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Large-Scale Proteomic Profiling of Incident Heart Failure and Its Subtypes in Older Adults
Joyce N Njoroge1, Sandra Sanders van Wijk2, Thomas R Austin3
1Division of Cardiology, Department of Medicine, Stanford University, Palo Alto, CA (J.N.N.).
Insights
This study identified 55 novel protein markers for heart failure (HF) and its subtypes in older adults. Seven new proteins show possible causal links, offering potential for improved risk prediction and therapeutic targets.
Area of Science:
- Cardiovascular Science
- Proteomics
- Gerontology
Background:
- Heart failure (HF), including HFpEF and HFrEF, significantly impacts the elderly population.
- Assessing the circulating proteome is crucial for understanding HF pathogenesis and developing new treatments.
Purpose of the Study:
- To conduct a plasma proteomics screen for incident HF and its subtypes in older adults.
- To identify novel protein biomarkers associated with HF, HFpEF, and HFrEF.
- To investigate potential causal relationships between proteins and HF subtypes using Mendelian randomization.
Main Methods:
- Plasma proteomics screening in two large, population-based cohorts (CHS and AGES-RS) using SomaLogic platforms.
- Meta-analysis of Cox models to identify protein associations with HF, HFpEF, and HFrEF.
- Replication in the ARIC cohort and Mendelian randomization for causal inference.
Main Results:
- Identified 119 proteins associated with HF, 15 with HFpEF, and 11 with HFrEF.
- Discovered 55 novel protein markers for HF or its subtypes, with 7 showing possible causal associations.
- Replicated 55 of 66 identified proteins externally.
Conclusions:
- This large-scale proteomic study identified novel protein markers for heart failure in older adults.
- These findings may improve HF risk prediction, pathobiology understanding, and therapeutic target prioritization.
- Seven proteins demonstrated new, possibly causal associations with HF subtypes.
Background:
Heart failure (HF) and its main subtypes, heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF), impose an enormous health burden on elders. Assessment of the circulating proteome to illuminate pathogenesis could open new opportunities for treatment.
Methods:
We conducted a plasma proteomics screen of incident HF and its subtypes in 2 older population-based cohorts, the CHS (Cardiovascular Health Study) and the AGES-RS (Aging, Gene/Environment Susceptibility-Reykjavik Study). The 2 studies used SomaLogic platforms, with 4404 aptamers in common. Multivariable Cox models were fit to evaluate individual-protein associations with HF, HFpEF, and HFrEF separately in each cohort, and study-specific associations were combined by fixed-effects meta-analysis. Replication was performed in the ARIC (Atherosclerosis Risk in Communities) cohort. Two-sample Mendelian randomization of HF and its subtypes, along with colocalization analysis, was performed to support causal inference.
Results:
Among 8599 participants, 1590 experienced incident HF (536 HFpEF, 471 HFrEF). There were 119 proteins associated with HF, 15 proteins with HFpEF, and 11 proteins with HFrEF, at Bonferroni-corrected significance. Among these, 9 have never previously been identified for cardiovascular diseases, and another 61 represent new associations with incident HF or its subtypes. Of these 70 proteins, 55 of the 66 available replicated externally. Mendelian randomization analysis revealed 7 proteins genetically associated with HF at nominal significance; 2 were separately associated with HFpEF, and another 2 with HFrEF. Seven of these 9 proteins (NPDC1 [neural proliferation differentiation and control protein 1], APOF [apolipoprotein F], LMAN2 [lectin, mannose-binding 2], ADIPOQ [adiponectin], CD14 [cluster of differentiation 14], ARHGAP1 [Rho GTPase-activating protein 1], C9 [complement 9]) showed new, possibly causal associations, although we did not detect evidence for colocalization.
Conclusions:
In this large-scale proteomic study involving 3 longitudinal cohorts of older adults, we identified and replicated 55 novel protein markers of HF or its subtypes, and 7 new, possibly causal proteins. These proteins may enhance risk prediction, improve understanding of pathobiology, and help prioritize targets for therapeutic development of these foremost disorders in elders.
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