Differential in vitro response of the human radial artery versus left internal thoracic artery to...

Differential In Vitro Response of the Human RadialArtery Versus Left Internal Thoracic Artery toCerivastatin: Implications to Bypass GraftingKoki Nakamura, MD, Sharif Al-Ruzzeh, FRCS, Adrian H. Chester, PhD,Charles Ilsley, FRCP, Magdi H. Yacoub, FRCS, and Mohamed Amrani, FRCSNational Heart and Lung Institute, Heart Science Centre, Harefield Hospital, Harefield, Middlesex, United Kingdom

Background. This study investigated acute (in vitro)and long-term (in vivo) effects of statins on the vascularfunction of human radial artery (RA) and left internalthoracic artery (LITA).

Methods. RA and LITA specimens were divided intovascular rings, which were incubated in the absence orpresence of 10�6 mol/L Cerivastatin for 2 or 24 hours. Interms of preoperative statin treatment, four groups in-cluded: group 1 [preop statin(-)/in vitro cerivastatin(-)];group 2 [preop(-)/in vitro(�)]; group 3 [preop(�)/invitro(-)]; and group 4 [preop(�)/in vitro(�)]. Endothelialfunction was assessed with acetylcholine (10�9 to 10�5

mol/L) following contraction by 3 � 10�8 mol/Lendothelin-1.

Results. Although endothelium-dependent vasodilata-tion was higher in RA (57.7% � 3.5%) than in LITA

(46.5% � 3.8%, p � 0.046), there was no significantevidence that it depended on the preoperative use ofstatins or incubation period. In vitro incubation withcerivastatin significantly increased endothelium-dependent vasodilatation by 14.2% � 2.4% (p < 0.0001)independent of artery types (RA/LITA). There was nosignificant evidence that endothelium-dependent vasodi-latation depended on the preoperative use of statins orincubation period.

Conclusions. In vitro incubation with cerivastatin pre-served endothelial function more effectively than preop-erative use of statins. This could have implications toperioperative use of statins for patients undergoing cor-onary surgery.

(Ann Thorac Surg 2003;76:2023–8)© 2003 by The Society of Thoracic Surgeons

The interest in the use of the radial artery (RA) as aconduit for coronary artery bypass grafting (CABG)

was revived in the early 1990s [1, 2]. The intraoperativepreparation of the RA, the minimal trauma involved in itsharvest, and the postoperative administration of calcium-channel blockers improved the performance in coronaryartery surgery [2–4]. However, problems of preparationand perioperative performance of arterial conduits aredifferent among the types of vessels because of theirendothelial heterogenuity [5].

Endothelial function could be ameliorated by pharma-cologic interventions. The reductase inhibitors 3-hy-droxy-3-methylglutaryl coenzyme A (HMG-CoA), orstatins, are well known as lipid-lowering drugs that haverecently been demonstrated to provide many other ben-efits [6–12]. Statins produce endothelium-dependent va-sodilatation [6, 7] and inhibition of the smooth musclecell proliferation [8], in addition to their antioxidant [9]and antiinflammatory [10, 11] effects. Furthermore, theyprovide an antisclerotic effect that had a major impact inreducing graft failure [12]. However, differential in vitroresponse of the human arterial grafts to cerivastatin havenot yet been investigated.

Therefore, the aim of this study was to assess theeffects of preoperative and in vitro exposure to statins onthe endothelial function of the human RA and left inter-nal thoracic artery (LITA) grafts used for CABG. It ishoped that this study would provide a rationale for theuse of statins to augment endothelial function followingCABG.

Material and Methods

Collection of SpecimensSpecimens of the distal segments of the RA and the LITAwere obtained from the patients who underwent isolatedCABG at Harefield Hospital between May 2001 andMarch 2002. Ethical approval for the study was obtainedfor the hospital ethics board and all patients gave writtenconsent to participate in the study. Using electrocautery,both graft conduits were harvested in a pedicle fashion.Following the harvest of the RA, approximately 1 cm ofdistal segment was taken as a specimen before flushingwith any preparatory solution. In the same way, 1 cm ofdistal segment of the LITA was also taken as a specimenbefore spraying it with vasodilators. During the harvest-ing procedure no systemic vasodilators were given. Thecollected specimens were kept in a 199 tissue culturemedium (Sigma, Dorset, UK) at 4°C and were dividedinto vascular rings within 30 minutes of collection.

Accepted for publication June 6, 2003.

Address reprint requests to Dr Amrani, Consultant Surgeon, HarefieldHospital, Harefield, Middlesex UB9 6JH, UK; e-mail: [email protected].

© 2003 by The Society of Thoracic Surgeons 0003-4975/03/$30.00Published by Elsevier Inc doi:10.1016/S0003-4975(03)01297-9

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Plan of InvestigationOn processing the specimens, excess connective tissuewas removed using a dissecting microscope followed bydividing each specimen into two to four pieces, approx-imately 3-mm each. In both types of artery specimenswere divided into the following four groups from thepoint of view of preoperative treatment with statins andin vitro exposure to cerivastatin (BAY w6228; Bayer AG,Wuppertal, Germany):

● Group 1 [preop statins(-)/in vitro cerivastatin(-)]:Specimens were obtained from the patients whowere not administered statins preoperatively, andvascular rings were incubated with vehicle for 2hours (n � 7 in LITA and n � 6 in RA) or 24 hours (n� 6 in LITA and n � 6 in RA).

● Group 2 [preop(-)/in vitro(�)]: Specimens from thesame patients as group 1 were incubated with 10�6

mol/L cerivastatin for 2 hours (n � 7 in LITA and n �6 in RA) or 24 hours (n � 6 in LITA and n � 6 in RA).

● Group 3 [preop(�)/in vitro(-)]: Specimens from pa-tients prescribed statins were incubated with vehiclefor 2 hours (n � 7 in LITA and n � 6 in RA) or 24hours (n � 7 in LITA and n � 6 in RA).

● Group 4 [preop(�)/in vitro(�)]: Specimens from thesame patients as group 3 were incubated with 10�6

mol/L cerivastatin for 2 hours (n � 7 in LITA and n �6 in RA) or 24 hours (n � 7 in LITA and n � 6 in RA).

Because groups 1 and 2, and groups 3 and 4 werenecessarily paired, sources of the rings were exactly thesame in the those groups. Patient preoperative charac-teristics including age, sex, smoking, hypertension, dia-betes mellitus, hyperlipidemia, serum lipid data, andmedications were compared.

For the 2-hour incubation, the specimens were imme-diately mounted on two L-shaped metal hooks in isolatedorgan baths without stretching. Vascular rings in groups2 and 4 were incubated in organ baths with 10�6 mol/Lcerivastatin, whereas those in the groups 1 and 3 wereincubated without cerivastatin. The organ baths con-tained modified Tyrode’s solution that is composed of (inmmol/L): NaCl, 136.9; NaHCO3, 11.9; KCl, 2.7; NaH2PO4,0.4; MgCl2, 2.5; CaCl2, 2.5; glucose, 11.1; and disodium-ethylenediaminetetraacetic acid, 0.04. The solution wascontinuously gassed with 95% O2 and 5% CO2 at thetemperature of 37°C. In each organ bath, one hook wasattached to a force-displacement transducer and this wasfixed to a Grass 7D polygraph (Grass Instruments,Quincy, MA), which monitored and recorded changes invessel-wall tension. The other hook was fixed to a screwgauge, which was used to stretch the vessel segments.

For the 24-hour incubation, the specimens were incu-bated in Dulbecco’s Modified Eagles Medium (DMEMD6046; Sigma) containing penicillin (100 U/mL), strepto-mycin (100 �g/mL), L-glutamine (2 mmol/L), and 15%heat-inactivated fetal bovine serum. Vascular rings ingroups 2 and 4 were incubated with 10�6 mol/L cerivas-tatin, whereas those in groups 1 and 3 were incubatedwithout cerivastatin. The rings were left in an incubator

for 24 hours at 37°C. These incubation conditions have nosignificant effect on the viability of vessel segments.

Vascular Function StudiesAfter the incubation period, vascular function studieswere started and contained 10�6 mol/L cerivastatin ingroups 2 and 4 as previously reported [13, 14]. Initialpretensions of 80 mN and 50 mN were applied to eachvascular ring of RA and LITA, respectively. Then theywere relaxed out and were allowed to equilibrate for 30minutes. Following that the rings were challenged with90 mmol/L potassium chloride solution (KCl). The bathwas washed out when the response reached a plateaufollowed by a return to the baseline. After the washout,10�6 mol/L cerivastatin was supplemented in the bath forgroups 2 and 4, and this allowed the study to keep thesame concentration of cerivastatin in the organ bathsthroughout the experiment. This series of procedureswas repeated again and the response to KCl at the secondtime was recorded as a result (pretensions of 80 mN forRA and 50 mN for LITA were applied on two separateoccasions). When re-equilibration was obtained, tensionwas induced in each ring by the addition of 3�10�8 mol/Lendothelin-1 (ET-1; Calbiochem, Nottingham, UK). Thisconcentration of ET-1 was determined by a pilot studythat was aimed to find out the minimum dose to achievea stable plateau (data not shown). After a stable plateauof vasoconstriction, acetylcholine (ACH; 10�9 to 10�5

mol/L) was added to the bath in a cumulative fashion in1⁄2 log10 units. The response to each concentration wasallowed to reach a plateau before addition of the nextconcentration of ACH. Finally, 10�5 mol/L sodium nitro-prusside (SNP) was added to the bath to ensure maximalrelaxation.

Analysis of the DataAll data were expressed as mean � standard error of themean (SEM). Changes in tension in response to ACHwere normalized to the magnitude of the maximal con-traction induced by ET-1. For analysis of the responses toACH, median effective concentration (EC50) was calcu-lated. The values of EC50 were transformed into geomet-ric means (pEC50 � �log10EC50). The results of vascularfunction test was analyzed with ANOVA when normaldistribution was confirmed, otherwise, nonparametricanalysis was performed. To analyze the data of patientspreoperative characteristics, �2 test was applied, exceptto patients’age and serum lipid data, which were ana-lyzed by either Student’s t test or Mann Whitney’s U test.Results were considered significant if p values less than0.05.

Results

Patients’ Preoperative CharacteristicsTwenty-two patients consented to join this study, theyincluded 20 males and 2 females. The average age was61.4 � 1.8 years (range 44 to 76 years old). Twelve patientsprovided both RA and LITA specimens, 4 patients pro-

2024 NAKAMURA ET AL Ann Thorac SurgSTATINS AND ARTERIAL CONDUITS 2003;76:2023–8

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vided RA specimens only, and 6 patients provided LITAspecimens only. An analysis of the preoperative charac-teristics is illustrated in Table 1. Ten of 22 patientsadministered statins chronically (at least half a year) andstopped them the night before surgery (at least 12 hoursbefore surgery), whereas 12 patients did not have anystatins. Among those 10 patients, 5 patients receivedatorvastatin, 3 patients received pravastatin, and 2 pa-tients received simvastatin.

The incidence of hyperlipidemia was significantlylower in groups 1 and 2 (50%) than in groups 3 and 4(100%, p � 0.015). On the other hand, serum low densitylipoprotein (LDL) was significantly higher in groups 1and 2 (3.2 � 0.4 mmol/L) than in groups 3 and 4 (2.4 � 0.2mmol/L, p � 0.042; Table 1).

Vascular Function StudiesVascular contraction by KCl was significantly higher inRA (113.2 � 10.3 mN) than in LITA (36.4 � 3.8 mN, p �0.001). Similarly, vascular contraction by ET-1 was signif-icantly higher in RA (78.4 � 7.1 mN) than in LITA (32.0 �3.4 mN, p � 0.001). There was no significant evidence thatcontraction by KCl and ET-1 depended on incubationperiod or preoperative use of statins. Cerivastatin signif-icantly decreased vascular contraction by KCl by 12.1 �5.1 mN independent of artery types, incubation periods,or preoperative use of statins. However, cerivastatin didnot significantly change vascular contraction by ET-1(decrease by 3.6 � 4.0 mN, p � 0.37).

Although endothelium-dependent vasodilatation washigher in RA (57.7% � 3.5%) than in LITA (46.5% � 3.8%,p � 0.046), there was no significant evidence that itdepended on the preoperative use of statins or incuba-tion period. In vitro incubation with cerivastatin signifi-

cantly increased endothelium-dependent vasodilatationby 14.2% � 2.4% (p � 0.0001) independent of artery types(RA/LITA). After a 2-hour incubation preoperative use ofstatins tend to lead to a lower increase in endothelium-dependent vasodilatation with cerivastatin (6.0% � 3.9%vs 18.6% � 5.2%), although after a 24-hour incubationpreoperative use of statins tend to lead to a higherincrease with cerivastatin (23.4% � 4.6% vs 8.2% � 3.7%,p � 0.004; Fig 1A–1D; Tables 2 and 3).

The value of pEC50 decreased from 7.27 � 0.07 at 2hours to 6.98 � 0.05 at 24 hours. There was no significantevidence that pEC50 depended on artery types or preop-erative use of statins. In vitro incubation with cerivastatinsignificantly increased the value of pEC50 by 0.17 � 0.05(p � 0.0024) independent of artery types, incubationperiods, or preoperative use of statins (Tables 2 and 3).

Vasodilatation by SNP was significantly higher in RA(116.9% � 3.5%) than in LITA (106.2% � 3.7%, p � 0.007).Preoperative use of statins decreased vasodilatation bySNP (103.1% � 2.0% vs 119.6% � 4.5%, p � 0.007). Therewas no significant evidence that vasodilatation by SNPdepended on incubation period. In vitro incubation withcerivastatin did not significantly change vasodilatationby SNP (1.5% � 3.6%, p � 0.67; Tables 2 and 3).

Comment

This in vitro study has demonstrated the differentialresponse of human arterial conduits to statins. Endothe-lium-dependent vasodilatation was significantly in-creased by in vitro incubation with cerivastatin indepen-dent of artery types. There was no significant evidencethat endothelium-dependent vasodilatation dependedon the preoperative use of statins or incubation period

Table 1. Patient Characteristics

Risk FactorsPreoperative statins(�)

(Groups 1 and 2; n � 12)Preoperative statins(�)

(Groups 3 and 4; n � 10) p Value

Age, years 60.0 � 2.5 62.7 � 2.6 0.47Female/male, number 2/10 0/10 0.48Smoker/ex-smoker, number (%) 0 (0)/7 (58) 3 (30)/4 (40) 0.12Hypertension, number (%) 7 (58) 5 (50) � 0.99Diabetes mellitus, number (%) 4 (33) 3 (30) � 0.99Hyperlipidemia, number (%) 6 (50) 10 (100) 0.015a

Serum cholesterol, mmol/L 5.1 � 0.4 4.3 � 0.2 0.076Serum triglycerides, mmol/L 1.9 � 0.2 1.8 � 0.3 0.75Serum HDL, mmol/L 0.9 � 0.2 1.0 � 0.1 0.68Serum LDL, mmol/L 3.2 � 0.4 2.4 � 0.2 0.042a

Medication, number (%)Statins 0 (0) 10 (100) —Nitrates 7 (58) 4 (40) 0.43ACE inhibitors 6 (50) 8 (80) 0.2Beta-blockers 8 (67) 9 (90) 0.32Ca-antagonists 5 (42) 4 (40) � 0.99Aspirin 10 (83) 10 (100) 0.48Insulin 1 (8) 2 (20) 0.57

a Statistically significant.

ACE � angiotensin converting enzyme; HDL � high density lipoprotein; LDL � low density lipoprotein.

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(there was no deterioration in the function of the vesselover time). This implies that the endothelial function ofthe arterial conduits improves significantly by the acutepostoperative exposure to cerivastatin, which could haveimportant implications for statins in the postoperativecare of patients receiving arterial grafts.

The main use of statins is for their lipid lowering effect,which could reduce graft failure after CABG by anantisclerotic effect [12]. In addition, statins also haveother beneficial effects, which include endothelium-dependent vasodilatation [6, 7], inhibition of the smoothmuscle cell proliferation [8], and antioxidant [9] andantiinflammatory [10, 11] effects. We believe that thesenonlipid-lowering actions of statins are largely responsi-ble for the enhanced endothelial function seen in thisstudy. Indeed patients may benefit from continued expo-sure to statins throughout the perioperative period (for

example, by giving statins from a naso-gastric tube inearly period).

Currently there are six different types of statins: lova-statin, simvastatin, pravastatin, fluvastatin, atorvastatin,and cerivastatin [15]. Only pravastatin is hydrophilic andthe others are lipophilic [15]. Inoue and colleagues [10]reported that lipophilic statins (simvastatin, fluvastatin,and cerivastatin) had an antiinflammatory effect on en-dothelial cells through reduction of mRNA levels forinterleukin-1�, interleukin-6, cyclooxygenase-2, andp22phox, however, pravastatin did not exhibit thesekinds of effects. The usual dosage is 10 to 80 mg forlovastatin, 5 to 80 mg for simvastatin, 5 to 40 mg forpravastatin, 20 to 80 mg for fluvastatin, 10 to 80 mg foratorvastatin, and 0.1 to 0.8 mg for cerivastatin [15]. Onlylovastatin and simvastatin are prodrugs, and bioavail-ability is less than 5% in lovastatin and simvastatin, 17%

Fig 1. Endothelium-dependent vasodilatation: (A) LITA 2-hours after incubation; (B) LITA 24-hours after incubation; (C) RA 2-hours afterincubation; and (D) RA 24-hours after incubation. Each circle (or triangle) and bar represents the mean � standard error of mean (% ofcontraction by ET-1). ● � group 1; � � group 2; � � group 3; ƒ � group 4. (ET-1 � endothelin-1; LITA � left internal thoracic artery; RA� radial artery.)


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in pravastatin, 10% to 35% in fluvastatin, 12% in atorva-statin, and 60% in cerivastatin [15]. Therefore, in thepresent study, cerivastatin was selected for in vitro incu-bation because of nonprodrug, lipophilicity, and lowdosage; although cerivastatin was withdrawn from theUnited States market in 2001 (http://www.fda.gov/cder/drug/infopage/baycol/default.htm). Cerivastatin is anentirely synthetic and enantiomerically pure HMG-CoAreductase inhibitor [16–18]. It was reported that 1-�Mcerivastatin revealed antiinflammatory (no effect underthis concentration) and antioxidant effect to protect en-dothelial nitric oxide synthase (eNOS) activity [9, 11].Therefore, 1-�M cerivastatin was used in this study,although it was reported that maximum plasma concen-tration of cerivastatin was 2.27 to 2.88 �g/L (0.0047 to0.0060 �M) after 200 �g of cerivastatin administration inhealthy male volunteers [16].

Our data suggest that the in vitro administration ofstatin is more essential than the preoperative one. It isunclear from the present study if this relates to theinhibition of HMG-CoA reductase, antioxidant and anti-inflammatory effects, stabilization of nitric oxide synthase(NOS) mRNA, or a yet undefined mechanism of action.However, it was reported that a 2-week treatment withCerivastatin improved endothelial-dependent vasodila-tation of human forearm vasculature, while this improve-ment was reversed by NOS inhibitor N(G)-monomethyl-

L-arginine [7]. This could suggest that one of theimportant effects of cerivastatin on endothelium is re-lated to NOS enhancement/preservation.

The RA and the LITA have been demonstrated to havedifferent biological characteristics [13, 14, 19]. The RA is athick-walled muscular artery with a mean width of themedia reported to be approximately 500 �m, comparedwith 300 �m for the ITA [19, 20]. Chardigny and cowork-ers [21] reported that the prostacyclin (PGI2) basal pro-duction was greater in the ITA than in the RA, concludingthat antispastic drugs were more indicated in case ofusing the RA as a conduit. We speculate that the regula-tion of NOS may also differ between LITA and RA. Inaddition, preexisting vascular disease might affect theresults in our study. Kaufer and colleagues [22] investi-gated the incidence and the degree of arteriosclerosis inRA and ITA by classifying them to grade 0 to 4. Patho-logically no atherosclerotic change (grade 0) was found in77.4% of LITA and 46.2% of RA. In addition, grade 3 and4 were 0% in LITA and 8.5% in RA. Kane-Toddhall andassociates [23] also histologically examined the 177 RA,168 IMA, and 86 long saphenous veins (SV) from thesame patients undergoing CABG. Minimal atheroscle-rotic change (� 5% stenosis) were seen in 91% of ITA,42% of RA, and 70% of SV. Thus the RA appears to be atrisk of endothelial damage, thereby making it more

Table 2. Response of LITA to ACH and SNP

Incubation Group (number)

Dilatation by ACH(% of contraction

by ET-1) pEC50

Dilatation by SNP(% of contraction

by ET-1)

2 hours 1 [preop(�)/in vitro(�)] (7) 42.6 � 6.6 7.21 � 0.10 118.8 � 10.92 [preop(�)/in vitro(�)] (7) 55.5 � 4.5 7.31 � 0.13 114.5 � 5.23 [preop(�)/in vitro(�)] (7) 40.9 � 9.0 7.20 � 0.16 96.7 � 7.74 [preop(�)/in vitro(�)] (7) 44.3 � 6.0 7.18 � 0.20 99.8 � 3.9


ACH � acetylcholine; EC50 � median effective concentration; ET-1 � endothelin-1; LITA � left internal thoracic artery; pEC50 � �log10EC50; preop � preoperative; SNP � sodium nitroprusside.

Table 3. Response of RA to ACH and SNP

Incubation Group (number)

Dilatation by ACH(% of contraction

by ET-1) pEC50

Dilatation by SNP(% of contraction

by ET-1)



ACH � acetylcholine; EC50 � median effective concentration; ET-1 � endothelin-1; pEC50 � �log10 EC50; preop � preoperative; RA� radial artery; SNP � sodium nitroprusside.

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amenable to the protective action of statins compared tothe LITA.

Although it was initially difficult to determine theoptimal incubation period, we decided on the periods of2 and 24 hours in order to look for immediate effectsmediated by cerivastatin and those associated withchanges in gene expression and protein synthesis [8, 9,11]. In vitro cerivastatin treatment displayed a betterendothelial function, although the data of pEC50 exhib-ited deterioration of endothelial function between 2 and24 hours. In addition, contraction by ET-1 did not de-crease with time. Therefore, we speculate that the bene-ficial effect of cerivastatin on endothelium-dependentvasodilatation might be due to preserving the endothe-lium rather than inducing additional effect on the NOS.Possible mechanisms of endothelial deterioration couldbe oxidative stress, inflammatory change, or reduction ofeNOS protein and mRNA [9–11, 24]. A limitation of thisstudy is that we did not perform histologic studies, suchas an immunohistochemistry and scanning with an elec-tron microscope, which might be useful to examine theendothelial cells in detail.

In conclusion, in vitro incubation with cerivastatinpreserved endothelial function more effectively than pre-operative use of statins. This suggests that the postoper-ative (may include intraoperative) administration ofstatins could improve the endothelial function of thearterial grafts in patients undergoing CABG.

We thank Dr Derek Robinson (Center for Statistics and Stochas-tic Modeling, School of Mathematical Sciences, University ofSussex, Brighton, Sussex, UK) for statistical analysis of the data.

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