Why SIT Works: Normal Function Despite Typical Myofiber Pattern in Situs Inversus Totalis (SIT) Hearts Derived by Shear-induced Myofiber Reorientation

The left ventricle (LV) of mammals with Situs Solitus (SS, normal organ arrangement) displays hardly any interindividual variation in myofiber pattern and experimentally determined torsion. SS LV myofiber pattern has been suggested to result from adaptive myofiber reorientation, in turn leading to efficient pump and myofiber function. Limited data from the Situs Inversus Totalis (SIT, a complete mirror image of organ anatomy and position) LV demonstrated an essential different myofiber pattern, being normal at the apex but mirrored at the base. Considerable differences in torsion patterns in between human SIT LVs even suggest variation in myofiber pattern among SIT LVs themselves. We addressed whether different myofiber patterns in the SIT LV can be predicted by adaptive myofiber reorientation and whether they yield similar pump and myofiber function as in the SS LV. With a mathematical model of LV mechanics including shear induced myofiber reorientation, we predicted myofiber patterns of one SS and three different SIT LVs. Initial conditions for SIT were based on scarce information on the helix angle. The transverse angle was set to zero. During reorientation, a non-zero transverse angle developed, pump function increased, and myofiber function increased and became more homogeneous. Three continuous SIT structures emerged with a different location of transition between normal and mirrored myofiber orientation pattern. Predicted SIT torsion patterns matched experimentally determined ones. Pump and myofiber function in SIT and SS LVs are similar, despite essential differences in myocardial structure. SS and SIT LV structure and function may originate from same processes of adaptive myofiber reorientation

Assessment and comparison of left ventricular shear in normal and situs inversus totalis hearts by means of magnetic resonance tagging

Situs inversus totalis (SIT) is characterized by complete mirroring of gross cardiac anatomy and position combined with an incompletely mirrored myofiber arrangement, being normal at the apex but inverted at the base of the left ventricle (LV). This study relates myocardial structure to mechanical function by analyzing and comparing myocardial deformation patterns of normal and SIT subjects, focusing especially on circumferential-radial shear. In nine control and nine SIT normotensive human subjects, myocardial deformation was assessed from magnetic resonance tagging (MRT) image sequences of five LV short-axis slices. During ejection, no significant difference in either circumferential shortening (epsilon(cc)) or its axial gradient (Delta epsilon(cc)) is found between corresponding LV levels in control and SIT hearts. Circumferential-radial shear (epsilon(cr)) has a clear linear trend from apex-to-base in controls, while in SIT it hovers close to zero at all levels. Torsion as well as axial change in ecr (Delta epsilon(cr)) is as in controls in apical sections of SIT hearts but deviates significantly towards the base, changing sign close to the LV equator. Interindividual variability in torsion and Delta epsilon(cr) values is higher in SIT than in controls. Apex-to-base trends of torsion and Delta epsilon(cr) in SIT, changing sign near the LV equator, further substantiate a structural transition in myofiber arrangement close to the LV equator itself. Invariance of epsilon(cc) and Delta epsilon(cc) patterns between controls and SIT subjects shows that normal LV pump function is achieved in SIT despite partial mirroring of myocardial structure leading to torsional and shear patterns that are far from normality

New insights from a computational model on the relation between pacing site and CRT response

Aims Cardiac resynchronization therapy (CRT) produces clinical benefits in chronic heart failure patients with left bundle-branch block (LBBB). The position of the pacing site on the left ventricle (LV) is considered an important determinant of CRT response, but the mechanism how the LV pacing site determines CRT response is not completely understood. The objective of this study is to investigate the relation between LV pacing site during biventricular (BiV) pacing and cardiac function. Methods and results We used a finite element model of BiV electromechanics. Cardiac function, assessed as LV dp/dtmax and stroke work, was evaluated during normal electrical activation, typical LBBB, fascicular blocks and BiV pacing with different LV pacing sites. The model replicated clinical observations such as increase of LV dp/dtmax and stroke work, and the disappearance of a septal flash during BiV pacing. The largest hemodynamic response was achieved when BiV pacing led to best resynchronization of LV electrical activation but this did not coincide with reduction in total BiV activation time (∼ QRS duration). Maximum response was achieved when pacing the mid-basal lateral wall and this was close to the latest activated region during intrinsic activation in the typical LBBB, but not in the fascicular block simulations. Conclusions In these model simulations, the best cardiac function was obtained when pacing the mid-basal LV lateral wall, because of fastest recruitment of LV activation. This study illustrates how computer modeling can shed new light on optimizing pacing therapies for CRT. The results from this study may help to design new clinical studies to further investigate the importance of the pacing site for CRT response

Relation between myofiber orientation and torsion.

<p>: At the base of the Situs Inversus Totalis (SIT) LV, myofibers follow a right-handed helical path at the sub-epicardium (<b>A</b>). Contraction of these myofibers, tends to rotate the midventricle in a clockwise direction with respect to the base, when viewed from the apex. The opposite is true for the sub-endocardium: myofibers follow a left-handed helical path, and contraction of these myofibers tends to rotate the midventricle in a counterclockwise direction with respect to the base (<b>A</b>). In general, a net clockwise rotation is measured at the base in SIT LV <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002611#pcbi.1002611-Delhaas1" target="_blank">[6]</a>, indicating that epicardial myofibers dominate endocardial myofibers (<b>B</b>). : At the apex of the SIT LV, myofibers follow the same pattern as in the Situs Solitus (SS) LV. The dominant myofibers at the sub-epicardium follow a left-handed helical path (<b>C</b>). During contraction, a net counterclockwise rotation is measured in the apical region with respect to the midventricle of the SIT LV or with respect to the base in the SS LV (<b>D</b>). In fact, <b>C</b> and <b>D</b> both represent a whole SS LV. Finally, the torsion angle in SIT is similar to SS at the apex and inverted at the base (<b>E</b>).</p

Evolution of local (left) and global (right) LV function in SIT simulation <i>MID</i> during the reorientation process.

<p>Local function is presented by means and standard deviations (SD) of variables natural myofiber strain during isovolumic contraction , during ejection , during isovolumic relaxation , and stroke work density . The values were calculated from the grey area indicated in the long-axis cross-section of the LV mesh (mid). Global function is presented by maximum LV pressure and stroke volume .</p

Determinants of biventricular cardiac function:a mathematical model study on geometry and myofiber orientation

In patient-specific mathematical models of cardiac electromechanics, usually a patient-specific geometry and a generic myofiber orientation field are used as input, upon which myocardial tissue properties are tuned to clinical data. It remains unclear to what extent deviations in myofiber orientation and geometry between model and patient influence model predictions on cardiac function. Therefore, we evaluated the sensitivity of cardiac function for geometry and myofiber orientation in a biventricular (BiV) finite element model of cardiac mechanics. Starting out from a reference geometry in which myofiber orientation had no transmural component, two new geometries were defined with either a 27 % decrease in LV short- to long-axis ratio, or a 16 % decrease of RV length, but identical LV and RV cavity and wall volumes. These variations in geometry caused differences in both local myofiber and global pump work below 6 %. Variation of fiber orientation was induced through adaptive myofiber reorientation that caused an average change in fiber orientation of [Formula: see text] predominantly through the formation of a component in transmural direction. Reorientation caused a considerable increase in local myofiber work [Formula: see text] and in global pump work [Formula: see text] in all three geometries, while differences between geometries were below 5 %. The findings suggest that implementing a realistic myofiber orientation is at least as important as defining a patient-specific geometry. The model for remodeling of myofiber orientation seems a useful approach to estimate myofiber orientation in the absence of accurate patient-specific information