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Magnetic Resonance Imaging (MRI) techniques such as Current Density Imaging (CDI) and Diffusion Tensor Imaging (DTI) provide a complementing set of imaging data that can describe both the functional and structural states of biological tissues. This paper presents a Joint Independent Component Analysis (jICA) based fusion approach which can be utilized to fuse CDI and DTI data to quantify the differences between two cardiac states: Ventricular Fibrillation (VF) and Asystolic/Normal (AS/NM). Such an approach could lead to a better insight on the mechanism of VF. Fusing CDI and DTI data from 8 data sets from 6 beating porcine hearts, in effect, detects the differences between two cardiac states, qualitatively and quantitatively. This initial study demonstrates the applicability of MRI-based imaging techniques and jICA-based fusion approach in studying cardiac arrhythmias.

Spatial distribution of injected current in a subject could be calculated and visualized through current density imaging (CDI). Calculated CDI paths however have a limited degree of accuracy due to both avoidable methodological errors and inevitable limitations dictated by MR imaging constraints. The source and impact of these limitations are scrutinized in this paper. Quantification of such limitations is an essential step prior to passing any judgment about the results especially in biomedical applications. An innovative technique along with metrics for evaluation of range of errors using baseline and phase cycle MR images is proposed in this work. The presented approach is helpful in pinpointing the local artifacts (areas for which CDI results are suspect), evaluation of global noises and artifacts and assessment of the effect of approximation algorithms on real and artifactual components. We will demonstrate how this error/reliability evaluation is applicable to interpretation of CDI results and in this framework, report the CDI results for an artificial phantom and a live pig heart in Langendorff setup. It is contended here that using this method, the inevitable trade-off between details and approximations of CDI components could be monitored which provides a great opportunity for robust interpretation of results. The proposed approach could be extended, adapted and used for statistical analysis of similar methods which aim at mapping current and impedance based on magnetic flux images obtained through MRI.

Marine derived long chain polyunsaturated fatty acids (PUFAs) were found to have benefits in reducing inducibility and maintenance of atrial fibrillation (AF) in a dog model. This study was conducted to evaluate the effect of PUFAs on local atrial electrical conduction properties acquired via a multi-electrode plaque sutured to the posterior wall of the left atrium of the heart in these dogs. Eleven dogs underwent simultaneous atrioventricular pacing (SAVP) for 2 weeks, and were organized into 2 groups: 5 dogs received no PUFAs (SAVP-PLACEBO), 6 dogs received Eicosapentaenoic or Docosahexaenoic acid derived from fish oils (SAVP-PUFA), where PUFAs were given for 21 days, starting 1 week prior to pacing and during the 2 week pacing period. Three features were extracted, which were the average conduction velocity, average intra atrial conduction time, and total activation time. The PUFA group had a faster average conduction velocity (0.82±0.19 m/s) than the PLACEBO group (0.47±0.21 m/s, P=0.02). Using the average conduction velocity feature, classification was performed with a linear classifier and leave-one-out method. In the SAVP-PLACEBO group, 60% of the dogs were correctly classified, and 66% of the dogs were correctly classified in SAVP-PUFA group, leading to an overall classification accuracy of 63.5%.

Incorporation of disulfide bridges in the core structure of silica nanoparticles modifies their intracellular fate within dermal fibroblasts, especially influencing their degradation pathway.

Low frequency current density imaging (LFCDI) is a magnetic resonance imaging (MRI) technique which enables calculation of current pathways within the medium of study. The induced current produces a magnetic flux which presents itself in phase images obtained through MRI scanning. A class of LFCDI challenges arises from the subject rotation requirement, which calls for reliability analysis metrics and specific image registration techniques. In this study these challenges are formulated and in light of proposed discussions, the reliability analysis of calculation of current pathways in a designed phantom and a pig heart is presented. The current passed is measured with less than 5% error for phantom, using CDI method. It is shown that Gauss's law for magnetism can be treated as reliability metric in matching the images in two orientations. For the phantom and pig heart the usefulness of image registration for mitigation of rotation errors is demonstrated. The reliability metric provides a good representation of the degree of correspondence between images in two orientations for phantom and pig heart. In our CDI experiments this metric produced values of 95% and 26%, for phantom, and 88% and 75% for pig heart, for mismatch rotations of 0 and 20 degrees respectively.

Ventricular arrhythmias seriously affects cardiac function. Of these arrhythmias, Ventricular fibrillation is considered as a lethal cardiac condition. Recent studies have reported that ventricular arrhythmias are not completely random and may exhibit regional spatio-temporal organizations. These organizations could be indicative of reoccurring signal patterns and might be embedded within the surface electrocardiograms (ECGs) during ventricular arrhythmias. In this work, we aim to identify such reoccurring ECG signal patterns during ventricular arrhythmias. The detection of such signal patterns and their distribution could be of help in sub-classifying the affected population for better targeted diagnosis and treatment. Our analysis on 14 ECG segments (on average 3.24 minutes per segment) obtained from the MIT-BIH ventricular arrhythmia database identified three reoccurring signal patterns. A wavelet based technique was developed for automating the pattern identification process using ECGs. The proposed method achieved automated detection accuracies of 73.3%, 75.0% and 86.6% for the proposed signal patterns.

Ventricular Fibrillation (VF) is a cardiac arrhythmia for which the only available treatment option is defibrillation by electrical shock. Existing literature indicates that VF could be the manifestation of different sources controlling the heart with different degrees of organization. In this work we test the hypothesis that the pre-shock waveforms of successful and unsuccessful shock outcomes could be related to the number of independent sources present in these waveforms. The proposed method uses Blind Source Separation (BSS) to extract independent components in frequency direction from a pig database consisting of 20 pre-shock waveforms. The slope of the energy capture curve was used as an indicator to demonstrate the number of independent sources required to model the pre-shock waveforms. The results were also quantified by performing a linear discriminant analysis based classification achieving an overall classification accuracy of 75%. The results indicate that successful cases can be modeled with less number of independent sources compared to unsuccessful cases.

Background: Epidemiological studies have assessed T-wave alternans (TWA) as a possible mechanism of cardiac arrhythmias related to air pollution in high-risk subjects and have reported associations with increased TWA magnitude., Objective: In this controlled human exposure study, we assessed the impact of exposure to concentrated ambient particulate matter (CAP) and ozone (O3) on T-wave alternans in resting volunteers without preexisting cardiovascular disease., Methods: Seventeen participants without preexisting cardiovascular disease were randomized to filtered air (FA), CAP (150 μg/m3), O3 (120 ppb), or combined CAP + O3 exposures for 2 hr. Continuous electrocardiograms (ECGs) were recorded at rest and T-wave alternans (TWA) was computed by modified moving average analysis with QRS alignment for the artifact-free intervals of 20 beats along the V2 and V5 leads. Exposure-induced changes in the highest TWA magnitude (TWAMax) were estimated for the first and last 5 min of each exposure (TWAMax_Early and TWAMax_Late respectively). ΔTWAMax (Late-Early) were compared among exposure groups using analysis of variance., Results: Mean ± SD values for ΔTWAMax were -2.1 ± 0.4, -2.7 ± 1.1, -1.9 ± 1.5, and -1.2 ± 1.5 in FA, CAP, O3, and CAP + O3 exposure groups, respectively. No significant differences were observed between pollutant exposures and FA., Conclusion: In our study of 17 volunteers who had no preexisting cardiovascular disease, we did not observe significant changes in T-wave alternans after 2-hr exposures to CAP, O3, or combined CAP + O3. This finding, however, does not preclude the possibility of pollution-related effects on TWA at elevated heart rates, such as during exercise, or the possibility of delayed responses.

It is unknown whether ventricular fibrillation (VF) studied in experimental models represents in vivo human VF. First, we examined closed chest in vivo VF induced at defibrillation threshold testing (DFT) in four patients with ischemic cardiomyopathy pretransplantation. We examined VF in these same four hearts in an ex vivo human Langendorff posttransplantation. VF from DFT was compared with VF from the electrodes from a similar region in the right ventricular endocardium in the Langendorff using two parameters: the scale distribution width (extracted from continuous wavelet transform) and VF mean cycle length (CL). In a second substudy group where multielectrode phase mapping could be performed, we examined early VF intraoperatively (in vivo open chest condition) in three patients with left ventricular cardiomyopathy. We investigated early VF in the hearts of three patients in an ex vivo Langendorff and compared findings with intraoperative VF using two metrics: dominant frequency (DF) assessed by the Welch periodogram and the number of phase singularities (lasting >480 ms). Wavelet analysis (P = 0.9) and VF CL were similar between the Langendorff and the DFT groups (225 ± 13, 218 ± 24 ms; P = 0.9), indicating that wave characteristics and activation rate of VF was comparable between the two models. Intraoperative DF was slower but comparable with the Langendorff DF over the endocardium (4.6 ± 0.1, 5.0 ± 0.4 Hz; P = 0.9) and the epicardium (4.5 ± 0.2, 5.2 ± 0.4 Hz; P = 0.9). Endocardial phase singularity number (9.6 ± 5, 12.1 ± 1; P = 0.6) was lesser in number but comparable between in vivo and ex vivo VF. VF dynamics in the limited experimental human studies approximates human in vivo VF.

Background: Integrin-linked kinase (ILK) is a widely conserved serine/threonine kinase that regulates diverse signal transduction pathways implicated in cardiac hypertrophy and contractility. In this study we explored whether experimental overexpression of ILK would up-regulate morphogenesis in the human fetal heart., Methodology/principal Findings: Primary cultures of human fetal myocardial cells (19-22 weeks gestation) yielded scattered aggregates of cardioblasts positive for the early cardiac lineage marker nk × 2.5 and containing nascent sarcomeres. Cardiac cells in colonies uniformly expressed the gap junction protein connexin 43 (C × 43) and displayed a spectrum of differentiation with only a subset of cells exhibiting the late cardiomyogenic marker troponin T (cTnT) and evidence of electrical excitability. Adenovirus-mediated overexpression of ILK potently increased the number of new aggregates of primitive cardioblasts (p<0.001). The number of cardioblast colonies was significantly decreased (p<0.05) when ILK expression was knocked down with ILK targeted siRNA. Interestingly, overexpression of the activation resistant ILK mutant (ILK(R211A)) resulted in much greater increase in the number of new cell aggregates as compared to overexpression of wild-type ILK (ILK(WT)). The cardiomyogenic effects of ILK(R211A) and ILK(WT) were accompanied by concurrent activation of β-catenin (p<0.001) and increase expression of progenitor cell marker islet-1, which was also observed in lysates of transgenic mice with cardiac-specific over-expression of ILK(R211A) and ILK(WT). Finally, endogenous ILK expression was shown to increase in concert with those of cardiomyogenic markers during directed cardiomyogenic differentiation in human embryonic stem cells (hESCs)., Conclusions/significance: In the human fetal heart ILK activation is instructive to the specification of mesodermal precursor cells towards a cardiomyogenic lineage. Induction of cardiomyogenesis by ILK overexpression bypasses the requirement of proximal PI3K activation for transduction of growth factor- and β1-integrin-mediated differentiation signals. Altogether, our data indicate that ILK represents a novel regulatory checkpoint during human cardiomyogenesis.

Organofunctionalized apatite nanoparticles were prepared using a one step process involving dissolution/precipitation of natural phosphate rock and covalent grafting of nitrilotris(methylene)triphosphonate (NTP). The synthesized materials were characterized by Brunauer-Emmett-Teller (BET) surface measurement, thermogravimetry, inductively coupled plasma emission spectroscopy (ICP-ES), elemental analysis, multinuclear solid state cross-polarization/magic angle spinning (CP/MAS) and single-pulse NMR spectroscopy, transmission electron microscopy (TEM) and energy dispersive x-ray analysis (EDXA). After grafting BET measurements yielded particle specific surface areas ranging from 88 to 193 m(2) g(-1) depending on the grafted phosphonate. The results show that the surfaces of the nanoapatite particles can be covered with functional groups bound through a variable number of R-P-O-Ca bonds to render them organoapatites.

Zirconia-hydroxyapatite nanocomposites were prepared by sol-gel deposition of zirconium oxide from a zirconium alkoxide in the presence of apatite colloidal suspension under ultrasonication. The material porosity evolves from mainly microporous zirconia to mesoporous hydroxyapatite, with decreasing surface area and increasing pore volume. XRD studies indicate that the apatite phase is well-preserved within the composite materials. The homogeneous dispersion of apatite colloids within the zirconia network was supported by TEM observations and nitrogen sorption measurements. (31)P solid-state NMR studies suggest that partial dissolution of apatite may have occurred during the preparation, leading to the adsorption of phosphate species on zirconia particles. This is confirmed by XRD studies of nanocomposites after thermal treatment that demonstrate the preferred formation of tetragonal over monoclinic ZrO(2) in the presence of hydroxyapatite. In order to investigate the surface properties of these novel materials, the adsorption of Pb(2+), Cr(3+), and Cr(2)O(7)(2-) was evaluated. Metal cations were preferentially adsorbed on apatite-rich composites, whereas Cr(2)O(7)(2-) shows a good affinity for the zirconia-rich phases. Zirconia-apatite materials showed the most promising performance in terms of recyclability. These nanocomposites that combine microporosity, mesoporosity and dual sorption properties for these species appear as interesting materials for metal ion remediation and may also find applications as biomaterials., (© 2011 American Chemical Society)

Objectives: We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization., Background: Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated., Methods: Each of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m(3) CAP; 120 parts per billion O(3); CAP + O(3); and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording., Results: Spatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O(3) (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O(3) - FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O(3) compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02)., Conclusions: CAP + O(3) exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ventricular arrhythmias arise from abnormal electrical activity of the lower chambers (ventricles) of the heart. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are the two major subclasses of ventricular arrhythmias. While VT has treatment options that can be performed in catheterization labs, VF is a lethal cardiac arrhythmia, often when detected the patient receives an implantable defibrillator which restores the normal heart rhythm by the application of electric shocks whenever VF is detected. The classification of these two subclasses are important in making a decision on the therapy performed. As in the case of all real world process the boundary between VT and VF is ill defined which might lead to many of the patients experiencing arrhythmias in the overlap zone (that might be predominately VT) to receive shocks by the an implantable defibrillator. There may also be a small population of patients who could be treated with anti-arrhythmic drugs or catheterization procedure if they can be diagnosed to suffer from predominately VT after objectively analyzing their intracardiac electrogram data obtained from implantable defibrillator. The proposed work attempts to arrive at a quantifiable way to scale the ventricular arrhythmias into VT, VF, and the overlap zone arrhythmias as VT-VF candidates using features extracted from the wavelet analysis of surface electrograms. This might eventually lead to an objective way of analyzing arrhythmias in the overlap zone and computing their degree of affinity towards VT or VF. A database of 24 human ventricular arrhythmia tracings obtained from the MIT-BIH arrhythmia database was analyzed and wavelet-based features that demonstrated discrimination between the VT, VF, and VT-VF groups were extracted. An overall accuracy of 75% in classifying the ventricular arrhythmias into 3 groups was achieved.

Ventricular fibrillation (VF) occurs due to disorganized electrical activity in the ventricles. This leads to rapid uncoordinated contractions of the ventricles and sudden cardiac death if not treated within minutes of its occurrence. The mechanism of VF initiation and maintenance is still elusive, however the mother rotor and multiple wavelet theories attempt to explain the mechanism behind this lethal arrhythmia. In mother rotor theory, VF is believed to be maintained by high frequency periodic sources called rotors that could be tracked using the phase progression along and through the myocardium using spatio-temporal electrical mapping of the heart. There are exiting works including our previous works that have related the formation of these rotors to anatomical and physiological heterogeneities observed in the myocardium. In this study we performed an correlation exercise of the locations of rotors with scar boundary maps and dominant frequency maps and elucidated this relation using human VF data acquired from isolated human hearts. The results suggest that in 14 rotors over 6 human hearts that we studied, all rotors co-localized to boundary zones of scar and low-high dominant frequency locations. The mean variance of the dominant frequency over the spatial location of the rotor was found to be 0.55 with average minimum of 4.15 Hz to a maximum of 5.71 Hz. This results in human VF data strongly suggest that boundary zones of healthy-non-healthy tissues and low-high frequency boundaries form a favorite substrate for rotor formation.

Ventricular fibrillation (VF) is a lethal cardiac arrhythmia that if untreated within minutes of its occurrence will lead to sudden cardiac death. Defibrillation using electric shocks is the only choice of treatment to restore the heart to normal rhythm especially in out-of-the-hospital VF incidents. Refibrillation (i.e., recurrence of VF) is a common and significant problem in cardiac resuscitation as it negatively impacts the survival rates. In such refibrillation cases administration of anti-arrhythmic drugs could improve the shock outcomes or prevent refibrillation. In cases of prolonged VF, cardio pulmonary resuscitation (CPR) prior to the shocks have been shown to improve the survival rates. The proposed work using wavelet analysis of the pre-shock VF electrograms attempts to predict the shock outcomes as successful, refibrillation, and unsuccessful categories. This feedback in real-time would be of immense assistance to the Emergency Medical Services (EMS) personnel in choosing the right combination of therapies (i.e., shock, CPR, pharmacology interventions) in improving the shock outcomes. Using a real-word database of 34 pre-shock VF electrograms obtained from Toronto area EMS personnel, the proposed method achieved classification accuracies of 76.5% and 75% for a two level binary classification of the three groups.

Organically-modified hydroxyapatite materials were synthesized through the addition of oxalic, succinic, adipic and citric acids to a calcium hydroxide solution before neutralization by ammonium dihydrogenphosphate. All carboxylic acids have a significant influence on apatite crystallinity and nanoparticle size, as indicated by XRD and TEM. Chemical and thermogravimetric analyses as well as FTIR and {(1)H}-(13)C CP MAS NMR spectroscopies indicate that the additives are present in the final material. (1)H, {(1)H}-(31)P HPDec MAS, CP MAS and 2D {(1)H}-(31)P CP-HETCOR MAS NMR experiments suggest that carboxylic acids are localized on the apatite nanocrystallite surface, resulting in the formation of a disordered outer layer. Nitrogen sorption measurements indicate minor modifications of the specific surface area of the resulting mesoporous materials upon carboxylic acid addition but more significant variations in the average dimensions of the pores as well as in the chemical nature of the pore surface. Although these evolutions are mainly in good agreement with the ligand affinity for calcium ions in solution, an unexpected difference was observed between succinic and adipic acid, that may be attributed to steric constraints resulting from the interfacial nature of the calcium-ligand interactions. These data should provide useful guidelines to identify novel efficient additives to control apatite growth.

During cardiac resuscitation from ventricular fibrillation (VF) it would be helpful if we could monitor and predict the optimal state of the heart to be shocked into a perfusing rhythm. Real-time feedback of this state to the emergency medical staff (EMS) could improve the survival rate after resuscitation. In this paper, using real world out-of-the-hospital human VF data obtained during resuscitation by EMS personnel, we present the results of applying wavelet markers in predicting the shock outcomes. We also performed comparative analysis of 5 existing techniques (spectral and correlation based approaches) against the proposed wavelet markers. A database of 29 human VF tracings was extracted from the defibrillator recordings collected by the EMS personnel and was used to validate the waveform markers. The results obtained by the comparison of the wavelet based features with other spectral, and correlation-based features indicates that the proposed wavelet features perform well with an overall accuracy of 79.3% in predicting the shock outcomes and hence demonstrate potential to provide near real-time feedback to EMS personnel in optimizing resuscitation outcomes.

Charcot-Marie-Tooth disease type 1A is the most common inherited neuropathy and is caused by duplication of chromosome 17p11.2 containing the peripheral myelin protein-22 gene. This disease is characterized by uniform slowing of conduction velocities and secondary axonal loss, which are in contrast with non-uniform slowing of conduction velocities in acquired demyelinating disorders, such as chronic inflammatory demyelinating polyradiculoneuropathy. Mechanisms responsible for the slowed conduction velocities and axonal loss in Charcot-Marie-Tooth disease type 1A are poorly understood, in part because of the difficulty in obtaining nerve samples from patients, due to the invasive nature of nerve biopsies. We have utilized glabrous skin biopsies, a minimally invasive procedure, to evaluate these issues systematically in patients with Charcot-Marie-Tooth disease type 1A (n = 32), chronic inflammatory demyelinating polyradiculoneuropathy (n = 4) and healthy controls (n = 12). Morphology and molecular architecture of dermal myelinated nerve fibres were examined using immunohistochemistry and electron microscopy. Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy. Axonal loss was measurable using the density of Meissner corpuscles and associated with an accumulation of intra-axonal mitochondria. Our study demonstrates that skin biopsy can reveal pathological and molecular architectural changes that distinguish inherited from acquired demyelinating neuropathies. Uniformly shortened internodal length in Charcot-Marie-Tooth disease type 1A suggests a potential developmental defect of internodal lengthening. Intra-axonal accumulation of mitochondria provides new insights into the pathogenesis of axonal degeneration in Charcot-Marie-Tooth disease type 1A.

The interactions of cyclic polyamines with tetraethoxysilane in the conditions of the Stöber synthesis of silica nanoparticles were studied and compared to the behavior of a linear polyamine. Granular core-plain shell hybrid particles were obtained whose morphology and size vary with the nature and amount of added ligand. The influence of polyamines on silica condensation could be understood on the basis of a SN(2) reaction involving a pentacoordinated Si complex and depends on the accessibility and nucleophilicity of the ligand. In this case, the polyamine conformation is the key factor determining its ability to activate silica formation. The final size of the hybrid particles was determined by the aggregation of resulting primary nanoparticles that is controlled by electrostatic interactions, and thus depends on the ligand positive charge. These results were compared to biological and biomimetic processes of silica formation where acid-base/electrostatic interactions of silica precursors with linear polyamines have been described.

Background: Action potential duration (APD) variation is an important determinant of wave break and reentry. The determinants of APD variability during early ventricular fibrillation (VF) in myopathic human hearts have not been studied. The objective of this study was to study the role of APD restitution and short-term cardiac memory on variation in human VF., Methods and Results: The study consisted of 7 patients (67+/-9 years old) with ejection fraction <35%. Monophasic action potentials were recorded from the right and/or left ventricular septum during VF. APD(60/90) was measured in sinus beat preceding induction of VF, and its amplitude was used to define 60%/90% repolarization in VF. The monophasic action potential upstroke (dV/dt(max)) was used to characterize local excitability. Simple linear regression showed that variability in APD(n60) was determined by APD/diastolic interval restitution (R(2)=0.48, P<0.0001) and short-term memory (APD(60) n-1, n-2, n-3, n-4; R(2)=0.55, 0.40, 0.33, and 0.27 respectively; P<0.001). Using multiple stepwise regression, short-term memory and restitution accounted for 62% of variance in APD(60) (P<0.001). Individually, memory effect had the greatest contribution to APD variability (R(2)=0.55, P<0.0001)., Conclusions: In early human VF, short-term memory and APD/diastolic interval restitution explain most of the APD variability, with memory effects predominating. This suggests that in early human VF, short-term cardiac memory may provide a novel therapeutic target to modulate progression of VF in myopathic patients.

Quantifying the regional frequency variation in ventricular fibrillation (VF) may lead to focal strategies in treating human VF. We hypothesized that during human VF there are quantifiable regional frequency variations in the ventricles and they relate to underlying fixed myocardial substrate. In eight myopathic human hearts, we studied 35 VF episodes. The electrograms during VF were acquired simultaneously from the epicardium and endocardium using 2 electrode arrays each consisting of 112 electrodes. Regional characterization was performed using a ratio parameter derived from the dominant frequency analysis of the electrograms. The findings were related to the anatomical substrate using bipolar voltage maps. The results of the analysis indicate that LV had a larger dominant frequency (DF) span than RV (p=0.0111) while there was no significant difference (p=0.1488) in the DF span between LV freewall (FW) and septum (SE). Correlation of areas of abnormal myocardium with the dominant frequency feature matched only in 50% of the cases indicating that ion channel heterogeneity and time-varying physiological factors may play an important role in maintaining VF.

The ability to generate human pluripotent stem cell-derived cell types at sufficiently high numbers and in a reproducible manner is fundamental for clinical and biopharmaceutical applications. Current experimental methods for the differentiation of pluripotent cells such as human embryonic stem cells (hESC) rely on the generation of heterogeneous aggregates of cells, also called "embryoid bodies" (EBs), in small scale static culture. These protocols are typically (1) not scalable, (2) result in a wide range of EB sizes and (3) expose cells to fluctuations in physicochemical parameters. With the goal of establishing a robust bioprocess we first screened different scalable suspension systems for their ability to support the growth and differentiation of hESCs. Next homogeneity of initial cell aggregates was improved by employing a micro-printing strategy to generate large numbers of size-specified hESC aggregates. Finally, these technologies were integrated into a fully controlled bioreactor system and the impact of oxygen concentration was investigated. Our results demonstrate the beneficial effects of stirred bioreactor culture, aggregate size-control and hypoxia (4% oxygen tension) on both cell growth and cell differentiation towards cardiomyocytes. QRT-PCR data for markers such as Brachyury, LIM domain homeobox gene Isl-1, Troponin T and Myosin Light Chain 2v, as well as immunohistochemistry and functional analysis by response to chronotropic agents, documented the impact of these parameters on cardiac differentiation. This study provides an important foundation towards the robust generation of clinically relevant numbers of hESC derived cells.

The aim of this study is to determine if some of the characteristics of reconstructed unipolar electrograms from the noncontact mapping system can be used to detect epicardial electrical activation in a canine heart. This would help the electrophysiologist know where exactly the origin or the critical point in tissue is located. Following this, arrhythmia can be successfully treated by ablating that part of the tissue of heart. Virtual electrograms were recorded while pacing the right ventricle of an open-chest dog at multiple endocardial and epicardial sites using the commercially available noncontact mapping system (EnSite 3000). The endocardial and epicardial paced virtual electrograms from the juxtaposing sites allow for analyzing systematically the differences in their morphologies. Maximal dV/dt, area under the depolarization curve and latency extracted from unipolar electrograms demonstrated significant difference between epicardial and endocardial pacing sites with a p-value of less than 0.01 in all three cases. The above features were fed to a linear discriminant analysis based classifier and high classification accuracy was achieved. In conclusion, reliable criteria can be proposed to allow for discrimination of an endocardial versus epicardial origin of electrical activation.

Ventricular fibrillation (VF) is the most lethal of cardiac arrhythmias that leads to sudden cardiac death if untreated within minutes of its occurrence. Defibrillation using electric shock resets the heart to return to spontaneous circulation (ROSC) state, however the success of which depends on various factors such as the viability of myocardium and the time lag between the onset of VF to defibrillation. Recent studies have reported that performing cardio pulmonary resuscitation (CPR) procedure prior to applying shock increases the survival rate especially when VF is untreated for more than 5 minutes. Considering the limited time within which the VF has to be treated for better survival rates, the choice of the right therapy (shock parameters, shock first or CPR first, drug administration) is vital. In aiding this choice, it would be of immense help for emergency medical staff (EMS) if an objective feedback could be provided at near real-time rate on the VF characteristics and its relation to the shock outcomes. Existing works in the literature have demonstrated correlation between the characteristics of the VF waveform and the outcome (ROSC) of the defibrillation. The proposed work improves on this by attempting to arrive at a near real-time monitoring tool in aiding the EMS staff. Using data collected from 16 pigs during VF, the proposed wavelet methodology achieved an overall accuracy of 94% in successfully predicting the shock outcomes.

Background: Complex fractionated atrial electrograms have been suggested as important targets for catheter ablation of atrial fibrillation. The etiology and the mechanism of these signals have not been completely elucidated because of limitations of interpretation of these signals in relation to simultaneously acquired signals in the neighboring atrial tissue., Objective: This study sought to study the origin of electrogram fractionation under the conditions of rotor formation and wave fragmentation, using atrial monolayer preparations., Methods: We performed optical mapping of 45 atrial monolayer preparations using a complementary metal oxide semiconductor (CMOS) Brainvision Ultima camera system (SciMedia-Brainvision, Tokyo, Japan)., Results: We observed stable rotors in 32 of the 45 recordings. The derived bipolar electrograms did not show complex fractionation at the core of the rotor in any of the 32 recordings. We were also able to show that 2 bipolar electrodes placed adjacent to the core of a stable rotor in a zone where there is no wave break will record electrical activity for the majority of the rotor's cycle length. In 13 of the 45 recordings, wave break or wave collision events were present. Of these, 8 of 13 recordings showed complex fractionation. In 19 of the 27, simulation of meandering rotors also showed complex fractionation., Conclusion: Complex fractionated electrograms can be recorded at sites of migrating rotors and wave break. No fractionation occurs at the core of a stable rotor. Electrograms that span the rotor cycle length and alternate between 2 bipoles that straddle the core can identify site of a stable rotor.

In our program to discover non-nucleoside, small molecule inhibitors of genotype 1 HCV polymerase, we investigated a series of promising analogs based on a benzothiadiazine screening hit that contains an ABCD ring system. After demonstrating that a methylsulfonylamino D-ring substituent increased the enzyme potency into the low nanomolar range, we explored a minimum core required for activity by truncating to a three-ring system. Described herein are the syntheses and structure-activity relationship of a set of inhibitors lacking the A-ring of an ABCD ring system. We observed that small aromatic rings and alkenyl groups appended to the 5-position of the B-ring were optimal, resulting in inhibitors with low nanomolar potencies.

In the view of designing functional nanoparticles, the encapsulation of 1,4,7,10-tetraazacyclododecane (cyclen) within silica nanoparticles using the Stöber process was studied. In the presence of cyclen and tetraethoxysilane (TEOS), silica particles exhibiting an unusual core-shell structure were obtained. On then basis of TEM, DLS, and NMR data, we suggest that the particle core is constituted of hybrid primary nanoparticles resulting from cyclen-silica interactions, whereas the shell formation results from further condensation of unreacted silica precursors. Control experiments performed with the zinc-cyclen complex and ammonia addition suggest that cyclen-TEOS interactions arise from the activation of the silicon alkoxide hydrolysis with the polyazamacrocycle amine groups. These data are discussed in the context of silica biomineralization mechanisms, where polyamine/silica interactions have been shown to play a major role. Moreover, the possibility to control the size and the structure of these nanoparticles makes them promising materials for pharmaceutical applications.

A major issue in the study of biosilicification processes is the harsh chemical conditions required for silica dissolution, which often lead to denaturation of the associated bio-organic matter. In order to demonstrate the potential of solid state NMR for investigating silicified materials of natural origin, this technique was applied to isotopically enriched Thalassiosira pseudonana diatom cells. (29)Si, (1)H,(31)P, (13)C and (15)N solid state NMR studies were performed on whole cells, SDS-extracted and H(2)O(2)-cleaned silica shells. Cross-polarization techniques were useful for identifying the presence of mobile and rigid molecules, allowing loosely bound and silica-entrapped species to be discriminated. Successive cleaning procedures efficiently eliminated weakly associated organic matter. The H(2)O(2)-cleaned silica shell still contained carbohydrates (mainly chitin) and proteins as well as lipids. This suggests that the role of lipids in diatom shell formation may have been underestimated so far, demonstrating the potential of solid state NMR for studying composite biomaterials.

A-790742 is a potent human immunodeficiency virus type 1 (HIV-1) protease inhibitor, with 50% effective concentrations ranging from 2 to 7 nM against wild-type HIV-1. The activity of this compound is lowered by approximately sevenfold in the presence of 50% human serum. A-790742 maintained potent antiviral activity against lopinavir-resistant variants generated in vitro as well as against a panel of molecular clones containing proteases derived from HIV-1 patient isolates with multiple protease mutations. During in vitro selection, A-790742 selected two primary mutations (V82L and I84V) along with L23I, L33F, K45I, A71V/A, and V77I in the pNL4-3 background and two other mutations (A71V and V82G) accompanied by M46I and L63P in the HIV-1 RF background. HIV-1 pNL4-3 clones with a single V82L or I84V mutation were phenotypically resistant to A-790742 and ritonavir. Taking these results together, A-790742 displays a favorable anti-HIV-1 profile against both the wild type and a large number of mutants resistant to other protease inhibitors. The selection of the uncommon V82L and V82G mutations in protease by A-790742 suggests the potential for an advantageous resistance profile with this protease inhibitor.

A series of gem-dialkyl naphthalenone derivatives with varied alkyl substitutions were synthesized and evaluated according to their structure-activity relationship. This investigation led to the discovery of potent inhibitors of the hepatitis C virus at low nanomolar concentrations in both enzymatic and cell-based HCV genotype 1a assays.

Compound A-837093, a non-nucleoside HCV RNA-dependent RNA polymerase inhibitor, displayed nanomolar potencies against HCV genotypes 1a and 1b replicons. It also exhibited an excellent metabolic profile and achieved high plasma and liver concentrations in animals. In order to characterize the development of resistance to this anti-HCV agent, HCV subgenomic 1b strain N replicon cells were cultured in the presence of A-837093 with G418. Mutations S368A, Y448H, G554D, Y555C, and D559G in the NS5B polymerase gene were identified that led to substantial decreases in the susceptibilities of 1b genotype replicons to the inhibitor A-837093. However, the resistant mutants remained susceptible to HCV protease inhibitor BILN-2061 and alpha interferon as well as to a different class of non-nucleoside HCV polymerase inhibitor. In addition, each single resistant mutation identified significantly reduced the replication capacity of mutant compared to wild-type replicon. These findings provide a strategic guide for the future development of non-nucleoside inhibitors of HCV NS5B polymerase.

Lopinavir (LPV)-ritonavir has demonstrated durable antiviral activity in human immunodeficiency virus type 1 (HIV-1)-infected antiretroviral-naïve and protease inhibitor (PI)-experienced patients. However, information on LPV activity against HIV-2 and the patterns of mutations in HIV-2 in response to selection by LPV is limited. The activity of LPV against three strains of HIV-2 was assessed and compared to activity against a reference HIV-1 strain. LPV demonstrated activity similar to that observed against HIV-1 in two HIV-2 strains (HIV-2(MS) and HIV-2(CBL-23)) tested. On the other hand, approximately 10-fold-reduced susceptibility was observed with the third HIV-2 strain, HIV-2(CDC310319). Passage of HIV-2(MS) with increasing concentrations of LPV selected mutations V47A and D17N in the HIV-2 protease gene. The introduction of both 17N and 47A either individually or together into HIV-2(ROD) molecular infectious clones showed that the single V47A substitution in HIV-2 resulted in a substantial reduction in susceptibility to LPV. In contrast, this mutant retained wild-type susceptibility to other PIs and appeared to be hypersusceptible to atazanavir and saquinavir.

Aims: The aim of this report was to review existing techniques for assessment of directionality in fibrillation and to describe the concept of wave similarity analysis in human VF., Methods: We applied a technique called wave similarity analysis to bipolar electrograms to study directionality during various rhythms (sinus rhythm, ventricular tachycardia and ventricular fibrillation) in humans. This technique uses the barycentre to determine the activation time and a similarity index is calculated using a technique described previously for AF studies., Results: We show here that using the wave similarity concept it is possible to recognize myocardial regions that are activated from multiple directions and differentiate those areas from regions that are activated by wave fronts in similar direction or at the exact mirror angle in ventricular fibrillation., Conclusions: Wave similarity analysis provides a tool for assessing directional organization in human VF. This analysis of directional organization may have implications for the study of mechanisms of VF in the clinical arena.

A new series of HIV protease inhibitors has been designed and synthesized based on the combination of the (R)-(hydroxyethylamino)sulfonamide isostere and the cyclic urea component of lopinavir. The series was optimized by replacing the 6-membered cyclic urea linker with an imidazolidine-2,4-dione which readily underwent N-alkylation to incorporate various methylene-linked heterocycle groups that bind favorably in site 3 of HIV protease. Significant improvements compared to lopinavir were seen in cell culture activity versus wild-type virus (pNL4-3) and the lopinavir-resistant mutant virus A17 (generated by in vitro serial passage of HIV-1 (pNL4-3) in MT-4 cells). Select imidazolidine-2,4-dione containing PIs were also more effective at inhibiting highly resistant patient isolates Pt1 and Pt2 than lopinavir. Pharmacokinetic data collected for compounds in this series varied considerably when coadministered orally in the rat with an equal amount of ritonavir (5 mg/kg each). The AUC values ranged from 0.144 to 12.33 microg h/mL.

Objectives: The purpose of this study was to evaluate the cardiac consequences of neuromuscular incapacitating device (NID)/stun gun discharge in an experimental model., Background: The large-voltage electrical discharges from NIDs have been suggested to pose a risk for triggering cardiac arrhythmias., Methods: Intracardiac catheters and blood pressure transducers were inserted before the application of NID discharges in six anesthetized pigs. Two different commercially available models (NID-1 and NID-2), two different vectors of discharges (thoracic: parallel to the long axis of the heart on the chest wall, and nonthoracic: away from the chest, across the abdomen), and two different durations of discharge (5 and 15 s) were tested. The effect of simulated adrenergic stress using epinephrine was also evaluated., Results: We studied a total of 150 discharges to 6 pigs; 74 of these discharges resulted in stimulation of the myocardium, as documented by electrical capture (mean ventricular rate during stimulation and capture, 324 +/- 66 beats/min). Of the 94 thoracic discharges, 74 stimulated the myocardium, compared with none from 56 nonthoracic discharges (p < 0.0001). During 16 discharges with epinephrine, there were 13 episodes of stimulation of the myocardium, of which 1 induced ventricular fibrillation and 1 caused ventricular tachycardia. Thoracic discharges from NID-1 were more likely to stimulate the myocardium than those from NID-2 (98% vs. 54%, p = 0.0007)., Conclusions: In an experimental model, NID discharges across the chest can produce cardiac stimulation at high rates. This study suggests that NIDs may have cardiac risks that require further investigation in humans.

A series of non-nucleoside HCV NS5B polymerase inhibitors based on the N-1-benzyl or N-1-[3-methylbutyl]-4-hydroxy-1,8-naphthyridon-3-yl benzothiadiazine core substituted in the D-ring aromatic moiety have been prepared and evaluated. Aromatic substituents extending from position 7 of the D-ring exhibited excellent potency against both genotypes 1a and 1b.

Substituted N-alkyl-4-hydroxyquinolon-3-yl-benzothiadiazine sulfamides were investigated as inhibitors of genotype 1 HCV polymerase. Structure-activity relationship patterns for this class of compounds are discussed.

Compounds A-782759 (an N-1-aza-4-hydroxyquinolone benzothiadiazine) and BILN-2061 are specific anti-hepatitis C virus (HCV) agents that inhibit the RNA-dependent RNA polymerase and the NS3 serine protease, respectively. Both compounds display potent activity against HCV replicons in tissue culture. In order to characterize the development of resistance to these anti-HCV agents, HCV subgenomic 1b-N replicon cells were cultured with A-782759 alone or in combination with BILN-2061 at concentrations 10 times above their corresponding 50% inhibitory concentrations in the presence of neomycin. Single substitutions in the NS5B polymerase gene (H95Q, N411S, M414L, M414T, or Y448H) resulted in substantial decreases in susceptibility to A-782759. Similarly, replicons containing mutations in the NS5B polymerase gene (M414L or M414T), together with single mutations in the NS3 protease gene (A156V or D168V), conferred high levels of resistance to both A-782759 and BILN-2061. However, the A-782759-resistant mutants remained susceptible to nucleoside and two other classes of nonnucleoside NS5B polymerase inhibitors, as well as interferon. In addition, we found that the frequency of replicons resistant to both compounds was significantly lower than the frequency of resistance to the single compound. Furthermore, the dually resistant mutants displayed significantly reduced replication capacities compared to the wild-type replicon. These findings provide strategic guidance for the future treatment of HCV infection.

Evidence suggests that frailer older patients benefit from a continuum of care rather than the admit/discharge model of our health system. This study examined patient outcomes after discharge from a geriatric day hospital (GDH) to determine what proportion continues to do well, what proportion declines, how the two groups differ, and if factors predictive of deterioration can be identified. Using telephone survey and Goal Attainment Scaling methodologies, the goals of 151 patients discharged from a GDH between 6 and 18 months previously were examined to determine whether GDH achievements were maintained or lost. All but 5 patients improved between GDH admission and discharge; after discharge, 39 per cent deteriorated. The need for more support in the community was predictive of deterioration, probably reflecting patient frailty. Number of medical diagnoses or medications were not predictive. Frailer older patients tend not to maintain goals achieved in a GDH after discharge and may benefit from ongoing maintenance.

The [PSI(+)] prion can be induced by overproduction of the complete Sup35 protein, but only in strains carrying the non-Mendelian [PIN(+)] determinant. Here we demonstrate that just as [psi (-)] strains can exist as [PIN(+)] and [pin(-)] variants, [PSI(+)] can also exist in the presence or absence of [PIN(+)]. [PSI(+)] and [PIN(+)] tend to be cured together, but can be lost separately. [PSI(+)]-related phenotypes are not affected by [PIN(+)]. Thus, [PIN(+)] is required for the de novo formation of [PSI(+)], not for [PSI(+)] propagation. Although [PSI(+)] induction is shown to require [PIN(+)] even when the only overexpressed region of Sup35p is the prion domain, two altered prion domain fragments circumventing the [PIN(+)] requirement are characterized. Finally, in strains cured of [PIN(+)], prolonged incubation facilitates the reappearance of [PIN(+)]. Newly appearing [PIN(+)] elements are often unstable but become stable in some mitotic progeny. Such reversibility of curing, together with our previous demonstration that the inheritance of [PIN(+)] is non-Mendelian, supports the hypothesis that [PIN(+)] is a prion. Models for [PIN(+)] action, which explain these findings, are discussed.

Background: Diastolic potentials are often sought as a possible site for catheter ablation in post-infarct ventricular tachycardia. However, delivery of energy at such sites is often unsuccessful. The purpose of this study was to determine the characteristics of local electrograms with diastolic potentials and to identify activation pattern which might indicate the critical portion of the return path of the ventricular tachycardia reentry circuit., Methods: In 17 patients with post-myocardial infarction ventricular tachycardia, 30 ventricular tachycardias were mapped with an 112 bipolar endocardial balloon at the time of surgery. Diastolic mapping of the return tract in ventricular tachycardia was performed. Four activation patterns were observed (15 figure 8 patterns, 2 circular patterns, 2 biregional patterns and 11 monoregional patterns). Of 3,360 local electrograms, 207 (6.2%) demonstrated a diastolic potential in ventricular tachycardia. They were classified into following four categories, based on the appearance and timing of the systolic component. Type A-1 electrogram: systolic activation was of low amplitude (< 2 mV) and was prolonged (> or = 100 msec), but preceded the onset of the surface QRS in ventricular tachycardia. Type A-2 electrogram: systolic activation was of low amplitude, was prolonged, but followed the onset of the surface QRS. Type B electrogram: systolic electrogram was fractionated, but relatively normal amplitude (2.0-3.6 mV). Type C electrogram: systolic electrogram was almost normal., Results: Of all electrograms with diastolic potentials, three type A-1 electrograms (1.4%) were located at the exit of the return pathway, 11 type A-1 electrograms (5.3%) were located at the pre-exit site. No type A-1 was found at an entrance/bystander area. 21 type A-2 electrograms (10.1%) were at the pre-exit and 83 type A-2 electrograms (40.2%) were located at the entrance/bystander area, but such electrograms were never found at the exit site. 71 type B electrograms (34.3%) and 18 type C electrograms (8.7%) were located at the entrance/bystander area. To distinguish the type A-2 electrograms at the pre-exit site from those at the entrance/bystander area, the diastolic potential to QRS interval was measured. This interval at the pre-exit was significantly shorter than that at the entrance/bystander area (-47.2 +/- 10.7 vs -96.3 +/- 31.3 msec, p = 0.0001)., Conclusion: Type A-1 electrograms indicated the exit or pre-exit site of return pathway. Type A-2 electrograms with diastolic potential to QRS interval < -50 msec indicated the pre-exit site. However, the other types of local electrograms with diastolic potential did not indicate the critical portion of the ventricular tachycardia circuit. These observations may be helpful during catheter mapping and ablation of patients with post-infarct ventricular tachycardia., Condensed Abstract: Diastolic potentials are often sought to direct catheter ablation in post-infarct ventricular tachycardia. We investigated the characteristics of local electrograms showing diastolic activity in an attempt to determine whether critical portions of the ventricular tachycardia circuit could be identified by a typical "signature." In 17 patients with a remote myocardial infarction, 30 ventricular tachycardias were mapped with 112 bipolar endocardial balloon at the time of surgery. Diastolic potentials in association with low amplitude (< 2 mV) and prolonged (> or = 100 msec) systolic electrograms preceding the onset of QRS were found at the exit site and pre-exit site of return pathway. A similar systolic electrogram occurring after QRS onset with a diastolic potential to QRS interval of < -50 msec was found at the pre-exit site. However, other local electrograms with diastolic activity were at sites remote from the exit or pre-exit of the return pathway. These observations may be helpful during catheter mapping and ablation in patients with ventricular tachycardia.

A screen was designed to identify Saccharomyces cerevisiae mutants that were defective in meiosis yet proficient for meiotic ectopic recombination in the return-to-growth protocol. Seven mutants alleles were isolated; two are important for chromosome synapsis (RED1, MEK1) and five function independently of recombination (SPO14, GSG1, SPOT8/MUM2, 3, 4). Similar to the spoT8-1 mutant, mum2 deletion strains do not undergo premeiotic DNA synthesis, arrest prior to the first meiotic division and fail to sporulate. Surprisingly, although DNA replication does not occur, mum2 mutants are induced for high levels of ectopic recombination. gsg1 diploids are reduced in their ability to complete premeiotic DNA synthesis and the meiotic divisions, and a small percentage of cells produce spores. mum3 mutants sporulate poorly and the spores produced are inviable. Finally, mum4-1 mutants produce inviable spores. The meiotic/sporulation defects of gsg1, mum2, and mum3 are not relieved by spo11 or spo13 mutations, indicating that the mutant defects are not dependent on the initiation of recombination or completion of both meiotic divisions. In contrast, the spore inviability of the mum4-1 mutant is rescued by the spo13 mutation. The mum4-1 spo13 mutant undergoes a single, predominantly equational division, suggesting that MUM4 functions at or prior to the first meiotic division. Although recombination is variably affected in the gsg1 and mum mutants, we hypothesize that these mutants define genes important for aspects of meiosis not directly related to recombination.

Objectives: This study was conducted to characterize the functional nature of the reentrant tract responsible for ventricular tachycardia due to ischemic heart disease., Background: A zone of slow conduction forming the return path is though to form a critical component of the reentrant mechanism in ventricular tachycardia. Despite its importance, detailed knowledge of the return path is rare in clinical studies., Methods: Multielectrode arrays were used intraoperatively to obtain unipolar and high gain bipolar recordings of left ventricular endocardium in patients undergoing map-directed surgical ablation of ventricular tachycardia. A total of 224 local electrograms were analyzed for each tachycardia., Results: Of 10 consecutive patients undergoing intraoperative cardiac mapping, detailed recording of the return tracts of eight ventricular tachycardias were obtained in three patients. The recordings demonstrated that return tracts can be complex and extensive, with multiple paths of entry and exit. Potential and actual alternate paths were observed. Spontaneous and induced block occurred within portions of the complex. Intermittent block in one of two paths of entry resulted in intermittent cycle length changes of the tachycardia without a change in configuration. Block in one exit path resulted in a shift to alternative exit paths, with dramatic changes in ventricular activation and tachycardia configuration. Termination of the tachycardia could result from block close to the entrant or exit portion of the return tract. Different tachycardias were seen to share common portions of a return tract., Conclusions: These observations enlarge and extend our knowledge of the functional repertoire of complex reentrant tracts that occur in infarct-related ventricular tachycardia. The use of common portions of a reentrant tract by several tachycardias is confirmed. Utilization of alternate pathways can account for changes in configuration and cycle length. Spontaneous and induced block can occur at points of entry and exit in a reentrant tract and may identify optimal targets for ablation attempts. Further advances will require greater emphasis on diastolic activation mapping.

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Objectives: The aim of this study was to examine, with multichannel direct cardiac mapping techniques, the mechanisms of spontaneous shift of the QRS configuration in the surface electrocardiogram during episodes of ventricular tachycardia., Background: Ventricular tachycardias demonstrating a spontaneous shift in their surface electrocardiographic (ECG) features are occasionally encountered. It is not known whether such changes in configuration are primarily due to a significant change in the tachycardia site of origin or represent alterations in patterns of endocardial and epicardial activation. Knowledge of these features would be helpful, particularly when ablative therapy is considered for the arrhythmias., Methods: During map-directed cardiac surgery, episodes of ventricular tachycardia were mapped from 224 epicardial and endocardial sites. Episodes of pleomorphic tachycardia were identified and isochronal maps of endocardial and epicardial activation were constructed from representative beats before and after the change in configuration., Results: From 52 consecutive patients who underwent detailed intraoperative mapping, 9 patients with pleomorphic ventricular tachycardia were identified in whom 14 episodes of spontaneous shift occurred. An analysis of the epicardial activation patterns revealed that the sites of earliest epicardial breakthrough showed significant alteration at the time of QRS shift in all occurrences. In 10 of these shift episodes, however, the sites of tachycardia origin, located on the endocardial surface, remained closely adjacent (< 2 cm apart). Although these sites of origin remained relatively constant, significant alterations in the patterns of endocardial activation were seen in most episodes. These included changes in the direction of propagation of the wave front of activation and shifts between monoregional and figure eight patterns of activation., Conclusions: In most episodes of pleomorphic ventricular tachycardia, the arrhythmia site of origin remains relatively constant. However, patterns of epicardial activation do undergo significant change and appear to be the major determinant of the QRS configuration on the surface ECG.