Leslie A. McClure

Achieved Blood Pressure and Outcomes in the Secondary Prevention of Small Subcortical Strokes Trial

Abstract—Studies suggest a J-shaped association between blood pressure and cardiovascular events in the setting of intensive systolic blood pressure control; whether there is a similar association with stroke remains less well established. The Secondary Prevention of Small Subcortical Strokes was a randomized trial to evaluate higher (130–149 mm Hg) versus lower (<130 mm Hg) systolic blood pressure targets in participants with recent lacunar infarcts. We evaluated the association of mean achieved blood pressure, 6 months after randomization, and recurrent stroke, major vascular events, and all-cause mortality. After a mean follow up of 3.7 years, there was a J-shaped association between achieved blood pressure and outcomes; the lowest risk was at ≈124 and 67 mm Hg systolic and diastolic blood pressure, respectively. For example, above a systolic blood pressure of 124 mm Hg, 1 standard deviation higher (11.1 mm Hg) was associated with increased mortality (adjusted hazard ratio: 1.9; 95% confidence interval: 1.4, 2.7), whereas below this level, this relationship was inverted (0.29; 0.10, 0.79), P<0.001 for interaction. Above a diastolic blood pressure of 67 mm Hg, a 1 standard deviation higher (8.2 mm Hg) was associated with an increased risk of stroke (2.2; 1.4, 3.6), whereas below this level, the association was in the opposite direction (0.34; 0.13, 0.89), P=0.02 for interaction. The lowest risk of all events occurred at a nadir of ≈120 to 128 mm Hg systolic blood pressure and 65 to 70 mm Hg diastolic blood pressure. Future studies should evaluate the impact of excessive blood pressure reduction, especially in older populations with preexisting vascular disease. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.

Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop

In view of continuing unanswered questions regarding the geographical and demographic distribution of cardiovascular disease, and recent discoveries about the effects of dietary nitrate on cardiovascular physiology, the National Heart, Lung, and Blood Institute (NHLBI) convened a workshop to

Racial Differences in the Incidence of Cardiovascular Risk Factors in Older Black and White Adults.

To describe the incidence of cardiovascular risk factors, or race‐related disparities in incidence, across the age spectrum in adults.

Where to Focus Efforts to Reduce the Black–White Disparity in Stroke Mortality: Incidence Versus Case Fatality?

Background and Purpose— At age 45 years, blacks have a stroke mortality ≈3× greater than their white counterparts, with a declining disparity at older ages. We assess whether this black–white disparity in stroke mortality is attributable to a black–white disparity in stroke incidence versus a disparity in case fatality. Methods— We first assess if black–white differences in stroke mortality within 29u2009681 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort reflect national black–white differences in stroke mortality and then assess the degree to which black–white differences in stroke incidence or 30-day case fatality after stroke contribute to the disparities in stroke mortality. Results— The pattern of stroke mortality within the study mirrors the national pattern, with the black-to-white hazard ratio of ≈4.0 at age 45 years decreasing to ≈1.0 at age 85 years. The pattern of black-to-white disparities in stroke incidence shows a similar pattern but no evidence of a corresponding disparity in stroke case fatality. Conclusions— These findings show that the black–white differences in stroke mortality are largely driven by differences in stroke incidence, with case fatality playing at most a minor role. Therefore, to reduce the black–white disparity in stroke mortality, interventions need to focus on prevention of stroke in blacks.

Neighborhood socioeconomic index and stroke incidence in a national cohort of blacks and whites

Objective: To assess the relationship between neighborhood socioeconomic characteristics and incident stroke in a national cohort of black and white participants. Methods: The study comprised black (n = 10,274, 41%) and white (n = 14,601) stroke-free participants, aged 45 and older, enrolled in 2003–2007 in Reasons for Geographic and Racial Differences in Stroke (REGARDS), a national population-based cohort. A neighborhood socioeconomic score (nSES) was constructed using 6 neighborhood variables. Incident stroke was defined as first occurrence of stroke over an average 7.5 (SD 3.0) years of follow-up. Proportional hazards models were used to estimate associations between nSES score and incident stroke, adjusted for demographics (age, race, sex, region), individual socioeconomic status (SES) (education, household income), and other risk factors for stroke. Results: After adjustment for demographics, compared to the highest nSES quartile, stroke incidence increased with each decreasing nSES quartile. The hazard ratio (95% confidence interval) ranged from 1.28 (1.05–1.56) in quartile 3 to 1.38 (1.13–1.68) in quartile 2 to 1.56 (1.26–1.92) in quartile 1 (p < 0.0001 for linear trend). After adjustment for individual SES, the trend remained marginally significant (p = 0.085). Although there was no evidence of a differential effect by race or sex, adjustment for stroke risk factors attenuated the association between nSES and stroke in both black and white participants, with greater attenuation in black participants. Conclusions: Risk of incident stroke increased with decreasing nSES but the effect of nSES is attenuated through individual SES and stroke risk factors. The effect of neighborhood socioeconomic characteristics that contribute to increased stroke risk is similar in black and white participants.

N-Terminal Pro-B-Type Natriuretic Peptide and Risk of Future Cognitive Impairment in the REGARDS Cohort

BACKGROUNDnImproved understanding of the etiology of cognitive impairment is needed to develop effective preventive interventions. Higher amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a biomarker of cardiac dysfunction associated with risk of cardiovascular diseases and stroke in apparently healthy people.nnnOBJECTIVEnTo study the association of NT-proBNP with risk of incident cognitive impairment.nnnMETHODSnThe Reasons for Geographic and Racial Differences in Stroke is a national cohort study of 30,239 black and white Americans age 45 and older at baseline, enrolled in 2003-7. Among participants without prebaseline stroke or cognitive impairment, baseline NT-proBNP was measured in 470 cases of incident cognitive impairment and 557 controls. Cases were participants scoring below the 6th percentile of demographically-adjusted means on at least 2 of 3 serially administered tests (word list learning, word list recall and semantic fluency) over 3.5 years follow-up.nnnRESULTSnAdjusting for age, gender, race, region of residence, education, and income, there was an increased odds ratio of incident cognitive impairment with increasing NT-proBNP; participants in the 4th versus 1st quartile (>127 versus ≤33u200apg/ml) had a 1.69-fold increased odds (95% CI 1.11-2.58). Adjustment for cardiovascular risk factors and presence of an apolipoprotein E4 allele had no substantial impact on the odds ratio. Results did not differ by age, race, gender, or presence of an apolipoprotein E4 allele.nnnCONCLUSIONnHigher NT-pro-BNP was associated with incident cognitive impairment in this prospective study, independent of atherogenic and Alzheimers disease risk factors. Future work should clarify pathophysiologic connections of NT-proBNP and cognitive dysfunction.

Experiential exposure to texting and walking in virtual reality: A randomized trial to reduce distracted pedestrian behavior

BACKGROUNDnDistracted pedestrian behavior is a significant public health concern, as research suggests distracted pedestrians have significantly higher risk of injury compared to fully attentive pedestrians. Despite this, efforts to reduce distracted pedestrian behavior are scant.nnnOBJECTIVEnUsing a repeated measures experimental research design, we implemented a behavioral intervention to reduce distracted pedestrian behavior in the high-risk environment of an urban college campus and simultaneously monitored behavior on a control urban college campus not exposed to the intervention. We had two primary aims: reduce perceived vulnerability to injury among individual pedestrians and reduce distracted pedestrian behavior in the environment through a change in community-based norms.nnnMETHODSnThe hallmark of the behavioral intervention was a week-long opportunity for community members to experience personally the risks of distracted pedestrian behavior by attempting to cross a virtual pedestrian environment street while text-messaging. This was supplemented by traditional and social marketing and publicity through various campus partners. A sample of 219 individuals completed self-report surveys about perceived vulnerability to distracted pedestrian injury before experiencing the distracted virtual street-crossing and again after 2 weeks and 5 months. Observational assessment of distracted pedestrian behavior was conducted at a busy intersection on the campus as well as at a control campus not exposed to the intervention at baseline, post-intervention, 10 weeks, and 6 months.nnnRESULTSnThe intervention achieved mixed results. Individuals exposed to texting within a simulated pedestrian environment reported changes in their intentions to cross streets while distracted and in perceived vulnerability to risk while crossing streets, but we did not witness evidence of changed community norms based on observed rates of distracted pedestrian behavior before and after the intervention compared to a control campus not exposed to the intervention.nnnDISCUSSIONnThe intervention created some change in self-reported intentions and thoughts but did not create significant behavior change on the campus exposed to it. Further efforts to develop interventions that will yield a reduction in distracted pedestrian behavior are needed.

Heat Maps of Hypertension, Diabetes Mellitus, and Smoking in the Continental United States

Background— Geographic variations in cardiovascular mortality are substantial, but descriptions of geographic variations in major cardiovascular risk factors have relied on data aggregated to counties. Herein, we provide the first description of geographic variation in the prevalence of hypertension, diabetes mellitus, and smoking within and across US counties. Methods and Results— We conducted a cross-sectional analysis of baseline risk factor measurements and latitude/longitude of participant residence collected from 2003 to 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Of the 30u2009239 participants, all risk factor measurements and location data were available for 28u2009887 (96%). The mean (±SD) age of these participants was 64.8(±9.4) years; 41% were black; 55% were female; 59% were hypertensive; 22% were diabetic; and 15% were current smokers. In logistic regression models stratified by race, the median(range) predicted prevalence of the risk factors were as follows: for hypertension, 49% (45%–58%) among whites and 72% (68%–78%) among blacks; for diabetes mellitus, 14% (10%–20%) among whites and 31% (28%–41%) among blacks; and for current smoking, 12% (7%–16%) among whites and 18% (11%–22%) among blacks. Hypertension was most prevalent in the central Southeast among whites, but in the west Southeast among blacks. Diabetes mellitus was most prevalent in the west and central Southeast among whites but in south Florida among blacks. Current smoking was most prevalent in the west Southeast and Midwest among whites and in the north among blacks. Conclusions— Geographic disparities in prevalent hypertension, diabetes mellitus, and smoking exist within states and within counties in the continental United States, and the patterns differ by race.

PCSK9 Variants, Low-Density Lipoprotein Cholesterol, and Neurocognitive Impairment: Reasons for Geographic and Racial Differences in Stroke Study (REGARDS)

Background: Despite concerns about adverse neurocognitive events raised by prior trials, pharmacological PCSK9 (proprotein convertase subtilisin/kexin type-9) inhibition was not associated with neurocognitive effects in a recent phase 3 randomized trial. PCSK9 loss-of-function (LOF) variants that result in lifelong exposure to lower levels of low-density lipoprotein cholesterol can provide information on the potential long-term effects of lower low-density lipoprotein cholesterol on neurocognitive impairment and decline. Methods: We investigated the association between PCSK9 LOF variants and neurocognitive impairment and decline among black REGARDS study (Reasons for Geographic and Racial Differences in Stroke) participants with (n=241) and without (n=10u2009454) C697X or Y142X LOF variants. Neurocognitive tests included the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) battery (Word List Learning, World List Delayed Recall, Semantic Animal Fluency) and Six-Item Screener (SIS) assessments, administered longitudinally during follow-up. Neurocognitive impairment was defined as a score ≥1.5 SD below age, sex, and education-based stratum-specific means on 2 or 3 CERAD assessments or, separately, a score <5 on any SIS assessment at baseline or during follow-up. Neurocognitive decline was assessed using standardized continuous scores on individual neurocognitive tests. Results: The mean sample age was 64 years (SD, 9), 62% were women, and the prevalence of neurocognitive impairment at any assessment was 6.3% by CERAD and 15.4% by SIS definitions. Adjusted odds ratios for neurocognitive impairment for participants with versus without PCSK9 LOF variants were 1.11 (95% confidence interval [CI], 0.58–2.13) using the CERAD battery and 0.89 (95% CI, 0.61–1.30) using the SIS assessment. Standardized average differences in individual neurocognitive assessment scores over the 5.6-year (range, 0.1–9.1) study period ranged between 0.07 (95% CI, −0.06 to 0.20) and −0.07 (95% CI, −0.18 to 0.05) among participants with versus without PCSK9 LOF variants. Patterns of neurocognitive decline were similar between participants with and without PCSK9 LOF variants (all P>0.10). Odds ratios for neurocognitive impairment per 20 mg/dL low-density lipoprotein cholesterol decrements were 1.02 (95% CI, 0.96–1.08) and 0.99 (95% CI, 0.95–1.02) for the CERAD and SIS definitions of impairment, respectively. Conclusions: These results suggest that lifelong exposure to low PCSK9 levels and cumulative exposure to lower levels of low-density lipoprotein cholesterol are not associated with neurocognitive effects in blacks.

Pharmacogenetic Associations of β1-Adrenergic Receptor Polymorphisms With Cardiovascular Outcomes in the SPS3 Trial (Secondary Prevention of Small Subcortical Strokes)

Background and Purpose— Functional polymorphisms (Ser49Gly and Arg389Gly) in ADRB1 have been associated with cardiovascular and &bgr;-blocker response outcomes. Herein we examined associations of these polymorphisms with major adverse cardiovascular events (MACE), with and without stratification by &bgr;-blocker treatment in patients with a history of stroke. Methods— Nine hundred and twenty-six participants of the SPS3 trial’s (Secondary Prevention of Small Subcortical Strokes) genetic substudy with hypertension were included. MACE included stroke, myocardial infarction, and all-cause death. Kaplan–Meier and multivariable Cox regression analyses were used. Because the primary component of MACE was ischemic stroke, we tested the association of Ser49Gly with ischemic stroke among 41 475 individuals of European and African ancestry in the NINDS (National Institute of Neurological Disorders and Stroke) SiGN (Stroke Genetics Network). Results— MACE was higher in carriers of the Gly49 allele than in those with the Ser49Ser genotype (10.5% versus 5.4%, log-rank P=0.005). Gly49 carrier status was associated with MACE (hazard ratio, 1.62; 95% confidence interval, 1.00–2.68) and ischemic stroke (hazard ratio, 1.81; 95% confidence interval, 1.01–3.23) in SPS3 and with small artery ischemic stroke (odds ratio, 1.14; 95% confidence interval, 1.03–1.26) in SiGN. In SPS3, &bgr;-blocker-treated Gly49 carriers had increased MACE versus non–&bgr;-blocker-treated individuals and noncarriers (hazard ratio, 2.03; 95% confidence interval, 1.20–3.45). No associations were observed with the Arg389Gly polymorphism. Conclusion— Among individuals with previous small artery ischemic stroke, the ADRB1 Gly49 polymorphism was associated with MACE, particularly small artery ischemic stroke, a risk that may be increased among &bgr;-blocker-treated individuals. Further research is needed to define &bgr;-blocker benefit among ischemic stroke patients by ADRB1 genotype. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00059306.