A novel method for quantifying in-vivo regional left ventricular myocardial contractility in the border zone of a myocardial infarction

Homogeneous contractility is usually assigned to the remote region, border zone (BZ), and the infarct in existing infarcted left ventricle (LV) mathematical models. Within the LV, the contractile function is therefore discontinuous. Here, we hypothesize that the BZ may in fact define a smooth linear transition in contractility between the remote region and the infarct. To test this hypothesis, we developed a mathematical model of a sheep LV having an anteroapical infarct with linearly-varying BZ contractility. Using an existing optimization method (Sun et al., 2009, "A Computationally Efficient Formal Optimization of Regional Myocardial Contractility in a Sheep With Left Ventricular Aneurysm," J. Biomech. Eng., 131(11), pp. 111001), we use that model to extract active material parameter T(max) and BZ width d(n) that "best" predict in-vivo systolic strain fields measured from tagged magnetic resonance images (MRI). We confirm our hypothesis by showing that our model, compared to one that has homogeneous contractility assigned in each region, reduces the mean square errors between the predicted and the measured strain fields. Because the peak fiber stress differs significantly (~15%) between these two models, our result suggests that future mathematical LV models, particularly those used to analyze myocardial infarction treatment, should account for a smooth linear transition in contractility within the BZ.     

MRI-based finite-element analysis of left ventricular aneurysm

Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling.     

The role of flow-independent viscoelasticity in the biphasic tensile and compressive responses of articular cartilage

A long-standing challenge in the biomechanics of connective tissues (e.g., articular cartilage, ligament, tendon) has been the reported disparities between their tensile and compressive properties. In general, the intrinsic tensile properties of the solid matrices of these tissues are dictated by the collagen content and microstructural architecture, and the intrinsic compressive properties are dictated by their proteoglycan content and molecular organization as well as water content. These distinct materials give rise to a pronounced and experimentally well-documented nonlinear tension-compression stress-strain responses, as well as biphasic or intrinsic extracellular matrix viscoelastic responses. While many constitutive models of articular cartilage have captured one or more of these experimental responses, no single constitutive law has successfully described the uniaxial tensile and compressive responses of cartilage within the same framework. The objective of this study was to combine two previously proposed extensions of the biphasic theory of Mow et al. [1980, ASME J. Biomech. Eng., 102, pp. 73-84] to incorporate tension-compression nonlinearity as well as intrinsic viscoelasticity of the solid matrix of cartilage. The biphasic-conewise linear elastic model proposed by Soltz and Ateshian [2000, ASME J. Biomech. Eng., 122, pp. 576-586] and based on the bimodular stress-strain constitutive law introduced by Curnier et al. [1995, J. Elasticity, 37, pp. 1-38], as well as the biphasic poroviscoelastic model of Mak [1986, ASME J. Biomech. Eng., 108, pp. 123-130], which employs the quasi-linear viscoelastic model of Fung [1981, Biomechanics: Mechanical Properties of Living Tissues, Springer-Verlag, New York], were combined in a single model to analyze the response of cartilage to standard testing configurations. Results were compared to experimental data from the literature and it was found that a simultaneous prediction of compression and tension experiments of articular cartilage, under stress-relaxation and dynamic loading, can be achieved when properly taking into account both flow-dependent and flow-independent viscoelasticity effects, as well as tension-compression nonlinearity.     

Numerical modeling of stress in stenotic arteries with microcalcifications: a parameter sensitivity study

As a follow-up to the work presented in Wenk et al. (2010, "Numerical Modeling of Stress in Stenotic Arteries With Microcalcifications: A Micromechanical Approximation," ASME J. Biomech. Eng., 132, p. 091011), a formal sensitivity study was conducted in which several model parameters were varied. The previous work only simulated a few combinations of the parameters. In the present study, the fibrous cap thickness, longitudinal position of the region of microcalcifications, and volume fraction of microcalcifications were varied over a broader range of values. The goal of the present work is to investigate the effects of localized regions of microcalcifications on the stress field of atherosclerotic plaque caps in a section of carotid artery. More specifically, the variations in the magnitude and location of the maximum circumferential stress were assessed for a range of parameters using a global sensitivity analysis method known as Sobol' indices. The stress was calculated by performing finite element simulations of three-dimensional fluid-structure interaction models, while the sensitivity indices were computed using a Monte Carlo scheme. The results indicate that cap thickness plays a significant role in the variation in the magnitude of the maximum circumferential stress, with the sensitivity to volume fraction increasing when the region of microcalcification is located at the shoulder. However, the volume fraction played a larger role in the variation in the location of the maximum circumferential stress. This matches the finding of the previous study (Wenk et al., 2010, "Numerical Modeling of Stress in Stenotic Arteries With Microcalcifications: A Micromechanical Approximation," ASME J. Biomech. Eng., 132, p. 091011), which indicates that the maximum circumferential stress always shifts to the region of microcalcification.     

On the electric potentials inside a charged soft hydrated biological tissue: streaming potential versus diffusion potential

The main objective of this study is to determine the nature of electric fields inside articular cartilage while accounting for the effects of both streaming potential and diffusion potential. Specifically, we solve two tissue mechano-electrochemical problems using the triphasic theories developed by Lai et al. (1991, ASME J. Biomech Eng., 113, pp. 245-258) and Gu et al. (1998, ASME J. Biomech. Eng., 120, pp. 169-180) (1) the steady one-dimensional permeation problem; and (2) the transient one-dimensional ramped-displacement, confined-compression, stress-relaxation problem (both in an open circuit condition) so as to be able to calculate the compressive strain, the electric potential, and the fixed charged density (FCD) inside cartilage. Our calculations show that in these two technically important problems, the diffusion potential effects compete against the flow-induced kinetic effects (streaming potential) for dominance of the electric potential inside the tissue. For softer tissues of similar FCD (i.e., lower aggregate modulus), the diffusion potential effects are enhanced when the tissue is being compressed (i.e., increasing its FCD in a nonuniform manner) either by direct compression or by drag-induced compaction; indeed, the diffusion potential effect may dominate over the streaming potential effect. The polarity of the electric potential field is in the same direction of interstitial fluid flow when streaming potential dominates, and in the opposite direction of fluid flow when diffusion potential dominates. For physiologically realistic articular cartilage material parameters, the polarity of electric potential across the tissue on the outside (surface to surface) may be opposite to the polarity across the tissue on the inside (surface to surface). Since the electromechanical signals that chondrocytes perceive in situ are the stresses, strains, pressures and the electric field generated inside the extracellular matrix when the tissue is deformed, the results from this study offer new challenges for the understanding of possible mechanisms that control chondrocyte biosyntheses.     

Functional and bioenergetic modulations in the infarct border zone following autologous mesenchymal stem cell transplantation

Preclinical and clinical studies have demonstrated that stem cell transplantation can improve the left ventricular (LV) contractile performance, yet the underlying mechanisms remain unknown. We examined whether mesenchymal stem cell (MSC) transplantation-induced beneficial effects are secondary to paracrine-associated improvements in LV contractile performance, wall stress, and myocardial bioenergetics in hearts with postinfarction LV remodeling. Myocardial contractile function and bioenergetics were compared 4 wk after acute myocardial infarction in normal pigs (n = 6), untreated pigs with myocardial infarction (MI group; n = 6), and pigs receiving autologous MSC transplantation (MI + MSC group; n = 5). A distal occlusion of the left anterior descending coronary artery instigated significant myocardial hypertrophy. Ejection fraction decreased from 55.3 +/- 3.1% (normal) to 30.4 +/- 2.3% (MI group; P < 0.01) and to 45.4 +/- 3.1% (MI + MSC group; P < 0.01 vs. MI). Hearts in the MI group developed severe contractile dyskinesis in the infarct zone and border zone (BZ). MSC transplantation significantly improved contractile performance from dyskinesis to active contraction (P < 0.01 vs. MI). BZ systolic wall stress was severely increased in MI hearts but significantly improved after MSC transplantation (P < 0.01 vs. MI). The BZ demonstrated profound bioenergetic abnormalities in MI pigs; this was significantly improved after MSC transplantation (P < 0.01 vs. MI). Patchy spared myocytes were found in the infarct zone of hearts receiving MSC transplantation but not in control hearts. These data demonstrate that MSC transplantation into the BZ causes significant improvements in myocardial contractile performance and reduction in wall stress, which ultimately results in significant bioenergetic improvements. Low cell engraftment indicates that MSCs did not provide a structural contribution to the damaged heart and that the observed beneficial effects likely resulted from paracrine repair mechanisms.     

Profound bioenergetic abnormalities in peri-infarct myocardial regions

Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F(1)F(0)-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 +/- 5.4% to 31 +/- 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio ((31)P-magnetic resonance spectroscopy) decreased from 2.06 +/- 0.19 in normal hearts to 1.07 +/- 0.10, with decreases in alpha-, beta-, OSCP, and IF(1) subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure.     

Effects of hydrogel injection on borderzone contractility post-myocardial infarction

Injectable hydrogels are a potential therapy for mitigating adverse left ventricular (LV) remodeling after myocardial infarction (MI). Previous studies using magnetic resonance imaging (MRI) have shown that hydrogel treatment improves systolic strain in the borderzone (BZ) region surrounding the infarct. However, the corresponding contractile properties of the BZ myocardium are still unknown. The goal of the current study was to quantify the in vivo contractile properties of the BZ myocardium post-MI in an ovine model treated with an injectable hydrogel. Contractile properties were determined 8 weeks following posterolateral MI by minimizing the difference between in vivo strains and volume calculated from MRI and finite element model predicted strains and volume. This was accomplished by using a combination of MRI, catheterization, finite element modeling, and numerical optimization. Results show contractility in the BZ of animals treated with hydrogel injection was significantly higher than untreated controls. End-systolic (ES) fiber stress was also greatly reduced in the BZ of treated animals. The passive stiffness of the treated infarct region was found to be greater than the untreated control. Additionally, the wall thickness in the infarct and BZ regions was found to be significantly higher in the treated animals. Treatment with hydrogel injection significantly improved BZ function and reduced LV remodeling, via altered MI properties. These changes are linked to a reduction in the ES fiber stress in the BZ myocardium surrounding the infarct. The current results imply that injectable hydrogels could be a viable therapy for maintaining LV function post-MI.     

Interaction between left ventricular wall motion and intraventricular flow propagation in acute and chronic ischemia

Myocardial ischemia has been associated with left ventricular (LV) postsystolic shortening. The combination of tissue Doppler imaging and high frame-rate acquisition of two-dimensional color flow makes it possible to study the interaction between LV wall motion and intraventricular flow propagation. The aim of this study was to examine in a clinical model the impact that acute myocardial ischemia and prior myocardial infarct might have on LV flow patterns and to explain the underlying mechanisms from the tissue Doppler data. LV flow propagation and tissue velocities during early diastole were studied in 18 healthy individuals, 17 patients with prior anterior myocardial infarct, and 16 patients before and during percutaneous coronary intervention (PCI) of the left anterior descending artery. Normal individuals had intraventricular flow propagation toward the apex during isovolumic relaxation. During this early diastolic time phase, myocardial velocities measured at mid- and apical septal segment were directed away from the apex. Before PCI, patients without myocardial infarction had similar findings as in normal individuals. In contrast, each patient with either prior myocardial infarction or PCI-induced acute ischemia had flow propagation opposite to normal individuals, and tissue velocities reversed toward the apex during early diastole. Reversal of early diastolic LV flow propagation in acute and chronic anterior myocardial ischemia reflects postsystolic shortening in the dyskinetic apical and septal myocardial segments.     

Cross-sectional profiles and volume reconstructions of soft tissues using laser beam measurements

Precise geometric reconstruction is a valuable tool in the study of soft tissues biomechanics. Optical methods have been developed to determine the tissue cross section without mechanical contact with the specimen. An adaptation of the laser micrometer developed by Lee and Woo [ASME J. Biomech. Eng., 110 (2), pp. 110-114]. is proposed in which the laser-collimated beam rotates around and moves along a fixed specimen to reconstruct its cross sections and volume. Beam motion is computer controlled to accelerate data acquisition and improve beam positioning accuracy. It minimizes time-dependent shape modifications and increases global reconstruction precision. The technique is also competent for the measurement of immersed collagen matrices.     

Effects of tension-compression nonlinearity on solute transport in charged hydrated fibrous tissues under dynamic unconfined compression

Cartilage is a charged hydrated fibrous tissue exhibiting a high degree of tension-compression nonlinearity (i.e., tissue anisotropy). The effect of tension-compression nonlinearity on solute transport has not been investigated in cartilaginous tissue under dynamic loading conditions. In this study, a new model was developed based on the mechano-electrochemical mixture model [Yao and Gu, 2007, J. Biomech. Model Mechanobiol., 6, pp. 63-72, Lai et al., 1991, J. Biomech. Eng., 113, pp. 245-258], and conewise linear elasticity model [Soltz and Ateshian, 2000, J. Biomech. Eng., 122, pp. 576-586; Curnier et al., 1995, J. Elasticity, 37, pp. 1-38]. The solute desorption in cartilage under unconfined dynamic compression was investigated numerically using this new model. Analyses and results demonstrated that a high degree of tissue tension-compression nonlinearity could enhance the transport of large solutes considerably in the cartilage sample under dynamic unconfined compression, whereas it had little effect on the transport of small solutes (at 5% dynamic strain level). The loading-induced convection is an important mechanism for enhancing the transport of large solutes in the cartilage sample with tension-compression nonlinearity. The dynamic compression also promoted diffusion of large solutes in both tissues with and without tension-compression nonlinearity. These findings provide a new insight into the mechanisms of solute transport in hydrated, fibrous soft tissues.     

Autologous stem cell transplantation for myocardial repair

Current therapies for heart failure due to transmural left ventricular (LV) infarction are limited. We have developed a novel patch method for delivering autologous bone marrow stem cells to sites of myocardial infarction for the purpose of improving LV function and preventing LV aneurysm formation. The patch consisted of a fibrin matrix seeded with autologous porcine mesenchymal stem cells labeled with lacZ. We applied this patch to a swine model of postinfarction LV remodeling. Myocardial infarction was produced by using a 60-min occlusion of the left anterior descending coronary artery distal to the first diagonal branch followed by reperfusion. Results were compared between eight pigs with stem cell patch transplantation, six pigs with the patch but no stem cells (P), and six pigs with left anterior descending coronary artery ligation alone (L). Magnetic resonance imaging data collected 19 +/- 1 days after the myocardial infarction indicated a significant increase of LV systolic wall thickening fraction in the infarct zone of transplanted hearts compared with P or L hearts. Blue X-gal staining was observed in the infarcted area of transplanted hearts. PCR amplification of specimens from the X-gal-positive area revealed the Ad5 RSV-lacZ vector fragment DNA sequence. Light microscopy demonstrated that transplanted cells had differentiated into cells with myocyte-like characteristics and a robust increase of neovascularization as evidenced by von Willebrand factor-positive angioblasts and capillaries in transplanted hearts. Thus this patch-based autologous stem cell procedure may serve as a therapeutic modality for myocardial repair.     

Physical signals and solute transport in human intervertebral disc during compressive stress relaxation: 3D finite element analysis

A 3D finite element model for charged hydrated soft tissues containing charged/uncharged solutes was developed based on the multi-phasic mechano-electrochemical mixture theory (Lai et al., J. Biomech. Eng. 113 (1991), 245-258; Gu et al., J. Biomech. Eng. 120 (1998), 169-180). This model was applied to analyze the mechanical, chemical and electrical signals within the human intervertebral disc during an unconfined compressive stress relaxation test. The effects of tissue composition [e.g., water content and fixed charge density (FCD)] on the physical signals and the transport rate of fluid, ions and nutrients were investigated. The numerical simulation showed that, during disc compression, the fluid pressurization was more pronounced at the center (nucleus) region of the disc while the effective (von Mises) stress was higher at the outer (annulus) region. Parametric analyses revealed that the decrease in initial tissue water content (0.7-0.8) increased the peak stress and relaxation time due to the reduction of permeability, causing greater fluid pressurization effect. The electrical signals within the disc were more sensitive to FCD than tissue porosity, and mechanical loading affected the large solute (e.g., growth factor) transport significantly, but not for small solute (e.g., glucose). Moreover, this study confirmed that the interstitial fluid pressurization plays an important role in the load support mechanism of IVD by sharing more than 40% of the total load during disc compression. This study is important for understanding disc biomechanics, disc nutrition and disc mechanobiology.     

Critical role of angiopoietins/Tie-2 in hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis

Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) are the two ligands of the Tie-2 receptor, a receptor tyrosine kinase that is expressed on the endothelium. A balanced angiopoietin/Tie-2 system is critical for the maintenance of vascular integrity. We investigated the potential role of a disrupted angiopoietin/Tie-2 system on hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Using streptozotocin (STZ) mice subjected to myocardial ischemia, we examined the effects of shifting the Ang-2-to-Ang-1 ratio on myocardial infarction size, apoptosis, bone marrow (BM) cell-endothelial progenitor cell (EPC) differentiation, and angiogenesis. In control mice, myocardial ischemia increased expression of both Ang-2 and Tie-2. In STZ mice, Ang-2 expression was elevated, whereas Tie-2 expression was reduced, and neither was significantly altered by ischemia. Myocardial infarct size and apoptosis were increased in STZ compared with control mice. Using in vivo administration of an adenovirus containing Ang-1 or Ang-2, we found that shifting the Ang-2-to-Ang-1 ratio to favor Ang-1 reduced myocardial apoptosis and infarct size in STZ mice, while shifting the Ang-2-to-Ang-1 ratio to favor Ang-2 resulted in a significant increase in myocardial infarct size and apoptosis in control mice. Myocardial ischemia-stimulated BM cell-EPC differentiation was inhibited and myocardial angiogenesis was reduced in STZ mice. Systemic administration of Ad-Ang-1 restored BM cell-EPC differentiation and increased myocardial VEGF expression and angiogenesis in STZ mice. Our data demonstrate that disturbed angiopoietin/Tie-2 signaling contributes to the hyperglycemic exacerbation of myocardial infarction and impaired angiogenesis. Restoration of the Ang-2-to-Ang-1 ratio may be a novel therapeutic strategy for the treatment of diabetic myocardial ischemic diseases.     

The deformation of an erythrocyte under the radiation pressure by optical stretch

In this paper, the mechanical properties of erythrocytes were studied numerically based upon the mechanical model originally developed by Pamplona and Calladine (ASME J. Biomech. Eng., 115, p. 149, 1993) for liposomes. The case under study is the erythrocyte stretched by a pair of laser beams in opposite directions within buffer solutions. The study aims to elucidate the effect of radiation pressure from the optical laser because up to now little is known about its influence on the cell deformation. Following an earlier study by Guck et al. (Phys. Rev. Lett., 84, p. 5451, 2000; Biophys. J., 81, p. 767, 2001), the empirical results of the radiation pressure were introduced and imposed on the cell surface to simulate the real experimental situation. In addition, an algorithm is specially designed to implement the simulation. For better understanding of the radiation pressure on the cell deformation, a large number of simulations were conducted for different properties of cell membrane. Results are first discussed parametrically and then evaluated by comparing with the experimental data reported by Guck et al. An optimization approach through minimizing the errors between experimental and numerical data is used to determine the optimal values of membrane properties. The results showed that an average shear stiffness around 4.611x10-6 Nm(-1), when the nondimensional ratio of shear modulus to bending modulus ranges from 10 to 300. These values are in a good agreement with those reported in literature.     

Viscerosomatic interaction induced by myocardial ischemia in conscious dogs.

Studies tested the hypothesis that myocardial ischemia induces increased paraspinal muscular tone localized to the T(2)-T(5) region that can be detected by palpatory means. This is consistent with theories of manual medicine suggesting that disturbances in visceral organ physiology can cause increases in skeletal muscle tone in specific muscle groups. Clinical studies in manual and traditional medicine suggest this phenomenon occurs during episodes of myocardial ischemia and may have diagnostic potential. However, there is little direct evidence of a cardiac-somatic mechanism to explain these findings. Chronically instrumented dogs [12 neurally intact and 3 following selective left ventricular (LV) sympathectomy] were examined before, during, and after myocardial ischemia. Circumflex blood flow (CBF), left ventricular contractile function, electromyographic (EMG) analysis, and blinded manual palpatory assessments (MPA) of tissue over the transverse spinal processes at segments T(2)-T(5) and T(11)-T(12) (control) were performed. Myocardial ischemia was associated with a decrease in myocardial contractile function and an increase in heart rate. MPA revealed increases in muscle tension and texture/firmness during ischemia in the T(2)-T(5) segments on the left, but not on the right or in control segments. EMG demonstrated increased amplitude for the T(4)-T(5) segments. After LV sympathectomy, MPA and EMG evidence of increased muscle tone were absent. In conclusion, myocardial ischemia is associated with significant increased paraspinal muscle tone localized to the left side T(4)-T(5) myotomes in neurally intact dogs. LV sympathectomy eliminates the somatic response, suggesting that sympathetic neural traffic between the heart and somatic musculature may function as the mechanism for the interaction.     

DITPA stimulates arteriolar growth and modifies myocardial postinfarction remodeling

Myocardial infarction (MI) is characterized by ventricular remodeling, hypertrophy of the surviving myocardium, and an insufficient angiogenic response. Thyroxine is a powerful stimulus for myocardial angiogenesis. Male rats that underwent coronary artery ligation and subsequent MI were given 3,5-diiodothyropropionic acid (DITPA; MI+DITPA group) during a 3-wk period. We evaluated ventricular remodeling using echocardiography and histology and myocardial vessel growth using image analysis. Protein expression was assessed using Western blotting and immunohistochemistry. This study tested the hypothesis that the thyroxine analog DITPA facilitates angiogenesis and influences postinfarction remodeling in the surviving hypertrophic myocardium. The increase in the region of akinesis (infarct expansion) was blunted in the MI+DITPA rats compared with the MI group (3 vs. 21%); the treated rats had smaller percent increases in the left ventricular (LV) volume (64 +/- 14 vs. 95 +/- 12) and the LV volume-to-mass ratio (47 +/- 13 vs. 84 +/- 10) as well as a blunted decrease in ejection fraction (-9 +/- 8 vs. -30 +/- 7%). Arteriolar length density was higher after treatment in the largest (>50% of the free wall) infarcts (64 +/- 3 vs. 43 +/- 7). Angiogenic growth factors [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)] and the angiopoietin receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie-2) values were elevated during the first week after infarction. DITPA did not cause additional increases in VEGF or Tie-2 values but did induce an increase in bFGF value after 3 days of treatment. This study provides the first evidence for an anatomical basis, i.e., attenuated ventricular remodeling and arteriolar growth, for improved function attributed to DITPA therapy of the infarcted heart. The favorable influences of DITPA on LV remodeling after large infarction are principally due to border zone preservation.     

Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty-nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES-induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non-infarct zone (NIZ) were determined by real-time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down-regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up-regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES-induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression.     

A model for the modulation of microvessel permeability by junction strands

To investigate the effect of junction strands on microvessel permeability, we extend the previous analytical model developed by Fu et al. (1994, J. Biomech. Eng., 116, pp. 502-513), for the interendothelial cleft to include multiple junction strands in the cleft and an interface between the surface glycocalyx layer and the cleft entrance. Based on the electron microscopic observations by Adamson et al. (1998, Am. J. Physiol., 274(43), pp. H1885-H1894), that elevation of intracellular cAMP levels would increase number of tight junction strands, this two-junction-strand and two-pore model can successfully account for the experimental data for the decreased permeability to water, small and intermediate-sized solutes by cAMP.     

Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats

In this study, the cardioprotective effects of nitric oxide (NO)-aspirin, the nitroderivative of aspirin, were compared with those of aspirin in an anesthetized rat model of myocardial ischemia-reperfusion. Rats were given aspirin or NO-aspirin orally for 7 consecutive days preceding 25 min of myocardial ischemia followed by 48 h of reperfusion (MI/R). Treatment groups included vehicle (Tween 80), aspirin (30 mg.kg(-1).day(-1)), and NO-aspirin (56 mg.kg(-1).day(-1)). NO-aspirin, compared with aspirin, displayed remarkable cardioprotection in rats subjected to MI/R as determined by the mortality rate and infarct size. Mortality rates for vehicle (n = 23), aspirin (n = 22), and NO-aspirin groups (n = 22) were 34.8, 27.3, and 18.2%, respectively. Infarct size of the vehicle group was 44.5 +/- 2.7% of the left ventricle (LV). In contrast, infarct size of the LV decreased in the aspirin- and NO-aspirin-pretreated groups, 36.7 +/- 1.8 and 22.9 +/- 4.3%, respectively (both P < 0.05 compared with vehicle group; P < 0.05, NO-aspirin vs. aspirin ). Moreover, NO-aspirin also improved ischemia-reperfusion-induced myocardial contractile dysfunction on postischemic LV developed pressure. In addition, NO-aspirin downregulated inducible NO synthase (iNOS; 0.37-fold, P < 0.01) and cyclooxygenase-2 (COX-2; 0.61-fold, P < 0.05) gene expression compared with the vehicle group after 48 h of reperfusion. Treatment with N(G)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg), a nonselective NOS inhibitor, aggravated myocardial damage in terms of mortality and infarct size but attenuated effects when coadministered with NO-aspirin. L-NAME administration did not alter the increase in iNOS and COX-2 expression but did reverse the NO-aspirin-induced inhibition of expression of the two genes. The beneficial effects of NO-aspirin appeared to be derived largely from the NO moiety, which attenuated myocardial injury to limit infarct size and better recovery of LV function following ischemia and reperfusion.