MOX-Report No. 29/2020

Modeling cardiac muscle fibers in ventricular and atrial electrophysiology simulations

Piersanti, R.; Africa, P.C.; Fedele, M.; Vergara, C.; Dede', L.;

Corno, A.F.; Quarteroni, A.

MOX, Dipartimento di Matematica Politecnico di Milano, Via Bonardi 9 - 20133 Milano (Italy)

mox-dmat@polimi.it http://mox.polimi.it

Modeling cardiac muscle fibers in ventricular and

atrial electrophysiology simulations

Roberto Piersantia, Pasquale C. Africaa, Marco Fedelea, ChristianVergarab, Luca Dedea, Antonio F. Cornoc, and Alfio Quarteronia,d

aModellistica e Calcolo Scientifico (MOX), Dipartimento di Matematica, Politecnico diMilano, Milan, Italy

bLaboratory of Biological Structure Mechanics (LaBS), Dipartimento di Chimica, Materiali eIngegneria Chimica, Politecnico di Milano, Milan, Italy

cEast Midlands Congenital Heart Center, University Hospitals of Leicester, University ofLeicester, Glenfield Hospital, Leicester, United Kingdom

dInstitute of Mathematics, Ecole Polytechnique Federale de Lausanne, Switzerland (Professoremeritus)

May 8, 2020

Keywords: Cardiac fiber architecture; Fiber reconstruction; Laplace-Dirichlet-Rule-Based-Methods; Mathematical models; Electrophysiology simulation; Fi-nite element method.

Abstract

Since myocardial fibers drive the electric signal propagation through-out the myocardium, accurately modeling their arrangement is essentialfor simulating heart electrophysiology (EP). Rule-Based-Methods (RBMs)represent a commonly used strategy to include cardiac fibers in computa-tional models. A particular class of such methods is known as Laplace-Dirichlet-Rule-Based-Methods (LDRBMs) since they rely on the solutionof Laplace problems. In this work we provide a unified framework, based onLDRBMs, for generating full heart muscle fibers. We first present a unifieddescription for existing ventricular LDRBMs, introducing some modelingimprovements with respect to the existing literature. We then carry out asystematic comparison of LDRBMs based on meaningful biomarkers pro-duced by numerical EP simulations. Next we propose, for the first time, aLDRBM to be used for generating atrial fibers. The new method, testedboth on idealized and realistic atrial models, can be applied to any arbi-trary geometries. Finally, we present numerical results obtained in a real-istic whole heart where fibers are included for all the four chambers usingthe discussed LDRBMs.

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1 Introduction

In numerical heart electrophysiology a critical issue is that of modeling the my-ocardial fibers arrangement that characterizes the cardiac tissue. Aggregationsof myofibers, namely the results of cardiomyocytes orientation, determine howthe electric signal propagates within the muscle [1, 2, 3]. This motivates the needto accurately include fiber orientations in order to obtain physically meaningfulresults [4, 5].

In the last decades, myofibers orientation have been studied using histologicaldata and Diffusion Tensor Imaging (DTI) acquisition [6, 7, 8]. DTI is a MagneticResonance Imaging (MRI) technique able to produce useful structural informa-tion about heart muscle fibers and largely applied to explanted ex-vivo hearts,coming from animal experiments [6, 7, 9, 10, 11] or from human corpses [8, 12].However, acquired in-vivo DTI protocol lasts hours and generally produces anoisy low-resolution fibers reconstruction [13, 14, 15]. Furthermore, since theatria thickness is smaller than the DTI voxel size, it is not possible to obtainin-vivo myofibers in the atria [16]. All the above considerations make nowa-days DTI technique unusable to reconstruct accurate 3D myofibers field in thecommon clinical practice.

Because of the difficulties to acquire patient-specific fibers data, differentmethodologies have been proposed in order to provide a realistic surrogate offiber orientation for in-vivo cardiac geometries [12, 16, 17, 18, 19, 20, 21, 22, 23].Among these, atlas-based methods map and project a detailed fiber field, previ-ously reconstructed on an atlas, on the geometry of interest , exploiting DTI orhistological data; see [12] for the ventricles and [16] for the atria. However, thesemethods require complex registration algorithms and are strictly dependent onthe original atlas data upon which they have been built.

Alternative strategies for generating myofiber orientations are the so calledRule-Based Methods (RBMs) [4, 24, 25, 26]. RBMs describe fiber orienta-tions with mathematically sound rules based on histological or DTI observationsand require information only about the myocardial geometry. These methodsparametrize the transmural and apico-basal directions in the entire myocardiumin order to assign orthotropic (longitudinal, transversal and normal) myofibers;see [5, 17, 18, 19, 20, 24] for the ventricles and [21, 22, 23, 27, 28] for the atria.

A particular class of RBMs, which rely on the solution of Laplace boundary-value problems, is known as Laplace-Dirichlet-Rule-Based-Methods (LDRBMs),addressed in [5, 17, 18, 19, 20] for the ventricular case. LDRBMs define thetransmural and apico-basal directions by taking the gradient of solutions corre-sponding to suitable Dirichlet boundary conditions. These directions are thenproperly rotated in order to match histological observations [29, 30, 31]. Theabove procedure ensures a smooth and continuous change in fibers directionsthroughout the whole myocardium.

Most of existing ventricular RBMs refer to left ventricle only and usuallyintroduce an artificial basal plane located well below the cardiac valves. Only

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recently, a LDRBM, that takes into account fiber directions in specific cardiacregions, such as the right ventricle, the inter-ventricular septum and the outflowtracks, has been developed [20]. This has provided a great improvement inRBMs since the right ventricle exhibits a different fiber orientation with respectto the left ventricle [7, 9, 12, 32]. The presence of a discontinuity in the inter-ventricular septal fibers is a crucial matter, still very debated [32, 33], eventhough the corresponding effects on electrical signal propagation have not beenstudied yet.

Regarding the atria, several RBMs have been developed. They either usesemi-automatic approaches [21, 22, 23, 27, 28, 34, 35, 36] or prescribe manuallythe fiber orientations in specific atrial regions [37, 38, 39, 40]. Often, theseprocedures require a manual intervention and, in many cases, are designed forspecific atrial morphologies [21, 23]. Hence, a general automatic processingpipeline for generating atrial fibers field still remains a knotty procedure [23,41]. Moreover, no LDRBMs have been proposed so far for the atria. As amatter of fact, an extension of the ventricular LDRBMs is not straightforward,mainly because the atrial fibers architecture is characterized by the presence ofmultiple overlapping bundles running along different directions, differently fromthe ventricles one where myofibers are aligned along regular patterns.

Over the past years several cardiac computational models were carried out inorder to study pathological conditions affecting either the electrical or mechan-ical response in individual heart chambers. However, in the quest for a morequantitative understanding of the heart functioning both in health and diseasedscenarios, it became fundamental to model and simulate the entire heart as anwhole organ [42]. Only recently, the scientific community moved towards thewhole heart modeling and simulations [43, 44, 45, 46, 47, 48, 49, 50]. Never-theless, we highlight that none of these computational studies makes use of aunified methodology to embed reliable and detailed cardiac fibers in the wholeheart muscle to take into account different fiber orientations specific of the fourchambers.

Driven by the previous open issues, in this work we provide a unified frame-work, based on LDRBMs, for generating full heart muscle fibers. We start bygiving a unified mathematical description for three existing LDRBMs in the ven-tricles, introducing also some modeling improvements [17, 19, 20]. In particular,we extend ventricular LDRBMs in order to include specific fiber directions forthe right ventricle. Next, we carry out a systematic comparison of the effectproduced by different LDRBMs on the electrophysiology in terms of meaning-ful biomarkers (e.g. activation times) computed from numerical simulations.Specifically, we study the importance of including different fiber orientations inthe right ventricle and we investigate the effect of the inter-ventricular septalfibers discontinuity.

Then, at the best of our knowledge, we propose for the first time an atrialLDRBM which is able to qualitatively reproduce all the important features, suchas fiber bundles, needed to provide a realistic atrial musculature architecture.

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Unlike most of the existing RBMs, the new method, tested both on idealizedand realistic atrial geometries, can be easily applied to any arbitrary geometries.Moreover, we analyse the strong effect of the complex atrial fiber architectureon the electric signal propagation obtained by numerical simulations.

In the last part of the work, we illustrate numerical results including thefull heart LDRBMs fiber generations and an electrophysiology simulation withphysiological activation sites in a four chamber realistic computational domainof the heart.

This paper is organized as follows. In Section 2 we review and provide a uni-fied description of existing LDRBMs for ventricular fiber generation. In Section3 we propose our new LDRBM for atrial fibers generation. Numerical methodsto perform electrophysiology simulations are explained in Section 4. Section 5is dedicated to numerical results where we present a comparison among differ-ent ventricular LDRBMs, we test by means of electrophysiological simulationsthe new atrial LDRBM and we show numerical simulation of the whole heartelectrophysiology including the presented fiber generation methods. Finally,conclusions follow.

2 Rule-Based-Methods for ventricular fibers genera-tion

In this section we review three popular LDRBMs introduced so far in the litera-ture: specifically, we consider LDRBMs by Rossi et al. [19], by Bayer et al. [17]and by Doste et al. [20]. In view of our review process of the former LDRBMs,we provide a unified framework of such methods, highlighting commonalities anddifferences.

We identify the following shared steps of the three ventricular LDRBMs 1,which are hereby reported:

1. Labelled mesh: Provide a labelled mesh of the ventricles domain Ωmyo todefine specific partitions of the ventricles boundary ∂Ωmyo, see Figure 1;

2. Transmural distance: A transmural distance is defined to compute thedistance of the epicardium from endocardium surfaces;

3. Transmural direction: The transmural distance gradient is used to buildthe unit transmural direction et of the ventricles, see Figure 1;

4. Normal direction: An apico-basal direction (directed from the apex to-wards the ventricles base) is introduced and it is used to build the unitnormal direction en, orthogonal to the transmural one, see Figure 1;

1In what follows, we consider the three LDRBMs applied to biventricular models, the mostgeneral case of ventricles domain.

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Figure 1: Left: Representation of the three directions employed by a LDRBMfor an idealized biventricular domain Ωmyo whose border ∂Ωmyo is partitioned inthe epicardium Γepi, left Γlv and right Γrv endocardium and the ventricles baseΓbase, ∂Ωmyo = Γepi∪Γlv∪Γrv∪Γbase. For visualization purpose, only directionson the left endocardium Γlv are represented. In blue: unit transmural direction,et; In green: unit normal direction, en; In red: unit longitudinal direction, el.Right: zoom on a slab of the left ventricle myocardium Ωmyo showing the threefinal myofibers orientations f , s, n.

5. Local coordinate system: Build for each point of the ventricles domainan orthonormal local coordinate axial system composed by et, en and theunit longitudinal direction el (orthogonal to the previous ones), see Figure1;

6. Rotate axis: Finally, properly rotate the reference frame with the purposeof defining the myofiber orientations: f the fiber direction, n the cross-fiber direction and s the sheet direction, see Figure 1(right). Rotations arechosen in order to match histology and DTI observations.

The ventricular LDRBM by Rossi et al [19, 46] (in what follows referred to as R-RBM) is a modified version of the algorithm studied in [18] for generating fibersin left ventricular geometries [19], then extended to the biventricular case in [46].R-RBM is based on the definition of the transmural direction. Bayer et al. [17]developed another LDRBM (B-RBM) for assigning myocardial fiber orientationintroducing two major contributions. The first improvement is the definition ofthe apico-basal direction [5]. The second one consists of using the bi-directionspherical interpolation (bislerp) [51, 52] to manage the fiber orientations inorder to guarantee a smooth and continuous change in the fiber field, particularlyin the proximity of the septum and around the ventricle junctions [17]. BothR-RBM and B-RBM introduce an artificial basal plane, located well below thecardiac valves, delimiting the ventricle regions. To overcome this restriction,

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Figure 2: Schematic pipeline of R-RBM for a biventricular geometry with anartificial basal plane.

Doste et al. [20] recently proposed a new LDRBM (D-RBM) which is able tobuild the fiber field in a full biventricular geometry without the need to cut itwith a basal plane. D-RBM fiber orientations are generated to take into accountspecific ventricular regions, such as the inter-ventricular septum and outflowtracts (OT), following observations from histological studies [20].

To characterize the three LDRBMs under review, it is useful to consider thefollowing Laplace-Dirichlet problem

−∆χ = 0 in Ωmyo,

χ = χa on Γa,

χ = χb on Γb,

∇χ · n = 0 on Γn,

(1)

for a generic unknown χ and suitable boundary data χa, χb ∈ R set on genericpartitions of the ventricles boundary Γa, Γb, Γn, with Γa∪Γb∪Γn = ∂Ωmyo. Thevariable χ will assume different meanings depending on the step and LDRBMconsidered. Moreover, the values χa, χb are fixed in order to evaluate specificinter-ventricular distances between boundary partitions Γa, Γb.

We detail in what follows the six points aforementioned. We refer to Figures2, 3 and 4, showing a schematic representations of R-RBM, B-RBM, and D-RBM, respectively, for a biventricular domain Ωmyo.

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Figure 3: Schematic pipeline of B-RBM for a full biventricular geometry.

1. Labelled mesh Prescribing the ventricles boundary ∂Ωmyo. All the threeLDRBMs define the following boundaries:

Γepi : the ventricles epicardium, Γbase : the ventricles base,

Γlv : the left ventricle endocardium, Γrv : the right ventricle endocardium.

Moreover, R-RBM subdivides the right ventricle endocardium Γrv into theright ventricle septum Γrs and the remaining part Γrv−s such that Γrv = Γrs ∪Γrv−s, see step 1 in Figure 2. This subdivision is usually performed manually bythe user, thus introducing some arbitrariness during the septum selection. For B-RBM and D-RBM the left ventricle apex Γla is also introduced, whereas the rightventricle apex Γra for D-RBM solely (see step 1 in Figures 3 and 4). Furthermore,D-RBM requires boundary tags for the four valve rings: Γmv (mitral valve), Γav(aortic valve), Γtv (tricuspid valve) and Γpv (pulmonary valve), see step 1 inFigure 4. It is also useful to define Γrings = Γlring∪Γrring, with Γlring = Γmv∪Γavand Γrring = Γtv ∪ Γpv. Notice that in B-RBM we considered the union of thefour valve rings as the ventricles base Γbase = Γrings. This allows the use ofB-RBM also in the case of a full biventricular geometry, see step 1 in Figure 3.In summary, the three methods define the boundary ∂Ωmyo as follows (see step1 in Figures 2, 3 and 4):

R-RBM : ∂Ωmyo = Γepi ∪ Γlv ∪ Γrs ∪ Γrv−s ∪ Γbase,

B-RBM : ∂Ωmyo = Γepi ∪ Γlv ∪ Γrv ∪ Γrings ∪ Γla,

D-RBM : ∂Ωmyo = Γepi ∪ Γlv ∪ Γrv ∪ Γmv ∪ Γav ∪ Γtv ∪ Γpv ∪ Γla ∪ Γra.

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LDRBM type Transmural distances χa Γa χb Γb Γn

R-RBM φ 1 Γlv ∪ Γrv−s 0 Γepi ∪ Γrs Γbase

B-RBMφ` 1 Γlv 0 Γepi ∪ Γrv Γrings

φr 1 Γrv 0 Γepi ∪ Γlv Γrings

φepi 1 Γepi 0 Γlv ∪ Γrv Γrings

D-RBM φ2 Γlv 0 Γepi Γrings-1 Γrv

Table 1: Transmural distance boundary conditions for R-RBM, B-RBM andD-RBM used in step 2.

Figure 4: Schematic pipeline of D-RBM for a full biventricular geometry.

2. Transmural distance Definition of transmural distances (generally indi-cated with the letter φ) obtained by solving Laplace-Dirichlet problems of theform (1). In particular, for R-RBM, the transmural distance φ is found by solv-ing (1) with χa = 1 on Γlv ∪ Γrv−s, χb = 0 on Γepi ∪ Γrs, and Γn = Γbase. ForD-RBM, φ is found by solving (1) with χa = 2 on Γlv, χa = −1 on Γrv, χb = 0on Γepi, and Γn = Γrings. B-RBM requires to solve three Laplace problems (1)in order to compute three different transmural distances φ`, φr and φepi. Werefer the reader to Table 1 for the specific choices in problem (1) made by thethree methods. Notice that in D-RBM the boundary conditions χa are assignedin order to identify the two ventricles (positive and negative values for left andright ventricle, respectively) and to associate roughly two-thirds of the septumto the left ventricle and one-third to the right one [20] (see step 2 in Figures 2,3 and 4).

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3. Transmural direction After solving the Laplace problems for findingthe transmural distances φ, φl, φr, φepi, their gradients define the transmuraldirections γ (see step 3 in Figures 2, 3 and 4). In particular, we have:

R-RBM : γ = ∇φ,B-RBM : γ = ∇φi, i = `, r, epi,

D-RBM : γ = ∇φ.

4. Normal direction Definition of the normal direction k. In R-RBM, thisis done using the vector nbase, i.e. the outward normal to the ventricular base,that is k = nbase (see step 4 in Figure 2). For the other two LDRBMs, furthervariables (identified by the letter ψ) are introduced: they are found by solving theLaplace problem in the form (1) with suitable boundary conditions. Specifically,for B-RBM the vector k is the gradient of the solution ψ (k = ∇ψ) obtainedwith χa = 1 on Γrings, χb = 0 on Γla, and Γn = Γepi ∪ Γlv ∪ Γrv, see step 4in Figure 3. In D-RBM, instead, two normal directions are introduced, one foreach ventricle:

k = wi∇ψab,i + (1− wi)∇ψot,i, i = `, r, (2)

where i = `, r refer to the left and right ventricle, respectively, so that the nor-mal direction is a weighted sum of apico-basal (∇ψab,i) and apico-outflow-tract(∇ψot,i) directions, obtained using an inter-ventricular interpolation function wi[20]; the latter are given again by solutions of problems like (1) (see step 4aand 4b in Figure 4). In particular, ψab,`, ψab,r, ψot,`, ψot,r, w`, wr are found bysolving (1) with χa = 1 on Γa and χb = 0 on Γb, where Γa and Γb are bound-ary subsets listed in Table 2. Summing up, the different methods compute thenormal direction k as follows (see step 4 in Figures 2, 3 and 4):

R-RBM : k = nbase,

B-RBM : k = ∇ψ,D-RBM : k = wi∇ψab,i + (1− wi)∇ψot,i, i = `, r.

5. Local coordinate system Building an orthonormal local coordinate sys-tem (defined by letter Q) at each point of the domain Ωmyo. All the threemethods make use of the following function axis:

P = [el, en, et] = axis(k,γ) =

et = γ

‖γ‖ ,

en = k−(k·et)et‖k−(k·et)et‖ ,

el = en × et,(3)

which takes as input a normal direction k and a transmural direction γ and re-turns the orthonormal system P whose columns are the three orthonormal direc-tions el, en, et which represent the longitudinal, the normal and the transmural

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Scalar potentials Γa Γb Γn

ψab,` Γmv Γla Γepi ∪ Γlv ∪ Γrv ∪ Γav ∪ Γrringψab,r Γtv Γra Γepi ∪ Γlv ∪ Γrv ∪ Γpv ∪ Γlringψot,` Γav Γla Γepi ∪ Γlv ∪ Γrv ∪ Γmv ∪ Γrringψot,r Γpv Γra Γepi ∪ Γlv ∪ Γrv ∪ Γtv ∪ Γlringw` Γmv ∪ Γla Γav Γepi ∪ Γlv ∪ Γrv ∪ Γrringwr Γtv ∪ Γra Γpv Γepi ∪ Γlv ∪ Γrv ∪ Γlring

Table 2: Scalar potentials used in D-RBM to build the normal direction.

unit directions, respectively. For R-RBM we haveQ = axis(k,∇φ). For B-RBMthree orthonormal coordinate systems are introduced, that is P` = axis(k,∇φ`),Pr = axis(k,∇φr) and Pepi = axis(k,∇φepi), which are then interpolatedthrough the function bislerp to obtain a continuous orthonormal coordinatesystem within the whole myocardium (see [17] for further details). Hence, B-RBM performs the following steps to obtain the final orthonormal coordinatesystem Q (see step 5 in Figure 3):

Pendo = bislerp(P`, Pr),

Q = bislerp(Pendo, Pepi).

D-RBM, instead, defines two different coordinate systems for left and right ven-tricle as a consequence of the normal directions defined in (2) (see step 5 inFigure 4):

Qi = axis(wi∇ψab,i + (1− wi)∇ψot,i,∇φ), i = `, r.

6. Rotate axis The orthonormal coordinate system, defined for each pointof the myocardium at the previous step, should be aligned in order to matchhistological knowledge about fiber and sheet orientations. To this aim, the threeLDRBMs introduce a rotation of el, en, et by means of suitable angles: thelongitudinal direction el rotates counter-clockwise around et by an angle αi,whereas the transmural direction et is rotated counter-clockwise around el byan angle βi, where i = `, r depend on the left or right ventricle the point belongsto. Indeed, it is known that in the left and right ventricles the fiber orientationsfeature a change in direction at the inter-ventricular septum [32]. In order to ob-tain a local orthonormal coordinate system, direction en is rotated accordingly.

These rotations produce a map from the original coordinate system to a newcoordinate system [f ,n, s]:

[el, en, et]αi,βi−−−→ [f ,n, s], i = `, r,

where f is the fiber direction, n is the cross-fiber direction and s is the sheetdirection.

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For all the three methods the rotation angles αi = αi(di) and βi = βi(di) arefunctions of the position within the myocardium, in particular of the transmuralnormalized distance di ∈ [0, 1], i = `, r, defined as:

R-RBM : d` = dr = φ,

B-RBM : d` = φ` dr = φr,

D-RBM : d` = φ/2 dr = |φ|.Accordingly, the rotation angles are written by means of the following linearrelationships:

αi(di) = αepi,i(1− di) + αendo,idi, βi(di) = βepi,i(1− di) + βendo,idi, i = `, r,(4)

where αendo,`, αepi,`, αendo,r, αepi,r, βendo,`, βepi,`, βendo,r and βepi,r are suitablerotation angles on the epicardium and endocardium chosen in order to matchhistological observations. For example, classical values found in the literature areαepi,` = +60o, αendo,` = −60o, αepi,r = −25o, αendo,r = +90o [12, 29, 31, 53, 54].

In order to differentiate between the left and right ventricles and to applythe correct angles, we propose here to use the solution of an additional Laplaceproblem (1) in the unknown χ = ξ with χa = 1 on Γlv, χb = −1 on Γrv, andΓn = Γbase ∪ Γepi

2. In particular, positive values of ξ identify the left ventricle,whereas negative values the right one [55]. This new feature enables to performdifferent rotations for left and right ventricles (see steps 6 in Figures 2, 3 and 4)that is crucial in order to generate realistic fiber fields. An alternative methodhas been proposed in [20] but only for D-RBM. It is worth mentioning that theoriginal R-RBM [19, 46] introduces a rotation to obtain the fiber field f only.Here we propose an extension in order to define also n and s.

Further, B-RBM exploits two other functions representing the rotation angleswithin the septum:

αs(di) = αendo,i(1− 2di), βs(di) = βendo,i(1− 2di), i = `, r,

whereas with similar expressions, D-RBM introduces also the possibility to setspecific fiber and sheet angles rotation in the OT regions (see [17] and [20] forfurther details).

We conclude pointing out that B-RBM and D-RBM can be applied to the fullbiventricular geometry and to the based biventricular case (that is obtained withan artificial basal plane well below the cardiac valves). Indeed, in the basedbiventricular geometry the whole procedure for B-RBM and D-RBM remainsthe same as long as the ring tags are replaced by the base tag, Γrings = Γbase.On the contrary, R-RBM is less suitable for a full biventricular case because itis not able to strictly identify the normal direction k as the outward normal tothe ventricular rings. Besides, the definition of right ventricle septum Γrs canbe arbitrary for a full biventricular geometry.

2Let us observe that, for B-RBM Γbase = Γrings in the case of a full biventricular geometry.Moreover, for D-RBM solely χa = 2 in order to be compliant with the transmural distance.

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3 A new rule-based method for atrial fibers genera-tion

Atrial fibers architecture is very different from that of the ventricles where my-ofibers are aligned in a regular pattern [1]. Indeed, fibers in the atria are or-ganized in individual bundles running along different directions throughout thewall chambers. Preferred orientation of myofibers in the human atria is char-acterized by multiple overlapping structures, which promote the formation ofseparate attached bundles [56]. This architecture has a strong influence in theelectric signal propagation inside the atrial muscle [21, 27, 57, 58, 59, 60, 61].

Over the past years many histological studies investigated the fibers arrange-ment of the atria revealing a very complex texture musculature [62, 63, 64, 65,66, 67, 68, 69]. Nevertheless, there is a paucity of imaging data on atrial fibersorientation with respect to the ventricles, mainly due to imaging difficulties incapturing the thin atrial walls [56]. Only recently, ex vivo atrial fibers have beenanalysed owing to submillimeter Diffusion Tensor MRI imaging [8, 70, 71].

In computational models of cardiac electrophysiology, atrial fiber orientationshave been generated in specific regions either manually [37, 38, 39, 40] or usinga variety of semi-automatic rule-based approaches [21, 22, 23, 27, 28, 34, 35, 36].Recently, atlas-based methods, in which fiber directions of a reference atrialgeometry are warped on a target geometry, have been introduced [16, 72, 73, 74].All the former procedures require manual intervention introducing, for example,various distinct landmarks, seed-points and a network of auxiliaries lines [21, 23].Hence, a processing pipeline for generating atrial fibers field still remains a knottyprocedure [23, 41].

In this section we propose for the first time a LDRBM for the generation ofatrial myofibers, which is able to qualitatively reproduce all the important fea-tures, such as fiber bundles, needed to provide a realistic atrial musculature ar-chitecture. Our newly developed method is inspired by [74] where Laplace prob-lems are introduced to map variables between two geometries and by LDRBMs,purposely built for the ventricles, presented in Section 2 [17, 19, 20]. The exten-sion of the latter is not straightforward due to the presence of bundles which runin different directions. For this reason, our atrial LDRBM combines the gradientof several harmonic functions to represent the fiber bundles.

In what follows we detail the four steps of the proposed atrial LDRBM. Werefer to Figure 5 for a schematic representation of the method in a realisticscenario.

1. Labelled mesh Label the mesh of the atrial computational domain Ωatrial

to define the boundary partitions of ∂Ωatrial. For both the left atrium (LA) andthe right atrium (RA) the following boundaries are defined (see step 1 in Figure

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Figure 5: Schematic pipeline of the atrial LDRBM in a realistic right atrium(RA) and left atrium (LA) geometries.

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Type χ χa Γa χb Γb Γn

LA

φ 1 Γepi 0 Γendo Γavr ∪ Γlpv ∪ Γrpv

ψab2 Γrpv 1 Γavr Γepi ∪ Γendo0 Γlpv -1 Γap

ψv 1 Γrpv 0 Γlpv Γavr ∪ Γepi ∪ Γendoψr 1 Γavr 0 Γlpv ∪ Γrpv ∪ Γap Γepi ∪ Γendo

RA

φ 1 Γepi ∪ Γr−epi 0 Γendo ∪ Γr−endo Γavr ∪ Γicv ∪ Γscv ∪ Γcs

ψab2 Γicv 1 Γavr Γepi ∪ Γendo ∪ Γroof ∪ Γcs0 Γscv -1 Γap

ψv 1 Γicv 0 Γscv ∪ Γap Γavr ∪ Γepi ∪ Γendo ∪ Γroof ∪ Γcs

ψr 1 Γavr 0 Γroof Γepi ∪ Γendo ∪ Γicv ∪ Γscv ∪ Γcs

ψw 1 Γavr−s -1 Γavr−w Γepi ∪ Γendo ∪ Γroof ∪ Γicv ∪ Γscv ∪ Γcs

Table 3: Boundary data chosen in the Laplace problem (1) for the transmuraldistance φ and the inter-atrial distances ψi (i = ab, v, r, w) in the left (LA) andright atrium (RA).

5):

Γendo : the atrium endocardium, Γepi : the atrium epicardium,

Γavr : the atrio-ventricular ring, Γap : the atrium appendage.

Moreover, we introduce boundary tags of the left and right pulmonary veinrings Γlpv, Γrpv for the LA, and the tags of the inferior and superior caval veinrings Γicv, Γscv and of the coronary sinus ring Γcs for the RA. In the RA, theatrio-ventricular ring Γavr is equally subdivided in one part facing the atrialseptum Γavr−s and another one related to the free wall Γavr−w, such that Γavr =Γavr−s ∪ Γavr−w (see step 1 in Figure 5). Furthermore, the RA encloses alsothe boundary tag for the atrial roof Γroof that is divided in two sections: apart lying on the epicardium Γroof−epi and another one on the endocardiumΓroof−endo, such that Γroof = Γroof−epi ∪ Γroof−endo (see step 1 in Figure 5). Insummary, the boundaries ∂Ωatrial for the RA and LA are, respectively:

RA : ∂Ωatrial = Γepi ∪ Γendo ∪ Γap ∪ Γicv ∪ Γscv ∪ Γcs ∪ Γavr−s ∪ Γavr−w∪∪ Γroof−epi ∪ Γroof−endo;

LA : ∂Ωatrial = Γepi ∪ Γendo ∪ Γap ∪ Γlpv ∪ Γrpv ∪ Γavr.

2. Laplace solutions Definition of the transmural distance φ and severalinter-atrial distances ψi, obtained by solving a Laplace-Dirichlet problem in theform of (1) with proper Dirichlet boundary conditions on the atrial boundaries,see step 2 in Figure 5. Refer to Table 3 for the specific choices in problem (1)made for the RA and LA. In particular, ψab is the solution of a Laplace problem(1) with three different boundary data prescribed on the atrio-ventricular ringΓavr, the atrial appendage Γap, and the rings of the caval veins for the RA andthe pulmonary veins for the LA; ψv represents the distance between the cavalveins for the RA and among the pulmonary veins for the LA; ψr stands forthe distance between the atrio-ventricular ring Γavr and the roof Γroof (RA)

14

Algorithm 1 Bundles selection for right atrium in the atrial LDRBM

Let τavr, τr, τicv, τscv, τct+ , τct− , τfw, and τsw be the parameters referring to thebundles dimension.

if ψr ≥ τavr set k = ∇ψrelse

if ψr < τrif ψw ≥ τct− and ψw ≤ τct+ set k = ∇ψwelse if ψw < τct−

if ψv ≥ τicv or ψv ≤ τscv set k = ∇ψvelse set k = ∇ψab

elseif ψv ≥ τicv or ψv ≤ τscv set k = ∇ψvelse

if ψw ≤ τfw set k = ∇ψvelse if ψw ≥ τsw set k = ∇ψrelse set k = ∇ψw

elseif ψv ≥ τicv or ψv ≤ τscv set k = ∇ψvelse

if ψw ≥ 0 set k = ∇ψrelse set k = ∇ψab

Algorithm 2 Bundles selection for left atrium in the atrial LDRBM

Let τavr, τlpv and τrpv be the parameters referring to the bundles dimension.

if ψr ≥ τavr set k = ∇ψrelse

if ψv ≥ τlpv or ψv ≤ τrpv set k = ∇ψvelse set k = ∇ψab

and between Γavr and the union of the pulmonary veins rings Γlpv ∪ Γrpv (LA).Moreover, for the RA ψw is the distance between the atrioventricular ring of thefree (Γavr−w) and the septum (Γavr−s) walls. See step 2 in Figure 5.

3. Bundles selection Definition of the atrial bundles and their dimensionthroughout the domain Ωatrial, in order to match histology and DTI observa-tions. With this aim, the atrial LDRBM assigns, for each point in Ωatrial, aunique inter-atrial distance ψi, among those defined in step 2, following therules reported in Algorithms 1 and 2 for the bundle selection in the right andleft atrium, respectively (see also step 3 in Figure 5). During this assignment,the atrial LDRBM defines a unique normal direction k by taking the gradientof the allocated inter-atrial distances, k = ∇ψi. Moreover, in order to specifythe bundles dimension, the parameters τi are introduced: for the RA τavr, τr,

15

τicv, τscv, τct+ , τct− , τfw and τsw referring to the atrio-ventricular, roof, infe-rior and superior caval veins, crista terminalis, free and septum wall bundles,respectively; for the LA τavr, τlpv and τrpv referring to the atrio-ventricular, leftand right pulmonary veins bundles, respectively. The complete bundles selec-tion procedures are displayed in details in Algorithms 1 and 2 (see also step 3in Figure 5).

4. Local coordinate system Definition of the myofiber orientations bymeans of an orthonormal local coordinate system, built at each point of theatrial domain. This step is performed in the same way as for the ventricles: thegradient of the transmural distance φ is used to build the transmural direction∇φ which is taken as one input of the function axis (3) together with the uniquenormal direction k:

Q = [el, en, et] = [f ,n, s] = axis(k,∇φ),

where el, en and et are the unit longitudinal, normal and transmural directions,respectively. Moreover, since we are not prescribing any transmural variation inthe fiber bundles, the three unit directions correspond to the final fiber, sheetand cross-fiber directions f , n and s (see step 4 in Figure 5).

4 Modelling cardiac electrophysiology

In this section we briefly recall the mathematical model for the description of theelectrophysiology activity in the cardiac tissue, that is the monodomain equation[75, 76] endowed with suitable ionic models for human action potential, i.e theCourtemanche-Ramirez-Nattel model for the atria [77] and the Ten-Tusscher-Panfilov model for the ventricles [78]. Moreover, we provide the correspondingmethods used for the numerical approximation (Section 4.2).

4.1 Mathematical models

Front propagation of cardiac action potential can be simulated by the mon-odomain model: a reaction-diffusion partial differential equation describing cur-rent flow through cardiac tissue, composed of myocytes that are electricallyconnected via a low-resistence gap junctions, coupled with an ionic model de-scribed by a system of ordinary differential and algebraic equations standing forionic exchange across cell membranes [46, 56, 75, 79, 80, 81, 82].

Cardiac tissue is an orthotropic material, arising from the cellular organi-zation of the myocardium in fibers, laminar sheet and cross-fibers, which ismathematically modelled by the conductivity tensor

D = σff ⊗ f + σss⊗ s+ σnn⊗ n, (5)

16

where σf , σs and σn are the conductivities along fibers (f), sheets (s), andcross-fibers (n) directions, respectively. Given a computational domain Ω and atime interval (0, T ], the monodomain equations read:find, for each t, the transmembrane action potential u : Ω× (0, T ]→ R and thegating variables w : Ω× (0, T ]→ Rn, such that

χCm∂u

∂t−∇ · (D∇u) + χIion(u,w) = Iapp(x, t) in Ω× (0, T ], (6a)

dw

dt= G(u,w) in Ω× (0, T ], (6b)

where χ is the surface area-to-volume ratio of cardiomyocytes, Cm is the specifictrans-membrane capacitance per unit area, Iapp is an external applied currentwhich serves to initiate the signal propagation, Iion and G ∈ Rn are the reactionterms, linking the macroscopic action potential propagation to the cellular dy-namics. The unknown w is a n–th dimensional vector function fulfilling a systemof differential algebraic equations representing the percentage of open channelsper unit area of the membrane. Specifically, we used the Courtemanche-Ramirez-Nattel (CRN, n = 20) in case of atrial action potential and the Ten-Tusscher-Panfilov (TTP, n = 18) for the ventricular one (for further details see [77] forCRN and [78] for TTP). Furthermore, system (6) is equipped with suitable ini-tial conditions for u and w and homogeneous Neumann boundary conditions foru at the boundary ∂Ω.

4.2 Numerical approximation

For the time discretization of the monodomain system (6) we introduce thediscrete times tn = n∆t, n ≥ 0, and, given a function of time z(t), we denoteby zn+1 the approximation of z(tn+1). Then, at each time step tn+1 we considera Backward Difference Formulae approximation of order σ = 1, 2, 3 (BDFσ)with an explicit treatment of the reaction term, obtaining the following semi-discretized in time formulation:

αBDFσwn+1 −wn

BDFσ

∆t+G(un+1

EXTσ,wn+1EXTσ) = 0, in Ω,

(7a)

χCmαBDFσu

n+1 − unBDFσ

∆t−∇ ·

(D∇un+1

)+ χIion

(un+1

EXTσ,wn+1)

= In+1app , in Ω,

(7b)

where unBDFσ =∑σ−1

i=0 αiun−i, wn

BDFσ =∑σ−1

i=0 αiwn−i, un+1

EXTσ =∑σ−1

i=0 βiun−i

and wn+1EXTσ =

∑σ−1i=0 βiw

n−i are extrapolations of order σ of solutions computedat the previous time steps, with αBDFσ, αi, βi suitable coefficients depending onthe order σ (refer to Table 4 for their specific values). Moreover, the diffusionterm is treated implicitly, whereas the ionic terms explicitly. At each time stepwe first update the gating variables wn+1 given wn

BDFσ, un+1EXTσ and wn+1

EXTσ by

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BDFσ αBDFσ α0 α1 α2 β0 β1 β2

BDF1 1 1 - - 1 - -

BDF2 3/2 2 -1/2 - 2 -1 -

BDF3 11/6 3 -3/2 1/3 3 -3 1

Table 4: Characteristic values of the considered BDFσ time discretization (withσ = 1, 2, 3) of the monodomain system (7).

means of (7a), then we solve (7b) for un+1 using un+1EXTσ and the up-to-date gating

variables wn+1. This type of time discretization leads to a conditionally stablemethod with a time step ∆t bound (independent of the space discretization)which is milder than that required to capture the propagating wave front [75,80, 83].

Regarding the space discretization, we used continuous Finite Elements (FE)on hexahedral meshes. The discretization of the ionic current term Iion isperformed following the Ionic Current Interpolation (ICI) approach [84]: first,Iion(u,w) is evaluated at each nodal points and then it is interpolated at quadra-ture nodes. The ICI method is less memory-demanding than computing Iiondirectly at quadrature nodes and it is not affected by numerical accuracy issuesat small mesh size required to capture the propagating front [46]. Finally, wesolved the linear system coming from the space discretization of (7b) with theGMRES method [85] preconditioned with the Jacobi preconditioner.

5 Numerical results

This section is dedicated to several results both for the fibers generation andthe numerical electrophysiology simulations. These have been performed bothon idealized and realistic human ventricular and atrial models. As realistic ge-ometry, we use the Zygote solid 3D heart model [86], a complete heart geometryreconstructed from high-resolution CT-scans representing an average healthyheart. Being a very detailed model of the human heart, it demonstrates theapplicability of the proposed methods to arbitrary patient-specific scenarios.

We organize the section as follows. After a brief description related to thesetting of numerical simulations (Section 5.1), we address the issue of estimatingthe parameters used in the electrophysiology simulations (Section 5.2). In Sec-tion 5.3, we show various comparisons among the three LDRBMs for ventriclesfiber generation presented in Section 2: we compare the fiber orientations andwe analyse their influence in terms of activation times computed as output of nu-merical electrophysiology simulations3. For this comparison, first we make use ofan idealized biventricular geometry built using the prolate spheroid coordinate

3The activation time of a given point in the cardiac muscle is defined as the time when thetransmembrane potential derivative du

dtreaches its maximal value.

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Figure 6: Processing pipeline applied to build a ventricles FE mesh [90]. Left:smoothing and tagging procedure; Right: FE mesh of hexahedral elements.

systems [87], and then we consider the Zygote biventricular model [86]. Section5.4 is devoted to the novel atrial LDRBM. We show fiber bundles reconstructionapplied to idealized [88] and the realistic Zygote [86] geometries. Afterwards,we investigate the influence of atrial fibers in electrophysiology simulations com-paring the fiber activation map with respect to a one obtained with an isotropicconductivity. Finally, in Section 5.5 we present an electrophysiology simulationof a realistic four chamber heart including fibers generated by LDRBMs for bothatria and ventricles.

5.1 Setting of numerical simulations

To build FE meshes, a pre-processing pipeline was applied to every ventricularand atrial geometry used in the simulations. This pipeline consists of multiplesteps including tagging, geometry smoothing and hexahedral FE mesh gener-ation. Specifically, the Vascular Modelling Toolkit vmtk software [89] (http://www.vmtk.org) together with a new meshing tool [90] were used to performthis pre-processing phase. In Figure 6 we report the former pipeline appliedto build a realistic biventricular FE mesh (for further details about the pre-processing pipeline refer to [90]).

All the LDRBMs for the ventricles (presented in Section 2), the novel atrialLDRBM (detailed in Section 3) and the numerical methods for the electrophys-iology presented in Section 4.2 have been implemented within lifex (https://lifex.gitlab.io/lifex), a new in-house high-performance C++ FE librarymainly focused on cardiac applications based on deal.II FE core [91] (https://www.dealii.org). All the numerical simulations were executed on the clus-ter iHeart (Lenovo SR950 8x24-Core Intel Xeon Platinum 8160, 2100 MHz and1.7TB RAM) at MOX, Dipartimento di Matematica, Politecnico di Milano.

To analyse the results we used ParaView (https://www.paraview.org) an

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Muscle type (ionic model) σf [mS/cm] σs[mS/cm] σn[mS/cm]

Ventricles (TTP) 1.07 0.49 0.16

Atria (CRN) 7.00 0.77 0.77

Table 5: Conductivity values σf , σs and σn obtained after the fitting procedure,displayed in Figure 7, for the ventricles (using TTP) and for the atria (usingCRN).

open-source, multi-platform data analysis and visualization application. In par-ticular, to visualize the fiber fields we applied in sequence the streamtracer

and the tube ParaView filters.

5.2 On the choice of physical and numerical parameters

We report the choices of parameters involved in the numerical approximation ofthe monodomain system (6). The latter requires the following physical data: thetransmembrane capacitance per unit area Cm, the membrane surface-to-volumeratio χ and the conductivities along the three direction of the myofibers σf , σsand σn appearing in the conductivity tensor D. The values chosen for the firsttwo quantities are Cm = 1 µF/cm2 and χ = 1400 cm−1, which are within thephysiological acceptable range of values reported in [24, 76, 92, 93].

The conductivity values σf , σs and σn were fitted by an iterative proceduredescribed in [94] (see also [23, 45]) in order to match the following conductionvelocity values: for the ventricles, 60 cm/s in the fiber direction f , 40 cm/s inthe sheet direction s and 20 cm/s in the normal direction n [45]; for the atria,120 cm/s in the fiber direction f and 40 cm/s along the sheet s and cross-fiber directions n [23]. In Figures 7(a) and 7(b) we show the results of thisfitting procedure. The estimated values for σf , σs and σn, reported in Table 5,lay within the confidence interval for the experimentally measured conductivityvalues reported in [2, 95, 96, 97, 98, 99].

Finally, to initiate the signal propagation in the cardiac muscle, the mon-odomain system (6) requires to specify the external applied current Iapp(x, t). Inthis work Iapp(x, t) represents a series of impulses (with radius 2.5 mm and du-ration 3 ms) applied in spherical subsets of the domain and prescribed alongsidethe ventricles and atria endocardium. Its amplitude is 50000 µA/cm3, for bothatria and ventricle domains, in agreement with [93]: this represents the lowestvalue allowing the electrical signal to develop. We used this value for all thesimulations performed in this work, while the stimuli locations will be specifiedfor each case reported in Sections 5.3, 5.4 and 5.5.

Regarding the mesh element size h and the time step ∆t, related to the spaceand time discretizations of the system (6), accuracy constraints are imposedwhen biophysical models (as CRN [77] and TTP [78]) are used: h = 100–500µm and ∆t = 1–50 µs [80, 83, 93]. These strong restrictions are motivated

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Figure 7: Top (a,b): Fitting procedure used to estimate the conductivity σ re-quired to match specific conduction velocity v [94]; (a): using the TTP ionicmodel to obtain 60, 40 and 20 cm/s; (b): using the CRN ionic model to ob-tain 120 and 40 cm/s. The values for σf , σs and σn are reported in Table 5.Bottom (c,d): Comparison between BDF3 and BDF1 time discretization for themonodomain system (6) in the slab benchmark problem [93]; (c): plot of theactivation time alongside the slab diagonal (displayed in black on the Right);Red: BDF1; Blue: BDF3. (d): activation time in a clipped slice of the slab forBDF3 time discretization.

mainly by the fast upstroke of cellular depolarization which produces a step-like wavefront over a small spatial extent [100]. For the space discretization,we used continuous FE of order 1 (Q1) on hexahedral meshes with an averagemesh size of h = 350 µm, an acceptable value at least for linear finite elementapproximation and for physiological cases [42, 46, 101, 102, 103]. Concerning thetime discretization, we used the BDF of order σ = 3 with a time step of ∆t = 50µs. Although, the most common time discretization used in literature for themonodomain system (6) is the BDF1 (commonly known as the backward Eulermethod), which requires a time step at most of 10 µs [83], BDF3 allows us touse a larger value of ∆t to obtain the same accuracy of BDF1. To confirm this,in Figures 7(c) and 7(d) we report a comparison between BDF3 with ∆t = 50µs and BDF1 ∆t = 10 µs on a benchmark problem proposed in [93]. BDF3

21

requires more storage than BDF1, however this extra cost is largely repaid bythe computational time saved in our simulations using a larger time step.

5.3 Ventricular fibers generation and electrophysiology

This section is dedicated to the comparison among the different fiber fields gen-erated by the three ventricular LDRBMs presented in Section 2. Moreover, wealso investigate the influence of the different fibers orientation in the activationtimes, produced by electrophysiology simulations. We perform both the analysesfirst in an idealized biventricular geometry [104] and then in the Zygote realistichuman model [86].

5.3.1 Idealized biventricular model

The first comparison among the three ventricles LDRBMs was performed on awell established idealized biventricular geometry that has been used in severalcomputational studies [18, 87, 104, 105, 106, 107] and for ventricles volumeestimation from 2D images [108]. The heart ventricles are approximated as twointersecting truncated ellipsoids.

We constructed the idealized biventricular geometry using the prolate spheroidcoordinate systems in the built-in CAD engine of gmsh, an open source 3D finiteelement mesh generator (http://gmsh.info), see Figure 8. For the details aboutthe geometrical definition of the idealized biventricular, we refer to [104, 107].

5.3.1.1 Idealized ventricles fiber generation

Fiber orientations obtained for the three LDRBMs (R-RBM, B-RBM and D-RBM) in the idealized biventricular model are shown in Figures 8(a-f). Theinput angles values αendo,`, αepi,`, αendo,r, αepi,r, βendo,`, βepi,`, βendo,r and βepi,rwere chosen for all the three methods based on the observations of histologicalstudies in the human heart [12, 29, 31, 53, 54, 109, 110] (see also [20]):

αepi,` = −60o, αendo,` = +60o, αepi,r = −25o, αendo,r = +90o;

βepi,` = +20o, βendo,` = −20o, βepi,r = +20o, βendo,r = 0o.(8)

We observe that all the LDRBMs represent the characteristic helical struc-ture of the left ventricle and a compatible fiber orientations both in the rightendocardium, not facing to the septum, and in the right epicardium, far enoughfrom the inter-ventricular junctions. Most of the differences occur in the rightventricle endocardium facing the septum (see Figures 8(a-c)) and in the inter-ventricular junctions between the two ventricles (see Figures 8(d-f)). Indeed,as expected by construction of the methods, for R-RBM the fibers in the wholeseptum belong to the left ventricle, while in B-RBM and D-RBM they are sharedbetween the two ventricles. In particular, for B-RBM the septum is equally split-ted between the two ventricles, while D-RBM associates two-third of septum to

22

Figure 8: Comparison among LDRBMs in the idealized biventricular model.Streamlines of the vector f is depicted for R-RBM (a,d), B-RBM (b,e) and D-RBM (c,f). Top: Frontal view (dashed box highlights the differences among thethree LDRBMs in the septal region); Centre: apex view; Bottom: Differencesdiffi,j among the three LDRBMs, diffR,B (g), diffR,D (h) and diffD,B (i); onlyvalues diffi,j ≥ 0.25 are displayed.

the left ventricle and one third to the right one. As a consequence, only for B-RBM and D-RBM the fibers direction is preserved in all the right endocardium,see Figures 8(a), 8(b) and 8(c). In the inter-ventricular junctions, both R-RBMand B-RBM exhibit a smooth transition passing from left to right ventricle (seeFigures 8(c) and 8(d)), while in D-RBM there is an abrupt change in the fiberdirections (see Figure 8(e)). Moreover, in D-RBM it is possible to see the fibers

23

Figure 9: Top: Activation time for R-RBM (a), B-RBM (b) and D-RBM (c)in the idealized biventricular model. Bottom: Absolute difference among theactivation maps, ∆AR,B (d), ∆AR,D (e) and ∆AD,B (f).

winding around the right ventricle apex (see Figure 8(e)). This feature is notpresent in the R-RBM and B-RBM, see Figures 8(c) and 8(d). All the aforemen-tioned discrepancies are caused by the different transmural and normal directiondefinitions of the three LDRBMs (explained in detail in Section 2).

We computed the difference diffi,j of the fiber field f among the three meth-ods, defined as:

diffi,j(x) = 1− |f i(x) · f j(x)| i, j = R,B,D (i 6= j), (9)

where fR, fB and fD are the vector fiber fields of R-RBM, B-RBM and D-RBM,respectively. If f i and f j are parallel, diffi,j = 0, otherwise, when orthogonal,diffi,j = 1. The result of these comparisons is reported in Figures 8(g), 8(h)and 8(i). As expected, most of the discrepancies are in the septum and in theinter-ventricular junctions.

5.3.1.2 Idealized ventricles electrophysiology

In order to evaluate the influence of the three LDRBMs fiber architectures inthe electric signal propagation through the cardiac muscle, we performed three

24

electrophysiology simulations (with the setting detailed in Section 5.2), one foreach LDRBM. To initiate the action potential propagation we applied four en-docardial stimuli: two for each ventricle, one in the mid-septal zone and onein the posterior endocardium. In Figures 9(a-c) we report the activation mapsobtained with the three fibers configurations. The activation pattern for all thethree methods are very similar in the left and right ventricles, while most ofthe differences are visible in the septum, see Figures 9(a), 9(b) and 9(c). Wecomputed also the absolute difference ∆Ai,j(x) in the activation pattern amongthe different methods as:

∆Ai,j(x) = |Ai(x)−Aj(x)| i, j = R,B,D (i 6= j), (10)

where AR, AB and AD are the activation times for R-RBM, B-RBM and D-RBM,respectively (see Figures 9(d), 9(e) and 9(f)).

The most remarkable differences in both ∆AR,B and ∆AR,D are exhibited inthe septum, particularly in the part facing the right endocardium, while ∆AB,D

never exceeds 15 ms, see Figures 9(d), 9(e) and 9(f). Also in the activation maps,as aspected, we retrieve differences in the septum zone caused by the differentfibers definition on that region made by the three methods, as seen in the fiberscomparison, see Figures 8.

Finally, we evaluated the maximal discrepancies, Mi,j = maxx∈Ωmyo ∆Ai,j(x),among the three methods, which are:

MR,B = 35 ms, MR,D = 33 ms, MB,D = 15 ms.

The location of both MR,B and MR,D is in the lower part of the right ventricleseptum, while MB,D is placed in the lower anterior region of the left ventricle, seeFigures 9(d), 9(e) and 9(f). Considering a total activation time of about Amax =120 ms for the all biventricular muscle, the maximum relative differences, M%

i,j =Mi,j/Amax, among the three ventricle LDRBMs are

M%R,B = 29%, M%

R,D = 28%, M%B,D = 13%.

5.3.2 Realistic full biventricular model

The second comparison among the ventricular LDRBMs was performed on a re-alistic full biventricular geometry. For this purpose, we used the Zygote solid 3Dheart model [86]. In order to obtain a smooth endocardium in both ventricles,we removed all the papillary muscles and the trabeculae carneae, using the CADmodeller SolidWorks (https://www.solidworks.com) in combination with thesoftware Meshmixer (http://www.meshmixer.com), see Figure 10. Consideringthe characteristics of the electrical signal propagation, and the anatomical con-stituents of the valvular and sub-valvular apparatus, we expect our calculationsshould not be substantially influenced by the papillary muscles elimination.

According to the motivations highlighted at the end of Section 2, we per-formed a comparison in the full biventricular model only between B-RBM andD-RBM.

25

Figure 10: Comparison for B-RBM and D-RBM in a realistic full biventricularmodel. Top (a-c): B-RBM. Centre (d-f): D-RBM. Bottom (g-i): differencesbetween B-RBM and D-RBM. Streamlines of the vector f : top (a,d) and lateralviews (b,e). Difference in the fiber orientations diffD,B (g,h), only the valuesdiffi,j ≥ 0.25 are displayed. Activation maps using B-RBM and D-RBM: B-RBM (c) and D-RBM (f). Absolute difference among B-RBM and D-RBMactivation maps, ∆AD,B (i).

5.3.2.1 Realistic ventricles fibers generation

Fiber orientation for B-RBM and D-RBM in the Zygote full biventricle aredisplayed in Figures 10(a-b) and 10(d-e). We prescribed the same input anglevalues used for the ideal geometry, reported in (8). Moreover, for D-RBM we

26

have also specified the angles in the OT regions as follows [20]:

αepi,OT = 0o, αendo,OT = +90o, βepi,OT = 0o, βendo,OT = 0o. (11)

The two LDRBMs well reproduce the helical structure of the left ventricle upto the mitral valve ring and exhibit a similar fiber orientation pattern in wholecardiac muscle, apart from the region between the tricuspid, the pulmonary andthe aortic valve rings and far enough from the inter-ventricular junctions, seeFigures 10(a-b) and 10(d-e). B-RBM presents a roll up in the fiber directionsjust after the aortic valve ring, while D-RBM has a more longitudinal fiberorientations in that region, see Figure 10(a) and 10(d). As also observed inthe idealized case, the B-RBM fiber field in the inter-ventricular junctions hasa smooth change passing from the left to the right ventricle, whereas D-RBMproduces a strong discontinuity in the transition across the two ventricles, seeFigure 10(b) and 10(e).

We evaluated the mismatch of the fiber fields diffD,B, defined in (9), betweenB-RBM and D-RBM. Also in this case, the discrepancies are caused by thedifferent transmural and normal direction definitions of the two methods (asdetailed in Section 2). Indeed, diffD,B highlights the most relevant differences ofthe two methods in the septum, in the inter-ventricular junctions, in the regionsof tricuspid, pulmonary and aortic valve rings and around the right ventricleapex, see Figures 10(g) and 10(h).

5.3.2.2 Realistic ventricles electrophysiology

We performed two electrophysiology simulations (with the setting detailed inSection 5.2), one with B-RBM and one with D-RBM. Two stimuli were applied toeach ventricle: one in the mid-septal zone and one in the posterior endocardium.Figures 10(c) and 10(f) depict the computed activation times which result verysimilar in the whole myocardium. Figure 10(i) shows the absolute differencebetween the two activation maps, ∆AD,B(x) = |AD(x)−AB(x)|, where AB andAD are the activation times for B-RBM and D-RBM, respectively. We observesome discrepancies in the activation pattern near the tricuspid, the aortic and thepulmonary valve rings, and also in the endocardium near the right ventricle apex,although ∆AD,B never exceeds the value 14 ms, see Figure 10(i). The maximalrelative discrepancy among the two methods is MD,B = maxx∈Ωmyo ∆AD,B(x) =

14 ms, corresponding to M%D,B = MD,B/Amax = 10 %, with Amax = 140 ms

the total activation time. The location of MD,B is in the lower part of theendocardium just above the right ventricle apex, see Figure 10(i).

5.4 Atrial fibers generation and electrophysiology

We applied our new atrial LDRBM (presented in Section 3) to reconstruct leftand right atria fiber architecture, first in idealized geometries [88] and thenin realistic ones [86]. We analysed the influence of atrial fiber bundles in the

27

electric signal propagation by means of electrophysiology simulations performedon realistic geometries. Finally, we studied how a change in size of a singlebundle affects the total activation sequence.

5.4.1 Atrial fibers generation

We began applying the novel atrial LDRBM on idealized geometries. To con-struct them, we started by the surface representations of the right and leftatrium generated as separated NURBS patches, as reported in [88, 111]. Foreach atrium, we created the corresponding triangular mesh using the construc-tive geometry module of Netgen (https://ngsolve.org). We considered thistriangular mesh as the endocardium of our 3D model. To generate the atriaepicardium we extruded (using the vmtk software [89]) the endocardial surfaceby 2 mm, which correspond to an average thickness of the atrial wall [16, 112].Finally, we produced 3D tagged hexahedral mesh following the preprocessingpipeline described in Section 5.1, and then we applied our atrial LDRBM, seeFigures 11(a-d).

Afterwards, we treated the case of realistic left and right atria taken fromthe Zygote 3D heart model [86]. Figures 11(e-h) show the corresponding fibersgenerated by our atrial LDRBM.

LA τavr τlpv τrpv RA τavr τicv τscv τct+ τct− τfw τsw τr

Ideal 0.65 0.65 0.10 Ideal 0.90 0.90 0.10 -0.10 -0.18 0.01 0.135 0.55Real 0.85 0.85 0.20 Real 0.90 0.85 0.30 -0.55 -0.60 -0.25 -0.10 0.60

Table 6: Bundles parameters used for fibers generation in the idealized (Ideal)and realistic (Real) LA and RA.

The input values of the parameters τi, which define the bundles dimensionof the atrial LDRBM, are reported in Table 6. We observe that the atrialLDRBM qualitatively capture the complex arrangement of fiber directions inalmost all the principal anatomical atrial regions (see Figure 11): in the rightatrium (RA), superior (SCV) and inferior caval veins (ICV), tricuspid valve ring(TV), right appendage (RAA), septum (RAS), inter-caval bundle (IB), cristaterminalis (CT), isthmus (IST) and later wall (RAW); for the left atrium (LA),left (LPV) and right pulmonary veins (RPV), mitral valve ring (MV), left ap-pendage (LAA), septum (LAS), septum wall (LSW), lateral wall (LAW) androof (LAR).

Circular fiber arrangements are exhibited around LPV, RPV, SCV, ICV,TV, MV, and encircle both appendages (RAA and LAA), see Figures 11(a-d)and 11(e-g). Fibers direction of CT runs longitudinally from the base of theSCV to the ICV, see Figures 11(d) and 11(h). RA structures like the IB andRAW are almost vertically oriented, whereas those of RAS are parallel to theCT, see Figures 11(c-d) and 11(g-h). IST fibers have the same direction of those

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Figure 11: Atrial LDRBM fiber generation applied to idealized (a-d) and realistic(e-h) atria models. Frontal (a,c,e,g) and dorsal (b,d,f,h) views of the atria. SCV,ICV: superior and inferior caval veins; LPV, RPV: left and right pulmonaryveins; TV, MV: tricuspid and mitral valve rings; RAA, LAA: right and leftappendage; RAS, LAS: right and left septum; RAW, LAW: right and left laterwall; LSW: left septum wall; LAR: left atrial roof; IB: inter-caval bundle; CT:crista terminalis; IST: isthmus.

of the TV, see Figures 11(d) and 11(h). The LAS fibers are aligned with theadjacent region of RAS, see Figures 11(a) and 11(e). Directions of the LAR andLAW descend perpendicularly to MV (Figures 11(b) and 11(f)), while fibers ofLSW present a smooth transition going to the LAS and LAA (Figures 11(a)and 11(e)). We observed that these behaviours of atrial fibers direction showeda good agreement with histological studies [64, 65, 8, 113] and other publishedRBMs [16, 21, 27, 23, 35, 114].

5.4.2 Atrial electrophysiology

In order to analyse the influence of atrial fiber bundles in the electric signal prop-agation we performed several electrophysiological simulations (with the settingspecified in Section 5.1) on the realistic Zygote atrial geometries.

Firstly, we made a comparison with an isotropic model. For the atrialLDRBM, we considered the parameters detailed in Table 6, while the isotropicsimulations were carried out by setting in (5) σf = σs = σn = 7.0 mS/cm, that isa representative value chosen for the conductivity along the atrial fiber direction,see Table 5. To initiate the signal propagation in the RA we applied a single

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Figure 12: Comparison between the activation maps of electrophysiology sim-ulations performed with the atrial LDRBM fiber generation and the isotropicmodel. Left (a,d): Fibers simulation; Centre (b,e): Isotropic simulation. Right(c,f): absolute difference ∆AiF,I in the activation times for LA (i = `) and RA(i = r). Top (a,b,c): LA; Bottom (d,e,f): RA.

Figure 13: Comparison between electrophysiology simulations with different val-ues of τavr in the atrial LDRBM fiber generation for the Zygote LA. Left (a):τavr = 0.65; Centre (b): τavr = 0.85; Right (c): absolute difference ∆A.

stimulus in the Sino-Atrial-Node (SAN) which lies in the musculature of CT atthe anterolateral junction with the SCV [65]. For the LA we stimulated the maininter-atrial connections: the Bachman’s Bundle (BB), located in the LSW; the

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upper part of the Fossa Ovalis (FO) in the centre of LAS; the Coronary SinusMusculature limbs (CSM) placed at the bottom of LAW [115]. Activation of FOand CSM was delayed, with respect to the BB stimulus, by 14 ms and 52 ms,respectively.

Figure 12 displays the results of the comparison among simulations performedwith the atrial LDRBM fibers and the isotropic model for both the RA and LA.Both the activation pattern and activation time present significant differences.To provide a quantification, we computed the absolute difference ∆AiF,I in theactivation time:

∆AiF,I(x) = |AiF(x)−AiI(x)| i = r, `, (12)

where i = r, ` refer to LA (i = `) and RA (i = r) and AiF and AiI arethe activation times obtained by the simulations with and without fibers, re-spectively. Most of the differences occur at LPV and LAA for LA, and atRAA and TV for RA. Finally, we computed the maximal discrepancy, M i

F,I =

maxx∈Ωatrial ∆AiF,I(x), i = `, r:

M `F,I = 60 ms (52 %), M r

F,I = 48 ms (44 %),

where in brackets we reported the relative values computed as M iF,I/A

imax, with

A`max = 116 ms and Armax = 108 ms the total activation times. For RA M rF,I is

placed in RAA, while for LA M `F,I is located in LPV.

Then, we investigated how a local change in a single LA bundle (the atri-oventricular one) affects the total activation pattern. We performed two elec-trophysiology simulations with the same fiber setting used for the comparisonwith an isotropic model, except for the value of τavr, which was set equal to 0.65and 0.85. Figures 13(a-b) depict the corresponding generated fibers: notice thatwith τavr = 0.65 the avr-bundle is thicker with respect to the one obtained withτavr = 0.85, see Figures 13(a-b). We also reported the absolute difference in thecomputed activation times for the two fiber architectures, see Figure 13(c). Themaximal discrepancy, located in the LAA, is of 28 ms which corresponds to 24%of the total activation time for the LA (116 ms).

5.5 Whole heart fibers and electrophysiology

In this section we present the whole heart fiber generation, using LDRBMs forboth atria and ventricles. Moreover, we show an electrophysiology simulation us-ing physiological activation sites and including the fiber generated by LDRBMs.We use the Zygote heart model [86] both for the full biventricle and the atriageometries introduced in Sections 5.3.2 and 5.4, respectively.

5.5.1 Whole heart fibers

For the fibers generation, we adopted D-RBM [20] (see Section 2) for the ventri-cles, with the same setting of Section 5.3.2, and the proposed LDRBM for the

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Figure 14: Left (a): Fiber generation applied to realistic Zygote Heart model;LDRBM by Doste (D-RBM) was applied to reconstruct the ventricles fibers onΩmyo, while the atrial LDRBM was employed for the atria fiber architectureon Ωra and Ωla. Centre (b): Stimuli applied in the four chamber model tomimic the Cardiac Conduction System (CCS) pathway; SAN: Sino-Atrial Node;BB: Bachmann’s Bundle; FO: Fossa Ovalis; CSM: Coronary Sinus Musculature;AVN: Atrio-Ventricular Node; AL: Left Anterior; PL: Left Posterior; SL, SR:Left and Right Septum; ER: Right Endocardium. Right (c): activation mapscomputed from the electrophysiology simulation.

atria (see Section 3), with the configuration of Section 5.4 (see also Table 6).Figure 14(a) displays the heart geometry equipped with the prescribed LDRBMsfibers.

5.5.2 Whole heart electrophysiology

To model the electrophysiology activity in the cardiac tissue we used the mon-odomain equation endowed with the TTP and CRN ionic models for the ventri-cles and for the atria, respectively, with the settings described in Section 5.1.

The interactions among atria and ventricles are based on the following as-sumptions on the cardiac conductions system (CCS) connections, showed inFigure 14(b). The ventricles are electrically isolated from the atria by the atri-oventricular grooves [116]; the atria are electrically separated by the insulatingnature of the atrial septum (dividing RA from LA) apart from muscular con-tinuity at the rim of Fossa Ovalis [65]. The CCS pathway was modelled asa series of spherical delayed stimuli along the heart geometry that mimic theinter-atrial connections, the atrio-ventricular node delay and the main area ofventricles electrical activation: specifically, when the transmembrane potentialfront reaches these points a stimulus current is triggered, see Figure 14(b).

The CCS electric signal originates at the Sino-Atrial Node (SAN, t = 0 ms)and travels from RA to LA through three inter-atrial connections, the Bach-

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Figure 15: Evolution of the transmembrane potentials for the ventricles uV andfor the atria uA in the Zygote heart model during a cardiac cycle.

mann’s Bundle (BB, t = 28 ms), the rim of Fossa Ovalis (FO, t = 42 ms)and the Coronary Sinus Musculature (CSM, t = 80 ms) [65, 115]. When theelectric signal reaches the Atrio-Ventricular Node (AVN), located at the lowerback section of the inter-atrial septum near the coronary sinus opening, it issubject to a delay (90 ms) that allows the complete activation of the atria beforeventricles electric propagation starts [65]. Finally, ventricle endocardial areasare activated: in the anterior para-septal wall (AL), in the left surface of inter-ventricular septum (SL) and in the bottom of postero-basal area (PL), for theleft ventricle (t = 160 ms); in the septum (SR) and in the free endocardial wall(ER), for the right ventricle (t = 165 ms) [117].

Figure 14(c) depicts the activation maps computed by the heart electrophys-iology simulation. We obtained a physiologically compatible timing for the heartactivation [46, 75, 76]: the complete atria depolarization occurs after about 120ms, while that of ventricles after about t = 270 ms. The last region to be acti-vated is LAA for the atria, while the postero-basal area of the right ventricle forthe ventricles, both in accordance with [115, 117].

The transmembrane potentials evolution for the ventricles uV and for theatria uA are shown in Figure 15. As expected, the electric signal initiates at theSAN and spreads from right to left atrium, see Figures 15(a) and 15(b). Then,

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after the delay at the AVN, the ventricles start to activate, see Figure 15(c). Theatria repolarization arises during ventricles depolarization, see Figures 15(c-e).Finally, after the isoelectric ventricles activity, the whole heart return to thedepolarized initial configuration, see Figure 15(f).

6 Conclusions

In this work, we provided a unified framework for generating cardiac musclefibers in a full heart computational domain. This allowed us to obtain physi-cally meaningful electrophysiology simulations of a four chambers heart realisticdomain.

We first reviewed three existing LDRBMs for fibers generation in the ven-tricles (R-RBM, B-RBM, D-RBM), by means of a unified description. We pro-posed some extensions that allow to include different fiber orientations for leftand right ventricle for R-RBM and B-RBM, the rotation of all the myofibersvectors for R-RBM and fibers generation up to cardiac valve rings for B-RBM.By comparing the three methods, we found that most of the differences are inthe right ventricle endocardium, in the septum, in the inter-ventricular junctionsand in the region between the valve rings. We also performed electrophysiologysimulations which highlighted that most of the differences occur at the septum,particularly in that part facing the right endocardium. This proved the impor-tance to include a different fiber orientation in the right ventricle with respectto the left one.

We proposed a novel LDRBM to be used for generating atrial fibers andwe applied it to both idealized and realistic geometries showing that the atrialLDRBM capture the complex arrangement of fiber directions in almost all theanatomical atrial regions. We analysed the influence of atria fiber bundles bymeans of electrophysiological simulations in a realistic geometry, verifying thestrong effect of their complex architecture in the electric signal propagation.

Finally, we presented an electrophysiology simulation of a realistic four cham-ber heart including fibers generated by LDRBMs for both atria and ventricles.

We remark that the proposed novel fibers generation methodology, basedon LDRBMs, is computationally inexpensive, efficient and easy to implement;moreover, it allows to include realistic cardiac muscle fibers architecture on wholeheart geometries of arbitrary shape. As a consequence, it is possible to generatepatient cohorts heart fibers, fed by input parameters inferred from histology orDTI studies, through an automated and computationally efficient pipeline. Weconsider the proposed methodology as an important contribution to incorporatepatient specific whole heart fiber field into electrophysiology and electromechan-ics simulations, aimed both to study clinical cases and to investigate medicalquestions.

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Acknowledgements

This project has received funding from the European Research Council (ERC)under the European Union’s Horizon 2020 research and innovation programme(grant agreement No 740132, iHEART - An Integrated Heart Model for thesimulation of the cardiac function, P.I. Prof. A. Quarteroni).

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MOX-Report No. 29/2020

Modeling cardiac muscle bers in ventricular and atrialelectrophysiology simulations

Piersanti, R.; Africa, P.C.; Fedele, M.; Vergara, C.; Dede', L.;

Corno, A.F.; Quarteroni, A.

MOX, Dipartimento di Matematica Politecnico di Milano, Via Bonardi 9 - 20133 Milano (Italy)

mox-dmat@polimi.it http://mox.polimi.it