Network Medicine Approaches to Classify Heart Failure With PReserved Ejection Fraction by Signatures of DNA Methylation and Point-of-carE Risk calculaTors (PRESMET) (PRESMET)

Network Medicine Approaches to Classify Patients Suffering Heart Failure in Relation to Left Ventricle Ejection Fraction (HFpEF, HFmrEF, HFrEF) by Circulating CD4+ T Cell-derived DNA Methylation Signatures, Clinical Data, and Point-of-care Risk Calculators

Heart failure (HF) is a syndrome, resulting from structural or functional impairment of ventricular filling or ejection of blood. Effective HF management depends on accurate and rapid diagnosis requiring assessment of symptoms and physical signs in combination with advanced and expensive imaging tools. However, several challenges arise from the traditional symptom-based diagnosis because co-morbidities of HF have similar presentations. This implies the need for a deeper knowledge of mechanistic links among genetic and epigenetic events governing the pathophysiology of HF leading to a novel molecular-based system to differentiate HF phenotypes. Now, it is emerging that the pathophysiology of HFpEF and HFrEF is different, it provides an opportunity to identify biomarker candidates that could aid in HF diagnosis and stratification between these two forms of the disease. The aim of PRESMET project is to perform liquid biopsy strategies to identify novel putative non-invasive epigenetic-sensitive biomarkers that could be used either alone or in combination with established diagnostic tests, such as natriuretic peptide, to help differentiate HFpEF from HFrEF. The Investigators will perform DNA methylation analysis on CD4+ T cells isolated from patients versus controls. Remarkably, big data generated from NGS tools will be analyzed by advanced network-oriented algorithms. Our results may provide a useful clinical roadmap in order to improve precision medicine and personalized therapy of HF.

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation; Pulmonary Hypertension; Heart Failure, Diastolic; Heart Failure, Systolic
• Intervention / Treatment: Other: RRBS

Detailed Description

The Investigators will perform the first Network Medicine approach to integrate the DNA methylome of circulating CD4+T cells and clinical parameters in patients with HFpEF and HFrEF.

Liquid biopsy strategies will be performed to isolate PBMCs and purificate CD4+ T cells. Successivelly, genomic DNA will be extracted on columns and will be send out for RRBS.

Network-oriented algorithms will be used to analyze DNA methylation signatures and to identify specific epigenetic changes in relation to left ventricle ejection fraction.

Network-oriented DNA methylation signatures will be integrated to the H2FPEF point-of-care calculator and, then, will be validated by the use of q-RT-PCR, WB, and ELISA.

• Study Type: Observational
• Enrollment (Actual): 60

Contacts and Locations

Study Locations

• Italy
  • Naples, Italy, 80138
    • University of Campania Luigi Vanvitelli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Our study population will be composed by:

• N=20 HFpEF (LVEF > 50%)
• N=20 HFrEF (LVEF < 40%)
• N=20 healthy subjects

Description

Inclusion Criteria:

• HFrEF (LVEF < 40%)
• HFpEF (LVEF > 50%)

Exclusion Criteria:

• Patients with HF with a history of a reduced LVEF ≤ 40% (HFrEF) who recover LV function (LVEF ≥ 50%)
• Chronic inflammatory diseases
• Cancer

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
HFpEF; We will recruit HFpEF (LVEF > 50%)	Other: RRBS; Reduced Representation Bisulfite Sequencing
HFrEF; We will recruit HFrEF (LVEF < 40%)	Other: RRBS; Reduced Representation Bisulfite Sequencing
Healthy controls; We will recruit volunteer blood donors	Other: RRBS; Reduced Representation Bisulfite Sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of differentially methylated regions (DMRs) in CD4+ T cells	The Investigators will identify the panel of DMRs able to distinguish HFpEF vs. HFrEF, HFpEF vs. healthy controls, and HFrEF vs. healthy controls.	3 months
Levels of differentially expressed genes in CD4+ T cells	The Investigators will measure the levels of gene expression of selected genes (qRT-PCR) in HFpEF vs. HFrEF, HFpEF vs. healthy controls, and HFrEF vs. healthy controls.	1 month

Collaborators and Investigators

• Sponsor: University of Campania "Luigi Vanvitelli"
• Collaborators: University of Alabama at Birmingham; Federico II University; Monaldi Hospital

Publications and helpful links

General Publications

• Napoli C, Benincasa G, Donatelli F, Ambrosio G. Precision medicine in distinct heart failure phenotypes: Focus on clinical epigenetics. Am Heart J. 2020 Jun;224:113-128. doi: 10.1016/j.ahj.2020.03.007. Epub 2020 Mar 12.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2021
• Primary Completion (Actual): January 14, 2022
• Study Completion (Actual): June 14, 2022

Study Registration Dates

• First Submitted: July 21, 2022
• First Submitted That Met QC Criteria: July 24, 2022
• First Posted (Actual): July 26, 2022

Study Record Updates

• Last Update Posted (Actual): July 26, 2022
• Last Update Submitted That Met QC Criteria: July 24, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Liquid biopsy; CD4+ T cells; HFrEF; HFpEF; Interactome; Network Medicine
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Arrhythmias, Cardiac; Hypertension; Heart Failure; Atrial Fibrillation; Hypertension, Pulmonary; Heart Failure, Diastolic; Heart Failure, Systolic
• Other Study ID Numbers: UniCampania

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No