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Archives of cardiovascular diseases
Volume 108, n° 12
pages 661-674 (décembre 2015)
Doi : 10.1016/j.acvd.2015.09.006
Received : 23 July 2015 ;  accepted : 7 September 2015
The no-reflow phenomenon: State of the art
Le no-reflow  : état de l’art
 

Claire Bouleti a, b, c, d, e, Nathan Mewton f, g, Stéphane Germain c, , d, e
a Service de cardiologie, hôpital Bichat, AP–HP, Paris, France 
b DHU FIRE, université Paris Diderot, Paris, France 
c Collège de France, Center for Interdisciplinary Research in Biology (CIRB), Paris, France 
d CNRS/UMR 7241, Paris, France 
e Inserm U 1050, Paris, France 
f Hôpital cardiovasculaire Louis-Pradel, centre d’investigation clinique unité, hospices civils de Lyon, Bron, France 
g Inserm U 1407, Lyon, France 

Corresponding author.
Summary

Primary percutaneous coronary intervention (PCI) is the best available reperfusion strategy for acute ST-segment elevation myocardial infarction (STEMI), with nearly 95% of occluded coronary vessels being reopened in this setting. Despite re-establishing epicardial coronary vessel patency, primary PCI may fail to restore optimal myocardial reperfusion within the myocardial tissue, a failure at the microvascular level known as no-reflow (NR). NR has been reported to occur in up to 60% of STEMI patients with optimal coronary vessel reperfusion. When it does occur, it significantly attenuates the beneficial effect of reperfusion therapy, leading to poor outcomes. The pathophysiology of NR is complex and incompletely understood. Many phenomena are known to contribute to NR, including leukocyte infiltration, vasoconstriction, activation of inflammatory pathways and cellular oedema. Vascular damage and haemorrhage may also play important roles in the establishment of NR. In this review, we describe the pathophysiological mechanisms of NR and the tools available for diagnosing it. We also describe the microvasculature and the endothelial mechanisms involved in NR, which may provide relevant therapeutic targets for reducing NR and improving the prognosis for patients.

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Résumé

L’angioplastie coronaire primaire en urgence est la méthode de choix de reperfusion coronarienne pour les patients présentant un infarctus du myocarde. Le taux de succès angiographique de l’angioplastie coronaire est actuellement de 95 %. Cependant, malgré la restauration du flux épicardique, l’angioplastie peut ne pas entraîner de reperfusion réellement efficace du tissue myocardique profond. Ce défaut de reperfusion de la microcirculation myocardique correspond au phénomène de no-reflow . Selon les études, celui-ci est retrouvé chez 10 à 60 % des patients ayant pourtant bénéficié d’une reperfusion angiographique optimale. Le no-reflow atténue le bénéfice de la reperfusion et est un facteur de mauvais pronostic clinique à la phase aiguë et à long terme avec alteration de la fraction d’éjection ventriculaire gauche, insuffisance cardiaque clinique et survenue d’événements rythmiques ventriculaires. La physiopathologie du no-reflow et sa cinétique sont complexes et mal comprises. Plus que l’embolisation distale de débris athéro-thrombotiques, de nombreux phénomènes tels que la vasoconstriction, l’œdème intra- et extra-cellulaire, l’inflammation avec infiltration leucocytaire et libération de signaux cytotoxiques, participent au no-reflow. De plus, des données récentes démontrent un rôle important des dommages endothéliaux et de l’hémorragie intra-myocardique. La perte d’integrité de la barrière endothéliale lors de la reperfusion brutale du myocarde ischémié entraîne une hyperperméabilité vasculaire qui semble être un acteur majeur du no-reflow . Dans cette revue, nous analyserons les mécanismes physiopathologiques impliqués dans le no-reflow , nous décrirons les outils diagnostiques disponibles, les éléments du pronostic et les différentes thérapeutiques à l’essai. Nous porterons une attention particulière à la protection de l’endothélium microvasculaire, qui pourrait constituer une nouvelle cible thérapeutique pour diminuer le no-reflow .

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Keywords : No-reflow, Ischaemia, Reperfusion, Primary coronary angioplasty, Vascular permeability

Mots clés : No-reflow , Infarctus du myocarde, Ischémie, Reperfusion, Angioplastie coronaire primaire, Perméabilité vasculaire

Abbreviations : AMI, ANGPTL4, ATP, CMR, ce-CMR, IV, MBG, MVO, NR, PCI, STEMI, TIMI, VE, VEGF


Background

Primary percutaneous coronary intervention (PCI) is the best available reperfusion strategy in patients with acute ST-segment elevation myocardial infarction (STEMI) [1]. Up to 95% of occluded coronary vessels can be reopened in the setting of STEMI [2, 3, 4, 5]. However, despite re-establishing the epicardial coronary vessel patency, primary PCI may fail to restore optimal myocardial reperfusion within the myocardial tissue in patients with STEMI. This reperfusion failure at the microvascular level is a condition known as no-reflow (NR) [6, 7, 8, 9, 10]. NR has been described in up to 60% of STEMI patients with optimal coronary vessel reperfusion [3, 11, 12, 13, 14, 15, 16, 17, 18, 19]. When NR occurs, it significantly attenuates the beneficial impact of reperfusion therapy, resulting in poor clinical and functional outcomes [6, 20, 21, 22]. But do we really know what the NR phenomenon is? The pathophysiology of NR is complex and is not fully understood; it involves much more than just distal embolization of thrombotic debris. Indeed, many phenomena contribute to NR: leukocyte infiltration, vasoconstriction, activation of inflammatory pathways and cellular oedema [23, 24] (Figure 1). Recently, experimental data demonstrated the important roles played by vascular damage and haemorrhage in the establishment of NR. Vascular permeability at the endothelial level appears to be a major factor in NR.



Figure 1


Figure 1. 

No-reflow pathophysiology. No-reflow or microvascular obstruction/reperfusion injury is a dynamic and complex phenomenon that starts with lethal ischaemia and ends ultimately with replacement of the injured myocardial tissue with a dense fibrotic scar. The phenomenon takes its seeds in a prolonged (>30minutes) lethal ischaemia to the healthy myocardium, resulting in cell death. The second phase is caused by the brutal reperfusion of the ischaemic myocardium. In the following 24hours, a cascade of deleterious phenomena take place, including intra- and extracellular oedema, microvessel obstruction with atherothrombotic material as well as cell debris, vasoconstriction induced by platelet hyperactivation and important cytotoxic signals delivered by the different myocardial cell components. After 24hours, an important inflammatory response in the ischaemic injured myocardium as well as the non-infarcted remote myocardium occurs and can cause additional damage to the myocardium.

Zoom

In this state-of-the-art review, we will cover all the described pathophysiological mechanisms and the tools available for diagnosing NR in clinical settings. We will also focus further on the microvasculature and the endothelial mechanisms involved in NR, which may provide relevant therapeutic targets to reduce NR and improve patient prognosis.

Pathophysiological mechanisms and predictive factors

The NR phenomenon was described for the first time by Kloner et al. in 1974 [25], in a canine experimental model of myocardial ischaemia-reperfusion.

Ischaemia injury

NR starts with the initial severe ischaemic insult. Lethal ischaemia, defined by a myocardial tissue blood flow<40mL/min for 100g of tissue, causes irreversible cardiomyocyte and endothelial damage. At the endothelial level, bleb formation and endothelial protrusion are observed, and obstruct the microcirculation. Endothelial cell necrosis leads to destruction of tight and adherens junctions and loss of vascular integrity, which, in turn, leads to extravascular accumulation of fluid and blood cells [26]. This extravascular expansion provokes vascular compression and a reduction in the microvessel lumen. Also, endothelial nitric oxide production is altered, and impairs the endothelium-dependent vasodilatation. At the cardiomyocyte level, ischaemia causes cell necrosis and cardiomyocyte swelling, which increases compression of intramural vessels [26, 27].

Reperfusion injury

The ischaemia-related injury is made worse by reperfusion injury. Reperfusion injury, caused by the brutal restoration of a normal blood supply (100mL/min for 100g) to damaged microvessels, accelerates myocardial swelling, tissue oedema, endothelial disruption and inflammation [28]. The production of oxygen-free radicals is enhanced by this reperfusion within the first few minutes of reflow and also takes part in reperfusion injury [29].

Neutrophils and platelets form microaggregates (plugs), which are responsible for luminal obstruction of the microvasculature [30, 31]. Autonomic dysfunction also occurs upon reperfusion, with alpha-adrenergic receptor-mediated constriction of coronary microvessels, which may contribute to NR [32].

Infarct size

Several studies have demonstrated a correlation between larger infarct size and NR, in terms of both frequency and importance [33, 34, 35, 36]. As necrosis is associated with tissue destruction, oedema and mechanical compression, which are pathophysiological factors in NR, the association between infarct size and NR has been demonstrated [27]. In line with this interpretation, a higher incidence of NR has been reported when the culprit vessel is the proximal left anterior descending coronary artery responsible for the largest myocardial infarction [36, 37, 38]. Similarly, longer pain-to-balloon time is related to the development of NR, as it is linked to a larger infarct area [36, 39].

Endothelial injury

A major regulator of endothelial integrity is vascular endothelial growth factor (VEGF), which was originally called vascular permeability factor [40]. VEGF is expressed in response to hypoxia during acute myocardial infarction (AMI) [41, 42, 43, 44, 45, 46]. In a resting state, VEGF receptor 2 forms a complex with vascular endothelial (VE)-cadherin, an endothelial-specific adhesion protein that stabilizes intercellular adherens junctions [47]. Ischaemia-induced VEGF, when binding to VEGF receptor 2, dissociates the VEGF receptor 2/VE-cadherin complex, leading to an increase in endothelial permeability [48]. VEGF activates Src phosphorylation, which then induces tyrosine phosphorylation of VE-cadherin and its internalization; this reduces the amount of VE-cadherin available at interendothelial junctions, thus leading to disruption of endothelial barrier integrity. In vivo, VE-cadherin phosphorylation is also modulated by the haemodynamic forces and shear stress to which endothelial cells are exposed [49]. So, driven by its phosphorylation state, VE-cadherin plays a major role in maintaining strong interendothelial junctions. In experimental models, vascular permeability plays a central role in NR. However there are few data from human patients on the basal and ischaemia-induced phosphorylation levels of VE-cadherin in the coronary microcirculation, which might represent a new angle for preventing or treating NR.

Distal atherothrombotic embolization

PCI performed upon a ruptured plaque with thrombus and atherosclerotic material leads to distal embolization of microthrombi and plaque components [50]. This distal embolization is involved in the NR phenomenon [51, 52, 53]. Distal microembolization results in an increase in distal resistance, multiple microinfarcts and increased levels of myocardial necrosis biomarkers, and therefore hampers the efficacy of PCI [54, 55]. Distal embolization is an attractive component of NR in terms of therapeutic approach, and has therefore been emphasized by some studies as a main contributor to NR; it is accessible to treatment with the use of thrombectomy catheters. Nevertheless, distal embolization is only one of the numerous factors that contribute to NR genesis. NR was first described in experimental models of ischaemia reperfusion without any thrombus or distal embolization. Also, Skyschally et al. reported that microembolization with microspheres during early reperfusion accounted for up to 15% of infarct size increase, which was reduced to 5% in case of postconditioning [56]. Thus, focusing only on coronary microembolization treatment to prevent the NR phenomenon appears biased, and the disappointing results from recent thrombectomy trials confirm the need to consider alternative coadjuvant treatments and take into account the complex pathophysiology of NR [57, 58].

Clinical implications of the no-reflow phenomenon

NR is associated with larger infarct size, lower left ventricular ejection fraction, adverse left ventricular remodelling in the remote stage of myocardial infarction, and increased incidences of heart failure, cardiac rupture [22] and death, compared with patients without NR [4, 5, 10, 16, 35]. Moreover, a study using magnetic resonance imaging showed that persistence of microvascular obstruction was a more powerful predictor of global and regional functional recovery than transmural extension of infarction [59]. Thus, during short-term management, it is not surprising that the NR phenomenon correlates with an increased duration of hospitalization compared with patients without NR [36], with economic consequences. Whether NR can affect the long-term clinical prognosis of patients is an important question, as it is usually a transient phenomenon that resolves over time in nearly 50% of patients. One might hope that the long-term consequences would be limited [14]. NR has also been found to be an independent predictor of 1-year mortality, with a 3-fold increase in the adjusted risk of death in patients with STEMI undergoing primary PCI [35]. NR also predicted an increased risk of death up to 5 years after primary PCI for STEMI (Kaplan-Meier estimates of 5-year mortality of 18.2% and 9.5%, respectively; odds ratio 2.02, 95% confidence interval 1.44–2.82; P <0.001) [60]. These findings emphasize that as a major risk marker of cardiovascular events, NR should be identified and treated as soon as possible or, ideally, prevented [7].

No-reflow diagnosis

Whatever the diagnostic method used, one must consider the dynamic nature of NR (Table 1). NR persists throughout the 48hours after reperfusion, although this time frame is hypothetical and is based upon experimental findings [61]. The severity of NR or microvascular obstruction also has consequences for its diagnosis. A transient slowing of myocardial blood flow in the infarcted area will not be assessed as easily as a complete and fixed obstruction of the myocardial microvasculature.

Coronary angiography

Coronary angiography performed during primary PCI at the acute phase of myocardial infarction was the first imaging technique to identify the NR phenomenon in humans. In fact, the term NR came naturally after the observation of the absence of coronary flow despite correct implantation of a coronary stent or an angioplasty procedure performed to reopen the occluded coronary vessel. The classification of different grades of angiographic coronary blood flow has been established according to the Thrombolysis in Myocardial Infarction (TIMI) scale [62]. The absence of reflow is classified according to the TIMI angiographic scale as a grade ≤ 1 in the culprit coronary artery after the PCI procedure [62]. Coronary angiography TIMI flow is simple, but this method lacks sensitivity and specificity for the assessment of NR. Indeed, capillary blood flow is not measured directly by angiography, and a significant proportion of TIMI grade 3 flow patients actually present NR [12, 63].

Myocardial blush grade (MBG) is another imaging technique for assessing myocardial microvasculature and tissue reflow by angiography [64]. With this method, angiographers assess the myocardial tissue opacification intensity with longer angiographic runs, performed until the venous phase of contrast passage. According to visual or computerized signal intensity automatic assessment, myocardial “blush” is graded according to a scale with four intensity grades: 0, no myocardial blush; 1, minimal myocardial blush or contrast density; 2, moderate myocardial blush or contrast density, but less than that obtained during angiography of a contralateral non-infarct-related coronary artery; and 3, normal myocardial blush or contrast density, similar to that obtained during angiography of a contralateral non-infarct-related coronary artery. However, this very low contrast-to-noise imaging method of myocardial tissue opacification suffers from the same limitations as the angiographic TIMI scale [65]. The timing of angiography is too early to assess all the reperfusion injuries and other complex phenomena that develop in the hours and days after reperfusion. This is one reason why post-PCI TIMI flow or MBG are not necessarily predictive of the presence of microvascular obstruction (MVO) as detected by cardiac magnetic resonance (CMR) [65, 66]. Indeed, whereas at a population level, a grade 3 MBG or TIMI flow indicates a good prognosis, on an individual basis, up to 60% of STEMI patients with optimal angiographic reperfusion indices (MBG and TIMI flow=3) show NR on a CMR image acquired in the following 72hours [67].

Cardiac magnetic resonance imaging

CMR imaging with gadolinium administration is the gold-standard non-invasive technique for assessing MVO with the highest spatial resolution and good levels of reproducibility [68]. The diagnosis of NR by contrast-enhanced CMR (ce-CMR) is based on the specific characteristics of myocardial capillary circulation within the injured myocardium, compared with the healthy myocardium. The extracellular contrast agent (gadolinium chelate), injected intravenously, circulates and is distributed differently according to the coronary microcirculation state. The differences in myocardial tissue concentration of gadolinium at the time of CMR image acquisition allow the classification of myocardial tissue as normal or infarcted with or without MVO [69]. The addition of pre-contrast T2 weighted sequences provides significant information about myocardial oedema and intramyocardial haemorrhage [70, 71]. CMR has also been validated against pathology in experimental models of ischaemia-reperfusion [61, 72].

There are two distinct approaches to diagnosing MVO by ce-CMR (also presented in Figure 2): the perfusional approach and the delayed enhancement approach.



Figure 2


Figure 2. 

Myocardial tissue characterization and cardiac magnetic resonance (CMR) techniques to assess microvascular obstruction with contrast-enhanced CMR. Mid-ventricular short-axis views in an anterior STEMI patient with optimal reperfusion on CMR performed 48hours after admission. A. T2-weighted (T2W) acquisition showing transmural extensive oedema in the anteroseptal wall (arrow). B. First-pass perfusion acquisition, at the same time as gadolinium intravenous bolus, where the hypoperfused area appears hypointense (red contour) in the subendocardium of the anteroseptal wall. C & D. Subsequent delayed enhancement views, performed (C) 3minutes and (D) 10minutes after gadolinium administration. The microvascular obstruction area on these views is hypointense (red contour); on the 10-minute acquisition it is surrounded by hyperintense myocardium that corresponds to the myocardial infarcted tissue. As gadolinium passively and slowly diffuses to the infarct core, the hypointense area shrinks, and the 10-minute microvascular obstruction area (D) is roughly half the size of the early microvascular obstruction area (C).

Zoom

Perfusional approach

The initial description of NR by ce-CMR was based upon the first-pass perfusion method in experimental models and STEMI patients [16, 61, 72]. The NR area is composed of injured myocardium where the microvasculature is severely damaged or destroyed; this results in the absence of or significant delay in the appearance of gadolinium within this area, and therefore a subsequent hypoenhancement (Figure 2B) within the core of the infarct, compared with other regions of the myocardium with normal microvascular architecture. MVO is characterized by low signal intensity early after contrast injection followed by a very slow or no growth of signal intensity. Some authors proposed setting the time for this hypointensity assessment at>1minute after contrast bolus [72] or as myocardial regions with a delay of>1 second to reach the time to 50% maximum signal intensity (T50%max ) for the non-infarcted myocardium [17]. However, these arbitrary thresholds are rarely used in clinical practice.

With the technological progress made in perfusional sequences, a significant proportion of STEMI patients (>50%) have a hypointense area on first-pass perfusion images. This hypointensity relates to the presence of NR, but also to the slowing of contrast media in the reperfused myocardium (oedema) on the first-pass perfusion acquisitions. However, on the 10-minute contrast-enhanced sequences, this hypointense area may disappear. This shows the good sensitivity of first-pass perfusion sequences, but their lower specificity [67].

Delayed enhancement approach

As shown in Figure 2C and Figure 2D, the NR zone is defined as the hypointense area within the core of the myocardial infarct on delayed enhancement sequences performed at 3minutes (early contrast enhancement) or 10minutes (late contrast enhancement) following a gadolinium intravenous (IV) bolus. Delayed enhancement sequences offer the advantage of better spatial resolution and complete left ventricular coverage compared with first-pass perfusion sequences. The hypointense myocardial area on these sequences corresponds to severely obstructed myocardium that the extracellular media did not reach, even after 10minutes of passive diffusion. The other myocardial regions (hypointense on the first-pass perfusion sequences), where contrast perfusion and diffusion persist, correspond to areas of “slow-flow” or “low-reflow”. The progressive signal intensity growth within the NR area between the early and late acquisitions is related to the passive diffusion of the contrast media within the severely injured myocardium and extracellular space (Figure 3).



Figure 3


Figure 3. 

Short-axis view of early and late contrast-enhanced cardiac magnetic resonance imaging in a patient with acute reperfused lateral myocardial infarction. The infarcted myocardium appears hyperintense on the late enhancement image, with a subendocardial area with persistent low signal intensity (black arrow) corresponding to severe microvascular obstruction (right panel). On the early late gadolinium enhancement (LGE) sequence (left panel), the whole myocardium is still saturated with gadolinium, but the microvascular obstruction area already appears hypointense (black arrow).

Zoom

There are currently no guidelines for the best timing or type of sequence to assess MVO/NR by ce-CMR. Various CMR sequences have been used, with significant differences in terms of results and clinical relevance. However, the late gadolinium enhancement approach at 10minutes appears to be the most reliable and relevant method to assess MVO. The persistence of a microvascular area where gadolinium does not penetrate after 10minutes is a marker of more severe injury. Also, late gadolinium enhancement sequences are robust and can be acquired in one breath hold, covering the whole ventricle with high spatial resolution [73]. Finally, recent papers have compared the respective predictive values of MVO defined by the first-pass perfusion technique versus late gadolinium enhancement technique (at 10minutes) for adverse cardiovascular events, and results the late enhancement gadolinium technique was a better predictor [67]. Recent papers in large cohorts of patients where MVO was assessed with the late-enhancement technique at 10minutes have shown the independent predictive value of MVO on subsequent major cardiac events [18, 74].

Of note, CMR, with its powerful tissue characterization properties, also enables the assessment of important factors of ischaemia-reperfusion injury that participate in the final MVO, such as oedema, haemorrhage and inflammation [70, 71, 75, 76, 77]. The development and use of these imaging abilities in future studies may be important for understanding MVO and treating it more efficiently.

Other techniques

Other diagnostic techniques have been used to assess NR, such as the post-reperfusion electrocardiogram [66], contrast echocardiography [3] and nuclear imaging, but their lack of sensitivity, their complexity and limited accessibility make these techniques less attractive for NR assessment in routine clinical practice.

No-reflow treatment

NR is a phenomenon that has been known for 40 years, but in this time very little progress has been made in terms of therapies directed towards the microcirculation [78, 79]. There are, in fact, no specific therapies targeting NR that are applicable and recommended for the routine management of STEMI patients. Although there are a lot of experimental data showing the significant positive effect of treatments applied before and after reperfusion in ischaemia-reperfusion models, these treatments have failed to show any positive effect in human patients [10, 80]. However, some strategies for NR treatment have shown effects that are at least controversial and at best beneficial. In the following paragraphs, we will focus specifically upon treatments that are readily available in routine clinical practice, but have to be used off-label for the NR indication, and treatments that are currently being assessed in phase III trials, which appear promising.

Non-pharmacological approach
Mechanical ischaemic postconditioning

In 2003, Zhao et al. showed in an experimental model of ischaemia-reperfusion that brief episodes of ischaemia-reperfusion performed immediately after reflow following prolonged ischaemia significantly reduced the final infarct size by 40% [81]. In addition, this group showed that mechanical postconditioning also significantly reduced myocardial oedema and many other cytotoxic reactions within the myocardial microvasculature following reperfusion [82]. These results were translated to STEMI patients in 2005 by Staat et al. [83]. In this proof-of-concept trial, ischaemic postconditioning was applied within 1minute after reflow by inflating/deflating the angioplasty balloon upstream of the culprit lesion in four successive 1-minute cycles. This strategy significantly reduced infarct size by 36%, as assessed by the creatine kinase area under the curve release. In another trial, Mewton et al. showed that ischaemic postconditioning significantly reduced MVO by around 50%, as assessed by ce-CMR at 72hours, thus suggesting a specific effect of ischaemic postconditioning on NR [84]. However, recent trials in larger groups of STEMI patients have failed to show any significant benefit of this technique [85, 86]. Even if the meta-analysis of all postconditioning trials shows a favourable effect of ischaemic postconditioning on infarct size surrogates [87], stronger evidence from phase III trials needs to be provided for this technique to be recommended for the management of STEMI patients. The ongoing DANAMI-3 trial (Danish Study of Optimal Acute Treatment of Patients with ST-elevation Myocardial Infarction-3; ClinicalTrials.gov Identifier NCT01435408) will assess the effect of three different reperfusion protocols, including ischaemic postconditioning, on clinical outcomes (all-cause death and heart failure) at 2 years in 2000 STEMI patients. Potential therapies such as ischaemic preconditioning and remote ischaemic preconditioning have shown benefit in reducing NR and clinical variables [88]. A recent systematic review and meta-analysis showed that remote ischaemic preconditioning appears to be an effective method for reducing ischaemia-reperfusion myocardial injury, and suggests that it may reduce long-term clinical events [88]. Nevertheless, this strategy has not yet been deployed in the clinical setting to reduce NR [89].

Struggles against distal coronary embolization

Thrombus aspiration or distal filters have been developed to reduce the risk of distal embolization involved in MVO pathogenesis. Several studies have demonstrated that thrombus aspiration before PCI is associated with an improvement in clinical outcomes in patients with STEMI [90, 91, 92, 93]. However, a recent multicentre randomized trial demonstrated that routine thrombus aspiration before PCI compared with PCI alone did not reduce 30-day mortality among patients with STEMI [57]. Another mechanical approach consists of deployment of distal embolic protection devices before stenting. Although this system effectively retrieved embolic debris [94], it failed to improve microvascular flow, infarct size or clinical outcome [94, 95, 96]. Finally, the mini-invasive strategy consisting of delayed stenting after reperfusion and several days of antithrombotic treatment may, in theory, limit the feared distal embolization when the stent is deployed, but its efficacy has yet to be proven in terms of mortality or infarct size reduction.

Thus, distal embolization plays a role in NR, but its involvement seems, in fact, quite limited [56]; this might explain the recent disappointing results of published trials focusing only on this variable for the prevention of NR. Prevention of microvessel coronary embolization should probably be integrated into a global approach with coadjuvant treatments to take into account the other contributors to NR pathogenesis. During the past 10 years, many phase II clinical trials have been performed to find coadjuvant pharmacological interventions to improve the myocardial damage associated with STEMI.

Pharmacological therapies
Metoprolol

Preclinical results from a pig model of myocardial infarction showed that IV metoprolol administered before reperfusion significantly reduced infarct size [97, 98]. The underlying mechanism for this infarct size reduction may be linked to a reduction in reperfusion injury caused by the effect of metoprolol on circulating neutrophils and platelets.

The METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction) showed that IV metoprolol administered before reperfusion significantly decreased infarct size assessed by CMR in anterior STEMI patients compared with placebo [99]. Moreover, the IV metoprolol group had a significantly higher left ventricular ejection fraction at 6-month follow-up [100]. These results are very promising, as the use of IV beta-blockers prior to reperfusion [99] is a readily accessible form of treatment in routine clinical practice. However, the COMMIT trial (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) failed to show any effect of metoprolol on mortality [101], although the study design may have contributed to this finding [101].

Other randomized trials are necessary to prove whether IV metoprolol does indeed have beneficial effects on ischaemia-reperfusion lesions [102], and whether these effects may translate into clinical benefit.

Adenosine

Activation of the adenosine triphosphate (ATP)-sensitive potassium channels inside mitochondria prevents mitochondrial calcium overload and cytochrome c release, thus avoiding mitochondrial permeability transition pore opening, which precludes cell apoptosis [103, 104]. Adenosine-induced opening of ATP-sensitive potassium channels thus explains, at least in part, the mechanism by which adenosine may elicit cardioprotection.

After promising results from small randomized studies [105, 106], large randomized trials have reported only potential beneficial effects but not definitive results [107, 108]. Finally, the Acute Myocardial Infarction Study of Adenosine II (AMISTAD-II), specifically designed to investigate the role of adenosine in STEMI, found no difference in the primary endpoint of new congestive heart failure, re-hospitalization for congestive heart failure or death from any cause at 6 months [109]. In a post hoc analysis, in patients receiving reperfusion therapy within 3hours of symptoms, adenosine reduced 1-month and 6-month mortality rates, but these results have to be interpreted with caution [110]. In the most recent trials, adenosine was administered by intracoronary injection at high doses, and was not associated with increased myocardial salvage assessed by CMR [111, 112]. So, although adenosine has been evaluated in several trials, we still do not have definite proof of efficacy on NR, infarct size or clinical prognosis.

Vasodilators (verapamil, nitroprusside, nicardipine)

Vasodilators are supposed to improve microvascular dysfunction by preventing microvessel spasm and regulating their endothelial function; results, however, are highly controversial.

Rezkalla et al. studied the efficacy of nitroprusside, nicardipine and verapamil after primary PCI, and showed an increase in TIMI flow grade and MBG score [113]. A recent meta-analysis showed that intracoronary verapamil injection reduced the 2-month rate of major adverse events in patients who underwent PCI [114]. However, in a double-blind randomized trial, intracoronary administration of nitroprusside before primary PCI failed to improve coronary flow and myocardial tissue reperfusion compared with placebo [115].

In summary, vasodilators appear to have, at best, a limited effect on NR, and the clinical significance of these findings is unclear.

Glycoprotein IIb/IIIa inhibitors

Glycoprotein IIb/IIIa inhibitors were developed to reduce thrombotic events because of their potent effect on platelet aggregation and vascular clotting. In a small phase II study in STEMI patients treated with thrombolysis combined with abciximab, Zoni et al. showed that abciximab significantly reduced infarct size and MVO size, as determined by CMR [116]. These findings confirm the role of in situ microvascular thrombosis with platelets and platelet-leukocyte aggregates in the pathogenesis of NR. More recently, the INFUSE-AMI trial performed in 452 anterior STEMI patients undergoing PCI showed that intracoronary administration of abciximab significantly reduced infarct size at 30 days, as determined by CMR [117]. Abciximab and other antiplatelet agents [118] seem to have a significant cardioprotective effect, which might be mediated through their inhibition of the explosive platelet activation following myocardial infarction. However, this specific benefit is counterbalanced by their induction of bleeding events. The current standard of care for STEMI patients already includes potent oral antiplatelet agents, and glycoprotein IIb/IIIa inhibitors are only recommended for their specific antithrombotic effect in selected STEMI patients [119].

Cyclosporine A

Cyclosporine A is a potent inhibitor of the mitochondrial permeable transition pore. Cyclosporine A prevents the mitochondria, the energy power-plants of all myocardial cells, from opening and being destroyed after the various intracellular stimuli triggered by the brutal reperfusion of the ischaemic myocardium [120, 121]. The mitochondria appear to play a central role in the various mechanisms involved in reperfusion injury and NR; they are therefore important therapeutic targets for therapies aimed at reducing NR. After validation in several experimental models, Piot et al. showed that a single bolus of cyclosporine A administered immediately before PCI significantly reduced infarct size in STEMI patients compared with placebo [122]. This study did not show a significant effect on NR, which was not assessed. However very recent results in a porcine model of ischaemia-reperfusion have shown a significant effect of cyclosporine on MVO and microcirculation [123]. Definitive proof for or against cyclosporine use in STEMI patients will soon be available after publication of the results from the ongoing phase III CIRCUS trial [124].

Beyond cardiomyocytes, only a few studies have focused on vessel treatment to prevent the NR phenomenon, which remains, after all, a vascular problem involving the cardiomyocytes, and not the other way around.

Vascular signalling pathways and future research avenues

The loss of vascular integrity, with destroyed tight and adherens junctions leading to increased vascular permeability, plays a key role in NR pathogenesis (Figure 1). It is mandatory to better understand the pathophysiology and signalling pathways involved in the loss of microvascular integrity to propose therapeutic strategies targeting the microvasculature itself. Pannitteri et al. showed that there were two waves of release of angiogenic factors during AMI in humans; they provided evidence for an early peak of VEGF (at 24hours) and a late peak of VEGF (at approximately 170hours) [125]. Whereas the late peak seems to support beneficial angiogenesis (with simultaneous angiopoietin-2 release, which is necessary for efficient angiogenesis, together with VEGF), the early peak was associated with proinflammatory cytokines, such as interleukin-6 and transforming growth factor-beta, suggesting a deleterious effect. We can thus hypothesize that the early VEGF release after AMI will lead to the endothelial junction destabilization and vascular permeability that is part of the NR pathogenesis, whereas the delayed phase could promote reactive angiogenesis. It would thus be interesting to counteract VEGF-induced vascular permeability in the acute phase of AMI, without impairing delayed angiogenesis.

We recently showed that angiopoietin-like 4 (ANGPTL4) counteracted early ischaemia-induced VEGF signalling and disruption of endothelial cell junctions, thereby leading to subsequent protection of the coronary capillary network and reduction of infarct size [126]. These data showed that ANGPTL4 might be a relevant target for therapeutic vasculoprotection, thus being crucial for preventing NR and conferring secondary cardioprotection during AMI [126, 127]. We also showed that ANGPTL4 had protective effects on the cerebrovascular and functional damage after ischaemic stroke that shares some pathophysiological factors with AMI [127]. ANGPTL4 would counteract the loss of vascular integrity in ischaemic stroke by restricting Src kinase signalling downstream from VEGF receptor 2. These results suggest that ANGPTL4 is a regulator of endothelial barrier integrity during cardiovascular ischaemic diseases [128], and might be a relevant target for NR prevention. Recently, we confirmed the involvement of ANGPTL4 in NR pathogenesis, with lower ANGPTL4 serum concentrations on admission in STEMI patients being associated with CMR-detected NR after reperfusion [36].

Moreover, beyond counteracting VEGF-induced VEGF receptor 2/VE-cadherin complex disruption, agents such as angiopoietin-1 [129] and fibroblast growth factor [130] have been reported to inhibit VE-cadherin internalization and to help with maintenance of vascular integrity. In a study by Sandhu et al., angiopoietin-1 expression was decreased in the infarcted area compared with control myocardium in a rat model of AMI [131], leading to impaired vascular integrity. Fibroblast growth factor-2 has also been demonstrated to exert a cardioprotective effect in a closed-chest model of cardiac ischaemia-reperfusion injury [132]. Whether fibroblast growth factor-2 acts predominantly on cardiomyocytes or also targets endothelium was not fully determined. As angiopoietin-1 and fibroblast growth factor-2 signalling plays a key role in the maintenance of vascular integrity [132], they appear to be potential targets for future development of vascular therapeutics [133] to prevent the NR phenomenon.

Ischaemia-reperfusion injury also involves surface adhesion molecules, such as P-selectin, P-selectin glycoprotein ligand-1, Mac-1 and intercellular adhesion molecule-1. The accumulation of red blood cells in the interstitium, caused by microvessel disruption, results in accumulation of degradation products of haeme that attract inflammatory cells. Transmigration of leukocytes through the vessel wall might also contribute to NR. Proteolytic enzymes from neutrophils can be important inducers of vascular permeability, and intercellular adhesion molecule-1 crosslinking was shown to trigger VE-cadherin phosphorylation, while endothelial nitric oxide synthase, Src and Rho guanosine triphosphatase activation were reported to be involved in this signalling mechanism [134]. Nevertheless, sites of permeability induction can be spatially and temporally distinct [135], and the coupled relationship between leucocyte/platelet activation and microvessel permeability should be re-evaluated in AMI.

Finally, a recent study showed that imatinib – a Food and Drug Administration-approved tyrosine kinase inhibitor – directly protects the endothelial barrier under inflammatory conditions [136]. Imatinib binds to an intracellular pocket located within tyrosine kinases, thereby inhibiting ATP binding and preventing phosphorylation and the subsequent activation of growth receptors, such as platelet-derived growth factor receptor, and their downstream signal transduction pathways. Imatinib attenuated vascular leakage in a murine model of sepsis, even when it was initiated a considerable time after induction of sepsis. Imatinib may thus be a suitable therapy for the treatment of diseases characterized by vascular leakage, such as the acute phase of AMI.

Conclusion

NR is a multifactorial and complex phenomenon, and an independent marker of clinical adverse outcome in STEMI patients. The limited access to performant diagnostic tools, as well as its dynamic nature in intensity and time restrict the therapeutic window in routine clinical practice for STEMI patients. There is currently no efficient therapy against myocardial haemorrhage, oedema and NR [137]. Several clinical studies are underway and are encouraging. A promising therapeutic target seems to be the coronary endothelium, which plays a central role in NR. The endothelial barrier involvement in NR, demonstrated in experimental in vitro and in vivo studies, might offer an original new avenue for clinical research in AMI patients.

Disclosure of interest

This work was supported in part by a grant from the La Fédération française de cardiologie, and has received support under the programme “Investissements d’avenir” launched by the French Government and implemented by the Agence nationale de la recherche (ANR), with the references: ANR-10-LABX-54 MEMO LIFE; ANR-11-IDEX-0001-02 PSL* Research University.

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