Risk of Infection, Endoplasmic Reticular Stress and Systemic Activation of NLRP3 Inflammasome in Patients Supported by Continuous Flow Left Ventricular Assist Devices

• Published in: The Journal of heart and lung transplantation Vol. 41; no. 4; p. S304
• Main Authors: Mondal, N.K., Gray, Z., Walther, C.P., Lamba, H.K., Hochman-Mendez, C., Shafii, A.E., Loor, G., Mattar, A., Ghanta, R.K., Chatterjee, S., Frazier, O., Liao, K.K.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.04.2022
• ISSN: 1053-2498; 1557-3117
• DOI: 10.1016/j.healun.2022.01.753

We investigated changes in stress-associated endoplasmic reticulum (ER) protein 1 (SERP1), ER-stress response proteins and inflammasome activation in heart failure (HF) patients before and after CF-LVAD implantation, and relationship to subsequent infection within 3 months. We analyzed blood samples from 24 CF-LVAD patients (pre- and 1week post-VAD) and 10 non-HF controls. Culture positive Infections was confirmed (median 42 days post-VAD) from bloodstream, GI, respiratory tracts, or driveline. SARP1, ER-stress proteins (ATF-6, GRP78) and NLRP3 inflammasome (NLRP3, ASC, Caspase1) in peripheral blood mononuclear cells (PBMC) were assessed. HF patients had significantly (p<0.05) elevated baseline (pre-VAD) PBMC protein levels of ATF6 (0.41±0.05 vs. 0.54±0.11), GRP78 (0.20±0.07 vs. 0.33±0.18), NLRP3 (0.28±0.17 vs. 0.78±0.28), and ASC (0.27±0.13 vs. 0.44±0.15) compared to controls. Among CF-LVAD recipients, SERP1 declined in those without subsequent infection (Group1) but significantly increased in those with infection (Group2) (Fig.A,B). Baseline ATF6 and GRP78 differed between Group1 and 2 (Fig.C,D). In Group2, the post-VAD ATF6, GRP78, NLRP3 and ASC were significantly elevated compared to pre-VAD; while in group1, only the post-VAD GRP78 was significantly elevated (Fig.C-G). Post-VAD caspase1 increased but not-significant (0.36±0.07 vs. 0.43±1.2) in group2 compared to pre-VAD (Fig.H). Baseline SERP1 and NLRP3 among patients who developed infection were positively correlated with ATF6 and GRP78 (Fig.I-L). Post-VAD upregulation of SERP1 may be associated with ER-stress response, which in turn may activate NLRP3 inflammasome and predispose to early infection. Post-VAD decrease in SERP1 in group1 may protect against ER stress and NLRP3 activation. Further investigation of the role of SERP1 in ER-stress and inflammasome activation in CF-LVAD recipients is needed.