Micro‐ and macrovascular cardiac allograft vasculopathy in relation to 91 cardiovascular biomarkers in heart transplant recipients—An exploratory study

Abstract

Background Cardiac allograft vasculopathy (CAV) limits survival after heart transplantation (HTx), and the pathogenesis is not fully clarified. We aimed to investigate a wide range of biomarkers and their correlation with micro‐ and macrovascular CAV and major adverse cardiac events in HTx patients. Methods We evaluated 91 cardiovascular disease‐related proteins in 48 HTx patients using a novel proteomic panel. Patients were dichotomized according to micro‐ and macrovascular CAV burden determined by coronary angiography, optical coherence tomography, and 15O‐H2O positron emission tomography imaging. Major adverse cardiac events included significant CAV progression, heart failure, treated rejection, and cardiovascular death. Results We found consistent differences in two proteins involved in cholesterol homeostasis: significantly increased proprotein convertase subtilisin/kexin type 9 (PCSK9) (p < .05) and significantly decreased paraoxonase 3 (PON3) (p < .05). N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) was significantly increased in patients with microvascular CAV (p < .05) and borderline significantly increased in patients experiencing major adverse cardiac events (p = .10) and patients with macrovascular CAV (p = .05). Conclusions We identified consistent changes in two proteins involved in cholesterol homeostasis which may be important players in the pathogenesis of CAV: PON3 and PCSK9. NT‐proBNP also showed consistent changes across all groups but only reached statistical significance in patients with microvascular CAV. Our results warrant further validation in future studies.

Cardiac Allograft Vasculopathy: Challenges and Advances in Invasive and Non-Invasive Diagnostic Modalities

“…A study in 2020 by Bjerre et al further evaluated 91 cardiovascular disease related proteins, identifying two novel, potentially significant recipient biomarkers [ 113 ]. Specifically, HTx patients with diagnosed CAV had significantly deranged serum levels of subtilisin/kexin type 9 (PCSK9) and paraoxonase 3 (PON3), both of which are involved in cholesterol homeostasis [ 113 ]. This adds evidence to the hypothesis that, despite its differences with native heart atherosclerosis, cholesterol accumulation is significant in the pathogenesis of CAV.…”

Contribution of Proteomics in Transplantation: Identification of Injury and Rejection Markers

“…Consistent changes in 2 proteins PON3 and PCSK9 were observed. 58 These proteins are involved in cholesterol homeostasis and thus may be important players in CAV pathogenesis. N-terminal pro-brain natriuretic peptide was found to be elevated in patients with microvascular CAV.…”

Cardiac allograft vasculopathy: A review

“…Other biomarkers, such as Troponin and CRP have been studied mainly in the adult population with mixed results. BNP, a hormone secreted by the ventricles in response to myocardial stress, has been shown in adult studies to be associated with the presence of CAV and allograft dysfunction 47,48 . A few studies looking at BNP as a biomarker were done in the pediatric population in the early 2000s demonstrating a role for BNP in the detection of acute rejection and graft loss with evidence of overlap with CAV 10 .…”

“…BNP, a hormone secreted by the ventricles in response to myocardial stress, has been shown in adult studies to be associated with the presence of CAV and allograft dysfunction. 47,48 A few studies looking at BNP as a biomarker were done in the pediatric population in the early 2000s demonstrating a role for BNP in the detection of acute rejection and graft loss with evidence of overlap with CAV. 10 A study looking at 37 patients post pediatric heart transplant demonstrated a significant difference in BNP levels in patients with graft pathology compared to those without (p < .001).…”