Endothelial Injury and Development of Coronary Intimal Thickening After Heart Transplantation

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.

Optical Coherence Tomography, OCT, Coronary Allograft Vasculopathy, Donor Specific Antibodies, Acetylcholine, Coronary endothelial function, Brachial Artery Flow Mediated Dilation, Heart transplantation

All subjects will undergo a Brachial Artery Flow Medicated Dilation prior to heart catheterization. After routine heart catheterization, images of their coronary artery will be recorded by Optical Coherence Tomography (OCT) during infusion of Acetylcholine.

The primary endpoint will be a comparison of intimal thickness in the coronary artery by Optical Coherence Tomography with presence or absence of donor specific antibodies.

Assessment of epicardial coronary endothelial function by measuring change in vessel size in response to acetylcholine and how this compares to peripheral endothelial function.

Prospectively determine the association of HLA and non-HLA donor specific antibodies that activate complement with endothelial dysfunction and intimal thickening.

Gene expression of white blood cells by microRNA and how this relates to endothelial function and intimal thickness.

Comparison of endothelial function in the coronary artery with presence or absence of donor specific antibodies.

Inclusion Criteria: Subjects who are 1 year post heart transplantation Subjects will include both male and females Be at least 18 years of age Exclusion Criteria: Known coronary artery disease after transplantation Evidence of strong or moderate antibodies already present at the time of the transplant Severe renal dysfunction defined as creatinine clearance of <30 or on hemodialysis. 3 or more episodes of acute cellular rejection Females who are pregnant Patients requiring endomyocardial biopsy at the time of catheterization Patients unable to tolerate heparin or systemic anticoagulation History of multi-organ transplant Patients unable to give consent

Khandhar SJ, Yamamoto H, Teuteberg JJ, Shullo MA, Bezerra HG, Costa MA, Selzer F, Lee JS, Marroquin OC, McNamara DM, Mulukutla SR, Toma C. Optical coherence tomography for characterization of cardiac allograft vasculopathy after heart transplantation (OCTCAV study). J Heart Lung Transplant. 2013 Jun;32(6):596-602. doi: 10.1016/j.healun.2013.02.005. Epub 2013 Mar 15.