Degeneration of biological heart valve grafts in a rat model of superoxide dismutase-3 deficiency.

While oxidative stress is known as key element in the pathogenesis of atherosclerosis and calcific aortic valve disease, its role in the degeneration of biological cardiovascular grafts has not been clarified yet. Therefore, the present study aimed to examine the impact of oxidative stress on the degeneration of biological cardiovascular allografts in a standardized chronic implantation model realized in rats exhibiting superoxide dismutase 3 deficiency (SOD3(-) ). Rats with SOD3 loss-of-function mutation (n = 24) underwent infrarenal implantation of cryopreserved valved aortic conduits, while SOD3-competent recipients served as controls (n = 28). After a follow-up period of 4 or 12 weeks, comparative analyses addressed degenerative processes, hemodynamics, and evaluation of the oxidative stress model. SOD3(-) rats presented decreased circulating SOD activity (p = .0079). After 12 weeks, 58% of the implant valves in SOD3(-) rats showed regurgitation (vs. 31% in controls, p = .2377). Intima hyperplasia and chondro-osteogenic transformation contributed to progressive graft calcification (p = .0024). At 12 weeks, hydroxyapatite deposition (p = .0198) and the gene expression of runt-related transcription factor-2 (Runx2) (p = .0093) were significantly enhanced in group SOD3(-) . This study provides the first in vivo evidence that impaired systemic antioxidant activity contributes to biological cardiovascular graft degeneration.

[Recommendations of the S3 Guideline "Use of Extracorporeal Circulation (ECLS/ ECMO) for Cardiac and Circulatory Failure" of the Association of Scientific Medical Societies in Germany]. / Empfehlungen der S3-Leitlinie (AWMF) "Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen".

In recent years, the use of mechanical support for patients with cardiac or circulatory failure has continuously increased, leading to 3,000 ECLS/ECMO (extracorporeal life support/extracorporeal membrane oxygenation) implantations annually in Germany. Due to the lack of guidelines, there is an urgent need for evidence-based recommendations addressing the central aspects of ECLS/ECMO therapy. In July 2015, the generation of a guideline level S3 according to the standards of the Association of the Scientific Medical Societies in Germany (AWMF) was announced by the German Society for Thoracic and Cardiovascular Surgery (GSTCVS). In a well-structured consensus process, involving experts from Germany, Austria and Switzerland, delegated by 16 scientific societies and the patients' representation, the guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" was created under guidance of the GSTCVS, and published in February 2021. The guideline focuses on clinical aspects of initiation, continuation, weaning and aftercare, herein also addressing structural and economic issues. This article presents an overview on the methodology as well as the final recommendations.

Coronary artery bypass grafting under sole Impella 5.0 support for patients with severely depressed left ventricular function.

Selection of the ideal surgical procedure for coronary revascularization in patients with severe cardiac dysfunction at times may represent a challenge. In recent years, with the advent of surgical large microaxial pumps, e.g., Impella 5.0 (Abiomed Inc., Boston, USA), specific support and effective unloading of the left ventricle has become available. In the interventional field, good results have been achieved with smaller microaxial pumps in the setting of so-called protected percutaneous coronary intervention. In this study, we would like to share our early experience with surgical coronary revascularization under the sole support of Impella 5.0, omitting the use of heart-lung machine in three cases of severe cardiac dysfunction due to complex ischemic heart disease. Effective circulatory support intraoperatively and postoperatively speaks in favor of this technique in selected patients.

A Role for Peroxisome Proliferator-Activated Receptor Gamma Agonists in Counteracting the Degeneration of Cardiovascular Grafts.

ABSTRACT: Aortic valve replacement for severe stenosis is a standard procedure in cardiovascular medicine. However, the use of biological prostheses has limitations especially in young patients because of calcifying degeneration, resulting in implant failure. Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist, was shown to decrease the degeneration of native aortic valves. In this study, we aim to examine the impact of pioglitazone on inflammation and calcification of aortic valve conduits (AoC) in a rat model. Cryopreserved AoC (n = 40) were infrarenally implanted into Wistar rats treated with pioglitazone (75 mg/kg chow; n = 20, PIO) or untreated (n = 20, controls). After 4 or 12 weeks, AoC were explanted and analyzed by histology, immunohistology, and polymerase chain reaction. Pioglitazone significantly decreased the expression of inflammatory markers and reduced the macrophage-mediated inflammation in PIO compared with controls after 4 (P = 0.03) and 12 weeks (P = 0.012). Chondrogenic transformation was significantly decreased in PIO after 12 weeks (P = 0.001). Calcification of the intima and media was significantly reduced after 12 weeks in PIO versus controls (intima: P = 0.008; media: P = 0.025). Moreover, echocardiography revealed significantly better functional outcome of the AoC in PIO after 12 weeks compared with control. Interestingly, significantly increased intima hyperplasia could be observed in PIO compared with controls after 12 weeks (P = 0.017). Systemic PPAR-gamma activation prevents inflammation as well as intima and media calcification in AoC and seems to inhibit functional impairment of the implanted aortic valve. To further elucidate the therapeutic role of PPAR-gamma regulation for graft durability, translational studies and long-term follow-up data should be striven for.

[Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure : Short version of the S3 guideline]. / Einsatz der extrakorporalen Zirkulation (ECLS/ECMO) bei Herz- und Kreislaufversagen : Kurzversion der AWMF-S3-Leitlinie.

In Germany, a remarkable increase regarding the usage of extracorporeal membrane oxygenation (ECMO) and extracorporeal life support (ECLS) systems has been observed in recent years with approximately 3000 ECLS/ECMO implantations annually since 2015. Despite the widespread use of ECLS/ECMO, evidence-based recommendations or guidelines are still lacking regarding indications, contraindications, limitations and management of ECMO/ECLS patients. Therefore in 2015, the German Society of Thoracic and Cardiovascular Surgery (GSTCVS) registered the multidisciplinary S3 guideline "Use of extracorporeal circulation (ECLS/ECMO) for cardiac and circulatory failure" to develop evidence-based recommendations for ECMO/ECLS systems according to the requirements of the Association of the Scientific Medical Societies in Germany (AWMF). Although the clinical application of ECMO/ECLS represents the main focus, the presented guideline also addresses structural and economic issues. Experts from 17 German, Austrian and Swiss scientific societies and a patients' organization, guided by the GSTCVS, completed the project in February 2021. In this report, we present a summary of the methodological concept and tables displaying the recommendations for each chapter of the guideline.

Computational investigation of hemodynamics in hardshell venous reservoirs: A comparative study.

Extracorporeal circulation using heart-lung-machines is associated with a profound activation of corpuscular and plasmatic components of circulating blood, which can also lead to deleterious events such as systemic inflammatory response and hemolysis. Individual components used to install the extracorporeal circulation have an impact on the level of activation, most predominantly membrane oxygenators and hardshell venous reservoirs as used in extracorporeal systems. The blood flows in two different hardshell reservoirs are computationally investigated. A special emphasis is placed on the prediction of an onset of transition and turbulence generation. Reynolds-averaged numerical simulations (RANS) based on a transitional turbulence model, as well as large eddy simulations (LES) are applied to achieve an accurate prediction. In the LES analysis, the non-Newtonian behavior of the blood is considered via the Carreau model. Blood damage potential is quantified applying the Modified Index of Hemolysis (MIH) based on the predicted flow fields. The results indicate that the flows in both reservoirs remain predominantly laminar. For one of the reservoirs, considerable turbulence generation is observed near the exit site, caused by the specific design for the connection with the drainage tube. This difference causes the MIH of this reservoir to be nearly twice as large as compared to the alternative design. However, a substantial improvement of these performance criteria can be expected by a local geometry modification.

Organization and Application of ECLS Therapy-A Nationwide Survey in German Cardiosurgical Departments.

BACKGROUND: In context of the multidisciplinary German scientific guideline "Use of extracorporeal circulation (extracorporeal life support [ECLS]/extracorporeal membrane oxygenation) for cardiac and circulatory failure," a nationwide survey should depict the status of organization and application of ECLS therapy in Germany. METHODS: Between June and October 2017, a standardized questionnaire consisting of 30 items related to ECLS therapy was sent to all German cardiosurgical departments, and all returned results were analyzed and evaluated. RESULTS: The return rate amounted to 92.9% (78 out of 84 departments). In the participating departments, ECLS therapy is subject to different responsibilities, and exhibits divergent processes and various ways for specialization of the involved personnel. This also concerns local application standards, such as cannulation strategies, anticoagulation management, left ventricular unloading, antiwatershed treatment, and weaning from circulatory support. CONCLUSION: This nationwide survey underlines the necessity of a multidisciplinary guideline concerning ECLS therapy.

Interferon-γ Released by Activated CD8+ T Lymphocytes Impairs the Calcium Resorption Potential of Osteoclasts in Calcified Human Aortic Valves.

In calcific aortic valve disease (CAVD), activated T lymphocytes localize with osteoclast regions; however, the functional consequences of this association remain unknown. We hypothesized that CD8+ T cells modulate calcification in CAVD. CAVD valves (n = 52) dissected into noncalcified and calcified portions were subjected to mRNA extraction, real-time quantitative PCR, enzyme-linked immunosorbent assay, and immunohistochemical analyses. Compared with noncalcified portions, calcified regions exhibited elevated transcripts for CD8, interferon (IFN)-γ, CXCL9, Perforin 1, Granzyme B, and heat shock protein 60. Osteoclast-associated receptor activator of NK-κB ligand (RANKL), tartrate-resistant acid phosphatase (TRAP), and osteoclast-associated receptor increased significantly. The stimulation of tissue with phorbol-12-myristate-13-acetate and ionomycin, recapitulating CAVD microenvironment, resulted in IFN-γ release. Real-time quantitative PCR detected mRNAs for CD8+ T-cell activation (Perforin 1, Granzyme B). In stimulated versus unstimulated organoid cultures, elevated IFN-γ reduced the mRNAs encoding for RANKL, TRAP, and Cathepsin K. Molecular imaging showed increased calcium signal intensity in stimulated versus unstimulated parts. CD14+ monocytes treated either with recombinant human IFN-γ or with conditioned media-derived IFN-γ exhibited low levels of Cathepsin K, TRAP, RANK, and tumor necrosis factor receptor-associated factor 6 mRNAs, whereas concentrations of the T-cell co-activators CD80 and CD86 increased in parallel with reduced osteoclast resorptive function, effects abrogated by neutralizing anti-IFN-γ antibodies. CD8+ cell-derived IFN-γ suppresses osteoclast function and may thus favor calcification in CAVD.

A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications.

Elastin-like polypeptides (ELPs) are promising for biomedical applications due to their unique thermoresponsive and elastic properties. ELP-based hydrogels have been produced through chemical and enzymatic crosslinking or photocrosslinking of modified ELPs. Herein, a photocrosslinked ELP gel using only canonical amino acids is presented. The inclusion of thiols from a pair of cysteine residues in the ELP sequence allows disulfide bond formation upon exposure to UV light, leading to the formation of a highly elastic hydrogel. The physical properties of the resulting hydrogel such as mechanical properties and swelling behavior can be easily tuned by controlling ELP concentrations. The biocompatibility of the engineered ELP hydrogels is shown in vitro as well as corroborated in vivo with subcutaneous implantation of hydrogels in rats. ELP constructs demonstrate long-term structural stability in vivo, and early and progressive host integration with no immune response, suggesting their potential for supporting wound repair. Ultimately, functionalized ELPs demonstrate the ability to function as an in vivo hemostatic material over bleeding wounds.

Dispersive aortic cannulas reduce aortic wall shear stress affecting atherosclerotic plaque embolization.

Neurologic complications during on-pump cardiovascular surgery are often induced by mobilization of atherosclerotic plaques, which is directly related to enhanced wall shear stress. In the present study, we numerically evaluated the impact of dispersive aortic cannulas on aortic blood flow characteristics, with special regard to the resulting wall shear stress profiles. An idealized numerical model of the human aorta and its branches was created and used to model straight as well as bent dispersive aortic cannulas with meshlike tips inserted in the distal ascending aorta. Standard cannulas with straight beveled or bent tips served as controls. Using a recently optimized computing method, simulations of pulsatile and nonpulsatile extracorporeal circulation were performed. Dispersive aortic cannulas reduced the maximum and average aortic wall shear stress values to approximately 50% of those with control cannulas, while the difference in local values was even larger. Moreover, under pulsatile circulation, dispersive cannulas shortened the time period during which wall shear stress values were increased. The turbulent kinetic energy was also diminished by utilizing dispersive cannulas, reducing the risk of hemolysis. In summary, dispersive aortic cannulas decrease aortic wall shear stress and turbulence during extracorporeal circulation and may therefore reduce the risk of endothelial and blood cell damage as well as that of neurologic complications caused by atherosclerotic plaque mobilization.

Simvastatin does not diminish the in vivo degeneration of decellularized aortic conduits.

BACKGROUND: All present biological cardiovascular prostheses are prone to progressive in vivo degeneration, which can be partially impaired by decellularization. The administration of statins may provide an additional beneficial effect. We provide the first in vivo data on the effect of statins on decellularized cardiovascular implants. METHODS: Wistar rats with aortic valve insufficiency (day 14) were fed either with a pro-calcific diet (group C; n = 17), or the same diet additionally supplemented with simvastatin (group S; n = 16). Aortic conduits from Sprague-Dawley rats were detergent-decellularized, infrarenally implanted (day 0) in all recipients and explanted at day 28 or day 84. RESULTS: Sonographic competence of the conduit perfusion was 100%, and overall survival amounted to 97%. Simvastatin decreased the low-density lipoprotein cholesterol serum levels; however, it did not affect the calcification of the implants. Histology revealed alpha-smooth muscle actin-positive intima hyperplasia in both groups. Extensive matrix metalloproteinase activity was observed in calcified areas, especially in group S. Quantitative RNA analysis resulted in no differences with regard to several markers of calcifying degeneration (alkaline phosphatase, osteopontin, osteocalcin, osteoprotegerin, bone morphogenetic protein-2, runt-related transcription factor-2) and inflammation (tumor necrosis factor α, interleukin 1ß, receptor for advanced glycation end products, CD39, CD73), but significantly lower levels of interleukin-6 in group S. CONCLUSIONS: In a standardized small animal model of accelerated cardiovascular calcification, simvastatin failed to diminish the calcification of decellularized aortic conduit implants. This finding confirms the observations of recent clinical trials. However, further experiments are warranted to elucidate the value of partial benefits associated with lower circulating lipid and proinflammatory cytokine levels.

Readmission to the intensive care unit in times of minimally invasive cardiac surgery: does size matter?

OBJECTIVES: It is well known that patients who undergo readmission to an intensive care unit (ICU) after cardiac surgery face an increased risk of morbidity and mortality. The present study sought to evaluate whether less invasive procedures might be associated with a reduction of this economically as well as individually important problem. The role of the quantity of ICU and intermediate care (IMC) beds was investigated as well. METHODS: Altogether, we reviewed 5,333 patients who underwent cardiac surgery in our department between 2005 and 2010. The incidence of and reasons for readmission were determined with regard to individual subgroups, particularly comparing minimally invasive procedures with conventional strategies. RESULTS: A total of 5,132 patients were primarily discharged from the ICU. Out of this group, 293 patients were readmitted to the ICU at least once. After readmission, the average length of stay in the hospital was 21.9 ± 11.3 days compared to 12.8 ± 5.0 days in all other patients. Comparing the readmission rate in separate years, it was evident that this rate decreased with a growing ICU and IMC capacity. In patients who underwent less invasive cardiac surgery (ie, minimally invasive cardiac surgery, off-pump coronary artery bypass grafting), the readmission rates were significantly lower than in the entirety of patients studied. CONCLUSION: Readmission to the ICU after cardiac surgery is associated with impaired outcome. Extended resources in terms of ICU and IMC capacity may positively influence this problem by decreasing the number of readmissions. Modern surgical strategies with less invasive procedures may be associated with a reduced incidence of readmission as well.

Aortic conduit valve model with controlled moderate aortic regurgitation in rats: a technical modification to improve short- and long-term outcome and to increase the functional results.

BACKGROUND: The objective of this study was to describe a small animal aortic conduit model that could analyze long-term conduit valve (CV) function by echocardiography. METHODS AND RESULTS: Recipient Wistar rats (200-250g, n=20) underwent aortic leaflet injury of their native aortic valve under echocardiographic control. After 2 weeks, U-shaped decellularized CVs obtained from other rats were implanted onto the abdominal aorta. Implanted CVs were analyzed via pulsed-wave echocardiography at day 0, 4 and 12 weeks. CV stenosis was assessed as systolic flow velocity (post-pre CV)/flow velocity in the ascending aorta. CV regurgitation was assessed as the ratio of the amount of reversed diastolic flow to forward systolic flow in post-pre CV. The endpoint was set at 12 weeks. Three rats died immediately after aortic valve injury and all surviving rats received CV implantation (n=17, 85%). The survival rate after conduit implantation was 100% at 4 weeks and 88% (15/17) at 12 weeks. Regarding the CV function at 0, 4 and 12 weeks, the average observed value of CV stenosis was 3.8±7.9%, 3.1±4.1% and 14±10% (P<0.01), respectively. The average value of CV regurgitation was 0%, 12±27% and 52±43%, respectively (P<0.001). CONCLUSIONS: By using this model, the degeneration of implanted CV could be assessed not only qualitatively, but also quantitatively.

The impact of socio-demographic factors on health-related quality of life after coronary artery bypass surgery.

OBJECTIVES: To achieve a beneficial impact on long-term outcome after coronary artery bypass grafting (CABG), the goal of the present study was the early identification of patients at risk of impaired postoperative health-related quality of life (HRQoL), particularly evaluating the significance of socio-demographic variables. METHODS: In this prospective, single-centre cohort study of patients having an isolated CABG (January 2004-December 2014), preoperative socio-demographic (preSOC) and preoperative medical variables as well as 6-month follow-up data including the Nottingham Health Profile were analysed in 3,237 patients. RESULTS: All preSOC (gender, age, marriage and employment) and follow-up (chest pain, dyspnoea) variables proved to have significant influence on HRQoL (P < 0.001), male patients below 60 years being particularly impaired. The effects of marriage and employment on HRQoL are modulated by age and gender. The significance of the predictors of reduced HRQoL differs between the 6 Nottingham Health Profile domains. Multivariable regression analyses revealed explained proportions of variance amounting to 7% for preSOC and 4% for preoperative medical variables. CONCLUSIONS: The identification of patients at risk of impaired postoperative HRQoL is decisive for providing additional support. This study reveals that the assessment of 4 preoperative socio-demographic characteristics (age, gender, marriage, employment) is more predictive of HRQoL after CABG than are multiple medical variables.

Development of a growing rat model for the in vivo assessment of engineered aortic conduits.

BACKGROUND: Numerous limitations of aortic valve grafts currently used in pediatric patients cause the need for alternative prostheses. For the purpose of in vivo evaluation of novel engineered aortic conduit grafts, we aimed at downsizing a previously described model to create a growing rodent model. MATERIALS AND METHODS: U-shaped aortic conduits were sutured to the infrarenal aorta of young Wistar rats (70-80 g, n = 10) in an end-to-side manner. Functional assessment was performed by Doppler sonography and high resolution rodent MRI. Histology and immunohistochemistry followed after 8 wk. RESULTS: Postoperative recovery rate was 80%. Conforming to clinical observations, postoperative MRI (d 5) and Doppler sonography (wk 8) revealed unimpaired conduit perfusion. Explanted implants were luminally completely covered by an endothelial cell layer with local hyperplasia and accumulation of α-smooth muscle actin (+) cells. Moreover microcalcification of the decellularized scaffolds was observed. CONCLUSIONS: Our downsized model of aortic conduit transplantation enables overall characterization with detailed analysis of maturation of engineered aortic grafts in a growing organism.

Appropriate timing of coronary artery bypass grafting after acute myocardial infarction.

OBJECTIVES: Optimal timing of coronary artery bypass grafting (CABG) after acute myocardial infarction (AMI) remains the subject of fierce debate. Therefore, the recommended deferral ranges from immediate intervention to surgery 4 weeks after infarction. Especially, the increasing cohorts of patients at old age or with poor left ventricular function, whose mortality rates are additionally enhanced, may profit from focused analyses. This study aims at clarifying the appropriate timing of CABG after AMI, with special regard to high-risk patients (Age >70 years, left ventricular ejection fraction (LVEF) <30%). METHODS: Retrospective analysis was performed in 3475 patients who had undergone isolated CABG between 2005 and 2009. Those 1168 patients with previous AMI (<30 days) were categorized in groups, depending on deferral of surgery: <6 hours after AMI (A), 6 hours-1 day (B), 2-3 days (C), 4-10 days (D), 11-20 days (E), and 21-30 days (F). Furthermore, subgroups with an age >70 years or a LVEF <30% were examined. RESULTS: The mortality rates in groups A-F were 14.8, 10.2, 8.8, 4.2, 2.3, and 2.0%, whereas only the values of groups A-D were significantly increased versus the mortality rate of patients without previous AMI (1.9%). In patients over 70 years, we observed operative mortalities of 26.3, 14.3, 11.9, 6.1, 4.2, and 3.1% (groups A-F) versus 2.5% (no previous AMI), while 27.4, 15.4, 11.7, 6.0, 3.7, and 2.8% (groups A-F) versus 2.7% (no previous AMI) of patients with a LVEF <30% died during the first 30 days after surgery. In both subanalyses of high-risk patients, the enhanced mortalities of groups A-E reached significance. Multivariate analysis of operative risk factors revealed that CABG within 10 days after AMI and age over 60 years are independently associated with operative mortality. CONCLUSIONS: CABG early after AMI (<10 days) is accompanied by significantly increased mortality, especially in elderly patients or in patients with a severely impaired LVEF. At least the critical time period of 3 days should be avoided-whenever the hemodynamics is stable enough.

Bilateral Internal Thoracic Artery Minimally Invasive CABG Management in COPD.

Background Off-pump multi-arterial minimally invasive coronary surgery via anterolateral mini-thoracotomy has become a feasible and safe procedure. Case Description We report on a 61-year-old patient with a coronary one-vessel disease with severely stenotic left anterior descending artery and diagonal branch, additionally suffering from chronic obstructive pulmonary disease with severely impaired lung function. Using a fan technique allowing for double lung ventilation, the patient was successfully operated grafting both internal thoracic arteries via a left anterolateral mini-thoracotomy. Conclusion Anaortic, minimally invasive off-pump coronary artery bypass grafting is an excellent technique to achieve myocardial revascularization with both internal thoracic arteries even in patients with impaired lung function.

Impact of PPAR-gamma activation on the durability of biological heart valve prostheses in hypercholesterolaemic rats.

OBJECTIVES: Hypercholesterolaemia and obesity are risk factors for the development of calcified aortic valve disease and common comorbidities in respective patients. Peroxisome proliferator-activated receptor gamma activation has been shown to reduce the progression of native aortic valve sclerosis, while its effect on bioprosthetic valve degeneration is yet unknown. This project aims to analyse the impact of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the degeneration of biological aortic valve conduits in an implantation model in obese and hypercholesterolaemic rats. METHODS: Cryopreserved allogenic rat aortic valve conduits (n = 40) were infrarenally implanted into Wistar rats on high-fat (34.6%) diet. One cohort was treated with pioglitazone (75 mg/kg chow; n = 20, group PIO) and compared to untreated rats (n = 20, group control). After 4 or 12 weeks, conduits were explanted and analysed by (immuno-)histology and real-time polymerase chain reaction. RESULTS: A significantly decreased intima hyperplasia occurred in group PIO compared to control after 4 (P = 0.014) and 12 weeks (P = 0.045). Calcification of the intima was significantly decreased in PIO versus control at 12 weeks (P = 0.0001). No significant inter-group differences were shown for media calcification after 4 and 12 weeks. Echocardiographically, significantly lower regurgitation through the implanted aortic valve conduit was observed in PIO compared to control after 4 (P = 0.018) and 12 weeks (P = 0.0004). Inflammatory activity was comparable between both groups. CONCLUSIONS: Systemic peroxisome proliferator-activated receptor gamma activation decreases intima hyperplasia and subsequent intima calcification of cryopreserved allografts in obese, hypercholesterolaemic recipients. Additionally, it seems to inhibit functional impairment of the implanted aortic valve. Further preclinical studies are required to determine the long-term impact of peroxisome proliferator-activated receptor gamma agonists on graft durability.