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Open Access Publications from the University of California

Scholarly Works (5 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2018)

Heart failure is the leading cause of death in the world and yet the mechanisms of disease progression are not well understood. Validated computer models which simulate physiologically accurate biomechanics can help provide insight into these mechanisms. Cardiac modeling is a multiphysics problem consisting of electrophysiology (EP), solid mechanics, and fluid mechanics. In this thesis, we develop a multiscale model of congestive heart failure, formulate a novel constitutive viscoactive model for contraction, and examine the necessary boundary conditions for replicating a physiological deformation profile during the cardiac cycle.

The congestive heart failure model was developed using a previous validated healthy EP model of a rabbit heart and modifying the cell model properties to capture the observed phenomena such as a longer action potential duration and lower amplitude calcium transient. Next, the failing cell model was incorporated into homogeneous and heterogeneous (transmural and apex-to-base gradients) cables and the conduction velocity was decreased from normal values to account for Connexin 43 downregulation. The cable with the failing cell model showed the presence of alternans and full conduction block at rapid pacing. The biventricular heart simulations with the failing cell model had significantly higher T-wave alternans and developed QRS alternans at high heart rates. Wavebreak and reentry were induced in the presence of premature ventricular stimuli: a train of 200ms beats followed by two 180ms beats. The mechanism of VF presented here is not due to a steepening of the restitution curve but rather due to a conduction block at the basal region of the ventricles. The failing cell model developed in this work shows that the heart is more susceptible to arrhythmias and potential drug therapies, such as the upregulation of SERCA, have shown to reduce the risk of the block-induced VF.

The heart undergoes two distinct phases during every beat: diastole, which is the passive filling of the chambers with blood, followed by systole, which is the muscle contraction to force the blood out of the ventricles. The presence of calcium in the cell initiates cross-bridge cycling and force generation in cardiac muscle. In this work, the passive and active phases of the heart are modeled using a Hill-like three element model. The hyperelastic behavior of tissue during filling and contraction is captured through the parallel and serial elements, respectively. The motion of the contractile element is parametrized by a set of internal variables, which are the stretch ratios in the fiber, cross-fiber, and the sheet normal directions. The evolution of these internal variables is governed by a kinetic potential, which is derived from experimental force-velocity relationships. For the three-element model, a single variational principle is developed from which incremental stress-strain relations are derived. In this model, we make the assumption that the amount of isometric tension developed in the fiber is directly proportional to the magnitude of intracellular calcium, obtained from the rabbit EP model. The model, when tested at a single material point, shows how active tension can develop in the model due to the shortening of the contractile element even when there is no visible deformation (F = I). Further, when simulating a strip of tissue with transmural fiber distribution, the model develops wall thickening and twist which are features observed in reality.

Boundary conditions in cardiac mechanics must capture the interaction of the outer surface of the heart with the pericardium and the other surrounding organs. Here, we explore those conditions and validate our model qualitatively and quantitatively using criteria from experimental literature. The geometry and microstructure of an ex-vivo swine heart are obtained using diffusion tensor magnetic resonance imaging (DTMRI). The model was constructed using 6109 quadratic tetrahedral elements and fiber orientations were interpolated at each quadrature point. The basal surface is allowed to translate in the longitudinal direction but rotation of the surface out of plane is penalized. The mesh for the pericardium boundary condition is constructed by projecting the epicardial nodes along the normal. The interaction between the pericardium and epicardium allows for free sliding along the surface but a resisting force is applied for inward and outward motions. Only this boundary condition showed the correct motion of the basal surface: during inflation the base moved upward with upward with minimal epicardial wall motion while in systole, there is apex-to-base shortening with significant wall thickening.

    Cover page: Cardiac Electromechanics Modeling and Validation
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2017)
    Quantitative measurement of the material properties (eg, stiffness) of biological tissues is poised to become a powerful diagnostic tool. There are currently several methods in the literature to estimating material stiffness, and we extend this work by formulating a framework that leads to uniquely identified material properties. We design an approach to work with full-field displacement data-ie, we assume the displacement field due to the applied forces is known both on the boundaries and also within the interior of the body of interest-and seek stiffness parameters that lead to balanced internal and external forces in a model. For in vivo applications, the displacement data can be acquired clinically using magnetic resonance imaging while the forces may be computed from pressure measurements, eg, through catheterization. We outline a set of conditions under which the least-square force error objective function is convex, yielding uniquely identified material properties. An important component of our framework is a new numerical strategy to formulate polyconvex material energy laws that are linear in the material properties and provide one optimal description of the available experimental data. An outcome of our approach is the analysis of the reliability of the identified material properties, even for material laws that do not admit unique property identification. Lastly, we evaluate our approach using passive myocardium experimental data at the material point and show its application to identifying myocardial stiffness with an in silico experiment modeling the passive filling of the left ventricle.
      Cover page: Method for the unique identification of hyperelastic material properties using full-field measures. Application to the passive myocardium material response.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2017)
      Traumatic brain injury (TBI) in children can cause persisting cognitive and behavioral dysfunction, and inevitably raises concerns about lost potential in these injured youth. Lateral fluid percussion injury (FPI) in weanling rats pathologically affects hippocampal N-methyl-d-aspartate receptor (NMDAR)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated glutamatergic neurotransmission subacutely within the first post-injury week. FPI to weanling rats has also been shown to impair enriched-environment (EE) induced enhancement of Morris water maze (MWM) learning and memory in adulthood. Recently, improved outcomes can be achieved using agents that enhance NMDAR function. We hypothesized that administering D-cycloserine (DCS), an NMDAR co-agonist, every 12 h (i.p.) would restore subacute glutamatergic neurotransmission and reinstate experience-dependent plasticity. Postnatal day 19 (P19) rats received either a sham or FPI. On post-injury day (PID) 1-3, animals were randomized to saline (Sal) or DCS. Firstly, immunoblotting of hippocampal NMDAR and AMPAR proteins were measured on PID4. Second, PID4 novel object recognition, an NMDAR- and hippocampal- mediated working memory task, was assessed. Third, P19 rats were placed in an EE (17 days), and MWM performance was measured, starting on PID30. On PID4, DCS restored reduced NR2A and increased GluR2 by 54%, and also restored diminished recognition memory in FPI pups. EE significantly improved MWM performance in shams, regardless of treatment. In contrast, FPI-EE-Sal animals only performed to the level of standard housed animals, whereas FPI-EE-DCS animals were comparable with sham-EE counterparts. This study shows that NMDAR agonist use during reduced glutamatergic transmission after developmental TBI can reinstate early molecular and behavioral responses that subsequently manifest in experience-dependent plasticity and rescued potential.
        Cover page: D-Cycloserine Restores Experience-Dependent Neuroplasticity after Traumatic Brain Injury in the Developing Rat Brain
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2016)
        Heart failure is a leading cause of death, yet its underlying electrophysiological (EP) mechanisms are not well understood. In this study, we use a multiscale approach to analyze a model of heart failure and connect its results to features of the electrocardiogram (ECG). The heart failure model is derived by modifying a previously validated electrophysiology model for a healthy rabbit heart. Specifically, in accordance with the heart failure literature, we modified the cell EP by changing both membrane currents and calcium handling. At the tissue level, we modeled the increased gap junction lateralization and lower conduction velocity due to downregulation of Connexin 43. At the biventricular level, we reduced the apex-to-base and transmural gradients of action potential duration (APD). The failing cell model was first validated by reproducing the longer action potential, slower and lower calcium transient, and earlier alternans characteristic of heart failure EP. Subsequently, we compared the electrical wave propagation in one dimensional cables of healthy and failing cells. The validated cell model was then used to simulate the EP of heart failure in an anatomically accurate biventricular rabbit model. As pacing cycle length decreases, both the normal and failing heart develop T-wave alternans, but only the failing heart shows QRS alternans (although moderate) at rapid pacing. Moreover, T-wave alternans is significantly more pronounced in the failing heart. At rapid pacing, APD maps show areas of conduction block in the failing heart. Finally, accelerated pacing initiated wave reentry and breakup in the failing heart. Further, the onset of VF was not observed with an upregulation of SERCA, a potential drug therapy, using the same protocol. The changes introduced at the cell and tissue level have increased the failing heart's susceptibility to dynamic instabilities and arrhythmias under rapid pacing. However, the observed increase in arrhythmogenic potential is not due to a steepening of the restitution curve (not present in our model), but rather to a novel blocking mechanism.
          Cover page: Electrophysiology of Heart Failure Using a Rabbit Model: From the Failing Myocyte to Ventricular Fibrillation.
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2014)
          We describe a sequence of methods to produce a partial differential equation model of the electrical activation of the ventricles. In our framework, we incorporate the anatomy and cardiac microstructure obtained from magnetic resonance imaging and diffusion tensor imaging of a New Zealand White rabbit, the Purkinje structure and the Purkinje-muscle junctions, and an electrophysiologically accurate model of the ventricular myocytes and tissue, which includes transmural and apex-to-base gradients of action potential characteristics. We solve the electrophysiology governing equations using the finite element method and compute both a 6-lead precordial electrocardiogram (ECG) and the activation wavefronts over time. We are particularly concerned with the validation of the various methods used in our model and, in this regard, propose a series of validation criteria that we consider essential. These include producing a physiologically accurate ECG, a correct ventricular activation sequence, and the inducibility of ventricular fibrillation. Among other components, we conclude that a Purkinje geometry with a high density of Purkinje muscle junctions covering the right and left ventricular endocardial surfaces as well as transmural and apex-to-base gradients in action potential characteristics are necessary to produce ECGs and time activation plots that agree with physiological observations.
            Cover page: Simulation Methods and Validation Criteria for Modeling Cardiac Ventricular Electrophysiology.
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