Erythropoietin (Epo) plays a crucial role in the formation and maturation of erythrocytes and is produced primarily by peritubular cells in the renal cortex. Previous studies suggest that renal sympathetic nerve activity (RSNA) may influence Epo regulation. Catheter-based renal denervation (RDN) has been shown to reduce renal noradrenaline spillover and blood pressure in patients with resistant hypertension. We therefore aimed to investigate whether RDN influences Epo levels. 33 patients with resistant hypertension (age 61 ± 12 y; baseline office blood pressure (BP) 165 ± 16/85 ± 18 mmHg despite treatment with an average of 4.9 ± 1.7 antihypertensive medications) underwent bilateral RDN. Plasma levels of Epo, office blood pressure, 24 h ambulatory blood pressure monitoring (ABPM), muscle sympathetic nerve activity (MSNA), renal function and haemoglobin were measured before the procedure and at 3 months follow-up. Antihypertensive medication was not changed during the first 3 months after RDN. Office blood pressure was reduced by 15 ± 19/5 ± 12 mmHg at 3 months after denervation (p < 0.001 for systolic BP; p = 0.033 for diastolic BP). 24h-mean systolic and diastolic BP were also reduced (from 145 ± 16 to 140 ± 18 mmHg; p = 0.036, and from 80 ± 11 to 77 ± 12 mmHg; p = 0.024), respectively. While haemoglobin levels remained unchanged, a significant increase in plasma Epo levels was observed at 3 months after RDN (7.81 ± 3.68 versus 9.88 ± 5.06 mIU/mL; p = 0.025). Changes in Epo levels correlated with baseline MSNA (r = 0.580, p = 0.004 for burst frequency; r = 0.471, p = 0.023 for burst incidence), such that the increase in Epo was most pronounced in patients with high baseline MSNA. The RDN-induced changes in MSNA tended to correlate inversely with changes in Epo levels (r = −0.402; p = 0.064). Our findings suggest that RDN is associated with increased plasma levels of Epo in the absence of changes in haemoglobin, and that these effects are possibly mediated via a reduction in sympathetic nerve activity.

Measures obtained from the full blood count have been shown to vary around a set point, are stable over years, and provide an indication of disease risk and mortality. In this study, we examined the association between sympathetic nerve activity and components of the full blood count. We performed a retrospective analysis of data drawn from our clinical database. Subjects were included if available data comprised full blood count and muscle sympathetic nerve activity (MSNA). Data were obtained from 160 individuals, comprising healthy volunteers, subjects who were overweight or with clinical obesity, and patients with high blood pressure. MSNA was correlated to the red cell distribution width (RDW, Spearman's rho 0.49 for MSNA b/min and 0.48 for MSNA b/100hb, p < 0.001 for both), but bore no association with any of the other blood variables. Regression analysis indicated that the RDW could be predicted by a combination of MSNA and BMI and to the number of components and diagnosis of the metabolic syndrome, measures of insulin resistance, and markers of inflammation. Our observations may provide insight into the possible mechanisms linking the RDW with mortality.

Abstract Loneliness is recognised as a risk factor for cardiovascular disease development. However, it is unclear whether loneliness itself or other closely related mental health symptoms, such as depression and social anxiety, are associated with the development of cardiovascular disease. In the present study, we examined the relationship between loneliness and several early cardiovascular disease markers in young adults, after controlling for depression and social anxiety. Sixty-six young adults (18–35 years old, M age = 22.70; 75.8% females) completed psychological questionnaires and took part in several physiological tests assessing cardiovascular health (e.g., vascular function). Results revealed higher loneliness was significantly associated with shorter pulse transit time (β = − 0.70, p = 0.002; shorter pulse transit time is a subclinical marker for arterial stiffness). Additionally, results show that while loneliness and depression were both related to vascular dysfunction in young adults, the underlining physiological mechanisms through which they affect vascular function may be different. Specifically, higher loneliness was associated with increased arterial stiffness, whereas depression was associated with increased endothelial dysfunction (β = − 0.43, p = 0.04). Our findings indicate that presence of loneliness and depression in young adults may be accompanied by early indicators of poor cardiovascular health, such as arterial stiffness and endothelial dysfunction. Results from the study further support the link between loneliness and cardiovascular disease development.

ObjectivesIn current study, we aim to extend previous research by investigating the unique impact of loneliness on health literacy and health-related factors of young adults, after controlling for social isolation, depressive symptomology, and social anxiety, as well as evaluate how social isolation and loneliness differ in their impact on health literacy, and health-related factors among young adults, after accounting for abovementioned concomitant variables.MethodsUsing a cross-sectional study design, 521 young adults completed an online survey in 2020, where they self-reported their loneliness, social isolation, health-related factors, and health literacy data.ResultsIncreased loneliness was associated with decrease in several health literacy domains (e.g., poorer social support for health, lower appraisal of health information, among others) and increase in some health-related factors (e.g., higher perceived stress, higher negative affect), among young adults, even after controlling for social anxiety, depressive symptomology, and social isolation. Contrastingly, increase in social isolation was associated with changes in some health-related factors - more somatic health complaints, higher alcohol use, poorer cognitive and physical functioning, and lower scores for only one health literacy domain (i.e., social support for health) among young adults, after adjusting for the influence of social anxiety, depressive symptomology, and loneliness.ConclusionEven after accounting for the influence of several co-occurring social and mental health symptoms, higher loneliness was associated poorer health literacy and health-related factors in young adults. We also found loneliness and social isolation may differ in the mechanisms through which they impact health literacy and health-related factors in young adults.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

COVID-19 pandemic and its associated social and physical distancing restrictions may have had a severe impact on health. In the present study, we investigate the changes in physical, social and mental health, as well as the health literacy of Australians subsequent to the onset of COVID-19 pandemic, and examine the influence of loneliness on these health-related factors. Using a retrospective cross-sectional study design, 607 Australian adults completed a self-report online survey which assessed their health-related factors before and after onset of the COVID-19 pandemic (data collected between June 2020 to November 2020). Australians reported statistically significant increase in a number of (poorer) health-related factors (e.g., weight gain, sleeping difficulties, poor somatic health, higher loneliness, more issues navigating the healthcare system) post onset of COVID-19 pandemic. Further, after adjusting for covariates, higher loneliness during pandemic predicted poorer health-related outcomes (e.g., more somatic health complaints, poorer quality of diet, poorer social support for health). The COVID-19 pandemic and its associated social and physical distancing restrictions may have contributed towards poorer health-related factors among Australian adults. Further, increased loneliness during the pandemic may have further worsened physical health and health literacy outcomes among Australians.

Objective: Young adults with Intellectual Disability (ID) are at higher risk of premature death, and present with increased prevalence of cardiovascular disease (CVD) than the general population. Cardiac autonomic neuropathy (CAN) is often associated with CVD risk factors including diabetes mellitus, metabolic syndrome and hypertension. Hence, it may be a predictor for cardiovascular morbidity and mortality. Screening for CAN risk through assessment of sudomotor function has been introduced as a method for early detection of autonomic dysfunction. Design and method: Adults with ID aged 18–45 years (n = 31) were compared to the general population (GP) (n = 29). Seated blood pressure, arterial stiffness (Pulse Wave Velocity [m/s] measured with Sphygmacor) and sudomotor function (measured with SUDOSCAN) were assessed. Results: Hand and feet electrical skin conductance (ESC) were lower in adults with ID ([Feet] ID = 72.8 microsiemens, GP = 80.4 microsiemens; p = 0.021 [Hands] ID = 65.6 microsiemens, GP = 76.8 microsiemens; p = 0.013) indicating elevated risk for CAN in the ID cohort. ESC in the ID population did not correlate with arterial stiffness, blood pressure nor body mass index (BMI), with both groups showing similar mean systolic blood pressures (ID = 127mmHg, GP = 122mmHg; p = 0.10) and PWV (ID = 8.0m/s, GP = 7.8m/s; p = 0.81), despite elevated BMI in the ID cohort (ID = 31.4 kg/m2, GP = 25.9 kg/m2; p = 0.002). However, ESC was related to Hb1Ac concentration, which was elevated in those with ID (ID = 34.4mmol/mol, GP = 29.7mmol/mol; p = 0.002). Conclusions: Our data indicates that sudomotor dysfunction is present in adults with ID and this was associated with impaired glucose metabolism. This suggest that CAN may play a role in the early development of CVD in young adults with ID. Given the increasing urgency to provide young individuals living with ID with the means to improve their health and wellbeing, screening for CAN could prove a useful tool in early detection of CVD risk, before the development of other typical risk factors including arterial stiffness and hypertension.

A growing number of clinical studies suggest that in heart failure renal denervation (RDN) has beneficial effects on the autonomic control of the heart. There is also experimental evidence that surgical RDN improves sodium handling and clearance in heart failure. The aim of this study was to determine the effects of catheter-based RDN on the sympathetic and parasympathetic control of the heart, and salt and water handling capacity of the kidneys, in sheep with established heart failure. A randomized, controlled study was conducted in 10 sheep with heart failure (ejection fraction<40%) induced by rapid ventricular pacing. Sheep underwent either bilateral RDN using the Symplicity denervation system or sham denervation and were studied 1 and 6 weeks after RDN. In established ovine heart failure, at 6 weeks after catheter-based RDN, heart rate significantly decreased, estimates of resting and maximal parasympathetic control of heart rate increased, and cardiac sympathetic nerve activity decreased. Compared with sham denervation, there was an increase in the resting sodium and water excretion 6 weeks after catheter-RDN and an improved ability of the kidneys to excrete a nonhypertensive saline load. After catheter-based RDN, renal norepinephrine levels were reduced by 70% compared with sham denervation. In established heart failure, RDN induced a beneficial shift in both arms of the autonomic nervous control of the heart and improved the ability of the kidneys to excrete sodium and water. Thus, effective catheter-based RDN may be beneficial to both the heart and kidneys in heart failure.

Background: Autonomic nervous system (ANS) dysfunction has been suggested to contribute to the high prevalence of cardiovascular complications in individuals with anorexia nervosa (AN), yet has not been thoroughly investigated. The current review aimed to synthesize the evidence of basal ANS function in individuals with a current diagnosis of AN and those with a previous diagnosis who had achieved weight restoration, as compared to controls. Methods: A systematic review of nine databases was conducted and studies that were published in a peer-review journal, in English, that included at least one assessment of ANS function in individuals with a current or previous diagnosis of AN were selected. Forty-six studies were included with a total of 811 participants with a current diagnosis of AN and 123 participants with a previous diagnosis of AN. Results: ANS function was assessed through heart rate variability ( n = 27), orthostatic challenge, blood pressure variability or baroreflex sensitivity ( n = 11), adrenergic activity ( n = 14), skin conductance level ( n = 4), and pupillometry ( n = 1). Individuals with AN demonstrated increased parasympathetic activity and decreased sympathetic activity, suggestive of autonomic dysregulation. Following weight restoration, autonomic function trended toward, or was equivalent to, control levels. Discussion: Autonomic dysregulation is indicated through a range of assessments in individuals with AN. Future investigations should utilize a variety of assessments together in order to conclusively establish the nature of autonomic dysfunction in AN, and following extended weight restoration. Moreover, investigation into the co-occurrence of ANS function and cardiovascular risk is required.

Cardiovascular complications have been demonstrated in patients with anorexia nervosa (AN) in both the state of starvation and during weight restoration, however, the underlying mechanisms remain unclear. The current study aimed to assess arterial stiffness via carotid-femoral pulse wave velocity (cfPWV) in the acute and weight-restored states of AN. The study also aimed to determine the association between psychological distress and cfPWV. The sample included 37 participants; 10 participants with AN, 17 who were weight-restored (AN-WR; minimum body mass index >18.5 for at least 12 months) and 10 healthy controls (HCs). cfPWV via applanation tonometry was conducted to assess arterial stiffness. Psychological distress was assessed using the depression anxiety stress scale (DASS-21) and the state-trait anxiety inventory (STAI). Between-group comparisons were performed to determine differences between groups, a two-stage hierarchical regression model was performed to determine the contribution of physiological and psychological variables on cfPWV and correlation analyses were also performed. Vascular stiffness was significantly increased in the AN and AN-WR groups, relative to HCs. The total DASS score was the only significant predictor of cfPWV across the sample. There were positive associations between cfPWV and depression, anxiety and stress, as assessed by the DASS. Furthermore, cfPWV was positively associated with STAI trait anxiety. Arterial stiffness was increased in individuals in the acute and weight-restored states of AN, demonstrating early signs of the development of arteriosclerotic cardiovascular disease. Increased arterial stiffness was associated with increased psychological distress, which may be a contributing mechanism to the increased cardiovascular risk in AN.

Recent findings in experimental models have shown that the microRNA miR-132 (mir-132) is an important regulator of liver homeostasis and lipid metabolism. We aimed to assess miR-132 expression in liver and fat tissues of obese individuals and examine its association with blood pressure (BP) and hepatic steatosis. We examined obese individuals undergoing bariatric surgery for weight loss (n = 19). Clinical and demographic information was obtained. Quantitative PCR was performed to determine tissue expression of miR-132 in liver and subcutaneous and visceral fat biopsies obtained during bariatric surgery. Liver biopsies were read by a single liver pathologist and graded for steatosis, inflammation and fibrosis. Participants (aged 39 ± 8.1 years) had a body mass index (BMI) of 42 ± 4.5 kg/m2 and presented with 2.2 ± 1.2 metabolic abnormalities. Supine BP was 127 ± 16/74 ± 11 mmHg. Hepatic and visceral fat expression of miR-132 were correlated (r = 0.59, P = 0.033). There was no correlation between subcutaneous and visceral expression of miR-132 (r = −0.31, P = 0.20). Hepatic and visceral fat miR-132 expression were associated with BMI (r = 0.62 and r = 0.68, P = 0.049 respectively) and degree of liver steatosis (r = 0.60 and r = 0.55, P < 0.05, respectively). Subcutaneous fat miRNA-132 expression was correlated to office systolic BP (r = 0.46, P < 0.05), several aspects of 24 h BP (24 h systolic BP: r = 0.52; day systolic BP: r = 0.59, P < 0.05 for all), plasma triglycerides (r = 0.51, P < 0.01) and liver enzymes (ALT: r = −0.52; AST: r = −0.48, P < 0.05 for all). We found an association between miR-132 and markers of cardiovascular and metabolic disease. Reduction of miR-132 may be a target for the regulation of liver lipid homeostasis and control of obesity-related blood pressure.

Amongst other immune cells, neutrophils play a key role in systemic inflammation leading to cardiovascular disease and can release inflammatory factors, including lipocalin-2 (LCN2). LCN2 drives cardiac hypertrophy and plays a role in maladaptive remodelling of the heart and has been associated with renal injury. While lifestyle factors such as diet and exercise are known to attenuate low-grade inflammation, their ability to modulate plasma LCN2 levels is unknown. Forty-eight endurance athletes and 52 controls (18–55 years) underwent measurement for various cardiovascular health indicators, along with plasma LCN2 concentration. No significant difference in LCN2 concentration was seen between the two groups. LCN2 was a very weak predictor or absent from models describing blood pressures or predicting athlete status. In another cohort, 57 non-diabetic overweight or obese men and post-menopausal women who fulfilled Adult Treatment Panel III metabolic syndrome criteria were randomly allocated into either a control, modified Dietary Approaches to Stop Hypertension (DASH) diet, or DASH and exercise group. Pre- and post-intervention demographic, cardiovascular health indicators, and plasma LCN2 expression were measured in each individual. While BMI fell in intervention groups, LCN2 levels remained unchanged within and between all groups, as illustrated by strong correlations between LCN2 concentrations pre- and 12 weeks post-intervention ( r = 0.743, P < 0.0001). This suggests that circulating LCN2 expression are stable over a period of at least 12 weeks and is not modifiable by diet and exercise.

There is increasing evidence that renal denervation is effective in alleviating hypertension associated with elevation of renal sympathetic nerve activity (RSNA) in chronic kidney disease (CKD), but whether this is due to reduction in renal afferent signaling is unclear. We determined the cardiovascular and sympathetic effects of total renal denervation or afferent renal denervation (topical capsaicin) on CKD induced by glomerular layer lesioning of the left kidney and right nephrectomy in conscious rabbits. CKD increased blood pressure by 18±2 mmHg and plasma creatinine by 40% over 2 to 4 weeks (both P <0.001), while RSNA (43%) and total norepinephrine spillover (28%) were elevated in CKD compared with sham (both P =0.04). After total or afferent renal denervation blood pressure, RSNA and norepinephrine spillover were similar or lower than non-CKD (sham) rabbits. While plasma creatinine in CKD rabbits was not affected by total renal denervation, deafferented rabbits had lower levels ( P =0.017). The greater hypotensive response to pentolinium in CKD was also normalized after total or afferent denervation. Heart rate and RSNA baroreflex gain were similar in all groups. The RSNA response to airjet stress was greater in CKD compared with sham but not after total or afferent renal denervation. By contrast, the sympathetic response to hypoxia was similar in sham and CKD intact or deafferented groups but elevated in total denervated CKD animals. We conclude that the elevated sympathetic activity and blood pressure in this model of CKD is predominantly driven by renal afferents.

Brown adipose tissue (BAT) activation is a possible therapeutic strategy to increase energy expenditure and improve metabolic homeostasis in obesity. Recent studies have revealed novel interactions between BAT and circulating lipid species—in particular, the non-esterified fatty acid (NEFA) and oxylipin lipid classes. This study aimed to identify individual lipid species that may be associated with cold-stimulated BAT activity in humans. A panel of 44 NEFA and 41 oxylipin species were measured using mass-spectrometry-based lipidomics in the plasma of fourteen healthy male participants before and after 90 min of mild cold exposure. Lipid measures were correlated with BAT activity measured via 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT), along with norepinephrine (NE) concentration (a surrogate marker of sympathetic activity). The study identified a significant increase in total NEFA concentration following cold exposure that was positively associated with NE concentration change. Individually, 33 NEFA and 11 oxylipin species increased significantly in response to cold exposure. The concentration of the omega-3 NEFA, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) at baseline was significantly associated with BAT activity, and the cold-induced change in 18 NEFA species was significantly associated with BAT activity. No significant associations were identified between BAT activity and oxylipins.

BPH/2J mice are a genetic model of hypertension with overactivity of the sympathetic nervous system (SNS) and renin–angiotensin system (RAS). BPH/2J display higher renal renin mRNA and low levels of its negative regulator microRNA-181a (miR-181a). We hypothesise that high renal SNS activity may reduce miR-181a expression, which contributes to elevated RAS activity and hypertension in BPH/2J. Our aim was to determine whether in vivo administration of a renal-specific miR-181a mimic or whether renal denervation could increase renal miR-181a abundance to reduce renal renin mRNA, RAS activity and hypertension in BPH/2J mice. Blood pressure (BP) in BPH/2J and normotensive BPN/3J mice was measured via radiotelemetry probes. Mice were administered miR-181a mimic or a negative control (1–25 nmol, i.v., n = 6–10) with BP measured for 48 h after each dose or they underwent renal denervation or sham surgery (n = 7–9). Injection of 5–25 nmol miR-181a mimic reduced BP in BPH/2J mice after 36–48 h (−5.3 ± 1.8, −6.1 ± 1.9 mmHg, respectively, P < 0.016). Treatment resulted in lower renal renin and inflammatory marker (TLR4) mRNA levels in BPH/2J. The mimic abolished the hypotensive effect of blocking the RAS with enalaprilat (P < 0.01). No differences between mimic or vehicle were observed in BPN/3J mice except for a higher level of renal angiotensinogen in the mimic-treated mice. Renal miR-181a levels that were lower in sham BPH/2J mice were greater following renal denervation and were thus similar to those of BPN/3J. Our findings suggest that the reduced renal miR-181a may partially contribute to the elevated BP in BPH/2J mice, through an interaction between the renal sympathetic nerves and miR-181a regulation of the RAS.

Unlike noradrenaline, the sympathetic neurotransmitter which overflows to the circulation, adrenaline (ADR) is a secreted hormone, with a low plasma concentration, and plasma concentration for biological action a log order lower than that of noradrenaline. The venous drainage of the left adrenal medulla into the left renal vein does expose this vein to uniquely high plasma ADR concentrations and possible risk of thrombosis at high rates of ADR secretion. There is typically a different timeframe for adrenal medullary and sympathetic nervous system responses: ADR release is short term in contrast with sympathetic activation persisting for years in heart failure and hypertension. The historic view of Walter Cannon, subject to recent review, that the sympathoadrenal system is a unified biological system, was deconstructed further with demonstration of frequent mismatching of adrenal medullary and sympathetic nervous responses. Under gravity stimulation with standing, there is prompt sympathetic activation without ADR release. In many diseases, notably obesity, hypertension, heart failure and depressive illness, an activated sympathetic nervous system and silent adrenal medulla coexist. The therapeutic corollary of this is that ADR blockade is much less commonly needed clinically than pharmacological antagonism of the sympathetic nervous system.

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-β, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

This is the first trial to examine both the effects of interrupting prolonged sitting on vascular function in type 2 diabetes and the effects of the frequency and duration of interruptions. Brief, simple resistance activity bouts every 30 min, but not every 60 min, increased mean femoral artery flow-mediated dilation over 7 h, relative to uninterrupted sitting. With further supporting evidence, these initial findings can have important implications for cardiovascular health in type 2 diabetes.