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(Circulation. 1996;93:853-856.)
© 1996 American Heart Association, Inc.

Articles

Simplicity's Virtue Scorned

Precision Comes to TIMI Flow Grading and the Results Are . . . Surprising

Carl W. White, MD

From the Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Minneapolis.

Correspondence to Carl W. White, MD, Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail white001@maroon.tc.umn.edu.

Key Words: Editorials • thrombolysis • coronary disease • angioplasty

	Introduction

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 
Utilization of a simple method for the angiographic characterization of coronary flow after thrombolytic therapy for myocardial infarction has become a hallmark of research efforts in this field since its introduction by the TIMI (Thrombolysis In Myocardial Infarction) investigators in 1985.¹ TIMI flow grades 0 (no flow), 1 (minimal flow), 2 (partial flow), or 3 (complete flow) are now an integral part of the unique vocabulary of cardiologists the world over. This flow characterization has the virtue of being as accessible as the nearest video monitor or cineangiographic viewer and can be obtained quickly, at no additional cost. TIMI flow measurements have appeared to be extremely useful as prognostic indicators of the long-term success or failure of thrombolysis,² to risk-stratify patients,³ and to compare the efficacy of various thrombolytic regimens.⁴ Since large mortality trials are expensive and difficult to perform, the 90-minute TIMI flow grade often has been used as a surrogate end point. Early investigators subdivided patients into two groups: TIMI flow grades 0 and 1 at 90 minutes (an undesirable outcome) and TIMI flow grades 2 and 3 (a favorable outcome). More recent investigators have shown considerable differences in the clinical results achieved between TIMI flow grades 2 and 3. A retrospective analysis of four German multicenter thrombolytic trials by Vogt et al⁵ showed that only patients achieving TIMI flow grade 3 after thrombolysis fared better than TIMI grades 0 and 1. Similar outcomes were obtained by the TEAM-2 investigators, who found that only TIMI flow grade 3 resulted in an improved outcome after thrombolysis.⁶ Patients achieving TIMI grade 2 flow followed the same course as grades 0 and 1.

Although widely used, the validity, reproducibility, and determinants of TIMI flow measurements have, unfortunately, received little attention. Most investigators, apparently convinced by the face validity of this measurement, spent little time worrying about the finer points of methodological detail or underlying mechanisms. These angiographic determinations were quickly applied to measure coronary velocity under a wide variety of other circumstances including after angioplasty and newer coronary interventional techniques.

This simple and convenient view of coronary flow after thrombolysis has now been shattered by the precise investigations of Gibson and colleagues,⁷ reported in this issue of Circulation. Working retrospectively with data from the TIMI 4 trial, these investigators developed a more precise method to assess coronary flow velocity from the angiogram. Using an angiographic frame counter and correcting for disparities in vessel length between the left anterior descending artery and the circumflex or right coronary artery, the investigators made several important observations.

First, the conventional visual classification of TIMI flow is greatly hampered by high interobserver variability. Second, even length-corrected TIMI frame counts show that angiographic coronary flow velocity varies substantially from vessel to vessel in the normal major coronary arteries. (Angiographic coronary flow velocity is slower in the left anterior descending than in the other two major epicardial arteries.) This vessel specificity in TIMI flow velocity underscores a fatal flaw in the usual relative comparison of flow velocity in the infarct-related artery to that seen in the noninfarct vessel. Only very prolonged velocities for circumflex-related infarctions will appear prolonged when compared with the TIMI flow in the adjacent left anterior descending artery, which under normal circumstances is slower than that in the circumflex artery. Consequently, a larger proportion of circumflex infarctions will appear to have TIMI 3 flow versus left anterior descending infarctions. This theoretical likelihood is confirmed by review of several small published series of infarcts in which TIMI flow was visually estimated.^{3 6} Additionally, since there is no comparison artery simultaneously injected at the time of right coronary angiography, a small prolongation of the flow velocity in this vessel probably would be difficult to detect. The data presented by Gibson et al⁷ thus show convincingly that visual estimates of TIMI flow, especially when performed in usual clinical settings, bear little relationship to the more precise corrected TIMI frame count at 90 minutes after thrombolysis.

Third, measurements of corrected TIMI flow show that even flow in non–infarct-related arteries at the time of acute infarction are mildly prolonged when compared with vessel-specific normal values. This small degree of flow prolongation seen in all noninfarct arteries 90 minutes after reperfusion subsequently normalized between 18 and 36 hours. These results have some similarity to previous provocative data of Uren et al⁸ from dipyridamole-augmented PET studies, which showed that the ability of the coronary resistance vessels in the remote region to dilate is significantly impaired even 1 week after infarction. This probably reflects a generalized increase in neurohormonal sympathetic activity that occurs acutely after infarction^{9 10} and results in an abnormal increase in microvascular resistance.

	Is Prolongation of Coronary Flow Velocity After Thrombolysis an Epicardial or Microvascular Problem?

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 
Prolongation of coronary flow velocity in the infarct-related artery may relate to residual epicardial vessel obstruction, to abnormal function of the coronary resistance vessels, or can reflect a variable contribution from both resistance sites. Improvements in TIMI flow in the infarct artery from grades 2 to 3 can occur over the first several days after infarction and have been shown to be associated with left ventricular functional improvement.¹¹ Whether such changes in flow are the cause or the result of these changes in function is not clear, since late improvements in coronary lesion diameter also have been shown to occur after thrombolysis.¹² With the use of the corrected TIMI frame counting method, however, no correlation has been seen between changes in flow velocity between 90 minutes and 18 to 36 hours and minimum lumen diameter of the epicardial arteries during this same time period.¹³

The ongoing work of Gibson et al¹⁴ using fluid dynamic modeling suggests that although at 90 minutes after thrombolysis, patients with TIMI 2 flow have a smaller minimum lesion diameter and percent stenosis than those with TIMI 3 flow, the lower coronary velocity results in a smaller transstenotic pressure drop across the epicardial stenosis and a higher microvascular resistance in TIMI 2 versus TIMI 3 patients. Taken together, these data implicate the microvasculature as the most important locus of prolonged TIMI flow.

Although a severe epicardial stenosis remaining after incomplete thrombolysis may constitute a small portion of this phenomenon, it is likely that the major component of this prolongation represents a form of the no-reflow phenomenon. Restoration of flow to a previously ischemic area is not always followed by homogenous reperfusion. After release of a coronary occlusion lasting more than 90 minutes in the dog, reactive hyperemia does not occur, reperfusion of the involved zone is heterogeneous, and average flow is much less than normal.¹⁵ Mechanisms contributing to this phenomenon are believed to include increases in vasomotor tone,¹⁶ capillary compression by swollen myocytes,¹⁵ direct capillary damage,¹⁷ and occlusion of capillaries by packed red cells, fibrin plugs, platelets, and white blood cells.¹⁸ Since the oxygen demands of the endothelium are low compared with myocytes and capillaries that are closest to the oxygen supply, capillaries are more resistant to the effects of ischemia.¹⁹ Signs of no reflow are greatest in the absence of collateral flow and in situations of greatest ischemia. Regional hypoperfusion (no reflow) can result after myocardial infarction as the result of microvascular occlusion despite a patent infarct-related artery.^{20 21} Komamura and colleagues²² have shown that myocardial salvage after successful thrombolytic therapy for acute infarction does not occur in patients who exhibit progressive decreases in great cardiac vein flow despite a patent epicardial artery with no high-grade residual stenosis. This would seem to represent clinical documentation of the deleterious effects of microvascular no reflow after successful epicardial thrombolysis.

When an epicardial coronary artery is occluded, the major determinants of infarct size are the perfusion field subtended (the risk area) and the level of residual ischemia.²³ Contrary to conventional wisdom, infarct size cannot be well predicted by conventional visual analysis of the coronary angiogram.²⁴ In general, the larger the perfusion field of the occluded vessel, the smaller its collateral flow. Thus, infarcts that result from occlusion of the left anterior descending tend to be significantly larger than those that result from occlusion of the right coronary or circumflex. This is probably the major explanation for the finding of Gibson et al that even the corrected TIMI frame count is significantly longer in patients with left anterior descending–related infarction than with infarction related to the right or circumflex arteries.

	Is Prolongation of Coronary Flow Velocity a Specific Sign of No Reflow?

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 
Although a slow washout of contrast from the coronary may occur following thrombolysis after myocardial infarction in the absence of a significant residual stenosis, this "slow flow" phenomenon is seen in other noninfarction conditions. Flow velocity is related to vessel size, and obvious delays in contrast washout are commonly seen in conditions of native coronary ectasia and ectasia of saphenous vein bypass grafts. Even with dramatic coronary flow slowing, measurement of coronary flow reserve in such vessels (assuming no flow-limiting epicardial stenoses and normal subtended myocardium) is usually normal.

Other conditions that involve transient dysfunction of coronary resistance vessels also may be recognized angiographically as "slow flow." The inadvertent small coronary air embolus occurring during catheterization frequently can be recognized by a tell-tale selective slowing of coronary velocity. If the amount of air is small, such resistance vessel dysfunction can be recognized angiographically only for a few minutes.

	Lessons From the `Slow Flow After Angioplasty' Experience

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 
A more frequent and troublesome cause of slow coronary flow has been described with increasing frequency after coronary or saphenous vein angioplasty or atherectomy in patients with unstable angina. In 1989, we reported five patients who developed angina, ST-segment elevation, and a striking reduction in angiographic coronary flow in the dilated coronary artery immediately after balloon deflation. No distal branch occlusions were visible, and the minimal gradient at the site of dilation indicated that the decline in blood flow was not due to residual obstruction at the site of the original lesion. The syndrome lasted 48 to 80 minutes and was not reversed with nitroglycerin or thrombolytic drugs. We postulated that potent vasoconstrictors were released from the clot during dilation and that the reduced blood flow seen after thrombolysis (TIMI 1 or 2 flow) might result from a similar mechanism.²⁵

The release of such vasoactive agents as serotonin, thromboxane, leukotrienes, and others and their resultant coronary vasoconstrictive effects have been well described.²⁶ Benedict et al²⁷ reported a correlation of plasma serotonin changes with platelet aggregation in a dog model of spontaneous coronary thrombus formation. Transcardiac serotonin concentration increases in selected patients with limiting angina and complex lesion morphology.²⁸ McFadden et al²⁹ showed in patients with coronary disease that intracoronary serotonin resulted in coronary vasoconstriction, reduction in collateral flow, and angina with ECG changes and postulated that serotonin released after intracoronary activation of platelets may aggravate ischemia. Leukocytes within fresh thrombi produce leukotrienes, which are potent microvascular constrictors.³⁰ Pharmacological agents that can inhibit the platelet GP IIb/IIIa receptor are presently being used with increasing frequency to treat slow flow states after angioplasty of coronary or saphenous vein atherosclerotic lesions containing thrombi.³¹ Thus, a large body of evidence suggests that coronary vasoconstrictors, released from the clot during thrombolysis as well as after angioplasty, result in prolongation and occasionally cessation of coronary flow by their effects on coronary resistance vessels. Even if epicardial patency is achieved after thrombolysis (or angioplasty), intense microvascular constriction may significantly limit myocardial salvage.

	Implications for Past and Future Investigations

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 
Previous data that have relied on distinctions between visually assessed TIMI 2 and 3 flow to reach conclusions regarding differences in the efficacy of a given thrombolytic agent or differences in outcomes after achieving a given degree of reperfusion after interventional techniques should be reanalyzed, if possible, using the new corrected TIMI frame counting methodology. This is particularly important for studies containing small numbers of patients or those investigations in which patients with comparably sized myocardial risk regions are not uniformly distributed among treatment groups.

There is increasing evidence that differences in the speed of reperfusion is of paramount importance in achieving the desired therapeutic outcome. A recent meta-analysis of 12 published angiographic studies concluded that TIMI 3 flow is associated with a 46% reduction in mortality compared with TIMI 2 flow.³² There is also suggestive evidence that partial reperfusion may be worse than no reperfusion at all.² In view of these observations, it has been suggested that since the rate of achieving TIMI 3 flow after the thrombolytic regimen of accelerated tissue-type plasminogen activator plus heparin and aspirin is about 55% compared with an over 90% TIMI 3 flow rate after direct angioplasty, direct angioplasty should now become treatment of choice for acute infarction.^{33 34} The work of Gibson et al,⁷ however, cautions against hasty acceptance of this conclusion and suggests that for the present, a definite answer must be tempered with restraint.

The importance of understanding basic concepts underlying the consequences of various methods used to restore flow to partially infarcted myocardium is clear. Other evaluation tools are needed in addition to this angiographic frame counting technique. Careful measurements of a maximally augmented flow reserve performed invasively with Doppler techniques or noninvasively with magnetic resonance imaging or other methodologies may add new insights. Newer echo contrast imaging agents also may permit more frequent examinations at different intervals. Until then, I would maintain some modicum of skepticism regarding the outcome of the thrombolysis versus direct angioplasty debate until decisions concerning the consequences of reperfusion are confirmed by more than a glance at the contrast's flow rate on a video monitor. Simplicity has its virtue. . . sometimes.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

Circulation. 1996;93:853-856.

	References

Top Introduction Is Prolongation of Coronary... Is Prolongation of Coronary... Lessons From the `Slow... Implications for Past and... References

 

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