Progression of Coronary Artery Atherosclerosis After Acute Myocardial Infarction: An Angiographic Study

ABSTRACT: Aims. Today’s knowledge concerning the progression of coronary artery disease (CAD) is mainly derived from randomised clinical studies performed in patients with stable CAD. Data on atherosclerosis progression (AP) after myocardial infarction are limited. The aim of this study was to assess the AP in such a population of patients. Methods and Results. A total of 186 patients were analyzed. After exclusion of patients not suitable for quantitative coronary angiography analysis, the final group was comprised of 154 patients. AP was recognized in 93 (60.4%) patients. A multivariate regression analysis revealed that the risk of AP in patients increases with lack of adequate microvascular perfusion, as assessed by the thrombolysis in myocardial infarction (TIMI) myocardial perfusion grade (TMPG) score (odds ratio [OR] 4.13; 95% confidence interval [CI] = 1.17–14.53), non-smoking status and lower baseline cholesterol value (OR = 2,74; 95% CI 1.19–6.31 and OR = 1.44; 95% CI = 1.04–1.98, respectively). Moreover, the risk of progression of a pre-existing coronary lesion was enhanced the most when the baseline minimal lumen diameter was greater (OR = 2.34; 95% CI = 1.83–3.00), and a lack of adequate microvascular perfusion (OR = 3.12; 95% CI = 1.67–5.85) was the strongest predictor of risk of developing new coronary lesions. Conclusions. Atherosclerosis progression concerns over 60% of patients 12 months after acute myocardial infarction. Poor myocardial perfusion, as assessed by TMPG score, may be a simple tool for the identification of patients at greater risk of atherosclerosis progression, especially the development of new lesions.

J INVASIVE CARDIOL 2010;22:209–215

align=center> Key words: atherosclerosis progression, acute myocardial infarction, atrial septal defect, Occlutech, patent foramen ovale Today’s knowledge on the progression of coronary artery disease (CAD) is mainly derived from randomized clinical studies analyzing the effectiveness of various therapeutic interventions in patients with stable CAD. Results of these studies suggest that atherosclerosis progression (AP) may influence the long-term outcomes in this group of patients. ^1–3 An acute myocardial infarction (AMI) may be the first and, at the same time, the most dangerous complication of CAD. There are compelling reasons to believe that rupture of atheromatous plaques play an important role in the pathophysiology of AMI, as well as lesion progression. ^4,5 Episodes of plaque disruption with local thrombin activation and subsequent re-sealing, with incorporation of the thrombus into the vessel wall, may be one of the major reasons for the rapid progression of atherosclerotic lesions. This hypothesis was validated by Guazzi et al in an angiographic study comparing AP in patients with stable CAD and AMI. ⁶ Moreover, there are a great deal of data suggesting that in a set of AMI that it is not only the infarct-related plaque that is destabilized. Both angiographic, intravascular ultrasound (IVUS) and angioscopic studies have revealed more than one unstable plaque in coronary arteries in patients with AMI. ^7–9 Besides the influence on established atheromatous plaques, the appearance of AMI may deteriorate endothelial functioning; endothelial dysfunction is probably one of the primary negative mechanisms taking part in the early stages of atherosclerosis. Modern coronary angiography offers the possibility of precise evaluation of CAD extent and indirect assessment of endothelial function. Quantitative angiography provides reliable measurements of each atherosclerotic plaque in a coronary tree, and the myocardial perfusion grade reflects the status of the endothelium. To the best of our knowledge, there are no data on AP in patients with AMI treated with modern reperfusion therapy. We have undertaken an observational, retrospective study to assess AP in such a population of patients, taking into consideration both clinical and angiographic factors that may affect this process.

Methods

Patient selection. The patients analyzed for their anatomical course of CAD were part of a single-center, prospective, randomized trial in which direct stenting versus stenting after balloon predilatation in those with AMI was studied (Direct Stenting in Acute Myocardial Infarction, DIRAMI). The study design and patient selection have been described elsewhere. ¹⁰ In brief, patients with ST-elevation myocardial infarction (STEMI) in Killip Class 1 or 2 were randomized either to direct stenting or stenting after predilatation of the culprit lesion. Out of 217 patients, 110 underwent a direct stenting procedure, and 107 were treated with stenting after predilatation. The hospital course was the standard care for STEMI patients treated with percutaneous coronary interventions (PCI). After 12 months, a control noninvasive assessment and angiography procedure were planned. During both hospitalizations, all clinical, laboratory and angiographic parameters were collected. The study protocol was approved by the local ethics committee and complies with the Declaration of Helsinki. Coronary angiography and quantitative analysis. Coronary angiography was performed during the acute phase of AMI and after 12 months. The coronary angiograms were evaluated offline with quantitative coronary angiography (QCA) by applying the Automated Coronary Analysis system (Philips Medical Systems, Leiden, The Netherlands). Angiograms of the left coronary artery were carried out in four to six projections and for the right coronary artery in two to three. To achieve adequate filling with the contrast medium of each segment, all injections were performed with the automatic syringe. The best projection showing a stenosis at its most severe was selected for further processing. To achieve maximal vasodilatation, a bolus of 100–200 µg of intracoronary nitroglycerin was given before contrast injection. Epicardial perfusion in the infarct-related artery (IRA) was estimated with thromobolysis in myocardial infarction flow grade (TIMI) and myocardial perfusion with TIMI myocardial perfusion grade (TMPG) according to the 4 grades scales previously described. ^11,12 For quantitative coronary angiography (QCA), the coronary tree was divided into 14 segments according to the ACC/AHA guidelines for PCI procedures. Only segments with diameter > 1.5 mm were analyzed. Those located distally to the occlusion, opacified only by collaterals and segments with a culprit lesion treated with PCI were excluded from further analysis. For artery contour detection, the edge detection algorithm with gradient filter transform was used. The system was calibrated by measuring the tip of the Judkins or Amplatz 6 Fr catheter. The end-diastolic frame was used for analysis to avoid blurring. QCA measurements were performed by two experienced interventional cardiologists who assessed the initial and follow-up angiograms. All lesions with a diameter stenosis (DS) > 20% or a minimal lumen diameter (MLD) Definition of atherosclerosis progression. We applied the widely accepted angiographic definition of AP. ¹³ For the lower limit of changes in DS or MLD to be accepted as a truly progressive one, we chose 20% and 0.4 mm, respectively. Similarly, a normal segment had to reveal a new localized narrowing of at least a 20% stenosis or a MLD of 0.4 mm less than the reference diameter of the vessel to be accepted as a newly formed stenosis. ¹⁴ After QCA analysis for AP, a comparative analysis between patients with and without AP was performed. Statistical analysis. Continuous variables were normally distributed, and are presented as means ± standard deviation (SD). Categorical variables are presented as numbers and percentages. Continuous variables were compared with a t-test, while categorical variables were compared with a chi-square test. To assess independent predictors of atherosclerosis progression, stepwise multivariate logistic regression analyses were performed, and results are shown as an odds ratio (OR) with 95% confidence intervals. The Kaplan-Meier method and log-rank tests were applied for testing differences in follow-up mortality and major cardiac adverse events in the study groups. P-values Results Patient characteristics. A total of 217 patients were included in the DIRAMI study protocol. A second coronary angiography after 12 months was performed in 186 patients. After QCA measurements, 154 of the study participants were included in the final AP analysis. Of the 32 excluded patients, 16 had angiograms not suitable for reliable QCA analysis due to differences in angulations between the first and second angiogram, 8 had at least 1 coronary artery not selectively visualized and multiple PCI procedures made the measurements impossible in 8 patients. Based on the criteria mentioned above, 93 (60.4%) patients were classified as progressors. Of these, 44 patients (47.3%) progressed only with preexisting coronary lesions, 29 (31.2%) progressed with newly formed lesions and 20 (21.5%) progressed with both preexisting and new lesions. Clinical characteristics. Baseline clinical characteristics of patients with and without progression are presented in Table 1. Patients with progression were more often males (83.9% vs. 70.5%, respectively; p = 0.04). Surprisingly, of the known risk factors, current smoking and hypercholesterolemia were observed substantially less often in patients with atherosclerosis progression (64.5% vs. 83.6%; p = 0.009 and 48.3% vs. 65.4%; p = 0.04, respectively). None of the other differences attained statistical significance. Diabetes mellitus was found twice as often among patients with progression, but this difference was not statistically significant, probably due to the small number of patients. Laboratory parameters from the first and second hospitalization are presented in Table 2. Total plasma cholesterol levels were significantly higher among patients without progression at the initial hospitalization as well as after 12 months. Baseline levels of HDL cholesterol were significantly lower and triglyceride levels significantly higher in patients with progression. We did not observe any differences in the in-hospital course including the creatinine kinase maximal level (2,436 ± 2,120 vs. 2862 ± 2188; p = 0.23), left ventricle ejection fraction (47.6 ± 6.8% vs. 45.6 ± 7.5%; p = 0.41) and duration of hospitalization (8.2 ± 2.9 days vs. 8.5 ± 3.1; p = 0.49). There were no differences in pharmacotherapy prescribed at hospital discharge between patients with and without AP, including administration of angiotensin-converting enzyme inhibitors and statins (53.8% vs. 54.1%; p = 0.96 and 76.3% vs. 72.1%; p = 0.55, respectively). After 12 months, the use of these two types of drugs was comparable in both groups (58.1% vs. 50.8%; p = 0.37 and 74.2% vs. 82%; p = 0.26, respectively), similar to the rest of the drugs. Angiographic findings. There were no differences in the initial epicardial and myocardial reperfusion parameters. Procedural success, defined as a final IRA TIMI 3 flow, was similar in both groups. However, a significant difference was observed regarding final TMPG. AP final TMPG of 0–1, which indicates no myocardial reperfusion, occurred in 21 (22.6%) patients, whereas among patients with no progression, it was observed only in 4 (6.5%), p = 0.01. In 8 patients, the assessment of TMPG after stenting was impossible due to no-reflow phenomenon (Table 3). Multivessel coronary artery disease was identified at a similar rate in both groups (45.2% in patients with AP vs. 34.4% in patients without AP; p = 0.18). Lesion characteristics. A total of 1,017 coronary lesions were assessed in the first angiograms. AP, on the basis of the criteria mentioned earlier, was recognized in 99 (9.7%) of them. Moreover, 62 new atherosclerotic plaques were identified at second angiogram in previously normal segments. At baseline, lesions with progression were located in segments with significantly greater mean diameter. Additionally, these lesions were significantly less severe than lesions without progression. In a second angiogram, the mean diameter of analysed segments was still greater, but there was a substantial increase in percent stenosis and plaque area of progressed lesions (Table 4). Risk of atherosclerosis progression. Including clinical and angiographic factors, a multivariate regression analysis of risk of AP was performed. First of all, we analyzed the risk of progression from the patient’s perspective. Moreover, the risk of progression of preexisting coronary plaques and of developing new coronary lesions were assessed. A risk of AP increased in patients with lack of adequate microvascular perfusion (OR 4.13; 95% CI = 1.17–14.53), non-smoking status and lower baseline cholesterol value (OR = 2.74; 95% CI 1.19–6.31 and OR = 1.44; 95% CI = 1.04–1.98, respectively). A risk of progression of a preexisting coronary lesion was enhanced when the baseline MLD was greater (OR = 2.34; 95% CI = 1.83–3.00), when statins were not applied during the 12-month period after discharge (OR = 1.88; 95% CI = 1.15–0 .07) and cholesterol levels on second hospitalization were lower (OR = 1.31; 95% CI = 1.06–1.62). A lack of adequate microvascular perfusion (OR = 3.12; 95% CI = 1.67–5.85), prior AMI (OR = 3.00; 95% CI = 1.65–5.44), lack of statin treatment during the 12-month period after discharge (OR = 2.24; 95% CI = 1.28–3.93) and lower baseline hemoglobin (OR = 1.39; 95% CI = 1.05–1.83) predict an increased risk of developing new coronary lesions. Clinical follow-up data. Three-year clinical follow up was available for all patients. Major adverse cardiac events (MACE) are listed in Table 5. No significant differences were observed between the study groups, and overall rates of major adverse cardiac events at 3 years was 22.6% in patients with progression and 18.0% in patients without progression of atherosclerotic lesions.

Discussion

This study of the angiographic progression of CAD differs from most previous studies insofar as it is an analysis of patients with AP complicated with AMI. Most previous angiographic lesion progression trials assessed patients with stable CAD in whom progression is a rather chronic and slow process. ¹⁴ There are compelling reasons to believe that during acute coronary syndromes, some pathologic mechanisms influence the stability of coronary plaques in the whole coronary tree. First, the systemic inflammatory response is increased, as reflected by elevated levels of C-reactive and amyloid protein, and inflammation of the fibrous cap is one of the major reasons for their instability. ¹⁵ Second, a positive effect of aspirin or high doses of statins on recurrent ischemia may be explained in part by its systemic anti-inflammatory effect. ^16,17 Finally, normal endothelial function is distorted, which promotes thrombosis and vasoconstriction and may lead to plaque rupture or intraplaque hemorrhage, causing sudden and rapid progression of the lesion. ¹⁸ This pathophysiological mechanism may be additionally enhanced by endogenous catecholamines, which intensify vasoconstriction and sheer stress. ^19,20 Multifocal plaque instability was confirmed in angiographic, IVUS and angioscopic studies. Goldstein et al found more than one unstable plaque, as assessed by angiography, in 39.5% of patients with AMI.7 In the IVUS study conducted by Riouful et al, 79% of patients had more than one unstable lesion. ⁸ Similar findings were reported by Asakura et al, who examined patients with angioscopy 1 month after AMI. Unstable plaques were found in 95% of non-infarct-related arterial segments. ⁹ The concept of multifocal plaque instability may be the explanation for the rapid progression of both culprit and nonculprit lesions over a period of 1 month, as observed by Guazzi et al, who found progression in 38% of lesions and 70% of patients after AMI, compared with 2.5% and 9%, respectively, in matched patients with stable CAD.6 Aside from Guazzi’s analysis, there are no other studies on AP in patients with AMI. In stable CAD, Waters found progression in 42% of patients and 11.2% of lesions over a period of 2 years, and Lichtlen found such progression in 56% and 10.2% of patients and lesions, respectively, on angiography conducted 3 years after inclusion. In both trials, lipid-lowering therapy was not used, and a number of the patients were treated with calcium channel-blockers, but this had a minor influence on the results. ^14,21 In our study, 12 months after MI, we recognized progression in 9.7% of preexisting coronary lesions. Moreover, 62 new lesions were found. AP concerned 60.3% of the patients, a finding that is somewhat less than in Guazzi’s report, but more than observed in stable coronary disease. A part of the explanation may be the time period of observation and the different pharmacotherapies administered. Within 1 year, some of the initially unstable plaques may reheal and regress under treatment with anti-atherosclerotic drugs such as beta-blockers, angiotensin-converting enzymes and statins. Of note, even when this pharmacotherapy was used, the percentage of patients with progression was greater than that of patients with stable CAD without lipid-lowering intervention. ^14,21 The patient was the primary unit of our analysis. This approach makes the results clinically relevant and statistically sound. ¹³ However, results of the patient-based multivariate regression analysis are confusing. Among patients with AMI, the risk of AP independently increased with low cholesterol values at admission, non-smoking status and poor myocardial reperfusion. The first of the mentioned findings is difficult to understand; however, some explanation is possible. First of all, AP is mostly dependent on the LDL cholesterol level, which was comparable in both groups. Secondly, other lipid fractions, like triglycerides and HDL cholesterol, may play a more important role in AP. A correlation between low levels of HDL and AP was confirmed in the LCAS study. Patients with normal LDL cholesterol and decreased HDL cholesterol (22 In the subanalysis of the MARS study, a role of triglycerides in AP was noticed. ²³ To some extent, results similar to ours were reported by Waters et al. Total cholesterol values and LDL levels were comparable between patients with and without AP, but among patients with progression, the HDL cholesterol level was lower and the triglycerides level was higher (1.15 vs. 1.3 mmol/L, p 1 Additionally, in the only analysis regarding AP in patients after AMI, Guazzi did not observe any correlation between cholesterol value and lesion progression, but the time period of observation was relatively short in this study. ⁶ Furthermore, we cannot exclude the influence of type and dose of statins used before and after AMI; this may be of great importance. It is postulated that in this condition, early benefits of statins are mediated by a lipid-independent process and may depend on dose and solubility. ^17,24 Patients with progression in our study had significantly lower HDL and higher triglyceride levels at the initial hospitalization. Unfortunately, we do not have precise data about statin therapy in our study population. However, it cannot be excluded that patients without progression achieve greater benefit from lipid-lowering treatment. The correlation between non-smoking status and the risk of AP can only be explained with the phenomenon called the “smoking paradox,” which has been described by Hasdai. ²⁵ In an angiographic trial of AP, active smoking significantly influenced the atherosclerotic process, especially through the relationship with the development of new lesions. ^14,26 By contrast, smoking was not related to AP in the REGRESS trial. ²⁷ The most interesting finding, in our opinion, is the correlation between AP and lack of myocardial reperfusion. TMPG 0–1 after successful treatment of IRA increases risk of AP by more than three-fold. Moreover, the risk of developing new coronary lesions was mostly increased by poor myocardial perfusion. Impaired myocardial perfusion is strictly associated with endothelial dysfunction, which may be provoked both by ischemia and reperfusion. In such a condition, nitric oxide (NO) bioavailability is decreased and vasodilatation is diminished. Endothelial cells are swollen with large intraluminal protrusions which favor adhesion of monocytes and neutrophils, with a subsequent increase in the proinflammatory response. Activated leukocytes produce oxygen free-radicals, which interfere with myocyte enzymes and increase lipid peroxidation. ²⁸ All of these mechanisms deteriorate endothelial function and cause flow disturbances in the myocardial microvasculature. On the other hand, endothelial dysfunction is decisive for the initiation of AP. Decreased NO bioavailability leads to a loss of integrity of the endothelium and promotes inflammatory reactions with monocytes and neutrophils. ¹⁸ To the best of our knowledge, there are no publications regarding the relationship between poor myocardial perfusion and atherosclerosis. Taking into consideration that poor myocardial perfusion, as well as the initial phase of atherosclerosis, is strictly connected with endothelial function, we assume hypothetically that poor myocardial perfusion, as assessed by TMPG score, may identify patients at increased risk of AP. The appearance of myocardial perfusion disturbances involves patients with endothelial dysfunction, which provokes this complication, and, on the other hand, made the endothelium susceptible to atherogenic particles which might have favored the development of new coronary lesions. This finding demands further investigation. Aside from poor myocardial perfusion, lower baseline hemoglobin content, prior MI and lack of statin treatment during the 12-month period following discharge were identified as independent predictors of the appearance of new lesions. All revealed factors influence endothelial function. Low values of hemoglobin or hematocrit may have an influence on endothelium similar in nature to that of acute ischemia. ²⁹ In the setting of AMI, it may additionally deteriorate endothelial function. Prior MI is evidence of established CAD, and multiple coronary lesions are very often observed in such patients. ³⁰ The presence of lesions in the coronary arteries affects flow characteristics, which become turbulent and favor the disruption of atherosclerotic plaques. ³¹ It may accelerate AP of fatty-streaks, which are very often present in patients with acute coronary syndromes, but rarely visible on angiography. ⁹ The beneficial effects of statins on endothelial function have been well established. Statin therapy among patients with stable CAD significantly reduces the number of new coronary lesions. ^32–34 The lack of such therapy after MI may be even more important with regard to the development of new lesions. A lack of statin treatment during the 12-month period after discharge was also one of the predictors for the progression of preexisting coronary lesions. In stable CAD, statin therapy stops atherosclerosis or even induces its regression. ^{22,23,33–37} The other factors were greater baseline MLD and lower value of cholesterol at the second hospitalization. It is postulated that greater MLD is associated with greater intraluminal mechanical forces and may enhance disruption of plaques and AP. ⁷ In the REGRESS trial, patients with progression had greater baseline MLD and mean segment diameter (1.91 mm vs. 1.76 mm; p = 0.0008 and 2.85 mm vs. 2.73 mm; p = 0.01, respectively).27 The lower values of cholesterol at the second hospitalization is as difficult to explain as in the per-patient analysis. We hypothesized that AP may influence long-term follow up in our study population. It was reported that angiographically-defined AP affects the frequency of MACE among patients with stable CAD. Waters et al analyzed 335 patients included in a randomized trial assessing the effects of nicardipine on AP. Patients were determined as a progressor or non-progressor regardless of earlier randomization. A control angiogram was performed 24 months after randomization. At that time point, there were no differences between groups regarding frequency of MACE, but after a subsequent 44 months (range 9–80 months) a relative risk of death and MI and MACE altogether were significantly higher among patients with AP (7.3; CI 2.2–24.7, p 1 Similar results were obtained in the POSCH trial. There were no differences after 3 years of observation, but patients with progression had poorer prognosis 10 years after randomization. ² Both authors emphasize that AP is a reliable predictor of MACE, but such a correlation could be revealed in an extended time of observation. We failed to demonstrate any correlation between AP and frequency of MACE in our study. The small quantity of the study population and the relatively short time of observation may be an explanation. Study limitations. Most previous AP trials involve patients with stable CAD. To the best of our knowledge, this is the first study of AP conducted in patients in the acute phase of a myocardial infarction. Nevertheless, our study has several limitations. First, it is a retrospective analysis of patients included in the DIRAMI trial. Of 186 patients with paired angiograms, 154 were finally included in the AP analysis. There were no statistically significant differences between patients with and without AP analysis. Second, angiograms were performed in the acute phase of MI, and there are several factors that may have an influenced the status of the coronary arteries. Endogenous catecholamines and sympathetic tone may induce coronary spasm and lead to overestimating the lesions. ³⁸ Routine nitroglycerin administration, as was done in this study, should have resolved this bias, at least in part. In addition, theoretically, it should lead to underestimation of AP because some lesions visible during MI angiography may disappear afterwards. For this reason, we believe that our analysis should be even more reliable. Third, there are important angiographic limitations. Foremost, angiography is not able to visualize very early atherosclerotic lesions or fatty-streaks. ¹⁴ In addition, atherosclerotic plaques often initially grow intramurally without impinging on the vessel lumen. ³⁹ Accordingly, the definition adopted here for a new lesion as a stenosis observed after 12 months in a previously angiographically normal segment is relative, as it concerns not only lesions created anew during the 12-month period, but also preexisting ones not yet visible on the first angiography. Moreover, the definition of localized narrowings is equivocal, as aside from atherosclerotic plaques, it also includes spasm and platelet deposition. Therefore, to exclude false-positive findings, our definition of an angiographically progressive stenosis to be accepted as biologically valid was based on the rather rigorous criterion of a change in diameter stenosis by at least 20% or of the MLC by ≥ 0.4mm. Furthermore, there is no possibility to assess reliably diffuse atherosclerosis on angiography. For that reason, we cannot evaluate precisely this type of atherosclerosis in our study. Finally, as this was an observational study, we do not have precise data regarding doses and types of drugs used during the 12-month period after discharge, especially statins, which may be of great importance in AP analysis. We want to emphasize that all mentioned limitations concern the entire study population and were similar in other angiographic AP trials as well. MI and quantitative angiography present limitations that cannot be overcome, therefore, we cautiously formulate the conclusions below.

Conclusions

Despite intensive pharmacotherapy, AP involves over 60% of patients 12 months after AMI. Poor myocardial perfusion, as assessed by TMPG score, may be a simple tool to identify patients at greater risk for AP, especially the development of new lesions. Further studies are required to explore these findings.

References

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__________________________________________________________________ From the Silesian Center for Heart Disease, IIIed Department of Cardiology, Zabrze, Poland. The authors report no financial relationships or conflicts of interest regarding the content herein. Manuscript submitted November 5, 2009, provisional acceptance given November 17, 2009, final version accepted January 19, 2010. Address for correspondence: Michal Hawranek, MD, Silesian Center for Heart Disease, IIIed Department of Cardiology, Szpitalna 2, Zabrze, 41-800, Poland. E-mail: mhawranek@poczta.fm

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