Roland von Känel

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.

Lack of Social Support in the Etiology and the Prognosis of Coronary Heart Disease: A Systematic Review and Meta-Analysis

Objective: To conduct a systematic review and meta-analysis on the relevance of low social support for the development and course of coronary heart disease (CHD). Methods: Three electronic databases were searched (MEDLINE, PsycINFO/PSYNDEX, and Web of Science 2007/03). More than 1700 papers were screened in a first step. We included prospective studies assessing the impact of social support in either an initially healthy study population (etiologic studies) or in a study population with preexisting CHD (prognostic studies). Outcomes: Myocardial infarction in etiologic studies; cardiovascular mortality and all-cause mortality in prognostic studies. Effects were reported as relative risk (RR) or hazard ratio (HR). Results: There is some evidence for an impact of low functional social support on the prevalence of CHD in etiologic studies (RR, range, 1.00–2.23). In contrast, there is no evidence of an impact of low structural social support on the prevalence of myocardial infarction in healthy populations (RR, range, 1.01–1.2). In prognostic studies, results consistently show that low functional support negatively affects cardiac and all-cause mortality (pooled RR, range, 1.59–1.71). These results were also confirmed in analyses adjusted for other risk factors for disease progression (pooled HR, 1.59). It remains unclear whether low structural social support increases mortality in patients with CHD (pooled RR, between 1.56; pooled HR, 1.12, NS). Conclusions: Because the perception of social support seems important for CHD prognosis, monitoring of functional social support is indicated in patients with CHD, and interventions to increase the perception of positive social resources are warranted. AMI = acute myocardial infarction; BDI = Beck Depression Inventory; CABG = coronary artery bypass grafting; CHD = coronary heart disease; CI = confidence interval; CPK = creatinine phosphokinase; DBP = diastolic blood pressure; f = females; LVEF = left ventricular ejection fraction; m = males; MI = myocardial infarction; NYHA = New York Heart Association; SBP = systolic blood pressure; SD = standard deviation; SES = socioeconomic status; yrs = years.

Effects of sympathetic activation by adrenergic infusions on hemostasis in vivo

Abstract: Overactivity of the sympathetic nervous system (SNS) has been related to increased cardiovascular morbidity. Historical reports suggest hastening of blood coagulation following intravenous administration of epinephrine. Given the important role of the hemostatic system in atherosclerosis and thrombosis, it is surprising that short‐term adrenergic effects on blood coagulation, fibrinolysis and platelet activity have not been scrutinized closely. To elucidate such effects in vivo, this paper reviews human studies in which α‐ and β‐sympathomimetic agents had been infused. The literature suggests a dose‐dependent stimulation of factor VIII clotting activity, von Willebrand factor antigen, tissue‐type plasminogen activator, and platelets within a 15‐ to 40‐min infusion of epinephrine. Precise mechanisms underlying hemostatic changes with sympathetic activation remain to some extent speculative. However, there is evidence from adrenoreceptor blockade studies that coagulation and fibrinolysis molecules are released into circulation by stimulation of vascular endothelial β‐adrenoreceptors (most likely β2‐receptors). Combined α2‐ and β2‐adrenoreceptor‐related mechanism(s) are responsible for platelet activation. Short‐term activation of the SNS effects regular hemostatic activity. While in healthy individuals the hemostatic balance between coagulation and fibrinolysis may be preserved, catecholamine surge may trigger a hypercoagulable state and enhance the odds of overt thrombosis in patients with atherosclerotic disease.

Inflammation as a psychophysiological biomarker in chronic psychosocial stress.

The measurement of inflammation by biomarkers not only documents clinically relevant infections but also offers an important tool to pin point potentially harmful effects of chronic psychosocial stressors. This article focuses firstly on basic biology of inflammation and lists main biomarkers currently used in psycho-physiologic research. In the second part, the effects of the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous system as pathways modulating stress-related inflammation are discussed. Furthermore, current evidence of how chronic psychosocial stressors are related to alterations in inflammatory activity is presented. In summary, job stress, low socioeconomic status, childhood adversities as well as life events, caregiver stress, and loneliness were all shown to exert effects on immunologic activity.

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.

Delayed response and lack of habituation in plasma interleukin-6 to acute mental stress in men

Acute mental stress induces a significant increase in plasma interleukin (IL)-6 levels as a possible mechanism for how psychological stress might contribute to atherosclerosis. We investigated whether the IL-6 response would habituate in response to a repetitively applied mental stressor and whether cortisol reactivity would show a relationship with IL-6 reactivity. Study participants were 21 reasonably healthy men (mean age 46+/-7 years) who underwent the Trier Social Stress Test (combination of a 3-min preparation, 5-min speech, and 5-min mental arithmetic) three times with an interval of 1 week. Plasma IL-6 and free salivary cortisol were measured immediately before and after stress, and at 45 and 105 min of recovery from stress. Cortisol samples were also obtained 15 and 30 min after stress. Compared to non-stressed controls, IL-6 significantly increased between rest and 45 min post-stress (p=.022) and between rest and 105 min post-stress (p=.001). Peak cortisol (p=.034) and systolic blood pressure (p=.009) responses to stress both habituated between weeks one and three. No adaptation occurred in diastolic blood pressure, heart rate, and IL-6 responses to stress. The areas under the curve integrating the stress-induced changes in cortisol and IL-6 reactivity were negatively correlated at visit three (r=-.54, p=.011), but not at visit one. The IL-6 response to acute mental stress occurs delayed and shows no adaptation to repeated moderate mental stress. The hypothalamus-pituitary-adrenal axis may attenuate stress reactivity of IL-6. The lack of habituation in IL-6 responses to daily stress could subject at-risk individuals to higher atherosclerotic morbidity and mortality.

Myocardial infarction and post-traumatic stress disorder: frequency, outcome, and atherosclerotic mechanisms

Background Post-traumatic stress disorder (PTSD) may develop in the aftermath of an acute myocardial infarction (MI). Whether PTSD is a risk factor for cardiovascular disease (CVD) is elusive. The biological mechanisms linking PTSD with atherosclerosis are unclear. Design A critical review of 31 studies in the English language pursuing three aims: (i) to estimate the prevalence of PTSD in post-MI patients; (ii) to investigate the association of PTSD with cardiovascular endpoints; and (iii) to search for low-grade systemic inflammatory changes in PTSD pertinent to atherosclerosis. Methods We located studies by PubMed electronic library search and through checking the bibliographies of these sources. Results The weighted prevalence of PTSD after MI was 14.7% (range 0–25%; a total of 13 studies and 827 post-MI patients). Two studies reported a prospective association between PTSD and an increased risk of cardiovascular readmission in post-MI patients and of cardiovascular mortality in combat veterans, respectively. In a total of 11 studies, patients with PTSD had increased rates of physician-rated and self-reported cardiovascular diseases. Various cytokines and C-reactive protein were investigated in a total of seven studies suggesting that PTSD confers a pro-inflammatory state. Conclusions Increasing evidence suggests that PTSD specifically related to MI develops considerably frequently in post-MI patients. More research is needed in larger cohorts applying a population design to substantiate findings suggesting PTSD is an atherogenic risk factor and to understand better the suspected behavioural and biological mechanisms involved.

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.

Exhaustion is associated with reduced habituation of free cortisol responses to repeated acute psychosocial stress

We investigated the association between exhaustion and the habituation of free cortisol responses to repeated stress exposure. The study comprised 25 healthy male subjects (38-59 years) who were confronted three times with the Trier Social Stress Test. Mean cortisol responses showed the well-known general habituation effect. A two-way interaction day by exhaustion (p<0.05) indicated that mean cortisol responses vary across stress sessions depending on the extent of exhaustion. Linear regression revealed a negative dose-response relationship between exhaustion and the degree of habituation (p<0.02). We identified 19 individuals showing a response habituation (negative slope) and 6 individuals showing a response sensitization over the three sessions (positive slope) with the latter reporting higher exhaustion scores. It might be hypothesized that impaired habituation to repeated exposure to the same stressor could reflect a state of increased vulnerability for allostatic load. Absence of normal habituation might be one potential mechanism how exhaustion relates to increased disease vulnerability.