Jose Gutierrez

A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply

The anatomy of the arterial system supplying blood to the brain can influence the development of arterial disease such as aneurysms, dolichoectasia and atherosclerosis. As the arteries supplying blood to the brain develop during embryogenesis, variation in their anatomy may occur and this variation may influence the development of arterial disease. Angiogenesis, which occurs mainly by sprouting of parent arteries, is the first stage at which variations can occur. At day 24 of embryological life, the internal carotid artery is the first artery to form and it provides all the blood required by the primitive brain. As the occipital region, brain stem and cerebellum enlarge; the internal carotid supply becomes insufficient, triggering the development of the posterior circulation. At this stage, the posterior circulation consists of a primitive mesh of arterial networks that originate from projection of penetrators from the distal carotid artery and more proximally from carotid-vertebrobasilar anastomoses. These anastomoses regress when the basilar artery and the vertebral arteries become independent from the internal carotid artery, but their persistence is not uncommon in adults (e.g., persistent trigeminal artery). Other common remnants of embryological development include fenestration or duplication (most commonly of the basilar artery), hypoplasia (typically of the posterior communicating artery) or agenesis (typically of the anterior communicating artery). Learning more about the hemodynamic consequence that these variants may have on the brain territories they supply may help understand better the underlying physiopathology of cerebral arterial remodeling and stroke in patients with these variants.

A decade of racial and ethnic stroke disparities in the United States

Stroke is the fourth leading cause of death and the leading cause of long-term disability in the United States. Stroke incidence and prevalence is not uniform. It occurs more frequently in some geographical areas of the United States and the rates are higher in minority groups.1,2 Some proposed causes for these disparities include increased rate of vascular risk factors that disproportionally affect some minority groups, differential effect of hypertension on stroke risk across racial groups, lack of access to health care and other social determinants of health, suboptimal control of risk factors, and, although lacking substantive data to date, an inherited predisposition to stroke associated with genetic differences. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) investigators found that the rate of suboptimal control of vascular risk factors and unhealthy lifestyles was significantly greater in African Americans compared to non-Hispanic whites (NHW).2 Moreover, regarding high blood pressure (BP), a triple threat has been described: blacks are not only more likely to have high BP, they are less likely, once diagnosed, to have their high BP controlled, and this suboptimal control has been shown to confer a stroke risk that is 3 times higher among blacks compared to whites for every 10-mm Hg increase in systolic BP (SBP).3

A Pathological Perspective on the Natural History of Cerebral Atherosclerosis

Background The natural history of intracranial large artery atherosclerosis has been mainly described from lumen-based imaging studies, and much of what is reported to be known about atherosclerosis is derived from non-cerebral arteries. Aims To test the hypothesis that atherosclerosis is only partially represented by stenosis and that advanced atherosclerosis is more common that severe stenosis in noncardioembolic infarcts. Methods Cerebral large arteries from 196 autopsy cases were studied. The revised American Heart Association classification for atherosclerosis was used to determine the phenotype in each available artery. Cross-sectional lumen stenosis was obtained as defined by the Glagovs method. Results As age of cases increased, there was a progressive increment in the frequency of atherosclerotic lesions, rising from 5% of all arteries at age 20–40, to more than 40% at age 60 or older. Stenosis also increased with age: less than 3% of the arteries in those ≤50 years had >40% stenosis, while one out of five arteries in those >80 years had >40% stenosis. In most cases (80%), atherosclerosis and stenosis were directly related. However, one out of five cases with advanced atherosclerosis had <30% stenosis. In arteries supplying brain areas with noncardioembolic infarcts, the majority of segments exhibiting advanced atherosclerosis had lumen stenosis of <40%. Conclusion Although intracranial atherosclerosis is typically associated with stenosis, a substantial minority of cases shows advanced atherosclerosis in the absence of stenosis >40%. Definitions based solely on stenosis may underestimate the extent and role of intracranial large artery atherosclerosis.

HIV infection as vascular risk: A systematic review of the literature and meta-analysis

Importance The vascular risk attributable to HIV infection is rising. The heterogeneity of the samples studied is an obstacle to understanding whether HIV is a vascular risk across geographic regions. Objective To test the hypothesis that HIV infection is a vascular risk factor, and that the risk conferred by HIV varies by geographical region. Data sources A systematic search of publications was carried out in seven electronic databases: PubMed, The Cochrane Library, EMBASE, Web of Science, LILACS, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform from inception to July 2015. Study selection We included longitudinal studies of HIV+ individuals and their risk of vascular outcomes of ≥ 50 HIV+ cases and excluded studies on biomarkers of vascular disease as well as clinical trials. Data extraction and synthesis Data was extracted by one of the authors and independently confirmed by the other two authors. We used incidence rate (IR), incidence risk ratio (IRR) and hazard ratio (HR) with their 95% confidence intervals as measures of risk. Main outcome All-death, myocardial infarction (MI), coronary heart disease (CHD), any stroke, ischemic stroke (IS) or intracranial hemorrhage (ICH). Results We screened 11,482 references for eligibility, and selected 117 for analysis. Forty-four cohorts represented 334,417 HIV+ individuals, 49% from the United States. Compared with their European counterparts, HIV+ individuals in the United States had higher IR of death (IRR 1.78, 1.69–1.88), MI (IRR 1.61, 1.29–2.01), CHD (IRR 2.27, 1.92–2.68), any stroke (IRR 1.94, 1.59–2.38), IS (IRR 1.56, 1.23–1.98), and ICH (IRR 4.03, 2.72–6.14). Compared with HIV- controls and independent of geographical region, HIV was a risk for death (HR 4.77, 4.55–5.00), MI (HR 1.60, 1.49–1.72), any CHD (HR 1.20, 1.15–1.25), any stroke (HR 1.82, 1.53–2.16), IS (HR 1.27, 1.15–1.39) and ICH (HR 2.20, 1.61–3.02). Use of antiretroviral therapy was a consistent risk for cardiac outcomes, while immunosuppression and unsuppressed viral load were consistent risks for cerebral outcomes. Conclusions HIV should be considered a vascular risk, with varying magnitudes across geographical and anatomical regions. We think that strategies to reduce the HIV-related vascular burden are urgent, and should incorporate the disparities noted here.

Dolichoectasia and the Risk of Stroke and Vascular Disease: A Critical Appraisal

Dolichoectasia (DE) in cerebral arteries is a poorly understood arteriopathy that has been associated with increased risk of vascular morbidity and mortality. Dolichoectasia tends to affects older individuals with vascular risk factors, but it can also be secondary to specific conditions related with extracellular matrix health. The range of methods used to study DE and the biases inherent to hospital-based samples weaken the generalizability of DE study results to the general population. Within the context of these limitations, there is growing evidence that DE is a serious condition that can increase the risk of vascular death. Recurrent strokes and compressive symptoms are among the major causes of morbidity, but cardiac ischemic disease and aortic aneurysms are not uncommon in populations with DE. The devastating outcomes of patients with DE are a call to action aimed at improving the quality of research on the topic and discovering therapies that can palliate the burden of DE in the population.

Indirect measures of arterial stiffness and cognitive performance in individuals without traditional vascular risk factors or disease.

IMPORTANCE Whether cognition is influenced by arterial stiffness in the absence of vascular disease remains uncertain. OBJECTIVE To test the hypotheses that indirect measures of arterial stiffness are important predictors of cognitive performance and that this relationship varies depending on the presence of vascular disease. DESIGN, SETTING, AND PARTICIPANTS Participants included 2573 noninstitutionalized US adults randomly selected from 2 cycles of the National Health and Nutrition Examination Survey (1999-2002). The sample was stratified by groups based on the presence (VASC+) vs the absence (VASC-) of vascular variables negatively associated with cognition to assess the effects of indirect measures of arterial stiffness on cognitive performance. We used logistic regression to obtain odds ratios (ORs) and their 95% CIs. P < .05 was considered statistically significant. MAIN OUTCOMES AND MEASURES The Digit Symbol Substitution Test score was used as a continuous variable, and the lowest quintile was designated as an indicator of poorer cognitive performance. RESULTS In the VASC+ group, poorer cognitive performance was more likely with increasing age (OR, 1.12 [95% CI, 1.08-1.17]; P < .001), a sedentary lifestyle (OR, 2.99 [95% CI, 1.62-5.55]; P = .002), and the use of dihydropyridine calcium channel blockers (OR, 9.24 [95% CI, 1.35-63.23]; P = .02). Poorer cognitive performance in the VASC+ group was less likely in women (OR, 0.37 [95% CI, 0.18-0.72]; P = .02), non-Hispanic white individuals (OR, 0.16 [95% CI, 0.09-0.26]; P < .001), those with higher educational attainment (OR, 0.23 [95% CI, 0.14-0.38]; P < .001), those with higher income levels (OR, 0.56 [95% CI, 0.72-0.76]; P < .001), and those who used renin-angiotensin system blockers (OR, 0.24 [95% CI, 0.07-0.79]; P = .02). In the VASC- group, the most important significant predictors of poorer cognitive performance were an ankle brachial index greater than 1.30 (OR, 18.56 [95% CI, 2.94-117.05]; P = .002) and increased blood pressure variability (OR, 3.49 [95% CI, 1.07-11.35]; P = .04). Among participants in the VASC- group who had both of these variables, the prevalence of poorer cognitive performance was greater (β = 16.65; P < .001). CONCLUSIONS AND RELEVANCE Two indirect measures of arterial stiffness, an ankle brachial index greater than 1.30 and increased blood pressure variability, are associated with poorer cognitive performance among adults 60 years or older without clinical atherosclerotic disease. Among those with vascular disease, factors capable of influencing arterial stiffness, such as exercise and the use of renin-angiotensin system blockers, may be protective against poorer cognitive performance.

Cardiovascular profile and events of US adults 20–49 years with HIV: Results from the NHANES 1999–2008

The incidence of vascular events in HIV-infected individuals is increasing. We investigated whether there is a higher prevalence of vascular risk factors in the adult US population with HIV compared to uninfected controls that could explain some of the increased vascular events. We obtained prevalence estimates of vascular risk factors, stratified by the HIV status, in sampled adults aged 20–49 years from the 1999 to 2008 National Health and Nutrition Examination Survey. Estimates were weighted to account for oversampling and nonresponse. Logistic regression models with adjustment for demographic and socioeconomic status were created to adjust for confounders. The analysis included 12,339 US adults, 76 with HIV infection. The weighted seroprevalence of HIV was 0.48% (95% CI 0.33–0.65). In univariate analysis, HIV infection was more prevalent in non-Hispanic blacks (odds ratio [OR] 7.4, 95% CI 3.6–15.2), men (OR 2.6, 95% CI 1.42–4.89), the physically inactive (OR 1.8, 95% CI 1.0–3.0), and current smokers (OR 2.4, 95% CI 1.3–4.4). Increased waist circumference (OR 0.5, 95% CI 0.3–1.0) was less common in HIV-infected individuals, although controlling for sex and ethnicity differences, this difference became nonsignificant (OR 0.6, 95% CI 0.3–1.2). Further controlling for differences in income and education rendered the associations with smoking and physical inactivity nonsignificant, but revealed associations of HIV infection with hypertension (OR 2.4, 95% CI 1.0–6.0) and diabetes (OR 4.1, 95% CI 1.1–16.1). These results underscore the need to further investigate the role of cardiovascular risk factors in the growing HIV population.

Varicella zoster virus (VZV) in cerebral arteries of subjects at high risk for VZV reactivation

With a decline in varicella zoster virus (VZV)-specific cell-mediated immunity, VZV can reactivate, infect cerebral arteries and cause stroke. Previous studies of cerebral arteries from subjects without a history of transient ischemic attacks or stroke revealed no VZV DNA or VZV antigen; however, VZV DNA and VZV antigen were found in the cerebral arteries of a subject with diabetes, a known risk factor for VZV reactivation and zoster. The present study analyzed an additional 55 cerebral arteries from 18 subjects with co-morbidities that may increase risk of VZV reactivation: a history of alcohol abuse, tricyclic antidepressant intoxication, cocaine abuse, HIV or being over age 70 years. VZV antigen was detected in 24 (44%) cerebral arteries from 14 (78%) subjects.

Letter by Gutierrez and Elkind Regarding Article, “Patterns and Implications of Intracranial Arterial Remodeling in Patients With Stroke”

We read with interest the article by Qiao et al,1 in which the authors affirm that there exists evidence of brain arterial outward remodeling that accommodates an expanding intracranial plaque. Our published data from a postmortem sample of brain arteries, however, suggests that such compensatory responses are not found.2 The reasons for this discrepancy may lie in the methods used for each study. First, and most important, the definition of plaque burden used in this study does not represent true plaque burden (ie, intima area) but rather it represents the proportion of the interadventitial area occupied by the wall area. Given this limitation, stating that brain arteries can accommodate plaque burden ≤55% before the lumen narrows is not …

An Epidemiological Perspective on Race/Ethnicity and Stroke

Stroke disparities among self-defined ethnic and racial groups exist in the USA and in other countries. While ethnicity carries an inherent cultural connotation, race is less well defined. Emerging evidence suggest that race is more a social construct than a biologically plausible category of humans. Nonetheless, disparities exist in multiple measures of cerebrovascular health across ethnic and racial groups. For example, the risk of stroke among non-Hispanic blacks and Hispanics in the USA is two-to-three times higher than non-Hispanic white population. Although examples of genetic segregation may be invoked to explain these disparities, the evidence reviewed here suggests that important difference exist in environmental and clinical factors that may contribute more importantly to the observed stroke disparities. Despite the caveats of using race and ethnicity as homogenous categories, there is value in using these constructs to target preventive measures in populations at a high risk of cerebrovascular disease.