(Circulation. 1996;93:879-888.)
© 1996 American Heart Association, Inc.
Articles |
TIMI Frame Count
A Quantitative Method of Assessing Coronary Artery Flow
From the Cardiovascular Division of the Department of Medicine, Brigham and Women's Hospital and West Roxbury Veteran's Administration Hospital, Harvard Medical School, Boston, Mass (C.M.G., C.P.C., W.L.D., J.T.D., S.J.M., C.H.M., L.R., T.F., E.B.), and Research Triangle Institute, Research Triangle Park, NC (B.A., W.K.P.). A complete listing of all participants in the TIMI 4 trial can be found in the appendix of Reference 8.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Although the Thrombolysis in Myocardial Infarction (TIMI) flow grade is a valuable and widely used qualitative measure in angiographic trials, it is limited by its subjective and categorical nature.
Methods and Results In normal patients and patients with acute myocardial infarction (MI) (TIMI 4), the number of cineframes needed for dye to reach standardized distal landmarks was counted to objectively assess an index of coronary blood flow as a continuous variable. The TIMI frame-counting method was reproducible (mean absolute difference between two injections, 4.7±3.9 frames, n=85). In 78 consecutive normal arteries, the left anterior descending coronary artery (LAD) TIMI frame count (36.2±2.6 frames) was 1.7 times longer than the mean of the right coronary artery (20.4±3.0) and circumflex counts (22.2±4.1, P<.001 for either versus LAD). Therefore, the longer LAD frame counts were corrected by dividing by 1.7 to derive the corrected TIMI frame count (CTFC). The mean CTFC in culprit arteries 90 minutes after thrombolytic administration followed a continuous unimodal distribution (there were not subpopulations of slow and fast flow) with a mean value of 39.2±20.0 frames, which improved to 31.7±12.9 frames by 18 to 36 hours (P<.001). No correlation existed between improvements in CTFCs and changes in minimum lumen diameter (r=-.05, P=.59). The mean 90-minute CTFC among nonculprit arteries (25.5±9.8) was significantly higher (flow was slower) compared with arteries with normal flow in the absence of acute MI (21.0±3.1, P<.001) but improved to that of normal arteries by 1 day after thrombolysis (21.7±7.1, P=NS).
Conclusions The CTFC is a simple, reproducible, objective, and quantitative index of coronary flow that allows standardization of TIMI flow grades and facilitates comparisons of angiographic end points between trials. Disordered resistance vessel function may account in part for reductions in flow in the early hours after thrombolysis.
Key Words: angiography • thrombolysis • myocardial infarction • blood flow • microcirculation
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The TIMI flow-grading system classifies successful reperfusion after thrombolysis as either grade 2 (partial) or grade 3 (complete) flow.1 Although this widely used method of grading coronary flow has been a valuable tool for comparing the efficacy of thrombolytic agents and identifying patients at higher risk for adverse outcomes,2 3 4 5 6 7 the assessment of this angiographic end point is subjective. Variability in the visual assessment of this end point hampers comparisons of flow data between agents and between trials. Furthermore, in addition to its subjective nature, the conventional flow-grading system is categorical, and no continuous angiographic index of coronary flow currently exists. To standardize the assessment of coronary flow and develop a simple continuous index of coronary flow, the number of cineframes required for contrast material to first reach standard distal coronary landmarks (the TIMI frame count) was determined after thrombolysis in the TIMI 4 trial. The results of this study were published previously.8
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The analysis was carried out on coronary angiograms from the previously reported randomized, double-blind TIMI 4 trial that compared the efficacy of three thrombolytic regimens8 : anistreplase (Eminase or APSAC), 30 U IV; rTPA (Activase or alteplase), 15 mg IV bolus followed by 0.75 mg/kg (up to 50 mg) IV over 30 minutes, then 0.5 mg/kg (up to 35 mg) IV over 60 minutes; or combination therapy, 20 U IV of APSAC plus a 15-mg bolus of rTPA followed by a 30-minute infusion of 0.75 mg/kg (up to 50 mg).
Cardiac Catheterization
Angiography was performed immediately
after arrival in the
cardiac catheterization laboratory and at 60, 75, and
90 minutes after administration of thrombolytic
therapy. Cardiac catheterization conditions at 90
minutes after therapy (angle and skew of the gantry, sequence of
standard angiographic views, contrast agent, and cardiac
catheterization suite used) were reproduced at 18 to 36
hours to minimize variability in imaging and
hemodynamic parameters. Sublingual or IV
nitroglycerin was administered at both time points and
was repeated every 15 minutes to preserve a state of maximum
vasodilation. All angiograms were filmed at 30 frames/s.
Quantitative Angiographic Analysis
The cinefilm reviewers
were blinded to the treatment group
assignment, the interpretation of the angiogram made by the clinical
center, and the clinical outcome of the patient. Three consecutive
frames from the same phase of the cardiac cycle (preferably end
diastole) in the optimal single-plane projection
that identified the stenosis in its greatest severity were
chosen for quantitative angiographic analysis with a previously
described and validated automated edge-detection
algorithm.9
Qualitative Angiographic Analysis: TIMI Flow Grade
Assessment
TIMI flow grade was assessed at the angiographic core
laboratory
as previously defined1 : Grade 0—No perfusion; no
antegrade flow beyond the point of occlusion. Grade 1—Penetration
without perfusion; contrast material passes beyond the area of
obstruction but fails to opacify the entire coronary bed distal
to the obstruction for the duration of the cineangiographic filming
sequence. Grade 2—Partial perfusion; contrast material passes across
the obstruction and opacifies the coronary artery distal to the
obstruction. However, the rate of entry of contrast material into the
vessel distal to the obstruction or its rate of clearance from the
distal bed (or both) is perceptibly slower than its flow into or
clearance from comparable areas not perfused by the previously occluded
vessel (eg, opposite coronary artery or the coronary
bed proximal to the obstruction). Grade 3—Complete perfusion;
antegrade flow into the bed distal to the obstruction occurs as
promptly as antegrade flow into the bed proximal to the obstruction,
and clearance of contrast material from the involved bed is as
rapid as clearance from an uninvolved bed in the same vessel or the
opposite artery.
TIMI Frame Count
To objectively evaluate an index of coronary
flow as a
continuous quantitative variable, the number of cineframes required
for contrast to first reach standardized distal coronary
landmarks in the infarct-related artery (the TIMI frame count) was
measured with a frame counter on the SONY SME 3500
cineviewer.10 The first frame used for TIMI frame counting
is the first frame in which dye fully enters the artery. This occurs
when three criteria are met: (1) A column of nearly full or fully
concentrated dye must extend across the entire width of the origin of
the artery; (2) Dye must touch both borders of the origin of the
artery; and (3) There must be antegrade motion to the dye (Fig
1
). If the LAD is subselectively engaged and the
LCx is the culprit vessel, the TIMI frame count begins when dye
first touches both borders at the origin of the LCx. The same rule
holds for subselective engagement of the circumflex artery.
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The last frame is counted or included as one of the frames and is defined as the frame when dye first enters the distal landmark branch. Full opacification of the branch is not required. Often, the last frame is best determined by running the cinefilm past the initial opacification of the end-point branch and then moving frame by frame in reverse until the end-point branch disappears. Care must be taken to advance one frame forward once the dye disappears to identify the frame in which dye first appears.
The following distal
landmark branches are used for analysis:
the distal bifurcation of the LAD (ie, the "mustache,"
"pitchfork," or "whale's tail"; Fig
2); in
the circumflex system, the distal bifurcation of the segment with the
longest total distance that includes the culprit lesion (Fig
3); and in the RCA, the first branch of the
posterolateral artery (Fig 4). Proper panning is
essential for counting the number of cineframes required to first
opacify the distal artery, particularly the LAD. The TIMI frame count
of the LAD and circumflex arteries often is assessed best in either the
right or left anterior oblique views with caudal angulation, and the
RCA often is assessed best in the left anterior oblique projection
with steep cranial angulation. The TIMI frame count in 77 nonculprit
arteries in the setting of MI was also assessed in all films that could
be evaluated from one center.
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Data from 78 consecutive patients who presented to the West Roxbury Veterans Administration Hospital cardiac catheterization laboratory and who had not sustained a myocardial infarction, visually had normal flow in their arteries, and had technically adequate films for analysis were used to correct or normalize the frame count of the LAD for its increased length. The LAD frame count divided by the ratio of its frame count to that of the mean values for the RCA and the LCx (all in the noninfarct setting) was used to derive the corrected TIMI frame count (CTFC). Additionally, a previously described11 three-dimensional vector algebra computational model based on orthogonal views of the coronary arteries was used to determine the distance to the TIMI landmarks in the 37 normal-sized human hearts to confirm this ratio.
Statistical Analysis
All analyses were performed with either
the SAS
statistical program12 or STATA.13 All
continuous variable values were reported as the mean±SD.
Analyses were performed with the 
2 test
for categorical data and ANOVA or Student's t test for
continuous data. Nonparametric tests were used if the data
were not normally distributed. Step-up multiple logistic regression
and linear regression models were developed that required a value of
P
.10 for retention in the model. The 
statistic was
used to calculate the magnitude and statistical significance of
interobserver agreement between the interpretation of angiograms at
participating clinical sites and the readings from the angiographic
core laboratory.
CK values were sampled every 8 hours, integrated over the first 24 hours, and corrected by the upper limit of normal for the submitting center (multiples of the IU upper limit of normal at each center multiplied by hours). The rate of rise of CK was calculated by subtracting the first CK value collected from the peak CK value in the first 24 hours and dividing by the number of hours between these two CK values (IU/h).
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Baseline Characteristics of Conventional TIMI Flow Grades
A total of 393 patients had lesions in the native coronary arteries that were analyzed in the present study (bypass graft lesions were excluded). There were no significant differences among the conventional TIMI flow grades in culprit arteries (assessed by the angiographic core laboratory) with respect to the baseline characteristics of sex, incidence of previous MI, and age. However, among patients with TIMI grade 2 flow, LAD lesions predominated (62.7% LAD versus 37.3% for other, P<.001) and conversely, among patients with TIMI grade 3 flow, RCA and circumflex lesions predominated (26.2% LAD versus 73.8% other, P<.001).
Interobserver Variability Between Clinical Center and Angiographic
Core Laboratory Assessment of Conventional TIMI Flow
Grades
The frequency of agreement between participating clinical
centers
and the angiographic core laboratory in the classification of TIMI flow
grades was assessed with use of the statistic (range of values,
-1 to +1). Values of >0.75 indicate excellent agreement
beyond chance between two observers, whereas values <0.40 indicate
poor agreement. Agreement was excellent in assessment of TIMI grade 0
or 1 flow, with an 89% rate of agreement between clinical centers and
the angiographic core laboratory (Table 1,
=0.84±0.05). There was a moderate (79%) rate of agreement
in
assessment of TIMI grade 3 flow (=0.55±0.05). In contrast,
for
assessment of TIMI grade 2 flow, the rate of agreement was poor at 52%
(=0.38±0.05). The overall value for assessment of all flow
grades
was =0.59±0.04, indicating moderate agreement.
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Variability in the TIMI Frame-Counting Method
The
reproducibility of the TIMI frame count was systematically
studied in 85 consecutive pairs of injections of the
infarct-related artery. The mean absolute value of the difference
between two consecutive hand injections spaced apart by 1 to 2 minutes
was 4.7±3.9 frames, with a range of 0 to 18 frames (coefficient of
variation=9.0%). Reproducibility did not vary significantly by
location of the infarct artery.
TIMI Frame Count in the Absence of Acute MI: The CTFC
In 78
consecutive patients presenting to the cardiac
catheterization laboratory in the absence of acute MI,
the TIMI frame count for the RCA (20.4±3.0 frames, n=38) did not
differ significantly from that of the circumflex artery (22.2±4.1
frames, n=21), but the frame count of the LAD was significantly higher
(36.2±2.6 frames, n=19, P<.001 for both comparisons)
(Table 2). This discrepancy in the distance to the
distal arterial landmarks was corrected or adjusted for by
dividing the TIMI frame count of the LAD by a factor of 1.7, the ratio
of the unadjusted TIMI frame count for the LAD to that of the average
of the RCA and circumflex, yielding a CTFC of 21.1±1.5 frames for the
LAD. A previously described three-dimensional vector algebra
computational model11 was used to determine that the
approximate distance to the TIMI landmark in the average human LAD is
14.7 cm, the length of the RCA to the midpoint of the first third of
the posterolateral branch (the usual location of the first small
branch) is 9.8 cm, and the length of the LCx to the midpoint of the
distal third of the third marginal branch is 9.3 cm, yielding
comparable ratios of 1.5 (LAD/RCA) and 1.6 (LAD/LCx), for an average
ratio of 1.55. Taken together, the mean CTFC for all 78 normal arteries
was 21.0 frames with an SD of 3.1 frames, yielding 95% CIs for normal
flow of 
15 to 27 frames.
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Relationship Between CTFC, Cardiac Catheterization,
and Hemodynamic Parameters
Among patent arteries, there was no
correlation between the number
of injections before 90-minute angiography and the CTFC at 90 minutes
(r=.055, P=.43). Furthermore, in a multiple
regression model that controlled for infarct-artery location (a
significant independent predictor of the CTFC, as discussed below),
there remained no correlation. There was also no clear
relationship between catheter size and CTFC (5F=32.2±10.6
frames, n=7; 6F=40.8±21.9 frames, n=106;
7F=39.5±19.5
frames, n=82; 8F=34.2±14.7 frames, n=23; four-way
P=.40). In the subgroup of patients studied at one center,
there was no correlation between the 90-minute CTFC and heart rate,
systolic or diastolic blood pressure, right atrial
pressure, difference between diastolic arterial
blood pressure and right atrial pressure, pulmonary capillary
wedge pressure, cardiac output, or cardiac index. When we corrected for
infarct-artery location in a multivariable model, there was
still no correlation with any of the above variables.
Clinical Center and Angiographic Core Laboratory Interpretation of
Conventional TIMI Flow Grades Versus CTFC
When clinical centers
interpreted TIMI flow grade, there was
nearly total overlap in the distribution of the CTFC for TIMI grade 2
versus TIMI grade 3 flow (Fig 5A). For the angiographic
core laboratory, overlap was also present but appeared to be
reduced compared with the clinical centers (Fig 5B). This is
demonstrated by the fact that among culprit lesions classified as
having TIMI grade 2 flow, the CTFC was <30 (flow was normal or only
modestly delayed) in 22 (28.6%) of the 77 culprit arteries assessed by
the clinical center, which was significantly higher than the 4 (5.5%)
of 73 culprit arteries assessed by the core laboratory
(P=.003). Similarly, among culprit arteries classified as
having TIMI grade 3 flow, the CTFC was >60 (ie, flow was actually
slow) in 6 (4.4%) of the 134 culprit arteries assessed by the clinical
center compared with none (0%) of the 148 culprits assessed by the
core laboratory (P=.03).
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CTFC in Nonculprit Arteries
In patients with acute MI, the
mean CTFC in nonculprit arteries at
90 minutes after thrombolysis was 25.5±9.8 frames,
which was significantly higher (reflecting slower flow) than that of
normal arteries in the absence of acute MI (21.0±3.1 frames,
P<.001) (Table 2
). By 18 to 36 hours, however, the
CTFC of
nonculprit arteries had improved significantly (-4.4±6.1 frames
for pairs of films, P=.007) to nearly that of normal vessels
in the absence of acute MI (21.7±7.1 versus 21.0±3.1 frames,
P=NS).
CTFC in Culprit Arteries
The CTFC for culprit arteries at 90
minutes after
thrombolysis was unimodally distributed with a single
peak. Two distinct subpopulations of "slow" (TIMI grade
2 flow) and "fast" flow (TIMI grade 3 flow) did not exist
(Fig 6). The distribution was not normal, and therefore
nonparametric tests were used in the statistical
analyses of these data. The cumulative distribution function of
the CTFC is shown in Fig 7, which displays the
proportion of the population on the y axis with a CTFC less
than the value shown on the x axis. As can be seen from this
plot, 32.6% of patients achieved a CTFC 27 frames, a value that can
be taken as representative of the upper boundary of the
CTFC for normal flow, as it was the upper bound of the 95% CI for the
CTFC observed in the absence of acute MI (21.0+1.96xSD of 3.1). The
mean 90-minute CTFC (read by the angiographic core laboratory) was
30.2±9.3 frames for TIMI grade 3 flow and 57.5±23.2 frames for
TIMI
grade 2 flow (P<.001).
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The mean CTFC in all patent culprit
arteries was 39.2±20.0 frames at
90 minutes, which improved significantly (-6.5±17.9 frames for
all paired values, P<.001) to 31.7±12.9 frames by 18 to 36
hours (Table 2). The magnitude of improvement in the CTFC over
the
course of the first day did not differ significantly between nonculprit
(-4.4±6.1 frames) and culprit arteries (-6.5±17.9
frames,
P=NS). However, whereas the CTFC had returned to normal in
nonculprit arteries by 18 to 36 hours (21.7±7.1 versus 21.0±3.1
frames, P=NS), it remained persistently slower in culprit
arteries (31.7±12.9 versus 21.0±3.1 frames, P<.001).
Relationship Between CTFC and Change in Lumen Diameter of Culprit
Arteries Over Time
In the 33 patients in whom it could be assessed at
all four time
points (60, 75, and 90 minutes and 18 to 36 hours after
thrombolysis), the CTFC decreased steadily over time,
reflecting more rapid and improved dye transit (P=.005 for
the linear trend over time) (Fig 8). The CTFC improved
by 18.5% between 60 and 90 minutes after thrombolysis
(P=.008) and by an additional 14.8% by 18 to 36 hours
(P=.001).
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The minimum diameter of culprit arteries increased from 0.86±0.40 mm at 90 minutes to 1.09±0.49 mm at 18 to 36 hours (n=246, P<.001), and percent diameter stenosis improved from 73.8±9.9% at 90 minutes to 66.7±13.2% at 18 to 36 hours (n=246, P<.001). The fact that the state of vasomotor tone was reproduced at the time of initial and follow-up studies is confirmed by the observation that the 90-minute diameter of the normal reference segments (3.37±0.92 mm, n=246) was identical to that at the time of repeat angiography at 18 to 36 hours (3.37±0.95 mm, n=246, P=.97). There was no correlation between the improvement in CTFC between 90 minutes and 18 to 36 hours and the change in either the minimum lumen diameter (mechanical interventions excluded) (r=-.045, P=.59), the percent diameter stenosis (r=.097, P=.23), or the normal reference segment diameter (r=.10, P=.22).
Relationship Between CTFC and Infarct-Artery Location
At 90
minutes after thrombolysis, the mean CTFC
for LAD culprit lesions (43.8±22.6 frames) was significantly higher
(ie, slower flow) than for the RCA (37.2±19.3 frames,
P=.029) and the circumflex artery (33.7±9.0 frames,
P=.034) (Table 2). Similarly, in nonculprit
arteries, flow
in the LAD was slower at 90 minutes after thrombolysis
than in the other two locations combined (30.6±11.5 versus
23.1±7.9
frames, P=.001). In contrast, by 18 to 36 hours, the mean
CTFC was similar among the three culprit artery locations (31.7±14.5
for LAD, 32.5±9.6 for LCx, and 31.6±12.8 for RCA,
P=NS).
There was a trend for the CTFC to improve more in LAD culprit arteries
than in the two other locations combined (P=.098).
There were no differences in systolic blood pressure, time to treatment, reference segment diameter, minimum diameter, or percent stenosis for the three culprit arteries. Patients with an LAD culprit had larger integrated CK leaks (213.8±175.2 U) compared with RCA culprit arteries (131.6±83.8 U, two-way P<.001), and these CK leaks tended to be larger than those involving the LCx (173.2±106.4 U, P=.164).
Correlation of CTFC With Angiographic, Ventriculographic, and
Enzymatic Outcomes
The 90-minute CTFC was only weakly correlated with
90-minute
minimal lumen diameter (r=-.16, P=.016),
percent diameter stenosis (r=.19,
P=.006), and rate of rise of CK over the first 24 hours
(r=.18, P=.009) and was inversely, weakly
correlated with the predischarge radionuclide ventriculogram left
ventricular ejection fraction (r=-.21,
P=.002). There was a trend toward a correlation of the CTFC
with the integrated CK over the first 24 hours (r=.13,
P=.07). There was no correlation between the CTFC and the
normal reference artery segment diameter or the elapsed time to
treatment. There was no significant difference in the CTFC for patients
with versus those without collaterals to the infarct-related
artery.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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Potential Pitfalls in the Conventional TIMI Flow-Grade System
The conventional TIMI flow-grade system1 has been widely used to compare thrombolytic agent efficacy and to stratify patients according to risk, but it has limitations. Whereas previous studies2 3 4 5 6 7 associated TIMI grade 2 flow after thrombolysis with suboptimal clinical outcomes, the present study demonstrates that there is a poor rate of agreement between an angiographic core laboratory and clinical centers in the assessment of TIMI grade 2 flow, which may limit the broad clinical applicability of this measure. Although the rate of agreement in assessment of the CTFC between the angiographic core laboratory and clinical centers remains to be determined, the variability at the core laboratory between two consecutive injections appears low (<5 frames, coefficient of variation=9.0%). Further evidence of the reproducibility and robust nature of this end point is the observation that the CTFC in one data set of normal arteries in the noninfarct setting (21.0±3.1) was nearly identical to the CTFC of a second independent data set of nonculprit arteries (21.7±7.1) 1 day after thrombolysis (Table 2
). Despite all the potential
factors that introduce variability into the CTFC (variability in the
distance to the landmark between patients, variability in rate of
injection, intraobserver variability in counting frames, variability in
catheter size, variability in the degree of engagement, variability in
heart rate, variability in the phase of the cardiac cycle injected,
etc) the SD of the CTFC in 78 normal arteries remained very low, at
only 3.1 frames. Flow also has been estimated angiographically in the
past by use of the mean contrast-appearance time, which involved
calculating the time between peaks in contrast intensity at two points
separated by known distances along the length of the artery.
Unfortunately, this radiographic technique was limited by
technical factors that confounded the videodensitometric
analysis of angiograms, such as adhesion of the dye to the wall
of the artery, scatter, veiling glare, variability in mask-mode
subtraction, and motion artifact from patient
movement.14 15
Even if excellent concordance
could be demonstrated within or between
experienced angiographic core laboratories in the assessment of TIMI
grade flow, several major limitations remain when this categorical
method is used to assess angiographic success after
thrombolysis. First, the present study shows that
coronary flow after thrombolysis is unimodally
distributed (Fig 6). Distinct subpopulations of patients with
either
slow (TIMI 2) or fast (TIMI 3) flow do not exist, and a categorical
classification of coronary flow is, at best, arbitrary. Second,
even if TIMI flow grading is proved to be reproducible, it may be
inaccurate or may misclassify flow as a result of the use of a flawed
gold standard to gauge "normal" flow. The original definition of
TIMI grade 3 flow requires that flow into or clearance of contrast
material from the involved bed be "as rapid as clearance from an
uninvolved bed in the same vessel or the opposite
artery."1 However, the present study demonstrates
that the velocity of contrast in an uninvolved bed may not be normal
and is actually 21% slower (ie, the frame count is higher, 25.5 versus
21.0 frames, P<.001). This observation of reduced basal
flow in nonculprit vessels at 90 minutes after
thrombolysis extends the findings of Uren et
al,16 who showed that at 1 week after MI, the vasodilatory
response of nonculprit arteries remains reduced, which has been
attributed to an abnormality in resistance vessel function. The fact
that by 1 day after thrombolysis, these uninvolved
arteries do eventually achieve flow virtually identical to that of
arteries in the absence of acute MI (21.7 versus 21.0 frames) indicates
that the delayed flow at 90 minutes was not an artifact of selecting a
subpopulation of vessels with slower flow for analysis. In
contrast to nonculprit vessels, flow in culprit vessels remained
persistently reduced by 32% at 1 day after
thrombolysis, which approximates the 26% flow
reduction documented at 1 week after MI by positron emission tomography
scanning.16 This persistent reduction in flow (which,
paradoxically, is frequently classified as normal TIMI grade 3 flow)
may be due either to the residual stenosis or to reduced
oxygen consumption secondary to diminished
contractility in the infarct zone. Changes in
epicardial vasomotor tone do not appear to be responsible for these
changes in frame counts over time, as the diameters of the normal
reference segments were identical at 90 minutes and 18 to 36 hours
(3.37 mm for both, P=.97).
An additional problem with the conventional TIMI flow-grading system is that uninvolved arteries that are used as the gold standard to classify the TIMI flow grade in the culprit artery may not all be slowed to the same degree, depending on their location. Flow in nonculprit LAD arteries was disproportionately slowed by 36% compared with that in uninvolved circumflex arteries, which confounds the classification of conventional TIMI flow grades. Although the present study shows that the CTFC in LAD culprits is, on the whole, higher (reflecting slower flow) than that in other locations at 90 minutes after successful thrombolysis, the CTFC for TIMI grade 3 flow was actually 32% lower for LAD culprits compared with the circumflex artery (25.7 versus 34.0 frames). This paradox is explained by the fact that TIMI grade 3 flow in culprit LAD arteries was gauged against faster flow in nonculprit circumflex arteries (22.5 frames), and consequently, few LAD culprits (26.2%) achieved a velocity rapid enough to be classified as achieving TIMI grade 3 flow. In contrast, flow in circumflex culprits was graded against the 36% slower flow in nonculprit LADs (30.6 frames), and consequently, the vast majority of circumflex arteries (92%) were classified as achieving TIMI grade 3 flow. Thus, the conventional notion that flow in uninvolved arteries is normal may be erroneous and may lead to the misclassification of TIMI flow grades. In the RCA, no adjacent comparative normal artery is even present. The problem of visual flow-grade assessment is further compounded by the fact that international cinefilms are filmed at a wide variety of speeds (12.5, 15, 25, 30, 50, or 60 frames/s). Another limitation of the conventional TIMI flow-grading system is that observers who grade flow might be biased by their concurrent assessment of the ejection fraction of the patient (which has been linked to clinical outcomes), and an objective frame-counting method might reduce this potential for bias.
The CTFC
could facilitate the standardization of TIMI flow grades and
flow assessment. However, devising a valid definition of normal flow is
complicated. The mean CTFC for culprit arteries with normal TIMI grade
3 flow (30.2 frames) was significantly higher than for nonculprit
arteries (25.5 frames, P<.001) and was higher yet (43.8%)
than for normal arteries in the absence of acute MI (21.0 frames,
P<.001). Thus, TIMI grade 3 flow in culprit arteries is not
truly representative of normal flow. In our view, a
valid threshold for defining normal flow would be to use the upper
bound of the 95% CI for arteries that have normal flow in the absence
of acute MI (27 frames with predominantly 6F and 7F catheters).
By this definition, only one third (32.6%) of patients with a patent
artery in the TIMI 4 trial actually achieved flow within the range
observed in normal arteries (Fig 7).
The use of either an objective classification system or the CTFC itself should facilitate the comparison of angiographic end points between trials. In addition, such an objective definition could improve on the large intraobserver variability experienced by submitting clinical centers, and such a comparison is currently under way. Use of the CTFC might permit meaningful analysis of the vast amount of angiographic data that are gathered by clinical centers and currently are not analyzed because a single core laboratory could not process tens of thousands of films from large clinical trials.1 2 This method is simple and should have broad applicability because it can be measured by any investigator with the frame counter that is present on most cineviewers. We have found that variability can be encountered in selecting the first frame for analysis, and care should be taken to ensure that all three criteria are fulfilled for the selection of the first frame as set forth in "Methods."
The use of a continuous variable such as the CTFC for comparison of angiographic outcomes might be superior to the use of a categorical variable such as TIMI flow grade in terms of statistical power and sensitivity. As newer thrombolytic agents reportedly achieve a higher incidence of TIMI grade 3 flow, a categorical scale may fail to distinguish their efficacies, because there is a range of dye velocities that constitute TIMI grade 3 flow. Even if two agents result in the same proportion of TIMI grade 3 flow, there may be a difference in dye velocity between the two agents when analyzed as a continuous variable with the CTFC. For instance, two future thrombolytic agents may both achieve TIMI grade 3 flow in 75% of patients, but one agent may achieve a mean CTFC of 30 frames and the other a mean CTFC of 40 frames.
Differences in Flow Among the Three Coronary
Arteries
The unadjusted TIMI frame count for LAD culprits was
corrected to
account for its longer length by dividing by 1.7, the ratio of the LAD
TIMI frame count to the mean of normal LCx and RCAs in the absence of
acute MI. This ratio is consistent with the mean ratio of 1.55
predicted by use of three-dimensional vector algebra devised by
Dodge et al11 to calculate the distance to the TIMI
landmarks in the normal-sized human heart. In addition to
controlling for differences in artery length and minimizing the effect
of discrepancies in the proportion of LAD culprit arteries between
agents and between trials, this correction improves the power of this
end point by reducing the SD of the TIMI frame count among patients
with culprit arteries in the LAD versus other locations.
TIMI grade 3 flow more frequently was achieved in patients with an infarct-related artery other than the LAD in the present trial (74% versus 26%, P<.001), a finding that was also observed in the TEAM-2 study (61% versus 37%, P=.06).6 Further objective documentation of this observation is the fact that the CTFC (ie, the frame count already corrected for the difference in artery length) was higher (reflecting slower flow) in LAD culprit arteries compared with the other two arteries. Furthermore, flow in nonculprit LADs was also delayed compared with the other two arteries. This apparent overrepresentation of LAD culprit arteries with TIMI grade 2 flow and the preponderance of RCA culprit arteries with TIMI grade 3 flow has major implications when the clinical outcomes of the various flow grades are compared. In several recent analyses of angiographic data, it was demonstrated that patients with TIMI grade 2 flow had poorer outcomes than patients with TIMI grade 3 flow. However, data pertaining to the location of the infarct artery were neither presented nor corrected for in these analyses of outcomes.2 17 18 Thus, it would be appropriate that any analysis comparing the clinical, enzymatic, ventriculographic, or electrocardiographic outcomes of the various TIMI flow grades should correct for the large potential imbalances in infarct-artery location.
Despite differences in the CTFC in the three coronary arteries, there were no differences in their lumen dimensions, and there was no correlation between the CTFC and hemodynamic variables. This discrepancy in flow was transient and resolved by 18 to 36 hours. A question that therefore arises is whether slowed flow causes larger infarcts in the LAD or, conversely, if larger infarctions in the LAD cause slower flow. Seiler et al19 showed that the length of an artery is proportional to the myocardial mass subtended by the artery, and Kloner et al20 21 showed in turn that the myocardial mass injured is proportional to the magnitude of no reflow. Thus, the higher CTFC of LADs and the preponderance of LAD culprits among patients with TIMI grade 2 flow may be related to more extensive necrosis (LAD CK leaks were larger) as a result of the large myocardial mass subtended by this 1.7-times-longer coronary artery.
Although both the epicardial lesion and the microvasculature are determinants of flow after thrombolysis, the role of the microvasculature is supported by the following observations: (1) flow is slowed in uninvolved nonculprit arteries at 90 minutes after thrombolysis but returns to normal by 1 day after thrombolysis; (2) in culprit arteries, there is no relationship between the improvement in the CTFC and the change in minimal lumen diameter over the first day after thrombolysis (with no documented change in vasomotor tone); and (3) the improvement in flow over the course of the first day after thrombolysis does not differ significantly between nonculprit and culprit arteries. These findings implicating the microvasculature are consistent with the myocardial contrast echocardiography studies of Ito et al,22 in which no relationship was observed between epicardial stenosis severity and the incidence of myocardial no reflow after successful thrombolysis. That group also demonstrated that intracoronary injections of verapamil in the setting of acute MI may improve microvascular perfusion and left ventricular function.23 We again emphasize that in the current study, TIMI grade 3 flow (30.2 frames) was slower than flow in the absence of acute MI (21.0 frames), and the relative contribution of microvascular and epicardial resistance as well as reduced oxygen consumption to this delay in TIMI grade 3 flow remains to be determined.
Limitations
Further studies are required to prospectively
validate this new
angiographic end point. The relationship of the CTFC to major clinical
end points, such as mortality, remains to be determined. The
correlation between angiographic core laboratories in the assessment of
this end point will also need to be determined. Circumflex and
saphenous vein graft lesions are underrepresented in
thrombolytic trials, and additional data are required
to characterize and fully evaluate the CTFC of these arteries.
Currently, we use the same distal native landmarks to characterize flow
in bypass grafts. Culprit lesions in the distal posterolateral branch
or the distal posterior descending artery may occasionally lie distal
to the TIMI landmark. Infrequently, there may only be a short distance
of delayed flow beyond a distal lesion located before the TIMI
landmark. Further prospective studies are needed to confirm that flow
in LAD culprit arteries is slower than in other locations as well as to
confirm the observation that flow in nonculprit arteries improves
slightly over time.
Usually, the rate at which images are captured to cinefilm is the same rate at which images are captured into the video format in the cardiac catheterization laboratory. This rate is generally 30 frames/s (SONY, Phillips, and General Electric Inc). The number of frames can be counted on line in the cardiac catheterization laboratory or on a VCR by simply advancing the video one frame at a time. The frame acquisition and display rate should be confirmed with the manufacturer of the laboratory equipment. Alternatively, for videotapes, a studio production recorder can be used to record the length of time in fractions of a second to the landmark. It should be confirmed that 30 single frames elapse per second. The time (in seconds) can then be multiplied by 30 frames/s to convert to frames. In some centers, cinefilming may instead be performed at 12.5, 15, 25, 50, or 60 frames/s. Therefore, a correction must be made for this difference by multiplying the TIMI frame count observed in these films by a factor of 30 divided by the actual number of frames filmed per second. The rate of frame acquisition must be communicated to the angiographic core laboratory.
The CTFC will vary depending on the length of the artery. Fortunately, this variability appears to be fairly low, as the SD of the CTFC among normal arteries was only 3.1 frames. Furthermore, if comparisons of the CTFC are made over time, then length is controlled for within the same artery. It must be emphasized that larger numbers of patients need to be studied to fully ascertain the influence of catheter size on the CTFC, the effects of which may have been overshadowed by a variety of confounding variables in acute MI. Predominantly 6F and 7F catheters were used in the present study, and more comparative data in the absence of acute MI are needed for the use of 8F and 9F catheters in restenosis trials, for instance. The mean catheter size or the distribution of catheter sizes should be confirmed to be the same among treatment groups and should be reported so that comparisons across trials can be evaluated for their applicability. Although the rate of entry of dye into the coronary tree may be affected by the force of the injection, the rate of egress or washout of dye may be more independent of the rate of injection and warrants further investigation. The view that is optimal for frame counting may not be the view that is optimal for quantitative angiography.
The TIMI frame count could not be measured in 9% of consecutive acute MI patients, and a technique of more rapid panning may be required for interventional trials in which the flow is more brisk and the magnification is often higher in the 5-in mode. If panning is insufficient, we advocate that an injection be obtained of the culprit vessel on 9-in mode so that the frame count can be ascertained in the vast majority of patients.
Conclusions
In contrast to the conventional TIMI flow-grade
system, the
CTFC is quantitative rather than qualitative, is a continuous rather
than a categorical variable, and is objective, reproducible, and
sensitive to flow changes. This simple index of coronary flow
allows calibration or standardization of flow grading and should
facilitate comparisons of flow data between angiographic trials. Flow
in nonculprit arteries routinely used to grade TIMI flow cannot be
presumed to be normal, as demonstrated by the 21% reduction in flow in
these arteries at 90 minutes after thrombolysis.
Despite high rates of TIMI grade 3 flow reported in the literature,
only a third of patients with an open artery actually achieve flow that
is truly within the normal range (CTFC 27). Outcome analyses
of TIMI flow grades should correct for imbalances in lesion location.
The current study supports the idea that the disordered
microvasculature tone plays a role in flow delays immediately after
thrombolysis.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by a grant from Smith Kline Beecham, Philadelphia, Pa. Additional support was provided by Genentech, Inc, South San Francisco, Calif.
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Footnotes |
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Reprint requests to C. Michael Gibson, MS, MD, Director, Interventional Cardiology, West Roxbury Veteran's Administration Hospital, 1400 VFW Parkway, West Roxbury, MA 02132.
Received September 11, 1995; revision received November 13, 1995; accepted November 19, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
-
The TIMI Study Group. The
Thrombolysis in Myocardial Infarction (TIMI) trial.
N Engl J Med. 1985;312:932-936. [Medline]
[Order article via Infotrieve]
-
The GUSTO Investigators. An international randomized
trial comparing four thrombolytic strategies for acute
myocardial infarction. N Engl J Med. 1993;329:673-682.
[Abstract/Free Full Text]
-
The GUSTO Angiographic Investigators. The effects of
tissue plasminogen activator, streptokinase, or
both on coronary artery patency, ventricular
function, and survival after acute myocardial infarction. N
Engl J Med. 1993;329:1615-1622.
[Abstract/Free Full Text]
-
Van de Werf F. Discrepancies between the
effects of coronary reperfusion on survival and left
ventricular function. Lancet. 1989;1:1367-1369. [Medline]
[Order article via Infotrieve]
-
Vogt A, von Essen R, Tebbe U, Feuerer W, Appel KF,
Neuhaus KL. Impact of early perfusion status of the
infarct-related artery on short-term mortality after
thrombolysis for acute myocardial infarction:
retrospective analysis of four German multicenter
studies. J Am Coll Cardiol. 1993;21:1391-1395. [Abstract]
-
Karagounis L, Sorensen SG, Menlove RL, Moreno F,
Anderson JL, for the TEAM-2 Investigators. Does
thrombolysis in myocardial infarction (TIMI) perfusion
grade 2 represent a mostly patent artery or a mostly occluded
artery? Enzymatic and electrocardiographic evidence from the TEAM-2
study. J Am Coll Cardiol. 1992;19:1-10. [Abstract]
-
Anderson JL, Karagounis LA, Becker LC, Sorensen SG,
Menlove RL, for the TEAM-3 Investigators. TIMI perfusion grade 3 but
not grade 2 results in improved outcome after
thrombolysis for myocardial infarction:
ventriculographic, enzymatic, and electrocardiographic evidence from
the TEAM-3 study. Circulation. 1993;87:1829-1839.
[Abstract/Free Full Text]
-
Cannon CP, McCabe CH, Diver DJ, Herson S, Greene RM,
Shah PK, Sequeira RF, Leya F, Kirshenbaum JM, Magorien RD, Palmeri S,
Davis V, Gibson CM, Poole WK, Braunwald E, and the TIMI 4
Investigators. Comparison of front-loaded recombinant
tissue-type plasminogen activator,
anistreplase and combination thrombolytic therapy for
acute myocardial infarction: results of the Thrombolysis in
Myocardial Infarction (TIMI) 4 trial. J Am Coll
Cardiol. 1994;24:1602-1610. [Abstract]
-
Gibson CM, Sandor T, Stone PH, Pasternak RC, Rosner B,
Sacks FM. Quantitative angiographic and statistical methods to
assess serial changes in coronary luminal diameter and
implications for atherosclerosis regression
trials. Am J Cardiol. 1992;69:1286-1290.[Medline]
[Order article via Infotrieve]
-
Gibson CM, Cannon CP, Piana RN, Maher KA, Davis SF,
Breall JA, Davis V, Diver DJ, for the TIMI 4 Study Group. Relationship
of coronary flow to myocardial infarction size: two simple new
methods to sub-classify TIMI flow grades.
Circulation. 1992;86(suppl I):I-453. Abstract.
-
Dodge JT, Brown BG, Bolson EL, Dodge HT.
Intrathoracic spatial location of specified coronary segments
on the normal human heart: applications in quantitative arteriography,
assessment of regional risk and contraction, and anatomic
display. Circulation. 1988;78:1167-1180.
[Abstract/Free Full Text]
-
SAS/STAT Users Guide: Statistics (Version
6). 4th ed. Cary, NC: SAS Institutes Inc; 1990:851-889, 891-949,
1071-1092, 1195-1200, 1633-1636.
-
STATA Reference Manual. 4th ed. Santa
Monica, Calif: Computing Resource Center; 1989.
-
Vogel R, LeFree M, Bates E, O'Neill W, Foster R,
Kirlin P, Smith D, Pitt B. Application of digital techniques to
selective coronary arteriography: use of myocardial contrast
appearance time to measure coronary flow reserve.
Am Heart J. 1984;107:153-164. [Medline]
[Order article via Infotrieve]
-
Hodgson JM, LeGrand V, Bates ER, Mancini GBJ, Aueron
FM, O'Neill WW, Simon SB, Beauman GJ, LeFree MT, Vogel RA.
Validation in dogs of a rapid digital angiographic technique to measure
relative coronary blood flow during routine cardiac
catheterization. Am J Cardiol. 1985;55:188-193. [Medline]
[Order article via Infotrieve]
-
Uren NG, Crake T, Lefroy DC, DeSilva R, Davies GJ,
Maseri A. Reduced coronary vasodilator function in
infarcted and normal myocardium after myocardial
infarction. N Engl J Med. 1994;331:222-227.
[Abstract/Free Full Text]
-
Cannon CP, Braunwald E. GUSTO, TIMI and the case
for rapid reperfusion. Acta Cardiol. 1994;49:1-8. [Medline]
[Order article via Infotrieve]
-
Ordoubadi FF, Huehns TY, Mohammad AA, Beatt KJ.
TIMI grade 2 flow is not equivalent to TIMI 3: implications for the use
of thrombolytic therapy—a
meta-analysis of the trials. J Am
Coll Cardiol. 1995;(suppl):401A. Abstract.
-
Seiler C, Kirkeeide RL, Gould KL. Measurement
from arteriograms of regional myocardial bed size distal to any point
in the coronary vascular tree for assessing anatomic area at
risk. J Am Coll Cardiol. 1993;21:783-797. [Abstract]
-
Kloner RA, Ganote CE, Jennings RB. The
no-reflow phenomenon after temporary coronary occlusion in
the dog. J Clin Invest. 1974;54:1496-1508.
-
Kloner RA, Alker KJ. The effect of streptokinase
on intramyocardial hemorrhage, infarct size, and the
no-reflow phenomenon during coronary reperfusion.
Circulation. 1984;70:513-521.
[Abstract/Free Full Text]
-
Ito H, Tomooka T, Sakai N, Yu H, Higashino Y, Fujii K,
Masuyama T, Kitabatake A, Minamino T. Lack of myocardial
perfusion immediately after successful thrombolysis: a
predictor of poor recovery of left ventricular function in
anterior myocardial infarction.
Circulation. 1992;85:1699-1705.
[Abstract/Free Full Text]
-
Taniyama Y, Ito H, Iwakura K, Takiuchi S, Maruyama A,
Fujii K. Effects of intracoronary injection of
verapamil and nicorandil on microcirculation and left
ventricular function in patients with reperfused
myocardial infarction. Circulation.
1995;92(suppl I):I-77. Abstract.
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