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BackgroundObservational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.MethodsIn this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.ResultsA total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.ConclusionsAmong pat

ObjectiveTo quantify drug-induced changes in right ventricular (RV) systolic function after administration of pimobendan and atenolol.Animals80 healthy privately-owned dogs.MethodsUsing a prospective, blinded, fully-crossed study design with randomized drug administration, RV systolic function was determined twice at two time periods; before and 3 h after administration of pimobendan (0.25 mg/kg PO) or atenolol (1 mg/kg PO). Indices of RV systolic function included tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed-wave tissue Doppler-derived systolic myocardial velocity of the lateral tricuspid annulus (S'), and speckle-tracking-derived global longitudinal RV free wall strain and strain rate. The effect of treatment on percent change from baseline RV function was analyzed with a linear mixed model including the covariates heart rate, body weight, age, gender, drug sequence, and time period.ResultsAll indices showed a significant (p < 0.0001) increase and decrease from baseline following pimobendan and atenolol, respectively. Significant differences from baseline were attributed to drug treatment (p < 0.0001); whereas, effects of other covariates were not significant. The greatest percent changes, but also highest variability, were observed for S' and strain rate (p < 0.0001). Post-atenolol, a significantly greater proportion of dogs exceeded the repeatability coefficient of variation for FAC and S' compared to TAPSE (p ≤ 0.007).ConclusionsEchocardiographic indices in healthy dogs tracked expected changes in RV systolic function following pimobendan and atenolol and warrant study in dogs with cardiovascular disease.

ObjectiveTo quantify drug-induced changes in right ventricular (RV) systolic function after administration of pimobendan and atenolol.Animals80 healthy privately-owned dogs.MethodsUsing a prospective, blinded, fully-crossed study design with randomized drug administration, RV systolic function was determined twice at two time periods; before and 3 h after administration of pimobendan (0.25 mg/kg PO) or atenolol (1 mg/kg PO). Indices of RV systolic function included tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), pulsed-wave tissue Doppler-derived systolic myocardial velocity of the lateral tricuspid annulus (S'), and speckle-tracking-derived global longitudinal RV free wall strain and strain rate. The effect of treatment on percent change from baseline RV function was analyzed with a linear mixed model including the covariates heart rate, body weight, age, gender, drug sequence, and time period.ResultsAll indices showed a significant (p < 0.0001) increase and decrease from baseline following pimobendan and atenolol, respectively. Significant differences from baseline were attributed to drug treatment (p < 0.0001); whereas, effects of other covariates were not significant. The greatest percent changes, but also highest variability, were observed for S' and strain rate (p < 0.0001). Post-atenolol, a significantly greater proportion of dogs exceeded the repeatability coefficient of variation for FAC and S' compared to TAPSE (p ≤ 0.007).ConclusionsEchocardiographic indices in healthy dogs tracked expected changes in RV systolic function following pimobendan and atenolol and warrant study in dogs with cardiovascular disease.

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants.

BACKGROUND: The Pediatric Heart Network designed a clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in children and young adults with Marfan syndrome randomized to receive atenolol or losartan. We report here the characteristics of the screened population and enrolled subjects. METHODS AND RESULTS: Between 2007 and 2011, 21 clinical sites randomized 608 subjects, aged 6 months to 25 years who met the original Ghent criteria and had a body surface area-adjusted aortic root diameter z-score >3.0. The mean age at study entry was 11.2 years, 60% were male, and 25% were older teenagers and young adults. The median aortic root diameter z-score was 4.0. Aortic root diameter z-score did not vary with age. Mitral valve prolapse and mitral regurgitation were more common in females. Among those with a positive family history, 56% had a family member with aortic surgery, and 32% had a family member with a history of aortic dissection. CONCLUSIONS: Baseline demographic, clinical, and anthropometric characteristics of the randomized cohort are representative of patients in this population with moderate to severe aortic root dilation. The high percentage of young subjects with relatives who have had aortic dissection or surgery illustrates the need for more definitive therapy; we expect that the results of the study and the wealth of systematic data collected will make an important contribution to the management of individuals with Marfan syndrome.

Caregiving by nonparents (alloparenting) and fathers is a defining aspect of human social behavior, yet this phenomenon is rare among mammals. Male prairie voles (Microtus ochrogaster) spontaneously exhibit high levels of alloparental care, even in the absence of reproductive experience. In previous studies, exposure to a pup was selectively associated with increased activity in oxytocin and vasopressin neurons along with decreased plasma corticosterone. In the present study, physiological, pharmacological and neuroanatomical methods were used to explore the autonomic and behavioral consequences of exposing male prairie voles to a pup. Reproductively naïve, adult male prairie voles were implanted with radiotransmitters used for recording ECG, temperature and activity. Males responded with a sustained increase in heart-rate during pup exposure. This prolonged increase in heart rate was not explained by novelty, locomotion or thermoregulation. Although heart rate was elevated during pup exposure, respiratory sinus arrhythmia (RSA) did not differ between these males and males exposed to control stimuli indicating that vagal inhibition of the heart was maintained. Blockade of beta-adrenergic receptors with atenolol abolished the pup-induced heart rate increase, implicating sympathetic activity in the pup-induced increase in heart rate. Blockade of vagal input to the heart delayed the males' approach to the pup. Increased activity in brainstem autonomic regulatory nuclei was also observed in males exposed to pups. Together, these findings suggest that exposure to a pup activates both vagal and sympathetic systems. This unique physiological state (i.e. increased sympathetic excitation of the heart, while maintaining some vagal cardiac tone) associated with male caregiving behavior may allow males to both nurture and protect infants.

We describe a method using atomic force microscopy (AFM) to quantify the mechanobiological properties of pluripotent, stem cell-derived cardiomyocytes, including contraction force, rate, duration, and cellular elasticity. We measured beats from cardiomyocytes derived from induced pluripotent stem cells of healthy subjects and those with dilated cardiomyopathy, and from embryonic stem cell lines. We found that our AFM method could quantitate beat forces of single cells and clusters of cardiomyocytes. We demonstrate the dose-responsive, inotropic effect of norepinephrine and beta-adrenergic blockade of metoprolol. Cardiomyocytes derived from subjects with dilated cardiomyopathy showed decreased force and decreased cellular elasticity compared to controls. This AFM-based method can serve as a screening tool for the development of cardiac-active pharmacological agents, or as a platform for studying cardiomyocyte biology.

We describe a method using atomic force microscopy (AFM) to quantify the mechanobiological properties of pluripotent, stem cell-derived cardiomyocytes, including contraction force, rate, duration, and cellular elasticity. We measured beats from cardiomyocytes derived from induced pluripotent stem cells of healthy subjects and those with dilated cardiomyopathy, and from embryonic stem cell lines. We found that our AFM method could quantitate beat forces of single cells and clusters of cardiomyocytes. We demonstrate the dose-responsive, inotropic effect of norepinephrine and beta-adrenergic blockade of metoprolol. Cardiomyocytes derived from subjects with dilated cardiomyopathy showed decreased force and decreased cellular elasticity compared to controls. This AFM-based method can serve as a screening tool for the development of cardiac-active pharmacological agents, or as a platform for studying cardiomyocyte biology.

We previously showed that betaxolol, a selective beta(1)-adrenergic receptor antagonist, administered during early phases of cocaine abstinence, ameliorated withdrawal-induced anxiety and blocked increases in amygdalar beta(1)-adrenergic receptor expression in rats. Here, we report the efficacy of betaxolol in reducing increases in gene expression of amygdalar corticotropin-releasing factor (CRF), a peptide known to be involved in mediating 'anxiety-like' behaviors during initial phases of cocaine abstinence. We also demonstrate attenuation of an amygdalar beta(1)-adrenergic receptor-mediated cell-signaling pathway following this treatment. Male rats were administered betaxolol at 24 and 44 h following chronic cocaine administration. Animals were euthanized at the 48-h time point and the amygdala was microdissected and processed for quantitative reverse transcriptase-polymerase chain reaction and/or western blot analysis. Results showed that betaxolol treatment during early cocaine withdrawal attenuated increases in amygdalar CRF gene expression and cyclic adenosine monophosphate-dependent protein kinase regulatory and catalytic subunit (nuclear fraction) protein expression. Our data also reveal that beta(1)-adrenergic receptors are on amygdalar neurons, which are immunoreactive for CRF. The present findings suggest that the efficacy of betaxolol treatment on cocaine withdrawal-induced anxiety may be related, in part, to its effect on amygdalar beta(1)-adrenergic receptor, modulation of its downstream cell-signaling elements and CRF gene expression.

[No abstract available]