1 „Prof. Dr. C.C. Iliescu” Emergency Institute of Cardiovascular Diseases, Bucharest, Romania
Abstract: Percutaneous coronary intervention in coronary artery disease has increased considerably over the past years, currently outnumbering the total amount of coronary artery bypass procedures. With the ever-increasing life expectancy and the improvements in cath-lab equipment and training, the number of percutaneous coronary intervention procedures is expected to rise in the near future. Thus, further research is needed to define and strengthen current indications and analyze available data.
Keywords: Cardiovascular disease, coronary artery disease, percutaneous coronary intervention, STEMI, TIMI flow grades.
LIFE expectancy is constantly increasing and with it coronary artery disease has become the predominant cause of substantial morbidity and mortality amongst population in the developed countries1-2. Interven-tions aimed at risk factor modification, optimization of medical therapy and patient education are effective methods of preventing and managing coronary artery disease3-4. When all these approaches fail, invasive the-rapy is often necessary.
Coronary balloon angioplasty was introduced for the first time in 1977 by Gruentzig and since then, aided by the evolution of equipment (mainly by the development of coronary stents) and vast improve-ments in operator experience, has come to address a large spectrum of coronary artery disease patients including those with mutivessel lesions5, total artery occlusions and occluded bypass grafts6. Furthermore, the addition of drug eluting stents (DES), aspiration, thrombectomy and rotational atherectomy techniqu-es increased the array of resources available for PCI.
Thus, safe and efficient revascularization can be achie-ved in almost any type of coronary lesion with techno-logical progress that has taken less than half a century.
Spontaneous rupture of a thin-capped atherosclero-tic plaque with a lipid-rich core is the first event that takes place in acute coronary syndromes7. Platelet ac-tivation and aggregation with thrombus formation is followed by progression towards complete obstructi-on of the vessel lumen with distal ischemia and myo-cardial infarction8. It is currently accepted that most of the thrombotic occlusion persists in patients presen-ting with acute ST-segment elevation myocardial in-farction and pharmacological or interventional therapy is necessary for rapid restoration of blood flow to the injured myocardium9.
The appropriate time interval for efficient intervention is well established – 12 hours according to the gui-delines and each 30-minute delay from symptom on-set increases 1-year mortality rates10. This therapeutic window may be hard to define in some patients with equivalents of ischemic symptoms or atypical presen-tations11. Although thrombolysis significantly reduces mortality compared to placebo, primary percutaneous coronary intervention is the standard preferred treat-ment for this category of patients on the condition that experienced operators in an adequate catheteri-zation laboratory12 perform it. This recommendation is supported by evidence, which shows lower morta-lity and additional long-term benefits in patients trea-ted in high-volume centers, per procedural complica-tions being more common than in the case of elective PCI due to patients, which are often hemodynamically, or electrically unstable13.
However, a majority of patients comes into first contact with a non-PCI capable center and often a pharmaco invasive strategy is employed with similar results as primary PCI strategy regarding mortality, although with higher rates of bleeding complicati-ons14-16.
The complexity involved in the variation of blood flow through an infarct related artery cannot fully be represented by a brief image in time with a simple an-giographic view17-18.
A standardized method for clinical practice and comparing different research data was necessary, hence a grading system termed TIMI flow grade, or TFG (Thrombolysis in Myocardial Infarction) was de-fined in the early 1980s. Several angiographic studies have shown correlation between the TIMI flow gra-des short-term, long-term outcomes and mortality in STEMI patients undergoing PCI19-21.
Grade TIMI 0 indicates no flow at all distal to the obstruction, while grade TIMI 1 indicates a tenden-cy for penetration with contrast material beyond the obstruction point without pacifying the entire artery. These patients have the highest rates of mortality, worse NYHA functional class at follow-up and requi-red more reinterventions22-23. Grade TIMI 2 repre-sents adequate perfusion of the affected vessel down to the distal bed, but with delayed flow while grade TIMI 3 suggests restoration of perfusion with normal vessel flow. These patients have the lowest rates of mortality registered by research (6.4% versus 32.9% in the TIMI 0-1 group) and thus the objective of all co-ronary interventions is to restore normal TIMI 3 flow within the affected coronary vessel24-25.
One of the first studies that researched TIMI flow in primary PCI for STEMI patients found that strong predictors for post-interventional fl ow are age, infarct localization, multivessel disease, diabetes mellitus, and inefficient thrombolytic therapy26.
Although TIMI flow grade is generally the most used tool in clinical practice, it is sometimes restric-ted by its several limitations such as the subjective description and being an operator dependent parame-ter27. Other angiographic criteria developed by Gib-son, the TIMI Frame Count, also known as correc-ted TIMI frame count (CTFC), is a semi-quantitative method for assessing blood flow defined as the num-ber of angiographic cine frames necessary for contrast substance to arrive in the distal circulation after the point of interest28. This index is considered simpler, more objective and reproducible and thus can be used to differentiate between low-risk and high-risk groups of TIMI 3 patients29.
The microvascular fl ow, assessed by myocardial blush grades (MBG) is described as follows: grade 0 refers to no myocardial blush or “persistent stain” suggesting the exit of contrast substance into the ex-travascular space, grade 1 indicates minimum myocar-dial blush, grade 2 – moderate myocardial blush and grade 3 refers to normal myocardial blush, similar to unaffected areas. For proper grading, it is necessary to run long enough fluoroscopy acquisitions to capture the venous phase of contrast clearance30. In HORI-ZONS-AMI trial, myocardial blush grades of 2-3 were achieved in 77% of patients and MBG was found to be an independent predictor of mortality and long-term benefits, but no correlation between MBG and ST segment resolution were found31. Another study, which evaluated the MBG in 2118 consecutive STEMI patients found this marker to be prognostic for 1 year all-cause mortality and noted that it should be used in addition to TIMI flow grade evaluation32.
Although the main focus of the reperfusion therapy is to alleviate and obtain an angiographically satisfying image of blood flow in the epicardial artery, the ulti-mate goal still remains to improve perfusion at the mi-crocirculation level. This concept is emphasized most notably while experiencing the “no reflow” phenome-non with persistence of poor myocardial perfusion af-ter resolution of the infarct related artery occlusion. First described in 1974 by Kloner, “no reflow” is a multi-factorial and complex complication that is not yet fully understood. It is generally agreed that there is a combination of underlying key mechanisms, which add to distal perfusion disruption. No refl ow is asso-ciated with left ventricular remodeling, poor clinical outcome and heart failure with reduced left ventricu-lar ejection fraction33.
Longer periods of ischemia (more than 90 minutes), distal thrombus embolization (promoted by fibrinoly-tic therapy), mechanical fragmentation of the athe-rosclerotic lesion during PCI and endothelial dysfunc-tion followed by platelet-mediated aggregation are de-cisive components that contribute to it. Reperfusion injury can also cause myocardial cell edema, oxygen free radical formation, local infl ammatory response with cytokine activation and coronary vasospasm34. A similar perfusion anomaly, called the slow flow phe-nomenon (CSFP) is an entity defined by late contrast artery opacification that is observed in up to 5% of pa-tients undergoing diagnostic coronarography and has poor prognostic implications35. Impaired myocardial flow is associated with cardiac arrhythmias, contrac-tile dysfunction and heart failure.
Amidst the techniques used for diagnosis and assessment of the no-reflow status, myocardial con-trast echocardiography (MCE) is considered the gold standard, while coronary angiography and magnetic resonance imaging are reasonable alternatives. Quali-tative evaluation involving coronary angiography relies on TIMI flow grades, corrected TIMI frame count and myocardial blush grade. Comparative data of TIMI gra-de 2 fl ow or lower and MCE evaluation show the pre-sence of substantial no-reflow zone in this subgroup. Also, ECG pattern that is not consistent with reper-fusion evolutivity (>50% resolution of ST elevation in less than 90 minutes) is also suggestive of no-reflow phenomenon. Literature data suggests that this group of patients has negative long-term prognostic with a higher risk of mortality and developing heart failure. Meanwhile, in patients where ST-segment resolution is achieved and early T wave inversion, comparative data with MCE show a high correlation with successful myocardial reperfusion and better long-term outco-mes36.
As for treatment of “no-reflow”, up to date, there are several studies that investigated the use of vaso-dilators such as verapamil or adenosine showing mo-derate or no benefi t37. Another proposed solution to this problem was the deferred stenting strategy as an addition to reduce microvascular load and to protect the distal microcirculation38. Recent studies showed controversial results in that perspective which promp-ted current guidelines advising against this procedure.
Thrombus aspiration may be used during primary PCI to avoid distal embolization and to protect tissue perfusion. There is conflicting evidence regarding this procedure. The TAPAS trial, which included 1071 patients undergoing PCI vs thrombus aspiration + PCI, investigated the post procedural frequency of myocardial blush grade 0 or 1 and post procedural frequency of TIMI 3 flow grade. This study showed a signifi cant 1-year clinical improvement and lower mortality rates in the thrombus aspiration group39.
The TASTE Swedish trial, which included 7244 pati-ents divided into the same groups, failed to show any significant differences between the PCI group and the group that received additional thrombus aspiration therapy40. Moreover, the recent TOTAL trial, with 10.063 patients showed that, while routine thrombec-tomy had no impact on total cardiovascular death and recurrent myocardial infarction, it increased the rate of stroke. Thus, current guidelines do not recommend the use of routine thrombus aspiration during primary PCI10.
There is scarce data in the literature with focus on intracoronary fibrinolysis or antithrombotic agents in patients with STEMI and large intraluminal thrombus, a situation associated with adverse results such as fa-ilure of thrombus aspiration and diffi culty in obtaining proper reperfusion.
Massive thrombi are often hard to aspirate through a narrow catheter increasing the risk of rupture and embolization downstream. Few case studies, which in-cluded less than 100 patients, showed TIMI flow and myocardial blush improvement by at least 1-grade and mortality benefi ts in such cases. One particular resear-ch displayed marked improvements from TIMI flow 0-1 in 84% patients before thrombolysis to TIMI flow 3 in 75% patients post intracoronary thrombolysis41.
The INFUSE-AMI randomized trial evaluated intra-coronary administration of abciximab and aspiration thrombectomy in patients with anterior myocardial infarction and showed smaller infarct size by bolus ab-ciximab and no benefit of thrombaspiration42. A meta-analysis overseeing eight randomized trials enrolling a total of 3259 patients compared mortality, recur-rent myocardial infarction, post procedural TIMI 3 and MBG perfusion grades and showed that intracoronary administration of abciximab was associated with signi-ficant benefi ts with regarding to myocardial perfusion.
The wide spectrum of coronary artery disease va-ries from stable angina to acute coronary syndro-mes. Atherosclerotic plaque rupture with subsequent thrombus formation is the main cause of coronary artery occlusion and ST elevation myocardial infarction. Brisk opening of the affected artery is crucial for restoring blood flow to the injured myocardium. Per-cutaneous coronary intervention is currently recom-mended by the guidelines as the standard treatment of choice, with large randomized studies that shown significant improvements in long-term mortality and morbidity. Nevertheless, normal myocardial perfusion is not currently achieved in all treated patients. Seve-ral problems arise, from logistical issues that prevent timely intervention to peri-procedural complications such as no reflow phenomenon and conflicting lite-rature data regarding the proper therapeutic attitude in particular scenarios. Different coronary flow eva-luation tools have been developed and standardized for aiding both clinical practice and research. TIMI flow grade, TIMI frame count and myocardial blush grade are well-established instruments with strong data supporting correlation between these and long term outcomes. Further research is needed to identify other indicators for evaluating coronary blood fl ow as well as myocardial perfusion.
Conflict of interest: none declared.
1. Zhu KF, Wang Ym, Prevalence of coronary heart disease and its re-lationship with human development index: A systematic review. Eur J Prev Cardiology 2016. 23; 530-43.
2. Gaziano TA, Bitton A, Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiology. 2010 35(2); 73-115.
3. NICE Public Health Guidance 25. Prevention of Cardiovascular dis-ease. (http://www.nice.org.uk/guidance).
4. Cooney MT, Dudina A, Whincup P, Capewell S, Menotti I. Re-eval-uating the Rose approach: comparative benefits of the population and high-risk preventive strategies. Eur J Cardiovasc Prev Rehabil 2009;16:541–549.
5. Bravata DM, Gienger AL, McDonald KM, Sundaram V, Perez MV, Varghese R, et al. Systematic Review: The Comparative Effectiveness of Percutaneous Coronary Interventions and Coronary Artery By-pass Graft Surgery. Ann Intern Med. 2007;147:703–716.
6. Serruys PW, Morice MC,: Percutaneous coronary intervention ver-sus coronary-artery bypass grafting for severe coronary artery dis-ease. N Engl J Med. 2009; 360:961
7. Davies, M. (2000). The pathophysiology of acute coronary syn-dromes. Heart, 83(3), 361–366.
8. Ambrose, J. A., & Singh, M. (2015). Pathophysiology of coronary ar-tery disease leading to acute coronary syndromes. F1000 Prime Re-ports, 7, 08.
9. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intrave-nous thrombolytic therapy for acute myocardial infarction: a quanti-tative review of 23 randomized trials. Lancet 2003;361(9351):13–20
10. 2017 ESC Guidelines for the management of acute myocardial in-farction in patients presenting with ST-segment elevation. European Heart Journal (2017) 00, 1–66.
11. Ahmed AH, Shankar K, Eftekhari H, et al. Silent myocardial ischemia: Current perspectives and future directions. Experimental & Clinical Cardiology. 2007;12(4):189-196.
12. Ao Badheka, NJ Patel, et al. Impact of annual operator and institu-tional volume on percutaneous coronary intervention outcomes: a 5-year United States experience. Circulation. 130(16): 1392. 2014.
13. West RM, Cattle BA, Bouyssie M, Squire I, et al. Impact of hos-pital proportionand volume on primary percutaneous coronary in-tervention performance in England and Wales. Eur Heart J 2011; 32(6):706–711.
14. Widimsky P, Budesinsky T, Vorac D, Groch L, Zelizko M, Ascher-mann M, ‘PRAGUE’ Study Group Investigators. Long distance trans-port for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multi-center trial—PRAGUE-2. Eur Heart J 2003;24(1):94–104.
15. Jeronimo S, Campante T. Primary PCI in ST-elevation myocardial in-farction: mode of referral and time to PCI, Rev. Port Cardiol 2012. 31(10):641-6
16. Gehani A, Arafa S. Primary coronary angioplasty for ST-Elevation Myocardial Infarction in Qatar: First nationwide program. Glob Car-diol Sci Pract.2013 Nov 1;2012(2):43-55.
17. Duncker DJ, Merkus D. Regulation of coronary blood flow. Ef-fect of coronary artery stenosis. Arch Mal Coeur Vaiss. 2004 Dec; 97(12):1244-50.
18. Duncker DJ, Koller A. Regulation of coronary blood fl ow in health and ischemic heart disease. Prog Cardiovasc Dis. 2015 Mar-Apr; 57(5):409-22,
19. De Luca G, Ernst N. Preprocedural TIMI flow and mortality in pa-tients with acute myocardial infarction treated by primary angioplas-ty. J Am Coll Cardiol. 2004 Apr 21;43(8):1363-7.
20. Kalińczuk L, Karcz M, Petryka J, Kaczmarska E, Comparison of prog-nostic value of epicardial blood flow and early ST-segment resolu-tion after primary coronary angioplasty. ANIN – Myocardial Infarc-tion Registry. Kardiol Pol. 2007 Jan;65(1):1-10;
21. Stringer KA. TIMI grade flow, mortality, and the GUSTO-III trial. Pharmacotherapy. 1998 Jul-Aug; 18(4):699-705.
22. Uyarel H, Ayhan E, Cicek G. Suboptimal coronary blood flow after primary percutaneous coronary intervention for acute myocardial infarction: incidence, a simple risk score, and prognosis. Coron Ar-tery Dis. 2012 Mar; 23(2):98-104.
23. C. Michael Gibson, MS, MD; Christopher P. Cannon, MD; Sabina A. Murphy 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. 2002; 105:1909-1913.
24. Kammler J et al. TIMI 3 flow after primary angioplasty is an important predictor for outcome in patients with acute myocardial infarction. Clin Res Cardiol 2009; 98(3):165–70.
25. Mehta RH1, Ou FS, Peterson ED, Clinical significance of post-pro-cedural TIMI flow in patients with cardiogenic shock undergoing pri-mary percutaneous coronary intervention. JACC Cardiovasc Interv. 2009 Jan; 2(1):56-64.
26. The TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) trial. N Engl J Med 1985, 932–6.
27. C. Michael Gibson, Christopher P. Cannon, William L. Daley. TIMI Frame Count, Circulation. 1996; 93:879-888.
28. Appleby MA, Michaels AD, Chen M, Michael CG. Importance of the TIMI frame count: implications for future trials. Current Controlled Trials in Cardiovascular Medicine. 2000; 1(1):31-34.
29. Hamada S, Nishiue T, Nakamura S; et al. (2001). «TIMI frame count immediately after primary coronary angioplasty as a predictor of functional recovery in patients with TIMI 3 reperfused acute myo-cardial infarction». J. Am. Coll. Cardiol. 38 (3): 666–71. PMID
30. Hoffmann R, Haager P, Arning J, Usefulness of myocardial blush grade early and late after primary coronary angioplasty for acute myocardial infarction in predicting left ventricular function. Am J Cardiol. 2003 Nov 1; 92(9):1015-9.
31. Brener SJ, Dizon JM, Mehran R, Complementary prognostic utility of myocardial blush grade and ST-segment resolution after primary percutaneous coronary intervention: analysis from the HORIZONS-AMI trial. Am Heart J. 2013 Oct;166(4):676-83
32. Kampinga MA1, Nijsten MW, Gu YL, Is the myocardial blush grade scored by the operator during primary percutaneous coronary in-tervention of prognostic value in patients with ST-elevation myo-cardial infarction in routine clinical practice? Circ Cardiovasc Interv. 2010 Jun 1; 3(3):216-23.
33. Ito H et al. (1996) Clinical implications of the ‘no reflow’ phenom-enon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 93: 223– 228.
34. Kloner RA. No-refl ow phenomenon: maintaining vascular integrity. J Cardiovasc Pharmacol Ther. 2011 Sep-Dec;16(3-4):244-50,
35. Wang X, Nie S-P. The coronary slow flow phenomenon: character-istics, mechanisms and implications. Cardiovascular Diagnosis and Therapy. 2011; 1(1):37-43.
36. SanjivKaul, The “no reflow” phenomenon following acute myocar-dial infarction: Mechanisms and treatment options, Journal of Cardi-ology Volume 64, Issue 2, August 2014, Pages 77-85
37. Harding SA. The role of vasodilators in the prevention and treat-ment of no reflow following percutaneous coronary intervention. Heart. 2006; 92(9):1191-1193.
38. Carrick D, Oldroyd KG, McEntegart M, et al. A Randomized Trial of Deferred Stenting Versus Immediate Stenting to Prevent No- or Slow-Reflow in Acute ST-Segment Elevation Myocardial Infarction (DEFER-STEMI). Journal of the American College of Cardiology. 2014; 63(20):2088-2098.
39. Sanjit S. Jolly, M.D., John A. Cairns, M.D., Randomized Trial of Pri-mary PCI with or without Routine Manual Thrombectomy. N Engl J Med 2015; 372:1389-1398.
40. Ole Fröbert, M.D., Ph.D., Bo Lagerqvist, M.D., Thrombus Aspiration during ST-Segment Elevation Myocardial Infarction. N Engl J Med 2013; 369:1587-1597
41. Boscarelli D, Vaquerizo B, Miranda-Guardiola F. Intracoronary thrombolysis in patients with ST-segment elevation myocardial in-farction presenting with massive intraluminal thrombus and failed as-piration. Eur Heart J Acute Cardiovasc Care. 2014 Sep; 3(3):229-36.
42. Stone GW1, Maehara A, Witzenbichler B, Intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocar-dial infarction: the INFUSE-AMI randomized trial. JAMA. 2012 May 2; 307(17):1817-26.
43. De Luca G1, Verdoia M, Suryapranata H. Benefits from intracoro-nary as compared to intravenous abciximab administration for STE-MI patients undergoing primary angioplasty: a meta-analysis of 8 ran-domized trials. Atherosclerosis. 2012 Jun; 222(2):426-33.
44. Simina Crisan, Cristina Vacarescu, Alina-Ramona Nicola, Microcir-culation as a target of myocardial reperfusion in acute coronary syn-dromes. Romanian Journal of Cardiology 2016 (26), 435-437.