers. The model is able to reproduce different patterns of hypertrophy in response to pressure and volume overload. We show that increases in myocyte diameter are adaptive in pressure overload not only because it normalizes wall shear stress, as others have shown before, but also because it limits excess volume accumulation and further elevation of cardiac stresses by maintaining cardiac output and renal sodium and water balance. The model also reproduces the clinically observed larger LV mass reduction with angiotensin receptor blockers than with beta blockers. We further provide a mechanistic explanation for this difference by showing that heart rate lowering with beta blockers limits the reduction in peak systolic wall stress (a key signal for myocyte hypertrophy) relative to ARBs.
心脏和肾脏功能通过血流动力学和神经激素机制紧密相连，这些器官系统之间的相互作用在心脏的适应性和病理生理重塑以及对肾脏作用疗法的反应中起着重要作用。对这些生理系统整合功能或功能障碍的理解不足导致了许多临床试验结果出乎意料或理解不全面的例子。心脏和肾脏生理学的数学模型长期以来一直被用于更好地理解这些器官的功能，但尚未发表肾功能、心脏功能和心脏重塑的综合模型。在此，我们描述了一个整合的心脏-肾脏模型，该模型将现有的心脏和肾脏模型结合起来，并进行扩展以模拟压力和容量超负荷引起的心脏重塑，以及血管紧张素受体阻滞剂和β受体阻滞剂引起的心肌肥厚消退。该模型能够重现压力和容量超负荷引起的不同肥厚模式。我们表明，心肌细胞直径的增加在压力超负荷中具有适应性，这不仅是因为它使壁面剪应力正常化（正如其他人之前所表明的那样），还因为它通过维持心输出量以及肾脏钠和水平衡来限制过多的容量积累和心脏应力的进一步升高。该模型还重现了临床上观察到的血管紧张素受体阻滞剂比β受体阻滞剂使左心室质量降低幅度更大的现象。我们通过表明β受体阻滞剂降低心率相对于血管紧张素受体阻滞剂限制了收缩期峰值壁应力（心肌肥厚的关键信号）的降低，进一步为这种差异提供了机制解释。
