UNLABELLED: Multiple studies have demonstrated low vagally-mediated heart rate variability (HRV) being associated with a range of risk factors for heart disease and stroke, including inflammation, hyperglycemia, hyperlipidemia, and hypertension. Yet, no cut point exists that indicates elevated risk. In the present study we sought to identify a cut point-value for HRV that is associated with elevated risk across a range of known risk factors. METHODS: A total of 9550 working adults from 19 study sites took part in a health assessment that included measures of inflammation, hyperglycemia, hyperlipidemia, and hypertension and vagally-mediated HRV (Root mean square of successive differences between normal heartbeats (RMSSD)). Multiple age and sex adjusted logistic regressions were calculated per risk factor (normal versus clinical range), with RMSSD being entered in binary at different cut points ranging from 15-39 msec with a 2 msec increment. RESULTS: For daytime RMSSD, values below 25 ± 4 indicated elevated risk (odds ratios (OR) 1.5-3.5 across risk factors). For nighttime RMSSD, values below 29 ± 4 indicated elevated risk (OR 1.2-2.0). CONCLUSION: These results provide the first evidence that a single value of RMSSD may be associated with elevated risk across a range of established cardiovascular risk factors and may present an easy to assess novel marker of cardiovascular risk.

In recent clinical practice, a biomarker of vagal neuroimmunomodulation (NIM), namely the ratio of vagally-mediated heart rate variability (vmHRV) and CRP, was proposed to index the functionality of the cholinergic anti-inflammatory pathway. This study aims to transfer and extend the previous findings to two general population-based samples to explore the hypothesis that NIM-ratio is associated with all-cause mortality. Two large population studies (MIDUS 2: N = 1255 and Whitehall II wave 5: N = 7870) with complete data from a total of N = 3860 participants (36.1% females; average age = 56.3 years; 11.1% deaths, last exit 18.1 years post inclusion) were available. NIM indices were calculated using the vagally-mediated HRV measure RMSSD divided by measures of CRP (NIM_CRP) or IL-6 (NIM_IL6). The NIM-ratios were quartiled and entered into age, ethnicity and body mass index adjusted Cox proportional hazards models. For NIM_IL6 the lowest quartile was 45% more likely to die during the observed period (max. 18 years follow-up) compared to the highest quartile (HR = 0.55 CI 0.41-0.73; p < .0001). NIM_CRP parallel these results. Here we show that an easily computable index of IL-6 inhibition is associated with all-cause mortality in two large general population samples. These results suggest that this index might be useful for risk stratification and warrant further examination.

BACKGROUND: Type-D personality, defined as a combination of high negative affect and high social isolation, has been associated with poor health outcomes. However, pathways underlying this association are largely unknown. We investigated the relationship between Type-D personality and several biological and behavioral pathways including the autonomic nervous system, the immune system, glucose regulation and sleep in a large, apparently healthy sample. METHODS: Data from a total of 646 respondents (age 41.6±11.5, 12,2% women) were available for analysis. Persons with Type-D (negative affect and social isolation score ≥10) were contrasted with those without Type-D. Measures of plasma fibrinogen levels, white blood cell count, high sensitivity C-reactive protein, fasting plasma glucose (FPG), cholesterol, high-density and low-density lipoprotein, glycated hemoglobin (HbA1c), creatinine, triglycerides, and albumin were derived from fasting blood samples. Urine norepinephrine and free cortisol were determined by high-performance liquid chromatography. Time-domain heart rate variability (HRV) measures were calculated for the 24hr recording period and for nighttime separately. RESULTS: Persons with Type-D had higher HbA1c, FPG, and fibrinogen, and lower nighttime HRV than those without Type-D, suggesting worse glycemic control, systemic inflammation and poorer autonomic nervous system modulation in Type-D persons. In addition, those with Type-D reported less social support and greater sleep difficulties while no group differences were observed for alcohol and cigarette consumption, physical activity and body mass index. CONCLUSIONS: Findings provide some of the first evidence for multiple possible biological and behavioral pathways between Type-D personality and increased morbidity and mortality.

INTRODUCTION: Depressive symptoms (DS) in humans are associated with decreased resting state vagal activity, but sex seems to moderate this association. Recently, in human females DS have been associated with greater or similar cardiac vagal activity compared to men in both, clinical and non-clinical samples. A previously validated animal model of behavioral depression was used in the present study to investigate the association of DS and cardiac vagal activity in non-human primates. METHODS: The root mean square of successive differences between adjacent heart beats (RMSSD) was used as an indicator of vagally-mediated heart rate variability in 24h heart rate recordings collected via telemetry in 42 adult female cynomolgus monkeys (Macaca fascicularis). Hierarchical regression models were used to estimate differences in RMSSD comparing monkeys with and without DS. To capture circadian variation patterns of RMSSD, additional quadratic, cubic and quartic terms of hour were added. RESULTS: Monkeys showing behavioral DS had higher overall 24-h RMSSD. The interaction term of daytime with DS and polynomials of hour contributed significantly to the variance across models. CONCLUSIONS: This is the first study investigating the association of DS and 24h cardiac vagal control in female non-human primates. Results replicate existing human studies showing higher cardiac vagal control in behavioral depressed vs. non-depressed female monkeys.

PURPOSE: A characteristic problem occurring in COVID-19 is excessive elevations of pro-inflammatory cytokines (e.g. IL-6 and CRP) which are associated with worse clinical outcomes. Stimulation of the vagally-mediated cholinergic anti-inflammatory reflex by slow paced breathing with prolonged exhalation may present a clinically relevant way to reduce circulating IL-6. METHOD: Single-center randomized controlled clinical trial with enrolment of 46 patients hospitalized with confirmed severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (primary diagnosis). Differences between intervention (4sec inhalation, 6sec exhalation for 20 minutes 3x daily) and control group in IL-6 calculated using multilevel mixed-effect linear regression models with random slope including the covariates relevant comorbidities, COVID-19 medication, and age. Both groups received standard care. RESULTS: Mean age was 57 years ± 13 years, N= 28 (60%) male, N=30 (65%) with relevant comorbidities. The model including group-by-time interaction revealed a significantly lower trajectory of IL-6 in the intervention group (effect size Cohens f2 = 0.11, LR-test p=.040) in the intention-to-treat sample, confirmed by per-protocol analysis (f2 = 0.15, LR-test p=.022). Exploratory analysis using the median split of practice time to predict IL-6 of the next morning indicated a dose-response relationship with beneficial effects of practice time above 45 minutes per day. Oxygen saturation remained unchanged during slow-paced breathing (95.1% ± 2.1% to 95.4% ± 1.6%). CONCLUSION: Patients practicing slow-paced breathing had significantly lower IL-6 values than controls with a small to medium effect size and without relevant side effects. Further trials should evaluate clinical outcomes and an earlier start of the intervention. Slow-paced breathing could be an easy to implement, low-cost, safe and feasible adjuvant therapeutic approach to reduce circulating IL-6 in moderate COVID-19 pneumonia. CLINICAL TRIAL REGISTRATION: https://www.drks.de, identifier DRKS00023971, Universal Trial Number (UTN) U1111-1263-8658.

Multiple studies have demonstrated low vagally-mediated heart rate variability (HRV) being associated with a range of risk factors for heart disease and stroke, including inflammation, hyperglycemia, hyperlipidemia, and hypertension. Yet, no cut point exists that indicates elevated risk. In the present study we sought to identify a cut point-value for HRV that is associated with elevated risk across a range of known risk factors. A total of 9550 working adults from 19 study sites took part in a health assessment that included measures of inflammation, hyperglycemia, hyperlipidemia, and hypertension and vagally-mediated HRV (Root mean square of successive differences between normal heartbeats (RMSSD)). Multiple age and sex adjusted logistic regressions were calculated per risk factor (normal versus clinical range), with RMSSD being entered in binary at different cut points ranging from 15-39 msec with a 2 msec increment. For daytime RMSSD, values below 25 ± 4 indicated elevated risk (odds ratios (OR) 1.5-3.5 across risk factors). For nighttime RMSSD, values below 29 ± 4 indicated elevated risk (OR 1.2-2.0). These results provide the first evidence that a single value of RMSSD may be associated with elevated risk across a range of established cardiovascular risk factors and may present an easy to assess novel marker of cardiovascular risk.

Interest in cardiac vagal activity (CVA; e.g., parasympathetically-mediated heart rate variability) as a biomarker of physical and mental health has increased exponentially in recent years. However, the understanding of sources of within-person change (i.e., intra-individual variance) in CVA is lagging behind. This systematic review and meta-analysis summarizes and quantifies current empirical evidence of within-person changes in measures of CVA across the menstrual cycle in naturally-cycling premenopausal females. We conducted an extensive literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement in five databases to identify observational studies with repeated measures of CVA in at least two menstrual cycle phases. A broad meta-analysis (nstudies = 37; nindividuals = 1,004) revealed a significant CVA decrease from the follicular to luteal phase (d = -0.39, 95% CI (-0.67, -0.11)). Furthermore, 21 studies allowed for finer-grained comparisons between each of two cycle phases (menstrual, mid-to-late follicular, ovulatory, early-to-mid luteal, and premenstrual). Significant decreases in CVA were observed from the menstrual to premenstrual (nstudies = 5; nindividuals = 200; d = -1.17, 95% CI (-2.18, -0.17)) and from the mid-to-late follicular to premenstrual phases (nstudies = 8; nindividuals = 280; d = -1.32, 95% CI (-2.35, -0.29)). In conclusion, meta-analyses indicate the presence of CVA fluctuations across the menstrual cycle. Future studies involving CVA should control for cycle phase. Recommendations for covarying or selecting cycle phase are provided.

New tools for non-specific primary prevention strategies covering somatic and mental health in occupational medicine are urgently needed. Heart rate variability (HRV) reflects the capacity of the body to adapt to environmental challenges and of the mind to regulate emotions. Hence, a 24 h-measurement of HRV offers a unique possibility to quantify the interaction between situation-specific emotional regulation within a specific psychosocial environment and physiological state, thereby increasing self-perception and inducing motivation to change behavior. The focus of the present study represents such a 24 h-measurement of HRV and its presentation as a comprehensive graph including protocol situations of the client. A special training program for occupational health physicians and questionnaires for clients were developed and administered. The article reports the first data of the study healthy leadership and work - body signals for managers and employees, an investigator-initiated, interventional, single-arm, open (non-blinded), multicenter, national trial with 168 participants. They reported a significantly improved perception of their bodily needs after the consultation (from Median = 7, interquartile range 5-8 to Median = 8, interquartile range 7-9; scale range from 1 to 10; p < 0.001, Wilcoxon rank test; effect size 0.49). The 16 occupational health physicians stated that the measurement of HRV was very well suited to enter into dialog with the managers and was feasible to show interactions between situations, thoughts, feelings, and bodily reactions. Taken together, we show that a 24 h-HRV-measurement can be a feasible and effective approach for holistic, psychosomatic primary prevention in occupational medicine. We discuss possible mechanisms for improving the individual health via the consultation, containing mindset and improved ANS activity.

BACKGROUND: A recent meta-analysis revealed that vagally mediated heart rate variability (vmHRV; a biomarker of emotion regulation capacity) significantly decreases in the luteal phase of the menstrual cycle. As two follow-up studies suggest, these vmHRV decreases are driven primarily by increased luteal progesterone (P4). However, analyses also revealed significant interindividual differences in vmHRV reactivity to the cycle, which is in line with longstanding evidence for interindividual differences in mood sensitivity to the cycle. The present study begins to investigate whether these interindividual differences in vmHRV cyclicity can explain who is at higher risk of showing premenstrual emotional changes. We expected a greater degree of midluteal vmHRV decrease to be predictive of a greater premenstrual increase in negative affect. METHODS: We conducted an observational study with a naturally cycling community sample (N = 31, M = 26.03 years). Over a span of six weeks, participants completed (a) daily ratings of negative affect and (b) counterbalanced lab visits in their ovulatory, midluteal, and perimenstrual phases. Lab visits were scheduled based on positive ovulation tests and included assessments of baseline vmHRV and salivary ovarian steroid levels. RESULTS: In line with previous research, multilevel models suggest that most of the sample shows ovulatory-to-midluteal vmHRV decreases which, however, were not associated with premenstrual emotional changes. Interestingly, it was only the subgroup with luteal increases in vmHRV whose negative affect markedly worsened premenstrually and improved postmenstrually. CONCLUSION: The present study begins to investigate cyclical changes in vmHRV as a potential biomarker of mood sensitivity to the menstrual cycle. The results demonstrate a higher level of complexity in these associations than initially expected, given that only atypical midluteal increases in vmHRV are associated with greater premenstrual negative affect. Potential underlying mechanisms are discussed, among those the possibility that luteal vmHRV increases index compensatory efforts to regulate emotion in those with greater premenstrual negative affect. However, future studies with larger and clinical samples and more granular vmHRV assessments should build on these findings and further explore associations between vmHRV cyclicity and menstrually related mood changes.

BACKGROUND: Work stress is associated with an increased risk of pre-diabetes, Type 2 diabetes, and inflammation, as well as decreased autonomic nervous system function as measured, for example, via heart rate variability. We investigated the extent to which the association between work stress and glycemic status is mediated by vagally-mediated heart rate variability (vmHRV) and/or inflammation. METHODS: Cross-sectional data from the Mannheim Industrial Cohort Study (MICS) with 9,937 participants were analyzed. The root mean squared successive differences (RMSSD) from long-term heart rate monitoring during work and night time periods was used to index vmHRV. Fasting plasma glucose and glycosylated hemoglobin were assessed to determine glycemic status. High sensitive C-reactive protein levels were observed as a measure of systemic inflammation and the Effort-Reward-Imbalance scale was used to evaluate work stress. Mediation models were adjusted for age, sex, and occupational status, and estimations were bootstrapped (5,000 replications). RESULTS: Effort-Reward-Imbalance was significantly negatively associated with RMSSD and both glycosylated hemoglobin and fasting plasma glucose during both work and night time periods. Effort-Reward-Imbalance was observed to have a significant direct effect on glycosylated hemoglobin and significant indirect effects, through RMSSD, on both glycemic measures during both time periods. Introducing C-reactive protein as a further mediator to the model did not alter the indirect effects observed. C-reactive protein, as an exclusive mediator, was observed to have smaller direct and indirect effects on the glycemic measures as compared to when Effort-Reward-Imbalance was included in the model. CONCLUSIONS: Our results suggest that the association between work stress and glycemic status is partially mediated through vmHRV independent of systemic inflammation as measured by C-reactive protein. We conclude that work stress may be an additional factor that promotes development of hyperglycemic-metabolic states. If supported by prospective evidence, these results may lead to new approaches for primary prevention of hyperglycemia in the workplace.