1887
Volume 2014, Issue 4
  • ISSN: 2305-7823
  • E-ISSN:

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.

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2015-03-01
2019-10-15
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References

  1. [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. [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. [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. [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. [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. [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. [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. [8]. Bowen   JM., , Connolly   HM. . Of Marfan's Syndrome, Mice and Medications. . N Engl J Med.   2014; ;371: 22 : 2127– 2128 .
    [Google Scholar]
  9. [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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