Pressure In Humans Research Articles

A Commentary on Effects of Ninety Minutes per Week of Continuous Aerobic Exercise on Blood Pressure in Hypertensive Obese Humans

We previously reported evidence about the positive effects of continuous aerobic training (CAT) in hypertensive obese people. We showed that 90 min/week of aerobic exercise on a treadmill (70%-80% of the Maximal Heart Rate [MHR]) was able to improve the systemic blood metabolism of obese subjects. Therefore, we believe that reducing the recommended amount of aerobic exercise (150 min/week) by American College of Sports Medicine (ACSM) is a valuable strategy to for sedentary individuals with pathological conditions, since the suggested protocol is easyto- perform, fast and enjoyable for the subjects. In this comment, we tempt to summarize the literature evidences regarding physical aerobic exercise on cardiac metabolism in hypertensive obese individuals. These findings may influence the consenting information over the prescription of physical activity for individuals with cardiac-associated pathologies.

Clinical and Experimental Evidences of Hydrogen Sulfide Involvement in Lead-Induced Hypertension.

Lead- (Pb-) induced hypertension has been shown in humans and experimental animals and cardiovascular effects of hydrogen sulfide (H2S) have been reported previously. However, no studies examined involvement of H2S in Pb-induced hypertension. We found increases in diastolic blood pressure and mean blood pressure in Pb-intoxicated humans followed by diminished H2S plasmatic levels. In order to expand our findings, male Wistar rats were divided into four groups: Saline, Pb, NaHS, and Pb + NaHS. Pb-intoxicated animals received intraperitoneally (i.p.) 1st dose of 8 μg/100 g of Pb acetate and subsequent doses of 0.1 μg/100 g for seven days and sodium hydrosulfide- (NaHS-) treated animals received i.p. NaHS injections (50 μmol/kg/twice daily) for seven days. NaHS treatment blunted increases in systolic blood pressure, increased H2S plasmatic levels, and diminished whole-blood lead levels. Treatment with NaHS in Pb-induced hypertension seems to induce a protective role in rat aorta which is dependent on endothelium and seems to promote non-NO-mediated relaxation. Pb-intoxication increased oxidative stress in rats, while treatment with NaHS blunted increases in plasmatic MDA levels and increased antioxidant status of plasma. Therefore, H2S pathway may be involved in Pb-induced hypertension and treatment with NaHS exerts antihypertensive effect, promotes non-NO-mediated relaxation, and decreases oxidative stress in rats with Pb-induced hypertension.

Cortical Structures Associated With Human Blood Pressure Control

A better understanding of the role of cortical structures in blood pressure control may help us understand cardiovascular collapse that may lead to sudden unexpected death in epilepsy (SUDEP). To identify cortical control sites for human blood pressure regulation. Patients with intractable epilepsy undergoing intracranial electrode implantation as a prelude to epilepsy surgery in the Epilepsy Monitoring Unit at University Hospitals Cleveland Medical Center were potential candidates for this study. Inclusion criteria were patients 18 years or older who had electrodes implanted in one or more of the regions of interest and in whom deep brain electrical stimulation was indicated for mapping of ictal onset or eloquent cortex as a part of the presurgical evaluation. Twelve consecutive patients were included in this prospective case series from June 1, 2015, to February 28, 2017. Changes in continuous, noninvasive, beat-by-beat blood pressure parameter responses from amygdala, hippocampal, insular, orbitofrontal, temporal, cingulate, and subcallosal stimulation. Electrocardiogram, arterial oxygen saturation, end-tidal carbon dioxide, nasal airflow, and abdominal and thoracic plethysmography were monitored. Among 12 patients (7 female; mean [SD] age, 44.25 [12.55] years), 9 electrodes (7 left and 2 right) all in Brodmann area 25 (subcallosal neocortex) in 4 patients produced striking systolic hypotensive changes. Well-maintained diastolic arterial blood pressure and narrowed pulse pressure indicated stimulation-induced reduction in sympathetic drive and consequent probable reduction in cardiac output rather than bradycardia or peripheral vasodilation-induced hypotension. Frequency-domain analysis of heart rate and blood pressure variability showed a mixed picture. No other stimulated structure produced significant blood pressure changes. These findings suggest that Brodmann area 25 has a role in lowering systolic blood pressure in humans. It is a potential symptomatogenic zone for peri-ictal hypotension in patients with epilepsy.

Changes of Cerebral and/or Peripheral Adenosine A₁ Receptor and IGF-I Concentrations under Extended Sleep Duration in Rats.

Extended sleep improves sustained attention and reduces sleep pressure in humans. Downregulation of adenosine A1 receptor (A1R) and modulation of the neurotrophic factor insulin growth factor-1 (IGF-I) in brain structures controlling attentional capacities could be involved. In the frontal cortex and hippocampus of rats, we measured adenosine A1R and IGF-I protein concentrations after photoperiod-induced sleep extension. Two groups of twelve rats were adapted over 14 days to a habitual (CON) 12:12 light–dark (LD) schedule and an extended (EXT) 16:8 LD schedule. IGF-I content was also measured in plasma, liver, and skeletal muscle. In EXT, compared to CON rats, A1R content in the frontal cortex was significantly lower (p < 0.05), while IGF-I content was higher (p < 0.001), and no significant change was observed in the hippocampus. IGF-I content in plasma and muscle was higher (p < 0.001 and p < 0.01), while it was lower in liver (p < 0.001). The absolute weight and weight gain were higher in EXT rats (p < 0.01). These data suggest that 14 days under a 16:8 LD photoperiod respectively down- and upregulated cortical A1R and IGF-I levels. This photoperiod induced an anabolic profile with increased weight gain and circulating and muscular IGF-I levels. An extension of sleep duration might favor cerebral and peripheral anabolism, which may help attentional and physical capacities.

Probenecid Inhibits α-Adrenergic Receptor-Mediated Vasoconstriction in the Human Leg Vasculature.

Coordination of vascular smooth muscle cell tone in resistance arteries plays an essential role in the regulation of peripheral resistance and overall blood pressure. Recent observations in animals have provided evidence for a coupling between adrenoceptors and Panx1 (pannexin-1) channels in the regulation of sympathetic nervous control of peripheral vascular resistance and blood pressure; however, evidence for a functional coupling in humans is lacking. We determined Panx1 expression and effects of treatment with the pharmacological Panx1 channel inhibitor probenecid on the vasoconstrictor response to α1- and α2-adrenergic receptor stimulation in the human forearm and leg vasculature of young healthy male subjects (23±3 years). By use of immunolabeling and confocal microscopy, Panx1 channels were found to be expressed in vascular smooth muscle cells of arterioles in human leg skeletal muscle. Probenecid treatment increased (P<0.05) leg vascular conductance at baseline by ≈15% and attenuated (P<0.05) the leg vasoconstrictor response to arterial infusion of tyramine (α1- and α2-adrenergic receptor stimulation) by ≈15%, whereas the response to the α1-agonist phenylephrine was unchanged. Inhibition of α1-adrenoceptors prevented the probenecid-induced increase in baseline leg vascular conductance, but did not alter the effect of probenecid on the vascular response to tyramine. No differences with probenecid treatment were detected in the forearm. These observations provide the first line of evidence in humans for a functional role of Panx1 channels in setting resting tone via α1-adrenoceptors and in the constrictive effect of noradrenaline via α2-adrenoceptors, thereby contributing to the regulation of peripheral vascular resistance and blood pressure in humans.

The Relationship Between Intracranial Pressure and Age-Chasing Age-Related Reference Values.

No true reference values for intracranial pressure (ICP) in humans exist; current values are estimated from measurements in adults who undergo treatment in order to correct ICP. We report ICP values in a "pseudonormal" group of children and adults to examine if age affects ICP. We analyzed data from all nonshunted patients undergoing a 24-hour ICP monitoring as part of a diagnostic work-up and included patients with no subsequent suspicion of increased ICP and no need for pressure-relieving treatment with a minimum follow-up period of 3years. From February 2008 to November 2014, a 24-hour ICP monitoring was performed in 221 patients. Of these patients, 35 (14 children, 21 adults) met the inclusion criteria. Follow-up time to confirm absence of ICP-related disease was 3-9 years. Daytime ICP was 2.8mmHg ± 2.2 in children and 1.9 mmHg ± 4.2 in adults (P=0.39). Of 35 patients, 32 had higher nighttime ICP. The difference between daytime and nighttime ICP was similar in children (ΔICP= 5.8 mmHg ± 4.0, P < 0.0001) and adults (ΔICP= 6.1 mm Hg ± 3.3, P < 0.0001). ICP could be described as a decreasing function of age, with an ICP decrement of 0.69 mmHg per decade (P= 0.015). We found similar differences in daytime and nighttime ICP between children and adults with no ICP-related disease. ICP seems to decrease with age across all ages. This has implications for therapeutic interventions (e.g., shunt valve selection or resistance in external ventricular drainage).

Towards Precision Medicine for Hypertension: A Review of Genomic, Epigenomic, and Microbiomic Effects on Blood Pressure in Experimental Rat Models and Humans.

Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the "structural backbone," this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex "triad" of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach.

Dexmedetomidine: A Potential Cause of Circulatory Collapse in Patient With Severe Pulmonary Arterial Hypertension

SESSION TITLE: Cardiothoracic Surgery SESSION TYPE: Global Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Dexmedetomidine is an alpha2 receptor agonist with unique mechanism of action for sedation and sympatholysis via receptors in the locus ceruleus, analgesia via receptors in the spinal cord without significant effect on respiration. Due to these properties, it has been increasingly used in the ICU and more recently in patient requiring non-invasive ventilation (NIV) who cannot tolerate this modality. A prostective randomized study compared dexmedetomidine vs midazolam in patients requiring NIV and sedation if they cannot tolerate the positive pressure ventilation.1 Dexmedetomidine was found to more desirable than midazolam in terms of level of awake sedation, shortened duration of mechanical ventilation and length of the ICU stay. However, patients treated with DM had statistical significant increase in bradycardia without needing intervention or stopping the medication. Although the study included patients with cardiogenic pulmonary edema they had normal EF. A retrospective multicenter international study found that about 80% of hospitalized patients with PAH who had circulatory collapse and cardiopulmonary rescusitation (CPR) did not survive the resuscitation effort despite minimal delay between collapse and initiation of CPR. ECG at the time of the CPR showed bradycardia in 45% of the patients. CASE PRESENTATION: We report the case of 75-year-old female with long-standing pulmonary fibrosis with secondary moderate to severe pulmonary arterial hypertension (PAH) who developed bradycardia requiring cardiovascular resuscitation believed secondary to dexmedetomidine (DM) infusion. Patient was on high oxygen for 4 weeks on acute-care floor before she had altered level of consciousness and worsening oxygenation requiring non- invasive ventilation (NIV) and transfer to the ICU. She was started on DM drip at 0.3 mcg/kg/min due to agitation, in part due to not being able to tolerate the NIV. Without developing hypoxemia, patient had a sudden onset of severe bradycadia with loss of blood pressure requiring advanced cardiopulmonary resuscitation. She responded to 1 mg epinephrine and brief chest compression with return of pulse and blood pressure. Dexmedetomidine was immediately stopped. After intubation, patient developed severe hypotension requiring multiple pressors. Bedside echo showed severe RV dilation and global hypokinesis. DISCUSSION: There is limited published studies on the use of DM in patients with PAH. Successful elective procedural sedations with DM were anecdotally reported in few adults and pediatric patients with severe PAH. Based on the above case, we caution against the use of DM in patients with severe PAH in the ICU due to risk of bradycardia that jeopardize the patient cardiac output that is highly dependent on heart rate. There are limited studies and inconclusive results on the effect of DM on pulmonary arterial pressure and pulmonary vascular resistance both in humans and animal models. CONCLUSIONS: Patients with severe PAH requiring NIV have significant comorbid condition, tenuous cardiac output and are at increased risk of acute de-compensation . DM should be avoided due to inceased risk of bradycardia and circulatory collapse. Any deterioration requiring acute resuscitation and emergency intubation are likely to be detrimental in this patient population. Reference #1: Dexmedetomidine versus Midazolam for sedation of Patients with Non-invasive Ventilation Failure. Huang, Z. Internal Medicine 2012; 51:2299-2305. Reference #2: Outcome after Cardiopulmonary Resuscitation in Patients with Pulmonary Arterial Hypertension. AM J Respir Crit Care Med 2002;165:341-344 Reference #3: Dexemedetomidine and Pulmonary Hypertension: A Case Report and Review of the Literature J Med Cases 2013; 4(7):481-484. DISCLOSURE: The following authors have nothing to disclose: Khaled Saleh, Fadi Hamed No Product/Research Disclosure Information

Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity.

Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years. CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (R=0.62; P<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (r=0.73; P<0.0001). Heritability of CEC was 0.31 (P=3.89×10-14) without adjustment for HDL-C and 0.13 (P=1.44×10-3) with adjustment. CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable.

Measuring arterial blood pressure in humans: Auscultatory and automatic measurement techniques for human biological field studies.

Human biologists have been examining arterial blood pressure since they began studying the effects of the environment and culture on the health of diverse populations. The Korotkoff auscultatory technique with a trained observer and aneroid sphygmomanometer is the method of choice for blood pressure measurement in many bioanthropological field contexts. Korotkoff sounds (the first and fifth phases) are the preferred determinants of systolic and diastolic pressure, even in infants, children, pregnant women, and the elderly. Training of observers, positioning of individuals, and selection of cuff size are all essential for obtaining standardized measurements. Automatic electronic devices are increasingly being used for blood pressure measurement in human biological studies. The automatic monitors often use the oscillometric method for measuring pressure, but must be validated before use. The emergence of automatic ambulatory blood pressure monitors has opened another avenue of research on blood pressure in human biology, where allostasis and circadian responses to environmental change and real life behavioral challenges can be defined and evaluated, largely because there is now the ability to make multiple measurements over time and in varying contexts. Stand-alone automatic monitors can also be substituted for manual auscultated readings in field contexts, although in studies where participants measure their own pressure, education about how the devices work and protocol specifics are necessary. Finally, computer-driven plethysmographic devices that measure pressure in the finger are available to evaluate short-term reactivity to specific challenges.

Abstract P501: Editing of Myosin Phosphatase Gene as a Novel Approach for Vasodilator Sensitization and Lowering of Blood Pressure

Myosin Phosphatase (MP) is the primary effector of vascular smooth muscle (VSM) relaxation and a key end target of signaling pathways that regulate vessel tone. Regulated splicing of alternative Exon24 (E24) of Myosin Phosphatase Regulatory/ Targeting subunit (MYPT1) sets vasodilator sensitivity. Skipping E24 codes for a Mypt1 isoform that contains a C-terminal leucine zipper (LZ) motif required for cGK1α binding and NO/cGMP activation of MP resulting in vasodilation. Inclusion of 31 nt E24 shifts the reading frame coding for a Mypt1 isoform with a distinct C-terminus (LZ-) that is unresponsive to NO/cGMP. We are using two editing approaches to test the function of Mypt1 E24 splice variants in the control of BP in vivo. First, LoxP sites were inserted in introns flanking E24, crossed with smMHCCre ER , and treated with Tamoxifen to achieve smooth muscle-specific cKO of E24 (SMcKO E24), thereby converting Mypt1 to the LZ+ isoform. E24 cKO mice had mean BP that was 15 + 3 mmHg lower than control (n=3-5; p&lt;0.05). Mesenteric arteries from these mice were significantly more sensitive to DEA/NO mediated relaxation (EC 50 : 2.1+0.5 nM vs 18.2+5.6 μM; n=5-6, p&lt;0.05). We now are developing CRISPR/CAS9 editing of Mypt1 for translation into humans with hypertension. Guide(g)RNAs targeting E24 were designed using Benchling.com and selected for further study based on predicted efficacy, specificity (&gt;10%,&gt;60%) and cross-species conservation. Plasmids were generated by sub-cloning of oligonucleotides into the parent pX601 plasmid for the purpose of co-expression of gRNA and saCas9. These plasmids were transfected into HEK293 cells singly and in combinations and Mypt1 gene editing assayed by PCR, Surveyor nuclease assays and sequencing of genomic DNA. Single gRNAs yielded deletions of 1-3 nt. Combinations yielded deletions of 104-334 nt that removed &gt;80% of E24 with an efficiency of editing that varied from 10% (gRNAs 6+9 and 5+9) to 40% (gRNAs 6+11 and 5+11). We have now generated AAVgE24 and are testing their efficiency of editing of VSM in vivo. These studies support that AAV mediated CRISPR/Cas9 editing of Mypt1 E24 could be a novel strategy for vasodilator sensitization and effective lowering of blood pressure in humans.

Histone 3 modifications and blood pressure in the Beijing Truck Driver Air Pollution Study

Context: Histone modifications regulate gene expression; dysregulation has been linked with cardiovascular diseases. Associations between histone modification levels and blood pressure in humans are unclear.Objective: We examine the relationship between global histone concentrations and various markers of blood pressure.Materials and methods: Using the Beijing Truck Driver Air Pollution Study, we investigated global peripheral white blood cell histone modifications (H3K9ac, H3K9me3, H3K27me3, and H3K36me3) associations with pre- and post-work measurements of systolic (SBP) and diastolic (DBP) blood pressure, mean arterial pressure (MAP), and pulse pressure (PP) using multivariable mixed-effect models.Results: H3K9ac was negatively associated with pre-work SBP and MAP; H3K9me3 was negatively associated with pre-work SBP, DBP, and MAP; and H3K27me3 was negatively associated with pre-work SBP. Among office workers, H3K9me3 was negatively associated with pre-work SBP, DBP, and MAP. Among truck drivers, H3K9ac and H3K27me were negatively associated with pre-work SBP, and H3K27me3 was positively associated with post-work PP.Discussion and conclusion: Epigenome-wide H3K9ac, H3K9me3, and H3K27me3 were negatively associated with multiple pre-work blood pressure measures. These associations substantially changed during the day, suggesting an influence of daily activities. Blood-based histone modification biomarkers are potential candidates for studies requiring estimations of morning/pre-work blood pressure.

Endoplasmic Reticulum Stress, a Driver or an Innocent Bystander in Endothelial Dysfunction Associated with Hypertension?

Hypertension (htn) is a polygenic disorder that effects up to one third of the US population. The endoplasmic reticulum (ER) stress response is a homeostatic pathway that regulates membrane structure, protein folding, and secretory function. Emerging evidence suggests that ER stress may induce endothelial dysfunction; however, it is unclear whether ER stress-associated endothelial dysfunction modulates htn. Exogenous and endogenous molecules activate ER stress in the endothelium, and ER stress mediates some forms of neurogenic htn, such as angiotensin II-dependent htn. Human studies suggest that ER stress induces endothelial dysfunction, though direct evidence that ER stress augments blood pressure in humans is lacking. However, animal and cellular models demonstrate direct evidence that ER stress influences htn. ER stress is likely one of many players in a complex interplay among molecular pathways that influence the expression of htn. Targeted activation of specific ER stress pathways may provide novel therapeutic opportunities.

Plasma Homocysteine Levels Are Associated With Circadian Blood Pressure Variation in Chinese Hypertensive Adults.

Homocysteine-lowering intervention with folate was recently shown to be able to increase day-night difference of blood pressure (BP) in humans indicating a potential relationship between homocysteine and circadian BP variation. We thus sought to investigate the association between plasma total homocysteine level (tHcy) and circadian BP variation in hypertensive adults. We enrolled 244 eligible dipping and 249 nondipping BP status adults from 560 adults who were randomly sampled from 5,233 Chinese hypertensive adults who received ambulatory BP monitoring (ABPM). We further enrolled 390 adults with CC/CT genotypes of the methylenetetrahydrofolate reductase (MTHFR) and 79 TT genotype who received ABPM at the same time from 1858 hypertensive adults with MTHFR polymorphisms detection. Plasma tHcy in nondippers was significantly higher than dippers (P < 0.001). Simple linear analysis revealed that tHcy significantly correlated with nocturnal systolic BP fall (r = -0.145, P = 0.001) and diastolic BP fall (r = -0.141, P = 0.002). Multivariate logistic regression analysis further identified tHcy as an independent factor correlated with the presence of nondipping BP status in hypertensive adults (odds ratio: 1.873, 95% confidence interval: 1.171-2.996, P = 0.009). The percentage of dipping BP status was 19.49% or 8.86% and the percentage of nondipping BP status was 80.51% or 91.14% in CC/CT or TT genotypes, respectively. The above different between CC/CT and TT genotypes was significant (P = 0.024). These results indicated that high homocysteine levels associate with disturbed circadian BP variation in Chinese hypertensive adults.

Normobaric hypoxic conditioning to maximize weight loss and ameliorate cardio-metabolic health in obese populations: a systematic review.

Normobaric hypoxic conditioning (HC) is defined as exposure to systemic and/or local hypoxia at rest (passive) or combined with exercise training (active). HC has been previously used by healthy and athletic populations to enhance their physical capacity and improve performance in the lead up to competition. Recently, HC has also been applied acutely (single exposure) and chronically (repeated exposure over several weeks) to overweight and obese populations with the intention of managing and potentially increasing cardio-metabolic health and weight loss. At present, it is unclear what the cardio-metabolic health and weight loss responses of obese populations are in response to passive and active HC. Exploration of potential benefits of exposure to both passive and active HC may provide pivotal findings for improving health and well being in these individuals. A systematic literature search for articles published between 2000 and 2017 was carried out. Studies investigating the effects of normobaric HC as a novel therapeutic approach to elicit improvements in the cardio-metabolic health and weight loss of obese populations were included. Studies investigated passive (n = 7; 5 animals, 2 humans), active (n = 4; all humans) and a combination of passive and active (n = 4; 3 animals, 1 human) HC to an inspired oxygen fraction ([Formula: see text]) between 4.8 and 15.0%, ranging between a single session and daily sessions per week, lasting from 5 days up to 8 mo. Passive HC led to reduced insulin concentrations (-37 to -22%) in obese animals and increased energy expenditure (+12 to +16%) in obese humans, whereas active HC lead to reductions in body weight (-4 to -2%) in obese animals and humans, and blood pressure (-8 to -3%) in obese humans compared with a matched workload in normoxic conditions. Inconclusive findings, however, exist in determining the impact of acute and chronic HC on markers such as triglycerides, cholesterol levels, and fitness capacity. Importantly, most of the studies that included animal models involved exposure to severe levels of hypoxia ([Formula: see text] = 5.0%; simulated altitude >10,000 m) that are not suitable for human populations. Overall, normobaric HC demonstrated observable positive findings in relation to insulin and energy expenditure (passive), and body weight and blood pressure (active), which may improve the cardio-metabolic health and body weight management of obese populations. However, further evidence on responses of circulating biomarkers to both passive and active HC in humans is warranted.

A simple method for reconstruction of continuous brachial artery pressure from continuous digital artery pressure in humans.

This paper presents a practical approach to reconstruct brachial artery pressure (BAP) distally from digital artery pressure (DAP). We hypothesize that continuous BAP can simply be approximated by sum of two halves of the continuous DAP shifted by the time delay. In order to test it, we enrolled 30 healthy volunteers for two experiments. We firstly showed that the pressure wave in the digital artery can be considered twice as much as the forward/backward wave in the finger. A simplified individualized transfer function was then derived so as to estimate BAP from DAP. Finally, by comparing with a reference BAP, we found that the proposed method can correct the DAP. The errors of the proposed method in estimating systolic and diastolic pressures are 2.82±3.58 and -2.32±4.06 mmHg, respectively. These results agree with the standard of Association for the Advancement of Medical Instrumentation (AAMI). Our method is therefore promising in estimating continuous proximal blood pressure from peripheral blood pressure in practice.

Patchable Ion Channel Pressure Sensors Inspired By Somatic Organs

Among vital elements in our body, ion channel are essential units which sustain life in all living cells as continuously transporting appropriate ions through plasma cell membranes. In addition, the somatic functions of ion channels are fundamentally indispensable for sensory organ homeostasis. For decades, biological ion channels have led to much inspiration because of their unique and exquisite operational functions in living cells. Specifically, their extreme and dynamic sensing abilities can be realized by the combination of receptors and pores coupled together to build ion channel systems. In this presentation, we demonstrate that artificial ion channel pressure sensors inspired by nature for detecting pressure are highly sensitive and wearable. Our ion channel pressure sensors basically consisted of receptors and nanopore membranes, enabling dynamic current responses to external forces for multiple applications. The ion channel pressure sensors had a sensitivity of ∼5.6 kPa−1 and a response time of ∼12 ms at a frequency of 1 Hz. The power consumption was recorded as less than a few μW. Moreover, linear regression was performed in terms of temperature, which showed no significant variations, and there were no significant current variations with humidity. The patchable ion channel pressure sensors were then used to detect blood pressure in humans, and different signals were clearly observed for each person. Additionally, modified ion channel pressure sensors detected complex motions including pressing and folding in a high-pressure range. In comparison to previous pressure sensors, our ion channel pressure sensors engaged sensory organs could provide feasible control of the bandwidth via selecting different electrolytes and unique signal shape according to the type of pressure receptor chosen, and the dynamic output signal may offer discrete information for an object. We expect that if the diverse functions of ion channels in nature could be further modified or mimicked for various applications, then artificial sensory systems such as the one described in this study would be tremendously greeted in a new era of sensors.

Blood Pressure in Healthy Humans Is Regulated by Neuronal NO Synthase.

NO is physiologically generated by endothelial and neuronal NO synthase (nNOS) isoforms. Although nNOS was first identified in brain, it is expressed in other tissues, including perivascular nerves, cardiac and skeletal muscle. Increasing experimental evidence suggests that nNOS has important effects on cardiovascular function, but its composite effects on systemic hemodynamics in humans are unknown. We undertook the first human study to assess the physiological effects of systemic nNOS inhibition on basal hemodynamics. Seventeen healthy normotensive men aged 24±4 years received acute intravenous infusions of an nNOS-selective inhibitor, S-methyl-l-thiocitrulline, and placebo on separate occasions. An initial dose-escalation study showed that S-methyl-l-thiocitrulline (0.1–3.0 µmol/kg) induced dose-dependent changes in systemic hemodynamics. The highest dose of S-methyl-l-thiocitrulline (3.0 µmol/kg over 10 minutes) significantly increased systemic vascular resistance (+42±6%) and diastolic blood pressure (67±1 to 77±3 mm Hg) when compared with placebo (both P<0.01). There were significant decreases in heart rate (60±4 to 51±3 bpm; P<0.01) and left ventricular stroke volume (59±6 to 51±6 mL; P<0.01) but ejection fraction was unaltered. S-methyl-l-thiocitrulline had no effect on radial artery flow-mediated dilatation, an index of endothelial NOS activity. These results suggest that nNOS-derived NO has an important role in the physiological regulation of basal systemic vascular resistance and blood pressure in healthy humans.

Molecular pathways associated with blood pressure and hexadecanedioate levels.

The dicarboxylic acid hexadecanedioate is associated with increased blood pressure (BP) and mortality in humans and feeding it to rats raises BP. Here we aim to characterise the molecular pathways that influence levels of hexadecanedioate linked to BP regulation, using genetic and transcriptomic studies. The top associations for hexadecanedioate in a genome-wide association scan (GWAS) conducted on 6447 individuals from the TwinsUK and KORA cohorts were tested for association with BP and hypertension in the International Consortium for BP and in a GWAS of BP extremes. Transcriptomic analyses correlating hexadecanedioate with gene expression levels in adipose tissue in 740 TwinsUK participants were further performed. GWAS showed 242 SNPs mapping to two independent loci achieving genome-wide significance. In rs414056 in the SCLO1B1 gene (Beta(SE) = -0.088(0.006)P = 1.65 x 10−51, P < 1 x 10−51), the allele previously associated with increased risk of statin associated myopathy is associated with higher hexadecanedioate levels. However this SNP did not show association with BP or hypertension. The top SNP in the second locus rs6663731 mapped to the intronic region of CYP4Z2P on chromosome 1 (0.045(0.007), P = 5.49x10-11). Hexadecanedioate levels also correlate with adipose tissue gene-expression of the 3 out of 4 CYP4 probes (P<0.05) and of alcohol dehydrogenase probes (Beta(SE) = 0.12(0.02); P = 6.04x10-11). High circulating levels of hexadecanedioate determine a significant effect of alcohol intake on BP (SBP: 1.12(0.34), P = 0.001; DBP: 0.70(0.22), P = 0.002), while no effect is seen in the lower hexadecanedioate level group. In conclusion, levels in fat of ADH1A, ADH1B and CYP4 encoding enzymes in the omega oxidation pathway, are correlated with hexadecanedioate levels. Hexadecanedioate appears to regulate the effect of alcohol on BP.

Elevated Sympathetic Nerve Activity Mediates Increases in Large Central Elastic Artery Stiffness Independent of Changes in Blood Pressure in Humans

Recent evidence suggests that elevated sympathetic nerve activity (SNA) may increase large central elastic artery stiffness (i.e., carotid, aorta), a robust independent predictor of cardiovascular disease. However, experimental manipulations involving increased (e.g., handgrip exercise) or decreased (e.g., ganglionic blockade) SNA in humans have also evoked concomitant changes in arterial blood pressure (BP) making interpretation difficult. Therefore, we tested the hypothesis that acute elevations in SNA increase central artery stiffness independent of BP. First, in 7 young healthy men (20 ± 1 yrs; 26 ± 1 kg/m2), carotid artery compliance was assessed at baseline and during a moderate level of lower body negative pressure (LBNP, −45mmHg), a stimulus known to significantly increase SNA without major changes in BP. Next, carotid‐femoral pulse wave velocity (PWV), the gold standard assessment of aortic stiffness, and resting muscle SNA (MSNA) were assessed in a larger sample of healthy individuals (n=30; 37 ± 3 yrs; 11 women) and correlated. During LBNP, baroreflex‐mediated increases in heart rate were observed (BL: 59 ± 3 vs. LBNP: 80 ± 5 bpm, P&lt;0.05), but mean BP was unchanged (BL: 79 ± 1 vs. LBNP: 81 ± 1 mmHg, P&gt;0.05). Carotid artery compliance was significantly reduced during LBNP compared with baseline (BL: 1.15 ± 0.11 vs. LBNP: 0.71 ± 0.1 mm2/mmHg×10−2, P&lt;0.05) in addition to reductions in brachial artery compliance (BL: 0.1 ± 0.03 vs. LBNP: 0.07 ± 0.02 mm2/mmHg×10−2, P&lt;0.05). In the larger sample, carotid artery compliance was moderately associated with resting MSNA (R=−0.374, P=0.055); however, there was a stronger association between carotid‐femoral PWV and resting MSNA (R=0.583, P&lt;0.01) that persisted after adjusting for BP and sex (R=0.471, P&lt;0.01). Together, these preliminary data suggest that SNA acutely increases large central elastic artery stiffness in humans independent of changes in BP, and that tonically elevated resting SNA may contribute to higher large central elastic artery stiffness.Support or Funding InformationNIH T32 HL007121, P01HL014388, U54TR001356 and American Heart Association 13SDG143400012