Characteristics of coronary artery disease and lipoprotein abnormalities in patients with heterozygous familial hypercholesterolemia associated with diabetes mellitus or impaired glucose tolerance

Atherosclerosis 132 (1997) 43 – 51

Characteristics of coronary artery disease and lipoprotein abnormalities in patients with heterozygous familial hypercholesterolemia associated with diabetes mellitus or impaired glucose tolerance Koji Yanagi, Shizuya Yamashita *, Shinji Kihara, Tadashi Nakamura, Shuichi Nozaki, Yoshiyuki Nagai, Tohru Funahashi, Kaoru Kameda-Takemura, Yuhya Ueyama, Sheng Jiao, Masaharu Kubo, Katsuto Tokunaga, Yuji Matsuzawa Second Department of Internal Medicine, Osaka Uni6ersity Medical School, 2 -2 Yamadaoka, Suita, Osaka 565, Japan Received 16 September 1996; received in revised form 18 February 1997; accepted 17 March 1997

Abstract Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of serum low density lipoprotein (LDL) cholesterol and premature coronary atherosclerosis. In order to elucidate the influence of abnormal glucose metabolism on the development of coronary artery disease (CAD) in FH patients, we examined the prevalence of CAD and characteristics of lipoprotein abnormalities in patients with heterozygous FH who were accompanied by diabetes mellitus (DM) or impaired glucose tolerance (IGT). The subjects of the present study were 150 patients with heterozygous FH, all over 40 years of age. Oral glucose tolerance tests demonstrated that 15 patients had DM and 27 had IGT. The combination of DM or IGT with FH was associated with a further increase in the prevalence of CAD (DM:IGT:normal glucose tolerance (N), 87:59:43%). Furthermore, the prevalence of the stenoses in the distal coronary arteries was significantly higher in the DM group than in the N group, while there was no significant difference in the prevalence of proximal and middle lesions. Serum triglyceride levels were significantly higher in the DM and IGT groups than in the N group (PB0.01, DM versus N group; PB 0.01, IGT versus N group), while total cholesterol levels were not significantly different. When lipoproteins were analyzed by polyacrylamide gel electrophoresis, the frequency of midband appearance, which implies an increase in remnant lipoproteins, was significantly higher in the DM and IGT groups than in the N group (DM:IGT:N, 87:72:29%, PB0.01, DM versus N group; P B0.01, IGT versus N group). Ultracentrifugation analysis of lipoproteins revealed that intermediate density lipoprotein cholesterol was increased in DM and IGT groups compared with the N group. These data suggest that abnormal glucose metabolism may accelerate the development of CAD in FH patients due to an increase in atherogenic remnant lipoproteins in addition to high concentration of LDL. Special attention should be paid in the treatment of FH patients with impaired glucose metabolism, to avoid the advancement of coronary atherosclerosis. © 1997 Elsevier Science Ireland Ltd. Keywords: Familial hypercholesterolemia; Diabetes mellitus; Coronary artery disease; Remnant lipoproteins

1. Introduction Abbre6iations: BMI, body mass index; CAD, coronary artery disease; DM, diabetes mellitus; FH, familial hypercholesterolemia; HDL, high density lipoprotein; IGT, impaired glucose tolerance; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; N, normal glucose tolerance; VLDL, very low density lipoprotein. * Corresponding author. Tel.: + 81 6 8793738; fax: + 81 6 8793739.

Familial hypercholesterolemia (FH) is a hereditary disorder due to mutations of low density lipoprotein (LDL) receptor gene and is characterized by high serum cholesterol levels and premature coronary artery disease (CAD) [1–4]. The prevalence of CAD in FH heterozygotes is markedly higher than that in the general

0021-9150/97/$17.00 © 1997 Elsevier Science Ireland Ltd. All rights reserved. PII S 0 0 1 - 9 1 5 0 ( 9 7 ) 0 0 0 7 6 - 2

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K. Yanagi et al. / Atherosclerosis 132 (1997) 43–51

population. According to our previous investigation, the prevalence of CAD in male and female Japanese patients over 40 years of age with heterozygous FH was 56 and 34%, respectively [5]. Although an elevated serum cholesterol level in FH heterozygotes is an important risk factor for the development of CAD, hypertriglyceridemia was also closely related to the development of CAD among FH heterozygotes investigated by the Research Group of Primary Hyperlipidemias among the Japanese sponsored by the Ministry of Education and the Ministry of Health and Welfare on Epidemiological Studies [5,6]. These data suggest that elevated serum cholesterol or LDL – cholesterol is not the only risk factor for CAD among FH heterozygotes. Abnormal glucose metabolism such as diabetes mellitus (DM) or impaired glucose tolerance (IGT) has been shown to be associated with atherosclerotic diseases such as CAD, cerebrovascular diseases and peripheral vascular diseases. The reason for the accelerated atherosclerosis in DM or IGT has been attributed partly to the impairment of lipoprotein metabolism. In FH patients, abnormalities of glucose metabolism are sometimes observed. However, there has been no report clarifying the characteristics of CAD and the lipoprotein abnormalities when FH patients also have DM or IGT. In the current study, we have investigated the effect of the coexistence of DM or IGT on the lipoprotein profiles in heterozygous FH patients. We have also investigated the prevalence of CAD in FH patients associated with DM or IGT and have clarified the characteristics of coronary atherosclerosis in these patients. We demonstrate that the prevalence of distal coronary stenosis and a midband-positive pattern on lipoprotein electrophoresis were significantly higher in FH patients with DM or IGT compared to those with normal glucose tolerance, suggesting that the increase in remnant lipoprotein may be a potent risk factor for the development of CAD in heterozygous FH with DM or IGT.

2. Methods

2.1. Subjects All 150 cases with heterozygous FH, over 40 years of age (82 men and 68 women), were enrolled in the present study. All the cases were newly and successively identified. DM and IGT were diagnosed by an oral glucose tolerance test after ingestion of 75 g glucose according to the criteria of the Japan Diabetes Society Committee on Diagnosis of Diabetes, which better fits the Japanese people whose dietary custom is different from that of Western countries [7,8]. It is well known in Japan that subjects who are diagnosed as normal ac-

cording to the WHO’S criteria [9] but as IGT (borderline) according to the criteria of the Japan Diabetes Society Committee develop DM in later years [8]. According to the results of the glucose tolerance test FH patients were divided into 3 groups as follows: (a) diabetic type: fasting plasma] 140 mg/dl and/or 2 h plasma] 200 mg/dl; (b) borderline type (IGT): fasting plasma glucose between 110–139 mg/dl, and/or 1 h plasma glucose]160 mg/dl and/or 2 h plasma glucose between 120–199 mg/dl; (c) normal type: fasting plasma glucoseB110 mg/dl, and 1 h plasma glucose B 160 mg/dl, and 2 h plasma glucoseB 120 mg/dl. Among the enrolled FH subjects, 15 patients (8 men and 7 women) had non-insulin-dependent diabetes mellitus, and 27 patients (15 men and 12 women) had IGT. None had insulin-dependent diabetes mellitus. Patients were considered to have CAD if they had a history or present illness of either myocardial infarction (MI) or angina pectoris. Angina pectoris was diagnosed when the patients showed a typical chest pain on exertion and a positive result on an exercise electrocardiographic test. MI was diagnosed by: (1) a typical clinical course; (2) increase in specific myocardial enzymes; (3) serial electrocardiograms. The diagnosis of CAD was further confirmed by coronary angiography in 58 of 75 patients with angina pectoris or MI. Selective coronary cineangiography was performed in multiple views using standard techniques. All angiograms were recorded on 35 mm cine film. Coronary stenoses in the three major coronary arteries were carefully and independently measured with calipers by at least two experienced angiographers and expressed as percent luminal diameter stenosis. The severity of stenosis was graded according to the American Heart Association Reporting System. The agreement between the two observers on classifying vessels as normal or only insignificantly stenosed ( B25% stenosis) was 96%, whereas the interobserver agreement on classifying vessels as having significant (]50%) stenoses was 99%. The extent of coronary atherosclerosis was estimated by utilizing the American Heart Association Reporting System as the sum of stenotic segments over 50% stenosis in 15 segments of the main branches of the coronary arteries. The CAD extent score was defined as the sum of stenotic segments over 50%. Thus, the highest possible score was 15. FH was diagnosed by the LDL receptor assay of cultured skin fibroblasts (n= 82). The subjects who had not taken the LDL receptor assay were clinically diagnosed as having FH according to the following criteria [10]; 1. Primary hypercholesterolemia of more than 260 mg/ dl with an increase in Achilles tendon thickness. 2. Primary hypercholesterolemia of more than mg/ dl and the presence of one or more direct relatives

15 559 7 1379 23 809 12 23.09 2.7 6/15 (40.0) 14.194.2 1699 52**,*** 9.391.7**,*** 3799 27**,*** 55.7933.5

8 52 95 131 920 80 9 13 24.0 92.7 6/8 (75.0) 16.2 9 4.6 170 9 53**,*** 9.2 9 1.4**,*** 374 936**,*** 60.4 936.4

7 59 9 8 142 924 80 9 10 21.7 92.2 0/7 (0) 12.2 92.8 169 9 52**,*** 9.5 9 1.9**,*** 385 942**,*** 51.2 930.4

The results are expressed as mean9S.D. a (mg · min/d1×10−2). b (mU · min/m1×10−2). * PB0.05 compared with N; ** PB0.01 compared with N; *** PB0.01 compared with IGT.

n Age (years) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) BMI Smoking (%) Achilles tendon thickness (mm) Fasting plasma glucose (mg/dl) HbA1c (%) Plasma glucose areaa Plasma insulin areab

27 53 98 137 920 80912 24.4 93.6* 11/27 (40.7) 15.7 96.7 99 9 12** 6.8 9 0.5** 208 925** 72.9 9 28.3

Total

Female

Total

Male

IGT

DM

Table 1 Clinical profiles of FH heterozygotes investigated

15 51 99 128 917 77 913 24.8 93.8** 10/15 (66.7) 16.4 95.7 100 912** 6.9 9 0.6** 202 926** 71.0 930.6

Male

12 55 9 7 1539 16** 85 99 24.6 93.6 1/12 (8.3) 14.59 7.5 98 912** 6.6 9 0.15** 1689 20** 76.4 9 23.2

Female

108 5398 132920 799 11 22.89 2.7 42/108 (38.9) 14.195.5 9199 5.990.50 1679 18 61.59 39.3

Total

N

59 5298 1319 20 78912 22.592.4 33/59 (55.9) 15.095.8 929 9 5.99 0.46 1689 20 66.5945.6

Male

49 53 97 133920 80 911 23.1 9 2.9 9/49 (18.4) 13.19 5.0 90 98 5.9 9 0.5 1659 15 56.5 9 31.1

Female

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K. Yanagi et al. / Atherosclerosis 132 (1997) 43–51

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Table 2 Prevalence of coronary artery disease in FH heterozygotes investigated DM

n Coronary artery disease (%) Myocardial infarction (%)

IGT

N

Total

Male

Female

Total

Male

Female

Total

Male

Female

15 13 (87)* 10 (67)*

8 8 (100)** 8 (100)**

7 5 (71) 2 (29)

27 16 (59) 8 (30)

15 10 (67) 5 (33)

12 6 (50) 3 (25)

108 46 (43) 20 (19)

59 30 (51) 16 (27)

49 16 (33) 4 (8)

* PB0.01 compared with N (total); ** PB0.01 compared with N (male).

with hypercholesterolemia of more than 260 mg/dl and an increase in Achilles tendon thickness. Achilles tendon thickness was determined by xeroradiography. We designated a thickness of more than 9 mm as abnormal tendon thickening, considering the values of normal controls (6.39 0.1 mm for 43 males and 5.7 90.2 mm for females, mean 9 S.D., respectively). In Japan, serum total cholesterol levels are lower than those in Western countries because the Japanese diet has far less fat than the Western diet. Therefore, patients with abnormal tendon thickening and hypercholesterolemia of more than 260 mg/dl are reported to have decreased LDL receptor activity [10].

2.2. Methods All the parameters were measured prior to therapy when informed consent was obtained. Blood samples were obtained after an overnight fast. Serum cholesterol and triglyceride were determined enzymatically, using commercial kits (Kyowa Medex, Tokyo, Japan). High density lipoprotein (HDL) cholesterol was measured after precipitation of apoprotein (apo) B-containing lipoproteins by the heparin – calcium precipitation method. Serum lipoproteins were prestained with Sudan black B and subjected to discontinuous electrophoresis in 3% polyacrylamide gel (PAG) [11]. Lipoprotein bands were densitometrically determined with a FD-IV densitometer (Fujiriken, Tokyo, Japan) at 600 nm. Each lipoprotein fraction was separated and analyzed by sequential ultracentrifugation at the following densities (VLDL, d B1.006 g/ml; IDL, 1.006B d B 1.019 g/ml; LDL, 1.019 Bd B1.063 g/ml; HDL2, 1.063BdB 1.125 g/ml; HDL3, 1.125B dB 1.210 g/ml) by the method of Havel et al. [12]. Apo E phenotyping was performed by isoelectric focusing of apo VLDL [13] or by immunoblotting after isoelectric focusing of serum lipoproteins with neuraminidase treatment [14]. For statistical analysis, one-way analysis of variance (ANOVA) and the x 2 test were performed for comparison of FH heterozygotes with DM, IGT and N (normal glucose tolerance).

3. Results

3.1. Clinical profiles of FH heterozygotes in6estigated The clinical profiles of subjects investigated are shown in Table 1. Patients with FH were divided into the following three groups; DM group (n= 15, 8 males and 7 females), IGT group (n=27, 15 males and 12 females) and N group (n= 108, 59 males and 49 females). There were no significant differences among the DM, IGT and N groups in age, prevalence of smoking and Achilles tendon thickness. Systolic blood pressure of the female IGT group was significantly higher than that of the female N group. Body mass index (BMI) of the IGT group was significantly higher than that of the N group (P B0.05). Fasting plasma glucose, hemoglobin A1c and plasma glucose area were significantly higher in the DM and IGT groups compared with the N group, while there was no significant difference in plasma insulin area among the three groups.

3.2. Incidence and extent of coronary artery disease in FH heterozygotes with and without abnormal glucose metabolism The incidence of CAD in FH heterozygotes is shown in Table 2. The incidence of CAD was high (46/108; 43%) even in the N group. Surprisingly, the association of DM or IGT caused a further increase of CAD incidence up to 87% (13/15) and 59% (16/27), respectively. The incidence of myocardial infarction (MI) was also high in the DM group (10/15; 67%) and the IGT group (8/27; 30%) compared to that in the N group (20/108; 19%). In male patients, the CAD incidence was 100, 67 and 51% in the DM, IGT and N groups, respectively. In female patients, the CAD incidence was lower than male patients, but was 71, 50 and 33%, respectively. The extent and location of coronary artery stenosis were further investigated (Table 3). The CAD extent score of the DM group was higher than that of the N group, although the difference did not reach statistical significance. The scores of the IGT group tended to be higher compared with the N group (DM:IGT:N = 8.09 3.1:6.19 3.1:4.692.5, mean9 S.D.). Secondly,

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Table 3 Extent and location of stenotic lesions of coronary arteries in FH heterozygotes with CAD DM

n Extent score Proximal or middlea % Distalb %

IGT

N

Total

Male

Female

Total

Male

Female

Total

Male

Female

13 8.0 93.1 53.0 43.6**

8 8.89 3.1 59.7* 47.9**

5 6.89 3.5 42.2 36.7**

12 6.1 93.1 43.5 29.5*

9 6.6 9 3.4 45.7 44.4**

3 4.7 9 1.7 37.0 16.7

34 4.6 92.5 41.8 17.6

23 4.7 92.5 42.0 18.2

11 4.6 9 2.2 41.4 13.6

The results are expressed as mean9 S.D. a Incidence of stenosis in proximal and middle segments (c 1, c 2, c3, c 5, c6, c7, c9, c 11, c12). b Incidence of stenosis in distal segments (c 4, c 8, c 10, c 13, c14, c15). * PB0.05 compared with N; ** PB0.01 compared with N.

we studied the location of stenotic lesions in the coronary arteries. The incidence of stenotic lesions in the distal coronary arteries ( c4, c 8, c10, c 14, c 15) was significantly higher in the DM group (P B 0.01) and in the IGT group (P B0.05) than in the N group, while there was no significant difference in the incidence of stenotic lesions in the proximal and middle portions ( c 1, c2, c 3, c 5, c6, c 7, c9, c 10, c 11, c12) among the three groups. In addition, the incidence of coronary stenosis was higher in male patients compared with females in all segments.

3.3. Lipoprotein abnormalities in FH heterozygotes associated with DM or IGT In order to clarify the mechanism of accelerated coronary atherosclerosis in FH associated with DM or IGT, serum lipoproteins were analyzed. As shown in Table 4, serum triglyceride levels were significantly higher in the DM group and in the IGT group compared with the N group (DM:IGT:N= 244 9 87:2089 68:1439 75 mg/dl; mean9S.D.) while total cholesterol and HDL cholesterol levels were not. Lipoproteins were further analyzed by PAG disc electrophoresis. In a substantial number of FH patients, an additional band or a shoulder close to the LDL band was present and designated as a midband, which shows the increase of remnant lipoproteins. The representative densitometric patterns of FH patients are shown in Fig. 1. The upper densitometric pattern was designated as midband-positive and the lower was identified as midband-negative. The frequency of the appearance of midband was compared among FH with DM, IGT or normal glucose metabolism in Fig. 2. The prevalence of the midband was significantly higher in the DM group (86.7%, PB 0.01) and in the IGT group (74.1%, PB0.01) than in N group (28.4%). Next we investigated the incidence of CAD in FH heterozygotes with and without the midband (Fig. 3). The midband-positive subgroup and the midband-negative subgroup include FH subjects with DM, IGT and

normal glucose tolerance. The midband-positive subgroup had a significantly higher incidence of CAD than the midband-negative subgroup (midband-positive:midband-negative subgroup= 73.3:31.2%, PB 0.01). These data suggest that the increase of remnant lipoproteins in FH patients with DM or IGT may accelerate CAD. There was no significant difference in the apo E isoform pattern between the two groups (data not shown). Table 5 shows the lipid composition in ultracentrifugally separated lipoprotein fractions. Although there was no significant difference in LDL, HDL2 and HDL3 cholesterol levels among the three groups, the DM group had significantly higher levels of both cholesterol (DM versus N, PB 0.05) and triglyceride (DM versus N, PB 0.01) in the VLDL. IGT group had higher levels of both cholesterol and triglyceride in the VLDL. The ratio of cholesterol to triglyceride in the VLDL fraction was higher in the DM and IGT groups than that in the N group. The IDL cholesterol level was significantly higher in the DM group than the N group (DM:25.49 8.9 versus 13.492.8 mg/dl; mean9 S.D., P B0.05). These data indicate that the impairment of glucose metabolism such as DM or IGT increases cholesterolrich VLDL and remnant lipoprotein in FH patients, which may result in the exaggeration of atherogenesis due to the accumulation of LDL.

4. Discussion It is well established that the high serum cholesterol level is one of the most important risk factors for CAD [15,16] and high LDL-cholesterol concentration in FH has been shown to be highly correlated to the development of CAD [1–4]. There seems to be no strong correlation between CAD and other coronary risk factors except hypercholesterolemia and age, since coronary risk factors overshadowed by inborn hypercholesterolemia and age in FH patients [17,18]. However, several reports have demonstrated that the

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Table 4 Comparison of serum lipids and HDL-cholesterol levels among FH patients with and without DM DM

n Total cholesterol (mg/dl) HDL-cholesterol (mg/dl) Triglyceride (mg/dl)

IGT

N

Total

Male

Female

Total

Male

Female

Total

Male

Female

15 345961 44913 244987**

8 3379 66 359 8.2 2809 93*

7 3569 54 55 98.5 2029 52*

27 357 9 49 43 9 13 208 9 68*

15 356 9 49 41 9 10 200 9 62*

12 357 9 49 46 915 218 973**

108 346 9 71 47 914 143 975

49 329 956 44 9 13 153 9 82

59 3699 70 51 914 1339 64

The results are expressed as mean9 S.D. * PB0.05 compared with N; ** PB0.01 compared with N.

serum triglyceride level is also correlated to CAD in FH [4,19,20]. We reported that the serum triglyceride level is more closely related to the development of CAD than the serum cholesterol level in FH patients [5,6]. In the current study, we have shown that the CAD extent score was higher in DM and IGT groups than in the N group. Especially, the incidence of stenotic lesions in the distal coronary arteries was significantly higher in the DM and IGT groups than in the N group, while no significant difference was observed in the prevalence of stenotic lesions in the proximal and middle portions among the three groups. We also demonstrated that serum triglyceride levels were significantly higher in the DM and IGT groups than in the N group while total cholesterol levels were not. The frequency of the midband in PAG disc electrophoresis was significantly higher in DM and IGT groups than in the N group.

Fig. 1. Typical densitometric patterns of PAG disc electrophoresis of serum lipoproteins in patients with FH. The arrow in the upper densitometric pattern of an FH heterozygote shows a midband. In the lower panel another FH heterozygote was identified as midband-negative.

The increase of remnant lipoproteins in the DM and IGT groups was confirmed by ultracentrifugation analyses. We have already reported that serum lipid levels and the incidence of impaired glucose metabolism were higher in the survivors of acute MI compared to the control group, and that both cholesterol and triglyceride levels in the VLDL and IDL fractions were higher in the MI group than in the control group [21,22]. In addition, the ratio of cholesterol to triglyceride in the VLDL and IDL fraction was significantly increased compared to the control group. These results are in agreement with the report of Hamsten et al. [23]. High levels of both lipids in the VLDL and IDL fractions implies an increase of remnant lipoproteins. Several in vitro studies indicate that the increased VLDL and remnant concentrations in DM are potentially capable of increasing cholesterol ester deposition in arterial wall

Fig. 2. The prevalence of the midband in patients with FH investigated. The prevalence of the midband was significantly higher in the DM group (87%) and in the IGT group (72%) than in the N group (29%) (DM vs. N, P B0.01; IGT vs. N, PB 0.01).

K. Yanagi et al. / Atherosclerosis 132 (1997) 43–51

Fig. 3. The incidence of CAD in FH patients with and without the midband. The midband-positive subgroup had a significantly higher incidence of CAD than the midband-negative subgroup (midbandpositive subgroup: 73.3% vs. midband-negative subgroup: 31.2%, P B 0.01).

cells [24–27]. Clinically, the increase of remnant lipoproteins is also well known to be associated with the development of CAD as reported by Stein et al. [28] and by Simons et al. [29]. Our present findings suggest that the increase of remnant lipoproteins caused by DM or IGT may accelerate coronary atherosclerosis in patients with FH. The fact that remnant lipoproteins are increased in the IGT group with high levels of plasma insulin area suggests that not only the absolute deficiency of insulin but also the relative deficiency of insulin due to insulin resis-

49

tance may be associated with the increase of remnant lipoproteins in FH patients. Although the mechanism for the increase of remnant lipoproteins in patients with DM has not been fully elucidated, we presume that exogenous lipoproteins (chylomicron remnant lipoproteins) may be increased in DM because of the enhancement of cholesterol absorption. Several investigators [30–33] have reported that plasma cholesterol levels in diabetic animals are markedly influenced by exogenous cholesterol loading compared with nondiabetic animals. The midband-positive pattern in PAG disc electrophoresis was shown to appear when cholesterol was loaded in rats with streptozotocin-induced diabetes [19,34]. We reported that the increase of exogenous lipoprotein in DM is partly due to the enhanced activity of intestinal acylCoA:cholesterol acyltransferase (ACAT) using streptozotocin-induced diabetic rats [35]. The activity of ACAT was decreased by insulin in a human intestinal cell line Caco-2 [36]. Moreover, Nozaki et al. [37] reported that cholesterol and triglyceride levels in the IDL fraction were remarkably higher in the FH group than in the control group. Gibson et al. [38] also reported that the apo E in the IDL fraction was increased in FH patients. These findings suggest that the increased IDL level might be due to the decreased LDL receptor activity in FH patients. Therefore, the combination of impaired glucose metabolism and FH may further increase remnant lipoproteins, which may accelerate the development of coronary atherosclerosis. These results suggest that the treatment of abnormal glucose metabolism is important for the management of FH heterozygotes. The reduction of remnant lipoproteins by medical control in addition to the lowering of LDL cholesterol is very important for the prevention of the development of CAD in FH patients

Table 5 Lipid concentration and composition of lipoprotein fraction

n VLDL

IDL

LDL HDL2 HDL3

Cholesterol Triglyceride Cholesterol/triglyceride ratio Cholesterol Triglyceride Cholesterol/triglyceride ratio Cholesterol Triglyceride Cholesterol Triglyceride Cholesterol Triglyceride

FH-DM

FH-IGT

FH-N

Control

7 32.3 9 9.9* 98.29 41.1** 0.369 0.12 25.498.9* 17.295.5 1.499 0.32** 230.8 981.5 41.5 92.5 19.5 9 5.7 7.1 92.1 22.2 93.8 10.5 92.6

6 27.1 9 10.2 83.0 936.8 0.35 90.07 17.6 9 5.4 13.8 92.8 1.19 90.24 249.9 9 55.4 41.7 97.9 23.5 96.6 6.9 91.6 25.2 9 4.8 8.6 9 2.1

19 16.6 9 13.7** 52.8 938.3 0.29 90.09 13.4 92.8 12.3 94.9 1.01 90.36 260.6 970.7 42.4 9 12.5 25.4 912.4 6.2 9 2.5 25.1 94.7 7.4 9 2.9

10 10.1 9 5.5 23.1 913.8 0.30 90.09 4.3 9 2.1 9.2 94.8 0.89 9 0.35 103.9 9 25.9 14.0 9 4.2 31.4 9 12.5 5.3 91.6 25.3 9 4.5 3.4 9 1.6

The results are expressed as mean9 S.D. * PB0.05 compared with FH-N; PB0.05 compared with control.

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Acknowledgements The skilful technical assistance of Kazuko Iwata, Yuki Nishida and Toyomi Takama is gratefully acknowledged. This study was supported by grants from the Japanese Ministry of Education (No.4404085 and 3557117).

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