Neuregulin-1 in Patient With Different Forms of Cardiovascular Diseases: a Pilot Study

NCT ID: NCT04391491

Last Updated: 2023-05-03

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2019-03-01
• Study Completion Date: 2023-02-01

Brief Summary

This is an observational study of Neuregulin-1 (NRG-1) plasma levels in patients with different forms of cardiovascular disease including microvascular angina (MVA), heart failure with preserved ejection fraction (HFpEF), as well as, heart failure with reduced ejection fraction (HFrEF) and pulmonary hypertension (PH). Investigators intend to identify cardiovascular diseases which are characterized by increased circulating NRG-1, considered to be a biomarker of therapeutic potential of NRG-1. Participants will undergo blood sampling over 3 days following randomisation. Patients demographics and clinical characteristics will be recorded and their associations with NRG-1 will be analysed.

Detailed Description

NRG-1 is a paracrine growth factor with physiological actions in the cardiovascular system which is primarily expressed by the endothelium of coronary microvessels. NRG-1 is a natural paracrine agonist of the ErbB4 receptor. The NRG-1/ErbB4 system is activated in chronic heart failure (HF) and some other chronic diseases, exerting disease mitigation and regenerative effects. Recombinant NRG-1 (rhNRG-1) is developed as a drug for HFrEF. Both the preclinical and clinical data (phase II and III clinical trials) have demonstrated the favourable effects of NRG-1 treatment on the heart. rhNRG-1 effectively enhances the heart function and reverses the remodelling of the left ventricle. The levels of circulating NRG-1 were found to correlate with outcomes in Stage III and IV CHF. NRG1 appeared to be potentially protective Therefore, NRG-1 concentrations are considered to be a biomarker of the therapeutic potential of NRG-1. However, little is known about the role of the NRG-1 pathway in other cardiovascular diseases (CVDs). This observational study is intended to identify CVDs which are characterized by an increase in NRG-1 levels for better positioning the NRG-1 treatment in heterogeneous field of CVDs. Based on preclinical data, investigators assume that plasma NRG-1 will be altered in patients with microvascular angina, pulmonary hypertension, and HFpEF and HFrEF.

The study intends to enroll twenty patients for each of the 4 study groups and 20 healthy controls. We will compare the NRG-1 protein levels in patients and of age-matched healthy subjects. Participants will undergo a blood sampling after randomization (+ 3 days) and a 12 month follow up to assess the outcomes. Demographics, clinical characteristics, laboratory values including biomarkers of inflammation and fibrosis, NTproBNP, along with transthoracic echo findings and outcomes will be recorded. After the active phase of the research is done, we are planning to proceed to observation of the prospective group of patients to verify the endpoints.

Conditions

Heart Failure With Preserved Ejection Fraction; Microvascular Angina; Pulmonary Hypertension; Heart Failure With Reduced Ejection Fraction

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

Heart failure with preserved ejection fraction

Patients of both sexes and \> 18 years with a confirmed diagnosis of HFpEF (Symptoms of HF (NYHA II-IV); LVEF \>50%; Elevated levels of natriuretic peptides (NT-pro BNP \> 300 pg/ml in sinus rhythm, \>600 pg/ml in AF);Relevant structural heart disease (Left ventricle hypertrophy (LVH) and/or Left atrium enlargement (LAE); left atrial volume index (LAVI) \>34 mL/m2 or a left ventricular mass index (LVMI) =115 g/m2 for males and =95 g/m2 for females)

Neuregulin-1β level in plasma

Intervention Type: DIAGNOSTIC_TEST

Peripheral blood will be collected after randomization (plus or minus 3 days), the plasma will be assayed for neuregulin-1b, biomarkers of inflammation and fibrosis, NTproBNP

Microvascular angina

Patients of both sexes and \> 18 years with a confirmed diagnosis of MVA (Angina-like chest pain: signs of exercise-induced ischemia (ST-depression on exercise ECG (\>1 mm down-sloping or rectilinear ST-segment depression in \>2 leads)); No fixed stenosis (\>50%) in epicardial coronary arteries or branches at baseline coronary arteriography)

Neuregulin-1β level in plasma

Intervention Type: DIAGNOSTIC_TEST

Peripheral blood will be collected after randomization (plus or minus 3 days), the plasma will be assayed for neuregulin-1b, biomarkers of inflammation and fibrosis, NTproBNP

Pulmonary hypertension

Patients of both sexes and \> 18 years with a confirmed diagnosis of secondary PH due to left heart disease (Left ventricular systolic dysfunction, left ventricular diastolic dysfunction, Valvular disease, Congenital/acquired left heart inflow/outflow obstruction and congenital cardiomyopathies) or chronic thromboembolic pulmonary hypertension defined by echo when peak tricuspid regurgitation velocity =2.8 m/s and presence of other echo 'PH signs'

Neuregulin-1β level in plasma

Intervention Type: DIAGNOSTIC_TEST

Peripheral blood will be collected after randomization (plus or minus 3 days), the plasma will be assayed for neuregulin-1b, biomarkers of inflammation and fibrosis, NTproBNP

Heart failure with redused ejection fraction

Patients of both sexes and \> 18 years with a confirmed diagnosis of HFrEF (Symptomatic HF (NYHA class II-IV), left ventricular ejection fraction ≤ 35% (at any time in the past))

Neuregulin-1β level in plasma

Intervention Type: DIAGNOSTIC_TEST

Peripheral blood will be collected after randomization (plus or minus 3 days), the plasma will be assayed for neuregulin-1b, biomarkers of inflammation and fibrosis, NTproBNP

Interventions

Neuregulin-1β level in plasma

Peripheral blood will be collected after randomization (plus or minus 3 days), the plasma will be assayed for neuregulin-1b, biomarkers of inflammation and fibrosis, NTproBNP

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Able to provide informed consent
• Confirmed diagnosis of HFpEF (Symptoms of HF (NYHA II-IV); LVEF >50%; Elevated levels of natriuretic peptides (NT-pro BNP > 300 pg/ml in sinus rhythm, >600 pg/ml in AF);Relevant structural heart disease (Left ventricle hypertrophy (LVH) and/or Left atrium enlargement (LAE); left atrial volume index (LAVI) >34 mL/m2 or a left ventricular mass index (LVMI) =115 g/m2 for males and =95 g/m2 for females)
• Confirmed diagnosis of MVA (Angina-like chest pain: signs of exercise-induced ischemia (ST-depression on exercise ECG (>1 mm down-sloping or rectilinear ST-segment depression in >2 leads)); No fixed stenosis (>50%) in epicardial coronary arteries or branches at baseline coronary arteriography)
• Confirmed diagnosis of PH (PH due to left heart disease (Left ventricular systolic dysfunction, Left ventricular diastolic dysfunction, Valvular disease, Congenital/acquired left heart inflow/outflow obstruction and congenital cardiomyopathies); Chronic thromboembolic pulmonary hypertension; Peak tricuspid regurgitation velocity =2.8 m/s and presence of other echo 'PH signs')
• Confirmed diagnosis of HFrEF (Symptomatic HF (NYHA class II-IV), left ventricular ejection fraction ≤ 35% (at any time in the past))

Exclusion Criteria

• Patients with hypertrophic cardiomyopathy, rheumatic heart disease, constrictive pericarditis, significant valvular pathological change or congenital heart diseases
• Primary pulmonary artery hypertension
• Acute MI in the last 3 months
• Unstable angina
• Chronic heart failure patients with acute decompensation in the last 1 month (symptoms and signs suggest worsening chronic heart failure and may require intravenous drug therapy)
• Cardiac surgery or cerebrovascular accident within the recent six months
• Severe hepatic or renal dysfunction
• Severe nervous system diseases
• History of any malignancy or suffering from cancer
• Lack of informed consent

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Universiteit Antwerpen

OTHER

Sponsor Role: collaborator

University of Basel

OTHER

Sponsor Role: collaborator

I.M. Sechenov First Moscow State Medical University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anastasia Shchendrygina

Role: PRINCIPAL_INVESTIGATOR

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Locations

Anastasia Shchendrygina

Moscow, , Russia

Countries

Russia

References

De Keulenaer GW, Feyen E, Dugaucquier L, Shakeri H, Shchendrygina A, Belenkov YN, Brink M, Vermeulen Z, Segers VFM. Mechanisms of the Multitasking Endothelial Protein NRG-1 as a Compensatory Factor During Chronic Heart Failure. Circ Heart Fail. 2019 Oct;12(10):e006288. doi: 10.1161/CIRCHEARTFAILURE.119.006288. Epub 2019 Oct 14.

Reference Type: BACKGROUND

PMID: 31607147 (View on PubMed)

Other Identifiers

03-19 13022019

Identifier Type: -

Identifier Source: org_study_id