• Animal Data Suggest Serotonin Receptor Antagonist Cyproheptadine May Block Post-MI Valve Remodeling

    The 5-hydroxytryptamine (5-HT: or serotonin) type 2B receptor (5-HT2BR) antagonist cyproheptadine reduces 5-HT levels after myocardial infarction (MI), prevents valvular fibrotic remodeling, and is associated with a larger increase in mitral valve size and less mitral regurgitation (MR), new lab and animal data suggest.

    The study, published online Monday and in the Aug. 2 issue of the Journal of the American College of Cardiology, noted that ischemic MR is a frequent complication of MI that has been shown to increase mortality risk.

    Led by Ons Marsit, PhD, at the Institut Universitaire de Cardiologie et de Pneumologie de Québec–Université Laval, the team noted that both mechanical (valve distortion by left ventricular [LV] deformation) and intrinsic leaflet changes characterized by increased remodeling and leaflet thickening are associated with MR.

    “Mitral valve remodeling can be helpful as an increase in leaflet area can prevent MR in the dilated heart. However, post-MI valve changes are associated with limited valve expansion, thickened and stiffened leaflets,” noted the team, adding that elevated circulating levels of serotonin are reported in patients following MI – with increased transcardiac 5-HT concentration reported in patients with complex coronary lesions.

    “Serotonin is a well-known cause of valvular fibrotic remodeling through its 5-HT type 2B receptor (5-HT2BR); the most illustrative examples being carcinoid syndrome and drug-induced valve diseases,” said the authors.

    Study setup

    Marsit and colleagues aimed to test the hypothesis that post-MI treatment with cyproheptadine – a 5-HT2BR antagonist – can prevent ischemic MR by reducing the effect of serotonin on mitral biology.

    The trial enrolled 36 sheep, which were divided into two groups, inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). All animals were treated with amiodarone (200 mg/d) 3 days before the intervention.

    Under general anesthesia, a left thoracotomy was performed to access and ligate the second and third marginal branches of the left circumflex artery and to create an inferoposterior MI, said the team.

    Of the 36 animals that underwent the planned MI procedure, 12 died from arrhythmias during or immediately post-procedure, noted the team, adding that the remaining 24 sheep survived (13 MI and 11 MI þ cyproheptadine animals). Infarct size was similar in both groups (11 g vs 9 g; P = 0.414).

    Cyproheptadine treatment was well-tolerated without observed adverse reaction, while animal behavior, feeding and weight were comparable between groups, they said.

    During the trial, the team monitored blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size – with animals followed for 90 days.

    Furthermore, in a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals.

    Key findings

    The research team reported that increased 5-HT levels were observed after MI in non-treated animals, but not in the group treated with cyproheptadine.

    “In the MI group, serotonin levels were 58% greater 24 hours after MI creation vs baseline (P < 0.0001),” said Marsit and colleagues. “In contrast, serotonin concentration did not increase in the MI + cyproheptadine group; a numerical decrease without statistical significance was observed at 24 hours (change, -22%; P = 0.15); with stable values in later time points.”

    There was no significant MR by echocardiography or MRI before the procedure; however, at 90 days, both groups had mild systolic dysfunction, with a trend for lower LV ejection fraction in the treated group (47% vs 41%; P = 0.06).

    Further, MR fraction was 16% in the MI group vs 2% in the MI + cyproheptadine group (P = 0.0001) at 90 days, they said.

    “Although the 90-day absolute value of mitral leaflet area was not significantly different between groups, the percent of increase in leaflet area from baseline to 90 days was 2-fold higher in the cyproheptadine group (+40% vs +22%; P = 0.001),” said the authors.

    At 90 days, the ratio between leaflet size and systolic closure area was comparable to baseline in the MI + cyproheptadine group (1.28 at baseline vs 1.30 at 90 days; P = 0.64) but reduced in the MI group (1.28 vs 1.16; P = 0.004).

    Finally, the team reported that when mitral interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals as an in vitro test, the cells overexpressed extracellular matrix genes when treated with post-MI serum from non-treated animals, but not when exposed to post-MI serum collected from treated animals.

    The team concluded that further clinical studies are needed to evaluate the safety and efficacy of cyproheptadine in patients with MI who are at risk of developing secondary MR.

    ‘A vexing problem’

    Writing in an accompanying editorial, Ronen Beeri, MD, from the Hadassah-Hebrew University Medical Center, Jerusalem, said that MR after MI “remains a vexing problem, despite implementation of early reperfusion strategies.”

    The editorialist notes that the associations of serotonin with valvular pathologies are well-known and manifest most evidently in carcinoid valvulopathy and in valvular damage from weight-loss drugs.

    “The main novelty of this research resides in the important insight that IMR [ischemic mitral regurgitation] development could be modified by pharmacotherapy,” said Beeri.

    “Admittedly, this is an animal study, which is inherently limited in scope and timing after MI,” he noted, adding that remodeling of the ventricle is a long and ongoing process.

    “As cardiac regeneration is an elusive concept, and not all patients undergo early revascularization, permanent myocardial damage and IMR are here to stay,” he cautioned. “It is thus satisfying that we may have another pharmacological arrow in our quiver.”

    Sources:

    Marsit O, Clavel M-A, Pauin A, et al. Effects of Cyproheptadine on Mitral Valve Remodeling and Regurgitation After Myocardial Infarction. J Am Coll Cardiol 2022;80:500-510.

    Beei R. Ischemic Mitral Regurgitation and Leaflet Remodeling: Another Arrow Hits the Target. J Am Coll Cardiol 2022;80:511-512.

    Image Credit: iushakovsky – stock.adobe.com

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