Publications by authors named "Jan Dieter Schmitto"

30 Publications

  • Page 1 of 1

Advanced Single-Cell Mapping Reveals that in hESC Cardiomyocytes Contraction Kinetics and Action Potential Are Independent of Myosin Isoform.

Stem Cell Reports 2020 05 16;14(5):788-802. Epub 2020 Apr 16.

Institute of Molecular and Cell Physiology, Hannover Medical School, Carl-Neuberg Straße 1, 30625 Hannover, Germany.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent an attractive model to investigate CM function and disease mechanisms. One characteristic marker of ventricular specificity of human CMs is expression of the ventricular, slow β-myosin heavy chain (MyHC), as opposed to the atrial, fast α-MyHC. The main aim of this study was to investigate at the single-cell level whether contraction kinetics and electrical activity of hESC-CMs are influenced by the relative expression of α-MyHC versus β-MyHC. For effective assignment of functional parameters to the expression of both MyHC isoforms at protein and mRNA levels in the very same hESC-CMs, we developed a single-cell mapping technique. Surprisingly, α- versus β-MyHC was not related to specific contractile or electrophysiological properties of the same cells. The multiparametric cell-by-cell analysis suggests that in hESC-CMs the expression of genes associated with electrical activity, contraction, calcium handling, and MyHCs is independently regulated.
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http://dx.doi.org/10.1016/j.stemcr.2020.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220955PMC
May 2020

Global perspectives on cardiothoracic, cardiovascular, and cardiac surgical training.

J Thorac Cardiovasc Surg 2020 Jan 28. Epub 2020 Jan 28.

Department of Cardiothoracic and Vascular Surgery, The University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Tex; Memorial Hermann Heart and Vascular Institute, Houston, Tex. Electronic address:

Objective: Various methods for cardiothoracic, cardiovascular, and cardiac surgical training exist across the globe, with the common goal of producing safe, independent surgeons. A comparative analysis of international training paradigms has not been undertaken, and our goal in doing so was to offer insights into how to best prepare future trainees and ensure the health of our specialty.

Methods: We performed a comparative analysis of available publications offering detailed descriptions of various cardiothoracic, cardiovascular, and cardiac surgical training paradigms. Corresponding authors from previous publications and other international collaborators were also reached directly for further data acquisition.

Results: We report various approaches to common challenges surrounding (1) selection of trainees and plans for the future surgical workforce; (2) trainee assessments and certification of competency before independent practice; and (3) challenges related to a changing practice landscape.

Conclusions: Cardiothoracic surgery remains a dynamic and rewarding specialty. Current and future trainees face several challenges that transcend national borders. To foster collaboration and adoption of best practices, we highlight international strengths and weaknesses of various nations in terms of workforce selection, trainee operative experience and assessment, board certification, and preparation for future changes anticipated in cardiothoracic surgery.
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http://dx.doi.org/10.1016/j.jtcvs.2019.12.111DOI Listing
January 2020

Infrastructural needs and expected benefits of telemonitoring in left ventricular assist device therapy: Results of a qualitative study using expert interviews and focus group discussions with patients.

Int J Artif Organs 2020 Jun 18;43(6):385-392. Epub 2019 Dec 18.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hanover Medical School, Hanover, Germany.

Background: Heart failure is one of the most expensive chronic diseases, as it leads to considerable expenses due to increasing hospitalisation rates. In addition to the implications of the demographic transition and the lack of available organs for transplantation, a major challenge in this context is that conservative treatment options are limited. This has led to the research and development of mechanical circulatory assist systems. Telemonitoring is anticipated to be an effective tool in outpatient management, which may be a key to improved outcomes of left ventricular assist devices therapy. In patients with chronic cardiac diseases, telemedicine is already used and has been shown to reduce premature mortality. This study aims to provide insights into the left ventricular assist device-specific requirements for telemonitoring and infrastructural translation from caregivers' and patients' points of view.

Method: A qualitative investigation based on guided interview and focus group techniques was conducted at two German heart centres. The study included 15 patients and 7 caregivers (4 cardiac surgeons, 3 ventricular assist device coordinators). Qualitative content analysis was used for data analysis. The categories for analysis were (1) benefits for patients, (2) benefits for hospitals and the healthcare system, (3) acceptance and causative factors and (4) infrastructural implementation.

Results: Patients and experts expect the following benefits for telemonitored patients: added safety, early detection of complications, rapid intervention in case of emergency, regular inspection of pump parameters, fewer outpatient clinic visits and the ability to provide more informed feedback and instructions to the family members who take care of the patient. However, the expected acceptance of telemonitoring in left ventricular assist device therapy differed among the interviewed groups. Alongside the aforementioned expected benefits, patients and clinical experts criticised the reduced self-determination for the patient, probable large amounts of time/effort required of the patient and caregiver and data protection/integrity issues (data misuse, device manipulation and mistransfer). Interviewees expected easy handling, proper education and safe data transmission to be necessary factors leading to acceptance. Complication rate reduction, fewer hospitalisations and cost reductions were benefits recorded for the healthcare system and clinics. Clinical experts preferred a telemonitoring centre run by ventricular assist device coordinators.

Conclusion: Although positive expectations are associated with the use of telemonitoring in left ventricular assist device therapy, further action is needed. For example, software and infrastructure developers will need to address issues such as variations among patients and may need to find a balance between designing individualised solutions for compliant patients and a safe and easy-to-handle set-up. In addition, proper elucidation of users will contribute to the successful implementation of a left ventricular assist device telemonitoring programme among patients and caregivers.
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http://dx.doi.org/10.1177/0391398819893702DOI Listing
June 2020

Low immunogenic endothelial cells endothelialize the Left Ventricular Assist Device.

Sci Rep 2019 08 5;9(1):11318. Epub 2019 Aug 5.

SPP2014 - Towards an implantable lung, Hannover, Germany.

Low haemocompatibility of left ventricular assist devices (LVAD) surfaces necessitates anticoagulative therapy. Endothelial cell (EC) seeding can support haemocompatibility, however, the availability of autologous ECs is limited. In contrast, allogeneic ECs are readily available in sufficient quantity, but HLA disparities induce harmful immune responses causing EC loss. In this study, we investigated the feasibility of using allogeneic low immunogenic ECs to endothelialize LVAD sintered inflow cannulas (SIC). To reduce the immunogenicity of ECs, we applied an inducible lentiviral vector to deliver short-hairpins RNA to silence HLA class I expression. HLA class I expression on ECs was conditionally silenced by up to 70%. Sufficient and comparable endothelialization rates were achieved with HLA-expressing or HLA-silenced ECs. Cell proliferation was not impaired by cell-to-Sintered Inflow Cannulas (SIC) contact or by silencing HLA expression. The levels of endothelial phenotypic and thrombogenic markers or cytokine secretion profiles remained unaffected. HLA-silenced ECs-coated SIC exhibited reduced thrombogenicity. In contrast to native ECs, HLA-silenced ECs showed lower cell lysis rates when exposed to allogeneic T cells or specific anti-HLA antibodies. Allogeneic HLA-silenced ECs could potentially become a valuable source for LVAD endothelialization to reduce immunogenicity and correspondingly the need for anticoagulative therapy which can entail severe side effects.
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http://dx.doi.org/10.1038/s41598-019-47780-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683293PMC
August 2019

The clinical impact of donor-specific antibodies in heart transplantation.

Transplant Rev (Orlando) 2018 10 8;32(4):207-217. Epub 2018 May 8.

Department of Cardiac Surgery, Medical University of Vienna, Währinge Gürtel 18-20, A-1090 Vienna, Austria.

Donor-specific antibodies (DSA) are integral to the development of antibody-mediated rejection (AMR). Chronic AMR is associated with high mortality and an increased risk for cardiac allograft vasculopathy (CAV). Anti-donor HLA antibodies are present in 3-11% of patients at the time of heart transplantation (HTx), with de novo DSA (predominantly anti-HLA class II) developing post-transplant in 10-30% of patients. DSA are associated with lower graft and patient survival after HTx, with one study suggesting a three-fold increase in mortality in patients who develop de novo DSA (dnDSA). DSA against anti-HLA class II, notably DQ, are at particularly high risk for graft loss. Although detection of DSA is not a criterion for pathologic diagnosis of AMR, circulating DSA are found in almost all cases of AMR. MFI thresholds of ~5000 for DSA against class I antibodies, 2000 against class II antibodies, or an overall cut-off of 5-6000 for any DSA, have been suggested as being predictive for AMR. There is no firm consensus on pre-transplant strategies to treat HLA antibodies, or for the elimination of antibodies after diagnosis of AMR. Minimizing the risk of dnDSA is rational but data on risk factors in HTx are limited. The effect of different immunosuppressive regimens is largely unexplored in HTx, but studies in kidney transplantation emphasize the importance of adherence and maintaining adequate immunosuppression. One study has suggested a reduced risk for dnDSA with rabbit antithymocyte globulin induction. Management of DSA pre- and post-HTx varies but typically most centers rely on a plasmapheresis or immunoadsorption, with or without rituximab and/or intravenous immunoglobulin. Based on the literature and a multi-center survey, an algorithm for a suggested surveillance and therapeutic strategy is provided.
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http://dx.doi.org/10.1016/j.trre.2018.05.002DOI Listing
October 2018

A Review of Induction with Rabbit Antithymocyte Globulin in Pediatric Heart Transplant Recipients.

Ann Transplant 2018 May 15;23:322-333. Epub 2018 May 15.

University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable.
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http://dx.doi.org/10.12659/AOT.908243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6248300PMC
May 2018

Treatment of an Intercostal Left Ventricular Assist Device Prolapse by Upgrading From HeartMate II to HeartMate 3.

Artif Organs 2018 02;42(2):242-244

Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1111/aor.12981DOI Listing
February 2018

Inert gas rebreathing - helpful tool in the management of left ventricular assist device patients.

Perfusion 2018 07 4;33(5):335-338. Epub 2018 Jan 4.

2 Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

In patients with left ventricular assist devices (LVAD), exercise capacity is a decisive factor regarding the quality of life. When evaluating exercise capacity, precise information about the total cardiac output generated is crucial. To date, complex measurements using a right-heart catheter were necessary in order to determine total cardiac output. The inert gas rebreathing method facilitates non-invasive, direct and valid measurement of total cardiac output as well as associated parameters, like the difference in arteriovenous oxygen saturation, both at rest and during exercise. It is the aim of this paper to focus on this conclusive method which is, despite its simplicity and low-risk reproducibility, rarely used within the framework of LVAD patient treatment at the present time. The test protocol used at our hospital is presented to facilitate the implementation of this helpful tool in other interested institutions.
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http://dx.doi.org/10.1177/0267659117751621DOI Listing
July 2018

Venoarterial Extracorporeal Membrane Oxygenation: Lower Speed, and You May Be Faster.

Ann Thorac Surg 2017 08;104(2):724-725

Department of Cardiology and Angiology, Cardiac Arrest Center, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1016/j.athoracsur.2016.10.050DOI Listing
August 2017

Telemonitoring and Medical Care of Heart Failure Patients Supported by Left Ventricular Assist Devices - The Medolution Project.

Stud Health Technol Inform 2017 ;236:267-274

Hannover Medical School, Hannover, Germany.

Long-term survival after left ventricular assist device (LVAD) implantation in heart failure patients is mainly determined by a sophisticated after-care. Ambulatory visits only take place every 12 weeks. In case of life-threatening complications (pump thrombosis, driveline infection) this might lead to delayed diagnosis and delayed intervention. It is the intention of the international project Medolution (Medical care evolution) to develop new approaches in order to create best structures for telemonitoring of LVAD patients. In the very early period of the project a questionnaire was sent to 180 LVAD patients to evaluate the need and acceptance of telemonitoring. Thereafter, a graphical user interface (GUI) mockup was developed as one of the first steps to improve the continuous contact between the LVAD patient and the physician. As a final goal the Medolution project aims to bundle all relevant informations from different data sources into one platform in order to provide the physician a comprehensive overview of a patient's situation. In the systems background a big data analysis should run permanently and should try to detect abnormalities and correlations as well. At crucial events, a notification system should inform the physician and should provide the causing data via a decision support system. With this new system we are expecting early detection and prevention of common and partially life-threatening complications, less readmissions to the hospital, an increase in quality of life for the patients and less costs for the health care system as well.
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April 2018

Adaptive Pump Speed Algorithms to Improve Exercise Capacity in Patients Supported with a Left-Ventricular Assist Device.

Stud Health Technol Inform 2017 ;236:235-240

OFFIS - Institute for Information Technology, Oldenburg, Germany.

For the treatment of terminal heart failure, the therapy with left-ventricular assist devices has already been established. In the systems used today, pump speed does not adjust during physical activity so that cardiac output and exercise capacity remain markedly limited. It is the aim of this study to develop an automatic pump speed control based on filling pressure values in order to improve exercise capacity and quality of life in these patients. Different approaches are planned, to be tested in an in vitro patient simulator. The algorithms aim to match the pump speed with the increased venous return. In addition, preservation of aortic valve function should be taken into account.
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April 2018

A Proposal for Early Dosing Regimens in Heart Transplant Patients Receiving Thymoglobulin and Calcineurin Inhibition.

Transplant Direct 2016 Jun 20;2(6):e81. Epub 2016 May 20.

Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria.

There is currently no consensus regarding the dose or duration of rabbit antithymocyte globulin (rATG) induction in different types of heart transplant patients, or the timing and intensity of initial calcineurin inhibitor (CNI) therapy in rATG-treated individuals. Based on limited data and personal experience, the authors propose an approach to rATG dosing and initial CNI administration. Usually rATG is initiated immediately after exclusion of primary graft failure, although intraoperative initiation may be appropriate in specific cases. A total rATG dose of 4.5 to 7.5 mg/kg is advisable, tailored within that range according to immunologic risk and adjusted according to immune monitoring. Lower doses (eg, 3.0 mg/kg) of rATG can be used in patients at low immunological risk, or 1.5 to 2.5 mg/kg for patients with infection on mechanical circulatory support. The timing of CNI introduction is dictated by renal recovery, varying between day 3 and day 0 after heart transplantation, and the initial target exposure is influenced by immunological risk and presence of infection. Rabbit antithymocyte globulin and CNI dosing should not overlap except in high-risk cases. There is a clear need for more studies to define the optimal dosing regimens for rATG and early CNI exposure according to risk profile in heart transplantation.
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http://dx.doi.org/10.1097/TXD.0000000000000594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946520PMC
June 2016

Repair of an acute Type A aortic dissection with LVAD patient after failed mitral and tricuspid operation.

Clin Case Rep 2016 Apr 4;4(4):387-9. Epub 2016 Mar 4.

Division of Cardiac, Thoracic, Transplantation and Vascular Surgery Hannover Medical School Hannover Germany.

An acute type A dissection in a patient with a left ventricular assist device was treated by replacement of the ascending aorta and the proximal arch using a prosthesis with a side branch which was connected to the left ventricular assist device outflow branch, greatly simplifying the procedure.
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http://dx.doi.org/10.1002/ccr3.332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831390PMC
April 2016

Aortic valve replacement with sutureless prosthesis: better than root enlargement to avoid patient-prosthesis mismatch?

Interact Cardiovasc Thorac Surg 2016 06 25;22(6):744-9. Epub 2016 Feb 25.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany

Objectives: Aortic valve replacement in patients with a small aortic annulus may result in patient-prosthesis mismatch (PPM). Aortic root enlargement (ARE) can reduce PPM, but leads to extended cardiac ischaemia times. Sutureless valves have the potential to prevent PPM while reducing cardiac ischaemia times.

Methods: Between January 2007 and December 2011, a total of 128 patients with a small aortic annulus underwent surgery for aortic valve stenosis at our centre. Thirty-six (17% male, n = 6) patients received conventional valve replacement with ARE and 92 (16% male, n = 18) subjects received sutureless valve implantation (Sorin Perceval). We conducted a comparative, retrospective study with follow-up.

Results: The sutureless group showed a significantly higher age (79 years) than the ARE patients (62 years, P < 0.001) and received significantly more concomitant cardiac procedures (33%, n = 30 vs 6%, n = 2, P = 0.001). The mean operation, cardiopulmonary bypass and cross-clamp times were significantly lower in sutureless patients (147 ± 42, 67 ± 26 and 35 ± 13 min, respectively) than in ARE patients (181 ± 41, 105 ± 29 and 70 ± 19 min, respectively, P < 0.001). The mean postoperative effective orifice area (EOA) indexed to the body surface area was 0.91 ± 0.2 cm(2)/m(2) in ARE patients and 0.83 ± 0.14 cm(2)/m(2) in sutureless patients (P = 0.040). The rate of patients with severe PPM was 6% (n = 2) in ARE patients and 11% (n = 8%) in sutureless patients (not significant, n.s.). The 30-day mortality rates were 2% (n = 2) in sutureless patients and 6% (n = 2) in ARE patients (n.s.). The 1- and 5-year survival rates of the sutureless group were 92 and 54% years, respectively, whereas the 1- and 5-year survival rates of the ARE group were 76% (n.s.).

Conclusions: Although the sutureless valve patients received significantly more concomitant procedures, all operation-associated times were significantly shorter. Despite sutureless valve patients being older, the 30-day mortality and survival rates were comparable in the two groups. Since the indexed EOA was only slightly lower and the incidence of severe PPM was not significantly higher in the sutureless valve patients, we conclude that sutureless valve implantation is an alternative to conventional ARE to treat a small aortic annulus and avoid PPM, especially in geriatric patients who benefit from the quick implantation process.
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http://dx.doi.org/10.1093/icvts/ivw041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4986785PMC
June 2016

Antiandrogenic therapy with finasteride attenuates cardiac hypertrophy and left ventricular dysfunction.

Circulation 2015 Mar 28;131(12):1071-81. Epub 2015 Jan 28.

From Medizinische Hochschule Hannover, Klinik für Kardiologie und Angiologie, Hanover, Germany (C.Z., E.S., M.S., B.K., N.F., H.H., J.W., J.B., J.H.); Klinik für Herz-, Thorax-, Transplantations- und Gefäßchirurgie, Hanover, Germany (J.D.S.); Institut für Molekulare und Translationale Therapiestrategien (IMTTS), Hannover, Germany (S.B., T.T.); National Heart and Lung Institute, Imperial College, London, United Kingdom (T.T.); and Medizinische Hochschule Hannover, Zentrale Forschungseinrichtung Metabolomics, Institut für Pharmakologie, Hannover, Germany (H.B., V.K.).

Background: In comparison with men, women have a better prognosis when experiencing aortic valve stenosis, hypertrophic cardiomyopathy, or heart failure. Recent data suggest that androgens like testosterone or the more potent dihydrotestosterone contribute to the development of cardiac hypertrophy and failure. Therefore, we analyzed whether antiandrogenic therapy with finasteride, which inhibits the generation of dihydrotestosterone by the enzyme 5-α-reductase, improves pathological ventricular remodeling and heart failure.

Methods And Results: We found a strongly induced expression of all 3 isoforms of the 5-α-reductase (Srd5a1 to Srd5a3) in human and mouse hearts with pathological hypertrophy, which was associated with increased myocardial accumulation of dihydrotestosterone. Starting 1 week after the induction of pressure overload by transaortic constriction, mice were treated with finasteride for 2 weeks. Cardiac function, hypertrophy, dilation, and fibrosis were markedly improved in response to finasteride treatment in not only male, but also in female mice. In addition, finasteride also very effectively improved cardiac function and mortality after long-term pressure overload and prevented disease progression in cardiomyopathic mice with myocardial Gαq overexpression. Mechanistically, finasteride, by decreasing dihydrotestosterone, potently inhibited hypertrophy and Akt-dependent prohypertrophic signaling in isolated cardiac myocytes, whereas the introduction of constitutively active Akt blunted these effects of finasteride.

Conclusions: Finasteride, which is currently used in patients to treat prostate disease, potently reverses pathological cardiac hypertrophy and dysfunction in mice and might be a therapeutic option for heart failure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.012066DOI Listing
March 2015

PET imaging of cardiac wound healing using a novel [68Ga]-labeled NGR probe in rat myocardial infarction.

Mol Imaging Biol 2015 Feb 11;17(1):76-86. Epub 2014 Jul 11.

Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany,

Purpose: Peptides containing the asparagine-glycine-arginine (NGR) motif bind to aminopeptidase N (CD13), which is expressed on inflammatory cells, endothelial cells, and fibroblasts. It is unclear whether radiolabeled NGR-containing tracers could be used for in vivo imaging of the early wound-healing phase after myocardial infarction (MI) using positron emission tomography (PET).

Procedures: Uptake of novel tracer [(68)Ga]NGR was assessed together with [(68)Ga]arginine-glycine-aspartic acid ([(68)Ga]RGD) and 2-deoxy-2-[(18) F]fluoro-D-glucose after myocardial ischemia/reperfusion (MI/R) injury using μ-PET and autoradiography, and relative expressions of CD13 and integrin β3 were assessed in fibroblasts, inflammatory cells, and endothelial cells by immunohistochemistry.

Results: In the infarcted myocardium, uptake of [(68)Ga]NGR was maximal from days 3 to 7 after MI/R, and correlated with fibroblast and inflammatory cell infiltration as well as [(68)Ga]RGD uptake.

Conclusions: [(68)Ga]NGR allows noninvasive and sequential determination of CD13 expression in fibroblasts and inflammatory cells by PET. This will facilitate monitoring of CD13 in the individual wound healing processes, allowing patient-specific therapies to improve outcome after MI.
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http://dx.doi.org/10.1007/s11307-014-0751-2DOI Listing
February 2015

Expression of fibulin-6 in failing hearts and its role for cardiac fibroblast migration.

Cardiovasc Res 2014 Sep 20;103(4):509-20. Epub 2014 Jun 20.

Department of Anesthesiology and Intensive Care Medicine, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany

Aims: The cardiac extracellular matrix (ECM) undergoes a dynamic transition following myocardial infarction. Fibulin-6 is expressed in cell junctions particularly in tissues subjected to significant mechanical stress. Fibulin-6 deficiency results in defective cell migration in nematodes and early embryonic lethality in mice. The role of fibulin-6 in healthy and failing myocardium is unknown. We have examined the expression and distribution pattern of fibulin-6 during myocardial remodelling (MR) and detailed its effect on the migratory function of cardiac fibroblasts (CFs) in response to TGF-β1.

Methods And Results: In healthy murine myocardium, fibulin-6 expression is largely confined to larger coronary arteries. It is induced during the early and the late phase of remodelling after infarction in murine hearts predominantly in the scar-muscle junction. Similar results are obtained in human ischaemic cardiomyopathy. Fibulin-6 is mostly expressed in close vicinity to vimentin-positive cells and is also abundantly expressed in vitro in cultured neonatal CF. TGF-β1 does not induce smooth muscle actin in fibroblasts deficient of fibulin-6, which also compromised their migration. Cells that had migrated expressed more fibulin-6 compared with stationary cells. Plated on fibulin-6-depleted matrix, stress fibre induction in fibroblast in response to TGF-β1 was impaired. In ex vivo explant cultures from post-infarct myocardium, the number of emigrating fibroblasts was also significantly reduced by fibulin-6 siRNA knockdown.

Conclusion: Fibulin-6, a fibroblast-released ECM protein, may play an important role during MR by imparting an effect on CF migration in close and complementary interplay with TGF-β1 signalling.
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http://dx.doi.org/10.1093/cvr/cvu161DOI Listing
September 2014

Bilateral femoral artery compression as a technique to increase vital organ perfusion during intraoperative hypotension.

Med Hypotheses 2014 Jul 25;83(1):127-9. Epub 2014 Mar 25.

Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany. Electronic address:

Intraoperative hypotension is associated with adverse outcomes. The preferred treatment for intraoperative hypotension is to address its cause. In the interim the blood pressure can be supported by the anesthesia team with volume resuscitation and vasopressors. Additionally, preferential perfusion of vital organs, such as the myocardium and cerebrum, at the expense of non-vital vascular beds, such as the extremities, is desirable. In the state of shock, the flight or fight response will ensure perfusion of the extremities in order to prepare the organism for a physical confrontation. However, in the context of intraoperative hypotension this response is counter-productive. Therefore we propose bilateral femoral artery compression as a new technique to increase vital organ perfusion during intraoperative hypotension. This results in shunting of blood flow from the legs and towards the vital organs. Bilateral femoral artery compression can be employed by the surgical team to immediately improve blood pressure until other counter-measures against intraoperative hypotension take effect.
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http://dx.doi.org/10.1016/j.mehy.2014.03.021DOI Listing
July 2014

Pacemaker dependency after isolated aortic valve replacement: do conductance disorders recover over time?

Interact Cardiovasc Thorac Surg 2013 Apr 8;16(4):476-81. Epub 2013 Jan 8.

Department of Cardio-Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany.

Objectives: Permanent pacemaker (PPM) implantation is required in 3-8% of all patients undergoing aortic valve replacement (AVR). Our aim was to evaluate long-term PPM dependency and recovery of atrioventricular (AV) conduction disorders during follow-up in these patients.

Methods: Since January 1997, a total of 2106 consecutive patients underwent isolated AVR at our institution. Of these, 138 patients (6.6%, 72 female, median age 71 (37-89) years) developed significant conduction disorders leading to PPM implantation postoperatively. Preoperative ECG showed normal sinus rhythm (n = 64), first degree AV block (n = 19), left bundle branch block (n = 13), right bundle branch block (n = 16), left anterior hemiblock (n = 14) and AV block with ventricular escape rhythm (n = 10). Atrial fibrillation was present in 23 patients. Pacemakers were implanted after a median of 7 (1-30) days following AVR. PPM dependency was analysed by ECG and pacemaker check during follow-up.

Results: A total of 45 of 138 patients with postoperative PPM Implantation died during a mean follow-up time of 5.3 ± 4.7 years. A further 9 patients were lost to follow-up. Long-term survivals at 1, 5 and 10 years were 88%, 79% and 59%, respectively. Only 8 (10%) of 84 survivors were no longer pacemaker-dependent. The majority of patients (n = 66, 79%) required permanent ventricular stimulation, and the remaining 10 (13%) showed intermittent stimulation with a mean ventricular stimulation fraction of 73% (22-98%).

Conclusions: The majority of patients do not recover from AV conduction disorders after AVR. Since higher-grade AV blocks expose patients to a high risk of sudden death after surgery, we recommend early implantation of permanent pacemaker.
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http://dx.doi.org/10.1093/icvts/ivs555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3598046PMC
April 2013

Extracorporeal circulation for rewarming in drowning and near-drowning pediatric patients.

Artif Organs 2010 Nov;34(11):1026-30

Department of Thoracic and CardiovascularSurgery, University of Göttingen, Göttingen, Germany.

Drowning and near-drowning is often associated with severe hypothermia requiring active core rewarming.We performed rewarming by cardiopulmonary bypass(CPB). Between 1987 and 2007, 13 children (9 boys and 4 girls) with accidental hypothermia were rewarmed by extracorporeal circulation (ECC) in our institution. The average age of the patients was 3.2 years. Resuscitation was started immediately upon the arrival of the rescue team and was continuously performed during the transportation.All patients were intubated and ventilated. Core temperature at admission ranged from 20 to 29°C (mean 25.3°C). Connection to the CPB was performed by thoracic (9 patients) or femoral/iliac means (4 patients). Restoration of circulation was achieved in 11 patients (84.6%). After CPB termination two patients needed an extracorporeal membrane oxygenation system due to severe pulmonary edema.Five patients were discharged from hospital after prolonged hospital stay. During follow-up, two patients died(10 and 15 months, respectively) of pulmonary complications and one patient was lost to follow-up. The two remaining survivors were without neurological deficit.Modes of rewarming, age, sex, rectal temperature, and serum electrolytes did not influence mortality. In conclusion,drowning and near-drowning with severe hypothermia remains a challenging emergency. Rewarming by ECC provides efficient rewarming and full circulatory support.Although nearly half of the children may survive after rewarming by ECC, long-term outcome is limited by pulmonary and neurological complications.
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http://dx.doi.org/10.1111/j.1525-1594.2010.01156.xDOI Listing
November 2010

Feasibility of implantable cardioverter defibrillator treatment in five patients with familial Friedreich's ataxia--a case series.

Artif Organs 2010 Nov;34(11):1061-5

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Germany.

Friedreich's ataxia (FRA) is an autosomal recessive disease of the central nervous system that is associated with familial cardiomyopathy. Cardiac involvement is seen in more than 90% of the patients and is the most common cause of death in these patients. We present a case series and discuss the indications for implantable cardioverter defibrillator (ICD) implantation in FRA with review of the literature. Five pediatric patients who suffer from FRA (four female and one male, mean age 17.4 years) underwent ICD implantation between 2007 and 2008 in the University Hospital of Goettingen. The diagnosis of FRA was established by standard clinical criteria and proven in each case by genotyping at the frataxin locus. The time from diagnosis to ICD implantation was 10.4±1.73 years (range 8-15 years). All patients received transvenous lead systems. There were no intraoperative and postoperative complications. At the latest follow-up, the neuromuscular symptoms exhibited no further progress and no ICD activations were noticed. Only minor repolarization changes were seen on electrocardiogram. All patients had normal echocardiographic findings and no angina has been reported. Coronary angiographies were normal. It is evident that many FRA patients develop ventricular dysfunction. In the absence of a definitive surgical cure an ICD is generally indicated in young patients with hemodynamically significant sustained ventricular tachyarrhythmias for prevention of sudden cardiac death. Our experience implies the safe use of ICD in children with FRA.
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http://dx.doi.org/10.1111/j.1525-1594.2010.01140.xDOI Listing
November 2010

Aortic valve surgery in congenital heart disease: a single-center experience.

Artif Organs 2010 Mar;34(3):E85-90

Department of Thoracic and Cardiovascular Surgery, University of Göttingen, Göttingen, Germany.

The optimal treatment of congenital aortic valve lesions is a controversial issue. This study was performed to evaluate the outcome after surgical treatment of aortic valve lesions in congenital aortic valve disease. Between the years of 2000 and 2008, 61 patients (mean age: 12.6 +/- 9.6 years, range: 1 day to 40 years) underwent aortic valve surgery for congenital aortic valve disease. Twenty-four patients had undergone previous cardiovascular operations. Indications for surgery were aortic regurgitation in 14.7% (n = 9), aortic stenoses in 26.2% (n = 16), and mixed disease in 59.1% (n = 36). The Ross procedure was performed in 37.7% (n = 23), aortic valve replacement with biological or mechanical prostheses in 29.5% (n = 18). Concomitant procedures were performed in 91.8% (n = 56) due to associated congenital cardiac defects. The overall mortality rate was 5%. Six patients needed reoperation. Implantation of permanent pacemakers occurred in six patients for permanent atrioventricular block. At the latest clinical evaluation, all survivors are in New York Heart Association class I-II and are living normal lives. Aortic valve surgeries in patients with congenital heart disease have had low mortality and morbidity rates in our series. Surgical technique as well as timing should be tailored for each patient. Aortic valve replacement should be delayed until the implantation of an adult-sized prosthesis is possible.
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http://dx.doi.org/10.1111/j.1525-1594.2009.00958.xDOI Listing
March 2010

Surgical treatment of left ventricular aneurysm.

Asian Cardiovasc Thorac Ann 2009 Oct;17(5):490-3

Department of Cardiovascular Surgery, Heart and Diabetes Center North-Rhine Westphalia, University of Bochum, Georg Strasse 11, 32545 Bad Oeynhausen, Germany.

When a left ventricular aneurysm leads to pulmonary congestive symptoms, aneurysmectomy may provide relief. This retrospective study included 269 patients who underwent aneurysmectomy between 1993 and 2002, by the classic Cooley operation in 164 and by Dor ventriculoplasty in 105. There were no significant differences in early and late survival between groups, although the frequency of extended anteroseptal infarction was higher in patients undergoing the Dor procedure. Postoperative echocardiographic findings showed significant improvements in left ventricular function in both groups, in terms of end-diastolic and end-systolic dimensions and ejection fraction. Left ventricular aneurysmectomy significantly improved the clinical status and hemodynamic parameters of symptomatic patients. The choice of surgical technique depends on the extent of the scar segment, especially the presence of an anteroseptal scarred area. The Dor procedure is more suitable for restoring normal left ventricular geometry in patients with extensive septal infarction.
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http://dx.doi.org/10.1177/0218492309348636DOI Listing
October 2009

Mechanical aortic valve replacement in children and adolescents after previous repair of congenital heart disease.

Artif Organs 2009 Nov 10;33(11):915-21. Epub 2009 Oct 10.

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Göttingen, Germany.

Due to improved outcome after surgery for congenital heart defects, children, adolescents, and grown-ups with congenital heart defects become an increasing population. In order to evaluate operative risk and early outcome after mechanical aortic valve replacement (AVR) in this population, we reviewed patients who underwent previous repair of congenital heart defects. Between July 2002 and November 2008, 15 (10 male and 5 female) consecutive patients (mean age 14.5 +/- 10.5 years) underwent mechanical AVR. Hemodynamic indications for AVR were aortic stenosis in four (27%), aortic insufficiency in eight (53%), and mixed disease in three (20%) after previous repair of congenital heart defects. All patients had undergone one or more previous cardiovascular operations due to any congenital heart disease. Concomitant cardiac procedures were performed in all of them. In addition to AVR, in two patients, a mitral valve exchange was performed. One patient received a right ventricle-pulmonary artery conduit replacement as concomitant procedure. The mean size of implanted valves was 23 mm (range 17-29 mm). There were neither early deaths nor late mortality until December 2008. Reoperations were necessary in five (33%) and included implantation of a permanent pacemaker due to complete atrioventricular block in two (15%), mitral valve replacement with a mechanical prosthesis due to moderate to severe mitral regurgitation in one (7%), aortocoronary bypass grafting due to stenosis of a coronary artery in one (7%), and in one (7%), a redo subaortic stenosis resection was performed because of a secondary subaortic stenosis. At the latest clinical evaluation, all patients were in good clinical condition without a pathological increased gradient across the aortic valve prosthesis or paravalvular leakage in echocardiography. Mechanical AVR has excellent results in patients after previous repair of congenital heart defects in childhood, even in combination with complex concomitant procedures. Previous operations do not significantly affect postoperative outcome.
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http://dx.doi.org/10.1111/j.1525-1594.2009.00886.xDOI Listing
November 2009

Hemodynamic changes in a model of chronic heart failure induced by multiple sequential coronary microembolization in sheep.

Artif Organs 2009 Nov 10;33(11):947-52. Epub 2009 Oct 10.

Department of Thoracic, Cardiac and Vascular Surgery, University of Goettingen, Goettingen, Germany.

Although a large variety of animal models for acute ischemia and acute heart failure exist, valuable models for studies on the effect of ventricular assist devices in chronic heart failure are scarce. We established a stable and reproducible animal model of chronic heart failure in sheep and aimed to investigate the hemodynamic changes of this animal model of chronic heart failure in sheep. In five sheep (n = 5, 77 +/- 2 kg), chronic heart failure was induced under fluoroscopic guidance by multiple sequential microembolization through bolus injection of polysterol microspheres (90 microm, n = 25.000) into the left main coronary artery. Coronary microembolization (CME) was repeated up to three times in 2 to 3-week intervals until animals started to develop stable signs of heart failure. During each operation, hemodynamic monitoring was performed through implantation of central venous catheter (central venous pressure [CVP]), arterial pressure line (mean arterial pressure [MAP]), implantation of a right heart catheter {Swan-Ganz catheter (mean pulmonary arterial pressure [PAP mean])}, pulmonary capillary wedge pressure (PCWP), and cardiac output [CO]) as well as pre- and postoperative clinical investigations. All animals were followed for 3 months after first microembolization and then sacrificed for histological examination. All animals developed clinical signs of heart failure as indicated by increased heart rate (HR) at rest (68 +/- 4 bpm [base] to 93 +/- 5 bpm [3 mo][P < 0.05]), increased respiratory rate (RR) at rest (28 +/- 5 [base] to 38 +/- 7 [3 mo][P < 0.05]), and increased body weight 77 +/- 2 kg to 81 +/- 2 kg (P < 0.05) due to pleural effusion, peripheral edema, and ascites. Hemodynamic signs of heart failure were revealed as indicated by increase of HR, RR, CVP, PAP, and PCWP as well as a decrease of CO, stroke volume, and MAP 3 months after the first CME. Multiple sequential intracoronary microembolization can effectively induce myocardial dysfunction with clinical and hemodynamic signs of chronic ischemic cardiomyopathy. The present model may be suitable in experimental work on heart failure and left ventricular assist devices, for example, for studying the impact of mechanical unloading, mechanisms of recovery, and reverse remodeling.
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http://dx.doi.org/10.1111/j.1525-1594.2009.00921.xDOI Listing
November 2009

The eNOS 786C/T polymorphism in cardiac surgical patients with cardiopulmonary bypass is associated with renal dysfunction.

Eur J Cardiothorac Surg 2009 Oct 11;36(4):651-6. Epub 2009 Jun 11.

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Robert-Koch-Strasse 40, 37099 Göttingen, Germany.

Objective: Renal dysfunction is one of the most serious complications following cardiac surgery with cardiopulmonary bypass. The causes of renal dysfunction following cardiac surgery are poorly understood. We hypothesised that T-786C endothelial NO synthase (eNOS) polymorphism may lead to an increase in the occurrence of postoperative renal dysfunction following cardiac surgery with cardiopulmonary bypass.

Methods: A total of 497 patients undergoing cardiac surgery with cardiopulmonary bypass were included in the study. The T-786C eNOS polymorphism was detected by a polymerase chain reaction. The patients were grouped on the basis of whether they were homozygous or heterozygous for the C allele (TC+CC; n=289) or only homozygous for the T allele (TT; n=208).

Results: No significance was demonstrated in the preoperative risk factors, with the exclusion of smoking habits (p=0.04) for the C-allele carrier. The administration of anti-lipid agents (p=0.01) and anti-arrhythmics (p=0.01) was significantly lower in the TC/CC group. The TC+CC genotype group had a significantly greater decrease in creatine clearance (p=0.024), the lowest creatine clearance (p=0.004) and more C-allele carriers received acute renal replacement therapy (p=0.04). The usage of norepinephrine (p=0.02) and dobutamine (p=0.02) was significantly higher in C-allele carriers. In the TC+CC genotype group, cross-clamp time (p=0.02) and administration of red cell transfusion (p=0.04) achieved statistically significant difference. The overall in-hospital mortality rate was 8.2% for all patients and was not significant between genotypes.

Conclusions: The present findings support the hypothesis that the T-786C eNOS polymorphism may play a role in the development of renal dysfunction and increase the occurrence of renal replacement therapy following cardiac surgery with cardiopulmonary bypass. This polymorphism may be useful in stratifying the risk for the development of postoperative renal dysfunction.
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http://dx.doi.org/10.1016/j.ejcts.2009.04.049DOI Listing
October 2009

Experiences with surgical treatment of ventricle septal defect as a post infarction complication.

J Cardiothorac Surg 2009 Jan 6;4. Epub 2009 Jan 6.

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Göttingen, Germany.

Background: Complications of acute myocardial infarction (AMI) with mechanical defects are associated with poor prognosis. Surgical intervention is indicated for a majority of these patients. The goal of surgical intervention is to improve the systolic cardiac function and to achieve a hemodynamic stability. In this present study we reviewed the outcome of patients with post infarction ventricular septal defect (PVSD) who underwent cardiac surgery.

Methods: We analysed retrospectively the hospital records of 41 patients, whose ages range from 48 to 81, and underwent a surgical treatment between 1990 and 2005 because of PVSD.

Results: In 22 patients concomitant coronary artery bypass grafting (CAGB) was performed. In 15 patients a residual shunt was found, this required re-op in seven of them. The time interval from infarct to rupture was 8.7 days and from rupture to surgery was 23.1 days. Hospital mortality in PVSD group was 32%. The mortality of urgent repair within 3 days of intractable cardiogenic shock was 100%. The mortality of patients with an anterior VSD and a posterior VSD was 29.6% vs 42.8%, respectively. All patients who underwent the surgical repair later than day 36 survived.

Conclusion: Surgical intervention is indicated for a majority of patients with mechanical complications. Cardiogenic shock remains the most important factor that affects the early results. The surgical repair of PVSD should be performed 4-5 weeks after AMI. To improve surgical outcome and hemodynamics the choice of surgical technique and surgical timing as well as preoperative management should be tailored for each patient individually.
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http://dx.doi.org/10.1186/1749-8090-4-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631454PMC
January 2009

Acute aortic dissection type A discloses Corpus alienum.

J Cardiothorac Surg 2009 Jan 2;4. Epub 2009 Jan 2.

Department of Thoracic and Cardiovascular Surgery, University of Göttingen, Germany.

We report an unusual case of an aortic type A dissection with a corpus alienum which compresses the right ventricle. The patient successfully underwent an aortic root replacement in deep hypothermia with re-implantation of the coronary arteries using a modified Bentall procedure and the resection of the corpus alienum. Intraoperative finding reveals 3 greatly adhered gauze compresses, which were most likely forgotten in the operation 34 years ago.
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http://dx.doi.org/10.1186/1749-8090-4-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628653PMC
January 2009

Impact of endothelin-1 Lys198Asn polymorphism on coronary artery disease and endorgan damage in hypertensives.

Coron Artery Dis 2008 Nov;19(7):429-34

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Germany.

Objective: Endothelin is the most potent endogenous vasoconstrictor and is involved in several vascular disorders such as arterial hypertension. Its intense interaction with other vasoactive hormone systems revealed the consideration about the endothelin gene as an interesting candidate for influencing the development of essential hypertension and hypertensive endorgan damage. The purpose of this study was to investigate the role of endothelin-1 Lys198Asn polymorphism in patients with severe arterial hypertension as well as associated endorgan damages.

Methods: In 400 hypertensive patients and 150 normotensive controls we examined the endothelin-1 Lys198Asn polymorphism by DNA sequencing and patients were divided according to their genotype (GG, GT, and TT). Moreover, the frequency of endothelin-1 Lys198Asn polymorphism was investigated with respect to the prevalence of several actual or historical endorgan damages (renal disorder, coronary artery disease, vascular events, vascular damage, and congestive heart failure) in hypertensive patients.

Results: Genotype distribution for endothelin-1 Lys198Asn polymorphism was 57.3% (GG), 41.3% (GT), and 1.43% (TT) in normotensive individuals; and in hypertensive individuals was 54.75% (GG), 43% (GT) and 2.25% (TT). Genotype distribution was unaffected in patients with severe hypertension, renal disorder, vascular events, vascular damage, and congestive heart failure. We, however, found a significant difference in hypertensive individuals with coronary artery disease and TT genotype (P=0.004).

Conclusion: Homozygous TT carrier contributes to a higher prevalence of coronary artery disease, especially for three-vessel disease in hypertensive individuals. Thus, the polymorphism at position 198 could serve as a possibility to differentiate high-risk subgroups in the heterogeneous population of hypertensive patients.
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http://dx.doi.org/10.1097/MCA.0b013e32830936e5DOI Listing
November 2008

Accelerated intimal hyperplasia in aortocoronary internal mammary vein grafts in minipigs.

J Cardiothorac Surg 2008 Apr 29;3:20. Epub 2008 Apr 29.

Department of Thoracic Cardiovascular Surgery, University of Göttingen, Germany.

Background: More than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is the initial critical step in the progression toward occlusion. Internal mammary veins, which are physiologically prone to less hydrostatic pressure, may undergo an accelerated progression to intimal hyperplasia and thus be suitable for investigation of the mechanisms of aortocoronary vein graft disease.

Methods: Six minipigs underwent aortocoronary bypass grafting using standard cardiopulmonary bypass and cardioplegic arrest. Mammary vein were grafted in a reversed manner from ascending aorta to left anterior descending coronary artery (LAD). The proximal LAD was ligated, rendering the anterior left ventricle vein graft-dependent. Minipigs were killed after 4 weeks, and vein grafts were harvested. Histological and immunohistological investigation were performed with respect to morphometric analysis, endothelial damage/dysfunction (v-Willebrand-factor (vWF)), smooth muscle cells (alpha-smooth actin) and proliferation rate (proliferation marker Ki 67).

Results: Mean intimal area of vein grafts was increased compared to ungrafted mammary veins. Intimal hyperplasia in vein grafts was characterized by massive accumulation of smooth muscle cells with a high proliferation rate and endothelial perturbation. Significant (p = 0.001) intimal hyperplasia of the grafted mammary vein compared to the ungrafted mammary vein was found. These changes were absent in ungrafted mammary veins.

Conclusion: The present study demonstrates a pig model of aortocoronary vein graft intimal hyperplasia which is characterized by an accelerated progression within internal mammary veins. The model is suitable to investigate the pathophysiology of aortocoronary vein graft intimal hyperplasia as well as therapeutic approaches.
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http://dx.doi.org/10.1186/1749-8090-3-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386461PMC
April 2008