Association of Plasma Trimethylamine-N-oxide and Serum Endothelin-1 with Cardiac Allograft Vasculopathy in Heart Transplant Recipients

Abstract

Cardiac allograft vasculopathy (CAV) is a major complication that affects long-term survival after heart transplantation (HT). Multiple factors contribute to the development of CAV, with inflammation playing an important role. Endothelin-1 (ET1) is a pro-inflammatory mediator that has been implicated in development of CAV. Trimethylamine-N-oxide (TMAO) is a gut-derived metabolite, recently linked to accelerated risk of atherosclerosis in non-HT pts. Herein, we sought to investigate the association of ET1 and TMAO with CAV in HT. Blood was collected in 116 HT pts (52.8±12.6 yo; F 19%). Plasma TMAO and serum ET1 were measured via LC-MS and ELISA, respectively. Presence of CAV on angiography was defined using the current ISHLT criteria or an intravascular ultrasound measurement of a maximal intimal thickness of >0.5mm. We used Wilcoxon test and logistic regression analyses to assess the association between CAV and TMAO/ET1 levels, controlling for several covariates. TMAO and ET1 were measured at a median [IQR] of 9.3 [4.7-52.7] months post-HT. CAV was assessed at a median of 4.70 [1.08-8.17]y. Median TMAO and ET1 levels were 4.79 [2.49-9.15] µM and 1.93 [1.36-2.61] pg/mL, respectively. CAV was present in 59 (51%) pts. There was no difference in baseline characteristics in pts with (CAV+) and without CAV (CAV-). CAV+ pts had a longer median follow up (5.98 [2.99-9.75] vs 1.92 [1.01-6.02]y). TMAO levels were similar in both groups (5.50 [2.67-11.5] vs 4.44 [2.61-7.58] µM, p = 0.56), while ET1 was significantly higher in the CAV+ group (2.20 [1.69-2.93] vs 1.68[1.21- 2.31] pg/mL, p<0.001) (Figure 1a and b). ET1 was independently associated with CAV incidence after adjusting for age, gender, HTN, diabetes, history of stroke and time post HT (p=0.003). Our findings indicate that ET1, but not TMAO, is independently associated with CAV in HT.