Biomedical subjects

M O Jeroudi

Publications and source records attributed to M O Jeroudi.

At least 19 recordsLinked to original sources

PubMed1997

Use of bare-mounted Palmaz-Schatz stents employing the stent saddle technique on the delivery balloon: a single center experience.

The major limitations of the Palmaz-Schatz stent stem from the design of its stent delivery system (SDS). The SDS is bulky and has poor trackability in lesions with proximal tortuosity and/or vessel calcification. The use of bare-mounted Palmaz-Schatz stents on low profile balloons represents an alternate approach for lesions that are not accessible for stenting with the SDS. Thus we evaluated the indications, procedural success rate, and in-hospital complications of patients undergoing bare stenting at a single center between 1 October 1995 through 30 September 1996. A total of 363 coronary interventions were performed during this period, including coronary stenting in 194 vessels. In 18 of these 194 vessels, bare-mounted Palmaz-Schatz stents were used. The indications for bare stenting were: inability to deliver the Palmaz-Schatz stent on SDS for suboptimal angioplasty results or acute/threatened abrupt closure; use of half stents; stenting in vessels < 3.0 mm; intermediate disease in the proximal segment that would have precluded optimal visualization of stent placement; and use of guides 7 French or smaller. Bare stenting was successful in 15 of the 18 patients (vessels) in whom it was attempted. There were no deaths, myocardial infarctions, stent thrombosis, repeat interventions, or significant bleeding in patients with successful bare stent delivery. The stents were successfully retrieved in the three patients in whom the stent could not be advanced into the target coronary segment. One of these patients had a propagated spiral dissection prior to attempts at bare stenting and required emergent bypass surgery. The remaining two patients with failed deployment had suboptimal angioplasty results but had an uncomplicated hospital course. Thus bare stenting represents an alternate percutaneous approach to tackle suboptimal procedural results and/or complications in patients who have failed stent deployment with the standard sheathed stent delivery system currently available in the United States.

Angioplasty, Balloon, Coronary↗

PubMed1995

Effect of adenosine on myocardial 'stunning' in the dog.

Recent evidence suggests a cardioprotective effect of adenosine in myocardial ischemia and reperfusion. The present study was undertaken to determine (1) whether adenosine attenuates myocardial stunning, (2) if so, whether the beneficial effect of adenosine takes place during ischemia or after reperfusion, and (3) whether adenosine preconditions against myocardial stunning. A total of 93 dogs were used. In phase A of the study, open-chest dogs undergoing a 15-minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion received an intracoronary infusion of either saline (group I [control], n = 14), 2 mg/min adenosine from 30 minutes before occlusion until 1 hour after reperfusion (group II, n = 10), or 2 mg/min adenosine from 2 minutes before reperfusion until 1 hour after reperfusion (group III, n = 11). Regional myocardial function (assessed as systolic wall thickening) was similar in the three groups at baseline and during ischemia. After reperfusion, dogs treated with adenosine before, during, and after ischemia (group II) demonstrated a significant improvement in the recovery of function that persisted throughout the 4 hours of reperfusion. In contrast, in dogs treated only during the reperfusion period (group III), the recovery of function was not statistically different from that in control dogs. The enhanced recovery effected by adenosine in group II could not be ascribed to differences in ischemic zone size, collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase B of the study, dogs received an intracoronary infusion of either saline (group IV [control], n = 6) or adenosine (4 mg/min from 40 to 10 minutes before occlusion [group V, n = 6]). Despite pretreatment with adenosine, the recovery of function in group V was indistinguishable from that in the control group. This study demonstrates that (1) continuous administration of adenosine before, during, and after ischemia results in a significant and sustained attenuation of myocardial stunning; (2) this improved recovery of function cannot be attributed to nonspecific variables, such as collateral flow during coronary occlusion, coronary flow after reperfusion, or other hemodynamic factors, and therefore reflects a direct cardioprotective action of adenosine; (3) the protection against stunning is lost or markedly diminished if adenosine is given only at reperfusion; and (4) administration of adenosine before ischemia does not precondition the myocardium against the stunning induced by a 15-minute occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗

PubMed1994

Myocardial reperfusion injury: role of oxygen radicals and potential therapy with antioxidants.

Experimental studies have demonstrated that reperfusion is associated with a host of distinctive pathophysiologic derangements, the most important of which are reperfusion arrhythmias, transient mechanical dysfunction or "myocardial stunning," and cell death. Reperfusion arrhythmias and myocardial stunning occur in experimental animals after transient ischemia followed by reperfusion, and there is considerable evidence that these derangements also develop in humans, although the existence of malignant reperfusion arrhythmias in humans remains uncertain. Reperfusion arrhythmias and myocardial stunning can be considered manifestations of sublethal, reversible cellular injury. The pathogenesis of reperfusion arrhythmias and stunning has not been conclusively established; however, there is considerable evidence that generation of oxygen radicals and perturbations of calcium homeostasis play an important role. Antioxidants and calcium antagonists have been shown to mitigate these manifestations of reperfusion injury. In contrast, the likelihood of lethal reperfusion-induced injury remains highly controversial. Although many studies have reported reduction of infarct size with antioxidants, numerous others have failed to reproduce these results. Consequently, intense controversy persists regarding whether oxygen radicals contribute to extending cell death following reperfusion and whether reperfusion itself causes cell death. Neither the resolution of this controversy nor the availability of clinical therapies to reduce reperfusion-induced cell death is likely in the near future.

Animals↗

PubMed1994

Prolonged wall motion abnormalities after chest pain at rest in patients with unstable angina: a possible manifestation of myocardial stunning.

Although myocardial "stunning" would be expected to occur in unstable angina, there is no published report in which the recovery of regional left ventricular function was serially monitored in this syndrome. To determine whether the time course of the regional wall motion abnormalities associated with unstable angina is consistent with myocardial stunning, 20 consecutive patients with unstable angina were studied prospectively. Regional left ventricular wall motion was assessed by two-dimensional echocardiography during or immediately after angina at rest and at serial times thereafter. Six of the 20 patients fulfilled the inclusion criteria. The recovery of segmental wall motion after chest pain was consistently found to be delayed in all six patients, but a considerable variability was observed. In at least two subjects, the improvement was rapid and the wall motion abnormalities disappeared almost completely within 2 hours after the chest pain. Both of these patients had the shortest duration of angina (approximately 10 minutes). In contrast, in three other patients with longer duration of chest pain, the improvement was slower and significant wall motion abnormalities were still present at 24 hours after the chest pain. In five control patients who had angiographically-documented coronary artery disease but no recent episode of angina, there was no significant change in segmental wall motion during a period of observation equivalent to that used in the unstable angina group. This study evaluated for the first time the time course of wall motion abnormalities in patients with unstable angina. The results demonstrate that angina at rest is followed by a prolonged depression of contractile function, which may persist for up to 24 hours or even longer. Because none of the patients had evidence of acute myocardial infarction or recurrent ischemia, our observations suggest myocardial stunning as the pathophysiologic substrate for the slow recovery of wall motion. The present results are consistent with the concept that myocardial stunning does occur in unstable angina and indeed may be a component of the natural history of this disorder; however, further investigations using simultaneous measurements of function and flow will be necessary to unequivocally distinguish myocardial stunning from hibernation and silent ischemia.

Angina, Unstable↗

PubMed1994

Beneficial effects of MDL 74,405, a cardioselective water soluble alpha tocopherol analogue, on the recovery of function of stunned myocardium in intact dogs.

OBJECTIVE: Postischaemic myocardial dysfunction ("stunning") is caused in part by the generation of reactive oxygen species resulting in oxidant stress. The aim of this study was to test the hypothesis that the systemic administration of MDL 74,405, a hydrophilic cardioselective alpha tocopherol analogue, is beneficial in attenuating myocardial stunning. METHODS: Open chest dogs undergoing a 15 min coronary artery occlusion and 4 h of reperfusion received an intravenous infusion of either saline (controls, n = 9) or MDL 74,405 (n = 8) at a dose of 0.3 mg.kg-1 x h-1 starting 30 min before coronary occlusion and ending 60 min after reflow. RESULTS: Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischaemia. Following reperfusion, however, the dogs treated with MDL 74,405 had significant improvement in the recovery of function, which was evident 2 h after restoration of flow and was sustained throughout the rest of the reperfusion phase. Analysis of covariance showed that the differences in wall thickening after reperfusion between the two groups were independent of collateral flow during occlusion. Furthermore, the enhanced recovery effected by MDL 74,405 could not be attributed to non-specific factors such as coronary flow after reperfusion, arterial pressure, heart rate, or other haemodynamic variables. Measurements of MDL 74,405 showed that the myocardial content of the antioxidant at 4 h of reperfusion was approximately 30 times greater than the plasma concentration at 1 h of reperfusion, suggesting preferential cardiac accumulation of this drug. CONCLUSIONS: This study shows (1) that systemic administration of the alpha tocopherol analogue MDL 74,405 in the setting of myocardial ischaemia and reperfusion does not result in adverse cardiovascular effects, at least in the first few hours after injection; (2) that the drug accumulates in myocardial tissue at concentrations much higher than in the plasma; (3) that intravenous infusion of MDL 74,405 produces an attenuation of myocardial stunning comparable to that previously observed with intracoronary administration of other antioxidants; and (4) that this beneficial effect is independent of non-specific actions on haemodynamic variables or coronary flow. The results suggest that the systemic administration of hydrophilic, cardioselective alpha tocopherol analogues represents an effective therapeutic approach to the alleviation of postischaemic dysfunction.

Animals↗

PubMed1993

Augmentation of endogenous adenosine attenuates myocardial 'stunning' independently of coronary flow or hemodynamic effects.

BACKGROUND: Mounting evidence suggests a protective effect of exogenous adenosine in myocardial ischemia and reperfusion. We tested the hypothesis that augmentation of endogenous adenosine levels, achieved by inhibiting adenosine catabolism and washout, is beneficial in postischemic myocardial dysfunction ("stunning"). METHODS AND RESULTS: In phase I of the study, open-chest dogs undergoing a 15-minute coronary artery occlusion and 4 hours of reperfusion received an intracoronary infusion of either saline (controls, n = 23) or 6-(4-nitrobenzyl)-mercapto: purine ribonucleoside (NBMPR, a selective nucleoside transport inhibitor) combined with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, a potent adenosine deaminase inhibitor) (EHNA + NBMPR, n = 15) starting 15 minutes before coronary occlusion and ending 15 minutes after the initiation of reflow. Regional myocardial function (assessed as systolic wall thickening) was similar in control and treated groups at baseline and during ischemia. After reperfusion, however, the dogs treated with EHNA + NBMPR exhibited a significant improvement in the recovery of function, which was evident as early as 30 minutes after restoration of flow and was sustained throughout the rest of the reperfusion phase. The enhanced recovery effected by EHNA + NBMPR could not be attributed to nonspecific factors such as differences in collateral flow during occlusion, coronary flow after reperfusion, arterial pressure, heart rate, or other hemodynamic variables. In phase II of the study, the myocardial content of adenine nucleotides and nucleosides was measured by high performance liquid chromatography in myocardial biopsies obtained serially from open-chest dogs undergoing the same protocol used in phase I. There were no significant differences between control (n = 8) and treated (n = 9) dogs with respect to myocardial levels of adenosine triphosphate (ATP) at 30 and 60 minutes after reperfusion, indicating that the beneficial effects of EHNA + NBMPR cannot be ascribed to repletion of ATP stores. Compared with controls, dogs treated with EHNA + NBMPR exhibited a much larger increase in myocardial adenosine (6.07 +/- 1.47 vs 1.03 +/- 0.16 nmol/mg protein, P < .05) and a much smaller increase in inosine (0.52 +/- 0.27 vs 3.04 +/- 0.54 nmol/mg protein, P < .05) at the end of ischemia, such that the inosine-to-adenosine ratio noted in controls was completely reversed (approximately 6:1 vs approximately 1:6, respectively). In the treated group, adenosine levels remained markedly increased compared with controls up to 1 hour after reperfusion. CONCLUSIONS: This study demonstrates that (1) administration of an adenosine deaminase inhibitor plus a nucleoside transport blocker is remarkably effective in augmenting myocardial adenosine levels during regional ischemia and subsequent reperfusion in vivo, (2) this augmentation of adenosine results in a significant and sustained attenuation of myocardial stunning, and (3) the attenuation of stunning is not due to ATP repletion or to nonspecific actions on hemodynamic variables or coronary flow. These findings suggest that endogenous adenosine production during ischemia serves as an important pathophysiological mechanism that protects against myocardial stunning. The results also suggest that augmentation of endogenous adenosine (without exogenous adenosine administration) represents an effective therapeutic approach to the alleviation of reversible postischemic dysfunction.

Adenine↗

PubMed1993

Demonstration of free radical generation in the "stunned" myocardium in the conscious dog and identification of major differences between conscious and open-chest dogs.

Conscious dogs undergoing a 15-min coronary occlusion were given alpha-phenyl N-tert-butyl nitrone (PBN) and the local coronary venous plasma was analyzed by electron paramagnetic resonance spectroscopy. A prolonged myocardial release of PBN radical adducts was observed, which exhibited a burst in the initial minutes of reflow (peaking at 3 min) and then abated but continued for 1-3 h after reperfusion. Computer simulation revealed the presence of at least two PBN adducts (aN = 15.2 G and a beta H = 6.0 G; aN = 14.6 G and a beta H = 3.0 G), both consistent with the trapping of secondary carbon-centered radicals. No appreciable PBN adduct production was observed when collateral flow exceeded 30-40% of nonischemic flow, indicating that a flow reduction of at least 60% is necessary to trigger free radical reactions. There was a direct relationship between the magnitude of PBN adduct production and the severity of contractile dysfunction (r = 0.77), suggesting that the radicals generated upon reperfusion play a causal role in the subsequent stunning. The total release of PBN adducts after 3 h of reperfusion following a 15-min coronary occlusion was found to be approximately five times greater in open-chest compared with conscious dogs; at the same time, the recovery of wall thickening was markedly less in open-chest dogs. This study represents the first application of spin trapping to a conscious animal model of myocardial ischemia. The results demonstrate (a) that free radicals are generated in the stunned myocardium in the absence of the artificial or abnormal conditions associated with previously used models (isolated hearts, open-chest preparations), and (b) that both the severity of postischemic dysfunction and the magnitude of the attendant free radical production are greatly exaggerated in the open-chest dog, implying that previous conclusions derived from this model may not be applicable to conscious animals or to humans. This investigation also provides a method to measure free radicals in awake animals.

Anesthesia, General↗

PubMed1990

Percutaneous transluminal coronary angioplasty in octogenarians.

OBJECTIVE: To assess the safety and short- and long-term outcomes of percutaneous transluminal coronary angioplasty in octogenarians. DESIGN: Retrospective chart review of clinical series. SETTING: Referral-based university medical center. PATIENTS: Consecutive series of 54 octogenarian patients (mean age, 82.4 years) who had percutaneous transluminal coronary angioplasty between March 1980 and December 1988. Of these patients, 91% presented with severe angina (Canadian Cardiovascular Society Class III or IV); 59% had unstable angina. Twenty-six patients (48%) had had a previous myocardial infarction and 15 (28%) had had previous coronary artery bypass surgery. Multivessel disease was present in 44 patients (81%). Follow-up ranged from 1 to 50 months (mean, 19 months). INTERVENTION: Percutaneous transluminal coronary angioplasty. MEASUREMENTS AND MAIN RESULTS: The angiographic success rate was 50 of 54 (93%; 95% CI, 81% to 98%) and the clinical success rate was 49 of 54 (91%; CI, 79% to 97%). Two patients had procedure-related myocardial infarction. Two patients died in the hospital, 1 from cardiac tamponade because of pacemaker perforation and 1 from cardiogenic shock after a myocardial infarction despite successful angioplasty. During the follow-up period 4 patients required bypass surgery, 2 had myocardial infarction, and 7 died (4 deaths were cardiac). Eleven patients (20%) had re-stenosis, 7 of whom were managed with repeat angioplasty, including 1 patient who had four procedures. At follow-up, 42 of 45 survivors (93%) were asymptomatic or had class II angina. The Kaplan-Meier survival for all patients, including those who died in the hospital, was 87% at 1 year and 80% at 3 years. Cumulative freedom from major cardiac events (death, myocardial infarction, or coronary bypass surgery) was 81% at 1 year and 78% at 3 years. CONCLUSIONS: Percutaneous transluminal coronary angioplasty can be done in octogenarians with a high rate of angiographic and clinical success, low complication rate, and a favorable long-term (3-year) outcome. As such, it is a treatment option in managing advanced coronary artery disease in this fragile group of patients.

Age Factors↗

PubMed1990

An accurate, nontraumatic ultrasonic method to monitor myocardial wall thickening in patients undergoing cardiac surgery.

Measurement of systolic wall thickening by sonomicrometry provides an accurate index of regional left ventricular function, but the trauma of crystal insertion limits its widespread clinical use. The first clinical application of a 10 MHz ultrasonic Doppler probe that can be either sutured or applied by suction to the epicardium and can measure wall thickening at any depth of the left ventricular wall is described. In 18 dogs, measurements obtained with the suction probe correlated well (r = 0.97) with those of a previously validated sutured probe. To assess clinical feasibility, the probe was applied to the epicardium of patients undergoing coronary bypass surgery. Good quality wall thickening signals were obtained with no complications. Transmural left ventricular thickening fraction before bypass surgery was 34 +/- 3% (mean value +/- SE) at the mid-ventricular lateral wall, 33 +/- 4% at the anterior basal wall and 26 +/- 4% at the mid-ventricular posterior wall. Right ventricular thickening fraction averaged 25 +/- 3%. Endocardial thickening fraction tended to exceed epicardial thickening fraction, although the difference attained statistical significance (p less than 0.05) only at the anterior basal wall. On average, thickening fraction during the immediate postoperative period remained unchanged compared with the preoperative values, but a marked individual variability was observed, with 7 of 15 patients exhibiting a decrease and 8 an increase. Exteriorization of the wires attached to the sutured probe allowed continuous in situ monitoring of wall thickening in the postoperative period and subsequent removal of the probe. In six patients the crystal was left in place for 48 to 72 h after surgery and then removed without complications; good wall thickening signals were obtained for the entire period during which the probe was implanted. Thus, the Doppler probe is an accurate, atraumatic method for measuring right and left ventricular regional function. Transmural, endocardial and epicardial function can be mapped at various sites during surgery, and post-operatively one can monitor serial changes of regional function and assess the effects of cardioplegia and other therapeutic interventions. This technique should be useful for both investigative and clinical purposes.

Adult↗

PubMed1990

Effect of human recombinant superoxide dismutase on canine myocardial infarction.

To determine whether human recombinant superoxide dismutase (h-SOD) produces sustained reduction of infarct size, anesthetized dogs underwent a 2-h coronary occlusion followed by either 48 or 4 h of reperfusion. In the 48-h study, dogs were randomized to three intravenous treatments: 1) "low-dose" h-SOD (2 mg/kg bolus 2 min before reperfusion followed by 4 mg/kg over 45 min), 2) "high-dose" h-SOD (8 mg/kg bolus 2 min before reperfusion followed by 8 mg/kg over 45 min), or 3) equivalent volumes of saline. In the 4-h study, dogs were randomized to high-dose h-SOD or saline. Occluded bed size was measured by postmortem perfusion and infarct size by triphenyl tetrazolium chloride staining and planimetry. Investigators performing the study and measuring infarct size were blinded to the treatment given. High plasma concentrations of h-SOD were present in the arterial blood of treated dogs in the early phase of reperfusion (greater than 60 and greater than 180 micrograms/ml in low- and high-dose groups, respectively). In both studies, control and treated groups were similar with respect to occluded bed size, collateral blood flow, and rate-pressure product during ischemia. In the 48-h study, infarct size, expressed as percent of occluded bed size, was 41.3 +/- 7.6% (mean +/- SE) in the control group, 37.1 +/- 7.2% in the low-dose h-SOD group, and 48.0 +/- 7.1% in the high-dose h-SOD group. In the 4-h study, infarct size was 30.6 +/- 4.9% in the control group and 31.5 +/- 9.6% in the high-dose h-SOD group. Analysis of the flow-infarct relationships confirmed that h-SOD did not reduce infarct size at any level of collateral flow in either the 48- or 4-h study. Recovery of regional myocardial function after reperfusion was also unaffected by h-SOD in both studies. Thus in this randomized blinded study, large doses of h-SOD given at the time of reperfusion failed to limit infarct size or enhance recovery of function, both early (4 h) and late (48 h) after reperfusion following a 2-h coronary occlusion.

Animals↗

PubMed1990

Effect of superoxide dismutase and catalase, given separately, on myocardial "stunning".

Controversy persists regarding which oxygen metabolites are cytotoxic. Although the combination of superoxide dismutase (SOD) and catalase has been shown to attenuate postischemic myocardial dysfunction ("stunning"), it is unknown whether this beneficial effect is due to scavenging of O2-., H2O2, or both. Accordingly, 85 open-chest dogs underwent a 15-min occlusion of the left anterior descending coronary artery followed by 4 h of reperfusion. In phase A, dogs received an intravenous infusion of saline (group I), SOD (5 mg/kg, group II), catalase (12,000 U/kg, group III), or the combination of SOD and catalase (same doses, group IV). Recovery of regional myocardial function (assessed as systolic wall thickening) after reperfusion was significantly improved by the combination of SOD and catalase but not by SOD alone or catalase alone. To determine whether higher doses of enzymes are more effective, in phase B dogs received an intracoronary infusion of normal saline (group V), SOD in low dose (1.5 mg/kg, group VI), SOD in high dose (6.3 mg/kg plus 1.5 mg/kg iv, group VII), catalase in low dose (18,000 U/kg, group VIII), or catalase in high dose (240,000 U/kg plus 40,000 U/kg iv, group IX). Despite the fact that the local plasma levels of enzymes were considerably higher than those achieved in phase A, none of the treatments in phase B significantly enhanced recovery of contractile function. This study demonstrates that the combination of SOD and catalase is more effective than either enzyme alone in attenuating postischemic myocardial dysfunction and that increasing the doses of SOD or catalase does not provide additional protection. The results suggest that both O2-. and H2O2 contribute significantly to the pathogenesis of myocardial stunning after regional ischemia in the intact animal. Furthermore, the data imply that if SOD and catalase are to be used clinically to prevent postischemic dysfunction, protection may be achieved most effectively by combining the two enzymes.

Animals↗

PubMed1990

Iron-mediated radical reactions upon reperfusion contribute to myocardial "stunning".

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") is mediated by iron-catalyzed free radical reactions, but the exact time window during which the critical iron-mediated damage develops remains unknown. Furthermore, the evidence that iron promotes free radical reactions in vivo is indirect. Thus open-chest dogs undergoing a 15-min coronary occlusion and 4 h of reperfusion were given one of the following intracoronary infusions: desferrioxamine (DF) beginning 2 min before reperfusion (group I), DF beginning 1 min after reperfusion (group II), iron-loaded DF in dosage identical to group I (group III), or vehicle (controls, group IV). Recovery of contractile function was substantially greater in group I than in controls, whereas in groups II and III it was indistinguishable from controls. To determine whether the protection afforded by DF was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In controls (group VI), radical adducts of PBN were released in the coronary venous blood after reperfusion. DF given as in group I (group V) markedly suppressed myocardial production of PBN adducts. These results strongly suggest that a substantial portion of the damage responsible for myocardial stunning is caused by iron-catalyzed free radical reactions that develop in the initial seconds of reperfusion and can be prevented by administration of iron chelators started just before reflow. Furthermore, the results demonstrate that attenuation of postischemic dysfunction by DF is associated with attenuation of free radical reactions in vivo, thereby providing direct evidence for a pathogenetic role of iron-catalyzed free radical reactions in myocardial stunning in the intact animal.

Animals↗

PubMed1990

Prolonged impairment of coronary vasodilation after reversible ischemia. Evidence for microvascular "stunning".

Reperfusion after brief, reversible myocardial ischemia is associated with prolonged depression of contractile function (myocardial "stunning"); however, the effect on coronary vascular function has not been defined. Thus, open-chest dogs (n = 14) underwent a 15-minute left anterior descending coronary artery (LAD) occlusion followed by reflow. Four hours after reperfusion, regional myocardial blood flow (microspheres) was significantly (p less than 0.01) lower and coronary vascular resistance significantly (p less than 0.01) higher in the postischemic as compared with the nonischemic endocardium. Furthermore, during maximal vasodilation elicited by intravenous adenosine (n = 6), myocardial blood flow was lower (p less than 0.05) and coronary vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic myocardium, both in the endocardial and in the epicardial layers. Similarly, during maximal dilation elicited by intravenous papaverine (n = 8), myocardial blood flow was lower (p less than 0.05) and vascular resistance higher (p less than 0.05) in the postischemic as compared with the nonischemic endocardium; a directionally similar trend was observed in the epicardium. Four hours after reperfusion, all indexes of reactive hyperemia after a 40-second coronary occlusion were significantly lower in the LAD than in the control circumflex coronary artery (n = 8). There was no appreciable correlation between systolic wall thickening in the stunned myocardium and 1) the resting myocardial perfusion, 2) the hyperemia attained during adenosine or papaverine, and 3) the hyperemic response to a 40-second coronary occlusion. In control dogs that did not undergo a 15-minute LAD occlusion (n = 15), there were no differences in myocardial blood flow or vascular resistance between the LAD-dependent and the circumflex-dependent bed, either before or during adenosine (n = 7) or papaverine (n = 8). Furthermore, reactive hyperemia after a 40-second occlusion did not differ between the LAD and the circumflex artery (n = 8). In conclusion, a brief (15 minute), reversible ischemic insult causes a prolonged increase in resting vascular resistance and a prolonged impairment in vasodilator responsiveness, both of which persist for at least 4 hours. The severity of these vascular derangements is not related to the severity of contractile depression, suggesting that they may represent a relatively independent phenomenon. It is proposed that, in addition to myocardial "stunning," reversible ischemia also causes a microvascular "stunning."

Adenosine↗

PubMed1989

Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog.

Electron paramagnetic resonance (EPR) spectroscopy was used to investigate whether (i) the free radicals produced in the "stunned" myocardium (myocardium with postischemic contractile dysfunction) are derived from O2, (ii) inhibition of radical reactions improves function, and (iii) i.v. spin traps are effective. Open-chest dogs undergoing a 15-min coronary occlusion received an i.v. infusion of the spin trap, alpha-phenyl N-tert-butylnitrone (PBN) (50 mg/kg). In group I (n = 6), EPR signals characteristic of radical adducts of PBN appeared in the coronary venous blood during ischemia and increased dramatically after reperfusion. In group II (n = 6), which received PBN and i.v. superoxide dismutase (SOD; 16,000 units/kg) plus catalase (12,000 units/kg), myocardial production of PBN adducts was undetectable during ischemia (delta = -100%, P less than 0.01 vs. group I) and markedly inhibited after reperfusion (delta = -86%, P less than 0.001). This effect was seen at all levels of ischemic zone flow but was relatively greater in the low-flow range. In group III (n = 8), the same dosages of SOD and catalase without PBN markedly enhanced contractile recovery (measured as systolic wall thickening) after reperfusion [P less than 0.01 at 3 hr vs. controls (group IV, n = 7)]. Systemic plasma activity of SOD and catalase averaged 127 +/- 24 and 123 +/- 82 units/ml, respectively, 2 min after reperfusion. PBN produced no apparent adverse effects and actually improved postischemic contractile recovery in group I (P less than 0.05 at 3 hr vs. controls). This study shows that (i) SOD and catalase are highly effective in blocking free radical reactions in vivo, (ii) the radicals generated in the "stunned" myocardium are derived from univalent reduction of O2, and (iii) inhibition of radical reactions improves functional recovery. The results provide direct, in vivo evidence to support the hypothesis that reactive oxygen metabolites play a causal role in the myocardial "stunning" seen after brief ischemia.

Animals↗

PubMed1989

Nonuniform transmural recovery of contractile function in stunned myocardium.

With the use of an epicardial Doppler probe, systolic wall thickening was selectively measured in the inner, mid, and outer layers of the left ventricular (LV) wall in 16 conscious dogs undergoing a 15-min left anterior descending artery (LAD) occlusion followed by 7 days of reperfusion (REP). Under control conditions, percent thickening fraction (ThF) was significantly greater (P less than 0.01) in the inner layer [36.0 +/- 2.3% (mean +/- SE)] than in the mid (28.6 +/- 2.1%) or outer (21.3 +/- 2.2%) layers. During LAD occlusion, 11 dogs exhibited transmural dyskinesis (group 1), whereas 5 had transmural hypokinesis (group 2). In group 1, all layers exhibited comparable degrees of paradoxical systolic thinning during LAD occlusion. After REP, however, recovery was delayed in the inner compared with the mid and outer layers. At 2 h, ThF averaged 34.2 +/- 11.9% of base line in the endocardium vs. 61.7 +/- 16.2% in the midmyocardium and 51.0 +/- 12.3% in the epicardium (F = 4.29, P less than 0.002); similar differences were noted at 3 and 4 h. In the mid and outer layers, ThF returned to base-line values by 24 h, whereas in the inner layer it was still significantly depressed (P less than 0.05) at 24 h (77.3 +/- 5.1% of base line) and recovered by 48 h. The inner-to-outer ThF ratio was decreased (P less than 0.01) for 24 h after REP, indicating maldistribution of thickening in the "stunned" myocardium. In group 2, all layers exhibited hypokinesis during LAD occlusion. Again, recovery of function after REP was delayed in the endocardium compared with the other layers. This study demonstrates that after both severe ischemia resulting in dyskinesis and mild ischemia resulting in hypokinesis, REP is associated with slower recovery of function in the inner than in the outer layers. Thus myocardial "stunning" is a nonuniform phenomenon with maximal severity in the subendocardium.

Animals↗

PubMed1989

Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Evidence that myocardial "stunning" is a manifestation of reperfusion injury.

Recent evidence suggests that postischemic myocardial dysfunction ("stunning") may be mediated by oxygen free radicals, but the exact time window during which the critical radical-mediated damage develops remains unknown. Furthermore, the evidence for the oxyradical hypothesis is indirect and, therefore, inconclusive. Thus, the potent and cell-permeable antioxidant N-(2-mercaptopropionyl)-glycine (MPG) was administered as an intra-coronary infusion (8 mg/kg/hr) to three groups of open-chest dogs undergoing a 15-minute coronary occlusion followed by 4 hours of reperfusion. In group I (n = 8), the infusion of MPG was started 15 minutes before occlusion and ended 2 hours after reperfusion; in group II (n = 9), MPG was started 1 minute before reperfusion and ended 2 hours thereafter; in group III (n = 10), MPG was started 1 minute after reperfusion and ended 2 hours and 15 minutes thereafter. Control dogs (group IV) (n = 10) received vehicle. Recovery of contractile function (assessed as systolic wall thickening) was equivalent in groups I and II, and in both groups it was substantially greater than in controls (p less than 0.005 at 4 hours). In contrast, in group III recovery of function was indistinguishable from controls. To determine whether the protection afforded by MPG was due to inhibition of free radical reactions, myocardial production of free radicals was directly assessed by intracoronary infusion of the spin trap alpha-phenyl N-tert-butyl nitrone (PBN). In control dogs (group VII, n = 6), radical adducts of PBN were released in the coronary venous blood after reperfusion, with a burst occurring in the first 5 minutes. MPG given as in group II (group V, n = 5) markedly suppressed myocardial production of PBN adducts (delta = -98% over 3 hours, p less than 0.01 vs. controls); this effect was evident immediately after reperfusion. MPG given as in group III (group VI, n = 5) also suppressed PBN adduct production (delta = -83% over 3 hours, p less than 0.025 vs. controls), but this effect was delayed. Hence, the radicals important in myocardial stunning appear to be those generated immediately after reperfusion. In vitro studies demonstrated that MPG is an exceptionally powerful scavenger of .OH (rate constant = 8.1 x 10(9) M-1 sec-1 by pulse radiolysis) but has no significant effect on .O2- (rate constant less than 10(3) M-1 sec-1), H2O2 (rate constant = 1.6 M-1 sec-1), or non-.OH-initiated lipid peroxidation, suggesting that removal of .OH is the major mechanism of the beneficial effects of MPG.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1989

Postischemic mechanical and vascular dysfunction (myocardial "stunning" and microvascular "stunning") and the effects of calcium-channel blockers on ischemia/reperfusion injury.

The purpose of this review is to summarize current concepts regarding the sequelae of myocardial ischemia and reperfusion and the effects of calcium-channel blockers. This article will focus on three topics: (1) the phenomenon of postischemic myocardial dysfunction (myocardial "stunning"); (2) the phenomenon of postischemic vascular dysfunction (microvascular "stunning"); (3) the effects of calcium-channel blockers on myocardial ischemia and reperfusion injury.

Animals↗

PubMed1988

Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile.

Myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile was investigated as a means to assess myocardial infarct size during coronary occlusion and to quantify the extent of salvaged myocardium after coronary occlusion followed by reperfusion. Open chest dogs underwent either a permanent coronary artery occlusion (Group 1, n = 16) or a 2 h occlusion followed by reperfusion (Group 2, n = 15). Animals in both groups were killed 48 h after occlusion. During coronary occlusion, 23 of the 25 dogs that survived the coronary occlusions had abnormal myocardial scintigrams. The scintigraphic perfusion defect size correlated well with the pathologic infarct size (r = 0.85 and 0.95 by planar and tomographic imaging, respectively). The planar scintigraphic defect size, but not the tomographic defect size, overestimated the pathologic size. The planar scintigraphic defect size observed during coronary occlusion was markedly reduced 48 h after reperfusion (24.8 +/- 12.8% to 10.6 +/- 9.7% of the left ventricle, p less than 0.003). The uptake of technetium-99m hexakis 2-methoxyisobutyl isonitrile in the ischemic myocardium increased significantly 48 h after reperfusion (p less than 0.003) and correlated with the increase in regional myocardial blood flow, as assessed by radioactive microspheres (r = 0.83, p less than 0.01). Thus, myocardial imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile allows reliable demonstration of the presence of acute infarction, estimation of infarct size and quantification of the extent of salvaged myocardium after coronary reperfusion.

Animals↗