Serotonin Receptor Blockers in Ischemic Mitral Regurgitation

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

Detailed Description
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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.

Official Title
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Blocking the Effects of Serotonin to Prevent Ischemic Mitral Regurgitation: a Randomized Trial (CYPRO-MR)

Conditions
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Ischemic Mitral Regurgitation

Intervention / Treatment
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* Drug: Cyproheptadine 4 Mg Oral Tablet
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients 18-80 years old with a 1st episode of STEMI with documented coronary obstruction. 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: Inability to provide informed consent Hemodynamic instability / cardiogenic shock / papillary muscle rupture Prior mitral valve procedure/surgery Permanent atrial fibrillation (limiting imaging and MR quantification) Primary mitral disease (endocarditis, rheumatic, degenerative or congenital) More than mild valvular disease (other than mitral) at baseline Planned cardiac surgery (CABG or valve intervention) within 3 months Contraindications for MRI Ongoing treatment with selective serotonin reuptake inhibitor (SSRI) Chronic use of sedative medication Ongoing or planned pregnancy Chronic renal failure with Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min Neurocognitive disorder Symptom or prior episode of urinary obstruction or glaucoma (relative contraindications for cyproheptadine)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyproheptadine 4 Mg Oral Tablet<br>Participants will receive cyproheptadine 4mg tablet orally three times a day for three months, with a daily increase of 4mg/dose if the previous dose was well tolerated, up to 0.5 mg/kg/day. | Drug: Cyproheptadine 4 Mg Oral Tablet<br>* Cyproheptadine treatment for 3 months<br>* Other names: Cyproheptadine;|
| Placebo Comparator: Placebo<br>Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm. | Other: Placebo<br>* Placebo administration for 3months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitral regurgitation severity | Incidence of more than mild MR (MRI regurgitant fraction ≥ 20%) at 3 months (measured by MRI) | Baseline, 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mitral leaflet size | Mitral leaflet size (3D echo) and its variation vs baseline (measured by echocardiography) | Baseline, 3 months | 
| Change in mitral regurgitation grade | Mitral regurgitation grade (measured by echocardiography). Mitral regurgitation is graded on a scale of I-IV (grade I (mild MR), grade II (moderate MR), grade III (moderate-to-severe MR) and grade IV (severe MR)). A higher mitral regurgitation grade is generally associated with a worse outcome for the patient. | Baseline, 3 months | 
| Change in left ventricle size | Left ventricle size (measured by MRI ) | Baseline, 3 months | 
| Change in left ventricle function | Left ventricle function (measured by MRI ) | Baseline, 3 months | 
| Incidence of other valve regurgitation | Incidence of other valve regurgitation (more than mild) (measured by echocardiography) | 3 months | 
| Change in mitral valve thickness | Mitral valve thickness (measured by echocardiography) | Baseline, 3 months | 
| Adverse events | Composite of: Mortality, Heart failure requiring hospital admission, Mitral valve intervention (surgical/percutaneous) | 3 months and 1 year | 
| Ischemic events | stroke and myocardial infarction | 3 months and 1 year | 
| Bleeding events | Bleeding Academic Research Consortium (BARC) definition | 3 months and 1 year | 
| Change in weight of participants | Weight gain during therapy (self-assessment by participants) | Baseline, 3 months | 
| Change in the patient's perception of their health status | Self-administered questionnaire : Kansas City Cardiomyopathy Questionnaire (KCCQ). All score are represented on a 0-to-100-point scale (lower scores represent more severe symptoms and/or limitations and scores of 100 indicate no symptoms, no limitations, and excellent quality of life). | Baseline, 3 months | 
| Change in the functional capacity of participants | 6-minutes walk test | 3 months, 1 year | 
| Incidence of sedation | Incidence of sedation (reported by participants) | Baseline, 3 months | 
| Change in depression score | Self-administered questionnaire: Patient Health Questionnaire (PHQ-9). The Patient Health Questionnaire has a scale of 0-27, with higher scores indicating a worse outcome for the patient, with more severe depression symptoms. | Baseline, 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic mitral regurgitation, Myocardial infarction, Mitral valve, Serotonin, Cyproheptadine