Effects Of Beta-blockers Research Articles

Effects of beta blockers on outcome in patients with PAH with and without comorbid conditions: a Multicenter Prospective Cohort Study (BNP-PL)

Abstract Background The current guidelines do not recommend the use of beta-blockers (BB) in patients with pulmonary arterial hypertension (PAH) unless necessitated by comorbidities. However, the evidence regarding the role of BB in PAH is contradictory. This study investigates the effects of BB on clinical outcomes in patients newly diagnosed with PAH, stratified by the presence of cardiovascular comorbidities that justify their use. Methods We analyzed data from 806 patients newly diagnosed with PAH, who were prospectively enrolled from March 1, 2018, to August 31, 2023, in the multicentre registry, Database of Pulmonary Hypertension in the Polish population (BNP-PL). The primary endpoints were all-cause mortality and a composite of hospitalization due to right heart exacerbation, syncope, or death. The follow-up period for these patients extended until August 31, 2023. Comorbidities in the study group that indicated the need for BB therapy included hypertension, significant arrhythmia, and coronary artery disease. In the Cox regression analysis, the association between BB use and the predefined endpoints was adjusted for age, baseline European Society of Cardiology risk score, and upfront therapy. Results Among the 806 patients, BBs were administered to 469 (58.2%) at the time of PAH diagnosis. In the entire cohort, BB therapy was linked to increased all-cause mortality (29.6% vs 21.4%; p=0.005, Fig 1.A) and a higher incidence of the composite endpoint (34.1% vs 22.6%; p<0.0001, Fig 1.B). The Number Needed to Harm (NNH) for BB treatment, regarding mortality and the composite endpoint, were 12.1 and 8.7, respectively. In patients without comorbidities, BB use significantly raised the risk of both all-cause mortality (Hazard Ratio [HR] 1.81, 95% Confidence Interval [CI]: 1.01-3.15) and the composite endpoint (HR 1.85, 95% CI 1.09-3.14), after adjustments for age, baseline three-strata PAH mortality risk, and upfront therapy. However, in patients with at least one comorbidity, BB therapy showed a neutral effect on both outcomes. Across the whole group, the use of nonselective BB was associated with a higher risk of the composite endpoint (HR 1.78, 95% CI 1.13-2.82, p=0.01) compared to selective β1 agents, although this did not extend to all-cause mortality (HR 1.34, 95% CI 0.79-2.25, p=0.28). Conclusion BBs, particularly nonselective, pose significant risks in patients with PAH who lack comorbidities that justify their use.

Continuation of beta-blockers at discharge is associated with improved outcome in patients with HFpEF and concomitant moderate aortic stenosis

Abstract Background In patients with severe aortic stenosis or decompensated heart failure with preserved ejection fraction (HFpEF), beta-blockers are usually discontinued despite the absence of unequivocal evidence. The data on the effect of beta-blockers in patients with moderate aortic stenosis (MAS) are scarce. Aim To investigate the relationship between beta-blocker use and outcome in patients with MAS, who were hospitalized for decompensated HFpEF. Methods The current study includes 61 patients admitted for decompensated HFpEF with concomitant MAS. The mean age of the population was 82.7±7.59 years old and 41% were females. The diagnosis MAS was established on criteria including aortic valve area between 1-1.5 cm², mean gradient - 20-39 mmHg, and max velocity between 3-3.9 m/s. For those with borderline measurements, the Doppler Velocity Index (DVI) was calculated (DVI < 0.25 indicates severe aortic stenosis). All echocardiographic data were assessed by an experienced echocardiographer. Patients with previous aortic valve replacement and a severe mixed of multivalvular disease were excluded. Result The median follow-up was 52 months (interquartile range 34-63 months). During this period 38 patients (62.3%) died from any cause while 42 (68.9%) individuals experienced a composite endpoint, of all-cause death or hospitalization due to worsening HFpEF. In survivors, we observed higher prescription of beta-blockers at hospital discharge (66% vs. 34%, p<0,05) and better diastolic function than in patients with endpoints. In multivariate Cox regression analysis the use of beta-blockers (HR = 0,27; 95% CI 0,13-0,57; p<0.01) and better diastolic function, defined as higher septal e` (HR=0,76; 95% CI 0,61-0,94; p=0.01) were identified as independent predictors for both - survival and composite endpoint (Figure 1). Advanced age was recognized as an associated factor for outcomes. Conclusion In the present study, continuation of beta-blockers at discharge was independently associated with better survival in patients with decompensated HFpEF and concomitant MAS. It remains to be addressed in future studies, whether or not beta-blockers should be started in these patients or if there is any prognostic interaction between beta-blockers and aortic valve intervention for MAS.Figure 1.Kaplan-Meier survival curve

Mortality effects of beta-blockers on myocardial infarction in patients without reduced ejection fraction or heart failure in the contemporary reperfusion era : a systematic review and meta-analysis

Abstract Background The 2023 ESC and AHA/ACC guidelines note that contemporary data are heterogenous regarding the use of beta-blockers (BB) post-myocardial infarction (MI) in patients without reduced ejection fraction (EF) or heart failure (HF). Purpose We performed a systematic review and meta-analysis to address the heterogeneity in existing literature around BB post-MI in patients without HF. Methods We searched 6 databases from Jan 1, 2000 to Jan 12, 2024 to identify modern randomized controlled trials (RCTs) or observational studies enrolling MI patients without reduced EF or history of HF who received BB at index MI, and comparing outcomes between BB users and non-users. Reduced EF was defined as EF ≤40%. The primary outcome was all-cause death. Subgroup analyses and meta-regression were conducted to explore heterogeneity. Meta-analysis was conducted using the restricted maximum likelihood method. Results There were 22 studies, including 1 RCT, involving 281,631 patients enrolled between 1997 and 2020. BB did not confer a significant reduction in all-cause death in patients with a 1-year event-free period (HR, 0.99; 95% CI, 0.94 to 1.06; I2 = 0%; Figure 1A), defined as no death, recurrent MI, or HF while on BB following index MI. In patients with a 3-year event-free period, a non-significant trend towards increased all-cause mortality was observed in BB users (HR, 1.39; 95% CI, 0.81 to 2.40; I2 = 0%; Figure 1A). For patients without a stable period, meta-regression showed BB morality benefits were modified by study inclusion period (P = 0.01; R2 = 51%; Figure 1B), indicating a temporal trend of decreasing mortality benefits of BB over time. Of note, BB exhibited no mortality benefits in patients enrolled after 2010 (HR, 0.97; 95% CI, 0.90 to 1.04; I2 = 0%; Figure 1C). Subgroup analysis showed BB led to a significantly lower all-cause death in patients with mildly-reduced EF (HR, 0.79; 95% CI, 0.68 to 0.91; I2 = 0%; Figure 2A). No mortality benefit of BB was observed in patients with preserved EF (HR, 0.83; 95% CI, 0.68 to 1.02; I2 = 66%; Figure 2A), however, with high statistical heterogeneity. Further exploration of this heterogeneity via meta-regression revealed a pronounced temporal trend of decreasing BB mortality benefits in patients with preserved EF (P <.0001; R2 = 100%; Figure 2B). The R2 value rising from 51% to 100% suggests that unexplained 49% heterogeneity is attributed to mildly-reduced EF patients. Similarly, BB's mortality benefit was not significant in patients enrolled after 2010 (HR, 1.02; 95% CI, 0.95 to 1.09; I2 = 0%; Figure 2C). Conclusion In the contemporary reperfusion era, BB do not confer additional mortality benefits beyond a 1-year event-free period post-MI in patients without reduced EF. Moreover, given the temporal decreases in observed mortality benefits, especially in studies post-2010, BB may not remain an essential medication in post-MI care for patients with preserved EF in modern practice.Patients with/without a stable periodMildly-reduced and preserved EF patients

Short- and long-term effects of beta-blockers on symptoms of anxiety and depression in patients with myocardial infarction and preserved left ventricular function: a pre-specified quality of life sub-study from the REDUCE-AMI trial.

Among patients with myocardial infarction (MI) with preserved left ventricular ejection fraction (LVEF), the REDUCE-AMI trial did not demonstrate a benefit of beta-blocker vs. no beta-blocker treatment on all-cause mortality and recurrent myocardial infarction. The aim of this pre-specified sub-study was to investigate effects of beta-blockers on self-reported symptoms of anxiety and depression. In this parallel-group, open-label, registry-based randomized trial, assessments with the Hospital Anxiety and Depression Scale were obtained at hospitalization and two follow-up points (6-10 weeks and 12-14 months) after MI. Analyses were based on the intention-to-treat principle using linear mixed models, calculating both short- and long-term effects. From August 2018 through June 2022, 806 patients were enrolled. At baseline, 27% of patients were possible cases of anxiety (m, 5.6; SD, 3.9) and 14% were possible cases of depression (m, 3.9; SD, 3.2). Beta-blocker treatment had a negative effect on depressive symptoms at both follow-ups 1 (β = 0.48; 95% CI 09-0.86; P = 0.015) and 2 (β = 0.41; 95% CI = 0.01-0.81; P = 0.047), but no effect on anxiety. Beta-blocker treatment led to a modest increase in depressive symptoms among MI patients with preserved LVEF. This observed effect was most pronounced in individuals with prior beta-blocker treatment. In routine initiation and continuation of beta-blocker treatment, a risk of slightly increased depressive symptoms should be considered.

TCT-38 The Effect of Beta-Blocker on Distal Aorta and Remnant False Lumen in the Distal Thoracic Residual Aorta After Surgery With Frozen Elephant Trunk Technique in Patients With Type A Aortic Dissection

TCT-38 The Effect of Beta-Blocker on Distal Aorta and Remnant False Lumen in the Distal Thoracic Residual Aorta After Surgery With Frozen Elephant Trunk Technique in Patients With Type A Aortic Dissection

Beta-Blocker in Heart Rate Control and Cardio Protection: The Role of ADRB1 Variants and HCN4 Regulation – A Systematic Review

Elevated heart rate is linked to adverse cardiovascular outcomes. Sinoatrial (SA) nodes, hyperpolarization-activated cyclic nucleotide-gated-4 (HCN4) channels, and beta1-adrenergic receptor (ADRB1) are responsible for generating the heart rate. Beta-blockers have a cardioprotective effect on heart failure, including controlling heart rate. However, the responses to beta-blockers can vary among individuals. ADRB1 genetic variability may be contributed to the differential beta-blocker effect in heart failure. HCN4 also performs a crucial function in the pacemaker cells of the heart. Exploring the effect of beta-blockers in pacemaker cells is expanding the view of their role and their therapeutic response in heart failure. The objectives of this study were to identify ADRB1 genetic variants affecting heart rate response in heart failure subjects with beta-blocker treatment and to explore the effect of beta-blockers on HCN4 channels and SA nodes. A systematic review was performed using three databases. Eight of 668 manuscripts were selected. The systematic review found that ADRB1 genetic variants (A145G (Ser49Gly) and C1165G (Arg389Gly)) can affect heart rate response in beta-blocker-treated heart failure. The study also found that the percentage of patients with the Ser49Ser-Gly389X haplotype achieved a heart rate target was higher than other haplotypes. Individuals with the Arg389Arg genotype necessitated a markedly increased amount of beta-blocker dose to reach the identical heart rate target compared to those with the Gly389X gene variation. In addition, the review found that carvedilol, a beta-blocker derivative, demonstrated beneficial effects in inhibiting HCN-gated channels. Bisoprolol and carvedilol improved channel regulation in the SA Node by reversing the downregulation of HCN4 and sodium channels. In general, this systematic review provides important insights into beta-blockers in treating heart failure, specifically concerning the genetic variability of ADRB1 and the beta-blockers effect on the SA node and HCN4 channels.

Effects of beta-blockers on quality of life and well-being in patients with myocardial infarction and preserved left ventricular function-a prespecified substudy from REDUCE-AMI.

In the Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) study, long-term beta-blocker use in patients after acute myocardial infarction (AMI) with preserved left ventricular ejection fraction demonstrated no effect on death or cardiovascular outcomes. The aim of this prespecified substudy was to investigate effects of beta-blockers on self-reported quality of life and well-being. From this parallel-group, open-label, registry-based randomized clinical trial, EQ-5D, and World Health Organization well-being index-5 (WHO-5) questionnaires were obtained at 6-10 weeks and 11-13 months after AMI in 4080 and 806 patients, respectively. We report results from intention-to-treat and on-treatment analyses for the overall population and relevant subgroups using Wilcoxon rank sum test and adjusted ordinal regression analyses. Of the 4080 individuals reporting EQ-5D (median age 64 years, 22% female), 2023 were randomized to beta-blockers. The main outcome, median EQ-5D index score, was 0.94 [interquartile range (IQR) 0.88, 0.97] in the beta-blocker group, and 0.94 (IQR 0.88, 0.97) in the no-beta-blocker group 6-10 weeks after AMI, OR 1.00 [95% CI 0.89-1.13; P>0.9]. After 11-13 months, results remained unchanged. Findings were robust in on-treatment analyses and across relevant subgroups. Secondary outcomes, EQ-VAS and WHO-5 index score, confirmed these results. Among patients after AMI with preserved left ventricular ejection fraction, self-reported quality of life and well-being was not significantly different in individuals randomized to routine long-term beta-blocker therapy as compared to individuals with no beta-blocker use. These results appear consistent regardless of adherence to randomized treatment and across subgroups which emphasizes the need for a careful individual risk-benefit evaluation prior to initiation of beta-blocker treatment.

Beta-blockers and their impact on metabolic processes

The aim of the study is to determine the effect of beta-blockers on lipid status, triglycerides and Body Mass Index (BMI) in patients using beta-blockers in the treatment of arterial hypertension. Our study included 120 patients at the Public Health Institution "Dom zdravlja" Živinice. The participants were monitored over a period of 3 years. Measurements were made after 12, 24 and 36 months of treatment. Patients were divided into two groups. The experimental group included 60 patients, who used beta-blockers in the treatment of arterial hypertension. The control group included 60 patients who used other antihypertensives as their first choice medication in the treatment of arterial hypertension. By monitoring cholesterol and triglyceride levels in patients using beta-blockers and other antihypertensive medications, and comparing these values within the group, no statistically significant difference in cholesterol and triglyceride levels was found in patients who used beta-blockers after 12, 24, and 36 months of treatment. There was also no statistically significant effect of therapy on the change in cholesterol and triglyceride values at observed time intervals, nor was there a statistically significant difference between these values. BMI monitoring showed a statistically significant difference between patients using beta-blockers and other antihypertensive drugs, with patients using beta-blockers having a higher BMI after 36 months of treatment. There was no statistically significant difference in BMI between patients using bisoprolol and carvedilol and patients using other beta-blockers, but patients using bisoprolol and carvedilol had lower BMI values. In studies conducted in recent years, it has been noted that many beta-blockers cause dose-dependent adverse metabolic effects on glucose and lipid metabolism, with the most adverse metabolic effects observed in patients treated with conventional non-selective beta-blockers. On the other hand, more favorable metabolic profile have drugs with β1 selective activity, such as atenolol and metoprolol, especially those with intrinsic sympathomimetic activity such as pindolol. In fact, with these beta-blockers, the adverse metabolic effects appear to be less prominent. In conclusion, beta-blockers do not lead to an increase in cholesterol and triglycerides, but they do lead to an increase in BMI in patients with arterial hypertension

Beta-Blockers of Different Generations: Features of Influence on the Disturbances of Myocardial Energy Metabolism in Doxorubicin-Induced Chronic Heart Failure in Rats.

Beta-blockers are first-line drugs in the treatment of chronic heart failure (CHF). However, there is no consensus on the specific effects of the beta-blockers of the I-III generation on energy metabolism in CHF. The aim of this study is to conduct a study of beta-blockers of different generations on myocardial energy metabolism in experimental CHF. CHF was modeled in white outbred rats by administering doxorubicin. The study drugs were administered intragastrically-new drug Hypertril (1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide)-3.5 mg/kg, Metoprolol-15 mg/kg, Nebivolol -10 mg/kg, Carvedilol 50 mg/kg, and Bisoprolol, 10 mg/kg. In the myocardium, the main indices of energy metabolism were determined-ATP, ADP, AMP, malate, lactate, pyruvate, succinate dehydrogenase (SDH) activity, and NAD-dependent malate dehydrogenase (NAD-MDH) activity. Traditional second-generation beta-blockers (Metoprolol and Bisoprolol) did not affect the studied indices of energy metabolism, and third-generation beta-blockers with additional properties-Carvedilol and, especially, Nebivalol and Hypertril-improved myocardial energy metabolism. The obtained results will help to expand our understanding of the effect of beta-blockers of various generations used to treat cardiovascular diseases on energy metabolism, and are also an experimental justification for the practical choice of these drugs in the complex therapy of CHF.

Predicting factors for omitting beta-blockers in patients with tachycardia-induced cardiomyopathy after successful catheter ablation for atrial fibrillation.

Tachycardia induces a reduction in the left ventricular ejection fraction (LVEF), which is defined as tachycardia-induced cardiomyopathy (TIC). Conversion to and maintenance of sinus rhythm by catheter ablation can improve LVEF in patients with TIC due to atrial fibrillation (AF). Beta-blockers are mandatory for the treatment of heart failure with reduced LVEF(HFrEF), but the necessity of beta-blockers in TIC patients even after catheter ablation remains unclear. We examined the effect of beta-blockers on cardiac function in TIC patients after catheter ablation. We retrospectively analyzed 124 patients with a history of heart failure and an LVEF of ≤ 50% who underwent catheter ablation for AF. TIC was defined as a ≥ 10% improvement in the baseline LVEF and an improvement to an LVEF of ≥ 50% at 6months after ablation. Patients with other cardiomyopathy diagnosed before the ablation were excluded. LVEF was significantly increased with the reductions of the left ventricular and left atrial volumes at the 6-month follow-up in all 80 patients with TIC. No beta-blockers were prescribed during the post-ablation follow-up in 21 patients with TIC. The absolute values of and changes in the echocardiographic parameters between before and after ablation were not significantly different between patients with and without beta-blockers after the ablation. A simple score using the history of hospitalization for heart failure and use of beta-blockers or diuretics prior to ablation was useful in identifying TIC patients who did not need prescription of beta-blockers after catheter ablation. LVEF similarly improved in both patients with and without prescription of beta-blockers after the ablation. Beta-blockers may not need to be prescribed after successful catheter ablation for AF in LVEF of ≤ 50% patients without other cause of cardiomyopathy diagnosed before the ablation, a history of hospitalization for heart failure and prescription of beta-blockers and diuretics before the ablation.

Beta-blockers and their impact on blood pressure and heart rate

The aim of the study is to determine the impact of beta-blockers on blood pressure and heart rate in patients that use these drugs during treatment of arterial hypertension. The sample included 120 patients from the "Dom Zdravlja'' Živinice. Patients were monitored for 3 years. No statistically significant difference in the values of systolic and diastolic blood pressure as well as heart rate in patients using beta-blockers and other groups of antihypertensives was determined during monitoring period after 12, 24 and 36 months of treatment. Also, there was no statistically significant impact of the applied therapy on these values in the observed time intervals. In order to determine statistically significant difference between treatments, we compared their values sorted by time. No statistically significant difference was found in systolic blood pressure and heart rate between groups, but a statistically significant difference in diastolic blood pressure was found between groups after 12 and 36 months of therapy. No statistically significant difference was found in the values of systolic and diastolic blood pressure, as well as heart rate after 12, 24 and 36 months of treatment by comparing the same values within the group of beta-blockers (patients using bisoprolol and carvedilol and patients using other beta-blockers). Also, there was no statistically significant impact of the applied therapy on the change of these values during observed period. In order to determine statistically significant difference between the treatments, we compared their values sorted by time. There was no statistically significant difference in the values of systolic and diastolic blood pressure and heart rate between the groups. Also, the condition of patients who used beta-blockers in the treatment of hypertension did not require increasing the dose in order to achieve the required parameters. Therefore, in our research, haven't been proven the worse effect of beta-blockers on blood pressure and heart rate when compared to other antihypertensive drugs. Also, all drugs showed equal effectiveness within the group of beta-blockers.

Beta-Blockers as an Immunologic and Autonomic Manipulator in Critically Ill Patients: A Review of the Recent Literature.

The autonomic nervous system plays a key role in maintaining body hemostasis through both the sympathetic and parasympathetic nervous systems. Sympathetic overstimulation as a reflex to multiple pathologies, such as septic shock, brain injury, cardiogenic shock, and cardiac arrest, could be harmful and lead to autonomic and immunologic dysfunction. The continuous stimulation of the beta receptors on immune cells has an inhibitory effect on these cells and may lead to immunologic dysfunction through enhancing the production of anti-inflammatory cytokines, such as interleukin-10 (IL-10), and inhibiting the production of pro-inflammatory factors, such as interleukin-1B IL-1B and tissue necrotizing factor-alpha (TNF-alpha). Sympathetic overstimulation-induced autonomic dysfunction may also happen due to adrenergic receptor insensitivity or downregulation. Administering anti-adrenergic medication, such as beta-blockers, is a promising treatment to compensate against the undesired effects of adrenergic surge. Despite many misconceptions about beta-blockers, beta-blockers have shown a promising effect in decreasing mortality in patients with critical illness. In this review, we summarize the recently published articles that have discussed using beta-blockers as a promising treatment to decrease mortality in critically ill patients, such as patients with septic shock, traumatic brain injury, cardiogenic shock, acute decompensated heart failure, and electrical storm. We also discuss the potential pathophysiology of beta-blockers in various types of critical illness. More clinical trials are encouraged to evaluate the safety and effectiveness of beta-blockers in improving mortality among critically ill patients.

The multifaceted role of beta-blockers in overcoming cancer progression and drug resistance: Extending beyond cardiovascular disorders.

Beta-blockers are commonly used medications that antagonize β-adrenoceptors, reducing sympathetic nervous system activity. Emerging evidence suggests that beta-blockers may also have anticancer effects and help overcome drug resistance in cancer treatment. This review summarizes the contribution of different isoforms of beta-adrenoceptors in cancer progression, the current preclinical and clinical data on associations between beta-blockers use and cancer outcomes, as well as their ability to enhance responses to chemotherapy and other standard therapies. We discuss proposed mechanisms, including effects on angiogenesis, metastasis, cancer stem cells, and apoptotic pathways. Overall, results from epidemiological studies and small clinical trials largely indicate the beneficial effects of beta-blockers on cancer progression and drug resistance. However, larger randomized controlled trials are needed to firmly establish their clinical efficacy and optimal utilization as adjuvant agents in cancer therapy.

P-035 Catecholamine neuroreceptors are differentially located in functional regions of the human sperm

Abstract Study question How are the expression and distribution of Adrenergic and Dopamine receptors in human sperm cells? Summary answer Using ultra-high-resolution microscopy techniques, we identified that each type of catecholamine receptor is expressed in a different functional region of the human sperm. What is known already Human sperm present complex cell signalling complexes with several neuroreceptors in their membrane. The spermatozoa is a terminal differentiated cell showing specialized regions optimized for physiological processes like motility, acrosome reaction and membrane fusion during fertilization. Although indirect methods have determined the presence of catecholamine receptors in human sperm, there is no direct evidence nor description of the exact localisation of these receptors. Catecholamine receptors are the direct target of medications used to treat very frequent health problems like hypertension (beta blockers), asthma (bronchodilators) and mental health disorders (antipsychotics and antidepressants). Study design, size, duration We design the study by developing new techniques that allow us to use high-resolution microscopes (i.e. Laser Scanning Confocal Microscopy LSCM and Field Emission Scanning Electron Microscopy or FE-SEM) to identify the localisation and distribution of catecholamine receptors. We determined sperm functional regions and quantified the relative amount of the different receptors on each one of those regions to perform a statistical analysis. Participants/materials, setting, methods After informed consent and ethical approval, sperm from young, healthy donors (n = 20) were included in the study. We used the neuroblastoma cell line SH-SY5Y as a positive control. Immunolabelling techniques used specific primary antibodies for each receptor, followed by the gold-conjugated secondary antibodies for FE-SEM. Negative controls were performed by omitting the primary antibody. In FE-SEM images, we quantify the number of gold nanoparticles in the sperm cells and the background. Main results and the role of chance We confirm the differential localisation of the different receptors studied. Dopamine D2 receptors are mainly expressed on the equatorial band of the acrosome, while beta-adrenergic receptors are restricted to the terminal piece of the flagellum. In both cases, the mean number of gold particles showed statistical differences (p < 0,001) between the region of expression and the rest of the regions and the background. Limitations, reasons for caution The present study only shows the presence of the receptors on the sperm plasma membrane. The activity of those receptors should be investigated by developing bioassays based on the use of agonists and/or antagonists. A more reliable genetic overexpression or knockout approach was impossible in human sperm. Wider implications of the findings The presence of receptors on restricted regions of the sperm suggests their participation in critical physiological events, like regulation of sperm motility hyperactivation or acrosome reaction. It may also suggest a possible side effect of beta-blockers or bronchodilators with the male fertility potential that needs to be investigated. Trial registration number not applicable

The heart rate response to the 6-min walk test in atrial fibrillation patients with or without beta-blockers: Referring to patients with sinus rhythm.

The aim was to evaluate the effect of beta-blockers (BB) on the response of heart rate (HR) to 6-min walk test (6MWT) in atrial fibrillation (AF) and whether the AF patients treated with BB have a similar HR response to 6MWT as the AF and sinus rhythm (SR) patients without BB treatment at the same resting HR level. The before-after study involving 74 AF patients was to evaluate the effect of BB treatment (pre-BB and with BB). The comparison study included 74 BB-treated AF patients (with BB), 74 matched AF patients without BB (no BB), and 74 SR patients. The percentage increase amplitude of HR (HR-PIA) in 6MWT was calculated: [(the exercise HR - the resting HR)/(the resting HR)] × 100%. The before-after study showed that BB treatment decreased the resting and mean exercise HR (98.6 ± 15.2 vs. 85.5 ± 11.2 bpm and 121.3 ± 17.3 vs. 109.0 ± 16.7 bpm) during 6MWT. The comparison study demonstrated that against the SR, the AF with BB and no BB groups have higher mean exercise HR-PIA (28.2 ± 17.1% and 22.0 ± 9.6%, vs. 6.9 ± 3.7%) when their resting HR is similar. Moreover, the mean exercise HR-PIA was also significantly higher in the with BB group than in the no BB group. In AF patients with relatively higher resting HR, BB treatment could decrease the resting and exercise HR during 6MWT. However, BB treatment could not effectively attenuate the exercise HR rise as compared with AF without BB treatment, even with similar resting HR levels.

Identifying target populations to align with decision makers' needs.

Randomized trials estimate the average treatment effect within individuals that are eligible, invited and agree to enroll. However, decision makers often require evidence that extends beyond the trial's enrolled population to inform policy or actions for their specific target population. Each decision maker has distinct target populations, the composition of which may not often align with that of the trial population. As researchers, we should identify a decision maker for whom we aim to generate evidence early in the research process. We can then specify a target population of their interest and determine if a policy or action can be informed using results from a trial alone, or if additional complementary real-world data and analysis are required. In this commentary, we outline five key groupings of decision makers: policymakers, payers, purchasers, providers, and patients. We then specify relevant target populations for decision makers interested in the effectiveness of beta-blockers following a myocardial infarction with preserved ejection fraction. Finally, we summarize the scenarios in which results from a randomized trial may or may not apply to these target populations and suggest relevant analytic approaches that can generate evidence to better align with a decision makers' needs.

Beta-blockade for the treatment of refractory hypoxaemia during venovenous extracorporeal membrane oxygenation: An in-silico study.

Venovenous extracorporeal membrane oxygenation (VV ECMO) is used for refractory hypoxemia, although despite this, in high cardiac output states, hypoxaemia may persist. The administration of beta-blockers has been suggested as an approach in this scenario, however the physiological consequences of this intervention are not clear. We performed an in-silico study using a previously described mathematical model to evaluate the effect of beta-blockade on mixed venous and arterial saturations (, SaO2), in three different clinical scenarios and considered the potential effects of beta-blockers on, cardiac output, oxygen consumption and recirculation. Additionally we assessed the interaction of beta-blockade with haemoglobin concentration. In scenario 1: simulating a patient with high cardiac output and partial lung shunt decreased from increased 53.5% to 44.7% despite SaO2 rising from 74.2% to 79.2%. In scenario 2 simulating a patient with high cardiac output and complete lung shunt remained unchanged at 52.2% and SaO2 rose from 71.9% to 85%. In scenario 3 a patient with normal cardiac output and high recirculation fell from 50.8% to 25.5% and also fell from 82.4% to to 78.3%. Across the remaining modelling examples the effect on varied but oxygen delivery was consistently reduced across all scenarios. The administration of beta-blockers for refractory hypoxemia during VV ECMO are unpredictable and may reduce oxygen delivery, although this will vary with patient and circuit features. This study does not support the use of beta-blockers for this indication.

Perinatal outcomes after in-utero exposure to beta-blockers in women with heart disease: Data from the ESC EORP registry of pregnancy and cardiac disease (ROPAC)

BackgroundBeta-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. MethodsIn 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). ResultsBeta-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. ConclusionsIn 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.

Combination therapy of beta-blockers and digoxin is associated with increased risk of major adverse cardiovascular events and all-cause mortality in patients with atrial fibrillation: a report from the GLORIA–AF registry

The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV) outcomes and death rates among patients with atrial fibrillation (AF) who were prescribed with beta-blockers, digoxin or combination therapy. Data from phase II/III of the prospective Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA–AF) were analysed. The risk of major cardiovascular events (MACE) and death among patients with different prescriptions using COX proportional hazard regression was considered. Propensity score (PS) matching and weighting were further used to adjust for potential confounders of prescription use. A total of 14,201 patients [median age: 71.0 (IQR 64.0–77.0) years; 46.2% female] were recruited. After a median follow-up of 3.0 (IQR 2.4–3.1) years, 864 MACE, and 988 all-cause deaths were recorded. The incidence rate (IR) of MACE was 22.4 (95%CI 21.0–24.0) per 1000 person-years, while the IR of all-cause death was 25.4 (95%CI 23.8–27.0) per 1000 person-years. After multivariate adjustment with Cox regression, the risk of MACE (HR 1.35, 95% CI 1.09–1.68) and the risk of all-cause death (HR 1.28, 95%CI 1.04–1.57) were significantly higher in the combination therapy group, compared to the beta-blockers alone group. The risks of MACE and all-cause death remained significant in both PS matched and PS weighted cohort Among AF patients, combination therapy of beta-blockers and digoxin was associated with higher risks of MACE and all-cause death compared to beta-blockers alone.

Use of beta-blockers in patients with ductal carcinoma in situ and risk of invasive breast cancer recurrence: a Swedish retrospective cohort study

BackgroundRetrospective observational studies suggest a potential role of beta-blockers as a protective strategy against progression and metastasis in invasive breast cancer. In this context, we investigated the impact of beta-blocker exposure on risk for progression to invasive breast cancer after diagnosis of ductal cancer in situ (DCIS).MethodsThe retrospective study population included 2535 women diagnosed with pure DCIS between 2006 and2012 in three healthcare regions in SwedenExposure to beta-blocker was quantified using a time-varying percentage of days with medication available. The absolute risk was quantified using cumulative incidence functions and cox models were applied to quantify the association between beta-blocker exposure and time from DCIS diagnosis to invasive breast cancer, accounting for delayed effects, competing risks and pre-specified confounders.ResultsThe median follow-up was 8.7 years. One third of the patients in our cohort were exposed to beta-blockers post DCIS diagnosis. During the study period, 48 patients experienced an invasive recurrence, giving a cumulative incidence of invasive breast cancer progression of 1.8% at five years. The cumulative exposure to beta-blocker was associated with a reduced risk in a dose-dependent manner, though the effect was not statistically significant.ConclusionOur observational study is suggestive of a protective effect of beta-blockers against invasive breast cancer after primary DCIS diagnosis. These results provide rationales for experimental and clinical follow-up studies in carefully selected DCIS groups.