Intracranial carotid arteriosclerosis mediates the association between blood pressure and cerebral small vessel disease: the Rotterdam Study

Abstract

Abstract Background Cerebral arteriosclerosis could explain the physiopathological mechanisms linking high blood pressure (BP) and cerebral small vessel disease (CSVD). Objectives To test the hypothesis that ICAC mediates the association between BP and CSVD. Methods 1458 stroke-free participants from the Rotterdam Study underwent nonenhanced computed tomography to quantify ICAC and brain magnetic resonance imaging scans to assess CSVD. ICAC subtypes included atherosclerotic (intimal) and non-atherosclerotic internal elastic lamina (IEL) calcifications. We analyzed systolic BP (SBP), diastolic BP (DBP), pulse pressure (PP), and mean arterial pressure (MAP). Mediation analysis included a two way decomposition to compute the natural direct effect (NDE), natural indirect effect (NIE) and percentage of mediation (%) of ICAC on the association between BP and CSVD. Results The study population had a mean age of 68.0 years old, and 52% (n=758) of the participants were women. In analyses including participants with predominantly IEL calcification, we observed that larger log-ICAC volume was positively related to a higher pulse pressure (β=0.020; P<0.001), and lower diastolic BP (β=0.024; P=0.001). None of the BP components were associated with log-ICAC volume among participants with predominantly intimal calcifications (β≤0.008; P≥0.060). Among all participants, log-ICAC volume mediated the association of DBP (NIE, 0.003; −14.5%) and PP (NIE,0.003; 16.5%) with log-white matter hyperintensities (log WMH). In participants with IEL calcification, log-ICAC volume mediated the association of DBP with log-WMH (NIE, 0.004, −19.5%); no mediations were observed for intimal ICAC. For Lacunes, in all participants, log-ICAC volume mediated the association of DBP (NIE, −0.015, −40%) and PP (NIE,0.015; 26.9%). In participants with IEL calcification; the NIE was 0.020 (45.8%) for DBP and 0.017 (18.2%) for PP. No interactions were detected. Conclusions ICAC mediated the association between BP and CSVD. Non-atherosclerotic IEL calcification, considered a proxy of arterial stiffness, was the main physiopathological mechanism explaining how BP links to CSVD due to cerebral arteriosclerosis. Funding Acknowledgement Type of funding sources: None.