Possible Relationship between Insulin Resistance and Remnant-Like ...

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Background:High insulin resistance and elevated remnant lipoprotein levels both correlate with impaired coronary vas- cular endothelial function.

Clin. Cardiol. 25, 532–536 (2002)

Possible Relationship between Insulin Resistance and Remnant-Like Lipoprotein Particles in Coronary Endothelial Dysfunction TERUO INOUE, M.D., TOSHIHIKO UCHIDA, M.D., HIROTOSHI KAMISHIRADO, M.D., MASASHI SAKUMA, M.D., YOSHIHIKO SAKAI, M.D., KAN TAKAYANAGI, M.D., TERUMI HAYASHI, M.D., SHIGENORI MOROOKA, M.D. Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, Saitama, Japan

Summary

Background: High insulin resistance and elevated remnant lipoprotein levels both correlate with impaired coronary vascular endothelial function. Hyperinsulinemia induces abnormalities of lipid metabolism. However, the correlation among insulin resistance, remnant lipoproteins, and endothelial function has not been clinically elucidated. Hypothesis: This study was designed to elucidate the correlation among insulin resistance, remnant lipoproteins, and acetylcholine (ACh)-induced coronary artery response. Methods: Forty-nine patients suspected of having ischemic heart disease, but without angiographically significant atherosclerotic coronary artery disease, underwent an ACh provocation test. Fasting venous blood was taken early in the morning on the day coronary angiography was performed. The insulin resistance index (IR) was determined from fasting plasma glucose and insulin concentrations, using the homeostasis model assessment (HOMA). Serum levels of remnant-like lipoprotein particle cholesterol (RLP-C) were measured. Results: Homeostasis model assessment IR was significantly higher (3.65 ± 1.38 vs. 0.75 ± 0.14, p < 0.05) and log-transformed HOMA (Log HOMA) was even more significantly higher (0.20 ± 0.12 vs. 0.29 ± 0.08, p < 0.001) in the AChpositive group (n = 23) than in the ACh-negative group (n = 26). The serum RLP-C level was also higher in the ACh-positive group than in the ACh-negative group (4.37 ± 0.63 vs. 2.52 ± 0.18 mg/dl, p < 0.01). Log HOMA and RLP-C levels

Address for reprints: Teruo Inoue, M.D. Department of Cardiology Koshigaya Hospital Dokkyo University School of Medicine 2-1-50 Minamikoshigaya, Koshigaya City Saitama 343-8555, Japan e-mail: [email protected] Received: June 25, 2001 Accepted with revision: January 28, 2002

correlated with each other (R = 0.54, p < 0.001). Multiple regression analysis indicated that only the RLP-C level was a dependent predictor of Log HOMA in various lipid profiles. Conclusions: Both high insulin resistance and elevated remnant lipoprotein levels correlated and might have a crucial role in the impairment of coronary vascular endothelial function, even in patients without angiographically significant coronary artery disease. Key words: insulin resistance, remnant-like lipoprotein, endothelial function, coronary artery disease, acetylcholine

Introduction Insulin resistance syndrome is characterized by glucose intolerance, hyperinsulinemia, obesity, hypertension, dyslipidemia, and an increased risk of coronary artery disease.1 Recent studies reported that insulin resistance was associated with impaired endothelial function of the coronary arteries,2, 3 which is considered to be an early event in atherosclerotic development and an important contributor to the pathogenesis of coronary artery disease.4 On the other hand, elevated plasma insulin concentrations enhance very-low-density lipoprotein (VLDL) synthesis, leading to hypertriglyceridemia.1 Remnants of triglyceride-rich lipoproteins have been shown to be atherogenic factors,5 and serum remnant-like lipoprotein particle cholesterol (RLP-C) levels were also considered to correlate with the impairment of coronary vascular endothelial function.6–8 Thus, it is thought that both insulin resistance and remnant lipoproteins correlate and contribute to modulation of coronary vasomotor tone, although this issue has not been elucidated clinically. This study was designed to elucidate the correlation among insulin resistance, remnant lipoproteins, and acetylcholine (ACh)-induced coronary artery response.

Methods Subjects

The study population included 49 patients suspected of having ischemic heart disease, but without angiographically sig-

T. Inoue et al.: Insulin resistance and lipoprotein particles in endothelian dysfunction

nificant atherosclerotic coronary artery disease, defined as a discrete stenosis (≥ 50% diameter stenosis) or intimal irregularity. All patients underwent an ACh provocation test on both right and left coronary arteries. Patients who had diabetes mellitus requiring hypoglycemic agents, or who had been medicated with lipid-lowering drugs, were excluded. In the study patients, all oral medications except sublingual nitroglycerin were discontinued at least 48 h prior to angiography. The study protocol was approved by the Dokkyo University Institutional Review Board, and written informed consent was obtained from each patient. Coronary Angiography and Acetylcholine Test

Coronary angiography was performed in the morning of the study day using the Judkins technique with a 6F Judkins catheter (Bard, Billerica, Mass., USA). Blood pressure was monitored through the catheter, and a standard 12-lead electrocardiogram (ECG) was recorded during the study with a 6channel recorder. After an intravenous bolus injection of 5000 IU of heparin, single-plane coronary cineangiograms were obtained at 30 frame/s by injection of a nonionic contrast material (Iomeprol 350, Eisai Co., Ltd., Tokyo, Japan). After baseline right and left coronary angiograms were obtained, the ACh test was performed to diagnose coronary vasospasm according to the routine protocol employed in our cardiac catheterization laboratory. Namely, serial doses of 30 and 50 µg of ACh and then 40 and 80 µg were injected into the right and left coronary artery, respectively, over a 60-s period. Angiograms were obtained 90 s after each injection was started. When ST-segment changes, chest pain, or both appeared after the ACh injection, the angiogram was performed immediately. In this study, a positive ACh test was defined as segmental or diffuse luminal narrowing of > 90% or total occlusion of the artery, with marked ST-T changes and/or typical chest pain. Measurements

Fasting venous blood was taken from the antecubital vein early in the morning on the day coronary angiography was performed to determine plasma glucose and insulin levels, serum total cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, apolipoprotein (apo) E, apo A-I and apo B, and lipoprotein (a) [Lp(a)]. The insulin resistance index (IR) was determined from fasting plasma glucose (mmol/l) and insulin concentrations (mU/l), using the homeostasis model assessment (HOMA) by the formula (HOMA IR = insulin  glucose/22.5) as described previously, which is believed to correlate with the insulin resistance measured by a euglycemic clamp method (clamp IR).9 The HOMA IR was then log transformed (Log HOMA).10 An RLP-C assay was performed according to previous reports.11–13 Briefly, serum was added to an immunoaffinity mixed gel suspension containing anti-apo B-100 and anti-apo A-1 gel. The supernant was taken to assay cholesterol with an RLP-C “JIMRO” II diagnostic kit (Japan Immunoresearch Laboratories, Gumma,

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Japan). The cholesterol level assayed by the above mentioned methods was defined as the RLP-C level. Statistical Analysis

Sample size was determined by assuming 0.3 in mean Log HOMA or 1.5 mg/dl in mean RLP-C to be the difference of interest. Fifty patients would be sufficient to detect this difference, with a significance level of 5% and a power of 8%. Values were expressed as mean ± standard error (SE). Intergroup comparisons were performed using the unpaired Student’s t-test for continuous variables and the chi-square test for categorical variables. Correlation of Log HOMA with serum RLP-C levels was assessed by a simple linear regression. Multiple regression analysis was performed for lipid profile variables, including RLP-C, to predict HOMA. A p value of < 0.05 was considered significant.

Results Results of the Acetylcholine Test

The results of the ACh provocation test were positive in 24 of 49 patients and negative in the remaining 25. Of the 24 ACh-positive patients, positive findings (coronary vasospasm with significant ST-T change and/or typical chest pain) were seen in a single vessel in 16 patients, two vessels in 7 patients, and three vessels in 1 patient. Between the ACh-positive and ACh-negative groups, there were no significant differences in age, gender, hypertension, smoking, or any underlying heart condition. The levels of fasting plasma glucose, total cholesterol, triglycerides, HDL-cholesterol, apo A-I, apo B, apo E, and Lp(a) were also similar between the two groups (Table I).

TABLE I Baseline characteristics

Age (years) Sex (M/F) Smoking (%) Hypertension (%) Diabetes (%) Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Apo A1 (mg/dl) Apo B (mg/dl) Apo E (mg/dl) Lp(a) (mg/dl)

ACh positive (n = 23)

ACh negative (n = 26)

p Value

58 ± 2 15/8 14 (61) 6 (26) 4 (17) 174 ± 8 76 ± 12 45 ± 3 110 ± 6 113 ± 4 90 ± 4 3.5 ± 0.2 29 ± 6

64 ± 1 17/9 13 (50) 4 (15) 3 (12) 172 ± 8 52 ± 8 51 ± 3 111 ± 5 123 ± 4 87 ± 4 3.1 ± 0.1 16 ± 2

0.422 0.866 0.542 0.086 0.162 0.865 0.091 0.143 0.926 0.100 0.657 0.140 0.073

Abbreviations: ACh = acetylcholine, HDL = high-density lipoprotein, LDL = low-density lipoprotein, Apo = apolipoprotein, Lp(a) = lipoprotein (a).

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Clin. Cardiol. Vol. 25, November 2002 p < 0.05

1.5

p < 0.001

p < 0.01

1.0

5

RLP-C (mg/dl)

Log HOMA

HOMA IR

10 0.5 0 0.5

10

5

1.0 1.5

0 ACh positive (n = 23)

ACh negative (n = 26)

0 ACh positive (n = 23)

ACh negative (n = 26)

ACh positive (n = 23)

ACh negative (n = 26)

FIG. 1 Comparison of HOMA IR, Log HOMA, and serum RLP-C levels in patients with positive and negative acetylcholine (ACh) tests.

Homeostasis Assessment Model and Remnant-Like Lipoprotein Particle Cholesterol

The HOMA IR (3.65 ± 1.38 vs. 0.75 ± 0.14, p < 0.05) was significantly higher and Log HOMA (0.20 ± 0.12 vs. 0.29 ± 0.08, p < 0.001) was even significantly higher in the AChpositive group than in the ACh-negative group. The serum RLP-C level was also higher in the ACh-positive group than in the ACh-negative group (4.37 ± 0.63 vs. 2.52 ± 0.18 mg/dl, p < 0.01) (Fig. 1). In analysis separated by gender, Log HOMA (0.20 ± 0.09 vs. 0.24 ± 0.06, p < 0.01 in men; 0.2 ± 0.14 vs. 0.32 ± 0.12, p < 0.05 in women) and RLP-C levels (4.6 ± 0.5 vs. 2.4 ± 0.2, p < 0.01 in men; 4.2 ± 0.7 vs. 2.4 ± 0.4, p < 0.05 in women) were also higher in the ACh-positive group than in the ACh-negative group, in both men and women (Fig. 2). In overall patients, Log HOMA and RLP-C levels

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Discussion In this study, we selected only patients without angiographically significant atherosclerotic coronary artery disease who underwent an ACh provocation test, as we were evaluating coronary vascular endothelial function in early-stage atherogenesis. We demonstrated that HOMA IR, Log HOMA, and RLP-C levels were higher in the ACh-positive group than in the ACh-negative group, although age, gender, hypertension, smoking, fasting plasma glucose, and other lipid profiles were

p < 0.01

NS NS

6

correlated (R = 0.54, p < 0.001) (Fig. 3). Multiple regression analysis indicated that only the RLP-C level was an independent predictor of Log HOMA of the various lipid profile parameters (Table II).

7

p < 0.05

6

p < 0.01 p < 0.05

0.5

4 3

RLP-C (mg/dl)

Log HOMA

HOMA IR

5

0

5 4 3

2

2

1

1

0

ACh positive

ACh negative

0.5

ACh positive: Men: n = 15, women: n = 8

ACh positive

ACh negative

0

ACh positive

ACh negative

ACh negative: Men: n = 17, women: n = 9

FIG. 2 Comparison of HOMA IR, Log HOMA, and serum RLP-C levels in patients with positive and negative acetylcholine (ACh) tests, separated by gender. NS = not significant. ● = Men, ● = women.

T. Inoue et al.: Insulin resistance and lipoprotein particles in endothelian dysfunction

1

Log HOMA

0.5

0 n = 39 y = 0.12  0.48 r = 0.54 p < 0.001

0.5 1 0

5

10 RLP-C (mg/dl)

FIG. 3 Relationship between Log HOMA and serum RLP-C levels.

identical in both groups. In analysis separated by gender, Log HOMA and RLP-C levels were also higher in the ACh-positive group than in the ACh-negative group, in both men and women, although women are believed to have vascular reactivity that is different from that of men. Since vascular relaxation in response to ACh is mediated by endothelium-derived nitric oxide,14 ACh-induced coronary vasospasm, which indicates impaired ACh-induced coronary artery relaxation, may reflect endothelial dysfunction.15 Thus, our results suggest that both high insulin resistance and elevated remnant lipoproteins correlate with impaired coronary vascular endothelial function. Recently, insulin resistance has been reported to be associated with impaired endothelial function of the coronary arteries,2, 3 which is believed to be an early event in atherosclerotic development and an important contributor to the pathogenesis of coronary artery disease.4 It is known that insulin infusion in healthy volunteers is associated with vasodilatation that may

TABLE II Multiple regression analysis of lipid profiles predicting Log HOMA

Total cholesterol Triglyceride HDL cholesterol LDL cholesterol Apo A1 Apo B Apo E Lp(a) RLP-C

Standard regression coefficient

t Value

p Value

0.063 0.274 0.266 0.245 0.134 0.364 0.095 0.272 0.547

0.190 1.123 0.986 0.717 0.530 1.032 0.518 1.985 15.716

0.850 0.268 0.330 0.478 0.599 0.308 0.608 0.062 0.004

Abbreviation: RLP-C = remnant-like lipoprotein particle cholesterol. Other abbreviations as in Table I.

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be mediated by endothelium-derived nitric oxide (NO). However, insulin-induced NO production is lacking in the insulinresistant subjects. Hyperinsulinemia increases renal sodium retention,16 Na+-H+ exchange on vascular wall cells,17 or sympathetic nerve activity,18 leading to hypertension, which is one of the major atherogenic evidences. In addition, insulin itself proliferates vascular smooth muscle cells, induces collagen synthesis, or stimulates insulin-like growth factor,19 which contribute to the atherosclerotic process. On the other hand, hyperinsulinemia also induces lipid metabolism abnormalities. There is much evidence that hyperinsulinemia enhances hepatic VLDL synthesis and contributes to elevated plasma triglyceride levels. Resistance to the action of insulin on lipoprotein lipase also contributes to hypertriglyceridemia.1 Hypertriglyceridemia can result from an accumulation of various lipoproteins, including chylomicrons and the smaller remnants of the triglyceride-rich lipoproteins. Remnant lipoproteins have been shown to be atherogenic,5 and serum RLPC levels were also considered to be associated with the impairment of coronary vascular endothelial function.6–8 We also demonstrated in this study that Log HOMA and serum RLP-C levels correlated. This is probably the first report that clinically evidenced a relationship between insulin resistance and remnant. In addition, our multiple regression analysis results indicated that only the RLP-C level was independently related to Log HOMA of the various lipid profile parameters. In this study, we used HOMA IR and Log HOMA as indices of insulin resistance. Log HOMA is likely to discriminate more sensitively between positive or negative AChinduced coronary artery responses and to correlate more sensitively with serum RLP-C levels. The HOMA has been suggested as a simple method to assess insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations. This method has been extensively evaluated, and the HOMA IR is believed to correlate with the clamp IR.9 However, HOMA IR is unlikely to be precise in patients with marked hyperglycemia;5 therefore, our study excluded such patients. Furthermore, Emoto et al.10 recently observed that the relationship between HOMA IR and clamp IR was not linear, but exponential, and that Log HOMA correlated more linearly with clamp IR, even in the population with marked hyperglycemia.

Potential Limitation In this study, coronary vascular endothelial function was evaluated only by observation of coronary vasoactivity as maximum vasoconstriction to bolus ACh, that is, coronary vasospasm. A more rigid approach to measure quantitative vasoactivity responses to graded concentration infusions should be required. However, we could perform the ACh test only according to the routine protocol employed in our cardiac catheterization laboratory to diagnose coronary vasospasm since coronary vasospasm is believed to be an ultimate vasoconstrictive action based on coronary vascular endothelial dysfunction; thus, we believe that our findings are not meaningless.

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Conclusion We suggested in this study that both high insulin resistance and elevated remnant lipoprotein levels correlated and that both might have a crucial role in the impairment of coronary vascular endothelial function, even in patients without angiographically significant coronary artery disease.

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