Serotonin Receptor Blockers in Ischemic Mitral Regurgitation

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.

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)