Summary
This large-scale plasma proteomics study identified 37 circulating proteins consistently associated with incident heart failure across three diverse cohorts, independent of established risk factors. Mendelian randomisation analysis supported causal roles for 10 proteins, including matricellular, senescence-associated, and inflammatory proteins such as SPON1, MFAP4, FSTL3, IGFBP7, SVEP1, CCL15, and ITIH3. Protein network analyses further identified five co-regulation modules associated with heart failure risk, two influenced by genetic variants in the VTN and CFH loci, suggesting potential therapeutic targets and novel mechanistic pathways in heart failure pathobiology.
Regional applicability
This international study included participants from the United States (Atherosclerosis Risk in Communities study) and Norway (Trøndelag Health Study), providing diverse geographical representation. Findings are applicable to United Kingdom clinical populations, though the proteomic signatures identified should be validated in UK cohorts to confirm generalisability across ethnically diverse populations and healthcare contexts.
Key measures
Plasma proteomics (4877 proteins measured); incident heart failure status; traditional cardiovascular risk factors; Mendelian randomisation analyses; protein co-regulation network modules
Outcomes reported
The study measured 4877 plasma proteins in 13,900 heart failure-free individuals across three cohorts to identify circulating proteins and protein networks predictive of incident heart failure development. Results identified 37 proteins consistently associated with heart failure independent of traditional risk factors, with Mendelian randomisation supporting causal effects of 10 proteins on heart failure, its risk factors, or left ventricular function.
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