AT1 Receptor Antagonism to Reduce Aortic Expansion in Marfan Syndrome
2014; Lippincott Williams & Wilkins; Volume: 35; Issue: 2 Linguagem: Inglês
10.1161/atvbaha.114.305173
ISSN1524-4636
Autores Tópico(s)Cardiovascular Issues in Pregnancy
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 35, No. 2AT1 Receptor Antagonism to Reduce Aortic Expansion in Marfan Syndrome Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBAT1 Receptor Antagonism to Reduce Aortic Expansion in Marfan SyndromeLost in Translation or in Need of Different Interpretation? Ziad Mallat and Alan Daugherty Ziad MallatZiad Mallat From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom (Z.M.); and Saha Cardiovascular Research Center, University of Kentucky, Lexington (A.D.) and Alan DaughertyAlan Daugherty From the Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom (Z.M.); and Saha Cardiovascular Research Center, University of Kentucky, Lexington (A.D.) Originally published30 Dec 2014https://doi.org/10.1161/ATVBAHA.114.305173Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:e10–e12Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 Marfan syndrome is an inherited autosomal dominant disorder of the connective tissue caused by mutations in the gene encoding fibrillin-1 (FBN1).1,2 This disease has affected the ATVB community with the loss of 1 of our highly respected members, David Williams.3 The most devastating health issues of patients with Marfan syndrome are dissection and rupture of the proximal aorta. Aortic dimensions are routinely monitored in patients with Marfan syndrome, and surgical graft imposition is performed to sustain life. However, surgical intervention is a formidable process. To abrogate surgical repair, there is a desperate need for a medical approach for attenuating aortic expansion. Presently, patients with Marfan syndrome are routinely provided with β-adrenoceptor blockade. This standard of care is derived from the study of Shores et al.4 However, the benefit derived from administration of β-adrenoceptor blockade is far from established.Although FBN1 is a component of extracellular matrix, mutations in this protein do not directly promote the structural fragility that characterizes the specific aortic regions of patients with Marfan syndrome. Instead, a concept has developed that Fbn1 mutations lead to enhanced transforming growth factor β (TGF-β) activation that is the mechanistic basis of Marfan pathology. This concept originated from the demonstration that Fbn1 deficiency led to excessive activation of TGF-β signaling because of reduced binding, sequestration, and inactivation of TGF-β.5 Activation of TGF-β in Fbn1-deficient mice was associated with a lung pathology similar to that observed in some patients with Marfan syndrome. This paradigm of FBN1 regulation of TGF-β activation was extended to aortic disease by generating heterozygous mice that express a C1039G mutation.6 These mice develop pronounced dilation of the ascending aorta associated with thickened media containing disrupted elastin fibers. In this model, the major proof of concept for the role of TGF-β was the attenuation of ascending aortic dilation by administration of a neutralizing antibody to all isoforms.6 Losartan was also highly effective in attenuating aortic dilation and medial pathology. Losartan was the first of the class of angiotensin II (AngII) type 1 (AT1) receptor antagonists that block the effects of AngII on the major receptor type responsible for most of the major physiological and pathological effects. Losartan has known effects beyond antagonism of AT1 receptors, although this does not extend to antagonism of TGF-β on any of its receptors.7 However, because AngII stimulates the release of TGF-β, losartan could indirectly reduce TGF-β–mediated responses.8 Therefore, the benefits of losartan administration infer that AT1 receptors are involved in these Fbn1 C1039G mice. Conversely, chronic infusion of AngII into mice leads to ascending aortic dilation and medial pathology that bears strong similarities to tissue characteristics of Fbn1 C1039G mouse.9,10 Collectively, these were convincing preclinical data that antagonism of AT1 receptors would be a beneficial approach for treating aortic disease in patients with Marfan syndrome. The translational potential of the preclinical results was greatly reinforced by the reported superiority of AT1 receptor blockade compared with β-adrenoceptor antagonism in Fbn1 C1039G mice, with losartan providing significantly better protection against aortic dilation and structural remodeling compared with propranolol.6The excitement of this preclinical demonstration of losartan effects provoked a retrospective analysis of children with Marfan syndrome whose aortic dimensions were sequentially monitored during administration of atenolol, and subsequently, treated with an AT1 receptor antagonist. Losartan was administered to all but one of the children, who received irbesartan.11 This small cohort study had the provocative conclusion that AT1 receptor antagonism reduced the rate of aortic expansion. This report noted the requirement for randomized trials to confirm the observations of this retrospective analysis.The combined data from animal studies and the retrospective analysis stimulated the initiation of several trials throughout the world.12 These trial designs have many differences, including patient age at study initiation, the group used to compare losartan treated individuals, and the sartan used. A few preliminary reports of small open-label clinical trials have subsequently provided support for this concept in patients with Marfan syndrome and suggested that losartan treatment, either alone or in combination with β-adrenoceptor antagonists, was associated with reduced rate of aortic dilatation.11,13One of the most anticipated trials of AT1 receptor antagonism on aortic root expansion was designed by the Marfan Trial Subcommittee of the Pediatric Heart Network.14 The results of this trial were eagerly awaited and many expected that it would definitely validate the superiority of losartan compared with atenolol in providing aortic protection through reductions of the aortic growth rate. However, Lacro et al15 reported no benefit of losartan when compared with atenolol for a 3-year period. There was even a tendency toward less decrease in (baseline-adjusted) the aortic root Z-score over time (P=0.08) in the losartan group, which was statistically significant when considering the aortic-annulus Z-score (P<0.001), and a trend toward increased risk (1.9 fold, P=0.10) for clinical events (aortic root surgery, aortic dissection, and death) in losartan compared with patients treated with atenolol.So, why did losartan fall so far short of its promise in this clinical trial? Several shortcomings were noted in the trial design that need to be accounted for in the evaluation of the data. One of the principal issues was the lack of a placebo group. This will be addressed in some of the completed and ongoing trials.16,17 Another critical issue was the optimization of losartan dosing. There was no indication of the extent of AT1 receptor antagonism.From a perspective of preclinical studies providing insight into aortic dilation in patients with Marfan syndrome, an important question is whether the study of Lacro et al15 invalidates the use of mouse studies that indicated the benefit of AT1 receptor antagonism in proximal aortic dilation. Before making such a damming conclusion, several facets of experimental design should be considered that may affect the extrapolation of effects from the preclinical to the clinical arena.HemodynamicsLosartan was superior to β-adrenoceptor antagonism with propranolol in attenuating aortic dilation in Fbn1 C1039G mice when both drugs were titrated to achieve comparable hemodynamic effects in vivo, including a 15% to 20% decrease in heart rate and a 10% to 20% decrease in blood pressure in both groups.6 However, hemodynamic data were not provided to assess the extent of blood pressure reduction in losartan versus propranolol-administered mice. Small, but sustained, differences in blood pressure over time may prove significant effects and could substantially affect disease progression. Although losartan has reproducibly been shown to induce significant reduction of blood pressure in mice,18 β-adrenoceptor antagonism is less effective at altering blood pressure, despite significant reductions of heart rate.19,20 If this was the case in Fbn1 C1039G mice,6 differences in blood pressure response to β-adrenoceptor antagonism between species might have accounted, at least in part, for the superiority of losartan compared with propranolol in Fbn1 C1039G mice and for the absence of any such advantage of losartan compared with atenolol in patients with Marfan syndrome. Another important difference is the substantial negative chronotropic effect of losartan seen in mice with Marfan syndrome,6 which has not been reported in humans.DoseAlthough the definition of dose response characteristics of drugs is a basic principle of pharmacology, its application to in vivo studies with chronic end points presents practical impediments. Despite these impediments, future work needs to execute pivotal studies on dose response. Although such studies would not be conceptually innovative, they would be critical to meaningful interpretation.Mode of AdministrationIn Marfan syndrome, the stimulus for aortic dilation is likely to be persistent throughout the duration of a day. Maintenance of adequate inhibition of AT1 receptor throughout the day is reliant on mode of administration and pharmacokinetics of the drug. In the case of mouse studies, delivery systems, such as osmotic minipumps, can be used to provide consistent AT1a receptor inhibition throughout the day.21 Losartan was administered in drinking water of the mice with Marfan syndrome.6 Mice imbibe throughout the day. Therefore, although plasma drug levels fluctuated more than administration via osmotic minipumps, it is likely that effective AT1 receptor antagonism occurred for major duration of the day.6 In contrast, the human study used a single dose per day of losartan. This mode of delivery probably led to inconsistent degrees of AT1 receptor inhibition throughout the day.Receptor Affinity and Pharmacokinetics of LosartanAlthough the sartan class of drugs has the common feature of preventing AngII stimulating the AT1 receptor, there are major divergences within the class in achieving this result. At the receptor level, there are marked differences in affinity, with telmisartan, irbesartan, and candesartan being at the upper end of the spectrum, whereas losartan is one of the least efficacious in the class. Also, half-lives of drugs within this class differ widely, with telmisartan being at the upper end of ≈24 hours, whereas losartan's half-life is ≈2 hours, the shortest half-life of this class.Stage of DiseaseThe initial studies demonstrated that aortic expansion was attenuated in Fbn1 C1039G mice when losartan was administered during gestation. Clearly, treatment at this stage of disease could not be mimicked in human studies. It was also demonstrated that losartan attenuated aortic expansion when administered post gestation. However, even in these postgestational experiments, losartan administration was started when mice were only 7 weeks of age. Indeed, in the clinical trial, it was inferred that more benefits were present in younger patients. Clearly, more studies are required to determine whether the beneficial effects of losartan are influenced by the stage of disease advancement.TGF-β InhibitionWith the disappointment of this clinical trial outcome, there is the potential for switching focus to direct TGF-β inhibition. However, this switch should be approached with considerable caution. Although TGF-β neutralization has been shown to decrease aortic expansion in Fbn1 C1039G mice, this promoted fatal abdominal and thoracic aortic rupture in AngII-infused mice, even within the ascending aorta.22,23 Moreover, loss of function mutations of TGF-β receptors leads to marked acceleration of aortic root expansion and to high incidence of early death because of dissection and rupture of the thoracic aorta,24 even in Fbn1 C1039G mice.24 Therefore, additional mechanistic work in this area needs to solve these controversies before any recommendation could be made for translational studies to block TGF-β signaling in patients with Marfan syndrome.What is the next step in pursuing whether AT1 receptor antagonism is helpful for the devastating effect of aortic expansion and rupture in patients with Marfan syndrome? More clinical data will be forthcoming when the other 8 major trials are completed.12 It will be of interest to determine whether some of the variances in designs will provide insights when other studies are completed. Of particular interest, one of the studies will use irbesartan,25 which is a much more effective inhibitor of AT1 receptors than losartan that has been used in all other trials. Also, the affinity and pharmacokinetic properties of candesartan and telmisartan make them attractive candidates to test. In preclinical studies, more in-depth knowledge is required for the extent and duration of AT1 receptor antagonism needed to attenuate diseases to determine the optimal mode of antagonism in the clinical world. In addition, beyond AT1 antagonism, it is important to determine whether progressive aortic dilation and rupture have distinct mechanisms that may require different approaches to therapy. Overall, we are still far away from completely understanding the mechanisms of aortic aneurysms to assist patients with Marfan syndrome by providing optimal medications. Enhanced research funds invested in this area would profoundly benefit this dire need.Sources of FundingAneurysm research in the Mallat lab is supported by the British Heart Foundation and by Inserm. Aneurysm research in the Daugherty lab is supported by HL107319. The content of this article is solely the responsibilities of the authors and does not necessarily represent the official views of the National Institutes of Health.DisclosuresNone.FootnotesThis manuscript was sent to William C. Sessa, Consulting Editor, for review by expert referees, editorial decision, and final disposition.Correspondence to Ziad Mallat, MD, PhD, Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, United Kingdom. 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February 2015Vol 35, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.114.305173PMID: 25550201 Originally publishedDecember 30, 2014 PDF download Advertisement
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