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Progression of Cardiovascular Manifestations in Adults and Children With Mucopolysaccharidoses With and Without Enzyme Replacement Therapy.

ABSTRACT: Background: Cardiovascular involvement is among the main features of MPS disorders and it is also a significant cause of morbidity and mortality. The range of manifestations includes cardiac valve disease, conduction abnormalities, left ventricular hypertrophy, and coronary artery disease. Here, we assessed the cardiovascular manifestations in a cohort of children and adults with MPS I, II, IV, and VI, as well as the impact of enzyme replacement therapy (ERT) on those manifestations. Methods: We performed a chart review of 53 children and 23 adults with different types of MPS that had performed echocardiograms from January 2000 until October 2018. Standardized Z scores were obtained for heart chamber sizes according to the body surface area. When available, echocardiographic measurements that were performed before ERT and at least 18 months after that date were used for the assessment of pre- and post-treatment parameters. Results: Left side valvular disease was a frequent finding, with mitral and aortic thickening being reported in most patients in all four MPS types. Left atrium dilatation was present in 26% of the patients; 25% had increased relative wall thickness; 28% had pulmonary hypertension. The cardiovascular involvement was, in general, more prevalent and more severe in adults than in children, including conduction disorders (40 vs. 16%), mitral stenosis (26 vs. 6%), aortic stenosis (13 vs. 4%), and systolic dysfunction (observed in only one adult patient). ERT promoted a significant reduction of the left ventricular hypertrophy parameters, but failed to improve valve abnormalities, pulmonary hypertension, and left atrial dilatation. Conclusions: Adult patients with MPS may develop severe cardiovascular involvement, not commonly observed in children, and clinicians should be aware of the need for careful monitoring and timely management of those potentially life-threatening complications. Our results also confirm the impact of long-term ERT on left ventricular hypertrophy and its limitations in reversing other prevalent cardiovascular manifestations.

SUBMITTER: Poswar FO

PROVIDER: S-EPMC8790121 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Following a drug manufacturing process change, safety/efficacy of agalsidase alfa were evaluated in enzyme replacement therapy (ERT)-naïve children with Fabry disease.In an open-label, multicenter, Phase II study (HGT-REP-084; Shire), 14 children aged ?7 years received 0.2 mg/kg agalsidase alfa every other week for 55 weeks. Primary endpoints: safety, changes in autonomic function (2-hour Holter monitoring). Secondary endpoints: estimated glomerular filtration rate, left ventricular mass index (LVMI), midwall fractional shortening, pharmacodynamic parameters, and patient-reported quality-of-life.Among five boys (median 10.2 [range 6.7, 14.4] years) and nine girls (14.8 [10.1, 15.9] years), eight patients experienced infusion-related adverse events (vomiting, n=4; nausea, n=3; dyspnea, n=3; chest discomfort, n=2; chills, n=2; dizziness, n=2; headache, n=2). One of these had several hypersensitivity episodes. However, no patient discontinued for safety reasons and no serious adverse events occurred. One boy developed immunoglobulin G (IgG) and neutralizing antidrug antibodies. Overall, no deterioration in cardiac function was observed in seven patients with low/abnormal SDNN (standard deviation of all filtered RR intervals; <100 ms) and no left ventricular hypertrophy: mean (SD) baseline SDNN, 81.6 (20.9) ms; mean (95% confidence interval [CI]) change from baseline to week 55, 17.4 (2.9, 31.9) ms. Changes in SDNN correlated with changes in LVMI (r=-0.975). No change occurred in secondary efficacy endpoints: mean (95% CI) change from baseline at week 55 in LVMI, 0.16 (-3.3, 3.7) g/m(2.7); midwall fractional shortening, -0.62% (-2.7%, 1.5%); estimated glomerular filtration rate, 0.15 (-11.4, 11.7) mL/min/1.73 m(2); urine protein, -1.8 (-6.0, 2.4) mg/dL; urine microalbumin, 0.6 (-0.5, 1.7) mg/dL; plasma globotriaosylceramide (Gb3), -5.71 (-10.8, -0.6) nmol/mL; urinary Gb3, -1,403.3 (-3,714.0, 907.4) nmol/g creatinine, or clinical quality-of-life outcomes.Fifty-five weeks' agalsidase alfa ERT at 0.2 mg/kg every other week was well tolerated. Disease progression may be slowed when ERT is started prior to major organ dysfunction.https://ClinicalTrials.gov identifier NCT01363492.

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Progression of Cardiovascular Manifestations in Adults and Children With Mucopolysaccharidoses With and Without Enzyme Replacement Therapy.

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