Clinical trial NCT05469165: Serotonin Receptor Blockers in Ischemic Mitral Regurgitation
Official title: Blocking the Effects of Serotonin to Prevent Ischemic Mitral Regurgitation: a Randomized Trial (CYPRO-MR)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Ischemic Mitral Regurgitation
Keywords: Ischemic mitral regurgitation
Myocardial infarction
Mitral valve
Serotonin
Cyproheptadine
Lead sponsor: Laval University
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
First posted: 2022-07-21
Enrollment: 214
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This study is intended to investigate the effect of cyproheptadine (a 5HT2B receptor blocker) on mitral regurgitation severity.

Detailed description: Ischemic mitral regurgitation (MR) is a common and morbid complication of myocardial infarction (MI), doubling heart failure and mortality with currently limited therapies. Its mechanisms have been previously linked to left ventricle (LV) remodeling with secondary deformation of otherwise normal mitral leaflets. Recent studies are introducing new mechanistic elements, allowing possibilities for potential pharmacotherapeutic approaches. Normal mitral leaflets have the capacity to enlarge and adapt to even the largest LV dilatation to prevent MR. However, this compensatory mechanism is insufficient after MI, and the leaflets are abnormally thick with fibrotic changes. Those fibrotic changes could be related to a variation in blood serotonin (5-HT) levels after MI, which has been previously reported. Serotonin is a known cause of valve fibrosis through its 5HT type 2B receptor. In sheep models, the investigators have tested the hypothesis that a 5HT type 2B receptor blocker (cyproheptadine) can prevent adverse remodeling in the valve after MI. Cyproheptadine treatment was associated with increased valve leaflet surface, attenuated leaflet thickening and collagen deposition. Importantly, treated animals had less MR compared to non-treated animals.

Thus the present study is a double-blind randomized trial to assess the effect of cyproheptadine on MR severity, mitral valve surface variation, and left ventricular size following MI. Serial imaging (3D echo and MRI) will assess valve adaptation, LV remodeling and MR.

Eligibility criteria: Inclusion Criteria:

1. Patients 18-80 years old with a 1st episode of STEMI with documented coronary obstruction.
2. Left ventricle ejection fraction (LVEF)\<50% and mitral tenting area ≥ 4 cm2, OR LVEF ≤ 40% and inferior/posterior wall motion anomaly, OR LVEF≤30% and wall motion in any territory.

Exclusion Criteria:

1. Inability to provide informed consent
2. Hemodynamic instability / cardiogenic shock / papillary muscle rupture
3. Prior mitral valve procedure/surgery
4. Permanent atrial fibrillation (limiting imaging and MR quantification)
5. Primary mitral disease (endocarditis, rheumatic, degenerative or congenital)
6. More than mild valvular disease (other than mitral) at baseline
7. Planned cardiac surgery (CABG or valve intervention) within 3 months
8. Contraindications for MRI
9. Ongoing treatment with selective serotonin reuptake inhibitor (SSRI)
10. Chronic use of sedative medication
11. Ongoing or planned pregnancy
12. Chronic renal failure with Estimated Glomerular Filtration Rate (eGFR) \< 30 mL/min
13. Neurocognitive disorder
14. Symptom or prior episode of urinary obstruction or glaucoma (relative contraindications for cyproheptadine)

Primary outcomes:
measure: Change in mitral regurgitation severity
timeFrame: Baseline, 3 months
Secondary outcomes:
measure: Change in mitral leaflet size
timeFrame: Baseline, 3 months
measure: Change in mitral regurgitation grade
timeFrame: Baseline, 3 months
measure: Change in left ventricle size
timeFrame: Baseline, 3 months
measure: Change in left ventricle function
timeFrame: Baseline, 3 months
measure: Incidence of other valve regurgitation
timeFrame: 3 months
measure: Change in mitral valve thickness
timeFrame: Baseline, 3 months
measure: Adverse events
timeFrame: 3 months and 1 year
measure: Ischemic events
timeFrame: 3 months and 1 year
measure: Bleeding events
timeFrame: 3 months and 1 year
measure: Change in weight of participants
timeFrame: Baseline, 3 months
measure: Change in the patient's perception of their health status
timeFrame: Baseline, 3 months
measure: Change in the functional capacity of participants
timeFrame: 3 months, 1 year
measure: Incidence of sedation
timeFrame: Baseline, 3 months
measure: Change in depression score
timeFrame: Baseline, 3 months
Other outcomes:
Locations:
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval
Study officials:
References: