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Synergistic effects of high blood cholesterol and hypertension on leukocyte and platelet recruitment in the cerebral microcirculation.

ABSTRACT: Hypertension or hypercholesterolemia can induce a proinflammatory and prothrombogenic phenotype in the microcirculation of the brain; however, less is known about how the combination of these risk factors affects the vasculature. We recently reported that a moderate (60%) increase in plasma cholesterol blunts the recruitment of leukocytes and platelets in the cerebral microvessels elicited by hypertension. In this study, we examined whether larger increments in blood cholesterol (4-fold) exerts a similar modulating influence on the vasculature in the presence of hypertension. Apolipoprotein E-knockout mice with deoxycorticosterone acetate salt-induced hypertension were placed on a high-cholesterol diet and exhibited exaggerated leukocyte and platelet adhesion responses in cerebral microvessels. Intermittent feeding (every fourth day) with high-cholesterol diet yielded similar phenotypic changes in the vasculature. Once the mice were placed on high-cholesterol diet, 4 days on normal diet (ND) were needed to revert to a normal vascular phenotype. Angiotensin II type 1 receptors and reactive oxygen species seem to contribute to the vascular responses induced by hypercholesterolemia and hypertension. Our findings indicate that the combination of hypertension and large increases in plasma cholesterol concentration results in a severe, but reversible, inflammatory and thrombogenic phenotype in the cerebral microvasculature.

SUBMITTER: Rodrigues SF

PROVIDER: S-EPMC3966559 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Synergistic effects of high blood cholesterol and hypertension on leukocyte and platelet recruitment in the cerebral microcirculation.

Rodrigues Stephen F SF Almeida-Paula Lidiana D LD Granger Daniel N DN

Hypertension (Dallas, Tex. : 1979) 20131230 4

Hypertension or hypercholesterolemia can induce a proinflammatory and prothrombogenic phenotype in the microcirculation of the brain; however, less is known about how the combination of these risk factors affects the vasculature. We recently reported that a moderate (60%) increase in plasma cholesterol blunts the recruitment of leukocytes and platelets in the cerebral microvessels elicited by hypertension. In this study, we examined whether larger increments in blood cholesterol (4-fold) exerts ...[more]

PMID: 24379186

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Project description:Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (? = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (? = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial.

Project description:BackgroundCerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining.ResultsA mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value <?0.001).ConclusionsAfter severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted.

Dataset Information

Synergistic effects of high blood cholesterol and hypertension on leukocyte and platelet recruitment in the cerebral microcirculation.

Publications

Synergistic effects of high blood cholesterol and hypertension on leukocyte and platelet recruitment in the cerebral microcirculation.

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