Angiotensin-II receptor blockade in Marfan syndrome
Authors: Laura Muiño-Mosquera, Julie De Backer
Journal: The Lancet (2019)

Because aortic root dilatation and resulting dissection are the most life-threatening problems in patients with Marfan syndrome, research has focused on mitigating the risk for these complications. Whereas surgical replacement of the dilated aorta remains the most effective intervention, medical treatment aimed at reducing aortic root growth also contributes to improved outcome. β blockers are considered the gold standard for this purpose, with an effect most likely achieved by reducing aortic wall shear stress.1Shores J, Berger K, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of long-term β-adrenergic blockade in Marfan's syndrome. N Engl J Med 330: 1335–41.Google Scholar A major discovery in the research to unravel the underlying pathogenesis of this condition was the demonstration of the transforming growth factor β (TGF-β) pathway involvement.2Neptune ER Frischmeyer PA Arking DE et al.Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome.Nat Genet. 2003; 33: 407-411Crossref PubMed Scopus (1161) Google Scholar This opened-up perspectives for new treatment options through blockade of TGF-β, where angiotensin-II receptor blockers (ARBs) seemed an attractive option. The precise contribution of TGF-β has still not been fully elucidated. It has been shown that TGF-β has dual effects and should be regarded as a marker rather than a cause of pathology.3Cook JR Clayton NP Carta L et al.Dimorphic effects of transforming growth factor-β signaling during aortic aneurysm progression in mice suggest a combinatorial therapy for Marfan syndrome.Arterioscler Thromb Vasc Biol. 2015; 35: 911-917Crossref PubMed Scopus (149) Google Scholar Nevertheless, the publication of the remarkable results, showing that losartan, an ARB, improved aortic growth in a mouse model of Marfan syndrome, had an impact in the Marfan syndrome community.4Habashi JP Judge DP Holm TM et al.Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.Science. 2006; 312: 117-121Crossref PubMed Scopus (1385) Google Scholar At least eight studies with losartan have been done.5Chiu H-H Wu M-H Wang J-K et al.Losartan added to β-blockade therapy for aortic root dilation in Marfan syndrome: a randomized, open-label pilot study.Mayo Clin Proc. 2013; 88: 271-276Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 6Muiño-Mosquera L De Nobele S Devos D Campens L De Paepe A De Backer J Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial.Acta Cardiol. 2017; 72: 616-624Crossref PubMed Scopus (26) Google Scholar, 7Teixido-Tura G Forteza A Rodríguez-Palomares J et al.Losartan versus atenolol for prevention of aortic dilation in patients with Marfan syndrome.J Am Coll Cardiol. 2018; 72: 1613-1618Crossref PubMed Scopus (57) Google Scholar, 8Li L Yamani N Al-Naimat S Khurshid A Usman MS Role of losartan in prevention of aortic dilatation in Marfan syndrome: a systematic review and meta-analysis.Eur J Prev Cardiol. 2019; (published online July 1.)DOI:10.1177/2047487319861231Crossref Scopus (10) Google Scholar Albeit with variable study design and populations, these studies showed that the results achieved in animal models could not be replicated in humans, leading to further speculation about possible explanations. One of the hypotheses was that the lower bioavailability (33%) and short half-life (2 h)9Abraham HMA White CM White WB The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.Drug Saf. 2015; 38: 33-54Crossref PubMed Scopus (86) Google Scholar of losartan might provide insufficient protection. Therefore, irbesartan, an ARB with longer bioavailability (up to 80%) and half-life (up to 15 h),9Abraham HMA White CM White WB The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases.Drug Saf. 2015; 38: 33-54Crossref PubMed Scopus (86) Google Scholar could result in a better outcome. For this reason, the study by Michael Mullen and colleagues10Mullen M Jin XY Child A et al.Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.Lancet. 2019; (published online Dec 10)https://doi.org/10.1016/S0140-6736(19)32518-8Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar in The Lancet is very interesting. This randomised placebo-controlled trial shows that the intake of irbesartan significantly reduced aortic root dilatation in patients with Marfan syndrome (mean aortic root growth 0·53 mm per year [95% CI 0·39 to 0·67] in the irbesartan group vs 0·74 mm per year [0·60 to 0·89] in the placebo group; difference −0·22 mm per year [–0·41 to −0·02]; p=0·030). This moderate effect was mainly achieved during the first year of treatment and was maintained throughout the 4 subsequent years. A parallel effect was observed on blood pressure, suggesting a possible association between lowering blood pressure and aortic growth. On the basis of these findings, previous conclusions are confirmed: the use of ARBs to inhibit aortic growth in patients with Marfan syndrome can certainly be considered. Several recurring and unresolved questions in the design and interpretation of studies of ARBs have unfortunately not been clarified by this study either. First, many such studies are confronted with the issue of difficult patient recruitment. In the study by Mullen and colleagues,10Mullen M Jin XY Child A et al.Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.Lancet. 2019; (published online Dec 10)https://doi.org/10.1016/S0140-6736(19)32518-8Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar not even half of the anticipated number of patients was achieved. This difficulty has to do with the rarity of the condition and with the difficulty of convincing patients to participate in research after the publication of preclinical trials. Second, another limiting factor is the low hard event rate (aortic dissection and death), which forces all studies to rely on indirect outcome parameters, such as aortic root growth. Furthermore, an additional limitation of this study is the inclusion of both children and adults (192 patients with Marfan syndrome with a median age of 18 years [IQR 12–28]). Apart from somatic growth in half of the study population, which is difficult to account for, there is the problem of the measurement of the aorta itself and the calculation of the Z scores. Although aortic Z score values were used as a secondary outcome in this study, applying methods for Z score calculation based on data obtained in different age populations and using different echocardiographic methods is cumbersome. The authors sought to solve this difficulty by calculating the Z score according to the Devereux method11Devereux RB de Simone G Arnett DK et al.Normal limits in relation to age, body size and gender of two-dimensional echocardiographic aortic root dimensions in persons ≥15 years of age.Am J Cardiol. 2012; 110: 1189-1194Summary Full Text Full Text PDF PubMed Scopus (247) Google Scholar (developed for application in adult patients) while using the Pettersen reference12Pettersen MD Du W Skeens ME Humes RA Regression equations for calculation of Z scores of cardiac structures in a large cohort of healthy infants, children, and adolescents: an echocardiographic study.J Am Soc Echocardiogr. 2008; 21: 922-934Summary Full Text Full Text PDF PubMed Scopus (526) Google Scholar (developed for application in paediatric patients) as a sensitivity analysis. A final consideration is that 108 (56%) patients in the cohort were taking β blockers. The authors tried to account for the confounding effect of β blockers through conventional stratified analysis, but the study was underpowered to perform meaningful subgroup evaluation (especially given the drop-out rate of 24% in the irbesartan group and 15% in the placebo group). Subsequently, evaluation of how the observed effect should be interpreted is difficult. Is the effect of the irbesartan better in comparison to no treatment or in comparison to β blocker treatment? What is the effect of combined treatment? Despite these limitations, the study by Mullen and colleagues10Mullen M Jin XY Child A et al.Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trial.Lancet. 2019; (published online Dec 10)https://doi.org/10.1016/S0140-6736(19)32518-8Summary Full Text Full Text PDF PubMed Scopus (57) Google Scholar is valuable and certainly adds to the ongoing discussion on how to best treat patients with Marfan syndrome. A planned meta-analysis of trials done thus far13Pitcher A Emberson J Lacro RV et al.Design and rationale of a prospective, collaborative meta-analysis of all randomized controlled trials of angiotensin receptor antagonists in Marfan syndrome, based on individual patient data: a report from the Marfan Treatment Trialists' Collaboration.Am Heart J. 2015; 169: 605-612Crossref PubMed Scopus (39) Google Scholar will hopefully provide some answers that are urgently needed for this community. We declare no competing interests. Irbesartan in Marfan syndrome (AIMS): a double-blind, placebo-controlled randomised trialIrbesartan is associated with a reduction in the rate of aortic dilatation in children and young adults with Marfan syndrome and could reduce the incidence of aortic complications. Full-Text PDF Open Access