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(Circulation. 1995;92:2058-2065.)
© 1995 American Heart Association, Inc.

Articles

Rapid Angiographic Progression of Coronary Artery Disease in Patients With Angina Pectoris

The Role of Complex Stenosis Morphology

Juan Carlos Kaski, MD, FACC; Michael R. Chester, MD; Lijia Chen, MD; Demosthenes Katritsis, MD, PhD

From the Coronary Artery Disease Research Group, Department of Cardiological Sciences, St George's Hospital Medical School, London, UK.

Correspondence to Dr Juan Carlos Kaski, Department of Cardiological Sciences, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, England.

	Abstract

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Background Rapid disease progression commonly underlies acute coronary events, and "complex" stenosis morphology may play a role in this phenomenon.

Methods and Results We studied the role of complex stenosis morphology in rapid disease progression in 94 consecutive patients awaiting routine coronary angioplasty. Coronary arteriography was repeated at 8±3 months' follow-up, immediately preceding angioplasty (68 patients) or after an acute coronary event (26 patients). Disease progression of 217 stenoses, of which 79 (36%) were "complex" and 138 (64%) were "smooth," was assessed by computerized angiography. At presentation, 63 patients had stable angina pectoris and 31 had unstable angina that settled rapidly with medical therapy. At follow-up, 23 patients (24%) had progression of preexisting stenoses and 71 (76%) had no progression. Patients with progression were younger (55±12 years) than those without (58±9 years) but did not differ with regard to risk factors, previous myocardial infarction, or severity and extent of coronary disease. Twenty-three lesions (11%) progressed, 15 to total occlusion (11 complex and 4 smooth; 65%). Progression occurred in 17 of the 79 complex stenoses (22%) and in 6 of the 138 smooth lesions (4%) (P=.002). Mean stenosis diameter reduction was also significantly greater in complex than in smooth lesions (11.6% versus 3.9% change; P<.001). Acute coronary events occurred in 57% of patients with progression compared with 18% of those without progression (P<.001) and were more frequent in patients who presented with unstable angina (P=.002).

Conclusions Rapid stenosis progression is not uncommon, and complex stenoses are at risk more than smooth lesions.

Key Words: stenosis • angiography • coronary disease • angina

	Introduction

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In patients with mild to moderate coronary artery stenosis, disease progression may be slow and evolve gradually over time.¹ However, in a substantial proportion of patients, stenosis progression is rapid.^{1 2 3 4 5 6 7} It has been shown both that coronary stenoses may "grow" rapidly, leading to total vessel occlusion, particularly in patients who develop serious coronary events,^{4 8} and that new stenoses often develop in segments of coronary arteries that were normal at previous angiography.^{1 9} Thus, disease progression appears to be neither linear nor predictable.^{10 11} The unpredictable and episodic nature of disease progression can be explained by rapid stenosis growth due to thrombosis, which occurs as a complication of the basic atherosclerotic process.^{12 13} Indeed, acute coronary syndromes are most commonly precipitated when mild or moderate coronary stenoses become severely obstructive,^{9 10 11} and this transformation is usually associated with plaque fissuring, intramural hemorrhage, and occlusive thrombosis.^{14 15 16 17} In long-term follow-up studies, risk factors and local coronary factors appear to contribute to stenosis progression.^{1 18 19 20 21 22} Recently, it has been shown that disease progression, whether "silent" or associated with clinical manifestations, is a strong, independent predictor of future coronary events.²³

The occurrence of rapid stenosis progression in patients with stable coronary syndromes has not been investigated systematically. In previous studies, intervals between angiograms were usually too long for the assessment of rapid disease progression. Several other limitations of these studies were recently identified.¹ Therefore, little is known about the incidence, angiographic characteristics, and clinical significance of rapid disease progression in this setting. In the present study, we took advantage of the current situation in our clinical care system, in which stable angina patients who require routine, nonurgent coronary angioplasty are put on waiting lists. We prospectively assessed the incidence, as well as clinical and angiographic features, associated with rapid disease progression in patients awaiting coronary angioplasty. We focused our attention on the role of angiographically complex stenosis morphology in view of the fact that myocardial infarction and unstable angina are usually associated with "complex" stenoses^{24 25} and that complicated lesions have been suggested to predict the occurrence of coronary stenosis progression and coronary events in patients with diverse coronary syndromes.^{26 27 28 29}

	Methods

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Study Patients
We studied 94 individuals from a series of 198 consecutive patients with angina pectoris who underwent coronary arteriography in our unit over a period of 7 months (September 1990 through March 1991) and who were considered candidates for routine coronary angioplasty. After diagnostic arteriography, the 94 patients (77 men and 17 women, aged 58±10 years) were put on a waiting list for angioplasty. All 94 patients were on the waiting list for at least 2 and for up to 12 months from the time of diagnostic coronary arteriography, usually depending on bed and catheter laboratory availability. Of the remaining 104 patients, 93 who underwent angioplasty within 2 months of diagnostic catheterization and 11 whose angiograms were not suitable for computerized analysis were excluded from study. We did not include patients with (1) previous coronary bypass surgery or coronary angioplasty; (2) planned bypass surgery; (3) clinically significant valvular heart disease, serious conduction disturbances, heart failure, or significant arrhythmia; (4) left ventricular aneurysm possibly requiring surgical treatment; (5) significant left main or left main equivalent disease; (6) >80% preseptal left anterior descending coronary stenosis; (7) myocardial infarction within the 12-week period before entry into the study; (8) pharmacological treatment for hyperlipidemia; and (9) time on the waiting list for coronary angioplasty of less than 2 months or more than 12 months.

Clinical features and angiographic characteristics in the 94 patients included in the study are shown in Table 1 and Table 2, respectively. We studied type of angina at presentation, history of myocardial infarction, conventional risk factors for coronary artery disease (family history, smoking, hypertension, diabetes mellitus, and plasma cholesterol), and extent and severity of coronary artery disease (Tables 1 and 2). At study entry, 63 patients presented with chronic stable angina pectoris (symptoms stable for the preceding 6 months) and 31 had unstable angina³⁰ (new onset angina, 3 patients; resting angina, 20 patients; and crescendo angina, 8 patients), which rapidly settled with conventional medical therapy in all. During follow-up, all patients received antianginal medication as prescribed by the treating physician, which consisted of diverse combinations of calcium antagonists, nitrates, and ß-blocking agents. Low-dose aspirin (75 to 150 mg/d) was prescribed for every patient when no specific contraindications existed (4 patients).

View this table: [in this window] [in a new window]   Table 1. Clinical Features in 31 Patients Who Presented With Unstable Angina and 63 Patients Who Presented With Chronic Stable Angina

View this table: [in this window] [in a new window]   Table 2. Angiographic Findings in 94 Patients With Angina Pectoris Awaiting Myocardial Revascularization

Angiographic Analysis
Coronary Arteriography
Diagnostic coronary arteriography at study entry was carried out with use of standardized projections, which were reproduced at the time of the second arteriogram. Patients fasted and did not smoke in the 12 hours preceding coronary arteriography. Baseline medical therapy was not discontinued. Nitrates were administered to all patients to minimize the effects of coronary vasomotor tone on coronary lumen diameter size. Sublingual glyceryltrinitrate (0.5 mg) or isosorbide dinitrate (5 mg) was given (2 to 10 minutes before contrast injection) to 63 patients who presented with stable angina. Intravenous glyceryltrinitrate (100 µg) or isosorbide dinitrate (1 mg) was administered to all patients who presented with acute coronary syndromes. After diagnostic angiography, patients were put on a waiting list for routine coronary angioplasty and followed up on a regular basis in the outpatient clinic. All patients gave written informed consent before study entry. All 94 patients underwent two coronary arteriograms as part of their clinical evaluation. The first angiogram was carried out at study entry and the second 8±3 months later, depending on the dynamics of the waiting list and the patient's clinical evolution. In 68 patients, who had no change in symptoms and who did not develop coronary events during follow-up, the second arteriogram was carried out immediately preceding routine coronary angioplasty. In the remaining 26 patients, who developed unstable angina (22 patients) or acute myocardial infarction (4 patients) during follow-up, coronary arteriography was carried out 7±6 days after the acute event. At follow-up angiography, nitrates were administered in identical fashion as during the first coronary angiogram.

Measurement of Coronary Artery Diameters
Quantitative assessment. Each pair of coronary arteriograms was assessed by two experienced cardiologists blinded to the identity and clinical characteristics of the patients and to the temporal sequence of the films. Coronary artery segments were selected between identifiable branching points. For each segment, measurements were carried out on end-diastolic frames. Coronary stenoses were measured where their severity appeared maximal. Coronary diameters were measured with use of the Coronary Angiography Analysis System (CAAS) (Pie Data Medical) developed by Reiber³¹ and validated by different authors.^{23 32 33} Our technique for measuring coronary artery diameter using CAAS has been reported in detail previously.^{33 34 35 36} The stem of the Judkins coronary catheter was used for calibration to determine absolute measurements in millimeters, and correction was made for radiographic pincushion distortion. Seven of the 217 stenoses were located in coronary arteries less than 1 mm in diameter and were therefore read visually, as CAAS is less reliable under these circumstances.²³ Orthogonal views were not measured and averaged because it is accepted that measurements of the views showing the stenosis at its most severe are sufficient.³² A total of 217 coronary stenoses (30% diameter reduction) and 650 angiographically normal segments were analyzed (6.9 per patient). We studied the reproducibility of our measurements using this system by calculating the accuracy (defined as the signed difference between the measured and true value) and the precision (defined as the standard deviation of these differences) of the system. Accuracy was 0.08 mm, and precision was 0.10 mm.²⁶ Coronary diameters were measured by two independent observers, and the angiograms were also reanalyzed blindly at a later time to ascertain the interobserver and intraobserver variabilities. Intraobserver variation (SEE) was 0.09 mm, and interobserver variation was 0.08 mm.

Percentage diameter reduction of a coronary stenosis was calculated on the basis of the diameter of the stenosis at its most severe and diameter of the reference segment (angiographically normal segment proximal to the lesion) measured in millimeters. The following formula was used:

Qualitative assessment. The morphology of coronary artery stenoses was assessed visually by two experienced cardiologists blinded to the identity and clinical characteristics of the patients and the temporal sequence of the films. Each stenosis was assessed selectively, viewed in two orthogonal projections. Stenoses were classified as "complex" or "smooth" on the basis of visual analysis, but the CAAS-derived symmetry index³⁷ was used to define stenoses as "concentric" (symmetric narrowing of a coronary artery, with an identical or near-identical appearance of the stenosis in orthogonal projections; symmetry index >0.5 to 1.0) or "eccentric" (asymmetric narrowing; index 0.0 to 0.5). Stenoses were classified as complex (eccentric, with overhanging edges, irregular borders, and/or showing ulceration or thrombus)^{24 25 26 28} or smooth (concentric or eccentric lesions with smooth edges, in the absence of complex features). When discrepancies arose (10 of 217 lesions), the stenoses were classified by consensus.

Stenosis Progression
Accepted criteria^{1 38} were used to define stenosis progression: (1) 20% reduction of minimal stenosis diameter of a preexisting lesion 30% and (2) progression of any lesion to a new total coronary occlusion on restudy.

Stenosis regression was defined as a reduction of stenosis severity 20% lumen diameter on restudy. A coronary stenosis was defined as "new" when a localized narrowing 30% arose in a segment that was angiographically normal at baseline angiography. In the study, stenosis progression was defined as "rapid" if it occurred within 1 year of diagnostic angiography.

Statistical Analysis
Within-lesion differences between first and repeat angiograms were compared by use of the paired Student's t test. Student's t test for unpaired data was used to compare differences between lesions. Differences in the frequency distribution of categorical variables between groups were determined by using Yates' technique (corrected ² analysis). Differences in reference diameters between the first and second angiograms were compared by use of one- or two-sample t tests as appropriate. Data are presented as mean±1 SD unless otherwise specified. Significance was defined as P<.05.

	Results

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Clinical and Angiographic Variables at Study Entry
Sixty-three patients presented with chronic stable angina pectoris and 31 with unstable angina (new onset angina, 3 patients; resting angina, 20 patients; and crescendo angina, 8 patients) that rapidly settled with conventional medical therapy. Patients' age, sex, risk factors, and history of myocardial infarction are summarized in Table 1.

Coronary Stenosis Severity and Morphology
In the first coronary angiogram, 46 patients had one-vessel disease, 36 had two-vessel disease, and 12 had three-vessel disease (Table 1). Twenty-three vessels in 23 patients were totally occluded, and 267 stenoses 30% were observed; of these, 217 (2.3 per patient) were suitable for CAAS analysis. Of the 217 analyzable stenoses, 131 were 30% but <50% and 86 were 50% diameter reduction. Coronary stenosis diameter reduction (percent) at study entry, excluding total occlusions (23 arteries) and including all analyzable stenoses 30%, ranged from 30% to 81% (mean±SD, 46±15%). Absolute stenosis diameter (in millimeters) ranged from 0.6 to 3.3 (mean±SD, 1.64±0.52 mm) (Table 2). Of the 217 stenoses suitable for analysis, 79 (36%) were complex and 138 (64%) were smooth.

Coronary Stenosis Progression
Progression of Preexisting Stenoses
At follow-up, 23 preexisting stenoses (13 of 131 stenoses <50% and 10 of 86 stenoses 50% diameter reduction; P=NS) had progressed in 23 patients (24%). The 13 stenoses <50% progressed from a mean of 38% to a mean of 71%, and the 10 stenoses 50% progressed from 56% to 100%. All but one of the 10 lesions 50% that progressed were the lesions intended for percutaneous transluminal coronary angioplasty (PTCA). Fifteen of the 23 stenoses (65%) that progressed developed total occlusion (Figs 1 and 2). Thus, within a year, total occlusion developed in 7% (15 stenoses) of the initial 217 analyzable stenoses. Changes in minimal stenosis diameter of the 23 stenoses that progressed are presented in Fig 1. At follow-up angiogram, only one lesion (>50% at study entry) showed a reduction in coronary diameter (13% change) compared with baseline (Fig 3).

View larger version (24K): [in this window] [in a new window]   Figure 1. Plot showing progression of stenoses from first to second angiogram. Twenty-three coronary artery stenoses had progressed on restudy. Of these, 15 (65%) progressed to total occlusion.

View larger version (10K): [in this window] [in a new window]   Figure 2. Plot of the 15 coronary stenoses that progressed to total occlusion (see also Fig 1). Of the 15, 4 were "smooth" and 11 had complex angiographic morphology (P=.003). The ordinate shows stenosis diameter (%) at study entry.

View larger version (15K): [in this window] [in a new window]   Figure 3. Computerized measurements were carried out in 217 stenoses. Of these, 71 (33%) were complex and 146 (67%) were smooth. The plot shows that complex stenoses progressed significantly more than smooth stenoses (11.6±17.5% vs 10.2%, change from baseline).

Stenosis progression was observed in 17 of the 79 (22%) complex stenoses and in 6 of the 138 (4%) smooth lesions (P=.002). Accordingly, total occlusion developed in 11 complex (14%) and 4 smooth (3%) stenoses (P=.003) (Fig 2).

At study entry, minimal diameter of complex stenoses was significantly smaller than that of smooth stenoses (1.51±0.42 mm versus 1.71±0.55 mm) (Table 2). Reduction of lumen diameter at follow-up angiogram was significantly (P<.001) larger in complex (11.6±17.5%) than in smooth lesions (3.9±10.2%) (Fig 3). Average stenosis severity progressed from 51±11% to 62±20% in complex stenoses and from 44±15% to 48±14% in smooth stenoses (P<.001) (Table 2). Change in lumen diameter of individual complex and smooth stenoses is presented in Fig 3.

Formation of New Coronary Stenoses
Only three new lesions developed during follow-up in segments that were angiographically normal at study entry. None of these resulted in total coronary occlusion. Severity of the new stenoses ranged from 31% to 45%.

Coronary Stenosis Progression and Clinical Presentation at Study Entry
Conventional risk factors were not significantly different in patients who showed disease progression compared with patients without progression (Table 3). However, patients with disease progression were younger than patients without progression (Table 3). Thirty-one patients presented with unstable angina, which settled on medical therapy, and 63 with chronic stable angina pectoris (Table 1). Seventy-nine stenoses were assessed in patients who presented with unstable angina: 37 (47%) were complex and 42 (53%) were smooth. In the 63 patients who presented with chronic stable angina, 138 stenoses were assessed; of these, 42 (30%) were complex and 96 (70%) were smooth. Severity of coronary stenosis and number of vessels involved were not significantly different in patients who presented with stable angina compared with those who presented with unstable angina (Tables 1 and 2). During follow-up, 17 of the 31 patients (55%) who presented with unstable angina developed a new acute event 7±3 months after study entry (7 had angina at rest, 8 crescendo angina, and 2 myocardial infarction), whereas only 9 of the 63 patients (14%) who presented with stable angina developed an acute coronary syndrome (3 had angina at rest, 4 crescendo angina, and 2 myocardial infarction) (P=.002; Fig 4). Eleven complex stenoses (30%) progressed in patients who presented with unstable angina and six (14%) in patients who presented with stable angina (P=.1). Four (10%) smooth lesions progressed in patients with unstable angina and two (2%) in patients with chronic stable angina (P=.1). Thus, 15 stenoses (11 complex and 4 smooth) progressed in patients who presented with unstable angina, and 8 stenoses (6 complex and 2 smooth) progressed in patients who presented with stable angina (P<.01). In the 63 patients with stable angina at study entry, complex stenoses progressed more than smooth lesions (10±18% versus 2±6%, respectively, P=.01). Likewise, complex stenoses progressed more than smooth lesions in the 31 patients with unstable angina at presentation (18±15% versus 5±10%, respectively, P<.01).

View this table: [in this window] [in a new window]   Table 3. Coronary Stenosis Progression and Coronary Events at Follow-up in 94 Patients Awaiting Coronary Angioplasty

View larger version (18K): [in this window] [in a new window]   Figure 4. Pie chart showing the association between the type of angina at presentation and the incidence of acute coronary events during follow-up. A significantly larger proportion of patients who presented with unstable angina developed coronary events during follow-up compared with patients who presented with chronic stable angina pectoris.

Clinical Coronary Events
The relations between acute events during follow-up and clinical and angiographic variables are presented in Table 3. Twenty-three patients showed stenosis progression during follow-up. Thirteen of these patients (57%) developed an acute coronary event. Of the 71 patients who did not show stenosis progression during follow-up, 13 (18%) had acute events (11 had unstable angina and 2 developed an acute infarction). Total coronary occlusion occurred in 15 patients and was associated with the development of unstable angina in 7 patients and myocardial infarction in 2 patients. Of the remaining 6 patients with total coronary occlusion who did not have clinically apparent events, 3 had visible collaterals at angiography. Both clinical events and angiographic stenosis progression were associated with unstable angina and the presence of at least one complex stenosis at the initial presentation.

Reference Diameters at First and Second Angiograms
Diameters of stenosis reference segments for patients grouped according to stenosis morphology and nitrate therapy at first and second angiogram are shown in Table 4. Overall reference diameters were similar at first angiography and at follow-up (3.16±0.66 versus 3.15±0.66 mm, respectively; P=.94). Importantly, the reference diameters of patients receiving oral or intravenous nitrates did not differ at either angiogram nor was there a change between angiograms (P=.79). Similarly, no differences were found when diameters of reference segments of smooth and complex stenoses were compared at first and second angiograms (P=.56).

View this table: [in this window] [in a new window]   Table 4. Reference Diameters to Smooth and Complex Stenoses in 94 Patients With Angina Pectoris Awaiting Myocardial Revascularization

	Discussion

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Our study showed that rapid progression of preexisting stenoses was relatively common in patients with moderate or severe coronary artery disease who were on a waiting list for coronary angioplasty. Indeed, approximately 25% of our patients showed significant stenosis progression while on the waiting list. The incidence of stenosis progression in our study (average follow-up, 8 months) was larger than that reported by the INTACT Study Group¹ (average follow-up, 3 years), but this discrepancy may be explained by different patient selection. Although the two studies included clinically stable patients with coronary artery disease, all patients in our study were candidates for coronary revascularization, and a proportion presented with unstable symptoms (which settled promptly on medication), whereas the INTACT study¹ included only patients with mild coronary artery disease who did not require myocardial revascularization.

Despite growing interest in rapid disease progression in recent years, the association between angiographic stenosis morphology and rapid stenosis progression has not been systematically investigated in patients with stable angina. In previous studies,^{1 2 3 4 5 6 8 18 19 20 23 28 39} the interval between initial and follow-up angiograms was longer than 1 year, and follow-up coronary arteriograms were usually dictated by clinical events or were used for diagnostic reasons. Only a few studies had a prospective design and used computerized angiographic analysis.^{1 23 28} With regard to disease progression, our study provides additional new information of clinical and pathophysiological relevance. We prospectively investigated, using computerized arteriography, consecutive patients with coronary artery disease, representative of the population that undergoes routine coronary angioplasty in a general hospital. Some of our patients had unstable angina at study entry, a syndrome that appears to be associated with stenosis progression,⁴⁰ but all settled rapidly with medical therapy at study entry and were considered by the treating physician to be suitable candidates for nonurgent revascularization. After diagnostic arteriography, our patients were prospectively put on a waiting list and followed up regularly. The interval between the two angiograms in our study was dictated by the dynamics of the waiting list for the routine revascularization procedure or by coronary events when these developed.

Stenosis Progression
In the present study, only a small proportion (10%) of all analyzable stenoses showed rapid progression. However, the majority of these lesions progressed to total coronary occlusion. Stenosis progression was associated with acute coronary events in 57% of the patients. Interestingly, however, serious coronary events occurred in only 9 of the 15 patients who developed total coronary occlusions during follow-up. This finding supports previous observations from our group³⁶ and others¹ that although stenosis progression is frequently associated with acute coronary events, it also may occur silently. The presence of visible collaterals in 3 of the 6 patients who developed asymptomatic stenosis progression may explain the phenomenon in these patients. In the remaining 3 patients, who did not have visible collaterals, the mechanism is speculative. Presence of nonvisible collateral vessels, gradual stenosis progression, and myocardial preconditioning may be postulated. A proportion of patients in our study had coronary events without stenosis progression. This is not surprising as it is known that transient dynamic events such as coronary artery spasm or mild plaque fissuring, with associated thrombosis followed by spontaneous thrombolysis, frequently take place in patients with coronary disease.

We observed that patients with disease progression were younger than those without progression. This finding is in agreement with clinical observations by other authors⁴¹ and histopathological studies^{42 43} that have demonstrated that atherosclerotic plaques in young patients with coronary artery disease are characterized by a large amount of lipid-containing foam cells and a relative lack of acellular scar tissue. These observations appear to suggest that atherosclerotic plaques in younger individuals could have developed rapidly, perhaps as a result of plaque disruption.⁴²

In our study, the severity of preexisting stenoses did not play a vital role in determining disease progression, as the proportion of stenoses <50% in diameter and stenoses 50% that progressed was similar, a finding that confirms results of previous studies.^{36 38} Also consistent with previous observations,^{1 10 11} total coronary occlusions in our study developed not only at the site of severe lesions but also in segments with mild preexisting stenoses. However, severe stenoses were more likely to occlude than mild lesions.

In our patients, the development of new angiographically visible stenoses was uncommon. This contrasts with data from the INTACT study,¹ in which 144 new stenoses were detected in 230 patients. The longer duration of follow-up in the INTACT study, allowing more time for lesions to develop in normal segments, may explain the different findings.

Role of Angiographic Stenosis Morphology
In a recent editorial article, Ambrose⁴⁴ indicated the need for studies that could provide evidence as to the clinical and prognostic role of complex lesions. We have obtained relevant information in this regard. In our study, rapid progression (including progression to total occlusion) occurred more frequently in complex stenoses than in smooth stenoses. This observation expands important findings by Davies et al,⁴⁵ who found a strong correlation between qualitative stenosis morphology and subsequent in-hospital outcome in patients who underwent thrombolysis. Levin and Fallon²⁷ suggested that coronary stenoses characterized angiographically by a "complicated" morphology are probably the "clinically more dangerous" type. They also give support to angiographic studies that indicate that lesion roughness is predictive of myocardial infarction²⁸ and that plaque ulceration identifies "high-risk" coronary lesions.²⁹ Complex stenoses occur in patients who develop myocardial infarction and unstable angina,^{24 25} and it is established that acute ischemic syndromes are most commonly precipitated when mild or moderate coronary stenoses become severely obstructive.^{9 10 17 21} This transformation is usually associated with fissuring of the fibrous cap of the atheroma, intramural hemorrhage, and mural or occlusive thrombosis, as originally postulated by Constantinides⁴⁶ and later elegantly demonstrated by other authors.^{12 13 15}

Our data show that both complex morphology and unstable angina at presentation are important factors for rapid stenosis progression. In addition, a sizable proportion of stable angina patients in our study showed rapid disease progression. Whether the mechanism responsible for rapid disease progression is the same in patients who present with unstable angina and patients who present with stable angina remains speculative. Both complex plaques and unstable angina appear to arise through plaque disruption and are therefore closely interrelated.^{14 25 27} Not surprisingly, there was considerable overlap between unstable angina and complexity at presentation and progression in our study. However, we observed that complex lesions progress more than smooth stenoses both in patients presenting with stable angina and in patients presenting with unstable angina. This observation is of considerable importance and indicates that morphological appearance is an independent factor in determining stenosis progression. This is consistent with recent observations by our group in patients with chronic stable angina²⁶ and in patients who stabilized following an unstable episode.⁴⁷ Our data indicate that in angina patients (particularly, but not exclusively, unstable angina patients) who are considered candidates for routine coronary angioplasty, "active" plaques may exist that may progress rapidly, leading to total vessel occlusion and acute coronary events. The relatively short time in which significant stenosis progression took place in our study suggests that acute changes, rather than slow linear events, occurred at the stenosis site. This is in agreement with current pathophysiological knowledge⁴⁸ whereby vascular injury and thrombus formation are key events in the origin and progression of coronary disease and in the pathogenesis of acute coronary syndromes.

Limitations of the Study
We are aware that our clinical findings may not apply where waiting lists for coronary angioplasty do not exist. However, our results are of pathophysiological importance, as they highlight the episodic nature of disease progression even in stable angina pectoris. Although patients were prospectively entered in the study, the interval between the two angiograms varied between patients. This was due to the complex dynamics of the waiting list, which in our institution includes several variables, such as bed and catheterization laboratory availability and patient clinical evolution.

The effect of coronary vasomotor tone is of importance when assessing stenosis progression or regression, and therefore intracoronary nitrates are often given in studies of this nature. Although in the present study we did not use intracoronary nitrates, all our patients received sublingual or intravenous nitrates. Diameters of coronary reference segments were not different in patients who received sublingual compared with those who received intravenous nitrates at either angiogram. Similarly, no differences were found in the diameters of reference segments of the oral and intravenous nitrate–treated patients when the first and second angiograms were compared. This indicates that the vasodilatation achieved during the first and second angiogram was similar and that effects achieved with sublingual and intravenous nitrates were also similar. Thus, it is unlikely that changes in vasomotion could explain our findings.

Qualitative analysis is subjective and partly depends on the experience of the operators, and it is possible that this is reflected in the reproducibility of qualitative analysis in our study. The observations are, however, internally consistent with observations by different observers in a separate population in our institution.^{26 47}

Conclusions
Our results thus suggest that rapid stenosis progression is not uncommon in patients with moderate or severe coronary artery disease who await coronary angioplasty. Stenoses of complex angiographic morphology are at a higher risk of rapid progression than smooth lesions. Patients who present with unstable angina are likely to develop rapid stenosis progression and further events, even when their symptoms settle rapidly with medical therapy.

	Acknowledgments

 
Dr L. Chen is supported by an educational grant from the Youde Foundation, St George's Hospital, London, England.

Received February 23, 1995; accepted March 27, 1995.

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