Therapy Progress for Vascular Pathology of Marfan Syndrome_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

GONG Bing , YANG Xiubin.

Department of Surgery，　Cardiovascular Institute and Fu Wai Hospital，　Chinese Academy of Medical Sciences＆Peking Union Medical College，　Beijing 100037， P. R. China;

Corresponding author：

Keywords：

Marfan syndrome; 　Vascular pathology; 　Therapy; 　Losartan; 　Transforming growth factor β

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Abstract：　Marfan syndrome （MFS） is a congenital and heritable autosomal dominant disorder of the connective tissue　which is often passed down through families. Its clinical presentation typically involves the skeletal， cardiovascular and ocular systems with a high natural mortality. Aortic root aneurysm and consecutive acute aortic dissection represent the main cardiovascular manifestations and main causes of morbidity and mortality in MFS. At present， the predominant therapeutic method is surgery， but surgical outcomes are quite unsatisfactory. Recent studies demonstrate that losartan， a common　antihypertensive agent， is useful to treat MFS， the mechanism of which may results from inhibiting overactivation of transforming growth factor β （TGF-β） signaling. This discovery will definitely promote the transition of traditional surgical treatment of MFS into pharmacotherapy. In this review， we focus on the molecular biological pathogenesis， traditional and new therapeutic strategies for MFS patients.　

Citation： GONG Bing,YANG Xiubin.. Therapy Progress for Vascular Pathology of Marfan Syndrome. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2012, 19(6): 668-670. doi: Copy

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2.	Yuan SM， Jing H. Marfan’s syndrome：an overview. Sao Paulo Med J， 2010，128 （6）：360-366.
3.	Lebreiro A， Martins E， Cruz C， et al. Marfan syndrome：clinical manifestations， pathophysiology and new outlook on drug therapy. Rev Port Cardiol， 2010， 29 （6）：1021-1036.
4.	Chung AW， Au Yeung K， Sandor GG， et al. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting　from the upregulated activities of matrix metalloproteinase-2 and-9　in the thoracic aortic aneurysm in Marfan syndrome. Circ Res， 2007， 101 （5）：512-522.
5.	Merk DR， Chin JT， Dake BA， et al. miR-29b participates in early aneurysm development in marfan syndrome. Circ Res， 2012， 110 （2）：312-324.
6.	Holm TM， Habashi JP， Doyle JJ， et al. Noncanonical TGFβ signaling　contributes to aortic aneurysm progression in Marfan syndrome mice. Science， 2011， 332 （6027）：358-361.
7.	Brooke BS， Habashi JP， Judge DP， et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med， 2008， 358 （26）：2787-2795.
8.	Habashi JP， Judge DP， Holm TM， et al. Losartan， an AT1 antag　onist， prevents aortic aneurysm in a mouse model of Marfan syndrome.　Science， 2006， 312 （5770）：117-121.
9.	Hartog AW， Franken R， Zwinderman AH， et al. Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome. Expert Opin Pharmacother， 2012， 13 （5）：647-662.
10.	Shimizu H， Kasahara H， Nemoto A， et al. Can early aortic root　surgery prevent further aortic dissection in Marfan syndrome ?　Interact Cardiovasc Thorac Surg， 2012， 14 （2）：171-175.
11.	Geisbuesch S， Schray D， Bischoff MS， et al. Frequency of reoperations in patients with Marfan syndrome. Ann Thorac Surg， 2012， 93 （5）：1496-1501.
12.	Zhang L， Gao LG， Zhang M， et al. Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2， including a type 2 Marfan syndrome familial study. Mol Vis， 2012，18：55-63.
13.	Neptune ER， Frischmeyer PA， Arking DE， et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet， 2003， 33 （3）：407-411.
14.	El-HamamsyⅠ， Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol， 2009， 6 （12）：771-786.
15.	ten Dijke P， Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol， 2007， 8 （11）：857-869.
16.	Le Goff C， Cormier-Daire V. From tall to short：the role of TGFβ signaling in growth and its disorders. Am J Med Genet C Semin Med Genet， 2012，160 （3）：145-153.
17.	Sengle G， Tsutsui K， Keene DR， et al. Microenvironmental regulation by fibrillin-1. PLoS Genet， 2012，8 （1）：e1002425.
18.	Kaartinen V， Warburton D. Fibrillin controls TGF-beta activation. Nat Genet， 2003， 33 （3）：331-332.
19.	Yang Y， Cui Y， Peng DQ. ARB May be superior to ACEI on treatment of Marfan’s syndrome by blocking TGF-β mediated activation of ERK. Int J Cardiol， 2012， 155 （3）：482-483.
20.	Aalberts JJ， Thio CH， Schuurman AG， et al. Diagnostic yield in adults screened at the Marfan outpatient clinic using the 1996 and 2010 Ghent nosologies. Am J Med Genet A， 2012， 158A （5）：982-988.
21.	Radonic T， de Witte P， Baars MJ， et al. Losartan therapy in adults with Marfan syndrome：study protocol of the multi-center randomized controlled compare trial. Trials， 2010，11：3.
22.	Detaint D， Aegerter P， Tubach F， et al. Rationale and design of a randomized clinical trial （Marfan Sartan） of angiotensinⅡreceptor blocker therapy versus placebo in individuals with Marfan syndrome. Arch Cardiovasc Dis， 2010， 103 （5）：317-325.
23.	Gambarin FI， Favalli V， Serio A， et al. Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association　of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations. J Cardiovasc Med （Hagerstown）， 2009， 10 （4）：354-362.
24.	Lacro RV， Dietz HC， Wruck LM， et al. Rationale and design of a randomized clinical trial of beta-blocker therapy （atenolol） versus angiotensinⅡreceptor blocker therapy （losartan） in individuals with Marfan syndrome. Am Heart J， 2007， 154 （4）：624-631.
25.	Dean JC. Marfan syndrome：clinical diagnosis and management. Eur J Hum Genet， 2007， 15 （7）：724-733.
26.	Matt P， Eckstein F. Novel pharmacological strategies to prevent aortic complications in Marfan syndrome. J Geriatr Cardiol， 2011， 8 （4）：254-257.
27.	Keane MG， Pyeritz RE. Medical management of Marfan syndrome. Circulation， 2008， 117 （21）：2802-2813.
28.	Pyeritz RE， Loeys B. The 8th international research symposium on the Marfan syndrome and related conditions. Am J Med Genet A， 2011，158：42-49.

1. 　Stheneur C， Laffond C， Rioux S， et al. Recent progress in Marfan syndrome. Arch Pediatr， 2012， 19 （5）：551-555.
2. 　Yuan SM， Jing H. Marfan’s syndrome：an overview. Sao Paulo Med J， 2010，128 （6）：360-366.
3. 　Lebreiro A， Martins E， Cruz C， et al. Marfan syndrome：clinical manifestations， pathophysiology and new outlook on drug therapy. Rev Port Cardiol， 2010， 29 （6）：1021-1036.
4. 　Chung AW， Au Yeung K， Sandor GG， et al. Loss of elastic fiber integrity and reduction of vascular smooth muscle contraction resulting　from the upregulated activities of matrix metalloproteinase-2 and-9　in the thoracic aortic aneurysm in Marfan syndrome. Circ Res， 2007， 101 （5）：512-522.
5. 　Merk DR， Chin JT， Dake BA， et al. miR-29b participates in early aneurysm development in marfan syndrome. Circ Res， 2012， 110 （2）：312-324.
6. 　Holm TM， Habashi JP， Doyle JJ， et al. Noncanonical TGFβ signaling　contributes to aortic aneurysm progression in Marfan syndrome mice. Science， 2011， 332 （6027）：358-361.
7. 　Brooke BS， Habashi JP， Judge DP， et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med， 2008， 358 （26）：2787-2795.
8. 　Habashi JP， Judge DP， Holm TM， et al. Losartan， an AT1 antag　onist， prevents aortic aneurysm in a mouse model of Marfan syndrome.　Science， 2006， 312 （5770）：117-121.
9. 　Hartog AW， Franken R， Zwinderman AH， et al. Current and future pharmacological treatment strategies with regard to aortic disease in Marfan syndrome. Expert Opin Pharmacother， 2012， 13 （5）：647-662.
10. 　Shimizu H， Kasahara H， Nemoto A， et al. Can early aortic root　surgery prevent further aortic dissection in Marfan syndrome ?　Interact Cardiovasc Thorac Surg， 2012， 14 （2）：171-175.
11. 　Geisbuesch S， Schray D， Bischoff MS， et al. Frequency of reoperations in patients with Marfan syndrome. Ann Thorac Surg， 2012， 93 （5）：1496-1501.
12. 　Zhang L， Gao LG， Zhang M， et al. Genotype-phenotype analysis of F-helix mutations at the kinase domain of TGFBR2， including a type 2 Marfan syndrome familial study. Mol Vis， 2012，18：55-63.
13. 　Neptune ER， Frischmeyer PA， Arking DE， et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet， 2003， 33 （3）：407-411.
14. 　El-HamamsyⅠ， Yacoub MH. Cellular and molecular mechanisms of thoracic aortic aneurysms. Nat Rev Cardiol， 2009， 6 （12）：771-786.
15. 　ten Dijke P， Arthur HM. Extracellular control of TGFbeta signalling in vascular development and disease. Nat Rev Mol Cell Biol， 2007， 8 （11）：857-869.
16. 　Le Goff C， Cormier-Daire V. From tall to short：the role of TGFβ signaling in growth and its disorders. Am J Med Genet C Semin Med Genet， 2012，160 （3）：145-153.
17. 　Sengle G， Tsutsui K， Keene DR， et al. Microenvironmental regulation by fibrillin-1. PLoS Genet， 2012，8 （1）：e1002425.
18. 　Kaartinen V， Warburton D. Fibrillin controls TGF-beta activation. Nat Genet， 2003， 33 （3）：331-332.
19. 　Yang Y， Cui Y， Peng DQ. ARB May be superior to ACEI on treatment of Marfan’s syndrome by blocking TGF-β mediated activation of ERK. Int J Cardiol， 2012， 155 （3）：482-483.
20. 　Aalberts JJ， Thio CH， Schuurman AG， et al. Diagnostic yield in adults screened at the Marfan outpatient clinic using the 1996 and 2010 Ghent nosologies. Am J Med Genet A， 2012， 158A （5）：982-988.
21. 　Radonic T， de Witte P， Baars MJ， et al. Losartan therapy in adults with Marfan syndrome：study protocol of the multi-center randomized controlled compare trial. Trials， 2010，11：3.
22. 　Detaint D， Aegerter P， Tubach F， et al. Rationale and design of a randomized clinical trial （Marfan Sartan） of angiotensinⅡreceptor blocker therapy versus placebo in individuals with Marfan syndrome. Arch Cardiovasc Dis， 2010， 103 （5）：317-325.
23. 　Gambarin FI， Favalli V， Serio A， et al. Rationale and design of a trial evaluating the effects of losartan vs. nebivolol vs. the association　of both on the progression of aortic root dilation in Marfan syndrome with FBN1 gene mutations. J Cardiovasc Med （Hagerstown）， 2009， 10 （4）：354-362.
24. 　Lacro RV， Dietz HC， Wruck LM， et al. Rationale and design of a randomized clinical trial of beta-blocker therapy （atenolol） versus angiotensinⅡreceptor blocker therapy （losartan） in individuals with Marfan syndrome. Am Heart J， 2007， 154 （4）：624-631.
25. 　Dean JC. Marfan syndrome：clinical diagnosis and management. Eur J Hum Genet， 2007， 15 （7）：724-733.
26. 　Matt P， Eckstein F. Novel pharmacological strategies to prevent aortic complications in Marfan syndrome. J Geriatr Cardiol， 2011， 8 （4）：254-257.
27. 　Keane MG， Pyeritz RE. Medical management of Marfan syndrome. Circulation， 2008， 117 （21）：2802-2813.
28. 　Pyeritz RE， Loeys B. The 8th international research symposium on the Marfan syndrome and related conditions. Am J Med Genet A， 2011，158：42-49.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Therapy Progress for Vascular Pathology of Marfan Syndrome

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