Reperfusion therapy has improved survival in acute myocardial infarction (AMI), and the survival benefit is strongly dependent on time to reperfusion in thrombolytic trials (1- 4). However, early reperfusion does not guarantee the recovery in left ventricular (LV) function in clinical trials (5- 8). In addition, recent data suggest that the outcomes of patients after primary angioplasty may be equally favorable with early or late treatment, and the duration of coronary occlusion may be less important for survival after primary angioplasty than after thrombolytic therapy (9). Therefore, factors that are independent on time to reperfusion in AMI deserve to be investigated for the understanding of general mechanisms of reperfusion benefit.

The coronary collateral circulation is an alternative source of blood supply to a myocardium jeopardized by abruptly occluded vessels, preventing myocardial death and favoring myocardial recovery after reperfusion therapy. However, the functional significance of collateral circulation in AMI has been a matter of debate for many years (10- 14). The reasons for this controversy may be related to the difficulty in assessing the collateral circulation. Coronary angiography, the most commonly used technique for studying collateral circulation, may not be accurate in assessing collateral circulation because most collaterals are too small to visualize angiographically (15). Intracoronary pressure measurement is a new technique to provide accurate and quantitative information about the collateral circulation (16- 19), and it can be easily applied during the coronary intervention.

We therefore hypothesized that 1) pressure-derived fractional collateral flow (PDCF) is a primary determinant of LV recovery after reperfused AMI, and 2) LV recovery is relatively independent on time to reperfusion in patients with sufficient collaterals. To test this hypothesis, we performed a time-course analysis of functional recovery of regional LV function and its determinants in patients with first AMI treated with primary angioplasty.

We prospectively studied 76 patients with first AMI referred to Asan Medical Center for emergency primary angioplasty between October 1997 and March 1999 and who met the following criteria: 1) chest pain >30 min in duration and presentation within 12 h after the onset of symptoms; 2) ST-segment elevation >0.1 mV in two contiguous electrocardiographic leads; 3) total occlusion of the infarct-related artery; and 4) successful primary angioplasty (defined as Thrombolysis in Myocardial Infarction [TIMI] flow grade 3 and residual diameter stenosis <30%). Exclusion criteria included the presence of cardiogenic shock, severe heart failure, previous bypass surgery, atrial fibrillation, ischemic events during the follow-up, valvular heart disease, inadequate quality of echocardiographic image, and life-limiting noncardiac disease. Of the 76 patients, 6 were excluded because of inadequate quality of echocardiographic images (n = 1), cardiogenic shock (n = 1), severe heart failure (n = 1), inability to adhere to follow-up (n = 1), or reinfarction during the follow-up (n = 2). Thus, 70 patients were enrolled in the study. All patients received conventional drug therapy in accordance with standard clinical practice. Written informed consent was obtained from all patients, and the study protocol was approved by our institutional review board.

Left and right coronary angiography was performed in all patients, and then primary angioplasty was performed according to the study protocol at our institution. A 0.014-in. (0.036 cm) fiber optic pressure monitoring guide wire (RADI Medical Systems, Uppsala, Sweden) was set at 0, calibrated, advanced through the guiding catheter and positioned distal to the occlusion site to be dilated; balloon inflation at the occlusion site was performed to measure the collateral flow. Pressure-derived fractional collateral flow (PDCF) was determined by simultaneous measurement of aortic pressure (Pao, mm Hg, obtained from the guiding catheter), the distal coronary pressure during the balloon occlusion (Pocc, mm Hg), and central venous pressure (CVP, mm Hg): PDCF index = (Pocc − CVP)/(Pao − CVP)∗100. Angiographic collateral vessels (0 to 3) were graded according to Rentrop’s classification (20).

All patients underwent complete echocardiographic examination with HP 2500 (Hewlett-Packard, Andover, Massachusetts) before primary angioplasty, and on day 3, day 7, and day 30 after primary angioplasty. Images were recorded on videotape by a S-VHS cassette recorder for analysis.

Two investigators unaware of clinical, collateral and angiographic data analyzed the echocardiograms, and discrepancies were resolved by consensus. Echocardiographic images were transferred to the hard disk of a TomTec Imaging System (TomTec, Unterschleissheim, Germany) to obtain quantitative data. The LV end-systolic and end-diastolic volumes were calculated by computer software according to a modified Simpson’s rule. Three measurements of the technically best cardiac cycles, avoiding postectopic beats, were taken from each examination, and the average volumes were obtained. The volume indexes were obtained by dividing the volume by the body surface area at each time point. The LV ejection fraction was calculated as stroke volume/end-diastolic volume.

Regional wall motion was assessed according to a 16-segment model. For each segment, wall motion was scored as 1 (normal), 2 (hypokinetic), 3 (akinetic) or 4 (dyskinetic). In evaluating regional wall-motion abnormality, attention was paid to the systolic thickening in the central portion of each segment. In each patient, both global and infarct-zone wall-motion score indexes were derived. Wall-motion recovery index was defined as improved wall motion at follow-up compared with the baseline study, being obtained by dividing the number of improved wall-motion segment (a reduction in segmental score of at least one grade) at follow-up by the number of abnormal wall-motion segments within the infarct zone at baseline.

Two experienced angiographers unaware of the study purpose analyzed the infarct-related artery using an on-line quantitative coronary angiography system (ANCOR V2.0, Siemens, Germany). Contrast flow through the epicardial vessel was graded using the standard TIMI flow grade of 0 to 3 (21).

Sufficient collateral was defined as PDCF index >24%, as described previously (16). Time to reperfusion was measured as the time from the onset of symptoms until coronary reperfusion was established with balloon inflation. The impact of preinfarction angina on wall-motion recovery was evaluated based on the presence or absence of antecedent angina within 24 h before the onset of AMI (22). Cardiac enzyme (creatine kinase, creatine kinase-MB) was serially measured at 4-h intervals up to 24 h and later at 8-h intervals up to 72 h after intervention, and the maximum level was used as an enzymatic marker of infarct size.

Interobserver reproducibility was checked by selecting 10 random study echocardiograms for reinterpretation by a second investigator. Intraobserver variability was also assessed by having the initial investigator reanalyze 10 randomly selected echocardiograms on a different occasion. The agreement was good for measurements of wall-motion score index (interobserver variability: r = 0.93, p < 0.01; intraobserver variability: r = 0.95, p < 0.01). Interobserver and intraobserver variability values in the evaluation of end-systolic and end-diastolic volumes were <5%.

Statistical analysis was performed using SPSS 7.5 for Windows. Data were expressed as mean ± SD for continuous variables and frequencies for the categorical variables. Continuous variables were compared by unpaired Student t test, and categorical variables by chi-square test. The comparisons between the two patient groups over time were done with a two-way repeated-measures analysis of variance (ANOVA). Linear regression analysis was performed on all variables to identify determinants of wall-motion recovery index, and variables found to be p < 0.1 by univariate analysis were entered into a stepwise multiple linear regression analysis to determine their independent relationship to wall-motion recovery index. A p value <0.05 was considered statistically significant.

The study population was divided into two groups according to the PDCF index: group I (PDCF index >24%, n = 30) and group II (PDCF index ≤24%, n = 40). As shown in (Table le1) and (Table le2), there were no significant differences between the two groups with respect to age, gender, risk factors, time to reperfusion, echocardiographic variables, and angiographic characteristics. However, patients in group II had higher peak levels of creatine kinase than did those in group I (4,100 ± 3,000 U/liter vs. 2,600 ± 1,900, respectively, p < 0.05).

Angiographic collateral grade was significantly related to PDCF index (r = 0.33, p < 0.05, Figure 1). However, a wide range of the PDCF index was observed in patients with angiographic collaterals < grade 1 (Figure 1). A significant correlation was also found between peak levels of creatine kinase and PDCF index (r = −0.38, p < 0.01, Figure 2).

(Figure 3) shows a significant progressive improvement in regional contractile function (wall-motion score index and recovery index) within the infarct zone in both groups. However, regional contractile function was more rapidly and greatly recovered in group I than in group II (p < 0.01 for the difference in the linear component of the group-by-time interaction). At baseline, LV ejection fraction (49.5 ± 6.6% vs. 48.4 ± 6.6, respectively, p = NS), LV end-systolic volume index (26.7 ± 6.9 ml/m² vs. 26.4 ± 9.5, p = NS), and LV end-diastolic volume index (52.8 ± 11.2 ml/m² vs. 51.2 ± 13.9, p = NS) were similar between the two groups. At one-month follow-up, LV ejection fraction was significantly higher in group I than in group II (52.8 ± 8.3 vs. 46.0 ± 9.0, respectively, p < 0.01). However, LV end-systolic volume index (27.4 ± 7.2 ml/m² vs. 35.8 ± 13.1, respectively, p < 0.01) and LV end-diastolic volume index (58.0 ± 10.6 ml/m² vs. 65.6 ± 18.0, respectively, p < 0.05) were smaller in group I than in group II.

To evaluate the predictors of infarct zone wall-motion recovery index at one-month follow-up, clinical, hemodynamic and angiographic factors were analyzed by regression analysis (Table le3). Wall-motion recovery index at one month was significantly associated with PDCF index (r = 0.61, p < 0.01, Figure 4), angiographic collaterals (r = 0.26, p < 0.05) and LV ejection fraction before reperfusion (r = 0.33, p < 0.01). However, the PDCF index was the only independent predictor of wall-motion recovery index at one month by multiple regression analysis. Time to reperfusion or the presence of preinfarction angina was not associated with wall-motion recovery index at one month (Figures le3, 4), whereas in group II time to reperfusion was significantly related to wall-motion recovery index at one month (r = −0.34, p < 0.05, Figure 4).

The major findings of this study are that 1) PDCF index is the most powerful predictor of LV recovery after successfully reperfused AMI, and 2) time to reperfusion is less important for recovery of LV function in patients with sufficient collaterals. These findings may provide a physiologic basis for the understanding of the time-“less dependent” beneficial effects of primary angioplasty on mortality (9). Furthermore, this study demonstrates that the PDCF index is more accurate than angiographic collaterals in assessing the functional significance of the collateral circulation in AMI.

After occlusion of a major coronary artery, the only blood flow to the ischemic myocardium arrives via coronary collaterals. In experimental animals, collateral blood flow is a major determinant of the extent of necrosis after coronary artery occlusion (23- 24). However, the role of the collateral circulation in humans remains speculative (10- 14). Some studies suggest that collateral channels do not reduce the infarct size (10- 12), and others indicate that coronary collateral can mitigate the myocardial necrosis in AMI (13- 14). The controversy may stem from limitation of previous clinical studies, including use of angiographic collaterals and delay in the assessment of collaterals after the onset of myocardial infarction. Unfortunately, angiographically visible collaterals represent only a fraction of the total collateral vessels because collaterals are angiographically demonstrable only when they reach 100 μm.

Moreover, angiography may not detect most collaterals situated intramurally, whereas intracoronary pressure measurements provide the opportunity to measure the contribution of total collateral flow in humans (16- 19), allowing quantitative assessment of collateral flow before reperfusion in AMI. Using this technique, the present study demonstrates that the PDCF index is a major determinant of LV recovery after successful primary angioplasty, which may in part explain the beneficial effects of late reperfusion in AMI. Furthermore, this study suggests that PDCF measurements can be used to predict LV recovery in patients undergoing catheterization for AMI.

In patients with angiographically robust collaterals, the correlation between angiographic collaterals and PDCF index was quite good, whereas in those with angiographically less visible collaterals there appears to be substantial scatter. The discrepancy between the angiographic collaterals and PDCF index in the latter patients remains uncertain. It is known that serotonin causes constriction of coronary artery vessels >90 μm in diameter, but dilation of arterioles <90 μm in diameter (25- 26). We therefore suppose that serotonin and thromboxane A₂ released by platelet activation may cause vasoconstriction of the epicardial collateral vessels, leading to angiographic underestimation of the collateral circulation in the very early phase of AMI (25- 28). This may be a plausible explanation, but further studies may be required to ascertain these issues.

Time to reperfusion has been of great interest ever since the advent of thrombolytic therapy. In experimental models, myocardial necrosis is time dependent, progressing a wave front from subendocardium to subepicardium, with complete necrosis after 6 h (29). These findings underlie the current clinical use of thrombolytic therapy. The time-related benefits of thrombolysis are well demonstrated by the randomized trials, showing a good correlation between reperfusion time and mortality (30). However, the reperfusion benefit does not appear to be translated into an LV function. This discrepancy between the impressive reduction in mortality and the relative lack of effect on LV function has been a source of debate (31). This paradox questions the traditionally accepted relationship among coronary artery patency, myocardial salvage, and LV function, leading to the hypothesis that patency is not equal to reperfusion (“illusion of reperfusion”) (32).

Primary angioplasty in AMI has been shown to result in lower rates of mortality, reinfarction, and stroke compared with thrombolysis, thus enhancing the quality of reperfusion therapy (33- 35). Interestingly, recent data from the PAMI trial (9) revealed that mortality and reinfarction are relatively constant with increasing time to reperfusion, suggesting that factors that are independent on time to reperfusion may be responsible for much of the survival benefit with primary angioplasty. In fact, a substantial number of patients with early reperfusion do not show reduction of the infarct size in the chronic phase. The results of the present study may in part account for a wide rage of clinical outcomes in patients with reperfused AMI.

The effect of preinfarction angina on LV function in AMI remains controversial (36- 39). Previous studies suggested that preinfarction angina was beneficial for event rate when the time between onset of angina and AMI was within 24 h. In our study, angina <24 h before AMI did not have a favorable effect on LV function (39). This does not necessarily mean that preinfarction angina is not effective in reducing infarct size. However, our results suggest that preinfarction angina seems to be of minor importance in limiting infarct size, as compared with collateral circulation.

Several potential limitations need to be addressed. First, 30-day follow-up angiogram was not obtained in this study, and therefore the possibility of silent reocclusion could not be excluded. Second, myocardial contrast echocardiography was not performed in this study, which is also an excellent tool to assess the collateral circulation. Therefore, we could not evaluate the relationship between the PDCF index and collaterals by myocardial contrast echocardiography. Third, our findings are derived from a select population of AMI patients who were successfully treated with primary angioplasty. In addition, patients with hemodynamic instability were excluded from the study because the PDCF index is difficult to obtain in this situation. Hence, our results may not be generalized to all patients receiving reperfusion therapy. Nevertheless, this study confirms the importance of collateral blood flow in AMI, and it reveals that time dependency in AMI may be changed by adequacy of collateral blood flow.

On the basis of our findings, we conclude that collateral blood flow, not detectable by angiography, may preserve the myocardium in acute phase of AMI, thus contributing to improvement in LV function after successful primary angioplasty.

We are indebted to Dong Soon Shin, RN, and Young-Hee Kim, RN, for their important contribution to data collection, and to Ho Jung Kim, CVT, for assistance in preparing coronary angiograms.