Carol Stillson

Electrophysiological Effects of Long, Linear Atrial Lesions Placed Under Intracardiac Ultrasound Guidance

BACKGROUND A curative atrial fibrillation procedure will most likely rely on creating transmural linear ablative lesions. However, it is currently unknown whether endocardial radiofrequency lesions can create lines of conduction block. METHODS AND RESULTS In six pigs, intracardiac echocardiography was used to guide the positioning of multiple coil array catheters to bridge endocardial structures in three right atrial locations: (1) from the crista terminalis to the tricuspid annulus; (2) from the fossa ovalis to the crista terminalis; and (3) from the inferior vena cava to the tricuspid annulus. Once the catheter was positioned, linear lesions were made by radiofrequency energy applied sequentially to each of the four coils. After 15 days, the chest was opened and a 112-electrode epicardial plaque was positioned over the atrial free wall lesion to determine activation patterns. Three lesions were placed in each animal, with a mean procedure time of 47+/-11 minutes. Once adequate contact was determined by intracardiac echocardiography, a single series of radiofrequency application was required to achieve tissue heating (65+/-4 degrees C) with a power of 21+/-10 W. Epicardial mapping demonstrated complete conduction block across the lesions in all animals, with split potentials and disparate activation times (64+/-16 ms) across the lesion. At autopsy, all lesions were discrete, continuous, and without evidence of charring. The lesions were within 0.3+/-0.5 mm of their targeted anatomic locations and measured 21+/-4 mm long and 2.8+/-0.6 mm wide. Histology revealed transmural fibrosis throughout the length of each lesion. CONCLUSIONS Linear lesions that are electrophysiologically transmural and continuous can be placed in the right atrium of normal pigs. With intracardiac echocardiography, adequate tissue contact over several coil electrodes can be ensured, resulting in short procedure times, efficient energy application, and accurate anatomically linked lesion placement.

Radiofrequency Catheter Modification of Sinus Pacemaker Function Guided by Intracardiac Echocardiography

BACKGROUND The sinus P wave arises from a pacemaker complex distributed along the crista terminalis. We investigated the feasibility of modification of sinus pacemaker function using graded applications of radiofrequency energy along the crista terminalis in dogs to achieve sinus rate control. METHODS AND RESULTS Modification of sinus pacemaker function (30 +/- 5% reduction in intrinsic heart rate with retention of a normal P-wave axis) was performed in 11 dogs (group 1). Total sinus pacemaker ablation (> 50% reduction in intrinsic heart rate with development of a low ectopic atrial or a junctional rhythm) was performed in 4 dogs (group 2). Intracardiac echocardiography was used to identify the crista terminalis as an anatomic marker of sinus node location. Sinus pacemaker modification caused a significant decrease in intrinsic heart rate (31% reduction, P < .001), heart rate responsiveness to isoproterenol (30% reduction, P < .0001), and average (20% reduction, P = .0002) and maximal (22% reduction, P = .0007) heart rates during 24-hour Holter monitoring. In 6 of the 11 animals, the targeted rate reduction of 30 +/- 5% was accurately achieved (mean, 31.6 +/- 4.3%; P < .001), and in the other 5, significant reduction of intrinsic heart rate was achieved but with greater variation (28.0 +/- 17.3%, P < .005). Corrected sinus node recovery time was not prolonged. After modification, earliest activation was mapped to the crista terminalis inferior to the lesion in all animals. In long-term follow-up (3.7 +/- 1.0 months), effects were maintained. After total sinus pacemaker ablation, junctional and low atrial escape pacemakers were unstable. CONCLUSIONS This study demonstrates the feasibility of modification of sinus pacemaker function for sinus rate control using catheter-based radiofrequency ablation guided by intracardiac echocardiography. This can be done while pacemaker stability and attenuated responsiveness to autonomic influences are preserved. Intracardiac echocardiography accurately defined the crista terminalis and provided a reliable means to anatomically localize catheter position in relation to the sinus node.

Heterogeneous Sympathetic Innervation in German Shepherd Dogs With Inherited Ventricular Arrhythmia and Sudden Cardiac Death

BACKGROUND Recently, a colony of German shepherd dogs with inherited spontaneous cardiac arrhythmias and associated sudden death has been developed and characterized. Due to the median age of onset of the arrhythmia (4.5 months), the tendency for the arrhythmia to occur during REM sleep or after exercise, and the absence of structural heart disease, we hypothesized a developmental abnormality of the sympathetic innervation to the heart. METHODS AND RESULTS We studied 11 dogs from this colony, ranging in age from 6 months to 6 years, and four 7-month-old German shepherd dogs unrelated to the colony as controls. We imaged the distribution of functional myocardial sympathetic innervation and perfusion with [123I]metaiodobenzylguanidine (MIBG) and 201Tl, respectively. Sympathetic nerve distribution was evaluated morphologically by immunocytochemical localization of tyrosine hydroxylase. All of the hearts showed evidence of a regional decrease in MIBG uptake, ranging from 5.3% to 53.4% of the myocardium, whereas control dogs showed homogeneous MIBG uptake. Immunocytochemical studies on sections from regions with decreased MIBG uptake showed a striking paucity of nerves compared with regions with normal MIBG uptake, confirming denervation. When the dogs were grouped into those with (n=6) and without (n=5) evidence of ventricular tachycardia on ambulatory ECG, the group with ventricular tachycardia showed 35+/-16.5% denervation, whereas the group without ventricular tachycardia showed 12+/-5.6% denervation (P<.02). CONCLUSIONS Abnormal heterogeneous sympathetic innervation exists in these dogs with inherited ventricular arrhythmia and sudden cardiac death. Mechanisms relating the presence and extent of regional denervation to the incidence of ventricular arrhythmia remain to be defined.

Safety and Efficacy of Endovascular Cooling and Rewarming for Induction and Reversal of Hypothermia in Human-Sized Pigs

Background and Purpose— Numerous studies indicate that mild hypothermia provides substantial neuroprotection. However, current systems transfer insufficient heat to rapidly vary core temperature. We thus evaluated the safety and efficacy of endovascular cooling and rewarming for the induction and reversal of hypothermia. Methods— In 10 anesthetized pigs (weight, 66±2 kg), a heat-exchange balloon catheter was inserted into the inferior vena cava and used to cool to a core temperature of 32°C and then rewarm to normothermia. Control animals had 38°C saline infused. Venous blood was sampled before, during, and after cooling. Three animals in each group were killed 1 week later, and the lungs and inferior vena cava were removed for gross and microscopic examination. In 5 additional animals, cardiac output was measured during cooling to 32°C. Results— Body temperature in the hypothermic animals decreased at a rate of 4.5±0.4°C/h. Animals were subsequently rewarmed to 36.0±0.04°C at 2.5±0.2°C/h. There was no difference in heart rate between hypothermic and control animals, whereas systolic pressure decreased during cooling. Cardiac output was well maintained during cooling. There were no thermal effects on blood elements or blood vessels. Conclusions— The endovascular heat-exchange system effectively cooled and rewarmed pigs with large thermal mass without producing any adverse effects on blood elements, blood vessel integrity, or cardiovascular function.

Heterogeneous Sympathetic Innervation Influences Local Myocardial Repolarization in Normally Perfused Rabbit Hearts

BACKGROUND Heterogeneity of sympathetic innervation is thought to contribute to the potential for fatal arrhythmia. However, little is known about the effects of heterogeneous innervation on repolarization. METHODS AND RESULTS To assess this relationship, we measured activation recovery intervals (ARIs) from 64 epicardial sites in 11 rabbits studied 2 weeks after regional denervation produced by phenol and 4 sham-operated rabbits. ARI results were compared with the distribution of sympathetic innervation measured from 3D reconstructions of serial autoradiographs of [(125)I]metaiodobenzylguanidine and (99m)Tc-sestamibi. ARIs were recorded during baseline sinus rhythm, norepinephrine (NE) infusion (0.1 microg. kg(-1). min(-1)), and left stellate ganglion stimulation (SS). NE shortened ARI in 98% of electrodes in the denervated region. The degree of ARI shortening and dispersion increased (P<0.001 and P<0.01, respectively) as denervation became more severe. SS shortened ARI in 30% of electrodes in the denervated area, with increased shortening and dispersion related to increased severity of denervation (P<0.01). SS prolonged ARI in 70% of electrodes in the denervated area, with no correlation with severity of denervation. CONCLUSIONS The magnitude and dispersion of local repolarization responses are related to the severity of denervation, as well as the type of stimulation: neural (SS) versus humoral (NE). The differences may relate to the concentration of NE released.

The effect of a peptide-modified thermo-reversible methylcellulose on wound healing and LV function in a chronic myocardial infarction rodent model

Myocardial infarction is the main contributor to heart failure. In this study we examined whether modification of a thermo-reversible cellulose-based polymer with extracellular-matrix derived functional groups could promote wound healing and improve cardiac function in a chronic rodent model of ischemic cardiomyopathy. To beneficially influence the microenvironment of the injured myocardium, we conjugated either the RGD peptide or the HepIII peptide to the polymer. In vitro cell adhesion studies showed that the peptide-modified polymer promoted cell attachment to the polymer surface. Injection of the thermo-reversible polymer into the aneurismal infarct region of the left ventricle showed that the peptide-modified polymer exhibited significantly improved left ventricular function, increased angiogenesis, decreased infarct size, and an increase in cardiomyocytes within the infarct region at 5 weeks post-treatment (P < 0.05). The results of this study demonstrate that a peptide-modified thermo-reversible polymer has the capability to alter left ventricular (LV) geometry, increase LV function, and promote myocardial regeneration in a chronic model of ischemic cardiomyopathy.

Combined SPECT and x-ray CT medical imaging system

We have designed and built a system for correlated x ray CT transmission and SPECT emission imaging with an array of photon counting detectors. The scanner operates in a third generation fan beam geometry by translating a 23 element high purity germanium detector across the fan to image phantoms and small animals. The x ray CT image is used to obtain an object specific, i.e., anatomically accurate, attenuation map for the reconstruction of the SPECT image. SPECT images are reconstructed with an MLEM code and the pixel values are scaled in physical units by determining a scaling factor from a uniform water phantom with homogeneous and known attenuation. Single myocardial slices of several pigs were imaged with a 99mTc sestamibi imaging agent which is taken up in proportion to regional myocardial blood flow. The results show that 99mTc uptake and regional myocardial blood flow, determined in vivo from reconstructed SPECT images, correlate with the measured in vitro data. Furthermore, the correlation is markedly improved by reconstructing the images with an object specific attenuation map obtained from the coregistered x ray CT image. We were also able to restore the 99mTc sestamibi uptake from the reconstructed images to an accuracy between 40% and 90% of the true in vitro value, depending on the selection of maximum or mean pixel values in the regions of interest.

Myocardial perfusion imaging with a correlated X-ray CT and SPECT system: an animal study

We have performed a quantitative SPECT study in a porcine model of myocardial perfusion with the correlated X-ray CT transmission and SPECT emission (ETCT) system developed at UCSF. Pixel values in the reconstructed SPECT images were calibrated in units of activity concentration and compared with the activity concentration determined from corresponding excised myocardial tissue samples. An object specific attenuation map was obtained by linear scaling from the X-ray CT. Attenuation maps with lower spatial resolution and higher signal to noise ratio were also derived from the X-ray CT image. The pixel values and intensity distribution in reconstructed myocardial SPECT image was not sensitive to spatial resolution or noise in the transmission map for the given examples. An MLEM algorithm with regularization was used to determine mean and maximum pixel values for ROIs in the myocardial SPECT images. The use of the maximum pixel value did not sufficiently compensate for contrast degradation due to partial volume errors. A separate measurement of the myocardial wall thickness was used to adequately correct for partial volume errors.

The relationship of myocardial contraction and electrical excitation—the correlation between scintigraphic phase image analysis and electrophysiologic mapping

BackgroundPhase imaging derived from equilibrium radionuclide angiography presents the ventricular contraction sequence. It has been widely but only indirectly correlated with the sequence of electrical myocardial activation.ObjectivesWe sought to determine the specific relationship between the sequence of phase progression and the sequence of myocardial activation, contraction and conduction, in order to document a noninvasive method that could monitor both.MethodsIn 7 normal and 9 infarcted dogs, the sequence of phase angle was correlated with the epicardial activation map in 126 episodes of sinus rhythm and pacing from three ventricular sites.ResultsIn each episode, the site of earliest phase angle was identical to the focus of initial epicardial activation. Similarly, the serial contraction pattern by phase image analysis matched the electrical epicardial activation sequence completely or demonstrated good agreement in approximately 85% of pacing episodes, without differences between normal or infarct groups.ConclusionsA noninvasive method to accurately determine the sequence of contraction may serve as a surrogate for the associated electrical activation sequence or be applied to identify their differences.

Endovascular biopsy: Technical feasibility of novel endothelial cell harvesting devices assessed in a rabbit aneurysm model

The lack of safe and reliable methods to sample vascular tissue in situ limits discovery of the underlying genetic and pathophysiological mechanisms of many vascular disorders, including aneurysms. We investigated the feasibility and comparable efficacy of in vivo vascular endothelial cell sampling using a spectrum of endovascular devices. Using the rabbit elastase carotid aneurysm model we evaluated the performance of existing aneurysmal coils, intracranial stents, and stent-like devices to collect vascular endothelial cells. Additionally, we modified a subset of devices to assess the effects of alterations to coil pitch, coil wire contour, and stent surface finishing. Device performance was evaluated by (1) the number of viable endothelial cells harvested, (2) the degree of vascular wall damage analyzed using digital subtraction angiography and histopathological analysis, and (3) the ease of device navigability and retrieval. Isolated cells underwent immunohistochemical analysis to confirm cell type and viability. Coil and stent specifications, technique, and endothelial cell counts were tabulated and statistical analysis performed. Using conventional detachable-type and modified aneurysm coils 11 of 14 (78.6%) harvested endothelial cells with a mean of 7.93 (±8.33) cells/coil, while 15 of 15 (100%) conventional stents, stent-like devices and modified stents harvested endothelial cells with a mean of 831.33 (±887.73) cells/device. Coil stiffness was significantly associated with endothelial cell count in univariate analysis (p = 0.044). For stents and stent-like devices univariate analysis demonstrated stent-to-aorta diameter ratios (p = 0.001), stent length (p = 0.049), and the use of a pulling retrieval technique (p = 0.019) significantly predictive of endothelial cell counts, though a multivariate model using these variables demonstrated only the stent-to-aorta diameter ratio (p = 0.029) predictive of endothelial cell counts. Modified devices did not significantly impact harvesting. The efficacy and safety of existing aneurysm coils, intracranial stents and stent-like devices in collecting viable endothelial cells was confirmed. The technique is reproducible and the quantity and quality of collected endothelial cells is adequate for targeted genetic analysis.