Jak2 gen mutasyonları hipertrofik kardiyomiyopati etiyolojisinde rol oynamıyor; kesitsel, gözlemsel bir çalışma

Öz

Amaç: Hipertrofik Kardiyomiyopati (HKMP) altta yatan herhangi bir neden olmaksızın ortaya çıkan sol ventrikülün kontrolsüz ve ciddi hipertrofisi ile karakterizedir. Miyokardiyal hipertrofiye yol açan mekanizmalar halen tam olarak anlaşılamamıştır. Literatürde Jak/Stat sinyal yolağının miyokard hipertrofisi ile ilgili olabileceğine dair hayvan çalışmaları bulunmaktadır. Bu çalışma HKMP’si olan hastalarda Jak mutasyonlarının rolünü araştırmayı hedeflemektedir. Yöntem: Çalışma Adnan Menderes Üniversitesi Tıp Fakültesi kardiyoloji polikliniğince takip ve tedavi edilen 26 HKMP hastası ile yapılmıştır. Kan örnekleri EDTA içeren tüplere alınarak, DNA izolasyon kiti yardımıyla total DNA genomu izole edilmiş ve ilgili ekzonlar PCR metoduyla amplifiye edilmiştir. PCR sonrası nükleotid dizileri DNA dizi analiz sistemi yardımıyla analiz edilmiştir. Bulgular: 11 kadın ve 15 erkek HKMP hastası çalışmaya dahil edilmiştir (ortalama yaş 52,2±12,5). Hastaların 19’unda septal, 3 ‘ünde apikal, 4’ünde konsantrik sol ventrikül hipertrofisi mevcuttu. 14’ünde sol ventrikül çıkış yolunda gradiyent saptandı. 13’nün ailesel geçiş öyküsü mevcuttu. 22’si sinüs ritmindeydi ve 4’ünde paroksismal atriyal fibrilasyon mevcuttu. Sonuçta 26 hastanın hiçbirisinde Jak2 gen mutasyonu saptanmadı. Sonuç: Çalışmamızın kısıtlılığı rölatif olarak küçük sayıdaki hasta popülasyonudur. Çalışmamızın verilerinin daha büyük randomize çalışmalar ile desteklenmesi gerekir. Çalışmamıza ait kısıtlı veri HKMP ile Jak2 mutasyonları arasında anlamlı bir ilişki olmayabileceğine işaret etmektedir.

Anahtar Kelimeler

• hipertrofi
• hipertrofik kardiyomyopati
• jak 2 mutasyonları
• sol ventrikül

Jak2 gene mutations seems not to play a role in the etiology of hypertrophic cardiomyopathy; cross-sectional, observational study

Öz

Objective: Hypertrophic Cardiomyopathy (HCMP) is characterized with uncontrolled and severe hypertrophy of left ventricle without any determined underlying reason. The mechanisms causing myocardial hypertrophy are still not fully understood. In the literature there are some data with animal studies about Jak/STAT signal pathway may be related to myocardial hypertrophy. This study aimed to surrogate the Jak mutations in patients with HCMP. Methods: The study included 26 patients with HCMP that were under management and monitorization of Adnan Menderes University cardiology out patient clinic. Blood samples were taken into collecting tubes with EDTA and with the help of DNA isolation kit, total genomic DNA was isolated and related exons were amplified with the PCR method. After PCR, sequence of nucleotids were analysed with the DNA sequence analysis system. Results: 11 woman and 15 male HCMP patients were included to the study (the median age was 52,2±12,5) 19 of them have septal, 3 of them have apical and 4 of them have concentric type LVH. 14 of them have gradient in left ventricular outflow tract.13 of them have familial history of HCMP. 22 of them have sinus rhythm and 4 of them have paroxysmal atrial fibrillation. At the end of the study Jak2 gene mutations were not determined in any of our 26 HCMP patients. Conclusion: The limitation of our study was relatively small number of patients. The confirmation of data with randomised bigger studies is needed. Our relatively small data is suggesting that there may be no relation with HCMP and Jak2 mutations.

Anahtar Kelimeler

• hypertrophy
• hypertrophic cardiomyopathy
• jak2 mutations
• left ventricle

Kaynakça

1. 1- Ommen SR, Ho CY, Asif IM, et al; Peer Review Committee Members. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2024 Jun 4;149(23):e1239-e1311.
2. 2- Tudurachi BS, Zăvoi A, Leonte A, et al. An Update on MYBPC3 Gene Mutation in Hypertrophic Cardiomyopathy. Int J Mol Sci. 2023 Jun 22;24(13):10510.
3. 3- Sedaghat-Hamedani F, Kayvanpour E, Tugrul OF, et al. Clinical outcomes associated with sarcomere mutations in hypertrophic cardiomyopathy: a meta-analysis on 7675 individuals. Clin Res Cardiol. 2018 Jan;107(1):30-41.
4. 4- Oldfield CJ, Duhamel TA, Dhalla NS. Mechanisms for the transition from physiological to pathological cardiac hypertrophy. Can J Physiol Pharmacol. 2020 Feb;98(2):74- 84.
5. 5- Fukuzawa J, Booz GW, Hunt RA, et. Al. Cardiotrophin- 1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy. Hypertension. 2000;35(6):1191-6.
6. 6- Pennica D, Shaw KJ, Swanson TA, et al. Cardiotrophin- 1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex. J Biol Chem. 1995;270(18):10915-22.
7. 7- Ying H, Xu MC, Tan JH, et al. Pressure overload-induced cardiac hypertrophy response requires janus kinase 2-histone deacetylase 2 signaling. Int J Mol Sci. 2014;15(11):20240- 53.
8. 8- Pan J, Fukuda K, Kodama H, et al. Role of angiotensin II in activation of the JAK/STAT pathway induced by acute pressure overload in the rat heart. Circ Res. 1997 ;81(4):611-7.

9. 9- Pan J, Fukuda K, Kodama H, et al. Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart. Heart V essels. 1998;13(4):199-208.
10. 10- Shi K, Zhao W, Chen Y, et al. Cardiac hypertrophy associated with myeloproliferative neoplasms in JAK2V617F transgenic mice. J Hematol Oncol. 2014 19;7:25.
11. 11- Gattenlohner S, Ertl G, Einsele H, et al. Cardiac JAK2 mutation V617F in a patient with cardiomyopathy and myeloproliferative disease. Ann Intern Med. 2008;149(1):69-71.
12. 12-Elliott PM, Anastasakis A, Borger MA, et al. Au2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC) ; Authors/Task Force members Eur Heart J. 2014 ;35(39):2733-79.
13. 13- Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005; 18: 1440-63.
14. 14- Gilbert BW, Pollick C, Adelman AG, et al. Hypertrophic cardiomyopathy: subclassification by M-mode echocardiography. Am J Cardiol. 1980;45:861-872.
15. 15- Zhao L, Wu D, Sang M, et al. Stachydrine ameliorates isoproterenol-induced cardiac hypertrophy and fibrosis by suppressing inflammation and oxidative stress through inhibiting NF-κB and JAK/STAT signaling pathways in rats. Int Immunopharmacol. 2017;48:102-109.
16. 16- Gan XT, Rajapurohitam V, et al. Myocardial Hypertrophic Remodeling and Impaired Left V entricular Function in Mice with a Cardiac-Specific Deletion of Janus Kinase 2. Am J Pathol. 2015;185(12):3202-10.
17. 17- Starksen NF, Simpson PC, Bishopric N, et al. Cardiac myocyte hypertrophy is associated with c-myc protooncogene expression. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8348-50.
18. 18- Xie S, Lin H, Sun T, Arlinghaus RB. Jak2 is involved in c-Myc induction by Bcr-Abl. Oncogene. 2002;21(47):7137-46.