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Cardiovascular Research 1997 34(3):568-574; doi:10.1016/S0008-6363(97)00081-3
© 1997 by European Society of Cardiology
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Copyright © 1997, European Society of Cardiology

Dyslipidemia and endothelium-dependent relaxation in internal mammary arteries used for coronary bypass surgery

Adriaan A. Voorsa,b,c,*, Margreeth Oostergaa,c, Hendrik Buikemaa, Johan F. Mayc, Jan G. Grandjeand, Azuwerus van Buitena and Wiek H. van Gilsta

aDepartment of Clinical Pharmacology, University of Groningen, A. Deusinglaan 1, 9713AV, Groningen, Netherlands
bR&D Cardiology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, Netherlands
cDepartment of Cardiology, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, Netherlands
dDepartment of Cardiothoracic Surgery, University Hospital Groningen, Hanzeplein 1, P.O. Box 30.001, 9700 RB, Groningen, Netherlands

* Corresponding author. Tel.: +31 (50) 3632810; fax: +31 (50) 3632812; e-mail: a.a.voors@med.rug.nl

Received 20 September 1996; accepted 11 February 1997


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective:Impairment of endothelium-dependent relaxation is related to dyslipidemia and may be an early marker for atherosclerosis in angiographically smooth arteries. The aim of the present study was to relate preoperative serum lipids to endothelium-dependent relaxation in internal mammary arteries of patients undergoing coronary bypass surgery. Methods: The study group consisted of 37 patients, from whom segments of the internal mammary artery were obtained during surgery. Measurements of endothelium-dependent relaxation were performed in organ baths by adding methacholine (10 nM–10 µM). Results: All internal mammary arteries dilated in response to methacholine, ranging from 4 to 112% of the precontraction to 10 µmol phenylephrine. In a multiple regression model, increased total serum cholesterol appeared to be the best predictor for impaired endothelium-dependent relaxation. A 1 mmol increase of total cholesterol was associated with a 11.2% decrease of endothelium-dependent relaxation (P=0.006). When total cholesterol was omitted from the model, LDL-cholesterol became the best predictor of endothelium-dependent relaxation (regression coefficient 10.3%/mmol; P=0.02). No other variable was significantly associated with endothelium-dependent relaxation, and none of the preoperative variables was associated with endothelium-independent relaxation, expressed as the response to sodium nitrite (10 mM). Conclusion: Our study showed that endothelium-dependent relaxation in apparently non-diseased internal mammary arteries used for coronary bypass surgery was independently related to preoperative (LDL)-cholesterol levels.

KEYWORDS Endothelial function; Coronary artery bypass; Cholesterol; LDL-cholesterol; Human, arteries


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
The endothelium plays a pivotal role in the pathogenesis of atherosclerosis [1]. In normal conditions, endothelial cells release endothelium-derived relaxing factor (EDRF), which inhibits smooth muscle cell contraction and proliferation, platelet aggregation, and platelet or monocyte adhesion to the endothelial surface. Acetylcholine and several other substances induce vasodilation by stimulating the release of EDRF. Endothelium dysfunction is functionally characterized by a loss of the vasodilatory response to acetylcholine. In patients with and without coronary artery disease, hypercholesterolemia was found to be an independent predictor for endothelial dysfunction [2–6] and others showed that serum total cholesterol and low-density lipoprotein (LDL)-cholesterol were inversely correlated with endothelium-dependent dilation [7–9]. Impaired response to acetylcholine was related to risk factors for coronary artery disease, and seemed to occur already at an early stage of atherosclerosis in patients with angiographically smooth arteries [7].

Patients undergoing coronary bypass surgery have angiographically proven coronary artery disease, although their internal mammary arteries are usually free of atherosclerosis [10–12]. However, differences in endothelial function are already present [13], and may be related to pre-procedural serum lipid levels. The aim of the present study was to determine endothelium-dependenty relaxation in internal mammary arteries of patients undergoing coronary bypass surgery, and to relate endothelial function to preoperative serum lipids.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
2.1 Patients
The patient group consisted of 69 elective coronary bypass surgery patients, who gave written informed consent. This study conforms with the principles outlined in the Declaration of Helsinki. Patients were operated between November, 1994 and February, 1996. Since this study was part of a randomized clinical trial, a standardized anesthesia regimen was performed on all patients. During surgery, internal mammary arteries were infused with papaverine, only after segments of the arteries had been harvested for endothelial measurements. These segments were obtained from 54 patients, and evaluable measurements of endothelial function were obtained from 37 patients. Clinical characteristics of these 37 patients are presented in Table 1.


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  		Table 1 Clinical characteristics

 
2.2 Measurements of endothelial function
During coronary bypass segments of the left or right internal mammary artery were obtained as excess graft material. The segments were dissected free, cleaned of surrounding tissues, and cut into several rings (2 mm) with a sharp razor blade, while care was taken not to disrupt the integrity of the endothelium. The rings were mounted in 15 ml organ baths, containing a buffer solution of the following (Krebs) composition (mM): NaCl (120.4), KCl (5.9), CaCl2 (2.5), MgCl2 (1.2), NaH2PO4 (1.2), glucose (11.5) and NaHCO3 (25.0). The medium was continuously aerated with 95% O2/5% CO2 and kept at 37°C. The rings were connected to an isotonic displacement transducer, where they received a preload of 1.4 g [14]. They were allowed to equilibrate for 60 min, during which regular washing periods were performed. Rings were primed and checked for viability by repeated stimulation (3–4 times) with 10 µM phenylephrine and intermediate washing and stabilization periods. After the last response to phenylephrine. the rings were equilibrated until they had reached a stable contraction. The endothelium-dependent relaxation was then measured by adding cumulative doses of methacholine (10 nM–10 µM). Endothelium-independent relaxation was obtained by measuring the response to a final dose of sodium nitrite (10 mM).

2.3 Lipid measurements
From all patients, venous blood samples were drawn within 3 weeks before coronary bypass surgery after an overnight fast. Total serum cholesterol was photometrically determined using an enzymatic dye method (CHOD PAP method, Merck, Darmstadt, Germany). Triglycerides were photometrically determined using the GPO PAP method (Merck, Darmstadt, Germany). High-density lipoproteins (HDL) was prepared from whole plasma by precipitation with phosphotungstate-MgCl2, and again cholesterol was measured with the CHOD PAP method. Low-density lipoprotein (LDL)-cholesterol levels were calculated according to the Friedewald formula (LDL cholesterol = total cholesterol – HDL cholesterol – [triglycerides/2.2]) [15]. Apolipoprotein B (apo-B) was measured by turbidimetric determination using a commercial kit (Boehringer Mannheim, Almere, The Netherlands), calibrated according to the Center of Disease Control standards. From all patients we obtained evaluable measurements of total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides and apo-B.

2.4 Statistical analysis
Endothelium-dependent relaxation was defined as the maximal percentage relaxation of the precontraction to phenylephrine. Endothelium-independent relaxation was defined as the maximal percentage relaxation of the precontraction to phenylephrine. Simple linear regression (PROC REG, SAS Institute Inc., Chicago, IL, USA) was performed on endothelium-dependent and -independent relaxation for the following preoperative variables: age, sex, smoking, family history of coronary artery disease (first-degree relatives <60 years), diabetes mellitus, body mass index, systolic and diastolic blood pressure, history of hypertension, history of myocardial infarction, previous coronary revascularization procedure, time to onset of coronary artery disease, angina pectoris NYHA class, number of diseased coronary arteries, left ventricular function, total serum cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides and apo-B. All variables were then introduced in a multiple regression model, using stepwise selection with an entry criterion of P<0.15. The appropriateness of the number of variables finally included in the model was checked by Mallow's C(p) [16], and collinearity between variables in the final model was checked according to recommendations by Belsley et al. [17]. Data are presented as means±standard deviation. A P-value of <0.05 was considered as statistically significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
All 69 patients underwent coronary bypass surgery between November, 1994 and February, 1996. For surgical reasons, no excess graft material was obtained from 15 patients. From 17 patients, no responses were evoked during the start-up phase. Of the remaining 37 patients, measurements of endothelium-dependent and -independent relaxation were performed. We found no differences in baseline characteristics between the 37 patients with and the 17 patients without evaluable endothelial function, except for body mass index. Body mass index of patients without evaluable endothelial function was significantly lower (25.5 versus 27.6, P=0.007). The use of preoperative cardiovascular medication was not statistically significant between the groups. However, the patients from this study were randomized 2 weeks before surgery to captopril or quinapril or placebo. Since during this analysis the study was blinded, an independent outside investigator performed a grouped analysis on the influence of the angiotensin-converting enzyme inhibitors on endothelium-dependent relaxation. No statistically significant differences were found in endothelium-dependent relaxation between the angiotensin-converting enzyme inhibitors and placebo. The mean time between harvesting of the internal mammary arteries by the surgeon and the actual measurement of endothelium-dependent relaxation was 164 (±12.5) min. No statistically significant correlation between the time delay and the endothelium-dependent relaxations was found. The patients from whom no material was obtained during surgery were significantly older (66.5 years versus 60.0 years, P=0.007), while no other variables were significantly different between these groups.

Mean endothelium-dependent relaxation to methacholine of the remaining 37 patients was 40.4% (±24.4%, range 4.1–112%) of the precontraction to phenylephrine. Mean endothelium-independent relaxation to sodium nitrite was 97.3% (±37.3%, range 24–178%). Univariately analyzed, an increase of total cholesterol of 1 mmol/l was associated with a statistically significant reduction of endothelium-dependent relaxation by 11% of the precontraction response to phenylephrine. Furthermore, 18% of the variability in endothelium-dependent relaxation was accounted for by variations in total serum cholesterol (P=0.008) (Fig. 1). Similarly, a 1 mmol/l increase in LDL-cholesterol resulted in a statistically significant reduction of endothelium-dependent relaxation by 12%, and 17% of the variability in endothelium-dependent relaxation was accounted for by variations in LDL-cholesterol (P=0.01) (Fig. 2). Other lipids were not found to be significantly associated with endothelium-dependent relaxation, as well as the preoperative variables described in Table 1. Endothelium-independent relaxation was not associated with any of the preoperative lipids (Table 2) or with any of the other preoperative variables.


Figure 1
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  		Fig. 1 Total serum cholesterol and endothelium-dependent relaxation of internal mammary arteries used for coronary bypass surgery in 37 patients. Displayed is a scatter plot of total serum cholesterol and the maximal dilation to cumulative doses of methacholine (ME, 10 nM–10 µM), expressed as percent dilation from precontraction to 10 µmol phenylephrine (PE).

 

Figure 2
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  		Fig. 2 Serum low-density lipoprotein (LDL)-cholesterol and endothelium-dependent relaxation of internal mammary arteries used for coronary bypass surgery in 37 patients. Displayed is a scatter plot of total serum cholesterol and the maximal dilation to cumulative doses of methacholine (ME, 10 nM–10 µM), expressed as percent dilation from precontraction to 10 µmol phenylephrine (PE).

 

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  		Table 2 Results of univariate regression analysis between preoperative serum lipids and endothelium-dependent and -independent relaxation

 
In a multiple regression model in which all preoperative variables were included, increased total serum cholesterol was the best predictor of impaired endothelium-dependent relaxation. A 1 mmol increase of total cholesterol was again associated with a 11% decrease of endothelium-dependent relaxation (Table 3). These results were adjusted for other preoperative variables, although they were not significantly associated with endothelium-dependent relaxation. The final model as presented in Table 3 accounted for 44% of the variations in endothelium-dependent relaxation. In an additional analysis, total cholesterol was omitted from the model. Without total cholesterol, LDL-cholesterol became the best predictor of endothelium-dependent relaxation (Table 4). Again, none of the preoperative variables was associated with endothelium-independent relaxation. The final model as presented in Table 4 accounted for 34% of the variations in endothelium-dependent relaxation.


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  		Table 3 Results of multiple regression analysis between all preoperative variables and endothelium dependent relaxation. All variables were entered and the inclusion criterion for the model was P<0.15

 

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  		Table 4 Results of multiple regression analysis between all preoperative variables, except for total cholesterol, and endothelium-dependent relaxation

 
Since both endothelium-dependent and -independent relaxation were presented as a percentage of the precontraction to phenylephrine, we also checked for the influence of all preoperative variables on the size of the precontraction. The mean precontraction to phenylephrine was 315 µm (±157, range 106–805 µm). Only preoperative diastolic blood pressure was significantly associated with the precontraction to phenyleprine (regression coefficient = –7.5 µm/mmHg, P=0.007). Preoperative serum lipid levels were not associated with the pre contraction to phenylephrine (Table 5).


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  		Table 5 Association between preoperative serum lipid levels and precontraction to 10 µmol phenylephrine

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
Endothelial dysfunction provides a reasonable pathophysiologic explanation for the deleterious effects of various risk factors on coronary artery disease. Previous studies showed that hypercholesterolemia was associated with impaired endothelium-dependent relaxation in atherosclerotic coronary arteries [9, 18–20], but also in angiographically smooth coronary arteries [2, 7]. In the brachial artery, usually free of atherosclerosis, hypercholesterolemia was also associated with endothelium-dependent relaxation [4–6, 8, 21]. Although coronary arteries of patients undergoing coronary bypass surgery are diseased, most of the internal mammary arteries used for coronary bypass graft are free of atherosclerotic disease at the time of surgery [10–12]. Although some studies assessed endothelium-dependent relaxation in internal mammary arteries [13, 22, 23], assessment of the relationship between preoperative lipid levels and endothelium-dependent relaxation in internal mammary arteries has, to our knowledge, not been reported before. In our study with probably non-atherosclerotic internal mammary arteries used for coronary bypass surgery, we found large differences in endothelium-dependent relaxation, and preoperative (LDL)-cholesterol levels were the best predictor of the differences observed. It might be interesting to know if endothelial function at the time of surgery influences the clinical results. However, whether endothelial function of internal mammary arteries at the time of surgery can determine the clinical short- and long-term outcome after coronary bypass surgery remains to be established in follow-up studies.

The final model, in which all preoperative variables were entered and only variables with a P-value of <0.15 were included, explained 43% of the variations in endothelium-dependent relaxation. The other 57% may be accounted for by both patient-related and procedural-related factors. Patient-related factors might have been a large number of variables which we included in the model, but did not reach the P-level for inclusion in the model. Also, there may have been additional factors which we did not obtain. For example, the time that the patients refrained from smoking before surgery might be important, and maybe we should have performed additional blood pressure measurements to obtain a more valid value. We tried to avoid large differences in procedure-related factors by using standardized protocols. However, although we did not find any procedure-related factors which could explain variations in endothelium-dependent relaxations, such as differences between surgeons, there may have been factors which we did not observe.

The deleterious effects of (LDL)-cholesterol on endothelium-dependent relaxation are probably related to a direct relation between LDL-cholesterol and the bioavailability of EDRF. Flavahan [24] concluded that a diminished bioavailability of EDRF caused by hypercholesterolemia did not result from a nonspecific impairment in the synthesis or release of EDRF, but probably resulted from an impairment of a signal transduction process in the endothelium. Another possible explanation for the association between cholesterol and endothelium-dependent relaxation is increased oxidative stress. The increased superoxide anion production in hypercholesterolemic patients [25, 26] and the oxidative modification of LDL-cholesterol may lead to impaired EDRF action through several mechanisms [27].

Our in vitro measurement of endothelium-dependent relaxation is different from other studies. Measurement of endothelium-dependent relaxation in coronary arteries is usually performed by infusion of several doses of acetylcholine into the coronary arteries during a coronary angiography procedure. This method is also used for measurements in the brachial and/or femoral artery while non-invasive measurements of endothelium-dependent relaxation are done with forearm blood-flow measurements as a reaction to several stimuli. In our method, the arteries were exposed to Krebs' solution instead of blood. The effects on methacholine-stimulated relaxation could therefore only be related to the (LDL)-cholesterol already present in the internal mammary arteries. Also, acute effects of other risk factors on endothelium-dependent relaxation cannot be measured. This might explain why smoking, in contrast with in vivo studies, did not appear to influence endothelium-dependent relaxation in our method. A large number of animal studies, using the same method as we did, showed that cholesterol-fed animals had impaired endothelium-dependent relaxations, compared to control animals. The fact that cholesterol can influence endothelium-dependent relaxations in the absence of blood might be explained by the findings of Kappagoda et al. [28]. They treated rabbits with a cholesterol-rich diet for 3 weeks. In the next 4 weeks they were given a standard rabbit diet. In vitro measurements after 7 weeks still showed impaired endothelium-dependent relaxations of aortic rings from the cholesterol-fed rabbits, compared to control animals. Moreover, they measured cholesterol content in the same aortas, and found a significantly increased aortic content in the cholesterol-fed animals. Thus, cholesterol is taken up by the arteries and may therefore influence arterial functional performance in the absence of blood.

Although our method is similar to organ bath experiments used by others, some differences may have influenced the results. First of all, we used methacholine instead of acetylcholine as the endothelium-dependent probe. Both methacholine and acetylcholine stimulate the cholinergic receptor; however, since methacholine is more stable than acetylcholine, we decided to use methacholine. Another difference with studies of the present type is the use of isotonic instead of isometric measurements. An increasing number of investigators nowadays value the more physiological conditions of setups such as the pressure perfusion chamber. This relatively new technique extends the study of arteries in vitro by allowing cannulated vessels to be examined under more physiological conditions, and marked differences have been observed in the responses of pressurized arteries and wire-mounted arteries in the wire myograph. Apart from a marked difference in vascular geometry between wire-mounted vessels and pressurized vessels, vasoconstriction of pressurized vessels as the response elicited in vivo (i.e., a change in vessel lumen diameter) is considered to be of great importance [29]. In line with such ideas, we think that the isotonic setup (with the freedom to change vessel diameter) is a more physiological approach to study isolated vessels than the isometric setup.

Despite its in vitro nature, our method also has some advantages. The degree of relaxation of an artery may depend on differences in arterial compliance. In our method, we related the endothelium-dependent relaxation to the pre-contraction response, and could therefore elute the possible confounding effect of the observed differences in distensibility. An interesting finding was that a blunted response to the precontraction with phenylephrine was significantly associated with an increased diastolic blood pressure, indicating a decreased vascular compliance in patients with increased diastolic blood pressure.

From the 69 patients included, we obtained excess graft material from 54 patients. In these 54 patients, no responses were evoked during the start-up phase in 17 patients, and therefore no evaluable measurements of endothelium-dependent relaxations were obtained from 17 of the 54 patients. Increased age was significantly associated with the availability of material, indicating the surgical difficulties of preparing arteries in elderly patients. Moreover, more venous grafts were used in elderly patients, and since we only performed measurements in internal mammary arteries, less material was available for measurement. The 17 patients from whom material was obtained, but in whom no evaluable measurements were performed, had a significantly lower body mass index. Normally, patients with a lower body mass index have smaller internal mammary arteries. Also, internal mammary artery reactivity tends to decrease with vessel size. Since we only evaluated endothelium-dependent relaxations when precontraction was >100 µM, this might explain why the mean body mass index was lower in patients without evaluable measurements of endothelium-dependent relaxation.

Thus, our in vitro study showed that in apparently non-diseased internal mammary arteries used for coronary bypass surgery, large differences in endothelium-dependent relaxation could be observed. These differences in endothelium-dependent relaxation were independently related to preoperative (LDL)-cholesterol levels, while endothelium-independent relaxation was not related to any preoperative variable. Whether endothelium-dependent relaxation can predict clinical follow-up after coronary bypass surgery remains to be established.

Time for primary review 31 days.


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

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