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At least 253 records · Page 14Linked to original sources
PubMed2004

Direction-dependent conduction abnormalities in a canine model of atrial fibrillation due to chronic atrial dilatation.

Chronic rapid atrial pacing (RAP) leads to changes that perpetuate atrial fibrillation (AF). Chronic atrial dilatation due to mitral regurgitation (MR) also increases AF inducibility, but it is not clear whether the underlying mechanism is similar. Therefore, we have investigated atrial electrophysiology in a canine MR model (mitral valve avulsion, 1 mo) using high-resolution optical mapping and compared it with control dogs and with the canine RAP model (6-8 wk of atrial pacing at 600 beats/min, atrioventricular block, and ventricular pacing at 100 beats/min). At followup, optical action potentials were recorded using a 16 x 16 photodiode array from 2 x 2-cm left atrial (LA) and right atrial (RA) areas in perfused preparations, with pacing electrodes around the field of view to study direction dependency of conduction. Action potential duration at 80% repolarization (APD(80)) was not different between control and MR but was reduced in RAP atria. Conduction velocities during normal pacing were not different between groups. However, the MR LA showed increased conduction heterogeneity during pacing at short cycle lengths and during premature extrastimuli, which frequently caused pronounced regional conduction slowing. Conduction in the MR LA during extrastimulation also displayed a marked dependence on propagation direction. These phenomena were not observed in the MR RA and in control and RAP atria. Thus both models form distinctly different AF substrates; in RAP dogs, the decrease in APD(80) may stabilize reentry. In MR dogs, regional LA conduction slowing and increased directional dependency, allowing unidirectional conduction block and preferential paths of conduction, may account for increased AF inducibility.

Action Potentials↗
PubMed2004

Left atrial dilatation resulting from chronic mitral regurgitation decreases spatiotemporal organization of atrial fibrillation in left atrium.

Atrial conduction properties have been shown to differ among animal atrial fibrillation (AF) models of rapid atrial pacing (RAP), chronic mitral regurgitation (MR), and control. We hypothesized that these conduction differences would continue with the onset of AF, which would affect AF spatiotemporal organization, resulting in model-specific characteristics of AF. With frequency domain analysis of electrograms acquired from high-density optical mapping, AF from the right (RA) and left (LA) atrium in animals with RAP and MR were compared with control animals. At follow-up, the hearts were excised and perfused, and optical action potentials were recorded from a 2 x 2-cm area each of the RA and LA free wall with a 16 x 16 photodiode array. AF was induced with extra stimuli, several 2.4-s AF episodes were recorded in each dog, and a fast Fourier transform was calculated. The dominant frequency (DF) was determined, and the organization (organization index, OI) was calculated as the ratio of the area under the dominant peak and its harmonics to the total area of the spectrum. All possible pairs of electrograms for each episode were cross-correlated. LA AF in the chronic MR model showed an increase in the highest DF, the number of DF domains, and in frequency gradient compared with AF in control or RAP models. In addition, there was a decrease in OI and in the correlation coefficients in the LA of the MR model. These results suggest that the AF substrate in the MR model may be different from that of control or RAP models.

Animals↗
PubMed2001

[The mechanism of impulse initiation: high-resolution epicardial pace-mapping in rat heart].

UNLABELLED: Simulations of cardiac tissue bidomain model indicate that point cathodal stimulation gives rise to a dog-bone depolarized region (virtual cathode) extending across fibers, limited by two symmetric hyperpolarized regions (virtual anode) extending along fibers. These predictions were experimentally confirmed by optical mapping studies of transmembrane potentials while no direct validation is reported at the extracellular level. The present study aims at defining the influence of the virtual cathode on extracellular potentials by means of high-density epicardial mapping. METHODS: Epicardial potentials were measured in seven exposed rat hearts by means of a 11 x 11 electrode array with 360 x 540 microns resolution. Cathodal current pulses, 100-200 microA intensity and 1 ms duration, to avoid superposition of stimulus and activation potentials, were delivered from one of the electrode array and unipolar potentials were measured from all other electrodes. RESULTS AND DISCUSSION: a) During stimulus, negative equipotential lines were elliptic along fibers, as expected, but for a 2 mm circular region at the pacing site. b) During 1-2 ms interval between stimulus offset and start of activation, equipotential lines became elliptic across fibers in the presence of the region directly excited by the stimulus field. Start of activation was either symmetric with isochrones initially circular around the pacing site and then elliptic along fibers, or asymmetric initiating at only one side of the pacing site across fibers with isochrones elliptic along fibers. In the latter case, the wave front was blocked through the refractory region directly excited by the stimulus field, subdivided into two wings which collided and merged at the opposite side, giving rise to a plane wave front propagating across fibers away from the pacing site. CONCLUSIONS: High spatial resolution epicardial potential mapping reveals the existence of the virtual cathode and its influence on impulse initiation and conduction. The unexpected existence of a region of conduction block at the pacing site, due to spatial asymmetry of normal cardiac tissue which enhances activation threshold at one of the two sides of the virtual cathode, is intriguing since it is one of the requirements for reentry of conduction in the presence of a circuit with decreased conduction velocity and short duration of refractory period.

Animals↗
PubMed2004

Molecular mechanisms and global dynamics of fibrillation: an integrative approach to the underlying basis of vortex-like reentry.

Art Winfree's scientific legacy has been particularly important to our laboratory whose major goal is to understand the mechanisms of ventricular fibrillation (VF). Here, we take an integrative approach to review recent studies on the manner in which nonlinear electrical waves organize to result in VF. We describe the contribution of specific potassium channel proteins and of the myocardial fiber structure to such organization. The discussion centers on data derived from a model of stable VF in the Langendorff-perfused guinea pig heart that demonstrates distinct patterns of organization in the left (LV) and right (RV) ventricles. Analysis of optical mapping data reveals that VF excitation frequencies are distributed throughout the ventricles in clearly demarcated domains. The highest frequency domains are found on the anterior wall of the LV at a location where sustained reentrant activity is present. The optical data suggest that a high frequency rotor that remains stationary in the LV is the mechanism that sustains VF in this model. Computer simulations predict that the inward rectifying potassium current (IK1) is an essential determinant of rotor stability and frequency, and patch-clamp results strongly suggest that the outward component of IK1 of cells in the LV is significantly larger than in the RV. Additional computer simulations and analytical procedures predict that the filaments of the reentrant activity (scroll waves) adopt a non-random configuration depending on fiber organization within the ventricular wall. Using the minimal principle we have concluded that filaments align with the trajectory of least resistance (i.e. the geodesic) between their endpoints. Overall, the data discussed have opened new and potentially exciting avenues of research on the possible role played by inward rectifier channels in the mechanism of VF, as well as the organization of its reentrant sources in three-dimensional cardiac muscle. Such an integrative approach may lead us toward an understanding of the molecular and structural basis of VF and hopefully to new preventative approaches.

Action Potentials↗
PubMed2003

Spatiotemporal correlation between phase singularities and wavebreaks during ventricular fibrillation.

UNLABELLED: Phase Singularity and Wavebreak. INTRODUCTION: Phase maps and the detection of phase singularities (PSs) have become a well-developed method for characterizing the organization of ventricular fibrillation (VF). How precisely PS colocalizes with wavebreak (WB) during VF, however, is unknown. METHODS AND RESULTS: We performed optical mapping of 27 episodes of VF in nine Langendorff-perfused rabbit hearts. A WB is a point where the activation wavefront and the repolarization waveback meet. A PS is a site where its phase is ambiguous and its neighboring pixels exhibit a continuous phase progression from -pi to +pi. The correlation coefficient between the number of WBs and PSs was 0.78 +/- 0.09 for each heart and 0.81 for all VF episodes (P < 0.001), indicating a significant temporal correlation. We then superimposed the WBs and PSs for every 100 frames of each episode. These maps showed a high degree of spatial colocalization. To quantify spatial colocalization, the spatial shifts between the cumulative maps of WBs and PSs in corresponding frames were calculated by automatic alignment to obtain maximum overlap between these two maps. The spatial shifts were 0.04 +/- 0.31 mm on the x-axis and 0.06 +/- 0.27 mm on the y-axis over a 20 x 20 mm2 mapped field, indicating highly significant spatial correlation. CONCLUSION: Phase mapping provides a convenient and robust approach to quantitatively describe wave propagation and organization during VF. The close spatiotemporal correlation between PSs and WBs establishes that PSs are a valid alternate representation of WB during VF and further validated the use of phase mapping in the study of VF dynamics.

Action Potentials↗
PubMed2000

Distribution of excitation frequencies on the epicardial and endocardial surfaces of fibrillating ventricular wall of the sheep heart.

Tissue heterogeneities may play an important role in the mechanism of ventricular tachycardia (VT) and fibrillation (VF) and can lead to a complex spatial distribution of excitation frequencies. Here we used optical mapping and Fourier analysis to determine the distribution of excitation frequencies in >20 000 sites of fibrillating ventricular tissue. Our objective was to use such a distribution as a tool to quantify the degree of organization during VF. Fourteen episodes of VT/VF were induced via rapid pacing in 9 isolated, coronary perfused, and superfused sheep ventricular slabs (3x3 cm(2)). A dual-camera video-imaging system was used for simultaneous optical recordings from the entire epi- and endocardial surfaces. The local frequencies of excitation were determined at each pixel and displayed as dominant frequency (DF) maps. A typical DF map consisted of several (8.2+/-3.6) discrete areas (domains) with a uniform DF within each domain. The DFs in adjacent domains were often in 1:2, 3:4, or 4:5 ratios, which was shown to be a result of an intermittent Wenckebach-like conduction block at the domain boundaries. The domain patterns were relatively stable and could persist from several seconds to several minutes. The complexity in the organization of the domains, the number of domains, and the dispersion of frequencies increased with the rate of the arrhythmia. Domain patterns on the epicardial and endocardial surfaces were not correlated. Sustained epicardial or endocardial reentry was observed in only 3 episodes. Observed frequency patterns during VT/VF suggest that the underlying mechanism may be a sustained intramural reentrant source interacting with tissue heterogeneities.

Animals↗
PubMed1989

Photoreceptor topography of the retina in the adult pigtail macaque (Macaca nemestrina).

In spite of the crucial role retinal photoreceptors play in mapping optical images into a pattern of neural excitation, there are no complete studies of photoreceptor topography in any primate retina. We have measured the spatial density and inner segment areas of cones and rods across the whole mounted retinas of three adult pigtail macaques (Macaca nemestrina) and constructed maps of photoreceptor density and inner segment diameter. These retinas contain an average of 3.1 million cones (2.8-3.3 million), with an average peak foveal cone density of 210,000 cones/mm2 (190,000-260,000 cones/mm2). Cone density falls steeply with increasing eccentricity, to 100,000 cones/mm2 at 200 microns from the fovea, and to 50,000 cones/mm2 at 750 microns. Imposed on this gradient is a "streak" of higher cone density along the horizontal meridian. At equivalent eccentricities, cone density is higher in nasal and inferior retina. Cone inner segments increase in diameter from 2.3 microns at the foveal center to 11 microns in far temporal retina and 10 microns in far nasal retina. These retinas contain an average of 60.1 million rods (44.9-75.3 million). Rod density is zero within 20 microns of the foveal center, increases to the crest of a "rod ring" at the eccentricity of the optic disk, and then declines. Central rod topography is asymmetric, with higher densities in superior retina. Density along the crest of the rod ring peaks in superior retina at 177,000 rods/mm2, dips as low as 120,000 rods/mm2 along the horizontal meridian, and increases to about 150,000 rods/mm2 in inferior retina. Far peripheral rod topography is relatively symmetric around the fovea. Rod inner segment diameter ranged from 1.5 microns in the fovea to 4 microns at the temporal edge and 3.4 microns at the nasal edge of the retina. At eccentricities exceeding 6 mm, rod inner segment diameter was greater temporally than nasally. Cone inner segments cover 85-90% of the central fovea, with extrareceptor space accounting for the remainder. Cone coverage declines with increasing eccentricity to 20% at the temporal edge and 35% at the nasal edge of the retina. In contrast, rod coverage increases from zero at the foveal center to a maximum of 65% in temporal retina and 50% in nasal retina. The photoreceptor topography of the pigtail macaque is qualitatively similar to that of other macaques and to humans. Photoreceptor topography is formed by a complex interaction between regional changes in cone and rod density and inner segment diameter.

Animals↗
PubMed2004

Correction of motion artifact in transmembrane voltage-sensitive fluorescent dye emission in hearts.

Fast voltage-sensitive dyes are widely used to image cardiac electrical activity. Typically, the emission spectrum of these fluorochromes is wavelength shifted with altered membrane potential, but the optical signals obtained also decay with time and are affected by contraction. Ratiometry reduces, but may not fully remove, these artifacts. An alternate approach has been developed in which the time decay in simultaneously acquired short- and long-wavelength signals is characterized nonparametrically and removed. Motion artifact is then identified as the time-varying signal component common to both decay-corrected signals and subtracted. Performance of this subtraction technique was compared with ratiometry for intramural optical signals acquired with a fiber-optic probe in an isolated, Langendorff-perfused pig heart preparation (n = 4) stained with di-4-ANEPPS. Perfusate concentration of 2,3-butanedione monoxime was adjusted (7.5-12.5 mM) to alter contractile activity. Short-wavelength (520-600 nm) and long-wavelength (>600 nm) signals were recorded over 8-16 cardiac cycles at 6 sites across the left ventricular free wall in sinus rhythm and during pacing. A total of 451 such data sets were acquired. Appreciable wall motion was observed in 225 cases, with motion artifact classed as moderate (less than modulation due to action potential) in 187 and substantial (more than modulation due to action potential) in 38. In all cases, subtraction performed as well as, or better than, ratiometry in removing motion artifact and decay. Action potential morphology was recovered more faithfully by subtraction than by ratiometry in 58 of 187 and 31 of 38 cases with moderate and substantial motion artifact, respectively. This novel subtraction approach may therefore provide a means of reducing the concentration of uncoupling agents used in cardiac optical mapping studies.

Action Potentials↗
PubMed1995

[A study of the intraorbital blood flow using ultrasound color Doppler mapping images in optic canal fracture cases].

Ultrasound color Doppler flow mapping image (CFMI) equipment, SSA-270A (Toshiba Co) was used to measure the blood flow velocity of the ophthalmic artery (OA) and the central retinal artery (CA) in eyes with optic canal fracture. The maximal blood flow velocity (V max), the minimal blood flow velocity (V min), the mean blood flow velocity (V mean), and the resistance index (RI) before and after transethmoidal decompression of the optic nerve were compared. The examination was conducted on 13 patients. There was no difference in blood flow velocity in the CA after the operation. Pre-operative V max and RI of the OA in the damaged eyes were lower than in normal eyes, but they increased the day after the operation. We measured the intraorbital blood flow velocity by CFMI because ultrasound does not penetrate bone. Since the peripheral artery from the optic foramen did not change after the operation, we concluded that the peripheral blood flow of OA had been quantitatively improved by the trans-ethmoidal decompression of the optic nerve.

Adolescent↗
PubMed2000

Structure of the set of paraxial optical systems.

The set of paraxial optical systems is the manifold of the group of symplectic matrices. The structure of this group is nontrivial: It is not simply connected and is not of an exponential type. Our analysis clarifies the origin of the metaplectic phase and the inherent limitations for optical map fractionalization. We describe, for the first time to our knowledge, an image girator and a cross girator whose geometric and wave implementations are of interest.

Lenses↗
PubMed2005

The Gurvich waveform has lower defibrillation threshold than the rectilinear waveform and the truncated exponential waveform in the rabbit heart.

Implantable cardioverter defibrillator studies have established the superiority of biphasic waveforms over monophasic waveforms. However, external defibrillator studies of biphasic waveforms are not as widespread. Our objective was to compare the defibrillation efficacy of clinically used biphasic waveforms, i.e., truncated exponential, rectilinear, and quasi-sinusoidal (Gurvich) waveforms in a fibrillating heart model. Langendorff-perfused rabbit hearts (n = 10) were stained with a voltage-sensitive fluorescent dye, Di-4-ANEPPS. Transmembrane action potentials were optically mapped from the anterior epicardium. We found that the Gurvich waveform was significantly superior (p < 0.05) to the rectilinear and truncated exponential waveforms. The defibrillation thresholds (mean +/- SE) were as follows: Gurvich, 0.25 +/- 0.01 J; rectilinear-1, 0.34 +/- 0.01 J; rectilinear-2, 0.33 +/- 0.01 J; and truncated exponential, 0.32 +/- 0.02 J. Using optically recorded transmembrane responses, we determined the shock-response transfer function, which allowed us to predict the cellular response to waveforms at high accuracy. The passive parallel resistor-capacitor model (RC-model) predicted polarization superiority of the Gurvich waveform in the myocardium with a membrane time constant (taum) of less than 2 ms. The finding of a lower defibrillation threshold with the Gurvich waveform in an in vitro model of external defibrillation suggests that the Gurvich waveform may be important for future external defibrillator designs.

Action Potentials↗
PubMed2005

Development of magnetic resonance imaging contrast material for in vivo mapping of tissue transglutaminase activity.

Transglutaminases are a family of enzymes that play an important role in tissue remodeling by catalyzing covalent cross-links between proteins of the extracellular matrix. Elevated activity of transglutaminase was shown at the boundaries of invading tumors, in association with angiogenesis, in stabilization of atherosclerotic plaques, and in generation of blood clots. The aim of this work was to develop a low molecular weight substrate of transglutaminase that could serve for noninvasive magnetic resonance and optical mapping of transglutaminase-mediated cross-linking activity. A 2 kDa contrast material was generated which showed cross-linking by either tissue transglutaminase or factor XIII in the context of multicellular tumor spheroids or fibrin clots, respectively. Successful detection by nuclear magnetic resonance microscopy of transglutaminase-mediated cross-linking of the contrast material to MCF7 multicellular spheroids provides hope that this approach could potentially be developed for clinical demarcation of sites of transglutaminase activity.

Breast Neoplasms↗
PubMed2006

History of arrhythmias.

A historical overview is given on the techniques to record the electrical activity of the heart, some anatomical aspects relevant for the understanding of arrhythmias, general mechanisms of arrhythmias, mechanisms of some specific arrhythmias and nonpharmacological forms of therapy. The unravelling of arrhythmia mechanisms depends, of course, on the ability to record the electrical activity of the heart. It is therefore no surprise that following the construction of the string galvanometer by Einthoven in 1901, which allowed high-fidelity recording of the body surface electrocardiogram, the study of arrhythmias developed in an explosive way. Still, papers from McWilliam (1887), Garrey (1914) and Mines (1913, 1914) in which neither mechanical nor electrical activity was recorded provided crucial insights into re-entry as a mechanism for atrial and ventricular fibrillation, atrioventricular nodal re-entry and atrioventricular re-entrant tachycardia in hearts with an accessory atrioventricular connection. The components of the electrocardiogram, and of extracellular electrograms directly recorded from the heart, could only be well understood by comparing such registrations with recordings of transmembrane potentials. The first intracellular potentials were recorded with microelectrodes in 1949 by Coraboeuf and Weidmann. It is remarkable that the interpretation of extracellular electrograms was still controversial in the 1950s, and it was not until 1962 that Dower showed that the transmembrane action potential upstroke coincided with the steep negative deflection in the electrogram. For many decades, mapping of the spread of activation during an arrhythmia was performed with a "roving" electrode that was subsequently placed on different sites on the cardiac surface with a simultaneous recording of another signal as time reference. This method could only provide reliable information if the arrhythmia was strictly regular. When multiplexing systems became available in the late 1970s, and optical mapping in the 1980s, simultaneous registrations could be made from many sites. The analysis of atrial and ventricular fibrillation then became much more precise. The old question whether an arrhythmia is due to a focal or a re-entrant mechanism could be answered, and for atrial fibrillation, for instance, the answer is that both mechanisms may be operative. The road from understanding the mechanism of an arrhythmia to its successful therapy has been long: the studies of Mines in 1913 and 1914, microelectrode studies in animal preparations in the 1960s and 1970s, experimental and clinical demonstrations of initiation and termination of tachycardias by premature stimuli in the 1960s and 1970s, successful surgery in the 1980s, the development of external and implantable defibrillators in the 1960s and 1980s, and finally catheter ablation at the end of the previous century, with success rates that approach 99% for supraventricular tachycardias.

Arrhythmias, Cardiac↗
PubMed2003

Development of an optrode for intramural multisite optical recordings of Vm in the heart.

INTRODUCTION: Optical mapping of transmembrane potential (Vm) is an important tool in the investigation of impulse propagation in the heart. It provides valuable information about spatiotemporal changes of Vm that cannot be obtained by other techniques, but it presently is limited to measurements from the heart surfaces. Therefore, the goal of this work was to develop a technique for intramural multisite optical measurements of Vm using fiberoptic technology. METHODS AND RESULTS: An optrode, a bundle of thin optical fibers, was developed for measuring intramural optical signals at multiple sites in the heart. The optrode consisted of seven fibers with diameter of 225 microm arranged in a hexagonal pattern that were used to deliver excitation light to the myocardium, to collect the emitted fluorescence, and to project the light onto a 16 x 16 array of photodiode detectors. Rabbit hearts were stained with the Vm-sensitive dye RH-237. Fluorescence was excited using a 100-W Hg lamp. Intramural action potentials were recorded at multiple sites separated by 2 mm inside the left ventricle. Signal-to-noise (RMS) ratio was 21.2 +/- 12 (n = 7) without averaging or ratiometry and with negligible cross-talk (<1.9%) between the neighboring photodiodes. The size of the recording area for an individual fiber was estimated at approximately 0.8 mm. CONCLUSION: These data demonstrate feasibility of multisite transmural measurements of Vm without signal averaging and ratiometry. This technique might become useful in studies of transmural impulse conduction during arrhythmias and defibrillation.

Action Potentials↗
PubMed1998

Differential effects of cytochalasin D and 2,3 butanedione monoxime on isometric twitch force and transmembrane action potential in isolated ventricular muscle: implications for optical measurements of cardiac repolarization.

INTRODUCTION: 2,3-Butanedione monoxime (BDM) has been widely used to inhibit contraction during optical recordings of cardiac membrane voltage changes, even though it markedly abbreviates cardiac action potentials. METHODS AND RESULTS: We compared the effects of BDM and of the F-actin disrupter cytochalasin D (cyto D) on isometric twitch force and transmembrane action potentials in isolated canine right ventricular trabeculae superfused with Tyrode's solution (2 mmol/L CaCl2, 37 degrees C) and stimulated at 0.5 Hz. BDM at 10 mmol/L and cyto D at 80 micromol/L were equally effective in reducing peak isometric force to 10%+/-3% (n = 6; mean+/-SEM) and 8%+/-1% (n = 8), respectively. Neither agent significantly altered resting tension. While 10 mmol/L BDM markedly shortened the action potential duration at 90% repolarization (APD90) from 198+/-7 msec to 146+/-9 msec (P < 0.001), 80 micromol/L cyto D had no significant effects on APD90 or on any other action potential parameter. The effects of BDM on peak isometric force and APD were completely reversible after 15 minutes of washout, whereas in the cyto D group contractile force continued to be reduced (13%+/-3%) and action potential characteristics did not show significant changes from control values after a 60-minute period of superfusion with cyto D-free Tyrode's solution. CONCLUSION: We conclude that cyto D should be considered an alternative excitation-contraction uncoupler for optical mapping studies of cardiac repolarization.

Action Potentials↗
PubMedDate not supplied

Receptive fields of primate retinal ganglion cells studied with a novel technique.

We have reinvestigated receptive-field structure of ganglion cells of the macaque parafovea using counterphase modulation of a bipartite field. Receptive fields were mapped with luminance, chromatic, and cone-isolating stimuli. Center sizes of middle (M) and long (L) wavelength cone opponent cells of the parvocellular (PC) pathway were consistent with previous estimates (Gaussian radii of 2-4 min of arc, corresponding to center diameters of 6-12 min of arc). We calculate that a large factor of the enlargement relative to cone radius could be blur due to the eye's natural optics. Maps were consistent with cone selectivity in surround mechanisms, which had radii of 5-8 min of arc. For magnocellular (MC) cells, center size estimates were also consistent with grating measurements from the literature (also Gaussian radii of 2-4 min of arc). The surround mechanism contributing the MC-cell frequency-doubled response to chromatic modulation appears to possess a subunit structure, and we speculate it derives from nonlinear summation of signals from M,L-cone opponent subunits, such as midget bipolar cells.

Animals↗
PubMedDate not supplied

Multipixel techniques for frequency-domain photon migration imaging.

The ability to map interior optical properties of a highly scattering medium from exterior measurements of light propagation is afforded by optical tomography. In this communication, we describe the problem of optical tomography, the techniques of photon migration measurements necessary to accomplish it, and the development of multipixel measurements for rapid collection of optical signals. These multipixel measurements are shown to provide detection of contrast owing to the optical properties of absorption and fluorescence associated with dye-laden heterogeneities embedded in a tissue-like scattering medium. From these rapid measurements, successful reconstruction of an interior optical property map may now be possible with clinically realistic data acquisition times. Applications for the technology arise for biomedical optical imaging for the in vivo detection of disease and the diagnosis of tissue (bio-) chemistry.

Absorption↗
PubMed2006

Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN Channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model.

BACKGROUND: The normal cardiac rhythm originates in the sinoatrial (SA) node that anatomically resides in the right atrium. Malfunction of the SA node leads to various forms of arrhythmias that necessitate the implantation of electronic pacemakers. We hypothesized that overexpression of an engineered HCN construct via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing in vivo. METHODS AND RESULTS: Using various electrophysiological and mapping techniques, we examined the effects of in situ focal expression of HCN1-DeltaDeltaDelta, the S3-S4 linker of which has been shortened to favor channel opening, on impulse generation and conduction. Single left ventricular cardiomyocytes isolated from guinea pig hearts preinjected with the recombinant adenovirus Ad-CMV-GFP-IRES-HCN1-DeltaDeltaDelta in vivo uniquely exhibited automaticity with a normal firing rate (237+/-12 bpm). High-resolution ex vivo optical mapping of Ad-CGI-HCN1-DeltaDeltaDelta-injected Langendorff-perfused hearts revealed the generation of spontaneous action potentials from the transduced region in the left ventricle. To evaluate the efficacy of our approach for reliable atrial pacing, we generated a porcine model of sick-sinus syndrome by guided radiofrequency ablation of the native SA node, followed by implantation of a dual-chamber electronic pacemaker to prevent bradycardia-induced hemodynamic collapse. Interestingly, focal transduction of Ad-CGI-HCN1-DeltaDeltaDelta in the left atrium of animals with sick-sinus syndrome reproducibly induced a stable, catecholamine-responsive in vivo "bioartificial node" that exhibited a physiological heart rate and was capable of reliably pacing the myocardium, substantially reducing electronic pacing. CONCLUSIONS: The results of the present study provide important functional and mechanistic insights into cardiac automaticity and have further refined an HCN gene-based therapy for correcting defects in cardiac impulse generation.

Animals↗