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The last few decades have seen great advances in the understanding of heart valves, and consequently, in the development of novel treatment modalities and surgical procedures for valves afflicted by disease. This is due in part to the profound advancements in computing technology and noninvasive medical imaging techniques that have made it possible to numerically model the complex heart valve systems characterized by distinct features at different length scales and various interacting processes. In this article, we highlight the importance of explicitly coupling these multiple scales and diverse processes to accurately simulate the true behavior of the heart valves, in health and disease. We examine some of the computational modeling studies that have a direct consequence on clinical practice.

In this portion of an extensive review of heart valve engineering, we focus on the current and emerging technologies and techniques to repair or replace the mitral valve. We begin with a discussion of the currently available mechanical and bioprosthetic mitral valves followed by the rationale and limitations of current surgical mitral annuloplasty methods; a discussion of the technique of neo-chordae fabrication and implantation; a review the procedures and clinical results for catheter-based mitral leaflet repair; a highlight of the motivation for and limitations of catheter-based annular reduction therapies; and introduce the early generation devices for catheter-based mitral valve replacement.

The engineering of technologies for heart valve replacement (i.e., heart valve engineering) is an exciting and evolving field. Since the first valve replacement, technology has progressed by leaps and bounds. Innovations emerge frequently and supply patients and physicians with new, increasingly efficacious and less invasive treatment options. As much as any other field in medicine the treatment of heart valve disease has experienced a renaissance in the last 10 years. Here we review the currently available technologies and future options in the surgical and transcatheter treatment of aortic valve disease. Different valves from major manufacturers are described in details with their applications.

As the first section of a multi-part review series, this section provides an overview of the ongoing research and development aimed at fabricating novel heart valve replacements beyond what is currently available for patients. Here we discuss heart valve replacement options that involve a biological component or process for creation, either in vitro or in vivo (tissue-engineered heart valves), and heart valves that are fabricated from polymeric material that are considered permanent inert materials that may suffice for adults where growth is not required. Polymeric materials provide opportunities for cost-effective heart valves that can be more easily manufactured and can be easily integrated with artificial heart and ventricular assist device technologies. Tissue engineered heart valves show promise as a regenerative patient specific model that could be the future of all valve replacement. Because tissue-engineered heart valves depend on cells for their creation, understanding how cells sense and respond to chemical and physical stimuli in their microenvironment is critical and therefore, is also reviewed.

Atherosclerosis at the carotid bifurcation is a major risk factor for stroke. As mechanical forces may impact lesion stability, finite element studies have been conducted on models of diseased vessels to elucidate the effects of lesion characteristics on the stresses within plaque materials. It is hoped that patient-specific biomechanical analyses may serve clinically to assess the rupture potential for any particular lesion, allowing better stratification of patients into the most appropriate treatments. Due to a sparsity of in vivo plaque rupture data, the relationship between various mechanical descriptors such as stresses or strains and rupture vulnerability is incompletely known, and the patient-specific utility of biomechanical analyses is unclear. In this article, we present a comparison between carotid atheroma rupture observed in vivo and the plaque stress distribution from fluid-structure interaction analysis based on pre-rupture medical imaging. The effects of image resolution are explored and the calculated stress fields are shown to vary by as much as 50% with sub-pixel geometric uncertainty. Within these bounds, we find a region of pronounced elevation in stress within the fibrous plaque layer of the lesion with a location and extent corresponding to that of the observed site of plaque rupture.

The regulation of valvular endothelial phenotypes by the hemodynamic environments of the human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis (CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular fibrosa layer. However, the mechanisms of this regional localization remain poorly characterized. In this study, we combine numerical simulation with in vitro experimentation to investigate the hypothesis that the previously documented differences between valve endothelial phenotypes are linked to distinct hemodynamic environments characteristic of these individual anatomical locations. A finite-element model of the aortic valve was created, describing the dynamic motion of the valve cusps and blood in the valve throughout the cardiac cycle. A fluid mesh with high resolution on the fluid boundary was used to allow accurate computation of the wall shear stresses. This model was used to compute two distinct shear stress waveforms, one for the ventricular surface and one for the aortic surface. These waveforms were then applied experimentally to cultured human endothelial cells and the expression of several pathophysiological relevant genes was assessed. Compared to endothelial cells subjected to shear stress waveforms representative of the aortic face, the endothelial cells subjected to the ventricular waveform showed significantly increased expression of the "atheroprotective" transcription factor Kruppel-like factor 2 (KLF2) and the matricellular protein Nephroblastoma overexpressed (NOV), and suppressed expression of chemokine Monocyte-chemotactic protein-1 (MCP-1). Our observations suggest that the difference in shear stress waveforms between the two sides of the aortic valve leaflet may contribute to the documented differential side-specific gene expression, and may be relevant for the development and progression of CAS and the potential role of endothelial mechanotransduction in this disease.

A new method is proposed for estimation of nonlinear elastic properties of soft tissues. The proposed approach involves a combination of nonlinear finite element methods with a genetic algorithm for estimating tissue stiffness profile. A multipoint scheme is introduced that satisfies the uniqueness condition, improves the estimation performance, and reduces the sensitivity to image noise. The utility of the proposed techniques is demonstrated using optical coherence tomography (OCT) images. The approach is, however, applicable to other imaging systems and modalities, as well, provided a reliable image registration scheme. The proposed algorithm is applied to realistic (2D) and idealized (3D) arterial plaque models, and proves promising for the estimation of intra-plaque distribution of nonlinear material properties.

A set of multiscale simulations has been created to examine the dynamic behavior of the human aortic valve (AV) at the cell, tissue, and organ length scales. Each model is fully three-dimensional and includes appropriate nonlinear, anisotropic material models. The organ-scale model is a dynamic fluid-structure interaction that predicts the motion of the blood, cusps, and aortic root throughout the full cycle of opening and closing. The tissue-scale model simulates the behavior of the AV cusp tissue including the sub-millimeter features of multiple layers and undulated geometry. The cell-scale model predicts cellular deformations of individual cells within the cusps. Each simulation is verified against experimental data. The three simulations are linked: deformations from the organ-scale model are applied as boundary conditions to the tissue-scale model, and the same is done between the tissue and cell scales. This set of simulations is a major advance in the study of the AV as it allows analysis of transient, three-dimensional behavior of the AV over the range of length scales from cell to organ.

Tissue elasticity reconstruction is a parameter estimation effort combining imaging, elastography, and computational modeling to build maps of soft tissue mechanical properties. One application is in the characterization of atherosclerotic plaques in diseased arteries, wherein the distribution of elastic properties is required for stress analysis and plaque stability assessment. In this paper, a computational scheme is proposed for elasticity reconstruction in soft tissues, combining finite element modeling (FEM) for mechanical analysis of soft tissues and a genetic algorithm (GA) for parameter estimation. With a model reduction of the discrete elasticity values into lumped material regions, namely the plaque constituents, a robust, adaptive strategy can be used to solve inverse elasticity problems involving complex and inhomogeneous solution spaces. An advantage of utilizing a GA is its insistence on global convergence. The algorithm is easily implemented and adaptable to more complex material models and geometries. It is meant to provide either accurate initial guesses of low-resolution elasticity values in a multi-resolution scheme or as a replacement for failing traditional elasticity estimation efforts.

High-resolution imaging provides a significant means for accurate material modulus estimation and mechanical characterization. Within the realm of in vivo soft tissue characterization, particularly on small biological length scales such as arterial atherosclerotic plaques, optical coherence tomography (OCT) offers a desirable imaging modality with higher spatial resolution and contrast of tissue as compared with intravascular ultrasound (IVUS). Based on recent advances in OCT imaging and elastography, we present a fully integrated system for tissue elasticity reconstruction, and assess the benefits of OCT on the distribution results of four representative tissue block models. We demonstrate accuracy, with displacement residuals on the order of 10(-6) mm (more than 3 orders of magnitude less than average calculated displacements), and high-resolution estimates, with the ability to resolve inclusions of 0.15 mm diameter.

Finite element analysis is a powerful tool for investigating the biomechanics of atherosclerosis and has thereby provided an improved understanding of acute myocardial infarction. Structural analysis of arterial walls is traditionally performed using geometry contours derived from histology. In this paper we demonstrate the first use of a new imaging technique, optical coherence tomography (OCT), as a basis for finite element analysis. There are two primary benefits of OCT relative to histology: 1) imaging is performed without excessive tissue handling, providing a more realistic geometry than histology and avoiding structural artifacts common to histologic processing, and 2) OCT imaging can be performed in vivo, making it possible to study disease progression and the effect of therapeutic treatments in animal models and living patients. Patterns of mechanical stress and strain distributions computed from finite element analysis based on OCT were compared with those from modeling based on "gold standard" histology. Our results indicate that vascular structure and composition determined by OCT provides an adequate basis for investigating the biomechanical factors relevant to atherosclerosis and acute myocardial infarction.

Atherogenesis is known to be associated with the stresses that act on or within the arterial wall. Still, the uneven distribution of atherosclerotic lesions and the impact of vessel remodeling on disease progression are poorly understood. A methodology is proposed to study the correlations between fluid dynamic parameters and histological markers of atherosclerosis. Trends suggested by preliminary data from four patients with advanced carotid bifurcation arterial disease are examined and compared to hypotheses in the literature. Four patients were scanned using MRI and ultrasound, and subsequently underwent carotid endarterectomy. For each patient. a geometric model and a numerical mesh were constructed from MR data, and velocity boundary conditions established. Computations yield values for average wall shear stress (WSS), maximum wall shear stress temporal gradient (WSSTG), and Oscillatory Shear Index (OSI). Following surgery, the excised plaques were sectioned, stained for smooth muscle cells (SMC), macrophages (M phi), lipid (LIP), and collagen (COL), and analyzed quantitatively. Correlations attempted between the various fluid dynamic variables and the biological markers were interesting but inconclusive. Tendencies of WSSTG and WSS to correlate negatively with M phi and LIP, and positively with COL and SMC, as well as tendencies of OSI to correlate positively with Mphi and LIP and negatively with COL and SMC, were observed. These trends agree with hypotheses in the literature, which are based on ex vivo and in vitro experimental studies.

The important influence of hemodynamic factors in the initiation and progression of arterial disease has led to numerous studies to computationally simulate blood flow at sites of disease and examine potential correlative factors. This study considers the differences in hemodynamics produced by varying heart rate in a fully coupled fluid-structure three-dimensional finite element model of a carotid bifurcation. Two cases with a 50% increase in heart rate are considered: one in which peripheral resistance is uniformly reduced to maintain constant mean arterial pressure, resulting in an increase in mean flow, and a second in which cerebral vascular resistance is held constant so that mean carotid artery flow is nearly unchanged. Results show that, with increased flow rate, the flow patterns are relatively unchanged, but the magnitudes of mean and instantaneous wall shear stress are increased roughly in proportion to the flow rate, except at the time of minimum flow (and maximum flow separation) when shear stress in the carotid bulb is increased in magnitude more than threefold. When cerebral peripheral resistance is held constant, the differences are much smaller, except again at end diastole. Maximum wall shear stress temporal gradient is elevated in both cases with elevated heart rate. Changes in oscillatory shear index are minimal. These findings suggest that changes in the local hemodynamics due to mild exercise may be relatively small in the carotid artery.

The coronary arteries are a common site of atherosclerotic plaque formation, which has been putatively linked to hemodynamic and mass transport patterns. The purpose of this paper was to study mass transport patterns in a human right coronary artery (RCA) model, focusing on the effects of local geometric features on mass transfer from blood to artery walls. Using a previously developed characteristic/finite element scheme for solving advection-dominated transport problems, mass transfer calculations were performed in a rigid, anatomically realistic model of a human RCA. A qualitative and quantitative examination of the RCA geometry was also carried out. The concentration field within the RCA was seen to closely follow primary and secondary flow features. Local variations in mass transfer patterns due to geometric features were significant and much larger in magnitude than local variations in wall shear stress. We conclude that the complex secondary flows in a realistic arterial model can produce very substantial local variations in blood-wall mass transfer rates, and may be important in atherogenesis. Further, RCA mass transfer patterns are more sensitive to local geometric features than are wall shear stress patterns.