365
Atherosclerosis, 33 (1979) 365-370 0 Elsevier/North-Holland Scientific
Publishers,
Ltd.
HIGH DENSITY LIPOPROTEIN LEVELS WITH ISCHAEMIC HEART DISEASE
IN CHILDREN
OF YOUNG
MEN
MICHAEL S. NUPUF and WAYNE H.F. SUTHERLAND Department
of Medicine, P.O. Box 913, Dunedin
(New Zealand)
(Received 19 February, 1979) (Revised, received 13 March, 1979) (Accepted 16 March, 1979)
summary This study was designed to assess HDL levels in children of young men with IHD, compared with children of asymptomatic men. Like their fathers, sons of patients with heart disease, had significantly lower HDL cholesterols‘ than controls. This difference was independent of fasting triglycerides, obesity, diet or physical activity, and was the only “coronary risk factor” in this young age group. Key words:
Familial disorder Triglyceride
-
High density
lipoprotein
-
Ischaemic
heart disease -
Introduction The familial aggregation of ischaemic heart disease has been well documented [l-4]. The contribution of genetic and/or environmental factors, however, has been the topic of considerable controversy. Twin studies have been inconclusive [5,6], and coronary risk factors, other than the rare familial hyperlipidaemia, appear no more prevalent in children of patients with coronary artery disease than controls [ 731. In recent years, both retrospective [ 9-111 and prospective studies [ 12-141 have focussed attention on the importance of high density lipoprotein (HDL) as an independent risk factor in the pathogenesis of ischaemic heart disease. This study vvas designed to examine HDLcholesterol, in the children of young men with ikhaemic heart disease, as a possible link or predisposition to the later develoljment of heart disease.
366
Study Population Twenty-five men under the age of 55, with known ischaemic heart disease, by either: comprise the study group. The diagnosis of IHD was documented (1) Electrocardiogram and cardiac enzyme changes suggesting a myocardial infarction (a rise in creatinine phosphokinase twice normal or a serum glutamine oxaloacetic transaminase greater than 33 IU). (2) A history of classical angina with a normal ECG, but with a positive coronary angiogram, or a positive exercise stress test. A period of at least 4 months was allowed from the time of the myocardial infarction to the inclusion in the study, to allow for stabilisation of serum lipids. The control group consisted of 25 male volunteers, under 55 years, who were referred to the ECG department at the Dunedin Public Hospital as part of a routine physical examination for a pilot’s licence, a heavy vehicle driver’s licence, or a railway worker’s permit. Included also were fathers of medical students in the second and third year classes at the University of Otago Medical School, living in the city of Dunedin. Men were accepted only if they were completely asymptomatic with regards to the cardiovascular system by history and physical examination, and they had a normal resting 12-lead electrocardiogram. Children of both groups were over 14 years of age, to allow for stabilisation of serum lipids after puberty [ 151. Daughters taking birth control pills were excluded due to the effects of oral contraceptives on HDL levels [ 161. No more than 3 children were included from any one father, and all children were direct blood-line descendants. None of the subjects tested were taking lipid lowering agents, although 50% of the adults in the ischaemic group were on beta-blocking drugs. Methods All subjects had their height, weight and blood pressure recorded, and interviewed for dietary habits, alcohol and cigarette consumption, and level of physical activity. Blood was drawn after a 12-h fast into two Vacutainer tubes containing 1 mg/ml of dry EDTA, and one Vacutainer tube without anticoagulant, according to the Lipid Research Clinic Protocol [17]. Plasma cholesterol and triglyceride levels were measured on a Technicon Autoanalyser II by standard laboratory methods. High density lipoproteins were measured in the supematant serum [18], after precipitation of VLDL and LDL cholesterol by the heparin-manganese chloride method of Wemick and Albers [ 191. Twenty percent of HDL samples were duplicated, and were reproducible within 0.078 mmol/l (3 mg/dl). Six adult samples (3 in each group) with high levels of serum triglyceride could not be precipitated by the heparin-manganese chloride method, and were treated by the method of Carlson [ 201, involving ultracentrifugation and heparin-manganese precipitation. The heparin-manganese chloride precipitation method gave plasma HDL-
367
cholesterol levels which were within 0.10 mmol/l (4 mg/dl) of those derived from ultracentrifugal separation of HDL. Values are given as mean + SD. Statistical analysis was achieved using the Student t-test. A P value greater than 0.05 was not considered significant. Results A subject profile appears in Table 1; there was no significant difference in age, height, weight, systolic or diastolic blood pressures between any of the matched groups. Table 2 lists the fasting cholesterol, triglyceride and high density lipoprotein for each group. There was no significant difference between any matched group except for the high density fraction. Fathers with ischaemic heart disease had a lower average HDL-cholesterol than control fathers (0.941 mmol/l +_ 0.313 vs 1.148 f 0.347, P < 0.05). They also tended to have higher fasting triglycerides; however, due to the large standard deviation, the difference was not statistically significant. Children of fathers with IHD also had lower HDL-cholesterols than matched controls; although due to the small number of daughters included, only the son’s data reached significance (sons: 1.067 f 0.275 vs 1.227 f 0.300, P< 0.05; daughters: 1.151 rt 0.209 vs 1.357 f 0.343, P = 0.05). Lastly, a comparison of alcohol intake, cigarette consumption and physical activity appears in Table 3. Fathers with ischaemic heart disease smoked considerably more in the past than did control fathers. Nineteen of 25 IHD fathers vs 9 of 25 control fathers smoked more than 20 cigarettes per day. This smoking tendency did not hold for the children of either group. There were no differences in physical activity or alcohol consumption. Logarithmic transformation of HDL-cholesterol concentration did not increase the significance of differences between groups.
TABLE
I
Age
(yr)
(mean)
IHD fathers (N = 25) Control fathers (N = 25) 1Hk1 sons (N = 30) Control sons (N = 27) IHD daughters (N = 16) Control daughters (N = 13)
Age
(yr)
(range)
Height
Weight
04
Weight/ height’
(mean)
(mean)
(kg/m*)
: (cm)
Systolic BP (mean)
Diastolic BP (mean)
41
41-50
170.2
11.3
26.7
125 f 10
86 r 10
48
35-52
175.3
80.1
26.1
122tr
8
8Ok
18
14-25
175.3
61.4
22.0
116 k
8
74 ?. 10
19
14-25
177.8
70.2
22.1
117 ? 10
76?
8
18
14-22
165.1
61.3
22.5
112 t
7
12r
8
18
14-20
162.6
58.4
22.3
113 +
7
71?
8
N = number of subjects.
8
368 TABLE 2 Total cholesterol
Triglyceride
HDLcholestqol
IHD fathers
6.084 * f 1.295
2.052
f 0.749
0.941
f 0.31! ” b
(N = 25) Control fathers
6.004
r 1.000
1.722
f 0.661
1.140
f 0.347
(N = 25) IHD sons
4.187
f 1.080
1.010
f 0.585
1.067
f 0.275 b
Control sons
4.362
f 0.654
0.989
f 0.521
1.227
f 0.306
(N = 27) IHD daughters
4.978
+ 0.882
1.135
r 0.500
1.151
?: 0.209
(N = 16) Control daughters
4.716
* 0.694
0.896
2 0.396
1.367
f 0.342
;
(N = 30,
I
(N = 13)
1
a To convert 31. units (mmol/I)
to traditional units (mg/dl)
multiply 31. times 33.6 for cholesterol and
86.6 for triglyceride. b P i 0.05.
/
TABLE 3 Cigarette consumption (average number/day) 10 years ago
Physical
activity
(6rading 1 = inactive to 4 = vigorous)
AIeohol cohsumption (aierage ozlweek)
Today 10 years ago
Today
4
2.6
2.4
3.i
2.8
2.8
3.i
IHD fathers (N = 25)
22 a
Control fathers (N= 25)
12
12
IHD sons (N = 30)
-
4
-
3.4
2-P
Control sons (N = 27)
-
5
-
3.5
2.0
IHD daughters (N = 16)
-
2
-
2.1
0.6
Control daughten (N = 13)
-
2
-
3.0
0.6
*P < 0.01.
Discussion The familial relationship of ischaemic heart disease is strongest in patients with early onset atherosclerosis [1,4,24]. Slack and Evans noted that the relatives of men under 55 years, and of women under 65 years dying of IHD had a 5-7-fold increased risk of sudden death compared with the general population [ 11. Phillips et al. concluded “that CHD aggregates in fatherson pairs in which the son has early onset CHD [3]“. This study examined coronary risk factors in children of men with premature atherosclerosis. The only factor that was significantly different in this study between the children of fathers with IHD and children of “normal” fathers was the level of HDL-cholesterol.
369
The lower HDL levels in these children were independent of fasting triglycerides [ 10,211, obesity [ 14,211, alcohol intake [ 221, physical activity [ 231, and smoking habits [23,24], all of which are thought to alter high density lipoprotein levels. In adults, HDL cholesterol has been closely linked with the metabolism of plasma triglycerides and VLDL, and an inverse relationship between HDL and VLDL has been established [10,14,21,25]. In the fasting state, triglyceride exists primarily as a component of VLDL, and can, therefore, be substituted for VLDL in clinical studies [ 10,261. While fathers with IHD had low levels of HDLcholesterol associated with elevated triglycerides, their sons had lower HDL-cholesterols, but the same fasting triglycerides as controls. This finding is in contrast to the Framingham Offspring Study [27], where it was found that children of patients with ischaemic heart disease had lower HDL-cholesterols, but higher VLDLcholesterols than children of normal adults. The Framingham children, however, were older (ages 20-49) [28] and may have already achieved a lipid pattern similar to the adult patients in this study. Our data reveals that the lower levels of HDL-cholesterol in children of young men with IHD are present in the teenage years, independent of fasting triglycerides and established by unknown genetic or environmental factors. The genetic control of HDLcholesterol has been suggested by previous studies. Tangier’s disease is a rare autosomal recessive disorder, in which an absence of ar-lipoprotein occurs, and cholesterol esters accumulate in many tissues [ 291. Glueck et al. reported on a familial hyper-cy-lipoproteinaemia in which kindreds had elevated levels of HDL, and appeared to be protected from ischaemic heart disease [ 301. Our study demonstrates a familial form of “hypoa-lipoproteinaemia” present in children of young men with premature atherosclerotic heart disease. While we do not postulate a genetic inheritance for the lower HDL levels, the children of both groups appeared to be well-matched for the environmental factors known to influence HDLcholesterol. In conclusion, our preliminary work reveals that the children of young men with IHD have lower HDL-cholesterol levels than children of asymptomatic fathers, and that this deficiency may account for the familial aggregation of coronary artery disease. References
1 Slack, J. and Evans, K.A.. The increased risk of death born ischaemic heart disease in first degree relatives of 121 men and 96 women with ischaemic heart disease, J. Med. Genet.. 3 (1966) 239. 2 Deutscher. S.. Ostrander. L.D. and Epstein, F.H.. Familial factors in premature coronary heart disease -A preliminary report from the Tecumseh Community Health Study, Amer. J. Epidem.. 91 (1970) 233. 3 Phillips. R.L.. Lilienfeld, A.M., Diamond, E.L. and Kagan, A., Frequency of coronary heart disease and cerebrovascular accidents in parents and sons of coronary heart disease index cases and controls, Amer. J. Epidem., 100 (1974) 87. 4 Rissanen, A.M. and Nikkila. E.A., Coronary artery disease and its risk factors in families of young men with angina pectoris and controls, Brit. Heart J.. 39 (1977) 875. 5 Harvald. B. and Hague, M.. A catamnestic investigation of Danish twins, Acta Genet.. 8 (1958) 288. 6 Cederlof, R.. Friberg, L. and Jonsson, E., Hereditary factors and “angina pectoris”, Arch. Environ. Health, 14 (1967) 397.
370 7 Forde. O.H. and Thelle, D.S.. The Troms6 Heart Study -Risk factors for coronary heart disease related to the occurrence of myocardial infarction in first degree relatives, Amer. J. ,Epidem., 105 (1977) 192. 8 Epstein. F.H.. Genetics of ischaemic heart disease, Postgrad. Med. J., 52 (1976) 477. 9 Berg, K.. Borresen. A. and Dahlen. G.. Serum high density lipoprotein and atherosclerotic heart dlsease, Lance& 1 (1976) 499. 10 Castelli, W.P., Doyle, J.T., Gordon, T., Hames. C.G.. Hjortland. M.C.. Hulley. S.B.. Kagan, A. and Zukel, W.J., HDL cholesterol and other lipids in coronary heart disease, Circulation, 56 (1977) 767. 11 Hsia. S.L.. Chao, Y., Hennekens. C.H. and Reader, W.B., Decreased serum cholesterol binding reserve in premature myocardial infarction, Lancet, 2 (1975) 1000. 12 Gofman. J.W.. Young, W. and Tandy, R., Ischaemic heart disease, atherosclerosis and longevity, Cir culation, 34 (1966) 679. 13 Miller, N.E.. Forde, O.H.. Thelle. OS. and Mjos. O.D.. The Troms6 Heart Study -High density lipoprotein and coronary heart disease: a prospective case-control study, Lancet. 1 (1977) 966. 14 Gordon, T., Castelli. W.P.. Hjortland, M.C.. Kannel. W.B. and Dawber. T.R.. High density lipoprotein as a protective factor against coronary heart disease -The Framingham Study, Amer. J. Med., 62 (1977) 707. 15 Ellefson. R.D., Elveback, L.R.. Hodgaon, P.A. and Weidman. W.H.. Cholesterol and triglycerides in serum lipoproteins of young persons in Rochester, Minnesota, Mayo Clin. Proc.. 63 (1978) 307. 16 Bradley, D.D.. Wingerd, J.. Petitti. D.B.. Krauss, R.M. and Ramcharan, S., Serum high-denslty-lipoprotein cholesterol in women using oral contraceptives, estrogens and progestlns, New Engl. Med. J., 299 (1978) 17. 17 Manual of Laboratory Operations, Lipid Research Clinics Program, Vol. 1 (Lipid and Lipoprotein Analysis), DHEW Publication No. (NIH) 75-628, May 1974, p. 9. 18 Abell. L.L.. Levy. B.B.. Brodie, B.B. and Kendal, F.E., Simpllfled method for the estimation of total cholesterol in serum and demonstration of its simplicity, J. Biol. Chem., 196 (1952) 357. 19 War&k, G.R. and Albers. J.J.. A comprehensive evaluation of the heparln--manganese precipitation procedure for estimating high density lipoprotein cholesterol, J. Lipid Res., 19 (1978) 66. 20 Carlson, K.. Lipoprotein fractionation, J. Clln. Path., 28. Suppl. 6 (1973) 32. 21 Wilson, D.E. and Lees, R.S., Metabolic relationships among the plasma lipoproteins, J. Clln. Invest., 51(1972) 1051. 22 Yano. K., Rhoads. G.G. and Kagan. A., Coffee, Alcohol and risk of coronary heart disease among Japanese men living in Hawaii, New Engl. J. Med., 297 (1977) 406. 23 Enger. S.C.. Herbjomsen, K.. Erikssen. J. and Fretland. A., High density lipoproteins (HDL) and physical activity: the influence of physical exercise. age and smoking on HDLeholesterol and the HDL-total cholesterol ratio, Scand. J. Clin. Lab. Invest., 37 (1977) 261. 24 Erikssen. J. and Enger. S.C.. Smoking, lung function, physical performance and latent coronary heart disease in presumably healthy middle-ged men. Acta Med. &and., 203 (1978) 27. 25 Nikkilii. E.A., Metabolic regulation of plasma high density lipoprotein concentrations, Europ. J. Clin. Invest., 8 (1978) 111. 26 Niahols. A.V.. Human serum lipoproteins and their inter-relationships, Adv. Biol. Med. Phys., 11 (1967) 109. 27 Felnleib. M.. Kannel, W.D., Garrison. R.J.. McNamara. P. and Caste& W.P., Relation of parental history of coronary heart disease to risk factors ln young adults - The Framingham Offspring Study, Circulation Abstracts, 64 (1976) H-52. 28 Garrison, R.J.. Kannel, W.B.. Feinleib. M., Castelli. W.P., McNamara. P.M. and Padgett. S.J.. Cigarette smoking and HDL cholesterol -The Framingham Offspring Study, Atherosclerosis, 30 (1978) 17. 29 Frederickson. D.S., Inheritance of high density lipoprotein deficiency (Tangier disease), J. Clln. Invest., 43 (1964) 228. 30 Glueck. C.J., Fallat. R.W., Millet, F.. Gartside. P.. Elston. R.C. and Go, R.C.P.. Familial hyper alphallpoproteinaemia - Studies in eighteen kindreds. Metabolism. 24 (1975) 1243.
Atherosclerosis, 33 (1979) 365-370 0 Elsevier/North-Holland Scientific
Publishers,
Ltd.
HIGH DENSITY LIPOPROTEIN LEVELS WITH ISCHAEMIC HEART DISEASE
IN CHILDREN
OF YOUNG
MEN
MICHAEL S. NUPUF and WAYNE H.F. SUTHERLAND Department
of Medicine, P.O. Box 913, Dunedin
(New Zealand)
(Received 19 February, 1979) (Revised, received 13 March, 1979) (Accepted 16 March, 1979)
summary This study was designed to assess HDL levels in children of young men with IHD, compared with children of asymptomatic men. Like their fathers, sons of patients with heart disease, had significantly lower HDL cholesterols‘ than controls. This difference was independent of fasting triglycerides, obesity, diet or physical activity, and was the only “coronary risk factor” in this young age group. Key words:
Familial disorder Triglyceride
-
High density
lipoprotein
-
Ischaemic
heart disease -
Introduction The familial aggregation of ischaemic heart disease has been well documented [l-4]. The contribution of genetic and/or environmental factors, however, has been the topic of considerable controversy. Twin studies have been inconclusive [5,6], and coronary risk factors, other than the rare familial hyperlipidaemia, appear no more prevalent in children of patients with coronary artery disease than controls [ 731. In recent years, both retrospective [ 9-111 and prospective studies [ 12-141 have focussed attention on the importance of high density lipoprotein (HDL) as an independent risk factor in the pathogenesis of ischaemic heart disease. This study vvas designed to examine HDLcholesterol, in the children of young men with ikhaemic heart disease, as a possible link or predisposition to the later develoljment of heart disease.
366
Study Population Twenty-five men under the age of 55, with known ischaemic heart disease, by either: comprise the study group. The diagnosis of IHD was documented (1) Electrocardiogram and cardiac enzyme changes suggesting a myocardial infarction (a rise in creatinine phosphokinase twice normal or a serum glutamine oxaloacetic transaminase greater than 33 IU). (2) A history of classical angina with a normal ECG, but with a positive coronary angiogram, or a positive exercise stress test. A period of at least 4 months was allowed from the time of the myocardial infarction to the inclusion in the study, to allow for stabilisation of serum lipids. The control group consisted of 25 male volunteers, under 55 years, who were referred to the ECG department at the Dunedin Public Hospital as part of a routine physical examination for a pilot’s licence, a heavy vehicle driver’s licence, or a railway worker’s permit. Included also were fathers of medical students in the second and third year classes at the University of Otago Medical School, living in the city of Dunedin. Men were accepted only if they were completely asymptomatic with regards to the cardiovascular system by history and physical examination, and they had a normal resting 12-lead electrocardiogram. Children of both groups were over 14 years of age, to allow for stabilisation of serum lipids after puberty [ 151. Daughters taking birth control pills were excluded due to the effects of oral contraceptives on HDL levels [ 161. No more than 3 children were included from any one father, and all children were direct blood-line descendants. None of the subjects tested were taking lipid lowering agents, although 50% of the adults in the ischaemic group were on beta-blocking drugs. Methods All subjects had their height, weight and blood pressure recorded, and interviewed for dietary habits, alcohol and cigarette consumption, and level of physical activity. Blood was drawn after a 12-h fast into two Vacutainer tubes containing 1 mg/ml of dry EDTA, and one Vacutainer tube without anticoagulant, according to the Lipid Research Clinic Protocol [17]. Plasma cholesterol and triglyceride levels were measured on a Technicon Autoanalyser II by standard laboratory methods. High density lipoproteins were measured in the supematant serum [18], after precipitation of VLDL and LDL cholesterol by the heparin-manganese chloride method of Wemick and Albers [ 191. Twenty percent of HDL samples were duplicated, and were reproducible within 0.078 mmol/l (3 mg/dl). Six adult samples (3 in each group) with high levels of serum triglyceride could not be precipitated by the heparin-manganese chloride method, and were treated by the method of Carlson [ 201, involving ultracentrifugation and heparin-manganese precipitation. The heparin-manganese chloride precipitation method gave plasma HDL-
367
cholesterol levels which were within 0.10 mmol/l (4 mg/dl) of those derived from ultracentrifugal separation of HDL. Values are given as mean + SD. Statistical analysis was achieved using the Student t-test. A P value greater than 0.05 was not considered significant. Results A subject profile appears in Table 1; there was no significant difference in age, height, weight, systolic or diastolic blood pressures between any of the matched groups. Table 2 lists the fasting cholesterol, triglyceride and high density lipoprotein for each group. There was no significant difference between any matched group except for the high density fraction. Fathers with ischaemic heart disease had a lower average HDL-cholesterol than control fathers (0.941 mmol/l +_ 0.313 vs 1.148 f 0.347, P < 0.05). They also tended to have higher fasting triglycerides; however, due to the large standard deviation, the difference was not statistically significant. Children of fathers with IHD also had lower HDL-cholesterols than matched controls; although due to the small number of daughters included, only the son’s data reached significance (sons: 1.067 f 0.275 vs 1.227 f 0.300, P< 0.05; daughters: 1.151 rt 0.209 vs 1.357 f 0.343, P = 0.05). Lastly, a comparison of alcohol intake, cigarette consumption and physical activity appears in Table 3. Fathers with ischaemic heart disease smoked considerably more in the past than did control fathers. Nineteen of 25 IHD fathers vs 9 of 25 control fathers smoked more than 20 cigarettes per day. This smoking tendency did not hold for the children of either group. There were no differences in physical activity or alcohol consumption. Logarithmic transformation of HDL-cholesterol concentration did not increase the significance of differences between groups.
TABLE
I
Age
(yr)
(mean)
IHD fathers (N = 25) Control fathers (N = 25) 1Hk1 sons (N = 30) Control sons (N = 27) IHD daughters (N = 16) Control daughters (N = 13)
Age
(yr)
(range)
Height
Weight
04
Weight/ height’
(mean)
(mean)
(kg/m*)
: (cm)
Systolic BP (mean)
Diastolic BP (mean)
41
41-50
170.2
11.3
26.7
125 f 10
86 r 10
48
35-52
175.3
80.1
26.1
122tr
8
8Ok
18
14-25
175.3
61.4
22.0
116 k
8
74 ?. 10
19
14-25
177.8
70.2
22.1
117 ? 10
76?
8
18
14-22
165.1
61.3
22.5
112 t
7
12r
8
18
14-20
162.6
58.4
22.3
113 +
7
71?
8
N = number of subjects.
8
368 TABLE 2 Total cholesterol
Triglyceride
HDLcholestqol
IHD fathers
6.084 * f 1.295
2.052
f 0.749
0.941
f 0.31! ” b
(N = 25) Control fathers
6.004
r 1.000
1.722
f 0.661
1.140
f 0.347
(N = 25) IHD sons
4.187
f 1.080
1.010
f 0.585
1.067
f 0.275 b
Control sons
4.362
f 0.654
0.989
f 0.521
1.227
f 0.306
(N = 27) IHD daughters
4.978
+ 0.882
1.135
r 0.500
1.151
?: 0.209
(N = 16) Control daughters
4.716
* 0.694
0.896
2 0.396
1.367
f 0.342
;
(N = 30,
I
(N = 13)
1
a To convert 31. units (mmol/I)
to traditional units (mg/dl)
multiply 31. times 33.6 for cholesterol and
86.6 for triglyceride. b P i 0.05.
/
TABLE 3 Cigarette consumption (average number/day) 10 years ago
Physical
activity
(6rading 1 = inactive to 4 = vigorous)
AIeohol cohsumption (aierage ozlweek)
Today 10 years ago
Today
4
2.6
2.4
3.i
2.8
2.8
3.i
IHD fathers (N = 25)
22 a
Control fathers (N= 25)
12
12
IHD sons (N = 30)
-
4
-
3.4
2-P
Control sons (N = 27)
-
5
-
3.5
2.0
IHD daughters (N = 16)
-
2
-
2.1
0.6
Control daughten (N = 13)
-
2
-
3.0
0.6
*P < 0.01.
Discussion The familial relationship of ischaemic heart disease is strongest in patients with early onset atherosclerosis [1,4,24]. Slack and Evans noted that the relatives of men under 55 years, and of women under 65 years dying of IHD had a 5-7-fold increased risk of sudden death compared with the general population [ 11. Phillips et al. concluded “that CHD aggregates in fatherson pairs in which the son has early onset CHD [3]“. This study examined coronary risk factors in children of men with premature atherosclerosis. The only factor that was significantly different in this study between the children of fathers with IHD and children of “normal” fathers was the level of HDL-cholesterol.
369
The lower HDL levels in these children were independent of fasting triglycerides [ 10,211, obesity [ 14,211, alcohol intake [ 221, physical activity [ 231, and smoking habits [23,24], all of which are thought to alter high density lipoprotein levels. In adults, HDL cholesterol has been closely linked with the metabolism of plasma triglycerides and VLDL, and an inverse relationship between HDL and VLDL has been established [10,14,21,25]. In the fasting state, triglyceride exists primarily as a component of VLDL, and can, therefore, be substituted for VLDL in clinical studies [ 10,261. While fathers with IHD had low levels of HDLcholesterol associated with elevated triglycerides, their sons had lower HDL-cholesterols, but the same fasting triglycerides as controls. This finding is in contrast to the Framingham Offspring Study [27], where it was found that children of patients with ischaemic heart disease had lower HDL-cholesterols, but higher VLDLcholesterols than children of normal adults. The Framingham children, however, were older (ages 20-49) [28] and may have already achieved a lipid pattern similar to the adult patients in this study. Our data reveals that the lower levels of HDL-cholesterol in children of young men with IHD are present in the teenage years, independent of fasting triglycerides and established by unknown genetic or environmental factors. The genetic control of HDLcholesterol has been suggested by previous studies. Tangier’s disease is a rare autosomal recessive disorder, in which an absence of ar-lipoprotein occurs, and cholesterol esters accumulate in many tissues [ 291. Glueck et al. reported on a familial hyper-cy-lipoproteinaemia in which kindreds had elevated levels of HDL, and appeared to be protected from ischaemic heart disease [ 301. Our study demonstrates a familial form of “hypoa-lipoproteinaemia” present in children of young men with premature atherosclerotic heart disease. While we do not postulate a genetic inheritance for the lower HDL levels, the children of both groups appeared to be well-matched for the environmental factors known to influence HDLcholesterol. In conclusion, our preliminary work reveals that the children of young men with IHD have lower HDL-cholesterol levels than children of asymptomatic fathers, and that this deficiency may account for the familial aggregation of coronary artery disease. References
1 Slack, J. and Evans, K.A.. The increased risk of death born ischaemic heart disease in first degree relatives of 121 men and 96 women with ischaemic heart disease, J. Med. Genet.. 3 (1966) 239. 2 Deutscher. S.. Ostrander. L.D. and Epstein, F.H.. Familial factors in premature coronary heart disease -A preliminary report from the Tecumseh Community Health Study, Amer. J. Epidem.. 91 (1970) 233. 3 Phillips. R.L.. Lilienfeld, A.M., Diamond, E.L. and Kagan, A., Frequency of coronary heart disease and cerebrovascular accidents in parents and sons of coronary heart disease index cases and controls, Amer. J. Epidem., 100 (1974) 87. 4 Rissanen, A.M. and Nikkila. E.A., Coronary artery disease and its risk factors in families of young men with angina pectoris and controls, Brit. Heart J.. 39 (1977) 875. 5 Harvald. B. and Hague, M.. A catamnestic investigation of Danish twins, Acta Genet.. 8 (1958) 288. 6 Cederlof, R.. Friberg, L. and Jonsson, E., Hereditary factors and “angina pectoris”, Arch. Environ. Health, 14 (1967) 397.
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