Search

Background —Blockade of the platelet glycoprotein IIb/IIIa receptor with the monoclonal antibody fragment abciximab was shown in a placebo-controlled randomized trial to reduce the incidence of acute ischemic complications within 30 days among a broad spectrum of patients undergoing percutaneous coronary revascularization. The durability of clinical benefit in this setting has not been established. Methods and Results —A total of 2792 patients enrolled in the Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade (EPILOG) trial were followed with maintenance of double-blinding for 1 year. Patients had been assigned at the time of their index coronary interventional procedure to receive placebo with standard-dose, weight-adjusted heparin (100 U/kg initial bolus), abciximab with standard-dose, weight-adjusted heparin, or abciximab with low-dose, weight-adjusted heparin (70 U/kg initial bolus). The primary outcome was the composite of death, myocardial infarction, or urgent repeat revascularization by 30 days; this composite end point and its individual components were also assessed at 6 months and 1 year. Rates of any repeat revascularization (urgent or elective), target vessel revascularization, and a composite of death, myocardial infarction, or any repeat revascularization were also reported. Follow-up at 1 year was 99% complete for survival status and 97% complete for other end points. By 1 year, the incidence of the primary composite end point was 16.1% in the placebo group, 9.6% in the abciximab with low-dose heparin group ( P P Conclusions —Acute reductions in ischemic events after percutaneous coronary intervention by abciximab are sustained over follow-up to at least 1 year. Early periprocedural myocardial infarctions suppressed by this therapy are associated with long-term mortality rates.

Background —The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab is approved for use in high-risk percutaneous coronary interventions. The purpose of the present study was to establish the pharmacodynamic profile and platelet-bound life span of abciximab. Methods and Results —The pharmacodynamics of abciximab (inhibition of ex vivo platelet aggregation and GP IIb/IIIa receptor blockade) were measured in 41 individuals who were randomized to receive a 0.25-mg/kg bolus and a 12-hour infusion of either 10 μg/min (EPIC regimen) or 0.125 μg · kg −1 · min −1 (EPILOG regimen) of the antiplatelet agent. At extended times, the amount and distribution of platelet-bound abciximab were monitored by flow cytometry. The EPIC and EPILOG infusion regimens exhibited equivalent blockade of both GP IIb/IIIa receptors and platelet aggregation throughout the duration of abciximab treatment. Flow cytometry revealed a single, highly fluorescent platelet population during treatment, consistent with complete saturation and homogeneous distribution of abciximab on circulating platelets. For 15 days after treatment, the fluorescence histograms remained unimodal with gradually diminishing fluorescence intensity, indicating decreasing levels of platelet-bound abciximab. At 8 and 15 days, which exceeds the normal circulating life span of platelets, median relative fluorescence intensity corresponded to 29 100 (29% GP IIb/IIIa receptor blockade) and 13 300 (13% GP IIb/IIIa receptor blockade) abciximab molecules bound per platelet, respectively. Conclusions —These results are consistent with continuous reequilibration of abciximab among circulating platelets and may explain the gradual recovery of platelet function and long-term prevention of ischemic complications by abciximab after coronary intervention.

Background The glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (c7E3 Fab, ReoPro) is approved for use in high-risk percutaneous transluminal coronary angioplasty (PTCA). At present, no “point of care” exists for measuring pharmacological GP IIb/IIIa blockade. To address this need, the Chrono-log Whole Blood Aggregometer, which measures platelet aggregation by electrical impedance, was adapted to test platelet function at the bedside. Methods and Results GP IIb/IIIa receptor blockade, impedance (5 μg/mL collagen), and turbidimetric aggregation (5 and 20 μmol/L ADP) measurements were obtained on 14 PTCA patients who received the standard bolus plus a 12-hour infusion of abciximab. During abciximab administration, mean GP IIb/IIIa receptor blockade was >91%, and both impedance and turbidimetric aggregation were inhibited by ≥90%. At 12 hours after abciximab treatment, the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 65±20% and 49±14%, respectively, and inhibition of impedance aggregation was 69±12%. GP IIb/IIIa receptor blockade was 67±8%. At 36 hours after abciximab treatment (n=8), the mean inhibition of turbidimetric platelet aggregation to 5 and 20 μmol/L ADP was 44±21% and 30±14%, respectively, whereas impedance aggregation was inhibited by 60±14%. GP IIb/IIIa receptor blockade was 57±7%. Conclusions During and at 12 hours after abciximab therapy, impedance and turbidimetric platelet aggregation to 5 μmol/L ADP were comparable and closely correlated with GP IIb/IIIa receptor blockade. However, at 36 hours after abciximab treatment, impedance platelet aggregation more closely paralleled GP IIb/IIIa receptor blockade and indicated a slower recovery of platelet function than turbidimetric aggregometry.

Background The potential for novel antiplatelet and antithrombin agents to contribute to periprocedural bleeding complications of percutaneous coronary revascularization is poorly defined. In the Evaluation of c7E3 Fab in Preventing Ischemic Complications of High-Risk Angioplasty (EPIC) trial, the periprocedural use of aspirin, heparin, and a chimeric antibody to the platelet glycoprotein IIb/IIIa integrin c7E3 Fab in 2099 patients significantly reduced postprocedural ischemic complications and 6-month clinical restenosis but was associated with increased procedural bleeding complications. We review these complications and describe clinical and procedural variables associated with increased bleeding complications in the EPIC trial. Methods and Results Patients with high-risk clinical or lesion morphological characteristics were randomized to receive placebo bolus plus placebo infusion, c7E3 Fab bolus plus placebo infusion, or c7E3 Fab bolus plus c7E3 Fab infusion. Patients received periprocedural aspirin and intravenous heparin continued for a minimum of 12 hours after the procedure. Outcomes reflecting bleeding complications were measured: transfusions, decreased hemoglobin, and an index including both parameters. Major bleeding complications unrelated to bypass surgery occurred in 3.3%, 8.6%, and 10.6%, and blood product transfusions were used in 7.5%, 14.0%, and 16.8% of patients treated with placebo, bolus c7E3 Fab, and bolus plus infusion c7E3 Fab, respectively (both P P =.38 and P =.14, respectively). Conclusions Bleeding complications unrelated to bypass surgery were two to three times more frequent in patients receiving c7E3 Fab than in those receiving placebo, but most were transient and well tolerated. Risk-factor analysis and modification of concomitant antithrombotic and antiplatelet treatment strategies may aid in reducing bleeding complications and enhancing clinical benefit in patients receiving c7E3 Fab during percutaneous coronary revascularization.

BACKGROUND Thrombosis has been implicated as central to the clinical complications of coronary angioplasty (PTCA). Chimeric monoclonal 7E3 Fab (c7E3 Fab) is the first of a new class of antiplatelet drugs directed at the platelet glycoprotein IIb/IIIa integrin. This study was performed to determine the pharmacodynamics of c7E3 Fab administration during PTCA and to gain an initial clinical experience with this novel agent. METHODS AND RESULTS The study was a multicenter, open-label, dose-escalation study conducted in two stages. Enrollment included 56 patients scheduled for elective PTCA who were estimated to be at moderate to high risk of sustaining ischemic complications. All patients were given aspirin and heparin. The study drug was given at least 10 minutes before PTCA. In stage 1, increasing bolus doses of c7E3 Fab were given to 15 patients; a bolus dose of 0.25 mg/kg was found to result in blockade of > 80% of the receptors and reduce platelet aggregation to < 20% compared with baseline, establishing this dose as that necessary to sufficiently suppress platelet activity. In stage 2, additional c7E3 Fab was administered by continuous infusion to 32 patients for progressively longer periods of time (up to 24 hours) to confirm that platelet inhibition could be maintained with prolonged drug infusion. Also, 9 patients otherwise meeting entry criteria were given placebo. There were no thrombotic events among patients receiving c7E3 Fab. Overall procedural and clinical success and complication rates as well as rates of bleeding were statistically similar among groups. However, minor bleeding was more frequent with administration of the active drug. CONCLUSIONS The novel antiplatelet agent c7E3 Fab can be administered during PTCA in combination with aspirin and heparin. Suppression of platelet activity is dose dependent and can be maintained for up to 24 hours. Further evaluation will be required to determine the extent of improvement in ischemic complication and restenosis rates and to provide additional insight into the safety profile of this potent monoclonal platelet antibody.

We analyzed the results of exercise testing performed in the absence of all antiarrhythmic drugs in 11 case patients with newly documented polymorphic ventricular tachycardia in response to type Ia antiarrhythmic agents. These results were compared with those found in 11 control patients matched for age, sex, and heart disease to determine whether the response of the QT interval to exercise testing was abnormal in patients who developed worsening of arrhythmia while taking antiarrhythmic drugs. QT, RR, and QTc intervals (by Bazett's method) were evaluated at rest and at 3 minutes of exercise in both groups. At rest, there was no significant difference in the QT interval (410 +/- 13 vs. 386 +/- 11 msec), RR interval (890 +/- 56 vs. 781 +/- 43 msec), or corrected QT interval (438 +/- 10 vs. 438 +/- 4 msec) in the case patients and the control patients. Both groups demonstrated a similar chronotropic response to exercise. The QT interval shortened in both groups with exercise (p less than 0.001), but the degree of shortening tended to be greater in the control patients (to 310 +/- 9 msec) than in the case patients (to 357 +/- 11 msec) (p = 0.06). Thus, there was a paradoxical increase in the QTc interval in the patients who experienced a proarrhythmic effect of type Ia drugs but not in the control patients (to 482 +/- 8 vs. 431 +/- 5 msec; p less than 0.001). Ten of 11 case patients but only one of 11 control patients had an increase in QTc interval of more than 10 msec with exercise (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND Reperfusion of acutely infarcted myocardium may be beneficial in limiting infarct expansion and ventricular remodeling even if established after the time that salvage of ischemic myocardium is possible. METHODS AND RESULTS To examine the permanency, time course, and mechanism of this effect of late reperfusion, 200 rats were randomized into one of four groups: (1) infarction with reperfusion after 1 to 2 hours, (2) infarction with reperfusion after 6 to 8 hours, (3) infarction without reperfusion, and (4) sham operation. Surviving rats were killed at either 7 days, when infarct expansion has plateaued, or 21 days, when infarct healing is complete. In both 7- and 21-day analyses, late reperfusion did not reduce infarct size or degree of transmural necrosis but significantly limited infarct expansion, as measured by an index based on infarct endocardial segment lengthening and infarct wall thinning (expansion index at 7 days: no reperfusion, 2.73 +/- 0.25, n = 13; reperfusion after 1 to 2 hours, 1.56 +/- 0.13, n = 23, P < .001; reperfusion after 6 to 8 hours, 1.78 +/- 0.15, n = 16, P = .002; at 21 days: no reperfusion, 3.45 +/- 0.39, n = 13; reperfusion after 1 to 2 hours, 2.21 +/- 0.24, n = 15, P = .01; reperfusion after 6 to 8 hours, 2.02 +/- 0.20, n = 9, P = .01). Reperfusion after 6 to 8 hours was equally effective in limiting expansion as reperfusion after 1 to 2 hours. Late reperfusion also significantly reduced ventricular remodeling at 21 days, as measured by an index based on left ventricular cavity dilatation and noninfarcted myocardial hypertrophy (remodeling index at 21 days: no reperfusion, 2.67 +/- 0.15, n = 13; reperfusion after 1 to 2 hours, 2.20 +/- 0.15, n = 15, P = .035; reperfusion after 6 to 8 hours, 2.12 +/- 0.10, n = 9, P = .012). Histological examination revealed that reperfusion accelerated the clearance of residual dead myofibrils, suggesting an increase in the rate of healing, and increased the degree of myocytolysis but did not change the final degree of infarct healing, tissue density, or viable subepicardial cells. CONCLUSIONS Late reperfusion causes a permanent reduction in postinfarction expansion that is present even after complete infarct healing. The time after coronary occlusion in which reperfusion is of benefit in reducing subsequent expansion and remodeling is substantially longer than previously established. The mechanism by which late reperfusion limits expansion may involve changing the rate of healing and the nature of myocardial necrosis but does not involve preserving subepicardial cells.

BACKGROUND To evaluate the in vivo safety, biodistribution, and diagnostic accuracy of a monoclonal Fab' antibody (S12) that is specific for the platelet membrane glycoprotein (GMP-140) expressed during platelet activation at vascular injury sites, 11 peripheral percutaneous transluminal angioplasty (PTA) patients (age, 61 +/- 8 years) with severe vascular disease had serial 99mTcS12 radionuclide imaging at 5 and 90 minutes, 4-6 hours, and 20-24 hours after a total of 23 angiographically successful PTA procedures. No acute allergic reactions or hematologic toxicity occurred. METHODS AND RESULTS The average PTA percent angiographic diameter stenosis (DS) at all 23 sites decreased from 85 +/- 12% to 12 +/- 11%, with a mean before-to-after-PTA change of 73 +/- 14% (p less than 0.01). The mean radionuclide image-derived ratio of 99mTc S12 activity in PTA versus contralateral non-PTA arterial segments for all angioplasty sites was 1.6 +/- 0.5. Vascular 99mTc S12 antibody activity was qualitatively evident in the majority (78%) of PTA sites at 4-6 hours after injection. 99mTc S12 target-to-background (muscle) ratio equaled 2.3 +/- 0.6 at PTA sites. Nine PTA sites (39%) had residual 99mTc S12 activity at 24 hours after injection (mean PTA site-to-contralateral artery ratio, 1.5 +/- 0.4). The mean vascular 99mTc S12 activity ratios in 10 procedurally complicated (defined as extensive dilation [greater than 2 cm] or grade I or greater arterial dissection) and 13 uncomplicated PTA segments were 1.9 +/- 0.5 versus 1.2 +/- 0.1, respectively (p less than 0.01). The associated before-to-after-PTA angiographic improvement was significantly less in procedurally complicated PTA sites (66 +/- 12% versus 80 +/- 12% DS; p less than 0.01). CONCLUSIONS 99mTc S12 activity is significantly increased at angiographically patent PTA sites that are procedurally complicated and are associated with less significant before-to-after-PTA angiographic improvement. 99mTc S12 monoclonal Fab' antibody imaging permits noninvasive identification of local vascular platelet activation resulting from angioplasty balloon injury in humans.

Reperfusion of ischemic myocardium may accelerate necrosis of injured myocytes. To determine the role of neutrophil leukocytes in this process, we examined whether neutrophil depletion during reperfusion could modify infarct size in anesthetized dogs. The proximal circumflex coronary artery was occluded for 90 minutes and then reperfused for 2 hours via an extracorporeal circuit with either whole blood (n = 11) or with blood depleted of neutrophils by leukocyte filters (n = 11). The leukocyte filters caused near-total neutropenia in blood reperfusing the ischemic myocardium (7 +/- 7 neutrophils/microliters compared with 2,551 +/- 317/microliters in controls, mean +/- SEM; p less than 0.001. Infarct size was measured by planimetry of myocardial slices stained with triphenyltetrazolium chloride (TTC), and the accuracy of TTC for identifying necrotic myocardium was verified by electron microscopy. The size of the ischemic risk region was the same in the control (41.6 +/- 1.0%) and neutropenic (41.8 +/- 2.1%) groups. Collateral blood flow to the risk region was the same in control (0.15 +/- 0.03 ml/min/g) and neutropenic (0.13 +/- 0.03 ml/min/g) groups. Among dogs with collateral flow less than 0.2 ml/min/g, infarct size was reduced in the neutropenic group (27.7 +/- 6.7% of risk region, n = 8), compared with control dogs (52.5 +/- 5.7%; n = 7; p = 0.02). Multiple linear regression described the relation between infarct size, risk region size, and collateral flow in the control group, and the same regression relation was used to predict infarct size for the neutropenic group. Mean predicted infarct size in the neutropenic group (n = 11) was 16.8 +/- 3.4% of left ventricle, whereas mean observed infarct size was 9.6 +/- 3.1% (p less than 0.01). The extent of the no-reflow zone (absence of thioflavin-S-fluorescence) was also less in the neutropenic than the control group (2.2 +/- 0.8% vs. 8.1 +/- 2.7% of the risk region, p less than 0.05). Neutropenia limited to the reperfusion period is associated with significant reductions in the extent of the infarct and no-reflow zones after 90 minutes of ischemia. These findings support the hypothesis that reperfusion necrosis occurs after prolonged myocardial ischemia and indicate that neutrophil leukocytes are important mediators of such reperfusion injury.

High-energy electrical ablation is a new experimental approach to control arrhythmias. In this study, the cellular electrophysiologic effects of high-energy shocks (5 to 40 J) delivered in vitro to 14 epicardial tissues from 11 dogs were studied in an attempt to understand the nature and extent of injury as well as potential arrhythmogenic mechanisms. In addition, this preparation was used to test the importance of cathode-anode configuration, current density, and fiber orientation in the induction of tissue injury in vitro. Electrophysiologic abnormalities were noted up to 10 mm from the electrode wall, and their extent was determined in part by current density and the cathode-anode orientation. A decrease in resting membrane potential, action potential amplitude, and dV/dT occurred in all tissues after high-energy shocks, which was worst nearest the cathode and of graded severity at increasing distances from the cathode. The most severe effects were noted with high current densities and in tissues located between the cathode and anode. In addition, impaired impulse conduction and abnormal repolarization were documented. Histologic study demonstrated contraction band necrosis immediately after delivery of high-energy shocks. The extent and distribution of the contraction bands was in part dependent on the energy delivered and the cathode-anode configuration. These findings suggest potential mechanisms for arrhythmogenesis and altered regional hemodynamic abnormalities that occur in vivo.

In normal isolated, perfused canine ventricles, increased ventricular volume leads to shortening of refractoriness. To test the hypothesis that myocardium within an infarction zone is more susceptible to volume-induced changes in refractoriness than is normal myocardium, we measured strength-interval curves at low and high end-diastolic volumes at control and infarcted sites in 14 isolated, blood perfused, canine hearts with chronic (greater than 25 days) infarctions. In addition, the effect of volume load on inducing ventricular arrhythmias was studied at one to six sites in 11 hearts. Differences in refractoriness and inducibility at low (22 +/- 5 ml) and high (48 +/- 6 ml) end-diastolic volumes were compared. At control sites, volume load reduced the absolute refractory period from 178 +/- 16.5 to 175 +/- 16.7 msec (p less than 0.05), but no significant change in the relative refractory period occurred. At infarcted sites, the change in refractoriness with volume load was greater, and the absolute refractory period decreased from 171.5 +/- 21 to 160.6 +/- 26.3 msec (p less than 0.01), and the relative refractory period decreased from 180.1 +/- 22.1 to 169.9 +/- 26 msec (p = 0.05). This differential effect of volume load on refractoriness led to an increased dispersion of overall refractoriness at high volume. Infarcted sites showing the largest changes in refractoriness were characterized by patchy scars extending at least to the midmyocardium, whereas sites located within areas of transmural scar, endocardial scar, or rare microfoci of fibrosis showed no increased sensitivity to volume load. Of eight hearts in which no tachyarrhythmias were inducible during programmed electrical stimulation at low volume, four had tachyarrhythmias induced at high volume. Sites of stimulation associated with a conversion from noninducible to inducible tachyarrhythmias showed a larger degree of shortening of refractoriness (change in absolute refractory period: 24.7 +/- 16.5 vs. 3.9 +/- 6.5 msec, p less than 0.05). These data indicate that volume loading may have electrophysiologic significance and that it may be of greater functional importance under pathologic conditions.

Infarct expansion is acute regional dilatation and thinning of the infarct zone. There are several possibilities for the mechanism of this alteration in cardiac shape: thinning could be caused by 1) cell rupture, 2) a reduction in the intercellular space, or 3) stretching of myocytes or 4) slippage of groups of myocytes so that less cells are distributed across the wall. To determine the relative contributions of these cellular mechanisms of wall thinning and dilatation, detailed study of transverse histological sections of rat hearts with infarct expansion was performed 1, 2, and 3 days after coronary ligation. The number of cells across the wall was determined in six regions within, adjacent to, and remote from the infarct. Cell counting was performed so that the total number of cells across the wall and the number of cells per unit length (cell density) across the wall were determined. The transmural cell count and the cell density were correlated with the wall thickness in each region. Myocyte cross-sectional areas and sarcomere lengths were also measured. The results from the infarct expansion hearts were compared with those of sham-operated control hearts that had been similarly analyzed. To ensure that mechanisms identified in the rat were applicable to human infarct expansion, five hearts from patients who died within 3 days of infarction and two hearts from patients without coronary disease were studied histologically in a similar fashion. Wall thinning occurred in all regions of the rat infarct expansion hearts compared with controls (p less than 0.0001) but, as expected, was most pronounced in the infarct zone. A decrease in the number of cells across the wall accompanied the wall thinning at each site (p less than 0.0001), and this change in cell number was highly correlated with the changes in wall thickness (r = 0.915, p less than 0.001). Cell density increased from controls only within the infarct zone (p less than 0.001) and accounted for at most 20% of the thinning in that region. The change in cell density was attributable to both cell stretch (measured by increased sarcomere length and decreased myocyte cross-sectional area) and a decrease in the intercellular space. A similar strong correlation between wall thinning and decreased number of cells across the wall was identified in the human hearts (r = 0.94, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Although a number of lines of evidence hint that an elevation of intracellular calcium leads to myocardial injury, the cellular consequences of transient Ca overload remain unclear. To determine the contractile, histologic, and metabolic sequelae of transient Ca overload, we measured developed pressure (DP) in isovolumetric Langendorff-perfused ferret hearts at 37 degrees C before and 20 min after three 5 min periods of perfusion with a 10 mM [Ca]o, 1 mM [Mg]o solution (high-Ca group, n = 8) without ischemia, and in control hearts (n = 5) exposed transiently to the same total divalent cation concentration without a change in [Ca]o (9 mM [Mg]o, 2mM [Ca]o). DP, measured at various [Ca]o (0.5 to 5 mM), was depressed in the high-Ca group relative to control (p less than .001). Representative hearts from the control group were histologically normal, whereas hearts from the high-Ca group exhibited rare foci of predominantly "reversible" injury (mitochondrial swelling, glycogen deposition, and clumping of nuclear chromatin). Maximal Ca++-activated pressure (MCAP), measured from tetani after exposure to ryanodine, was also decreased in the high-Ca group (230 +/- 4 vs 262 +/- 6 mm Hg, p less than .001). Cao sensitivity, determined by normalization of the DP-[Ca]o relationship to the corresponding MCAP, was shifted to higher [Ca]o in the high-Ca group. Phosphorus nuclear magnetic resonance spectra were obtained in four high-Ca hearts. [ATP] declined by 30% to 40% after exposure to high [Ca]o, but inorganic phosphate, phosphocreatine, and pH remained unchanged. These results indicate that transient exposure to high [Ca]o without ischemia leaves behind distinctive contractile, metabolic, and histologic sequelae. The possible implications for the pathogenesis of postischemic contractile dysfunction are discussed.

The cellular electrophysiologic effects of myocardial ablation performed in vitro with argon laser energy were compared with those of high-energy electrical shocks. A border zone of injured but nonnecrotic tissue surrounding the site of energy delivery was present after tissue ablation by both energy modalities. A decrease in resting membrane potential, action potential amplitude, and maximum rate of upstroke velocity was noted in each tissue sample, was greatest nearest the site of energy delivery, and was of graded severity at increasing distances from the crater edge. The extent of injury, as indexed by changes in action potential variables and necrosis, histologically determined, was greater for tissues exposed to high-energy shocks. The relatively focal injury after argon laser photoablation may explain the lower incidence of arrhythmias and hemodynamic dysfunction noted with the use of this method of ablation in vivo.

To determine the importance of reperfusion injury and the ability of the free-radical scavenger recombinant human superoxide dismutase (h-SOD) to prevent it, open-chest dogs underwent 90 min of proximal circumflex coronary artery occlusion, and only at the moment of reperfusion received either h-SOD (400,000 IU bolus into the left atrium followed by a 300,000 IU iv infusion over 1 hr) or saline. After 48 hr the surviving animals were killed and measurements were made of the risk region (by postmortem angiography) and infarct size (by gross pathology). All measurements were made by investigators blinded to treatment given, and the code was broken only at the end of the study. Hemodynamic variables and collateral flow during ischemia were similar in the two groups. Infarct size in control animals (n = 8) averaged 22.4 +/- 3.1% of the left ventricle and 52.2 +/- 7.1% of the risk region, compared with 13.3 +/- 0.8% of the left ventricle and 33.6 +/- 2.1% of the risk region in h-SOD-treated dogs (n = 8) (p less than .05). Infarcts in treated animals were not only smaller, but also exhibited a distinctive "patchiness," suggesting protection along vascular distributions. Furthermore, analysis of the relationship between infarct size and collateral flow measured during ischemia in the two groups indicated that protection by h-SOD was greatest in animals with the lowest collateral flows. This study supports the concept that reperfusion of ischemic myocardium results in a separate component of cell damage, presumably linked to the generation of oxygen free radicals on reflow. Since the h-SOD preventable reperfusion component of injury was most pronounced in hearts with the most severe ischemia, scavenging of oxygen radicals at the time of reflow may offer a novel and particularly promising therapeutic approach for the protection of ischemic myocardium.

Amiodarone therapy leads to a significant impairment in myocardial conduction, yet it causes only a modest decrease in the maximum rate of depolarization of the action potential (dV/dT). To determine whether the decrease in dV/dT solely accounts for the impaired myocardial conduction or whether passive membrane properties may also be involved, we studied 21 ventricular epicardial tissues from 14 beagles; six dogs received long-term treatment (3-6 weeks) of amiodarone orally, and the remaining dogs served as controls. Amiodarone therapy was associated with a decrease in conduction velocity (0.41 +/- 0.15 vs. 0.56 +/- 0.05 m/sec; p less than 0.01). There was a trend toward a decrease in dV/dT and a significant decrease in the space constant (0.69 +/- 0.27 vs. 1.05 +/- 0.25 mm; p = 0.01), of which the latter correlated closely with the decrease in conduction velocity measured in the amiodarone-treated tissues (r = 0.85, p less than 0.05). These data indicate that the decrease in myocardial conduction velocity caused by amiodarone is primarily due to effects on overall resistance to passive current flow rather than effects on the inward sodium current.