Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.

The pretreatment of rats with nebivolol ameliorates bladder contractile dysfunction caused by ischemia-reperfusion injury.

OBJECTIVE: The present study aimed to investigate the protective effect of nebivolol in the bladder isolated from rats exposed to ischemia-reperfusion (IR) injury. METHODS: Sprague-Dawley rats were divided into control, IR, and nebivolol+IR groups. In the nebivolol+IR group, nebivolol was administered (0.4 mg/kg, subcutaneous) in rats prior to IR insult. At the end of the experimental protocol, the urinary bladder was rapidly isolated and bladder strips were mounted in an organ bath. After the equilibration period, potassium chloride (KCl, 20-100 mM) or carbachol (0.01-10 µM) was cumulatively added to the organ bath to generate cumulative concentration-response curves (CCRCs). Oxidative stress and interleukin 6 (IL-6) levels were also evaluated in the bladder tissue. RESULTS: The CCRCs of KCl and carbachol were significantly reduced in the IR group compared to those of the control, and this inhibition was reversed by the pretreatment of rats with nebivolol (P < .05). The IR group's total antioxidant status was significantly lower with a concomitant increase in IL-6 levels than that of the control and nebivolol+IR groups (P < .05). CONCLUSIONS: The present study indicates that pretreatment of rats with nebivolol (0.4 mg/kg) could improve bladder contractile dysfunction caused by IR injury through suppression of increased oxidative stress and IL-6 levels.

Application of dopamine combined with dobutamine in children with pneumonia and heart failure.

Pediatric pneumonia and heart failure is a common critical illness in pediatrics. This article observes the clinical effects of dopamine and dobutamine in the treatment of pneumonia and heart failure. As a key neurotransmitter in the hypothalamus and pituitary gland, dopamine plays a very important role in the central nervous excitement of the human body. Dopamine could also promote excitement in the respiratory center and reduces oxygen consumption in the breath, thereby improving the symptoms of respiratory failure in children. Observe and compare the clinical efficacy of the two groups of children, the disappearance of lung rales, the time to correct heart failure and the length of hospital stay. The total effective rate in the observation group was 91%; the total effective rate in the control group was 65.4%. There was a significant difference in the total effective rate between the two groups of children. The time of disappearance of lung rales, the time of correction of heart failure and the length of hospital stay in the observation group were significantly shorter than those in the control group (P <0.05). The clinical effects of dopamine and dobutamine on pneumonia and heart failure are significant.

Dobutamine Versus Vasopressin After Mesenteric Ischemia.

BACKGROUND: Gastrointestinal blood flow may be compromised during and after vasopressor support. Endothelin expression may lead to microcirculatory dysfunction. The aim of this study was to analyze the effect of vasopressin and dobutamine after mesenteric ischemia on the gastrointestinal mucosal microcirculation, endothelin expression, and morphologic injury. MATERIALS AND METHODS: Pigs were studied in four groups (six pigs in each group): 1, sham; 2-4 ischemia (1 h superior mesenteric artery occlusion with 30 min reperfusion and 30 min of vehicle [2], dobutamine [3], or vasopressin [4] administration, followed by 30-min break and thiopental-induced hypotension [3, 4]). Blood flow of the gastric, jejunal, and rectosigmoidal mucosa was measured. At the end of the experiment, the mucosal expression of endothelin-1 (ET-1) and its receptor subtypes A (ETA) and B were determined by polymerase chain reaction. Mucosal injury, apoptotic cell death, and leukocytic infiltration were determined by histology and immunohistochemical analysis of cleaved caspase-3 and myeloperoxidase. RESULTS: Mesenteric ischemia increased jejunal mucosal ET-1 gene expression, arterial ET-1, intestinal fatty acid binding protein, and jejunal mucosal injury compared with sham. Dobutamine increased arteriovenous shunting at the cost of the jejunal mucosal blood perfusion. This was associated with an increased expression of ET-1 and ETA and mucosal leukocytic infiltration. In contrast, vasopressin increased postischemic capillary density and tissue blood flow. This was associated with a lower ET-1 gene expression. Vasopressin did not induce jejunal mucosal leukocytic infiltration. CONCLUSIONS: Vasopressin reduces mesenteric ischemia-associated alterations of the microcirculation and tissue integrity, whereas dobutamine does not.

Relationship between heart failure, concurrent chronic obstructive pulmonary disease and beta-blocker use: a Danish nationwide cohort study.

AIMS: To compare the hazard of all-cause, chronic obstructive pulmonary disease (COPD) and heart failure (HF) hospitalization in carvedilol vs. metoprolol/bisoprolol/nebivolol users with COPD and concurrent HF from 2009 to 2012, and to evaluate the use and persistence in treatment of these ß-blockers, their impact on the risk of COPD-related hospitalization, and the factors important for their selection. METHODS AND RESULTS: Cox and logistic regression were used for both unadjusted and adjusted analyses. Carvedilol users had a higher hazard of being hospitalized for HF compared with metoprolol/bisoprolol/nebivolol users in both the unadjusted [hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.65-1.83] and adjusted (HR 1.61; 95% CI 1.52-1.70) analyses. No significant differences were found for all-cause and COPD hospitalization between the two groups. Carvedilol users had a significant lower restricted mean persistence time than metoprolol/bisoprolol/nebivolol users. Patients exposed to carvedilol had an odds ratio (OR) of 1.38 (95% CI 1.23-1.56) for being hospitalized due to COPD within 60 days after redeeming the first carvedilol prescription, which was similar to that observed in metoprolol/bisoprolol/nebivolol users (OR 1.37; 95% CI 1.27-1.48). Patients with concurrent chronic kidney disease had a higher probability of receiving carvedilol (OR 1.16; 95% CI 1.04-1.29). CONCLUSION: Carvedilol prescription carried an increased hazard of HF hospitalization and lower restricted mean persistence time among patients with COPD and concurrent HF. Additionally, we found a widespread phenomenon of carvedilol prescription at variance with the European Society of Cardiology guidelines and potential for improving the proportion of patients treated with ß-blockers.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer's disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

Efficacy of nebivolol-valsartan single-pill combination in obese and nonobese patients with hypertension.

Antihypertensive efficacy of single-pill combinations (SPCs) consisting of a ß1 -selective adrenergic blocker with vasodilatory properties via ß3 -agonism (nebivolol) and an angiotensin II receptor blocker (valsartan) was demonstrated in an 8-week phase 3 trial (NCT01508026). In this post hoc analysis, seated blood pressure, heart rate, 24-hour ambulatory blood pressure monitoring, plasma aldosterone, estimated glomerular filtration rate, and safety measures were assessed in obese (body mass index >32 kg/m2 ; n=1823) and nonobese (body mass index <27 kg/m2 ; n=847) adults with hypertension (stage I or II) treated with nebivolol-valsartan SPCs, nebivolol or valsartan monotherapy, or placebo. At week 8, reductions from baseline in blood pressure and ambulatory blood pressure monitoring were greater with SPCs and most nebivolol and valsartan monotherapy doses vs placebo regardless of obesity status. Aldosterone declined with all active treatments and estimated glomerular filtration rate remained steady. The nebivolol-valsartan 5/80 mg/d SPC was efficacious regardless of degree of obesity.

Impact of Dobutamine in Patients With Septic Shock: A Meta-Regression Analysis.

Septic shock frequently requires vasopressor agents. Conflicting evidence exists for use of inotropes in patients with septic shock. Data from English studies on human adult septic shock patients were collected. A total of 83 studies were reviewed, while 11 studies with 21 data sets including 239 patients were pooled for meta-regression analysis. For VO2, pooled difference in means (PDM) was 0.274. For cardiac index (CI), PDM was 0.783. For delivery of oxygen, PDM was -0.890. For heart rate, PDM was -0.714. For left ventricle stroke work index, PDM was 0.375. For mean arterial pressure, PDM was -0.204. For mean pulmonary artery pressure, PDM was 0.085. For O2 extraction, PDM was 0.647. For PaCO2, PDM was -0.053. For PaO2, PDM was 0.282. For pulmonary artery occlusive pressure, PDM was 0.270. For pulmonary capillary wedge pressure, PDM was 0.300. For PVO2, PDM was -0.492. For right atrial pressure, PDM was 0.246. For SaO2, PDM was 0.604. For stroke volume index, PDM was 0.446. For SvO2, PDM was -0.816. For systemic vascular resistance, PDM was -0.600. For systemic vascular resistance index, PDM was 0.319. Meta-regression analysis was performed for VO2, DO2, CI, and O2 extraction. Age was found to be significant confounding factor for CI, DO2, and O2 extraction. APACHE score was not found to be a significant confounding factor for any of the parameters. Dobutamine seems to have a positive effect on cardiovascular parameters in patients with septic shock. Prospective studies with larger samples are required to further validate this observation.

Nebivolol suppresses asymmetric dimethylarginine and attenuates cyclosporine-induced nephrotoxicity and endothelial dysfunction in rats.

BACKGROUND: Cyclosporine A (CsA)-induced nephrotoxicity is a challenging problem complicating its chronic use in a large array of autoimmune diseases, as well as in organ transplantation. A considerable body of evidence points to the involvement of nitric oxide (NO) and its endogenous synthesis inhibitor, asymmetric dimethylarginine (ADMA), in CsA-induced renal and cardiovascular adverse effects. In this study, the potential of the third generation ß-blocker, nebivolol, to modify the NO/ADMA system is hypothesized to play a role in protection against CsA-induced renal injury and endothelial dysfunction. METHODS: Both in vivo and in vitro studies were carried out on 36 male Wistar rats randomly divided into three groups; normal control, CsA (30mg/kg/day)-treated or CsA+nebivolol (30mg/kg and 1mg/kg daily, respectively)-treated groups. After four weeks, blood pressure, lipid profile, renal functions, renal oxidative status, NO, inducible NO synthase and ADMA were assessed. In vitro evaluation of vascular relaxant responses of norepinephrine pre-contracted aortic rings to acetylcholine (ACh) and sodium nitroprusside were evaluated. RESULTS: Concurrent nebivolol treatment significantly attenuated CsA-induced hypertension, impairment of renal functions, oxidative stress and restored the balance in renal NO system with lowering of the elevated ADMA. This was associated with favourable effects on lipid profile. Nebivolol treatment also abrogated the CsA-induced impairment of relaxant responses of aortic rings to ACh. CONCLUSIONS: Nebivolol possesses multifaceted actions that make it advantageous to combat the CsA-induced toxic effects on renal and endothelial functions.

Nebivolol suppresses cardiac ryanodine receptor-mediated spontaneous Ca2+ release and catecholaminergic polymorphic ventricular tachycardia.

ß-Blockers are a standard treatment for heart failure and cardiac arrhythmias. There are ∼30 commonly used ß-blockers, representing a diverse class of drugs with different receptor affinities and pleiotropic properties. We reported that among 14 ß-blockers tested previously, only carvedilol effectively suppressed cardiac ryanodine receptor (RyR2)-mediated spontaneous Ca2+ waves during store Ca2+ overload, also known as store overload-induced Ca2+ release (SOICR). Given the critical role of SOICR in arrhythmogenesis, it is of importance to determine whether there are other ß-blockers that suppress SOICR. Here, we assessed the effect of other commonly used ß-blockers on RyR2-mediated SOICR in HEK293 cells, using single-cell Ca2+ imaging. Of the 13 ß-blockers tested, only nebivolol, a ß-1-selective ß-blocker with nitric oxide synthase (NOS)-stimulating action, effectively suppressed SOICR. The NOS inhibitor (N-nitro-l-arginine methyl ester) had no effect on nebivolol's SOICR inhibition, and the NOS activator (histamine or prostaglandin E2) alone did not inhibit SOICR. Hence, nebivolol's SOICR inhibition was independent of NOS stimulation. Like carvedilol, nebivolol reduced the opening of single RyR2 channels and suppressed spontaneous Ca2+ waves in intact hearts and catecholaminergic polymorphic ventricular tachycardia (CPVT) in the mice harboring a RyR2 mutation (R4496C). Interestingly, a non-ß-blocking nebivolol enantiomer, (l)-nebivolol, also suppressed SOICR and CPVT without lowering heart rate. These data indicate that nebivolol, like carvedilol, possesses a RyR2-targeted action that suppresses SOICR and SOICR-evoked VTs. Thus, nebivolol represents a promising agent for Ca2+-triggered arrhythmias.

An imperfect "PAST" Lessons learned from the National Review of Asthma Deaths (NRAD) UK.

Asthma deaths are a barometer of the quality of asthma care. The principal care for patients with severe asthma is often a joint partnership between primary and secondary services. Communication between the two services determines the effectiveness of treatment. Undertaking an audit on asthma in either primary or separately in secondary care is a relatively straightforward process. However, when the audit spans both primary and secondary care in a country as large as the United Kingdom which is further sub-divided into the separate healthcare systems of England, Wales, Scotland, and Northern Island, then the audit becomes considerably more challenging. The National Review of Asthma Deaths (NRAD) reported in May 2014 was a confidential enquiry tasked with identifying circumstances surrounding asthma deaths across the whole of the UK, in order to ascertain avoidable factors and make recommendations to improve care and reduce future asthma deaths (Why asthma still kills: the National Review of Asthma Deaths (NRAD) Confidential Enquiry report, 2014, http://www.rcplondon.ac.uk/sites/default/files/why-asthma-still-kills-full-report.pdf ). The idea for NRAD arose from a longstanding East of England confidential enquiry started in 1988 by Dr Brian Harrison and then handed onto me in 2001 until funding for the national review of asthma deaths was secured in 2010.

Dobutamine stress echocardiography resulting in acute gastric dilatation and pneumoporta.

Acute gastric dilatation is a rare cause of gas within the hepatic portal vein, but one that is important to recognise as prompt decompression via a nasogastric tube is usually successful in resolving the situation. We report the rare case of a 68-year-old man with spontaneous acute gastric dilatation 50 minutes after a dobutamine stress echo that resulted in pneumoporta. The patient had a Nissen's fundoplication 18 months previously; patients with previous antireflux surgery or who have a degree of gastric outlet obstruction may be at increased risk of this unusual condition. Conservative management, with placement of a nasogastric tube was successful in resolving his symptoms.

Olodaterol for the treatment of chronic obstructive pulmonary disease.

PURPOSE: Published data on the pharmacology, pharmacokinetics, efficacy, and safety of the once-daily, long-acting ß2-agonist (LABA) olodaterol are reviewed. SUMMARY: Olodaterol (Striverdi Respimat, Boehringer Ingelheim), a LABA with high selectivity for ß2-adrenergic receptors, is indicated for the treatment of chronic obstructive pulmonary disease (COPD); the recommended dose is 5 µg, to be delivered once daily via the Respimat inhaler. In 48- and 6-week Phase III clinical trials of olodaterol evaluating various lung function and symptomatic outcomes in patients with moderate to very severe COPD, olodaterol use was associated with significant improvements in spirometry outcomes, such as postbronchodilator forced expiratory volume in one second (FEV1), as well as dyspnea severity and quality-of-life measures. Other clinical trials demonstrated that olodaterol produced beneficial effects on FEV1 measures throughout the 24-hour dosing interval. A meta-analysis of data from 20 published research reports indicated that olodaterol's efficacy was comparable to that of the once-daily LABA indacaterol and that the combination of olodaterol and tiotropium provided improvements in lung function greater than those provided by tiotropium alone. Analysis of pooled data from four long-term trials showed that olodaterol's safety profile was comparable to that of formoterol; the most frequently reported adverse effects associated with olodaterol use were bronchitis, nasopharyngitis, and upper respiratory tract infection. CONCLUSION: Once-daily olodaterol 5 µg is an effective therapy in improving lung function and symptomatic outcomes in patients with moderate to very severe COPD receiving other maintenance therapy, with a satisfactory safety profile.

Nebivolol versus Carvedilol or Metoprolol in Patients Presenting with Acute Myocardial Infarction Complicated by Left Ventricular Dysfunction.

OBJECTIVE: The aim of this study was to evaluate the efficacy of nebivolol, carvedilol or metoprolol succinate on the outcome of patients presenting with acute myocardial infarction (AMI) complicated by left ventricular dysfunction. SUBJECTS AND METHODS: Patients (n = 172, aged 28-87 years) with AMI and left ventricular ejection fraction ≤0.45 were randomized to the nebivolol (n = 55), carvedilol (n = 60) and metoprolol succinate (n = 57) groups. Baseline demographic and clinical characteristics and composite event rates of nonfatal MI, cardiovascular mortality, hospitalization due to unstable angina pectoris or heart failure, stroke or revascularization during the 12-month follow-up were compared among the groups using the x03C7;2 test, t test or log-rank test as appropriate. RESULTS: Baseline demographic and clinical characteristics were similar in the three groups. The composite end point during follow-up was lower in the patients treated with nebivolol than those treated with metoprolol (14.5 vs. 31.5%; p = 0.03). However, event rates were similar between the patients treated with carvedilol and those treated with the metoprolol (20.3 vs. 31.5%, p > 0.05) and between the patients treated with nebivolol and carvedilol (14.5 vs. 20.3%, p > 0.05). CONCLUSION: The patients treated with nebivolol experienced 12-month cardiovascular events at a lower rate than those treated with metoprolol succinate. However, event rates were similar between the carvedilol and the metoprolol succinate groups and between the nebivolol and the carvedilol groups.

Nebivolol prevents indomethacin-induced gastric ulcer in rats.

Gastric ulcer is a very common gastrointestinal disease that may lead to dangerous complications and even death. This study was conducted to evaluate the prophylactic effect of nebivolol against indomethacin [INDO]-induced gastric ulcer. Male Wistar rats were divided into four groups: normal control, ulcer control (INDO only), omeprazole before INDO and nebivolol before INDO. Each rat to receive nebivolol and omeprazole was given the agent orally (by gavage) daily for 10 days prior to induction of ulcer by oral dosing with INDO. Four hours after INDO treatment, all rats were euthanized and their stomachs obtained for measures of gastric acidity, oxidative stress and inflammatory markers, as well as cytoprotective mediators. The results showed that a single oral dose of INDO (100 mg/kg) induced gastric acidity, an ulcer index of 2900 and significantly increased levels of gastric tumor necrosis factor (TNF)-α and malondialdehyde (MDA) and significantly decreased levels of gastric prostaglandin E2 (PGE2), glutathione (GSH) and nitric oxide (NO), compared to in normal control counterpart stomachs. Giving nebivolol before INDO corrected the gastric acidity and resulted in a significant increase in GSH, PGE2 and NO and a significant decrease in TNFα and MDA gastric levels, compared to ulcer control values. Results obtained with nebivolol were comparable to those with omeprazole; the preventive index in the nebivolol group was 90.7% compared to 94.5% in rats in the omeprazole group. These studies showed that nebivolol provided a valuable role in preventing gastric ulcers induced by INDO and provided a promise for potentially protecting hypertensive patients from experiencing gastric ulcer. Thus, it is possible that, pending further studies, nebivolol could be used for pre-exposure prophylaxis from gastric ulcer in these patients.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction / Efeito do Nebivolol sobre Parâmetros do MIBG e Exercício na Insuficiência Cardíaca com Fração de Ejeção Normal

Abstract Background: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Resumo Fundamento: Mais de 50% dos pacientes com insuficiência cardíaca têm fração de ejeção preservada (ICFEN). A cintilografia marcada com iodo 123 com metaiodobenzilguanidina (123I-MIBG) e o teste cardiopulmonar do exercício (TCPE) são marcadores de prognóstico da ICFEN. O nebivolol é um betabloqueador com propriedade vasodilatadora. Objetivos: Avaliar o impacto da terapia com nebivolol sobre as variáveis da cintilografia com 123I-MIBG e do TCPE em pacientes com ICFEN. Métodos: Vinte e cinco pacientes realizaram cintilografia com 123I-MIBG para avaliar a taxa de washout e a relação coração/mediastino precoce e tardia. Durante o TCPE, foi analisado o comportamento da pressão arterial sistólica (PAS), frequência cardíaca (FC) durante o esforço e a recuperação (FCR) e o consumo de oxigênio (VO2). Após avaliação inicial, separamos nossa amostra em grupos controle versus intervenção, iniciamos o nebivolol e repetimos os exames após 3 meses. Resultados: Após o tratamento, o grupo intervenção apresentou melhora na PAS (149 mmHg [143,5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0,016]), FC em repouso (78 bpm [65,5-84 bpm] versus 64,5 bpm [57,5-75,5 bpm, p = 0,028]), PAS no pico do esforço (235 mmHg [216,5-249 mmHg] versus 198 mmHg [191-220,5 mmHg], p = 0,001), FC no pico do esforço (124,5 bpm [115-142 bpm] versus 115 bpm [103,7-124 bpm], p = 0,043) e FCR no 1º minuto (6,5 bpm [4,75-12,75 bpm] versus 14,5 bpm [6,7-22 bpm], p = 0,025) e no 2º minuto (15,5 bpm [13-21,75 bpm] versus 23,5 bpm [16-31,7 bpm], p = 0,005), porém não apresentou mudança no VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. Conclusão: Apesar de um melhor controle da PAS e na FC em repouso e durante o esforço e uma melhora na FCR, o nebivolol não ocasionou efeito positivo sobre o VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. A ausência de efeito sobre a atividade adrenérgica pode ser a causa da falta de efeito sobre a capacidade funcional.

Nebivolol, a ß1-adrenergic blocker, protects from peritoneal membrane damage induced during peritoneal dialysis.

UNLABELLED: Peritoneal dialysis (PD) is a form of renal replacement treatment, which employs the peritoneal membrane (PM) to eliminate toxins that cannot be removed by the kidney. The procedure itself, however, contributes to the loss of the PM ultrafiltration capacity (UFC), leading consequently to the technique malfunction. ß-blockers have been considered deleterious for PM due to their association with loss of UFC and induction of fibrosis. Herein we analyzed the effects of Nebivolol, a new generation of ß1-blocker, on PM alterations induced by PD fluids (PDF).In vitro: We found that mesothelial cells (MCs) express ß1-adrenergic receptor. MCs were treated with TGF-ß to induce mesothelial-to-mesenchymal transition (MMT) and co-treated with Nebivolol. Nebivolol reversed the TGF-ß effects, decreasing extracellular matrix synthesis, and improved the fibrinolytic capacity, decreasing plasminogen activator inhibitor-1 (PAI-1) and increasing tissue-type plasminogen activator (tPA) supernatant levels. Moreover, Nebivolol partially inhibited MMT and decreased vascular endothelial growth factor (VEGF) and IL-6 levels in supernatants.In vivo: Twenty-one C57BL/6 mice were divided into 3 groups. Control group carried a catheter without PDF infusion. Study group received intraperitoneally PDF and oral Nebivolol during 30 days. PDF group received PDF alone. Nebivolol maintained the UFC and reduced PM thickness, MMT and angiogenesis promoted by PDF. It also improved the fibrinolytic capacity in PD effluents decreasing PAI-1 and IL-8 and increased tPA levels. CONCLUSION: Nebivolol protects PM from PDF-induced damage, promoting anti-fibrotic, anti-angiogenic, anti-inflammatory and pro-fibrinolytic effects.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction.

BACKGROUND: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. OBJECTIVES: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. METHODS: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. RESULTS: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. CONCLUSION: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Effect of Perioperative Goal-Directed Hemodynamic Resuscitation Therapy on Outcomes Following Cardiac Surgery: A Randomized Clinical Trial and Systematic Review.

OBJECTIVES: To evaluate the effects of goal-directed therapy on outcomes in high-risk patients undergoing cardiac surgery. DESIGN: A prospective randomized controlled trial and an updated metaanalysis of randomized trials published from inception up to May 1, 2015. SETTING: Surgical ICU within a tertiary referral university-affiliated teaching hospital. PATIENTS: One hundred twenty-six high-risk patients undergoing coronary artery bypass surgery or valve repair. INTERVENTIONS: Patients were randomized to a cardiac output-guided hemodynamic therapy algorithm (goal-directed therapy group, n = 62) or to usual care (n = 64). In the goal-directed therapy arm, a cardiac index of greater than 3 L/min/m was targeted with IV fluids, inotropes, and RBC transfusion starting from cardiopulmonary bypass and ending 8 hours after arrival to the ICU. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite endpoint of 30-day mortality and major postoperative complications. Patients from the goal-directed therapy group received a greater median (interquartile range) volume of IV fluids than the usual care group (1,000 [625-1,500] vs 500 [500-1,000] mL; p < 0.001], with no differences in the administration of either inotropes or RBC transfusions. The primary outcome was reduced in the goal-directed therapy group (27.4% vs 45.3%; p = 0.037). The goal-directed therapy group had a lower occurrence rate of infection (12.9% vs 29.7%; p = 0.002) and low cardiac output syndrome (6.5% vs 26.6%; p = 0.002). We also observed lower ICU cumulative dosage of dobutamine (12 vs 19 mg/kg; p = 0.003) and a shorter ICU (3 [3-4] vs 5 [4-7] d; p < 0.001) and hospital length of stay (9 [8-16] vs 12 [9-22] d; p = 0.049) in the goal-directed therapy compared with the usual care group. There were no differences in 30-day mortality rates (4.8% vs 9.4%, respectively; p = 0.492). The metaanalysis identified six trials and showed that, when compared with standard treatment, goal-directed therapy reduced the overall rate of complications (goal-directed therapy, 47/410 [11%] vs usual care, 92/415 [22%]; odds ratio, 0.40 [95% CI, 0.26-0.63]; p < 0.0001) and decreased the hospital length of stay (mean difference, -5.44 d; 95% CI, -9.28 to -1.60; p = 0.006) with no difference in postoperative mortality: 9 of 410 (2.2%) versus 15 of 415 (3.6%), odds ratio, 0.61 (95% CI, 0.26-1.47), and p = 0.27. CONCLUSIONS: Goal-directed therapy using fluids, inotropes, and blood transfusion reduced 30-day major complications in high-risk patients undergoing cardiac surgery.