Characterizing the transient electrocardiographic signature of ischemic stress using Laplacian Eigenmaps for dimensionality reduction.

OBJECTIVE: Despite a long history of ECG-based monitoring of acute ischemia quantified by several widely used clinical markers, the diagnostic performance of these metrics is not yet satisfactory, motivating a data-driven approach to leverage underutilized information in the electrograms. This study introduces a novel metric for acute ischemia, created using a machine learning technique known as Laplacian eigenmaps (LE), and compares the diagnostic and temporal performance of the LE metric against traditional metrics. METHODS: The LE technique uses dimensionality reduction of simultaneously recorded time signals to map them into an abstract space in a manner that highlights the underlying signal behavior. To evaluate the performance of an electrogram-based LE metric compared to current standard approaches, we induced episodes of transient, acute ischemia in large animals and captured the electrocardiographic response using up to 600 electrodes within the intramural and epicardial domains. RESULTS: The LE metric generally detected ischemia earlier than all other approaches and with greater accuracy. Unlike other metrics derived from specific features of parts of the signals, the LE approach uses the entire signal and provides a data-driven strategy to identify features that reflect ischemia. CONCLUSION: The superior performance of the LE metric suggests there are underutilized features of electrograms that can be leveraged to detect the presence of acute myocardial ischemia earlier and more robustly than current methods. SIGNIFICANCE: The earlier detection capabilities of the LE metric on the epicardial surface provide compelling motivation to apply the same approach to ECGs recorded from the body surface.

Effects of Interpolation on the Inverse Problem of Electrocardiography.

Electrocardiographic Imaging (ECGI) aims to reconstruct electrograms from the body surface potential measurements. Bad leads are usually excluded from the inverse problem solution. Alternatively, interpolation can be applied. This study explores how sensitive ECGI is to different bad-lead configurations and interpolation methods. Experimental data from a Langendorff-perfused pig heart suspended in a human-shaped torso-tank was used. Epicardial electrograms were acquired during 30 s (31 beats) of RV pacing using a 108-electrode array, simultaneously with torso potentials from 128 electrodes embedded in the tank surface. Six different bad lead cases were designed based on clinical experience. Inverse problem was solved by applying Tikhonov regularization i) using the complete data, ii) bad-leads-removed data, and iii) interpolated data, with 5 different methods. Our results showed that ECGI accuracy of an interpolation method highly depends on the location of the bad leads. If they are in the high-potential-gradient regions of the torso, a highly accurate interpolation method is needed to achieve an ECGI accuracy close to using complete data. If the BSP reconstruction of the interpolation method is poor in these regions, the reconstructed electrograms also have lower accuracy, suggesting that bad leads should be removed instead of interpolated. The inverse-forward method was found to be the best among all interpolation methods applied in this study in terms of both missing BSP lead reconstruction and ECGI accuracy, even for the bad leads located over the chest.

Image-based modeling of acute myocardial ischemia using experimentally derived ischemic zone source representations.

BACKGROUND: Computational models of myocardial ischemia often use oversimplified ischemic source representations to simulate epicardial potentials. The purpose of this study was to explore the influence of biophysically justified, subject-specific ischemic zone representations on epicardial potentials. METHODS: We developed and implemented an image-based simulation pipeline, using intramural recordings from a canine experimental model to define subject-specific ischemic regions within the heart. Static epicardial potential distributions, reflective of ST segment deviations, were simulated and validated against measured epicardial recordings. RESULTS: Simulated epicardial potential distributions showed strong statistical correlation and visual agreement with measured epicardial potentials. Additionally, we identified and described in what way border zone parameters influence epicardial potential distributions during the ST segment. CONCLUSION: From image-based simulations of myocardial ischemia, we generated subject-specific ischemic sources that accurately replicated epicardial potential distributions. Such models are essential in understanding the underlying mechanisms of the bioelectric fields that arise during ischemia and are the basis for more sophisticated simulations of body surface ECGs.

Reduction of Effects of Noise on the Inverse Problem of Electrocardiography with Bayesian Estimation.

To overcome the ill-posed nature of the inverse problem of electrocardiography (ECG) and stabilize the solutions, regularization is used. Despite several studies on noise, effect of prefiltering of ECG signals on the regularized inverse solutions has not been explored. We used Bayesian estimation for solving the inverse ECG problem with and without applying various prefiltering methods, and evaluated our results using experimental data that came from a Langendorff-perfused pig heart suspended in a human-shaped torso-tank. Epicardial electrograms were recorded during RV pacing using a 108-electrode array, simultaneously with ECGs from 128 electrodes embedded in the tank surface. Leave-one-beat-out protocol was used to obtain the prior probability density function (pdf) of electro-grams and noise statistics. Noise pdf was assumed to be zero mean-Gaussian, with covariance assumptions: a) independent and identically distributed (noi-iid), b) correlated (noi-corr). Reconstructed electrograms and activation times were compared to those directly recorded by the sock for 3 beats selected from the recording. Noi-corr is superior to noi-iid when the training set is a good match to data, but for applications requiring activation time derivation, careful selection of preprocessing methods, in particular to adequately remove high-frequency noise, and an appropriate noise model is needed.

Effects of ECG Signal Processing on the Inverse Problem of Electrocardiography.

The inverse problem of electrocardiography is ill-posed. Errors in the model such as signal noise can impact the accuracy of reconstructed cardiac electrical activity. It is currently not known how sensitive the inverse problem is to signal processing techniques. To evaluate this, experimental data from a Langendorff-perfused pig heart (n=1) suspended in a human-shaped torso-tank was used. Different signal processing methods were applied to torso potentials recorded from 128 electrodes embedded in the tank surface. Processing methods were divided into three categories i) high-frequency noise removal ii) baseline drift removal and iii) signal averaging, culminating in n=72 different signal sets. For each signal set, the inverse problem was solved and reconstructed signals were compared to those directly recorded by the sock around the heart. ECG signal processing methods had a dramatic effect on reconstruction accuracy. In particular, removal of baseline drift significantly impacts the magnitude of reconstructed electrograms, while the presence of high-frequency noise impacts the activation time derived from these signals (p<0.05).

Quantitative fiber tracking of the optic radiation is correlated with visual-evoked potential amplitude in preterm infants.

BACKGROUND AND PURPOSE: Children born preterm are at risk for adverse outcome, including visual impairment. We examined the relationship between neonatal DTI and sVEP in children born preterm to determine whether visual outcomes are related to early measurements of brain microstructure. MATERIALS AND METHODS: Subjects were born at <34 weeks gestation and imaged before term-equivalent age. DTI fiber tracking was used to delineate the optic radiations and measure tract-specific average FA, D(av), and parallel and transverse diffusivity. Visual-evoked response amplitudes were measured as a function of spatial frequency, contrast, and vernier offset size with sVEP at 6-20 months after birth. The association between DTI and sVEP was assessed by using the Spearman correlation coefficient and linear regression for repeated measures. RESULTS: Nine children with 15 scans were included. The peak response amplitudes for spatial frequency sweeps were associated with increasing FA and decreasing D(av) and transverse diffusivity (P ≤ .006) but not with parallel diffusivity (P = 1). There was only modest association with the swept contrast condition and no detectable association with the vernier offset sweeps. CONCLUSIONS: Microstructure of the optic radiations measured shortly after birth is associated with quantitatively measured responses elicited by moderate-to-high contrast spatiotemporal gratings in infancy. These findings are in keeping with studies showing a relationship between brain microstructure and function. While the clinical impact is not known, quantitative neuroimaging of white matter may ultimately be important for predicting outcome in preterm neonates.

Ketamine anaesthesia for paediatric ophthalmology surgery.

AIMS: Children with treatable, vision impairing conditions may not have access to surgical care when they live in regions where anaesthesia is unavailable. The use of ketamine anaesthesia in a developing region was studied to determine its safety and effectiveness. METHODS: This is a consecutive series of 679 children who had a variety of paediatric eye disorders necessitating a short general anaesthesia. Ketamine was administered intravenously by a paediatrician with training in paediatric resuscitation procedures. Both intraocular and extraocular procedures were performed. The location of treatment was the Tilganga Eye Hospital in Kathmandu, Nepal, a developing region of the world. The study took place over a 5 year period. RESULTS: All procedures were performed without any anaesthetic complications. No child required unanticipated resuscitation or laryngeal intubation. Postoperative dysphoria occurred occasionally and was difficult to measure quantitatively. This side effect of ketamine resolved by the first postoperative day. CONCLUSION: Ketamine is an effective agent for both intraocular and extraocular surgery in the paediatric age group. None of the children in this series needed resuscitation or intubations, and the ophthalmic surgery was carried out safely. Ketamine can be used safely in any ophthalmic procedure of short duration by a person having some training in anaesthetic resuscitation procedures. Because of its simplicity and safety, ketamine may be useful in a simple ophthalmic setup in the developing word.

Tubedown-1 in remodeling of the developing vitreal vasculature in vivo and regulation of capillary outgrowth in vitro.

Tubedown-1 (tbdn-1) is a mammalian homologue of the N-terminal acetyltransferase subunit NAT1 of Saccharomyces cerevisiae and copurifies with an acetyltransferase activity. Tbdn-1 expression in endothelial cells becomes downregulated during the formation of capillary-like structures in vitro and is regulated in vivo in a manner which suggests a functional role in dampening blood vessel development. Here we show that tbdn-1 is expressed highly in the vitreal vascular network (tunica vasculosa lentis and vasa hyaloidea propria) during the pruning and remodeling phases of this transient structure. The vitreal blood vessels of mice harboring a targeted inactivation of TGF-beta2 fail to remodel and abnormally accumulate, a phenomenon reminiscent of the ocular pathology resembling persistent fetal vasculature (PFV) in humans. Since suppression of normal tbdn-1 expression has been previously observed in retinal vessel proliferation, we analyzed vitreal vascular changes and tbdn-1 expression in TGF-beta2(-/-) eyes. The nuclei of vitreal vessel endothelial cells in TGF-beta2(-/-) eyes express proliferating cell nuclear antigen (PCNA) and exhibit increased levels of active (P42/44)mitogen-activated protein kinase (phospho-(P42/44)MAPK), characteristics consistent with proliferative endothelial cells. In contrast to normal vitreal vessels, collagen IV expression exhibited a disorganized pattern in the TGF-beta2(-/-) vitreal vessels, suggesting vessel disorganization and possibly a breakdown of vessel basal laminae. Moreover, vitreal vessels of TGF-beta2(-/-) mice lack expression of pericyte markers (CD13, alpha smooth muscle actin) and show ultrastructural changes consistent with pericyte degeneration. The accumulating vitreal blood vessels of TGF-beta2(-/-) mice, while maintaining expression of the endothelial marker von Willebrand Factor, show a significant decrease in the expression of tbdn-1. We addressed the functional role of tbdn-1 in the regulation of vitreal blood vessels using an in vitro model of choroid-retina capillary outgrowth. Clones of the RF/6A fetal choroid-retina endothelial cell line showing suppression of tbdn-1 levels after overexpression of an antisense TBDN-1 cDNA display a significant increase in the formation of capillary-like structures in vitro compared with controls. These findings suggest that tbdn-1 inhibits capillary-like formation in vitro and may serve to dampen vitreal blood vessel formation preceding the regression of the vitreal vasculature during development. Our results also suggest that tbdn-1 may participate with TGF-beta2 in regulating normal development of the vitreal vasculature.

Suppressed expression of tubedown-1 in retinal neovascularization of proliferative diabetic retinopathy.

PURPOSE: Retinal neovascularization occurring as a complication of diabetes mellitus can cause vision loss and blindness. The identification and study of novel genes involved in retinal angiogenesis may define new targets to suppress retinal neovascularization in diabetes and other ocular diseases. A novel acetyltransferase subunit, tubedown-1 (tbdn-1), has been isolated, the expression of which is regulated during blood vessel development. Tbdn-1 is not detected in most adult vascular beds but persists at high levels in the adult ocular vasculature. The purpose of this study was to gain insight into the possible role of tbdn-1 in retinal blood vessels by characterizing its expression patterns in adult homeostasis and in retinal neovascularization associated with diabetes. METHODS: Western blot analysis and immunohistochemistry were performed to study the expression patterns of tbdn-1 during adult homeostasis in normal human retinas, in a model of choroid-retina endothelial capillary outgrowth in vitro, and in retinas showing neovascularization in patients with proliferative diabetic retinopathy (PDR). RESULTS: In adults during homeostasis, tbdn-1 was expressed highly in normal endothelium of retinal and limbic blood vessels. Tbdn-1 was also expressed in RF/6A, a rhesus macaque choroid-retina-derived endothelial cell line. In an in vitro model system using the RF/6A cell line, tbdn-1 expression was downregulated during the outgrowth of these cells into capillary-like structures on a reconstituted basement membrane matrix. Similar to this in vitro model, tbdn-1 expression is specifically suppressed in the endothelial cells of blood vessels and capillary fronds in vivo in both the neural retinal tissue and in preretinal membranes in eyes of patients with PDR. CONCLUSIONS: High levels of expression of tbdn-1 are associated with ocular endothelial homeostasis in adults. Conversely, low levels of tbdn-1 expression are associated with endothelial capillary outgrowth in vitro and retinal neovascularization in vivo. Because the tbdn-1 acetyltransferase subunit is a member of a family of regulatory enzymes that are known to control a range of processes, including cell growth and differentiation, through posttranslational modification, the current results support a hypothesis that tbdn-1 may be involved in maintaining homeostasis and preventing retinal neovascularization.

Retinopathy of prematurity.

The majority of cases of ROP regress spontaneously, but better treatment methods are needed to prevent retinal detachment and other effects of ROP such as myopia. In the future, molecular mechanisms may be exploited to treat ROP.