Showing papers in "Cardiovascular Engineering and Technology in 2012"

Assessment of CFD Performance in Simulations of an Idealized Medical Device: Results of FDA’s First Computational Interlaboratory Study

Abstract: While computational fluid dynamics (CFD) is commonly used for medical device development, its usefulness for demonstrating device safety has not been proven. Reliable standardized methods for this specialized need are lacking and are inhibiting the use of computational methods in the regulatory review of medical devices. To meet this need, participants from academia, industry, and the U.S. Food and Drug Administration recently completed a computational interlaboratory study to determine the suitability and methodology for simulating fluid flow in an idealized medical device. A technical working committee designed the study, defined the model geometry and flow conditions, and identified comparison metrics. The model geometry was a 0.012 m diameter cylindrical nozzle with a conical collector and sudden expansion on either side of a 0.04 m long, 0.004 m diameter throat, which is able to cause hemolysis under certain flow conditions. Open invitations to participate in the study were extended through professional societies and organizations. Twenty-eight groups from around the world submitted simulation results for five flow rates, spanning laminar, transitional, and turbulent flows. Concurrently, three laboratories generated experimental validation data on geometrically similar physical models using particle image velocimetry. The simulations showed considerable variation from each other and from experiment. One main source of error involved turbulence model underestimations of the centerline velocities in the inlet and throat regions, because the flow was laminar in these regions. Turbulence models were also unable to accurately predict velocities and shear stresses in the recirculation zones downstream of the sudden expansion. The wide variety in results suggest that CFD studies used to assess safety in medical device submissions to the FDA require careful experimental validation. Better transitional models are needed, as many medical devices operate in the transitional regime. It is imperative that the community undertake and publish quality validation cases of biofluid dynamics and blood damage that include complications such as pulsatility, secondary flows, and short and/or curved inlets and outlets. The results of this interlaboratory study will be available in a benchmark database to help develop improved modeling techniques, and consensus standards and guidelines for using CFD in the evaluation of medical devices.

A Computational Test-Bed to Assess Coronary Stent Implantation Mechanics Using a Population-Specific Approach

Abstract: The implantation behaviour of coronary stents is of great interest to clinicians and engineers alike as in-stent restenosis (ISR) remains a critical issue with the community. ISR is hypothesized to occur for reasons that include injury to the vessel wall caused by stent placement. To reduce the incidence of ISR, improved design and testing of coronary stents is needed. This research aims to facilitate more comprehensive evaluation of stents in the design phase, by generating more realistic arterial environments and corresponding stress states than have been considered heretofore, as a step towards reducing the prevalence of ISR. Furthermore it proposes improvements to the current requirements for coronary stent computational stress analyses as set out by the Food and Drug Administration (FDA). A systematic geometric test-bed with varying levels of arterial curvature and stenosis severity is developed and used to evaluate the implantation behaviour of two stent designs using finite element analysis. A parameter study on atherosclerotic tissue behaviour is also carried out. Results are analysed using tissue damage estimates and lumen gain comparisons for each design. Results indicate that stent design does not have a major impact on lumen gain behaviour but may have an influence on the potential for tissue damage. The level of stenosis in the arterial segments is seen to have a strong impact on the results while the effects of arterial curvature appear to be design dependent.

An Integrated Statistical Investigation of Internal Carotid Arteries of Patients Affected by Cerebral Aneurysms

Abstract: Cerebral aneurysm formation is the result of a complex interplay of systemic and local factors. Among the latter, the role of the geometry of the vessel hosting an aneurysm, of the upstream vasculature and the induced hemodynamics still need to be carefully investigated. In this paper we combine computational fluid dynamics analysis and morphological characterization and carry out the statistical investigation of the features of the internal carotid artery (ICA) of 52 patients affected by a cerebral aneurysm. The functional principal component analysis performed on the geometric and fluid dynamics features of the patients reveals correlations with the location of the aneurysm in the cerebral circulation and its rupture status. This allows a clustering of the patients that is anticipated to contribute to the design of an index for the rupture risk. In particular, ICA featuring a pronounced WSS peak are statistically inclined to hosting ruptured aneurysms. Moreover, our statistical results suggest that patients with a double-bend siphons (S-class) are less prone to the development of cerebral aneurysms.

Mechanisms of Platelet Capture Under Very High Shear

Abstract: As a thrombus grows in a stenosis, the lumen narrows producing very high shear rates as blood velocities increase. Binding platelets are subjected to drag forces exceeding 10,000 pN. These forces could be balanced by 100 simultaneous 100 pN GPIbα-vWF-A1 bonds. The density of GPIbα ligands on platelets is sufficiently high; however, platelet capture under high shear would require the vWF-A1 density on the thrombus surface to be increased to over 416 μm−2. A computational model is used to determine platelet capture as a function of shear rate, surface receptor density, surface contact and kinetic binding rate. vWF-A1 density could be increased by: (i) plasma vWF attaching to the thrombus surface and elongating under shear; (ii) elongated vWF strands creating nets with 3-D pockets; and (iii) vWF releasing from activated platelets. With all three events, A1 densities increase with high shear to provide sufficient multivalency (>850 bonds) for capture even at 500,000 s−1. If the on-rate is greater than 108 M−1 s−1, then a platelet could be captured within 3 μs, the time limit to form bonds before the platelet is swept away. This mechanism of vWF nets can capture circulating platelets at a sufficiently high rate to cause arterial thrombotic occlusion.

Reducing In-Stent Restenosis Through Novel Stent Flow Field Augmentation

Abstract: In-stent restenosis (ISR), manifested as a re-narrowing of the arterial lumen post-implantation of a stent, is a detrimental limitation of stent technology. Understanding and consequently devising ways of reducing the frequency of ISR has been a continuing goal of research into improved stent designs. The biological processes that can lead to ISR have been found to be partially flow dependent with the local hemodynamics at the arterial wall of crucial importance. This paper investigates these biological processes and their instigating factors. Furthermore, the history and theory behind three stent technologies which endeavour to reduce ISR rates through stent flow field augmentation are presented: a flow divider which increases the blood-flow velocity and consequently the wall shear stress through a stented region, and two novel stent technologies which induce helical flow that mimics the natural blood flow present in healthy arteries. This paper serves as a thorough introduction to both the investigation of ISR, particularly the influence of the local hemodynamics, and to the three novel stent technologies which aim to reduce ISR rates.

Targeted Delivery of VEGF after a Myocardial Infarction Reduces Collagen Deposition and Improves Cardiac Function

Abstract: The development of adjunctive therapies which attenuate adverse remodeling and improve LV function post myocardial infarction (MI) is of significant clinical interest. Previously, we have shown that targeted delivery of therapeutic vascular endothelial growth factor (VEGF) to the infarct border zone significantly increases vascular perfusion and results in improvements in LV function. In this study, we tested the hypothesis that improvements in cardiac function observed with this novel targeted drug delivery system strongly correlate with reductions in collagen deposition in the scar tissue after an MI. Rats received anti-P-selectin conjugated immunoliposomes containing VEGF immediately post-MI. Over 4 weeks, evolutionary changes in LV geometry and function were correlated with collagen deposition and infarct size quantified by Gomori's trichrome and picrosirius red staining. Targeted VEGF treated hearts showed a 37% decrease in collagen deposition in the anterior wall, as well as significant improvements in LV filling pressures. Multi-regression analysis showed that the extent of collagen deposition post MI can be predicted by a linear combination of normalized LV mass and ejection fraction. Targeted delivery of VEGF post-MI results in significant decreases in collagen deposition and adverse remodeling. Improvements in cardiac function in this model are related to degree of collagen deposition and extent of scar formation.

Experimentally Validated Hemodynamics Simulations of Mechanical Heart Valves in Three Dimensions

Abstract: Mechanical heart valves (MHV) have been widely deployed as a routine surgical treatment option for patients with heart valve diseases due to its durability and performance. Understanding hemodynamics of MHV plays a key role in performance assessment as well as design. In this work, we propose a numerical method for simulations of full three dimensional MHV with moving valve leaflets in a typical human cardiac cycle. A cell-centered finite volume method is employed to model incompressible flows in MHV. As the flow experiences from laminar to turbulence over every cardiac cycle, the unsteady Reynolds average Navier–Stokes (URANS) equations is solved with $$k{-}\epsilon$$ and Spalart–Allmaras turbulence models to resolve large scaled turbulent eddies in high Reynolds number flow regimes. URANS approach chosen for the balance of turbulence resolution and computational cost shows good agreement with more detailed turbulence models as well as experimental data. For capturing the large amplitude movement of the valves, we develop an optimization-based moving mesh technique with objective functions operating on different mesh quality metrics. The method is capable of extensively providing an effective way to maintain and improve the mesh quality due to large movement of domain boundaries. The numerical results for laminar and turbulent flows are validated against experimental data using Particle Image Velocimetry technique. The simulation is able to capture essential features of flows in MHV. The triple jet structure is observed in the simulations together with a switching of central orifice jet flow from horizontal axis to vertical axis downstream of the leaflets and the results are well compared with the experimental data. The moving mesh technique has enabled us to simulate a whole cardiac cycle with pulsatile physiological conditions and prescribed motions of the leaflets. The simulations can essentially reproduce the varying pressure profiles at the left ventricle and aorta. The wall shear stress and vorticity can then be deduced from the simulation results to further access the valve performance. This study also constitutes an important step towards understanding hemodynamics in MHV and contributing to the advancement in study of improved MHV.

Comparison of Aortic Flow Patterns Before and After Transcatheter Aortic Valve Implantation

Abstract: Little is known of the likely changes in blood flow velocity profiles and aortic wall shear stress (WSS) following transcatheter aortic valve implantation (TAVI). The objective of this study was to investigate the effects of TAVI on flow patterns in the thoracic aorta by using cardiovascular magnetic resonance imaging (CMR) and computational fluid dynamics (CFD). An elderly patient with aortic stenosis was examined using MRI pre- and post-TAVI, and CFD simulations were carried out incorporating MRI-derived patient-specific anatomy and upstream flow conditions. Pre-TAVI velocity profiles demonstrated the highly disturbed turbulent flow and jet impacting the wall of the arch owing to the partial opening of the stenosed aortic valve, with likely pathological effects. In the Post-TAVI aorta, velocity profiles were similar to those of healthy aortas with spatially more uniform WSS and lower turbulence levels, demonstrating the favourable effects of the TAVI procedure in restoring normal aortic flow. This study has shown both the effectiveness of TAVI on an individual patient and the advantage of the combined CMR and CFD method for a comprehensive patient-specific assessment of pre- and post-TAVI aortic flow patterns and WSS over CMR alone.

Evaluation of Rupture Properties of Thoracic Aortic Aneurysms in a Pressure-Imposed Test for Rupture Risk Estimation

Abstract: Rupture properties of thoracic aortic aneurysms (TAAs) were measured in vitro in a pressure-imposed test to predict the ultimate stress of TAAs from their mechanical behavior in a physiological pressure range. Each quadrilateral (ca. 20 × 20 mm2) specimen of TAAs or porcine thoracic aortas (PTAs) was pressurized from the inner wall until rupture or up to 4500 mmHg, while its deformation was being monitored. In-plane stress σ and strain e of the specimen were calculated using Laplace’s law and deformations of the markers drawn on the specimen surface, respectively. Ultimate stress σ max and tangent elastic modulus H were determined from the σ–e curve as its maximum stress and slope, respectively. The tangent elastic modulus H of PTA specimens tended to increase with the increase in σ, while that of TAA specimens tended to reach a plateau in a low-σ region. This tendency was confirmed by fitting a function H = C σ (1 − exp(−σ/τ σ )) to the H−σ relation of specimens: The yielding parameter τ σ was significantly lower in TAAs than PTAs. Furthermore, the logarithm of the parameter τ σ correlated significantly with σ max, for all specimens. These results may indicate that τ σ is one of the candidate indices for rupture risk estimation.

Enhanced Autologous Re-endothelialization of Decellularized and Extracellular Matrix Conditioned Allografts Implanted Into the Right Ventricular Outflow Tracts of Juvenile Sheep

Abstract: Decellularized allografts are promising options for pediatric valve replacement due to reduced immunogenicity and the potential for in vivo autologous recellularization, extracellular matrix (ECM) remodeling and re-endothelialization, which may be enhanced with post-decellularization processing steps. This study investigated the performance and morphology of decellularized and ECM conditioned pulmonary valves implanted in the right ventricular outflow tracts (RVOT) of juvenile sheep. RVOT reconstructions in juvenile sheep using cryopreserved pulmonary allografts (Cryo; n = 2), porcine aortic root bioprostheses (Biopros; n = 2) or decellularized/ECM conditioned pulmonary allografts (Conditioned; n = 4) were performed. Valve performance and morphology were evaluated at 20 weeks after implant. Uniaxial tensile testing was performed on a subset of unimplanted valves from each group. At explant, Biopros had significantly higher peak/mean gradients vs. Conditioned and Cryo, which were similar. No cusp calcification occurred in any valve; arterial wall calcification was present only in Cryo (mild/moderate) and Biopros (severe). No autologous recellularization or inflammation occurred in Biopros; cellularity was decreased in Cryo. Autologous recellularization was present in Conditioned arterial walls and variably extending into the cusps, with consistent cusp re-endothelialization. Conditioned valves had reduced cusp extensibility, increased stiffness and similar tensile strength vs. Cryo. Although Conditioned valves were slightly stiffer and less extensible than Cryo valves, their hemodynamic performance was comparable, indicating they behave as functional heart valves immediately following implant. Because both autologous recellularization and re-endothelialization were seen, ECM conditioning shows promise for encouraging renewal of the cellularity of decellularized allograft valves without the need for pre-implant endothelial cell seeding.

Comparative Evaluation of Mitral Valve Strain by Deformation Tracking in 3D-Echocardiography

Abstract: We present new algorithms to compute patient specific strain maps for mitral valve leaflets, by tracking and modeling deformations of the mitral valve apparatus in 3D echocardiography. We can then quantify comparisons of mitral leaflets strain maps between normal patients and cases of mitral valve prolapse or regurgitation. For patients with mitral valve regurgitation, we compare mitral leaflets strain maps between pre-surgery and post-surgery, to quantify the strain reduction due to mitral valve repair surgery.

Impact of Pulmonary Venous Locations on the Intra-Atrial Flow and the Mitral Valve Plane Velocity Profile

Abstract: In this paper we present a three-dimensional computational fluid dynamics (CFD) framework of the left atrium (LA) and its pulmonary veins (PVs). The framework uses magnetic resonance imaging (MRI) to render the subject-specific atrial and venous geometries. The aim was first to investigate the diastolic flow field in an anatomically representative model of the LA and PVs. Second, to investigate the impact of different positions of the PVs on the intra-atrial flow and on the resulting velocity distribution at the mitral valve (MV) plane. Three 3D models with different venous entry locations were created for this purpose. In the model with anatomically based PV positions, the velocity profile at the MV plane showed qualitatively good agreement with the MRI flow measurements. When comparing the flow field in the three models, the results clearly illustrate that the PVs have a significant impact on the intra-atrial flow and the final velocity profile at the MV plane. Because the interpatient variability in PV number and branching patterns is large, the velocity profile at the MV plane should be considered as a subject-specific property. Therefore, we suggest that in order to obtain a physiological correct simulation of ventricular filling and MV opening dynamics, a subject-specific representation of the atrial and venous anatomies should be included in the simulation model.

Transitional Flow in a Cylindrical Flow Chamber for Studies at the Cellular Level

Abstract: Fluid shear stress is an important regulator of vascular and endothelial cell (EC) functions. Its effect is dependent not only on magnitude but also on flow type. Although laminar flow predominates in the vasculature, transitional flow can occur and is thought to play a role in vascular diseases. While a great deal is known about the mechanisms and signaling cascades through which laminar shear stress regulates cells, little is known on how transitional shear stress regulates cells. To better understand the response of endothelial cells to transitional shear stress, a novel cylindrical flow chamber was designed to expose endothelial cells to a transitional flow environment similar to that found in vivo. The velocity profiles within the transitional flow chamber at Reynolds numbers 2200 and 3000 were measured using laser Doppler anemometry (LDA). At both Reynolds numbers, the velocity profiles are blunt (non-parabolic) with fluctuations larger than 5% of the velocity at the center of the pipe indicating the flows are transitional. Based on near wall velocity measurements and well established data for flow at these Reynolds numbers, the wall shear stress was estimated to be 3–4 and 5–6 dynes/cm2 for Reynolds number 2200 and 3000, respectively. In contrast to laminar shear stress, no cell alignment was observed under transitional shear stress at both Reynolds numbers. However, transitional shear stress at the higher Reynolds number caused cell elongation similar to that of laminar shear stress at 3 dynes/cm2. The fluctuating component of the wall shear stress may be responsible for these differences. The transitional flow chamber will facilitate cellular studies to identify the mechanisms through which transitional shear stress alters EC biology, which will assist in the development of vascular therapeutic treatments.

Regional Finite Strains in an Angiotensin-II Induced Mouse Model of Dissecting Abdominal Aortic Aneurysms

Abstract: Abdominal aortic aneurysms are focal dilatations of the aorta; they typically progress to rupture, which is responsible for increasing morbidity and mortality in our aging society. It is well accepted that rupture occurs when wall stress exceeds strength, and there have been many advances over the past two decades in predicting local stresses based on patient-specific computational models. Nevertheless, two of the primary continuing limitations of such models are the assumptions of constant (i.e., non-evolving) and spatially homogeneous material properties. Mouse models of aortic aneurysms provide a means to measure evolving heterogeneous properties, but heretofore such attempts have been limited because of the complex geometries of these lesions. In this paper, we present a technical advance—panoramic digital image correlation—that can aid in the final goal of determining regional mechanical properties in mouse models of aneurysms. We show, as illustrative data, the first detailed quantification of full field surface strains for experimentally distended mouse aneurysms, data which will be fundamental to future inverse determinations of regional material properties.

Fluid Mechanics of Mixing in the Vertebrobasilar System: Comparison of Simulation and MRI

Abstract: Recent magnetic resonance imaging (MRI) studies have demonstrated that perfusion to the posterior fossa of the brain can be surprisingly unilateral, with specific vascular territories supplied largely by a single vertebral artery (VA) rather than a mixture of the two. It has been hyposthesized that this is due to a lack of mixing in the confluence of the VA into the basilar artery (BA), however the local mechanisms of mixing (or lack thereof) have not been previously examined in detail. This study aims to assess the mixing characteristics and hemodynamics of the vertebrobasilar junction using subject specific computational fluid dynamics (CFD) simulations, and perform quantitative comparisons to arterial spin labeling (ASL) MRI measurements. Subject specific CFD simulations and unsteady particle tracking were performed to quantitatively evaluate vertebrobasilar mixing in four subjects. Phase-contrast MRI was used to assign inflow boundary conditions. A direct comparison of the fractional flow contributions from the VAs was performed against perfusion maps generated via vessel-encoded pseudo-continuous arterial spin labeling (VEPCASL) MRI. The laterality of VA blood supply in 7/8 simulated cerebellar hemispheres and 5/7 simulated cerebral hemispheres agree with ASL data. Whole brain laterality of the VA supply agrees within 5% for measured and computed values for all patients. However, agreement is not as strong when comparing perfusion to individual regions. Simulations were able to accurately predict laterality of VA blood supply in four regions of interest and confirm ASL results, showing that very little mixing occurs at the vertebrobasilar confluence. Additional particle tracking analysis using Lagrangian coherent structures is used to augment these findings and provides further physical insight that complements current in vivo imaging techniques. A quantitative mix-norm measure was used to compare results, and sensitivity analysis was performed to assess changes in the results with pertubations in the boundary condition values.

Computational Fluid Dynamics for Medical Device Design and Evaluation: Are We There Yet?

Abstract: Medical device analysis using Computational Fluid Dynamics (CFD) is not yet a required component of premarket notifications and applications submitted to the US FDA. Nevertheless, CFD has already established itself as a pervasive tool in cardiovascular hemodynamics research. This is evident by numerous papers published in CVET and other journals in the field and/or presented at major conferences and workshops that employ CFD to analyze flow patterns and draw conclusions about the performance of a variety of medical devices. In fact CFD is so widespread that is quite common these days to hear in conference presentations or read in journal papers plain references to CFD or ‘‘standard CFD’’ as the method employed to carry out the simulations, with little or no details provided about the specific computational techniques and/or other modeling assumptions. It is, thus, believed by many that CFD is a mature, off-the-shelf, and universally-accepted technology that can be used with little or no scrutiny to guide the design and evaluation of medical devices and make decisions that could ultimately impact patient health and quality of life. It is because of the prevalence and wide-spread use of CFD in the community that the results presented in the recent study by Stewart et al. are so striking and noteworthy. This paper summarizes the findings of a computational inter-laboratory study, conducted by industry, academia and the US FDA, which employed as a test case a relatively simple, idealized model of a medical device: a cylindrical nozzle with a conical collector and sudden expansion on either side. Complexities commonly encountered in real-life medical devices, like 3D complex geometries with moving boundaries, fluid structure interaction, flow pulsatility, small gaps, etc., were not part of this study. Yet the model problem was cleverly selected to provide a challenging test bed for evaluating the performance of CFD codes across a range of flow regimes, spanning laminar to transitional flows, in a geometry where a host of complex flow phenomena associated with blood damage in real-life medical devices arise—e.g. favorable and adverse pressure gradients, flow separation, intense shear layers and transition to turbulence. The computational phase of the project was accompanied by Particle Image Velocimetry (PIV) experiments conducted by three laboratories concurrently with the computational studies, which provided benchmark data for validating the predictive capabilities of the various CFD codes. As shown by Stewart et al., none of the 28 CFD simulations contributed by an international group of researchers, of varying degree of experience and expertise, yielded results that agreed well with the experimental data. What is even more disheartening, however, is the fact that essentially all simulations showed considerable scatter and variation not only from the experimental data but also from each other. Even though the relatively few computational approaches included in this study by no means represent the state-of-the-art in numerical simulation of cardiovascular hemodynamics today (see Sotiropoulos et al. for a recent review of computational methods for cardiovascular flows), the results do serve to challenge the notion about the universality of the so-called ‘‘standard CFD’’ discussed above. Not all CFD codes are created equal and the details of their inner workings as well as other details pertaining to a specific simulation do matter a great deal in the end. Issues like the order of accuracy of spatial and temporal discretization techniques, the iterative solvers and schemes used to achieve convergence and the level of convergence achieved in a given simulation, the quality of the mesh and the sensitivity of the solver to mesh quality and density, the treatment of inflow, outflow, and wall boundaries, and, last but not least, the manner via which laminar-to-turbulence transition and fully turbulent flow regimes are handled by the code are of great importance and deserve attention and extensive discussion in CFD studies. Furthermore, this study also underscores the need for continuous, systematic, and thorough experimental validation of CFD codes that will be used one day to assess safety in medical device submissions to the FDA. A common feature of all CFD models presented in Stewart et al. is the use of statistical turbulence modeling approaches, i.e. the Reynolds-averaged Navier–Stokes equations closed with one or two equation turbulence models. Such models, expedient as they are from a computational standpoint, have been Cardiovascular Engineering and Technology, Vol. 3, No. 2, June 2012 ( 2012) pp. 137–138 DOI: 10.1007/s13239-012-0095-5

Echocardiographic Characterization of Postnatal Development in Mice with Reduced Arterial Elasticity

Abstract: Decreased expression of elastin results in smaller, less compliant arteries, and high blood pressure. In mice, these differences become more significant with postnatal development. It is known that arterial size and compliance directly affect cardiac function, but the temporal changes in cardiac function have not been investigated in elastin insufficient mice. The aim of this study is to correlate changes in arterial size and compliance with cardiac function in wildtype (WT) and elastin haploinsufficient (Eln +/−) mice from birth to adulthood. Ultrasound scans were performed at the ages of 3, 7, 14, 21, 30, 60, and 90 days on male and female WT and Eln +/− mice. 2-D ultrasound and pulse wave Doppler images were used to measure the dimensions and function of the left ventricle (LV), ascending aorta, and carotid arteries. Eln +/− arteries are smaller and less compliant at most ages, with significant differences from WT as early as 3 days old. Surprisingly, there are no correlations (R 2 < 0.2) between arterial size and compliance with measures of LV hypertrophy or systolic function. There are weak correlations (0.2 < R 2 < 0.5) between arterial size and compliance with measures of LV diastolic function. Eln +/− mice have similar cardiac function to WT throughout postnatal development, demonstrating the remarkable ability of the developing cardiovascular system to adapt to mechanical and hemodynamic changes. Correlations between arterial size and compliance with diastolic function show that these measures may be useful indicators of early diastolic dysfunction.

Detection of Coronary Artery Disease Using Automutual Information

Abstract: Coronary artery disease (CAD) is the leading cause of death in the United States, but there is no detection method that is suitable as an early screening tool. The exercise stress test can be performed noninvasively but requires physical exertion and has low accuracy. A nuclear stress test has higher accuracy, but requires the use of a radio-nucleotide that exposes the patient to radiation. Detection of CAD using acoustic signals recorded from the chest is inexpensive, uses no radiation and is noninvasive. Therefore, the acoustic method is an ideal early screening tool. CAD sounds (bruits) are produced by turbulent blood flow caused by partially obstructed arteries and turbulence is a nonlinear process. Therefore, this study evaluated a nonlinear signal analysis method, the automutual information function (AMIF(τ)), for detection of CAD bruits. The AMIF(τ) was applied to diastolic signals from 16 normal and 15 diseased subjects. Four parameters of the AMIF(τ) curve were evaluated: (1) \(lag_{\epsilon}, \) the lag when the value of the curve is 1/e; (2) the lag of the first AMIF(τ) peak; (3) the value of the first AMIF(τ) peak; and (4) the integral of the curve. Using the standard deviation (std) and mean value of AMIF(τ) parameters as features in a linear support vector machine classifier, the best individual AMIF(τ) parameter was \(lag_{\epsilon}. \) This classified normal and diseased subjects retrospectively with a sensitivity–specificity of 80–69%, with 74% accuracy. Using a combination of AMIF(τ) measurements further improved accuracy. The combination of std values for first peak lag and \(lag_{\epsilon}\) gave a sensitivity–specificity of 87–75% with an 81% accuracy. Since the mutual information function is similar to the linear autocorrelation, the autocorrelation was also considered, using the same parameters to quantify the correlation function. The best combination of autocorrelation parameters, the first peak lag and mean of the sum of the autocorrelation function, gave an accuracy of 75%. The best individual autocorrelation measurement was the first peak lag, with a sensitivity–specificity of 67–75% and an accuracy of 71%. These results indicate AMIF(τ) is sensitive to signatures of CAD bruits and may be useful for acoustic detection of CAD. However, linear correlation analysis discriminated normal and diseased subjects nearly as well, indicating that the acoustic signals recorded contain mostly linear information.

In Vitro System for Measuring Chordal Force Changes Following Mitral Valve Patch Repair.

Abstract: Attention toward optimization of mitral valve (MV) repair methods is increasing. Patch augmentation is one strategy utilized to correct functional mitral regurgitation or systolic anterior motion in complex MV repairs. This article describes a system for investigating the redistribution of chordae tendineae tension as a reflection of altered stress distribution of the valve leaflet following patch augmentation. An in vitro test setup was constructed to hold native porcine MVs containing an annulus and papillary muscle positioning system. The alterations caused by patch augmentation should be visual from both the atrial and ventricular views. Ventricular pressure was regulated stepwise in a range of 0–150 mmHg. To test the system, the anterior mitral leaflet was extended by a pericardial patch sutured to the mid/basal part of the leaflet, and the chordae tendineae force was measured as the ventricular pressure was applied. The system demonstrated the capacity to hold native porcine MVs and introducing patch repairs according to clinical practice. The porcine MV test setup indicated strong correlation between the forces in the MV secondary chordae tendineae and the applied transvalvular pressure, R 2 = 0.95. This test setup proved the ability to obtain normal mid-systolic MV function, secondary chordae force measurements, and important preservation of the visual access: Hence, obtaining the pressure-force relationship as well as identifying any shift of the secondary chordae insertion point on the anterior leaflet relative to the coaptation zone was made possible.

Effect of Threshold Value r on Multiscale Entropy based Heart Rate Variability

Abstract: Heart rate variability (HRV) is the output of multiple physiological control mechanisms that occurs over a wide range of complex time scales. The multiscale entropy (MSE) of RR interval time series is a well established complexity based nonlinear technique, to analyze HRV at different time-scales using sample entropy (SampEn). Determination of SampEn requires a priori determination of two parameters; pattern length (m) to be compared and tolerance threshold value (r) to accept the similarity between the patterns. This study aims to investigate the applicability of previously recommended value of r to be 0.1–0.2 times the standard deviation of time series for MSE analysis. MSE at higher scales are found to be inappropriate with recommended range of r. Therefore to find maximum MSE at higher time scales, calculation of MSE with different possible values of r need to considered. But this approach is very time consuming and arduous. Further, MSE is found to be decreased significantly in function of time scales.

Mechanisms of Periodic Acceleration Induced Endothelial Nitric Oxide Synthase (eNOS) Expression and Upregulation Using an In Vitro Human Aortic Endothelial Cell Model

Abstract: Following severe injury in cases like ischemia reperfusion, recovery and tissue repair are compromised due to microvascular failure. Nitric oxide (NO) has been shown to have both vasodilatory and anti-inflammatory effects, and to enhance recovery and tissue repair by increasing microcirculation. Therefore, techniques that induce endothelial derived nitric oxide (eNO) may provide a suitable supplemental treatment following injury. Periodic acceleration (pGz) applied to the supine positioned body in a repetitive head-foot direction increases pulsatile shear stress to the vascular endothelium. pGz provides cytoprotection in part because it increases expression of eNOS and eNOS phosphorylation (p-eNOS) in the heart and vasculature in models of whole body and focal ischemia reperfusion injuries in vivo. To confirm that endothelial cells are indeed the central mediator of NO production and to understand the signal transduction pathway through which pGz upregulates eNOS, we used an in vitro model of human aortic endothelial cells coated tubing, mimicking realistic conditions of blood vessels in vivo that are exposed to linear pulsatile flow (PF) or PF plus pGz (PF + pGz). PF + pGz produced significantly higher values of total eNOS and p-eNOS content than PF alone. Periodic acceleration also increased the ratio of phosphorylated Akt (p-Akt) to total Akt, as well as the ratio of p-ERK1/2 to total ERK1/2. Further, Wortmannin (PI3K inhibitor) inhibited phosphorylation of Akt and eNOS but not eNOS upregulation, while PD98059 (MEK inhibitor) inhibited phosphorylation of ERK1/2 and eNOS upregulation, but not eNOS phosphorylation. Therefore, this investigation shows that, pGz increases eNO and p-eNOS through the PI3K–Akt pathway and upregulated eNOS expression through the MEK-ERK1/2 pathway in cultured endothelial cells.

Influence of Mitral Valve Anterior Leaflet in vivo Shape on Left Ventricular Ejection

Abstract: Recent studies have demonstrated that, due to the active involvement of leaflet contractile elements, the anterior mitral leaflet (AML) is very stiff and maintains a compound curvature during ventricular systole. Studies based on structural mechanics have shown that both leaflet stiffness and compound curvature are key factors limiting AML deformation in the presence of high left ventricular (LV) systolic pressures. In the present study, we tested the hypothesis that maintenance of this physiological AML compound curvature also plays a role in the optimization of LV outflow during ejection. The LV cavity, mitral valve and aortic root of a healthy human were reconstructed from cardiac magnetic resonance images on 18 evenly rotated long-axis cut-planes at peak systole. Computational fluid dynamics was used to assess hemodynamics within the ventricular outflow tract in the presence of three different AML profiles: (i) physiologically compound as measured in vivo, (ii) flat, (iii) concave (i.e., prolapsed) towards the ventricle. Relative to the physiologic profile, AML flat and concave profiles induced progressively increasing hemodynamic alterations at the LV outflow and immediately downstream to the aortic valve, characterized at peak systole by flow detachment, a mean vorticity increase of 15.6 and 53.1% and an instantaneous power loss increase of 12 and 46%, respectively. These results support the hypothesis that the physiological AML shape plays an important role in optimizing LV ejection. This implies that AML profile alterations associated with valvular disease or surgical repair procedures can significantly reduce LV ejection efficiency.

Biofluid Mechanics: The Human Circulation (second edition)

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Wall Shear Stress Measurements in an Arterial Flow Bioreactor

Abstract: In vitro arterial flow bioreactor systems are widely used in tissue engineering to investigate response of endothelial cells to shear However, the assumption that such models reproduce physiological flow has not been experimentally tested Furthermore, shear stresses experienced by the endothelium are generally calculated using a Poiseuille flow assumption Understanding the performance of flow bioreactor systems is of great importance, since interpretation of biological responses hinges on the fidelity of such systems and the validity of underlying assumptions Here we test the physiologic reliability of arterial flow bioreactors and the validity of the Poiseuille assumption for a typical system used in tissue engineering A particle image velocimetry system was employed to experimentally measure the flow within the vessel with high spatial and temporal resolution Two types of vessels were considered: first, fluorinated ethylene propylene (FEP) tubing representative of a human artery without cells; and second, FEP tubing with a confluent layer of endothelial cells on the vessel lumen Instantaneous wall shear stress (WSS), time-averaged WSS, and oscillatory shear index were computed from velocity field measurements and compared between cases The flow patterns and resulting wall shear were quantitatively determined to not accurately reproduce physiological flow, and that the Poiseuille flow assumption was found to be invalid This work concludes that analysis of cell response to hemodynamic parameters using such bioreactors should be accompanied by corresponding flow measurements for accurate quantification of fluid stresses

An Inverse Numerical Approach for Modeling Aortic Heart Valve Leaflet Tissue Oxygenation

Abstract: Modeling oxygen diffusion within the aortic heart valve leaflet tissue is challenging. This is because the aortic valve cusp is highly heterogeneous with varying physical properties with respect to location and direction. The conventional numerical solutions such as the finite element method, the finite difference method and other methods applicable to modeling the oxygen diffusion within the tissue contain error regardless of the nature of the given problem or modeling parameters. The major concern with numerical methods is computational cost such as the execution-time and the accuracy. This study focuses on modeling oxygen diffusion within the heart valve leaflet tissue using a novel inverse numerical technique. The Lagrange multiplier method and the least-squares algorithm are used to define a cost function which is discretized using the finite difference method and is optimized to reduce erroneous results. While our model proposes accuracy similar to that of an equivalent finite element approach, the execution-time of the solution is reduced. The numerical method developed in this study can have a broad application in tissue engineering/repair and regenerative medicine in which oxygenation of the cells residing within the scaffold/tissue is of particular importance.

Pressure Sensitivity of Axial-Flow and Centrifugal-Flow Left Ventricular Assist Devices

Abstract: Continuous-flow ventricular assist devices (CF-VADs) defy normal physiologic principles associated with pulsatile flow. Despite being programmed at set speeds, pump flow can be modified by variations in the pressure differential across the pump, termed pressure sensitivity (PS). Currently, PS has been reported using steady-state closed-loop systems that are unable to provide physiologically-relevant assessment of PS or account for partially- or fully-unloaded ventricles. We report a unique model system to examine PS and its influence on efficiency of CF-VADs. A mock-circulation loop was designed that measures low and high extremes of pressure differential. Two axial-flow and two centrifugal-flow VADs were tested. Device output flow rate, preload, and afterload were measured and PS was calculated. Numerical models were implemented to simulate “fully-loaded,” “partially-unloaded,” and “fully-unloaded” cardiac cycles. Our open-loop model successfully generated pressure gradients that were lower than typical when using static, closed-loop systems. All devices exhibit highest PS during early diastole; however, average PS values of centrifugal-flow were 3× greater than axial-flow devices. The average maximum PS for the axial and centrifugal VADs under physiologic conditions was 0.08 and 0.42 L/min/mmHg, respectively. Compared to the axial-flow pumps, the two centrifugal-flow VADs in our study demonstrate increased PS at intermediate to low flow rates. Enhanced device PS allows for more effective self-regulation of device output, thus allowing a given VAD to better mimic the native heart under exercise conditions, and minimize undesirable effects, including ventricular suck-down or atrial collapse.

In Vitro Pumping Performance Evaluation of the Ension Pediatric Cardiopulmonary Assist System for Venoarterial and Venovenous ECMO

Abstract: The purpose of this study is to determine the pumping performance of Revision 7 of the Ension pediatric cardiopulmonary assist system (pCAS) when used with cannulae for venoarterial (VA) or venovenous (VV) extracorporeal membrane oxygenation (ECMO). It was hypothesized that the pCAS could deliver flow rates within recommended ranges needed to provide adequate cardiopulmonary support for neonates and infants. Rev 7 pCAS pumping performance was evaluated with the pCAS incorporated into an ECMO circuit connected to an instrumented pediatric mock circulation with cannulae combinations commonly used clinically for VA ECMO or dual lumen cannulae for VV ECMO. The pCAS motor speed was operated from 0 to 4500 rpm while the pCAS pumped blood analog solutions representing a clinically relevant range of viscosity. Maximum flow rates were inversely related to viscosity and were directly proportional to cannulae size. At 4500 rpm, maximum pCAS flow for the VA ECMO configuration was 2.14 L/min for the lowest viscosity and largest cannula combination and 0.72 L/min for the highest viscosity and the smallest cannulae combination. At a flow of 0.5 L/min, the pressure drop across the pCAS ranged from 121 to 323 mmHg depending on viscosity and cannulae combination. For the VV ECMO configuration at 4500 rpm, the maximum pCAS flow was 1.21 L/min for the lowest viscosity and largest cannula and 0.58 L/min for the highest viscosity and smallest cannula. For a flow of 0.5 L/min, the pressure drop across the pCAS ranged from 82 to 407 mmHg depending on the viscosity and cannula. Possible transition to turbulent flow (Re > 2100 at cannula inlet) was found at the higher flow rates achieved with the lower viscosity test fluid for all cannulae tested. In conclusion, across the range of pump speeds and fluid viscosities evaluated, the pCAS can generate the flow rates recommended to provide adequate cardiopulmonary support for neonates and infants with commonly used clinical cannulae combinations, thus confirming the hypotheses.

Feasibility of Subcutaneous ECG Leads for Synchronized Timing of a Counterpulsation Device

Abstract: A counterpulsation device (Symphony) that works synchronously with the native heart to provide partial circulatory support was developed to treat patients with advanced heart failure. Symphony is implanted in a ‘pacemaker pocket’ without entry into the chest, and requires timing with ECG for device filling and ejection. Surface leads are limited to short-term use due to signal distortion and lead management issues. Transvenous leads are a clinical standard for pacemakers and internal defibrillators, but increase the complexity of the implant procedure. In this study, the feasibility of using subcutaneous leads for synchronized timing of Symphony was investigated. ECG waveforms were simultaneously measured and recorded using epicardial (control) and subcutaneous (test) leads in a bovine model for 7-days (n = 6) and 14-days (n = 2) during daily activity and treadmill exercise. Landmark features and R-wave triggering detection rates for each lead configuration were calculated and compared. Lead placement, migration, durability, and infection were quantified using fluoroscopy and histopathological examination. There were 2,849 data epochs (30-s each) recorded at rest (133,627 analyzed beats) and 35 data epochs (20 min each) recorded during treadmill exercise (37,154 analyzed beats). The subcutaneous leads provided an accurate and reliable triggering signal during routine daily activity and treadmill exercise (99.1 ± 0.4% positive predictive value, 96.8 ± 1.5% sensitivity). The subcutaneous leads were also easily placed with minimal lead migration (0.5 ± 0.1 cm), damage (no fractures or failures), or infection. These findings demonstrate the feasibility of using subcutaneous leads for synchronized timing of mechanical circulatory support while offering the advantage of less invasive surgery and associated risk factors.

Transient Analysis of Force–Frequency Relationships in Rat Hearts Perfused by Krebs-Henseleit and Tyrode Solutions with Different [Ca2+]o

Abstract: Healthy hearts respond to enhancement of pacing rate by an increase of contractility exhibiting positive force–frequency relations (FFR). In failing hearts rhythm acceleration leads to the progressive decline in force that reflects negative FFR. Our goal is to estimate the effect of [Ca2+]o on the force transient dynamics and resulting FFR in perfused rat hearts. We study in details the transient force responses of Langendorff perfused hearts of rats to step changes in pacing period from 200 to 100 ms and back with a step of 20 ms. We find that the transient responses for both directions are biphasic and can last for more than 3–5 min, indicating that one must be careful in the interpretation of traditional FFR measurements. Also, we study the effects of different [Ca2+]o in Tyrode and Krebs-Henseleit solutions on FFR and show that FFR in rat heart can be changed from positive at 1 mM of [Ca2+]o in Tyrode solution to negative at 4 mM of [Ca2+]o. Furthermore, we find that perfusion with lower [Ca2+]o will give bigger at fast rates and longer lasting transient responses. On the other hand, transients are smaller and less sensitive to pacing period at higher [Ca2+]o. Force–frequency relationships can be analyzed not only upon steady state conditions; the structure of force transient after step changes in pacing period is dependent on extracellular calcium. Our data should be useful in the construction of detailed model of force generation in a cardiac tissue; they can be used to test the validity of models.

Automatic Parameter Extraction from Capacitive ECG Measurements

Abstract: Capacitive ECG sensing allows acquiring an ECG, even through clothing. Due to its simple handling it is suitable for unsupervised monitoring. However, because capacitively coupled signals may differ from conventional ECGs, direct application of algorithms for parameter extraction to capacitive ECGs still needs to be analyzed. This paper analyzes the applicability of algorithms for ECG segmentation to capacitive ECG measurements. Data from a medical study with 107 subjects, where conventional and capacitive ECG were recorded simultaneously, was used for a two step parameter extraction by means of multi-scale morphological derivative transform and time-frequency analysis based algorithms. RR interval, QT interval, PQ interval and QRS duration resulting from the capacitive ECG were calculated by means of the algorithms and compared to the manually annotated data from the reference ECG. RR intervals were computed by the algorithms appropriately (mean deviation: 50 ms), calculation of QT interval, PQ interval and QRS duration yielded mean deviations of 60, 20, and 30 ms respectively. Differences of the mean value of QT duration for subjects with sinus rhythm and atrial fibrillation (p = 0.0414) and the QRS duration for patients with and without bundle branch block (p = 0.05) could be observed. An algorithmic detection of the RR intervals and the detection of heart rhythm disturbances in capacitive ECG signals are possible. Reasons for the deviation of QT interval, QT and QRS duration are deformations of the capacitive ECG signal. Their reasons should be reconsidered before unsupervised monitoring by means of capacitive ECG is possible.