Ischemic Mitral Regurgitation
Conditions
Keywords
Ischemic mitral regurgitation, Myocardial infarction, Mitral valve, Serotonin, Cyproheptadine
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.
Interventions
DRUGCyproheptadine 4 Mg Oral Tablet
Cyproheptadine treatment for 3 months
OTHERPlacebo
Placebo administration for 3months
Sponsors
Canadian Institutes of Health Research (CIHR)
Laval University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in mitral regurgitation severity | Baseline, 3 months | Incidence of more than mild MR (MRI regurgitant fraction ≥ 20%) at 3 months (measured by MRI) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in mitral regurgitation grade | Baseline, 3 months | 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. |
| Change in left ventricle size | Baseline, 3 months | Left ventricle size (measured by MRI ) |
| Change in left ventricle function | Baseline, 3 months | Left ventricle function (measured by MRI ) |
| Incidence of other valve regurgitation | 3 months | Incidence of other valve regurgitation (more than mild) (measured by echocardiography) |
| Change in mitral valve thickness | Baseline, 3 months | Mitral valve thickness (measured by echocardiography) |
| Adverse events | 3 months and 1 year | Composite of: Mortality, Heart failure requiring hospital admission, Mitral valve intervention (surgical/percutaneous) |
| Change in mitral leaflet size | Baseline, 3 months | Mitral leaflet size (3D echo) and its variation vs baseline (measured by echocardiography) |
| Bleeding events | 3 months and 1 year | Bleeding Academic Research Consortium (BARC) definition |
| Change in weight of participants | Baseline, 3 months | Weight gain during therapy (self-assessment by participants) |
| Change in the patient's perception of their health status | Baseline, 3 months | 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). |
| Change in the functional capacity of participants | 3 months, 1 year | 6-minutes walk test |
| Incidence of sedation | Baseline, 3 months | Incidence of sedation (reported by participants) |
| Change in depression score | Baseline, 3 months | 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. |
| Ischemic events | 3 months and 1 year | stroke and myocardial infarction |
Countries
Canada
Contacts
Primary ContactJonathan Beaudoin, MD
Backup ContactOns Marsit, PhD
Outcome results
None listed