Sushrima Gan

All Publications

• Proteome-Wide Mendelian Randomization Identifies Natriuretic Peptide-B and Novel Proteins as Potential Regulators of Pulse Pressure in Humans. Journal of the American Heart Association Dib, M. J., Meena, D., Yarmolinsky, J., Azzo, J. D., Salman, O., Tavolinejad, H., Gan, S., Beeche, C., Pourmussa, B., Gill, D., Burgess, S., Chirinos, J. A. 2025: e037596

  Abstract

  Large-artery stiffness (LAS) significantly contributes to cardiovascular morbidity and death and is characterized by increased pulse pressure (PP). The biology underlying large-artery stiffness in humans remains incompletely understood.We investigated associations between PP and circulating levels of 2941 proteins among 53 016 UK Biobank participants. Analyses were adjusted for age, sex, mean arterial pressure, body mass index and stroke volume. Interaction analyses assessed the effect modification by sex on these relationships. We evaluated causal associations between plasma protein levels and PP, using inverse variance-weighted Mendelian randomization as the main analysis and Bayesian colocalization as a sensitivity analysis. A 5% false discovery rate threshold was used to account for multiple comparisons. Measured levels of 871 proteins were significantly associated with PP when adjusting for age, sex, mean arterial pressure, and body mass index, and 61 remained significantly associated after further adjusting for stroke volume. Top associations included NPPB (natriuretic peptide B), thrombospondin-2, paraoxonase-2, and sclerostin. Genetic analyses indicated that genetically predicted levels for 16 proteins were significantly associated with PP after false discovery rate correction, including fibroblast growth factor 5 (βIVW per SD change in protein levels=0.47 [95% CI, 0.34-0.61]), NPPB (βIVW=-1.40 [95% CI, -1.85 to -0.95]), insulin-like growth factor binding 3 (βIVW=-1.143 [95% CI, -1.57 to -0.71]), and furin (βIVW, 1.31 [95% CI, 0.88-1.73]).Using complementary epidemiological approaches to triangulate findings, our study identifies novel proteins with a putative causal effect on PP. Notably, our findings identify NPPB with high statistical confidence. This may have potentially impactful implications given the current availability of Food and Drug Administration-approved medications to boost NPPB effects.

  View details for DOI 10.1161/JAHA.124.037596

  View details for PubMedID 40792569

• Plasma Proteomics of the Fontan Circulation Reveal Signatures of Oxidative Stress and Cell Death. Circulation. Heart failure Lecointe, J., Gan, S., Tripathi, D., Ichimura, S., Clouthier, K. L., Kushwaha, A., Mercer-Rosa, L., Reddy, S. 2025: e012136

  Abstract

  Single ventricle congenital heart disease like hypoplastic left heart syndrome with a Fontan circulation constitutes, the largest group of children hospitalized with circulation failure, experiencing an in-hospital mortality rate of 20% to 50%. We investigated the mechanisms leading to Fontan failure to identify novel therapeutic targets.Blood was collected from patients with hypoplastic left heart syndrome post-Fontan and controls (n=6/group). Plasma microvesicles were isolated, and proteomics assessed using data-independent acquisition mass spectroscopy. Dysregulated proteins with a fold change >1.5 or ≤1.5, P<0.05, were evaluated using DAVID and Ingenuity pathway analysis. Correlation of highly dysregulated proteins was assessed with New York Heart Association class, right ventricular fractional area change, oxygen saturation, and hemoglobin.The age of Fontan patients versus controls was 16.0±2.1 versus 15.3±2.2. Three of six Fontan patients were in New York Heart Association class II, and 3 of 6 were in New York Heart Association III/IV; 4 of 6 had Fontan-associated liver disease. Overall, 72 proteins were upregulated, and 187 proteins were downregulated in Fontan failure. Proteins upregulated in Fontan failure predicted cell death pathways (Solute carrier family 2, Angiotensinogen, CD14) and mitochondrial reactive oxygen species signaling (ATP5F1A, S100A8); downregulated proteins predicted impaired cell survival (tyrosine-protein kinase, endothelial growth factors) and mitochondrial antioxidant enzymes (GPX1, PRDX5) Increasing expression of the following proteins was associated with worsening New York Heart Association class, ventricular function and cyanosis: complement system (C1QA, r=0.91), mitochondrial reactive oxygen species generation (HSPD1, r=0.81; ATP5F1A, r=0.75), and cytoskeletal proteins (ANK1, r=0.63; ACTN1, r=0.76).Proteins from circulating microvesicles from patients with hypoplastic left heart syndrome post-Fontan are mostly from the liver. While this pilot study is limited by its sample size and may not represent the broader Fontan population, the proteomic changes were associated with worsening heart failure and cyanosis, suggesting their potential utility as biomarkers.

  View details for DOI 10.1161/CIRCHEARTFAILURE.124.012136

  View details for PubMedID 40235440