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K Przyklenk

Publications and source records attributed to K Przyklenk.

At least 73 records · Page 4Linked to original sources
PubMed1992

Preconditioning does not attenuate myocardial stunning.

BACKGROUND: Despite numerous reports that one or more episodes of brief coronary artery occlusion preconditions the myocardium and dramatically reduces myocardial infarct size produced by a subsequent prolonged ischemia, we recently demonstrated that preconditioning does not attenuate contractile dysfunction in the peri-infarct tissue. However, the specific effects of preconditioning on myocardium in which wall motion has not been compromised by the preconditioning regimen per se and is further submitted to a short ischemic insult (that is, not confounded by necrosis) remain unknown. METHODS AND RESULTS: We addressed these issues in the canine model of myocardial stunning. Eighteen anesthetized dogs underwent 15 minutes of coronary occlusion followed by 3 hours of reperfusion. Before the 15-minute coronary occlusion, each dog received one of three treatments: no intervention (control group, n = 6), one episode of 5-minute coronary occlusion/5-minute reperfusion (PC5 group, n = 6), or one episode of 2.5-minute coronary occlusion/5-minute reperfusion (PC2.5 group, n = 6). Segment shortening (SS) in the ischemic/reperfused midmyocardium was monitored by sonomicrometry, and myocardial blood flow was assessed by injection of radiolabeled microspheres. All three groups were equally ischemic during the 15-minute coronary occlusion: Midmyocardial blood flow averaged 0.05 +/- 0.02, 0.07 +/- 0.04, and 0.08 +/- 0.03 ml/min/g in control, PC2.5, and PC5 groups, respectively. Before the 15-minute coronary occlusion, PC5 dogs exhibited significant stunning (SS = 55% baseline; p less than 0.01 versus control), whereas PC2.5 dogs did not (SS = 91% baseline; p = NS versus control). However, segment shortening during the subsequent 15-minute coronary occlusion was equally depressed at -25% to -42% of baseline values among the three groups. Furthermore, all three groups demonstrated a similar degree of stunning after reperfusion: SS at 3 hours after reflow averaged 24 +/- 12%, 34 +/- 16%, and 48 +/- 12% of baseline in control, PC2.5, and PC5 groups, respectively (p = NS). The degree of recovery of function after reperfusion correlated with the amount of midmyocardial blood flow during coronary artery occlusion. However, this relation was not different among the three groups: Specifically, for any given collateral flow during ischemia, preconditioning did not reduce the degree of stunning. CONCLUSIONS: Preconditioning neither preserves contractile function during a reversible ischemic insult nor prevents myocardial stunning during the initial hours of reflow.

Adenosine Triphosphate↗
PubMed1992

Partial coronary stenosis is sufficient and complete reperfusion is mandatory for preconditioning the canine heart.

Repeated brief episodes of total coronary artery occlusion (i.e., severe ischemia), each separated by brief periods of reperfusion, reduce infarct size after a subsequent sustained ischemia. The importance of the intensity of ischemia during these coronary artery occlusions and the role of the following transient reflow are poorly understood. Therefore, our objective was to determine whether moderate preconditioning ischemia induced by partial coronary artery stenosis (reducing coronary flow to approximately 50% of its baseline values), with or without a brief period of total reperfusion, could precondition the canine myocardium. Dogs were randomized to receive one of three preconditioning "treatments": the R(-) group underwent 15 minutes of partial coronary stenosis without subsequent brief reperfusion (n = 8); the R(+) group underwent 15 minutes of partial coronary stenosis followed by 10 minutes of full reflow (n = 8); and the control group underwent no intervention (n = 8). All dogs then underwent 1 hour of total coronary artery occlusion and 4.5 hours of reperfusion. Both treated groups were equally and moderately ischemic during partial stenosis: myocardial blood flow in the inner two thirds of the left ventricular wall averaged 0.25 +/- 0.05 and 0.31 +/- 0.07 ml/min per gram in the R(-) and R(+) groups, respectively (p = NS). Furthermore, all three groups were equally and severely ischemic during sustained total occlusion: myocardial blood flow in the inner two thirds of the left ventricular wall averaged 0.06 +/- 0.05, 0.05 +/- 0.03, and 0.07 +/- 0.03 ml/min/g in control, R(-), and R(+) groups, respectively (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1991

Calcium antagonists and stunned myocardium: importance for clinicians?

Experimental evidence indicates that calcium antagonists enhance the recovery of contractile function in canine myocardium stunned by a brief, 15-minute episode of transient coronary artery occlusion. In fact, both nifedipine and verapamil have been shown to improve systolic contraction, even when treatment was delayed, that is, when the agents were administered 30 minutes after reperfusion. The beneficial effects of delayed treatment were not a consequence of myocardial high-energy phosphate preservation. Furthermore, as low-dose intracoronary nifedipine enhanced the recovery of function in the absence of systemic hemodynamic or coronary vasodilatory effects, the improved function associated with delayed administration of calcium antagonists could not be attributed solely to afterload reduction or increased coronary blood flow. These data suggest that calcium-channel blockers exert a direct effect on the previously ischemic tissue, perhaps by subtle modulation of calcium transport or flux within the stunned myocytes. Although the precise mechanism of action of these agents remain unresolved, these intriguing experimental results raise the possibility that calcium antagonists may provide a clinically useful means of attenuating postischemic dysfunction of viable myocardium salvaged by thrombolysis, angioplasty, or cardiopulmonary bypass. The potential role of calcium-channel blockers in these clinical instances of stunned myocardium awaits further evaluation.

Animals↗
PubMed1991

Angiotensin converting enzyme inhibitors improve contractile function of stunned myocardium by different mechanisms of action.

Angiotensin converting enzyme (ACE) inhibitors enhance contractile function of myocardium "stunned" by a brief episode of coronary artery occlusion, yet their mechanism(s) of action remain unresolved. In addition to possible hemodynamic effects, ACE inhibitors may stimulate the synthesis of cardioprotective prostaglandins. Furthermore, the beneficial effects of ACE inhibitors that contain a sulfhydryl group may be due in part to the ability of thiol compounds to act as nonspecific antioxidants or direct scavengers of cytotoxic oxygen-derived free radicals. To investigate this question we compared the effects of (1) the sulfhydryl-containing ACE inhibitor zofenopril, (2) the sulfhydryl-containing stereoisomer of captopril (SQ 14,534) with essentially no ACE inhibitor properties, (3) the nonsulfhydryl-containing ACE inhibitor enalaprilat, and (4) solvent alone, given at the time of reperfusion, on recovery of contractile function after 15 minutes of coronary occlusion in the anesthetized open-chest dog. Segment shortening in control animals remained depressed or "stunned" after reperfusion, recovering to only -5 +/- 12% of baseline preocclusion values at 3 hours after reperfusion. In contrast, all three treatment agents attenuated postischemic dysfunction: segment shortening was restored to 33 +/- 12%, 54 +/- 6%, and 83 +/- 5% of baseline values at 3 hours after reflow in dogs treated with SQ 14,534 (p less than 0.05), zofenopril (p less than 0.01), and enalaprilat (p less than 0.01), respectively (all vs control value). These improvements in segment shortening did not appear to be the result of altered oxygen supply or demand after reperfusion, inasmuch as no significant differences in systemic hemodynamic parameters or myocardial blood flow were observed among the groups. In the second phase of the study, we found that the improved contractile function associated with enalaprilat treatment could largely be reversed by infusion of the potent cyclooxygenase inhibitor indomethacin: segment shortening was reduced from 69 +/- 12% at 2 hours after treatment/reperfusion to 38 +/- 12% at 2 hours after indomethacin infusion (p less than 0.01 vs 2 hours after reperfusion). Infusion of indomethacin had no effect, however, on the improved contractile function associated with zofenopril treatment. We therefore conclude that sulfhydryl- versus nonsulfhydryl-containing agents enhance contractile function of stunned myocardium by different mechanisms of action: enalaprilat attenuates postischemic dysfunction at least in part by a prostaglandin-mediated mechanism, whereas the salutary effects of zofenopril and SQ 14,534 may be due in part to the antioxidant properties of the sulfhydryl moiety.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Stunned myocardium and myocardial collagen damage: differential effects of single and repeated occlusions.

It has been suggested that collagen loss and damage is responsible for the dysfunction seen in stunned myocardium. To test this hypothesis we compared collagen in canine hearts stunned by repeated occlusion with collagen in hearts stunned by a single occlusion. Regional contractile function was equally depressed in both groups: segment shortening at 1 hour after reperfusion averaged 37% +/- 9% versus 32% +/- 9% of preocclusion values in repeated and single occlusion models, respectively. Midmyocardial collagen content was not different in either single occlusion (10.5% +/- 0.4%) or repeated occlusion models (9.5% +/- 0.7%) when compared with nonischemic hearts (8.5 +/- 0.8%). Collagen damage, which was revealed with polarized light microscopy, was seen in 5 of 6 dogs after repeated occlusion but was not apparent after a single occlusion. Thus although both models of stunned myocardium produce similar dysfunction, there was no apparent collagen loss. Furthermore, collagen damage was only seen after repeated occlusion. Therefore it appears unlikely that collagen damage is a primary mechanism of stunned myocardium.

Animals↗
PubMed1991

Pretreatment with the iron chelator desferrioxamine fails to provide sustained protection against myocardial ischaemia-reperfusion injury.

STUDY OBJECTIVE: The aim was to determine whether the potent iron chelator desferrioxamine, previously shown by our laboratory and others to cause acute limitation of infarct size, would provide sustained protection against myocardial ischaemia-reperfusion injury. DESIGN: Anaesthetised dogs underwent a 2 h transient coronary artery occlusion. After surgical preparation, each dog was randomised into one of two groups receiving either desferrioxamine or equivalent infusion of saline. Infusion of desferrioxamine was initiated 30 min before occlusion at an initial dose of 10 mg.kg-1 for the first hour of the protocol, followed by a maintenance dose of 1.5 mg.kg-1.h-1 throughout the remainder of the ischaemic period and the initial 4 h of reperfusion. The animals were reanaesthetised the following day and killed 20-24 h following reperfusion. Variables measured included heart rate and arterial pressures; regional myocardial blood flow; urinary iron content; and infarct size. In addition, % wall thickening in the ischaemic-reperfused myocardium was assessed by echocardiography in a limited number of animals. EXPERIMENTAL MATERIAL: 12 mongrel dogs weighing 22(SEM 4) kg were used, n = 6 in each group. MEASUREMENTS AND MAIN RESULTS: Both groups were equally and severely ischaemic during coronary artery occlusion. Desferrioxamine caused a modest and transient reduction in mean arterial pressure during the ischaemic episode, but had no effect on heart rate or myocardial blood flow. As expected, urinary iron content was significantly higher in treated animals v controls, at 465(SEM 107) v 55(23) micrograms, p less than 0.01, indicating that desferrioxamine effectively chelated free iron. However, it failed to exert a significant cardioprotective effect: infarct size did not differ between control and treated groups [54(4)% v 58(5)% of the myocardium at risk], and wall thickening was similar throughout occlusion and reperfusion in control and desferrioxamine treated animals. CONCLUSIONS: Despite substantial reduction in infarct size previously observed at 4 h following reflow with the same dose and regimen of desferrioxamine treatment, results of the present study indicate that desferrioxamine did not provide sustained protection against myocardial ischaemia-reperfusion injury. We therefore conclude that desferrioxamine delays--but does not prevent--myocyte necrosis in this canine model.

Animals↗
PubMed1991

Stunned and hibernating myocardium.

Myocardium that is not functioning may be dead (infarct or scar), viable but stunned (postischemic ventricular dysfunction), viable but hibernating (chronic low flow state), or acutely ischemic. Stunned myocardium has clearly been documented (a) in experimental studies of brief coronary artery occlusion followed by reperfusion, and (b) in myocardial infarct models in which early reperfusion salvages viable tissue. Recent clinical studies have confirmed the existence of stunned myocardium in humans. Evidence supporting the concept of hibernating myocardium comes from clinical studies in which patients with chronic low flow ischemia exhibit improvement in left ventricular function (sometimes immediately) following revascularization.

Animals↗
PubMed1991

Calcium antagonists and the stunned myocardium.

"Stunned myocardium" is defined as the prolonged but transient contractile dysfunction of viable myocardium salvaged by reperfusion. For example, a brief 15-min episode of coronary artery occlusion does not result in myocyte necrosis, yet contractile function of the previously ischemic tissue remains profoundly depressed at 0-30% of baseline values for hours to days following reflow. This phenomenon, first characterized in the experimental canine model, has more recently been documented in clinical instances of angina, following cardiac surgery, after angioplasty, and following successful reperfusion for the treatment of acute myocardial infarction. Considerable evidence indicates that calcium antagonists administered prior to coronary occlusion attenuate postischemic stunning in the canine model: verapamil, diltiazem, and amlodipine have been shown to restore contractile function to 50-100% of baseline values during the initial hours following relief of ischemia. Furthermore, both verapamil and nifedipine improved systolic contraction of stunned myocardium even when treatment was "delayed"--i.e., when the agents were administered 30 min after reflow had been established. This improved recovery of contractile function associated with calcium antagonist treatment may be due in part to the well-documented afterload reducing and coronary vasodilatory properties of these agents. However, as low doses of intracoronary nifedipine infused after reperfusion restored systolic contraction to 75-90% of baseline values in the absence of afterload reduction or increases in coronary blood flow, these data suggest that calcium antagonists may act in part by favorably modulating calcium flux within the stunned, previously ischemic myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Progress in cardioprotection: the role of calcium antagonists.

Calcium antagonists are now widely used for the treatment of clinical hypertension and angina pectoris. They are efficacious for the treatment of vasospastic, fixed atherosclerotic and mixed angina; they reduce the incidence of silent ischemia; and they have been shown to reduce postmyocardial infarct angina. Experimental data suggest that they may have certain cardioprotective properties in cases of acute myocardial ischemia and infarction, stunned myocardium, diastolic dysfunction, left ventricular hypertrophy and atherosclerosis. Moreover, they have been shown to improve exercise performance, as well as the diastolic abnormalities in patients with hypertrophic cardiomyopathy. In animals, they may delay or reduce the extent of myocardial necrosis after coronary occlusion or coronary occlusion followed by reperfusion, and in low doses that do not alter the hemodynamic profile, they have been shown to enhance the return of ventricular function in animals with stunned myocardium. However, the early first-generation calcium antagonists (nifedipine, verapamil, diltiazem) have not been shown to reduce myocardial infarct size or to enhance survival in patients with acute myocardial infarction. There now are clinical studies that suggest that, unlike beta blockers or nitrates, nifedipine may slow the development of atherosclerotic progression in humans over a 2-year period, and it seems likely that in the 1990s there will be further expansion of the use of calcium antagonists for not only angina and hypertension but also for aspects of cardioprotection. That calcium antagonists may delay, prevent or possibly regress atherosclerotic lesions is an exciting possibility.

Amlodipine↗
PubMed1990

In vivo infusion of oxygen free radical substrates causes myocardial systolic, but not diastolic dysfunction.

Contractile dysfunction of viable, previously ischemic stunned myocardium is thought to be due to reactive oxygen species generated during ischemia/reperfusion. Direct in vivo evidence that oxidants cause systolic or diastolic dysfunction of viable myocardium has, however, been lacking. We sought to determine whether in vivo exposure of canine myocardium to exogenously generated reactive oxygen species could--in the absence of myocardial ischemia or necrosis--"mimic" the depressed systolic contractile function, paradoxical contraction during early diastole, and prolonged diastolic relaxation time characteristic of stunned myocardium. Anesthetized open-chest dogs were randomly assigned to receive either (1) the free radical generating substrates xanthine oxidase + purine + iron-saturated transferrin or (2) saline, infused directly into an anterior coronary vein. Infusion of free radical substrates did not cause ischemia: regional myocardial blood flow and myocardial high-energy phosphate stores were normal in both groups. Furthermore, infusion of xanthine oxidase + purine + transferrin was not associated with histologic or electron microscopic evidence of myocyte injury or death in this model. Xanthine oxidase + purine + transferrin did, however, produce marked abnormalities in regional systolic contractile function; at 2 hours after the onset of infusion, segment shortening (assessed by sonomicrometry) in the perfused region of the heart averaged 62 +/- 5% of baseline, preinfusion values in animals infused with free radical substrates versus 113 +/- 8% of baseline values in saline-administered control dogs (p less than 0.004). This systolic dysfunction was effectively reversed by administration of the free radical scavenging agents superoxide dismutase + catalase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Cardioprotective effects of captopril in myocardial ischaemia, ischaemia/reperfusion and infarction.

Several experimental studies have suggested that the sulphydryl-containing angiotensin-converting enzyme inhibitor, captopril, has cardioprotective effects in the setting of acute myocardial ischaemia, ischaemia/reperfusion and infarction. We have observed that captopril can reduce the degree of dilatation and early functional myocardial infarct expansion produced by 3 h of permanent coronary artery occlusion in anaesthetized, open-chest dogs. In addition, captopril has been shown to limit experimental infarct size, reduce the incidence of reperfusion arrhythmias, and improve contractile function of stunned myocardium. When administered chronically after myocardial infarction, both experimental and clinical evidence suggests that captopril reduces left ventricular dilatation. Captopril is currently being tested in large clinical trials as adjuvant therapy to thrombolysis.

Animals↗
PubMed1989

What factors predict recovery of contractile function in the canine model of the stunned myocardium?

Recovery of contractile function of myocardium stunned by a brief, transient period of regional ischemia is highly variable. In our experience, segment shortening (an index of regional systolic contractile function) assessed during the initial hours after a 15-minute period of coronary artery occlusion in anesthetized open-chest dogs ranged from -84 to +99% of normal preocclusion values. In this retrospective study, regression analysis was used to assess the effects of various parameters on segment shortening 2 hours after reperfusion. Parameters assessed included regional myocardial blood flow both during occlusion and after reperfusion, high-energy phosphate content of previously ischemic tissue, systemic hemodynamic parameters (heart rate, mean arterial pressure and double product), occluded bed size and segment shortening measured during coronary artery occlusion. Recovery of systolic contractile function was not influenced by the degree of ischemia during coronary artery occlusion, myocardial blood flow after reperfusion, high-energy phosphate content, hemodynamic parameters or occluded bed size (correlation coefficients, r, ranged from 0.001 to 0.37 [p = not significant]). Only the degree of dyskinesia/hypokinesia exhibited during coronary occlusion significantly and reliably predicted recovery of segment shortening measured 2 hours after reflow (r = 0.70, p less than 0.001). Thus, recovery of systolic contractile function in the anesthetized canine model of the stunned myocardium is determined primarily by the degree of dysfunction exhibited during the preceding period of ischemia.

Adenosine Triphosphate↗
PubMed1989

Altered myocardial states. The stunned and hibernating myocardium.

There are several potential outcomes of myocardial ischemia. When ischemia is severe and prolonged, myocyte cell death occurs and there is no recovery of contractile function of these cells. When myocardial ischemia is less severe but still prolonged, myocytes may remain viable but exhibit depressed contractile function, which may be a protective mechanism whereby these cells attempt to reduce their oxygen demand in the setting of reduced oxygen supply. The resultant chronic left ventricular dysfunction has been termed "hibernating myocardium." Finally, myocardial ischemia may be reversed with coronary artery reperfusion resulting in salvage of the myocytes. However, the viable myocardium may demonstrate relatively prolonged but transient postischemic contractile dysfunction, the situation termed "stunned myocardium." The concepts of stunned myocardium are reviewed as they apply to both coronary reperfusion during evolving acute myocardial infarction, as well as brief periods of ischemia that may occur during angina pectoris, or coronary vasospasm, or both. The concept of hibernating myocardium is reviewed as it applies to left ventricular function prior to and after coronary artery bypass surgery.

Coronary Circulation↗
PubMed1989

Is "stunned myocardium" a protective mechanism? Effect of acute recruitment and acute beta-blockade on recovery of contractile function and high-energy phosphate stores at 1 day post-reperfusion.

There is little doubt that the "stunned myocardium" is amenable to therapeutic intervention, as a host of diverse pharmacologic agents have all been shown to improve short-term contractile function of viable, previously ischemic myocardium. However, few studies have addressed the question: Should the stunned myocardium be forced to contract? If the stunned myocardium is a protective mechanism, then acute recruitment could have later deleterious consequences on recovery of contractile function and high-energy phosphate stores. Conversely, acutely "resting" the heart (i.e. by beta-adrenergic blockade) could conceivably enhance or accelerate recovery of the stunned, postischemic tissue. We therefore sought to assess the immediate and longer-term effects of acute recruitment and acute beta-blockade on regional wall thickening (WT: using two-dimensional echocardiography) and adenosine triphosphate (ATP) content in the canine model of the stunned myocardium. Anesthetized open-chest dogs underwent 15 minutes of transient coronary artery occlusion. At 30 minutes following reperfusion, the dogs acutely received either: the ultrashort-acting beta-blocker esmolol, the afterload reducing and cardiostimulatory agent hydralazine, or saline. As anticipated, hydralazine enhanced contractile function of the stunned tissue in the short term: WT at 2 hours after treatment was 53.7 +/- 6.9% versus 7.1 +/- 6.5% in treated versus saline controls (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1989

Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic "stunned" myocardium.

Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged by reperfusion ("stunned myocardium") may be a consequence of abnormal calcium flux within the previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile function of stunned postischemic tissue, but it is not certain whether these improvements in function are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine, given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized open chest dogs subjected to 15 min of transient coronary artery occlusion. As anticipated, intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned, previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged 102 +/- 8% versus 26 +/- 11% of baseline at 2 h after treatment in treated versus control dogs, respectively (p less than 0.003). Low dose intracoronary infusion of nifedipine did not alter hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 +/- 9% versus 37 +/- 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion [that is, pretreatment], respectively; p less than 0.03). These data indicate that the calcium channel blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of postischemic stunned myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗