CLINICAL STUDY: ACUTE CORONARY SYNDROMES
Two different coronary blood flow velocity patterns in thrombolysis in myocardial infarction flow grade 2 in acute myocardial infarction
Insight into mechanisms of microvascular dysfunction
Koichi Yamamoto, MD*,
Hiroshi Ito, MD, FACC*,*,
Katsuomi Iwakura, MD*,
Shigeo Kawano, MD*,
Masashi Ikushima, MD*,
Tohru Masuyama, MD, FACC ,
Toshio Ogihara, MD and
Kenshi Fujii, MD*
* Division of Cardiology, Sakurabashi Watanabe Hospital, Osaka, Japan
Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, Osaka, Japan
Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
Manuscript received April 12, 2002;
revised manuscript received June 14, 2002,
accepted July 17, 2002.
* Reprint requests and correspondence: Dr. Hiroshi Ito, Division of Cardiology, Sakurabashi Watanabe Hospital, 2-4-32 Umeda, Kita-ku, Osaka 530-0001, Japan.
itomd{at}osk4.3web.ne.jp
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Abstract
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OBJECTIVES: We sought to determine which of the two main potential mechanisms underlying Thrombolysis In Myocardial Infarction flow grade 2 (TIMI-2 flow) operate in an individual patient who has had an acute myocardial infarction (AMI).
BACKGROUND: Systolic flow reversal (SFR) is a specific finding of capillary damage, the no-reflow phenomenon. The coronary blood flow velocity (CBFV) pattern of thromboemboli, however, remains unknown.
METHODS: Data on 105 patients with AMI (57 with anterior and 48 with nonanterior cases) who underwent a coronary intervention were analyzed. The CBFV was recorded by a Doppler guide wire, and tissue perfusion was assessed with myocardial contrast echocardiography (MCE).
RESULTS: Study patients were classified into three groups according to TIMI grade and the presence or absence of SFR: 1) TIMI-3 flow (n = 80); 2) TIMI-2 flow with SFR (SFR[+], n = 14); and 3) TIMI-2 flow without SFR (SFR[-], n = 11). Diastolic CBFV was the lowest in SFR(-) (TIMI-3 vs. SFR[+] vs. SFR[-]: 34 vs. 31 vs. 9 cm/s), and the systolic to diastolic CBFV ratio was also the highest in SFR(-) (0.43 vs. –0.18 vs. 0.66). The no-reflow phenomenon documented by MCE was found in all patients in the SFR(+) group, but in only one patient (10%) in the SFR(-) group. Intracoronary thrombus was more frequently found in SFR(-) than in SFR(+) (91% vs. 14%, p < 0.05).
CONCLUSIONS: At least two different CBFV patterns are noted in patients with reperfused AMI who have TIMI-2 flow. Capillary damage is mostly responsible for SFR(+), and SFR(-) is seen in thromboemboli possibly due to increased coronary arterial resistance.
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Abbreviations and Acronyms
| | AMI | | acute myocardial infarction | | APV | | average peak velocity | | CBFV | | coronary blood flow velocity | | ICT | | intracoronary thrombus | | MCE | | myocardial contrast echocardiography | | PCI | | percutaneous coronary intervention | | SFR | | systolic flow reversal | | TIMI | | Thrombolysis In Myocardial Infarction | | TIMI-2/3 flow | | Thrombolysis In Myocardial Infarction flow grade 2/3 |
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The patency of the infarct-related artery does not necessarily guarantee the success of perfusion at the microvascular level in patients with an acute myocardial infarction (AMI) (1). The success of reperfusion therapy is usually evaluated clinically by the Thrombolysis In Myocardial Infarction (TIMI) flow grade, and a higher grade has been associated with the better clinical and functional outcomes (2,3).
Although percutaneous coronary intervention (PCI) can reduce the residual stenosis or prevent dissection as a cause of TIMI flow grade 2 (TIMI-2 flow), TIMI-2 flow after PCI can still be observed. Our previous study using myocardial contrast echocardiography (MCE) demonstrated that the no-reflow phenomenon, which implies a lack of tissue perfusion due to capillary damage, is a cause of TIMI-2 flow in patients with an anterior AMI (4). This flow pattern has typical coronary blood flow velocity (CBFV) characteristics, such as systolic flow reversal (SFR) followed by forward diastolic flow with a rapid deceleration slope (5–7). However, it remains unknown whether this pattern is consistently observed in all patients with TIMI-2 flow.
Percutaneous coronary intervention may cause microembolization of small arteries or arterioles, and this impairs coronary blood flow and regional contractile function in the absence of an atherosclerotic obstruction of an epicardial coronary artery (8–13). In this instance, coronary arterial resistance increases, and the CBFV pattern should be different from that of capillary damage. In this study, we hypothesized that an increase in coronary arterial resistance should be associated with slow forward flow, with relative augmentation of systolic flow, which is typically seen in epicardial coronary stenosis.
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Methods
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Study population.
A total of 117 consecutive patients with AMI who met the following criteria were prospectively enrolled: 1) chest pain lasting >30 min and presenting within 24 h after symptom onset; 2) ST-segment elevation  2 mm in at least two contiguous electrocardiographic leads; 3) more than a threefold increase in serum creatine kinase; 4) TIMI flow grade 0 or 1 of the infarct-related artery on the baseline angiogram; and 5) successful coronary recanalization (residual diameter stenosis <25%) after PCI. Twelve patients were excluded because of severe congestive heart failure (n = 5), an incomplete Doppler study (n = 4), recurrent infarction during follow-up (n = 2), and previous coronary artery bypass graft surgery (n = 1). Thus, data from 105 patients were analyzed. The study protocol was approved by the ethics committee of our hospital, and written, informed consent was obtained from all patients before cardiac catheterization by an investigator.
Protocols
Aspirin (243 mg) was administrated to all patients before PCI. After administration of heparin (100 U/kg), coronary angiography and left ventriculography were performed. Percutaneous coronary intervention was performed using a Doppler guidewire. If TIMI-2 flow was persistent after balloon angioplasty, we performed stenting or intravascular ultrasonography to make sure that there was no dissection or residual stenosis as a cause of TIMI-2 flow. We graded TIMI flow by assessing the final coronary angiogram after intracoronary administration of nitroglycerin (0.3 mg).
The tip of the Doppler guidewire was positioned distal to either the second diagonal branch of the left anterior descending coronary artery or the obtuse marginal branch of the left circumflex artery or in the atrioventricular branch of the right coronary artery (7,14). After optimization of the Doppler signal, CBFV was continuously recorded. Myocardial contrast echocardiography was then performed using intracoronary injection of microbubbles, as previously described (1,15,16). Coronary angiography and left ventriculography were repeated one month after PCI.
Analysis of the CBFV pattern
The CBFV spectrum, recorded at a mean of 10 min after the final balloon inflation, was analyzed (5). The following parameters were calculated from the CBFV waveform: the time average of peak CBFV (average peak velocity [APV], cm/s), systolic and diastolic peak velocities, and deceleration time of the diastolic velocity (ms). We also calculated the time-velocity integral of CBFV and the effective coronary flow volume (ml/min). The latter was determined as a product of the time-velocity integral, heart rate, and cross-sectional area of the coronary artery, with 0.5 used as a constant to correct for the parabolic nature of the blood flow velocity profile within the vessel. The cross-sectional area was calculated at 5 mm distal to the tip of the Doppler guide wire, with the use of a validated edge-detection program (Cardiovascular Measurement System, Medis Medical Imaging System, Leiden, the Netherlands). If SFR was present, the time-velocity integral of reversed flow was subtracted from the forward CBFV integral. These parameters were calculated by averaging five continuous cardiac cycles.
Evaluation of angiographic data
The presence of intracoronary thrombus (ICT) was demonstrated on the coronary angiograms before PCI. Previously defined criteria, including filling defects, contrast staining, haziness, and overhanging shoulders at the culprit lesion (17–19) were employed. The grade of TIMI flow was evaluated after the final PCI procedure, and the corrected TIMI frame count was assessed (20,21). Left ventricular volume and ejection fraction were measured from the biplane left ventriculograms using the area-length method, and these two variables were corrected for body surface area. Regional wall motion (standard deviation/chord) within the infarct zone was calculated using the centerline method. The diameter of the reference vessel and the minimal lumen diameter of the culprit lesion were determined using quantitative angiography (Cardiovascular Measurement System, Medis Medical Imaging System), and residual percent diameter stenosis was calculated. Collateral channels were graded using Rentrop’s classification (22). All measurements were performed by an independent observer in a blinded manner.
Assessment of myocardial perfusion
An experienced echocardiographer analyzed the MCE images independently to determine the presence or absence of the no-reflow phenomenon (1,15,16), which was determined to be present when the endocardial length of the contrast defect exceeded a quarter of that of the risk area.
Statistical methods
Continuously distributed variables were expressed as the mean value ± SD. One-way analysis of variance and the Fisher post-hoc test were used to compare continuous variables, and the chi-square test was used to compare categorical variables. Multiple logistic regression analysis was performed to identify independent factors that were related to TIMI-2 flow without SFR. A p value of <0.05 was considered statistically significant (two-sided).
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Results
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Patterns of CBFV with TIMI-2 flow.
Of 105 patients, 24 (23%) had TIMI-2 flow after PCI. Figure 1 shows the two typical predominant CBFV patterns in these patients. One pattern shows SFR followed by rapid diastolic flow with a steep deceleration slope, and the other pattern is characterized by slow anterograde systolic and diastolic flow velocity waveforms. Thus, we classified the study patients into three subgroups based on TIMI flow grade and the presence or absence of SFR: 1) TIMI flow grade 3 (TIMI-3, n = 80); 2) TIMI-2 flow with SFR (SFR[+], n = 14); and 3) TIMI-2 flow without SFR (SFR[-], n = 11).
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Figure 1 Coronary blood flow velocity patterns in patients with reperfused acute myocardial infarction with Thrombolysis In Myocardial Infarction flow grade 2 (TIMI-2 flow). These two patients showed TIMI-2 flow after a successful coronary intervention. (Left) Systolic flow reversal (SFR) is observed in systolic followed by rapid diastolic flow, with a steep deceleration slope. (Right) SRF is not observed. Very slow anterograde flow was found throughout one cardiac cycle. Diastolic flow deceleration was gentle.
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Thirteen (93%) of 14 patients with SFR(+) had an anterior myocardial infarction. In contrast, 8 (72%) of 11 patients with SFR(-) had an inferior myocardial infarction (Table 1). There was no difference in the other baseline characteristics among the three subgroups. All patients showed a patent infarct-related artery at 28 days, with a coronary diameter stenosis that was similar to that after PCI. Stent deployment was more frequent in the SFR(-) group, but the difference did not reach statistical significance. The corrected TIMI frame count was the lowest in the TIMI-3 group at day 1, but it was comparable at day 28 among the three subgroups. Heart rate and pulmonary capillary wedge pressure were the highest in the SFR(+) group.
Variables of CBFV
The APV was the highest in the TIMI-3 group and was comparable between the SFR(+) and SFR(-) groups (Fig. 2). Systolic APV was lower in the SFR(+) group, whereas diastolic APV was lower in the SFR(-) group (Table 2). The systolic to diastolic APV ratio was the highest in the SFR(-) group, followed by the TIMI-3 group, and then the SFR(+) group. The diastolic deceleration time was the shortest in the SFR(+) group, and it was the longest in the SFR(-) group. Systolic flow reversal was observed in 10 patients with TIMI-3 flow, but their APV was higher than that in the SFR(+) group (25.7 ± 8.5 cm/min vs. 13.8 ± 7.1 cm/min, p < 0.05). A similar comparison of CBFV and hemodynamic variables among the patients with an inferior AMI is illustrated in Table 3. The APV was also lower and the systolic to diastolic APV ratio was higher in the SFR(-) group than in the TIMI-3 group. The time-velocity integral of CBFV and effective coronary flow volume were higher in the TIMI-3 group than in the SFR(+) and SFR(-) groups, and these variables were comparable between SFR(+) and SFR(-). Aortic pressure and right arterial pressure were comparable among the three groups.
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Figure 2 Distribution of the average peak velocity (APV) among the three subgroups: Thrombolysis In Myocardial Infarction flow grade 2 (TIMI-2 flow) and TIMI-2 flow with systolic flow reversal (SFR)(+) and without SFR(-). The APV was highest in the TIMI-3 group and comparable between the SFR(+) and SFR(-) groups (25.5 ± 11.8 vs. 13.8 ± 7.1 vs. 7.1 ± 3.6 cm/s [mean ± SD]).
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Functional, morphologic, and clinical outcomes
Table 4 compares the functional and morphologic outcomes among the three groups. Peak creatine kinase was the highest in the SFR(+) group, followed by the SFR(-) group and the TIMI-3 group. Regional wall motion and left ventricular ejection fraction at 28 days were the lowest in the SFR(+) group. The magnitude of changes in regional wall motion between days 1 and 28 was the highest in the TIMI-3 group and was comparable for the SFR(+) and SFR(-) groups. The left ventricular end-diastolic or end-systolic volume index at 28 days was also the highest in the SFR(+) group. Congestive heart failure and malignant arrhythmia were most frequently observed in the SFR(+) group, implying that in-hospital clinical outcomes seem to be the worst in SFR(+).
Factors related to TIMI-2 flow without SFR
All 14 patients (100%) with SFR(+) showed the no-reflow phenomenon, and this frequency was significantly (p < 0.001) higher than that in those with TIMI-3 flow (6 [5%] of 80 patients) and in those with SFR(-) (1 [9%] of 11 patients). Before PCI, ICT was most frequently (p < 0.01 vs. other groups) observed in the SFR(-) group (10 [91%] of 11 patients), compared with the TIMI-3 group (27 [34%] of 80 patients) and SFR(-) group (2 [14%] of 14 patients). Multiple logistic regression analysis using age, gender, heart rate, pulmonary capillary wedge pressure, mean aortic pressure, collateral grade, infarct-related artery, history of pre-AMI angina, ICT, reference vessel diameter, and interval from onset to reperfusion showed that ICT was the only independent predictor of SFR(-) (p < 0.05).
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Discussion
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The new finding of this study is that there are at least two different CBFV patterns in patients with TIMI-2 flow: SFR(+) associated with the no-reflow phenomenon and SFR(-) associated with a thrombus burden. As expected, both patterns were associated with worse functional and clinical outcomes, as compared with TIMI-3 flow, and patients with SFR(+), in particular, showed poor outcomes. Slow forward flow seen in the SFR(-) group is associated with the highest systolic to diastolic velocity ratio, implying an increase in arterial resistance, possibly associated with an increased thrombus burden.
Thrombus burden as a cause of TIMI-2 flow.
A potential problem in the treatment of AMI is a possibility of distal embolization, which may be even more important during catheter-based treatment (11–13). The consequences of coronary embolism depend on the size (and number) of emboli. The smaller the embolus, the greater the chance that it will migrate distally to a small artery and the less likelihood of myocardial necrosis. For particle sizes ranging from 15 to 45 µm, baseline blood flow into the embolized area may actually increase secondary to reactive hyperemia in the myocardium surrounding the embolized regions (23). Conversely, the larger the embolic particle, the greater the chance that it will lodge proximally in a large coronary artery and result in ischemic myocardial necrosis. Coronary arterial resistance increases if massive embolization of the coronary arterial bed occurs. Recently, Gregorini et al. (24) reported that coronary intervention might also cause neurohormonal reflexes and vasoconstriction, thus provoking a reduction in CBFV in patients with AMI. If coronary resistance could play an important role, it is likely that an increase in coronary resistance might even abate over time and, therefore, might possibly manifest as a transient phenomenon.
An increase in coronary arterial resistance lowers CBFV throughout the cardiac cycle, with relative augmentation of systolic flow velocity in patients with SFR(-). The ratio of systolic to diastolic APV in this group was the highest among the three subgroups studied. In contrast, the frequency of the no-reflow phenomenon is much lower in the SFR(-) group than in the SFR(+) group, implying the relatively preserved capillary function in the former. Because of preservation of capillary perfusion, the functional outcome was better in the SFR(-) group than in the SFR(+) group, perhaps because of ultimate dissolution of the microthrombi.
The CBFV pattern of the right coronary artery is different from that of the left coronary artery and is characterized by the relative dominance of systolic flow. We compared CBFV variables among the patients with an inferior AMI. The SFR(-) group was quite different from the TIMI-3 group. Also, ICT was more frequently observed in the right coronary artery (19 [29%] vs. 19 [49%], p = 0.07), and SFR(-) was most commonly seen in the right coronary artery. However, multivariate analysis did not determine the type of infarct-related artery (right or left) as an independent predictor of SFR(-).
Capillary damage as a cause of TIMI-2 flow
Gibsons et al. (25) indicated that SFR was a powerful multivariate predictor of slow flow, along with residual stenosis and anterior AMI. It is well known that SFR is a sensitive and specific finding (91% and 97%, respectively) of the no-reflow phenomenon (5), and that it is a result of increased capillary resistance. The increase in capillary resistance in the area of the no-reflow phenomenon is explained by interstitial and myocardial cell edema, endothelial blistering, and/or microvascular spasm and plugging of capillaries by erythrocytes or leukocytes. In patients with the no-reflow phenomenon, myocardial blood is not smoothly squeezed into the venous circulation in systole because of the diffuse obstruction of capillaries; thus, it may be pushed back to the coronary artery to produce SFR.
A rapid deceleration of diastolic CBFV is another characteristic of capillary damage. The intramyocardial blood volume decreases with damage to the capillaries and/or postcapillary venules. If the coronary inflow exceeds the capacitance, an impeding effect occurs on the diastolic coronary inflow by altering perivascular strains, resulting in a rapid decrease in CBFV. This finding is also supported by recent findings that a shorter diastolic deceleration time is associated with poorer tissue perfusion and worse functional outcomes (7). Indeed, SFR(+) showed the shortest diastolic deceleration time among the three subgroups. Because 58% of the TIMI-2 group had SFR(+), the capillary (and postcapillary venule) damage should still be a main cause of TIMI-2 flow.
Study limitations
Several potential limitations need to be addressed. First, our findings are derived from a selected population of patients with AMI who were successfully treated with primary PCI. Patients in shock and those with hemodynamic instability or recurrent AMI were excluded from the study, because CBFV data were difficult to obtain. Coronary stenosis was assessed by quantitative angiography. Intracoronary thrombus on the culprit lesion makes it more difficult to correctly estimate the degree of stenosis. We used intravascular ultrasound to rule out the presence of residual stenosis, when required.
We documented that slow flow is associated with ICT, but we cannot conclude that a thrombus burden is the sole cause of TIMI-2 flow in these cases. However, we can state that an increase in coronary arterial resistance can be a cause of TIMI-2 flow in the SFR(-) group, as there was no difference in aortic and right arterial pressures between the SFR(-) and TIMI-3 groups.
Clinical implications
A differentiation between these two types of TIMI-2 flow using Doppler flow velocity measurements may facilitate decisions regarding additional interventions in patients with AMI after successful PCI. Myocardial contrast echocardiography provides the ultimate information on the grade and spatial extent of capillary obstruction in the individual patient. Use of improved antiplatelet therapy and, ultimately, the application of emboli entrapment devices in cases of TIMI-2 flow without SFR may be considered. In contrast, extensive capillary damage in the area of myocardial necrosis is a main cause of TIMI-2 flow in cases of SFR(+). In these patients, antiplatelet therapy and/or emboli entrapment devices may be of little value.
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Abstract
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