Introduction

Primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy for treating acute ST-segment elevation myocardial infarction (STEMI). The main goals are to restore epicardial infarct-related artery patency and achieve microvascular reperfusion as early as possible, thus limiting the extent of irreversibly injured (necrotic) myocardium.1 Angiographic assessment of myocardial blood flow is reported as thrombolysis in myocardial infarction (TIMI) flow, and although TIMI flow grade relates to outcome, even in the presence of TIMI-3 flow tissue level perfusion can still be disturbed as measured by other indexes such as corrected TIMI frame count (cTFC) or more invasive measures of coronary blood flow. Thus, depending on how it is measured, inadequate tissue level reperfusion can occur in up to 50% of cases. No-reflow is the term used to describe inadequate myocardial perfusion of a given coronary segment without angiographic evidence of mechanical vessel obstruction.2 Despite optimal evidence-based PPCI, myocardial no-reflow can still occur, negating many of the benefits of restoring culprit vessel patency, and is associated with a worse in-hospital and long-term prognosis.2

It is important to outline that no-reflow is only one of the four types of cardiac dysfunction (myocardial stunning, no-reflow, reperfusion arrhythmias, and lethal reperfusion injury) caused by myocardial reperfusion as recently summarized by Yellon and Hausenloy,3 and it refers to the high impedance of microvascular blood flow encountered during opening of the infarct-related coronary artery. In this manuscript, we concentrate on the processes of no-reflow while recognizing the relationships with reperfusion injury and the complexity of each of the interactions involved. The multifactorial nature of no-reflow has been summarized recently into four interacting processes: ischaemic injury, reperfusion injury, distal embolization, and susceptibility of microcirculation to injury (Figure 1).4 Ischaemia–reperfusion (IR) injury is central to the pathophysiology of no-reflow and is associated with a profound disturbance of the vasoregulation pathways.5 The ischaemia duration is the key predictor of its occurrence in PPCI.4 Advances in basic science have now highlighted that the process of reperfusion itself may amplify tissue injury, and the paradigm of modulating reperfusion injury in its first minutes has developed.3 It is a complex process and involves interplay between neutrophils and platelets which may mechanically plug the microcirculation and release oxygen radicals and proteases, causing endothelial and interstitial damage.5

Figure 1

Schematic of no-reflow mechanisms. Ischaemic injury, reperfusion injury, and distal embolization (from left to right) along with the individual response to each of these mechanisms are variably involved in the pathogenesis of no-reflow in the single patient. The figure shows changes at vessel and the cardiomyocyte level (from up to bottom) caused by these mechanisms. Ischaemic injury affects endothelial cells, causing the formation of intraluminal blebs, which obliterate vessel lumen, and expression of P-selectins. Cardiomyocytes, in turn, exhibit intracellular acidosis and overload of Na+ and Ca++, thus leading to cell swelling and mild opening of membrane permeability transition (MPT) pores. Reperfusion injury causes further obliteration of vessel lumen by neutrophil-platelet aggregates which in turn produce large amount of vasoconstrictors and inflammatory mediators. At the cardiomyocyte level, reperfusion stimulates the production of radical oxygen species (ROS) by mitochondria. In turn, ROS and rapid normalization of intracellular pH lead to severe opening of MPT pores with subsequent cellular and mitochondrial swelling and cell disruption. Both cell swelling and interstitial oedema contribute to microvascular obstruction due to compression. Vasoconstriction also contributes to microvascular obstruction. Finally, embolization of thrombus/plaque material leads to sustained ischaemia and necrosis of embolized regions. CM, cardiomyocytes; EC, endothelial cells; ET-1, endothelin-1; ICAM, cell adhesion molecule-1; L-S, L-selectin; ET-1, endothelin-1; PE, proteolytic enzymes; P-S, P-selectin; SMC, smooth muscle cells; TXA2, thromboxane-A2.

Figure 1

Schematic of no-reflow mechanisms. Ischaemic injury, reperfusion injury, and distal embolization (from left to right) along with the individual response to each of these mechanisms are variably involved in the pathogenesis of no-reflow in the single patient. The figure shows changes at vessel and the cardiomyocyte level (from up to bottom) caused by these mechanisms. Ischaemic injury affects endothelial cells, causing the formation of intraluminal blebs, which obliterate vessel lumen, and expression of P-selectins. Cardiomyocytes, in turn, exhibit intracellular acidosis and overload of Na+ and Ca++, thus leading to cell swelling and mild opening of membrane permeability transition (MPT) pores. Reperfusion injury causes further obliteration of vessel lumen by neutrophil-platelet aggregates which in turn produce large amount of vasoconstrictors and inflammatory mediators. At the cardiomyocyte level, reperfusion stimulates the production of radical oxygen species (ROS) by mitochondria. In turn, ROS and rapid normalization of intracellular pH lead to severe opening of MPT pores with subsequent cellular and mitochondrial swelling and cell disruption. Both cell swelling and interstitial oedema contribute to microvascular obstruction due to compression. Vasoconstriction also contributes to microvascular obstruction. Finally, embolization of thrombus/plaque material leads to sustained ischaemia and necrosis of embolized regions. CM, cardiomyocytes; EC, endothelial cells; ET-1, endothelin-1; ICAM, cell adhesion molecule-1; L-S, L-selectin; ET-1, endothelin-1; PE, proteolytic enzymes; P-S, P-selectin; SMC, smooth muscle cells; TXA2, thromboxane-A2.

Importantly, neutrophils have been shown to have a causative role in reperfusion injury.4 Indeed, neutrophils are a major source of oxidants in hearts reperfused in vivo after prolonged ischaemia.3,4 Accordingly, a reduction in radical generation by R15.7, a monoclonal antibody against neutrophil CD18 adhesion molecule, was associated with a significant reduction in infarct size and no-reflow.6 Adenosine also has been shown to inhibit neutrophil function and, in particular, neutrophil-mediated injury to endothelial cells.7 Of note, it has been demonstrated in experimental models that exogenous or endogenous adenosine can inhibit neutrophil adhesion and injury to myocytes by an A2-mediated mechanism on cells activated with TNF-α.8 Moreover, experimental studies have shown reductions in infarct size of up to 50% with other interventions targeting neutrophils during myocardial reperfusion.3 Finally, the beneficial effects of abciximab in man may in part be mediated by neutrophil inhibition. In particular, abciximab binds to the vitronectin receptor on endothelial, smooth muscle, and inflammatory cells, including neutrophils, and to an activated conformation of the aMb2 receptor on leucocytes, thus reducing neutrophil adhesion to the endothelium.9

In addition, there are physical factors, contributing to no-reflow, related to distal embolization from the culprit plaque and thrombus.4 Of note, Zalewski et al.10 showed that patients with STEMI undergoing PPCI showing no-reflow at the end of the procedure had less clot permeability and more resistance to lysis of thrombus when compared with those having reflow. Interestingly, we recently demonstrated that STEMI patients on previous aspirin therapy had lower thrombotic burden at angiography when compared with those without previous aspirin therapy.11 Thus, the composition of the clot itself and modulating its sensitivity to spontaneous lysis may be targeted in the future.

Finally, the individual susceptibility of the microcirculation to reperfusion injury determined by traditional risk factors12,13 or genetic factors14 may modulate its occurrence.

No-reflow can be directly assessed in different ways ranging from simple angiographic TIMI grade score to more complex angiographic indexes, direct invasive measures of coronary flow, imaging techniques such as myocardial contrast echo (MCE) or cardiac magnetic resonance (CMR), or using surrogate endpoints such as ST segment resolution (STR;Figure 2).4

Figure 2

Diagnosis of no-reflow. CCU, coronary care unit; CE-CMR, contrast-enhanced magnetic cardiac resonance; MCE, myocardial contrast echocardiography; TIMI, thrombolysis in myocardial infarction; MBG, myocardial blush grade; PPCI, primary percutaneous coronary intervention.

Figure 2

Diagnosis of no-reflow. CCU, coronary care unit; CE-CMR, contrast-enhanced magnetic cardiac resonance; MCE, myocardial contrast echocardiography; TIMI, thrombolysis in myocardial infarction; MBG, myocardial blush grade; PPCI, primary percutaneous coronary intervention.

In this article, we review the available data regarding pharmacological drug prevention and summarize the debate about treatment of established no-reflow. We highlight potential drawbacks of current pharmacological approaches and question whether alternative targets for future studies should be considered.

Prevention of no-reflow

Prevention comprises strategies adopted before complete vessel re-opening in order to prepare the microcirculation for reperfusion. It may be targeted to different mechanisms of no-reflow (Table 1).

Table 1

Main studies focused on the prevention of mechanisms of no-reflow

Preventive measures Study Study design Number of patients Dose Timing of intervention Primary endpoints Main results 
Ischaemic injury 
 Cariporide Théroux et al.17 RCT 3.439 20, 80, 120 mg i.v. Pre-PCI Death or MI after 36 days No effect on infarct size or clinical outcomes 
 Eniporide Zeymer et al.18 RCT 1.389 50,100,150, 200 mg i.v. During thrombolysis pre-PCI Infarct size No effect on infarct size or clinical outcomes 
Reperfusion injury 
 Abciximab Thiele (2008)34 RCT 154 0.25 mg/kg i.c + 12 h infusion at 0.125 µg/kg/min i.v. vs. 0.25 mg/kg + 12 h infusion at 0.125 µg/kg/min i.v. Pre-during-post- PCI Infarct size and extent of microvascular obstruction Significant reduction in infarct size and microvascular obstruction by i.c. Abciximab 
 Adenosine Marzilli et al.19 RCT 54 4 µg i.c. Pre-PCI Feasibility, safety, and TIMI flow Safe and feasible in MI, reduction in the incidence no-reflow, and improvement of LVEF 
Ross (2008)41 RCT 2.118 50 or 70 µg/kg/min i.v. Pre- and post-PCI In-hospital heart failure, repeat hospital stay for heart failure, or 6-month death No effect on clinical outcomes and infarct size reduction with the 70-µg/kg/min adenosine infusion 
 Nitroprusside Amit et al.21 RCT 98 60 µg i.c. During PCI cTFC and STR >70% No effect on coronary flow and myocardial tissue reperfusion, improvement of clinical outcomes at 6 months 
 Nicorandil Ishii et al.22  360 12 mg i.v. Pre-PCI Cardiovascular death or rehospitalization for congestive heart failure Improved myocardial reperfusion and fewer deaths and less cardiac failure after 2.4-year follow-up 
 Pexelizumab APEX AMI Investigators24 RCT 5.745 2 mg/kg i.v. followed by 0.05 mg/kg/h Pre-PCI and for 24 h after All-cause mortality through Day 30 No effect on mortality 
 FX06 Atar et al.25 RCT 234 400 mg i.v. During PCI Infarct size at CMR at Day 5 No effect on infarct size 
 Atrial natriuretic peptide Kitakaze et al.26 RCT 569 0.025 µg/kg/min i.v. Pre-PCI and for 3 days after Infarct size and LVEF Reduction in infarct size, improvement of LVEF but no effect on mortality 
 Cyclosporine Piot et al.27 RCT 58 2.5 mg/kg i.v. Pre-PCI Infarct size Smaller infarct size but no effects on final TIMI flow 
 Intermittent arm ischaemia Bøtker et al.61 RCT 251 Four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff Pre-PCI Myocardial salvage index at 30 days Increased myocardial salvage with a favourable safety profile 
Distal embolization 
 Thrombus aspiration Svilaas et al.29 RCT 1.071 — During PCI MBG 0–1 Better reperfusion, MBG, STR, and clinical outcome 
Individual susceptibility 
 Insulin Malmberg et al.37 RCT 620 Insulin–glucose infusion ≥24 h Pre-, during, and post-PCI Mortality at 3 months in diabetic patients Reduction in mortality 
 Statins Iwakura et al.38 OS 293 Chronic statins pre-treatment Pre-PCI Incidence of no-reflow and EF Lower incidence of no-reflow, better wall motion, smaller LV dimensions, and better EF 
 Nitrates Ambrosio et al.58 OS 52.693 Chronic nitrates pre-treatment Pre-PCI Incidence of acute ischaemic events Shift away from STEMI in favour of NSTE-ACS and with less release of markers of cardiac necrosis 
Preventive measures Study Study design Number of patients Dose Timing of intervention Primary endpoints Main results 
Ischaemic injury 
 Cariporide Théroux et al.17 RCT 3.439 20, 80, 120 mg i.v. Pre-PCI Death or MI after 36 days No effect on infarct size or clinical outcomes 
 Eniporide Zeymer et al.18 RCT 1.389 50,100,150, 200 mg i.v. During thrombolysis pre-PCI Infarct size No effect on infarct size or clinical outcomes 
Reperfusion injury 
 Abciximab Thiele (2008)34 RCT 154 0.25 mg/kg i.c + 12 h infusion at 0.125 µg/kg/min i.v. vs. 0.25 mg/kg + 12 h infusion at 0.125 µg/kg/min i.v. Pre-during-post- PCI Infarct size and extent of microvascular obstruction Significant reduction in infarct size and microvascular obstruction by i.c. Abciximab 
 Adenosine Marzilli et al.19 RCT 54 4 µg i.c. Pre-PCI Feasibility, safety, and TIMI flow Safe and feasible in MI, reduction in the incidence no-reflow, and improvement of LVEF 
Ross (2008)41 RCT 2.118 50 or 70 µg/kg/min i.v. Pre- and post-PCI In-hospital heart failure, repeat hospital stay for heart failure, or 6-month death No effect on clinical outcomes and infarct size reduction with the 70-µg/kg/min adenosine infusion 
 Nitroprusside Amit et al.21 RCT 98 60 µg i.c. During PCI cTFC and STR >70% No effect on coronary flow and myocardial tissue reperfusion, improvement of clinical outcomes at 6 months 
 Nicorandil Ishii et al.22  360 12 mg i.v. Pre-PCI Cardiovascular death or rehospitalization for congestive heart failure Improved myocardial reperfusion and fewer deaths and less cardiac failure after 2.4-year follow-up 
 Pexelizumab APEX AMI Investigators24 RCT 5.745 2 mg/kg i.v. followed by 0.05 mg/kg/h Pre-PCI and for 24 h after All-cause mortality through Day 30 No effect on mortality 
 FX06 Atar et al.25 RCT 234 400 mg i.v. During PCI Infarct size at CMR at Day 5 No effect on infarct size 
 Atrial natriuretic peptide Kitakaze et al.26 RCT 569 0.025 µg/kg/min i.v. Pre-PCI and for 3 days after Infarct size and LVEF Reduction in infarct size, improvement of LVEF but no effect on mortality 
 Cyclosporine Piot et al.27 RCT 58 2.5 mg/kg i.v. Pre-PCI Infarct size Smaller infarct size but no effects on final TIMI flow 
 Intermittent arm ischaemia Bøtker et al.61 RCT 251 Four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff Pre-PCI Myocardial salvage index at 30 days Increased myocardial salvage with a favourable safety profile 
Distal embolization 
 Thrombus aspiration Svilaas et al.29 RCT 1.071 — During PCI MBG 0–1 Better reperfusion, MBG, STR, and clinical outcome 
Individual susceptibility 
 Insulin Malmberg et al.37 RCT 620 Insulin–glucose infusion ≥24 h Pre-, during, and post-PCI Mortality at 3 months in diabetic patients Reduction in mortality 
 Statins Iwakura et al.38 OS 293 Chronic statins pre-treatment Pre-PCI Incidence of no-reflow and EF Lower incidence of no-reflow, better wall motion, smaller LV dimensions, and better EF 
 Nitrates Ambrosio et al.58 OS 52.693 Chronic nitrates pre-treatment Pre-PCI Incidence of acute ischaemic events Shift away from STEMI in favour of NSTE-ACS and with less release of markers of cardiac necrosis 

TIMI, thrombolysis in myocardial infarction; cTFC, corrected TIMI frame count; CMR, cardiac magnetic resonance; i.c., intracoronary; i.v., intravenous; LVEF, left ventricular ejection fraction; NSTE-ACS, non-ST elevation acute coronary syndromes; MBG, myocardial blush grade; MI, myocardial infarction; OS, observational study; PCI, percutaneous coronary intervention; RCT, randomized controlled study; STEMI, ST-elevation myocardial infarction; STR, ST resolution.

The deleterious effects of prolonged ischaemia may be limited by drugs able to modulate myocardial oxygen consumption. Beneficial effects of carvedilol, fosinopril, or valsartan on coronary no-reflow and infarct size have been recently demonstrated in an animal model of coronary ligation and reperfusion.15 However, there are no published data on the effects of these drugs on indexes of no-reflow in humans. Protection of myocardial cells during ischaemia has also been attempted with drugs able to inhibits the Na+/H+ exchange system, which prevents calcium overload and cell swelling.16 However, large-scale multicentre trials failed to show any benefit of cariporide or eniporide in man.17,18

A number of pharmacological interventions have been tested to modulate reperfusion injury as mechanisms of no-reflow in STEMI. 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.4 Interestingly, in a small randomized trial, intracoronary administration of 4 mg of adenosine before complete vessel re-opening resulted in a lower rate of no-reflow when compared with the control arm.19 Of note, a large trial of a lower dose of adenosine (120 μg) after thrombus aspiration did not result in better STR when compared with placebo, thus suggesting that appropriate doses may be relevant.20

Nitroprusside is a nitric oxide donor that does not depend on intracellular metabolism to derive nitric oxide, with potent vasodilator properties as well as antiplatelet effects.4 The only randomized trial for the prevention of no-reflow using nitroprusside in the PPCI setting was conducted by Amit et al. in 98 patients presenting with STEMI in whom intracoronary nitroprusside was given beyond the occlusion prior to balloon dilatation. Angiographic parameters, cTFC and myocardial blush grade (MBG), and STR were similar between nitroprusside and control groups.21

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 the experimental model, probably by suppressing free radical generation and by modulation of neutrophil activation.4 It exerts also stimulating effect on preconditioning and has vasodilator properties. A single intravenous administration of nicorandil before PPCI was shown to improve angiographic indexes of no-reflow and clinical outcome.22

Verapamil is a calcium-channel blocker that has been utilized for the prevention of no-reflow. In a small randomized study by Taniyama et al.23 in 40 patients with first STEMI, intracoronary verapamil when compared with placebo was associated with better microvascular function assessed by MCE.

Only few trials targeting lethal reperfusion injury have evaluated indexes of no-reflow, whereas they mainly focused on various indexes of infarct size.3,4 As there is an interplay between lethal reperfusion injury and no-reflow, drugs able to reduce lethal reperfusion injury might have beneficial effects on no-reflow. Two large-scale trials in the setting of PPCI, APEX-AMI,24 and F.I.R.E.25 assessed the efficacy of pexelizumab, a humanized monoclonal antibody that binds the C5 component of complement, and FX06, a peptide derived from human fibrin, respectively. In the APEX-AMI trial, pexelizumab failed to improved 30 days mortality and rate of TIMI-3 flow was similar between pexelizumab-treated patients and controls.24 In the F.I.R.E. trial, FX06 failed to reduce the infarct size, when compared with placebo, whereas it improved the necrotic core zone and tended to improve the microvascular obstruction, as assessed by CMR.25 The RISK pathway, a family of protein involved in cardioprotection during reperfusion, is another potential therapeutic target.3 In particular, in the J-Wind trial, ANP, which activates the RISK pathways, was found to reduce the infarct size, estimated from creatine kinase, and to improve the ejection fraction, gauged by angiography of the left ventricle, and to reduce the reperfusion injury, as assessed by the occurrence of malignant ventricular arrhythmia during reperfusion, recurrence of ST segment elevation, or worsening of chest pain before discharge from coronary care unit, when administered at the time of PPCI; however, the rate of final TIMI-3 flow was similar between cases and controls.26 The opening of mitochondrial permeability transition pores has a central role in reperfusion injury leading to mitochondria swelling and cell death.3 Cyclosporin-A may prevent their opening and has been shown in a small study to reduce the infarct size when given at the time of reperfusion during PPCI; however, final TIMI flow were similar between patients and controls.27 New studies targeting reperfusion injury are currently ongoing by using protein kinase C delta (Protection-AMI), erythropoietin (Epaminondas, Intra-CO-EpoMI, HEBE), acetaminophen (APRIORI Pilot), combination of high dosage of atorvastatin, cyclosporin-A, and erythropoietin (ACE), high dosages of adenosine or nitroprusside (Reopen-AMI). It is worth noting, however, that in order to define the benefit of study drugs on infarct size and on no-reflow, accurate diagnostic techniques are needed. In the case of no-reflow, for instances, TIMI flow evaluation is not enough, as clearly demonstrated by Ito et al.28 No-reflow occurs in up to 25% of patients exhibiting TIMI-3 flow.

Thrombus aspiration has a proven role in PPCI and its beneficial action is probably via a reduction in distal embolization.29 Distal embolization may impair the microcirculation by mechanical obstruction due to thrombotic or plaque material release both spontaneous and iatrogenic.30 Furthermore, it contributes to sustained vasoconstriction and thrombus propagation. The risk of distal embolization is related to thrombus burden which may be reduced by the use of glycoprotein IIb/IIIa inhibitors.31 Among IIb/IIIa antagonsists, abciximab has been found to improve myocardial perfusion when started in the catheterization laboratory prior to balloon inflation and infused for 12 h thereafter, as assessed by a higher rate of STR >50% at 60 min post-PCI.32 The beneficial effects of abciximab on microvascular reperfusion in the setting of PPCI parallel and might at least partially account for those on clinical endpoints.33 Interestingly, intracoronary abciximab has been proved to be superior to intravenous abciximab in some patients treated by PPCI,34 which might be explained by the high local doses that may facilitate the diffusion of the antibody to platelets inside the flow-limiting thrombus and to the anti-inflammatory properties of abciximab.34 Accordingly, eptifibatide also has been shown to improve the microcirculation when administered by intracoronary route due to a higher occupancy of the IIb/IIIa receptor.35

Individual response to injury is modulated by acquired risk factors such as diabetes and hypercholesterolaemia.12,13 Recent studies have demonstrated an association between acute hyperglycaemia and no-reflow, independent of previous glycaemic control evaluated by Ha1c levels, suggesting a direct detrimental effect of acute hyperglycaemia on reperfusion injury.36 Indeed, optimal and prompt treatment of hyperglycaemia is likely to be an important target in the prevention of no-reflow. Accordingly, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study demonstrated that a periprocedural reduction in blood glucose was associated with a reduction in infarct size.37 Furthermore, statins are emerging as drugs potentially able to reduce reperfusion injury. Iwakura et al.38 have demonstrated that chronic statin therapy in patients with or without hypercholesterolaemia is associated with lower prevalence of no-reflow and with better functional recovery.

Taken together, these data suggest that no-reflow prevention is possible, especially when high drug dosages are administered at an intracoronary level.

Pharmacological treatment of no-reflow

Treatment of no-reflow is needed when prevention fails. In this context, the treatment agent needs to be effective during ongoing and progressive IR injury, and in the presence of no-reflow, the agent may not reach the target microcirculation. Primary angioplasty affords an ability to deliver high local doses of pharmacological agents directly into the culprit coronary vessel.

Adenosine has been tested for the treatment of no-reflow by both intracoronary and intravenous infusion. Stoel et al.39 enrolled 51 patients with STEMI undergoing PPCI, showing that intracoronary administration of a very high dose of adenosine (60 mg) was associated, compared with placebo, with an early improvement of electrocardiographic derived indexes of no-reflow. Yet, STR >70% in the coronary care unit was similar in the adenosine- and placebo-treated patients, thus suggesting that adenosine accelerates only STR but was not able to increase the final rate of STR. Intravenous adenosine has been tested in two large randomized trials (AMISTAD I and II).40,41 In the setting of PPCI, the drug was started before the intervention and continued for 3 h thereafter; thus both prevention and treatment phases were addressed. Both studies showed better 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 has been tested for the treatment of no-reflow in small registries, showing an improvement of final TIMI flow after administration of intracoronary nitroprusside given in the attempt to reverse no-reflow during PPCI,42,43 but no conclusive data are available for other indexes of no-reflow and more importantly clinical outcome.

Intravenous infusion of nicorandil for 24 h after PPCI resulted in better angiographic, functional, and clinical outcome when compared with placebo in two randomized studies,44,45 but another study in which 276 patients were randomly assigned to intravenous nicorandil or placebo showed similar infarct size and left ventricular ejection fraction between study group and controls.26 Finally, a small trial suggested some improvement in TIMI flow after intracoronary verapamil used to reverse no-reflow after PPCI.46 Thus, for both nicorandil and verapamil, conclusive data for no-reflow reversal are lacking.

In summary, pharmacological treatment of established no-reflow is not feasible at the present time.

Why do drugs fail in the treatment of no-reflow?

Lack of beneficial effects for drugs used after no-reflow has occurred may be due to the progressive impairment of microcirculation, as initially shown by Ambrosio et al.47 Accordingly, Rochitte et al.48 demonstrated in dogs that at CMR hypoperfused regions at first pass showed a 3-fold increase during 48 h of reperfusion paralleled by an increase in late hyperenhancement regions and by an increase in the microvascular obstruction/infarct size ratio. Persistent impairment of the microcirculation may be in part due to distal embolization of plaque.49 Taken together, these observations suggest that microvascular obstruction progresses over time, thus limiting the efficacy of treatments given when microvascular damage is already established. Although no-reflow may spontaneously reverse in ∼50% of patients after 1 month as shown by Galiuto et al.,50 patients with reversible no-reflow have, however, worse left ventricular function indexes when compared with those with reflow after reperfusion thus confirming that achieving early reflow is the way to go rather than attempting to reverse the phenomenon.

Furthermore, the complex multifactorial nature of no-reflow makes unlikely that any single agent will be effective in the treatment of established no-reflow for all patients. In particular, pleiotropic effects mediated by adenosine are obtained at higher dosages than that achievable by intravenous administration. Combination therapy has not been tested in large trials, but, as for other medical conditions, increasing dosages of drugs or combination therapy increase the rate of complications and side effects, and they are not necessarily tolerated by all patients, especially if haemodynamically unstable.

Exploitation of endogenous protective mechanisms

The most potent endogenous mechanism to limit infarction is ischaemic preconditioning (IPC).51 This notion has driven extensive research into its underlying mechanisms and clinical applications.51 Ischaemic preconditioning is able to reduce the infarct size by half after coronary ligation and reperfusion.52 In addition to its effects on myocardial cells which become resistant to ischaemia stimulus when preconditioned, a number of observations suggest that IPC may also prevent IR injury at a microcirculatory level.53 A study by Posa et al.54 showed that in pigs, IPC attenuated release of myeloperoxidase and platelet activation after IR, thus improving perfusion. Indirectly, IPC by reducing cell swelling may also reduce myocardial obstruction by external compression. Ischaemic preconditioning may finally prevent endothelial alterations during reperfusion.51 Taken together, these observations suggest that stimulating IPC may be a target for no-reflow prevention. Importantly, IPC may be modulated by risk factors, drugs, or beverages.52,55–57 The deleterious effects of risk factors may be reduced by accurate treatment of subjects at risk of acute myocardial infarction.52 In addition, knowledge of deleterious effects on IPC of drugs like glibenclamide55 or beverages like high dose of coffee56 and alcoholic beverages57 may be utilized for the avoidance of such blocking agents. On the other hand, drugs such as nitrates have been shown to produce a late preconditioning effect both in animals and in humans, while chronic nitrate therapy is associated with a shift from STEMI in favour of NSTEMI and with less release of markers of cardiac necrosis, suggesting that nitrates may pharmacologically precondition the heart towards ischaemic episodes.58 Beyond that, IPC may be stimulated both before (by remote preconditioning in those patients in which IPC was not operating as occlusion occurred not preceded by repetitive IR phases) and after reperfusion in the cath-lab (by postconditioning).

Brief ischaemia in an organ that is distant or remote from the heart, such as limb, also reduces myocardial infarction in experimental models.59 Cycles of intermittent limb ischaemia provide an acceptable method for inducing cardioprotection, and early proof-of-concept studies have confirmed the effectiveness of remote IPC in cardiac surgery and coronary angioplasty, as assessed by reduced markers of cardiac injury.60 Remote ischaemia is unique in that it can also be applied during myocardial ischaemia prior to reperfusion.60 In a recent randomized study, Bøtker et al.61 found that remote preconditioning by intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff increased the myocardial salvage index measured by myocardial perfusion imaging [median salvage index 0.75 (IQR 0.50–0.93, n = 73) in the remote conditioning group vs. 0.55 (0.35–0.88, n = 69) in the control group]. Interestingly, Rentoukas et al.62 showed that the beneficial effect of remote IPC on STR in patients treated by PPCI is increased by the concomitant administration of morphine. Finally, the remote conditioning stimulus has complex effects on neutrophil adhesion function.63

In recent years, the notion of ischaemic postconditioning (IPostC) developed through an increased understanding of the pathobiology of reperfusion.64,65 This prompted studies in which early reperfusion was interrupted by intermittent brief periods of ischaemia prior to extended reperfusion which was able to reduce myocardial infarction66, and has renewed interest in identifying potential therapeutic uses.67 Primary angioplasty provides an ideal mechanical means to implement IPostC in STEMI and six randomized translational proof-of-concepts studies have been reported.66 A recent meta-analysis including 244 patients, treated by PPCI, suggested that this form of preconditioning resulted in a lower mean peak creatine-kinase release, better left ventricular ejection fraction and myocardial reperfusion when compared with control subjects.66 More focused studies investigating the additional effects of remote IPC and IPostC on indexes of no-reflow are warranted.

A clinical approach to no-reflow: prevention is better than treatment

Prevention of no-reflow starts with risk factor control and avoidance of drugs, such as glibenclamide, or beverages, like coffee and alcohol at high-dose intake, blocking IPC in asymptomatic patients at risk of myocardial infarction (Figure 3). The potential advantages offered by remote IPC should be offered to all patients without pre-infarction angina. Then an efficient emergency system that guarantees the reduction in ischaemic time is crucial for no-reflow prevention in all patients undergoing PPCI or thrombolysis (Figure 1). Indeed, the rate of no-reflow when reperfusion is performed within 1h of ischaemic time is low independently of the use of any specific preventive measures.4 When ischaemic time becomes longer, modulation of deleterious effects of ischaemia should be faced as early as possible by administration of anti-ischaemic drugs. A careful history focused on the assessment of cardiovascular risk factors and of pre-infarction angina may help as well as the evaluation of laboratory data such as lipid levels and glycaemia3 (Figure 1). Indeed, statin administration and control of hyperglycaemia might be of benefit in this early phase (Figure 1).

Figure 3

Prevention more than treatment has a central role in the management of no-reflow. It starts before infarction pain occurs by targeting risk factors and by avoiding the blockage prevention of ischaemic preconditioning. After the onset of infarction pain and before hospital arrival, the reduction in ischaemic time, an early administration of IIb/IIIa inhibitors, and remote ischaemic preconditioning have an important role. In the catheterization laboratory, the use of thrombus aspiration, high doses of intracoronary adenosine, and ischaemic postconditioning are good opportunities to prevent no-reflow. No drugs have been shown to reverse established no-reflow.

Figure 3

Prevention more than treatment has a central role in the management of no-reflow. It starts before infarction pain occurs by targeting risk factors and by avoiding the blockage prevention of ischaemic preconditioning. After the onset of infarction pain and before hospital arrival, the reduction in ischaemic time, an early administration of IIb/IIIa inhibitors, and remote ischaemic preconditioning have an important role. In the catheterization laboratory, the use of thrombus aspiration, high doses of intracoronary adenosine, and ischaemic postconditioning are good opportunities to prevent no-reflow. No drugs have been shown to reverse established no-reflow.

Among patients undergoing PPCI, both thrombus aspiration and IIb/IIIa have been shown to improve no-reflow as well as outcome4 (Figure 1). Early administration of IIb/IIIa inhibitors in the ambulance or in the emergency department is strongly recommended by guidelines. In this setting, adenosine administration at high dosage before vessel re-opening may prepare the microcirculation to reperfusion, at least in part counteracting reperfusion injury (Figure 1). Finally, IPostC should be implemented in clinical practice (Figure 1).

No-reflow can be considered as the last barricade before optimal reperfusion can be achieved for all STEMI patients. Prevention rather than treatment should be the way forward as treatment after no-reflow is established is unlikely to succeed.

Conflict of interest: none declared.

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Author notes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

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