Simulation of mechanical environment in active lead fixation: effect of fixation helix size

The risk of myocardial penetration due to active-fixation screw-in type pacing leads has been reported to increase as the helix electrodes become smaller. In order to understand the contributing factors for lead penetration, we conducted finite element analyses of acute myocardial micro-damage induced by a pacemaker lead screw-in helix electrode. We compared the propensity for myocardial micro-damage of seven lead designs including a baseline model, three modified designs with various helix wire cross-sectional diameters, and three modified designs with different helix diameters. The comparisons show that electrodes with a smaller helix wire diameter cause more severe micro-damage to the myocardium in the early stage. The damage severity, represented by the volume of failed elements, is roughly the same in the middle stage, whereas in the later stage the larger helix wire diameter generally causes more severe damage. The onset of myocardial damage is not significantly affected by the helix diameter. As the helix diameter increases, however, the extent of myocardial damage increases accordingly. The present findings identified several of the major risk factors for myocardial damage whose consideration for lead use and design might improve acute and chronic lead performance.     

Conductance catheter measurements of lumen area of stenotic coronary arteries: theory and experiment

An injection of saline solution is required for the measurement of vessel lumen area using a conductance catheter. The injection of room temperature saline to displace blood in a vessel inevitably involves mass and heat transport and electric field conductance. The objective of the present study is to understand the accuracy of conductance method based on the phenomena associated with the saline injection into a stenotic blood vessel. Computational fluid dynamics were performed to simulate flow and its relation to transport and electric field in a stenotic artery for two different sized conductance catheters (0.9 and 0.35 mm diameter) over a range of occlusions [56-84% cross-sectional area (CSA) stenosis]. The results suggest that the performance of conductance catheter is dependent on catheter size and severity of stenosis more significantly for 0.9 mm than for 0.35 mm catheter. Specifically, the time of detection of 95% of injected saline solution at the detection electrodes was shown to range from 0.67 to 3.7 s and 0.82 to 0.94 s for 0.9 mm and 0.35 mm catheter, respectively. The results also suggest that the detection electrodes of conductance catheter should be placed outside of flow recirculation region distal to the stenosis to minimize the detection time. Finally, the simulations show that the accuracy in distal CSA measurements, however, is not significantly altered by whether the position of detection electrodes is inside or outside of recirculation zone (error was within 12% regardless of detection electrodes position). The results were experimentally validated for one lesion geometry and the simulation results are within 8% of actual measurements. The simulation of conductance catheter injection method may lead to further optimization of device and method for accurate sizing of diseased coronary arteries, which has clinical relevance to percutaneous intervention.     

Mis-sizing of stent promotes intimal hyperplasia: impact of endothelial shear and intramural stress

Stent can cause flow disturbances on the endothelium and compliance mismatch and increased stress on the vessel wall. These effects can cause low wall shear stress (WSS), high wall shear stress gradient (WSSG), oscillatory shear index (OSI), and circumferential wall stress (CWS), which may promote neointimal hyperplasia (IH). The hypothesis is that stent-induced abnormal fluid and solid mechanics contribute to IH. To vary the range of WSS, WSSG, OSI, and CWS, we intentionally mismatched the size of stents to that of the vessel lumen. Stents were implanted in coronary arteries of 10 swine. Intravascular ultrasound (IVUS) was used to size the coronary arteries and stents. After 4 wk of stent implantation, IVUS was performed again to determine the extent of IH. In conjunction, computational models of actual stents, the artery, and non-Newtonian blood were created in a computer simulation to yield the distribution of WSS, WSSG, OSI, and CWS in the stented vessel wall. An inverse relation (R(2) = 0.59, P < 0.005) between WSS and IH was found based on a linear regression analysis. Linear relations between WSSG, OSI, and IH were observed (R(2) = 0.48 and 0.50, respectively, P < 0.005). A linear relation (R(2) = 0.58, P < 0.005) between CWS and IH was also found. More statistically significant linear relations between the ratio of CWS to WSS (CWS/WSS), the products CWS × WSSG and CWS × OSI, and IH were observed (R(2) = 0.67, 0.54, and 0.56, respectively, P < 0.005), suggesting that both fluid and solid mechanics influence the extent of IH. Stents create endothelial flow disturbances and intramural wall stress concentrations, which correlate with the extent of IH formation, and these effects were exaggerated with mismatch of stent/vessel size. These findings reveal the importance of reliable vessel and stent sizing to improve the mechanics on the vessel wall and minimize IH.     

Reaction of hemoglobin with HOCl: mechanism of heme destruction and free iron release

Hypochlorous acid (HOCl) is generated by myeloperoxidase using chloride and hydrogen peroxide as substrates. HOCl and its conjugate base (OCl⁻) bind to the heme moiety of hemoglobin (Hb) and generate a transient ferric species whose formation and decay kinetics indicate it can participate in protein aggregation and heme destruction along with subsequent free iron release. The oxidation of the Hb heme moiety by OCl⁻ was accompanied by marked heme destruction as judged by the decrease in and subsequent flattening of the Soret absorbance peak at 405 nm. HOCl-mediated Hb heme depletion was confirmed by HPLC analysis and in-gel heme staining. Exposure of Hb to increasing concentrations of HOCl produced a number of porphyrin degradation products resulting from oxidative cleavage of one or more of the carbon-methene bridges of the tetrapyrrole ring, as identified by their characteristic HPLC fluorescence and LC-MS. A nonreducing denaturing SDS-PAGE showed several degrees of protein aggregation. Similarly, porphyrin degradation products were identified after exposure of red blood cells to increasing concentrations of HOCl, indicating biological relevance of this finding. This work provides a direct link between Hb heme destruction and subsequent free iron accumulation, as occurs under inflammatory conditions where HOCl is formed in substantial amounts.     

A novel arterial constitutive model in a commercial finite element package: Application to balloon angioplasty

Recently, a novel linearized constitutive model with a new strain measure that absorbs the material nonlinearity was validated for arteries. In this study, the linearized arterial stress-strain relationship is implemented into a finite element method package, ANSYS, via the user subroutine USERMAT. The reference configuration is chosen to be the closed cylindrical tube (no-load state) rather than the open sector (zero-stress state). The residual strain is taken into account by analytic calculation and the incompressibility condition is enforced with Lagrange penalty method. Axisymmetric finite element analyses are conducted to demonstrate potential applications of this approach in a complex boundary value problem where angioplasty balloon interacts with the vessel wall. The model predictions of transmural circumferential and compressive radial stress distributions were also validated against an exponential-type Fung model, and the mean error was found to be within 6%.     

Cofilin determines the migration behavior and turning frequency of metastatic cancer cells

We have investigated the effects of inhibiting the expression of cofilin to understand its role in protrusion dynamics in metastatic tumor cells, in particular. We show that the suppression of cofilin expression in MTLn3 cells (an apolar randomly moving amoeboid metastatic tumor cell) caused them to extend protrusions from only one pole, elongate, and move rectilinearly. This remarkable transformation was correlated with slower extension of fewer, more stable lamellipodia leading to a reduced turning frequency. Hence, the loss of cofilin caused an amoeboid tumor cell to assume a mesenchymal-type mode of movement. These phenotypes were correlated with the loss of uniform chemotactic sensitivity of the cell surface to EGF stimulation, demonstrating that to chemotax efficiently, a cell must be able to respond to chemotactic stimulation at any region on its surface. The changes in cell shape, directional migration, and turning frequency were related to the re-localization of Arp2/3 complex to one pole of the cell upon suppression of cofilin expression.     

The high reactivity of peroxiredoxin 2 with H(2)O(2) is not reflected in its reaction with other oxidants and thiol reagents

Peroxiredoxin 2 is a member of the mammalian peroxiredoxin family of thiol proteins that is important in antioxidant defense and redox signaling. We have examined its reactivity with various biological oxidants, in order to assess its ability to act as a direct physiological target for these species. Human erythrocyte peroxiredoxin 2 was oxidized stoichiometrically to its disulfide-bonded homodimer by hydrogen peroxide, as monitored electrophoretically under nonreducing conditions. The protein was highly susceptible to oxidation by adventitious peroxide, which could be prevented by treating buffers with low concentrations of catalase. However, this did not protect peroxiredoxin 2 against oxidation by added H(2)O(2). Experiments measuring inhibition of dimerization indicated that at pH 7.4 catalase and peroxiredoxin 2 react with hydrogen peroxide at comparable rates. A rate constant of 1.3 x 10(7) M(-1) s(-1) for the peroxiredoxin reaction was obtained from competition kinetic studies with horseradish peroxidase. This is 100-fold faster than is generally assumed. It is sufficiently high for peroxiredoxin to be a favored cellular target for hydrogen peroxide, even in competition with catalase or glutathione peroxidase. Reactions of t-butyl and cumene hydroperoxides with peroxiredoxin were also fast, but amino acid chloramines reacted much more slowly. This contrasts with other thiol compounds that react many times faster with chloramines than with hydrogen peroxide. The alkylating agent iodoacetamide also reacted extremely slowly with peroxiredoxin 2. These results demonstrate that peroxiredoxin 2 has a tertiary structure that facilitates reaction of the active site thiol with hydrogen peroxide while restricting its reactivity with other thiol reagents.     

A hybrid one-dimensional/Womersley model of pulsatile blood flow in the entire coronary arterial tree

Using a frequency-domain Womersley-type model, we previously simulated pulsatile blood flow throughout the coronary arterial tree. Although this model represents a good approximation for the smaller vessels, it does not take into account the nonlinear convective energy losses in larger vessels. Here, using Womersley's theory, we present a hybrid model that considers the nonlinear effects for the larger epicardial arteries while simulating the distal vessels (down to the 1st capillary segments) with the use of Womersley's Theory. The main trunk and primary branches were discretized and modeled with one-dimensional Navier-Stokes equations, while the smaller-diameter vessels were treated as Womersley-type vessels. Energy losses associated with vessel bifurcations were incorporated in the present analysis. The formulation enables prediction of impedance and pressure and pulsatile flow distribution throughout the entire coronary arterial tree down to the first capillary segments in the arrested, vasodilated state. We found that the nonlinear convective term is negligible and the loss of energy at a bifurcation is small in the larger epicardial vessels of an arrested heart. Furthermore, we found that the flow waves along the trunk or at the primary branches tend to scale (normalized with respect to their mean values) to a single curve, except for a small phase angle difference. Finally, the model predictions for the inlet pressure and flow waves are in excellent agreement with previously published experimental results. This hybrid one-dimensional/Womersley model is an efficient approach that captures the essence of the hemodynamics of a complex large-scale vascular network. The present model has numerous applications to understanding the dynamics of coronary circulation.     

Validation of a novel noninvasive cardiac index of left ventricular contractility in patients

Although there are several excellent indexes of myocardial contractility, they require accurate measurement of pressure via left ventricular (LV) catheterization. Here we validate a novel noninvasive contractility index that is dependent only on lumen and wall volume of the LV chamber in patients with normal and compromised LV ejection fraction (LVEF). By analysis of the myocardial chamber as a thick-walled sphere, LV contractility index can be expressed as maximum rate of change of pressure-normalized stress (d sigma*/dt(max), where sigma* = sigma/P and sigma and P are circumferential stress and pressure, respectively). To validate this parameter, d sigma*/dt(max) was determined from contrast cine-ventriculography-assessed LV cavity and myocardial volumes and compared with LVEF, dP/dt(max), maximum active elastance (E(a,max)), and single-beat end-systolic elastance [E(es(SB))] in 30 patients undergoing clinically indicated LV catheterization. Patients with different tertiles of LVEF exhibit statistically significant differences in d sigma*/dt(max). There was a significant correlation between d sigma*/dt(max) and dP/dt(max) (d sigma*/dt(max) = 0.0075 dP/dt(max) - 4.70, r=0.88, P<0.01), E(a,max) (d sigma*/dt(max) = 1.20E(a,max) + 1.40, r=0.89, P<0.01), and E(es(SB)) [d sigma*/dt(max)=1.60 E(es(SB)) + 1.20, r=0.88, P<0.01]. In 30 additional individuals, we determined sensitivity of the parameter to changes in preload (intravenous saline infusion, n = 10 subjects), afterload (sublingual glyceryl trinitrate, n = 10 subjects), and increased contractility (intravenous dobutamine, n=10 patients). We confirmed that the index is not dependent on load but is sensitive to changes in contractility. In conclusion, d sigma*/dt(max) is equivalent to dP/dt(max), E(a,max), and E(es(SB)) as an index of myocardial contractility and appears to be load independent. In contrast to other measures of contractility, d sigma*/dt(max) can be assessed with noninvasive cardiac imaging and, thereby, should have more routine clinical applicability.