Circulating proteins as predictors of incident heart failure in the elderly

Abstract

Aims To identify novel risk markers for incident heart failure using proteomic profiling of 80 proteins previously associated with cardiovascular pathology. Methods and results Proteomic profiling (proximity extension assay) was performed in two community‐based prospective cohorts of elderly individuals without heart failure at baseline: the Prospective Investigation of the Vasculature in Uppsala Seniors [PIVUS, n = 901, median age 70.2 (interquartile range 70.0–70.3) years, 80 events]; and the Uppsala Longitudinal Study of Adult Men [ULSAM, n = 685, median age 77.8 (interquartile range 76.9–78.1) years, 90 events]. Twenty‐nine proteins were associated with incident heart failure in the discovery cohort PIVUS after adjustment for age and sex, and correction for multiple testing. Eighteen associations replicated in ULSAM. In pooled analysis of both cohorts, higher levels of nine proteins were associated with incident heart failure after adjustment for established risk factors: growth differentiation factor 15 (GDF‐15), T‐cell immunoglobulin and mucin domain 1 (TIM‐1), tumour necrosis factor‐related apoptosis‐inducing ligand receptor 2 (TRAIL‐R2), spondin‐1 (SPON1), matrix metalloproteinase‐12 (MMP‐12), follistatin (FS), urokinase‐type plasminogen activator surface receptor (U‐PAR), osteoprotegerin (OPG), and suppression of tumorigenicity 2 (ST2). Of these, GDF‐15, U‐PAR, MMP‐12, TRAIL‐R2, SPON1 and FS were associated with worsened echocardiographic left ventricular systolic function at baseline, while only TIM‐1 was positively associated with worsened diastolic function (P < 0.02 for all). Conclusion Proteomic profiling identified several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident heart failure in elderly individuals. Our results encourage additional studies investigating the underlying mechanisms and the clinical utility of our findings.

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

“…In the last decade, circulating biomarkers, such as N-terminal pro brain natriuretic peptide (NT-proBNP), have been studied for prediction of incident HF [7][8][9][10] . A recently published study 10 , also investigated the association of multiple proteins with incident HF for "prediction" purposes; these proteins (n=80) added little gain to the prognostic model including natriuretic peptides. However, above and beyond "prediction", biomarkers may reflect pathophysiological processes and thus may help in assessing the underlying pathways that contribute to the progression towards HF.…”

Plasma proteomic approach in patients with heart failure: insights into pathogenesis of disease progression and potential novel treatment targets

“…focused on a depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms that could explain the association between HDL and clinical outcome, while this study covered the whole plasma proteome in patients with HF. In another proteomic study by Stenemo et al ., 18 proteins were identified with several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident HF. However, this study was performed in a HF cohort with elderly individuals and Proseek Multiplex cardiovascular disease I96 x 96 proximity extension assay technique was used to assess proteins previously associated with cardiovascular pathology.…”

“…However, Emmens et al 23 focused on a depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms that could explain the association between HDL and clinical outcome, while this study covered the whole plasma proteome in patients with HF. In another proteomic study by Stenemo et al, 49 18 proteins were identified with several novel associations between proteins involved in apoptosis, inflammation, matrix remodelling, and fibrinolysis with incident HF. However,…”

Serum proteomic approach for differentiation of frail and non-frail elderly

“…It is reported that this protein releases TNFα which initiate a cascade of inflammatory pathway eventually [31]. Studies suggested that MMP-12 was one of the nine circulating proteins which were associated with heart failure incidence in elderly [32]. Role of MMP-12 has also been explored in neurodegenerative disorders as it degrades myelin basic protein (MBP), a protein expressed by oligodendrocytes [33] and abnormal expression was also reported in microglial cells upon by Aβ1-42 application [34].…”