Determination of Angiographic (TIMI Grade) Blood Flow by Intracoronary Doppler Flow Velocity During Acute Myocardial Infarction
Background This study compared angiographically graded coronary blood flow with intracoronary Doppler flow velocity in patients during percutaneous transluminal coronary angioplasty (PTCA) for acute myocardial infarction. Different TIMI angiographic flow grades (flow grades based on results of the Thrombolysis In Myocardial Infarction trial) have been associated with different clinical results after reperfusion for acute myocardial infarction. However, intracoronary blood flow velocity has not been compared with the angiographic method of determining flow grade in patients.
Methods and Results Coronary flow velocity (measured by use of a Doppler guidewire) during primary or rescue PTCA in 41 acute myocardial infarction patients was compared with TIMI grade and cineframes-to-opacification count. Before PTCA, 34 patients had TIMI grade 0 or 1, 5 had TIMI grade 2, and 2 had TIMI grade 3 flow in the infarct artery. Flow velocity was similar among patients with TIMI grades 0, 1, or 2 but was lower than in those with TIMI grade 3 flow (9.4±5.4 versus 16.0±5.4 cm/s for TIMI grades ≤2 versus TIMI grade 3, respectively; P<.05). After PTCA, 1 patient had TIMI grade 1, 5 had TIMI 2, and 35 had TIMI 3 flow. Poststenotic flow velocity increased from 6.6±6.1 to 20.0±11.1 cm/s (P<.01). TIMI grade 3 flow increased to 21.8±10.9 cm/s (P<.05 versus before PTCA). Although post-PTCA flow velocity correlated with angiographic cineframes-to-opacification count (r=.45; P<.02) for TIMI grade 3, there was a large overlap with TIMI grades ≤2 that had low flow velocity (<20 cm/s). Nine of 11 clinical events (unstable angina and coronary artery bypass graft surgery) occurred in patients with low coronary flow velocity.
Conclusions Determination of flow velocity after reperfusion may enhance patient characterization and provide the physiological rationale for clinical variations after reperfusion therapy.
The Thrombolysis In Myocardial Infarction (TIMI) study group developed a grading scale for coronary blood flow based on visual assessment of the rate of contrast opacification of the infarct artery. The TIMI flow grade has become the standard for semiquantitative evaluation of myocardial perfusion before and after coronary reperfusion therapies.1 2 Determination of TIMI flow grade after coronary reperfusion yields important prognostic information in patients with acute myocardial infarction.3 4 5 6 7 8 9 In early analyses, both TIMI flow grades 2 and 3 were considered indicative of successful reperfusion.10 However, more recent studies7 have identified a disparity with regard to clinical outcomes after thrombolysis when patients are stratified between TIMI flow grades ≤2 and TIMI grade 3. Patients with TIMI flow grade 3 show improved regional and global left ventricular function, lower enzyme peaks, and reduced morbidity and mortality rates compared with patients with TIMI flow grades 0, 1, or 2.4 6 7 8 9
Acute coronary artery occlusion and subsequent reperfusion produce profound changes in coronary physiology and myocardial function. After reperfusion, reestablishment and maintenance of normal antegrade coronary blood flow is dependent on a combination of interactive factors, including postreperfusion vessel lumen dimension at the site of a recanalized occlusion and the extent of ischemic damage to both the epicardial conduit endothelium and myocardial microvasculature. Coronary angioplasty rapidly and effectively enlarges the stenotic epicardial conduit lumen and increases coronary blood flow.11 The use of a Doppler-tipped angioplasty guidewire12 13 provides a unique opportunity to study coronary blood flow (especially poststenotic flow) directly in patients in the milieu of an acute myocardial infarction before and immediately after infarct-artery reperfusion. Coronary blood flow can be accurately determined by use of directly measured intracoronary Doppler blood flow velocity and can be compared with the semiquantitative but clinically predictive TIMI angiographic grade estimation of blood flow. Angiographic flow grade and intracoronary blood flow velocity in the setting of acute myocardial infarction have not been compared previously with this methodology.
The purpose of the present study was to investigate the relationship between angiographic (TIMI) blood-flow grading and quantitative intracoronary Doppler flow velocity in patients undergoing primary or rescue angioplasty for acute myocardial infarction. We tested the hypothesis that directly measured coronary flow velocity would correlate with angiographic TIMI flow grading. Coronary flow velocity could thus be used as an objective, reproducible measurement to facilitate comparison of interventions used to establish infarct-artery patency among clinical reperfusion trials.
The study population comprised 41 consecutive patients undergoing urgent cardiac catheterization and primary or rescue coronary angioplasty for acute myocardial infarction. All patients presented with ischemic chest pain of >20 minutes' duration, unrelieved by standard antianginal therapy and accompanied by ECG changes indicative of acute myocardial infarction. Patients with recurrent anginal symptoms >24 hours after intravenous thrombolysis for acute myocardial infarction were also included. Eligible patients underwent direct or rescue angioplasty after we obtained their written informed consent in a form approved by the Human Research Committee of the Institutional Review Board at Saint Louis University Health Sciences Center. All patients received intravenous heparin (10 000 U), nitroglycerin, diazepam (2 to 4 mg), and diphenhydramine (25 to 50 mg) in clinically used standard doses and continued their current medical regimen on entry into the cardiac catheterization laboratory.
Coronary Balloon Angioplasty
Coronary balloon angioplasty was performed in the usual manner for the clinical setting by use of the femoral arterial technique, standard guiding and balloon catheters, and either a 0.014- or 0.018-in Doppler-tipped angioplasty guidewire (FloWire, Cardiometrics, Inc).12 13 An intravenous heparin bolus (10 000 U) and infusion (1000 U/h) were given to maintain an activated clotting time >300 seconds. Aspirin (325 mg PO) was also given. Angioplasty success was defined angiographically as <50% residual stenosis with TIMI 2 or 3 antegrade flow.
Quantitative Coronary Angiography and TIMI Flow Grading
Quantitative coronary angiography was performed with an 8F guiding catheter used as a reference and with use of the Philips QCA DCI-ACA program before and after angioplasty.14 Angiographic TIMI flow grade of the infarct artery was estimated before and after completion of coronary balloon angioplasty according to four grades of flow, as previously described.1 2 All cineangiograms were reviewed by two independent observers. Comparisons between the two observers and between duplicate readings made by a single observer were used to compute interobserver and intraobserver variability (discordance in TIMI grades >1 occurred in 8±7% and 9±6% of readings, respectively).
Angiographic collateral flow was assessed before angioplasty according to the method of Rentrop et al,15 with grade 0 representing no evidence of collateral flow; grade 1, faint opacification of the poststenotic vessel; grade 2, partial filling of the epicardial vessel; and grade 3, complete epicardial opacification.
Using a cine projector equipped with a frame counter (General Electric CAP12), we assessed the number of cineframes acquired from the first frame of opacification of the coronary ostium to prespecified poststenotic landmarks of the individual coronary arteries. The distal landmarks included the apical “forking” branch (usually viewed in the left anterior oblique cranial view) for the left anterior descending coronary artery; the most distal obtuse marginal branch (viewed in the right anterior oblique projection) for the circumflex artery; and opacification of the most distal posterolateral branch or posterior descending artery (viewed in the left anterior oblique, cranial projection) for the right coronary artery.16 Cinefilm speed was 30 frames/s.
Coronary Flow Velocity Measurements
Coronary blood flow velocity was obtained by use of a 0.014- or 0.018-in Doppler-tipped angioplasty guidewire system (FloWire and FloMap, Cardiometrics, Inc). Blood flow velocity was calculated from the Doppler frequency shift of a reflected 12- to 15-MHz signal by fast Fourier transformation and displayed in a spectral format as previously described.12 13 Flow velocity signals were also recorded continuously on standard 0.5-in videotape. Average peak velocity, diastolic peak velocity integral, and diastolic/systolic velocity ratio were derived automatically by the integrated signal-analyzing computer. In 22 patients after angioplasty, coronary vasodilatory reserve was calculated by use of the ratio of maximal hyperemic to resting average peak velocity. Hyperemia was induced with intracoronary adenosine (12 to 18 μg).17 To normalize for vessel size, volumetric coronary blood flow was calculated as the product of average peak velocity ×0.5 (correction factor for assumed parabolic flow profile) × the cross-sectional area of the target vessel 5 to 10 mm distal to the angioplasty guidewire tip location.12
After balloon angioplasty, distal velocity measurements were reacquired (Fig 1⇓). Satisfactory postangioplasty, poststenotic velocity data were recorded for all 41 patients. In 19 patients, velocity measurements were obtained both proximal and distal to the coronary occlusion. Final coronary angiography was performed after the Doppler guidewire was withdrawn from the artery.
Clinical Correlations of Myocardial Infarction
Myocardial creatine phosphokinase (CPK) and CPK-MB enzyme analysis was performed in a routine clinical fashion by use of the central hospital chemistry laboratory. The highest values during the acute infarction period were reported. Left ventricular function after myocardial infarction was assessed by two-dimensional echocardiography and/or contrast left ventriculography at repeat catheterization by use of routine clinical techniques. Clinical events (unstable angina and need for bypass surgery) during the follow-up period were determined by record review and contact with the patient or referring physician.
Because of the small number of patients with individual TIMI grades 0, 1, or 2 after angioplasty, results also were compared by TIMI flow with data grouped by TIMI grades ≤2 and TIMI 3. To compensate for potential nonuniform distribution, similar comparisons were analyzed by the Mann-Whitney U test for a nonparametric sample distribution. Paired Student's t test were used for preangioplasty and postangioplasty comparisons and unpaired t tests for proximal to poststenotic data comparisons. Simple linear regression and correlation statistics determined with the use of a commercially available statistical analysis package (StatView 4.0, Abacus Concepts) were used for coronary flow velocity variables and angiographic data. Differences were considered statistically significant when probability values were <.05. Group values are expressed as mean±1 SD.
Forty-one patients (31 men, 10 women) with a mean age of 56±14 years (range, 30 to 83 years) were studied (Table 1⇓). Twenty-five patients had anterior, 10 had inferior, and 6 had lateral wall myocardial infarcts. The CPK and CPK-MB enzyme levels for each TIMI grade are shown in Table 2⇓. No patient was studied during cardiogenic shock, although 19 patients were receiving intra-aortic balloon pumping for stabilization during angioplasty or to enhance postangioplasty patency.
Twenty-seven patients presented ≤6 hours after initial symptom onset, seven between 6 and 24 hours, and seven at >24 hours. Thirty-three patients had primary angioplasty for acute myocardial infarction without antecedent thrombolytic therapy and eight had rescue angioplasty after failed thrombolysis. The majority of patients were smokers or hypertensives. All patients were receiving aspirin, nitroglycerin, and heparin at the time of intervention. Six patients received intracoronary urokinase (500 000 to 750 000 U every 20 to 60 minutes) in the catheterization laboratory immediately before or during coronary angioplasty.
Before angioplasty, 34 patients had TIMI grade 0 or 1 flow of the infarct artery (Table 3⇓). Preangioplasty quantitative coronary angiographic diameter stenosis was 97±7%, 91±14%, and 100% in the left anterior descending, circumflex, and right coronary arteries, respectively. Angiographic grade 0 or 1 collateral supply was present in 35 patients.
Angioplasty was successful in 40 patients (98%). The percent diameter stenosis was reduced to 22±10%, 21±12%, and 29±7% for the left anterior descending, circumflex, and right coronary arteries, respectively. After angioplasty, TIMI grade 3 flow was present in 35 patients, 5 had persistent TIMI grade 2 flow (4 in the left anterior descending artery, 1 in the right coronary artery), and 1 had TIMI grade 1 flow (left anterior descending coronary artery).
Hemodynamic and Coronary Flow Velocity Data
There were no differences in heart rate or mean arterial pressure between TIMI flow groups. Before angioplasty, proximal and poststenotic (distal) coronary flow velocities were obtained in 20 and 37 patients, respectively. After angioplasty, proximal and distal coronary flow velocities were obtained in 19 and 41 patients, respectively.
Average peak flow velocities in the left anterior descending, circumflex, and right coronary arteries obtained before and after angioplasty are shown in Fig 2⇓. Before angioplasty, proximal average peak velocity was significantly higher (15.4±12.0 cm/s) than poststenotic average peak velocity (6.6±6.1 cm/s; P<.01). Average peak velocity was highest in the left anterior descending artery. After angioplasty, poststenotic average peak flow velocity increased significantly (20.0±11.1 cm/s; P=.0001) from baseline values and was similar to the postangioplasty proximal velocity (26.1±13.4 cm/s).
Table 4⇓ lists the proximal and distal coronary flow velocities stratified by individual TIMI flow grade. Before angioplasty, distal coronary flow velocity was similar in patients with angiographic TIMI flow grades 0, 1, or 2 but was significantly higher in infarct-related arteries with TIMI grade 3 flow. After angioplasty, distal coronary flow velocity values in vessels with TIMI 3 flow was higher than in those with TIMI flow grades ≤2 (P<.003) and higher than preangioplasty distal flow values (21.8±10.9 versus 16.0±5.4 cm/s; P<.05).
When only postangioplasty flow velocity data were examined (Table 5⇓), the distal average peak velocity was higher in patients with TIMI 3 than in those with TIMI ≤2 (TIMI 3, 21.8±11.0 versus TIMI ≤2, 10.1±4.1 cm/s; P=.0009). TIMI 3 flow velocity was similar in the left anterior descending, right coronary, and circumflex arteries (Table 6⇓).
When both preangioplasty and postangioplasty TIMI ≤2 and TIMI 3 flow grades were examined (Table 7⇓), both proximal and distal average peak velocities and diastolic flow velocity integrals were higher for TIMI 3 than for TIMI ≤2 flow values (distal average peak velocity, 21.5±10.7 versus 9.1±4.6 cm/s, P<.0001; distal diastolic velocity integral, 12.5±7.2 versus 5.1±2.6 cm/s, P<.0001) (Fig 3⇓). Similar responses were observed when the volumetric coronary blood flow calculation was used to normalize velocity data for vessel dimension.
Correlation of Velocity and Angiographic Data
Fig 4⇓ illustrates the relationship of TIMI angiographic grades and frames-to-opacification count with infarct vessel distal flow velocity and volumetric flow, respectively. Higher angiographic flow grades and faster infarct-artery opacification were associated with greater poststenotic coronary flow velocities. There was a significant difference in the frames-to-opacification count between angiographic TIMI ≤2 (112±9 frames) and TIMI 3 (41±9 frames) flow grades (P<.0001). Whereas TIMI 2 flow was always associated with frame counts of >60 frames/s and poststenotic coronary flow velocities of <20 cm/s, a wide dispersion of TIMI 3 flow was observed. Among patients with TIMI 3 flow, 13 had low flow velocity (≤20 cm/s). There was no relationship between other angiographic parameters (eg, residual stenosis, infarct-artery location, or diameter) or reference-segment diameter and postangioplasty flow velocity in patients with TIMI 3 flow.
Eleven patients had clinical events (unstable angina=7, coronary artery bypass graft surgery=4) during a follow-up period of 18±12 months (range, 1 to 44 months); of these events, 9 occurred in patients with distal flow velocities <20 cm/s, all of whom had TIMI 3 flow (Fig 4A and 4B⇑⇑).
This study demonstrates an association between semiquantitative methods of angiographic grading of coronary blood flow (TIMI grade flow) and directly measured quantitative intracoronary blood flow velocity. In general, infarct-related vessels with TIMI grades ≤2 had lower flow velocity values than those with TIMI grade 3 flow. However, a heterogeneity of TIMI 3 flow velocity values was observed that overlapped with the uniformly low velocity values of TIMI grades ≤2. Importantly, the range of postangioplasty TIMI grade 3 flow velocities is not explained by differences in reference-vessel diameter, residual stenosis, CPK levels, or location of the infarct-related vessel. Larger-diameter vessels did not necessarily have correspondingly lower flow velocities, an observation that indicates that there are probably significant differences in shear rates among target vessels in the postangioplasty period.
Clinical Differences Stratified by TIMI Flow Grade
Anderson et al8 and others7 9 have shown that the TIMI perfusion grades represent a semiquantitative index of myocardial tissue perfusion and that TIMI grades ≤2 are associated more with reperfusion failure than with reperfusion success. This conjecture is supported by the clinical observation that vessels with TIMI grade 2 flow have a greater tendency to rethrombose,18 possibly attributable to lower flow state as a result of significant residual epicardial stenosis or impaired microvascular integrity in the infarct zone.
In comparing 1-day coronary artery patency among 298 acute myocardial infarction patients treated with intravenous thrombolysis, Anderson et al7 8 found that patients with TIMI grade 2 flow did not differ from patients with TIMI grades 0 or 1 with regard to ejection fraction, CPK enzyme peaks, ECG markers of ischemia, or morbidity index but that those with TIMI grade 3 flow showed better global and regional infarct-zone ejection fractions with reduced enzyme peaks, reduced time to maximal CPK peak, and lower QRS (ischemia) scores. Pooled data and larger clinical studies have also shown enhanced survival among patients who exhibit “normal” or TIMI grade 3 flow compared with those with incomplete grades of reperfusion (TIMI ≤2). The current study demonstrated higher flow velocity values when TIMI grade 3 as opposed to grades 0, 1, or 2 was noted principally after reperfusion. Because of the skewed distribution of patients with TIMI grade 0 or 1 flow before and again after reperfusion, TIMI grade 3 could be well differentiated from perfusion grades ≤2 after angioplasty.
Angiographic Determinants of Flow
The limited correlation of angiographic perfusion grades with flow velocity is likely due to several potentially interrelated factors. Poststenotic flow velocity depends on blood flow across stenoses, branching vessels, and the status of the microvascular bed. It is interesting that TIMI grade 3 flow may be present both before and after angioplasty for stable angina with critically narrowed stenoses, despite dramatic differences in preangioplasty and postangioplasty flow velocity values.19 In addition, visual TIMI flow grading assumes that the radiographic contrast media flow rate parallels coronary blood flow. Although this assumption has been tested by digital subtraction imaging with algorithms for quantitative coronary blood flow estimations,20 21 visual assessments of flow have not been validated against directly measured flow velocity in patients. In other postmyocardial infarction studies,22 23 postinfarction microvasculature impairment was demonstrated by the uniformly reduced coronary vasodilatory reserve. Thus, blood flow through the immediately reperfused myocardial bed may be abnormal despite a relatively brisk angiographic appearance.
The large range of coronary velocities observed with TIMI grade 3 flow may also be a factor in the disparities between expected and observed mortality rates among acute infarct patients undergoing primary angioplasty. In a study by Simes et al,24 postinfarction mortality rates after thrombolysis were predicted from 90-minute angiographic TIMI flow grades on the basis of regression modeling of data from the GUSTO investigations. On the basis of this model, acute infarct mortality rates of <4% would not be expected even if >95% of patients experienced early TIMI grade 3 perfusion after thrombolysis. However, primary angioplasty trials1 2 in which the vast majority of successful reperfusion was TIMI grade 3 have consistently demonstrated mortality rates <4%. Wider ranges of coronary flow velocity among patients with TIMI grade 3 perfusion after thrombolysis or enhanced microvascular integrity after primary angioplasty may help explain these observations. Additional confirmatory studies are required.
After angiographically successful angioplasty, persistently incomplete infarct-artery perfusion (ie, TIMI grades ≤2) may reflect extensive myocardial injury with tissue edema and microvascular plugging that leads to significant perfusion impairment.25 Also, given the limitations of angiography for identification of luminal geometry, a significant epicardial luminal obstruction may persist after an angiographically successful coronary angioplasty. A quantitative method in addition to visual assessment of flow may be more useful for determining myocardial infarct reperfusion physiology for outcome assessment.
Coronary Flow Reserve After Reperfusion
Microvascular injury occurs to a variable degree after infarction and reperfusion. As in similar studies,7 11 22 23 coronary flow reserve in the small subset of patients in the present study (coronary flow reserve 1.67±0.88 for TIMI ≤2 and 1.49±0.49 for TIMI 3; Table 7⇑) was markedly impaired in the immediate postangioplasty reperfusion period. Suryapranata et al23 reported that coronary vasodilatory reserve (as determined by digital subtraction cineangiography technique) after reperfusion in patients with acute myocardial infarction increased from 1.8±0.7 to 2.6±1.0 (normal, >3.5 by digital technique) after coronary angioplasty and corresponded to increases in global left ventricular ejection fraction (52% to 58%) associated with significant improvement in regional infarct-zone function. The current study was not designed to address left ventricular functional changes as related to flow velocity or coronary flow reserve.
This initial study of quantitative flow velocity data obtained in patients during acute myocardial infarction is limited in several respects. The small number of patients and the skewed TIMI flow distributions preclude a high statistical confidence in the analysis between individual TIMI flow grades and measured flow velocity. However, despite small numbers, statistically significant differences were observed. The frame-count method of determining angiographic flow, although more objective than visual grading alone, remains semiquantitative and somewhat subjective among observers. Nonetheless, there was a statistically significant relationship to measured flow velocity. The disparity between techniques points to the relative insensitivity of subjective angiographic flow grading for the measurement of myocardial reperfusion. The wide range of TIMI 3 flow velocities is not unexpected; in a study19 of routine angioplasty patients, all with TIMI 3 flow, poststenotic average peak velocity increased from 15±7 cm/s to 42±30 cm/s without appreciable differences in angiographic flow rates. Collateral flow to the study vessel may alter the intracoronary flow velocity measurements, principally in the preangioplasty period. However, 35 patients in the present study had angiographic grade 0 or 1 collateral flow associated with little or no measurable flow velocity.
An accurate interpretation of the Doppler flow velocity signal should exclude signal artifact related to position within the artery. Suboptimal positioning would result in failure to capture the maximal flow velocity. We addressed this problem by examining the spectral envelope to ensure an optimal signal. Satisfactory spectral signals were obtained after angioplasty in 95% of patients. This laboratory has extensive experience with interventional flow velocity signal interpretation.26 Because of the clinical presentations and critical nature of the procedure, proximal and poststenotic measurements at rest and during hyperemia were not made for all patients both before and after angioplasty. Although coronary flow reserve was obtained in some patients in the immediate postangioplasty period, the clinical significance of these data remains unknown.
Quantitative angiographic estimates of coronary TIMI flow perfusion grades are distinguished by differences in intracoronary Doppler flow velocity. TIMI angiographic grades 0, 1, and 2 are consistently associated with low Doppler flow values and thus represent a low perfusion state that may be associated with reocclusion, ischemic sequelae, and greater extent of myocardial damage. Complete TIMI perfusion (ie, grade 3 flow) has a wide range of flow velocity values that may partially explain differences in clinical responses observed among multicenter trials. A larger study using quantitative assessment of coronary flow velocity after reperfusion could establish the correlation between quantitative analysis of postreperfusion blood flow and clinical outcome and confirm the clinical usefulness of augmenting low flow velocity with adjunctive pharmacological27 or mechanical (eg, intra-aortic balloon counterpulsation)28 therapies after successful reperfusion.
The authors wish to thank the J.G. Mudd Cardiac Catheterization Laboratory Team and Marilyn Cauley and Donna Sander for manuscript preparation.
Reprint requests to Morton J. Kern, MD, Director, J.G. Mudd Cardiac Catheterization Laboratory, St Louis University Hospital, 3635 Vista Ave at Grand, St Louis, MO 63110.
Presented in part at the American College of Cardiology Scientific Session, New Orleans, La, March 20-23, 1995.
- Received July 31, 1995.
- Revision received April 12, 1996.
- Accepted April 16, 1996.
- Copyright © 1996 by American Heart Association
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