Heritable changes of epialleles near genes in maize can be triggered in the absence of CHH methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (Mediator of paramutation1), with that of their parents, wild-type siblings, and backcrossed progeny in maize (Zea mays). Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of these DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that both TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in most TCM DMRs in F1 plants required Mop1, initiation of a new epigenetic state of these DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is independent of RNA-directed DNA methylation.

Heritable changes of epialleles in maize can be triggered in the absence of DNA methylation.

Trans-chromosomal interactions resulting in changes in DNA methylation during hybridization have been observed in several plant species. However, very little is known about the causes or consequences of these interactions. Here, we compared DNA methylomes of F1 hybrids that are mutant for a small RNA biogenesis gene, Mop1 (mediator of paramutation1) with that of their parents, wild type siblings, and backcrossed progeny in maize. Our data show that hybridization triggers global changes in both trans-chromosomal methylation (TCM) and trans-chromosomal demethylation (TCdM), most of which involved changes in CHH methylation. In more than 60% of these TCM differentially methylated regions (DMRs) in which small RNAs are available, no significant changes in the quantity of small RNAs were observed. Methylation at the CHH TCM DMRs was largely lost in the mop1 mutant, although the effects of this mutant varied depending on the location of the CHH DMRs. Interestingly, an increase in CHH at TCM DMRs was associated with enhanced expression of a subset of highly expressed genes and suppressed expression of a small number of lowly expressed genes. Examination of the methylation levels in backcrossed plants demonstrates that TCM and TCdM can be maintained in the subsequent generation, but that TCdM is more stable than TCM. Surprisingly, although increased CHH methylation in F1 plants did require Mop1, initiation of the changes in the epigenetic state of TCM DMRs did not require a functional copy of this gene, suggesting that initiation of these changes is not dependent on RNA-directed DNA methylation.

Excision and reinsertion of Ac macrotransposons in maize.

Eukaryotic Macrotransposons (MTns) can be formed by 2 nearby elements flanking a segment of host DNA. The maize Ac transposon can form Ac::MTns, but little is known about Ac::MTn transposition activities. Here, we studied 3 Ac::MTns at the maize p1 locus, each of which is composed of a segment of maize p1 genomic DNA (up to 15 kb) bounded by a fractured Ac element (fAc, 2039 bp), and a full-length Ac element in direct orientation. The resulting Ac::MTns are of 16, 16.5, and 22 kb total length. From these 3 Ac::MTns, we identified 10 independent cases of macrotransposition, and observed similar features of transposition between Ac::MTn and standard Ac/Ds, including characteristic excision footprints and insertion target site duplications. Nine out of the 10 Ac::MTn reinsertion targets were genetically linked to the donor sites, another similarity with Ac/Ds standard transposition. We also identified a MTn-like structure in the maize B73 reference genome and 5 NAM founder lines. The MTn in diverse lines is flanked by target site duplications, confirming the historic occurrence of MTn transposition during genome evolution. Our results show that Ac::MTns are capable of mobilizing segments of DNA long enough to include a typical full-length plant gene and in theory could erode gene colinearity in syntenic regions during plant genome evolution.

RNA-directed DNA methylation prevents rapid and heritable reversal of transposon silencing under heat stress in Zea mays.

In large complex plant genomes, RNA-directed DNA methylation (RdDM) ensures that epigenetic silencing is maintained at the boundary between genes and flanking transposable elements. In maize, RdDM is dependent on Mediator of Paramutation1 (Mop1), a gene encoding a putative RNA dependent RNA polymerase. Here we show that although RdDM is essential for the maintenance of DNA methylation of a silenced MuDR transposon in maize, a loss of that methylation does not result in a restoration of activity. Instead, heritable maintenance of silencing is maintained by histone modifications. At one terminal inverted repeat (TIR) of this element, heritable silencing is mediated via histone H3 lysine 9 dimethylation (H3K9me2), and histone H3 lysine 27 dimethylation (H3K27me2), even in the absence of DNA methylation. At the second TIR, heritable silencing is mediated by histone H3 lysine 27 trimethylation (H3K27me3), a mark normally associated with somatically inherited gene silencing. We find that a brief exposure of high temperature in a mop1 mutant rapidly reverses both of these modifications in conjunction with a loss of transcriptional silencing. These reversals are heritable, even in mop1 wild-type progeny in which methylation is restored at both TIRs. These observations suggest that DNA methylation is neither necessary to maintain silencing, nor is it sufficient to initiate silencing once has been reversed. However, given that heritable reactivation only occurs in a mop1 mutant background, these observations suggest that DNA methylation is required to buffer the effects of environmental stress on transposable elements.

The mop1 mutation affects the recombination landscape in maize.

Meiotic recombination is a fundamental process that generates genetic diversity and ensures the accurate segregation of homologous chromosomes. While a great deal is known about genetic factors that regulate recombination, relatively little is known about epigenetic factors, such as DNA methylation. In maize, we examined the effects on meiotic recombination of a mutation in a component of the RNA-directed DNA methylation pathway, Mop1 (Mediator of paramutation1), as well as a mutation in a component of the trans-acting small interference RNA biogenesis pathway, Lbl1 (Leafbladeless1). MOP1 is of particular interest with respect to recombination because it is responsible for methylation of transposable elements that are immediately adjacent to transcriptionally active genes. In the mop1 mutant, we found that meiotic recombination is uniformly decreased in pericentromeric regions but is generally increased in gene rich chromosomal arms. This observation was further confirmed by cytogenetic analysis showing that although overall crossover numbers are unchanged, they occur more frequently in chromosomal arms in mop1 mutants. Using whole genome bisulfite sequencing, our data show that crossover redistribution is driven by loss of CHH (where H = A, T, or C) methylation within regions near genes. In contrast to what we observed in mop1 mutants, no significant changes were observed in the frequency of meiotic recombination in lbl1 mutants. Our data demonstrate that CHH methylation has a significant impact on the overall recombination landscape in maize despite its low frequency relative to CG and CHG methylation.

Evolutionary and functional genomics of DNA methylation in maize domestication and improvement.

DNA methylation is a ubiquitous chromatin feature, present in 25% of cytosines in the maize genome, but variation and evolution of the methylation landscape during maize domestication remain largely unknown. Here, we leverage whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) data on populations of modern maize, landrace, and teosinte (Zea mays ssp. parviglumis) to estimate epimutation rates and selection coefficients. We find weak evidence for direct selection on DNA methylation in any context, but thousands of differentially methylated regions (DMRs) are identified population-wide that are correlated with recent selection. For two trait-associated DMRs, vgt1-DMR and tb1-DMR, HiChIP data indicate that the interactive loops between DMRs and respective downstream genes are present in B73, a modern maize line, but absent in teosinte. Our results enable a better understanding of the evolutionary forces acting on patterns of DNA methylation and suggest a role of methylation variation in adaptive evolution.

Small RNA-Mediated De Novo Silencing of Ac/Ds Transposons Is Initiated by Alternative Transposition in Maize.

Although transposable elements (TEs) comprise a major fraction of many higher eukaryotic genomes, most TEs are silenced by host defense mechanisms. The means by which otherwise active TEs are recognized and silenced remains poorly understood. Here we analyzed two independent cases of spontaneous silencing of the active maize Ac/Ds transposon system. This silencing is initiated by alternative transposition, a type of aberrant transposition event that engages the termini of two nearby separate TEs. Alternative transposition during DNA replication can generate Composite Insertions that contain inverted duplications of the transposon sequences. We show that the inverted duplications of two Composite Insertions are transcribed to produce double-stranded RNAs that trigger the production of two distinct classes of small interfering RNAs: a 24-nt class complementary to the TE terminal inverted repeats and noncoding subterminal regions, and a 21- to 22-nt class corresponding to the TE transcribed regions. Plants containing these small interfering RNA-generating Composite Insertions exhibit decreased levels of Ac transcript and heritable repression of Ac/Ds transposition. Further, we demonstrate that Composite Insertions can heritably silence otherwise active elements in trans This study documents the first case of transposon silencing induced by alternative transposition and may represent a general initiating mechanism for silencing of DNA transposons.

4D cardiac electromechanical activation imaging.

Cardiac abnormalities, a major cause of morbidity and mortality, affect millions of people worldwide. Despite the urgent clinical need for early diagnosis, there is currently no noninvasive technique that can infer to the electrical function of the whole heart in 3D and thereby localize abnormalities at the point of care. Here we present a new method for noninvasive 4D mapping of the cardiac electromechanical activity in a single heartbeat for heart disease characterization such as arrhythmia and infarction. Our novel technique captures the 3D activation wave of the heart in vivo using high volume-rate (500 volumes per second) ultrasound with a 32 × 32 matrix array. Electromechanical activation maps are first presented in a normal and infarcted cardiac model in silico and in canine heart during pacing and re-entrant ventricular tachycardia in vivo. Noninvasive 4D electromechanical activation mapping in a healthy volunteer and a heart failure patient are also determined. The technique described herein allows for direct, simultaneous and noninvasive visualization of electromechanical activation in 3D, which provides complementary information on myocardial viability and/or abnormality to clinical imaging.

Opsin spectral sensitivity determines the effectiveness of optogenetic termination of ventricular fibrillation in the human heart: a simulation study.

KEY POINTS: Optogenetics-based defibrillation, a theoretical alternative to electrotherapy, involves expression of light-sensitive ion channels in the heart (via gene or cell therapy) and illumination of the cardiac surfaces (via implanted LED arrays) to elicit light-induced activations. We used a biophysically detailed human ventricular model to determine whether such a therapy could terminate fibrillation (VF) and identify which combinations of light-sensitive ion channel properties and illumination configurations would be effective. Defibrillation was successful when a large proportion (> 16.6%) of ventricular tissue was directly stimulated by light that was bright enough to induce an action potential in an uncoupled cell. While illumination with blue light never successfully terminated VF, illumination of red light-sensitive ion channels with dense arrays of implanted red light sources resulted in successful defibrillation. Our results suggest that cardiac expression of red light-sensitive ion channels is necessary for the development of effective optogenetics-based defibrillation therapy using LED arrays. ABSTRACT: Optogenetics-based defibrillation has been proposed as a novel and potentially pain-free approach to enable cardiomyocyte-selective defibrillation in humans, but the feasibility of such a therapy remains unknown. This study aimed to (1) assess the feasibility of terminating sustained ventricular fibrillation (VF) via light-induced excitation of opsins expressed throughout the myocardium and (2) identify the ideal (theoretically possible) opsin properties and light source configurations that would maximise therapeutic efficacy. We conducted electrophysiological simulations in an MRI-based human ventricular model with VF induced by rapid pacing; light sensitisation via systemic, cardiac-specific gene transfer of channelrhodopsin-2 (ChR2) was simulated. In addition to the widely used blue light-sensitive ChR2-H134R, we also modelled theoretical ChR2 variants with augmented light sensitivity (ChR2+), red-shifted spectral sensitivity (ChR2-RED) or both (ChR2-RED+). Light sources were modelled as synchronously activating LED arrays (LED radius: 1 mm; optical power: 10 mW mm-2 ; array density: 1.15-4.61 cm-2 ). For each unique optogenetic configuration, defibrillation was attempted with two different optical pulse durations (25 and 500 ms). VF termination was only successful for configurations involving ChR2-RED and ChR2-RED+ (for LED arrays with density ≥ 2.30 cm-2 ), suggesting that opsin spectral sensitivity was the most important determinant of optogenetic defibrillation efficacy. This was due to the deeper penetration of red light in cardiac tissue compared with blue light, which resulted in more widespread light-induced propagating wavefronts. Longer pulse duration and higher LED array density were associated with increased optogenetic defibrillation efficacy. In all cases observed, the defibrillation mechanism was light-induced depolarisation of the excitable gap, which led to block of reentrant wavefronts.

Self-esteem, Self-efficacy, and Appearance Assessment of Young Female Patients Undergoing Facial Cosmetic Surgery: A Comparative Study of the Chinese Population.

IMPORTANCE: The psychological traits of cosmetic surgery patients (CSP) are important for selecting patients and postoperative patient satisfaction. A patient's self-esteem, self-efficacy, and self-assessment affect his or her motivation for cosmetic surgery, but the association among these traits remains unclear, especially in the Asian population. OBJECTIVE: To clarify the association of a patient's psychological traits, decision to undergo cosmetic surgery, and the effectiveness of facial cosmetic surgery on the psychological conditions of young, female Chinese patients. DESIGN, SETTING, AND PARTICIPANTS: Three different groups of young women (aged 18-30 years) from the Plastic Surgery Hospital, Chinese Academy of Medical Sciences, and 7 universities were enrolled from January 1, 2012, through December 31, 2014: CSPs (n = 161), general population controls (GPCs) (n = 355), and facial appearance raters (FARs) (n = 268). The last date of follow-up was January 20, 2015. Patient data from questionnaires were obtained preoperatively and 6 months postoperatively, and the data from the control groups were obtained immediately after enrollment. Front-view facial images of the study participants were taken and then shown to independent raters to assess the participants' facial appearances on a rating scale. MAIN OUTCOMES AND MEASURES: Evaluation of self-esteem and self-efficacy, subjective and objective assessment of facial appearance, and structural equation models. RESULTS: A total of 163 CSPs and 387 GPCs were recruited for the study, and complete and valid data were obtained from 161 CSPs and 355 GPCs. All responses from the 268 FARs met the criteria for subsequent analysis. Of the questionnaires issued to the CSPs 6 months postoperatively, 126 valid responses were returned (response rate, 78.3%). Self-esteem and self-efficacy decreased significantly in preoperative patients compared with controls (P < .001) (mean [SD] scores, 22.60 [1.80] for CSPs and 27.39 [2.11] for GPCs for self-esteem and 21.50 [2.40] for CSPs and 28.59 [4.23] for GPCs for self-efficacy) and were found to be at nearly normal levels 6 months postoperatively (mean [SD] scores, 25.88 [3.65] and 26.38 [2.45] for self-esteem and self-efficacy, respectively). The patients' objective assessments of facial appearance did not differ significantly from those of the control group participants (mean [SD] scores, 4.51 [0.77] and 4.55 [0.74] for CSPs and GPCs, respectively; P = .86); however, a significant decrease in patient self-assessment was noted (mean [SD scores], 6.45 [1.15] and 7.31 [1.42] for CSPs and GPCs, respectively; P = .01). Moreover, the structural equation models revealed a path from low self-esteem and self-efficacy after decreased self-assessment to decision for cosmetic surgery. CONCLUSIONS AND RELEVANCE: Self-esteem and self-efficacy mediate the negative effects of self-assessment on the decision of young women to undergo facial cosmetic surgery. The impairment of self-esteem and self-efficacy may indicate the need for preoperative psychological intervention. Facial cosmetic surgery can have positive effects on self-esteem and self-efficacy. LEVEL OF EVIDENCE: 2.

Alternative Transposition Generates New Chimeric Genes and Segmental Duplications at the Maize p1 Locus.

The maize Ac/Ds transposon family was the first transposable element system identified and characterized by Barbara McClintock. Ac/Ds transposons belong to the hAT family of class II DNA transposons. We and others have shown that Ac/Ds elements can undergo a process of alternative transposition in which the Ac/Ds transposase acts on the termini of two separate, nearby transposons. Because these termini are present in different elements, alternative transposition can generate a variety of genome alterations such as inversions, duplications, deletions, and translocations. Moreover, Ac/Ds elements transpose preferentially into genic regions, suggesting that structural changes arising from alternative transposition may potentially generate chimeric genes at the rearrangement breakpoints. Here we identified and characterized 11 independent cases of gene fusion induced by Ac alternative transposition. In each case, a functional chimeric gene was created by fusion of two linked, paralogous genes; moreover, each event was associated with duplication of the ∼70-kb segment located between the two paralogs. An extant gene in the maize B73 genome that contains an internal duplication apparently generated by an alternative transposition event was also identified. Our study demonstrates that alternative transposition-induced duplications may be a source for spontaneous creation of diverse genome structures and novel genes in maize.

Verification of cardiac mechanics software: benchmark problems and solutions for testing active and passive material behaviour.

Models of cardiac mechanics are increasingly used to investigate cardiac physiology. These models are characterized by a high level of complexity, including the particular anisotropic material properties of biological tissue and the actively contracting material. A large number of independent simulation codes have been developed, but a consistent way of verifying the accuracy and replicability of simulations is lacking. To aid in the verification of current and future cardiac mechanics solvers, this study provides three benchmark problems for cardiac mechanics. These benchmark problems test the ability to accurately simulate pressure-type forces that depend on the deformed objects geometry, anisotropic and spatially varying material properties similar to those seen in the left ventricle and active contractile forces. The benchmark was solved by 11 different groups to generate consensus solutions, with typical differences in higher-resolution solutions at approximately 0.5%, and consistent results between linear, quadratic and cubic finite elements as well as different approaches to simulating incompressible materials. Online tools and solutions are made available to allow these tests to be effectively used in verification of future cardiac mechanics software.

Transposition-mediated DNA re-replication in maize.

Every DNA segment in a eukaryotic genome normally replicates once and only once per cell cycle to maintain genome stability. We show here that this restriction can be bypassed through alternative transposition, a transposition reaction that utilizes the termini of two separate, nearby transposable elements (TEs). Our results suggest that alternative transposition during S phase can induce re-replication of the TEs and their flanking sequences. The DNA re-replication can spontaneously abort to generate double-strand breaks, which can be repaired to generate Composite Insertions composed of transposon termini flanking segmental duplications of various lengths. These results show how alternative transposition coupled with DNA replication and repair can significantly alter genome structure and may have contributed to rapid genome evolution in maize and possibly other eukaryotes.

New Additions to the Toolkit for Forward/Inverse Problems in Electrocardiography within the SCIRun Problem Solving Environment.

Cardiac electrical imaging often requires the examination of different forward and inverse problem formulations based on mathematical and numerical approximations of the underlying source and the intervening volume conductor that can generate the associated voltages on the surface of the body. If the goal is to recover the source on the heart from body surface potentials, the solution strategy must include numerical techniques that can incorporate appropriate constraints and recover useful solutions, even though the problem is badly posed. Creating complete software solutions to such problems is a daunting undertaking. In order to make such tools more accessible to a broad array of researchers, the Center for Integrative Biomedical Computing (CIBC) has made an ECG forward/inverse toolkit available within the open source SCIRun system. Here we report on three new methods added to the inverse suite of the toolkit. These new algorithms, namely a Total Variation method, a non-decreasing TMP inverse and a spline-based inverse, consist of two inverse methods that take advantage of the temporal structure of the heart potentials and one that leverages the spatial characteristics of the transmembrane potentials. These three methods further expand the possibilities of researchers in cardiology to explore and compare solutions to their particular imaging problem.

Isolation of sequences flanking Ac insertion sites by Ac casting.

Localizing Ac insertions is a fundamental task in studying Ac-induced mutation and chromosomal rearrangements involving Ac elements. Researchers may sometimes be faced with the situation in which the sequence flanking one side of an Ac/Ds element is known, but the other flank is unknown. Or, a researcher may have a small sequence surrounding the Ac/Ds insertion site and needs to obtain additional flanking genomic sequences. One way to rapidly clone unknown Ac/Ds flanking sequences is via a PCR-based method termed Ac casting. This approach utilizes the somatic transposition activity of Ac during plant development, and provides an efficient means for short-range genome walking. Here we describe the principle of Ac casting, and show how it can be applied to isolate Ac macrotransposon insertion sites.

Inverse Electrocardiographic Source Localization of Ischemia: An Optimization Framework and Finite Element Solution.

With the goal of non-invasively localizing cardiac ischemic disease using body-surface potential recordings, we attempted to reconstruct the transmembrane potential (TMP) throughout the myocardium with the bidomain heart model. The task is an inverse source problem governed by partial differential equations (PDE). Our main contribution is solving the inverse problem within a PDE-constrained optimization framework that enables various physically-based constraints in both equality and inequality forms. We formulated the optimality conditions rigorously in the continuum before deriving finite element discretization, thereby making the optimization independent of discretization choice. Such a formulation was derived for the L2-norm Tikhonov regularization and the total variation minimization. The subsequent numerical optimization was fulfilled by a primal-dual interior-point method tailored to our problem's specific structure. Our simulations used realistic, fiber-included heart models consisting of up to 18,000 nodes, much finer than any inverse models previously reported. With synthetic ischemia data we localized ischemic regions with roughly a 10% false-negative rate or a 20% false-positive rate under conditions up to 5% input noise. With ischemia data measured from animal experiments, we reconstructed TMPs with roughly 0.9 correlation with the ground truth. While precisely estimating the TMP in general cases remains an open problem, our study shows the feasibility of reconstructing TMP during the ST interval as a means of ischemia localization.

Finite-element-based discretization and regularization strategies for 3-D inverse electrocardiography.

We consider the inverse electrocardiographic problem of computing epicardial potentials from a body-surface potential map. We study how to improve numerical approximation of the inverse problem when the finite-element method is used. Being ill-posed, the inverse problem requires different discretization strategies from its corresponding forward problem. We propose refinement guidelines that specifically address the ill-posedness of the problem. The resulting guidelines necessitate the use of hybrid finite elements composed of tetrahedra and prism elements. Also, in order to maintain consistent numerical quality when the inverse problem is discretized into different scales, we propose a new family of regularizers using the variational principle underlying finite-element methods. These variational-formed regularizers serve as an alternative to the traditional Tikhonov regularizers, but preserves the L(2) norm and thereby achieves consistent regularization in multiscale simulations. The variational formulation also enables a simple construction of the discrete gradient operator over irregular meshes, which is difficult to define in traditional discretization schemes. We validated our hybrid element technique and the variational regularizers by simulations on a realistic 3-D torso/heart model with empirical heart data. Results show that discretization based on our proposed strategies mitigates the ill-conditioning and improves the inverse solution, and that the variational formulation may benefit a broader range of potential-based bioelectric problems.

A toolkit for forward/inverse problems in electrocardiography within the SCIRun problem solving environment.

Computational modeling in electrocardiography often requires the examination of cardiac forward and inverse problems in order to non-invasively analyze physiological events that are otherwise inaccessible or unethical to explore. The study of these models can be performed in the open-source SCIRun problem solving environment developed at the Center for Integrative Biomedical Computing (CIBC). A new toolkit within SCIRun provides researchers with essential frameworks for constructing and manipulating electrocardiographic forward and inverse models in a highly efficient and interactive way. The toolkit contains sample networks, tutorials and documentation which direct users through SCIRun-specific approaches in the assembly and execution of these specific problems.

An optimization framework for inversely estimating myocardial transmembrane potentials and localizing ischemia.

By combining a static bidomain heart model with a torso conduction model, we studied the inverse electrocardiographic problem of computing the transmembrane potentials (TMPs) throughout the myocardium from a body-surface potential map, and then used the recovered potentials to localize myocardial ischemia. Our main contribution is solving the inverse problem within a constrained optimization framework, which is a generalization of previous methods for calculating transmembrane potentials. The framework offers ample flexibility for users to apply various physiologically-based constraints, and is well supported by mature algorithms and solvers developed by the optimization community. By avoiding the traditional inverse ECG approach of building the lead-field matrix, the framework greatly reduces computation cost and, by setting the associated forward problem as a constraint, the framework enables one to flexibly set individualized resolutions for each physical variable, a desirable feature for balancing model accuracy, ill-conditioning and computation tractability. Although the task of computing myocardial TMPs at an arbitrary time instance remains an open problem, we showed that it is possible to obtain TMPs with moderate accuracy during the ST segment by assuming all cardiac cells are at the plateau phase. Moreover, the calculated TMPs yielded a good estimate of ischemic regions, which was of more clinical interest than the voltage values themselves. We conducted finite element simulations of a phantom experiment over a 2D torso model with synthetic ischemic data. Preliminary results indicated that our approach is feasible and suitably accurate for the common case of transmural myocardial ischemia.

Resolution strategies for the finite-element-based solution of the ECG inverse problem.

Successful employment of numerical techniques for the solution of forward and inverse ECG problems requires the ability to both quantify and minimize approximation errors introduced as part of the discretization process. Our objective is to develop discretization and refinement strategies involving hybrid-shaped finite elements so as to minimize approximation errors for the ECG inverse problem. We examine both the ill-posedness of the mathematical inverse problem and the ill-conditioning of the discretized system in order to propose strategies specifically designed for the ECG inverse problem. We demonstrate that previous discretization and approximation strategies may worsen the properties of the inverse problem approximation. We then demonstrate the efficacy of our strategies on both a simplified and a realistic 2-D torso model.