Abstract
Increasing evidence suggests a role for endothelial cell (EC) dysfunction in pathogenesis of cerebral small vessel disease. Commonly used medications including certain antihypertensives and statins have EC-stabilizing effects. We used individual patient data from completed acute stroke trials to assess whether prior exposure to EC-stabilizing medications was associated with lacunar stroke, using lacunar stroke as a clinical proxy for cerebral small vessel disease. Across 12,002 patients with relevant data, 2,855 (24%) had a lacunar stroke presentation. Univariable analyses suggested potential confounding from vascular diseases treated with EC-stabilizing medications. Initial multivariable logistic regression gave conflicting results when describing the independent association of exposure to EC-stabilizing medication and lacunar stroke in the complete population (O.R. 0.87, 95% C.I.: 0.77– 0.98) and limited to those taking any antihypertensive (O.R. 1.51, 95% C.I.: 1.21–1.88). Re-running the analyses including statins in the EC-stabilizing category suggested a beneficial effect of EC-stabilizing medication exposure on lacunar stroke incidence (O.R. 0.83, 95% C.I.: 0.73–0.93). These results align with recent pre-clinical data and would support interventional trials of EC-stabilizing medication for preventing cerebral small vessel disease. Our results also suggest that analyses of EC-stabilizing interventions need to adjust for potential endothelial effects of other co-prescribed medication.
Highlights
Cerebrovascular small vessel disease (SVD) is common, increases with age [1] and accounts for almost half of all dementias [2], one fifth of all strokes [3], especially lacunar strokes, and more than four fifths of all intracerebral hemorrhages [4]
The small number of pure sensory strokes likely relates to RCT inclusion criteria, where a minimum level of National Institute of Health Stroke Scale (NIHSS) would be needed to be eligible for inclusion
Due to our previous findings of endothelial cell (EC)-stabilizing medication reversing SVD pathology in a rat model [9], we took a novel approach of using pre-existing stroke trial data to test for an association between exposure to EC-stabilizing drugs and lacunar stroke in humans, allowing us to search a large amount of data
Summary
Cerebrovascular small vessel disease (SVD) is common, increases with age [1] and accounts for almost half of all dementias [2], one fifth of all strokes [3], especially lacunar strokes, and more than four fifths of all intracerebral hemorrhages [4]. Mechanistic links have been shown between dysfunction of endothelial cells (EC) in cerebral small blood vessels and white matter damage in a rat model of SVD and in human SVD tissue [9]. Endothelium Stabilizers and Lacunar Stroke proliferation, reduced tight junctions between cells and increased production of HSP90a [10]. The pathological changes of EC dysfunction and white matter damage in a rat model of SVD were reversed by use of drugs known to stabilize endothelial function, by increasing nitric oxide production [9]. EC-stabilizing drugs included perindopril (an Angiotensin Converting Enzyme Inhibitor) and simvastatin (a HMG Co-A reductase inhibitor), both are drugs that are in common use in clinical practice
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