Inflammation and remodeling pathways and risk of cardiovascular events in patients with ischemic heart failure and reduced ejection fraction

Abstract

Patients with heart failure (HF) and coronary artery disease (CAD) have a high risk for cardiovascular (CV) events including HF hospitalization, stroke, myocardial infarction (MI) and sudden cardiac death (SCD). The present study evaluated associations of proteomic biomarkers with CV outcome in patients with CAD and HF with reduced ejection fraction (HFrEF), shortly after a worsening HF episode. We performed a case–control study within the COMMANDER HF international, double-blind, randomized placebo-controlled trial investigating the effects of the factor-Xa inhibitor rivaroxaban. Patients with the following first clinical events: HF hospitalization, SCD and the composite of MI or stroke were matched with corresponding controls for age, sex and study drug. Plasma concentrations of 276 proteins with known associations with CV and cardiometabolic mechanisms were analyzed. Results were corrected for multiple testing using false discovery rate (FDR). In 485 cases and 455 controls, 49 proteins were significantly associated with clinical events of which seven had an adjusted FDR < 0.001 (NT-proBNP, BNP, T-cell immunoglobulin and mucin domain containing 4 (TIMD4), fibroblast growth factor 23 (FGF-23), growth differentiation factor-15 (GDF-15), pulmonary surfactant-associated protein D (PSP-D) and Spondin-1 (SPON1)). No significant interactions were identified between the type of clinical event (MI/stroke, SCD or HFH) and specific biomarkers (all interaction FDR > 0.20). When adding the biomarkers significantly associated with the above outcome to a clinical model (including NT-proBNP), the C-index increase was 0.057 (0.033–0.082), p < 0.0001 and the net reclassification index was 54.9 (42.5 to 67.3), p < 0.0001. In patients with HFrEF and CAD following HF hospitalization, we found that NT-proBNP, BNP, TIMD4, FGF-23, GDF-15, PSP-D and SPON1, biomarkers broadly associated with inflammation and remodeling mechanistic pathways, were strong but indiscriminate predictors of a variety of individual CV events.

Emerging Biomarkers for Predicting Clinical Outcomes in Patients with Heart Disease

“…A matched case–control study evaluated the association of proteomic biomarkers with CV outcomes in 455 controls and 485 cases with CAD and HFrEF after an episode of worsening HF [ 85 ]. A total of 276 plasma proteins were analyzed, resulting in 49 proteins significantly associated with clinical outcomes.…”

“…Seven of these proteins had an adjusted false discovery rate < 0.001: BNP, NT-proBNP, FGF23, growth differentiation factor 15 (GDF15), T-cell immunoglobulin, and mucin domain containing 4 (TIMD4), spondin 1 (SPON1), and pulmonary surfactant-associated protein D (PSP-D). Neither of these proteins were associated with individual clinical events (HF hospitalization, sudden cardiac death, and combined MI or stroke) [ 85 ]. Therefore, these proteins were considered strong but indiscriminate predictors of diverse CV events.…”

“…Therefore, these proteins were considered strong but indiscriminate predictors of diverse CV events. The addition of these biomarkers to a clinical model significantly improved its predictive value [ 85 ].…”

Protocol for Biospecimen Collection and Analysis Within the BACPAC Research Program

“…Mass spectrometry-(MS) based proteomics has the unique advantage of being unbiased and quantitative. Previous reported work suggest that large-scale proteomics analysis is a promising way of discovering novel biomarkers that could substantially improve the prediction of Alzheimer's disease, 24,25 ischemic stroke, 26,27 and cancer. 28 Furthermore, the importance of sufficiently large discovery cohorts has become increasingly evident.…”

Multiple Beneficial Effects of Aloesone from Aloe vera on LPS-Induced RAW264.7 Cells, Including the Inhibition of Oxidative Stress, Inflammation, M1 Polarization, and Apoptosis

“…However, excessive inflammation induces an unpredicted increase in inflammatory mediators, such as cytokines (tumor necrosis factor-α (TNF-α), interleukins, inducible nitric oxide synthase (iNOS)), chemokines, and reactive oxygen species (ROS). Inflammatory mediators have implications in heart disease (ischemic heart failure and cardiac ischemia/reperfusion injury) [ 1 , 2 ], brain disorders (depression and anxiety) [ 3 , 4 ], and lung disease (chronic obstructive pulmonary disease and acute lung injury) [ 5 , 6 ]. Recent studies have confirmed that ROS could also cause oxidative stress, leading to the activation of inflammatory pathways, the stimulation of macrophage polarization, and the triggering of cell damage [ 7 , 8 ].…”