Young women post-MI have higher plasma concentrations of interleukin-6 before and after stress testing.

OBJECTIVES: Young women have poorer prognosis after myocardial infarction (MI) and a higher rate of mental stress-induced ischemia compared with similarly aged men. A higher inflammatory status may help explain these sex differences. METHODS: We examined 98 patients (49 women and 49 men) age 18-59years with recent MI (past 6months). Women and men were matched for age, type of MI, and time since MI. Interleukin 6 (IL-6) concentrations were measured at baseline, after mental stress using a speech task, and after exercise/pharmacologic stress (60 and 90min). Depressive symptoms were measured with the Beck Depression Inventory (BDI-II) and angiographic coronary artery disease (CAD) severity was quantified with the Gensini score. Single-photon emission computed tomography (SPECT) was used to obtain a computerized measurement of stress-induced ischemia (summed difference score, or SDS) and determine whether severity of stress-induced ischemia affects the inflammatory response to stress. Analysis was stratified by the median age of 50. Geometric mean concentrations of IL-6 were obtained from general linear regression models. RESULTS: In both age groups, women had less angiographic CAD and a similar level of conventional risk factors compared with men. Despite this, baseline IL-6 geometric means before both mental and physical stress were twice as high in women ⩽50years of age compared to age-matched men (3.8 vs. 1.8pg/mL, p=0.001, across both conditions), while they were similar in women and men age >50years (2.3 vs. 2.2pg/mL, p=0.83). After mental stress, IL-6 concentrations increased in both women and men in a similar fashion and remained twice as high in women ⩽50years than men at both 60min (5.4 vs. 2.6pg/mL, p=0.002) and 90min (5.9 vs. 3.4pg/mL, p=0.01). No significant difference was found between women and men >50years of age at any time point after mental stress. Results were similar for physical stress. After accounting for SDS, IL-6 concentrations in young women remained higher after both mental and physical stress. Baseline IL-6 concentrations were not significantly related to inducible ischemia. CONCLUSIONS: After MI, young women aged 50years or younger, compared with age-matched men, have remarkably higher concentrations of inflammation at baseline and after both mental and physical stress, with a similar inflammatory response to both stressors. Sustained concentrations of inflammation in young women, not their response to stress, may contribute to their adverse outcomes post-MI.

Long-Term Consequences of Early Trauma on Coronary Heart Disease: Role of Familial Factors.

Early childhood trauma has been associated with increased risk for subsequent coronary heart disease (CHD), but little is known regarding what role genetic and shared familial factors play in this relationship. Early trauma was measured retrospectively in 562 male middle-aged twins with the Early Trauma Inventory. CHD was assessed by history and by myocardial perfusion imaging with positron emission tomography [(13)N] ammonia. Coronary flow reserve, a measure of coronary microcirculatory function, was defined as the ratio of myocardial blood flow at rest to flow during stress. Early trauma was associated with a higher prevalence of CHD by clinical history, OR = 1.48 per early trauma inventory quartile increase, 95% CI [1.18, 1.86]. When within- and between-pair effects were estimated, only the between-pair association was significant, OR = 1.76, 95% CI [1.30, 2.40], showing that the odds of CHD in the twin pair increased as the average early trauma exposure in the pair increased. A marginal between-pair (but not within-pair) relationship was also found between early trauma and coronary flow reserve (n = 416, unstandardized B = -0.04, SE B = 0.02, p = .036). In conclusion, early trauma was associated with CHD and familial factors played a key role.

Angina and mental stress-induced myocardial ischemia.

OBJECTIVE: Mental stress-induced myocardial ischemia is a common phenomenon in patients with coronary artery disease (CAD) and an emerging prognostic factor. Mental stress ischemia is correlated with ambulatory ischemia. However, whether it is related to angina symptoms during daily life has not been examined. METHODS: We assessed angina frequency (past month) in 98 post-myocardial infarction (MI) subjects (age 18-60 years) using the Seattle Angina Questionnaire. Patients underwent [(99m)Tc]sestamibi SPECT perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. RESULTS: The mean age was 50 years, 50% were female and 60% were non-white. After adjustment for age, sex, smoking, CAD severity, depressive, anger, and anxiety symptoms, each 1-point increase in mental stress-SDS was associated with 1.73-unit increase in the angina frequency score (95% CI: 0.09-3.37) and 17% higher odds of being in a higher angina frequency category (OR: 1.17, 95% CI: 1.00-1.38). Depressive symptoms were associated with 12% higher odds of being in a higher angina frequency category (OR: 1.12, 95% CI: 1.03-1.21). In contrast, exercise/pharmacological stress-induced SDS was not associated with angina frequency. CONCLUSION: Among young and middle-aged post-MI patients, myocardial ischemia induced by mental stress in the lab, but not by exercise/pharmacological stress, is associated with higher frequency of retrospectively reported angina during the day. Psychosocial stressors related to mental stress ischemia may be important contributory factor to daily angina.

Association between anger and mental stress-induced myocardial ischemia.

BACKGROUND: Mental stress-induced myocardial ischemia is associated with adverse prognosis in coronary artery disease patients. Anger is thought to be a trigger of acute coronary syndromes and is associated with increased cardiovascular risk; however, little direct evidence exists for a link between anger and myocardial ischemia. METHODS: [(99m)Tc]-sestamibi single-photon emission tomography was performed at rest, after mental stress (a social stressor with a speech task) and after exercise/pharmacologic stress. Summed scores of perfusion abnormalities were obtained by observer-independent software. A summed-difference score, the difference between stress and rest scores, was used to quantify myocardial ischemia under both stress conditions. The Spielberger's State-Trait Anger Expression Inventory was used to assess different anger dimensions. RESULTS: The mean age was 50 years, 50% were female, and 60% were non-white. After adjusting for demographic factors, smoking, coronary artery disease severity, depressive, and anxiety symptoms, each IQR increment in state-anger score was associated with 0.36 U-adjusted increase in ischemia as measured by the summed-difference score (95% CI 0.14-0.59); the corresponding association for trait anger was 0.95 (95% CI 0.21-1.69). Anger expression scales were not associated with ischemia. None of the anger dimensions was related to ischemia during exercise/pharmacologic stress. CONCLUSION: Anger, both as an emotional state and as a personality trait, is significantly associated with propensity to develop myocardial ischemia during mental stress but not during exercise/pharmacologic stress. Patients with this psychologic profile may be at increased risk for silent ischemia induced by emotional stress, and this may translate into worse prognosis.

Depressive symptoms are associated with mental stress-induced myocardial ischemia after acute myocardial infarction.

OBJECTIVES: Depression is an adverse prognostic factor after an acute myocardial infarction (MI), and an increased propensity toward emotionally-driven myocardial ischemia may play a role. We aimed to examine the association between depressive symptoms and mental stress-induced myocardial ischemia in young survivors of an MI. METHODS: We studied 98 patients (49 women and 49 men) age 38-60 years who were hospitalized for acute MI in the previous 6 months. Patients underwent myocardial perfusion imaging at rest, after mental stress (speech task), and after exercise or pharmacological stress. A summed difference score (SDS), obtained with observer-independent software, was used to quantify myocardial ischemia under both stress conditions. The Beck Depression Inventory-II (BDI-II) was used to measure depressive symptoms, which were analyzed as overall score, and as separate somatic and cognitive depressive symptom scores. RESULTS: There was a significant positive association between depressive symptoms and SDS with mental stress, denoting more ischemia. After adjustment for demographic and lifestyle factors, disease severity and medications, each incremental depressive symptom was associated with 0.14 points higher SDS. When somatic and cognitive depressive symptoms were examined separately, both somatic [ß = 0.17, 95% CI: (0.04, 0.30), p = 0.01] and cognitive symptoms [ß = 0.31, 95% CI: (0.07, 0.56), p = 0.01] were significantly associated with mental stress-induced ischemia. Depressive symptoms were not associated with ischemia induced by exercise or pharmacological stress. CONCLUSION: Among young post-MI patients, higher levels of both cognitive and somatic depressive symptoms are associated with a higher propensity to develop myocardial ischemia with mental stress, but not with physical (exercise or pharmacological) stress.

Meta-analysis of mental stress-induced myocardial ischemia and subsequent cardiac events in patients with coronary artery disease.

Mental stress-induced myocardial ischemia (MSIMI) has been associated with adverse prognosis in patients with coronary artery disease (CAD), but whether this is a uniform finding across different studies has not been described. We conducted a systematic review and meta-analysis of prospective studies examining the association between MSIMI and adverse outcome events in patients with stable CAD. We searched PubMed, EMBASE, Web of Science, and PsycINFO databases for English language prospective studies of patients with CAD who underwent standardized mental stress testing to determine presence of MSIMI and were followed up for subsequent cardiac events or total mortality. Our outcomes of interest were CAD recurrence, CAD mortality, or total mortality. A summary effect estimate was derived using a fixed-effects meta-analysis model. Only 5 studies, each with a sample size of <200 patients and fewer than 50 outcome events, met the inclusion criteria. The pooled samples comprised 555 patients with CAD (85% male) and 117 events with a range of follow-up from 35 days to 8.8 years. Pooled analysis showed that MSIMI was associated with a twofold increased risk of a combined end point of cardiac events or total mortality (relative risk 2.24, 95% confidence interval 1.59 to 3.15). No heterogeneity was detected among the studies (Q=0.39, I2=0.0%, p=0.98). In conclusion, although few selected studies have examined the association between MSIMI and adverse events in patients with CAD, all existing investigations point to approximately a doubling of risk. Whether this increased risk is generalizable to the CAD population at large and varies in patient subgroups warrant further investigation.

Sex differences in mental stress-induced myocardial ischemia in young survivors of an acute myocardial infarction.

OBJECTIVES: Emotional stress may disproportionally affect young women with ischemic heart disease. We sought to examine whether mental stress-induced myocardial ischemia (MSIMI), but not exercise-induced ischemia, is more common in young women with previous myocardial infarction (MI) than in men. METHODS: We studied 98 post-MI patients (49 women and 49 men) aged 38 to 60 years. Women and men were matched for age, MI type, and months since MI. Patients underwent technetium-99m sestamibi perfusion imaging at rest, after mental stress, and after exercise/pharmacological stress. Perfusion defect scores were obtained with observer-independent software. A summed difference score (SDS), the difference between stress and rest scores, was used to quantify ischemia under both stress conditions. RESULTS: Women 50 years or younger, but not older women, showed a more adverse psychosocial profile than did age-matched men but did not differ for conventional risk factors and tended to have less angiographic coronary artery disease. Compared with age-matched men, women 50 years or younger exhibited a higher SDS with mental stress (3.1 versus 1.5, p = .029) and had twice the rate of MSIMI (SDS ≥ 3; 52% versus 25%), whereas ischemia with physical stress did not differ (36% versus 25%). In older patients, there were no sex differences in MSIMI. The higher prevalence of MSIMI in young women persisted when adjusting for sociodemographic and life-style factors, coronary artery disease severity, and depression. CONCLUSIONS: MSIMI post-MI is more common in women 50 years or younger compared with age-matched men. These sex differences are not observed in post-MI patients who are older than 50 years.

Post-traumatic stress disorder and incidence of coronary heart disease: a twin study.

OBJECTIVES: The aim of this study was to determine whether post-traumatic stress disorder (PTSD) is associated with coronary heart disease (CHD) using a prospective twin study design and objective measures of CHD. BACKGROUND: It has long been hypothesized that PTSD increases the risk of CHD, but empirical evidence using objective measures is limited. METHODS: We conducted a prospective study of middle-aged male twins from the Vietnam Era Twin Registry. Among twin pairs without self-reported CHD at baseline, we selected pairs discordant for a lifetime history of PTSD, pairs discordant for a lifetime history of major depression, and pairs without either condition. All underwent a clinic visit after a median follow-up of 13 years. Outcomes included clinical events (myocardial infarction, other hospitalizations for CHD and coronary revascularization) and quantitative measures of myocardial perfusion by [(13)N] ammonia positron emission tomography, including a stress total severity score and coronary flow reserve. RESULTS: A total of 562 twins (281 pairs) with a mean age of 42.6 years at baseline were included in this study. The incidence of CHD was more than double in twins with PTSD (22.6%) than in those without PTSD (8.9%; p < 0.001). The association remained robust after adjusting for lifestyle factors, other risk factors for CHD, and major depression (odds ratio: 2.2; 95% confidence interval: 1.2 to 4.1). Stress total severity score was significantly higher (+95%, p = 0.001) and coronary flow reserve was lower (-0.21, p = 0.02) in twins with PTSD than in those without PTSD, denoting worse myocardial perfusion. Associations were only mildly attenuated in 117 twin pairs discordant for PTSD. CONCLUSIONS: Among Vietnam-era veterans, PTSD is a risk factor for CHD.

Status of cardiovascular health in US adolescents: prevalence estimates from the National Health and Nutrition Examination Surveys (NHANES) 2005-2010.

BACKGROUND: The American Heart Association recently developed definitions and metrics for monitoring the spectrum of cardiovascular health in adolescents and children. Current nationally representative prevalence estimates according to sex and race/ethnicity are unavailable. METHODS AND RESULTS: We examined the components of cardiovascular health in 4673 participants aged 12 to 19 years (representing ≈33.2 million US adolescents) from the 2005-2010 National Health and Nutrition Examination Surveys. Population prevalence of individual cardiovascular health behaviors and factors was estimated according to American Heart Association criteria for poor, intermediate, and ideal levels. Ideal blood pressure was most prevalent (males, 78%; females, 90%), whereas a dramatically low prevalence of ideal Healthy Diet Score was observed (males, <1%; females, <1%). Females exhibited a lower prevalence of ideal total cholesterol (65% versus 72%, respectively) and ideal physical activity levels (44% versus 67%, respectively) yet a higher prevalence of ideal blood glucose (89% versus 74%, respectively) compared with males. Approximately two thirds of adolescents exhibited ideal body mass index (males, 66%; females, 67%) and ideal smoking status (males, 66%; females, 70%). Less than 50% of adolescents exhibited ≥5 ideal cardiovascular health components (45%, males; 50%, females). Prevalence estimates according to sex were consistent across race/ethnic groups. CONCLUSIONS: The low prevalence of ideal cardiovascular health behaviors in US adolescents, particularly physical activity and dietary intake, will likely contribute to a worsening prevalence of obesity, hypertension, hypercholesterolemia, and dysglycemia as the current US adolescent population reaches adulthood. Population-wide emphasis on establishment of ideal cardiovascular health behaviors early in life is essential for maintenance of ideal cardiovascular health throughout the lifespan.

Early trauma and inflammation: role of familial factors in a study of twins.

OBJECTIVE: Although early trauma (trauma in childhood) has been linked to adult inflammation and adult disease of inflammatory origin, it remains unknown whether this relationship is due to long-term consequences of early life stress or other familial factors. METHODS: We examined 482 male middle-aged twins (241 pairs) born between 1946 and 1956 from the Vietnam Era Twin Registry. Childhood traumatic experiences, before the age of 18 years, were measured retrospectively with the Early Trauma Inventory and included physical, sexual, emotional abuse and general trauma. Lifetime major depressive disorder and posttraumatic stress disorder were assessed with the Structured Clinical Interview for DSM-IV. Traditional risk factors for cardiovascular disease were also assessed. Plasma C-reactive protein and interleukin 6 were measured to determine levels of inflammation. Mixed-effects regression models with a random intercept for pair were used to separate between- and within-twin pair effects. RESULTS: When twins were analyzed as individuals, increasing levels of early trauma were positively related to C-reactive protein (p = .03) but not to interleukin 6 (p = .12). When estimating within- and between-pair effects, only the between-pair association of early trauma with the inflammatory markers remained significant. CONCLUSIONS: The link between early trauma and inflammation is largely explained by familial factors shared by the twins because levels of inflammation were highest when both twins were exposed to trauma. Exposure to early trauma may be a marker for an unhealthy familial environment. Clarification of familial factors associated with early stress and adult inflammation will be important to uncover correlates of stress and disease.

Acute exercise improves endothelial function despite increasing vascular resistance during stress in smokers and nonsmokers.

The present study examined the effect of acute exercise on flow mediated dilation (FMD) and reactivity to neurovascular challenges among female smokers and nonsmokers. FMD was determined by arterial diameter, velocity, and blood flow measured by Doppler ultrasonography after forearm occlusion. Those measures and blood pressure and heart rate were also assessed in response to forehead cold and the Stroop Color-Word Conflict Test (CWT) before and after 30 min of rest or an acute bout of cycling exercise (∼50% VO2 peak). Baseline FMD and stress responses were not different between smokers and nonsmokers. Compared to passive rest, exercise increased FMD and decreased arterial velocity and blood flow responses during the Stroop CWT and forehead cold in both groups. Overall, acute exercise improved endothelial function among smokers and nonsmokers despite increasing vascular resistance and reducing limb blood flow during neurovascular stress.

Effects of smoking on coronary microcirculatory function: a twin study.

BACKGROUND: In asymptomatic smokers, coronary microcirculatory dysfunction, assessed by coronary flow reserve (CFR), is an early indicator of cardiovascular risk. Inflammation and oxidative stress may be the mechanisms through which smoking affects the microvasculature. OBJECTIVES: The purpose of this study was to determine the relationship between smoking and CFR, taking into account potential shared genetic effects. METHODS: We examined 360 male middle aged twins (288 non-smokers and 72 smokers), including 46 twin pairs discordant for current smoking. Coronary flow reserve (CFR) in response to adenosine was measured with positron emission tomography [N(13)] ammonia and quantitation of coronary blood flow at rest and after adenosine stress. Inflammation was assessed by measuring interleukin-6 and C-reactive protein, and oxidative stress was determined by measuring plasma hydroperoxides, glutathione (GSH), the oxidized form of GSH, GSSG, and the ratio of GSH to GSSG. RESULTS: CFR was significantly lower in smokers compared to nonsmokers (2.25 vs. 2.75, p<0.01). This relationship persisted after accounting for known cardiovascular disease risk factors, and was marginally affected by adjusting for inflammatory and oxidative stress biomarkers. In addition, in smoking-discordant twin pairs, CFR in the smoking twin was significantly lower than in the non-smoking co-twin (2.25 vs. 2.67, p=0.03) even after adjustment for cardiovascular risk factors. CONCLUSIONS: Our results demonstrate the adverse effects of smoking in the early phases of cardiovascular disease. Mechanisms other than peripherally measured inflammation and oxidative stress are involved.

Meeting U.S. Healthy People 2010 levels of physical activity: agreement of 2 measures across 2 years.

BACKGROUND: Measuring the way people vary across time in meeting recommended levels of physical activity should be a fundamental component of public health surveillance. However, we were unaware of prospective cohort studies that had examined this in a population base using convergent measures. PURPOSE: We examined agreement between two validated measures used to estimate periodic change in the rate of meeting U.S. Healthy People 2010 guidelines for participation in moderate or vigorous physical activity. METHODS: A cohort (N = 497) from a random, multiethnic sample of adults living in Hawaii was assessed every 6-months for 2 years starting spring 2004. Latent transition analysis classified people as meeting or not meeting the guidelines. Intra-class kappa statistics and multinomial logistic regression analysis were used to evaluate agreement. RESULTS: Agreement for classifying stable classes of people who met or did not meet the guideline each time was substantial for vigorous activity (kappa approximately 0.65-0.70) but fair-to-moderate for moderate activity (kappa approximately 0.38-0.48). Agreement was poorer for classifying people who transitioned between meeting and not meeting the vigorous guideline (kappa approximately 0.45) or the moderate guideline (kappa approximately 0.21-0.29). CONCLUSIONS: Rates of meeting the guidelines varied across time and were estimated differently by the two measures, especially for moderate activity. This finding illustrates an understudied problem for public health promotion. Accurate classification of change within people is necessary for determining exposure in outcome studies, personal determinants of sufficient activity, and for evaluating whether interventions are successful in sustaining increases in rates of meeting physical activity guidelines.

Effects of incremental exercise on cerebral oxygenation measured by near-infrared spectroscopy: a systematic review.

We conducted a systematic review and meta-regression analysis to quantify effects of exercise on brain hemodynamics measured by near-infrared spectroscopy (NIRS). The results indicate that acute incremental exercise (categorized relative to aerobic capacity (VO(2)peak) as low - <30% VO(2)peak; moderate - ≥30% VO(2)peak to <60% VO(2)peak; hard - ≥60% VO(2)peak to

Failure of post-action stages of the transtheoretical model to predict change in regular physical activity: a multiethnic cohort study.

BACKGROUND: Predicting variation in meeting recommended levels of physical activity is important for public health evaluation. PURPOSE: The purpose of this study is to determine the predictive value of stages of the Transtheoretical Model (TTM) for classifying people who meet the US Healthy People 2010 guideline for regular physical activity. METHODS: A cohort (N = 497) from a random, multiethnic sample of 700 adults living in Hawaii was assessed at 6-month intervals three or more times for 2 years. Latent transition analysis was used to classify people according to TTM stages and separately according to whether they met the guideline. The predictive value of pre- vs. post-action stages was then tested. RESULTS: Stages were more likely to falsely classify people as meeting the guideline than to falsely classify them as not meeting it. Probabilities of predicting 6-month transitions were about 50% for the stable class of meeting the guideline each time and just 25% for transitions between meeting and not meeting the guideline. CONCLUSION: The TTM post-action stages had limited usefulness in this cohort. Further longitudinal study is needed to determine whether TTM stages can accurately classify transitions from physical inactivity to physical activity below recommended levels.

Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin.

Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 microg leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 microg leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots.

Compensation for an increase in body fat caused by donor transplants into mice.

Rodents tend to compensate for experimental obesity in which both adipocyte size and number are increased. In contrast, it was recently reported that Siberian hamsters do not compensate for dorsal subcutaneous transplants of fat, which increase body fat without changing the size of adipocytes. In the first experiment described here we tested whether mice changed the size of their endogenous fat stores 2 or 5 wk after donor fat was added as subcutaneous transplants. Each epididymal fat pad from donor mice was cut in half and placed ventrally in recipient mice, increasing body fat by approximately 10%. After 2 wk, there was no effect of the transplants on the size of endogenous fat depots or the size of adipocytes in epididymal fat depots. There was a substantial decrease in mass and adipocyte size in transplanted fat. Five weeks after surgery the endogenous epididymal and retroperitoneal fat depots of recipient mice were significantly decreased, serum leptin was reduced, and the size of adipocytes in endogenous epididymal fat was significantly reduced, although cell number had not changed. The size of transplanted cells was the same as at 2 wk. In a second experiment, epididymal fat was placed as either dorsal or ventral subcutaneous fat transplants. Five weeks after surgery the endogenous fat depots were decreased in all recipient mice but none of the differences reached statistical significance. These results suggest that mice have mechanisms to maintain total body fat mass that respond to an increase in the number of fat cells present.