STATE-OF-THE-ART PAPER
Myocardial No-Reflow in Humans
Giampaolo Niccoli, MD, PhD*,
Francesco Burzotta, MD, PhD,
Leonarda Galiuto, MD, PhD and
Filippo Crea, MD, PhD
Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy
Manuscript received July 24, 2008;
revised manuscript received March 17, 2009,
accepted March 17, 2009.
* Reprint requests and correspondence: Dr. Giampaolo Niccoli, Institute of Cardiology, Catholic University of the Sacred Heart, L.go Agostino Gemelli, 8, Rome 00168, Italy (Email: gniccoli73{at}hotmail.it).
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Abstract
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In a variable proportion of patients presenting with ST-segment elevation myocardial infarction, ranging from 5% to 50%, primary percutaneous coronary intervention achieves epicardial coronary artery reperfusion but not myocardial reperfusion, a condition known as no-reflow. Of note, no-reflow is associated with a worse prognosis at follow-up. The phenomenon has a multifactorial pathogenesis including: distal embolization, ischemia-reperfusion injury, and individual predisposition of coronary microcirculation to injury. Moreover, it is spontaneously reversible in some patients, thus suggesting that it might be amenable to treatment also when we fail to prevent it. Several recent studies have shown that biomarkers and other easily available clinical parameters can predict the risk of no-reflow and can help in the assessment of the multiple mechanisms of the phenomenon. Several therapeutic strategies have been tested for the prevention and treatment of no-reflow. In particular, thrombus aspiration before stent implantation prevents distal embolization and has been recently shown to improve myocardial perfusion and clinical outcome as compared with the standard procedure. However, it is conceivable that the relevance of each pathogenetic component of no-reflow is different in different patients, thus explaining the occurrence of no-reflow despite the use of mechanical thrombus aspiration. Thus, in this review article, for the first time, we propose a personalized management of no-reflow on the basis of the assessment of the prevailing mechanisms of no-reflow operating in each patient.
Key Words: microcirculation • myocardial no-reflow • primary percutaneous coronary intervention • ST-segment elevation myocardial infarction
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Abbreviations and Acronyms
| | ATP = adenosine triphosphate | | CMR = cardiac magnetic resonance | | ECG = electrocardiogram/electrocardiographic | | ET = endothelin | | IR = ischemia-reperfusion | | IRA = infarct-related artery | | LV = left ventricle | | MBG = myocardial blush grade | | MCE = myocardial contrast echocardiography | | m-PTP = mitochondrial permeability transition pore | | PPCI = primary percutaneous coronary intervention | | STEMI = ST-segment elevation myocardial infarction | | STR = ST-segment elevation resolution | | TIMI = Thrombolysis In Myocardial Infarction | | TxA2 = thromboxane-A2 |
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Definition and Clinical Relevance of No-Reflow
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Prompt referral for mechanical reperfusion by urgent primary percutaneous coronary intervention (PPCI) represents the pivotal step in the current management of ST-segment elevation myocardial infarction (STEMI) (1). Yet, in a sizable proportion of patients PPCI achieves epicardial coronary artery reperfusion but not myocardial reperfusion, a condition known as no-reflow (2). In particular, the term "no-reflow" has been increasingly used in published medical reports to describe microvascular obstruction and reduced myocardial flow after opening an occluded artery.
The existence of no-reflow phenomenon was initially debated; however, a large amount of experimental and clinical data have clearly shown that it occurs after reperfusion with a variable prevalence, ranging from 5% up to 50%, according to the methods used to assess the phenomenon and to the population under study (2,3).
In 1993, at the climax of the thrombolytic era, Lincoff and Topol (4) wrote a provocative editorial wondering whether reperfusion was just an illusion. At that time, they estimated that only "25% or less" of patients treated by thrombolysis had an optimal reperfusion, defined as a rapid, complete, and sustained coronary recanalization with adequate myocardial tissue perfusion. What is this figure after 15 years at the climax of the PPCI era? As shown in Figure 1, a reasonable estimate of the proportion of patients who get optimal myocardial reperfusion, among those without cardiogenic shock undergoing PPCI, is approximately 35%.
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Figure 1 Prevalence of Myocardial No-Reflow
Estimate of the number of patients (pts) receiving optimal reperfusion according to Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment resolution (STR) of 100 patients without cardiogenic shock treated by primary percutaneous coronary intervention (PPCI). *Estimation derived from 20 randomized trials comparing standard percutaneous coronary intervention with thrombectomy or distal protection (75). **Estimation derived from core laboratory analysis of the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial (8). STEMI = ST-segment elevation myocardial infarction.
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A series of consistent data has clearly shown that no-reflow has a strong negative impact on outcome, negating the potential benefit of PPCI (5–11). Indeed, patients with no-reflow exhibit a higher prevalence of: 1) early post-infarction complications (arrhythmias, pericardial effusion, cardiac tamponade, early congestive heart failure); 2) left adverse ventricular remodeling; 3) late repeat hospital stays for heart failure; and 4) mortality (Fig. 2).
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Figure 2 Prognostic Value of No-Reflow According to Angiographic, Electrocardiographic, and Echocontrastographic Indexes
The end point was cardiac death (9) or total mortality (4,6–8,64). Data are presented as odds ratio (OR) and 95% confidence interval (CI). MCE = myocardial contrast echocardiography; TMPG = TIMI myocardial perfusion grade; other abbreviations as in Figure 1.
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Therefore, detection, prevention, and treatment of no-reflow are likely to have an important impact on the outcome of PPCI. Here we propose possible personalized forms of prevention and treatment, on the basis of the notion that no-reflow is a dynamic process characterized by multiple pathogenetic components.
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Time-Course and Pathogenetic Components of No-Reflow
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Kloner et al. (12) described no-reflow for the first time in a canine model, demonstrating that it occurs after prolonged (90 min) coronary occlusion followed by reperfusion. The consequences of coronary ligation of a nonatherosclerotic coronary artery, however, cannot be directly extrapolated to the human situation where myocardial infarction is caused by occlusive coronary thrombosis superimposed onto an atherosclerotic unstable plaque (13).
Galiuto et al. (14), with sequential measurements of myocardial perfusion by myocardial contrast echocardiography (MCE), have recently shown that in humans no-reflow detected 24 h after successful PCI spontaneously improves over time in approximately 50% of patients. Thus, no-reflow can be categorized as sustained and reversible. Sustained no-reflow is probably the result of anatomical irreversible changes of coronary microcirculation, whereas reversible no-reflow is the result of functional and, thus reversible, changes of microcirculation. Interestingly, whereas patients with sustained no-reflow undergo unfavorable left ventricle (LV) remodeling, patients with reversible no-reflow maintain their LV volumes unchanged over time (14). Similar findings were shown by Hoffman et al. (15) by analyzing changes of myocardial blush grade (MBG) over time. In this study also the evolution of MBG was a potent predictor of LV remodeling.
Taken together these studies demonstrate that no-reflow, at least in some patients, is reversible, thus opening a new scenario on the search for no-reflow reversal.
In humans, no-reflow is caused by the variable combination of 4 pathogenetic components: 1) distal atherothrombotic embolization; 2) ischemic injury; 3) reperfusion injury; and 4) susceptibility of coronary microcirculation to injury (Fig. 3). As a consequence, appropriate strategies to prevent or treat each of these components are expected to reduce the prevalence of sustained no-reflow.
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Figure 3 Mechanisms Responsible for No-Reflow
Four interacting mechanisms (distal embolization, ischemia-related injury, reperfusion related injury, and individual susceptibility to microvascular injury) are responsible for no-reflow phenomenon. The individual contribution of these mechanisms to the pathogenesis of no-reflow is likely to vary in different patients.
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Distal embolization.
Emboli of different sizes can originate from epicardial coronary thrombus and from fissured atherosclerotic plaques, in particular during PPCI (16). Experimental observations have shown that myocardial blood flow decreases irreversibly when microspheres obstruct more than 50% of coronary capillaries (17). Okamura et al. (18) used a Doppler guidewire in humans to detect high-intensity transient signals, which allowed the counting of the number of embolic particles. The average number of emboli throughout PPCI was 25. Thus, this small number of emboli is unlikely to affect coronary blood flow. Yet, large emboli (>200-µm diameter) can obstruct pre-arterioles, causing infarctlets.
Ischemia-related injury.
Changes in endothelial cells, visible after prolonged ischemia, are represented by endothelial protrusions and membrane-bound bodies, which often fill the capillaries up to luminal obliteration. Furthermore, large endothelial gaps with extra vascular erythrocytes are common (19). Morphological findings are accompanied by a reduction of regional myocardial blood flow within the previously ischemic region (20). Moreover, myocardial cell swelling associated with interstitial edema might cause microvascular compression (21).
Reperfusion-related injury.
A massive infiltration of coronary microcirculation by neutrophils and platelets occurs at the time of reperfusion (19,22). Indeed, reintroduction of neutrophils in post-ischemic myocardium results in their activation, with subsequent adhesion to the endothelial surface and migration in the surrounding tissue. Activated neutrophils, in turn, release oxygen free radicals, proteolytic enzymes, and pro-inflammatory mediators that can directly cause tissue and endothelial damage. Neutrophils also form aggregates with platelets that plug capillaries, thus mechanically blocking flow (23,24). Finally, vasoconstrictors released by damaged endothelial cells, neutrophils, and platelets contribute to sustained vasoconstriction of coronary microcirculation (25).
From a molecular point of view inflammatory mediators are involved in a complex interaction between platelets, neutrophils, and endothelium. In particular, tumor necrosis factor-alpha expression is induced by reperfusion, and it can impair endothelium-dependent coronary flow reserve (26). Furthermore, interleukin-1β has recently been associated with ischemia-reperfusion (IR) injury, because interleukin-1β knockout animals exhibit marked reduction of ischemic induced inflammation (27). Selectin expression on cell surfaces is also important for mechanical plugging of the microcirculation (28). Finally, the balance between nitric oxide and superoxide is tipped in favor of superoxide within minutes of reperfusion of ischemic tissues, due to increased production of xantine oxidase by neutrophils, endothelial cells, and cardiac myocytes, which leads to an exacerbation of the inflammatory state (29).
Reperfusion might also cause irreversible injury to myocytes (30). During ischemia there is an increase of intracellular content of sodium (Na+) due to accumulation of hydrogen (H+) that are exchanged by the Na+/H+ exchanger. The subsequent exchange of doubly charged positive calcium ion (Ca++) with Na+ by sarcolemmal Na+/Ca++ exchanger produces a calcium overload that triggers uncontrolled hypercontraction and stimulates opening of the mitochondrial permeability transition pore (m-PTP), which further enhances calcium overload. Furthermore, Na+ extrusion trough Na+/potassium (K+) adenosine triphosphate (ATP)-ase is impaired and together with Ca++ accumulation leads to myocyte cell swelling, which contributes to subsequent rupture of the cell membrane when the extracellular osmolality is rapidly normalized by reperfusion. Of note, cyclosporine, which blocks the m-PTP, has been recently shown to reduce infarct size by 20% when administered intravenously in patients undergoing PPCI (31). Finally, ischemic pre-conditioning might also reduce infarct size by blockade of m-PTP (32).
Natriuretic peptides might modulate IR injury. Atrial natriuretic peptide might suppress the renin angiotensin-aldosterone system and endothelin (ET)-1 that increase infarct size, microvascular obstruction, and cardiac remodeling (33). Accordingly, Hayashi et al. (34) showed that infusion of atrial natriuretic peptide in patients with their first anterior myocardial infarction is associated with lower concentration of ET-1, angiotensin-II, and aldosterone. Of note, B-type natriuretic peptide limits infarct size when administered before and during coronary occlusion through a KATP channel-dependent mechanism, which requires nitric oxide synthase activity (35).
Individual predisposition of coronary microcirculation to injury.
In humans, no-reflow associated with ST-segment elevation is occasionally observed during elective procedures (36), whereas it can be absent after PPCI carried out several hours after coronary occlusion. Predisposition might be genetic and/or acquired. In particular, diabetes has been associated with impaired microvascular reperfusion after PPCI, and hypercholesterolemia in the animal model aggravates reperfusion injury by enhancing endothelial oxidative stress (37,38). Finally, pre-conditioning seems to have a beneficial effect on microvascular function (39).
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Predictors of the Pathogenetic Components of No-Reflow
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Predictors of distal embolization.
Some angiographic findings predict the risk of distal embolization possibly favoring no-reflow (Table 1). Yip et al. (40) proposed a score to assess thrombus burden on the basis of the following features: 1) an angiographic thrombus with the greatest linear dimension more than 3 times the reference lumen diameter; 2) cutoff pattern (lesion morphology with an abrupt cutoff without taper before the occlusion); 3) presence of accumulated thrombus (>5 mm of linear dimension) proximal to the occlusion; 4) presence of floating thrombus proximal to the occlusion; 5) persistent contrast medium distal to the obstruction; and 6) reference lumen diameter of the infarct-related artery (IRA) >4.0 mm. All of these features were independent predictors of no-reflow in 800 patients undergoing PPCI. The relevance of high thrombus burden at the site of the culprit artery in predicting distal embolization has also been shown by Limbruno et al. (41). Indeed, in a series of patients with STEMI undergoing PPCI with distal filter protection, they found that Yip's score was an independent predictor of total debris volume captured in the filter's basket. Of note, distal embolization of thrombotic debris typically occurs after stent placement in large coronary vessels, whereas in small vessels it is possible that the stent itself might fix the thrombus to the vessel wall, especially if the thrombus is not fresh anymore, as also suggested by the analysis of Yip et al. (40).
Predictors of ischemia-related injury.
A longer time to reperfusion is associated with a higher prevalence of no-reflow and with a larger no-reflow region (42) (Table 2). Interestingly, Turschner et al. (43) showed that prolonged ischemia followed by reperfusion is associated with increased thickness of the myocardium due to tissue edema, which eventually leads to no-reflow for mechanical reasons.
The extent of the ischemic region is another important determinant of no-reflow, as demonstrated in animal models (Table 2). This is confirmed in man by the association of electrocardiographic (ECG) and echocardiographic indexes of the extent of ischemic region, such as QRS score and wall motion score index, respectively, and prevalence of no-reflow (44,45). The higher prevalence of no-reflow when the left anterior descending is the IRA artery as compared with other epicardial coronary arteries confirms that a larger extent of the ischemic area is an important predictor of no-reflow (45).
Predictors of reperfusion-related injury.
An easily available clinical predictor of no-reflow is neutrophil count, which has been recently associated with microvascular injury after PPCI (46) (Table 2). Platelets also play an important role in no-reflow. Accordingly, platelet reactivity on admission, as assessed by the Platelet Function Analyzer–100 (Dade Behring, Milan, Italy), is associated with the prevalence of no-reflow and adverse remodeling (47). Furthermore, Huczek et al. (48) demonstrated that mean platelet volume on admission is an important predictor of impaired reperfusion. Interestingly, early data from our group indicate that plasma levels of thromboxane-A2 (TxA2) predict no-reflow (49) (Table 2).
Natural antioxidant levels might protect from no-reflow as suggested by Matsumoto et al. (50), who demonstrated that levels of vitamin C, vitamin E, and glutathione peroxidase obtained from coronary sinus before PPCI were significantly lower in patients exhibiting no-reflow than in patients exhibiting myocardial reperfusion.
ET-1 plays a key role in no-reflow, depending on its strong vasoconstrictive effect exerted on small-resistance coronary arteries, on the enhancement of neutrophil adhesion to the endothelium, and on the induction of elastase release, which might also mediate tissue injury and edema (51). Of note, we recently demonstrated that ET-1 levels on admission are an independent predictor of no-reflow (51) (Table 2). ET-1 is a possible therapeutic target, and this notion is supported by the beneficial effect of selective ET-1 antagonist in animal models of IR (52).
Thus, the severity of reperfusion injury might be assessed with clinical predictors such as neutrophil count, mean platelet volume, platelet reactivity, TxA2, and ET-1 levels.
Predictors of individual susceptibility to microvascular injury.
Genetic and acquired susceptibility to microvascular injury might play an important role in the modulation of no-reflow (Table 2).
Interestingly, a recent study suggested that the 1976T>C polymorphism of the adenosine 2A receptors gene is associated with a higher prevalence of no-reflow (53). Furthermore, patients with no-reflow show a more compact fibrin network, possibly suggesting a genetic mediated resistance to lysis (54).
Baseline reactivity of inflammatory cells also might modulate the severity of no-reflow. Yet, we failed to find a correlation between C-reactive protein serum levels measured within 6 h of chest pain onset and the prevalence of no-reflow (55). In contrast, peak C-reactive protein reflecting necrosis extent has been associated with no-reflow (56).
Acquired risk factors such as diabetes and hypercholesterolemia might predispose to no-reflow, as suggested by observation carried out in humans and in animal models (37,38).
Recent studies have demonstrated an association between acute hyperglycemia and no-reflow, which was independent of previous glycemic control evaluated by glycosylated hemoglobin A1c levels and might suggest a direct detrimental effect of acute hyperglycemia on reperfusion injury (57). Finally, pre-infarction angina might have a protective effect, because it induces ischemic pre-conditioning (58), which, in contrast, is abolished by binge drinking (59).
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Diagnosis
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Coronary angiography.
No-reflow can be assessed during PPCI with Thrombolysis In Myocardial Infarction (TIMI) flow grade and MBG in the coronary care unit by assessing the ST-segment elevation resolution (STR) after PPCI and can be better quantified by noninvasive imaging techniques, such as MCE and contrast-enhanced cardiac magnetic resonance (CMR) (Fig. 4).
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Figure 4 No-Reflow as Assessed by Angiography (MBG), ECG, and Imaging Techniques
(A) Right: MBG 0 (white arrows); left: MBG 3 (white arrows). (B) Right: lack of STR; left: complete STR. (C) Right: no-reflow assessed by MCE (white arrows); left: reflow assessed by MCE (white arrows). (D) Right: no-reflow assessed by magnetic resonance imaging with first-pass of gadolinium (top) or the delayed enhancement (bottom) (white arrows); left: reflow assessed by magnetic resonance imaging with first-pass of gadolinium (top) or the delayed enhancement (bottom) (white arrows). Abbreviations as in Figures 1 and 2.
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No-reflow can initially be demonstrated by analysis of TIMI flow grade (60). Indeed, TIMI flow grade 0 to 2, observed in 5% to 10% of patients, is predictably associated with no-reflow. The latter, however, also occurs in a sizeable proportion of patients with apparent successful large epicardial vessel reopening resulting in TIMI flow grade 3. Thus, the sensitivity of TIMI flow assessment in the detection of no-reflow is rather low. At the time of PPCI, no-reflow can be inferred more efficiently by assessing MBG, which describes the relative "blush" or intensity of the radio-opacity of myocardial tissue achieved with an epicardial coronary injection of contrast medium and the rapidity that this enhancement clears with. The more intense the myocardial blush and the faster its clearance, the better the microvascular perfusion. The MBG is scored on a scale of 0 to 3, with higher scores indicating better perfusion. An MBG 0 to 1, suggestive of no-reflow, is observed in as high as 50% of patients with TIMI flow grade 3 (61). Taken together, angiographic no-reflow can be defined as a TIMI flow grade <3 or 3 with an MBG 0 to 1.
ECG.
Largely used in the clinical arena and in trials is the measurement of STR 1 h after PPCI. Different methods have been proposed to measure STR. Lack of STR <50% or 70% is considered as an established marker of no-reflow, because its predictive value was demonstrated at the start of the pharmacological reperfusion era and has been confirmed in the contemporary mechanical reperfusion era (62). Notably, approximately one-third of patients with TIMI flow grade 3 and MBG 2 to 3 do not exhibit STR (63).
Because TIMI flow grade, MBG, and STR might be obtained from the routine management of STEMI patients, are inexpensive, and provide additional prognostic information, their assessment should become current clinical practice. Notably, the integration of MBG and STR has been shown to improve patient risk stratification. Indeed, 2 independent studies, in patients treated by either PPCI (64) or pharmacological reperfusion (63), have reported very good outcomes in patients with an MBG 2 to 3 and STR >70%, very poor outcomes in patients with MBG 0 to 1 and STR<70%, and an intermediate prognosis in patients with discordant results of angiographic and ECG indexes of no-reflow.
Noninvasive imaging techniques.
Although easily available in the clinical arena, neither blush grade nor ECG resolution provide a direct assessment of myocardial perfusion. In contrast, noninvasive imaging techniques such as MCE and CMR provide a more direct assessment of myocardial perfusion.
Myocardial contrast echocardiography uses ultrasound to visualize contrast microbubbles that freely flow within patent microcirculation. Such microbubbles are injected in the peripheral circulation, safely pass the pulmonary circulation, and reach intact coronary bed. They have a rheology similar to that of red blood cells and thus freely flow within coronary microvessels, as the only 1 pure intravascular tracer. Lack of intramyocardial contrast opacification is due to microvascular obstruction; thus, it represents the extent of no-reflow (65,66). In the AMICI study, the extent of no-reflow at MCE was demonstrated to be the best predictor of adverse LV remodeling after acute myocardial infarction, being superior to STR and to MBG among patients exhibiting TIMI flow grade 3 (10).
Cardiac magnetic resonance imaging uses gadolinium to assess regional cardiac perfusion. No-reflow can be diagnosed as: 1) lack of gadolinium enhancement during first pass; and 2) lack of gadolinium enhancement within a necrotic region, identified by late gadolinium hyper-enhancement (67). In particular, very good correlation has been found between gadolinium enhancement during first pass and MBG, thus suggesting that these 2 parameters might reflect the microvascular integrity within the infarct zone (68). Studies performed by CMR have confirmed that no-reflow is a powerful predictor of LV remodeling and of patient survival (11).
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Prevention and Treatment of No-Reflow According to Timing and Pathogenetic Components
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Several therapeutic strategies have been tested for the prevention and treatment of no-reflow with inconsistent results, possibly because they have been applied indiscriminantly to all patients. It is conceivable that the relevance of each pathogenetic component of no-reflow is different in different patients. Therefore, the assessment of the multiple mechanisms of no-reflow might guide the development of personalized forms of treatment (Table 2). Thus, it is possible to envision a personalized treatment of no-reflow that stems from the assessment of the predictors of the 4 pathogenetic components of the phenomenon. The treatment should then aim at counteracting the prevailing mechanism(s) of no-reflow (Fig. 5).
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Figure 5 Therapies of No-Reflow Targeted to Main Pathogenetic Mechanisms
A comprehensive figure showing multiple mechanisms involved in the pathogenesis of no-reflow that might be targeted by appropriate therapy. Figure illustration by Rob Flewell. ET = endothelin; TxA2 = thromboxane-A2.
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Management of distal embolization.
Although the detrimental effects of distal embolization during PCI are well-recognized, thus prompting its prevention during reperfusion, no specific technique is currently recommended in guidelines to prevent distal embolization during PPCI. Direct stent implantation, by avoiding balloon-induced thrombus fragmentation and by entrapping the atherothrombus under the stent struts, has been suggested as a possible technique to reduce distal embolization. One trial (69) showed improved reperfusion in selected patients randomized to direct stenting as compared with standard PPCI. However, only a specific subset of patients (those with good distal visualization of the IRA after guidewire passage through the culprit lesion) is suitable for direct stenting.
A more promising technical approach to prevent no-reflow during mechanical reperfusion is the use of thrombectomy devices and of distal filters. Yet, skepticism arose after publication of 2 large trials showing that rheolytic thrombectomy (70) and distal occlusive protection (71) do not improve reperfusion, as compared with standard PPCI. The negative results of these trials, however, should be interpreted within the limitations of their design, which was characterized by the enrollment of patients at low risk of no-reflow and by the use of first-generation, complex devices. Another study conducted by skilled operators with another complex thrombectomy device (the X-sizer) in high-risk patients did show improvement of myocardial reperfusion (72). These inconsistencies prompted us to design the REMEDIA (Randomized Evaluation of the Effect of Mechanical Reduction of Distal Embolization by Thrombus-Aspiration in Primary and Rescue Angioplasty) trial, which was the first randomized trial to assess the role of thrombectomy performed with a simple manual aspiration catheter, as compared with conventional PPCI (73). The results of the REMEDIA trial were promising, because manual thrombectomy was safe and resulted in better myocardial perfusion indexes as compared with standard PPCI. The benefit was particularly evident in the subset of patients with higher thrombus burden and with total IRA occlusion, thus suggesting that the efficacy of thrombectomy might be dependent on individual patient characteristics (73). In the MCE substudy of the same trial thrombus-aspiration significantly reduced no-reflow (74). A recent meta-analysis showed that thrombectomy was associated with a significant improvement of reperfusion as assessed by STR and MBG, whereas distal protection was not (75). Finally, a very recent, large trial by Svilaas et al. (76) confirmed the improvement of reperfusion associated with manual thrombus-aspiration as compared with standard PPCI. This landmark study has been the first to show that improvement of myocardial perfusion by manual thrombus aspiration translated in a strikingly lower mortality at 12-month follow-up (77). Taken together, these studies suggest that manual thrombus aspiration should be used in the setting of PPCI, particularly in patients with a high thrombus burden (78).
Management of ischemia-related injury.
Strategies aimed at reducing pain-onset-to-balloon time are currently widely investigated and might reduce the prevalence of no-reflow by reducing total ischemic time. Similarly, drugs known to reduce myocardial oxygen consumption and consequently the severity of ischemia might improve the outcome, at least partially, through an improvement of myocardial perfusion (79). The beneficial effects of carvedilol, fosinopril, and valsartan on coronary no-reflow have indeed been recently demonstrated (80,81).
Management of reperfusion-related injury.
Patients at high risk of no-reflow on the basis of the presence of predictors of reperfusion-related injury can be treated with drugs like glycoprotein IIb/IIIa antagonists, adenosine, nicorandil, and nitroprusside aimed at counteracting endothelial, platelet, and neutrophil activation. Selective ET-1 or TxA2 antagonism might represent novel therapeutic approaches.
Among glycoprotein IIb/IIIa antagonists, abciximab has been found to improve myocardial perfusion when started during PPCI and infused for 12 h thereafter, as assessed by a higher rate of STR >50% at 60 min after PCI (73% vs. 57%, p < 0.05) (82). The beneficial effects of abciximab on microvascular reperfusion in the setting of PPCI parallel and might at least partially account for those on clinical end points (83). Conversely, the effects of peptidic glycoprotein IIb/IIIa antagonists on no-reflow and long-term mortality still need to be tested in randomized trials. Interestingly, in a small randomized study of abciximab versus tirofiban for patients undergoing PPCI, Danzi et al. (84) demonstrated similar rates of final TIMI flow grade 3 (86% vs. 88%), of adverse cardiac remodeling, and of clinical events at 1 month in the 2 arms. Taken together, these findings suggest that glycoprotein IIb/IIIa antagonists prevent no-reflow. Interestingly, intracoronary abciximab has been proven to be superior to intravenous abciximab in patients treated by primary PPCI (85). The evidence that this beneficial effect on myocardial perfusion translates into an improvement of the outcome, however, has convincingly been obtained for abciximab only.
Adenosine is an endogenous nucleoside mainly produced by the degradation of adenosine triphosphate, which antagonizes platelets and neutrophils, reduces calcium overload and oxygen free radicals, and induces vasodilation (86). In a randomized trial, intracoronary administration of 4 mg of adenosine before complete vessel reopening resulted in a lower rate of no-reflow as compared with the control arm (86). More recently, intracoronary administration of a very high dose of adenosine (60 mg) was found to reduce the rate of incomplete STR after PPCI. In this study, patients were randomized to intracoronary adenosine or placebo if STR after PPCI was <70%. The authors found that more patients showed STR after adenosine as compared with placebo (33% vs. 9%) (87). Intravenous adenosine has been tested in 2 large randomized trials (AMISTAD [Acute Myocardial Infarction STudy of Adenosine] I and II) (88,89). Both studies showed a reduction of incomplete STR with a 3-h infusion of adenosine, but in-hospital and 6-month clinical outcome were similar to those observed in the placebo group.
Nitroprusside is a nitric oxide donor that does not depend on intracellular metabolism to derive nitric oxide, with potent vasodilator properties. Intracoronary administration of nitroprusside, compared with control, failed to improve corrected TIMI frame count and rate of complete STR (90). Conversely, 2 small registries showed an improvement of final TIMI flow grade after administration of intracoronary nitroprusside given in the attempt to reverse no-reflow (91,92).
Nicorandil is a hybrid drug of ATP-sensitive K+ channel opener and nicotinamide nitrate and has been shown to decrease infarct size and incidence of arrhythmias after coronary ligation and reperfusion in experimental animals, probably by suppressing free radical generation and by modulating neutrophil activation (93). Intravenous infusion of nicorandil for 24 h after PPCI resulted in better angiographic, functional, and clinical outcome as compared with placebo in 2 randomized studies (94,95).
Among potential new therapeutic approaches against IR injury, the use of atrial natriuretic peptide has been tested recently in a large-scale randomized trial. Indeed, Kitakaze et al. (96) in the J-WIND (Japan-Working Groups of Acute Myocardial Infarction for the Reduction of Necrotic Damage) trial, which randomized 227 patients to receive intravenous atrial natriuretic peptide and 292 patients to placebo, demonstrated that atrial natriuretic peptide treatment was associated with a reduction of 14.7% in infarct size, an increase in the 6 to 12 months of LV ejection fraction by 5%, and an improved myocardial perfusion. In the same trial the authors randomized 276 patients to intravenous nicorandil or placebo but failed to show any reduction in the infarct size or improvement in LV ejection fraction in the nicorandil group. However, oral nicorandil prescribed during the follow-up improved LV ejection fraction.
Verapamil is a calcium-channel blocker that has been used for the prevention and therapy of no-reflow. In a small randomized study by Taniyama et al. (97) in 40 patients with first STEMI, intracoronary verapamil as compared with placebo was associated with better microvascular function as assessed by MCE. Accordingly, intracoronary verapamil has been successfully used to reverse no-reflow after PPCI (98).
Management of individual susceptibility to microcirculatory injury.
Although genetically determined susceptibility to microcirculatory injury is difficult to modulate, acquired susceptibility might be treated. Indeed, optimal and prompt treatment of hyperglycemia is likely to be an important target in the prevention of no-reflow. Accordingly, the DIGAMI (Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction) study demonstrated that periprocedural reduction of blood glucose was associated with a reduction of infarct size (99). Furthermore, statins are emerging as drugs potentially able to reduce reperfusion injury (99). Iwakura et al. (100) have demonstrated that chronic statin therapy in patients with or without hypercholesterolemia is associated with lower prevalence of no-reflow and better functional recovery.
Finally, induction of ischemic pre-conditioning by drugs or nonpharmacologic stimuli such as remote ischemia of the arms (101) and avoidance of substances potentially blocking pre-conditioning like sulfonylureas and high doses of alcohol might be other measures able to prevent no-reflow (102).
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Future Perspectives
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The understanding of the prevailing pathogenic mechanism(s) of no-reflow in the individual patient is probably important in the selection of the most appropriate therapeutic approach. Indeed, patients with a high thrombus score are more likely to benefit from thrombus aspiration, whereas those at high risk of reperfusion injury are more likely to benefit from pharmacotherapy. New drugs such as ET-1 or TxA2 antagonists and the combination of old drugs such as adenosine, nitroprusside, and nicorandil should be tested in large controlled randomized trials in patients at high risk of reperfusion injury. Finally, optimal and prompt risk factor control and induction of pre-conditioning represent additional therapeutic options that, again, should be tested in large controlled randomized trials.
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Acknowledgments
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The authors thank Drs. Nicola Cosentino and Cristina Spaziani for their helpful review of the manuscript and Dr. Luigi Natale for kindly providing precious magnetic resonance images.
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References
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1. Keeley EC, Boura JA, Grines Cl. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials Lancet 2003;361:13-20.[CrossRef][Web of Science][Medline]2. Rezkalla SH, Kloner RA. Coronary no-reflow phenomenon: from the experimental laboratory to the cardiac catheterization laboratory Catheter Cardiovasc Interv 2008;72:950-957.[CrossRef][Web of Science][Medline] 3. Eeckhout E, Kern MJ. The coronary no-reflow phenomenon: a review of mechanisms and therapies Eur Heart J 2001;22:729-739.[Free Full Text] 4. Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction?. Circulation 1993;88:1361-1374.[Abstract/Free Full Text] 5. Brosh D, Assali AR, Mager A, et al. Effect of no-reflow during primary percutaneous coronary intervention for acute myocardial infarction on six-month mortality Am J Cardiol 2007;99:442-445.[CrossRef][Web of Science][Medline] 6. Henriques JP, Zijlstra F, van't Hof AW, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade Circulation 2003;107:2115-2119.[Abstract/Free Full Text] 7. Gibson CM, Cannon CP, Murphy SA, Marble SJ, Barron HV, Braunwald E, TIMI Study Group Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction Circulation 2002;105:1909-1913.[Abstract/Free Full Text] 8. McLaughlin MG, Stone GW, Aymong E, et al. Prognostic utility of comparative methods for assessment of ST-segment resolution after primary angioplasty for acute myocardial infarction: the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial J Am Coll Cardiol 2004;44:1215-1223.[Abstract/Free Full Text] 9. Bolognese L, Carrabba N, Parodi G, et al. Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction Circulation 2004;109:1121-1126.[Abstract/Free Full Text] 10. Galiuto L, Garramone B, Scarà A, et al. AMICI Investigators The extent of microvascular damage during myocardial contrast echocardiography is superior to other known indexes of post-infarct reperfusion in predicting left ventricular remodeling: results of the multicenter AMICI study J Am Coll Cardiol 2008;51:552-559.[Abstract/Free Full Text] 11. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction Circulation 1998;97:765-772.[Abstract/Free Full Text] 12. Kloner RA, Ganote CE, Jenning RB. The "no-reflow" phenomenon after temporary coronary occlusion in dogs J Clin Invest 1974;54:1496-1508.[Web of Science][Medline] 13. Fuster V, Moreno PR, Fayad ZA, Corti R, Badimon JJ. Atherothrombosis and high-risk plaque: part I: evolving concepts J Am Coll Cardiol 2005;46:937-954.[Abstract/Free Full Text] 14. Galiuto L, Lombardo A, Maseri A, et al. Temporal evolution and functional outcome of no-reflow: sustained and spontaneously reversible patterns following successful coronary recanalization Heart 2003;89:731-737.[Abstract/Free Full Text] 15. Hoffmann R, Haager R, Arning J, et al. Usefulness of myocardial blush grade early and late after primary coronary angioplasty for acute myocardial infarction in predicting left ventricular function Am J Cardiol 2003;92:1015-1019.[CrossRef][Web of Science][Medline] 16. Skyschally A, Leineweber K, Gres P, Haude M, Erbel R, Heusch G. Coronary microembolization Basic Res Cardiol 2006;101:373-382.[CrossRef][Web of Science][Medline] 17. Hori M, Inoue M, Kitakaze M, Koretsune Y, et al. Role of adenosine in hyperemic response of coronary blood flow in microembolization Am J Physiol 1986;250:H509-H518.[Web of Science][Medline] 18. Okamura A, Ito H, Iwakura K, et al. Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction: efficacy of distal protection device J Am Coll Cardiol 2005;45:212-215.[Abstract/Free Full Text] 19. Reffelmann T, Kloner RA. The no-reflow phenomenon: a basic mechanism of myocardial ischemia and reperfusion Basic Res Cardiol 2006;101:359-372.[CrossRef][Web of Science][Medline] 20. Ambrosio G, Weisman HF, Mannisi JA, Becker LC. Progressive impairment of regional myocardial perfusion after initial restoration of postischemic blood flow Circulation 1989;80:1846-1861.[Abstract/Free Full Text] 21. Tranum-Jensen J, Janse MJ, Fiolet WT, Krieger WJ, D'Alnoncourt CN, Durrer D. Tissue osmolality, cell swelling, and reperfusion in acute regional myocardial ischemia in the isolated porcine Circ Res 1981;49:364-381.[Free Full Text] 22. Yellon DM, Hausenloy DJ. Myocardial reperfusion injury N Engl J Med 2007;357:1121-1135.[CrossRef][Web of Science][Medline] 23. Engler RL, Schmid-Schönbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog Am J Pathol 1983;111:98-111.[Web of Science][Medline] 24. Ambrosio G, Tritto I. Reperfusion injury: experimental evidence and clinical implications Am Heart J 1999;138:S69-S75.[CrossRef][Web of Science][Medline] 25. Ito BR, Schmid-Schönbein G, Engler RL. Effects of leukocyte activation on myocardial vascular resistance Blood Cells 1990;16:145-163.[Web of Science][Medline] 26. Lefer AM, Tsao PS, Aoki N, Palladino Jr MA. Mediation of cardioprotection by transforming growth factor-beta Science 1990;249:61-64.[Abstract/Free Full Text] 27. Furuichi K, Wada T, Iwata Y, et al. Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia-reperfusion injury Crit Care Med 2006;342447–5. 28. Chamoun F, Burne M, O'Donnell M, Rabb H. Pathophysiologic role of selectins and their ligands in ischemia reperfusion injury Front Biosci 2000;5:E103-E109.[Web of Science][Medline] 29. Carden DL, Granger DN. Pathophysiology of ischemia-reperfusion injury J Pathol 2000;190:255-266.[CrossRef][Web of Science][Medline] 30. Skyschally A, Schulz R, Heusch G. Pathophysiology of myocardial infarction: protection by ischemic pre- and postconditioning Herz 2008;33:88-100.[CrossRef][Web of Science][Medline] 31. Piot C, Croisille P, Staat P, et al. Effect of cyclosporine on reperfusion injury in acute myocardial infarction N Engl J Med 2008;359:473-481.[CrossRef][Medline] 32. Jaffe R, Charron T, Puley G, Dick A, Strauss BH. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention Circulation 2008;117:3152-3156.[Free Full Text] 33. Mizumura T, Nithipatikom K, Gross GJ. Infarct size-reducing effect of nicorandil is mediated by the KATP channel but not by its nitrate-like properties in dogs Cardiovasc Res 1996;32:274-285.[Abstract/Free Full Text] 34. Hayashi M, Tsutamoto T, Wada A, et al. Administration of atrial natriuretic peptide prevents left ventricular remodeling in patients with first anterior acute myocardial infarction J Am Coll Cardiol 2001;37:1820-1826.[Abstract/Free Full Text] 35. Baxter GF. Natriuretic peptides and myocardial ischaemia Basic Res Cardiol 2004;99:90-93.[CrossRef][Web of Science][Medline] 36. Montalescot G, Ongen Z, Guindy R, et al. RIVIERA Investigators Predictors of outcome in patients undergoing PCI. Results of the RIVIERA study. Int J Cardiol 2009;129:379-387.[CrossRef][Web of Science] 37. Collet JP, Montalescot G. The acute reperfusion management of STEMI in patients with impaired glucose tolerance and type 2 diabetes Diabetes Vasc Dis Res 2005;2:136-143.[CrossRef] 38. Golino P, Maroko PR, Carew TE. The effect of acute hypercholesterolemia on myocardial infarct size and the no-reflow phenomenon during coronary occlusion-reperfusion Circulation 1987;75:292-298.[Abstract/Free Full Text] 39. Rezkalla SH, Kloner RA. Ischemic preconditioning and preinfarction angina in the clinical arena Nat Clin Pract Cardiovasc Med 2004;1:96-102.[CrossRef][Web of Science][Medline] 40. Yip HK, Chen MC, Chang HW, et al. Angiographic morphologic features of infarct-related arteries and timely reperfusion in acute myocardial infarction: predictors of slow-flow and no-reflow phenomenon Chest 2002;122:1322-1332.[Abstract/Free Full Text] 41. Limbruno U, De Carlo M, Pistolesi S, et al. Distal embolization during primary angioplasty: histopathologic features and predictability Am Heart J 2005;150:102-108.[CrossRef][Web of Science][Medline] 42. Nallamothu BK, Bradley EH, Krumholz HM. Time to treatment in primary percutaneous coronary intervention N Engl J Med 2007;357:1631-1638.[CrossRef][Web of Science][Medline] 43. Turschner O, D'hooge J, Dommke C, et al. The sequential changes in myocardial thickness and thickening which occur during acute transmural infarction, infarct reperfusion and the resultant expression of reperfusion injury Eur Heart J 2004;25:794-803.[Abstract/Free Full Text] 44. Uyarel H, Cam N, Okmen E, et al. Level of Selvester QRS score is predictive of ST-segment resolution and 30-day outcomes in patients with acute myocardial infarction undergoing primary coronary intervention Am Heart J 2006;151:1239.e1-1239.e7.[CrossRef][Medline] 45. Iwakura K, Ito H, Kawano S, et al. Predictive factors for development of the no-reflow phenomenon in patients with reperfused anterior wall acute myocardial infarction J Am Coll Cardiol 2001;38:472-477.[Abstract/Free Full Text] 46. Takahashi T, Hiasa Y, Ohara Y, et al. Relation between neutrophil counts on admission, microvascular injury, and left ventricular functional recovery in patients with an anterior wall first acute myocardial infarction treated with primary coronary angioplasty Am J Cardiol 2007;100:35-40.[CrossRef][Web of Science][Medline] 47. Campo G, Valgimigli M, Gemmati D, et al. Value of platelet reactivity in predicting response to treatment and clinical outcome in patients undergoing primary coronary intervention: insights into the STRATEGY study J Am Coll Cardiol 2006;48:2178-2185.[Abstract/Free Full Text] 48. Huczek Z, Kochman J, Filipiak KJ, et al. Mean platelet volume on admission predicts impaired reperfusion and long-term mortality in acute myocardial infarction treated with primary percutaneous coronary intervention J Am Coll Cardiol 2005;46:284-290.[Abstract/Free Full Text] 49. Niccoli G, Giubilato S, Russo E, et al. Plasma levels of thromboxane A2 on admission are associated with no-reflow after primary percutaneous coronary intervention Eur Heart J 2008;29:1843-1850.[Abstract/Free Full Text] 50. Matsumoto H, Inoue N, Takaoka H, et al. Depletion of antioxidants is associated with no-reflow phenomenon in acute myocardial infarction Clin Cardiol 2004;27:466-470.[Web of Science][Medline] 51. Niccoli G, Lanza GA, Shaw S, et al. Endothelin-1 and acute myocardial infarction: a no-reflow mediator after successful percutaneous myocardial revascularization Eur Heart J 2006;27:1793-1798.[Abstract/Free Full Text] 52. Galiuto L, DeMaria AN, del Balzo U, et al. Ischemia-reperfusion injury at the microvascular level: treatment by endothelin A-selective antagonist and evaluation by myocardial contrast echocardiography Circulation 2000;102:3111-3116.[Abstract/Free Full Text] 53. Vignali L, Talanas G, Saia F, et al. Genetic association between the 1976T>C polymorphism in the adenosine A2 receptor and angiographic no-reflow phenomenon(abstr) Il giornale italiano di Cardiologia Invasiva 2007;3(Suppl 1):109. 54. Zalewski J, Undas A, Godlewski J, Stepien E, Zmudka K. No-reflow phenomenon after acute myocardial infarction is associated with reduced clot permeability and susceptibility to lysis Arterioscler Thromb Vasc Biol 2007;27:2258-2265.[Abstract/Free Full Text] 55. Niccoli G, Lanza GA, Spaziani C, et al. Baseline systemic inflammatory status and no-reflow phenomenon after percutaneous coronary angioplasty for acute myocardial infarction Int J Cardiol 2007;117:306-311.[CrossRef][Web of Science][Medline] 56. Hoffmann R, Suliman H, Haager P, et al. Association of C-reactive protein and myocardial perfusion in patients with ST-elevation acute myocardial infarction Atherosclerosis 2006;186:177-183.[CrossRef][Web of Science][Medline] 57. Iwakura K, Ito H, Ikushima M, et al. Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction J Am Coll Cardiol 2003;41:1-7.[Abstract/Free Full Text] 58. Karila-Cohen D, Czitrom D, Brochet E, et al. Decreased no-reflow in patients with anterior myocardial infarction and pre-infarction angina Eur Herat J 1999;20:1724-1730.[CrossRef] 59. Niccoli G, Altamura L, Fabretti A, et al. Ethanol abolishes ischemic preconditioning in humans J Am Coll Cardiol 2008;51:271-275.[Abstract/Free Full Text] 60. The TIMI Study Group The Thrombolysis In Myocardial Infarction [TIMI] trial. Phase I findings. N Engl J Med 1985;312:932-936.[Medline] 61. van't Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F, Zwolle Myocardial Infarction Study Group Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade Circulation 1998;97:2302-2306.[Abstract/Free Full Text] 62. Schröder R. Prognostic impact of early ST-segment resolution in acute ST-elevation myocardial infarction Circulation 2004;110:e506-e510.[Free Full Text] 63. Giugliano RP, Sabatine MS, Gibson CM, et al. Combined assessment of thrombolysis in myocardial infarction flow grade, myocardial perfusion grade, and ST-segment resolution to evaluate epicardial and myocardial reperfusion Am J Cardiol 2004;93:1362-1367.[CrossRef][Web of Science][Medline] 64. Sorajja P, Gersh BJ, Costantini C, et al. Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous coronary intervention in acute myocardial infarction Eur Heart J 2005;26:667-674.[Abstract/Free Full Text] 65. Iliceto S, Marangelli V, Marchese A, Amico A, Galiuto L, Rizzon P. Myocardial contrast echocardiography in acute myocardial infarction. Pathophysiological background and clinical applications. Eur Heart J 1996;17:344-353.[Abstract/Free Full Text] 66. Hayat SA, Senior R. Myocardial contrast echocardiography in ST elevation myocardial infarction: ready for prime time? Eur Heart J 2008;29:299-314.[Abstract/Free Full Text] 67. Albert TS, Kim RJ, Judd RM. Assessment of no-reflow regions using cardiac MRI Basic Res Cardiol 2006;101:383-390.[CrossRef][Web of Science][Medline] 68. Porto I, Burzotta F, Brancati M, et al. Relation of myocardial blush grade to microvascular perfusion and myocardial infarct size after primary or rescue percutaneous coronary intervention Am J Cardiol 2007;99:1671-1673.[CrossRef][Web of Science][Medline] 69. Loubeyre C, Morice MC, Lefèvre T, Piéchaud JF, Louvard Y, Dumas P. A randomized comparison of direct stenting with conventional stent implantation in selected patients with acute myocardial infarction J Am Coll Cardiol 2002;39:15-21.[Abstract/Free Full Text] 70. Ali A, Cox D, Dib N, et al. AIMI Investigators Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study J Am Coll Cardiol 2006;48:244-252.[Abstract/Free Full Text] 71. Dangas G, Stone GW, Weinberg, MD, et al. EMERALD Investigators Contemporary outcomes of rescue percutaneous coronary intervention for acute myocardial infarction: comparison with primary angioplasty and the role of distal protection devices (EMERALD trial) Am Heart J 2008;155:1090-1096.[CrossRef][Web of Science][Medline] 72. Young JJ, Cox DA, Stuckey T, et al. Prospective, multicenter study of thrombectomy in patients with acute myocardial infarction: the X-Tract AMI registry J Interv Cardiol 2007;20:44-50.[CrossRef][Medline] 73. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus-aspiration improves myocardial reperfusion: the randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus-aspiration in primary and rescue angioplasty (REMEDIA) trial J Am Coll Cardiol 2005;46:371-376.[Abstract/Free Full Text] 74. Galiuto L, Garramone B, Burzotta F, et al. REMEDIA Investigators Thrombus aspiration reduces microvascular obstruction after primary coronary intervention: a myocardial contrast echocardiography substudy of the REMEDIA trial J Am Coll Cardiol 2006;48:1355-1360.[Abstract/Free Full Text] 75. Burzotta F, Testa L, Giannico F, et al. Adjunctive devices in primary or rescue PCI: a meta-analysis of randomized trials Int J Cardiol 2008;123:313-321.[CrossRef][Web of Science][Medline] 76. Svilaas T, Vlaar PJ, van der Horst IC, et al. Thrombus aspiration during primary percutaneous coronary intervention N Engl J Med 2008;358:557-567.[CrossRef][Medline] 77. Vlaar PJ, Svilaas T, van der Horst IC, et al. Cardiac death and reinfarction after 1 year in the Thrombus Aspiration during Percutaneous coronary intervention in Acute myocardial infarction Study (TAPAS): a 1-year follow-up study Lancet 2008;371:1915-1920.[CrossRef][Web of Science][Medline] 78. Burzotta F, Crea F. Thrombus-aspiration: a victory in the war against no reflow Lancet 2008;371:1889-1890.[CrossRef][Web of Science][Medline] 79. Opie LH. Reperfusion injury and its pharmacologic modification Circulation 1989;80:1049-1062.[Abstract/Free Full Text] 80. Zhao J, Yang Y, You S, Cui C, Gao R. Carvedilol preserves endothelial junctions and reduces myocardial no-reflow after acute myocardial infarction and reperfusion Int J Cardiol 2007;115:334-341.[CrossRef][Web of Science][Medline] 81. Zhao JL, Yang YJ, You SJ, et al. Pretreatment with fosinopril or valsartan reduces myocardial no-reflow after acute myocardial infarction and reperfusion Coron Artery Dis 2006;17:463-469.[CrossRef][Web of Science][Medline] 82. Petronio AS, De Carlo M, Ciabatti N, et al. Left ventricular remodeling after primary coronary angioplasty in patients treated with abciximab or intracoronary adenosine Am Heart J 2005;150:1015.[Medline] 83. Montalescot G, Antoniucci D, Kastrati A, et al. Abciximab in primary coronary stenting of ST-elevation myocardial infarction: a European meta-analysis on individual patients' data with long-term follow-up Eur Heart J 2007;28:443-449.[Abstract/Free Full Text] 84. Danzi GB, Sesana M, Capuano C, Mauri L, Berra Centurini P, Baglini R. Comparison in patients having primary coronary angioplasty of abciximab versus tirofiban on recovery of left ventricular function Am J Cardiol 2004;94:35-39.[Web of Science][Medline] 85. Thiele H, Schindler K, Friedenberger J, et al. Intracoronary compared with intravenous bolus abciximab application in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: the randomized Leipzig immediate percutaneous coronary intervention abciximab IV versus IC in ST-elevation myocardial infarction trial Circulation 2008;118:49-57.[Abstract/Free Full Text] 86. Marzilli M, Orsini E, Marraccini P, Testa R. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction Circulation 2000;101:2154-2159.[Abstract/Free Full Text] 87. Stoel MG, Marques KM, de Cock CC, Bronzwaer JG, von Birgelen C, Zijlstra F. High dose adenosine for suboptimal myocardial reperfusion after primary PCI: a randomized placebo-controlled pilot study Catheter Cardiovasc Interv 2008;7:283-289. 88. Mahaffey KW, Puma JA, Barbagelata NA, et al. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial J Am Coll Cardiol 1999;34:1711-1720.[Abstract/Free Full Text] 89. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW, AMISTAD-II Investigators A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II) J Am Coll Cardiol 2005;45:1775-1780.[Abstract/Free Full Text] 90. Amit G, Cafri C, Yaroslavtsev S, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. Am Heart J 2006;152:887.e9-887.e14.[CrossRef][Medline] 91. Pasceri V, Pristipino C, Pelliccia F, et al. Effects of the nitric oxide donor nitroprusside on no-reflow phenomenon during coronary interventions for acute myocardial infarction Am J Cardiol 2005;95:1358-1361.[CrossRef][Web of Science][Medline] 92. Airoldi F, Briguori C, Cianflone D, et al. Frequency of slow coronary flow following successful stent implantation and effect of nitroprusside Am J Cardiol 2007;99:916-920.[CrossRef][Web of Science][Medline] 93. Ohno Y, Minatoguchi S, Uno Y, et al. Nicorandil reduces myocardial infarct size by opening the K(ATP) channel in rabbits Int J Cardiol 1997;62:181-190.[CrossRef][Web of Science][Medline] 94. Ito H, Taniyama Y, Iwakura K, et al. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction J Am Coll Cardiol 1999;33:654-660.[Abstract/Free Full Text] 95. Ono H, Osanai T, Ishizaka H, et al. Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: role of inhibitory effect on reactive oxygen species formation Am Heart J 2004;148:E15.[Medline] 96. Kitakaze M, Asakura M, Kim J, et al. Human atrial natriuretic peptide and nicorandil as adjuncts to reperfusion treatment for acute myocardial infarction (J-WIND): two randomised trials Lancet 2007;370:1483-1493.[CrossRef][Web of Science][Medline] 97. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronary verapamil on microvascular and myocardial salvage in patients with acute myocardial infarction J Am Coll Cardiol 1997;30:1193-1199.[Abstract] 98. Werner GS, Lang K, Kuehnert H, Figulla HR. Intracoronary verapamil for reversal of no-reflow during coronary angioplasty for acute myocardial infarction Catheter Cardiovasc Interv 2002;57:444-451.[CrossRef][Web of Science][Medline] 99. Malmberg K, Rydén L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year J Am Coll Cardiol 1995;26:56-65. 100. Iwakura K, Ito H, Kawano S, et al. Chronic pre-treatment of statins is associated with the reduction of the no-reflow phenomenon in the patients with reperfused acute myocardial infarction Eur Heart J 2006;27:534-539.[Abstract/Free Full Text] 101. Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial Lancet 2007;370:575-579.[CrossRef][Web of Science][Medline] 102. Tomai F, Crea F, Gaspardone A, et al. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker Circulation 1994;90:700-705.[Abstract/Free Full Text]
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G. Niccoli, R. K. Kharbanda, F. Crea, and A. P. Banning
No-reflow: again prevention is better than treatment
Eur. Heart J.,
October 2, 2010;
31(20):
2449 - 2455.
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C. J. French, A. K. M. T. Zaman, R. J. Kelm Jr, J. L. Spees, and B. E. Sobel
Vascular rhexis: loss of integrity of coronary vasculature in mice subjected to myocardial infarction
Exp Biol Med,
August 1, 2010;
235(8):
966 - 973.
[Abstract]
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M. De Vita, F. Burzotta, I. Porto, D. Dudek, T. Lefevre, C. Trani, W. Mielecki, G. Niccoli, G. G. L. Biondi-Zoccai, and F. Crea
Thrombus aspiration in ST elevation myocardial infarction: comparative efficacy in patients treated early and late after onset of symptoms
Heart,
August 1, 2010;
96(16):
1287 - 1290.
[Abstract]
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R. K. Kharbanda
Cardiac conditioning: a review of evolving strategies to reduce ischaemia-reperfusion injury
Heart,
August 1, 2010;
96(15):
1179 - 1186.
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R. McGeoch, S. Watkins, C. Berry, T. Steedman, A. Davie, J. Byrne, S. Hillis, M. Lindsay, S. Robb, H. Dargie, et al.
The Index of Microcirculatory Resistance Measured Acutely Predicts the Extent and Severity of Myocardial Infarction in Patients With ST-Segment Elevation Myocardial Infarction
J. Am. Coll. Cardiol. Intv.,
July 1, 2010;
3(7):
715 - 722.
[Abstract]
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M. A. Kampinga, M. W. N. Nijsten, Y. L. Gu, W. A. Dijk, B. J. G. L. de Smet, A. F. M. van den Heuvel, E.-S. Tan, and F. Zijlstra
Is the Myocardial Blush Grade Scored by the Operator During Primary Percutaneous Coronary Intervention of Prognostic Value in Patients With ST-Elevation Myocardial Infarction in Routine Clinical Practice?
Circ Cardiovasc Interv,
June 1, 2010;
3(3):
216 - 223.
[Abstract]
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G. Ndrepepa, K. Tiroch, M. Fusaro, D. Keta, M. Seyfarth, R. A. Byrne, J. Pache, P. Alger, J. Mehilli, A. Schomig, et al.
5-Year Prognostic Value of No-Reflow Phenomenon After Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction
J. Am. Coll. Cardiol.,
May 25, 2010;
55(21):
2383 - 2389.
[Abstract]
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M. Endo, K. Hibi, T. Shimizu, N. Komura, I. Kusama, F. Otsuka, T. Mitsuhashi, N. Iwahashi, J. Okuda, K. Tsukahara, et al.
Impact of Ultrasound Attenuation and Plaque Rupture as Detected by Intravascular Ultrasound on the Incidence of No-Reflow Phenomenon After Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction
J. Am. Coll. Cardiol. Intv.,
May 1, 2010;
3(5):
540 - 549.
[Abstract]
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G. Niccoli, F. Burzotta, L. Galiuto, and F. Crea
Reply
J. Am. Coll. Cardiol.,
January 19, 2010;
55(3):
265 - 265.
[Full Text]
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D. Zahger and A. Wolak
Grade of Ischemia to Assess No Reflow After Reperfusion
J. Am. Coll. Cardiol.,
January 19, 2010;
55(3):
264 - 265.
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G. Niccoli, F. Burzotta, L. Galiuto, and F. Crea
Reply.
J. Am. Coll. Cardiol.,
December 8, 2009;
54(24):
2341 - 2341.
[Full Text]
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J. R. Kapoor and R. Kapoor
Stent Overexpansion and Myocardial No-Reflow
J. Am. Coll. Cardiol.,
December 8, 2009;
54(24):
2340 - 2341.
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J. A. Goldstein, C. Grines, T. Fischell, R. Virmani, D. Rizik, J. Muller, and S. R. Dixon
Coronary Embolization Following Balloon Dilation of Lipid-Core Plaques
J. Am. Coll. Cardiol. Img.,
December 1, 2009;
2(12):
1420 - 1424.
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G. Heusch, P. Kleinbongard, D. Bose, B. Levkau, M. Haude, R. Schulz, and R. Erbel
Coronary Microembolization: From Bedside to Bench and Back to Bedside
Circulation,
November 3, 2009;
120(18):
1822 - 1836.
[Abstract]
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F. Burzotta, M. De Vita, Y. L. Gu, T. Isshiki, T. Lefevre, A. Kaltoft, D. Dudek, G. Sardella, P. S. Orrego, D. Antoniucci, et al.
Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials
Eur. Heart J.,
September 2, 2009;
(2009)
ehp348v1.
[Abstract]
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E. Eeckhout
Thrombectomy in acute ST-elevation myocardial infarction: keep it simple
Eur. Heart J.,
September 2, 2009;
(2009)
ehp349v1.
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Top
Abstract
Definition and Clinical...