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1.  Dynamic Conduction and Repolarisation Changes in Early Arrhythmogenic Right Ventricular Cardiomyopathy versus Benign Outflow Tract Ectopy Demonstrated by High Density Mapping & Paced Surface ECG Analysis 
PLoS ONE  2014;9(7):e99125.
The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.
22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol.
Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls.
Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters.
PMCID: PMC4094482  PMID: 25014132
2.  Software algorithm and hardware design for real-time implementation of new spectral estimator 
Real-time spectral analyzers can be difficult to implement for PC computer-based systems because of the potential for high computational cost, and algorithm complexity. In this work a new spectral estimator (NSE) is developed for real-time analysis, and compared with the discrete Fourier transform (DFT).
Clinical data in the form of 216 fractionated atrial electrogram sequences were used as inputs. The sample rate for acquisition was 977 Hz, or approximately 1 millisecond between digital samples. Real-time NSE power spectra were generated for 16,384 consecutive data points. The same data sequences were used for spectral calculation using a radix-2 implementation of the DFT. The NSE algorithm was also developed for implementation as a real-time spectral analyzer electronic circuit board.
The average interval for a single real-time spectral calculation in software was 3.29 μs for NSE versus 504.5 μs for DFT. Thus for real-time spectral analysis, the NSE algorithm is approximately 150× faster than the DFT. Over a 1 millisecond sampling period, the NSE algorithm had the capability to spectrally analyze a maximum of 303 data channels, while the DFT algorithm could only analyze a single channel. Moreover, for the 8 second sequences, the NSE spectral resolution in the 3-12 Hz range was 0.037 Hz while the DFT spectral resolution was only 0.122 Hz. The NSE was also found to be implementable as a standalone spectral analyzer board using approximately 26 integrated circuits at a cost of approximately $500. The software files used for analysis are included as a supplement, please see the Additional files 1 and 2.
The NSE real-time algorithm has low computational cost and complexity, and is implementable in both software and hardware for 1 millisecond updates of multichannel spectra. The algorithm may be helpful to guide radiofrequency catheter ablation in real time.
PMCID: PMC4057578  PMID: 24886214
Algorithm; Analog computer; Circuit design; Digital computer; Spectral analyzer
3.  Implementation of a polling protocol for predicting celiac disease in videocapsule analysis 
AIM: To investigate the presence of small intestinal villous atrophy in celiac disease patients from quantitative analysis of videocapsule image sequences.
METHODS: Nine celiac patient data with biopsy-proven villous atrophy and seven control patient data lacking villous atrophy were used for analysis. Celiacs had biopsy-proven disease with scores of Marsh II-IIIC except in the case of one hemophiliac patient. At four small intestinal levels (duodenal bulb, distal duodenum, jejunum, and ileum), video clips of length 200 frames (100 s) were analyzed. Twenty-four measurements were used for image characterization. These measurements were determined by quantitatively processing the videocapsule images via techniques for texture analysis, motility estimation, volumetric reconstruction using shape-from-shading principles, and image transformation. Each automated measurement method, or automaton, was polled as to whether or not villous atrophy was present in the small intestine, indicating celiac disease. Each automaton’s vote was determined based upon an optimized parameter threshold level, with the threshold levels being determined from prior data. A prediction of villous atrophy was made if it received the majority of votes (≥ 13), while no prediction was made for tie votes (12-12). Thus each set of images was classified as being from either a celiac disease patient or from a control patient.
RESULTS: Separated by intestinal level, the overall sensitivity of automata polling for predicting villous atrophy and hence celiac disease was 83.9%, while the specificity was 92.9%, and the overall accuracy of automata-based polling was 88.1%. The method of image transformation yielded the highest sensitivity at 93.8%, while the method of texture analysis using subbands had the highest specificity at 76.0%. Similar results of prediction were observed at all four small intestinal locations, but there were more tie votes at location 4 (ileum). Incorrect prediction which reduced sensitivity occurred for two celiac patients with Marsh type II pattern, which is characterized by crypt hyperplasia, but normal villous architecture. Pooled from all levels, there was a mean of 14.31 ± 3.28 automaton votes for celiac vs 9.67 ± 3.31 automaton votes for control when celiac patient data was analyzed (P < 0.001). Pooled from all levels, there was a mean of 9.71 ± 2.8128 automaton votes for celiac vs 14.32 ± 2.7931 automaton votes for control when control patient data was analyzed (P < 0.001).
CONCLUSION: Automata-based polling may be useful to indicate presence of mucosal atrophy, indicative of celiac disease, across the entire small bowel, though this must be confirmed in a larger patient set. Since the method is quantitative and automated, it can potentially eliminate observer bias and enable the detection of subtle abnormality in patients lacking a clear diagnosis. Our paradigm was found to be more efficacious at proximal small intestinal locations, which may suggest a greater presence and severity of villous atrophy at proximal as compared with distal locations.
PMCID: PMC3711062  PMID: 23858375
Automata; Celiac disease; Small intestine; Videocapsule; Villous atrophy
4.  Review of biomedical signal and image processing 
This article is a review of the book “Biomedical Signal and Image Processing” by Kayvan Najarian and Robert Splinter, which is published by CRC Press, Taylor & Francis Group. It will evaluate the contents of the book and discuss its suitability as a textbook, while mentioning highlights of the book, and providing comparison with other textbooks.
PMCID: PMC3851155
Biomedical; Fourier; Image processing; Signal processing; Textbook
5.  Comparison of spectral estimators for characterizing fractionated atrial electrograms 
Complex fractionated atrial electrograms (CFAE) acquired during atrial fibrillation (AF) are commonly assessed using the discrete Fourier transform (DFT), but this can lead to inaccuracy. In this study, spectral estimators derived by averaging the autocorrelation function at lags were compared to the DFT.
Bipolar CFAE of at least 16 s duration were obtained from pulmonary vein ostia and left atrial free wall sites (9 paroxysmal and 10 persistent AF patients). Power spectra were computed using the DFT and three other methods: 1. a novel spectral estimator based on signal averaging (NSE), 2. the NSE with harmonic removal (NSH), and 3. the autocorrelation function average at lags (AFA). Three spectral parameters were calculated: 1. the largest fundamental spectral peak, known as the dominant frequency (DF), 2. the DF amplitude (DA), and 3. the mean spectral profile (MP), which quantifies noise floor level. For each spectral estimator and parameter, the significance of the difference between paroxysmal and persistent AF was determined.
For all estimators, mean DA and mean DF values were higher in persistent AF, while the mean MP value was higher in paroxysmal AF. The differences in means between paroxysmals and persistents were highly significant for 3/3 NSE and NSH measurements and for 2/3 DFT and AFA measurements (p<0.001). For all estimators, the standard deviation in DA and MP values were higher in persistent AF, while the standard deviation in DF value was higher in paroxysmal AF. Differences in standard deviations between paroxysmals and persistents were highly significant in 2/3 NSE and NSH measurements, in 1/3 AFA measurements, and in 0/3 DFT measurements.
Measurements made from all four spectral estimators were in agreement as to whether the means and standard deviations in three spectral parameters were greater in CFAEs acquired from paroxysmal or in persistent AF patients. Since the measurements were consistent, use of two or more of these estimators for power spectral analysis can be assistive to evaluate CFAE more objectively and accurately, which may lead to improved clinical outcome. Since the most significant differences overall were achieved using the NSE and NSH estimators, parameters measured from their spectra will likely be the most useful for detecting and discerning electrophysiologic differences in the AF substrate based upon frequency analysis of CFAE.
PMCID: PMC3728006  PMID: 23855345
Atrial fibrillation; Dominant frequency; Paroxysmal; Persistent; Spectral estimation
6.  Detection of the Diastolic Pathway, Circuit Morphology and Inducibility of Human Post-Infarction Ventricular Tachycardia from Mapping in Sinus Rhythm. Ciaccio, Detection of the VT Diastolic Pathway 
We sought to determine whether sinus rhythm activation maps could be used to detect the origin and characteristics of reentrant ventricular tachycardia in postinfarction patients.
In each of 11 post-MI patients, unipolar electrograms were acquired at 256 virtual endocardial sites using non-contact mapping. Electrograms were marked for activation time and mapped on a three-dimensional grid. Spatial differences in sinus-rhythm activation time were correlated to isthmus characteristics, and to activation through the diastolic pathway during tachycardia, based on presence of contiguous lines of slow conduction and block.
Twenty tachycardia morphologies were analyzed. Fourteen sustained reentrant circuit morphologies occurred in 9 patients, with dual morphologies having a shared isthmus occurring in 5/9. Dual morphologies were caused by changes in entrance-exit point location about a common isthmus. One transient circuit morphology of <10 beats occurred in 3/9 patients also having sustained reentry. The estimated isthmus determined from sinus rhythm activation overlapped the diastolic pathway determined from tachycardia maps with 83.8% sensitivity and 89.2% specificity. Mean difference in sinus rhythm activation time across the isthmus border was larger in transient as compared to sustained morphologies (32.8±9.5ms versus 22.8±1.8ms), with smaller isthmus size (4.8±1.1cm2 versus 10.0±1.1cm2, p<0.05) narrower entrance-exit points (7.0±1.5mm versus 9.3±0.8mm, p<0.05), and greater activation time difference across them (16.3±3.5ms versus 10.1±1.0ms, p<0.05).
In post-MI patients, the reentry isthmus can be localized in the endocardial border zone from sinus rhythm activation maps. Nonsustained reentry occurs when isthmus size is small and entrance-exit points are narrow and more electrically discontinuous.
PMCID: PMC2593141  PMID: 18598952
ablation; activation mapping; reentry; sinus rhythm; ventricular tachycardia
7.  Characterization of Gap Junction Remodeling in Epicardial Border Zone of Healing Canine Infarcts and Electrophysiological Effects of Partial Reversal by Rotigaptide 
The border zone of healing myocardial infarcts is an arrhythmogenic substrate partly due to structural and functional remodeling of the ventricular gap junction protein, Connexin43 (Cx43). Cx43 in arrhythmogenic substrates is a potential target for antiarrhythmic therapy.
Methods and Results
We characterized Cx43 remodeling in the epicardial border zone (EBZ) of healing canine infarcts, 5 days after coronary occlusion and examined whether the gap junction specific agent, Rotigaptide, could reverse it. Cx43 remodeling in the EBZ was characterized by a decrease in Cx43 protein, lateralization and increased Cx43 phosphorylation at serine (S) 368. Rotigaptide partially reversed the loss of Cx43 but did not affect the increase in S368 phosphorylation nor did it reverse Cx43 lateralization. Rotigaptide did not prevent conduction slowing in EBZ nor did it decrease the induction of sustained ventricular tachycardia (SMVT) by programmed stimulation, although it did decrease the EBZ effective refractory period (ERP).
We conclude that partial reversal of Cx43 remodeling in healing infarct border zone may not be sufficient to restore normal conduction or prevent arrhythmias.
PMCID: PMC3116056  PMID: 21493965
myocardial infarction; arrhythmias; gap junctions; remodeling
8.  Model of Reentrant Ventricular Tachycardia based upon Infarct Border Zone Geometry Predicts Reentrant Circuit Features as Determined by Activation Mapping 
Infarct border zone (IBZ) geometry likely affects inducibility and characteristics of postinfarction reentrant ventricular tachycardia, but the connection has not been established.
To determine characteristics of post infarction ventricular tachycardia in the IBZ.
A geometric model describing the relationship between IBZ geometry and wavefront propagation in reentrant circuits was developed. Based on the formulation, slow conduction and block was expected to coincide with areas where IBZ thickness (T) is minimal and the local spatial gradient in thickness (ΔT) is maximal, so that the degree of wavefront curvature ρ ∝ ΔT/T is maximal. Regions of fastest conduction velocity were predicted to coincide with areas of minimum ΔT. In seven arrhythmogenic postinfarction canine heart experiments, tachycardia was induced by programmed stimulation, and activation maps were constructed from multichannel recordings. IBZ thickness was measured in excised hearts from histologic analysis or magnetic resonance imaging. Reentrant circuit properties were predicted from IBZ geometry and compared with ventricular activation maps following tachycardia induction.
Mean IBZ thickness was 231±140µm at the reentry isthmus and 1440±770µm in the outer pathway (p<0.001). Mean curvature ρ was 1.63±0.45mm−1 at functional block line locations, 0.71±0.18mm−1 at isthmus entrance-exit points, and 0.33±0.13mm−1 in the outer reentrant circuit pathway. The mean conduction velocity about the circuit during reentrant tachycardia was 0.32±0.04mm/ms at entrance-exit points, 0.42±0.13mm/ms for the entire outer pathway, and 0.64±0.16mm/ms at outer pathway regions with minimum ΔT. Model sensitivity and specificity to detect isthmus location was 75.0±5.7% and 97.2±0.7%.
Reentrant circuit features as determined by activation mapping can be predicted on the basis of IBZ geometrical relationships.
PMCID: PMC2626544  PMID: 17675078
arrhythmia; border zone; conduction velocity; infarction; mapping; MRI; propagation; ventricular tachycardia
9.  Improved frequency resolution for characterization of complex fractionated atrial electrograms 
The dominant frequency of the Fourier power spectrum is useful to analyze complex fractionated atrial electrograms (CFAE), but spectral resolution is limited and uniform from DC to the Nyquist frequency. Herein the spectral resolution of a recently described and relatively new spectral estimation technique is compared to the Fourier radix-2 implementation.
In 10 paroxysmal and 10 persistent atrial fibrillation patients, 216 CFAE were acquired from the pulmonary vein ostia and left atrial free wall (977 Hz sampling rate, 8192 sample points, 8.4 s duration). With these parameter values, in the physiologic range of 3–10 Hz, two frequency components can theoretically be resolved at 0.24 Hz using Fourier analysis and at 0.10 Hz on average using the new technique. For testing, two closely-spaced periodic components were synthesized from two different CFAE recordings, and combined with two other CFAE recordings magnified 2×, that served as interference signals. The ability to resolve synthesized frequency components in the range 3–4 Hz, 4–5 Hz, …, 9–10 Hz was determined for 15 trials each (105 total).
With the added interference, frequency resolution averaged 0.29 ± 0.22 Hz for Fourier versus 0.16 ± 0.10 Hz for the new method (p < 0.001). The misalignment error of spectral peaks versus actual values was ±0.023 Hz for Fourier and ±0.009 Hz for the new method (p < 0.001). One or both synthesized peaks were lost in the noise floor 13/105 times using Fourier versus 4/105 times using the new method.
Within the physiologically relevant frequency range for characterization of CFAE, the new method has approximately twice the spectral resolution of Fourier analysis, there is less error in estimating frequencies, and peaks appear more readily above the noise floor. Theoretically, when interference is not present, to resolve frequency components separated by 0.10 Hz using Fourier analysis would require an 18.2 s sequence duration, versus 8.4 s with the new method.
PMCID: PMC3681331  PMID: 22472065
Atrial fibrillation; Ensemble averaging; Fourier analysis; Spectral estimation; Spectral resolution
10.  A new LMS algorithm for analysis of atrial fibrillation signals 
A biomedical signal can be defined by its extrinsic features (x-axis and y-axis shift and scale) and intrinsic features (shape after normalization of extrinsic features). In this study, an LMS algorithm utilizing the method of differential steepest descent is developed, and is tested by normalization of extrinsic features in complex fractionated atrial electrograms (CFAE).
Equations for normalization of x-axis and y-axis shift and scale are first derived. The algorithm is implemented for real-time analysis of CFAE acquired during atrial fibrillation (AF). Data was acquired at a 977 Hz sampling rate from 10 paroxysmal and 10 persistent AF patients undergoing clinical electrophysiologic study and catheter ablation therapy. Over 24 trials, normalization characteristics using the new algorithm with four weights were compared to the Widrow-Hoff LMS algorithm with four tapped delays. The time for convergence, and the mean squared error (MSE) after convergence, were compared. The new LMS algorithm was also applied to lead aVF of the electrocardiogram in one patient with longstanding persistent AF, to enhance the F wave and to monitor extrinsic changes in signal shape. The average waveform over a 25 s interval was used as a prototypical reference signal for matching with the aVF lead.
Based on the derivation equations, the y-shift and y-scale adjustments of the new LMS algorithm were shown to be equivalent to the scalar form of the Widrow-Hoff LMS algorithm. For x-shift and x-scale adjustments, rather than implementing a long tapped delay as in Widrow-Hoff LMS, the new method uses only two weights. After convergence, the MSE for matching paroxysmal CFAE averaged 0.46 ± 0.49μV2/sample for the new LMS algorithm versus 0.72 ± 0.35μV2/sample for Widrow-Hoff LMS. The MSE for matching persistent CFAE averaged 0.55 ± 0.95μV2/sample for the new LMS algorithm versus 0.62 ± 0.55μV2/sample for Widrow-Hoff LMS. There were no significant differences in estimation error for paroxysmal versus persistent data. From all trials, the mean convergence time was approximately 1 second for both algorithms. The new LMS algorithm was useful to enhance the electrocardiogram F wave by subtraction of an adaptively weighted prototypical reference signal from the aVF lead. The extrinsic weighting over 25 s demonstrated that time-varying functions such as patient respiration could be identified and monitored.
A new LMS algorithm was derived and used for normalization of the extrinsic features in CFAE and for electrocardiogram monitoring. The weighting at convergence provides an estimate of the degree of similarity between two signals in terms of x-axis and y-axis shift and scale. The algorithm is computationally efficient with low estimation error. Based on the results, proposed applications include monitoring of extrinsic and intrinsic features of repetitive patterns in CFAE, enhancement of the electrocardiogram F wave and monitoring of time-varying signal properties, and to quantitatively characterize mechanistic differences in paroxysmal versus persistent AF.
PMCID: PMC3442996  PMID: 22449196
Atrial fibrillation; Electrocardiogram; F wave; Fractionation; LMS algorithm; Mean-squared error
11.  Identification of recurring patterns in fractionated atrial electrograms using new transform coefficients 
Identification of recurrent patterns in complex fractionated atrial electrograms (CFAE) has been used to differentiate paroxysmal from persistent atrial fibrillation (AF). Detection of the atrial CFAE patterns might therefore be assistive in guiding radiofrequency catheter ablation to drivers of the arrhythmia. In this study a technique for robust detection and classification of recurrent CFAE patterns is described.
CFAE were obtained from the four pulmonary vein ostia, and from the anterior and posterior left atrium, in 10 patients with paroxysmal AF and 10 patients with longstanding persistent AF (216 recordings in total). Sequences 8.4 s in length were analyzed (8,192 sample points, 977 Hz sampling). Among the 216 sequences, two recurrent patterns A and B were substituted for 4 and 5 of the sequences, respectively. To this data, random interference, and random interference + noise were separately added. Basis vectors were constructed using a new transform that is derived from ensemble averaging. Patterns A and B were then detected and classified using a threshold level of Euclidean distance between spectral signatures as constructed with transform coefficients.
In the presence of interference, sensitivity to detect and distinguish two patterns A and B was 96.2%, while specificity to exclude nonpatterns was 98.0%. In the presence of interference + noise, sensitivity was 89.1% while specificity was 97.0%.
Transform coefficients computed from ensemble averages can be used to succinctly quantify synchronized patterns present in AF data. The technique is useful to automatically detect recurrent patterns in CFAE that are embedded in interference without user bias. This quantitation can be implemented in real-time to map the AF substrate prior to and during catheter ablation.
PMCID: PMC3390903  PMID: 22260298
atrial fibrillation; catheter ablation; ensemble averaging; pattern recognition; transform
12.  Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study 
European Heart Journal  2012;33(15):1942-1953.
Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin.
Methods and results
Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution.
Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.
PMCID: PMC3409421  PMID: 22240500
Arrhythmia; Conduction; ARVC; Repolarization; Desmosome; Desmoplakin
13.  Review of Biomedical Image Processing 
This article is a review of the book: 'Biomedical Image Processing', by Thomas M. Deserno, which is published by Springer-Verlag. Salient information that will be useful to decide whether the book is relevant to topics of interest to the reader, and whether it might be suitable as a course textbook, are presented in the review. This includes information about the book details, a summary, the suitability of the text in course and research work, the framework of the book, its specific content, and conclusions.
PMCID: PMC3250948
14.  The renin-angiotensin system mediates the effects of stretch on conduction velocity, connexin43 expression and redistribution in intact ventricle 
In disease states such as heart failure, myocardial infarction and hypertrophy, changes in the expression and location of Connexin43 (Cx43) occur (Cx43 remodeling), and may predispose to arrhythmias. Stretch may be an important stimulus to Cx43 remodeling; however, it has only been investigated in neonatal cell cultures, which have different physiological properties to adult myocytes. We hypothesized that localized stretch in vivo causes Cx43 remodeling, with associated changes in conduction, mediated by the renin/angiotensin system (RAS).
Methods and Results
In an open-chest canine model a device was used to stretch part of the right ventricle (RV) by 22% for 6 hours. Activation mapping using a 312-electrode array was performed before and after stretch. Regional stretch did not change longitudinal conduction velocity (post-stretch vs. baseline: 51.5±5.2 vs. 55.3±8.1cm/s p=0.24, n=11), but significantly reduced transverse conduction velocity (28.7±2.5 vs. 35.4±5.4cm/s, p<0.01). It also reduced total Cx43 expression, by Western blotting, compared to a nonstretched area RV of the same animal (86.1±32.2 vs. 100±19.4%, p<0.02, n=11). Cx43 labeling redistributed to the lateral cell borders. Stretch caused a small but significant increase in the proportion of the dephosphorylated form of Cx43 (stretch 9.95±1.4% vs. control 8.74±1.2%, p<0.05).
Olmesartan, an angiotensin-II blocker, prevented the stretch induced changes in Cx43 levels, localization and conduction.
Myocardial stretch in vivo has opposite effects to that in neonatal myocytes in vitro. Stretch in vivo causes conduction changes associated with Cx43 remodeling that are likely caused by local stretch-induced activation of the RAS.
PMCID: PMC2937061  PMID: 20487124
Conduction; stretch; gap junctions
15.  Robust spectral analysis of videocapsule images acquired from celiac disease patients 
Dominant frequency (DF) analysis of videocapsule endoscopy images is a new method to detect small intestinal periodicities that may result from mechanical rhythms such as peristalsis. Longer periodicity is related to greater image texture at areas of villous atrophy in celiac disease. However, extraneous features and spatiotemporal phase shift may mask DF rhythms.
The robustness of Fourier and ensemble averaging spectral analysis to compute DF was tested. Videocapsule images from the distal duodenum of 11 celiac patients (frame rate 2/s and pixel resolution 576 × 576) were analyzed. For patients 1, 2, ... 11, respectively, a total of 10, 11, ..., 20 sequential images were extracted from a randomly selected time epoch. Each image sequence was artificially repeated to 200 frames, simulating periodicities of 0.2, 0.18, ..., 0.1Hz, respectively. Random white noise at four different levels, spatiotemporal phase shift, and frames with air bubbles were added. Power spectra were constructed pixel-wise over 200 frames, and an average spectrum was computed from the 576 × 576 individual spectra. The largest spectral peak in the average spectrum was the estimated DF. Error was defined as the absolute difference between actual DF and estimated DF.
For Fourier analysis, the mean absolute error between estimated and actual DF was 0.032 ± 0.052Hz. Error increased with greater degree of random noise imposed. In contrast, all ensemble average estimates precisely predicted the simulated DF.
The ensemble average DF estimate of videocapsule images with simulated periodicity is robust to noise and spatiotemporal phase shift as compared with Fourier analysis. Accurate estimation of DF eliminates the need to impose complex masking, extraction, and/or corrective preprocessing measures.
PMCID: PMC3203259  PMID: 21906318
celiac disease; ensemble average; Fourier transform; small intestine; spectral analysis
16.  A new transform for the analysis of complex fractionated atrial electrograms 
Representation of independent biophysical sources using Fourier analysis can be inefficient because the basis is sinusoidal and general. When complex fractionated atrial electrograms (CFAE) are acquired during atrial fibrillation (AF), the electrogram morphology depends on the mix of distinct nonsinusoidal generators. Identification of these generators using efficient methods of representation and comparison would be useful for targeting catheter ablation sites to prevent arrhythmia reinduction.
A data-driven basis and transform is described which utilizes the ensemble average of signal segments to identify and distinguish CFAE morphologic components and frequencies. Calculation of the dominant frequency (DF) of actual CFAE, and identification of simulated independent generator frequencies and morphologies embedded in CFAE, is done using a total of 216 recordings from 10 paroxysmal and 10 persistent AF patients. The transform is tested versus Fourier analysis to detect spectral components in the presence of phase noise and interference. Correspondence is shown between ensemble basis vectors of highest power and corresponding synthetic drivers embedded in CFAE.
The ensemble basis is orthogonal, and efficient for representation of CFAE components as compared with Fourier analysis (p ≤ 0.002). When three synthetic drivers with additive phase noise and interference were decomposed, the top three peaks in the ensemble power spectrum corresponded to the driver frequencies more closely as compared with top Fourier power spectrum peaks (p ≤ 0.005). The synthesized drivers with phase noise and interference were extractable from their corresponding ensemble basis with a mean error of less than 10%.
The new transform is able to efficiently identify CFAE features using DF calculation and by discerning morphologic differences. Unlike the Fourier transform method, it does not distort CFAE signals prior to analysis, and is relatively robust to jitter in periodic events. Thus the ensemble method can provide a useful alternative for quantitative characterization of CFAE during clinical study.
PMCID: PMC3125385  PMID: 21569421
decomposition; ensemble average; Fourier transform; reconstruction; spectral analysis
17.  A novel desmocollin-2 mutation reveals insights into the molecular link between desmosomes and gap junctions 
Heart Rhythm  2011;8(5):711-718.
Cellular adhesion mediated by cardiac desmosomes is a prerequisite for proper electric propagation mediated by gap junctions in the myocardium. However, the molecular principles underlying this interdependence are not fully understood.
The purpose of this study was to determine potential causes of right ventricular conduction abnormalities in a patient with borderline diagnosis of arrhythmogenic right ventricular cardiomyopathy.
To assess molecular changes, the patient's myocardial tissue was analyzed for altered desmosomal and gap junction (connexin43) protein levels and localization. In vitro functional studies were performed to characterize the consequences of the desmosomal mutations.
Loss of plakoglobin signal was evident at the cell junctions despite expression of the protein at control levels. Although the distribution of connexin43 was not altered, total protein levels were reduced and changes in phosphorylation were observed. The truncation mutant in desmocollin-2a is deficient in binding plakoglobin. Moreover, the ability of desmocollin-2a to directly interact with connexin43 was abolished by the mutation. No pathogenic potential of the desmoglein-2 missense change was identified.
The observed abnormalities in gap junction protein expression and phosphorylation, which precede an overt cardiac phenotype, likely are responsible for slow myocardial conduction in this patient. At the molecular level, altered binding properties of the desmocollin-2a mutant may contribute to the changes in connexin43. In particular, the newly identified interaction between the desmocollin-2a isoform and connexin43 provides novel insights into the molecular link between desmosomes and gap junctions.
PMCID: PMC3085091  PMID: 21220045
Cardiomyopathy; Conduction; Connexin43; Desmocollin-2; Desmoglein-2; Desmosome; Functional studies; Gap junction; Mutation; Plakoglobin; ARVC, arrhythmogenic right ventricular cardiomyopathy; Cx43, connexin43; DAPI, 4′,6-diamidino-2-phenylindole; DSC2, desmocollin-2; DSG2, desmoglein-2; DSP, desmoplakin; GFP, green fluorescent protein; GST, glutathione-S-transferase; ICS, intracellular cadherin segment; PG, plakoglobin; PKP2, plakophilin-2; RV, right ventricle; YFP, yellow fluorescent protein
18.  Book review of applied medical image processing: A basic course 
This article is a review of the book: 'Applied Medical Image Processing: A Basic Course', by Wolfgang Birkfellner, which is published by CRC Press. Basic information that should be helpful in deciding whether to read the book and whether to use it as a course textbook is presented. This includes an introduction, the suitability of the book for use in coursework, its coverage of medical imaging and image processing, discussion and conclusions, and an appendix with a relevant computer program for extracting medical images.
PMCID: PMC3056831
19.  Classification of videocapsule endoscopy image patterns: comparative analysis between patients with celiac disease and normal individuals 
Quantitative disease markers were developed to assess videocapsule images acquired from celiac disease patients with villous atrophy, and from control patients.
Capsule endoscopy videoclip images (576 × 576 pixels) were acquired at 2/second frame rate (11 celiacs, 10 controls) at regions: 1. bulb, 2. duodenum, 3. jejunum, 4. ileum and 5. distal ileum. Each of 200 images per videoclip (= 100s) were subdivided into 10 × 10 pixel subimages for which mean grayscale brightness level and its standard deviation (texture) were calculated. Pooled subimage values were grouped into low, intermediate, and high texture bands, and mean brightness, texture, and number of subimages in each band (nine features in all) were used for quantifying regions 1-5, and to determine the three best features for threshold and incremental learning classification. Classifiers were developed using 6 celiac and 5 control patients' data as exemplars, and tested on 5 celiacs and 5 controls.
Pooled from all regions, the threshold classifier had 80% sensitivity and 96% specificity and the incremental classifier had 88% sensitivity and 80% specificity for predicting celiac versus control videoclips in the test set. Trends of increasing texture from regions 1 to 5 occurred in the low and high texture bands in celiacs, and the number of subimages in the low texture band diminished (r2 > 0.5). No trends occurred in controls.
Celiac videocapsule images have textural properties that vary linearly along the small intestine. Quantitative markers can assist in screening for celiac disease and localize extent and degree of pathology throughout the small intestine.
PMCID: PMC2941491  PMID: 20815911
20.  Measurement and monitoring of electrocardiogram belt tension in premature infants for assessment of respiratory function 
Monitoring of the electrocardiogram (ECG) in premature infants with conventional adhesive-backed electrodes can harm their sensitive skin. Use of an electrode belt prevents skin irritation, but the effect of belt pressure on respiratory function is unknown. A strain gauge sensor is described which measures applied belt tension.
The device frame was comprised of an aluminum housing and slide to minimize the device weight. Velcro tabs connected housing and slide to opposite tabs located at the electrode belt ends. The slide was connected to a leaf spring, to which were bonded two piezoresistive transducers in a half-bridge circuit configuration. The device was tested for linearity and calibrated. The effect on infant respiratory function of constant belt tension in the normal range (30 g–90 g) was determined.
The mechanical response to a step input was second order (fn = 401 Hz, ζ = 0.08). The relationship between applied tension and output voltage was linear in the range 25–225 gm of applied tension (r2 = 0.99). Measured device sensitivity was 2.18 mV/gm tension using a 5 V bridge excitation voltage. When belt tension was increased in the normal range from 30 gm to 90 gm, there was no significant change in heart rate and most respiratory functions during monitoring. At an intermediate level of tension of 50 gm, pulmonary resistance and work of breathing significantly decreased.
The mechanical and electrical design of a device for monitoring electrocardiogram electrode belt tension is described. Within the typical range of application tension, cardiovascular and respiratory function are not substantially negatively affected by electrode belt force.
PMCID: PMC1868740  PMID: 17445262

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