Abstract
Background and Aims Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed. Methods In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score. Results Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10-5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10-5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C-statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P = .001). C-statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787). Conclusions Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2752-2767 |
| Number of pages | 16 |
| Journal | European heart journal |
| Volume | 45 |
| Issue number | 30 |
| DOIs | |
| State | Published - Aug 7 2024 |
Funding
NHLBI R01HL153499 (R.F.D. and P.G.). NHLBI K23HL150236 (R.M.). U01DK1061022, DK116095, DK1061022, DK120886 (M.R.W.). Funding for this study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Disease (5U01DK108809) (R.F.D., R.D., P.G.). Funding for the CRIC Study was obtained under a cooperative agreement from the National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, and U24DK060990). In addition, this work was supported in part by: the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award National Institutes of Health (NIH)/NCATS UL1TR000003, Johns Hopkins University UL1 TR-000424, University of Maryland GCRC M01 RR-16500, Clinical and Translational Science Collaborative of Cleveland, UL1TR000439 from the National Center for Advancing Translational Sciences (NCATS) component of the National Institutes of Health and NIH roadmap for Medical Research, Michigan Institute for Clinical and Health Research (MICHR) UL1TR000433, University of Illinois at Chicago CTSA UL1RR029879, Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases P20 GM109036, Kaiser Permanente NIH/National Center for Research Resources UCSF-CTSI UL1 RR-024131, University of New Mexico School of Medicine Albuquerque, NM R01DK119199. The opinions expressed in this paper do not necessarily reflect those of the National Institute of Diabetes Digestive and Kidney Diseases, the National Institutes of Health, the Department of Health and Human Services, or the Government of the United States of America.
Keywords
- Chronic kidney disease
- Heart failure
- Mendelian randomization
- Risk model
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine