The origin and fate of complex coronary lesions

The origin and fate of complex coronary lesions

Complex irregular coronary artery stenoses, representing plaque rupture/thrombosis, are associated with the acute coronary syndromes. However, the natural history (origin and fate) of these lesions Is not known. To examine this issue we studied 255 patients who had had two to four arteriograms wlthin a mean interval of 2.6 ? 1.7 years. Of 53 irregular lesions that had progressed on a later arterlogram, 35 (66%) originated from areas that were smooth and <50% in stenosis diameter. Of 44 irregular lesions on an earlier study, 10 (23%) became totally occluded, five (11%) progressed in severity (all remained irregular), 25 (57%) showed no change in severity (all remained irregular), and four (9%) regressed (two became smooth). Nine of the 10 lesions progressing to occlusion were 295% stenosed on the earlier study. Only 2 of 44 lesions (5%) showed smoothing. These findings are in agreement with the concept that irregular lesions represent ruptured atherosclerotic plaques and demonstrate that they usually originate from mildly occlusive smooth plaques. Markedly narrowed irregular lesions (295% stenosis) frequently progress to occlusion. Irregular lesions less than 90% narrowed commonly remain angiographlcally stable, and Irregular over several years. They were found rarely to evolve into smooth-walled plaques. (AM HEART J 1991;121:1050.)

Jacob I. Haft, MD, and Amer M. Al-Zarka, MD. Newark, NJ.

Atherosclerotic plaque rupture with superimposed thrombosis has become widely accepted as the underlying event leading to myocardial infarction, unstable angina, and sudden ischemic death.’ These ruptured plaques and thrombi can be identified on postmortem angiography as narrowings with irregular or overhanging borders with or without intraluminal lucencies.2 Recently with improved radio- graphic equipment these irregular lesions were observed in patients undergoing coronary arteriography and were found commonly in patients with unstable angina3-5 and after thrombolysis for acute infarction.6

However, little data are available on the natural history of these lesions. It is unknown whether they tend to progress in severity, regress, or remain stable. They have been assumed to heal and become indis- tinguishable from other atherosclerotic plaques, but this has never been shown. Also unknown is whether we can angiographically identify the plaques that tend to rupture, producing these lesions. Clarifying these natural history issues can have important implications regarding preventive and therapeutic in- terventions and regarding our basic understanding of

From the Department of Cardiology at St. Michael’s Medical Center.

Received for publication July 26, 1990; accepted Sept. 14, 1990.

Reprint requests: Jacob I. Haft, MD, Department of Cardiology, St. Mich- ael’s Medical Center, 268 King Blvd., Newark, NJ 07102.

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the progression of atherosclerosis. We attempted to answer some of these questions by studying the arteriograms of 255 patients who had sequential coronary arteriograms. We identified the irregular lesions and examined their fate and the segments of the coronary tree in which they developed. Partial reports of these data have appeared in abstract form.7y 8

METHODS Study population. All patients who have had more than

one coronary arteriogram at St. Michael’s Medical Center with an interval of more than 30 days and whose first arteriogram was done between January 1981 and August 1985 were identified. That period was chosen because in Janu- ary 1981 a new catheterization labratory was installed in our hospital with equipment that had greatly improved resolution, permitting detailed analysis of angiographic morphology. After mid 1985, with the widespread use of angioplasty, it became rare to encounter a patient with significant coronary artery disease who was not subjected to angioplasty or bypass surgery. Occasional patients whose first arteriogram was done after August 1985 were included. Patients who had angioplasty before the second arteriogram were excluded.

Interpretation of arteriograms. The pairs of films were reviewed simultaneously on two high resolution projectors (Vanguard XR35, Vanguard Instrument Corp., Melville, N.Y.). Each lesion was visually assessed as to percent diameter stenosis and lesion morphology by both authors independently and on at least two occasions. There was usually excellent agreement; the few difficult cases were settled by consensus. Lesions that were not visualized well

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enough to judge their morphology were excluded. Judg- ment on morphology of each lesion was done using the moving tine film and multiple single frames in orthogonal views. Artifactual causes of irregularity were carefully looked for and excluded. These included poor opacification, streaming of contrast material, presence of overlying structures (especially small branches that, on a single frame, might be easily confused with irregularity), tortuos- ity, and foreshortening of the segment. A lesion was considered smooth if it had smooth borders and no filling defects, whether it was concentric or eccentric. A lesion was considered irregular if it had (1) irregular or hazy borders, (2) sharp leading or trailing edges that were overhanging or perpendicular to the vessel wall, (3) outpouchings of dye outside the apparant lumen of the vessel, or (4) intraluminal lucencies or filling defects2 The last two categories (outpouchings and filling defects) were noted separately. Progression in severity was defined as (1) a change in percent stenosis from <30”( to ~50’~, (2) ~20’;; change in a vessel already narrowed 5OC;, or more, and (3) a new total occlusion in any vessel. Regression was defined in an oppo- site manner.

RESULTS

Two hundred fifty-five patients with two, three, or four arteriograms with intervals of more than 30 days between were entered into the study. Patients with films that were incomplete, that were of poor quality, or that were damaged were excluded. In patients entered in the study, 7% of the lesions were excluded because morphology could not be reliably deter- mined. The causes for this were most commonly poor opacification of the segment or lack of a view perpendicular to the axis of the segment that eliminated foreshortening.

Figs. 1 to 13 show illustrative examples of serial arteriograms with the corresponding case histories. The data were analyzed to study the origin of complex lesions and their fate. First, to study the precursors of complex lesions, we identified lesions 150% (diameter stenosis) that were irregular on a later angiogram and examined the previous angiogram. This analysis identified but did not exclude patients with intervening bypass surgery (Table I). Second, to study the fate of irregular lesions we identified lesions that were irregular on an earlier angiogram and de- termined what happened to them on a later angiogram in terms of morphology and percent stenosis. Patients with intervening bypass surgery were excluded.

Of 106 irregular lesions identified on a later angiogram, 49 had not changed in percent stenosis (or morphology) from the previous arteriogram. Of the 57 with change, four had regressed and 53 had progressed. The majority of those progressing (37 of 53 or 70 ?A ) originated from areas that were angiograph-

Fig. 1. This figure shows the persistence of this irregular lesion with overhanging borders and outpouching of dye. This &year-old man presented with unstable angina not well controlled medically. He had severe three-vessel and left main coronary artery disease. The lesion in the right coronary artery is seen in (A). He was treated medically but continued to have occasional pains. Two years later he presented again with intractable severe symptoms and ECG changes in the inferior leads. The lesion in the right coronary is unchanged (B).

ically normal or midly narrowed (<50% diameter stenosis). Only 2 of these 37 lesions was irregular on the first study. The other 16 (30%) originated from areas that were 50% to 75% narrowed, and five of these had been irregular on the first study. Thus most irregular lesions originated from normal or mildly narrowed segments that were smooth. Only 7 of 53 (13 % ) irregular lesions with progression compared with the earlier study had been irregular on the first study. Four of 106 irregular lesions showed regression compared with the earlier arteriogram. This percent- age of regression is similar to that in other reported studies of progression that did not examine morphol- %Y*

Fig. 14 shows the fate (change in percent stenosis)

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Fig. 3. This figure demonstrates the filling in of lesions with outpouching of dye. A 74-year-old woman presented with crescendo angina for 3 weeks. The right coronary artery (A) showed a 50 % narrowing with outpouching of the dye in an “ulcer-like” lesion, She stabilized with medical therapy. One year and 10 months later, she was readmit- ted with recurrent episodes of ventricular tachycardia and with chest pain at night. The outpouching has filled in, rendering the stenosis smooth(B). Only one outpouching in this series of patients failed to fill in (see Fig. 1).

Fig. 2. This figure demonstrates the persistence of an irregular lesion over more than 6 years. A 6%year-old man with an old anterior MI presented with increasing chest pain. The right coronary artery [A) shows a 65% narrowing with a rough irregular surface. Bypass surgery was performed. Two years and 4 months later, angina recurred. The lesion has not changed (B). Three grafts were occluded. Four years later, he presented with class IV angina. The lesion in the right coronary looks exactly the same (C).

of irregular lesions in patients without intervening bypass surgery. Of 44 irregular lesions 10 (23%) became totally occluded, five (11% ) progressed (all remained irregular), 25 (57%) showed no significant change in severity (all remained irregular), and four (9%) regressed (two became smooth).

Fig. 15 illustrates the fate of these 44 lesions with respect to change in morphology. Of the 34 irregular lesions that did not become totally occluded, 32 (94%) remained irregular, and most of these (25 of 32) did not change in severity. Two lesions (6% ) became smooth; both had had filling defects that disappeared. Thus with rare exception, irregular lesions either remained irregular or became occluded. Of five lesions with filling defects, three became totally occluded and two disappeared.

Fig. 16 focuses on the irregular lesions progressing to occlusion. Nine of 10 lesions becoming totally occluded had 295 % stenosis. Of 19 lesions with 295 % stenosis, nine (47%) became occluded, whereas of

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Fig. 4. This figure demonstrates two sequences: the rapid progression from a normal to a significant irregular lesion, and then the persistence of the irregular lesion over 14 months. This 46-year-old male diabetic and smoker presented with a l-month history of atypical chest pain. The coronaries showed very mild luminal irregularities (A). Two years and 3 months later, he was admitted after an episode of prolonged constrictive retrosternal pain associated with nonspecific ST-T changes in the anterolateral leads. A 50% lesions (B) with an overhanging edge (similar to Fig. 5 in reference 2) was seen in the mid left anterior descending coronary artery. One year and 2 months later, he was read- mitted with crescendo and rest angina of 1 week’s duration. No significant change in the lesion or the arteriogram is seen (C).

Fig. 5. Another example of a lesion with a rough irregular surface persisting on follow-up. This 53-year-old man with an old MI presented with angina at rest. The circumflex artery (A) showed a 55% narrowing with a rough surface and an overhanging border. One month following coronary bypass surgery, he returned with unstable angina and was treated medically. Fifteen months later, unstable angina recurred. Two grafts were occluded. The lesion in the circumflex still shows the luminal irregularity (B).

those with <95 % stenosis, only 4 % became occluded (p < 0.001).

The fate of irregular lesions in patients with intervening bypass surgery was examined separately, since the development of total occlusion may have been related to surgery. Indeed, there was a higher incidence of occlusion (28 of 61 or 46 % ). Of the 33 lesions remaining open, 23 (70%) were without change, six (18%) improved, and four (12 % ) became more severely narrowed (but not occluded). Only four of these lesions had become smooth, two with improve- ment, one with worsening, and one without change.

DISCUSSION

In this study of coronary lesion morphology in patients with serial coronary arteriograms, we found

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Fig. 6. This figure demonstrates the persistence of this severe lesion with a sharp perpendicular edge and an irregular surface. This 67-year-old man came in with exertional angina of 5 months’ duration increasing over 2 weeks. The severe irregular lesion in the right coronary artery is shown (A). Two years and 7 months later, he returned with a recurrence of exertional angina. The lesion in the right coronary artery shows no change (B).

that: (1) Complex lesions usually originate,in normal or near normal areas in the coronary tree. (2) Many complex lesions did not change their morphology over time. (3) High-grade irregular lesions (195 % occlusion) and only high-grade lesions frequently went on to total occlusion. (4) Filling defects always resolved or became totally occluded. (5) Smoothing of complex lesions rarely occurred except in ulcer- like lesions (outpouching) that filled in. These findings may have important implications with respect to the etiology of myocardial infarction and to the mechanism of progression of atherosclerosis in coronary arteries.

In the early nineteen thirties, several patholo- gistsgp lo reported that in thrombosed coronary arter-

ies the atherosclerotic plaque underlying the thrombus very frequently showed ulceration of the intima with hemorrhage into the deeper layers of the plaque. These findings were repeatedly confirmed in the early sixties by careful pathologic studies employing serial sectioning techniquesli These pathologic observations, however, were largely ignored because of the ongoing debate over whether coronary thrombo-

sis was the cause or the result of myocardial infarction. It was not until 1980, when total occlusion by thrombus became widely accepted as the cause of myocardial infarction, that plaque rupture underlying the lethal thrombi became the focus of attention.

Levin and Fallon first showed that postmortem contrast angiography could be used to identify complex atherosclerotic lesions-those with histologically demonstrated plaque rupture, plaque hem- morhage, superimposed partially occluding thrombus, or recanalized thrombus. They found that these “more dangerous” complicated plaques could be identified by postmortem angiograms with 88 % sen- sitivity and 79% specificity. Ambrose et al.” used similar morphologic analysis of coronary arteriograms in living patients with unstable angina and found that there was a higher incidence (71%) of similar irregular complex-appearing lesions in these patients than in patients with stable angina (16% ).

From similar angiographic studies,4 we also found that complex morphology with the occurrence of irregular lesions and/or filling defects suggesting clot or plaque rupture is common in patients with unstable angina and is more frequent than in those with stable angina (73% versus 47% ).

In 1983, Moise et a1.12 studied patients with unstable angina who had arteriograms before and after the clinical event and found that unstable angina was frequently associated with new atherosclerotic lesions or with marked progression in the severity of previous lesions. We had previously reported data on symptomatic patients with serial arteriograms and found that (1) progression was as common and as rapid in patients with mild disease as in those with severe atherosclerosis elsewhere in the coronary treeI and (2) that severely occlusive lesions on later angiogram were frequently in areas of the coronary tree that had been only mildly diseased or were normal on the previous arteriogram.14 In these studies, lesion morphology was not reported.

Studies such as these have suggested a modifica- tion of the thrombogenic (accretion) theory for progression of atherosclerosis, first conceived by Van Rokitansky in 185215 and revived and supported with

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Fig. 7. This figure demonstrates the persistence of an irregular lesion over almost 7 years and through two bypass surgery procedures. A 53-year-old man presented with a non-Q wave MI. The circumflex artery (A) shows an eccentric irregular lesion with overhanging border just before the takeoff of the obtuse marginal branch (OM). He underwent bypass surgery. Two years and 3 months later, he came again with unstable angina of 1 week’s duration. Although the OM is occluded (grafted), the lesion in the circumflex is the same (6). One year and 5 months later, he presented with crescendo angina. The circumflex lesion is unchanged (C). Repeat bypass surgery was performed. Three years later, recurrence of angina prompted repeat angiography (D). Although slight smoothing of the surface has occurred, the lesion is still irregular with an overhanging border.

experimental evidence by Duguid in 1946.16 The theory suggests that a major factor in the formation and progression of an atherosclerotic plaque is the incorporation of thrombus into the wall of the artery. Although there has been experimental and anatomic evidence to support that transformation of thrombus into an atherosclerotic plaque can occur, the relative contribution of this phenomenon to the clinical progression of atherosclerosis has remained unclear. With the acknowledgment that ruptured atherosclerotic plaque with nonocclusive thrombus is a common mechanism for the occurrence of unstable angina, and that unstable angina is frequently associated with progression of coronary occlusive disease, it has become widely held17 that a common sequence of events that leads to severe atherosclerosis is (1) the

development of a nonocclusive atherosclerotic plaque, (2) rupture of the plaque with development of a nonocclusive thrombus and a severe complex coronary lesion on arteriography, and then (3) reen- dothelialization of the ruptured plaque surface and growth of the plaque. In this study, we attempted to provide clinical angiographic support for this theo- retical concept. We found from studying the precursors of significantly occlusive complex lesions that the first part of this conceptual mode of progression is applicable in many instances. Severely occlusive complex lesions are frequently preceded by smooth- walled mild abnormalities or by normal-appearing or near normal arterial segments, suggesting that much of the progression is associated with mild smooth lesions suddenly becoming irregular and more occlu-

1056 Huft and Al-Zarha April 1991


Fig. 8. This figure shows the persistence of an irregular lesion and the disappearance of an associated filling defect. This 55-year-old man presented with a non-Q wave MI. The circumflex artery shows subtotal irregular obstruction with a filling defect (A). He underwent bypass surgery. Seven months later, he returned because of persistent angina. Three grafts were occluded. The circumflex lesion is still irregular, but the filling defect has disappeared (B).

sive by plaque rupture with or without nonocclusive thrombus. However, we did not find the evolution of complex lesions into smooth-walled lesions, except in rare instances. Rather, we found that in most cases a complex lesion would remain complex and irregular for years, without changing. Some lesions, especially the irregular lesions that were severely occlusive (95%), went on to total occlusion but not to smoothing.

It is possible that had the interval between arteriograms been longer, we would have found persistence of irregular lesions to be less common and smoothing to be more frequent. But this is unlikely, since we found complex lesions to be stable in serial arteriograms with as long as 5 to 7 years between

Fig. 9. This figure demonstrates the disappearance of a filling defect. A 54year-old man with a 6-month history of angina presented after a prolonged episode of chest pain. The right coronary artery (A) shows a short skip lesion with a convex distal border, suggesting a filling defect. He was subjected to bypass surgery. One year and 8 months later, he presented with nocturnal chest pain. The filling defect has disappeared, leaving the vessel with only minimal luminal irregularity (6). All filling defects in this study either resolved or turned into total occlusion.

studies. Similarly, in the study of Ambrose et a1.,3 patients with unstable angina within 2 months of the study (the traditional definition) and those between 2 and 6 months after an episode of unstable angina had an identical incidence of irregular lesions, suggesting that no smoothing occurred in up to 6 months. In a recent study by Davies and Thomas’* in 74 patients with sudden (<6 hours) ischemic death and coronary thrombosis, there were 115 separate instances of thrombosis, of which 103 were associated with plaque fissuring. The existence of more than one ruptured plaque in a patient suggests that either both occurred at the same time or more likely, that

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Fig. 10. Another example of an “ulcer-like” outpouching of dye (A) that filled in, leaving a severe smooth lesion (B). This &&year-old man presented with three episodes of rest pain over the previous 2 months. Three-vessel bypass surgery was performed. Seven months later, he presented with unstable angina following nephrolithotomy. The graft to the right coronary was occluded. The outpouching had disappeared.

ruptured plaques can persist unchanged for an in- definite period.

The surprising finding that irregular lesions usually remain irregular over a mean interval of 2.2 years has several possible explanations. First, because these patients were restudied for clinical indications (usually persistence or recurrence of chest pain), they may be a selected group in whom the healing of the ruptured plaque did not take place. That the persistence of ruptured plaques without healing may occur is an intriguing possibility that may explain other clinical observations. In the Canadian MultiCenter Trial of unstable angina, I9 the curve representing the occurrence of cardiac death in the aspirin-treated group was almost flat, while the curve for those not treated with aspirin continued to diverge at a con-

Fig. 11. This figure demonstrates the progression from intraluminal disease to severe complex stenosis. This 60-year-old man had a small true posterior infarction 4 years ago. The right coronary showed only intraluminal disease (A). He presented this time with unstable angina (B). The right coronary artery now has a severe complex lesion.

stant rate for the full follow-up period of 2 years. This suggests that the lesion of unstable angina may indeed remain unstable for up to 2 years.

Second, although a ruptured plaque may heal, it may remain irregular. Twenty-one percent of the irregular plaques seen angiographically were not found to be complicated lesions histologically2 and thus may well represent healed ruptured plaques. Al- though lesions may be smooth with an intact endo- thelium on histologic cross section, they may still be irregular when examined longitudinally with angiography. Also, the plaques that were only mildly irregular and thus more likely to become smooth with healing may have been missed because of the relative insensitivity of angiography in detecting minor de- grees of irregularity. In this study we used a strict

1058 Haft and Al-Zarka April 1991


Fig. 12. This figure demonstrates the persistence of this lesion with a rough irregular surface. The patient is 65 years old. She presented with severe retrosternal pain that awakened her from sleep. The right coronary artery shows a 70% lesion with a rough surface (A). Two and a half years, later she presented with unstable symptoms again. The lesion is still complex (6).

definition of lesion irregularity and only lesions that were definitely irregular were considered as such.

Another possible explanation is that some of these lesions represent recanalized thrombi (meticulously studied by Friedman20) that may appear irregular on angiography. In the study of Levin and Fallon, recanalized thrombi were included in the pathologically defined complicated lesions that correlated with complex coronary morphology on postmortem angiography. Although Friedman20 emphasized that these are susceptible to hemorrhage, leading to rein- farction and death, it is possible that most remain unchanged for years.

Regardless of these explanations, however, the rarity of smoothing of irregular plaques suggests the

Fig. 13. This lesion with a sharp perpendicular edge persisted over more than 3 years. The patient presented with unstable angina each time. The first (A) and second (8) arteriograms are separated by 1 year, and the second and third (C) arteriograms are separated by 2’4 years.

possibility that plaque rupture/thrombosis may not commonly be a phase in the evolution of the usual uncomplicated plaque, but rather represents an al- ternate pathway in the progression process, and plaques that evolve in this manner may remain dis- tinguishable from uncomplicated plaques.

These findings support the concept that progression of atherosclerosis can occur in two modes21-

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% 7O%J

60% -

F 60% -

40% -

& 30%-

T 20%- A L

lO%-

0%'

23%

REG NO CHANGE PROG T.O.

FATE ON FOLLOW UP

0 TOTAL m REMAINING COMPLEX

Fig. 14. The fate (change in percent stenosis) of complex lesions. Progression to occlusion occurred in 23 “;#. Of lesions remaining open, most (57 “0 ) did not change. Hatched bars show how many lesions were still complex on follow-up. All lesions were still complex except two of the lesions that regressed. REG, Re- gressed; PROG, progressed; T.O., total occlusion.

one, time-dependent with gradual slow growth of smooth atherosclerotic plaque, and the other, time- independent, characterized by a rapid (possibly abrupt) increase in severity. The mechanism of this second time-independent mode of progression is probably via acute plaque rupture with or without overlying thrombus, with complex angiographic lesion morphology then remaining stable for a long period of time, without reforming or remodeling of the morphology of the plaque.

Our findings suggest that an angiographically assessed irregular coronary lesion may be a marker of an acute event that may have occurred either recently or many months before, and may not necessarily im- ply current instability unless associated with new symptoms. The higher incidence of irregular lesions in patients with unstable angina than in those with stable angina does not necessarily contradict this. In studies examining this issue,3s 4 a considerable per- centage of patients with stable angina had irregular lesions. These may be patients who had a period of unstable angina in the past, while those without irregular lesions may have never had such an episode. Therefore in a patient with unstable symptoms and multiple lesions, it cannot be automatically assumed that an irregular lesion is the “culprit” lesion. In identifying the culprit lesion, morphology should be used in conjunction with other evidence (e.g., loca- tion of electrocardiographic (ECG) changes). Other features of the lesions in addition to irregularity may be more important in indicating a recent onset, such as the presence of filling defects, staining, or haziness.

In this study we also examined two relatively de-

Table I. Precursors of complex lesions

No Surgery Surgery Total

No change 26 23 49 Improved 4 0 4

From total occlusion 2 From filling defects 2

Progressed 40 13 53 From normal 12 4 16 From intraluminal 12 4 16

disease (<30”< ) From 30°C -49 “( 3 (II) 2 (11) 5 (21) From 5O’a -60”CS 8 (11) 2 10 (11) From 70 “;) -75 c,j 5 (31) 1 (11) 6 (41) Total 70 36 106

I, Precursor was an irregular complex lesion.

finable subgroups in the irregular category. These were filling defects (probable clots) and outpouchings of dye outside the apparent lumen of the vessel (ulcers) (Figs. 9 and 10). There were no filling defects that persisted; they either resolved or became totally occluded. Most outpouchings disappeared (filled in). If there was irregularity in the lesion other than the outpouching, that irregularity usually persisted. Most often with the filling of the outpouching the lesion became smooth. This angiographic appearance (outpouching) was shown to represent ruptured plaque in a recent report of a patient dying soon after angiography.‘” That these outpouchings usually fill in should not be surprising, since stagnation of blood would be expected in such a lesion.

The study of precursors of irregular lesions dem-

1060 Haft and Al-Zarha April 1991


SEVERITY OF LESIONS REMAINING CxL

MORPHOLOGY ON FOLLOW UP

CxL- COMPLEX LESION, Sm- SMOOTH LESION T.O.. TOTAL OCCLUSION

Fig. 15. Change in morphology of complex lesions (large pie). The small pie shows the change in severity of lesions remaining complex on follow-up. REG, Regressed; PROG, progressed.

%

L 60% Go . 40%

T 0 30%

: c 20%

b 7 10%

0 N

0% :

1 ,- P’O.001 -

‘

F 71 I

’ 96% STENOSIS ( 96% STENOSIS

% STENOSIS ON INITIAL CATH

Fig. 16. Influence of stenosis severity of complex lesions on their progression to occlusion.

onstrates that of lesions that were more severe on the latter arteriogram, most (66 % ) had progressed from areas that were previously smooth and only midly narrowed (0% to 49% ). This may correspond to the rapid time-independent form of progression of atherosclerosis. However, for the first time we have shown that this rapid progression in severity is almost always associated with a change in morphology from smooth to irregular, suggesting that it represents rupturing of plaques ( + superimposed thrombus). Progression from an irregular plaque to a more severe nontotally occluding irregular plaque occurred rarely, and usually in plaques that already had caused > 70 % stenosis.

Much more often when progression occurred in an irregular plaque (which was uncommon) it was to to-

tal occlusion. This occurred most often in severely narrowed irregular lesions. Thus it appears that rapid progression to total occlusion is often a two-step process: first from mild smooth plaque to a severe irregular lesion and then from a severe irregular lesion to total occlusion. If the intervening irregular lesion is not very tight, it may persist unchanged for years. This finding is in accordance with the pathologic studies of Falk,23 showing that most occlusive thrombi (88%) occur on top of ruptured plaques that are severely occlusive (185 % ), while it is rare (9 % ) for occluding thrombi to develop on ruptured plaques causing less severe (<85%) narrowing.

These findings may also have a clinical correlation in patients with unstable angina, approximately 20 % of whom go on to myocardial infarction or sudden

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death within 2 years. In our study, 23% of irregular lesions (possibly a sign of unstable angina) went on to total occlusion (clinically possibly myocardial infarction [MI] or death). We have also been able to identify those lesions that have a higher incidence of progression to total occlusion as irregular lesions 295 % stenosis or those with filling defects. This may have importance in determining which patients with an episode of unstable angina should have interven- tion with angioplasty or bypass surgery.

In conclusion, we have shown that: (1) High-grade irregular coronary lesions usually arise from mild smooth lesions, supporting the concept that these are plaques that suddenly rupture, becoming irregular and severely obstructive. (2) Irregular lesions have a low incidence (23 ‘5% ) of progressing to total occlusion, with usually only those with severely obstructive (295 ‘% ) lesions or those with filling defects becoming totally occluded. (3) Irregular lesions that do not become totally occluded rarely progress in severity. (4) Except for filling defects and ulcer-like outpouchings, irregular lesions rarely become smooth.

These findings support the concept of a pathway for the progression of coronary disease other than a time-dependent slow progression. This suggested pathway is rapid or abrupt and is characterized angiographically by a change from a smooth mild lesion to a more severe irregular lesion. If the resulting lesion is very severe or is associated with visible filling defects, then the risk for progression to total occlusion is high. Otherwise, the lesion remains angiographically irregular (and possibly pathologically complex) for up to several years and rarely goes back to a smooth lesion.

We thank Faye Marley for expert secretarial assistance.

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