Depressive Symptoms During Childhood and Cardiovascular Risk Factors in Black and White Men.

OBJECTIVE: Depressive symptoms and major depression predict cardiovascular disease (CVD) and CVD risk factors in adulthood. Evidence regarding the role of depression in the development of CVD risk in youth is minimal. The study evaluated the prospective relationship of depressive symptoms in childhood and adolescence with adult CVD risk factors in black and white men. METHODS: Health behaviors and medical history were measured in 165 black and 146 white men (mean age = 32); a subset in the Pittsburgh area had a fasting blood draw to measure metabolic syndrome and inflammation. Adult CVD risk factors were related to depressive symptoms and childhood socioeconomic status (SES) prospectively measured annually from ages 7 to 16 years, followed by adjustments for adult SES and depressive symptoms. RESULTS: Men with higher depressive symptoms ages 7 to 16 smoked more cigarettes, B = 0.28 (standard error = 0.12), p = .015, and ate fewer servings of fruits and vegetables, B = -0.08 (0.04), p = .040, as adults. The association for smoking was independent of adult depressive symptoms (concurrent) and childhood and adult SES as well as race. Depressive symptoms during childhood were unrelated to the metabolic syndrome or biomarkers of inflammation in adulthood. CONCLUSIONS: Depressive symptoms in childhood may predict later adverse health behaviors in black and white men. No evidence was found for an association between childhood depressive symptoms with metabolic syndrome or inflammation markers at ages approximately 32 years. The nature of the sample and lack of measurement of depressive disorder diagnosis tempers the conclusions, and future research is needed to determine associations with biological measures at later life span phases.

Physiologically assessed hot flashes and endothelial function among midlife women.

OBJECTIVE: Hot flashes are experienced by most midlife women. Emerging data indicate that they may be associated with endothelial dysfunction. No studies have tested whether hot flashes are associated with endothelial function using physiologic measures of hot flashes. We tested whether physiologically assessed hot flashes were associated with poorer endothelial function. We also considered whether age modified associations. METHODS: Two hundred seventy-two nonsmoking women reporting either daily hot flashes or no hot flashes, aged 40 to 60 years, and free of clinical cardiovascular disease, underwent ambulatory physiologic hot flash and diary hot flash monitoring; a blood draw; and ultrasound measurement of brachial artery flow-mediated dilation to assess endothelial function. Associations between hot flashes and flow-mediated dilation were tested in linear regression models controlling for lumen diameter, demographics, cardiovascular disease risk factors, and estradiol. RESULTS: In multivariable models incorporating cardiovascular disease risk factors, significant interactions by age (P < 0.05) indicated that among the younger tertile of women in the sample (age 40-53 years), the presence of hot flashes (beta [standard error] = -2.07 [0.79], P = 0.01), and more frequent physiologic hot flashes (for each hot flash: beta [standard error] = -0.10 [0.05], P = 0.03, multivariable) were associated with lower flow-mediated dilation. Associations were not accounted for by estradiol. Associations were not observed among the older women (age 54-60 years) or for self-reported hot flash frequency, severity, or bother. Among the younger women, hot flashes explained more variance in flow-mediated dilation than standard cardiovascular disease risk factors or estradiol. CONCLUSIONS: Among younger midlife women, frequent hot flashes were associated with poorer endothelial function and may provide information about women's vascular status beyond cardiovascular disease risk factors and estradiol.

Psychophysiological correlates of systemic inflammation in black and white men.

Inflammation plays a critical role in the pathophysiology of cardiovascular disease (CVD) and levels of circulating inflammatory markers are associated with future CVD risk. However, the physiological mechanisms that control systemic levels of circulating inflammatory markers are not well understood. Here, we explore possible autonomic nervous system mechanisms by testing whether resting and stressor-evoked cardiovascular responses are associated with two markers of systemic inflammation: interleukin (IL)-6 and C-reactive protein (CRP). Subjects were 159 black and 129 white men (M=33.0years) who completed a laboratory protocol including an anger recall speech task. Electrocardiography and impedance cardiography data were collected during a resting baseline, the speech task, and a final recovery period. Hierarchical regressions tested whether resting or stressor-evoked levels of heart rate (HR), high-frequency heart rate variability (HF-HRV), pre-ejection period (PEP), and pulse transit time (PTT) were associated with CRP or IL-6. Higher resting HR was associated with higher CRP (ß=0.19, p=0.003) and IL-6 (ß=0.13, p<0.05). Similarly, shorter resting PTT was associated with higher CRP (ß=-0.21, p<0.001) and IL-6 (ß=-0.14, p=0.02). In addition, greater stressor-evoked decreases in HF-HRV were associated with higher CRP (ß=-0.14, p=0.01). Associations were independent of age, race, body mass index (BMI), smoking behavior, and socioeconomic status. Resting HF-HRV and PEP were also associated with CRP and IL-6, but associations were not significant after controlling for BMI and smoking behavior. These findings indicate that resting HR and PTT, as well stressor-evoked HF-HRV reactivity, are associated with systemic inflammation. Our results suggest that both tonic and stressor-evoked sympathetic and parasympathetic nervous system activity may contribute to regulation of systemic inflammation.

Childhood socioeconomic status and cardiovascular reactivity and recovery among Black and White men: Mitigating effects of psychological resources.

OBJECTIVE: To evaluate a possible physiological mechanism underlying links between low childhood socioeconomic status (SES) and poor adult health by (a) testing whether childhood SES is prospectively related to cardiovascular responses to laboratory stress in adulthood, and (b) by determining whether psychological resources buffer cardiovascular reactivity and promote better recovery from stress. METHOD: Participants (n = 246; 55% Black; mean age = 32 years) were from a population-based sample of men in Pittsburgh, PA. Childhood SES was measured through the Hollingshead index (parental education and occupation) across 10 waves between the ages of 6 and 16. In adulthood, cardiovascular measures, including systolic and diastolic blood pressure (SBP, DBP), heart rate (HR), and high-frequency heart rate variability (HF-HRV), were taken during and following standardized laboratory psychological stressors. Participants completed measures of optimism, purpose in life, self-esteem, positive affect, and self-mastery, which were combined into a psychological resource factor. RESULTS: Lower childhood SES predicted higher HR and SBP at recovery, independent of age, race, body mass index, current smoking, task demand, and current SES. Psychological resources moderated the association between childhood SES and SBP. Lower childhood SES predicted SBP recovery only among men with fewer psychological resources. CONCLUSIONS: Psychological resources may buffer the relation between low childhood SES and cardiovascular recovery from stress. This buffering may improve adult health to the extent that cardiovascular recovery contributes to the risk of low childhood SES for subsequent disease. (PsycINFO Database Record

White matter hyperintensities in middle-aged adults with childhood-onset type 1 diabetes.

OBJECTIVE: Although microvascular complications are common in type 1 diabetes mellitus (T1DM), few studies have quantified the severity, risk factors, and implications of cerebral microvascular damage in these patients. As life expectancy in patients with T1DM increases, patients are exposed to age- and disease-related factors that may contribute to cerebral microvascular disease. METHODS: Severity and volume of white matter hyperintensities (WMH) and infarcts were quantified in 97 middle-aged patients with childhood-onset T1DM (mean age and duration: 50 and 41 years, respectively) and 81 non-T1DM adults (mean age: 48 years), concurrent with cognitive and health-related measures. RESULTS: Compared with non-T1DM participants, patients had more severe WMH (Fazekas scores 2 and 3 compared with Fazekas score 1, p < 0.0001) and slower information processing (digit symbol substitution, number correct: 65.7 ± 10.9 and 54.9 ± 13.6; pegboard, seconds: 66.0 ± 9.9 and 88.5 ± 34.2; both p < 0.0001) independent of age, education, or other factors. WMH were associated with slower information processing; adjusting for WMH attenuated the group differences in processing speed (13% for digit symbol, 11% for pegboard, both p ≤ 0.05). Among patients, prevalent neuropathies and smoking tripled the odds of high WMH burden, independent of age or disease duration. Associations between measures of blood pressure or hyperglycemia and WMH were not significant. CONCLUSIONS: Clinically relevant WMH are evident earlier among middle-aged patients with childhood-onset T1DM and are related to the slower information processing frequently observed in T1DM. Brain imaging in patients with T1DM who have cognitive difficulties, especially those with neuropathies, may help uncover cerebral microvascular damage. Longitudinal studies are warranted to fully characterize WMH development, risk factors, and long-term effects on cognition.

Blood pressure interacts with APOE ε4 to predict memory performance in a midlife sample.

OBJECTIVE: Elevated blood pressure and the Apolipoprotein ε4 allele (APOE ε4) are independent risk factors for Alzheimer's disease. We sought to determine whether the combined presence of the APOE ε4 allele and elevated blood pressure is associated with lower cognitive performance in cognitively healthy middle-aged adults. METHODS: A total of 975 participants aged 30-54 (mean age = 44.47) were genotyped for APOE. Cardiometabolic risk factors including blood pressure, lipids, and glucose were assessed and cognitive function was measured using the Trail Making Test and the Visual Reproduction and Logical Memory subtests from the Wechsler Memory Scale. RESULTS: Multivariable regression analysis showed that the association between APOE ε4 and episodic memory performance varied as a function of systolic blood pressure (SBP), such that elevated SBP was predictive of poorer episodic memory performance only in APOE ε4 carriers (ß = -.092; t = -2.614; p = .009). Notably, this association was apparent at prehypertensive levels (≥130 mmHg), even after adjusting for physical activity, depression, smoking, and other cardiometabolic risk factors. CONCLUSIONS: The joint presence of APOE ε4 and elevated SBP, even at prehypertensive levels, is associated with lower cognitive performance in healthy, middle-aged adults. Results of this study suggest that the combination of APOE ε4 and elevated SBP may synergistically compromise memory function well before the appearance of clinically significant impairments. Interventions targeting blood pressure control in APOE ε4 carriers during midlife should be studied as a possible means to reduce the risk of cognitive decline in genetically susceptible samples.

An inflammatory pathway links atherosclerotic cardiovascular disease risk to neural activity evoked by the cognitive regulation of emotion.

BACKGROUND: Cognitive reappraisal is a form of emotion regulation that alters emotional responding by changing the meaning of emotional stimuli. Reappraisal engages regions of the prefrontal cortex that support multiple functions, including visceral control functions implicated in regulating the immune system. Immune activity plays a role in the preclinical pathophysiology of atherosclerotic cardiovascular disease (CVD), an inflammatory condition that is highly comorbid with affective disorders characterized by problems with emotion regulation. Here, we tested whether prefrontal engagement by reappraisal would be associated with atherosclerotic CVD risk and whether this association would be mediated by inflammatory activity. METHODS: Community volunteers (n = 157; 30-54 years of age; 80 women) without DSM-IV Axis-1 psychiatric diagnoses or cardiovascular or immune disorders performed a functional neuroimaging task involving the reappraisal of negative emotional stimuli. Carotid artery intima-media thickness and inter-adventitial diameter were measured by ultrasonography and used as markers of preclinical atherosclerosis. Also measured were circulating levels of interleukin-6 (IL-6), an inflammatory cytokine linked to CVD risk and prefrontal neural activity. RESULTS: Greater reappraisal-related engagement of the dorsal anterior cingulate cortex was associated with greater preclinical atherosclerosis and IL-6. Moreover, IL-6 mediated the association of dorsal anterior cingulate cortex engagement with preclinical atherosclerosis. These results were independent of age, sex, race, smoking status, and other known CVD risk factors. CONCLUSIONS: The cognitive regulation of emotion might relate to CVD risk through a pathway involving the functional interplay between the anterior cingulate region of the prefrontal cortex and inflammatory activity.

Relation of systemic blood pressure to sudden cardiac death.

The role of systolic blood pressure (SBP) as an independent risk factor for sudden cardiac death (SCD) is not well defined in a general population. Thus, we assessed the association between BP at rest and risk of SCD. BP and other risk factors were measured in a representative population-based sample of 2,666 Finnish men (42 to 61 years of age). During an average follow-up period of 18.9 years (interquartile range 17.9 to 22.6), 213 SCDs occurred. Each increment 10-mm Hg of SBP at rest was associated with an increased risk of SCD (relative hazard 1.15, 95% confidence interval 1.07 to 1.25, p <0.001) after adjustment for age, alcohol consumption, cigarette smoking, serum low-density lipoprotein cholesterol, type 2 diabetes, body mass index, left ventricular hypertrophy, previous myocardial infarction, family history of coronary heart disease, and use of antihypertensive medications. Men with increased SBP of >145 mm Hg had a 2.04-fold (95% confidence interval 1.23 to 2.52, p = 0.003) adjusted risk for SCD compared to those with SBP <123 mm Hg. In conclusion, this study emphasizes the importance of the definition of SBP at rest because it provides a valuable prognostic measurement for SCD.

Gene and gene by sex associations with initial sensitivity to nicotine in nonsmokers.

Genetic variation may influence initial sensitivity to nicotine (i.e. during early tobacco exposure), perhaps helping to explain differential vulnerability to nicotine dependence. This study explored associations of functional candidate gene polymorphisms with initial sensitivity to nicotine in 101 young adult nonsmokers of European ancestry. Nicotine (0, 5, 10 microg/kg) was administered through nasal spray followed by mood, nicotine reward (e.g. 'liking') and perception (e.g. 'feel effects') measures, physiological responses, sensory processing (prepulse inhibition of startle), and performance tasks. Nicotine reinforcement was assessed in a separate session using a nicotine versus placebo spray choice procedure. For the dopamine D4 receptor [DRD4 variable number of tandem repeats (VNTR)], presence of the 7-repeat allele was associated with greater aversive responses to nicotine (decreases in 'vigor', positive affect, and rapid information processing; increased cortisol) and reduced nicotine choice. Individuals with at least one DRD4 7-repeat allele also reported increased 'feel effects' and greater startle response, but in men only. Other genetic associations were also observed in men but not women, such as greater 'feel effects' and anger, and reduced fatigue, in the dopamine D2 receptor (DRD2 C957T single nucleotide polymorphism) TT versus CT or CC genotypes. Very few or no significant associations were seen for the DRD2/ANKK1 TaqIA polymorphism, the serotonin transporter promoter VNTR or 5HTTLPR (SLC6A4), the dopamine transporter 3' VNTR (SLC6A3), and the mu opioid receptor A118G single nucleotide polymorphism (mu opioid receptor polymorphism 1). Although these results are preliminary, this study is the first to suggest that genetic polymorphisms related to function in the dopamine D4, and perhaps D2, receptor may modulate initial sensitivity to nicotine before the onset of dependence and may do so differentially between men and women.

Trait negative affect: toward an integrated model of understanding psychological risk for impairment in cardiac autonomic function.

OBJECTIVE: To assess depression, anxiety, and anger as well as the variance that these emotions share (conceptualized as negative affect) in relationship to high-frequency heart rate variability (HF-HRV), a specific indicator of parasympathetic cardiac autonomic function related to premature cardiovascular morbidity and mortality. Although individual trait negative emotions have been studied in relation to risk for coronary heart disease (CHD) as well as biological mechanisms leading to CHD end points (e.g., autonomic nervous system [ANS] dysfunction), the degree to which a general tendency to experience negative emotions may account for these relations is not known. METHODS: The sample included 653 community volunteers (51.0% female; 15.8% Black) aged 30 to 54 years (mean +/- standard deviation = 43.8 +/- 7.1 years). Latent constructs of depression, anxiety, and anger were each measured by three scales from well-validated self-report questionnaires. Resting HF-HRV was derived from 5-minute segments of continuous electrocadiographs recorded during both unpaced and paced respiration conditions. RESULTS: Structural equation models (SEM) of the individual trait emotions showed depression and anxiety related inversely to HF-HRV and anger unrelated to HF-HRV. SEM also showed negative affect related inversely to HF-HRV. All associations were present after covariate adjustment for traditional cardiovascular risk factors, including age, sex, race, education, body mass index, smoking status, and blood pressure. CONCLUSIONS: Negative affect as a common pathway between depression, anxiety, and anger and impairments in cardiac autonomic function was supported, suggesting negative affect may be the unifying and potentially toxic element linking individual trait negative emotions to ANS dysregulation.

Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability.

OBJECTIVE: To examine whether high-frequency heart rate variability, an indirect measure of parasympathetic (vagal) control over variations in heart rate, is associated with immune reactivity to an in vitro inflammatory challenge. Convergent evidence from the animal literature shows that the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation. As yet, no direct human evidence links parasympathetic activity to inflammatory competence. METHODS: We examined the relationship of variations in heart rate, recorded during paced respiration, to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, and IL-10 among a community sample of 183 healthy adults (mean age = 45 years; 59% male; 92% White, 7% African-American). RESULTS: Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration were associated with lower production of the proinflammatory cytokines TNF-alpha and IL-6 (r = -.18 to -.30), but were not related to production of the anti-inflammatory cytokine IL-10. These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count. CONCLUSIONS: These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease.

Regional cerebral blood flow correlates with heart period and high-frequency heart period variability during working-memory tasks: Implications for the cortical and subcortical regulation of cardiac autonomic activity.

The aim of the present study was to characterize the functional relationships between behaviorally evoked regional brain activation and cardiac autonomic activity in humans. Concurrent estimates of regional cerebral blood flow (rCBF; obtained by positron emission tomography), heart period, and high-frequency heart period variability (HF-HPV; an indicator of cardiac parasympathetic activity) were examined in 93 adults (aged 50-70 years) who performed a series of increasingly difficult working-memory tasks. Increased task difficulty resulted in decreased heart period (indicating cardioacceleration) and decreased HF-HPV (indicating decreased cardiac parasympathetic activity). Task-induced decreases in heart period and HF-HPV were associated with concurrent increases and decreases in rCBF to cortical and subcortical brain regions that are speculated to regulate cardiac autonomic activity during behavioral processes: the medial-prefrontal, insular, and anterior cingulate cortices, the amygdala-hippocampal complex, and the cerebellum. These findings replicate and extend a small number of functional neuroimaging studies that suggest an important role for both cortical and subcortical brain systems in human cardiac autonomic regulation.

Is cardiovascular reactivity associated with atherosclerosis among hypertensives?

Exaggerated cardiovascular reactivity to behavioral challenges among otherwise healthy individuals has been associated with carotid atherosclerosis. We evaluated whether a similar relationship exists among hypertensives, who are at a heightened atherosclerotic risk. Untreated, hypertensive men (n=251; age range, 40 to 70 years; 197 white, 54 black) completed a standardized battery of behavioral challenges while their blood pressure responses to the battery were measured. Mean and maximum carotid intima-media thickness and the occurrence of carotid plaques were subsequently determined using B-mode ultrasonography. Although greater systolic and diastolic responses to the battery were associated with greater mean and maximum intima-media thickness in univariate analyses (P<0.01), only diastolic reactivity showed a unique association with mean and maximum carotid intima-media thickness after multivariate adjustment for age, race, socioeconomic status, smoking and alcohol use, body mass index, lipid profile, glucose and insulin concentrations, and resting blood pressure (P<0.05). Carotid plaque occurrence was associated with greater systolic reactivity (P=0.05) and was marginally associated with greater diastolic reactivity (P=0.07) in univariate analyses, but neither systolic nor diastolic reactivity was uniquely associated with the presence of carotid plaques after multivariate risk-factor adjustment. Among hypertensives, exaggerated behaviorally evoked cardiovascular reactivity appears to be uniquely associated with greater carotid intima-media thickness but not with carotid plaque occurrence.

Greater intima-media thickness in the carotid bulb is associated with reduced baroreflex sensitivity.

The aim of this study was to evaluate the association between resting baroreflex sensitivity (BRS) and carotid intima-media thickness (IMT), a putative marker of subclinical atherosclerosis. Participants were 64 men and 18 women (median age, 57 years; range, 40 to 70 years), who did not have a previous history of coronary artery disease or treatment for hypertension. Resting BRS was measured during a 9-min baseline period using the noninvasive sequence technique; carotid IMT was subsequently determined using ultrasonography. Hierarchical multiple regression analyses showed that greater IMT in the carotid bulb (an area with a high density of baroreceptors) was associated with reduced BRS. These findings remained after adjusting BRS for resting mean arterial pressure, age, body mass index, gender, and smoking history, R2 = 0.06, P = .03. In contrast, IMT in the common and internal carotid regions (areas with presumably lower baroreceptor densities) did not account for a significant proportion of the variance in BRS. These results suggest that subclinical atherosclerosis, specifically in a region with high baroreceptor density, is associated with a reduced sensitivity of the baroreflex.