Biomarkers to Assess Right Heart Pressures in Recipients of a Heart Transplant: A Proof-of-Concept Study

Qi-Fang Huang, Sander Trenson, Zhen-Yu Zhang, Jan Van Keer, Lucas N L Van Aelst, Wen-Yi Yang, Esther Nkuipou-Kenfack, Lutgarde Thijs, Fang-Fei Wei, Blerim Mujaj, Agnieszka Ciarka, Walter Droogné, Johan Vanhaecke, Stefan Janssens, Johan Van Cleemput, Harald Mischak, Jan A Staessen, Qi-Fang Huang, Sander Trenson, Zhen-Yu Zhang, Jan Van Keer, Lucas N L Van Aelst, Wen-Yi Yang, Esther Nkuipou-Kenfack, Lutgarde Thijs, Fang-Fei Wei, Blerim Mujaj, Agnieszka Ciarka, Walter Droogné, Johan Vanhaecke, Stefan Janssens, Johan Van Cleemput, Harald Mischak, Jan A Staessen

Abstract

Background: This proof-of-concept study investigated the feasibility of using biomarkers to monitor right heart pressures (RHP) in heart transplanted (HTx) patients.

Methods: In 298 patients, we measured 7.6 years post-HTx mean pressures in the right atrium (mRAP) and pulmonary artery (mPAP) and capillaries (mPCWP) along with plasma high-sensitivity troponin T (hsTnT), a marker of cardiomyocyte injury, and the multidimensional urinary classifiers HF1 and HF2, mainly consisting of dysregulated collagen fragments.

Results: In multivariable models, mRAP and mPAP increased with hsTnT (per 1-SD, +0.91 and +1.26 mm Hg; P < 0.0001) and with HF2 (+0.42 and +0.62 mm Hg; P ≤ 0.035), but not with HF1. mPCWP increased with hsTnT (+1.16 mm Hg; P < 0.0001), but not with HF1 or HF2. The adjusted odds ratios for having elevated RHP (mRAP, mPAP or mPCWP ≥10, ≥24, ≥17 mm Hg, respectively) were 1.99 for hsTnT and 1.56 for HF2 (P ≤ 0.005). In detecting elevated RHPs, areas under the curve were similar for hsTnT and HF2 (0.63 vs 0.65; P = 0.66). Adding hsTnT continuous or per threshold or HF2 continuous to a basic model including all covariables did not increase diagnostic accuracy (P ≥ 0.11), whereas adding HF2 per optimized threshold increased both the integrated discrimination (+1.92%; P = 0.023) and net reclassification (+30.3%; P = 0.010) improvement.

Conclusions: Correlating RHPs with noninvasive biomarkers in HTx patients is feasible. However, further refinement and validation of such biomarkers is required before their clinical application can be considered.

Conflict of interest statement

H.M. is the cofounder and a shareholder of Mosaiques Diagnostics AG (Hannover, Germany). E.N.-K. is an employee of Mosaiques Diagnostics AG. The other authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Frequency distributions of hsTnT, HF1 and HF2 by RHPS (0, 1). This score is 1 if any mean RHP is equal to or higher than the 75th percentile (mean right atrial pressure, ≥10 mm Hg; mean pulmonary arterial pressure, ≥24 mm Hg; or pulmonary capillary wedge pressure, ≥17 mm Hg) and 0 otherwise. Mean values (given at the top of the distribution plots) were in patients with elevated RHPS or not (P ≤ 0.0005).
FIGURE 2
FIGURE 2
mRAP, mPAP, and mPCWP plotted as a function of the time interval since HTx. Plotted values are averages for each time point. n indicates the number of patients contributing to the estimates. Vertical bar denote the SD. P values are for linear trend.
FIGURE 3
FIGURE 3
Mean normalized values of hsTnT, HF1, and HF2 by fourths of the distributions of mRAP, mPAP, and mPCWP. P values are for linear trend. Associations were adjusted for years since transplantation, age, body mass index, mean arterial pressure on office measurement, heart rate during the right heart catheterization, serum creatinine, and use of immunosuppressive (by class), and antihypertensive drugs.
FIGURE 4
FIGURE 4
ROC curves for differentiating between RHPS 1 versus 0 for hsTnT and HF2 in all patients (n = 298) and patients with a history of ischemic (n = 121 [ICM]) or dilated (n = 116 [DCM]) cardiomyopathy. The AUCs did not differ among the biomarkers (P ≥ 0.66) with the exception of a slight increase in the AUC for HF2 compared with hsTnT in patients with ischemic cardiomyopathy (0.56 vs 0.67; P = 0.079).

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