Impact of Diffuse Myocardial Fibrosis on the Ventricular Function in Regurgitant Left-Sided Valve Heart Diseases ( The DIFFUsE Study) (DIFFUsE)

Impact of Diffuse Myocardial Fibrosis on the Ventricular Function in Regurgitant Left-Sided Valve Heart Diseases " The DIFFUsE Study "

New strategies are needed to early detect myocardial involvement in these diseases. Histological studies showed that diffuse fibrosis and cardiomyocyte hypertrophy precede the LV remodelling (dilatation) observed by cardiac imaging. Quantification of LV diffuse myocardial fibrosis using magnetic resonance imaging (MRI) could reach this goal. Recently, contrast enhanced cardiac MRI has been used to measure the extracellular volume fraction (ECV) of the myocardium, and it has been able to detect diffuse myocardial fibrosis. In diseases in which increased collagen deposition enlarges the extra-cellular space, the ECV can act as a fibrosis index. ECV is correlated with the amount of fibrosis measured by histology. Left ventricular overloads induced by regurgitant VHD result in cardiomyocyte hypertrophy and diffuse fibrosis. Other methods can be used to estimate the degree of myocardial fibrosis such as the serum level of galectine-3 or ST2. Moreover, although the pathophysiological mechanisms leading to the occurrence of myocardial fibrosis differ in patients with various cardiac diseases, the cellular effectors of fibrotic remodelling are common and involve similar signalling pathways. At the cellular level, key progression of ventricular hypertrophy is associated with increased cardiomyocytes apoptosis and fibrosis, suggesting that these two processes are responsible for the transition.

To our knowledge, no study has analysed the impact of the rate of myocardial diffuse fibrosis, non-invasively estimated by ECV, in the risk of LV dysfunction during MR and AR, especially after surgery. The measurement of ECV could become an important tool for risk stratification in left-sided regurgitant VHD. Thus, it would provide an early marker of LV myocardial involvement before the occurrence of global remodeling, might help physicians in surgical decision, and would improve prognosis. This is an innovative original project because it uses modern imaging modalities to answer to a crucial question. The clinical implications would be important because this work would modify the international surgical indications of MR and AR in order to finally improve the prognosis of patients with this frequent heart disease. Moreover, investigators will analyze the genetic factors that can influence the myocardial reaction resulting from these regurgitations, which will improve the quality of this work and offer new future perspectives.

Investigators hypothesize that the ECV measurement could be used as an early predictor of LV dysfunction in the left-sided valve regurgitations.

Study Overview

• Status: Active, not recruiting
• Conditions: Valve Heart Diseases
• Intervention / Treatment: Device: Cardiac MRI; Biological: blood samples; Procedure: myocardial biopsy; Genetic: blood samples

• Study Type: Interventional
• Enrollment (Estimated): 316
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Bouche DU Rhone
    • Marseille, Bouche DU Rhone, France, 13354
      • Assistance Publique Hopitaux de Marseille

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• All consecutive patients referred for organic MR and/or AR at least moderate to severe according to the ESC guidelines criteria⁴ will be eligible. The moderate to severe criteria will defined by echocardiography as followed:
• MR: an effective regurgitant orifice area (EOA) >30mm2 and/or a regurgitant volume (RV) >45mL
• AR: an EOA >20mm2 and/or a RV >45mL

Exclusion Criteria:

• Age < 18 years
• Pregnancy
• Impossibility to maintain a decubitus position
• Arrhythmia that do not allow an ECG synchronization during MRI
• Hemodynamic instability
• Indication of urgent surgery
• Known coronary artery disease
• Severe arterial hypertension
• Cardiomyopathy
• Claustrophobia
• Gadolinium intolerance
• Implantable medical devices that do allow to perform MRI
• Severe renal insufficiency with clearance <35 mL/min
• Vulnerable patients
• Acute infective endocarditis
• Aortic dissection
• Moderate or severe mitral stenosis (mitral area <1.5cm2/m2)
• Moderate or severe aortic stenosis (aortic area <0.8cm2/m2, or Vmax>3m/s, or mean gradient>30mmHg)
• Previous cardiac surgery

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: organic left-sided regurgitant valve	Device: Cardiac MRI; Biological: blood samples; Serum levels of biomarkers of myocardial fibrosis (galectine-3 and ST2) will be measured; Procedure: myocardial biopsy; Genetic: blood samples; extract DNA to look for genomic mutations associated with the disease.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
the rate of diffuse myocardial fibrosis	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Correlations between ECV and the global longitudinal strain and the serum level of Galectin-3 and ST2	42 months
Correlations between ECV changes and genetic factors	42 months
correlations between ECV and the severity of the regurgitation	42 months
correlation between ECV and the myocardial deformation quantified by speckle tracking echocardiography (2D Strain)	42 months

Collaborators and Investigators

• Sponsor: Assistance Publique Hopitaux De Marseille
• Investigators: Study Director: Catherine GEINDRE, Assistance Publique Hopitaux de Marseille

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2016
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026

Study Registration Dates

• First Submitted: April 19, 2016
• First Submitted That Met QC Criteria: April 20, 2016
• First Posted (Estimated): April 21, 2016

Study Record Updates

• Last Update Posted (Actual): May 19, 2026
• Last Update Submitted That Met QC Criteria: May 18, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Heart Valve Diseases; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: 2016-11; 2015-A00587-42 (Other Identifier: ansm)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED