The Open-Artery Hypothesis Revisited

Acute myocardial infarction (AMI) continues to be a major public health problem in the United States and other industrialized countries. According to the American Heart Association, 13.2 million Americans have coronary disease, including 7.2 million with previous AMI. In 2001, approximately 233 thousand people died of an AMI.¹ Since the early 1980s, the development of pharmacological and mechanical reperfusion therapies has helped reduce mortality rates by allowing rapid, complete, and sustained restoration of coronary blood flow. This is in keeping with the “open-artery” hypothesis first proposed by Eugene Braunwald in 1989,² when he noted that patients with spontaneous recanalization of an infarct-related artery (IRA) had fewer adverse events during the following weeks and months. He observed that the difference in outcomes was not likely to be attributable to the small benefit in infarct salvage, because of the nearly identical left ventricular ejection fractions (LVEFs). Research on the benefits of the open artery, such as improved healing and electrical stabilization, has been inconclusive. This uncertainty has resulted in widespread inconsistencies of beliefs among cardiologists regarding the benefits of recanalization and, more specifically, the best time to recanalize. The development of groundbreaking reperfusion therapies, such as drug-eluting stents, makes a review of the data essential to expose the gaps in the research concerning the open artery. Herein, we present a critical evaluation of the available data and of the need for further research in this field.

Opening Infarct-Related Arteries

In the absence of collateral circulation, coronary occlusion causes myocyte necrosis,³ the extent of which correlates directly with the speed and duration of the occlusion.^4–6 During the late 1960s and the 1970s, randomized clinical trials showed that thrombolytic therapy administered within 1 to 12 hours of an AMI could reduce both short- and long-term mortality rates.^5–8 In the 1980s, studies showed early reperfusion to be the critical determinant of myocardial salvage and the major mechanism by which reperfusion therapy affects mortality rates.^9–12 Kim and Braunwald hypothesized that early reperfusion of an IRA would decrease myocardial necrosis, improve left ventricular (LV) function, and reduce mortality rates.¹³ This hypothesis has become especially relevant in light of the growing evidence that AMI is often due to acute thrombosis secondary to vulnerable plaque rupture.¹⁴

Opening an occluded IRA, whether early or late, produces survival rates disproportionate to the amount of myocardium salvaged. Myocardial reperfusion has been shown to improve both short- and long-term survival in patients who have experienced an AMI. The open-artery hypothesis suggests that survival after AMI depends more on improved LV remodeling and healing, electrical stability, and myocardial perfusion than on reduction in infarct size (that is, myocardial salvage).^13,15–19 The literature also suggests that survival may improve even when thrombolytic therapy is administered late, after irreversible necrosis has occurred. In recent studies, late patency of an IRA, as opposed to persistent occlusion, was independently associated with better 1-year survival.^19–21 In a long-term follow-up study of 505 patients who underwent percutaneous transluminal coronary angioplasty (PTCA) for post-MI ischemia,²² patients with an open IRA had a lower 5-year mortality rate than did patients with a closed IRA (4.9% vs 19.4%; P =0.001). This held true even for patients with LVEFs less than 0.50.

Early Reperfusion

Early thrombolytic therapy has significantly improved the outcomes of patients with AMI. Early reperfusion (<24 hours after AMI) may increase the chances of survival by reducing infarct size, promoting infarct healing, and restoring function to hibernating myocardium. Key innovations were the introduction of intravenous (IV) streptokinase administration in 1958²³ and of intracoronary fibrinolysin administration in 1976.²⁴ Clinical trials have since confirmed that early thrombolytic therapy can reduce mortality rates5,7,18,25–27 and beneficially affect LV function, infarct size, and clinical outcome, especially when administered within 90 minutes after the onset of chest pain.^7,28 In 9 trials of the Fibrinolytic Therapy Trialists' Collaborative Group comprising more than 1,000 patients with AMI,²⁷ thrombolytic therapy administered 7 to 12 hours after the onset of symptoms reduced the mortality rate by 14% and by even more when administered within 60 to 90 minutes.

Randomized Clinical Trials of Thrombolytic Therapy

Both catheter-based and thrombolytic reperfusion therapies offer a clear survival benefit to patients with AMI. Clinical trials have shown that thrombolysis reduces mortality rates compared with those occurring with placebo, while the rates of reinfarction and stroke increase in groups receiving thrombolytic therapy. Using death and severe LV damage as the combined endpoint, the initial randomized Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto (GISSI) trial²⁹ involving 11,712 patients proved the safety and efficacy of early thrombolytic reperfusion. Compared with no thrombolytic treatment, treatment with IV streptokinase within 12 hours of a myocardial infarction (MI) led to an 18% relative reduction in mortality rates 21 days later and 10% 1 year later. Marino and colleagues³⁰ studied 331 consecutive patients enrolled in the GISSI trial to determine the relationship between thrombolytic therapy and LV remodeling and function after AMI. They found that patients who underwent streptokinase treatment showed smaller ventricular volumes at pre-discharge examination than did patients who received standard care (end-diastolic volume, 119.3 ± 49.7 vs 134.5 ± 57.8 mL; end-systolic volume, 65.4 ± 36.4 vs 74.9 ± 45.7 mL). The streptokinase group also showed a smaller regional wall motion index (2.2 ± 1.9 vs 2.7 ± 1.9 segments) but no difference in LVEFs. The differences in regional dysfunction and volume were still apparent after 6 months. The authors concluded that LV modeling and function were improved by streptokinase administration in patients with AMI, and post-infarction ventricular dilation and the extent of regional wall motion abnormalities were reduced.³⁰ Secondary ventricular fibrillation was decreased by approximately 20% in patients receiving thrombolytic therapy (streptokinase, 2.4% vs control, 2.9%; relative risk, 0.80).³¹

Analysis of data from the GISSI trial established the relation between time to thrombolytic therapy and risk of cardiac rupture, which confirmed that providing thrombolytic therapy early after AMI not only improves survival rates but lowers the risk of cardiac rupture. However, the risk of cardiac rupture may increase with late administration of thrombolytic therapy.³²

The subsequent GISSI-2 trial assigned 12,490 patients with AMI to early reperfusion with streptokinase or with the synthetic tissue plasminogen activator (tPA) alteplase³³ and found the therapies to be equally effective. The Second International Study of Infarct Survival (ISIS-2) randomized 17,187 patients with suspected AMI to receive streptokinase, aspirin, both, or neither within 24 hours of symptom onset.⁷ In that study, both streptokinase alone and aspirin alone significantly reduced 5-week mortality rates (by 25% and 23%, respectively), but together reduced it by 42%. During the next 10 years of follow-up, however, streptokinase offered no further survival benefit. In addition to showing that early thrombolytic therapy was effective, the ISIS-2 trial was also the 1st randomized trial to demonstrate that aspirin's benefits are largely independent of and additive to those of thrombolytic therapy and that aspirin, with or without thrombolytic therapy, is an effective therapy after AMI. Patients receiving streptokinase and aspirin combined showed a significantly lower rate of reinfarction (1.8% vs 2.9%), stroke (0.6% vs 1.1%), and death (8.0% vs 13.2%) than those receiving neither drug.

The randomized Anglo-Scandinavian Study of Early Thrombolysis (ASSET)³⁴ involved a total of 13,318 patients with AMI, in whom treatment with recombinant tPA (n=2,516) versus placebo (n=2,495) led to a 26% relative reduction in overall mortality rate at 1 month, 21% at 6 months, and 12.6% at 1 year. In the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial²⁶ involving 41,021 patients with AMI, an accelerated regimen of tPA plus IV heparin reduced the mortality rate by about 14% (95% CI, 5.9%–21.3%) compared with 2 different streptokinase regimens (streptokinase combined with either subcutaneous or IV heparin) (P= 0.001). The group given accelerated tPA also showed a considerably lower rate of death or disabling stroke (6.9%), compared with the groups given streptokinase alone (7.8%, P =0.006).

Together, the results of the GISSI, GISSI-2, ISIS-2, and GUSTO-1 trials showed that post-AMI mortality rates depend more on the timing of treatment (early vs late) than it does on the type of thrombolytic agent.

Late Reperfusion

Myocardial salvage after AMI is time dependent. Therefore, it seems unlikely that late opening of an IRA would improve patient survival if its only benefit were myocardial salvage. Instead, as a number of clinical studies have suggested, the benefit may be related more to the restoration and maintenance of collateral artery flow after late reperfusion. Late reperfusion (>24 hours after AMI) may improve survival rates by promoting ventricular remodeling, preventing ventricular arrhythmias, and restoring blood flow to collateral coronary arteries. Possible mechanisms of this benefit include prevention of LV dilation,³⁵ improvement in electrical stability,³⁶ and the provision of a conduit for collateral flow should a contralateral coronary artery become occluded.²

In the double-blind, randomized Late Assessment of Thrombolytic Efficacy (LATE) trial,³⁷ patients who received IV alteplase 6 to 24 hours after an AMI had a lower 35-day mortality rate than did patients who received placebo (8.86% vs 10.31%, respectively), which was a 14.1% relative reduction (95% CI, 0–28.1%). In another study of 40 patients who received no thrombolytic therapy after an AMI,³⁸ coronary angiography 7 to 10 days later revealed a patent IRA in 16 patients, a closed IRA with good collateral blood flow in 10 patients, and a closed IRA with no collateral flow in 14 patients. One month after AMI, LV volume had not changed in the patients with a patent IRA or good collateral flow, but it had increased 28% in those with a closed IRA and no collateral flow. In a study by Sabia's group,³⁹ the interval between AMI and attempted angioplasty made no difference in the degree of improvement of myocardial function. This study showed that myocardium remains viable for a long period in many patients with AMI and an occluded IRA, possibly due to the presence of collateral blood flow in the infarcted area. At about the same time, Hirayama and colleagues⁴⁰ showed that late reperfusion (>6 hours from the onset of AMI) can avoid ventricular dilatation regardless of infarct size.

Late IRA reperfusion by thrombolysis or PTCA can enhance the electrical stability of the infarcted zone^41,42 and reduce the incidence of unstable angina, congestive heart failure, and death.⁴³ Five clinical trials^44–48 randomized patients to PTCA or other (medical) therapies (Table I). In the Thrombolysis and Angioplasty in Myocardial Infarction-6 (TAMI-6) trial,⁴⁴ 197 patients, within 6 to 24 hours after the onset of AMI, were randomly given tPA or placebo. After 24 hours, patients with occluded IRAs (determined by angiography) underwent either PTCA or no PTCA. At 6 months, IRA patency was 59% in both the tPA and the placebo groups with no difference at 1 or 6 months in LVEF or infarct-zone regional wall motion; however, end-diastolic volume was markedly greater in the placebo group than in the tPA group. Patients who underwent PTCA showed improvement of ventricular function in 1 month, but no benefit was observed at late follow-up.

TABLE I. Results of 5 Randomized Clinical Trials of PTCA as Late Reperfusion Therapy^a

Patients in the randomized Total Occlusion Post-Myocardial Infarction Intervention Study (TOMIIS)⁴⁵ underwent either PTCA or no PTCA for an average of 21 days after AMI. At 4 months, 43% of the PTCA patients had a patent IRA (despite an initial patency rate of 72%) compared with 19% of the control patients. Neither LV size nor LV function was affected by PTCA in this trial. Horie and co-authors, in another randomized trial, showed that LVEF and regional wall motion 6 months after AMI did not differ between patients who underwent PTCA and those who did not.⁴⁶ In the Open Artery Trial (TOAT) of late reperfusion versus conservative therapy for symptom-free patients after AMI, late reperfusion (26 ± 18 days post-AMI) led to significantly improved LV size within the next year and to a greater absolute increase in exercise duration and peak workload.⁴⁷ Unlike previously discussed trials, during 1-year follow-up in this study, adverse clinical events (death, MI, stroke, congestive heart failure, and revascularization) increased considerably in PTCA patients compared with those not undergoing PTCA.

The Desobstruction Coronaire en Post-Infarctus (DECOPI) study⁴⁸ is the largest randomized trial to compare angioplasty with conventional medical therapy, 2 to 15 days after an AMI, in patients with occluded IRAs. About 80% of patients in the PTCA group underwent stenting. After 33 to 36 months of follow-up, there was no significant difference between the PTCA and non-PTCA groups with regard to cardiovascular death, nonfatal MI, or ventricular tachycardia. In the PTCA group, LVEF was significantly higher at the 6-month follow-up than it was in the non-PTCA group.

PTCA versus Thrombolysis

Although the benefits of the open artery after AMI have been established, the relative benefit of using primary PTCA versus thrombolytic therapy to achieve patency has not. Early clinical trials from the late 1980s⁴⁹ showed short-term outcome improvement in AMI patients after PTCA compared with thrombolytic therapy. Other trials have shown that thrombolytic therapy reduces mortality rates and improves LV function after AMI⁵⁰ but that it can result in mild residual stenosis (<50%) and occlusion of the treated artery within 90 minutes.⁵¹ This residual stenosis increases the risk of future ischemia and reocclusion. Although PTCA generally results in less IRA stenosis, it too is accompanied by the problem of reocclusion. Multiple trials in patients admitted to angioplasty centers with highly experienced operators have shown the superiority of PTCA to fibrinolysis in the treatment of AMI with ST-segment elevation.^52,53 In a large cohort study, Andersen and colleagues⁵⁴ found that there were advantages of primary PTCA over thrombolytic therapy in patients with AMI, even when the patients were admitted to a local hospital without angioplasty facilities and had to be transported to another hospital for PTCA. The primary endpoint (death, clinical reinfarction, or disabling stroke at 30 days) in patients at referral hospitals was lower in the angioplasty group (8.5%) than in the fibrinolysis group (14.2%) (P =0.002).⁵⁴ A clinical trial comparing primary coronary angioplasty with tPA for AMI (GUSTO IIb)⁵⁵ showed a slight benefit with angioplasty at 30 days with respect to all elements of the primary endpoints (death, reinfarction, and stroke).

Primary angioplasty has been compared with thrombolytic therapy and with PTCA performed following thrombolytic therapy. A meta-analysis⁵⁶ of multiple randomized trials showed that primary angioplasty compared with thrombolytic therapy decreases the rate of short-term mortality and nonfatal reinfarction.

In a recent meta-analysis that compared outcomes of thrombolytic therapy versus primary angioplasty in 2,573 subjects,⁵⁷ the angioplasty group had a significant relative reduction in risk (RRR) in short-term death (32%), reinfarction (52%), recurrent ischemia (54%), and combined death or reinfarction (46%). Keeley's group⁵⁸ reviewed 23 trials involving patients with AMI (total number of patients, 7,739), all of whom were eligible for thrombolytic therapy. The patients received primary PTCA (n=3,872) or thrombolytic therapy (n= 3,867). Primary angioplasty yielded significant decreases in short-term death (P =0.0002), nonfatal reinfarction (P <0.0001), and the combined endpoint (P <0.0001), compared with streptokinase treatment.

Opening a blocked coronary artery may reverse the blood flow through collateral vessels toward the contralateral coronary artery which, in case of any stenosis in that vessel, may by itself serve as a back-up to provide blood flow into the contralateral territory.

Collateral Coronary Artery Flow

Collateral blood flow clearly contributes to myocardial salvage and post-AMI survival in patients with occluded IRAs. Such flow is well developed in patients with severe stenosis of one or more major coronary vessels.^59,60 Therefore, patients with a totally occluded coronary artery but ample collateral flow may show no evidence of MI in the distribution of the blocked artery.

Collateral flow influences infarct size and LV function.^61,62 Such flow may also decrease the incidence of wall motion abnormalities and ST-segment changes, decrease lactate production, reduce perioperative infarct and mortality rates, and improve outcomes.⁶³ In a study of patients who underwent intracoronary thrombolysis of an occluded IRA within 6 hours after a 1st AMI,⁶⁴ higher degrees of stenosis were associated directly with collateral vessel formation and inversely with therapeutic efficacy. Other studies have shown that collateral arteries are associated with a smaller infarct size and preserved LV function after successful reperfusion. However, Boehrer and colleagues,⁶⁵ in a long-term angiographic study involving 146 patients, found no apparent effect of collateral blood flow on long-term morbidity and mortality rates after AMI.

By preventing AMI and heart failure, collateral flow may confer myocardial protection and improve survival rates, as suggested by long-term studies showing that, in patients with angina⁶⁶ and no impairment of ventricular function but with an occluded LAD,⁶⁷ survival is greater when collateral flow is adequate. Some authors, however, believe that surgery or angioplasty should still be performed in patients with good collateral flow to restore anterograde blood flow⁶⁸ or to lower the risk of death or MI.⁶⁹

In patients with a 1st AMI, the presence of functioning collateral vessels or a partially occluded coronary artery is associated with better cardiac function and decreased myocardial damage than is the presence of fully occluded coronary arteries. Nonjeopardized collateral vessels can protect myocardial function during the early hours of an AMI.⁷⁰ In patients with complete LAD occlusion that leads to anteroseptal AMI, successful thrombolysis and well-developed collateral vessels result in higher ejection fractions and better regional wall motion of infarcted areas, in contrast to the results in patients who have poorly developed collateral vessels or failed thrombolysis.⁷¹

Perfusion of the infarct area could have further benefits over time, because this area might provide collateral support to other areas of the myocardium if they were to become jeopardized. For example, a patient with an anterior wall infarction caused by LAD occlusion might have a better outcome with subsequent right coronary artery occlusion if the LAD had previously been opened to provide collateral flow.⁷²

Collateral arteries have bidirectional flow functionality. In an interesting study, Miyamoto and colleagues⁷³ selected coronary arteries, ranging from completely occluded to severely stenotic, that received flow through the collateral vessels fed by a contralateral artery with severe occlusion. Performing PTCA in the index artery resulted in retrograde filling of the contralateral artery through the available collateral arteries, showing the potential bidirectionality of collateral flow.⁷³

Variability in symptoms, presentation, and outcome in patients with coronary atherosclerosis may be caused by the existence and recruitment of collateral vessels within the coronary circulation. Collateral blood flow may result from repetitive episodes of ischemia that produce the stimuli needed for new vessel formation. In a subset of patients, available collateral vessels can limit myocardial damage during acute ischemic events.⁷⁴ On the basis of the above-mentioned studies, keeping the IRA patent (especially the perfusing artery) should serve to limit future myocardial necrosis during acute coronary syndromes in the contralateral territory. However, there is no evidence to support such a protective effect of collateral vessels against AMI in a contralateral territory. New trials need to be designed to assess the value of opening collateral vessels.

Discussion

Investigation of the relationship between thrombotic coronary artery occlusion and AMI led to the development of therapies to achieve the early reperfusion of occluded IRAs.⁷⁵ Several studies have confirmed LV function to be an important long-term prognostic factor in patients undergoing thrombolytic therapy and have also shown that an occluded IRA is an independent predictor. These 2 factors are intimately related, as evidenced by the fact that in AMI, early reperfusion of an occluded IRA results in myocardial salvage, preservation of LV function, and improvement in LV function, which in turn decreases mortality rates. Although thrombolytic therapy improves the patency rates of IRAs, reocclusion still occurs in about 10% of patients after initial successful reperfusion.⁷⁵

Several other observations have shown an association between late patency of the IRA (2–42 days) and improved clinical outcome. This association is particularly evident in high-risk patients and may be independent of LV function and the coronary anatomy.¹⁹

There are no definitive data for evidence-based decisions on late revascularization; however, if there were such data, more patients with an occluded IRA after AMI would be candidates for coronary intervention.⁷⁵

In the case of an acute coronary artery occlusion, well-developed collateral vessels have been found to reduce MI size, protect against ventricular aneurysm formation, and improve systolic ventricular function.⁶¹ Theoretically, those beneficial effects from a well-developed collateral circulation should translate directly into a lower incidence of future cardiac ischemic events among patients with jeopardized coronary vascular territories. In patients with stable angina pectoris undergoing PTCA and quantitative collateral assessment, the occurrence of major adverse cardiac events (but not stable angina) was significantly lower in patients who had good collateral flow, compared with patients whose collateral flow was poorly developed.⁷⁶

The latest advances in telemedicine have reduced the time to treatment in patients with AMI by allowing electrocardiograms to be sent to the hospital by medical personnel from the ambulance or on site, or even by the patient from home. New thrombolytic drugs (such as tenecteplase) are being developed as a single bolus that can be administered rapidly and easily by medical personnel or the patients themselves. The results of the Assessment of the Safety of a New Thrombolytic (ASSENT)-3 randomized trial⁷⁷ showed that administering tenecteplase to AMI patients in the ambulance provided reperfusion treatment within 2 hours of symptom-onset to as many as 53% of patients.

In short, the open artery is not the same as the opened artery. It is clear that additional randomized trials with larger patient populations are required to clear up the confusion and contradictory evidence. Surprisingly, the 5 trials reported to date have not resolved the issues.^44–48 Patients randomized to PTCA have had a better improvement in LVEF in 4 of the 5 trials, but the difference is modest. The frustrating finding has been the difference in clinical outcomes. In 3 of the 5 clinical trials, patients randomized to PTCA, as opposed to other treatments, had more adverse clinical events over the ensuing 4 to 12 months. However, in 2 larger trials, the opposite was found (Table I). Further controlled randomized studies are needed to resolve such ambiguities.

The opportunities to open occluded arteries are increasing dramatically. Stenting has made intervention accessible and safer to low-volume interventionalists. Drug-eluting stents have markedly reduced the risk of restenosis, and clopidogrel and ticlopidine have decreased the risk of early and late thrombotic events. New devices for distal protection should further reduce the risk of embolic microinfarcts. Moreover, the recently established benefits of percutaneous intervention in AMI are increasing the number of patients choosing angiography. The Open Artery Trial and other recent trials in early intervention, along with new technological improvements, have occurred during the early stages of vulnerable plaque research. It is now widely accepted that most infarcts develop from rupture or erosion of plaques that—only weeks or months earlier—conferred a non-flow-limiting stenosis. These plaques are often multifocal.¹⁴ It is the sudden occlusion of these arteries, presumably too abrupt for the opening of collateral vessels or the angiogenic response to ischemia, that triggers most infarctions and many or most sudden ischemic cardiac deaths. Therefore, an important advantage of recanalizing a total occlusion could be that the open artery may supply blood, through existing or future collateral vessels, to another territory, served by a different artery that might harbor another vulnerable plaque upstream. The provision of blood downstream from these vulnerable plaques can prevent ischemia, which can occur after plaque rupture, and the subsequent local occlusion. Randomized clinical trials using the emerging techniques to detect vulnerable plaque are needed to evaluate the impact of providing blood downstream from high-risk plaques.

New developments in imaging and biomarker screening are likely to lead to even more intervention, both in AMI and in chronic ischemia. Moreover, just on the horizon is a new group of patients who may undergo catheterization because they are identified as high-risk by new invasive and noninvasive imaging techniques or by more extensive screening for established or new biomarkers.^78,79 These advances may well lead to an unprecedented number of patients undergoing catheterization and to an increased focus on perplexing issues such as the usefulness of intervention on lesions of intermediate severity and, particularly, on the occluded artery.