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Volume 46 / Number 1 / 2017

Vasa European Journal of Vascular Medicine

Editor-in-Chief Andreas Creutzig Editors Beatrice Amann-Vesti Erich Minar Pavel PoredoĹĄ Omke Teebken

Die Arzt-Patient Kommunikation verbessern

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Findet eine patientenzentrierte Kommunikation wirklich statt oder bleibt sie Utopie? „Shared Decision Making“ ist das vollständige Teilen aller Informationen über Art, Prognose und Behandlung von Erkrankungen zwischen Arzt und Patient. Das vorliegende Buch beleuchtet in einer umfassenden und qualitativen Untersuchung die Abläufe ärztlicher Konsultationen in allgemeinmedizinischen und spezialfachärztlichen Praxen.

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Vasa European Journal of Vascular Medicine

Volume 46 / Number 1 / 2017

Editor-in-Chief Andreas Creutzig Editors Beatrice Amann-Vest Erich Minar Pavel PoredoĹĄ Omke Teebken

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A. Creutzig, Hannover, andreas@creutzig.de

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ISSN-L 0301-1526 ISSN 0301-1526 (Print) ISSN 1664-2872 (online)

Vasa (2017), 46 (1), 2

© 2017 Hogrefe

Content Reviews

Endovascular management of infected iliofemoral pseudoaneurysms – a systematic review

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Konstantinos G. Moulakakis, Vangelis G. Alexiou, George S. Sfyroeras, John Kakisis, Andreas Lazaris, Spyridon N. Vasdekis, Elias N. Brountzos, and George Geroulakos Registry and health insurance claims data in vascular research and quality improvement

11

Christian-Alexander Behrendt, Franziska Heidemann, Henrik Christian Rieß, Konstanze Stoberock, and Sebastian Eike Debus Original communications

Relationship between endothelial function of micro- and macrocirculation in patients with peripheral arterial disease

17

Pavel Poredoš, Hana Bešič, and Luka Jeraj Critical limb ischaemia and the response to bone marrow-derived cell therapy according to tcPO2 measurement

23

Mario Maufus, Marie Antoinette Sevestre-Pietri, Carmine Sessa, Bernard Pignon, Harald Egelhofer, Stephane Dupas, Philippe Nguyen, Celine Genty, and Gilles Pernod Carotid artery stenting with double cerebral embolic protection in asymptomatic patients – a diffusion-weighted MRI controlled study

29

Ertan Vuruskan, Erhan Saracoglu, Ugur Ergun, Fatih Poyraz, and İrfan Veysel Duzen Long-term individual shear rate therapy counterpulsation enhances plasma nitrite release in patients with peripheral arterial disease

37

Michèle Brix, Eva-Elina Buschmann, Andreas Zietzer, Jonnel Anthony Jaurigue, Lulu Li, Constantin Jungk, Ivo Buschmann, Doreen Janke, and Philipp Hillmeister Increased vascular occlusion in patients with pseudoxanthoma elasticum

47

Simon Pingel, Kristin Solveig Pausewang, Sebastian Gorgonius Passon, Anna Katharina Blatzheim, Martin Gliem, Peter Charbel Issa, Doris Hendig, Fritz Horlbeck, Izabela Tuleta, Georg Nickenig, Nadjib Schahab, Dirk Skowasch, and Christian Alexander Schaefer Comparison of temporary abdominal aortic occlusion with internal iliac artery occlusion for patients with placenta accreta – a non-randomised prospective study

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Yan-Li Wang, Xu-Hua Duan, Xin-Wei Han, Ling Wang, Xian-Lan Zhao, Zhi-Min Chen, Qin-Jun Chu, and Wei Zhang

© 2017 Hogrefe

Vasa (2017), 46 (1), 3

Case reports

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Brucellosis and thrombosis of the inferior vena cava Kristina Rüegger, Philip Tarr, Konstantinos Karatolios, Jörg Humburg, Rolf Hügli,and Christina Jeanneret

64

Intra-arterial thrombolysis of digital artery occlusions in a patient with polycythemia vera Philipp Jud, Franz Hafner, Thomas Gary, Leyla Ghanim, Rainer Lipp, and Marianne Brodmann Letter to the editor

Industry sponsorship and positive outcome in vascular and endovascular randomised trials

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Shahab Hajibandeh, Shahin Hajibandeh, Stavros A. Antoniou, George A. Antoniou, and Francesco Torella Journal club

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From the societies

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Vasa (2017), 46 (1), 4

© 2017 Hogrefe

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Review

Endovascular management of infected iliofemoral pseudoaneurysms – a systematic review Konstantinos G. Moulakakis1, Vangelis G. Alexiou1,3, George S. Sfyroeras1, John Kakisis1, Andreas Lazaris1, Spyridon N. Vasdekis1, Elias N. Brountzos2, and George Geroulakos1 1 2 3

Department of Vascular Surgery, Athens University Medical School, Attikon University Hospital, Athens, Greece Department of Radiology, Athens University Medical School, Attikon, University Hospital, Athens, Greece.

Alfa Institute of Biomedical Sciences (AIBS), Athens, Greece

Summary: We conducted a systematic review regarding the efficacy and outcome of endovascular treatment of infected iliofemoral arterial pseudoaneurysms with covered stents. 35 cases were identified, including 5 own. 22 pseudoaneurysms were located in the femoral area and 13 in the iliac vessels. The most commonly reported complaints were pulsatile groin mass (40 %), sepsis (37.1 %), active bleeding (31.4 %), and groin infection with purulent discharge (17.1 %). S. aureus (65.7 %) and Streptococcus species (22.9 %) were the most common microbes isolated. Factors for the development of infected pseudoaneurysms were intravenous drug use (20 %), infection of anastomosis in bypass surgery (22.9 %), cancer (14.3 %), history of multiple hip operations (14.3 %), renal transplantation (2.9 %), and obesity (5.7 %). The most commonly used covered stents were Viabahn (22.9 %),Jostent (17.1 %), Fluency (14.3 %), and Wallgraft (14.3 %). In 15 cases, surgical debridement and/or drainage was also performed.The mean follow-up was 15.8 months. There were only 2 cases of stent graft thrombosis (5.7 %).

2 patients required an open vascular bypass procedure at a later stage. One death was attributed to procedure-related complications (2.9 %). The infection rate of the deployed stent graft in follow-up was 3.4 %. Endovascular exclusion of an infected pseudoaneurysm with primary stent grafting and drainage may be an option in high-risk patients.

Keywords: Femoral artery, iliac; pseudoaneurysm, infected aneurysm, covered stent, endovascular

Introduction Infected iliac or femoral artery pseudoaneurysms are associated with a high risk of rupture if not treated promptly. These aneurysms appear in intravenous drug users, in patients that have immunodeficiency, and in patients with the acquired immunodeficiency syndrome [1–3].

Surgical management of infected pseudoaneurysms can be extremely challenging because of the extensive damage that the infection has inflicted on the arterial wall [4, 5]. The mortality in open repair ranges from 0 to 4.5 % and can be even higher in emergency arterial reconstructions [4, 6–8].

The use of stent grafts is less invasive but the outcome is unproven in the setting of infected aneurysms. Case reports and small series have reported successful endovascular exclusion of an infected pseudoaneurysm with the use of covered stents associated with surgical debridement and appropriate antibiotic therapy [9–11].

In an attempt to better elucidate the role of stent grafts in this setting, a systematic analysis was performed to examine the outcome in patients with infected iliac or © 2016 Hogrefe

femoral artery pseudoaneurysms that were treated with covered stents.

Methods Systematic literature review An extensive literature review was conducted according to the guidelines proposed at the PRISMA statement. To identify relevant studies, we systematically searched PubMed and Scopus databases (until May 2016) using the following search patterns: (mycotic pseudoaneurysm) OR (infected pseudoaneurysm) OR (mycotic false aneurysm) OR (infected false aneurysm) and (femoral OR iliac). Only patients that were treated with covered stents were included in the study. No limitation on the year of publication or language was set. Furthermore, the references in the relevant articles, including review studies, were checked to identify additional resources. Abstracts of conference proceedings were not searched.

Vasa (2017), 46 (1), 5–9 DOI 10.1024/0301-1526/a000572

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Study selection Two of the authors (VGA and KGM) independently performed the literature search to locate potentially eligible studies (ESM 1. Figure) All studies, including case reports and case series, reporting on presentation, management, and outcomes of patients with infected pseudoaneurysms of the iliac and/or femoral artery treated with covered stents, were considered for inclusion in this systematic review. Studies reporting on non-infected pseudoaneurysms were excluded. There were no language restrictions.

Additionally, we retrospectively reviewed medical files in our department with patients having infected pseudoaneurysms which were treated with covered stents. We included in this review a series of 5 cases from our department [12].

This study was approved by the Committee on Research Ethics at Attikon University Hospital, Athens, Greece.

Data extraction and outcomes The following data were extracted from all eligible articles: first author, year of publication, causes and predisposing factors, detailed data on presenting complaint, treatment, follow-up, re-infection rate, stent graft patency, and outcome. The most important clinical outcomes were tabulated.

Results The database search yielded 385 potentially relevant articles; after studying the titles, abstracts, and full texts, 17 qualified for inclusion. An additional 3 articles were retrieved through the references of these articles. In total, 21 articles reporting 35 cases with infected iliofemoral arterial pseudoaneurysms treated with covered stents fulfilled the inclusion criteria for this systematic review [4–24].

In ESM Tables I and II we present the characteristics and outcomes of the reviewed cases with infected iliofemoral pseudoaneurysms that were treated with endovascular techniques.

The mean and median age of the patients was 57 years.

There were 13, 10, and 9 cases of infected pseudoaneurysms of the common femoral artery (CFA), external iliac artery, and superficial femoral artery, respectively. There were 3 cases of common iliac artery pseudoaneurysms.

The following presenting complaints were most commonly reported: pulsatile groin mass (14 cases, 40 %), sepsis (13 cases, 37.1 %), active bleeding (11 cases, 31.4 %), and groin infection with purulent discharge (6 cases, 17 %). Microorganisms to be detected in blood cultures or pus samples were: Staphylococcus aureus in 23 patients (65.7 %), Streptococcus species (epidermidis, milleri, peptostreptococcus, and agalactiae) in 8 patients (22.9 %). Other microbes were isolated less frequently, including Pseudomonas aeruginosa, Salmonella typhi, Escherichia coli, Vasa (2017), 46 (1), 5–9

K. G. Moulakakis et al., Infected iliofemoral pseudoaneurysms

Enterococcus, and Mycobacterium tuberculosis. Some of the pseudoaneurysms were infected with multiple microbes. In 5 cases (14.3%) there was evident clinical infection but no microbes were isolated and/or reported. The factors that may be associated with the development of the infected pseudoaneurysms were use of intravenous drugs (7 cases, 20 %), anastomotic pseudoaneurysms (8 cases, 22.9 %), cancer (5 cases, 14.3 %), orthopedic operation and especially total hip replacement (5 cases, 14.3%), renal transplantation (1 case, 2.9%), obesity (2 cases, 5.7 %), iatrogenic diseases (2 cases, 5.7 %).

Regarding management of the infected pseudoaneurysms, the most commonly used covered stents were Viabahn (8 cases, 22.9 %), Jostent (6 cases, 17.1 %), Fluency (5 cases, 14.3 %), and Wallgraft (5 cases, 14 .3%). In 2 cases, including the very first report of endovascular management of infected pseudoaneurysm [22], homemade stents were used. It should be noted that in 15 cases graft stenting was combined with surgical debridement and/or drainage.

In most cases the deployment of the stent graft was intended to be a bridging therapy. However, 2 cases required an open vascular bypass procedure at a later stage. 1 patient developed gangrene (2.9 %) and had to be amputated and one required further debridement of the infected groin.

The mean and median duration of hospital stay was 29 and 21 days, respectively. Only 1 death may be attributed to procedure-related complications. Specifically, Karkos et al. reported that their patient suffered a massive pulmonary embolism (PE) 2 h post-op [8]. This PE may have been precipitated by stent grafting. They hypothesized that a preexisting thrombus in the femoral vein may have been compressed during balloon post-dilation of the stent graft in the neighboring femoral artery and been dislodged to cause PE. In 6 other cases the patients died within the same admission or during the follow-up. However, their deaths were not related to the pseudoaneurysm. Thus, procedure-related mortality was 2.9 % and all-cause mortality was 20 %. The mean and median follow-up of the reported cases was 15.8 and 12 months, respectively. Within this time, there were only 2 case reports of stent graft thrombosis (5.7 %). The rest remained patent and the patients were asymptomatic. There was only 1 report of infection of the deployed stent graft (2.9 %). In this case, the graft had to be removed and a bypass with vein graft was performed. In total, 6 patients had a follow-up of less than 5 months either because they were lost to follow-up or died. The reinfection rate within the rest was 3.4 % and the patency rate was 90 %.

Discussion Standard surgical treatment of infected aneurysms consists of radical excision of the infected aneurysm and debridement with (extra-anatomic bypass or in situ graft placement) or without revascularization, followed by longterm antibiotic therapy [2, 25, 26]. It is accepted that revas© 2016 Hogrefe

K. G. Moulakakis et al., Infected iliofemoral pseudoaneurysms

cularization is not mandatory when there is adequate collateralization via the deep femoral artery [27]. However, Naqi et al. have reported a high amputation rate (23 %) after vessel ligation without immediate revascularization [28]. Their report was confirmed by Georgiadis et al., who reviewed the outcomes of this management in intravenous drug users and found high rates of claudication and disability (early 54.4 % and late 44.3 %) [29]. Furthermore, in cases where immediate revascularization, either in situ or by extra-anatomic bypass, was performed, through noninfected tissue planes, there were high rates of graft infection (early 21.1 % and late 32.4 %), sepsis and anastomotic dehiscence (14 %), and amputation (early 9.8 % and late 11.3 %). Despite the fact that the incidence of infection in autologous grafts is low compared to prosthetic grafts, the risk is considerable and should not be ignored. Bacterial infection may, in some cases, break down the anastomosis of autologous arterial or vein grafts.

The role of endoluminal stent grafts in the presence of infection is controversial. We performed a systematic review analysis of the current literature regarding the efficacy and outcome of endovascular treatment of infected iliofemoral arterial pseudoaneurysms with covered stents. In our review, with a mean follow-up of 15.8 months, the reinfection rate was low (3.4 %) and the patency rate was high (90 %). These results are fairly encouraging. The option to exclude the pseudoaneurysm endovascularly and to treat the infection both locally with debridement/drainage and systematically with antibiotic therapy is appealing and provides rapid bleeding control and maintenance of distal perfusion [9, 11, 32]. Surgical management of infected pseudoaneurysms can be extremely challenging because of the extensive damage that an infection has inflicted on the arterial wall [28, 33]. Stent grafting has the advantage of avoiding surgical maneuvers in an already contaminated area and reduces the risk of further bleeding and arterial wall damage in hemodynamically unstable patients. Drug users commonly suffer from suppurative or septic thrombophlebitis and a have history of deep venous thrombosis. This is extremely important when considering treatment, as there is poor availability of autologous venous grafts [34, 35]. Patients with cancer or multiple orthopedic hip operations often have a hostile femoral region anatomy. Furthermore, open repair is not a safe option for patients with cancer who often have several comorbidities, a history of radiotherapy, and a limited life expectancy.

A critical issue is that deployment of stent grafts in an infected environment may lead to closed-space infection with catastrophic complications. In the current review, the incidence of covered stent infectious complications was rather low (3.4 %). Exclusion of pseudoaneurysm with a stent was intended to be a bridging therapy and damage control measure, as was described by most authors. However, in most cases it has been proven a definite and effective therapy. Conceptually, a high bacterial load may impair healing by causing a wound environment not conducive to healing [36]. The high bacterial load normally leads to the development of adherent bac© 2016 Hogrefe

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teria-laden biofilm, perigraft exudate, absence of graft incorporation and, eventually, graft infection [37]. Biofilms consist of microcolonies produced by the bacteria irreversibly attached to a substratum or interface or to each other. This happens in two steps: first, an attachment to a surface and, secondly, a cell-to-cell adhesion, with pluristratification of bacteria onto the artificial surface [38]. Bacteria growing in biofilms cannot be eradicated by antibiotics and biofilms resist the immunological and non-specific defense mechanisms of the body [39]. This has clearly not happened in the reviewed cases of our analysis, leading us to hypothesize that the bacterial load that the covered stents were exposed to was rather low and did not permit the formation of a biofilm. We also explain this with the hypothesis that a relatively minimal arterial defect, which leads to the development of the pseudoaneurysm, may not provide a clinically substantial exposure to cause a prosthesis infection. Appropriate antibiotic therapy combined with debridement and provisional drainage may control or even treat sepsis.

It should be noted that placement of a covered stent across the length of the CFA may compromise the profunda femoral artery origin and undoubtedly is an undesirable event. In other cases, embolization of the profunda may be needed to exclude the pseudoaneurysm. There is also a concern of device damage by the repeated flexion and extension of the hip joint [38]. In addition, placement of a covered stent in the CFA is likely to impede percutaneous puncture or access for vascular or cardiac intervention at a later date [32]. Previous studies, in patients with atherosclerotic disease receiving endovascular treatment, have shown that the technique is safe and has acceptable clinical outcomes [41, 42]. New-generation covered stents have improved their mechanical properties in terms of behavior in the stresses of repetitive motion [43]. In most cases, patients with infected pseudoaneurysms do not have atherosclerotic disease. Placement of stents in vessels with no atherosclerosis or narrowing may provide better long-term patency.

Limitations Our study has several limitations. First, the number of patients treated with this technique is rather low. Most importantly, the results of our analysis were based on case reports and small series and may be biased by confounding factors such as variation in disease severity and progression, co-occurring treatment, and treatment selection. In addition, the follow-up period was relatively short and doesn’t provide evidence for long-term patency and durability. Finally, the “file-drawer effect” [44] should be acknowledged when interpreting the results of this review, meaning that authors tend to publish cases of patients who had good outcomes, and put the cases with complications in the file drawer when using a novel technique.

Vasa (2017), 46 (1), 5–9

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K. G. Moulakakis et al., Infected iliofemoral pseudoaneurysms

Conclusions Our study provides evidence that endovascular exclusion of an infected pseudoaneurysm with primary stent grafting and drainage seems to be effective with low incidence of stent infection and should be considered in hemodynamically unstable patients, patients with unavailability of autologous venous grafts, and patients with hostile femoral anatomy. Although the number of published cases, as summarized by the current review, is low, the results are encouraging and support the need to conduct larger studies in order to evaluate the durability of the endovascular management.

Electronic supplementary material The electronic supplementary material is available with the online version of the article at http://dx.doi.org/ 10.1024/0301-1526/a000572.

ESM 1. Figure.

Description of the selection process followed to identify reports included in this systematic review.

ESM 2. Table I. Main clinical characteristics of the reviewed cases with infected iliofemoral pseudoaneurysms that were treated with endovascular techniques.

ESM 3. Table II. Intraoperative characteristics, stent patency and outcome of the reviewed cases with infected iliofemoral pseudoaneurysms.

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29. Georgiadis GS, Lazarides MK, Polychronidis A, et al. Surgical treatment of femoral artery infected false aneurysms in drug abusers. ANZ J Surg. 2005;75:1005–10.

30. Salimi J, Shojaeefar A, Khashayar P. Management of infected femoral pseudoaneurysms in intravenous drug abusers: a review of 57 cases. Arch Med Res. 2008;39:120–4.

31. Lashkarizadeh MR, Ashrafganguie M, Ashrafganguie M. Surgical management of femoral artery pseudoaneurysms secondary to drug abuse. J Coll Physicians Surg Pak. 2011;21:672–5.

32. Klonaris C, Katsargyris A, Papapetrou A, et al. Infected femoral artery pseudoaneurysm in drug addicts: the beneficial use of the internal iliac artery for arterial reconstruction. J Vasc Surg.

2007;45:498–504.

33. Tsao JW, Marder SR, Goldstone J, et al. Presentation, diagnosis, and management of arterial mycotic pseudoaneurysms in injection drug users. Ann Vasc Surg 2002;16:652–62.

34. Padberg F, Hobson R, Lee B, et al. Femoral pseudoaneurysm from drugs of abuse: ligation or reconstruction? J Vasc Surg.

1992;15:642–68.

35. Reddy DJ, Shepard AD, Evans JR, et al. Management of infected aortoiliac aneurysms. Arch Surg. 1991;126:873–8; discussion 878–9.

36. Xu L, McLennan S V, Lo L, et al. Bacterial load predicts healing rate in neuropathic diabetic foot ulcers. Diabetes Care.

2007;30:378–80.

37. Bergamini TM, Bandyk DF, Govostis D, et al. Infection of vascular prostheses caused by bacterial biofilms. J Vasc Surg.

1988;7:21–30.

38. Donlan RM. Biofilms: microbial life on surfaces. Emerg Infect Dis. 2002;8:881–90.

39. Costerton JW, Montanaro L, Arciola CR. Biofilm in implant infections: its production and regulation. Int J Artif Organs.

2005;28:1062–8.

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40. Cheng CP, Choi G, Herfkens RJ, et al. The effect of aging on deformations of the superficial femoral artery resulting from hip and knee flexion: potential clinical implications. J Vasc Interv Radiol. 2010;21:195–202.

41. Azéma L, Davaine JM, Guyomarch B, et al. Endovascular repair of common femoral artery and concomitant arterial lesions.

Eur J Vasc Endovasc Surg. 2011;41:787–93.

42. Baumann F, Ruch M, Willenberg T, et al. Endovascular treatment of common femoral artery obstructions. J Vasc Surg.

2011;53:1000–6.

43. Aghel A, Armstrong EJ. Recent advances in self-expanding stents for use in the superficial femoral and popliteal arteries.

Expert Rev Cardiovasc Ther. 2014;12:833–42.

44. Rosenthal R. The file drawer problem and tolerance for null results. Psychol Bull. 1979;86:638–41.

Submitted: 20.04.2016 Accepted after revision: 15.06.2016 There are no conflicts of interest to report.

Published online: 07.12.2016

Correspondence address Dr. Konstantinos G. Moulakakis Department of Vascular Surgery University of Athens, Attikon Hospital Athinon 132 st.

16561 Athens Greece konmoulakakis@yahoo.gr

Vasa (2017), 46 (1), 5–9

46. Jahrestagung

Deutsche Gesellschaft für Angiologie Gesellschaft für Gefäßmedizin e.V.

13. – 16. September 2017 in Berlin

Die Gefäßinternisten Sichere Wege für Patienten WISSENSCHAFTLICHE LEITUNG Dr. med. Clemens Fahrig, Gefäßzentrum Berlin-Brandenburg

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Review

Registry and health insurance claims data in vascular research and quality improvement Christian-Alexander Behrendt, Franziska Heidemann, Henrik Christian Rieß, Konstanze Stoberock, and Sebastian Eike Debus University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany Department of Vascular Medicine GermanVasc

Summary: The expansion of procedures in multidisciplinary vascular medicine has sparked a controversy regarding measures of quality improvement. In addition to primary registries, the use of health insurance claims data is becoming of increasing importance. However, due to the fact that health insurance claims data are not collected for scientific evaluation but rather for reimbursement purposes, meticulous validation is necessary before and during usage in research and quality improvement matters. This review highlights the advantages and disadvantages of such data sources. A recent comprehensive expert opinion panel examined the use of health insurance claims data and other administrative data sources in medicine. Results from several studies concerning the validity of administrative data varied significantly. Validity of these data sources depends on the clinical relevance of the diagnoses considered. The rate of implausible information was 0.04 %, while the validity of the considered diagnoses varied between 80 and 97 % across multiple validation studies. A matching study between health insurance claims data of the third-largest German health insurance provider, DAK-Gesundheit, and a prospective primary registry of the German Society for Vascular Surgery demonstrated a good level of validity regarding the mortality of endovascular and open surgical treatment of abdominal aortic aneurysm in German hospitals. In addition, a large-scale international comparison of administrative data for the same disorder presented important results in treatment reality, which differed from those from earlier randomized controlled trials. The importance of administrative data for research and quality improvement will continue to increase in the future. When discussing the internal and external validity of this data source, one has to distinguish not only between its intended usage (research vs. quality improvement), but also between the included diseases and/or treatment procedures. Linkage between primary registry data and administrative data could be a reasonable solution to some current major issues of validity.

Keywords: Registry, administrative data, health insurance claims data, data validity, quality improvement, routine data

Introduction Global networking and modern information technology have become essential to current medical practice. While the medical records of clinics from 20 years ago once occupied the space of entire buildings, we are now observing an ever-increasing trend towards the digitalization of treatment and accounting data. This trend has been adapted and made useful in the areas of quality control and health care research, where paper-based records are also being traded in for their digital counterparts. “Big Data” has become an inconsistently defined catch phrase for the observed rapid development of large data banks [1]. As a result, data registries, in all their varying forms, are becoming increasingly valuable sources of information (ESM 1). The Latin-derived word “register”, in its original form, is defined as nothing more than a central catalogue of © 2016 Hogrefe

knowledge. With respect to studies concerning health care research and quality, such corresponding registries (e. g., health care research and quality control registries) provide central collection points for project-relevant information, independent of the type of information, as well as the route of transmission. In contrast to randomized controlled trials, where only strict, previously defined patient cohorts can be included (therefore making such studies unsuitable for quality control and health care research), registries allow for the inclusion of a much larger population and thereby more closely reflect the inhomogeneous nature of health care reality. For example, a consolidation of 11 international registry initiatives of the International Consortium of Vascular Registries, in cooperation with the Vascunet Initiative of the European Society for Vascular Surgery, was able to show that, for the years 2010–2013, countries that employed case-based remuneration of abVasa (2017), 46 (1), 11–15 DOI 10.1024/0301-1526/a000589

12

dominal aneurysms operated earlier and more frequently when compared to countries with a community-based compensation structure. Since then, similar projects concerning extracranial carotid artery stenosis and peripheral arterial occlusive disease have been undertaken and are awaiting publication.

The potential danger of the uncontrolled expansion of billable services is currently the subject of controversial debate in Germany. In 2016, the National Association of Statutory Health Insurance Funds in Germany counted 118 different companies insuring approximately 72 million German citizens with statutory health care insurance. Another 9 million citizens are insured by approximately 50 private health insurance companies. In a 2012 Institute for Quality and Patient Safety expert panel of the Federal Ministry of Health, the authors laid the initial groundwork for discussion on the topic of “Pay for Performance in Health Care” and, with that, established the general future direction of the development of the German health care system [2].

The central question of valid method selection for the determination of quality of care within the field of vascular medicine remains unanswered; registries are also not without their limitations. For example, due to the lack of consistent monitoring and the often varying methods of input, the validity of data collected in primary registries is limited. Validity can be described via external and internal processes: External validity is defined by the complete, uninterrupted acquisition of the planned number of cases, and allows one to draw valid conclusions from the entire cohort or study population. Internal validity, on the other hand, describes the accurate, error-free input of study observations. The implementation of plausibility tests and data monitoring methods should ultimately increase validity. It should be noted that the conceptualization and operation of registries of such magnitudes require great effort from all those involved. In times of ever-increasing clinical workload, the input of treatment data into register platforms represents for many an additional task to be performed, without direct compensation. This is particularly

C.-A. Behrendt et al., Administrative data in vascular medicine

problematic when the prescribed principles of data minimization are not implemented or enforced. It is therefore understandable that the field of health care research has thus far been reliant on the utilization of so-called administrative data (i. e., secondary data). This includes, in addition to socio-demographic details of the insured persons, comprehensive information on treatment (both in- and outpatient) and prescribed medication [3]. Administrative data are compiled for routine health insurance claim purposes and therefore generally do not require additional action from clinicians. As early as in the 1990s, efforts were made to utilize such data sets for questions concerning quality control [4]. These data, however, are not generated or collected within the framework of scientific inquiry and, as a result, are subjected to a certain amount of bias. This brings the validity of such data sources into question, particularly with regard to their appropriateness for use for quality control purposes, and is a current topic of critical discussion among surgeons [5].

As a result, the validity of administrative data should be subject to continuous verification, as is the case with primary surveys. Despite the above-mentioned limitations, arguments that advocate the use of such data sources do exist. This article aims to provide an in-depth overview of primary registries and administrative data within the field of vascular medicine, and presents a comparison of their benefits and disadvantages as data sources.

A narrative review was conducted to obtain an overview of available scientific articles concerning the validation of primary registries and administrative data.

Results In their extensive data assessment for the German Institute of Medical Documentation and Information, Schubert et al. [6] demonstrated that the benefits of administrative data selection result predominantly from it being thorough, comprehensive and population-based. In addi-

Table I. Advantages and disadvantages of administrative data from Schubert et al. 2014 [6], and Braun and Müller 2006 [22].

Advantages of administrative data

Disadvantages of administrative data

– Pseudonymized personal data: estimates of incidence and prevalence, long-term accounts of disease progress and care history, degree of health care utilization – Population-oriented: comparison of the general population with the insured population, including socio-demographic data – Precise extrapolation due to the representativeness of the sample cohort possible – Non-biased involvement of all insured persons in the sample: no self-selection by researchers, inclusion of less accessible groups – Completeness from routine acquisition – Cross-sector detection (intersectorality) – Low cost of collection and use – Long periods of observation – Large observation groups – Mass data: detectability of rare events or risks

– Not originally acquired for research purposes: verification of validity and reliability necessary – Acquisition solely of invoiced treatment data – Lack of population representativeness from individual health insurance providers (comparison of socio-demographic factors) – Flat service charges: not all individual consultations recorded – Lack of clinical information (e.g., BMI, lab results, severity of disease) – Lack of data for self-medication or private prescriptions – No information regarding individual dosages – Nonreactive data: no observer influence (bias) – Possible changes in the long term (accounting system, classifications)

Vasa (2017), 46 (1), 11–15

© 2016 Hogrefe

C.-A. Behrendt et al., Administrative data in vascular medicine

tion, such data are not subjected to selection bias and allow for the examination of large populations over long periods of time. Major disadvantages of such a system, on the other hand, stem from the lack of data concerning non-refundable services (e. g., self-medication), as well as from the absence of clinical parameters for diagnostic validation (Table I). The authors therefore stress the need for indepth examination or verification of data sources before their use in scientific investigation.

In the German Society for Social Medicine and Prevention and the German Society for Epidemiology workgroup’s guideline “Gute Praxis Sekundäranalyse (GPS)” (good practical secondary analysis), which was last updated in 2014, the authors define a set of standards for the scientific use of secondary data [7]. In agreement with the abovementioned recommendation, the authors advocate the employment of plausibility controls both before and during secondary data analysis, as well as careful consideration of potential interfering factors. An important prerequisite for the methodological use of administrative data is the establishment of the target population; conclusions concerning the total population cannot be readily drawn from the data acquired from a single health insurance provider. Hoffmann and Icks come to the same conclusion following a comparison of client profiles and morbidity structures of 10 German health insurance providers. They determined differences that could not alone be explained by age or sex.

The authors therefore recommend the consideration of such differences, as well as the naming of cooperating health insurance providers for such studies, but also reiterate the importance of data gained from individual insurance providers for health care research [8]. Hartmann et al. performed a review of the internal validity of administrative data from the fifth-largest German health insurance fund, AOK Baden-Württemberg. 3.8 million persons were insured by this provider. In this study, it was found that the proportion of implausible information was relatively low (0.04 %). The authors concluded that administrative data from statutory health insurance providers represent a legitimate source of information for numerous scientific inquiries within the area of health care research, provided an appropriate validation process is in place [9]. Schubert et al. also conducted an internal validation of the diagnoses heart failure, tuberculosis, and dementia, three inhomogeneous chronic diseases, using administrative data from another large regional health insurance fund, counting approximately 1.3 million insured persons. Due to the lack of validation standards, a comparison of, among other things, multiple quarterly periods was performed using alternative available data sources. The internal validity of inpatient diagnoses was between 80 and 97 % [10].

Neubauer et al. demonstrated that administrative data could be validly used to examine the implementation of guideline recommendations in daily clinical routine. Limitations were however observed in the study of lifestyle habits and various clinical parameters [11].

In a current survey of 2,000 German chief physicians, the Professional Association of German Surgeons recently © 2016 Hogrefe

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determined that, in spite of the evidence, almost 96 % of the respondents were of the opinion that a procedure for quality assurance of inpatient care using administrative data does not in fact objectively measure quality. Approximately 34 % were of the opinion that their own department was falsely assessed. Following a literature review, the authors furthermore came to the conclusion that the validity of current indicators of quality (derived from administrative data), are “generally poor” when placed within the international context [5]. The backdrop of this survey was a consortia project, led by a large association of regional health care insurance funds, which in 2002 had already begun to develop solutions for quality assurance in administrative data. They published their results and introduced a conception on how to measure quality in medicine in 2007 [12]. In a statement from the German Medical Association, released under the title “administrative data still not an alternative to Institute for Quality and Patient Safety procedures”, the authors argued first and foremost that only the so-called BQS procedure, with defined quality indicators, reference ranges, and risk adjustment measures, enables insight into medical processes and performance [13]. The key issue of the controversial debate was not so much vascular health care research, but rather the assessment of performance or quality of surgical institutions on the basis of administrative data. Inadequate risk adjustment could lead to the danger of placing departments with particularly complex case profiles, such as university clinics, at a disadvantage. To avoid this, the inclusion of supplementary clinical parameters (not found in administrative data) would be necessary. Furthermore, it is generally not possible to identify the individual treating department, but rather only the respective accounting unit. Difficult or complicated cases, for example, are often assigned to the intensive care department. It is thus not valid to draw retrospective conclusions from such data sources regarding the treating surgical or interventional department.

Birkmeyer et al. performed a particularly thorough analysis of quality control in the field of surgery [14]. In their study, the authors conclude that the sheer range of interventional possibilities dictates the need for multiple quality parameters, and furthermore recommend that focus be placed on the respective frequencies, as well as on the general risk of the varying procedures. Interventions with high mortality and fatality rates could be thus suitably measured. In a systematic review, Ploeg et al. also studied indicators of quality in the field of vascular surgery. On the basis of 57 selected publications, the authors conclude that the majority of studies use outcome as a major indicator of quality. Fatality rates, either from primary treatment or over the course of time, as well as treatment-specific mortality (e. g., stroke following carotid surgery) were particularly emphasized. Due to the high level of procedural complexity in vascular surgery, the authors recommend that the focus be placed on structure and process quality [15]. For intact and ruptured abdominal aortic aneurysm (AAA), a comprehensive comparison of adminVasa (2017), 46 (1), 11–15

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istrative data from the third-largest German health insurance provider with approximately 6.3 million insured persons, DAK-Gesundheit (DAK-G), with primary data from the prospective registry on AAA of the German Society for Vascular Surgery was performed. The results showed that, across the board, hospital mortality appears to represent a major parameter of quality [16]. Furthermore, in subsequent analyses of the DAK-G and the BARMER GEK (second-largest health insurance provider with approximately 8.4 million insured persons), consensus between administrative and register data, as well as that from RCT of intact and ruptured AAA, was observed, which is indicative of validity with respect to treatment mortality. According to the authors, a major advantage of administrative data is the non-selective inclusion of all treating specialists and treatment of the insured population, whereas registries from specific expert associations generally only involve one specialization [17].

A large-scale international comparison of administrative data sets regarding treatment of ruptured AAA was recently published by Karthikesalingam et al. More than 35,000 hospital cases were investigated and compared, with data generated from the Hospital Episode Statistics for England (HES) and the US Nationwide Inpatient Sample. In contrast to earlier randomized controlled trials, this retrospective study of the health care situation was able to demonstrate an improved outcome of endovascularlytreated ruptured AAA [18]. In their study, Holt et al. built upon this and concerned themselves with the validity of the employed HES data. In a comparison of data sets regarding intact AAA with those of the “gold standard” Office for National Statistics, the comprehensiveness and the accuracy of coding were examined. Here, it was shown that 86 % of cases were correctly documented. In particular, living status (the most important outcome parameter) was correctly recorded over 99 % of the time. The authors conclude that an effective comparison of treatment fatality rates between hospitals is possible and relegate the responsibility of accurate documentation to the clinicians [19]. Schermerhorn et al. also investigated changes in the medical treatment situation of ruptured AAA between 1995 and 2008. For this study, administrative data from the US Medicare (ESM 1) beneficiaries was employed.

With the help of over 400,000 analyzed administrative data sets, the authors were able to make important observations regarding international vascular medicine. For example, the percentage of intact AAA patients over 80 years of age receiving treatment has increased substantially over the years; a possible reason for this trend discussed by the authors includes the development of endovascular therapies (EVAR). In their conclusion, Schermerhorn et al. note that the acquired administrative data did not contain any anatomical information, and that only the in-hospital deaths following rupture were included [20]. In general, it appears that the differing results of validation are highly dependent on clinical relevance; data concerning diseases or diagnoses such as myocardial infarction and stroke demonstrate a high level of validity (up to 99 %), whereas Vasa (2017), 46 (1), 11–15

C.-A. Behrendt et al., Administrative data in vascular medicine

cases involving, e. g., acute liver damage due to pharmacological treatment are only validly acquired and/or documented 16 % of the time [21].

Conclusions The importance of administrative data for research and quality improvement will continue to increase in the future. When discussing the internal and external validity of this data source, one has to distinguish not only between its intended usages (research vs. quality improvement), but also between the included diseases and/or treatment procedures. Data validity is largely dependent on the clinical relevance of diagnosis, where major complications such as myocardial infarction and stroke demonstrate a high level of validity. The lack of standards available to objectively assess the validity of administrative data further complicates the matter. Nevertheless, when used under conscientious consideration of the above-mentioned limitations and after fulfilling certain predefined requirements, such data sets can serve as valuable information sources. As currently no other valid vascular medicine primary data registries exist in Germany, researchers must in part rely on alternatives to answer relevant questions in the areas of health care research and quality assurance. At the present time, internal and external validity verification measures of data banks, such as the prospective register for AAA, are not available. As a result, the Medical Service of the Health Insurance Funds performs random sample analyses of documentation/coding quality, in an attempt to partially counteract this problem, using claims data.

Logically, administrative data sets can only provide correlation information of items that have been included within the data set. Clinical parameters, such as the diameter of treated aortic aneurysms or the reduction in quality of life, are not included in the registries. It is not even possible to gain information regarding the treating discipline, let alone that of the particular surgeons involved. An assessment of individual parameters is therefore only possible at the level of accounting, and not at the level of the surgical department. As a result, this form of data is generally unsuitable for a valid examination of quality assurance. Linking the information in administrative data sets with that of primary registries may provide a solution to counteract the above-mentioned limitations. The Berlin Heart Attack Registry has already performed such an undertaking, and has successfully linked pseudonymized primary data with administrative data from a large regional health insurance provider [23]. Within the overall framework of the currently available information, along with conscientious consideration of the advantages and disadvantages of both administrative and primary data registries, the use of administrative data in research can be summarized as follows: a good compromise and sometimes the only alternative. © 2016 Hogrefe

C.-A. Behrendt et al., Administrative data in vascular medicine

Electronic Supplementary Material The electronic supplementary material is available with the online version of the article at http://dx.doi.org/ 10.1024/0301-1526/a000589.

ESM 1. Table I. Selected primary registries (P), registries with administrative data (A), and study registries (S).

References 1. Binder H, Blettner M. Big data in medical science – a biostatistical view. Dtsch Arztebl Int. 2015;112:137–42.

2. Veit C, Hertle D, Bungard S, et al. Pay-for-Performance im Gesundheitswesen: Sachstandsbericht zu Evidenz und Realisierung sowie Darlegung der Grundlagen für eine künftige Weiterentwicklung. Ein Gutachten im Auftrag des Bundesministeriums für Gesundheit. 2012. Online at http://www.bmg. bund.de/fileadmin/dateien/Pressemitteilungen/2012/ 2012_03/120817_PM_58_Anlage_Gutachten_BQS_01.pdf [last accessed September 2016].

3. Ohlmeier C, Frick J, Prütz F, et al. [Use of routine data from statutory health insurances for federal health monitoring purposes]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz. 2014;57:464–72. [German] 4. Iezzoni LI, Foley SM, Heeren T, et al. A method for screening the quality of hospital care using administrative data: preliminary validation results. Qual Rev Bull. 1992;18:361–71.

5. Hanisch E, Weigel TF, Buia A, et al. [The validity of routine data on quality assurance: A qualitative systematic review]. Chirurg.

2016;87:56–61. [German] 6. Schubert I, Ihle P, Köster I, et al. Gutachten: Daten für die Versorgungsforschung. Zugang und Nutzungsmöglichkeiten. Datengutachten für das DIMDI. 2014. Online at www.dimdi.de [last accessed September 2016].

7. Swart E, Gothe H, Geyer S, et al. Gute Praxis Sekundärdatenanalyse (GPS): Leitlinien und Empfehlungen. Gesundheitswesen. 2015;77:120–6.

8. Hoffmann F, Icks A. Unterschiede in der Versichertenstruktur von Krankenkassen und deren Auswirkungen für die Versorgungsforschung: Ergebnisse des Bertelsmann-Gesundheitsmonitors. Gesundheitswesen. 2011;74:291–7.

9. Hartmann J, Weidmann C, Biehle R. Validierung von GKV-Routinedaten am Beispiel von geschlechtsspezifischen Diagnosen. Gesundheitswesen. 2015. DOI: 10.1055/s-0035-1565072.

10. Schubert I, Ihle P, Köster I. Interne Validierung von Diagnosen in GKV-Routinedaten: Konzeption mit Beispielen und Falldefinition. Gesundheitswesen. 2010;72:316–22.

11. Neubauer S, Zeidler J, Schilling T, et al. Eignung und Anwendung von GKV-Routinedaten zur Überprüfung von Versorgungsleitlinien am Beispiel der Indikation Linksherzinsuffizienz. Gesundheitswesen. 2016. DOI: 10.1055/s-0042-100727.

12. AOK-Bundesverband, FEISA, Helios-Kliniken, et al. Qualitätssicherung der stationären Versorgung mit Routinedaten (QSR)

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– Abschlussbericht. Wissenschaftliches Institut der AOK (WIdO). 2007.

13. Zorn U. Qualitätssicherung: Routinedaten noch keine Alternative zum BQS-Verfahren. Dtsch Arztebl Int. 2007;104:A-2172.

14. Birkmeyer JD, Dimick JB, Birkmeyer NJ. Measuring the quality of surgical care: structure, process, or outcomes? J Am Coll Surg. 2004;198:626–32.

15. Ploeg AJ, Flu HC, Lardenoye JH, et al. Assessing the quality of surgical care in vascular surgery; moving from outcome towards structural and process measures. Eur J Vasc Endovasc Surg. 2010;40:696–707.

16. Debus ES, Torsello G, Behrendt CA, et al. [Perioperative mortality following repair for abdominal aortic aneurysm in Germany: Comparison of administrative data of the DAK health insurance and clinical registry data of the German Vascular Society]. Chirurg. 2015;86:1041–50. [German] 17. Behrendt CA, Marschall U, L’Hoest H, et al. Current treatment of abdominal aortic aneurysms in Germany – Outcomes and trends in a 5-year follow-up from registry and health insurance data. In: Greenhalgh R (ed.). Charing Cross 2016 – Vascular and Endovascular Challenges Update. London: BIBA Medical 2016.

18. Karthikesalingam A, Holt PJ, Vidal-Diez A, et al. Mortality from ruptured abdominal aortic aneurysms: clinical lessons from a comparison of outcomes in England and the USA. Lancet.

2014;383:963–9.

19. Holt PJ, Poloniecki JD, Thompson MM. Multicentre study of the quality of a large administrative data set and implications for comparing death rates. Br J Surg. 2012;99:58–65.

20. Schermerhorn ML, Bensley RP, Giles KA, et al. Changes in abdominal aortic aneurysm rupture and short-term mortality, 1995–2008: a retrospective observational study. Ann Surg 2012;256:651–8.

21. Hoffmann F, Andersohn F, Giersiepen K, et al. Validierung von Sekundärdaten. Bundesgesundheitsblatt – Gesundheitsforschung – Gesundheitsschutz. 2008;51:1118–26.

22. Braun B, Müller R. Gesundheitsberichterstattung mit GKV-Daten. Schriftenreihe zur Gesundheitsanalyse – Vom Quer- zum Längsschnitt mit GKV-Daten. 2006; Band 51.

23. Maier B, Behrens S, Busse R, et al. Das Berliner Herzinfarktregister als Beispiel für ein klinisches Register. Public Health Forum. 2012;20.

Submitted: 21.07.2016 Accepted after revision: 25.08.2016 There are no conflicts of interest to report.

Published online: 21.11.2016

Correspondence address Dr. Christian-Alexander Behrendt Department of Vascular Medicine University Heart Center Hamburg Martinistraße 52 20246 Hamburg Germany ch.behrendt@uke.de

Vasa (2017), 46 (1), 11–15

Gesundheit, Krankheit und das Gesundheitssystem verstehen

David Klemperer

Sozialmedizin – Public Health Gesundheitswissenschaften Lehrbuch für Gesundheits- und Sozialberufe 3., überarb. Aufl. 2015. 384 S., 153 Abb., Kt € 29,95 / CHF 39.90 ISBN 978-3-456-85550-9 Auch als eBook erhältlich

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Dazu zählt das Wissen über • Individualmedizin und Bevölkerungsgesundheit (Public Health) • Modelle von Gesundheit und Krankheit • Epidemiologie und Forschungsmethoden • Prinzipien einer evidenzbasierten beruflichen Praxis • Theorie und Praxis von Gesundheitsförderung und Krankheitsprävention • soziale Ungleichheiten der Gesundheit.

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Angesprochen sind ebenfalls Patientenvertreter in der Selbstverwaltung, Krankenkassenmitarbeiter, Mitglieder und Mitarbeiter der gesundheitsbezogenen Selbsthilfe, Journalisten und an Gesundheitspolitik Interessierte.

17

Original communication

Relationship between endothelial function of micro- and macrocirculation in patients with peripheral arterial disease Pavel Poredoš, Hana Bešič, and Luka Jeraj University Medical Centre Ljubljana, Department of Vascular Disease, Slovenia

Summary: Background: In the pathogenesis of peripheral arterial occlusive disease (PAD), different risk factors of atherosclerosis are involved which stimulate the development of the functional and morphological deterioration of vessel walls in macroand microcirculation. The endothelial dysfunction (ED) of macrovessels has been proven, however, data on ED in microcirculation are sparse. Therefore, we have studied the relationship between micro- and macrocirculation in PAD patients. Patients and methods: The study included 85 participants: 30 patients had PAD without diabetes mellitus, 30 patients had PAD and diabetes mellitus type 2, and 25 were healthy controls. Flow-mediated dilation (FMD) and endothelium-independent dilation (NMD) were studied as markers of macrocirculation, while ED of microcirculation was determined by peripheral arterial tonometry, which enabled calculation of the reactive hyperemia index (RHI). Simultaneously, the augmentation index (AI) as a measure of arterial stiffness was calculated. Results: In comparison to healthy subjects, PAD patients had reduced FMD (5.7 ± 1.3 % vs.

10.0 ± 2.4 %, p < 0.001) and significantly decreased NMD (11.0 ± 2.9 % vs 23.0 ± 9.0 %, p < 0.001). Low-flow-mediated constriction was not significantly different between the groups. In both groups of patients, RHI was significantly lower than in the controls (1.75 ± 0.45 vs. 2.05 ± 0.54, p = 0.033). Furthermore, AI as an indicator of arterial stiffness was significantly higher in patient groups than in controls. However, there were no significant differences between the groups of PAD patients with and without diabetes mellitus in indicators of the functional capability of micro- and macrocirculation. An interrelationship was shown between risk factors and both FMD and NMD. Significant correlation was also found between FMD and RHI, as was a borderline correlation between FMD and AI. Conclusions: In PAD patients with and without diabetes, the functional capability of the entire arterial system is deteriorated. These patients have ED in micro- and macrocirculation, as well as increased arterial stiffness.

Keywords: Endothelial dysfunction, peripheral arterial occlusive disease, circulation, vascular, diabetes mellitus

Introduction Peripheral arterial occlusive disease (PAD) represents one of the most advanced forms of atherosclerosis. Therefore, it is expected that in this group of patients advanced functional and morphological systemic deterioration of arterial walls, including endothelial dysfunction (ED), is present [1].

ED is an integrating index of the burden of atherosclerotic risk factors and one of the earliest measurable markers of atherosclerosis. Therefore, tremendous interest exists in its measurement and the determination of the clinical utility of the evaluation of the endothelial function. Since ED is usually a systemic disorder, the peripheral arteries, because of their easy accessibility, represent the basis for the assessment of the function of the artery system [2]. © 2016 Hogrefe

Some investigations indicated that patients with PAD have significantly reduced endothelial-dependent flowmediated dilation (FMD) of the brachial artery and that ED is an independent predictor of the progression of atherosclerosis and of cardiovascular events in this group of patients [3]. The results of another study provide evidence that the non-invasive assessment of ED of the brachial artery is useful as a marker for cardiovascular risk [4]. However, there is little data on endothelial function in PAD patients on the microcirculatory level. Although microangiopathy most probably has a crucial role in the development of critical limb ischemia, because it is directly responsible for tissue oxygenation, its detection is complicated and its relation to macroangiopathy is not well known.

Different invasive and non-invasive techniques exist for exploring various aspects of the pathobiology of endotheliVasa (2017), 46 (1), 17–22 DOI 10.1024/0301-1526/a000587

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um on the microcirculatory level. One of the most widely used is FMD of peripheral conduit arteries, such as the brachial artery. Still, it does not give insight into the vascular activity on the microcirculatory level.

Recently some techniques for the determination of ED of microcirculation have been developed, including peripheral arterial tonometry (PAT). PAT measures the flow response to hyperemia induced by occlusion, which is related to the endothelial function of small arteries and to the endothelial function of microcirculation [5, 6]. Therefore, this technique is used for the investigation of ED of small arteries and microcirculation [7].

Due to the absence of data on the relationship between endothelial function in micro- and macrocirculation in PAD patients, we have investigated the endothelial function of macro- and microcirculation in patients with PAD. We wanted to answer the question of whether there is an interrelationship in the appearance of endothelial function on the micro- and macrocirculatory levels or whether the ED of large conduit peripheral arteries precedes the ED in microcirculation, and what is the role of diabetes mellitus in the development of ED.

Patients and methods The study included a total of 85 participants: 30 patients with PAD without diabetes mellitus, 30 patients with PAD and diabetes mellitus type 2, and 25 healthy controls.

Included were patients with intermittent claudication (between 200 and 500 meters, Fontaine stage IIa), without manifest coronary artery disease or other diseases which could significantly influence ED. After careful clinical examination, which included the staging of PAD and the registration of accompanying risk factors of atherosclerosis, the ankle pressures of both legs were measured and the ankle-brachial index (ABI) was calculated in all patients. To avoid nondiagnostic results of ABI in diabetic patients as a consequence of media sclerosis, patients with ABI ≥ 0.9 were excluded.

Patients were treated conservatively, with the focus on managing the risk factors for atherosclerosis. Physical activity was encouraged, but patients did not follow a specific exercise program. Most of the included diabetic patients were treated with oral antidiabetic drugs (79 %), while others were treated with insulin (21 %). Average time since diagnosis of diabetes mellitus type 2 was 11.7 ± 6.7 years.

Laboratory analyses In all patients, blood samples were taken, and the following hematological and biochemical analyses were performed: erythrocytes, leukocytes, platelets, hemoglobin, and hematocrit were determined using a Cobas Minos STX® device for automatic hematology measurements (Roche, Switzerland).

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Serum concentrations of inflammatory, procoagulant, and endothelial markers were determined using commercially available kits according to the manufacturers’ instructions. Fibrinogen concentration was determined according to the Clauss method, which is based on the determination of fibrinogen with thrombin clotting time, using commercially available reagents (Multifiber®, Behring, Germany). D-dimer was determined with an immunoturbidimetric assay Auto-Dimer (Axis-Shield, Sweden) on an automated coagulation analyzer CS2100i (Sysmex, Japan). High-sensitivity C-reactive protein (hsCRP) was determined with an immunoturbidimetric assay (Vitros® Fusion 5.1, Ortho-Clinical Diagnostics, USA).

Investigation of endothelial function of large conduit arteries Endothelium-dependent (FMD), low-flow-mediated constriction (L-FMC) and nitroglycerine trinitrate(GTN)induced (endothelium-independent) dilatation (NMD) of the right brachial artery were studied using a high-resolution B-mode ATL 5000 ultrasound system with a 7-MHz linear array transducer. The subjects rested in a supine position for 10 min before hemodynamic measurements were performed. The right brachial artery was scanned in the longitudinal section 2–15 cm above the elbow to find the clearest images of posterior wall layers.

The mean arterial diameter was measured at the end of the diastole, which was determined with the simultaneous monitoring of electrocardiograms. At least three cardiac cycles were analyzed for each scan and the measurements averaged. The flow velocity was measured at a fixed incident angle of 60 % to the vessel with a range of 1.5 mm located in the center of the artery. The baseline (resting) blood flow was estimated by multiplying the velocity time integral of the Doppler flow signal, corrected for the incident angle, by vessel cross-sectional area. Hyperemic flow increase was induced by inflation of blood pressure tourniquet, placed around the forearm, to a pressure of 200 mmHg or at least 50 mmHg above systolic blood pressure for 4.5 min. Hyperemic flow was recorded for the first 15 s, and diameter measurements were taken 45–60 s after cuff deflation. Endothelium-dependent FMD was expressed as the percentage change of the diameter after reactive hyperemia relative to the baseline scan. Low-flow-mediated constriction was calculated from the mean arterial diameter during the last 30 s before cuff release and expressed as the percentage change compared to the baseline diameter. A period of 10 min was allowed for vessel recovery, after which a further resting scan was taken, and endothelium-independent dilation was provoked by sublingual administration of 400 mg of GTN. The first scan was performed 4.5 min later. Endothelium-independent dilation was also expressed as the percentage change in diameter after GTN administration relative to the baseline scan. © 2016 Hogrefe

P. Poredoš et al., Endothelial function in arterial disease

Investigation of endothelial function of microcirculation using PAT Peripheral arterial tonometry (PAT) is a non-invasive technique that enables plethysmographic recording of finger arterial pulse wave amplitude (PWA), which is a measure of pulsatile volume changes. PWA was assessed before and during reactive hyperemia. Baseline PWA was determined using plethysmographic finger cuffs placed simultaneously on the index fingers of both hands for 5 min. Hyperemia was induced by occluding blood flow through the brachial artery for 5 min using an inflatable cuff. Reactive hyperemia index (RHI) was calculated as the ratio of average PWA between post- and pre-occlusion. These values were normalized to the values of measurements of the contralateral arm, which served as a control of the non-endothelial-dependent systemic effects of reactive hyperemia.

As a measure of arterial stiffness, the augmentation index (AI) was calculated via pulse wave analysis of the PAT signal. As a pressure wave moves through the arterial tree, it encounters impedance, resulting in a reflected wave that moves back towards the heart and may augment peak systolic pressure. The endo-PAT derived AI provides a measure for arterial stiffness by considering the timing and magnitude of this wave reflection in the digital pulse.

Calculated from baseline resting pulse waves, AI represents the relative contribution of augmented pressure due to wave reflection to the pressure wave form. Because AI is inversely related to the heart rate, values were mathematically adjusted to represent arterial stiffness at the standard heart rate of 75 beats per minute (AI75) [8].

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Both groups of patients had significantly higher levels of leukocytes than the subjects in the control group (Table I).

Total cholesterol and LDL levels were significantly lower than in the controls, which was probably a consequence of treatment with statins. PAD patients with diabetes had significantly higher values of LDL cholesterol than those without diabetes and controls. More than 50 % of PAD patients, with or without diabetes, were treated with statins; however, in the control group only 3 (10 %) subjects used statins.

Both groups of patients (with and without diabetes mellitus) had increased blood flow at rest and significantly reduced endothelium-dependent FMD of the brachial artery, and no significant differences were registered between PAD patients with or without diabetes mellitus (Table II). Patients with diabetes mellitus had a significantly larger diameter of the brachial artery (Table III). AI was increased in both groups of patients, however without significant differences between both groups; RHI was significantly lower in both groups of patients in comparison to controls (Table IV).

In both groups of PAD patients, FMD was related to the body mass index and the presence of type 2 diabetes, but endothelium-independent NMD of the brachial artery was related to age, body mass index, systolic and diastolic blood pressure and was expressed more in males (Table IV). The presence of diabetes mellitus and PAD most significantly influenced FMD and NMD. ED was detected in both macro- and microcirculation of PAD patients with and without diabetes mellitus and was closely interrelated (FMD:RHI – r = 0.49, p = 0.01). There was a borderline interrelationship between FMD and arterial stiffness (FMD:AI – r = 0.29, p = 0.05).

Statistical methods Categorical variables were presented as a ratio with the number of valid observations and continuous variables as average values. In basic comparative statistics, we applied the Chi-squared test or Fisher’s exact test, and the Mann-Whitney U test or t-test for categorical and continuous variables, respectively. A multivariate analysis was adjusted for all independent outcomes predictors. We identified a final multivariate model for each major outcome using a backward stepwise approach. A 2-tailed pvalue < 0.05 was considered significant. Analyses were carried out using SPSS for Windows, version 22.

Results In all investigated groups, there were non-significantly more males than females. The presence of risk factors of atherosclerosis was also not significantly different between the groups of patients, but hypertension and hyperlipidemia were significantly less frequently present in the control group than in both groups of patients (Table I). © 2016 Hogrefe

Discussion PAD represents one of the most frequent manifestations of atherosclerosis and can cause intermittent claudication and gangrene. Development of atherosclerosis including PAD depends on the presence of risk factors for atherosclerosis [9]. Our study showed that PAD patients with and without diabetes had decreased levels of HDL cholesterol and increased levels of triglycerides in comparison to healthy controls. However, LDL cholesterol and total cholesterol levels were significantly lower than in control subjects. This finding is most probably a consequence of the more frequent treatment of hyperlipidemia in PAD patients than in the controls.

The pathogenesis of PAD and its complications are related to the disturbances on the levels of macro- and microcirculation. Usually, the atherosclerotic process starts on the level of macrocirculation, and in advanced stenosis or occlusion of large vessels microcirculation is disturbed, which has a crucial role in oxygen supply and in the development of tissue necrosis. Even so, in diabetes mellitus microangiopathy may appear independently of the affection of macrocirculation [10].

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P. Poredoš et al., Endothelial function in arterial disease

Table I. Clinical characteristics, risk factors, ankle-brachial index and laboratory results of the patients with and without diabetes mellitus in comparison to the control group.

A – PAD (n = 30) Age (years)

B – PAD and DM (n = 30)

C – Controls (n = 25)

p A :B

p A :C

p B :C

68.8 ± 8.6

70.8 ± 8.4

56.6 ± 12.9

0.409

< 0.001

< 0.001

16 (64%)

17 (68%)

10 (40%)

0.768

0.093

0.049

28.0 ± 4.4

28.5 ± 3.6

24.9 ± 4.4

0.703

0.018

0.003

99.5 ± 10.1

102.6 ± 11.4

88.0 ± 12.0

0.317

0.001

< 0.001

Systolic blood pressure (mmHg)

145.0 ± 20.9

145.8 ± 24.0

123.2 ± 16.6

0.896

< 0.001

< 0.001

Diastolic blood pressure (mmHg)

79.6 ± 11.1

73.6 ± 11.1

76.2 ± 11.0

0.060

0.277

0.409

ABI

0.68 ± 0.19

0.71 ± 0.18

1.15 ± 0.21

0.180

< 0.05

< 0.05

143.4 ± 10.1

136.4 ± 15.0

130.3 ± 15.9

0.051

0.049

0.811

Leukocytes (x109/L)

6.6 ± 1.5

6.6 ± 1.2

4.9 ± 1.0

0.877

< 0.001

< 0.001

Glucose (mmol/L)

5.7 ± 1.1

8.9 ± 3.9

4.8 ± 0.2

0.001

0.001

< 0.001

Total cholesterol (mmol/L)

4.6 ± 0.9

4.1 ± 0.8

5.1 ± 0.9

0.052

0.011

< 0.001

HDL cholesterol (mmol/L)

1.4 ± 0.4

1.2 ± 0.3

1.8 ± 0.4

0.009

0.060

< 0.001

LDL cholesterol (mmol/L)

2.5 ± 0.9

1.9 ± 0.7

2.8 ± 1.0

0.022

0.007

< 0.001

Triglycerides (mmol/L)

1.7 ± 0.8

2.4 ± 0.9

1.1 ± 0.4

0.005

0.028

< 0.001

CRP (mg/L)

7.5 ± 2.9

6.8 ± 4.6

8.9 ± 2.8

0.387

0.527

0.404

Fibrinogen (g/L)

3.3 ± 0.4

4.0 ± 3.6

2.6 ± 0.9

0.348

< 0.001

0.114

702 ± 680

694 ± 359

215 ± 159

0.796

0.016

0.003

46.5 ± 20.7

46.7 ± 20.7

49.5 ± 19.0

0.980

0.627

0.641

Sex-male (%) BMI (kg/m2) Waist circumference (cm)

Hemoglobin (g/L)

D-dimer (ng/mL) Vitamin D

PAD: peripheral arterial disease; DM: diabetes mellitus; BMI: body mass index; ABI: ankle-brachial index.

Table II. Endothelium-dependent flow-mediated dilation and flow-mediated constriction of brachial artery and augmentation index determined by peripheral arterial tonometry in patients with peripheral arterial disease and controls.

Patients with PAD (n = 60)

Controls (n = 25)

p

BA diameter – at rest (mm)

4.7 ± 0.7

4.2 ± 0.7

0.086

BA diameter – vasoconstriction (mm)

4.4 ± 0.4

4.0 ± 0.8

0.053

BA diameter – hyperemia (mm)

4.7 ± 0.6

4.6 ± 0.8

0.435

BA diameter – after NTG (mm)

5.2 ± 0.6

5.1 ± 0.8

0.583

271 ± 165

129 ± 79

0.003

67 ± 37

51 ± 45

0.157

Blood flow – hyperemia (mL/min)

622 ± 379

749 ± 432

0.117

Blood flow – after NTG (mL/min)

243 ± 142

129 ± 109

0.023

FMD (%)

5.4 ± 1.2

10 ± 2.4

< 0.001

L-FMC (%)

1.3 ± 0.4

-0.1 ± 0.1

0.237

12.1 ± 3.1

23.0 ± 9.0

< 0.001

17.1 ± 19.8

10.4 ± 23.2

0.014

AI 75

10.1 ± 6.7

3.5 ± 23.5

0.030

RHI

1.82 ± 0.47

2.05 ± 0.54

0.033

Blood flow – at rest (mL/min) Blood flow – vasoconstriction (mL/min)

NMD (%) AI (Endo PAT)

PAD: peripheral arterial disease; BA: brachial artery; FMD: flow-mediated dilatation; L-FMC: low-flow-mediated constriction; NMD: nitroglycerine trinitrate mediated dilation; AI: augmentation index; PAT: peripheral arterial tonometry; AI75: augmentation index normalized to heart rate of 75 bpm; RHI: reactive hyperemia index.

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Table III. Endothelium-dependent and independent flow-mediated dilation, low-flow- mediated constriction of the brachial artery and augmentation index determined by peripheral arterial tonometry in patients with peripheral arterial disease with and without diabetes.

Patients with PAD (n = 30)

Patients with PAD and DM (n = 30)

p

BA diameter – at rest (mm)

4.5 ± 0.5

5.0 ± 0.7

0.020

BA diameter – vasoconstriction (mm)

4.6 ± 0.5

4.9 ± 0.7

0.046

BA diameter – hyperemia (mm)

4.8 ± 0.5

5.1 ± 0.7

0.085

BA diameter – after NTG (mm)

5.0 ± 0.6

5.5 ± 0.9

0.035

260 ± 198

197 ± 137

0.195

70 ± 43

44 ± 25

0.013

Blood flow – hyperemia (mL/min)

557 ± 418

557 ± 363

0.870

Blood flow – after NTG (mL/min)

229 ± 179

213 ± 186

0.752

FMD (%)

7.9 ± 1.3

2.6 ± 0.5

0.071

L-FMC (%)

1.2 ± 0.6

1.3 ± 0.6

0.269

11.0 ± 3.2

8.3 ± 4.2

0.124

AI (Endo PAT)

16.3 ± 20.0

18.7 ± 25.1

0.711

AI 75

10.4 ± 15.8

12.9 ± 24.3

0.665

RHI

1.75 ± 0.45

1.72 ± 0.46

0.842

Blood flow – at rest (mL/min) Blood flow – vasoconstriction (mL/min)

NMD (%)

PAD: peripheral arterial disease; BA: brachial artery; FMD: flow-mediated dilatation; L-FMC: low-flow-mediated constriction; NMD: nitroglycerine trinitrate mediated dilation; AI: augmentation index; PAT: peripheral arterial tonometry; AI75: augmentation index normalized to heart rate of 75 bpm; RHI: reactive hyperemia index.

Table IV. Correlations between risk factors for atherosclerosis, flow-mediated dilation, flow-mediated constriction and nitroglycerine provoked (endothelial-independent) dilation of brachial artery in all investigated patients (r: Pearson correlation coefficient; p: p-value).

FMD

L-FMC

NMD

Risk factors

r

p

r

p

r

p

Age (years)

0.019

0.836

–0.123

0.176

–0.294

0.001

Sex (male)

0.062

0.492

0.052

0.565

0.259

0.004

BMI (kg/m2)

–0.218

0.015

–0.040

0.662

–0.205

0.023

Waist (cm)

–0.207

0.021

0.205

0.023

–0.316

0.005

0.012

0.892

0.154

0.090

–0.341

0.003

Diastolic blood pressure (mmHg)

–0.014

0.881

0.219

0.015

–0.034

0.706

PAD

–0.066

0.461

–0.094

0.299

–0.342

< 0.001

DM type 2

–0.302

0.001

–0.098

0.454

–0.345

< 0.001

0.90

0.324

0.121

0.183

–0.219

0.015

–0.133

0.144

0.110

0.226

–0.183

0.043

0.010

0.910

–0.233

0.009

0.042

0.648

Systolic blood pressure (mmHg)

Arterial hypertension Dyslipidemia Smoking

FMD: flow-mediated dilatation; L-FMC: low-flow-mediated constriction; NMD: nitroglycerine trinitrate mediated dilation; BMI: body mass index; PAD: peripheral arterial disease; DM: diabetes mellitus.

ED is one of the earliest measurable functional deteriorations of vessel walls in atherogenesis. There are much evidence-based data on ED in patients with risk factors for atherosclerosis and atherosclerotic disease [7]. Nevertheless, ED of microcirculation, which is probably critical in the development of ischemic lesions in PAD as well as in © 2016 Hogrefe

other organ systems, is less well known. In our study it was shown that PAD patients with and without diabetes mellitus have significantly reduced endothelium-dependent FMD of brachial artery as well as the RHI, determined by PAT. A correlation between FMD and RHI was found in PAD patients included in our study, which is in line with Vasa (2017), 46 (1), 17–22

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other studies that reported such correlation in patients with atherosclerotic disease [11, 12]. These results differ from those of Allan et al., who initially found no change of RHI in PAD patients [13]. In their subsequent study of PAD patients, a decreased RHI was found as well, however without a correlation with the endothelial function of macrocirculation, which could be due to different study populations [14]. Although PAT and FMD measure endothelial function of two different vascular compartments, the results of our study indicate that ED is a systemic disorder that simultaneously affects micro- and macrocirculation in PAD patients, not only in PAD patients with diabetes mellitus but also in those without.

The results of our study indicated that not only in diabetic patients but also in PAD patients without diabetes, microcirculation is importantly deteriorated, and that the combination of microvascular and macrovascular dysfunction is probably involved in the pathophysiology of PAD progression [9, 15]. Furthermore, our study showed that PAD patients had reduced endothelium-independent nitroglycerin-induced smooth-muscle-cell-based vasodilatory response. This finding indicates that atherosclerosis affects different layers of the arterial wall including the tunica media, with its main constituent (smooth muscle cells) located beside the endothelium, which produces vasodilatory and vasoconstrictive molecules responsible for vasomotion.

The functional deterioration of the arterial wall is also supported by the finding of our study that arterial stiffness determined by AI is increased in PAD patients. These results are supported by other findings: Tsuchicura et al. showed that PAD patients had increased arterial stiffness in different parts of the circulatory system (coronary, cerebrovascular) [16]. It was also shown that in type 2 diabetic patients without clinical manifestation of PAD increased arterial wall stiffness limits flow volume in the lower extremities. This indicates an increased arterial stiffness is present before the clinical manifestation of PAD and is probably involved in the pathogenesis of the disease.

Limitations Groups of participants are not age- and sex-matched, which can influence the results, as older patients are known to have a higher degree of endothelial dysfunction.

A larger sample size would also improve the reliability of the results.

Conclusions We found a decreased RHI and decreased endothelial function in PAD patients both with and without diabetes.

This indicates that the arterial system of both micro- and macrocirculation is deteriorated in PAD patients.

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References 1. Brevetti G, Schiano V, Chiariello M. Endothelial dysfunction: a key to the pathophysiology and natural history of peripheral arterial disease? Atherosclerosis. 2008;197:1–11.

2. Targonski PV, Bonetti PO, Pumper GM, et al. Coronary endothelial dysfunction is associated with an increased risk of cerebrovascular events. Circulation. 2003;107:2805–9.

3. Brevetti G, Silvestro A, Schiano V, et al. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003; 108:2093–8.

4. Hafner F, Kieninger A, Meinitzer A, et al. Endothelial dysfunction and brachial intima-media thickness: long term cardiovascular risk with claudication related to peripheral arterial disease: a prospective analysis. PLoS One. 2014;9:e93357.

5. Bonetti PO, Pumper GM, Higano ST, et al. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol.

2004;44:2137–41.

6. McCrea CE, Skulas-Ray AC, Chow M, et al. Test-retest reliability of pulse amplitude tonometry measures of vascular endothelial function: implications for clinical trial design. Vasc Med. 2012;17:29–36.

7. Poredos P, Jezovnik MK. Testing endothelial function and its clinical relevance. J Atheroscler Thromb. 2013;20:1–8.

8. Lantelme P, Mestre C, Lievre M, et al. Heart rate: an important confounder of pulse wave velocity assessment. Hypertension.

2002;39:1083–7.

9. Mohler ER. Peripheral arterial disease: identification and implications. Arch Intern Med. 2003;163:2306–14.

10. Adeghate E, New York Academy of Sciences. Diabetes mellitus and its complications : molecular mechanisms, epidemiology, and clinical medicine. Blackwell Pub. on behalf of the New York Academy of Sciences 2006.

11. Woo JS, Jang WS, Kim HS, et al. Comparison of peripheral arterial tonometry and flow-mediated vasodilation for assessment of the severity and complexity of coronary artery disease. Coron Artery Dis. 2014;25:421–6.

12. Wilk G, Osmenda G, Matusik P, et al. Endothelial function assessment in atherosclerosis: comparison of brachial artery flowmediated vasodilation and peripheral arterial tonometry.

Pol Arch Med Wewnętrznej. 2013;123:443–52.

13. Allan RB, Delaney CL, Miller MD, et al. A comparison of flowmediated dilatation and peripheral artery tonometry for measurement of endothelial function in healthy individuals and patients with peripheral arterial disease. Eur J Vasc Endovasc Surg. 2013;45:263–9.

14. Allan RB, Vun S V, Spark JI. A Comparison of measures of endothelial function in patients with peripheral arterial disease and age and gender matched controls. International Journal of Vascular Medicine, vol. 2016, Article ID 2969740.

15. Maeda H, Sugiyama S, Jinnouchi H, et al. Advanced peripheral microvascular endothelial dysfunction and polyvascular disease in patients with high cardiovascular risk. J Cardiol.

2016;67:455–62.

16. Tsuchikura S, Shoji T, Kimoto E, et al. Central versus peripheral arterial stiffness in association with coronary, cerebral and peripheral arterial disease. Atherosclerosis 2010;211:480–5.

Submitted: 25.07.2016 Accepted after revision: 01.09.2016 There are no conflicts of interest to declare.

Published online: 22.11.2016 Correspondence address Luka Jeraj Department of vascular disease University Medical Centre Ljubljana Zaloska 7 1000 Ljubljana Slovenia luka.jeraj@gmail.com © 2016 Hogrefe

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Original communication

Critical limb ischaemia and the response to bone marrow-derived cell therapy according to tcPO2 measurement Mario Maufus1, Marie Antoinette Sevestre-Pietri2,3, Carmine Sessa4, Bernard Pignon5, Harald Egelhofer6,7, Stephane Dupas2, Philippe Nguyen8, Celine Genty9, and Gilles Pernod1,3 1 2 3 4 5 6 7 8 9

Department of Vascular Medicine, University Hospital Grenoble-Alpes, France Department of Vascular Medicine, University Hospital Amiens, France Université Grenoble Alpes – CNRS, TIMC-IMAG UMR 5525/Themas, Grenoble, France Department of Vascular Surgery, University Hospital Grenoble-Alpes, France Cell Therapy Unit, University Hospital Reims, France Cell Therapy Unit, University Hospital Grenoble-Alpes, France Etablissement Français du Sang, Rhône-Alpes Grenoble, France Hematology Laboratory, University Hospital Reims, France Centre of Clinical Research, University Hospital Grenoble-Alpes, France

Summary: Background: Cell therapy is an emerging potential biotherapy for critical limb ischaemia (CLI) patients who are not eligible for revascularization. However, the findings on this technique’s efficacy are inconsistent. Trials investigating this topic focused on the more severe CLI patients who were often beyond any therapy. Therefore, identifying those who may truly benefit from cell transplantation is now warranted. To this end, we studied the prognostic value of tcPO2 for major amputation after 1 year in patients treated with bone marrow-derived cells. Patients and methods: CLI patients ineligible for revascularization were included in a cell-therapy pilot study. On inclusion, patients underwent tcPO2 measurement in supine and sitting positions. For a tcPO2 < 10 mmHg in the supine position, the vascular reserve was defined by tcPO2 > 30 mmHg in the sitting position.

Patients were administered intramuscular injections of mononuclear cells derived from aspirated bone marrow. Results: In total, 25 patients (a lower limbs) were included for analysis. At inclusion, 11 lower limbs had tcPO2 at rest > 10 mmHg, and 16 lower limbs had a tcPO2 < 10 mmHg. The success probability for cell therapy was 0.79 (95 % CI 0.38–0.94) and 0.44 (95 % CI 0.18–0.67), respectively (p = 0.1). Of the 16 limbs with tcPO2 < 10 mmHg, the success rate was considerably higher in patients demonstrating a tcPO2 increase in a sitting position of over 30 mmHg (6/8, success probability 0.71, 95 % CI 0.26–0.92) compared to those without (2/8, success probability 0.15, 95 % CI 0.01–0.48, p = 0.03). Conclusions: For patients with chronic CLI for whom cellular therapy is a therapeutic option, a tcPO2 < 10 mmHg at rest, without vascular reserve (i. e. < 30 mmHg when sitting), is a prognostic indicator for poor outcome.

Keywords: Critical limb ischaemia, CLI, cell therapy, TcPO2

Introduction Critical lower limb ischaemia (CLI), defined as rest pain or non-healing ulceration due to ischaemia, is an extremely severe disease, with 20 % mortality and 10–20 % limb amputation in the first 6 months [1, 2]. Its incidence currently appears to be increasing, with approximately 500 to 1000 new CLI cases reported per million each year in the European and North American population. Of all CLI patients, about 20 % are not eligible for revascu© 2016 Hogrefe

larization [2, 3] and the treatment options for these patients are limited. In this case, no long-term benefit of prostanoid administration has been clearly demonstrated [4]. In patients unsuitable for revascularization, alternative therapies such as gene therapy are currently under development. However, based on the negative results of a recent large clinical trial that focused on non-viral fibroblast growth factor [5], conclusive proof of the benefit of angiogenic gene therapy in terms of limb salvage has yet to be provided.

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Cell therapy is emerging as another potential biotherapy [6]. The technique is based on transferring progenitor cells into an ischaemic limb and offers certain theoretical advantages over angiogenic peptides, including its ability to respond to local environmental signals and to stimulate extracellular matrix remodelling and angiogenesis [7].

Nevertheless, the data from randomised controlled trials are still limited and results on efficacy have been inconsistent [8, 9]. However, all these trials focused on the more severe CLI patients, who were unsuitable for surgery or had experienced revascularization failure, and were often beyond any medical or surgical help.

Several clinical risk factors, such as diabetic mellitus, smoking, lipid abnormalities, age, and renal impairment, have already been described as risk factors for amputation, and a CLI score was proposed for the prediction of amputation-free survival after infra-inguinal bypass [10].

However, there is actually a need to improve risk stratification in CLI [11], and there is a lack of data regarding risk stratification specifically for patients who are unsuitable for surgery or that may benefit from biotherapies. Therefore, as already highlighted for the surgical treatment [12], it is crucial to identify patients who might truly benefit from cell transplantation. Transcutaneous oximetry (tcPO2) has been used clinically to characterise CLI and to evaluate the viability of the skin in severely ischaemic arterial disease. The administration of oxygen, or dependent positioning, has been shown to dramatically improve both the sensitivity and specificity of the measurement, and to be an excellent predictor of the outcome of amputation [12–17].

Therefore, the aim of this study was to investigate the prognostic value of tcPO2 for major amputation in CLI patients who are unsuitable for surgery and who were treated with bone marrow autotransplantation.

Patients and methods Trial design CLI patients ineligible for revascularization were included in a pilot study to evaluate the feasibility and safety of cell therapy that was conducted in two university hospitals in France (Amiens-Reims and Grenoble). The protocol was approved by the local ethics committees of the hospitals and was registered with the French Health Products Safety Agency (AFSSAPS, now ANSM) (N° TC143A4/041092).

Information regarding pathology and therapeutic options was presented to the patients. Option for cell therapy and its limitations were discussed with the patients, and the procedure fully explained. Written informed consent was obtained from all patients.

M. Maufus et al., TcPO2 and cell therapy

Patients CLI was defined according to the Trans-Atlantic Inter-Society Consensus Document on Management of Peripheral Arterial Disease (TASC II) [1]. Objective test results of TcPO2 < 30 mmHg, toe pressure < 30 mmHg (for rest pain) or < 50 mmHg (for ulcers), or ankle pressure (posterior tibial artery or dorsalis pedis artery) < 50 mmHg (for rest pain) or < 70 mmHg (for ulcers) were required for patient selection. A lower-limb arteriography had to have been performed within the 3 months prior to inclusion. All included patients were unsuitable for revascularization or were considered at unacceptably high risk for vascular surgery. At inclusion, cardiovascular risk factors were recorded [2], and patients underwent tcPO2 measurement in supine and sitting positions.

Patients were excluded from the study if their serology tested positive for human immunodeficiency viruses 1 or 2, human T-lymphotropic viruses 1 or 2, hepatitis B or C virus, or syphilis. Other exclusion factors were systemic infection, uncontrolled proliferative or oedematous diabetic retinopathy in the previous 2 years, previous (< 5 years) neoplasia (with the exception of basal cell carcinoma) or suspected neoplasia as detected by specific examination on inclusion, contra-indication to general anaesthesia, chronic haemodialysis, stroke or myocardial infarction in the past < 3 months, and a life expectancy < 6 months.

Procedure The procedure was similar to the one previously described [17]. Briefly, 500 mL of bone marrow cells was aspirated under general anaesthesia from both posterior iliac crests using a Jamshidi needle (13-gauge × 3½”) into a mixture of anticoagulant citrate dextrose solution-A (ACD-A) and heparin (Maco Pharma® Ref MSE 0100Q ). Mononuclear cells were isolated by means of a CS3000-Plus blood-cell separator to 95 % purity and concentrated to a final volume of 40 mL. Patients were administered intramuscular injections of mononuclear cells (0.75 mL per 3 × 3 cm grid) derived from aspirated bone marrow through 1 round of 40 intramuscular injections into the gastrocnemius and soleus muscles of the ischaemic leg using a 16-gauge needle (1.5 cm depth).

Endpoint Patients were followed-up for 1 year. The primary clinical endpoint was major amputation at 1 year. “Treatment success” was defined as no major amputation at 1 year.

TcPO2 measurement TcPO2 was measured at inclusion in both a supine position, with 15–30 min adaptation time, and a sitting position, on

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25

the dorsal surface of the foot, as previously described [18].

This assessment was conducted in a room with controlled temperature (19–22 °C) in standardised conditions using a TCM 400 apparatus (Radiometer, France). For a tcPO2 < 10 mmHg in the supine position, the vascular reserve was defined by tcPO2 >30 mmHg in a sitting position.

Statistical analysis Statistical analyses were performed using StataTM (Stata Corporation, College Station, TX, USA). Quantitative data are expressed as mean ± standard deviation (SD). Descriptive statistics are presented as number and percentage.

Qualitative variables were compared using Fisher’s test, with a p-value < 0.05. Cumulative incident event curves and success probability were calculated by the KaplanMeier method. A Cox model univariate analysis was conducted to identify statistically significant cardiovascular risk factors for amputation. Afterwards, a multivariate analysis was performed that integrated parameters from the univariate analysis that had a p-value < 0.20.

ed for 2 limbs, each separately at 1 month apart. None died from the procedure.

The 25 treated patients were followed-up over 1 year and underwent complete oximetry. The main patient characteristics are presented in Table I. All but 3 patients (4 legs) had already undergone vascular surgery or angioplasty before cell therapy. The mean number of endothelial progenitor cells, i. e. CD34 cells, was 28.7 × 106 (SD 13.6 × 106), without any difference between the two centres [28.5 × 106 (SD 13.3 × 106) and 29 × 106 (SD 15.1 × 106) for

Table I. Baseline characteristics of the patients. *The mean number of prior interventions was 2.3 ± 2.2. n = 25 patients (27 lower limbs)

n = 20 patients (21 lower limbs) without Buerger patients

Age – years (mean, SD)

60.5 (14)

65 (14)

Males

21 (84 %)

17 (85 %)

– Diabetes mellitus

6 (24 %)

6 (30 %)

– Active tobacco

5 (20 %)

3 (15 %)

– History of tobacco use

14 (56 %)

12 (60 %)

– Hypercholesterolaemia

11 (44 %)

11 (55 %)

– Arterial hypertension

11 (44 %)

12 (60 %)

7 pts / 8 limbs

7 pts / 8 limbs

17 pts / 18 limbs

13 pts / 13 limbs

18 pts / 19 limbs*

18 pts / 19 limbs

Cardiovascular risk factors

Results Patient characteristics A total of 27 CLI patients (29 lower limbs) that were ineligible for revascularization were screened, among them 25 patients (27 limbs) were treated with bone marrow autografts (Fig. 1) and included in the study analysis. 5 patients suffered from Buerger disease. 2 patients were treat-

– Rutherford < 5 – Rutherford 5–6 – Prior interventions (surgery or endovascular)

Treated patients n = 27 (lower limbs n = 29)

Patients excluded: n = 2 TcPO2 > 30 mmHg TcPO2 at resting position missing

Patients for analysis n = 25 (lower limbs n = 27)

TcPO2 at rest < 10 mmHg lower limbs: n = 16

TcPO2 at rest > 10 mmHg lower limbs: n = 11

No “vascular reserve” n = 8 limbs

“Vascular reserve” n = 8 limbs

Lost of follow up n=1 patient major amputation n = 6 limbs Success probability: 0.15 (0.01 – 0.48)

Death n=1 patient major amputation n = 2 limbs Success probability: 0.71 (0.26 – 0.92)

Death n =2 patients major amputation n = 2 limbs Success probability: 0.79 (0.38 – 0.94)

Figure 1. Flow chart of the patients included in the study. © 2016 Hogrefe

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M. Maufus et al., TcPO2 and cell therapy

Grenoble and Amiens, respectively]. The mean cell viability was 95.6 % (SD 2.2), similar between the two centres.

Endpoints Among the treated patients, 9 patients (10 limbs) were subjected to major amputation during follow-up. The mean time for major amputation was 3.1 ± 2.6 months after cell implantation. None of the classical cardiovascular risk factors or Rutherford-based severity classification was predictive for amputation (Table II).

Major amputation (%)

1.00

0.75

0.50

0.25

0.00 0

2

4

6

8

10

12

Time (months) Number at risk supine > 10 supine ≤ 10 sitting > 30 supine ≤ 10 sitting ≤ 30

11 8 8

11 7 5

9 6 2

8 6 1

7 6 1

7 5 1

7 5 1

At inclusion, the mean tcPO2 was 9.6 ± 9.1 mmHg in the supine position, and 33.4 ± 12.8 mmHg in the sitting position. 11 lower limbs had tcPO2 at rest >10 mmHg, and 16 lower limbs had a tcPO2 < 10 mmHg. The success probability for cell therapy was 0.79 (95 % CI 0.38–0.94) and 0.44 (95 % CI 0.18–0.67), respectively (p = 0.1).

The primary efficacy results according to tcPO2 in either a supine or a sitting position are presented in Figure 2. Of the 16 limbs exhibiting tcPO2 < 10 mmHg, the rate of success was considerably higher in patients demonstrating a tcPO2 increase in a sitting position of over 30 mmHg (6/8, success probability 0.71, 95 % CI 0.26–0.92) compared to those without (2/8, success probability 0.15, 95 % CI 0.01–0.48, p = 0.03). Therefore the patients exhibiting a tcPO2 < 10 mmHg with an absent vascular reserve constituted an observed rate of 6/8 (75 %) for major amputation following cell therapy. Similar results were observed even when excluding Buerger disease from the analysis (data not shown). After adjustment for Rutherford classification, tcPO2 < 10 mmHg in the supine position and < 30 in the sitting position remains statistically significant for amputation (HR 10.2, 95 % CI 1.8–58.8) (p = 0.009). This remains significant even when focusing only on purely atherosclerotic patients excluding Buerger disease (Table II).

The solid line represents patients with a tcPO2 > 10 mmHg in the supine position. The dashed line represents patients with a tcPO2 < 10 mmHg in the supine position and > 30 mmHg in a sitting position. The dotted line represents patients with a tcPO2 < 10 mmHg in the supine position and < 30 mmHg in a sitting position.

Figure 2. Kaplan-Meyer curves of time to main outcome criteria (major amputation) according to tcPO2 measurements.

Table II. Cox univariate analysis of individual risk factor for major amputation.

Entire cohort (n = 25 pts / 27 limbs) Risk factors

Excluding Buerger patients : (n = 20 pts / 21 limbs)

HR [CI 95 %]

p-value

HR [CI 95 %]

p-value

Age ≥ 60 years

1.35 [0.36–5.06]

0.66

1.88 [0.36–9.84]

0.45

Male gender

2.14 [0.27–17.2]

0.47

1.37 [0.16–11.4]

0.77

Diabetes mellitus

1.96 [0.48–8.05]

0.35

4.30 [0.83–22.3]

0.08

Active tobacco use

1.34 [0.27–6.51]

0.72

1.14 [0.13–9.62]

0.90

Hypercholesterolaemia

0.87 [0.23–3.23]

0.83

1.33 [0.3–5.96]

0.71

Arterial hypertension

1.53 [0.41–5.72]

0.53

2.22 [0.43–11.5]

0.34

Prior interventions

0.68 [0.14–3.21]

0.63

ND

ND

Rutherford – <5 – 5–6

ref 5.14 [0.65–40.7]

/ 0.12

ref 4.72 [0.57–39.4]

/ 0.15

TcPO2 – supine >10 – supine ≤ 10 and sitting >30 – supine ≤ 10 and sitting ≤ 30

ref 1.45 [0.2–10.3] 9.14 [1.77–47.1]

/ 0.71 0.008

ref 2.09 [0.29–14.9] 7.37 [1.19–45.5]

/ 0.46 0.03

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Discussion

Limitations

Revascularization is the optimum treatment for CLI. Unfortunately, 20–40 % of these patients are not suitable for surgery owing to severe distal peripheral artery disease (PAD) or repetitive bypass failure. Among these patients, 40 % are reported to undergo major amputation at 6 months.

In patients that are unsuitable for revascularization, the standard medical treatment is inadequate even when including prostanoid use [4]. To improve limb salvage in these patients, new biotherapies have emerged over the last few decades, such as gene therapy and cell therapy.

Cellular therapy was first reported in a pilot study by Tateishi-Yuyama et al. in 2002 [17], with promising results and no side-effects. Since this paper, several other pilot studies and randomised trials have been conducted using bone marrow-derived or peripheral cells to treat extremely severe cases [19–23]. Recent trials and metaanalyses evaluating stem-cell therapy reported that the technique provided only modest benefits [9, 24, 25]. One probable cause for this lack of consistent success is that the disease is too advanced in elderly CLI patients for neovascularization to be able to offer any meaningful clinical benefit. One potential strategy that could overcome this obstacle would be to better select the patients for whom such therapies could be beneficial and accurately evaluated. Unfortunately, no information is currently available to identify patients in terms of prognosis markers after such a therapy.

TcPO2 measurement was described as more specific and sensible than ABI after transluminal angioplasty.

Combined with clinical determination, it has been cited as a predictor of the success for arterial reconstruction, ulcer or gangrene healing and healing of various levels of amputation [26–29]. The predictive value was found to be more accurate after oxygen inhalation or specific positioning, such as measurement in the sitting position enabling detection of the so-called “vascular reserve” [27]. Therefore, such a predictive value of sitting/supine tcPO2 was already reported by Becker et al. [30]. In a series of 88 patients with CLI, exhibiting a sitting tcPO2 < 10 mmHg and all benefiting from revascularisation, the authors reported a 1-year amputation rate of 11 and 63 % in case (n = 28) or not (n = 60) of rising of tcPO2 in a supine position, respectively, similar to our own results. For this reason, we aimed to test the predictive value of arterial flow determination on the occurrence of major amputation. Our study demonstrated that in patients with a tcPO2 > 10 mmHg and those with a “vascular reserve”, i. e. with a tcPO2 < 10 mmHg in the supine position and > 30 mmHg in a sitting position, cellular therapy was more successful. In contrast, we also demonstrated that patients with a tcPO2 < 10 mmHg and no vascular reserve exhibited a poor outcome. This is of particular interest for physicians having to decide whether to continue with treatment, implicating increased pain and cost, or to perform amputation for pain relief.

Our study has some limitations. First, this was a post-hoc analysis from a pilot prospective yet non-randomised study. Secondly, due to the pilot nature of the study, the number of patients was small, thereby impacting on the study’s power. This could explain that there was no difference in outcome between patients with rest pain and wounds, possibly a random effect due to the small number of cases in the groups. However, such a discrepancy between predictive value of tcPO2 and trophic ulceration was already reported. Therefore, Keyser-Dekker et al. [31] showed by multivariate analysis regarding 170 patients, that TcPO2 was an independent risk factor for re-amputations, although “gangrene” was not significant (OR 1.58, 95 % CI 0.47–5.35). Thirdly, mortality was lower in our group compared to the average CLI cohort previously described, but quite similar compared to a recent cohort [2]; this may be explained by the improvement in medical treatment, especially regarding cardiovascular complications. Finally, in contrast to tcPO2, other haemodynamic parameters, such as ABI or toe pressure, were not available for all patients during the follow-up, and correlation with these measures could not be drawn.

© 2016 Hogrefe

Conclusions For patients with chronic CLI who are not eligible or are at high risk for surgery and for whom cellular therapy is a therapeutic option, a tcPO2 < 10 mmHg at rest and without vascular reserve (i. e. < 30 mmHg when sitting) is a prognostic indicator for poor outcome. This could be a helpful complementary examination to assist physicians in therapeutic decision-making. Although this now requires prospective validation in new angiogenic, larger, and fully controlled studies, we also would like to draw attention in future clinical trials using cell or gene therapy to better define treated population among all patients unsuitable for revascularisation,

Acknowledgements We thank Prof. F. Becker, Department of Angiology, University Hospital Geneva, Switzerland) for helpful discussion regarding predictive value of tcPO2.

This study was sponsored by an academic grant from the Grenoble Clinical Research and Innovation Department (Délégation à la Recherche Clinique et Innovation) and the Reims University Hospital.

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2. Reinecke H, Unrath M, Freisinger E, Bunzemeier H, Meyborg M, Lüders F, et al. Peripheral arterial disease and critical limb ischaemia: still poor outcomes and lack of guideline adherence.

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3. Marston WA, Davies SW, Armstrong B, Farber MA, Mendes RC, Fulton JJ, et al. Natural history of limbs with arterial insufficiency and chronic ulceration treated without revascularization. J Vasc Surg 2006;44:108–14.

4. Ruffolo AJ, Romano M, Ciapponi A. Prostanoids for critical limb ischaemia. Cochrane Database Syst Rev 2010;1:CD006544.

5. Belch J, Hiatt WR, Baumgartner I, Driver IV, Nikol S, Norgren L, et al. Effect of fibroblast growth factor NV1FGF on amputation and death: a randomised placebo-controlled trial of gene therapy in critical limb ischaemia. Lancet 2011;377:1929–37.

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8. Powell RJ, Comerota AJ, Berceli SA, Guzman R, Henry TD, Tzeng E, et al. Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia. J Vasc Surg 2011;54:1032–41.

9. Moazzami K, Moazzami B, Roohi A, Nedjat S, Dolmatova E. Local intramuscular transplantation of autologous mononuclear cells for critical lower limb ischaemia. Cochrane Database Syst Rev 2014; Issue 12. Art. No.: CD008347.

10. Schanzer A, Goodney PP, Li Y, Eslami M, Cronenwett J, Messina L, et al. Vascular Study Group of Northern New England. Validation of the PIII CLI risk score for the prediction of amputation-free survival in patients undergoing infrainguinal autogenous vein bypass for critical limb ischemia. J Vasc Surg 2009;50:769–75.

11. Chung J, Modrall JG, Valentine RJ. The need for improved risk stratification in chronic critical limb ischemia. J Vasc Surg 2014;60:1677–85.

12. Becker F, Raoux M, Brenot R, David M. Predictive value of TcPO2 in chronical severe ischemia of the lower limbs. Int J Microdir Clin Exp 1988;7:261– 71.

13. Johnson WC, Grant HI, Baldwin D, Hamilton JV, Dion JM. Supplemental oxygen and dependent positioning as adjunctive measures to improve forefoot tissue oxygenation. Arch Surg 1988;123:1227–30.

14. Harward TR, Volny J, Golbranson F, Bernstein EF, Fronek A. Oxygen inhalation-induced transcutaneous PO2 changes as a predictor of amputation level. J Vasc Surg 1985;2:220–7.

15. Moosa HH, Peitzman AB, Makaroun MS, Webster MW, Steed DL. Transcutaneous oxygen measurements in lower extremity ischemia: effects of position, oxygen inhalation, and arterial reconstruction. Surgery 1988;103:193–8.

16. Hauser CJ, Appel P, Shoemaker WC. Pathophysiologic classification of peripheral vascular disease by positional changes in regional transcutaneous oxygen tension. Surgery 1984; 95:689–93.

17. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002;360:427–35.

18. Krahenbuhl B, Dubas JM. Transcutaneous oxygen pressure on the foot of normal subjects and patients suffering from arteri-

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al occlusive disease. In: Jageneau AH (ed.). Noninvasive methods on cardiovascular hemodynamics. Amsterdam: Elsevier 1981:469–74.

19. Murphy MP, Lawson JH, Rapp BM, Dalsing MC, Klein J, Wilson MG, et al. Autologous bone marrow mononuclear cell therapy is safe and promotes amputation-free survival in patients with critical limb ischemia. J Vasc Surg 2011;53:1565–74.

20. Wester T, Jorgensen JJ, Stranden E, Sandbaek G, Tjonnfjord G, Bay D, et al. Treatment with autologous bone marrow mononuclear cells in patients with critical lower limb ischaemia. A pilot study. Scand J Surg 2008;97:56–62.

21. Benoit E, O’Donnell TF, Iafrati MD, Asher E, Bandyk DF, Hallett JW, et al. The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design. J Transl Med 2011;9:165.

22. Barc P, Skora J, Pupka A, Turkiewicz D, Dorobisz AT, Gargarek J, et al. Bone-marrow cells in therapy of critical limb ischemia of lower extremities – our own experience. Acta Angiologica 2006;12:155–66.

23. Huang P, Li S, Han M, Xiao Z, Yang R, Han ZC. Autologous transplantation of granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells improves critical limb ischemia in diabetes. Diabetes Care 2005;28:2155–60.

24. Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone marrow derived cell therapy in critical limb ischemia: A meta-analysis of randomized placebo controlled trials. Eur J Vasc Endovasc Surg 2015; 50:775–83.

25. Teraa M, Sprengers RW, Schutgens RE, et al. Effect of repetitive intra-arterial infusion of bone marrow mononuclear cells in patients with no-option limb ischemia: the randomized, double-blind, placebo-controlled Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial. Circulation 2015;131:851–60.

26. Oh PI, Provan JL, Ameli FM. The predictability of the success of arterial reconstruction by means of transcutaneous oxygen tension measurements. J Vasc Surg 1987;5:356–62.

27. Ruangsetakit C, Chinsakchai K, Mahawongkajit P, Wongwanit C, Mutirangura P. Transcutaneous oxygen tension: a useful predictor of ulcer healing in critical limb ischaemia. J Wound Care 2010;19:202–6.

28. Fife CE, Smart DR, Sheffield PJ, Hopf HW, Hawkins G, Clarke D. Transcutaneous oximetry in clinical practice: consensus statements from an expert panel based on evidence. Undersea Hyperb Med 2009;36:43–53.

29. Melillo E, Ferrari M, Balbarini A, Pedrinelli R. Transcutaneous oxygen and carbon dioxide levels with iloprost administration in diabetic critical limb ischemia. Vasc Endovascular Surg 2006;40:303–11.

30. Becker F, Brenot D, David M. A review of the Leriche et Fontaine classification of peripheral occlusive disease. STV 1990; 2:387–95.

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Submitted: 06.06.2016 Accepted after revision: 10.08.2016 There are no conflicts of interest to declare.

Published online: 21.11.2016 Correspondence address Prof. Gilles Pernod Vascular Medical Unit Grenoble-Alpes University Hospital CS10217 F-38043 Grenoble France GPernod@chu-grenoble.fr

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Original communication

Carotid artery stenting with double cerebral embolic protection in asymptomatic patients – a diffusionweighted MRI controlled study Ertan Vuruskan1, Erhan Saracoglu, Ugur Ergun, Fatih Poyraz, and İrfan Veysel Duzen 1

Ersin Arslan Education and Research Hospital, Gaziantep, Turkey

Summary: Background: The aim of this study was to compare the simultaneous double-protection method (proximal balloon plus distal filter) with distal-filter protection or proximal-balloon protection alone in asymptomatic patients during carotid artery stenting. Patients and methods: 119 consecutive patients were investigated for carotid artery stentings in the extracranial internal carotid artery with the use of distal filters (n = 41, 34.4 %), proximal balloon (MoMa) protection (n = 40, 33.6 %) or double protection (n = 38, 31.9 %). Magnetic resonance imaging (MRI) was performed on all patients before the procedure, and control diffusion-weighted MRI (DW-MRI) was obtained within 24–48 h after the procedure. Procedural data, complications, success rate, major adverse cardiovascular events, and MRI findings were collected. Results: New cerebral high-intensity (HI) lesions were observed in 47 (39.4 %) patients. HI lesions were observed in 22 (53.6 %), 15 (37.5 %), and 10 (26.3 %) of the patients with distal filters, proximal protection, and double protection, respectively (p = 0.004). The average number of HI lesions on DW-MRI was 1.80 in the distal-filter group, 0.90 in the proximal-balloon group, and 0.55 in the double-protection group (p < 0.001). Procedure and fluoroscopy times were slightly longer in the double-protection group compared to the distal- or proximal-protection groups (p = 0.001). Conclusions: The double (proximal plus distal) cerebral embolic protection technique is safe and effective for minimizing the risk of cerebral embolization, even in patients with asymptomatic carotid artery stenosis, despite slightly longer procedure and fluoroscopy times.

Keywords: Cerebral protection, carotid, stent, magnetic resonance imaging

Introduction Recent advances in carotid artery stenting (CAS) techniques, new less-embologenic stents, and improved expertise have made stenting of carotid arteries a viable alternative to carotid endarterectomy (CEA) [1–3]. However, the most important drawback of CAS is still potential cerebral embolism due to the intervention. In order to prevent this problem, proximal-protection methods were developed as alternatives to distal anti-embolic filter protection. The proximal-protection method was found to be less embologenic to the brain, despite some limitations [4, 5].

Regarding this issue, Varbella et al. used the doubleprotection (anti-embolic filter protection plus proximal protection) method and found it to be effective in preventing cerebral embolisms in high-risk lesions and symptomatic patients [6]. However, they used neurocognitive function tests instead of transcranial Doppler or magnetic resonance imaging (MRI) findings to evaluate the efficacy of this technique. We have investigated asymptomatic ca© 2016 Hogrefe

rotid artery patients (i. e., absence of stroke, transient ischemic attack, and amaurosis fugax for the preceding 6 months) for the dual-protection method, using diffusionweighted MRI (DW-MRI) as an objective tool for investigating the efficacy of this method.

The purpose of this study was to compare the simultaneous double-protection method (proximal balloon plus distal anti-embolic filter protection) with the methods of distal filter protection or proximal balloon protection in asymptomatic patients during CAS.

Patients and methods After approval from the Local Review Board, this prospective study was performed on carotid stentings from July 2014 to February 2016. Informed consent was obtained from all patients and first-degree relatives. 119 consecuVasa (2017), 46 (1), 29–35 DOI 10.1024/0301-1526/a000584

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E. Vuruskan et al., Carotid stenting double protection

tive patients who were neurologically asymptomatic (absence of stroke, transient ischemic attack, and amaurosis fugax for the preceding 6 months) were included in the study. All patients were evaluated by an independent neurologist before and after the procedure.

The study patients were divided into three groups: 1) the distal anti-embolic filter-protection group (n = 41, 34.4 %), 2) the proximal (MoMa)-protection group (n = 40, 33.6 %) and 3) the double-protection group (anti-embolic filter plus MoMa protection) (n = 38, 31.9 %). Figure 1 depicts the patient flow diagram for the stenting procedure. If there was no proper landing zone for placement of a distal anti-embolic filter, proximal protection was chosen. In patients with external carotid artery occlusion or severe stenosis, distal filter protection was used.

Patient demographics, atherosclerosis risk factors (diabetes mellitus, smoking, hypertension, hyperlipidemia), presence of atrial fibrillation on electrocardiogram, and history of coronary artery disease or peripheral artery disease were recorded.

Stenting technique

cm 6-French Cook Shuttle sheath (Cook, Bloomington, IN, USA) and an Emboshield Nav9 anti-embolic filter (Abbott Vascular, Abbott Park, IL, USA). In the proximal-protection group, a 9-French MoMa catheter (Medtronic, Minneapolis, MN, USA) was used as usual. The distal balloon was dilated in the external carotid artery, the proximal balloon was dilated in the common carotid artery, and flow reversal was achieved. After stenting, at least 60 mL of blood was aspirated. Finally, in the double-protection group, an Emboshield Nav9 anti-embolic filter was placed instead of a 0.014-inch guidewire to the distal part of the internal carotid artery (ICA) after placement of a 9-French MoMa catheter (Fig. 2). Filter crossing was done after inflation of both the proximal and the distal balloons. If necessary, pre-dilation was performed with a 3.0 × 20 mm rapid-exchange coronary balloon catheter (Simpass Plus, Simeks Medical, Istanbul, Turkey) and post-dilation was performed with a 5.0 × 20 mm rapid-exchange balloon catheter (Simpass Plus, Simeks Medical, Istanbul, Turkey).

All patients were stented with a closed-cell-design carotid stent (Xact stent, Abbott Vascular, Abbott Park, IL, USA).

Filter baskets and aspirates from the MoMa catheters were checked for possible debris or thrombus. Additionally, pro-

All patients were prepared for the stenting procedure with dual anti-platelet therapy (clopidogrel 75 mg/day and acetylsalicylic acid 300 mg/day) 1 week before the procedure.

After the procedure, the dual anti-platelet regimen was continued for 1 month, afterwards only acetylsalicylic acid was given. Before the procedure, 5000 IU of unfractionated heparin was given intravenously and activated clotting time was checked; if necessary, an additional 2500 IU dose was given.

CAS in the distal-protection group was performed via common femoral artery or radial artery access with a 90-

Asymptomatic severe carotid stenosis (n = 119)

Distal protection (n = 41)

Proximal protection (n = 40)

Double protection (n = 38)

Clamping intolerance (n = 8)

No clamping intolerance (n = 30)

Deflating Reinflating Ballons

Stenting

Figure 1. Patient flow diagram of the stenting procedure for the three study groups.

Vasa (2017), 46 (1), 29–35

Figure 2. Procedural images of a double-protection carotid stenosis patient. (A) Left internal carotid artery critical stenosis. (B) Both proximal and distal balloons are inflated and the anti-embolic filter crosses the lesion. (C) Filter is placed distally, proximal and distal balloons are inflated, and stent is post-dilated by a rapid-exchange coronary balloon catheter. (D) Final image of the carotid stenting after retrieval of the anti-embolic filter and MoMa catheter. © 2016 Hogrefe

E. Vuruskan et al., Carotid stenting double protection

cedure and fluoroscopy times were measured and recorded for all patients.

If clamping intolerance was encountered with the double-protection method, the proximal MoMa balloon was deflated transiently, then re-inflated after 1 min, and the procedure was continued and finished quickly while the anti-embolic filter was still in place in the distal ICA. For the same situation in the proximal-protection group, the procedure was continued and finished as soon as possible without deflation of the MoMa balloons.

Assessment of procedural outcomes Before and 24–48 h after the carotid stenting, cranial MRI and DW-MRI examinations were performed by an experienced radiologist in our institution for the evaluation of high-intensity (HI) lesions. The evaluations were done in a

31

blinded fashion. The location, distribution and number of HI lesions were recorded (Fig. 3). After evaluation of the carotid digital subtraction angiographic (DSA) images, stenosis severity was calculated with the NASCET formula, and the lesion side (right ICA, left ICA or bilateral) was determined [7].

Procedural characteristics, such as pre- or post-dilation of the carotid stent, clamping intolerance, presence of debris in the retrieved anti-embolic filter basket or MoMa aspirates, were recorded. The success of the procedure (defined as less than 30 % residual stenosis after stenting) and any major adverse cardiovascular events (death, minor stroke, major stroke or myocardial infarction) were recorded.

MRI analysis The evaluation of HI lesions on cranial MRI was performed with a 1.5 Tesla whole-body scanner (Siemens Magnetic Resonance Imaging, Siemens Healthcare GmbH, Erlangen, Germany). In addition to DW-MRI, other sequences were obtained, including axial spin-echo T1-weighted images, fast spin-echo T1-weighted images, fast spin-echo T2-weighted images, and FLAIR (fluid-attenuated inversion-recovery) images. DW-MRI was acquired with the echo-planar method. MR images were evaluated by an experienced radiologist in a blinded fashion.

Statistical analysis Continuous variables were defined as mean ± standard deviation and categorical variables as percentages. The Kolmogorov–Smirnov test was used to evaluate whether the distribution of continuous variables was normal. Continuous variables between groups were compared using Student’s t-test. Categorical variables were compared using the Chi-squared test. The three study groups were compared using the ANOVA test, and post-hoc analysis was done with Tukey’s test. P-values of < 0.05 were considered to have statistical significance. Data were analyzed by using SPSS version 20.0 (SPSS Inc., Chicago, IL, USA).

Results

Figure 3. DW-MRI and ADC mapping of three study patients. (A-B) 1 HI lacunar ischemic lesion in the right periventricular area. (C-D) 1 ischemic HI lesion in the left frontoparietal subcortical area. (E-F) 1 left frontal and 2 right frontal HI lesions in a patient with bilateral cerebral embolisms. © 2016 Hogrefe

The study population consisted of 119 patients with asymptomatic carotid artery stenosis (mean age 67.5 ± 7.4 years, 62.2 % male). The baseline clinical and carotid artery lesion characteristics of the patients of each study group are presented in Table I. Carotid lesions were predominantly on the right side, and some bilaterally stenosed patients were also included in the study. The presence of atherosclerosis risk factors, such as diabetes mellitus, smoking, hypertension, hyperlipidemia and a history of coronary or peripheral artery disease, were not Vasa (2017), 46 (1), 29–35

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E. Vuruskan et al., Carotid stenting double protection

significantly different between the three groups (p > 0.05).

The atrial fibrillation rate was also similar in the three groups (p = 0.60).

Table II demonstrates the procedural characteristics and results of the study groups, as well as the DW-MRI findings. Pre-dilation and post-dilation of carotid lesions was performed if necessary; these rates were not statistically significant among the three groups (p = 0.30 and p = 0.85, respectively). The success of the procedure was 100 %, 97.5 %, and 97.3 % in the distal-protection group, the proximal-protection group, and the double-protection group, respectively (p = 0.75). Clamping intolerance was not different between the proximal-protection and doubleprotection groups. The presence of debris in the filter basket and/or MoMa aspirates was not statistically significant between the groups (p = 0.69).

Death occurred in 1 patient in the filter group 6 h after the stenting procedure, probably due to hemodynamic insufficiency because of concomitant severe aortic stenosis.

Myocardial infarction was observed in 1 patient the day after the index procedure in the distal-protection group; this patient was referred for surgery for triple-vessel coronary artery disease. No major stroke was observed in the three groups. The minor stroke rate was similar in the three groups (two patients in the distal-protection group, two in the proximal-protection group and one in the double-protection group) (p = 0.54).

The procedure and fluoroscopy times were slightly increased in the double-protection group compared to the other two groups (p = 0.001 and p = 0.001, respectively).

This was probably due to the time required for introducing two protection devices in the same patient.

HI lesions were seen in 53.6 % of the distal-protection group, 37.5 % of the proximal-protection group, and 26.3 % of the double-protection group (p = 0.004). The mean numbers of HI lesions were 1.80, 0.90, and 0.55 for the three groups, respectively (p < 0.001). Most of the patients with these lesions only had 1 or 2. In the proximal-protection and double-protection groups, no patients had 3 or more HI lesions (p = 0.01). The lesions were mostly located ipsilateral to the stented carotid artery. In a few cases, contralateral or bilateral cerebral embolisms were also detected (p = 0.62).

Table III shows the comparison of patients with or without clamping intolerance in the double-protection group.

HI lesions and debris found in the aspirates and anti-embolic filters were determined to be higher in the clampingintolerant patients compared to those without clamping intolerance (p <0.05).

Discussion Procedure-related stroke is the main drawback of carotid artery interventions. Comparison of CAS with carotid endarterectomy has demonstrated that the risk of cerebral embolism is slightly elevated in CAS [8]. However, the SAPPHIRE trial (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy trial), which was the first controlled randomized trial of CAS using a protection device, demonstrated that CAS was not inferior to CEA [9]. In recent years, improvement of expertise in CAS, new double-meshed carotid stents and

Table I. Baseline clinical and carotid artery lesion characteristics of the study groups.

Variables

Distal group (n = 41)

Proximal group (n = 40)

Double group (n = 38)

P-value

Age (year)

67.1 ± 6.5

68.5 ± 8.1

65.0 ± 7.8

0.62

Gender (male), n (%)

26 (63.4)

24 (60.0)

24 (63.2)

0.94

Hypertension, n (%)

20 (48.8)

24 (60.0)

21 (55.3)

0.59

Diabetes mellitus, n (%)

11 (26.8)

12 (30.0)

14 (36.8)

0.62

Smoker, n (%)

12 (29.3)

11 (27.5)

14 (36.8)

0.64

Hyperlipidemia, n (%)

16 (39.0)

9 (22.5)

15 (39.5)

0.18

PAD, n (%)

9 (22.0)

9 (22.5)

13 (34.2)

0.38

CAD, n (%)

15 (36.6)

11 (27.5)

14 (36.8)

0.60

7 (17.1)

5 (12.5)

8 (21.1)

0.60

RICA

21 (51.2)

23 (57.5)

23 (60.5)

0.62

LICA

15 (36.5)

15 (37.5)

14 (36.8)

5 (12.3)

2 (5.0)

1 (2.7)

81.4 ± 6.8

79.1 ± 6.6

80.6 ± 6.9

Atrial fibrillation, n (%) Stenosis side, n (%)

RICA + LICA Stenosis grade (%)

0.18

PAD: peripheral artery disease; CAD: coronary artery disease; RICA: right internal carotid artery; LICA: left internal carotid artery.

Vasa (2017), 46 (1), 29–35

© 2016 Hogrefe

E. Vuruskan et al., Carotid stenting double protection

33

proximal-protection techniques have decreased the most feared complications of these interventions [10, 11]. Milosevic et al. described the dual-protection technique in 2007 for high-grade stenosis and large, soft atherosclerotic plaques [12].

The ACT 1 trial, which is the most recent trial comparing CAS and CEA for the prevention of strokes in asymptomatic carotid stenosis patients, demonstrated that stenting was not inferior to endarterectomy with regard to outcomes over a period of 5 years [13].

Another ongoing debate concerns the necessity of treating asymptomatic high-grade carotid stenosis. So far, the randomized evidence for CAS in asymptomatic patients is limited, and no study has compared endovascular treatment with medical therapy. In the European guidelines, carotid intervention is recommended for class IIa, level of evidence A, for endarterectomy, and class IIb, level of evidence B, for stenting [14].

Although transcranial Doppler ultrasound could also be used, DW-MRI is considered to be the most sensitive imaging modality for early detection of cerebral embolism [15]. In addition, clinically silent embolic lesions after CAS have been reported at a rate of 17.3–73 % in DW-MRI controlled trials [16, 17]. In our study, this rate was 26.3–53.6 %, based on interpretation of DW-MRI images.

Proximal-protection techniques are limited by endovascular clamping intolerance [18, 19]. We encountered clamping intolerance in approximately 25 % of the patients in our study. The double-protection method provided us the opportunity to deflate the proximal and/or distal MoMa balloons transiently, with the protective effect of the anti-embolic filter still in place in the distal ICA. Therefore, the patients tolerated CAS well with less clamping intolerance, while still having some cerebral protection. In our patients, we observed no problems with achieving flow reversal, as the pores of the anti-embolic filters permit

Table II. Diffusion-weighted MRI findings, procedural characteristics and procedural results of the study groups.

Variables

Distal group (n = 41)

Proximal group (n = 40)

Double group (n = 38)

15 (37.5)

10 (26.3)

P-value

DW-MRI findings HI lesion patients, n (%)

22 (53.6)

HI lesions (mean), n (%)

1.80 ± 0.98

0.90 ± 0.52 0.55 ± 0.26

0.004

<0.001

HI lesion count, n (%) 1

13 (31.7)

9 (22.5)

7 (18.4)

2

7 (17.0)

6 (15.0)

3 (7.8)

2 (4.8)

0 (0)

0 (0)

19 (86.5)

13 (86.8)

9 (90.0)

Contralateral

1 (4.5)

1 (6.6)

0 (0)

Bilateral

2 (9.0)

1 (6.6)

1 (10.0)

Predilation, n (%)

15 (36.6)

20 (50.0)

13 (34.2)

0.30

Postdilation, n (%)

30 (73.2)

27 (67.5)

27 (71.1)

0.85

Debris, n (%)

19 (46.3)

16 (40.0)

16 (42.1)

0.69

0 (0)

7 (17.5)

8 (21.0) 0.01

41 (100)

39 (97.5)

37 (97.3)

0.75

Death

1 (2.4)

0 (0)

0 (0)

0.54

Minor stroke

2 (4.8)

2 (5.0)

1 (2.6)

Major stroke

0 (0)

0 (0)

0 (0)

1 (2.4)

1 (2.5)

0 (0)

Procedure time, min

39.4 ± 4.0

41.0 ± 5.1

45.6 ± 5.7

0.001

fluoroscopy, min

14.8 ± 1.7

15.5 ± 2.7

17.8 ± 2.8

0.001

3 and <

0.01

HI location, n (%) Ipsilateral

Clamping intolerance, n (%) Success, n (%)

0.62

MACE, n (%)

MI

DW-MRI: diffusion-weighted magnetic resonance imaging; HI: high intensity; MACE: major adverse cardiovascular events; MI: myocardial infarction. © 2016 Hogrefe

Vasa (2017), 46 (1), 29–35

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E. Vuruskan et al., Carotid stenting double protection

Table III. Diffusion-weighted MRI findings, procedural characteristics and procedural results of double-protection group with or without clamping intolerance.

Variables

Clamping intolerance (n = 8)

No clamping intolerance (n = 30)

P-value

DW-MRI findings HI lesion patients, n (%)

2 (25.0)

8 (26.6)

0.08

HI lesions (mean), n (%)

0.66 ± 0.38

0.49 ± 0.34

0.01

1

2 (25.5)

5 (16.6)

0.001

2

1 (12.5)

2 (6.6)

0 (0.0)

0 (0.0)

2 (25.5)

7 (23.3)

0 (0.0)

0 (0.0)

Bilateral

1 (12.5)

0 (0.0)

Predilation, n (%)

2 (25.5)

11 (36.6)

0.04

Postdilation, n (%)

5 (62.5)

22 (67.5)

0.66

Debris, n (%)

5 (62.5)

11 (36.6)

0.001

Success, n (%)

7 (87.5)

30 (100.0)

0.06

0 (0.0)

0 (0)

0.37

Minor stroke

1 (12.5)

0 (0.0)

Major stroke

0 (0)

0 (0)

0 (0.0)

0 (0.0)

Procedure time, min

47.6 ± 6.0

44.0 ± 8.2

fluoroscopy , min

18.5 ± 2.6

16.3 ± 2.9

HI lesion count, n (%)

3 and < HI location, n (%) Ipsilateral Contralateral

0.42

MACE, n (%) Death

MI

0.12

0.16

DW-MRI: diffusion-weighted magnetic resonance imaging; HI: high intensity, MACE: major adverse cardiovascular events; MI: myocardial infarction.

back-flow. Another concern was the risk of filter-retrieval problems after completion of the procedure. We found this risk to be similar to the risk with standard distal filter protection. Turning the patient’s head from side to side or compressing the index carotid artery easily solved this problem.

Appropriate selection of patients is another essential aspect of this technique. If the patient’s ICA is very tortuous, there is no appropriate place for the proper landing of the anti-embolic filter basket and there is a potential risk of filter malapposition. If the lesion is subtotal and filter advancement is difficult, then the classical proximal-blockage method using a 0.014-inch coronary guidewire must be performed [20, 21]. Another limitation are patients with occluded external carotid arteries, in whom no proximal-blockage technique can be used. To increase the patient’s clamping tolerance in bilateral carotid artery stenosis, as mentioned above, some blood can be aspirated with transient deflation of the proximal balloon, Vasa (2017), 46 (1), 29–35

and a few seconds later reinflation of the proximal balloon can be performed [22].

According to our screening of the literature, this is the first study to demonstrate the efficacy and safety of double cerebral embolic protection in patients with asymptomatic carotid artery stenosis. Previous studies were designed to prove the efficacy of this method for high-risk lesions or in symptomatic patients with cerebral embolism.[6, 11] Asymptomatic patients are accepted to have a relatively low embolism risk compared to symptomatic ones, but our study demonstrated that the double-protection technique was also effective in these patient subsets.

© 2016 Hogrefe

E. Vuruskan et al., Carotid stenting double protection

Limitations This study was a single-center, single-operator non-randomized, prospective study with a limited number of patients. DW-MRI controls were done on the first day of intervention and HI lesions were calculated by an experienced radiologist. However, using gadolinium-enhanced techniques and volumetric analysis of lacunar infarcts could enhance the accuracy of the results in future studies.

We used relatively objective evidence of cerebral embolism by obtaining DW-MRI images instead of neurocognitive tests.

Conclusions The concomitant use of distal filter protection with proximal protection (MoMa) is feasible and safe, and it dramatically decreased the incidence of cerebral embolism in asymptomatic CAS patients, despite a slightly increased duration of the procedure and the fluoroscopy. Doubleprotection patients without clamping intolerance had better procedural results than the other groups, so the appropriate selection of patients for double protection seems to be important. Although a limited number of patients were included in this study and no systematic randomization was performed, the results were promising due to demonstrating a lower major adverse cardiovascular events rate with the double-protection method. Future studies will also determine the cost-effectiveness of this technique in asymptomatic carotid artery stenosis patients.

References 1. The SPACE collaborative group. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: A randomised noninferiority trial. Lancet 2006; 368: 1239–1247.

2. International Carotid Stenting Study Investigators. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): An interim analysis of a randomised controlled trial.

Lancet 2010; 375: 985–987.

3. Brott TG, Hobson RW, Howard G, et al. Stenting versus Endarterectomy for Treatment of Carotid artery stenosis (CREST) Trial. N Engl J Med 2010; 363: 11–23.

4. Schmidt A, Diederich KW, Scheinert S, et al. Effect of two different neuroprotection systems on microembolization during carotid artery stenting. J Am Coll Cardiol 2004; 44: 1966 – 1969.

5. Lee JH, Sohn HE, Chung SY, et al. Clinical analysis comparing efficacy between a distal filter protection device and proximal balloon occlusion device during carotid artery stenting. J Korean Neurosurg Soc 2015; 58: 316–320.

6. Varbella F, Gagnor A, Rolfo C, et al. Feasibility of carotid artery stenting with double cerebral embolic protection in high-risk patients. Cathet Cardiovasc Interv 2016; 87: 432–427.

7. Liapis CD, Bell PR, Mikhailidis D, et al., for the ESVS Guidelines Collaborators. ESVS guidelines: Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg 2009; 37: 1–19. © 2016 Hogrefe

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8. Mas JL, Chatellier G, Beyssen B, et al., for the EVA-3S Investigators. Endarterectomy versus stenting in patients with symptomatic carotid stenosis. N Engl J Med 2006; 355: 1660–1671.

9. Yadav JS, Wholey MH, Kuntz RE, et al. Protected carotid-artery stenting versus endarterectomy in high-risk patients. N Engl J Med 2004; 351: 1493–1501.

10. Castagno C, Varetto G, Sperti F, et al. Preoperative and postoperative evaluation of new double mesh carotid stents with contrast-enhanced ultrasound and diffusion-weighted imaging. Ann Vasc Surg 2016; 33: 228.

11. Kedev S, Petkoska D, Zafirovska B, et al. Safety of slender 5 Fr transradial approach for carotid artery stenting with a novel double-layer micromesh stent. Am J Cardiol 2015; 116: 977–981.

12. Milosevic ZV, Kocijancic IJ, Bunc M, et al. Dual cerebral protection technique during carotid stenting. J Endovasc Ther 2007; 14: 86–90.

13. Rosenfield K, Matsumara JS, Chaturvedi S, et al. Randomized trial of stent versus surgery for asymptomatic carotid stenosis.

N Engl J Med 2016; 374: 1011–1020.

14. Tendera M, Aboyans V, Bartelink ML, et al. ESC guidelines on the diagnosis and treatment of peripheral artery diseases. Eur Heart J 2011; 32: 2851–2906.

15. Cristomo RA, Garcia MM, Tong DC, et al. Detection of diffusionweighted MRI abnormalities in patients with transient ischemic attacks: Correlation clinical characteristics. Stroke 2003; 34: 932–937.

16. Stojanov D, Ilic M, Bosnjakovic P, et al. New ischemic brain lesions on diffusion weighted MRI after carotid artery stenting with filter protection: Frequency and relationship with plaque morphology. AJNR Am J Neuroradiol 2012; 33: 708–714.

17. Jaeger HJ, Mathias KD, Hauth E, et al. Cerebral ischemia detected with diffusion-weighted MR imaging after stent implantation in the carotid artery. AJNR Am J Neuroradiol 2002; 23: 200–207.

18. Reimers B, Sievert H, Schuler GC, et al. Proximal endovascular flow blockage for cerebral protection during carotid artery stenting: Results from a prospective multicenter registry. J Endovasc Ther 2005; 12: 156–165.

19. Bersin RM, Stabile E, Ansel GM, et al. A meta-analysis of proximal occlusion device outcomes in carotid artery stenting.

Catheter Cardiovasc Interv 2012; 80: 1072–1078.

20. Sakamoto S, Kiura Y, Kajihara Y, et al. Carotid artery stenting using the proximal or dual protection method for near occlusion of the cervical internal carotid artery. Neurosurg Rev 2013; 36: 551–558.

21. Kajihara Y, Sakamoto S, Kiura Y, et al. Comparison of dual protection and distal filter protection as a distal embolic protection method during carotid artery stenting: A single-center carotid artery stenting experience. Neurosurg Rev 2015; 38: 671–676.

22. Sakamoto S, Kiura Y, Okazaki T, et al. Carotid artery stenting for vulnerable plaques on MR angiography and ultrasonography: Utility of dual protection and blood aspiration method. J Neurointerv Surg 2015; 9: 120–122.

Submitted: 27.05.2016 Accepted after revision: 11.08.2016 There are no conflicts of interest to report.

Published online: 21.11.2016

Ertan Vuruskan, M.D. Education and Research Hospital Hurriyet Cad 27000 Gaziantep Turkey ertanvuruskan@hotmail.com Vasa (2017), 46 (1), 29–35

Trends und Entwicklungen des Gesundheitssystems

Gerhard Schulze

Schöne neue Gesundheitswelt Wie sich das medizinische Denken verändert 2016. 192 S., Abb., Tabellen, Kt € 24,95 / CHF 32.50 ISBN 978-3-456-85603-2 Auch als eBook erhältlich In der Gesundheitspolitik geht es immer auch um die Möglichkeit einer Regulierung, doch neue Trends lassen sich nicht regulieren. Denn sie bestehen in der Art und Weise, wie die Menschen mit dem Gesundheitssystem umgehen. Je mehr Wahlmöglichkeiten das System anbietet, desto mehr verlagert sich die Macht zu den Menschen, die in ihm agieren.

• Schon längst stehen Heilberufe und unsere alltägliche Lebenswelt in einer Koevolution - begleitet von Fernsehen, Printmedien, Werbung und Internet.

• Unsere Vorstellungen über Schulmedizin und Alternativmedizin, über Natur, über psychosoziale Phänomene, über Evidenz, Wissensfortschritt und Erkenntnis haben sich grundlegend verändert.

www.hogrefe.com

• Warum werden Selbstmedikation, tradiertes Wissen und Naturheilmittel immer wichtiger?

Erstmalig wird dieser Prozess lehrreich und zugleich sehr unterhaltsam analysiert. Welche Kräfte treiben den Wandel an? Wie verändern sich die Beziehungen von Experten und Laien, wie die Rollen der Akteure mit der längsten heilberuflichen Tradition – Arzt und Apotheker? Auch Gesundheitspolitiker erkennen die wachsende Bedeutung der Gesundheitskultur, haben sie jedoch noch nicht auf die Agenda gesetzt. Mit diesem Buch könnte sich das ändern.

37

Original communication

Long-term individual shear rate therapy counterpulsation enhances plasma nitrite release in patients with PAD Michèle Brixa, 2, Eva-Elina Buschmanna, 1,2,3, Andreas Zietzer2, Jonnel Anthony Jaurigue2, Lulu Li1,2, Constantin Jungk2, Ivo Buschmann1,2,3, Doreen Jankea, 4,5, and Philipp Hillmeistera, 1,2,3 a 1 2

3 4 5

These authors contributed equally Medical University of Brandenburg (MHB), Center for Internal Medicine I, Dept. for Angiology, Brandenburg an der Havel, Germany Charité-Universitaetsmedizin Berlin (CCM), Center for Cardiovascular Research, Richard-Thoma-Laboratories for Arteriogenesis Berlin, Berlin, Germany Charité-Universitaetsmedizin Berlin (CCM), Institute of Physiology, Berlin, Germany Charité-Universitaetsmedizin Berlin (CVK), Berlin-Brandenburg School for Regenerative Therapies Berlin, Berlin, Germany FU Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany

Summary: Background: Individual shear rate therapy (ISRT) has been designed as a novel non-invasive treatment option for peripheral artery disease (PAD) patients and has been shown to improve endothelial function and walking distance. The aim of this study was to elucidate the impact of ISRT on the level of nitric oxide in patient blood plasma and the expression of related molecular markers in peripheral blood mononuclear cells (PBMCs). Molecular diagnostic tests were performed for two ISRT trials. Patients and methods: In ISRT-1 26 healthy subjects underwent one session of treadmill training and one session of ISRT respectively in a cross-over design. In ISRT-2 14 PAD patients with a stable intermittent claudication underwent a 30 hours long-term treatment. Plasma nitrite release as well as the mRNA expression of NOS2 and key regulators of the kallikrein-kinin system were measured in PBMCs at different time points. Results: Short-term ISRT revealed significantly decreased NOS2 expression in PBMCs of healthy volunteers and PAD patients. Long-term ISRT, in turn, demonstrated a significant plasma nitrite increase in PAD patients. Conclusions: We verified that long-term ISRT stimulates the vascular system and exerts a comparable effect to physical exercise in regards to NO release, which coincide with recent findings regarding an improvement of endothelial function. However, further studies are necessary to investigate the role for circulating leukocytes.

Keywords: Peripheral vascular disease, exercise, exercise testing, rehabilitation, gene expression endothelium, vascular type, nitric oxide

Introduction Peripheral arterial disease (PAD) is a major atherosclerotic disease and approximately affects 16 % of the population aged over 55 across Europe [1]. Even though regularly performed physical exercise has been shown to improve symptoms of intermittent claudication, PAD patients are severely limited in performing active exercise.

Furthermore, they have to observe strict training plans due to intense claudication pain and long training durations of up to six months [2]. Hence, multi-disciplinary approaches and novel therapeutic strategies are of high © 2016 Hogrefe

clinical interest and necessary for an optimal medical care of PAD patients.

To simulate the positive outcome of intensive physical training we developed individual shear rate therapy (ISRT), an adaptation of external counterpulsation (ECP), as a novel non-invasive treatment option for PAD patients. The ECP device has initially been proven as a therapeutic approach for coronary artery disease patients. There, it has been validated to improve endothelial function, to induce regenerative vascular remodeling (arteriogenesis), and to increase quality of life [3, 4]. Current ECP devices are constructed to inflate three cuffs wrapped around the hips, thighs, and Vasa (2017), 46 (1), 37–45 DOI 10.1024/0301-1526/a000600

38

M. Brix et al., Individual shear rate (ISRT)

calves by applying high pressures of 250–300 mmHG. This high pressure concept might have to be scientifically reconsidered since it indeed leads to an increase of blood flow in the upper part of the body, but also results in decreased arterial flow velocity in the lower limb as shown by Werner et al. [5]. Furthermore, it has been proven that blood flow velocity rather than blood pressure is the decisive component of inducing arteriogenesis; the relative pulse slope index has been calculated as relevant parameter [6, 7].

ISRT is based on the assement of peripheral perfusion and allows to calculate adequate treatment pressures for the long-term treatment of each individual patient. Hereby, two cuffs of an ECP device are wrapped around the hip and thighs of PAD patients. Since the ISRT device is ECGtriggered, the cuffs are inflated in the early diastole and deflated in the systole of each cardiac cycle; peripheral perfusion is increased upon cuff inflation. Noteworthy, applying ISRT as long-term PAD treatment, we were the first to demonstrate a significant improvement of endothelial function, an enhanced claudication distance, and an increased well-being of PAD patients [8]. Notably, exercise and ECP treatment are known to stimulate fluid shear stress (FSS) dependant vascular remodeling processes.

Additionally, FSS-induced nitric oxide (NO) was shown to stimulate the innate immune system resulting in an activation of NOS2 in circulating leukocytes [9].

However, underlying molecular effects of ISRT counterpulsation are still not understood. Hence, we now have investigated nitrite plasma levels and the expression of nitric

oxide synthase in peripheral blood mononuclear cells (PBMCs) as well as the expression of kallikrein-kinin system (KKS) key molecules. All these factors have been reported to (1) regulate nitric oxide metabolism, (2) to be highly significant for improving endothelial dysfunction, and (3) to strongly stimulate vascular remodelling (arteriogenesis) [10, 11]. On that account, we compared the impact of a single ISRT session with treadmill training in healthy volunteers (ISRT-1 study) and furthermore investigated the effects of short- and long-term ISRT on PAD patients (ISRT-2 study).

Patients and methods Individual shear rate therapy concept ISRT is based on the ECP principle and serves as a novel therapeutic approach for PAD patients to improve peripheral perfusion. In contrast to ECP, there are only cuff pairs around the hip and thighs. The calves are left free to assure adequate peripheral perfusion. The compression of the cuffs is ECG-triggered and adjusted from the late systole to early diastole of each cardiac cycle. Peripheral perfusion is initially measured by an individual shear rate diagnosis, which assesses Doppler-flow parameters to determine the adequate cuff pressure as described previously [8].

ISRT-1 study TableI I. Baseline characteristics Data are given as mean ± SEM. BMI: body mass index; Fontaine stage IIb is defined by claudication distance < 200 meters; ICD: initial claudication distance; ACD: absolute claudication distance; ABI: ankle brachial index.

ISRT-1

(n = 26)

Age, y

23.37 ± 0.36

Male n

13

Female n

13 2

BMI,kg/m ISRT-2 Age, y Male n Female n

Fontaine stage IIb n

22.22 ± 0.44 (n = 14) 60.46 ± 2.34 12 2 14

ICD, m

92.57 ± 8.21

ACD,m

167.82 ± 18.04

ABI BMI, kg/m2

0.58 ± 0.03 28.95 ± 0.87

ISRT-2 study

Ongoingtreatments Anti platelet drug n

14

Beta blockers n

10

Lipid lowering drug n

12

Anti-diabetes medication n

Vasa (2017), 46 (1), 37–45

Twenty-six healthy volunteers were enrolled in the ISRT-1 study. There were no sex-based (male = 13 and female = 13) or racial differences present. Volunteers were randomly selected in a cross-over design to either undergo the passive (ISRT) or active (exercise) training session first. Between the first and second training session, a resting period of one week was set (Table I). Volunteers in ISRT-1 fullfilled the following inclusion criteria: 18-35 years, nonsmokers, no cardiovascular diseases, no endocrine or metabolic disorders, no current treatment for any acute or chronic diseases, and no pregnancy. ISRT counterpulsation was executed with treatment levels between 160– 200 mm Hg (Cardiomedics Inc, USA) for 45 minutes upon an adaption time of 15 minutes. Active training was carried out for 30 minutes on a treadmill (H/p/cosmos, NussdorfTraunstein, Germany), using variable running speed settings to maintain a constant pulse between 120–130 bpm after an adaption time of five minutes [12].

4

Fourteen PAD patients (male = 12 and female = 2) were enrolled in the pre-test and post-test trial to receive a total of 30 hours of ISRT over a period of five weeks (five days/ week) (Table I). There were no racial-based differences. Pa© 2016 Hogrefe

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tients between 50–85 years of age showed a stable claudication over five weeks (Fontaine stage IIb), were nonsmokers, and had a femoral popliteal occlusion. All patients were assessed for eligibility by Doppler ultrasound examination and ankle brachial index (ABI) measurement prior to recruitment for the ISRT-2 study (if suitable). Patients were instructed to keep their previous medication during the whole time of ISRT-2. Therapy pressure for ISRT-2 was between 120–160 mm Hg (Cardiomedics Inc, USA), patients’ individual pressure values were dependant on initally assessed Doppler-flow parameters, such as maximal flow velocity (Vmax) in the calf arteries. For the investigation of short- and long-term effects of passive training, study parameters were analysed at the following points of time: before the first training session, directly after the first training session, and after 30 hours of training time.

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(Promega, Germany). Therefore, plasma samples were thawed on ice and concentrated by the use of Amicon Ultra-0.5 mL Centrifugal Filter Devices (Merck Millipore, Germany) via centrifugation at 14,000 g for 8 minutes. Results were obtained by spectrophotometrical analysis (540 nm absorbance).

Gen expression analysis PBMCs were thawed on ice. RNA was isolated according to the Zymo Research-Duet DNA/RNA Mini Prep Kit (Zymo Research, California, USA). RNA quantity and purity were measured using the NanoDrop ND-1000 spectrophotometer. cDNA synthesis was performed using 1 μg RNA, as described in the manual of the High capacity cDNA Reverse Transcription Kit with RNase Inhibitor (Life Technologies, Germany).

Clinical trial registration and ethics approval Quantitative real time PCR analysis The study protocol was approved by the Ethics Committee of the Charité-Universitaetsmedizin Berlin, Charité Campus Virchow, (Reference no. EA2/108/13 and no.

EA2/140/13) and registered at the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (ISRCTN88693704 and ISRCTN19661956). All subjects gave their written informed consent.

Blood sample For blood sample collection venipuncture was performed twice in the ISRT-1 study, the first one before therapy start and the one second 10 minutes [13] after the end of either passive or active training. In the ISRT-2 study, blood samples were collected by venipuncture, first before passive training, second directly after the very first training session, and third after the last therapy session post 30 hours training time. Blood samples were collected in three 10 ml EDTA tubes: one tube was taken for plasma analysis and two tubes for the isolation of PBMCs. Plasma was collected by blood centrifugation at 4,000 rpm and 4° C for 10 minutes. Plasma was frozen on dry ice for storage at –80° C. EDTA anti-coagulated blood was diluted 1:3 in Mg2+/Ca2+-free PBS and layered at a proportion of 4:3 on Ficoll (GE Healthcare, Germany). After centrifugation at 400 g for 35 minutes the PBMC layer was isolated, washed twice with 40 ml PBS and centrifuged at 200 g for 10 minutes. The pellet was frozen on dry ice and stored at –80° C until use for molecular analysis.

Plasma nitrite measurement

The qRT-PCR was performed in 30 μl final volume, using 96-well plates. The reaction mixture contained 5 μl diluted cDNA (1:100), 15 μl 2x Power SYBR-Green PCR Master Mix (Applied Biosystems, Germany), 3.4 μl RNase/ DNase-free water (GIBCO, Germany) and 3.3 μl of forward and reverse primer (10 μM). No-template controls were included. The following thermal protocol was used: 10 minutes at 95° C; 40 cycles of 15 s at 95° C, 15 s at 60° C, 30 s at 72° C; 1 minute at 50° C and 15 s at 95° ; a subsequent dissociation curve at 60° C for 20 s and 95° C for 30 s; continuously 10° C.

Primer The following exon-intron-spanning gene-specific primer sequences (Life Technologies, Germany) were used for semi-quantitative qRT-PCR: NOS2 forward primer 5’CGGTGCTGTATTTCCTTACGAGGCGAAGAAGG-3’ and reverse primer 5’-GGTGCTGCTTGTTAGGAGGTCAAGTAAAGGGC-3’; RPLPO forward primer 5’-ACGGGTACAAACGAGTCCTG-3’ and reverse primer 5’-AGCCACAAAGGCAGATGGAT-3’; B1R forward primer 5’-ATTCTCCCACCTCAGCCTCT-3’ and reverse primer 5’-CTCTGGTTGGAGGATTGGAG-3’; B2R forward primer 5’-CTTCATGGCCTACAGCAACA-3’ and reverse primer 5’-GCACACTCCCTGGTACACCT-3’; kallikrein forward primer 5’-GCCAAGCAGACGAGGACTAC-3’ and reverse primer 5’-AACTCCACGACCTTCACAGC-3’; kininogen forward primer 5’-GTGGTGGCTGGATTGAACT T-3’ and reverse primer 5’-CACCATTCCAAAGGGACTTG-3’.

Since the griess reagent system is well established to quantify nitrite concentrations in human plasma [14] the assay was performed according to the manufacturer’s protocol © 2016 Hogrefe

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Statistical analysis

Results

Statistical analyses were done using the SPSS software version 23.0 (IBM SPSS Statistics 23, USA). All results are expressed as relative difference to basal conditions ± standard error of mean (SEM). Data were tested for normal distribution with the Shapiro-Wilk test; statistical outliers were obtained from boxplot analysis and excluded in the statistical analysis. Plasma nitrite and PBMC qRT-PCR data were analysed with a non-parametric Wilcoxon test for paired samples. For each biological replicate, technical triplicates (qRT-PCR) or duplicates (nitrite measurements) were performed. A p-value of p ≤ 0.05 (two-sided) was considered to indicate statistical significance.

ISRT-1 study: acute downregulation of NOS2 and KKS mRNA expression Each of the 26 healthy volunteers performed one passive (ISRT) and one active (treadmill) training session, starting with one of the two. Blood samples were taken before and 10 minutes after each training session (Figure 1). To investigate the acute effect of training on NO metabolism, plasma nitrite levels as well as the expression of NOS2 and KKS molecules in circulating PBMCs were measured.

Notably, the plasma nitrite concentration neither changed upon a single ISRT session (1.24 ± 0.13) nor upon

Figure 1. Flow chart of the ISRT-1 trial with a cross-over study design. 26 healthy volunteers were first assessed for eligibility and second allocated to either one session of ISRT or treadmill training. After a recovery period of 1 week, all subjects performed the other training method.

Vasa (2017), 46 (1), 37–45

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Figure 2. Short-term ISRT and treadmill training of young and healthy volunteers.

A) Relative plasma nitrite concentration before and after ISRT or treadmill training. n = 26. B-F) Differential gene expression upon 45 minutes of ISRT or 35 minutes of treadmill training (active therapy). Data are given as mean ± SEM relative to each starting point. Mean values relative to baseline PBMC expression before training are shown for B) NOS2 (ISRT: n = 19; active training: n = 18), C) B1R (ISRT: n = 16; active training: n = 10), D) B2R (ISRT: n = 19; active training: n = 20), E) kallikrein (ISRT: n = 22; active training: n = 19), and F) kininogen (ISRT: n = 23; active training: n = 21). *p ≤ 0.05.

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treadmill therapy (1.06 ± 0.10) (Figure 2A). However, NOS2 mRNA expression levels significantly decreased after ISRT counterpulsation (0.46 ± 0.11), but did not change upon treadmill running (0.82 ± 0.18) (Figure 2B).

Since leukocytic Bradykinin receptors are known regulators of NOS expression and FSS dependant vascular remodeling processes, B1R and B2R expression patterns were analysed in PBMCs. B1R expression significantly increased after ISRT (2.17 ± 0.44) and decreased upon active therapy (0.57 ± 0.10) (Figure 2C). In contrast, mRNA expression of B2R significantly decreased after ISRT (0.58 ± 0.14) and did not change upon treadmill running (1.32 ± 0.31) (Figure 2D). Expression analysis of kallikrein and kininogen, molecules upstream the KKS, revealed no change upon either ISRT or active therapy (Figure 2E and 2F).

M. Brix et al., Individual shear rate (ISRT)

ISRT-2 study: long-term ISRT counterpulsation increased plasma nitrite level The ISRT-2 study aimed at analysing short- and long-term effects of passive training (ISRT) on both plasma nitrite production and the transcriptional regulation of NOS2 as well as the KKS in PBMCs. In contrast to healthy volunteers, PAD patients were not able to perform active treadmill training.

All PAD patients enrolled in this study, finished 30 hours of ISRT, no adverse effects occurred (Figure 3). Target gene expression and plasma nitrite concentration were measured before and after the first ISRT session of 45 minutes as well as after 30 hours of ISRT counterpulsation.

After a single session of 45 minutes passive training (short-term) no changes in the plasma nitrite concentration were found (1.12 ± 0.10) (Figure 4A). However, long-term

Figure 3. Flow chart of the ISRT-2 pre-test, post-test study design.

56 Patients were assessed for eligibility and 14 patients met the inclusion criteria for short-and long-term ISRT program. Blood samples to analyse plasma nitrite concentrations as well as the expression of selected molecular markers were taken at three different points of time. One patient was excluded from PBMC gene expression analysis.

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Figure 4. Long-term ISRT of PAD patients led to increased plasma nitrite levels and a decreased mRNA expression of B2R and kininogen.

A) Relative plasma nitrite concentration of PAD patients upon short- and long-term ISRT. n = 14, *p ≤ 0.05. B-F) Gene expression analysis of PBMCs from PAD patients. Data are given as mean ± SEM relative to the baseline condition before short- or long-term ISRT. mRNA expression of B) NOS2 (n = 11), C) B1R (after 45 minutes ISRT: n = 9; after 30 h ISRT: n = 10), D) B2R (n = 9), E) kallikrein (n = 9), and F) kininogen (n = 9). *p ≤ 0.05. © 2016 Hogrefe

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ISRT resulted in a significant increase in plasma nitrite level after 30 hours of training (1.64 ± 0.25) (Figure 4A). In line with ISRT-1, NOS2 gene expression in PBMCs of PAD patients significantly decreased after 45 minutes (0.57 ± 0.20) of ISRT. Nevertheless, no statistically significant deregulation after 30 hours of therapy (0.68 ± 0.20) was observed (Figure 4B).

Considering a relevant role of the KKS, mRNA expression of B1R, B2R, kallikrein, and kininogen was analysed.

Just as in the ISRT-1 study, B1R expression was found to be upregulated upon ISRT in PAD patients. Nevertheless, statistical significance was not observed upon both shortterm (2.85 ± 1.67) and long-term ISRT (1.54 ± 0.64) (Figure 4C). The expression of B2R did not change after 45 minutes of ISRT (0.64 ± 0.23), but significantly decreased after 30 hour of long-term treatment (0.44 ± 0.18) (Figure 4D). Kallikrein was neither differentially expressed upon 45 minutes (0.77 ± 0.28) nor upon 30 hours of ISRT (1.09 ± 0.56) (Figure 4E). However, mRNA levels of kininogen were downregulated upon short-term treatment (0.52 ± 0.22) and significantly decreased after long-term ISRT (0.51 ± 0.20) (Figure 4F).

Discussion The ISRT-2 study is the first clinical trial showing a strong positive effect on the nitrite release in PAD patients upon long-term ISRT counterpulsation. This result represents the link between underlying molecular mechanisms of ISRT as treatment option for PAD patients and the positive clinical outcome of long-term ISRT that has been demonstrated previously for endothelial function, peripheral perfusion, and walking distance of PAD patients [8]. Additionally, the ISRT1 and ISRT-2 trials were designed to evaluate transcription of molecules related to NO metabolism and relevant for improving endothelial dysfunction as well as enhancing vascular remodeling. Accordingly, we present a comprehensive gene expression analysis of NOS2 and its upstream regulators B1R, B2R, kallikrein, and kininogen in PBMCs. The primary ISRT-1 and ISRT-2 study endpoint was the quantification of plasma nitrite. Since inorganic anion nitrate (NO3-) is an end product of endogenous NO metabolism and may be recycled to form NO again [15], plasma nitrite can be defined as endogenous NO storage pool, reflecting NO-synthase activity. Notably, nitrite is the most relevant vasoactive plasma NO compound and precisely regulated in response to physical exercise [16]. In contrast to Allen et al. [17, 18] who investigated the effect of longterm active exercise on nitrite release and endothelial function for PAD patients, we observed a dramatic increase of nitrite release in patients’ plasma after 30 hours of passive therapy within the ISRT-2 study. In this regard we refer to our recent publication where we showed that long-term ISRT enhanced endothelial function in PAD patients via flow-mediated vasodilation [8]. Taken together that ISRT improves flow-mediated dilation and NO release Vasa (2017), 46 (1), 37–45

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in PAD patients, we conclude that long-term ISRT results in an improved endothelial function, thus leading to a stimulated vascular response.

In contrast, ISRT and/or treadmill running did not affect plasma nitrite levels in healthy volunteers (ISRT-1). Indeed, short-term effects of exercise on nitrite release have recently been discussed controversially: on the one hand, Rassaf et al. enrolled 55 healthy subjects with a mean age of 40 in a clinical trial, showing a significant increase in nitrite concentration after a single ergometric exercise test [13]. On the other hand, Cubrilo et al. revealed that different kinds of short-term exercise programs did not influence nitrite plasma levels in athletes [19]. Notably, our ISRT-1 population was composed of trained and untrained individuals. Regarding the NOS2 expression, modest trained volunteers showed a significant decrease after one ISRT session and no effect after treadmill training. Similarly to ISRT-1, NOS2 expression also decreased after short-term ISRT in PAD patients.

Hence, we assume that ISRT counterpulsation targets NOS3 for producing NO upon the activation of endothelial cells via enhanced FSS rather than NOS2 in circulating PBMC. Regarding the upstream regulators of NOS2, gene expression analysis revealed heterogeneous results. Bradykinin receptor activity has been shown to regulate NOS activity, inflammation, and vascular remodeling [20, 21].

ISRT long-term counterpulsation resulted in a downregulation of B2R and kininogen in PBMCs from PAD patients.

Since the KKS is known to be activated upon pro-inflammatory signals and NF-kB as a transcriptional regulator [20], our results indicate that ISRT has anti-inflammatory effects on PBMCs. These results are in line with the study in Dopheide et al. [22]. Here, it was demonstrated that physical exercise performed by PAD patients results in enhanced walking distance and monocytes. Furthermore dendritic cells changed their inflammatory phenotype towards an increased anti-inflammatory pattern.

Upon short-term ISRT only the expression of B1R was upregulated in PBMCs. Interestingly, B1R was shown to govern FSS-induced arteriogenesis [21]. However, the downregulation of both KKS and NOS2 expression in the overall PBMC pool indicate a complex interplay of differently regulated leukocyte subpopulations which later on mediate paracrine regulatory functions via Bradykinin receptor signal and/or NO release [23]. Hence, for future studies we suggest a more specific analysis of monocytic or dendritic cell subpopulations in the context of FSS-induced vascular remodelling and training.

Limitations ISRT-1 was designed as a cross-over study in which each subject served as its own control. ISRT-2 was conducted as a pre-test/post-test study, therefore lacking suitable control groups. Moreover, active training could not be performed in our PAD population group, due to severe claudi© 2016 Hogrefe

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cation pain. A study design with a larger study population of PAD patients with a mild claudication (only Fontaine stage IIa) would be necessary to evaluate the effects of ISRT in comparison to treadmill running. Notably, we were also limited in patients’ material and hence could not FACS analyse PBMC subpopulations or protein expression patterns of e. g. NOS2.

Conclusions In summary, we demonstrate for the first time a strong increase in plasma nitrite release upon long-term ISRT of PAD patients which correlates with our recent finding that ISRT enhances endothelial function. However, we did not observe a direct link between increased nitrite plasma levels and the expression of NOS2 and KKS molecules in isolated PBMCs.

Acknowledgements This study was supported by the following: the (KKP) clinical collaboration project (ECRC, Charité & Max-Delbrück Center for Molecular Medicine), the Research Grant of German Hypertension Society (Deutsche Hochdruck Liga e. V., DHL), as well as the Deutsche Herzstiftung e. V. (DH).

Philipp Hillmeister was supported by KKP and DHL. Doreen Janke was supported by DHL. Andreas Zietzer, Constantin Jungk, and Michèle Brix were recipients of the Kaltenbach-scholarship (DH). Jonnel Jaurigue was supported by the German Academic Exchange Service (DAAD).

We would like to thank Meijing Li for assisting with the ISRT device.

The authors declare no conflict of interest. No author has professional relationships with companies or manufacturers who will benefit from the results of the present study. The results of the present study do not constitute endorsement by ACSM.

References 1. Stehouwer CD, Clement D, Davidson C, et al. Peripheral arterial disease: a growing problem for the internist. Eur J Intern Med. 2009;20(2):132–8.

2. Bondke Persson A, Buschmann EE, Lindhorst R, et al. Therapeutic arteriogenesis in peripheral arterial disease: combining intervention and passive training. Vasa. 2011;40(3):177–87.

3. Buschmann EE UW, Pagonas N, Gross M, et al. ANA. Improvement of fractional flow reserve and collateral flow by treatment with external counterpulsation (Art.Net.-2 Trial), Eur J Clin Invest. 2009 Oct:39(10):866–75.

4. Braith RW CC, Nichols WW, Choi CY, et al. Enhanced External Counterpulsation Improves Peripheral Artery Flow-Mediated Dilation in Patients With Chronic Angina. Circulation. 2010 Oct 4;122(16):1612–20.

5. Werner D MF, Hinz B, Werner U, et al. Impact of enhanced external counterpulsation on peripheral circulation Angiology.

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6. Buschmann I, Pries A, Styp-Rekowska B, et al. Pulsatile shear and Gja5 modulate arterial identity and remodeling events during flow-driven arteriogenesis. Development. 2010;137(13): 2187–96.

7. Eitenmüller I, Volger O, Kluge A, et al. The range of adaptation by collateral vessels after femoral artery occlusion. Circ Res. 2006;99(6):656–62.

8. Buschmann EE, Brix M, Li L, et al. Adaptation of external counterpulsation based on individual shear rate therapy improves endothelial function and claudication distance in peripheral artery disease. Vasa. 2016;45(4):317–24.

9. Troidl K TS, Cai WJ, Rüding I, et al. Effects of endogenous nitric oxide and of DETA NONOate in arteriogenesis. J Cardiovasc Pharmacol. 2010 Feb;55(2):153–60.

10. Rodríguez I, González M. Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation. Front Pharmacol. 2014;5:209.

11. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27–32.

12. M. Fioranelli GFE. From Diagnosis to Clinical Management.

Sports Cardiology. Italy2012. 321 p.

13. Rassaf T, Lauer T, Heiss C, et al. Nitric oxide synthase-derived plasma nitrite predicts exercise capacity. Br J Sports Med. 2007;41(10):669–73; discussion 73.

14. Aguilar EM, Miralles JeH, González AF, et al. In vivo confirmation of the role of statins in reducing nitric oxide and C-reactive protein levels in peripheral arterial disease. Eur J Vasc Endovasc Surg. 2009;37(4):443–7.

15. Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov. 2008;7(2):156–67.

16. Lauer T, Preik M, Rassaf T, et al. Plasma nitrite rather than nitrate reflects regional endothelial nitric oxide synthase activity but lacks intrinsic vasodilator action. Proc Natl Acad Sci USA. 2001;98(22):12814–9.

17. Allen JD, Miller EM, Schwark E, et al. Plasma nitrite response and arterial reactivity differentiate vascular health and performance. Nitric Oxide. 2009;20(4):231–7.

18. Allen JD, Stabler T, Kenjale A, et al. Plasma nitrite flux predicts exercise performance in peripheral arterial disease after 3months of exercise training. Free Radic Biol Med. 2010; 49(6):1138–44.

19. Cubrilo D, Djordjevic D, Zivkovic V, et al. Oxidative stress and nitrite dynamics under maximal load in elite athletes: relation to sport type. Mol Cell Biochem. 2011;355(1–2):273–9.

20. Bader M. Kallikrein-kinin system in neovascularization. Arterioscler Thromb Vasc Biol. 2009;29(5):617–9.

21. Hillmeister P, Gatzke N, Dülsner A, et al. Arteriogenesis is modulated by bradykinin receptor signaling. Circ Res. 2011; 109(5):524–33.

22. Dopheide JF, Scheer M, Doppler C, et al. Change of walking distance in intermittent claudication: impact on inflammation, oxidative stress and mononuclear cells: a pilot study. Clin Res Cardiol. 2015;104(9):751–63.

23. Troidl C, Jung G, Troidl K, et al. The temporal and spatial distribution of macrophage subpopulations during arteriogenesis.

Curr Vasc Pharmacol. 2013 Jan;11(1):5–12.

Submitted: 17.09.2016

Accepted after revision: 28.10.2016 There are no conflicts of interest existing.

Published online: 14.12.2016 Correspondence address Philipp Hillmeister, PhD Medical University of Brandenburg (MHB) Center for Internal Medicine I, Dept. for Angiology Hochstrasse 29 14770 Brandenburg an der Havel Germany p.hillmeister@klinikum-brandenburg.de Vasa (2017), 46 (1), 37–45

Herausforderungen des Alterns meistern Klaus Müller

Alternde Bevölkerung und gesundheitliche Versorgung Zehn Herausforderungen und ihre Konsequenzen für Prävention, Rehabilitation und das Versorgungsmanagement in Deutschland und der Schweiz 2014. 648 S., 5 farbige Abb., 10 farbige Tab., Kt € 69,95 / CHF 95.00 ISBN 978-3-456-85337-6 Auch als eBook erhältlich

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Das umfassende, anschauliche und mit hoher Informationsdichte geschriebene Manual beschreibt und analysiert spezifische Herausforderungen und Konsequenzen des demografischen Wandels für die gesundheitliche Versorgung in Deutschland und der Schweiz.

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Der Autor bietet ein argumentationsstarkes, faktenreiches, aktuelles und gut belegtes Plädoyer für die Stärkung der Prävention, Rehabilitation und geriatrischen Versorgung sowie für eine sektorenübergreifende Integration aller Versorgungsleistungen, um Alterungsfolgen, Multimorbidität und Pflegebedürftigkeit zu verringern und zu verdichten.

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Original communication

Increased vascular occlusion in patients with pseudoxanthoma elasticum Simon Pingel1,a, Kristin Solveig Pausewang1,a, Sebastian Gorgonius Passon1, Anna Katharina Blatzheim1, Martin Gliem2, Peter Charbel Issa2, Doris Hendig3, Fritz Horlbeck1, Izabela Tuleta1, Georg Nickenig1, Nadjib Schahab1, Dirk Skowasch1, and Christian Alexander Schaefer1 1 2 3

a

University Hospital Bonn, Internal Medicine II – Department of Cardiology, Angiology and Pneumology, Germany University Hospital Bonn, Department of Ophthalmology, Germany Heart and Diabetes Center NRW, Institute of Laboratory and Transfusion Medicine, University Hospital of Ruhr-University Bochum, Bad Oeynhausen, Germany These authors contributed equally.

Summary: Background: Pseudoxanthoma elasticum (PXE) is an autosomal recessive inherited multisystem disorder of the connective tissue caused by a loss-of-function mutation of the ABCC6 gene. It can affect the cardiovascular system, presumably leading to a high prevalence of atherosclerosis. Patients and methods: 46 PXE patients and 18 controls underwent an angiological examination consisting of measurement of ankle-brachial index (ABI), strain-gauge arterial reserve (SGAR), arterial resting perfusion, pulse wave index (PWI), central pulse wave velocity, and ultrasound examination. Results: With an average age of 51.4 ± 12.4 years, 35/46 (76.1 %) of the PXE patients had atherosclerotic lesions, and 10 of them (28.6 %) had a chronic vascular occlusion of one or more peripheral vessels. 34/46 (73.9 %) had a pathologic ABI < 0.9, 15/42 (35.7 %) had a pathological SGAR < 10 mL/100 mL tissue/min, and 23/38 (60.5 %) had a pathological PWI > 180. The differences between the groups were statistically significant for ABI, arterial reserve, and PWI. Conclusions: In PXE patients atherosclerosis was found with a much higher prevalence than expected. Moreover, they were at very high risk for total vessel occlusions.

Keywords: PXE, ABCC6, atherosclerosis, peripheral artery disease, chronic vascular occlusion

Introduction Pseudoxanthoma elasticum (PXE), also known as Groenblad-Strandberg syndrome, has an estimated prevalence of 1:25.000 to 1:100.000 [1], hence affecting 80.000– 320.000 people worldwide. It is an autosomal recessive inherited multisystem disorder of the connective tissue [2].

PXE is caused by a mutation of the ABCC6 (ATP-binding cassette subfamily C member 6) gene, which encodes a transmembrane transporter expressed primarily in liver and kidney [3]. Using a cellular model, generally, by releasing ATP the carrier leads to an increase of pyrophosphate (PPi), which inhibits ectopic mineralization. In PXE patients this mechanism is dysfunctional, resulting in a reduced PPi plasma level [4] and in an increased progressive mineralization and fragmentation of elastic fibres [5].

Being a multisystem disorder, clinical appearance of PXE can be variable. It is characterized by substantial intra- and inter-familial heterogeneity. Mostly affected are eyes and skin. Transformations of skin structure often become visi© 2016 Hogrefe

ble during childhood or adolescence. The cutaneous manifestations mostly begin as small, asymptomatic, yellowish or skin-coloured papules forming a reticular pattern, which unite to a larger plaque. This usually affects the lateral and posterior parts of the neck and flexural areas. These regions show typically a lax, wrinkled, and redundant skin. [3] The ocular manifestations have characteristic funduscopic findings: angioid streaks, peau d’orange, peripheral comet lesions, and choroidal neovascularization [6]. A thickening and calcification of the Bruch’s membrane appears to be the primary ophthalmologic pathology of PXE patients. Some publications describe cardiovascular manifestations of PXE. This inherited multisystem disorder seems to increase the cardiovascular risk and is associated with an increased occurrence of atherosclerotic changes [7–9]. However, untill today there is little knowledge about the distribution and the pathomechanism of atherosclerosis in patients with PXE. The aim of our study was to examine and determine the changes specifically of the peripheral arterial system in a large German collective.

Vasa (2017), 46 (1), 47–52 DOI 10.1024/0301-1526/a000583

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Patients and methods This prospective observational study was performed at the Department of Cardiology, Angiology and Pneumology – Internal Medicine, University of Bonn, between August 2014 and October 2015. Institutional review board approval (Ethics Commission, Medizinische Fakultät, Rheinische Friedrich-Wilhelms-Universität Bonn) and patients’ consents were obtained.

Patients’ characteristics 46 consecutive patients with PXE underwent an extensive angiological and ophthalmological examination. Minimal criteria for the diagnosis of PXE were the characteristic funduscopic findings angioid streaks or characteristic skin lesion as previously described [10]. Additionally, in 42 patients a direct sequencing and multiplex ligation-dependent probe amplification analysis of the ABCC6 gene was performed (Institute for Laboratory and Transfusion Medicine, Heart and Diabetes Center Bad Oeynhausen).

18 controls with no findings of PXE or atherosclerosis and a corresponding age distribution underwent similar examinations as the PXE patients.

Arterial hypertension, diabetes, smoking, coronary artery disease, fat metabolism disorder, and renal impairment were assessed by a questionnaire. Age, weight, body height, and body mass index (BMI) were additionally determined. As patients with PXE have a high risk for coronary artery disease, they were all assigned to undergo a more specific cardiac examination.

S. Pingel et al., Vascular occlusions are increased in PXE

nar flow), peak systolic velocity and peak velocity ratio corresponding to clinical standards. A vascular occlusion was defined when the B-mode examination showed a large plaque in two axes completely occluding the vessel, the Cmode examination no perfusion of the vessel, and the PWmode no flow.

Functional measurements Several vascular functional parameters were non-invasively examined. An ankle-brachial index (ABI) < 0.9 defines a peripheral arterial disease (PAD), whereas an ABI > 1.4 is associated with a mediasclerosis. [11] Strain-gauge arterial reserve (SGAR) quantifies the peak flow perfusion after 3 min of ischemia in form of reactive hyperaemia (values < 10 mL/100 mL tissue/min are considered pathological), whereas arterial resting perfusion (ARP), pathological < 1 mL/100 mL tissue/min, demonstrates the blood flow at rest. ABI, SAGR, and ARP were assessed with Vasoquant VQ 4000: ELCAT, Wolfratshausen, Germany. Central pulse wave velocity (cPWV) sizes arterial elasticity, as the pulse wave, which is generated by the cardiac output, has specific velocities in the different arterial sections depending on the arterial stiffness. Pulse wave index (PWI) is a blood-pressure-independent parameter being calculated by analysing the pulse wave form. PWI was calculated using following formula: higher amplitude of upper limb pulse wave amplitude of corresponding lower limb pulse wave

× peak time

Ultrasound examinations Ultrasound examination was performed by three experienced ultrasound physicians using an iE 33 xMatrix echocardiography system (Philips Healthcare, PC Best, Netherlands) equipped with a 3–11 MHz line array scanner. Long and short axis images were recorded in B-mode and Cmode from the following arteries bilaterally: common carotid artery, internal carotid artery, external carotid artery, vertebral artery, common femoral artery, deep femoral artery, superficial femoral artery, and the popliteal artery.

Segments V0-V3 of the vertebral arteries were examined, whereas carotid arteries were displayed in the whole extracranial area and femoral arteries were assessed in their whole length. PW-mode was used determining local flow velocity.

We monitored atherosclerotic lesions, stenoses, and total vascular occlusions. Lesions were defined as calcification or inhomogeneous vessel wall deformation and an intima-media thickness (IMT) more than 1.1 mm. Stenoses of the carotid arteries were classified according to revised DEGUM criteria [13]. Stenoses of the femoral arteries were subdivided considering the plaque characteristics, flow characteristics (appearance of laminar or non-lamiVasa (2017), 46 (1), 47–52

Values > 180 are regarded as pathological. [12] cPWV and PWI were explored using Angio Experience Pro 8 (Sonotechnik Karl Glantschnig GmbH, Kärnten, Austria). These non-invasive vascular laboratory assessments indicate cardiovascular risk and the process of peripheral atherosclerosis lesions. Using these methods, the severity of atherosclerosis can be estimated.

Statistical analysis Statistical analysis was performed using statistical software (IBM SPSS, v.23.0, Armonk, New York, USA). For distribution analysis Chi-squared test was applied. Gaussian distribution of parametric variables was assessed. The difference of parametric variables showing a Gaussian distribution was tested with a t-test, whereas the non-Gaussian distribution was tested with a Mann-Whitney U test. The two-sided p-value was defined significant below 0.05.

Continuous variables are shown as mean ± standard deviation.

© 2016 Hogrefe

S. Pingel et al., Vascular occlusions are increased in PXE

49

Results

Table II. Atherosclerotic changes by ultrasound findings in PXE patients.

The baseline characteristics of patients with PXE and controls are shown in Table I.

Number of patients with:

None

Plaque

Stenosis

Occlusion

Extracranial arteries

23

20

2

1

Femoral arteries

13

18

6

9

Ultrasound findings In 35/46 (76.1 %) patients we found atherosclerotic manifestations by ultrasound examinations, whereas 11/46 (23.9 %) patients had no evidence of atherosclerosis. The majority had both, carotid artery disease (CAD) and PAD (n = 21, 45.7 %), followed by atherosclerotic lesions of the lower extremities only (n = 12, 26.1 %). Only in 4.3 % (n = 2) a sole CAD was found. The PXE patients showed a higher occurrence of atherosclerotic changes in their lower extremities than in the extracranial arteries (Table II). Additionally, in 10/35 patients with atherosclerosis (28.6 %), vascular occlusions were found. One was located in the right internal carotid artery (asymptomatic), the other occlusions were found in the lower extremities (2 unilateral, 7 bilateral occlusions of the superficial femoral artery) (Table III).

Displayed is the severest ultrasonographic finding and not the distribution of all atherosclerotic changes per patient.

Table III. Localisation of stenoses and occlusions in PXE patients.

Stenosis

Occlusion

ICA right

1

1

ICA left

2

0

ECA right

2

0

ECA left

1

0

SFA right

6

8

SFA left

5

8

Displayed is the total quantity of stenoses/occlusions. Multiple findings per patient are included. ICA: internal carotid artery; ECA: external carotid artery; SFA: superficial femoral artery.

Table IV. Average functional angiological parameters of patients with PXE.

Functional parameters The average ABI of PXE patients was 0.87 ± 0.20 vs. 1.09 ± 0.06 within the control group (p < 0.001). The average SGAR (12.3 ± 4.6 mL/100 mL tissue/min vs. 22.3 ± 3.8 mL/100 mL tissue/min, p < 0.001) and the average PWI (235.8 ± 121.5 vs. 113.1 ± 33.3 p < 0.001) differed significantly from the control group. In contrast, the average arterial resting perfusion (ARP) of PXE patients was similar to that of our control group (2.87 ± 0.92 mL/100 mL tissue/min vs. 2.54 ± 1.03 mL/100 mL tissue/min, p = n. s.)

(Table IV).

PXE (n = 46)

Control (n = 18)

p

0.87 ± 0.20

1.09 ± 0.06

< 0.001

Average SGAR [mL/ 100 mL tissue/min]

12.3 ± 4.6

22.3 ± 3.8

< 0.001

Average ARP [mL/ 100 mL tissue/min]

2.87 ± 0.92

2.54 ± 1.03

n. s.

235.8 ± 121.5

113.1 ± 33.3

< 0.001

5.08 ± 1.08

6.09 ± 2.82

n. s.

Average ABI

Average PWI Average cPWV [m/s]

ABI: ankle-brachial index; SGAR: strain-gauge arterial reserve; ARP: arterial resting perfusion; PWI: pulse wave index; cPWV: central pulse wave velocity.

Table I. Baseline Characteristics of patients with PXE. PXE (n = 46)

Control (n = 18)

p

Age [years]

51.35 ± 12.40

48.00 ± 13.50

n. s.

BMI [kg/m²]

27.54 ± 6.15

23.39 ± 3.08

0.005

Sex: male [%]

16

[34.8]

8

[44.4]

n. s.

Nicotine [%]

8

[17.4]

2

[11.1]

n. s.

Diabetes mellitus [%]

0

[0.0]

0

[0.0]

Hypertension [%]

19

[41.3]

7

[38.9]

n. s.

Fat metabolism disorder [%]

17

[37.0]

2

[11.1]

0.042

0

[0.0]

0

[0.0]

5/45

[11.1]

0

[0.0]

n. s.

1

[2.2]

0

[0.0]

n. s.

Renal impairment [%] Coronary artery disease [%] Myocardial infarction [%] BMI: body mass index. © 2016 Hogrefe

Vasa (2017), 46 (1), 47–52

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Clinical symptoms and atherosclerotic burden Generally, the diagnostic findings correlated with an increasing Fontaine stage (Fig. 1). 32.6 % of the patients (n = 15) had an asymptomatic lower extremity arterial disease (Fontaine stage I). Within this group, 1 patient with a bilateral vascular occlusion of the superficial femoral artery was identified. 12 patients (26.1 %) presented with a Fontaine stage IIa, out of which 5 patients showed vascular occlusions. 6 out of the 46 patients (13.0 %) claimed a Fontaine stage IIb, here 66 % (n = 4) had proof of vascular occlusions. No patient reported Fontaine stage III or IV. The ABI showed a significant difference between patients with vascular occlusions (0.64 ± 0.20) and patients without PAD (1.01 ± 0.10) (p < 0.01). Moreover, the SGAR differed significantly between the group with no PAD and CAD (14.64 ± 4.72 mL/100 mL tissue/min) and the group with vascular occlusions (9.28 ± 2.88 mL/100 mL tissue/min) (p < 0.01). Additionally, the PWI of patients with vascular occlusions (353.8 ± 108.5) was significantly higher than in patients without (165.5 ± 84.3) (p < 0.01).

Discussion With an average age of 51 years, the PXE patients showed a much higher frequency of atherosclerosis as expected in an age-matched common population. The getABI-study reported a total prevalence of PAD in 21 % of the cohort with an average age over 65 years [14]. There are few publications describing patients with PXE and increased appearance of atherosclerosis. Leftheriotis et al. demonstrated in 2014 a prevalence of PAD (defined by an ABI < 0.9) of 56 % in a cohort of 71 PXE patients with a mean age of 48 ± 14 years [15], and in 2011 a prevalence of 45 % in a group of 53 PXE patients (49 ± 14 years) [9]. We recorded an even higher frequency of PAD. In 72 % of our patient cohort atherosclerotic lesions in the lower extremities were found by sonographic examination, while 74 % had a pathological ABI < 0.9. This numerous appearance of an ABI < 0.9 has a clinical and prognostic relevance for the patients, as a pathological ABI is an independent risk indicator for increased cardiovascular morbidity and mortality. The 10year total mortality is nearly twice as high as indicated by each Framingham category [16]. The overall mortality does not differ relevantly between patients with or without symptoms of PAD [17].

We could demonstrate that the functional angiological parameters in PXE patients were changed to an important degree. The average PWI was highly pathological and also the average SGAR showed a significant tendency towards the pathological value of < 10 mL/100 mL tissue/min compared to our control group. Even though the ARP of PXE patients was decreased, this difference reached no statistiVasa (2017), 46 (1), 47–52

S. Pingel et al., Vascular occlusions are increased in PXE

cal significance maybe due to a too small number of patients being compared.

Furthermore, to our knowledge we are the first to describe a high frequency (10/35, 29 %) of total chronic vascular occlusions in patients with PXE and atherosclerosis.

Interestingly, even with severe vascular disorders, the clinical symptoms were rather low. No critical limb ischaemia was reported within our collective so far.

There are several possible explanations for the lack of symptoms. First, similar to the ocular changes with known choroidal neovascularisation [18], by a yet unknown pathway the vessel occlusion could be compensated by enforced arterial collateralization. Secondly, the period of time required to develop vascular occlusions in our patients is unknown. Generally, a slow progress could favour an enhanced compensatory collateralization and therefore diminish clinical manifestations. Thirdly, peripheral nerves are encased by connective tissue consisting of collagenous and elastic fibres. This encasement protects and containing blood vessels nourishes the nerve. As PXE leads to an increased mineralization and fragmentation of elastic fibres, there might be neurological affections of peripheral axons [19] caused by a disturbed diffusion. Additionally, the extracellular matrix of the connective tissue is, amongst others, composed of proteoglycans. Likewise, Kornet et al. reported an accumulation of proteoglycans in skin biopsies [10], which might, applied to the neurological system in PXE patients, lead to a malfunctioning intercellular signalling [20].

In comparison to our control collective, PXE patients had an elevated BMI and a higher frequency of fat metabolism disorder. Moreover, their cardiovascular risk profile in relation to BMI, fat metabolism disorder (37.0 %), and hypertension (41.3 %) was slightly higher than in the general population. On the other hand, other cardiovascular risk factors such as nicotine consumption (17.4 %), diabetes (0 %), and renal impairment (0 %) occurred with a low prevalence compared to the general public of the same age. [21] Considering the ocular manifestation of PXE, this disease results in impaired vison, which might lead to decreased mobility. This could facilitate development of obesity, fat metabolism disorder, and hypertension, the main cardiovascular risk factors in developed countries.

Additionally, this can also explain the lack of symptoms.

Limited motion prevents patients from feeling the intermittent claudication.

As the prevalence of coronary artery disease is likely higher in patients with severe PAD [17], a more extensive cardiovascular examination could be beneficial in this subgroup of PXE patients. Prunier et al. performed a cardiac examination including perfusion myocardial scintigrams in 28 patients with no evidence of an increased ischaemic cardiomyopathy [7]. Whereas Nguyen et al. describe an appearance of 37 % of diastolic dysfunction in a cohort of 19 asymptomatic PXE patients [22]. Therefore, we suggest a further exploration of the cardiac involvement in a larger collective. © 2016 Hogrefe

S. Pingel et al., Vascular occlusions are increased in PXE

For further investigations two questions need to be addressed. It currently remains unknown which PXE patients develop a severe peripheral atherosclerosis while others have no sign of atherosclerosis. In our study standard diagnostic tools (such as ABI) generally correlated with the se-

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verity. However, as clinical symptoms often were not present or only mild, an even closer medical supervision should be performed in this special collective, as long as there are no independent risk factors identified for the occurrence of severe atherosclerosis.

Figure 1. Correlation between the average functional angiological parameters and patients grouped by PAD-Fontaine stages or by PAD+CAD and vascular occlusions.

ABI: Ankle-brachial index; SGAR: strain-gauge arterial reserve; PWI: pulse wave index; PAD: peripheral artery disease, CAD: carotid artery disease *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001. © 2016 Hogrefe

Vasa (2017), 46 (1), 47–52

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Limitations Limitation to this study is the sample size of 46 patients and 18 controls. Even though it is the second-largest published collective so far, it is relatively small and could affect the statistical analysis. Additionally, our PXE patients underwent an initial examination by the Department of Ophthalmology. Therefore, this report includes only patients with an ocular manifestation of PXE.

Conclusions PXE is a disease that can lead to severe atherosclerosis which is more frequent and more pronounced in these patients, even though they show less symptoms than would be expected based on the sonographic findings. Moreover, the symptoms occur at a younger age than expected in a healthy population. Furthermore, we could show for the first time that PXE patients are at high risk for developing total peripheral vessel occlusions. As PXE could be a model disease for the development of atherosclerosis, a better understanding of the pathway leading to the vascular abnormalities might lead to novel therapeutic strategies.

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2. Lefthériotis G, Omarjee L, Le Saux O, et al. The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification. Front Genet. 2013;4:4. DOI: 10.3389/ fgene.2013.00004.

3. Marconi B, Bobyr I, Campanati A, et al. Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment. Intractable Rare Dis Res. 2015;4:113–22. DOI: 10.5582/irdr.2015.01014.

4. Jansen RS, Duijst S, Mahakena S, Sommer D, et al. ABCC6mediated ATP secretion by the liver is the main source of the mineralization inhibitor inorganic pyrophosphate in the systemic circulation-brief report. Arterioscler Thromb Vasc Biol.

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7. Prunier F, Terrien G, Le Corre Y, et al. Pseudoxanthoma elasticum: cardiac findings in patients and Abcc6-deficient mouse model. PLoS ONE. 2013;8:e68700. DOI: 10.1371/journal. pone.0068700.

8. Campens L, Vanakker OM, Trachet B, et al. Characterization of cardiovascular involvement in pseudoxanthoma elasticum families. Arterioscler Thromb Vasc Biol. 2013;33:2646–52. DOI: 10.1161/ATVBAHA.113.301901.

9. Lefthériotis G, Abraham P, Le Corre Y, et al. Relationship between ankle brachial index and arterial remodeling in pseudoxanthoma elasticum. J Vasc Surg. 2011;54:1390–4. DOI: 10.1016/j.jvs.2011.04.041.

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10. Kornet L, Bergen AAB, Hoeks APG, et al. In patients with pseudoxanthoma elasticum a thicker and more elastic carotid artery is associated with elastin fragmentation and proteoglycans accumulation. Ultrasound Med Biol. 2004;30:1041–8.

DOI: 10.1016/j.ultrasmedbio.2004.06.004.

11. Tendera M, Aboyans V, Bartelink M, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011;32:2851–906. DOI: 10.1093/eurheartj/ ehr211.

12. Pizarro C, Schaefer C, Kimeu I, et al. Underdiagnosis of obstructive sleep apnoea in peripheral arterial disease. Respiration. 2015. DOI: 10.1159/000371355.

13. Arning C, Widder B, von Reutern GM, et al. Revision of DEGUM ultrasound criteria for grading internal carotid artery stenoses and transfer to NASCET measurement. Ultraschall Med. 2010;31:251–7. DOI: 10.1055/s-0029-1245336.

14. getABI: German epidemiological trial on ankle brachial index for elderly patients in family practice to detect peripheral arterial disease, significant marker for high mortality. VASA. 2002;31:241–8. DOI: 10.1024/0301-1526.31.4.241.

15. Leftheriotis G, Kauffenstein G, Hamel JF, et al. The contribution of arterial calcification to peripheral arterial disease in pseudoxanthoma elasticum. PLoS ONE. 2014;9:e96003. DOI: 10.1371/journal.pone.0096003.

16. Fowkes FGR, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008;300:197–208. DOI: 10.1001/jama.300.2.197.

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18. Georgalas I, Tservakis I, Papaconstaninou D, et al. Pseudoxanthoma elasticum, ocular manifestations, complications and treatment. Clin Exp Optom. 2011;94:169–80. doi: 10.1111 /j.1444-0938.2010.00559.x.

19. Kavukcuoglu NB, Li Q, Pleshko N, Uitto J. Connective tissue mineralization in Abcc6-/- mice, a model for pseudoxanthoma elasticum. Matrix Biol. 2012;31:246–52. doi: 10.1016/j.mat bio.2012.02.004.

20. Masu M. Proteoglycans and axon guidance: a new relationship between old partners. J Neurochem. 2015. doi:10.1111 /jnc.13508.

21. Robert Koch-Institut. Gesundheit in Deutschland: Gesundheitsberichterstattung des Bundes. Gemeinsam getragen von RKI und Destatis. 2015. Berlin. Online at https://www.rki.de/ DE/Content/Gesundheitsmonitoring/Gesundheitsberichterstattung/GesInDtld/gesundheit_in_deutschland_2015.html (September 2016) 22. Nguyen L, Terbah M, Daudon P, et al. Left ventricular systolic and diastolic function by echocardiogram in pseudoxanthoma elasticum. Am J Cardiol. 2006;97:1535–7. doi:10.1016/j. amjcard.2005.11.091.

Submitted: 31.05.2016 Accepted after revision: 15.08.2016 There are no conflicts of interest existing.

Published online: 08.12.2016 Correspondence address Dr. med. Simon Pingel University Hospital Bonn Internal Medicine II Sigmund-Freud-Str. 25 53127 Bonn Germany simon.pingel@ukb.uni-bonn.de © 2016 Hogrefe

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Original communication

Comparison of temporary abdominal aortic occlusion with internal iliac artery occlusion for patients with placenta accreta – a non-randomised prospective study Yan-Li Wang1, Xu-Hua Duan1, Xin-Wei Han1, Ling Wang1, Xian-Lan Zhao2, Zhi-Min Chen2, Qin-Jun Chu3, and Wei Zhang3 1 2 3

Department of Interventional Radiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Province, China Department of Obstetrics, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Province, China Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan Province, China

Summary: Background: To compare the efficacy of temporary abdominal aortic occlusion with internal iliac artery occlusion for the management of placenta accreta. Patients and methods: 105 patients with placenta accreta were selected for treatment with temporary abdominal aortic occlusion (n = 57, group A) or bilateral iliac artery occlusion (n = 48, group B). Temporary abdominal aortic and internal iliac artery balloon occlusions were performed during caesarean sections. Data regarding the clinical success, blood loss, blood transfusion, balloon insertion time, fluoroscopy time, balloon occlusion time, foetal radiation dose, and complications were collected. Results: Temporary abdominal aortic occlusion and bilateral internal iliac artery occlusion were technically successful in all patients. The amount of blood loss (P < 0.001), amount of blood transfusion (P < 0.001), balloon insertion time (P < 0.001), foetal radiation dose (P < 0.001) and fluoroscopy time (P < 0.01) in group A were significantly lower than those of patients in group B. No marked differences were found between these 2 groups with respect to age, mean postoperative hospital stay, balloon occlusion time, and Apgar score (p > 0.05). Conclusions: Temporary abdominal aortic balloon occlusion resulted in better clinical outcomes with less blood loss, blood transfusion, balloon insertion time, fluoroscopy time and foetal radiation dose than those in bilateral internal iliac balloon occlusion.

Keywords: Abdominal aorta, balloon catheter, placenta accrete, caesarean, embolisation

Introduction Placenta accreta refers to the abnormal attachment of the placenta to the uterine wall, such that the chorionic villi invade the myometrium or even penetrate adjacent organs [1]. It has an overall incidence of about 1 in 500 with the strongest risk factors including previous caesarean delivery, placenta previa, and advanced maternal age [1]. It is a serious complication of pregnancy, and is associated with massive postpartum haemorrhage and high maternal morbidity and mortality [2, 3] and accounts for 23–64 % of peripartum hysterectomies [4]. Hysterectomy is considered the definitive treatment and is effective [5, 6]. However, it is often rejected by the patient, particularly by young women and/or those who are primigravida. Conservative management of both the uterus and abnormal placenta, which is left inside the uterus at the time of delivery, has been developed [78], but is associated with the risk of delayed uterine bleeding and a need for subsequent hysterectomy [7, 8]. © 2016 Hogrefe

Recently, temporary balloon occlusion of the uterine arteries during caesarean section has been reported as successful in minimising post-delivery blood loss with preservation of the uterus in placenta accreta [9–14]. Different sites of occlusion have been reported, including the abdominal aorta, the common iliac arteries and the internal iliac arteries, but it remains unclear which is the optimal technique. We report a prospective, non-randomised controlled study comparing abdominal aortic occlusion with internal iliac artery occlusion.

Patients and methods The study was approved by the university committee on human investigation and informed consent was obtained from each patient. Consecutive patients with placenta accreta referred for prevention of postpartum haemorrhage Vasa (2017), 46 (1), 53–57 DOI 10.1024/0301-1526/a000577

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X.-W. Han et al., Aortic occlusion for placenta accreta

and preservation of the uterus with temporary abdominal aortic balloon occlusion (group A, from November 2013 and December 2014) or bilateral internal iliac artery balloon occlusion (group B, from January 2013 and October 2013) during caesarean section were enrolled in this nonrandomised, prospective study.

Inclusion criteria were as follows: a diagnosis of placenta accreta based on clinical examination findings and ultrasound or magnetic resonance imaging appearances (Fig. 1); clinical risk factors for placenta accreta; a desire to preserve fertility; gestational age >28 weeks; and the absence of antepartum bleeding.

Patients were excluded if they were unsuitable for general anaesthesia, had a history of allergy to contrast medium, coagulopathy, or evidence of renal dysfunction.

Interventional procedures All occlusions were performed by one of two interventional radiologists experienced in gynaecological procedures in a hybrid operating theatre equipped with digital subtraction angiography ((Allura Xper FD20, Philips, Best, The Netherlands). Caesarean sections were performed

A

B

C

D

under general anaesthesia by two gynaecologists. The patients’ vital signs were monitored by left forefinger pulse oximetry. Additional pulse oximeters placed on each great toe were used to determine when occlusion of the aorta had occurred, using the method of Paull et al. [9].

Temporary abdominal aorta occlusion Prior to balloon occlusion, angiography of the abdominal aorta was performed in all patients via the right femoral artery with a 5-Fr Pigtail catheter (Cook Inc.) in order to locate the origins of the renal arteries. Ultrasound or magnetic resonance imaging was used to determine the diameter of the balloon required. In most patients, an 8-F balloon catheter (Bard Peripheral Vascular Inc., USA) that was 16–18 mm in diameter and 40 mm in length was used.

Five minutes prior to the caesarean section, the balloon catheter was inserted into the abdominal aorta via a 0.035-inch stiff guidewire (THSF; Cook, Bloomington, IN, USA) with the balloon covering the renal arteries. Immediately after foetal delivery and umbilical cord clamping, the balloon was inflated to occlude the abdominal aorta (Fig.

Figure 1. A 29-year-old woman with placenta accreta presented with postpartum hemorrhage. (A, B) Coronal T2-weighted MRI shows placenta previa with invasion into the myometrium, suggestive of placenta increta. (C) Before cesarean section, a balloon is inflated to occlude the abdominal aorta. (D) After completion of the surgical procedure, bilateral iliac artery angiography shows a normal uterine artery without obvious vessel staining.

Vasa (2017), 46 (1), 53–57

© 2016 Hogrefe

X.-W. Han et al., Aortic occlusion for placenta accreta

1). Complete occlusion of the abdominal aorta was deemed to have been achieved when the patient’s pulse and oxygen saturation could no longer be obtained on the great toe pulse oximeters, and the curve of the blood pressure sensor was an approximately straight line when no blood pressure reading could be obtained.

During caesarean section, consecutive 5 Minute inflations and 1 Minute deflations of the balloon were used to control postpartum haemorrhage. During each occlusion, 50 ml 0.01 % heparin saline was administered via the catheter to prevent clot formation. Blood gas analyses, electrolytes and clotting were monitored before, during and after the procedure.

After removal of the placenta and the ligation of bleeding vessels, the balloon was deflated for 1–5 Minutes to observe whether further bleeding occurred. If necessary, further occlusion was performed. On completion of caesarean section, an abdominal angiogram was undertaken to exclude aortic dissection or rupture or thrombosis of the renal, internal iliac or external iliac arteries.

Temporary internal iliac artery occlusion The details of the procedures were previously described [10, 12] and is only summarized here. Prior to the caesarean section, using a standard Seldinger technique, both femoral arteries were punctured, and 6 F sheaths were introduced. The bilateral internal iliac arteries were selectively catheterized by a contralateral approach. Once access to both internal iliac arteries was gained, 4–8 mm diameter, 20–30 mm long Bard balloons (Bard Peripheral Vascular Inc., USA) were positioned with the tip in the proximal portion of the contralateral internal iliac artery, just after the common iliac artery bifurcation. Immediately after foetal delivery and umbilical cord clamping, the balloons were inflated to occlude the internal iliac artery.

During caesarean section, the balloons were also inflated for 5 Minutes and deflated for 1 Minute. During each occlusion, 50 ml 0.01 % heparin saline was also administered via the catheter to prevent clot formation. The other procedures were the same as temporary abdominal aorta occlusion.

Uterine artery embolisation After removal of the balloon catheters, if necessary, both uterine arteries were embolised using 710–1000 μm gelatine sponge particles (Alicon Pharm, Hangzhou, China) in patients with tortuous and/or thickened uterine arteries when postpartum haemorrhage was continued or not easy to control. Catheter sheaths were then removed, and puncture sites compressed manually for at least 10–15 Minutes. Hysterectomy was performed in those patients in whom balloon occlusions and uterine artery embolisation failed to control postpartum haemorrhage from the placental bed. © 2016 Hogrefe

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Postoperative outcome evaluation Patients were evaluated clinically by two of the authors at the time of the caesarean section and at 1, 3 and 6 months post-procedure. Data on the clinical success, blood loss, blood transfusion, balloon insertion time, fluoroscopy time, radiation dose, balloon occlusion time, and complications were collected and estimated at the time of the procedures, and at the end of follow-up.

Clinical success was defined as preservation of the uterus and the control of bleeding without delayed uterine bleeding or surgical interventions, such as laparotomy or hysterectomy. Blood loss was estimated by weighing swabs and surgical pads and by measuring the contents of the suction jar in the operating theatre. Balloon insertion time was defined as the time from femoral artery puncture to balloon insertion in the target artery or arteries. Fluoroscopy time and radiation dose (in milligrays) were obtained from the fluoroscope at the end of the procedure. The entrance skin radiation dose in the area of the irradiated field was considered an approximation for the foetal radiation dose. The total balloon occlusion time was calculated by summation of the individual occlusion times.

Complications related to the procedures were divided into major and minor categories. Major complications occurring during and after the procedures were postoperative thromboembolism requiring surgical or interventional management, perforations or pseudoaneurysms of the abdominal aorta or internal iliac artery requiring a surgical or interventional repair immediately, death due to rupture of the abdominal aorta, etc. Minor complications defined as complications that led to no consequence were transient lumbosacral pain, post-embolisation syndrome or discomfort, etc.

In addition, serum beta-human chorionic gonadotrophin (β-hCG) levels were measured before and 1 month after the procedure. Serum creatinine and blood urea nitrogen levels 7 days after the procedure were compared to pre-procedure levels to detect changes in renal function.

Statistical analysis Descriptive data are given as the means ± SD. Dichotomous and categorical data are reported as numbers and percentages. Comparison of variables between two groups was performed using the Mann–Whitney test, χ2-test or Fisher’s exact test, as appropriate. All statistical analyses were performed using SPSS, version 13.0 (Chicago, USA).

Results A total of 112 patients with placenta accreta were enrolled. Initially, 59 and 53 patients were assigned to the group A and group B, respectively. Of these, 7 patients were excluded from the study, with general anaesthesia Vasa (2017), 46 (1), 53–57

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in three patients (one in group A and two in group B), allergy to contrast medium in two patients (one in each group), coagulopathy in one patients in group B and evidence of renal dysfunction in one patient in group B. Therefore, 57 and 48 patients were included in groups A and B, respectively.

Temporary abdominal aorta occlusion (Fig. 1), and bilateral internal iliac artery occlusion were technically successful and well tolerated in all patients. There were no major procedure-related complications and all monitored parameters remained stable. In addition, uterine artery embolisations were performed in sixteen patients in group A and fourteen in group B. Successful caesarean section with preservation of the uterus was achieved in all but two patients, both in group A. In both of these patients, the placenta accreta involved the bladder, which could not be separated from the uterus, and partial hysterectomy was required.

There were statistically significant differences between the two groups in a number of outcome variables. In particular, patients in group A lost less blood, required less blood to be transfused, had shorter balloon insertion times, shorter fluoroscopy times and lower foetal radiation doses (Table I). We found no statistically significant differences in other outcome variables, including mean postoperative hospital stay and Apgar scores (Table I).

At the end of follow-up, there were no maternal or foetal mortality. Mild lumbosacral pain for 2–3 days after the procedure was reported by seven patients from group A and five from group B. Post-embolisation syndrome, with fever and lower abdominal pain 1–3 days after the procedure, developed in six patients in group A and four in group B. It was managed conservatively in all cases. No late intervention-related complications occurred, and maternal and infant health and development was normal in all cases. There was no evidence of any post-procedure renal impairment. Serum β-hCG level decreased to normal in all patients within 1 month.

Discussion This non-randomised study was designed to compare the clinical outcomes of two endovascular regimens in patients with placenta accreta. The two procedures were technically successful in all patients, with no major procedure related complications. However, there were significant differences between the two regimes in a number of the outcome measures. These differences suggest that occlusive balloon catheterisation of the internal iliac arteries is, in some respects, not as effective as occlusive balloon catheterisation of the aorta. Collateral circulation via the obturator, lumbar, sacral, rectal, ovarian and femoral arteries may prevent pelvic ischaemia during balloon occlusion of the internal iliac artery [15]. These inherent anastomoses may be the cause of the disappointing results. Temporary abdominal aortic balloon occlusion will block collateral Vasa (2017), 46 (1), 53–57

X.-W. Han et al., Aortic occlusion for placenta accreta

Table 1. Patient characteristics, technical data and selected outcome measures.

Group A (n = 57) Age (years)

Group B (n = 48)

p-value

25.44 ± 4.11

25.71 ± 4.23

0.995

Blood loss (mL)

450.4 ± 146.8

619.2 ± 171.2

< 0.001

Blood transfusion (mL)

480.7 ± 144.5

614.6 ± 139.9

< 0.001

Balloon insertion time (min)

12.47 ± 1.57

27.98 ± 5.32

< 0.001

Fluoroscopy time (min)

5.05 ± 1.51

11.85 ± 2.56

< 0.001

Fetal radiation dose (mGy)

3.79 ± 1.61

6.63 ± 2.06

< 0.001

Occlusion time (min)

22.14 ± 5.40

23.75 ± 5.89

0.147

Apgar score at 5 min

10.25 ± 1.26

10.13 ± 1.27

0.629

Postoperative hospital stay (days)

5.72 ± 1.24

5.90 ± 1.09

0.445

Creatinine level at 7 days

58.59 ± 6.32

58.50 ± 5.93

0.842

5.37 ± 0.84

5.31 ± 0.85

0.736

Urea nitrogen at 7 days

flow from the external iliac and femoral arteries, and significantly decrease haemorrhage with improved perioperative outcomes [9, 15, 16]. Our results in group A showed significantly less blood loss (450.4 ± 146.8) and amount of blood transfused (480.7 ± 144.5) compared to patients managed with occlusive balloon catheterisation of the internal iliac arteries [17, 18]. Dubois et al. described the use of occlusive balloon catheters plus embolisation in 2 subjects with placenta accreta and reported blood loss ranging from 1500 to 2000 Ml [17]. Shrivastava et al. presented 19 subjects with placenta accreta, who had preoperative occlusive balloon catheter placement and embolisation prior to initiating hysterectomy, and reported blood loss of 2700 mL (ranging from 800 to 8000 mL) and blood transfusion of 2000 mL (ranging from 0 to 8600 mL) [18].

We have demonstrated that operative times were shorter and the foetal radiation dose was lower in those treated with occlusion of the aorta compared to those treated with occlusion of the internal iliac arteries. This is a consequence of the need for two sets of balloons, guidewires and sheaths, and bilateral catheter insertion and the need to cross the abdominal bifurcation in order to reach the contralateral internal iliac artery. In contrast, aortic occlusion only requires one balloon, guidewire, sheath, and catheter insertion, and does not require abdominal bifurcation. The overall effect is treatment with occlusion of the internal iliac arteries, which takes at least twice as long as © 2016 Hogrefe

X.-W. Han et al., Aortic occlusion for placenta accreta

the treatment with aortic occlusion on average [19], resulting in a greater foetal radiation dose. Aortic occlusion time should be as short as possible to avoid reperfusion injury and thrombotic and embolic complications in the lower limbs [15, 20]. In our study, the balloons were inflated for 5 Minutes and deflated for 1 Minute, and 50 ml 0.01 % heparin saline was also administered during each occlusion with the total occlusion time of less than 30 min.

We consider that these measures may explain our lack of thrombo-embolic complications. Larger studies should further evaluate renal function and ischaemia of abdominal viscera following endovascular procedures.

Limitations This was a single-centre study. Future randomised multicentre trials that compare the different techniques are still required to evaluate their efficacy and safety fully, and to assess the value of prophylactic measures such as anticoagulation and short occlusion times. Measures to reduce foetal radiation exposure should also be used in future studies.

Conclusions Temporary abdominal aorta and bilateral internal iliac artery balloon occlusion were found to be safe and effective for patients with placenta accreta, but temporary abdominal aortic balloon occlusion resulted in less blood loss, shorter procedure times, shorter exposure times, and lower foetal radiation doses than bilateral internal iliac balloon occlusion. Temporary abdominal aortic balloon occlusion should be considered the first-line option to reduce the risk of unplanned hysterectomy for patients with placenta accreta.

References 1. Chattopadhyay SK, Kharif H, Sherbeeni MM. Placenta praevia and accreta after previous caesarean section. Eur J Obstet Gynecol Reprod Biol 1993;52:–-156.

2. Pelage JP, Le Dref O, Soyer P, et al. Arterial anatomy of the female genital tract: variations and relevance to transcatheter embolisation of the uterus. AJR Am J Roentgenol. 1999;172:989–94.

3. Knight M, UKOSS. Peripartum hysterectomy in the UK: management and outcomes of the associated haemorrhage. BJOG. 2007;114:1380–7.

4. Silver RM1, Landon MB, Rouse DJ, et al. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Maternal morbidity associated with multiple repeat cesarean deliveries. Obstet Gynecol. 2006;107:1226–32.

5. Oyelese Y, Smulian JC. Placenta previa, placenta accreta, and vasa previa. Obstet Gynecol 2006;107:927–94.

© 2016 Hogrefe

57

6. Kayem G, Davy C, Goffinet F, et al. Conservative versus extirpative management in cases of placenta accreta. Obstet Gynecol 2004;104:531–536.

7. Timmermans S, van Hof AC, Duvekot JJ. Conservative management of abnormally invasive placentation. Obstet Gynecol Surv 2007;62:529–539.

8. Steins Bisschop CN, Schaap TP, et al. Invasive placentation and uterus preserving treatment modalities: a systematic review.

Arch Gynecol Obstet 2011;284:491–502.

9. Paull JD, Smith J, Williams L, et al. Balloon occlusion of the abdominal aorta during caesarean hysterectomy for placenta percreta. Anaesth Intensive Care 1995;23:731–734.

10. Carnevale FC1, Kondo MM, de Oliveira Sousa W Jr, et al. Perioperative temporary occlusion of the internal iliac arteries as prophylaxis in cesarean section at risk of hemorrhage in placenta accreta. Cardiovasc Intervent Radiol. 2011;34:758–64.

11. Gipson MG, Smith MT. Endovascular therapies for primary postpartum hemorrhage: techniques and outcomes. Semin Intervent Radiol. 2013;30:333–9.

12. Hishikawa K, Koshiyama M, Ueda M, et al. Exchange of intraoperative balloon occlusion of the internal iliac artery for the common iliac artery during cesarean hysterectomy in a patient with placenta percreta. Am J Case Rep. 2013;14:409–11.

13. Duan XH, Wang YL, Han XW, et al. Caesarean section combined with temporary aortic balloon occlusion followed by uterine artery embolisation for the management of placenta accreta.

Clin Radiol. 2015;70:932–7.

14. D’Souza DL, Kingdom JC, Amsalem H, et al. Conservative Management of Invasive Placenta Using Combined Prophylactic Internal Iliac Artery Balloon Occlusion and Immediate Postoperative Uterine Artery Embolisation. Can Assoc Radiol J. 2015;66:179–84.

15. Masamoto H, Uehara H, Gibo M, et al. Elective use of aortic balloon occlusion in cesarean hysterectomy for placenta previa percreta. Gynecol Obstet Invest 2009;67:92–95.

16. Panici PB, Anceschi M, Borgia ML, et al. Intraoperative aorta balloon occlusion: fertility preservation in patients with placenta previa accreta/increta. J Matern Fetal Neonatal Med. 2012;25:2512–6.

17. Dubois J, Garel L, Grignon A, et al. Placenta percreta: balloon occlusion and embolisation of the internal iliac arteries to reduce intraoperative blood losses. Am J Obstet Gynecol.

1997;176:723–6.

18. Shrivastava V, Nageotte M, Major C, et al. Case-control comparison of cesarean hysterectomy with and without prophylactic placement of intravascular balloon catheters for placenta accreta. Am J Obstet Gynecol 2007;197:402. e401–405.

19. Dilauro MD, Dason S, Athreya S. Prophylactic balloon occlusion of internal iliac arteries in women with placenta accreta: literature review and analysis. Clin Radiol. 2012;67:515–20.

20. Luo Y, Duan H, Liu W, et al. Clinical evaluation for lower abdominal aorta balloon occluding in the pelvic and sacral tumor resection. J Surg Oncol. 2013;108:148–51.

Submitted: 19.04.2016 Accepted after revision: 01.07.2016 There are no conflicts of interest existing.

Published online: 06.09.2016

Correspondence address Dr. Xin-Wei Han Department of Interventional Radiology Zhengzhou University East Jian She Road No.1 450052 Zhengzhou Henan Province China hanxinwei@tom.com

Vasa (2017), 46 (1), 53–57

Sonderbericht

Diabetisches Fusssyndrom

Effektive Behandlung der Durchblutungsstörung ist das A und O Bei der Versorgung von Patienten mit diabetischem Fußsyndrom (DFS) gibt es in Deutschland nach wie vor eine hohe Diskrepanz zwischen dem, was möglich ist und dem, was in der Breite erreicht wird. Werden diabetologische und gefäßmedizinische Therapiestandards eingehalten, kann ein großer Teil der drohenden Major-Amputationen und auch der prognostisch ungünstigen Minor-Amputationen verhindert werden. Das von medac unterstützte AUGUST-3-Register zielt darauf ab, die Versorgungsrealität kritisch durchblutungsgestörter diabetischer Fußpatienten detailliert zu erfassen und auf diesem Weg die Behandler für die Bedeutung des DFS für Beinerhalt und Überleben der Patienten zu sensibilisieren.

Die Zahl der Patienten mit Diabetes mellitus nimmt rapide zu. Die International Diabetes Federation (IDF) erwartet bis zum Jahr 2035 einen Anstieg der Diabetesprävalenz um 53 Prozent auf dann knapp 600 Millionen Patienten weltweit. Neben anderen Komplikationen entwickelt ein relevanter Anteil dieser Patienten als Folge der Grunderkrankung ein DFS. „Die Lebenszeitwahrscheinlichkeit für Fußulzera bei Diabetespatienten beträgt 15 bis 25 Prozent“, sagte Dr. Nasser Malyar aus der Abteilung für Kardiologie und Angiologie am Universitätsklinikum Münster.

Gelingt es nicht, diese Ulzera unter Kontrolle zu bringen, bleibt in vielen Fällen nur noch die Amputation. „Sieben von zehn aller nicht-traumatischen Amputationen betreffen Diabetespatienten“, betonte Malyar.

Krankenkassendaten deuten auf erhebliche Defizite Neu ist das nicht: Schon 1989 wurde von der WHO in der St. Vincent Deklaration das Ziel vorgegeben, die Amputationsrate bei Diabetespatienten innerhalb von fünf Jahren zu halbieren.

27 Jahre später sei Deutschland aber immer noch weit von einer optimalen Versorgung von DFS-Patienten entfernt, so Malyar: „Wir erreichen in Exzellenzzentren gute Ergebnisse. Aber die Realität ist, dass 85 Prozent der Patienten nicht an Exzellenzzentren behandelt werden.“ Hinweise darauf, wie es in der breiten Versorgung aussieht, liefert eine Analyse anonymisierter Versorgungsdaten einer großen, bundesweiten Krankenkasse, die mit ihren Versicherten etwa 10% der deutschen Bevölkerung abdeckt. In diesem Kollektiv fanden sich 40.335 Patienten, die zwischen 2009 und 2011 entweder wegen einer peripheren arteriellen Verschlusskrankheit (PAVK) oder eines DFS stationär behandelt wurden. Das Studiensetup erlaubte eine Unterscheidung zwischen Patienten mit DFS, Patienten mit Diabetes mellitus und PAVK sowie Patienten, die lediglich eine PAVK, aber keinen Diabetes mellitus aufwiesen. (1) Die Analyse zeigt, dass das Amputationsrisiko beim DFS in Deutschland nach wie vor hoch ist: Im Nachbeobachtungszeitraum von im Mittel drei Jahren kam es bei 31,9% der DFS-Patienten zu einer Amputation, in acht von zehn Fällen erfolgte eine Minor-Amputation. Bei Patienten mit PAVK wurden insgesamt nur 6,0% der Patienten amputiert, vier von zehn waren Major-Amputationen. Patienten mit Diabetes mellitus und PAVK hatten ein Amputationsrisiko von 11,1%. „Durch einen Diabetes mellitus erhöht sich das Amputationsrisiko bei einer PAVK demnach deutlich“, so Malyar.

Schlechte Prognose auch bei Minor-Amputationen Dass Amputationen eine hohe prognostische Bedeutung haben, zeigt die Auswertung der Re-Amputationen. 7,5% der DFS-Patienten mit Major-Amputation hatten innerhalb von drei Jahren eine erneute Major-Amputation ipsilateral, 6,9% kontralateral. Dieses Risiko war nach einer Minor-Amputation fast genauso hoch, und jeder fünfte Patient mit Minor-Amputation benötigte auf der ipsilateralen Seite innerhalb von drei Jahren eine weitere Minor-Amputation (Abbildung 1).

7.4%

Ipsilaterale Major-Amputation

3.0%

Kontralaterale Major-Amputation

19.0%

Ipsilaterale Minor-Amputation

10.2%

Kontralaterale Minor-Amputation

0%

5%

10%

15%

20%

Abbildung 1. Re-Amputationsraten bei DFS-Patienten mit Minor-Amputation über drei Jahre (1)

„Diese Daten zeigen, dass auch Patienten mit Minor-Amputation ein hohes Langzeitrisiko aufweisen, und dass wir deswegen alles daran setzen sollten, Minor-Amputationen zu verhindern“, betonte Malyar.

Genau hier gebe es allerdings deutliche Defizite. So sei im Auswertungszeitraum lediglich bei 24,7% eine diagnostische Angiographie erfolgt, und nur 14,5% der Patienten erhielten eine endovaskuläre Intervention. Bei PAVK-Patienten mit und ohne Diabetes mellitus lag diese Quote dagegen bei knapp 60% für die Angiographie und bei knapp 50% für die endovaskuläre Intervention. Eine Gefäßoperation erfolgte bei DFS-Patienten in nur 3,7% der Fälle, gegenüber mehr als 20% bei PAVK mit und ohne Diabetes mellitus. Da 50% bis 70% aller DFS-Patienten eine begleitende PAVK aufwiesen, seien diese Quoten inakzeptabel niedrig, so Malyar, zumal 37% der amputierten Patienten im Zeitraum von zwei Jahren vor Amputation weder eine Angiographie noch eine Intervention erhalten hatten. (2) Grundprinzipien des DFS-Managements Was möglich ist bei der Versorgung von DFS-Patienten zeigen Registerdaten, bei denen ausschließlich Patienten aus Exzellenzzentren Berücksichtigung fanden. So betrug die primäre Amputationsrate im deutschen CRITISCH-Register, das 1200 Patienten mit kritischer Extremitätenischämie (CLI) umfasst, lediglich 2,5%. (3) Solche Quoten ließen sich nur erreichen, wenn die Patienten konsequent leitliniengerecht behandelt würden, betonte Dr. Holger Lawall aus der Gemeinschaftspraxis Diehm/Lawall in Ettlingen.

Sonderbericht

Relevant für Deutschland seien unter anderem die Empfehlungen der International Working Group on the Diabetic Foot (4), die Nationale Versorgungsleitlinie Therapie des Diabetes mellitus (5) und die Praxisleitlinie Diabetisches Fußsyndrom der Deutschen Diabetes Gesellschaft (6).

Zu den vorrangigen Zielen der DFS-Versorgung gehörten neben der Therapie auch die Prävention von Läsionen sowie das Screening, um entstehende Läsionen möglichst früh zu erkennen. „Letztlich geht es darum, Amputationen zu verhindern, und zwar nicht nur Major-Amputationen, sondern auch Minor-Amputationen“, so Lawall.

Grundprinzipien des DFS-Managements sind Lawall zufolge • Stoffwechselkontrolle und Therapie internistischer Erkrankungen • Infektionsbehandlung • Wunddebridement und stadienadaptierte lokale Wundbehandlung • Wirksame Druckentlastung • Therapie von peripheren arteriellen Durchblutungsstörungen • Patientenschulung und Information • Medizinische Fußpflege in der Nachsorge Da das Vorliegen einer PAVK der Hauptrisikofaktor für Amputationen ist, sei die invasive und konservative PAVK-Therapie ein zentraler Pfeiler der Ulkus-Prävention bei Diabetespatienten.

Zur Abschätzung des Gefäßstatus empfahl Lawall insbesondere die Messung des Zehen-Arm-Indexes (TBI), da der Zehendruck bei Diabetespatienten ein besserer prädiktiver Parameter sei als der bei PAVK sonst eingesetzte Knöcheldruck. (7) (Abbildung 2)

Zusätzlich sei im Sinne einer Vermeidungsstrategie eine Druckentlastung gefährdeter Areale durch entsprechend angepasstes Schuhwerk erforderlich, betonte Tigges. Bei Patienten, bei denen keine endovaskulären und operativen Optionen mehr bestehen, kämen dann teils noch experimentelle Rescue-Verfahren wie die Sympathikolyse, die Stammzelltherapie und die Neurostimulation zum Einsatz, außerdem die seit Langem etablierte medikamentöse Therapie mit Urokinase.

AUGUST-3-Register nimmt Fahrt auf Um für Deutschland multizentrische Daten zur Effektivität unterschiedlicher Therapieansätze bei DFS und kritischer Extremitätenischämie zusammenzutragen, wurde das von medac unterstützte AUGUST-3-Register ins Leben gerufen. Geleitet wird es von Professor Dr. Sebastian Schellong von der II. Medizinischen Klinik am Städtischen Klinikum Dresden-Friedrichstadt: „Unser Ziel ist die Dokumentation der Behandlungspfade und Therapieergebnisse von 1000 Patienten“, so Schellong.

Primärer Endpunkt ist das majoramputationsfreie Überleben nach einem Jahr. Erfasst werden Major- und Minor-Amputationen, Sterblichkeit, zurückliegende Fußbehandlungen und Mobilität. Nach einer Anlaufphase hat die Patientenrekrutierung mittlerweile Fahrt aufgenommen. Zehn Krankenhäuser rekrutieren aktiv, zehn weitere stehen kurz davor. Im Sommer 2017 dürfte die angestrebte Zahl von 25 teilnehmenden Zentren erreicht sein.

Stand Anfang September waren 81 Patienten registriert. Gut 40% haben eine Revaskularisierung hinter sich, und rund ein Drittel bereits eine Minor-Amputation. Begleiterkrankungen sind häufig: Die große Mehrheit ist hypertensiv, mehr als die Hälfte hat eine KHK und/oder eine Herzinsuffizienz, knapp die Hälfte ist niereninsuffizient und drei von vier Patienten sind unter Insulintherapie. „Das spiegelt unsere Zielpopulation sehr gut wider“, so Schellong, der optimistisch ist, im Jahr 2019 die Ergebnisse vorlegen zu können.

Diabetes

kein Diabetes

TBI > 1,08

20%

11%

TBI 0,62 – 1,08

33%

19%

Wissenswertes zur Versorgung des diabetischen Fußsyndroms 17. Dreiländertagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Angiologie

TBI 0,40 – 0,61

49%

29%

TBI < 0,40

55%

48%

Veranstaltung

Dresden, 09.09.2016, 15.00h-16.30h

Abbildung 2. Zehen-Arm-Index (TBI) und kardiovaskuläre Mortalität über 7 Jahre bei Patienten mit Verdacht auf PAVK mit und ohne Diabetes (7)

Bericht: Philipp Grätzel Mit freundlicher Unterstützung von: medac GmbH, 22880 Wedel

Druckentlastung und gute Durchblutung als Vermeidungsstrategien Auch der Gefäßchirurg Dr. Wolfgang Tigges vom Agaplesion Diakonieklinikum Hamburg unterstrich die hohe Bedeutung endovaskulärer Eingriffe und operativer Rekonstruktionen in der Prävention und Therapie von Fußkomplikationen des Diabetes mellitus: „Ein DFS wird durch die diabetische Polyneuropathie verursacht, aber seine Abheilung wird durch die PAVK verhindert.“ Da die Polyneuropathie weiterhin keinen therapeutischen Ansatzpunkt biete, müsse die PAVK umso konsequenter angegangen werden: „Entscheidend ist, frühzeitig den Gefäßstatus zu erfassen, die Grenzwerte der Perfusionsdrucke zu definieren und rechtzeitig zu intervenieren.“

Literatur 1.

2.

3.

4.

5.

6.

7.

Malyar NM et al. J Diabetes Complications 2016; 30(6):1117-22 Reinecke H et al. Eur Heart J 2015; 36(15):932-8 Bisdas T et al. J Vasc Surg 2015; 62(4):965-73 Schaper NC et al. Diabetes Metab Res Rev 2012; 28:218-24 Nationale Versorgungsleitlinie (NVL) Therapie des Typ-2-Diabetes, 1. Auflage, Version 4, August 2013, www.leitlinien.de Morbach S et al. Diabetologie und Stoffwechsel 2015; 10: S172-S180 Hyun S et al. J Vasc Surg 2014; 43:1-6

60

Case report

Brucellosis and thrombosis of the inferior vena cava Kristina Rüegger1, Philip Tarr2, Konstantinos Karatolios3, Jörg Humburg4, Rolf Hügli5, and Christina Jeanneret3 1 2 3 4 5

University Department of Internal Medicine, Kantonsspital Baselland, Bruderholz, Switzerland Infectious Diseases Service, Kantonsspital Baselland, Bruderholz, Switzerland Division of Angiology, Kantonsspital Baselland, Bruderholz, Switzerland Gynaecology Department, Kantonsspital Baselland, Bruderholz, Switzerland Radiology Department, Kantonsspital Baselland, 4101 Bruderholz, Switzerland

Summary: We describe the case of a 23-year old woman with a newly diagnosed thrombosis of the inferior vena cava associated with a Brucella melitensis infection. We suggest possible mechanisms leading to brucellosis-associated venous thrombosis and review 14 previously reported cases.

Keywords: Thrombosis of the inferior vena cava, hepatic brucellosis

Introduction

Case report

12-5 (CA 12-5), as well as antibodies for Echinococcus granulosus and multilocularis, and Entamoeba histolytica were negative, as was an agglutination test for Brucella.

The patient was anticoagulated with intravenous heparin. The ovarian lesion was removed and histology showed a cystic teratoma, without any evidence of malignancy.

Intra-operatively, a punch biopsy of the liver lesion was performed which showed granulomatous inflammation, and polymerase chain reaction (PCR) was positive for Brucella melitensis, but negative for Mycobacterium tuberculosis and Bartonella henselae and quintana. Serologic investigations for toxoplasmosis and Lues were negative. Anticoagulation was continued with low-molecular-weight heparin in addition to antibiotic treatment with doxycycline

A young female patient was admitted to the hospital because of pain in the right upper abdominal quadrant. There was no swelling or pain of the legs on physical examination and the patient was afebrile. A CT scan showed a partially occluding thrombus in the inferior vena cava and a circular lesion in liver segment VI (see Fig. 1, 2). Laboratory tests showed anaemia (haemoglobin level, 110 g/L), elevated gamma-glutamyl transferase (gGT) (84 U/L, normal < 40) and elevated C-reactive protein level (38 mg/L, normal < 5).

D-Dimer was 4.07 μg/L (normal, < 0.5), and fibrinogen was 5.3 g/L (normal < 4 g/L). Cytomegalovirus (CMV) serology was negative. Duplex sonography confirmed a wall-adherent thrombus in the inferior vena cava (see Fig. 3). The portal and hepatic veins were not occluded. In addition, a mass in the left ovary was detected, which on MRI scan most likely corresponded to a dermoid cyst. Carcino-embryonic antigen (CEA), alpha-fetoprotein (AFP) and cancer antigen

Figure 1. CT scan without contrast agent shows a circular lesion in liver segment VI, with contrast enhancement.

Brucellosis is one of the most common zoonoses worldwide. Human infection is typically acquired by consuming unpasteurized milk products from infected animals. Brucellosis can involve almost any organ system (most often liver, spleen, and bone marrow). In this paper we present a case of a thrombosis of the inferior vena cava associated with acute brucellosis. Additionally, we give an overview of similar cases published so far.

Vasa (2017), 46 (1), 60–63 DOI 10.1024/0301-1526/a000585

© 2016 Hogrefe

K. Rüegger et al., Brucellosis and thrombosis

61

Discussion

Figure 2. CT scan of the abdomen in sagittal view showing the circumscribed thrombus in the inferior vena cava (arrow).

Brucellosis is a major zoonosis worldwide, eradicated in many countries but endemic in others, with Brucella melitensis being found in goats and sheep. Human disease occurs after consuming unpasteurized milk products from affected animals [1]. Brucellosis often affects the liver [2].

Night sweats, as seen in our patient, are common. Vascular complications in brucellosis disease are rare, occurring in less than 1 % of reported brucellosis cases [3]. The cardiovascular system is more often affected than veins [4], including endocarditis, in native as well as in prosthetic valves [5, 6].

To our knowledge, 14 cases of venous thrombosis (8 in leg veins) in association with brucellosis have been published (summarized in Table I) [7]. We present the first case of a brucellosis-associated thrombosis of the vena cava. It is well documented that venous thrombosis can be triggered by acute infections, e. g. infection with Cytomegalovirus, Salmonella [8], Streptococci, Mycoplasma pneumonia, Mycobacterium tuberculosis, Varicella zoster virus [9], Human Immunodeficiency Virus (HIV) [10], and others. The pathogenesis of thrombosis in the setting of brucellosis is not known. Suggested mechanisms include induction of inflammation by the infectious process in the surrounding tissue [11], direct endothelial damage, induction of a transient hypercoagulable state as well as local invasion by the infectious agent in the adjacent tissue [12].

Transient protein S deficiency has been described in a case with deep vein thrombosis and infection with Salmonella thyphimurium [8].

This case of brucellosis, which occurred in association with a non-occlusive thrombosis of the vena cava, is unusual and to our knowledge the first case published so far. In the literature, a Budd-Chiari syndrome is described in association with hepatocellular damage [13]. We suspect that brucellosis has been acquired during a stay in Chiapas/ Mexico, the patient also indicated having consumed unpasteurized cheese from a local village farm.

Figure 3. Duplexsonography transabdominal longitudinal scanning showing non-occluding thrombosis in the inferior vena cava.

Conclusions 100 mg twice daily and rifampicin 600 mg once daily for 3 months, additionally gentamicin 5 mg/kg once daily was given intravenously for the first 10 days. The anticoagulation was stopped by the patient herself before the 7-month follow-up. She had at least anticoagulation for 3 months. A screening test for thrombophilia was unremarkable.

In retrospect, the patient reported having travelled to Chiapas/Mexico several times, where she had consumed home-made fresh cheese on her family’s farm. She never had any fever, but reported night sweats for the past 2 months. At the last follow-up, 12 months later, the patient was asymptomatic. Duplex sonography of the vena cava showed normal venous flow without any residual thrombus after less than 7 months of anticoagulation treatment. © 2016 Hogrefe

The presented case and the other reported cases suggest that an infection such as brucellosis should be considered in patients suffering from deep venous thrombosis, particularly if they have travelled to endemic areas, such as Mexico [14].

Acknowledgement We thank Dr. Claude Merlin for the translation of the case description in “Romem M, Singer L, Isakov J. Benign central vein thrombosis due to brucellosis. Harefuah 1973; 85: 587–588” [16].

Vasa (2017), 46 (1), 60–63

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K. Rüegger et al., Brucellosis and thrombosis

Table I. Published cases of deep venous thrombosis (DVT) and/or pulmonary embolism (PE) in setting of brucellosis.

Author

Year

Patient age in years (y) gender

Country

Location DVT

Treatment and outcome

Lawson [15]

1954

2 cases 34 y, male 42 y, male

Great Britain

Cerebral venous thrombosis

Hemiplegia chloramphenicol for 7 days / tetracycline for 10 days, complete recovery

Romem [16]

1973

25 y, female

Israel

Central vein thrombosis (eye)

AB and thrombolysis

Marfil Rivera [17]

1986

18 y, female

Mexico

DVT lower limb bilateral Antiphospholipid antibody pos.

AB and AC 4 months, cured

Gregori [18]

1990

72 y, male

Spain

Portal vein thrombosis

AB complete recovery

Zaidan [19]

1999

23 y, female

Saudi Arabia

Cerebral venous thrombosis associated to neurobrucellosis

AB and AC R, D, CTM after 2 weeks H iv and W improved

Odeh [20]

2000

52 y, male

Israel

Right leg DVT, (FV, PV)

AC and AB H iv, W 3 months, AB 6 weeks, cured

Memish [21]

2001

41 y, male

Saudi Arabia

Right calf DVT (PTV)

AC and AB D, R full recovery

Gul [12]

2008

21 y, male

Turkey

Right leg DVT (CFV, FV, DFV)

AC and AB D, R full recovery

Sen [22]

2011

43 y, female

Turkey

Thrombus entrapped in patent foramen ovale, PE

Open heart surgery with thrombus removal recovery

Meidani [23]

2012

28 y, male

Iran, Isfahan

Left leg DVT and PE

AC and AB PE occurred under AC without AB, recovery

Koubaa [7]

2013

52 y, male

Tunisia

Left leg (FV)

AB and AC R 900 mg/day D 200 mg/day LMWH 3 months cured

Tolaj [24]

2014

37 y, male

Kosovo

Left leg DVT after diagnosis of brucellosis Veins with DVT (CIV, EIV, CFV, DFV, FV, PV, GSV, LSV)

AB and AC D, S 6 months, after 3 weeks W partially recovered, recanalized thrombus

Davoudi [25]

2014

15 y, male

Iran

Left leg DVT (CIV, EIV, CFV, FV, DFV, PV)

AC and AB LMWH and W 6 months R 600 mg/day D 100 mg 2/day both for 3 months A 500 mg twice a day for 2 weeks cured

Iv: intravenously; NM: not mentioned; AB: antibiotics; AC: anticoagulation; A: amikacin; D: doxycycline; CTM: co-trimoxazole; S: streptomycin; R: rifampicin; LMWH: low-molecular-weight heparin; H: heparin; W: warfarin; CFV: common femoral vein; FV: femoral vein; PV: popliteal vein; DFV: deep femoral vein; CIV: common iliac vein; EIV: external iliac vein; PTV: posterior tibial vein; GSV: great saphenous vein; LSV: lesser saphenous vein.

References 1. Corbel M. Brucellosis: an overview. Emerg Infect Dis 1997; 3:213–21.

2. Geyik M, Gürb A, Nasb K, et al. Musculoskeletal involvement in brucellosis in different age groups: a study of 195 cases. Swiss Med Wkly 2002;132:98–105.

3. Young E. An overview of human brucellosis. Clin Infect Dis 1995;21:283–90.

Vasa (2017), 46 (1), 60–63

4. Sanchez-Gonzalez J, Garcia-Delange T, Martos F, et al. Thrombosis of the abdominal aorta secondary to Brucella spondylitis. Infection 1996;24:261–2.

5. Zisis C, Argyriou M, Kokotsakis I, et al. Brucella endocarditis presentation of two cases and literature review. Hellenic J Cardiol 2002;43:174–7.

6. Al Dahouk S, Schneider T, Jansen A, et al. Brucella endocarditis in prosthetic valves. Can J Cardiol 2006;22:971–4. © 2016 Hogrefe

K. Rüegger et al., Brucellosis and thrombosis

7. Koubaa M, Frigui M, Cherif Y, et al. Deep vein thrombosis associated with acute brucellosis: a case report and review of the literature. Korean J Intern Med 2013;28:628–30.

8. Ceyhan M, Kanra G, Benderlioglu B, et al. Transient protein S deficiency with deep venous thrombosis during Salmonella typhimurium infection. Arch Dis Child 1993;68:138–9.

9. Gogos C, Apostolidou E, Bassaris H, et al. Three cases of varicella thrombophlebitis as a complication of varicella zoster virus infection. Eur J Clin Microbiol Infect Dis 1993;12:43–5.

10. Becker D, Saunders T, Wispelwey B, et al. Case report: venous thromboembolism in AIDS. Am J Med Sci 1992;303:395–7.

11. Ferrero M, Bregante J, Delpino M, et al. Proinflammatory response of human endothelial cells to Brucella infection. Microbes Infect 2011;13:852–61.

12. Gul H, Mert G, Erdem H, et al. Brucellosis associated with thrombophilebitis: a case report. Am J Case Rep 2008;9:31–3.

13. Martens P, Nevens F. Budd-Chiari syndrome. United European Gastroenterol J 2015;3:489–500.

14. Morales-Garcia M, Lopez-Mendez J, Pless R, et al. Brucellosis outbreak in a rural endemic region of Mexico – a comprehensive investigation. Vet Ital 2015;51:185–90.

15. Lawson C, Leeson C. Cerebral thrombosis complicating abortus fever. Br Med J 1954;2:1400–1.

16. Romem M, Singer L, Isakov J. Benign central vein thrombosis due to brucellosis. Harefuah 1973;85:587–8.

17. Marfil Rivera L, Mares Ramírez M, Mora Brondo P, et al. Deep venous thrombosis in a patient with brucellosis and a probable lupoid inhibitor. Report of a case. Rev Invest Clin 1986; 38:311–5.

18. Gregori J, Ortuño J, Ruiz Rivas J, et al. Brucellosis and portal thrombosis. Rev Esp Enferm Dig 1990;78:187–8.

19. Zaidan R, Al Tahan A. Cerebral venous thrombosis: a new manifestation of neurobrucellosis. Clin Infect Dis 1999;28:399–400.

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20. Odeh M, Pick N, Oliven A. Deep venous thrombosis associated with acute brucellosis – a case report. Angiology 2000;51: 253–6.

21. Memish Z, Bannatyne R, Alshaalan M. Endophlebitis of the leg caused by brucella infection. J Infect 2001; 42:281–3.

22. Sen T, Cağlı K, Gölbaşı Z, et al. Thrombus-in-transit entrapped in a patent foramen ovale: a complication of brucellosis. Turk Kardiyol Dern Ars 2011;39:487–90.

23. Meidani M, Mirzadeh F. Simultaneous deep vein thrombosis and acute brucellosis: case report. Razi J Med Sci 2012; 19:40–3.

24. Tolaj I, Mehmeti M, Ramadani H, et al. Brucellosisi associated with deep vein thrombosis. Infect Dis Rep 2014;6:48–50.

25. Davoudi A, Tayebi A, Najafi N, et al. Deep vein thrombosis as a rare complication of brucellosis. Caspian J Intern Med 2014; 5:127–9.

Submitted: 02.07.2016 Accepted after revision: 31.08.2016 There are no conflicts of interest to report.

Published online: 22.11.2016

Correspondence address Christina Jeanneret, PD Dr. Division of Angiology Kantonsspital Baselland University of Basel 4101 Bruderholz Switzerland christina.jeanneret@ksbl.ch

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Vasa (2017), 46 (1), 60–63

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Case report

Intra-arterial thrombolysis of digital artery occlusions in a patient with polycythemia vera Philipp Jud, Franz Hafner, Thomas Gary, Leyla Ghanim, Rainer Lipp, and Marianne Brodmann Medizinische Universität Graz, Austria

Summary: There are limited therapeutic options for the resolution of digital artery occlusions. Intra-arterial thrombolysis with anticoagulative and thrombolytic drugs successfully restored the blood flow in the affected digital arteries.

Keywords: Digital artery occlusions, intra-arterial thrombolysis, polycythemia vera, upper extremity ischemia

Introduction Digital artery occlusions can be caused by atrial fibrillation, connective tissue diseases, atherosclerosis, and also by hematologic diseases [1]. Therapeutic options are commonly limited due to small artery size. Additionally, the diagnosis is often not recognized in time. In cases of acute digital artery occlusion, one therapeutic option could be an intra-arterial thrombolysis, which showed in reviews [2, 3] a relatively good overall effectiveness and clinical outcome, but due to further doubts in safety and effectiveness, intra-arterial lytic therapy is rarely used.

We present a 52-year-old male with digital artery occlusions that were successfully treated with an intra-arterial thrombolysis.

Case report A 52-year-old male patient presented to the clinic department for angiology with crampy pain and paleness in his right forearm and hand. The pain ameliorated after 1 h, but the paleness persisted further. Additionally, the patient observed intermediate numbness of the right index finger and a loss of the right radial pulse. He denied such previous episodes. In the patient’s history, polycythemia vera had been known for 2 years, it was treated with preceded phlebotomies, 20 mg ruxolitinib and 100 mg acetylsalicylate once daily, of which the patient had stopped taVasa (2017), 46 (1), 64–66 DOI 10.1024/0301-1526/a000586

king 100 mg acetylsalicylate one week earlier. The patient suffered no trauma of the upper extremities and did not work with vibrating or flapping tools.

In the physical examination, the activity as well as the sensibility of both arms and hands remained, but the right fingers were colder and the radial pulse was attenuated in comparison to the left side. The right index and the middle finger showed also a slight cyanosis. Electrocardiography revealed a sinus rhythm. Laboratory findings showed a normal count of thrombocytes (372 × 109/L) and erythrocytes (4.97 × 1012/L) with a low hematocrit (36.7 %). Additionally, the hemoglobin level was low (12 g/dL) and megakaryocytes could be detected. Myoglobin (38.5 ng/mL) as well as muscle-type creatine kinase (113 U/L) were not elevated. Arterial color-coded duplex ultrasonography revealed a proper flow of the right radial and ulnar artery with a physiological vascular morphology, but digital artery occlusions of the right index finger and middle fingers were present. A critically reduced perfusion of the right index and middle fingers was detected in a pulse oscillography, which showed a loss of the pulse’s amplitude. The pulse oscillography of the other right fingers showed flattened pulse amplitudes compared to the left fingers. Other diseases like atrial fibrillation (which was excluded by a Holter device), thoracic outlet compression syndrome (which was excluded via motion-dependent pulse oscillography and MR angiography), and some autoimmune connective tissue disorders like scleroderma, systemic lupus erythematosus or Sjögren’s syndrome (which were excluded by laboratory findings) could be ruled out.

We initiated daily 8000 IU enoxaparin subcutaneously and 100 mg acetylsalicylate orally. Additionally, we administered alprostadil 40 μg/250 mL by an infusion pump with an infusion rate of 83 mL/h over 3 h daily. Despite that therapy, the patient developed a noticeable sensitivity to cold with paleness and numbness as well as an extended capillary refill time of the second and of the third finger.

We performed further a magnetic resonance (MR) angiography of the right forearm and hand, which revealed occlusions in the digital arteries of the index and middle fingers.

Due to that deterioration we increased enoxaparin to © 2016 Hogrefe

P. Jud et al., Thrombolysis of digital artery occlusion

8000 IU twice daily and performed an intra-arterial thrombolysis.

Under local anesthesia, we punctured the right brachial artery at elbow level using guided ultrasound. A peripheral angiography of the right-arm arteries revealed a patent right brachial and ulnar artery, a not relevant stenosis of the radial artery, and digital artery occlusions of the index and of the middle finger (Fig. 1A). After angiography, we pushed a Rebar 0.27 microcatheter forward into the distal radial artery at the level of the wrist joint. 10 mg/50 mL alteplase was administered by an infusion pump with an infusion rate of 6 mL/h every 6 h. Additionally, we administered 25 000 IU/50 mL enoxaparin by an infusion pump at 2 mL/h over 24 h. In the first thrombolysis control after 12 h, an amelioration of the blood flow in the digital arteries could be observed but there were still some filling defects. Therefore, we continued the lytic therapy and administered again 10 mg/50 mL alteplase by an infusion pump every 6 h. In the second thrombolysis control, the blood flow of the occluded digital arteries could be restored and no filling defects or residual stenoses of the right forearm and digital arteries could be detected in the angiography (Fig. 1B). Overall, 40 mg alteplase was administered via the catheter and 25 000 IU enoxaparin was administered via the sheath. The sheath and the lysis catheter were removed and a vascular closing system was used for the puncture sealing. To avoid a rethrombosis, 25 000 IU/50 mL enoxaparin was administered by an infusion pump with an infusion rate of 2 mL/h over 24 h for the next 2 days. Additionally, alprostadil 40 μg/250 mL was administered by an infusion pump at 83 mL/h over 3 h for the next 2 days to prevent a post-interventional vasospasm.

The patient noticed a clear amelioration without paleness or numbness of the right fingers after thrombolysis.

The capillary refill time was not extended anymore and the patient’s affected right fingers showed a good blood circulation with a physiological pulse oscillography. The patient could be discharged in a good condition with 20 mg ruxolitinib and 100 mg acetylsalicylate once daily.

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with a not significant risk ratio [6]. Our patient was treated with all three therapeutic strategies but he stopped his acetylsalicylate medication, which could be the cause for his acute hand ischemia.

The treatment of an acute extremity ischemia consists of anticoagulant therapy, thrombolysis, minimally invasive embolectomy or surgical interventions. An embolectomy could not be performed either surgically or via catheter due to the occlusion location in the small digital arteries. Therefore, the only possible option was a conservative medicinal therapy, which includes anticoagulative drugs like heparin and antiplatelet agents as well as thrombolysis with thrombolytic drugs like (recombinant) tissue plasminogen activators [7].

There are different results for the clinical outcome and the effectiveness of intra-arterial thrombolysis. Palfrey-

Discussion The etiology of hand ischemia is multifactorial with an occurrence in Buerger disease, atrial fibrillation, connective tissue diseases, and hematologic diseases [1]. Patients with polycythemia vera have a higher risk to develop arterial thrombosis and consecutively emboli due to the increased blood viscosity and enhanced interactions between platelet and vessel wall [4]. Antiplatelet and antineoplastic agents as well as phlebotomies are common therapeutic strategies in patients with polycythemia vera [5], but they have also their limitations. Sole phlebotomy therapy can cause a higher incidence of thrombosis, and antiplatelet therapy seems to be unsuccessful if the number of red cells is inappropriately reduced [4]. A risk reduction with ruxolitinib treatment could be also shown, but © 2016 Hogrefe

Figure 1. Digital subtraction angiography of the right arm arteries. A. Before intra-arterial thrombolysis. B. After the second administration of lytic therapy. White arrows point to the stenosis of the right radial artery and occlusion of the right finger artery.

Vasa (2017), 46 (1), 64–66

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man et al. [8] showed in their meta-analysis for lower limb ischemia no significant differences between intra-arterial thrombolysis and surgery in terms of major amputation and mortality, but vascular occlusions with durations of less than 14 days might benefit from thrombolysis. Intraarterial thrombolysis in the hand and digital ischemia are mostly sporadically described in the literature as case reports [9, 10] or with a small patient collective [1, 2]. Those reviews showed a relative good overall effectiveness and clinical outcome but due to further doubts in safety and effectiveness and the lack of large randomized controlled trials, intra-arterial thrombolysis is still rarely used in this special patient cohort.

In our case, intra-arterial thrombolysis was our secondline therapeutic approach and so we started first with 8000 IU enoxaparin subcutaneously, 100 mg acetylsalicylate orally, and an intravenous infusion therapy with alprostadil 40 μg daily, which seemed to be ameliorating the symptoms at the first glance. But then the patient developed a subacute critical ischemia. Due to this deterioration despite the anticoagulant therapy, and to avoid an amputation of the fingers, we had to change our therapeutic approach and decided to perform an intra-arterial thrombolysis of the right digital arteries, by which we successfully restored the blood flow in the affected digital artery.

Conclusions We want to remind that intra-arterial thrombolysis of the digital arteries can be a therapeutic option in patients with acute digital artery occlusions, especially in the case when anticoagulant agents fail.

P. Jud et al., Thrombolysis of digital artery occlusion

References Zimmerman NB. Occlusive vascular disorders of the upper extremity. Hand Clin. 1993;9:139–50.

Pfyffer M, Schneider E, Jäger K, et al. [Local thrombolysis of acute and subacute forearm, hand and finger artery occlusions. Early and late results]. Vasa. 1989;18:128–35. [German] Islam A, Edgerton C, Stafford JM, et al. Anatomic findings and outcomes associated with upper extremity arteriography and selective thrombolysis for acute finger ischemia. J Vasc Surg.

2014;6:410–7.

Spivak JL. Polycythemia vera: myths, mechanisms, and management. Blood. 2002;100:4272–90.

Passamonti F. How I treat polycythemia vera. Blood. 2012; 120:275–84.

Samuelson BT, Vesely SK, Chai-Adisaksopha C, et al. The impact of ruxolitinib on thrombosis in patients with polycythemia vera and myelofibrosis: a meta-analysis. Blood Coagul Fibrinolysis.

2016;27:648–52.

Kasirajan K; Ouriel K. Current options in the diagnosis and management of acute limb ischemia. Prog Cardiovasc Nurs.

2002;17:26–34.

Palfreyman SJ, Booth A, Michaels JA. A systematic review of intraarterial thrombolytic therapy for lower-limb ischaemia. Eur J Vasc Endovasc Surg. 2000;19:143–57.

Barbiero G, Cognolato D, Casarin A, et al. Intra-arterial thrombolysis of acute hand ischaemia with or without microcatheter: preliminary experience and comparison with the literature.

Radiol Med. 2011;116:919–31.

Bounameaux H, Schneider PA, Huber-Sauteur E, et al. Severe ischemia of the hand following intra-arterial promazine injection: effects of vasodilation, anticoagulation, and local thrombolysis with tissue-type plasminogen activator. Vasa. 1990; 19:68–71.

Submitted: 28.07.2016 Accepted after revision: 01.09.2016 There are no conflicts of interest to report.

Published online: 16.11.2016 Correspondence address Philipp Jud, MD Division of Angiology Medical University Graz Auenbruggerplatz 15 8036 Graz Austria philipp.jud@medunigraz.at

Vasa (2017), 46 (1), 64–66

© 2016 Hogrefe

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Letter to the editor

Industry sponsorship and positive outcome in vascular and endovascular randomised trials Shahab Hajibandeha,1, Shahin Hajibandeha,1, Stavros A. Antoniou2, George A. Antoniou3, and Francesco Torella4 1 2 3 4 a

Department of General Surgery, Royal Blackburn Hospital, Haslingden Rd, Blackburn, UK Department of General Surgery, University Hospital of Heraklion, University of Crete, Heraklion, Greece Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK Department of Mathematical Sciences, School of Physical Sciences, University of Liverpool, UK Shahab Hajibandeh and Shahin Hajibandeh equally contributed to this paper and joined first authorship is proposed

To the editor Association between industry sponsorship and positive outcomes favourable to the sponsor’s product have been reported by several systematic reviews. [1, 2] Industry sponsorship can influence the outcome of a study in different ways such as the framing of research questions, the design of the study, the conduct of the study, how data are analysed, selective reporting of favourable results, and spin in reporting conclusions. [1] To our knowledge, there is no study that evaluated association between industry sponsorship and positive research outcomes in vascular and endovascular surgery randomised controlled trials (RCTs); therefore, we aimed to investigate a potential association between industry sponsorship and positive research outcomes in RCTs in vascular and endovascular surgery.

We interrogated an electronic dataset that was created in previous reviews conducted by our collaborative evidence synthesis group. [3, 4] The dataset included data from 150 vascular and endovascular surgery RCTs published during a 10-year period between 2003 and 2012 in leading journals in vascular and endovascular surgery, general surgery, and medicine. It contained information about bibliometric variables, industry sponsorship, and report of positive or negative primary outcomes. The literature search strategy, study selection, eligibility criteria, and data extraction for this study have been described in our previous reviews [3, 4]. Statistical analyses were performed using Minitab 17 (Minitab® 17.1.0). Binary logistic regression was used to examine whether industry sponsorship or other bibliometric variables were associated with a positive primary outcome. We considered industry sponsorship and other bibliometric variables as covariates and a positive primary outcome as the dependent variable. © 2017 Hogrefe

Of the 150 trials, 111 reported a positive primary outcome and 39 reported a negative primary outcome. There was no significant difference between the studies with positive primary outcome and those with negative primary outcome in terms of the following bibliometric variables: vascular surgery journal; general surgery journal; subject area; title reporting study findings; study design reported in title; number of pages; number of references; number of institutions; international collaboration; open access trial; external funding; sample size; time of publication (old or new); and number of citations in year one and two after publication. There was no significant difference in industry sponsorship rate between the two groups (15 % vs 23 %, P = 0.326). Out of 150 trials, 75 were grouped as new studies and 75 as old studies. The new studies were more frequently industry-sponsored (28 % vs 6.67, P = 0.001). Binary logistic regression analysis showed no association between industry sponsorship (Odds ratio: 0.60, 95 % confidence interval: 0.24, 1.49, P: 0.282) or bibliometric variables and positive primary outcome (Table I).

The advent of minimally invasive surgery, technological achievements, evolution of techniques and therapies has increased the number of endovascular-related trials in recent years, which might have lead to increase in industry funding or reduction in other sources of sponsorship. [5] Some argued that industry sponsored trials are more likely to have positive outcomes as these have a high chance of achieving success. Furthermore, industry sponsored trials have larger sample sizes, increasing the chance of achieving statistically significant results. Others argued that industry sponsored trials may produce more favourable outcomes by using placebo control, active comparators in inferior doses, or inappropriate administration of drugs.

In conclusion, we found no association between industry sponsorship or bibliometric variables and positive research Vasa (2017), 46 (1), 67–68 DOI 10.1024/0301-1526/a000592

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S. Hajibandeh et al., Industry sponsorship and trials’ outcome

Table I. Bibliometric characteristics of included studies and results of binary regression analysis Positive primary outcome§

Negative primary outcome§

Binary regression analysis Odds ratio (95% CI)

No of studies

111

P Value

39

Journal (%)

0.80 (0.33, 1.96)

0.625

Vascular surgery journal

84 (76)

31 (80)

–

–

Non-vascular surgery journal

27 (24)

8 (21)

–

–

1.93 (0.80, 4.65)

0.166

Subject area Arterial-related

68 (61)

30 (77)

–

–

Venous-related

35 (32)

8 (21)

–

–

8 (7)

1 (3)

–

–

Endovascular-related study

28 (25)

10 (26)

0.98 (0.42, 2.26)

0.959

Title reporting study findings

16 (14)

2 (5)

3.11 (0.68, 14.22)

0.098

Study design reported in title

84 (76)

34 (87)

0.46 (0.16, 1.29)

0.116

16 (13, 20)

17 (17, 21)

0.98 (0.91, 1.05)

0.543

7 (6,9)

7 (6, 8)

1.12 (0.92, 1.37)

0.259

27 (20, 34)

24 (20,32)

1.01 (0.97, 1.047)

0.595

Number of institutions

1 (1, 3)

2 (1,8)

0.99 (0.96, 1.01)

0.303

International collaboration

10 (9.)

5 (13)

0.67 (0.22, 2.11)

0.505

Open access

85(77)

33 (85)

0.59 (0.22, 1.58)

0.279

External funding

62 (56)

25 (64)

0.71 (0.33, 1.51)

0.367

101 (58, 178)

109 (50, 335)

0.98 (0.97, 1.01)

0.097

17 (15)

9 (23)

0.60 (0.24, 1.49)

0.282

27 (11, 48)

17 (5, 49)

1.00 (0.99, 1.00)

0.831

Citations year 1

1 (0, 3)

1 (0, 3)

0.97 (0.93, 1.01)

0.127

Citations year 2

4 (2, 9)

3 (1, 11)

0.99 (0.98, 1.02)

0.803

Old studies

56 (51)

19 (49)

1.07 (0.52, 2.22)

0.852

Vascular access

Number of words per title Number of pages Number of references

Sample size Industry sponsorship Citations total

§

Median (lower and upper quartiles) for continuous data and number (%) for binomial data

outcome in vascular and endovascular surgery RCTs. This is a novel finding which may influence assessment of risk of bias in vascular and endovascular surgery RCTs. Existence of such an association should be checked periodically by different authors to ensure that industry bias is controlled in vascular and endovascular surgery RCTs.

4. Hajibandeh S, Hajibandeh S, Antoniou GA, Green PA, Maden M, Torella F. Reporting and Methodological Quality of Randomised Controlled Trials in Vascular and Endovascular Surgery. Eur J Vasc Endovasc Surg. 2015; Aug 19.

5. Antoniou GA, Antoniou SA, Georgakarakos EI, Sfyroeras GS, Georgiadis GS. Bibliometric analysis of factors predicting increased citations in the vascular and endovascular literature.

Ann Vasc Surg. 2015;Feb 29(2):286–92.

References

Submitted: 04.10.2016 Accepted: 09.10.2016 There are no conflicts of interest existing.

1. Lundh A, Sismondo S, Lexchin J, Busuioc OA, Bero L. Industry sponsorship and research outcome. Cochrane Database Syst Rev. 2012;12:MR000033.

2. Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review.

JAMA. 2003;289(4):454–65.

3. Hajibandeh S, Hajibandeh S, Antoniou GA, Green PA, Maden M, Torella F. Association between bibliometric parameters, reporting and methodological quality of randomised controlled trials in vascular and endovascular surgery. Vascular. 2016; Jun 1.

Vasa (2017), 46 (1), 67–68

Correspondence address Shahab Hajibandeh Royal Blackburn Hospital Haslingden Rd Blackburn BB2 3HH United Kingdom shahab_hajibandeh@yahoo.com © 2017 Hogrefe

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Journal club

Adherence to medication – underutilized therapeutic potential

In the field of cardiovascular medicine it has been indicated that a consequent intake of the prescribed medication is of outstanding importance for the long-term outcome and secondary prevention. However, data on the impact of these measures are scarce.

Bansilal et al. recently addressed this highly topical subject on approx. 17,000 patients based on routine data of a large US American health insurance between 2010 and 2013 [1]. Thereof, 4,015 patients were hospitalized after myocardial infarction and another 12,976 patients with atherosclerotic disease (defined as two out of coronary, cerebrovascular, or peripheral artery diseases including one revascularization procedure). In both cohorts, a prospective analysis was performed to investigate the adherence to the medication regimen with respect to angiotensin-converting-enzyme (ACE) inhibitors and statins.

Methodically, prescription frequency and refill were used to validate medication adherence over a period of 6 months for myocardial infarction and 12 months for atherosclerosis. Accordingly, patients were classified into three categories: intake ≥ 80 % per days indicated (fully adherent), 40–79 % (partially adherent), and < 40 % (non-adherent). The primary outcome measure was a composite of all-cause death, myocardial infarction, stroke, or coronary revascularization over a timespan of 3 years.

In the myocardial infarction subgroup, only 43 % of patients presented with full adherence to the prescribed medication with ACE inhibitors and statins, 31 % showed a partial adherence, and 26 % were non-adherent. The fully adherent subgroup had a significantly lower rate of major adverse cardiovascular events (MACE) compared to the partially adherent (18.9 vs. 24.7 %, HR 0.81, p = 0.02) and non-adherent (18.9 vs. 26.3 %, HR 0.73, p = 0.0004) groups at 2 years. In the subgroup hospitalized with atherosclerosis, adherence to ACE inhibitors and statins was even lower with only 34 % full adherence, 38 % partial adherence, and 28 % non-adherence. Again, in the fully adherent category a significantly lower rate of MACE could be observed compared to the partially adherent (8.42 vs. 12.18 %, HR 0.76, p < 0.0001) and non-adherent (8.42 vs. 17.17 %, HR 0.56, p < 0.0001) categories.

Moreover, the partially adherent patients had a significantly lower risk than those in the non-adherent category (HR 0.73, 95 % CI 0.67–0.80, p < 0.0001) at 2 years. After a follow-up period of 4 years these trends persisted, corresponding to a MACE risk reduction of –28 % of fully adherent compared to non-adherent patients in myocardial infarction and a –46 % risk reduction in atherosclerosis, respectively. © 2017 Hogrefe

The analysis unfortunately does not include any information on platelet inhibition; the authors argue that data on adherence to aspirin are not reliably collectable because of its over-the-counter distribution.

In a sub-analysis, the study further provides insight into cost data of both subgroups related to the adherence category. It could be shown that full medication adherence was associated with a highly significant reduction of per-patient annual direct medical costs compared to non-adherent patients with myocardial infarction and atherosclerosis. These cost savings were mainly driven by a lower rate of cardiovascular events and revascularization procedures with higher adherence. Thus, adherence to both ACE inhibitors and statins was shown to be not just beneficial in terms of clinical outcome but also highly cost-effective.

In an accompanying editorial [2], the underlying reasons for the overall low adherence of cardiovascular patients to medication were pointed out as an extremely complex problem on the sides of patients, physicians, but also of various settings of the health care system. Particularly the frequency of physician consultation as well as provider continuity were positively associated with higher adherence. Moreover, repeated briefings regarding the medication regimen at each visit had also a markedly positive impact on patient compliance. Hence, approaches to improve medication adherence must involve multiple strategies to increase patient’s compliance, feedback, and particularly the frequency and consistency of follow-up care.

In summary, the results of this large analysis on improving adherence to standard medication indicate a higher potential for a better clinical outcome and cost-benefit ratio than proven for most invasive therapies.

References 1. Bansilal S, et al. Assessing the impact of medication adherence on long-term cardiovascular outcomes. J Am Coll Cardiol 2016; 68: 789–801.

2. Armstrong PW, McAlister FA. Searching for adherence: Can we fulfill the promise of evidence-based medicines? J Am Coll Cardiol 2016; 68: 802–804.

Eva Freisinger and Holger Reinecke Division of Vascular Medicine, Department of Cardiovascular Medicine University Hospital Muenster, Muenster, Germany eva.freisinger@ukmuenster.de Vasa (2017), 46 (1), 69 DOI 10.1024/0301-1526/a000591

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DGA vergibt wissenschaftliche Preise Im Rahmen der 17. Dreiländertagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Angiologie in Dresden ehrte die DGA Wissenschaftler für ihre herausragenden Arbeiten auf dem Gebiet der Gefäßmedizin. Am 9. September 2016 überreichten Prof.

Dr. Ulrich Hoffmann, Präsident der DGA, und Prof. Dr. Norbert Weiss, Kongresspräsident und Geschäftsführer der DGA, den Promotionspreis, den Max-Ratschow-Preis und den Young Investigator Award (YIA). Mit dem Promotionspreis und dem YIA wird der angiologische Nachwuchs unterstützt und gefördert, was der Fachgesellschaft ein wichtiges Anliegen ist.

Promotionspreis geht an Dr. Franziska Ebertz

From the societies

“Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation – Results from the Dresden NOAC registry.

Background, objective target, study design.”

About 2 million people in Germany suffer from atrial fibrillation associated with an about 5-fold increased risk of stroke. Dabigatran (Pradaxa®) is a blood-thinning medication accredited to prevent stroke in these patients. Related to its efficacy and safety it was shown to be non-inferior to warfarin in the pivotal study (strict selection of patients, optimal study conditions). Due to the randomized trial design of RE-LY, it is imperative to confirm this pointed efficacy and safety also in the daily routine. The local Dresden NOAC registry aimed to evaluate data on efficacy, safety, and therapy persistence in patients in daily care. On the basis of periodic telephone calls, data on cardiovascular and bleeding events, therapy discontinuation, and fatality under dabigatran were collected to create analysis on efficacy, safety, and therapy persistence.

A total of 341 dabigatran patients were enrolled in the registry. 300 mg dabigatran was given to 46.3 % of the patients, and 220 mg dabigatran to 53.7 %. The follow-up period averaged to 671.2 ± 184.9 days. Patients on lowerdose dabigatran were shown to be significantly older, more often had relevant comorbidities, and as a result these patients had a higher risk for cardiovascular and bleeding events. Under ongoing dabigatran therapy arterial obstruction due to atrial fibrillation occurred at a rate of 1.90/100 patient years (py) (dabigatran 220 mg: 2.88/100 py; dabigatran 300 mg: 0.86/100 py). Major bleeding under dabigatran occurred at a rate of 2.30/100 py (dabigatran 220 mg: 2.85/100 py; dabigatran 300 mg: 172/100 py). Therapy discontinuation was shown to be 25.80/100 py, predominantly due to gastrointestinal side effects, rarely due to bleeding.

Patients in every day practice suffering from atrial fibrillation present a variety of concomitant diseases with an increased risk for stroke and bleeding. Even in these cases dabigatran appeared as a potent and reliable anticoagulant to prevent stroke. Precise selection of dosage regimes as well as an accurate benefit-risk consideration would minimize therapy risks, undesirable effects, and discontinuation rates.

Dr. Franziska Ebertz vom Universitätsklinikum Carl Gustav Carus in Dresden gewann den DGA-Promotionspreis.

Der Preis ist mit 2.500 Euro dotiert und würdigt die wissenschaftliche Arbeit

Vasa (2017), 46 (1), 70–72

© 2017 Hogrefe

From the societies

Max-Ratschow-Preis für Assoc. Prof. Priv-Doz. Dr. Oliver Schlager

71

Young Investigator Award geht an Assoc. Prof. Priv-Doz. Dr. Thomas Gremmel Mit dem Young Investigator Award (YIA) wird die beste Abstracteinreichung eines jungen Wissenschaftlers unter 35 Jahren ausgezeichnet. Die fünf Finalisten T. Gremmel (Wien), E. Freisinger (Münster), C.-A. Behrendt (Hamburg), C. Radosa (Dresden) und M. Schneider (Wien) präsentierten ihre Abstracts in der Preisträgersitzung der Jury.

Assoc. Prof. Priv-Doz. Dr. Thomas Gremmel von der Universitätsklinik Wien erhielt den mit 500 Euro dotierten YIA für seine Arbeit mit dem Titel

Assoc. Prof. Priv-Doz. Dr. Oliver Schlager ist in der Klinischen Abteilung für Angiologie der Universitätsklinik Wien tätig. Der Max-Ratschow-Preis ist mit 5.000 Euro dotiert und würdigt seine Arbeit

“Relation of nailfold capillaries and autoantibodies to mortality in patients with Raynaud’s phenomenon.”

Raynaud’s phenomenon is a common, but understudied condition. Patients with Raynaud’s phenomenon routinely undergo nailfold capillaroscopy as well as laboratory tests for antinuclear antibodies (ANA) and ANA subsets to detect an emerging connective tissue disease.

In our study we assessed associations between baseline nailfold capillary findings as well as baseline ANA and ANA subsets and mortality in patients with Raynaud’s phenomenon. Therefore, 2958 patients with Raynaud’s phenomenon (78 % women, median age 45 years) were followed over a median observational period of 9.3 years.

In comparison with a demographically matched standard population, we found an increased mortality in our cohort of patients with Raynaud’s phenomenon. In male patients, survival was worse than in female patients with Raynaud’s phenomenon. In both sexes mortality depended on patients’ age and renal function. In female patients with Raynaud’s phenomenon, abnormal nailfold capillaries, ANA, and anti-Scl-70 antibodies were associated with an increase in all-cause mortality. In male patients, abnormal nailfold capillaries and ANA were not associated with mortality.

The findings of this study show that – especially in female patients – nailfold capillaroscopy and immunological tests are of high clinical relevance, not only to detect an emerging connective tissue disease, but also to identify patients at risk of increased mortality.

© 2017 Hogrefe

“Synergistic inhibition of both P2Y1 and P2Y12 adenosine diphosphate receptors as novel approach to rapidly attenuate platelet-mediated thrombosis”.

Unlike currently approved adenosine diphosphate (ADP) receptor antagonists, the new diadenosine tetraphosphate derivative GLS-409 targets not only P2Y12 but also the second human platelet ADP receptor P2Y1, and may therefore be a promising antiplatelet drug candidate. The current study is the first to investigate the in vivo antithrombotic effects of GLS-409.

We studied (1) the in vivo effects of GLS-409 on agonist-stimulated platelet aggregation in anesthetized rats, (2) the antithrombotic activity of GLS-409 and the associated effect on the bleeding time in a canine model of platelet-mediated coronary artery thrombosis, and (3) the inhibition of agonist-stimulated platelet aggregation by GLS-409 versus selective P2Y1 and P2Y12 inhibition in vitro in samples from healthy human subjects before and 2 h after aspirin intake. In vivo treatment with GLS-409 significantly inhibited ADP- and collagen-stimulated platelet aggregation in rats. Further, GLS-409 attenuated cyclic low variation, i. e., platelet-mediated thrombosis, in vivo in our canine model of unstable angina. The improvement in coronary patency was accompanied by a non-sig-

Vasa (2017), 46 (1), 70–72

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From the societies

nificant 30-% increase in bleeding time. Of note, GLS409 exerted its effects without affecting rat and canine hemodynamics. Finally, in vitro treatment with GLS-409 showed effects similar to that of cangrelor and the combination of cangrelor with the selective P2Y1 inhibitor MRS 2179 on agonist-stimulated platelet aggregation in human platelet-rich plasma and whole blood before and 2 h after aspirin intake. Synergistic inhibition of both P2Y1 and P2Y12 ADP receptors by GLS-409 immediately attenuates platelet-mediated thrombosis and effectively blocks agonist-stimulated platelet aggregation irrespective of concomitant aspirin therapy.

Deutsche Gesellschaft für Angiologie vergibt erneut den DGA-Journalistenpreis Die Deutsche Gesellschaft für Angiologie – Gesellschaft für Gefäßmedizin e. V. hat bei der 17. Dreiländertagung der Deutschen, Österreichischen und Schweizerischen Gesellschaften für Angiologie in Dresden zum zweiten Mal den DGA-Journalistenpreis in Höhe von jeweils 2.000 Euro verliehen.

Ausgezeichnet wurden Beiträge, die anschaulich und kompetent formuliert über Gefäßerkrankungen, deren Prävention, Verbreitung, Behandlung, Nachsorge und Folgen berichten. Der Preis wurde in den Kategorien Print/ Online sowie Hörfunk/TV vergeben.

Edith Heitkämper, Journalistin und Redakteurin beim NDR, gewann den Preis für ihren Artikel im Magazin Stern „Verhütung – Gefährliche Nebenwirkung“. Darin berichtet sie anhand von zwei Patientengeschichten über das er-

Vasa (2017), 46 (1), 70–72

DGA-Preisverleihung. Edith Heitkämper (links), Präsident Prof. Dr. Ulrich Hoffmann (Mitte), Erika Brettschneider (rechts). Fotograf: Matthias Hultsch

höhte Thromboserisiko durch die Einnahme der neuen Generationen der Anti-Baby-Pille.

Erika Brettschneider, Medizinjournalistin, wurde ausgezeichnet für ihre TV-Reportage „Gesunde Gefäße – gesunde Beine, Therapien im Check“, die im RBB ausgestrahlt wurde. Sie begleitet darin vier Patienten mit PAVK und Krampfaderleiden und stellt verschiedene Therapiemöglichkeiten, wie das Stripping und die Stent-Erweiterung, vor.

© 2017 Hogrefe

Das kompakte Lehrbuch

Olaf Preuß

Krankenhausmanagement kompakt Aktionsfelder und Managementinstrumente 2., durchgesehene u. erw. Auflage 2016.

152 S., 36 Abb., 19 Tab., € 29,95 / CHF 39.90 ISBN 978-3-456-85583-7 Auch als eBook erhältlich

Das kompakte Lehrbuch bietet eine einführende Systematik für das Fachgebiet Management im Krankenhaus für Mediziner und Pflegemanager. Es werden grundlegende krankenhausbetriebswirtschaftliche Sachverhalte vermittelt, ohne dass dazu umfangreiche Vorkenntnisse erforderlich sind.

Für das Fachgebiet Krankenhausmanagement hat sich dieses Werk mit den essenziellen und didaktisch gut aufbereiteten Lehrinhalten etabliert. Der erfahrene Autor beschreibt Gesundheits- und Krankenhausversorgung aus betriebswirtschaftlicher Sicht. Er stellt krankenhausspezifische Funktionsbereiche wie Controlling, Qualitätsmanagement und Marketing in komprimierter Form vor.

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Neu in der zweiten erweiterten Auflage sind die Themenfelder PEPP-Vergütungssystem sowie Risikomanagement, Medizinisches Versorgungszentrum (MVZ) in Krankenhaus-Trägerschaft und betriebliche Gesundheitsförderung.

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Ist Schnelligkeit wirklich immer wichtiger als Sicherheit?

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