LIPIDS AND CORONARY ARTERY DISEASE/Gotto et al.
and 19 PVR was elevated in the normally draining lung but
not in the lungs with PAPVD. In patients 14 and 18 it was
elevated in each. In patients 15, 16 and 17 it was normal in
the normally draining lung and elevated in the lobes with
PAPVD. Thus, these studies give no clear-cut answer to the
question of the location of the stimulus for the increase of
PVR in mitral stenosis.
References
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1. Snellen HA, Van Ingen HC, Hoefsmit EChM: Patterns of anomalous
pulmonary venous drainage. Circulation 38: 45, 1968
2. Frye RL, Krebs M, Rahimtoola SH, Ongley PA, Hallermann FJ, Wallace RB: Partial anomalous pulmonary venous connection without atrial
septal defect. Am J Cardiol 22: 242, 1968
3. Baker CG, Benson PF, Joseph MC, Ross DN: Congenital mitral
stenosis. Br Heart J 24: 498, 1962
4. Nichols HT, Woldow A, Goldberg H: Partial anomalous pulmonary
venous drainage associated with mitral stenosis: Report of a case with
surgical correction of both lesions. Am Heart J 51: 475, 1956
5. Adler LN, Berger RL, Starkey GWB, Abelmann WH: Anomalous pulmonary venous drainage associated with mitral stenosis - report of a
case successfully repaired. N Engl J Med 270: 166, 1964
6. Wassermil M, Hoffman MS: Partial anomalous pulmonary venous
drainage associated with mitral stenosis with an intact atrial septum. Am
J Cardiol 10: 894, 1962
7. Lendrum BL, Lichtman AM: Pulmonary vascular resistance in man at
different intravascular distending pressures measured in a case of mitral
stenosis complicated by anomalous pulmonary venous connection. Circulation 16: 1090, 1957
875
8. Aldridge HE, Wigle ED: Partial anomalous pulmonary venous drainage
with intact interatrial septum associated with congenital mitral stenosis.
Circulation 31: 579, 1965
9. Halpern BL, Murray GC, Conti CR, Humphries JO, Gott VL: Continuous murmur due to the combination of rheumatic mitral stenosis and
a rare type of anomalous pulmonary venous drainage. Circulation 42:
165, 1970
10. Mascarenhas E, Javier RP, Samet P: Partial anomalous pulmonary
venous connection and drainage. Am J Cardiol 31: 512, 1973
11. Flamm MD, Cohn KE, Hancock EW: Measurement of systemic cardiac
output at rest and exercise in patients with atrial septal defect. Am J Cardiol 23: 258, 1969
12. Bryan AC, Bentivoglio LG, Beerel F, MacLeish H, Zidulka A, Bates
DV: Factors affecting regional distribution of ventilation and perfusion in
the lung. J Appl Physiol 19: 395, 1964
13. Altman PL, Dittmer DS (eds): Respiration and Circulation Handbook.
Bethesda, Fed Am Soc Exper Biol, 1971, table 19 III, p 45
14. Hawker RE, Freedom RM, Krovetz LJ: Preferential shunting of venous
return from normally connected left pulmonary veins in secundum atrial
septal defect. Am J Cardiol 34: 339, 1974
15. Saalouke MG, Shapiro SR, Perry LW, Scott LP: Isolated partial
anomalous pulmonary venous drainage associated with pulmonary vascular obstructive disease. Am J Cardiol 39: 439, 1977
16. Dexter L, Dow JW, Haynes FW, Whittenberger JL, Ferris BG, Goodale
WT, Hellems HK: Studies of the pulmonary circulation in man at rest.
Normal variations and the interrelations between increased pulmonary
blood flow, elevated pulmonary arterial pressure, and high pulmonary
capillary pressures. J Clin Invest 29: 602, 1950
17. Gorlin R, Haynes FW, Goodale WT, Sawyer CG, Dow JW, Dexter L:
Studies of the circulatory dynamics in mitral stenosis. II. Altered
dynamics at rest. Am Heart J 41: 30, 1951
18. Lewis BM, Gorlin R, Houssay HEJ, Haynes FW: Clinical and physiological correlations in patients with mitral stenosis. Am Heart J 43: 2,
1952
Relationship between Plasma Lipid Concentrations
and Coronary Artery Disease in 496 Patients
ANTONIO M. GOTTO, M.D., D.PHIL., G. ANTHONY GORRY, PH.D.,
JAMES R. THOMPSON, PH.D., JAMES S. COLE, M.D., RUDOLPH TROST, PH.D.,
DANIEL YESHURUN, M.D., AND MICHAEL E. DEBAKEY, M.D.
SUMMARY The relationship between fasting plasma cholesterol
and triglyceride concentrations and the frequency and extensiveness
of coronary artery disease (CAD) was studied in 496 subjects
evaluated for chest pain by coronary arteriography at The Methodist
Hospital. One hundred six of the patients had no CAD while 390 had
25% or greater stenosis of one or more major vessels. Ninety-one percent had 75% or greater stenosis of at least one major vessel. Mean
age for the group with CAD was 55.7 ± 8.7 and without disease
49.4 ± 11.6 (P < 0.01). Both cholesterol and triglyceride concen-
trations were higher (P < 0.001) in the group with CAD. Mean
cholesterol concentration in males increased from 195 ± 36 mg/dl in
the group without CAD to 219 ± 41 in the group with three vessel
disease and in females from 207 ± 40 to 252 ± 42. A progressive increase in triglyceride values was also detected but was less consistent.
At the level of 25% and greater obstruction, the partial correlation
coefficients between the number of vessels involved and the cholesterol and triglyceride concentrations, respectively, were +0.201 and
ELEVATED CONCENTRATIONS of serum cholesterol
and triglycerides have both been implicated in the pathogenesis of coronary artery disease (CAD).1-7 Hypercholesterolemia is one of the three major risk factors for
coronary atherosclerosis.2' The relationship between hyper-
triglyceridemia and CAD is less well defined.13', 7 A study
of familial hyperlipidemia in relatives of survivors of myocardial infarctions suggested that hypercholesterotemia in
combination with hypertriglyceridemia was more common
in these patients than was isolated hypercholesterolemia or
hypertriglyceridemia.8
Although hyperlipidemia is generally recognized as a risk
factor, the physician may be uncertain as to its significance
in a given patient. From the results of the Framingham
study, it appears that cholesterol is a risk factor for CAD
From the Department of Medicine and the Department of Surgery, Baylor
College of Medicine and The Methodist Hospital, and the Department of
Mathematical Sciences, Rice University, Houston, Texas.
Supported in part by NIH Contract 71-2156 for a Lipid Research Clinic,
by HEW Grant HL 17269-02 for a National Research and Demonstration
Center, and by Office of Naval Research NR042-283 for Dr. Thompson.
Address for reprints: Antonio M. Gotto, M.D., Department of Medicine,
Baylor College of Medicine, 6516 Bertner Blvd., Houston, Texas 77030.
Received November 11, 1976; revision accepted May 18, 1977.
+0.181.
over the entire range of concentrations studied. Hence the
physician cannot define a single threshold above which the
patient is at risk. In managing patients with hyperlipidemia,
VOL 56, No 5, NOVEMBER 1977
CIRCULATION
876
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the physician needs a clearer delineation of the relationship
between elevated serum lipids and the possible extent and
severity of coronary artery disease.
Neither the severity nor the extent of CAD can be
precisely determined from the clinical history or from electrocardiographic changes, so the relationship between
hyperlipidemia and CAD can best be studied in patients for
whom angiographic findings are available. Large groups of
such patients provide an important opportunity to add to
our understanding of the clinical significance of hyperlipidemia in CAD. For this reason, we undertook a study of
almost 500 patients to assess the correlations between
plasma cholesterol and plasma triglyceride concentrations
and the frequency and the extensiveness of CAD as indicated
by angiography. We realize that a single measure of the
plasma lipids represents a static view of substances which
are in dynamic equilibrium within the body. Furthermore,
atherosclerosis is a disease which develops over a period of
years. Nonetheless, single measurements of cholesterol at
the time of entry in epidemiological studies have been shown
to correlate with the risk of developing coronary heart disease.'-"l Also, single measurements of blood pressure have
been correlated with coronary heart disease death in
epidemiologic studies.9-'" We used selective cine-coronary
angiography to obtain measurements of the "severity" or
the percent of the obstruction of the vessel's lumen and "extent" as measured by the number of vessels involved. Our
results have been reported in preliminary form.12 No critical
cut-off point could be identified which defined those with disease and those without disease. A report by Cohn et al.,
published after this study was completed, supports our finding that CAD has continuous relationship with concentrations of serum cholesterol and to a lesser extent serum
triglyceride. 13
Methods
Patient Selection
The patients selected for this study were 496 subjects
referred to the cardiology unit of The Methodist Hospital
between January 1972 and March 1976 for evaluation of
chest pain. Since these patients were preselected for chest
pain, they did not constitute a random sample of the general
population. However, they do represent a consecutive group
of patients studied for chest pain in this laboratory. They
were not referred because of hyperlipidemia. Each patient
was examined by one of three cardiologists of the unit who
determined the indication for cardiac catheterization.
Patients were excluded if adequate visualization of both the
right and left coronary artery systems was not obtained
because of difficulties in the manipulation of the catheter.
This occurred in less than 5% of the patient population.
Patients with valvular disease, cardiomyopathy or with recent myocardial infarctions were also excluded. Because of
these exclusions, the 496 subjects did not represent
successive cases.
Lipid and Lipoprotein Measurements
A blood sample for plasma lipid determination was obtained after a 12 hour fast on the day after admission and
prior to coronary arteriography. That determination was
never more than 15 days before the arteriography. Plasma
cholesterol and triglyceride concentrations were determined
according to the procedures of The Lipid Research Clinics
Program.14 The autoanalyzer II methodology was employed
and the machines used were standardized by The Lipid
Research Clinic protocol. Plasma lipoprotein quantification
and lipoprotein typing were performed by the methodology
of the Lipid Research Clinics Program.'4 Lipoprotein quantification was performed if either the plasma cholesterol or
triglyceride value was above the levels given in table 1. Since
different cutpoints of plasma lipids and lipoproteins were
used for operational purposes in various phases of the
collaborative Lipid Research Clinics Program, the levels
shown in table 1 apply to the noncollaborative project
described in the communication. The values in this table
cannot be equated with cut-offs to define hyperlipidemia for
the entire Lipid Research Clinics Program. Such values have
not yet been published. Type II was defined by an elevation
of LDL-cholesterol (table 1) and by the absence of the
floating beta lipoprotein which occurs in type III. Type IV
was defined by an increase in the fasting plasma triglyceride
concentration (table 1). The diagnosis required normal levels
of LDL-cholesterol and the absence of both floating beta
lipoprotein and fasting chylomicrons.
Coronary Arteriography
All patients were brought to the catheterization
laboratory without sedation and in the fasting state. A cut
down was performed on the brachial artery and an accompanying vein. After all right and left heart pressures were
measured, a Fick cardiac output obtained, and a left ventricular cineangiogram recorded, selective coronary arteriograms were obtained using the Sones procedure."' Both the
right and left coronary arteries were selectively cannulated
and injected with 3-5 cc of Renografin-76. In all cases multiple injections in the right and left anterior oblique projections were obtained for both right and left coronary arteries.
Filming was obtained using a nine inch image intensifier and
35 mm cine film. In the majority of cases, single, large film
(8 x 10 inch) radiographs were also obtained following selective injection of each coronary artery. Cine film was
processed in the conventional manner and viewed on a
Tagarno projector. The location and percentage stenosis of
the individual coronary lesions were recorded on a computer
readable mark sense form.16
The format for the mark sense form, illustrated in figure
1, was determined in the following manner. Five experienced
coronary angiographers independently reviewed cineangiographic films from ten patients. On the initial evaluation,
each observer was allowed to make his own interpretation of
the film. After evaluating these initial data, it was apparent
TABLE 1. Cut-off Values for Fasting Plasma Cholesterol,
Triglyceride and LDL-Cholesterol
Plasma cholesterol Plasma triglyeeride Ldl-eholesterol
Age
0-19
20-29
30-39
40-49
50-59
(mg/100 ml)
(mg/100 ml)
(mg/100 ml)
205
140
140
150
160
190
170
170
190
210
240
260
280
190
210
LIPIDS AND CORONARY ARTERY DISEASE/Gotto et al.
A
B
RIGHT CORONARY ARTERY
PATIENT'S NAME
877
LEFT CORONARY ARTERY
PATIENT'S NAMETNAE
USE A NO. 2 PENCIL ONLY.
i
°
MAKE MARKS HEAVY AND DARK.
ERASE COMPLETELY ANYTHTNG YOU WISH
J
e
-3
NORMAL
EXAMLE
25% OCCLUDED
VRIGHT
75% OCCLUDED
H95% OCCLUDED
CC COMPLETELY OCCLUDED
43-
AMONG
3J
3-
;
1
c|
r
ar
1.3
RETROGRADE COLLATERAL
^:ANTEGRADE COLLATERAL
ff LEFT DOMINANT
0 RIGHT
OMIANAT
I SALARED
SN
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FIGURE 1.
M
sn
fme
() c
sgDC
94l5ef
FIGURE 1. Mark sense forms for recording the degree of stenosis in the right (A) and left (B) coronary arteries.
that the reviewers varied by as much as 25-30% in their estimation of diameter narrowing of coronary artery lesions.
There was also some variation in the nomenclature used in
describing the various branches of the coronary tree. It was
therefore decided that the coronary arterial system would be
identified, and the extent of the disease determined at each
of the appropriate locations as indicated on the form. It was
also agreed that at each location, the artery would be
classified as either normal (i.e., there was no detectable disease) or as abnormal. In the latter case, one of five
categories of cross sectional narrowing was specified. These
categories were 25%, 50%, 75%, 95% narrowing or completely occluded (i.e., 100%). Using this set of criteria,
another 10 cineangiograms were reviewed by the same
observers. The 10 cineangiograms were randomly selected
from 50 cases referred because of chest pain just prior to the
beginning of the study. Two of the 10 were judged to be free
of coronary artery disease. The other eight had narrowing of
the coronary arteries ranging from 25% to 95%. Using these
criteria, the agreement in classifying the severity of diameter
stenosis was greater than 90%.
Each section of the arterial tree was viewed in multiple
projections and the diameter of the stenosed region was
compared with the nearest normal vessel diameter. Calipers
were used on all 496 cases to compare normal and abnormal
segments and stenoses were then classified as 25%, 50%,
75%, 95% or 100% reduction of the original diameter. If a
significant difference existed between two views the average
of the two views was used.
All of the coronary cineangiograms used in this study
were viewed independently by two observers. If there was a
difference in classification of specific lesions between the two
observers (i.e., one observer thought a stenosis was 75% and
another thought it was 95%) then a third observer reviewed
the film independently. After discussion among the three
observers, a consensus of opinion was reached regarding the
specific lesion. One set of data was entered into the computer on each subject studied.
Data from the mark sense form were entered into the
computer to calculate two different CAD scores based on
the percentage stenosis of lesions in the four major coronary arteries (left main, circumflex, left anterior descending,
right coronary arteries). "Severity" of CAD was defined as a
percentage equal to the maximum percentage stenosis found
among each of the four major coronary arteries in a given
patient. "Extent" of CAD was defined in terms of the total
number of major coronary vessels (NOV) which contained
at least one stenosis of 25% or greater. For example, a
patient with a 25% stenosis in the left main, 50% stenosis in
the right, and a 75% stenosis in the circumflex coronary
arteries would be scored with the severity of disease as 75%
while the extent of disease would be scored as NOV = 3.
Coronary arteriograms were classified as normal
(NOV = 0) if the left main, circumflex, left anterior descend-
CIRCULATION
878
ing. and right coronary arteries each contained less than
25% stenosis. Abnormal arteriograms were scored with
NOV = 1, 2, 3 or 4 depending upon how many of these four
major branches contained 25% or more stenosis.
Data Analysis
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In our comparison of patients with and without CAD, we
conducted a variety of statistical analyses. In addition to the
conventional use of the t-test, we used nonparametric techniques including the Wilcoxon or Mann-Whitney test to
confirm the significance of differences in group means and
the Kruskal-Wallis test to compare group distributions.'7
Because of possible correlations between serum lipid
levels and age in our patient population, we computed agecorrected correlations* between serum lipid levels and
NOV. Such correlation coefficients reflect the relation
between NOV and lipid levels over and above that resulting
from an independent tendency of serum lipids to increase
with age.
In order to facilitate the comparison of our results with
those of Cohn et al.," we have also presented our data by
quartiles. Because in general we had unequal numbers of diseased and nondiseased patients, we have normalized our
data in this analysis. It should be noted that the more powerful methods mentioned above confirmed the results
presented here.
Results
Clinical Profile
Four hundred ninety-six patients participated in the study.
One hundred six of them (21.4%) had no detectable CAD as
defined in Methods and as determined by arteriography;
their chest pain was not attributed to CAD. The rest of the
patients, 390 (78.6%), had 25% or greater stenosis of one or
more of the coronary arteries and were classified as having
CAD. Eighty-two percent of the 390 patients with CAD
were males, while only 48% of the group without CAD were
males. The mean age differed significantly (P < 0.01)
between the two groups, being 49.4 ± 11.6 for the group
without CAD and 55.7 ± 8.7 for those with CAD. Mean age
for males without CAD was 48.0 ± 12.8 vs 55.4 ± 8.9 for
those with CAD (P < 0.001). Comparable values for
females were 50.7 ± 10.3 and 57.2 7.8, respectively
(P < 0.001).
Comparison between the plasma cholesterol and triglyceride concentrations for the groups with and without
CAD are given in table 2. Both cholesterol and triglyceride
levels were significantly higher in patients with than without
CAD (see table 2 for P values). The cholesterol values were
higher in females than in males for both groups (P < 0.05),
being the highest in females with CAD (P < 0.001). Concentrations of plasma triglycerides did not exhibit this preferential sex distribution.
*We first computed the correlation coefficients between the variables CHL,
TRG, NOV, and AGE in the usual manner. These
are
denoted by
rcHL-AGE,
for example, as the correlation coefficient between the variables cholesterol
and age. The age-corrected correlation is the partial correlation coefficient
defined by"8
rCHL.NOV
-
(rCHL-AGE * rNOV-AGE)
rCHL NOV.AGE
/
(I
-
r2CHL-AGE) (
r NOV -AGE)
VOL 56, No 5, NOVEMBER 1977
TABLE 2. Comparison of Lipid Levels (mean - SD) between
Patients with and without Coronary Artery Disease
Males
Females
Total
Patients Without Coronary Artery Disease
No. patients
51
106
55
Mean age (yr)
48 - 12.8 50.7 = 10.3 49.4 11.6
Cholesterol SD
195 - 36 207 - 40
201 - 38
(mg/dl)
Triglyceride
(mg/dl)
SD
140 = 74
135 , 62
138 - 68
Patients With Coronary Artery Disease*
No. patients
320
70
390
Mean age (yr)
55.4 = 8.9 57.2 7.8 55.7 - 8.7
Cholesterol SD
216 - 43
238 = 50
220 = 45
(mg/dl)
Triglyceride SD 179 102 177 i 88 179 i99
(mg/dl)
Cholesterol
Significant Difference
P <0.001
P <0.001
P <0.001
Triglyceride
P <0.005
P <0.002
P <0.001
*25% or greater stenosis in one or more of the major coronary artery
branches.
The 390 patients with CAD were classified on the basis of
the severity of disease in their coronary arteries (table 3).
Approximately 91% of the patients in this group had 75% or
greater stenosis of at least one of their coronary arteries.
The distribution of the extent of CAD on the basis of the
number of vessels with 25% or more stenosis is given in
tables 4-6 for males, females and total patients, respectively.
Eighty-eight percent of the males and 70% of the females
had two or more affected coronary arteries. This difference
was significant (P < 0.01). Thirty-nine percent of the group
with CAD had two or fewer vessels involved.
Relations of Plasma Cholesterol to Extent
of Coronary Artery Disease
The number of vessels with 25% or more stenosis was
compared with cholesterol levels for males, females and the
total patient group (tables 4-6). Mean cholesterol concentrations for males increased from 195 ± 36 mg/dl to
219 ± 41 mg/dl in the group with three vessel disease, and
to 223 ± 51 mg/dl in the group with four vessel disease
(table 4). These differences between the mean cholesterol for
the male control group and those with three and four vessel
disease were significant (P < 0.001). An even sharper rise in
mean plasma cholesterol for the females was observed with
an increase in extent of vessel involvement. The difference
between the mean plasma cholesterol for the female group
(table 5) without CAD, 207 ± 40 mg/dl, and those with
three vessel disease, 252 ± 42 mg/dl, was highly significant
(P < 0.001).
TABLE 3. Severity of Coronary Artery Disease in Patients
with Abnormal Coronary Angiograms
Severity of coronary
artery disease
Maximum stenosis
25%
50%
75%-100%
Total
-Maes
Females
Total
11 (:3.4%) 10 (14.3%) 21 (5.4%)
10 (3.1%)
3 (4.3%)
13 (3.3%)
299 (93.5%) 57 (81.4%) 356 (91.3%)
320 (100%) 70 (100%) 390 (100%)
879
LIPIDS AND CORONARY ARTERY DISEASE/Gotto et al.
TABLE 4. Mean Age, Cholesterol, and Triglyceride Levels for 371 Males
No. of male patients
With
Without
Extent of
disease
NOV
=
CAD*
Mean age h sD
(yr)
39 (12.2%)
173 (54.0%)
69 (21.6%)
39 (12.2%)
57.0 | 7.5
9.1
55.2
8.2
55.0
55.3 10.3
CAD
4
NOV = 3
NOV = 2
NOV = 1
NOV = 0
Total
48.0 12.8
51
51
Mean cholesterol ± SD
(mg/dl)
Mean triglyceride
(mg/dl)
223
51
168
219
213
201
195
41
40
47
36
190 97
166 90
167 40
140 74
Ss D
96
320 (100%)
*25% stenosis or greater.
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NOV = 0, 1 and 2. The mean triglyceride concentration for
females with no disease, 135 ± 62 mg/dl, was significantly
different from the mean of 181 ± 86 mg/dl for females with
three and four vessel involvement (P < 0.01).
When the triglyceride data for males and females were
combined (table 6), the relationship between increased vessel
involvement and increased mean triglyceride concentrations
was maintained from NOV = 0 through NOV = 3. The
number of female patients with four vessel involvement was
too small to allow statistical comparison.
An age-corrected correlation coefficient between triglyceride level and the number of vessels with 25% or greater
stenosis was calculated for all patients (r = 0.181, N = 496).
Age-corrected correlation coefficients were also computed
separately for males (r = 0.139, N = 371) and females
(r = 0.266, N = 125). The Kruskal-Wallis test was used
again to confirm that a significant difference (P = 0.033) exists among the four triglyceride distributions for each subgroup defined by one, two, three and four vessel involve-
When data of males and females were combined (table 6)
the same relationship was noted between the number of
vessels involved and plasma cholesterol concentrations. The
significance of this trend was further supported by computing the age-corrected correlation coefficient between
levels of plasma cholesterol and the number of vessels involved. Using a criterion of 25% stenosis, the extent of disease (NOV) was found to be positively correlated with the
plasma cholesterol concentration for all patients (r = 0.226,
N = 496). Age-corrected correlation coefficients were also
computed separately for males (r = 0.266, N = 371) and
females (r = 0.352, N = 125). There was no correlation
between age and lipid levels, although there was a correlation between age and NOV which was smaller than that
between NOV and cholesterol. We have found no agecorrected correlation between blood pressure (systolic or
diastolic) measured at the time of catheterization and the
number of vessels involved.
Finally, application of the Kruskal-Wallis test also confirmed that a significant difference (P = 0.037) exists among
the four cholesterol distributions for each subgroup defined
by one, two, three and four vessel involvement. In other
words, differences between the mean cholesterol levels of
patients with CAD, though small, are significant and increase with the extent of disease as measured by vessel in-
ment.
Frequency of Coronary Artery Disease in
Different Lipid Quartiles
The total patient population was divided into quartiles
based on either their plasma cholesterol or triglyceride concentration. Cholesterol values ranged from less than 184
mg/dl for the first quartile to greater than 236 mg/dl for the
fourth quartile (table 7). Triglyceride quartile levels ranged
from less than 101 mg/dl for the first to greater than 179
mg/dl for the last (table 8). For both cholesterol and triglyceride concentrations, the percentage of patients with
CAD increased progressively from quartile I to quartile IV.
These increases were significant (P < 0.02) for males,
females and the total patient population. There was no
significant difference between males and females in the frequency of CAD within each quartile.
volvement.
Relation of Plasma Triglyceride to Extent
of Coronary Artery Disease
Table 4 shows data for comparison of triglyceride levels to
the number of vessels involved. Mean triglyceride concentrations for males increased significantly from 140 ± 74
mg/dl in the group with no CAD to 190 ± 97 mg/dl in the
group with three vessel involvement (P < 0.001). A very
sharp rise in the mean plasma triglyceride for the females
(table 5) was observed with increasing vessel involvement for
TABLE 5. Mean Age, Cholesterol, and Triglyceride Levels for 125 Females
Extent of
disease
No. of female patients
With
Without
CAD*
CAD
= 4
2)
NOV = 3
NOV = 2
NOV = 1
NOV = 0
23)
NOV
Total
55
55
*25% stenosis or greater.
Mean age
(yr)
4
SD
7.4
(35.7%)
57.7
24
21
(34.3%)
(30%)
9.3
57.2
56.7 = 6.6
50.7 10.3
70
(100%)
-
Mean cholesterol
(mg/dl)
252
42
243 49
214 56
207 40
4 SD
Mean triglyceride
(mg/dl)
181
-
86
200 - 97
147 72
135 -l62
4 SD
VOL 56, No 5, NOVEMBER 1977
CIRCULATION
880
TABLE 6. Mean Age, Cholesterol, and Triglyceride Levels for 496 Patients
No. of patients
With
Without
CAD
CAD*
Extent of
diseae
NOV
NOV =
NOV =
NOV =
NOV =
Total
=
41(10.5%)
4
3
2
196 (50.3%)
93 (23.8%)
60 (15.4%)
1
0
106
106
Mean age
(yr)
4 SD
57.2
55.4 55.6 55.8 49.4 i
7.4
9.0
8.5
9.1
11.6
Mean cholesterol d4 sD
(mg/dl)
224
223
221
205
201
52
42
44
50
38
-
-
Mean triglyceride 4i sD
(mg/dl)
170
189
96
96
92
121
68
175
160
138
390 (100%)
*25% stenosis or greater.
ple, the age-corrected correlation coefficient between
It should be pointed out that for each of the three columns
in table 7 we normalized the data so as to produce an
average frequency of 50% coronary artery disease in males,
females and total patient population. This is equivalent to
adjusting the data for equal numbers of patients with and
without disease. Therefore, our results for the total population can be compared directly to Cohn's results.'3
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
cholesterol and the number of vessels involved was
r = 0.156, while between triglyceride and NOV it was
r = 0.196 (N = 462). When the quartiles and the frequency
of CAD were computed for the 75% criterion, the percentages of patients with disease in quartiles I through IV,
respectively, were 42%, 42%, 48% and 69% for cholesterol
(P < 0.02), and 35%, 46%, 51% and 69% for triglyceride
(P < 0.01).
Results for Coronary Artery Disease Defined
by >50% and >75% Stenosis
Frequency of Coronary Artery Disease in
Various Lipid Combinations
The above results in tables 4 through 7 were obtained for
the 390 patients with CAD defined as >25% stenosis in any
one or more of the four major coronary arteries. In order to
evaluate the effect of using different criteria for defining
CAD, we reclassified the 390 patients according to a 50%
criterion, and again for a 75% criterion.
When a 50% criterion was applied, 21 patients with a
maximum stenosis of 25% (table 3) were excluded from
analysis. Thus, 369 patients had the extent of their CAD
redefined for NOV = 1 through NOV = 4 (69, 113, 166,
and 21 patients in each category, respectively). For a 75%
criterion, 34 patients with a maximum stenosis not exceeding 50% were excluded from analysis. The distribution
of the extent of disease for the remaining 356 patients was
redefined for NOV = 1 through NOV = 4 (93, 126, 124 and
13 patients, respectively). Regardless of the criterion used to
define CAD, the same 106 patients were used in each
analysis as the control group with NOV = 0 (i.e., all vessels
had 0% stenosis).
Analysis of the data using 50% and 75% stenosis criteria
did not significantly alter our findings when compared to
those using 25% criterion. With a 75% criterion, for exam-
To examine the relationship between the combination of
cholesterol and triglyceride levels and CAD, the patients
were divided into four groups. Group A contained the lower
two quartiles for both cholesterol and triglycerides, group B
had the higher two quartiles of cholesterol and the lower two
quartiles for triglycerides, group C had the higher two quartiles for triglycerides and the lower two quartiles for
cholesterol and group D had the higher two quartiles for
both cholesterol and triglycerides. The frequency of CAD in
group A was 33%, in group B 45%, in group C 51% and in
group D 65% (table 9). These frequencies are statistically
significant at P = 0.013 using the Chi-squared goodness of
fit test.
Frequency of Coronary Artery Disease for
Different Lipoprotein Phenotypes
Patients were categorized into lipoprotein phenotypes in
accordance with the World Health Organization classification and the criteria suggested by the Lipid Research Clinic
protocol.14 15 Cut-off values for cholesterol and tri-
TABLE 7. Results of Cholesterol Quartile Analysis
Cholesterol quartiles
Quartile IV limits (mg/dl)
% CAD*
Mean age
Mean triglyceride (mg/dl)
Quartile III limits (mg/dl)
% CAD
Mean age
Mean triglyceride (mg/dl)
Quartile II limits (mg/dl)
% CAD
Mean age
Mean triglyceride (mg/dl)
Quartile I limits (mg/dl)
% CAD
Mean age
Mean triglyceride (mg/dl)
-
*CAD defined
as
25% and greater stenosis.
Males
>234
371
70%
54.5 9.5
196 , 117
205-234
52%
53.7 8.
188 " 103
178-204
48%
54.3 9.6
163 i 78
< 178
34%
55.4
-
12
144
-
102
125 Females
496 Total patients
>249
>236
67%
54.8 = 9.3
194 = 110
209-236
69%
-
54.1
186
9.3
94
221-249
61%
56.2 S 8.1
174 *=79
194-220
42%
54.3
-
147
9.4
67
<194
30%
52.8
128
-
11.1
67
47%
54.4 8.7
181 - 99
184-208
45%
53.7 9.8
167 76
<184
41%
54.5 - 11.4
130 - 70
=
881
LIPIDS AND CORONARY ARTERY DISEASE/Gotto et al.
TABLE 8. Results of Triglyceride Quartile Analysis
Triglyceride quartiles
371 Males
125 Females
496 Total patients
Quartile IV limits (mg/dl)
% CAD*
Mean age
Mean cholesterol (mg/dl)
Quartile III limits (mg/dl)
% CAD
Mean age
Mean cholesterol (mg/dl)
Quartile II limits (mg/dl)
% CAD
Mean age
Mean cholesterol (mg/dl)
Quartile I limits (mg/dl)
% CAD
Mean age
Mean cholesterol (mg/dl)
>179
71%
>188
65%
54.5 - 7.2
>179
69%
54.2
246
233
=
53.9
9.0
43
228
57.7
-
i
202
36
< 101
221
-
11.9
193
-
42
46%
-
55.9
10.1
9.3
38
207
44
<103
< 101
34%
35%
33%
52.3
9.7
41
221
101-140
44
53.1
8.9
=
54.9
103-141
48%
101-139
48%
56.7
9.2
:
229
41
221
51%
54%
9.7
8.6
46
141-179
142-188
140-179
50%
54.2
51
51.7
-
201
10.6
52.1
195
45
=
11.5
43
*CAD defined as 25% and greater stenosis.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
glycerides were those used by the Lipid Research Clinic. The
results are summarized in tables 10 and 11. There were no
significant differences in the frequency of CAD (25%
stenosis criterion) between 53 patients with type II hyperlipidemia, 128 patients with type IV hyperlipidemia, and 315
patients without hyperlipidemia, as defined by the Lipid
Research Clinic criteria (table 10). The percentages were
computed twice again for a 50% and 75% criteria in defining
those patients with CAD and still there were no significant
differences between the type II, type IV and normolipemic
groups.
We were unable to find any difference in
or the severity of disease between patients
either the extent
with type II and
type IV patterns (table 11). Type II patients did not differ
from normolipemic subjects when analyzed for extent of
coronary artery disease. A significant difference (P < 0.01)
was observed when the type IV and normolipemic groups
were compared. However, when the comparison was confined to only those patients with CAD, there was no significant difference between the frequencies of single and multivessel disease in the type IV and normolipemic groups.
Analysis of the severity of CAD showed no significant
differences between the type II, type IV and normolipemic
groups.
Discussion
Numerous studies have reported that hypercholesterolemia, hypertriglyceridemia or both carry an in-
creased risk of developing premature CAD.' Many of the
studies have defined hyperlipidemia or hyperlipoproteinemia based on arbitrary cut-off points for the
concentrations of serum plasma lipids or lipoproteins,
although the Framingham study' suggested that serum
cholesterol is related to risk of CAD as a continuous function. The clinical history itself cannot precisely define the
extent and/or severity of CAD, nor can the electrocardiographic changes or exercise tolerance test. Introduction of selective coronary cineangiography by Sones et al.'5
in 1962 and subsequent refinements of these techniques have
made it possible to determine with a considerable degree of
accuracy the extent and severity of stenosis of the coronary
arteries. Earlier attempts have been made to relate
cineangiographic findings to hyperlipidemia.20-11 Proudfit et
al.20 concluded that the level of serum cholesterol was of
limited diagnostic value in the individual patient, although
the frequency of normal coronary arteriograms was high
when the serum cholesterol was less than 225 mg/dl and that
of abnormal coronary arteriograms was high when the
serum cholesterol was greater than 300 mg%. Cramer et
al.,21 in a study of 224 patients subjected to coronary
cineangiography reported that the total serum cholesterol
had only a minor influence in the frequency of CAD in
males, but that hypertriglyceridemia was found with a
greater frequency in diseased patients. Falsetti et al.,22
reporting on 27 patients with arteriographically established
CAD, found that 63% had an elevation of serum cholesterol
TABLE 9. Percentage of Patients Having Coronary Artery Disease (26% and Greater Stenosis) within Each
Subgroup Defined by Combining the Cholesterol and Triglyceride Upper and Lower Two Quartiles
Group
A
B
C
D
Definition
CHOL < 209
and
TRIG < 141
CHOL > 208
and
TRIG < 141
CHOL < 209
and
TRIG > 140
CHOL > 208
and
TRIG > 140
Cholesterol
Triglyceride
No. pts.
% CAD
129
33%
53.7
10.8
175
-
23
101
24
91
45%
54.9
10.1
240
-
27
105
24
97
51%
54.6
10.3
185
A
18
213
73
179
65%
54.4
8.5
251
-
36
230
106
Age
882
CIRCULATION
TABLE 10. Comparison of the Frequency of Coronary Artery
Disease (25% and Greater Stenosis) in Type II, Type IV and
Normolipemic Patients*
No disease
With disease
TypeII
Type IV
Normolipemic
8 (15%)
22 (17%)
106 (83%)
128 (100%)
76 (24%)
239 (76%)
315 (100%)
45 (85%)
53 (100%o)
*N'o significant difference (P > 0.10) between the percentages for type
II, type IV and normolipemic groups.
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
or triglyceride or both. Heinle et al.23 in 1969 described 134
patients with coronary artery disease. Fifty-four percent had
hyperlipoproteinemia and 67% had an abnormal glucose
tolerance test. Ninety-six percent of patients under age 50
had at least one of these metabolic abnormalities. They concluded that recognition and treatment of hyperlipoproteinemia and diabetes mellitus are very important in
the management and prevention of atherosclerosis.
Crowly24 compared findings in 70 patients with CAD and
in 50 patients having no disease. Hypercholesterolemia, as
defined by an age-dependent cut-off point of between
240-330 mg/dl, occurred almost equally in the two groups.
Hypertriglyceridemia, defined as an age-dependent
threshold of 140-190 mg/dl occurred with greater frequency
in the group with CAD. In 1974, Kubler et al.25 studied 71 of
541 patients who underwent coronary arteriography. They
subdivided the patients with coronary artery disease into
four quartiles based on the extent and severity of coronary
occlusion and separately with the degree of peripheral
arteriosclerosis. They observed correlations between the
severity of CAD without peripheral arteriosclerosis and with
serum cholesterol concentrations and with the frequency of
occurrence of type II hyperlipidemia. They were unable to
establish correlations between the severity of CAD and the
concentration of plasma triglycerides or elevation of blood
pressure.
Cohn et al.'3 have recently published results from 100
patients with angiographically documented CAD matched
with 100 patients who had no CAD on cineangiography.
These authors studied the correlations between concentrations of serum cholesterol, triglyceride and both with the
TABLE 11. Comparison of the Extent and Severity of Coronary
Artery Disease (25% Stenosis and Greater) in 496 Patients
with Type II, Type IV or Normolipemic Patterns
Extent*
NOV = 4
NOV = 3
NOV = 2
NOV = 1
NOV = 0
Maxcimum %J
Stenosist
0%
25%
50%
75-100%
Type II
Type IV
Normolipemic
5( 9%)
24 (45%)
9 (17%)
7 (14%)
8 (15%)
53 (100%)
9( 7%)
67 (52%)
19 (15%)
11 ( 9%)
22 (17%)
128 (100%)
27( 9%)
105 (33%)
65 (21%)
42 (13%)
76 (24%0)
315 (100%)
8 (15%)
22 (17%)
76 (24%)
14 (4%)
8( 3%)
217 (69%)
315 (100%)
3( 6%)
1 (2%)
41 (77%)
53 (100%)
4( 3%)
4( 3%)
98 (77%)
128 (100%)
*Only significant difference between the percentages is for type IV and
normrblipemic group (P <0.01).
tNo significant difference between the percentage for type II, type IV
and normolipemic groups.
VOL 56, No 5, NOVEMBER 1977
occurrence of CAD. They
defined as >75% stenosis,
found that the group with CAD,
had significantly higher concentrations of both serum cholesterol and triglyceride than did
those without disease. By performing analyses of quartile
distribution of these serum lipids, they concluded that serum
cholesterol has a stronger degree of correlation with CAD
than does triglyceride, particularly in multi-vessel disease.
They also concluded that the association between concentrations of serum lipids and CAD was continuous and they
were unable to establish any critical serum level which would
separate risk from non-risk for either the cholesterol or triglyceride concentrations or both. For purposes of comparison, we have adjusted some of our data to the method
used by these workers. They did not analyze their results on
the basis of extent of disease involved and did not assess correlations with degrees of stenosis less than 75%. A comparison of the extent of disease was limited to one of
"healthy" versus single vessel or multi-vessel disease. Also,
their study did not classify subjects with respect to lipoprotein phenotype and did not make correlations based on
lipoprotein patterns.
In the present study we evaluated 496 patients for both the
severity and extent of coronary artery disease by
cineangiography. We analyzed the relationship of frequency
and extent of CAD to the levels of plasma cholesterol and
triglycerides. Fewer than 5% of the patients were on lipid
lowering medication, the most common of which was
clofibrate. Some of the patients had received dietary instructions at one time or another, but it was impossible to
generalize about the dietary characteristics of the overall
groups.
Approximately 21% of the patients undergoing the study
were found to have less than 25% stenosis of any coronary
artery. This incidence of normal coronary arteries is consistent with other reported series.26' 27 The mean ages of the two
groups were 49.6 years for those without coronary artery
disease and 55.7 years for those with CAD. The differences
in age were taken into account in calculating the agecorrected correlation coefficients to establish the relationship between serum and number of vessels involved.
We found significant correlations between the frequency
of CAD and the levels of plasma cholesterol and triglyceride concentrations. The correlations between plasma
cholesterol concentration and the number of vessels involved
was greater than that between plasma triglyceride and
number of vessels involved. The group of subjects in the
highest quartiles of cholesterol and triglyceride concentrations had the highest frequency of CAD. We were unable
to identify a critical cut-off point for either cholesterol or triglyceride levels which separated those with CAD and those
without disease. This observation is consistent with that of
Cohn et al.'3
We were unable to confirm the observation by Bloch et
al.28 concerning the differences in extent and severity of
CAD in type II versus type IV hyperlipoproteinemia. We
wish to emphasize again the point that many patients with
severe coronary disease had lipid levels below the criteria
usually applied for defining hyperlipidemia. The fourth and
highest quartile in our patients starts from 236 mg/dl. Based
on criteria commonly used for defining hyperlipoproteinemia, we could distinguish no significant
LIPIDS AND CORONARY ARTERY DISEASE/Gotto
differences in the extent of severity of CAD between patients
with types II and IV hyperlipoproteinemia.
In our population we found a continuous relation between
cholesterol and triglyceride levels and the frequency and extent of the CAD. We conclude from this study that the use of
arbitrary cut-off values to define hyperlipidemia or hyperlipoproteinemia may be misleading. In regard to CAD, the
physician may find it of greater value to consider the actual
plasma lipid levels in the patient's management.
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A M Gotto, G A Gorry, J R Thompson, J S Cole, R Trost, D Yeshurun and M E DeBakey
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Circulation. 1977;56:875-883
doi: 10.1161/01.CIR.56.5.875
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1977 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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