Paul J. Mills

Effects of Psychological Stress and Psychiatric Disorders on Blood Coagulation and Fibrinolysis: A Biobehavioral Pathway to Coronary Artery Disease?

Objective A hypercoagulable state before overt thrombosis resulting from an imbalance between the coagulation and fibrinolysis systems is related to cardiovascular disease progression and acute coronary syndromes. Psychological stressors and depressive and anxiety disorders also are associated with coronary artery disease. This review explores whether changes in blood coagulation, anticoagulant, and fibrinolytic activity may constitute psychobiological pathways that link psychological factors with coronary syndromes. Methods Literature on coagulation, anticoagulation, and fibrinolysis measures in conjunction with psychological factors (mental stress, psychosocial strain, and psychiatric disorders) was identified by MEDLINE search back to 1966 and through checking the bibliographies of these sources. Sixty-eight articles were critically reviewed. Results In healthy subjects, acute mental stress simultaneously activates coagulation (ie, fibrinogen or von Willebrand factor) and fibrinolysis (ie, tissue-type plasminogen activator) within a physiological range. In patients with atherosclerosis and impaired endothelial anticoagulant function, however, procoagulant responses to acute stressors may outweigh anticoagulant mechanisms and thereby promote a hypercoagulable state. Chronic psychosocial stressors (job strain or low socioeconomic status) are related to a hypercoagulable state reflected by increased procoagulant molecules (ie, fibrinogen or coagulation factor VII) and by reduced fibrinolytic capacity. There is also some evidence that points to hypercoagulability in depression. Conclusions Different categories of psychological measures to varying extent are associated with characteristic patterns of coagulation and fibrinolysis activity. Associations between psychological factors and several coagulation and fibrinolysis variables related to atherosclerosis provide a plausible biobehavioral link to coronary artery disease.

Effects of Continuous Positive Airway Pressure Versus Supplemental Oxygen on 24-Hour Ambulatory Blood Pressure

Obstructive sleep apnea (OSA) is associated with recurrent episodes of nocturnal hypoxia and increased risk for development of systemic hypertension. Prior studies have been limited, however, in their ability to show reduction in blood pressure after continuous positive airway pressure (CPAP) therapy, and the effect of supplemental oxygen alone on blood pressure in OSA has not been evaluated. We performed a randomized, double-blind, placebo-controlled study comparing the effects of 2 weeks of CPAP versus sham-CPAP versus supplemental nocturnal oxygen on 24-hour ambulatory blood pressure in 46 patients with moderate-severe OSA. We found that 2 weeks of CPAP therapy resulted in a significant reduction in daytime mean arterial and diastolic blood pressure and nighttime systolic, mean, and diastolic blood pressure (all Ps <0.05). Although nocturnal supplemental oxygen therapy improved oxyhemoglobin saturation, it did not affect blood pressure. We conclude that CPAP therapy reduces both daytime and nighttime blood pressure in patients with OSA, perhaps through mechanisms other than improvement of nocturnal oxyhemoglobin saturation.

Interleukin-6 and tumor necrosis factor-alpha production after acute psychological stress, exercise, and infused isoproterenol: differential effects and pathways.

Objective The aim of the study was to assess the effects of three different methods of acute activation of the sympathetic nervous system on lipopolysaccharide-induced in vitro production of interleukin-6 (IL-6) and tumor necrosis factor-&agr; (TNF-&agr;). Methods Thirty-two healthy volunteers performed speech and exercise tasks and underwent a 30-minute infusion of isoproterenol. Results As expected, acute activation of the sympathetic nervous system led to leukocytosis, including increases in lymphocyte, monocyte, and granulocyte populations (p values < .05). Lipopolysaccharide-induced IL-6 production was increased after both the speaking and exercise tasks (p values < .001), whereas TNF-&agr; production was elevated only after exercise (p < .05). In contrast, infusion of isoproterenol inhibited TNF-&agr; production (p < .001) and caused no change in IL-6 production. Conclusions In response to the challenges, IL-6 and TNF-&agr; production showed different profiles. Purely &bgr;-agonist stimulation led to downregulation of TNF-&agr; production, providing evidence of the antiinflammatory effect of in vivo &bgr;-receptor activation. The enhanced production of both cytokines after exercise, and of IL-6 after the speech task, can be best explained by a simultaneous upregulation of proinflammatory and inflammation-responding mediators. These effects may have an important role in controlling the immune response to acute psychological and physical stress.

Poor Sleep Is Associated with Higher Plasma Proinflammatory Cytokine Interleukin-6 and Procoagulant Marker Fibrin D-Dimer in Older Caregivers of People with Alzheimer's Disease

OBJECTIVES: To determine whether objective measures of sleep correlate with plasma levels of the proinflammatory cytokine interleukin (IL)‐6 and the procoagulant marker fibrin D‐dimer in caregivers of patients with dementia.

Association Between Polysomnographic Measures of Disrupted Sleep and Prothrombotic Factors

BACKGROUND Subjective sleep disturbances have been associated with increased risk of coronary artery disease (CAD). We hypothesized that disrupted sleep as verified by polysomnography is associated with increased levels of prothrombotic hemostasis factors previously shown to predict CAD risk. METHODS Full-night polysomnography was performed in 135 unmedicated men and women (mean age +/- SD, 36.8 +/- 7.8 years) without a history of sleep disorders. Morning fasting plasma levels of von Willebrand Factor (VWF) antigen, soluble tissue factor (sTF) antigen, d-dimer, and plasminogen activator inhibitor (PAI)-1 antigen were determined. Statistical analyses were adjusted for age, gender, ethnicity, body mass index, BP, and smoking history. RESULTS Higher total arousal index (ArI) was associated with higher levels of VWF (beta = 0.25, p = 0.011, DeltaR(2) = 0.045), and longer wake after sleep onset was associated with higher levels of sTF (beta = 0.23, p = 0.023, DeltaR(2) = 0.038). More nighttime spent at mean oxygen saturation < 90% (beta = 0.20, p = 0.020, DeltaR(2) = 0.029) and higher apnea-hypopnea index (AHI) [beta = 0.19, p = 0.034, DeltaR(2) = 0.024] were associated with higher PAI-1. There was a trend for a relationship between mean oxygen desaturation < 90% and PAI-1 (p = 0.053), even after controlling for AHI. Total ArI (beta = 0.28, p = 0.005, DeltaR(2) = 0.056) and WASO (beta = 0.25, p = 0.017, DeltaR(2) = 0.042) continued to predict VWF and sTF, respectively, even after controlling for AHI. CONCLUSIONS Polysomnographically verified sleep disruptions were associated with prothrombotic changes. Measures of sleep fragmentation and sleep efficiency were related to VWF and sTF, respectively. Apnea-related measures were related to PAI-1. Our findings suggest that sleep disruptions, even in a relatively healthy population, are associated with potential markers of prothrombotic cardiovascular risk.

Acute psychological stress and exercise and changes in peripheral leukocyte adhesion molecule expression and density.

Objective This study e-amined the effects of acute psychological stress and e-haustive e-ercise on the e-pression and density of adhesion molecules (L-selectin, lymphocyte function antigen-1 [LFA-1], and intracellular adhesion molecule-1 [ICAM-1]) on monocytes, granulocytes, and lymphocytes. Methods Forty-five healthy volunteers performed a 15-minute public speaking task and a 15- to 18-minute bicycle ergometer challenge. Results In general, both the e-ercise and speaking tasks led to increases in the number of circulating leukocytes and lymphocyte subsets. The density of L-selectin (CD62L) on mi-ed lymphocytes and T lymphocytes was decreased in response to e-ercise (p values < .001). Both stressors led to an increased density of LFA-1 (CD11a) on mixed lymphocytes (p values < .01), whereas CD11a density on monocytes and granulocytes remained unchanged. ICAM-1 (CD54) density was unaffected, but the number of lymphocytes, monocytes, and granulocytes expressing CD54 increased in the circulation on both stressors. Conclusions The data indicate that both psychological stress and e-ercise have significant effects on cellular e-pression of adhesion molecules on circulating leukocytes. Given the crucial role that adhesion molecules on circulating cells play in inflammation and disease, these findings may have clinical relevance in sympathetic nervous system–induced immune activation.

Higher Population-Based Incidence Rates of Triple-Negative Breast Cancer Among Young African-American Women Implications for Breast Cancer Screening Recommendations

Differences in the breast cancer burden of African‐American women compared with white American women are well documented. Recent controversies have emerged regarding age‐appropriate mammographic screening guidelines, and these surveillance recommendations may influence future breast cancer disparities. The objective of the current study was to evaluate age‐specific breast cancer stage distributions and incidence rates of triple‐negative breast cancer (TNBC) in a population‐based tumor registry.

Low-intensity light therapy: exploring the role of redox mechanisms.

Low-intensity light therapy (LILT) appears to be working through newly recognized photoacceptor systems. The mitochondrial electron transport chain has been shown to be photosensitive to red and near-infrared (NIR) light. Although the underlying mechanisms have not yet been clearly elucidated, mitochondrial photostimulation has been shown to increase ATP production and cause transient increases in reactive oxygen species (ROS). In some cells, this process appears to participate in reduction/oxidation (redox) signaling. Redox mechanisms are known to be involved in cellular homeostasis and proliferative control. In plants, photostimulation of the analogous photosynthetic electron transport chain leads to redox signaling known to be integral to cellular function. In gene therapy research, ultraviolet lasers are being used to photostimulate cells through a process that also appears to involve redox signaling. It seems that visible and near visible low-intensity light can be used to modulate cellular physiology in some nonphotosynthetic cells, acting through existing redox mechanisms of cellular physiology. In this manner, LILT may act to promote proliferation and/or cellular homeostasis. Understanding the role of redox state and signaling in LILT may be useful in guiding future therapies, particularly in conditions associated with pro-oxidant conditions.

A Meta-Analysis of Mental Health Treatments and Cardiac Rehabilitation for Improving Clinical Outcomes and Depression Among Patients With Coronary Heart Disease

Objective To quantify the efficacy of mental health (antidepressants & psychotherapies) and cardiac rehabilitation treatments for improving secondary event risk and depression among patients with coronary heart disease (CHD). Methods Using meta-analytic methods, we evaluated mental health and cardiac rehabilitation therapies for a) reducing secondary events and 2) improving depression severity in patients with CHD. Key word searches of PubMed and Psychlit databases and previous reviews identified relevant trials. Results Eighteen mental health trials evaluated secondary events and 22 trials evaluated depression reduction. Cardiac rehabilitation trials for the same categories numbered 17 and 13, respectively. Mental health treatments did not reduce total mortality (absolute risk reduction [ARR] = −0.001, confidence interval [95% CI] = −0.016 to 0.015; number needed to treat [NNT] = ∞), showed moderate efficacy for reducing CHD events (ARR = 0.029, 95% CI = 0.007 to 0.051; NNT = 34), and a medium effect size for improving depression (Cohen d = 0.297). Cardiac rehabilitation showed similar efficacy for treating depression (d = 0.23) and reducing CHD events (ARR = 0.017, 95% CI = 0.007 to 0.026; NNT = 59) and reduced total mortality (ARR = 0.016, 95% CI = 0.005 to 0.027; NNT = 63). Conclusions Among patients with CHD, mental health treatments and cardiac rehabilitation may each reduce depression and CHD events, whereas cardiac rehabilitation is superior for reducing total mortality risk. The results support a continued role for mental health treatments and a larger role for mental health professionals in cardiac rehabilitation.

Increased Framingham Coronary Heart Disease Risk Score in Dementia Caregivers Relative to Non-Caregiving Controls

Background: Elderly individuals who provide care to a spouse suffering from dementia bear an increased risk of coronary heart disease (CHD). Objective: To test the hypothesis that the Framingham CHD Risk Score would be higher in dementia caregivers relative to non-caregiving controls. Methods: We investigated 64 caregivers providing in-home care for their spouse with Alzheimer’s disease and 41 gender-matched non-caregiving controls. All subjects (mean age 70 ± 8 years, 75% women, 93% Caucasian) had a negative history of CHD and cerebrovascular disease. The original Framingham CHD Risk Score was computed adding up categorical scores for age, blood lipids, blood pressure, diabetes, and smoking with adjustment made for sex. Results: The average CHD risk score was higher in caregivers than in controls even when co-varying for socioeconomic status, health habits, medication, and psychological distress (8.0 ± 2.9 vs. 6.3 ± 3.0 points, p = 0.013). The difference showed a medium effect size (Cohen’s d = 0.57). A relatively higher blood pressure in caregivers than in controls made the greatest contribution to this difference. The probability (area under the receiver operator curve) that a randomly selected caregiver had a greater CHD risk score than a randomly selected non-caregiver was 65.5%. Conclusions: Based on the Framingham CHD Risk Score, the potential to develop overt CHD in the following 10 years was predicted to be greater in dementia caregivers than in non-caregiving controls. The magnitude of the difference in the CHD risk between caregivers and controls appears to be clinically relevant. Clinicians may want to monitor caregiving status as a routine part of standard evaluation of their elderly patients’ cardiovascular risk.