Search

Background: A deep Y descent in the jugular venous pulse (JVP) is associated with diseases such as a decrease in right ventricular (RV) preload reserve. The present study investigated the relationship between RV-pulmonary arterial (PA) coupling and a deep Y descent, examined risk factors for a deep Y descent and clarified whether a deep Y descent was an independent risk factor for cardiac events irrespective of RV-PA coupling in patients with heart failure (HF). Methods: We enrolled 350 patients with HF who underwent echocardiography and JVP examination. A deep Y descent was identified by a deeper ‘Y’ descent than ‘X’ descent in the JVP waveform. We defined cardiac events of HF as follows: sudden death, death from HF, the emergent infusion of loop diuretics, or hospitalization for decompensated HF. Results and Conclusions: A deep Y descent and cardiac events were observed in 129 and 83 patients, respectively. The prevalence of a deep Y descent increased with decreases in the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary arterial pressure (SPAP) ratio. Not only the TAPSE/SPAP ratio (odds ratio,0.756 per0.1 mm/mmHg, 95 %confidence interval [CI], 0.660–0.866, p

Background: Septic shock is associated with systemic inflammatory response, hemodynamic instability, impaired sympathetic control, and the development of multiorgan dysfunction that requires vasopressor or inotropic support. The regulation of immune function in sepsis is complex and varies over time. However, activating Beta-2 receptors and blocking Beta-1 receptors reduces the proinflammatory response by influencing cytokine production. Evidence that supports the concomitant use of ultra short beta-blockers with inotropes and vasopressors in patients with septic shock is still limited. This study aimed to evaluate the use of ultra short beta-blockers and its impact on the ICU related outcomes such as mortality, length of stay, heart rate control, shock resolution, and vasopressors/inotropes requirements. Methods: A systematic review and meta-analysis of randomized controlled trials including critically ill patients with septic shock who received inotropes and vasopressors. Patients who received either epinephrine or norepinephrine without beta-blockers “control group” were compared to patients who received ultra short beta-blockers concomitantly with either epinephrine or norepinephrine “Intervention group”. MEDLINE and Embase databases were utilized to systematically search for studies investigating the use of ultra short beta-blockers in critically ill patients on either epinephrine or norepinephrine from inception to October 10, 2023. The primary outcome was the 28-day mortality. While, length of stay, heart rate control, and inotropes/ vasopressors requirements were considered secondary outcomes. Results: Among 47 potentially relevant studies, nine were included in the analysis. The 28-day mortality risk was lower in patients with septic shock who used ultra short beta-blockers concomitantly with either epinephrine or norepinephrine compared with the control group (RR (95%CI): 0.69 (0.53, 0.89), I2=26%; P=0.24). In addition, heart rate was statistically significantly lower with a standardized mean difference (SMD) of -22.39 (95% CI: -24.71, –20.06) among the beta-blockers group than the control group. The SMD for hospital length of stay and the inotropes requirement were not statistically different between the two groups (SMD (95%CI): -0.57 (-2.77, 1.64), and SMD (95%CI): 0.08 (-0.02, 0.19), respectively). Conclusion: The use of ultra short beta-blockers concomitantly with either epinephrine or norepinephrine in critically ill patients with septic shock was associated with better heart rate control and survival benefits without increment in the inotropes and vasopressors requirement.

Our study provides valuable insights into the photoinduced degradation of nadolol in the Danube River through catalytic oxidation with radicals. The presence of H2O2 under UV and UV-LED irradiation significantly enhanced degradation efficiency. The water matrix complexity had a significant impact on process efficiency. Nitrate, chloride, and sulfate ions exhibited an inhibitory effect on nadolol degradation by quenching •OH radicals. Additional analyses, including catalase activity, lipid peroxidation, and computational analysis, revealed proposed degradation intermediates. Six degradation intermediates were proposed, along with their NMR chemical shifts. The degree of mineralization and in vitro toxicity were assessed.

The presence of some drugs in meat samples can cause threat to human health, therefore, its analysis is highly desirable for food safety purposes. In this work, a solid-phase extraction procedure for the determination of oxprenolol, a non-selective beta-blocker, and such anabolic agents as methandienone and testosterone in beef meat samples has been developed. Extraction conditions were optimized to achieve high sensitivity and accuracy of the results. The procedure was validated using meat samples free from target analytes. As a result, high selectivity and sensitivity were observed with the detection limits between 0.25 and 1.25 ng/g, and the results were not affected by matrix components. The proposed procedure was applied to the analysis of real beef samples purchased in the market, and the results have revealed the presence of contaminated samples. The concentration of oxprenolol in the contaminated sample was 7 ng/g, methandienone content in the sample was 30 ng/g, while testosterone level was 4 ng/g.

Purpose: Favorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC., Methods: 36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant., Results: Comparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03)., Conclusion: Transplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Summary: Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. Methods: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. Findings: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. Interpretation: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. Funding: This study was funded by institutional grants and charities.

Anesthetic agents and/or surgical positions, the total volume of hemangioma may increase under general anesthesia; thus, airway management of patients with a hemangioma may be very difficult. Our patient in this case report has a periorbital and oropharyngeal hemangioma that reaches down to the esophagus. We observed that the size and volume of the hemangioma increased significantly during elective nephrectomy surgery. After adequate therapy with steroids and beta-blockers, the size of the hemangioma decreased during the postoperative care unit monitoring period. We report this case to show the importance of airway management of hemangiomas with the potential for life-threatening complications.

Catecholaminergic polymorphic ventricular tachycardia is a genetic disorder that causes ventricular tachyarrhythmias via increased release of intracellular calcium. The standard diagnostic measure is an exercise stress test that reveals ventricular ectopy. We present an extraordinary case marked by a normal stress test and no relation to exertion. (Level of Difficulty: Intermediate.)

Ginkgo biloba is a commonly used herbal supplement in the United States. We describe a 63-year-old man with a significant ventricular ectopic burden (32.7%) that was refractory to metoprolol tartrate (41.7%) and resolved (

Introduction: Contrasting with the lymphopenia classically reported after administration of glucocorticoids, a lymphocytosis has been sometimes observed in patients after glucocorticoid administration. We here determine prospectively the timing and magnitude of methylprednisolone (mPDN)-induced lymphocytosis and study the effects of concomitant propranolol administration on lymphocyte count (Ly)., Methods: Ly was measured before and 24 to 72hours after initiating mPDN treatment in 20 patients with immune-mediated inflammatory disorders (IMID). After one week, patients with increased Ly were divided in two groups receiving, in addition to mPDN, either propranolol or a placebo; Ly was determined 4 days later. Lymphocyte subpopulations and mPDN plasma levels were determined in subsets of the patients. Values are expressed as median with 25%-75% interquartile range., Results: A 73.4% (37-305) increase of Ly was observed in 18/20 patients as soon as 48 (48-72) hours after initiating mPDN (32mg; 16-32). Lymphocytosis (Ly≥4000/μL) was observed in 7 patients and hyperlymphocytosis (Ly≥5000/μL) in 4 of them. The increase in Ly was noted both for B and T cells. Median mPDN plasma levels (n=13) were 97.4ng/mL (IQR 67-489) and 3.2 (IQR 2.1-5.1) respectively 8hours and 24hours after oral mPDN administration. No significant change in Ly was shown under propranolol (p=0.570)., Conclusion: A morning lymphocytosis observed during mPDN treatment occurs in the very first days of mPDN administration. Our results do not support the hypothesis of an increased adrenergic tone responsible for this phenomenon. Identifying this unexpected etiology of lymphocytosis could mitigate the need for unnecessary supplementary investigations in clinical practice., (Copyright © 2024 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Background: Beta-blockers are commonly used drugs during pregnancy, especially in women with heart disease, and are regarded as relatively safe although evidence is sparse. Differences between beta-blockers are not well-studied., Methods: In the Registry of Pregnancy And Cardiac disease (ROPAC, n = 5739), a prospective global registry of pregnancies in women with structural heart disease, perinatal outcomes (small for gestational age (SGA), birth weight, neonatal congenital heart disease (nCHD) and perinatal mortality) were compared between women with and without beta-blocker exposure, and between different beta-blockers. Multivariable regression analysis was used for the effect of beta-blockers on birth weight, SGA and nCHD (after adjustment for maternal and perinatal confounders)., Results: Beta-blockers were used in 875 (15.2%) ROPAC pregnancies, with metoprolol (n = 323, 37%) and bisoprolol (n = 261, 30%) being the most frequent. Women with beta-blocker exposure had more SGA infants (15.3% vs 9.3%, p < 0.001) and nCHD (4.7% vs 2.7%, p = 0.001). Perinatal mortality rates were not different (1.4% vs 1.9%, p = 0.272). The adjusted mean difference in birth weight was -177 g (-5.8%), the adjusted OR for SGA was 1.7 (95% CI 1.3-2.1) and for nCHD 2.3 (1.6-3.5). With metoprolol as reference, labetalol (0.2, 0.1-0.4) was the least likely to cause SGA, and atenolol (2.3, 1.1-4.9) the most., Conclusions: In women with heart disease an association was found between maternal beta-blocker use and perinatal outcomes. Labetalol seems to be associated with the lowest risk of developing SGA, while atenolol should be avoided., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background & Aims: Treatment with non-selective beta-blockers (NSBBs) reduces the risk of ascites, which is the most common decompensating event in cirrhosis. This study aimed to assess the ability of a serum microRNA (miRNA) signature to predict ascites formation and the hemodynamic response to NSBBs in compensated cirrhosis. Methods: Serum levels of miR-452-5p, miR-429, miR-885-5p, miR-181b-5p, and miR-122-5p were analyzed in patients with compensated cirrhosis (N = 105). Hepatic venous pressure gradient (HVPG) was measured at baseline, after intravenous propranolol, and 1 year after randomization to NSBBs (n = 52) or placebo (n = 53) (PREDESCI trial). miRNAs were analyzed at baseline and at 1 year. Results: Nineteen patients (18%) developed ascites, of whom 17 developed ascites after 1 year. miR-181b-5p levels at 1 year, but not at baseline, were higher in patients that developed ascites. The AUC of miR-181b-5p at 1 year to predict ascites was 0.7 (95% CI 0.59–0.78). miR-429 levels were lower at baseline in acute HVPG responders to NSBBs (AUC 0.65; 95% CI, 0.53–0.76), but levels at baseline and at 1 year were not associated with the HVPG response to NSBBs at 1 year. Conclusions: Serum miR-181b-5p is a promising non-invasive biomarker to identify patients with compensated cirrhosis at risk of ascites development. Lay summary: Ascites marks the transition from the compensated to decompensated stage in cirrhosis and indicates a worsening in prognosis. There are currently no easily accessible tools to identify patients with compensated cirrhosis at risk of developing ascites. We evaluated the levels of novel molecules termed microRNAs in the blood of patients with compensated cirrhosis and observed that miR-181b-5p can predict which patients are going to develop ascites.

Background: Risk assessment tools and effective prevention strategies for sudden cardiac death (SCD) in pediatric patients with hypertrophic cardiomyopathy (HCM) have not been established. This study aimed to evaluate the efficacy of beta-blockers and exercise restriction for SCD prevention in this population., Methods: We retrospectively reviewed the medical records of patients aged <18 years who were diagnosed with HCM at our center between January 1996 and December 2021. SCD and aborted SCD were defined as SCD equivalents. We divided patients based on whether they were prescribed beta-blockers or exercise restriction and compared the outcomes among the groups. The primary outcome was the overall survival (OS), and the secondary outcome was the cumulative SCD equivalent rate. Outcomes were analyzed using Kaplan-Meier curves and Cox proportional hazard analysis. We also compared patients according to the occurrence of SCD equivalents to identify SCD risk predictors., Results: Among the 43 included patients [mean age, 7.7 (1.6-12.1) years; 23 male individuals], SCD equivalents occurred in 13 patients over 11.2 (4.5-15.6) years of follow-up, among whom 12 were resuscitated and 1 died. The OS rate was significantly higher in the beta-blocker and exercise restriction groups than in the non-beta-blocker and non-exercise restriction groups (81.3 % vs. 19.1 %, p < 0.01 and 57.4 % vs. 12.7 %, p < 0.01, respectively). Among the 13 patients with SCD equivalents, 5 had 9 recurrent SCD equivalents. A significant difference was observed between the SCD equivalent and non-SCD equivalent groups in the history of suspected arrhythmogenic syncope (p < 0.01) in the univariable but not in the multivariable analysis., Conclusions: Beta-blockers and exercise restriction may decrease the risk of SCD in pediatric patients with HCM and should be considered for SCD prevention in this population, particularly because predicting SCD in these patients remains challenging., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: This systematic review aimed to assess the tolerability of patients with cardiac amyloidosis (CA) to beta-blockers (BBs) and evaluate its association with adverse outcomes., Methods: We performed a comprehensive search from January 1, 2000 to October 20, 2023. Studies examining BB use and tolerance or the relationship between BB use and outcomes in patients with CA were included. Pooled adjusted hazard ratios (aHRs) for all-cause mortality were calculated using random- and fixed-effects models., Results: Eight observational studies involving 4002 patients with CA (87.5% with transthyretin CA [ATTR-CA] and 12.5% with immunoglobulin light chain CA [AL-CA]) were assessed. BBs were used by 52.5% of the patients. However, 26.3% of the patients discontinued BBs because of hypotension, bradycardia, or fatigue. Regarding the association between BB use and all-cause death, four studies were identified that included 2874 patients with ATTR-CA and 16 patients with AL-CA. The meta-analysis revealed no apparent relationship between BB use and all-cause mortality (pooled aHR = 0.78, 95% confidence interval (CI) = 0.40-1.51). Two studies on patients with ATTR-CA found no impact of BB use on all-cause mortality in the subgroup with left ventricular ejection fraction (LVEF) > 40%, but conflicting results exist for those with LVEF ≤40% (pooled aHR = 0.78, 95% CI = 0.40-1.54)., Conclusion: The limited number of observational studies that predominantly enrolled patients with ATTR-CA showed that BBs were used in almost half of the patients with CA, with varying tolerability. However, no significant association was observed between BB use and all-cause mortality., (Copyright © 2024. Published by Elsevier B.V.)

Decompensated cirrhosis is associated with a significantly increased risk of mortality. Variceal hemorrhage (VH) further increases the risk of mortality, and of future variceal bleed events. Non-selective beta-blockers (NSBBs) are effective therapy for primary and secondary prophylaxis of VH and have become the cornerstone of pharmacologic therapy in cirrhosis. Beta-blockers are associated with reduced overall mortality and GI-bleeding related mortality in patients with decompensated cirrhosis; they may also confer hemodynamically independent beneficial effects. Long-term treatment with beta-blockers may improve decompensation-free survival in compensated cirrhosis with clinically significant portal hypertension (CSPH). Carvedilol more effectively lowers the hepatic vein portal gradient than traditional NSBBs and has been shown to improve survival in compensated cirrhosis. Treatment goals in compensated cirrhosis with CSPH should focus on early utilization of beta-blockers to prevent decompensation and reduce mortality., Competing Interests: Declaration of competing interest There are no conflicts of interest for any authors involved with this paper., (Copyright © 2024 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF., Objectives: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF., Methods: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF., Results: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; P interaction  = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use., Conclusions: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Bart has received research grant support (paid to institution) from AstraZeneca, Cardurion, and Daxor; and has participated in clinical trial committees for studies sponsored by Daxor and Nuwellis. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has received personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Lam has received supported from a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and us2.ai; and has served as cofounder and nonexecutive director of us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the advisory board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol-Myers Squibb, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and has served as a director of Global Clinical Trial Partners. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and us2.ai; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. Dr Vardeny has received research support from AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Cardior. Mr Kulac has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) such as pembrolizumab have revolutionized the treatment of metastatic non-small cell lung cancer (mNSCLC). Beta-adrenergic activation contributes to cancer initiation and progression. While non-selective beta-blocker were found to improve the efficacy of ICIs therapy, the role of beta-1 (β 1 )-selective -blocker (β 1 B) in lung cancer patients is unknown., Objective: To evaluate the effect of β 1 B on overall survival (OS) and progression-free survival (PFS) in patients diagnosed with mNSCLC and treated with pembrolizumab., Methods: We performed a retrospective analysis of patients diagnosed with mNSCLC and treated with first-line pembrolizumab at our center., Results: Of 200 eligible patients, 53 (27%) were pretreated with β 1 B. Patients in the β 1 B cohort were older (73 ± 8 vs. 67 ± 10 years, p < 0.001) with a higher prevalence of cardiac risk factors and cardiovascular (CV) diseases including ischemic heart disease (32% vs. 16%, p = 0.010), heart failure (9% vs. 3%, p = 0.043) and atrial fibrillation (23% vs. 3%, p < 0.001). Compared to the non-β 1 B group, patient pretreated with β 1 B had a significant shorter median OS (12 vs. 24 months, p = 0.004) and PFS (6 vs. 8 months, p < 0.001). In a multivariate analysis, including all CV risk factors and diseases, the use of baseline β 1 B was a strong and independent predictor for accelerated disease progression (HR 1.92, 95%CI 1.32-2.79, p < 0.001) and shorter OS (HR 1.8, 95%, CI 1.18-2.75, p = 0.007)., Conclusions: The use of baseline β 1 B showed a strong and independent association for shorter OS and PFS in patients diagnosed with mNSCLC and treated with pembrolizumab., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Although medical management of patients with coronary artery disease (CAD) is often based on scientific guidelines, a number of everyday clinical situations are not specifically covered by recommendations or the level of evidence is low. The aim of this study was to assess practice patterns regarding routine management of patients with stable CAD. Methods: A survey comprising six questions on two clinical scenarios regarding stable CAD management was sent to 345 cardiologists from the Nord-Pas-de-Calais Region (France). We first assessed practice patterns globally and then searched for associations with physician characteristics (age, gender, sub-specialty, and type of practice). Findings: The response rate was 92%. Regarding management of asymptomatic CAD, 86% of the cardiologists performed routine exercise testing, before which, 69% withdrew β-blockers. After a positive exercise test, 26% immediately performed coronary angiography and 67%, further imaging tests. In the absence of left ventricular dysfunction or history of myocardial infarction, routine β-blocker prescription for stable CAD was selected by 43%. When anticoagulation was needed for atrial fibrillation, 41% initiated direct oral anticoagulants rather than vitamin-K antagonists and 50% combined aspirin with anticoagulants. For recurrent stable angina in patients with known CAD, 24% performed coronary angiography directly, 49% requested a stress test, and 27% opted for medical therapy without further diagnostic testing. Age, gender of the cardiologist, academic environment, and practice of interventional cardiology were associated with certain management patterns. Interpretation: When not guided by high-level recommendations, practice patterns for routine clinical situations in stable CAD vary considerably. Future clinical trials should address these clinical interrogations.

Infantile hemangiomas (IHs) of the lips are associated with an increased risk of incomplete involution and ulceration, causing disfigurement. Treatment with oral propranolol (OPT) has credible efficacy but takes months to complete. Thus, this study aimed to investigate the efficacy of intralesional betamethasone injection (IBI) as an alternative treatment for protruding localized IHs of the lips. To investigate the efficacies of OPT and IBI, we designed a prospective, noninferiority, parallel-group study. The primary outcome assessed was treatment response rate. Secondary outcome assessments included lesion size changes and surgical rate. Additionally, complication rates and treatment durations of OPT and IBI were compared. The treatment response rate of IBI was not inferior to that of OPT (95.7% vs. 76.0%, respectively; a difference of 19.7%, 95% confidence interval [CI], -4.4% to 41.6%). The average surgical rate in the IBI group was significantly lower than that in the OPT group (8.7% vs. 40%, respectively; p = 0.012), and the average duration of treatment for IBI was shorter than that of OPT (2.1 months vs. 6.3 months, respectively; p < 0.001). There were no severe adverse drug events in either group. If not managed properly, small, localized lip IHs may cause disfigurement in a child. Our study demonstrated that IBI is as effective as OPT in treating protruding localized lip IHs. Moreover, IBI treatment has a shorter duration and lower surgical rate than OPT. With proper care, IBI is an effective treatment modality for small and localized lip IHs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest related to the content of the manuscript., (Copyright © 2023 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The bone marrow microenvironment is characterized by its multicellular nature, and perhaps less obviously by the high mobility of multiple transient and stationary cell lineages present in this environment. The trafficking of hematopoietic and mesenchymal cells between the bone marrow and blood compartments is regulated by a number of bone marrow-derived factors. It is suspected that transformed metastatic cells “hijack” these processes to engraft into the skeleton and eventually cause the skeletal complications associated with metastatic disease. In this short review, experimental and association data supporting the contribution of a less recognized cell type of the bone marrow – the nerves of the sympathetic nervous system – to early events of the breast cancer bone metastatic process, are summarized.

Background: Although studies consistently show that beta-blockers reduce morbidity and mortality in patients with reduced ejection fraction (EF), data are inconsistent in patients with heart failure with mildly reduced ejection fraction (HFmrEF) and suggest potential negative effects in heart failure with preserved ejection fraction (HFpEF)., Objectives: The purpose of this study was to examine the association of beta-blockers with heart failure (HF) hospitalization and death in patients with HF and EF ≥40% METHODS: Beta-blocker use was assessed at first encounter in outpatients ≥65 years of age with HFmrEF and HFpEF in the U.S. PINNACLE Registry (2013-2017). The associations of beta-blockers with HF hospitalization, death, and the composite of HF hospitalization/death were assessed using propensity-score adjusted multivariable Cox regression models, including interactions of EF × beta-blocker use., Results: Among 435,897 patients with HF and EF ≥40% (HFmrEF, n = 75,674; HFpEF = 360,223), 289,377 (66.4%) were using a beta-blocker at first encounter; more commonly in patients with HFmrEF vs HFpEF (77.7% vs 64.0%; P < 0.001). There were significant interactions between EF × beta-blocker use for HF hospitalization, death, and composite of HF hospitalization/death (P < 0.001 for all), with higher risk with beta-blocker use as EF increased. Beta-blockers were associated with decreased risk of HF hospitalization and death in patients with HFmrEF but a lack of survival benefit and a higher risk of HF hospitalization in patients with HFpEF, particularly when EF was >60%., Conclusions: In a large, real-world, propensity score-adjusted cohort of older outpatients with HF and EF ≥40%, beta-blocker use was associated with a higher risk of HF hospitalization as EF increased, with potential benefit in patients with HFmrEF and potential risk in patients with higher EF (particularly >60%). Further studies are needed to understand the appropriateness of beta-blocker use in patients with HFpEF in the absence of compelling indications., Competing Interests: Funding Support and Author Disclosures The PINNACLE Registry is part of the National Cardiovascular Data Registry and is managed by the American College of Cardiology (ACC) and Veradigm. The sponsors of the registry had no role in data analysis or interpretation, manuscript development, publication review, or approval for this study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Administration of nonselective beta-blockers in prophylaxis of first variceal bleeding is not suitable for all patients. Thus, we evaluated endoscopic variceal band ligation (EVBL) in primary prevention of bleeding in patients with cirrhosis and large esophageal varices. A total of 73 consecutive patients with liver cirrhosis and large esophageal varices without a history of gastrointestinal bleeding were randomized to receive either EVBL or propranolol and were followed for up to 18 months. Forty patients underwent EVBL and 33 patients received propranolol. Variceal bleeding occurred in 2 patients in the EVBL (5%) and in 2 patients in the propranolol group (6%, NS). The 18 month actuarial risk for first variceal bleed was 5% in the EVBL (95% CI, 0-12%) and 20% in the propranolol group (95% CI, 0-49%, NS). The actuarial probability of death at 18 months of follow-up was 5% (95% CI, 0-11%) in the EVBL group and 7% (95% CI, 0-17%, NS) in the propranolol arm. In conclusion, EVBL was an effective and safe alternative to propranolol in primary prophylaxis of bleeding in patients with large esophageal varices.

Background. Gastroesophageal variceal bleeding is a common complication of portal hypertension. Current guidelines recommend β-blockers for primary prophylaxis. However, evidence suggests that endoscopic variceal ligation (EVL) reduce bleeding episodes.Aims. To compare endoscopic EVL with propranolol (PPL) for primary prophylaxis of variceal bleeding.Methods. We conducted a randomized controlled trial. Over a 9-year period, 75 patients with cirrhosis and high-risk esophageal varices (HREV) were recruited and allocated to EVL (n=39) or PPL (n=36). Primary outcome was variceal bleeding. Secondary outcomes were survival, source of bleeding and serious adverse events. Analyses were made by intention-to-treat.Results. Baseline characteristics were similar. Medium follow-up was 1647±1096 days. Complete follow-up was achieved in 85% of patients. Variceal bleeding occurred in 12% of EVL and in 25% of PPL group (p=0.17). The actuarial risks of bleeding after 2 years were similar in both groups. Overall mortality was 51% in EVL and 33% in PPL group (p=0.17). Patients in the EVL group showed a lower rate of esophageal variceal bleeding (5.1% v/s 25%, p=0.027) and a higher rate of subcardial variceal bleeding compared with PPL group (7.7% v/s 0%, p=0.027). Serious adverse events related to EVL occurred in 2 patients, including 1 death.Conclusions. The present study supports that PPL should be considered the first choice in primary prophylaxis of variceal bleeding offering similar effects and lower severe adverse events compared with EVL.

A sample preparation method involving tandem implementation of protein precipitation and salting-out homogenous liquid-liquid extraction was developed for the determination of beta-blockers in serum. The entire procedure was automated using a computer-controlled syringe pump following the Lab-In-Syringe approach. It is based on the denaturation of serum proteins with acetonitrile followed by salt-induced phase separation upon which the proteins accumulate as a compact layer at the interphase of the solutions. The extract is then separated and diluted in-syringe before being submitted to online coupled UHPLC-MS/MS. A 1 mL glass syringe containing a small stir bar for solution mixing at up to 3000 rpm, was used to deal with sample volumes as small as 100 μL. A sample throughput of 7 h -1 was achieved by performing the chromatographic run and sample preparation procedure in parallel. Linear working ranges were obtained for all analytes between 5 and 100 ng mL -1 , with LOD values ranging from 0.4 to 1.5 ng mL -1 . Accuracy values in the range of 88.2-106% and high precision of <11% RSD suggest applicability for routine analysis that can be further improved using deuterated standards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Blood pressure medications are used to treat hypertension; however, low concentrations of beta-blockers in water systems can negatively impact aquatic wildlife. Here, we conducted a metabolic and behavioral study investigating atenolol, a beta-blocker frequently detected in global wastewater systems. The objectives were to determine the effects of low-level atenolol exposure on early stages of zebrafish. We measured survival, deformities, heartbeat, mitochondrial function, lipid and amino acid profiles, and locomotor activity to discern mechanisms of metabolic disruption. We hypothesized that atenolol disrupts lipid metabolism, which would negatively impact locomotor activity. Atenolol showed no overt toxicity to larval zebrafish up to 10 μg/L and deformities were infrequent (<5 %), and included cardiac edema and larvae with kinked tails. A hatch delay was observed at 2-day post-fertilization (dpf) for fish exposed to >5 μg/L atenolol. Heart rates were reduced in 2 and 3 dpf in fish treated with >500 ng/L atenolol. There was no change in oxygen consumption rates (basal and maximum respiration) of embryos when exposed to a range of atenolol concentrations, suggesting mitochondrial respiration was intact. Oil red staining for lipid content in larvae showed a global reduction in lipids with 10 μg/L exposure, prompting deeper investigation into the lipid profiles. Lipidomics quantified 86 lipids and revealed reduced abundance in Ceramide 18: 1 16:0 (Cer&#95;NS d18:1&#95;16:0), Ether linked Phosphatidylethanolamine 16:0 22:6 (EtherPE 16:0e&#95;22:6), and Ether linked Phosphatidylcholine 16:0 22:6 (EtherPC 16:0e&#95;22:6). We also quantified 12 amino acids and observed a subtle dose-dependent reduction in the levels of L-Histidine. Exposure to atenolol did not impact larval locomotor activity based on a Visual Motor Response test. Taken together, atenolol at environmentally relevant levels decreased heart rate of developing zebrafish and altered lipid content. As such, exposure to beta-blockers like atenolol may have negative consequences for developmental trajectories and growth of aquatic species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Fatal ventricular arrhythmias and heart failure are the common modes of death in patients with cardiovascular diseases. Intracardiac defibrillator (ICD) implantation reduces arrhythmic mortality to a significant extent in the high risk patient. However, there continues to be a need for effective drug therapy to reduce the arrhythmic and overall mortality in patients with or without an ICD. Although anti-arrhythmic drugs (AAD) appear inferior to ICD, the role of beta-blockers and to an extent amiodarone along with non AAD like angiotensin converting enzyme inhibitors (ACE-I), mineralocorticoid blockers (MRB) and HMG-CoA reductase inhibitors (statins) need to be emphasized. There have been many drug trials and meta-analysis to this effect and we review the role of drugs especially in their ability to reduce arrhythmic mortality and sudden cardiac death (SCD). The focus is on post myocardial infarction (MI) and heart failure patients with a brief overview of role of drugs in channelopathies.

Recent preclinical studies have associated beta-adrenergic receptor (β-AR) signaling with breast cancer pathways such as progression and metastasis. These findings have been supported by clinical and epidemiological studies which examined the effect of beta-blocker therapy on breast cancer metastasis, recurrence and mortality. Results from these studies have provided initial evidence for the inhibition of cell migration in breast cancer by beta-blockers and have introduced the beta-adrenergic receptor pathways as a target for therapy. This paper analyzes gene expression profiles in breast cancer patients, utilising Artificial Neural Networks (ANNs) to identify molecular signatures corresponding to possible disease management pathways and biomarker treatment strategies associated with beta-2-adrenergic receptor (ADRB2) cell signaling. The adrenergic receptor relationship to cancer is investigated in order to validate the results of recent studies that suggest the use of beta-blockers for breast cancer therapy. A panel of genes is identified which has previously been reported to play an important role in cancer and also to be involved in the beta-adrenergic receptor signaling.

Aims: To assess the impact of secondary prevention medical therapies (statins, ACE-inhibitors/Angiotensin Receptor Blockers (ARB), beta-blockers (BB) and Dual Antiplatelet Therapy (DAPT)) on outcomes of patients with myocardial infarction with nonobstructive coronary artery disease (MINOCA)., Methods: Five adjusted observational studies encompassing 10,546 were included in this meta-analysis. All-cause death was the primary endpoint, while Major Adverse Cardiovascular Events (MACE) and acute myocardial infarction (AMI) were the secondary endpoints., Results: After 24 months of follow up, statins (tested in 8093 patients) were associated with a reduced risk of all-cause death (HR 0.60:0.45-0.81, p 〈0,001), while ACE-inhibitors/ARB (on 9666 patients) were not. Aggregate data from two studies (n = 9720, 7719 on beta-blockers, 6423 on DAPT) indicated that beta-blockers and DAPT (median follow-up 34.1 and 15.7 months, respectively) were both associated with a significant reduction of all-cause death (HR0.81:0.66-0.99, p = 0.04, and HR0.73:0.55-0.98, p = 0.03, for beta-blockers and DAPT, respectively). Among the investigated therapies, only ACE-inhibitors/ARBs entailed a reduced risk of MACE (HR0.65:0.44-0.94, p = 0.02, all CI 95%) over 36.5 months (four studies, n = 10,150). None of the investigated therapies was associated with a reduced risk of AMI., Conclusions: Data from adjusted observational studies suggest that beta-blockers, statins and DAPT are associated with a survival benefit among MINOCA patients. ACE-inhibitors/ARB entail a reduced risk of MACE while none of the investigated secondary prevention therapies is associated with a reduced risk of AMI. Randomized controlled trials are warranted to confirm these findings., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 Elsevier B.V. All rights reserved.)

The ecotoxicological effects of beta-blockers (i.e. Diltiazem and Bisoprolol) and their interactions with the microplastic polyvinyl chloride on marine meiofauna were tested in laboratory microcosms. An experimental factorial design was applied, using meiobenthic fauna collected from the Old Harbor of Bizerte (NE Tunisia), but with a main focus on the nematode communities. The meiobenthic invertebrates were exposed to two concentrations of Diltiazem and Bisoprolol, of 1.8 µg.L -1 and 1.8 mg.L -1 , respectively, and one concentration of polyvinyl chloride (i.e. 20 mg.kg -1 ), separately and mixed. The overall meiofauna abundance was significantly reduced in all treatments, mainly that of polychaetes and amphipods. Moreover, the juveniles-gravid female ratios of the nematode communities were the lowest in the 1.8 µg.L -1 Bisoprolol treatment and for the 1.8 mg.L -1 mixture of Diltiazem and microplastics, suggesting that different dosages influence the maturity status of the examined species. The demographic results were also supported by in silico approach. The simulation of molecular interactions revealed acceptable binding affinities (up to -8.1 kcal/mol) and interactions with key residues in the germ line development protein 3 and sex-determining protein from Coenorhabditis elegans. Overall, the experimental outcome strongly indicates synergistic interactions among the beta-blockers Diltiazem and Bisoprolol and the microplastic polyvinyl chloride on marine nematode communities., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Exercise training has a profound impact on immunity, exerting a multitude of positive effects in indications such as immunosenescence, cancer, viral infections and inflammatory diseases. The immune, endocrine and central nervous systems work in a highly synergistic manner and it has become apparent that catecholamine signaling through leukocyte β-adrenergic receptors (β-ARs) is a key mechanism by which exercise mediates improvements in immune function to help mitigate numerous disease conditions. Central to this is the preferential mobilization and redistribution of effector lymphocytes with potent anti-viral and anti-tumor activity, their interaction with muscle-derived cytokines, and the effects of catecholamine signaling on mitochondrial biogenesis, immunometabolism and the resulting inflammatory response. Here, we review the impact of acute and chronic exercise on adrenergic regulation of immunity in the context of aging, cancer, viral infections and inflammatory disease. We also put forth our contention that exercise interventions designed to improve immunity, prevent disease and reduce inflammation should consider the catecholamine-AR signaling axis as a therapeutic target and ask whether or not the adrenergic signaling machinery can be 'trained' to improve immune responses to stress, disease or during the normal physiological process of aging. Finally, we discuss potential strategies to augment leukocyte catecholamine signaling to boost the effects of exercise on immunity in individuals with desensitized β-ARs or limited exercise tolerance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) synthesized by endothelial cells and responsible for the regulation of blood pressure was purified from the bovine lung with affinity chromatography method. The purification rate of the ACE of the bovine lung was calculated as 1748- fold. Optimum pH and optimum temperature for the purified ACE were found to be 7.6 and 35-40 °C, respectively. The purity and molecular weight of the ACE were designated with SDS-PAGE. The ACE was found to have three subunits with molecular weights of 57 kDa, 66 kDa, and 190 kDa. Then, the total molecular weight of the ACE was designated as 303 kDa with gel filtration chromatography. The effects of ACE inhibitors captopril, fosinopril, lisinopril, and beta-blockers propranolol, atenolol, and diuretic triamterene on ACE activity were studied. ACE inhibitors lisinopril, captopril, fosinopril, and diuretic triamterene demonstrated an inhibition effect on ACE activity. Beta-blockers indicated no effect on ACE. IC 50 values of captopril, fosinopril, lisinopril, and triamterene from the graphical equation were calculated as 0.835 nM, 1.159 μM, 4.085 nM, and 227 μM, respectively. The inhibition type and K i values of these compounds were determined from Lineweaver-Burk plots. Captopril, fosinopril, lisinopril, and triamterene demonstrated a non-competitive inhibition effect on ACE activity. K i constants were found as 1.057 nM, 1.675 μM, 6.449 nM, and 419.5 μM, respectively. Captopril indicated the highest inhibitor effect with an IC 50 value of 0.835 nM., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The aim of our study was to investigate the benefit of antiarrhythmic drugs (AAD) - beta-blockers, sotalol or amiodarone - in a cohort of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) patients with long-term longitudinal follow up., Background: AAD are prescribed in ARVC to prevent ventricular arrhythmias and control symptoms. However, there are no controlled clinical trials and knowledges regarding the efficacy of AAD in ARVC are limited., Methods: The study population included 123 patients with definite diagnosis of ARVC and ≥ 2 clinical evaluations. The primary outcome was a composite of sudden cardiac death (SCD)/recurrent major ventricular arrythmias (MVA): sudden cardiac arrest, sustained ventricular tachycardia (VT) and appropriate implantable cardioverter defibrillator interventions, including recurrent events in patients with >1 MVA. Time to first event (SCD or MVA) was considered as secondary composite endpoint., Results: Sixteen patients were taking AAD at baseline and 75 started at least one AAD during a median follow-up of 132 months [61-255]. A total of 37 patients experienced ≥1 MVA with a total count of 83 recurrent MVA. After adoption of a propensity score analysis, no AAD were associated with lower risk of recurrent MVA. However, if dosage of AAD was considered, beta-blockers at >50% target dose were associated with a significant reduction in the risk of MVA compared to patients not taking beta-blockers (HR 0.10, 95% CI 0.02-0.46, p = 0.004)., Conclusions: In a large cohort of ARVC patients with a long-term follow-up, only beta-blockers administrated at >50% target dose were associated with lower risk of SCD/recurrent MVA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Beta-blockers (BB) are an heterogenous set of molecules actively blocking β adrenergic receptors. Their pharmacological properties depend on their various effects on the adrenergic signalling. Although they are no longer a first-choice treatment in hypertensive patients, they remain a cornerstone of pharmacological strategy in several cardiovascular diseases such as stable angina, heart failure, arrythmia and aortic related connective diseases. Beyond their usual non cardiovascular indications such as migraine, hepatic cirrhosis, glaucoma, infantile hemangioma, and hyperthyroidism, new therapeutic fields are under scrutiny. Potential BB therapeutic repurposing is being investigated in COPD and cancer patients. This narrative review first encompasses the basic pharmacological knowledge that may be useful for the clinician. Then it will detail BB main indications before exploring new therapeutic fields., (Copyright © 2020. Published by Elsevier Masson SAS.)

Background: Whether beta-blockers improve the clinical outcomes for heart failure with preserved ejection fraction (HFpEF) characterized by variable cardiac pathophysiology remains controversial. This study aimed to clarify cardiac dysfunction affecting the effectiveness of beta-blockers in patients with HFpEF., Methods: Four hundred and nine patients with HFpEF were enrolled retrospectively, and echocardiography and jugular venous pulse were examined to evaluate their cardiac function. The left ventricular (LV) ejection fraction, mean mitral e', mean mitral E/e' ratio, right ventricular (RV) systolic pressure, tricuspid annular plane systolic excursion, and jugular venous pulse waveform were used as indicators of LV contractility, LV relaxation ability, LV filling pressure, RV afterload, RV contractility, and RV diastolic function, respectively. The dominant 'Y' descent of the jugular venous waveform was detected as an established hemodynamic sign of a less-distensible right ventricle., Results: Two hundred and thirteen patients with HFpEF received beta-blockers. During a mean follow-up period of 33±20 months, 92 patients had cardiovascular events of HFpEF. A less-distensible right ventricle and RV systolic pressure were independent risk factors for cardiovascular events of HFpEF (p=0.016 and p=0.002, respectively). The administration of beta-blockers was not an independent factor, but patients with HFpEF and a distensible right ventricle who received them had fewer events than those who did not (p=0.017). Patients with HFpEF and lower RV systolic pressure (<33mmHg) who received beta-blockers also had fewer events than those who did not (p=0.028). A less-distensible right ventricle or higher RV systolic pressure (≥33mmHg) prevented the beneficial effects of beta-blockers for HFpEF., Conclusions: Beta-blocker usage was not associated with a reduction in the rate of cardiovascular events of HFpEF, but it may have beneficial effects on HFpEF with preserved RV function. RV function may serve as an indicator to administer beta-blockers to patients with HFpEF., (Copyright © 2020 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) with cardiovascular complications is very common. Due to fear of exacerbating airway spasm, β-blockers are rarely used in such patients. Many observational studies suggest that β-blockers can reduce the disease progression and the risk of mortality in patients with COPD, but lack of confirmation from randomized controlled trials. This article reviews the application of β-blockers in patients with COPD based on the results of the latest published randomized controlled trials., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

This work extends the present working range of isotachophoresis (ITP) with electrospray-ionization mass-spectrometric (ESI-MS) detection and describes for the first time a functional cationic electrolyte system for analyses at medium-alkaline pH. So far no ITP-MS application was published on the analysis of medium strong bases although there is a broad spectrum of potential analytes like biogenic amines, alkaloids or drugs, where this technique promises interesting gains in both sensitivity and specificity. The presented results include a selection of suitable sufficiently volatile ESI-compatible system components, discussion of factors affecting system properties, and recommendations for functional ITP electrolyte systems. Theoretical conclusions based on calculations and computer simulations are confirmed by experiments with a model mixture of beta-blockers. Practical applicability of the method is demonstrated on the example of analysis of sotalol in dried blood spots where direct injection of aqueous extract, ITP stacking and MS detection provide a fast, simple and sensitive technique with limits of quantitation on the sub-nM level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The pharmacological class of β-blockers includes a plea of molecules with largely different pharmacokinetic and pharmacodynamic characteristics with a protective effect that may span far beyond the cardiovascular system. Although all these compounds share the pharmacological blockade of the adrenergic receptors, each of them is characterized by specific pharmacological properties, including selectivity of action depending on the adrenergic receptors subtypes, intrinsic sympathomimetic activity (ISA), lipid solubility, pharmacokinetic profile, and also other ancillary properties that impact their clinical effect. Their use in the treatment of hypertension has been extensively debated and at the moment a class indication is not present. However, in specific niche of patients, such as in those young individuals in which hypertension is mainly driven by a sympathetic hyperactivation, strong evidence pose β-Blockers as a highly reasonable first-line treatment. Lipophilic β-blockers, specifically propranolol and metoprolol, can cross the Blood Brain Barrier and have a Class A indication for the prophylactic treatment of migraine attacks. Moreover, since β-adrenergic receptors affect the proliferative process of both cancer and immune cells, their blockade has been associated with metastasis reduction in several epithelial and solid organ tumors posing β-Blockers as a new attractive, inexpensive and relatively safe therapeutic strategy in patients with several types of cancer. However, further dedicated prospective, randomized, placebo-controlled studies are needed to determine the real efficacy of these compounds., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Atrial fibrillation and atrial flutter occur commonly in patients with heart failure. Ultrashort-acting β-blockers, including landiolol, can rapidly control heart rate. As part of postmarketing surveillance for landiolol in Japan, a real-world drug-use survey (AF-CHF landiolol survey) was established for the treatment of atrial fibrillation and atrial flutter in patients with heart failure. We report the safety and effectiveness of landiolol from this survey, focusing on adverse events/adverse drug reactions., Methods: Consecutive patients with cardiac dysfunction who received landiolol (continuous intravenous infusion, starting at 1μg/kg/min) for atrial fibrillation or atrial flutter in routine clinical practice in Japan were enrolled between June 2014 and May 2016. Safety variables included adverse events and adverse drug reactions (number of patients and events, incidence rate, types, seriousness). Effectiveness variables included the proportion of patients with a ≥20% decrease in heart rate., Results: Data were available for 1121 patients (safety analysis set); 888 patients were evaluable for effectiveness parameters. Mean (± standard deviation) patient age was 72.5±13.5 years, 57.2% were male. Most patients (84.2%) received landiolol for atrial fibrillation. Overall, 174 adverse events occurred in 140 patients (12.5%), including 105 serious adverse events. The most common type of adverse events was cardiac (60 events). Seventy-five events in 63 patients were categorized as adverse drug reactions (5.6% of patients). Mean heart rate decreased substantially after treatment with landiolol, by ≥20% in 77.5% of patients., Conclusions: In a real-world setting in Japan, landiolol for the treatment of atrial fibrillation or atrial flutter with heart failure was acceptable without new safety concerns, and most patients achieved effective heart rate control during their arrhythmias., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Heart failure (HF) and chronic obstructive pulmonary disease (COPD) coincide in a significant number of patients. Recent population-based registries suggest that spirometry is largely underused in patients with HF to diagnose comorbid COPD and that patients with COPD frequently do not receive the recommended beta-blocker (BB) treatment. This state-of-the-art review summarizes: 1) current challenges in the implementation of recommended spirometry for COPD diagnosis in patients with HF; and 2) current underuse and underdosing of BBs in patients with HF and COPD despite guideline recommendations. Open issues in the therapeutic management of patients with HF and COPD are discussed in the third section, including the use of the nonselective BB carvedilol, target BB doses in patients with HF and COPD, BB and bronchodilator management during HF hospitalization with and without COPD exacerbation, and the use of BBs in patients with COPD with right HF or free from cardiovascular disease. The whole scenario described herein advocates for a bipartisan initiative to drive immediate attention to the translation of guideline recommendations into clinical practice for patients with HF with co-occurring COPD., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Recent decades have revealed a growing use of medicines for non-disease conditions, especially among university students. The prevalence rates for the use of study drugs (SDs), i.e. prescription stimulants and β-blockers, range from 2 to 20% among students worldwide. However, SD use does not take place in a vacuum. Like any other health-related behavior, medicine use takes place in specific social and cultural contexts, and there is very little scholarly work on these contextual aspects of SD use., Objective: This article aims to explore university students' use of SDs through the perceptions and practices of university counselors, general practitioners (GPs), psychiatrists, and from student polls in Denmark, in order to advocate for a contextual approach to SD use., Methods: The article relies on data from three different data sets involving a total of 18 semi-structured interviews, seven study counselors, nine GPs, and two psychiatrists, as well as votes from eight in-class polls conducted among approximately 300 university students in total. Data were collected between 2012 and 2017 and analyzed through meaning condensation and categorization., Results: The study shows that a great variety of perceptions and practices concerning SDs exists. While study counselors generally do not hear much about SDs from students, except for those seeking help with regard to β-blockers, they link the pressure, competition and perfectionism among students to a more general explanation of why some students may feel the need to use SDs. GPs meet students seeking SDs, but differ significantly in how they align their perceptions with their prescribing practices. The psychiatrists who participated in the study expressed widely different perceptions and practices regarding SDs. Finally, student polls indicate that students' opinions on SDs are also highly divided., Conclusion: The lack of consensus on SDs among professionals in health and education may contribute to students' divided opinions about SDs, just as it provides students with an opportunity to legitimize their use of SDs., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: This study sought to assess the safety of carvedilol therapy among heart failure (HF) patients with a cocaine-use disorder (CUD)., Background: Although carvedilol therapy is recommended among certain patients with HF, the safety and efficacy of carvedilol among HF patients with a CUD is unknown., Methods: This was a single-center study of hospitalized patients with HF. Cocaine use was self-reported or defined as having a positive urine toxicology. Patients were divided by carvedilol prescription. Subgroup analyses were performed by strata of ejection fraction (EF) ≤40%, 41% to 49%, or ≥50%. Major adverse cardiovascular events (MACE) were defined as cardiovascular mortality and 30-day HF readmission., Results: From a cohort of 2,578 patients hospitalized with HF in 2011, 503 patients with a CUD were identified, among whom 404 (80%) were prescribed carvedilol, and 99 (20%) were not. Both groups had similar characteristics; however, those prescribed carvedilol had a lower LVEF, heart rate, and N-terminal pro-B-type natriuretic peptide concentrations at admission and on discharge, and more coronary artery disease. Over a median follow-up of 19 months, there were 169 MACEs. The MACE rates were similar between the carvedilol and the non-carvedilol groups (32% vs. 38%, respectively; p = 0.16) and between those with a preserved EF (30% vs. 33%, respectively; p = 0.48) and were lower in patients with a reduced EF taking carvedilol (34% vs. 58%, respectively; p = 0.02). In a multivariate model, carvedilol therapy was associated with lower MACE among patients with HF with a CUD (hazard ratio: 0.67; 95% confidence interval; 0.481 to 0.863)., Conclusions: Our findings suggest that carvedilol therapy is safe for patients with HF with a CUD and may be effective among those with a reduced EF., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)