Composition of Atherosclerotic Plaques in the Epicardial Coronary Arteries in Juvenile (Type I) Diabetes Mellitus Susanne L. Mautner, MD, Fengru Lin, MD, and William C. Roberts, MD
The composition of atherosclerotic plaques in 331 five-mm segments of the 4 major (left main, left anterior descending, left circumflex, and right) epicardial coronary arteries of 8 patients with juvenile (mean age at onset, 9 years; mean age at death, 29 years) diabetes mellitus was determined by computerized planimetric analysis. Analysis of all coronary segments disclosed that the plaques consisted primarily of dense (53%) and cellular (38%) fibrous tissue. Pultaceous debris (7%), foam cells (1.2%) and calcific deposits (0.7%) occupied a small percentage of the plaques. Thus, 91% of the coronary plaques in these young diabetic patients consisted of fibrous tissue and nearly all of the remaining 9% consisted of lipid deposits. Analysis of composition according to degrees of cross-sectional luminal narrowing revealed marked increases in dense fibrous tissue (from 31 to 74%), pultaceous debris (from 3 to 12%), and calcific deposits (from 0% to 3%) as the cross-sectional area narrowing increased from 125% to >75%. Compared with older patients with fatal coronary artery disease, the patients with juvenile diabetes had more dense fibrous tissue and pultaceous debris and less calcific deposits. (Am J Cardiol 1992;70:1264-1268)
From the Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received April 24,1992; revised manuscript received and accepted July 6, 1992. Address for reprints: Susanne L. Mautner, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N258,9000 Rockville Pike, Bethesda, Maryland 20892.
1264
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
I
t is well recognized that patients with diabetes mellitus have an increased risk of significant atherosclerosis compared with similar aged nondiabetic patients. Despite this fact, the composition of the atherosclerotic plaques in such patients has not been reported. Accordingly, we examined quantitatively the composition of atherosclerotic plaques in the 4 major epicardial coronary arteries in 8 patients with juvenile diabetes mellitus. METHODS Clinical features: Certain observations in the 8 patients are summarized in Table I. The patients ranged in age from 19 to 38 years (mean 29) at death, and at ages 2 to 13 (average 9) the onset of symptoms or signs of diabetes appeared. The duration of insulin therapy in the 8 patients averaged 20 years. The serum total cholesterol was >240 mg/dl in 5 of 6 patients. Three of the 8 patients had indirect systemic systolic arterial pressures >160 or diastolic pressures > 100 mm Hg, or both, on multiple occasions. Although no patient had a clinical event recognized as acute myocardial infarction, 2 patients (cases 7 and 8, Table I) had transmural acute myocardial infarcts at nccropsy , and death in each of them was attributed to the infarct. Methods of examining the coromuy arteries at necropsy: All 4 major epicardial coronary arteries were
dissected from the heart intact, decalcified, and sectioned transversely at 5-mm intervals. They were dehydrated, cleared, embedded in paraffin, cut and stained by the Movat method. A total of 331 five-mm segments were examined. Evaluation was done by planimetry (described in detail in a previous publication’), outlining the internal elastic membrane, residual lumen, and components of the plaque, such as dense fibrous tissue, cellular fibrous tissue, calcilic deposits, pultaceous debris, foam cells, foam cells with lymphocytes, and inflammatory cells without foam cells (Figure 1). The area of each component of plaque was then converted to a percentage of the total plaque area. For each patient the mean plaque composition was determined by calculating the mean of all 5-mm segments of the 4 coronary arteries of each patient. The total mean for the 8 patients was calculated as the mean of all 331 segments (Table II, Figures 2 and 3). For comparison with previous studies the total mean was calculated in the same fashion used in those studies, i.e., the total mean was based on the mean of each patient rather than on all segments (Figure 4). The degree of cross-sectional lumi-
NOVEMBER
15. 1992
nal narrowing was categorized into 5 groups: 0 to 25%, 26 to 50%, 51 to 75%, 76 to 95%, and 96 to 100%.
were narrowed by atherosclerotic plaque >75% in crosssectional area. Of the 331 five-mm coronary segments examined, 68 (21%) were narrowed >75% in cross-sectional area by plaque. Plaque composition: Plaque composition in all 331 five-mm segments in each of the 8 patients is summarized in Table II. Fibrous tissue was the domi-
RESULTS Cross-se&ional area narrowing: The results are summarized in Table II and in Figures 2 and 3. In 6 of the 8 patients, 1 or more epicardial coronary arteries TABLE
I Clinical
Observations
in the Eight Patients
Age Case 1 2 3 4 5 6 7 8 Total or Mean
(years) at Death 19
20 25 26 28 35 37 38 29
Age Sex F M F M M M M F 3F:5M
(years) at Onset DM
with Juvenile Duration of DM (years)
Diabetes
NS
TC* (mg/dl)
BUN? mg/dl
BPt (mmHg) (s/d)
CHF
Cause of Death Infection Hodgkin’s Renal Renal Renal CNS bleed AMI AMI
174
10
0
244 254 240 365 249 -
20 60 60 60 50 30
100/80 130/80 120/70 240/ 140 270/150 -240/140 130/70 130/80
0 0 0 + 0 + + 0
4
254
41
170/101
3
10 11
9 9
0 0
9 2 9 9 9 13
16 25 19 26 28 25
+ + + +
9
20
*Highest value recorded. iUsual value one to six months beforedeath. AMI = acute myocardial infarction; BP = blood pressure; BUN = blood urea nitrogen; nephrotlc syndrome; s/d = peak systoleiend diastole; TC = serum total cholesterol.
Mellitus
-
CHF = congestive
ATHEROSCLEROTIC
heartfailure:
PLAQUE
CNS = central newo~s system; DM = diabetes
COMPOSITION
IN DIABETES
mellitus;
MELLITUS
NS =
1265
160 310 300 340 430 450 450 340
348
1 2 3 4 5 6 7 8
Total or Mean
3
0 0 0 0 0 + + +
N
2
0 0 0 0 0 + + 0
F
ii3
bif
Mean % Plaque
Composition
(30) (11) (32) (3) (161 (35) (7) (17)
62 (19%)
14 4 9 1 7 17 4 6
Mellitus
(15) (0) (3) (0) (35) (42) (38) (19)
F = fibrosis;
71 (19%)
7 0 1 cl 15 20 21 7
51-75% (4) (Of (3) (0) (28) (19) (47) (33)
(0) (0) (0) (0) (5) (2) (6) (0)
6 (2%)
0 0 0 0 2 1 3 0
96-100%
FC = foam cells; FC+L
62 (17%)
2 0 1 0 12 9 26 1.2
76-95%
of Percent of 5 mm Segments Narrowed to 5 Categories of CSA by Plaque
26-50%
Number
Diabetes
area; DFT = dense fibrous tissue;
(31)
(2)
(51) (891 (62) (97) (16) (2)
130 (43%)
24 32 18 36 7 1 1 11
O-25%
with Juvenile
CSA = cross-sectional
331 (100%)
47 36 29 37 43 48 55 36
Number of5mm Segments
in the Eight Patients
Gross LV
Findings
CFT = cellular fibrous tissue; CD = calcific deposits; ventricular; N = necrosis; PD = pultaceous debris.
HW(g)
II Necropsy
Case
TABLE
= foam cells plus lymphocytes;
37.9%
43.3 23.9 91.7 95.9 32.0 7.2 14.0 23.0
39.8 64.1 2.6 4.1 62.8 84.8 76.5 61.5 53.3%
CFT
DFT
HW = heart weight:
PD
Plaques
1.2%
2.4 6.2 1.6 0.0 0.2 0.4 0.1 0.2
FC
Consisting
ICWFC = inflammatory
6.7%
14.4 5.8 4.1 0.0 4.8 7.2 4.3 14.9
of Coronary
0.7%
0.0 0.0 0.0 0.0 0.0 0.0 4.2 0.0
CD
Percent
cells without
0.1%
0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0
FC+L
of:
foam cells; LV = left
0.1%
0.0 0.0 0.0 0.0 0.2 0.1 0.2 0.1
ICWFC
Dense 80
Fibrous
Tissue
Cellular
Fibrous
Tissue
1 E ; aas s o
.
60-
f . B i 40ac . 5 3
a-25 %
26.50%
Calcific
51 -i5%
DeDos
0’
76.1.00%
ii
20-
, 0-25 %
3
26.50%
Pultaceous
/
/
51.75%
76.100%
Debrig
P
/
/---
....
UAP
--e-
F
The composition of atherosclerotic plaques in 331 five-mm segments of the 4 major (left main, left anterior descending, left circumflex, and right) epicardial coronary arteries of 8 patients with juvenile (mean age at onset, 9 years; mean age at death, 29 years) diabetes mellitus was determined by computerized planimetric analysis. Analysis of all coronary segments disclosed that the plaques consisted primarily of dense (53%) and cellular (38%) fibrous tissue. Pultaceous debris (7%), foam cells (1.2%) and calcific deposits (0.7%) occupied a small percentage of the plaques. Thus, 91% of the coronary plaques in these young diabetic patients consisted of fibrous tissue and nearly all of the remaining 9% consisted of lipid deposits. Analysis of composition according to degrees of cross-sectional luminal narrowing revealed marked increases in dense fibrous tissue (from 31 to 74%), pultaceous debris (from 3 to 12%), and calcific deposits (from 0% to 3%) as the cross-sectional area narrowing increased from 125% to >75%. Compared with older patients with fatal coronary artery disease, the patients with juvenile diabetes had more dense fibrous tissue and pultaceous debris and less calcific deposits. (Am J Cardiol 1992;70:1264-1268)
From the Pathology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. Manuscript received April 24,1992; revised manuscript received and accepted July 6, 1992. Address for reprints: Susanne L. Mautner, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 2N258,9000 Rockville Pike, Bethesda, Maryland 20892.
1264
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
I
t is well recognized that patients with diabetes mellitus have an increased risk of significant atherosclerosis compared with similar aged nondiabetic patients. Despite this fact, the composition of the atherosclerotic plaques in such patients has not been reported. Accordingly, we examined quantitatively the composition of atherosclerotic plaques in the 4 major epicardial coronary arteries in 8 patients with juvenile diabetes mellitus. METHODS Clinical features: Certain observations in the 8 patients are summarized in Table I. The patients ranged in age from 19 to 38 years (mean 29) at death, and at ages 2 to 13 (average 9) the onset of symptoms or signs of diabetes appeared. The duration of insulin therapy in the 8 patients averaged 20 years. The serum total cholesterol was >240 mg/dl in 5 of 6 patients. Three of the 8 patients had indirect systemic systolic arterial pressures >160 or diastolic pressures > 100 mm Hg, or both, on multiple occasions. Although no patient had a clinical event recognized as acute myocardial infarction, 2 patients (cases 7 and 8, Table I) had transmural acute myocardial infarcts at nccropsy , and death in each of them was attributed to the infarct. Methods of examining the coromuy arteries at necropsy: All 4 major epicardial coronary arteries were
dissected from the heart intact, decalcified, and sectioned transversely at 5-mm intervals. They were dehydrated, cleared, embedded in paraffin, cut and stained by the Movat method. A total of 331 five-mm segments were examined. Evaluation was done by planimetry (described in detail in a previous publication’), outlining the internal elastic membrane, residual lumen, and components of the plaque, such as dense fibrous tissue, cellular fibrous tissue, calcilic deposits, pultaceous debris, foam cells, foam cells with lymphocytes, and inflammatory cells without foam cells (Figure 1). The area of each component of plaque was then converted to a percentage of the total plaque area. For each patient the mean plaque composition was determined by calculating the mean of all 5-mm segments of the 4 coronary arteries of each patient. The total mean for the 8 patients was calculated as the mean of all 331 segments (Table II, Figures 2 and 3). For comparison with previous studies the total mean was calculated in the same fashion used in those studies, i.e., the total mean was based on the mean of each patient rather than on all segments (Figure 4). The degree of cross-sectional lumi-
NOVEMBER
15. 1992
nal narrowing was categorized into 5 groups: 0 to 25%, 26 to 50%, 51 to 75%, 76 to 95%, and 96 to 100%.
were narrowed by atherosclerotic plaque >75% in crosssectional area. Of the 331 five-mm coronary segments examined, 68 (21%) were narrowed >75% in cross-sectional area by plaque. Plaque composition: Plaque composition in all 331 five-mm segments in each of the 8 patients is summarized in Table II. Fibrous tissue was the domi-
RESULTS Cross-se&ional area narrowing: The results are summarized in Table II and in Figures 2 and 3. In 6 of the 8 patients, 1 or more epicardial coronary arteries TABLE
I Clinical
Observations
in the Eight Patients
Age Case 1 2 3 4 5 6 7 8 Total or Mean
(years) at Death 19
20 25 26 28 35 37 38 29
Age Sex F M F M M M M F 3F:5M
(years) at Onset DM
with Juvenile Duration of DM (years)
Diabetes
NS
TC* (mg/dl)
BUN? mg/dl
BPt (mmHg) (s/d)
CHF
Cause of Death Infection Hodgkin’s Renal Renal Renal CNS bleed AMI AMI
174
10
0
244 254 240 365 249 -
20 60 60 60 50 30
100/80 130/80 120/70 240/ 140 270/150 -240/140 130/70 130/80
0 0 0 + 0 + + 0
4
254
41
170/101
3
10 11
9 9
0 0
9 2 9 9 9 13
16 25 19 26 28 25
+ + + +
9
20
*Highest value recorded. iUsual value one to six months beforedeath. AMI = acute myocardial infarction; BP = blood pressure; BUN = blood urea nitrogen; nephrotlc syndrome; s/d = peak systoleiend diastole; TC = serum total cholesterol.
Mellitus
-
CHF = congestive
ATHEROSCLEROTIC
heartfailure:
PLAQUE
CNS = central newo~s system; DM = diabetes
COMPOSITION
IN DIABETES
mellitus;
MELLITUS
NS =
1265
160 310 300 340 430 450 450 340
348
1 2 3 4 5 6 7 8
Total or Mean
3
0 0 0 0 0 + + +
N
2
0 0 0 0 0 + + 0
F
ii3
bif
Mean % Plaque
Composition
(30) (11) (32) (3) (161 (35) (7) (17)
62 (19%)
14 4 9 1 7 17 4 6
Mellitus
(15) (0) (3) (0) (35) (42) (38) (19)
F = fibrosis;
71 (19%)
7 0 1 cl 15 20 21 7
51-75% (4) (Of (3) (0) (28) (19) (47) (33)
(0) (0) (0) (0) (5) (2) (6) (0)
6 (2%)
0 0 0 0 2 1 3 0
96-100%
FC = foam cells; FC+L
62 (17%)
2 0 1 0 12 9 26 1.2
76-95%
of Percent of 5 mm Segments Narrowed to 5 Categories of CSA by Plaque
26-50%
Number
Diabetes
area; DFT = dense fibrous tissue;
(31)
(2)
(51) (891 (62) (97) (16) (2)
130 (43%)
24 32 18 36 7 1 1 11
O-25%
with Juvenile
CSA = cross-sectional
331 (100%)
47 36 29 37 43 48 55 36
Number of5mm Segments
in the Eight Patients
Gross LV
Findings
CFT = cellular fibrous tissue; CD = calcific deposits; ventricular; N = necrosis; PD = pultaceous debris.
HW(g)
II Necropsy
Case
TABLE
= foam cells plus lymphocytes;
37.9%
43.3 23.9 91.7 95.9 32.0 7.2 14.0 23.0
39.8 64.1 2.6 4.1 62.8 84.8 76.5 61.5 53.3%
CFT
DFT
HW = heart weight:
PD
Plaques
1.2%
2.4 6.2 1.6 0.0 0.2 0.4 0.1 0.2
FC
Consisting
ICWFC = inflammatory
6.7%
14.4 5.8 4.1 0.0 4.8 7.2 4.3 14.9
of Coronary
0.7%
0.0 0.0 0.0 0.0 0.0 0.0 4.2 0.0
CD
Percent
cells without
0.1%
0.0 0.0 0.0 0.0 0.0 0.0 0.2 0.0
FC+L
of:
foam cells; LV = left
0.1%
0.0 0.0 0.0 0.0 0.2 0.1 0.2 0.1
ICWFC
Dense 80
Fibrous
Tissue
Cellular
Fibrous
Tissue
1 E ; aas s o
.
60-
f . B i 40ac . 5 3
a-25 %
26.50%
Calcific
51 -i5%
DeDos
0’
76.1.00%
ii
20-
, 0-25 %
3
26.50%
Pultaceous
/
/
51.75%
76.100%
Debrig
P
/
/---
....
UAP
--e-
F
