Computational modeling of Takotsubo cardiomyopathy: effect of spatially varying β-adrenergic stimulation in the rat left ventricle

Abstract

In Takotsubo cardiomyopathy, the left ventricle shows apical ballooning combined with basal hypercontractility. Both clinical observations in humans and recent experimental work on isolated rat ventricular myocytes suggest the dominant mechanisms of this syndrome are related to acute catecholamine overload. However, relating observed differences in single cells to the capacity of such alterations to result in the extreme changes in ventricular shape seen in Takotsubo syndrome is difficult. By using a computational model of the rat left ventricle, we investigate which mechanisms can give rise to the typical shape of the ventricle observed in this syndrome. Three potential dominant mechanisms related to effects of β-adrenergic stimulation were considered: apical-basal variation of calcium transients due to differences in L-type and sarco(endo)plasmic reticulum Ca2+-ATPase activation, apical-basal variation of calcium sensitivity due to differences in troponin I phosphorylation, and apical-basal variation in maximal active tension due to, e.g., the negative inotropic effects of p38 MAPK. Furthermore, we investigated the interaction of these spatial variations in the presence of a failing Frank-Starling mechanism. We conclude that a large portion of the apex needs to be affected by severe changes in calcium regulation or contractile function to result in apical ballooning, and smooth linear variation from apex to base is unlikely to result in the typical ventricular shape observed in this syndrome. A failing Frank-Starling mechanism significantly increases apical ballooning at end systole and may be an important additional factor underpinning Takotsubo syndrome.

Impact of Malignancies in the Early and Late Time Course of Takotsubo Cardiomyopathy

“…signaling pathway, 15 suggesting possible synergistic effects of stress and inflammation in the pathogenesis of takotsubo cardiomyopathy in cancer patients. Our current findings of higher peak leukocyte counts and higher CRP levels in patients with malignancy compared with those without expands our previous work indicating that these inflammatory markers may be involved in the pathogenesis of takotsubo cardiomyopathy.…”

Epidemiology and pathophysiology of Takotsubo syndrome

“…This observation was replicated in another preclinical model where pertussis toxin prevented acute apical dysfunction induced by high dose isoproterenol injection, albeit with a high mortality in the pertussis toxin treated group 76 . Recently computer modelling studies evaluated the impact of varying βAR gradients across the left ventricle under different haemodynamic situations and could replicate the acute apical dysfunction observed when the βAR density was highest at the apex 77 .…”

A model of cardiac contraction based on novel measurements of tension development in human cardiomyocytes

“…When constructing multi-scale models of human function, there are currently many options for characterizing the cellular electrophysiology [19,52] or material properties [66,48]. Detailed biophysical models of cardiac contraction do exist for other species [56,8,36] and have been used to great effect in multi-scale computational models, particularly in the mouse [59,40] and rat [51,39]. These models have the advantage that they can be used to link changes in sub-cellular properties to whole organ contractile performance, predicting key indicators of cardiac function from changes to individual channels or proteins involved in calcium regulation and contractile dynamics.…”