Protective Monocytes and Macrophages to Limit Decompensation and Heart Damaging

Left Ventricular Hypertrophy Clinical Trial

— PROMOMA  

Official title:

Protective Gr1low Monocytes and Macrophages in Compensated Cardiac Hypertrophy to Limit Decompensation and Heart Damaging

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04022330
• Other study ID #: APHP190224
• Secondary ID: 2019-A000751-56
• Status: Not yet recruiting
• Phase: N/A
• Start date: October 15, 2019
• Est. completion date: April 15, 2024

Study information

• Verified date: July 2019
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Reza TAVAKOLI, Dr
• Phone: 07 69 89 40 52
• Email: r.tavakoli[@]ican-institute.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The working hypothesis is that cardiac macrophages specific for the compensated cardiac hypertrophic phase limit the progression toward the decompensated state of heart failure by promoting an inflammatory environment favouring cardiomyocyte survival and preservation of the pump function. The investigators will perform studies in human plasma and monos, cardiac tissues and macrophages to validate this hypothesis.

Description:

Left ventricular hypertrophy (LVH) occurs following acute and chronic phases of ischemic heart disease as well as during pressure and/or volume overload (arterial hypertension, valvular heart disease). Persistence of the pathological stimuli, i.e. pressure and/or volume overload, will ultimately lead to the decompensation of cardiac function described as heart failure (HF). HF is worldwide one of the major healthcare concerns both in terms of the loss of human life and economic burden due to the expanding costs of care for patients with this condition (Ambrosy 2014). HF is associated with cardiomyocyte death, exacerbated inflammatory reaction with ensuing fibrosis and alteration of local angiogenesis. A better understanding of the mechanisms involved in the maintenance of the compensated state and in the transition to heart failure will promote the conception of new pharmacological interventions to prevent or even to reverse the transition to heart failure. Based on preclinical studies, the aim of this study is to advance our knowledge of relevant mechanisms involved in this process.

In an experimental setting in mice, the protective role of macrophages presenting an anti-inflammatory polarization in the progression of isuprel-induced left ventricular hypertrophy to irreversible heart failure has been recently demonstrated (Keck et al., submitted). These findings in the experimental model encourage their confirmation in the clinical setting. In the latter case, new therapeutic strategies can be projected to prevent or even to reverse the transition of compensated cardiac hypertrophy to heart failure.

To this purpose, the investigators will study cardiac tissue and blood sample of patients presenting compensated cardiac hypertrophy compared to those with end-stage heart failure.

Patients undergoing aortic valve replacement associated with septal myomectomy for aortic valve stenosis and asymmetric septal hypertrophy as well as patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing septal myomectomy are included in the group of compensated cardiac hypertrophy. Patients undergoing heart transplantation or implantation of mechanical life supporting system are included in the group of end-stage heart failure.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 75
• Est. completion date: April 15, 2024
• Est. primary completion date: April 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Older than 18 years

• Patients affiliated to a social security regimen

• Informed signed consent

Group 1 : compensated

• Symptomatic patients with severe aortic valve stenosis associated with asymmetric septal hypertrophy or patients with hypertrophic obstructive cardiomyopathy (HOCM), with echocardiographic transvalvular gradient = 40 mmHg associated with echocardiographic septal/posterior wall thickness = 1.3 ejection fraction = 50%, planned for aortic valve replacement with septal myomectomy or septal myomectomy for HOCM

Group 2 : transition • Symptomatic patients with severe aortic valve stenosis associated with asymmetric septal hypertrophy or patients with hypertrophic obstructive cardiomyopathy (HOCM), with echocardiographic transvalvular gradient = 40 mmHg associated with echocardiographic septal/posterior wall thickness = 1.3 ejection fraction < 50%, planned for aortic valve replacement with septal myomectomy or septal myomectomy for HOCM

Group 3 : decompensated

• End-stage heart failure on the waiting list for cardiac transplantation or undergoing ventricular assist device implantation as a bridge to transplantation

Exclusion Criteria:

• Combined aortic valve replacement and coronary artery bypass grafting or mitral/tricuspid surgery

• Emergency operation

• Acute endocarditis

• Patient unable to give his consent

• Patient deprived of freedom or under legal protection (guardianship or curatorship)

• Pregnant or breastfeeding woman

Related Conditions & MeSH terms

• Hypertrophy
• Hypertrophy, Left Ventricular
• Left Ventricular Hypertrophy

Intervention

Other:
• Blood sampling
The blood sampling will be done just before surgery

Locations

Country	Name	City	State
France	Pitié Salpêtrière Hospital	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Institute of Cardiometabolism and Nutrition, France

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identification of the complete spectrum of expressed mRNA of cardiac tissue macrophages.	This complete mRNA profile obtained in patients will be compared to the one found in preclinical studies in mice. The genes that are expressed during compensated cardiac hypertrophy in both human and mouse will be sorted out. The expression of the latter genes will be correlated to the cardiac pump function in order to select in the macrophage transcriptome potential markers of compensated cardiac hypertrophy. The presence of these specific macrophage markers will be investigated on frozen cardiac tissue sections by immune-histochemistry and by real time polymerase chain reaction (rtPCR).	18 months from start date
Secondary	Identification of the complete transcriptome (including surface markers) of circulating monocytes from the blood collected for this project	The transcriptome of circulating monocytes will be identified by mRNA sequencing. This complete mRNA profile obtained in patients will be compared to the one found in preclinical studies in mice and the genes that are expressed during compensated cardiac hypertrophy in both human and mouse will be sorted out. The expression of the latter genes will be correlated to the cardiac pump function in order to select in the circulating monocyte transcriptome potential markers of compensated cardiac hypertrophy. The presence of these specific circulating monocyte markers will be investigated by rtPCR.	24 months from start date
Secondary	Determination of the plasmatic factors in correlation with cardiac macrophage that may be specific for the compensated or decompensated state of left ventricular hypertrophy	Assessment of the presence of plasmatic factors: Based on preclinical studies showing circulating plasmatic markers of the compensated cardiac hypertrophic state, the same biomarkers will be assessed in plasma of the patients by ELISA. The concentration of these plasmatic factors will be correlated to the cardiac pump function in order to select potential markers of compensated cardiac hypertrophy.	24 months from start date
Secondary	mRNA of the circulating monocytes	Characterization of mRNA of the circulating monocytes that in correlation with those of cardiac tissue macrophages may be specific for the compensated or decompensated state of left ventricular hypertrophy and thus protective against transition to heart failure.	24 months from start date