Plasma Proteomic Associations With Incident Ischemic Stroke in Older Adults: The Cardiovascular Health Study

Plasma proteomics may elucidate novel insights into the pathophysiology of ischemic stroke (IS), identify biomarkers of IS risk, and guide development of nascent prevention strategies. We evaluated the relationship between the plasma proteome and IS risk in the population-based Cardiovascular Health Study (CHS).

Eligible CHS participants were free of prevalent stroke and underwent quantification of 1,298 plasma proteins using the aptamer-based SOMAScan assay platform from the 1992-1993 study visit. Multivariable Cox proportional hazards regression was used to evaluate associations between a 1-SD increase in the log₂-transformed estimated plasma protein concentrations and incident IS, adjusting for demographics, IS risk factors, and estimated glomerular filtration rate. For proteins independently associated with incident IS, a secondary stratified analysis evaluated associations in subgroups defined by sex and race. Exploratory analyses evaluated plasma proteomic associations with cardioembolic and noncardioembolic IS and proteins associated with IS risk in participants with left atrial dysfunction but without atrial fibrillation.

Of 2,983 eligible participants, the mean age was 74.3 (±4.8) years, 61.2% were women, and 15.4% were Black. Over a median follow-up of 12.6 years, 450 participants experienced an incident IS. N-terminal probrain natriuretic peptide (NTproBNP, adjusted HR 1.37, 95% CI 1.23-1.53, p = 2.08 × 10^-08) and macrophage metalloelastase (MMP12, adjusted HR 1.30, 95% CI 1.16-1.45, p = 4.55 × 10^-06) were independently associated with IS risk. These 2 associations were similar in men and women and in Black and non-Black participants. In exploratory analyses, NTproBNP was independently associated with incident cardioembolic IS, E-selectin with incident noncardioembolic IS, and secreted frizzled-related protein 1 with IS risk in participants with left atrial dysfunction.

In a cohort of older adults, NTproBNP and MMP12 were independently associated with IS risk. We identified plasma proteomic determinants of incident cardioembolic and noncardioembolic IS and found a novel protein associated with IS risk in those with left atrial dysfunction.