Beta-blockers are often suggested as the first-line therapy for the treatment of a variety of cardiovascular problems, such as hypertension, aortic dissection, arrhythmia, and others [1–6]. Its negative inotropic and chronotropic effects can decrease proximal aortic shear stress or change in pressure over time (dP/dT). Thereby, β-blockers may slow the progression of aortic root dilatation and decrease the risk of cardiovascular events (aortic insufficiency, dissection, cardiovascular surgery, congestive heart failure, or death) [7–9]. This strategy was first proposed in 1971 by Halpern et al. [10] and was advocated by subsequent small trials for patients with Marfan syndrome. From a mouse study, β-blockers were also noted to stimulate cross-linking of extracellular matrix components and to improve aortic elastic properties [33].

However, various studies reported heterogeneous responses and suggested that the β-blockers either had limited effect or even worsened the aortic stiffness, especially in patients with increased body weight or end-diastolic aortic root diameter of >40 mm [34, 35]. A meta-analysis did not show that β-blockers reduce mortality or the incidence of aortic dissection in patients with Marfan syndrome [36]. Although the effects are controversial, β-blockers are still regarded as first-line drug to slow down the progression of aortic dilatation in patients with syndromic connective tissue disorders or other congenital heart diseases and an aortic root diameter of >40 mm [1–6]. The recent AHA/ACC guidelines recommend the use of β-blockers for aortic dilatation in non-Marfan patients and keep blood pressure as low as well tolerated [5].

Salim MA et al. reported the changes of aortic root growth rate over a patient’s lifetime, which reaches a peak between 6 and 14 years [9]. Therefore, in patients with connective tissue disorder such as Marfan syndrome or high risk for aortic dissection, β-blockers are recommended to use at the time of diagnosis especially before puberty and are maintained throughout life, even after aortic surgery [1–6]. The dose could be titrated to keep the heart rate around 60–70 bpm at rest and less than 100 bpm during submaximal exercise in older children or adults and less than 110 bpm in young children [2, 5, 6]. Up to now, widely used β-blockers in pediatric patients are propranolol or atenolol due to scanty safety evidences of other β-blockers. Atenolol is more beta-1 selective than propranolol and may be more effective in the treatment of aortic root dilation [1–6]. Recently, some ongoing studies used beta-1 selective blockades including bisoprolol, metoprolol, or nebivolol in the treatment of aortopathy to reduce the possible side effects. Among them, nebivolol is the highest selectively for β1 receptors and differs chemically, pharmacologically, and therapeutically from all other β-blockers which seems to directly target matrix metalloproteinases (MMPs) and/or transforming growth factor (TGF)-β cascade.

Extracellular matrix homeostasis is controlled and balanced by matrix metalloproteinases (MMPs) and their specific tissue inhibitors (TIMPs). Increased MMPs activity will cause apoptosis and degeneration of the aortic wall and lead to aortic dilatation or aneurysm formation [3–5]. Studies in mice models of Marfan syndrome suggest that a fibrillin-1 gene mutation might lead to excessive transforming growth factor (TGF)-β signaling and activate MMPs [37, 38].

Losartan, an angiotensin II type I (AT1) receptor blocker, has been shown to be effective in preventing aortic root dilatation in a mouse model of Marfan syndrome through blocking the AT1 receptor and the subsequent TGF-β signal cascade [11]. Several prospective clinical studies with different study designs had been conducted and shown the safety and the efficacy of losartan in operated or unoperated Marfan patients [12–16]. The efficacy of losartan correlates with treatment at earlier age and longer therapy duration, but not correlates with the type of phenotypes.

However, other studies did not confirm the results. The Pediatric Heart Network study, a large-scale, prospective randomized trial, which compared the efficacy of losartan and atenolol in children and young adult Marfan patients (608 patients, mean age 11 years, range 0.5–25.0 years) with dilated aortic roots failed to demonstrate superiority of losartan in reducing the rate of aortic dilatation (−0.107 vs. −0.139 z score/year; P = 0.08) over a 3-year period [39]. The Marfan Sartan study, a randomized, double-blind, placebo-controlled, add-on trial, which compared losartan vs. placebo in >10 years Marfan patients (303 patients, mean age 29.9 years, 86 % receiving β-blocker therapy) also reported no significant difference in limiting aortic dilatation between the losartan and placebo groups [40]. Forteza A et al. used magnetic resonance imaging to compare the benefits of losartan vs. atenolol as a monotherapy in Marfan patients (140 patients, mean age 25.2 ± 13.7 years, range 0.5–25.0 years) [41]. After 3 years of follow-up, aortic root diameter increased in both groups: 1.1 mm (95 % CI 0.6–1.6) in the losartan and 1.4 mm (95 % CI 0.9–1.9) in the atenolol group, with aortic dilatation progression being similar in both groups. The discrepancies between these studies may be due to different study design, inclusion criteria, drug doses, and endpoints. More methodologically rigorous studies currently in progress are needed to evaluate the impact of drug therapy on clinical outcomes.

The FBN1 mutation might influence the drug response. In Marfan Sartan study, losartan tended to be more beneficial in patients with an FBN1 mutation compared with those without (−0.04 vs. 0.00 z score/year and 0.40 vs. 0.51 mm/year; P value not reported) [40]. In COMPARE trial, patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy in slowing the rate of aortic root dilatation compared with dominant negative patients (0.5 ± 0.8 mm/3 years vs. 0.8 ± 1.3 mm/3 years; P value not reported) [16].

In summary of current trials with different study design and results, losartan seems not to provide better protection against aortic dilatation than β–blockers. Therapy with a combination of β–blockers and losartan may be more effective than β–blockers alone in both children and adults with Marfan syndrome and should be considered at least if aortic dilatation is severe or progressive. Until the results of ongoing trials and meta–analyses are known, losartan can safely be administered as an alternative treatment to β–blockers or add-on β–blockers.

Inappropriate activation of the renin-angiotensin system in human aortic aneurysms had been described [17, 42, 43]. Angiotensin II signaling will be transduced via activation of two different receptors: type I and type II (AT1 and AT2) receptors. Signaling through AT1 receptor induces fibrosis and apoptosis by increasing TGF-β expression and MMPs activities. In contrast, the signaling through AT2 receptor is protective by decreasing cell proliferation, MMPs activities, and fibrosis [3].

ACE inhibitors are suggested to reduce large artery stiffness and slow the progression of aortic aneurysm in animal and human subjects [17, 42, 43]. The effects are not fully understood and may attribute to blood pressure control or inhibition of the extracellular signal-regulated kinases (ERK1/2) [17, 44]. ERKs were implicated to be involved in the progression of aortic aneurysm through stimulation of TGF-β and AT1 receptor-dependent signals [45, 46]. Some small retrospective or nonrandomized clinical studies have reported that ACE inhibitors reduced both aortic stiffness and aortic root diameter and improved aortic distensibility as compared with β-blockers in patients with Marfan syndrome or abdominal aortic aneurysm [17, 18]. However, Phomakay V et al. [19] retrospectively compared aortic growth rate in pediatric Marfan patients (67 patients, 13 ± 10 years, follow-up 7.6 ± 5.8 years) who received β-blockers, ACE inhibitors, or no therapy and showed that aortic growth rate was higher than normal in ACE inhibitor and untreated groups but nearly normal in β-blockers group. A small randomized, double-blind, crossover study (18 patients, 30.4 ± 11.7 years, follow-up 0.35 years) indicated limited effect of ACE inhibitors on aortic growth [20]. In addition, ACE inhibitors showed to be less effective in slowing aortic dilatation compared with losartan in a mouse model [44]. This may be due to simultaneous inhibition of AT1 and AT2 pathway of ACE inhibitors, leading to a less protective effect than AT1 receptor blockade alone. Larger, randomized clinical trials are needed to better evaluate the safety and potential benefits of ACE inhibitors on aortic growth.