Evaluation of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI

A Randomized Clinical Trial to Evaluate the Effects of Losartan on Cardiovascular Disease in Patients With Mucopolysaccharidoses IV A and VI

Mucopolysaccharidoses (MPS) are multisystemic diseases with significant clinical overlap between their types, with cardiac problems being among the most commonly observed manifestations and are also among the main causes of mortality in these patients. For some of the cardiovascular manifestations, such as aortic root dilation and valve diseases, there is no effective treatment currently available. Losartan, on the other hand, has been shown to be an effective drug for dilation of the aortic root, at least in animal models. This study aims to evaluate the safety and efficacy of losartan in patients with MPS VI and other mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) are a group of lysosomal diseases characterized by deficiency of enzymes responsible for the degradation of glycosaminoglycans. MPS are multisystemic diseases with significant clinical overlap between their types, with cardiac problems being among the most commonly observed manifestations and are also among the main causes of mortality in these patients. Enzyme replacement therapy and bone marrow transplantation, despite being well established treatments, are not yet capable of reversing or preventing the progression of some of the cardiological manifestations of MPS. On the other hand, these patients may benefit from other conventional drug or surgical treatment, which can be instituted at an appropriate time if there is a better understanding of how these manifestations progress. In particular, the occurrence of aortic root dilation, although described in animal models, has only recently been evaluated in the studies on mucopolysaccharidoses. In addition, verifying the effectiveness of losartan in controlling these manifestations in the animal model opens the perspective of clinical use of this drug. Losartan is a low-cost drug and, if its efficacy is demonstrated, may represent an accessible therapy directed at the unmet needs of these patients.

Mucopolysaccharidosis IV A, Mucopolysaccharidosis VI, Mucopolysaccharidoses, MPS IV A, MPS VI, MPS - Mucopolysaccharidosis, Morquio A Syndrome, Morquio Syndrome A, Morquio Syndrome

Experimental group: 15 patients, both sexes, will receive Losartan 25 mg orally for 12 months. Control group: 15 patients, both sexes, will receive oral placebo for 12 months. Eligible research participants for treatment will be randomly assigned to a treatment group or a control group in a ratio of 1: 1. The groups will be stratified by age and type of MPS in the following strata: A) Diagnosis of MPS IVA: 20 patients expected B) Diagnosis of MPS VI: 10 patients expected

Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months.

Losartan group: 15 patients, both sexes, will receive Losartan 0.4 to 1.4 mg/kg/day orally for 12 months.

Reduction over time in the Z score of maximal aortic root diameter measured by Valsalva sinus echocardiogram between the baseline assessment and 12 months after treatment with losartan.

Changes of serum levels of N-terminal pro b-type natriuretic (NT-ProBNP) peptide between baseline and 12 months

Changes of ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months.

Reduction over time in the ventricular-vascular coupling measures as assessed by echocardiography between the baseline and 12 months.

Alteration of the parameter of mitral valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months.

Alteration of the parameter of aortic valve regurgitation as assessed by a semi-quantitative echocardiographic method between the baseline and 12 months.

Alteration of the ejection fraction measurement as assessed by echocardiography between the baseline and 12 months.

Alteration of the measurement of left ventricular longitudinal strain as assessed by echocardiography between the baseline and 12 months.

Alteration of the parameter E/A ratio as assessed by echocardiography between the baseline and 12 months .

Alteration of the parameter E/e' ratio as assessed by echocardiography between the baseline and 12 months.

Inclusion Criteria: Confirmed biochemical or molecular diagnosis of MPS VI or MPS IVA. Age between 10 and 40 years. Presence of aortic root diameter greater than 1.0 standard deviation, as determined by local measurement. Be in a stable treatment regime in the last 3 months (without performing Enzyme replacement therapy (ERT), or performing ERT on a regular basis). Patient who agree to participate in the study protocol by signing a free informed consent form. Exclusion Criteria: Patient who underwent previous aortic surgery. Patient with aortic root diameter greater than 5 cm. Patient on angiotensin-converting-enzyme (ACE) inhibitor. In case of use of beta-blocker, or calcium channel blocker, patient without adequate control of blood pressure in the last 3 months. Patients with previous adverse events related to treatment with losartan or contraindication to this treatment. Inability, in the opinion of the investigator, to complete the study procedures.