Cardiac baroreflex sensitivity is not correlated to sympathetic baroreflex sensitivity within healthy, young humans

The purpose of this study was to evaluate the relationship between the cardiac and sympathetic baroreflex sensitivities within healthy, young humans. The sensitivities of the cardiac and sympathetic baroreflexes were compared in 53 normotensive individuals (28 men and 25 women; age: 24.0 ± 0.9 years; body mass index: 24.0 ± 0.3 cm/kg2, mean ± SEM). Heart rate, arterial blood pressure, and peroneal muscle sympathetic nerve activity were recorded under resting conditions (heart rate: 58 ± 1 bpm; systolic blood pressure: 126 ± 2 mm Hg; diastolic blood pressure: 72 ± 1 mm Hg; mean arterial blood pressure: 89 ± 1 mm Hg; muscle sympathetic nerve activity: 18 ± 1 bursts per min) and during rapid changes in blood pressure induced by sequential boluses of nitroprusside and phenylephrine. Cardiac and sympathetic baroreflex sensitivities were analyzed using the slopes of the linear portions of the muscle sympathetic nerve activity-diastolic blood pressure and R-R interval-systolic blood pressure relationships, respectively. When individual cardiac baroreflex sensitivity was compared with sympathetic baroreflex sensitivity, no correlation (R-R interval: r = -0.13; heart rate: r = 0.21) was observed when studied as a group. Analysis by sex unveiled a correlation in women between the cardiac and sympathetic baroreflex sensitivities (R-R interval: r = -0.54; P = 0.01; no correlation with hazard ratio: r = 0.29). No relationship was found in men (R-R interval: r = 0.17; heart rate: r = 0.12). These results indicate that, although both cardiac and sympathetic efferents function in baroreflex control of arterial pressure, there is no correlation in their sensitivities within healthy normotensive humans. However, sex-stratified data indicate that sex-based differential correlations might exist.     

Leptin,sympathetic nervous system,and baroreflex function

In addition to its direct effects on energy metabolism and caloric intake, leptin exerts several circulatory effects that appear to be mediated by an interaction with the sympathetic nervous system and the major reflexogenic area involved in cardiovascular homeostatic control—that is, the arterial baroreflex. In this paper, the relationships between the adipocyte hormone and the neuroadrenergic function are reviewed, taking into account data collected in experimental animal models as well as in human cardiovascular (hypertension and heart failure) and noncardiovascular (obesity) diseases that are characterized by a hyperadrenergic state coupled with a hyperleptinemia.     

Clinical trials update from the American College of Cardiology 2009: ADMIRE‐HF,PRIMA, STICH,REVERSE, IRIS,partial ventricular support,FIX‐HF‐5, vagal stimulation,REVIVAL‐3, pre‐RELAX‐AHF,ACTIVE‐A,HF‐ACTION,JUPITER, AURORA,and OMEGA

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the American College of Cardiology meeting in 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. ¹²³I‐mIBG myocardial scintigraphy was a good predictor of mortality in patients with heart failure in ADMIRE‐HF. In PRIMA, use of individualized target NT‐proBNP levels failed to improve outcomes compared with usual care in patients hospitalized with symptomatic heart failure. In the STICH trial, additional ventricular reconstruction surgery failed to improve outcomes in patients with ischaemic heart failure undergoing CABG. Cardiac resynchronization therapy may modify disease progression in patients with mild heart failure, according to data from REVERSE. Implantation of a defibrillator early after MI in high‐risk patients in the IRIS study failed to improve outcomes compared with usual care. Cardiac contractility modulation showed some beneficial effects on symptoms and exercise capacity in the unblinded FIX‐HF‐5 study. Data from pre‐RELAX‐AHF show that relaxin may have potential as a treatment for acute heart failure. HF‐ACTION showed that patients who complied with an exercise training regime achieved a better outcome, although this may be confounded by the ability of patients with a good prognosis to exercise for longer.     

Complete blood count parameters for healthy,small‐for‐gestational‐age,full‐term newborns

No previous study has investigated the full range of complete blood count (CBC) parameters in small‐for‐gestational‐age (SGA) newborns. The main aim of this study was to compare CBC and peripheral smear parameters in term, healthy SGA neonates and appropriate‐for‐gestational‐age (AGA) neonates, and to establish CBC reference values for full‐term SGA newborns. One hundred thirty‐two healthy, term newborns (73 SGA and 59 AGA) were included. On day 1, we obtained 109 samples and on day 7 we obtained 77 samples. A CBC and peripheral smear were analyzed for each sample collected and group data were compared. We observed higher mean values for normoblast count, hemoglobin, hematocrit, and red blood cell (RBC) count in the SGA babies than in the AGA babies on day 1. The mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration values for the SGA babies were decreased because of the relatively high RBC count and relatively high mean corpuscular volume we observed in this group. Of the SGA newborns, 21.9% had neutropenia and 4.7% had absolute neutrophil counts lower than 1500/μl on day 1. On both day 1 and day 7, the SGA newborns had higher mean absolute metamyelocyte counts and higher mean I : T (immature : total neutrophil ratio) values than the AGA group. The SGA babies had a lower mean absolute lymphocyte count on day 7 than the AGA group. We detected thrombocytopenia in almost one‐third of the 64 SGA newborns tested on day 1. In summary, our study clearly demonstrates that CBC parameters for healthy, full‐term, SGA newborns are different from those of healthy, term AGA newborns. This is the first study that has documented different mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, metamyelocyte counts, lymphocyte counts, and I : T in SGA babies compared with AGA babies.     

Metformin extended‐release versus immediate‐release: An international,randomized, double‐blind,head‐to‐head trial in pharmacotherapy‐naïve patients with type 2 diabetes

This international, randomized, double‐blind trial (NCT01864174) compared the efficacy and safety of metformin extended‐release (XR) and immediate‐release (IR) in patients with type 2 diabetes. After a 4‐week placebo lead‐in, pharmacotherapy‐naïve adults with glycated haemoglobin (HbA1c) at 7.0% to 9.2% were randomized (1:1) to receive once‐daily metformin XR 2000 mg or twice‐daily metformin IR 1000 mg for 24 weeks. The primary endpoint was change in HbA1c after 24 weeks. Secondary endpoints were change in fasting plasma glucose (FPG), mean daily glucose (MDG) and patients (%) with HbA1c <7.0% after 24 weeks. Overall, 539 patients were randomized (metformin XR, N = 268; metformin IR, N = 271). Adjusted mean changes in HbA1c, FPG, MDG and patients (%) with HbA1c <7.0% after 24 weeks were similar for XR and IR: ?0.93% vs ?0.96%; ?21.1 vs ?20.6 mg/dL (?1.2 vs ?1.1 mmol/L); ?24.7 vs ?27.1 mg/dL (?1.4 vs ?1.5 mmol/L); and 70.9% vs 72.0%, respectively. Adverse events were similar between groups and consistent with previous studies. Overall, metformin XR demonstrated efficacy and safety similar to that of metformin IR over 24 weeks, with the advantage of once‐daily dosing.     

Atacicept in patients with rheumatoid arthritis: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating,single‐ and repeated‐dose study

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

     

Anti‐Tumor Effects and Pharmacokinetics of S‐40542, a Novel Non‐Steroidal Anti‐Androgen,in Mice

Objectives: The current study was undertaken to explore novel anti‐androgens. We investigated a series of tetrahydroquinoline compounds and identified 1‐(8‐nitro‐3a,4,5,9b‐tetrahydro‐3H‐cyclopenta[c]quinolin‐4‐yl)ethane‐1,2‐diol (S‐40542). Methods: Affinity for androgen receptor of S‐40542 was evaluated in receptor binding assay. Effects of repeated treatment with S‐40542 and bicalutamide on prostate weight were examined in mice subcutaneously treated for 14days. Efficacy of S‐40542 and bicalutamide against prostate cancer was evaluated in an androgen‐dependent prostate cancer xenograft model using KUCaP‐2 cell line. Plasma concentrations of these agents in mice after oral and subcutaneous administration were measured by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) system. Results: S‐40542 displayed twofold higher affinity to androgen receptor than bicalutamide in vitro. Subcutaneous repeated administration of S‐40542 (10–100 mg/kg) significantly reduced the prostate weight. Oral repeated treatment with S‐40542 (30, 100 mg/kg) for 28 days significantly suppressed growth of KUCaP‐2 tumor. Similar administration of bicalutamide also exerted significantly anti‐tumor effect in the model. The serum prostate‐specific antigen level was little influenced by the S‐40542 treatment, while significantly decreased by bicalutamide. Oral treatment with S‐40542 resulted in a dose‐dependent elevation of the plasma concentration, and its C_max and AUC were much lower than those of bicalutamide. The pharmacokinetic study showed that this agent had relatively short plasma half‐life and low oral bioavailability. Conclusion: S‐40542 as well as bicalutamide has shown as an anti‐androgen by reducing the prostate weight of mice. Repeated oral treatment with S‐40542 was shown to significantly suppress tumor growth in the KUCaP‐2 xenograft model.     

Arterial baroreflex sensitivity, plasma catecholamines, and pressor responsiveness in essential hypertension

Arterial baroreflex sensitivity, plasma norepinephrine (NE) and epinephrine (E), and pressor and depressor responses were assessed in 25 patients with essential hypertension and 29 normotensive control subjects. Sensitivity of the cardiac limb of the baroreflex was determined by blood pressure and interbeat interval responses associated with the Valsalva maneuver, externally applied neck suction and pressure, and injection of phenylephrine and nitroglycerin. By all these techniques, patients with essential hypertension had significantly decreased baroreflex sensitivity, even after adjustment for age mismatching between the hypertensive and normotensive groups. Hypertensive patients also had significantly higher mean levels of plasma NE and E in both brachial arterial and antecubital venous blood (246 vs 154 pg/ml arterial NE, 286 vs 184 pg/ml venous NE, 99 vs 55 pg/ml arterial E, and 65 vs 35 pg/ml venous E) and significantly larger pressor responses to injected phenylephrine (30.9 mm Hg/100 micrograms vs 16.7 mm Hg/100 micrograms). When baroreflex-cardiac sensitivity values measured by the various techniques were averaged, there was a significant inverse relationship between sensitivity and venous NE and between sensitivity and pressor responsiveness. The results indicate that decreased baroreflex-cardiac sensitivity, increased sympathetic outflow, and pressor hyperresponsiveness tend to occur together in some patients with essential hypertension. Decreased arterial distensibility and altered central neural integration can account for these findings.