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.
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 .
Background
Primary percutaneous coronary intervention (PCI) is the best available reperfusion strategy in patients with acute ST-segment elevation myocardial infarction (STEMI) . Up to 95% of occluded coronary vessels can be reopened in the setting of STEMI . 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) . NR has been described in up to 60% of STEMI patients with optimal coronary vessel reperfusion . When NR occurs, it significantly attenuates the beneficial impact of reperfusion therapy, resulting in poor clinical and functional outcomes . 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 ( Fig. 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.
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 , 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 < 40 mL/min for 100 g 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 . 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 .
Reperfusion injury
The ischaemia-related injury is made worse by reperfusion injury. Reperfusion injury, caused by the brutal restoration of a normal blood supply (100 mL/min for 100 g) to damaged microvessels, accelerates myocardial swelling, tissue oedema, endothelial disruption and inflammation . 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 .
Neutrophils and platelets form microaggregates (plugs), which are responsible for luminal obstruction of the microvasculature . Autonomic dysfunction also occurs upon reperfusion, with alpha-adrenergic receptor-mediated constriction of coronary microvessels, which may contribute to NR .
Infarct size
Several studies have demonstrated a correlation between larger infarct size and NR, in terms of both frequency and importance . 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 . 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 . Similarly, longer pain-to-balloon time is related to the development of NR, as it is linked to a larger infarct area .
Endothelial injury
A major regulator of endothelial integrity is vascular endothelial growth factor (VEGF), which was originally called vascular permeability factor . VEGF is expressed in response to hypoxia during acute myocardial infarction (AMI) . 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 . Ischaemia-induced VEGF, when binding to VEGF receptor 2, dissociates the VEGF receptor 2/VE-cadherin complex, leading to an increase in endothelial permeability . 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 . 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 . This distal embolization is involved in the NR phenomenon . 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 . 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 . 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 .
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 and death, compared with patients without NR . 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 . 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 , 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 . 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 . 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) . 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 .
No-reflow diagnosis
Whatever the diagnostic method used, one must consider the dynamic nature of NR ( Table 1 ). NR persists throughout the 48 hours after reperfusion, although this time frame is hypothetical and is based upon experimental findings . 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.
| First author | Population ( n ) | Duration of ischaemia (hours) | Reperfusion strategy | Diagnostic method | NR prevalence a (%) |
|---|---|---|---|---|---|
| Santoro | 37 | <12 | PPCI with final TIMI flow = 3 | ST-segment regression < 50% at 30 minutes post-reperfusion | 43 |
| Morishima | 120 | <6 | PPCI | TIMI score < 2 | 25 |
| Henriques | 924 | – | PPCI with final TIMI flow = 3 | MBG score < 2 | 11 |
| Hamada | 104 | <6 | PPCI with final TIMI flow = 3 | Corrected TIMI frame count | 42 |
| Galiuto | 24 | <6 | PPCI or thrombolysis | Transthoracic echocardiography with intravenous contrast injection | 66 |
| Ito | 126 | <24 | PPCI or thrombolysis | Transthoracic echocardiography with intracoronary contrast injection | 37 |
| Wu | 44 | <24 | PPCI or thrombolysis | First-pass perfusion ce-CMR (persistent hyposignal 1–2 minutes after gadolinium injection) | 25 |
| Taylor | 20 | <12 | PPCI | First-pass perfusion ce-CMR (T50%max delay > 1 second) | 95 |
| Eitel | 738 | <12 | PPCI or thrombolysis | Late ce-CMR (persistent hyposignal at 10 minutes on delayed enhancement image) | 42 |
| Hombach | 110 | <12 | PPCI or thrombolysis | Late ce-CMR (persistent hyposignal at 10 minutes on delayed enhancement image) | 46 |
| Mewton | 50 | <12 | PPCI or rescue PPCI | Early and late ce-CMR (persistent hyposignal at 3 and 10 minutes on delayed enhancement image) | 80 (early); 75 (late) |
a The prevalence of no-reflow varies widely from 11 to 95%; this can be explained by the different diagnostic tools with various degrees of sensitivity and specificity, but also other factors such as time from reperfusion to diagnosis and reperfusion quality.
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