Genes, endothelial function and cerebral small vessel disease in man

Cerebral small vessel disease results from ischaemia in the perforating arteries supplying the white matter and deep grey matter nuclei. It results in both focal lacunar infarction and more diffuse areas of chronic ischaemia (leukoaraiosis). Two subtypes may exist. One subtype (isolated lacunar infarction) is associated with single or a few larger lacunar infarcts without leukoaraiosis, and may result from microatheroma in the larger perforating arteries. The second subtype (ischaemic leukoaraiosis) results in multiple small lacunar infarcts with leukoaraiosis secondary to a diffuse arteriopathy affecting the smaller perforating arteries, usually occurring in the presence of hypertension. In this subtype, chronic hypoperfusion and impaired cerebral autoregulation have been reported. A number of lines of evidence support a pathogenic role of endothelial activation and dysfunction. Genetic predisposition has also been implicated. Associations with genes involved in endothelial function, including those regulating the renin–angiotensin system, endothelial nitric oxide and homocysteine levels, have been reported. However, not all results have been replicated and there are few robust replicable associations. Larger studies are required to determine definitively which associations represent important risk factors.