Search

Introduction: Sphingolipids are fundamental components of brain structure and function. They are located in the myelin sheath insulating neuronal axons and in the cell membranes of neurons, astrocytes, and microglia involved in signal transduction. Although circulating sphingolipid profiles reflect clinical neurodegeneration, few prospective studies have investigated their utility as pre-clinical risk markers in community-based cohorts. For heart disease and diabetes, themselves risk factors for dementia, associations with sphingolipids differed across species and the length of the saturated fatty acid carried. Hypothesis: We hypothesized that plasma levels of sphingolipid species containing palmitic acid (16:0) would be positively associated with incident dementia risk and cognitive decline, while those with arachidic acid (20:0), behenic acid (22:0), and lignoceric acid (24:0) would be associated with lower risk. Methods: We measured 18 sphingolipid species in plasma samples from 4612 participants of the Cardiovascular Health Study (CHS) (mean age 76.2 years; 40% male; and 25% APOE ε4 allele carriers). Cognitive decline was assessed across 6 years using annual 100-point modified Mini-Mental State Examination (3MSE) and Digital Symbol Substitution Test (DSST) scores. A total of 3088 non-demented participants were enrolled in the CHS Cognition Study and followed with adjudication for dementia. To correct the analyses for multiple comparisons, we applied a false discovery rate (FDR) correction and used a significance threshold of 0.05. Results: Higher baseline levels of lactosylceramide-24:0 (LacCer-24) were associated with a faster 6-year cognitive decline (time x sphingolipid interaction p=0.04 for 3MSE and 0.03 for DSST). Conversely, higher baseline plasma levels of hexosylceramide -16:0 (HexCer-16) and sphingomyelin-22:0 (SM-22) were associated with slower cognitive decline measured with DSST (time x sphingolipid interaction p=0.02 for HexCer and p=0.05 for SM-22). During a median follow-up of 4.5 years, we identified 366 incident dementia cases. In proportional Cox regression analyses, higher plasma levels of ceramide-16:0 (Cer-16) were positively associated with incident dementia upon adjustment for demographics, lifestyle factors, medical history, C-reactive protein, and lipids [hazard ratio per SD: 1.18 (95% CI, 1.06; 1.31)]. Conclusions: In older adults without dementia, higher plasma levels of Cer-16, a species previously associated with cardiovascular disease and mortality, were associated with higher risk of clinical dementia as we hypothesized. LacCer-24 was associated with faster, and HexCer-16 and SM-22 with slower, cognitive decline, but these species were not statistically associated with dementia risk. These novel and inconsistent findings will need to be replicated in other longitudinal studies.

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed >24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

Introduction: Stroke is a leading cause of morbidity and mortality in the United States. Identification of individuals at risk for stroke is important for implementation of preventive therapies. Prevalent valvular calcification (VC) has been shown to be associated with stroke but less is known about associations of VC progression with stroke. Methods: Progression (interval increase >0 Agatston units/year) of aortic valvular calcification (AVC) and mitral annular calcification (MAC) was assessed by two cardiac CTs over a median of 2.4 years. We determined the risk of adjudicated total and ischemic stroke using Cox regression adjusted for cardiovascular disease (CVD) risk factors. Results: We studied 5,606 multiethnic participants (39.6% White, 26.9% Black, 21.4% Hispanic, 12.2% Chinese) free of baseline CVD enrolled in MESA. Baseline mean ± SD age was 62 ± 10 years; 53% were women; 12% had prevalent AVC and 9% prevalent MAC at the baseline visit; 83% had no progression of VC, 14%, progression at one site (AVC or MAC), and 3% progression at both sites (AVC and MAC) at follow-up. Over a median of 12 years, 214 total and 170 ischemic strokes occurred. The number of sites with VC progression (range 0-2) was not associated with total and ischemic stroke (all p>0.05). We found MAC progression to be associated with increased risk of total stroke [adjusted hazard ratios (95% CI) 1.59 (1.11 - 2.27)] and ischemic stroke [1.64 (1.10 - 2.43)] in the whole cohort (model 3) and after further adjustment for baseline coronary artery calcification (model 4) ( Table ). Results remained significant for total stroke risk after excluding participants with interim atrial fibrillation or coronary heart disease [1.60 (1.01 - 2.54)]. In women, AVC progression was associated with ischemic stroke [1.87 (1.04 - 3.36)] (p-for-interaction=0.03). Conclusion: Progression of MAC over 2.4 years is associated with increased risk of total and ischemic stroke, and in women, AVC progression with higher ischemic stroke risk.

Introduction: Serum non-esterified fatty acids (NEFAs) have been linked to both local and systemic inflammation and are higher in individuals with obesity, diabetes, cardiovascular disease, and ischemic stroke risk. Significant associations between total plasma NEFA concentrations and incident ischemic stroke have been reported in some but not all prospective studies. Given the functional and structural diversity among circulating NEFA, the associations of individual or clusters of circulating NEFAs may provide additional insight into their relationship with incident stroke. Hypothesis: Fasting serum n-3 NEFAs are inversely associated, and saturated and trans NEFAs are positively associated with incident stroke. Methods: We analyzed the incidence of stroke among Cardiovascular Health Study (CHS) participants who were free of stroke in 1996-1997 and underwent fasting NEFA profile measurement. At baseline, mean age was 77.8±4.5, body mass index was 26.7±4.4 and 61% were female. A total of 38 individual NEFAs in 5 classes (saturated, monounsaturated, polyunsaturated n-6, polyunsaturated n-3 and trans NEFAs) were measured using gas chromatography. Cox regression was used to evaluate the association of individual NEFA species with incident stroke, adjusting for: age, sex, race, and field center (model 1); model 1 covariates plus smoking, education, physical activity, alcohol consumption, eGFR, BMI, aspirin use, waist circumference, hypertension, prevalent diabetes, and cholesterol (model 2). Results: A total of 338 cases of incident stroke occurred during median follow-up of 10.5 years. In the fully adjusted model, trans -palmitoleic acid was inversely associated with incident stroke (HR per 1 mol% of NEFA composition: 0.03 [95% CI: 0.00 to 0.77], P P Conclusion: Among fasting serum NEFA, docosahexaenoic acid and trans -palmitoleic acid were inversely associated with incident stroke, suggesting that these fatty acids may protect older adults from stroke.

Objective: We investigated two hypotheses: First, incident CHD, defined as myocardial infarction or definite angina, leads to faster long-term cognitive decline. Second, among those with CHD, treatment with CABG surgery or PCI leads to slower long-term cognitive decline. Methods: The Cardiovascular Health Study is a cohort of US adults aged 65+. Global cognitive ability was assessed annually up to 9 times from 1990 to 1998 with the 100-point Modified Mini-Mental State Examination (3MS). We estimated trajectories of 3MS scores in the absence of stroke, adjusting for demographics, health behaviors, and comorbidities. For hypothesis 1, we compared 3MS trajectory after incident CHD with 3MS trajectory in the absence of CHD, censoring at first receipt of CABG/PCI. For hypothesis 2, among participants with CHD, we compared 3MS trajectory after first receipt of CABG/PCI with 3MS trajectory without CABG/PCI. Results: For hypothesis 1, of 4,122 participants, 398 had incident CHD during a mean of 5.9 years of follow-up. Figure Panel A shows model-predicted mean 3MS trajectories without CHD (blue) and after incident CHD (red) diagnosed at ages 70, 75, 80, or 85. Model-predicted 3MS score declined faster after incident CHD, especially for CHD diagnosed at age 80 or later. For example, after incident CHD at age 85, predicted 5-year decline in mean 3MS score through age 90 was 13.9 points (95% CI: 11.0, 16.7) versus 8.9 points (95% CI: 8.1, 9.7) among those without CHD. For hypothesis 2, of 1,183 participants who had prevalent or incident CHD, 118 had their first CABG/PCI during a mean of 4.1 years of follow-up. Model-predicted 3MS score declined faster after first receipt of CABG/PCI ( Figure Panel B ). Conclusions: Older adults diagnosed with incident CHD had faster average cognitive decline than those without CHD. However, treatment with CABG/PCI did not slow cognitive decline among those with CHD. This finding may be due to adverse effects of CABG/PCI on brain health or CABG/PCI recipients having more severe CHD or more cerebral atherosclerosis.

Introduction: Alcohol intake has been related with a complex group of associations with brain structure in cross-sectional analyses, but to our knowledge, its prospective relationship with structural brain abnormalities detected by MRI has never been reported. Hypothesis: We hypothesized that consumers of 1- Methods: As part of the Cardiovascular Health Study, 1 996 adults aged ≥65 years underwent MRI scanning in 1991-94 and again in 1997-99, having excluded 120 participants with a history of cerebrovascular disease before the initial scan. Alcohol consumption was assessed at each annual visit by self-reported intake of wine, beer and liquor. A 10-point white matter grade (WMG) and ventricular grade (VG) were assessed in a standardized and blinded manner in both scans; hippocampal and total brain volumes were also quantified on the second scan. We estimated the associations of alcohol intake in categories (as reported closest to the date of initial scan), with MRI findings at follow-up with multinomial ordered logistic regression (WMG ≤ 3 ref and ≥ 4; VG ≤ 3 ref , =4 and ≥5) using inverse probability weighting to account for attrition. Results: We observed a U-shaped association with WMG, with significantly lower risk among participants consuming 1-quadtrend = 0.01). For VG, the association was inverse (P trend = 0.06), with significantly less progression among drinkers of 1- Conclusions: Compared with long-term abstention, consumption of 1

Introduction: As many as 20-50% of persons with chronic kidney disease have mild-to-moderate cognitive impairment or overt dementia. Shared risk factors, such as aging, sex, hypertension, and diabetes have been suggested to play a role in this association. Our objective was to examine the contribution of non-modifiable and modifiable risk factors to this association. Hypothesis: We hypothesize that non-modifiable and modifiable risk factors could explain part, but not all, of the association between worse kidney function with incidence of dementia. Methods: We included 6025 CVD free participants (mean age 62 yrs, 51% women, 38% white). Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Participants were followed for an average of 12±4 yrs for dementia ICD code hospitalization. Multiple Cox regression models, adjusted for baseline non-modifiable (age, sex, race, and APOE4 carriership) and modifiable risk factors (BMI, smoking, SBP, diabetes, cholesterol, alcohol intake, education, physical activity, and healthy diet score) were used to estimate the association of worse kidney function with incidence of dementia hospitalization. Results: During follow-up, 268 (4.4%) participants were hospitalized for dementia. Non-modifiable risk factors vs. modifiable risk factors were associated with greater reduction in HRs from a crude model for association between each SD lower eGFR and risk of dementia (70% vs. 8%). Non-modifiable risk factors explained a higher percentage of the association of doubling ACR with risk of dementia than modifiable risk factors (14% vs. 7%) (Figure). Adjusting for all factors, worse kidney function remained associated with incident dementia. Conclusions: Findings suggest that conventional modifiable and non-modifiable risk factors cannot fully explain higher risk of dementia in relation to worse kidney function. This finding warrants exploring other potential novel vascular and nonvascular mechanisms of this association.

Objective: The AHA Life’s Simple 7 (LS7) defines cardiovascular health with smoking, physical activity, diet quality, body mass index (BMI), blood pressure, total cholesterol, and blood glucose. We examined changes in LS7 score and its components in older adults over seven years of follow-up. Methods: We analyzed 2,234 adults aged 65+ in the Cardiovascular Health Study who had all LS7 components measured at baseline (1989) and seven years later (1996). We scored each component as ideal (2), intermediate (1), or poor (0). LS7 score was the sum of components, ranging from 0 (worst) to 14 (best), then categorized as ideal (10-14), intermediate (5-9), or poor (0-4). Results: Mean LS7 score at baseline was 8.71, declining by 0.24 points (95% CI: 0.17, 0.31) to 8.47 seven years later. At baseline, LS7 score was ideal in 35% of participants, intermediate in 63%, and poor in 1.7%. Seven years later, the distribution shifted down, with 31% scoring ideal, 67% scoring intermediate, and 2.0% scoring poor. Of those scoring ideal at baseline, 57% (95% CI: 53%, 60%) maintained ideal scores seven years later (Figure, Panel A). Of those scoring intermediate at baseline (Panel B), 18% (95% CI: 16%, 20%) improved to ideal. Of those scoring poor at baseline (Panel C), 76% (95% CI: 63%, 90%) improved to intermediate, but none improved to ideal. For components, maintenance of baseline ideal status was 95% for smoking, 86% for glucose, 80% for BMI, 77% for cholesterol, and 55% for physical activity, but only 35% for blood pressure and 7% for diet (Panel A). Decline of baseline intermediate status to poor was 33% for blood pressure and 24% for diet (Panel B). Improvement of baseline poor status to intermediate or ideal was >50% for cholesterol and physical activity and >40% for smoking and diet (Panel C). Conclusions: While cardiovascular health declined on average in an aging population, some older adults improved their cardiovascular health as they aged. Declines in diet quality and blood pressure control contributed to overall declines in cardiovascular health.

Objective: The AHA Life’s Simple 7 (LS7) defines cardiovascular health with smoking, physical activity, diet quality, body mass index (BMI), blood pressure, total cholesterol, and blood glucose. We examined associations of LS7 score and its components with cognitive decline in older adults. Methods: The Cardiovascular Heart Study is a longitudinal cohort of 5,888 adults aged 65 and above. We analyzed 4,165 who had LS7 score measured at baseline (1989), complete covariate data, and at least one Modified Mini-Mental State Examination (3MS) score during follow-up (through 1998). We scored each LS7 component as ideal (2), intermediate (1), or poor (0), summed all components to a total LS7 score ranging from 0 (worst) to 14 (best), and categorized total LS7 score as ideal (10-14), intermediate (5-9), or poor (0-4). 3MS is a measure of global cognition ranging from 0 (worst) to 100 (best) and was obtained annually during a mean follow-up of 6.8 years. Using linear mixed models, we estimated associations of LS7 score and its components with annual rate of cognitive decline, adjusted for demographic, behavioral, and clinical factors. Results: In adjusted models, mean annual decline in 3MS score was 0.83 points (95% CI: 0.61, 1.04) for those with poor LS7 scores at baseline, 0.63 points (95% CI: 0.59, 0.67) with intermediate scores, and 0.42 points (95% CI: 0.37, 0.47) with ideal scores (p < 0.0001 for difference in mean annual decline across LS7 categories). Better physical activity, diet quality, blood pressure control, and blood glucose control were all associated with slower cognitive decline (Table). BMI, however, was opposite, with obesity (poor) associated with slower decline, and normal weight (ideal) associated with faster decline (p Conclusions: Better cardiovascular health measured by LS7 in old age is associated with slower average cognitive decline. The role of BMI as a component of LS7 in older adults may warrant reconsideration, as lower BMI in late-life may represent frailty and increased risk for cognitive decline.

Background: Plasma free fatty acids (FFAs) are a byproduct of lipolysis largely derived from adipose tissue. High plasma FFA levels have toxic effects on a variety of organs central to cardiometabolic disease. Whether FFAs associates with cognitive decline or dementia remains unknown. Objective: To assess the association of plasma FFAs with risk of cognitive decline and dementia. Methods: Plasma FFAs were measured in participant samples from the 1992-1993 study visit of the Cardiovascular Health Study (CHS) (mean age 74 yrs; 59% female; 14% African American [AA]; 24% APOE4 carriers). A total of 3,242 non-demented participants were followed with adjudication for dementia through 1998-1999 (n=456 cases). In addition, cognitive decline was assessed annually among all CHS participants using the 100-point modified Mini-Mental State examination (3MSE; n=4,417) and the Digital Symbol Substitution Test (DSST; n=4,254). Results: Higher plasma FFAs levels were positively associated with risk of dementia (Figure: Log-rank p-value=0.04). In Cox regression analysis adjusted for demographics, FFAs remained associated with risk of dementia (HR per SD [0.20 mEq/L] =1.10; 95% CI, 1.00-1.22). In fully adjusted models that included lifestyle factors, medical history, C-reactive protein, LDL-C, HDL-C, and 3MSE at baseline, the hazard ratio per SD was 1.13 (1.01-1.26), with a particularly strong association observed among AA participants (HR=1.49 [1.10-2.01], p interaction=0.08). FFA levels did not differ by APOE genotype, and adjustment for genotype did not influence results. FFA levels from the baseline visit were also associated with a decline in both cognitive assessments over 6 years of follow-up, with significant time x FFA interactions (p=0.04 for 3MSE and p=0.002 for DSST). We observed no interactions with APOE genotype or race for cognitive outcomes. Conclusions: In non-demented older men and women, higher plasma FFA levels are associated with faster cognitive decline and higher risk of dementia over the subsequent years.

The contributors to this statement were selected to ensure expertise in all the disciplines relevant to post–cardiac arrest care. In an attempt to make this document universally applicable and generalizable, the authorship comprised clinicians and scientists who represent many specialties in many regions of the world. Several major professional groups whose practice is relevant to post–cardiac arrest care were asked and agreed to provide representative contributors. Planning and invitations took place initially by e-mail, followed a series of telephone conferences and face-to-face meetings of the cochairs and writing group members. International writing teams were formed to generate the content of each section, which corresponded to the major subheadings of the final document. Two team leaders from different countries led each writing team. Individual contributors were assigned by the writing group cochairs to work on 1 or more writing teams, which generally reflected their areas of expertise. Relevant articles were identified with PubMed, EMBASE, and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Drafts of each section were written and agreed on by the writing team authors and then sent to the cochairs for editing and amalgamation into a single document. The first draft of the complete document was circulated among writing team leaders for initial comment and editing. A revised version of the document was circulated among all contributors, and consensus was achieved before submission of the final version for independent peer review and approval for publication. This scientific statement outlines current understanding and identifies knowledge gaps in the pathophysiology, treatment, and prognosis of patients who regain spontaneous circulation after cardiac arrest. The purpose is to provide a resource for optimization of post–cardiac arrest care and to pinpoint the need for research focused on gaps in knowledge that would potentially improve outcomes …

Background— Although guidelines suggest that older adults engage in regular physical activity (PA) to reduce cardiovascular disease (CVD), surprisingly few studies have evaluated this relationship, especially in those >75 years. In addition, with advancing age the ability to perform some types of PA might decrease, making light-moderate exercise such as walking especially important to meet recommendations. Methods and Results— Prospective cohort analysis among 4207 US men and women of a mean age of 73 years (standard deviation=6) who were free of CVD at baseline in the Cardiovascular Health Study were followed from 1989 to 1999. PA was assessed and cumulatively updated over time to minimize misclassification and assess the long-term effects of habitual activity. Walking (pace, blocks, combined walking score) was updated annually from baseline through 1999. Leisure-time activity and exercise intensity were updated at baseline, 1992, and 1996. Incident CVD (fatal or nonfatal myocardial infarction, coronary death, or stroke) was adjudicated using medical records. During 41 995 person-years of follow-up, 1182 CVD events occurred. After multivariable adjustment, greater PA was inversely associated with coronary heart disease, stroke (especially ischemic stroke), and total CVD, even in those ≥75 years. Walking pace, distance, and overall walking score, leisure-time activity, and exercise intensity were each associated with lower risk. For example, in comparison with a walking pace 3 mph had a lower risk of coronary heart disease (0.50; confidence interval, 0.38–0.67), stroke (0.47; confidence interval, 033–0.66), and CVD (0.50; confidence interval, 0.40–0.62). Conclusions— These data provide empirical evidence supporting PA recommendations, in particular, walking, to reduce the incidence of CVD among older adults.

OBJECTIVE: To determine whether older adults who develop incident heart failure (HF) experience faster cognitive decline than those without HF. METHODS: We analyzed longitudinal cognitive test data from the Cardiovascular Health Study, a community-based study of adults aged 65 years and older. Participants in this analysis did not have HF or history of stroke at baseline and were censored when they experienced incident clinical stroke. Incident HF was identified by self-report of physician-diagnosed HF and confirmed by adjudicated review of inpatient and outpatient medical records and medication use. Outcomes were mean score and rate of decline in mean score on the 100-point Modified Mini-Mental State Examination (3MSE), administered annually up to nine times from 1990 to 1998. A linear mixed effects model was used to model the relationship of cognitive decline with HF and age, adjusted for demographics, health behaviors, and comorbid conditions including hypertension and diabetes. RESULTS: Analyses included 5,211 participants with mean age 74 years at baseline, of whom 545 (10.5%) developed incident HF over a median follow-up of 7.8 years. Mean 3MSE score was lower at the time of HF diagnosis compared with no HF, and declined faster after incident HF compared with no HF. For example, at age 80, covariate-adjusted predicted mean 3MSE score was 88.6 points (95% CI: 88.3, 89.0) in participants without HF, but 87.6 points (95% CI: 87.3, 87.9) in those with newly diagnosed HF. Predicted five-year decline in mean 3MSE score from age 80 to age 85 was 5.9 points (95% CI: 5.7, 6.0) in participants without HF, but 10.0 points (95% CI: 8.6, 11.3) in those diagnosed with incident HF at age 80. Faster decline in 3MSE score after HF diagnosis was seen at all ages studied. The figure shows predicted mean 3MSE score trajectories without HF (solid line) and after HF diagnosed at ages 70, 75, 80, and 85 (dashed lines), with 95% CI shaded. CONCLUSIONS: Older adults diagnosed with incident HF experience faster average cognitive decline than those without HF.

Background— Recent clinical studies have demonstrated that mild hypothermia (32°C to 34°C) induced by surface cooling improves neurological outcome after resuscitation from out-of-hospital cardiac arrest. Results from animal models suggest that the effectiveness of mild hypothermia could be improved if initiated as soon as possible after return of spontaneous circulation. Infusion of cold, intravenous fluid has been proposed as a safe, effective, and inexpensive technique to induce mild hypothermia after cardiac arrest. Methods and Results— In 17 hospitalized survivors of out-of-hospital cardiac arrest, we determined the effect on temperature and hemodynamics of infusing 2 L of 4°C cold, normal saline during 20 to 30 minutes into a peripheral vein with a high-pressure bag. Data on vital signs, electrolytes, arterial blood gases, and coagulation were collected before and after fluid infusion. Cardiac function was assessed by transthoracic echocardiography before fluid administration and 1 hour after infusion. Passive (fans, leaving patient uncovered) or active (cooling blankets, neuromuscular blockade) cooling measures were used to maintain mild hypothermia for 24 hours. Infusion of 2 L of 4°C cold, normal saline resulted in a mean temperature drop of 1.4°C 30 minutes after the initiation of infusion. Rapid infusion of fluid was not associated with clinically important changes in vital signs, electrolytes, arterial blood gases, or coagulation parameters. The initial mean ejection fraction was 34%, and fluid infusion did not affect ejection fraction or increase central venous pressure, pulmonary pressures, or left atrial filling pressures as assessed by echocardiography. Passive measures were ineffective in maintaining hypothermia compared with active measures. Conclusions— Infusion of 2 L of 4°C cold, normal saline is safe and effective in rapidly lowering body temperature in survivors of out-of-hospital cardiac arrest.

Introduction: Recent reports have linked visit-to-visit blood pressure (BP) variability to risk of mortality and stroke, independent of the effect of mean BP level. We sought to confirm these findings in the Cardiovascular Health Study (CHS), a cohort study of cardiovascular risk factors. Hypothesis: Variability in visit-to-visit SBP, defined as intraindividual SBP SD, is directly associated with risk of mortality, myocardial infarction (MI), and stroke, independent of intraindividual SBP mean and trend over time. Methods: Participants from CHS were eligible if they attended their first five annual clinic visits and did not have stroke, MI, or death by the 5th visit (N=3513). Follow-up started at the 5th visit and extended through June 2008. Analyses were further restricted to subjects who used no antihypertensive medications during the entire 5-year baseline period (non-users, n=1570) and subjects who used the same antihypertensive regimen during that time (users, n=978). Intraindividual SBP variables were defined using each subject’s 5-visit BPs. Cox proportional hazards models estimated adjusted hazard ratios (HR) per standard deviation (SD) increase in intraindividual SD (iSD) SBP or intraindividual mean (iMean) SBP. Results were stratified on medication use or non-use. Results: Participants’ mean age was 71 years, 42% were men, and 95% were white. Mean(SD) of iSD SBP was 9.8(4.6) mmHg for anti-hypertensive medications non-users and 12.0(6.0) mmHg for users. iMean SBP was significantly associated with all 3 outcomes among non-users and with stroke among users (table). iSD SBP was significantly associated with mortality in all participants and with MI among non-users; associations for stroke were not significant. Conclusion: Long-term visit-to-visit SBP variability may be an important determinant of MI and mortality risk in the elderly. Results for stroke are not consistent with other, previous reports. More research is needed to determine the clinical implications.

Objective. We sought to determine among people whose initial atrial fibrillation (AF) terminated whether use of statins, beta-blockers, and ACE inhibitors or ARBs was associated with lower risk of recurrent AF or progression to permanent AF. Methods. In Group Health, an integrated health care system, we identified an inception cohort of people aged 30-84 with newly diagnosed AF in 2001-2004 whose initial AF terminated within six months. Follow-up was through 2009. Medication use throughout follow-up was determined from the pharmacy database. Recurrent AF and permanent AF were determined from medical records and ECG and procedure code databases. Permanent AF was defined as AF present on two dates at least six months apart with no evidence of sinus rhythm in between. Cox proportional hazards models were used to estimate hazard ratios. We compared current statin use with nonuse. To reduce healthy user bias, we compared statin use one year prior with nonuse one year prior. To reduce confounding by indication, we compared beta-blocker use with nondihydropyridine calcium channel blocker use. We compared current ACE inhibitor or ARB use with nonuse. Results. Analyses included 1,511 people. Mean age was 70 years and 51% were men. Statins were used for 36% of person-time, beta-blockers for 48%, and ACE inhibitors or ARBs for 42%. Five-year cumulative incidence of recurrent AF was 74% and of permanent AF was 24%. Current statin use vs. nonuse was associated with lower permanent AF risk. However, statin use vs. nonuse one year prior was not associated with permanent AF ( Table ). Use of beta-blockers and ACE inhibitors or ARBs was not associated with recurrent AF or permanent AF. Adjusted hazard ratios of recurrent AF and permanent AF according to medication use. Medication use Recurrent AF Adjusted HR * (95% CI) Permanent AF Adjusted HR * (95% CI) Statins -- current use analysis Nonuse 1.00 (reference) 1.00 (reference) Current use 0.96 (0.82, 1.12) 0.76 (0.58, 0.99) Statins -- lagged analysis Nonuse one year prior 1.00 (reference) 1.00 (reference) Use one year prior 0.94 (0.79, 1.13) 0.98 (0.74, 1.30) Beta-blockers Current nondihydropyridine CCB use 1.00 (reference) 1.00 (reference) Current beta-blocker use 0.91 (0.74, 1.12) 1.04 (0.69, 1.56) ACE inhibitors or ARBs Nonuse 1.00 (reference) 1.00 (reference) Current use 0.99 (0.86, 1.14) 0.98 (0.77, 1.25) * Adjusted for age, sex, BMI, diabetes, hypertension, coronary heart disease, valvular heart disease, heart failure, prior stroke, and chronic kidney disease. Conclusion. The lagged statin analysis suggests that the association of current statin use with lower permanent AF risk may have been due to an acute effect of statins that did not persist after discontinuation of use, or to a healthy user bias. We found little evidence that use of statins, beta-blockers, or ACE inhibitors or ARBs reduces risk of recurrent AF or permanent AF.

Objective. We sought to determine whether atrial fibrillation (AF) was associated with cognitive decline in the absence of stroke. Methods. We included Cardiovascular Health Study participants aged 65+ who did not have AF or prior stroke at baseline and had at least one Modified Mini-Mental State Examination (3MSE) during the study. AF was identified by hospital discharge diagnoses and annual study ECGs. The 3MSE (score range 0–100) was administered annually up to nine times from 1990/91 to 1998/99. Mixed effects linear regression was used to characterize the relationship of cognitive decline with AF and age, adjusted for birth year, sex, race, education, smoking, alcohol use, diabetes, hypertension, systolic blood pressure, coronary heart disease, and heart failure. Interaction terms for AF and age variables with incident clinical stroke were used to allow estimation of cognitive decline in the absence of stroke. Results. Analyses included 5,199 participants with a mean of 6.7 3MSE scores. During follow-up 11% of participants (554 of 5,199) had AF identified. Panel A of the Figure shows mean 3MSE score trajectories for participants without AF (solid line) and after AF was identified at ages 70, 75, 80, and 85 (dashed lines). Panel B shows the trajectory for participants without AF set to zero (solid horizontal line) and differences in mean trajectories after AF was identified relative to participants without AF (dashed lines). Gray shading shows 95% CIs. Having newly-identified AF was not associated with a difference in 3MSE score relative to participants of the same age without AF. However, after AF was identified, 3MSE scores declined 2.3 points faster per five years, relative to participants without AF. For example, after AF was identified at age 80, mean 3MSE score declined 9.1 points by age 85, versus 6.8 points for participants without AF. Conclusions. In older adults without clinical stroke, the average rate of cognitive decline was greater after AF was identified.

BACKGROUND In selecting patients with acute myocardial infarction for thrombolytic therapy, it is important to identify patients who are at high risk for intracranial hemorrhage, for whom thrombolytic therapy is ill advised. We hypothesized that presenting pulse blood pressure, representing the "hammer" effect on cerebral vessels and the effects of age on arterial compliance, might predict thrombolysis-related intracranial hemorrhage better than systolic, diastolic, or mean arterial blood pressures. METHODS AND RESULTS Of 3483 Thrombolytic Predictive Instrument (TPI) Project subjects receiving thrombolytic therapy for acute infarction, we identified and obtained detailed clinical data on the 19 with treatment-related intracranial hemorrhages confirmed by computed tomography and on 175 matched controls. Systolic, diastolic, mean arterial, and pulse blood pressures were each significantly related to the occurrence of intracranial hemorrhage, with pulse pressure most highly related. The mean pulse pressure in patients who developed intracranial hemorrhage was 63 mm Hg, 34% higher than the 47 mm Hg mean value for those not developing hemorrhage (P = .0001). Excess pulse pressure, defined as the extent to which a patient's pulse pressure exceeded 40 mm Hg for systolic blood pressures of at least 120 mm Hg, was even more strongly related: its mean value of 23 mm Hg for patients was 130% higher than its mean value of 10 mm Hg for controls (P < .0001). With logistic regression models to estimate the relative risks (odds ratios) for intracranial hemorrhage conferred by each form of blood pressure, the relative risk for hemorrhage was greatest for excess pulse pressure: for each 10-point pulse pressure excess, the relative risk for intracranial hemorrhage was increased by 1.85 (P = .0002; 95% confidence interval [CI], 1.34 to 2.55) by itself and 1.76 (P = .001; 95% CI, 1.26 to 2.46) when adjusted for age. In this sample, excess pulse pressure by itself predicted hemorrhage as well as systolic pressure and age together. When excess pulse pressure was combined with age to make a logistic regression model predicting intracranial hemorrhage, age contributed less to the prediction than when combined with the other blood pressure forms, even though this model predicted better than any other combination of age and pressure (receiver-operating characteristic curve area, 0.82 versus 0.77 with systolic pressure and age, 0.75 with mean arterial pressure, 0.71 with diastolic pressure, and 0.81 with both systolic and diastolic pressures). CONCLUSIONS We found that excess pulse blood pressure predicted thrombolysis-related intracranial hemorrhage better than other forms of pretreatment blood pressure, perhaps better describing the pathophysiology of intracranial hemorrhage, including the effect of age. These findings will need confirmation in larger studies with comparable clinical detail.

Background— Although delayed hospital cooling has been demonstrated to improve outcome after cardiac arrest, in-field cooling started immediately after the return of spontaneous circulation may be more beneficial. The aims of the present pilot study were to assess the feasibility, safety, and effectiveness of in-field cooling. Methods and Results— We determined the effect on esophageal temperature, before hospital arrival, of infusing up to 2 L of 4°C normal saline as soon as possible after resuscitation from out-of-hospital cardiac arrest. A total of 125 such patients were randomized to receive standard care with or without intravenous cooling. Of the 63 patients randomized to cooling, 49 (78%) received an infusion of 500 to 2000 mL of 4°C normal saline before hospital arrival. These 63 patients experienced a mean temperature decrease of 1.24±1°C with a hospital arrival temperature of 34.7°C, whereas the 62 patients not randomized to cooling experienced a mean temperature increase of 0.10±0.94°C ( P Conclusions— These pilot data suggest that infusion of up to 2 L of 4°C normal saline in the field is feasible, safe, and effective in lowering temperature. We propose that the effect of this cooling method on neurological outcome after cardiac arrest be studied in larger numbers of patients, especially those whose initial rhythm is ventricular fibrillation.

Background —Limited information exists on risk factors for mortality after thrombolysis-related intracranial hemorrhage. We wished to determine the characteristics associated with 30-day mortality after thrombolysis-related intracranial hemorrhage. Methods and Results —We performed an observational analysis within a randomized trial of 4 thrombolytic therapies, conducted in 1081 hospitals in 15 countries. Patients presented with ST-segment elevation within 6 hours of symptom onset. Our population was composed of the 268 patients who had primary intracranial hemorrhage after thrombolysis. With univariable and multivariable analyses, we identified clinical and brain imaging characteristics that would predict 30-day mortality among these patients. CT or MRI were available for 240 patients (90%). The 30-day mortality rate was 59.7%. Glasgow Coma Scale score, age, time from thrombolysis to symptoms of intracranial hemorrhage, hydrocephalus, herniation, mass effect, intraventricular extension, and volume and location of intracranial hemorrhage were significant univariable predictors. Multivariable analysis of 170 patients with complete data, 98 of whom died, identified the following independent, significant predictors: Glasgow Coma Scale score (χ 2 , 19.3; P 2 , 15.8; P 2 , 11.6; P 2 , 10.3; P =0.001). The final model had a C-index of 0.931. Conclusions —This model provides excellent discrimination between patients who are likely to live and those who are likely to die after thrombolytic-related intracranial hemorrhage; this may aid in making decisions about the appropriate level of care for such patients.

Background In a population-based study, we examined the relationship between the risk of myocardial infarction (MI) among young women and plasma total homocysteine (tHCY), folate, vitamin B 12 , and a common cytosine (C) to thymine (T) polymorphism in the gene for 5,10-methylenetetrahydrofolate reductase (MTHFR). Methods and Results In-person interviews and nonfasting blood samples were obtained from 79 women P =.0004) and lower mean folate concentrations (12.4±13.4 versus 16.1±12.2 nmol/L, P =.018). There was no difference in vitamin B 12 concentrations between case patients and control subjects (346.8±188.4 versus 349.7±132.4 pmol/L, P =.90). After adjusting for cardiovascular risk factors, we found that women with tHCY ≥15.6 μmol/L were at approximately twice the risk of MI as women with tHCY 12 concentration. Among control subjects, 12.7% were homozygous for the MTHFR T 677 allele, and these women had higher plasma tHCY and lower plasma folate than women with other genotypes. Ten percent of case patients were homozygous for te T 677 allele, and there was no association of homozygosity for T 677 with MI risk (OR, 0.90; 95% CI, 0.31 to 2.29). Conclusions These data support the hypothesis that elevated plasma tHCY and low plasma folate are risk factors for MI among young women. Although homozygosity for MTHFR T 677 is related to increased plasma tHCY and low plasma folate, this genetic characteristic is not a risk factor for MI in this population.