Biomedical subjects

A D McCulloch

Publications and source records attributed to A D McCulloch.

At least 37 records · Page 2Linked to original sources

PubMed2000

Regional dysfunction correlates with myofiber disarray in transgenic mice with ventricular expression of ras.

A hallmark of certain cardiac diseases such as familial hypertrophic cardiomyopathy is focal myofiber disarray. Regional ventricular dysfunction occurs in human subjects with hypertrophic cardiomyopathy; however, no direct evidence exists to correlate regional dysfunction with myofiber disarray. We used a transgenic mouse, which exhibits regional myofiber disarray via ventricular expression of the human oncogene ras, to investigate the relationship between myofiber disarray and septal surface strain. An isolated ejecting mouse heart preparation was used to record deformation of markers on the septal surface and to determine nonhomogeneous septal surface strain maps. Myofiber disarray made in histological tissue sections was correlated with gradients in surface systolic shortening. Significantly smaller maximum principal shortening was associated with disarray located near the right ventricle (RV) septal surface. There was also significantly smaller surface shear strain associated with disarray located either near the RV surface or at the midwall. Because surface shear is a local indicator of torsion, we conclude that myofiber disarray is associated with reduced septal torsion and reduced surface shortening.

Animals↗

PubMed1999

Differential responses of adult cardiac fibroblasts to in vitro biaxial strain patterns.

Different patterns of extracellular matrix (ECM) remodeling in the heart are thought to be dependent on altered mechanical and chemical conditions and can contribute to cardiac dysfunction. Cardiac fibroblasts are the primary regulators of the ECM and may respond to mechanical factors in vitro. We hypothesized that different types of in vitro strains, e.g. tensile or compressive, can stimulate different functional responses in cultured adult rat cardiac fibroblasts. In this study, we first showed that a single step in strain applied by a uniaxial stretch system stimulated collagen III and fibronectin mRNA levels and transforming growth factor-beta(1) (TGF-beta(1)) activity in the adult phenotype of rat cardiac fibroblasts. Two-dimensional deformations were measured by tracking fluorescent microspheres attached to the substrate and cultured cells. For 10% uniaxial strain, mean principal strains were 0. 104 +/- 0.018 in the direction of stretch and -0.042 +/- 0.013 in the perpendicular direction, verifying that the fibroblasts were simultaneously subjected to tensile (positive) and compressive (negative) strains. Furthermore, these cells were also subjected to area change and to shear. In order to examine the distinct effects of different types of deformation on cardiac fibroblasts, an equibiaxial stretch system was used to apply either pure tensile or compressive area strains, in the absence of shear. Magnitudes of equibiaxial strain were selected to apply local cell area changes identical to those applied in the uniaxial system. Results showed that pure tensile and compressive area strains induced divergent responses in ECM mRNA levels. TGF-beta(1) activity was dependent on the magnitude of applied area strain regardless of the mode of deformation. These findings demonstrate that adult cardiac fibroblasts may respond differently to varied types of mechanical loading, suggesting that ECM remodeling may be locally regulated by specific mechanical stimuli in the heart.

Animals↗

PubMed1999

Laminar fiber architecture and three-dimensional systolic mechanics in canine ventricular myocardium.

Previous studies suggest that the laminar architecture of left ventricular myocardium may be critical for normal ventricular mechanics. However, systolic three-dimensional deformation of the laminae has never been measured. Therefore, end-systolic finite strains relative to end diastole, from biplane radiography of transmural markers near the apex and base of the anesthetized open-chest canine anterior left ventricular free wall (n = 6), were referred to three-dimensional laminar microstructural axes reconstructed from histology. Whereas fiber shortening was uniform [-0.07 +/- 0.04 (SD)], radial wall thickening increased from base (0. 10 +/- 0.09) to apex (0.14 +/- 0.13). Extension of the laminae transverse to the muscle fibers also increased from base (0.08 +/- 0. 07) to apex (0.11 +/- 0.08), and interlaminar shear changed sign [0. 05 +/- 0.07 (base) and -0.07 +/- 0.09 (apex)], reflecting variations in laminar architecture. Nevertheless, the apex and base were similar in that at each site laminar extension and shear contributed approximately 60 and 40%, respectively, of mean transmural thickening. Kinematic considerations suggest that these dual wall-thickening mechanisms may have distinct ultrastructural origins.

Animals↗

PubMed1998

Automated measurement of myofiber disarray in transgenic mice with ventricular expression of ras.

Quantitative assessment of myofiber disarray associated with diseases such as familial hypertrophic cardiomyopathy (FHC) can be performed by estimating local angular deviation of fiber orientation in histologic sections. The large number of measurements required to estimate angular deviation prohibits manual measurement. We describe methods for automated measurement of local orientation and angular deviation in tissue sections from transgenic mice with ventricular expression of ras, proposed as a model of FHC. Images of histologic tissue sections from normal and transgenic mice were analyzed using image processing techniques to estimate local orientation of myofibers. Results from the automated methods were compared with manual measurements. Automated methods estimated differing mean orientation in 7-20% of normal sections and 17-29% of transgenic tissue sections with differing dispersions in 23-30% of normal sections and 25% of transgenic tissue sections. Automated methods estimate 24.47+/-13.03% of total ventricular mass affected by disarray that is comparable to a previous estimate of 21.7% in the same mouse model. Automated methods are a rapid and accurate alternative to manual measurement for estimation of mean orientation and angular deviation in myocardial tissue sections. Differences between manual and automated methods may be attributed to the substantially larger number of measurements made by automated methods. Automated methods are particularly appropriate for use in determining local variation in orientation such as focal myofiber disarray associated with FHC. The generality of these methods suggests they may have use in other biological fields such as quantifying cellular alignment.

Animals↗

PubMed1998

Flow-function relations during graded coronary occlusions in the dog: effects of transmural location and segment orientation.

OBJECTIVE: The sensitive relationship between regional myocardial perfusion and local systolic deformation during acute myocardial ischemia is not independent of the transmural location or segment orientation. The aim of this study was to determine the effects of fiber orientation and transmural location on the relationships between regional myocardial flow and three-dimensional systolic wall strain during graded coronary artery occlusions. METHODS: Transmural distributions of three-dimensional strain (by biplane radiography of implanted radiopaque markers) and myocardial blood flows (using fluorescent microspheres) were measured in the ischemic region during graded left anterior descending (LAD) coronary artery occlusions in 12 anesthetized dogs. RESULTS: Occlusion of the coronary artery did not significantly alter mean heart rate or end-systolic pressure. As flow decreased during graded occlusions, ischemia significantly changed systolic circumferential, longitudinal, radial, fiber and cross-fiber strains (p < 0.004). There was a significant effect of transmural position on circumferential, cross-fiber and radial strains, but not on fiber or longitudinal strains. Ischemia significantly altered all normal strains: circumferential, longitudinal, fiber, cross-fiber and radial. There was a strong interaction effect between transmural location and blood flow for circumferential, cross-fiber and radial strains, but not fiber or longitudinal strains. CONCLUSION: During non-transmural ischemia, there is evidence of strong transmural tethering in the cross-fiber direction, whereas the fiber-strain flow relation is independent of transmural position. Thus, whether the relationship between local myocardial bloodflow and systolic strain during acute ischemia is dependent on transmural location, depends on segment orientation.

Animals↗

PubMed1998

Cellular mechanisms for the slow phase of the Frank-Starling response.

Following a step increase in sarcomere length, isometric cardiac muscle tension increases instantaneously by the Frank-Starling mechanism. In isolated papillary muscle and myocytes, there is an additional significant rise in developed tension over the following 15 min due to an unknown mechanism. This slow change in tension could not be explained by mechanical heterogeneity of the muscle preparations or by an increase in myofilament sensitivity to Ca2+. The slow change in tension was not dependent on sarcoplasmic reticulum Ca2+ loading assessed with rapid cooling contractures, and was not significantly altered by sarcoplasmic reticulum Ca2+ depletion (ryanodine) or inhibition of sarcoplasmic reticulum Ca2+ reuptake (cyclopiazonic acid). We used the Luo-Rudy ionic model of the ventricular myocyte together with a model of the length-dependent myofilament activation by Ca2+ to examine the effects of step changes in the parameters of sarcolemmal ion fluxes as possible mechanisms for the slow change in stress. The slow increase in tension was simulated by step changes in the Na+-K+ pump or Na+ leak currents, suggesting that the slow change in stress may be caused by length induced changes in Na+ fluxes. The model also predicted a slow increase in the magnitude of the initial repolarization during phase 1 of the action potential. The combination of experimental and computational models used in this investigation represents a valuable technique in elucidating the cellular mechanisms of fundamental processes in cardiac excitation-contraction coupling.

Animals↗

PubMed1998

Three-dimensional analysis of regional cardiac function: a model of rabbit ventricular anatomy.

The three-dimensional geometry and anisotropic properties of the heart give rise to nonhomogeneous distributions of stress, strain, electrical activation and repolarization. In this article we review the ventricular geometry and myofiber architecture of the heart, and the experimental and modeling studies of three-dimensional cardiac mechanics and electrophysiology. The development of a three-dimensional finite element model of the rabbit ventricular geometry and fiber architecture is described in detail. Finally, we review the experimental results, from the level of the cell to the intact organ, which motivate the development of coupled three-dimensional models of cardiac electromechanics and mechanoelectric feedback.

Animals↗

PubMed1998

Modelling the mechanical properties of cardiac muscle.

A model of passive and active cardiac muscle mechanics is presented, suitable for use in continuum mechanics models of the whole heart. The model is based on an extensive review of experimental data from a variety of preparations (intact trabeculae, skinned fibres and myofibrils) and species (mainly rat and ferret) at temperatures from 20 to 27 degrees C. Experimental tests include isometric tension development, isotonic loading, quick-release/restretch, length step and sinusoidal perturbations. We show that all of these experiments can be interpreted with a four state variable model which includes (i) the passive elasticity of myocardial tissue, (ii) the rapid binding of Ca2+ to troponin C and its slower tension-dependent release, (iii) the kinetics of tropomyosin movement and availability of crossbridge binding sites and the length dependence of this process and (iv) the kinetics of crossbridge tension development under perturbations of myofilament length.

Actin Cytoskeleton↗

PubMed1998

Homogenization modeling for the mechanics of perfused myocardium.

Altered coronary perfusion can change the apparent diastolic stiffness of ventricular myocardium--the 'garden hose' effect. Our recent findings showed that myocardial strains are reduced during ventricular filling, primarily along the directions transverse to the coronary microvessels. In this article, we review hypotheses and theoretical models regarding the role that regional wall stress plays in the mechanical interaction between myocardium and coronary circulation. Various mechanisms have been used to explain the effects of the tissue stress on coronary flow, as well as the effect of coronary dynamics on myocardial mechanics. Many models of coronary pressure-flow relations using lumped parameter circuit analogs. Poroelasticity and swelling theories have been used to model the mechanics of perfused muscle. Here, we describe a new mathematical model of the mechanics of perfused myocardium derived using homogenization theory. In this model, perfused myocardium is treated as a nonlinear anisotropic elastic solid embedded with cylindrical vessels of known distensibility. The solid compartment is incompressible but the vascular compartment may change volume according to a simple relation between vessel diameter and perfusion pressure. The work done by the perfusion pressure in changing vascular volume contributes to the macroscopic strain energy and hence affects the stress and stiffness of the composite. Conversely, the stress in the tissue affects microvessel diameter and volume, since tractions transverse to the vessel axis oppose the internal blood pressure. Finite element simulations of passive filling show good agreement of model with experimental results.

Animals↗

PubMed1998

Residual strain in ischemic ventricular myocardium.

Structural remodeling during acute myocardial infarction affects ventricular wall stress and strain. To see whether acute myocardial infarction alters residual stress and strain in the left ventricle (LV), we measured opening angles in rat hearts after 30 minutes of left coronary artery occlusion. The mean opening angle in 18 ischemic hearts (51 +/- 20 deg) was significantly greater than in five sham-operated controls (29 +/- 11 deg, P < 0.05). To determine whether these alterations in residual strain may be associated with strain softening caused by systolic overstretch of the noncontracting ischemic tissue, we also measured opening angles in isolated hearts that had been passively inflated to high LV pressures (120 mmHg). The mean opening angle of the strain-softened hearts was not significantly different from the sham-operated hearts (34 +/- 27 deg, P = 0.74). Mean collagen area fractions in the myocardium were not significantly different between ischemic hearts (0.027 +/- 0.014) and the nonischemic group (0.022 +/- 0.011). Although there were significant differences in opening angles measured with ischemia, they do not appear to be a result of altered extracellular collagen content or softening associated with overstretch. Thus, there is a significant change in residual strain associated with acute ischemia that may be related to changes in collagen fiber structure, myocyte structure, or metabolic state.

Animals↗

PubMed1998

Left ventricular geometric remodeling and residual stress in the rat heart.

Theoretical considerations and observations of residual stress suggest that geometric remodeling in the heart may also alter residual stress and strain. We investigated whether changes in left ventricular geometry during physiologic growth were associated with corresponding changes in myocardial residual strain. In anesthetized rats from eight age groups ranging from 2-25+ weeks, the heart was arrested and isolated, and equatorial slices were obtained. The geometry of the intact, unloaded state was recorded, as well as the "opening angle" of the stress-free configuration after radial resection of the tissue slice. The tissue was fixed and embedded for histological examination of collagen area fraction. Heart weight increased 10-fold with age and unloaded internal radius increased almost 4-fold. However, wall thickness increased only 66 percent, so that the ratio of wall thickness to internal radius decreased significantly from 2.22 +/- 0.29 (mean +/- SD) at 2 weeks to 0.81 +/- 0.47 at 25 weeks. Opening angle of the stress-free slice decreased significantly from 87 +/- 16 deg at 2 weeks to 51 +/- 16 deg, and correlated linearly with wall thickness/radius ratio. Collagen area fraction increased with age. Hence physiologic ventricular remodeling in rats decreases myocardial residual strain in proportion to the relative reduction in wall thickness-radius ratio.

Aging↗

PubMed1998

Mechanisms of length history-dependent tension in an ionic model of the cardiac myocyte.

The ionic model of the ventricular myocyte developed by Luo and Rudy (Circ. Res. 74: 1071-1096, 1994) was used to investigate potential mechanisms of the slow changes in stress (SCS) that follow step changes in muscle length. A step change in myofilament sensitivity alone caused an immediate increase in active tension, but no SCS. The effects of additional step changes in the parameters of sarcolemmal ion fluxes were examined for each ion flux in the model. Changes in the coefficients of Ca2+ or K+ channels did not produce SCS. SCS was produced by step changes in parameters of the Na(+)-K+ pump or the Na+ leak current. This simulated mechanism was mediated through a slow increase in intracellular Na+ concentration and a resulting increase in systolic Ca2+ entry through the Na+/Ca2+ exchanger. The model reproduced the effects of several experimental interventions such as sarcoplasmic reticulum Ca2+ depletion, "diastolic" length changes, and changes in extracellular Ca2+. Thus SCS in cardiac muscle may be caused by length-induced changes in sarcolemmal Na+ fluxes.

Action Potentials↗

PubMed1998

Anterior-posterior strain variation in normally hydrated and swollen rabbit cornea.

PURPOSE: To investigate the variation in anterior and posterior straining under intraocular pressure changes for the central cornea of normally hydrated and swollen rabbit eyes. METHODS: A new method of measuring regional corneal strains, by imaging a specific tissue location at various intraocular pressures, was developed. Sixteen freshly enucleated, New Zealand White rabbit eyes were investigated either in their normal hydration state or after swelling of the deepithelialized cornea. The eyes were mounted on a specially designed eye fixture, and laser-scanning confocal microscopic images of a selected region in the anterior stroma or endothelium were taken at intraocular pressures of 5, 12.5, 20, 35, and 65 mm Hg. The positions of individual keratocytes or endothelial cells were used to calculate the nonhomogeneous two-dimensional strain field over the image. Corneal thickness was measured at the lowest and highest intraocular pressures (5 mm Hg and 65 mm Hg). RESULTS: All pressure strain curves were highly nonlinear for intraocular pressures between 5 mm Hg and 65 mm Hg; the maximal posterior strains (normally hydrated, 2.1 +/- 0.1%; swollen, 4.8 +/- 0.8%) were larger than the maximal anterior strains (normally hydrated, 1.8 +/- 0.1%; swollen, 1.5 +/- 0.2%). Swelling significantly decreased the anterior strain response but increased the posterior one. The corneal thickness decreased 7.4 +/- 0.4% for the normally hydrated and 6.3 +/- 0.5% for the swollen corneas for an intraocular pressure step from 5 mm Hg to 65 mm Hg. CONCLUSIONS: Bending was found to play a significant role in central corneal deformation of swollen eyes but not in the normal hydration state. Microscopic strain measurements of the cornea, using a laser-scanning confocal microscope, are a valuable tool for the assessment of regional nonhomogeneous strains in various depths and locations of the cornea.

Animals↗

PubMed1997

Multiaxial myocardial mechanics and extracellular matrix remodeling: mechanochemical regulation of cardiac fibroblast function.

Substantial evidence suggests that not only does the structure of the cardiac extracellular matrix affect the mechanical properties of myocardium, but that mechanical loading affects the synthesis of the extracellular matrix. However, loading conditions in vivo are nonhomogeneous and multiaxial. An experimental approach that combines mechanics and cell biology is used to examine the mechanisms of extracellular matrix remodeling in the heart. The results indicate that differential biological responses in adult cardiac fibroblasts can be correlated with specific physical signals, such as the magnitude and two dimensional (2D) pattern of strain. Some effects of flow-function relations are discussed.

Angiotensin II↗

PubMed1997

Strain softening in rat left ventricular myocardium.

We investigated whether strain softening (or the Mullins effect) may explain the reduced left ventricular stiffness previously associated with the strain-history-dependent preconditioning phenomenon. Passive pressure-volume relations were measured in the isolated, arrested rat heart during LV balloon inflation and deflation cycles. With inflation to a new higher maximum pressure, the pressure-volume relation became less stiff, particularly in the low (diastolic) pressure range, without a significant change in unloaded ventricular volume. In five different loading protocols in which the maximum passive cycle pressure ranged from 10 to 120 mmHg, we measured increases at 10 mmHg in LV volume up to 350 percent of unloaded volume that depended significantly on the history (p < 0.05) and magnitude (p < 0.01) of maximum previous pressure. Although a quasi-linear viscoelastic model based on the pressure-relaxation response could produce a nonlinear pressure-volume relation with hysteresis, it was unable to show any significant change in ventricular stiffness with new maximum pressure. We incorporated a strain softening theory proposed by Johnson and Beatty (1992) into the model by modifying the elastic response with a volume-amplification factor that depended on the maximum previous pressure. This model more accurately reproduced the experimentally observed behavior. Thus, the preconditioning behavior of the myocardium is better explained by strain softening rather than viscoelasticity and may be due to damage to elastic components, rather than the effect of viscous tissue components.

Animals↗

PubMed1997

Anterior and posterior left ventricular sarcomere lengths behave similarly during ejection.

Previous studies of regional differences in myocardial deformation between the anterior and posterior walls of the canine left ventricle were based on strain, which is not an absolute measure of deformation. We thus compared sarcomere lengths at anterior and posterior sites during ejection in isolated dog hearts. Cineradiographic imaging of regional deformation with radiopaque markers implanted near the midwall in five hearts and just below the epicardium in six hearts, combined with postmortem histology, allowed sarcomere length reconstruction throughout the cardiac cycle. The amount of sarcomere shortening accompanying left ventricular ejection was similar in both walls of the left ventricle for sarcomeres located at epicardial and midwall sites. The mean sarcomere length (taken at the middle of the ejecting range) was also similar between the anterior and posterior sites when averaged over all hearts. The similarity of sarcomere function held not only at end systole but throughout ejection and over wide ranges of ventricular pre- and afterloads. Hence functional measurements of relative myocardial shortening may not be indicative of regional sarcomere length heterogeneity.

Animals↗

PubMed1997

Biaxial mechanics of the passively overstretched left ventricle.

Overstretching the intact ventricle increases global compliance as a function of maximum previously experienced load and may have an important role in the diseased heart, but the corresponding changes in local myocardial mechanics and structure are unknown. Therefore, we measured two-dimensional strain on the left ventricular (LV) epicardium in isolated arrested rat hearts sequentially inflated to increasing cavity pressures of 10, 30, and 120 mmHg. Strains at matched LV pressures increased significantly (P < 0.002) as the maximum pressure previously experienced by the LV (Pmax) increased. Compared with Pmax = 10 mmHg, relative increases in fiber strain for Pmax = 30 and 120 mmHg (100 and 149%, respectively) were significantly greater (P < 0.001) than the corresponding increases in cross-fiber (51 and 78%, respectively) and fiber shear (57 and 86%, respectively) strains. Using an optimized prolate spheroidal finite-element model of the rat LV that reliably reproduced experimental strains, we estimated progressive decreases in epicardial biaxial wall stiffness up to 87% with increasing Pmax that were not different in the fiber and cross-fiber directions. Thus, although passive ventricular overloading causes direction-dependent increases in epicardial strain, these changes are the consequence of local myocardial softening that is actually independent of direction.

Animals↗

PubMed1997

Microstructural model of perimysial collagen fibers for resting myocardial mechanics during ventricular filling.

To study the structural contribution of perimysial collagen fibers to the passive mechanics of ventricular myocardium, we modeled the coiled fibers as helical springs using elastica theory to represent the fibers as initially curved, inextensible rods that could bend and twist. The extensional behavior in the physiological range of left ventricular (LV) pressures was dependent on structural parameters that were estimated histologically for rat and dog: collagen fiber diameter, coil period, collagen fiber tortuosity (fiber length in 2 dimensions/midline length), and number density (Nd) of collagen fibers per cross-sectional area of tissue. The difference in each geometric parameter was not great (27% maximal difference for Nd). However, the combined effect of all parameters accounted for a 102% difference in tissue stiffness. The only other model parameter was the Young's modulus (E) for bending of collagen, which was calculated from a linear regression of stress and strain scaled according to the geometric parameters. Despite an approximately fivefold difference in tissue stiffness, the resulting E was only 18.5% different (135 vs. 160 MPa for rat and dog, respectively). With the mean values from each species, the model was able to predict the stress-strain behavior of both rat and dog myocardium in the physiological range of LV pressures, suggesting that the perimysial collagen fibers may be the most important contributors to passive stiffness of the myocardium in the direction of the muscle fibers. It also appears that these large collagen fibers are not stretching to generate stress in the normal range of ventricular pressures, but rather stress gradually increases as collagen fibers straighten through bending and twisting. Finally, to understand the importance of differences in collagen architecture, one should measure the detailed collagen structure, not simply collagen density.

Animals↗