Rectus sheath hematoma complicating low-molecular weight heparin therapy.

Rectus sheath hematoma (RSH) is an uncommon but serious bleeding complication of anticoagulant therapy that has received little attention in the literature. Two cases of RSH among recent admissions to an inpatient medicine service and four archival cases were reviewed. All six patients were on low-molecular weight heparin (LMWH) therapy. Five of the six patients had a creatinine clearance of 40 ml/min or less, and five also had cough. Two patients with the most serious outcome were aged 90 and 92 years. RSH complicating LMWH therapy appears to constitute a clinical syndrome consisting of sudden onset of abdominal pain in the setting of renal insufficiency, advanced age and abdominal straining (e.g. cough). Risk of RSH may be reduced in patients receiving LMWH by assessing renal function, monitoring heparin levels (e.g. when the creatinine clearance is 40 ml/min or less) and adjusting the dose accordingly; by avoidance of abdominal strain (e.g. by treating cough); and by attention to technique when the abdominal wall is used as the injection site. Patients of advanced age may be at particular risk for RSH.

Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis.

Exisulind (Aptosyn) is a novel antineoplastic drug being developed for the prevention and treatment of precancerous and malignant diseases. In colon tumor cells, the drug induces apoptosis by a mechanism involving cyclic GMP (cGMP) phosphodiesterase inhibition, sustained elevation of cGMP, and protein kinase G activation. We studied the effect of exisulind on bladder tumorigenesis induced in rats by the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine. Exisulind at doses of 800, 1000, and 1200 mg/kg (diet) inhibited tumor multiplicity by 36, 47, and 64% and tumor incidence by 31, 38, and 61%, respectively. Experiments on the human bladder tumor cell line, HT1376, showed that exisulind inhibited growth with a GI(50) of 118 microM, suggesting that the antineoplastic activity of the drug in vivo involved a direct effect on neoplastic urothelium. Exisulind also induced apoptosis as determined by DNA fragmentation, caspase activation, and morphology. Analysis of phosphodiesterase (PDE) isozymes in HT1376 cells showed PDE5 and PDE4 isozymes that were inhibited by exisulind with IC(50)s of 112 and 116 microM, respectively. Inhibition of PDE5 appears to be pharmacologically relevant, because treatment of HT1376 cells increased cGMP and activated protein kinase G at doses that induce apoptosis, whereas cyclic AMP levels were not changed. Immunocytochemistry showed that PDE5 was localized in discrete perinuclear foci in HT1376 cells. Immunohistochemistry showed that PDE5 was overexpressed in human squamous and transitional cell carcinomas compared with normal urothelium. The data lead us to conclude that future clinical trials of exisulind for human bladder cancer treatment and/or prevention should be considered and suggest a mechanism of action involving cGMP-mediated apoptosis induction.

Exisulind induction of apoptosis involves guanosine 3',5'-cyclic monophosphate phosphodiesterase inhibition, protein kinase G activation, and attenuated beta-catenin.

Sulindac sulfone (exisulind), although a nonsteroidal anti-inflammatory drug derivative, induces apoptosis in tumor cells by a mechanism that does not involve cyclooxygenase inhibition. SW480 colon tumor cells contain guanosine 3',5'-monophosphate (cGMP) phosphodiesterase (PDE) isoforms of the PDE5 and PDE2 gene families that are inhibited by exisulind and new synthetic analogues. The analogues maintain rank order of potency for PDE inhibition, apoptosis induction, and growth inhibition. A novel mechanism for exisulind to induce apoptosis is studied involving sustained increases in cGMP levels and cGMP-dependent protein kinase (PKG) induction not found with selective PDE5 or most other PDE inhibitors. Accumulated beta-catenin, shown to be a substrate for PKG, is decreased by exisulind, suggesting a mechanism to explain apoptosis induction in neoplastic cells harboring adenomatous polyposis coli gene mutations.

"Rate-drop response" cardiac pacing for vasovagal syncope. Rate-Drop Response Investigators Group.

Recent reports suggest that cardiac pacing incorporating a rate-drop response algorithm is associated with a reduction in the frequency of syncopal episodes in patients with apparent cardioinhibitory vasovagal syncope. The detection portion of the algorithm employs a programmable heart rate change-time duration "window" to both identify abrupt cardiac slowing suggestive of an imminent vasovagal event and trigger "high rate" pacing. The purpose of this study was to develop recommendations for programming the rate-drop response algorithm. Pacemaker programming, symptom status, and drug therapy were assessed retrospectively in 24 patients with recurrent vasovagal syncope of sufficient severity to warrant consideration of pacemaker treatment. In the 53 +/- 19 months prior to pacing, patients had experienced an approximate syncope burden of 1.2 events/month. During follow-up of 192 +/- 160 days, syncope recurred in 4 patients (approximate syncope burden, 0.3 events/month, p < 0.05 vs. pre-pacing), and pre-syncope in 5 patients. In these patients, rate-drop response parameters were initially set based on electrocardiographic and/or tilt-table recordings, and were re-programmed at least once in 14 (58%) individuals. A 20 beat/min window height (top rate minus bottom rate), a window width of 10 beats (61% of patients), and 2 or 3 confirmation beats (79% of patients) appeared to be appropriate in most patients. Treatment intervention rate was set to > 100 beats/min in 89% of patients, with a duration of 1 to 2 min in 79%. In conclusion, a narrow range of rate-drop response parameter settings appeared to be effective for most individuals in this group of highly symptomatic patients.

Prehospital discharge defibrillation testing in ICD recipients: a prospective study based on cost analysis.

Prehospital discharge defibrillation testing is often performed to verify the function of newly implanted cardioverter defibrillators (ICDs). To determine whether elimination of predischarge testing could reduce costs without placing patients at additional risk, 31 patients were randomized in this prospective clinical evaluation to either receive or not receive a predischarge ICD defibrillation test. Expenses associated with postimplant care was the primary endpoint. All patients underwent induction of ventricular fibrillation after 6 months to evaluate ICD function. The groups were well matched in terms of patient characteristics, initial lead implant parameters, and defibrillation thresholds. Elimination of prehospital discharge testing resulted in a savings of $1,800/patient after 6 months, with no difference between groups in terms of ICD complication rates or unanticipated hospital admissions. Further studies are needed to better define the most appropriate time to assess defibrillation thresholds in the first year after implantation.

Physiologic cardiac pacing in patients with contemporary implantable cardioverter-defibrillators.

Contemporary implantable cardioverter-defibrillators (ICD) incorporate single-chamber ventricular pacing capability. However, because poor ventricular function and/or congestive heart failure is common in the ICD population, the provision of more "physiologic" pacing modes has been receiving increased attention. To evaluate the potential impact of ICDs with physiologic pacing features, we assessed the frequency with which atrial-based pacing modes with or without rate responsiveness are currently used in ICD recipients. Further, we characterized those clinical variables at initial ICD implant that tended to be associated with subsequent need for physiologic pacing. Clinical findings were reviewed in 250 consecutive patients who received ICDs with VVI pacing capability at the University of Minnesota Cardiac Arrhythmia Center between January 1991 and February 1997. Adjunctive physiologic pacing was undertaken in 35 patients (14%): 13 before or at the same time as their ICD, and 22 within a mean of 2.5 years after initial ICD surgery. A history of atrial tachyarrhythmia before ICD implantation (p <0.0001) and treatment with antiarrhythmic drugs at the time of ICD surgery (p <0.05) were predictors of subsequent need for physiologic pacing. The type of presenting ventricular tachyarrhythmia and electrophysiologic parameters (such as the HV interval and the shortest atrial pacing cycle length associated with 1:1 anterograde atrioventricular conduction) were not associated with a subsequent decision to implant a physiologic pacing system. Thus, we conclude that despite the need to implant a second device, physiologic pacing is currently used in an important subset of ICD recipients. Further, certain clinical features at time of ICD implant appear to characterize these patients and may prove helpful in patient selection for the next generation "dual-chamber" ICD.

Digital cellular telephone interaction with implantable cardioverter-defibrillators.

OBJECTIVES: This study sought to determine, in vivo, whether electromagnetic interference (EMI), generated by North American Digital Communications (NADC)/Time Division Multiple Access-50-Hz (TDMA-50) mobile cellular digital telephone model AT&T 6650, disturbs normal implantable cardioverter-defibrillator (ICD) operation and to verify these observations in vitro by testing a selection of telephones representing worldwide systems. METHODS: The effects of cellular phone interference on the operation of various models of market-released ICDs from a single manufacturer, Medtronic, Inc., were tested. The in vivo clinical test was undertaken in 41 patients using the AT&T 6650 digital telephone with the NADC/TDMA-50 technology. The in vitro component of the study was examined twofold: 1) antenna generated far field; and 2) analog/digital cellular telephone near field. RESULTS: None of the ICDs tested in 41 patients were affected by oversensing of the EMI field of the cellular telephones during the in vivo study. Therefore, the binomial upper 95% confidence limit for the failure rate of 0% is 7%. The in vitro antenna-generated field testing showed that telephone modulation frequencies used in the international Global System Mobile and TDMA-50 cellular telephone technologies did not result in ICD sensing interference at the predicted electric field intensity. The in vitro near field tests were performed using both analog and digital cellular telephones in service, or in the test mode, and indicated no interaction with normal operation. However, the static magnetic field generated by the cellular telephone placed over the ICD at a distance < or = 0.5 cm will activate the internal reed switch, resulting in temporary suspension of ventricular tachycardia and fibrillation detection. CONCLUSIONS: We conclude that TDMA-50 cellular telephones did not interfere with these types of ICDs. However, we recommend that the patient not carry or place the digital cellular telephone within 15 cm (6 in.) of the ICD.

Clinical experience with Thera DR rate-drop response pacing algorithm in carotid sinus syndrome and vasovagal syncope. The International Rate-Drop Investigators Group.

This study examined the effectiveness of cardiac pacing using the Thera DR rate-drop response algorithm for prevention of recurrent symptoms in patients with carotid sinus syndrome (CSS) or vasovagal syncope. The algorithm comprises both diagnostic and treatment elements. The diagnostic element consists of a programmable "window" used to identify heart rate changes compatible with an evolving neurally mediated syncopal episode. The treatment arm consists of pacing at a selectable rate and for a programmable duration. Forty-three patients (mean age 53 +/- 20.4 years) with CSS alone (n = 8), CSS in conjunction with vasovagal syncope (n = 4), or vasovagal syncope alone (n = 31) were included. Thirty-nine had recurrent syncope, while the remaining four reported multiple presyncopal events. Prior to pacing, 40 +/- 152 syncopal episodes (range from 1 to approximately 1,000 syncopal events) over the preceding 56 +/- 84.5 months. Postpacing follow-up duration was 204 +/- 172 days. Three patients have been lost to follow-up and in one patient the algorithm was disabled. Among the remaining 39 individuals, 31 (80%) indicated absence or diminished frequency of symptoms, or less severe symptoms. Twenty-three patients (23/29, or 59%) were asymptomatic with respect to syncope or presyncope. Sixteen patients had symptom recurrences. Of these, seven experienced syncope (7/39, or 18%) and 9 (29%) had presyncope: the majority of patients with recurrences (6/7 syncope and 7/9 presyncope) were individuals with a history of vasovagal syncope. Consequently, although symptoms were observed during postpacing follow-up, they appeared to be of reduced frequency and severity. Thus, our findings suggest that a transient period of high rate pacing triggered by the Thera DR rate-drop response algorithm was beneficial in a large proportion of highly symptomatic patients with CSS or vasovagal syncope.

Site-directed mutagenesis of residues lining a putative proton transfer pathway in cytochrome c oxidase from Rhodobacter sphaeroides.

Several putative proton transfer pathways have been identified in the recent crystal structures of the cytochrome oxidases from Paracoccus denitrificans [Iwata et al. (1995) Nature 376, 660-669] and bovine [Tsukihara (1996) Science 272, 1138-1144]. A series of residues along one face of the amphiphilic transmembrane helix IV lie in one of these proton transfer pathways. The possible role of these residues in proton transfer was examined by site-directed mutagenesis. The three conserved residues of helix IV that have been implicated in the putative proton transfer pathway (Ser-201, Asn-207, and Thr-211) were individually changed to alanine. The mutants were purified, analyzed for steady-state turnover rate and proton pumping efficiency, and structurally probed with resonance Raman spectroscopy and FTIR difference spectroscopy. The mutation of Ser-201 to alanine decreased the enzyme turnover rate by half, and was therefore further characterized using EPR spectroscopy and rapid kinetic methods. The results demonstrate that none of these hydrophilic residues are essential for proton pumping or oxygen reduction activities, and suggest a model of redundant or flexible proton transfer pathways. Whereas previously reported mutants at the start of this putative channel (e.g., Asp-132-Asn) dramatically influence both enzyme turnover and coupling to proton pumping, the current work shows that this is not the case for all residues observed in this channel.

Fatty acids stimulate activity and restore respiratory control in a proton channel mutant of cytochrome c oxidase.

(1) Removal of a carboxyl at residue 132 of subunit I of Rhodobacter sphaeroides cytochrome c oxidase significantly inhibits electron transfer and makes proton pumping undetectable [Fetter et al. (1995) Proc. Natl. Acad. Sci. USA 92, 1604-1608]. When reconstituted into phospholipid vesicles (COV), wild-type oxidase shows respiratory control that is partially released by either valimomycin or nigericin and fully released by the two ionophores combined. Under the same conditions, the D132A mutant COV show anomalous ionophore responses, including inhibition by valinomycin or by CCCP. Nevertheless, oxidase activity results in development of a similar membrane potential in COV containing either wild-type or D132A oxidase, and the ionophore responses of the membrane potential are similar for both enzymes. (2) Long chain fatty acids such as arachidonic acid, but not fatty alcohols, stimulate steady-state electron transfer activity 3-7-fold, with either detergent-solubilized (purified) D132A oxidase or the reconstituted form. The effect is specific for this mutant and is not seen with wild-type or other mutants of similar overall activity. Arachidonate-treated D132A COV show normal ionophore responses to valinomycin and nigericin and full release of respiration in presence of both ionophores or of CCCP. Thus, arachidonate and some other fatty acids abolish the ionophore anomalies seen when the D132A enzyme is reconstituted in their absence. (3) Fatty acid addition does not restore proton pumping, likely because fatty acids also induce proton permeability and some degree of uncoupling. A model of D132A function is presented and possible roles for the fatty acids in 'chemical rescue' of the mutant are discussed.

Electromagnetic interference from welding and motors on implantable cardioverter-defibrillators as tested in the electrically hostile work site.

OBJECTIVES: This study was designed to determine the susceptibility of an implanted cardioverter-defibrillator to electromagnetic interference in an electrically hostile work site environment, with the ultimate goal of allowing the patient to return to work. BACKGROUND: Normal operation of an implanted cardioverter-defibrillator depends on reliable sensing of the heart's electrical activity. Consequently, there is concern that external electromagnetic interference from external sources in the work place, especially welding equipment or motor-generator systems, may be sensed and produce inappropriate shocks or abnormal reed switch operation, temporarily suspending detection of ventricular tachycardia or ventricular fibrillation. METHODS: The effects of electromagnetic interference on the operation of one type of implantable cardioverter-defibrillator (Medtronic models 7217 and 7219) was measured by using internal event counter monitoring in 10 patients operating arc welders at up to 900 A or working near 200-hp motors and 1 patient close to a locomotive starter drawing up to 400 A. RESULTS: The electromagnetic interference produced two sources of potential interference on the sensing circuit or reed switch operation, respectively: 1) electrical fields with measured frequencies up to 50 MHz produced by the high currents during welding electrode activation, and 2) magnetic fields produced by the current in the welding electrode and cable. The defibrillator sensitivity was programmed to the highest (most sensitive) value: 0.15 mV (model 7219) or 0.3 mV (model 7217). The ventricular tachycardia and ventricular fibrillation therapies were temporarily turned off but the detection circuits left on. CONCLUSIONS: None of the implanted defibrillators tested were affected by oversensing of the electric field as verified by telemetry from the detection circuits. The magnetic field from 225-A welding current produced a flux density of 1.2 G; this density was not adequate to close the reed switch, which requires approximately 10 G. Our testing at the work site revealed no electrical interference with this type of defibrillator. Patients were allowed to return to work. The following precautions should be observed by the patient: 1) maintain a minimal distance of 2 ft (61 cm) from the welding arc and cables or large motors, 2) do not exceed tested currents with the welding equipment, 3) wear insulated gloves while operating electrical equipment, 4) verify that electrical equipment is properly grounded, and 5) stop welding and leave the work area immediately if a therapy is delivered or a feeling of lightheadedness is experienced.

Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy.

PURPOSE AND METHODS: A review of the literature was performed to determine the number of cases of port site recurrences (PSR) after laparoscopy or thoracoscopy. CANCERLINE and MEDLINE were searched, as were citings from retrieved and related papers. RESULTS: There have been 35 reported cases of PSR after laparoscopic colectomy for colorectal carcinoma, and 23 cases after thoracoscopic procedures for lung neoplasms. All of these have been reported since 1993. Since 1991, 12 cases have been described after laparoscopic cholecystectomy of unsuspected gallbladder carcinoma, and another case after biopsy of a known gallbladder carcinoma. Ten cases of PSR have been reported after laparoscopic procedures for ovarian lesions, often in the presence of peritoneal seeding at diagnosis. Other rare PSRs have been documented after several procedures in various malignancies. CONCLUSION: Enrollment of patients onto the ongoing intergroup study evaluating open versus laparoscopic resection of colon cancer should be encouraged. Until valid prospective data on PSR frequency are available, laparoscopic or thoracoscopic resection of malignancy off-protocol should be undertaken with circumspection.

A ligand-exchange mechanism of proton pumping involving tyrosine-422 of subunit I of cytochrome oxidase is ruled out.

The molecular mechanism by which proton pumping is coupled to electron transfer in cytochrome c oxidase has not yet been determined. However, several models of this process have been proposed which are based on changes occurring in the vicinity of the redox centers of the enzyme. Recently, a model was described in which a well-conserved tyrosine residue in subunit I (Y422) was proposed to undergo ligand exchange with the histidine ligand (H419) of the high-spin heme a3 during the catalytic cycle, allowing both residues to serve as part of a proton transporting system. Site-directed mutants of Y422 have been constructed in the aa3-type cytochrome c oxidase of Rhodobacter sphaeroides to test this hypothesis (Y422A, Y422F). The results demonstrate that Y422 is not an essential residue in the electron transfer and proton pumping mechanisms of cytochrome c oxidase. However, the results support the predicted proximity of Y422 to heme a3, as now confirmed by crystal structure. In addition, it is shown that the pH-dependent reversed electron transfer between heme a and heme a3 is normal in the Y422F mutant. Hence, these data also demonstrate that Y422 is not the residue previously postulated to interact electrostatically with heme a3, nor is it responsible for the unique EPR characteristics of heme a in this bacterial oxidase.

Transtelephonic monitoring and transmission of stored arrhythmia detection and therapy data from an implantable cardioverter defibrillator.

A new transtelephonic monitoring device designed for use with implantable cardioverter defibrillators (ICDs) was evaluated. It is capable of interrogating ICDs and transmitting the following data via telephone: programmed parameters (e.g., ventricular tachycardia [VT] and ventricular fibrillation [VF] detection, therapies), number of VT and VF episodes, identification of successful therapies, the 20 cycle lengths preceding the last episode detected, the 10 cycle lengths after the last delivered therapy, battery voltage, and real-time transmission of the patient's rhythm. Eighteen patients (mean age 64 +/- 17 years; 15 males) were implanted with an ICD and epicardial lead system. The patients who did not live near the primary hospital were provided with this transmitter and instructed to transmit monthly and whenever presyncope, syncope, or a shock were experienced. Five hundred ten episodes of spontaneous arrhythmia (495 VT, 15 VF) were detected in 14 of 18 patients in a 24-month period and the success of each therapy (antitachycardia pacing, cardioversion 0.4-34 J, defibrillation 34 J) was analyzed. The number of therapies delivered and their success (%) in terminating the arrhythmia were: 380 ramp/86%, 116 burst/84%, 119 cardioversion/57%, and 15 defibrillations/100%. Sixty-three (42%) of the 152 transmissions indicated an arrhythmia. Twenty-five (16%) of the 152 were transmitted because of symptoms. Sixteen (9.7%) of 165 VT episodes could not be terminated by the full set of programmed VT therapies. Analysis of the pre- and post-episode intervals along with the patient's transmitted rhythm indicated that sinus tachycardia or atrial fibrillation were likely responsible for these episodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Prevention of distal limb ischemia during cardiopulmonary support via femoral cannulation.

The indications for prolonged cardiopulmonary support or extracorporeal membrane oxygenation are expanding. A potential serious complication of these techniques is distal limb ischemia. Techniques have been developed to provide the distal limb with blood flow. Unfortunately, specialized skills and materials are required. We describe a simple method of providing distal limb perfusion using ordinary pressure tubing and a standard cordis catheter. This technique is capable of reproducing normal superficial femoral artery blood flow.

Possible proton relay pathways in cytochrome c oxidase.

As the final electron acceptor in the respiratory chain of eukaryotic and many prokaryotic organisms, cytochrome c oxidase (EC 1.9.3.1) catalyzes the reduction of oxygen to water and generates a proton gradient. To test for proton pathways through the oxidase, site-directed mutagenesis was applied to subunit I of the Rhodobacter sphaeroides enzyme. Mutants were characterized in three highly conserved regions of the peptide, comprising possible proton loading, unloading, and transfer sites: an interior loop between helices II and III (Asp132Asn/Ala), an exterior loop between helices IX and X (His411Ala, Asp412Asn, Thr413Asn, Tyr414Phe), and the predicted transmembrane helix VIII (Thr352Ala, Pro358Ala, Thr359Ala, Lys362Met). Most of the mutants had lower activity than wild type, but only mutants at residue 132 lost proton pumping while retaining electron transfer activity. Although electron transfer was substantially inhibited, no major structural alteration appears to have occurred in D132 mutants, since resonance Raman and visible absorbance spectra were normal. However, lower CO binding (70-85% of wild type) suggests some minor change to the binuclear center. In addition, the activity of the reconstituted Asp132 mutants was inhibited rather than stimulated by ionophores or uncoupler. The inhibition was not observed with the purified enzyme and a direct pH effect was ruled out, suggesting an altered response to the electrical or pH gradient. The results support an important role for the conserved II-III loop in the proton pumping process and are consistent with the possibility of involvement of residues in helix VIII and the IX-X loop.

Termination and acceleration of ventricular tachycardia with autodecremental pacing, burst pacing, and cardioversion in patients with an implantable cardioverter defibrillator. Multicenter PCD Investigator Group.

This multicenter study reports the outcome of ventricular tachycardia (VT) therapy (conversion or acceleration) and the relationship to initial tachycardia cycle length and other clinical variables using an implantable device with the capability of autodecremental or burst pacing, cardioversion, and defibrillation. The device was implanted in 444 patients (mean age 58 +/- 15 years) with 1,240 episodes of VT induced with noninvasive programming and reported in a multicenter database. Only the first sequence attempted for conversion by pacing or cardioversion was assessed, and cardioversion energies were 0.2-5 J. Autodecremental pacing was used to treat 700 induced episodes of VT during titration of pacing therapies (57% converted and 12% accelerated), burst pacing to treat 357 episodes (49% converted under 11% accelerated), and cardioversion to treat 183 episodes (82% converted and 4% accelerated). Cardioversion was the most effective treatment and had the lowest acceleration rate. Shorter VT cycle lengths were more likely to accelerate with burst pacing and longer VT cycle lengths to convert with both burst and autodecremental pacing. Patients with higher ejection fractions were more likely to convert with autodecremental and burst pacing. Use of cardioversion, higher ejection fraction, absence of unrepaired aneurysm, longer VT cycle lengths, coronary artery disease, and use of autodecremental pacing predicted conversion. Lower ejection fraction and VT cycle lengths < or = 300 msec predicted tachycardia acceleration.

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.