Abstract

The most critical determinant of prognosis in patients with acute myocardial infarction (MI) is infarct magnitude, which can be established within several hours of an attack. The importance of the subsequent healing process is not negligible, however. In fact, much experimental and clinical evidence suggests that late reperfusion of the infarct-related coronary artery—i.e. at times too late to salvage the myocardium within the area at risk—is beneficial for reducing left ventricular remodelling and decreasing mortality (‘open artery hypothesis’). For instance, one recent study highlighted the beneficial effects of late reperfusion therapy on the infarct tissue cell dynamics following acute MI. Nonetheless, several recent large, randomized clinical trials have failed to provide evidence of such benefits, refuting the clinical efficacy of late reperfusion. In addition, they also underscore the need for revised clinical studies in which there is less heterogeneity in the timing of reperfusion and in the initial infarct size, as well as the need for sustained patency of the recanalized artery. This review focuses on the effects of late reperfusion on the pathophysiology of MI in the context of the infarct tissue dynamics and clinical outcomes. We also discuss the issues that need to be resolved to improve clinical application.

Introduction

Large myocardial infarctions (MIs) lead to severe chronic heart failure with adverse remodelling of the left ventricle (LV) characterized by cavity dilatation and diminished cardiac performance.1 The most critical determinants of subsequent heart failure are the magnitude of the acute MI, which can be determined within several hours of an attack.2 The risk of developing heart failure increases proportionally with increasing areas of abnormal LV wall motion.3 Clinical heart failure accompanies areas of abnormal contraction exceeding 25%, and cardiogenic shock accompanies loss of more than 40% of the LV myocardium.

Subsequently occurring LV remodelling has emerged as one of the dominant factors that determine the long-term survival of the postinfarct patients. A strong relation was found between LV volumes and cardiac death within 2 years.4 It was reported that the primary predictor of survival was LV end-systolic volume; end-systolic volume greater than 130 mL resulted in a 5-year survival rate of only 52%.5 Progressive LV remodelling followed by serial examinations by echocardiography identifies a patient population at particularly high risk.6

Recanalization of the infarct-related artery, which, if performed early enough for myocardial salvage, reduces the size of the acute infarct, prevents subsequent heart failure, and improves prognosis.7 In addition, the ‘open artery hypothesis’ formulated by Kim and Braunwald8 proposes that late reperfusion, beyond the window for myocardial salvage, also reduces LV remodelling and decreases mortality.9 This proposal is supported by much experimental and clinical evidence, and a number of possible mechanisms by which an open infarct-related artery could confer benefits in ways other than by salvaging ischaemic myocardium have been proposed. Indeed, the information collected on this topic over a period of more than a decade is the subject of a number of excellent reviews.10–15

The infarcted myocardium is not simply dead, nor is it inert. It is a highly dynamic tissue that undergoes remarkable changes during the course of healing. Moreover, recent examination of infarct tissue dynamics has helped us to better understand the pathophysiological mechanisms underlying the benefits of late reperfusion, and recent progress in technology and the devices used for coronary artery intervention is making it easier not only to reopen infarct-related arteries, but also to maintain their patency after recanalization, even during the chronic stages of MI. In that context, this review focuses on the pathophysiology of late reperfusion and its effects on infarct tissue dynamics and clinical outcomes. We also discuss the issues that still need to be resolved for better clinical application.

Infarct tissue dynamics

Infarct tissue dynamics during the repair process that follows acute MI have been well studied (Figure 1A and B).16–18 Initially, there is extensive necrosis among the affected cardiomyocytes, and the necrotic tissue is massively invaded by inflammatory cells, mainly polymorphonuclear leucocytes. Thereafter, macrophages phagocytose the necrotic myocardium (debris) and, at the same time, myofibroblasts and endothelial cells proliferate and migrate into the infarct zone.18–21 The dead tissue is thus replaced by granulation tissue, which is a provisional tissue with a matrix rich in proteoglycans and matricellular proteins such as collagen, fibronectin, tenascin, and osteopontin.22–25 As the repair proceeds, myofibroblasts deposit a network of collagen, the provisional matrix is absorbed, and there is extensive apoptosis among the granulation tissue cells resulting in the formation of a thin, hypocellular scar.26–28 This postinfarction healing is thought to be complete within 2–6 months in humans,16,17 6–8 weeks in dogs,29 3–6 weeks in rats,18,30 and 2–4 weeks in mice.28 Although the infarct scar had been viewed as inert tissue—simply cross-linked collagen fibrils that resist deformation and rupture—it is, in fact, a dynamic tissue that is cellular, vascular, metabolically active, and contractile.31

Figure 1

Effect of the postinfarction healing process on cardiac geometry and its relation to wall stress and heart failure. (A) Transverse ventricular sections taken from mouse hearts on Day 3, 7, or 28 post-MI and stained with Masson's trichrome. (B) Photomicrographs of infarct tissue collected from mouse hearts on Day 3, 7, or 28 post-myocardial infarction (MI). (C) With the passage of time after the onset of MI, the infarct length and left ventricular cavity become larger, whereas the infarct wall thickness becomes thinner. Wall stress is proportional to the cavity diameter and intracavitary pressure, and inversely proportional to the wall thickness (Laplace's law). Thus, wall stress and ventricular remodelling (dilatation and wall thinning) have a vicious relationship, accelerating one another, and exacerbating heart failure.

Figure 1

Effect of the postinfarction healing process on cardiac geometry and its relation to wall stress and heart failure. (A) Transverse ventricular sections taken from mouse hearts on Day 3, 7, or 28 post-MI and stained with Masson's trichrome. (B) Photomicrographs of infarct tissue collected from mouse hearts on Day 3, 7, or 28 post-myocardial infarction (MI). (C) With the passage of time after the onset of MI, the infarct length and left ventricular cavity become larger, whereas the infarct wall thickness becomes thinner. Wall stress is proportional to the cavity diameter and intracavitary pressure, and inversely proportional to the wall thickness (Laplace's law). Thus, wall stress and ventricular remodelling (dilatation and wall thinning) have a vicious relationship, accelerating one another, and exacerbating heart failure.

Ventricular remodelling, which is characterized by progressive ventricular wall thinning and chamber dilation (Figure 1A and C), is associated with increasing incidences of congestive heart failure, aneurysm formation, and mortality following MI.32–36 This is because infarct tissue geometry has significant meaning for ventricular function. Laplace's law tells us that wall stress is proportional to cavity diameter and intracavitary pressure, and inversely proportional to the wall thickness.37 Increased wall stress adversely affects not only the infarcted wall but also the non-infarcted wall, causing cardiomyocyte hypertrophy, myocardial fibrosis, and, ultimately, reduced contractility.38 Thus, wall stress and ventricular remodelling (dilatation and wall thinning) have a vicious relationship, accelerating one another and exacerbating heart failure (Figure 1C).

Pathophysiology of late reperfusion

Although the open artery hypothesis remains somewhat controversial, the results of both experimental and observational studies support the concept that late reperfusion likely has certain therapeutic benefits.8–14,39 For instance, Hochman and Choo40 subjected rats to left coronary artery ligation for 30 min or 2 h and subsequent reperfusion or to permanent coronary artery ligation without reperfusion and examined the hearts 2 weeks later. In their study, an ‘expansion index’ was used to evaluate infarct expansion, which took into account both the degree of LV cavity dilatation and the degree of thinning of the infarct wall with respect to the non-infarcted LV wall thickness. As compared with rats with permanent coronary occlusion, rats reperfused after 30 min of occlusion exhibited smaller, less transmural myocardial infarcts and less infarct expansion. In addition, although infarcts in rats reperfused after 2 h of coronary occlusion were of the same size and transmurality as those in rats subjected to a permanent coronary occlusion, they showed less infarct expansion. Hale and Kloner41 assessed the effects of early vs. later reperfusion on longer term LV topography. They subjected rats to coronary artery occlusion for 30 (early reperfusion) or 90 (late reperfusion) min with subsequent reperfusion or to permanent coronary occlusion and examined the rats 6 weeks later. They found that early reperfusion reduced scar circumference and thinning of the infarcted wall and prevented LV cavity dilation. Late reperfusion still thickened the scar but did not significantly affect scar circumference. It also resulted in a non-significant trend towards a smaller LV cavity diameter and area and a smaller expansion index, when compared with permanent coronary occlusion. The greater wall thickness of the infarcted ventricle brought about by late reperfusion is, at least in part, attributable to the greater cellularity reflecting the presence of larger numbers of myofibroblasts and endothelial cells—the major components of granulation tissue (Figure 2).42

Figure 2

Effect of late perfusion on infarct tissue dynamics. Left panels: Masson's trichrome-stained transverse sections of left ventricle collected 4 weeks after myocardial infarction from hearts subjected to permanent occlusion or late reperfusion. Middle panels: infarcted wall at high magnification (boxed areas in the left panels). Right panels: hematoxylin–eosin stained sections of infarct tissue. Note the smaller left ventricular cavity, shorter infarct segment, and thicker infarct wall with higher cellularity in the heart with late reperfusion. Bars: 1 mm in the left panels, 20 µm in the right panels. (Reproduced from Nakagawa et al.42.)

Figure 2

Effect of late perfusion on infarct tissue dynamics. Left panels: Masson's trichrome-stained transverse sections of left ventricle collected 4 weeks after myocardial infarction from hearts subjected to permanent occlusion or late reperfusion. Middle panels: infarcted wall at high magnification (boxed areas in the left panels). Right panels: hematoxylin–eosin stained sections of infarct tissue. Note the smaller left ventricular cavity, shorter infarct segment, and thicker infarct wall with higher cellularity in the heart with late reperfusion. Bars: 1 mm in the left panels, 20 µm in the right panels. (Reproduced from Nakagawa et al.42.)

A number of possible mechanisms have been proposed by which an open infarct-related artery could confer benefits in ways other than by salvaging ischaemic myocardium. For clarity, we will separately evaluate the mechanisms underlying the beneficial effects on infarct tissue and the salvaged myocardium (especially that at the ischaemic border zone) (Table 1).

Table 1

Proposed mechanisms underlying the beneficial effects of late reperfusion

1. Effect on infarct tissue 
 1) Acceleration of infarct healing: 
  Absorption of myocardial debris 
  Acceleration of collagen synthesis 
 2) Retention of haematic scaffolding: 
  Haemorrhage, oedema, and contraction band necrosis 
 3) Reduction of collagen degradation 
 4) Preservation of the non-myocyte cell component: 
  Acceleration of proliferation of granulation tissue cells 
  Suppression of apoptosis of granulation tissue cells 
2. Effect on salvaged cardiomyocytes 
 1) Awakening hibernating myocardium: 
  Mitigation of cardiomyocyte degeneration 
 2) Reduction of cardiomyocyte apoptosis 
1. Effect on infarct tissue 
 1) Acceleration of infarct healing: 
  Absorption of myocardial debris 
  Acceleration of collagen synthesis 
 2) Retention of haematic scaffolding: 
  Haemorrhage, oedema, and contraction band necrosis 
 3) Reduction of collagen degradation 
 4) Preservation of the non-myocyte cell component: 
  Acceleration of proliferation of granulation tissue cells 
  Suppression of apoptosis of granulation tissue cells 
2. Effect on salvaged cardiomyocytes 
 1) Awakening hibernating myocardium: 
  Mitigation of cardiomyocyte degeneration 
 2) Reduction of cardiomyocyte apoptosis 

Effects on infarct tissue

Restoration of blood flow and the resultant influx of inflammatory cells into the infarct area appear to improve healing of infarct tissue and prevent ventricular remodelling.8 The importance of the early inflammatory reaction to the formation of a stout scar is supported by the finding that administration of glucocorticoid or non-steroidal anti-inflammatory agents within hours after experimental induction of MI inhibits the inflammatory process, which allows greater infarct expansion, resulting in thinner scars.43,44 Likewise, anti-inflammatory cytokine therapy targeting tumour necrosis factor-α also has adverse effects on the postinfarction healing process when administered around the onset of MI.45 Conversely, increased infiltration of infarct tissue by polymorphonuclear leucocytes stimulated by granulocyte colony-stimulating factor promotes healing after MI,46 whereas late reperfusion of infarcted rat hearts accelerates absorption of the necrotic myocardium (debris).42

An open, blood-filled infarct-related artery and vascular bed may also provide a supporting scaffold that helps maintain the structural integrity of the necrotic myocardium and limits infarct expansion and ventricular remodelling.47 In addition, late reperfusion induces intramyocardial haemorrhage, oedema, and contraction band necrosis, within which sarcolemmal tubes persist and may prevent collapse of the necrotic tissue.48

Collagen turnover is reportedly more pronounced in patients with an occluded infarct-related artery, suggesting that the prevention of interstitial collagen turnover may be another beneficial effect.49,50 In rats with MI, cardiac expression of matrix metalloproteinase-2 and -9, which degrade extracellular matrix, was actually downregulated in the hearts with late reperfusion.42

Although cardiomyocytes (cadiac parenchymal cells) attract most attention, non-myocytes including interstitial and vascular cells account for 65–75% of the cells in the normal heart, occupying ∼20–33% of the heart by volume.51–54 After MI, moreover, the numbers of non-myocytes in the heart dramatically increase through both migration and proliferation, and late reperfusion further augments the proliferative activity of non-myocytes within the infarct tissue during the early stage after MI (4 days post-MI in rats) (Figure 3A).42

Figure 3

Proliferative and antiapoptotic effects of late reperfusion on postinfarct granulation tissue cells. (A) Time courses of the changes in Ki-67-positive proliferating cells in hearts with permanent occlusion and in those with late reperfusion. Photomicrographs obtained 4 days post-MI showing Ki-67-positive cells in the infarct area of a heart with permanent occlusion and one with late reperfusion (%Ki-67+ cells: 5.1 ± 0.85 vs. 8.8 ± 0.77%, P < 0.05). (B) Time-dependent changes in the incidences of in situ nick end-labelling (TUNEL)-positive apoptotic cells in hearts with permanent occlusion and in those with late reperfusion. Photomicrographs obtained 7 days post-MI showing TUNEL-positive cells in the infarct area of a heart with permanent occlusion and one with late reperfusion (%TUNEL+ cells: 0.66 ± 0.10 vs. 0.25 ± 0.04%, P < 0.05). #P < 0.05 vs. the permanent occlusion group (t-test). Bars: 20 µm. (Reproduced from Nakagawa et al.42.)

Figure 3

Proliferative and antiapoptotic effects of late reperfusion on postinfarct granulation tissue cells. (A) Time courses of the changes in Ki-67-positive proliferating cells in hearts with permanent occlusion and in those with late reperfusion. Photomicrographs obtained 4 days post-MI showing Ki-67-positive cells in the infarct area of a heart with permanent occlusion and one with late reperfusion (%Ki-67+ cells: 5.1 ± 0.85 vs. 8.8 ± 0.77%, P < 0.05). (B) Time-dependent changes in the incidences of in situ nick end-labelling (TUNEL)-positive apoptotic cells in hearts with permanent occlusion and in those with late reperfusion. Photomicrographs obtained 7 days post-MI showing TUNEL-positive cells in the infarct area of a heart with permanent occlusion and one with late reperfusion (%TUNEL+ cells: 0.66 ± 0.10 vs. 0.25 ± 0.04%, P < 0.05). #P < 0.05 vs. the permanent occlusion group (t-test). Bars: 20 µm. (Reproduced from Nakagawa et al.42.)

Most cellular components that infiltrate and proliferate within an infarct, including acute inflammatory and granulation tissue cells, disappear via apoptosis during the subacute and chronic stages of MI.26,27 Inhibition of apoptosis among granulation tissue cells during the subacute stage alters infarct tissue dynamics, making the infarct scar thicker and rich in preserved cellular components.55–57 Such effects mitigate the adverse remodelling and dysfunction otherwise seen during the chronic stage, most likely by attenuating wall stress. Interestingly, late reperfusion was found to downregulate the expression of both Fas (death receptor) and Fas ligand58 and suppress the rate of apoptosis among non-myocytes through the early and chronic stages (4 weeks after MI in rats) (Figure 3B).42 Thus, late reperfusion not only promotes the proliferation of granulation tissue cells, it also protects those cells from apoptotic loss, which likely explains the greater abundance of cells within infarct scars during the chronic stage of MI in infarcted hearts with late reperfusion.

Effects on salvaged myocardium

Late revascularization of ‘hibernating’ myocardium present within the peri-infarct region is also a possible benefit of a patent infarct-related artery.59 Hibernation is a chronic condition of severe myocardial energy deprivation caused by chronically low blood perfusion associated with reversible contractile dysfunction.60 These cardiomyocytes are said to be ‘dedifferentiated’ and show degenerative changes such as myofibrillar loss and mitochondriosis, which is somewhat similar to the foetal phenotype.61 These cells also reportedly exhibit autophagy, although its function is not yet understood.62,63 Another recent study noted that the degenerative changes associated with myocardial hibernation are mitigated by late reperfusion, which is accompanied by the restoration of GATA-4 expression.42 GATA-4 is a transcription factor that stimulates expression of important sarcomeric proteins (e.g. myosin heavy chain and troponin I)64,65 and is downregulated in hearts with permanent occlusion.42

Finally, a significantly higher rate of apoptosis was reported among cardiomyocytes in patients with persistent occlusion of the infarct-related artery.66,67 This increased apoptosis was apparent well beyond the acute phase of MI, and it was proposed that late reperfusion might inhibit the apoptotic loss of salvaged cardiomyocytes, thereby preventing the progression of heart failure. However, this hypothesis remains highly controversial because of the lack of ultrastructural evidence of cardiomyocyte apoptosis,42,68 which is the gold standard for diagnosis.69,70

Clinical aspects of late reperfusion

Coronary artery occlusion induces a wave front of myocardial necrosis that extends from the subendocardium to the subepicardium in a time-dependent manner.2,71 Although the rate of myocardial necrosis varies among experimental models of MI, it is typically complete within ∼6 h after the onset of occlusion.2 Thus, one would expect a reduction in infarct size—i.e. preservation of viable myocardium—if reperfusion could be initiated within 6 h. Consistent with that idea, randomized clinical trials have clearly shown that reperfusion within 6 h reduces mortality although the 6 h cut-off for reperfusion in acute MI patients is based primarily on thrombolysis studies.72,76 More recent trials with longer cut-off levels were performed with percutaneous transluminal coronary angioplasty (PTCA) or percutaneous coronary intervention (PCI) with stenting. Notably, the benefits of late reperfusion do not depend on the amount of salvaged myocardium at risk, and reperfusion as late as 12 h and possibly up to 24 h post-MI exert a beneficial effect.11 Beyond 24 h, however, the data are less encouraging, and the results of most recent clinical trials further diminish the enthusiasm for late reperfusion (Table 2).

Table 2

Randomized clinical studies of late reperfusion more than 24 h after the onset of acute myocardial infarction

Study No. of patients rep.: +/− Method for rep. Time to rep. Sustained patency rep.: +/− Overall outcome 
Topol et al.80, TAMI-6 71, 34/37 tPA+/−PTCA 12–48 h 60%/38% at 6 months Negative (mortality, LV volume, LV systolic function at 6 months) 
Dzavik et al.81, TOMIIS 44, 25/19 PTCA 5–42 days; mean, 21 days 43%/19% at 4 months Negative (clinical outcomes, LV size and EF at 4 months); positive in the subset (LVEF at 4 months) 
Horie et al.82 83, 44/39 PTCA >24 h 96%/13% at 6 months Positive (LV volume at 6 months; death, recurrent MI, congestive heart failure at 50 months) 
Yousef et al.83, TOAT 66, 32/34 Stenting 3 days–6 weeks; mean, 26 days 91%/19% at 12 months Greater LV dilation but improved exercise tolerance and QOL with reperfusion at 12 months 
Steg et al.84, DECOPI 212, 109/103 Stenting 2–15 days 83%/34% at 6 months Improved LVEF but no difference in clinical outcomes at 2 years 
Hochman et al.85, OAT 2166, 1082/1084 Stenting 3–28 days; median, 8 days  Negative (event-free survival at 4 years); trend toward higher reinfarction rates in reperfusion 
Davik et al.86, TOSCA-2 381, 150/136 Stenting 3–28 days; median, 10 days 83%/25% at 1 year Negative (LVEF at 4 years); trend toward less LV dilation in reperfusion 
Study No. of patients rep.: +/− Method for rep. Time to rep. Sustained patency rep.: +/− Overall outcome 
Topol et al.80, TAMI-6 71, 34/37 tPA+/−PTCA 12–48 h 60%/38% at 6 months Negative (mortality, LV volume, LV systolic function at 6 months) 
Dzavik et al.81, TOMIIS 44, 25/19 PTCA 5–42 days; mean, 21 days 43%/19% at 4 months Negative (clinical outcomes, LV size and EF at 4 months); positive in the subset (LVEF at 4 months) 
Horie et al.82 83, 44/39 PTCA >24 h 96%/13% at 6 months Positive (LV volume at 6 months; death, recurrent MI, congestive heart failure at 50 months) 
Yousef et al.83, TOAT 66, 32/34 Stenting 3 days–6 weeks; mean, 26 days 91%/19% at 12 months Greater LV dilation but improved exercise tolerance and QOL with reperfusion at 12 months 
Steg et al.84, DECOPI 212, 109/103 Stenting 2–15 days 83%/34% at 6 months Improved LVEF but no difference in clinical outcomes at 2 years 
Hochman et al.85, OAT 2166, 1082/1084 Stenting 3–28 days; median, 8 days  Negative (event-free survival at 4 years); trend toward higher reinfarction rates in reperfusion 
Davik et al.86, TOSCA-2 381, 150/136 Stenting 3–28 days; median, 10 days 83%/25% at 1 year Negative (LVEF at 4 years); trend toward less LV dilation in reperfusion 

tPA, tissue plasminogen activator; PTCA, percutaneous transluminal coronary angioplasty; LV, left ventricular; LVEF, left ventricular ejection fraction; rep., reperfusion; MI, myocardial infarction; QOL, quality of life.

Late reperfusion within 24 h

A meta-analysis of several trials of thrombolytic agents in the treatment of MI showed that streptokinase has a significant beneficial effect on the mortality rate, even when administered after a 6 h delay.77 Similarly, the ISI-2 trial showed a significant beneficial effect of streptokinase and aspirin on mortality among patients receiving treatment between 5 and 12 h after the onset of symptoms.73 Moreover, there was a 19% reduction in mortality among patients in the ISI-2 trial receiving therapy between 12 and 24 h after the onset of MI.73 Similarly, MI patients in the EMERAS trial showed a 15% reduction in mortality when administered streptokinase between 7 and 12 h after the onset of symptoms.78 However, this trial showed streptokinase to have no significant beneficial effect on the mortality rate among patients treated later than 12 h post-MI. In addition, the LATE investigators found a significant 25.6% reduction in the 35-day mortality rate among patients treated between 6 and 12 h after the onset of symptoms, but no significant benefit was seen among patients treated later than 12 h post-MI.79 Nonetheless, a subgroup of patients in the LATE trial who suffered with ongoing symptoms or had marked changes in their electrocardiogram showed a 22% reduction in mortality with treatment 12–24 h post-MI.79 Finally, the meta-analysis carried out by the FTT collaborative group reported a highly significant reduction in mortality rate among 13 000 patients treated with late reperfusion 7–12 h after the onset of symptoms.72 Collectively, these data established a time window of ∼12 h after the onset of symptoms as a golden time for reperfusion therapy in the treatment of acute MI.

Late reperfusion beyond 24 h

Table 2 summarizes the major randomized clinical studies of late reperfusion carried out more than 24 h after the onset of acute MI. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-6) study randomized 197 patients with ST-segment elevation MI (STEMI) 12–48 h after acute MI into primary therapy with tissue plasminogen activator and placebo groups, and patients with persistent coronary artery occlusion at 36 h into secondary therapy with PTCA and no-PTCA groups.80 Although initial patency was established in 81% of patients in the PTCA group, only 60% had a patent coronary artery at 6 months. In addition, patients in the no-PTCA group had a spontaneous patency rate of 38%. Consequently, at 6 months, there was no significant difference between the PTCA and no-PTCA groups with respect to mortality, ventricular volumes, and systolic function.

The Total Occlusion Post-Myocardial Infarction Intervention Study (TOMIIS) was a pilot study that evaluated 44 patients with an occluded infarct-related artery who were randomized into PTCA performed 5–42 days (mean, 21 days) after Q-wave MI and no-PTCA groups.81 The initial success rate for the PTCA was 72%, but reocclusion reduced the patency at 4 months to only 43%. No significant difference was seen in the clinical outcomes, LV size, and systolic function. However, a significant improvement in LV systolic function was noted in the subset of patients with sustained patency.

Horie et al.82 studied the effect of late reperfusion in patients with anterior MI who received PTCA more than 24 h after the onset of symptoms. The PTCA group showed significantly less LV dilatation at 6 months, and long-term follow-up over 50 months revealed significant reductions in the combined endpoint of death, reinfarction, and congestive heart failure.

In The Open Artery Trial (TOAT), PCI with stenting was performed in patients 3 days to 6 weeks after a first Q-wave anterior MI and was associated with a worsening of LV remodelling and increased dilatation.83 Paradoxically, patients receiving PCI had a better overall quality of life (exercise tolerance), and no significant difference was noted in endpoints such as death and heart failure. Given the conflicting data, the large, randomized DEsobstruction COronaire en Post-Infarctus (DECOPI) trial was designed specifically to evaluate the clinical benefits of late reperfusion achieved with PTCA performed 2–15 days after MI.84 No difference in mortality was found between the PTCA and medical therapy groups, but a 5% benefit in left ventricular ejection fraction (LVEF) was seen at 6 months in patients treated with PTCA. Another interesting finding of this trial was that when patients were categorized on the basis of patency at 6 months, independent of randomization, patients with a patent infarct-related artery had markedly improved outcomes: lower mortality, higher ejection fractions, and a trend towards a lower incidence of the primary endpoint. This suggests that prevention of restenosis and reocclusion is key to the clinical benefit of late reperfusion.

That said, two recent parallel trials markedly diminished the enthusiasm for late reperfusion in the clinical setting. The Occluded Artery Trial (OAT) and the Total Occlusion Study of Canada (TOSCA)-2 trial, respectively, evaluated the effects of late PCI after MI on the incidence of clinical events and LV size and function.85,86 The OAT trial was a large, multicentre, randomized study of 2166 patients with acute MI who had total occlusion of the infarct-related artery 3–28 days (median, 8 days) post-MI and were deemed to be high risk, with an LVEF of less than 50% or a proximal coronary artery occlusion with a large risk region. When those patients were randomized into PCI with stenting (n = 1082) or no-PCI (n = 1084) groups, there was no significant difference between the two with respect to the incidence of the primary endpoints (death, reinfarction, and NYHA class IV heart failure) over 4 years. In addition, the TOSCA-2 study found no significant difference between the LVEF and the LV volume index in the PCI (n = 150) and no-PCI (n = 136) groups.

Issues to be resolved in future

Whereas experimental studies have repeatedly shown reduction of infarct expansion and LV dilation and improvement of LV function when reperfusion is initiated late—i.e. too late to reduce myocardial infarct size—recent randomized clinical studies have failed to show such benefits. Indeed, there are many differences in models and protocols between human and animal studies because models and/or protocols are far simpler in animal studies—e.g. single duration of coronary occlusion, single coronary artery (mostly left anterior descending artery) occlusion only, large area at risk, almost regular size of acute MIs, and no collaterals in many species. One possible explanation for the discrepancy, however, relates to: (i) the variation in the timing of the late reperfusion in the clinical studies and (ii) in the magnitudes of the acute MIs, as well as (iii) differences in the rates of sustained recanalization of the infarct-related artery in those studies. Such within-group variation makes it difficult to resolve differences between groups.

Timing of late reperfusion

The time at which reperfusion was accomplished varied from 3 to 28 days after MI in both the OAT and TOSCA-2 studies.85,86 The median interval between MI and randomization was 8 days for the OAT study and 10 days for TOSCA-2. According to an early description of infarct expansion in humans, however, the process is well underway within the first week of acute MI.87 Therefore, reperfusion initiated 8–10 days post-MI may simply be too late to have a beneficial effect on remodelling. That reperfusion at this time is too late to prevent infarct expansion and LV dilatation is also suggested by an ancillary study of OAT. In addition, the huge heterogeneity of the timing of reperfusion might have made the within-group variation large in human studies.

What remains unknown from the preclinical studies is the exact duration of the window of opportunity during which late reperfusion can still enhance the healing benefit of the remodelling process.39 Most likely, there is a finite time window of opportunity in which late reperfusion can be initiated and still have a benefit; if reperfusion is induced beyond this window of opportunity, then LV remodelling is not affected. A recent study by Nakagawa et al.42 suggest that in rats, coronary reperfusion, even 24 h after occlusion, is beneficial. Somewhat later reperfusion might be expected to work well in humans, as the healing after MI progresses more slowly.

Magnitude of acute myocardial infarction

Transmural infarcts that develop an aneurysm, such as those observed in experimental animal studies, are relatively rare in human MIs, probably because of collateral development. In the case of small non-transmural MIs, the beneficial effects of late reperfusion are likely far smaller, given their mechanisms. However, the benefits of late reperfusion therapy are greatly needed by patients with large transmural MIs, who have a high probability of developing severe heart failure and a high mortality rate during the chronic stage. For that reason, clinical trials using more homogeneous populations of patients suffering with large transmural MIs would be desirable.

Patency of recanalized artery

Several clinical studies have indicated that sustained patency of the infarct-related artery is key to a better prognosis, irrespective of whether late reperfusion was performed.81,84 Thus, attention should be paid to reocclusion or restenosis that can occur soon after PCI.88–90 When the patency is lost early, patients assigned to the PCI group are, in fact, nearly the same as those assigned to the non-PCI group. The rate of reinfarction due to reocclusion tends to be higher in the PCI groups,85 which, by itself, worsens the prognosis of patients, and may negate any benefit of late reperfusion. Sustained patency is therefore desirable for validating the group assignment and properly evaluating the difference between groups. A clinical study designed to use drug-eluting stents may be a good choice for that purpose.

Conclusion

Although recent clinical trials appear to refute the suggestion that late reperfusion therapy is beneficial after acute MI, preclinical studies providing new insights into the pathophysiology of late reperfusion suggest that there is still a need to revisit the issue with an OAT-like trial in which PCI is initiated at an earlier time point after the onset of acute MI, the patient population is more homogeneous with large transmural MIs, and the reocclusion rates are lower.

Acknowledgements

The authors thank Akiko Tsujimoto for technical assistance.

Conflict of interest: none declared.

References

1
Pfeffer
MA
Left ventricular remodeling after acute myocardial infarction
Annu Rev Med
 , 
1995
, vol. 
46
 (pg. 
455
-
466
)
2
Reimer
KA
Vander Heide
RS
Richard
VJ
Reperfusion in acute myocardial infarction: effect of timing and modulating factors in experimental models
Am J Cardiol
 , 
1993
, vol. 
72
 (pg. 
13G
-
21G
)
3
Forrester
JS
Wyatt
HL
Da Luz
PL
Tyberg
JV
Diamond
GA
Swan
HJ
Functional significance of regional ischemic contraction abnormalities
Circulation
 , 
1976
, vol. 
54
 (pg. 
64
-
70
)
4
Hammermeister
KE
DeRouen
TA
Dodge
HT
Variables predictive of survival in patients with coronary disease. Selection by univariate and multivariate analyses from the clinical, electrocardiographic, exercise, arteriographic, and quantitative angiographic evaluations
Circulation
 , 
1979
, vol. 
59
 (pg. 
421
-
430
)
5
White
HD
Norris
RM
Brown
MA
Brandt
PW
Whitlock
RM
Wild
CJ
Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction
Circulation
 , 
1987
, vol. 
76
 (pg. 
44
-
51
)
6
St John Sutton
M
Pfeffer
MA
Plappert
T
Rouleau
JL
Moyé
LA
Dagenais
GR
, et al.  . 
Quantitative two-dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. The protective effects of captopril
Circulation
 , 
1994
, vol. 
89
 (pg. 
68
-
75
)
7
White
HD
Cross
DB
Elliott
JM
Norris
RM
Yee
TW
Long-term prognostic importance of patency of the infarct-related coronary artery after thrombolytic therapy for acute myocardial infarction
Circulation
 , 
1994
, vol. 
89
 (pg. 
61
-
67
)
8
Kim
CB
Braunwald
E
Potential benefits of late reperfusion of infarcted myocardium. The open artery hypothesis
Circulation
 , 
1993
, vol. 
88
 (pg. 
2426
-
2436
)
9
Marroquin
OC
Lamas
GA
Beneficial effects of an open artery on left ventricular remodeling after myocardial infarction
Prog Cardiovasc Dis
 , 
2004
, vol. 
42
 (pg. 
471
-
483
)
10
Yousef
ZR
Marber
MS
The open artery hypothesis: potential mechanisms of action
Prog Cardiovasc Dis
 , 
2000
, vol. 
42
 (pg. 
419
-
438
)
11
Sadanandan
S
Hochman
JS
Early reperfusion, late reperfusion, and the open artery hypothesis: an overview
Prog Cardiovasc Dis
 , 
2000
, vol. 
42
 (pg. 
397
-
404
)
12
Abbate
A
Biondi-Zoccai
GG
Baldi
A
Trani
C
Biasucci
LM
Vetrovec
GW
The ‘Open-Artery Hypothesis’: new clinical and pathophysiologic insights
Cardiology
 , 
2003
, vol. 
100
 (pg. 
196
-
206
)
13
Centurión
OA
The open artery hypothesis: beneficial effects and long-term prognostic importance of patency of the infarct-related coronary artery
Angiology
 , 
2007
, vol. 
58
 (pg. 
34
-
44
)
14
Brueck
M
Bandorski
D
Kramer
W
Vogt
PR
Heidt
MC
The late open infarct-related artery hypothesis: evidence-based medicine or not?
Clin Cardiol
 , 
2007
, vol. 
30
 (pg. 
541
-
545
)
15
Elmariah
S
Smith
SC
Jr
Fuster
V
Late medical versus interventional therapy for stable ST-segment elevation myocardial infarction
Nat Clin Pract Cardiovasc Med
 , 
2008
, vol. 
5
 (pg. 
42
-
52
)
16
Mallory
CK
White
PD
Sacedo-Salger
J
The speed of healing of myocardial infarction. A study of pathologic anatomy in seventy-two cases
Am Heart J
 , 
1939
, vol. 
18
 (pg. 
647
-
671
)
17
Lodge-Patch
I
The aging of cardiac infarcts and its influence on cardiac rupture
Br Heart J
 , 
1951
, vol. 
13
 (pg. 
37
-
42
)
18
Fishbein
MC
Maclean
D
Maroko
PR
Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution
Am J Pathol
 , 
1978
, vol. 
90
 (pg. 
57
-
70
)
19
Frangogiannis
NG
Smith
CW
Entman
ML
The inflammatory response in myocardial infarction
Cardiovasc Res
 , 
2002
, vol. 
53
 (pg. 
31
-
47
)
20
Cleutjens
JPM
The role of matrix metalloproteinases in heart disease
Cardiovasc Res
 , 
1996
, vol. 
32
 (pg. 
816
-
821
)
21
Bing
RJ
Myocardial ischemia and infarction: growth of ideas
Cardiovasc Res
 , 
2001
, vol. 
51
 (pg. 
13
-
20
)
22
Murry
CE
Giachelli
CM
Schwartz
SM
Vracko
R
Macrophages express osteopontin during repair of myocardial necrosis
Am J Pathol
 , 
1994
, vol. 
145
 (pg. 
1450
-
1462
)
23
Casscells
W
Kimura
H
Sanchez
JA
Yu
ZX
Ferrans
VJ
Immunohistochemical study of fibronectin in experimental myocardial infarction
Am J Pathol
 , 
1990
, vol. 
137
 (pg. 
801
-
810
)
24
Willems
IE
Arends
JW
Daemen
MJ
Tenascin and fibronectin expression in healing human myocardial scars
J Pathol
 , 
1996
, vol. 
179
 (pg. 
321
-
325
)
25
Ulrich
MM
Janssen
AM
Daemen
MJ
Rappaport
L
Samuel
JL
Contard
F
, et al.  . 
Increased expression of fibronectin isoforms after myocardial infarction in rats
J Mol Cell Cardiol
 , 
1997
, vol. 
29
 (pg. 
2533
-
2543
)
26
Desmouliere
A
Redard
M
Darby
I
Gabbiani
G
Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar
Am J Pathol
 , 
1995
, vol. 
146
 (pg. 
56
-
66
)
27
Takemura
G
Ohno
M
Hayakawa
Y
Misao
J
Kanoh
M
Ohno
A
, et al.  . 
Role of apoptosis in the disappearance of infiltrated and proliferated interstitial cells after myocardial infarction
Circ Res
 , 
1998
, vol. 
82
 (pg. 
1130
-
1138
)
28
Virag
JI
Murry
CE
Myofibroblast and endothelial cell proliferation during murine myocardial infarct repair
Am J Pathol
 , 
2003
, vol. 
163
 (pg. 
2433
-
2440
)
29
Jugdutt
BI
Amy
RWM
Healing after myocardial infarction in the dog: changes in infarct hydroyproline and topography
J Am Coll Cardiol
 , 
1986
, vol. 
7
 (pg. 
91
-
102
)
30
Hale
SL
Kloner
RA
Left ventricular topographic alterations in the completely healed rat infarct caused by early and late coronary artery reperfusion
Am Heart J
 , 
1988
, vol. 
116
 (pg. 
1508
-
1513
)
31
Sun
Y
Weber
KT
Infarct scar: a dynamic tissue
Cardiovasc Res
 , 
2000
, vol. 
46
 (pg. 
250
-
256
)
32
Weisman
HF
Healy
B
Myocardial infarct expansion, infarct extension, and reinfarction: pathophysiologic concepts
Prog Cardiovasc Dis
 , 
1987
, vol. 
30
 (pg. 
73
-
110
)
33
Schuster
EH
Bulkley
BH
Expansion of transmural myocardial infarction: a pathophysiologic factor in cardiac rupture
Circulation
 , 
1979
, vol. 
60
 (pg. 
1532
-
1538
)
34
Pfeffer
MA
Braunwald
E
Ventricular remodeling after myocardial infarction: experimental observations and clinical implications
Circulation
 , 
1990
, vol. 
81
 (pg. 
1161
-
1172
)
35
Lutgens
E
Daemen
MJ
de Muinck
ED
Debets
J
Leenders
P
Smits
JF
Chronic myocardial infarction in the mouse: cardiac structural and functional changes
Cardiovasc Res
 , 
1999
, vol. 
41
 (pg. 
586
-
593
)
36
Braunwald
E
Pfeffer
MA
Ventricular enlargement and remodeling following acute myocardial infarction: mechanisms and management
Am J Cardiol
 , 
1991
, vol. 
68
 (pg. 
1D
-
6D
)
37
Yin
FC
Ventricular wall stress
Circ Res
 , 
1981
, vol. 
49
 (pg. 
829
-
842
)
38
McKay
RG
Pfeffer
MA
Pasternak
RC
Markis
JE
Come
PC
Nakao
S
, et al.  . 
Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion
Circulation
 , 
1986
, vol. 
74
 (pg. 
693
-
702
)
39
Kloner
RA
Hwang
H
New insights into the open artery hypothesis
Circ Res
 , 
2008
, vol. 
103
 (pg. 
1
-
3
)
40
Hochman
JS
Choo
H
Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage
Circulation
 , 
1987
, vol. 
75
 (pg. 
299
-
306
)
41
Hale
SL
Kloner
RA
Left ventricular topographic alterations in the completely healed rat infarct caused by early and late coronary artery reperfusion
Am Heart J
 , 
1988
, vol. 
116
 (pg. 
1508
-
1513
)
42
Nakagawa
M
Takemura
G
Kanamori
H
Goto
K
Maruyama
R
Tsujimoto
A
, et al.  . 
Mechanisms by which late coronary reperfusion mitigates postinfarction cardiac remodeling
Circ Res
 , 
2008
, vol. 
103
 (pg. 
98
-
106
)
43
Hammerman
H
Kloner
RA
Hale
S
Schoen
FJ
Braunwald
E
Dose-dependent effects of short-term methylprednisolone on myocardial infarct extent, scar formation, and ventricular function
Circulation
 , 
1983
, vol. 
68
 (pg. 
446
-
452
)
44
Hammerman
H
Schoen
FJ
Braunwald
E
Kloner
RA
Drug-induced expansion of infarct: morphologic and functional correlations
Circulation
 , 
1984
, vol. 
69
 (pg. 
611
-
617
)
45
Monden
Y
Kubota
T
Tsutsumi
T
Inoue
T
Kawano
S
Kawamura
N
, et al.  . 
Soluble TNF receptors prevent apoptosis in infiltrating cells and promote ventricular rupture and remodeling after myocardial infarction
Cardiovasc Res
 , 
2007
, vol. 
73
 (pg. 
794
-
805
)
46
Minatoguchi
S
Takemura
G
Chen
XH
Wang
N
Uno
Y
Koda
M
, et al.  . 
Acceleration of the healing process and myocardial regeneration may be important as a mechanism of improvement of cardiac function and remodeling by postinfarction granulocyte colony-stimulating factor treatment
Circulation
 , 
2004
, vol. 
109
 (pg. 
2572
-
2580
)
47
Pfeffer
MA
Lamas
GA
Vaughan
DE
Parisi
AF
Braunwald
E
Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction
N Engl J Med
 , 
1988
, vol. 
319
 (pg. 
80
-
86
)
48
Pirzada
FA
Weiner
JM
Hood
WB
Jr
Experimental myocardial infarction. 14. Accelerated myocardial stiffening related to coronary reperfusion following ischemia
Chest
 , 
1978
, vol. 
74
 (pg. 
190
-
195
)
49
Uusimaa
P
Risteli
J
Niemela
M
Lumme
J
Ikaheimo
M
Jounela
A
, et al.  . 
Collagen scar formation after acute myocardial infarction: relationships to infarct size, left ventricular function, and coronary artery patency
Circulation
 , 
1997
, vol. 
96
 (pg. 
2565
-
2572
)
50
Jugdutt
BI
Ventricular remodeling after infarction and the extracellular collagen matrix. When is enough enough?
Circulation
 , 
2003
, vol. 
108
 (pg. 
1395
-
1403
)
51
Weber
KT
Anversa
P
Armstrong
PW
Brilla
CG
Burnett
JC
Jr
Cruickshank
JM
, et al.  . 
Remodeling and reparation of the cardiovascular system
J Am Coll Cardiol
 , 
1992
, vol. 
20
 (pg. 
3
-
16
)
52
Zak
R
Development and proliferative capacity of cardiac muscle cells
Circ Res
 , 
1974
, vol. 
35
 (pg. 
17
-
26
)
53
Nag
AC
Study of non-muscle cells of the adult mammalian heart: a fine structural analysis and distribution
Cytobios
 , 
1980
, vol. 
28
 (pg. 
41
-
61
)
54
Eghbali
M
Czaja
MJ
Zeydel
M
Weiner
FR
Zern
MA
Seifter
S
, et al.  . 
Collagen chain mRNAs in isolated heart cells from young and adult rats
J Mol Cell Cardiol
 , 
1988
, vol. 
20
 (pg. 
267
-
276
)
55
Hayakawa
K
Takemura
G
Kanoh
M
Li
Y
Koda
M
Kawase
Y
, et al.  . 
Inhibition of granulation tissue cell apoptosis during the subacute stage of myocardial infarction improves cardiac remodeling and dysfunction at the chronic stage
Circulation
 , 
2003
, vol. 
108
 (pg. 
104
-
109
)
56
Li
Y
Takemura
G
Kosai
K
Takahashi
T
Okada
H
Miyata
S
, et al.  . 
Critical roles for the Fas/Fas ligand system in postinfarction ventricular remodeling and heart failure
Circ Res
 , 
2004
, vol. 
95
 (pg. 
627
-
636
)
57
von Harsdorf
R
‘Fas-ten’ your seat belt: anti-apoptotic treatment in heart failure takes off
Circ Res
 , 
2004
, vol. 
95
 (pg. 
554
-
556
)
58
Nagata
S
Apoptosis by death factor
Cell
 , 
1997
, vol. 
88
 (pg. 
355
-
365
)
59
Kloner
RA
Coronary angioplasty: a treatment option for left ventricular remodeling after myocardial infarction?
J Am Coll Cardiol
 , 
1992
, vol. 
20
 (pg. 
314
-
316
)
60
Braunwald
E
Kloner
RA
The stunned myocardium: prolonged, postischemic ventricular dysfunction
Circulation
 , 
1982
, vol. 
66
 (pg. 
1146
-
1149
)
61
Elsässer
A
Schlepper
M
Klövekorn
WP
Cai
WJ
Zimmermann
R
Müller
KD
, et al.  . 
Hibernating myocardium: an incomplete adaptation to ischemia
Circulation
 , 
1997
, vol. 
96
 (pg. 
2920
-
2931
)
62
Elsässer
A
Vogt
AM
Nef
H
Kostin
S
Möllmann
H
Skwara
W
, et al.  . 
Human hibernating myocardium is jeopardized by apoptotic and autophagic cell death
J Am Coll Cardiol
 , 
2004
, vol. 
43
 (pg. 
2191
-
2199
)
63
Yan
L
Vatner
DE
Kim
SJ
Ge
H
Masurekar
M
Massover
WH
, et al.  . 
Autophagy in chronically ischemic myocardium
Proc Natl Acad Sci USA
 , 
2005
, vol. 
102
 (pg. 
13807
-
13812
)
64
Molkentin
JD
Kalvakolanu
DV
Markham
BE
Transcription factor GATA-4 regulates cardiac muscle-specific expression of the alpha-myosin heavy-chain gene
Mol Cell Biol
 , 
1994
, vol. 
14
 (pg. 
4947
-
4957
)
65
Murphy
AM
Thompson
WR
Peng
LF
Jones
L
2nd
Regulation of the rat cardiac troponin I gene by the transcription factor GATA-4
Biochem J
 , 
1997
, vol. 
322
 (pg. 
393
-
401
)
66
Abbate
A
Bussani
R
Biondi-Zoccai
GG
Rossiello
R
Silvestri
F
Baldi
F
, et al.  . 
Persistent infarct-related artery occlusion is associated with an increased myocardial apoptosis at postmortem examination in humans late after an acute myocardial infarction
Circulation
 , 
2002
, vol. 
106
 (pg. 
1051
-
1054
)
67
Baldi
A
Abbate
A
Bussani
R
Patti
G
Melfi
R
Angelini
A
, et al.  . 
Apoptosis and post-infarction left ventricular remodeling
J Mol Cell Cardiol
 , 
2002
, vol. 
34
 (pg. 
165
-
174
)
68
Takemura
G
Fujiwara
H
Morphological aspects of apoptosis in heart diseases
J Cell Mol Med
 , 
2006
, vol. 
10
 (pg. 
56
-
75
)
69
Kerr
JF
Winterford
CM
Harmon
BV
Apoptosis. Its significance in cancer and cancer therapy
Cancer
 , 
1994
, vol. 
73
 (pg. 
2013
-
3026
)
70
Galluzzi
L
Maiuri
MC
Vitale
I
Zischka
H
Castedo
M
Zitvogel
L
, et al.  . 
Cell death modalities: classification and pathophysiological implications
Cell Death Differ
 , 
2007
, vol. 
14
 (pg. 
1237
-
1243
)
71
DeWood
MA
Spores
J
Notske
R
Mouser
LT
Burroughs
R
Golden
MS
, et al.  . 
Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction
N Engl J Med
 , 
1980
, vol. 
303
 (pg. 
897
-
902
)
72
Fibrinolytic Therapy Trialists' (FTT) Collaborative Group
Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients
Lancet
 , 
1994
, vol. 
343
 (pg. 
311
-
322
)
73
Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI)
Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction
Lancet
 , 
1986
, vol. 
1
 (pg. 
397
-
402
)
74
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group
Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2
Lancet
 , 
1988
, vol. 
2
 (pg. 
349
-
360
)
75
The GUSTO investigators
An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction
N Engl J Med
 , 
1993
, vol. 
329
 (pg. 
673
-
682
)
76
Berger
PB
Ellis
SG
Holmes
DR
Jr
Granger
CB
Criger
DA
Betriu
A
, et al.  . 
Relationship between delay in performing direct coronary angioplasty and early clinical outcome in patients with acute myocardial infarction: results from the global use of strategies to open occluded arteries in Acute Coronary Syndromes (GUSTO-IIb) trial
Circulation
 , 
1999
, vol. 
100
 (pg. 
14
-
20
)
77
Yusuf
S
Collins
R
Peto
R
Furberg
C
Stampfer
MJ
Goldhaber
SZ
, et al.  . 
Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side-effects from 33 randomized controlled trials
Eur Heart J
 , 
1985
, vol. 
6
 (pg. 
556
-
585
)
78
EMERAS (Estudio Multicéntrico Estreptoquinasa Repúblicas de América del Sur) Collaborative Group
Randomised trial of late thrombolysis in patients with suspected acute myocardial infarction
Lancet
 , 
1993
, vol. 
342
 (pg. 
767
-
772
)
79
LATE Study Group
Late Assessment of Thrombolytic Efficacy (LATE) study with alteplase 6–24 hours after onset of acute myocardial infarction
Lancet
 , 
1993
, vol. 
342
 (pg. 
759
-
766
)
80
Topol
EJ
Califf
RM
Vandormael
M
Grines
CL
George
BS
Sanz
ML
, et al.  . 
A randomized trial of late reperfusion therapy for acute myocardial infarction. Thrombolysis and Angioplasty in Myocardial Infarction-6 Study Group
Circulation
 , 
1992
, vol. 
85
 (pg. 
2090
-
2099
)
81
Dzavik
V
Beanlands
DS
Davies
RF
Leddy
D
Marquis
JF
Teo
KK
, et al.  . 
Effects of late percutaneous transluminal coronary angioplasty of an occluded infarct-related coronary artery on left ventricular function in patients with a recent (<6 weeks) Q-wave acute myocardial infarction (Total Occlusion Post-Myocardial Infarction Intervention Study [TOMIIS]—a pilot study)
Am J Cardiol
 , 
1994
, vol. 
73
 (pg. 
856
-
861
)
82
Horie
H
Takahashi
M
Minai
K
Izumi
M
Takaoka
A
Nozawa
M
, et al.  . 
Long-term beneficial effect of late reperfusion for acute anterior myocardial infarction with percutaneous transluminal coronary angioplasty
Circulation
 , 
1998
, vol. 
98
 (pg. 
2377
-
2382
)
83
Yousef
ZR
Redwood
SR
Bucknall
CA
Sulke
AN
Marber
MS
Late intervention after anterior myocardial infarction: effects on left ventricular size, function, quality of life, and exercise tolerance: results of the Open Artery Trial (TOAT Study)
J Am Coll Cardiol
 , 
2002
, vol. 
40
 (pg. 
869
-
876
)
84
Steg
PG
Thuaire
C
Himbert
D
Carrié
D
Champagne
S
Coisne
D
, et al.  . 
DECOPI Investigators
DECOPI (DEsobstruction COronaire en Post-Infarctus): a randomized multi-centre trial of occluded artery angioplasty after acute myocardial infarction
Eur Heart J
 , 
2004
, vol. 
25
 (pg. 
2187
-
2194
)
85
Hochman
JS
Lamas
GA
Buller
CE
Dzavik
V
Reynolds
HR
Abramsky
SJ
, et al.  . 
for the Occluded Artery Trial Investigators
Coronary intervention for persistent occlusion after myocardial infarction
N Engl J Med
 , 
2006
, vol. 
355
 (pg. 
2395
-
2407
)
86
Davik
V
Buller
CE
Lamas
GA
Rankin
JM
Mancini
GBJ
Cantor
WJ
, et al.  . 
for the TOSCA-2 Investigators
Randomized trial of percutaneous coronary intervention for subacute infarct-related coronary occlusion to achieve long-term patency and improve ventricular function. The Total Occlusion Study of Canada (TOSCA)-2 Trial
Circulation
 , 
2006
, vol. 
114
 (pg. 
2449
-
2457
)
87
Eaton
LW
Weiss
JL
Bulkley
BH
Garrison
JB
Weisfeldt
ML
Regional cardiac dilatation after acute myocardial infarction: two-dimensional echocardiography
N Engl J Med
 , 
1979
, vol. 
300
 (pg. 
57
-
62
)
88
Hamon
M
Bauters
C
McFadden
EP
Wernert
N
Lablanche
JM
Dupuis
B
, et al.  . 
Restenosis after coronary angioplasty
Eur Heart J
 , 
1995
, vol. 
16
 
Suppl. I
(pg. 
33
-
48
)
89
Bass
TA
Post-PCI cardiac events? The answer is the lumen, or is it in the wall?
Catheter Cardiovasc Interv
 , 
2002
, vol. 
55
 (pg. 
338
-
339
)
90
Kivelä
A
Hartikainen
J
Restenosis related to percutaneous coronary intervention has been solved?
Ann Med
 , 
2006
, vol. 
38
 (pg. 
173
-
187
)