Computational modeling of Takotsubo cardiomyopathy: effect of spatially varying β-adrenergic stimulation in the rat left ventricle.
Bottom Line: 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 Ca(2+)-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.
Affiliation: Department of Biomedical Engineering, King's College London, London, United Kingdom;Show MeSH
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Mentions: In many cases studied in the previous sections, the amount of apical ballooning decreases significantly between mid- and end systole. We hypothesized this effect to be due to compensation produced by the length dependence of tension in cardiac muscle, the same mechanism that is responsible for the Frank-Starling response of the heart. Reports of Takotsubo cardiomyopathy feature significant apical ballooning at end systole, and changes in length dependence of tension have been suggested to be related to both heart failure and β-adrenergic stimulation (7). Driven by these observations we investigated the effect of an impaired length dependence of tension in maintaining apical ballooning at end systole. To test the effects of an impaired length dependence of tension, we changed the magnitude of the length-dependent change in calcium sensitivity from β1 = −1.5 to β1 = −0.75 and β1 = 0. All simulations from the previous section were run again with this change in parameter. Figure 6 shows the effect of an impaired length dependence of tension on the A:B index. Note the large number of cases that now show significant apical ballooning which previously showed normal contraction motion without apical ballooning. Figure 7 shows some selected examples where this change is maximal, including the clear differences in the decrease in A:B throughout systole.
Affiliation: Department of Biomedical Engineering, King's College London, London, United Kingdom;