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

Abstract

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Conflict of interest statement

Harald Mischak is the cofounder and a shareholder of Mosaiques Diagnostics AG (Hannover, Germany). Esther Nkuipou-Kenfack is an employee of Mosaiques Diagnostics AG. This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the other authors declares a conflict of interest.

Figures

Fig 1

β-Blockers use (A) and heart rate during right heart catheterization (B) by years since heart transplantation. The number of patients contributing to each statistic is given alongside the columns (A) or plotted points (B).

Fig 2. Levels of the urinary classifiers HF1 and HF2 in non-users of β-blockers and in users started on β-blockade within 1 year of heart transplantation (n = 54) or later (n = 64).

Estimates given with SE were adjusted for time since transplantation, age, mean arterial pressure, body mass index, total-to-HDL cholesterol ratio, glomerular filtration rate estimated from serum creatinine and the presence of diabetes mellitus. p values denote the significance of the difference between non-users and users.

Fig 3. V-plots generated by partial least squares discriminant analysis.

Variable Importance in Projection (VIP) scores indicate the importance of each urinary fragment in the construction of the partial least squares factors and are plotted against the centered and rescaled correlation coefficients. These correlation coefficients reflect the associations of β-blockers use vs. non-use with the urinary fragments. The urinary peptides associated with non-use (left side of the V plot) included collagen I fragments. The urinary peptides associated with use of β-blockers included fragments of collagen II and III and a fragment of collagen IV, the fibrinogen α chain and the mucin-1 subunit α. Colors identify fragments derived from collagen I (blue), II (grey), III (red), IV (brown), V (pink), mucin-1 subunit α (orange), fibrinogen (green), and uromodulin (black).