Author + information
- Received November 9, 1995
- Revision received May 10, 1996
- Accepted May 24, 1996
- Published online October 1, 1996.
- GIUSEPPE PIZZETTI,
- GIUSEPPINA BELOTTI,
- ALBERTO MARGONATO,
- ALBERTO CAPPELLETTI and
- SERGIO L CHIERCHIA*
- ↵*Address for correspondence: Dr. Sergio L. Chierchia, Department of Cardiology, IRCCS Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy.
Objectives. In a prospective study we evaluated whether late recanalization of the left anterior descending coronary artery (LAD) affects ventricular volume and function after anterior myocardial infarction.
Background. Persistent coronary occlusion after anterior myocardial infarction leads to ventricular dilation and heart failure.
Methods. We studied 73 consecutive patients with acute anterior myocardial infarction as a first cardiac event; all had an isolated lesion or occlusion of the proximal LAD. Six patients died before hospital discharge. The 67 survivors were classified into two groups: group I (patent LAD and good distal flow, n = 40) and group II (LAD occlusion or subocclusion, n = 27). The 20 patients in group I who had significant residual stenosis and all patients in group II underwent elective percutaneous transluminal coronary angioplasty (PTCA) within 18 days of myocardial infarction. The procedure was successful in 17 patients in group I (group IB) and in 16 patients in group II (group IIA): in the remaining 11 patients of group II, patency could not be reestablished (group IIB). Left ventricular volumes, ejection fraction and a dysfunction score were measured by echocardiography on admission, before PTCA, at discharge and after 3 and 6 months.
Results. Although cumulative ST segment elevation was similar in groups I and II, ejection fraction and dysfunction score were significantly worse in group II. However, ventricular function and volumes progressively improved in group IIA, whereas group IIB exhibited progressive deterioration of function (dysfunction score [mean ± SD] increased from 21 ± 6 to 25 ± 8, p < 0.05; ejection fraction decreased from 43 ± 10% to 37 ± 11%, p < 0.05); and end-systolic volume increased from 34 ± 10 to 72 ± 28 ml/m2, p < 0.05). Patients in group IIB also had worse effort tolerance, higher heart rate at rest, lower blood pressure and significantly greater prevalence of chronic heart failure.
Conclusions. Delayed PTCA of an occluded LAD can frequently restore vessel patency. Success appears to be associated with better ventricular function and a lack of chronic dilation. Large randomized studies are warranted to evaluate the effect of delayed PTCA on late mortality.
Several studies performed in patients with acute myocardial infarction [1, 2]have conclusively shown that contractile function consistently improves when early reperfusion is achieved by either thrombolysis or percutaneous transluminal coronary angioplasty (PTCA). Growing evidence [3, 4]also supports the idea that the contractility of significant amounts of hibernating myocardium may improve when adequate perfusion is reestablished by delayed revascularization.
More recent studies [5, 6]have also shown that residual anterograde perfusion to the infarct area prevents left ventricular expansion after acute myocardial infarction; in fact, late restoration of flow seems to beneficially affect left ventricular remodeling, both clinically and experimentally, independent of tissue viability [7, 8].
However, the hypothesis that a more delayed recanalization of an occluded infarct-related artery by coronary angioplasty may prevent ventricular dilation and remodeling and improve patients' functional status, has not been appropriately tested in humans. Assessment of this hypothesis would appear to be particularly important in patients with a large anterior myocardial infarction, a condition that is often associated with severe left ventricular dysfunction, aneurysm formation, progressive increase in ventricular volume and a high long-term mortality rate [9, 10].
In a carefully characterized group of consecutive patients presenting with a large anterior myocardial infarction as a first cardiac event, we performed elective PTCA within 3 weeks of initial presentation. Our results show that in patients with single-vessel disease and total or subtotal occlusion of the proximal left anterior descending coronary artery (LAD), vessel recanalization by elective PTCA prevents progressive left ventricular dilation and results in better exercise tolerance and functional capacity. The possible prognostic implications of our findings are discussed.
Patient selection. All patients admitted to our coronary care unit from November 1992 to December 1994 within 24 h of the onset of symptoms of acute myocardial infarction were eligible for inclusion if they met all the following criteria: 1) age ≤75 years; 2) anterior ST segment elevation ≥2 mm followed by significant cardiac enzyme release; 3) adequate echocardiographic visualization of the endocardial borders throughout the cardiac cycle; 4) lesion or obstruction of the proximal LAD before the first septal perforator; 5) no angio-graphically obvious lesions in the other epicardial vessels.
Patients were excluded if they had a history or electrocardiographic (ECG) evidence of a previous myocardial infarction, multivessel disease, significant valvular disease, left ventricular hypertrophy, atrial fibrillation, left bundle branch block or systemic illnesses that could potentially affect left ventricular function or 6-month survival rate.
Medications. All patients received intravenously administered nitrates titrated to the blood pressure response for 3 days after admission. Patients admitted within 6 h from the onset of symptoms and having no known contraindications received thrombolytic therapy with either recombinant tissue-type plasminogen activator (rt-PA) (100 mg) or streptokinase (1.5 million IU) followed by heparin (partial thromboplastin time ratio range 1.8 to 2.3). Anticoagulant therapy was continued for an average of 5 days (range 3 to 7) and gradually discontinued. Patients who did not receive thrombolytic therapy were given only intravenous heparin; all received oral aspirin, 325 mg daily, unless contraindicated. Patients with an ejection fraction <50% or with signs or symptoms of chronic heart failure received angiotensin-converting enzyme (ACE) inhibitors (56%) and furosemide (21%). During follow-up, four patients had to discontinue ACE inhibitors because of symptomatic orthostatic hypotension. Long-term treatment with other cardioactive agents (nitrates, calcium channel blocking agents, beta-adrenergic blocking agents) was left to the discretion of the attending cardiologist.
Noninvasive assessment of coronary reperfusion. Blood samples were collected every 4 h for cardiac enzyme determination. The peak of the creatine kinase release curve was considered to have occurred early when observed within 12 h from the onset of symptoms. A 16-lead ECG (standard limb and precordial leads plus V3R, V4R, V7 and V8) was obtained on admission and at 2, 6 and 12 h after admission; additional ECGs were recorded during and after thrombolytic therapy and whenever appropriate. Reperfusion was defined as the occurrence of an early creatine kinase peak in association with a 50% reduction of ST segment elevation after thrombolysis.
Subgroup classification. On the basis of angiographic findings, patients were classified into two groups (Fig. 1): Group I, patients with a patent LAD and Thrombolysis in Myocardial Infarction (TIMI) grade II or III flow; group II, patients with total or subtotal (>90%) occlusion and TIMI grade 0 or I flow, with or without retrograde perfusion by way of collateral channels. Patients of both groups were further classified into subgroups A and B depending on whether or not they had significant residual stenosis (group I) or whether or not they had undergone successful recanalization by PTCA (group II).
Echocardiography. All patients underwent two-dimensional echocardiography on admission, at discharge (mean 21 ± 2 days from admission, range 18 to 23), and at 3 and 6 months discharge. Patients undergoing PTCA also underwent echocardiography before the procedure.
A phased array electronic ultrasound system (SONOS 500, Hewlett-Packard), equipped with 2- and 2.5-MHz probes was used, and gain settings were adjusted to optimize the definition of endocardial borders. Images were recorded on video tape, and end-diastolic and end-systolic frames were selected from the three standard apical views. End-diastolic and end-systolic volumes were calculated by the biplane area-length method [11, 12]. Measurements were obtained in duplicate from each view and averaged and corrected for body surface area to be expressed as volume indexes. Left ventricular systolic frames were obtained from the parasternal short-axis view at the level of the papillary muscles and from the apical four-chamber, two-chamber and long-axis views, and digitized. Image acquisition was triggered by the R wave. The computer (PRE-VUE III, Nova Microsonics-ATL) was programmed to capture eight sequential frames, at 50-ms intervals, throughout the entire systolic phase. Data were acquired from all image planes in a digital cine loop format, stored on a floppy disk and reviewed on the dedicated review station (REVUE TM, Nova Microsonics-ATL). For each single view, the four echocardiographic examinations obtained in the individual patients were played back on a quad-display. The slow motion or frame by frame review mode was used as required.
Regional wall motion was assessed in 18 left ventricular segments by two independent observers unaware of patient identity or clinical data. A score (0 = normal, 1 = hypokinetic, 2 = akinetic, and 3 = dyskinetic) was given to each segment, and a global score was obtained by adding individual segment scores. There was <10% interobserver and intraobserver variation in left ventricular volume measurements and dysfunction scores. Therefore, for both volumes and dysfunction score, changes ≥20% were considered significant.
Coronary angiography. All patients with anterior myocardial infarction underwent cardiac catheterization within 2 weeks (mean 10 ± 3 days) of admission. Left ventriculography and selective coronary angiography were performed by the Judkins technique. The left and right coronary arteries were imaged in multiple views including craniocaudal angulations. To minimize the potential effect of coronary vasoconstriction, contrast injections were also performed after intracoronary administration of nitroglycerin (200 μg). Anterograde perfusion of the infarct-related vessel was graded by TIMI criteria , and retrograde collateral flow was scored according to the classification of Rentrop et al. . The presence of grade 2 or 3 collateral flow was considered significant.
Quantitative assessment of coronary stenoses was performed after selection of the projection demonstrating maximal lesion severity; care was taken to avoid overlap of adjacent branches. Maximal percent stenosis was calculated by using a validated automatic contour detection technique in two orthogonal views by using the angiographic catheter as a scaling device . Stenosis severity was expressed as percent of the mean diameter of angiographically normal segments proximal and distal to the lesion. Values were calculated as the mean of three separate determinations obtained by two independent experienced cardiologists unaware of patient identity or study design. Residual stenosis diameter after PTCA was determined in a similar fashion. Within-patient interobserver variability was <10%.
PTCA. PTCA was performed with standard techniques in patients with significant residual stenosis (≥50%) or occlusion of the LAD within 18 days (mean 15 ± 1) of admission. PTCA was considered successful when residual stenosis was <30% with grade III TIMI flow and no major complications (death, acute myocardial infarction or emergency bypass surgery) .
Follow-up. All patients underwent repeat echocardiography 3 and 6 months after discharge. Occurrence of cardiovascular events such as chronic heart failure, postinfarction angina, reinfarction and death was also recorded during the follow-up period. On the 6-month visit, 46 patients also underwent a maximal exercise stress test with use of the modified Bruce protocol. The test was performed after a 3-day washout period of all cardioactive medications. To assess the occurrence of restenosis, those patients who underwent PTCA underwent repeat angiography 6 months after PTCA.
Statistical analysis. Variables are expressed as mean value ± SD. Two-way analysis of variance for repeated measures was used. Orthogonal polynomials were also calculated to test whether the slopes of the groups differed. Greenhouse-Geisser probability for F values are given when the assumption of sphericity applied to orthogonal components was not satisfied . The chi-square test or Fisher exact test was used to analyze discrete variables among the four groups. Paired data were compared by paired t test. A p value <0.05 was considered significant.
Study group. Of 85 patients admitted to our coronary care unit with a first anterior acute myocardial infarction, 12 (14%) were excluded from study because of inadequate acoustic window. The remaining 73 (60 men, mean age 56 years, range 37 to 74) were enrolled. The majority (62%) had been admitted to the coronary care unit within 6 h of the onset of symptoms and 35 had received thrombolysis (rt-PA in 19 and streptokinase in 16). The main clinical and angiographic characteristics of the study patients and the treatment received are summarized in Fig. 1 and Table 1. Six patients died before discharge (five of cardiogenic shock and one after a massive stroke). Of the 67 remaining patients, 40 (group I) had a patent LAD, whereas 27 (group II) had LAD occlusion or subocclusion. Of the 40 patients in group I, 17 (group IA) had nonsignificant disease, whereas 23 (group IB) had significant residual stenosis (85 ± 10% diameter reduction). Twenty of the latter patients underwent PTCA (three patients refused the procedure), which was successful in 17 and resulted in <30% residual stenosis and TIMI grade 3 flow. In all patients in group II PTCA was attempted within 18 days of infarction. Angiographic reperfusion was achieved in 16 of these patients (group IIA); in the remaining 11 (group IIB), the procedure was unsuccessful because of inability to cross the lesion.
All groups were comparable for age, risk factors, degree of ST segment elevation and creatine kinase peak values. Fewer patients in group II had received thrombolytic therapy and had shown signs of early reperfusion (Table 1), but no significant differences were observed between patients in subgroups IIA and IIB. Five of seven patients in group IIB who had been admitted early did not receive thrombolytic treatment because of various contraindications (three reported previous gastrointestinal bleeding, one had received prolonged cardiac massage and one had presented with syncope and head trauma).
Clinical follow-up. In the 6 months after discharge, three patients (one from group IA and two from group IB) had a reinfarction, two others died (one of sudden death in group IA, one of cancer in group IIA); one patient in group IIB had a stroke. Heart failure developed in 11 patients: 1 (6%) in group IA, 2 (9%) in group IB, 3 (19%) in group IIA and 7 (64%) in group IIB. One patient in group IIB underwent heart transplantation 6 months after discharge.
All 33 patients who underwent successful PTCA had a patent LAD on repeat angiography; 7 (4 in group IB and 3 in group IIA) had significant restenosis. The medications received by the different patients are shown in Table 2.
Echocardiographic measurements at baseline. In all patients the first echocardiogram was obtained during intravenous nitrate infusion after an average of 12 h from the onset of symptoms. Predictably, the patients with an occluded LAD (group II) had a more severely impaired ejection fraction (43 ± 10% vs. 50 ± 6%, p < 0.01) and a higher dysfunction score (20 ± 5 vs. 16 ± 6, p < 0.01). In fact, although the end-diastolic volume index was not significantly different between groups (68 ± 15 vs. 58 ± 15 ml/m2, p = NS), the end-systolic volume index was significantly greater in group II (36 ± 9 vs. 27 ± 10 ml/m2, p < 0.05). Conversely, left ventricular volumes and ejection fraction were similar in subgroups A and B, respective, in groups I and II. Mild mitral regurgitation was observed in only one patient in group IB and was confirmed by ventriculography in this patient.
Echocardiographic measurements during follow-up.Table 3Table 4 show the changes in dysfunction score, ejection fraction and left ventricular volumes observed during the follow-up period in groups I and II, respectively.
Dysfunction score. In all patients with an initially patent LAD (groups IA and IB), the contractile function of the infarct area progressively improved and the dysfunction score progressively decreased. This was true whether or not these patients had undergone PTCA. In patients in group IIA the dysfunction score remained constant during admission and showed a slight, nonsignificant decrease during follow-up. By contrast, in all but one patient in group IIB the score increased and remained higher than that observed on admission throughout follow-up. In five patients the increase exceeded by ≥20% the value observed on admission; in these five patients the number of dysfunctional segments also increased significantly (9 ± 2 on admission vs. 12 ± 1 at follow-up, p < 0.05).
Ejection fraction. Ejection fraction progressively increased in groups IA and IB and was significantly greater on the predischarge study than on admission. It remained unchanged during follow-up (Table 3). Again, PTCA did not influence this index. In groups IIA and IIB ejection fraction did not significantly change during follow-up, but its behavior in the two groups was significantly different (p < 0.001) (Table 4).
Volume indexes. End-diastolic and end-systolic volume indexes increased progressively and significantly in patients in group IIB and remained practically unchanged in groups IA and IB (Table 3). In group IIA, a progressive trend toward reduction of end-systolic volume became statistically significant at 6 months (Fig. 2).
Exercise tolerance. Results of the exercise test in the four groups are shown in Table 5. Patients in group IIB exhibited higher heart rates at rest and lower systolic blood pressure. They achieved lower rate-pressure product levels at peak exercise than did patients in groups IA, IB and IIA.
Residual stenosis or restenosis and left ventricular systolic function and volumes. Six patients in group IB were discharged with significant residual stenosis (81 ± 7%); three had refused PTCA and in three the procedure had not been successful. Restenosis developed in an additional four patients during follow-up after successful PTCA. However, all four had TIMI grade 3 flow and <90% reduction of lumen diameter on coronary angiography. In these 10 patients the behavior of the dysfunctional score, ventricular volumes and ejection fraction was similar to that in the remaining 13 patients in group IB who showed continuing success after PTCA. Specifically, these patients showed a similar decrease in dysfunction score (respectively, 6.9 ± 5 and 7.1 ± 5, p = NS) and a similar increase in ejection fraction (respectively, 9 ± 10% and 8 ± 9%, p = NS). Similarly, the three patients in group IIA whose LAD was patent after PTCA but who later had restenosis did not differ significantly in dysfunction score, ventricular volumes or ejection fraction from the remaining 13 patients without restenosis.
Collateral vessels and left ventricular systolic function and volumes. On admission, patients in group II with significant collateral flow showed a lower dysfunction score and higher values for ejection fraction than did patients with poor or absent collateral flow (respectively, 17 ± 2 vs. 21 ± 3, p < 0.05 and 51 ± 5 vs. 40 ± 3%, p < 0.05). However, in patients of group IIB, the behavior of left ventricular volumes in the follow-up period was similar regardless of the presence (five patients) or absence (six patients) of significant collateral flow.
Myocardial infarction and left ventricular dilation. A progressive increase in left ventricular dimensions is common after anterior myocardial infarction and predicts a poor prognosis, particularly when associated with reduced ejection fraction . The magnitude of the necrotic area plays a significant role in determining this process , and a variety of pharmacologic interventions including thrombolytic therapy and administration of unloading agents such as nitrates and ACE inhibitors has been shown [1, 19–23]to prevent left ventricular dilation by reducing infarct size.
However, the size of the infarct is not the only factor influencing ventricular expansion, which, in fact, is more often associated with total occlusion of the infarct-related vessel [24–26]. Indeed, late restoration of flow has been suggested to prevent ventricular dilation in both experimental and clinical studies performed in patients receiving thrombolytic treatment 6 to 24 h from the onset of symptoms [8, 27–30]. Nidorf et al. observed that the absence of residual perfusion identifies patients likely to have subsequent significant dilation, whereas reperfusion seems to exert a positive preventive role. Popovic et al. performed an echocardiographic follow-up study in patients with a transmural myocardial infarction and suggested that early thrombolytic therapy and late vessel patency have an additive and independent effect on left ventricular remodeling. A randomized trial, the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) 6 study, failed to demonstrate a significant benefit for coronary angioplasty performed in patients with late hospital admission and an occluded infarct-related vessel . The heterogeneity of the patient group, the high rate of spontaneous recanalization of initially occluded vessels that did not undergo angioplasty and the design of the trial probably accounted for this negative result.
Our study enrolled a homogeneous group of patients with similar infarct location and size. All had a comparable degree of ST segment elevation on admission and similar left ventricular volumes recorded in the initial echocardiogram; the location of LAD lesions was also similar. Accordingly, all patients had a similar prospective risk of having a large akinetic area prone to subsequent dilation [5, 6, 33].
Effects of coronary patency and late recanalization. Patients with an initially patent artery (group I) more often exhibited an early creatine kinase peak and, on discharge, had better global and regional systolic function than did patients in group II. During both hospital admission and follow-up their end-systolic volume index showed a slight, nonsignificant decrease and the end-diastolic volume index remained unchanged, whereas the dysfunction score decreased and the ejection fraction improved, probably as a result of reversal of stunning. In these patients, the presence of residual stenosis or the occurrence of restenosis after PTCA did not seem to significantly affect the behavior of left ventricular volumes and the recovery of systolic function, probably because of the presence of good distal flow without critical residual stenosis.
By contrast, the outcome of PTCA appeared to exert a significant effect in patients whose vessel was initially occluded. In fact, persistent occlusion of the LAD (group IIB) induced a progressive increase in left ventricular volume as well as deterioration of regional wall motion. Conversely, successful PTCA (group IIA) enabled all volume indexes to remain practically unchanged for 3 months and the ejection fraction to improve significantly at 6 months. The favorable evolution observed in group IIA suggests that restoring patency of the infarct-related artery is important even when obtained late after the initial insult.
Beneficial effect of late recanalization: potential mechanisms. The mechanisms by which late reperfusion improves ventricular remodeling are not fully understood. The “open artery hypothesis” is based on the observation that, despite equivalent degrees and extension of myocardial injury, those hearts in which experimental coronary ligation is released develop less left ventricular dilation than do those whose occlusion is maintained . Obviously, we cannot completely prove this hypothesis in our patients. In fact, the beneficial effect on left ventricular volumes that we observed after successful PTCA could had been due to recovery of contractile function by viable, hibernating myocardium.
However, in patients in group IIA the dysfunction score remained practically unchanged, whereas a large proportion of patients in group IIB exhibited progressive worsening of regional contractility along with ventricular dilation. Patients in group IIB also showed extension of the dyssynergic area, because previously normal adjacent segments also became dysfunctional. Indeed, left ventricular dilation after myocardial infarction can be caused by lengthening of normally contracting segments , and a patent infarct-related artery may limit remodeling by enabling earlier formation of a firmer myocardial scar .
Secondary effects of late recanalization. Avoidance of unfavorable left ventricular geometry results in many secondary later benefits, such as reduction of wall stress, prevention of volume overload hypertrophy and improvement of ejection fraction. Indeed, patients in whom vessel patency was reestablished by PTCA had a significantly better exercise tolerance and significantly lower prevalence of chronic heart failure than did patients with complete and persistent occlusion. In fact, a previous report demonstrated that, among patients with anterior myocardial infarction, those with dilation leading to a spheric ventricular shape have the poorest exercise capacity.
Limitations of the study. Our study has some limitations. 1) Patients in group II were not randomized to undergo PTCA. Although coronary revascularization was attempted in all patients, the lack of increase in volumes observed in those in whom recanalization was achieved may be due to yet unidentified anatomic or functional factors rather than to the procedure itself.
2) Echocardiographic assessment of cardiac volumes is based on several geometric assumptions that are not necessarily met in the setting of myocardial infarction. Furthermore, measurements can be heavily influenced by variations in endocardial edge detection. However, over the last 10 years, echocardiography has become established as a noninvasive tool for serial determinations of ventricular volumes [38–40]. The digital approach that we used for our study further improves the accuracy of the technique and reduces interobserver and intraobserver variability. Furthermore, even allowing for the possibility of a “random error,” this should have equally affected results in all groups.
3) Residual viability within the infarct area was not assessed in our patients. Obviously, a greater prevalence of residual viable tissue might have influenced the better outcome observed in patients with an occluded LAD in whom PTCA was successful. However, patients in groups IIA and IIB were apparently similar in age, presence of preinfarction angina, elapsed time between onset of symptoms and hospital admission, and prevalence of early reperfusion markers. Peak creatine kinase, ejection fraction and dysfunction score, coronary anatomy and prevalence of angiographically visible collateral vessels were also similar. Therefore, it is reasonable to assume that the likelihood that residual viable tissue would be present was also similar in the two groups. In fact, despite successful PTCA, the regional dysfunction score remained practically unchanged in the majority of patients in group IIA.
4) The number of patients in groups IIa and IIb is small, but this is the result of an accurate selection. The results of our study are representative of a particular clinical condition, that is, large anterior myocardial infarction with single-vessel disease and occlusion of the proximal segment of the LAD undergoing revascularization within 18 days of the acute event.
Conclusions. Despite these limitations, we believe that our study provides important information by showing that late recanalization of an occluded infarct-related artery by elective PTCA prevents progressive dilation after a large anterior myocardial infarction. The effect appears to be predominantly mediated by reduced left ventricular remodeling, although functional recovery of hibernating myocardium cannot be completely ruled out. The beneficial effect on cardiac volumes and ejection fraction is paralleled by a lower prevalence of chronic heart failure and better exercise tolerance.
Large randomized studies are warranted. If our preliminary data are confirmed, the results may bear important prognostic implications and considerably affect our approach to patients after the acute stage of anterior myocardial infarction.
We thank Orietta Parmesan and Elena Sala for kind secretarial assistance.
A.1 Abbreviations and Acronyms
ACE = angiotensin-converting enzyme
ECG = electrocardiogram
LAD = left anterior descending coronary artery
PTCA = percutaneous transluminal coronary angioplasty
rt-PA = recombinant tissue-type plasminogen activator
TIMI = Thrombolysis in Myocardial Infarction
- Received November 9, 1995.
- Revision received May 10, 1996.
- Accepted May 24, 1996.
- THE AMERICAN COLLEGE OF CARDIOLOGY
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