Antiplatelet Therapy and Endothelial-stabilizing Agents in Cerebral Small Vessel Diseases

Cerebral small vessel disease (cSVD) is a common accompaniment of aging. It refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. On neuroimaging, notably on magnetic resonance imaging (MRI), SVD has several visible signs, including recent small subcortical infarcts (i.e symptomatic cSVD in our study), lacunes of presumed vascular origin; white matter hyperintensities (WMH), perivascular spaces, cerebral microbleeds, cerebral microinfarcts and brain atrophy. SVD causes about a quarter of ischaemic strokes, is the main cause of vascular dementia, often occurs with Alzheimer's disease, contributing to about 50% of dementias worldwide. Although previous studies recommend BP control and antiplatelet therapy in symptomatic cSVD, secondary prevention strategies are mostly inferred from studies of ischemic stroke in general, the majority of which did not specifically investigate patients with symptomatic cSVD. In addition, long term dual antiplatelet therapy using clopidogrel and aspirin was shown to increase the risk of hemorrhage stroke in symptomatic cSVD, without any decrease in recurrent ischemic stroke.

Endothelial dysfunction plays an important part in cSVD. In addition to mild antiplatelet effects through the increase of cyclic adenosine monophosphate (cAMP), the phosphodiesterase (PDE) 3' inhibitor cilostazol is shown to be endothelial protective by several pathways, such as activation of endothelial nitric oxide (NO) synthase (NOS), regulation of endothelin-1. Isosorbide mononitrate (ISMN) is a NO donor, by augmenting the NO-cyclic guanosinemonophosphate phosphodiesterase-inhibitor pathway. Recent trial showed that the combined use of ISMN plus cilostazol was well tolerated and safe, and may reduce recurrent stroke and cognitive impairment after lacunar stroke.

Brain and retina possess numerous anatomical and functional similarities. Retinal capillary microvessels revealed by optical coherence tomography angiography (OCTA) have been found to be related to brain microvessels, reflecting the burden of cSVD. Retinal perfusion is also linked with cognitive function.

This cohort study will prospectively evaluate the effect of different antiplatelet agents on cSVD and retina in patients with cSVD (recent small subcortical infarcts or WMH, respectively).