Hypothesis: Unrecognized actions of ENaC blockade in improving refractory-resistant hypertension and residual cardiovascular risk.
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ABSTRACT:
SUBMITTER: Elijovich F
PROVIDER: S-EPMC7803029 | biostudies-literature | 2020 Dec
REPOSITORIES: biostudies-literature
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Hypothesis: Unrecognized actions of ENaC blockade in improving refractory-resistant hypertension and residual cardiovascular risk.
Elijovich Fernando F Kirabo Annet A Laffer Cheryl L CL
International Journal of Cardiology. Hypertension 20200912
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Project description:Importance:The Institute of Medicine described diagnostic error as the next frontier in patient safety and highlighted a critical need for better measurement tools. Objectives:To estimate the proportions of emergency department (ED) visits attributable to symptoms of imminent ruptured abdominal aortic aneurysm (AAA), acute myocardial infarction (AMI), stroke, aortic dissection, and subarachnoid hemorrhage (SAH) that end in discharge without diagnosis; to evaluate longitudinal trends; and to identify patient characteristics independently associated with missed diagnostic opportunities. Design, Setting, and Participants:This was a retrospective cohort study of all Medicare claims for 2006 to 2014. The setting was hospital EDs in the United States. Participants included all fee-for-service Medicare patients admitted to the hospital during 2007 to 2014 for the conditions of interest. Hospice enrollees and patients with recent skilled nursing facility stays were excluded. Main Outcomes and Measures:The proportion of potential diagnostic opportunities missed in the ED was estimated using the difference between observed and expected ED discharges within 45 days of the index hospital admissions as the numerator, basing expected discharges on ED use by the same patients in earlier months. The denominator was estimated as the number of recognized emergencies (index hospital admissions) plus unrecognized emergencies (excess discharges). Results:There were 1 561 940 patients, including 17 963 hospitalized for ruptured AAA, 304 980 for AMI, 1 181 648 for stroke, 19 675 for aortic dissection, and 37 674 for SAH. The mean (SD) age was 77.9 (10.3) years; 8.9% were younger than 65 years, and 54.1% were female. The proportions of diagnostic opportunities missed in the ED were as follows: ruptured AAA (3.4%; 95% CI, 2.9%-4.0%), AMI (2.3%; 95% CI, 2.1%-2.4%), stroke (4.1%; 95% CI, 4.0%-4.2%), aortic dissection (4.5%; 95% CI, 3.9%-5.1%), and SAH (3.5%; 95% CI, 3.1%-3.9%). Longitudinal trends were either nonsignificant (AMI and aortic dissection) or increasing (ruptured AAA, stroke, and SAH). Patient characteristics associated with unrecognized emergencies included age younger than 65 years, dual eligibility for Medicare and Medicaid coverage, female sex, and each of the following chronic conditions: end-stage renal disease, dementia, depression, diabetes, cerebrovascular disease, hypertension, coronary artery disease, and chronic obstructive pulmonary disease. Conclusions and Relevance:Among Medicare patients, opportunities to diagnose ruptured AAA, AMI, stroke, aortic dissection, and SAH are missed in less than 1 in 20 ED presentations. Further improvement may prove difficult.
| S-EPMC5876812 | biostudies-literature
Project description:BackgroundAnimal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A(1c) (HbA(1c)) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA(1c) in PAH patients and to correlate HbA(1c) levels with functional assessment.MethodsHbA(1c) was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA(1c) ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM.ResultsTwenty-three patients (56%) had HbA(1c) ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA(1c) ≥ 6.5%). Age and body mass index were similar in patients with HbA(1c) ≥ 6.0% vs < 6.0%. There was a trend towards lower mean 6-minute walk distance in patients with elevated HbA(1c) (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA(1c).ConclusionsUnrecognized glucose intolerance as assessed by HbA(1c) is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.
| S-EPMC3129440 | biostudies-literature
Project description:BackgroundSalt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel EnaC (epithelial sodium channel) leads to the formation of IsoLGs (isolevuglandins) and release of proinflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NLRP3 (NOD [nucleotide-binding and oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome via IsoLG formation leading to salt-sensitive hypertension.MethodsWe performed RNA sequencing on human monocytes treated with elevated sodium in vitro and Cellular Indexing of Transcriptomes and Epitopes by Sequencing analysis of peripheral blood mononuclear cells from participants rigorously phenotyped for salt sensitivity of blood pressure using an established inpatient protocol. To determine mechanisms, we analyzed inflammasome activation in mouse models of deoxycorticosterone acetate salt-induced hypertension as well as salt-sensitive mice with ENaC inhibition or expression, IsoLG scavenging, and adoptive transfer of wild-type dendritic cells into NLRP3 deficient mice.ResultsWe found that high levels of salt exposure upregulates the NLRP3 inflammasome, pyroptotic and apoptotic caspases, and IL (interleukin)-1β transcription in human monocytes. Cellular Indexing of Transcriptomes and Epitopes by Sequencing revealed that components of the NLRP3 inflammasome and activation marker IL-1β dynamically vary with changes in salt loading/depletion. Mechanistically, we found that sodium-induced activation of the NLRP3 inflammasome is ENaC and IsoLG dependent. NLRP3 deficient mice develop a blunted hypertensive response to elevated sodium, and this is restored by the adoptive transfer of NLRP3 replete APCs.ConclusionsThese findings reveal a mechanistic link between ENaC, inflammation, and salt-sensitive hypertension involving NLRP3 inflammasome activation in APCs. APC activation via the NLRP3 inflammasome can serve as a potential diagnostic biomarker for salt sensitivity of blood pressure.
| S-EPMC9357159 | biostudies-literature
Project description:BackgroundNeuromuscular monitoring should be applied routinely to avoid residual neuromuscular block. However, anaesthetists often refrain from applying it, even when the equipment is available. We aimed to increase neuromuscular monitoring in six Danish anaesthesia departments via e-learning.MethodsInterrupted time series study, with baseline data from a previous study and prospective data collection after implementation of the module, which was available for 2 weeks from 21 November 2016. We included all patients receiving general anaesthesia with muscle relaxants until 30 April 2017. Main outcome was application of acceleromyography, grouped as succinylcholine only and non-depolarising relaxants. Secondary outcomes were last recorded train-of-four ratio (non-depolarising) relaxants and score on a ten-question pre- and post-course multiple-choice test.ResultsThe post-intervention data consisted of 6525 cases (3099 (48%) succinylcholine only, 3426 (52%) non-depolarising relaxants). Analysing all departments, we found a positive pre-intervention trend in application of acceleromyography for both groups, of estimated 7.5% and 4.8% per year, respectively (p < .001). The monitoring rate increased significantly for succinylcholine in two departments post-intervention (p = .045 and .010), and for non-depolarising relaxants in one department (p = .041), but followed by a negative trend of -37.0% per year (p = .041). The rate was already close to 90% at the time of the intervention and the mean last recorded train-of-four ratio was 0.97 (SD 0.21), also without a significant change. The median score on the post-course test increased from 7 (IQR 5-8) to 9 (IQR 8-10) (p < .001, Wilcoxon Signed-Ranks Test).ConclusionWe found no overall effect of the e-learning module on application of neuromuscular monitoring, although the post-course test indicated an effect on anaesthetists' knowledge in this field.Trial registrationTrial registration: Clinicaltrials.gov identifier: NCT02925143. https://clinicaltrials.gov/ct2/show/NCT02925143.
| S-EPMC9541262 | biostudies-literature
Project description:BackgroundHypertension is a leading cause of cardiovascular disease (CVD) and affects nearly one in two adults in the United States when defined as a blood pressure of at least 130/80 mm Hg or on antihypertensive medication (Virani et al., 2021, Circulation, 143, e254). Long-standing disparities in hypertension awareness, treatment, and control among racial and ethnic populations exist in the United States. High-quality evidence exists for how to prevent and control hypertension and for the role nurses can play in this effort. In response to the 2020 Surgeon General's Call to Action to Control Hypertension, nursing leaders from 11 national organizations identified the critical roles and actions of nursing in improving hypertension control and cardiovascular health, focusing on evidence-based nursing interventions and available resources.AimsTo develop a unified "Call to Action for Nurses" to improve control of hypertension and cardiovascular health and provide information and resources to execute this call.MethodsThis paper outlines roles that registered nurses, advanced practice nurses, schools of nursing, professional nursing organizations, quality improvement nurses, and nursing researchers can play to control hypertension and prevent CVD in the United States. It describes evidence-based interventions to improve cardiovascular health and outlines actions to bring hypertension and CVD to the forefront as a national priority for nursing.Linking evidence to actionEvidence-based interventions exist for nurses to lead efforts to prevent and control hypertension, thus preventing much CVD. Nurses can take actions in their communities, their healthcare setting, and their organization to translate these interventions into real-world practice settings.
| S-EPMC9305122 | biostudies-literature
Project description:Background and objectiveAlthough millions of patients receive neuromuscular blocking agents (NMBAs) each year as part of an anesthetic, residual neuromuscular blockade (NMB) remains a too-frequent occurrence and its adverse consequences continue to negatively impact patient outcomes. The goal of this manuscript is to provide clinicians with the information they need to decrease the incidence of residual NMB.MethodsPublished literature was reviewed and incorporated into the narrative as appropriate. Search terms for articles included nondepolarizing NMBAs, residual NMB, monitoring depth of NMB, qualitative monitoring, quantitative monitoring, reversal agents, sugammadex, and anticholinesterases.Key content and findingsThis review will define what is currently considered adequate recovery of neuromuscular function, discuss and compare the different modalities to determine the depth of NMB, discuss the currently available NMBAs-including their durations of action and dosing, describe the incidence and complications associated with residual NMB, and discuss reversal of nondepolarizing NMB with neostigmine or sugammadex. Nondepolarizing NMBAs are commonly used as part of a general anesthetic. Understanding the pharmacology of the neuromuscular blocking and reversal agent, in combination with quantitative monitoring of depth of NMB is essential to avoid residual paralysis.ConclusionsQuantitative monitoring and dosing of either neostigmine or sugammadex based on the results of monitoring is essential to eliminate residual NMB associated with the use of nondepolarizing NMBAs.
| S-EPMC11304418 | biostudies-literature
Project description:BackgroundMuscle relaxants facilitate endotracheal intubation under general anesthesia and improve surgical conditions. Residual neuromuscular blockade occurs when the patient is still partially paralyzed when awakened after surgery. The condition is associated with subjective discomfort and an increased risk of respiratory complications. Use of an objective neuromuscular monitoring device may prevent residual block. Despite this, many anesthetists refrain from using the device. Efforts to increase the use of objective monitoring are time consuming and require the presence of expert personnel. A neuromuscular monitoring e-learning module might support consistent use of neuromuscular monitoring devices.ObjectiveThe aim of the study is to assess the effect of a neuromuscular monitoring e-learning module on anesthesia staff's use of objective neuromuscular monitoring and the incidence of residual neuromuscular blockade in surgical patients at 6 Danish teaching hospitals.MethodsIn this interrupted time series study, we are collecting data repeatedly, in consecutive 3-week periods, before and after the intervention, and we will analyze the effect using segmented regression analysis. Anesthesia departments in the Zealand Region of Denmark are included, and data from all patients receiving a muscle relaxant are collected from the anesthesia information management system MetaVision. We will assess the effect of the module on all levels of potential effect: staff's knowledge and skills, patient care practice, and patient outcomes. The primary outcome is use of neuromuscular monitoring in patients according to the type of muscle relaxant received. Secondary outcomes include last recorded train-of-four value, administration of reversal agents, and time to discharge from the postanesthesia care unit as well as a multiple-choice test to assess knowledge. The e-learning module was developed based on a needs assessment process, including focus group interviews, surveys, and expert opinions.ResultsThe e-learning module was implemented in 6 anesthesia departments on 21 November 2016. Currently, we are collecting postintervention data. The final dataset will include data from more than 10,000 anesthesia procedures. We expect to publish the results in late 2017 or early 2018.ConclusionsWith a dataset consisting of thousands of general anesthesia procedures, the INVERT study will assess whether an e-learning module can increase anesthetists' use of neuromuscular monitoring.Trial registrationClinicaltrials.gov NCT02925143; https://clinicaltrials.gov/ct2/show/NCT02925143 (Archived by WebCite® at http://www.webcitation.org/6s50iTV2x).
| S-EPMC5650673 | biostudies-literature
Project description:Renovascular hypertension (RH), a secondary hypertension, can significantly impact heart health, resulting in heart damage and dysfunction, thereby elevating the risk of cardiovascular diseases. Coniferol (CA), which has vascular relaxation properties, is expected to be able to treat hypertension-related diseases. However, its potential effects on cardiac function after RH remain unclear. In this study, in combination with network pharmacology, the antihypertensive and cardioprotective effects of CA in a two-kidney, one-clip (2K1C) mice model and its ability to mitigate angiotensin II (Ang II)-induced hypertrophy in H9C2 cells were investigated. The findings revealed that CA effectively reduced blood pressure, myocardial tissue damage, and inflammation after RH. The possible targets of CA for RH treatment were screened by network pharmacology. The interleukin-17 (IL-17) and tumor necrosis factor (TNF) signaling pathways were identified using a Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The inflammatory response was identified using a Gene Ontology (GO) enrichment analysis. Western blot analysis confirmed that CA reduced the expression of IL-17, matrix metallopeptidase 9 (MMP9), cyclooxygenase 2 (COX2), and TNF α in heart tissues and the H9C2 cells. In summary, CA inhibited cardiac inflammation and fibrohypertrophy following RH. This effect was closely linked to the expression of MMP9/COX2/TNF α/IL-17. This study sheds light on the therapeutic potential of CA for treating RH-induced myocardial hypertrophy and provides insights into its underlying mechanisms, positioning CA as a promising candidate for future drug development.
| S-EPMC11444148 | biostudies-literature
Project description:BackgroundThe mechanisms by which salt increases blood pressure in people with salt sensitivity remain unclear. Our previous studies found that high sodium enters antigen-presenting cells (APCs) via the epithelial sodium channel and leads to the production of isolevuglandins and hypertension. In the current mechanistic clinical study, we hypothesized that epithelial sodium channel-dependent isolevuglandin-adduct formation in APCs is regulated by epoxyeicosatrienoic acids (EETs) and leads to salt-sensitive hypertension in humans.MethodsSalt sensitivity was assessed in 19 hypertensive subjects using an inpatient salt loading and depletion protocol. Isolevuglandin-adduct accumulation in APCs was analyzed using flow cytometry. Gene expression in APCs was analyzed using cellular indexing of transcriptomes and epitopes by sequencing analysis of blood mononuclear cells. Plasma and urine EETs were measured using liquid chromatography-mass spectrometry.ResultsBaseline isolevuglandin+ APCs correlated with higher salt-sensitivity index. Isolevuglandin+ APCs significantly decreased from salt loading to depletion with an increasing salt-sensitivity index. We observed that human APCs express the epithelial sodium channel δ subunit, SGK1 (salt-sensing kinase serum/glucocorticoid kinase 1), and cytochrome P450 2S1. We found a direct correlation between baseline urinary 14,15 EET and salt-sensitivity index, whereas changes in urinary 14,15 EET negatively correlated with isolevuglandin+ monocytes from salt loading to depletion. Coincubation with 14,15 EET inhibited high-salt-induced increase in isolevuglandin+ APC.ConclusionsIsolevuglandin formation in APCs responds to acute changes in salt intake in salt-sensitive but not salt-resistant people with hypertension, and this may be regulated by renal 14,15 EET. Baseline levels of isolevuglandin+ APCs or urinary 14,15 EET may provide diagnostic tools for salt sensitivity without a protocol of salt loading.
| S-EPMC10918035 | biostudies-literature
Project description:The NPHS2 gene, encoding the slit diaphragm protein podocin, accounts for genetic and sporadic forms of nephrotic syndrome (NS). Patients with NS often present symptoms of volume retention, such as oedema formation or hypertension. The primary dysregulation in sodium handling involves an inappropriate activation of the epithelial sodium channel, ENaC. Plasma proteases in a proteinuria-dependent fashion have been made responsible; however, referring to the timeline of symptoms occurring and underlying mechanisms, contradictory results have been published. Characterizing the mouse model of podocyte inactivation of NPHS2 (Nphs2∆pod ) with respect to volume handling and proteinuria revealed that sodium retention, hypertension and gross proteinuria appeared sequentially in a chronological order. Detailed analysis of Nphs2∆pod during early sodium retention, revealed increased expression of full-length ENaC subunits and αENaC cleavage product with concomitant increase in ENaC activity as tested by amiloride application, and augmented collecting duct Na+ /K+ -ATPase expression. Urinary proteolytic activity was increased and several proteases were identified by mass spectrometry including cathepsin B, which was found to process αENaC. Renal expression levels of precursor and active cathepsin B were increased and could be localized to glomeruli and intercalated cells. Inhibition of cathepsin B prevented hypertension. With the appearance of gross proteinuria, plasmin occurs in the urine and additional cleavage of γENaC is encountered. In conclusion, characterizing the volume handling of Nphs2∆pod revealed early sodium retention occurring independent to aberrantly filtered plasma proteases. As an underlying mechanism cathepsin B induced αENaC processing leading to augmented channel activity and hypertension was identified.
| S-EPMC6787568 | biostudies-literature