Kerckhoffs Roy C P, Omens Jeffrey, McCulloch Andrew D
Department of Bioengineering, Institute of Engineering in Medicine, University of California, San Diego, La Jolla, CA 92093-0412, USA.
Mech Res Commun. 2012 Jun 1;42:40-50. doi: 10.1016/j.mechrescom.2011.11.004. Epub 2011 Nov 22.
Adult cardiac muscle adapts to mechanical changes in the environment by growth and remodeling (G&R) via a variety of mechanisms. Hypertrophy develops when the heart is subjected to chronic mechanical overload. In ventricular pressure overload (e.g. due to aortic stenosis) the heart typically reacts by concentric hypertrophic growth, characterized by wall thickening due to myocyte radial growth when sarcomeres are added in parallel. In ventricular volume overload, an increase in filling pressure (e.g. due to mitral regurgitation) leads to eccentric hypertrophy as myocytes grow axially by adding sarcomeres in series leading to ventricular cavity enlargement that is typically accompanied by some wall thickening. The specific biomechanical stimuli that stimulate different modes of ventricular hypertrophy are still poorly understood. In a recent study, based on in-vitro studies in micropatterned myocyte cell cultures subjected to stretch, we proposed that cardiac myocytes grow longer to maintain a preferred sarcomere length in response to increased fiber strain and grow thicker to maintain interfilament lattice spacing in response to increased cross-fiber strain. Here, we test whether this growth law is able to predict concentric and eccentric hypertrophy in response to aortic stenosis and mitral valve regurgitation, respectively, in a computational model of the adult canine heart coupled to a closed loop model of circulatory hemodynamics. A non-linear finite element model of the beating canine ventricles coupled to the circulation was used. After inducing valve alterations, the ventricles were allowed to adapt in shape in response to mechanical stimuli over time. The proposed growth law was able to reproduce major acute and chronic physiological responses (structural and functional) when integrated with comprehensive models of the pressure-overloaded and volume-overloaded canine heart, coupled to a closed-loop circulation. We conclude that strain-based biomechanical stimuli can drive cardiac growth, including wall thickening during pressure overload.
成年心肌通过多种机制的生长和重塑（G&R）来适应环境中的机械变化。当心脏受到慢性机械性过载时会发生肥大。在心室压力过载（例如由于主动脉瓣狭窄）时，心脏通常通过向心性肥厚生长做出反应，其特征是当肌节平行添加时，由于心肌细胞径向生长导致壁增厚。在心室容量过载时，充盈压力增加（例如由于二尖瓣反流）会导致离心性肥大，因为心肌细胞通过串联添加肌节而轴向生长，导致心室腔扩大，通常伴有一些壁增厚。刺激不同模式心室肥大的特定生物力学刺激仍知之甚少。在最近一项基于对受拉伸的微图案化心肌细胞培养物进行的体外研究中，我们提出心肌细胞会变长以响应纤维应变增加来维持优选的肌节长度，并变厚以响应跨纤维应变增加来维持丝间晶格间距。在此，我们在与循环血流动力学闭环模型耦合的成年犬心脏计算模型中测试这种生长规律是否能够分别预测对主动脉瓣狭窄和二尖瓣反流的向心性和离心性肥大。使用了与循环耦合的跳动犬心室的非线性有限元模型。诱导瓣膜改变后，让心室随时间响应机械刺激而在形状上发生适应性变化。当与压力过载和容量过载犬心脏的综合模型以及闭环循环耦合时，所提出的生长规律能够重现主要的急性和慢性生理反应（结构和功能）。我们得出结论，基于应变的生物力学刺激可以驱动心脏生长，包括压力过载期间的壁增厚。
