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J Am Coll Cardiol, 2002; 40:257-265 © 2002 by the American College of Cardiology Foundation |
a Servei de Cardiologia, Hospital de Bellvitge, Universitat de Barcelona, Barcelona, Spain
Manuscript received October 11, 2001; revised manuscript received April 4, 2002, accepted April 18, 2002.
* Reprint requests and correspondence: Dr. Angel Cequier, Unitat d’Hemodinàmica i Cardiologia Intervencionista, Servei de Cardiologia, Hospital de Bellvitge, C/Feixa Llarga s/n, L’Hospitalet de Llobregat, 08907 Barcelona, Spain.
acequier{at}csub.scs.es
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Abstract |
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BACKGROUND: Coronary flow reserve alterations in the IRA after thrombolysis have been described, but the endothelium-dependent vasomotion has not been investigated, to date.
METHODS: Endothelial function in patients after thrombolysis was assessed by infusion of acetylcholine (ACh) at increasing doses in the IRA. Diameter changes in the distal segments were evaluated using quantitative coronary angiography. Patients with coronary atherosclerosis constituted the control group. Clinical variables, electrocardiography and biochemical markers were used to determine the timing of reperfusion and the extent of the infarct. Patients in the AMI group were re-evaluated one year later.
RESULTS: In the initial assessment, 16 patients showed a vasoconstriction response to ACh in the IRA compared to the control group (–20 ± 21% vs. 4 ± 4%; p < 0.01). Significant correlations between the degree of vasoconstriction and maximum value of the creatine kinase-MB fraction and number of new Q waves were observed. Of the 12 patients re-evaluated, 4 had complete occlusion of the IRA. In the remaining eight patients with patent artery, an improvement in response to ACh was observed relative to the initial study (+3 ± 11%, vs. –19 ± 15%, p < 0.05).
CONCLUSIONS: In patients with AMI treated with thrombolysis, severe endothelial dysfunction in the IRA is observed early. In patients who retain patency of the IRA, the endothelial dysfunction improves during the follow-up and suggests a component of stunned endothelium in the first few days post-AMI.
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The functional reaction of the vascular endothelium under determinate conditions of ischemia is complex. In animal models, the presence of endothelial dysfunction during episodes of ischemia and reperfusion has been documented (5,6). In post-acute myocardial infarction (AMI) patients with thrombolytic treatment, alterations in coronary flow reserve have been noted (7,8). However, to date, there have been no studies that have evaluated the state of endothelial function in the infarct-related artery (IRA) after thrombolysis, and whether there is a relationship with the extent of the infarct and the timing of reperfusion. Studies have documented that the coronary endothelial function can improve in different situations (9–13), but it is not known whether endothelial dysfunction after ischemia reperfusion is a transient phenomenon.
The present study was conducted in a series of patients with AMI treated with thrombolytic agents to assess the state of endothelial function early in the IRA, its relationship with the extent of the infarct and the timing of reperfusion, and the coronary endothelial function at one year of follow-up.
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Methods |
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Serial electrocardiograms (ECGs) pre-, immediately post-, and at 2, 6, 12, 24 and 48 h after thrombolysis were performed. At baseline and at 15, 30 and 60 min and 2, 4, 6, 12, 24 and 48 h following thrombolysis, the levels of MB fraction of creatine kinase (CK-MB) and myoglobin were determined. A questionnaire evaluated the moment of pain remission. The appearance of post-AMI angina necessitating vasodilator agents was considered an exclusion criterion. Coronary angiography and the assessment of endothelial function were scheduled for between 7 and 10 days post-AMI.
Estimation of reperfusion.
Infarct size
The time intervals between pain onset, implementation of thrombolysis and pain remission were recorded. Normalization of the ST-segment and the appearance of new Q-waves were analyzed in the serial ECGs. Appearance of arrhythmias on reperfusion was noted. Serial enzymatic values of CK-MB and myoglobin (14,15) were measured and from which delta values (changes with time) were calculated (16); the ratio (individual value divided by the baseline value), the relative increase (the difference between the individual value and the basal value divided by the basal value) and the area under the curve (AUC) were all analyzed.
Cardiac catheterization and the assessment of endothelial function. All the vasodilation and anticoagulant medications were withdrawn at least 48 h before the hemodynamic study. Coronary angiography was performed via the percutaneous femoral using an 8F catheter. Heparin (2,500 IU) was administered at the start of the procedure. Selective coronary angiograms and left ventriculography were performed, and the administration of nitroglycerin (NTG) was avoided. An analysis of the global and segmental contractility of the left ventricle was conducted. Angiographic criteria of exclusion from the study of endothelial function were the inability to identify the artery responsible for the AMI, a Thrombolysis In Myocardial Infarction (TIMI) flow grade <3, or the presence of a significant lesion in the left main coronary artery.
On identifying the IRA, an additional 7,500 IU of heparin was administered. Endothelium-dependent and -independent coronary vasomotor responses were studied as described previously (2). The two projections that best visualize the trajectory of the artery were selected for analyses (Bicor, Siemens, Munich, Germany). A 2.5/3F infusion catheter (Transit, Cordis, Miami, Florida) was advanced over a guidewire (0.014 in.) and placed proximally to the lesion responsible for the AMI. To preclude wire-induced coronary spasm, the wire was removed. To determine baseline vasomotor response, physiologic saline was infused for 1 min through the catheter, and an angiogram was recorded. To assess endothelium-dependent coronary vasomotor response, the saline infusion was replaced by intracoronary infusion of serial doses of acetylcholine (ACh), with estimated intracoronary final concentrations of 10–8 mol/l to 10–6 mol/l. Because ACh causes endothelium-dependent vessel relaxation in experimental models and in humans, a paradoxical vasoconstriction after the infusion of this substance is an indicator of endothelial dysfunction (2). The duration of each infusion was 2.5 min and, at each stage, an angiogram was taken. All angiograms were performed with identical views and radiographic characteristics. All infusions were delivered at a rate of 2 ml/min using a precision pump injector (Harvard, Southnatick, Massachusetts). The final blood concentrations of ACh were estimated with the assumption that blood flow in the coronary artery was 80 ml/min (17).
Finally, to evaluate endothelium-independent vasomotor response, NTG bolus (2 mg) was administered through the guiding catheter, and an angiogram identical to the others was performed (2). Throughout the procedures, heart rate, systemic arterial pressure and ECG were monitored continuously. All details of the catheterization and radiography were recorded so as to ensure duplication of the procedures at the proposed follow-up.
Quantitative coronary analysis. Quantitative coronary angiography was performed after the infusion of the saline solution, at the end of each infusion of ACh and after NTG bolus. Angiograms were performed in the two orthogonal projections that best showed the artery of interest, without overlapping of side branches and with less foreshortening. Angiograms were obtained on a real-time digital image acquisition and processing system (Digitron-3, Siemens). Images were acquired at 25 frames/s with a 512 x 512 pixel matrix with 10-bit depth for subsequent computer analysis. End-diastolic frames were taken for quantification. This system is based on a modular, fully automated border-detection algorithm developed by Pope et al. (18) and described in detail elsewhere. Variability of this method has been previously reported (19).
Calibration of the system was based on dimensions of the guiding catheter not filled with contrast medium. Mean luminal diameters of the segments distal to the lesion responsible in the studied artery were averaged for the two projections, at baseline, after infusion of stepwise doses of ACh and after NTG. Mean luminal diameter was determined in two or three segments (depending on the site of the culprit lesion, proximal or middle), each of 15 to 20 mm in length and in relation to anatomical landmarks. The percentage of change in mean luminal diameter after each infusion relative to the baseline was noted. All quantitative measurements were performed by the same investigator (M. S.). Intraobserver variability was assessed by analyzing a series of 20 studies (200 repeated measurements in total) at least three months apart. The intraobserver differences (mean ± 2 SD) in luminal diameter were as follows: 2.0 ± 3.9% for baseline values, 1.8 ± 4.0% after maximal dose of ACh and 1.7 ± 3.8% after NTG. The intraclass correlation coefficients (R2) for repeated measurements were 0.95 for baseline values, 0.96 for maximal-dose ACh values and 0.98 for NTG values. Endothelial dysfunction was defined as a vasoconstriction of the segment at maximal dose of ACh beyond the variability of the method of analysis (>4%).
Control group. The control group consisted of 12 patients without antecedents of infarction, with significant single-vessel disease that had been previously treated with coronary angioplasty and without restenosis in an angiographic study six months after angioplasty. The assessment of endothelial function was performed in the previously dilated artery with identical methodology as the study group of patients.
Endothelial function reevaluation. In the group of patients post-AMI, the reevaluation of endothelial function was scheduled for the following year. The patients were followed in our outpatient clinic. Reassessment of endothelial function was performed under identical conditions as the first assessment.
Statistical analyses. The SPSS software for Windows (SPSS Inc., Chicago, Illinois) was used for all analyses. The results for continuous variables are presented as mean ± SD. Comparisons between two groups were made by the Student t test for continuous variables and by either the chi-square test or the Fisher exact test for categorical variables, as appropriate. Comparison of coronary segment diameters at different ACh dosages were made by analysis of variance (ANOVA) for repeated measurements, which is based on a general linear model for repeated measurements, with multiple paired comparisons corrected by the Tukey method, so as to assess the effect of belonging to the treated or control groups. Interactions between group and coronary diameter, and between group and the initial and follow-up percentage of changes in coronary diameter after ACh infusion, were assessed. Analysis of residuals (dfbeta and typified dfbeta) was performed. Correlations between quantitative variables were conducted by the Pearson correlation coefficient. Statistical significance was defined as a value of p < 0.05.
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Results |
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The baseline characteristics of patients and control group are presented in Table 1. No statistically significant differences existed between the groups with respect to age, gender, prevalence of risk factors and extent of coronary disease. In the study group, thrombolysis was performed within 140 ± 60 min from the onset of chest pain. The IRA was the anterior descending artery in 10 patients (63%), right coronary artery in 5 (31%) and circumflex in 1 patient (6%). The left ventricular ejection fraction was greater in the control group.
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Reassessment study of endothelial function in the IRA in follow-up. During the follow-up, patients were asked to follow secondary prevention measures, and all patients were treated with aspirin. Additionally, two had angiotensin-converting enzyme (ACE) inhibitors, four had beta-blockers and three had hypolipidemic drugs prescribed. Cholesterol levels were 5.46 mmol/l and 5.20 mmol/l in the first and second study, respectively.
Of the 16 patients in whom we had performed the initial endothelial function study, 4 asymptomatic patients decided not to participate in the second study. Of the 12 remaining patients, the second study showed complete occlusion of the IRA in 4 patients. As such, the reevaluation of endothelial function was performed in 8 patients at 12 ± 3 months’ post-AMI. The ejection fraction was 51 ± 12% (p = NS vs. the first study). In those patients who retained permeability of the artery, a significant improvement in the grade of endothelial dysfunction was observed (Fig. 2). In the first study and at the maximum concentration of ACh, an intense vasoconstriction response was noted, whereas in the second study and at the same concentration of ACh, a vasodilation response was observed (–19 ± 15% vs. 3 ± 11%; p = 0.04), similar to the response noted in the control group at the first study (4 ± 4%; p = NS; Fig. 3). No significant correlations existed between endothelial function at follow-up and the initial parameters of reperfusion or the extent of the infarct. Neither was there any relationship observed between the type and number of drugs received by each patient during follow-up and the improvement in the endothelial function. Figure 4 shows the response of the IRA in one of the patients at the maximum concentration of ACh in the initial study and in the reevaluation. Five patients who presented with angina and/or ischemia induced in an exercise tolerance test were scheduled for angioplasty at the end of the endothelial function assessment.
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Discussion |
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To date, there have not been any studies evaluating endothelial function status in the IRA following thrombolysis. Okamura et al. (20) observed a significant vasoconstriction response to ACh in the IRA between 1 and 24 months after AMI in patients who had not been treated with thrombolytic agents. Bridges et al. (21), using factor VIII von Willebrand factor antigen as a marker of endothelial dysfunction, observed a significant increase in plasma levels of the marker in a series of patients following thrombolytic therapy; this suggested that the ischemia-reperfusion in patients with AMI would cause a lesion on the endothelium.
Studies in experimental animals indicate that abnormal vasomotor response after a myocardial infarct could be related to the liberation of serotonin, thromboxane A or thrombin, which would induce constriction of the smooth muscle around the site of the thrombosis or in the distal segments (22). In contrast, models of ischemia-reperfusion show that occlusion of the epicardial arteries with subsequent reestablishment of the flow can produce a migration of neutrophils toward the endothelium and the elastic lamina (23), an accumulation of mastocytes (24) and the production of superoxide anions.
Human cells are altered substantially during exposure to hypoxia. Transient expression of preformed proteins stored within the endothelium promotes leukocyte endothelial cell interaction and coagulation. Alternatively, in response to tumor necrosis factor, interleukin-1 and interleukin-6, transcriptional activation of several genes is initiated in the endothelial cells, and translation of specific transcripts into protein products on the endothelial surface is completed over the course of several hours. These proteins include leukocyte adhesion molecules, tissue factor and leukocyte activators. In this situation there is an increase of adherence of leukocytes to endothelial cells (25), an up-regulation of intercellular adhesion molecule, and release of interleukin-1-alpha, E-selectin and interleukin-8.
Free radicals may induce significant functional alterations in endothelial cells that promote and extend the inflammatory reaction (26). In particular, free radicals stimulate platelet-activating factor release from the endothelium, which in turn can further activate cells in the growing neutrophil infiltrate in an amplifying feedback loop (27).
Correlates of the initial endothelium-dependent vasodilation. No significant correlations were observed between the grade of endothelial dysfunction and the noninvasive parameters of reperfusion that we had measured. Conversely, the grade of dysfunction in the first study correlated with the variables indicative of the extent of myocardial necrosis. These findings suggest that, confronted with a situation of ischemia-reperfusion, the coronary endothelium behaves, functionally, in a poorly specific manner, similar to the response documented in the myocardium postreperfusion. Crea et al. (8) observed, in patients post-AMI, that coronary blood flow reserve, soon after successful thrombolysis, was strikingly variable and extremely low in some patients despite widely patent epicardial coronary arteries. Similarly, Ishihara et al. (28) observed a significant alteration of coronary flow reserve at two weeks’ post-AMI despite successful angioplasty.
Endothelial cell dysfunction occurs moments after reperfusion following regional ischemia, and it progresses with time (29). Endothelium may be more vulnerable to injury than the myocyte or endothelial injury that might precede myocyte injury (30). When rendered hypoxic and reoxygenated, endothelial cells become activated to express pro-inflammatory properties, pro-coagulant factors and vasoconstrictive agents that increase vasomotor tone (26). These changes may contribute to the myocardial dysfunction. Heart failure per se can influence endothelial function due to a reduced ability of endothelium to synthesize or release nitric oxide (31). However, it was unlikely in our patients because the ejection fraction did not change during the follow-up and, in contrast, the endothelial dysfunction improved significantly during this period. Also, the reduction in the ejection fraction was modest, and no patient showed signs of heart failure during the study.
Endothelial dysfunction changes at follow-up. In the patients who retained patency of the artery, the endothelial dysfunction in the IRA had improved dramatically in the year post-AMI and demonstrated an ACh response similar to that documented in the noninfarct control group. Our study demonstrated the capacity of the human endothelium to recover its function after an episode of ischemia-reperfusion.
Using positron emission tomography, Uren et al. (7) investigated 9 patients at one and six months’ postinfarction who were treated with thrombolysis. They observed that the severe vasodilator abnormality initially detected, involving resistant vessels in the infarcted myocardium, improved during the follow-up. Ishihara et al. (28) documented that the coronary flow reserve improves during follow-up in patients after MI. It has also been observed that endothelial dysfunction induced by the ischemia-reperfusion processes can be minimized by specific interventions. Ischemic preconditioning in humans (32) and pharmacologic treatment with ibopamine, captopril and heparin (33,34), prior exposure to peroxinitrite (35) and hepatic hydroxymethylglutaryl-coenzyme A reductase inhibitors (36) have been shown to preserve endothelial function in animal models. No specific interventions during follow-up were conducted in our patients except for the general secondary prevention measures in patients post-AMI. No significant correlations were observed between any of these measures and the grade of improvement in response to ACh and which was, in general, superior to the improvement documented in studies with hypolipidemic agents or ACE inhibitors (10–12).
Mechanisms proposed for the improvement in endothelial function during follow-up in patients with patent arteries are speculative. Following brief periods of ischemic insult to the myocardium, considerable alterations in the coronary vasodilation responsiveness without changes in the structure of the coronary small vessels have been described (37). Bhagat et al. (38) define endothelial stunning as a transient endothelial dysfunction that persists after the injury and takes a long period to recover. Sheridan et al. (39) documented a reversible dysfunction of pulmonary vasorelaxation through stunning of vascular endothelial and smooth muscle cells.
Study limitations. To assess endothelial function in the IRA accurately, we excluded those patients with TIMI flow grade <3 as well as those who, for post-AMI angina, were under vasodilator treatment. These criteria could imply that the patients included in the study represented a very selected subgroup of postthrombolysis patients. Nevertheless, these patients represent 55% of a consecutive series of patients with AMI treated with thrombolytic agents. Furthermore, the expected frequency of a patent artery at nine days’ post-AMI despite a noneffective thrombolysis has been reported as being between 4% to 22% (40,41). Although we had not used very early angiographic evaluation for determining the timing of reperfusion (40) we had, nevertheless, used a series of noninvasive parameters that have been validated recently (14–16).
It could be argued that the considerable endothelial dysfunction that we observed early in the IRA was already present pre-AMI (42). Endothelial dysfunction is more prevalent in the setting of acute coronary syndrome than in chronic coronary artery disease. In patients with unstable angina, severe endothelial dysfunction has been described in the culprit lesion. However, the coronary artery downstream from the culprit lesion in these patients shows minor degrees of vasoreactivity in response to exercise, with a magnitude similar to the distal segments of patients with stable angina (43). In contrast, our post-AMI patients showed a severe endothelial dysfunction downstream from the culprit lesion, with important differences compared to the response shown in the distal segments of the control group, which consisted of patients with stable coronary artery disease. Furthermore, the documented reversibility during the follow-up period would also suggest that the dysfunction was secondary to the infarct.
The relatively reduced number of patients could be a limitation of the study. Nevertheless, the endothelial response in our group of patients was uniform in the initial assessment and in the assessment at follow-up. To demonstrate a definite relationship between IRA patency and endothelial dysfunction, improvement would require a much larger number of patients. Likewise, even though no correlation was found, no definite conclusion can be drawn regarding the influence of the medication received during the follow-up and improvement in the endothelial function.
Clinical implications. In this study we demonstrate that, in post-AMI patients treated with thrombolytic agents and with patent IRA artery, there is severe endothelial dysfunction and, as such, it is an attractive model in which to evaluate different forms of intervention so as to preserve endothelial function. Aspects that may be addressed could include hypoxic endothelial cell injury contribution to the no-reflow phenomenon (26), relationship between the endothelial-dependent vasodilation in the epicardial arteries during follow-up, and the endothelium function of the micro-circulation and its influence in the long-term ventricular dysfunction, as has been suggested previously (44).
Conclusions. In patients with AMI treated with thrombolytic agents, an important degree of initial endothelial dysfunction that correlates with the extent of infarct is observed. In those patients who retain a patent IRA, the endothelial dysfunction improves during the follow-up period, which suggests a component of stunned endothelium in the first few days post-AMI.
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