Balloon electrode catheter for transesophageal atrial pacing and transesophageal ECG recording. A new balloon electrode catheter (10 French) with five or six balloon electrodes placed on the cardiac side was developed for transesophageal atrial pacing and bipolar ECG recording. The diameter of the hemispheric electrodes is 6 mm and the length of the esophageal balloon is 10 cm. The transesophageal atrial pacing threshold was measured with the balloon electrode catheter by transesophageal programmed atrial stimulation (TPS) (n = 54). At the onset of TPS, the feeling, capture (n = 54), and pain voltage threshold (n = 6) were measured by increasing the amplitude of the pacing voltage during high rate bipolar atrial pacing and bipolar atrial ECG recording. In 38 TPS, the capture threshold was lower than the feeling threshold (n = 28). In 16 TPS, the capture threshold was higher than the feeling threshold. In conclusion, painless atrial pacing and excellent ECG recording can be achieved with a multipolar esophageal balloon electrode catheter with a low pacing voltage amplitude and a high P wave amplitude.


Prediction of permanent atrial sensing by preoperative esophageal atrial wave evaluation. Atrial undersensing is a common problem in permanent atrial and dual chamber pacing. The purpose of this study was to evaluate the relationship between transesophageal atrial wave (EsAW) and right atrial endocavitary (RA). Forty-seven patients 72 +/- 9.7 years of age, with symptomatic bradyarrhythmias were studied. The EsAW was filtered with a high pass filter of 10 Hz (Arzco preamplifier-filter), using 1, 2, and 3 cm bipolar transesophageal catheters. Atrial bipolar floating 1, 2, and 3 cm electrograms from the high RA (HRA) and from the mid RA (MRA), as well as unipolar electrograms from the right auricle (RAUR) were recorded 1 day later. Comparison by paired t-test showed no significant differences between EsAW and bipolar sensing in RA, but significant differences between EsAW and RAUR (P = 0.0001). The results of the Spearman correlation coefficient for sensing (mV) for EsAW, HRA, and MRA, respectively, were: 1 cm, 1.8 +/- 0.9, 1.7 +/- 0.9, and 1.9 +/- 0.9 (z > 3.5; P < 0.0003); 2 cm, 2.2 +/- 0.9, 1.9 +/- 0.8, and 2.1 +/- 0.9 (z > 2.3; P < 0.03); 3 cm, 2.1 +/- 1, 2 +/- 0.9, and 2.2 +/- 1.0 (z > 2.9; P < 0.003); and the result for the monopolar RAUR was 3.0 +/- 1.0 (z < 1.4; P > 0.17). These findings, if confirmed in more patients, indicate that preoperative EsAW recording could be useful in estimating the quality of bipolar floating electrograms from the RA but not of unipolar RAUR.


Termination of tachycardias by transesophageal electrical pacing. To evaluate the therapeutic significance of noninvasive transesophageal pacing for termination of tachycardias the method of rapid atrial or ventricular transesophageal pacing was used in 233 patients with different tachycardiac arrhythmias. We were able to terminate atrial flutter in 136 of 162 patients by transesophageal rapid atrial stimulation (conversion to sinus rhythm in 75 cases, induction of atrial fibrillation in 61 cases). Atrial tachycardias were interrupted in 17 of 23 patients (sinus rhythm in 11 cases, atrial fibrillation in six cases). AV reciprocating/AV nodal supraventricular reentry tachycardias were terminated in 62 of 63 patients (sinus rhythm in 58 cases, atrial fibrillation in four cases). By transesophageal rapid ventricular pacing ventricular tachycardias could be terminated in ten of 15 patients. The success rate of transesophageal pacing was influenced by the pacing rate, by the type of tachycardiac arrhythmia inclusive by the type of atrial flutter and by the tachycardia's cycle length. Because the success rates are comparable with invasive technique and the procedure is simpler, the noninvasive transesophageal antitachycardiac pacing should be respected as the method of the first choice in patients with supraventricular tachycardias.


Is polyurethane lead insulation still controversial? A controversy arose some 10 years ago over the reliability of polyurethane lead insulation. On the basis of one of the longest standing and largest databanks worldwide, the authors compare the cumulative survival of several thousand polyurethane, standard silastic, and high-performance silastic electrodes as it pertains to the failure criterion described as insulation degradation. With the possible exception of the Medtronic 6972 (Medtronic, Inc.) electrode, polyurethane electrodes have a 100% reliability at 84 months, which is similar to silastic electrodes.


Threshold and polarization properties of modern active fixation atrial leads. The purpose of the study was to compare the stimulation characteristics of two modern active fixation leads (Ela 583F, vitreous carbon tip [ELA] and Intermedics 82-0008-1601, iridium oxide tip [IROX]) with a standard lead (Osypka KY 67 VC, carbon-covered elgiloy tip [OSY]). In three groups of ten patients each, minimum charge threshold delta Qmin and polarization properties were determined via charge telemetry of the pacemaker (Intermedics Cosmos II and Relay) 0, 2, 5, 10, 28, 90, and 180 days after implant (dai). The polarization parameters global capacitance Cg, global resistance Rg, polarization voltage U(p), and a time constant t* (t* = Cg.Rg) were obtained by nonlinear regression. U(p) was always significantly (sig) lower in ELA and IROX (0.04-0.10 V) compared to OSY (0.54-0.76 V). Rg was sig lower in ELA (330-437 omega) compared to OSY and IROX (414-588 omega) from 0 to 28 dai. From 2 to 10 dai, Cg was sig higher in ELA and IROX (3.8-4.2 microF) compared to OSY (3.3-3.4 microF). In the three groups, delta Qmin reached a comparable maximum (1-1.2 microC) at 5 dai. Therefore, vitreous carbon and iridium oxide atrial fixation leads exhibit low chronic polarization effects compared to a standard elgiloy lead, but do not show a sig reduction in charge threshold.


Atrial stimulation by means of floating electrodes: a multicenter experience. The Multicenter Study Group. It is well established that single lead VDD pacing is a physiological, reliable, and easy to use mode of pacing. The major limitation of VDD pacing is the need of a normal sinus node function, confirming its indication to patients with isolated atrioventricular conduction disturbances. The Phymos 830 pacing lead was originally designed for VDD pacing in association with the Phymos MPS pulse generator; it has a floating atrial dipole with an interelectrode distance of 3 cm; the distal electrode is 11, 13, or 15 cm proximal to the tip. As a result of the incidental observation of atrial captures occurring at very low pulse amplitudes delivered from the floating dipole of this lead, a 13-center Italian study was initiated to test the systematic feasibility of this type of atrial pacing. Pacing parameters were set and strength-duration curves were acquired with the PSA Master 470 external device. The investigation was performed at pacemaker implant in 114 patients in the supine position. The tip of the electrode was positioned at the right ventricular apex and the atrial dipole at the site of the highest endocavitary signal. Atrial bipolar pacing was performed with the proximal electrode as the cathode. Stable atrial capture was obtained in 108 of 114 patients (94.7%); pacing threshold was < 3.5 V with a pulse width of 1 msec in 85 of 108 patients. Results of voltage threshold were: 2.99 +/- 1.25 and 2.59 +/- 1.13 V at pulse widths of 0.5 and 1 msec, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of an in-line bipolar polyurethane ventricular pacing lead. A study was undertaken to evaluate the performance of the Medtronic 4012 polyurethane in-line bipolar pacing electrode. One hundred twenty six patients implanted with the 4012 lead were followed by our clinic with 116 of these leads implanted at our institution. Patients were followed a minimum of every 4 months. Testing included the performance of stimulation thresholds, sensing thresholds, and provocative maneuvers to evaluate for myopotential inhibition testing a minimum of every eight months. There were 12 documented lead failures of the total 126 patients. Further analysis was limited to the ten failures occurring in the 116 leads implanted at our center. All ten failed leads utilized the suture anchoring sleeve. Six of the leads were left cephalic implants, three were right cephalic, and one was right subclavian. Manifestations of failure included: seven oversensing abnormalities, three undersensing, four loss of ventricular capture, one premature end of service, four lead impedance decreases to < 250 omega and some presentations in combination. No leads were explanted for evaluation. The Kaplan-Meier product limit method was used to estimate the time to lead failure. The probability of not experiencing a lead failure within the first 4 years of implant is estimated to be 0.9103 (SE = 0.0338). Pacemaker dependent patients implanted with the 4012 lead should be given special consideration for prophylactic replacement.


Thin bipolar leads: a solution to problems with coaxial bipolar designs. A new type of bipolar lead has been designed to be thinner and more reliable than the standard coaxial design. The new lead has passed numerous bench tests to ensure its reliability. Improved fatigue performance was shown during comparisons between the new type of coil (bifilar DFT [drawn filled tube]) and previous standard coils (trifilar MP35N). During the initial animal studies no reliability concerns were raised and stable electrode thresholds were measured. If success in the test process of this lead continues, a bipolar lead may soon be marketed with a size and reliability comparable to unipolar leads.


Pacing lead survival: performance of different models. Recent reports have shown poor survival of some leads currently in use. Long-term survival analysis of 2,444 leads (1,059 atrial and 1,385 ventricular) implanted in this institution since January 1980, and having at least 1 month of follow-up was performed. The survival of 123 different models was compared with the average survival of all the leads implanted in the corresponding chamber. Failure was defined as inactivation of the lead (electrical abandonment, explant, or cap) due to insulator and/or conductor fracture. The mean follow-up was 33 +/- 32 months. The cumulative survival for different atrial lead models was consistent with the average performance in the atrium. No atrial lead showed better or worse survival compared to the others. In the ventricular group, the Medtronic 4012 lead showed statistically significant poorer survival (P = 0.01) compared with the average survival of the ventricular leads. The Cardiac Pacemakers, Inc. (CPI) 4010 lead showed a nonsignificant (P = 0.12) worse performance than the average for ventricular leads. (1) The Medtronic 4012 had a significantly poorer performance than the rest of the leads. A trend in similar direction was found for the CPI 4010, also in the ventricular group; (2) Atrial lead models showed a stable survival; and (3) Frequent follow-up is required for some leads, especially in pacemaker dependent patients.


The measurement of the paced depolarization integral using the braided endocardial lead. Previous studies have shown that the paced depolarization integral (PDI) data recorded in unipolar configuration could potentially improve the specificity of tachyarrhythmia classification in an implantable cardioverter defibrillator (ICD). However, the defibrillation protection would be compromised if the ICD case were used as an indifferent electrode. Since transvenous defibrillation leads are being investigated to be used with ICDs, this study determined if reliable PDI data could be obtained using the braided endocardial defibrillation lead (BEDL). The results demonstrated that comparable PDI values and PDI changes with epinephrine induced sinus tachycardia were obtained with all three tested sensing configurations: conventional unipolar, tip electrode to right ventricular defibrillation electrode, and tip electrode to superior vena cava defibrillation electrode. Therefore, the BEDL can be used to measure PDI data, which possibly may improve tachyarrhythmia classification in an ICD, without compromising its defibrillation protection.


Analysis of set screw and side-lock connector reliability. A retrospective review of complications with connectors and lead-to-header interfaces was performed following 649 pacing procedures between 1980 and 1990. There were 88 lead revisions (13.6%), 81 device replacements or modifications (12.5%), and 480 new implants (74%) using devices of five manufacturers. Two basic connector types were studied, one utilizing a set screw and the other using a side-lock compression fitting. The set screw makes electrical contact and mechanically secures the lead connector pin with a set screw insulated by a self-sealing grommet or an integral or separate set screw cover. The side-lock makes electrical contact with an automatic spring mechanism while the plastic lead terminal is secured in the connector block of the pacemaker by a Delrin side-lock compression fitting. Four hundred fifty-nine set screw connector devices were followed for up to 12 years with 14 complications (3.1%) whereas 82 side-lock connector devices were followed for up to 5 years with one complication (1.2%). The set screw and side-lock connectors were reliable over the period of follow-up. Although the complication rate appeared lower with the side-lock, follow-up was shorter and the number of implants smaller. With the leads used in this study, the side-lock proved to be a desirable feature due to simplicity, speed, safety, and ease of use. One limitation is the requirement for a precise IS-1 connector terminal diameter.


In vitro evaluation of new design lead anchoring sleeves. The purpose of this study was to evaluate various new lead anchoring sleeve designs. These designs were intended to allow coaxial bipolar leads to be tied down and remain securely in position with minimal damage to the lead body, whether tied down with moderate or high tie forces. Axial grooves were made on the outer and/or inner walls of various anchoring sleeve designs. Anchoring sleeves made of extra tear resistant (ETR) platinum catalyzed and peroxide catalyzed (MDX) silicone rubber of various shore, hardness were tested on various Siemens Pacesetter (S-P) and other manufacturers' lead bodies. Tests to slide the sleeves were conducted with the leads in dry and wet conditions, and with and without the Fast-Pass (Siemens Pacesetter, Inc.) coating for lubriciousness. Tie-down deformation of coils was measured from x-ray photos. Mechanical tests and stress calculations were also done to evaluate the mechanical properties of the different lead bodies being tested. The test results showed that compared with existing sleeves, the new design MDX sleeves with axial grooves on the outer wall of the anchoring sleeves provided much lower resultant deformation (62%-84%) on leads when tied down tightly, and exhibited similar sliding forces. Also, it was determined that the MDX anchoring sleeves provided much improved slip forces of two to three times higher than the ETR sleeves. Tie-down damage can also be significantly reduced by strengthening lead bodies. With the protection of the new sleeves, the tie-down damage of S-P leads was the lowest among all the manufacturers' polyurethane or silicone leads tested.(ABSTRACT TRUNCATED AT 250 WORDS)


Septal His-Purkinje ventricular pacing in canines: a new endocardial electrode approach. Ventricular activation sequences and cardiac performance are influenced by pacing sites. Stimulation of or close to the specialized atrioventricular (AV) conduction system optimizes paced ventricular function compared to alternative epi- or endocardial muscle conduction sites. This study reports a new endocardial electrode implant approach to approximate septal His-Purkinje ventricular pacing. Five 6-month-old beagles were used. A custom, platinum-iridium, exposed helical screw electrode (Medtronic, Inc.), 4.5-mm long, with a 17.8-mm2 surface area, was designed with a polyurethane covered 4 filar MP35N nickle conductor lead. An 8 French sheath (USCI, Inc.) was modified as introducer to permit simultaneous implant intracardiac pressure and electrogram recordings. Following a thoracotomy, the introducer was inserted through the right atrial appendage and advanced to record optimal His-bundle electrogram while maintaining atrial pressure along the septal tricuspid valve annulus. After electrode implant, ECG demonstrated narrow paced QRS morphology. Mean implant values showed sensed R wave 6.3 mV, slew rate 0.65 V/sec, pacing impedance 319 ohms, and threshold 0.9 V/3.3 mA at 0.5-msec output. Necropsy showed implant above the tricuspid annulus with electrode extension into and contained within the proximal ventricular septum. This study demonstrates that an endocardial septal approach to His-Purkinje ventricular pacing to optimize paced ventricular function is feasible with a new electrode design and precise septal implant technique. Alternative introducer designs may permit transvenous application of this approach.


Testing of work environments for electromagnetic interference. A challenge for pacemaker therapists is whether a patient working in an environment with the potential for electromagnetic interference (EMI) can return to their work after a pacemaker has been implanted. Common practice has been to prohibit pacemaker patients from using electric welding machines. Twelve work environments and a new method for monitoring the pacemaker rhythm in the presence of EMI were tested. The new method uses a special memory called the event record found in several Siemens Pacesetter pacemaker models. Surface ECGs with a marking system, intracardiac electrograms, and a digital monitor were used to verify the results with event records. The results from several sources of EMI are reported. Twenty-one in vivo and in vitro tests were performed in the work environments of 12 patients. Event records were useful and accurate both in vivo and in vitro. Electric are welding machines up to 225 A did not affect these pacemakers. Arc welding machines using 1,000 A or more inhibited the in vitro test system within 1 or 2 meters of the weld or power generator. Electric welding machines with high frequency voltage superimposed on the welding current affected the pacemaker when it was within 2 meters of the power unit and 1 meter of the weld. Very large industrial degaussing coils affected pacemakers within 2 meters. The test method using event records was found to be an effective addition to monitoring the pacemaker. These results are specific for the pacemaker models tested. Such testing allows the physician to make a knowledgeable decision regarding return to work for the pacemaker patient in a high EMI environment.


The clinical relevance of electromyopotential oversensing in current unipolar devices. Electromyopotential oversensing of unipolar pacemakers was first appreciated 20 years ago, but its prevalence in present day devices is less well defined. Thirty-four pacemaker patients, only two with symptoms suggestive of oversensing, were evaluated in unipolar settings to assess the frequency of provocation of oversensing in one or, if present, both pacing channels. The sensing threshold of each patient, whenever possible, was recorded as well. Atrial oversensing occurred in 11/18 patients (61%), all at sensitivities in the 0.4-1.0 mV range. Ventricular oversensing was noted in 13/33 patients (39%), with all but one programmed to settings of 1.25 mV or more sensitive (i.e. < 1.25 mV). Twenty six of 26 patients amenable to testing had ventricular sensing thresholds of at least 4.0 mV or more. Of the 15 patients amenable to atrial sensing threshold testing, 4 had a threshold of 1.0 mV or < 1.0 mV, 6 had thresholds between 1.0-2.0 mV, and 5 sensed at settings > 2.0 mV. Electromyopotential oversensing remains a relevant issue in current day unipolar pacemakers. Most patients do not describe symptoms related to electromyopotential interference, yet such interference is frequently provoked. Oversensing is common at high sensitivities typically utilized for atrial sensing, but quite unusual at settings necessary for adequate ventricular sensing. Programming unipolar devices to unnecessarily high sensitivities should be avoided or serious consequences may result.


Interaction between permanent cardiac pacing and electrocautery: the significance of electrode position. The danger in utilizing electrocautery during a surgical procedure on a pacemaker patient depends, to a great extent, on the position of the electrodes. We have studied this influence in an experimental model consisting of a plexiglass tank filled with a saline solution. Seven pacemakers were successively attached to an immersed and fixed frame and connected to a lead whose tip remains in the same location throughout the experiments. An ERBOTOM T 400 C generator (450 kHz) was used in an unmodulated unipolar mode at a maximum output (400 W). The high frequency current was delivered between a patch located successively at six preset positions in the tank and another electrode applied to 176 surface locations. For each position, we measured the currents in the lead with a separate measurement circuit connected in parallel on the same lead. Results were displayed on a map. Regardless of the patch position, currents were: (1) at a maximum when high frequency was delivered close to the pacemakers and around the tip of the lead; (2) negligible when applied to the path followed by the lead; and (3) a function of the distance between electrodes. These results may help to formulate recommendations to prevent accidents when using electrocautery in pacemaker patients.


The lithium/iodine battery: a historical perspective. The lithium/iodine-polyvinylpyridine battery, first implanted 20 years ago, has become the power source of choice for the cardiac pacemaker. Over the last 20 years, improvements in cell chemistry, cell design, and modeling of cell performance have been made. Cells today exhibit an energy density over three times as great as cells produced in 1972. Well over 2 million pacemakers have been implanted with this chemistry, and the system has exhibited excellent reliability.


Pacemaker dependency after coronary artery bypass. A retrospective study was carried out on 36 patients (33 males and 3 females) to determine the incidence of VVI pacemaker dependency following coronary artery bypass surgery. Pacemaker dependency was defined as the presence of pacemaker activity when pacing rate was programmed at 50 beats/min and/or when no hemodynamic adequate rhythm was present during pulse generator replacement. The patients were divided into two groups: (group I) 26 patients with complete atrioventricular (AV) block developing in the early postoperative period. In most of them a pacemaker was implanted up to 3 weeks following surgery (range 2 days to 1 year); (group II) ten patients in whom the indication for pacemaker implantation was sick sinus syndrome with sinus arrest and/or tachy-bradycardia. These patients underwent pacemaker implantation at varying periods of time following surgery (range 12 days to 4 years). Unipolar endocardial leads with VVI programmable pacemakers were implanted in all patients included in this study. Mean follow-up time was 3 years. In group I the pacemaker dependency rate was 65%, whereas in group II it was 30% throughout the follow-up period. It is concluded that the low incidence of pacemaker dependency in patients who undergo pacemaker implantation after coronary bypass surgery necessitates frequent evaluation in the nondependent patient, in order to reassess the need for the pacemaker before pulse generator replacement. Such reassessment should probably include prolonged ambulatory monitoring as well as invasive evaluation of the conduction system, if avoidance of pulse generator replacement is considered.


Can the heart be chronically paced with electrodes on the pericardial surface? During implantable defibrillator (ICD) operations, we measured acute and chronic transpericardial bipolar pacing thresholds through standard myocardial surface electrodes sewn on the pericardium for chronic ICD QRS rate-sensing use. We compared observations in 24 patients on day 0 with chronic measurements in seven patients at 27.4 +/- 12.1 (median 31.7) months. The leads were used only for QRS rate-sensing, not for pacing, during the time between acute and chronic measurements. Acute transpericardial pacing threshold at 0.5-msec stimulus duration on day 0 was 4.5 +/- 2.19 V (standard deviation), median 3.5 V, and at median time 964 days postimplantation was 3.8 +/- 2.07 V, median 3.5 V. Mean acute pacing current threshold was 3.7 +/- 1.90 mA, n = 23, and chronic was 2.7 +/- 1.79 mA, n = 6. Acute bipolar impedance was 1,209 +/- 383 ohms, median 1,138 ohms, and chronic was 1,550 +/- 358 ohms, median 1,410 ohms, n = 7. Acute bipolar QRS amplitude was 12.3 +/- 5.93 mV, median 12.1 mV, n = 24, and chronic was 13.5 +/- 8.5 mV, median 17.2 mV, n = 7. None of the changes between the acute and chronic states was statistically significant, with the exception of bipolar impedance (P = 0.054). We concluded that: (1) transpericardial pacing threshold did not increase with time; (2) initial and chronic pacing impedances were high and current low; (3) QRS amplitudes were highly satisfactory for defibrillator rate-sensing; and (4) this approach to ICD implantation left the surgically virgin heart unscarred to make future transplantation easier, and enhanced safety when previous cardiac operations had been done.


Cardiac pacing in neonates, infants, and preschool children. A series of 37 children < 5 years old at pacemaker implant were followed from 1 to 105 months. Five of 37 patients required reoperation for battery depletion while two required reoperation for exit block of epicardial ventricular leads. Each patient paced in the DDD or AAI mode was still in the original mode at the end of follow up.


Incidence and predictors of loss of pacing in the atrium in patients with sick sinus syndrome. Atrial and dual-chamber pacemakers may be associated with reduced morbidity in patients with the sick sinus syndrome (SSS). In some patients, however, subsequent development of chronic atrial fibrillation or atrial lead failure make long-term pacing in the atrium not feasible. We analyzed the incidence and predictors of loss of atrial pacing in 395 consecutive patients with SSS (376 with dual-chamber pacemakers and 19 with single-chamber atrial pacemakers). None of them was in established atrial fibrillation at time of implant. Patients were followed-up for 55 +/- 35 months. Actuarial survival of effective atrial pacing was 92.5% at 1 year, 85% at 5 years, and 76.5% at 10 years. Overall, 60 patients lost atrial pacing. The most frequent cause was the development of chronic atrial fibrillation (53 patients). By multivariate analysis (Cox proportional-hazards model), independent predictors of loss of pacing in the atrium were preimplant episodes of paroxysmal atrial fibrillation (PAF) lasting more than 1 hour (P < 0.001; hazard ratio (HR) = 4.3); prior history of PAF for more than 5 years (P < 0.001; HR = 2.67; and endocardial P wave < 2 mV (P = 0.014; HR = 1.96). In a subgroup of patients (n = 187) who had echocardiograms, a left atrium > 50 mm was also an independent predictor of loss of atrial pacing (P = 0.028; HR = 2.28).(ABSTRACT TRUNCATED AT 250 WORDS)


Incidence and predictors of syncope in paced patients with sick sinus syndrome. In spite of a normal pacemaker function, syncope still occurs in some patients with sick sinus syndrome (SSS). Causes often remain unknown. To identify predictors and etiologies of this bothersome symptom, we studied 507 patients who received atrial, ventricular, and dual-chamber pacemakers for SSS. During a mean follow-up of 62 +/- 38 months, actuarial incidence of syncope was 3% at 1 year, 8% at 5 years, and 13% at 10 years. Causes were vasovagal (18%), orthostatic hypotension (25.5%), rapid atrial tachyarrhythmias (11.5%), ventricular tachycardia (5%), acute myocardial ischemia (2.5%), and pacemaker/lead malfunction (6.5%). In 13 patients (29.5%), syncope remained unexplained. The only preimplant predictor for syncope was syncope as primary indication for pacemaker implant. Electrocardiographic correlation with bradycardia was not a predictor of relief of syncope during the follow-up. (1) syncope in paced patients with SSS has multiple etiologies and may be multifactorial; (2) the only predictor of syncope after pacemaker implant is the occurrence of preimplant syncope as the main indication for pacing; (3) extensive Holter monitoring is not useful to document bradycardiac origin of syncope nor to predict its recurrence; (4) SSS probably overlaps with other entities such as autonomic dysfunction, vasovagal syncope, carotid sinus hypersensitivity, and venous pooling, which would provide an explanation for recurrent syncope in patients with normal pacemaker function.


Long-term intrinsic pacemaker function in patients paced for sinus node deficiency after cardiac transplantation. Fifteen cardiac transplant recipients requiring permanent pacing (AAI, n = 9; VVI, n = 6; rate responsive devices, n = 11) for postoperative sinus node (SN) insufficiency underwent evaluation of long-term SN function 240 to 1,461 days after transplantation. The intrinsic rhythm at the time of discharge was sinus in 7 patients; junctional escape in 6 patients; and pacemaker dependent in 2 patients. At follow-up, 5 patients had regained regular sinus rhythm, accounting for a total of 11 patients in sinus rhythm while 4 patients were in junctional bradycardia. The SN recovery time as determined by the permanent pacemaker was normal (< 1,500 msec) in only 1/8 patients in whom it was determined, although 4 of these 8 patients were temporarily overriding the pacemaker during ambulatory monitoring. Patients with pathological SN recovery times included 3 patients with late return of sinus rhythm and 4 patients who had recovered normal sinus rhythm before their discharge from the hospital. Three patients developed late symptoms despite apparent early normalization and underwent delayed pacemaker implantations on postoperative days 35, 52, and 225, respectively. We conclude that, in patients requiring pacemaker implantation after cardiac transplantation, normalization of SN function cannot be inferred from just return of sinus rhythm, regardless of whether it occurs early or late. These findings may have implications when a pacemaker exchange or explantation is being considered.


Intravenous adenosine: a noninvasive diagnostic test for sick sinus syndrome. Adenosine has a well established negative chronotropic effect on the sinoatrial node. The most widely utilized test of sinus node function remains the sinus node recovery time (SNRT), which generally requires catheterization. We compared the effect of adenosine (150 mcg/kg IV) on the lengthening of sinus cycle length (ADO:SCL) in 12 control patients (group I) and in 11 patients with clinical sick sinus syndrome (SSS) (group II), eight of whom had undergone prior permanent pacemaker implantation. Using 675 msec as an abnormal result indicating sinus node dysfunction (two standard deviations above the mean value established in controls), ADO:SCL had a sensitivity and specificity of 64% and 100%, which were equal to that observed for the corrected sinus node recovery time (CSNRT) (abnormal value > or = 550 msec). There was a significant difference in the CSNRT between group I (304 +/- 149 msec) and group II (1,199 +/- 916 msec, P = 0.003). There was no significant difference in ADO:SCL between groups I (256 +/- 210 msec) and group II (1,213 +/- 1,719 msec, P = 0.069); however, there was substantial overlap between patients exhibiting an abnormal ADO:SCL and CSNRT. As such, a significant difference in ADO:SCL was evident between group II patients (1,784 +/- 1,950 msec, n = 7) exhibiting an abnormal CSNRT and group I patients, P = 0.014. In conclusion, ADO:SCL has the same sensitivity and specificity for sinus node dysfunction as compared to the CSNRT. Intravenous adenosine may prove to be a useful noninvasive test to assess the need for permanent pacemaker implantation.


Atrioventricular conduction disturbances in patients with sinoatrial node disease and atrial pacing. In sinoatrial node disease (SND) atrial pacing may be limited by progression of AV block. The incidence of AV block after AAI systems implantation range, according to various authors, from 0% to 12%. The aim of this study was to examine the AV conduction disturbances that forced a change in the mode of pacing in patients with AAI pacemakers. The information was collected retrospectively from a cohort of 122 patients. The follow-up period ranged from 5 to 83 months (mean = 35). Among these patients there were 37 with sinus bradycardia and 85 with bradycardia-tachycardia syndrome. Their mean age was 63 years. Before AAI pacemaker insertion, all patients had normal AV conduction on 12-lead ECG, and all but five had a Wenckebach cycle length shorter than 500 msec. Seven out of these 122 patients (5.7%) developed symptomatic conduction disturbances (second-degree type I AV block in five, second degree type II AV block in one, and third-degree AV block in one), necessitating a change from AAI to another mode of pacing. We conclude that progression of AV block after atrial pacemaker implantation in patients with SND is infrequent and mild in the majority of cases. Intraventricular disturbances such as left anterior hemiblock represent contraindication to AAI pacing particularly in patients who may be in need of antiarrhythmic drugs.


Predictive value of the P wave at implantation for atrial fibrillation after VVI pacemaker implantation. This study assesses the value of P wave measurements on the surface ECG at implantation, in the prediction of atrial fibrillation in VVI paced patients. From a consecutive series of 320 pacemaker implantations 172 VVI paced patients for symptomatic atrioventricular block (AVB) (n = 126; mean age 69 +/- 14) or sick sinus syndrome (SSS) (n = 56; mean age 68.6 +/- 12) and in sinus rhythm at implantation were used in this study. P wave duration in V1 is correlated with the incidence of atrial fibrillation during 5 years of follow-up. V1 at implantation was significantly longer (114.6 +/- 2.7 msec) in the patients who developed atrial fibrillation than in those who did not (91.9 +/- 2.7 msec) (P < 0.001). Although positive predictive accuracy increases progressively for higher V1 values for AVB and SSS, the negative predictive and diagnostic accuracy of V1 criteria were less in SSS. Application of the Bayes' theorem showed that in SSS the probability to develop atrial fibrillation is 33% for V1 < 110 msec and is for V1 < 90 msec still higher than that reported in DDD paced patients. In the AVB group the probability to develop atrial fibrillation is 8% for V1 < 110 msec and 6% for V1 < 100 msec. It seems, therefore, that atrial stimulation (AAI or DDD) is always indicated in SSS. In AVB with V1 < 100 msec, DDD pacing, if not needed for other indications, apparently does not offer much benefit in the prophylaxis of atrial fibrillation.


Electrophysiological effect of the maze procedure on canine sinoatrial node function. The maze procedure is an operation that has had great initial success in curing atrial fibrillation. This procedure includes several right atrial incisions that may interrupt the integrity of the sinoatrial node or its arterial supply. To assess the effect of the maze procedure on sinus node function (SNF), the following studies were performed: sinus node recovery times (SNRT), corrected SNRT (CSNRT), CSNRT under autonomic blockade maximal heart rate and intrinsic heart rates. Thirty-four dogs underwent a right thoracotomy with cardiopulmonary bypass (CPB). The dogs were divided into three groups. Group 1 (n = 9), the sham group, underwent CPB without any incisions. Group 2 (n = 8) underwent CPB and one of the right atrial incisions. Group 3 (n = 18) underwent CPB and all three of the right atrial incisions. SNF was determined before and after the procedure. Groups 1 and 2 had no significant difference in measured SNF acutely after the procedure. In Group 3 the mean SNRT increased from 552 msec to 1,984 msec (P = 0.005). Sinus node dysfunction was corroborated by all studies. In the chronic studies, a trend toward recovery of SNF was observed. The maze procedure results in significant acute sinus node dysfunction. This dysfunction may resolve spontaneously over the ensuing months. Modifications of the maze procedure that avoid the sinus node or its blood supply area may reduce procedure related sinus node dysfunction.


A simple in vivo model to evaluate the effects of antiarrhythmic agents. Antiarrhythmic agents alter cardiac conduction, refractoriness, and action potential duration in a rate dependent fashion. A simple in vivo model was developed to measure these variables over a wide range of cycle lengths. Complete heart block was produced in dogs using an 8 French hexapolar ablation catheter, anterior skin electrode, and radiofrequency current (30 W, 13.6 +/- 2.6 seconds). Ventricular pacing and monophasic action potential recordings were performed using a single combination catheter. QRS and action potential durations were measured at multiple cycle lengths and after an abrupt change in paced cycle length. Ventricular effective refractory periods were also measured at multiple cycle lengths. Data obtained during flecainide and d-Sotalol infusions are presented. This simple model allows detailed in vivo evaluation of the electrophysiological effects of antiarrhythmic agents and combinations.


Reverse use dependence of antiarrhythmic class Ia, Ib, and Ic: effects of drugs on the action potential duration? The prolongation of the action potential duration (APD) induced by sotalol has been shown to be diminished with increasing heart rate. This phenomenon is called "reverse use dependence." We examined the Ia, Ib, and Ic effects of different Class I drugs on the APD under normal and fast stimulation rates (1.0 and 2.5 Hz) in isolated rabbit atrial and ventricular muscles by means of intracellular microelectrodes. Results (n = 98): With 1.0 Hz lidocaine (Ib, 4.3 x 10(-5) M) shortened the APD at 90% repolarization (APD90) in the atrium by 9% and in the ventricle by 8% (NS), whereas quinidine (Ia, 2.2 x 10(-5) M) and prajmaline (Ia, 10(-6) M) prolonged the APD90 in the atrium (quinidine +45%; prajmaline +10%, P < 0.001) and in the ventricle (+42%, P < 0.001; +17%, P < 0.05). Propafenone (Ic, 2.6 x 10(-6) M) showed this effect only in the atrium (APD90 +33%; P < 0.01). With the faster stimulation rate of 2.5 Hz we could not find a significant influence of any drug on the APD90 in the ventricle and only quinidine prolonged the APD90 in the atrium by 16% (P < 0.05). The subclassification of Class I antiarrhythmic drugs that is based on APD modifying influences is only valid under normal heart rates (1.0 Hz). During tachycardia these actions are absent and the phenomenon of "reverse use dependence" is found in Class I drugs. Therefore, an additional antiarrhythmic effect due to APD modification by the examined drugs should not be expected at rapid heart rates.


Frequency dependent effects of d-sotalol and amiodarone on the action potential duration of the human right ventricle. Frequency dependent effects of d-Sotalol (2.0 mg/kg IV, n = 6) and amiodarone (400 mg/day for 3 months, n = 9) were studied on the action potential duration (APD) in 14 patients who underwent electrophysiological testing. Monophasic action potentials were recorded from the right ventricle at five different steady-state paced cycle lengths (700 msec, 600 msec, 500 msec, 400 msec, and 350 msec), and during ventricular extrastimuli with coupling intervals between 300 msec and 1000 msec, before and after d-sotalol and amiodarone, respectively. D-sotalol caused a prolongation of the APD at slow steady-state stimulation rates (11 +/- 5% at cycle length of 700 msec), which became attenuated at faster cycle lengths (5 +/- 3% at cycle length of 350 msec). Prolongation of APD after amiodarone was independent of pacing rate, e.g., 12 +/- 9% at cycle length of 700 msec, and 11 +/- 6% at cycle length of 350 msec. Similar frequency dependent prolongation of the APD was observed during abrupt changes of cycle lengths after d-sotalol, whereas amiodarone caused uniform prolongation of the APD at different extrastimulus intervals. Thus, d-sotalol, a nonselective potassium channel blocker, has reverse use-dependent effects on the human ventricular APD, while amiodarone with greater potassium channel selectivity, has equal ability to prolong the ventricular APD at fast and slow heart rates.


Dual chamber rate responsive pacing to allow sotalol therapy for ventricular tachycardia. In order to allow the use of sotalol to control ventricular tachycardia (VT), dual chamber rate responsive (DDDR) pacemakers were implanted in ten patients aged 6 to 73 years (mean 50 years). Nine presented with monomorphic VT (seven inducible at baseline electrophysiological study [EPS]) and one with syncope (monomorphic VT at EPS). On sotalol, VT was initiated in only one. This patient received sotalol in the absence of an effective alternative agent. The mean dose was 468 +/- 269 mg/day. Indications for pacing were symptomatic sotalol induced bradycardia (7), sinus node dysfunction (1), postoperative complete heart block (1), and infra-His block at baseline EPS (1). At least five of these patients would have been candidates for an implantable cardioverter defibrillator had sotalol required discontinuation. Initially, nine patients were paced in DDDR mode and one, with normal AV conduction on sotalol, in AAIR. One patient was unable to tolerate sotalol despite pacing. One patient died suddenly after 35 months of symptom-free follow-up. There was a significant improvement in symptomatic status (P = 0.03) after pacing among the other eight patients with no recurrence of VT. The implantation of a DDDR pacemaker may be indicated in selected patients with serious cardiac arrhythmias. With such a device programmed to an appropriate mode, sotalol can be used successfully where otherwise contraindicated by bradycardia or preexisting conduction disease. For some patients this may obviate the expense, inconvenience, and attendant risks of implantable cardioverter defibrillator implantation.


Atrial fibrillation in Wolff-Parkinson-White syndrome: reversal of isoproterenol effects by sotalol. Sotalol has Class II and III antiarrhythmic effects. Its efficacy and safety as a treatment of atrial fibrillation in patients with the Wolff-Parkinson-White (WPW) syndrome is controversial. We evaluated the effects of isoproterenol and IV sotalol (1.5 mg/kg in 10 minutes) given together versus isoproterenol alone on anterograde conduction through the AV node and accessory pathway. Atrial fibrillation was induced in 22 patients with WPW (13 men, 9 women, 36 +/- 16 years old). AV node and accessory pathway conduction were both enhanced by isoproterenol, although the effect was greater on the AV node. The minimum interval between preexcited QRS complexes shortened in all patients. Conversely, sotalol caused a significant prolongation of the shortest preexcited QRS interval as well as of the shortest interval between narrow QRS complexes. In addition, sotalol reversed all the effects of isoproterenol during atrial fibrillation. The percent of preexcited QRS complexes was not significantly modified because variations in ventricular preexcitation results from a balance between the relative effects on refractoriness of the accessory pathway versus of the AV node and in the amount of respective anterograde and retrograde concealed conduction. There were no serious adverse effects. Reversion to sinus rhythm was documented in 12 patients (60%). These short-term observations suggest that sotalol may be safe and effective in the treatment of patients with WPW and atrial fibrillation.


Prediction of antiarrhythmic efficacy of class I and III agents in patients with ventricular tachycardia by signal-averaged ECG analysis. The effects of procainamide and dofetilide (pure Class III antiarrhythmic agent) on the signal-averaged ECG (SAECG) were examined in relation to the results of programmed ventricular stimulation studies in 25 patients with inducible sustained monomorphic ventricular tachycardia. Procainamide prolonged significantly the total QRS and low amplitude signal durations (140 +/- 31 msec vs 166 +/- 48 msec, P < 0.0001; 50 +/- 25 msec vs 65 +/- 38 msec, P < 0.002, respectively) whereas the root mean square voltage of the last 40 msec of the QRS complex was significantly reduced (22 +/- 21 microV vs 13 +/- 12 microV, P < 0.006). Procainamide was effective (prevention of the inducibility of sustained ventricular tachycardia or prolongation of the cycle length of ventricular tachycardia by > 100 msec) in 15 of 27 drug trials. Of the procainamide induced SAECG changes, the fractional prolongation of the total QRS duration was the best parameter that identified effectively treated patients (24% +/- 16% in responders vs 10% +/- 11% in nonresponders, P < 0.014). A fractional prolongation of the total QRS duration by > 15% identified effectively treated patients with a sensitivity of 87%, specificity of 81%, and an overall predictive accuracy of 84%. Dofetilide did not change the SAECG, and no SAECG parameter predicted the results of programmed ventricular stimulation. The effects of both drugs on the spectral analysis (area ratios) and on the spectral temporal mapping (the values of normality factor) of the SAECG were not consistent. In conclusion, antiarrhythmic efficacy of procainamide can be predicted by the degree of drug induced prolongation of the signal-averaged QRS complex.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of verapamil and diltiazem in the suppression of idiopathic ventricular tachycardia. This study examines the efficacy of verapamil and diltiazem in the suppression of idiopathic ventricular tachycardia (VT). Eight patients (mean age 29.8 +/- 12.3 years, two males and six females) with VT, without any underlying cardiac abnormality on clinical examination and noninvasive investigation, were studied. The inducibility of the clinical VT was examined by treadmill exercise testing and programmed ventricular stimulation (PVS). In six patients, VT was inducible by exercise testing and in the remaining two by PVS. Following baseline testing, verapamil (120-mg thrice daily) and diltiazem (60-mg thrice daily) were administered in random order, allowing 5 half-lives for the drug to load before evaluation. Two patients had complete suppression of the VT and the remaining six patients demonstrated a partial response to both calcium antagonists. In the patients with a partial response, the duration of the longest run of VT was reduced (baseline 96.0, 34.2 SEM); verapamil 19.2 (7.5); diltiazem 45.3 (21.4 beats), whereas, there was no change in the rate of VT (baseline 199.7 (8.0); verapamil 184.5 (11.4); diltiazem 201.0 (9.5 beats/min). No proarrhythmic effect was observed with either of the drugs in these patients. We conclude that idiopathic VT can be suppressed in some patients by calcium antagonists. In patients with a partial response, the length of run of the VT can be reduced, but the rate is unaffected. Verapamil and diltiazem do not differ in their ability to suppress VT in individual patients.


Acute and chronic electrophysiological effects of pentisomide on the sinus and AV nodal function, noninvasive evaluation by a pacemaker with temporary pacing inhibition. The acute and chronic electrophysiological effects on sinus function and AV nodal conduction of pentisomide (Pen), a new antiarrhythmic agent, were studied in ten patients with sick sinus syndrome (SSS) (group I) and in ten patients with normal sinus function (group II) using a permanent pacemaker with temporary pacing inhibition (Symbios 7005 Medtronic, Inc.). We measured noninvasively the corrected sinus node recovery time (CSNRT), the sino-atrial conduction time (SACT), according to Narula's method and the Wenckebach point before and after Pen administration, acutely and orally for 10 days. In group I intravenous injection (4 mg/kg) and oral administration (450 mg bid) of Pen significantly prolonged the CSNRT (+217% and +149%, respectively) and the SACT (+63% and +49%, respectively). In group II only the intravenous injection of Pen provoked a significant modification of CSNRT (+12%) and SACT (+14%). No modification in AV nodal conduction was noted in any patient. These results suggest that Pen must be used with caution in patients with sinus nodal dysfunction.


Mexiletine and propafenone: a comparative study of monotherapy, low, and full dose combination therapy. The electrophysiological effects of combination therapy of mexiletine and propafenone were assessed using standard 12-lead electrocardiogram (standard ECG), signal-averaged ECG (SAECG), and ambulatory ECG in 31 patients with ventricular arrhythmias. All patients underwent mexiletine monotherapy (M-mono), propafenone monotherapy (P-mono), low dose combination therapy (low M+P), and full dose combination therapy (full M+P). Full M+P increased the PQ interval and QRS duration to the same extent as P-mono did. Low M+P increased PQ interval and QRS duration to a lesser extent than P-mono and full M+P did. P-mono and full M+P significantly decreased root mean square (RMS) and increased f-QRS in SAECG, while M-mono and low M+P showed only a weak trend. SAECGs with late potentials increased in number with treatments; 9 in predrug control, 11 on M-mono, 15 on P-mono, 10 on low M+P, and 14 on full M+P. The percent suppression of frequent premature ventricular contractions (PVCs) (> 1,000/day) with M-mono, P-mono, low M+P, and full M+P were 46.4 +/- 9.0, 56.6 +/- 10.4, 64.4 +/- 9.2, and 71.4 +/- 7.1, respectively, and those of frequent couplets (> 10/day) were 58.3 +/- 17.7, 62.6 +/- 23.6, 87.5 +/- 6.2, and 92.1 +/- 4.0, respectively. Thus, full dose combination of mexiletine and propafenone exhibited the maximum antiarrhythmic efficacy without enhancement of effects on standard ECG and SAECG. Low dose combination therapy showed better antiarrhythmic efficacy in association with lesser effects on standard ECG and SAECG compared with propafenone monotherapy.


Antiarrhythmic efficacy of ethacizine assessed by programmed electrical stimulation in patients with ventricular tachycardia. The efficacy of ethacizine, a Class Ic drug, was assessed by programmed electrical stimulation (PES), delivering single, double, and triple extrastimuli at paced drives of 100 and 140 beats/min from two right ventricular sites (apex and outflow tract) in 38 patients with recurrent sustained ventricular tachycardia (VT). Underlying disease was coronary artery disease (CAD) in 26 (group I) and other conditions in 12 patients (group II; hypertrophic cardiomyopathy in 7, mitral valve prolapse in 1, and no apparent heart disease in 4). In the baseline study VT was induced in all patients. After a single intravenous dose (0.6-0.7 mg/kg) of ethacizine, VT was still inducible in six patients in group I and seven patients in group II. Ethacizine was administered on a long-term basis to all patients in a dose of 200-400 mg per day. All but one CAD patient remained free of recurrences after a mean follow-up of 16.5 (range 3-22) months, while there were recurrences in six of 12 patients in group II. We conclude that: (1) ethacizine appears to be effective in the treatment of VT in CAD patients; (2) the study demonstrates the clinical utility of PES in the management of VT, although some patients in whom VT remains inducible on ethacizine may have good clinical outcome; and (3) the efficacy of ethacizine in other forms of heart disease remains to be studied.


Electrogram patterns predictive of successful radiofrequency catheter ablation of accessory pathways. We assessed anterograde conduction electrogram parameters at successful ablation sites according to accessory pathway (AP) location and compared them to the most favorable electrograms at unsuccessful sites. A median of three radiofrequency energy impulses was applied to ablate 97% of 136 APs versus four impulses to ablate 90% of 65 concealed APs. Electrograms at successful sites showed variable A/V ratio (0.04-7), and a QS pattern of unipolar ventricular wave in 90%. Electrograms were different in right versus left AP: AV time 29 +/- 7 versus 38 +/- 10; and timing of ventricular deflection: 17 +/- 9 versus 2 +/- 9 msec, respectively. Analysis in each patient of the mapping parameters at successful versus "most favorable" unsuccessful sites showed an improvement in at least one parameter in 55%, no apparent change in all parameter values in 30%, and even less favorable parameters in 15% of patients. In patients with manifest AP, overall comparison of electrograms at successful versus unsuccessful sites showed no difference in A/V ratio (1.3 +/- 1.5 vs 1.2 +/- 1.6), unipolar pattern distribution, and AV time (34 +/- 10 vs 35 +/- 9), but earlier bipolar main ventricular potential (-4 +/- 12 vs -1.5 +/- 10 msec) and unipolar intrinsic deflection timings (-5.2 +/- 11 vs -1.8 +/- 10 msec). In patients with concealed AP, a retrograde continuous electrical activity was recorded in 72% of successful versus 38% of unsuccessful sites (P = 0.03). Electrogram characteristics at successful radiofrequency ablation are different in right and left manifest AP.(ABSTRACT TRUNCATED AT 250 WORDS)


Separation of ventricular tachycardia from sinus rhythm using a practical, real-time template matching computer system. Template matching morphology analysis of the intraventricular electrogram (IVEG) has been proposed for inclusion in implantable cardioverter defibrillators (ICDs) to reduce the number of false ventricular tachyarrhythmia detections caused by rate overlap between ventricular tachycardia (VT) and sinus tachycardia and/or supraventricular tachycardia. Template matching techniques have been developed that reduce the computational complexity while preserving the perceived important aspects of electrogram amplitude and baseline independence found in such computationally unsolved methods as correlation waveform analysis (CWA). These methods have been shown to work as well as CWA for separation of VT, however, they have not been proven in real-time on a system that incorporates many of the constraints of present day ICDs. The present study was undertaken with two purposes: (1) to determine if real-time IVEG template matching analysis on an ICD sensing emulator was accurate in separating VT from sinus rhythm (SR) electrograms; and (2) to compare amplitude normalized area of difference (NAD) with signature analysis (SIG), a new, computationally less expensive technique that normalizes for amplitude variation within the expected physiological level of variability. In this study, IVEGs, obtained from 16 patients who underwent electrophysiological study (EPS) for evaluation of sustained ventricular arrhythmia, were digitized to 250 Hz with 6-bit quantization after filtering (16-44 Hz) and differentiation. After an SR template was selected and periodically updated, it was compared to subsequent IVEGs using NAD and SIG. In general, SIG calculates the fraction of samples occurring outside template window boundaries. Eleven-beat running medians from beat-by-beat NAD and SIG results were determined.(ABSTRACT TRUNCATED AT 250 WORDS)


Ventricular tachycardia detection using bipolar electrogram analysis is site specific. While algorithms for bipolar intraventricular electrogram analysis have potential use in complementing rate criteria for ventricular tachycardia (VT) detection by implantable antitachycardia devices, the sensitivity of such algorithms to the intracavitary site of electrogram detection has not been determined. In this study, unfiltered (1-500 Hz) electrograms were recorded from a bipolar electrode catheter initially positioned at the right ventricular (RV) apex (site 1) of 12 patients during sinus rhythm (SR1) and during induced monomorphic VT (VT1). Sinus rhythm (SR2) and the identical VT (VT2) were recorded a second time after repositioning the same electrode catheter within the RV apex (site 2) 7-44 mm (mean +/- SD = 15 +/- 10) from its original site. The data were digitized at 1,000 Hz. Templates from SR1 and SR2, respectively, were compared subsequently with individual intraventricular electrograms from 15-25 sec passages of SR1 and VT1 and SR2 and VT2, respectively, using correlation waveform analysis. At site 1, the mean patient correlation coefficient ranged from 0.982-0.998 during SR1 and 0.062-0.975 during VT1. At site 2, the mean patient correlation coefficient ranged from 0.995-0.998 during SR2 and 0.113-0.983 during VT2. Using a correlation threshold of 0.9, VT was differentiated from SR in 11/12 patients (91%) overall: 8/12 patients (67%) at site 1, 9/12 patients (75%) at site 2, and 6/12 patients (50%) at both sites. Thus, while discrimination of VT from SR is feasible with morphological analysis of bipolar right ventricular intracavitary electrograms, the accuracy of bipolar intraventricular electrogram analysis may depend upon intracavitary electrode location in selected patients.


Role of early afterdepolarization in familial long QTU syndrome and torsade de pointes. Torsade de pointes (TdP) syncopal episodes were almost invariably precipitated by emotional stress or menstruation in a 17-year-old girl. U wave accentuation occurred during sinus rhythm without pauses in periods of heightened sympathetic tone. To examine the role of early afterdepolarization (EAD), monophasic action potentials were recorded during ventricular extrasystoles and TdP occurring spontaneously and induced by ventricular pacing. The effects of lidocaine, verapamil, propranolol, and epinephrine were assessed. Our data show that: (1) EAD plays a significant role in the genesis of familial long QTU syndrome and TdP; (2) rapid ventricular pacing causes postpause-dependent EADs, U waves, and TdP; and (3) EAD is enhanced by epinephrine infusion in the absence of pause, whereas EAD-triggered firing is inhibited by verapamil and propranolol but not by lidocaine.


Survival after a first episode of ventricular tachycardia or fibrillation. Recent outcome analyses in ventricular tachycardia (VT) and ventricular fibrillation (VF) have included patients undergoing electrophysiological study (EPS) at tertiary care centers. The selection process involved could introduce bias in the reported populations. We analyzed the outcome of 42 consecutive patients (aged 63 +/- 11 years) admitted to a coronary care unit within 48 hours of a first episode of VT/VF not associated with reversible causes. All patients recovered neurologically and were candidates for EPS. Nine patients (21%) died during the initial hospitalization (none had EPS), and another nine died during a follow-up of 17 +/- 12 months. Actuarial survival at 1 and 2 years was 64% and 62%, respectively. By Cox's model, congestive heart failure functional Class III-IV (P = 0.008; hazard ratio = 3.7) was the only independent prognostic factor. Among patients discharged, subsequent survival did not depend on the performance of EPS or on the antiarrhythmic therapeutic modalities used. Mortality after a first episode of VT/VF is high. Severe congestive heart failure is the most powerful prognostic factor. Studies including successfully referred patients undergoing EPS may not reflect the true natural history of patients with VT/VF.


Changes in ventricular effective refractory periods after two extrastimuli and ventricular electrical instability. Using programmed stimulation with one and three extrastimuli delivered in the right ventricular apex, we compared the effective refractory period (ERP) during sinus rhythm (ERP-SR) and during the third extrastimulus (ERP-S3) in patients without ventricular tachycardias (control group, n = 87) and in patients with documented ventricular tachycardia (VT group, n = 76). The protocol was not completed to determine ERP-S3 in one patient in the control group and in 15 patients in the VT group. We observed a significantly greater change (i.e., shortening) in ERP after two extrastimuli in the VT group compared with patients without VT (delta ERP = 45 +/- 20 msec in the control group and 70 +/- 16 msec in the VT group, P < 0.001). This electrophysiological phenomenon, along with conduction delay, may play an important role in VT induction.


Programmed electrical stimulation protocols: variations on a theme. A series of prospective protocols were designed to determine the yield ratio (true positives vs. false positives = nonclinical) in various patient groups using a variety of programmed electrical stimulation (PES) variables. First, a PES protocol was used in 772 patients. Single, double, and triple extrastimuli were delivered in sequence (leaving each successive extrastimulus just beyond its refractory period before moving to the next extrastimulus) during sinus rhythm and two ventricular paced rates at the RV apex, before moving to the outflow tract and repeating the sequence and then moving on to isoproterenol infusion with the PES sequence repeated at the apex. This protocol met NASPE standards for induction of VT in patients with coronary artery disease and a history of VT, while failing to induce monomorphic VT in any control patient. The best yield ratios combined with the greatest likelihood of inducing clinical tachycardia were achieved with sinus rhythm and three extrastimuli, and pacing at the lower rate and three extrastimuli. Pacing at the faster rate and triple extrastimuli was highly inductive of clinical arrhythmias, but had a low yield ratio due to induction of more nonclinical arrhythmias than other steps. The next protocol was performed in 61 patients with inducible ventricular tachycardia. In each case, the protocol described above was completed at the RV apex, even if tachycardia was also induced at an earlier point in the protocol. This allowed for more accurate yield ratios to be established for each step in the protocol, since each patient was exposed to each of these steps.(ABSTRACT TRUNCATED AT 250 WORDS)


Phase plane plot of electrograms as a marker of ventricular electrical instability during acute ischemia: initial experimental results and potential clinical applications. We used a phase plane plots method (a plot of voltage [V(t)] vs rate of change of voltage [dV/dt]) derived from nonlinear dynamics to transform a sinus rhythm strip into a geometric form. The geometric form thus obtained detects variations in the ECG over time and therefore may aid in identifying patterns of vulnerability to ventricular fibrillation (VF). The trajectories of consecutive ventricular depolarizations and repolarizations of sinus rhythm in dogs that evolve to VF showed characteristic differential band thickening (inhomogeneities) that were absent in the dogs that did not develop VF. This method of analysis can be a useful complementary tool to detect cardiac electrical instability, and with simple hardware, can easily be displayed in real time.


Increased temporo-spatial dispersion of repolarization during double premature stimulation in the intact ventricle. The degree of temporo-spatial variation of repolarization during single (S2) and double (S3) premature stimulation was evaluated in five closed-chest anesthetized dogs. Monophasic action potentials (MAP) were simultaneously recorded with contact electrode and MAP duration (MAPD) restitution curves constructed from right ventricular (RV) and left ventricular (LV) endocardial sites. At a given coupling interval, S3 was associated with significantly greater dispersion of MAPD then S2 (spatial dispersion, i.e., between RV and LV). Similarly, at a given diastolic interval, S3 at RV and LV sites, was associated with significantly greater dispersion of MAPD then S2 (temporal dispersion). It is concluded that S3 is associated with greater temporo-spatial dispersion of repolarization then S2.


Autonomic manipulation influences both temporal and frequency analyses of late potentials. Previous studies of late potentials have not standardized the autonomic milieu at the time of testing. We studied the effects of autonomic manipulation in seven patients with previous Q wave myocardial infarction. Late potentials were evaluated using standard temporal (TD) and spectral temporal mapping techniques (STM) in the drug free state, and during separate intravenous administration of each of the following: isoproterenol, esmolol, and atropine. Isoproterenol was titrated to achieve a heart rate of 130% of baseline. Esmolol was infused at a rate of 250 micrograms/kg per minute, after a loading dose of 500 micrograms/kg. Atropine was given as a 2-mg bolus. In addition, five patients who received no drug infusions acted as controls, undergoing four serial signal-averaging studies in the baseline state: a "baseline" study, and then three additional studies at time intervals similar to those incurred by the study patients. Therefore, a total of 21 TD and 21 STM tests were done in the study group (seven patients; three drugs per patient) during the drug infusions, and 15 TD and 15 STM tests were done in the control group (five patients; three "nonbaseline" tests per patient). A change (normal to abnormal, or vice versa) in TD during a drug infusion occurred in 24% of the tests. No such change occurred in the control group (P < 0.01). A change in STM during a drug infusion occurred in 38% of tests, versus 13% of tests in the control group (P = 0.14). Overall, six of seven patients had a change in TD and/or STM diagnosis with infusion of one or more of the study drugs.(ABSTRACT TRUNCATED AT 250 WORDS)


Relationship between spectral measures of heart rate variability and ventricular ectopic activity in patients with idiopathic ventricular tachycardia. This study examines the relationship of hourly spectral measures of heart rate variability (HRV) to the occurrence of ventricular ectopic (VE) activity in 20 patients with idiopathic ventricular tachycardia and frequent VE's. Spectral measures of HRV were obtained from 24-hour Holter recordings from the patients in a drug free state and included the total energies in the spectrum, the low frequency components (L) (0.04-0.15 Hz) representing predominantly sympathetic tone with some contribution from the parasympathetic and high frequency components (H) (0.15-0.4 Hz) representing mainly parasympathetic tone. A high H component (parasympathetic) was defined as area > 12 msec and high L components (sympathetic) as area > 30 msec. On an hourly analysis of spectral components in relation to VE activity, VE's occurred significantly more frequently during periods of low H and low L (F = 20.5, DF = 3, P < 0.0001). The number of VE's did not differ statistically in the other combinations of H and L components (low H, low L = 612.8 (50.1); high H, low L = 180.1 (36.8); low H, high L = 338.4 (58.9); high H, high L = 204.9 (17.7) VE's/hr (SEM). The results suggest that VE's are more frequent during periods of low H and low L and are diminished when either H or L are increased in patients with idiopathic ventricular tachycardia. The results would be consistent with the hypothesis that the parasympathetic nervous system has an electrophysiologically stabilizing effect on the myocardium.


Intraindividual reproducibility of heart rate variability. Heart rate variability was determined from three consecutive Holter recordings performed on days 1, 7, and 28 in 17 normal subjects, in 13 patients with angiographically normal coronary arteries, and in 9 patients with remote myocardial infarctions. Group data of several time and frequency domain measures of heart rate variability were highly reproducible (correlation coefficients 0.629-0.894). However, some individuals exhibited considerably larger day-to-day variations in heart rate variability. Single heart rate indices differed by up to 50% between two Holter recordings. Such potential differences must be considered when repeated heart rate variability determinations are used to assess changes in neurocardiac reflex regulation or effects of therapeutic interventions.


Prognostic value of heart rate variability in patients awaiting cardiac transplantation. Time and frequency domain parameters of heart rate variability (HRV) were determined in patients with severe endstage heart failure awaiting cardiac transplantation (HTX). These parameters were then correlated with mortality to investigate the performance of HRV in discriminating between groups with high and low risk of death. The standard deviation of five consecutive RR intervals (SDANN) was found to be the parameter with the greatest sensitivity (90%) and specificity (91%). Patients with SDANN values of < 55 msec had a twenty-fold increased risk of death (90% confidence limits: 4-118, P < 0.001). The results furthermore suggest that measurements of HRV are superior to other prognostic markers such as left ventricular ejection fraction, pulmonary artery wedge pressure, cardiac index, and serum sodium levels. We conclude that HRV is a powerful, noninvasive tool to assess the risk of death in candidates for HTX. HRV measurements can therefore be used as a supplement to other markers of risk to determine the optimal therapeutic strategy in patients with severe congestive heart failure.


Heart rate variability in patients with vasovagal syndrome. The aim of this study was to assess the heart rate variability in patients with vasovagal syndrome (VVS). Heart rate variability was expressed as: (1) the standard deviation (SD) of the mean RR interval; and (2) the SD as a percentage of the mean RR interval (%SD). Heart rate variability was measured in VVS patients and compared with control individuals. Eighteen patients (mean age 50 +/- 14 years) with a history of recurrent syncope and positive tilt testing were included in the study. Fifteen asymptomatic individuals (mean age 53 +/- 13 years) with no history of syncope and negative tilt testing were used as a control group. The SD and %SD (39 +/- 38 and 5 +/- 4 msec) in the VVS group were statistically higher at the tenth minute of tilt testing than in the control group (20 +/- 14 and 2.5 +/- 1.8 msec, P = 0.03 and P < 0.05, respectively). The mean RR interval (mean heart rate) was shorter after the 15th minute of tilt testing in the VVS group than in the control group (RR-VVS 687 +/- 136 msec, RR-control 801 +/- 131 msec, P < 0.05). It is concluded that heart rate variability, as expressed by the SD of the mean RR interval, and the SD as a percentage of the mean RR interval (%SD) are significantly higher in VVS patients than in control asymptomatic individuals.


Osmotic regulation of substance P and neurokinin A peptide content and substance P binding sites in distinct hypothalamic nuclei of the rat. Quantitative receptor autoradiography using Bolton-Hunter iodinated substance P (SP) was used to localize specific sites in the rat hypothalamus. The amount of SP and neurokinin A (NkA) in extracts from discrete areas of the hypothalamus was measured using specific radioimmunoassays. A high density of SP binding sites was observed in the perimeter of the magnocellular paraventricular and supraoptic nuclei, while the magnocellular nuclei themselves possessed a low receptor density. In control animals, the number of SP binding sites was also low in the arcuate nucleus and the median eminence. Substance P and NkA peptide concentrations were highest in the paraventricular nucleus (PVN), decreasing in the following order: arcuate nucleus (Arc) greater than median eminence (ME) greater than supraoptic nucleus (SON) greater than subfornical organ (SFO). In animals given 340 mmol/l NaCl instead of tap water to drink for 12 days, significant increases in the number of SP binding sites occurred in the medial parvocellular subdivision of the PVN, periamygdaloid cortex, medial preoptic nucleus, Arc, and ME, but other hypothalamic areas were unaffected. In saline-treated animals, significant increases in SP and NkA peptide concentrations were observed in the ME, while in the SFO only the concentration of NkA increased significantly. In the SON, substance P and neurokinin A levels were doubled, whereas in the PVN and Arc no changes in peptide levels were observed. Chronic osmotic stimulation is associated with lowered circulating levels of adrenocorticotropin releasing hormone (ACTH), and the present data further substantiate the hypothesis that hypothalamic tachykinin-containing neuronal terminals are centrally involved in the inhibition of anterior pituitary ACTH release observed during chronic osmotic stimulation.


Coexistence of calcitonin gene-related peptide and galanin immunoreactivity in female rat pelvic and lumbosacral dorsal root ganglia. Coexistence of immunoreactivity for calcitonin gene-related peptide (CGRP) and galanin (GAL) was examined in varicose nerve endings in female rat pelvic paracervical ganglia (PG) and in perikarya of lumbosacral dorsal root ganglia (DRG). Varicose peptide-containing nerves were closely adjacent to somata of neurons in the PG, certain somata being virtually surrounded by immunoreactive varicosities. Some nerve endings were immunoreactive for either CGRP or GAL; in others, immunoreactivity for CGRP and GAL coexisted. Likewise, many perikarya in DRG were CGRP immunoreactive, fewer were GAL immunoreactive, and in some immunoreactivity for CGRP and GAL coexisted. The results suggest there are subpopulations of neuropeptide-containing sensory nerve endings in the PG; some contain CGRP, some contain GAL, and in some CGRP and GAL coexist. These substances contained in sensory nerve endings could have important roles in pelvic ganglionic functions.


Development of a potent bombesin receptor antagonist with prolonged in vivo inhibitory activity on bombesin-stimulated amylase and protein release in the rat. Of the various types of potent bombesin(Bn)/gastrin releasing peptide receptor antagonists that have been discovered, the desMet14-methyl ester peptides are devoid of residual agonist activity and are among the most potent in terms of in vitro receptor blockade and also in terms of their prolonged inhibition of bombesin-stimulated amylase and protein release in the rat. We have now examined the in vitro and in vivo properties of a new series of methyl ester analogues, [D-Phe6]Bn(6-13)OMe, [D-Phe6,D-Ala11]Bn(6-13)OMe, N alpha-propionyl-[D-Ala24]GRP(20-26)OMe, and [D-pentafluoro-Phe6,D-Ala11]Bn(6-13)OMe, which have an additional D-amino acid substituent and some highly lipophilic moieties at the N-terminus. All analogues were able to potently antagonize the ability of Bn to stimulate amylase release from rat acinar cells, with IC50 values of 2.4, 2.5, 0.6, and 1.3 nM, respectively. The four peptides were found to have binding affinities for these cells comparable to Bn itself, with K(i)s of 10.3, 2.8, 5.5, and 3.6 nM, respectively, but all had little or no affinity for neuromedin B receptors on murine C6 cells. Single bolus IV injections of these peptides were found to potently inhibit amylase and protein release caused by IV infusion of bombesin into the rat. Generally the peptides containing the D-Ala substituent were longer acting than [D-Phe6]Bn(6-13)OMe, so that [D-Phe6,D-Ala11]Bn(6-13)OMe and N alpha-propionyl-[D-Ala24]GRP(20-26)OMe displayed significant inhibitory effects for up to 1.5 h after administration.(ABSTRACT TRUNCATED AT 250 WORDS)


Modulation of hypothalamic galanin gene expression by estrogen in peripubertal rats. Hypothalamic galanin gene expression was investigated during reproductive maturation in peripubertal rats. Rat galanin-like immunoreactivity (rGAL-LI) increased in the median eminence and anterior pituitary during the extended first estrous and diestrous phases relative to anestrous phase female or male rats. In the neurointermediate lobe, rGAL-LI was elevated in first diestrous phase compared to anestrous phase females or males. In a second study, hypothalamic tissue was divided into quadrants for analysis of rat galanin (rGAL) mRNA by Northern blot hybridization. Two days after the injection of pregnant mare's serum gonadotropin (PMSG), rGAL mRNA increased approximately twofold in the paraventricular area and preoptic area quadrants. No effects of PMSG on galanin gene expression were found in medial basal or supraoptic hypothalamic quadrants. Because PMSG acts through the stimulation of ovarian estrogen secretion, these studies conclude that galanin gene expression in dorsal hypothalamic nuclei is under the stimulatory influence of estrogen and suggest that galanin may be a mediator of central ovarian steroid feedback.


Intravenously infused substance P enhances basal and growth hormone (GH) releasing hormone-stimulated GH secretion in normal men. The effect of synthetic substance P (SP), infused intravenously (IV) in doses of 0.5, 1, or 1.5 pmol/kg-1/min-1 over 60 min, on GH secretion was evaluated in seven healthy men. Substance P tests and a control test with normal saline were randomly performed at weekly intervals. No untoward side effects or changes in blood pressure were observed during SP infusions. Serum GH concentrations did not change when normal saline, the lowest dose, or the middle dose of SP were infused. In contrast, GH levels rose significantly when the highest dose of SP was given, with a mean peak two times higher than baseline. Further studies were performed to test the possible influence of SP on the GH response to GH-RH. For this purpose, seven other healthy men were tested with GH-RH (1 micrograms/kg body weight in an IV bolus) during saline or SP (1.5 pmol/Kg-1/min-1 x 60 min) infusion. The GH-RH induced a significant GH rise, with a mean peak seven times higher than baseline. When subjects were infused with SP, the GH response to GH-RH was greatly enhanced, with a mean peak 12 times higher than baseline. These results demonstrate for the first time in humans that the systemic infusion of SP stimulates GH secretion, and suggest that SP might interact with GH-RH in the stimulation of GH secretion.


[Myocardial infarction-related arrhythmia after rehabilitation treatment in a sanatorium]. The study involved 100 patients (80 men and 20 women), aged between 27 and 69 years treated at the Department of Cardiology, Medical Academy in Lublin for the first myocardial infarction, and classified for a 4-week rehabilitation in sanatorium. A 24-hours ECG recording with Holter technique (Medilog 3000 manufactured by Oxford Medilog Timed) was performed twice. In the first record cardiac arrhythmias ( extrasystole both supra- and ventricular, ventricular tachycardia) were more frequent in comparison with the results of the second recording carried out after a 4-week rehabilitation.


[A case of phyto-mucous bezoar of the stomach]. A case of gastric phyto-mucous bezoar++ in an edentulous patient with chronic gastritis is reported. The effective medical treatment consisted of partial gastroscopic bezoar crumbling, gastric lavage with 1% sodium bicarbonate solution, and endoscopic removal of residual bezoar. The pathogenesis, symptoms, and treatment of gastric phytobezoars are discussed.


[Evaluation of ambulatory treatment of advanced forms of Hodgkin's disease with special reference to psychological, social and economic aspects]. Patients with advanced lymphogranulomatosis were divided into two subgroups. One, including 9 patients was treated in the hospital, and the second, including 21 patients, was treated at out-patient department. Results of the treatment and its adverse reactions were not significantly different in patients treated on out-patient basis and in hospital. However, unfavourable effect of therapy on patient's psychological status (anxiety) was less expressed in out-patient conditions. Such a way of treatment enables also considerable savings related to the repeated hospitalizations.


The distribution of PSA, cathepsin-D, and pS2 in BPH and cancer of the prostate. In view of the limitations associated with the present tumor markers for prostate cancer, we have examined the potential expression of two further markers, Cathepsin-D and pS2, in human prostate and attempted to link their concentrations with the histopathology of the tissue, the PSA levels and the androgenic status of the gland. Cathepsin-D and pS2 were measured in cytosol fractions obtained from 22 patients with benign prostatic hyperplasia (BPH) and 20 patients with prostate cancer (CaP) employing immunoassays specific for these markers. The concentrations of Cathepsin-D (BPH: mean +/- SEM = 18.50 +/- 1.88 nmol/g protein; CaP = 19.75 +/- 2.49 nmol/g protein) and pS2 (BPH = 1,024.7 +/- 348.06 ng/g protein; CaP = 1,513.88 +/- 268.60 ng/g protein) were not different in the two tissue types, whereas PSA in BPH tissue (1,952.27 +/- 249.93 micrograms/g protein) was significantly higher than the measurements in CaP (583.75 +/- 104.33 micrograms/g protein). However, none of the tumor marker concentrations correlated with the degree of differentiation of the tumors, and we were unable to establish any correlation with the levels of testosterone and dihydrotestosterone in the tissue. In conclusion, although Cathepsin-D and pS2 are expressed in prostate tissue, it is doubtful whether they will have an active role in the management of prostate cancer.


Bifunctional pharmacophores. Biological activities of the peptide analog containing both casomorphine-like and substance P antagonist-like active elements. SP-antagonistic properties of a newly synthesized peptide Tyr-Pro-D-Phe-Phe-D-Phe-D-Trp-MetNH2 (AWL-60) were investigated both in vitro and in vivo. In vitro AWL-60 effectively antagonized the action of SP-agonist (SP6-11); however, this antagonism was non-competitive. Antagonistic properties of AWL-60 were also observed in vivo: in doses as low as 0.1 nmol/kg iv AWL-60 markedly attenuated the fall in blood pressure produced by [less than Glu]6SP6-11. Since AWL-60 exerts weak opioid agonistic properties (as a casomorphine analog) the possible involvement of an opioid agonistic component in their SP inhibitory action is considered.


Validation of a symptoms questionnaire for benign prostatic hyperplasia. We developed a questionnaire to assess the effect of finasteride on symptoms of benign prostatic hyperplasia (BPH) by modifying that of Boyarsky (1977). To validate the questionnaire, a cohort study was conducted in 2 groups of patients with BPH and 3 control groups without BPH. The BPH groups were: (1) 34 patients before TURP (transurethral resection of the prostate), average age 68 years; (2) 65 patients after TURP, average age 68 years; (3) 40 patients after other nonserious nonurological surgery, average age 50 years; (4) 14 healthy non-BPH volunteers, average age 58 years; and (5) 73 healthy non-BPH volunteers, average age 37 years. The questionnaire was administered once to all subjects, and a subset responded to a second administration. Mean total symptoms scores (TSS) from the initial questioning were 6.4, 3.2, 2.9, 2.6, and 1.6 for the 5 groups, respectively (pooled SD = 3.3); mean total troublesome symptoms scores (TTSS) were 4.8, 2.1, 1.4, 1.1, and 0.6, respectively (pooled SD = 2.2). All other groups were significantly less symptomatic and troubled than the pre-TURP group, and all surgical groups were significantly more so than the younger volunteer group. These data demonstrate the discriminant validity of the questionnaire. Corroborating prior data [Gregg et al., 1990], responsiveness was shown by the 3.7-point mean TSS improvement in response to TURP, which was significantly different from the near-zero changes in the other groups. Reproducibility was shown by kappa statistics being nearly all greater than 0.75 and an intraclass correlation coefficient of 0.64; construct validity and reliability were demonstrated by correlation (r = 0.7) with a general urination problems question; and internal consistency was documented by Cronbach's alpha values of approximately 0.6. We conclude that this questionnaire is a useful and validated tool for assessing BPH symptoms.


Synthesis and biological activity in the GPI test of scyliorhinin I and its Val7 and Ile7 analogs. Scyliorhinin I, a decapeptide, of tachykinin family, and its two analogs containing Val or Ile in position 7, have been synthesized using the solid-phase method, and tested for agonistic activity on isolated guinea pig ileum. Both analogs were slightly more active than scyliorhinin I, but they were significantly less potent than substance P.


Dynamic changes in the intermediate filaments of the epithelial cells during development of the chicken's bursa of Fabricius. The development of bursal follicles and the differentiation of the follicle-associated epithelium and interfollicular epithelium were studied immunohistochemically using monoclonal anti-vimentin and anti-cytokeratin antibodies. In 10-day-old embryos the entodermal and cloacal epithelia coexpressed vimentin- and cytokeratin-intermediate filaments. Both undifferentiated and differentiated bursal surface epithelium simultaneously expressed vimentin- and cytokeratin-intermediate filaments during the entire period of embryogenesis. Vimentin expression in reticuloepithelial cells was related to bursal cell differentiation but was not linked to immune function. Sequential loss of vimentin from interfollicular epithelium, follicle-associated epithelium, and reticuloepithelial cells may reflect sequential acquisition of maturity in these three compartments. The presence of cytokeratin-intermediate filaments suggested that follicle-associated epithelium was not of mesenchymal origin. Testosterone treatment did not influence the vimentin and cytokeratin filament expression in the epithelial cell.


Reversal of signs of induced cotton effects of dicumarol-alpha 1-acid glycoprotein systems by phenothiazine neuroleptics through ternary complexation. The interaction of dicumarol and phenothiazine neuroleptics binding to alpha 1-acid glycoprotein (AGP) was investigated by circular dichroism (CD) and equilibrium dialysis. The induced CD spectra of the dicumarol-AGP complex were affected differently by the different substituents of the phenothiazine molecule. The sign of the induced Cotton effect of dicumarol bound to AGP was reversibly changed with the introduction of the propyldimethylamine substituent at position 10 or chloride group at position 2 of the phenothiazine molecule. Chlorpromazine, which contains both of these substituents reversed the sign of the induced Cotton effect with the highest intensity. The addition of trifluoperazine, fluphenazine, and promethazine containing neither of the two substituents generated a new negative CD band. However, the addition of opromazine, which contains sulfoxide at position 5, decreased the CD intensity of the dicumarol-AGP complex without changing the shape of the CD spectra. Equilibrium dialysis studies revealed that the interaction of dicumarol-AGP with phenothiazine derivatives occurred simultaneously, and the interaction followed a cooperative and anticooperative binding model. Further, among the six phenothiazine derivatives that reversed the signs of the induced Cotton effects of the dicumarol-AGP complex, a linear relationship was observed between coupling constants and the difference in the induced optical ellipticity. The opromazine and dicumarol interaction was competitive for a common binding site on the AGP molecule. Removal of sialic acid did not have any effect on this interaction. These data support the hypothesis that the acidic and the basic drug binding sites overlap each other.


Nedocromil sodium modulates the function of long-term rat peritoneal mast cell cultures. Long-term rat peritoneal mast cell (MC) cultures consisting of MC co-cultured with 3T3 fibroblasts (MC/3T3) were employed to study the effects of repeated and prolonged incubation with nedocromil sodium (10(-3) and 10(-5) M) on MC activation. When nedocromil sodium was added simultaneously with compound 48/80 to MC/3T3 on the first day of the experiment, it inhibited histamine release to the same extent as when added to the cultures a week later upon rechallenge. In other experiments activated MC/3T3 were incubated with nedocromil sodium for a week and on the last day of the experiment fresh nedocromil sodium was added simultaneously with compound 48/80. Under these conditions the drug was as potent in inhibiting histamine release from the activated MC as it was in cultures incubated for a week with medium alone. In addition, preincubation of naive MC with nedocromil sodium for two days inhibited histamine release from these cells when activated for the first time. Salbutamol (10(-3) and 10(-5) M) exhibited a similar inhibitory effect to nedocromil sodium upon simultaneous incubation with MC/3T3. However, prolonged incubation of salbutamol with MC/3T3 cultures resulted in tachyphylaxis. We conclude that nedocromil sodium is an effective MC stabilizing drug since it similarly inhibits histamine release from both primarily and secondarily challenged MC. Moreover this drug does not lose its efficacy upon prolonged incubation with MC.


Multiple oral administration of a ketoprofen-dextran ester prodrug in pigs: assessment of gastrointestinal bioavailability by deconvolution. Deconvolution has been applied to estimate the in vivo dissolution/release process of ketoprofen from a ketoprofen-dextran ester prodrug in pigs. The prodrug was given to three pigs at intervals of 12 hr and in seven doses corresponding to 4 mg ketoprofen/kg body weight. Frequent blood sampling was carried out at the first, third, and seventh intervals. Plasma steady-state concentrations of ketoprofen following the prodrug administration were between 2 and 4 micrograms/ml. The reference consisted of a single p.o. dose of parent ketoprofen (4 mg/kg body weight). For each pig the response following the multiple dosing was deconvolved with the reference response using an algebraic deconvolution procedure adopted from the literature. The obtained cumulated in vivo dissolution/release profiles revealed similar release rates for the three pigs and similar extents of release (59, 70, and 65%). The mean in vivo dissolution/release times (MDT) were calculated to be 5.4, 6.1, and 5.7 hr, respectively. In conclusion, following administration of the dextran prodrug the plasma concentration curves and the dissolution/release profiles are uniform, with small interindividual variations.


Interactions between substance P and norepinephrine in the regulation of nociception in mouse spinal cord. This study examined interactions between effects of the undecapeptide substance P and norepinephrine and the alpha-adrenoceptor agonist clonidine in the mouse spinal cord. All compounds were injected into the lumbar subarachnoid space, and effects on the tail-flick reflex and the behavioural response to intrathecal substance P were evaluated. The tail-flick response latencies were markedly increased 5-20 min. after intrathecal application of norepinephrine (0.0125-0.1 microgram) or clonidine (0.0125-0.1 microgram). The actions of both intrathecal norepinephrine (0.025 microgram) and intrathecal clonidine (0.025 microgram) were significantly attenuated when substance P (5 micrograms) was given intrathecally 55 and 45 min. before the agonists. There was a significant relationship between the tail-flick response latencies and the tail skin temperature. However, the tail-flick results were not due to changes in the skin temperature. Intrathecally applied substance P (10 ng) produced a response consisting of biting of the caudal part of the body and a few hindlimb scratches. The number of bites was significantly reduced 5 min. after injection of norepinephrine (0.1 micrograms) or clonidine (0.05-0.1 microgram), but the number of scratches was unchanged. The data show that increased stimulation of spinal alpha-adrenoceptors inhibits a spinal nociceptive reflex as well as the action of substance P in the spinal cord. Substance P modulates the action of alpha-adrenoceptor agonists on the tail-flick reflex, which may tentatively be explained by downregulation of alpha-adrenoceptors by substance P.


Ouabain enhancement of compound 48/80 induced histamine secretion from rat peritoneal mast cells: dependence on extracellular sodium. Purified populations of rat peritoneal mast cells were used to study the effect of ouabain on compound 48/80-induced histamine secretion and on 86Rb+ uptake. 86Rb+ was used as a tracer for extracellular K+. The calculated value of the ouabain-sensitive uptake of K+ and 86Rb+ was considered a measure of the Na(+)-K+ pump activity of the cells. Ouabain caused an immediate inhibition of the pump activity and a time-dependent increase in histamine secretion in the absence of extracellular calcium. No effect on the secretion was observed in the presence of calcium. The effect of ouabain on the secretion occurs in the presence of sodium but not when sodium was replaced by lithium. Preservation by ouabain of a high intracellular sodium content in sodium-loaded cells was associated with preservation of the secretory response in a calcium-free medium. In the presence of lanthanum in a calcium-free medium, the pump activity was inhibited and the enhancement by ouabain of the secretion of histamine was blocked. A less marked inhibition of the pump was found in a calcium-free medium containing magnesium. The inhibition exerted by magnesium was concentration-dependent (0-5 mM) as was the counteraction of magnesium of the enhancement of ouabain of the secretion of histamine. These observations indicate that the enhancement by ouabain of the secretory response of mast cells preincubated in a calcium-free medium is associated with accumulation of sodium inside the cell. In addition to a decreased rate of sodium-calcium exchange caused by a decreased inward directed sodium gradient, the mechanism by which ouabain enhances the secretory response is likely to involve an increased binding of calcium to membrane binding sites.


Involvement of opioid mechanisms in peripheral motor control of detrusor muscle. Isometric recordings of mechanical activity in muscle strips from rat and human detrusor were performed and the effect of mu- and delta-opioid receptor stimulation and blockade on detrusor contraction induced by electrical field stimulation was tested. Stimulation of the opioid mu-receptor with morphine (10(-13)-10(-4) M) and DAGO (10(-13)-10(-6) M) had no significant effect on electrical field stimulation except at one concentration of morphine (10(-6) M). Naloxone (10(-10)-10(-5) M) caused a significant facilitation of the electrical field stimulation-induced contraction, which was counteracted by morphine (10(-8) M) and the delta-agonist DPDPE (10(-8) M) in both rat and human detrusor. Addition of atropine (10(-6) M) or hexamethonium chloride (10(-6) M) or spantide (10(-6) M) did not alter the facilitating effect of naloxone in the rat detrusor. Hexamethonium (10(-5) M) decreased the facilitating effect of naloxone on electrical field stimulation-induced contractions in the human detrusor, indicating involvement of ganglionic mechanisms. In human detrusor about 15% of the contractile response was found to be atropine-resistant (10(-6) M) and one third of this was found to be resistant to tetrodotoxin (1.5 x 10(-6) M). The atropine resistant-response in human detrusor was facilitated by naloxone to the same extent as the atropine-sensitive part. Adrenergic blockade per se, achieved with phentolamine mesylate (10(-6) M) and propranolol (10(-6) M), caused a significant facilitation of the electrical field stimulation-induced contraction in the rat detrusor but did not affect the facilitating effect of naloxone (10(-13)-10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)


["Risk children": the importance of biological and psychosocial risks for child development in the first two years of life]. In a prospective longitudinal study the development of N = 362 children will be followed over four time points (T1-T4) from birth to school age utilizing a comprehensive battery of instruments. Aims of the study are the description of the developmental course of children born at differing degrees of biological and psychosocial risk, the identification of early predictors of developmental disorders and their compensation, as well as the analysis of the processes and mechanisms underlying differential developmental patterns. The results of waves 1 and 2 show that early development from 3 to 24 months is quite unstable. Depending on the examined domain of development up to 3/4 of the disturbances of infancy have remitted by the later age, whereas nearly a fifth of the hitherto well children developed new disturbances. Both risks have a marked negative effect on development. While biological risks go hand in hand with impaired motor functioning, psychosocial risks adversely affect cognitive and social-emotional competence. However, the relative weight of risk factors changes during the first two years with biological risks becoming less important and psychosocial risk factors gaining influence. Single risk factors identified as being prognostically very unfavourable are very low birth weight and neonatal seizures. Of the psychosocial risks a pattern of unfavourable family characteristics such as low educational level, history of broken home or mental health problems of parents and chronic difficulties is related most strongly to poor outcome.


Increased maternal serum alpha-fetoprotein and human chorionic gonadotropin in compromised pregnancies other than for neural tube defects or Down syndrome. Intrauterine fetal death occurred in four women who were 'screen-positive' in a screening programme for neural tube defects (NTDs) and Down syndrome (DS). These women had very high levels of maternal serum alpha-fetoprotein (MSAFP) and maternal serum human chorionic gonadotropin (MShCG). Therefore, we evaluated all 'screen-positive' women in whom both of these markers were greater than or equal to 2.0 multiples of the median. The cases fulfilling these criteria totalled 11, and only one of them had no complications. High concentrations of both MSAFP and MShCG in a number of these cases might have been caused by an increased placental volume, which, in turn, might have been induced by decreased perfusion of the placenta. We conclude that screening programmes wrongly determine a high risk of fetal NTD or DS if the concentrations of both these parameters are very high. Invasive diagnostic procedures should be avoided in these cases, particularly in view of the increased risk of an adverse pregnancy outcome.