Bacterial toxins affect early events of T lymphocyte activation.

The effects of pertussis toxin and cholera toxin on early events of T lymphocyte activation were examined in the T lymphocyte cell line, Jurkat. Pertussis toxin treatment of these T cells increased inositol phosphates production and led to increases in intracellular free calcium concentration. These effects were produced by the isolated B (binding) subunit of pertussis toxin, alone. Inositol phosphates production resulting from perturbation of the T cell antigen receptor-CD3 complex by MAb was not affected by pertussis toxin treatment but was markedly inhibited by cholera toxin. This effect of cholera toxin paralleled elevations in cAMP content. However, forskolin, in concentrations equipotent for cAMP production, was a weaker inhibitor of inositol phosphates production. Cholera toxin inhibition of inositol phosphates production did not result from inhibition of baseline incorporation of inositol into phosphoinositide substrates of phospholipase C. These studies underline the complexity of toxin effects on cellular systems and suggest that other approaches will be required to implicate guanine nucleotide-binding regulatory proteins in control of the early events of T lymphocyte activation. However, the data presented here provide a molecular basis for the clinical observations of lymphocytosis and the in vitro observations of lymphocyte mitogenesis after pertussis toxin stimulation.

Beneficial effects of low dose amiodarone in patients with congestive cardiac failure: a placebo-controlled trial.

The effects of amiodarone in a low dosage (200 mg every 8 h for 2 weeks, then 200 mg/day) was assessed in a double-blind placebo-controlled trial in 34 patients with a history of severe congestive heart failure but no sustained ventricular arrhythmia. Left ventricular ejection fraction, treadmill exercise tolerance and 48 h electrocardiographic monitoring were assessed before and repeatedly after beginning amiodarone or placebo therapy over 6 months, and side effects were monitored. In patients receiving amiodarone, the ejection fraction increased significantly from 19 +/- 7 to 29 +/- 15% at 6 months (p less than 0.01 from baseline), but not significantly in 14 placebo-treated patients (18 +/- 5 to 22 +/- 9%). Exercise tolerance increased significantly in amiodarone-treated patients (median 433 s to 907 s, p less than 0.05), but not significantly in placebo-treated patients (757 to 918 s). Nonsustained ventricular tachycardia was present in 88% of amiodarone-treated patients before, but in only 21% of patients after 6 months of treatment (p = 0.06); it was seen in 43% of placebo-treated patients at baseline and in 50% after 6 months. Fifty percent of amiodarone-treated patients had side effects (principally nausea) and the drug was withdrawn in 28% of cases; no life-threatening effects were seen. Low dose amiodarone appears to have a multifaceted potential to produce benefits in arrhythmia control, exercise tolerance and ventricular function in patients with a history of severe congestive heart failure, but better control of side effects (principally nausea) appears essential. Effects on mortality could not be determined from this study; such assessment requires a larger cohort of patients.

Steroid-eluting epicardial pacing leads in pediatric patients: encouraging early results.

OBJECTIVES: This study evaluated the pacing and sensing characteristics of a new porous-tipped steroid-eluting epicardial lead in a group of pediatric patients. BACKGROUND: Pacing in children may be complicated by small patient size, patient growth and the prevalence of structural congenital heart disease in children requiring pacing. Epicardial pacing has been associated with a high incidence of problems with sensing and capture, prompting the use of transvenous endocardial pacing when possible. In some children, epicardial pacing may still be desirable because of small patient size, potential for caval obstruction, previous cardiac surgery limiting transvenous access to the heart, or the need to repair congenital heart disease at the time of pacemaker insertion. METHODS: Twelve patients aged 3 weeks to 18 years underwent placement of 23 epicardial pacing leads (8 atrial, 15 ventricular). Pulse width thresholds, sensing thresholds and lead impedance were measured weekly for 6 weeks, then at 3, 6, 12 and 18 months after pacemaker implantation. The median duration of follow-up was 12 months. RESULTS: Ventricular pulse width thresholds did not change over time, whereas atrial pulse width thresholds improved significantly. At 6 months, the mean pulse width threshold at 2.5 V for the atrial and ventricular leads was 0.10 +/- 0.03 and 0.19 +/- 0.09 ms, respectively. The thresholds were slightly lower at 12 and 18 months. At the most recent follow-up, all atrial leads sensed appropriately at 2.5 mV and all ventricular leads at 5 mV. CONCLUSIONS: These encouraging early results suggest that steroid-eluting epicardial pacing leads may be an attractive option for children needing epicardial pacing. Their excellent pacing and sensing characteristics may allow reliable dual-chamber pacing in infants who are too small for transvenous pacing.

Echocardiographic estimation of critical left ventricular size in infants with isolated aortic valve stenosis.

With the current trend to performing surgical valvotomy for infantile aortic stenosis without cardiac catheterization, there is a need to develop echocardiographic criteria for adequacy of left ventricular size. The echocardiograms and catheterization data of all 25 infants less than 3 months of age undergoing aortic valvotomy for isolated aortic valve stenosis from September 1980 through July 1990 were reviewed. Significant differences (p less than 0.05) between the survivors and nonsurvivors were noted for age at operation (30 +/- 28 vs. 3 +/- 1.5 days), mitral valve diameter (10.1 +/- 1.7 vs. 7.7 +/- 1.5 mm), left ventricular end-diastolic dimension (18.4 +/- 6.4 vs. 11.4 +/- 3 mm), left atrial dimensions (15.3 +/- 3.8 vs. 10 +/- 2.4 mm), left ventricular cross-sectional area on the parasternal long-axis echocardiogram (4 +/- 1.9 vs. 2 +/- 1.9 cm2) and angiographically determined left ventricular end-diastolic volume (43 +/- 23 vs. 11 +/- 5 ml/m2). There was no difference with respect to patient weight, body surface area, aortic root dimension or left ventricular ejection fraction. Left ventricular cross-sectional area less than 2 cm2 as measured on the parasternal long-axis echocardiogram was found in 5 of 7 nonsurvivors and 0 of 12 survivors, making this a risk factor for perioperative death (p less than 0.05). Left ventricular end-diastolic dimension less than 13 mm was found in 5 of 6 nonsurvivors and 2 of 17 survivors, making this another risk factor for early mortality (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Thrombolytic therapy for unstable angina pectoris: rationale and results.

The coronary lesion in unstable angina consists of disrupted atherosclerotic plaque with nonocclusive intraluminal thrombus, which frequently persists despite heparin anticoagulation. A 12 hour infusion of recombinant tissue-type plasminogen activator combined with heparin effectively lyses the thrombus and stabilizes the clinical syndrome but is associated with a high incidence of bleeding. Therapeutic schemes of thrombolytic therapy associated with a lower bleeding frequency may be useful for the treatment of unstable angina.

Quantitation of acute myocardial infarct size by nuclear magnetic resonance imaging.

Nuclear magnetic resonance (NMR) imaging has shown potential in the detection and characterization of acute myocardial infarction in humans. This study was performed to evaluate the capability of NMR imaging in the measurement of infarct size in patients with recent myocardial infarction. Electrocardiographic (ECG)-gated spin-echo NMR imaging was performed in 26 patients a mean of 9 +/- 3 days (range 5 to 20) after infarction. The imaging technique used provided single-slice, spin-echo (time to echo [TE] = 60 ms) images of the left ventricle in its true short axis, allowing direct correlation of NMR infarct location and size with the region of severe hypokinesia on left ventriculography. In all 20 patients with complete NMR studies, infarct location was correctly identified by using specific, objective criteria. The correlation between the mean infarct volume (29 +/- 11 ml) and the quantitated left ventricular hypokinetic segment (7.5 +/- 4.0 cm) was good (r = 0.84, p = 0.0002), suggesting that NMR imaging of the heart may have a role in the noninvasive assessment of myocardial infarct size in patients.

Detection of coronary artery reperfusion with creatine kinase-MB determinations during thrombolytic therapy: correlation with acute angiography.

Increases in plasma creatine kinase-MB (MB CK) were correlated with the onset of coronary artery reperfusion determined angiographically in 32 patients with acute myocardial infarction who were treated with recombinant human tissue-type plasminogen activator (rt-PA). Reperfusion occurred in 14 (70%) of 20 patients with left anterior descending coronary artery occlusion and in 8 (73%) of 11 patients with right coronary artery occlusion. One patient had persistent left circumflex coronary artery occlusion. Plasma MB CK levels (radioimmunometric assay) did not increase significantly in patients with persistent occlusion, but increased by a mean (+/- SEM) of 8 +/- 1 and 6 +/- 1 times over pretreatment levels at the end of the infusion in patients with a reperfused left anterior descending and right coronary artery, respectively. When a greater than or equal to 2.5-fold increase in MB CK levels at the end of the rt-PA infusion was taken as evidence of reperfusion of the left anterior descending coronary artery, 13 (93%) of 14 patients with reperfusion and 5 (83%) of 6 with persistent occlusion were correctly identified. When a greater than or equal to 2.2-fold increase in MB CK levels was used to identify right coronary artery reperfusion, seven (89%) of eight patients with persistent occlusion were correctly identified. The sensitivity and specificity of these indexes, derived from and applied to the same patient group, were 91 and 89%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Absence of left ventricular volume loading in infants with coarctation of the aorta and a large ventricular septal defect.

Clinical characteristics and angiographic ventricular volume data were obtained in 25 infants aged 1 to 66 days who presented with coarctation of the aorta, ventricular septal defect and congestive heart failure to determine if left ventricular volume loading was present and if there were hemodynamic or volumetric variables that were predictive of operative mortality in this group. Pulmonary to systemic flow ratio averaged 2.8 +/- 0.8 and right ventricular/left ventricular peak pressure ratio was 0.96 +/- 0.12. Left ventricular end-diastolic volume averaged 116 +/- 49% of normal and was less than the investigators' lower limit of normal in 5 (20%) of 25 patients. In contrast, right ventricular end-diastolic volume, measured in eight patients, averaged 173 +/- 47% of normal and was greater than the investigators' upper limit of normal in seven (88%) of eight. Left ventricular ejection fraction averaged 0.47 +/- 0.17 and was below normal (less than 0.55) in 14 (58%) of 24 patients. Preoperative volume and ejection fraction data did not differ in infants with coarctation plus ventricular septal defect and a similar group of 19 infants with isolated coarctation. Abnormal left ventricular operative volume distensibility was inferred by normal or decreased left ventricular end-diastolic volume and increased left ventricular end-diastolic pressure (greater than 12 mm Hg) in 12 (55%) of 24 patients. Early plus late mortality was related to left ventricular size: 3 of 5 patients with a small left ventricular end-diastolic volume died, compared with only 4 of 20 with a normal or increased volume (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative properties of two clinical preparations of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction.

The biologic properties of two clinical preparations of recombinant human tissue-type plasminogen activator were studied in 52 patients with acute myocardial infarction. The first preparation (G11021) has been used in all clinical trials reported to date, whereas the second preparation (G11035) is now produced for future clinical use. When both preparations were infused intravenously for 90 minutes at rates of 4 to 11 micrograms/kg per min, plateau levels of the drug in plasma ranged from 0.52 +/- 0.15 to 1.8 +/- 0.4 micrograms/ml and were linearly correlated with the infusion rate. However, G11035 yielded plasma levels that were approximately 35% lower than those obtained with G11021 (p less than 0.025). The postinfusion disappearance rate of the drug from plasma could be described by a two compartment disposition model with the following pharmacokinetic variables. For G11021, an alpha half-life of 4.1 to 6.3 minutes, a beta half-life of 41 to 50 minutes, a central compartment volume of 3.5 to 5.4 liters, a total distribution volume of 28 to 44 liters and a plasma clearance of 450 to 640 ml/min. For G11035 these variables were 3.6 to 4.6 minutes, 39 to 53 minutes, 3.8 to 6.6 liters, 27 to 40 liters and 520 to 1,000 ml/min, respectively, indicating that G11035 is cleared more rapidly from the circulation. G11021 at 4 micrograms/kg per min and G11035 at 7 micrograms/kg per min did not effectively produce thrombolysis. A coronary reperfusion rate of 81% (13 of 16 patients) was obtained with 5.3 micrograms/kg per min of G11021 and a rate of 86% (6 of 7 patients) was obtained with 9.4 micrograms/kg per min of G11035.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute myocardial infarct imaging with indium-111-labeled monoclonal antimyosin Fab.

Indium-111 monoclonal antimyosin Fab scintigraphy was used to detect myocardial necrosis in 52 of 54 patients (96.3%) with acute myocardial infarction. Infarcts were visualized when coronary arteries were persistently occluded (n = 10), became patent after thrombolysis (n = 33), or became patent after spontaneous reperfusion (n = 7). Posteroinferolateral visualizations were obtained in two patients with clinical and enzymatic evidence of infarction but normal electrocardiograms. Of the two patients in whom no infarcts were visualized, one had an anterior myocardial infarct. This patient underwent successful thrombolytic therapy, with attendant minimization of creatine kinase release. The other patient had a small, nonreperfused inferior myocardial infarct. Five patients with a history of remote infarction and acute necrosis showed antimyosin uptake only in regions concordant with the acute episodes of infarction, and radiolabeled antimyosin Fab localized in neither old infarcts nor normal, noninfarcted myocardium. Antimyosin Fab scintigraphy, thus, appears to be a highly specific means of delineating necrotic myocardium, at least in this limited and selected group of patients.

Characteristics and management of chaotic atrial tachycardia of infancy.

Chaotic atrial tachycardia was observed in 7 infants without underlying structural heart disease. Clinical presentation and approach to management are discussed, with particular attention to the use of propafenone for this uncommon pediatric arrhythmia.

Dose-dependent thrombolysis, pharmacokinetics and hemostatic effects of recombinant human tissue-type plasminogen activator for coronary thrombosis.

The pharmacokinetics, thrombolytic profile and effects on hemostasis of graded intravenous doses of recombinant human tissue-type plasminogen activator (rt-PA) were studied in 45 patients with acute myocardial infarction. Infusion of rt-PA at a rate of 4 to 8.3 micrograms/kg/min resulted in plateau levels of the drug in plasma of 0.52 to 1.4 micrograms/ml. A linear relation between infusion rate and plasma rt-PA concentration was observed, although plasma drug levels varied substantially among subjects who received infusions at the same rate. The ratio between plateau levels of rt-PA in plasma and infusion rate was inversely related to initial distribution volume (7.3 +/- 2.9 liters, n = 21). The decline in plasma concentration of rt-PA, x(t), as a function of time after cessation of the infusion, was described adequately by the biexponential equation: x(t) = 0.71exp(-0.13t) + 0.29exp(-0.015t). The initial and terminal half-lives of rt-PA in the blood were 5.3 +/- 1.7 and 46.2 +/- 14 minutes, respectively. The efficacy of rt-PA for coronary thrombolysis was dose-dependent. With 4 micrograms/kg/min of rt-PA for 90 minutes, no reperfusion was achieved, whereas infusion rates of 5 micrograms/kg/min or more for 90 minutes accomplished reperfusion in more than 80% of the patients. However, the frequency of occurrence of residual intraluminal thrombus was significantly lower with an infusion rate of 7 micrograms/kg/min for 90 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Detection of caval obstruction by magnetic resonance imaging after intraatrial repair of transposition of the great arteries.

Vena caval obstruction may cause significant morbidity after intraatrial repair of transposition of the great arteries (TGA). Two noninvasive methods of diagnosing vena caval obstruction were compared with cardiac catheterization. Echocardiographically gated magnetic resonance imaging (MRI) and echocardiographic evaluation (2-dimensional saline contrast echocardiography and pulsed Doppler flow measurement) were performed on 15 patients 0.7 to 13.5 years after intraatrial repair of TGA (8 Mustard, 7 Senning). At catheterization, complete superior vena cava or partial caval obstruction (gradient greater than 5 mm Hg from cava to systemic venous atrium) was present in 7 of 15 patients. Superior vena cava obstruction was directly visualized by MRI in both patients with catheterization-proved complete superior vena cava occlusion. A dilated azygous/hemiazygous venous complex (greater than or equal to 5 mm cross-sectional diameter) was seen by MRI in 5 of 7 patients with complex or partial vena caval obstruction and in no patient without vena caval obstruction. MRI showed superior vena caval dilatation (ratio of superior vena caval diameter to aortic diameter greater than 1.45) in 3 of 5 patients with partial vena caval obstruction and in 0 of 8 without vena caval obstruction. Direct visualization of narrowing within the atrium was unreliable for any MRI plane because of the 3-dimensional nature of the intraatrial baffle. Two-dimensional saline contrast echocardiography, successfully performed in 12 of 15 patients, detected complete superior vena caval obstruction only in the 2 patients with catheterization-proved complete superior vena cava occlusion. Contrast echocardiography failed to identify any of the 5 patients with partial vena caval obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Retinal vascular abnormalities in patients with coarctation of the aorta.

Pulsatile three-dimensional retinal arteriolar tortuosity has been previously reported in about 50% of patients with coarctation of the aorta. In a contemporary series of 20 patients with coarctation of the aorta, none exhibited this characteristic retinal vascular abnormality. Our findings suggest that the retinal vascular abnormalities in patients with coarctation of the aorta represent secondary hemodynamic changes. The prevalence of these abnormalities may be decreasing because of earlier surgical repair of coarctation.

Laboratory monitoring of hemostasis during thrombolytic therapy with recombinant human tissue-type plasminogen activator.

Recombinant tissue-type plasminogen activator (rt-PA) was administered intravenously to 93 patients with acute myocardial infarction and coronary thrombosis in doses of 30 to 150 mg over 1.5 to 6 hours. During this infusion plateau levels of rt-PA in plasma ranged between 0.4 and 2.2 micrograms/ml. Activation of the plasma fibrinolytic system and fibrinogen breakdown both in vivo and in vitro was observed with this therapy. In vitro fibrinogenolysis in plasma was more effectively prevented by collection of blood samples on aprotinin (200 kallikrein inhibitor units/ml blood), a conventional serine protease inhibitor, than on either of two monoclonal antibodies against t-PA (200 micrograms/ml plasma), or on D-phenylalanyl-prolyl-arginine-chloromethyl ketone (PPACK), a newly developed synthetic inhibitor of t-PA. Results of fibrinogen measurements during infusion of rt-PA were dependent on the method of assay. In a subgroup of 36 patients after completion of a thrombolytic infusion, fibrinogen decreased in vivo by 27% when measured as total coagulable protein and by 33% with a coagulation rate assay, but increased by 26% with an automated assay system. The extent of fibrinogenolysis was proportional to the plasma level of rt-PA but substantial intersubject variation was observed. Fibrinogenolysis in vivo was also associated with alpha 2-antiplasmin depletion and was more pronounced with a two-chain (G11021) than with a single-chain preparation (G11035) of rt-PA.

Cardiac pacing in infants and children.

Pacemakers have been implanted in pediatric patients since the late 1960s. Indications for cardiac pacing in infants and children have evolved to include controlling symptoms as well as providing a life-sustaining cardiac rhythm. Pacemakers have become smaller and able to perform more complex functions. Current pacemakers offer a variety of operation modes, which are chosen on the basis of the pacing indication or the potential hemodynamic benefit. Today's pacemakers have the ability to maintain AV synchrony, perform rate-responsive pacing, and sometimes prevent or treat tachyarrhythmias. Recent advances in pacing lead technology, such as steroid elution, have narrowed the gap between epicardial and endocardial leads in terms of chronic pacing thresholds and sensing characteristics. The choice of a permanent pacing system is determined by the patient's size, underlying arrhythmia, and the anatomic details of any structural heart disease. Selection of temporary pacing modalities depends on the urgency of initiating pacing and the anticipated duration of temporary pacing. The decision to implant a permanent pacemaker in a pediatric patient commits the patient to long-term follow-up of pacemaker function. Such follow-up is important to ensure adequate safety margins for pacing and sensing, anticipate the need for pacemaker replacement, screen for pacemaker malfunctions, and optimize programmable settings. Pediatric cardiac pacing has evolved into its own subspecialty over the past decade. As more infants with complex congenital heart disease are being successfully treated with surgical palliation and repair, the population of pediatric patients with permanent pacemakers is likely to increase.

Pre-operative assessment of ventricular function in patients considered for Fontan procedure.

In 1978 Choussat and Fontan established ten criteria, which should be fulfilled to achieve a successful outcome in Fontan operation. Recent data suggest that while some of these ten criteria need not be necessarrily be fulfilled, new criteria should be added. These include 1. good diastolic function, 2. normal or only slightly increased ventricular mass, and 3. absence of systemic outflow obstruction. In addition the morphology of the single ventricle may be important as long-term results in patients with single ventricle of right ventricular morphology may be worse than results in patients with single ventricle of left ventricular morphology. Ventricular size and pump function can be assessed by cardiac catherization, echocardiography or magnetic resonance imaging. Estimation of ejection fraction under stress by nuclear angiography may be indicated. Diastolic function can be examined using Doppler echocardiography or nuclear angiography. Myocardial mass may be assessed by echocardiography or magnetic resonance imaging. Normal reference values for different parameters of systolic and diastolic function are listed in the enclosed tables. Patients scheduled for a Fontan operation should have an ejection fraction less than 50%. Patients with borderline ejection fraction should be examined by echocardiography to determine the end-systolic wall stress, a parameter of ventricular contraction, which is independent of pre- and afterload. As afterload may decrease after a Fontan operation some patients with reduced ejection fraction but normal end-systolic wall stress may still be suitable candidates for Fontan operation.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical implications of the morphological features of central pulmonary artery thromboemboli shown by transoesophageal echocardiography.

OBJECTIVES: To illustrate the use of transoesophageal echocardiography in the detection of the morphological features of central pulmonary artery thromboemboli and their clinical implications. DESIGN: Review of five cases of central pulmonary artery thromboemboli detected by transoesophageal echocardiography. SETTING: University teaching hospital. PATIENTS: Five patients (three men and two women) admitted under general medical units. RESULTS: Central pulmonary artery thromboemboli were detected by the use of transoesophageal echocardiography in all the patients presented. Presentations were acute, subacute, or chronic. The morphological features of the thromboemboli on transoesophageal echocardiography were used to correlate with the time course of the illness, and to guide treatment. Two patients received thrombolytic treatment, one patient was treated with anticoagulation alone, and two patients had inferior vena caval filters implanted. CONCLUSIONS: Transoesophageal echocardiography is an alternative diagnostic tool in the detection of central pulmonary artery thromboemboli. Morphological features of central pulmonary thromboemboli on echocardiography can provide useful information that may help to guide treatment.

Colocalization of F-actin and 34-kilodalton actin bundling protein in Dictyostelium amoebae and cultured fibroblasts.

The Ca2+-sensitive actin-binding protein isolated from Dictyostelium discoideum, 30,000-D protein (Fechheimer and Taylor: J. Biol. Chem. 259:4514-4520, 1984;) has recently been localized in filipodia of substrate-adhered amoebae (Fechheimer: J. Cell Biol. 104:1539-1551, 1987). We have determined that this protein has a Mr of 34,000 daltons and is strictly colocalized with actin filaments in both substrate-attached Dictyostelium amoebae and cultured fibroblasts. 3T3 fibroblasts, as well as normal and virally transformed rat kidney fibroblasts (NRK) contain a 34-kilodalton (kD) protein that cross-reacts specifically with antibody to the Dictyostelium bundling protein. Mammalian 34-kD protein is colocalized with F-actin in stress fibers and the cortical cytoskeleton in substrate-adhered fibroblasts. In substrate-adhered vegetative Dictyostelium, F-actin and 34-kD protein are concentrated in regions of the cell cortex exhibiting filipodia and membrane ridges. Multiple filipodia formed after exposure to the chemoattractant folic acid stain intensely for 34-kD protein, implying participation in the assembly of actin bundles during filipod formation. The cortex of pseudopodia also contained high concentrations of bundling protein, but pseudopod interiors did not. In contrast to vegetative Dictyostelium, F-actin and 34-kD protein were not colocalized in cells that had progressed through the developmental cycle. In fruiting bodies, 34-kD protein was detected by immunofluorescence microscopy only in prespore cells, while F-actin appeared in stalk cells and spores.