Transmural APD heterogeneity determines ventricular arrhythmogenesis in LQT8 syndrome: Insights from Bidomain computational modeling.

Long QT Syndrome type 8 (LQT8) is a cardiac arrhythmic disorder associated with Timothy Syndrome, stemming from mutations in the CACNA1C gene, particularly the G406R mutation. While prior studies hint at CACNA1C mutations' role in ventricular arrhythmia genesis, the mechanisms, especially in G406R presence, are not fully understood. This computational study explores how the G406R mutation, causing increased transmural dispersion of repolarization, induces and sustains reentrant ventricular arrhythmias. Using three-dimensional numerical simulations on an idealized left-ventricular model, integrating the Bidomain equations with the ten Tusscher-Panfilov ionic model, we observe that G406R mutation with 11% and 50% heterozygosis significantly increases transmural dispersion of repolarization. During S1-S4 stimulation protocols, these gradients facilitate conduction blocks, triggering reentrant ventricular tachycardia. Sustained reentry pathways occur only with G406R mutation at 50% heterozygosis, while neglecting transmural heterogeneities of action potential duration prevents stable reentry, regardless of G406R mutation presence.

Epicardial Dispersion of Repolarization Promotes the Onset of Reentry in Brugada Syndrome: A Numerical Simulation Study.

The Brugada syndrome (BrS) is a cardiac arrhythmic disorder responsible for sudden cardiac death associated with the onset of ventricular arrhythmias, such as reentrant ventricular tachycardia and fibrillation. The mechanisms which lead to the onset of such electrical disorders in patients affected by BrS are not completely understood, yet. The aim of the present study is to investigate by means of numerical simulations the electrophysiological mechanisms at the basis of the morphology of electrocardiogram (ECG) and the onset of reentry associated with BrS. To this end, we consider the Bidomain equations coupled with the ten Tusscher-Panfilov membrane model, on an idealized wedge of human right ventricular tissue. The results have shown that: (1) epicardial dispersion of repolarization, generated by the coexistence of regions of early and late repolarization, due to different modulation of the [Formula: see text] current, produces ECG waveforms exhibiting qualitatively the typical BrS morphology, characterized by ST elevation and partially negative T-waves; (2) epicardial dispersion of repolarization promotes the onset of reentry during the implementation of the programmed stimulation protocol, because of the conduction block occurring when a premature beat reaches the border of late repolarizing regions; and (3) the modulation of the [Formula: see text] current affects the duration of reentry, which becomes sustained with a remarkable increase of [Formula: see text] in the subepicardial layers.

Unexpected impairment of INa underpins reentrant arrhythmias in a knock-in swine model of Timothy syndrome.

Timothy syndrome 1 (TS1) is a multi-organ form of long QT syndrome associated with life-threatening cardiac arrhythmias, the organ-level dynamics of which remain unclear. In this study, we developed and characterized a novel porcine model of TS1 carrying the causative p.Gly406Arg mutation in CACNA1C, known to impair CaV1.2 channel inactivation. Our model fully recapitulated the human disease with prolonged QT interval and arrhythmic mortality. Electroanatomical mapping revealed the presence of a functional substrate vulnerable to reentry, stemming from an unforeseen constitutional slowing of cardiac activation. This signature substrate of TS1 was reliably identified using the reentry vulnerability index, which, we further demonstrate, can be used as a benchmark for assessing treatment efficacy, as shown by testing of multiple clinical and preclinical anti-arrhythmic compounds. Notably, in vitro experiments showed that TS1 cardiomyocytes display Ca2+ overload and decreased peak INa current, providing a rationale for the arrhythmogenic slowing of impulse propagation in vivo.

Role of Scar and Border Zone Geometry on the Genesis and Maintenance of Re-Entrant Ventricular Tachycardia in Patients With Previous Myocardial Infarction.

In patients with healed myocardial infarction, the left ventricular ejection fraction is characterized by low sensitivity and specificity in the prediction of future malignant arrhythmias. Thus, there is the need for new parameters in daily practice to perform arrhythmic risk stratification. The aim of this study is to identify some features of proarrhythmic geometric configurations of scars and border zones (BZ), by means of numerical simulations based on left ventricular models derived from post myocardial infarction patients. Two patients with similar clinical characteristics were included in this study. Both patients exhibited left ventricular scars characterized by subendo- and subepicardial BZ and a transmural BZ isthmus. The scar of patient #1 was significantly larger than that of patient #2, whereas the transmural BZ isthmus and the subdendo- and subepicardial BZs of patient #2 were thicker than those of patient #1. Patient #1 was positive at electrophysiologic testing, whereas patient #2 was negative. Based on the cardiac magnetic resonance (CMR) data, we developed a geometric model of the left ventricles of the two patients, taking into account the position, extent, and topological features of scars and BZ. The numerical simulations were based on the anisotropic monodomain model of electrocardiology. In the model of patient #1, sustained ventricular tachycardia (VT) was inducible by an S2 stimulus delivered at any of the six stimulation sites considered, while in the model of patient #2 we were not able to induce sustained VT. In the model of patient #1, making the subendo- and subepicardial BZs as thick as those of patient #2 did not affect the inducibility and maintenance of VT. On the other hand, in the model of patient #2, making the subendo- and subepicardial BZs as thin as those of patient #1 yielded sustained VT. In conclusion, the results show that the numerical simulations have an effective predictive capability in discriminating patients at high arrhythmic risk. The extent of the infarct scar and the presence of transmural BZ isthmuses and thin subendo- and subepicardial BZs promote sustained VT.

Prevention and control of OQDS (olive quick decline syndrome) outbreaks caused by Xylella fastidiosa.

In Southern Italy, since 2013, there has been an ongoing Olive Quick Decline Syndrome (OQDS) outbreak, due to the bacterium Xylella fastidiosa, which has caused a dramatic impact from both socio-economic and environmental points of view. The main players involved in OQDS are represented by the insect vector, Philaenus spumarius, its host plants (olive trees and weeds) and the bacterium, X. fastidiosa. Current agronomic practices are mainly based on uprooting the sick olive trees and their surrounding ones, with later installment of olive cultivars more resistant to the bacterium infection. Unfortunately, both of these practices are having an undesirable impact on the environment (most of these olive trees were monumental ones) and on the economy. Based on a mathematical model expressed in terms of a nontrivial system of ordinary differential equations, our analysis has provided a clear picture of all possible steady states (feasible equilibria) and their stability properties, corresponding to a variety of different parameter scenarios; all of this has been illustrated by a set of computational experiments. A significant original contribution of this paper is the proof of the global asymptotic stability of each of the feasible equilibria under its existence assumptions, a fact that excludes multiple equilibria under the given conditions. It has emerged that the removal of a suitable amount of weed biomass (host plants of the juvenile stages of the insect vector of X. fastidiosa) from olive orchards and surrounding areas leads to the eradication of the epidemic, without requiring neither the removal nor the substitution of the existing olive trees.

Cardiac electro-mechanical activity in a deforming human cardiac tissue: modeling, existence-uniqueness, finite element computation and application to multiple ischemic disease.

In this study, the cardiac electro-mechanical model in a deforming domain is taken with the addition of mechanical feedback and stretch-activated channel current coupled with the ten Tusscher human ventricular cell level model that results in a coupled PDE-ODE system. The existence and uniqueness of such a coupled system in a deforming domain is proved. At first, the existence of a solution is proved in the deformed domain. The local existence of the solution is proved using the regularization and the Faedo-Galerkin technique. Then, the global existence is proved using the energy estimates in appropriate Banach spaces, Gronwall lemma, and the compactness procedure. The existence of the solution in an undeformed domain is proved using the lower semi-continuity of the norms. Uniqueness is proved using Young's inequality, Gronwall lemma, and the Cauchy-Schwartz inequality. For the application purpose, this model is applied to understand the electro-mechanical activity in ischemic cardiac tissue. It also takes care of the development of active tension, conductive, convective, and ionic feedback. The Second Piola-Kirchoff stress tensor arising in Lagrangian mapping between reference and moving frames is taken as a combination of active, passive, and volumetric components. We investigated the effect of varying strength of hyperkalemia and hypoxia, in the ischemic subregions of human cardiac tissue with local multiple ischemic subregions, on the electro-mechanical activity of healthy and ischemic zones. This system is solved numerically using the [Formula: see text] finite element method in space and the implicit-explicit Euler method in time. Discontinuities arising with the modeled multiple ischemic regions are treated to the desired order of accuracy by a simple regularization technique using the interpolating polynomials. We examined the cardiac electro-mechanical activity for several cases in multiple hyperkalemic and hypoxic human cardiac tissue. We concluded that local multiple ischemic subregions severely affect the cardiac electro-mechanical activity more, in terms of action potential (v) and mechanical parameters, intracellular calcium ion concentration [Formula: see text], active tension ([Formula: see text]), stretch ([Formula: see text]) and stretch rate ([Formula: see text]), of a healthy cell in its vicinity, compared to a single Hyperkalemic or Hypoxic subregion. The four moderate hypoxically generated ischemic subregions affect the waveform of the stretch along the fiber and the stretch rate more than a single severe ischemic subregion.

Controlling the Spatial Spread of a Xylella Epidemic.

In a recent paper by one of the authors and collaborators, motivated by the Olive Quick Decline Syndrome (OQDS) outbreak, which has been ongoing in Southern Italy since 2013, a simple epidemiological model describing this epidemic was presented. Beside the bacterium Xylella fastidiosa, the main players considered in the model are its insect vectors, Philaenus spumarius, and the host plants (olive trees and weeds) of the insects and of the bacterium. The model was based on a system of ordinary differential equations, the analysis of which provided interesting results about possible equilibria of the epidemic system and guidelines for its numerical simulations. Although the model presented there was mathematically rather simplified, its analysis has highlighted threshold parameters that could be the target of control strategies within an integrated pest management framework, not requiring the removal of the productive resource represented by the olive trees. Indeed, numerical simulations support the outcomes of the mathematical analysis, according to which the removal of a suitable amount of weed biomass (reservoir of Xylella fastidiosa) from olive orchards and surrounding areas resulted in the most efficient strategy to control the spread of the OQDS. In addition, as expected, the adoption of more resistant olive tree cultivars has been shown to be a good strategy, though less cost-effective, in controlling the pathogen. In this paper for a more realistic description and a clearer interpretation of the proposed control measures, a spatial structure of the epidemic system has been included, but, in order to keep mathematical technicalities to a minimum, only two players have been described in a dynamical way, trees and insects, while the weed biomass is taken to be a given quantity. The control measures have been introduced only on a subregion of the whole habitat, in order to contain costs of intervention. We show that such a practice can lead to the eradication of an epidemic outbreak. Numerical simulations confirm both the results of the previous paper and the theoretical results of the model with a spatial structure, though subject to regional control only.

Numerical evaluation of cardiac mechanical markers as estimators of the electrical activation time.

Recent advances in the development of noninvasive cardiac imaging technologies have made it possible to measure longitudinal and circumferential strains at a high spatial resolution also at intramural level. Local mechanical activation times derived from these strains can be used as noninvasive estimates of electrical activation, in order to determine, eg, the origin of premature ectopic beats during focal arrhythmias or the pathway of reentrant circuits. The aim of this work is to assess the reliability of mechanical activation time markers derived from longitudinal and circumferential strains, denoted by ATell and ATecc , respectively, by means of three-dimensional cardiac electromechanical simulations. These markers are compared against the electrical activation time (ATv ), computed from the action potential waveform, and the reference mechanical activation markers derived from the active tension and fiber strain waveforms, denoted by ATta and ATeff , respectively. Our numerical simulations are based on a strongly coupled electromechanical model, including bidomain representation of the cardiac tissue, mechanoelectric (ie, stretch-activated channels) and geometric feedbacks, transversely isotropic strain energy function for the description of passive mechanics and detailed membrane and excitation-contraction coupling models. The results have shown that, during endocardial and epicardial ectopic stimulations, all the mechanical markers considered are highly correlated with ATv , exhibiting correlation coefficients larger than 0.8. However, during multiple endocardial stimulations, mimicking the ventricular sinus rhythm, the mechanical markers are less correlated with the electrical activation time, because of the more complex resulting excitation sequence. Moreover, the inspection of the endocardial and epicardial isochrones has shown that the ATell and ATecc mechanical activation sequences reproduce only some qualitative features of the electrical activation sequence, such as the areas of early and late activation, but in some cases, they might yield wrong excitation sources and significantly different isochrones patterns.

Electromechanical effects of concentric hypertrophy on the left ventricle: A simulation study.

In this work, we analyze the way concentric hypertrophy, triggered by mild aortic stenosis, affects the electromechanical activity of the left ventricle during a cardiac cycle by employing a 3D finite-element strongly-coupled model. Three mechanical feedbacks on electrophysiology are considered: the conduction feedback, acting on conductivity tensors, the convection feedback, dependent on the deformation rate, and the mechanoelectric feedback due to stretch-activated membrane channels. In case of a multiple endocardial electrical stimulation for a healthy ventricle, the convection feedback raises the values of action potential duration APD while modifying the corresponding distribution patterns, mainly in the latest activated regions. Hypertrophy stresses the latter effect. If an endocardial ectopic stimulation is applied to the healthy ventricle, the convection feedback enhances its effects on APD (by increasing the corresponding dispersion too), especially on the opposite side with respect to the stimulation site; the mechanoelectric feedback reduces APD values on the midmyocardium instead. By including all feedbacks, it turns out that the hypertrophic ventricle exhibits lower values and a modified epicardial pattern of APD if compared with the healthy and stenotic (without growth) ventricles, but its transmural dispersion of repolarization does not increase and its epicardial electrograms have the same morphological features. Despite a decrease of the end-diastolic volume, hypertrophy compensates for the stenotic increase of the end-systolic volume and of the internal pressure during the efflux phase, while normalizing stroke work.

A Numerical Study of Scalable Cardiac Electro-Mechanical Solvers on HPC Architectures.

We introduce and study some scalable domain decomposition preconditioners for cardiac electro-mechanical 3D simulations on parallel HPC (High Performance Computing) architectures. The electro-mechanical model of the cardiac tissue is composed of four coupled sub-models: (1) the static finite elasticity equations for the transversely isotropic deformation of the cardiac tissue; (2) the active tension model describing the dynamics of the intracellular calcium, cross-bridge binding and myofilament tension; (3) the anisotropic Bidomain model describing the evolution of the intra- and extra-cellular potentials in the deforming cardiac tissue; and (4) the ionic membrane model describing the dynamics of ionic currents, gating variables, ionic concentrations and stretch-activated channels. This strongly coupled electro-mechanical model is discretized in time with a splitting semi-implicit technique and in space with isoparametric finite elements. The resulting scalable parallel solver is based on Multilevel Additive Schwarz preconditioners for the solution of the Bidomain system and on BDDC preconditioned Newton-Krylov solvers for the non-linear finite elasticity system. The results of several 3D parallel simulations show the scalability of both linear and non-linear solvers and their application to the study of both physiological excitation-contraction cardiac dynamics and re-entrant waves in the presence of different mechano-electrical feedbacks.

Cardiac kinematic parameters computed from video of in situ beating heart.

Mechanical function of the heart during open-chest cardiac surgery is exclusively monitored by echocardiographic techniques. However, little is known about local kinematics, particularly for the reperfused regions after ischemic events. We report a novel imaging modality, which extracts local and global kinematic parameters from videos of in situ beating hearts, displaying live video cardiograms of the contraction events. A custom algorithm tracked the movement of a video marker positioned ad hoc onto a selected area and analyzed, during the entire recording, the contraction trajectory, displacement, velocity, acceleration, kinetic energy and force. Moreover, global epicardial velocity and vorticity were analyzed by means of Particle Image Velocimetry tool. We validated our new technique by i) computational modeling of cardiac ischemia, ii) video recordings of ischemic/reperfused rat hearts, iii) videos of beating human hearts before and after coronary artery bypass graft, and iv) local Frank-Starling effect. In rats, we observed a decrement of kinematic parameters during acute ischemia and a significant increment in the same region after reperfusion. We detected similar behavior in operated patients. This modality adds important functional values on cardiac outcomes and supports the intervention in a contact-free and non-invasive mode. Moreover, it does not require particular operator-dependent skills.

Simulating the effects of growth and fiber dispersion on the electromechanical response of a cardiac ventricular wedge affected from concentric hypertrophy.

In this paper, we analyze the epicardial electromechanical response of an in silico cardiac ventricular wedge under both healthy and concentric hypertrophic conditions. This is achieved by taking into account the growth of the wedge thickness and the fiber dispersion that may follow. The electromechanical response is described in terms of some macroscopic measures, i.e. the action potential duration, the conduction velocity, the contractility and the contraction force. Our results suggest that growth reduces the action potential duration and conduction velocity, whilst it increases the contractility and contraction force, yielding an overall negative effect. In presence of fiber dispersion, the action potential duration and conduction velocity are not affected further, whilst the effect on the contractility and contraction force is enhanced.

Modelling the effect of thickness on the electromechanical properties of in vitro cardiac cultures: A simulation study.

Nowadays, in vitro cardiac cultures offer a valid tool to study the bioelectrical activity and the biomechanics of the heart tissue. Modelling their properties could be helpful for researchers involved in this field. In this paper, we develop a three-dimensional electromechanical model to study how thickness affects the bioelectrical and biomechanical performances of an in vitro culture made of ventricular cells. In particular, by our in silico simulations we want to verify if thickness variations can be a key factor in modifying the response of the whole culture when this one is grown to become a cardiac patch. Therefore, for this parameter we choose three increasing values while keeping a fiber architecture among layers that is similar to the one of the in vivo heart but it is randomly stated at the beginning of each simulation. We prove that, independently from the selected architectures, the more thickness increases the more mechanical improvements are attained, but the more electrical problems may arise too.

In silico modelling and analysis of the electrical and mechanical properties of in vitro cardiac cultures with different fiber architectures.

Today, in vitro cardiac cultures are widely exploited to investigate several aspects of the electromechanical behavior of the cardiac tissue. Thus, new forecasts may derive from modelling their properties. In particular, in this paper, we focus on the fiber architecture of cultures, i.e. on the way cellular sarcomeres are locally oriented, when they are designed to be cardiac patches. We employ a three-dimensional model to simulate the bioelectrical activity and the biomechanics of a multilayered culture made of ventricular cells and with four possible architectures consisting of: i) random fibers in all cells; ii) randomly rotating fibers among layers; iii) structurally rotating fibers from the bottom layer to the top one; iv) parallel fibers among layers. Our results suggest that the best configuration for a patch may be the architecture with structurally rotating fibers, which is the one that most approaches the anisotropic structure of the in vivo heart, thanks to its better electrical and mechanical performances.

Effects of premature anodal stimulations on cardiac transmembrane potential and intracellular calcium distributions computed by anisotropic Bidomain models.

AIMS: Cardiac unipolar electrode stimulations induce a particular structure of the transmembrane potential distribution (Vm), called virtual electrode polarization (VEP), which plays an important role in the mechanisms of cardiac excitation, reentry induction, and ventricular defibrillation. Recent experimental studies, based on the optical mapping techniques, have shown that premature stimulations also induce significant changes in the intracellular calcium (Cai) spatial distribution. The aim of this work is to investigate and compare by means of numerical simulations the morphology of the Vm and Cai patterns, generated by applying an S1-S2 stimulation protocol with a premature S2 anodal pulse. METHODS AND RESULTS: We perform parallel finite element simulations of a three-dimensional orthotropic Bidomain model on a block of ventricular tissue by using four membrane models of two species (guinea pig and rabbit), that incorporate the phenomenological or more detailed mechanistic descriptions of the calcium dynamics. During the S2 anodal stimulus, the Cai spatial distribution, computed with all the considered models, presents a configuration similar to the typical VEP pattern of Vm, with a minimum inside the virtual anode and two maxima in the virtual cathodes. After the S2 stimulus turns off, the anode break excitation mechanism yields a Vm pattern exhibiting a clearly propagating wavefront. Differently, the Cai patterns do not show a clear separation between the resting and the activated regions, with the exception of one of the phenomenological models considered, but they show warped dog-bone shaped equi-level lines around an elevation in the virtual anode region. CONCLUSION: The VEP pattern of the Cai spatial distribution during the S2 stimulus is in agreement with the previous experimental studies. Moreover, the Cai minimum in the virtual anode can be mainly attributable to the outflow of calcium ions produced by the sodium-calcium (NCX) exchanger, without a significant contribution of the ICaL current.