One of the major causes of hypertension (HT) is the transition of normal weight (NW) status to overweight (OW) status and obesity in a population, which leads to cardiovascular disease (CVD) and other disorders. A variety of factors/variables are involved in the development of HT and OW-related hypertension (OHT). However, we planned to investigate the pathophysiological role of serum leptin (Lep), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total cholesterol (TC) and serum testosterone (ST) in OHT in middle-aged men.

We consulted three groups of middle-aged men (age: 51-60 years)-an HT group (n: 97, high normal weight (HNW), body mass index (BMI): 23-24.9 kg/m2); an OHT group (n: 97, high overweight (HOW), BMI: 28-29.9 kg/m2) and a normal control group (NC, n: 98, HNW)-to investigate the variations in and correlations of Lep, IL-6, TNF-α, ST, TC and other variables.

Significant variations were obtained for the comparisons of TNF-α, Lep, ST and TC for the patient groups. OHT vs. NC showed a significant difference for ST. OHT vs. NC and OHT vs. HT had significant variations for IL-6. Significant changes were obtained for the serum levels of TNF-α, Lep, IL-6, ST and TC among groups. Significant and positive linear associations were obtained for TNF-α, Lep, TC and IL-6. Significant and negative linear associations were found for ST plotted against Lep, TNF-α and IL-6.

The current report provides pathophysiological evidence of the interactive role of serum Lep, TNF-α, ST, TC and IL-6 in middle-aged men with HT and OHT. We suggest that the changes we noted in the present study would be helpful for further BMI-based studies in various subcategories of NW, OW and obese subjects with/without HT.

A 52-year-old male comes to the internal medicine clinic for a follow-up for the management of hypertension. He was initially diagnosed with hypertension 5 years ago. His other past medical history includes obesity and hyperlipidemia. His current medications currently include losartan 100 mg daily, hydrochlorothiazide 25 mg, and amlodipine 10 mg. His physical exam is significant for an elevated in-office blood pressure of 160/105 mmHg, BMI 38, and neck circumference > 40 cm. He also reports snoring at night and having significant daytime sleepiness despite getting over 8 hours of sleep each night. This patient meets the most recent diagnostic criteria per the American Heart Association for resistant hypertension. Resistant hypertension is an increasingly prevalent phenotype encountered in both primary care and subspecialty clinics. Multiple comorbidities, including obesity, sleep apnea, chronic kidney disease, heart failure, and diabetes mellitus, are associated with resistant hypertension. Our understanding of the potential etiologies for this condition continues to evolve rapidly. We used a narrative review to explore four research areas in the pathophysiology of resistant hypertension (the sympathetic nervous system, aldosterone excess, endothelial dysfunction, and inflammation) and explore the novel therapies currently in development.

Use of type 2 sodium-glucose cotransporter inhibitors (SGLT2i) gliflozines have first been applied to treatment of diabetic patients. In this setting, unexpected benefits on concomitant heart failure (HF) were seen in large trials. This clinical benefit was initially traced back to their natriuretic properties and as such they were also included in the therapeutic armamentarium of HF treatment. However, further insight into their mechanism of action has clarified their complex interaction with kidney function which better explains their prompt effectiveness in ameliorating HF outcome in the long-term, independent of left ventricular ejection fraction (LVEF) phenotype and concomitant presence of diabetes and/or chronic renal disease. This mainly results from the ability of SGLT2i to counteract the HF-associated hyperactivity of the sympathetic system and neurohormonal activation by modifying the pattern of renal tubular sodium and glucose reabsorption which results in curbing the overall sodium reabsorption. Their action results in decreased kidney workload and related oxygen consumption thus indirectly reducing sympathetic activity. The complex renal functional changes associated with HF and their modifications during SGLT2i administration will be reviewed.

Transcatheter renal denervation (RDN) remains inconsistent despite developments in ablation technologies, due to the lack of an intraprocedural physiological end point. The aim of this study was to identify if aorticorenal ganglion (ARG) guided RDN using microwave (MW) catheter leads to more consistent denervation outcomes compared with empirical MW ablation.

Pigs underwent sham procedure (n=8) or bilateral RDN using an in-house built open-irrigated MW catheter. Before denervation, ipsilateral ARG pacing was performed leading to renal artery vasoconstriction. MW ablation group (MW-group; n=7) received 1 ablation (100-120 W for 360 seconds) in the mid-main renal artery based on artery caliber. ARG-guided-MW ablation group (ARG-MW-group; n=7) was permitted an additional ablation more distally or at higher power until a vasoconstrictive response was abolished. Animals were euthanized at 4 to 5 weeks post-procedure.

ARG pacing caused an ipsilateral reduction in renal artery caliber from 4.67 to 4 mm; P=0.0006 in MW-group and 4.8 to 3.9 mm; P=0.001 in ARG-MW-group. Repeat ARG pacing at euthanasia led to a reduction in renal artery caliber in MW-group from 5.1 to 4.8 mm; P=0.006, but not in ARG-MW-group from 4.88 to 4.55 mm; P=0.08. There were no differences in ablation injury volumes between the groups. Compared with undenervated sham controls, ARG-MW-RDN versus MW-RDN caused median reductions in viable nerve area (antityrosine hydroxylase staining) at 4 to 5 weeks by 92.6% (interquartile range, 0.94-19.59%; P<0.0001) versus 55.02% (interquartile range, 15.87-75.11%; P=0.006) and median renal cortical norepinephrine content by 68.06% (interquartile range, 27.16-38.39%; P<0.0001) versus 25.25% (interquartile range, 56.97-157.7%; P=NS).

ARG pacing serves as a physiological procedural end point to guide MW denervation to improve denervation outcomes.

Obesity, along with hypoxia, is known to be a risk factor for pulmonary hypertension (PH), which can lead to right ventricular hypertrophy and eventually heart failure. Both obesity and PH influence the autonomic nervous system (ANS), potentially aggravating changes in the right ventricle (RV). This study investigates the combined effects of obesity and hypoxia on the autonomic innervation of the RV in a mouse model. Male C57BL/6N mice were subjected to a control diet (CD) or a high-fat diet (HFD) for 30 weeks, with subsets of the mice exposed to chronic normobaric hypoxia (13% O2) during the final 3 weeks. Light and electron microscopic stereology was used to quantify various parameters of nerve fibres innervating the RV myocardium. HFD-induced obesity significantly increased the total length of nerve fibres and axons in the RV under normoxic conditions, indicating hyperinnervation. Quantitatively, the length density of nerve fibres per unit volume of RV (unit: x10-3 µm-2) was similar in CD (0.158 ± 0.04), CD-Hyp (0.176 ± 0.06) and HFD-Hyp (0.147 ± 0.05). In contrast, in HFD the length density of nerve fibres showed higher values 0.206 ± 0.054. The total length of nerve fibres increased by 67% from 2.61 m ± 0.77 m in CD to 4.37 m ± 1.51 m in HFD. The total length of axons increased by 80% from 8.87 m ± 2.75 m to 15.95 m ± 4.62 m. However, when obesity was combined with hypoxia, the total axon length was significantly reduced by 27% in HFD-Hyp compared with HFD. In addition, the mean number of axon profiles per nerve fibre profile decreased from 3.44 ± 0.68 in HFD to 2.95 ± 0.43 in HFD-Hyp. Interestingly, chronic hypoxia alone did not significantly alter RV innervation but led to RV hypertrophy, independent of the diet. The attenuation of obesity-induced hyperinnervation by hypoxia suggests a complex and potentially antagonistic interaction between these conditions. In conclusion, obesity induced by a HFD caused hyperinnervation of the RV, whereas chronic hypoxia alone did not significantly alter RV innervation. Surprisingly, chronic hypoxia attenuated the obesity-induced changes in RV innervation. These findings indicate that the effects of obesity and hypoxia-induced PH on RV innervation are distinct and potentially antagonistic.

Background and Objectives: This study aimed to evaluate and compare the functional capacity of post-COVID-19 patients with a control group and analyze cardiac hemodynamics and muscle tissue oxygenation responses during assessment protocols in both groups. Materials and Methods: A cross-sectional study was conducted involving patients with COVID-19 and a control group who were all aged ≥18 years. Participants underwent two functional capacity tests: the one-minute sit-stand test (1-STS) and the six-minute walk test (6MWT). Cardiac hemodynamic responses were evaluated using impedance during the 1-STS, and tissue perfusion responses in the oxygenation were recorded during and after both tests. The Friedman test was used for within-group and the Mann-Whitney test was used for between-group comparisons. Results: Thirty-six post-COVID-19 patients (median age 36 years, BMI 26.51 kg/m2) and eleven control subjects (median age 25 years, BMI 23.71 kg/m2) were enrolled. The post-COVID-19 group showed a 20% decrease in 6MWT distance (p = 0.0001) and a 28% decrease in 1-STS repetitions (p = 0.01) versus the control group. Cardiac hemodynamic differences were observed in the post-COVID-19 group during the 1-STS, with reductions in the stroke volume index (18%, p = 0.004), cardiac index (21%, p = 0.0009), Contractility Index (78%, p = 0.0001), and Ejection Fraction (29%, p = 0.0003) and increases in Systemic Vascular Resistance (25%, p = 0.03) and the Systemic Vascular Resistance Index (27%, p = 0.0007). Tissue oxygenation during the 6MWT and 1-STS showed no significant differences between groups. Conclusions: The post-COVID-19 subjects exhibited a reduction in functional capacity, changes in hemodynamic responses related to cardiac and systemic vascular resistance, and a similar pattern of muscle oxygen delivery and consumption in both tests.

Sympathoexcitation, a manifestation of heart-brain axis dysregulation, contributes to the progression of heart failure (HF). Our recent study revealed that circulating mitochondria (C-Mito), a newly identified mediator of multi-organ communication, promote sympathoexcitation in HF by aggravating endothelial cell (EC)-derived neuroinflammation in the subfornical organ (SFO), the cardiovascular autonomic neural center. The precise molecular mechanism by which C-Mito promotes SFO-induced endothelial neuroinflammation has not been fully elucidated.

C-Mito carrying cGAS promote sympathoexcitation by targeting PLA2G2A in ECs of the SFO in HF rats.

Male Sprague-Dawley (SD) rats received a subcutaneous injection of isoprenaline (ISO) at a dosage of 5 mg/kg/day for seven consecutive days to establish a HF model. C-Mito were isolated from HF rats and evaluated. The level of cGAS, a dsDNA sensor recently discovered to be directly localized on the outer membrane of mitochondria, was detected in C-Mito. C-Mito from HF rats (C-MitoHF) or control rats (C-MitoCtrl) were intravenously infused into HF rats. The accumulation of C-Mito in the ECs in the SFO was detected via double immunofluorescence staining. The SFO was processed for RNA sequencing (RNA-Seq) analysis. Secreted group IIA phospholipase A2 (PLA2G2A), the key gene involved in C-MitoHF-associated SFO dysfunction, was identified via bioinformatics analysis. Upregulation of PLA2G2A in the SFO ECs was assessed via immunofluorescence staining and immunoblotting, and PLA2G2A activity was evaluated. The interaction between cGAS and PLA2G2A was detected via co-immunoprecipitation. The dowstream molecular mechanisms of which PLA2G2A induced astroglial/microglial activation were also investigated. AAV9-TIE-shRNA (PLA2G2A) was introduced into the SFO to specifically knockdown endothelial PLA2G2A. Neuronal activation and glial proinflammatory polarization in the SFO were also evaluated. Renal sympathetic nerve activity (RSNA) was measured to evaluate central sympathetic output. Cardiac sympathetic hyperinnervation, myocardial remodeling, and left ventricular systolic function were assessed in C-Mito-treated HF rats.

Respiratory functional incompetence and oxidative damage were observed in C-MitoHF compared with C-MitoCtrl. Surprisingly, cGAS protein levels in C-MitoHF were significantly higher than those in C-MitoCtrl, while blocking cGAS with its specific inhibitor, RU.521, mitigated respiratory dysfunction and oxidative injury in C-MitoHF. C-Mito entered the ECs of the SFO in HF rats. RNA sequencing revealed that PLA2G2A is a key molecule for the induction of SFO dysfunction by C-MitoHF. The immunoblotting and immunofluorescence results confirmed that, compared with C-MitoCtrl, C-MitoHF increased endothelial PLA2G2A expression in the SFO of HF rats, which could be alleviated by attenuating C-MitoHF-localized cGAS. Furthermore, we found that cGAS directly interacts with PLA2G2A, increased the activity of PLA2AG2, which produced arachidonic acid, and also promoted PLA2G2A secretion in brain ECs. In addition, the inhibition of PLA2G2A in brain ECs significantly mitigated the proinflammatory effect of conditioned cell culture medium from C-MitoHF-treated ECs on astroglia and microglia. Also, we found that PLA2G2A secreted from ECs insulted by C-Mito induced neuroinflammation through activating astriglial/microglial Integrin-alphavbeta3 in the SFO, which further promote central sympathetic overdrive in HF rats. Specific knockdown of endothelial PLA2G2A in the SFO mitigated C-MitoHF-induced presympathetic neuronal sensitization, cardiac sympathetic hyperinnervation, RSNA activation, myocardial remodeling, and systolic dysfunction in HF rats.

C-Mito carrying cGAS promoted cardiac sympathoexcitation by directly targeting PLA2G2A in the ECs of the SFO in HF rats. Secreted PLA2G2A derived from ECs insulted by C-Mito induced neuroinflammation through activating astriglial/microglial Integrin-alphavbeta3 in the SFO, which further promote central sympathetic overdrive in HF rats. Our study indicated that inhibiting cGAS in C-Mito might be a potential treatment for central sympathetic overdrive in HF.

While brainstem regions are central regulators of blood pressure, the neuronal mechanisms underlying their role in hypertension remain poorly understood. Here, we investigated the structural and genetic relationships between global and regional brainstem volumes and blood pressure. We used magnetic resonance imaging data from n = 32,666 UK Biobank participants, and assessed the association of volumes of the whole brainstem and its main regions with blood pressure. We applied powerful statistical genetic tools, including bivariate causal mixture modeling (MiXeR) and conjunctional false discovery rate (conjFDR), to non-overlapping genome-wide association studies of brainstem volumes (n = 27,034) and blood pressure (n = 321,843) in the UK Biobank cohort. We observed negative associations between the whole brainstem and medulla oblongata volumes and systolic blood and pulse pressure, and positive relationships between midbrain and pons volumes and blood pressure traits when adjusting for the whole brainstem volume (all partial correlation coefficients ∣r∣ effects between 0.03 and 0.05, p ≤ 0.0042). We observed the largest genetic overlap for the whole brainstem, sharing 77% of its trait-influencing variants with blood pressure. We identified 65 shared loci between brainstem volumes and blood pressure traits and mapped these to 71 genes, implicating molecular pathways linked to sympathetic nervous system development, metal ion transport, and vascular homeostasis. The present findings support a link between brainstem structures and blood pressure and provide insights into their shared genetic underpinnings. The overlapping genetic architectures and mapped genes offer mechanistic information about the roles of brainstem regions in hypertension.

Hypertension is a leading risk factor for stroke, heart disease and chronic kidney disease. Multiple interacting factors and organ systems increase blood pressure and cause target-organ damage. Among the many molecular elements involved in the development of hypertension are reactive oxygen species (ROS), which influence cellular processes in systems that contribute to blood pressure elevation (such as the cardiovascular, renal, immune and central nervous systems, or the renin-angiotensin-aldosterone system). Dysregulated ROS production (oxidative stress) is a hallmark of hypertension in humans and experimental models. Of the many ROS-generating enzymes, NADPH oxidases are the most important in the development of hypertension. At the cellular level, ROS influence signalling pathways that define cell fate and function. Oxidative stress promotes aberrant redox signalling and cell injury, causing endothelial dysfunction, vascular damage, cardiovascular remodelling, inflammation and renal injury, which are all important in both the causes and consequences of hypertension. ROS scavengers reduce blood pressure in almost all experimental models of hypertension; however, clinical trials of antioxidants have yielded mixed results. In this Review, we highlight the latest advances in the understanding of the role and the clinical implications of ROS in hypertension. We focus on cellular sources of ROS, molecular mechanisms of oxidative stress and alterations in redox signalling in organ systems, and their contributions to hypertension.

People living with resistant hypertension (RH) are at high risk of adverse cardiovascular events. The British and Irish Hypertension Society has identified suspected RH as a condition for which specialist guidance may improve rates of blood pressure control and help clinicians identify those individuals who may benefit from specialist review. In this position statement we provide a practical approach for the investigation and management of adults with RH. We highlight gaps in the current evidence and identify important future research questions. Our aim is to support the delivery of high-quality and consistent care to people living with RH across the UK and Ireland.

The sympathetic nervous system (SNS) is a major mediator of cardiovascular physiology during exercise in healthy people. However, its role in heart failure with preserved ejection fraction (HFpEF), where exercise intolerance is a cardinal symptom, has remained relatively unexplored. The present review summarizes and critically explores the currently limited data on SNS changes in HFpEF patients with a particular emphasis on caveats of the data and the implications for its subsequent interpretation. While direct measurements of SNS activity in HFpEF patients is scarce, modest increases in resting levels of muscle sympathetic nerve activity are apparent, although this may be due to the co-morbidities associated with the syndrome rather than HFpEF per se. In addition, despite some evidence for dysfunctional sympathetic signaling in the heart, there is no clear evidence for elevated cardiac sympathetic nerve activity. The lack of a compelling prognostic benefit with use of β-blockers in HFpEF patients also suggests a lack of sympathetic hyperactivity to the heart. Similarly, while renal and splanchnic denervation studies have been performed in HFpEF patients, there is no concrete evidence that the sympathetic nerves innervating these organs exhibit heightened activity. Taken together, the totality of data suggests limited evidence for elevated sympathetic nerve activity in HFpEF and that any SNS perturbations that do occur are not universal to all HFpEF patients. Finally, how the SNS responds during exertion in HFpEF patients remains unknown and requires urgent investigation.

The aim of this study was to describe and compare echocardiographic findings before renal sympathetic denervation (RDN) and 6 and 24 months after the procedure.

Patients with treatment resistant hypertension (TRH) were included in this non-randomised intervention study. RDN was performed by a single experienced operator using the Symplicity Catheter System. Echocardiographic measurements were performed at baseline, and after 6 and 24 months.

The cohort consisted of 21 patients with TRH, with a mean systolic office blood pressure (BP) of 163 mmHg and mean diastolic BP 109 mmHg. Mixed model analysis showed no significant change in left ventricular (LV) mass index (LVMI) or left atrium volume index (LAVI) after the RDN procedure. Higher LVMI at baseline was significantly associated with greater reduction in LVMI (p < 0.001). Relative wall thickness (RWT) increased over time (0.48 mm after two years) regardless of change in BP. There was a small but significant reduction in LV end-diastolic (LVIDd) and end-systolic (LVIDs) diameters after RDN, with a mean reduction of 2.6 and 2.4 mm, respectively, after two years. Progression to concentric hypertrophy was observed only in in patients who did not achieve normal BP values, despite BP reduction after RDN.

There was no reduction of LV mass after RDN. We found a small statistically significant reduction in LVIDd and LVIDs, which together with increase in RWT can indicate progression towards concentric hypertrophy. BP reduction after RDN on its own does not reverse concentric remodelling if target BP is not achieved.

Hypertension is a leading risk factor for disability and deaths worldwide. Evidence indicates that alpha-mangostin(α-MG) can reduce blood pressure and improve target organ damage. Nonetheless, its pharmacological targets and potential mechanisms of action remain inadequately elucidated.

We used SwissTargetPrediction to identify α-MG's drug targets and DisGeNET, GeneCards, CTD, and GEO databases for hypertension-related targets, and then determined antihypertensive therapeutic targets of α-MG by intersecting these targets. GO functional enrichment analysis, KEGG pathway analysis, and disease association analysis were conducted using the DAVID database and R package "clusterprofile", visualized with Cytoscape software. The binding affinity of α-MG to identified targets was confirmed through molecular docking using Autodock Vina v.1.2.2 software. The impact of α-MG on target genes was validated using an Angiotensin II-induced hypertensive mouse model and RT-qPCR.

A total of 51 potential antihypertensive therapeutic targets for α-MG were identified by intersecting 109 drug targets with 821 disease targets. Furthermore, 10 cellular component terms, 10 disease terms, and the top 20 enriched biological processes, molecular functions, and KEGG pathways related to α-MG's antihypertensive effects were documented. Molecular docking studies indicated a strong binding affinity of α-MG with the HSP90AA1 domain. In Ang II-induced hypertensive mice aorta, treatment with α-MG effectively reversed the aberrant mRNA expression of TNF, HSP90AA1, NFKB1, PPARG, SIRT1, PTGS2, and RELA.

Our analyses showed that TNF, HSP90AA1, NFKB1, PPARG, SIRT1, PTGS2, and RELA might be α-MG's potential therapeutic targets for hypertension, laying groundwork for further investigation into its pharmacological mechanisms and clinical uses.

The gut microbiome primarily generates short-chain fatty acids (SCFAs) by fermenting dietary fibers. Though previous studies have linked SCFAs to blood pressure, there remains a lack of research on the relationship between SCFAs levels in the serum of elderly individuals and blood pressure. Based on this, we investigated the associations of serum SCFAs with blood pressure in Chinese older adults in a cross-sectional study. In this report, we recruited 1013 older adults over 60 years of age from June to September 2016 in Lu 'an City, China. Using Ultra High Performance Liquid Chromatography-Quadrupole-Exactive-Orbitrap-Mass Spectrometry (UHPLC-QE-Orbitrap MS), we measured the level of various SCFAs, including acetic acid (AA), propanoic acid (PA), butyric acid (BA), isobutyric acid (iso-BA), valeric acid (VA), isovaleric acid (iso-VA), and caproic acid (CA), in serum samples collected from Chinese elderly adults. The study recruited 1013 older adults in total. Multiple logistic regression analysis shows that AA (OR = 0.696, 95%CI: 0.501-0.966) and VA (OR = 0.713, 95%CI: 0.516-0.985) are negatively associated with hypertension. Linear regression analysis shows a negative correlation between AA (β = -3.89, 95% CI: -7.12 - -0.66) and the systolic blood pressure (SBP) levels, and a significant negative association between iso-VA (β = -2.11, 95% CI: -3.94 - -0.29) and diastolic blood pressure (DBP) levels. Whether in unadjusted or adjusted linear regression models, we all observe significant positive associations between CA and blood pressure levels. In the Bayesian kernel-machine regression (BKMR) models, the trends between the mixture of SCFAs and hypertension, SBP are inverse, but not significant; we also observe a significant negative correlation between AA and SBP, and a significant negative association between iso-VA and DBP levels, while CA is significantly positively correlated with SBP and DBP. Collectively, our results advocate for considering SCFA as a potential intervention to lower blood pressure, and especially AA may be a possible target for research. This may provide new perspectives for understanding the role of SCFAs in hypertension.

Salt-sensitive hypertension is associated with insulin resistance in nonobese individuals. However, no data have been reported for normotensive offspring of hypertensive salt-sensitive parents.

To evaluate in normotensive salt-sensitive or salt-resistant offspring of hypertensive parents (offSS-HT and offSR-HT, respectively): the possible association between insulin resistance and endothelial dysfunction, and the risk of developing hypertension in a 10-year follow-up.

Forty-one offSS-HT (29 ± 2 years; 20 female) and 36 offSR-HT (25 ± 3 years; 16 female) were followed up for 10 years. Both groups were considered lean. At baseline, creatinine clearance (CrCl), 24 h urinary albumin excretion (UAE), glycemia, and insulinemia were measured before and after 60 and 120 min of glucose overload (75 g). HOMA Index and the area under the curve (AUC) were calculated. Blood pressure (BP) and 24 h urine sodium excretion was measured annually. Postischemic minimum vascular resistance (forearm plethysmography) was assessed at baseline.

In offSS-HT, UAE (53 ± 3 mg/min) and CrCl (136 ± 8 ml/min) were higher in offSS-HT than in offSR-HT. (UAE: 12 ± 4 mg.min; p,0.01 and CrCl 107 ± 6 ml.min; P  < 0.01). An impaired vasodilatory postischemic response was observed in offSS-HT compared with offSR-HT ( P  < 0.01). In offSS-HT glycemia, insulin, AUC at 69 and 120 min post OTG were greater than in offSR-HT, p  < 0.02. In offSS-HT, blood pressure rose ( P  < 0.01) the 10 years follow-up compared with offSR-HT.

Salt sensitivity in the offspring of hypertensive salt-sensitive individuals is associated with insulin resistance and endothelial dysfunction and is prone to hypertension over a short period of time.

Resistant arterial hypertension (RAH) is one of the main causes of increased cardiovascular risk around the world. The benefits of ultrasound renal denervation (uRDN) as a non-invasive treatment are still not fully clear.

 We aim to demonstrate the efficacy of uRDN in reducing office blood pressure of patients in treatment for RAH.

PubMed, Embase, and Cochrane were searched for randomized trials comparing uRDN to sham or medical control groups in RAH patients undergoing renal denervation. Mean Differences (MD) with 95% confidence intervals (CIs) were calculated, and I2 statistics assessed heterogeneity. Statistical significance was set at p < 0.05. Statistical analysis was performed using R software version 4.2.3.

It was included 5 studies with 709 patients, of which 395 (55.71%) received uRDN treatment and 314 (44.29%) in the sham group. Mean follow-up time ranged from 2 to 48 months and mean age ranged from 52.3 to 62 years. The uRDN decreased systolic blood pressure (SBP) and diastolic blood pressure (DBP) in all measures significantly, including reductions in Office SBP (MD - 4.459 mmHg; 95% CI - 7.710 to - 1.208; p = 0.007; I2 = 47%) and Office DBP (MD - 2.039 mmHg; 95% CI - 3.975 to - 0.102; p = 0.039; I2 = 27%).

This meta-analysis highlights uRDN's superiority over the sham group in controlling SBP and DBP in RAH. However, further studies are needed to fully understand the efficacy of uRDN procedure in the management of RAH.

Resistant hypertension is defined as office blood pressure >140/90 mm Hg with a mean 24-hour ambulatory blood pressure of >130/80 mm Hg in patients who are compliant with 3 or more antihypertensive medications. Those who persistently fail pharmaceutical therapy may benefit from interventional treatment, such as renal denervation. Sympathetic nervous activity in the kidney is a known contributor to increased blood pressure because it results in efferent and afferent arteriole vasoconstriction, reduced renal blood flow, increased sodium and water reabsorption, and the release of renin. The Recor Paradise Renal Denervation System is designed to target renal sympathetic nerves via ultrasound ablation. The RADIANCE trials have demonstrated that patients who underwent renal denervation had a significant decrease in systolic blood pressure as compared with those who underwent a sham procedure. Furthermore, the device was found to have a favorable safety profile, with minimal major adverse events. The Food and Drug Administration granted approval to Recor, and the Paradise system is expected to serve as an adjunctive therapy for patients with true-resistant hypertension.

Nocturnal sympathetic overdrive is an early indicator of cardiovascular (CV) disease, emphasizing the importance of reliable remote patient monitoring (RPM) for autonomic function during sleep. To be effective, RPM systems must be accurate, non-intrusive, and cost-effective. This review evaluates non-invasive technologies, metrics, and algorithms for tracking nocturnal autonomic nervous system (ANS) activity, assessing their CV relevance and feasibility for integration into RPM systems. A systematic search identified 18 relevant studies from an initial pool of 169 publications, with data extracted on study design, population characteristics, technology types, and CV implications. Modalities reviewed include electrodes (e.g., electroencephalography (EEG), electrocardiography (ECG), polysomnography (PSG)), optical sensors (e.g., photoplethysmography (PPG), peripheral arterial tone (PAT)), ballistocardiography (BCG), cameras, radars, and accelerometers. Heart rate variability (HRV) and blood pressure (BP) emerged as the most promising metrics for RPM, offering a comprehensive view of ANS function and vascular health during sleep. While electrodes provide precise HRV data, they remain intrusive, whereas optical sensors such as PPG demonstrate potential for multimodal monitoring, including HRV, SpO2, and estimates of arterial stiffness and BP. Non-intrusive methods like BCG and cameras are promising for heart and respiratory rate estimation, but less suitable for continuous HRV monitoring. In conclusion, HRV and BP are the most viable metrics for RPM, with PPG-based systems offering significant promise for non-intrusive, continuous monitoring of multiple modalities. Further research is needed to enhance accuracy, feasibility, and validation against direct measures of autonomic function, such as microneurography.

The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.

Renal sympathetic denervation (RDN) reduces blood pressure (BP).

This single-arm open-label study enrolled patients with resistant hypertension (RH) and treat them by CT-guided ozone mediated lumbar-renal sympathetic denervation (L-RDN). The primary endpoint was to assess the changes of BP over 24-h ambulatory BP monitoring (ABPM) and to evaluate the anti-hypertensive medication burden (AHMB) at 3-month follow-up. This study was registered in Chictr.org.cn (ChiCTR2300071375).

17 patients (mean age 65.12 ± 10.77 years) with AHMB of 4.12 ± 1.11 were enrolled. After the procedure, 7 patients (46.7 %) matched the criteria for antihypertensive medication reduction. The AHMB decreased to 3.87 ± 0.96 for the whole objectives and from 3.87 ± 0.96 to 3.55 ± 0.78 for patients with normal baseline renal function. On top of the lessened AHMB, L-RDN further reduced morning systolic BP (SBP) by -8.6 ± 4.0 mmHg (p = 0.034) and diastolic BP (DBP) by -4.6 ± 2.1 mmHg (p = 0.032) for all participants and morning SBP by -13.2 ± 3.6 mmHg (p < 0.001), morning DBP by -6.2 ± 2.4 mmHg (p = 0.011) and daytime SBP by -4.1 ± 1.6 mmHg (p = 0.009) for those with normal baseline renal function at 3-month of follow-up. No adverse events were reported intra- and post operation.

CT-guided ozone-mediated L-RDN might be an innovative approach of RDN for treating RH. Confirmatory studies are warranted.

Metabolic syndrome (MetS) is associated with an increased risk of cardiovascular diseases. Compelling evidence supports the key role of dysfunction in the autonomic nervous system in that association, as well as mutual correlation among the components of MetS. The autonomic nervous system index (ANSI) is a percentile-ranked unitary proxy of cardiac autonomic regulation (CAR) that is designed to be free of age and sex bias, with higher values indicating better autonomic control. This study investigates CAR using the ANSI in patients with MetS.

A total of 133 patients referred to the Exercise Medicine Clinic of Istituto Auxologico Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) underwent CAR assessment using the ANSI and answered lifestyle questions in ad hoc questionnaires. The participants were retrospectively subdivided into two groups according to the presence or absence of MetS criteria.

Of the subjects, 58 were diagnosed with MetS, and 75 were not (no MetS). The ANSI was significantly impaired (32.9 vs. 44.8, P<0.01) in the MetS group, and ANSI scores showed a decreasing trend (P=0.004) as the number of MetS components increased. No significant lifestyle differences were found between the groups.

The ANSI was significantly reduced in subjects with MetS, and, net of age and sex effects, CAR impairment became progressively more apparent as the number of MetS components increased.

The mechanisms responsible for glomerular hemodynamic regulation with sodium-glucose co-transporter 2 (SGLT2) inhibitors in kidney disease due to type 2 diabetes remain unclear. Therefore, we investigated changes in glomerular hemodynamic function using an animal model of type 2 diabetes, treated with an SGLT2 inhibitor alone or in combination with a renin-angiotensin-aldosterone system inhibitor using male Zucker lean (ZL) and Zucker diabetic fatty (ZDF) rats. Afferent and efferent arteriolar diameter and single-nephron glomerular filtration rate (SNGFR) were evaluated in ZDF rats measured at 0, 30, 60, 90, and 120 minutes after the administration of a SGLT2 inhibitor (luseogliflozin). Additionally, we assessed these changes under the administration of the adenosine A1 receptor (A1aR) antagonist (8-cyclopentyl-1,3-dipropylxanthine), along with coadministration of luseogliflozin and an angiotensin II receptor blocker (ARB), telmisartan. ZDF rats had significantly increased SNGFR, and afferent and efferent arteriolar diameters compared to ZL rats, indicating glomerular hyperfiltration. Administration of luseogliflozin significantly reduced afferent vasodilatation and glomerular hyperfiltration, with no impact on efferent arteriolar diameter. Urinary adenosine levels were increased significantly in the SGLT2 inhibitor group compared to the vehicle group. A1aR antagonism blocked the effect of luseogliflozin on kidney function. Co-administration of the SGLT2 inhibitor and ARB decreased the abnormal expansion of glomerular afferent arterioles, whereas the efferent arteriolar diameter was not affected. Thus, regulation of afferent arteriolar vascular tone via the A1aR pathway is associated with glomerular hyperfiltration in type 2 diabetic kidney disease.

Hypertension (HTN) is a major contributor to cardiovascular mortality. Many patients with drug-resistant hypertension (DRH) also require permanent pacing (PP). This large retrospective study evaluated the effect of PP for conventional PP indications in older patients with DRH. We reviewed the charts of 176 patients with dual-chamber PP and DRH. The effects of PP on systolic and diastolic blood pressure (sBP and dBP), the number of HTN-related medications, and left ventricular ejection fraction (LVEF) were assessed at 6 months post-implantation and compared with pre-implantation values. Patients were followed up with for ≥72 months. Patients with a decline of >5 mmHg in sBP and decrease in at least one anti-HTN medication were defined as responders (126/176; P < .01). The mean decline in sBP was 9 mmHg, while that in dBP was 3 mmHg (P < .001 for both). Among responders, optimal reductions in sBP, dBP, and medications were seen at a stratification of >50% atrial pacing and <40% ventricular pacing (-12, -6.3, and -1.6, respectively). When right ventricular pacing of <50% was used for dichotomizing, the optimal atrial/ventricular pacing stratification was atrial pacing > 50% and ventricular pacing < 40% (-11.3, -6.3, and -1.6, respectively). A relationship between increasing atrial pacing and a decline in sBP was noted but did not reach statistical significance. However, of those responders who had a >10-mmHg decline in sBP, the majority were paced between 60%-100% in the atria. The LVEF did not change post-PP in either group. In conclusion, PP results in significant improvement in BP control. The observed association warrants further investigation.

Although it is well established that hormones like glucagon stimulates gluconeogenesis via the PKA-mediated phosphorylation of CREB and dephosphorylation of the cAMP-regulated CREB coactivators CRTC2, the role of neural signals in the regulation of gluconeogenesis remains uncertain.

Here, we characterize the noradrenergic bundle architecture in mouse liver; we show that the sympathoexcitation induced by acute cold exposure promotes hyperglycemia and upregulation of gluconeogenesis via triggering of the CREB/CRTC2 pathway. Following its induction by dephosphorylation, CRTC2 translocates to the nucleus and drives the transcription of key gluconeogenic genes. Rodents submitted to different models of sympathectomy or knockout of CRTC2 do not activate gluconeogenesis in response to cold. Norepinephrine directly acts in hepatocytes mainly through a Ca2+-dependent pathway that stimulates CREB/CRTC2, leading to activation of the gluconeogenic program.

Our data demonstrate the importance of the CREB/CRTC2 pathway in mediating effects of hepatic sympathetic inputs on glucose homeostasis, providing new insights into the role of norepinephrine in health and disease.

Isoleucine-proline-proline (Ile-Pro-Pro, IPP) is a natural food source tripeptide that inhibits angiotensin-converting enzyme (ACE) activity. The aim of this study was to determine the central and peripheral roles of IPP in attenuating sympathetic activity, oxidative stress and hypertension. Male Sprague-Dawley rats were subjected to sham-operated surgery (Sham) or two-kidney one-clip (2K1C) surgery to induce renovascular hypertension. Renal sympathetic nerve activity and blood pressure were recorded. Bilateral microinjections of IPP to hypothalamic paraventricular nucleus (PVN) attenuated sympathetic activity (-16.1 ± 2.5%, P < 0.001) and hypertension (-8.7 ± 1.5 mmHg, P < 0.01) in 2K1C rats by inhibiting ACE activity and subsequent angiotensin II and superoxide production in the PVN. Intravenous injections of IPP also attenuated sympathetic activity (-15.1 ± 2.1%, P < 0.001) and hypertension (-16.8 ± 2.3 mmHg, P < 0.001) via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. The duration of the effects of the intravenous IPP was longer than those of the PVN microinjection, but the sympatho-inhibitory effect of intravenous injections occurred later than that of the PVN microinjection. Intraperitoneal injection of IPP (400 pmol/day for 20 days) attenuated hypertension and vascular remodeling via inhibiting ACE activity and oxidative stress in both PVN and arteries of 2K1C rats. These results indicate that IPP attenuates hypertension and sympathetic activity by inhibiting ACE activity and oxidative stress. The sympathoinhibitory effect of peripheral IPP is mainly caused by the ACE inhibition in PVN, and the antihypertensive effect is related to the sympathoinhibition and the arterial ACE inhibition. Long-term intraperitoneal IPP therapy attenuates hypertension, oxidative stress and vascular remodeling.

Clinical trials of renal denervation for the treatment of hypertension have shown a variety of off-target improvements in conditions associated with sympathetic overactivity. This may be due to the ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. Renal IL (interleukin)-1β is elevated in the deoxycorticosterone acetate-salt model of hypertension, and its activity may be responsible for the elevation in afferent renal nerve activity and arterial pressure.

Continuous blood pressure recording of deoxycorticosterone acetate-salt mice with IL-1R (IL-1 receptor) knockout or antagonism was used individually and combined with afferent renal denervation (ARDN) to assess mechanistic overlap. Protein quantification and histological analysis of kidneys were performed to characterize renal inflammation.

ARDN attenuated deoxycorticosterone acetate-salt hypertension (-20±2-Δmm Hg mean arterial pressure [MAP] relative to control at study end) to a similar degree as total renal denervation (-21±2-Δmm Hg MAP), IL-1R knockout (-16±4-Δmm Hg MAP), or IL-1R antagonism (-20±3-Δmm Hg MAP). The combination of ARDN with knockout (-18±2-Δmm Hg MAP) or antagonism (-19±4-Δmm Hg MAP) did not attenuate hypertension any further than ARDN alone. IL-1R antagonism was found to have an acute depressor effect (-15±3-Δmm Hg MAP, day 10) in animals with intact renal nerves but not those with ARDN.

These findings suggest that IL-1R signaling is partially responsible for the elevated afferent renal nerve activity, which stimulates central sympathetic outflow to drive deoxycorticosterone acetate-salt hypertension.

Clinical trials have shown that in type 2 diabetes mellitus (T2D) resting office heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk, a worse prognosis and an unfavorable outcome. The present study was aimed at investigating whether the above mentioned treshold HR values reflect a sympathetic overdrive of marked degree.

In 58 T2D patients (age range: 39-57 years) without signs of autonomic neuropathy and in 52 age-matched healthy controls, we assessed muscle sympathetic nerve activity (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC), subdividing the study population in different subgroups according to their clinic and 24-h HR values.

In T2D progressively greater clinic and 24-h HR values were accompanied by progressive increases in MSNA and NE. HR cutoff values indicated by clinical trials as associated with an increased cardiovascular risk (> 70 beats/minute) were accompanied by MSNA values significantly higher than those detected in patients with lower HR, this being the case also for NE. In T2D both MSNA and NE were significantly related to clinic (r = 0.93, P < 0.0001 and r = 0.87, P < 0.0001, respectively) and 24-h (r = 0.92, P < 0.0001 and r = 0.84, P < 0.0001, respectively) HR. The MSNA and NE behaviour observed in T2D was not detected in healthy controls.

In T2D clinic HR values allow to detect patients with a greater sympathetic overactivity. Considering the adverse clinical impact of the sympathetic overdrive on prognosis, our data emphasize the need of future studies investigating the potential usefulness of lifestyle and pharmacological interventions exerting sympathomodulatory effects.

Hypertension (HTN) is a significant health concern, with a recent increase in HTN-related cardiovascular deaths in the United States. Refractory hypertension, a form of treatment-resistant HTN, poses a challenge for physicians and patients due to its association with increased morbidity and mortality. Risk factors for refractory HTN include African ancestry, female gender, younger age, diabetes mellitus, obesity, obstructive sleep apnea, chronic kidney disease, end-stage renal disease, and smoking. While the exact pathophysiology of refractory HTN is not fully understood, sympathetic overdrive appears to be a significant contributing factor. Arterial stiffness, chronic kidney disease, obstructive sleep apnea, obesity, and diabetes mellitus are comorbid conditions associated with increased sympathetic activity and refractory HTN. The knowledge behind carotid sinus stimulation suggested promising outcomes due to the known physiology. However, the introduction of devices, surgical complications, and the development of new antihypertensive soon took over the innovation of these devices. The authors aim to highlight three important aspects related to refractory hypertension: the risk factors for the development of refractory hypertension, the role of surgery in managing hypertension, and the referral systems available for the management of refractory hypertension.

In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention.

Traditional pharmacological interventions are well tolerated in the management of elevated blood pressure (BP) for individuals with resistant hypertension. Although neuromodulation has been investigated as an alternative solution, its open-loop (OL) modality cannot follow the patient's physiological state. In fact, neuromodulation for controlling highly fluctuating BP necessitates a closed-loop (CL) stimulation modality based on biomarkers to monitor the patient's continuously varying physiological state.

By leveraging its intuitive linkage with BP responses in ongoing efforts aimed at developing a CL system to enhance temporal BP reduction effect, this study proposes a CL neuromodulation modality that controls nucleus tractus solitarius (NTS) activity to effectively reduce BP, thus reflecting continuously varying physiological states.

While performing neurostimulation targeting the NTS in the rat model, the arterial BP response and neural activity of the NTS were simultaneously measured. To evaluate the temporal BP response effect of CL neurostimulation, OL (constant parameter; 20 Hz, 200 μA) and CL (Initial parameter; 11 Hz, 112 μA) stimulation protocols were performed with stimulation 180 s and rest 600 s, respectively, and examined NTS activity and BP response to the protocols.

In-vivo experiments for OL versus CL protocol for direct NTS stimulation in rats demonstrated an enhancement in temporal BP reduction via the CL modulation of NTS activity.

This study proposes a CL stimulation modality that enhances the effectiveness of BP control using a feedback control algorithm based on neural signals, thereby suggesting a new approach to antihypertensive neuromodulation.

A prevalent condition linked to an elevated risk of cardiovascular disease is sleep apnea. This review examines the connections between cardiac risk, the sympathetic nervous system, and sleep apnea. The increased risk of hypertension, arrhythmias, myocardial infarction, and heart failure was highlighted in the pathophysiology of sleep apnea and its effect on sympathetic activation. It is also important to consider potential processes such as oxidative stress, inflammation, endothelial dysfunction, and autonomic imbalance that may relate sleep apnea-induced sympathetic activation to cardiac risk. With implications for creating innovative diagnostic and treatment approaches to lessen the cardiovascular effects of sleep apnea, the goal of this investigation is to improve the understanding of the intricate link between sympathetic activity, cardiac risk, and sleep apnea. This study aimed to clarify the complex relationship between cardiovascular health and sleep apnea by synthesizing the available research and highlighting the crucial role played by the sympathetic nervous system in moderating this relationship. Our thorough investigation may have important therapeutic ramifications that will direct the creation of focused therapies to enhance cardiovascular outcomes in sleep apnea sufferers.

Autonomic dysregulation, including sympathetic hyperactivity, is a common feature of hypertension (HT) and other cardiovascular diseases. The CNS plays a role in driving chronic sympathetic activation in disease, but several lines of evidence suggest that neuroplasticity in the periphery may also contribute. The potential contribution of postganglionic sympathetic neurons to sustained sympathetic hyperactivity is not well understood. We recently discovered that noradrenergic sympathetic neurons in the stellate ganglion (SG) have excitatory cholinergic collateral connections to other neurons within the ganglion. We hypothesize that remodelling of these neurons and increased cholinergic collateral transmission contributes to sustained sympathetic hyperactivity in cardiovascular diseases, including HT. To test that hypothesis, we examined the activity of sympathetic neurons in isolated SG under control conditions and after 1 week of HT induced by peripheral angiotensin II infusion, using whole-cell patch clamp recordings. Despite the absence of central inputs, we observed elevated spontaneous activity and synaptic transmission in sympathetic SG neurons from hypertensive mice that required generation of action potentials. Genetically disrupting cholinergic transmission in noradrenergic neurons decreased basal neuronal activity and prevented angiotensin II-mediated enhancement of activity. Similar changes in activity, driven by increased collateral transmission, were identified in cardiac projecting neurons and neurons projecting to brown adipose tissue. These changes were not driven by altered A-type K+ currents. This suggests that HT stimulates increased activity throughout the intraganglionic network of collateral connections, contributing to the sustained sympathetic hyperactivity characteristic in cardiovascular disease. KEY POINTS: Sympathetic neurons in ganglia isolated from angiotensin II-treated hypertensive mice are more active than neurons from control mice despite the absence of central activation. The enhanced activity is the result of a ganglionic network of cholinergic collaterals, rather than altered intrinsic excitability. Increased neuronal activity was observed in both cardiac neurons and brown adipose tissue-projecting neurons, which are not involved in cardiovascular homeostasis.

Intestinal fibrosis is a prevalent complication of IBD that that can frequently be triggered by prolonged inflammation. Fibrosis in the gut can cause a number of issues, which continue as an ongoing challenge to healthcare systems worldwide. The primary causes of intestinal fibrosis are soluble molecules, G protein-coupled receptors, epithelial-to-mesenchymal or endothelial-to-mesenchymal transition, and the gut microbiota. Fresh perspectives coming from in vivo and in vitro experimental models demonstrate that fibrogenic pathways might be different, at least to some extent, independent of the ones that influence inflammation. Understanding the distinctive procedures of intestinal fibrogenesis should provide a realistic foundation for targeting and blocking specific fibrogenic pathways, estimating the risk of fibrotic consequences, detecting early fibrotic alterations, and eventually allowing therapy development. Here, we first summarize the inflammatory and non-inflammatory components of fibrosis, and then we elaborate on the underlying mechanism associated with multiple cytokines in fibrosis, providing the framework for future clinical practice. Following that, we discuss the relationship between modernization and disease, as well as the shortcomings of current studies. We outline fibrosis diagnosis and therapy, as well as our recommendations for the future treatment of intestinal fibrosis. We anticipate that the global review will provides a wealth of fresh knowledge and suggestions for future fibrosis clinical practice.

The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin-angiotensin system (RAS) pathway.

Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR.

The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN.

These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

Osteopathic treatments regulate the neurovegetative system through joint mobilizations and manipulations, and myofascial and craniosacral techniques. Despite the growing body of research, the precise impact of osteopathic medicine on the autonomic nervous system (ANS) is not yet fully elucidated. As to Kuchera's techniques, the stimulation of the sympathetic trunk and prevertebral ganglia contributed to harmonization of the sympathetic activity. However, potential relationships between the harmonization of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis largely remain uncertain and warrant further exploration.

This study was designed to evaluate the effectiveness of the osteopathic sympathetic harmonization (OSH) on the SNS and the HPA axis in youth with major depressive disorder (MDD).

The study included 39 youths aged 15-21 years and diagnosed with MDD. The participants were randomly assigned into either the OSH or the placebo group. Stimulation was performed on the sympathetic truncus and prevertebral ganglia in the OSH group. The stimulation of the placebo group was performed with a lighter touch and a shorter duration in similar areas. Each participant completed the Beck Depression Inventory (BDI) and the State and Trait Anxiety Inventory (SAI and TAI) before the application. Blood pressure (BP) and pulse measurements were made, and saliva samples were taken before, immediately after, and 20 min after application.

The baseline BDI (p=0.617) and TAI (p=0.322) scores were similar in both groups. Although the SAI scores decreased in both groups postintervention, no statistically significant difference was found between the two groups. Subjects who received OSH had a decrease in α-amylase level (p=0.028) and an increase in cortisol level (p=0.009) 20 min after the procedure.

Following OSH application in depressed youth, SNS activity may decrease, whereas HPA axis activity may increase. Future studies may examine the therapeutic efficacy of repeated OSH applications in depressed individuals.

The interplay of various body systems, encompassing those that govern cardiovascular and metabolic functions, has evolved alongside the development of multicellular organisms. This evolutionary process is essential for the coordination and maintenance of homeostasis and overall health by facilitating the adaptation of the organism to internal and external cues. Disruption of these complex interactions contributes to the development and progression of pathologies that involve multiple organs. Obesity-associated cardiovascular risks, such as hypertension, highlight the significant influence that metabolic processes exert on the cardiovascular system. This cardiometabolic communication is reciprocal, as indicated by substantial evidence pointing to the ability of the cardiovascular system to affect metabolic processes, with pathophysiological implications in disease conditions. In this review, I outline the bidirectional nature of the cardiometabolic interaction, with special emphasis on the impact that metabolic organs have on the cardiovascular system. I also discuss the contribution of the neural circuits and autonomic nervous system in mediating the crosstalk between cardiovascular and metabolic functions in health and disease, along with the molecular mechanisms involved.

Hypertension is associated with cardiovascular dysfunction, dysregulation of the antioxidant system and alteration of the level of some enzymes in the metabolic pathway. The possible modulatory effect of acute renal denervation (ARD) on cardiovascular function and the antioxidant system is still a subject of intense debate. This study sought to ascertain the ameliorative effects of ARD on cardiovascular parameters, antioxidant system, creatine kinase and lactate dehydrogenase levels.

Thirty-six Sprague-Dawley rats (5-6 weeks old) were divided into 6 groups of 6 animals each consisting of Normal Salt, High Salt, Normal Salt + Sham Denervation, High Salt + Sham Denervation, Normal Salt + Renal Denervation and High Salt + Renal Denervation. Induction of hypertension with 8 % salt in the diet lasted for 8 weeks. Renal or Sham denervation was thereafter done on selected groups. At the end of the experimental period, cardiovascular parameters, plasma antioxidant status, plasma creatine kinase (CK) and lactate dehydrogenase (LDH) levels were assessed. Significance level was set at p < 0.05.

Salt-loading significantly increased systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MABP), rate pressure product (RPP) while reducing superoxide dismutase (SOD), reduced glutathione (GSH) and catalase (CAT). Acute renal denervation significantly (p < 0.0001) reduced SBP, DBP, MABP, RPP, LDH and norepinephrine level while increasing SOD, GSH and CAT. ARD did not significantly alter CK level.

Acute renal denervation, by reducing sympathetic activity, ameliorates cardiovascular and antioxidant functions as well as reduces LDH level without significantly altering CK level in salt-induced hypertension.

Glucagon-like peptide-1 (GLP-1) and its analogs are widely used for diabetes treatment. The paraventricular nucleus (PVN) is crucial for regulating cardiovascular activity. This study aims to determine the roles of GLP-1 and its receptors (GLP-1R) in the PVN in regulating sympathetic outflow and blood pressure. Experiments were carried out in male normotensive rats and spontaneously hypertensive rats (SHR). Renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded. GLP-1 and GLP-1R expressions were present in the PVN. PVN microinjection of GLP-1R agonist recombinant human GLP-1 (rhGLP-1) or EX-4 increased RSNA and MAP, which were prevented by GLP-1R antagonist exendin 9-39 (EX9-39) or GLP-1R antagonist 1, superoxide scavenger tempol, antioxidant N-acetylcysteine, NADPH oxidase (NOX) inhibitor apocynin, adenylyl cyclase (AC) inhibitor SQ22536 or protein kinase A (PKA) inhibitor H89. PVN microinjection of rhGLP-1 increased superoxide production, NADPH oxidase activity, cAMP level, AC, and PKA activity, which were prevented by SQ22536 or H89. GLP-1 and GLP-1R were upregulated in the PVN of SHR. PVN microinjection of GLP-1 agonist increased RSNA and MAP in both WKY and SHR, but GLP-1 antagonists caused greater effects in reducing RSNA and MAP in SHR than in WKY. The increased superoxide production and NADPH oxidase activity in the PVN of SHR were augmented by GLP-1R agonists but attenuated by GLP-1R antagonists. These results indicate that activation of GLP-1R in the PVN increased sympathetic outflow and blood pressure via cAMP-PKA-mediated NADPH oxidase activation and subsequent superoxide production. GLP-1 and GLP-1R upregulation in the PVN partially contributes to sympathetic overactivity and hypertension.

Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.