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

J. C. Hupf, D. Onat, A. Javaid, G. M. Mondellini, L. Braghieri, K. J. Clerkin, J. M. Griffin, F. Latif, S. W. Restaino, M. V. Habal, M. A. Farr, K. Takeda, Y. Naka, G. T. Sayer, N. Uriel, R. T. Demmer, P. C. Colombo, M. Yuzefpolskaya

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Abstract

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSION: Our findings indicate that ET1, but not TMAO, is independently associated with CAV in HT.

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    Hupf, J. C., Onat, D., Javaid, A., Mondellini, G. M., Braghieri, L., Clerkin, K. J., Griffin, J. M., Latif, F., Restaino, S. W., Habal, M. V., Farr, M. A., Takeda, K., Naka, Y., Sayer, G. T., Uriel, N., Demmer, R. T., Colombo, P. C., & Yuzefpolskaya, M. (2020). Association of Plasma Trimethylamine-N-oxide and Serum Endothelin-1 with Cardiac Allograft Vasculopathy in Heart Transplant Recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation, 39(4), S231. https://doi.org/10.1016/j.healun.2020.01.888