Mh Marieke Pluijmert

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.

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.

Effects of activation pattern and active stress development on myocardial shear in a model with adaptive myofiber reorientation

It has been hypothesized that myofiber orientation adapts to achieve a preferred mechanical loading state in the myocardial tissue. Earlier studies tested this hypothesis in a combined model of left ventricular (LV) mechanics and remodeling of myofiber orientation in response to fiber cross-fiber shear, assuming synchronous timing of activation and uniaxial active stress development. Differences between computed and measured patterns of circumferential-radial shear strain E(cr) were assumed to be caused by limitations in either the LV mechanics model or the myofiber reorientation model. Therefore, we extended the LV mechanics model with a physiological transmural and longitudinal gradient in activation pattern and with triaxial active stress development. We investigated the effects on myofiber reorientation, LV function, and deformation. The effect on the developed pattern of the transverse fiber angle α(t,0) and the effect on global pump function were minor. Triaxial active stress development decreased amplitudes of E(cr) towards values within the experimental range and resulted in a similar base-to-apex gradient during ejection in model computed and measured E(cr). The physiological pattern of mechanical activation resulted in better agreement between computed and measured strain in myofiber direction, especially during isovolumic contraction phase and first half of ejection. In addition, remodeling was favorable for LV pump and myofiber function. In conclusion, the outcome of the combined model of LV mechanics and remodeling of myofiber orientation is found to become more physiologic by extending the mechanics model with triaxial active stress development and physiological activation pattern.

Computer modelling for better diagnosis and therapy of patients by cardiac resynchronisation therapy

Mathematical or computer models have become increasingly popular in biomedical science. Although they are a simplification of reality, computer models are able to link a multitude of processes to each other. In the fields of cardiac physiology and cardiology, models can be used to describe the combined activity of all ion channels (electrical models) or contraction-related processes (mechanical models) in potentially millions of cardiac cells. Electromechanical models go one step further by coupling electrical and mechanical processes and incorporating mechano-electrical feedback. The field of cardiac computer modelling is making rapid progress due to advances in research and the ever-increasing calculation power of computers. Computer models have helped to provide better understanding of disease mechanisms and treatment. The ultimate goal will be to create patient-specific models using diagnostic measurements from the individual patient. This paper gives a brief overview of computer models in the field of cardiology and mentions some scientific achievements and clinical applications, especially in relation to cardiac resynchronisation therapy (CRT).

Adaptive reorientation of myofiber orientation in a model of biventricular cardiac mechanics:The effect of triaxial active stress, passive shear stiffness, and activation sequence

Patient-specific finite element models of cardiac mechanics may assist in clinical decision making by estimating maps of electrical and mechanical tissue properties from clinically observed cardiac deformation. In models of left ventricular mechanics, cardiac deformation was shown to be crucially dependent on cardiac myofiber orientation. Since in vivo assessment of myofiber orientation is inaccurate, a model of adaptive reorientation of myofiber orientation was proposed as method for estimating myofiber orientation. In the present study, we evaluate this adaptation model in a model of biventricular mechanics. Adaptive reorientation of myofibers resulted in an endo-to-epicardial component of fiber orientation, an improved pump function, and more realistic shear strain patterns. Predicted fiber orientation was well defined, and fairly independent of settings of passive shear stiffness, triaxial active stress development, and activation sequence. This finding supports the suggestion to use the model for estimating myofiber orientation in patient-specific models.Patient-specific finite element models of cardiac mechanics may assist in clinical decision making by estimating maps of electrical and mechanical tissue properties from clinically observed cardiac deformation. In models of left ventricular mechanics, cardiac deformation was shown to be crucially dependent on cardiac myofiber orientation. Since in vivo assessment of myofiber orientation is inaccurate, a model of adaptive reorientation of myofiber orientation was proposed as method for estimating myofiber orientation. In the present study, we evaluate this adaptation model in a model of biventricular mechanics. Adaptive reorientation of myofibers resulted in an endo-to-epicardial component of fiber orientation, an improved pump function, and more realistic shear strain patterns. Predicted fiber orientation was well defined, and fairly independent of settings of passive shear stiffness, triaxial active stress development, and activation sequence. This finding supports the suggestion to use the model for estimating myofiber orientation in patient-specific models.

How to choose myofiber orientation in a biventricular finite element model

Biventricular (BiV) finite element (FE) models of cardiac electromechanics are evolving to a state where they can assist in clinical decision making. Carefully designed patient-specific geometries are combined with generic myofiber orientation data, because of lack of accurate techniques to measure myofiber orientation. However, it remains unclear to what extent the assumption of a generic myofiber orientation influences predictions on cardiac function from BiV FE models. As an alternative approach, it was suggested to let the myofiber orientation adapt in response to fiber cross-fiber shear. The aim of this study was to investigate to what extent variations in myofiber orientation as induced by adaptive myofiber reorientation caused variations in global stroke work in a BiV FE model and whether the adaptation model could be used as an alternative approach to prescribe the myofiber orientation in these models. An average change in myofiber orientation over an angle of about 8\(^\circ \), predominantly in transmural direction, resulted in a 91 % increase of LV and 20 % increase of RV stroke work. These findings indicate the importance for a more thorough effort to address a realistic myofiber orientation. The currently used model for adaptive myofiber reorientation seems a useful approach to prescribe the myofiber orientations in BiV FE models.

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 (εcc) or its axial gradient (Δεcc) is found between corresponding LV levels in control and SIT hearts. Circumferential-radial shear (εcr) 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 εcr (Δεcr) 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 Δεcr values is higher in SIT than in controls. Apex-to-base trends of torsion and Δεcr in SIT, changing sign near the LV equator, further substantiate a structural transition in myofiber arrangement close to the LV equator itself. Invariance of εcc and Δεcc 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.

The effect of active cross-fiber stress on shear-induced myofiber reorientation

It has been hypothesized that myofiber orientation adapts to achieve a preferred mechanical loading state. To test this hypothesis, a model has been proposed in which myofiber orientation adapts in a response to fiber cross-fiber shear. However, the model lacked active cross-fiber stress that significantly reduces shear amplitudes, according to models of left ventricular (LV) mechanics. Therefore, we included generation of active stress perpendicular to the myofiber direction in an LV mechanics model with shear-induced myofiber reorientation. We tested the effect on fiber orientation, global and local LV function, and shear deformation. The developed pattern of the transverse component in myofiber orientation was similar with and without active cross-fiber stress. Angles of the transverse component were smaller with active cross-fiber stress. In both cases, global and local function increased during restructuring of the LV wall. Amplitudes of circumferential-radial shear strain were decreased after reorientation in both cases, and predicted and measured circumferential-radial shear strain matched better when active cross-fiber stress was included.