Heart rate variability (HRV),a measure of the fluctuations in the intervals between consecutive heartbeats, is an indicator of changes in the autonomic nervous system. A chronic reduction in HRV has been repeatedly linked to clinical depression. However, the chronological and mechanistic aspects of this relationship, between the neural, physiological, and psychopathological levels, remain unclear. In this review we present evidence by which changes in HRV might precede the onset of depression. We describe several pathways that can facilitate this relationship. First, we examine a theoretical model of the impact of autonomic imbalance on HRV and its role in contributing to mood dysregulation and depression. We then highlight brain regions that are regulating both HRV and emotion, suggesting these neural regions, and the Insula in particular, as potential mediators of this relationship. We also present additional possible mediating mechanisms involving the immune system and inflammation processes. Lastly, we support this model by showing evidence that modification of HRV with biofeedback leads to an improvement in some symptoms of depression. The possibility that changes in HRV precede the onset of depression is critical to put to the test, not only because it could provide insights into the mechanisms of the illness but also because it may offer a predictive anddiagnosticphysiological marker for depression. Importantly, it could also help to develop new effective clinical interventions for treating depression.

We are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection.

Assessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus).

We analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls.

AD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk.

Cardiovascular autonomic neuropathy should be taken into account in COVID-19 patients' assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.

We are facing the outburst of coronavirus disease 2019 (COVID-19) defined as a serious, multisystem, disorder, including various neurological manifestations in its presentation. So far, autonomic dysfunction (AD) has not been reported in patients with COVID-19 infection.

Assessment of AD in the early phase of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus).

We analyzed 116 PCR positive COVID-19 patients. After the exclusion of 41 patients with associate diseases (CADG), partitioned to patients with diabetes mellitus, hypertension, and syncope, the remaining patients were included into a severe group (45 patients with confirmed interstitial pneumonia) and mild group (30 patients). Basic cardiovascular autonomic reflex tests (CART) were performed, followed by beat-to-beat heart rate variability (HRV) and systolic and diastolic blood pressure variability (BPV) analysis, along with baroreceptor sensitivity (BRS). Non-linear analysis of HRV was provided by Poincare Plot. Results were compared to 77 sex and age-matched controls.

AD (sympathetic, parasympathetic, or both) in our study has been revealed in 51.5% of severe, 78.0% of mild COVID-19 patients, and the difference compared to healthy controls was significant (p = 0.018). Orthostatic hypotension has been established in 33.0% COVID-19 patients compared to 2.6% controls (p = 0.001). Most of the spectral parameters of HRV and BPV confirmed AD, most prominent in the severe COVID-19 group. BRS was significantly lower in all patients (severe, mild, CADG), indicating significant sudden cardiac death risk.

Cardiovascular autonomic neuropathy should be taken into account in COVID-19 patients' assessment. It can be an explanation for a variety of registered manifestations, enabling a comprehensive diagnostic approach and further treatment.

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.

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).

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.

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.

Parasympathetic activity is often reduced in hypertension and can elicit anti-inflammatory mechanisms. Thus we hypothesized that chronic vagal nerve stimulation (VNS) may alleviate cardiovascular end-organ damage in stroke-prone spontaneously hypertensive rats. Vagal nerve stimulators were implanted, a high-salt diet initiated, and the stimulators turned on (VNS, n = 10) or left off (sham, n = 14) for 4 wk. Arterial pressure increased equally in both groups. After 4 wk, endothelial function, assessed by in vivo imaging of the long posterior ciliary artery (LPCA) after stimulation (pilocarpine) and inhibition (N(ω)-nitro-l-arginine methyl ester) of endothelial nitric oxide synthase (eNOS), had significantly declined (-2.3 ± 1.2 μm, P < 0.05) in sham, but was maintained (-0.7 ± 0.8 μm, nonsignificant) in VNS. Furthermore, aortic eNOS activation (phosphorylated to total eNOS protein content ratio) was greater in VNS (0.83 ± 0.07) than in sham (0.47 ± 0.08, P < 0.05). After only 3 wk, ultrasound imaging of the aorta demonstrated decreased aortic strain (-9.7 ± 2.2%, P < 0.05) and distensibility (-2.39 ± 0.49 1,000/mmHg, P < 0.05) and increased pulse-wave velocity (+2.4 ± 0.7 m/s, P < 0.05) in sham but not in VNS (-3.8 ± 3.8%, -0.70 ± 1.4 1,000/mmHg, and +0.1 ± 0.7 m/s, all nonsignificant). Interleukin (IL)-6 serum concentrations tended to be higher in VNS than in sham (34.3 ± 8.3 vs. 16.1 ± 4.6 pg/ml, P = 0.06), and positive correlations were found between NO-dependent relaxation of the LPCA and serum levels of IL-6 (r = +0.70, P < 0.05) and IL-10 (r = +0.56, P < 0.05) and between aortic eNOS activation and IL-10 (r = +0.48, P < 0.05). In conclusion, chronic VNS prevents hypertension-induced endothelial dysfunction and aortic stiffening in an animal model of severe hypertension. We speculate that anti-inflammatory mechanisms may contribute to these effects.

Inflammation and vagally mediated heart rate variability (vmHRV) have been implicated in a number of conditions including diabetes and cardiovascular disease. Consistent with the inflammatory reflex termed the 'cholinergic anti-inflammatory pathway', numerous cross-sectional studies have demonstrated negative associations between vmHRV and inflammatory markers such as C-reactive protein (CRP). The only prospective study, however, showed the opposite: higher CRP at baseline predicted higher high-frequency heart rate variability (HF-HRV) at follow-up. Thus, additional studies are needed to examine the prospective association between vmHRV and CRP.

Healthy employees participated in a voluntary on-site health assessment. Blood samples and ambulatory heart rate recordings were obtained, and night-time HF-HRV was calculated. Useable heart rate data were available in 2007 for 106 nonsmoking employees (9% women; age 44.4 ± 8 years), all of whom returned for an identical follow-up health assessment in 2011. Bootstrapped (500 replications) bivariate (r) and partial Pearson's correlations (ppc) adjusting for sex, age and body mass index at baseline (2007) were calculated.

Zero-order correlations indicated that higher HF-HRV was associated with lower levels of CRP at both time-points (2007: r = -0.19, P < 0.05; 2011: r = -0.34, P < 0.001). After adjustment, HF-HRV remained a significant predictor of CRP (ppc = -0.20, P < 0.05).

In this study, we have provided in vivo support for the cholinergic anti-inflammatory pathway in humans. Cardiac vagal modulation at baseline predicts level of CRP 4 years later. Our findings have important implications for the role of vmHRV as a risk factor for cardiovascular disease morbidity and mortality. Interventions targeted at vmHRV might be useful in the prevention of diseases associated with elevated systemic inflammation.

Vascular biology, endothelial and vascular smooth muscle and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients can prevent, control and treat hypertension through numerous mechanisms related to vascular biology. Oxidative stress, inflammation and autoimmune dysfunction initiate and propagate hypertension and cardiovascular disease. There is a role for the selected use of single and component nutraceutical supplements, vitamins, antioxidants and minerals in the treatment of hypertension based on scientifically controlled studies which complement optimal nutrition, coupled with other lifestyle modifications.

Vascular biology, endothelial and vascular smooth muscle, and cardiac dysfunction play a primary role in the initiation and perpetuation of hypertension, cardiovascular disease, and target organ damage. Nutrient-gene interactions and epigenetics are predominant factors in promoting beneficial or detrimental effects in cardiovascular health and hypertension. Macronutrients and micronutrients may be able to prevent, control, or treat hypertension through numerous mechanisms related to vascular biology or other mechanisms. Oxidative stress, inflammation, and autoimmune dysfunction are some of the primary factors that initiate and propagate hypertension and cardiovascular disease. The literature suggests that there may be a complementary role of single and component nutraceutical supplements, vitamins, antioxidants, and minerals in the treatment of hypertension when combined with optimal nutrition and other lifestyle modifications. However, many of these studies are small and do not have long-term follow-up for efficacy and safety. The role of these nutrition and nutraceutical supplements will require careful review and additional studies to determine their exact role in the management of hypertension.

This systematic review evaluates and summarizes the evidence of the association between psychosocial work environment as indicated by several work-stress models such as Job-Demand-Control (JDC), Effort-Reward-Imbalance (ERI), or Organizational Justice (OJ) and autonomic nervous system (ANS) function as indexed by heart rate variability (HRV).

We conducted a systematic literature search following the PRISMA-Statement in eleven databases including Medline, Web of Science and PsycINFO to address medical as well as psychological aspects of the relation between psychosocial work-stress models and HRV.

We identified 19 publications with a total of 8382 employees from ten countries reporting data from the years 1976-2008. Overall, nine of all studies report a negative and significant association between vagally-mediated HRV and measures of stress at work, while eight of all studies report a negative and significant association to mixed sympathetic and parasympathetic measures of HRV.

This systematic review provides evidence that adverse psychosocial work conditions are negatively associated with ANS function as indexed by HRV.

Inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and hypertension-induced target-organ damage. The renin-angiotensin-aldosterone system can initiate not only innate but also acquired immunity. The latter process includes formation of activating antibodies directed at the angiotensin (Ang) II receptor. Ang II not only regulates vascular tone and sodium balance, but also activates immune cells and promotes cell infiltration into target organs. Studies showed that macrophages and various T cell subtypes play a pivotal role in target-organ damage and even in the regulation of blood pressure and responses to Ang II. Experimental and clinical evidence shows that adaptive transfer of immune cells, rendering mice deficient for a certain subset of immune cells, or immunosuppressive treatment affects blood pressure and ameliorates target-organ damage. Neural mechanisms interact with and regulate these processes. Understanding the mechanisms could direct us to novel therapies.