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K Przyklenk

Publications and source records attributed to K Przyklenk.

At least 55 records · Page 3Linked to original sources
PubMed1995

Clinical aspects of preconditioning and implications for the cardiac surgeon.

Ischemic preconditioning is one of the most powerful means to reduce myocardial ischemic cell death in the experimental laboratory. Data are now emerging suggesting that ischemic preconditioning also can occur in the human heart. Studies performed on human myocardial biopsies, angioplasty studies, clinical studies assessing acute tolerance to angina, and some studies evaluating the effect of angina prior to myocardial infarction, lend support to the concept that the human heart can be preconditioned. The ultimate objective is to develop preconditioning-mimetic agents that can be administered prophylactically prior to the time of cardiopulmonary bypass surgery or administered to hearts that have been harvested for transplant in order to better preserve the ischemically jeopardized myocyte.

Angina Pectoris↗
PubMed1995

Low-dose i.v. acetylcholine acts as a "preconditioning-mimetic" in the canine model.

Brief episodes of ischemia paradoxically protect or "precondition" the heart and reduce infarct size caused by a subsequent, more sustained, coronary artery occlusion, perhaps by stimulation of adenosine receptors coupled to muscarinic receptors via the inhibitory G protein. However, brief ischemia is not a desirable form of therapy. Using the anesthetized canine model, we therefore sought to determine if small intravenous (i.v.) doses of the muscarinic agonist acetylcholine would provide a therapeutically feasible means to mimic preconditioning. Four groups of dogs underwent a 40-minute intervention period, followed by 1 hour of coronary occlusion and 5 hours of reperfusion: 8 received two i.v. doses of acetylcholine (0.01 mg each) at 40 minutes and 5 minutes before the sustained occlusion; 8 received equipotent doses of nitroglycerin (0.05 mg; a vasodilator that does not act via the M2 muscarinic receptor); 7 received conventional ischemic preconditioning (four 5-minute episodes of coronary occlusion, each interrupted by 5 minutes of reperfusion); and 8 controls received no intervention. Coronary blood flow and hemodynamic parameters were monitored throughout the protocol, regional myocardial blood flow was measured during the sustained occlusion by injection of radiolabeled microspheres, and infarct size was assessed by tetrazolium staining. All four groups were equally ischemic during coronary occlusion. However, infarct size was reduced significantly in both the preconditioned and acetylcholine-treated dogs when compared with controls (6% +/- 2% [p < 0.01 vs controls], 10% +/- 2% [p < 0.05 vs controls], and 19% +/- 3% of the myocardium at risk).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

Clinical evidence for stunned myocardium after coronary artery bypass surgery.

Stunned myocardium is defined as postischemic dysfunction of viable myocardium. This phenomenon was initially described in animal models of brief ischemia followed by reperfusion, but is becoming increasingly recognized in clinical situations. One of these situations is ventricular dysfunction following coronary artery bypass surgery. Several clinical reports have demonstrated depressed ventricular function in the initial hours after coronary artery bypass surgery: this dysfunction is usually resolved within 24 to 48 hours, and does not appear to be dependent upon alterations in preload, afterload, or temperature. New therapies for improving postischemic myocardial function following cardiopulmonary bypass are under investigation.

Coronary Artery Bypass↗
PubMed1994

Stunned myocardium following prolonged cardiopulmonary bypass: effect of warm versus cold cardioplegia in the canine model.

"Stunned myocardium" is defined as the prolonged but transient postischemic contractile dysfunction of viable myocardium that has been salvaged by reperfusion. This phenomenon, although first characterized in the experimental canine model of coronary artery occlusion/reperfusion, also occurs following transient global ischemia. Moreover, despite the superb cardioprotection conferred by administration of cold cardioplegia during aortic cross-clamping, stunned myocardium is a well-recognized sequela of prolonged cardiopulmonary bypass. Using the anesthetized open chest dog, we tested the concept that continuous retrograde infusion of warm blood cardioplegia would effectively prevent ischemia during prolonged aortic cross-clamping and thereby preclude the development of stunned myocardium following bypass. Thirteen dogs were placed on cardiopulmonary bypass and randomized to receive: (1) continuous retrograde administration of warm blood cardioplegia (n = 8); or (2) intermittent retrograde cold blood cardioplegia (n = 5) during a 3-hour cross-clamp period. Left ventricular (LV) systolic function (i.e., area LV ejection fraction and posterior LV free wall thickening assessed by two-dimensional echocardiography) and hemodynamic parameters were monitored at baseline and at 1 and 2 hours postbypass and, at the end of the protocol, transmural myocardial biopsies were obtained for electron microscopic analysis. All dogs in both treatment groups showed electron microscopic evidence of mild and reversible morphological injury indicative of stunned myocardium, with no difference between dogs that received warm versus cold cardioplegia. Direct comparison of LV function between the two groups was confounded by a profound decrease in afterload in dogs that received cold cardioplegia. However, incorporation of systemic vascular resistance as a covariate revealed that LV function following bypass was modestly depressed at approximately 85% of baseline values, and that continuous administration of warm cardioplegia did not prevent this hypokinesis. Thus, in our canine model: (1) morphological injury and LV dysfunction induced by 3 hours of aortic cross-clamping is subtle; and (2) continuous retrograde infusion of warm blood cardioplegia during the cross-clamp period failed to preclude myocardial stunning following prolonged cardiopulmonary bypass.

Animals↗
PubMed1994

Stretch preconditions canine myocardium.

Preconditioning is believed to be directly triggered by brief ischemia-reperfusion. However, brief ischemia results in transient dilation (or stretching) of the heart. We therefore sought to determine whether stretch per se, induced by rapid volume overload instead of brief coronary occlusion, could precondition the heart via stretch-activated ion channels. Forty-two anesthetized dogs underwent 1 h of coronary artery occlusion followed by 4.5 h of reperfusion. Before this, each dog underwent either no intervention (control) or acute volume overload. In three additional groups, Gd3+, a potent blocker of stretch-activated channels was injected as a bolus into the left atrium of each dog at the onset of the treatment period. Then the dogs underwent either acute volume overload, a 5-min episode of coronary occlusion followed by 10 min of reperfusion, or no intervention. Myocardial stretch significantly reduced infarct size after a subsequent 60-min ischemic insult. Protection afforded by stretch was completely prevented by Gd3+. Reduction in infarct size afforded by ischemic preconditioning was partially reversed by Gd3+. Gd3+ per se did not, however, alter the extent of necrosis. The present study suggests that myocardial stretch per se can precondition the canine heart, probably by activation of stretch-activated ion channels.

Animals↗
PubMed1994

Nicotine exacerbates postischemic contractile dysfunction of 'stunned' myocardium in the canine model. Possible role of free radicals.

BACKGROUND: There is no doubt that high doses of nicotine have deleterious effects on cardiovascular function. However, the effects of lower and more clinically relevant doses of nicotine have received little attention, and the consequences of nicotine in the setting of ischemia/reperfusion are virtually unknown. The first objective of this study was to determine whether nicotine, given either before or after ischemia and at a dose mimicking that absorbed by humans during inhalation of one cigarette, exacerbated contractile dysfunction of canine myocardium "stunned" by brief transient ischemia. The second aim was to provide preliminary insight into the mechanism of action of nicotine on the stunned myocardium. METHODS AND RESULTS: Anesthetized open chest dogs underwent 15 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In protocol 1, each dog was randomized to receive nicotine at 30 minutes before LAD occlusion (80 micrograms/kg dissolved in 15 mL of saline, given i.v. over 10 minutes), nicotine at 1 hour after reperfusion (80 micrograms/kg as above), or saline. Segment shortening (assessed by sonomicrometry) in both the LAD and circumflex beds, heart rate, arterial pressure, and coronary blood flow were monitored throughout the protocol, and regional myocardial blood flow (by injection of radiolabeled microspheres) was measured during LAD occlusion and at 5 minutes after nicotine/saline infusion. All groups were equally ischemic during LAD occlusion. As expected, segment shortening in the LAD bed of control animals was depressed after reperfusion, averaging 54 +/- 6% and 50 +/- 4% of baseline at 1 and 3 hours after reflow. Nicotine given before occlusion did not alter segment shortening before LAD occlusion and did not exacerbate dyskinesis during occlusion. However, segment shortening in the LAD bed recovered to only 29 +/- 9% and 22 +/- 5% of baseline at 1 and 3 hours after reperfusion (P < .01 versus corresponding control values). Furthermore, nicotine given at 1 hour after reperfusion caused a significant deterioration in segment shortening, from 47 +/- 11% immediately before infusion (P = NS versus control at 1 hour after reflow) to 7 +/- 13% at 3 hours after reperfusion (P < .01 versus 1 hour after reperfusion; P < .01 versus control at 3 hours after reflow). This dose of nicotine did not alter heart rate, arterial pressure, or blood flow; did not cause myocyte necrosis; and did not impair contractile function in the normally perfused circumflex bed. In protocol 2, all dogs received a continuous infusion of the free radical scavenging agent N-2-mercaptopropionyl glycine (MPG; 50 mg.kg-1 x h-1) beginning 45 minutes after reperfusion and, at 1 hour after reflow, received either nicotine or saline as described in protocol 1. MPG given after reperfusion did not alter contractile function in control animals. However, MPG prevented the deterioration in postischemic function observed with nicotine in protocol 1; segment shortening averaged 54 +/- 11% and 56 +/- 9% of baseline at 1 and 3 hours after reperfusion (P = NS). CONCLUSIONS: Nicotine, given before occlusion or after reflow, significantly exacerbated contractile dysfunction of post-ischemic stunned myocardium in this canine model. This exacerbated dysfunction was not a secondary consequence of unfavorable alterations in hemodynamics or coronary blood flow and may be mediated by free radicals acting on myocytes that had been reversibly injured by the brief ischemic insult.

Animals↗
PubMed1993

Cardioprotection with angiotensin-converting enzyme inhibitors: redefined for the 1990s.

The concept of "cardioprotection" with ACE inhibitors has evolved over the last decade. In the 1980s, protective benefits of ACE inhibitors in hypertension were established, regression of left ventricular hypertrophy was demonstrated, and improved ventricular function and survival in mild-to-moderate and severe congestive heart failure was documented. A further "protective" role of ACE inhibitors in coronary artery disease is emerging as more attention is focused on the concept of local tissue renin-angiotensin systems. Recent contributions to the literature describe significant benefits of ACE-inhibitor therapy in acute myocardial infarction, including suppression of ventricular arrhythmias and reduction of both early and late ventricular dilation, preservation of left ventricular function, and improved survival. All of the above effects can be considered "cardioprotective." However, as new benefits are reported in the 1990s, a broadened view of "cardiovascular protection" emerges from investigative studies in the literature. ACE inhibitors may reduce tolerance to nitrates, reduce angina in some but not all studies, and limit smooth muscle cell proliferation (and perhaps restenosis) induced by experimental balloon angioplasty. Local vascular effects may attenuate atherosclerotic changes in the arterial wall in experimental animals and may decrease the incidence of aneurysm formation in hypertensive animals. The effectiveness of ACE inhibitors in acute myocarditis, suggested by reports that captopril may reduce lesions of murine myocarditis when administered early after infection with coxsackievirus B3, requires clinical confirmation. Despite these apparently diverse "cardiovascular protective" consequences of ACE inhibitor therapy, the mechanism(s) of action of these agents remain to be elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina Pectoris↗
PubMed1993

"Cardioprotection" by ACE-inhibitors in acute myocardial ischemia and infarction?

Coronary artery occlusion results in the acute activation of the renin-angiotensin system and production of angiotensin II, a potent vasoconstrictor and positive inotropic agent. This has raised the possibility that angiotensin converting enzyme (ACE) inhibitors might be "cardioprotective" (that is, might attenuate myocardial injury, dysfunction and necrosis) in the setting of acute ischemia and infarction. Captopril, enalapril and ramipril have, in fact, been reported to acutely limit myocardial injury and necrosis in models of permanent coronary artery occlusion. The mechanisms responsible for this cardioprotection are complex, but include favorable alterations in myocardial oxygen supply/demand, and, in some instances, inhibition of bradykinin metabolism and/or increased prostaglandin synthesis. Other studies, however, have failed to document a reduction in infarct size with ACE inhibitor treatment. Results obtained in models of coronary occlusion/reperfusion have also been mixed. In models of brief transient ischemia not associated with necrosis, captopril and zofenopril have consistently been found to attenuate postischemic contractile dysfunction of the viable but "stunned" myocardium during the early hours following relief of ischemia. In contrast, there is no consensus on the effects of enalapril on the stunned myocardium: both positive and negative results have been obtained. Similar disparity has been reported in models of more prolonged ischemia/reperfusion resulting in subendocardial necrosis: some studies have reported myocardial salvage, while others have provided disturbing evidence of apparent exacerbation of myocardial necrosis with captopril and enalapril therapy. Thus, after a decade of investigative effort, the question of whether ACE inhibitors are "cardioprotective" in the setting of acute myocardial ischemia and infarction remains unresolved. Nonetheless, clinical protocols are in progress to assess the effects of early ACE inhibitor treatment in patients with acute myocardial infarction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Laser-mediated transmural myocardial channels do not salvage acutely ischemic myocardium.

OBJECTIVES: We sought to determine whether the presence of transmural laser-made channels could provide blood flow to ischemic myocardium. BACKGROUND: Laser-made transmural channels have been used in patients to restore blood flow to ischemic myocardium. Whether such channels actually relieve ischemia is unclear. We therefore tested the concept in an animal model of acute ischemia. METHODS: Eighteen dogs underwent 6 h of permanent coronary artery occlusion. At 30 min after occlusion, 8 dogs were randomized to the laser-treated group (30 to 40 transmural channels, 1 mm in diameter, were made in the cyanotic area using a holmium: yttrium-aluminum-garnet laser), and 10 were randomized to the control group (no treatment). Transmural blood flow was measured before and after treatment using radiolabeled microspheres. Regional segment shortening and myocardial lactate content were measured in four of the control and two of the laser-treated dogs. Infarct size was measured in all animals using triphenyltetrazolium chloride staining. RESULTS: Laser channels failed to increase blood flow to ischemic tissue. After laser channels were made, mean transmural flow averaged 0.10 +/- 0.03 versus 0.11 +/- 0.03 ml/min per g in treated versus control dogs, respectively. Furthermore, infarct size was similar in both groups (46 +/- 6% vs. 43 +/- 7%, respectively, of the myocardium at risk, p = NS). In addition, the presence of laser channels neither improved regional myocardial function nor enhanced washout of accumulated lactate. CONCLUSIONS: Direct laser revascularization of the heart did not provide any immediate benefit to ischemic myocardium in this canine model of coronary artery occlusion. Thus, it is doubtful that direct laser-mediated myocardial revascularization would be of immediate benefit in the treatment of patients with acute ischemia.

Acute Disease↗
PubMed1993

Oxygen radical scavenging agents as adjuvant therapy with tissue plasminogen activator in a canine model of coronary thrombolysis.

OBJECTIVES: Early thrombolysis can reduce infarct size and enhance the long term recovery of contractile function after acute myocardial infarction. These benefits of early reperfusion may be confounded, however, by platelet mediated reocclusion after initial lysis, and "reperfusion injury" mediated by oxygen derived free radicals. Superoxide dismutase (SOD)--as well as its action as a potent free radical scavenging agent--inhibits platelet aggregation in vitro. Thus our primary objectives were to determine whether SOD+catalase, given as adjuvant therapy with recombinant human tissue plasminogen activator, could inhibit platelet aggregation and thereby reduce the time to lysis and maintain arterial patency. Whether SOD+catalase enhanced myocardial salvage or improved acute recovery of contractile function in the setting of thrombosis/thrombolysis was also assessed. METHODS: Two anaesthetised open chest canine models were used: a model of thrombosis/thrombolysis and an in vivo model of platelet aggregation. In protocol I coronary thrombosis was induced by endothelial injury and injection of blood+thrombin+CaCl2. At three hours after occlusion, control animals received saline and tissue plasminogen activator and treated dogs received SOD+catalase and tissue plasminogen activator. Variables measured included coronary blood flow (for assessment of the time to lysis and incidence and duration of spontaneous reocclusion); regional myocardial blood flow; segment shortening; and infarct size. In protocol II dogs underwent endothelial injury and coronary stenosis, resulting in cyclic variations in coronary blood flow caused by formation and dislodgement of platelet thrombi. At 30 minutes after placement of the stenosis, dogs received either saline and tissue plasminogen activator or SOD+catalase and tissue plasminogen activator. Variables measured included the frequency of cyclic flow variations and the duration of occlusion per 30 minute time interval. RESULTS: SOD+catalase slightly reduced the time required to achieve reflow: time to lysis was 35(SEM 5) v 22(4) minutes for control v treated groups (p < 0.05). Protocol II showed that this accelerated time to lysis was due to acute inhibition of platelet aggregation by the scavenging agents. Despite continuous infusion however, SOD+catalase failed to maintain vessel patency in either limb of the study. In protocol I, reocclusion occurred in 90% of control dogs (with 49(8)% of the time after initial lysis spent reoccluded), v 83% in the treated group (36(12)% of the time reoccluded; NS v controls). Also, both groups remained dyskinetic after reflow: at one hour after initial lysis, segment shortening was -6(9)% v -6(20)% of baseline preocclusion values in the subset of control v treated dogs in which the left anterior descending coronary artery was patent at the time of measurement (NS). Finally, infarct size was similar in both groups, averaging 32(9)% v 38(9)% of the myocardium at risk in control v treated animals (NS). CONCLUSIONS: Although SOD+catalase acutely attenuated platelet aggregation and slightly accelerated lysis, these agents failed to limit platelet mediated rethrombosis. Furthermore, SOD+catalase did not enhance myocardial salvage and did not improve acute recovery of contractile function after thrombosis/thrombolysis. Thus SOD+catalase given as adjuvant therapy with tissue plasminogen activator did not have a substantial beneficial effect on either the efficacy of thrombolysis or on "reperfusion injury" in this canine model.

Animals↗
PubMed1993

Ischemic preconditioning and long-chain acyl carnitine in the canine heart.

BACKGROUND: This study investigated the effects of ischemic preconditioning on myocardial carnitine-linked metabolism and high-energy phosphates in the canine model of ischemia and reperfusion. METHODS: Anesthetized dogs underwent 1 hour of coronary artery occlusion and 4.5 hours of reperfusion. The dogs were randomly assigned to a control group (no intervention for 30 minutes), a preconditioned group (four repeated episodes of 3 minutes of mechanical coronary occlusion, each followed by 5 minutes of reperfusion), and a coronary cyclic flow variation (CFV) group (coronary artery stenosis and endothelial injury, resulting in an average of four episodes of platelet thrombosis and dislodgment). After completion of the protocol, ATP, creatine phosphate, and long-chain acyl carnitine concentrations were studied in both nonischemic and previously ischemic myocardium. RESULTS: In Part I of this study (Ovize et al., Circulation 1992, 85:779-789), it was reported that both mechanical occlusion and CFV before sustained occlusion resulted in a decrease in infarct size. In the present paper, we report changes in high-energy phosphates and long-chain acyl carnitine in these groups. Control, preconditioned, and CFV groups showed similar depletion in ATP content and "overshoot" in creatine phosphate stores. Control dogs exhibited a significant accumulation of long-chain acyl carnitine in the previously ischemic tissue (219 +/- 61 vs 131 +/- 38 nmoles/g wet weight in the nonischemic tissue; P < 0.05). No significant increase in long-chain acyl carnitine occurred in the mechanically preconditioned and CFV groups. CONCLUSIONS: These results indicate that brief episodes of transient ischemia before sustained coronary occlusion prevent long-chain acyl carnitine accumulation in the ischemic and reperfused canine myocardium.

Acetylcarnitine↗
PubMed1993

Regional ischemic 'preconditioning' protects remote virgin myocardium from subsequent sustained coronary occlusion.

BACKGROUND: One or more brief episodes of coronary artery occlusion protect or "precondition" the myocardium perfused by that artery from a subsequent episode of sustained ischemia. We sought to determine whether ischemic preconditioning protects only those myocytes subjected to brief coronary occlusion or whether brief occlusions in one vascular bed also limit infarct size and/or attenuate contractile dysfunction in remote virgin myocardium subjected to subsequent sustained coronary occlusion. METHODS AND RESULTS: In the preliminary limb of the study, six anesthetized dogs underwent four episodes of 5-minute circumflex branch occlusion plus 5-minute reperfusion, followed by 1 hour of sustained left anterior descending coronary artery occlusion and 4.5 hours of reflow. Subendocardial blood flow during left anterior descending coronary artery occlusion (measured by injection of radiolabeled microspheres) was 0.07 +/- 0.03 mL.min-1 x g tissue-1, similar to the value of 0.07 +/- 0.02 mL.min-1 x g-1 observed in a group of eight concurrent control dogs. However, infarct size (assessed by triphenyltetrazolium staining) in the circumflex preconditioned group averaged 4 +/- 1% of the myocardium at risk, significantly less (p < 0.05) than the value of 13 +/- 4% observed in the concurrent controls. An additional 18 dogs were then randomized to undergo either four episodes of circumflex branch occlusion (n = 8) or no intervention (n = 10) before 1 hour of left anterior descending coronary artery occlusion and 4.5 hours of reflow. Subendocardial blood flow averaged 0.08 +/- 0.02 versus 0.08 +/- 0.03 mL.min-1 x g-1 in the control versus circumflex preconditioned groups, yet infarct size was significantly smaller in circumflex preconditioned dogs than in the controls (6 +/- 2% versus 16 +/- 5% of the risk region; p < 0.05). At 4.5 hours following reperfusion, segment shortening in the left anterior descending coronary artery bed (assessed by sonomicrometry) averaged -21 +/- 19% of baseline in control animals versus 13 +/- 12% of baseline in the preconditioned group (p = NS). Circumflex preconditioning did not, however, have an independent beneficial effect on contractile function: Regression analysis revealed that the trend toward improved function in circumflex preconditioned dogs reflected the smaller infarct sizes in this group. CONCLUSIONS: Brief episodes of ischemia in one vascular bed protect remote, virgin myocardium from subsequent sustained coronary artery occlusion in this canine model. These data imply that preconditioning may be mediated by factor(s) activated, produced, or transported throughout the heart during brief ischemia/reperfusion.

Animals↗
PubMed1993

Does preconditioning protect the coronary vasculature from subsequent ischemia/reperfusion injury?

BACKGROUND: "Preconditioning" with brief episodes of coronary artery occlusion reduces infarct size caused by subsequent sustained ischemia. However, the effects of preconditioning on the coronary vasculature are poorly understood. We sought to determine whether preconditioning would attenuate "low reflow" (ie, the deterioration in resting myocardial perfusion) and blunt the loss in coronary vasodilator reserve after sustained occlusion/reperfusion in the anesthetized open-chest canine model. METHODS AND RESULTS: Thirty-two dogs underwent 1 hour of sustained left anterior descending (LAD) coronary artery occlusion and 4 hours of reperfusion. Each dog was randomly assigned to the preconditioned group (four episodes of 5 minutes of LAD occlusion plus 5 minutes of reperfusion before sustained ischemia) or control group (no intervention). Submaximal vasodilator reserve was determined by measuring the increase in CBF in response to 0.01 mg acetylcholine (an endothelium-dependent dilator) and 0.05 mg nitroglycerin (an endothelium-independent dilator); low reflow was assessed by measurement of regional myocardial blood flow at 30 minutes and 4 hours after reflow; and infarct size was delineated by triphenyltetrazolium staining. In protocol 1 (n = 14), vasodilator reserve was measured at baseline and at 30 minutes and 4 hours after reflow. There was no change in the response to acetylcholine and nitroglycerin at 30 minutes after reperfusion compared with baseline. However, all dogs exhibited a loss in vasodilator reserve during the subsequent 3.5 hours of reflow, with no difference between control and preconditioned groups. That is, in control dogs, acetylcholine increased CBF from a baseline value of 10.1 +/- 1.3 mL/min to 18.0 +/- 2.6, 18.2 +/- 2.1, and 15.4 +/- 1.7 mL/min before occlusion, 30 minutes after reflow, and 4 hours after reperfusion, respectively (P < .05 for 30 minutes vs 4 hours after reperfusion). Similarly, in the preconditioned group, acetylcholine increased CFB from a baseline value of 12.0 +/- 2.9 mL/min to 19.6 +/- 3.8, 23.6 +/- 5.3, and 15.6 +/- 3.5 mL/min, respectively (P < .01 for 30 minutes vs 4 hours after reperfusion; P = NS between groups). In addition, all dogs exhibited low reflow, with no difference between control and preconditioned groups: subendocardial blood flow deteriorated between 30 minutes and 4 hours after reflow, from 0.91 +/- 0.20 to 0.40 +/- 0.03 mL min-1 x g-1 in control animals (P = .05 for 30 minutes vs 4 hours after reperfusion) and from 1.03 +/- 0.25 to 0.35 +/- 0.02 mL.min-1 x g-1 in the preconditioned group (P < .05 for 30 minutes vs 4 hours after reperfusion). However, all dogs in protocol 1 had small infarcts (3 +/- 1% and 2 +/- 1% of the risk region in control and preconditioned groups; P = NS), suggesting that control dogs may have been "preconditioned" by the vasodilators. An additional 18 dogs were entered into protocol 2, which was identical to protocol 1 except that acetylcholine and nitroglycerin were given only after reperfusion. In this case, we observed the expected reduction in infarct size in preconditioned dogs vs control dogs (2 +/- 1% vs 11 +/- 3% of the risk region; P < .01). However, the loss in vasodilator reserve was similar to that observed in protocol 1, with no difference between groups. Subendocardial blood flow at 30 minutes after reperfusion was higher in control animals than in preconditioned dogs (1.84 +/- 0.50 vs 0.74 +/- 0.08 mL.min-1 x g-1; P < .05), but subendocardial flow then deteriorated during the subsequent 3.5 hours to a similar value in both groups (0.55 +/- 0.11 and 0.50 +/- 0.06 mL.min-1 x g-1 in control and preconditioned dogs; P < .05 vs 30 minutes after reperfusion for both groups). CONCLUSIONS: The protective effects of preconditioning do not extend to the coronary vasculature in this canine model: Preconditioning neither prevented the deterioration in resting myocardial perfusion nor blunted the loss in submaximal vasodilator reserve obs

Acetylcholine↗
PubMed1992

Reperfusion of hibernating myocardium: contractile function, high-energy phosphate content, and myocyte injury after 3 hours of sublethal ischemia and 3 hours of reperfusion in the canine model.

Hibernating myocardium has been defined as a persistent impairment of contractile function resulting from reduced coronary blood flow that can be partially or completely resolved once coronary perfusion is restored. In fact, recent clinical reports have documented a dramatic improvement in contractile function after relief of chronic sublethal ischemia. To investigate the phenomenon of sublethal ischemia followed by reperfusion, we assessed myocyte morphology, high-energy phosphate content, and regional contractile function in dogs undergoing (1) 3 hours of subtotal coronary artery occlusion (CO) and 3 hours of reflow or (2) 3 hours of total CO followed by reflow, in which myocyte viability was maintained by extensive collateral perfusion during ischemia (total CO/negligible necrosis). Data were compared with findings in a third group of dogs with total CO and low collateral blood flow during ischemia, in which large confluent infarcts developed. Endocardial blood flow averaged 30 +/- 6% (p less than 0.01) and 27 +/- 4% (p less than 0.01) of baseline preocclusion values during ischemia in the groups with subtotal CO and total CO/negligible necrosis, versus 3 +/- 1% of baseline values in dogs with total CO/confluent necrosis. Both the subtotal CO and total CO/negligible necrosis groups exhibited only mild-to-moderate reversible myocyte injury (assessed by electron microscopy) and had essentially no necrosis: infarct size was 1 +/- 1% (p less than 0.01) and 4 +/- 2% (p less than 0.01) of the risk region in the subtotal CO and total CO/negligible necrosis groups, versus 55 +/- 9% of the risk region in the total CO/confluent necrosis group. Furthermore, myocardial high-energy phosphate stores were in part preserved in all dogs that underwent sublethal ischemia: endocardial adenosine triphosphate (ATP) content was 55 +/- 11% (p less than 0.01) and 56 +/- 8% (p less than 0.01) versus 11 +/- 2% of baseline values in the subtotal CO, total CO/negligible necrosis, and total CO/confluent necrosis groups, respectively. At 3 hours post occlusion, segment shortening averaged +21 +/- 10% of baseline values in dogs with subtotal CO, (p less than 0.01 versus both total CO groups), -29 +/- 9% in dogs with total CO/negligible necrosis, and -36 +/- 13% in dogs with total CO/confluent necrosis. Reperfusion after sublethal ischemia produced an acute improvement in contractile function in both the subtotal CO and total CO/negligible necrosis groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1992

Coronary cyclic flow variations "precondition" ischemic myocardium.

BACKGROUND: Repeated brief episodes of myocardial ischemia performed by mechanical clamping of a coronary artery "precondition" the heart and reduce infarct size after a subsequent sustained ischemia. It is not known, however, whether spontaneous episodes of transient ischemia caused by formation of platelet thrombi, which may occur in unstable angina, have a similar cardioprotective effect. METHODS AND RESULTS: Therefore, our objective was to determine whether brief spontaneous thrombotic episodes of ischemia/reperfusion could limit infarct size and preserve contractile function following 60 minutes (protocol 1) or 90 minutes (protocol 2) of sustained ischemia and 4-4.5 hours of reperfusion in the canine model. Before the sustained coronary occlusion, dogs underwent a 30-minute "treatment" period consisting of: no intervention (control group), four repeated episodes of 3-minute mechanical occlusion plus 5-minute reperfusion (preconditioned group), or coronary artery stenosis and endothelial injury, resulting in a mean of four spontaneous episodes of cyclic flow variations (CFV group) caused by formation and dislodgment of platelet thrombi. In protocol 1 (60-minute sustained ischemia plus 4.5-hour reperfusion), infarct size was significantly smaller in both the preconditioned and CFV groups compared with controls (3.5 +/- 1.4%,* 3.4 +/- 2.1%,* and 9.9 +/- 2.7% of the myocardium at risk, respectively; *p less than 0.05 versus control). In contrast, neither preconditioning nor CFV preserved contractile function: Segment shortening during sustained occlusion was equally depressed at -15% to -20% of baseline values among the three groups and equally stunned at +12% to +18% of baseline during the 4.5 hours of reflow. In protocol 2 (90-minute sustained ischemia plus 4-hour reperfusion), only CFV continued to exert a cardioprotective effect: Infarct size averaged 15.0 +/- 4.1%, 7.4 +/- 2.5%,* and 16.5 +/- 4.4% of the region at risk in the preconditioned, CFV, and control groups, respectively (*p less than 0.05 versus control). Contractile function, however, was similar among all three groups both during 90 minutes of sustained occlusion and throughout 4 hours of reperfusion. CONCLUSIONS: We therefore conclude that repeated coronary thrombus formation preconditions the ischemic myocardium: In fact, in contrast to mechanical preconditioning, cardioprotection provided by CFV persisted following 90 minutes of sustained coronary occlusion. However, preconditioning by thrombotic or mechanical occlusion neither preserved myocardial contractile function during sustained coronary occlusion nor prevented stunning after reperfusion. These data raise the possibility that clinical episodes of unstable angina prior to acute myocardial infarction may precondition the ischemic myocardium.

Animals↗