Profiling of the plasma proteome across different stages of human heart failure

Anna Egerstedt,Gunnar Engström,Göran Rådegran,Laurie Farrell,Olof Gidlöf,Mark D Benson ,Melanie H Smith ,Dongxiao Shen,Sumita Sinha,Jakob Lundgren,Roland Nilsson,Selvi Celik,Quinn S Wells,John Berntsson,Thomas J Wang,Qiong Yang,Carl Lejonberg,Robert E Gerszten,Debby Ngo,J G Smith

doi:10.1038/s41467-019-13306-y

Abstract

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. The systematic characterization of circulating proteins across different stages of HF may provide pathophysiological insights and identify therapeutic targets. Here we report application of aptamer-based proteomics to identify proteins associated with prospective HF incidence in a population-based cohort, implicating modulation of immunological, complement, coagulation, natriuretic and matrix remodeling pathways up to two decades prior to overt disease onset. We observe further divergence of these proteins from the general population in advanced HF, and regression after heart transplantation. By leveraging coronary sinus samples and transcriptomic tools, we describe likely cardiac and specific cellular origins for several of the proteins, including Nt-proBNP, thrombospondin-2, interleukin-18 receptor, gelsolin, and activated C5. Our findings provide a broad perspective on both cardiac and systemic factors associated with HF development.

Highlights

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood
Our results provide a comprehensive perspective on the plasma proteome in HF and identify both cardiac and extracardiac circulating proteins associated with HF incidence which display a graded increase across nonfailing, early HF and advanced HF populations
Our findings are consistent with activation of a number of pathways in early stages of HF, including immunological, complement, coagulation, natriuretic and extracellular matrix remodeling pathways, whereas pervasive perturbation of the plasma proteome was observed in manifest HF

Summary

Introduction

Heart failure (HF) is a major public health problem characterized by inability of the heart to maintain sufficient output of blood. Circulating levels of angiotensin II, aldosterone, catecholamines and natriuretic peptides are all increased in heart failure, associated with increased mortality 4, and constitute the principal targets for HF therapy[1]. These targets were originally identified from candidate-based physiological studies. Our results provide a comprehensive perspective on the plasma proteome in HF and identify both cardiac and extracardiac circulating proteins associated with HF incidence which display a graded increase across nonfailing, early HF and advanced HF populations

Methods

Results

Conclusion