Feasibility of atrial fibrillation detection and use of a preceding synchronization interval as a criterion for shock delivery in humans with atrial fibrillation.

OBJECTIVES: This study assessed the feasibility of detecting atrial fibrillation (AF) and delivery of appropriately timed R wave shocks using an implantable atrial defibrillator. BACKGROUND: For atrial defibrillation therapy to be feasible in an implantable form, AF must be detected in a specific fashion, and the risk of ventricular proarrhythmia should be minimized. METHODS: Eleven patients with AF underwent testing with an implantable atrial defibrillator (METRIX 3000 Automatic Atrial Defibrillator, InControl, Inc.). Wideband electrograms (EGMs) were recorded from the right ventricular (RV) bipolar catheter and from the multipolar catheters located in the right atrium (RA) and coronary sinus (CS). Atrial fibrillation detection was performed using two serial algorithms-quiet interval analysis and baseline crossing analysis-that detect atrial activity on the RA-CS channel. Ventricular sensing using a minimal preceding synchronization interval of 500 ms as a criterion for synchronous shock delivery was performed from filtered RV and RV-CS EGMs. RESULTS: The AF detection algorithms were applied to 53 AF data segments and 18 normal sinus rhythm data segments. Atrial fibrillation was detected appropriately in 49 instances, and the specificity for detecting AF and normal sinus rhythm was 100%. Synchronization criterion efficacy was assessed by delivering shock markers and shocks. Of the 2,025 R waves processed, 557 (27.5%) were marked as suitable for shock delivery. In addition, 69 therapeutic and 11 test shocks were delivered during AF. All shock markers and shocks were delivered synchronously with the R wave, and the synchronization criterion was never violated. CONCLUSIONS: Atrial fibrillation can be detected in a specific fashion using the RA-CS lead configuration and serial detection algorithms for atrial sensing. The delivery of properly timed shocks is feasible and should minimize the risk of ventricular proarrhythmia.

Efficacy of the implantable cardioverter-defibrillator in the elderly.

OBJECTIVES: We sought to assess the effect of advanced age on the outcome of patients with an implantable cardioverter-defibrillator (ICD). BACKGROUND: ICDs are effective in preventing sudden cardiac death in susceptible patients, but their beneficial effect on survival is attenuated by the high rate of nonsudden cardiac death in those treated. Although advanced age is an important variable in determining cardiovascular mortality, its impact on the outcome of patients with an ICD has been inadequately studied. METHODS: We performed multivariate analysis of a data base consisting of 769 consecutive patients with an ICD. Seventy-four patients > or = 75 years old at ICD implantation (Group 1) were compared with the remaining 695 patients (Group 2). RESULTS: The two groups were similar in clinical presentation, left ventricular function and gender distribution. The mean follow-up time was 29 and 42 months, respectively, for patients in Group 1 and Group 2. Actuarial survival at 4 years was 57% in Group 1 versus 78% in Group 2 (p = 0.0001). This difference was primarily due to a higher rate of nonsudden cardiac death in Group 1. On multivariate analysis, age > or = 75 years, New York Heart Association functional class III, left ventricular ejection fraction < 30% and appropriate shocks during follow-up were independently associated with increased mortality (odds ratio 3.56, 1.8, 1.6 and 1.39, respectively). CONCLUSIONS: Among patients with similar functional class and ejection fraction, the mortality risk is increased threefold in those > or = 75 years old at the time of ICD implantation. Extrapolation of results from younger patients is likely to overestimate ICD benefit in the elderly.

Imaging vascular endothelial activation: an approach using radiolabeled monoclonal antibodies against the endothelial cell adhesion molecule E-selectin.

UNLABELLED: E-selectin is an endothelial cell-specific adhesion molecule for leukocytes expressed on the luminal surface of vascular endothelium during inflammatory responses. Because E-selectin expression is dependent upon ongoing stimulation by cytokines, this molecule offers a potentially useful target for imaging tissues in disease states involving cytokine-mediated endothelial cell activation. METHOD: To assess the imaging potential of an anti-E-selectin monoclonal antibody (Mab) 1.2B6, the accumulation of intravenously injected 111In-labeled Mab 1.2B6 was compared to that of 111In-control antibody in a model of arthritis in the pig. Injection of phytohaemagglutinin (PHA) into a knee led to E-selectin expression on vessels in the synovium and draining deep inguinal lymph nodes, as demonstrated by immunohistology. No E-selectin expression was seen in the control knee injected with buffer alone. Animals were given 111In-Mab 1.2B6 or 111In-control antibody intravenously 3 hr after the intra-articular injection of PHA. Radiolabeled antibody uptake was measured by direct counting of tissues 25 hr postmortem. RESULTS: The accumulation of radiolabeled control IgG in synovium and draining deep inguinal lymph nodes of PHA-injected knees was significantly higher than accumulation in tissues injected with buffer alone; however, the comparable ratios in animals receiving radiolabeled Mab 1.2B6 were significantly greater. Scintigraphy performed 24 hr after 111In-Mab 1.2B6 injection showed obvious localization of activity in the inflamed knee in each of three animals. CONCLUSION: Radiolabeled anti-E-selectin Mab can be used to image localized inflammatory tissues. This approach may be useful for investigating activated endothelium in human disease.

Comparison of immediate and long-term outcome of coronary angioplasty performed for unstable angina and rest pain in men and women.

OBJECTIVE: To determine whether a sex-related difference in outcome is present among patients who undergo percutaneous transluminal coronary angioplasty (PTCA) for unstable angina. DESIGN: We retrospectively analyzed the results after PTCA was performed between January 1981 and June 1993 in a series of 2,073 men and 941 women with unstable angina and rest pain. RESULTS: The success rates of PTCA were similar for women and men (87.9% and 87.2%, respectively), as were the in-hospital mortality rates (4.1% and 3.2%, respectively) and the need for emergency coronary artery bypass operation (3.1% and 3.5%, respectively). Fewer women than men had Q-wave myocardial infarction (0.5% versus 1.6%; P = 0.02). During the follow-up period (mean, 4 years), no significant differences were noted between women and men in overall survival (81% and 85% at 6 years, respectively) or survival free of Q-wave myocardial infarction (81% and 83% at 6 years, respectively) with use of the Kaplan-Meier method. Women were less likely than men to have had coronary artery bypass grafting (19% versus 22% at 6 years; P = 0.02), and the occurrence of severe angina was higher in women than in men (52% versus 44% at 6 years; P = 0.001). A subgroup analysis of patients who had myocardial infarction within 7 days preceding PTCA showed a similar pattern of results. CONCLUSION: After PTCA performed for unstable angina and rest pain, survival rates were excellent in both women and men, and no difference was observed in subsequent myocardial infarction rates. During follow-up, however, women were more likely to have severe angina and were less likely to have had coronary artery bypass grafting. Concerns about possible sex-related complications should not dissuade physicians from performing PTCA when clinically indicated for unstable angina and rest pain.

Indices of obesity and body fat distribution in arteriographically defined coronary artery disease in men.

Anthropometric measurements descriptive of obesity, body fat distribution and body build were made in 186 males undergoing diagnostic coronary arteriography. Using stepwise multiple logistic regression analysis, two indices of body fat distribution were independently associated with coronary disease, while the widely used indices of obesity, namely body mass index and percentage body fat, were not. A significant association with disease was found for the ratio of waist to thigh circumferences (waist/thigh ratio), which emerged in the first step of the multivariate model (p < 0.005). The ratio of waist to hip circumferences (waist/hip ratio), a widely used index of body fat distribution, was found to have a negative association with disease (p < 0.05). This study suggests that use of body fat distribution indices may assist in the assessment of the risk factor profile of cardiac patients.

Use of a radiolabeled monoclonal antibody against E-selectin for imaging of endothelial activation in rheumatoid arthritis.

OBJECTIVE: To determine the potential of 111In-labeled anti-E-selectin monoclonal antibody (MAb) to image localized endothelial activation in rheumatoid arthritis (RA). METHODS: Fourteen patients with RA were studied after intravenous administration of 111In-labeled F(ab')2 fragments of MAb against the cytokine-inducible endothelial cell activation antigen E-selectin (MAb 1.2B6). To compare uptake of 1.2B6 with that of nonspecific immunoglobulin, 111In-labeled polyclonal human immunoglobulin (HIG) was separately administered to 6 of these patients and the relative uptake of each tracer was determined. RESULTS: Prominent and discrete uptake of the radiolabeled MAb 1.2B6 was clearly visible in inflamed joints of all patients. Compared with 111In-HIG, 111In-1.2B6 provided superior images in terms of sensitivity and image intensity. Furthermore, the distribution of uptake in inflamed joints was different for the 2 tracers, with 1.2B6 showing a more focal localization in synovium. CONCLUSION: This study demonstrates that it is possible to objectively assess E-selectin expression on activated endothelium in vivo in patients with RA, using a radiolabeled MAb. This technique has considerable potential for monitoring disease activity and response to therapy in inflammatory diseases.

Characterization of E-selectin expression in vivo with use of a radiolabeled monoclonal antibody.

We have studied endothelial luminal surface expression of E-selectin in vivo in the pig. Intravenous interleukin-1 (IL-1, 5-micrograms/kg bolus +/- 50-ng.kg-1 x min-1 infusion for 2 h) induced E-selectin expression in many organs, as shown by immunostaining and selective clearance of intravenous 111In- or 99mTc-labeled anti-E-selectin monoclonal antibody (MAb 1.2B6) compared with radiolabeled immunoglobulin G1 control. Specific clearance of MAb 1.2B6 commenced 30-45 min after intravenous IL-1. Skin sites injected with IL-1, tumor necrosis factor, phytohemagglutinin, or phorbol myristate acetate at various times (45 min-24 h) before exsanguination showed specific accumulation of MAb 1.2B6 when 99mTc-MAb 1.2B6 and 111In-control immunoglobulin G1 were injected intravenously 10 min before exsanguination. This was maximal in 2-h IL-1 and tumor necrosis factor lesions and after 9 h in phytohemagglutinin and phorbol myristate acetate lesions. This novel approach has allowed us to quantify changes in vascular luminal expression of E-selectin in models of inflammation involving systemic and localized endothelial cell activation and has considerable potential for analyzing these changes in relation to leukocyte traffic and other manifestations of inflammatory responses in vivo.

Management of balloon rupture during rigid stent deployment.

Balloon rupture may occur during stent placement and will only become apparent when the stent has been maneuvered across the target stenosis and deployment is attempted. Withdrawal may be complicated by displacement of the stent off the balloon. We describe two cases in which a power injector was used to momentarily inflate the balloon and partially expand the stent in place. The punctured balloon could then be withdrawn and the stent fully deployed, using a new balloon.

A novel approach to the placement of Palmaz-Schatz biliary stents in saphenous vein grafts.

The placement of Palmaz-Schatz biliary stents has become a successful method to treat stenoses in large saphenous vein grafts. Unlike coronary stents, the biliary stents are not routinely delivered with a selective delivery sheath and may be more difficult to deliver and prone to detachment from the balloon and even embolization during delivery. In order to enhance the ability to deliver these stents, a guide-within-a-guide system was developed. A 7F guiding catheter was used as a selective delivery sheath within a standard guiding catheter. Nineteen biliary stents were successfully placed in vein grafts in 15 patients using this system. One procedure was complicated by an embolic event documented angiographically following intragraft delivery of urokinase but prior to stent implantation.

In vivo E-selectin upregulation correlates early with infiltration of PMN, later with PBL entry: MAbs block both.

The endothelial molecule E-selectin binds most leukocyte subsets in vitro. Yet its role in regulating the very different kinetics of inflammatory infiltration of different leukocyte subsets in vivo is unclear. The kinetics of E-selectin upregulation and polymorphonuclear leukocyte (PMN) and blood lymphocyte (PBL) localization in inflammation induced by interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), phytohemagglutinin (PHA), and phorbol myristate acetate (PMA) were investigated in a well-established inbred pig trafficking model. They differed markedly both for these three labeled indicators of inflammation and in each of the four inflammatory processes. In each, E-selectin upregulation correlated with early PMN entry and later with PBL infiltration but was more protracted than both. The importance of E-selectin was confirmed by marked inhibition of PMN and PBL entry (up to > 60%) by F(ab')2 anti-E-selectin. Involvement of other molecules was illustrated by similar or greater inhibition with anti-CD18 F(ab')2. We conclude that, like CD18, E-selectin is necessary for most PMN and PBL infiltration but alone is insufficient, consistent with the involvement of several alternative multistep molecular mechanisms in this entry.

Coronary hemodynamics before and after rotational atherectomy with adjunctive balloon angioplasty.

The phenomenon of "no-reflow" has been described frequently after rotational atherectomy. The aim of this study was to determine the coronary hemodynamic changes by Doppler flow wire before and after rotational atherectomy and adjunctive balloon angioplasty in 10 patients. All patients had TIMI-III flow at baseline. After rotational atherectomy alone, two patients had TIMI-I, four patients had TIMI-II, and four patients had TIMI-III flow. In addition, the number of Cineframes to Opacification of a preselected distal landmark increased twofold (from 49 +/- 12 to 118 +/- 27 frames; P < 0.05). Intracoronary nitroglycerin and verapamil was associated with return to baseline of both measurements. Following adjunctive balloon angioplasty, there was an increase in lumen diameter (1.29 +/- 0.1 vs. 2.6 +/- 0.1 mm; P < 0.05), coronary flow (81 +/- 14 to 154 +/- 18 ml/min; P < 0.05), maximal absolute velocity (23 +/- 4 to 52 +/- 4 cm/sec; P < 0.05), and vascular resistance decreased (1.74 +/- 0.4 to 0.74 +/- 0.4 mm Hg/ml/min; P < 0.05). However, no change in coronary flow reserve was noted (1.24 +/- 0.1 vs. 1.5 +/- 0.3). Immediately after rotational atherectomy alone, there is a reduction in angiographically determined coronary flow, suggesting either distal microvascular spasm or distal microvascular obstruction. Regardless of the mechanism, the transient reduction of coronary flow was rapidly reversed by coronary vasodilators. Despite the significant improvement of coronary hemodynamics noted immediately after combined rotational atherectomy and balloon angioplasty, coronary flow reserve remained abnormal. Similarly, no change in coronary flow reserve has been reported immediately after balloon angioplasty alone. The lack of improvement in flow reserve after both balloon angioplasty and rotational atherectomy suggests that the mechanisms of improved flow reserve may be device independent, and remain unexplained.

Safety of atrial defibrillation shocks synchronized to narrow and wide QRS complexes during atrial pacing protocols simulating atrial fibrillation in dogs.

BACKGROUND: The potential ventricular proarrhythmic effect of atrial defibrillation shocks (ADS) remains a concern with automatic internal atrial defibrillation. Optimal R-wave synchronization alone may not be sufficient to prevent the induction of ventricular fibrillation (VF). METHODS AND RESULTS: The proarrhythmic effect of ADS synchronized to normally conducted QRS complexes (NQRS) and to supraventricular complexes with left or right bundle-branch block (L/RBBB) was investigated in a canine atrial pacing study. Short-long-short, single premature, and burst pacing protocols from the high right atrium were performed at baseline, during isoproterenol infusion, and after intravenous procainamide. The ADS were delivered between decapolar catheters in the coronary sinus and lateral right atrium. They were initially delivered 20 milliseconds (ms) after the end of the last conducted QRS complex and then scanned decrementally through that complex until VF was induced. For NQRS complexes, VF occurred only when the ADS were delivered at or before the onset of the QRS complex and never during the complex itself. In the presence of LBBB or RBBB, VF was induced by ADS delivered at the onset of or within the first 45 ms of the QRS complex in 16 animals. The longest RR (VV) intervals preceding ADS-induced VF were 345 ms at baseline and 380 ms after procainamide. CONCLUSIONS: In this study, ADS synchronized to NQRS complexes appeared to be safe regardless of the preceding RR interval. In the presence of LBBB or RBBB, RR intervals preceding the ADS of >345 ms at baseline and >380 ms in the presence of procainamide would have been required to avoid VF. Alternatively, ADS delivered 50 ms after the onset of the RV electrogram appeared to be safe in all circumstances regardless of the preceding RR interval.

Impact of stent size and indication for stent placement on immediate outcome.

The immediate outcome of 271 procedures involving the intracoronary implantation of 305 stents was determined. Data were analyzed with regard to indication for stenting and stent size. Elective indication was associated with a higher success rate than emergency indication (95.6% vs. 86.6%, P = 0.013) and a lower Q-wave infarction rate (0 vs. 6.4%, P = 0.006). Univariate analysis showed that the odds ratio for procedural success was significantly favored by elective indication (3.37, P = 0.018) but was unrelated to stent size (1.10, P = 0.087). These findings were confirmed on multivariate analysis. The likelihood of Q-wave infarction was lower for elective placement (P = 0.0008) but was not related to size. Requirement for emergency bypass surgery, incidence of subacute closure, and death were not related to indication or to stent size on either univariate or multivariate analysis. Therefore, the immediate outcome of stent placement is related to the indication for stenting, but not to the size of stent implanted. Procedural success is significantly favored by elective indication.

Clearance pathways of soluble immune complexes in the pig. Insights into the adaptive nature of antigen clearance in humans.

Efficient delivery of immune complexes (ICs) to the mononuclear phagocytic system, and subsequent IC processing, may prevent their potentially harmful effects in other tissues and may also be important in the development of humoral immune responses. In mice, rabbits, and primates, the liver and spleen are the main sites of IC clearance. It has been demonstrated previously that the pulmonary capillaries in the pig are lined with macrophages and that certain particulates, including bacteria, localize to this organ. In this study, we used gamma scintigraphy to explore the sites and kinetics of clearance of soluble IC comprising 123I-labeled hepatitis B surface Ag (HBsAg):porcine anti-HBsAg in the Large White pig. At t = 10 min after i.v. injection, 43 +/- 5% (mean +/- SE) IC localized in the lungs, and 36 +/- 6% counts in the liver. At t = 85 min, values were: lungs, 15 +/- 4% and liver, 29 +/- 2%. Findings were similar following intraarterial injection. Complement depletion resulted in more rapid initial IC clearance (t1/2 = 5 min), reduced lung uptake (23 +/- 3% at 10 min), and impaired IC catabolism. In normal animals, 5 to 7% injected IC bound to PBMCs, but no E binding was seen. A fall in PBMC numbers (46 to 59% of baseline), was observed following IC injection. These findings contrast with our previous observations using analogous IC in humans, in which we did not observe any change in peripheral blood leukocyte counts consequent upon complex processing, suggesting that in humans, Es may function as a buffering system for complement-bearing IC in the circulation, preventing their interaction with leukocytes bearing complement and FcR, and the potential activation of these cells.

The effect of polarity of the initial phase of a biphasic shock waveform on the defibrillation threshold of pectorally implanted defibrillators.

The effect of initial phase polarity on the DFT of two pectorally implanted biphasic ICDs was tested in a randomized, prospective manner at the time of implantation. Twenty-two consecutive patients with VT-VF who received either the Medtronic PCD 7219C Jewel device (10 patients) or PCD 7219D Jewel device (12 patients) were studied. DFT testing was performed in a standard step-down manner. Both initial phase polarities--initial defibrillation current flowing from active can/SVC coil +/- subcutaneous patch) to the RV coil (RV coil to active can/SVC (RV+)--were tested in random order. The mean DFT achieved with RV+ compared with RV-was lower for the 7219C patient group (6.6 +/- 3.1 vs 10.8 +/- 5.5 J; P = 0.007). A similar trend was observed for the 7219D group, though the difference did not reach statistical significance (12.0 +/ 4.0 vs 16.3 +/- 7.3 J; P = 0.07). Seven of the 10 patients in the 7219C group had a lower DFT with RV+, while the initial phase polarity made no difference in 3. In the 7219D group, 7 patients had a lower DFT using RV+, 2 patients had a lower DFT using RV-, and the initial phase polarity made no difference in 3. In conclusion, this study demonstrates that changing the polarity of the initial phase of a biphasic shock waveform can have a significant impact on the DFT achieved at the time of ICD implantation.