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Volume 2014, Issue 4
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Abstract

A landmark study by Habashi et al1 in 2006 documented for the first time both the prevention and reversal of structural changes in the aorta associated with Marfan syndrome, via pharmacological means. This study, carried out in a rat model, concluded that such results were due to an inhibitor effect by the drug losartan on TGB-β1 (Figure 1).Figure 1.  Homo dimer of TGF-β 1. Courtesy of Poornima Rao, QCRC.

Habashi's paper prompted some physicians, in the absence of human trials, to begin the clinical off-label use of losartan on Marfan patients, arguing that this was justified due to the drug's excellent safety profile. This has caused some controversy.

Two significant randomized human trials of losartan in Marfan patients have since been conducted, which contribute different but valuable elements to the debate; the COMPARE trial demonstrated a significantly lower increase in aortic root diameter among study subjects receiving losartan compared with a placebo group after 3 years, although no significant differences were observed in aortic diameter beyond the root itself. A more recently concluded trial by Lacro et al2 from the Paediatric Heart Network, comparing losartan with atenolol (and no placebo group), appeared to show no comparative benefit with respect to the rate of aortic dilatation over three years among the losartan users compared with study patients given atenolol, with both groups of patients experiencing a similar decrease in the rate of dilatation over the 3 year follow-up.

Both studies suggest a positive impact of losartan on aortic dilation in humans with Marfan, but they also highlight a number of important questions that remain unanswered. Further trials are clearly needed in order to assess optimal dosing and to guide timing of therapy, and also to further assess the potential and comparative effectiveness of both losartan and β-blockers, individually and in combination, as therapeutic treatments for aortic protection of different groups of patients with Marfan syndrome.

© 2014 Yacoub, Radford, licensee Bloomsbury Qatar Foundation Journals.
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2015-03-01
2024-04-19
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References

  1. Habashi J, Judge D, Holm T, Cohn R, Loeys B, Cooper T, Myers L, Klein E, Liu G, Calvi C, Podowski M, Neptune E, Halushka M, Bedja D, Gabrielson K, Rifkin D, Carta L, Ramirez F, Huso D, Diaz H. Losartan, an AT1 Antagonist, Prevents Aortic Aneurysms in a Mouse Model of Marfan Syndrome. Science. 2006; 312:5770:117–121, April 7.
     [Google Scholar]
  2. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, E , Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L. Atenol versus Losartan in Children and Young Adults with Marfan's Syndrome. N Eng J Med. 2014; 371:22:2061–2071.
     [Google Scholar]
  3. Nagashima H, Sakomura Y, Kasanuki H, Aoka Y, Uto K, Kameyama Ki, Ogawa M, Aomi S, Koyanagi H, Ishizuka N, Naruse M, Kawana M. Angiotensin II type 2 receptor mediates vascular smooth muscle cell apoptosis in cystic medial degeneration associated with Marfan Syndrome. Circulation. 2001; 104:12 September 2001:1282–1287.
     [Google Scholar]
  4. DePaepe A, Devereux RB, Dietz H, Hennekam R, Pyeritz RE. Revised diagnostic criteria for the Marfan Syndrome. Am J Med Genetic. 1996; 62::417–426.
     [Google Scholar]
  5. Van der Velde ET, Vriend JW, Mannens M, Uiterwaal C, Brand R, Mulder B. CONCOR, an initiative towards a national registry and DNA Bank of patients with congenital heart disease in the Netherlands: rationale, design and first results. Eur J Epidemiol. 2005; 20::549–557.
     [Google Scholar]
  6. Groenick M, Hartog AW den, Franken R, Radonic T, Waard V de, Timmermans J, Scholte AJ, Berg MP van den, Spijkerboer AM, Marquering HA, Zwinderman AH, Mulder BJM. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. European Heart Journal 2013; 34:45:3491–3500. doi:10.1093/eurheartj/eht334..
     [Google Scholar]
  7. Brooke B, Habashi J, Judge D, Patel N, Loeys B, Dietz H. Angiotensin II Blockade and Aortic Root Dilation in Marfan Syndrome. N Engl J Med. 2008; 358::2787–2795.
     [Google Scholar]
  8. Bowen JM, Connolly HM. Of Marfan's Syndrome, Mice and Medications. N Engl J Med. 2014; 371:22:2127–2128.
     [Google Scholar]
  9. Loeys B, Schwarze U, Holm T, Callewaert B, Thomas G, Pannu H, De Backer J, Oswald G, Symoens S, Manouvrier S, Roberts A, Faravelli F, Greco M, Pyerittz R, Milewicz D, Coucke P, Cameron D, Braveman A, Byers P, De Paepe A, Dietz H. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24; 355:8:788–798.
     [Google Scholar]
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COMPARE and Pediatric Heart Network Investigator trials: Losartan finally validated in humans with Marfan, but much work remains!
Global Cardiology Science and Practice 2014, 51 (2015); https://doi.org/10.5339/gcsp.2014.51
/content/journals/10.5339/gcsp.2014.51
/content/journals/10.5339/gcsp.2014.51
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  • Article Type: Research Article
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