Pathogenetic therapy of mitral valve prolapse

Aim. To evaluate the effect of angiotensin II receptor blocker (ARB) therapy on the expression of transforming growth factor-β (TGF-β) in the myxomatous mitral valve, on the serum levels of TGF-β1/TGF-β2 and the left ventricular (LV) systolic function in patients with mitral valve prolapse (MVP).

Material and methods. The retrospective non-randomized single-center study included 233 patients who underwent surgical treatment of severe mitral regurgitation due to MVP. Preoperative drug therapy was assessed using case records. Transthoracic echocardiography was performed in all patients before surgery. Pathological and immunohistochemical analysis of mitral valve fragments removed during surgery were performed. The serum content of TGF-β1 and TGF-β2 was determined by the enzyme immunoassay.

Results. According to echocardiography, mitral valve leaflets were significantly longer and thicker in patients in the control group than in the ARB group. These data were confirmed by pathological study — most patients in the control group had excessive myxomatous mitral valve leaflets (χ²=7,9; p=0,005). In the ARB group, the expression of type III collagen in the mitral valve leaflets was lower compared to the control group and the expression of fibulin-5 did not differ. Also, in the main group, an increased density of valvular interstitial cells was found, including those expressing TGF-β1 and TGF-β2 compared to the control group. The serum level of TGF-β1 and TGF-β2 was significantly higher in the control group than in the ARB group.

Despite the absence of differences in LV ejection fraction between the groups, global longitudinal systolic strain and strain rate were significantly higher in the main group.

Conclusion. This is the first study to reveal a positive effect of ARB therapy on myxomatous mitral valve degeneration and LV function due to inhibition of the TGF-β signaling pathway, which opens up potential for pathogenetic therapy in patients with MVP.

1. Malev EG. Mitral valve prolapse. In: Faculty therapy (selected sections): in 3 v.: a textbook for medical universities. SPb: SpecLit, 2022. V. II: Diseases of the heart and vessels: 137-41. (In Russ.) ISBN: 978-5-299-01156-2.

2. Roselli C, Yu M, Nauffal V, et al. Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse. Eur Heart J. 2022;43(17): 1668-80. doi:10.1093/eurheartj/ehac049.

3. Malev EG, Zemtsovskiy EV, Omelchenko MI, et al. The role of transforming growth factor-b in the pathogenesis of mitral valve prolapse. Kardiologiia. 2012;52(12):34-9. (In Russ.)

4. Tang Q, McNair AJ, Phadwal K, et al. The role of transforming growth factor-β signaling in myxomatous mitral valve degeneration. Front Cardiovasc Med. 2022;9:872288. doi:10.3389/fcvm.2022.872288.

5. Yagoda AV, Gladkikh NN, Gladkikh LN, et al. Mediators of intracellular interactions and endothelial function in myxomatous mitral valve prolapse. Russian Journal of Cardiology. 2013;(1):28-32. (In Russ.) doi:10.15829/1560-4071-2013-1-28-32.

6. Malev E, Luneva E, Reeva S, et al. Circulating transforming growth factor-beta levels and myocardial remodeling in young adults with mitral valve prolapse patients. Prog Pediatr Cardiol. 2021;62:101347. doi:10.1016/j.ppedcard.2021.101347.

7. van Andel MM, Indrakusuma R, Jalalzadeh H, et al. Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial. Eur Heart J. 2020;41(43):4181-7. doi:10.1093/eurheartj/ehaa377.

8. Ronco D, Buttiglione G, Garatti A, et al. Biology of mitral valve prolapse: from general mechanisms to advanced molecular patterns — a narrative review. Front Cardiovasc Med. 2023;10:1128195. doi:10.3389/fcvm.2023.1128195.

9. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA Guideline for the management of patients with valvular heart disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e35-e71. doi:10.1161/CIR.0000000000000932.

10. Mitrofanova LB, Kovalsky GB. Morphological characteristics and differential diagnosis of heart valve diseases. Arkhiv patologii. 2007;69(10):24-31. (In Russ.)

11. Sadeghinia MJ, Aguilera HM, Urheim S, et al. Mechanical behavior and collagen structure of degenerative mitral valve leaflets and a finite element model of primary mitral regurgitation. Acta Biomater. 2023;164:269-81. doi:10.1016/j.actbio.2023.03.029.

12. Sun B, Tomita B, Salinger A, et al. PAD2-mediated citrullination of fibulin-5 promotes elastogenesis. Matrix Biol. 2021;102:70-84. doi:10.1016/j.matbio.2021.07.001.

13. Stark VC, Olfe J, Diaz-Gil D, et al. TGFβ level in healthy and children with Marfan syndrome-effective reduction under sartan therapy. Front Pediatr. 2024;12:1276215. doi:10.3389/fped.2024.1276215.

14. Pace N, Sellal JM, Venner C, et al. Myocardial deformation in malignant mitral valve prolapse: A shifting paradigm to dynamic mitral valve-ventricular interactions. Front Cardiovasc Med. 2023;10:1140216. doi:10.3389/fcvm.2023.1140216.

15. Vistnes M. Hitting the target! Challenges and opportunities for TGF-β inhibition for the treatment of cardiac fibrosis. Pharmaceuticals (Basel). 2024;17(3):267. doi:10.3390/ph17030267.