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Serum cholesterol and high density lipoprotein-cholesterol in coronary patients and healthy persons
9
Atherosclerosis, 33 (1979) 9-16 0 Elsevier/North-Holland Scientific Publishers, Ltd.
SERUM CHOLESTEROL AND HIGH DENSITY LIPOPROTEIN-CHOLESTEROL IN CORONARY HEALTHY PERSONS
D. BRUNNER, and S. LEVIN
J. WEISBORT,
K. LOEBL,
PATIENTS
AND
S. SCHWARTZ, S. ALTMAN, J.E. BEARMAN
Medical Department A, Government Hospital, Jaffa, and Donolo Institute of Physiological Hygiene, Medical School, Tel Aviv University, Tel Aviv (Israel) (Received 11 August, 1978) (Revised, received 29 November, 1978) (Accepted 7 December, 1978)
Summary Serum cholesterol (CH) and high density lipoprotein-cholesterol (HDL-CH) were determined in 154 male and in 68 female post-myocardial infarction (MI) patients and in 2706 healthy males and 1888 healthy females. CH values showed no significant differences between healthy subjects and MI patients (except in males 35-44 years old). HDL-CH values were significantly lower in MI patients than in healthy subjects. In addition, in subgroups with equal CH values, MI patients had significantly lower HDL-CH than healthy people. Healthy females had higher HDL-CH than healthy males with same CH levels, but there was no difference in HDL-CH between male and female coronary patients with equal CH values. The term HDL-CH%, indicating the percentage of total CH in the HDL, seems preferable to HDL-CH mg/lOO ml, because it is independent of the level of CH. In the population surveyed, HDL-CH showed itself as a more reliable indicator for ischemic heart disease than CH. The hypothesis is advanced that the first step in the development of an atherogenic lipoprotein pattern is a re-distribution of CH between HDL on the one hand, and LDL plus VLDL on the other hand, the second step only being an increase of CH, mainly in the low density lipoprotein fractions. This study was supported in part by grant HE-04520 Government, Bethesda. MD, U.S.A.
from the National Institutes of Health, US
10
Key words:
Cholesterol - Coronary artery disease -High
density lipoprotein-cholesterol
Introduction Lipids and lipoproteins are implicated in coronary atherosclerosis and its major symptomatic manifestations, such as myocardial infarction (MI) and angina pectoris (Al?) [ 11. Gofman [2], using analytical ultracentrifugal determinations, advanced the hypothesis that low density lipoprotein (LDL) and very low density lipoprotein (VLDL) fractions are predictive of ischemic heart disease (IHD). Barr [3] demonstrated in 1951 that post-MI patients had lower a-lipoprotein concentrations than healthy persons. In 1958 we presented data which showed that Yemenite Jews, who had recently immigrated to Israel, had low serum cholesterol (CH), with a high percentage of it bound to the a-lipoproteins, and they were almost free of IHD [4,5]. Over the years some changes have occurred in chemical methods and in nomenclature. Electrophoretically or ultracentrifugally determined a-lipoproteins correspond to chemically determined HDL, /3-lipoproteins to LDL, and pre-@lipoproteins to VLDL. More recent studies indicate that high levels of HDL and/or HDL-CH may to some extent protect against IHD, a hypothesis which needs further evaluation [ 6-81. The aim of this study is to determine the relations between CH and HDL-CH in male and female post-MI patients and in healthy subjects.
TABLE 1 BODY WEIGHT AND HEIGHT M&S Age 3544
No. of patients Weight (kg) Height (cm)
yrs
IHD
HC
29
918
76.6 (10.3)
74.7 (10.1)
170.4
169.5 (6.7)
(5.7)
Age 35-54 IHD No. of patients
Age 45-54
19
Weight (kg)
67.2 (10.7)
Height (cm)
155.6 (6.3)
IHD 54
HC 1404 65.7 (10.8) 155.9 (6.6)
Age 55-64
HC 1063
YR
IHD
HC
71
727
73.0
73.1
75.5
(8.6)
(9.6)
(8.7)
72.6 (10.1)
167.9
168.2
(5.6)
Age 56+4
yrs
yrs
(6.5)
yrs
IHD
HC
49
484
66.5 (9.8)
65.8 (10.8)
155.9 (5.7)
156.4 (6.6)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
168.4 (5.9)
168.2 (6.4)
11
Material and Methods The group studied comprises 154 male and 68 female patients, consecutively admitted to the hospital ward for definite MI. The diagnostic criteria of MI were: typical pains, serial ECG changes consistent with acute MI, and transient elevation of serum glutamic oxalo-acetic transaminase and creatinine phosphokinase . The control group consists of 4596 subjects with normal ECG and without clinical history of IHD, who were examined in the course of the Tel Aviv Donolo Prospective Ischemic Heart Disease Study. Table 1 shows body weight and body height in age-specific groups. There were no differences between patients and healthy subjects. Blood samples were drawn in the morning, following a 12-h overnight fast. From the post-MI patients blood samples were drawn 3 months after the acute event. The mean of two samples, drawn one week apart, was accepted as the valid level. CH was determined by the method described by Anderson and Keys [ 91. HDL-CH was determined after precipitating LDL and VLDL by heparin-manganesechloride. HDL-CH is expressed in two ways, in mg/lOO ml (HDL-CH mg/lOO ml) and in percentage of total CH bound to the HDL-CH (HDL-CH%). For statistical evaluation the t-test was used. Results Tables 2 and 3 present CH and HDL-CH values and standard deviations in males of 35-44, 45-54, and 55-64 years, and in females of 35-54 and 5564 years. No significant differences in CH levels were found between coronary patients and healthy subjects, with the exception of the youngest age group of males, 35-44 years old. On the other hand, in all age groups, HDL-CH mg/ 100 ml and HCL-CH% were highly significantly lower in coronary patients than in healthy subjects. Tables 4 and 5 present HDL-CH values by sex, in coronary
TABLE 2 CHOLESTEROL
AND HDL-CHOLESTEROL
-MALES
The differences in aU subgroups of HDL-CHI and HDLCH mg/lOO ml are statistically significant (P < 0.01). The differences of CH are only significant in males 3544 years old (P < 0.05).
No. of patients Cholesterol (mg/lOO ml) HDGCH HDGCH%
(mg/lOO ml)
Age 3544
yrs
Age 45-54
yrs
Age 55-64
YES
IHD
HC
IHD
HC
IHD
HC
29
91s
54
71
727
1063
236.2 (55.2)
221.3 (30.4)
226.4 (45.5)
224.2 (38.2)
227.2 (50.3)
231.4 (40.6)
33.4
47.1 (10.5)
36.2
46.2 (11.2)
36.5
(6.9)
(9.6)
46.8 (13.1)
14.1
21.3
16.0
20.6
16.0
20.2
(3.5)
(6.4)
(6.1)
(6.2)
(6.0)
(6.3)
(8.9)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
12 TABLE 3 CHOLESTEROL
AND HDL-CHOLESTEROL
-
FEMALES
The differences in all subgroups of HCGCH% and HCGCH (P < 0.01). The differences of CH are not significant. Age 35-54
HC
19
No. of patients ml)
HDL-CH (mg/lOO ml)
Age 55-64
yrs
IHD
Cholesterol @g/100
mg/lOO ml are of high statistical significance
1404
yrs
IHD
HC
49
404
237.4
226.2
263.5
254.3
(31.5)
(36.2)
(58.2)
(40.2)
40.2 (11.4)
58.3 (13.2)
38.5 (12.3)
59.5 (12.6)
16.9
25.7
14.3
23.3
(3.6)
(7.3)
(4.3)
(6.8)
HDL-CH%
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
patients and in healthy persons with comparable total CH values, less than 200 mg/lOO ml, 200-224 mg/lOO ml, 225-249 mg/lOO ml, 250-299 mg/lOO ml, and 300 mg/lOO ml and more. The differences of HDL-CH mg/lOO ml and of HDL-CH% were highly significant in all subgroups. In Table 6 HDL-CH mg/lOO ml and HDL-CH% of healthy males were compared with those of healthy females, and male coronary patients were compared with female patients in groups with equal CH. Whereas in all classes with equal CH healthy females had significantly higher HDL-CH than healthy males, in IHD patients there was no difference between male and female subjects.
TABLE 4 MEAN HDL-CH IN IHD PATIENTS
AND IN HEALTHY
SUBJECTS WITH EQUAL
In all subgroups the differences are of high statistical significance
(P <
CH -
MALES
0.01).
CH mg/lOO ml Less than 200
200-224
IHD
HC
IHD
HC
IHD
HC
IHD
HC
IHD
HC
No. of patients
53
975
34
758
27
542
25
311
15
122
HDL-CH mg/lOO ml
35.2
42.3 (10.2)
35.3
45.1
34.6
(9.3)
(7.7)
48.2 (12.2)
37.2
(9.5)
52.3 (10.6)
HDL-CH%
18.5 (5.3)
22.9
16.3 (3.5)
20.5
15.6 (3.8)
19.9 (5.5)
(6.2)
(6.1)
225-249
(5.7)
250-299
300 and more
48.5 (10.1)
38.1
(9.8) 13.7 (4.7)
17.4 (5.3)
12.1
16.5
(3.8)
(4.3)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
(9.1)
13
TABLE 5 MEAN HDL-CH IN IHD PATIENTS
AND IN HEALTHY
SUBJECTS WITH EQUAL
CH -
FEMALES
In all subgroups the differences are of high statistical significance (P < 0.01). CH mg/lOO ml 225-249
250-299
300 and more
Less than 200
200-224
IHD
HC
IHD
HC
IHD
HC
IHD
HC
IHD
HC
No. of patients
11
412
10
442
12
634
19
214
16
126
HDGCH mg/lOO ml
32.0
HDL-CH%
57.5
31.3 (10.8)
59.2 (16.1)
40.6 (10.7)
62.3 (15.6)
43.2
(16.4)
16.6
26.3
15.8
24.4
14.7
22.1
13.5
20.3
(4.2)
(7.0)
(3.6)
(6.3)
(4.1)
(6.1)
(3.8)
(5.9)
52.2 (13.6)
36.8
18.3
28.5
(8.6)
(6.6)
(6.4)
(9.0)
(9.5)
65.2 (14.6)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
Discussion Serum CH values decrease after an acute event, and return to the pre-disease level after about 12 week8 [lo]. For this reason we performed the blood examinations 3 months after the myocardial infarction. Compared to reports from Western countries, our coronary patients had relatively low CH values. 56% of the male and 30% of the female patients had less than 225 mg/lOO ml CH, and 34% of the male and 16% of the female patient8 had less than 200 mg/ 100 ml. The average CH value8 of the coronary patients of both sexes were not different from those of the controls, with the only exception of healthy males, 35-44 years old. Unlike the CH values, HDL-CH values were significantly lower in age-specific groups of patients than of controls of both sexes. Furthermore, in cholesterolspecific subgroups, less than 200 mg/lOO ml, 200-224 mg/lOO ml, 225-249 mg/lOO ml, 250-299 mg/lOO ml, and 300 mg/lOO ml and more, significantly lower HDL-CH mg/lOO ml and HDL-CH% were found in patients than in healthy subjects. It seems us preferable to express HDL-CH as a percentage of serum CH (HDL-CH%) instead of units of mg/lOO ml. If, for example, the serum CH level of a male coronary patient is 300 mg/lOO ml and the HDL-CH% is 16%which is the average HDL-CH% plus one standard deviation of this CH-specific subgroup -then the HDL-CH mg/lOO ml is 48 mg/lOO ml, which is 5 mg/lOO ml higher than the HDL-CH mg/lOO ml values of a healthy male with serum CH of 200 mg/lOO ml, and 3 mg/lOO ml higher than that of a healthy male with serum CH of 200-224 mg/lOO ml range. Thus, in using HDL-CH% (instead of mg/lOO ml) the HDL-CH fraction becomes independent from the level of serum CH, and the misleading interpretation can be avoided that subjects with relatively low CH have low HDL-CH mg/lOO ml, even if a rather high percentage of the CH is bound to HDL and, vice versa, patients with high CH have
14
rather high HDL-CH mg/lOO ml, even if a low percentage of CH is bound to the HDL. HDL-CH% decreases in patients and in healthy persons with rising CH (Tables 4 and 5). The higher the serum CH, the smaller the percentage of it bound to the HDL. But because the rate of increase of CH exceeds the rate of decrease of HDL-CH%, HDL-CH mg/lOO ml increases somewhat with rising CH. Throughout the range of CH, from less than 200 mg/lOO ml to 300 mg/lOO ml and more, average HDL-CH mg/lOO ml and HDL-CH% were higher in healthy subjects than in IHD patients, with the exception of healthy males with CH values higher than 250 mg/lOO ml, whose HDL-CH% was lower than that of IHD patients with CH less than 200 mg/lOO ml. In the population surveyed, HDL-CH was a meaningful lipid indicator, discerning between healthy people and IHD patients. Healthy females have higher HDL-CH than healthy males with the same CH level. This sex difference might be responsible for the lower incidence of IHD in females. However, HDL-CH of females suffering from IHD is not different from that of male patients. These findings emphasize the strong relationship between IHD and HDL-CH (Table 6). Recently, Castelli et al., summarizing 5 American epidemiological studies, found that with respect to IHD the most important finding was the inverse relation between HDL-CH and IHD prevalence, which was characterized by a high degree of generality and strength [ 111. These data are similar to our previously reported findings in Yemenite Jews [ 41. The mechanism which controls the level of HDL-CH, and the way in which HDL-CH protects against coronary atherosclerosis, is not yet thoroughly understood. The difference of HDL-CH between healthy males and females indicates a possible influence of hormonal determinants. Tyroler et al. found higher HCL-CH in black than in white people [ 121. They suggested that this may be a genetic difference which may explain the lower incidence of IHD in Blacks, even if all other coronary risk factors were equal. On the other hand, it has been reported that body weight loss and strenuous physical activity do raise HDL-CH levels [ 13,141. We found, in an earlier study, extremely high HDL-CH% in racing bicyclists [ 151. These findings, which point to the influence of non-genetic factors on HDL-CH, as well as the fact that, also in patients with rather low CH (less than 225 mg/lOO ml or 200 mg/lOO ml), HDL-CH% was significantly lower than in healthy persons with equal CH, may suggest that the first step in the development of atherogenic lipoprotein pattern is a re-distribution of the CH between HDL and LDL plus VLDL, the second only being an increase in CH, which occurs mostly in the LDL fraction. Miller and Miller assume that HDL is the carrier of CH from the peripheral tissues to the liver, where it is catabolized and excreted. Hence, higher levels of HDL-CH will be associated with less atherosclerosis [ 161. It has been demonstrated that in tissue cultures the apoprotein of HDL enhances the efflux of CH from aortic smooth muscle cells [17]. It has also been suggested that HDL inhibits the uptake of LDL by cultured aortic smooth muscle cells and human fibroblasts [ 181. If -as it seems - HDL-CH is an anti-atherogenic factor, efforts should be directed to identify those factors which may influence HDL-CH levels.
6
mg/100 ml AND HDL-CH%
nu?/lOOml
mg/lOOml
mg/l00ml
(9.3) (5.7)
122 52.3 (10.6) 16.5 (4.3)
311 48.5 (10.1) 17.4 (5.3)
542 48.2 (12.2) 19.9 (5.5)
758 45.3 20.5
42.3 (10.2) 22.9 (6.1)
975
Male
Healthy controls
WITH EQUAL
126 65.2 (14.6) 20.3 (5.9)
214 62.3 (15.6) 22.1 (6.1)
634 59.2 (16.1) 24.4 (6.3)
442 57.5 (16.4) 26.3 (7.0)
51.2 (13.6) 28.5 (6.6)
472
Female
IN MEN AND WOMEN
( ) = standard deviation: N.S. = not significant.
HDGCH (mg/lOO ml) HDL-CH%
No.
300 or more m&?/l00 ml
HDGCH (mg/lOO ml) HDGCHI
No.
250-299
HDL-CH (mg/lOO ml) HDL-CH%
No.
225-249
HDL-CH (mg/lOO ml) HDGCH%
No.
200-224
HDL-CH (mg/lOO ml) HDL-CH%
No.
Less than 200 mg/lOO ml
Cholesterol (mg/lOO ml)
HDL-CH
TABLE
I
i
i
,j
1
co.01
P
CHOLESTEROL
15 38.1 (9.1) 12.1 (3.8)
25 37.2 (9.8) 13.7 (4.7)
27 34.6 (7.7) 15.6 (3.8)
34 35.3 (9.5) 16.3 (3.5)
53 35.2 (6.5) 18.5 (6.3)
Male
IHD patients
(9.0) (4.2)
(6.4) (8.6)
16 43.2 13.5
(9.5) (3.8)
19 40.6 (10.7) 14.7 (4.1)
12 37.3 (10.8) 15.8 (3.6)
10 36.8 16.6
11 32.0 18.3
Female
1
i
i
J
>
N.S..
N.S.
N.S.
. .
N s
N.S.
P
16
References
5
6 7 8 9 10 11
12 13 14 15 16 17
18
StantIer, J.. In: Lectures in Preventive Cardiology, Gnme and Stratton, New York, London, 1967. Gofman. J.W.. Lindgren, F., Elliot. II., Mautz. W.. Hewitt, J.. Strisowea, B. and Herring, N., The role of lipids am&lipoproteins in atherosclerosis, Science, 111 (1950) 166-173. Barr. D.P., Russ, E.M. and Eder, HA., Protein lipid relationship in human plasma, Amer. J. Med., 11 (1951) 480-491. Brunner. D. and Loebl. K., Serum cholesterol, electrophoretic lipid pattern, diet and coronary artery disease -A study in coronary patients and in healthy men of different origin and occupations in Israel, Ann. Int. Med., 49 (1958) 732-750. Brunner. D.. Altman, S.. Loebl, K. and Schwartz. S.. Alpha cholesterol percentages in coronary patients with an without increased total serum cholesterol levels and in healthy controls, J. Atheroscler. Res.. 2 (1962) 424437. Rhoads, G.G., Gulbrandsen, CL. and Kagan, A., Serum lipoprotein and coronary heart disease in a population study of Hawaii Japanese men, New Engl. J. Med., 294 (1976) 293-297. Berg, K., Borresen, A. and DahIen, G., Serum high density lipoprotein and atherosclerotic heart disease, Lance& 1 (1976) 499-501. Gordon, T.. CasteBi. W.P., HjortIand. M.C., Kannel, W.B. and Dawber, T.R., High density lipoprotein as a protective factor against coronary heart disease, Amer. J. Med.. 62 (1977) 707-714. Anderson, J.T. and Keys, A., Cholesterol in serum and lipoprotein fraction - Its measurement and stability. Clin. Chem.. 2 (1956) 145-169. Fyfe, T., Baxter, R.H. and Cochran. K.M.. Plasma lipid changes after myocardiai infarction, Lancet, 2 (1971) 997-1001. Caste& W.P., Doyle, J.T.. Gordon, T., Hames. C.G.. HiortIand. M.C., HuIIey, S.B., Kagan. A. and Zukel. W.J., HDL cholesterol and other lipids in coronary heart disease - The cooperative lipoprotein phenotyping study, Circulation. 55 (1977) 767-772. Tyroler, M.A., Hames. C.G.. Krishan. J.. Heyden. S.. Cooper, G. and Cassel, J.C., Black-white differences in serum lipids and lipoproteins in Evans County, Preventive Med., 4 (1975) 541-549. Carlson, L.A. and Ericson. M., Quantitative and qualitative serum lipoprotein analvsis.Atherosclerosis, 21(1975) 417433. Wood, P.D., Klein, H., Lewis, S. and Ha&tell. W.L., Plasma lipoprotein concentrations in middle-aged male runners, Circulation, 60 (1974) 111-116. Jung, K., tier die energieliefernden Prozesse bei Ausdauerbelastung, dargestellt am Beispiel eines sechstltigen Radrennens. Med. Welt, 33 (1972) 1105-1110. Miller. N.E. and Miller, G.J., High density lipoprotein and atherosclerosis, Lancet, 1 (1975) 1033. Stein, Y.. Glangeaud. M.C.. Fainaru. M. and Stein, 0.. The removal of cholesterol from aortic smooth muscle cells in culture and Landschutz ascites ceBs by fractions of human high density apohpoprotein. Biochim. Biophys. Acta, 380 (1975) 106-118. Koschinsky. T.. Carew, T.E. and Steinberg, D.. Effects of high density lipoprotein (HDL) on low density lipoprotein (LDL) metabolism by pig smooth muscle cells. Circulation, 61 (1975) H-273.
Atherosclerosis, 33 (1979) 9-16 0 Elsevier/North-Holland Scientific Publishers, Ltd.
SERUM CHOLESTEROL AND HIGH DENSITY LIPOPROTEIN-CHOLESTEROL IN CORONARY HEALTHY PERSONS
D. BRUNNER, and S. LEVIN
J. WEISBORT,
K. LOEBL,
PATIENTS
AND
S. SCHWARTZ, S. ALTMAN, J.E. BEARMAN
Medical Department A, Government Hospital, Jaffa, and Donolo Institute of Physiological Hygiene, Medical School, Tel Aviv University, Tel Aviv (Israel) (Received 11 August, 1978) (Revised, received 29 November, 1978) (Accepted 7 December, 1978)
Summary Serum cholesterol (CH) and high density lipoprotein-cholesterol (HDL-CH) were determined in 154 male and in 68 female post-myocardial infarction (MI) patients and in 2706 healthy males and 1888 healthy females. CH values showed no significant differences between healthy subjects and MI patients (except in males 35-44 years old). HDL-CH values were significantly lower in MI patients than in healthy subjects. In addition, in subgroups with equal CH values, MI patients had significantly lower HDL-CH than healthy people. Healthy females had higher HDL-CH than healthy males with same CH levels, but there was no difference in HDL-CH between male and female coronary patients with equal CH values. The term HDL-CH%, indicating the percentage of total CH in the HDL, seems preferable to HDL-CH mg/lOO ml, because it is independent of the level of CH. In the population surveyed, HDL-CH showed itself as a more reliable indicator for ischemic heart disease than CH. The hypothesis is advanced that the first step in the development of an atherogenic lipoprotein pattern is a re-distribution of CH between HDL on the one hand, and LDL plus VLDL on the other hand, the second step only being an increase of CH, mainly in the low density lipoprotein fractions. This study was supported in part by grant HE-04520 Government, Bethesda. MD, U.S.A.
from the National Institutes of Health, US
10
Key words:
Cholesterol - Coronary artery disease -High
density lipoprotein-cholesterol
Introduction Lipids and lipoproteins are implicated in coronary atherosclerosis and its major symptomatic manifestations, such as myocardial infarction (MI) and angina pectoris (Al?) [ 11. Gofman [2], using analytical ultracentrifugal determinations, advanced the hypothesis that low density lipoprotein (LDL) and very low density lipoprotein (VLDL) fractions are predictive of ischemic heart disease (IHD). Barr [3] demonstrated in 1951 that post-MI patients had lower a-lipoprotein concentrations than healthy persons. In 1958 we presented data which showed that Yemenite Jews, who had recently immigrated to Israel, had low serum cholesterol (CH), with a high percentage of it bound to the a-lipoproteins, and they were almost free of IHD [4,5]. Over the years some changes have occurred in chemical methods and in nomenclature. Electrophoretically or ultracentrifugally determined a-lipoproteins correspond to chemically determined HDL, /3-lipoproteins to LDL, and pre-@lipoproteins to VLDL. More recent studies indicate that high levels of HDL and/or HDL-CH may to some extent protect against IHD, a hypothesis which needs further evaluation [ 6-81. The aim of this study is to determine the relations between CH and HDL-CH in male and female post-MI patients and in healthy subjects.
TABLE 1 BODY WEIGHT AND HEIGHT M&S Age 3544
No. of patients Weight (kg) Height (cm)
yrs
IHD
HC
29
918
76.6 (10.3)
74.7 (10.1)
170.4
169.5 (6.7)
(5.7)
Age 35-54 IHD No. of patients
Age 45-54
19
Weight (kg)
67.2 (10.7)
Height (cm)
155.6 (6.3)
IHD 54
HC 1404 65.7 (10.8) 155.9 (6.6)
Age 55-64
HC 1063
YR
IHD
HC
71
727
73.0
73.1
75.5
(8.6)
(9.6)
(8.7)
72.6 (10.1)
167.9
168.2
(5.6)
Age 56+4
yrs
yrs
(6.5)
yrs
IHD
HC
49
484
66.5 (9.8)
65.8 (10.8)
155.9 (5.7)
156.4 (6.6)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
168.4 (5.9)
168.2 (6.4)
11
Material and Methods The group studied comprises 154 male and 68 female patients, consecutively admitted to the hospital ward for definite MI. The diagnostic criteria of MI were: typical pains, serial ECG changes consistent with acute MI, and transient elevation of serum glutamic oxalo-acetic transaminase and creatinine phosphokinase . The control group consists of 4596 subjects with normal ECG and without clinical history of IHD, who were examined in the course of the Tel Aviv Donolo Prospective Ischemic Heart Disease Study. Table 1 shows body weight and body height in age-specific groups. There were no differences between patients and healthy subjects. Blood samples were drawn in the morning, following a 12-h overnight fast. From the post-MI patients blood samples were drawn 3 months after the acute event. The mean of two samples, drawn one week apart, was accepted as the valid level. CH was determined by the method described by Anderson and Keys [ 91. HDL-CH was determined after precipitating LDL and VLDL by heparin-manganesechloride. HDL-CH is expressed in two ways, in mg/lOO ml (HDL-CH mg/lOO ml) and in percentage of total CH bound to the HDL-CH (HDL-CH%). For statistical evaluation the t-test was used. Results Tables 2 and 3 present CH and HDL-CH values and standard deviations in males of 35-44, 45-54, and 55-64 years, and in females of 35-54 and 5564 years. No significant differences in CH levels were found between coronary patients and healthy subjects, with the exception of the youngest age group of males, 35-44 years old. On the other hand, in all age groups, HDL-CH mg/ 100 ml and HCL-CH% were highly significantly lower in coronary patients than in healthy subjects. Tables 4 and 5 present HDL-CH values by sex, in coronary
TABLE 2 CHOLESTEROL
AND HDL-CHOLESTEROL
-MALES
The differences in aU subgroups of HDL-CHI and HDLCH mg/lOO ml are statistically significant (P < 0.01). The differences of CH are only significant in males 3544 years old (P < 0.05).
No. of patients Cholesterol (mg/lOO ml) HDGCH HDGCH%
(mg/lOO ml)
Age 3544
yrs
Age 45-54
yrs
Age 55-64
YES
IHD
HC
IHD
HC
IHD
HC
29
91s
54
71
727
1063
236.2 (55.2)
221.3 (30.4)
226.4 (45.5)
224.2 (38.2)
227.2 (50.3)
231.4 (40.6)
33.4
47.1 (10.5)
36.2
46.2 (11.2)
36.5
(6.9)
(9.6)
46.8 (13.1)
14.1
21.3
16.0
20.6
16.0
20.2
(3.5)
(6.4)
(6.1)
(6.2)
(6.0)
(6.3)
(8.9)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
12 TABLE 3 CHOLESTEROL
AND HDL-CHOLESTEROL
-
FEMALES
The differences in all subgroups of HCGCH% and HCGCH (P < 0.01). The differences of CH are not significant. Age 35-54
HC
19
No. of patients ml)
HDL-CH (mg/lOO ml)
Age 55-64
yrs
IHD
Cholesterol @g/100
mg/lOO ml are of high statistical significance
1404
yrs
IHD
HC
49
404
237.4
226.2
263.5
254.3
(31.5)
(36.2)
(58.2)
(40.2)
40.2 (11.4)
58.3 (13.2)
38.5 (12.3)
59.5 (12.6)
16.9
25.7
14.3
23.3
(3.6)
(7.3)
(4.3)
(6.8)
HDL-CH%
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
patients and in healthy persons with comparable total CH values, less than 200 mg/lOO ml, 200-224 mg/lOO ml, 225-249 mg/lOO ml, 250-299 mg/lOO ml, and 300 mg/lOO ml and more. The differences of HDL-CH mg/lOO ml and of HDL-CH% were highly significant in all subgroups. In Table 6 HDL-CH mg/lOO ml and HDL-CH% of healthy males were compared with those of healthy females, and male coronary patients were compared with female patients in groups with equal CH. Whereas in all classes with equal CH healthy females had significantly higher HDL-CH than healthy males, in IHD patients there was no difference between male and female subjects.
TABLE 4 MEAN HDL-CH IN IHD PATIENTS
AND IN HEALTHY
SUBJECTS WITH EQUAL
In all subgroups the differences are of high statistical significance
(P <
CH -
MALES
0.01).
CH mg/lOO ml Less than 200
200-224
IHD
HC
IHD
HC
IHD
HC
IHD
HC
IHD
HC
No. of patients
53
975
34
758
27
542
25
311
15
122
HDL-CH mg/lOO ml
35.2
42.3 (10.2)
35.3
45.1
34.6
(9.3)
(7.7)
48.2 (12.2)
37.2
(9.5)
52.3 (10.6)
HDL-CH%
18.5 (5.3)
22.9
16.3 (3.5)
20.5
15.6 (3.8)
19.9 (5.5)
(6.2)
(6.1)
225-249
(5.7)
250-299
300 and more
48.5 (10.1)
38.1
(9.8) 13.7 (4.7)
17.4 (5.3)
12.1
16.5
(3.8)
(4.3)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
(9.1)
13
TABLE 5 MEAN HDL-CH IN IHD PATIENTS
AND IN HEALTHY
SUBJECTS WITH EQUAL
CH -
FEMALES
In all subgroups the differences are of high statistical significance (P < 0.01). CH mg/lOO ml 225-249
250-299
300 and more
Less than 200
200-224
IHD
HC
IHD
HC
IHD
HC
IHD
HC
IHD
HC
No. of patients
11
412
10
442
12
634
19
214
16
126
HDGCH mg/lOO ml
32.0
HDL-CH%
57.5
31.3 (10.8)
59.2 (16.1)
40.6 (10.7)
62.3 (15.6)
43.2
(16.4)
16.6
26.3
15.8
24.4
14.7
22.1
13.5
20.3
(4.2)
(7.0)
(3.6)
(6.3)
(4.1)
(6.1)
(3.8)
(5.9)
52.2 (13.6)
36.8
18.3
28.5
(8.6)
(6.6)
(6.4)
(9.0)
(9.5)
65.2 (14.6)
IHD = ischemic heart disease; HC = healthy controls; ( ) = standard deviation.
Discussion Serum CH values decrease after an acute event, and return to the pre-disease level after about 12 week8 [lo]. For this reason we performed the blood examinations 3 months after the myocardial infarction. Compared to reports from Western countries, our coronary patients had relatively low CH values. 56% of the male and 30% of the female patients had less than 225 mg/lOO ml CH, and 34% of the male and 16% of the female patient8 had less than 200 mg/ 100 ml. The average CH value8 of the coronary patients of both sexes were not different from those of the controls, with the only exception of healthy males, 35-44 years old. Unlike the CH values, HDL-CH values were significantly lower in age-specific groups of patients than of controls of both sexes. Furthermore, in cholesterolspecific subgroups, less than 200 mg/lOO ml, 200-224 mg/lOO ml, 225-249 mg/lOO ml, 250-299 mg/lOO ml, and 300 mg/lOO ml and more, significantly lower HDL-CH mg/lOO ml and HDL-CH% were found in patients than in healthy subjects. It seems us preferable to express HDL-CH as a percentage of serum CH (HDL-CH%) instead of units of mg/lOO ml. If, for example, the serum CH level of a male coronary patient is 300 mg/lOO ml and the HDL-CH% is 16%which is the average HDL-CH% plus one standard deviation of this CH-specific subgroup -then the HDL-CH mg/lOO ml is 48 mg/lOO ml, which is 5 mg/lOO ml higher than the HDL-CH mg/lOO ml values of a healthy male with serum CH of 200 mg/lOO ml, and 3 mg/lOO ml higher than that of a healthy male with serum CH of 200-224 mg/lOO ml range. Thus, in using HDL-CH% (instead of mg/lOO ml) the HDL-CH fraction becomes independent from the level of serum CH, and the misleading interpretation can be avoided that subjects with relatively low CH have low HDL-CH mg/lOO ml, even if a rather high percentage of the CH is bound to HDL and, vice versa, patients with high CH have
14
rather high HDL-CH mg/lOO ml, even if a low percentage of CH is bound to the HDL. HDL-CH% decreases in patients and in healthy persons with rising CH (Tables 4 and 5). The higher the serum CH, the smaller the percentage of it bound to the HDL. But because the rate of increase of CH exceeds the rate of decrease of HDL-CH%, HDL-CH mg/lOO ml increases somewhat with rising CH. Throughout the range of CH, from less than 200 mg/lOO ml to 300 mg/lOO ml and more, average HDL-CH mg/lOO ml and HDL-CH% were higher in healthy subjects than in IHD patients, with the exception of healthy males with CH values higher than 250 mg/lOO ml, whose HDL-CH% was lower than that of IHD patients with CH less than 200 mg/lOO ml. In the population surveyed, HDL-CH was a meaningful lipid indicator, discerning between healthy people and IHD patients. Healthy females have higher HDL-CH than healthy males with the same CH level. This sex difference might be responsible for the lower incidence of IHD in females. However, HDL-CH of females suffering from IHD is not different from that of male patients. These findings emphasize the strong relationship between IHD and HDL-CH (Table 6). Recently, Castelli et al., summarizing 5 American epidemiological studies, found that with respect to IHD the most important finding was the inverse relation between HDL-CH and IHD prevalence, which was characterized by a high degree of generality and strength [ 111. These data are similar to our previously reported findings in Yemenite Jews [ 41. The mechanism which controls the level of HDL-CH, and the way in which HDL-CH protects against coronary atherosclerosis, is not yet thoroughly understood. The difference of HDL-CH between healthy males and females indicates a possible influence of hormonal determinants. Tyroler et al. found higher HCL-CH in black than in white people [ 121. They suggested that this may be a genetic difference which may explain the lower incidence of IHD in Blacks, even if all other coronary risk factors were equal. On the other hand, it has been reported that body weight loss and strenuous physical activity do raise HDL-CH levels [ 13,141. We found, in an earlier study, extremely high HDL-CH% in racing bicyclists [ 151. These findings, which point to the influence of non-genetic factors on HDL-CH, as well as the fact that, also in patients with rather low CH (less than 225 mg/lOO ml or 200 mg/lOO ml), HDL-CH% was significantly lower than in healthy persons with equal CH, may suggest that the first step in the development of atherogenic lipoprotein pattern is a re-distribution of the CH between HDL and LDL plus VLDL, the second only being an increase in CH, which occurs mostly in the LDL fraction. Miller and Miller assume that HDL is the carrier of CH from the peripheral tissues to the liver, where it is catabolized and excreted. Hence, higher levels of HDL-CH will be associated with less atherosclerosis [ 161. It has been demonstrated that in tissue cultures the apoprotein of HDL enhances the efflux of CH from aortic smooth muscle cells [17]. It has also been suggested that HDL inhibits the uptake of LDL by cultured aortic smooth muscle cells and human fibroblasts [ 181. If -as it seems - HDL-CH is an anti-atherogenic factor, efforts should be directed to identify those factors which may influence HDL-CH levels.
6
mg/100 ml AND HDL-CH%
nu?/lOOml
mg/lOOml
mg/l00ml
(9.3) (5.7)
122 52.3 (10.6) 16.5 (4.3)
311 48.5 (10.1) 17.4 (5.3)
542 48.2 (12.2) 19.9 (5.5)
758 45.3 20.5
42.3 (10.2) 22.9 (6.1)
975
Male
Healthy controls
WITH EQUAL
126 65.2 (14.6) 20.3 (5.9)
214 62.3 (15.6) 22.1 (6.1)
634 59.2 (16.1) 24.4 (6.3)
442 57.5 (16.4) 26.3 (7.0)
51.2 (13.6) 28.5 (6.6)
472
Female
IN MEN AND WOMEN
( ) = standard deviation: N.S. = not significant.
HDGCH (mg/lOO ml) HDL-CH%
No.
300 or more m&?/l00 ml
HDGCH (mg/lOO ml) HDGCHI
No.
250-299
HDL-CH (mg/lOO ml) HDL-CH%
No.
225-249
HDL-CH (mg/lOO ml) HDGCH%
No.
200-224
HDL-CH (mg/lOO ml) HDL-CH%
No.
Less than 200 mg/lOO ml
Cholesterol (mg/lOO ml)
HDL-CH
TABLE
I
i
i
,j
1
co.01
P
CHOLESTEROL
15 38.1 (9.1) 12.1 (3.8)
25 37.2 (9.8) 13.7 (4.7)
27 34.6 (7.7) 15.6 (3.8)
34 35.3 (9.5) 16.3 (3.5)
53 35.2 (6.5) 18.5 (6.3)
Male
IHD patients
(9.0) (4.2)
(6.4) (8.6)
16 43.2 13.5
(9.5) (3.8)
19 40.6 (10.7) 14.7 (4.1)
12 37.3 (10.8) 15.8 (3.6)
10 36.8 16.6
11 32.0 18.3
Female
1
i
i
J
>
N.S..
N.S.
N.S.
. .
N s
N.S.
P
16
References
5
6 7 8 9 10 11
12 13 14 15 16 17
18
StantIer, J.. In: Lectures in Preventive Cardiology, Gnme and Stratton, New York, London, 1967. Gofman. J.W.. Lindgren, F., Elliot. II., Mautz. W.. Hewitt, J.. Strisowea, B. and Herring, N., The role of lipids am&lipoproteins in atherosclerosis, Science, 111 (1950) 166-173. Barr. D.P., Russ, E.M. and Eder, HA., Protein lipid relationship in human plasma, Amer. J. Med., 11 (1951) 480-491. Brunner. D. and Loebl. K., Serum cholesterol, electrophoretic lipid pattern, diet and coronary artery disease -A study in coronary patients and in healthy men of different origin and occupations in Israel, Ann. Int. Med., 49 (1958) 732-750. Brunner. D.. Altman, S.. Loebl, K. and Schwartz. S.. Alpha cholesterol percentages in coronary patients with an without increased total serum cholesterol levels and in healthy controls, J. Atheroscler. Res.. 2 (1962) 424437. Rhoads, G.G., Gulbrandsen, CL. and Kagan, A., Serum lipoprotein and coronary heart disease in a population study of Hawaii Japanese men, New Engl. J. Med., 294 (1976) 293-297. Berg, K., Borresen, A. and DahIen, G., Serum high density lipoprotein and atherosclerotic heart disease, Lance& 1 (1976) 499-501. Gordon, T.. CasteBi. W.P., HjortIand. M.C., Kannel, W.B. and Dawber, T.R., High density lipoprotein as a protective factor against coronary heart disease, Amer. J. Med.. 62 (1977) 707-714. Anderson, J.T. and Keys, A., Cholesterol in serum and lipoprotein fraction - Its measurement and stability. Clin. Chem.. 2 (1956) 145-169. Fyfe, T., Baxter, R.H. and Cochran. K.M.. Plasma lipid changes after myocardiai infarction, Lancet, 2 (1971) 997-1001. Caste& W.P., Doyle, J.T.. Gordon, T., Hames. C.G.. HiortIand. M.C., HuIIey, S.B., Kagan. A. and Zukel. W.J., HDL cholesterol and other lipids in coronary heart disease - The cooperative lipoprotein phenotyping study, Circulation. 55 (1977) 767-772. Tyroler, M.A., Hames. C.G.. Krishan. J.. Heyden. S.. Cooper, G. and Cassel, J.C., Black-white differences in serum lipids and lipoproteins in Evans County, Preventive Med., 4 (1975) 541-549. Carlson, L.A. and Ericson. M., Quantitative and qualitative serum lipoprotein analvsis.Atherosclerosis, 21(1975) 417433. Wood, P.D., Klein, H., Lewis, S. and Ha&tell. W.L., Plasma lipoprotein concentrations in middle-aged male runners, Circulation, 60 (1974) 111-116. Jung, K., tier die energieliefernden Prozesse bei Ausdauerbelastung, dargestellt am Beispiel eines sechstltigen Radrennens. Med. Welt, 33 (1972) 1105-1110. Miller. N.E. and Miller, G.J., High density lipoprotein and atherosclerosis, Lancet, 1 (1975) 1033. Stein, Y.. Glangeaud. M.C.. Fainaru. M. and Stein, 0.. The removal of cholesterol from aortic smooth muscle cells in culture and Landschutz ascites ceBs by fractions of human high density apohpoprotein. Biochim. Biophys. Acta, 380 (1975) 106-118. Koschinsky. T.. Carew, T.E. and Steinberg, D.. Effects of high density lipoprotein (HDL) on low density lipoprotein (LDL) metabolism by pig smooth muscle cells. Circulation, 61 (1975) H-273.