Oestrus status does not alter breeding suitability assessments regarding medial patellar luxation in female small breed dogs: A blinded multi-observer study.

Study aims were to evaluate if medial patellar luxation clinical grades changed with oestrus status, and to determine interobserver agreement for different classification methods for grading patellar luxation. Intact female dogs were recruited for grading by 3 independent observers on 2 occasions (pro-oestrus/oestrus and dioestrus/anoestrus) using a published grading system. Observers were blinded to oestrus status. Oestrus status was confirmed by vaginal cytology. Observer agreement was determined using Fleiss' multirater kappa on the original grading scores, simplification to the Norwegian Kennel Club system, and further simplification to a binary suitable/not-suitable for breeding system. The exact McNemar's test was used to assess the effect of oestrus on classification. Of 70 dogs recruited, 53 underwent paired observations. Interobserver agreement was considered moderate to very good for the study sub-groups, with overall kappa values of 0.68 (95% CI 0.63-0.72), 0.79 (0.73-0.84) and 0.92 (0.85-0.99), and percentage agreements of 65%, 81% and 94%, for the original, simplified and binary classifications. Oestrus status did not have a significant effect on classification of breeding suitability. Clinicians and owners should not be concerned about the timing of patellar luxation grading in relation to oestrus. Experienced observers show good or very good agreement using the Norwegian Kennel Club and binary categorisations.

The effects of tubulin-binding agents on stretch-induced ventricular arrhythmias.

Stretch-activated ion channels have been identified as transducers of mechanoelectric coupling in the heart, where they may play a role in arrhythmogenesis. The role of the cytoskeleton in ion channel control has been a topic of recent study and the transmission of mechanical stresses to stretch-activated channels by cytoskeletal attachment has been hypothesized. We studied the arrhythmogenic effects of stretch in 16 Langendorff-perfused rabbit hearts in which we pharmacologically manipulated the microtubular network of the cardiac myocytes. Group 1 (n=5) was treated with colchicine, which depolymerizes microtubules, and Group 2 (n=6) was treated with taxol, which polymerizes microtubules. Stretch-induced arrhythmias were produced by transiently increasing the volume of a fluid-filled left ventricular balloon with a volume pump driven by a computer-controlled stepper motor. Electrical events were recorded by a contact electrode which provided high-fidelity recordings of monophasic action potentials and stretch-induced depolarizations. The probability of eliciting a stretch-induced arrhythmia increased (0.22+/-0.11 to 0.62+/-0.19, p=0.001) in hearts treated with taxol (5 microM), whereas hearts treated with colchicine (100 microM) showed no statistically significant change. We conclude that proliferation of microtubules increased the arrhythmogenic effect of transient left ventricle diastolic stretch. This result indicates a possible mode of arrhythmogenesis in chemotherapeutic patients and patients exhibiting uncompensated ventricular hypertrophy. The data would indicate that the cytoskeleton represents a possible target for antiarrhythmic therapies.

Volume recruitment and oxygenation in pulmonary edema: a comparison between HFOV and CMV.

PURPOSE: In acute lung injury, edema floods alveoli decreasing mean lung volume (MLV) and increasing pulmonary venous admixture (Ova/Qt). We reasoned that a ventilatory strategy that uses large tidal volumes (VT) might recruit volume differently than a strategy that uses very small VT (high-frequency oscillatory ventilation, HFOV) which may require an inflation maneuver to total lung capacity (TLC) for full recruitment. MATERIALS AND METHODS: We studied six dogs with pulmonary edema induced by oleic acid injury and compared HFOV with conventional mechanical ventilation (CMV). Increasing mean airway opening pressure (Pao) from 6 to 14 cm H2O raised MLV from 932+/-162 to 1,550+/-210 mL and from 872+/-145 to 1,242+/-192 mL during CMV and HFOV, respectively, whereas Qva/Qt decreased from 24.1+/-8.5 to 9.3+/-4.3% and from 42.2+/-6.8 to 30.4+/-9.3%. We repeated our measurements at a Pao of 14 cm H2O after an inflation maneuver to TLC. RESULTS: Intlation to TLC recruited additional lung volume and decreased Qva/Qt further only during HFOV. After an inflation to TLC, we observed a rapid isobaric volume loss from the deflation limb of the pressure-volume curve during both CMV and HFOV. CONCLUSIONS: We conclude that after oleic acid injury in dogs pressure-volume hysteresis has two components: a recruitable portion associated with gas exchange improvement and a nonrecruitable portion. At the level of PEEP used in this study (8.5 cm H2O), full lung recruitment during HFOV required inflation to TLC, whereas during CMV it was accomplished by the relatively large VT.

Resolution of vegetations with anticoagulation after myocardial infarction in primary antiphospholipid syndrome.

We report here a case of primary antiphospholipid syndrome with all three clinical features with acute myocardial infarction. Echocardiography showed large vegetations at both mitral valve leaflets. Laboratory evaluation showed presence of antiphospholipid antibodies. High-intensity anticoagulation was begun, and repeat echocardiographic study in 4 months showed disappearance of the mitral valve vegetations.

Neuropsychological features and differential diagnosis of sleep apnea syndrome in children.

Recognizing the signs and effects of pediatric apnea is essential for accurate diagnosis and treatment of children with psychological difficulties. Sleep apnea can have serious deleterious effects on children's cognitive, behavioral, and physiological functioning. Diurnal effects include inattention, decreased academic performance, oppositionality, and restlessness, stemming from frequent nocturnal arousals, excessive daytime sleepiness, and hypoxia. Clinically, the effects of pediatric apnea appear similar to characteristics of other childhood disorders, most notably attention deficit hyperactivity disorder. Efforts to screen for sleep apnea should be regularly employed, especially for children who present with the symptoms discussed. Additional study of pediatric apnea is needed to heighten clinicians' awareness and improve diagnostic accuracy.

Seroprevalence of antibodies to Sarcocystis neurona in horses residing in Oregon.

OBJECTIVE: To determine seroprevalence of antibodies to Sarcocystis neurona in neurologically normal horses residing in 4 regions of Oregon and to describe the effects of age, gender, breed, and housing on seroprevalence within each region. DESIGN: Prevalence survey. SAMPLE POPULATION: Serum samples from 334 horses systematically selected by practicing veterinarians. PROCEDURE: Antibodies to S neurona were measured in sera, using a western blot. Information including age, gender, breed, housing, geographic location, and duration of residence was obtained for each horse. Data were analyzed, using descriptive statistics. RESULTS: 45% (149/334) of horses evaluated were seropositive for antibodies to S neurona with significant differences in the percentage of seropositive horses from different regions of the state. Seroprevalances of antibodies to S neurona in horses in regions I and II, west of the Cascade Range, were 65 and 60%, respectively; whereas seroprevalances in central and eastern Oregon, regions III and IV, were 43 and 22%, respectively. Seroprevalence consistently increased with age of horse for each region. Gender, breed, and housing were not associated with significant differences in seroprevalence of antibodies to S neurona in the overall sample population, or in comparisons of samples obtained from horses within a particular region, or among samples obtained from horses residing in different regions. CLINICAL IMPLICATIONS: The high seroprevalence of antibodies to S neurona in neurologically normal horses indicates that analysis of serum alone would not be useful for definitive diagnosis of equine protozoal myeloencephalitis in horses in Oregon.

Calcium- and sodium-dependent modulation of stretch-induced arrhythmias in isolated canine ventricles.

Gadolinium-sensitive stretch-activated channels have been implicated in the process of mechanotransduction signaling of ventricular myocardium. Such channels nonspecifically transport Na+ and Ca2+ in the inward direction. We tested the hypothesis that Na+ and Ca2+ influx are important in the genesis of stretch-induced arrhythmias (SIAs) in an isolated, blood-perfused canine ventricle. To elicit SIAs, left ventricular volume was transiently increased in early diastole using a computerized servo-pump system. Monophasic action potential recordings revealed stretch-induced depolarizations (SIDs) that preceded the arrhythmias. In five ventricles, raising the perfusate Ca2+ concentration from 1 to 3 mM increased ventricular sensitivity to SIAs, manifested by a decrease in the volume change required to precipitate an arrhythmia 50% of the time (delta V50) from 19.5 +/- 2.7 to 15.2 +/- 1.9 ml (P < 0.05). When the perfusate Na+ concentration was decreased from 150 to 90 mM in seven ventricles, delta V50 greatly increased (31.1 +/- 14.4 vs. 17.7 +/- 5.3 ml, P < 0.05), and SID amplitude decreased by 47% (P = 0.002). The suppression of SIAs with low extracellular Na+ is unlikely to be mediated by voltage-gated Na+ channels because lidocaine (5 mg/dl) did not alter SID amplitude. Thus the transsarcolemmal Na+ gradient (and probably that of Ca2+) modulates the amplitude of SIDs, which, in turn, initiate SIAs. These data provide initial evidence that Na+ and Ca2+ help mediate the mechanotransduction processes that underly the genesis of SIAs.

Mechanical characteristics of tachycardia-induced left-ventricular failure as evaluated in isolated dog hearts.

Left ventricles of control dog hearts and dog hearts failing due to chronic tachycardia were examined in vivo by echocardiography for systolic function and size, then subsequently studied with an isolated-heart system (artificial perfusion, artificial loading). During 3 weeks of tachycardia (250 bt/min), area ejection fraction fell by 58%, while end-diastolic transverse area increased by 56% (measurements at 120 bt/min). Judging from post-perfusion left-ventricular weights, the dilation occurred with no hypertrophy, raising the question whether the failure model may be associated with anabolic dysfunction. End-diastolic pressure-volume (P-V) relations occurred at higher volumes in failing chambers than in controls, and this was marked by increases in two indices of chamber size (candidate reference volumes): the volume resulting in a diastolic stress of 16 g/cm2, and the volume at which the nearly straight, low-stiffness segment of the end-diastolic P-V relation meets the upward bending, high-stiffness segment. Developed P-V relations of failing chambers were shifted to higher volumes and to lower pressures, the lower pressures being due more to reduced stress-developing ability (contractility) than to reduced wall/cavity ratio (pressure/stress ratio). On average, shortening ability (normalized difference between reference volume and extrapolated volume-axis intercept, i.e., apparent ejection fraction from reference volume in absence of afterload) was not different from that of controls. Isovolumic pressure waves of the failing and dilated chambers were of almost normal duration and shape, extending further the range of conditions where isovolumic pressure can be predicted by fitting a model isovolumic wave function to the isovolumic phases of ejecting beats.

Effect of ryanodine on the initiation and perpetuation of stretch-induced arrhythmias in isolated canine ventricle.

Ventricular arrhythmias can be initiated by a mechanism of transient diastolic dilation. To test the hypothesis that Ca2+ release from sarcoplasmic reticulum (SR) is important in initiation of such stretch-induced arrhythmias (SIAs), we studied effects of ryanodine in an isolated canine heart model. Arrhythmias were induced by a computerized ventricular volume servo-pump system that transiently increased left ventricular volume by precise amounts (delta V) during diastole. The probability of eliciting an SIA (PSIA) was compared at the minimum delta V that resulted in PSIA of > or = 90% under baseline conditions. Block of SR Ca2+ release with 10(-5) M ryanodine in 11 ventricles produced mild inhibition of SIAs, reducing PSIA by 19.4% (P = 0.039). Because ryanodine produces leakage of SR Ca2+ at low concentration and block of SR Ca2+ release at high concentration, ryanodine concentration was varied from 10(-9) to 10(-5) M in six ventricles. Ryanodine had minimal effect on PSIA over this concentration range. In six ventricles with elevated intracellular Ca2+ produced by pretreatment with 0.1-0.3 microM strophanthidin, 10(-5) M ryanodine did not significantly reduce PSIA. Probability of inducing ventricular pairs or nonsustained ventricular tachycardia was greater in strophanthidin-treated ventricles than in controls, but induction of these repetitive ventricular beats in the strophanthidin group was virtually abolished by addition of 10(-5) M ryanodine.(ABSTRACT TRUNCATED AT 250 WORDS)

Initiation of ventricular extrasystoles by myocardial stretch in chronically dilated and failing canine left ventricle.

BACKGROUND: Stretch-induced arrhythmias (SIAs) can be elicited in normal canine left ventricles by transient diastolic dilatation. Since clinically important ventricular arrhythmias arise most commonly in failing and dilated ventricles, we hypothesized that the arrhythmogenic effect of transient diastolic stretch would be enhanced in chronically dilated failing canine hearts. METHODS AND RESULTS: Heart failure was induced in seven dogs by right ventricular pacing at 250 min-1 for 20.2 +/- 1.6 days. Left ventricular (LV) mechanical properties were measured in vivo with serial echocardiograms in these seven dogs with the dogs awake and tranquilized to confirm the development of LV dilation and failure. By the third week of pacing, average short-axis area ejection fraction decreased by 64.3% (P < .001) as end-diastolic and end-systolic diameters increased by 25.9% and 50.7%, respectively (P < .001). After heart failure was established, the hearts were harvested and in vitro data were obtained as an isolated, blood-perfused ventricle preparation. A computerized servo pump system connected to an LV intracavitary balloon was used to measure and control LV volume. Results were compared with in vitro data obtained from eight ventricles not subjected to pacing (controls). LV contractility, quantitated in vitro as the slope of the peak isovolumic pressure-volume relation (Emax) normalized to LV cavity size, was much lower in the heart failure group than in controls (182 +/- 18 versus 365 +/- 38 mm Hg, P < .001). In all isolated hearts, SIAs were induced using an electromechanical stimulation protocol in which eight paced beats at 2 Hz were followed by a transient increase in LV volume during early diastole. Prestretch volume (Vi) was selected to yield end-diastolic pressures of 4 to 8 mm Hg in all hearts. The fractional increase in LV volume (delta V) that produced SIAs 50% of the time (delta V 50/Vi) was smaller in failing hearts than in controls (0.78 +/- 0.04 versus 1.18 +/- 0.17, P = .009), indicating an increased sensitivity to SIAs in the failing hearts. Although ventricular pairs were occasionally induced in both groups, the great majority of the arrhythmias induced in both groups were single extrasystoles, and nonsustained runs of ventricular tachycardia were never elicited in either group. LV end-diastolic and peak stretch pressures were similar in the two groups, but LV end-diastolic wall stress was higher by 35.7% (P = .029) in the dilated failing ventricles because LV hypertrophy, which tends to normalize wall stress as the heart dilates, did not occur during the 3 weeks of pacing. For stretch stimuli of comparable arrhythmogenic effectiveness, peak LV wall stress during stretch was similar in the two groups, whereas the fractional increase in volume was significantly smaller in the heart failure group, indicating impaired viscoelastic properties in the failing ventricles. In five control ventricles, acute exposure to 0.5 mumol/L dobutamine increased ventricular sensitivity to the induction of SIAs, as shown by a decrease in delta V50/Vi from 1.27 +/- 0.16 to 1.06 +/- 0.11 (P = .04). CONCLUSIONS: Altered mechanical properties and/or neurohumoral adaptations associated with chronic dilation and failure predispose the ventricle to induction of ventricular extrasystoles by transient LV diastolic stretch.

Photosensitization associated with exposure to Pithomyces chartarum in lambs.

An epidemic of photosensitization was observed in a group of lambs on irrigated autumn pasture in western Oregon. Signs included crusting, necrosis, and sloughing of the skin over the nostrils, lips, and ears, and of the mucous membranes of the buccal regions. Microscopic examination of plant material from the pasture disclosed spores of Pithomyces chartarum. This fungus has been documented as a causal factor in photosensitization in sheep and cattle (facial eczema) in other parts of the world. An infective agent or other plant material that could have induced the clinical signs in the lambs was not evident. Weather and humidity conditions were ideal for fungal growth during the grazing period, and the fungus was detected in large numbers before and during the epidemic. Even though facial eczema has not been reported previously in northwestern United States, we feel the circumstances surrounding this epidemic warrant such a diagnosis.

An approach to sequence-specific antibody proteases. The use of haptens mimicking both a transition state and a distorted ground state.

We describe here a novel strategy for the isolation of antibodies with sequence-specific protease activity: the synthesis of dipeptide haptens in which the targeted peptide bond has been replaced by a ring-strained or torsionally strained hydroxyethylene transition-state analog. Thus, the analogs mimic both a peptide bond in a distorted, reactive conformation and the transition state for peptide bond hydrolysis. In order to obtain sequence-specific antibody proteases, these analogs have been flanked with additional amino acid residues in preparation for immunization. In particular, we have synthesized peptides containing analogs such as 2-cis-amino-3-cis-hydroxycyclobutane carboxylic acid and endo-(3-amino-2-hydroxy)bicyclo[2.2.1]-heptane-7-anti-carboxylic acid. We have also prepared a series of peptide derivatives containing analogs, such as 2-[3-amino-2-oxo-1-azetidinyl]-3-methylbutanoic acid, in which the targeted peptide bond has been incorporated into a beta-lactam ring. Since the "peptide bond" has been left intact, these species mimic only a distorted ground state. At present, antibodies are being elicited against a number of the above peptide derivatives.

Characteristics of left-ventricular isovolumic pressure waves in isolated dog hearts.

The peak pressure which a chamber would develop in isovolumic contraction at end-diastolic distention (peak source pressure) is an expression of contractile vigor and a determinant of systolic performance. One can predict source pressure of an ejecting beat by fitting its isovolumic phases with a model isovolumic-wave function. Characteristics of the left-ventricular isovolumic pressure wave (amplitude, duration, shape) were studied in isolated, perfused, artificially loaded dog hearts, where strictly isovolumic conditions could be obtained over a wide range of cavity volumes at constant heart rate and approximately constant contractile state. The characterization involved two steps: (1) beginning and ending points were identified by a transition-locating algorithm, and (2) Fourier analysis was performed on points in between. The amplitude of the isovolumic pressure wave increased with cavity volume as expected, the duration of contraction increased with cavity volume, and the shape of the wave (normalized Fourier coefficients) depended slightly on the cavity volume. Duration of contraction declined slightly with increasing heart rate, but the shape of the isovolumic pressure wave was independent of heart rate. The mean shape was similar to that found in dog hearts subjected to one-beat aortic-root clamping in vivo-the wave being less sharply peaked than a cosine wave and tilted to the left because relaxation was slower than contraction. When ejecting beat duration declined linearly with increasing ejection fraction. This relation could be used to predict the duration of the isovolumic beat corresponding to the duration of an ejecting beat. Source pressure could then be predicted by fitting a model isovolumic wave of predicted duration to the isovolumic contraction phase of the ejecting beat. In 270 comparisons, the ratio of predicted peak source pressure to observed peak source pressure was 1.04 +/- 0.10 (SD). This method provides a reasonably accurate prediction of an important determinant of systolic performance.

Alterations in left ventricular twist mechanics with inotropic stimulation and volume loading in human subjects.

BACKGROUND: Left ventricular (LV) twist, the longitudinal gradient of circumferential rotation about the LV long axis, may play an important role in the storage of potential energy at end systole and its subsequent release as elastic recoil during early diastole; however, the effects of load and inotropic state on LV systolic twist and diastolic untwist in human subjects have not previously been characterized. METHODS AND RESULTS: Six cardiac transplant recipients with 12 implanted radiopaque midwall LV myocardial markers were studied 1 year after transplantation. Biplane cinefluoroscopic marker images and LV pressure were recorded during control conditions and after afterload augmentation (methoxamine, 5 to 10 micrograms.kg-1 x min-1), inotropic stimulation (dobutamine, 5 micrograms.kg-1 x min-1), and preload augmentation (volume loading with normal saline). Systolic twist dynamics were assessed by maximum twist (Tmax[rad/cm]), peak negative twist rate (-dT/dtmin[rad.cm-1 x s-1]), and the slope of the twist normalized-ejection fraction relation (T-nEFR, Msys[rad/cm]) during systole. Diastolic untwist was assessed by the peak positive untwist rate (+dT/dtmax [rad.cm-1 x s-1]) and the slopes (rad/cm) of the T-nEFR during early diastole (Mear-dia) and mid diastole (Mmid-dia). Compared with control values, LV pressure and volume loading had no significant effect on Tmax, -dT/dtmin, or Msys; however, inotropic stimulation significantly increased all parameters describing systolic twist (Tmax: -0.10 +/- 0.03 versus -0.06 +/- 0.02 rad/cm, P < .001; -dT/dtmin: -0.72 +/- 0.19 versus -0.44 +/- 0.22 rad.cm-1 x s-1, P < .001; Msys: -0.10 +/- 0.03 versus -0.06 +/- 0.01 rad/cm, P < .001). Pressure loading had no effect on early diastolic untwisting; however, dobutamine significantly increased M(ear)-dia (-0.24 +/- 0.06 versus -0.13 +/- 0.04 rad/cm, P < .0001) and +dT/dtmax (0.78 +/- 0.24 versus 0.45 +/- 0.16 rad.cm-1 x s-1, P < .001). Conversely, volume loading significantly decreased M(ear)-dia (-0.08 +/- 0.04 versus -0.13 +/- 0.04 rad/cm, P < .05). M(ear)-dia correlated directly with LV contractile state (as assessed as maximum dP/dt, r = .60, P < .0001) and inversely with end-systolic volume (r = -.87, P < .0001) but was unrelated to stroke volume (r = .08, P = .30) or LV afterload (estimated as effective arterial elastance, r = .08, P = .29). Mmid-dia did not change during any intervention. CONCLUSIONS: In conscious human transplant patients, (1) pressure and volume loading do not affect systolic LV twist; (2) dobutamine augments systolic twist and early diastolic untwisting, suggesting more end-systolic potential energy storage and early diastolic elastic recoil with enhanced inotropic state; (3) volume loading decreases early diastolic untwisting, possibly reflecting diminished recoil forces after preload augmentation associated with larger end-systolic volumes (ESV); and (4) M(ear)-dia correlates strongly with ESV (in an inverse fashion), and less strongly, but directly, with LV dP/dtmax.

Mechanoelectrical feedback effects of altering preload, afterload, and ventricular shortening.

Electrophysiological consequences of altering ventricular load (mechanoelectrical feedback) were characterized in an isolated canine heart preparation. A computerized servo pump system controlled left ventricular volume and allowed ventricular ejection against a simulated arterial load (3-element Windkessel model). In 12 ventricles, end-diastolic volume (Ved) was held constant (end-diastolic pressure 6-12 mmHg) as arterial resistance (R) was varied (0.5-12 mmHg.s.ml-1), but afterload-dependent changes in the monophasic action potential (MAP) were not observed despite a large stroke volume effect. In contrast, when R was held constant in eight ventricles while Ved was increased from 20 to 40 ml, the plateau phase of the MAP was abbreviated, the terminal portion of phase 3 repolarization was delayed, and MAP duration measured at 20, 70, and 90% repolarization decreased (P < 0.05). In six ventricles, immediate transitions from isovolumic to ejecting mode at constant Ved did not alter MAP duration, but the magnitude of early afterdepolarizations (EADs), observed during isovolumic beats at high Ved, was reduced with resumption of ventricular ejection. As stroke volume of the initial ejecting contraction was increased by stepwise reductions of R, the magnitude of the EADs decreased progressively. Thus altering ventricular afterload does not modulate action potential duration in ventricles subjected to elevated, physiological, or even greatly reduced levels of afterload, whereas diastolic filling to high Ved does. Under conditions that lead to reduced stroke volume and high end-systolic volume, EADs are produced that are virtually abolished when ventricular ejection fraction is normalized.

The use of a spectrophotometric assay to study the interaction of S-adenosylmethionine synthetase with methionine analogues.

We have developed a continuous spectrophotometric assay for S-adenosylmethionine synthetase and, using this assay, have examined the interaction of five potential inhibitors with the E. coli enzyme. S-Vinylhomocysteine and S-allylhomocysteine were found to be substrates, while S-(methanethio)cysteine and S-(methanethio)homocysteine were found to be competitive inhibitors. S-Cyanohomocysteine is neither a substrate nor an inhibitor.

Preoperative embolization of the spleen in children with hypersplenism.

Splenomegaly associated with myelodysplastic disorders in children may be massive and can result in pancytopenia, abdominal discomfort, and respiratory distress. When these symptoms cannot be relieved by nonsurgical means, splenectomy may be indicated. Under such conditions, surgical splenectomy carries increased risks, as the thrombocytopenia is difficult to correct secondary to splenic sequestration. Additionally, the surgical anatomy is often distorted secondary to the massive spleen and dissection can be difficult. These factors can lead to uncontrollable hemorrhage. In an attempt to decrease intraoperative blood loss, the authors successfully performed preoperative splenic artery embolization in 11 of 12 children (age range, 1-11 years) with pancytopenia due to hypersplenism. Hypersplenism requiring surgical splenectomy was due to leukemia (n = 9), myelodysplastic syndrome (n = 1), immune thrombocytopenia (n = 1), and osteopetrosis (n = 1). Embolization was performed under general anesthesia, prior to surgery, with gelatin sponge particles alone, Gianturco coils alone, or a combination of polyvinyl alcohol sponge particles and Gianturco coils. Embolization allowed for safe surgical splenectomy.

Stretch-induced depolarizations as a trigger of arrhythmias in isolated canine left ventricles.

Transient diastolic stretch of the left ventricle predictably elicits arrhythmias. To investigate the mechanism of such stretch-induced arrhythmias, monophasic action potentials were recorded from six blood-perfused isolated canine left ventricles with an epicardial contact electrode. Stretch-induced arrhythmias were elicited using a computerized servo-pump system that increased left ventricular volume for 250 ms during early diastole. Depolarizations that coincided with the onset of stretch were observed that always preceded the stretch-induced arrhythmia. As stretch volume (delta V) increased from 10 to 30 ml, the amplitude of the stretch-induced depolarization increased progressively and the probability of eliciting an arrhythmia rose from 30 to 94%. To exclude motion artifact, additional recordings were made after the heart was depolarized by increasing the perfusate K+ concentration to 154 mM (K arrest). After K arrest, the stretch-induced depolarizations were reduced by 95% or more (P less than 0.05) at all stretch volumes. Thus the change in monophasic action potential signal during transient diastolic stretch reflects actual depolarization of the myocardium with negligible motion artifact. When the stretch-activated channel blocker, Gd3+ (10 microM), was administered, which produces potent inhibition of stretch-induced arrhythmias in our model, the stretch-induced depolarizations were substantially reduced in magnitude. Our results show that as diastolic stretch increases, stretch-induced depolarizations become larger and reach threshold potential more often; consequently, the probability of eliciting a stretch-induced arrhythmia increases. This mechanism of arrhythmogenesis may be particularly important in patients with regionally or globally dilated left ventricles.

Dose-dependent inhibition of stretch-induced arrhythmias by gadolinium in isolated canine ventricles. Evidence for a unique mode of antiarrhythmic action.

Transient diastolic dilatation of the isolated canine left ventricle predictably elicits arrhythmias. To test the hypothesis that such arrhythmias may be mediated by sarcolemmal stretch-activated channels, we attempted to inhibit stretch-induced arrhythmias with gadolinium (Gd3+), a potent stretch-activated channel blocker. In experiments with six isolated canine hearts, left ventricular volume was increased for 50 msec during early diastole and then returned to initial volume by a computerized servopump. The stretch volume was adjusted to yield a probability of eliciting a stretch-induced arrhythmia of 95 +/- 2% before treatment with Gd3+. When Gd3+ (1-10 microM) was administered, dose-dependent suppression of stretch-induced arrhythmias was observed. The probability of a stretch-induced arrhythmia was reduced to 13 +/- 10% (p less than 0.05) with 10 microM Gd3+. Washout of Gd3+ completely reversed this effect. Since Gd3+ is known to be a calcium channel antagonist, we compared the effect of Gd3+ on stretch-induced arrhythmias with that of verapamil and nifedipine. These calcium channel blockers produced no demonstrable inhibition of stretch-induced arrhythmias when administered at concentrations (1 microM) that substantially depressed left ventricular pressure development. Thus, our results indirectly implicate stretch-activated channels in the genesis of stretch-induced arrhythmias and provide preliminary evidence for a potential new mode of antiarrhythmic drug action--blockade of stretch-activated channels.