Potential anxiogenic effects of cannabinoid CB1 receptor antagonists/inverse agonists in rats: comparisons between AM4113, AM251, and the benzodiazepine inverse agonist FG-7142.

Cannabinoid CB1 inverse agonists suppress food-motivated behaviors, but may also induce psychiatric effects such as depression and anxiety. To evaluate behaviors potentially related to anxiety, the present experiments assessed the CB1 inverse agonist AM251 (2.0-8.0mg/kg), the CB1 antagonist AM4113 (3.0-12.0mg/kg), and the benzodiazepine inverse agonist FG-7142 (10.0-20.0mg/kg), using the open field test and the elevated plus maze. Although all three drugs affected open field behavior, these effects were largely due to actions on locomotion. In the elevated plus maze, FG-7142 and AM251 both produced anxiogenic effects. FG-7142 and AM251 also significantly increased c-Fos activity in the amygdala and nucleus accumbens shell. In contrast, AM4113 failed to affect performance in the plus maze, and did not induce c-Fos immunoreactivity. The weak effects of AM4113 are consistent with biochemical data showing that AM4113 induces little or no intrinsic cellular activity. This research may lead to the development of novel appetite suppressants with reduced anxiogenic effects.

Mitral valve repair is superior to valve replacement for the early preservation of cardiac function: relation of ventricular geometry to function.

The immediate effect or mitral valve repair (MVP) or replacement (MVR) on cardiac function was compared in patients with mitral regurgitation in relation to the changes in left ventricular (LV) function and geometry by using intraoperative transesophageal echocardiography in 29 patients with MVP and 21 patients with MVR, before and immediately after cardiopulmonary bypass. The LV volumes, ejection fraction, and long-axis and short-axis lengths and eccentricity index (ratio of long axis to short axis) at end-systole and end-diastole were measured. After both MVP and MVR, there were significant decreases in LV end-diastolic volume (p < 0.0001). However, the ejection fraction did not change after MVP, whereas it decreased after MVR (p < 0.0001). After MVP, there was an increase in eccentricity index at end-systole (p < 0.0001). After MVR, there was no decrease in end-systolic volume, and the eccentricity index was lower than that after MVP (p < 0.0001). The change in LV ejection fraction correlated with the changes in eccentricity index at end-systole (r = 0.55; p < 0.0001) and end-diastole (r = 0.42; p < 0.0003). Immediate intraoperative LV function is preserved after MVP but is depressed after MVR for mitral regurgitation. The changes in ejection fraction correlate with changes in ventricular geometry.

Effects of cardiomyoplasty on biventricular function in canine chronic heart failure.

Dynamic cardiomyoplasty, the use of skeletal muscle to assist the heart, is a new therapy for the treatment of heart failure. However, the effects of cardiomyoplasty on biventricular function and the synchrony of ventricular contraction are not fully known. We assessed the efficacy of latissimus dorsi muscle (LDM) dynamic cardiomyoplasty in a chronic model of biventricular failure. Five dogs received doxorubicin (1 mg.kg-1.wk-1) for up to 12 weeks to induce heart failure and then underwent a biventricular cardiomyoplasty. After operation, the muscle was progressively stimulated according to an established protocol. When training was complete (10 weeks), radionuclide ventriculographic and catheterization data were obtained. Peak left ventricular (LV) systolic pressure and its first derivative were unchanged, whereas LV end-diastolic pressure decreased slightly with LDM assistance (11.0 +/- 1.6 to 9.6 +/- 1.5 mm Hg; p < 0.05). Right ventricular (RV) systolic pressure increased significantly with LDM assistance from 21 +/- 2 to 26 +/- 3 mm Hg (p < 0.05), whereas its first derivative and RV end-diastolic pressure were unchanged. Dynamic cardiomyoplasty significantly improved LV ejection fraction from 0.18 +/- 0.07 without LDM assistance to 0.31 +/- 0.05 with LDM assistance (p < 0.05); similarly RV ejection fraction increased from 0.32 +/- 0.07 to 0.45 +/- 0.06 with LDM assistance (p < 0.05). The temporal sequence of LV wall motion was assessed by phase analysis of the radionuclide ventriculograms. With skeletal muscle assistance, standard deviation ("spread") decreased from 31.6 +/- 17.4 to 20.0 +/- 15.4 degrees (p < 0.06), whereas skewness ("symmetry") was unchanged. Dynamic cardiomyoplasty improved both LV and RV ejection fractions without increasing diastolic pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamic cardiomyoplasty acutely impairs left ventricular diastolic function.

In patients with congestive heart failure, medical treatment has a high rate of mortality and morbidity, and transplantation is limited by the availability of donor hearts. Dynamic cardiomyoplasty is being investigated as surgical therapy to improve left ventricular function in these patients. To evaluate the early postoperative effects of this procedure on left ventricular diastolic function, we studied seven dogs through the use of sonomicrometry and micromanometry in a canine model of dynamic cardiomyoplasty. Left ventricular diastolic parameters were determined before wrapping the latissimus dorsi muscle (baseline), after latissimus dorsi muscle wrap but without stimulation, and with synchronous left ventricular contraction-latissimus dorsi muscle stimulation. End-diastolic pressure was increased in both conditions after latissimus dorsi muscle wrap (without stimulation, 5 +/- 1; with stimulation, 6 +/- 2 mm Hg; p < 0.05) compared with baseline (3 +/- 2 mm Hg). The peak rate of diastolic pressure decay was greater at baseline (1560 +/- 370 mm Hg/sec) than after latissimus dorsi muscle wrap, both without (1260 +/- 330 mm Hg/sec, p < 0.01) and with (1120 +/- 420 mm Hg/sec, p < 0.01) stimulation. The constant of pressure decay was prolonged both without (53 +/- 10 seconds, p < 0.05) and with (62 +/- 11 seconds, p < 0.01) latissimus dorsi muscle stimulation compared with the baseline (38 +/- 5 seconds). Compared with baseline (0.2 +/- 0.2 cm-2), the constant of passive chamber stiffness increased after the latissimus dorsi muscle was wrapped around the heart (1.6 +/- 0.7 cm-2, p < 0.05) and with stimulation (2.1 +/- 1.0 cm-2, p < 0.01). The maximal diastolic filling rate (baseline, 18.1 +/- 6.7; without stimulation, 16.6 +/- 8.9; with stimulation, 16.6 +/- 4.1 cm2/sec, not significant) and end-diastolic short-axis area (baseline, 7.3 +/- 2.3; without stimulation, 7.4 +/- 2.1; with stimulation, 7.5 +/- 2.3 cm2, not significant) were similar among the three conditions. The latissimus dorsi muscle wrap prolonged relaxation and increased left ventricular passive stiffness. Synchronous latissimus dorsi muscle stimulation with left ventricular contraction did not improve diastolic function in this model. The results suggest that in the early postoperative period, dynamic cardiomyoplasty impairs diastolic function.

Effects of dynamic cardiomyoplasty on indices of left ventricular systolic and diastolic function in a canine model of chronic heart failure.

The effects of cardiomyoplasty were evaluated with multiple-gated equilibrium radionuclide angiocardiography and catheterization in a canine model of chronic heart failure. Doxorubicin was administered to 12 dogs at a dose of 1 mg/kg/wk intravenously for 10 weeks. Left ventricular ejection fraction was reduced from a mean of 53.6% +/- 3.4% to 33.5% +/- 2.3% preoperatively. Two dogs died of presumed arrhythmia during this period. Cardiomyoplasty with the left latissimus dorsi muscle was performed on 10 dogs. The muscle was wrapped around both the left and right ventricles. Five dogs died of infection or arrhythmia after the operation. Postoperatively the muscle remained unstimulated for 2 weeks to allow adhesion to the heart. After this period, the latissimus dorsi muscle was conditioned by a progressive stimulation protocol. After the muscle was conditioned, multiple-gated equilibrium radionuclide angiocardiography studies showed that left ventricular global ejection fraction was 18.4% +/- 7.2% at 0 volts (nonstimulation), 26.2% +/- 3.7% at 5-volt stimulation (p less than 0.05), and 31.0% +/- 5.4% at 10-volt stimulation (p less than 0.05). Regional ejection fractions in low lateral, apical, and low septal regions at 5 volts and 10 volts were higher than those at 0 volts (p less than 0.05). Regional wall motion (percent radial shortening) of the low lateral region was higher than that during nonstimulation (p less than 0.05). Peak emptying rate was 2.07 +/- 0.95 end-diastolic counts per second at 0-volt, 3.10 +/- 0.67 at 5-volt, and 3.34 +/- 0.89 at 10-volt stimulation (p less than 0.05). Peak filling rate was 1.81 +/- 0.52 end-diastolic counts per second at 0-volt, 2.67 +/- 1.18 at 5-volt, and 3.11 +/- 0.65 at 10-volt stimulation (p less than 0.05). Cardiac catheterization data showed a nonsignificant increase in left ventricular rate of pressure rise with increasing voltage (1302 +/- 355 mm Hg/sec at 0 volts, 1450 +/- 413 mm Hg/sec at 5 volts, and 1568 +/- 455 mm Hg/sec at 10 volts). Left ventricular systolic pressures were unchanged. End-diastolic pressures decreased (11.2 +/- 1.48 mm Hg at 0 volts, 10.4 +/- 2.30 mm Hg at 5 volts, and 9.6 +/- 1.52 at 10 volts; p less than 0.05). These data show that cardiomyoplasty can improve indices of systolic and diastolic function in a canine model of chronic heart failure.

Reduction of myocardial infarct size by poloxamer 188 and mannitol in a canine model.

Poloxamer 188 has been reported to inhibit thrombosis, decrease whole blood viscosity, and improve perfusion of damaged tissue. Mannitol has free radical scavenging capabilities that might contribute to myocardial salvage after ischemia. Because these agents appear to work in different ways, we studied their cardioprotective properties when they were used separately and in combination. After 75 minutes of left anterior descending coronary artery (LAD) occlusion, dogs received poloxamer 188 (48 mg/kg), mannitol (0.5 gm/kg), or both intravenously during an additional 15 minutes of LAD occlusion and for 45 minutes of reperfusion, whereas control dogs received an equal volume of saline solution. After surgery the animals were maintained for 24 hours and then killed. Areas of myocardial infarction (MI) and risk of infarction (R) were calculated by means of planimetric analysis of slices of myocardium stained with 1.5% triphenyltetrazolium and 0.5% Evans blue dye. The ratio of MI/R (mean +/- standard error of the mean) were: control, 25.6 +/- 1.8% (n = 10); poloxamer 188, 12.7 +/- 2.0% (n = 10); mannitol, 10.6 +/- 2.5% (n = 11); and poloxamer 188 plus mannitol, 8.0 +/- 4.1% (n = 10). Measurement of microvascular blood flow indicated a similar 86% to 91% reduction of blood flow to the area at risk in all treatment groups. Consequently both poloxamer 188 and mannitol appear to increase salvage of ischemic myocardium and a combination of the two may be more effective than either agent alone.

Latissimus dorsi dynamic cardiomyoplasty of the right ventricle. Potential for use as a partial myocardial substitute.

Full-thickness right ventricular latissimus dorsi dynamic cardiomyoplasty with the Medtronic Cardiomyostimulator (Medtronic, Inc., Minneapolis, Minn.) was performed in a chronic canine model. In one group (n = 2) the latissimus dorsi was electrically preconditioned before cardiomyoplasty. In a second group (n = 3) cardiomyoplasty was performed and the muscle was progressively stimulated, with conditioning accomplished while the latissimus dorsi was functioning on the ventricle. The contribution of the stimulated latissimus dorsi to global ventricular function was assessed, and the effects of varying muscle stimulation parameters on latissimus dorsi function and hemodynamics were examined. Right ventricular systolic pressure increased 8%, from 23.2 +/- 0.95 to 25.1 +/- 1.5 mm Hg. The rate of pressure rise increased 37% from 226 +/- 13 to 309 +/- 12 mm Hg/sec. Right ventricular ejection fraction was measured in two dogs and increased 29% with latissimus dorsi stimulation, from 51.5% +/- 13.5% to 66.5% +/- 14.5%. Although the sample size was small, there was no difference observed between the preconditioned and nonpreconditioned groups. Right ventricular systolic pressure, rate of pressure rise, and percent latissimus dorsi fiber shortening increased as voltage and burst frequency of the muscle stimulus increased, whereas increasing the burst duration had little effect in two dogs so studied. Latissimus dorsi dynamic cardiomyoplasty can function as a partial myocardial replacement in a chronic canine model, apparently without preconditioning of the muscle. The degree of cardiac assist obtained with cardiomyoplasty appears to be influenced by the voltage and frequency of the stimulus applied to the muscle. Although it is unclear whether these results can be extrapolated to the left ventricle, this technique may find application in the treatment of ventricular aneurysm or ventricular tumor.

Preischemic perfusion of hypertrophied myocardium with perfluorocarbons.

The increased susceptibility of hypertrophied myocardium to ischemic injury is well known. Hypertrophied hearts possess lower preischemic high energy phosphate stores and develop ischemic contracture following a shorter ischemic interval than normal hearts. The purpose of this study was to determine the ability of preischemic, arrested perfusion of the hypertrophied rat heart with oxygenated, glucose-containing perfluorocarbon cardioplegia (FC-43) to restore myocardial ATP stores to normal and prolong the duration of global ischemia prior to contracture initiation. Hearts from normal (NL) rats and hypertrophied hearts from spontaneously hypertensive rats (SHR) were subjected to 2 or 15 min of preischemic, arrested perfusion with FC-43 utilizing a modified Langendorff preparation. ATP was determined via HPLC and time to initiation of ischemic contracture was measured. Two minutes of FC-43 perfusion restored ATP in the SHR group to normal levels (P = NS compared to normal controls) and prolonged the time to initiation of ischemic contracture by 107%. Perfluorocarbons, with their unique oxygen-carrying properties, may be an ideal vehicle for intervention designed to enhance the tolerance of hypertrophied hearts to ischemia.

Hemangioma of the right ventricle causing outflow tract obstruction.

A 3 1/2-year-old child had a murmur of pulmonary stenosis. Echocardiography and cardiac catheterization revealed a pulmonary infundibular obstruction. Magnetic resonance imaging of the heart demonstrated a mass in the interventricular septum. The mass was successfully resected and a pathologic diagnosis of capillary hemangioma was made. Only two previous cases of hemangioma causing right ventricular outflow obstruction have been reported; both of these cases involved adults. This case represents the first report of a hemangioma causing right ventricular outflow tract obstruction in a child. An exploratory operation with resection is the treatment of choice.

Management of postoperative mediastinitis in infants and children by muscle flap rotation.

Between July 1, 1976, and June 30, 1986, at the Henrietta Egleston Hospital for Children, 2,242 infants and children underwent palliation or repair of a congenital heart defect. Twenty-one (0.94%) of these patients developed mediastinitis following a median sternotomy. Nineteen of these twenty-one patients had required cardiopulmonary bypass. All patients had positive mediastinal cultures. The first 8 patients were managed traditionally by debridement and irrigation. Three of these patients suffered serious metabolic complications related to the povidone-iodine irrigant, which resulted in 1 death. Another patient died from persistent sepsis following debridement. Subsequently, 13 patients were managed by early debridement and rotation of the pectoralis major or rectus abdominis muscle flaps, or both. Following muscle flap rotation and early wound closure, 2 patients had subsequent incisional complications. One patient had incisional dehiscence and 1 had a superficial skin separation. Two deaths in this group, 28 and 51 days, respectively, following muscle flap rotation, resulted from nonincisional problems in patients with healed median sternotomies. The group having muscle flap rotation required a significantly shorter duration of postoperative ventilatory support (3.2 versus 24 days, p less than 0.05) and a significantly shorter confinement in the intensive care unit (6.2 versus 33 days, p less than 0.01). Also, the physiological and physical trauma of continued wound care in the awake child was minimized in the group with muscle flap rotation.

Self-reported excessive daytime somnolence and impaired respiration in sleep.

The purpose of this study was to determine which measures of impaired respiration in sleep relate to self-reported excessive daytime somnolence (EDS). Previous studies conflict regarding the relative importance of arterial hypoxemia and brief awakenings in relating to EDS. A group of 37 elderly clinic patients with complaints of snoring, a clinical diagnosis of sleep apnea, and varying degrees of self-reported somnolence were evaluated polysomnographically and psychometrically. Results showed that a subgroup of somnolent patients were characterized by more severe oxygen desaturations relative to nonsomnolent patients. These differences were obtained even when obesity was controlled. Psychologic symptoms related to the symptom of EDS but not to the sleep measures. This suggested that patients were clearly distressed by their hypersomnolence, but that individual differences played a major role in how the distress was manifested.

Characterization of the giant myofiber in bovine skeletal muscle.

Semitendinosus (ST) muscle samples were excised pre- and postrigor from 32 experimental animals (Bos taurus). Four intact and 4 castrate males were exsanguinated when they reached age endpoints of 8, 12, 16, and 20 months. The samples were sectioned, histochemically fiber-typed for SDH and ATPase activity, and examined for giant myofibers. Of the 32 muscles analyzed, only one (8-month intact male) postrigor ST contained a giant myofiber that was hematoxylin and eosin positive, SDH negative, ATPase positive, and 2 X the size of the surrounding fibers. Subsequent studies demonstrated these giant type II white myofibers are an anomaly of muscle contraction and not a distinct fiber type as has been previously reported. This is a first report of giant white or type II myofibers in postrigor bovine skeletal muscle.

Postoperative left ventricular contractility in the cardiac surgical patient: an evaluation of the force-interval relationship.

The force-interval relationship--the dependence of cardiac contractility on the rate and pattern of stimulation--was evaluated for its potential use in monitoring patients in the period immediately following heart surgery. Six patients were studied for three days after coronary artery bypass grafting. The monitoring instrumentation used during operation included a catheter-tip micromanometer introduced into the left ventricle, a pair of ultrasonic transducers placed on the left ventricular (LV) epicardium to monitor minor-axis dimension, pacing electrodes placed on the right atrium, and systemic arterial and venous catheters. During the experiments, heart rate was controlled by atrial pacing. After every twentieth systole (the control systole), a pause in the heart rate was introduced during which an extrasystole (SE) and a postextrasystole (SPES) were elicited at test intervals tE and tPES, respectively. The intervals between the control systole and test systoles SE and SPES were experimentally manipulated. When the test intervals were increased, the peak first derivative of LV pressure (Pmax) of SE and of SPES increased monophasically. To eliminate the effects of LV end-diastolic volume, we used only SPES and control systoles with the same LV end-diastolic dimension in construction of PES ratio curves (Pmax of SPES/Pmax of the control systole, as a function of tPES). The PES ratio rose monophasically with an increase in tPES; these curves were well fitted by an exponential relationship. The PES ratio exceeded unity at long tPES intervals. This ratio, denoting postextrasystolic potentiation, was inversely dependent on tE. The patients experienced no complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynamics of physiological changes in bovine myofibers during growth and sexual development.

Semitendinosus (ST) muscle samples were excised from 8 intact and 8 castrate male animals (Bos taurus) when they reached age end-points of 8, 12, 16, and 20 months. All three principal myofiber phenotypes (IC, IIA, IIB) increased in size with increasing age, with the IIA (fast-white) fibers usually larger than the other two types. Only at 16 and 20 months were the type II myofibers from intact males consistently larger than that from castrates. The amount of IIA fibers always exceeded that of the other two phenotypes at every age. Myofiber characteristics were more highly correlated with animal age than with either total body weight or total muscle mass. An ontogenetic scheme is proposed to illustrate the dynamic interrelationships of the three ST myofiber phenotypes.

Management of critical aortic stenosis in infancy.

Critical aortic valvular stenosis presents in infancy with severe congestive heart failure. Clinical assessment and electrocardiography are of value, but cardiac catheterization with angiography has been considered mandatory prior to surgical treatment. With cross-section echocardiography an accurate diagnosis of aortic stenosis and associated lesions is possible. Over the past 2 years, we have established a protocol according to which, if a clinical diagnosis of critical aortic stenosis is confirmed by cross-sectional echocardiography in the absence of major associated cardiac anomalies, infants are submitted for aortic valvotomy under inflow occlusion without invasive studies. This protocol was used in an effort to decrease the mortality rate by avoiding the preoperative stress of cardiac catheterization and angiography, as well as the hazards of cardiopulmonary bypass in the severely ill infant. Eight infants with critical aortic stenosis have been operated upon, five without prior cardiac catheterization. Ages at operation ranged from 2 days to 7 months, with six children less than 2 weeks of age. The noninvasive diagnosis was confirmed at operation in each case. There was one early postoperative death and one late death. No death has been related to the technique of inflow occlusion. A decision tree for the noninvasive assessment of suspected critical aortic stenosis based on the clinical features and echocardiographic findings is presented.

Myocardial blood flow and oxygen consumption in the empty-beating, fibrillating, and potassium-arrested hypertrophied canine heart.

Myocardial oxygen consumption and blood flow distribution were examined in severely hypertrophied canine hearts in the empty-beating, fibrillating, and pharmacologically arrested states. Hypertrophy was produced using a subcoronary valvular aortic stenosis model that mimics the clinical situation of aortic valvular stenosis. Oxygen content of the total coronary sinus collection was compared with a large volume arterial sample using a Lex-O2-Con-TL analyzer, which had been validated by the Van Slyke-Neill method. Transmural blood flow was measured in each state using microspheres, and perfusion pressure was maintained at 80 mm Hg. Oxygen consumption in the empty-beating hypertrophied heart was found to be the same as that previously reported for normal hearts. Blood flow was evenly distributed in the empty-beating heart, with an endocardial/epicardial ratio of 0.99 +/- 0.15 (SEM) milliliters per minute per gram of left ventricular weight. Oxygen consumption failed to increase significantly with fibrillation; however, blood flow distribution favored the subepicardium, suggesting that oxygen consumption determinations in the fibrillating hypertrophied heart may not accurately reflect metabolic demand. Basal oxygen consumption of the hypertrophied heart as determined by the potassium-arrested, blood-perfused model was the same as that previously described for normal hearts. Blood flow during potassium arrest favored the subendocardium (endocardial/epicardial ratio = 1.14 +/- 0.27 ml/min/gm LV weight).