Multi-Scale Analysis of Phenotypes in Heart Failure (MAP-HEART)

Study Description:

Our general hypothesis is that clinical and molecular data will generate new mechanistic knowledge and transform our understanding of the heterogeneous forms of heart failure (HF) syndrome. To do so, we will create a data-rich ecosystem by building a population-based registry. By grounding our work in the community within the District of Columbia / Maryland/Virginia metropolitan region (DMV), we will optimize inference and facilitate community translation. We will prospectively recruit a community cohort of 2000 participants with clinical HF from the DMV area and collect blood samples to measure multi-omics (specifically proteomics, metabolomics)signatures. We will integrate the results of the multi-omics assays to electronic medical records (EMR)-driven phenotypic representation (e.g., symptoms at clinical presentation, comorbid conditions, frailty, imaging data, ejection fraction, and laboratory values) collected during clinical care. Patients' records will be followed for up to 10 years after recruitment to monitor key characteristics and events, including death.

Objectives:

Primary Objective:

-To study the association between multi-omics signatures with all-cause mortality

Secondary Objectives:

• To study the association between multi-omics signatures with cardiovascular mortality
• To study the cross-sectional association between multi-omics signatures with clinical sub-phenotypes of heart failure

Exploratory Objectives:

• To study the association between multi-omics signatures with HF-related hospitalizations.
• To study the cross-sectional association between multi-omics signatures and HF sub-phenotypes based on clinical biomarkers across the spectrum of heart failure.
• To explore both germline (i.e., inherited) and somatic (i.e., de novo or acquired) genetic variants contributing to HF sub phenotypes.
• To explore epigenetic and gene expression alterations contributing to HF sub phenotypes.

Endpoints:

Primary Endpoint will be all-cause mortality.

Secondary Endpoints will be:

• Cardiovascular mortality
• Clinical sub-phenotypes of heart failure are defined by the following:
• Ejection Fraction, by echocardiogram (\>=50% vs. \< 50%)
• Severity measured by New York Heart Association class (3-4 vs. 1-2)
• HF duration (\>=18 months vs. \< 18 months)
• Etiology (Ischemic vs. Non-Ischemic)
• Comorbidity - diabetes, hypertension, chronic obstructive pulmonary disease, atrial fibrillation, cerebrovascular disease, body mass index (\>=30 vs. \< 30), age (median cut)

Exploratory Endpoints will be:

• HF-related hospitalization
• Biomarkers related to HF including N-terminal pro-brain natriuretic peptide (NT-proBNP), Cystatin C, Neutrophil gelatinase-associated lipocalin (NGAL), Galectin-3, soluble interleukin 1 1 (ST2), Troponin T, I, or C, Vascular cell adhesion protein 1 (VCAM-one), ICAM, E-selectin, CRP, TNF- alpha, interleukins, cortisol, and/or adiponectin
• Genomic analyses including whole exome or whole genome sequencing (WGS) to determine pathways, genes, genetic variants, and structural changes to DNA that may be related to HF syndrome.
• Epigenetic analyses including DNA methylation measurements to characterize differentially methylated sites that may be related to HF syndrome.
• Transcriptomic analyses to characterize alterations to gene expression that may be related to HF syndrome.

Heart Failure

Time frame: 10 years

The heterogeneous HF syndrome encompasses different and poorly defined entities. Multi-omics can improve its characterization and the prediction of mortality, which remains high. All-cause mortality will be analyzed as the time from enrollment to all-cause death.

Time frame: >=18 months vs. < 18 months

Cardiovascular mortality is an important part of all-cause mortality and will be evaluated as a secondary outcome. Cardiovascular mortality will be analyzed as the time from enrollment to cardiovascular death

Time frame: 5 years

Clinical phenotypes defined by:Ejection Fraction (\>=50 vs. \< 50) NYHA (3-4 vs. 1-2)Duration of HF (\>=18 months vs. \< 18 months) Etiology (Ischemic vs. Non- Ischemic) Comorbidity - diabetes, hypertension, chronic

Multi-scale Phenotyping of Heart Failure: From Precision Phenotyping to Population Inference (PHENO-HEART)