Gut dendritic cell activation links an altered colonic microbiome to mucosal and systemic T-cell activation in untreated HIV-1 infection.

HIV-1-associated disruption of intestinal homeostasis is a major factor contributing to chronic immune activation and inflammation. Dendritic cells (DCs) are crucial in maintaining intestinal homeostasis, but the impact of HIV-1 infection on intestinal DC number and function has not been extensively studied. We compared the frequency and activation/maturation status of colonic myeloid DC (mDC) subsets (CD1c(+) and CD1c(neg)) and plasmacytoid DCs in untreated HIV-1-infected subjects with uninfected controls. Colonic mDCs in HIV-1-infected subjects had increased CD40 but decreased CD83 expression, and CD40 expression on CD1c(+) mDCs positively correlated with mucosal HIV-1 viral load, with mucosal and systemic cytokine production, and with frequencies of activated colon and blood T cells. Percentage of CD83(+)CD1c(+) mDCs negatively correlated with frequencies of interferon-γ-producing colon CD4(+) and CD8(+) T cells. CD40 expression on CD1c(+) mDCs positively associated with abundance of high prevalence mucosal Prevotella copri and Prevotella stercorea but negatively associated with a number of low prevalence mucosal species, including Rumminococcus bromii. CD1c(+) mDC cytokine production was greater in response to in vitro stimulation with Prevotella species relative to R. bromii. These findings suggest that, during HIV infection, colonic mDCs become activated upon exposure to mucosal pathobiont bacteria leading to mucosal and systemic immune activation.

An altered intestinal mucosal microbiome in HIV-1 infection is associated with mucosal and systemic immune activation and endotoxemia.

Human immunodeficiency virus-1 (HIV-1) infection disrupts the intestinal immune system, leading to microbial translocation and systemic immune activation. We investigated the impact of HIV-1 infection on the intestinal microbiome and its association with mucosal T-cell and dendritic cell (DC) frequency and activation, as well as with levels of systemic T-cell activation, inflammation, and microbial translocation. Bacterial 16S ribosomal DNA sequencing was performed on colon biopsies and fecal samples from subjects with chronic, untreated HIV-1 infection and uninfected control subjects. Colon biopsies of HIV-1-infected subjects had increased abundances of Proteobacteria and decreased abundances of Firmicutes compared with uninfected donors. Furthermore at the genus level, a significant increase in Prevotella and decrease in Bacteroides was observed in HIV-1-infected subjects, indicating a disruption in the Bacteroidetes bacterial community structure. This HIV-1-associated increase in Prevotella abundance was associated with increased numbers of activated colonic T cells and myeloid DCs. Principal coordinates analysis demonstrated an HIV-1-related change in the microbiome that was associated with increased mucosal cellular immune activation, microbial translocation, and blood T-cell activation. These observations suggest that an important relationship exists between altered mucosal bacterial communities and intestinal inflammation during chronic HIV-1 infection.

Impaired plasmacytoid dendritic cell maturation and differential chemotaxis in chronic hepatitis C virus: associations with antiviral treatment outcomes.

BACKGROUND: Dendritic cell (DC) defects may contribute to chronicity in hepatitis C virus (HCV) infection and determine response to PEG-interferon and ribavirin therapy via poor T cell stimulation. Studies to date have produced inconsistent results regarding DC maturation and function: no large study has examined DCs before and after therapy. AIMS: We examined if DC defects in maturation and chemotaxis are present by comparing therapeutic responders to non-responders. METHODS: We analysed peripheral DCs of 64 HCV genotype 1-infected patients from the Virahep-C study 2 weeks before and 24 weeks after therapy. We used flow cytometry to enumerate plasmacytoid DC (pDC) and myeloid DCs (mDC) and quantify expression of chemokine receptors and maturation markers. Chemotaxis was measured with an in vitro assay. RESULTS: Pre-treatment frequencies of pDCs and mDCs were significantly lower in HCV patients than controls and successful therapy normalised pDCs. Levels of CXCR3 and CXCR4 on pDCs were higher at baseline compared to normal controls and decreased with therapy. Pre-therapy levels of co-stimulatory marker CD40 and the maturation marker CD83 were higher in pDCs of patients chronically infected with HCV compared to normal patients, and levels of both markers dropped significantly with therapy in the SVR+ group only. Other maturation markers (CD86 and CCR7) were not elevated suggesting a partially activated phenotype. Baseline chemotaxis of pDCs to CXCL12 and CXCL10 predicted failure of antiviral response and correlated with the histological activity index inflammation score. CONCLUSIONS: Plasmacytoid DC defects exist in chronic HCV and successful antiviral therapy normalises many phenotypic and functional abnormalities.

Effects of linear, irrigated-tip radiofrequency ablation in porcine healed anterior infarction.

INTRODUCTION: Radiofrequency (RF) catheter ablation for ventricular tachycardia (VT) in healed infarction is modestly successful. More extensive, anatomically based procedures and irrigated RF delivery may improve outcome. However, limited data exist regarding the characteristics of irrigated RF lesions in infarcted myocardium. This study addresses this shortcoming. METHODS AND RESULTS: Linear lesions were created at the medial border of a healed anterior infarct in eight pigs using irrigated RF energy guided by sinus rhythm electroanatomic voltage mapping and intracardiac echocardiography (ICE). Lesion morphology and effects on ventricular function were assessed with ICE imaging and pathologic analysis (n = 5). The response to programmed stimulation also was determined before and after linear lesions (n = 6). A mean of 9.4 +/- 1.3 RF applications created linear lesions 37.0 +/- 10.6 mm long, 5 to 12 mm wide, and 4 to 8 mm deep. Thrombus formation was not observed. Lesion delivery resulted acutely in increased local wall thickness at the RF site (26.9% +/- 27.5%; P < 0.0001) and transient systolic dysfunction in adjacent normal myocardium (fractional shortening -38% +/- 34%; P < 0.01). Uniform sustained VT (cycle length 232 +/- 41 msec) was induced in 4 of 6 pigs before ablation, but sustained VT could not be induced afterward. CONCLUSION: Irrigated RF energy produced relatively large lesions in infarcted myocardium without thrombus formation. Changes in tissue thickness and echo density observed with ICE verify irrigated RF lesion delivery. Temporary left ventricular dysfunction is consistently observed in the normal myocardium adjacent to the linear lesion.

Intracardiac echocardiographic evaluation of ventricular mural swelling from radiofrequency ablation in chronic myocardial infarction: irrigated-tip versus standard catheter.

INTRODUCTION: The production of larger, particularly deeper lesions may improve the success rate for radiofrequency (RF) ablation of post infarction ventricular tachycardia (VT). Therapeutic RF ablation causes left ventricular (LV) mural swelling. This swelling can be detected as increased wall thickness at the ablation site by intracardiac echocardiography (ICE) and correlates with pathologic lesion size. This study compared the extent of mural swelling caused by linear ablation lesions created with irrigated tip and standard RF ablation in a porcine model of healed anterior infarction. METHODS AND RESULTS: In anesthetized closed-chest swine ICE guided multiple RF applications to construct linear lesions at the border zone of the infarct region using an irrigated RF (n=6 swine) and a standard RF (n=6 swine) ablation catheter. 47 individual lesions were created with irrigated RF ablation; 57 lesions created with standard RF ablation. At all sites, wall thickness (measured at end-diastole Pre- and 1 min Post-RF delivery) increased following either irrigated (p<0.0001) or standard (p<0.004) RF deployment. Irrigated RF ablation produced more mural swelling at border zone sites than standard RF ablation (wall thickness increase of 21.2 versus 15.1 %, p<0.003). This difference was more pronounced at RF sites within the infarct (40.7 versus 12.0 %, p<0.0007). Thrombus formation or intramural explosion were not observed; surface crater formation was not more frequent with irrigated compared to standard RF ablation (14/47 versus 12/57 lesions, p=NS). CONCLUSION: Irrigated RF ablation may produce larger lesions than standard RF ablation, particularly for ablation targets within infarcted tissue. ICE imaging provides on line data about the characteristics of the developing lesion which may prove useful in dosing irrigated-tip RF energy application.

Electroanatomic left ventricular mapping in the porcine model of healed anterior myocardial infarction. Correlation with intracardiac echocardiography and pathological analysis.

BACKGROUND: Catheter ablation for ventricular tachycardia in healed infarction is limited to patients with inducible, tolerated arrhythmias. Strategies that would allow mapping during sinus rhythm might obviate this limitation. METHODS AND RESULTS: Two sets of experiments were performed in adult pigs to refine a new technique for left ventricular mapping. First, detailed endocardial maps were done in 5 normal pigs and 7 pigs 6 to 10 weeks after left anterior descending coronary artery infarction to characterize electrograms in normal and infarcted tissue by electroanatomic mapping (CARTO, Biosense). Electrogram recording sites were verified by intracardiac echo (ICE, 9 MHz) and grouped by location: infarct (area of akinesis by ICE), border (0.5-cm perimeter of akinetic area), and remote. Compared with remote sites, electrograms from infarct sites had smaller amplitudes (1.2+/-0.5 versus 5.1+/-2.1 mV, P<0.001), longer durations (74.2+/-26.3 versus 36.3+/-6.4 ms, P<0.001), and more frequent notched or late components. Border zone electrograms were intermediate in amplitude and duration. Second, infarct characterization by electroanatomic mapping was compared with pathological (exclusion of triphenyltetrazolium chloride staining) and ICE measurements. Infarct size by pathology correlated with the area defined by contiguous electrograms with amplitude

Recording of pacing stimulus artifacts by endovascular defibrillation lead systems: comparison of true and integrated bipolar circuits.

BACKGROUND: The occurrence ICD undersensing of ventricular fibrillation due to the presence of a pacing stimulus artifact (PSA) is in part related to the amplitude of the artifact recorded on the ICD rate sensing circuit. There is little comparative data regarding PSA amplitude recorded by commercial ICD rate-sensing circuits. PURPOSE: To compare PSA amplitude recorded by commercial endovascular defibrillation leads utilizing integrated or true bipolar sensing circuits. METHODS: Nineteen large (60-120 kg) pigs were utilized. Two different commercial endovascular defibrillation leads were evaluated, each with its distal tip located at the right ventricular apex: (1) Medtronic Transvene; and (2) CPI Endotak. Three different rate-sensing circuits were evaluated: (1) Transvene true bipolar (tip-ring); (2) Transvene integrated bipolar (tip-coil); and (3) Endotak integrated bipolar (tip-coil). Using a separate pacing lead located at the left ventricular apex (n = 19 animals) or right ventricular outflow tract (n = 10 animals), pacing was performed at a pulse width of 0.5 milliseconds at outputs of 1.5, 5 and 10 volts. PSA amplitude was recorded at each output by each circuit. RESULTS: During pacing from the left ventricular apex, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.6 +/- 0.1 mV at 1.5 volts, 2.0 +/- 0.5 mV at 5 volts, 3.7 +/- 0.8 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.4 +/- 0.3 mV at 1.5 volts, 3.8 +/- 0.7 mV at 5 volts, 4.1 +/- 0.8 mV at 10 volts) or the Endotak integrated circuit (1.8 +/- 0.4 mV at 1.5 volts, 4.2 +/- 1.0 mV at 5 volts, 6.3 +/- 1.8 mV at 10 volts). During pacing from the right ventricular outflow tract, at each pacing output voltage the PSA amplitude recorded by the true bipolar circuit (0.7 +/- 0.1 mV at 1.5 volts, 1.7 +/- 0.4 mV at 5 volts, 4.0 +/- 0.7 mV at 10 volts) was significantly smaller than recorded by the Transvene integrated circuit (1.1 +/- 0.4 mV at 1.5 volts, 3.9 +/- 1.2 mV at 5 volts, 7.5 +/- 1.8 mV at 10 volts) or the Endotak integrated circuit (1.6 +/- 0.7 mV at 1.5 volts, 4.3 +/- 1.7 mV at 5 volts, 7.5 +/- 2.6 mV at 10 volts). For both pacing sites, the PSA amplitude recorded by the two integrated circuits was not significantly different. CONCLUSIONS: For a given pacing output voltage, PSA amplitude recorded by commercial endovascular rate sensing/defibrillation leads is greater when the sensing circuit is integrated than when it is true bipolar. These data may be helpful in planning ICD implantation in patients with previously implanted permanent pacemakers.

A long-lasting interferon-gamma response is induced to a single inoculation of antigen-pulsed dendritic cells.

Vaccines against infectious organisms must produce not only long-lasting immunity but also the appropriate immune response to clear the infection. Obligate intracellular parasites, such as mycobacteria, require a predominantly cell-mediated immune response rather than antibody. Presentation of antigen by dendritic cells (DC) has been associated with the development of strong cell-mediated responses generating the production of interferon-gamma (IFN-gamma). This cytokine has an essential role in the elimination of mycobacteria. Therefore, we investigated both the duration and the nature of the immune response after priming with DC pulsed with mycobacterial antigen and compared this with priming using a conventional adjuvant. We used two strains of mice: C57BL/6, which inherently produces a T-helper 1 (Th1)-type response to mycobacterial antigen, and BALB/c, which does not. DC-enriched cell suspensions, purified DC or cultured bone marrow cells resembling DC (BMAPC) were prepared, pulsed overnight with PPD and injected intravenously (i.v.) into naive mice. Six and 12 weeks later, splenic T lymphocytes from these mice were challenged in vitro with antigen and their proliferative response and cytokine production was determined. Significant antigen-specific proliferation was observed in all assays on rechallenge with antigen in vitro 6 and 12 weeks after the initial priming with DC. IFN-gamma was detected in both strains but was only antigen specific in the C57BL/6 strain. Purified protein derivative (PPD)-pulsed BMAPC generated similar responses 6 weeks after priming. Thus, long-term T-lymphocyte responses and the production of IFN-gamma can be generated using a single inoculation of PPD-pulsed DC.

Progressive depolarization: a unified hypothesis for defibrillation and fibrillation induction by shocks.

Experimental studies of defibrillation have burgeoned since the introduction of the upper limit of vulnerability (ULV) hypothesis for defibrillation. Much of this progress is due to the valuable work carried out in pursuit of this hypothesis. The ULV hypothesis presented a unified electrophysiologic scheme for linking the processes of defibrillation and shock-induced fibrillation. In addition to its scientific ramifications, this work also raised the possibility of simpler and safer means for clinical defibrillation threshold testing. Recent results from an optical mapping study of defibrillation suggest, however, that the experimental data supporting the ULV hypothesis could instead be interpreted in a manner consistent with traditional views of defibrillation such as the critical mass hypothesis. This review will describe the evidence calling for such a reinterpretation. In one regard the ULV hypothesis superseded the critical mass hypothesis by linking the defibrillation and shock-induced fibrillation processes. Therefore, this review also will discuss the rationale for developing a new defibrillation hypothesis. This new hypothesis, progressive depolarization, uses traditional defibrillation concepts to cover the same ground as the ULV hypothesis in mechanistically unifying defibrillation and shock-induced fibrillation. It does so in a manner consistent with experimental data supporting the ULV hypothesis but which also takes advantage of what has been learned from optical studies of defibrillation. This review will briefly describe how this new hypothesis relates to other contemporary viewpoints and related experimental results.

Characterization of the excitable gap in human type I atrial flutter.

OBJECTIVES: We sought to characterize the excitable gap of the reentrant circuit in atrial flutter. BACKGROUND: The electrophysiologic substrate of typical atrial flutter has not been well characterized. Specifically, it is not known whether the properties of the tricuspid valve isthmus differ from those of the remainder of the circuit. METHODS: Resetting was performed from two sites within the circuit: proximal (site A) and distal (site B) to the isthmus in 14 patients with type I atrial flutter. Resetting response patterns and the location where interval-dependent conduction slowing occurred were assessed. RESULTS: Some duration of a flat resetting response (mean +/- SD 40.1 +/- 20.9 ms, 16 +/- 8% of the cycle length) was observed in 13 of 14 patients; 1 patient had a purely increasing response. During the increasing portion of the resetting curve, interval-dependent conduction delay most commonly occurred in the isthmus. In most cases, the resetting response was similar at both sites. In three patients, the resetting response differed significantly between the two sites; this finding suggests that paced beats may transiently change conduction within the circuit or the circuit path, or both. CONCLUSIONS: Some duration of a flat resetting response was observed in most cases of type I atrial flutter, signifying a fully excitable gap in all portions of the circuit. The isthmus represents the portion of the circuit most vulnerable to interval-dependent conduction delay at short coupling intervals.

Priming to mycobacterial antigen in vivo using antigen-pulsed antigen presenting cells generated in vitro is influenced by the dose and presence of IL-4 in APC cultures.

Antigen presenting cells (APC) similar to immature dendritic cells can be generated in vitro from bone marrow precursors. The authors have compared the yield, the phenotype and the function of murine bone marrow cells cultured for 7 or 11 days in either granulocyte macrophage colony stimulating factor alone (GM BMAPC) or in combination with interleukin-4 (GM/IL-4 BMAPC). The results showed that GM/IL-4 BMAPC expressed the highest levels of MHC Class 2 molecules, CD86/B7-2 and CD80/B7-1 co-stimulatory molecules and the lowest levels of F4/80 macrophage marker. However, when these APC were pulsed with BCG culture filtrate antigen or PPD they were not correspondingly more effective at stimulating activated T lymphocytes in vitro or priming naive T lymphocytes in vivo. Also, in contrast to GM BMAPC, high backgrounds recorded following injections of GM/IL-4 BMAPC without antigen were not consistently reduced by lowering the dose and irradiating the cells prior to administration. The authors conclude that the degree of maturity of BMAPC varies with culture conditions and that this may be an important consideration where BMAPC are to be used in vivo in immunotherapeutic regimens.

Prospective analysis of genital ulcer disease in Brooklyn, New York.

We prospectively studied 82 men and women with first episodes of genital ulceration. By using newer diagnostic techniques, a definite microbial etiology of 84 infections in 65 of the 82 patients evaluated was found. There were 33 cases of definite primary syphilis, 27 of definite chancroid, and 24 of definite genital herpes simplex. Conclusive evidence of more than one microbial etiology was found for 19 (23%) of the patients. Simultaneous primary syphilis and chancroid was the third most common ulcer infection. This finding underscores the need for both clinical suspicion of multiple infections in patients with genital ulcers and comprehensive testing for all suspicious etiologies.

Lower frequency (5 MHZ) intracardiac echocardiography in a large swine model: imaging views and research applications.

Our previous investigation indicated that, in the 50-114-kg weight range, the swine model provides transeosophageal echocardiographic normal values for cardiac structures comparable to those found in human adults. Intracardiac echocardiographic imaging using a 12.5-MHz ultrasound catheter is limited, due to ultrasonic attenuation. Transesophageal echocardiographic imaging of the right heart is also limited with its anterior anatomic location. To further study the utility of intracardiac imaging, we placed a 5-MHz (30 Fr) multiplane transducer at the junction of the superior vena cava and right atrium, in the right atrium and right ventricle in 8 closed-chest swine (weight 129 +/- 61 kg). In each animal, complete whole heart imaging was obtained, with tomographic views including the cardiac 4-chamber, right atrium, right ventricle and outflow, left atrium and ventricle, and basal great vessels. Major intracardiac anatomic landmarks (i.e., crista terminalis, right atrial appendage, coronary sinus orifice, interatrial septum, tricuspid valve, right ventricular outflow, pulmonary veins, mitral valve and left ventricular papillary muscles) were visualized in every swine. Thus, this 5-MHz multiplane transducer, as a prototype for a steerable low-frequency intracardiac ultrasound catheter, improved both whole heart and individual cardiac structure imaging from a single intracardiac location. Further technological development and refinement is needed for routine use in research and clinical imaging practice.

Low-energy impedance-compensating biphasic waveforms terminate ventricular fibrillation at high rates in victims of out-of-hospital cardiac arrest. LIFE Investigators.

INTRODUCTION: New automatic external defibrillators (AEDs), which are smaller, lighter, easier to use, and less costly make the goal of widespread AED deployment and early defibrillation for out-of-hospital cardiac arrest feasible. The objective of this study was to observe the performance of a low-energy impedance-compensating biphasic waveform in the out-of-hospital setting on 100 consecutive victims of sudden cardiac arrest. METHODS AND RESULTS: AEDs incorporating a 150-J impedance-compensating biphasic waveform were used by 12 EMS systems. Data were obtained from the AED PC card reporting system. Defibrillation was defined as conversion to an organized rhythm or to asystole. Endpoints included: defibrillation efficacy for ventricular fibrillation (VF); restoration of an organized rhythm at the time of patient transfer to an advanced life support (ALS) team or to the emergency department (ED); and time from AED power-on to first defibrillation. The AED correctly identified 44 of 100 patients presenting in VF as requiring a shock (100% sensitivity) and 56 of 100 patients not in VF as not requiring a shock (100% specificity). The time from 911 call to first shock delivery averaged 8.1 +/- 3.0 minutes. A single 150-J biphasic shock defibrillated the initial VF episode in 39 of 44 (89%) patients. The average time from power-on to first defibrillation was 25 +/- 17 seconds. At patient transfer to ALS or ED care, an organized rhythm was present in 34 of 44 (77%) patients presenting with VF. Asystole was present in 7 (16%) and VF in 3 (7%). CONCLUSIONS: Low-energy impedance-compensating biphasic waveforms terminate long-duration VF at high rates in out-of-hospital cardiac arrest. Use of this waveform allows AED device characteristics consistent with widespread AED deployment and early defibrillation.

Shock-induced depolarization of refractory myocardium prevents wave-front propagation in defibrillation.

The elimination of most, if not all, propagating wave fronts of electrical activation by a shock constitutes a minimum prerequisite for successful defibrillation. However, the factors responsible for the prevention of postshock propagating activity are unknown. We investigated the determinants of this effect of defibrillation shocks in 23 Langendorff-perfused rabbit hearts by optically mapping cardiac cellular electrical activity by means of laser scanning. The optical action potentials obtained by this method were continuously recorded from 100 ventricular epicardial sites before, during, and after shock delivery during fibrillation. Analysis of activation maps showed that postshock propagating activity arose from areas depolarized by the shock. In 273 shock episodes, 898 sites at the border of shock-depolarized areas (BSDAs) from which wave-front propagation could have arisen were identified. The incidence of postshock propagation from BSDA sites was inversely related to refractoriness, as indexed by coupling interval (CI) or the optical takeoff potential (Vm). Specifically, there was a near-zero probability of postshock propagation if the shock caused depolarization at CIs < 50% of the fibrillation cycle length or from myocardium still depolarized to > or = 60% of the amplitude of a paced action potential (APA). Furthermore, incidences of wave-front propagation following shocks were consistently lower than the propagation incidences of naturally occurring unshocked fibrillation wave fronts, at comparable CIs and Vms. We conclude that the incidence of postshock wave-front propagation decreases with increasing refractoriness at the BSDA and that shock-induced depolarization of effectively refractory myocardium (ie, depolarized to > or = 60% APA) is required to guarantee the cessation of continued wave-front propagation in defibrillation.

Conduction block in the inferior vena caval-tricuspid valve isthmus: association with outcome of radiofrequency ablation of type I atrial flutter.

OBJECTIVES: We sought to 1) correlate conduction block in the isthmus of the right atrium between the inferior vena cava and the tricuspid annulus with the efficacy of catheter ablation of type I atrial flutter, and 2) characterize the effects of ablative lesions on the properties of isthmus conduction. BACKGROUND: There are few data on the mechanism of persistent suppression of recurrence of atrial flutter by catheter ablation. METHODS: Thirty-five patients with type I atrial flutter underwent catheter mapping and ablation. Radiofrequency lesions were applied in the isthmus. Transisthmus conduction before and after the lesions was assessed during atrial pacing in sinus rhythm from the medial and lateral margins of the isthmus at cycle lengths of 600, 400 and 300 ms and the native flutter cycle length. Isthmus conduction block was defined using multipolar recording techniques. There were three treatment groups: group 1 = radiofrequency energy applied during flutter, until termination (n = 14); group 2 = radiofrequency energy applied during atrial pacing in sinus rhythm from the proximal coronary sinus at a cycle length of 600 ms, until isthmus conduction block was observed (n = 14); and group 3 = radiofrequency energy applied until an initial flutter termination, after which further energy was applied during atrial pacing in sinus rhythm until isthmus conduction block was observed (n = 7). RESULTS: In group 1, after the initial flutter termination, isthmus conduction block was observed in 9 of the 14 patients. In each of these nine patients, flutter could not be reinitiated. In each of the remaining five patients, after the initial flutter termination, isthmus conduction was intact and atrial flutter could be reinitiated. Ultimately, successful ablation in each of these patients was also associated with isthmus conduction block. In groups 2 and 3, isthmus conduction block was achieved during radiofrequency energy application, and flutter could not subsequently be reinitiated. Before achieving conduction block, marked conduction slowing or intermittent block, or both, was observed in some patients. In some patients, isthmus conduction block was pacing rate dependent. In addition, recovery from conduction block was common in the laboratory and had a variable time course. At a mean follow-up interval of 10 months (range 1 to 21), the actuarial incidence of freedom from type I flutter was 80% (recurrence in three patients at 7 to 15 months). CONCLUSIONS: Isthmus conduction block is associated with flutter ablation success. Conduction slowing or intermittent block, or both, in the isthmus can occur before achieving persistent block. Recovery of conduction after achieving block is common. Follow-up has revealed a low rate of flutter recurrence after achieving isthmus conduction block, whether the block was achieved in conjunction with termination of flutter.

Effects of high and low shock energies on sinus electrograms recorded via integrated and true bipolar nonthoracotomy lead systems.

INTRODUCTION: The purpose of this investigation was to prospectively evaluate the voltage- and time-dependent characteristics of a biphasic defibrillator discharge on the amplitude of the rate sensing electrogram recorded from two "integrated" and one true bipolar nonthoracotomy lead system. Prolongation of redetection time has been noted after a failed first shock with nonthoracotomy lead systems. However, a prospective evaluation of the time- and voltage-dependent effects of biphasic shocks on electrogram amplitude with clinically utilized lead systems has not been systematically performed. METHODS AND RESULTS: Five- then 30-J R wave synchronous biphasic discharges were delivered during the supraventricular rhythm through three nonthoracotomy lead systems (Medtronic Transvene, Ventritex TVL, and CPI Endotak C 60 Series). The R wave amplitude was measured immediately postshock and for up to 1 minute. Amplitude changes were compared with preshock baseline value. A 5-J discharge had minimal effect on the R wave amplitude recorded from the three lead systems; however, 30 J resulted in significant diminution in R wave amplitude recorded from the integrated bipolar leads (in the Endotak lead to a greater extent than the TVL lead) with minimal effects on the Transvene lead. Following a 30-J discharge, the time constant for R wave recovery was 4.2, 14.9, and 15.3 seconds for Transvene, TVL, and Endotak 60 leads, respectively. CONCLUSION: There are voltage- and time-dependent reductions in postshock R wave amplitude. Integrated bipolar systems appear more affected than the "true" bipolar lead evaluated. This may be due, in part, to lead design, distance of distal defibrillating surface from rate sensing cathode, and the incorporation of the defibrillating surface as the rate sensing anode. The influence of post-shock R wave diminution on subsequent redetection remains speculative but may have implications for subsequent lead development.