Top

Published in:

Open Access 01-12-2024 | Cardiomyopathy | Research

Association of uncertain significance genetic variants with myocardial mechanics and morphometrics in patients with nonischemic dilated cardiomyopathy

Authors: Karolina Mėlinytė-Ankudavičė, Marius Šukys, Gabrielė Kasputytė, Ričardas Krikštolaitis, Eglė Ereminienė, Grytė Galnaitienė, Vaida Mizarienė, Gintarė Šakalytė, Tomas Krilavičius, Renaldas Jurkevičius

Published in: BMC Cardiovascular Disorders | Issue 1/2024

Abstract

Background

Careful interpretation of the relation between phenotype changes of the heart and gene variants detected in dilated cardiomyopathy (DCM) is important for patient care and monitoring.

Objective

We sought to assess the association between cardiac-related genes and whole-heart myocardial mechanics or morphometrics in nonischemic dilated cardiomyopathy (NIDCM).

Methods

It was a prospective study consisting of patients with NIDCM. All patients were referred for genetic testing and a genetic analysis was performed using Illumina NextSeq 550 and a commercial gene capture panel of 233 genes (Systems Genomics, Cardiac-GeneSGKit®). It was analyzed whether there are significant differences in clinical, two-dimensional (2D) echocardiographic, and magnetic resonance imaging (MRI) parameters between patients with the genes variants and those without. 2D echocardiography and MRI were used to analyze myocardial mechanics and morphometrics.

Results

The study group consisted of 95 patients with NIDCM and the average age was 49.7 ± 10.5. All echocardiographic and MRI parameters of myocardial mechanics (left ventricular ejection fraction 28.4 ± 8.7 and 30.7 ± 11.2, respectively) were reduced and all values of cardiac chambers were increased (left ventricular end-diastolic diameter 64.5 ± 5.9 mm and 69.5 ± 10.7 mm, respectively) in this group. It was noticed that most cases of whole-heart myocardial mechanics and morphometrics differences between patients with and without gene variants were in the genes GATAD1, LOX, RASA1, KRAS, and KRIT1. These genes have not been previously linked to DCM. It has emerged that KRAS and KRIT1 genes were associated with worse whole-heart mechanics and enlargement of all heart chambers. GATAD1, LOX, and RASA1 genes variants showed an association with better cardiac function and morphometrics parameters. It might be that these variants alone do not influence disease development enough to be selective in human evolution.

Conclusions

Combined variants in previously unreported genes related to DCM might play a significant role in affecting clinical, morphometrics, or myocardial mechanics parameters.

Available only for authorised users

Pinto YM, Elliott PM, Arbustini E, Adler Y, Anastasakis A, Bo¨hm M, Duboc D, Gimeno J, de Groote P, Imazio M, et al. Proposal for a revised definition of dilated cardiomyopathy, hypokinetic non-dilated cardiomyopathy, and its implications for clinical practice: a position statement of the ESC working group on myocardial and pericardial diseases. Eur Heart J. 2016;37:1850–8. https://doi.org/10.1093/eurheartj/ehv727.CrossRefPubMed

McKenna WJ, Judge DP. Epidemiology of the inherited cardiomyopathies. Nat Rev Cardiol. 2021;18:22–36. https://doi.org/10.1038/s41569-020-0428-2.CrossRefPubMed

Martins E, Sousa A, Canedo P, Leite S, Pinto R, Campelo M, Amorim S, Moura B, Lopes JM, Machado JC, et al. Genetic variants identified by target next-generation sequencing in heart transplant patients with dilated cardiomyopathy. Rev Port Cardiol. 2019;38:441–7. https://doi.org/10.1016/j.repc.2019.02.006.CrossRefPubMed

McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res. 2017;121:731–48. https://doi.org/10.1161/CIRCRESAHA.116.309396.CrossRefPubMedPubMedCentral

Pirruccello JP, Bick A, Wang M, Chaffin M, Friedman S, Yao J, Guo X, Venkatesh BA, Taylor KD, Post WS, et al. Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy. Nat Commun. 2020;211:2254. https://doi.org/10.1038/s41467-020-15823-7.CrossRef

Escobar-Lopez L, Ochoa JP, Mirelis JG, Espinosa MÁ, Navarro M, Gallego-Delgado M, Barriales-Villa R, Robles-Mezcua A, Basurte-Elorz MT, Gutiérrez García-Moreno L, et al. Association of Genetic Variants with Outcomes in patients with nonischemic dilated cardiomyopathy. J Am Coll Cardiol. 2021;78:1682–99. https://doi.org/10.1016/j.jacc.2021.08.039.CrossRefPubMed

Tayal U, Ware JS, Lakdawala NK, Heymans S, Prasad SK. Understanding the genetics of adult-onset dilated cardiomyopathy: what a clinician needs to know. Eur Heart J. 2021;42:2384–96. https://doi.org/10.1093/eurheartj/ehab286.CrossRefPubMedPubMedCentral

Stroeks SLVM, Hellebrekers DMEI, Claes GRF, Tayal U, Krapels IPC, Vanhoutte EK, van den Wijngaard A, Henkens MTHM, Ware JS, Heymans SRB et al. (2021) Clinical impact of re-evaluating genes and variants implicated in dilated cardiomyopathy. Genet Med 23:2186–2193 (2021). https://doi.org/10.1038/s41436-021-01255-1.

Dellefave L, McNally EM. The genetics of dilated cardiomyopathy. Curr Opin Cardiol. 2010;25:198–204. https://doi.org/10.1097/HCO.0b013e328337ba52.CrossRefPubMedPubMedCentral

10.

Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, et al. Report of the 1995. World Health Organization/International Society and Federation of Cardiology Task Force on the definition and classification of cardiomyopathies. Circulation. 1996;93:841–2. https://doi.org/10.1161/01.cir.93.5.841.CrossRefPubMed

11.

Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, Flachskampf FA, Foster E, Goldstein SA, Kuznetsova T, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:233–70. https://doi.org/10.1093/ehjci/jew041.CrossRefPubMed

12.

Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T, D’Hooge J, Donal E, Fraser AG, Marwick T, et al. Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation 379 imaging. Eur Heart J Cardiovasc Imaging. 2018;19:591–600. https://doi.org/10.1093/ehjci/jey042.CrossRefPubMed

13.

Voigt JU, Pedrizzetti G, Lysyansky P, Marwick H, Houle H, Baumann R, Pedri S, Ito Y, Abe Y, Metz S, et al. Definitions for a common standard for 2D speckle tracking echocardiography: consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J – Cardiovasc Imaging. 2015;16:1–11. https://doi.org/10.1093/ehjci/jeu184.CrossRefPubMed

14.

Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, Fogel MA, Friedrich MG, Kim RJ, von Knobelsdorff-Brenkenhoff F, Kramer CM, Pennell DJ, et al. Standardized image interpretation and post-processing in cardiovascular magnetic resonance – 2020 update: Society for Cardiovascular magnetic resonance (SCMR): Board of Trustees Task Force on standardized post-processing. J Cardiovasc Magn Reson. 2020;22:19. https://doi.org/10.1186/1532-429X-15-35.CrossRefPubMedPubMedCentral

15.

Barreiro-Pérez M, Curione D, Symons R, Claus P, Voigt JU, Bogaert J. Left ventricular global myocardial strain assessment comparing the reproducibility of four commercially available CMR-feature tracking algorithms. Eur Radiol. 2020;28:5137–47. https://doi.org/10.1007/s00330-018-5538-4.CrossRef

16.

Rodríguez C, Martínez-González J. The role of Lysyl Oxidase Enzymes in cardiac function and remodeling. Cells. 2019;8:1483. https://doi.org/10.3390/cells8121483.CrossRefPubMedPubMedCentral

17.

López B, González A, Hermida N, Valencia F, de Teresa E, Díez J. Role of lysyl oxidase in myocardial fibrosis: from basic science to clinical aspects. Am J Physiol Heart Circ Physiol. 2010;299:H1–9. https://doi.org/10.1152/ajpheart.00335.2010.CrossRefPubMed

18.

López B, Querejeta R, González A, Beaumont J, Larman M, Díez J. Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure. Hypertension. 2009;53:236–42. https://doi.org/10.1161/HYPERTENSIONAHA.108.125278.CrossRefPubMed

19.

Al-U’datt D, Allen BG, Nattel S. Role of the lysyl oxidase enzyme family in cardiac function and disease. Cardiovasc Res. 2019;115:1820–37. https://doi.org/10.1093/cvr/cvz176.CrossRefPubMed

20.

Lee VS, Halabi CM, Hoffman EP, Carmichael N, Leshchiner I, Lian CG, Bierhals AJ, Vuzman D, Brigham Genomic Medicine, Mecham RP, et al. Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans. Proc Natl Acad Sci U S A. 2016;113:8759–64. https://doi.org/10.1073/pnas.1601442113.CrossRefPubMedPubMedCentral

21.

Sivakumar P, Gupta S, Sarkar S, Sen S. Upregulation of lysyl oxidase and MMPs during cardiac remodeling in human dilated cardiomyopathy. Mol Cell Biochem. 2008;307:159–67. https://doi.org/10.1007/s11010-007-9595-2.CrossRefPubMed

22.

Zhang HF, Zhao KJ, Xu Y, Hong B, Zhao WY, Liu JM, Huang QH. Lysyl oxidase polymorphisms and ischemic stroke–a case control study. Mol Biol Rep. 2012;39:9391–7. https://doi.org/10.1007/s11033-012-1803-9.CrossRefPubMed

23.

Tsuruga T, Kanamoto T, Kato T, Yamashita H, Miyagawa K, Mishima HK. Ocular development-associated gene (ODAG), a novel gene highly expressed in ocular development. Gene. 2002;290:125–30. https://doi.org/10.1016/s0378-1119(02)00563-2.CrossRefPubMed

24.

Theis JL, Sharpe KM, Matsumoto ME, Chai HS, Nair AA, Theis JD, de Andrade M, Wieben ED, Michels VV, Olson TM. Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ Cardiovasc Genet. 2011;4:585–94. https://doi.org/10.1161/CIRCGENETICS.111.961052.CrossRefPubMedPubMedCentral

25.

Yang J, Shah S, Olson TM, Xu X. Modeling GATAD1-Associated Dilated Cardiomyopathy in adult zebrafish. J Cardiovasc Dev Dis. 2016;3:6. https://doi.org/10.3390/jcdd3010006.CrossRefPubMedPubMedCentral

26.

Zhang Y, Li Y, Wang Q, Su B, Xu H, Sun Y, Sun P, Li R, Peng X, Cai J. Role of RASA1 in cancer: a review and update (review). Oncol Rep. 2020;44:2386–96. https://doi.org/10.3892/or.2020.7807.CrossRefPubMedPubMedCentral

27.

Albakri A. RASopathy-associated cardiomyopathy. Int Med Care. 2019;3:1–13. https://doi.org/10.15761/IMC.1000134.CrossRef

28.

Wooderchak-Donahue WL, Johnson P, McDonald J, Blei F, Berenstein A, Sorscher M, Mayer J, Scheuerle AE, Lewis T, Grimmer JF, et al. Expanding the clinical and molecular findings in RASA1 capillary malformation-arteriovenous malformation. Eur J Hum Genet. 2018;26:1521–36. https://doi.org/10.1038/s41431-018-0196-1.CrossRefPubMedPubMedCentral

29.

Ramos-Kuri M, Meka SH, Salamanca-Buentello F, Hajjar RJ, Lipskaia L, Chemaly ER. Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies. Biol Res. 2021;54:23.CrossRefPubMedPubMedCentral

30.

Paré-Brunet L, Glubb D, Evans P, Berenguer-Llergo A, Etheridge AS, Skol AD, Di Rienzo A, Duan S, Gamazon ER, Innocenti F. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway. Hum Mutat. 2014;35:227–35. https://doi.org/10.1002/humu.22475.CrossRefPubMed

31.

Ricci C, Cerase A, Riolo G, Manasse G, Battistini S. KRIT1 gene in patients with cerebral cavernous malformations: clinical features and molecular characterization of Novel variants. J Mol Neurosci. 2021;71:1876–83. https://doi.org/10.1007/s12031-021-01814-w.CrossRefPubMedPubMedCentral

32.

Kim H, Pawlikowska L, Young WL. Genetics and Vascular Biology of Brain Vascular malformations. Stroke. 2011;169–86. https://doi.org/10.1016/b978-1-4160-5478-8.10012-0.

33.

Garnier S, Harakalova M, Weiss S, Mokry M, Regitz-Zagrosek V, Hengstenberg C, Cappola TP, Isnard R, Arbustini E, Cook SA, et al. Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23. Eur Heart J. 2021;42:2000–11. https://doi.org/10.1093/eurheartj/ehab030.CrossRefPubMedPubMedCentral

34.

Tayal U, Prasad S, Cook SA. Genetics and genomics of dilated cardiomyopathy and systolic heart failure. Genome Med. 2017;9:20. https://doi.org/10.1186/s13073-017-0410-8.CrossRefPubMedPubMedCentral

35.

Meder B, Rühle F, Weis T, Homuth G, Keller A, Franke J, Peil B, Lorenzo Bermejo J, Frese K, Huge A, et al. A genome-wide association study identifies 6p21 as novel risk locus for dilated cardiomyopathy. Eur Heart J. 2014;35:1069–77. https://doi.org/10.1093/eurheartj/eht251.CrossRefPubMed

36.

Esslinger U, Garnier S, Korniat A, Proust C, Kararigas G, Müller-Nurasyid M, Empana JP, Morley MP, Perret C, Stark K, et al. Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy. PLoS ONE. 2017;12:e0172995. https://doi.org/10.1371/journal.pone.0172995.CrossRefPubMedPubMedCentral

37.

Nurk S, Koren S, Rhie A, Rautiainen M, Bzikadze AV, Mikheenko A, Vollger MR, Altemose N, Uralsky L, Gershman A, et al. The complete sequence of a human genome. Science. 2022;376:44–53. https://doi.org/10.1126/science.abj6987.CrossRefPubMedPubMedCentral

Title: Association of uncertain significance genetic variants with myocardial mechanics and morphometrics in patients with nonischemic dilated cardiomyopathy
Authors: Karolina Mėlinytė-Ankudavičė
Marius Šukys
Gabrielė Kasputytė
Ričardas Krikštolaitis
Eglė Ereminienė
Grytė Galnaitienė
Vaida Mizarienė
Gintarė Šakalytė
Tomas Krilavičius
Renaldas Jurkevičius
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Cardiomyopathy
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Echocardiography
Echocardiography
Heart Failure
Published in: BMC Cardiovascular Disorders / Issue 1/2024
Electronic ISSN: 1471-2261
DOI: https://doi.org/10.1186/s12872-024-03888-x

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Association of uncertain significance genetic variants with myocardial mechanics and morphometrics in patients with nonischemic dilated cardiomyopathy

Abstract

Background

Objective

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2024

Clinical comparative analysis of 3D printing-assisted extracorporeal pre-fenestration and Castor integrated branch stent techniques in treating type B aortic dissections with inadequate proximal landing zones

Mir-195-5p targets Smad7 regulation of the Wnt/β-catenin pathway to promote osteogenic differentiation of vascular smooth muscle cells

Levels of adherence to treatment, illness perception and acceptance of illness in patients with coronary artery disease - descriptive and correlational study

Elucidating the mechanisms of formononetin in modulating atherosclerotic plaque formation in ApoE-/- mice

Safe and promising outcomes of in-hospital preoperative rehabilitation for coronary artery bypass grafting after an acute coronary syndrome

Predictors of non-obstructive coronary slow flow in poorly controlled type 2 diabetes mellitus: a cross-sectional study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page