Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

Parasympathetic neural activity and the reciprocal regulation of innate antiviral and inflammatory genes in the human immune system.

The vagus nerve mediates parasympathetic nervous system control of peripheral physiological processes including cardiovascular activity and immune response. In mice, tonic vagal activation down-regulates inflammation via nicotinic acetylcholine receptor-mediated inhibition of the pro-inflammatory transcription factor NF-κB in monocyte/macrophages. Because Type I interferon and pro-inflammatory genes are regulated reciprocally at the level of transcription factor activation and cell differentiation, we hypothesized that vagal activity would up-regulate Type I interferon response genes concurrently with inflammatory downregulation in human immune cells. We mapped empirical individual differences in the circulating leukocyte transcriptome and vagal activity indexed by high frequency (0.15-0.40 Hz) heart rate variability (HF-HRV) in 380 participants in the Midlife in the US study. Here we show that promoter-based bioinformatics analyses linked greater HF-HRV to reduced NF-κB activity and increased activity of IRF transcription factors involved in Type I interferon response (independent of ß-antagonists, BMI, smoking, heavy alcohol consumption, and demographic factors). Transcript origin analyses implicated myeloid lineage immune cells as targets, representing per-cell alterations in gene transcription as HF-HRV was not associated with differential prevalence of leukocyte subsets. These findings support the concept of parasympathetic inhibition of pro-inflammatory gene expression in humans and up-regulation of Type I interferons that could augment host defense against viral infections.

Aerobic Exercise Training and Inducible Inflammation: Results of a Randomized Controlled Trial in Healthy, Young Adults.

Background Consensus panels regularly recommend aerobic exercise for its health-promoting properties, due in part to presumed anti-inflammatory effects, but many studies show no such effect, possibly related to study differences in participants, interventions, inflammatory markers, and statistical approaches. This variability makes an unequivocal determination of the anti-inflammatory effects of aerobic training elusive. Methods and Results We conducted a randomized controlled trial of 12 weeks of aerobic exercise training or a wait list control condition followed by 4 weeks of sedentary deconditioning on lipopolysaccharide (0, 0.1, and 1.0 ng/mL)-inducible tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and on toll-like receptor 4 in 119 healthy, sedentary young adults. Aerobic capacity by cardiopulmonary exercise testing was measured at study entry (T1) and after training (T2) and deconditioning (T3). Despite a 15% increase in maximal oxygen consumption, there were no changes in inflammatory markers. Additional analyses revealed a differential longitudinal aerobic exercise training effect by lipopolysaccharide level in inducible TNF -α ( P=0.08) and IL-6 ( P=0.011), showing T1 to T2 increases rather than decreases in inducible (lipopolysaccharide 0.1, 1.0 versus 0.0 ng/mL) TNF- α (51% increase, P=0.041) and IL-6 (42% increase, P=0.11), and significant T2 to T3 decreases in inducible TNF- α (54% decrease, P=0.007) and IL-6 (55% decrease, P<0.001). There were no significant changes in either group at the 0.0 ng/mL lipopolysaccharide level for TNF- α or IL-6. Conclusions The failure to support the primary hypotheses and the unexpected post hoc findings of an exercise-training-induced proinflammatory response raise questions about whether and under what conditions exercise training has anti-inflammatory effects. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01335737.

The Association of Cigarette Smoking With High-Frequency Heart Rate Variability: An Ecological Momentary Assessment Study.

OBJECTIVE: Evidence from both laboratory and observational studies suggests that acute and chronic smoking leads to reduced high-frequency heart rate variability (HF-HRV), a measure of cardiac vagal regulation. We used ecological momentary assessment (EMA) to study the effect of smoking on concurrent HF-HRV in a trial measuring the effects of hostility reduction and compared 24-hour HF-HRV in smokers and nonsmokers. METHOD: Ambulatory electrocardiogram data were collected before randomization from 149 healthy individuals with high hostility levels (20-45 years, body mass index ≤ 32 kg/m) and paired with concurrent EMA ratings of smoking and physical position during waking hours. A multilevel mixed model was estimated associating ln(HF-HRV) from smoking status (between-person factor) and person-centered momentary smoking (within-person factor, treated as a random effect), adjusting for momentary physical position, medication use, and consumption of alcohol and caffeine. RESULTS: Thirty-five smokers and 114 nonsmokers provided both EMA and HF-HRV data. Within smokers, ln HF-HRV was reduced by 0.31 millisecond (p = .04) when participants reported having recently smoked cigarettes, compared with when they had not. The 24-hour HF-HRV was significantly lower in smokers (M [SD] = 5.24 [0.14] milliseconds) than nonsmokers (5.63 ± 0.07 milliseconds, p = .01). CONCLUSIONS: In healthy smokers with high hostility levels used as their own controls during daily living, smoking acutely reduced HF-HRV. HF-HRV was also reduced in smokers as compared with nonsmokers. Although limited by a small sample of individuals with high hostility levels, these findings nonetheless provide additional evidence that cardiac vagal regulation is lowered by cigarette smoking, which may be one of the numerous pathophysiological effects of smoking.

Linking Daily Stress Processes and Laboratory-Based Heart Rate Variability in a National Sample of Midlife and Older Adults.

OBJECTIVE: This study evaluates the associations between people's trait-like patterns of stress in daily life (stressor frequency, perceived stressor severity, affective reactivity to stressors, and negative affect) and laboratory-assessed heart rate variability (HRV). METHODS: Data were collected from 909 participants aged 35 to 85 years in the Midlife in the United States Study. Participants reported negative affect and minor stressful events during telephone interviews on 8 consecutive evenings. On a separate occasion, HRV was measured from electrocardiograph recordings taken at rest during a laboratory-based psychophysiology protocol. Regression models were used to evaluate the associations between daily stress processes and three log-transformed HRV indices: standard deviation of R-R intervals (SDRR), root mean square of successive differences (RMSSD), and high-frequency power (high-frequency HRV [HF-HRV]). Analyses were adjusted for demographics, body mass index, comorbid conditions, medications, physical activity, and smoking. RESULTS: Stressor frequency was unrelated to HRV (r values ranging from -0.04 to -0.01, p values >.20). However, people with greater perceived stressor severity had lower resting SDRR (fully adjusted B [standard error {SE}] = -0.05 [0.02]), RMSSD (-0.08 [0.03]), and HF-HRV (-0.16 [0.07]). Individuals with more pronounced affective reactivity to stressors also had lower levels of all three HRV indices (SDRR: B [SE] = -0.28 [0.14]; RMSSD: -0.44 [0.19]; HF-HRV: -0.96 [0.37]). Furthermore, aggregated daily negative affect was linked to reduced RMSSD (B [SE] = -0.16 [0.08]) and HF-HRV (-0.35 [0.15]). CONCLUSIONS: In a national sample, individual differences in daily negative affect and responses to daily stressors were more strongly related to cardiovascular autonomic regulation than the frequency of such stressors.

Heart rate variability predicts levels of inflammatory markers: Evidence for the vagal anti-inflammatory pathway.

Evidence from numerous animal models shows that vagal activity regulates inflammatory responses by decreasing cytokine release. Heart rate variability (HRV) is a reliable index of cardiac vagal regulation and should be inversely related to levels of inflammatory markers. Inflammation is also regulated by sympathetic inputs, but only one previous paper controlled for this. In a larger and more representative sample, we sought to replicate those results and examine potential sex differences in the relationship between HRV and inflammatory markers. Using data from the MIDUS II study, we analyzed the relationship between 6 inflammatory markers and both HF-HRV and LF-HRV. After controlling for sympathetic effects measured by urinary norepinephrine as well as a host of other factors, LF-HRV was found to be inversely associated with fibrinogen, CRP and IL-6, while HF-HRV was inversely associated with fibrinogen and CRP. We did not observe consistent sex differences. These results support the existence of the vagal anti-inflammatory pathway and suggest that it has similar effects in men and women.

Brain hypoactivation, autonomic nervous system dysregulation, and gonadal hormones in depression: a preliminary study.

The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence of these disorders will have major public health significance. MDD is associated with an abnormal stress response, manifested in brain circuitry deficits, gonadal dysfunction, and autonomic nervous system (ANS) dysregulation. Contribution of the relationships between these systems to the pathophysiology of MDD is not well understood. The objective of this preliminary study was to investigate, in parallel, relationships between HPG-axis functioning, stress response circuitry activation, and parasympathetic reactivity in healthy controls and women with MDD. Using fMRI with pulse oximetry [from which we calculated the high frequency (HF) component of R-R interval variability (HF-RRV), a measure of parasympathetic modulation] and hormone data, we studied eight women with recurrent MDD in remission and six controls during a stress response paradigm. We demonstrated that hypoactivations of hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subgenual ACC were associated with lower parasympathetic cardiac modulation in MDD women. Estradiol and progesterone attenuated group differences in the effect of HF-RRV on hypoactivation in the amygdala, hippocampus, ACC, and OFC in MDD women. Findings have implications for understanding the relationship between mood, arousal, heart regulation, and gonadal hormones, and may provide insights into MDD and CVD risk comorbidity.

Exposure to smoking cues: cardiovascular and autonomic effects.

Laboratory exposures to smoking cues have been shown to reliably induce self-reported cigarette cravings among smokers, a model of environmentally triggered urges to smoke that can contribute to poorer cessation success. Several studies have also demonstrated that cue exposures give rise to changes in heart rate and blood pressure. Few studies, however, have investigated possible cue effects on heart rate and blood pressure variability (HRV and BPV). Particularly intriguing in this regard are cardiac oscillations in the low (i.e., 0.04-0.15 Hz), and high (i.e., 0.15-0.50 Hz) frequency range, which are thought to reflect components of autonomic control and response to environmental challenges. A closer examination of cardiovascular reactivity may thus help characterize the autonomic response to smoking cue exposure. To that end, an experimental study was conducted in which nicotine dependent daily smokers (n=98) were exposed to guided imagery of neutral and smoking situations, while continuous, noninvasive, beat-to-beat cardiovascular data were collected. Consistent with previous research, the findings revealed significant increases in both systolic and diastolic blood pressure during smoking imagery, relative to neutral imagery. In addition, power spectral density analyses of heart rate and blood pressure variability revealed elevated HRV and BPV in both the low- and high-frequency ranges during the smoking imagery. The results suggest the presence of an autonomic component to smoking cue reactivity, and also raise the possibility of long-term negative cardiac consequences for smokers who ubiquitously encounter cues in their daily environments.

Depression is associated with increased mortality 10 years after coronary artery bypass surgery.

OBJECTIVE: To determine if depression is independently associated with cardiac and all-cause mortality 10 years after coronary artery bypass graft (CABG) surgery. Although many studies have examined the relationship of depression and mortality in patients with myocardial infarction, there is less understanding of the relationship between depression and long-term mortality after CABG surgery. METHODS: In a prospective study, we collected data on 309 patients hospitalized after CABG surgery. Before discharge, patients were assessed for depression using the Diagnostic Interview Schedule and the Beck Depression Inventory (BDI). Subsequently, mortality data were obtained from the National Center for Health Statistics and supplemented with phone interviews. RESULTS: Sixty-three (20%) patients met modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depressive disorder (MDD) and 87 (28%) had BDI scores of ≥10, indicating elevated depressive symptoms. Time-to-event or last follow-up phone contact ranged from 9 days to 11.5 years (median, 9.3 years). The overall mortality rate was 37.9% (117 of 309), with 20.1% (62 of 309) due to cardiac causes. Cox proportional hazard modeling showed that age (hazard ratio [HR], 1.04; p = .005), left ventricular ejection fraction (EF) (EF <0.35 [HR], 3.9; p < .001; EF, 0.35-0.49 [HR], 1.9; p = .03), and MDD (HR, 1.8; p = .04) were independent predictors of cardiac mortality. The BDI and the cognitive-affective symptoms subset of BDI symptoms were also predictors of cardiac mortality. Age, EF, and diabetes predicted all-cause mortality, but MDD did not. CONCLUSIONS: Depression, assessed both in structured interview and by BDI, was significantly associated with elevated cardiac mortality 10 years after CABG surgery.

A computerized Stroop task to assess cancer-related cognitive biases.

Biases in processing information related to sources of stress have widely been demonstrated with the use of Stroop emotional color word tasks. One study reported such biases among women with histories of breast cancer in a first-degree relative (FH+) who were given a Stroop cancer word task. This study aimed to replicate and extend these findings with a computerized version of the task. Response latencies and errors were recorded during administration of the task to FH+ and FH- women. A cancer list and 5 comparison lists were administered. Results indicated that FH+ women exhibited longer response latencies for cancer words than did FH- women (p < 0.04), providing further support for cognitive biases in FH+ women. Confirming the psychometric properties of the task, lists exhibited high reliability for both latency (alphas 0.96-0.98) and error rate (alphas 0.61-0.79). In sum, results support the favorable psychometrics and predictive validity of the Stroop cancer word task.

Randomized controlled trial of an interactive internet smoking cessation program with long-term follow-up.

BACKGROUND: Internet programs for smoking cessation are widely available but few controlled studies demonstrate long-term efficacy. PURPOSE: To determine the 13-month effectiveness of an Internet program presenting a set sequence of interactive steps, and the role of depressed affect. METHODS: In a randomized controlled trial sponsored by the American Cancer Society, a treatment condition (n = 1,106) was compared to a control site (n = 1,047). RESULTS: More treatment condition participants were abstinent (30-day point prevalence) than control site participants (12.9% vs. 10.1%, p < .05) at 13 months. This effect was greater among participants not reporting depressed affect (15.0% vs. 10.1%, p < .01). Among smokers who reported depressed affect, there was no difference in abstinence between the treatment and control conditions. CONCLUSIONS: Data support the long-term efficacy of an Internet intervention for cessation modeled on a structured, in-person treatment approach, especially for participants not experiencing daily depressed affect.

Heart rate recovery after cognitive challenge is preserved with age.

OBJECTIVE: To investigate the effect of age on heart rate recovery (HRR) from cognitive challenge. BACKGROUND: Aging is an independent risk factor for the development of cardiovascular disease. HRR from exercise is an established predictor of cardiac morbidity and mortality, and evidence suggests that HRR from cognitive challenge is predictive of cardiac morbidity as well. Aging is associated with delayed HRR from exercise stress, but little is known about the effect of aging on HRR from psychological stress. We tested the hypothesis that age would be related to delayed HRR from psychological stress. METHODS: HRR post exposure to cognitive challenge (mental arithmetic and Stroop) was investigated in a sample of 436 participants aged 35 to 84 years in MIDUS II, a national study of health and well-being. HRR was measured as 1) the amount of change from the stress level; 2) time to recover; and 3) the area under the curve. The analyses were controlled for medical comorbidities and medications that influence HR, such as body mass index, smoking, sex, menopausal status, and amount of physical activity/exercise. RESULTS: There was no effect for age on HRR as evaluated by all three recovery assessment methods. CONCLUSIONS: Contrary to expectation and in contrast to findings concerning HRR from exercise, HRR from cognitive challenge was preserved with age. These findings require further inquiry into differential mechanism(s) underlying HRR from psychological versus exercise stress, including any role for improved emotion regulation with greater age.

Aerobic exercise attenuates inducible TNF production in humans.

Aerobic exercise reduces coronary heart disease risk, but the mechanisms of this protection are not fully understood. Atherosclerosis is an inflammatory disease mediated by monocyte-derived macrophages, which accumulate in arterial plaques and become activated to release factors, including cytokines, that cause damage. Here we studied the effects of aerobic training on monocyte production of tumor necrosis factor (TNF) in whole blood ex vivo. Healthy young sedentary adults (n = 61, age 20-45 yr) were randomized to a moderate- (M) or a high- (H) intensity 12-wk training program. Whole blood was extracted before and after training, and then it was stimulated by addition of lipopolysaccharide (LPS); inducible TNF was measured in the plasma. Data were analyzed according to intention to treat principles using a random-effect model to determine the impact of training group on maximal aerobic capacity and LPS-stimulated TNF after correcting for covariates. Analyses revealed improvement in aerobic capacity in both the H (9%) and the M (7%) groups. However, aerobic training led to significant (P < 0.001) decreases in TNF release only in the H group. These data suggest that in healthy young adults, a 12-wk high-intensity aerobic training program downregulates blood monocyte production of stimulated cytokine release.

RR interval variability is inversely related to inflammatory markers: the CARDIA study.

Recent evidence reveals that the immune system is under the direct control of the vagus nerve via the "cholinergic anti-inflammatory pathway." Stimulation of vagus nerve activity significantly inhibits cytokine levels in animal models, and cholinergic agents inhibit cytokine release by human macrophages. Moreover, when vagus nerve activity is decreased or absent, cytokines are overproduced. Atherosclerosis is an inflammatory disease characterized by elevated levels of CRP and IL-6, but the relationship between cardiac vagal activity and cytokine levels in healthy humans is not well understood. Here we measured RR interval variability, an index of cardiac vagal modulation, and CRP and IL-6 in 757 subjects participating in a subset of the year 15 data collection in the CARDIA study of the evolution of risk factors in young adults. Univariate analysis revealed that all indices of RRV were strongly and inversely related to IL-6 (log pg/mL b=-0.08 and -0.17 for HF and LF power, P<0.001 respectively) and CRP (log mg/L b=-0.14 and -0.26 for HF and LF power, P<0.001 respectively) levels. In the multivariate model including gender, race, age, smoking, physical activity, SBP, BMI, and disease, the inverse relationship between RRV and inflammatory markers, although slightly attenuated, remained significant. These findings are consistent with the hypothesis that diminished descending vagal anti-inflammatory signals can allow cytokine overproduction in humans.

Religious attendance as a predictor of survival in the EPESE cohorts.

BACKGROUND: Interest has arisen in recent years in the relationship between religious involvement and health outcomes. Although most of the early literature consists of studies with methodological flaws, some recent well-conducted reports show that religious attendance is associated with reduced mortality in selected subgroups and populations. METHODS: In this study, we investigated the relationship between religious attendance and mortality using the 14,456 participants in the National Institute of Aging-funded 'Established Populations for Epidemiologic Studies of the Elderly'. RESULTS: Our analyses show that after controlling for important prognostic factors, frequent religious attendance was associated with increased survival in the entire cohort [risk ratio (RR) = 0.78, 95% Confidence interval (CI) 0.70-0.88]. However, stratified analyses show that this association exists for only two of the four sites. CONCLUSIONS: We conclude that the association between religious attendance and survival is not robust and may depend upon unknown confounders and covariates.

Deriving heart period variability from blood pressure waveforms.

International standards for calculating heart period variability (HPV) from a series of R-wave intervals (R-R) in an electrocardiographic (ECG) recording have been widely accepted. It is possible, and potentially useful in various settings, to use systolic blood pressure waveform intervals to estimate HPV, but the validity of HPV derived from blood pressure (BP) waveforms has not been established. To test the reliability between BP- and ECG-derived HPV indexes, we evaluated data from 234 healthy adults in four studies of HPV reactivity to stress. Study conditions included resting baseline, arithmetic, Stroop test, speech presentation, and orthostatic tilt. Continuous ECG and BP recordings were sampled at a rate of 500 Hz, scored by the same methods, and used to calculate heart rate and time- and frequency-domain measures of HPV. Overall, reliability between the two methods was very high for computing heart rate and HPV indexes. High-frequency HPV indexes were somewhat less reliably computed. In conclusion, in healthy adults, with the use of appropriate methods, BP waveforms can produce reliable indexes of HPV.