Efficacy of pacing therapies for treating atrial tachyarrhythmias in patients with ventricular arrhythmias receiving a dual-chamber implantable cardioverter defibrillator.

BACKGROUND: Although overdrive pacing for treating atrial flutter is well established, the efficacy of device-based atrial pacing for treating spontaneous atrial tachyarrhythmias in patients with implantable cardioverter defibrillators (ICD) is unknown. This study evaluated the efficacy of novel pacing therapies for treating atrial tachyarrhythmias in patients receiving a dual-chamber ICD to treat ventricular tachyarrhythmias. METHODS AND RESULTS: A Jewel AF ICD was implanted in 537 patients with ventricular arrhythmia who were followed for 11.4+/-8.2 months (74% had a documented history of atrial tachyarrhythmias). The device discriminated atrial tachycardia (AT) from atrial fibrillation (AF) on the basis of cycle length and regularity, and it used 3 different methods of overdrive atrial pacing (Ramp, Burst+, and 50-Hz burst) to treat AT episodes and one method (50-Hz burst) to treat AF episodes. Pacing successfully terminated 59% of 1500 spontaneous AT episodes in 127 patients and 30% of 880 AF episodes in 101 patients (P<0.001). With AT and AF episodes combined, pacing efficacy was 48%. Pacing efficacy was significantly reduced at AT cycle lengths

Optimal electrode position for transvenous defibrillation: a prospective randomized study.

OBJECTIVES: This study was performed to determine the optimal position for the proximal electrode in a two-electrode transvenous defibrillation system. BACKGROUND: Minimizing the energy required to defibrillate the heart has several potential advantages. Despite the increased use of two-electrode transvenous defibrillation systems, the optimal position for the proximal electrode has not been systematically evaluated. METHODS: Defibrillation thresholds were determined twice in random sequence in 16 patients undergoing implantation of a two-lead transvenous defibrillation system; once with the proximal electrode at the right atrial-superior vena cava junction (superior vena cava position) and once with the proximal electrode in the left subclavian-innominate vein (innominate vein position). RESULTS: The mean (+/- SD) defibrillation threshold with the proximal electrode in the innominate vein position was significantly lower than with the electrode in the superior vena cava position (13.4 +/- 5.7 J vs. 16.3 +/- 6.6 J, p = 0.04). Defibrillation threshold with the proximal electrode in the innominate vein position was lower or equal to that achieved in the superior vena cava position in 75% of patients. In patients with normal heart size (cardiothoracic ratio < or = 0.55), the improvement in defibrillation threshold with the proximal electrode in the innominate vein position was more significant than in patients with an enlarged heart (innominate vein 13.0 +/- 6.5 J vs. superior vena cava 17.9 +/- 5.1 J, p < 0.01). In patients with an enlarged heart, no difference between the two sites was observed (innominate vein 13.9 +/- 4.5 J vs. superior vena cava 13.6 +/- 8.3 J, p = NS). CONCLUSIONS: During implantation of a two-lead transvenous defibrillation system, positioning the proximal defibrillation electrode in the subclavian-innominate vein will lower defibrillation energy requirements in the majority of patients.

Mechanical correlates of contraction-excitation feedback during acute ventricular dilatation.

OBJECTIVE: The purpose was to examine the mechanical correlates of the electrophysiological changes that occur during acute left ventricular dilatation. METHODS: Ten isolated, retrogradely perfused, ejecting rabbit hearts were studied. Left ventricular volume was adjusted by varying left atrial perfusion pressure. Left ventricular pressure was measured directly. Changes in left ventricular chamber dimensions at the level of an epicardial electrode were evaluated with two dimensional echocardiography and wall stress was calculated from these measures. Regional left ventricular electrophysiological properties were measured at two left atrial perfusing pressures. RESULTS: Increases in left atrial perfusion pressure resulted in significant increases in left ventricular end diastolic and end systolic pressures, epicardial and endocardial circumference, and wall stress. Only changes in diastolic wall stress correlated with changes in ventricular refractoriness (r = 0.69, p = 0.027). CONCLUSIONS: Left ventricular dilatation results in shortening of ventricular refractoriness in the isolated, ejecting rabbit heart. Regional changes in refractoriness are best correlated with changes in wall stress.

Syncope associated with exercise, a manifestation of neurally mediated syncope.

A retrospective review of patients evaluated at a university-based referral hospital was performed to assess the basis for syncope associated with exercise in young patients. Over an 8-year period, 54 consecutive young patients (aged 12 to 30 years) were referred for evaluation of frank syncope. Twelve patients had syncope associated with exercise (group I) and 42 patients had syncope not associated with exercise (group II). Patients underwent physical examination, chest x-ray, 2-dimensional echocardiography, and in selected cases, cardiac catheterization. Head-up tilt-table testing was performed in 11 of 12 group I patients. Ten group I patients had no evidence of structural heart disease: 9 of these 10 (90%) developed syncope with tilt-table testing. Head-up tilt-table testing was performed in 41 of 42 group II patients: 34 (83%) developed syncope with tilt-table testing. Standard cardiac electrophysiologic study was performed in 9 of 12 group I and in 30 of 42 group II patients, and identified a basis for syncope in only 2 group I and 1 group II patients. Among 9 group I patients with a positive result on head-up tilt-table testing and no evidence of structural heart disease (mean follow-up 4.3 years), 7 are without further episodes of syncope; 3 have discontinued medication and 5 have resumed at least limited exercise. In conclusion, susceptibility to tilt-induced syncope was the most frequent finding in young patients without structural heart disease referred for evaluation of exercise-associated syncope. Tilt-table testing may be an important diagnostic tool for the evaluation of these patients.

Antipain and leupeptin restrict uterine DNA synthesis and function in mice.

As in rats, administration of estradiol to ovariectomized mice results in a trypsin-like proteolytic activity in the uterus. After fractionation of uteri from estradiol-treated ovariectomized mice the protease activity was found in the 12,000 times g pellet and the nucleus, appearing first in the former. Further fractionation of the pellet by discontinuous sucrose gradient centrigugation resulted in sedimentation of the protease with 5'-nucleotidase, a marker enzyme for plasma membrane and separate from mitochondrial and lysosomal enzyme markers. Solubilization was best accomplished by lysis at 37 degrees. The soluble enzyme from mouse uterus had optimal activity at about 43 degrees and pH 8.3 and was inhibited by diisopropylfluorophosphate, tosylarginine methyl ester, antipain, and leupeptin, but not by soybean trypsin inhibitor. Inhibition in vitro by antipain and leupeptin, two low molecular weight peptides, prompted the study of their effect in vivo on the mouse uterus. After intact, cycling female mice received subcutaneous injections of antipain and leupeptin for 16 days, their uteri showed significant diminution in weight and total DNA when compared to untreated controls. Fertility rates were also diminished. Trypsin-like protease activity may be essential to normal uterine metabolism and function.

Effect of immunization on the genesis of pneumococcal endocarditis in rabbits.

The effect of immunization with whole organisms on the development of Streptococcus pneumoniae endocarditis was examined by in vivo and in vitro methods. Immunization protected rabbits from pneumococcal endocarditis when the in vivo catheterization model was used. The inoculum size that caused endocarditis in 50% of the unimmunized rabbits was 1.1 X 10(5) colony-forming units, whereas 1.2 X 10(7) colony-forming units were required for infecting 50% of the immunized rabbits (P less than 0.001). Investigations were carried out to determine the mechanism which enabled immunization to prevent the development of pneumococcal endocarditis; they indicated that a reduction in bacterial adherence could not explain this phenomenon. In vitro studies showed that subagglutinating quantities of antibody increased the adherence (P less than 0.05) of pneumococci to rabbit aortic valve cusps. The adherence ratio of pneumococci to fibrin-platelet clots was at least doubled by the presence of subagglutinating dilutions of immune sera (P less than 0.001). Further studies showed that immunoglobulin G in the immune sera accounted for this increased in vitro adherence. However, further in vivo studies showed that immunized rabbits were able to clear live pneumococci from their bloodstreams within 4.5 h, whereas unimmunized rabbits failed to clear the organism within 24 h.

Validation of a new noncontact catheter system for electroanatomic mapping of left ventricular endocardium.

BACKGROUND: Improvements in cardiac mapping are required to advance our understanding and treatment of arrhythmias. This study validated a new noncontact multielectrode array catheter and accompanying analysis system to provide electroanatomic mapping of the entire left ventricular (LV) endocardium during a single beat. METHODS AND RESULTS: A 9F 64-electrode balloon array catheter with an inflated size of 1.8x4.6 cm was used to simultaneously record electrical potentials generated by the heart and locate a standard electrophysiology (EP) catheter within the same chamber. By use of the recorded location of the EP-catheter tip, LV geometry was determined. Array potentials served as inputs to a high-order boundary-element method to produce 3360 potential points on the endocardial surface translatable into electrograms or color-coded activation maps. Three methods of validation were used: (1) driven electrodes in an in vitro tank were located; (2) waveforms generated from the array catheter were compared with catheter contact waveforms in canine LV; and (3) sites of local LV endocardial activation were located and marked with radiofrequency lesions. Tank testing located a driven electrode to within 2.33+/-0.44 mm. Correlation of timing and morphology of computed versus contact electrograms was 0.966. Radiofrequency lesions marked 17 endocardial pacing sites to within 4.0+/-3.2 mm. CONCLUSIONS: This new system provides anatomically accurate endocardial isopotential mapping during a single cardiac cycle. The locator component enabled placement of a separate EP catheter to any site within the mapped chamber.

Palpitations occur frequently following radiofrequency catheter ablation for supraventricular tachycardia, but do not predict pathway recurrence.

Radiofrequency ablation of extranodal pathways is an effective treatment for supraventricular tachycardia, but late recurrences of pathway conduction do occur. To determine if recurrence of palpitations following ablation predicts pathway recurrence, we interviewed 77 patients who were at least 4 weeks status-post successful ablation of an accessory pathway (43 overt, 11 concealed) or slow pathway (23) for AV nodal reentrant tachycardia. Palpitations were reported by 45 (58%) patients postablation, and 28 (36%) patients reported palpitations lasting > or = 10 seconds and/or felt their symptoms represented recurrent tachycardia (major palpitations). Repeat electrophysiological testing was performed 3 months postablation in 53 patients, including 34 patients with palpitations (22 with major symptoms). Eight (10%) patients had recurrent pathway conduction demonstrated on repeat testing: two had no symptoms prior to restudy and six had major symptoms. One patient had major symptoms, but was found to have inducible atrial tachycardia and not pathway recurrence on restudy. Thus, 15 (68%) of 22 patients with major symptoms who were restudied had no pathway recurrence or inducible arrhythmia to explain their symptoms. Of the 24 patients not restudied, none has had documented recurrent tachycardia or overt pathway conduction by electrocardiogram over a mean follow-up of 335 +/- 138 (range 132-616) days. Thus, palpitations, including palpitations reminiscent of preablation symptoms, are common following radiofrequency ablation and often do not predict pathway recurrence. Repeat electrophysiological testing is frequently required to document long-term success of radiofrequency ablation for supraventricular tachycardia in patients with recurrence of major symptoms.

Low dose disopyramide often fails to prevent neurogenic syncope during head-up tilt testing.

Low dose disopyramide has been used to prevent neurally-mediated syncope during head-up tilt testing but a correlation between blood levels and efficacy has not been described. We measured disopyramide levels in 15 patients with recurrent syncope and positive 70 degrees head-up tilt tests who underwent one or more repeat tests on the drug. There were 9 males and 6 females, age range 15-78 years. Fourteen of the 15 patients had structurally normal hearts. The daily disopyramide dose was 645 +/- 165 mg (mean +/- SD). Patients developed syncope during 9 tests and had no syncope during 12 tests. The mean disopyramide level in patients with positive tests was significantly lower than the level in patients with negative tests (2.4 +/- 0.15 mu/mL vs 3.2 +/- 0.22 mu/mL, P = 0.018). Six patients were tested twice on different disopyramide doses. Five of these six patients had syncope during head-up tilt testing on the lower dose and negative tests on the higher dose (disopyramide levels 2.2 +/- 0.17 mu/mL vs 3.2 +/- 0.17 mu/mL, P = 0.004). Thus, disopyramide is effective in preventing neurogenic syncope during head-up tilt testing, but higher blood levels are often necessary for efficacy. In a given patient, failure to respond to low dose disopyramide does not preclude success on higher doses.

Predictors of successful radiofrequency ablation of extranodal slow pathways.

Catheter positioning for radiofrequency ablation of extranodal slow pathways is often guided by local electrogram recordings. To determine the predictors of successful ablation sites, we reviewed data from 32 successful and 104 unsuccessful sites. Univariate predictors of a successful site included the occurrence of junctional rhythm during ablation (P < 0.001), shorter time to onset of junctional rhythm (P = 0.05), the presence of a discrete slow pathway potential (P < 0.001), a smaller ratio of the amplitude of the atrial:ventricular electrogram (P = 0.04), later timing (P = 0.001) and longer duration (P < 0.001) of the atrial slow pathway electrogram, and the duration of (P < 0.001), and maximal voltage used during ablation (P < 0.001). By multivariate analysis junctional rhythm (P < 0.001), a discrete slow pathway potential (P = 0.003), a longer duration of the atrial slow pathway electrogram (P = 0.01) and the duration of ablation (P = 0.02) were predictors of success. Because ablations at unsuccessful sites were often aborted at 10-30 seconds, a separate analysis was performed using only the 41 unsuccessful sites where the duration of ablation was > or = 30 seconds. The results were nearly identical. Thus, the occurrence of junctional rhythm during ablation and the morphology and duration of the atrial slow pathway electrogram may serve as guides for slow pathway ablation site selection.

Low-energy transvenous cardioversion defibrillation of atrial tachyarrhythmias in the canine: an assessment of electrode configurations and monophasic pulse sequencing.

Prevention of recurrent atrial fibrillation and flutter remains a difficult clinical problem. Consequently, development of an easily implantable automatic atrial cardioverter defibrillator is appealing. In this context we have examined the feasibility of intracavitary low-energy shocks delivered via transvenously positioned electrodes for termination of induced atrial tachyarrhythmias in canine models. This study extends these observations with use of single-pathway (5 msec pulse duration) and dual-pathway sequential (5/5 msec, 0.2 msec separation) shocks of varying leading edge voltages (100 to 400 V) in a closed-chest canine talc-pericarditis model. Bipolar 9.5 French electrode catheters (electrode surface areas, 0.62 cm2) were positioned at the superior vena cava-right atrium (SVC-RA) junction (labeled SVC) and right ventricular (RV) apex, with a subcutaneous plate over the chest wall. For single-pathway shocks, overall treatment effectiveness was comparable among the three vectors tested (RV apex to SVC, 35%; RV apex to subcutaneous plate, 17%; and SVC to subcutaneous plate, 35%). Furthermore, there was no evident relationship between leading edge voltage and shock effectiveness. In contrast, although each of the dual-pathway shock vector combinations tested also showed similar overall effectiveness, there was an apparent dose-response effect as leading edge voltage increased. The SVC (common) to RV apex (pulse 1) and subcutaneous plate (pulse 2) achieved 60% effectiveness at 400 V (approximately 4 joules). Thus this study provides additional evidence favoring feasibility of low-energy transvenous atrial cardioversion defibrillation. However, further refinement of energy delivery is essential for the implantable automatic atrial cardioverter defibrillator concept to become clinically accepted.

Stimulation of human prostatic carcinoma tumor growth in athymic mice and control of migration in culture by extracellular matrix.

The tumorigenicity, migration, growth and invasiveness of certain tumor cells is stimulated by basement membranes. Here we have examined the effect of Matrigel, an extract of basement membrane proteins, on the behavior of several prostate cancer cell lines, testing their growth and invasiveness in vitro and in vivo. Cells of the Tsu-prI line were more invasive than PC-3, Du-145, or LNCaP cells. Peptide inhibitors implicated laminin in the migration and invasion of these cells. When these cells were suspended in Matrigel and injected into nude mice, their growth was greatly enhanced, since large tumors formed in athymic nude mice whereas virtually no tumors were observed in the absence of Matrigel. The growth of a slowly growing line, LNCaP, was increased by exogenous basic fibroblast growth factor when injected with Matrigel. A laminin cell adhesion peptide, YIGSR, was a potent inhibitor of Matrigel-stimulated tumor growth implicating cell-laminin interactions in this process. These results suggest that tumor growth of prostate adenocarcinoma cells may be dependent both on cellular growth factors and on cell-matrix interactions mediated by laminin which facilitate the development of transplanted tumors in nude mice.

Evaluation of standard and active compression-decompression CPR in an acute human model of ventricular fibrillation.

BACKGROUND: The mechanisms that underlie cardiopulmonary resuscitation (CPR) in humans remain controversial and difficult to study. This report describes a new human model to evaluate CPR during the first 1 to 2 minutes after the onset of ventricular fibrillation (VF). With this model, standard CPR was compared with active compression-decompression (ACD) CPR, a method that uses a handheld suction device to actively compress and actively decompress the chest. METHODS AND RESULTS: During routine inductions of VF as part of a transvenous lead cardioverter/defibrillator implantation procedure, CPR was performed in 21 patients if the first defibrillation shock failed and until a successful rescue shock was delivered. Compressions during CPR were performed according to American Heart Association guidelines. For ACD CPR, decompression was performed with up to -30 lbs. Radial arterial and right atrial pressures were measured in all patients. Esophageal pressures, intratracheal pressures, or minute ventilation was measured in the last 13 patients. Application of both CPR techniques increased arterial and right atrial pressures. The mean coronary perfusion pressure was increased throughout the entire CPR cycle with ACD CPR (compression, 21.5 +/- 9.0 mm Hg; decompression, 21.9 +/- 8.7 mm Hg) compared with standard CPR (compression, 17.9 +/- 8.2 mm Hg; decompression, 18.5 +/- 6.9 mm Hg; P < .02 and P < .02, respectively). Ventilation per compression-decompression cycle was 97.3 +/- 65.6 mL with standard CPR and 168.4 +/- 68.6 mL with ACD CPR (n = 7, P < .001). Negative inspiratory pressure was -0.8 +/- 4.8 mm Hg with standard CPR and -11.4 +/- 6.3 mm Hg with ACD CPR (n = 6, P < .04). CONCLUSIONS: Patients undergoing multiple inductions of VF during cardioverter/defibrillator implantation with transvenous leads provide a well-controlled and reproducible model to study the mechanisms of CPR. Using this model, ACD CPR significantly increased arterial blood pressure, coronary perfusion pressure, minute ventilation, and negative inspiratory pressure compared with standard CPR.

Effect of parenteral d-sotalol on transvenous atrial defibrillation threshold in a canine model of atrial fibrillation.

In an effort to reduce energy requirements for atrial defibrillation to a level low enough to perform painless electrical cardioversion with an implantable atrial defibrillator, we tested the hypothesis that drug therapy with the class III agent d-sotalol, when used concurrently with a low-energy shock, reduces atrial defibrillation threshold. In a nonthoracotomy canine model of atrial fibrillation, intracardiac shocks were delivered between the distal coronary sinus and the mid-right atrium. Based on a step-up energy delivery protocol the atrial defibrillation threshold was defined as the least amount of energy that resulted in a >10% and <90% rate of successful defibrillation. At a dose associated with class III antiarrhythmic effects (5 mg/kg), d-sotalol significantly reduced atrial defibrillation threshold from 1.72 +/- 1.12 J to 0.59 +/- 0.60 J (p < 0.01). These results support the feasibility of using antiarrhythmic drug therapy with d-sotalol to minimize energy requirements for intracardiac electrical cardioversion of atrial fibrillation.