Impaired Endothelial Function of Forearm Resistance Arteries in CADASIL Patients

Abstract

Background and Purpose-Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary arteriopathy, which mainly involves the brain causing stroke and dementia. Mice expressing the mutated protein display early dysfunction in vasoreactivity in resistance arteries, but studies of patients have been inconclusive so far. Methods-We examined peripheral endothelium-dependent vasodilatation in 10 CADASIL-patients and 20 controls using 3 methods: venous occlusion plethysmography of forearm blood flow with intraarterial acetylcholine and sodium nitroprusside infusions for evaluation of resistance arteries, ultrasound with flow mediated vasodilatation (FMD) of the brachial artery for evaluation of a conduit artery, and the pulse wave method with measurements before and after terbutaline for evaluation of systemic endothelium-dependent vasodilation. Results-The CADASIL patients displayed reductions in both basal (Pϭ0.034) and stimulated blood flow (Pϭ0.023 for the highest dose of acetylcholine) and an impaired endothelium-dependent vasodilation when investigated in forearm resistance arteries (Pϭ0.019). The FMD and the pulse wave method did not show any reduction in endotheliumdependent vasodilation in the patients. Conclusions-Endothelium-dependent vasodilation was impaired in resistance arteries, but not in a conduit artery, in the forearm of CADASIL patients.

CADASIL: pathogenesis, clinical and radiological findings and treatment

“…For instance, the kinetics of reactive hyperemia after cuff occlusion displays a delayed and slow curve 17 . Endothelium-dependent vasodilation is impaired in resistance arteries (not conductive ones) in the forearm of patients 18 . Transgenic mice expressing mutant Notch 3 develop CADASIL typical vascular alterations 19 .…”

Cadasil

“…Therefore, stenosis of vessels supplying the white matter and hemodynamic factors may be the basis of white matter lesions and lacunar infarcts, respectively. 17 Finally, the following physiological parameters may be abnormal: endothelial-dependent vasodilatation in resistance arteries and vasoconstrictor responses 18,19 ; heart rate variability 20 ; systemic blood pressure profile (lower than expected) 21 ; and cerebrovascular CO 2 reactivity. 22 A recently published guidance statement recommends genetic testing for CADASIL as being reasonable in patients with progressive cognitive impairment, appropriate imaging findings, and a family history suggestive of autosomaldominant inheritance (class IIa and level of evidence A), and it may be considered in sporadic patients with suggestive clinical and imaging findings (class IIb and level of evidence B).…”

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

“…The rationale for targeting endothelium-dependent vasodilation in CADASIL rests on the molecular mechanisms of the disease, NOTCH3 accumulation in vascular smooth muscle cells cytoplasmic membrane and within the basement membrane of capillaries between the pericytes and endothelial cells, on previously reported morphological abnormalities in endothelial cells and laboratory alterations of endothelial function in CADASIL patients, 1,[23][24][25]39 and on the association between biomarkers of endothelial function and the clinical phenotype. 40 RH-PAT expresses microvascular function, and its correlation with cerebral blood flow 35 in patients with CADASIL suggests that characterization of peripheral vascular function may represent a convenient, although indirect, marker of brain vascular function, potentially useful to limit the number of patients needed in therapeutic studies addressing the onset and progression of clinical manifestation of CADASIL.…”

“…Previous studies in CADASIL patients described impaired vasoreactivity both in the cerebral 21,22 and peripheral circulation. [23][24][25][26] However ED was shown in resistance arteries, but not in conduit vessels. 24 Flow perturbance by mutated NOTCH3 proteins in capillary pericytes may largely mediate impaired vasoreactivity and pathophysiology of brain damage in CADASIL.…”

“…[23][24][25][26] However ED was shown in resistance arteries, but not in conduit vessels. 24 Flow perturbance by mutated NOTCH3 proteins in capillary pericytes may largely mediate impaired vasoreactivity and pathophysiology of brain damage in CADASIL. Therefore, a method that tests microvascular, rather than conduit artery, reactivity is appropriate to investigate treatment effects in this population.…”