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

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Effects of Cerivastatin on Vascular Function of Human Radial and Left Internal Thoracic Arteries Koki Nakamura, MD, Sharif Al-Ruzzeh, FRCS, Adrian H. Chester, PhD, Ilona Schmidt, MD, Mahmoud Barbir, FRCP, Magdi H. Yacoub, FRCS, and Mohamed Amrani, FETCS National Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, United Kingdom Background. Statins may enhance vascular function independently of effects on cholesterol. This study inves- tigated 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 vascu- lar rings, which were incubated in the absence or pres- ence 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 310 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 va- sodilation 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, respec- tively (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. (Ann Thorac Surg 2002;73:1860 –5) © 2002 by The Society of Thoracic Surgeons C oronary artery bypass grafting (CABG) using the radial artery (RA) was first proposed and per- formed in 1971 [1]. It was subsequently abandoned be- cause 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 develop- ments is the use of 3-hydroxy-3-methylglutaryl coen- zyme 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 vasodila- tion [7–9] and inhibition of smooth muscle cell prolifer- ation [10], in addition to their antioxidant [11] and anti- inflammatory [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 Specimen Collection Specimens of the distal segments of the RA and the left internal thoracic artery (LITA) were obtained from pa- tients who underwent isolated CABG at Harefield Hos- pital between May 2001 and August 2001. Ethical ap- proval 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. Accepted for publication Feb 2, 2002. Address reprint requests to Mr Amrani, Harefield Hospital, Harefield, Middlesex UB9 6JH, UK; e-mail: [email protected]. © 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00 Published by Elsevier Science Inc PII S0003-4975(02)03498-7

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

Effects of Cerivastatin on Vascular Function ofHuman Radial and Left Internal Thoracic ArteriesKoki Nakamura, MD, Sharif Al-Ruzzeh, FRCS, Adrian H. Chester, PhD,Ilona Schmidt, MD, Mahmoud Barbir, FRCP, Magdi H. Yacoub, FRCS, andMohamed Amrani, FETCSNational Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, United Kingdom

Background. Statins may enhance vascular functionindependently of effects on cholesterol. This study inves-tigated the ability of statins to modulate the vascularrecovery of arteries used as coronary bypass grafts.

Methods. Specimens of radial artery and left internalthoracic artery were obtained during coronary arterybypass grafting. The specimens were divided into vascu-lar rings, which were incubated in the absence or pres-ence of cerivastatin (10�6 mol/L) for either 2 or 24 hours.Using an organ bath technique, endothelial function wasexamined using acetylcholine (10�9 to 10�5 mol/L) aftercontraction by 3�10�8 mol/L of endothelin-1.

Results. Time-related endothelial dysfunction wasshown in the control group of radial artery but not in thecerivastatin group: maximal endothelium-dependent va-

sodilation in the control and cerivastatin groups were56.8% � 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 internalthoracic artery, those in the control and cerivastatingroups were 38.3% � 8.2% and 45.0% � 5.5% at 2 hoursand 38.1% � 8.2% and 56.5% � 8.8% at 24 hours, respec-tively (NS).

Conclusions. In radial artery, cerivastatin significantlypreserved endothelium-dependent vasodilation, whichdiminished with time in the control group. This couldhave very important implications in the clinical practiceof coronary artery bypass grafting.

(Ann Thorac Surg 2002;73:1860–5)© 2002 by The Society of Thoracic Surgeons

Coronary artery bypass grafting (CABG) using theradial artery (RA) was first proposed and per-

formed in 1971 [1]. It was subsequently abandoned be-cause of the high rate of graft failure, which was mainlycaused by spasm. Recently, the use of calcium channelblockers, minimization of trauma in harvesting, and useof special methods to prepare the RA has allowed thistechnique to become a favorable means of treatment incoronary artery surgery [2–6].

Keeping pace with advancements in coronary surgery,medical treatment for ischemic heart disease has alsodeveloped. Indeed, one of the most important develop-ments is the use of 3-hydroxy-3-methylglutaryl coen-zyme A (HMG-CoA) reductase inhibitors, which arecollectively called statins. Statins are lipid-loweringdrugs that have recently been shown to provide manyother benefits [7–18]. Statins inhibit the progress ofaging-related diseases in the short and long term.Acutely, they produce endothelium-dependent vasodila-tion [7–9] and inhibition of smooth muscle cell prolifer-ation [10], in addition to their antioxidant [11] and anti-inflammatory [12, 13] effects. In the longer term they havebeen shown to exhibit an antisclerotic effect in vivo thathas had a major impact on the reduction of graft failure

[14]. However, in vitro effects of statins on the vascularfunction of arterial grafts including RA and internalthoracic artery (ITA) have not been studied.

The aim of this study was to examine the in vitro effectsof cerivastatin on the vascular function of human RA andITA grafts used for CABG in an attempt to determinehow the beneficial effects of cerivastatin on graft functionare mediated.

Material and Methods

Specimen CollectionSpecimens of the distal segments of the RA and the leftinternal thoracic artery (LITA) were obtained from pa-tients who underwent isolated CABG at Harefield Hos-pital between May 2001 and August 2001. Ethical ap-proval for the study was obtained for the hospital ethicsboard and all patients gave written consent to participatein the study. After harvest of the RA, approximately 1 cmof the distal segment was taken as a specimen beforeflushing with any preparatory solution. Similarly, 1 cm ofthe distal segment of the LITA was also taken as aspecimen before spraying it with vasodilators. During theharvesting procedure, no systemic vasodilators weregiven. The collected specimens were kept in a 199 tissueculture medium (Sigma, Dorset, UK) at 4°C and weredivided into vascular rings within 30 minutes ofcollection.

Accepted for publication Feb 2, 2002.

Address reprint requests to Mr Amrani, Harefield Hospital, Harefield,Middlesex UB9 6JH, UK; e-mail: [email protected].

© 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00Published by Elsevier Science Inc PII S0003-4975(02)03498-7

Grouping and Preparation For Organ BathsOn processing the specimens, excess connective tissuewas removed using a dissecting microscope followed bydividing each specimen into 4 pieces, approximately3 mm each. Specimens were divided into following eightgroups: (1) [LITA 2 hours/cerivastatin]: vascular ringswere incubated with 10�6 mol/L cerivastatin for 2 hours(n � 9). (2) [LITA 2 hours/control]: incubated withoutcerivastatin for 2 hours (n � 9). (3) [LITA 24 hours/cerivastatin]: incubated with 10�6 mol/L cerivastatin for24 hours (n � 9). (4) [LITA 24 hours/control]: incubatedwithout cerivastatin for 24 hours (n � 9). (5) [RA 2hours/cerivastatin]: incubated with 10�6 mol/L cerivasta-tin for 2 hours (n � 6). (6) [RA 2 hours/control]: incubatedwithout cerivastatin for 2 hours (n � 6). (7) [RA 24hours/cerivastatin]: incubated with 10�6 mol/L cerivasta-tin 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 cerivastatingroups were necessarily paired, the sources of the ringswere exactly same in the two groups.

For 2 hours of incubation, the [LITA 2 hours] and [RA2 hours] specimens were immediately mounted on twoL-shaped metal hooks in isolated organ baths withoutstretching. Vascular rings in the cerivastatin groups wereincubated in organ baths with 10�6 mol/L cerivastatin,whereas those in the control groups were incubatedwithout cerivastatin. The organ baths contained modifiedTyrode’s solution, which is composed of the following (inmmol/L): NaCl 136.9, NaHCO311.9, KCl 2.7, NaH2PO4 0.4,MgCl2 2.5, CaCl2 2.5, glucose 11.1, and disodiumethyl-enediaminetetraacetic acid 0.04. The solution was contin-uously gased with 95% O2 and 5% CO2 at 37°C. In eachorgan bath, one hook was attached to a force-displace-ment transducer, which was fixed to a Grass 7D poly-graph (Grass Instruments, Quincy, MA), which moni-tored and recorded changes in vessel wall tension. Theother hook was fixed to a screw gauge, which was used tostretch the vessel segments.

For 24 hours of incubation, the [LITA 24 hours] and [RA24 hours] specimens were incubated in Dulbecco’s mod-ified Eagle’s medium (DMEM, D6046; Sigma) containingpenicillin (100 U/mL), streptomycin (100 �g/mL), L-glutamine (2 mmol/L), and 15% heat–inactivated fetalbovine serum. Vascular rings in the cerivastatin groupwere incubated with 10�6 mol/L cerivastatin, whereasthose 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 onthe viability of vessel segments.

Ular Function StudiesAfter incubation with or without cerivastatin, vascularfunction studies were carried out as we previously re-ported [19, 20]. An initial tension of 80 mN and 50 mNwas applied to each vascular ring of RA and LITA,respectively. They were then relaxed out and were al-lowed to equilibrate for 30 minutes. After that, the ringswere challenged with 90 mmol/L potassium chloride

(KCl) solution. The bath was washed out when theresponse reached a plateau followed by a return to baseline. After the washout, 10�6 mol/L cerivastatin wassupplemented in the bath for the cerivastatin group,which allowed us to keep the same concentration ofcerivastatin in the organ baths throughout the experi-ment. This series of procedures was repeated again andthe response to KCl the second time was recorded. Whenreequilibration was achieved, each vascular ring waschallenged with 3�10�8 mol/L endothelin-1 (ET-1) (Cal-biochem, Nottingham, UK). This concentration of ET-1was determined by a pilot study that aimed to determinethe minimal dose needed to achieve a stable plateau(data not shown). After a stable plateau of vasoconstric-tion, acetylcholine (Ach; 10�9 to 10�5 mol/L) was addedto the bath in a cumulative fashion in 1/2log10 units. Theresponse to each concentration was allowed to reach aplateau before the addition of the next concentration ofAch. Finally, 10�5 mol/L sodium nitroprusside (SNP) wasadded to the bath to ensure maximal relaxation.

Data AnalysisAll data are expressed as mean � standard error of themean (SEM). Results for vasodilation were expressed as apercentage contraction by ET-1. For analysis of the re-sponses to Ach, median effective concentration (EC50)was calculated. The values of EC50 were transformed intogeometric means (pD2 � �log10EC50). For comparisonsbetween the two groups, data were analyzed using Stu-dent’s t test if normal distribution was confirmed by theF test; otherwise, the Mann-Whitney U test was applied.One-factor analysis of variance was used for comparingmultiple groups, and Fisher’s Protected Least SignificantDifference (Fisher’s PLSD) was used for the post hoc test.Results were considered significant with p values of lessthan 0.05.

Results

Patient CharacteristicsA total of 13 patients (11 men and 2 women) participatedin this study. The average age was 61.6 � 2.7 years (range44 to 76 years). An analysis of the preoperative riskfactors, serum lipid profile, and medications used onadmission is shown in Table 1. Eight of 13 patientsprovided RA and LITA specimens; 1 patient provided RAspecimens only; and 4 patients provided LITA specimensonly. With regard to the RA, 3 of 9 patients contributed toboth 2 hours and 24 hours of incubation by providingfour vascular rings, and 6 of 12 patients contributed toboth incubation periods in the LITA. Segments werepaired so that each patient provided segments for thecerivastatin and control groups.

Vascular Function StudiesIn both arteries, vascular contractions by KCl and ET-1were not statistically significantly different between thecerivastatin and control groups, although the values wereslightly greater in the control group. Those values were

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not significantly different between 2 hours and 24 hoursof incubation. As expected, the contraction was signifi-cantly greater in RA than in LITA groups (Table 2).

There were no significant differences of endothelium-dependent vasodilation between the cerivastatin andcontrol groups in [LITA 2 hours] and [RA 2 hours] (Fig 1Aand 1B). In the [LITA 24 hours], there was a trend towardhigher endothelium-dependant vasodilation in the cer-ivastatin group, although the differences were not signif-icant (Fig 1C). However, in the [RA 24 hours], endothe-lium-dependant vasodilation was significantly higher inthe cerivastatin group than in the control (Fig 1D).

As shown in Table 3, maximal vasodilation by Ach didnot drop between 2 and 24 hours of incubation except inthe control group of RA (56.8% � 10.2% to 39.4% � 4.7%),although this was not statistically significant. Conse-quently, in [RA 24 hours], the maximal value of endothe-lium-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 byone-factor analysis of variance). Only in the controlgroup of LITA did the pD2 value significantly drop from7.21 � 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 signif-icant differences between all the groups regarding theresponse to sodium nitroprusside (Table 3).

Comment

This study demonstrated that endothelium-dependentvasodilation of the RA after 24 hours of in vitro incuba-tion with cerivastatin was significantly higher than thecontrol group. In the same way, a similar trend ofendothelium-dependent vasodilation was noticed in theLITA group after 24 hours of in vitro incubation withcerivastatin, although the difference was not statisticallysignificant. On the other hand, effect on the pD2 valuesshowed that cerivastatin preserved the response of ace-tylcholine in the LITA after 24 hours of incubation. Thedifference in the action of cerivastatin between the twoblood vessels may be due to variation between theexpression and function of either endothelial nitric oxidesynthase (eNOS) or muscarine receptors in each bloodvessel. Further experiments using different stimulators ofnitric oxide (NO) release would clarify this issue. Botharteries RA and LITA did not show any significantdifferences of endothelium-dependent vasodilation after2 hours of in vitro incubation with cerivastatin.

Cerivastatin is an entirely synthetic and enantiomeri-cally pure HMG-CoA reductase inhibitor [16–18]. It hasbeen reported that cerivastatin enhanced eNOS proteinexpression and NO release resulting in preserved vaso-dilation [7–11, 13]. Endothelium-dependent vasodilationis very important in inhibiting the graft spasm andensuring a satisfactory blood flow, especially in earlyperiod after CABG. The ability of cerivastatin to protectthe endothelium could have important applications inclinical practice, possibly by the administration of statinsto patients in the early postoperative period. Clinically,oral administration of cerivastatin is started with 100 mginitially and could be increased up to 300 mg. It was

Table 1. Patient Characteristics

Risk FactorsRA

(n � 9)LITA

(n � 12)

Age, y 62.8 � 2.9 62.8 � 2.8Female/male, n 0/9 2/10Smoker/ex-smoker, n (%) 3 (33)/3 (33) 2 (17)/6 (50)Hypertension, n (%) 5 (56) 7 (58)Diabetes mellitus, n (%) 2 (22) 2 (17)Hyperlipidemia, n (%) 9 (100) 12 (100)Serum cholesterol, mmol/L 4.3 � 0.2 4.3 � 0.2Serum triglycerides, mmol/L 1.9 � 0.3 1.8 � 0.3Serum HDL, mmol/L 1.0 � 0.1 1.0 � 0.1Serum LDL, mmol/L 2.4 � 0.2 2.6 � 0.2Medication, n (%)

Statins 9 (100) 9 (75)Nitrates 4 (44) 7 (58)ACE inhibitors 7 (78) 10 (83)�-Blockers 8 (89) 11 (92)Ca antagonists 4 (44) 3 (25)Aspirin 9 (100) 12 (100)Insulin 1 (11) 1 (8)

ACE � angiotensin converting enzyme; HDL � high-density lipopro-tein; LDL � low-density lipoprotein; LITA � left internal thoracicartery; RA � radial artery.

Table 2. Vasocontractive Response to KC1 and ET-1

Graft Incubation Group Contraction by KCl (mN) Contraction by ET-1 (mN)

LITA 2 Hours Control 37.6 � 8.5 34.1 � 8.7Cerivastatin 30.5 � 3.2 30.2 � 5.3

LITA 24 Hours Control 41.8 � 8.1 35.6 � 6.7Cerivastatin 35.2 � 8.5 30.0 � 7.4

RA 2 Hours Control 119.5 � 15.2a 83.6 � 15.2c

Cerivastatin 106.5 � 15.8b 77.0 � 13.5c

RA 24 Hours Control 136.0 � 15.4a 100.6 � 8.3a

Cerivastatin 115.8 � 28.6a 98.7 � 20.0a

a p � 0.0001; b p � 0.001; c p � 0.01 vs. the control group of [LITA 2 hours]. There were no significant differences between the control andcerivastatin groups, and between 2 and 24 hours of incubation.

ET-1 � endothelin-1; KC1 � potassium chloride; LITA � left internal thoracic artery; RA � radial artery.

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reported that maximal plasma concentration of cerivas-tatin was 2.27 to 2.88 �g/L after 200 mg of cerivastatinadministration in healthy male volunteers [18]. There-

fore, the concentration of cerivastatin we used in thisstudy (1 �g/L) can be considered to be clinically relevant.

The RA and the LITA have been shown to have

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 representcontrol 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.)

Table 3. Vasodilatative at Response to Ach and SNP

Graft Incubation GroupDilatation by Ach

(% of contraction by ET-1) pD2

Dilatation by SNP(% of contraction by ET-1)

LITA 2 Hours Control 36.1 � 7.6 7.21 � 0.12 110.2 � 11.1Cerivastatin 44.1 � 4.9 7.20 � 0.15 105.5 � 5.1

LITA 24 Hours Control 38.1 � 8.2 6.78 � 0.15a 106.2 � 10.3Cerivastatin 56.5 � 8.8a 7.15 � 0.10 106.8 � 3.4

RA 2 Hours Control 56.8 � 10.2 7.06 � 0.25 113.0 � 2.6Cerivastatin 65.9 � 10.1a 7.37 � 0.11 105.3 � 2.6

RA 24 Hours Control 39.4 � 4.7 6.84 � 0.18 107.2 � 1.5Cerivastatin 68.4 � 5.0bc 7.10 � 0.07 102.1 � 1.8

a p � 0.05; b p � 0.01 vs. control group of [LITA 2 hours]; c p � 0.05 vs. control group of [RA 24 hours] by one-factor analysis of variance, and p� 0.01 vs. the control group of [RA 24 hours] by Student’s t-test. Otherwise, there were no significant differences between the control and cerivastatingroups, and between 2 and 24 hours of incubation.

Ach � acetylcholine; ET-1 � endothelin-1; EC50 � median effective concentration; LITA � left internal thoracic artery; pD2 �log10EC50 ; RA � radial artery; SNP � sodium nitroprusside.

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different biological characteristics [19–21]. That is RA is athick-walled muscular artery with a mean width of themedia reported to be approximately 500 �m, comparedwith 300 �m 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; andtype III, limb arteries. Type II and III arteries are morespastic than type I arteries. According to this classifica-tion, the RA is a type III arteries and is more spastic thantype I arteries, such as ITA. In addition, Chardigny andcolleagues [24] showed that the prostacyclin (PGI2) basalproduction was greater in the ITA than in the RA,concluding that antispastic drugs were more indicated incase of using the RA as a conduit. We speculate that theregulation of nitric oxide synthase (NOS) may also differbetween LITA (type I) and RA (type III). Our findingssuggested that the thicker walled vessel was sensitive toreduction in the maximal effects mediated by NO,whereas the thinner wall artery only showed reductionsin potency with time.

Regarding the duration of the incubation, cerivastatinenhanced endothelium-dependent vasodilation after 24hours of in vitro incubation, but not after 2 hours. It hasbeen shown that 6 hours was the shortest duration of invitro incubation with cerivastatin [11]. It was reportedthat eNOS mRNA was upregulated in rat aortic ringsafter 6 hours of incubation with cerivastatin [11]. Inanother study, in vivo cerivastatin reduced the [14C]cholesterol content in the liver by 80%, 2 hours after drugadministration [16]. Although it was initially difficult todetermine the optimal incubation period, we decided onperiods of 2 and 24 hours to look for immediate effectsmediated by cerivastatin and those associated withchanges in gene expression and protein synthesis [10, 11,13]. In the present study, different buffers were usedamong 2 and 24 hours of incubation: modified Tyrode’ssolution and Dulbecco’s modified Eagle’s medium withantibiotics, L-glutamine and fetal borine serum, respec-tively. We think that this difference was a minor issueand was unlikely to have influenced the results, as theresponses to KCl, ET-1, and sodium nitroprusside werenot significantly different between 2 and 24 hours ofincubation in all groups.

As time-related changes, maximal vasodilation by Achdropped from 56.8% � 10.2% to 39.4% � 4.7% in thecontrol group of RA between 2 hours and 24 hours ofincubation; however, it was unchanged in the cerivastatingroup. In addition, contraction by ET-1 did not decreasewith time in both groups. Consequently, the beneficialeffect of cerivastatin on endothelium-dependent vasodi-lation might be due to preserving the endothelium ratherthan inducing additional effects in the NOS. On the otherhand, in the LITA, such time-related reduction of endo-thelium-dependent vasodilation was marked in thepD2of the control group of LITA. Possible mechanism ofendothelial deterioration could be oxidative stress, in-flammatory change, and reduction of eNOS protein andmRNA [11–13, 25]. It also remains unclear why cerivas-tatin 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 mightbe very little during 2 hours of incubation. Anotherpossible explanation could be that the membrane-permeability of cerivastatin in nonhepatic tissue is lowbecause of its hydrophilicity [16].

In conclusion, the in vitro incubation of radial arterywith cerivastatin for 24 hours enhanced endothelium-dependent vasodilation. This could have very importantimplications and applications in the clinical practice ofcoronary surgery.

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21. Chester AH, Amrani M, Borland JAA. Vascular biology ofthe radial artery. Curr Opin Cardiol 1998;13:447–52.

22. Van Son JA, Smedts F, Vincent JG, van Lier HJ, Kubat K.Comparative anatomic studies of various arterial conduitsfor myocardial revascurization. J Thorac Cardiovasc Surg1990;99:703–7.

23. He G-W, Yang C-Q. Comparison among arterial grafts andcoronary artery: an attempt at functional classification.J Thorac Cardiovasc Surg 1995;109:707–15.

24. Chardigny CI, Van der Perre K, Simonet S, Descombes JJ,Fabiani JN, Verbeuren TJ. Platelets and prostacyclin inarterial bypasses: implications for coronary artery surgery.Ann Thorac Surg 2000;69:513–9.

25. Di Napoli P, Taccardi AA, Grilli A, et al. Simvastatin reducesreperfusion injury by modulating nitric oxide synthase ex-pression: an ex vivo study in isolated working rat hearts.Cardiovasc Res 2001;51:283–93.

INVITED COMMENTARY

Arterial grafts in coronary artery bypass grafting (CABG)are being increasingly used due to superior long-termpatency. The left internal thoracic artery (ITA) and theradial artery (RA) are the two major grafts. Endothelialfunction of the grafts is vitally important in preventingvasospasm, particularly in the early postoperative periodand in maintaining long-term patency [1, 2]. Endothelialcells produce a number of vasodilating substances thatare inhibitors of platelet aggregation. Endothelium-dependent relaxation is an index of endothelial function.

This article studied the effect of “statins” on the endo-thelial function of grafts. The conclusion that cerivastatinsignificantly preserves endothelium-dependent vasodila-tation may have clinical implications. There are a fewpoints that should be considered by the reader. First,incubation with cerivastatin during surgery can only befor a short time, such as half an hour or so. As this studyindicated, the effect of cerivastatin is not significant evenat 2 hours of incubation. Second, the possibility thatpreoperative intake of the drug may preserve endothelialfunction is not addressed. Third, the concentration ofcerivastatin used for incubation (1 �M/L) is much higherthan the plasma concentration (2.27 to 2.88 �g/L; see“Comment” in the article). The statement in “Comment”that the concentration of cerivastatin used in the presentstudy is 1 �g/L may be a writing error. Whether earlypostoperative administration of cerivastatin at a dose thatproduces a much lower plasma concentration than thatused in this study is effective is questionable and needsfurther study. Lastly, the drug preserves endothelialfunction in RA and has a similar trend in ITA, althoughnot significant (see Fig 1C). We have recently demon-strated that basal and stimulated release of nitric oxideand endothelium-derived hyperpolarizing factor-

mediated hyperpolarization in the ITA are significantlygreater than that in the RA. However, whether cerivas-tatin only preserves RA endothelium, and why if true,needs further investigation.

In brief, this study provides useful information forimprovement of graft function in CABG from a newaspect, but there is still a gap between the laboratorystudy and future clinical application.

Guo-Wei He, MD, PhD

Division of Cardiothoracic SurgeryDepartment of SurgeryThe Chinese University of Hong KongPrince of Wales Hospital, Block B, 5AShatin, New TerritoriesHong Kong, People’s Republic of Chinae-mail: [email protected].

Clinical Professor of SurgeryDepartment of SurgeryOregon Health and Science UniversityPortland, OR

References

1. He G-W. Arterial grafts for coronary artery bypass: biologicalcharacteristics, functional classification, and clinical choice.Ann Thorac Surg 1999;67:277–84.

2. He G-W. Arterial grafts for coronary surgery: vasospasm andpatency rate [Editorial]. J Thorac Cardiovasc Surg 2001;121:431–3.

3. He G-W, Liu Z-G. Comparison of nitric oxide release andendothelium-derived hyperpolarizing factor-mediated hy-perpolarization between human radial and internal mam-mary arteries. Circulation 2001;104(Suppl I):I344–9.

1865Ann Thorac Surg NAKAMURA ET AL2002;73;1860–5 CERIVASTATIN AND ARTERIAL CONDUITS

© 2002 by The Society of Thoracic Surgeons 0003-4975/02/$22.00Published by Elsevier Science Inc PII S0003-4975(02)03597-X23