Automated spatially targeted optical micro proteomics identifies fibroblast- and macrophage-specific regulation of myocardial infarction scar maturation in rats.

Myocardial infarction (MI) results from occlusion of blood supply to the heart muscle causing death of cardiac muscle cells. Following myocardial infarction (MI), extracellular matrix deposition and scar formation mechanically stabilize the injured heart as damaged myocytes undergo necrosis and removal. Fibroblasts and macrophages are key drivers of post-MI scar formation, maturation, and ongoing long-term remodelling; however, their individual contributions are difficult to assess from bulk analyses of infarct scar. Here, we employ state-of-the-art automated spatially targeted optical micro proteomics (autoSTOMP) to photochemically tag and isolate proteomes associated with subpopulations of fibroblasts (SMA+) and macrophages (CD68+) in the context of the native, MI tissue environment. Over a time course of 6-weeks post-MI, we captured dynamic changes in the whole-infarct proteome and determined that some of these protein composition signatures were differentially localized near SMA+ fibroblasts or CD68+ macrophages within the scar region. These results link specific cell populations to within-infarct protein remodelling and illustrate the distinct metabolic and structural processes underlying the observed physiology of each cell type.

Individual variability in animal-specific hemodynamic compensation following myocardial infarction.

Ventricular enlargement and heart failure are common in patients who survive a myocardial infarction (MI). There is striking variability in the degree of post-infarction ventricular remodeling, however, and no one factor or set of factors have been identified that predicts heart failure risk well. Sympathetic activation directly and indirectly modulates hypertrophic stimuli by altering both neurohormonal milieu and ventricular loading. In a recent study, we developed a method to identify the balance of reflex compensatory mechanisms employed by individual animals following MI based on measured hemodynamics. Here, we conducted prospective studies of acute myocardial infarction in rats to test the degree of variability in reflex compensation as well as whether responses to pharmacologic agents targeted at those reflex mechanisms could be anticipated in individual animals. We found that individual animals use very different mixtures of reflex compensation in response to experimental coronary ligation. Some of these mechanisms were related - animals that compensated strongly with venoconstriction tended to exhibit a decrease in the contractility of the surviving myocardium and those that increased contractility tended to exhibit venodilation. Furthermore, some compensatory mechanisms - such as venoconstriction - increased the extent of predicted ventricular enlargement. Unfortunately, initial reflex responses to infarction were a poor predictor of subsequent responses to pharmacologic agents, suggesting that customizing pharmacologic therapy to individuals based on an initial response will be challenging.

The connexin 43 carboxyl terminal mimetic peptide αCT1 prompts differentiation of a collagen scar matrix in humans resembling unwounded skin.

Phase II clinical trials have reported that acute treatment of surgical skin wounds with the therapeutic peptide alpha Connexin Carboxy-Terminus 1 (αCT1) improves cutaneous scar appearance by 47% 9-month postsurgery. While Cx43 and ZO-1 have been identified as molecular targets of αCT1, the mode-of-action of the peptide in scar mitigation at cellular and tissue levels remains to be further characterized. Scar histoarchitecture in αCT1 and vehicle-control treated skin wounds within the same patient were compared using biopsies from a Phase I clinical trial at 29-day postwounding. The sole effect on scar structure of a range of epidermal and dermal variables examined was that αCT1-treated scars had less alignment of collagen fibers relative to control wounds-a characteristic that resembles unwounded skin. The with-in subject effect of αCT1 on scar collagen order observed in Phase I testing in humans was recapitulated in Sprague-Dawley rats and the IAF hairless guinea pig. Transient increase in histologic collagen density in response to αCT1 was also observed in both animal models. Mouse NIH 3T3 fibroblasts and primary human dermal fibroblasts treated with αCT1 in vitro showed more rapid closure in scratch wound assays, with individual cells showing decreased directionality in movement. An agent-based computational model parameterized with fibroblast motility data predicted collagen alignments in simulated scars consistent with that observed experimentally in human and the animal models. In conclusion, αCT1 prompts decreased directionality of fibroblast movement and the generation of a 3D collagen matrix postwounding that is similar to unwounded skin-changes that correlate with long-term improvement in scar appearance.

Automated Spatially Targeted Optical Microproteomics Investigates Inflammatory Lesions In Situ.

Tissue microenvironment properties like blood flow, extracellular matrix, or proximity to immune-infiltrate are important regulators of cell biology. However, methods to study regional protein expression in the native tissue environment are limited. To address this need, we developed a novel approach to visualize, purify, and measure proteins in situ using automated spatially targeted optical microproteomics (AutoSTOMP). Here, we report custom codes to specify regions of heterogeneity in a tissue section and UV-biotinylate proteins within those regions. We have developed liquid chromatography-mass spectrometry (LC-MS)/MS-compatible biochemistry to purify those proteins and label-free quantification methodology to determine protein enrichment in target cell types or structures relative to nontarget regions in the same sample. These tools were applied to (a) identify inflammatory proteins expressed by CD68+ macrophages in rat cardiac infarcts and (b) characterize inflammatory proteins enriched in IgG4+ lesions in human esophageal tissues. These data indicate that AutoSTOMP is a flexible approach to determine regional protein expression in situ on a range of primary tissues and clinical biopsies where current tools and sample availability are limited.

Role of boundary conditions in determining cell alignment in response to stretch.

The ability of cells to orient in response to mechanical stimuli is essential to embryonic development, cell migration, mechanotransduction, and other critical physiologic functions in a range of organs. Endothelial cells, fibroblasts, mesenchymal stem cells, and osteoblasts all orient perpendicular to an applied cyclic stretch when plated on stretchable elastic substrates, suggesting a common underlying mechanism. However, many of these same cells orient parallel to stretch in vivo and in 3D culture, and a compelling explanation for the different orientation responses in 2D and 3D has remained elusive. Here, we conducted a series of experiments designed specifically to test the hypothesis that differences in strains transverse to the primary loading direction give rise to the different alignment patterns observed in 2D and 3D cyclic stretch experiments ("strain avoidance"). We found that, in static or low-frequency stretch conditions, cell alignment in fibroblast-populated collagen gels correlated with the presence or absence of a restraining boundary condition rather than with compaction strains. Cyclic stretch could induce perpendicular alignment in 3D culture but only at frequencies an order of magnitude greater than reported to induce perpendicular alignment in 2D. We modified a published model of stress fiber dynamics and were able to reproduce our experimental findings across all conditions tested as well as published data from 2D cyclic stretch experiments. These experimental and model results suggest an explanation for the apparently contradictory alignment responses of cells subjected to cyclic stretch on 2D membranes and in 3D gels.

Implications of scar structure and mechanics for post-infarction cardiac repair and regeneration.

Regenerating cardiac muscle lost during a heart attack is a topic of broad interest and enormous potential impact. One promising approach is to regenerate or re-engineer new myocardium in situ, at the site of damage, by injecting cells, growth factors, and other materials, or by reprogramming aspects of the normal wound healing process. A wide variety of strategies have been explored, from promoting angiogenesis to injection of a variety of different progenitor cell types, to re-engineering resident cells to produce key growth factors or even transdifferentiate into myocytes. Despite substantial progress and continued promise, clinical impact of this work has fallen short of expectations. One contributing factor may be that many efforts focus primarily on generating cardiomyocytes, with less attention to re-engineering the extracellular matrix (ECM). Yet the role of the ECM is particularly crucial to consider following myocardial infarction, which leads to rapid formation of a collagen-rich scar. This review combines a brief summary of current efforts to regenerate cardiomyocytes with what is currently known about the structure and mechanics of post-infarction scar, with the goal of identifying principles that can guide efforts to produce new myocytes embedded in an extracellular environment that facilitates their differentiation, maintenance, and function.

Development, reliability and validity of the Safe Use of Mobility Aids Checklist (SUMAC) for 4-wheeled walker use in people living with dementia.

BACKGROUND: Balance and gait problems are common and progressive in dementia. Use of a mobility aid provides physical support and confidence. Yet, mobility aid use in people with dementia increases falls three-fold. An assessment tool of mobility aid safety in people with dementia does not currently exist. The objectives of this study were: 1) to develop a tool for the evaluation of physical function and safe use of a 4-wheeled walker in people with dementia, and 2) to evaluate its construct and criterion validity, inter-rater and test-retest reliability and minimal detectable change. METHODS: Healthcare professionals (HCP) experienced in rehabilitation of people with dementia participated in focus groups for item generation of the new tool, The Safe Use of Mobility Aid Checklist (SUMAC). The SUMAC evaluates physical function (PF) and safe use of the equipment (EQ) on nine tasks of daily life. Reliability was evaluated by HCP (n = 5) scored participant videos of people with dementia (n = 10) using a 4-wheeled walker performing the SUMAC. Inter-rater and test-retest reliability was assessed using intra-class correlation coefficients (ICC). Construct validity evaluated scores of the HCPs to a consensus HCP panel using Spearman's rank-order correlations. Criterion validity evaluated SUMAC-PF to the Performance-Oriented Mobility Assessment (POMA) gait subscale using Spearman's rank-order correlations. RESULTS: Three focus groups (n = 17) generated a tool comprised of nine tasks and the components within each task for physical function and safe use. Inter-rater reliability was statistically significant for SUMAC-PF (ICC = 0.92, 95%CI (0.81, 0.98), p < 0.001) and SUMAC-EQ. (ICC = 0.82, 95%CI (0.54, 0.95), p < 0.001). Test-retest reliability was statistically significant for SUMAC-PF (ICC = 0.89, 95%CI (0.81, 0.94), p < 0.001) and SUMAC-EQ. (ICC = 0.88, 95%CI (0.79, 0.93), p < 0.001). As hypothesized, the POMA gait subscale correlated strongly with the SUMAC-PF (rs = 0.84), but not EQ (rs = 0.39). CONCLUSIONS: The focus groups and research team developed a tool of nine tasks with evaluation on physical function and safe use of a 4-wheeled walker for people with dementia. The SUMAC tool has demonstrated content validity for the whole scale and good construct and criterion validity for the SUMAC-PF and SUMAC-EQ. The subscores of the SUMAC demonstrated excellent to good inter-rater and test-retest reliability.

Longitudinal Reinforcement of Acute Myocardial Infarcts Improves Function by Transmurally Redistributing Stretch and Stress.

A wide range of emerging therapies, from surgical restraint to biomaterial injection to tissue engineering, aim to improve heart function and limit adverse remodeling following myocardial infarction (MI). We previously showed that longitudinal surgical reinforcement of large anterior infarcts in dogs could significantly enhance systolic function without restricting diastolic function, but the underlying mechanisms for this improvement are poorly understood. The goal of this study was to construct a finite element model that could match our previously published data on changes in regional strains and left ventricular function following longitudinal surgical reinforcement, then use the model to explore potential mechanisms for the improvement in systolic function we observed. The model presented here, implemented in febio, matches all the key features of our experiments, including diastolic remodeling strains in the ischemic region, small shifts in the end-diastolic pressure-volume relationship (EDPVR), and large changes in the end-systolic pressure-volume relationship (ESPVR) in response to ischemia and to patch application. Detailed examination of model strains and stresses suggests that longitudinal reinforcement reduces peak diastolic fiber stretch and systolic fiber stress in the remote myocardium and shifts those peaks away from the endocardial surface by reshaping the left ventricle (LV). These findings could help to guide the development of novel therapies to improve post-MI function by providing specific design objectives.

Open-Source Routines for Building Personalized Left Ventricular Models From Cardiac Magnetic Resonance Imaging Data.

Creating patient-specific models of the heart is a promising approach for predicting outcomes in response to congenital malformations, injury, or disease, as well as an important tool for developing and customizing therapies. However, integrating multimodal imaging data to construct patient-specific models is a nontrivial task. Here, we propose an approach that employs a prolate spheroidal coordinate system to interpolate information from multiple imaging datasets and map those data onto a single geometric model of the left ventricle (LV). We demonstrate the mapping of the location and transmural extent of postinfarction scar segmented from late gadolinium enhancement (LGE) magnetic resonance imaging (MRI), as well as mechanical activation calculated from displacement encoding with stimulated echoes (DENSE) MRI. As a supplement to this paper, we provide MATLAB and Python versions of the routines employed here for download from SimTK.

A Comparison of Outcomes of Revision Surgical Options for the Treatment of Failed Bulk Talar Allograft Transfer: A Systematic Review.

Talar bulk osteochondral allograft transplantation is a useful treatment strategy for large, uncontained osteochondral lesions of talus. Complications and high revision rates from osteochondral talar allograft transfer can be common. Talar graft failure is a devastating complication that results from failure of allograft incorporation within the host bone and subsequent resorption and sometimes subsidence can occur. Treatment options and outcomes for graft failure have rarely been reported. The purpose of this study is to evaluate treatment options and their outcomes for treating talar allograft failure. A systematic review was completed to find all reports of salvage treatments for talar graft failure and outcomes of these reports were analyzed. Eleven studies involving a total of 522 ankles, in 520 patients, met the inclusion criteria. The allograft failure rate was 11.5% in these studies with a reoperation rate of 18.9%. With limited reports, satisfactory outcomes for treatment of graft failure with ankle arthrodesis were 77.3%, 50% for revision allograft procedures, and 50% for total ankle arthroplasty. Considering the large failure rate and reoperation rate for bulk talar allograft transplantations, superior revision, and salvage options are needed. More prospective cohort studies focusing on consistent and standard outcome measures are needed to further assess revision options for failed talar allograft procedures.

Complications of En Bloc Osteochondral Talar Allografts and Treatment of Failures: Literature Review and Case Report.

Reoperation rates and complication rates can be high for patients receiving an osteochondral talar allograft transplant. Complications can include graft failure, delamination of the graft, arthrofibrosis, advancing osteoarthritis, nonunion of malleolar osteotomies, and partial or complete osteonecrosis of the talus. Graft failure refers to failure of graft incorporation with subsequent necrosis and subsidence. Treatment options for talar graft failure are limited, and outcomes for these treatments have rarely been reported. We present a review of the published data on the complications and treatments for failed talar allograft transplantation. A case report is presented on a young woman who experienced graft failure and osteonecrosis of her talar allograft transplant. Because of the size of the present osteonecrosis, an ankle arthrodesis was performed as the initial revision procedure. Talar necrosis was removed and revascularized from the ankle fusion with solid fusion was confirmed with computed tomography. Symptomatic adjacent joint pain quickly developed in the hindfoot after the ankle fusion, and 12 months later an ankle fusion conversion to total ankle arthroplasty was performed. The patient has returned to normal activity with significant reduction in pain at most recent follow-up visit. This patient was followed for 7 years from initial osteochondral talar allograft transplantation and for 2 years from conversion of ankle fusion to total ankle arthroplasty. It is important to understand the techniques, indications, and outcomes for the various revision options for talar allograft failure. This case report illustrates how multiple revision options can be used to provide the best outcome for the patient.

Including 60 mg Elemental Iron in a Multiple Micronutrient Supplement Blunts the Increase in Serum Zinc after 12 Weeks of Daily Supplementation in Predominantly Anemic, Nonpregnant Cambodian Women of Reproductive Age.

BACKGROUND: Multiple micronutrient (MMN) supplementation may result in interaction effects due to competing absorptive pathways of trace elements. OBJECTIVES: The aim of this study was to investigate the effect of MMN supplementation with or without iron on serum zinc, selenium, and copper concentrations in Cambodian women. METHODS: In a 2 × 2 factorial double-blind randomized 12-wk trial, predominantly anemic, nonpregnant women (aged 18-45 y) received daily 60 mg of iron (Fe; n = 201); 14 other micronutrients including zinc (15 mg), selenium (65 µg), and copper (2 mg), but no iron (MMN; n = 202); 60 mg iron plus MMN (Fe + MMN; n = 206); or a placebo (n = 200). Fasting morning blood was collected at baseline and 12 wk from women in 26 villages in Kampong Chhnang province. Serum zinc, selenium, and copper concentrations (secondary outcomes of the randomized controlled trial) were measured using inductively coupled plasma mass spectrometry. Generalized linear regression was used to estimate intervention effects [ß coefficient (95% CI)] for Fe (with or without MMN) and MMN (with or without Fe) after testing for the presence of an Fe × MMN interaction. RESULTS: A total of 760 women completed the trial. Zinc deficiency prevalence at baseline was 45% (inflammation-adjusted serum zinc <10.7 µmol/L). A significant Fe × MMN interaction (P = 0.02) was detected in the 2 × 2 analysis with serum zinc concentration as the outcome: the MMN group had a higher mean serum zinc concentration at 12 wk (12.3 µmol/L; 95% CI: 12.2, 12.4 µmol/L) compared with all other groups, and the Fe + MMN group had a higher mean serum zinc concentration (11.6 µmol/L; 95% CI: 11.5, 11.7 µmol/L) compared with the Fe group (11.0 µmol/L; 95% CI: 10.9, 11.0 µmol/L) and the placebo group (11.2 µmol/L; 95% CI: 11.1, 11.4 µmol/L). CONCLUSIONS: The inclusion of 60 mg iron in the daily MMN formulation may be interfering with the absorption and/or metabolism of supplemental zinc in Cambodian women. This is of particular concern when MMN supplementation is implemented in populations with risk of zinc deficiency. This trial was registered at clinicaltrials.gov as NCT-02481375.

Multiscale computational model of Achilles tendon wound healing: Untangling the effects of repair and loading.

Mechanical stimulation of the healing tendon is thought to regulate scar anisotropy and strength and is relatively easy to modulate through physical therapy. However, in vivo studies of various loading protocols in animal models have produced mixed results. To integrate and better understand the available data, we developed a multiscale model of rat Achilles tendon healing that incorporates the effect of changes in the mechanical environment on fibroblast behavior, collagen deposition, and scar formation. We modified an OpenSim model of the rat right hindlimb to estimate physiologic strains in the lateral/medial gastrocnemius and soleus musculo-tendon units during loading and unloading conditions. We used the tendon strains as inputs to a thermodynamic model of stress fiber dynamics that predicts fibroblast alignment, and to determine local collagen synthesis rates according to a response curve derived from in vitro studies. We then used an agent-based model (ABM) of scar formation to integrate these cell-level responses and predict tissue-level collagen alignment and content. We compared our model predictions to experimental data from ten different studies. We found that a single set of cellular response curves can explain features of observed tendon healing across a wide array of reported experiments in rats-including the paradoxical finding that repairing transected tendon reverses the effect of loading on alignment-without fitting model parameters to any data from those experiments. The key to these successful predictions was simulating the specific loading and surgical protocols to predict tissue-level strains, which then guided cellular behaviors according to response curves based on in vitro experiments. Our model results provide a potential explanation for the highly variable responses to mechanical loading reported in the tendon healing literature and may be useful in guiding the design of future experiments and interventions.

Model First and Ask Questions Later: Confessions of a Reformed Experimentalist.

This paper is an invited perspective written in association with the awarding of the 2018 American Society of Mechanical Engineers Van C. Mow Medal. Inspired by Professor Mow's collaboration with Professor Michael Lai and the role mathematical modeling played in their work on cartilage biomechanics, this article uses our group's work on myocardial infarct healing as an example of the potential value of models in modern experimental biomechanics. Focusing more on the thought process and lessons learned from our studies on infarct mechanics than on the details of the science, this article argues that the complexity of current research questions and the wealth of information already available about almost any cell, tissue, or organ should change how we approach problems and design experiments. In particular, this paper proposes that constructing a mathematical or computational model is now in many cases a critical prerequisite to designing scientifically useful, informative experiments.

The Impact of Hemodynamic Reflex Compensation Following Myocardial Infarction on Subsequent Ventricular Remodeling.

Patients who survive a myocardial infarction (MI) are at high risk for ventricular dilation and heart failure. While infarct size is an important determinant of post-MI remodeling, different patients with the same size infarct often display different levels of left ventricular (LV) dilation. The acute physiologic response to MI involves reflex compensation, whereby increases in heart rate (HR), arterial resistance, venoconstriction, and contractility of the surviving myocardium act to maintain mean arterial pressure (MAP). We hypothesized that variability in reflex compensation might underlie some of the reported variability in post-MI remodeling, a hypothesis that is difficult to test using experimental data alone because some reflex responses are difficult or impossible to measure directly. We, therefore, employed a computational model to estimate the balance of compensatory mechanisms from experimentally reported hemodynamic data. We found a strikingly wide range of compensatory reflex profiles in response to MI in dogs and verified that pharmacologic blockade of sympathetic and parasympathetic reflexes nearly abolished this variability. Then, using a previously published model of postinfarction remodeling, we showed that observed variability in compensation translated to variability in predicted LV dilation consistent with published data. Treatment with a vasodilator shifted the compensatory response away from arterial and venous vasoconstriction and toward increased HR and myocardial contractility. Importantly, this shift reduced predicted dilation, a prediction that matched prior experimental studies. Thus, postinfarction reflex compensation could represent both a source of individual variability in the extent of LV remodeling and a target for therapies aimed at reducing that remodeling.

Surgical reinforcement alters collagen alignment and turnover in healing myocardial infarcts.

Previous studies have suggested that the composition and global mechanical properties of the scar tissue that forms after a myocardial infarction (MI) are key determinants of long-term survival, and emerging therapies such as biomaterial injection are designed in part to alter those mechanical properties. However, recent evidence suggests that local mechanics regulate scar formation post-MI, so that perturbing infarct mechanics could have unexpected consequences. We therefore tested the effect of changes in local mechanical environment on scar collagen turnover, accumulation, and alignment in 77 Sprague-Dawley rats at 1, 2, 3 and 6 wk post-MI by sewing a Dacron patch to the epicardium to eliminate circumferential strain while permitting continued longitudinal stretching with each heart beat. We found that collagen in healing infarcts aligned parallel to regional strain and perpendicular to the preinfarction muscle and collagen fiber direction, strongly supporting our hypothesis that mechanical environment is the primary determinant of scar collagen alignment. Mechanical reinforcement reduced levels of carboxy-terminal propeptide of type I procollagen (PICP; a biomarker for collagen synthesis) in samples collected by microdialysis significantly, particularly in the first 2 wk. Reinforcement also reduced carboxy-terminal telopeptide of type I collagen (ICTP; a biomarker for collagen degradation), particularly at later time points. These alterations in collagen turnover produced no change in collagen area fraction as measured by histology but significantly reduced wall thickness in the reinforced scars compared with untreated controls. Our findings confirm the importance of regional mechanics in regulating scar formation after infarction and highlight the potential for therapies that reduce stretch to also reduce wall thickness in healing infarcts. NEW & NOTEWORTHY This study shows that therapies such as surgical reinforcement, which reduce stretch in healing infarcts, can also reduce collagen synthesis and wall thickness and modify collagen alignment in postinfarction scars.

Guidelines for experimental models of myocardial ischemia and infarction.

Myocardial infarction is a prevalent major cardiovascular event that arises from myocardial ischemia with or without reperfusion, and basic and translational research is needed to better understand its underlying mechanisms and consequences for cardiac structure and function. Ischemia underlies a broad range of clinical scenarios ranging from angina to hibernation to permanent occlusion, and while reperfusion is mandatory for salvage from ischemic injury, reperfusion also inflicts injury on its own. In this consensus statement, we present recommendations for animal models of myocardial ischemia and infarction. With increasing awareness of the need for rigor and reproducibility in designing and performing scientific research to ensure validation of results, the goal of this review is to provide best practice information regarding myocardial ischemia-reperfusion and infarction models. Listen to this article's corresponding podcast at ajpheart.podbean.com/e/guidelines-for-experimental-models-of-myocardial-ischemia-and-infarction/.

Imaging left-ventricular mechanical activation in heart failure patients using cine DENSE MRI: Validation and implications for cardiac resynchronization therapy.

PURPOSE: To image late mechanical activation and identify effective left-ventricular (LV) pacing sites for cardiac resynchronization therapy (CRT). There is variability in defining mechanical activation time, with some studies using the time to peak strain (TPS) and some using the time to the onset of circumferential shortening (TOS). We developed improved methods for imaging mechanical activation and evaluated them in heart failure (HF) patients undergoing CRT. MATERIALS AND METHODS: We applied active contours to cine displacement encoding with stimulated echoes (DENSE) strain images to detect TOS. Six healthy volunteers underwent magnetic resonance imaging (MRI) at 1.5T, and 50 patients underwent pre-CRT MRI (strain, scar, volumes) and echocardiography, assessment of the electrical activation time (Q-LV) at the LV pacing site, and echocardiography assessment of LV reverse remodeling 6 months after CRT. TPS at the LV pacing site was also measured by DENSE. RESULTS: The latest TOS was greater in HF patients vs. healthy subjects (112 ± 28 msec vs. 61 ± 7 msec, P < 0.01). The correlation between TOS and Q-LV was strong (r > 0.75; P < 0.001) and better than between TPS and Q-LV (r < 0.62; P ≥ 0.006). Twenty-three of 50 patients had the latest activating segment in a region other than the mid-ventricular lateral wall, the most common site for the CRT LV lead. Using a multivariable model, TOS/QRS was significantly associated with LV reverse remodeling even after adjustment for overall dyssynchrony and scar (P < 0.05), whereas TPS was not (P = 0.49). CONCLUSION: Late activation by cine DENSE TOS analysis is associated with improved LV reverse remodeling with CRT and deserves further study as a tool to achieve optimal LV lead placement in CRT. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. MAGN. RESON. IMAGING 2017;46:887-896.

Effect of ablation pattern on mechanical function in the atrium.

BACKGROUND: Atrial fibrillation (AF) is often treated with catheter ablation, which induces scar formation to isolate misfiring electrical signals in the left atrium. Successful ablation restores sinus rhythm at the cost of replacing viable myocardium with scar. The impact of ablation scar on mechanical function of the left atrium is poorly understood. OBJECTIVE: We used a computational model to simulate various ablation patterns and determine their effect on atrial global and regional mechanical function. METHODS: A coupled finite-element and hemodynamic circuit model of the left atrium that represents the regional and global mechanics in paroxysmal AF patients was modified to simulate different ablation patterns: step-wise pulmonary vein isolation (PVI), wide area circumferential ablation (WACA), and a posterior ablation developed by nContact, Inc (Morrisville, NC, USA). Atrial pressure-volume relationships and regional wall motion were compared among the models. RESULTS: Ablation increased passive stiffness and decreased active work performed by the atrium. Active emptying volume decreased with increasing scar by up to 44% (11 mL) at a scar volume of 31%. At matched scar volumes, WACA decreased active emptying more severely than PVI and nContact. Similarly, wall motion was depressed most in the WACA model because WACA involved portions of the lateral wall with higher baseline motion. CONCLUSION: Simulated ablation depressed atrial mechanical function to an extent that depended on both scar volume and location, primarily through reducing active emptying. Placing ablation scar in regions with high baseline motion resulted in greater depression of active function, while ablation of the posterior wall was less disruptive.

Assessment of Caregiving Constructs: Toward a Personal, Familial, Group, and Cultural Construction of Dementia Care through the Eyes of Personal Construct Psychology.

Conditions that cause cognitive impairment and behavioural and personality changes, such as Alzheimer's disease (AD) and related dementia, have global impact across cultures. However, the experience of dementia care can vary between individuals, families, formal caregivers, and social groups from various cultures. Self-reported measures, caregiving stress models, and conceptual theories have been developed to address the physical, financial, psychological, and social factors associated with the experience of dementia care. Given the cross-cultural variability in the experience of dementia care, it is important for such methodologies to take individual and cultural construct systems into account. We contend that personal and group constructs associated with dementia care should be explored in both the formal and informal caregiving contexts. Therefore, in this paper we introduce the theory of Personal Construct Psychology (PCP) with its explicit philosophy, well-elaborated theory, and derived assessment methods as a potential constructivist research approach to examine the personal, familial, group, and cultural construct systems that determine the experience of dementia caregiving. These concepts and assessment procedures are illustrated in this paper through case study examples and scenarios from the context of dementia care with a focus on family home caregivers. This paper elaborates the assessment and therapeutic approaches of personal construct theory (PCT) to further expand alternatives for support services and program interventions and to amplify policies for dementia care within and across cultures.