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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2008.12.054 Byline: Katarzyna Januszewska, Edward Malec, Gerd Juchem, Ingo Kaczmarek, Ralf Sodian, Peter Uberfuhr, Bruno Reichart Abbreviations: CMV, cytomegalovirus; CPB, cardiopulmonary bypass; HLTX, heart-lung transplantation; MAPCA, major aortopulmonary collateral artery; PA+VSD, pulmonary atresia with ventricular septal defect Abstract: Heart-lung transplantation for patients with pulmonary atresia and ventricular septal defect is challenging. The aim of the study was to present a single-center experience with heart-lung transplantation in this difficult group of patients. Author Affiliation: Department of Cardiac Surgery, Klinikum Grosshadern, Ludwig Maximilians University, Munich, Germany Article History: Received 12 September 2008; Revised 18 November 2008; Accepted 25 December 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2008.05.041 Byline: Calin Vicol, Diana Kellerer, Paraskevi Petrakopoulou, Ingo Kaczmarek, Peter Lamm, Bruno Reichart Abbreviations: AF, atrial fibrillation; ECG, electrocardiogram; NYHA, New York Heart Association Abstract: Microwave ablation has been reported as efficient for the surgical treatment of long-standing atrial fibrillation. However, the influence of ablation lesions on long-term results is not known. Author Affiliation: Department of Cardiac Surgery, GroAhadern Medical Center, Ludwig Maximilian University Munich, Munich, Germany Article History: Received 25 October 2007; Revised 22 February 2008; Accepted 9 May 2008

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.11.017 Byline: Bettina Jungwirth (a), G. Burkhard Mackensen (a)(b), Manfred Blobner (a), Frauke Neff (d), Bruno Reichart (c), Eberhard F. Kochs (a), Georg Nollert (c) Abbreviations: CPB, cardiopulmonary bypass; DHCA, deep hypothermic circulatory arrest; MAP, mean arterial blood pressure; mHBT, modified hole board test Abstract: Neurodevelopmental impairments after repair of congenital heart disease with cardiopulmonary bypass and deep hypothermic circulatory arrest continue to affect the lives of children. To date, the preclinical investigation of cerebral injury mechanisms related to deep hypothermic circulatory arrest has been restricted to expensive, personnel-demanding, and cumbersome large-animal models without validated neuropsychologic assessment. We aimed to establish a rodent recovery model of deep hypothermic circulatory arrest to overcome these disadvantages. Author Affiliation: (a) Klinik fur Anaesthesiologie, Technische Universitat Munchen, Klinikum rechts der Isar, Munich, Germany (d) Institut fur Allgemeine Pathologie und Pathologische Anatomie, Technische Universitat Munchen, Klinikum rechts der Isar, Munich, Germany (b) Department of Anesthesiology, Duke University Medical Center, Durham, NC (c) Herzchirurgische Klinik im Klinikum GroAhadern, Ludwigs-Maximilian Universitat Munchen, Munich, Germany. Article History: Received 29 July 2005; Revised 27 October 2005; Accepted 8 November 2005 Article Note: (footnote) This work was supported in part by the Deutsche Forschungsgemeinschaft (NO 344/3-1).

Byline: Hermann Reichenspurner (a), Jose A. Navia (b), Gerald Berry (c), Robert C. Robbins (c), Denise Barbut (d), Jeffrey P. Gold (d), Bruno Reichart (a) Abstract: Objective: Particulate embolization is associated with neurologic morbidity after cardiac surgery. Crossclamp manipulation has been identified as the single most significant cause of particulate emboli release during cardiac surgery. A new intra-aortic filtration method has been assessed with regard to its safety and its ability to capture particulate emboli before they enter the central circulation. Methods: Patients undergoing cardiac surgery with cardiopulmonary bypass through standard median sternotomy were selected for emboli management by means of intra-aortic filtration. A novel intra-aortic filter device was inserted through a modified 24F arterial cannula immediately before releasing the crossclamp in 77 patients. Filters remained in the aorta until cardiopulmonary bypass was discontinued and the heart was fully ejecting. The procedure was assessed for facility, safety, and effect on routine cardiopulmonary bypass operation and function. Results: The insertion and removal of the intra-aortic filter were safe, easy, and uneventful in most patients. Patient hemodynamics and bypass flow rates remained normal throughout the filter dwell period. No strokes or gross neurologic defects were noted. Electron microscopic analysis of 12 filters revealed an insignificant degree of platelet adhesion on filter surfaces. Histology samples (n = 44) were examined, and 66% (n = 29) showed evidence of atheromatous material, 36% (n = 16) with platelet-fibrin, 25% (n = 11) with true thrombus and/or blood clot, 7% (n = 3) with normal vessel wall, and 2% (n = 1) with aggregates of cholesterol or grumous portion of atheromatous plaque. Conclusion: The intra-aortic filter can be safely deployed and captures particulate emboli, the predominant origin of which is atheromatous. The beneficial effects of this device on neurologic outcomes have yet to be determined. (J Thorac Cardiovasc Surg 2000;119:233-41) Author Affiliation: (a) University Hospital Munich-Grosshadern, Munich, Germany (b) Italian Hospital of Buenos Aires, Buenos Aires, Argentina (c) Stanford University Medical Center, Stanford, Calif (d) Cornell University Medical College, New York, NY. Article History: Received 22 April 1999; Revised 7 July 1999; Revised 14 October 1999; Accepted 14 October 1999 Article Note: (footnote) [star] Drs Reichenspurner, Navia, Robbins, Gold, and Barbut serve as clinical consultants to Embol-X, Inc., [star][star] Read at the Seventy-ninth Annual Meeting of The American Association for Thoracic Surgery, New Orleans, La, April 18-21, 1999., a Address for reprints: Hermann Reichenspurner, MD, PhD, Department of Cardiac Surgery, University Hospital Grosshadern, Marchioninistrasse 15, Munich, Germany D-81377 (E-mail: hcr@hch.med.uni-muenchen.de) ., aa 0022-5223/2000 $12.00 + 0 12/6/103733

Study objective: Arterial thermal dye dilution (TDDart) with the COLD system (Munich, Germany) allows measurement of cardiac index (CI), partial blood volumes, lung water, and liver function. The aim of [...]

Byline: Herbert Vetter, Andreas Nerlich, Ulrich Welsch, Kangxiong Liao, Andreas Dagge, Christine Strenkert, Bruno Reichart Abstract: Mitral valves, including the papillary muscles, were harvested from freshly slaughtered sheep and implanted in 10 recipient growing sheep. A strip of ovine pericardium was used to reinforce the anulus and a patch of expanded polytetrafluoroethylene was used to cover the donor papillary muscle. In four valves the natural chordae tendineae at the anterior cusp were supported by two pairs of 5-0 expanded polytetrafluoroethylene sutures. At the beginning of the experiment two animals died early of valve incompetence. Another animal had to be put to death because of paraplegia after extracorporeal circulation and one died on postoperative day 41 of endocarditis. Six sheep were electively put to death, five after 153 [+ or -] 8 days and one after 43 days. At the time of follow-up, a complete hemodynamic study including echocardiography and stress testing was performed. Heart rate at rest was 91 [+ or -] 14 beats/min, left ventricular systolic pressure 96 [+ or -] 20 mm Hg, left ventricular end-diastolic pressure 11 [+ or -] 5 mm Hg, cardiac output 2.04 [+ or -] 0.40 L/min, and the mean transvalvular pressure gradient was 4.9 [+ or -] 2.8 mm Hg as measured by cardiac catheterization. Echocardiography showed excellent movement of all valve components. However, minor regurgitation was evident in one case. Gross morphologic characteristics showed good healing at the anulus and host papillary muscle; in one case there was a rupture of one small first-order chorda. On radiography no signs of calcification were evident. Light microscopy revealed minor to moderate collagen degeneration in all valve components. However, on electron microscopy the presence of numerous fibroblasts within the long-term implants indicated the biosynthesis of new collagen. In summary, allograft mitral valve replacement seems to be a promising procedure if the chordae tendineae are reinforced by expanded polytetrafluoroethylene sutures. (J THORAC CARDIOVASC SURG 1996;111:595-604) Article History: Received 28 December 1994; Accepted 31 May 1995 Article Note: (footnote) [star] From the Departments of Cardiac Surgery,a Pathology,b and Anatomy,c Ludwig-Maximilians University, Munich, Germany, and the Cardiothoracic Research Laboratory,d The Albert Einstein College of Medicine of Yeshiva University, Bronx, N.Y., [star][star] Supported by a grant from the Deutsche Stiftung fur Herzforschung, Frankfurt, Germany., a Address for reprints: Herbert Vetter, MD, Department of Cardiac Surgery, University of Munich, Herzklinik Augustinum, Wolkerweg 16, 81375 Munich, Germany., aa 0022-5223/96 $5.00 + 0, acents 12/1/66607

Patients who undergo heart surgery may require extracorporeal circulation, a method of oxygenating the blood in which venous blood is diverted outside the body to a heart-lung machine for oxygenation and then returned to the body. Patients who undergo this surgery receive a massive insult to their immune system as a result of the combination of tissue injury, blood transfusions, and inflammation-like state affecting the entire body from the contact between blood and foreign material. These patients have an increased susceptibility to infection. A prospective study was undertaken of 60 patients who were undergoing open heart surgery. Combination therapy with thymopentin and indomethacin was aimed at restoring the patient's immune potential. Immunologic studies were performed prior to surgery. Twenty patients received indomethacin only; 20 received both indomethacin and thymopentin; and 20 patients represented a control group, receiving no immunologic treatment. Significant restoration of immune suppression was achieved in the group that received both indomethacin and thymopentin. Patients receiving combination therapy showed restoration of impaired expression of T-cell receptors, proliferation of lymphocytes, and synthesis of interleukin-2 (a cytokine that stimulates the growth of T-cells). It is concluded that combination therapy with indomethacin and thymopentin is more effective than indomethacin alone in preserving and/or restoring immune potential as defined as intact monocyte T-cell interaction. This approach may be useful in maintaining normal immune system defenses in injured or traumatized patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2007.12.072 Byline: Andres Beiras-Fernandez (a), Patrick Moehnle (b), Ingo Kaczmarek (a), Florian Weis (b), Bruno Reichart (a), Calin Vicol (a) Author Affiliation: (a) Department of Cardiac Surgery, Grosshadern University Hospital, Munich, Germany (b) Department of Anesthesiology, Grosshadern University Hospital, Munich, Germany Article History: Received 4 November 2007; Revised 20 December 2007; Accepted 22 December 2007

Xenotransplantation offers the potential to meet the critical need for heart and lung transplantation presently constrained by the current human donor organ supply. Much was learned over the past decades regarding gene editing to prevent the immune activation and inflammation that cause early organ injury, and strategies for maintenance immunosuppression to promote longer-term xenograft survival. However, many scientific questions remain regarding further requirements for genetic modification of donor organs, appropriate contexts for xenotransplantation research (including non-human primates, recently deceased humans, and living human recipients), and risk of xenozoonotic disease transmission. Related ethical questions include appropriate selection of clinical trial participants, challenges with obtaining informed consent, animal rights and welfare considerations, and cost. Research involving recently deceased humans has also emerged as a potential novel way to understand how xeno-organs will impact the human body. Clinical xenotransplantation and research involving decedents also raise ethical questions, and will require consensus regarding regulatory oversight and protocol review. These considerations and the related opportunities for xenotransplantation research were discussed in a workshop sponsored by the National Heart, Lung, and Blood Institute, and are summarized in this meeting report.

Synthetic vascular graft material does not perform as well as naturally endothelialized grafts. The innermost coat (tunica intima) of a blood vessel consists of a surface layer of endothelium, surrounded by a layer of connective tissue, and then an elastic layer. A method has been needed to create an endothelial lining for vascular prostheses. Recently, a quick and reliable culture technique was developed and shown to provide enough endothelial cells to line cardiovascular (heart vessel) grafts. This procedure involves detaching the endothelial layer of a small segment of a blood vessel using a collagenase solution. It was found that the best vessel from which to harvest endothelial cells was the external jugular vein in the neck, a nonessential vessel which can be easily accessed. Use of a microgrid technique allowed daily assessment of the amount of endothelium available to be sure there would be a sufficient quantity to line the chosen prosthesis. This technique was applied to 124 cultures from baboons and 13 cultures from humans; there was no difference in endothelial cell growth behavior between the two groups. It was found that, by applying this technique, sufficient endothelial cells were obtained after 26.2 days to line long vascular prostheses, such as might be used for aortocoronary bypass grafting. (Consumer Summary produced by Reliance Medical Information, Inc.)

Byline: Peter Lamm, Gerd Juchem, Peter Weyrich c, Stephan Nees, Bruno Reichart Abstract: J Thorac Cardiovasc Surg 1999;117:1217-9 Author Affiliation: Munich, Germany From the Departments of Cardiac Surgery.sup.a and Anesthesiology,.sup.b Klinikum GroAhadern, and the Department of Physiology,.sup.c Ludwig-Maximilians-Universitat Munchen, Munich, Germany Article History: Received 4 December 1998; Accepted 20 January 1999 Article Note: (footnote) [star] Address for reprints: Peter Lamm, MD, Herzklinik der Universitat Munchen am Augustinum, Wolkerweg 16, 81375 Munich, Germany., [star][star] 12/54/97380

Heart transplantation is the only cure for patients with terminal cardiac failure, but the supply of allogeneic donor organs falls far short of the clinical need1–3. Xenotransplantation of genetically modified pig hearts has been discussed as a potential alternative4. Genetically multi-modified pig hearts that lack galactose-α1,3-galactose epitopes (α1,3-galactosyltransferase knockout) and express a human membrane cofactor protein (CD46) and human thrombomodulin have survived for up to 945 days after heterotopic abdominal transplantation in baboons5. This model demonstrated long-term acceptance of discordant xenografts with safe immunosuppression but did not predict their life-supporting function. Despite 25 years of extensive research, the maximum survival of a baboon after heart replacement with a porcine xenograft was only 57 days and this was achieved, to our knowledge, only once6. Here we show that α1,3-galactosyltransferase-knockout pig hearts that express human CD46 and thrombomodulin require non-ischaemic preservation with continuous perfusion and control of post-transplantation growth to ensure long-term orthotopic function of the xenograft in baboons, the most stringent preclinical xenotransplantation model. Consistent life-supporting function of xenografted hearts for up to 195 days is a milestone on the way to clinical cardiac xenotransplantation7.

Study objectives: A transpulmonary thermal-dye dilution (TDD) technique using cold indocyanine green dye was utilized to monitor cardiac index (CI) and preload in patients after heart transplantation. Preload, determined by [...]

Influence of Cardiac Allograft Vasculopathy Study objective: The reduced exercise capacity observed in most patients after heart transplantation may be due to treatment with immunosuppressive drugs, deconditioning, cardiac denervation, and [...]

The 2-month-survival of a terminally ill patient who received a genetically modified pig heart has demonstrated that cardiac xenotransplantation could provide a therapeutic option for patients who cannot receive a human organ. Genetic engineering to overcome transplant rejection mechanisms, coagulation dysregulation and overgrowth of xeno-hearts has been the key to this success. The concept of exogenesis – the replacement of specific cellular populations and tissue structures of a pig heart with human cells – is a promising extension of xenotransplantation because it could further reduce immunological and physiological obstacles. Additionally, in the aim of preventing the need for heart transplant, tailored pig models mimicking monogenic cardiac disorders have been developed to test new cellular and molecular therapies. Thus, genetically engineered pigs provide a powerful platform for xenogeneic, exogenic and endogenic restoration of cardiac function.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2009.05.019 Byline: Michael Schmoeckel (a), Peter Boekstegers (b), Konstantin Nikolaou (c), Bruno Reichart (a) Author Affiliation: (a) Department of Cardiac Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany (b) Department of Internal Medicine I, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany (c) Department of Radiology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany Article History: Received 4 May 2009; Accepted 17 May 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2005.04.013 Byline: Helmut Mair, Ingo Kaczmarek, Martin Oberhoffer, Jan Groetzner, Sabine Daebritz, Bruno Reichart Author Affiliation: Department of Cardiac Surgery, University of Munich, Munich, Germany Article History: Received 24 March 2005; Accepted 11 April 2005

Byline: Hermann Reichenspurner, Dieter H. Boehm, Helmut Gulbins, Christian Detter, Ralph Damiano, Michael Mack, Bruno Reichart Author Affiliation: Department of Cardiac Surgery, University Hospital Grosshadern, Munich, Germany Article History: Received 23 June 1999; Accepted 27 July 1999 Article Note: (footnote) [star] Address for reprints: Hermann Reichenspurner, MD, PhD, Department of Cardiac Surgery, University Hospital Grosshadern, Marchioninistr 15, D-81377 Munich, Germany (E-mail: hcr@hch.med.uni-muenchen.de )., [star][star] J Thorac Cardiovasc Surg 1999;118:960-1, a 0022-5223/99 $8.00 + 0 12/54/101738

Among other mismatches between human and pig, incompatibilities in the blood coagulation systems hamper the xenotransplantation of vascularized organs. The provision of the porcine endothelium with human thrombomodulin (hTM) is hypothesized to overcome the impaired activation of protein C by a heterodimer consisting of human thrombin and porcine TM.

The aim of the study was to compare the behavior of seeded cells on synthetic and natural aortic valve scaffolds during a low-flow conditioning period. Polyurethane (group A) and aortic homograft valves (group B) were consecutively seeded with human fibroblasts (FB), and endothelial cells (EC) using a rotating seeding device. Each seeding procedure was followed by an exposure to low pulsatile flow in a dynamic bioreactor for 5 days. For further analysis, samples were taken before and after conditioning. Scanning electron microscopy showed confluent cell layers in both groups. Immunohistochemical analysis showed the presence of EC and FB before and after conditioning as well as the establishment of an extracellular matrix (ECM) during conditioning. A higher expression of ECM was observed on the scaffolds’ inner surface. Real-time polymerase chain reaction showed higher inflammatory response during the conditioning of homografts. Endothelialization caused a decrease in inflammatory gene expression. The efficient colonization, the establishment of an ECM, and the comparable inflammatory cell reaction to the scaffolds in both groups proved the biocompatibility of the synthetic scaffold. The newly developed bioreactor permits conditioning and cell adaption to shear stress. Therefore, polyurethane valve scaffolds may offer a new option for aortic valve replacement.

Long-term results of prospective randomized trials comparing triple immunosuppressive strategies combining tacrolimus (TAC) or cyclosporine A (CsA) with mycophenolate mofetil (MMF) and steroids after heart transplantation (HTX) are rarely published. Therefore, we collected long-term follow-up data of an intervention cohort 10 years after randomization.

Cardiac allograft vasculopathy (CAV) still limits survival after heart transplantation. Currently available noninvasive tests are of inferior value to detect CAV, and thus invasive coronary angiography (ICA) is frequently performed. Cardiac dual-source computed tomography calcium scoring (DSCTCS) offers the possibility to detect coronary calcifications, which might serve as a noninvasive marker of CAV. This study sought to evaluate its clinical feasibility.

Background For short-term ventricular and pulmonary support the extracorporeal membrane oxygenation (ECMO) system using the Bio-Medicus centrifugal pump (Medtronic®, Minneapolis, MN, USA) was applied in 108 patients with cardiac low-output.Methods From December 1996 to July 2006 the ECMO was implanted in 108 patients (73 adult, mean age: 49.3±18.0 yrs and 35 children, mean age: 1.3 ± 2.7 yrs) with mostly postcardiotomy cardiac low output. The surgical procedures included congenital heart surgery (n=35), heart transplantation (HTx) (n=21), coronary artery bypass operation (CABG) and/or valvular operation (n=33), other operations (n=6) and 13 patients with ECMO support for bridge to recovery.Results The mean supporting time was 5.1±5.6 days. Overall, 30-day-survival was 40.2%. Best survival rates were seen after congenital heart surgery (24/35, 65.7%) and after HTx (9/21, 42.9%); the worst rates were in the group of CABG and/or valvular operations (5/33, 15.2%), only ECMO support (3/13, 23.1%) and other operations (1/6, 16.7%). Fifty-four patients died while supported by ECMO, 15 were weaned from ECMO but died in hospital, 39 patients were weaned and survived. Causes of death were multi-organ failure (40.6%), bleeding (23.2%), persistent cardiac low output (21.7%), thrombembolic events (8.7%), and graft failure (5.8%). Markers for adverse outcome were identified as older age, high body weight, increased AST/GOT levels, and lower thrombocyte count in adults; and as higher levels of serum creatinine in pediatric patients.Conclusions ECMO support showed best results in pediatric patients after congenital heart surgery and in patients after HTx in contrast to multimorbid, older patients with often irreversible myocardial damage.

Currently, one approach to tissue engineering has been to develop in vitroconditions to fabricate functional cardiovascular structures such as heart valves before final implantation. In vivoconditions are simulated using a bioreactor system that supplies cells with oxygen and culture media while providing mechanical stimulation to promote tissue maturation. In our experiment, we developed a novel combined optical monitoring and conditioning device. The entire system is made of acrylic glass and is completely transparent. The bioreactor is connected to an air-driven respirator pump, and the cell culture medium continuously circulates through a closed-loop system. By adjusting stroke volume, stroke rate, and inspiration/expiration time of the ventilator, the system allows various pulsatile flows and different levels of pressure. Our optical monitoring and conditioning device provides a sterile environment, mechanical stimulation, and optical monitoring for the in vitromaturation of a tissue-engineered heart valve. With the camera module attached, tissue-engineered valves can be observed during the entire in vitrophase. This setting helps to find the optimal dynamic conditions for tissue-engineered heart valves to mature by adjusting flow and pressure conditions to provide physiological opening and closing behavior of the heart valve construct.

The ventricular assist device (VAD) is a life-saving option for patients in heart failure refractory for conventional therapy. The aim of study was to assess the influence of VAD on heart transplantation (HT) outcome in children <16 years. Between October 1988 and August 2008, 73 children underwent HT: Group 1 (n=9) who received VAD as bridge to HT (left ventricular - 4, biventricular - 5), and Group 2 (n=64), without previous VAD. Diagnoses included cardiomyopathy (n=50 (68.5%)) and congenital heart defects (n=23 (31.5%)). Retrospective analysis of perioperative and long-term follow-up data was performed. The mean follow-up was 7.22+/-4.7 years. The diagnosis of cardiomyopathy appeared more often in Group 1 (P=0.074), but the difference was not significant. The two groups did not differ with respect to age (P=0.123) and weight (P=0.183). Mortality in long follow-up was: 11.1% (n=1) in Group 1 and 14.1% (n=9) in Group 2 (P=0.782). Analysis of preoperative end-organs function did not reveal significant differences between groups. There was also no significant differences with respect to waiting time for transplant (P=0.948), postoperative ventilatory support time (P=0.677), duration of hospital stay (P=0.711) and incidence of acute rejection episodes (P=0.156). VAD used as a bridge for HT in children does not negatively influence the outcome.

Calcineurin-inhibitor-(CNI)-induced renal failure is one major cause of morbidity in cardiac transplantation (HTx). In this prospective, randomized, multicenter trial, the impact of immunosuppressive conversion toward CNI-free (mycophenolate mofetil MMF and sirolimus) or a CNI-reduced immunosuppressive regimen on renal function, efficacy, and safety was evaluated.

Current techniques to resolve heart valve defects involve the use of prosthetic and bioprosthetic materials. These materials lack the potential to grow and are not ideal, especially not for pediatric patients. Novel techniques like tissue engineering involve the use of biodegradable polymers coated with autologous myofibroblast and endothelial cells. We inspected morphological and marker gene expression differences between cells harvested from the saphenous vein, or from veins and arteries of the umbilical cord, and the cells they are designed to replace: the interstitial and endothelial cells of the pulmonary heart valve. We assessed the extent to which the endothelial cells from the inspected sources in vitroresemble endothelial cells of human pulmonary heart valves, and we found that myofibroblast cells, respective of their source, in vitrodiffer from the interstitial cells from human pulmonary heart valves regarding collagen and smooth muscle -actin. Therefore we conclude that the cells isolated from the saphenous veins, or from veins and arteries of the umbilical cord might be feasible cell sources for tissue engineering of heart valve for the pulmonary position.

Pharmacokinetics of mycophenolate mofetil (MMF) show large interindividual variability. Concentration-controlled dosing of MMF based on routine therapeutic drug monitoring, which requires area under the concentration-time curve (mycophenolic acid [MPA]-AUC0-12h) determinations, is uncommon. Dose adjustments are based on predose concentrations (C0h) or side effects. The aim of this study was to compare C0hwith postdose concentrations (C0.5h-C12h) and to develop practical methods for estimation of MPA-AUCs on the basis of a limited sampling strategy (LSS) in heart transplant recipients under MMF and tacrolimus maintenance immunosuppression. Full MPA-AUC0-12hprofiles were generated by high-performance liquid chromatography in 28 patients. Statistical analysis for MPA-AUC0-12hwas performed by a case resampling bootstrap method. Bland and Altmann analysis was performed to test agreement between “predicted AUC” and “measured AUC.” C1hprovided the highest coefficient of determination (r2= 0.57) among the concentrations determined during the 12-hour interval, which were correlated with AUC. All other MPA levels were better surrogates of the MPA-AUC0-12hwhen compared with C0h(r2= 0.14). The best estimation of MPA-AUC0-12hwas achieved with four sampling points with the algorithm AUC = 1.25*C1h+ 5.29*C4h+ 2.90*C8h+ 3.61*C10h(r2= 0.95). Since LSS with four time points appeared unpractical, the authors prefer models with three or two points. To optimize practicability, LSS with sample points within the first 2 hours were evaluated resulting in the algorithms: AUC = 1.09*C0.5h+ 1.19*C1h+ 3.60*C2h(r2= 0.84) and AUC = 1.65*C0.5h+ 4.74*C2h(r2= 0.75) for three and two sample points, respectively. The results provide strong evidence for the use of either LSS or the use of time points other than C0hfor therapeutic drug monitoring of MMF. Using the algorithms for the estimation of MPA-AUC0-12hbased on LSS within the first 2 hours after MMF dosing may help to optimize treatment with MMF by individualization of dosing.

Coronary vasomotor dysfunction is a common finding in cardiac transplant recipients and is an early marker for the development of graft atherosclerosis. The present prospective study tested whether endothelial dysfunction independently predicts cardiovascular-related events and death after heart transplantation (HTx).

A definitive diagnosis of cardiac sarcoidosis relies on the results of endomyocardial biopsy. In this Case Study Greifet al. describe a patient whose biopsy was negative for sarcoidosis—leading to a diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Sarcoidosis was only revealed after the patient had progressed to end-stage heart failure and undergone cardiac transplantation several years later.

Solid organ xenograft rejection is associated with vascular injury resulting at least in part in platelet activation, and rejected xenografts invariably demonstrate intravascular thrombosis and interstitial hemorrhage. Complement activation plays a prominent role in platelet-endothelial interaction. We tested the effects of platelet GPIIb/IIIa inhibitor tirofiban during perfusion of hDAF pig hearts.

Bronchiolitis obliterans syndrome (BOS) is the major problem after lung and heart-lung transplantation (LTx/HLTx). Sirolimus (Sir) and Mycophenolate (MMF) showed a promising efficacy in the treatment of BOS in animal models. The first clinical experience in converting LTx/HLTx-recipients with BOS from calcineurin inhibitor-(CNI)-based immunosuppression to a Sir-MMF based immunosuppression is reported herein.

Bronchiolitis obliterans syndrome (BOS) is the limiting factor to long-term survival after lung transplantation. Previous studies suggested respiratory viral tract infections are associated with the development of BOS. To identify the impact of virus detection in bronchoalveolar lavage (BAL) fluid, we analyzed BAL samples from 87 consecutive lung transplant recipients for human herpesvirus (HHV)-6, Epstein-Barr virus, Herpes simplex virus 1/2, Cytomegalovirus, respiratory syncytical virus and adenovirus by PCR. Acute rejection, BOS and death were recorded for a mean follow-up time of 3.27 ± 0.47 years. Results of PCR analysis and other potential risk factors were entered into a Cox regression analysis of BOS predictors and death. Only acute rejection was a distinct risk factor for BOS of all stages, death and death from BOS. HHV-6 was detected in 20 patients. Univariate and multivariate analysis revealed that HHV-6 was associated with an increased risk to develop BOS ≥ stage 1 and death, separate from the risk attributable to acute rejection. Identification of HHV-6 DNA in BAL fluid is a potential risk factor for BOS. Our results warrant further studies to elucidate a possible causal link between HHV-6 and BOS.

The long-term outcome after heart transplantation (HTx) is essentially influenced by the occurrence and extent of cardiac allograft vasculopathy (CAV). Single photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) has been shown to be a useful and cost-effective non-invasive method in patients with known or suspected coronary artery disease, but its role in detecting CAV remains unclear.

The aim of this pilot study was to investigate whether de novocalcineurin-inhibitor-free immunosuppression after cardiac transplantation is efficacious and can prevent post-operative renalimpairment. Eight patients were treated by combining trough level adjusted sirolimus and mycophenolate mofetil; corticosteroids were given for the first 6 post-operative months only. Survival data, acute rejection episodes and adverse events with a special emphasis on renal impairment, myelosuppression, hypercholesterolemia, hypertriglyceridemia and infections, were recorded. With a follow-up of 3–12 months, patient survival was 100% and freedom from rejection 75%. The mean creatinine levels initially decreased and remained stable thereafter. A moderate myelosuppressive effect did not necessitate dose reduction of immunosuppressants, intermittently elevated cholesterol- and triglyceride levels decreased over time. Most frequent adverse events were pericardial effusions and peripheral edema. Complete abandonment of calcineurin inhibitor therapy by de novo use of the combination sirolimus/mycophenolate mofetil resultedin low rejection rate and avoidance of renal impairment, but should not be used without further evaluation of potential complications in a lager setting.

The aim of this pilot study was to investigate whether de novo calcineurin-inhibitor-free immunosuppression after cardiac transplantation is efficacious and can prevent post-operative renal impairment. Eight patients were treated by combining trough level adjusted sirolimus and mycophenolate mofetil; corticosteroids were given for the first 6 post-operative months only. Survival data, acute rejection episodes and adverse events with a special emphasis on renal impairment, myelosuppression, hypercholesterolemia, hypertriglyceridemia and infections, were recorded. With a follow-up of 3–12 months, patient survival was 100% and freedom from rejection 75%. The mean creatinine levels initially decreased and remained stable thereafter. A moderate myelosuppressive effect did not necessitate dose reduction of immunosuppressants, intermittently elevated cholesterol- and triglyceride levels decreased over time. Most frequent adverse events were pericardial effusions and peripheral edema. Complete abandonment of calcineurin inhibitor therapy by de novo use of the combination sirolimus/mycophenolate mofetil resulted in low rejection rate and avoidance of renal impairment, but should not be used without further evaluation of potential complications in a lager setting.

Thrombogenity of small-diameter vascular prostheses might be reduced by complete coverage of the luminal surface with vascular cells. We investigated cell seeding on polyurethane vascular prostheses.

The aim of this single-center study was to investigate whether trough level adjusted mycophenolate mofetil (MMF) is more efficacious in combination with tacrolimus (TAC) or cyclosporine (CsA) and to evaluate the impact of either drug on MMF dosage.

The impact of sirolimus on hormone levels involved in the hypothalamus-pituitary-gonad axis in male heart transplant recipients was investigated.

Calcineurin-inhibitor (CNI)-related renal failure is a common problem after cardiac transplantation (HTx). The aim of this study was to introduce a CNI-free immunosuppressive regimen to HTx recipients with late posttransplant renal impairment and to evaluate the impact of conversion to this new immunosuppression (mycophenolate mofetil MMF and sirolimus Sir) treatment on renal function.

Objectives:Cyclosporine (INN: ciclosporin) A or tacrolimus have been used mostly in combination with azathioprine as primary immunosuppression after lung transplantation. Benefit or risk deriving from the combination with mycophenolate mofetil are yet unknown. Methods:In a prospective, 2-center, open randomized trial, the combination of cyclosporine A, mycophenolate mofetil, and steroids was compared with tacrolimus, mycophenolate mofetil, and steroids as primary therapy after primary lung transplantation. All patients underwent induction therapy with rabbit antithymocyte globulin for 3 days. The 2 groups were compared with regard to patient survival, freedom from acute rejection, bronchiolitis obliterans, infectious episodes, and side effects. Results:Between September 1997 and April 1999, 74 lung transplant recipients were randomized to receive either cyclosporine A (n = 37) or tacrolimus (n = 37). Groups were comparable with regard to age, sex, transplant procedure, and cytomegalovirus match. Mean follow-up was 507 ± 258 and 508 ± 248 days, respectively. Six- and 12-month survival was similar in both groups (89% vs 84% and 82% vs 71%, respectively; P=.748 at 12 months). Two patients from the cyclosporine A group were retransplanted. Freedom from acute rejection at 6 and 12 months was comparable between groups (46% vs 51% and 35% vs 46%, respectively; P=.774 at 12 months). The mean number of treated acute rejection episodes per 100 patient-days was higher in the cyclosporine A than in the tacrolimus group, but the difference was not statistically significant (0.32 ± 0.42 vs 0.22 ± 0.30, respectively; P=.097). Four patients from the cyclosporine A group had to be switched to tacrolimus to control ongoing rejection, whereas no patient from the tacrolimus group had to be switched to cyclosporine A. There was a trend toward more infections (0.7 ± 0.36 vs 0.55 ± 0.31, P=.059) in the cyclosporine A group. New-onset diabetes mellitus was observed in the tacrolimus group only (11% vs 0%, P=.151), whereas there was a higher incidence of hypertension (60% vs 11%, P=.03) in the cyclosporine A group. Conclusion:This 2-center, prospective randomized study showed high immunosuppressive potency of both cyclosporine A and tacrolimus in combination with mycophenolate mofetil. No significant difference in incidence of acute rejection was observed between the 2 groups. Moreover, survival and incidence of infection were similar. Incidence of drug-related adverse events were similar, yet their spectrum was different.

Objective:This study represents the development of a treatment and seeding procedure to improve endothelial cellular adhesion on glutaraldehyde-fixed valves. Methods:Porcine aortic valves were fixed with 0.2% glutaraldehyde. Wall pieces of these valves had either no additional treatment (n = 4), incubation in M199 Earle (1×), with sodium carbonate at 2.2 g/L without l-glutamine for 24 hours (n = 4), or additional pretreatment with 5%, 10%, or 15% citric acid (three groups, n = 4 each). Thereafter the pieces were washed and buffered to a physiologic pH. This was followed by seeding of human endothelial cells (5 × 106cells). On the basis of the results of these pilot tests, complete glutaraldehyde-fixed aortic roots treated with 10% citric acid were subjected to cell seeding. The valves were seeded with endothelial cells (4.3 × 106cells) either alone (n = 4) or in combination with preseeding of autologous fibroblasts (2.4 × 107cells, n = 4). After each seeding procedure specimens of the free wall of the grafts were taken. In addition, one leaflet was taken for histologic examination after endothelial cell seeding, after 7 days, and after 21 days. Finally, two commercially available stentless aortic valve prostheses (Freestyle; Medtronic, Inc, Minneapolis, Minn) were treated with 10% citric acid and seeded with human fibroblasts and endothelial cells. Specimen were taken according to the glutaraldehyde-fixed aortic roots. Specimen of all experiments were examined with scanning electron microscopy. Frozen sections were stained immunohistochemically for collagen IV, factor VIII, and CD31. Results:On untreated glutaraldehyde-fixed aortic wall pieces, only poor adhesion (24%) was seen. No viable cells were found after 1 week. Cellular adhesion was best on aortic wall pieces pretreated with 10% citric acid. After 7 days, the cells formed a confluent layer. Endothelial cell seeding on citric acid-treated complete aortic valves showed 45% adhesion, but no confluent layer was found after 1 week. Preseeding of these valves with autologous fibroblasts resulted in an endothelial cellular adhesion of 76% and a confluent endothelial cell layer after 7 days. The layer remained stable for at least 21 days. Results of staining for collagen IV, factor VIII, and CD31 were positive on the luminal side of these valves, indicating the synthesis of matrix proteins and viability of the cells. Pretreatment of commercially available porcine valves with 10% citric acid and preseeding with autologous fibroblasts followed by endothelial cell seeding resulted in an adhesion of 78%. The cells formed a confluent cell layer after 7 days. Conclusions:Pretreatment of glutaraldehyde-fixed porcine aortic valves with citric acid established a surface more suitable for cellular attachment. Preseeding these valves with autologous fibroblasts resulted in a confluent endothelial cell layer on the luminal surface. Flow tests and animal experiments are necessary for further assessment of durability and shear stress resistance.

In selected patients with severe end-stage combined cardiopulmonary diseases, heart-lung transplantation (HLTx) remains the only therapeutical option for improving survival and quality of life.

For more than 15 years, immunosuppression after heart transplantation followed a standard protocol that was based on a triple drug regimen (consisting of cyclosporine, azathioprine, and steroids) with or without antibody induction therapy. Lately, intensive pharmacological research has produced a number of new agents with a variety of immunosuppressive actions. Most clinical experience with these compounds has been gained in renal transplant studies. Possible advantages but also likely disadvantages of these agents for the specific setting of cardiac transplantation need to be critically evaluated.

Background. The purpose of the study was to analyze the long-term results of aortic valvotomy and the risk factors associated with reoperation and survival.

Mitral valve repair with annuloplasty has become a widely accepted technique for correction of pathologic lesions of the mitral valve. Advantages over mitral valve replacement include improved hemodynamic performance and improved ventricular function. The rate of operative mortality in appropriately selected patients is low. The success of the mitral valve repair has led to increased scrutiny of mitral valve function and a growing realization that rigid rings may be detrimental. Flexible rings are increasingly replacing the rigid ring traditionally used for annuloplasty, with consequent further improvements in ventricular function and cardiac hemodynamics. Other types of rings recently introduced include partially flexible rings and adjustable flexible rings. The advantages of each are discussed. Relatively new procedures involving shortening of the annulus with suture or pericardium show promise.

Cerebral injury after cardiac surgery is still a major cause of mortality and morbidity after cardiac surgery. In an aging patient population the incidence is likely to increase. Comparisons between cardiac and other major surgery suggested that cardiopulmonary bypass CPB causes the neurological sequelae. Strategies to avoid brain injury target the reduction of emboli floating in the cerebral circulation, adequacy of cerebral oxygenation, and minimization of the whole body inflammatory response to the bypass circuit. Experimental and clinical studies demonstrated that manipulation of CPB can reduce abundant cerebral blood flow and the embolic load to the brain. Hematocrit, temperature, blood pressure, and acidbase status during CPB are parameters that have impact on the neurological outcome and can be optimized. Other possibilities to avoid cerebral complications include improvements of surgical techniques and devices or the application of new therapeutic drugs. However, further experimental studies and, most importantly, prospective randomized clinical trials are warranted to prove new innovative concepts in clinical practice.