Abstract
Cardiac allograft vasculopathy (TAV) is a diffuse and progressive form of coronary artery disease occurring after heart transplantation (HT) characterized by endothelial dysfunction (ED) and negative arterial remodeling. However, TAV risk factors are not well understood. We hypothesized that asymmetric dimethylarginine (ADMA), a circulating inhibitor of nitric oxide synthase, mediates HT related ED and remodeling. Methods and Results Forty eight consecutive cardiac transplant recipients underwent baseline angiography within 8 weeks of cardiac transplantation and at 1 year after transplantation. Intravascular ultrasound indices were measured at baseline and 1 year in all and coronary response to infused acetylcholine and glyceryl trinitrate at 1 year as a measure of ED in 31 subjects. ADMA and its circulating metabolite symmetric DMA (SDMA) were measured at 8 weeks and 1 year by LC-mass spectroscopy. Rejection was diagnosed histologically in endomyocardial biopsies and subjects were subdivided into those with without treated rejection in the first year after HT. Responses to Ach were significantly impaired in patients with a history of treated rejection in the first year after transplant versus those without rejection (mean % change vessel diameter ± SD; −19.4 ± 12.7 versus −8.4 ± 10.2, p = 0.026). There was no difference in response to glyceryl trinitrate in those with and without rejection. Plasma ADMA levels decreased significantly after HT (0.55 ±0.12 versus 0.48 ± 0.09 micromol/l, p <0.001). Using stepwise multivariate regression in a model including age, gender, lipid levels, glucose and blood pressure, plasma ADMA was an independent correlate of Ach coronary artery response 1 year after transplant (p = 0.004, R2 = 46%). Other predictors were female gender and rejection. The ADMA/SDMA ratio (a marker of ADMA breakdown) was correlated inversely with change in vessel volume and change in lumen volume as measured by IVUS between baseline and 1 year (r = −0.036, p = 0.04). Conclusion Levels of ADMA correlated with impaired endothelial function as did episodes of treated rejection. The ADMA/SDMA ratio, a marker of ADMA breakdown, correlated with negative arterial remodeling. Abnormalities in ADMA metabolism may contribute to the pathogenesis of CAV.
Published Version
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