No-reflow phenomenon: Difference between revisions
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Shown above is an animated image and a static image depicting TIMI flow grade 0 in the [[RCA]]. Outlined in blue in the second | |||
image is the flow of the dye which completely stops at the level of the stenosis. Outlined with a yellow dashed line is the pathway that the dye would have filled in case the stenosis was absent. | |||
====Assessment of Myocardial Perfusion==== | ====Assessment of Myocardial Perfusion==== | ||
Perfusion of the myocardium has been shown to be an independent predictor of outcome.<ref name="Gibson-2002">{{Cite journal | last1 = Gibson | first1 = CM. | last2 = Cannon | first2 = CP. | last3 = Murphy | first3 = SA. | last4 = Marble | first4 = SJ. | last5 = Barron | first5 = HV. | last6 = Braunwald | first6 = E. | title = Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. | journal = Circulation | volume = 105 | issue = 16 | pages = 1909-13 | month = Apr | year = 2002 | doi = | PMID = 11997276 }}</ref> This can be assessed directly by using [[TIMI myocardial perfusion grade#Qualitative Blush Analysis|myocardial blush grade (MBG)]], [[TIMI myocardial perfusion grade|TIMI Myocardial Perfusion Grade (TMPG)]], coronary clearance frame count or digital subtraction angiography or can be assessed indirectly by quantitative measurements of epicardial flow rates with use of corrected TIMI frame counts. | Perfusion of the myocardium has been shown to be an independent predictor of outcome.<ref name="Gibson-2002">{{Cite journal | last1 = Gibson | first1 = CM. | last2 = Cannon | first2 = CP. | last3 = Murphy | first3 = SA. | last4 = Marble | first4 = SJ. | last5 = Barron | first5 = HV. | last6 = Braunwald | first6 = E. | title = Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction. | journal = Circulation | volume = 105 | issue = 16 | pages = 1909-13 | month = Apr | year = 2002 | doi = | PMID = 11997276 }}</ref> This can be assessed directly by using [[TIMI myocardial perfusion grade#Qualitative Blush Analysis|myocardial blush grade (MBG)]], [[TIMI myocardial perfusion grade|TIMI Myocardial Perfusion Grade (TMPG)]], coronary clearance frame count or digital subtraction angiography or can be assessed indirectly by quantitative measurements of epicardial flow rates with use of corrected TIMI frame counts. | ||
====Myocardial Contrast Echocardiography==== | ====Myocardial Contrast Echocardiography==== | ||
This is the gold standard technique for investigating no-reflow phenomenon. This involves the use of intravascular contrast agents that contain tracers. This modality can be used to assess microvascular perfusion. It has the advantage of defining the extent of myocardium affected and also producing a good prognostic value which correllates with the TIMI flow grade. | This is the gold standard technique for investigating no-reflow phenomenon. This involves the use of intravascular contrast agents that contain tracers. This modality can be used to assess microvascular perfusion. It has the advantage of defining the extent of myocardium affected and also producing a good prognostic value which correllates with the TIMI flow grade. | ||
====Coronary Doppler Imaging==== | ====Coronary Doppler Imaging==== | ||
This involves the study of the coronary blood flow velocity patterns. No-reflow has a pathognomonic features which is the presence of: | This involves the study of the coronary blood flow velocity patterns. No-reflow has a pathognomonic features which is the presence of: | ||
Revision as of 20:59, 9 September 2013
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Jennifer Giuseffi, M.D.; David M. Leder, M.D.; Ayokunle Olubaniyi, M.B,B.S [3]
Synonyms and keywords: Slow-flow, slow re-flow, low-flow
Overview
Many definitions have been given to this phenomenon based on individual's area of specialty, but the definition that unites all fields was by Kloner et al in 1974 who described the condition as the inability to adequately perfuse myocardium after temporary occlusion of an epicardial coronary artery without evidence of persistent mechanical obstruction, thus implying ongoing myocardial ischaemia. When defined angiographically, it is an acute reduction in coronary flow (TIMI grade 0-1) in the absence of dissection, thrombus, spasm, or high-grade residual stenosis at the original target lesion. In other words, it is the failure of blood to reperfuse an ischemic area after the physical obstruction has been removed or bypassed.[1][2] It has been clearly shown that a complete restoration of epicardial blood flow (TIMI Flow Grade 3) does not correlate with a better myocardial perfusion in achieving better clinical outcomes. Therefore, over the years, attention has shifted towards methods to evaluate myocardial perfusion. A lesser degree of obstruction to coronary blood flow (TIMI grade 2) is sometimes referred to as slow-flow. No-reflow is an important predictor of mortality after PCI [3].
Historical Perspective
This phenomenon was first described by Krug et al [4] during induced myocardial infarction in dog subjects in 1966, but the term 'no-reflow' was first used by Majno and colleagues in 1967 when they observed that brains of rabbits exposed to prolonged ischemia suffered significant changes in the microvasculature which impeded blood flow to the brain cells.
Pathophysiology
Distal Embolization of Plaques and/or Thrombus
The primary mechanism of no-reflow is likely due to distal embolization of atheromatous and thrombotic debris dislodged by balloon inflation or stent implantation.[5][6] During PCI, microthrombi and small particles of plaques are thought to be showered downstream, occluding small arteries, arterioles, and collateral microvasculature. Analysis of the aspirate obtained from patients without no-reflow revealed a greater amount of atheromatous plaques and significantly more platelet and fibrin complex, macrophages, and cholesterol crystals than those who experienced no-reflow. The 30-day mortality was significantly higher (27.5%) in patients with no-reflow phenomenon than in patients with normal coronary blood flow after PCI (5.3%, P < 0.001). Predictors of no-reflow include a higher plaque burden, thrombus, lipid pools by IVUS, higher lesion elastic membrane cross-sectional area, pre-infarction angina, and TIMI flow grade 0 on the initial coronary angiogram, among other factors.
Other pathophysiologic mechanisms include:
- Release of active tissue factor from the dislodged plaque[7]
- Vasoconstriction secondary to serotonin, adenosine diphosphate, thromboxane A2, released by the embolized platelet-rich atheromatous material[8]
- Reperfusion injury from the release of oxygen free radicals during inflammation
- Myocardial necrosis and stunning
- Microvascular damage[9]
- Microvascular plugging with platelets or leukocytes
- Endothelial swelling and tissue edema compressing vasculature
Epidemiology and Demographics
The reported incidence of no-reflow phenomenon ranges between 0.6-42% depending on the defining criteria and the clinical setting. It has been reported in anywhere from 11-30% of patients following thrombolysis or intervention in acute myocardial infarction. However, in routine, elective coronary intervention, the prevalence has been reported to be as low as 0.6-2%. This phenomenon appears to be more frequent during interventions on saphenous vein grafts (SVG) or thrombus containing lesions as well as during the use of rotational atherectomy. Gender does not appear to play a role in this phenomenon, but it seems to occur more frequently in older patients and in those who did not experience pre-infarct angina. Admission hyperglycemia has also been associated with higher incidence of no-reflow as well as worse outcomes. Lesions at high-risk for no-reflow include: diffuse atherosclerotic involvement, angiographic demonstrable thrombus, irregular or ulcerative lesions, and long lesions with large plaque volume. No-reflow is a common (15%) finding during primary angioplasty for acute MI.
Natural History, Complications and Prognosis
In the cathetarization laboratory, no-reflow may be clinically silent or appear suddenly associated with severe chest pain, ischemic (EKG) changes, conduction abnormalities, and/or hemodynamic deterioration. This needs to be distinguished from slow-flow which can be caused by coronary dissection, macrothrombus formation, coronary vasospasm, or distal macroembolization. The presence of no-reflow is clinically important as its presence has been associated with a five to ten fold increase in mortality,[10] as well as a high incidence of myocardial infarction (MI), left ventricular dysfunction, ventricular arrhythmias, early congestive heart failure and cardiogenic shock. Predictors of outcome include:
- Duration of coronary occlusion
- Extent of myocardium supplied by the occluded artery
- Patency of infarct-related artery
- Quality of collateral circulation
- Presence of pre-infarction angina which produces a preconditioning-like effect and might correlate with preservation of collateral circulation.
Hyperglycemia in acute myocardial infarction is associated with an increased risk of in-hospital mortality, as well as no-reflow phenomenon.
Diagnosis
Coronary Angiography
Assessment of Epicardial Blood Flow
This involves the use of Thrombolysis in Myocardial Infarction (TIMI) blood flow grades (TFG) to evaluate epicardial coronary blood flow in acute coronary syndromes. This method measures the coronary artery clearance of the injected radiographic dye. It is graded from 0 to 3. Click here to view the grading system. Although TFG has been associated with clinical outcomes in the past,[11] its use has been limited by many confounding variables such as the location of infarct. For example, the majority of TFG 3 are located in the right coronary artery, while the majority of TFG 2 are observed in the left anterior descending artery.[11] A more accurate technique to evaluate epicardial coronary blood flow is by using the number of angiographic frames required for a dye to reach a specified distal segment in the coronary artery, this was referred to as the TIMI frame count (TFC) by Gibson et al in 1999. Although this method was associated with improved clinical outcomes, however, it is now understood that restoration of epicardial blood flow does not necessarily improve perfusion at the tissue level or microvascular perfusion.[12]
Shown above is an animated image and a static image depicting TIMI flow grade 0 in the RCA. Outlined in blue in the second
image is the flow of the dye which completely stops at the level of the stenosis. Outlined with a yellow dashed line is the pathway that the dye would have filled in case the stenosis was absent.
Assessment of Myocardial Perfusion
Perfusion of the myocardium has been shown to be an independent predictor of outcome.[13] This can be assessed directly by using myocardial blush grade (MBG), TIMI Myocardial Perfusion Grade (TMPG), coronary clearance frame count or digital subtraction angiography or can be assessed indirectly by quantitative measurements of epicardial flow rates with use of corrected TIMI frame counts.
Myocardial Contrast Echocardiography
This is the gold standard technique for investigating no-reflow phenomenon. This involves the use of intravascular contrast agents that contain tracers. This modality can be used to assess microvascular perfusion. It has the advantage of defining the extent of myocardium affected and also producing a good prognostic value which correllates with the TIMI flow grade.
Coronary Doppler Imaging
This involves the study of the coronary blood flow velocity patterns. No-reflow has a pathognomonic features which is the presence of:
- Systolic flow reversal
- Reduced antegrade systolic flow
- Forward diastolic flow with a rapid deceleration slope
This method also helps in distinguishing those with microthrombi from those without.
Other Modalities
- Nuclear imaging single-photon emission computed tomography using thallium or technetium-99m.
- Positron emission tomography
- Contrast-enhanced MRI
Treatment
When no-reflow phenomenon is diagnosed, the mainstay of treatment is pharmacologic. The optimal management of no-reflow after restoration of coronary blood flow is unknown. More emphases are laid on prevention rather than the treatment.
Supportive Care
Most patients experience chest pain, hypotension and cardiac arrhythmias, therefore, attention to supportive measures is highly recommended. This involves analgesia, intravenous fluids, intravenous inotropic agents, temporary cardiac pacing, and the use of intraaortic balloon pump support if necessary.
Exclude All Mechanical Causes
Restore normal blood flow through epicardial coronary arteries and microvasculature to prevent persistence of myocardial ischemia. No-reflow needs to be distinguished from slow-flow resulting from coronary artery dissection, thrombus, coronary vasospasm, or residual stenosis. These etiologies must be excluded as part of the treatment of no-reflow. Ultimately, the goals are to improve outcomes, relieve chest pain and alleviate myocardial ischemia.
Administration of Vasodilators
Medications such as verapamil,[14] adenosine and nitroprusside[15] through the intracoronary route have been used with results.
Prevention
Thrombectomy
This procedure is usually done to improve perfusion in STEMI patients before they undergo PCI. It can be done using either a manual thrombus aspiration device or a mechanical thrombectomy device, with the manual device having an edge over the mechanical device in some studies. A meta-analysis study proved that among patients with AMI treated with PCI, the use of manual thrombectomy device is associated with better epicardial and myocardial perfusion, less distal embolization and significant reduction in 30-day mortality.[16] Care should be exercised when aspirating in the proximal LAD or proximalcircumflex locations so that clot does not go down the other adjacent artery.
Distal Embolic Protection Devices
Distal protection devices may be used in SVGs to prevent distal embolization of clot, debris, and vasoactive mediators. However, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) and the Protection Devices in PCI Treatment of Myocardial Infarction for Salvage of Endangered Myocardium (PROMISE) trials showed inconsistent results with regards to embolic protection devices in use for primary PCI of native vessels.
Direct stenting
When intervening on high-risk lesions, limit the amount of instrumentation within the target vessel, which includes minimizing overaggressive balloon or stent expansion. In patients undergoing rotational atherectomy, shorter runs, slower speeds and smaller initial burr size with small stepwise increases in burr size should be employed to help prevent no reflow.
Systemic GP IIb/IIIa inhibitors
Systemic glycoprotein IIb/IIIa receptor antagonists are recommended as pre-treatment in patients presenting with unstable coronary syndromes undergoing PCI. The TITAN-TIMI 34 trial showed early initiation of eptifibatide in the emergency room prior to primary PCI improved myocardial perfusion without an increased risk of bleeding.
Intracoronary Treatment
- Intracoronary administration of adenosine, verapamil, streptokinase, or abciximab have been used during PCI to reduce reperfusion injury and improve myocardial perfusion, but none have been associated with good prognostic outcomes.
Vasodilators
In addition, a cocktail of heparin, nitroglycerin and calcium channel blockers (CCB) should be infused simultaneously. Adding two arteriolar vasodilators, i.e. nicardipine and adenosine, to the flush "cocktail" may be helpful in further reducing incidence of no reflow, however traditionally the CCB used is verapamil. A recent study found no evidence that the administration of adenosine and verapamil can reduce all-cause mortality and improve outcomes, but there was an increase incidence of adenosine-induced hypotension and bradycardia.
Chronic statin therapy
A recent study by Zhao JL et al in 2009 showed patients presenting with acute MI and hyperglycemia had lower incidence of no reflow if they were pretreated with HMG-CoA reductase inhibitors prior to angiography.
ACCF/AHA/SCAI 2011 Guidelines for Percutaneous Coronary Intervention (DO NOT EDIT)[17]
No-Reflow Pharmacological Therapies (DO NOT EDIT)[17]
| Class IIa |
| "1. Administration of an intracoronary vasodilator (adenosine, calcium channel blocker, or nitroprusside) is reasonable to treat PCI-related no-reflow that occurs during primary or elective PCI.[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33] (Level of Evidence: B)" |
References
- ↑ "Medscape".
- ↑ Kishi T, Yamada A, Okamatsu S, Sunagawa K (2007). "Percutaneous coronary arterial thrombectomy for acute myocardial infarction reduces no-reflow phenomenon and protects against left ventricular remodeling related to the proximal left anterior descending and right coronary artery" ([dead link] – [1]). Int Heart J. 48 (3): 287–302. doi:10.1536/ihj.48.287. PMID 17592194. Unknown parameter
|month=ignored (help) - ↑ Resnic FS, Wainstein M, Lee MK, Behrendt D, Wainstein RV, Ohno-Machado L; et al. (2003). "No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention". Am Heart J. 145 (1): 42–6. doi:10.1067/mhj.2003.36. PMID 12514653.
- ↑ Krug, A.; Du Mesnil de Rochemont, G.; Korb, . (1966). "Blood supply of the myocardium after temporary coronary occlusion". Circ Res. 19 (1): 57–62. PMID 5912914. Unknown parameter
|month=ignored (help) - ↑ Henriques, JP.; Zijlstra, F.; Ottervanger, JP.; de Boer, MJ.; van 't Hof, AW.; Hoorntje, JC.; Suryapranata, H. (2002). "Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction". Eur Heart J. 23 (14): 1112–7. doi:10.1053/euhj.2001.3035. PMID 12090749. Unknown parameter
|month=ignored (help) - ↑ Kawaguchi, R.; Oshima, S.; Jingu, M.; Tsurugaya, H.; Toyama, T.; Hoshizaki, H.; Taniguchi, K. (2007). "Usefulness of virtual histology intravascular ultrasound to predict distal embolization for ST-segment elevation myocardial infarction". J Am Coll Cardiol. 50 (17): 1641–6. doi:10.1016/j.jacc.2007.06.051. PMID 17950144. Unknown parameter
|month=ignored (help) - ↑ Bonderman, D.; Teml, A.; Jakowitsch, J.; Adlbrecht, C.; Gyöngyösi, M.; Sperker, W.; Lass, H.; Mosgoeller, W.; Glogar, DH. (2002). "Coronary no-reflow is caused by shedding of active tissue factor from dissected atherosclerotic plaque". Blood. 99 (8): 2794–800. PMID 11929768. Unknown parameter
|month=ignored (help) - ↑ Gregorini, L.; Marco, J.; Kozàkovà, M.; Palombo, C.; Anguissola, GB.; Marco, I.; Bernies, M.; Cassagneau, B.; Distante, A. (1999). "Alpha-adrenergic blockade improves recovery of myocardial perfusion and function after coronary stenting in patients with acute myocardial infarction". Circulation. 99 (4): 482–90. PMID 9927393. Unknown parameter
|month=ignored (help) - ↑ Kloner, RA.; Rude, RE.; Carlson, N.; Maroko, PR.; DeBoer, LW.; Braunwald, E. (1980). "Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first?". Circulation. 62 (5): 945–52. PMID 7418179. Unknown parameter
|month=ignored (help) - ↑ Resnic, FS.; Wainstein, M.; Lee, MK.; Behrendt, D.; Wainstein, RV.; Ohno-Machado, L.; Kirshenbaum, JM.; Rogers, CD.; Popma, JJ. (2003). "No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention". Am Heart J. 145 (1): 42–6. doi:10.1067/mhj.2003.36. PMID 12514653. Unknown parameter
|month=ignored (help) - ↑ 11.0 11.1 Gibson, CM.; Cannon, CP.; Daley, WL.; Dodge, JT.; Alexander, B.; Marble, SJ.; McCabe, CH.; Raymond, L.; Fortin, T. (1996). "TIMI frame count: a quantitative method of assessing coronary artery flow". Circulation. 93 (5): 879–88. PMID 8598078. Unknown parameter
|month=ignored (help) - ↑ Ito, H.; Tomooka, T.; Sakai, N.; Yu, H.; Higashino, Y.; Fujii, K.; Masuyama, T.; Kitabatake, A.; Minamino, T. (1992). "Lack of myocardial perfusion immediately after successful thrombolysis. A predictor of poor recovery of left ventricular function in anterior myocardial infarction". Circulation. 85 (5): 1699–705. PMID 1572028. Unknown parameter
|month=ignored (help) - ↑ Gibson, CM.; Cannon, CP.; Murphy, SA.; Marble, SJ.; Barron, HV.; Braunwald, E. (2002). "Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long-term outcomes after thrombolytic administration in acute myocardial infarction". Circulation. 105 (16): 1909–13. PMID 11997276. Unknown parameter
|month=ignored (help) - ↑ Werner, GS.; Lang, K.; Kuehnert, H.; Figulla, HR. (2002). "Intracoronary verapamil for reversal of no-reflow during coronary angioplasty for acute myocardial infarction". Catheter Cardiovasc Interv. 57 (4): 444–51. doi:10.1002/ccd.10375. PMID 12455077. Unknown parameter
|month=ignored (help) - ↑ Hillegass, WB.; Dean, NA.; Liao, L.; Rhinehart, RG.; Myers, PR. (2001). "Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience". J Am Coll Cardiol. 37 (5): 1335–43. PMID 11300444. Unknown parameter
|month=ignored (help) - ↑ De Luca, G.; Dudek, D.; Sardella, G.; Marino, P.; Chevalier, B.; Zijlstra, F. (2008). "Adjunctive manual thrombectomy improves myocardial perfusion and mortality in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction: a meta-analysis of randomized trials". Eur Heart J. 29 (24): 3002–10. doi:10.1093/eurheartj/ehn389. PMID 18775918. Unknown parameter
|month=ignored (help) - ↑ 17.0 17.1 Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, Chambers CE, Ellis SG, Guyton RA, Hollenberg SM, Khot UN, Lange RA, Mauri L, Mehran R, Moussa ID, Mukherjee D, Nallamothu BK, Ting HH (2011). "2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: Executive Summary A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions" (PDF). Journal of the American College of Cardiology. 58 (24): 2550–83. doi:10.1016/j.jacc.2011.08.006. PMID 22070837. Retrieved 2011-12-08. Text "PDF" ignored (help); Unknown parameter
|month=ignored (help) - ↑ Amit G, Cafri C, Yaroslavtsev S, Fuchs S, Paltiel O, Abu-Ful A, Weinstein JM, Wolak A, Ilia R, Zahger D (2006). "Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial". American Heart Journal. 152 (5): 887.e9–14. doi:10.1016/j.ahj.2006.05.010. PMID 17070151. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Assali AR, Sdringola S, Ghani M, Denkats AE, Yepes A, Hanna GP, Schroth G, Fujise K, Anderson HV, Smalling RW, Rosales OR (2000). <27::AID-CCD7>3.0.CO;2-0 "Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of "no reflow" phenomenon". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 51 (1): 27–31, discussion 32. PMID 10973014. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Barcin C, Denktas AE, Lennon RJ, Hammes L, Higano ST, Holmes DR, Garratt KN, Lerman A (2004). "Comparison of combination therapy of adenosine and nitroprusside with adenosine alone in the treatment of angiographic no-reflow phenomenon". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 61 (4): 484–91. doi:10.1002/ccd.20010. PMID 15065143. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Fischell TA, Haller S, Pulukurthy S, Virk IS (2008). "Nicardipine and adenosine "flush cocktail" to prevent no-reflow during rotational atherectomy". Cardiovascular Revascularization Medicine : Including Molecular Interventions. 9 (4): 224–8. doi:10.1016/j.carrev.2008.03.002. PMID 18928946. Retrieved 2011-12-15.
- ↑ Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR (2001). "Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience". Journal of the American College of Cardiology. 37 (5): 1335–43. PMID 11300444. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Huang RI, Patel P, Walinsky P, Fischman DL, Ogilby JD, Awar M, Frankil C, Savage MP (2006). "Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 68 (5): 671–6. doi:10.1002/ccd.20885. PMID 17034064. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Ito H, Taniyama Y, Iwakura K, Nishikawa N, Masuyama T, Kuzuya T, Hori M, Higashino Y, Fujii K, Minamino T (1999). "Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction". Journal of the American College of Cardiology. 33 (3): 654–60. PMID 10080465. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Kaplan BM, Benzuly KH, Kinn JW, Bowers TR, Tilli FV, Grines CL, O'Neill WW, Safian RD (1996). "Treatment of no-reflow in degenerated saphenous vein graft interventions: comparison of intracoronary verapamil and nitroglycerin". Catheterization and Cardiovascular Diagnosis. 39 (2): 113–8. doi:10.1002/(SICI)1097-0304(199610)39:2<113::AID-CCD1>3.0.CO;2-I. PMID 8922307. Unknown parameter
|month=ignored (help);|access-date=requires|url=(help) - ↑ Marzilli M, Orsini E, Marraccini P, Testa R (2000). "Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction". Circulation. 101 (18): 2154–9. PMID 10801755. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Ono H, Osanai T, Ishizaka H, Hanada H, Kamada T, Onodera H, Fujita N, Sasaki S, Matsunaga T, Okumura K (2004). "Nicorandil improves cardiac function and clinical outcome in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: role of inhibitory effect on reactive oxygen species formation". American Heart Journal. 148 (4): E15. doi:10.1016/j.ahj.2004.05.014. PMID 15459610. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Piana RN, Paik GY, Moscucci M, Cohen DJ, Gibson CM, Kugelmass AD, Carrozza JP, Kuntz RE, Baim DS (1994). "Incidence and treatment of 'no-reflow' after percutaneous coronary intervention". Circulation. 89 (6): 2514–8. PMID 8205658. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW (2005). "A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II)". Journal of the American College of Cardiology. 45 (11): 1775–80. doi:10.1016/j.jacc.2005.02.061. PMID 15936605. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Sdringola S, Assali A, Ghani M, Yepes A, Rosales O, Schroth GW, Fujise K, Anderson HV, Smalling RW (2000). <394::AID-CCD4>3.0.CO;2-G "Adenosine use during aortocoronary vein graft interventions reverses but does not prevent the slow-no reflow phenomenon". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 51 (4): 394–9. PMID 11108667. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Stoel MG, Marques KM, de Cock CC, Bronzwaer JG, von Birgelen C, Zijlstra F (2008). "High dose adenosine for suboptimal myocardial reperfusion after primary PCI: A randomized placebo-controlled pilot study". Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions. 71 (3): 283–9. doi:10.1002/ccd.21334. PMID 17985384. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Werner GS, Lang K, Kuehnert H, Figulla HR (2002). "Intracoronary verapamil for reversal of no-reflow during coronary angioplasty for acute myocardial infarction". Catheterization and Cardiovascular Interventions :Official Journal of the Society for Cardiac Angiography & Interventions. 57 (4): 444–51. doi:10.1002/ccd.10375. PMID 12455077. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help) - ↑ Weyrens FJ, Mooney J, Lesser J, Mooney MR (1995). "Intracoronary diltiazem for microvascular spasm after interventional therapy". The American Journal of Cardiology. 75 (12): 849–50. PMID 7717298. Retrieved 2011-12-15. Unknown parameter
|month=ignored (help)
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