Hyperreactivity of Salivary Alpha-Amylase to Acute Psychosocial Stress and Norepinephrine Infusion in Essential Hypertension

It is unknown whether the observed general physiological hyperreactivity to acute psychosocial stress in essential hypertension also extends to salivary alpha-amylase (sAA), a surrogate sympathetic nervous system marker. Here, we investigated sAA reactivity to acute psychosocial stress in essential hypertensive males (HT) as compared to normotensive controls (NT). To shed light on underlying mechanisms, we moreover tested for sAA reactivity following a standardized norepinephrine (NE) infusion. We hypothesized that both acute psychosocial stress and an NE infusion of similar duration would lead to greater sAA reactivity in HT than in NT. In the stress study, we examined sAA reactivity to 15 min of acute psychosocial stress induced by the Trier Social Stress Test (TSST) in 19 HT and 23 NT up to 40 min after stress. In the infusion study, 20 HT and 22 NT received a standardized NE infusion (5 μg/mL/min) over 15 min mimicking NE release in reaction to acute psychosocial stress. HT exhibited greater sAA reactivity to the TSST as compared to NT (p = 0.049, ηp2 = 0.08, f = 0.29). In reaction to the standardized NE infusion, HT showed higher sAA reactivity as compared to NT (p = 0.033, ηp2 = 1.00, f = 0.33). Our findings suggest stress-induced sAA hyperreactivity in essential hypertension that seems to be at least in part mediated by a higher reactivity to a standardized amount of NE in HT. With respect to clinical implications, sAA stress reactivity may serve as a noninvasive marker indicative of early cardiovascular risk

Alpha-Adrenergic Mechanisms in the Cardiovascular Hyperreactivity to Norepinephrine-Infusion in Essential Hypertension.

Aims Essential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the role of α-adrenergic receptors (α-AR) in the cardiovascular reactivity to a norepinephrine (NE)-stress reactivity-mimicking NE-infusion in essential hypertensive individuals (HT) as compared to normotensive individuals (NT). Methods 24 male HT and 24 male NT participated in three experimental trials on three separate days with a 1-min infusion followed by a 15-min infusion. Trials varied in infusion-substances: placebo saline (Sal)-infusions (trial-1:Sal+Sal), NE-infusion without (trial-2:Sal+NE) or with non-selective α-AR blockade by phentolamine (PHE) (trial-3:PHE+NE). NE-infusion dosage (5µg/ml/min) and duration were chosen to mimic duration and physiological effects of NE-release in reaction to established stress induction protocols. We repeatedly measured systolic (SBP) and diastolic blood pressure (DBP) as well as heart rate before, during, and after infusions. Results SBP and DBP reactivity to the three infusion-trials differed between HT and NT (p's≤.014). HT exhibited greater BP reactivity to NE-infusion alone compared to NT (trial-2-vs-trial-1: p's≤.033). Group differences in DBP reactivity to NE disappeared with prior PHE blockade (trial-3: p=.26), while SBP reactivity differences remained (trial-3: p=.016). Heart rate reactivity to infusion-trials did not differ between HT and NT (p=.73). Conclusion Our findings suggest a mediating role of α-AR in DBP hyperreactivity to NE-infusion in EHT. However, in SBP hyperreactivity to NE-infusion in EHT, the functioning of α-AR seems impaired suggesting that the SBP hyperreactivity in hypertension is not mediated by α-AR

Taking appreciation to heart: appreciation at work and cardiovascular risk in male employees.

INTRODUCTION While perceived appreciation at work has been associated with self-reported health and wellbeing, studies considering biological health markers are lacking. In this study, we investigated whether appreciation at work would relate to coronary heart disease (CHD) risk as well as the specificity of this proposed association. METHODS Our study comprised a total of 103 male participants, including apparently healthy, medication-free, non-smoking men in the normotensive to hypertensive range (n = 70) as well as medicated hypertensive and CHD patients (n = 33). CHD risk was assessed by blood pressure [mean arterial pressure (MAP)], the diabetes marker glycated hemoglobin A1c (HbA1c), blood lipids [total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C) ratio], coagulation activity (D-dimer and fibrinogen), and inflammation [interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP)]. Perceived appreciation at work, as well as potentially confounding psychological factors (social support, self-esteem, and work strain due to a lack of appreciation), were measured by self-report questionnaires. RESULTS We found higher appreciation at work to relate to lower overall composite CHD risk (p's ≤ 0.011) and, in particular, to lower MAP (p's ≤ 0.007) and lower blood lipids (p's ≤ 0.031) in medication-free participants as well as all participants. This overall association was independent of confounding factors, including related psychological factors (p's ≤ 0.049). DISCUSSION Our findings indicate that appreciation at work might be an independent health-promoting resource in terms of CHD risk. Implications include that encouraging appreciation at work may help reduce the development and progression of CHD

Acute Stress-Induced Blood Lipid Reactivity in Hypertensive and Normotensive Men and Prospective Associations with Future Cardiovascular Risk.

Hyperreactivity to stress may be one explanation for the increased risk of cardiovascular disease (CVD) in individuals with essential hypertension. We investigated blood lipid reactivity to the Montreal Imaging Stress Task (MIST), a psychosocial stressor, in hypertensive and normotensive men and tested for prospective associations with biological risk factors. Fifty-six otherwise healthy and medication-free hypertensive and normotensive men underwent the MIST. We repeatedly measured cortisol and blood lipid profiles (total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG)) immediately before and up to 1 h after stress. Lipid levels were corrected for stress hemoconcentration. Thirty-five participants completed follow-up assessment 2.9 ± 0.12 (SEM) years later. CVD risk was assessed by prospective changes in TC/HDL-C ratio, IL-6, D-dimer, and HbA1c from baseline to follow-up. The MIST induced significant changes in all parameters except TC (p-values ≤ 0.043). Compared with normotensives, hypertensives had higher TC/HDL-C-ratio and TG (p-values ≤ 0.049) stress responses. Blood lipid stress reactivity predicted future cardiovascular risk (p = 0.036) with increases in HbA1c (ß = 0.34, p = 0.046), IL-6 (ß = 0.31, p = 0.075), and D-dimer (ß = 0.33, p = 0.050). Our results suggest that the greater blood lipid reactivity to psychosocial stress in hypertensives, the greater their future biological CVD risk. This points to lipid stress reactivity as a potential mechanism through which stress might increase CVD risk in essential hypertension

Sympathetic nervous system responses to acute psychosocial stress in male physicians with clinical burnout

Background: Occupational burnout has been associated with an increased risk of cardiovascular disease, with sympathetic nervous system (SNS) dysfunction as one explanation. This study examined the effects of burnout on responses of SNS activity measures to acute psychosocial stress in male physicians, a population at risk for burnout. Methods: Study participants were 60 male physicians, 30 with clinical burnout, assessed with the Maslach Burnout Inventory, and 30 without burnout (controls). All participants underwent the 15-min Trier Social Stress Test. Heart rate, blood pressure, salivary alpha-amylase, and plasma levels of epinephrine (EPI) and norepinephrine were assessed pre-stress, immediately post-stress, and 15 min and 45 min post-stress. Results: Physicians with burnout and controls differed in EPI changes over time, controlling for age, job stress and anxiety symptoms (F (3,147) = 5.18, p = .002 for 'Time by Group' interaction; η2p = .096). Burnout was associated with a smaller increase in EPI from pre-stress to immediately post-stress (r(54) = -.40, p = .004). The emotional exhaustion dimension of burnout was a significant driver of this effect. The area under the curve with respect to increase in EPI was also smaller in the burnout group (F (1,49) = 6.06, p = .017, η2p = .110). Group differences were not significant for the other SNS activity measures. Conclusions: Burnout may be linked to dysfunction of the sympathoadrenal medullary (SAM) system, when exposed to acute psychosocial stress. In keeping with the allostatic load concept, an insufficient SAM stress response in burnout could potentially contribute to cardiovascular disease

Lower diurnal HPA-axis activity in male hypertensive and coronary heart disease patients predicts future CHD risk.

BACKGROUND Coronary heart disease (CHD) and its major risk factor hypertension have both been associated with altered activity of the hypothalamus-pituitary-adrenal (HPA)-axis but the biological mechanisms underlying prospective associations with adverse disease outcomes are unclear. We investigated diurnal HPA-axis activity in CHD-patients, hypertensive (HT) and healthy normotensive men (NT) and tested for prospective associations with biological CHD risk factors. METHODS Eighty-three male CHD-patients, 54 HT and 54 NT men repeatedly measured salivary cortisol over two consecutive days. Prospective CHD risk was assessed by changes between baseline and follow-up in the prothrombotic factors D-dimer and fibrinogen, the pro-inflammatory measures interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and acute phase protein C-reactive protein (CRP), as well as blood lipids in terms of total cholesterol (tChol)/high-density-lipoprotein cholesterol (HDL)-ratio. We aggregated coagulation and inflammatory measures to respective indices. RESULTS The groups differed in repeated daytime cortisol (dayCort) secretion (p=.005,η2 p=.03,f=0.18) and cortisol awakening response (CAR) (p=.006,η2 p=.03,f=0.18), with similarly lower overall dayCort and CAR in CHD-patients and HT, as compared to NT. The groups differed further in cortisol at awakening (p=.015,η2 p=.04,f=0.20) with highest levels in HT (p´s≤.050), and in diurnal slope between waking and evening cortisol (p=.033,η2 p=.04,f=0.20) with steepest slopes in HT (p´s≤.039), although in part not independent of confounders. Lower aggregated dayCort and CAR in terms of area-under-the-curve (AUC) independently predicted increases in future overall CHD risk (AUCdayCort: p=.021,η2 p=.10,f=0.33;AUCCAR: p=.028,η2 p=.09,f=0.31) 3.00 ± 0.06(SEM) years later, with risk prediction most pronounced in fibrinogen (AUCdayCort: p=.017,ΔR 2= 0.12;AUCCAR: p=.082). CONCLUSION We found evidence for an HPA-axis hypoactivity in CHD and HT with lower diurnal HPA-axis activity predicting increases in cardiovascular risk as evidenced by increases in circulating levels of biomarkers of atherothrombotic risk. Down-regulation of basal HPA-axis activity may contribute to the pathogenesis of atherosclerosis and thrombosis in CHD via effects on coagulation

Psychophysiological Stress Reactivity in Monozygotic Twins with and without Takotsubo Syndrome

Objective: Takotsubo syndrome (TTS) is characterized by transient left ventricular dysfunction, often elevated myocardial enzymes, and electrocardiographic changes. Previous studies suggested that an overstimulation of the sympathetic nervous system might cause TTS. However, the pathogenesis of TTS is largely unknown. Therefore, we investigated physiological stress reactivity with a standardized stress test in monozygotic twin sisters, only one of whom had experienced TTS. Methods: The 60-year-old Caucasian monozygotic twins, one with and one without a previous episode of TTS, were recruited in the Department of Cardiology at the University Hospital Zurich, Switzerland. We applied the Trier Social Stress Test (TSST) to investigate stress reactivity six weeks after the TTS. Hemodynamic measures (heart rate (HR), blood pressure (BP)), heart rate variability (HRV), plasma norepinephrine and epinephrine and salivary cortisol levels were collected immediately before and after the TSST, and 15, 45, and 90 min after TSST. The monozygotic twins differed in their hemodynamic stress response with the TTS twin showing blunted HR and BP reactivity and vagal withdrawal beyond the acute phase of stress. In contrast, the TTS twin showed a higher catecholamine and cortisol stress response with a steady increase in norepinephrine during the recovery period from stress compared to her non-TTS twin sister. Conclusion: Large studies applying a case-control design are needed to confirm blunted hemodynamic reactivity, increased catecholamine reactivity, vagal withdrawal, and increased cortisol reactivity to stress in TTS. This may advance the knowledge of psychophysiological mechanisms in TTS

Cross-sectional study on the impact of adverse childhood experiences on coronary flow reserve in male physicians with and without occupational burnout

OBJECTIVE Physicians face documented challenges to their mental and physical well-being, particularly in the forms of occupational burnout and cardiovascular disease. This study examined the previously under-researched intersection of early life stressors, prolonged occupational stress, and cardiovascular health in physicians. METHODS Participants were 60 practicing male physicians, 30 with clinical burnout, defined by the Maslach Burnout Inventory, and 30 non-burnout controls. They completed the Adverse Childhood Experiences (ACE) Questionnaire asking about abuse, neglect and household dysfunctions before the age of 18, and the Perceived Stress Scale to rate thoughts and feelings about stress in the past month. Endothelium-independent (adenosine challenge) coronary flow reserve (CFR) and endothelium-dependent CFR (cold pressor test) were assessed by positron emission tomography-computed tomography. The segment stenosis score was determined by coronary computed tomography angiography. RESULTS Twenty-six (43%) participants reported at least one ACE and five (8%) reported ≥4 ACEs. A higher ACEs sum score was associated with lower endothelium-independent CFR (r partial (r$_{p}$) = -0.347, p = .01) and endothelium-dependent CFR (r$_{p}$ = -0.278, p = .04), adjusting for age, body mass index, perceived stress and segment stenosis score. In exploratory analyses, participants with ≥4 ACEs had lower endothelium-independent CFR (r$_{p}$ = -0.419, p = .001) and endothelium-dependent CFR (r$_{p}$ = -0.278, p = .04), than those with <4 ACEs. Endothelium-dependent CFR was higher in physicians with burnout than in controls (r$_{p}$ = 0.277, p = .04). No significant interaction emerged between burnout and ACEs for CFR. CONCLUSION The findings suggest an independent association between ACEs and CFR in male physicians and emphasize the nuanced relationship between early life stressors, professional stress, and cardiovascular health

Association Between Changes in Post-hospital Cardiac Symptoms and Changes in Acute Coronary Syndrome-Induced Symptoms of Post-traumatic Stress.

Background After acute coronary syndrome (ACS), one in eight patients develops clinically significant symptoms of Post-traumatic stress disorder (PTSD). We hypothesized that changes in cardiac symptoms from 3 to 12 months after ACS are associated with changes in ACS-induced PTSD symptoms. Methods At 3 (n = 154) and/or 12 months (n = 106) post-ACS, patients (n = 156, mean age 59 years, 85% men) completed a clinical interview assessing chest tightness/pain (at rest and/or during exertion), heartbeat symptoms (heart palpitations, racing of heart, heart stumbling or skipping a beat) and PTSD symptoms during the prior 4 weeks. Random mixed regression models examined the association between the onset (or remission) from 3 to 12 months in cardiac symptoms with changes in PTSD symptoms, adjusting for a range of potential predictors of ACS-induced PTSD symptoms. Results The onset of chest tightness/pain [estimate = 0.588, 95% confidence interval: 0.275, 0.090; p < 0.001] and of heartbeat symptoms [0.548 (0.165, 0.931); p = 0.005] from 3 to 12 months was independently associated with an increase in total PTSD symptoms. There were also independent associations between the onset of chest tightness/pain and heartbeat symptoms with an increase in PTSD symptom clusters. Specifically, the onset of chest tightness/pain showed associations with an increase in re-experiencing [0.450 (0.167, 0.733); p = 0.027] and avoidance/numbing [0.287 (0.001, 0.574); p = 0.049]. The onset of heartbeat symptoms showed associations with an increase in re-experiencing [0.392 (0.045, 0.739); p = 0.002], avoidance/numbing [0.513 (0.161, 0.864); p = 0.004] and hyperarousal [0.355 (0.051, 0.659); p = 0.022]. An increase in the total number of cardiac symptoms (score range 0-6) was also associated with an increase in total PTSD symptoms [0.343 (0.202, 0.484); p < 0.001]. Psychotherapy in the post-hospital period moderated the association between the change in heartbeat symptoms and the change in total PTSD symptoms [-0.813 (-1.553, -0.074); p = 0.031 for interaction]; the association between the onset of heart beat symptoms and an increase in total PTSD symptoms was weaker in patients who attended psychotherapy [0.437 (-0.178, 1.052); p = 0.16] than in those who did not [0.825 (0.341, 1.309); p < 0.001]. Conclusion Changes in cardiac symptoms between 3 and 12 months after hospitalization are associated with changes in ACS-induced PTSD symptoms. ClinicalTrials.gov #NCT01781247

Association Between Changes in Post-hospital Cardiac Symptoms and Changes in Acute Coronary Syndrome-Induced Symptoms of Post-traumatic Stress

Background: After acute coronary syndrome (ACS), one in eight patients develops clinically significant symptoms of Post-traumatic stress disorder (PTSD). We hypothesized that changes in cardiac symptoms from 3 to 12 months after ACS are associated with changes in ACS-induced PTSD symptoms. Methods: At 3 (n = 154) and/or 12 months (n = 106) post-ACS, patients (n = 156, mean age 59 years, 85% men) completed a clinical interview assessing chest tightness/pain (at rest and/or during exertion), heartbeat symptoms (heart palpitations, racing of heart, heart stumbling or skipping a beat) and PTSD symptoms during the prior 4 weeks. Random mixed regression models examined the association between the onset (or remission) from 3 to 12 months in cardiac symptoms with changes in PTSD symptoms, adjusting for a range of potential predictors of ACS-induced PTSD symptoms. Results: The onset of chest tightness/pain [estimate = 0.588, 95% confidence interval: 0.275, 0.090; p < 0.001] and of heartbeat symptoms [0.548 (0.165, 0.931); p = 0.005] from 3 to 12 months was independently associated with an increase in total PTSD symptoms. There were also independent associations between the onset of chest tightness/pain and heartbeat symptoms with an increase in PTSD symptom clusters. Specifically, the onset of chest tightness/pain showed associations with an increase in re-experiencing [0.450 (0.167, 0.733); p = 0.027] and avoidance/numbing [0.287 (0.001, 0.574); p = 0.049]. The onset of heartbeat symptoms showed associations with an increase in re-experiencing [0.392 (0.045, 0.739); p = 0.002], avoidance/numbing [0.513 (0.161, 0.864); p = 0.004] and hyperarousal [0.355 (0.051, 0.659); p = 0.022]. An increase in the total number of cardiac symptoms (score range 0–6) was also associated with an increase in total PTSD symptoms [0.343 (0.202, 0.484); p < 0.001]. Psychotherapy in the post-hospital period moderated the association between the change in heartbeat symptoms and the change in total PTSD symptoms [−0.813 (−1.553, −0.074); p = 0.031 for interaction]; the association between the onset of heart beat symptoms and an increase in total PTSD symptoms was weaker in patients who attended psychotherapy [0.437 (−0.178, 1.052); p = 0.16] than in those who did not [0.825 (0.341, 1.309); p < 0.001]. Conclusion: Changes in cardiac symptoms between 3 and 12 months after hospitalization are associated with changes in ACS-induced PTSD symptoms