Eric L. Pierce

Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts

Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt tq209). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe–2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe–2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe–2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.

Suture Forces in Undersized Mitral Annuloplasty: Novel Device and Measurements

PURPOSE To demonstrate the first use of a novel technology for quantifying suture forces on annuloplasty rings to better understand the mechanisms of ring dehiscence. DESCRIPTION Force transducers were developed, attached to a size 24 Physio ring, and implanted in the mitral annulus of an ovine animal. Ring suture forces were measured after implantation and for cardiac cycles reaching peak left ventricular pressures (LVP) of 100, 125, and 150 mm Hg. EVALUATION After implantation of the undersized ring to the flaccid annulus, the mean suture force was 2.0±0.6 N. During cyclic contraction, the anterior ring suture forces were greater than the posterior ring suture forces at peak LVPs of 100 mm Hg (4.9±2.0 N vs 2.1±1.1 N), 125 mm Hg (5.4±2.3 N vs 2.3±1.2 N), and 150 mm Hg (5.7±2.4 N vs 2.4±1.1 N). The largest force was 7.4 N at 150 mm Hg. CONCLUSIONS The preliminary results demonstrate trends in annuloplasty suture forces and their variation with location and LVP. Future studies will significantly contribute to clinical knowledge by elucidating the mechanisms of ring dehiscence while improving annuloplasty ring design and surgical repair techniques.

Mitral Valve Chordae Tendineae: Topological and Geometrical Characterization

Mitral valve (MV) closure depends upon the proper function of each component of the valve apparatus, which includes the annulus, leaflets, and chordae tendineae (CT). Geometry plays a major role in MV mechanics and thus highly impacts the accuracy of computational models simulating MV function and repair. While the physiological geometry of the leaflets and annulus have been previously investigated, little effort has been made to quantitatively and objectively describe CT geometry. The CT constitute a fibrous tendon-like structure projecting from the papillary muscles (PMs) to the leaflets, thereby evenly distributing the loads placed on the MV during closure. Because CT play a major role in determining the shape and stress state of the MV as a whole, their geometry must be well characterized. In the present work, a novel and comprehensive investigation of MV CT geometry was performed to more fully quantify CT anatomy. In vitro micro-tomography 3D images of ovine MVs were acquired, segmented, then analyzed using a curve-skeleton transform. The resulting data was used to construct B-spline geometric representations of the CT structures, enriched with a continuous field of cross-sectional area (CSA) data. Next, Reeb graph models were developed to analyze overall topological patterns, along with dimensional attributes such as segment lengths, 3D orientations, and CSA. Reeb graph results revealed that the topology of ovine MV CT followed a full binary tree structure. Moreover, individual chords are mostly planar geometries that together form a 3D load-bearing support for the MV leaflets. We further demonstrated that, unlike flow-based branching patterns, while individual CT branches became thinner as they propagated further away from the PM heads towards the leaflets, the total CSA almost doubled. Overall, our findings indicate a certain level of regularity in structure, and suggest that population-based MV CT geometric models can be generated to improve current MV repair procedures.

A Comprehensive Framework for the Characterization of the Complete Mitral Valve Geometry for the Development of a Population-Averaged Model

Simulations of the biomechanical behavior of the Mitral Valve (MV) based on simplified geometric models are difficult to interpret due to significant intra-patient variations and pathologies in the MV geometry. Thus, it is critical to use a systematic approach to characterization and population-averaging of the patient-specific models. We introduce a multi-scale modeling framework for characterizing the entire MV apparatus geometry via a relatively small set of parameters. The leaflets and annulus are analyzed using a superquadric surface model superimposed with fine-scale filtered level-set field. Filtering of fine-scale features is performed in a spectral space to allow control of resolution, resampling and robust averaging. Chordae tendineae structure is modeled using a medial axis representation with superimposed filtered pointwise cross-sectional area field. The chordae topology is characterized using orientation and spatial distribution functions. The methodology is illustrated with the analysis of an ovine MV microtomography imaging data.

Population-Averaged Geometric Model of Mitral Valve From Patient-Specific Imaging Data

The mitral valve (MV) is one of the atrioventricular heart valves and regulates the blood flow between the left atrium and ventricle during the cardiac cycle. Its anatomical structure is comprised of anterior and posterior leaflets, chordae tendineae, and papillary muscles. The main function of the MV is to prevent blood flow regurgitation back into the left atrium during systole. Abnormalities in geometry of MV can lead to mitral insufficiency disorder, which requires either valve replacement or surgical repair to restore proper MV coaptation. Annually, over 40,000 patients in the U.S. alone are treated for MV disorders [1]. In the past two decades, the emphasis in MV treatment has been shifting from replacement toward repair due to lower morbidity and mortality of the latter approach [2]. However, the natural anatomical variability of human MV geometry precludes the use of single or simplified geometries for the simulation of surgical repair. One of the ways to address this issue is by using patient-specific diagnosis and modeling [3], or population-averaged geometric models of MV. The existing approaches for characterization and reconstruction of the cardiovascular organ-level geometry include fitting of predefined sets of nonuniform rational B-splines (NURBS) to the imaging data [4], and using spheroidal harmonics representations [5]. Even though it is possible to construct average geometric models this way, the analysis of anatomical shape variations becomes difficult in this setting because of the confounding of dimensional and shape descriptors. At the same time, none of the existing methods allow integration of the high-fidelity in vitro data with lower-resolution in vivo imaging in a consistent manner. In this work, we formulate the framework for building the population-averaged geometric model of MV, which lends to straightforward analysis of dimensional and anatomical variations. In the sections to follow, we discuss the procedure and advantages of this method for the development of robust medical devices and treatment procedures.

Real-time recording of annuloplasty suture dehiscence reveals a potential mechanism for dehiscence cascade

From The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Ga; Gorman Cardiovascular Research Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; and InSciTech, Inc, Alpharetta, Ga. This study was supported by the National Science Foundation (Fellowship DGE-1148903, to E.L.P.) and the National Heart, Lung, and Blood Institute (Grant HL113216). Disclosures: Authors have nothing to disclose with regard to commercial support. Received for publication Nov 8, 2015; revisions received Jan 7, 2016; accepted for publication Jan 23, 2016; available ahead of print March 11, 2016. Address for reprints: Ajit P. Yoganathan, PhD, 387 Technology Circle NW, Suite 200, Atlanta, GA 30313 (E-mail: ajit.yoganathan@bme.gatech.edu). J Thorac Cardiovasc Surg 2016;152:e15-7 0022-5223/

Mitral annuloplasty ring suture forces: Impact of surgeon, ring, and use conditions

36.00 Copyright 2016 by The American Association for Thoracic Surgery http://dx.doi.org/10.1016/j.jtcvs.2016.01.043 Dehiscence of an annuloplasty suture adds significant tension to its adjacent 2 sutures.

Multi-modal Validation Framework of Mitral Valve Geometry and Functional Computational Models

Objective The study objective was to quantify the effect of ring type, ring‐annulus sizing, suture position, and surgeon on the forces required to tie down and constrain a mitral annuloplasty ring to a beating heart. Methods Physio (Edwards Lifesciences, Irvine, Calif) or Profile 3D (Medtronic, Dublin, Ireland) annuloplasty rings were instrumented with suture force transducers and implanted in ovine subjects (N = 23). Tie‐down forces and cyclic contractile forces were recorded and analyzed at 10 suture positions and at 3 levels of increasing peak left ventricular pressure. Results Across all conditions, tie‐down force was 2.7 ± 1.4 N and cyclic contractile force was 2.0 ± 1.2 N. Tie‐down force was not meaningfully affected by any factor except surgeon. Significant differences in overall and individual tie‐down forces were observed between the 2 primary implanting surgeons. No other factors were observed to significantly affect tie‐down force. Contractile suture forces were significantly reduced by ring‐annulus true sizing. This was driven almost exclusively by Physio cases and by reduction along the anterior aspect, where dehiscence is less common clinically. Contractile suture forces did not differ significantly between ring types. However, when undersizing, Profile 3D forces were significantly more uniform around the annular circumference. A sutures tie‐down force did not correlate to its eventual contractile force. Conclusions Mitral annuloplasty suture loading is influenced by ring type, ring‐annulus sizing, suture position, and surgeon, suggesting that reports of dehiscence may not be merely a series of isolated errors. When compared with forces known to cause suture dehiscence, these in vivo suture loading data aid in establishing potential targets for reducing the occurrence of ring dehiscence.

Fluid-Structure Interaction Analysis of Ruptured Mitral Chordae Tendineae

Computational models of the mitral valve (MV) exhibit significant potential for patient-specific surgical planning. Recently, these models have been advanced by incorporating MV tissue structure, non-linear material properties, and more realistic chordae tendineae architecture. Despite advances, only limited ground-truth data exists to validate their ability to accurately simulate MV closure and function. The validation of the underlying models will enhance modeling accuracy and confidence in the simulated results. A necessity towards this aim is to develop an integrated pipeline based on a comprehensive in-vitro flow loop setup including echocardiography techniques (Echo) and micro-computed tomography. Building on [1] we improved the acquisition protocol of the proposed experimental setup for in-vitro Echo imaging, which enables the extraction of more reproducible and accurate geometrical models, using state-of-the art image processing and geometric modeling techniques. Based on the geometrical parameters from the Echo MV models captured during diastole, a bio-mechanical model is derived to estimate MV closure geometry. We illustrate the framework on two data sets and show the improvements obtained from the novel Echo acquisition protocol and improved bio-mechanical model.

Personalized mitral valve closure computation and uncertainty analysis from 3D echocardiography

The chordal structure is a part of mitral valve geometry that has been commonly neglected or simplified in computational modeling due to its complexity. However, these simplifications cannot be used when investigating the roles of individual chordae tendineae in mitral valve closure. For the first time, advancements in imaging, computational techniques, and hardware technology make it possible to create models of the mitral valve without simplifications to its complex geometry, and to quickly run validated computer simulations that more realistically capture its function. Such simulations can then be used for a detailed analysis of chordae-related diseases. In this work, a comprehensive model of a subject-specific mitral valve with detailed chordal structure is used to analyze the distinct role played by individual chordae in closure of the mitral valve leaflets. Mitral closure was simulated for 51 possible chordal rupture points. Resultant regurgitant orifice area and strain change in the chordae at the papillary muscle tips were then calculated to examine the role of each ruptured chorda in the mitral valve closure. For certain subclassifications of chordae, regurgitant orifice area was found to trend positively with ruptured chordal diameter, and strain changes correlated negatively with regurgitant orifice area. Further advancements in clinical imaging modalities, coupled with the next generation of computational techniques will enable more physiologically realistic simulations.