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of Cardiology, Hospital De Weezenlanden, Zwolle, the Netherlands
*On behalf of the Zwolle Myocardial Infarction Study Group
BACKGROUND AND INTRODUCTION
Over the past decades, great efforts have been made to improve the outcome of patients with acute myocardial infarction (1-7). Many trials have relied on mortality as the end point (1, 2). The recent data from the Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) trial suggest that patency of the epicardial infarct-related coronary artery is an appropriate alternative end point (4). However, the primary objective of reperfusion therapies is not only restoration of blood flow in the epicardial coronary artery but also complete and sustained reperfusion of the infarcted myocardium. Echocardiographic assessment of myocardial perfusion after intracoronary injection of sonicated microbubbles is an investigational technique that has been used to describe myocardial reperfusion in patients with restored patency of the infarct-related coronary artery. The so-called "no-reflow" phenomenon, an open epicardial artery without flow into the myocardium, predicts complications and left ventricular dilation (8, 9). A simple clinical tool that describes the effectiveness of myocardial reperfusion is lacking because noninvasive means so far have not been applicable in routine clinical practice and the widely used angiographic parameter, Thrombolysis In Myocardial Infarction (TIMI) flow grade, describes epicardial instead of myocardial blood flow (3). Therefore, we have introduced an angiographic parameter to describe the effectiveness of myocardial reperfusion: the myocardial blush grade. To validate this new tool we compared the myocardial blush grades with 12-lead ECG, enzymatic infarct size, left ventricular function, and clinical outcome in a cohort of patients after primary coronary angioplasty and assessed whether this new parameter might give additional prognostic value compared with that of TIMI flow grade.
From August 1990 until April 1997, 1206 patients fulfilled the criteria for entry into one of our published or ongoing trials (6, 10-12). Two hundred and sixty-five patients were treated with thrombolytic therapy. Forty-three patients underwent primary coronary bypass surgery because of severe left main or three-vessel disease, and 62 patients were treated conservatively because of nonsignificant disease and TIMI grade 3 flow of the infarct-related vessel. In 836 patients, primary angioplasty was performed. In 46 patients, the quality of the coronary angiogram did not allow adequate assessment of myocardial blush grade and for 13 patients, angiographic data were missing. The remaining 777 patients form the basis of this report ( ).
TIMI FLOW GRADES AND MYOCARDIAL BLUSH GRADES
TIMI flow grades were assessed as previously described (3, 10). Both TIMI flow and myocardial blush were graded on the angiograms made immediately after the primary coronary angioplasty procedure, by two experienced investigators, who were blinded to all data apart from the coronary angiograms. Grading was done on cinefilm at 25 frames/s made in a Philips digital coronary imaging catheterization laboratory. In each patient, the best projection was chosen to assess the myocardial region of the infarct-related coronary artery, preferably without superpositioning of noninfarcted myocardium. Left anterior oblique or left lateral projections were used in 49%, right anterior oblique projections in 23%, both left anterior oblique or left lateral and right anterior oblique projections in 23%, and a cranial view in 5%. Angiographic runs had to be long enough to allow some filling of the venous coronary system, and back-flow of the contrast agent into the aorta (Hexabrix, 5-15 mL) had to be present to be certain of adequate contrast filling of the epicardial coronary artery. All angiograms were made with 7F or 8F guiding catheters in a standardized fashion after 400 mg nitroglycerin IC had been given immediately after the primary angioplasty procedures, and this procedure allowed quantitative coronary artery analysis (10). Myocardial blush grades were defined as follows: 0, no myocardial blush or contrast density; 1, minimal myocardial blush or contrast density; 2, moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery; and 3, normal myocardial blush or contrast density, comparable with that obtained during angiography of a contralateral or ipsilateral non-infarct-related coronary artery. When myocardial blush persisted ("staining"), this phenomenon suggested leakage of the contrast medium into the extravascular space (13), and was graded 0. Reproducibility and variabilities of the myocardial blush grades are shown in .
ECGs were done on admission (first ECG), and shortly after arrival in the coronary care unit (second ECG) after the primary coronary angioplasty procedure. The sum of ST-segment elevations was measured 20 ms after the end of the QRS complex in leads I, aVL, and V1 to V6 for anterior and leads II, III, aVF, V5 and V6 for non-anterior myocardial infarction. The second ECGs were classified with regard to the ST segment in the same way as previously described (14): 1, normalized, defined as no residual ST-segment elevation; 2, improved, defined as a residual ST-segment elevation <70% of with that on the first ECG; and 3, unchanged, defined as a residual ST-segment elevation >70% of that on the first ECG.
ENZYMATIC INFARCT SIZE
The methodology for estimation of infarct size is equal to that obtained by the a-hydroxybutyrate dehydrogenase method and has been described previously (15). In brief, infarct size was estimated by measurements of enzyme activities by using lactate dehydrogenase as the reference enzyme. Cumulative enzyme release from five to seven serial measurements up to 72 hours after symptom onset was calculated. A two-compartment model was used, which has been validated in several studies with respect to the turnover of radio-labeled plasma proteins and circulating enzymes (16).
LEFT VENTRICULAR FUNCTION
Before the patients were discharged, left ventricular ejection fraction was measured by radionuclide ventriculography. The multiple-gated equilibrium method was used after in vivo labeling of red blood cells of the patient with 99mTc-pertechnetate (6,17). A General Electric 300 g-camera with a low-energy, all-purpose, parallel-hole collimator was used. Global ejection fraction was calculated by a General Electric Star View computer and the fully automated PAGE program. Use of this software program protects against operator bias. The reproducibility of this method is excellent, with a mean difference (±SD) between first and second values of duplicate measurements of 1.2±1.1%.
Mortality was assessed in August 1997. Records of patients who visited our outpatient clinic were reviewed. For all other patients, information was obtained from the patients general physician or by direct telephone interview with the patient. For patients who died during follow-up, hospital records and necropsy data were reviewed. No patient was lost to follow-up.
Differences between group means were tested by two-tailed Student's t test. For comparison of rates of discrete outcome variables, a x2 test or Fisher's exact test was used. Trend analyses were done as described by Schlesselman (18). In our presentation of the data, continuous baseline and outcome variables are given as mean ±SD, whereas discrete variables are given as absolute values, percentages, or both. In 566 patients in whom TIMI flow as well as myocardial blush grading, enzymatic infarct size, and left ventricular ejection fraction (LVEF) were obtained, a multivariate logistic regression analysis was performed to determine independent predictors of long-term mortality. Continuous variables were divided into three categories, with the 25th and 75th percentiles as cutoff points. Odds ratios and 95% confidence intervals were calculated. Survival was represented by Kaplan-Meier curves. A log-rank test was done to assess significant differences in survival between patient subgroups.
Myocardial blush grades could be assessed in 777 of the 836 patients (93%). Baseline and angiographic characteristics of the patients classified by myocardial blush grade are shown in . Myocardial blush grades 0 and 1 were present in 5.8% and 24.6% of patients, respectively. In the presentation of the results, these two groups were combined. Patients with lower blush grades were older and more often presented in Killip class 2 or higher. There was a strong association between infarct location as well as infarct-related artery and myocardial blush grade. Furthermore, patients with higher blush grades had a higher incidence of antegrade flow into the infarct zone before the angioplasty procedure. There is an inverse relation between ischemic time and myocardial blush grade. TIMI flow of the infarct-related vessel could be assessed in all patients.
Interpretable ECGs on admission as well as those performed after the primary coronary angioplasty procedure were available for 647 patients (83%). In 2% of the patients one or both ECGs did not allow an assessment of the ST-segments owing to rhythm or conduction abnormalities. The results of the TIMI flow classification and extent of ST-segment elevation resolution are shown in . Trend analysis revealed a distinct relation between TIMI flow, ST-segment recovery, and myocardial blush grades. Enzymatic infarct size, LVEF, and long-term mortality at 1.9±1.7 years after the event are shown in . Enzymatic infarct size could be measured in 659 patients (85%). LVEF measurements were obtained for 584 patients (75%).
There was a relation between myocardial blush grade, infarct size, and LVEF: the higher the blush grade, the lower the infarct size and the better the LVEF. During follow-up, 81 patients died (10%). There was also an inverse relation between myocardial blush grades and long-term mortality. In 566 patients, TIMI flow, myocardial blush grade, enzymatic infarct size, and LVEF were known. Multivariate analysis showed that the myocardial blush grade predicted mortality, independent of other-well known variables associated with long-term outcome after myocardial infarction, such as age and Killip class (). TIMI flow, and LVEF were no longer independent predictors of mortality after inclusion of myocardial blush grade into the multivariate model.
The principle finding of our study is, that in patients after primary angioplasty for acute infarction, myocardial perfusion, as described by the myocardial blush grade, is reflected by the resolution of ST-elevations on the 12-lead ECG; the extent of damage to the infarcted myocardium, as evident from enzymatic infarct size; and radionuclide ventriculography, and is independently related to long-term mortality. The myocardial blush grade can therefore be used as a predictor of clinical outcome.
We previously described the relation between myocardial flow reserve assessed by densitometric analyses of contrast-medium passage in the infarcted myocardium, and left ventricular function (19). However, this semiquantitative method has several pitfalls and limitations and may not be applicable in routine clinical practice (20). Several studies have shown that myocardial perfusion can be assessed visually with intracoronary injection of sonicated microbubbles during echocardiography in the catheterization laboratory. This technique has been used to describe the effectiveness of myocardial reperfusion and predict clinical outcome (8,9). Myocardial contrast echocardiography can be used to categorize patients as having reflow or no-reflow, and it has been shown that even in the presence of TIMI 3 flow in the epicardial coronary artery, a patient may have no-reflow into the myocardium (21). Because the venous phase of the coronary angiogram is often clearly visible in patients with no-reflow, the echocardiographic or angiographic contrast agent passes from the arterial coronary vessels into the venous system by another route than the myocardial microcirculation in the infarct zone. We developed the angiographic myocardial blush grade based on the visually assessed contrast density in the infarcted myocardium after reperfusion therapy. The angiographic myocardial blush grades are analogous to the TIMI grades for flow in the epicardial infarct-related coronary artery. This information can be obtained during routine high-quality coronary angiography and can be used to describe the effectiveness of reperfusion therapies.
THE PATHOPHYSIOLOGY OF THE NO-REFLOW PHENOMENON
Coronary occlusion leads to cellular necrosis and myocardial damage. During a short period of occlusion, a variable amount of myocytes may become necrotic while the microvascular network is still intact. If coronary occlusion is prolonged, the microvasculature shows loss of its anatomic integrity (9,22). At the time of coronary reopening, myocardial reperfusion is achieved only in areas with anatomically preserved microvasculature, whereas reflow does not occur in myocardium with extensive microvascular damage. The no-reflow phenomenon is therefore associated with relatively more extensive necrosis and, as a consequence, is a predictor of poor regional and global contractile function (8,9). Contrariwise, adequate myocardial reflow shortly after epicardial coronary reperfusion is an accurate indication of microvascular integrity and consequently, of regional and overall functional recovery in patients with acute myocardial infarction (9,19).
Comparison of myocardial blush grades with TIMI flow grades Myocardial blush grade was related to TIMI flow. However, from Table 3, it is clear that the majority of patients with myocardial blush grade < 2 had "normal" TIMI flow. The patients with TIMI 3 flow but low blush grades can be regarded as having no-reflow in a comparable way as patients who lack myocardial contrast on their echocardiogram after intracoronary injection of sonicated microbubbles (8,9). A recent study from our group showed that a substantial number of patients with TIMI 3 flow have persistent ST-segment elevation on the post-angioplasty ECG, suggesting impairment of myocardial reperfusion (14). A further differentiation amongst patients with TIMI 3 flow is, therefore, needed and of clinical relevance.
Multivariate logistic regression analyses showed that the myocardial blush grade was related to long-term mortality independent of TIMI flow. Therefore, an angiographic variable that takes the extent of myocardial reperfusion into account is of additional prognostic value.
The inter-observer and intra-observer variabilities associated with subjective angiographic assessments are certainly a limitation of the myocardial blush grades and are comparable with the variabilities in TIMI flow grades for epicardial coronary blood flow (3,23).
Early and sustained restoration of flow into the infarcted myocardium is the aim of reperfusion therapies for acute myocardial infarction. Angiographic studies of reperfusion therapies should assess myocardial perfusion as well as flow in the epicardial infarct-related coronary artery. A new standard for success of reperfusion therapy has been proposed: "90% TIMI 3 flow at 90 minutes" (24). We think that the future standard should include the phrase, "with evidence of adequate myocardial reperfusion".
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