Proteomic Profiles Of Left Ventricular Assist Device Implantation

Abstract

Introduction Left ventricular assist devices (LVADs) are widely used to support patients with advanced heart failure, but conversion from normal pulsatile flow is known to lead to vascular remodeling and ultimately may contribute to adverse vascular events. The underlying biology of such changes remains poorly understood. Hypothesis: High-throughput plasma proteomic profiling before and after LVAD implantation will identify novel biomarkers and protein mediators of LVAD cardiovascular effects. Methods Fifteen patients undergoing HeartMate II implantation at University of Colorado Hospital had serial plasma samples collected pre-LVAD (day 0) as well as days 14 and 60 after LVAD implant. Proteomic profiling was performed with 1,196 antibody-based proteomic probes on the Olink® platform. Linear mixed effects models of log2-scaled proteomic measurements, adjusted for renal function, compared protein levels between time points. GO Biological Pathway analysis was performed using both over-representation analysis (ORA) and gene set enrichment analysis (GSEA). A false discovery rate (FDR) of 5% adjusted for multiple comparisons within each analysis. Results The mean age was 57 years; 3 participants (20%) were female, 3 (20%) were Black, and 9 (60%) had a non-ischemic cardiomyopathy. At day 14, 300 proteins were significantly different from day 0 at FDR<5%. At day 60, 161 proteins differed from day 0 at FDR<5% (Figure 1a). Known biomarkers showed expected changes: B-type natriuretic peptide decreased significantly (day 14 vs day 0 β = -0.87 ± 0.26, p = 0.002; day 60 vs day 0 β = -1.19 ± 0.23, p = 1 × 10−5) as did ST2 (day 60 vs day 0 β = -0.72 ± 0.26, p = 0.01). Four proteins had statistically significant (FDR < 5%) differences at 0 vs 14 and 14 vs 60 days, highlighting novel findings (Figure 1b): CCN3, DSG3, THBS4, and COMP are all involved in extracellular matrix biology, and DSG3 and CCN3 are implicated in cell-cell communication in myocardium. Indeed, ORA and GSEA identified enrichment for blood vessel development (p = 4 × 10−6, p = 4 × 10−5, respectively) and cell adhesion (p = 9 × 10−5, p = 8 × 10−5). Conclusions Proteomic profiling identified novel protein changes following LVAD implantation, particularly among proteins involved in blood vessel development and cell adhesion. Further work is needed to understand biological implications and determine if these proteins also associate with clinical outcomes in larger cohorts and in axial compared to centrifugal flow LVADs. Left ventricular assist devices (LVADs) are widely used to support patients with advanced heart failure, but conversion from normal pulsatile flow is known to lead to vascular remodeling and ultimately may contribute to adverse vascular events. The underlying biology of such changes remains poorly understood. Hypothesis: High-throughput plasma proteomic profiling before and after LVAD implantation will identify novel biomarkers and protein mediators of LVAD cardiovascular effects. Fifteen patients undergoing HeartMate II implantation at University of Colorado Hospital had serial plasma samples collected pre-LVAD (day 0) as well as days 14 and 60 after LVAD implant. Proteomic profiling was performed with 1,196 antibody-based proteomic probes on the Olink® platform. Linear mixed effects models of log2-scaled proteomic measurements, adjusted for renal function, compared protein levels between time points. GO Biological Pathway analysis was performed using both over-representation analysis (ORA) and gene set enrichment analysis (GSEA). A false discovery rate (FDR) of 5% adjusted for multiple comparisons within each analysis. The mean age was 57 years; 3 participants (20%) were female, 3 (20%) were Black, and 9 (60%) had a non-ischemic cardiomyopathy. At day 14, 300 proteins were significantly different from day 0 at FDR<5%. At day 60, 161 proteins differed from day 0 at FDR<5% (Figure 1a). Known biomarkers showed expected changes: B-type natriuretic peptide decreased significantly (day 14 vs day 0 β = -0.87 ± 0.26, p = 0.002; day 60 vs day 0 β = -1.19 ± 0.23, p = 1 × 10−5) as did ST2 (day 60 vs day 0 β = -0.72 ± 0.26, p = 0.01). Four proteins had statistically significant (FDR < 5%) differences at 0 vs 14 and 14 vs 60 days, highlighting novel findings (Figure 1b): CCN3, DSG3, THBS4, and COMP are all involved in extracellular matrix biology, and DSG3 and CCN3 are implicated in cell-cell communication in myocardium. Indeed, ORA and GSEA identified enrichment for blood vessel development (p = 4 × 10−6, p = 4 × 10−5, respectively) and cell adhesion (p = 9 × 10−5, p = 8 × 10−5). Proteomic profiling identified novel protein changes following LVAD implantation, particularly among proteins involved in blood vessel development and cell adhesion. Further work is needed to understand biological implications and determine if these proteins also associate with clinical outcomes in larger cohorts and in axial compared to centrifugal flow LVADs.