Maintenance of acetylcholine receptor number by neuregulins at the neuromuscular junction in vivo.

ARIA (for acetylcholine receptor-inducing activity), a protein purified on the basis of its ability to stimulate acetylcholine receptor (AChR) synthesis in cultured myotubes, is a member of the neuregulin family and is present at motor endplates. This suggests an important role for neuregulins in mediating the nerve-dependent accumulation of AChRs in the postsynaptic membrane. Nerve-muscle synapses have now been analyzed in neuregulin-deficient animals. Mice that are heterozygous for the deletion of neuregulin isoforms containing an immunoglobulin-like domain are myasthenic. Postsynaptic AChR density is significantly reduced, as judged by the decrease in the mean amplitude of spontaneous miniature endplate potentials and bungarotoxin binding. On the other hand, the mean amplitude of evoked endplate potentials was not decreased, due to an increase in the number of quanta released per impulse, a compensation that has been observed in other myasthenic states. Thus, the density of AChRs in the postsynaptic membrane depends on immunoglobulin-containing neuregulin isoforms throughout the life of the animal.

Differential expression of ARIA isoforms in the rat brain.

ARIA, heregulin, neu differentiation factor, and glial growth factor are members of a new family of growth and differentiation factors whose effects have been assayed on Schwann cells, skeletal muscle cells, and mammary tumor cell lines. To gain insight into their roles in the CNS, we studied the expression of ARIA in the rat brain. We found ARIA mRNA in all cholinergic neurons throughout the CNS, including motor neurons and cells of the medial septal nucleus and the nucleus basalis of Meynert. We also found that ARIA induces tyrosine phosphorylation of a 185 kDa protein in central and peripheral targets of these cholinergic neurons. ARIA mRNA, however, is not restricted to cholinergic neurons, suggesting that it may also play a role at other types of synapses. Its distribution in germinal layers of the telencephalon and cerebellum suggests that it may also play a role in the proliferation and/or migration of neuronal and glial precursor cells.

The electrophysiological effects of ouabain on sinus node and atrium in man.

Electrophysiological studies were performed in 16 patients before and 30 min after intravenous administration of ouabain (0.1 mg/kg). P-A interval (mean+/-SEM) was 40+/-2.1 ms before and 44+/- 1.5 ms after ouabain (P less than 0.001). Atrial effective and functional refractory periods (ERP and FRP) were measured in all patients during sinus rhythm and during driving at equivalent paced rates in 12 patients. The mean atrial ERP and FRP during sinus rhythm were, respectively, 244+/-10.5 and 307+/-11.0 ms before and 253+/-9.7 and 318+/-11.4 ms after infusion of ouabain (NS). Mean atrial ERP and FRP during driving were, respectively, 231+/-15.3 and 264+/-14.9 ms before and 266+/-18.6 and 296+/-19.7 ms after ouabain (P less than 0.01 and P less than 0.01). Mean sinus cycle length and sinus recovery times were, respectively, 887+/-31.2 and 1,113+/-38.7 ms before and 905+/-38.2 and 1,008+/-30.7 ms after infusion of ouabain (NS and P less than 0.005). Calculated sinoatrial conduction times before and after ouabain were 90+/-6.8 and 110+/-8.5 ms, respectively (P less than 0.005). In summary, ouabain produced depression of intraatrial conduction as manifested by increase in P-A interval and atrial effective and functional refractory periods. Ouabain significantly increased calculated sinoatrial conduction time without significant effect on spontaneous sinus cycle length.

Concordance and discordance of drug responses in atrioventricular reentrant tachycardia.

Whether the results of some drug studies could be used to predict the results of other drug studies was examined during serial electrophysiologic drug testing in patients with sustained atrioventricular reentrant tachycardia. The drugs studied were intravenous propranolol, 0.1 mg/kg; intravenous ouabain, 0.01 mg/kg; the combination of propranolol plus ouabain; intravenous procainamide, 0.75 to 1.5 g; oral quinidine, 1.2 to 2.4 g/day; and oral disopyramide, 0.8 to 1.6 g/day. Response was inability to induce sustained tachycardia after administration of a drug. Responses due to increased anterograde limb refractoriness. Six of 10 patients with response to propranolol plus ouabain versus 0 of 9 patients without response to this combination had response to propranolol alone (p less than 0.01). Seven of 14 patients with response to the combination versus 0 of 9 patients without response to the combination had response to ouabain alone (p less than 0.05). Responses due to increased retrograde limb refractoriness. Eight of 9 patients with response to procainamide versus 2 of 17 patients without response to this drug had response to quinidine (p less than 0.01). There was not a significant relation between response to procainamide and response to disopyramide, or between response to quinidine and response to disopyramide. Anterograde limb versus retrograde limb. There was not a significant relation between response to propranolol plus ouabain and response to any class I drug. In conclusion, there are relations between drug responses during electrophysiologic studies in patients with atrioventricular reentrant tachycardia. Thus, it should be possible to simplify these studies.

Portable electrocardiographic monitoring: performance in patients with short P-R intervals without delta waves.

Twenty-four-hour continuous protable tape-recorded electrocardiograms were obtained in 24 patients with short P-R intervals without delta waves. Atrial premature beats were noted in 15 patients (62%), paroxysmal supraventricular tachycardia (PSVT) in 5 (21%), ventricular premature beats in 14 (58%), and noticeable ventricular arrhythmia in 5 (21%). All episodes of PSVT reflected either unifocal or multifocal atrial ectopic firing. Atrioventricular nodal reentrant PSVT was not observed. Electrocardiographic correlation of symptoms with arrhythmias was not striking. In 21 of the patients, the P-R interval remained short constant through the 24-hour recording period. Patients with a short P-R interval without delta waves have frequent arrhythmias involving multiple areas of the conduction system. The presence of an accessory atrioventricular connection (James tract) would not explain the arrhythmias recorded in these patients.

Familial atrial tachyarrhythmia with short PR interval.

A family had an unusual and perhaps unique familial dysrhythmia. The proband had a short PR interval with normal QRS and chronic recurrent paroxysmal atrial tachycardia (Lown-Ganong-Levine syndrome). The arrhythmia produced left ventricular dysfunction. Both paroxysmal atrial tachycardia (PAT) and left ventricular dysfunction were reversed with administration of digoxin and propranolol hydrochloride. Three family members had paroxysmal or chronic atrial fibrillation, first diagnosed at a relatively young age (23 years, 38 years, and early 40s, respectively). Five additional family members had short PR intervals with normal QRS, and eight other family members had borderline short PR intervals. The mode of inheritance appeared to be autosomal dominant with varying expressivity. We have described a familial syndrome characterized by PAT or atrial fibrillation in its advanced form with short PR interval as a possible identifying trait. The future course of members with isolated short PR is unknown.

Long-term follow-up of patients receiving aprindine. Safety and efficacy.

Aprindine hydrochloride is an antiarrhythmic agent presently undergoing clinical trials in the United States. Because of the narrow therapeutic-toxic ratio observed for aprindine, the long-term follow-up of these patients is important in determining the potential clinical effectiveness of this drug. In this report we examine our experience with 30 patients with drug-resistant arrhythmias who were discharged receiving aprindine and who were followed up for a mean period of 25 months.

Sudden death caused by benign tumor of the atrioventricular node.

Histologic study of the conduction system of the heart of a 16-year-old girl who died suddenly demonstrated a benign mesothelioma of the AV node, with almost complete replacement of the structure by the tumor. Teh past history was unremarkable, except for few syncopal episodes at 9 and 11 years of age and during pregnancy. Immediately postpartum, she developed a 2:1 AV block and intermittent complete AV block. Six weeks later, during diagnostic work-up in the cardiac catheterization laboratory, she died suddenly. Electrophysiological studies during this work-up disclosed complete AV dissociation, with normal QRS complexes. The block was proximal to the His-bundle recording site, with a normal H-V interval. Occasional syncopal attacks in young adults should alert the physician to the possibility of this diagnosis and lead to pacemaker insertion.

Sudden death in patients with chronic bifascicular block.

Prospective follow-up studies of 277 patients with chronic bifascicular block showed that 30 patients developed sudden cardiac death (SCD). Cumulative one-, two-, and three-year SCD mortality was computed. The patients that developed SCD were compared with the remaining patients (209 alive and 38 dead). The groups were similar in regard to age, sex, AH, and HV intervals. The following were more frequent in the SCD group (P less than .05): angina, previous myocardial infarction, heart failure, cardiomegaly, left bundle-branch block, premature ventricular beats, and ventricular tachycardia. Ventricular fibrillation was the cause of death in four cases of SCD where terminal ECG documentation was available. We concluded that SCD is a major cause of mortality in patients with chronic bifascicular block. The association of SCD with coronary disease and ventricular dysrhythmia suggested ventricular fibrillation as a frequent mechanism.

Left ventricular performance after acute myocardial infarction. Sectrum of functional abnormalities and importance of wall motion disturbances during convalescent phase.

Seventeen patients underwent catheterization of the right and left sides of the heart and left ventricular (LV) angiography three to six weeks after acute myocardial infarction. Fourteen of 17 patients had abnormal LV function. Three patients had altered LV diastolic properties; five patients had abnormalities of diastolic properties and of systolic function; and six patients had abnormal systolic function, but diastolic function could not be assessed. Thirteen of the 14 patients with abnormal LV function had LV wall motion abnormalities, which were quantitatively related to impaired LV systolic function.

Insulin-like growth factor II expression in the developing human brain.

Insulin-like growth factor II (IGF-II) is a polypeptide hormone with insulin-like metabolic activity and neurotrophic activity in vitro that has been implicated in human brain development. In this study, we used northern blot analysis to examine the patterns of IGF-II mRNA expression in selected regions of 18 human brains from cases ranging in age from 20 gestational weeks to 2.5 years (median age 31 gestational weeks). The expression of IGF-II mRNA was widespread throughout the brain from midgestation through the perinatal period. Each region showed a distinct developmental pattern of expression and IGF-II mRNA levels varied considerably between regions. The highest levels of expression at all ages were in leptomeninges and choroid plexus. After two postnatal months, IGF-II mRNA virtually disappeared from parenchymal regions. Beyond the perinatal period, IGF-II expression persisted primarily in choroid plexus. Transcripts of both 6.0 and 4.8 kb were detected in most brain regions. A developmental change in the relative amounts of the two transcripts occurred in choroid plexus, leptomeninges and medulla. The expression of IGF-II mRNA in the brain parenchyma during the last half of gestation correlates with a period of major brain growth and supports the hypothesis that high levels of IGF-II stimulate the proliferation and differentiation of neural cells early in development.

Specific, temporally regulated expression of the insulin-like growth factor II gene during muscle cell differentiation.

We have compared the expression of insulin-like growth factor II (IGF-II) messenger RNA (mRNA) to the expression of other mRNAs encoding proteins known to play pivotal roles during the differentiation of continuously cultured, fusing muscle cell lines. These cell lines respond to changes in culture conditions by undergoing a well characterized alteration in gene expression which leads to a change in their phenotype from dividing, mononucleate myoblasts to fused, multinucleate myotubes. The hallmarks of this differentiation program include the induction of myogenic regulatory genes as well as the genes that encode the contractile proteins. We have found that the differentiation of these cells leads to the production of multiple IGF-II transcripts. In one of the cell lines studied, C2C12, IGF-II mRNA levels were rapidly induced during differentiation. Increases in IGF-II mRNA levels preceded the expression of the contractile protein genes but occurred only after the activation of the myogenic regulatory gene myogenin. The same regulated pattern of IGF-II mRNA expression was seen in both rapidly and slowly fusing subclones of this cell line, indicating a requirement for IGF-II at a specific point during muscle differentiation. These results suggest that IGF-II plays an important role during the terminal differentiation of skeletal muscle cells and are consistent with the existence of an autocrine loop through which IGF-II may act to regulate the differentiation process.

Left atrial transport function in myocardial infarction. Importance of its booster pump function.

After myocardial infarction (MI), left ventricular (LV) end-diastolic pressure (EDP) is higher than mean pulmonary artery wedge pressure because of powerful atrial contraction. To evaluate the significane of atrial contraction to left ventricular function we studied 10 control (C) patients without cardiac disease and 17 patients from three to six weeks after acute myocardial infarction. Cardiac catheterization with simultaneous left ventricular diastolic pressure (DP) and left ventricular cineangiograms were obtained. Left ventricular volumes and pressure were (mean +/- SD): (SEE ARTICLE). Although left ventricular stroke volume was lower in the patients with myocardial infarction than in the control subjects (46 versus 56 ml/m2), atrial contraction contributed more to left ventricular filling during diastole (which is the same as left ventricular stroke volume) in the patients with myocardial infarction than in the controls (16 versus 10 ml/m2). The average atrial contribution to left ventricular end-diastolic volume was 11.9 per cent (C), 15.4 per cent (MI); to left ventricular end-diastolic pressure 20 per cent (C), 38.7 per cent (MI); and to left ventricular stroke volume 21.7 per cent (C), 35.1 per cent (MI). Atrial contribution to left ventricular stroke volume was 56 per cent in patients with a cardiac index less than or equal to 2.0 liters/min/m2 and 31 per cent in those with a cardiac index greater than 2 liters/min/m2 (p less than 0.01). Atrial contraction contributed 35 per cent to left ventricular stroke volume in patients with normal end-diastolic volume and in those with increased end-diastolic volume and 10 per cent to end-diastolic volume in patients with increased end-diastolic volume (p less than 0.001). In patients with myocardial infarction, atrial contraction made a large contribution to left ventricular filling and stroke volume irrespective of the type of left ventricular functional derangement that was present. The "booster pump" function of the atrium cannot be ignored in assessing left ventricular performance.

Optimizing the northern blot procedure.

We describe methods for preparing formaldehyde-agarose gels for use in Northern blotting which yield consistent high quality results. Using these methods, we tested seven different commercially available membranes in Northern blots. Each membrane was handled as specified by the manufacturer in a course of hybridization, stripping and rehybridization. Filter background was low in all cases, but the intensity of the signal generated by specific hybridization varied markedly between filters after both the first and second hybridization.

Multiple reentrant tachycardias due to retrograde conduction of dual atrioventricular bundles with atrioventricular nodal-like properties.

A patient is presented who had two paroxysmal supraventricular tachycardias, one slow and incessant and the other fast. Both paroxysmal tachycardias appeared to be atrioventricular (A-V) reentrant, with anterograde conduction by way of a normal A-V pathway. Two pathways conducting in retrograde manner were demonstrated, characterized by different conduction times (fast and slow), identical abnormal atrial activation sequence and A-V nodal-like properties (retrograde Wenckebach periodicity with rapid ventricular pacing, and depression with ouabain and propranolol). Thus, there appeared to be two anomalous A-V bundles with nodal-like properties conducting in retrograde fashion. Whether the paroxysmal tachycardia was fast or slow depended on which of these pathways was utilized. Spontaneous cure of incessant paroxysmal tachycardia was observed and coincided with unexplained total loss of ability for ventriculoatrial conduction.

Arrhythmias documented by 24 hour continuous electrocardiographic monitoring in 50 male medical students without apparent heart disease.

Results are reported of portable 24 hour dynamic electrocardiographic monitoring in 50 male medical students without cardiovascular disease, as defined by normal clinical and noninvasive cardiovascular examination. During waking periods, maximal sinus rates ranged from 107 to 180 beats/min (mean +/- 5). Twenty-five subjects (50 percent) had episodes of marked sinus arrhythmia as defined by spontaneous changes in adjacent cycle lengths of 100 percent or more. Fourteen subjects (28 percent) had sinus pauses of more than 1.75 seconds, usually during sinus arrhythmia. Transient nocturnal type I second degree atrioventricular (A-V) block was noted in three subjects (6 percent). Of 28 patients (56 percent) having atrial premature beats, only 1 (2 percent) had more than 100 such beats (141) in 24 hours. Of 25 patients (50 percent) having premature ventricular contractions, only 1 (2 percent) had more than 50 such contractions (86) in 24 hours. In conclusion, frequent atrial and ventricular premature beats are unusual in a young adult male population. In contrast, bradyarrhythmias (including marked sinus arrhythmia with sinus pauses, sinus bradycardia and nocturnal A-V block) are common. These findings are useful in evaluating the clinical significance of arrhythmias detected with portable monitoring.

Retrograde block during dual pathway atrioventricular nodal reentrant paroxysmal tachycardia.

There are limited reported data regarding the occurrence of retrograde block during dual pathway atrioventricular (A-V) nodal reentrant paroxysmal tachycardia. This study describes two patients with this phenomenon. The first patient had 2:1 and type 1 retrograde ventriculoatrial block during the common variety of A-V nodal reentrance (slow pathway for anterograde and fast pathway for retrograde conduction). Fractionated atrial electrograms suggested that the site of block was within the atria. The second patient had type 1 retrograde block (between the A-V node and the low septal right atrium) during the unusual variety of A-V nodal reentrance (slow pathway for retrograde and fast pathway for anterograde conduction). The abolition of retrograde block by atropine suggested that the site of block was within A-V nodal tissue. Both cases demonstrate that intact retrograde conduction is not necessary for the continuation of A-V nodal reentrant paroxysymal tachycardia. Case 2 supports the hypothesis that the atria are not a requisite part of the A-V nodal reentrant pathway.

Pathologic correlations in three cases of bilateral bundle branch disease with unusual electrophysiologic manifestations in two cases.

Examination of the conduction system in three patients with bifascicular block who had electrophysiologic studies forms the basis for this report. Patients 1 and 2 had left bundle branch block and Patient 3 right bundle branch block and left axis deviation. The H-V interval was prolonged in each case (70, 65 and 60 msec, respectively). Serial section examination of the conduction system revealed sclerodegenerative involvement of both bundle branches in all cases. In Case 1, atrial extrastimulus testing converted left to right bundle branch block; in Case 2, it delineated a sinus echo zone with repetitive sinus nodal reentrance. In the latter case serial section revealed extensive amyloid infiltration of the approaches to the sinoatrial (S-A) node and the atrial preferential pathways. In Case 3, with right bundle branch block and left axis deviation, serial section revealed greater involvement of the anterior part of the main left bundle branch than of the posterior portion as well as involvement of the second part of the right bundle branch. The study revealed excellent correlation between electrophysiologic and pathologic findings in three cases of intraventricular conduction disease and demonstrated an anatomic basis for the electrophysiologic findings resembling alternating bilateral bundle branch block. Sinus nodal reentrance may be related to disease in the approaches to the S-A node thereby causing delay in perinodal tissue allowing sinus reentrance. Finally in Case 3, the anatomic substrate for left axis deviation may lie in a greater involvement of the anterior portion than of the posterior portion of the main left bundle rather than in the corresponding portions of the periphery.

Self-initiated conversion of paroxysmal atrial flutter utilizing a radio-frequency pacemaker.

A patient is described with drug-resistant recurrent paroxysmal atrial flutter. Electrophysiologic studies demonstrated that flutter was inducible with rapid atrial stimulation (stimulation rates of 375 to 400/min) and convertible with rapid atrial stimulation (rates of 400 to 460/min). Because of the latter response, a radio-frequency atrial pacemaker was implanted, which allowed self-initiated conversion of flutter episodes with rapid stimulation.

Electrophysiologic observations in a patient with bradycardia-dependent atrioventricular block.

In a patient with atrioventricular (A-V) block distal to the His bundle (H), 1:1 A-V conduction with right bundle branch block and H-V interval of 70 msec was established with atrial pacing at rates of 120 to 150/min, suggesting that the A-V block was bradycardia-dependent. Advanced second degree A-V block distal to the H deflection occurred with atrial pacing at 160/min after completion of A-V nodal Wenckebach periodicity proximal to the H deflection because of the long H-H encompassing the blocked P wave. Atrial extrastimulus testing coupled with sinus rhythm (with A-V block) demonstrated that critical H1-H2 intervals of less than 545 msec allowed conduction to the ventricles. The H2-V2 interval shortened progressively from 290 to 70 msec with shortening of these critical H1-H2 intervals. Atrial extrastimulus testing coupled with an atrial driven cycle lenght of 500 mesc (with intact A-V conduction) revealed block of the H2 deflection with an H1-H2 interval longer than 540 msec. In conclusion, at critical diastolic intervals, impulses were blocked, creating a state of decreased responsiveness. If a cycle length of subsequent impulses was shorter than the critical diastolic blocking interval, membrane responsiveness gradually improved and conduction resumed. If a cycle length of subsequent impulses was longer than the critical blocking diastolic interval, A-V block was sustained. Blocked impulses continually penetrated to the site of block and reset the state of membrane responsiveness.