Cholesterol Solutions Today:The Good & The Bad

Background and Purpose— Certain characteristics of early blood pressure (BP) profiles were reported to be independent predictors of long-term outcome in the first European Cooperative Acute Stroke Study (ECASS-I) trial. The aim of the study was to find out the association of BP profiles with functional outcome, mortality, and hemorrhagic complications in the ECASS-II database.

Methods— We studied 793 patients with acute ischemic hemispheric stroke in the ECASS-II. After randomization, BP was measured every 15 minutes during the first 2 hours, then every 30 minutes during the first 8 hours, and thereafter at 1-hour intervals up to 24 hours. Individual 0- to 24-hour BP profiles were characterized by baseline, maximum, minimum, and mean BP and successive variation of the profile. The end points were favorable outcome (modified Rankin Scale score of 0 or 1) at day 90, all-cause mortality at day 90, and hemorrhagic transformation within the first 7 days.

Results— High baseline, maximum, mean level, and variability of systolic BP profiles were each inversely associated with favorable outcome (OR=0.84, 95% CI: 0.74 to 0.94; OR=0.82, 95% CI: 0.73 to 0.91; OR=0.81, 95% CI: 0.71 to 0.93; OR=0.57, 95% CI: 0.35 to 0.92, respectively) and associated with an increased risk of parenchymal hemorrhage within the first 7 days (OR=1.27, 95% CI: 1.07 to 1.51; OR=1.49, 95% CI: 1.27 to 1.75; OR=1.52, 95% CI: 1.23 to 1.87; OR=2.62, 95% CI: 1.40 to 4.87; respectively) in recombinant tissue plasminogen activator-treated patients. In placebo-treated patients, high maximum, mean level, and successive variation of systolic BP profiles were inversely associated with favorable outcome (OR=0.76, 95% CI: 0.66 to 0.86; OR=0.76, 95% CI: 0.65 to 0.89; OR=0.41, 95% CI: 0.22 to 0.76; respectively), although the association of baseline systolic BP and favorable outcome was not significant (OR=0.91, 95% CI: 0.80 to 1.03). No association with hemorrhagic transformation was found, even after the adjustment.

Conclusions— The hemorrhagic transformation within the first 7 days and favorable outcome were independently associated with dynamics of BP within the first 24 hours after an acute ischemic stroke in patients treated with thrombolysis, but in placebo-treated patients, only with favorable outcome. Continuous BP monitoring is hence important for the prognosis and gives implications to optimize BP management, particularly regarding a reasonable BP level and stability.

Background and Purpose— Although current guidelines state that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) in patients with carotid stenosis, significant controversies to this recommendation still persist. Carotid artery stenting has been recently introduced as an alternative revascularization modality in high-risk patients. The aim of this study was to define, based on the published information, if carotid artery stenting is beneficial in this setting.

Methods— A search of MEDLINE and a manual search of the literature from selected articles were performed. A total of 6 studies with 277 patients reporting carotid stenting followed by staged CABG were available for this clinical outcome analysis. All were retrospective and single-center studies.

Results— The mean age was 69 years; 78% were males. Asymptomatic carotid stenosis was present in 76% of patients. The mean time to CABG was 32 days. The incidence of stroke and death associated with the stent procedure was 4.7%. Only 6 patients (2.2%) developed stroke associated with CABG. The overall combined 30-day event rate after CABG, including all events during carotid artery stenting, were as follows: minor stroke, 2.9%; major stroke, 3.2%; mortality, 7.6%; and combined death and any stroke, 12.3%.

Conclusions— In this pooled analysis, the combined incidence of death and stroke in patients undergoing carotid artery stenting and staged CABG remains elevated. These results confirm that the presence of carotid stenosis is per se a marker of risk that might persists independent of its treatment. A systematic or randomized evaluation appears warranted.

Background and Purpose— Few data exist on the relationship between differential subpopulations of peripheral leukocytes and early cerebral infarct size in ischemic stroke. Using diffusion-weighted MR imaging (DWI), we assessed the relationship of early total and differential peripheral leukocyte counts and volume of ischemic tissue in acute stroke.

Methods— All included patents had laboratory investigations and neuroimaging collected within 24 hours of stroke onset. Total peripheral leukocyte counts and differential counts were analyzed individually and by quartiles. DWI lesions were outlined using a semiautomated threshold technique. The relationship between leukocyte quartiles and DWI infarct volumes was examined using multivariate quartile regression.

Results— 173 patients met study inclusion criteria. Median age was 73 years. Total leukocyte counts and DWI volumes showed a strong correlation (Spearman rho=0.371, P<000.1). Median DWI volumes (mL) for successive neutrophil quartiles were: 1.3, 1.3, 3.2, and 20.4 (P for trend <0.001). Median DWI volumes (mL) for successive lymphocyte quartiles were: 3.2, 8.1, 1.3, and 1.5 (P=0.004). After multivariate analysis, larger DWI volume remained strongly associated with higher total leukocyte and neutrophil counts (both probability values <0.001), but not with lymphocyte count (P=0.4971). Compared with the lowest quartiles, DWI volumes were 8.7 mL and 12.9 mL larger in the highest quartiles of leukocyte and neutrophil counts, respectively.

Conclusions— Higher peripheral leukocyte and neutrophil counts, but not lymphocyte counts, are associated with larger infarct volumes in acute ischemic stroke. Attenuating neutrophilic response early after ischemic stroke may be a viable therapeutic strategy and warrants further study.

Background and Purpose— The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain.

Methods— rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups.

Results— Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices.

Conclusions— rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.

Background and Purpose— Our understanding of factors influencing stroke risk among patients with coronary artery disease is incomplete. Accordingly, factors predicting stroke risk in hypertensive, clinically stable coronary artery disease patients were determined with data from the INternational VErapamil SR-trandolapril STudy (INVEST).

Methods— The effect of baseline characteristics and on-treatment blood pressure (BP) were analyzed to determine the risk of stroke (fatal or nonfatal) among the 22 576 patients enrolled. Cox proportional-hazards models (unadjusted, adjusted, and time dependent) were used to identify predictors of stroke among subgroups with these characteristics present at entry and on-treatment BP.

Results— Excellent BP control (at 24 months, >70% <140/90 mm Hg) was achieved during 61 835 patient-years of follow-up, as 377 patients had a stroke (6.1 strokes/1000 patient-years) and 28% of those patients had a fatal stroke. Increased age, black race, US residency, and history of prior myocardial infarction, smoking, stroke/transient ischemic attack, arrhythmia, diabetes, and coronary bypass surgery were associated with an increased risk of stroke. Achieving a systolic BP <140 mm Hg and a diastolic BP <90 mm Hg was associated with a decreased risk of stroke. There was no statistically significant difference in stroke risk comparing the verapamil SR–based with the atenolol-based treatment strategy (adjusted hazard ratio=0.87; 95% CI, 0.71 to 1.06; P=0.17).

Conclusions— Among hypertensive patients with chronic coronary artery disease, stroke was an important complication associated with significant mortality. Black race, US residency, and conditions associated with increased vascular disease severity and arrhythmia predicted increased stroke risk, whereas achieving a BP <140/90 mm Hg on treatment predicted a reduced stroke risk.

Background and Purpose— Cerebrovascular responses to hypoxia and hypocapnia in Peruvian altitude dwellers are impaired. This could contribute to the high incidence of altitude-related illness in Andeans. Ethiopian high altitude dwellers may show a different pattern of adaptation to high altitude. We aimed to examine cerebral reactivity to hypoxia and hypocapnia in healthy Ethiopian high altitude dwellers. Responses were compared with our previous data from Peruvians.

Methods— We studied 9 Ethiopian men at their permanent residence of 3622 m, and one day after descent to 794 m. We continuously recorded cerebral blood flow velocity (CBFV; transcranial Doppler). End-tidal oxygen (P_ETo₂) was decreased from 100 mm Hg to 50 mm Hg with end-tidal carbon dioxide (P_ETco₂) clamped at the subject’s resting level. P_ETco₂ was then manipulated by voluntary hyper- and hypoventilation, with P_ETo₂ clamped at 100 mm Hg (normoxia) and 50 mm Hg (hypoxia).

Results— During spontaneous breathing, P_ETco₂ increased after descent, from 38.2±1.0 mm Hg to 49.8±0.6 mm Hg (P<0.001). There was no significant response of CBFV to hypoxia at either high (–0.19±3.1%) or low (1.1±2.9%) altitudes. Cerebrovascular reactivity to normoxic hypocapnia at high and low altitudes was 3.92±0.5%.mm Hg^–1 and 3.09±0.4%.mm Hg^–1; reactivity to hypoxic hypocapnia was 4.83±0.7%.mm Hg^–1 and 2.82±0.5%.mm Hg^–1. Responses to hypoxic hypocapnia were significantly smaller at low altitude.

Conclusions— The cerebral circulation of Ethiopian high altitude dwellers is insensitive to hypoxia, unlike Peruvian high altitude dwellers. Cerebrovascular responses to P_ETco₂ were greater in Ethiopians than Peruvians, particularly at high altitude. This, coupled with their high P_ETco₂ levels, would lead to high cerebral blood flows, and may be advantageous for altitude living.

Background and Purpose— Atheroma vulnerability to rupture is increased in the presence of a large lipid core. Factors associated with a lipid core in the general population have not been studied.

Methods— The Multi-Ethnic Study of Atherosclerosis (MESA) is a multicenter cohort study of individuals free of clinical cardiovascular disease designed to include a high proportion of ethnic minorities. We selected MESA participants from the top 15th percentile of maximum carotid intima media thickness by ultrasound and acquired high-resolution black blood MRI images through their carotid plaque before and after the intravenous administration of gadodiamide (0.1 mmol/kg). Lumen and outer wall contours were defined using semiautomated analysis software. We analyzed only plaques with a maximum thickness ≥1.5 mm by MRI (n=214) and assessed cross-sectional risk factor associations with lipid core presence by multivariable logistic regression.

Results— A lipid core was present in 151 (71%) of the plaques. After controlling for age, ethnicity, sex, maximum arterial wall thickness, hypertension, cigarette smoking, diabetes, and C-reactive protein, compared with participants in the lowest tertile of total plasma cholesterol, the ORs of having a lipid core for participants in the middle and highest tertiles were 2.76 (95% CI: 1.01 to 7.51) and 4.63 (95% CI: 1.56 to 13.75), respectively. None of the other risk factors was associated with lipid core.

Conclusions— In persons with thickened carotid walls, plasma total cholesterol, but not other established coronary heart disease risk factors, is strongly associated with lipid core presence by MRI. High total cholesterol may be associated with rupture proneness of atherosclerotic lesions in the general population.

Background and Purpose— Even though adiponectin is associated with many traditional cardiovascular risk factors, studies assessing the association between adiponectin and cerebrovascular disease (CVD) are scarce. We assessed the odds of CVD at different plasma levels of adiponectin.

Methods— A nested case–control study was conducted involving 5243 subjects, drawn from 12 490 subjects of the Jichi Medical School Cohort Study, whose blood samples had been drawn between 1992 and 1995. Over an average of 9.7 years of follow-up, through 2005, 179 patients with cerebrovascular events were identified, in addition to 630 controls matched for age, sex, and community (total n=809). Odds ratios were estimated relative to the highest quartile of adiponectin level.

Results— There was neither a significant difference in the odds of stroke between the lowest and highest adiponectin quartiles, nor a significant linear trend toward a reduced risk of stroke at higher adiponectin levels. These results did not change after excluding participants with diabetes, impaired glucose metabolism, or metabolic syndrome. The odds of ischemic stroke in the lowest quartile were significantly higher than in the highest quartile, when adjusted for age and sex (OR 2.04 [95% CI, 1.09 to 3.80]). However, the odds failed to achieve statistical significance when adjusted further for other cardiovascular risk factors. Again exclusion of subjects with diabetes, impaired glucose metabolism, or metabolic syndrome did not alter results.

Conclusions— Adiponectin levels are not independently associated with stroke or brain infarction. The use of adiponectin as a cerebrovascular disease predictor may be premature.

Background and Purpose— The aim of this study was to describe the prevalence of a number of neurological signs in a large population of patients with vascular dementia (VaD) and to compare the relative frequency of specific neurological signs dependent on type of cerebrovascular disease.

Methods— Seven hundred six patients with VaD (NINDS-AIREN) were included from a large multicenter clinical trial (registration number NCT00099216). At baseline neurological examination, the presence of 16 neurological signs was assessed. Based on MRI, patients were classified as having large vessel VaD (18%; large territorial or strategical infarcts on MRI), small vessel VaD (74%; white matter hyperintensities [WMH], multiple lacunes, bilateral thalamic lesions on MRI), or a combination of both (8%).

Results— A median number of 4.5 signs per patient was presented (maximum 16). Reflex asymmetry was the most prevalent symptom (49%), hemianopia was most seldom presented (10%). Measures of small vessel disease were associated with an increased prevalence of dysarthria, dysphagia, parkinsonian gait disorder, rigidity, and hypokinesia and as well to hemimotor dysfunction. By contrast, in the presence of a cerebral infarct, aphasia, hemianopia, hemimotor dysfunction, hemisensory dysfunction, reflex asymmetry, and hemiplegic gait disorder were more often observed.

Conclusions— The specific neurological signs demonstrated by patients with VaD differ according to type of imaged cerebrovascular disease. Even in people who meet restrictive VaD criteria, small vessel disease is often seen with more subtle signs, including extrapyramidal signs, whereas large vessel disease is more often related to lateralized sensorimotor changes and aphasia.

Background and Purpose— PHACES syndrome is a neurocutaneous disorder of unknown etiology. We studied the spectrum of associated congenital and progressive cerebral vascular anomalies.

Methods— The medical records of 7 patients with PHACES syndrome were reviewed and combined with an additional 108 PHACES cases identified from the literature. We reviewed the clinical characteristics, calculated the relative frequencies of each type of vascular anomaly, and assessed site of vessel involvement relative to hemangioma location.

Results— Among a total of 115 PHACES cases, 89 (77.4%) had congenital and/or progressive cerebral vascular anomalies. The most commonly detected congenital arterial anomalies included dysplasia, aberrant origin or course, hypoplasia, and absence or agenesis. Arterial occlusions and stenoses were detected in 24 (20.9%) and 21 (18.3%) cases, respectively. Twenty (17.4%) had persistent embryonic arteries; 15 (13%) had saccular aneurysms. There appears to be a close relation between the regional distributions of cervicofacial hemangiomas and the locations of intracranial and extracranial vascular (and cardiac) anomalies.

Conclusion— The vasculopathy of PHACES chiefly comprises a spectrum of congenital and progressive large artery lesions. Based on known embryology and the relative frequencies of specific congenital vascular anomalies, we can predict that the initial cerebral vascular changes occur early in embryogenesis, by the fifth gestational week or earlier. There appears to be both a temporal and a regional link between the arterial anomalies of PHACES and the cutaneous infantile hemangioma.