Rebecca F. Gottesman

Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial

IMPORTANCE Uncertainty remains about the efficacy of folic acid therapy for the primary prevention of stroke because of limited and inconsistent data. OBJECTIVE To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension. DESIGN, SETTING, AND PARTICIPANTS The China Stroke Primary Prevention Trial, a randomized, double-blind clinical trial conducted from May 19, 2008, to August 24, 2013, in 32 communities in Jiangsu and Anhui provinces in China. A total of 20,702 adults with hypertension without history of stroke or myocardial infarction (MI) participated in the study. INTERVENTIONS Eligible participants, stratified by MTHFR C677T genotypes (CC, CT, and TT), were randomly assigned to receive double-blind daily treatment with a single-pill combination containing enalapril, 10 mg, and folic acid, 0.8 mg (n = 10,348) or a tablet containing enalapril, 10 mg, alone (n = 10,354). MAIN OUTCOMES AND MEASURES The primary outcome was first stroke. Secondary outcomes included first ischemic stroke; first hemorrhagic stroke; MI; a composite of cardiovascular events consisting of cardiovascular death, MI, and stroke; and all-cause death. RESULTS During a median treatment duration of 4.5 years, compared with the enalapril alone group, the enalapril-folic acid group had a significant risk reduction in first stroke (2.7% of participants in the enalapril-folic acid group vs 3.4% in the enalapril alone group; hazard ratio [HR], 0.79; 95% CI, 0.68-0.93), first ischemic stroke (2.2% with enalapril-folic acid vs 2.8% with enalapril alone; HR, 0.76; 95% CI, 0.64-0.91), and composite cardiovascular events consisting of cardiovascular death, MI, and stroke (3.1% with enalapril-folic acid vs 3.9% with enalapril alone; HR, 0.80; 95% CI, 0.69-0.92). The risks of hemorrhagic stroke (HR, 0.93; 95% CI, 0.65-1.34), MI (HR, 1.04; 95% CI, 0.60-1.82), and all-cause deaths (HR, 0.94; 95% CI, 0.81-1.10) did not differ significantly between the 2 treatment groups. There were no significant differences between the 2 treatment groups in the frequencies of adverse events. CONCLUSIONS AND RELEVANCE Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke. These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00794885.

Stroke incidence and mortality trends in US communities, 1987 to 2011.

IMPORTANCE Prior studies have shown decreases in stroke mortality over time, but data on validated stroke incidence and long-term trends by race are limited. OBJECTIVE To study trends in stroke incidence and subsequent mortality among black and white adults in the Atherosclerosis Risk in Communities (ARIC) cohort from 1987 to 2011. DESIGN, SETTING, AND PARTICIPANTS Prospective cohort study of 14,357 participants (282,097 person-years) free of stroke at baseline was facilitated in 4 different US communities. Participants were recruited for the purpose of studying all stroke hospitalizations and deaths and for collection of baseline information on cardiovascular risk factors (via interviews and physical examinations) in 1987-1989. Participants were followed up (via examinations, annual phone interviews, active surveillance of discharges from local hospitals, and linkage with the National Death Index) through December 31, 2011. The study physician reviewers adjudicated all possible strokes and classified them as definite or probable ischemic or hemorrhagic events. MAIN OUTCOMES AND MEASURES Trends in rates of first-ever stroke per 10 years of calendar time were estimated using Poisson regression incidence rate ratios (IRRs), with subsequent mortality analyzed using Cox proportional hazards regression models and hazard ratios (HRs) overall and by race, sex, and age divided at 65 years. RESULTS Among 1051 (7%) participants with incident stroke, there were 929 with incident ischemic stroke and 140 with incident hemorrhagic stroke (18 participants had both during the study period). Crude incidence rates were 3.73 (95% CI, 3.51-3.96) per 1000 person-years for total stroke, 3.29 (95% CI, 3.08-3.50) per 1000 person-years for ischemic stroke, and 0.49 (95% CI, 0.41-0.57) per 1000 person-years for hemorrhagic stroke. Stroke incidence decreased over time in white and black participants (age-adjusted IRRs per 10-year period, 0.76 [95% CI, 0.66-0.87]; absolute decrease of 0.93 per 1000 person-years overall). The decrease in age-adjusted incidence was evident in participants age 65 years and older (age-adjusted IRR per 10-year period, 0.69 [95% CI, 0.59-0.81]; absolute decrease of 1.35 per 1000 person-years) but not evident in participants younger than 65 years (age-adjusted IRR per 10-year period, 0.97 [95% CI, 0.76-1.25]; absolute decrease of 0.09 per 1000 person-years) (P = .02 for interaction). The decrease in incidence was similar by sex. Of participants with incident stroke, 614 (58%) died through 2011. The mortality rate was higher for hemorrhagic stroke (68%) than for ischemic stroke (57%). Overall, mortality after stroke decreased over time (hazard ratio [HR], 0.80 [95% CI, 0.66-0.98]; absolute decrease of 8.09 per 100 strokes after 10 years [per 10-year period]). The decrease in mortality was mostly accounted for by the decrease at younger than age 65 years (HR, 0.65 [95% CI, 0.46-0.93]; absolute decrease of 14.19 per 100 strokes after 10 years [per 10-year period]), but was similar across race and sex. CONCLUSIONS AND RELEVANCE In a multicenter cohort of black and white adults in US communities, stroke incidence and mortality rates decreased from 1987 to 2011. The decreases varied across age groups, but were similar across sex and race, showing that improvements in stroke incidence and outcome continued to 2011.

Cognitive and Neurologic Outcomes after Coronary-Artery Bypass Surgery

For patients undergoing coronary-artery bypass grafting (CABG), adverse neurologic outcomes, including stroke and cognitive decline, are major concerns. Even mild cognitive deficits before surgery may be a marker for cerebrovascular disease and increased risk.

Watershed Strokes After Cardiac Surgery. Diagnosis, Etiology, and Outcome

Background and Purpose— Watershed strokes are more prevalent after cardiac surgery than in other stroke populations, but their mechanism in this setting is not understood. We investigated the role of intraoperative blood pressure in the development of watershed strokes and used MRI to evaluate diagnosis and outcomes associated with this stroke subtype. Methods— From 1998 to 2003 we studied 98 patients with clinical stroke after cardiac surgery who underwent MRI with diffusion-weighted imaging. We used logistic regression to explore the relationship between mean arterial pressure and watershed infarcts, between watershed infarcts and outcome, and &khgr;2 analyses to compare detection by MRI versus CT of watershed infarcts. Results— Bilateral watershed infarcts were present on 48% of MRIs and 22% of CTs (P<0.0001). Perioperative stroke patients with bilateral watershed infarcts, compared with those with other infarct patterns, were 17.3 times more likely to die, 12.5 and 6.2 times more likely to be discharged to a skilled nursing facility and to acute rehabilitation, respectively, than to be discharged home (P=0.0004). Patients with a decrease in mean arterial pressure of at least 10 mm Hg (intraoperative compared with preoperative) were 4.1 times more likely to have bilateral watershed infarcts than other infarct patterns. Conclusions— Bilateral watershed infarcts after cardiac surgery are most reliably detected by diffusion-weighted imaging MRI and are associated with poor short-term outcome, compared with other infarct types. The mechanism may include an intraoperative drop in blood pressure from a patients baseline. These findings have implications for future clinical practice and research.

Predictors and assessment of cognitive dysfunction resulting from ischaemic stroke

Stroke remains a primary cause of morbidity throughout the world mainly because of its effect on cognition. Individuals can recover from physical disability resulting from stroke, but might be unable to return to their previous occupations or independent life because of cognitive impairments. Cognitive dysfunction ranges from focal deficits, resulting directly from an area of infarction or from hypoperfusion in adjacent tissue, to more global cognitive dysfunction. Global dysfunction is likely to be related to other underlying subclinical cerebrovascular disease, such as white-matter disease or subclinical infarcts. Study of cognitive dysfunction after stroke is complicated by varying definitions and lack of measurement of cognition before stroke. Additionally, stroke can affect white-matter connectivity, so newer imaging techniques, such as diffusion-tensor imaging and magnetisation transfer imaging, that can be used to assess this subclinical injury are important tools in the assessment of cognitive dysfunction after stroke. As research is increasingly focused on the role of preventable risk factors in the development of dementia, the role of stroke in the development of cognitive impairment and dementia could be another target for prevention.

Delirium after coronary artery bypass graft surgery and late mortality

Delirium is common after cardiac surgery, although under‐recognized, and its long‐term consequences are likely underestimated. The primary goal of this study was to determine whether patients with delirium after coronary artery bypass graft (CABG) surgery have higher long‐term out‐of‐hospital mortality when compared with CABG patients without delirium.

Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study.

IMPORTANCE Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age. OBJECTIVE To evaluate the association between midlife (48-67 years of age) hypertension and the 20-year change in cognitive performance. DESIGN, SETTING, AND PARTICIPANTS The Atherosclerosis Risk in Communities cohort (1990-1992 through 2011-2013) underwent evaluation at field centers in Washington County, Maryland, Forsyth County, North Carolina, Jackson, Mississippi, and the Minneapolis, Minnesota, suburbs. Of 13 476 African American and white participants with baseline cognitive data, 58.0% of living participants completed the 20-year cognitive follow-up. EXPOSURES Hypertension, prehypertension, or normal blood pressure (BP) at visit 2 (1990-1992) constituted the primary exposure. Systolic BP at visit 2 or 5 (2011-2013) and indication for treatment at visit 2 based on the Eighth Joint National Committee (JNC-8) hypertension guidelines constituted the secondary exposures. MAIN OUTCOMES AND MEASURES Prespecified outcomes included the 20-year change in scores on the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test and in global cognition. RESULTS During 20 years, baseline hypertension was associated with an additional decline of 0.056 global z score points (95% CI, -0.100 to -0.012) and prehypertension was associated nonsignificantly with 0.040 more global z score points of decline (95% CI, -0.085 to 0.005) compared with normal BP. Individuals with hypertension who used antihypertensives had less decline during the 20 years than untreated individuals with hypertension (-0.050 [95% CI, -0.003 to -0.097] vs -0.079 [95% CI, -0.156 to -0.002] global z score points). Having a JNC-8-specified indication for initiating antihypertensive treatment at baseline was associated with a greater 20-year decline (-0.044 [95% CI, -0.085 to -0.003] global z score points) than not having an indication. We observed effect modification by race for the continuous systolic BP analyses (P = .01), with each 20-mm Hg increment at baseline associated with an additional decline of 0.048 (95% CI, -0.074 to -0.022) points in global cognitive z score in whites but not in African Americans (decline, -0.020 [95% CI, -0.026 to 0.066] points). Systolic BP at the end of follow-up was not associated with the preceding 20 years of cognitive change in either group. Methods to account for bias owing to attrition strengthened the magnitude of some associations. CONCLUSIONS AND RELEVANCE Midlife hypertension and elevated midlife but not late-life systolic BP was associated with more cognitive decline during the 20 years of the study. Greater decline is found with higher midlife BP in whites than in African Americans.

Predicting the limits of cerebral autoregulation during cardiopulmonary bypass.

BACKGROUND: Mean arterial blood pressure (MAP) targets are empirically chosen during cardiopulmonary bypass (CPB). We have previously shown that near-infrared spectroscopy (NIRS) can be used clinically for monitoring cerebral blood flow autoregulation. The hypothesis of this study was that real-time autoregulation monitoring using NIRS-based methods is more accurate for delineating the MAP at the lower limit of autoregulation (LLA) during CPB than empiric determinations based on age, preoperative history, and preoperative blood pressure. METHODS: Two hundred thirty-two patients undergoing coronary artery bypass graft and/or valve surgery with CPB underwent transcranial Doppler monitoring of the middle cerebral arteries and NIRS monitoring. A continuous, moving Pearson correlation coefficient was calculated between MAP and cerebral blood flow velocity and between MAP and NIRS data to generate mean velocity index and cerebral oximeter index. When autoregulated, there is no correlation between cerebral blood flow and MAP (i.e., mean velocity and cerebral oximetry indices approach 0); when MAP is below the LLA, mean velocity and cerebral oximetry indices approach 1. The LLA was defined as the MAP at which mean velocity index increased with declining MAP to ≥0.4. Linear regression was performed to assess the relation between preoperative systolic blood pressure, MAP, MAP in 10% decrements from baseline, and average cerebral oximetry index with MAP at the LLA. RESULTS: The MAP at the LLA was 66 mm Hg (95% prediction interval, 43 to 90 mm Hg) for the 225 patients in which this limit was observed. There was no relationship between preoperative MAP and the LLA (P = 0.829) after adjusting for age, gender, prior stroke, diabetes, and hypertension, but a cerebral oximetry index value of >0.5 was associated with the LLA (P = 0.022). The LLA could be identified with cerebral oximetry index in 219 (94.4%) patients. The mean difference in the LLA for mean velocity index versus cerebral oximetry index was −0.2 ± 10.2 mm Hg (95% CI, −1.5 to 1.2 mm Hg). Preoperative systolic blood pressure was associated with a higher LLA (P = 0.046) but only for those with systolic blood pressure ⩽160 mm Hg. CONCLUSIONS: There is a wide range of MAP at the LLA in patients during CPB, making estimation of this target difficult. Real-time monitoring of autoregulation with cerebral oximetry index may provide a more rational means for individualizing MAP during CPB.

Genome-wide association studies of cerebral white matter lesion burden

White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

Restoring Cerebral Blood Flow Reveals Neural Regions Critical for Naming

We identified areas of the brain that are critical for naming pictures of objects, using a new methodology for testing which components of a network of brain regions are essential for that task. We identified areas of hypoperfusion and structural damage with magnetic resonance perfusion- and diffusion-weighted imaging immediately after stroke in 87 individuals with impaired picture naming. These individuals were reimaged after 3–5 d, after a subset of patients underwent intervention to restore normal blood flow, to determine areas of the brain that had reperfused. We identified brain regions in which reperfusion was associated with improvement in picture naming. Restored blood flow to left posterior middle temporal/fusiform gyrus, Brocas area, and/or Wernickes area accounted for most acute improvement after stroke. Results show that identifying areas of reperfusion that are associated with acute improvement of a function can reveal the brain regions essential for that function.