View clinical trials related to Cardiac Allograft Vasculopathy.
Filter by:Heart transplantation (HT) is a lifesaving procedure for patients with end-stage heart failure and provides a better survival and quality of life if compared to medical treatment. HT is subject to alloimmune response, which, if left uncontrolled, is capable of jeopardizing long-term cardiac function. Advances in immunosuppression have enhanced the survival of HT patients. Nearly 2500 HT per year have been performed in the US during the last 10 years and despite significant improvements, long-term survival rates remain poor. More than 20% of patients do not survive more than 3 years, and those who survive are afflicted by long-term complications of alloimmunity and chronic immunosuppression. Life expectancy of patients who lose cardiac allografts is dramatically poor due to the absence of any therapeutic tool apart from re-transplantation, which is plagued by poor outcomes. The identification of novel therapeutic targets is thus mandatory. ATP/P2X7R signaling in T cells is highly relevant for cardiac allograft survival. ATP is a small molecule present at high concentrations inside cells; it is released as extracellular ATP (eATP) following cell damage or death where it acts as a danger signal. ATP is sensed by the P2X receptors (seven receptors named P2X1-7), mainly expressed by T lymphocytes. We have recently demonstrated that the ATP/P2X7R axis has a key role in cardiac allograft survival in humans and mice. Cardiac allograft vasculopathy (CAV) is a major limiting factor for HT survival; indeed CAV occurs in 50% of HT recipients by 5 years after transplantation and invariably results in allograft failure. CAV is clearly of immunological origin, as syngeneic murine grafts do not develop it. Once CAV occurs, the most definitive treatment is re-transplantation, but survival remains poor. We hypothesize that a single nucleotide polymorphysm (SNP) loss-of-function P2X7R mutation (p.Glu496Ala / c.1513A>C, rs3751143) generates a compensatory upregulation of the other purinergic receptors (P2XsR), thus creating a state of hypersensitivity to eATP. This eATP hypersensitivity results in an abnormal generation of Th1/Th17 cells, that leads to CAV and early cardiac allograft loss. Our study will answer a fundamental question: What is the effect of the P2X7R loss-of-function mutation on the immune system? Our goal is to generate the first targeted-therapy for a selected group of cardiac transplant recipients.
All individuals who receive a heart transplant are at risk for developing antibody-mediated rejection (AMR). An antibody is a protein produced by the body's immune system when it detects a foreign substance, called an antigen. The mechanism of an antibody is to attack an antigen. In antibody mediated rejection, antibodies will attack the transplanted heart, causing injury to the heart. The purpose of this investigation is to determine if a study drug, called eculizumab (Soliris), is safe to use in heart transplant recipients, and determine if it reduces risk of antibody-mediated rejection.
Coronary allograft vasculopathy (CAV) is the leading cause of late graft failure and second leading cause of late mortality after heart transplantation. CAV has been associated with a variety of traditional risk factors for atherosclerosis; however, immune mediated injury from development of de-novo donor-specific antibodies after transplantation also likely plays an important role. Similar to the progression of traditional atherosclerosis, it is likely that endothelial dysfunction is the precursor to the development of intimal thickening and CAV. The investigators hypothesize that coronary allograft vasculopathy after heart transplantation as defined by progressive neointimal hyperplasia is preceded by endothelial dysfunction, which in turn is at least partly mediated by donor specific antibodies. The investigators are proposing a prospective study in humans to test the above hypothesis and further mechanistically understand how CAV progresses. In this study the investigators will test for coronary endothelial function by infusing acetylcholine into the coronary artery and measure intimal hyperplasia by optical coherence tomography (OCT) and compare findings in patients with and without donor specific antibodies.
Hypothesis 1: Treatment of heart transplant recipients with sildenafil, a PDE-5 inhibitor, will improve small artery elasticity (SAE) when compared to placebo. Hypothesis 2: PDE-5 inhibition will improve endothelial function, resulting in increased production of nitric oxide, reduced activation of circulating endothelial cells, and increased endothelial progenitor cells.
Heart transplantation is the best option for patients with end-stage heart failure. Cardiac allograft vasculopathy (CAV) is the leading cause of death following cardiac transplantation and is not managed by current therapies. Its pathogenesis traduces in an accelerated form of coronary artery disease (CAD) with similarities to atherosclerosis but also particular features of endothelial dysfunction associated to the alloimmune conflict and humoral responses toward the graft. Intravascular ultrasound (IVUS) is the validated invasive method for late CAV diagnosis, but occurs lesions are established. Identification of reliable non-invasive early endothelial injury biomarkers that reflect mechanisms of cardiac damage thus remain a major challenge to optimize therapeutic management of post transplant morbidity. Endothelial dysfunction is a central feature of both CAV and CAD and results from a desquilibrium in the balance of endothelial lesion and repair that is partly controlled by recipient immune system. Through their expression of receptors sensing antibodies (FcR CD16) and endothelial stress-induced signals (CX3CR1 fractalkine receptor and NKG2D MICA receptors), Natural Killer (NK) cells represent effector cells with unique potential to generate both humoral and innate immune injury of graft endothelium.
Cardiac allograft vasculopathy (CAV) is a progressive disease of the coronary arteries in transplanted hearts which is a significant cause of morbidity and mortality. The broad objective of this research study is to advance our ability to diagnose as early as possible the presence of CAV and to non-invasively predict those patients at increased risk of CAV with novel techniques. Optical coherence tomography (OCT) is a novel intracoronary imaging technique using an optical analog of ultrasound with a resolution 10 times greater resolution than intravascular ultrasound (IVUS). Endothelial progenitor cells (EPCs) in peripheral blood have been shown to play a role in the pathogenesis of atherosclerosis and peripheral arterial tonometry is a clinical tool used to predict endothelial dysfunction (a precursor of atherosclerosis) which has been validated in non-transplant patients. Patients scheduled for routine cardiac catheterization with IVUS at the Mayo Clinic Rochester, Minnesota (MN) that reach inclusion and exclusion criteria for the study will be approached on the day to get informed consent to perform OCT, blood sampling and peripheral endothelial function testing. The investigators aim to 1) compare the frequency and plaque type of CAV as defined with OCT versus IVUS-Virtual Histology (IVUS-VH), 2) predict the presence and severity of CAV with absolute counts of EPCs and 3) with peripheral endothelial function scores.
Post transplant vasculopathy is a major negative outcome in heart transplantation. Current methods of detection are highly invasive and pose a risk to transplant recipients. Noninvasive markers of endothelial function can be used to detect transplant vasculopathy. Endothelial biomarkers such as: endothelial nitric oxide synthase, vascular cellular adhesion molecules, intracellular adhesion molecules, endothelin-1, thromboplastin, circulating endothelial cells, uric acid, and C-reactive play a role in the pathophysiologic mechanism of vasculopathy. Therefore, the investigators would like to assess the association between various endothelial biomarkers and the presence or absence of transplant vasculopathy.
Cardiac allograft vasculopathy (CAV) is a unique form of accelerated plaque formation seen in the coronary arteries of patients who have received heart transplantation. It is a major cause of morbidity and mortality in patients after heart transplant. Little progress has been made in characterizing this disease process, with more sophisticated imaging allowing for more detailed analysis of CAV, superior stratification of transplant recipients is possible and earlier interventions can be performed if necessary to prevent mortality and graft loss. Optical Coherence Tomography (OCT) is a novel imaging modality with much higher resolution then Intra-Vascular Ultrasound (IVUS). This study will involve examining patients post-heart transplant using this high-resolution imaging modality. It is currently the standard care for patients post-heart transplant to receive annual coronary angiograms with close follow up. Patients will be imaged using OCT at the time of their routine annual angiogram, and will be re-imaged one year later at the time of the next annual angiogram or earlier if clinically indicated. The study goal is to better characterize CAV in vivo with OCT imaging and to try to identify patterns of the disease, including intra-coronary risk assessment.
1. Early initiation of sirolimus will prevent or delay the development of intimal thickening and subsequent graft failure. 2. Treatment guided by the development of cardiac allograft vasculopathy (CAV) on intravascular ultrasound (IVUS) will be more effective in delaying progression of CAV compared to treatment guided by angiography. 3. Prevention of the development and progression of intimal thickness on IVUS will prevent the development of heart failure, graft dysfunction, and cardiovascular death related to CAV. 4. Small artery elasticity predicts progression of cardiac allograft vasculopathy and is modified by sirolimus 5. Patients who have no progression of CAV will have favorable improvement in biomarkers and endothelial cells compared to patients who have progression of CAV
Abnormal peripheral endothelial function and alterations in circulating biomarkers that are associated with endothelial activation and inflammation correlate with angiographic evidence of cardiac allograft vasculopathy, defined as greater than 25% stenosis in a major coronary artery.