Prof. Alessio La Manna
Dr. Corrado Tamburino,
The no-reflow phenomenon has become a new marker of 1) myocardial dysfunction following acute myocardial infarction, and 2) a worsened prognosis. Thanks to its high tissue contrast and spatial resolution, cardiac magnetic resonance allows for accurate localisation and quantification on the no-reflow region within the area of myocardial necrosis.
Current therapeutic strategies in patients with ST-segment elevation myocardial infarction (STEMI) aim for timely recanalisation of the infarct-related artery to reduce the progression of the ischemic-necrotic wavefront of myocardial injury (1,2). However, reperfusion after prolonged occlusion does not always translate into adequate vascularisation of the microvascular bed. This phenomenon is called micro-vascular obstruction (MVO) or no-reflow and has been shown both in experimental and clinical studies (3,4). Previous studies have shown that no-reflow is an independent predictor of left ventricular remodelling and poor prognosis (5,6) therefore accurate assessment is vital.
There are several techniques to assess no reflow including:
Indeed, the use of magnetic resonance imaging in the management of acute myocardial infarction has changed the therapeutic approach to patients affected by STEMI. When patients present outside the diagnostic window of cardiac troponins, delay enhancement- cardiovascular magnetic resonance (DE-CMR) may be especially useful. Moreover, because DE-CMR can uniquely differentiate between ischemic and various non-ischemic forms of myocardial injury, it may be helpful in cases of diagnostic uncertainty, such as in patients with classical features of myocardial infarction (MI) in whom coronary angiography does not show a culprit lesion. Even after the diagnosis of MI has been made, CMR provides clinically relevant information by identifying residual viability, microvascular damage, stunning, and right ventricular infarction (10). In addition, the high spatial resolution of DE-CMR even enables visualisation of microinfarctions, which may occur during otherwise successful percutaneous coronary interventions (11).
The patho-physiologic mechanism of the no-reflow phenomenon is likely multi-factorial. It derives from a balance between benefits and damage from myocardial reperfusion, depending on the timing of the occlusion. If reperfusion occurs beyond 12 hours, the damage created by free radicals and the release of calcium ions exceeds the benefits of reperfusion. In particular, prolonged ischemia results in endothelial damage, with endothelial cell disruption, lure of neutrophils, red blood cells and platelets that cause microvascular obstruction. Microvessel rupture causes extravasation of these cells and further compression of other capillary. These changes lead to reduced perfusion with death of surrounding viable myocytes (12). Another important factor is the damage caused by the distal coronary microembolisation of plaque and thrombus debris following angioplasty. The rate of coronary microembolisation is highest in documented epicardial coronary thrombosis, reaching 30% to 54% (13,14) and even a higher rate (79%) in STEMI patients (15). Angiographic evidence of distal embolisation has been shown to occur in approximately 15% to 19% of patients treated with primary percutaneous coronary intervention (PCI) (16,17). Micro-vascular obstruction is not a stable phenomenon but varies over time and space. It first develops in the core of the infarcted region and then extends towards the epicardium. In addition, it progresses over time and a further increase in the size of a MVO has been demonstrated up to 48 hours after initiation of reperfusion (18).
Techniques used to detect a MVO in cardiovascular MRI are both based on gadolinium contrast enhancement. The first uses first-pass perfusion of gadolinium: there is an uniform increase of signal intensity in the normal and infarcted area, while there is an area of hypointensity at the core of the infarction (early MVO) (Figure 1). The second technique concerns the use of late enhancement. After a wash-out period of approximately 10-12 minutes from intravenous bolus of contrast, the infarcted area is highlighted as an area of hyperenhancement or "bright" area, while the MVO appears as a central area of hypointensity within the infarct hyperintensity (Figure 2-3). The technique of first-pass has proved more sensitive than late-enhancement, because at times, the gadolinium can not penetrate into the zone of the MVO and consequently will underestimate the affected area (19).
The presence of no-reflow in patients with acute myocardial infarction has been found to be a predictor of adverse events, with higher incidence of left ventricular (LV) remodelling, congestive heart failure, and death. An initial study by Wu et al. (n. 44; follow-up 16 months) demonstrated that patients with MVO had more cardiovascular events (45% versus 9%, P 0.016) independently of the total infarct size (6). Since then, several studies have succeeded in demonstrating such a correlation. A larger study by Hombach et al. (20) found that infarct size, MVO, LV end-diastolic volume, and EF predicted major adverse cardiac events (MACE), with MVO being the strongest predictor (13.2% more events). Cochet et al (21) showed that MVO and the Global Registry of Acute Coronary Events (GRACE) score were significant predictors of MACE (odds ratio [OR], 8.7; CI, 3.6 to 21.1; P<0.001; OR, 2.8; CI, 1.3 to 6; P<0.01, respectively). Nijveldt et al. (22) examined the relation between angiographic, electrocardiographic, and gadolinium-enhanced CMR characteristics of MVO and they found that early and late MVO were both related to incomplete ST-segment resolution (6 (17%) versus 30 (83%), p < 0.002 and 11 (31%) versus 25 (69%), p < 0.01, respectively) but not to TIMI flow grade and MBG. Among angiographic, electrocardiographic and CMR variables, late MVO was the strongest parameter to predict changes in LV end-diastolic volume (β = 0.53; p < 0.001), end-systolic volume (β = 8.67; p < 0.001), and ejection fraction (β = 3.94; p < 0.006) at follow-up. Another fundamental point is the role of primary PCI. Francone et al. (23) showed that shorter time-to-reperfusion was associated with smaller infarct size and microvascular obstruction and larger salvaged myocardium. In particular MVOs were larger in patients reperfused later (0.5%, 1.5%, 3.7%, and 6.6%, in < 90, min, > 90 to150 min > 150 to 360 min and > 360 min respectively, p < 0.047), suggesting that any strategy to shorten the delay in the reperfusion of patients with STEMI is crucial.
Figure 1. Short-axis gradient echo images Short-axis gradient echo images at base, mid and apical ventricular level during rest first-pass perfusion scan, showing a localised microvascular obstruction as a dark rim (red arrows) in the posteroseptal and inferior LV wall (early MVO). A concomitant involvement of the postero-lateral papillary muscle is also evident (green arrow). Figure 2. Short-axis late enhancement images Short-axis late enhancement images at base, mid and apical ventricular level, showing a large area of hyperenhancement (infarct size), with a central zone of hypoenhancement due to microvascular obstruction (late MVO). Figure 3. Late enhancement images Late enhancement images of LVOT, two chamber and four chamber views, showing a large area of hyperenhancement (infarct size), with a central zone of hypoenhancement due to microvascular obstruction (late MVO, red arrows). An apical thrombus is evident as a dark mass (blue arrows).
Contrast-enhanced CMR is a useful non-invasive technique for assessing the presence and extent of microvascular obstruction. No-reflow phenomenon has important prognostic implications, and the use of CMR can help to identify and quantify areas of microvascular damage in patients with STEMI. It could become a powerful tool to stratify the risk of patients and in future to differentiate the effectiveness of different techniques of reperfusion.
1. Reimer KA, Jennings RB. The “wavefront phenomenon” of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest 1979;40:633– 44. 2. Gerber BL. Risk area, infarct size, and the exposure of the wavefront phenomenon of myocardial necrosis in humans. Eur Heart J 2007;28: 1670–2. 3. Ito H, Tomooka T, Sakai N, et al. Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction. Circulation 1992;85:1699 –705. 4. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974;54:1496–508. 5. Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation 2000;101:2734–41. 6. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998;97:765–72. 7. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol 2000;36:1202– 8. van’t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F; Zwolle Myocardial Infarction Study Group. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation 1998;97:2302– 6. 9. Greaves K, Dixon SR, Fejka M, et al. Myocardial contrast echocardiography is superior to other known modalities for assessing myocardial reperfusion after acute myocardial infarction. Heart 2003;89:139–44. 10. Kim H.W., Farzaneh-Far A., Kim R. J. Cardiovascular Magnetic Resonance in Patients With Myocardial Infarction Current and Emerging Applications. JACC 2009 210;55:1. 11. Locca D, Bucciarelli-Ducci C, Ferrante G, La Manna A, Keenan N.G, Grasso A, Barlis P, Del Furia F, Prasad SK, Kaski JC, Pennell DJ,. Di Mario C. New Universal Definition of Myocardial Infarction Applicable After Complex Percutaneous Coronary Interventions? JACC: Cardiovascular Intervention 3; 9, 2010. 12. Bekkers SCAM, Yazdani SK, Virmani R, Waltenberger J. Microvascular Obstruction. Underlying Pathophysiology and Clinical Diagnosis J Am Coll Cardiol 2010;55:1649–60). 13. Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986;73:418 –27. 14. Falk E. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation 1985;71:699 –708. 15. Frink RJ, Rooney PA Jr., Trowbridge JO, Rose JP. Coronary thrombosis and platelet/fibrin microemboli in death associated with acute myocardial infarction. Br Heart J 1988;59:196 –200. 16. Silva-Orrego P, Colombo P, Bigi R, et al. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: the DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. J Am Coll Cardiol 2006;48:1552–9. 17. Henriques JP, Zijlstra F, Ottervanger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J 2002;23:1112–7. 18. Rochitte CE, Lima JA, Bluemke DA, et al. Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation 1998;98:1006 –14. 19. Lund GK, Stork A, Saeed M, et al. Acute myocardial infarction: evaluation with first-pass enhancement and delayed enhancement MR imaging compared with 201Tl SPECT imaging. Radiology 2004;232:49–57. 20. Hombach V, Grebe O, Merkle N, Waldenmaier S, Ho¨her M, Kochs M, Wo¨hrle J, Kestler HA. Sequelae of acute myocardial infarction regarding cardiac structure and function and their prognostic significance as assessed by magnetic resonance imaging. Eur Heart J. 2005;26:549 –557. 21. Cochet A, Zeller M, Lalande A, Lorgis L, Touzery C, Walker P, Wolf J, Brunotte F, Cottin Y. Major prognostic impact of persistent microvascular obstruction as assessed by contrast-enhanced cardiac magnetic resonance imaging in the setting of reperfused myocardial infarction. Eur Heart J. 2008;29(Suppl):529. 22. Nijveldt R, Beek AM, Hirsch A, et al. Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury. J Am Coll Cardiol 2008;52:181–9. 23. Francone M, Bucciarelli-Ducci C, Carbone I, Canali E, Scardala R, Calabrese FA, Sardella G, Mancone M, Catalano C, Fedele F, Passariello R, Bogaert J, Agati L. Impact of primary coronary angioplasty, delay on myocardial salvage, infarct size, and microvascular damage in patients with ST-segment elevation myocardial infarction. Insight From Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2009;54:2145–5 3.
Alessandra Sanfilippo, Alessio La Manna, Corrado Tamburino. Division of Cardiology, Ferrarotto Hospital, University of Catania Via Citelli – 95124 – Catania - Italy.
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