TY - JOUR
T1 - Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction
AU - Salman, Oday
AU - Zhao, Lei
AU - Cohen, Jordana B.
AU - Dib, Marie Joe
AU - Azzo, Joe David
AU - Gan, Sushrima
AU - Richards, A. Mark
AU - Pourmussa, Bianca
AU - Doughty, Rob
AU - Javaheri, Ali
AU - Mann, Douglas L.
AU - Rietzschel, Ernst
AU - Zhao, Manyun
AU - Wang, Zhaoqing
AU - Ebert, Christina
AU - van Empel, Vanessa
AU - Kammerhoff, Karl
AU - Maranville, Joseph
AU - Gogain, Joseph
AU - Dennis, Jaclyn
AU - Schafer, Peter H.
AU - Seiffert, Dietmar
AU - Gordon, David A.
AU - Ramirez-Valle, Francisco
AU - Cappola, Thomas P.
AU - Chirinos, Julio A.
PY - 2024/9/3
Y1 - 2024/9/3
N2 - BACKGROUND: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear. METHODS AND RESULTS: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort. CONCLUSIONS: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.
AB - BACKGROUND: Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear. METHODS AND RESULTS: Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort. CONCLUSIONS: KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.
KW - cardiorenal interactions
KW - chronic kidney disease
KW - HFpEF
KW - kidney injury
KW - outcomes
KW - proteomics
U2 - 10.1161/JAHA.123.033660
DO - 10.1161/JAHA.123.033660
M3 - Article
SN - 2047-9980
VL - 13
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 17
M1 - e033660
ER -