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Z Kardiol 89: Suppl 2, II/49–II/53 (2000)

© Steinkopff Verlag 2000

A. P. Burke Coronary calcification: insights from


A. Taylor
A. Farb sudden coronary death victims
G. T. Malcom
R. Virmani

Summary We studied 108 cases of plaque ruptures, and the least for
sudden coronary death at autopsy. Any plaque erosion. Calcification in coro-
R. Virmani (Y) · A. P. Burke · A. Taylor calcification was present in 55 % of nary atherosclerosis appears to be
A. Farb
men and women under 40 years; all delayed in women, is greatest in
Department of Cardiovascular Pathology
Armed Forces Institute of Pathology hearts showed some calcification women diabetics, and is associated
Washington, D.C. 20306-6000, USA by age 50 in men, and by age 60 in with one type of plaque instability,
e-mail: burke@afip.osd.mil women. The only risk factor indepen- namely plaque rupture.
dently associated with increased
G. T. Malcom
Department of Pathology
calcification was diabetes mellitus, in Key words Calcification – diabetes
Louisiana State University, Medical Center women only. The degree of calcifica- mellitus – coronary atherosclerosis –
New Orleans, Louisiana, USA 70112 tion was greatest for acute and healed plaque rupture

Disclaimer The opinions or assertions contained herein are the private


views of the authors and are not to be construed as official or reflecting Materials and methods
the views of the Department of the Army, the Department of the Air Force,
or the Department of Defense. One hundred and eight hearts were studied from 70 men (age
50.4 ± 12.2) and 38 women (age 49.6 ± 12.2), who died
suddenly from severe coronary artery disease. Risk factor data
were compiled as previously described (9). Ninety cases
Introduction derive from a series of sudden coronary deaths previously
published (9–13).
Coronary clacification is an excellent marker for the presence Arterial sections were examined for the presence of
of atherosclerotic plaque (1, 2). Electron beam computed coronary artery calcification and relationship to risk factors.
tomography (EBCT) is a useful adjunct to clinical screening Arterial segments were sectioned at 3 mm intervals, and all
for the presence of occlusive coronary atherosclerosis (3–5). areas with ≥ 50 % luminal narrowing studied histologically.
In patients under 50 years, the sensitivity of calcification is Plaques were classified (Fig. 1) as plaque ruptures, plaque
approximately 85 % (6, 7) and approaches 100 % in older erosion, thinned-cap fibroatheroma (vulnerable plaque, or
individuals (8). plaque with thin fibrous cap with infiltration of macrophages),
It is uncertain whether coronary calcification is a marker for hemorrhage into plaque, and healed plaque rupture (interrup-
plaque instability, and there is little known about the relation- tion of the fibrous cap as demonstrated by Sirius red staining
ship between coronary artery calcification and traditional risk viewed under polarized light, without acute thrombus). Healed
factors. The purpose of this study is to compare the presence plaque ruptures were defined as reported by Mann and Davies
and extent of histologically documented coronary calcification (14). Calcification was graded on a semi-quantitative scale
to coronary plaque morphology and traditional risk factors after decalcification overnight with acetic acid and was based
obtained at autopsy. on presence of calcified matrix on hematoxylin-eosin stained
II/50 Z Kardiol 89, Suppl 2 (2000)
© Steinkopff Verlag 2000

Because the calcification score was performed on formalin-


fixed, decalcified tissues, the histologic evaluation of the extent
of calcium was based on the visualization of calcified matrix,
and not calcium per se. To validate this approach, postmortem
radiographs were performed on 22 arterial sections with some
degree of calcification and 13 without calcification. Correla-
tion between area on the radiograph was compared blindly to
histologic grading scale. All segments were correctly assigned
to the presence or absence of calcification by histologic eval-
uation. In the 22 segments with some calcification, radi-
ographic calcification measured by planimetry correlated with
histologic assessment of extent of calcification (r= 0.75, p <
0.0001, simple regression).

Results

Frequency and degree of calcification, by age and gender

From the 108 sudden coronary deaths the incidence of any


calcification, as well as the mean calcification score, increased
with age (Fig. 1). This increase with age showed a delay in
women as compared to men (Fig. 1). The maximum calcifica-
tion score appeared to peak in the sixth decade; however, a
statistically significant difference was found only between the
deaths under age 45 compared to those over age 50.

Frequency and degree of calcification,


Fig. 1 A) Incidence of coronary calcification in sudden coronary death,
relation to age and gender. As age increases, there is an increase in the by plaque morphology/plaque instability
incidence of any calcification in the coronary arteries. This increase
appears to demonstrate a delay of approximately one decade in women Among the total of 108 cases of sudden death, the culprit
as compared to men. The incidence of calcification showed a statistically plaque was classified as 37 plaque ruptures, 33 plaque ero-
significant increase with age. The p value (student’s T-test) between under
sions, 18 healed ruptures, and 20 stable plaques. Of the total
35 and 45–49 is p = 0.04; between 35–39 and 50–64 p = 0.03; and under
35 and 55-59 or > 60 p = 0.0003). B) Extent of coronary calcification in 108 cases, any degree of calcification, as well as the total cal-
sudden coronary death, relation to age and gender. The peak degree of cium score per heart, was lowest when the culprit plaque was
calcification in sudden coronary death appears to be in the 50’s for men plaque erosion and highest when the culprit plaque was healed
and in the 60’s for women. The extent of calcification showed a statisti- plaque rupture (Fig. 2). When plaque segments were studied
cally significant difference between younger and older ages; for example,
the p value (student’s T-test) between under 35 and 55–59 is p = 0.05;
individually, plaque erosions were the least likely to contain
between 35–39 and 55–59 p = 0.01; and between 40–44 and 55–59 calcification (Fig. 3). The most frequently calcified plaques
p = 0.01. were acute ruptures, and the most extensively calcified healed
ruptures (Fig. 3).

sections. The histologic grading scheme was as follows: Grade Calcification and risk factors
0 (no calcification); grade 1: calcifications < 40 mm; grade 2:
calcifications > 40 mm involving one quadrant; grade 3: By univariate analysis (n = 90), there was no significant effect
Calcifications involving 2 quadrants; grade 4: calcifications of risk factors on calcification score (sum), with the exception
involving 3 quadrants; grade 5: calcifications involving entire of age (p = 0.01, r = .27, simple regression) and percent glyco-
circumference (Fig. 1). The total calcification score per heart sylated hemoglobin (p = 0.04, simple regression). By univari-
was the sum of grades. ate analysis, the correlation between glycosylated hemoglobin
A. P. Burke et al. II/51
Coronary calcification: insights from sudden coronary death victims

Fig. 3 Frequency of any calcification by individual coronary sections


(total number, 297) from victims of sudden coronary death. The differ-
ence in frequency of any calcification was significant when acute ruptures
were compared to plaque erosions (p = 0.002), vulnerable plaques
(p = 0.008), and stable plaques (p = 0.004), and when healed ruptures
were compared to stable plaques (p = 0.03), plaque erosions (p = 0.01),
and vulnerable plaques (p = 0.04).

density lipoprotein cholesterol (Table 1). In women, an


independent association between glycosylated hemoglobin
persisted when total plaque load was included as an indepen-
dent variable (p = 0.03, ANOVA).

Fig. 2 A) Incidence of coronary calcification by culprit plaque, sudden


coronary death, relation to gender. Hearts with acute plaque ruptures and
healed ruptures had the highest incidence of any calcification, and plaque
erosions the lowest incidence. There was a statistically significant differ-
ence between the incidence of calcification between erosions and healed
ruptures (p < 0.0001), erosions and acute ruptures (p = 0.001), and stable
plaques vs. healed ruptures (p = 0.002), when men and women were com-
bined. B) extent of coronary calcification in sudden coronary death, by
culprit plaque. The mean calcification score essentially mirrors Fig. 2A.
There is a significant difference between erosions and healed (< 0.0001)
and acute ruptures (p = 0.0004). There is likewise a significant difference
between stable plaques and healed (0.0007) and acute ruptures (0.05).

and calcification score (sum) was significant only in women (p


= 0.004) and not in men (p = 0.51). In women, the total
calcification score was 6.4 ± 5.6 in those with glycosylated
hemoglobin > 8.0 % and 1.9 ± 2.3 in those with a glycosylated
hemoglobin < 8.0 % (P = 0.004). By multivariate analysis in Fig. 4 Degree of any calcification by individual coronary sections (only
men, no risk factor was associated with calcification; in those with any calcification). Note that in calcified segments, healed
women, glycosylated hemoglobin (p = 0.003, ANOVA) was plaque ruptures are those with the greatest degree of calcification. The
difference in mean calcification score was significant when acute ruptures
significantly associated with calcification, with increased body were compared to plaque erosions (p = 0.01), and when healed ruptures
mass index of borderline significance (p = 0.07), independent were compared to stable plaques (p = 0.04), plaque erosions (p = 0.002),
of age, hypertension, cigarette smoking, total cholesterol, high and vulnerable plaques (p = 0.03).
II/52 Z Kardiol 89, Suppl 2 (2000)
© Steinkopff Verlag 2000

Table 1 Risk factors and calcification, multivariate analysis (ANOVA), other than diabetes did not show any significant association
90 sudden coronary deaths with coronary plaque calcification.
Risk factor Men Women
t P t P
Calcification, plaque erosion, and Framingham index
GlyHgb 1.1 0.26 3.6 0.003*
BMI 0.9 0.37 2.0 0.07 In a recent autopsy study of sudden death victims, we demon-
Htn 0.6 0.55 1.9 0.08
Smoking – 0.4 0.72 1.4 0.20 strated that coronary calcification combined with the Framing-
TC/HDL-C 0.4 0.70 0.7 0.50 ham index increases the sensitivity to predict severe coronary
atherosclerosis. In this study, a combined Framingham risk
* significant also when plaque load figured as independent variable, and coronary calcification index resulted in an 84 % sensitivity
p = 0.04
for sudden coronary death, compared to 62 % for calcification
Abbreviations: GlyHgb = glycosylated hemoglobin; BMI = body mass
index; htn = hypertension; TC = total cholesterol; HDL-C = high density alone and 62 % for the Framingham risk alone (> average risk
lipoprotein cholesterol for age alone) (13). The lack of sensitivity for both methods
could largely be attributed to the fact that plaque erosions are
typically relatively uncalcified, and account for up to 1/3 of
deaths in young men and women dying suddenly with coro-
nary atherosclerosis (15). The current study corroborates the
relative lack of calcium in plaque erosions, as compared
to plaques that are prone to rupture or which have already
Discussion ruptured.

Incidence of calcification in sudden death Calcification as a marker for plaque instability

The current study supports previous investigations showing The current study demonstrates that if plaque instability is
that coronary calcification in patients with symptomatic coro- defined as plaques that have undergone rupture, calcification
nary disease increases with age (6, 7). In older individuals, the is a reliable marker for plaque instability. Acutely ruptured
sensitivity of arterial calcification in predicting severe luminal plaques were more likely to demonstrate calcification than
stenosis approaches 100 %, but there is a concomitant drop in thin-capped atheromas, and healed ruptures had the greatest
specificity due to the high prevalence of coronary calcification mean calcification score. The data suggest that healed ruptures
in individuals over 70 years (8). The current histologic study contribute to coronary plaque calcification, and the calcifica-
also supports clinical studies that a small but significant num- tion may contribute to acute plaque rupture. Furthermore,
ber of patients < 50 years old with angiographically significant because healed ruptures are those plaques likely to demon-
coronary artery disease do not have coronary calcification (6). strate the greatest degree of calcification, it is unclear if, at a
later stage of plaque progression, calcification may actually
impart a degree of stability. In addition, as mentioned above,
Gender differences, risk factors, and calcification a significant minority of acute coronary thrombi in young
sudden death victims occur as a result of plaque erosion, which
In the current study, calcification increased with age at a slower is not associated with coronary calcification. Plaques that are
rate in women than men, and diabetes was associated with prone to plaque erosion, or those that have undergone plaque
calcification among women dying suddenly with coronary erosion, are not readily identified, and as such, markers for
artery disease. These results suggest that calcium screening for plaque erosion are not available. Because of the heterogeneity
the presence or progression of coronary artery disease may be of coronary thrombi overlying atherosclerotic plaque, it is
especially helpful in middle-aged and diabetic women, and premature and overly simplistic to state that calcification is a
that calcification screening may be relatively insensitive in marker for plaque stability or instability, but rather a marker
younger women. In the current study, traditional risk factors of a particular type of plaque progression.
A. P. Burke et al. II/53
Coronary calcification: insights from sudden coronary death victims

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