Restoration Of Coronary Blood Flow Research Articles

Amelioration of microvascular myocardial ischemia by gene transfer of vascular endothelial growth factor in rabbits

Objectives: Restoration of coronary blood flow by angiogenesis may offer a new approach to intractable ischemic heart disease. In the present study, we investigated the angiogenic effects of gene transfer of vascular endothelial growth factor 165 on microvascular myocardial ischemia. Methods: A rabbit model of microvascular myocardial ischemia was created by plugging coronary microvessels with microspheres (15 μm in diameter, 2.8 × 105/kg, n = 29). Gene transfer was performed by semi-selective intracoronary injection of recombinant adenovirus expressing vascular endothelial growth factor 165 forty minutes after microsphere injection (n = 9). Results: Microsphere injection reduced myocardial perfusion (78% ± 9% of baseline tissue flow) and diminished myocardial contraction (61% ± 12% of the baseline ejection fraction) and cardiac performance (elevated left ventricular end-diastolic pressure and decreased systemic flow) in the acute phase. At 17 ± 3 days, gene transfer of vascular endothelial growth factor 165 had had the following effects: (1) promoted coronary angiogenesis as evidenced by myocardial flow above the baseline (121% ± 24%), (2) increased vascular density revealed by synchrotron radiation microangiography and histologic analysis, (3) ameliorated the degree of myocardial ischemia as evidenced by myocardial lactate content and the extent of histologic necrosis, and (4) restored heart function as evidenced by increased ejection fraction (95% ± 10%), reduced left ventricular end-diastolic pressure, and restored body weight. Conclusions: In vivo vascular endothelial growth factor 165 gene transfer promoted angiogenesis and was an effective approach to treating microvascular myocardial ischemia. (J Thorac Cardiovasc Surg 2000;120:720-8)

The use of glycoprotein IIb/IIIa inhibitor therapy in acute ST-segment elevation myocardial infarction: current practice and future trends

The goal of therapy in acute myocardial infarction is complete and timely restoration of coronary blood flow. Current strategies for reperfusion fail to achieve ideal results and resolution of ischemia in all patients. The platelet plays a pivotal role in the pathophysiology of an acute myocardial infarction, and antiplatelet therapy has been shown to improve clinical outcomes. The final common pathway for platelet activation and aggregation in acute myocardial infarction is the activation of the glycoprotein (GP) IIb/IIIa receptor. Newer reperfusion strategies target the GP IIb/IIIa receptor, thereby preventing the prothrombotic effects of platelets in an acute myocardial infarction. In the past decade, several strategies targeting the use of GP IIb/IIIa inhibitors have been evaluated. GP IIb/IIIa inhibitors have been shown to improve angiographic Thrombolysis in Myocardial Infarction (TIMI) 3 flow rates when used as reperfusion therapy given with heparin and aspirin as compared with heparin and aspirin alone. When GP IIb/IIIa inhibitors are used with full-dose fibrinolytics, early studies have suggested a trend toward more rapid and more complete reperfusion in an acute myocardial infarction. Later trials have examined the use of GP IIb/IIIa inhibitors in conjunction with reduced-dose fibrinolytics. Results from TIMI 14 and Global Use of Strategies to Open occluded arteries–IV pilot trials support the use of combination therapy with reduced- dose fibrinolytics and the GP IIb/IIIa inhibitor abciximab. Given the promising role of GP IIb/IIIa inhibitor therapy in acute myocardial infarction, investigators questioned the need for concomitant antithrombin therapy. However, data from several investigations suggest that antithrombin therapy is required when GP IIb/IIIa inhibitors are used with fibrinolytics, although it appears that the dose of heparin may be reduced. Finally, recent investigations have addressed the safety and efficacy of facilitated early percutaneous intervention. In this strategy, patients presenting with an acute myocardial infarction are treated with reduced-dose fibrinolytics and GP IIb/IIIa inhibitors and are taken to the interventional cardiac catheterization laboratory within the first 60 minutes of therapy.

Ischemic preconditioning, myocardial stunning and anesthesia

Brief periods of ischemia have been shown to protect the heart against a subsequent prolonged ischemic insult, a phenomenon known as ischemic preconditioning. The protective effects of preconditioning markedly reduce myocardial ischemic injury in vivo. Volatile anesthetics have been shown to protect myocardium against infarction by a mechanism similar to that of ischemic preconditioning. Contractile dysfunction occurs after a brief period of myocardial ischemia, despite restoration of coronary blood flow in the absence of tissue necrosis. This process is known as myocardial stunning and has important clinical ramifications. Evidence indicates that adenosine triphosphate-regulated potassium channel function plays a central role in ischemic preconditioning, stunned myocardium, and in anesthetic-induced protection against ischemic injury.

Surgical angioplasty of left main coronary stenosis complicating supravalvular aortic stenosis

We successfully treated obstruction of the main coronary artery, not aortic valve leaflet adhesion to the intimal shelf, complicating supravalvular aortic stenosis by modifying the Brom aortoplasty. An autologous pericardial patch was used to enlarge the left main coronary artery as well as the stenotic aorta. This modification allows simple and effective restoration of coronary blood flow, while maintaining the Brom procedure’s merit of achieving anatomic geometry of the aortic root in such patients.

Thrombolysis in accident and emergency: The exception not the rule. Are we denying patients lifesaving treatment?

A recent report by Hood et al. (1998) that thrombolytic therapy was routinely available in only 35% UK Accident and Emergency (A&E) departments, raises some important issues about the role of A&E staff in the management of patients with acute myocardial infarction. Acute myocardial infarction is a common reason for emergency admission to hospital, and is associated with a considerable mortality. While most fatal events occur in the community, presumably because of fatal arrhythrnia, those patients reaching hospital alive have improved outcome if there is prompt restoration of coronary blood flow, usually through the administration of a thrombolytic agent. Moreover, the early mortality benefit appears to be maintained at 10-year follow-up (Baigent et al. 1998). That thrombolytic therapy is a time dependent intervention, more effective when given within the first 6 hours from symptom onset, and even more effective when administered within the first hour or two (Boersma et al. 1996) is well established. National guidelines recommend that suitable patients should receive treatment within 30 minutes of hospital arrival (the 'door to needle' time) (de Bono & Hopkins 1994), with more recent opinion suggesting that this target could be reduced to 20 minutes in well organized centres (European Society of Cardiology 1996). The lifesaving potential of this treatment is such that patients requiring thrombolytic treatment should probably be afforded the same priority as patients in cardiac arrest. Would A&E nurses accept the transfer of patients in cardiac arrest to the cardiac care unit (CCU) before definitive treatment was commenced? Of course not. That the majority of A&E departments do not provide thrombolysis was met with frank disbelief by an American colleague with whom this author recently discussed the Hood et al. (1998) paper. Many factors delay the administration of thrombolytic therapy, not least the actions of patients, carets and pro-hospital health professionals. Birkhead (1992) reported that the major component of delay in a six-centre survey occurred before the patient reached hospital. The focus of this paper, however, is on those delays occurring once the patient enters the hospital system. These are best described using the '4Ds' model developed in the USA (National Heart Attack Alert Program Co-ordinating Committee 1994) and have been adapted for use in the UK by Quinn & Thompson (1995). The 4Ds represent door (triage), data (time to first ECG recording), decision (to initiate thrombolytic therapy) and drug (the overall 'door to needle' time).

The Restoration of Coronary Blood Flow in Acute Myocardial Infarction

When an acute coronary syndrome degenerates into a myocardial infarction the centerpiece of therapy is the normalization of myocardial blood flow to the extent that it can be achieved in the shortest interval possible after the onset of symptoms. A variety of strategies including mechanical intervention have been used to achieve this goal, but the benchmark therapy to which all other therapeutic alternatives must be compared involves the use of thrombolytic agents. However, given the availability of catheter laboratories and interventional expertise, mechanical reperfusion appears to be at least as good and probably better than thrombolytic therapy. Because of the universal access to thrombolytic therapy, certain clinical issues must be underscored. More important than pursuing the ideal thrombolytic agent is the administration of thrombolytic therapy at the earliest possible juncture after the onset of symptoms heralding myocardial infarction. Adjunctive therapy includes aspirin and intravenous heparin. Altering platelet activity by glycoprotein IIb/IIIa receptor blockers holds enormous promise for thrombolytic therapy and PTCA, but as yet enjoys limited availability on a global scale.

Guidelines to reducing delays in administration of thrombolytic therapy in acute myocardial infarction.

The thrombotic coronary accident that triggers a myocardial infarction initiates a 'wavefront' of ischaemic cell death that can be aborted by timely restoration of blood flow. Myocardium destined for necrosis can be salvaged by quick lysis of the culprit clot to restore perfusion, reduce infarct size and save lives. While a number of useful thrombolytic regimens have been investigated, the greatest barrier to optimising efficacy is reducing the delay between the onset of symptoms and administration of thrombolytic therapy. Clinical experience has confirmed laboratory evidence that prompt restoration of coronary blood flow can salvage more than 50% of ischaemic myocardium if achieved within 2 hours. However, after 6 hours of sustained ischaemia, the opportunity to achieve meaningful salvage is largely lost. Analysis of pooled data estimates that for each hour of delay 1.6 fewer lives are saved per 1000 patients treated. Other investigators have estimated 60 to 80 lives saved per 1000 patients treated within 1 hour of symptom onset. More realistically, the time from symptom onset to treatment averages 2.5 to 5 hours in various studies. Reluctance to seek medical help results in a delay of more than 4 hours in at least 40% of patients. There may be some benefits of late, time-independent reperfusion from 12 to 24 hours after symptoms. Some hibernating myocardium may be salvaged resulting in less adverse late ventricular remodelling, reduced infarction expansion and improved electrical stability. Barriers to timely thrombolytic treatment may be classified as presentation delay or treatment delay. Strategies to optimise timely treatment have included pre-hospital administration of thrombolytics. This achieves greatest benefit when used in a more rural setting where transportation times tend to be longer. In this setting, as much as 140 minutes has been shaved off the symptom-to-needle time with a 50% reduction in 3-month mortality sustained as a 30% reduction in 5-year mortality. Most hospitals can improve their treatment (door-to-needle) time by focusing on chronic sources of delay. An emergency room culture of quick, coordinated response to chest pain must involve registration clerks, triage nurses, ECG technicians and emergency physicians. The authority to decide thrombolytic therapy must reside with the primary care physicians in any emergency room that encounters an acute infarction. The profound, life-saving benefits of thrombolytic therapy when used in a timely way should evoke a new sense of urgency in medical personnel when encountering the individual with a potential myocardial infarction.

Prehospital Thrombolysis in Acute Myocardial Infarction Salvages Myocardium

Early thrombolysis can be given at home, by a medical intensive care unit ambulance team, in the emergency room, or in the coronary care unit. Thrombolysis should be given very early (<2 or 4 hours) and reestablish normal or near normal coronary blood flow. Methods of management include home monitoring of high risk patients with a transtelephonic 12‐lead monitor ECG, the management of the patient at home by a trained GP, physician, or medical technician controlled intensive care ambulance team, or a rapid “door to needle” time in the emergency room. Each of these systems requires patient and physician reeducation, to make each group aware of the advantages of early and complete revascularization. An alternative fast track can be provided by immediate percutaneous transluminal coronary angioplasty if the hospital can be prewarned by the physician outside. This article reviews the current published literature and also our experience in 760 patients in Jerusalem. Infarct size, complication rate, and long‐term prognosis is related to early complete restoration of coronary blood flow.

Short-term low dose intracoronary diltiazem administered at the onset of reperfusion reduces myocardial infarct size

Background: Currently, controversy exists regarding the use of calcium-channel blockers in the treatment of acute myocardial infarction (AMI), due to apparent conflicting results from clinical trials and animal models. One hypothesis to explain such a discrepancy proposes that the timing and duration of drug administration might influence its cardioprotective effect. Pretreatment with calcium-channel blockers or their administration during coronary artery occlusion is associated with the diminished infarct size in animal models. While verapamil failed to reduce infarct size when the drug was given at the onset of reperfusion, similar effects of low dose diltiazem are not known. Methods and Results: This experiment evaluated the effect of intracoronary short term low dose diltiazem administration given immediately with postischemic myocardial reperfusion. Yorkshire swine underwent thoracotomy and 50 min of LAD occlusion, followed by 3 h of reperfusion. In the first group, diltiazem (2.5 mg diluted in 60 cc saline) was infused into the left anterior descending (LAD) over 12 min, beginning with the onset of reperfusion ( n=8). In the second group, animals received saline instead of diltiazem and served as controls ( n=6). Infarct size was 0.13±0.06 g/kg of body weight for diltiazem group, and 0.42±0.04 g/kg for controls ( P=0.01). Conclusions: Short-term low dose diltiazem delivered exclusively during early reperfusion can significantly diminish infarct size in swine. Local intracoronary diltiazem may be valuable adjunct in patients subject to myocardial ischemia/reperfusion during coronary artery bypass grafting, primary angioplasty for AMI, or thrombolysis for AMI if given immediately after restoration of coronary blood flow.

Management of acute myocardial infarction: Evaluating the past, practicing in the present, elaborating the future

The management of acute myocardial infarction initially focused on treatment and/or prevention of complications. In the prethrombolytic era, therapeutic regimens mainly comprised the use of antianginal and antiarrhythmic drugs. The development of semi-invasive hemodynamically guided treatment concepts led to remarkable improvement in clinical outcome. After the introduction of the “wave-front phenomenon,” multiple pharmacologic treatment strategies were developed with the goal of infarct size reduction. The use of thrombolytic agents reduced infarct size and improved prognosis of patients with acute myocardial infarction. Acute angioplastic intervention was introduced in specialized centers to achieve rapid restoration of coronary blood flow. The protection of the myocardium from reperfusion injury, however, remains an unresolved issue. Intravenous magnesium administration in conjunction with new and better recanalization techniques could therefore be a promising therapy strategy in patients with acute myocardial infarction.

Acute myocardial infarction, reperfusion injury, and intravenous magnesium therapy: Basic concepts and clinical implications

The concept of reperfusion-induced injury has aroused special interest during the past decade as thrombolysis and direct angioplasty were introduced for early restoration of coronary blood flow in patients with acute myocardial infarction. There is experimental and clinical evidence that oxygen-derived free radicals (oxyradical hypothesis), activation of the complement system (complement hypothesis), and disturbance in calcium homeostasis (calcium hypothesis) may account for the development of reperfusion injury. Data from numerous animal experiments and clinical trials suggest that magnesium, a physiologic calcium blocker, may be efficacious for reduction of reperfusion injury. Despite encouraging results from previous clinical trials that revealed beneficial effects of intravenous magnesium therapy with respect to mortality, left ventricular function, and infarct size, a recently published large-scale trial (ISIS-4) provided conflicting data and caused major controversy. Further clinical trials, well-designed and carefully conducted, should elucidate the beneficial effects of magnesium in acute myocardial infarction, especially in conjunction with new and aggressive reperfusion techniques.

Ventricular premature beat—driven intermittent restoration of coronary blood flow reduces the incidence of reperfusion-induced ventricular fibrillation in a cat model of regional ischemia

With a cat model of regional cardiac ischemia, we examined whether the incidence of reperfusion-induced ventricular fibrillation (VF) could be reduced by ventricular premature beat (VPB)-driven intermittent reperfusion. In addition, we assessed whether the effect of the intermittent reperfusion was comparable with that of ischemic preconditioning in suppressing the VF. Of 15 cats subjected to uninterrupted reperfusion after 20-minute occlusion of the left anterior descending coronary artery, 13 (86.7%) had VF, whereas only 1 (7.1%) of 14 cats subjected to the VPB-driven intermittent reperfusion had VF. This incidence of VF was significantly lower than that of the animal group subjected to uninterrupted reperfusion. However, it was not statistically different from that (3 of 15) of the group subjected to a 10-minute episode of the coronary artery occlusion before the 20-minute occlusion (i.e., “ischemic preconditioning”). Our results suggest that the VPB-driven intermittent reperfusion (i.e., “postconditioning”) is very effective in preventing reperfusion-induced VF and as good as, if not better than, ischemic preconditioning.

Coronary vasomotion of the stunned myocardium.

The term “stunned” moycardium describes a dysfunction of the myocardium which may persist for hours, days or even weeks after restoration of coronary blood flow following thrombolysis, percutaneous transluminal coronary angioplasty (PTCA) or aorto-coronary bypass grafting (7, 9). The “stunned” myocardium is characterized — despite marked dyskinesis — by near normal levels of myocardial perfusion and normal or even enhanced oxygen consumption (2), probably due to higher oxygen requirements of the contractile elements. Thus, a mismatch between function and flow exists which has been recognized to be a characteristic finding of the “stunned” myocardium. However, coronary reperfusion may result in an attenuation of the endothelial response to coronary vasodilators such as acetylcholine, bradykinin, etc. (3). It is well established that prolonged myocardial ischemia is associated with irreversible myocardial damage and profound structural and functional derangements of the coronary microvasculature which may persist even if perfusion is restored (1). Local vasoactive substances such as the endothelium-dependent relaxing factor (EDRF) also play an important role in the regulation of myocardial perfusion. EDRF is a potent vasodilator which is released from the coronary endothelium but is reduced in patients with atherosclerotic plaques or hypercholesterolemia (= endothelial dysfunction). Since there are shear-stress dependent flow receptors, EDRF is released proportionally to coronary flow, i.e., the higher the flow the larger the artery and vice versa. However, flow regulation is dependent on several factors such as perfusion pressure, peripheral resistance, sympathetic activation, oxygen saturation, metabolic factors etc. EDRF is synthetized in the endothelial cells and is rapidly broken down during ischemia by superoxide radicals which inactivate EDRF and, thus, decrease flow-induced vasodilation (6). Neutrophil aggregation may further contribute to this process by the release of proteolytic enzymes which can convert oxygen to superoxide anions, i.e., oxygen free radicals. These radicals may injure the endothelium when generated in large amounts such as during ischemia (4) and may sensitize the smooth vasculature to contraction by alpha-adrenergic mechanisms (8).

Scientific session of the Cardiological Scientific Center of the Russian Academy of Medical Sciences "Emergencies in Cardiology" (Moscow, January 20-21, 1994)

Various aspects of the problem were discussed at the plenary and breakout sessions, as well as at the round table. Prof. M. Ya. Ruda (Moscow) in his report Modern approaches to the treatment of acute myocardial infarction noted that restoration of coronary blood flow is the key to successful treatment of the disease. Pointing out that myocardial necrosis begins 30 minutes after the occlusion of the coronary artery, after 2 hours 50% of the affected area "dies", and after 4 hours - all 100%, he stressed that from these positions, after 4 hours from the onset of the disease, thrombolytic therapy already ineffective. Therefore, it should be started at the prehospital stage. The most widely used tissue plasminogen activator and, especially, streptase (ST), with the use of which less often develop retrombosis and cerebral strokes. In addition, the CT is cheaper. In the prevention of retrombosis, aspirin, heparin can be useful (5000 units intravenously, then infusion of 1000 units per hour for 2 days under the control of blood clotting time). Prof. M. Ya. Ruda also said that at present, the administration of magnesium salts is widely used abroad in the acute period of myocardial infarction, which significantly reduces mortality. Perhaps, he added, "they will soon start with magnesium salts."

Combination of platelet fibrinogen receptor antagonist and direct thrombin inhibitor at low doses markedly improves thrombolysis.

We evaluated the effects of a novel platelet fibrinogen receptor antagonist, Integrelin, and a direct thrombin inhibitor, recombinant hirudin, given together with recombinant tissue plasminogen activator (rTPA) in a canine experimental model of intracoronary thrombosis. We tested the hypothesis that combination of both agents at low doses would have an additive antithrombotic effect, resulting in a significant improvement in the efficacy of rTPA. Thirty-two dogs with an electrically induced coronary thrombus were treated with rTPA (1 mg/kg over 20 minutes) together with one of the following adjunctive treatments in a random fashion. Eight dogs received saline for 90 minutes; Integrelin (5 micrograms.kg-1.min-1 for 90 minutes) was given to 8 dogs; 8 dogs received recombinant hirudin (20 micrograms.kg-1.min-1 for 90 minutes); and 8 dogs were treated with a low-dose combination of Integrelin (2.5 micrograms.kg-1.min-1) plus recombinant hirudin (10 micrograms.kg-1.min-1) for 90 minutes. Integrelin or recombinant hirudin, when given as single adjunct to rTPA, enhanced the lysis of the occlusive thrombus, causing full restoration of coronary blood flow (100% of its baseline value) for 29 +/- 16 and 26 +/- 5 minutes, respectively, whereas coronary blood flow was fully restored for only 5 +/- 1 minutes in dogs receiving rTPA plus saline (both P < .05). However, either Integrelin or recombinant hirudin failed to modify the reocclusion rate (57% and 63%, respectively) compared with saline (83%; all P = NS). Conversely, the low-dose combination therapy led to complete restoration of coronary blood flow for 92 +/- 19 minutes (P < .01 versus all treatments) and significantly reduced the reocclusion rate (25%; P < .05 versus saline). These data show that inhibition of specific pathways of platelet and thrombin activity improves the extent and duration of rTPA-induced thrombolysis in the electrolytic canine model. Furthermore, our findings suggest that low doses of platelet IIb/IIIa and direct thrombin antagonists in combination may be used successfully during thrombolysis.

Restoration of coronary blood flow in severely narrowed and chronically occluded coronary arteries before and after angioplasty: Implications regarding restenosis

The restenosis rate after recanalization of chronic totally occluded coronary arteries is high. This may be due to a competitive flow or a low coronary flow velocity. This study was designed to assess differences in coronary blood flow velocity between severely narrowed and occluded arteries before and after successful percutaneous transluminal coronary angioplasty. Thirty-five patients were studied including 12 with an occuluded vessel (group 1) and 23 with a stenosis (group 2). Rest and peak hyperemic (papaverine) coronary blood flow velocities were measured. Before successful percutaneous transluminal coronary angioplasty, velocity was lower in occlusions than in stenoses (3.8 ± 2.1 vs 7.9 ± 4.8 cm/sec; p < 0.02), whereas resistance was higher (31.7 ± 20.8 vs 13.7 ± 7.0 mm hg/cm/sec, respectively; p = 0.0009). There was no significant difference in vasodilator reserve between the two groups. After successful percutaneous transluminal coronary angioplasty, the velocity increased in both groups and the resistance index decreased. Velocity and resistance were similar in the two groups. The vasodilator reserve did not change after the procedure. It was concluded that the coronary flow velocity achieved after successful recanalization of chronic totally occluded arteries is similar to that observed after dilatation of stenoses. These results do not support the hypothesis that the high rate of restenosis in recanalized chronically occluded vessels is due to differences in post-percutaneous transluminal coronary angioplasty blood flow velocity.

Recurrent myocardial ischemia following thrombolytic therapy: guidelines for practicing clinicians

The natural history of patients with acute myocardial infarction treated with thrombolytic therapy includes two distinct phases: the initial or acute phase is characterized pathologically by atheromatous plaque rupture and thrombotic coronary arterial occlusion, and clinically by the abrupt onset of symptoms. Prompt restoration of coronary blood flow and myocardial reperfusion during this phase, achieved in a majority of patients given thrombolytic therapy, limits myocardial necrosis, preserves ventricular function, and lowers mortality. Although the thrombus can be pharmacologically removed, an unstable anatomic substrate persists. Therefore following thrombolytic therapy, a subacute phase occurs, during which patients are at risk for recurrent ischemic events. More than a theoretical concept, experience has shown that recurrent ischemia and reinfarction develop in 20% to 30% and 5% of patients, respectively. Morbidity and mortality are elevated considerably in these patients, dictating an aggressive diagnostic and treatment approach.

Hibernating myocardium: a historical perspective.

Hibernating myocardium refers to the presence of persistent myocardial and left ventricular dysfunction at rest, associated with conditions of severely reduced coronary blood flow. This left ventricular dysfunction probably represents an adaptive mechanism preventing irreversible myocardial cell damage, since myocardial and left ventricular dysfunction in hibernating myocardium improve following the restoration of coronary blood flow. This review examines the evolution of the concept of hibernation from a clinical observation of the potential underlying mechanisms recently proposed.

Protection of the Myocardium Against Postischemic Reperfusion Damage

Restoration of coronary blood flow in the ischemic myocardium is necessary to prevent irreversible cellular damage, although it may result in hazardous consequences. Because thrombolysis during myocardial infarction is designed to salvage a maximal number of myocardial cells threatened by ischemia, a concomitant intervention that reduces cellular damage caused by reperfusion will improve the net result of such a procedure. The adjunctive use of angiotensin-converting enzyme (ACE) inhibitors with thrombolytic therapy early during acute myocardial infarction offers theoretic advantages. In the acute phase, captopril may scavenge free radicals, blunt the catecholamine response, elicit coronary vasodilation, and increase prostacyclin and bradykinin levels. In the chronic phase, remodeling may be attenuated. This article summarizes study results that indicate that ACE inhibitors play an important role in cardioprotection in the acute phase of myocardial ischemia followed by reperfusion. The sulfhydryl group-containing ACE inhibitors probably have an additional protective effect through an interaction with bradykinin or through scavenging of free radicals. At present, a large number of controlled clinical trials mainly focusing on the effects of ACE inhibition in the chronic phase are under way. However, only a few studies concentrate on the effect of acute intervention with ACE inhibitors in ischemia-reperfusion, i.e., thrombolysis in myocardial infarction. In April 1990, under the auspices of the Interuniversity Cardiology Institute of The Netherlands, a large nationwide acute intervention trial with captopril in 280 patients receiving thrombolytic therapy was started, the Captopril and Thrombolysis Study. The primary hypothesis of this study supposes a very early effect of converting enzyme inhibition on evolving myocardial damage due to ischemia and the consequences of early reperfusion.

Streptokinase improves reperfusion blood flow after coronary artery occlusion

Streptokinase is an effective thrombolytic agent which, with early restoration of coronary blood flow, has the potential for limiting infarct size. Distinct from thrombolysis, we studied the effects of streptokinase on reperfusion coronary blood flow and infarct size. Open-chest anesthetized canines underwent a 90 minute snare occlusion of the left circumflex coronary artery followed by release and reperfusion through a critical stenosis for 6 hours. The animals were assigned randomly to two groups. Intracoronary streptokinase [group 1 ( n = 8): 6000 IU/kg in 3 ml of saline] or saline [group 2 ( n = 8): 3 ml of saline] was infused at 0.05 ml/min for 60 minutes beginning 30 minutes before reperfusion. Coronary blood flow was stable in group 1 during reperfusion, while in group 2 it fell during 6 hours of reperfusion (30 ± 4 ml/min to 18 ± 2 ml/min, P = 0.05). The ST-segment elevation on the limb lead II electrocardiogram 15 minutes after coronary artery occlusion was similar in both groups (group 1: 3.9 ± 0.6 mV, group 2: 2.3 ± 0.5 mV), suggesting the extent of myocardial ischemia was also similar in both groups. The infarct sizes were similar when expressed both as a percent of the total left ventricular mass [( IZ LV ) group 1: 17 ± 2.5%, group 2: 17.5 ± 2.5%] or as a percent of the area at risk of infarction [( IZ AR ) group 1: 39 ± 6%, group 2: 39 ± 5%]. In both groups, the mass of left ventricle dependent on the blood flow distribution of the left circumflex coronary artery was similar when compared to total left ventricular mass [( AR LV ) group 1: 41 ± 3%, group 2: 44 ± 4%]. These results demonstrate that streptokinase maintains reperfusion coronary blood flow through a critical stenosis at a rate similar to baseline levels. Despite the fact that coronary blood flow remained stable with streptokinase during reperfusion, infarct size was not limited after 90 minutes of fixed coronary artery occlusion in this canine model of myocardial injury.