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Cardiovascular Research 2002 53(2):496-501; doi:10.1016/S0008-6363(01)00504-1
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Copyright © 2001, European Society of Cardiology

Insulin resistance but not hypertriglyceridemia per se is associated with endothelial dysfunction in chronic hypertriglyceridemia

I.J.A.M Jonkersa,*, M.A van de Reea, A.H.M Smelta, F.H.A.F de Manb, H Jansenc, A.E Meindersa, A van der Laarseb and G.J Blauwa

aDepartment of General Internal Medicine, Leiden Universiy Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
bDepartment of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
cInternal Medicine, Biochemistry and Clinical Chemistry, Erasmus University Rotterdam, Rotterdam, The Netherlands

* Corresponding author. Tel.: +31-71-526-4654; fax: +31-71-524-8159

Received 8 August 2001; accepted 5 October 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: To infer the relative impact of elevated triglyceride levels and insulin resistance on endothelial dysfunction in patients with chronic hypertriglyceridemia (HTG). Methods: Endothelial function was studied in 11 HTG patients and 16 normolipidemic controls. Cumulative-dose infusions of 5-hydroxytryptamine (5HT) and sodium nitroprusside were infused locally into the brachial artery to study endothelium-dependent and endothelium-independent vasodilation, respectively. Data of the HTG patients were dichotomized around the median of insulin resistance, calculated as HOMA-index, forming HTG groups with mild (HTG-MIR) and severe insulin resistance (HTG-SIR). Results: HTG patients had higher triglyceride levels and smaller LDL particle size than controls (both P≤0.001), whereas these parameters did not differ between both HTG groups. Insulin resistance was higher in both HTG groups than in controls (11.1 (7.0–14.5) and 4.9 (4.0–6.7) vs. 2.4 (4.9–5.2), respectively, both P<0.001). Similarly, free fatty acid levels, another indicator of insulin resistance, were highest in the HTG-SIR group, followed by those in the HTG-MIR and control group (0.7 (0.6–0.8), 0.5 (0.4–0.6) and 0.4 (0.3–0.4) mmol/l, respectively, all P<0.05). Endothelial-dependent vasodilation was similar in HTG-MIR and controls. In contrast, the response to 5HT was attenuated in the HTG-SIR group compared to controls (low and high dose by, respectively, –60 and –44%, both P<0.01), and tended to be lower than in the HTG-MIR group (–43%, P=0.068 and –41%, P=0.100, respectively). Endothelium-independent vasodilation did not differ between the three groups. Conclusion: These findings indicate that chronic hypertriglyceridemia per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG.

KEYWORDS Endothelial function; Lipid metabolism; Vasoconstriction/dilation


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Hypertriglyceridemia (HTG) is part of a complex metabolic disorder, associated with the occurrence of obesity, hypertension, insulin resistance and small dense LDL, resulting in a high cardiovascular risk [1]. Mainly due to the strong interrelationships between serum TG and these metabolic alterations, the independency of serum TG as a cardiovascular risk factor has been questioned over recent years. However, with the limitations of the use of a statistical model, Hokanson and Austin pointed out in a large meta-analysis that a substantial part (almost 50%) of the triglycerides-associated cardiovascular risk must be attributed to the interrelationships between triglycerides and metabolic alterations [2].

Endothelial dysfunction has been marked as an early feature of atherosclerosis. Recent studies showed that future cardiovascular events could be predicted by the presence of endothelial dysfunction, suggesting an important role for endothelial dysfunction in the occurrence of cardiovascular disease [3,4]. The debate concerning the independency of HTG as a risk factor for cardiovascular disease is reflected in controversy about whether chronic HTG is associated with endothelial dysfunction as well. Chowynczek et al. [5] and Schnell et al. [6] reported that chronic HTG is associated with normal endothelium-dependent vasodilation, whereas others reported the presence of impaired endothelium-dependent vasodilation in chronic HTG [7–9]. However, insulin resistance often accompanies HTG [1] and has been shown to cause endothelial dysfunction as well [10–12]. Based on the existing controversy about the relationship between HTG and endothelial dysfunction and the fact that insulin resistance itself can induce endothelial dysfunction, we hypothesized that insulin resistance and not HTG per se is responsible for the observed impaired endothelium-dependent vasodilation in chronic HTG. To test this hypothesis, we compared endothelial function between normolipidemic controls and HTG patients with both mild and severe insulin resistance.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Patients and controls
The study population included 11 patients with chronic hypertriglyceridemia and 16 healthy normolipidemic control subjects. Normolipidemic controls were recruited using a newspaper advertisement, whereas patients with hypertriglyceridemia were recruited from the out-patient lipid clinic of the Leiden University Medical Center. Patients with hypertriglyceridemia were eligible if they had a total serum triglycerides between 4.0 and 15.0 mmol/l, VLDL-cholesterol >1.0 mmol/l, and LDL-cholesterol <4.5 mmol/l on two separate occasions under fasting conditions. Consecutively serum total cholesterol levels were elevated in the hypertriglyceridemic patients as well (range 5.3–9.0 mmol/l). Exclusion criteria were the apo E2E2 phenotype, secondary hyperlipidemia (renal, liver or thyroid disease, fasting glucose >7.0 mmol/l, alcohol consumption of more than 40 g/day and body mass index >30 kg/m2) and the presence of diabetes or cardiovascular disease. The presence of cardiovascular disease was excluded by history, physical examination and the presence of a normal ECG. In case lipid-lowering drugs were taken, these were stopped at least 6 weeks prior to the study-onset. All individuals were male, non-smoking, and normotensive. The study protocol was approved by the Medical Ethics Committee of the Leiden University Medical Center and all subjects gave informed consent.

2.2 Endothelial function
All subjects were studied under fasting conditions in a quiet room with a constant temperature of 21–23°C. Alcohol and caffeine-containing beverages were withheld at least 24 h before the study. During the experiments, the subjects were in supine position with the nondominant arm stabilized slightly above the level of the heart. After local anesthesia, a 20-gauge polyethylene catheter (Ohmeda, Swindon, UK) was inserted in the brachial artery of the nondominant arm for determination of blood pressure and infusion of drugs with a Graseby 3200 constant rate infusion pump (Graseby, Watford, UK). The subjects rested for 30 min after the insertion of the intra-arterial catheter to achieve a stable baseline. Forearm blood flow (FBF) was measured by computerized, R-wave triggered, venous occlusion plethysmography, using mercury in silastic strain gauges and a rapid cuff inflator (Hokanson Inc., Bellevue, USA) as has been described previously [13,14]. During the measurements of FBF, the hand was excluded from the circulation, using a small wrist cuff inflated to 40 mmHg above the systolic blood pressure. Endothelium-dependent vasodilation was determined during cumulative dose-infusions of the specific endothelium-dependent vasodilator compound 5-hydroxytryptamine (5HT; 0.3 and 0.9 ng kg–1 min–1) [15]. Sodium-nitroprusside (SNP; 30 and 90 ng kg–1 min–1) was infused as endothelium-independent vasodilator. The drugs were given in a random order and each dose was infused for 7 min. FBF, blood pressure, and heart rate were measured during 2 min immediately prior to the start of each intra-arterial infusion, and during the last 2 min of each infusion step. A wash-out period of 20 min was applied between the different vasoactive drugs in order to allow the blood flow to return to baseline levels. FBF was expressed as ml 100 ml–1 forearm tissue min–1. The vasodilating effects of 5HT and SNP are expressed as relative changes in FBF, thereby adjusting for differences in basal FBF.

2.3 Drugs and solutions
5-Hydroxytryptamine HCl (ICN Pharmaceuticals, Costa Mesa, CA, USA) and SNP (Merck, Darmstadt, Germany) were used for intra-arterial infusions. 5HT was dissolved in 0.9% saline, whereas SNP was dissolved in 5% glucose. The solutions were prepared from sterile stock solutions and ampoules on the day of the study, and stored at 4°C until use.

2.4 Biochemistry
Venous blood was collected after an overnight fast. Serum was obtained after centrifugation at 1500xg for 15 min at room temperature. Three ml of fresh serum were ultracentrifuged for 15 h at 232,000xg at 15°C. The ultracentrifugate was carefully divided in a density <1.006 and density 1.006–1.25 g/ml fraction, designated as the VLDL and LDL-HDL fraction, respectively. HDL cholesterol was measured in the LDL-HDL fraction after precipitation of apoB-containing particles with phosphotungstic acid and MgCl2. Triglyceride, cholesterol and free fatty acids (FFA) concentrations were measured enzymatically using commercially available kits. Insulin was measured with a conventional radio-immuno assay (Medgenix, Brussels, Belgium). Glucose was measured with a Hitachi 747 analyzer according to standard procedures (Roche Diagnostics, Mannheim, Germany). Insulin resistance was assessed using the homeostasis model approximation, by the following formula: insulin resistance=insulin/(22.5e–ln glucose) [16]. LDL particle size was measured by electrophoresis of 5 µl of serum on 2–16% polyacrylamide gels according to a method described before [17]. A set of LDL standards (ranging from 246 to 287 Å) were used and run on the same gel as the samples.

2.5 Statistical analysis
The data of the HTG patients were dichotomised around the median of insulin resistance (median of insulin resistance: 6.8), resulting in the formation of a HTG group with mild insulin resistance (HTG-MIR, n=6) and a HTG group with severe insulin resistance (HTG-SIR, n=5). Data between HTG-MIR, HTG-SIR and normolipidemic controls were assessed using non-parametric tests: overall difference between the groups was tested using Kruskal–Wallis test, whereas post-hoc analyses were performed using Mann–Whitney U-test. P-values <0.05 were considered as significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1 Group characteristics
No differences were observed in age and body mass index between the three groups. As expected, the lipid pattern differed significantly between the three groups (all P≤0.01), except for LDL-cholesterol (P=0.08): both HTG groups had higher total triglycerides, VLDL-triglycerides and VLDL-cholesterol levels compared to controls whereas HDL-cholesterol was significantly lower in both HTG groups in comparison to controls (all P≤0.01). LDL cholesterol, known to impair endothelial function as well, however, was significantly lower in HTG-SIR patients than in controls (Table 1). The lipid pattern from the HTG-MIR group did not significantly differ from that of the HTG-SIR group. Diastolic and systolic blood pressure were similar in the three groups (both P≥0.2, respectively, Table 1).


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  		Table 1 Group characteristics

 
3.2 Insulin resistance, free fatty acids and LDL particle size
Because of stratification, insulin resistance significantly differed between the three groups (P<0.001). Compared to controls, insulin resistance was higher in both the HTG-MIR and the HTG-SIR group (+104 and +363%, respectively). Insulin levels differed between the three groups (P≤0.001): both the HTG-MIR and HTG-SIR group had higher insulin levels compared to controls (+82 and +291%, both P≤0.001, respectively), whereas the HTG-SIR group had higher insulin levels compared to the HTG-MIR group (+215%, P=0.006). Glucose levels differed between the three groups (P=0.01): the HTG-MIR group had marginally, but significantly, higher glucose levels compared to controls (+15%, P<0.002), whereas glucose levels did not differ between both HTG groups (P=0.580). Thus, the increased insulin resistance in the HTG-SIR group compared to the HTG-MIR group must be viewed as a consequence of the presence of increased insulin levels only.

In conjunction with the difference in insulin resistance between the three groups, FFA levels differed significantly between the three groups as well (P=0.01): FFA levels were higher in the HTG-MIR and the HTG-SIR group compared to controls (+21% vs. controls, P=0.046 and +80% vs. controls, respectively, P=0.004) and were significantly higher in the HTG-SIR than in the HTG-MIR group (+49% vs. HTG-MIR, P=0.018). In addition, LDL-particle size differed between the three groups (P≤0.001): LDL-particle size was significantly smaller in both the HTG-MIR and HTG-SIR group compared to controls (–8 and –9%, both P≤0.001; respectively), whereas it did not differ between both HTG groups (P=0.520, Table 1).

3.3 Endothelial function
No significant differences were observed in median basal FBF between the three groups (basal FBF before 5HT 2.2 (1.6–2.9), 2.8 (2.1–3.6) and 3.6 (2.4–4.3) ml/min per 100 ml forearm tissue and basal FBF before SNP 2.3 (1.7–3.0), 2.3 (1.7–3.8) and 3.4 (2.5–4.3) ml/min per 100 ml forearm tissue for controls, HTG-MIR and HTG-SIR, respectively). Local intra-arterial infusions of 5HT and SNP did not induce significant changes in intra-arterial blood pressure and heart rate (data not shown). Therefore the FBF changes can be interpreted as local vascular effects of the vasoactive substances used [13].

5HT-induced endothelium-dependent vasodilation significantly differed between the three groups (P=0.02 and P=0.03 for low and high dose, respectively) but did not differ between controls and the HTG-MIR group (Fig. 1A). However, 5HT-induced endothelium-dependent vasodilatation was significantly lower in the HTG-SIR group than in the control group (–60 and –44% for low and high dose 5HT compared to controls, P=0.01 and P=0.008, respectively). In addition, 5HT-induced endothelium-dependent vasodilatation tended to be lower in the HTG-SIR group than in the HTG-MIR group as well (–43 and –41% for low and high dose 5HT compared to HTG-MIR, P=0.068 and P=0.10, respectively; Fig. 1A). No significant differences were observed in SNP-induced endothelium-independent vasodilation between the three groups (Fig. 1B).


Figure 1
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  		Fig. 1 (A) Endothelium-dependent vasodilation in controls, HTG-MIR and the HTG-SIR group. Data are presented as medians and corresponding interquartile ranges. Grey, white and striped bars denote endothelium-dependent vasodilation in controls, HTG-MIR and the HTG-SIR group, respectively. Endothelium-dependent vasodilation is significantly impaired in the HTG-SIR group compared to controls (–60% and –44% compared to controls on low and high dose 5HT, both P<0.01, respectively). (B) Endothelium-independent vasodilation in controls, HTG-MIR and the HTG-SIR group. Data are presented as medians and corresponding interquartile ranges. Grey, white and striped bars denote endothelium-independent vasodilation in controls, HTG-MIR and the HTG-SIR group, respectively. Endothelium-independent vasodilation did not significantly differ between controls, HTG-MIR and the HTG-SIR group.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study demonstrates that chronic HTG per se is not associated with endothelial dysfunction. In contrast, the presence of insulin resistance in chronic HTG contributes to the induction of impaired endothelium-dependent vasodilation.

Over the past years chronic hypercholesterolemia (elevated total and LDL cholesterol) has been associated with endothelial dysfunction [18]. Several studies have investigated whether chronic HTG is associated with endothelial dysfunction as well, resulting in conflicting reports: some reports did observe normal endothelial function [5,6], whereas others described the presence of impaired endothelial function in HTG [7–9]. In the current study, endothelial function did not differ between the HTG-MIR group and controls, suggesting that chronic HTG per se does not induce endothelial dysfunction. Thus, in those studies observing endothelial dysfunction in chronic HTG [7–9], it seems likely that other factors than triglycerides induced the observed endothelial dysfunction. In the report of Lewis et al. [7] patients with HTG had a significantly higher body mass index compared to the studied controls. Since body mass index has been shown to affect endothelial function [19], it may be that the observed endothelial dysfunction in the HTG group is a consequence of obesity instead of HTG. De Man et al. [8] observed impaired endothelial function in chronic HTG in conjunction with FFA elevation. Elevated circulating levels of FFA may be viewed as a result of insulin resistance [20,21] and have been shown to impair endothelium-dependent vasodilation [22,23]. Thus, it may be hypothesized that FFA elevation and not triglycerides per se were responsible for the impaired endothelial function in HTG in that study [8]. This hypothesis is further supported by unaffected endothelial function in patients with chronic HTG based on LPL deficiency [5], since insulin and FFA levels are normal in these patients [24]. In addition, Lupatelli et al. [9] reported impaired endothelial function in chronic HTG in conjunction with higher insulin levels and decreased LDL particle size. Several studies showed that both the presence of small dense LDL and insulin resistance are associated with endothelial dysfunction [10–12,25]. LDL particle size did not differ between the HTG-MIR and the HTG-SIR group in our study. In contrast, a higher insulin resistance, as represented by hyperinsulinemia and FFA elevation, was observed in conjunction with a tendency to impaired endothelium-dependent vasodilation in the HTG-SIR group compared to the HTG-MIR group, hereby proposing an important role for insulin resistance in the induction of endothelial dysfunction in chronic HTG. This hypothesis is supported by the observed positive correlation between insulin sensitivity, as expressed by HOMA-index, and endothelium-dependent vasodilation in healthy individuals and diabetics [26,27].

The underlying mechanism for the insulin resistance-induced endothelial dysfunction has not been revealed yet. The insulin resistance associated impaired endothelium-dependent vasodilation could be mediated through diminished NO bioavailability due to either increased NO degradation or decreased NO production. Increased NO degradation might occur as a result of increased circulating oxidation products [28]. Alternatively, Petrie et al. described a positive relationship between insulin sensitivity and basal vascular endothelial nitric oxide production [29], suggesting that the insulin resistance state is associated with impaired NO production. Interestingly, it has been shown that FFA elevation inhibits NO production by decreasing nitric oxide synthase in vitro [30,31]. In addition, Steinberg et al. reported that FFA elevation reduces NO production as demonstrated by a blunted leg blood flow response to NG-monomethyl-L-arginine (L-NMMA) in healthy subjects during euglycemic–hyperinsulinemic clamp with superimposed FFA elevation [32].

In conclusion, this study demonstrates that chronic HTG per se is not associated with endothelial dysfunction. In contrast, our data suggest that the presence of insulin resistance, characterized by hyperinsulinemia and FFA elevation, contributes to the induction of endothelial dysfunction in chronic HTG. This hypothesis is of potential clinical relevance, suggesting that whenever cardiovascular risk is targeted in HTG patients, one should not only focus on serum triglycerides, but also take into account insulin resistance. However, evidence for this hypothesis should be provided by prospective studies in HTG patients using insulin-sensitizing strategies as fibrates and thiazolidinediones.

Time for primary review 27 days


   Acknowledgements
 
Minka Bax, Bep Ladan-Eygenraam, Ineke Sierat, Adrie Zonneveld and Ton Vroom are thanked for expert technical assistance.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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