LAUSR

To the Editor, We read with great interest the manuscript titled BAngiotensin receptor blockade mediated amelioration of mucopoly saccharidosis type I cardiac and craniofacial pathology^ recently published in the Journal of Inherited Metabolic Disorders (Osborn et al., 2016). Simultaneously, we have been conducting a similar study, with results that are partially in accordance, and we thus have some additional important considerations concerning the content of their paper. We treated juvenile (8-week-old) Idua mice with losartan or other antihypertensive drug (propranolol) as an additional control (Suppl. Material andMethods) to determine the benefit of angiotensin receptor blockade (ARB) in mucopolysaccharidosis I (MPS I) and if this effect was specific to losartan. Mice were sacrificed at 6 months of age. Our data showed an increase in aortic diameter measured by a digital caliper in untreated Idua mice without significant gender differences (Suppl. Fig. 1). Treatment analysis was performed according to gender and without differentiation (Suppl. Fig. 2). Unlike Osborn et al.’s results, our data indicate that losartan is effective in decreasing aortic dilatation in MPS I at a similar rate for both genders (∼20%). As a comparison, we also treated female mice with propranolol (a betablocker), which was not able to reduce aortic dilatation. In agreement with Osborn et al., our echocardiographic analysis showed that losartan also improves ventricular contraction, expressed through left ventricular fraction shortening (LVSF) and suggesting an improved heartpumping ability. It also prevented enlargement of left ventricular chamber dimensions (Suppl. Table 1). However, it is important to point out that propranolol also improved cardiac function, which suggests that heart dysfunction may be independent from angiotensin receptor (AT-1R) activation. Propranolol might have its beneficial effect by reducing hemodynamic stress on the aortic vasculature. In contrast, we believe that losartan targets the underlying pathophysiology in MPS possibly by antagonism of transforming growth factor (TGF)-β or other pathways, which will be investigated. Aortic diameter was also measured by echo, which confirmed that only losartan prevented abnormalities in the aorta. The authors highlight the possibility that matrix metalloproteinase-12 (MMP-12) increase via AT-1R activation is one of the mechanisms involved in the pathogenesis of cardiovascular disease in MPS. Nonetheless, in a previous study, MPS I and VII mice developed aortic dilatation by similar mechanisms, and knocking out MMP-12 in MPS VII mice did not prevent aortic abnormalities (Baldo et al. 2011). This probably suggestst that multiple mechanisms and genes are responsible for this effect. Communicated by: Carla E. Hollak