Plasma Proteomic Signature Implicates Impaired Calcium Handling and Cell-matrix Adhesion in Repaired Tetralogy of Fallot with Right Ventricular Volume and Pressure Overload

Background: Patients who have undergone tetralogy of Fallot (TOF) repair are subject to chronic volume and pressure overload, leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive, circulating signature of the systemic response to right heart stress to better understand the mechanisms of RV failure and to develop novel therapies.

Methods: High throughput mass spectroscopy was used to assess circulating plasma proteins from control individuals with structurally normal hearts (N=14) and those with TOF status post repair (N=74): no residual lesion (N=4), severe right heart volume overload (N=28), severe right heart pressure overload (N=20), and moderate right heart volume and pressure overload (N=22). Ingenuity pathway analysis was used to identify enriched biological processes using proteins with log2 fold change>0.6, and q value <0.05.

Results: Mean age in controls was 152yrs, 50% male and in TOF s/p repair 1714yrs, 34% male. The RV was moderately dilated with normal function in those with volume and/or pressure overload. We identified (i) excellent proteomic coverage identifying >1500 proteins/sample; (ii) unique subset of proteins distinguishing plasma proteome of control versus TOF with residual defects (Fig 1); (iii) upregulated pathways governing signal transduction (e.g. CREBBP), catabolic processes (e.g. NT5M), cell death and aging (e.g. FUCOA 2-fold); (iv) downregulated pathways governing immune response (e.g. IGHV4), complement and coagulation activation (e.g. VWF), regulation of calcium handling (e.g. S100A, largest change 12-fold) and cell-extracellular matrix adhesion.

Conclusion: Patients with repaired TOF with RV volume and pressure overload have a distinct plasma profile implicating heightened cell death pathways and impaired calcium handling which may predispose to heart failure and arrhythmias. These data suggest peripheral blood proteins can provide insight into the mechanisms of RV failure and can be used for monitoring disease progression.