Search

Left ventricular assist devices (LVADs) have been used as a standard treatment option for patients with advanced heart failure. However, these devices are prone to adverse events. Nonsurgical bleeding (NSB) is the most common complication in patients with continuous flow (CF) LVADs. The development of acquired von Willebrand syndrome (AVWS) in CF-LVAD recipients is thought to be a key factor. However, AVWS is seen across a majority of LVAD patients, not just those with NSB. The purpose of this study was to examine the link between acquired platelet defects and NSB in CF-LVAD patients.Blood samples were collected from 62 CF-LVAD patients at pre- and 4 post-implantation timepoints. Reduced adhesion receptor expression (GPIbα and GPVI) and activation of platelets (GPIIb/IIIa activation) were used as markers for acquired platelet defects.Twenty-three patients experienced at least one NSB episode. Significantly higher levels of platelet activation and receptor reduction were seen in the postimplantation blood samples from bleeders compared with non-bleeders. All patients experienced the loss of high molecular weight monomers (HMWM) of von Willebrand Factor (vWF), but no difference was seen between the two groups. Multivariable logistic regression showed that biomarkers for reduced platelet receptor expression (GPIbα and GPVI) and activation (GPIIb/IIIa) have more predictive power for NSB, with the area under curve (AUC) values of 0.72, 0.68, and 0.62, respectively, than the loss of HMWM of vWF (AUC: 0.57).The data from this study indicated that the severity of acquired platelet defects has a direct link to NSB in CF-LVAD recipients.

Noninvasive monitoring of heart allograft health is important to improve clinical outcomes. MicroRNAs (miRs) are promising biomarkers of cardiovascular disease and limited studies suggest they can be used to noninvasively diagnose acute heart transplant rejection.The Genomic Research Alliance for Transplantation (GRAfT) is a multicenter prospective cohort study that phenotyped heart transplant patients from 5 mid-Atlantic centers. Patients who had no history of rejection after transplant were compared to patients with acute cellular rejection (ACR) or antibody-mediated rejection (AMR). Small RNA sequencing was performed on plasma samples collected at the time of an endomyocardial biopsy. Differential miR expression was performed with adjustment for clinical covariates. Regression was used to develop miR panels with high diagnostic accuracy for ACR and AMR. These panels were then validated in independent samples from GRAfT and Stanford University. Receiver operating characteristic curves were generated and area under the curve (AUC) statistics calculated. Distinct ACR and AMR clinical scores were developed to translate miR expression data for clinical use.The GRAfT cohort had a median age of 52 years, with 35% females and 45% Black patients. Between GRAfT and Stanford, we included 157 heart transplant patients: 108 controls and 49 with rejection (50 ACR and 38 AMR episodes). After differential miR expression and regression analysis, we identified 12 miRs that accurately discriminate ACR and 17 miRs in AMR. Independent validation of the miR panels within GRAfT led to an ACR AUC 0.92 (95% confidence interval [CI]: 0.86-0.98) and AMR AUC 0.82 (95% CI: 0.74-0.90). The externally validated ACR AUC was 0.72 (95% CI: 0.59-0.82). We developed distinct ACR and AMR miR clinical scores (range 0-100), a score ≥ 65, identified ACR with 86% sensitivity, 76% specificity, and 98% negative predictive value, for AMR score performance was 82%, 84% and 97%, respectively.We identified novel miRs that had excellent performance to noninvasively diagnose acute rejection after heart transplantation. Once rigorously validated, the unique clinical ACR and AMR scores usher in an era whereby genomic biomarkers can be used to screen and diagnose the subtype of rejection. These novel biomarkers may potentially alleviate the need for an endomyocardial biopsy while facilitating the initiation of targeted therapy based on the noninvasive diagnosis of ACR or AMR.