Impaired vasoreactivity in mildly disabled CADASIL patients

Area of Science:

• Neurology
• Vascular Biology
• Genetics

Background:

• Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare genetic disorder caused by NOTCH3 mutations.
• Vascular dysfunction is a proposed early pathogenic event in CADASIL.
• Assessing vasoreactivity can reveal early disease mechanisms.

Purpose of the Study:

• To investigate endothelial-dependent and independent vasoreactivity in CADASIL patients.
• To compare vasoreactivity between CADASIL patients and healthy controls.
• To identify potential early vascular alterations in CADASIL.

Main Methods:

• A non-invasive plethysmographic method was used to assess vasoreactivity.
• 49 mildly disabled CADASIL patients and 25 controls participated.
• Endothelium-dependent vasodilation was measured by reactive hyperemia (FMD-PAT), and endothelium-independent vasoreactivity by glyceryl trinitrate (GTN-PAT).

Main Results:

• CADASIL patients exhibited significantly lower glyceryl trinitrate-peripheral arterial tone (GTN-PAT) values compared to controls, indicating impaired endothelium-independent vasoreactivity.
• Flow-mediated dilation-peripheral arterial tone (FMD-PAT) scores did not significantly differ, but 35% of CADASIL patients had scores below the control fifth percentile.
• Lower GTN-PAT was independently associated with reduced FMD-PAT in CADASIL patients.

Conclusions:

• Impaired vasoreactivity, including both endothelial and smooth muscle dysfunction, is present in mildly disabled CADASIL patients.
• These findings highlight early vascular alterations in the pathogenesis of CADASIL.
• Improving vascular function may represent a novel therapeutic target for CADASIL.