Limited data exist on the utilization of a transvenous A-sense; V-pace/sense (VDD) pacing system with a chronically retained nonfunctioning endocardial V-sense/pace (VVI) pacing lead. In an acute canine model, no atrial oversensing was observed with lead-lead interaction between the VDD lead and the pseudo-retained VVI lead. Undersensing occurred < 10% of all beats observed.

Hyperammonemia-induced increases in brain lactate have been studied mainly with protocols designed to mimic hepatic encephalopathy, but it has been suggested that there is a physiological flux of ammonium from neurons to astrocytes as part of glutamate-glutamine shuttling (1). In vitro, ammonium activates enzymes of glycolysis and inhibits the TCA cycle, and so tends to increase lactate production. Also, NH4 + is avidly taken up by astrocytes (2,3) and there is evidence for a metabolic flux through lactate in the brain during normal activity (4). Minimum conditions for a possible role of ammonium in regulating lactate production are that ammonium-induced increases in lactate be rapid and reversible. We have used localized 1H NMR spectroscopy at 7 Tesla to monitor changes in the concentrations of brain metabolites. Rats were anæsthetised with 5% isofluorane and maintained with mechanical ventilation with 1–1.5% isofluorane in air enriched with O2 to 35%. A 4 x 4 x 4 mm 3 voxel was centred on the striatum, the echo time was 136 ms, and spectra were acquired over 3 min 12 s. We measured the areas of peaks corresponding to choline compounds (tCho), creatine /creatineP (tCr), N-acetyl aspartate (NAA) and lactate. In Fig. 1, when 1M NaCl was infused through a femoral vein over 4 min at a rate that gave a total quantity of 2.5 mmol/(kg body wt) the lactate signal did not change. A second infusion, identical except that NaCl was replaced by NH4Cl, caused lactate to increase 5-fold. All but about 2.4% of the ammonium had been cleared from the blood by 1 min after the end of the infusion. On average, control infusions of NaCl caused no change in the signals for lactate or other metabolites except for tCr (–3.07%, s.e.m. = 0.81%, 5 infusions in 5 rats, P < 0.02, all Ps by Student’s twotailed t test). With NH4Cl, the lactate signal started to increase during the infusion and reached a peak 3.10 ± 0.35 times baseline (P < 0.0001) at 13.2 ± 2.1 min after the infusion (9 infusions in 5 rats). It then recovered halfway to baseline by 31.2 ± 5.7 min after the infusion. tCr and tCho signals were unchanged. The NAA signal increased by 3.52 ± 0.68% (P < 0.0006). In parallel experiments, changes in cerebral blood flow were measured by inverting the magnetization of water protons in the carotid arteries and detecting the ensuing signal changes in the brain (5). After ammonium infusion, cerebral blood flow increased by a factor of 2.15 ± 0.16 (5 infusions in 3 rats, P = 0.0002), suggesting that the lactate increase was not caused by hypoxia. Ammonium-induced increases in lactate signal could be observed at least three times in one experiment. Figure 1. Time course of changes in the area of the lactate peak in an illustrative experiment. Infusion of NaCl over 4 min caused no change, but NH4Cl did. Data acquisition lasting 3 min 12 s was started simultaneously with the beginning of the NH4Cl infusion, and this point already showed an increase. Benjamin A & Quastel J (1975). J Neurochem 25, 197-206.

Background— Pharmacological ventricular rate control is an acceptable atrial fibrillation (AF) therapy limited by systemic toxicity. We postulate that focal catheter-based drug delivery into the atrioventricular nodal (AVN) region may effectively control ventricular rate during AF without systemic toxicity. This study evaluated the effects of focally administered acetylcholine on AVN conduction and refractoriness during sinus rhythm and AF. Methods and Results— Canines (n=7) were anesthetized and instrumented to assess cardiac electrophysiology and blood pressure. A custom drug delivery catheter was implanted in the AVN region. Incremental doses of acetylcholine starting at 10 &mgr;g/min were infused until complete AV block was achieved. Acetylcholine induced dose-dependent AV block. AF induction and electrophysiology measurements were performed during baseline and acetylcholine-induced first-degree and third-degree AV block. During AF, infusion of acetylcholine decreased ventricular rates from 182±32 to 77±28 and 28±8 bpm (first-degree and third-degree AV block, respectively; P<0.05). At the first-degree AV block dose, AVN effective refractory period increased from 186±37 to 282±33 ms, and Wenckebach cycle length increased from 271±29 to 378±58 ms (P<0.05). The first-degree AV block dose prolonged AV and AH intervals by 26% and 23% (P<0.05), whereas AA intervals and blood pressure remained unchanged, demonstrating a local effect. All effects were reversed 20 minutes after infusion was stopped. Conclusions— Focal acetylcholine delivery into the AVN increased AVN refractoriness and significantly decreased ventricular rate response during induced AF in a dose-related, reversible manner without systemic side effects. This may represent a novel therapy for AF whereby ventricular rate is controlled with the use of an implantable drug delivery system.

It is believed that pacing sites that provide a more rapid, normal activation of the left ventricle (LV) results in improved performance of the heart. Utilization of non-contact electrical mapping (NCM) techniques has been limited in the assessment of alternative pacing sites. Recently, NCM techniques have been developed to characterize and assess global depolarization and repolarization changes associated with cardiac pacing. High-resolution, NCM was employed to reconstruct LV geometry and record electrical activation in anesthetized swine (N=10). Bipolar pacing was performed from the right atrial appendage (RAA), right ventricular apex (RVA), and the right ventricular outflow tract (RVOT) under fluoroscopic guidance. There were no differences between RAA and RVOT pacing with respect to global activation sequences, QRS durations, total and local endocardial activation durations, conduction velocity and repolarization parameters. Conversely, RVA pacing resulted in impaired electrophysiologic performance, which correlated with decreased global hemodynamic function of the heart. Evaluation of alternative pacing sites employing NCM techniques was successfully demonstrated and supports the need for clinical application of these methodologies. Keywords—Activation, Cardiac, Left Ventricle, Mapping, Pacing.

A link between the cardioprotective benefits of pharmacological preconditioning and natural mammalian hibernation is considered to involve the cellular activation of opioid receptors and subsequent opening of K-ATP channels. In previous studies, we have demonstrated the protective effects of specific delta-opioid agonists against porcine cardiac ischemia/reperfusion injury. We hypothesize here that preincubation with hibernation induction trigger (HIT) should confer a similar protection in skeletal muscles. Therefore, muscle bundles from swine were pretreated with plasma from hibernating woodchucks (HWP) for 30 min, then exposed to hypoxia for 90 min and reoxygenation for 120 min. Stimulated twitch forces were assessed. The functional effects of pretreatment with nonhibernation (summer) woodchuck plasma, a K-ATP blocker, or opioid antagonist were also studied. During the reoxygenation period, significantly greater force recoveries were observed only for bundles pretreated with HWP; this response was blocked by naloxone (P < 0.05). We conclude that HIT pretreatment could be used to confer protection against hypoxia/reperfusion injury of skeletal muscles of nonhibernators; it could potentially be utilized to prevent injury during surgical procedures requiring ischemia.

Introduction: Myocardial edema is a clinically relevant problem found in post-ischemic reperfused hearts. The objective of this study was to understand the effects of hetastarch-supplemented cardioplegia on post-ischemic edema and cardiac function.Materials and methods: Swine hearts were arrested with either St. Thomas Hospital cardioplegia with (n = 6) or without (n = 7) 1.5% hetastarch. Following hypothermic global ischemia, hearts were crystalloid reperfused in a four-chamber isolated working mode.Results: Hetastarch decreased myocardial water content gains after three hours of reperfusion (control versus hetastarch, hour 0: 67 +/- 5% versus 67 +/- 3% NS; hour 3: 82 +/- 2% versus 78 +/- 1%, p = 0.1). Post-ischemic control group left ventricular end-diastolic pressures were elevated after 1 h (in mm Hg, hour 0: 13 +/- 12, hour 1: 19 +/- 3, hour 2: 19 +/- 3, hour 3: 20 +/- 2) but remained stable (< 16 mm Hg) in the hetastarch group. Post-reperfusion creatine phosphokinase perfusate levels in the hetastarch treated hearts were decreased (control: 1.6 IU/l/g versus hetastarch: 0.6 IU/l/g, p = 0.15).Discussion/conclusions: Hetastarch treatment delayed myocardial edema development and attenuated myocardial creatine kinase efflux, thereby preserving diastolic function. (c) 2005 Elsevier Inc. All rights reserved.

Background. Isolated mammalian hearts have been used in numerous studies that have led to many important discoveries in cardiac physiology, pharmacology, and surgery. Multiple methods of perfusion have been described including retrograde and/or antegrade flows and crystalloid or blood perfusates. Furthermore, multiple species have been utilized for such studies including the following: rat, rabbit, guinea pig, canine, and swine. The objective of this study was to describe a unique isolated heart preparation, utilizing human hearts not viable for transplant, which allows for physiologic perfusion and endocardial imaging.Methods. Utilizing standard cardiac transplantation procedures, 12 human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A clear, modified Krebs-Henseleit buffer was used as a blood substitute, which allowed for endocardial imaging utilizing 6.0 mm endoscopic video cameras inserted into the cardiac chambers. The hearts were perfused in Langendorff (retrograde) and/or working (physiologic) mode.Results. Eleven of 12 hearts achieved the following performance in working mode: peak left ventricular pressure of 21.5 to 75.8 min Hg, with an average of 42.7 +/- 19.9 mm Hg. Intracardiac anatomical imaging was possible in all hearts, providing unique views of normal and pathological endocardial anatomy as well as biomedical device-heart interactions.Conclusions. We have described a unique isolated heart preparation with which we have successfully reanimated 11 human hearts deemed not viable for transplant, perfused them by working mode, and performed intracardiac anatomical imaging. This approach provides a novel means for obtaining images of functional human cardiac anatomy and various types of unique biomedical assessments.

Due to increasing interest in using the coronary venous system for placement of intracardiac devices, the functional anatomy of the coronary sinus ostium is clinically important. Using Plegisol cardioplegia and stan-dard cardiac surgery procedures, six human hearts deemed not viable for transplant were explanted to an isolated heart apparatus. A modified Krebs-Henseleit buffer was used as a blood substitute to sustain the hearts, allowing for visualization of internal structures of the functioning hearts. Video footage of the coronary sinus ostia was obtained using a 6-mm diameter flexible videoscope inserted into the hearts through the superior vena cava or the right atrial appendage. A wide range of coronary sinus morphologies was observed including remnant Thebesian valves covering approximately 50% of the coronary sinus ostium and a large fenestrated Thebesian valve covering greater than 50% of the coronary sinus ostium. These images demonstrate why difficulties are sometimes encountered while cannulating the coronary sinus during surgical procedures. Figure 1 shows still images of the coronary sinus ostia of six human hearts. Each image represents a single frame captured from beta video recordings. In each image, the ostium of the coronary sinus is marked "O" and the Thebesian valve is marked "v." Images in Figures 1A , 1B, and 1D show well-developed Thebesian valves covering large portions of the coronary sinus ostium. Images in Figures 1C, 1E, and 1F show remnant Thebesian valves. Figure 2 illustrates serial images showing the movement of Thebesian valves that cover the coronary sinus ostia in three hearts. Consecutive frames in images in Figures 2A and 2B are 0.033 seconds apart and frames in images in Figure 2C are 0.067 seconds apart. The image in Figure 2A is a different view of the Thebesian valve shown in Figure 1A. The Thebesian valves in images in Figures 2A and 2B completely cover the coronary sinus ostium during systole, except for the small fenestrations in both valves. The Thebesian valve image in Figure 2C, although large enough to cover the entire coronary sinus ostium, never actually completely covers the ostium. Drs Cole, Sigg, and Laske disclose a financial relationship with Medtronic, Inc. Drs Cole, Sigg, and Laske disclose a financial relationship with Medtronic, Inc. We would like to thank the Lilleihei Heart Institute, University of Minnesota, and Medtronic, Inc for their funded research, and LifeSource, Inc for their assistance.

We asked whether, in a steady state, neurons and glial cells both take up glucose sufficient for their energy requirements, or whether glial cells take up a disproportionate amount and transfer metabolic substrate to neurons. A desheathed rat vagus nerve was held crossways in a laminar flow perfusion chamber and stimulated at 2 Hz. 14C‐labelled substrate was applied from a micropipette for 5 min over a < 0.6 mm band of the surface of the nerve. After 10‐55 min incubation, the nerve was lyophilized and the longitudinal distribution of radioactivity measured. When the weakly metabolizable analogue of glucose, 2‐deoxy‐[U‐14C]d‐glucose (*DG), was applied, the profiles of the radioactivity broadened with time, reaching distances several times the mean length of the Schwann cells (0.32 mm; most of the Schwann cells are non‐myelinating). The profiles were well fitted by curves calculated for diffusion in a single compartment, the mean diffusion coefficient being 463 ± 34 μm2 s−1 (±s.e.m., n= 16). Applications of *DG were repeated in the presence of the gap junction blocker, carbenoxolone (100 μm). The profiles were now narrower and better fitted with two compartments. One compartment had a coefficient not significantly different from that in the absence of the gap junction blocker (axons), the other compartment had a coefficient of 204 ± 24 μm2 s−1, n= 4. Addition of the gap junction blocker 18‐α‐glycyrrhetinic acid, or blocking electrical activity with TTX, also reduced longitudinal diffusion. Ascribing the compartment in which diffusion was reduced by these treatments to non‐myelinating Schwann cells, we conclude that 78.0 ± 3.6 % (n= 9) of the uptake of *DG was into Schwann cells. This suggests that there was transfer of metabolic substrate from Schwann cells to axons. Local application of [14C]glucose or [14C]lactate led to variable labelling along the length of the nerve, but with both substrates narrow peaks were often present at the application site; these were greatly reduced by subsequent treatment with amylase, a glycogen‐degrading enzyme.

Pharmacological preconditioning with kappa-opioid receptor agonists is proarrhythmic and exerts antipreconditioning effects in rats. In swine, it is unknown whether kappa-opioid receptor stimulation plays a role in pharmacological preconditioning. Swine were preconditioned with 1) saline (controls), 2) [d-Ala(2),d-Leu(5)]enkephalin (DADLE), 3) morphine, 4) pentazocine, 5) norbinaltorphimine (nor-BNI), 6) DADLE + nor-BNI, 7) morphine + nor-BNI, or 8) pentazocine + nor-BNI before occlusion (45 min) and reperfusion (180 min) of the left anterior descending coronary artery. Infarct size to area at risk (IS), regional (systolic shortening) and global (pressures and flows) myocardial function, and arrhythmia occurrence were assessed. Only DADLE + nor-BNI preconditioning significantly decreased infarct size compared with controls (47 +/- 13 vs. 65 +/- 5%, P < 0.05); morphine preconditioning was not cardioprotective with or without kappa-opioid receptor blockade (nor-BNI). DADLE preconditioning significantly increased ischemia-induced arrhythmias relative to controls, whereas pentazocine-preconditioned animals (n = 2) experienced intractable ventricular fibrillation during ischemia. kappa-Opioid receptor blockade with DADLE or pentazocine preconditioning alleviated proarrhythmic effects. These results suggest that kappa-opioid receptor activation during pharmacological preconditioning is proarrhythmic in swine.