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.
Infarct tissue dynamics
Left ventricular remodelling
Open artery hypothesis
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.
2. 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
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).
3. 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
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).
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
3.1 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
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.
3.2 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
4. 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).
Randomized clinical studies of late reperfusion more than 24 h after the onset of acute myocardial infarction
No. of patients rep.: +/−
Method for rep.
Time to rep.
Sustained patency rep.: +/−
Topol et al.80, TAMI-6
60%/38% at 6 months
Negative (mortality, LV volume, LV systolic function at 6 months)
Dzavik et al.81, TOMIIS
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
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
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
83%/34% at 6 months
Improved LVEF but no difference in clinical outcomes at 2 years
Hochman et al.85, OAT
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
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.
4.1 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.
4.2 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.
5. 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.
5.1 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.
5.2 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.
5.3 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.
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.
The authors thank Akiko Tsujimoto for technical assistance.
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