Systemic Blood Research Articles

T1 mapping to assess hepatic and myocardial characteristics in children with single ventricle circulation

Abstract Background Single ventricle (SV) palliation, culminating with the Fontan operation, results in passive systemic venous blood flow directly to the pulmonary circulation. Resulting inevitable hepatic venous congestion can lead to hepatic fibrosis. Previous studies suggest hepatic changes can occur prior to the Fontan completion. Besides fibrotic myocardial remodeling may lead to systolic and diastolic ventricular dysfunction, transmitting back pressure to the pulmonary system. Purpose To compare quantitative T1 cardiovascular magnetic resonance (CMR) imaging of the myocardium and liver between SV patients and controls, as a potential measure of myocardial and hepatic fibrosis. Methods Retrospective review of 16 SV patients with dominant single left ventricle (SLV, n=6) or single right ventricle (SRV, n=10), at various stages of palliation (pre-Glenn=6, post-Glenn=3, Fontan=7) underwent CMR with myocardial T1 mapping with the liver also in the plane of view. Biventricular patients found to have structurally normal hearts and normal cardiac function on CMR were used as controls (n=21). Native T1 times using a modified Look-Locker inversion recovery (MOLLI) approach in free-wall of the dominant ventricle at a mid-ventricular short axis in SV and the ventricular septum in controls and, a region of interest in the liver (avoiding any vessels) were measured in all patients. Median and inter-quartile ranges of continuous variables were compared between SV and controls using the Mann-Whitney U test. Results As compared to controls SV patients were (1) significantly younger, (2) had lower ejection fraction, (3) higher median myocardial T1, and (4) higher median liver T1. Also, there was no difference between SLV vs. SRV median myocardial T1 (1056 vs. 1065ms, p=0.43) or liver T1 (678 vs. 729ms, p=0.30) Conclusion Despite younger age, findings of increased myocardial T1 may suggest an element of myocardial fibrosis responsible for the ventricular dysfunction in this population, and that raised liver T1 may be an earlier marker of liver fibrosis, which warrants further study. Funding Acknowledgement Type of funding source: None

Hemodynamic Assessment and In vivo Catabolism of Adenosine 5'-triphosphate in Doxorubicin or Isoproterenol-induced Cardiovascular Toxicity.

Previous studies have shown that catabolism of adenosine 5'-triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity. We compared the acute toxicity of high doses of doxorubicin (DOX) and isoproterenol (ISO) on hemodynamics and ATP catabolism in the systemic circulation. sprague Dawley (SD) rats (n = 8 - 11) were each given either a single dose of 30 mg/kg ISO, or a twice-daily dose of 10 mg/kg of DOX or 4 doses of normal saline (control) by subcutaneous injection. Blood samples were collected up to 6 hours for measuring concentrations of ATP and its catabolites. Hemodynamics was recorded continuously. The difference was considered significant at p < 0.05 (ANOVA). Mortality was 1/8, 5/11, and 0/11 for the DOX, ISO, and control groups, respectively. Systolic blood pressure was significantly lower in the DOX and ISO treated rats than in control measured at the last recorded time (76 ± 9 for DOX vs. 42 ± 8 for ISO vs. 103 ± 5 mmHg for control, p < 0.05 for all). Blood pressure fell gradually after the final injection for both DOX and control groups, but abruptly after ISO, followed by a rebound and then gradual decline till the end of the experiment. Heart rate was significantly higher after ISO, but there were no differences between the DOX and control rats (p > 0.05). RBC concentrations of ADP and AMP, and plasma concentrations of adenosine and uric acid were significantly higher in the ISO group. In contrast, hypoxanthine concentrations were significantly higher in the DOX treated group (p < 0.05). Acute cardiovascular toxicity induced by DOX and ISO may be measured by changes in hemodynamics and breakdown of ATP and adenosine in the systemic circulation, albeit a notable qualitative and quantitative difference was observed.

NUMERICAL INVESTIGATION ON PRELOAD AND AFTERLOAD SENSITIVITY FOR USING VENTRICULAR ASSIST DEVICE ON HEART FAILURE PATIENTS

A left ventricular assist device (LVAD) is a surgically implanted mechanical pump being used for patients with end-stage heart failure (HF). One of the significant clinical challenges in using LVADs is its remarkable changes in hemodynamic parameters during a change in body position from supine to standing. In standing position, vasodilatation of veins occurs in the legs, which decreases left ventricular end-diastolic pressure, and, in turn, the preload to the LVAD. In this research, a numerical investigation is carried out to evaluate the effect of LVAD in cardiac hemodynamic parameters such as cardiac output (CO) and stroke work (SW) under preload, normal, and afterload conditions. A Proportional–integral–derivative (PID) controller associated with an LVAD pump model and cardiovascular system (CVS) model is developed to study the cardiac hemodynamic and its performance during HF condition by changing system parameters in one cardiac cycle. The performance of the proposed model is then evaluated using a pump cannulae model, real-time status detection of the aortic valve (av), and left ventricular stroke volume. The model parameters associated with HF, including contractility of the left and right ventricle ([Formula: see text] &amp; [Formula: see text]), systemic peripheral resistance ([Formula: see text]) and total blood volume ([Formula: see text]) were set 0.71[Formula: see text]mmHg.s.mL[Formula: see text], 0.53[Formula: see text]mmHg.s.mL[Formula: see text], 1.11[Formula: see text]mmHg.s.mL[Formula: see text] and 5800[Formula: see text]mL, respectively, to allow simulation of HF conditions. The findings of this study show that the CO is increasing linearly with end-diastolic left ventricular volume (LVEDV) and end-diastolic right ventricular volume (RVEDV). However, other vital parameters behavior has a nonlinear relation to CO. Results of this study prove that the LVAD model is more sensitive to preload than afterload condition under different hemodynamical conditions.

The epicardium as a biological filter of the heart

In the epicardium of many mammals, animals, including humans, were found to have typical arteriovenular anastomoses. However, they do not correspond to the description of those direct anastomoses between arteries and veins located under the epicardium, which were previously identified. The authors who described them, using injection methods, showed the passage of carcass suspension from sub-epicardial arteries to sub-epicardial veins. But they could not accurately identify the type of vessels carrying out these connections. It is possible that these are arteriovenular anastomoses, since their diameter not exceeds the diameter of the blood capillaries. At the same time, it was shown that the vascular structures of the epicardium carry out the separation of the blood in the coronary artery system. As a result, blood with high hematocrit and freed from most various analytes and neutrophilic granulocytes enters the microvascular bed of the myocardium. The ultrafiltrate of the blood plasma in the sub-epicardial loose connective tissue undergoes biodegradation and is utilized in the lymphatic micro vessels. The aim of the work is the morphological and functional substantiation of the concept about of the epicardium as a biological filter of the heart. The vascular bed of the epicardium of hearts of mature dogs was studied (n=5), revealed by various routine histological and original intra- and extravascular methods. It is proved that the microvascular bloodstream of the sub-epicardial connective tissue has pronounced organ specificity. It is determined by the presence of arteriovenular anastomoses and permanent plasma capillaries, as well as the high permeability of all vascular components. The microvascular bed of the epicardium causes an ascending dilatation of the coronary arteries and contributes to ultrafiltration of a significant amount of blood plasma into the sub-epicardial interstitial space. Thus, the process of the separation of the blood is carried out, as a result of which blood with high hematocrit and free of neutrophilic granulocytes enters the myocardium. In the epicardial connective tissue, analytes accumulate that cannot be resorbed by venous micro vessels. This «biological debris» undergoes destruction in the sub-epicardial connective tissue, which proves the role of the epicardium as a biological filter of the heart.

Use of Inflammatory Biomarkers and Real-Time Cardiac Catheterisation to Evaluate the Left Ventricular Diastolic Function in Patients With Diastolic Heart Failure

Interleukin (IL)-17 and its related cytokines have been shown to be involved in myocardial fibrosis and irreversible ventricular remodelling, which have predictive values in the development of left ventricular diastolic dysfunction (LVDD). This study aimed to assess the correlation between IL-17 and LVDD, and investigate the prognostic value of IL-17 among patients with normal left ventricular ejection fraction (LVEF). A total of 120 patients with normal LVEF underwent left ventricular (LV) catheterisation for LV end-diastolic pressure (LVEDP) measurement and routine echocardiography. The follow-up period was 30 (18, 35) months. The levels of IL-17 and IL-6 from the systemic blood were significantly increased in non-heart failure (HF) patients with LVDD (p<0.001). Receiver operating characteristic (ROC) revealed that the combination of IL-17 and IL-6 showed the highest diagnostic accuracy in predicting LVDD (AUC, 0.890; 95% CI, 0.835-0.945; p<0.001), and the cut-off value was 41.5 pg/mL. On logistic regression analysis, the increment of the combination of IL-17 and IL-6 was an independent predictor for the prognosis of LVDD (odds ratio, 1.25; 95% CI, 1.01-1.12; p<0.05). According to the cut-off value of the combination of IL-17 and IL-6, the patients with lower levels of IL-17 and IL-6 (<41.5 pg/mL group) had a better prognosis. The increased levels of IL17 and IL-6 were significantly correlated with the levels of fibrotic parameters. Assessment of LVDD by measuring the combination of IL-17 and IL-6 might provide valuable prognostic significance for non-HF patients with LVDD.

THE RELATIONSHIP BETWEEN FAT, FIBER, SODIUM, POTASSIUM, AND CALCIUM INTAKE AND HYPERTENSION AMONG ADOLESCENTS IN PALEMBANG

Hypertension is a condition characterized by a rise in systemic arterial blood pressure above the threshold/normal value. The incidence of hypertension can increase due to various risk factors. High intake of dietary fats and sodium, and low of intake of fibers, potassium and calcium are some risk factors of hypertension. Inadequate intake of nutrients is often ignored by adolescents because of their irregular eating patterns. This study aim was to determine the relationship between fat, fiber, sodium, potassium and calcium intake with hypertension among adolescent. A cross sectional study has been conducted in Palembang from July to December 2019. A total of 475 samples were taken by proportioned stratified random sampling technique who fulfilled the inclusion criteria. Data was taken by measuring blood pressure and using a food recall questionnaire for 3 days, then it was estimated through the nutrisurvey software. The data were analyzed by chi square test. This study showed that the incidence of hypertension among adolescent was 23.4%. There was no significant relationship between fiber intake (p = 1,000, OR = 1,844), sodium intake (p = 0,255, OR = 1,602) potassium intake (p = 1,000, OR = 1,532) and calcium intake (p = 0,316, OR = 3,750) with hypertension. A significant relationship was found between fat intake and hypertension (p = 0,000, OR = 3,425) among adolescents in Palembang.

Long-term stability of insulin glulisine loaded nanoparticles formulated using an amphiphilic cyclodextrin and designed for intestinal delivery

Long-term stability is one of the main challenges for translation of therapeutic proteins into commercially viable biopharmaceutical products. During processing and storage, proteins are susceptible to denaturation. The aim of this work was to evaluate the stability of amphiphilic cyclodextrin-based nanoparticles (NPs) containing insulin glulisine. The stability of the NP dispersion was systematically evaluated following storage at three different temperatures (4 °C, room temperature (RT) and 40 °C). While the colloidal parameters of the NPs in terms of size and zeta potential were maintained (109 ± 9 nm, polydispersity index 0.272, negative zeta potential –25 ± 3 mV), insulin degraded over 60 days during storage. To enhance the shelf life of the product and to circumvent the need for cold-chain maintenance, a lyophilized formulation containing insulin glulisine NPs (1.75 mg/mL of NPs) and 25 mg/mL trehalose was produced. The freeze-dried powder extended the stability of the product for up to 30 days at ambient temperature and 90 days at 4 °C (with 95% and >80% insulin recovery, respectively). Following intra-intestinal administration of the freeze-dried formulation, while no lowering of blood glucose was seen, insulin glulisine was detected in both portal and systemic blood indicating that potential exists for further development of the formulation to simultaneously achieve prolonged stability and therapeutic efficacy.

P1435RELATIONSHIP BETWEEN INTRA-DIALYTIC OXYGEN EXTRACTION RATIO (OER) CHANGE AND IDH

Abstract Background and Aims Intradialytic hypotension (IDH) involves a reduced tolerance to hemodialysis (HD), a poor quality of life and is associated with mortality. Intradialytic monitoring systems (blood pressure, heart rate, volemia) are not able to identify patients at greater risk of IDH. IDH is a hemodynamic phenomenon and attention has recently been given to the evaluation of oxygen saturation to evaluate its role in IDH. Oxygen Extraction Ratio (OER), the ratio between SaO2 and ScvO2, is a parameter used to monitor parenchyma oxygen consumption and stress. Recent evidence showed that HD patients with a greater delta OER (ΔOER) during HD (threshold 40%)had higher mortality risk. OER could be a new monitoring instrument to measure hemodialysis induced sub-clinical parenchyma hypoxia and stress, two elements included in the pathogenesis of IDH. The aim of the study was to evaluate the relationship between OER and IDH incidence. Method Inclusion criteria: age ≥18 years, chronic HD treatment by means of permanent jugular CVC, no evidence of acute underlying illness. We evaluated OER ([(SaO2 − ScvO2)/SaO2] × 100) before HD and at 15’, 30’, 60’ and post HD in three HD sessions (HD OER sessions). For the statistic analysis we considered for each patient the median OER value obtained from the three HD OER sessions. Then we started the follow-up study with a minimum follow-up of three months and end follow-up of two years, to record IDH (defined according to K/DOQI guidelines) for each patient. We divided the population in two groups using as a threshold the median percentage number of IDH in our population and evaluate the differences between the obtained two groups in pre HD OER, Delta OER and intradialytic OER trends. Results During the follow-up period (mean 12 ± 1.2 months), we enrolled 28 patients with permanent jugular CVC: 13 males and 15 females, aged 74±2.6 years, HD vintage 46 ± 6.5 months. The HD OER sessions for each patient were asymptomatic. Pre HD OER was 34 ± 1.4, post HD OER 46 ± 1.8, with a Delta OER of 39 ± 5 %. OER change during HD was evident since after 15 minutes (OER% 15’: 40 ± 1.2 p&amp;lt;.001) and continued to increase progressively (OER% end HD 46 ± 1.8; p&amp;lt;.0001). During the follow up period we monitored 4342 HD sessions of which 186 with IDH, the median incidence of IDH was 3.6% of all HD sessions. We divided patients into two groups based on the median value of IDH incidence: (IDH % ≤ 3.6 and IDH % &amp;gt; 3.6). The two groups were not different for age (76 ± 2.4 vs 73 ± 3.0 years; p &amp;lt;ns), HD vintage (52 ± 8.6 vs 40 ± 4.0 months; p &amp;lt;ns), systolic (125 ± 3.2 vs 129 ± 4.0 mmHg; p &amp;lt;ns) and diastolic blood pressure (67 ± 2.2 vs 70 ± 2.2 mmHg; p &amp;lt;ns) and heart rate (70 ± 2.2 vs. 76 ± 2.3 bpm; p &amp;lt;ns) (Tab. 2). The IDH % &amp;gt;3.6 group had 159 IDH out of a total of 1911 sessions (9%), while IDH % ≤ 3.6 group had 27 IDH out of 2431 sessions (0.9%). Pre HD OER values were not different between the groups while the IDH % &amp;gt;3.6 group had greater delta OER% than the IDH % ≤ 3.6 group (43 ± 4.8 vs. 35 ± 3.0 %; p &amp;lt;.05) (Figure). Evaluating the OER trend during HD session a higher ΔOER% was found at 15 minutes of HD treatment in the IDH % &amp;gt; 3.6 group (ΔOER 20± 3.0 % vs. 8.0 ± 3.0 %; IDH % &amp;gt; 3.6 group vs. IDH % ≤ 3.6 group, p &amp;lt;.05), data confirmed at 30' (24 ± 3.0 % vs. 13 ± 5.0 %; p &amp;lt;.05), and post HD (43 ± 5.0 % vs 35 ± 3.0 %; p &amp;lt;.05), but not at 60 minutes of HD treatment (19 ± 4.0 % vs. 17 ± 4.6 %; p &amp;lt;ns). Conclusion Our data show that intradialytic ΔOER, representative of the extent of tissue hypoxic stress, identifies patients at greater risk of IDH. In particular, a ΔOER of 20% after the first 15 minutes of HD and of 43% at the end of the HD session characterizes the more hemodynamically fragile patients. The measurement of the OER can be a new and easy monitoring instrument to identify the most hemodynamically fragile patients already after the first 15 minutes of HD treatment.

Association of chronotype and pain at baseline in ovarian cancer survivors participating in a lifestyle intervention (NRG/GOG 0225).

6018 Background: Chronotype is defined as an individual’s propensity to sleep at a specific time in a 24-hour cycle with late chronotype associated with poorer health outcomes including cancer. Chronotype remains relatively undefined in ovarian cancer. The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) study is testing whether 1205 women randomized to a diet and physical activity intervention for 24-months will have longer progression-free survival versus an attention control. Here we determine the association of late and early vs mid chronotypes and patient reported outcomes (PROs), lifestyle behaviors and biomarkers of metabolic health and inflammation in ovarian cancer survivors post-treatment (≤ 6.5 months). Methods: Chronotype was determined using self-reported time to bed (early &lt; 9 pm; mid ≥ 9 pm - ≤12 am; late &gt; 12 am) captured through the Pittsburg Sleep Quality Index and PROs were measured using subscales of the Rand-36 questionnaire. Validated questionnaires for diet and physical activity were used and biomarkers were collected at routine clinic visits. A total subsample of 438 ovarian cancer survivors enrolled in NRG/GOG 0225- LIVES study with all available baseline measures were included in analyses. Descriptive statistics, general linear mixed models, and Pearson correlations were performed. Results: Reported pain was significantly higher in late chronotypes (P &lt; 0.05) when compared to early and mid-chronotypes. Total sleep duration was significant between the 3 chronotypes (P &lt; 0.05) with late chronotype experiencing less sleep (6.77 ± 1.67 hrs) than mid chronotype (7.04 ± 1.31 hrs) and early chronotype (7.56 ± 1.33 hrs). Higher reported pain was significantly correlated to poorer CRP levels (r = -0.198, P &lt; 0.001) suggesting higher systemic inflammation and poorer blood insulin levels (r = -0.116, P &lt; 0.05) independent of chronotype classification. All other subscales of the RAND 36 and physical activity were not associated with chronotype. Diet quality trended towards significance with a positive association observed in early and an inverse association in late chronotypes (P = 0.06). Conclusions: Late chronotypes reported higher levels of pain which was associated with poorer sleep and diet quality and higher levels of inflammation and insulin. More robust data, including actigraphy, are being analyzed and will provide additional insight of the role of circadian rhythm and phenotype on pain and key biomarkers in ovarian cancer survivors. Clinical trial information: NCT00719303.

Clasificación del deterioro cognitivo en adultos mayores con diabetes mellitus tipo 2

&lt;p&gt;&lt;strong&gt;Objetivo:&lt;/strong&gt; clasificar el deterioro cognitivo en adultos mayores con diabetes mellitus tipo 2 (dm2) adscritos a una Unidad de Medicina Familiar (umf) de la Ciudad de México. &lt;strong&gt;Métodos:&lt;/strong&gt; estudio transversal realizado de marzo a junio de 2018. Se incluyeron 139 pacientes con dm2, de ambos sexos, mayores de 60 años, sin diagnóstico de demencia o deterioro cognitivo. Se utilizó el cuestionario Mini Mental de Folstein para clasificar el grado de deterioro cognitivo. &lt;strong&gt;Resultados:&lt;/strong&gt; en deterioro cognitivo moderado, el sexo femenino representó 7.2% (n=10%). Los adultos mayores que tuvieron de seis a diez años de diagnóstico de dm2 reportaron 5% de deterioro cognitivo leve (n=7) y aquellos con más de diez años de diagnóstico representaron 5.8% (n=8). La hipertensión arterial sistémica fue la comorbilidad mayormente asociada a dm2 para desarrollar deterioro cognitivo grave en 4% (n=6).&lt;strong&gt;Conclusiones:&lt;/strong&gt; el sexo femenino fue el más afectado, con mayor porcentaje en deterioro cognitivo leve y moderado, los factores asociados a mayor riesgo de presentarlo fueron más de seis años de evolución del diagnóstico de dm2 y su asociación con hipertensión arterial sistémica.&lt;/p&gt;

Acute sensorineural hearing loss in hemodialysis patients

Background: Approximately, 30–40% of patients experienced hearing loss under regular hemodialysis.Objective: This study reviewed our experience on treating acute hearing loss in patients under regular hemodialysis over the past two decades.Methods: Twenty-six patients having acute hearing loss under hemodialysis were divided into two groups based on their etiologies. Sixteen patients (16 ears) with sudden sensorineural hearing loss (SSHL) were assigned to Group A and 10 patients (13 ears) with endolymphatic hydrops (EH) were assigned to Group B.Results: No significant difference was noted between Groups A and B, regardless of hemodialysis duration, clinical manifestation, underlying systemic diseases, blood examination, and vestibular test battery. In contrast, serum osmolality was significantly lower in Group B (292 ± 11 mOsm/kg) than in Group A (310 ± 11 mOsm/kg). Furthermore, Group B (40 ± 14 dB) had better mean hearing level than Group A (87 ± 21 dB) in the initial audiogram, and a higher hearing improvement rate (69%) than Group A (19%).Conclusions and significance: Both SSHL and EH are major causes for precipitating acute hearing loss in hemodialysis patients. Compared to SSHL, the less deteriorated MHL and lower serum osmolality in EH provide two clues for differentiating acute hearing loss in hemodialysis patients.

Diabetes is Associated with Increased Passage of Bacterial Metabolite TMA, a TMAO Precursor, Through the Intestinal Barrier

Trimethylamine N‐oxide (TMAO) is suggested to be a marker of cardiovascular outcome in diabetic patients. However, mechanism of the TMAO increase remains unclear. TMAO is a product of liver oxidation of trimethylamine (TMA), a metabolite of gut bacteria. Diabetes is associated with gut barrier disruption, which may result in increased passage of bacterial metabolites to the bloodstream. We hypothesized that higher gut barrier permeability to TMA is responsible for TMAO elevation in diabetic patients with increased cardiovascular risk. We assessed gut permeability to TMA and TMA liver clearance in animal model of diabetes. Additionally we studied therapeutic potential of ACE‐I (angiotensin‐converting enzyme inhibitor) in restoring proper gut barrier function.12‐week‐old Sprague Dawley rats received either streptozotocin (65 mg/kg bw i.p.) (diabetic group, n=15, and ACE‐I group, n=12) or saline i.p. (control group, n=12). Fasting glucose level above 250mg/dl was considered a successful diabetes induction. Rats with ineffective diabetes induction were not included in the analysis. ACE‐I group was treated with enalapril (Polpharma, Poland), dissolved in drinking water 50mg/L (a dose of 6.5±0.3 mg/kg bw) for 4 weeks. Diabetic and control group were maintained on tap water. 4‐weeks after induction of diabetes, rats were anesthetized with urethane (1.5 g/kg bw i.p.) and blood samples from portal vein and inferior vena cava were collected. Rats were euthanized and tissues and colon content (stools) were harvested for histological and biochemical analysis, respectively. The concentration of TMA and TMAO in blood and stool samples were evaluated using liquid chromatography coupled with mass spectrometry. Gut permeability was estimated by the ratio of TMA stool concentration to TMA portal blood concentration. TMA liver clearance was calculated using the equation: 1−(systemic blood concentration/portal blood concentration).Histological examination revealed pronounced changes in intestinal morphology in rats with induced diabetes. Diabetic group showed significantly increased concentration of TMA in portal blood and increased gut permeability to TMA in comparison to control group and ACE‐I group (diabetic rats treated with enalapril). Additionally, diabetic group demonstrated higher liver clearance of TMA in comparison to healthy rats, which was also reflected by a trend towards higher concentration of TMAO in diabetic rats.Diabetes is associated with disruption of gut barrier, which results in increased permeability to TMA, and these changes are ameliorated by enalapril. Increased availability of TMA, a TMAO precursor, together with higher TMA liver clearance appear to be probable mechanisms of TMAO increase in diabetes. Given the potential harmful effects of TMA or TMAO our study indicates gut barrier as a therapeutic target with the promising use of ACE‐I.Support or Funding InformationThis work was supported by the Ministry of Science and Higher Education Republic of Poland, Diamond grant no: DI2017 009247.Selected parameters in experimental groups: diabetic rats (diabetes), diabetic rats on enalapril (ACE‐I) and rats without diabetes on tap water (control). Gut permeability was assessed by the ratio: TMA stool concentration/TMA portal blood concentration; liver clearance was calculated: 1‐(systemic blood concentration/portal blood concentration). TMA ‐ trimethylamine, TMAO ‐ trimethylamine N‐oxide. Values are means ± SE, * ‐ p&lt;0.05, by one‐way ANOVA followed by Duncan’s test.Figure 1

Valeric Acid, a Gut Microbiota Product, Lowers Arterial Blood Pressure in Rats.

Valeric acid (VA), a short‐chain fatty acid (SCFA), is produced by gut bacteria. The aim of the study was to evaluate if VA affect arterial blood pressure (BP) in rats. Furthermore, we investigated physiological concentrations of VA, and distribution of VA‐D9 to organs involved in the control of the circulatory system after the administration of VA‐D9 into the colon, a major site of microbiota metabolism. Hemodynamics were recorded in anesthetized, male, 14‐week‐old Wistar rats. A vehicle (0.9% NaCl), VA, or 3‐hydroxybutyrate, an antagonist of SCFA receptors GPR41/43 (ANT) were administered into the colon (IC) or intravenously (IV). Reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries was tested in ex vivo conditions. SCFAs concentration was measured using ultra performance liquid chromatograph with mass spectrometer.Physiological concentration of VA in the colon content was ≈ 650μM and ≈ 0.4μM in systemic blood. VA‐D9 was detected in the liver, the heart, the brain and kidneys 5 min after the administration into the colon. The vehicle did not affect BP and heart rate (HR). VA acid produced a dose‐dependent decrease in BP, and at higher doses decrease in HR. The hypotensive effect of VA was inhibited by the ANT. In vitro, VA dilated GMA and MA. In MA the dilatory effect was reduced by the ANT.In conclusion, VA rapidly penetrates from the colon to systemic tissues exerting a hypotensive effect. The latter is mediated by vasodilation. The hypotensive effect of colon‐derived VA may have a therapeutic potential.Support or Funding InformationThis work was supported by the National Science Centre, Poland grant no. UMO‐2016/21/B/NZ5/02544.

Effect of Platinum Nanoparticles on the Structure of Protein Molecules and Regulation of the Tone of Brain Vessels in Experimental Animals.

The effects of platinum nanoparticles on the morphological structures of the solid phase of blood serum and the tone of cerebral microvessels as indicators of the dynamics of homeostasis were studied on outbred albino male rats (n=40) weighing 300-350 g. Platinum nanoparticles were injected to experimental animals in 1 ml of physiological saline. For systemic BP measurements and blood sampling, the femoral artery was isolated and catheterized. The study of solid phase structures of blood serum was conducted by the method of cuneiform dehydration. The results showed that injection of platinum nanoparticles significantly affected the body of experimental animals.

Valeric acid lowers arterial blood pressure in rats

Valeric acid (VA) is a short-chain fatty acid produced by microbiota and herbs such as Valeriana officinalis. Moreover, VA is released from medicines such as estradiol valerate by esterases. We evaluated the concentrations of endogenous VA in male, 14-week-old rats in the liver, heart, brain, kidneys, lungs, blood and in the colon, a major site of microbiota metabolism, using liquid chromatography coupled with mass spectrometry. In addition, the tissue distribution of VA D9-isotope (VA-D9) administered into the colon was assessed. Finally, we investigated the effect of exogenous VA on arterial blood pressure (BP) and heart rate (HR) in anesthetized rats, and the reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries ex vivo. Physiological concentration of VA in the colon content was ≈650 μM, ≈ 0.1–1 μM in the investigated tissues, and ≈0.4 μM in systemic blood. VA-D9 was detected in the tissues 5 min after the administration into the colon. The vehicle did not affect BP and HR. VA produced a dose-dependent decrease in BP, and at higher doses lowered HR. The hypotensive effect of VA was inhibited by 3-hydroxybutyrate, an antagonist of GPR41/43-receptors but not by the subphrenic vagotomy. Hexamethonium prolonged the hypotensive effect of VA while atropine did not influence the hypotensive effect. VA dilated GMA and MA. In conclusion, the exogenous VA produces vasodilation and lowers BP. The colon-derived VA rapidly penetrates to tissues involved in the control of BP. Further studies are needed to evaluate the effects of endogenous and exogenous VA on the circulatory system.

Impaired Tubular Reabsorption Is the Main Mechanism Explaining Increases in Urinary NGAL Excretion Following Acute Kidney Injury in Rats.

Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted low-molecular weight iron-siderophore-binding protein. NGAL overexpression in injured tubular epithelia partly explains its utility as a sensitive and early urinary biomarker of acute kidney injury (AKI). Herein, we extend mechanistic insights into the source and kinetics of urinary NGAL excretion in experimental AKI. Three models of experimental AKI were undertaken in adult male Wistar rats; renal ischemia-reperfusion injury (IRI) and gentamicin (G) and cisplatin (Cisp) nephrotoxicity. Alongside standard histological and biochemical assessment of AKI, urinary NGAL excretion rate, plasma NGAL concentration, and renal NGAL mRNA/protein expression were assessed. In situ renal perfusion studies were undertaken to discriminate direct shedding of NGAL to the urine from addition of NGAL to the urine secondary to alterations in the tubular handling of glomerular filtrate-derived protein. Renal NGAL expression and urinary excretion increased in experimental AKI. In acute studies in both the IRI and G models, direct renal perfusion with Kreb's buffer eliminated urinary NGAL excretion. Addition of exogenous NGAL to the Kreb's buffer circuit, reestablishment of perfusion with systemic blood or reperfusion with renal vein effluent restored high levels of urinary NGAL excretion. Urinary NGAL excretion in AKI arises in large proportion from reduced reabsorption from the glomerular filtrate. Hence, subclinical cellular dysfunction could increase urinary NGAL, particularly in concert with elevations in circulating prerenal NGAL and/or pharmacological inhibition of tubular reabsorption. More granular interpretation of urinary NGAL measurements could optimize the scope of its clinical utility as a biomarker of AKI.

Estimation of intracardiac shunts in young children with a novel indicator dilution technology

Clinical evaluation of intracardiac shunts in children is not straightforward. Echocardiography can only diagnose the presence of a shunt but does not estimate the shunt ratio. This can be a critical factor that influences treatment options. In this single-center, prospective, observational, method-comparison study, we validate the ability of a novel monitoring device COstatus to estimate the intracardiac shunt ratio (Qp/Qs) of pulmonary (Qp) to systemic (Qs) blood flow in young children before and after corrective cardiac surgery. The indicator dilution technology COstatus monitor was compared to two other more invasive reference techniques, perivascular ultrasonic flow probes (placed around the pulmonary truncus and ascending aorta) and the oximetric shunt equation (using arterial and venous blood gases). Our study revealed that the COstatus monitor detected intracardiac shunts with high sensitivity and specificity but there was some underestimation of the shunt ratios compared to the reference techniques.

Inhibition of Hepatic Bile Acid Uptake by Myrcludex B Promotes Glucagon-Like Peptide-1 Release and Reduces Obesity.

Background & AimsBile acids are important metabolic signaling molecules. Bile acid receptor activation promotes body weight loss and improves glycemic control. The incretin hormone GLP-1 and thyroid hormone activation of T4 to T3 have been suggested as important contributors. Here, we identify the hepatic bile acid uptake transporter Na+ taurocholate co-transporting polypeptide (NTCP) as target to prolong postprandial bile acid signaling.MethodsOrganic anion transporting polypeptide (OATP)1a/1b KO mice with or without reconstitution with human OATP1B1 in the liver were treated with the NTCP inhibitor Myrcludex B for 3.5 weeks after the onset of obesity induced by high fat diet-feeding. Furthermore, radiolabeled T4 was injected to determine the role of NTCP and OATPs in thyroid hormone clearance from plasma.ResultsInhibition of NTCP by Myrcludex B in obese Oatp1a/1b KO mice inhibited hepatic clearance of bile acids from portal and systemic blood, stimulated GLP-1 secretion, reduced body weight, and decreased (hepatic) adiposity. NTCP inhibition did not affect hepatic T4 uptake nor lead to increased thyroid hormone activation. Myrcludex B treatment increased fecal energy output, explaining body weight reductions amongst unaltered food intake and energy expenditure.ConclusionsPharmacologically targeting hepatic bile acid uptake to increase bile acid signaling is a novel approach to treat obesity and induce GLP1- secretion.

БЛОКАДА АДРЕНОРЕЦЕПТОРОВ В ГОЛОВНОМ МОЗГЕ ЗАДЕРЖИВАЕТ РАЗВИТИЕ СУДОРОГ ПРИ ДЫХАНИИ КИСЛОРОДОМ ПОД ДАВЛЕНИЕМ

The main prodromal sign of seizures developing when breathing hyperbaric oxygen is a high activity of sympathetic outflow, as manifested in altered external respiration, impaired cardiac and vascular activity. We tested the hypothesis that the brain adrenergic receptors, as part of the central adrenergic system, are involved in the development of sympathetic hyperactivity and generalized seizures during hyperbaric oxygen breathing. In experiments on rats, α - and β -adrenoreceptors were blocked by non-selective and selective antagonists (propranolol, atenolol, phentolamine and prazosin) injected into the cerebral ventricles. Reactions of the CNS and autonomic nervous system to oxygen breathing at 5 ATA were evaluated. We found that in animals with intact adrenoreceptors, hyperbaric oxygen caused convulsions preceded by two-phase reactions of the cardiovascular system, external respiration and cerebral blood flow. All antagonists used in experiments attenuated visceral reactions and the development of oxygen convulsions, although propranolol showed most pronounced antihypertensive and anticonvulsant properties. The data obtained indicate the involvement of brain adrenergic receptors in the reactions of the autonomic nervous system to hyperoxia and in the mechanisms underlying the development of oxygen seizures during breathing hyperbaric oxygen. Our results can be used to develop new methods for the prevention of seizures under extreme hyperoxia and to ensure the safe use of hyperbaric oxygen in clinical practice and diving.

Relationship between Oxidative Stress, Serum Zinc Level and Systemic Arterial Blood Pressure in Smokers and Non-smokers

Background and Aim: Either active or passive smoking causes damage to the heart and blood vessels. The aim of this study is to investigate the relationship between oxidative stress, serum zinc level and systemic arterial blood pressure in smokers and non-smokers. Methods: A cross sectional comparative study was done. Apparently healthy subjects of age 18-45 years including 40 smokers and 40 non-smokers residing in Magway Township, Myanmar were recruited. Serum zinc level was measured by atomic absorption spectrophotometry method. Serum malondialdehyde level was used as oxidative stress marker and measured by spectrophotometry. Systemic arterial blood pressure was measured by indirect method using mercury sphygmomanometer. Results: Mean serum zinc level of smokers (51.25±7.5 μg/dL) was significantly lower than that of non-smokers (92.91±27.46 μg/dL) (P< 0.001). Mean serum malondialdehyde level of smokers (0.78±0.14 μmol/L) was significantly higher than that of non-smokers (0.24±0.09 μmol/L) (P< 0.001). Mean Systolic Blood Pressure (SBP) of non-smokers was 120.95±5.02 mmHg and that of smokers was 126.55±6.14 mmHg (P<0.05). There was significant negative correlation between serum malondialdehyde level and serum zinc level (r = - 0.75, P< 0.001, n=80). There was also significant negative correlation between serum zinc level and SBP (r = - 0.477, p< 0.001, n=80). There was positive correlation between serum malondialdehyde level and SBP (r = 0.487, p< 0.001, n=80). Conclusion: It could be concluded that smoking increases oxidative stress and decreases serum zinc level and these two changes might contribute to increase in blood pressure in smokers.