Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction.

Background: Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR).
Objectives: This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology.
Methods: Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals.
Results: Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals.
Conclusions: Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR.
Competing Interests: Funding Support and Author Disclosures This work has been funded by the Canadian Institutes for Health Research (CIHR—grant #399323). Dr Clavel is supported by a New National Investigator from the Heart and Stroke Foundation of Canada and an Early Carrier Investigator Award from the CIHR. Dr Beaudoin is supported by the Fonds de Recherche du Québec-Santé (FRQS). The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)