Research Article: Urinary proteomic signatures associated with β-blockade and heart rate in heart transplant recipients

Date Published: September 24, 2018

Publisher: Public Library of Science

Author(s): Qi-Fang Huang, Jan Van Keer, Zhen-Yu Zhang, Sander Trenson, Esther Nkuipou-Kenfack, Lucas N. L. Van Aelst, Wen-Yi Yang, Lutgarde Thijs, Fang-Fei Wei, Agnieszka Ciarka, Johan Vanhaecke, Stefan Janssens, Johan Van Cleemput, Harald Mischak, Jan A. Staessen, Vincenzo Lionetti.


Heart transplant (HTx) recipients have a high heart rate (HR), because of graft denervation and are frequently started on β-blockade (BB). We assessed whether BB and HR post HTx are associated with a specific urinary proteomic signature.

In 336 HTx patients (mean age, 56.8 years; 22.3% women), we analyzed cross-sectional data obtained 7.3 years (median) after HTx. We recorded medication use, measured HR during right heart catheterization, and applied capillary electrophoresis coupled with mass spectrometry to determine the multidimensional urinary classifiers HF1 and HF2 (known to be associated with left ventricular dysfunction), ACSP75 (acute coronary syndrome) and CKD273 (renal dysfunction) and 48 sequenced urinary peptides revealing the parental proteins.

In adjusted analyses, HF1, HF2 and CKD273 (p ≤ 0.024) were higher in BB users than non-users with a similar trend for ACSP75 (p = 0.06). Patients started on BB within 1 year after HTx and non-users had similar HF1 and HF2 levels (p ≥ 0.098), whereas starting BB later was associated with higher HF1 and HF2 compared with non-users (p ≤ 0.014). There were no differences in the urinary biomarkers (p ≥ 0.27) according to HR. BB use was associated with higher urinary levels of collagen II and III fragments and non-use with higher levels of collagen I fragments.

BB use, but not HR, is associated with a urinary proteomic signature that is usually associated with worse outcome, because unhealthier conditions probably lead to initiation of BB. Starting BB early after HTx surgery might be beneficial.

Partial Text

Heart transplantation (HTx) is the treatment of choice for a highly selected group of terminally ill heart failure patients with severe symptoms not responding to optimal medical combined with device-based therapy [1]. Denervation of the graft explains why HTx recipients commonly have a high heart rate, which is an independent predictor of mortality [2–4]. The current study builds on previous observations in a single-center cohort of HTx patients [5,6]. A higher heart rate 3 months after surgery and non-use of β-blockers were associated with increased mortality [5]. In the same cohort [6], elevated right heart pressures were associated with increased urinary levels of the multidimensional urinary classifier HF2 [7]. In line with a position paper of the American Heart Association supporting the use of omics technologies in research on cardiovascular disease [8], the aim of our current study was to explore whether the use of β-blockers or tachycardia after HTx were associated with a specific urinary peptidomic signature. We studied the multidimensional urinary classifiers HF1 [9,10], HF2 [7], ACSP75 [11] and CKD273 [12,13], respectively consisting of 85, 671, 75 and 273 peptide fragments, mainly dysregulated peptide fragments. These markers were developed for the diagnosis of asymptomatic diastolic left ventricular dysfunction [9,10], symptomatic heart failure [7], the prediction of acute coronary events [11], and the decline in glomerular filtration rate [12,13]. We also studied single sequenced urinary peptides, which identify parental proteins and can thereby reveal underlying pathophysiological processes.

The key finding of our manuscript was that use vs. non-use of β-blockers was associated with specific urinary proteomic signatures, whereas heart rate was not (Table 3). β-blocker use correlated with higher levels of the multidimensional classifiers HF1, HF2, ACSP75 and CKD273, which in other studies were indicative of a worse haemodynamic condition [7] or predicted cardiovascular [26], cardiac [26] or coronary [11] events or decline in renal function [12,27]. Along similar lines, β-blockade was associated with higher levels of various fragments of collagen II and III and a fragment of the fibrinogen α chain and the mucin-1 subunit α, which are indicative of diastolic left ventricular dysfunction [28] or renal impairment [13,27]. These observations probably reflect reverse causality, indicating that unhealthier HTx patients, as reflected by their urinary biomarkers, were more likely to be started on a β-blocker. In keeping with this idea, patients on β-blockers compared with non-users, had a higher frequency of hypertension and diabetes mellitus, were older and more obese, and had lower eGFR (Table 1).




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