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

J Am Coll Cardiol. 2022 Aug 2;80(5):500-510. doi: 10.1016/j.jacc.2022.05.025.


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.

Keywords: 5-hydroxytryptamine 2 receptor antagonist; cyproheptadine; mitral regurgitation; mitral valve; myocardial infarction; serotonin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aortic Valve
  • Aortic Valve Stenosis*
  • Calcinosis*
  • Cells, Cultured
  • Cyproheptadine / pharmacology
  • Cyproheptadine / therapeutic use
  • Fibrosis
  • Mitral Valve / diagnostic imaging
  • Mitral Valve Insufficiency* / etiology
  • Myocardial Infarction* / complications
  • Myocardial Infarction* / drug therapy
  • Serotonin
  • Sheep
  • Ventricular Remodeling / physiology


  • Cyproheptadine
  • Serotonin

Grant support