Impaired HDL response to fat in men with coronary artery disease

Atherosclerosis 150 (2000) 159 – 165 www.elsevier.com/locate/atherosclerosis

Impaired HDL response to fat in men with coronary artery disease Peter M. Clifton *, Manny Noakes CSIRO Human Nutrition, PO Box 10041, BC Adelaide, South Australia 5000 Received 7 April 1999; received in revised form 2 August 1999; accepted 3 September 1999

Abstract A low HDL cholesterol is found frequently in subjects with premature coronary artery disease. We speculated that individuals with a normal total cholesterol and coronary artery disease have an impaired HDL response to dietary fat. Twenty-one men with recently diagnosed coronary artery disease and total plasma cholesterol of B 6 mmol/l were matched by age, weight and cholesterol with 26 men with no personal or family history of coronary artery disease. They were placed sequentially on a 25% fat diet for 2 weeks, a high carbohydrate supplement which reduced fat to 16% of energy for 3 weeks and a high monounsaturated fat supplement which increased fat to 35% for a final 3-week period. Half of the subjects underwent an intravenous glucose tolerance test at the end of the intervention periods. The high fat supplement increased HDL cholesterol from 0.79 to 0.89 mmol/l in the men with coronary artery disease while HDL increased from 0.88 to 1.05 mmol/l in the control group (PB 0.05 for group difference). Plasma triglyceride fell by 0.79 and 0.45 mmol/l in cases and controls respectively (P B0.05 for group difference). LDL cholesterol fell by 0.2 mmol/l in both groups. Men with coronary artery disease had an enhanced insulin response during the intravenous glucose tolerance test (P B0.03) particularly in the low fat phase. Thus men with premature coronary artery disease and a low HDL cholesterol appear to have an impaired elevation of HDL cholesterol in response to dietary fat, and insulin resistance may underlie this response. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Insulin resistance; Monounsaturated fat; Carbohydrate; HDL; LDL; Coronary artery disease

1. Introduction Up to 30% of subjects with premature coronary artery disease may have a low HDL cholesterol alone Table 1 Baseline characteristics of volunteersa

Age (years) BMI Total cholesterol (mmol/l) Triglyceride (mmol/l) HDL cholesterol (mmol/l)

Controls

Cases

53.39 8.2 26.49 2.2 5.239 0.84 1.509 0.74* 0.979 0.23*

54.397.0 26.0 9 3.1 5.349 0.76 1.959 0.80 0.849 0.21

Values are mean 9 S.D. * PB0.05 cases vs controls. a

* Corresponding author. Tel.: + 61-8-83038826; fax: +61-883038899. E-mail address: [email protected] (P.M. Clifton)

while another 10% have a low HDL cholesterol associated with hypertriglyceridemia [1]. Over 70% of cases with a cholesterol of less than 5.2 mmol/l have a low HDL cholesterol [1]. Although obesity and insulin resistance may underlie some of the cases with low HDL cholesterol, particularly those with associated high plasma triglyceride [2,3], the cause of an isolated low HDL cholesterol is unclear although some are clearly familial [4–7] and tend to be associated with enhanced catabolism of apo A1 [8]. Because of the relationship between HDL2 cholesterol levels and postprandial lipemia in normolipidemic subjects [9,10], it has been suggested that subjects with a low HDL cholesterol and a normal triglyceride level have an abnormal postprandial metabolism but Cohen and Grundy [11] have clearly demonstrated that this is not the case in subjects without coronary disease. However men and women with coronary artery disease with normotriglyceridemia and low total or HDL2 cholesterol tend to have delayed clearance of chylomicrons and their remnants [12–16]

0021-9150/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 0 2 1 - 9 1 5 0 ( 9 9 ) 0 0 3 6 3 - 9

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compared with control subjects without coronary artery disease. Hypertriglyceridemia, whether accompanied or not by a low HDL cholesterol and/or coronary artery disease is invariably associated with an enhanced postprandial response [17 – 19]. We speculated that subjects with premature coronary artery disease and a normal plasma cholesterol may be less responsive to the stimulating effect of fat on HDL production [20,21] and experience little or no rise in HDL cholesterol. Thus on the high fat diet commonly consumed in developed societies, their HDL cholesterol would remain low. We also tested the hypothesis that insulin resistance may be implicated in the HDL response, as insulin resistance either measured directly or assessed using a fasting plasma insulin level has been associated with coronary disease [22–25], HDL cholesterol [26 – 29] and cholesterol/HDL ratios [30].

2. Methods

2.1. Subjects Twenty-one men with recent a coronary bypass or angioplasty (within the preceding 12 months) and a plasma cholesterol of less than 6.5 mmol/l were recruited from the Royal Adelaide Hospital. Twenty-six control subjects were recruited by public advertisement. The controls had no personal or family history of premature (B 65 years of age) coronary artery disease and were matched with cases for age, BMI and total cholesterol. Five cases had two matching controls. Baseline characteristics are shown in Table 1. Controls differed from cases in two important areas: their HDL cholesterol was higher (0.97 vs 0.84 mmol/l; P B 0.05) and their triglyceride was lower (1.50 vs 1.95 mmol/l; PB 0.05); 45% of cases and 16% of controls had hypertriglyceridemia (] 2.0 mmol/l) while 75% of cases and 100% of controls with high triglycerides and 40% of those with normal triglycerides had a low HDL (B 0.9 mmol/l). Overall only five out of 21 cases and nine out of 26 controls had an HDL cholesterol greater than 0.9 mmol/l (x 2, P\0.4). All of the controls were non-smokers while three cases still smoked (one, three and 10 cigarettes/day). Ten cases and only three controls drank no alcohol, but the average alcohol intake in standard drinks per week was similar in both groups (3.5 and 5.9 respectively). Fat intake as assessed by a 13-point questionnaire was higher in the control group (P B 0.02) while exercise levels were similar as assessed by a nine-point questionnaire. Blood pressure levels were very similar at 131/84 and 132/86 in the controls and cases respectively. Fifteen of the 21 cases had a family history of coronary artery disease in first degree relatives at age B65. Body weight did not change significantly, with a rise of 0.42

kg in the control group and 0.18 kg in the coronary artery disease group (CAD) at the end of the high fat phase compared with the beginning of the study. Exercise patterns and alcohol intake did not vary during the study.

2.2. Study design All subjects were placed on a baseline low fat diet (25% energy) for 2 weeks. At the end of this period all subjects continued on the low fat diet but supplemented the diet with a low fat, high carbohydrate drink, based on glucose polymers (polycose) and skim milk (2.6 MJ/day) for 3 weeks. In the final 3-week dietary phase, subjects switched to a high monounsaturated fat drink, equal in energy and protein level to the previous drink. This design was aimed at reducing HDL cholesterol to as low a level as possible in order to maximize the response to fat. Monounsaturated fat was used rather than saturated fat in order to avoid elevating LDL cholesterol in the CAD group. Fasting blood samples were taken on two consecutive days at baseline, and on 3 days in each test phase for measurement of total cholesterol, triglyceride, HDL cholesterol and glucose. In half of the subjects an intravenous glucose tolerance test was performed at the end of each supplement phase with 0.3 g/kg of glucose intravenously at time zero and 0.04 U/kg of insulin intravenously at 20 min. Blood samples were taken every 2 min for 40 min. Waist circumference was measured as the minimum dimension between the costar margin and the pelvic bone on mid expiration, while hip circumference was measured at the level of the greater trochanter.

2.3. Laboratory measurements Venous blood samples (10 ml) were taken after an overnight fast of ] 12 h into tubes containing Na2EDTA (1 g/l final concentration) as anticoagulant. Plasma was separated by low-speed centrifugation (Beckman GS-6R centrifuge, USA) at 2060× g for 10 min and stored at − 20°C. At the end of the study, total cholesterol, triacylglycerol and glucose concentrations were measured on a Cobas-Bio centrifugal analyser (Roche Diagnostica, Basle, Switzerland) using enzymatic kits (Hoffman-La Roche Diagnostica, Basle, Switzerland) and control sera. Plasma HDL cholesterol concentration was measured after precipitation of LDL and VLDL with polyethylene glycol 6000 solution [31]. The following modification of the Friedewald equation [32] for molar concentrations was used to calculate LDL cholesterol: LDL (mmol/l) =total cholesterol − triacylglycerol/2.18 − high-density lipoprotein cholesterol. Insulin was measured by commercial radio-immunoassay (Pharmacia, Uppsala, Sweden).

P.M. Clifton, M. Noakes / Atherosclerosis 150 (2000) 159–165 Table 2 Dietary intake from 3-day weighed food recordsa Nutrient

Baseline

Controls Energy (kJ) 7233 9 1654 % Carbohydrate 51.2 99.0 % Fat 25.1 96.0 % Protein 19.7 95.1 % Saturated fat 9.492.7 % Monounsatu8.9 92.9 rated fat % Polyunsaturated 4.39 1.9 fat Cholesterol (mg/ 190 986 day) Fibre (g/day) 24.9 9 8.3 Alcohol (g/day) 10.4 9 11.5 Cases Energy (kJ) 6010 91456* % Carbohydrate 53.4 9 9.1 % Fat 22.0 96.6 % Protein 21.6 95.9 % Saturated fat 8.2 94.0 % Monounsatu7.6 92.7 rated fat % Polyunsaturated 3.6 9 1.2 fat Cholesterol (mg/ 1639 86 day) Fibre (g/day) 24.6 910.1 Alcohol (g/day) 6.6 9 11.3

161

3. Results

Low fat

High fat

90649 1657 63.89 5.3 15.99 3.3 17.89 2.4 5.09 1.6 5.59 1.7

93559 1125 46.69 6.2 35.39 4.8 16.49 2.9 6.99 1.6 17.49 2.6

3.29 1.7

8.59 1.7

1909 69

1659 57

26.19 7.7 8.7 9 10.2

27.0 9 7.9 7.39 9.5

82079 1494 64.99 6.1 13.99 3.8 19.59 3.0 5.29 2.2 4.79 2.0

82799 1425* 44.49 6.2 36.79 5.5 17.29 3.0 6.6 9 1.6 18.69 3.8

2.39 0.9

9.0 9 1.3

1689 88

1559 81

24.99 9.2 5.79 9.3

23.69 8.9 6.29 10.2

Values are mean 9 S.D. * PB0.02 between cases and controls. a

2.4. Statistics Data were analysed using GLM repeated measures with covariates (SPPS 7.0). Data are expressed as mean 9S.D.

The measured dietary changes are shown in Table 2. Total fat increased by 20–22% from the low fat to the high fat phase with two-thirds of this increase being monounsaturated fat and about one-third polyunsaturated fat, with no difference between the two groups. Compliance with the supplements was greater than 90% in both groups. The reported energy intakes are low during the 2-week baseline period but in the two supplementation periods they fall within the range expected for very sedentary males with a BMI of 26 (6700–10 100 kJ). No significant weight changes occurred. Although energy intake was significantly lower in all three phases in the cases (which was probably due to a difference in exercise intensity which was not detected by the exercise questionnaire) it did not influence the results. The percentage total fat and percentage saturated fat were not different between groups in any of the phases. The high monounsaturated fat diet lowered total (PB0.001) and LDL cholesterol (P= 0.01) in both groups compared with the high carbohydrate diet and there was no significant diet/group interaction (Table 3). Total cholesterol was lowered by between 5 and 7.1% and LDL cholesterol by 6.1%. There was no significant change in LDL cholesterol between the baseline and low fat periods in either group. The increase in HDL cholesterol between the low fat and high fat periods was highly significant overall, with a greater increase in the control group (0.16 vs 0.10 mmol/l). This diet/group interaction was significant at PB 0.05. The 95% confidence interval for the difference between the two groups was 0.01–0.13 mmol/l. The most important determinant of the change in HDL cholesterol overall was the baseline HDL cholesterol (PB 0.001) but this was true only in the normal group (r= 0.53, PB 0.01), not the coronary group. Once the change in HDL cholesterol was adjusted for the base-

Table 3 Plasma lipids in the baseline, low fat and high fat phasea Group/diet

Total cholesterol

TG

LDL cholesterol

HDL

LDL/HDL

Cases Baseline Low fat High fat

5.349 0.76 5.449 0.74 5.05 90.73

1.95 9 0.80 2.579 1.14 1.789 0.64*

3.62 9 0.89 3.47 90.84 3.27 9 0.87*

0.849 0.21 0.79 9 0.20 0.89 90.24*

4.49 91.34 4.52 91.29 3.78 91.17

Controls Baseline Low fat High fat

5.239 0.84 5.199 0.89 4.939 0.87

1.48 9 0.72 1.899 1.06 1.44 9 0.62*

3.59 9 0.83 3.47 91.00 3.25 90.80*

0.979 0.23 0.88 9 0.18 1.05 90.25*

3.85 9 1.18 4.04 9 1.29 3.27 90.97

Values are mean 9 S.D. * PB0.01 for difference between low and high fat diets. Change in TG, PB0.05 difference between groups. Change in HDL, PB0.01 difference between groups. a

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between 2 and 16 min in the men with CAD (Fig. 1). Insulin levels were higher on the low fat diet (P=0.001 for diet, insulin interaction) with much of this difference seen in the CAD group (PB 0.02 for group/diet interaction). Fasting insulin levels were not different (8.6 and 8.5 mU/ml). Baseline HDL cholesterol levels and change in HDL cholesterol with the high fat diet were unrelated to the rate of glucose disappearance or to the insulin levels in the first 20 min.

4. Discussion

Fig. 1. Plasma insulin response in the intravenous glucose tolerance test after the low fat diet.

cline HDL cholesterol the difference between cases and controls became non-significant. There was no correlation between change in HDL cholesterol and BMI or WHR, but there was a significant correlation between the exercise rating scale and the change in HDL cholesterol with the fat supplement (r=0.4, P B0.01). After adjustment of the change in HDL cholesterol for smoking, alcohol intake, exercise patterns and change in fat intake the diet/group interaction remained significant (P= 0.03). The fall in HDL cholesterol from the baseline period to the low fat period (8 – 9% of energy fat change) although different in the two groups (0.05 vs 0.09 mmol/l) was not significant (P =0.1). Change in HDL cholesterol was unrelated to the presence of a family history of premature coronary artery disease. In contrast to the HDL cholesterol, the plasma triglyceride decreased more (30.9 vs 23.9% P B 0.05) in the coronary artery group when the subjects shifted from a high carbohydrate to a high fat diet. There was no correlation between the change in triglyceride and the change in HDL cholesterol, nor was there any correlation with BMI or WHR. Once an adjustment was made for baseline triglyceride, which was higher in the CAD group, there was no difference between groups in change in triglyceride with the high fat diet. Twenty-six subjects underwent an insulin-modified intravenous GTT at the end of each diet phase (16 normal men and 10 men with CAD). The rate of glucose fall was the same at the end of each diet and did not differ between the groups. The men with coronary disease had a rate of −0.25 9 0.09 mmol/l per min between 10 and 20 min while the control men had a rate of − 0.199 0.09 mmol/l per min (P =0.2). Between 20 and 40 min, the rates were − 0.24 and − 0.23 respectively. On a repeated measures test, plasma insulin levels at zero, 2, 4, 6, 8 and 16 min differed significantly between the controls and the men with CAD (P= 0.03), with the insulin level 50% higher

The increase in HDL cholesterol seen with a high fat diet was 0.06 mmol/l greater in the control men than in the cases. Thus men with coronary artery disease and a normal LDL cholesterol and low HDL cholesterol appear to be less sensitive to the HDL elevating effect of monounsaturated fat than controls matched for age, BMI and total cholesterol. These men would appear to have a poor adaptive response to a high fat, western diet, as high levels of HDL cholesterol when on such a diet are protective against coronary disease. It is assumed their response to saturated fat would be similar to their response to monounsaturated fat. Although part of this difference could be explicable by the higher baseline HDL cholesterol in the control group this does not invalidate the argument that men with coronary disease are less responsive to fat. The difference between the groups in baseline HDL cholesterol could reflect differences in the change in HDL cholesterol from a theoretical zero fat diet to the baseline low fat diet (22–25% fat), although we have not tested our hypothesis in this low range of fat intakes. If the HDL cholesterol changes in the same way with a further 20% reduction in dietary fat, then on a 5% fat diet HDL cholesterol would be 0.74 and 0.80 in the cases and controls respectively. These levels are very similar to the HDL cholesterol levels seen in 8- to 9-year-old Kenyan boys on a 12% fat diet [33]. Brinton et al. [20] have found that changes in HDL with changes in fat intake correlate best with changes in apo A1 transport rate, not clearance, suggesting the men with coronary artery disease may have impaired synthesis of apo A1 in response to fat, but we did not examine apo A1 levels or apo A1 synthesis rates. The differences between the groups in HDL cholesterol on a very low fat diet would then be mostly attributable to differences in clearance rate, as has been noted by Brinton et al. [20]. The equations of Mensink and Katan [34], which were based on men and women with no coronary artery disease, would predict a rise of 0.15 mmol/l in HDL in the control group compared with the observed value of 0.17 mmol/l, while in the men with coronary artery disease the observed value was 0.10 mmol/l compared with a predicted rise of 0.19 mmol/l. In a meta-analysis of dietary studies with type II diabetics, the substitution

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of a high monounsaturated fat diet for a high carbohydrate diet increased HDL cholesterol in only five of nine studies analysed, with overall an increase of 0.05 mmol/l or 4% [35] for a 15 – 25% increase in energy as fat, which is a much lower increase in HDL cholesterol than predicted for normal subjects. The men with coronary artery disease in our study are insulin resistant compared with weight-matched normal men, based on their insulin response during the intravenous glucose tolerance test. Thus part of the reason their HDL is relatively unresponsive to fat may be early insulin resistance. Insulin resistance has been postulated to be an important underlying condition in many patients with coronary artery disease. The Paris Prospective study [24] and the Quebec Prospective study [25] showed that fasting insulin was a predictor of coronary disease even in the latter study after correction for other associated abnormalities such as low HDL cholesterol and high triglyceride. Case control studies, such as that done by Bressler et al. [22], have shown that normal weight men with coronary disease and normal glucose tolerance have increased insulin levels after an oral glucose tolerance test and decreased glucose disposal (almost entirely due to decreases in non-oxidative disposal) during a clamp, compared with weight-matched control men. Fasting plasma insulin was also higher in the coronary group, although we did not see that in our group. In the normal population, low HDL cholesterol, high triglyceride and a high TC/HDL ratio [26 – 30] is associated with insulin resistance, either assessed by clamp, fasting insulin or oral GTT, and with glucose intolerance [36]. The subject of dietary-induced HDL changes in men with coronary artery disease has not been closely examined before. In the CLAS study [37], 82 men with coronary artery disease on placebo and a 26% fat diet (5% saturated and 10% polyunsaturated) experienced no change in HDL cholesterol from baseline to the trial period and in the St Thomas’ Atherosclerosis Regression Study [38] a 27% fat diet led to no significant changes in HDL cholesterol compared with the baseline period in 24 men treated with diet alone. In both of these trials there is no data on fat intake during the baseline period but it is likely to be at least 35%. In the Lifestyle Heart Trial [39], HDL cholesterol (which was low) did not change with a change in fat intake from 31 to 7% of energy. Based on studies in normal subjects HDL would be expected to fall by at least 20% with this very low fat diet. In both groups in our study, the addition of a monounsaturated fat supplement in place of a high carbohydrate supplement lowered plasma triglyceride and LDL cholesterol and increased HDL cholesterol with an improvement in the LDL to HDL ratio from 4.3 to 3.5. It could be argued that the high polycose

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carbohydrate drink has a very high glycemic index and the rise in triglyceride and fall in HDL seen with this drink may not be seen if the carbohydrate source has a lower glycemic index and is fibre-enriched. However Mensink and co-workers [40,41] have found that starch and fibre-rich foods also cause a fall in HDL cholesterol in comparison with monounsaturated fat. In our study a comparison of the high monounsaturated fat period to the baseline low fat period (in which no supplement was used) reveals a fall in LDL/HDL ratio from 4.1 to 3.5. This result is very similar to that seen by Grundy [42] in a metabolic ward liquid diet study in which a high monounsaturated fat diet led to a 40% fall in triglycerides, a 22% rise in HDL cholesterol and a fall in LDL/HDL ratio from 4.7 to 3.5 in comparison to a glucose-rich, 20% fat diet. LDL cholesterol was lower on the high monounsaturated fat diet although not significantly so, whereas in our study the 6% fall in LDL cholesterol was highly significant. The fall in LDL cholesterol in our study was the same in both groups (0.20–0.22 mmol/l) compared with a predicted fall of 0.11 mmol/l. Clearly LDL is not unresponsive to change in men with coronary artery disease. We saw a fall in plasma triglyceride of 24–32% with the 22% dietary fat increase. The equations of Mensink and Katan [34] would predict a change of 0.48–0.50 mmol/l while we saw a change of 0.44 mmol/l in the normal men and 0.79 mmol/l in the men with coronary disease who had hypertriglyceridemia. Hypertriglyceridemia subjects tend to have a greater percentage lowering of triglyceride with fish oil [43] and fibrates [44]. In a meta-analysis of the use of a monounsaturated fat diet compared with a high carbohydrate diet in diabetes, Garg [35] found a fall in plasma triglyceride of only 19% for a 20–25% of calories change, suggesting perhaps that subjects with frank diabetes may be less responsive than normal subjects. As noted above, changes in HDL cholesterol were also muted. In a study of postmenopausal women Jeppesen et al. [45] found that steady state plasma glucose levels, after an infusion of somatostatin, glucose and insulin, were correlated with the change in triglyceride levels with a shift from a 40% carbohydrate diet to a 60% carbohydrate diet, so mild insulin resistance in non-diabetic subjects leads to exaggerated triglyceride responses to carbohydrate, which is consistent with our data. In their study triglycerides increased by almost 50%. In conclusion, we have demonstrated that men with coronary artery disease and low HDL cholesterol have an impaired HDL response to dietary fat, compared with age and weight-matched men free of coronary disease. In addition, the high monounsaturated fat diet produced a significantly better lipoprotein profile than a high carbohydrate diet.

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