[Isolated iliac artery aneurysms : Interventional treatment]. / Isolierte Aneurysmen der Iliakalarterien : Interventionelle Therapie.

CLINICAL ISSUE: Isolated iliac artery aneurysms occur considerably less often than abdominal aortic aneurysms. Mainly older men are affected by this disease. Most of these aneurysms are asymptomatic and are incidentally detected during cross-sectional imaging. Iliac aneurysms with a diameter larger than 3 cm are at risk for rupture, which is associated with high morbidity and mortality. STANDARD TREATMENT: To prevent their rupture as well as for symptomatic or ruptured aneurysms, endovascular treatment has recently been established as the primary approach due to the decreased morbidity and mortality compared to open repair. Endovascular aneurysm exclusion is performed with stent grafts, and depending on the anatomy, by adjunctive internal iliac artery embolization. TREATMENT INNOVATIONS: Up to a quarter of treated patients will require additional endovascular revisions during the long term. Reliable imaging follow-up likely increases the safety of elective or emergent endovascular iliac artery aneurysm repair.

A Multicentre Trial of Patient specific Rehearsal Prior to EVAR: Impact on Procedural Planning and Team Performance.

OBJECTIVE: Patient specific rehearsal (PsR) prior to endovascular aneurysm repair (EVAR) enables the endovascular team to practice and evaluate the procedure prior to treating the real patient. This multicentre trial aimed to evaluate the utility of PsR prior to EVAR as a pre-operative planning and briefing tool. MATERIAL AND METHODS: Patients with an aneurysm suitable for EVAR were randomised to pre-operative or post-operative PsR. Before and after the PsR, the lead implanter completed a questionnaire to identify any deviation from the initial treatment plan. All team members completed a questionnaire evaluating realism, technical issues, and human factor aspects pertinent to PsR. Technical and human factor skills, and technical and clinical success rates were compared between the randomised groups. RESULTS: 100 patients were enrolled between September 2012 and June 2014. The plan to visualise proximal and distal landing zones was adapted in 27/50 (54%) and 38/50 (76%) cases, respectively. The choice of the main body, contralateral limb, or iliac extensions was adjusted in 8/50 (16%), 17/50 (34%), and 14/50 (28%) cases, respectively. At least one of the abovementioned parameters was changed in 44/50 (88%) cases. For 100 EVAR cases, 199 subjective questionnaires post-PsR were completed. PsR was considered to be useful for selecting the optimal C-arm angulation (median 4, IQR 4-5) and was recognised as a helpful tool for team preparation (median 4, IQR 4-4), to improve communication (median 4, IQR 3-4), and encourage confidence (median 4, IQR 3-4). Technical and human factor skills and technical and initial clinical success rates were similar between the randomisation groups. CONCLUSION: PsR prior to EVAR has a significant impact on the treatment plan and may be useful as a pre-operative planning and briefing tool. Subjective ratings indicate that this technology may facilitate planning of optimal C-arm angulation and improve non-technical skills. TRIAL REGISTRATION: URL://www.clinicaltrials.gov. Unique identifier: NCT01632631.

Mid-term Results of Chimney and Periscope Grafts in Supra-aortic Branches in High Risk Patients.

PURPOSE: Report mid-term outcomes of thoracic endovascular aneurysm repair (TEVAR) with chimney and periscope grafts (CPG) in supra-aortic branches (SAB). METHODS: Retrospective analysis, from October 2009 to May 2014, of patients with aneurysms requiring TEVAR with zone 0/1/2 proximal landing in association with at least one CPG in the SAB. All patients were considered at high risk for conventional surgery. Peri-operative mortality and morbidity, retrograde type A dissection, maximum aortic transverse diameter (TD) and its post-operative evolution, endoleak, survival, freedom from cardiovascular re-interventions, and CPG freedom from occlusion during the follow-up were analysed. RESULTS: Forty-one patients (28.05% EuroScore II) with thoraco-abdominal aortic aneurysm (17%), arch aneurysm (39%), descending aneurysm (34%), and aneurysm extending from the arch to the visceral aorta (10%) were included. Fifteen (37%) patients were treated non-electively. Fifty-nine SABs were treated with the CPG technique: one, two, three, and four CPG were employed in 71%, 19%, 5%, and 5% of patients, respectively. The proximal landing was in zone 0 in 49% of patients, zone 1 in 17%, and zone 2 in 34%. Technical success was 95%. Peri-operative complications and neurological events were registered in six (14.6%) patients and there were 5 deaths (12%). At a median follow-up of 21.2 (mean 22, SD 18; range 0-65) months, type I/III endoleaks were registered in three (7%) cases and re-intervention in six (15%) patients. A significant aneurysm sac shrinkage (p<.001) was reported at mean follow-up and no significant aneurysm sac increase (>5 mm). The estimated 2 year survival, freedom from re-intervention, freedom from endoleak, and freedom from branch occlusion were 75%, 77%, 86%, and 96%, respectively. CONCLUSION: The chimney and periscope grafts technique was shown to be safe in aortic aneurysm disease involving the supra aortic branches, even in an emergency setting using off the shelf devices. Mid-term follow-up results in this high risk population are good, but longer follow-up is mandatory before this technique is used in intermediate-risk patients.

Mid- and Longer-term Follow up of Chimney and/or Periscope Grafts and Risk Factors for Failure.

OBJECTIVE: The aim was to report on chimney and periscope grafts (CPGs) and their mid- and longer-term outcomes when they are used to preserve reno-visceral artery (RVA) perfusion in endovascular repair of pararenal (PRAAs) or thoraco-abdominal aortic aneurysm (TAAAs). In addition, factors associated with CPG failure are presented. Limited data exist on the outcomes of CPGs, and mid- and long-term results are generally not reported. METHODS: This was a prospective study in a cohort of 100 patients with PRAA (69) or TAAA (31). A total of 224 (mean 2.24 per patient) RVAs were preserved with 136 (61%) chimney and 88 (39%) periscope grafts. CPGs were constructed mainly using self expandable stent grafts. Patients were followed by clinical examination, CTA (82%), and/or duplex (18%). Data were collected until February 2015. RESULTS: CPG immediate technical success was 99% (222/224 branches). Mean follow up was 29 months (range 0-65; SD 17); 59% patients were followed > 2 years, 30% > 3 years, and 16% > 4 years. Post-operatively, CPG occlusion was observed early (≤30 days) in three (1.3%) branches and during follow up in 10 (4.5%). At 36 and 48 months, the estimated primary patency was 93% and 93%. After corrective percutaneous (10) or surgical (3) re-interventions, the estimated secondary patency was 96% and 96%. Thirty day mortality was 2%; at 36 and 48 months the estimated patient survival was 79%. Significant shrinkage (72 [SD 23] vs. 62 [SD 24] mm; p < .001) was observed, with a substantial reduction (>5 mm) in 55 patients, and sac enlargement in four. Incomplete aneurysm sac sealing was treated successfully by a secondary intervention in 15 patients. CONCLUSIONS: Self expandable CPGs have proved to be a highly successful and durable treatment for RVA preservation up to 5 years. Incomplete CPG expansion, inadequate length, and CPG use in small and diseased target arteries were risk factors for occlusion. These mid- and longer-term results support CPG use to treat PRAAs or TAAAs in patients unfit for open surgery or fenestrated/branched stent grafts.

Editor's Choice ­ Durability of Endovascular Repair in Blunt Traumatic Thoracic Aortic Injury: Long-Term Outcome from Four Tertiary Referral Centers.

OBJECTIVES: To analyze the early and long-term survival and re-intervention rate in patients undergoing TEVAR for blunt traumatic thoracic aortic injury. METHODS: This was a consecutive case series. Between the years 2001 and 2010, a total of 74 patients underwent TEVAR for blunt traumatic thoracic aortic injury at four tertiary referral centers, three in Sweden and one in Switzerland. The median age of the patients was 41 years, and 16% were women. Demographic, procedural, and outcome data were collected and reviewed retrospectively. The patients were followed up during 2013-2014. RESULTS: Early (30 day) mortality was 9% (7 patients), with only two cases directly related to the aortic injury; in hospital mortality was 14% as three patients died during the primary hospital admission within the first 6 months. Most patients had sustained severe injuries to other organ systems, and among all in hospital deaths brain injury was the predominant cause. Five year survival in the whole group was 81%. Re-intervention was needed in 16% (12 patients) during the first year, half of them within the first month. Only one patient underwent re-intervention more than 1 year after the initial procedure. Infolding and partial stentgraft collapse was the reason for the secondary procedure in five of the 13 patients; in three it occurred within 3 weeks of the acute TEVAR. CONCLUSION: TEVAR allows rapid and effective therapy in trauma patients with blunt aortic injury. The outcome is dependent on the severity of the concomitant injuries. The treatment is durable during the first decade after the procedure, but even longer follow up is needed to determine the impact of TEVAR in young patients on the degenerative changes that take place in the aging aorta.

Distinction between acute and chronic type B aortic dissection: is there a sub-acute phase?

OBJECTIVES: This study aims to assess the relevance of the definition of acute dissection, to analyse whether there is a sub-acute phase and to determine early outcome of thoracic endovascular aortic repair (TEVAR) in acute complicated type B aortic dissection. DESIGN: Dual-centre consecutive case series. MATERIALS: Between 1999 and 2011, 102 patients underwent TEVAR for non-traumatic acute complicated type B dissection in Zurich, Switzerland, and Uppsala, Sweden. In addition, 22 patients treated for an acute dissection-related complication occurring >14 days after onset of symptoms were included. Median age was 68 years, 35% were women. METHODS: Demographic, procedural and outcome data were collected prospectively. The patients were followed up on 1 January 2012. RESULTS: In the 22 sub-acute patients (18%), there were no early deaths or neurological complications. The predominant complication in these patients was rapid aortic enlargement, whereas rupture was more prevalent in patients treated within 14 days. In total, there were nine (7%) early deaths, three (2%) post-intervention paraplegias and six cases of stroke (5%). CONCLUSIONS: TEVAR was performed with low early mortality and few neurological complications. A significant proportion of patients presented with acute complications >14 days after onset of symptoms, indicative of a sub-acute phase in the transition between acute and chronic dissection, questioning the relevance of the current definition.

Less invasive (common) femoral artery aneurysm repair using endografts and limited dissection.

OBJECTIVE: We report our experience with the treatment of femoral artery aneurysms (FAAs) under local anaesthesia with limited dissection, using endografts to facilitate the proximal anastomosis and some distal anastomoses. METHOD: Between January 2006 and December 2010, six males, mean age 72 years (range, 65-80 years) with FAAs were treated at the University Hospital of Zurich. All operations were performed under local anaesthesia with analgosedation, except for one performed under spinal anaesthesia. After limited dissection and puncture of the anterior wall of the FAA, a sheath and a self-expanding endograft were introduced over a guide wire and with fluoroscopy they were guided intraluminally into the proximal normal neck of the FAA and deployed. Proximal arterial control was achieved with a balloon catheter introduced through the endograft. Then the FAAs were opened and distal arterial control is obtained with balloon catheters. The distal end of the stent graft was then sutured to the normal-sized distal arteries or to stent grafts placed within them. RESULTS: Of the six FAAs, four were true and two were false anastomotic aneurysms. Mean FAA diameter was 5.0 cm (range, 3.0-6.5 cm). Four patients also had aneurysmal involvement of the external iliac artery, one patient also had deep femoral aneurysms, but deep femoral circulation was always preserved. In three of the patients, the distal anastomosis was created to the femoral artery bifurcation, in two patients to the deep femoral artery when the superficial femoral artery (SFA) was chronically occluded and in one patient to the SFA. Immediate technical success was achieved in all six patients, and graft patency was observed from 9 to 48 months (mean 29 months). There were no amputations, complications or deaths. CONCLUSION: This technique for repair of FAAs can be performed under local anaesthesia, minimises dissection and complications and simplifies exclusion of these lesions. It is of particular value in high-risk patients with large FAAs.

Patient-specific rehearsal prior to EVAR: a pilot study.

OBJECTIVES: This study aims to evaluate feasibility, face validity, influence on technical factors and subjective sense of utility of patient-specific rehearsal (PsR) prior to endovascular aortic aneurysm repair (EVAR). DESIGN: A prospective, multicentre pilot study. METHODS: Patients suitable for EVAR were enrolled and a three-dimensional (3D) model of the patient's anatomy was generated. Less than 24 h prior to the real case, rehearsals were conducted in the laboratory or clinical angiosuite. Technical metrics were recorded during both procedures. A subjective questionnaire was used to evaluate realism, technical and human factor aspects (scale 1-5). RESULTS: Ten patients were enrolled. In one case, the treatment plan was altered based on PsR. In 7/9 patients, the rehearsal significantly altered the optimal C-arm position for the proximal landing zone and an identical fluoroscopy angle was chosen in the real procedure. All team members found the rehearsal useful for selecting the optimal fluoroscopy angle (median 4). The realism of the EVAR procedure simulation was rated highly (median 4). All team members found the PsR useful to prepare the individual team members and the entire team (median 4). CONCLUSIONS: PsR for EVAR permits creation of realistic case studies. Subjective evaluation indicates that it may influence optimal C-arm angles and be valuable to prepare the entire team. A randomised controlled trial (RCT) is planned to evaluate how this technology may influence technical and team performance, ultimately leading to improved patient safety.

Complete replacement of open repair for ruptured abdominal aortic aneurysms by endovascular aneurysm repair: a two-center 14-year experience.

OBJECTIVE: To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. BACKGROUND: Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. METHODS: We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Örebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR-ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. RESULTS: Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Örebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). CONCLUSIONS: The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA.

Reprinted article "Endovascular repair with bifurcated stent-grafts under local anaesthesia to improve outcome of ruptured aortoiliac aneurysms".

INTRODUCTION: Acute haemodynamic changes and/or loss of abdominal muscle tone can occur during induction of general anaesthesia and may be the Achilles' tendon in endovascular aneurysm repair (EVAR) of ruptured aortoiliac aneurysms (rAIA). The purpose of this study was to evaluate the use of local anaesthesia (LA) for EVAR to overcome these limitations. METHODS: Twenty-one consecutive patients with rAIA are included in this study. Twenty patients underwent EVAR under LA, and 1 patient was treated under general anaesthesia. Haemodynamics were stabilised during assessment of EVAR feasibility by CT-scan and during the procedure itself by controlled hypotension (MAP 50-60 mmHg) and moderate fluid resuscitation. RESULTS: Median procedure time was 120 min. Haemodynamics remained stable in all but 3 patients who required transfemoral balloon occlusion of the supra-renal aorta. Perioperative intubation was necessary in 5 patients because of respiratory distress (n = 3), or retroperitoneal access (n = 2). Temporary deterioration of renal function occurred in 6 patients, with 2 requiring hemofiltration. CT-scan confirmed sealing of the rAIA in all patients at discharge. 30-day mortality was 9.5% (2 deaths). In the median follow-up of 19 months, there were no deaths, but 3 endovascular re-interventions, 1 crossover femoro-femoral bypass, and 1 open surgical graft repair. DISCUSSION: Our series is the first to show that EVAR for rAIA can be safely performed under LA. This approach allows implantation of commercially available bifurcated SG and improves patient outcome.

[Scientific research in family medicine: practitioners' experience, barriers and needs]. / Recherche scientifique en médecine de famille: expériences, barrières et besoins des praticiens.

Scientific data from family medicine are relevant for the majority of the population. They are therefore essential from an ethical and public health perspective. We need to promote quality research in family medicine despite methodological, financial and logistic barriers. To highlight the strengths and weaknesses of research in family medicine in the French-speaking part of Switzerland we asked practitioners from this region to share their experience, critics and needs in relation to research. This article summarizes their contribution in light of the international literature.

Abdominal compartment syndrome.

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are frequently encountered in critically ill patients and carry a high morbidity and mortality risk. Despite these facts, IAH/ACS are still overlooked by many physicians and therefore timely diagnosis is not made and treatment is often inadequate. All clinicians should be aware of the risk factors predicting IAH/ACS, the profound implications and derangements on all organ systems, the clinical presentation, the appropriate measurement of intra-abdominal pressure to detect IAH/ACS and the current treatment options for these detrimental syndromes. This comprehensive review provides knowledge about known facts, unresolved issues and future directions for research to improve patient survival and long-term outcome.

Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib.

BACKGROUND: The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. METHODS: To investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium. RESULTS: Conditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI. CONCLUSIONS: Overall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors.

Pull-down technique to allow complete endovascular relining of failed AAA Vanguard endografts with Excluder bifurcated endografts.

INTRODUCTION: Endovascular replacement of failed Vanguard endoprosthesis with a newly inserted bifurcated Excluder endograft in 6 selected patients over a 10-year period is reported. REPORT: Six male patients were treated by secondary EVAR procedures for endograft failure (type I and/or III endoleaks caused by endograft disintegration and/or migration). All failed endografts (1 tube, 5 bifurcated) were Vanguard prostheses. Technically, a new bifurcated Excluder endograft was placed within the old failing Vanguard endograft. All reinterventions were performed under local anesthesia supplemented by systemic analgesia/sedation. In 3 patients, insertion of the new Excluder endograft was possible without any additional technical measure as the failing Vanguard endograft trunk had migrated distally. In another 3 patients, the failed Vanguard endograft trunk was still in place. In these patients, the Vanguard main body was pulled caudally with a transfemoral cross-over guide wire in order to gain sufficient length to allow the short limb of the Excluder endograft to open within the trunk of the failed Vanguard endoprosthesis. This guide wire was introduced through a second femoral 5F in the main access and exeteriorized with a snare through the contralateral 12 Fr sheath. The main body and short limb of the Excluder was then deployed whilst pulling on the cross-over wire. RESULTS: Six patients initially treated by a Vanguard endograft underwent complete relining with a newly inserted Excluder bifurcated stentgraft. The mean interval from the first EVAR procedure to the described replacement procedure was 75+/-20.2 months (range: 53-109). The new bifurcated Excluder endografts were successfully deployed in all patients (technical success: 100%). Primary sealing (defined as absence of endoleaks type I, III or IV in the postoperative contrast enhanced CT scan) was achieved in 6 of the 6 patients. There was no operative mortality. No further endovascular or open treatment was needed in the other 5 patients. During the mean follow-up period of 26+/-20.1 months (range 2.5-50 months), 2 patients died from unrelated causes. CONCLUSION: Secondary endovascular replacement of failed Vanguard endografts with a bifurcated Excluder endograft proved to be feasible and safe with no 30-day mortality. Technical detail requires traction on a cross-over wire to pull the old graft caudally and create enough space for the new bifurcated graft to be deployed.

Choice of treatment for the patient with urgent AAA: practical tips.

Since the first successful attempts of emergency endovascular aneurysm repair (eEVAR) for patients with ruptured AAAs in the mid 1990s, surgeons have had to decide whether to treat patients by conventional open surgery or by minimally invasive but technically more demanding eEVAR. To date, selection of patients for eEVAR is still heavily debated and factors like hemodynamic instability, fear of treatment delay for patient transfer or imaging procedures and logistic issues often lead to the exclusion of anatomically suitable patients from eEVAR. However, these adverse factors may be overcome by adherence to an appropriate (intention-to-treat) protocol employing the use of a hypotensive hemostatic approach, transfemoral aortic balloon occlusion technique (when needed), different types of devices and an appropriate plan to resolve logistic issues, leaving anatomic suitability as the single most important determinant of suitability for EVAR.

Tissue endothelin-converting enzyme activity correlates with cardiovascular risk factors in coronary artery disease.

BACKGROUND: Endothelin-converting enzymes (ECEs) are the key enzymes in endothelin-1 (ET-1) generation. However, their pathophysiological role in patients with cardiovascular disease remains elusive. METHODS AND RESULTS: Vascular reactivity to big endothelin-1 (bigET-1; 10(-9) to 10(-7) mol/L) and ET-1 (10(-9) to 10(-7) mol/L) were examined in the internal mammary artery (IMA, n=33) and saphenous vein (SV, n=27) of patients with coronary artery disease with identified cardiovascular risk factors. Vascular ECE activity was determined by conversion of exogenously added bigET-1 to ET-1. Tissue contents of bigET-1 and ET-1 were measured by radioimmunoassay. In addition, the effects of LDL and oxidized LDL on ECE-1 protein levels were determined by Western blot analysis in human IMA endothelial cells. In the IMA, vascular ECE activity showed an inverse correlation with serum LDL levels (r=-0.76; P<0.01) and systolic and diastolic blood pressure and a positive correlation with fibrinogen (r=0.58; P<0.05). In the SV, fibrinogen was the only parameter to be correlated with vascular ECE activity. Vascular tissue content of bigET-1 was attenuated in the IMA of patients with hyperfibrinogenemia but increased in patients with elevated systolic blood pressure and increased serum LDL levels (P<0.05). Most interestingly, LDL and oxidized LDL downregulated ECE-1 protein levels in human IMA endothelial cells (P<0.05). CONCLUSIONS: These data demonstrate, for the first time, that vascular ECE activity is (1) inversely correlated with serum LDL levels and blood pressure and (2) positively associated with fibrinogen in human vascular tissue. Hence, ECE-1 activity may modulate cardiovascular risk in patients with coronary artery disease.

HMG-CoA reductase inhibition improves endothelial cell function and inhibits smooth muscle cell proliferation in human saphenous veins.

OBJECTIVES: This study examined effects of 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor cerivastatin on human saphenous vein (SV), endothelial cells (EC) and smooth muscle cells (SMC). BACKGROUND: Venous bypass graft failure involves EC dysfunction and SMC proliferation. Substances that improve EC function and inhibit SMC proliferation would be of clinical relevance. METHODS: Both EC and SMC were isolated from SV. Endothelial nitric oxide synthase (eNOS) expression and nitric oxide (NO) production were analyzed by immunoblotting and porphyrinic microsensor. The SMC proliferation was assayed by 3H-thymidine incorporation. Protein kinases and cell cycle regulators were analyzed by immunoblotting. RESULTS: Cerivastatin (10(-9) to 10(-6) mol/liter) enhanced eNOS protein expression and NO release (about two-fold) in EC in response to Ca2+ ionophore (10(-6) mol/liter). This was fully abrogated by the HMG-CoA product mevanolate (2 x 10(-4) mol/liter). In SMC, platelet-derived growth factor (5 ng/ml) enhanced 3H-thymidine incorporation (298 +/- 23%, n = 4), activated cyclin-dependent kinase (Cdk2), phosphorylated Rb and down-regulated p27Kip1 (but not p21CiP1). Cerivastatin reduced the 3H-thymidine incorporation (164 +/- 11%, p < 0.01), inhibited Cdk2 activation and Rb phosphorylation, but did not prevent p27Kip1 down-regulation, nor p42mapk and p70S6K activation. Mevalonate abrogated the effects of cerivastatin on Cdk2 and Rb but only partially rescued the 3H-thymidine incorporation (from 164 +/- 11% to 211 +/- 13%, n = 4, p < 0.01). CONCLUSIONS: In humans, SVEC inhibition of HMG-CoA/mevalonate pathway contributes to the enhanced eNOS expression and NO release by cerivastatin, whereas in SMC, inhibition of this pathway only partially explains cerivastatin-induced cell growth arrest. Inhibition of mechanisms other than p42mapk and p70S6K or Cdk2 are also involved. These effects of cerivastatin could be important in treating venous bypass graft disease.