Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: A randomized controlled trial

Renata De Maria, Jonica Campolo, Marina Frontali, Franco Taroni, Antonio Federico, Domenico Inzitari, Alessandra Tavani, Silvia Romano, Emanuele Puca, Francesco Orzi, Ada Francia, Caterina Mariotti, Chiara Tomasello, Maria Teresa Dotti, Maria Laura Stromillo, Leonardo Pantoni, Francesca Pescini, Raffaella Valenti, Claudio Pelucchi, Marina ParoliniOberdan Parodi, Valentina Sedda, Elisabetta Spagnolo, Nicola De Stefano

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare autosomal dominant disorder caused by NOTCH3 mutations, is characterized by vascular smooth muscle and endothelial cells abnormalities, altered vasoreactivity, and recurrent lacunar infarcts. Vasomotor function may represent a key factor for disease progression. Tetrahydrobiopterin, essential cofactor for nitric oxide synthesis in endothelial cells, ameliorates endothelial function. We assessed whether supplementation with sapropterin, a synthetic tetrahydrobiopterin analog, improves endothelium-dependent vasodilation in CADASIL patients. METHODS: In a 24-month, multicenter randomized, double-blind, placebo-controlled trial, CADASIL patients aged 30 to 65 years were randomly assigned to receive placebo or sapropterin 200 to 400 mg BID. The primary end point was change in the reactive hyperemia index by peripheral arterial tonometry at 24 months. We also assessed the safety and tolerability of sapropterin. Analysis was done by intention-to-treat. RESULTS: The intention-to-treat population included 61 patients. We found no significant difference between sapropterin (n=32) and placebo (n=29) in the primary end point (mean difference in reactive hyperemia index by peripheral arterial tonometry changes 0.19 [95% confidence interval, -0.18, 0.56]). Reactive hyperemia index by peripheral arterial tonometry increased after 24 months in 37% of patients on sapropterin and in 28% on placebo; however, after adjustment for age, sex, and clinical characteristics, improvement was not associated with treatment arm. The proportion of patients with adverse events was similar on sapropterin and on placebo (50% versus 48.3%); serious adverse events occurred in 6.3% versus 13.8%, respectively. CONCLUSIONS: Sapropterin was safe and well-tolerated at the average dose of 5 mg/kg/day, but did not affect endothelium-dependent vasodilation in CADASIL patients. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrialsregister.eu. Unique identifier: 2007-004370-55.

Original languageEnglish
JournalStroke
DOIs
Publication statusAccepted/In press - Sep 2 2014

ASJC Scopus subject areas

  • Advanced and Specialised Nursing
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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    De Maria, R., Campolo, J., Frontali, M., Taroni, F., Federico, A., Inzitari, D., Tavani, A., Romano, S., Puca, E., Orzi, F., Francia, A., Mariotti, C., Tomasello, C., Dotti, M. T., Stromillo, M. L., Pantoni, L., Pescini, F., Valenti, R., Pelucchi, C., ... De Stefano, N. (Accepted/In press). Effects of sapropterin on endothelium-dependent vasodilation in patients with CADASIL: A randomized controlled trial. Stroke. https://doi.org/10.1161/STROKEAHA.114.005937