Effects of Sapropterin on Endothelium-Dependent Vasodilation in Patients With CADASIL

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

Low-frequency and common genetic variation in ischemic stroke

“…34 Supplementation with a synthetic BH4 analog has previously been tested in a trial in monogenic SVD. 35 Aside from GUCY1A3 and GCH1, we found other low-frequency variants with p values , 1E-4 for association and consistent effect directions across all samples. These include NACC2 as well as an intergenic locus near KCNN2 (both LVD), TMEM108 (SVD), and CBFA2T3 (CE).…”

Nitric oxide signaling in health and disease

“…Clinical trials in CVD have shown diverging results, and there is currently not enough evidence to support L-arginine substitution (Bednarz et al, 2005;Hadi et al, 2019). Other dietary means to support NOS output in CVD have been proposed, where administration of the BH4 precursors folate or sepiapterin has been tested in small clinical trials, but data are inconclusive and larger trials are needed to clarify any beneficial role of BH4 analogs (De Maria et al, 2014;Gori et al, 2001).…”

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

“…Likewise, supplementation with the BH 4 analogue folic acid improves endothelial function in human subjects [235,236] or treatment with the BH 4 precursor sepiapterin restored endothelial function in experimental hypertension as well as atherosclerosis [118,230]. Despite promising preclinical data on a protective role of BH 4 in ischemic stroke models, a small cohort human study (multicenter randomized, double-blind, placebo-controlled trial) found no significant effects on the prognosis of 61 stroke patients by sapropterin (BH 4 drug) therapy (200–400 mg twice per day for two months) [237], which may be related to the activation of iNOS (a potential pharmacological target in stroke) by increased BH 4 levels. In a double-blind multicenter clinical trial 40 patients with cirrhosis and portal hypertension either received sapropterin (5 mg/kg/d for two weeks) or placebo, but hepatic blood flow, systemic hemodynamics, endothelial dysfunction markers, and liver function tests remained unchanged [238].…”