Successful Cardiac Resynchronization Therapy Reduces Negative Septal Work in Patient-Specific Models of Dyssynchronous Heart Failure.

In patients with dyssynchronous heart failure (DHF), cardiac conduction abnormalities cause the regional distribution of myocardial work to be non-homogeneous. Cardiac resynchronization therapy (CRT) using an implantable, programmed biventricular pacemaker/defibrillator, can improve the synchrony of contraction between the right and left ventricles in DHF, resulting in reduced morbidity and mortality and increased quality of life. Since regional work depends on wall stress, which cannot be measured in patients, we used computational methods to investigate regional work distributions and their changes after CRT. We used three-dimensional multi-scale patient-specific computational models parameterized by anatomic, functional, hemodynamic, and electrophysiological measurements in eight patients with heart failure and left bundle branch block (LBBB) who received CRT. To increase clinical translatability, we also explored whether streamlined computational methods provide accurate estimates of regional myocardial work. We found that CRT increased global myocardial work efficiency with significant improvements in non-responders. Reverse ventricular remodeling after CRT was greatest in patients with the highest heterogeneity of regional work at baseline, however the efficacy of CRT was not related to the decrease in overall work heterogeneity or to the reduction in late-activated regions of high myocardial work. Rather, decreases in early-activated regions of myocardium performing negative myocardial work following CRT best explained patient variations in reverse remodeling. These findings were also observed when regional myocardial work was estimated using ventricular pressure as a surrogate for myocardial stress and changes in endocardial surface area as a surrogate for strain. These new findings suggest that CRT promotes reverse ventricular remodeling in human dyssynchronous heart failure by increasing regional myocardial work in early-activated regions of the ventricles, where dyssynchrony is specifically associated with hypoperfusion, late systolic stretch, and altered metabolic activity and that measurement of these changes can be performed using streamlined approaches.

Model of Human Fetal Growth in Hypoplastic Left Heart Syndrome: Reduced Ventricular Growth Due to Decreased Ventricular Filling and Altered Shape.

INTRODUCTION: Hypoplastic left heart syndrome (HLHS) is a congenital condition with an underdeveloped left ventricle (LV) that provides inadequate systemic blood flow postnatally. The development of HLHS is postulated to be due to altered biomechanical stimuli during gestation. Predicting LV size at birth using mid-gestation fetal echocardiography is a clinical challenge critical to prognostic counseling. HYPOTHESIS: We hypothesized that decreased ventricular filling in utero due to mitral stenosis may reduce LV growth in the fetal heart via mechanical growth signaling. METHODS: We developed a novel finite element model of the human fetal heart in which cardiac myocyte growth rates are a function of fiber and cross-fiber strains, which is affected by altered ventricular filling, to simulate alterations in LV growth and remodeling. Model results were tested with echocardiogram measurements from normal and HLHS fetal hearts. RESULTS: A strain-based fetal growth model with a normal 22-week ventricular filling (1.04 mL) was able to replicate published measurements of changes between mid-gestation to birth of mean LV end-diastolic volume (EDV) (1.1-8.3 mL) and dimensions (long-axis, 18-35 mm; short-axis, 9-18 mm) within 15% root mean squared deviation error. By decreasing volumetric load (-25%) at mid-gestation in the model, which emulates mitral stenosis in utero, a 65% reduction in LV EDV and a 46% reduction in LV wall volume were predicted at birth, similar to observations in HLHS patients. In retrospective blinded case studies for HLHS, using mid-gestation echocardiographic data, the model predicted a borderline and severe hypoplastic LV, consistent with the patients' late-gestation data in both cases. Notably, the model prediction was validated by testing for changes in LV shape in the model against clinical data for each HLHS case study. CONCLUSION: Reduced ventricular filling and altered shape may lead to reduced LV growth and a hypoplastic phenotype by reducing myocardial strains that serve as a myocyte growth stimulus. The human fetal growth model presented here may lead to a clinical tool that can help predict LV size and shape at birth based on mid-gestation LV echocardiographic measurements.

Patient-Specific Models of Cardiac Biomechanics.

Patient-specific models of cardiac function have the potential to improve diagnosis and management of heart disease by integrating medical images with heterogeneous clinical measurements subject to constraints imposed by physical first principles and prior experimental knowledge. We describe new methods for creating three-dimensional patient-specific models of ventricular biomechanics in the failing heart. Three-dimensional bi-ventricular geometry is segmented from cardiac CT images at end-diastole from patients with heart failure. Human myofiber and sheet architecture is modeled using eigenvectors computed from diffusion tensor MR images from an isolated, fixed human organ-donor heart and transformed to the patient-specific geometric model using large deformation diffeomorphic mapping. Semi-automated methods were developed for optimizing the passive material properties while simultaneously computing the unloaded reference geometry of the ventricles for stress analysis. Material properties of active cardiac muscle contraction were optimized to match ventricular pressures measured by cardiac catheterization, and parameters of a lumped-parameter closed-loop model of the circulation were estimated with a circulatory adaptation algorithm making use of information derived from echocardiography. These components were then integrated to create a multi-scale model of the patient-specific heart. These methods were tested in five heart failure patients from the San Diego Veteran's Affairs Medical Center who gave informed consent. The simulation results showed good agreement with measured echocardiographic and global functional parameters such as ejection fraction and peak cavity pressures.

Myofiber prestretch magnitude determines regional systolic function during ectopic activation in the tachycardia-induced failing canine heart.

Electrical dyssynchrony leads to prestretch in late-activated regions and alters the sequence of mechanical contraction, although prestretch and its mechanisms are not well defined in the failing heart. We hypothesized that in heart failure, fiber prestretch magnitude increases with the amount of early-activated tissue and results in increased end-systolic strains, possibly due to length-dependent muscle properties. In five failing dog hearts with scars, three-dimensional strains were measured at the anterolateral left ventricle (LV). Prestretch magnitude was varied via ventricular pacing at increasing distances from the measurement site and was found to increase with activation time at various wall depths. At the subepicardium, prestretch magnitude positively correlated with the amount of early-activated tissue. At the subendocardium, local end-systolic strains (fiber shortening, radial wall thickening) increased proportionally to prestretch magnitude, resulting in greater mean strain values in late-activated compared with early-activated tissue. Increased fiber strains at end systole were accompanied by increases in preejection fiber strain, shortening duration, and the onset of fiber relengthening, which were all positively correlated with local activation time. In a dog-specific computational failing heart model, removal of length and velocity dependence on active fiber stress generation, both separately and together, alter the correlations between local electrical activation time and timing of fiber strains but do not primarily account for these relationships.

Mechanical discoordination increases continuously after the onset of left bundle branch block despite constant electrical dyssynchrony in a computational model of cardiac electromechanics and growth.

AIMS: To test whether a functional growth law leads to asymmetric hypertrophy and associated changes in global and regional cardiac function when integrated with a computational model of left bundle branch block (LBBB). METHODS AND RESULTS: In recent studies, we proposed that cardiac myocytes grow longer when a threshold of maximum fibre strain is exceeded and grow thicker when the smallest maximum principal strain in the cellular cross-sectional plane exceeds a threshold. A non-linear cardiovascular model of the beating canine ventricles was combined with the cellular growth law. After inducing LBBB, the ventricles were allowed to adapt in shape over time in response to mechanical stimuli. When subjected to electrical dyssynchrony, the combined model of ventricular electromechanics, haemodynamics, and growth led to asymmetric hypertrophy with a faster increase of wall mass in the left ventricular (LV) free wall (FW) than the septum, increased LV end-diastolic and end-systolic volumes, and decreased LV ejection fraction. Systolic LV pressure decreased during the acute phase of LBBB and increased at later stages. The relative changes of these parameters were similar to those obtained experimentally. Most of the dilation was due to radial and axial fibre growth, and hence altered shape of the LVFW. CONCLUSION: Our previously proposed growth law reproduced measured dyssynchronously induced asymmetric hypertrophy and the associated functional changes, when combined with a computational model of the LBBB heart. The onset of LBBB leads to a step increase in LV mechanical discoordination that continues to increase as the heart remodels despite the constant electrical dyssynchrony.

A single strain-based growth law predicts concentric and eccentric cardiac growth during pressure and volume overload.

Adult cardiac muscle adapts to mechanical changes in the environment by growth and remodeling (G&R) via a variety of mechanisms. Hypertrophy develops when the heart is subjected to chronic mechanical overload. In ventricular pressure overload (e.g. due to aortic stenosis) the heart typically reacts by concentric hypertrophic growth, characterized by wall thickening due to myocyte radial growth when sarcomeres are added in parallel. In ventricular volume overload, an increase in filling pressure (e.g. due to mitral regurgitation) leads to eccentric hypertrophy as myocytes grow axially by adding sarcomeres in series leading to ventricular cavity enlargement that is typically accompanied by some wall thickening. The specific biomechanical stimuli that stimulate different modes of ventricular hypertrophy are still poorly understood. In a recent study, based on in-vitro studies in micropatterned myocyte cell cultures subjected to stretch, we proposed that cardiac myocytes grow longer to maintain a preferred sarcomere length in response to increased fiber strain and grow thicker to maintain interfilament lattice spacing in response to increased cross-fiber strain. Here, we test whether this growth law is able to predict concentric and eccentric hypertrophy in response to aortic stenosis and mitral valve regurgitation, respectively, in a computational model of the adult canine heart coupled to a closed loop model of circulatory hemodynamics. A non-linear finite element model of the beating canine ventricles coupled to the circulation was used. After inducing valve alterations, the ventricles were allowed to adapt in shape in response to mechanical stimuli over time. The proposed growth law was able to reproduce major acute and chronic physiological responses (structural and functional) when integrated with comprehensive models of the pressure-overloaded and volume-overloaded canine heart, coupled to a closed-loop circulation. We conclude that strain-based biomechanical stimuli can drive cardiac growth, including wall thickening during pressure overload.

Computational modeling of cardiac growth in the post-natal rat with a strain-based growth law.

INTRODUCTION: The postnatal heart grows mostly in response to increased hemodynamic load. However, the specific biomechanical stimuli that stimulate cardiac growth as a reaction to increased hemodynamic load are still poorly understood. It has been shown that isolated neonatal rat cardiac myocytes normalize resting sarcomere length by adding sarcomeres in series when subjected to uniaxial static strain. Because there is experimental evidence that myocytes can distinguish the direction of stretch, it was postulated that myocytes also may normalize interfilament lattice spacing as a response to cross-fiber stretch. METHODS: A growth law was proposed in which fiber axial growth was stimulated by fiber strain deviating from zero and fiber radial growth by cross-fiber strain (parallel to the wall surface) deviating from zero. Fiber radial growth rate constant was 1/3 of the fiber axial growth rate constant. The growth law was implemented in a finite element model of the newborn Sprague-Dawley rat residually stressed left ventricle (LV). The LV was subjected to an end-diastolic pressure of 1 kPa and about 25 weeks of normal growth was simulated. RESULTS: Most cellular and chamber dimension changes in the model matched experimentally measured ones: LV cavity and wall volume increased from 2.3 and 54 µl, respectively, in the newborn to 276 µl and 1.1 ml, respectively, in the adult rat; LV shape became more spherical; internal LV radius increased faster than wall thickness; and unloaded sarcomere lengths exhibited a transmural gradient. The major discrepancy with experiments included a reversed transmural gradient of cell length in the older rat. CONCLUSION: A novel strain-based growth law has been presented that reproduced physiological postnatal growth in the rat LV.

Cardiac assist with a twist: apical torsion as a means to improve failing heart function.

Changes in muscle fiber orientation across the wall of the left ventricle (LV) cause the apex of the heart to turn 10-15 deg in opposition to its base during systole and are believed to increase stroke volume and lower wall stress in healthy hearts. Studies show that cardiac torsion is sensitive to various disease states, which suggests that it may be an important aspect of cardiac function. Modern imaging techniques have sparked renewed interest in cardiac torsion dynamics, but no work has been done to determine whether mechanically augmented apical torsion can be used to restore function to failing hearts. In this report, we discuss the potential advantages of this approach and present evidence that turning the cardiac apex by mechanical means can displace a clinically significant volume of blood from failing hearts. Computational models of normal and reduced-function LVs were created to predict the effects of applied apical torsion on ventricular stroke work and wall stress. These same conditions were reproduced in anesthetized pigs with drug-induced heart failure using a custom apical torsion device programmed to rotate over various angles during cardiac systole. Simulations of applied 90 deg torsion in a prolate spheroidal computational model of a reduced-function pig heart produced significant increases in stroke work (25%) and stroke volume with reduced fiber stress in the epicardial region. These calculations were in substantial agreement with corresponding in vivo measurements. Specifically, the computer model predicted torsion-induced stroke volume increases from 13.1 to 14.4 mL (9.9%) while actual stroke volume in a pig heart of similar size and degree of dysfunction increased from 11.1 to 13.0 mL (17.1%). Likewise, peak LV pressures in the computer model rose from 85 to 95 mm Hg (11.7%) with torsion while maximum ventricular pressures in vivo increased in similar proportion, from 55 to 61 mm Hg (10.9%). These data suggest that: (a) the computer model of apical torsion developed for this work is a fair and accurate predictor of experimental outcomes, and (b) supra-physiologic apical torsion may be a viable means to boost cardiac output while avoiding blood contact that occurs with other assist methods.

Improvement in pump function with endocardial biventricular pacing increases with activation time at the left ventricular pacing site in failing canine hearts.

Recently, attention has been focused on comparing left ventricular (LV) endocardial (ENDO) with epicardial (EPI) pacing for cardiac resynchronization therapy. However, the effects of ENDO and EPI lead placement at multiple sites have not been studied in failing hearts. We hypothesized that differences in the improvement of ventricular function due to ENDO vs. EPI pacing in dyssynchronous (DYSS) heart failure may depend on the position of the LV lead in relation to the original activation pattern. In six nonfailing and six failing dogs, electrical DYSS was created by atrioventricular sequential pacing of the right ventricular apex. ENDO was compared with EPI biventricular pacing at five LV sites. In failing hearts, increases in the maximum rate of LV pressure change (dP/dt; r = 0.64), ejection fraction (r = 0.49), and minimum dP/dt (r = 0.51), relative to DYSS, were positively correlated (P < 0.01) with activation time at the LV pacing site during ENDO but not EPI pacing. ENDO pacing at sites with longer activation delays led to greater improvements in hemodynamic parameters and was associated with an overall reduction in electrical DYSS compared with EPI pacing (P < 0.05). These findings were qualitatively similar for nonfailing hearts. Improvement in hemodynamic function increased with activation time at the LV pacing site during ENDO but not EPI pacing. At the anterolateral wall, end-systolic transmural function was greater with local ENDO compared with EPI pacing. ENDO pacing and intrinsic activation delay may have important implications for management of DYSS heart failure.

Patient-specific modeling of dyssynchronous heart failure: a case study.

The development and clinical use of patient-specific models of the heart is now a feasible goal. Models have the potential to aid in diagnosis and support decision-making in clinical cardiology. Several groups are now working on developing multi-scale models of the heart for understanding therapeutic mechanisms and better predicting clinical outcomes of interventions such as cardiac resynchronization therapy. Here we describe the methodology for generating a patient-specific model of the failing heart with a myocardial infarct and left ventricular bundle branch block. We discuss some of the remaining challenges in developing reliable patient-specific models of cardiac electromechanical activity, and identify some of the main areas for focusing future research efforts. Key challenges include: efficiently generating accurate patient-specific geometric meshes and mapping regional myofiber architecture to them; modeling electrical activation patterns based on cellular alterations in human heart failure, and estimating regional tissue conductivities based on clinically available electrocardiographic recordings; estimating unloaded ventricular reference geometry and material properties for biomechanical simulations; and parameterizing systemic models of circulatory dynamics from available hemodynamic measurements.

Ventricular dilation and electrical dyssynchrony synergistically increase regional mechanical nonuniformity but not mechanical dyssynchrony: a computational model.

BACKGROUND: Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. METHODS AND RESULTS: All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97+/-0.004, 0.010+/-0.002, and 78+/-1 milliseconds, respectively. With dilation alone, CURE decreased 2.0+/-0.07%, ISF increased 58+/-47%, and WTpeak increased 31+/-3%. With dyssynchronous activation alone, CURE decreased 15+/-0.6%, ISF increased 14-fold (+/-3), and WTpeak increased 121+/-4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23+/-0.8%, ISF increased 20-fold (+/-5), and WTpeak increased 147+/-5%. CONCLUSIONS: Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy.

Current progress in patient-specific modeling.

We present a survey of recent advancements in the emerging field of patient-specific modeling (PSM). Researchers in this field are currently simulating a wide variety of tissue and organ dynamics to address challenges in various clinical domains. The majority of this research employs three-dimensional, image-based modeling techniques. Recent PSM publications mostly represent feasibility or preliminary validation studies on modeling technologies, and these systems will require further clinical validation and usability testing before they can become a standard of care. We anticipate that with further testing and research, PSM-derived technologies will eventually become valuable, versatile clinical tools.

Multi-scale modeling of excitation-contraction coupling in the normal and failing heart.

Here we describe new computational models of cardiac electromechanics starting from the cellular scale and building to the tissue, organ and system scales. We summarize application to human genetic diseases (LQT1 and LQT3) and to modeling of congestive heart failure.

Effect of transmurally heterogeneous myocyte excitation-contraction coupling on canine left ventricular electromechanics.

The excitation-contraction coupling properties of cardiac myocytes isolated from different regions of the mammalian left ventricular wall have been shown to vary considerably, with uncertain effects on ventricular function. We embedded a cell-level excitation-contraction coupling model with region-dependent parameters within a simple finite element model of left ventricular geometry to study effects of electromechanical heterogeneity on local myocardial mechanics and global haemodynamics. This model was compared with one in which heterogeneous myocyte parameters were assigned randomly throughout the mesh while preserving the total amount of each cell subtype. The two models displayed nearly identical transmural patterns of fibre and cross-fibre strains at end-systole, but showed clear differences in fibre strains at earlier points during systole. Haemodynamic function, including peak left ventricular pressure, maximal rate of left ventricular pressure development and stroke volume, were essentially identical in the two models. These results suggest that in the intact ventricle heterogeneously distributed myocyte subtypes primarily impact local deformation of the myocardium, and that these effects are greatest during early systole.

Effects of biventricular pacing and scar size in a computational model of the failing heart with left bundle branch block.

OBJECTIVES: To study the impact of biventricular pacing (BiV) and scar size on left ventricular (LV) regional and global function using a detailed finite element model of three-dimensional electromechanics in the failing canine heart. BACKGROUND: Cardiac resynchronization therapy (CRT) clinical trials have demonstrated that up to 30% of patients may be classified as non-responders. The presence of a scar appears to contribute to those that do not respond to CRT. A recent study in patients with myocardial scar showed that LV dyssynchrony was the sole independent predictor of reverse remodeling, and not scar location or size. METHODS: Two activation sequences were simulated: left bundle branch block (LBBB) and acute simultaneous BiV (with leads in the left and right ventricle) in hearts with chronic scars of various sizes. The dependence of regional function (mean fiber ejection strain, variance of fiber isovolumic strain and fraction of tissue stretched during ejection) and global function (left ventricular dP/dt(max), ejection fraction, stroke work) on scar size and pacing protocol was tested. RESULTS: Global function and regional function averaged over the whole LV during LBBB and BiV decreased as a function of scar size. In the non-scarred regions, however, regional function was largely independent of scar size for a fixed pacing site. CONCLUSIONS: The model results suggest that uniformity of mechanical contraction in non-scarred regions in the failing heart during biventricular pacing is independent of scar size for a fixed pacing site.

Computational modeling for bedside application.

Advances in computer power, novel diagnostic and therapeutic medical technologies, and an increasing knowledge of pathophysiology from gene to organ systems make it increasingly feasible to apply multiscale patient-specific modeling based on proven disease mechanisms. Such models may guide and predict the response to therapy in many areas of medicine. This is an exciting and relatively new approach, for which efficient methods and computational tools are of the utmost importance. Investigators have designed patient-specific models in almost all areas of human physiology. Not only will these models be useful in clinical settings to predict and optimize the outcome from surgery and non-interventional therapy, but they will also provide pathophysiologic insights from the cellular level to the organ system level. Models, therefore, will provide insight as to why specific interventions succeed or fail.

Coupling of a 3D finite element model of cardiac ventricular mechanics to lumped systems models of the systemic and pulmonic circulation.

In this study we present a novel, robust method to couple finite element (FE) models of cardiac mechanics to systems models of the circulation (CIRC), independent of cardiac phase. For each time step through a cardiac cycle, left and right ventricular pressures were calculated using ventricular compliances from the FE and CIRC models. These pressures served as boundary conditions in the FE and CIRC models. In succeeding steps, pressures were updated to minimize cavity volume error (FE minus CIRC volume) using Newton iterations. Coupling was achieved when a predefined criterion for the volume error was satisfied. Initial conditions for the multi-scale model were obtained by replacing the FE model with a varying elastance model, which takes into account direct ventricular interactions. Applying the coupling, a novel multi-scale model of the canine cardiovascular system was developed. Global hemodynamics and regional mechanics were calculated for multiple beats in two separate simulations with a left ventricular ischemic region and pulmonary artery constriction, respectively. After the interventions, global hemodynamics changed due to direct and indirect ventricular interactions, in agreement with previously published experimental results. The coupling method allows for simulations of multiple cardiac cycles for normal and pathophysiology, encompassing levels from cell to system.

Three dimensional electromechanical model of porcine heart with penetrating wound injury.

The aim of this study is development a prototype computational model of the pig heart that can be used to predict physiological responses to a penetrating wound injury. The pig has been chosen for this model studies because it shares many anatomical similarities with humans. Three-dimensional cubic Hermite finite element meshes based on detailed measurements of porcine anatomy combined into an integrated anatomic model. The pig ventricular model includes detailed left and right ventricular geometry and myofiber and laminar sheet orientations throughout the mesh. The cardiac mesh was refined and monodomain equations for action potential propagation solved using well-established collocation-Galerkin finite element methods. The membrane kinetic equations for the action potential model was based on detailed cellular models of transmembrane ionic fluxes and intracellular calcium fluxes in canine ventricular myocytes and human atrial myocytes. We modified the anisotropic myocardial conductivity tensor on the endocardial surface of the ventricles by making use of a surface model fitted to measured of Purkinje fiber network anatomy. The mechanical model compute regional three-dimensional stress and strain distributions using anisotropic constitutive laws referred to local material coordinate axes defined by local myofiber and laminar sheet orientations. Passive myocardial mechanics modeled using exponential orthotropic strain energy functions. Active systolic myocardial stresses computed from a multi-scale model that uses crossbridge theory to predict calcium-activated sarcomere length- and velocity-dependent tension filament tension. Since the electrical and mechanical models use a common finite element mesh as the parent parametric framework and both models are solved within our custom finite element package, it is straightforward to couple these models, as we have recently done for a model of coupled ventricular electromechanics. We apply the coupled electromechanical model to predict alterations in regional diastolic and systolic wall mechanics associated with rhythm disturbances and possible arrhythmias with decreased blood volume, tamponade, myocardial injury, and regional ischemia caused by a penetrating wound.

Cardiac fiber orientation and the left-right asymmetry determining mechanism.

The invariant nature of body situs within and across vertebrate species implies that a highly conserved pathway controls the specification of the left-right (L/R) axis. Situs-specific morphogenesis begins at the end of this pathway and leads to normal organ arrangement, also known as situs solitus. Occasionally, individuals have a complete, mirror image reversal of this asymmetry, called situs inversus totalis (SIT). In these individuals, gross anatomy is mirror imaged. However, the helical myofiber pattern within the left ventricle (LV) wall is only partially mirror imaged: apical and superficial basal fiber orientation are as in normal persons, whereas the deeper basal layers have an inverted fiber orientation. Because of this bivalent fiber orientation pattern, LV deformation in humans with SIT is mirror imaged only near the base, but near the apex it is as in normal subjects. Apparently, the embryonic L/R controlling genetic pathway does determine situs-specific gross anatomy morphogenesis, but it is not the only factor regulating fiber architecture within the LV wall.