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Ann Thorac Surg 2002;73:1860-1865
© 2002 The Society of Thoracic Surgeons

Original article: cardiovascular

Effects of cerivastatin on vascular function of human radial and left internal thoracic arteries

Koki Nakamura, MDa, Sharif Al-Ruzzeh, FRCSa, Adrian H. Chester, PhDa, Ilona Schmidt, MDa, Mahmoud Barbir, FRCPa, Magdi H. Yacoub, FRCSa, Mohamed Amrani, FETCS*a

a National Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, United Kingdom

Accepted for publication February 2, 2002.

* Address reprint requests to Mr Amrani, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK
e-mail: mr.amrani{at}rbh.nthames.nhs.uk


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 References
 
Background. Statins may enhance vascular function independently of effects on cholesterol. This study investigated the ability of statins to modulate the vascular recovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internal thoracic artery were obtained during coronary artery bypass grafting. The specimens were divided into vascular rings, which were incubated in the absence or presence of cerivastatin (10-6 mol/L) for either 2 or 24 hours. Using an organ bath technique, endothelial function was examined using acetylcholine (10-9 to 10-5 mol/L) after contraction by 3x10-8 mol/L of endothelin-1.

Results. Time-related endothelial dysfunction was shown in the control group of radial artery but not in the cerivastatin group: maximal endothelium-dependent vasodilation in the control and cerivastatin groups were 56.8% ± 10.2% and 65.9% ± 10.1% at 2 hours and 39.4% ± 4.7% and 68.4% ± 5.0% (p < 0.01, vs control) at 24 hours, respectively. On the other hand, in the left internal thoracic artery, those in the control and cerivastatin groups were 38.3% ± 8.2% and 45.0% ± 5.5% at 2 hours and 38.1% ± 8.2% and 56.5% ± 8.8% at 24 hours, respectively (NS).

Conclusions. In radial artery, cerivastatin significantly preserved endothelium-dependent vasodilation, which diminished with time in the control group. This could have very important implications in the clinical practice of coronary artery bypass grafting.


   Introduction
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 Abstract
 Introduction
Material and methods
 Results
 Comment
 References
 
Coronary artery bypass grafting (CABG) using the radial artery (RA) was first proposed and performed in 1971 [1]. It was subsequently abandoned because of the high rate of graft failure, which was mainly caused by spasm. Recently, the use of calcium channel blockers, minimization of trauma in harvesting, and use of special methods to prepare the RA has allowed this technique to become a favorable means of treatment in coronary artery surgery [2–6].

Keeping pace with advancements in coronary surgery, medical treatment for ischemic heart disease has also developed. Indeed, one of the most important developments is the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are collectively called statins. Statins are lipid-lowering drugs that have recently been shown to provide many other benefits [7–18]. Statins inhibit the progress of aging-related diseases in the short and long term. Acutely, they produce endothelium-dependent vasodilation [7–9] and inhibition of smooth muscle cell proliferation [10], in addition to their antioxidant [11] and antiinflammatory [12, 13] effects. In the longer term they have been shown to exhibit an antisclerotic effect in vivo that has had a major impact on the reduction of graft failure [14]. However, in vitro effects of statins on the vascular function of arterial grafts including RA and internal thoracic artery (ITA) have not been studied.

The aim of this study was to examine the in vitro effects of cerivastatin on the vascular function of human RA and ITA grafts used for CABG in an attempt to determine how the beneficial effects of cerivastatin on graft function are mediated.


   Material and methods
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 Abstract
 Introduction
 Material and methods
Results
 Comment
 References
 
Specimen collection
Specimens of the distal segments of the RA and the left internal thoracic artery (LITA) were obtained from patients who underwent isolated CABG at Harefield Hospital between May 2001 and August 2001. Ethical approval for the study was obtained for the hospital ethics board and all patients gave written consent to participate in the study. After harvest of the RA, approximately 1 cm of the distal segment was taken as a specimen before flushing with any preparatory solution. Similarly, 1 cm of the distal segment of the LITA was also taken as a specimen before spraying it with vasodilators. During the harvesting procedure, no systemic vasodilators were given. The collected specimens were kept in a 199 tissue culture medium (Sigma, Dorset, UK) at 4°C and were divided into vascular rings within 30 minutes of collection.

Grouping and preparation for organ baths
On processing the specimens, excess connective tissue was removed using a dissecting microscope followed by dividing each specimen into 4 pieces, approximately 3 mm each. Specimens were divided into following eight groups: (1) [LITA 2 hours/cerivastatin]: vascular rings were incubated with 10-6 mol/L cerivastatin for 2 hours (n = 9). (2) [LITA 2 hours/control]: incubated without cerivastatin for 2 hours (n = 9). (3) [LITA 24 hours/cerivastatin]: incubated with 10-6 mol/L cerivastatin for 24 hours (n = 9). (4) [LITA 24 hours/control]: incubated without cerivastatin for 24 hours (n = 9). (5) [RA 2 hours/cerivastatin]: incubated with 10-6 mol/L cerivastatin for 2 hours (n = 6). (6) [RA 2 hours/control]: incubated without cerivastatin for 2 hours (n = 6). (7) [RA 24 hours/cerivastatin]: incubated with 10-6 mol/L cerivastatin for 24 hours (n = 6). (8) [RA 24 hours/control]: incubated without cerivastatin for 24 hours (n = 6).

As the subgroup within the control and cerivastatin groups were necessarily paired, the sources of the rings were exactly same in the two groups.

For 2 hours of incubation, the [LITA 2 hours] and [RA 2 hours] specimens were immediately mounted on two L-shaped metal hooks in isolated organ baths without stretching. Vascular rings in the cerivastatin groups were incubated in organ baths with 10-6 mol/L cerivastatin, whereas those in the control groups were incubated without cerivastatin. The organ baths contained modified Tyrode’s solution, which is composed of the following (in mmol/L): NaCl 136.9, NaHCO311.9, KCl 2.7, NaH2PO4 0.4, MgCl2 2.5, CaCl2 2.5, glucose 11.1, and disodiumethylenediaminetetraacetic acid 0.04. The solution was continuously gased with 95% O2 and 5% CO2 at 37°C. In each organ bath, one hook was attached to a force-displacement transducer, which was fixed to a Grass 7D polygraph (Grass Instruments, Quincy, MA), which monitored and recorded changes in vessel wall tension. The other hook was fixed to a screw gauge, which was used to stretch the vessel segments.

For 24 hours of incubation, the [LITA 24 hours] and [RA 24 hours] specimens were incubated in Dulbecco’s modified Eagle’s medium (DMEM, D6046; Sigma) containing penicillin (100 U/mL), streptomycin (100 µg/mL), L-glutamine (2 mmol/L), and 15% heat–inactivated fetal bovine serum. Vascular rings in the cerivastatin group were incubated with 10-6 mol/L cerivastatin, whereas those in the control were incubated without cerivastatin. The rings were left in an incubator for 24 hours at 37°C. These incubation conditions have no significant effect on the viability of vessel segments.

Ular function studies
After incubation with or without cerivastatin, vascular function studies were carried out as we previously reported [19, 20]. An initial tension of 80 mN and 50 mN was applied to each vascular ring of RA and LITA, respectively. They were then relaxed out and were allowed to equilibrate for 30 minutes. After that, the rings were challenged with 90 mmol/L potassium chloride (KCl) solution. The bath was washed out when the response reached a plateau followed by a return to base line. After the washout, 10-6 mol/L cerivastatin was supplemented in the bath for the cerivastatin group, which allowed us to keep the same concentration of cerivastatin in the organ baths throughout the experiment. This series of procedures was repeated again and the response to KCl the second time was recorded. When reequilibration was achieved, each vascular ring was challenged with 3x10-8 mol/L endothelin-1 (ET-1) (Calbiochem, Nottingham, UK). This concentration of ET-1 was determined by a pilot study that aimed to determine the minimal dose needed to achieve a stable plateau (data not shown). After a stable plateau of vasoconstriction, acetylcholine (Ach; 10-9 to 10-5 mol/L) was added to the bath in a cumulative fashion in 1/2log10 units. The response to each concentration was allowed to reach a plateau before the addition of the next concentration of Ach. Finally, 10-5 mol/L sodium nitroprusside (SNP) was added to the bath to ensure maximal relaxation.

Data analysis
All data are expressed as mean ± standard error of the mean (SEM). Results for vasodilation were expressed as a percentage contraction by ET-1. For analysis of the responses to Ach, median effective concentration (EC50) was calculated. The values of EC50 were transformed into geometric means (pD2 = -log10EC50). For comparisons between the two groups, data were analyzed using Student’s t test if normal distribution was confirmed by the F test; otherwise, the Mann-Whitney U test was applied. One-factor analysis of variance was used for comparing multiple groups, and Fisher’s Protected Least Significant Difference (Fisher’s PLSD) was used for the post hoc test. Results were considered significant with p values of less than 0.05.


   Results
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 Abstract
 Introduction
 Material and methods
 Results
Comment
 References
 
Patient characteristics
A total of 13 patients (11 men and 2 women) participated in this study. The average age was 61.6 ± 2.7 years (range 44 to 76 years). An analysis of the preoperative risk factors, serum lipid profile, and medications used on admission is shown in Table 1. Eight of 13 patients provided RA and LITA specimens; 1 patient provided RA specimens only; and 4 patients provided LITA specimens only. With regard to the RA, 3 of 9 patients contributed to both 2 hours and 24 hours of incubation by providing four vascular rings, and 6 of 12 patients contributed to both incubation periods in the LITA. Segments were paired so that each patient provided segments for the cerivastatin and control groups.


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  		Table 1. Patient Characteristics

 
Vascular function studies
In both arteries, vascular contractions by KCl and ET-1 were not statistically significantly different between the cerivastatin and control groups, although the values were slightly greater in the control group. Those values were not significantly different between 2 hours and 24 hours of incubation. As expected, the contraction was significantly greater in RA than in LITA groups (Table 2).


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  		Table 2. Vasocontractive Response to KC1 and ET-1

 
There were no significant differences of endothelium-dependent vasodilation between the cerivastatin and control groups in [LITA 2 hours] and [RA 2 hours] (Fig 1A and 1B). In the [LITA 24 hours], there was a trend toward higher endothelium-dependant vasodilation in the cerivastatin group, although the differences were not significant (Fig 1C). However, in the [RA 24 hours], endothelium-dependant vasodilation was significantly higher in the cerivastatin group than in the control (Fig 1D).



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  		Fig 1. Vasodilatation by acetylcholine. (A) Left internal thoracic artery 2 hours after incubation. (B) Radial artery 2 hours after incubation. (C) Left internal thoracic artery 24 hours after incubation. (D) Radial artery 24 hours after incubation. Open circles and filled circles represent control and cerivastatin groups, respectively. Circles and bars represent mean ± standard error of the mean (% of contraction by ET-1). (ET -1 = endothelin-1; #p< 0.01, vs. control group.)

 
As shown in Table 3, maximal vasodilation by Ach did not drop between 2 and 24 hours of incubation except in the control group of RA (56.8% ± 10.2% to 39.4% ± 4.7%), although this was not statistically significant. Consequently, in [RA 24 hours], the maximal value of endothelium-dependent vasodilation was significantly higher in the cerivastatin group (68.4% ± 5.0%) than in the control (39.4% ± 4.7%, p < 0.01 by Student’s t test and p < 0.05 by one-factor analysis of variance). Only in the control group of LITA did the pD2 value significantly drop from 7.21 ± 0.12 at 2 hours to 6.78 ± 0.15 at 24 hours (p < 0.05). However, this effect was reversed in the cerivastatin-treated group. On the other hand, there were no significant differences between all the groups regarding the response to sodium nitroprusside (Table 3).


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  		Table 3. Vasodilatative at Response to Ach and SNP

 

   Comment
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
References
 
This study demonstrated that endothelium-dependent vasodilation of the RA after 24 hours of in vitro incubation with cerivastatin was significantly higher than the control group. In the same way, a similar trend of endothelium-dependent vasodilation was noticed in the LITA group after 24 hours of in vitro incubation with cerivastatin, although the difference was not statistically significant. On the other hand, effect on the pD2 values showed that cerivastatin preserved the response of acetylcholine in the LITA after 24 hours of incubation. The difference in the action of cerivastatin between the two blood vessels may be due to variation between the expression and function of either endothelial nitric oxide synthase (eNOS) or muscarine receptors in each blood vessel. Further experiments using different stimulators of nitric oxide (NO) release would clarify this issue. Both arteries RA and LITA did not show any significant differences of endothelium-dependent vasodilation after 2 hours of in vitro incubation with cerivastatin.

Cerivastatin is an entirely synthetic and enantiomerically pure HMG-CoA reductase inhibitor [16–18]. It has been reported that cerivastatin enhanced eNOS protein expression and NO release resulting in preserved vasodilation [7–11, 13]. Endothelium-dependent vasodilation is very important in inhibiting the graft spasm and ensuring a satisfactory blood flow, especially in early period after CABG. The ability of cerivastatin to protect the endothelium could have important applications in clinical practice, possibly by the administration of statins to patients in the early postoperative period. Clinically, oral administration of cerivastatin is started with 100 mg initially and could be increased up to 300 mg. It was reported that maximal plasma concentration of cerivastatin was 2.27 to 2.88 µg/L after 200 mg of cerivastatin administration in healthy male volunteers [18]. Therefore, the concentration of cerivastatin we used in this study (1 µg/L) can be considered to be clinically relevant.

The RA and the LITA have been shown to have different biological characteristics [19–21]. That is RA is a thick-walled muscular artery with a mean width of the media reported to be approximately 500 µm, compared with 300 µm for the ITA [21, 22]. He and Yang [23] classified all arterial grafts into the following three types: type I, somatic arteries; type II, splachnic arteries; and type III, limb arteries. Type II and III arteries are more spastic than type I arteries. According to this classification, the RA is a type III arteries and is more spastic than type I arteries, such as ITA. In addition, Chardigny and colleagues [24] showed that the prostacyclin (PGI2) basal production was greater in the ITA than in the RA, concluding that antispastic drugs were more indicated in case of using the RA as a conduit. We speculate that the regulation of nitric oxide synthase (NOS) may also differ between LITA (type I) and RA (type III). Our findings suggested that the thicker walled vessel was sensitive to reduction in the maximal effects mediated by NO, whereas the thinner wall artery only showed reductions in potency with time.

Regarding the duration of the incubation, cerivastatin enhanced endothelium-dependent vasodilation after 24 hours of in vitro incubation, but not after 2 hours. It has been shown that 6 hours was the shortest duration of in vitro incubation with cerivastatin [11]. It was reported that eNOS mRNA was upregulated in rat aortic rings after 6 hours of incubation with cerivastatin [11]. In another study, in vivo cerivastatin reduced the [14C] cholesterol content in the liver by 80%, 2 hours after drug administration [16]. Although it was initially difficult to determine the optimal incubation period, we decided on periods of 2 and 24 hours to look for immediate effects mediated by cerivastatin and those associated with changes in gene expression and protein synthesis [10, 11, 13]. In the present study, different buffers were used among 2 and 24 hours of incubation: modified Tyrode’s solution and Dulbecco’s modified Eagle’s medium with antibiotics, L-glutamine and fetal borine serum, respectively. We think that this difference was a minor issue and was unlikely to have influenced the results, as the responses to KCl, ET-1, and sodium nitroprusside were not significantly different between 2 and 24 hours of incubation in all groups.

As time-related changes, maximal vasodilation by Ach dropped from 56.8% ± 10.2% to 39.4% ± 4.7% in the control group of RA between 2 hours and 24 hours of incubation; however, it was unchanged in the cerivastatin group. In addition, contraction by ET-1 did not decrease with time in both groups. Consequently, the beneficial effect of cerivastatin on endothelium-dependent vasodilation might be due to preserving the endothelium rather than inducing additional effects in the NOS. On the other hand, in the LITA, such time-related reduction of endothelium-dependent vasodilation was marked in the pD2of the control group of LITA. Possible mechanism of endothelial deterioration could be oxidative stress, inflammatory change, and reduction of eNOS protein and mRNA [11–13, 25]. It also remains unclear why cerivastatin did not have any effect after 2 hours of incubation. However, we think that a longer period may be necessary for the translation process of mRNA to the protein eNOS; furthermore, time-related endothelial dysfunction might be very little during 2 hours of incubation. Another possible explanation could be that the membrane-permeability of cerivastatin in nonhepatic tissue is low because of its hydrophilicity [16].

In conclusion, the in vitro incubation of radial artery with cerivastatin for 24 hours enhanced endothelium-dependent vasodilation. This could have very important implications and applications in the clinical practice of coronary surgery.


   References
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 Abstract
 Introduction
 Material and methods
 Results
 Comment
 References
 

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