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出境医 / 临床实验 / Protective Monocytes and Macrophages to Limit Decompensation and Heart Damaging (PROMOMA)

Protective Monocytes and Macrophages to Limit Decompensation and Heart Damaging (PROMOMA)

Study Description
Brief 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.

Condition or disease Intervention/treatment Phase
Left Ventricular Hypertrophy Other: Blood sampling Not Applicable

Detailed 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.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 75 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Protective Gr1low Monocytes and Macrophages in Compensated Cardiac Hypertrophy to Limit Decompensation and Heart Damaging
Estimated Study Start Date : October 15, 2019
Estimated Primary Completion Date : April 15, 2023
Estimated Study Completion Date : April 15, 2024
Arms and Interventions
Arm Intervention/treatment
Blood sampling Other: Blood sampling
The blood sampling will be done just before surgery

Outcome Measures
Primary Outcome Measures :
  1. Identification of the complete spectrum of expressed mRNA of cardiac tissue macrophages. [ Time Frame: 18 months from start date ]
    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).


Secondary Outcome Measures :
  1. Identification of the complete transcriptome (including surface markers) of circulating monocytes from the blood collected for this project [ Time Frame: 24 months from start date ]
    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.

  2. Determination of the plasmatic factors in correlation with cardiac macrophage that may be specific for the compensated or decompensated state of left ventricular hypertrophy [ Time Frame: 24 months from start date ]
    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.

  3. mRNA of the circulating monocytes [ Time Frame: 24 months from start date ]
    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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Reza TAVAKOLI, Dr 07 69 89 40 52 r.tavakoli@ican-institute.org

Locations
Layout table for location information
France
Pitié Salpêtrière Hospital
Paris, France, 75013
Contact: Reza TAVAKOLI, Dr    07 69 89 40 52    r.tavakoli@ican-institute.org   
Contact: Catherine PAVOINE, Dr    01 40 77 96 62    catherine.pavoine@inserm.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Institute of Cardiometabolism and Nutrition, France
Investigators
Layout table for investigator information
Principal Investigator: Reza TAVAKOLI, Dr Pitié Salpêtrière Hospital AP-HP
Tracking Information
First Submitted Date  ICMJE July 15, 2019
First Posted Date  ICMJE July 17, 2019
Last Update Posted Date July 25, 2019
Estimated Study Start Date  ICMJE October 15, 2019
Estimated Primary Completion Date April 15, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
Identification of the complete spectrum of expressed mRNA of cardiac tissue macrophages. [ Time Frame: 18 months from start date ]
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
  • Identification of the complete transcriptome (including surface markers) of circulating monocytes from the blood collected for this project [ Time Frame: 24 months from start date ]
    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.
  • Determination of the plasmatic factors in correlation with cardiac macrophage that may be specific for the compensated or decompensated state of left ventricular hypertrophy [ Time Frame: 24 months from start date ]
    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.
  • mRNA of the circulating monocytes [ Time Frame: 24 months from start date ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Protective Monocytes and Macrophages to Limit Decompensation and Heart Damaging
Official Title  ICMJE Protective Gr1low Monocytes and Macrophages in Compensated Cardiac Hypertrophy to Limit Decompensation and Heart Damaging
Brief 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.
Detailed 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Left Ventricular Hypertrophy
Intervention  ICMJE Other: Blood sampling
The blood sampling will be done just before surgery
Study Arms  ICMJE Blood sampling
Intervention: Other: Blood sampling
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2019)
75
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 15, 2024
Estimated Primary Completion Date April 15, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Reza TAVAKOLI, Dr 07 69 89 40 52 r.tavakoli@ican-institute.org
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04022330
Other Study ID Numbers  ICMJE APHP190224
2019-A000751-56 ( Registry Identifier: ANSM )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Institute of Cardiometabolism and Nutrition, France
Investigators  ICMJE
Principal Investigator: Reza TAVAKOLI, Dr Pitié Salpêtrière Hospital AP-HP
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP