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(Circulation. 1995;92:1731-1736.)
© 1995 American Heart Association, Inc.

Articles

Unstable Angina

A Comparison of Angioscopic Findings Between Diabetic and Nondiabetic Patients

Presented in part at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Ga, March 1994.

Jose A. Silva, MD; Alvaro Escobar, MD; Tyrone J. Collins, MD; Stephen R. Ramee, MD; Christopher J. White, MD

From the Department of Internal Medicine, Section on Cardiology, Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, La, and Invasive Cardiology (C.J.W.), HCI Medical Center, Clydebank, Scotland.

Correspondence to Christopher J. White, MD, Director of Invasive Cardiology, HCI Medical Center, Beardmore St, Clydebank, Scotland, G81 4HX.

	Abstract

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Background Patients with diabetes mellitus have a higher prevalence of atherosclerotic heart disease and a higher incidence of myocardial infarction than the general population. Diabetic patients also have several hematologic, rheologic, and metabolic abnormalities not present in their nondiabetic counterparts that may predispose them to atherosclerotic plaque rupture and intraluminal thrombosis and consequently may lead to the formation of morphologically complex plaques and the development of acute coronary syndromes.

Methods and Results Percutaneous coronary angioscopy was performed in 55 consecutive patients with unstable angina. We observed plaque color, texture, and the incidence of intracoronary thrombus associated with the culprit lesions of these patients. The population consisted of 17 (31%) diabetic and 38 (69%) nondiabetic patients. The presence of coronary risk factors was not significantly different between the two populations. Ulcerated plaque was found in 16 of 17 (94%) diabetic patients versus 23 of 38 (60%) nondiabetic patients (P=.01). Intracoronary thrombi were seen in 16 of 17 (94%) diabetic patients versus 21 of 38 (55%) nondiabetic patients (P=.004).

Conclusions The results of the angioscopic examination show that diabetic patients with unstable angina have a higher incidence of plaque ulceration and intracoronary thrombus formation than nondiabetic patients. This increased frequency of complex lesion morphology is consistent with the disproportionately higher risk for development of acute coronary syndromes in these patients.

Key Words: diabetes mellitus • angina • angioscopy • plaque

	Introduction

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Diabetes mellitus, a well-established risk factor for development of coronary artery disease,^{1 2} is commonly found in patients admitted to the hospital with unstable coronary syndromes. Several in vivo and postmortem studies have shown that diabetic patients have more diffuse and severe coronary artery disease than the general population.^{1 3 4} In addition, the relative risk of myocardial infarction is greater in diabetic patients than in the normal population,⁵ and acute myocardial infarction may be the cause of death in a significant proportion of these patients.⁶

The cause of this difference in the diabetic population is not well understood. The increased incidence of myocardial infarction may simply reflect the higher prevalence of significant coronary artery disease. However, diabetic patients have several hematologic, rheologic, and metabolic abnormalities not present in their nondiabetic counterparts^{7 8 9 10 11 12 13 14} that may predispose them to plaque disruption and thrombus formation and lead to the development of unstable coronary syndromes.

To date, very few studies, all of which have been postmortem studies, have attempted to explain these differences between diabetic and nondiabetic patients. Our study is the first to analyze differences in plaque morphology between diabetic and nondiabetic patients in vivo with the use of coronary angioscopy in a cohort of unstable angina patients.

	Methods

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Patient Selection
Percutaneous coronary angioscopy was performed in 55 consecutive patients with unstable angina before intervention. Unstable angina was defined as (1) crescendo angina (more severe, prolonged, or frequent) superimposed on a preexisting pattern of stable, exertion-related angina pectoris, or angina pectoris of new onset (within 1 month), (2) angina pectoris at rest, or (3) postinfarction unstable angina (within 2 weeks of a documented myocardial infarction).¹⁵ Upon admission, all of the patients were treated with a standard medical regimen, which included aspirin, heparin, nitrates, ß-blockers, and calcium channel blockers. If they responded to medical treatment, the procedure was electively performed within 48 hours. If the patient remained unstable despite full medical treatment, the procedure was performed immediately. All patients gave informed consent, and the protocol was approved by the hospital's institutional review board.

Coronary Angiography and Culprit Lesion Assessment
Coronary angiography was performed in every patient before angioscopy and angioplasty with the use of standard catheters and techniques. Each coronary artery was selectively viewed in multiple projections. In cases of significant single-vessel disease, this lesion was considered to be the culprit lesion. In cases of multivessel disease, the culprit lesion was identified by one of the following criteria: ST-T changes on ECGs obtained during anginal episodes at rest in the territory of a vessel with a significant stenosis (greater than 70%); significant segmental wall motion abnormalities in the left ventriculogram in the distribution of a vessel with a significant stenosis; or the presence of an Ambrose type II eccentric lesion.¹⁶

Coronary Angioscopy Assessment
The coronary angioscopic procedure has been described elsewhere.¹⁷ Briefly, we used a standard coronary angioplasty technique in which the stenotic lesion was crossed with the 0.014-in guide wire. The angioscope (Imagecath, Baxter Healthcare) then was advanced over the guide wire under fluoroscopic guidance so that the distal tip marker on the angioscope was located proximal to the target lesion but did not come into contact with the lesion. The angioscope occlusion balloon then was inflated with low pressure (1 to 2 atm). After balloon inflation, warmed lactated Ringer's solution (0.5 to 1.0 mL/s) was infused through the distal port to create a blood-free field during viewing. Angioscopic images were recorded on videotape for immediate review and archiving. Guiding catheter pressure, ST segment changes, cardiac rhythm, and patient comfort were monitored continuously during angioscopy.

Assessment of Other Clinical Variables
Other clinical variables assessed included age, sex, treatment received before and at admission, and time elapsed since the patient arrived until the procedure was performed. Coronary risk factors, including hypertension, tobacco use, and hypercholesterolemia, also were noted. All of the patients had at least one cholesterol test some time during the previous 3 months. All the smokers consumed at least 10 cigarettes per day. The diagnosis of diabetes mellitus and diabetic neuropathy were made according to established criteria.^{18 19} The activity level was assessed in each patient with use of the New York Heart Association functional classification.

Data Analysis
The coronary angioscopic findings were reviewed by two interventional cardiologists with extensive angioscopy experience who were blinded to the clinical and angiographic status of the patients. Atheromatous plaque was defined as raised yellow or white material within the arterial lumen. The surface texture of the plaque was determined to be either smooth or rough. The presence of ulceration was defined as an atheromatous plaque with an irregular, ragged surface (Fig 1). We defined thrombus as a collection of red, solid material adherent to the luminal surface despite flushing (Fig 2). The angioscopic end points were differences between diabetic and nondiabetic patients in plaque color, surface texture, presence of ulceration, and presence of intracoronary thrombus.

View larger version (0K): [in this window] [in a new window]   Figure 1. Angiograph with magnified inset: Complex plaque morphology with plaque ulceration and intracoronary thrombus in a diabetic patient.

View larger version (0K): [in this window] [in a new window]   Figure 2. Angiograph and magnified section: Yellow plaque with intracoronary thrombus in a diabetic patient.

Data are expressed as mean values±1 SD. Comparisons between the groups for continuous variables were performed using a two-tailed unpaired Student's t test and for discrete variables using Fisher's exact test. A value of P<.05 was considered significant.

	Results

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Of the 55 patients, 17 (31%) had diabetes mellitus and 38 (69%) did not. All of the diabetic patients had type II diabetes mellitus. Although no statistical differences were found in age, sex, clinical presentation, or coronary risk factors, diabetic patients were slightly older and tended to smoke less (Table 1). There was no difference in the time elapsed from the last episode of chest pain to the angioscopy for the diabetic group at 29.3±14.4 hours compared with 29.8±14.2 hours in the nondiabetic group (P=.90). The type of unstable angina and the activity level before development of unstable angina were not different between the groups (Table 2).

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of Diabetic and Nondiabetic Patients

View this table: [in this window] [in a new window]   Table 2. Activity Level Before Development of Unstable Angina and Type of Unstable Angina

The mean duration of diabetes mellitus was 8.2±8.9 years (range, 2 months to 35 years). Four (23%) patients had diabetic neuropathy (one patient had peripheral, two patients had peripheral and autonomic, and one patient had autonomic neuropathy; see Table 3). The four patients with diabetic neuropathy had had diabetes mellitus for more than 18 years.

View this table: [in this window] [in a new window]   Table 3. Clinical Characteristics of the Diabetic Population

The prevalence of coronary artery disease (more than 50% diameter stenosis) and culprit lesion location are described in Table 4. Diabetic patients had a higher prevalence of three-vessel disease (47% versus 31%) and lower prevalence of single-vessel disease (18% versus 32%) than nondiabetic patients, although these differences were not statistically significant. Although the culprit lesion was more frequently located in a saphenous vein graft in diabetic patients, this difference was not significant (35% versus 19%, P=.18).

View this table: [in this window] [in a new window]   Table 4. Angiographic Findings in Diabetic and Nondiabetic Patients

The angioscopic characteristics of both groups are described in Table 5. Yellow plaque was found in 88% of diabetic patients and 84% of nondiabetic patients. Roughness of the plaque surface was somewhat more frequent in diabetic patients than in nondiabetic patients (88% versus 68%), but this difference was not statistically significant. Plaque ulceration was found in 16 of 17 (94%) diabetic patients compared with 23 of 38 (60%) nondiabetic patients (P=.01). Intracoronary thrombi were seen in 16 of 17 (94%) diabetic patients versus 21 of 38 (55%) nondiabetic patients (P=.004).

View this table: [in this window] [in a new window]   Table 5. Angioscopic Findings in Diabetic and Nondiabetic Patients

	Discussion

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Prevalence of Coronary Artery Disease
Coronary atherosclerosis not only is more prevalent in diabetic patients but is more severe. The reported prevalence of coronary artery disease in diabetic patients ranges from 9.5% to 55%,^{20 21 22 23 24} whereas prevalences of 1.6% to 4.1% have been observed in the general population.^{25 26} Patients with diabetes have a higher incidence of two- and three-vessel disease and a lower incidence of single-vessel disease at coronary angiography or autopsy than do their nondiabetic counterparts.^{1 3} The incidence of severe left main coronary disease also is significantly higher (13% versus 6%) in diabetic patients than in nondiabetic patients.⁴ In one large autopsy study, Waller et al⁴ reported that 91% of patients with adult-onset diabetes (type II) had severe (>75%) narrowing of at least one major coronary artery and 81% had severe two- or three-vessel involvement. In a cohort of patients of similar age without overt diabetes or known coronary heart disease, Baroldi et al²⁷ found that only 33% had severe single-vessel coronary narrowing and 17% had severe two- or three-vessel disease at autopsy.

Whether or not coronary atherosclerosis is more diffuse in diabetic patients is controversial.^{4 28} In the autopsy study of Waller and coworkers,⁴ the diabetic patients had more severe stenoses, but there was no difference in other arterial segments when compared with nondiabetic patients. However, in another autopsy study by Crall and Roberts,²⁹ more extensive and diffuse coronary artery disease was found in diabetic patients.

Incidence of Myocardial Infarction
The relative risk of myocardial infarction is 50% greater in diabetic men and 150% greater in diabetic women, and myocardial infarction may be the cause of death in up to 30% of diabetic patients.^{5 6} The cause of this increased incidence of myocardial infarction among diabetic patients is not clear. In part, it may be a reflection of the higher prevalence of coronary artery disease in this population. Nevertheless, diabetic patients have significant abnormalities in their hematologic, rheologic, and metabolic systems that may increase their risk for myocardial infarction.

Hematologic, Rheologic, and Metabolic Abnormalities
Platelet aggregation, an essential step in occlusive thrombus formation, is enhanced in diabetic patients.^{9 10 11 12 13 14 30 31} Furthermore, platelet consumption is higher in diabetic patients, and ß-thromboglobulin and platelet factor 4, two platelet-specific proteins thought to reflect in vivo platelet activation, are elevated in these patients.^{7 30} Plasma fibrinogen levels also are increased in diabetic patients^{30 32} and have been shown to correlate with myocardial infarction and sudden death in this population.⁹

There are other conditions in diabetic patients that may increase their risk of a cardiac event. Procoagulant factors such as factor VIII and factor VIII ristocetin cofactor antigen and fibrinopeptide A, which reflect in vivo thrombosis, are elevated in diabetic patients.^{7 9 30 33} Endogenous fibrinolysis also has been found to be decreased in diabetic patients,^{30 32 33} whereas endothelial damage in patients with diabetes results in deficient production of prostacyclin.^{30 34 35 36}

Rheologic abnormalities include high levels of plasma proteins, which increase red cell aggregation and lead to decreased red cell deformability.^{7 8} Diabetic patients also have elevated plasma and whole blood viscosity, which increase shear forces, thereby increasing the likelihood of plaque rupture.^{8 37}

Among the multiple biochemical abnormalities produced by diabetes mellitus is the formation of protein-linked advanced glycosylation end products such as low-density lipoproteins.^{38 39 40} High levels of advanced glycosylation end products have been found within the atherosclerotic plaque in diabetic patients.⁴¹ Advanced glycosylation end products also may induce an inflammatory reaction by promoting cytokine release and monocyte chemotaxis.⁴² Previous studies have shown that atherosclerotic plaques rich in lipid-laden macrophages and extracellular lipids are more prone to rupture.⁴³ In addition, inflammation may play a role in destabilizing the fibrous cap tissue of the atherosclerotic plaque and thus enhance the risk of rupture and thrombosis.⁴⁴

Enhanced Development of Complex Plaques in Diabetics
In the present study, the overall incidence of plaque ulceration (71%) and intracoronary thrombi (67%) are in agreement with previous angioscopic and postmortem studies in unstable angina patients.^{45 46 47 48} When we divided the population between diabetic and nondiabetic patients, we found a significantly increased incidence of both plaque ulceration (94%) and thrombosis (94%) in diabetic patients as compared with 60% and 55%, respectively, for nondiabetic patients (Table 5).

To our knowledge, no comparative information exists regarding the in vivo differences in plaque morphology of unstable angina patients with or without diabetes mellitus. However, there does appear to be an association between diabetes mellitus and coronary ischemic syndromes in which the development of complex plaque morphology is very frequently implicated.^{49 50}

In a postmortem study of 168 patients with sudden ischemic death, Davies et al⁵¹ found that patients with diabetes or hypertension or both appeared to have a greater number of fissured atherosclerotic plaques than persons without diabetes. Jacoby and Nesto⁵² suggested that diabetes is associated with an increased tendency for both atherosclerotic plaque formation and intraluminal thrombosis, which may increase the propensity to develop myocardial infarction. Several studies have determined that the major factor precipitating coronary thrombosis is plaque rupture,^{53 54 55 56} which is more common in diabetic and hypertensive patients.⁵¹

Comparability of Groups
In the present study, the clinical characteristics and coronary risk factors were comparable between the two groups. Although not statistically significant, the culprit lesion was located in a saphenous vein graft more frequently in diabetic patients than in nondiabetic patients. It is unlikely, however, that this small difference explains the significantly higher incidence of thrombosis and ulceration found in diabetic patients, since there is evidence in the literature suggesting no differences regarding frequency of complex plaque morphology during unstable angina between native coronary arteries and saphenous vein grafts.^{46 47 48 57 58 59}

Finally, although our two populations were homogeneous in terms of their premorbid activity level and unstable angina classification, it is possible that some of our diabetic patients may have presented at a more advanced stage of coronary ischemia than the nondiabetic patients. Diabetic patients may have a blunted awareness of ischemic chest pain or may become aware of their symptoms later in the course of myocardial ischemia, which could lead to an increased incidence of complex plaque morphology at the time of their initial presentation.⁶⁰

Conclusions
The present study is the first to report a significant difference in the incidence of complex plaque morphology between diabetic and nondiabetic patients with unstable angina. The overall incidence of plaque ulceration and thrombus formation was similar to previous studies, but when we divided the population between diabetic and nondiabetic patients, we found a significantly increased incidence of both plaque ulceration and intracoronary thrombus in diabetic patients. It is possible that the metabolic, hematologic, and rheologic abnormalities present in diabetic patients may predispose their atherosclerotic plaque to be less stable, more prone to disruption and ulceration, and to develop intracoronary thrombus. This would increase the likelihood that these patients would progress toward more severe stages of acute coronary ischemia. This increased incidence of plaque ulceration and thrombus formation is consistent with the disproportionately higher incidence of acute coronary syndromes in diabetic patients.

	Acknowledgments

 
The authors would like to express their appreciation to James O'Meara for technical and computer assistance and to Angela Lorio for editorial assistance during the preparation of the manuscript.

Received January 25, 1995; revision received April 3, 1995; accepted May 3, 1995.

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				Z. Milicevic, I. Raz, S. D. Beattie, B. N. Campaigne, S. Sarwat, E. Gromniak, I. Kowalska, E. Galic, M. Tan, and M. Hanefeld Natural History of Cardiovascular Disease in Patients With Diabetes: Role of hyperglycemia Diabetes Care, February 1, 2008; 31(Supplement_2): S155 - S160. [Abstract] [Full Text] [PDF]

				A. Kapur and R. De Palma Mortality after myocardial infarction in patients with diabetes mellitus Heart, December 1, 2007; 93(12): 1504 - 1506. [Abstract] [Full Text] [PDF]

				J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]

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				T. J. Orchard, T. Costacou, A. Kretowski, and R. W. Nesto Type 1 diabetes and coronary artery disease. Diabetes Care, November 1, 2006; 29(11): 2528 - 2538. [Full Text] [PDF]

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				K.-H. Mak and D. P. Faxon Clinical studies on coronary revascularization in patients with type 2 diabetes Eur. Heart J., June 2, 2003; 24(12): 1087 - 1103. [Abstract] [Full Text] [PDF]

				M. Laakso and J. Kuusisto Diabetology for cardiologists Eur. Heart J. Suppl., January 1, 2003; 5(suppl_B): B5 - B13. [Abstract] [PDF]

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