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Biomedical subjects

Nicolas P Smith

Publications and source records attributed to Nicolas P Smith.

11 recordsLinked to original sources
PubMed2006

Acidosis in models of cardiac ventricular myocytes.

The effects of acidosis on cardiac electrophysiology and excitation-contraction coupling have been studied extensively. Acidosis decreases the strength of contraction and leads to altered calcium transients as a net result of complex interactions between protons and a variety of intracellular processes. The relative contributions of each of the changes under acidosis are difficult to establish experimentally, however, and significant uncertainties remain about the key mechanisms of impaired cardiac function. In this paper, we review the experimental findings concerning the effects of acidosis on the action potential and calcium handling in the cardiac ventricular myocyte, and we present a modelling study that establishes the contribution of the different effects to altered Ca2+ transients during acidosis. These interactions are incorporated into a dynamical model of pH regulation in the myocyte to simulate respiratory acidosis in the heart.

Acidosis↗
PubMed2006

Modelling slow wave activity in the small intestine.

We have developed an anatomically based model to simulate slow wave activity in the small intestine. Geometric data for the human small intestine were obtained from the Visible Human project. These data were used to create a one-dimensional finite element mesh of the entire small intestine using an iterative fitting procedure. The electrically active components of the intestinal walls were modelled using a modified Fitzhugh-Nagumo cell model embedded within a longitudinal smooth muscle layer and a layer containing Interstitial Cells of Cajal. Within these layers, the monodomain equation was used to describe slow wave propagation. To solve the monodomain equation, a high-resolution finite difference grid, with an average spatial resolution of 0.95 mm, was embedded within each finite element. The resulting simulations of intestinal activity agree with the experimental observation that slow wave frequency gradually declines from 12 cycles per minute (cpm) in the duodenum to 8 cpm at the terminal ileum. Furthermore, the simulations demonstrated a decrease in conduction velocity with distance along the small intestine (10.7 cm/s in the duodenum, 5.1cm/s in the jejunum and 1.4 cm/s in the ileum), matching experimental recordings from the canine small intestine. We conclude that the framework presented here is capable of qualitatively simulating normal slow wave activity in an anatomical model of the small intestine.

Finite Element Analysis↗
PubMed2006

A dynamic model of excitation-contraction coupling during acidosis in cardiac ventricular myocytes.

Acidosis in cardiac myocytes is a major factor in the reduced inotropy that occurs in the ischemic heart. During acidosis, diastolic calcium concentration and the amplitude of the calcium transient increase, while the strength of contraction decreases. This has been attributed to the inhibition by protons of calcium uptake and release by the sarcoplasmic reticulum, to a rise of intracellular sodium caused by activation of sodium-hydrogen exchange, decreased calcium binding affinity to Troponin-C, and direct effects on the contractile machinery. The relative contributions and concerted action of these effects are, however, difficult to establish experimentally. We have developed a mathematical model to examine altered calcium-handling mechanisms during acidosis. Each of the alterations was incorporated into a dynamical model of pH regulation and excitation-contraction coupling to predict the time courses of key ionic species during acidosis, in particular intracellular pH, sodium and the calcium transient, and contraction. This modeling study suggests that the most significant effects are elevated sodium, inhibition of sodium-calcium exchange, and the direct interaction of protons with the contractile machinery; and shows how the experimental data on these contributions can be reconciled to understand the overall effects of acidosis in the beating heart.

Acidosis↗
PubMed2006

Structural morphology of renal vasculature.

An automatic segmentation technique has been developed and applied to two renal micro-computer tomography (CT) images. With the use of a 20-microm voxel resolution image, the arterial and venous trees were segmented for the rat renal vasculature, distinguishing resolving vessels down to 30 microm in radius. A higher resolution 4-microm voxel image of a renal vascular subtree, with vessel radial values down to 10 microm, was segmented. Strahler ordering was applied to each subtree using an iterative scheme developed to integrate information from the two segmented models to reconstruct the complete topology of the entire vascular tree. An error analysis of the assigned orders quantified the robustness of the ordering process for the full model. Radial, length, and connectivity data of the complete arterial and venous trees are reported by order. Substantial parallelism is observed between individual arteries and veins, and the ratio of parallel vessel radii is quantified via a power law. A strong correlation with Murray's Law was established, providing convincing evidence of the "minimum work" hypothesis. Results were compared with theoretical branch angle formulations, based on the principles of "minimum shear force," were inconclusive. Three-dimensional reconstructions of renal vascular trees collected are made freely available for further investigation into renal physiology and modeling studies.

Animals↗
PubMed2006

Three-dimensional models of individual cardiac histoanatomy: tools and challenges.

There is a need for, and utility in, the acquisition of data sets of cardiac histoanatomy, with the vision of reconstructing individual hearts on the basis of noninvasive imaging, such as MRI, enriched by reference to detailed atlases of serial histology obtained from representative samples. These data sets would be useful not only as a repository of knowledge regarding the specifics of cardiac histoanatomy, but could form the basis for generation of individualized high-resolution cardiac structure-function models. The current article presents a step in this general direction: it illustrates how whole-heart noninvasive imaging can be combined with whole-heart histology in an approach to achieve automated construction of histoanatomically detailed models of cardiac 3D structure and function at hitherto unprecedented resolution and accuracy (based on 26.4 x 26.4 x 24.4 microm MRI voxel size, and enriched by histological detail). It provides an overview of the tools used in this quest and outlines challenges posed by the approach in the light of applications that may benefit from the availability of such data and tools.

Animals↗
PubMed2004

Multi-scale modelling and the IUPS physiome project.

We review the development of models of cellular and tissue function and in particular address issues of multi-scale modelling, including the transition from stochastic models to continuum models and the incorporation of cell and tissue structure. The heart is used as an example of linking models at the molecular level to cell, tissue and organ level function.

Animals↗
PubMed2004

A computational study of the interaction between coronary blood flow and myocardial mechanics.

An anatomically based computational model of coronary blood flow, coupled to cardiac mechanics, is verified with experimental data and used to investigate the mechanisms by which myocardial contraction inhibits coronary blood flow. From finite deformation mechanics solutions the regional variation in intramyocardial pressure (IMP) exerted on coronary vessels embedded in the ventricular wall is calculated. This pressure is then coupled to a haemodymanic model of vascular blood flow to predict the spatial-temporal characteristics of perfusion throughout the myocardium. The calculated IMP is shown to vary approximately linearly between ventricular pressure at the endocardium and atmospheric pressure at the epicardium through the diastolic loading and isovolumic contraction phases. During the ejection and isovolumic relaxation phases IMP values rise slightly above ventricular pressure. The average radius of small arterial vessels embedded in the myocardium decreases during isovolumic contraction (18% at left ventricular endocardium) before increasing during ejection (10% at left ventricular endocardium) due to a rise in inflow pressure. Embedded venous vessels show a reduction in radius through both phases of contraction (35% at left ventricular endocardium). Calculated blood flows in both the large epicardial and small myocardial vessels show a 180 degrees phase difference between arterial and venous velocity patterns with arterial flow occurring predominantly during diastole and venous flow occurring predominantly during systole. These results indicate that the transmission of ventricular cavity pressure through the myocardium is the dominant mechanism by which coronary blood flow is reduced during the isovolumic phase of contraction. In the ejection phase of contraction myocardial stiffening plays a more significant role in inhibiting blood flow.

Biomechanical Phenomena↗
PubMed2003

Cardiac electrical activity--from heart to body surface and back again.

We report here on our latest developments in the forward and inverse problems of electrocardiology. In the forward problem, a coupled cellular model of cardiac excitation-contraction is embedded within an anatomically realistic model of the cardiac ventricles, which is itself embedded within a torso model. This continuum modelling framework allows the effects of cellular-level activity on the surface electrocardiogram (ECG) to be carefully examined. Furthermore, the contributions of contraction and local ischemia on body surface recordings can also be elucidated. Such information can provide theoretical limits to the sensitivity and ultimately the detection capability of body surface ECG recordings. Despite being very useful, such detailed forward modelling is not directly applicable when seeking to use densely sampled ECG information to assess a patient in a clinical environment (the inverse problem). In such a situation patient specific models must be constructed and, due to the nature of the inverse problem, the level of detail that can be reliably reproduced is limited. Extensive simulation studies have shown that the accuracy with which the heart is localised within the torso is the primary limiting factor. To further identify the practical performance capabilities of the current inverse algorithms, high quality experimental data is urgently needed. We have been working towards such an objective with a number of groups, including our local hospital in Auckland. At that hospital, in patients undergoing catheter ablation surgery, up to 256 simultaneous body surface signals were recorded by using various catheter pacing protocols. The geometric information required to customize the heart and torso model was obtained using a combination of ultrasound and laser scanning technologies. Our initial results indicate that such geometric imaging modalities are sufficient to produce promising inversely-constructed activation profiles.

Algorithms↗
PubMed2003

From sarcomere to cell: an efficient algorithm for linking mathematical models of muscle contraction.

Two classes of mathematical framework have previously been developed to model active tension generation in contracting muscle. Cross-bridge models of muscle are biophysically based but computationally expensive to solve, and thus unsuitable for embedding in spatially distributed continuum representations. Fading memory models are computationally efficient but provide limited biophysical insight. In this study a novel computational method is proposed for coupling these two frameworks such that biophysical events can be determined and computational tractability maintained. Within the cross-bridge model, the functional forms of the distribution of cross-bridges, as a function of strain in each state, are approximated using the distribution moment approach. Using the variables of area, mean and standard deviation of each distribution, analytic expressions are developed to calculate the temporal dynamics of stiffness, tension and energy. A root finding method is employed to adjust the variables such that the temporal dynamics of the cross-bridge model match those of an equivalent fading memory model. The method is demonstrated for sinusoidal perturbations in length at two frequencies, with an approximate 30-fold increase in computational efficiency over a conventional technique for finding a solution to the cross-bridge model.

Adenosine Triphosphate↗
PubMed2003

Altered T wave dynamics in a contracting cardiac model.

INTRODUCTION: The implications of mechanical deformation on calculated body surface potentials are investigated using a coupled biophysically based model. METHODS AND RESULTS: A cellular model of cardiac excitation-contraction is embedded in an anatomically accurate two-dimensional transverse cross-section of the cardiac ventricles and human torso. Waves of activation and contraction are induced by the application of physiologically realistic boundary conditions and solving the bidomain and finite deformation equations. Body surface potentials are calculated from these activation profiles by solving Laplace's equation in the passive surrounding tissues. The effect of cardiac deformation on electrical activity, induced by contraction, is demonstrated in both single-cell and tissue models. Action potential duration is reduced by 7 msec when the single cell model is subjected to a 10% contraction ramp applied over 400 msec. In the coupled electromechanical tissue model, the T wave of the ECG is shown to occur 18 msec earlier compared to an uncoupled excitation model. To assess the relative effects of myocardial deformation on the ECG, the activation sequence and tissue deformation are separated. The coupled and uncoupled activation sequences are mapped onto the undeforming and deforming meshes, respectively. ECGs are calculated for both mappings. CONCLUSION: Adding mechanical contraction to a mathematical model of the heart has been shown to shift the T wave on the ECG to the left. Although deformation of the myocardium resulting from contraction reduces the T wave amplitude, cell stretch producing altered cell membrane kinetics is the major component of this temporal shift.

Action Potentials↗