Computational modelling of stress (Takotsubo) cardiomyopathy.

Stress cardiomyopathy is a clinical syndrome characterized by acute apical dysfunction, where the shape of the left ventricle resembles the Japanese fisherman's octopus pot (takotsubo) during systole. Results from a recent animal study have uncovered adrenaline-induced stunning of the myocardium as a potential mechanism (1,2). Exposing cardiac cells with human ß2 receptors to high concentrations of epinephrine cause a decrease in force generated by these cells (3). However, both the quantitative gradients in tension generated by the myocardium, as well as the biophysical mechanisms underpinning this phenomenon remain poorly understood. In our work we have used biophysically based computational models of the left ventricle to investigate these potential mechanisms. Our first model assumes cellular calcium transients vary from apex to base due to differences in adrenergic stimulation. The properties of this gradient were varied in this model study in combination with the calcium sensitivity of the myofilaments. Selected results are shown in Figure 1. These show that combination of a gradient in adrenergic effects on the calcium transient, combined with a homogeneous decrease in calcium sensitivity, are potentially sufficient to reproduce apical ballooning at mid-systole. However, by end-systole, apical ballooning is significantly decreased. We hypothesised this to be due to compensation produced by the Frank-Starling mechanism. Further model results confirm that a weakened length-dependent response of cardiac muscle increases apical ballooning at both mid- and end systole. Incorporating this mechanism resulted in a deformation of the ventricle with significant reduction in stroke volume, consistent with reported clinical cases where significant end-systolic ballooning was observed (1). In conclusion, changes in calcium regulation through adrenergic mechanisms are sufficient to reproduce the magnitude of apical ballooning seen in Takotsubo cardiomyopathy. Significant apical ballooning at end systole may indicate a failure of the Frank-Starling mechanism. [ABSTRACT FROM AUTHOR]