New Perspectives on beta-Adrenergic Mediation of Innate and Learned Fear Responses to Predator Odor

In the present study, we investigated the role of noradrenergic transmission in unconditioned and conditioned responses to predatory threats. First, we examined the effects of systemically injected beta-blockers on unconditioned and contextual conditioned response to cat odor. The centrally acting beta-blocker (propranolol) was able to impair unconditioned responses, as well as the acquisition of the contextual fear to cat odor; however, the peripherally acting (nadolol) was not effective. Next, we examined the neural substrate underlying the noradrenergic modulation of the defensive response to cat odor and focused on the dorsal premammillary nucleus (PMd), because it represents the hypothalamic site most responsive to predatory threats and, at the same time, presents a dense plexus of noradrenergic fibers. We were able to see that propranolol significantly reduced PMd-Fos expression in response to cat odor and that beta-adrenoceptor blockade in the PMd, before cat odor exposure, reduced defensive responses to the cat odor and to the cat odor-related environment. We have also shown that beta-adrenoceptor blockade in the PMd, before the exposure to cat odor-related context, impaired the contextual conditioned responses. Overall, the present results provide convincing evidence suggesting that central noradrenergic mediation is critical for the expression of unconditioned and contextual conditioned antipredatory responses. We have further shown that the PMd appears to be an important locus to mediate these beta-adrenoceptor effects.

β-blockers reduce bone resorption marker in early postmenopausal women

Background: There is evidence to suggest that β-blockers used in the management of cardiovascular disease may also modulate bone metabolism and reduce bone fragility.

Aim: The study aimed to determine the association between β-blocker use, serum markers of bone turnover and bone loss in early postmenopausal women.

Subjects and methods: In this observational study, we evaluated β-blocker exposure in association with serum levels of C-telopeptide and bone-specific alkaline phosphatase, and rates of bone loss. β-blocker use, concomitant therapy and lifestyle were documented for 197 women (50–59 years), 175 of whom had changes in whole body bone mineral density monitored over a 2–year period.

Results: Twenty-four β-blocker users were identified at baseline. After controlling for concomitant use of hormone therapy, C-telopeptide levels were 6.7% lower among β-blocker users (p = 0.02). No association was detected between bone-specific alkaline phosphatase and β-blocker use. Analysis of 15 β-blocker users and 152 non-users identified 2 years post-baseline showed that levels of C-telopeptide but not bone-specific alkaline phosphatase were predictors of adjusted rates of bone loss (p = 0.008 and p>0.05, respectively). Adjusted rates of bone loss were −0.001 ± 0.026 g cm−2 over 2 years for the users and −0.004 ± 0.025 g cm−2 over 2 years for non-users, but this difference was not significant.

Conclusion: β-blockers might suppress bone resorption with relative preservation of bone formation. A study with greater power is required to determine whether β-blocker use is associated with lower rates of bone loss.

β-Adrenergic blockers reduce the risk of fracture partly by increasing bone mineral density : Geelong Osteoporosis Study

This population-based study documented β-blocker use in 59/569 cases with incident fracture and 112/775 controls. OR for fracture associated with β-blocker use was 0.68 (95%CI, 0.49–0.96). β-Blockers were associated with higher BMD at the total hip (2.5%) and UD forearm (3.6%) after adjusting for age, anthropometry, and thiazide use. β-Blocker use is associated with reduced fracture risk and higher BMD.

Introduction: Animal data suggests that bone formation is under β-adrenergic control and that β-blockers stimulate bone formation and/or inhibit bone resorption.

Materials and Methods: We evaluated the association between β-blocker use, bone mineral density (BMD), and fracture risk in a population-based study in Geelong, a southeastern Australian city with a single teaching hospital and two radiological centers providing complete fracture ascertainment for the region. β-Blocker use was documented for 569 women with radiologically confirmed incident fractures and 775 controls without incident fracture. Medication use and lifestyle factors were documented by questionnaire.

Results: Odds ratio for fracture associated with β-blocker use was 0.68 (95% CI, 0.49–0.96) for any fracture. Adjusting for age, weight, medications, and lifestyle factors had little effect on the odds ratio. β-Blocker use was associated with a higher BMD at the total hip (2.5%, p = 0.03) and ultradistal forearm (3.6%, p = 0.04) after adjustment for age, anthropometry, and thiazide use.

Conclusion: β-Blockers are associated with a reduction in fracture risk and higher BMD.

Predictors of Beta-Blocker Intolerance and Mortality in Patients After Acute Coronary Syndrome

Purpose: To investigate the predictors of intolerance to beta-blockers treatment and the 6-month mortality in hospitalized patients with acute coronary syndrome (ACS).Methods: This was a single-center, prospective, and longitudinal study including 370 consecutive ACS patients in Killip class I or II. BBs were prescribed according to international guidelines and withdrawn if intolerance occurred. The study was approved by the institutional ethics committee of our university. Statistics: the clinical parameters evaluated at admission, and the related intolerance to BBs and death at 6 months were analyzed using logistic regression (p<0.05) in PATIENTS.Results: BB intolerance was observed in 84 patients and was associated with no prior use of statins (OR: 2.16, 95%CI: 1.26-3.69, p= 0.005) and Killip class II (OR: 2.5, 95%CI: 1.30-4.75, p=0.004) in the model adjusted for age, sex, blood pressure, and renal function. There was no association with ST-segment alteration or left anterior descending coronary artery plaque. Intolerance to BB was associated with the greatest risk of death (OR: 4.5, 95%CI: 2.15-9.40, p<0.001).Conclusions: After ACS, intolerance to BBs in the first 48 h of admission was associated to non previous use of statin and Killip class II and had a high risk of death within 6 months.

Effects of age on aerobic capacity in heart failure patients under beta-blocker therapy: Possible impact in clinical decision-making?

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Secondary left ventricular ejection fraction response to beta blocker therapy in heart failure patients

Chronic β-blocker treatment improves survival and left ventricular ejection fraction (LVEF) in patients with systolic heart failure (HF). Data on whether the improvement in LVEF after β-blocker therapy is sustained for a long term or whether there is a loss in LVEF after an initial gain is not known. Our study sought to determine the prevalence and prognostic role of secondary decline in LVEF in chronic systolic HF patients on β-blocker therapy and characterize these patients. Retrospective chart review of HF hospitalizations fulfilling Framingham Criteria was performed at the MEDVAMC between April 2000 and June 2006. Follow up vital status and recurrent hospitalizations were ascertained until May 2010. Three groups of patients were identified based on LVEF response to beta blockers; group A with secondary decline in LVEF following an initial increase, group B with progressive increase in LVEF and group C with progressive decline in LVEF. Covariate adjusted Cox proportional hazard models were used to examine differences in heart failure re-hospitalizations and all cause mortality between the groups. Twenty five percent (n=27) of patients had a secondary decline in LVEF following an initial gain. The baseline, peak and final LVEF in this group were 27.6±12%, 40.1±14% and 27.4±13% respectively. The mean nadir LVEF after decline was 27.4±13% and this decline occurred at a mean interval of 2.8±1.9 years from the day of beta blocker initiation. These patients were older, more likely to be whites, had advanced heart failure (NYHA class III/IV) more due to a non ischemic etiology compared to groups B & C. They were also more likely to be treated with metoprolol (p=0.03) compared to the other two groups. No significant differences were observed in combined risk of all cause mortality and HF re-hospitalization [hazard ratio 0.80, 95% CI 0.47 to 1.38, p=0.42]. No significant difference was observed in survival estimates between the groups. In conclusion, a late decline in LVEF does occur in a significant proportion of heart failure patients treated with beta blockers, more so in patients treated with metoprolol.^

Carvedilol blocks beta(2)- more than beta(1)-adrenoceptors in human heart

Objective: To understand the basis of the effectiveness of carvedilol in heart failure by determining its specific properties at human heart and beta(2)-adrenoceptors. Methods: The positive inotropic effects of noradrenaline (in the presence of the beta(2)-selective antagonist ICI118551) and adrenaline (in the presence of the beta(1)-selective antagonist CGP20712), mediated through beta(1)- and beta(2)-adrenoceptors, respectively, were investigated in atrial and ventricular trabeculae. The patch-clamp technique was used to investigate effects of noradrenaline and adrenaline on L-type Ca2+ current in human atrial myocytes. Results: Carvedilol was a 13-fold more potent competitive antagonist of the effects of adrenaline at 1 2-adrenoceptors (-logK(B) = 10.13 +/- 0.08) than of noradrenaline at beta(1)-adrenoceptors (-logK(B) = 9.02 +/- 0.07) in human right atrium. Chronic carvedilol treatment of patients with non-terminal heart failure reduced the inotropic sensitivity of atrial trabeculae to noradrenaline and adrenaline 5.6-fold and 91.2-fold, respectively, compared to beta(1)-blocker-treated patients, consistent with persistent preferential blockade of beta(2)-adrenoceptors. In terminal heart failure carvedilol treatment reduced 1.8-fold and 25.1-fold the sensitivity of right ventricular trabeculae to noradrenaline and adrenaline, respectively, but metoprolol treatment did not reduce the sensitivity to the catecholamines. Increases of current (I-Ca,I-L) produced by noradrenaline and adrenaline were not different in atrial myocytes obtained from non-terminal heart failure patients treated with metoprolol or carvedilol, consistent with dissociation of both beta-blockers from the receptors. Conclusions: Carvedilol blocks human cardiac beta(2)-adrenoceptors more than beta(1)-adrenoceptors, thereby conceivably contributing to the beneficial effects in heart failure. The persistent blockade of beta-adrenoceptors is attributed to accumulation of carvedilol in cardiac tissue. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Ventricular Fibrillation in Patient with Multi-vessel Coronary Spasm Four Days after the Initiation of Oral Beta-blocker

We describe a case of ventricular fibrillation occurring in a patient with multi-vessel coronary spasm after the initiation of an oral beta-blocker. A 56-year-old man began to experience chest discomfort and his computed tomography revealed intermediate coronary stenoses. He was administered medications including an oral beta-blocker but suddenly collapsed while walking 4 days later. An automated external defibrillator detected ventricular fibrillation and delivered successful electrical cardioversion. An acetylcholine provocation test after stabilization of the status revealed triple-vessel coronary spasm. Beta-blockers may provoke exacerbation of coronary spasm and result in lethal arrhythmia.

Pre-Admission and Post-Hospital Management of Heart Failure in Patients not Enrolled in Specialist Programs

Aim: To review the management of heart failure in patients not enrolled in specialist multidisciplinary programs. Method: A prospective clinical audit of patients admitted to hospital with either a current or past diagnosis of heart failure and not enrolled in a specialist heart failure program or under the direct care of the cardiology unit. Results: 81 eligible patients were enrolled (1 August to 1 October 2008). The median age was 81 9.4 years and 48% were male. Most patients (63%) were in New York Heart Association Class II or Class III heart failure. On discharge, 59% of patients were prescribed angiotensin converting enzyme inhibitors and 43% were prescribed beta-blockers. During hospitalisation, 8.6% of patients with a past diagnosis of heart failure were started on an angiotensin converting enzyme inhibitor and 4.9% on a beta-blocker. There was evidence of suboptimal dosage on admission and discharge for angiotensin converting enzyme inhibitors (19% and 7.4%) and beta-blockers (29% and 17%). The results compared well with international reports regarding the under-treatment of heart failure. Conclusion: The demonstrated practice gap provides excellent opportunities for the involvement of pharmacists to improve the continuation of care for heart failure patients discharged from hospital in the areas of medication management review, dose titration and monitoring.

What We Have Here is a Failure to Communicate! Improving Communication between Tertiary to Primary Care for Chronic Heart Failure Patients

Background:  The aims of this study were to determine the documentation of pharmacotherapy optimization goals in the discharge letters of patients with the principal diagnosis of chronic heart failure. Methods:  A retrospective practice audit of 212 patients discharged to the care of their local general practitioner from general medical units of a large tertiary hospital. Details of recommendations regarding ongoing pharmacological and non-pharmacological management were reviewed. The doses of medications on discharge were noted and whether they met current guidelines recommending titration of angiotensin-converting enzyme inhibitors and beta-blockers. Ongoing arrangements for specialist follow up were also reviewed. Results:  The mean age of patients whose letters were reviewed was 78.4 years (standard deviation ± 8.6); 50% were men. Patients had an overall median of six comorbidities and eight regular medications on discharge. Mean length of stay for each admission was 6 days. Discharge letters were posted a median of 4 days after discharge, with 25% not posted at 10 days. No discharge letter was sent in 9.4% (20) of the cases. Only six (2.8%) letters had any recommendations regarding future titration of angiotensin-converting enzyme inhibitors and 6.6% (14) for beta-blockers. Recommendations for future non-pharmacological management, for example, diuretic action plans, regular weight monitoring and exercise plans were not found in the letters in this audit. Conclusion:  Hospital discharge is an opportunity to communicate management plans for treatment optimization effectively, and while this opportunity is spurned, implementation gaps in the management of cardiac failure will probably remain.

Molecular and structural requirements of the ß1L-adrenoceptor

Noradrenaline which occurs naturally in the body binds to beta-adrenoceptors on the heart, causing the heart to beat faster and with greater force in response to increased demand. This enables the heart to provide oxygenated blood to vital organs. Prolonged overstimulation by noradrenaline can be harmful to the heart and lead to the progression of heart disease. In these circumstances beta-adrenoceptors are blocked with drugs called beta-blockers. Beta-blockers block the effects of noradrenaline by binding to the same site on the beta-adrenoceptor. Some beta-blockers such as CGP12177 can also cause increases in heart rate. Therefore it was proposed that CGP12177 could bind in a different place to noradrenaline. The aim of this study was to determine where CGP12177 binds to on the beta-adrenoceptor. The results have revealed a separate binding site named beta-1-low. These results may lead to the development of improved -blockers for the management of heart conditions.

Carvedilol induces greater control of β2- than β1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium

The beta-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 mu M) or PDE4-selective inhibitor rolipram (1 mu M) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through beta(1)-adrenoceptors (beta(2)-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through beta(2)-adrenoceptors (beta(1)-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC(50)s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-beta-blocker-treated patients, consistent with the previously reported beta(2)-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular beta(2)-adrenoceptors compared to beta(1)-adrenoceptors. The beta(2)-adrenoceptor-selectivity of carvedilol may provide protection against beta(2)-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control beta(1)- and beta(2)-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.

Osteoprotective effect of propranolol in ovariectomized rats: a comparison with zoledronic acid and alfacalcidol

Currently beta-adrenergic receptor blockers are considered to be potential drugs under investigation for preventive or therapeutic effect in osteoporosis. However, there is no published data showing the comparative study of beta-blockers with well accepted agents for the treatment of osteoporosis. To address this question, we compared the effects of propranolol with well accepted treatments like zoledronic acid and alfacalcidol in an animal model of postmenopausal osteoporosis. Five days after ovariectomy, 36 ovariectomized (OVX) rats were divided into 6 equal groups, randomized to treatments zoledronic acid (100 mu g/kg, intravenous single dose); alfacalcidol (0.5 mu g/kg, oral gauge daily); propranolol (0.1 mg/kg, subcutaneously 5 days per week) for 12 weeks. Untreated OVX and sham OVX were used as controls. At the end of treatment serum calcium and alkaline phosphatase were assayed. Femurs were removed and tested for bone density, bone porosity, bone mechanical properties and trabecular micro-architecture. Propranolol showed a significant decrease in alkaline phosphatase levels and bone porosity in comparison to OVX control. Moreover, propranolol significantly improved bone density, bone mechanical properties and inhibited the deterioration of trabecular microarchitecture when compared with OVX control. The osteoprotective effect of propranolol was comparable with zoledronic acid and alfacalcidol. Based on this comparative study, the results strongly suggest that propranolol can be a candidate therapeutic drug for the management of postmenopausal osteoporosis.

Impacto dos polimorfismos genéticos da enzima conversora de angiotensina sobre desfechos clínicos e ecocardiográficos em pacientes com insuficiência cardíaca não isquêmica

O papel dos polimorfismos genéticos da ECA (PGECA) na insuficiência cardíaca (IC) como preditor de desfechos clínicos e ecocardiográficos ainda não está estabelecido. É necessário identificar o perfil genotípico local para se observar se o impacto clínico desses genótipos é igual entre populações estrangeiras e a brasileira. O objetivo deste trabalho foi determinar a frequência das variantes do PGECA e sua relação com a evolução clínica de pacientes com IC de etiologia não isquêmica de uma população do Rio de Janeiro, utilizando desfechos clínicos, ecocardiográficos e do Seattle Heart Failure Model (SHFM).Para isso, realizou-se análise secundária de prontuários de 111 pacientes, acompanhados de forma prospectiva e retrospectiva, além da análise genética com identificação da variante do PGECA e sua classificação. Os pacientes foram acompanhados em média por 64,93,9 meses, tinham 59,51,3 (26-89) anos, predomínio do sexo masculino (60,4%) e da cor da pele branca (51,4 %), mas com alta prevalência de pretos (36 %). A distribuição do PGECA observada foi: 51,4 % DD, 44,1 % DI e apenas 4,5 % II. Hipertensão arterial foi a comorbidade mais frequentemente observada (70,3 %). O tratamento farmacológico estava bastante otimizado: 98,2 % em uso de betabloqueadores e 89,2 % em uso de inibidores da ECA ou losartana. Nenhuma das características clínicas ou do tratamento medicamentoso variou entre os grupos. Cerca de metade da coorte (49,5 %) apresentou fração de ejeção de VE (FEVE) ≤35 %. O diâmetro sistólico do VE (DSVE) final foi a única variável ecocardiográfica isolada significativamente diferente entre os PGECA: 59,21,8 DD x 52,31,9 DI x 59,25,2 (p=0,029). Quando analisadas de maneira evolutiva, todas as variáveis (FEVE, DSVE e DDVE) diferiram de maneira significativa entre os genótipos: p=0,024 para ∆FE, p=0,002 para ∆DSVE e p=0,021 para ∆DDVE. O genótipo DI se associou ao melhor parâmetro ecocardiográfico (aumento de FEVE e diminuição de diâmetros de VE), enquanto que o DD e II apresentaram padrão inverso. Os valores derivados do SHFM (expectativa de vida, mortalidade em um ano e mortalidade em cinco anos) não variaram de forma significativa entre os genótipos, mas notou-se um padrão com o DD associado a piores estimativas, DI a estimativas intermediárias e II a valores mais benignos. Não houve diferença significativa entre desfechos clínicos isolados (óbitos: p=0,552; internação por IC: p=0,602 e PS por IC: p=0,119) ou combinados (óbitos + internação por IC: p=0,559). Na análise multivariada, o peso alelo D foi preditor independente da variação do DSVE (p=0,023). Em relação aos preditores independentes de óbito + internação por IC, foram identificados classe funcional NYHA final (p=0,018), frequência cardíaca final (p=0,026) e uso de furosemida (p=0,041). Em suma, a frequência alélia e das variantes do PGECA foram diferentes da maioria do estudos internacionais. O alelo D foi associado de forma independente à pior evolução ecocardiográfica. Não houve diferenças significativas em relação aos parâmetros derivados do SHFM, embora o genótipo II pareça estar associado com o melhor perfil clínico. Por último, não houve diferenças em relação aos desfechos clínicos entre os PGECA.