Impaired L-arginine induced vasoreactivity suggests endothelial dysfunction in CADASIL

Background: Mutations in the Notch3 gene are the cause of CADASIL, a hereditary microangiopathy leading to stroke and vascular dementia. The disease is characterized by ultrastructural granular deposits within small arterial vessels and degeneration of vascular smooth muscle cells. Little is known about endothelial function in CADASIL. Vasoreactivitiy induced by L-Arginine, which is the substrate for endothelial NO synthase (eNOS), is an established parameter of endothelial function and has been shown to be strongly elevated in patients with stroke.

Methods: To analyse possible endothelial dysfunction in CADASIL, L-Arginine induced vascoreactivity was studied in 25 patients (9 male/16 female; aged 48.9+9.7 [mean + SD]) and 24 matched healthy control subjects (11/13; 45.3 + 8.7) by transcranial dopplersonography (TCD) of the middle cerebral artery (MCA). Thirty grams of L-Arginine were applied intravenously over 30 minutes. Mean flow velocity (MFV) of the MCA was assessed continuously. L-Arginine induced vasoreactivity was calculated as the percent change of MCA-MFV. To analyse whether HMG-CoA-reductase inhibitors, which have been shown to influence eNOS function, may improve L-Arginine induced vasoreactivity, patients were treated over a period of 8 weeks with atorvastatin (40mg for 4 weeks, followed by 80mg for the remaining 4 weeks). TCD measurements were performed at baseline and follow-up of the treatment period.

Results: MFV before L-Arginine application was significantly reduced in patients (43.7 + 14.5cm/s) compared to controls (57.0 + 10.4cm/s) [p<0.001]. L-Arginine induced vasoreactivity was significantly increased in patients (36.1 + 15.5% at baseline) versus controls (27.9 + 8.5%) [p<0.05]. This effect was slightly augmented when comparing patients at treatment follow-up (38.0 + 14.6%) to controls [p<0.01]. However, no significant effect of statin-treatment on L-Arginine induced vasoreactivity was seen when comparing results within the patient group at baseline versus follow up.

Conclusions: In CADASIL, MCA-MFV is strongly reduced. Impaired L-Arginine vasoreactivity, which is not significantly influenced by statin-treatment, implies endothelial dysfunction in the disease.