Targeting the Innate Immune Response to Improve Cardiac Graft Recovery after Heart Transplantation: Implications for the Donation after Cardiac Death.
ABSTRACT: Heart transplantation (HTx) is the ultimate treatment for end-stage heart failure. The number of patients on waiting lists for heart transplants, however, is much higher than the number of available organs. The shortage of donor hearts is a serious concern since the population affected by heart failure is constantly increasing. Furthermore, the long-term success of HTx poses some challenges despite the improvement in the management of the short-term complications and in the methods to limit graft rejection. Myocardial injury occurs during transplantation. Injury initiated in the donor as result of brain or cardiac death is exacerbated by organ procurement and storage, and is ultimately amplified by reperfusion injury at the time of transplantation. The innate immune system is a mechanism of first-line defense against pathogens and cell injury. Innate immunity is activated during myocardial injury and produces deleterious effects on the heart structure and function. Here, we briefly discuss the role of the innate immunity in the initiation of myocardial injury, with particular focus on the Toll-like receptors and inflammasome, and how to potentially expand the donor population by targeting the innate immune response.
Project description:The influence of preexisting donor-transmitted atherosclerosis (DA) on cardiac allograft vasculopathy (CAV) development remains unclear.We performed 3-dimensional intravascular ultrasound (3D-IVUS) analysis in 42 heart transplantation (HTx) recipients at 2.1 ± 0.9 months (baseline) and 12.2 ± 0.4 months post-HTx, as well as consecutive 3D-IVUS analyses up to 3 years post-HTx in 35 of the 42 recipients. Donor-transmitted atherosclerosis was defined as a maximal intimal thickness of 0.5 mm or greater at baseline. Changes in volumetric IVUS parameters were compared in recipients with (DA group) and without DA (DA-free group) at baseline, 1 year, and 3 years post-HTx.Donor-transmitted atherosclerosis was observed in 57.1% of 42 recipients. The DA group exhibited a significantly greater increase in plaque volume at 1 year post-HTx (P < 0.001), leading to increased percent plaque volume (plaque volume/vessel volume, [%]) (P < 0.001) and decreased luminal volume (P = 0.021). Donor-transmitted atherosclerosis was independently associated with a greater increase in percent plaque volume during the first post-HTx year (P = 0.011). From 1 to 3 years post-HTx, the DA group underwent continuous reduction in luminal volume (P = 0.022). These changes resulted in a higher incidence of angiographic CAV at 3 years post-HTx in the DA group (58.8% vs 5.6%, P = 0.002).This volumetric IVUS study suggests that DA correlates with the worsening change in CAV several years post-HTx. Donor-transmitted atherosclerosis recipients may require more aggressive treatment to prevent subsequent CAV progression.
Project description:Heart transplantation (HTx) has become standard treatment for selected patients with end-stage heart failure. Improvements in immunosuppressant, donor procurement, surgical techniques, and post-HTx care have resulted in a substantial decrease in acute allograft rejection, which had previously significantly limited survival of HTx recipients. However, limitations to long-term allograft survival exist, including rejection, infection, coronary allograft vasculopathy, and malignancy. Careful balance of immunosuppressive therapy and vigilant surveillance for complications can further improve long-term outcomes of HTx recipients.
Project description:Background:Trauma victims could be an important source of organs. This article presents two cases of successful organ donation and transplant, after Maastricht category III cardiac death in patients with successfully repaired AAST grade V traumatic cardiac injuries. Case presentation:The first donor was an adult patient with self-inflicted heart stab wound and non-survivable burn injury. The second one was an adult patient with blunt cardiac and abdominal trauma and an anoxic brain injury due to a car accident. The cardiac injury was promptly repaired in both patients. In the first case, adequate organ perfusion ante-mortem was achieved thanks to venoarterial extracorporeal membrane oxygenation and intensive care unit support. The above procedure allowed successful organ donation and transplantation even after Maastricht category III cardiac death. This is the first case reported where, for organ donation purposes, it was made necessary first thing to avoid the immediate death of the patient, due to a rare and frequently not survivable cardiac injury. The challenge of preserving organ perfusion, due to major burn injury effects, was faced afterwards. Conclusions:The outcomes of these two cases suggest that a repaired heart injury should not be considered as an absolute contraindication to organ donation, even if it is associated with non-survivable major burns. Therefore, cardiac death could provide an opportunity for these kinds of patients to contribute to the pool of potential organ donors.
Project description:Application of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity.The rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) ? LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry.Mixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC.Srl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.
Project description:Aim:To investigate the prognostic value of early post-transplant hemodynamic measurements on 5-year mortality in cardiac recipients (HTx). Methods:A right heart catheterization was performed in 290 heart transplantation (HTx) recipients at a one-year post-HTx evaluation. To study the effect of post-HTx hemodynamic variables on 5-year outcome, the cohort was stratified into several subgroups. For right atrial pressure (RAP), mean pulmonary artery pressure (MPAP), pulmonary artery wedge pressure (PAWP), and pulmonary vascular resistance (PVR), patients with values from the upper 10th percentile (high), were compared with those with values from the remaining lower 90th percentile (normal). For cardiac index (CI), patients with values from the lower 10th percentile (low) were compared with those with values from the remaining upper 90th percentile (normal). Results:Death or re-transplantation within 5?years after the one-year control occurred in 44 patients (13%). Of those, death or re-HTx was related to graft failure in 20 of cases (45%) and non-cardiac causes in 24 of cases (55%). The risk of death or re-HTx was higher in the subgroup with MPAP above 23?mmHg than those equal to or below this value [hazard ratio 3.22, 95% confidence interval (CI) 1.49-6.97; P?=?0.003]. The association remained significant despite adjustment for several comorbidities. There were no differences in outcome between subgroups stratified with respect to high versus low RAP, PAWP, CI or PVR. Conclusion:Elevated pulmonary artery pressure at a first annual evaluation after HTx was the only hemodynamic variable that predicted impaired outcome in cardiac recipients.
Project description:Cardiovascular disease is the largest contributor to worldwide mortality, and the deleterious impact of heart failure (HF) is projected to grow exponentially in the future. As heart transplantation (HTx) is the only effective treatment for end-stage HF, development of mechanical circulatory support (MCS) technology has unveiled additional therapeutic options for refractory cardiac disease. Unfortunately, despite both MCS and HTx being quintessential treatments for significant cardiac impairment, associated morbidity and mortality remain high. MCS technology continues to evolve, but is associated with numerous disturbances to cardiac function (e.g., oxidative damage, arrhythmias). Following MCS intervention, HTx is frequently the destination option for survival of critically ill cardiac patients. While effective, donor hearts are scarce, thus limiting HTx to few qualifying patients, and HTx remains correlated with substantial post-HTx complications. While MCS and HTx are vital to survival of critically ill cardiac patients, cardioprotective strategies to improve outcomes from these treatments are highly desirable. Accordingly, this review summarizes the current status of MCS and HTx in the clinic, and the associated cardiac complications inherent to these treatments. Furthermore, we detail current research being undertaken to improve cardiac outcomes following MCS/HTx, and important considerations for reducing the significant morbidity and mortality associated with these necessary treatment strategies.
Project description:BACKGROUND:Postcardiotomy cardiogenic shock (PCS) that is refractory to inotropic support remains a major concern in cardiac surgery and is almost universally fatal unless treated with mechanical support. While reported mortality rates on ECMO vary from center to center, aim of the current report is assess if the outcomes differ between centres according to volume and heart transplantation status. METHODS:A systematic search was performed according to PRISMA statement using PubMed/Medline databases between 2010 and 2018. Relevant articles were scrutinized and included in the meta-analysis only if reporting in-hospital/30-day mortality and heart transplantation status of the centre. Paediatric and congenital heart surgery-related studies along with those conducted in the setting of veno-venous ECMO for respiratory distress syndrome were excluded. Differences were assessed by means of subgroup meta-analysis and meta-regression. RESULTS:Fifty-four studies enrolling N?=?4421 ECMO patients were included. Of those, 6 series were performed in non-HTx centres (204 pts.;4.6%). Overall 30-day survival (95% Confidence Intervals) was 35.3% (32.5-38.2%) and did not statistically differ between non-HTx: 33.3% (26.8-40.4%) and HTx centres: 35.7% (32.7-38.8%); Pinteraction?=?0.531. There was no impact of centre volume on survival as well: ßcoef?=?0.0006; P?=?0.833. No statistical differences were seen between HTx and non-HTx with respect to ECMO duration, limb complications, reoperations for bleeding, kidney injury and sepsis. There were however significantly less neurological complications in the HTx as compared to non-HTx centres: 11.9% vs 19.5% respectively; P?=?0.009; an inverse relationship was seen for neurologic complications in centres performing more ECMOs annually ßcoef?=?-?0.0066; P?=?0.031. Weaning rates and bridging to HTx and/or VADs were higher in HTx facilities. CONCLUSIONS:There was no apparent difference in survival after ECMO implantation for refractory PCS according to centre's ECMO volume and transplantation status. Potentially different risk profiles of patients in these centres must be taken account for before definite conclusions are drawn.
Project description:We have previously reported a subpopulation of mesenchymal stromal cells (MSCs) within the platelet-derived growth factor receptor-alpha (PDGFR?)/CD90 co-expressing cardiac interstitial and adventitial cell fraction. Here we further characterise PDGFR?/CD90-expressing cardiac MSCs (PDGFR??+?cMSCs) and use human telomerase reverse transcriptase (hTERT) over-expression to increase cMSCs ability to repair the heart after induced myocardial infarction. hTERT over-expression in PDGFR??+?cardiac MSCs (hTERT?+?PDGFR??+?cMSCs) modulates cell differentiation, proliferation, survival and angiogenesis related genes. In vivo, transplantation of hTERT?+?PDGFR??+?cMSCs in athymic rats significantly increased left ventricular function, reduced scar size, increased angiogenesis and proliferation of both cardiomyocyte and non-myocyte cell fractions four weeks after myocardial infarction. In contrast, transplantation of mutant hTERT?+?PDGFR??+?cMSCs (which generate catalytically-inactive telomerase) failed to replicate this cardiac functional improvement, indicating a telomerase-dependent mechanism. There was no hTERT?+?PDGFR??+?cMSCs engraftment 14 days after transplantation indicating functional improvement occurred by paracrine mechanisms. Mass spectrometry on hTERT?+?PDGFR??+?cMSCs conditioned media showed increased proteins associated with matrix modulation, angiogenesis, cell proliferation/survival/adhesion and innate immunity function. Our study shows that hTERT can activate pro-regenerative signalling within PDGFR??+?cMSCs and enhance cardiac repair after myocardial infarction. An increased understanding of hTERT's role in mesenchymal stromal cells from various organs will favourably impact clinical regenerative and anti-cancer therapies.
Project description:Heart transplantation (HTx) is the gold standard therapy to improve quality and quantity of life in end-stage heart failure patients. However, recipients are at risk of experiencing allograft rejection and post-transplant complications, in the acute as well as chronic phase. A 43-year-old man with a history of left ventricular non-compaction underwent orthotopic HTx. On Day 7, transthoracic echocardiography showed a sudden decrease in cardiac function with hypokinesis in a left ventricular anterior wall distribution. Coronary angiography revealed a large thrombus in the left main trunk. With intra-aortic balloon pump support, emergency percutaneous coronary intervention was performed. Endomyocardial biopsy showed no rejection. A left main trunk thrombus is rare in the early phase after HTx, but it can be a life-threatening complication. Transthoracic echocardiography is well known to be important in the management of heart transplant recipients, and coronary angiography as well as myocardial biopsy should be considered when left ventricular wall motion is impaired.
Project description:<h4>Objectives</h4>Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET; NCT03152422) aims: (i) to construct new multidimensional urinary proteomic (UP) classifiers that after heart transplantation (HTx) help in detecting graft vasculopathy, monitoring immune system activity and graft performance, and in adjusting immunosuppression; (ii) to sequence UP peptide fragments and to identify key proteins mediating HTx-related complications; (iii) to validate UP classifiers by demonstrating analogy between UP profiles and tissue proteomic signatures (TP) in diseased explanted hearts, to be compared with normal donor hearts; (iv) and to identify new drug targets. This article describes the uPROPHET database construction, follow-up strategies and baseline characteristics of the HTx patients.<h4>Methods</h4>HTx patients enrolled at the University Hospital Gasthuisberg (Leuven) collected mid-morning urine samples. Cardiac biopsies were obtained at HTx. UP and TP methods and the statistical work flow in pursuit of the research objectives are described in detail in the Data supplement.<h4>Results</h4>Of 352 participants in the UP study (24.4% women), 38.9%, 40.3%, 5.7% and 15.1% had ischemic, dilated, hypertrophic or other cardiomyopathy. The median interval between HTx and first UP assessment (baseline) was 7.8 years. At baseline, mean values were 56.5 years for age, 25.2 kg/m2 for body mass index, 142.3/84.8 mm Hg and 124.2/79.8 mm Hg for office and 24-h ambulatory systolic/diastolic pressure, and 58.6 mL/min/1.73 m2 for the estimated glomerular filtration rate. Of all patients, 37.2% and 6.5% had a history of mild (grade = 1B) or severe (grade ? 2) cellular rejection. Anti-body mediated rejection had occurred in 6.2% patients. The number of follow-up urine samples available for future analyses totals over 950. The TP study currently includes biopsies from 7 healthy donors and 15, 14, and 3 patients with ischemic, dilated, and hypertrophic cardiomyopathy.<h4>Conclusions</h4>uPROPHET constitutes a solid resources for UP and TP research in the field of HTx and has the ambition to lay the foundation for the clinical application of UP in risk stratification in HTx patients.