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(Circulation. 1995;92:2033-2035.)
© 1995 American Heart Association, Inc.

Articles

Angina Pectoris and Disease Progression

Erling Falk, MD, PhD; Valentin Fuster, MD, PhD

From Mount Sinai Medical Center, New York, NY.

Correspondence to Valentin Fuster, MD, PhD, Director, Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Pl, Box 1030, New York, NY 10029-6574.

Key Words: Editorials • angina • angiography • plaque • prognosis

	Introduction

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 
A seemingly paradoxical finding for years puzzled cardiologists who were engaged in evaluating coronary angiograms: the number and severity of coronary stenoses were similar in patients with stable and unstable angina, despite the worse short-term prognosis of the latter.^{1 2} In 1985, Ambrose et al³ offered an explanation that since has been confirmed by many others: the difference between these two ischemic syndromes relates to the morphology of the culprit lesion rather than the number and severity of coronary stenoses. The distinct angiographic morphology characteristically seen in unstable angina was originally classified as a type II eccentric lesion and described as "an asymmetric stenosis usually in the form of a convex intraluminal obstruction with a narrow base or neck, due to one or more overhanging edges or borders that were very irregular or scalloped."³ Culprit stenoses in unstable angina, however, are not necessarily eccentric, and the term "complex" lesions is now generally preferred. Postmortem studies and coronary angioscopy in living patients have revealed that plaque disruption, often with superimposed nonocclusive thrombosis, is usually responsible for the "complex" morphology seen by angiography.^{4 5 6}

In patients with angina pectoris, previous studies on short-term prognosis have focused primarily on unstable angina-producing stenoses, ie, culprit lesions. Patients with stable or unstable angina pectoris, however, have many nonculprit plaques in their coronary arteries that could also influence the prognosis. Nonetheless, not much attention has been paid to nonculprit plaques in such patients. Therefore, the approach taken by Kaski, Chen, and colleagues,^{7 8} assessing the entire coronary tree rather than just looking for culprit lesions, is sound, and the results reported in this and a recent issue of Circulation illustrate clearly that the "conventional medical therapy" usually offered patients with angina pectoris is far from optimal.

	Disease Progression in Patients in the United Kingdom Awaiting Angioplasty

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 
Kaski et al,⁷ from St George's Hospital in London, UK, took advantage of the situation at their institution (relatively long waiting period for nonurgent coronary angioplasty) and prospectively assessed disease progression in 94 patients with angina pectoris who were considered "stable" and were therefore put on a waiting list for routine coronary angioplasty. At study entry, 63 patients presented with chronic stable angina and 31 had unstable angina (rest angina in 20), which rapidly resolved with conventional medical therapy. Several high-risk subgroups, such as patients with postinfarction angina and patients with significant left main or left main equivalent disease or >80% preseptal left anterior descending coronary stenosis, were excluded from the study. Disease progression was assessed by computerized angiography in 217 analyzable stenoses (2.3 per patient) showing >30% diameter reduction at baseline examination. Repeat coronary arteriography was performed 2 to 12 months later (mean, 8 months), immediately preceding the scheduled angioplasty in 68 patients who remained stable during follow-up and after an acute coronary event in the remaining 26 patients (myocardial infarction in 4; no deaths).

At baseline examination, 36% of the 217 stenoses were classified as "complex" and 64% were "smooth." Complex stenoses were more frequent in patients presenting with unstable angina than in patients with chronic stable angina: 47% versus 30% of stenoses. Separate analyses for culprit and nonculprit lesions are not given. At follow-up, 11% of the 217 preexisting stenoses progressed in 24% of patients. Progression occurred in 22% of the complex stenoses and in 4% of the smooth lesions. Of the stenoses that progressed, 65% developed total occlusion. Acute coronary events occurred in 57% of progressors and 18% of nonprogressors. Although clinically stabilized, patients presenting with unstable angina fared worse than patients with chronic stable angina (stenosis progression, 48% versus 13%; new acute event, 55% versus 14%). Both complex and smooth lesions appeared to progress more in "stabilized" unstable angina compared with stable angina (complex, 30% versus 14%; smooth, 10% versus 2%), and complex lesions progressed more than smooth lesions in both syndromes.

The authors conclude that (1) rapid stenosis progression is not uncommon in patients awaiting elective coronary angioplasty; (2) complex stenoses are at higher risk of rapid progression than smooth lesions; and (3) 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.

	High Frequency of Complex Lesions and Their Progression in Stable Angina Pectoris and in "Stabilized" Unstable Angina

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 
Complex lesions are much more common in patients with angina pectoris than one would expect from evaluating culprit stenoses alone. Previous studies indicate that only 10% to 20% of culprit lesions are complex in stable angina, but in the present study, as many as 42 complex lesions were found in 63 such patients. In unstable angina, fewer than 75% of culprit lesions are usually classified as complex,^{3 8} but this study identified 37 complex stenoses in 31 patients who presented with unstable angina.⁷ Although many acute lesions are probably missed by coronary angiography, these results substantiate previous observations made at autopsy: during atherogenesis, plaque disruption and rapid plaque growth occur frequently and usually asymptomatically.^{9 10 11}

The present study⁷ confirms that complex morphology, irrespective of the ischemic syndrome, is an important factor in the progression of coronary stenoses.¹² The novel observation is that a sizable proportion of patients who are clinically stable harbor complex lesions at relatively high risk of rapid progression. In patients with stable angina, 6% of the stenoses (6 complex and 2 smooth) progressed, and 14% of the patients developed an acute coronary event (2 myocardial infarctions). In contrast, in patients with "stabilized" unstable angina, 19% of the stenoses (11 complex and 4 smooth) progressed, and 55% of the patients developed an acute coronary event (2 myocardial infarctions). These are surprisingly high figures, considering that a favorable response to medical therapy usually identifies a low-risk subgroup of patients with unstable angina.¹³ During an 8-month follow-up previously reported,⁸ 25% of culprit lesions progressed versus 7% of nonculprit lesions. Thus, new clinical events are not necessarily due to disease "reactivation" at the site of the original culprit lesion. More diffuse disease activity may, in fact, characterize many patients with unstable angina, before unstable symptoms arise. Ambrose et al¹⁴ restudied 46 patients with angina pectoris and found progression of coronary disease in 76% of patients who developed unstable angina (mean follow-up, 30 months), and 21% of the progressors showed disease progression in more than one vessel.

	Mechanisms of Disease Progression

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 
Do culprit stenoses responsible for unstable angina subsequently regress due to endogenous thrombolysis and remodeling, as culprit lesions usually do in myocardial infarction,^{15 16} or do they heal by smooth muscle proliferation and matrix synthesis—as a response-to-injury mechanism, thrombosis, or both—resulting in further short-term plaque growth and stenosis progression?¹⁷ In the present study,⁷ including both stable and "stabilized" patients, only one nonspecified lesion regressed. In the previously reported study,⁸ including "stabilized" unstable angina, only three nonspecified lesions regressed, whereas 25% of the culprit lesions progressed during an 8-month follow-up. Thus, the culprit lesions responsible for unstable angina often progress further in the short term and rarely regress. These results, together with the lack of substantial improvement in lumen diameter by thrombolytic therapy in most patients with unstable angina,^{18 19} indicate that thrombus is rarely bulky in lesions responsible for this syndrome, as it usually is in infarct-related lesions. Nonetheless, thrombosis does play a dominant role in plaque progression for months after "stabilization," indicated by the high short-term occlusion rate; 65% of the stenoses that progressed in the present study developed into total occlusion, including all 10 stenoses >50% that progressed.⁷ As previously noted, the greater the preexisting stenosis, the higher the risk of progression to thrombotic occlusion.^{8 20 21} Appropriate antithrombotic therapy, also after "stabilization," may hold the key to keeping the vessel open not only during hospitalization for unstable angina but also after hospital discharge.²² It remains uncertain whether the mechanism responsible for rapid disease progression is the same in patients who present with unstable angina and patients with chronic stable angina.²²

	Present Medical Therapy Does Not Totally Stabilize or Prevent Progression of the Complex Lesions: A Role for Aggressive Risk Factor Modification?

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 
In the present study,⁷ conventional medical treatment in the form of antianginal therapy (combinations of calcium antagonists, nitrates, and ß-blockers) and low-dose aspirin (75 to 150 mg/d) stabilized all the patients, but it did not control the underlying coronary artery disease. During the 8-month follow-up, the progression rate was high in both stable angina (13%) and "stabilized" unstable angina (48%), although relatively few patients developed serious clinical events (4 myocardial infarctions, no deaths). Nearly half of the progressors remained clinically stable (silent progression). Fifteen patients developed total coronary occlusion, of which 6 passed unnoticed. Importantly, progression was not confined to culprit lesions, which clearly illustrates that atherosclerosis is a multifocal disease with many minor but potentially dangerous plaques for every obstructive plaque. Obviously, more needs to be done to stabilize not only the patients but also the underlying disease process itself.

Of importance, the high rate of progression in the present study may reflect patient selection. All the patients had such severe coronary artery disease that angioplasty was considered necessary. However, the lack of disease control could also relate to (1) the high proportion of smokers (62%), (2) the relatively high serum cholesterol level (mean, 6.4 mmol/L), and (3) the weak antithrombotic regimen (aspirin 75 to 150 mg/d). Regarding smoking, angiographic studies in stable patients have shown a strong association between smoking and progression of coronary artery disease.^{23 24} Regarding cholesterol, all patients treated with lipid-lowering drugs were excluded from the study, and the included patients had relatively high serum cholesterol levels. Recent clinical trials have now convincingly shown that patients with coronary artery disease and high serum cholesterol levels benefit from effective cholesterol-lowering therapy; both disease progression and acute clinical events are markedly reduced,^{25 26 27} and the two phenomena are clearly related.^{22 28} Regarding antithrombotic therapy, low-dose aspirin alone may not be enough in patients with active coronary disease. Stronger antiplatelet agents or combined low-dose aspirin and low-intensity anticoagulation may prove to be more effective in preventing disease progression, particularly the progression to total coronary occlusion that was so frequently observed in the present study.⁷

Overall, it may be time to reconsider whether "conventional medical therapy," as given in the present study, is the best way of treating patients in whom the disease has progressed so far that coronary revascularization is contemplated. Compelling scientific evidence demonstrates that comprehensive risk-factor interventions decrease the need for revascularization procedures and prevent heart attack and death in patients with coronary artery disease.²⁹

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.

	References

Top Introduction Disease Progression in Patients... High Frequency of Complex... Mechanisms of Disease... Present Medical Therapy Does... References

 

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This Article Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Falk, E. Articles by Fuster, V. Search for Related Content PubMed PubMed Citation Articles by Falk, E. Articles by Fuster, V.