How do baseline aortic root diameter, age and fibrillin-1 mutation affect the pooled effect of losartan on aortic dilatation?

Abstract

Dear Editor, We read with interest the study published in European Journal of Preventive Cardiology which synthesized five randomized clinical trials with 1313 cases for examining effects of losartan on prevention of aortic dilatation in Marfan syndrome (MFS). The research found that losartan cannot significantly prevent aortic dilatation because of six insignificant findings including aortic root diameter change, ascending aorta diameter change, descending aorta diameter change, aortic root surgery, aortic dissection events, and death. Our research also found similar results though we concluded differently. We completely agree with some explanations by Li et al. about the ineHcacy of losartan, and also understand their critics on a previous synthesis of this topic. Those explanations mainly relate with advanced disease, age and gene Ebrillin-1 (FBN1) mutation. However, they did not include three randomized clinical trials; and also did not explain the reasons for exclusion (Supplementary Material Table S1 online). Notably, two of the three trials investigated young populations (mean age <18 years old). Li et al. emphasized that age is an important factor, yet they lost these two trials. Therefore, the purpose of this letter aims to foster the understanding of how baseline aortic root diameter, age and FBN1 mutation affect the effects of losartan on prevention of aortic root diameter change by using available data from all randomized clinical trials of this topic. After we pooled eight randomized clinical trials on this topic, the result of aortic root diameter change was still insignificant without serious small study bias (Supplementary Figures S1 and S2), and our metaregression also did not find any significant finding. Nevertheless, besides age, two factors frommeta-regression were worth being discussed (Table 1 and Supplementary Figures S3 to S5). First, baseline aortic root diameter showing a positive trend in the effects of losartan on aortic root diameter change reached marginal significance (point estimate1⁄4 0.028, p1⁄4 .086). It indicated that losartan may result in more aortic root diameter change when patients have bigger aortic root at baseline. In other words, losartan may have lesser benefits among advanced MFS. Second, FBN1 mutation demonstrated the largest effect size (point estimate1⁄4 0.352, p1⁄4 .181) in affecting the effect of losartan on aortic root diameter change though it was insignificant. Limited evidence for the meta-regression of FBN1 mutation may cause the insignificance. This result reflected that FBN1 mutation might be an important factor when we discuss the effects of losartan on the prevention of aortic dilatation. In overall, our meta-regressions partially support the explanations of the ineHcacy of losartan on prevention of aortic dilatation though current evidence may be under power and without statistical significance. It is under debate in the past decade that losartan maybe benefits patients with MFS through inhibiting transforming growth factor b signaling, which was released excessively in FBN1 mutation. However, previous trials found controversial results for this hypothesis. Our findings provide a positive trend between FBN1 mutation rate and aortic root diameter change among those trials. This trend emphasizes the influences of FBN1 mutation and baseline aortic root diameter when they investigate impact of losartan on prevention of aortic