Are Drivers Recurring or Ephemeral? Observations from Serial Mapping of Persistent Atrial Fibrillation.

RATIONALE: Rotational reentries and ectopic foci, or "drivers", are proposed mechanisms for persistent atrial fibrillation (persAF), but driver-based interventions have had mixed success in clinical trials. Selective targeting of drivers with multimonth stability may improve these interventions, but no prior work has investigated whether drivers can be stable on such a long timescale. OBJECTIVE: We hypothesized that drivers could recur even several months after initial observation. METHODS AND RESULTS: We performed serial electrophysiology studies on paced canines (n=18, 27-35 kg) at 1-, 3-, and 6-months post-initiation of continual persAF. Using a high-density 64-electrode catheter, we captured endocardial electrograms in the left atrium (LA) and right atrium (RA) to determine the presence of drivers at each major anatomical site. We defined drivers which were repeatedly observed across consecutive studies to be recurrent. Mean probability any driver would recur was 66% (LA: 73%, RA: 41%). We also found evidence of "multirecurring" drivers, i.e., those seen in all three studies. Multirecurring drivers constituted 53% of initially observed drivers with at least one found in 92% of animals, and we found more multirecurring drivers per animal than predicted by random chance (2.6±1.5 vs. 1.2±1.1, p<0.001). Driver sites showed more enhancement than non-drivers during late gadolinium enhancement-magnetic resonance imaging (p=0.04), but we observed no relationship between enhancement and driver recurrence type. CONCLUSIONS: We observed recurring drivers over a 6-month period at fixed locations, confirming our hypothesis. We also found drivers to be associated with fibrosis, implying a structural basis.

Emerging ECG methods for acute coronary syndrome detection: Recommendations & future opportunities.

Despite being the mainstay for the initial noninvasive assessment of patients with symptomatic coronary artery disease, the 12­lead ECG remains a suboptimal diagnostic tool for myocardial ischemia detection with only acceptable sensitivity and specificity scores. Although myocardial ischemia affects the configuration of the QRS complex and the STT waveform, current guidelines primarily focus on ST segment amplitude, which constitutes a missed opportunity and may explain the suboptimal diagnostic performance of the ECG. This possible opportunity and the low cost and ease of use of the ECG provide compelling motivation to enhance the diagnostic accuracy of the ECG to ischemia detection. This paper describes numerous computational ECG methods and approaches that have been shown to dramatically increase ECG sensitivity to ischemia detection. Briefly, these emerging approaches can be conceptually grouped into one of the following four approaches: (1) leveraging novel ECG waveform features and signatures indicative of ischemic injury other than the classical ST-T amplitude measures; (2) applying body surface potentials mapping (BSPM)-based approaches to enhance the spatial coverage of the surface ECG to detecting ischemia; (3) developing an inverse ECG solution to reconstruct anatomical models of activation and recovery pathways to detect and localize injury currents; and (4) exploring artificial intelligence (AI)-based techniques to harvest ECG waveform signatures of ischemia. We present recent advances, shortcomings, and future opportunities for each of these emerging ECG methods. Future research should focus on the prospective clinical testing of these approaches to establish clinical utility and to expedite potential translation into clinical practice.

Identifying locations of re-entrant drivers from patient-specific distribution of fibrosis in the left atrium.

Clinical evidence suggests a link between fibrosis in the left atrium (LA) and atrial fibrillation (AF), the most common sustained arrhythmia. Image-derived fibrosis is increasingly used for patient stratification and therapy guidance. However, locations of re-entrant drivers (RDs) sustaining AF are unknown and therapy success rates remain suboptimal. This study used image-derived LA models to explore the dynamics of RD stabilization in fibrotic regions and generate maps of RD locations. LA models with patient-specific geometry and fibrosis distribution were derived from late gadolinium enhanced magnetic resonance imaging of 6 AF patients. In each model, RDs were initiated at multiple locations, and their trajectories were tracked and overlaid on the LA fibrosis distributions to identify the most likely regions where the RDs stabilized. The simulations showed that the RD dynamics were strongly influenced by the amount and spatial distribution of fibrosis. In patients with fibrosis burden greater than 25%, RDs anchored to specific locations near large fibrotic patches. In patients with fibrosis burden below 25%, RDs either moved near small fibrotic patches or anchored to anatomical features. The patient-specific maps of RD locations showed that areas that harboured the RDs were much smaller than the entire fibrotic areas, indicating potential targets for ablation therapy. Ablating the predicted locations and connecting them to the existing pulmonary vein ablation lesions was the most effective in-silico ablation strategy.

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits.

The cross-talk between blood proteins, immune cells, and brain function involves complex mechanisms. Plasma protein C1 inhibitor (C1INH) is an inhibitor of vascular inflammation that is induced by activation of the kallikrein-kinin system (KKS) and the complement system. Knockout of C1INH was previously correlated with peripheral vascular permeability via the bradykinin pathway, yet there was no evidence of its correlation with blood-brain barrier (BBB) integrity and brain function. In order to understand the effect of plasma C1INH on brain pathology via the vascular system, we knocked down circulating C1INH in wild-type (WT) mice using an antisense oligonucleotide (ASO), without affecting C1INH expression in peripheral immune cells or the brain, and examined brain pathology. Long-term elimination of endogenous C1INH in the plasma induced the activation of the KKS and peritoneal macrophages but did not activate the complement system. Bradykinin pathway proteins were elevated in the periphery and the brain, resulting in hypotension. BBB permeability, extravasation of plasma proteins into the brain parenchyma, activation of glial cells, and elevation of pro-inflammatory response mediators were detected. Furthermore, infiltrating innate immune cells were observed entering the brain through the lateral ventricle walls and the neurovascular unit. Mice showed normal locomotion function, yet cognition was impaired and depressive-like behavior was evident. In conclusion, our results highlight the important role of regulated plasma C1INH as it acts as a gatekeeper to the brain via the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.

Characterization of edema after cryo and radiofrequency ablations based on serial magnetic resonance imaging.

INTRODUCTION: Radiofrequency (RF) and cryoablation are routinely used to treat arrhythmias, but the extent and time course of edema associated with the two different modalities is unknown. Our goal was to follow the lesion maturation and edema formation after RF and cryoablation using serial magnetic resonance imaging (MRI). METHODS AND RESULTS: Ventricular ablation was performed in a canine model (n = 11) using a cryo or an irrigated RF catheter. T2-weighted (T2w) edema imaging and late gadolinium enhancement (LGE)-MRI were done immediately (0 day: acute), 1 to 2 weeks (subacute), and 8 to 12 weeks (chronic) after ablation. After the final MRI, excised hearts underwent pathological evaluation. As a result, 45 ventricular lesions (cryo group: 20; RF group: 25) were evaluated. Acute LGE volume was not significantly different but acute edema volume in cryo group was significantly smaller (1225.0 ± 263.5 vs 1855.2 ± 520.5 mm3 ; P = 0.01). One week after ablation, edema still existed in both group but was similar in size. Two weeks after ablation there was no edema in either of the groups. In the chronic phase, the lesion volume for cryo and RF in LGE-MRI (296.7 ± 156.4 vs 281.6 ± 140.8 mm3 ; P = 0.73); and pathology (243.3 ± 125.9 vs 214.5 ± 148.6 mm3 ; P = 0.49), as well as depth, was comparable. CONCLUSIONS: When comparing cryo and RF lesions of similar chronic size, acute edema is larger for RF lesions. Edema resolves in both cryo and RF lesions in 1 to 2 weeks.

Changes in atrial electrophysiological and structural substrate and their relationship to histology in a long-term chronic canine atrial fibrillation model.

BACKGROUND: Atrial fibrillation (AF) is related to numerous electrophysiological changes; however, the extent of structural and electrophysiological remodeling with long-term AF is not well characterized. METHODS: Dogs (n = 6) were implanted with a neurostimulator in the right atrium (AF group). No implantation was done in the Control group (n = 3). Electroanatomical mapping was done prior to and following more than 6 months of AF. Magnetic resonance imaging was also done to assess structural remodeling. Animals were euthanized and tissue samples were acquired for histological analysis. RESULTS: A significant increase was seen in the left atrial (LA) volume among all AF animals (22.25 ± 12.60 cm3 vs 34.00 ± 12.23 cm3 , P = .01). Also, mean bipolar amplitude in the LA significantly decreased from 5.96 ± 2.17 mV at baseline to 3.23 ± 1.51 mV (P < .01) after chronic AF. Those significant changes occurred in each anterior, lateral, posterior, septal, and roof regions as well. Additionally, the dominant frequency (DF) in the LA increased from 7.02 ± 0.37 Hz to 10.12 ± 0.28 Hz at chronic AF (P < .01). Moreover, the percentage of fibrosis in chronic AF animals was significantly larger than that of control animals in each location (P < .01). CONCLUSIONS: Canine chronic AF is accompanied by a significant decrease in intracardiac bipolar amplitudes. These decreased electrogram amplitude values are still higher than traditional cut-off values used for diseased myocardial tissue. Despite these "normal" bipolar amplitudes, there is a significant increase in DF and tissue fibrosis.

The Effective Contact Force to Minimize Edema Relative to Chronic Lesion Formation During Radiofrequency Ablation in Ventricular Wall.

Radiofrequency (RF) ablation results in creation of acute edema which can lead to temporary disruption of electrical propagation.The goal of this study was to find the effective contact force (CF) to minimize edema formation in comparison to the lesion size.Ventricular RF lesions (n = 49) were created by a CF-sensing catheter in a canine model (n = 10) with varying force for 30 seconds. Animals underwent T2-weighted (T2w) and late gadolinium enhancement MRI (LGE-MRI) immediately after ablation and at 12 weeks. Acute LGE lesion volume, acute edema, and chronic LGE lesion volume were measured. Acute edema/acute LGE lesion volume ratio was used to divide the lesions into two groups.Mean edema/lesion volume ratio was 5.0 ± 2.8. The lesions were divided into greater edema group (n = 8) and smaller edema group (n = 41) based on a cutoff edema/lesion volume ratio. When comparing the two groups, the CF and force time integral (FTI) were significantly lower in the greater edema group. There was no difference in catheter power setting, tip temperature change, impedance drop, and bipolar electrogram voltage change. Acute LGE volume and chronic lesion depth were significantly smaller in the greater edema group. Moreover, receiver-operator characteristic curve for the smaller edema lesion group showed that the most discriminant cutoff values for CF and FTI were 12.4 g and 584 gs, respectively.To minimize edema size while still forming permanent lesions, ablation should be performed with FTI > 584 gs or CF > 12.4 g.

Assessment of regularization techniques for electrocardiographic imaging.

A widely used approach to solving the inverse problem in electrocardiography involves computing potentials on the epicardium from measured electrocardiograms (ECGs) on the torso surface. The main challenge of solving this electrocardiographic imaging (ECGI) problem lies in its intrinsic ill-posedness. While many regularization techniques have been developed to control wild oscillations of the solution, the choice of proper regularization methods for obtaining clinically acceptable solutions is still a subject of ongoing research. However there has been little rigorous comparison across methods proposed by different groups. This study systematically compared various regularization techniques for solving the ECGI problem under a unified simulation framework, consisting of both 1) progressively more complex idealized source models (from single dipole to triplet of dipoles), and 2) an electrolytic human torso tank containing a live canine heart, with the cardiac source being modeled by potentials measured on a cylindrical cage placed around the heart. We tested 13 different regularization techniques to solve the inverse problem of recovering epicardial potentials, and found that non-quadratic methods (total variation algorithms) and first-order and second-order Tikhonov regularizations outperformed other methodologies and resulted in similar average reconstruction errors.

Inhibition of MER proto-oncogene tyrosine kinase by an antisense oligonucleotide enhances treatment efficacy of immunoradiotherapy.

BACKGROUND: The combination of radiotherapy and immunotherapy (immunoradiotherapy) has been increasingly used for treating a wide range of cancers. However, some tumors are resistant to immunoradiotherapy. We have previously shown that MER proto-oncogene tyrosine kinase (MerTK) expressed on macrophages mediates resistance to immunoradiotherapy. We therefore sought to develop therapeutics that can mitigate the negative impact of MerTK. We designed and developed a MerTK specific antisense oligonucleotide (ASO) and characterized its effects on eliciting an anti-tumor immune response in mice. METHODS: 344SQR cells were injected into the right legs on day 0 and the left legs on day 4 of 8-12 weeks old female 129sv/ev mice to establish primary and secondary tumors, respectively. Radiation at a dose of 12 Gy was given to the primary tumors on days 8, 9, and 10. Mice received either anti-PD-1, anti-CTLA-4 or/and MerTK ASO starting from day 1 post tumor implantation. The composition of the tumor microenvironment and the level of MerTK on macrophages in the tumor were evaluted by flow cytometry. The expression of immune-related genes was investigated with NanoString. Lastly, the impact of MerTK ASO on the structure of the eye was histologically evaluated. RESULTS: Remarkably, the addition of MerTK ASO to XRT+anti-PD1 and XRT+anti-CTLA4 profoundly slowed the growth of both primary and secondary tumors and significantly extended survival. The ASO significantly reduced the expression of MerTK in tumor-associated macrophages (TAMs), reprograming their phenotype from M2 to M1. In addition, MerTK ASO increased the percentage of Granzyme B+ CD8+ T cells in the secondary tumors when combined with XRT+anti-CTLA4. NanoString results demonstrated that the MerTK ASO favorably modulated immune-related genes for promoting antitumor immune response in secondary tumors. Importantly, histological analysis of eye tissues demonstrated that unlike small molecules, the MerTK ASO did not produce any detectable pathology in the eyes. CONCLUSIONS: The MerTK ASO can significantly downregulate the expression of MerTK on TAMs, thereby promoting antitumor immune response. The combination of MerTK ASO with immunoradiotherapy can safely and significantly slow tumor growth and improve survival.

Transfer Learning for Improved Classification of Drivers in Atrial Fibrillation.

"Drivers" are theorized mechanisms for persistent atrial fibrillation. Machine learning algorithms have been used to identify drivers, but the small size of current driver datasets limits their performance. We hypothesized that pretraining with unsupervised learning on a large dataset of unlabeled electrograms would improve classifier accuracy on a smaller driver dataset. In this study, we used a SimCLR-based framework to pretrain a residual neural network on a dataset of 113K unlabeled 64-electrode measurements and found weighted testing accuracy to improve over a non-pretrained network (78.6±3.9% vs 71.9±3.3%). This lays ground for development of superior driver detection algorithms and supports use of transfer learning for other datasets of endocardial electrograms.

LncRNA PVT1 Is a Poor Prognosticator and Can Be Targeted by PVT1 Antisense Oligos in Gastric Adenocarcinoma.

Gastric adenocarcinoma (GAC) is inherently resistant or becomes resistant to therapy, leading to a poor prognosis. Mounting evidence suggests that lncRNAs can be used as predictive markers and therapeutic targets in the right context. In this study, we determined the role of lncRNA-PVT1 in GAC along with the value of inhibition of PVT1 using antisense oligos (ASOs). RNA scope in situ hybridization was used to analyze PVT1 expression in tumor tissue microarrays (TMAs) of GAC and paired normal tissues from 792 patients. Functional experiments, including colony formation and invasion assays, were performed to evaluate the effects of PVT1 ASO inhibition of PVT1 in vitro; patient-derived xenograft models were used to evaluate the anti-tumor effects of PVT1 ASOs in vivo. LncRNA-PVT1 was upregulated in GACs compared to the matched adjacent normal tissues in the TMA. LncRNA PVT1 expression was positively correlated with larger tumor size, deeper wall invasion, lymph node metastases, and short survival duration. Inhibition of PVT1 using PVT1 ASOs significantly suppressed tumor cell growth and invasion in vitro and in vivo. PVT1 expression was highly associated with poor prognosis in GAC patients and targeting PVT1 using PVT1 ASOs was effective at curtailing tumor cell growth in vitro and in vivo. Thus, PVT1 is a poor prognosticator as well as therapeutic target. Targeting PVT1 using PVT1 ASOs provides a novel therapeutic strategy for GAC.

Application of stochastic finite element methods to study the sensitivity of ECG forward modeling to organ conductivity.

Because numerical simulation parameters may significantly influence the accuracy of the results, evaluating the sensitivity of simulation results to variations in parameters is essential. Although the field of sensitivity analysis is well developed, systematic application of such methods to complex biological models is limited due to the associated high computational costs and the substantial technical challenges for implementation. In the specific case of the forward problem in electrocardiography, the lack of robust, feasible, and comprehensive sensitivity analysis has left many aspects of the problem unresolved and subject to empirical and intuitive evaluation rather than sound, quantitative investigation. In this study, we have developed a systematic, stochastic approach to the analysis of sensitivity of the forward problem of electrocardiography to the parameter of inhomogeneous tissue conductivity. We apply this approach to a two-dimensional, inhomogeneous, geometric model of a slice through the human thorax. We assigned probability density functions for various organ conductivities and applied stochastic finite elements based on the generalized polynomial chaos-stochastic Galerkin (gPC-SG) method to obtain the standard deviation of the resulting stochastic torso potentials. This method utilizes a spectral representation of the stochastic process to obtain numerically accurate stochastic solutions in a fraction of the time required when employing classic Monte Carlo methods. We have shown that a systematic study of sensitivity is not only easily feasible with the gPC-SG approach but can also provide valuable insight into characteristics of the specific simulation.

Supplemented standard 12-lead electrocardiogram for optimal diagnosis and reconstruction of significant body surface map patterns.

In this study, based on 120-lead body surface potential maps (BSPMs), we explored the improvement in electrocardiogram (ECG) diagnosis obtained by adding additional leads and using estimation of unmeasured leads. We found that adding a few leads observed to be optimal for diagnosis or signal capture combined with the existing 12-lead ECG improves diagnostic performance. Separately, using reconstruction (estimation) of BSPMs and using diagnostic criteria derived for maps also improve diagnostic performance over that provided by the recorded 12-lead ECG alone. Combining these 2 ideas, namely, addition of optimal leads and estimation of BSPMs improves performance even more.

Distance between the left atrium and the vertebral body is predictive of esophageal movement in serial MR imaging.

PURPOSE: MRI or CT imaging can be used to identify the esophageal location prior to left atrial ablation, but the esophagus may move making the location unreliable when ablating to minimize esophageal injury. The aim of this study was to evaluate esophageal position and movement based on serial MRI imaging with the goal of identifying imaging and clinical characteristics that can predict the esophageal movement. METHODS: Fifty patients undergoing 190 MRI scans were analyzed. The relative position of the esophagus in each MRI along with clinical and imaging characteristics was quantified, including the gap between the left atrium (LA) and the vertebral body (GAP), an anatomic space in which the esophagus can move. RESULTS: A mean of 3.8 MRIs was analyzed per patient. Sixteen patients (32.0%) experienced significant lateral esophageal movement of more than 10 mm. In the significant movement group, body mass index (BMI) was higher (33.0 ± 6.5 vs 28.8 ± 5.3, p = 0.02) and the GAP was significantly larger (7.1 ± 2.5 vs 4.8 ± 5.1 mm, p = 0.04). Multivariate logistic regression analysis revealed that the GAP ≤ 4.5 mm was the only independent predictor of the esophagus not moving (odds ratio = 9.25, 95% confidence interval = 1.72 to 49.67, p = 0.0095). CONCLUSIONS: A GAP of less than 4.5 mm between the LA and the vertebral body is associated with lack of esophageal movement (< 10 mm). This suggests that the measurement of GAP < 4.5 mm may be used to predict the esophageal location in patients undergoing atrial ablation.

Methods of solving reduced lead systems for inverse electrocardiography.

In the context of inverse electrocardiography, we examine the problem of using measurements from sets of electrocardiographic leads that are smaller than the number of nodes in the associated geometric models of the torso. We compared several methods to estimate the solution from such reduced-lead measurements sets both with and without knowledge of prior statistics of the measurements. We present here simulation results that indicate that deleting rows of the forward matrix corresponding to the unmeasured leads performs best in the absence of prior statistics, and that Bayesian (or least-squares) estimation performs best in the presence of prior statistics.

Ischemic preconditioning protects against arrhythmogenesis through maintenance of both active as well as passive electrical properties in ischemic canine hearts.

BACKGROUND: The mechanisms for the antiarrhythmogenic effects of preconditioning in ischemic hearts, although well demonstrated, are not clear. We measured indices of activation and repolarization using data from a high-resolution epicardial sock electrode array in preconditioned (PC) and non-PC hearts in an attempt to gain further insight into protective mechanisms. METHODS AND RESULTS: Five canine hearts were subjected to a coronary artery occlusion lasting at least 1 hour, and 5 were subjected to a similar occlusion preceded by a preconditioning protocol. Epicardial electrograms were recorded using a 490-electrode sock. Representative beats were selected at intervals of 1 minute for analysis. The mean ST elevation for the PC group both rose slowly after occlusion and also resolved more slowly than the non-PC group. Electrocardiographic markers for propagation such as Total Activation Time, the QRSRMS width, and magnitude of steepest downstroke of the QRS complex all showed that the PC group maintained conduction velocity initially and also varied less dramatically than the control group. The regression line slope computed on a scatter plot of QT width vs cycle length was 0.23 for the PC group and 0.58 for non-PC. During occlusion, the incidence of premature ventricular contractions (PVCs) peaked at approximately 17 minutes followed by a second peak at approximately 27 minutes in the non-PC group, the PC group showed similar peaks at approximately 24 and approximately 53 minutes respectively. CONCLUSION: The slower rate of resolution of ST elevation in PC hearts suggests a delay in gap junction closure, thus maintaining intracellular resistivity and reducing the likelihood of arrhythmia. The speed of conduction is adequately maintained during the early stages of ischemia in PC hearts. The mQTi-mRR regression line, a surrogate measure of rate dependency of repolarization (restitution), has a lower slope in the PC case, thus suggesting a mechanism of reduced arrhythmogenesis. The conclusions are supported by a delay of peak PVCs in PC hearts.

Generalized training subset selection for statistical estimation of epicardial activation maps from intravenous catheter measurements.

Catheter-based electrophysiological studies of the epicardium are limited to regions near the coronary vessels or require transthoracic access. We have developed a statistical approach by which to estimate high-resolution maps of epicardial activation from very low-resolution multi-electrode venous catheter measurements. This technique uses a linear estimation model that derives a relationship between venous catheter measurements and unmeasured epicardial sites from a set of previously recorded, high-resolution epicardial activation-time maps used as a training data set based on the spatial covariance of the measurement sites. We performed 14 dog experiments with various interventions to create an epicardial activation-time map database. This database included a total of 592 epicardial activation maps which were recorded using a sock array placed on the ventricles of dog hearts. We present five approaches, which examined sequential addition and removal of maps to select a generalized training set for the estimation technique. The selection consisted of choosing a subset of epicardial ectopic activation-time maps from the database of beats which resulted in estimation accuracy levels better than or at least similar to using all the maps in database. Our aim was to minimize the redundancy in the database and to be able to guide the eventual procedures required to obtain training data from open-chest surgery patients. The results from this study illustrated this redundancy and suggested that by including an optimal subset (around 100 maps) of the full database the estimation technique was able to perform as well as and even in some cases better than including all the maps in the database. The results also suggest that such an approach is feasible for providing accurate reconstruction of complete epicardial activation-time maps in a clinical setting and with fewer maps we can obtain similar reconstruction accuracy levels.

Improved performance of bayesian solutions for inverse electrocardiography using multiple information sources.

The usual goal in inverse electrocardiography (ECG) is to reconstruct cardiac electrical sources from body surface potentials and a mathematical model that relates the sources to the measurements. Due to attenuation and smoothing that occurs in the thorax, the inverse ECG problem is ill-posed and imposition of a priori constraints is needed to combat this ill-posedness. When the problem is posed in terms of reconstructing heart surface potentials, solutions have not yet achieved clinical utility; limitations include the limited availability of good a priori information about the solution and the lack of a "good" error metric. We describe an approach that combines body surface measurements and standard forward models with two additional information sources: statistical prior information about epicardial potential distributions and sparse simultaneous measurements of epicardial potentials made with multielectrode coronary venous catheters. We employ a Bayesian methodology which offers a general way to incorporate these information sources and additionally provides statistical performance analysis tools. In a simulation study, we first compare solutions using one or more of these information sources. Then, we study the effects of varying the number of sparse epicardial potential measurements on reconstruction accuracy. To evaluate accuracy, we used the Bayesian error covariance as well as traditional error metrics such as relative error. Our results show that including even sparsely sampled information from coronary venous catheters can substantially improve the reconstruction of epicardial potential distributions and that a Bayesian framework provides a feasible approach to using this information. Moreover, computing the Bayesian error standard deviations offers a means to indicate confidence in the results even in the absence of validation data.

Wavefront-based models for inverse electrocardiography.

We introduce two wavefront-based methods for the inverse problem of electrocardiography, which we term wavefront-based curve reconstruction (WBCR) and wavefront-based potential reconstruction (WBPR). In the WBCR approach, the epicardial activation wavefront is modeled as a curve evolving on the heart surface, with the evolution governed by factors derived phenomenologically from prior measured data. The body surface potential/wavefront relationship is modeled via an intermediate mapping of wavefront to epicardial potentials, again derived phenomenologically. In the WBPR approach, we iteratively construct an estimate of epicardial potentials from an estimated wavefront curve according to a simplified model and use it as an initial solution in a Tikhonov regularization scheme. Initial simulation results using measured canine epicardial data show considerable improvement in reconstructing activation wavefronts and epicardial potentials with respect to standard Tikhonov solutions. In particular the WBCR method accurately finds the anisotropic propagation early after epicardial pacing, and the WBPR method finds the wavefront (regions of sharp gradient of the potential) both accurately and with minimal smoothing.

The 50 Most Cited Articles in Rotator Cuff Repair Research.

Analysis of the number of citations within a given specialty provides information on the classic publications of that specialty. The goals of this study were to identify the 50 most cited articles on rotator cuff repair and to analyze various characteristics of these articles. The ISI Web of Science (Thomson Reuters, Philadelphia, Pennsylvania) was used to conduct a search for the term rotator cuff repair. The 50 most cited articles were retrieved, and the following objective characteristics of each article were recorded: number of times cited, citation density, journal, country of origin, and language. The following subjective characteristics of each article were also recorded: article type (clinical vs basic science), article subtype, and level of evidence for clinical articles. Of the 50 most cited articles on rotator cuff repair, the number of citations ranged from 138 to 677 (mean, 232±133 citations) and citation density ranged from 3.8 to 53.5 citations per year (mean, 16.9±9.2 citations per year). The articles were published between 1974 and 2011, with most of the articles published in the 2000s (29 articles), followed by the 1990s (16 articles). The articles originated from 8 countries, with the United States accounting for 30 articles (60%). Overall, 66% of the articles were clinical and 34% were basic science. The most common article subtype was the clinical case series (48%). Of the 33 clinical articles, 24 (73%) were level IV. Among the 50 most cited articles on rotator cuff repair, the case series was the most common article subtype, showing the effect that publication of preliminary outcomes and new surgical techniques has had on surgeons performing rotator cuff repair. [Orthopedics. 2016; 39(6):e1045-e1051.].