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PubMed1999

Characterization of conduction in the ventricles of normal and heterozygous Cx43 knockout mice using optical mapping.

INTRODUCTION: Gap junction channels are important determinants of conduction in the heart and may play a central role in the development of lethal cardiac arrhythmias. The recent development of a Cx43-deficient mouse has raised fundamental questions about the role of specific connexin isoforms in intercellular communication in the heart. Although a homozygous null mutation of the Cx43 gene (Cx43-/-) is lethal, the heterozygous (Cx43+/-) animals survive to adulthood. Reports on the cardiac electrophysiologic phenotype of the Cx43+/- mice are contradictory. Thus, the effects of a null mutation of a single Cx43 allele require reevaluation. METHODS AND RESULTS: High-resolution video mapping techniques were used to study propagation in hearts from Cx43+/- and littermate control (Cx43+/+) mice. Local conduction velocities (CVs) and conduction patterns were quantitatively measured by determining conduction vectors. We undertook the characterization of ECG parameters and epicardial CVs of normal and Cx43+/- mouse hearts. ECG measurements obtained from 12 Cx43+/+ and 6 Cx43+/- age matched mice did not show differences in any parameter, including QRS duration (14.5 +/- 0.9 and 15.7 +/- 2.3 msec for Cx43+/+ and Cx43+/-, respectively). In addition, using a sensitive method of detecting changes in local CV, video images of epicardial wave propagation revealed similar activation patterns and velocities in both groups of mice. CONCLUSION: A sensitive method that accurately measures local CVs throughout the ventricles revealed no changes in Cx43+/- mice, which is consistent with the demonstration that ECG parameter values in the heterozygous mice are the same as those in wild-type mice.

Animals↗
PubMed1996

Optical mapping in a new guinea pig model of ventricular tachycardia reveals mechanisms for multiple wavelengths in a single reentrant circuit.

BACKGROUND: Although the relationship between cardiac wavelength (lambda) and path length importantly determines the stability of reentrant arrhythmias, the physiological determinants of lambda are poorly understood. To investigate the cellular mechanisms that control lambda during reentry, we developed an experimental system for continuously monitoring lambda within a reentrant circuit with the use of voltage-sensitive dyes and a new guinea pig model of ventricular tachycardia (VT). METHODS AND RESULTS: Action potentials were recorded simultaneously from 128 ventricular sites in Langendorff-perfused hearts (n = 15) in which propagation was confined to a two-dimensional rim of epicardium by an endocardial cryoablating procedure. The reentrant path was precisely controlled by creating an epicardial obstacle (2 x 10 mm) with an argon laser. To control for fiber orientation and rate-dependent membrane properties, lambda during reentry was compared with lambda during plane wave propagation transverse and longitudinal to cardiac fibers at a stimulus cycle length (CL) comparable to the VT CL. Reentrant VT (CL = 97.0 +/- 6.2 ms) was reproducibly induced by programmed stimulation in 93% of preparations. lambda varied considerably within the reentrant circuit (range, 10.6 to 22.5 mm), because of heterogeneities of conduction rather than action potential duration. lambda was significantly shorter during reentrant propagation (ie, with pivoting) parallel to fibers (10.6 +/- 4.2 mm) compared with plane wave propagation (ie, without pivoting) parallel to fibers (32.8 +/- 6.5 mm, P < .02), indicating that wave-front pivoting was primarily responsible for shortening of lambda during reentry. The mechanism of lambda shortening was conduction slowing from increased current load experienced by the pivoting wave front. CONCLUSIONS: We provide direct experimental evidence that multiple wavelengths are present even within a relatively simple reentrant circuit. Abrupt changes in loading during wave-front pivoting, rather than membrane ionic properties or fiber structure, were a major determinant of lambda and, therefore, may play an important role in the stability of reentry.

Action Potentials↗
PubMed1995

Optical mapping reveals that repolarization spreads anisotropically and is guided by fiber orientation in guinea pig hearts.

Guinea pig hearts were stained with a voltage-sensitive dye and imaged on a photodiode array to record fluorescent action potentials (APs) from 124 sites. Activation and repolarization patterns were recorded from the epicardium during stimulation at different loci and correlated with the underlying fiber architecture. Endocardial APs were recorded by inserting a light guide into the ventricular cavity or by dissecting out the ventricular free wall to expose the endocardium. In hearts paced on the right atrium to simulate sinus rhythm, activation emerged synchronously over a large area of the ventricular epicardium and spread laterally in 5 to 7 ms. The apparent longitudinal and transverse velocities were 2.66 +/- 0.11 and 1.65 +/- 0.09 m/s (n = 12). In contrast, repolarization began near the apex on the endocardium and spread transmurally in 6 +/- 1.3 ms (n = 12) and then anisotropically along the epicardium in 25 to 30 ms with apparent maximum (0.53 +/- 0.11 m/s) and minimum (0.31 +/- 0.10 m/s) repolarization velocities that aligned with the longitudinal and transverse axes of epicardial fibers. When paced on the epicardium, activation of intact hearts (n = 12) and perfused sheets (n = 8) was anisotropic, with longitudinal (0.85 +/- 0.05 m/s) and transverse (0.44 +/- 0.04 m/s) conduction velocities that aligned with the epicardial fiber orientation. When activation was initiated at different sites on the epicardium, repolarization always began near the apex and exhibited patterns similar to those obtained under right atrial pacing, but with slower longitudinal (0.41 +/- 0.09 m/s) and transverse (0.23 +/- 0.07 m/s) repolarization velocities (n = 18). In sheets stretched parallel to the longitudinal axis of surface fibers, AP durations (APDs) increased as a function of fiber length, from the length at zero developed tension to 120% of the length at maximum developed tension (Lmax). Spatial distributions of APDs did not change during stretches along the rising phase of the length-tension curve. In sheets stretched to 50% of Lmax, APDs were shorter and more homogeneous on the endocardium (mean APD, 188 ms; delta APD, 195-186 = 9 ms) than on the epicardium (mean APD, 204 ms; delta APD, 212-186 = 26 ms; n = 8). In guinea pig hearts, activation is rapid; therefore, repolarization depends primarily on intrinsic spatial heterogeneities of APDs. Consequently, repolarization begins at endocardial cells with the shortest APDs and spreads transmurally and then anisotropically on the surface according to the epicardial cell orientation.

Animals↗
PubMed1999

Genomics via optical mapping. III: Contiging genomic DNA.

In this paper, we describe our algorithmic approach to constructing an alignment of (contiging) a set of restriction maps created from the images of individual genomic (uncloned) DNA molecules digested by restriction enzymes. Generally, these DNA segments are sized in the range of 1-4 Mb. The goal is to devise contiging algorithms capable of producing high-quality composite maps rapidly and in a scaleable manner. The resulting software is a key component of our physical mapping automation tools and has been used to create complete maps of various microorganisms (E. coli, P. falciparum and D. radiodurans). Experimental results match known sequence data.

Algorithms↗
PubMed2002

Intraoperative optical intrinsic signal imaging: a clinical tool for functional brain mapping.

Optical imaging of intrinsic signals (OIS) is a well-established neuroimaging modality by which functional cortical activity is mapped by detecting activity-related changes in cortical light reflectance. Light reflectance changes are detected by a charged-coupled device camera that captures images of the exposed cortex both at rest and during activity. Although to date OIS has only been used for research purposes, intraoperative OIS (iOIS) holds promise as a clinical mapping tool. In general, iOIS demonstrates good spatial correlation with electrocortical stimulation mapping (ECSM) and other electrophysiological modalities. Additionally, iOIS offers high spatial resolution (in microns), does not make contact with the surface of the brain, and introduces no potentially harmful compounds. Moreover, mapping is relatively rapid. The authors review the potential contribution of iOIS to the intraoperative environment. Specifically, they review iOIS methodology, discuss signal origin, compare OIS with other functional mapping modalities, and explain its potential benefits and limitations. They propose that iOIS may, in the future, be used in conjunction with ECSM to improve the resolution and accuracy of intraoperative mapping, decrease total time of intraoperative mapping, and possibly improve neurological outcomes. Additional studies will be required to quantify the sensitivity and specificity of optical maps relative to ECSM before it can be implemented clinically.

Brain Mapping↗
PubMed1998

A uniform framework for ordered restriction map problems.

Optical Mapping is an emerging technology for constructing ordered restriction maps of DNA molecules. The underlying computational problems for this technology have been studied and several models have been proposed in recent literature. Most of these propose combinatorial models; some of them also present statistical approaches. However, it is not a priori clear as to how these models relate to one another and to the underlying problem. We present a uniform framework for the restriction map problems where each of these various models is a specific instance of the basic framework. We achieve this by identifying two "signature" functions f() and g() that characterize the models. We identify the constraints these two functions must satisfy, thus opening up the possibility of exploring other plausible models. We show that for all of the combinatorial models proposed in literature, the signature functions are semi-algebraic. We also analyze a proposed statistical method in this framework and show that the signature functions are transcendental for this model. We also believe that this framework would provide useful guidelines for dealing with other inferencing problems arising in practice. Finally, we indicate the open problems by including a survey of the best known results for these problems.

Algorithms↗
PubMed1999

An EM-type Algorithm for Ordered Restriction Map Alignment.

Constructing restriction maps is one of the important steps towards the determination of DNA sequences. Recently, the single-molecule approaches to constructing restriction maps, such as Optical Mapping by D. Schwartz et al., have developed. In practice, with the single-molecule approach like Optical Mapping, the identification of the restriction sites is complicated by several error factors due to resolving power of biological experiments. The ordered restriction map alignment problem is a problem to estimate the actual restriction sites from many imprecise copies of map from single molecule. In this paper, we formulate the problem on the basis of the statistical maximum likelihood estimate, and propose a new efficient local search algorithm for this problem, by applying the Expectation-Maximization (EM) algorithm along with the concept of two-clustering. Our algorithm works well for a lot of sets of simulated data, some of which we believe more difficult than the actual cases.

Journal Article↗
PubMed2001

A topographic instructive signal guides the adjustment of the auditory space map in the optic tectum.

Maps of auditory space in the midbrain of the barn owl (Tyto alba) are calibrated by visual experience. When owls are raised wearing prismatic spectacles that displace the visual field in azimuth, the auditory receptive fields of neurons in the optic tectum shift to compensate for the optical displacement of the visual field. This shift results primarily from a shift in the tuning of tectal neurons for interaural time difference. The visually based instructive signal that guides this plasticity could be based on a topographic, point-by-point comparison between auditory and visual space maps or on a foveation-dependent visual assessment of the accuracy of auditory orienting responses. To distinguish between these two possibilities, we subjected owls to optical conditions that differed in the center of gaze and the visual periphery. A topographic signal would cause the portions of the space map representing the central and peripheral regions of visual space to adjust differently, according to the optical conditions that exist in each region. In contrast, a foveation-based signal would cause both portions of the map to adjust similarly, according to the optical conditions that exist at the center of gaze. In six of seven experiments, adaptive changes were as predicted by a topographic instructive signal. Although the results do not rule out the possible contribution of a foveation-based signal, they demonstrate that a topographic instructive signal is, indeed, involved in the calibration of the auditory space map in the barn owl optic tectum.

Adaptation, Physiological↗
PubMed2006

Electro-optical microscopy: mapping nonlinear polymer films with micrometric resolution.

The first demonstration, to the best of our knowledge, of electro-optical microscopy is presented and applied to a polymer-based optical device. A confocal transmission microscope with interferometric homodyne detection is implemented to measure Pockels phase shifts with micrometric spatial resolution and an accuracy level down to 4 x 10(-7) rad. This technique is applied to poled polymer films in which noncentrosymmetric molecular orientation is preliminarily achieved in the sample plane between transverse planar electrodes. The electro-optic mapping of this structure exhibits nonuniform and asymmetric patterns of the nonlinear response that are characteristic of the poling spatial inhomogeneity as confirmed by second-harmonic generation microscopy.

Journal Article↗
PubMed2026

Evaluation of the efficacy of optical genome mapping in prenatal diagnosis: a retrospective cohort study.

BACKGROUND: Optical genome mapping (OGM) is an emerging cytogenetic method for concurrently detecting structural variants (SVs) and copy number variants (CNVs). However, its clinical application in prenatal diagnosis remains underexplored. METHODS: This study retrospectively evaluated the clinical validity of OGM in prenatal diagnosis by comparing with two routine genetic testing methods: karyotyping and chromosomal microarray analysis (CMA). Both positive and negative cases detected by routine genetic methods were enrolled to evaluate the technical concordance of OGM and its capability to improve diagnostic rate in negative cases. The exclusion criteria were balanced centromeric translocations, mosaic cases with cellular fractions&#x2009;<&#x2009;20%, and loss of heterozygosity (LOH)&#x2009;<&#x2009;25&#xa0;Mb. All samples subjected to OGM testing were anonymized and analyzed blindly. The results from OGM were compared with those from routine genetic testing, and statistical analyses were performed to assess technical concordance and diagnostic rate. RESULTS: Of 217 samples (166 positive samples and 51 negative samples for routine genetic testing), all were successfully tested with OGM, including 2 umbilical cord blood samples, 4 chorionic villi samples, and 211 cultured amniotic fluid samples. Of the 207 reportable chromosomal aberrations from 166 positive samples, the blinded concordance between OGM and CMA, karyotyping, and combination of karyotyping plus CMA was 97.81%, 96.36%, and 97.10%, respectively. OGM missed six aberrations initially, including one LOH, two marker chromosomes, and three microdeletions. However, after reanalysis, its concordance improved to 100% with CMA and 99.03% with karyotyping plus CMA. OGM also diagnosed one additional case of a 3-kb deletion in 51 negative samples, improving the diagnostic rate by 1.96%. Moreover, OGM reclassified the pathogenicity of two microdeletions from pathogenic to uncertain significance in 2 positive cases. Furthermore, OGM clarified the diagnosis suspected by routine genetic testing and improved diagnostic accuracy in some cases. CONCLUSION: As far as we know, this is the largest retrospective study on OGM in prenatal diagnosis, and it includes a broad range of sample types. The results showed that OGM exhibits high concordance among the tested methods and increases the diagnostic rate. Thus, OGM has the potential to become a first-line technique for prenatal diagnosis in the future.

Humans↗
PubMed2000

Simultaneous maps of optical action potentials and calcium transients in guinea-pig hearts: mechanisms underlying concordant alternans.

1. The mechanisms underlying electro-mechanical alternans caused by faster heart rates were investigated in perfused guinea-pig hearts stained with RH237 and Rhod-2 AM to simultaneously map optical action potentials (APs) and intracellular free Ca2+ (Ca2+i). 2. Fluorescence images of the heart were focused on two 16 x 16 photodiode arrays to map Ca2+i (emission wavelength (lamdda;em) = 585 +/- 20 nm) and APs (lamdda;em > 715 nm) from 252 sites. Spatial resolution was 0.8 mm x 0.8 mm per diode and temporal resolution 4000 frames s-1. 3. The mean time-to-peak for APs and [Ca2+]i was spatially homogeneous (8.8 +/- 0.5 and 25.6 +/- 5.0 ms, respectively; n = 6). The durations of APs (APDs) and Ca2+i transients were shorter at the apex and progressively longer towards the base, indicating a gradient of ventricular relaxation. 4. Restitution kinetics revealed increasingly longer delays between AP and Ca2+i upstrokes (9.5 +/- 0.4 to 11.3 +/- 0.4 ms) with increasingly shorter S1-S2 intervals, particularly at the base, despite nearly normal peak [Ca2+]i. 5. Alternans of APs and Ca2+i transients were induced by a decrease++ in cycle length (CL), if the shorter CL captured at the pacing site and was shorter than refractory periods (RPs) near the base, creating heterogeneities of conduction velocity. 6. Rate-induced alternans in normoxic hearts were concordant (long APD with large [Ca2+]i) across the epicardium, with a magnitude (difference between odd-even signals) that varied with the local RP. Alternans were initiated by gradients of RP, producing alternans of conduction that terminated spontaneously without progressing to fibrillation.

Action Potentials↗
PubMed1989

Factors influencing the structure and shape of stenotic and regurgitant jets: an in vitro investigation using Doppler color flow mapping and optical flow visualization.

To evaluate factors influencing the structure and shape of stenotic and regurgitant jets, Doppler color flow mapping and optical flow visualization studies were performed with use of a syringe model with a constant rate of ejection to simulate jets of valvular regurgitation and a pulsatile flow model of the right heart chambers to simulate jets of mild, moderate and severe valvular pulmonary stenosis. Ink-(0 to 40%) glycerol-water jets (viscosity 1 to 3.5 centiPoise) were produced by injecting the fluid at a constant rate into a 10 gallon rectangular reservoir of the same still fluid through 1.4 and 3.4 mm needles. The Doppler color flow scanners imaged the laminar jet length within 3 mm of actual jet length (2 to 6 cm) and the jet width within 2 to 3 mm of the actual jet width. Jet flows with Reynolds numbers ranging from 230 to 1,200 injected into still fluid yielded jet length/width ratios that decreased with increasing Reynolds numbers and leveled off to a length/width ratio of 5-6:1 at a Reynolds number near 600. When the fluid reservoir was swirled to better mimic the effect of flow entering the same cardiac chamber from a second source, the jets showed diminution of the jet length/width ratio and a clearly defined zone of turbulence. Studies of the pulsatile flow model were performed at cardiac outputs of 1 to 6 liters/min for the normal and each stenotic valve. Mild stenosis had an orifice area of 2.8 cm2, moderate stenosis an area of 1.0 cm2 and severe stenosis an area of 0.5 cm2. Laminar jet length represented the length of the total jet, which had a symmetric width and was measured from the valve opening to a region where the jet exhibited a spray effect. Laminar jet lengths (0.2 to 1.1 cm) were imaged by Doppler color flow mapping and optical visualization only in the moderate and severely stenotic valves and only at flows less than or equal to 3 liters/min (mean Reynolds numbers less than or equal to 3,470). Beyond this flow rate the jets exhibited a spray effect. Laminar jet length/width ratio approached unity with an increased amount of valvular stenosis and higher flow volumes (cardiac output). Proximal aliasing was present in each valve studied. the length of aliasing (0 to 3.2 cm) proximal to the valve was longer with increased flow rates and increased amounts of stenosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Flow Velocity↗
PubMed1982

Visual cells of zebrafish optic tectum: mapping with small spots.

The zebrafish optic tectum is anatomically similar to those of goldfish and other teleosts, both in its laminar structure and the morphology of intrinsic neurons as studied with Golgi stains. We have applied standard electrophysiological techniques to study the visual properties of tectal cells, utilizing a computer system for stimulus control and data recording. All tectal cells have very large receptive fields, averaging 25-39 degrees in linear dimensions. Retinal receptive fields are smaller, averaging 7-13 degrees. In many cases the receptive fields of tectal cells, but never of retinal cells, consist of two parts (main field and accessory field) separated by tens of degrees. The two parts are differentially adapted by background illumination, accessory fields becoming unresponsive under lit conditions while main fields do not. This may reflect separate retinal input channels. Four types of tectal cells are described, which differ in their spontaneous activity in the dark and response to stationary spots. Type I are not spontaneously active in the dark, but respond phasically at response to ON and OFF. Type T are tonically active and give more prolonged phasic responses to ON and OFF. They may also have pure-inhibitory receptive fields in which spot ON suppresses the spontaneous firing with no phasic excitation. Type S are also silent in the dark, but give sustained firing as long as a spot is ON in the receptive field. Cells of type B fire spontaneously in bursts; the burst rate may be raised or lowered by stationary spots, but there is no phasic response. Each of the four physiological types is found to occur among the cells of the periventricular layer, all of which share a stereotyped overall morphology. Tectal cells do not exhibit spatially separated ON and OFF areas or orientation specificity.

Animals↗
PubMed2003

Catheter ablation of ventricular fibrillation in rabbit ventricles treated with beta-blockers.

BACKGROUND: A therapeutic implication of the focal-source hypothesis of ventricular fibrillation (VF) is that VF can be terminated by focal ablation. We hypothesize that beta-adrenergic receptor blockade converts multiple-wavelet VF to focal-source VF and that this focal source is located near the papillary muscle (PM). METHODS AND RESULTS: We used optical mapping techniques to study the effects of propranolol (0.3 mg/L) on VF dynamics in Langendorff-perfused rabbit hearts. The left ventricular (LV) anterior wall was mapped and optical action potential duration restitution (APDR) was determined at 25 epicardial sites. We performed ablation during VF of the left anterior PM in hearts with (N=6) or without (N=6) cytochalasin infusion, the LV lateral epicardium (Epi group, N=3), and the LV endocardium (Endo group, N=3). The PM was also ablated in 3 hearts without propranolol (control group). Propranolol converted multiple-wavelet VF to slow VF with reentry localized to the PM. Propranolol decreased the maximal slope of the APDR curve (P<0.001) as well as its spatial heterogeneity (P<0.01) and conduction velocity (P=0.01) while increasing the VF cycle length (P<0.001). PM ablation terminated VF during propropranolol infusion with (6 of 6, 100%) or without (4 of 6, 67%) cytochalasin D and significantly reduced inducibility. VF did not terminate in the Epi, Endo, and control groups (P<0.001). CONCLUSIONS: Propranolol flattens the APDR curve and reduces conduction velocity, converting multiple-wavelet VF into VF with a focal source anchored to the PM. Ablation of this focal source may terminate VF.

Action Potentials↗
PubMed2026

Optical genome mapping improves structural variant detection and characterization in syndromic and neurogenetic disorders.

Optical Genome Mapping (OGM) offers superior resolution compared to standard diagnostic methods such as karyotyping and FISH, enabling the detection of nearly all types of chromosomal aberrations with non-centromeric breakpoints. This study evaluated OGM's potential to enhance the genetic findings in unsolved cases of neurogenetic and syndromic disease requiring further investigation after standard genetic testing. In 10 patients with various neurogenetic diagnoses, OGM confirmed all structural findings previously detected by karyotyping, chromosomal microarray (CMA), and/or NGS. Moreover, OGM provided additional structural insights in five cases, such as identifying a novel candidate gene in a patient with a balanced translocation, redefining of breakpoint regions in familial translocations, characterization of complex rearrangements, and revising of initial diagnostic interpretations. Most importantly, we present OGM results for three individuals with ring chromosomes 18, 20, and 22, highlighting the need to adjust filter settings and to incorporate the rare variant pipeline for accurate detection. Based on our experiences, we propose a strategic approach for identifying ring chromosomes using OGM. On the other hand, OGM did not identify causative variants in three unsolved cases with strong clinical suspicion of hereditary neuropathy. In summary, while OGM did not yield new insights for hereditary neuropathy, it provided additional or refined information in 6 out of 10 cases with other syndromic diseases. These findings underscore the value of OGM in increasing the diagnostic yield and precision of genetic testing.

Humans↗