Heart failure occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body's needs. Symptoms of heart failure include shortness of breath, leg swelling and tiredness and the prognosis is comparable to most cancers. Heart failure disproportionately affects the elderly who predominantly develop heart failure with preserved ejection fraction (i.e. pumping function) (HFpEF) for which limited disease-specific therapy currently exists. There is an urgent need to identify pathways leading to this disease that can be targeted by novel therapies.
Aptamer-based proteomics is a new, state-of-the-art method to precisely identify and quantify several thousand proteins in a small amount of blood. The aim of this project is to use this new method to define the contributions of new pathways causing the development of heart failure.
Our hypothesis is that specific pathways identified by proteomics will differentially predict type of heart failure, and that detailed data from proteomics will allow for discovery of new biologic pathways and prognostic risk markers for heart failure. We also hypothesize that the markers identified by proteomics will explain the association between inherited risk (risk-genes) with development of heart failure.
This investigation will be conducted in the Atherosclerosis Risk in Communities (ARIC) study from four US centers. Parallel analyses will we performed in the Nord-Trøndelag Health study (HUNT) study for independent replication. By determining the importance of pathways targeted by existing drugs, our findings could rapidly translate into new preventative therapies for heart failure an essential step to decrease the morbidity and mortality caused by this disease.
Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular ejection fraction (HFpEF) for which no disease-specific therapy currently exists. There is an urgent need for novel targetable pathways and basic/translational data implicate systemic inflammation as a potential unexploited therapeutic target, although human data is limited. Novel aptamer-based proteomics allow for the precise quantification of 4,931 circulating proteins and unprecedented profiling of relevant inflammatory and non-inflammatory pathways. The objective of this application is to use large-scale proteomics to define the contributions of inflammatory pathways to, and identify novel causal pathways for, the development of HF. The central hypothesis is that specific inflammatory and neurohormonal pathways will differentially predict LV dysfunction and incident HF phenotype (HFpEF vs HFrEF), and that detailed proteomic and phenotypic data will allow for discovery of novel biologic pathways and prognostic risk markers for HF. Employing rigorous epidemiologic approaches, we will address the following specific aims: 1) To identify individual circulating proteins and protein networks that predict incident HF and HF phenotype (HFpEF vs HFrEF); 2) To determine proteins associated with LV diastolic and systolic dysfunction; 3) To identify candidate proteins and protein networks most likely to be mediators of LV dysfunction and HF using detailed genomic data. Primary analysis will be in the Atherosclerosis Risk in Communities (ARIC) study, and parallel analyses – in addition to new HF adjudication and classification – will we performed in the Nord-Trøndelag Health study (HUNT) study for independent replication. By determining the importance of pathways targeted by several existing agents, our findings could rapidly translate into novel preventative interventions for HF – an essential step to decrease HF-associated morbidity and mortality.