Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure

Abstract

Background: Identifying the mechanistic pathways potentially associated with incident HF may provide a basis for novel preventive strategies. Methods and Results:To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as first hospitalization for HF, a nestedmatched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20,000 individuals). Controls were matched on cohort, follow-up time, age, and sex.Two independent sample sets (a "discovery" set, with 286 cases and 591 controls and a "replication" set with 276 cases and 280 controls) were used to discover and replicate the findings. 252 circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase.These 38 proteins pointed to 4 main network clusters underlying incident HF: 1) inflammation and apoptosis, indicated by the expression of the TNF-family members; 2) extracellular matrix remodelling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function and vascular homeostasis; 3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin angiotensin aldosterone system; and 4) metabolism, associated with cholesterol and atherosclerosis.Conclusion: Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodelling, blood pressure control and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF.

Yixin‐Shu Capsules Ameliorated Ischemia‐Induced Heart Failure by Restoring Trx2 and Inhibiting JNK/p38 Activation

“…Apart from that, cell apoptosis induced by inflammatory cytokines also participates in the occurrence and development of chronic HF [34]. Related studies have found clusters of biomarkers related to the mechanism of HF in the aspects of inflammation, apoptosis, vascular function, and so on [35]. Our results showed that YXS decreased the TUNEL-positive rate and caspase-3 activity while it increased the mitochondrial membrane potential, which demonstrated an obvious inhibition of cell apoptosis by YXS.…”

Cardiovascular Consequences of Acute Kidney Injury

“…S2). [34][35][36][37][38] Such observations further support the concept of incident heart failure triggered by acute kidney injury.…”

“…[35][36][37] Recently, in a nested, matched, case-control study involving patients with incident heart failure, 89 of 252 circulating plasma proteins in the discovery set and 38 in the replication set were associated with heart failure. 38 Furthermore, for these validated proteins, four major pathways were involved: inflammation and apoptosis; growth, angiogenesis, and extracellular-matrix remodeling; metabolism; and the renin-angiotensin-aldosterone system. [34][35][36][37][38] Two of the identified proteins, insulin-like growth factor-binding protein 7 (IGF-BP7), a biomarker of cell-cycle arrest, and kidney injury molecule 1 (KIM-1), are also increased during kidney injury.…”

“…38 Furthermore, for these validated proteins, four major pathways were involved: inflammation and apoptosis; growth, angiogenesis, and extracellular-matrix remodeling; metabolism; and the renin-angiotensin-aldosterone system. [34][35][36][37][38] Two of the identified proteins, insulin-like growth factor-binding protein 7 (IGF-BP7), a biomarker of cell-cycle arrest, and kidney injury molecule 1 (KIM-1), are also increased during kidney injury. With the use of a complex-network approach, several biomarkers have been shown to be linked by known protein interactions, biochemical interactions, or gene regulatory pathways (including a cluster depicting inflammation or apoptosis and the renin-angiotensin-aldosterone system) involved in acute kidney injury (Fig.…”

Insulin-like growth factor binding protein 2: A prognostic biomarker for heart failure hardly redundant with natriuretic peptides

“…The fact that IGFBP2 surprisingly and notably adds to the diagnostic and prognostic value of BNP suggests that IGFBP2 features a different pathophysiological background than natriuretic peptides. Yet, achieving a comprehensive view on the current evidence regarding IGFBP2 and its link with natriuretic peptides and HF remains challenging: complex network analysis is an increasingly used 3 analysis strategy allowing such integrated view of available evidence.…”