Aortic Dimensions, Biophysical Properties, and Plasma Biomarkers in Children and Adults with Marfan or Loeys-Dietz Syndrome

Overview

Journal CJC Open

Specialty Cardiology & Vascular Diseases

Date 2021 May 24

PMID 34027363

Citations 8

Authors

Jason Z Cui

Kevin C Harris

Koen Raedschelders

Zsuzsanna Hollander

James E Potts

Astrid de Souza

Marla Kiess

Bruce M McManus

Pascal Bernatchez

Leslie A Raffin

Heidi Paine

Cornelis van Breemen

George G S Sandor

Mitra Esfandiarei

Affiliations

Soon will be listed here.

Abstract

Background: Aortic dilation, stiffening, and dissection are common and potentially lethal complications of Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), which involve abnormal transforming growth factor beta (TGF-β) signalling. The relation of aortic dimensions, stiffness, and biomarker levels is unknown. The objective of this study was to measure aortic dimensions, stiffness, TGF-β and matrix metalloproteinase (MMP) levels, and endothelial function in patients with MFS, and to compare TGF-β levels in patients with MFS receiving different therapeutic regimens.

Methods: This was a cohort study of 40 MFS and 4 LDS patients and 87 control participants. Aortic dimension and stiffness indexes, including pulse wave velocity (PWV), were measured using echocardiography and Doppler. Total and free TGF-β and MMP blood levels were measured using Quantikine (R&D Systems, Inc, Minneapolis, MN) and Quanterix (Billerica, MA) kits. Endothelial function was measured using brachial artery flow-mediated dilation.

Results: PWV was increased in patients with MFS. There were increased MMP-2 levels in those with MFS but no increase in free or total TGF-β or MMP-9 levels compared with control participants. There was no difference in TGF-β levels between MFS patients receiving no medications, angiotensin receptor blockers, and β-blockers. PWV correlated most strongly with age. Endothelial function showed premature gradual decline in patients with MFS.

Conclusions: Despite the increased PWV, monitoring aortic stiffness or TGF-β levels would not be helpful in patients with MFS. TGF-β levels were not increased and the increased MMP-2 levels suggest consideration of a different therapeutic target.

Citing Articles

Are aortic biomechanical properties early markers of dilatation in patients with Marfan syndrome? A systematic review and meta-analysis.

Rosnel C, Sivera R, Cervi E, Danton M, Schievano S, Capelli C Biomech Model Mechanobiol. 2024; 23(6):2043-2061.

PMID: 39073692 PMC: 11554766. DOI: 10.1007/s10237-024-01881-z.

Impact of Genotype-Phenotype Interactions on Cardiovascular Function in Paediatric Loeys-Dietz Syndrome.

Khodabakhshian N, Howell A, Lopez P, Hui W, Mertens L, Guerra V CJC Pediatr Congenit Heart Dis. 2024; 3(2):47-54.

PMID: 38774681 PMC: 11103043. DOI: 10.1016/j.cjcpc.2023.12.003.

TGFβ level in healthy and children with Marfan syndrome-effective reduction under sartan therapy.

Stark V, Olfe J, Diaz-Gil D, von Kodolitsch Y, Kozlik-Feldmann R, Reincke J Front Pediatr. 2024; 12:1276215.

PMID: 38379908 PMC: 10877724. DOI: 10.3389/fped.2024.1276215.

A phenotypic screen of Marfan syndrome iPSC-derived vascular smooth muscle cells uncovers GSK3β as a new target.

Davaapil H, McNamara M, Granata A, Macrae R, Hirano M, Fitzek M Stem Cell Reports. 2023; 18(2):555-569.

PMID: 36669494 PMC: 9968988. DOI: 10.1016/j.stemcr.2022.12.014.

Can 10 000 Healthy Steps a Day Slow Aortic Root Dilation in Pediatric Patients With Marfan Syndrome?.

Tierney E, Chung S, Stauffer K, Brabender J, Collins 2nd R, Folk R J Am Heart Assoc. 2022; 11(23):e027598.

PMID: 36453629 PMC: 9851465. DOI: 10.1161/JAHA.122.027598.

References

Gallo E, Loch D, Habashi J, Calderon J, Chen Y, Bedja D . Angiotensin II-dependent TGF-β signaling contributes to Loeys-Dietz syndrome vascular pathogenesis. J Clin Invest. 2013; 124(1):448-60. PMC: 3871227. DOI: 10.1172/JCI69666. View

Quon B, Dai D, Hollander Z, Ng R, Tebbutt S, Paul Man S . Discovery of novel plasma protein biomarkers to predict imminent cystic fibrosis pulmonary exacerbations using multiple reaction monitoring mass spectrometry. Thorax. 2015; 71(3):216-22. DOI: 10.1136/thoraxjnl-2014-206710. View

Chung A, Yang H, Au Yeung K, van Breemen C . Mechanical and pharmacological approaches to investigate the pathogenesis of Marfan syndrome in the abdominal aorta. J Vasc Res. 2008; 45(4):314-22. DOI: 10.1159/000113603. View

Wilkinson I, Qasem A, Mceniery C, Webb D, Avolio A, Cockcroft J . Nitric oxide regulates local arterial distensibility in vivo. Circulation. 2002; 105(2):213-7. DOI: 10.1161/hc0202.101970. View

Wang Y, Martin-McNulty B, Freay A, Sukovich D, Halks-Miller M, Li W . Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein E-deficient mice. Am J Pathol. 2001; 159(4):1455-64. PMC: 1850514. DOI: 10.1016/S0002-9440(10)62532-1. View

Chung A, Au Yeung K, Cortes S, Sandor G, Judge D, Dietz H . Endothelial dysfunction and compromised eNOS/Akt signaling in the thoracic aorta during the progression of Marfan syndrome. Br J Pharmacol. 2007; 150(8):1075-83. PMC: 2013910. DOI: 10.1038/sj.bjp.0707181. View

Lee M . Heparin inhibits activation of latent transforming growth factor-β1. Pharmacology. 2013; 92(5-6):238-44. DOI: 10.1159/000355837. View

Meffert P, Tscheuschler A, Beyersdorf F, Heilmann C, Kocher N, Uffelmann X . Characterization of serum matrix metalloproteinase 2/9 levels in patients with ascending aortic aneurysms. Interact Cardiovasc Thorac Surg. 2016; 24(1):20-26. DOI: 10.1093/icvts/ivw309. View

Kiotsekoglou A, Moggridge J, Saha S, Kapetanakis V, Govindan M, Alpendurada F . Assessment of aortic stiffness in marfan syndrome using two-dimensional and Doppler echocardiography. Echocardiography. 2011; 28(1):29-37. DOI: 10.1111/j.1540-8175.2010.01241.x. View

10.

Franken R, den Hartog A, de Waard V, Engele L, Radonic T, Lutter R . Circulating transforming growth factor-β as a prognostic biomarker in Marfan syndrome. Int J Cardiol. 2013; 168(3):2441-6. DOI: 10.1016/j.ijcard.2013.03.033. View

11.

Khan S, Joyce J, Tsuda T . Quantification of active and total transforming growth factor-β levels in serum and solid organ tissues by bioassay. BMC Res Notes. 2012; 5:636. PMC: 3556312. DOI: 10.1186/1756-0500-5-636. View

12.

Singh M, Lacro R . Recent Clinical Drug Trials Evidence in Marfan Syndrome and Clinical Implications. Can J Cardiol. 2016; 32(1):66-77. DOI: 10.1016/j.cjca.2015.11.003. View

13.

Loeys B, Schwarze U, Holm T, Callewaert B, Thomas G, Pannu H . Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006; 355(8):788-98. DOI: 10.1056/NEJMoa055695. View

14.

Peng X, Haldar S, Deshpande S, Irani K, Kass D . Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. Hypertension. 2003; 41(2):378-81. DOI: 10.1161/01.hyp.0000049624.99844.3d. View

15.

Freestone T, Turner R, Coady A, Higman D, Greenhalgh R, Powell J . Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1995; 15(8):1145-51. DOI: 10.1161/01.atv.15.8.1145. View

16.

Judge D, Dietz H . Therapy of Marfan syndrome. Annu Rev Med. 2007; 59:43-59. DOI: 10.1146/annurev.med.59.103106.103801. View

17.

Lavoie P, Robitaille G, Agharazii M, Ledbetter S, Lebel M, Lariviere R . Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic rats. J Hypertens. 2005; 23(10):1895-903. DOI: 10.1097/01.hjh.0000182521.44440.c5. View

18.

Wilson D, Bellamy M, Ramsey M, Goodfellow J, Brownlee M, Davies S . Endothelial function in Marfan syndrome: selective impairment of flow-mediated vasodilation. Circulation. 1999; 99(7):909-15. DOI: 10.1161/01.cir.99.7.909. View

19.

Coupes B, Williams S, Roberts I, Short C, Brenchley P . Plasma transforming growth factor beta(1) and platelet activation: implications for studies in transplant recipients. Nephrol Dial Transplant. 2001; 16(2):361-7. DOI: 10.1093/ndt/16.2.361. View

20.

Chung A, Yang H, Radomski M, van Breemen C . Long-term doxycycline is more effective than atenolol to prevent thoracic aortic aneurysm in marfan syndrome through the inhibition of matrix metalloproteinase-2 and -9. Circ Res. 2008; 102(8):e73-85. DOI: 10.1161/CIRCRESAHA.108.174367. View