The term “myxomatous degeneration of the cardiac valves” refers to a non-inflammatory progressive disorder of the valve structure brought on by a mechanical integrity defect in the leaflet as a result of altered extracellular remodelling. Mitral valve prolapse (MVP), which is characterized by an atrial bulging of the mitral leaflets of greater than 2 mm during systole beyond the annular plane, a valvular thickness of less than ≥3 mm, and ruptured chordae tendineae, is the most common complication of myxomatous valves. Serotonin signalling may regulate naturally occurring degenerative valvulopathies in addition serotonergic valve degeneration, according to a substantial number of recent findings. Telotristat ethyl, a recently developed medication for carcinoid disease, works by specifically blocking tryptophan hydroxylase 1, the enzyme that determines the rate of peripheral serotonin production. To further support the influence of local serotonin synthesis on heart valves, and to test the possibility of serotonin synthesis inhibition in vivo without affecting brain serotonin, telotristat ethyl administration may provide the solution.
In a new study published in the journal Frontiers in Cardiovascular Medicine, Professor Carla Lacerda from the University of Texas at Tyler together with Dr. Xinmei Wang at Shenyang Univeristy and Dr. Danielle Kuban-Johnston and Dr. Pablo Lapuerta from Lexicon Pharmaceuticals predicted that serotonin inhibition will lessen the extent of hypertension-induced myxomatous mitral valve disease. Using normotensive mice as controls, animals were made hypertensive by subcutaneous angiotensin II injection with or without telotristat ethyl injection. Through the use of this mouse model, they sought to uncover the role of telotristat ethyl on myxomatous mitral valves in hypertensive mice; prove that mitral myxomatous degeneration can be stimulated in hypertensive mice that were given a short-term angiotensin administration; illustrate that myxomatous degeneration and elevated blood pressure correlate with high circulating serotonin; and elucidate the relationship between serotonin and myxomatous valvular disease.
In order to understand the function of serotonin in myxomatous mitral valve disease, they used this model as an inducer of the illness. According to the authors, telotristat ethyl administration appeared to reduce the impact of angiotensin on blood pressure while keeping the blood pressure of animals with normal blood pressure. Elevated levels of angiotensin increase blood pressure because of their contractile effects on vascular smooth muscle cells, according to a number of lines of evidence. The research team found that telotristat ethyl treatment decreased serotonin levels in mice with hypertensive and normotensive blood pressure. The interaction involving serotonin and angiotensin, which might not occur to the same extent in clinical systemic hypertension, may be the cause of the drop in serotonin in hypertensive mice. Although the alterations in circulating serotonin with hypertension and myxomatous disease have been independently addressed in the past, this is the first study to establish the synergistic impact of angiotensin and telotristat ethyl on circulating serotonin in a hypertensive animal model. The authors showed that telotristat ethyl treatment prevented hypertensive mice from effectively initiating myxomatous remodelling on their mitral valves. The research identified a unique method for blocking peripheral serotonin specifically to prevent or reverse myxomatous mitral disease. Moreover, the findings indicate that peripheral serotonin closely controls the expression of myxomatous markers.
In summary, Professor Carla Lacerda and colleagues developed the first in vivo model that thoroughly examines the association between serotonin and myxomatous mitral valve disease and reveals the regulatory function of serotonin in myxomatous valvular disease. Most crucially, serotonin suppression by telotristat ethyl, which was effective in both parallel and late delivery forms, may stop the progression of myxomatous degeneration of mitral valves. To date, there is no medical therapy for the treatment of myxomatous mitral valve disease, the study proposes telotristat ethyl as a potential therapeutics that is worthy of a clinical investigation in human disease.
Wang X, Kuban-Johnston D, Lapuerta P, Lacerda CM. Telotristat ethyl reverses myxomatous changes in mice mitral valves. Frontiers in Cardiovascular Medicine. 2022;9.