Selective Β1-blocker Research Articles

Differential Effects of Landiolol in Patients with Atrial Fibrillation and Atrial Tachycardia

Landiolol, an ultra-short-acting β1-selective blocker, is more effective in controlling heart rate compared with digoxin in patients with atrial tachyarrhythmias and left ventricular dysfunction. However, the effect of atrial tachyarrhythmia type on the effectiveness of landiolol remains unknown. Hence, this study aimed to evaluate the effectiveness of landiolol in patients with atrial fibrillation (AF) and atrial tachycardia (AT), not limited to those with heart failure with a reduced ejection fraction. To this end, we evaluated the efficacy and safety of landiolol in managing tachycardiac AF and tachycardiac atrial flutter/AT in 44 patients with reduced left ventricular function. We found that while landiolol was effective in managing patients with AF and heart failure with a preserved or mid-range ejection fraction, however, it might be more challenging to control heart rate in patients with AT using a similar dosage of landiolol.

β-Blockers and Asthma: Surprising findings from the FAERS database

Introductionβ-Blockers are essential for cardiovascular disease management but can induce respiratory issues, particularly with non-selective β-blockers. Their safety in asthmatic patients is debated. ObjectiveThis study investigates the link between different classes of β-blockers and the risk of asthma and asthma-like adverse events (AEs) using data from the Food and Drug Administration's Adverse Event Reporting System (FAERS). Methodsβ-Blockers were first reviewed according to European Society of Cardiology classification and then using the Vashistha and Kumar classification. The risk associated with different β-blocker classes was evaluated through disproportionality analysis using the reporting odds ratio (ROR). ResultsAmong 251,145 AEs reported for β-blockers, 4104 were asthma-related. Selective β1-blockers had a higher asthma risk signal (ROR: 1.15) compared to non-selective β-blockers (ROR: 0.90). α- and β-Blockers showed the lowest risk (ROR: 0.51). The Vashistha and Kumar classification detailed risk profiles for various β-blockers, highlighting differences even within the same class. Dual α- and β-blockers, hydrophilic, and lipophilic β-blockers posed lower asthma risks, while selective β1-blockers had higher risks regardless of intrinsic sympathomimetic activity. ConclusionAlthough the signals detected by disproportionality analysis are only candidate risks, the risk stratification resulting from our analysis highlights the need for cautious β-blocker selection in asthmatic patients or those predisposed to asthma. Furthermore, despite the limitations associated with the FAERS data, the study reveals significant variability in risk among different β-blocker classes, crucial for clinical decisions and patient management. Drugs like esmolol, metoprolol, nebivolol, and nadolol may be safer for asthmatic patients, whereas betaxolol, bisoprolol, timolol, and propranolol should be avoided.

Prescription Pattern of Beta Blockers in Patients Diagnosed with Heart Failure

This study will be helpful to detect the dosage, frequency and duration of beta blockers which is prescribed for heart failure patients that is followed the guideline. The goal of the study was to describe the prescription pattern of beta blockers in patients diagnosed with heart failure. Hypothyroidism, hypertension, type 2 diabetes mellitus patients are very prone to get Heart failure. Beta blockers should be prescribed, respective with the symptoms that occurred specifically to a particular patient. This study helped to detect the parameters of prescribing beta blockers in different symptoms and co morbidities. A Total of 39 patients, among them It was observed that (46.05%) patients having heart failure were from age group 48-57, followed by (2.5%) of 78-87 age group, of which the males (58.96%) proportion where seems more than the females (41.04%). The prescription pattern for heart failure patients were found as 100% Beta adrenergic blockers, such as metoprolol-65%, bisoprolol-22%, Carvedilol-15% were given. It is evident that the beta blockers are mainly prescribed according to the symptoms, carvedilol exhibits a more pronounced BP lowering effect as a consequence of its α1- receptor blocking activities and thus causes more frequent dizziness and hypotension. In patients predisposed to symptomatic hypotension, metoprolol succinate may be the more desirable whereas in patients with uncontrolled hypertension, carvedilol may be preferred. A selective β1-blocker such as metoprolol succinate is a reasonable option for patients with reactive airway disease.

Improving oxygenation in severe ARDS treated with VV-ECMO: comparative efficacy of moderate hypothermia and landiolol in a swine ARDS model

BackgroundAcute respiratory distress syndrome (ARDS) remains a significant challenge in critical care, with high mortality rates despite advancements in treatment. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is employed as salvage therapy for refractory cases. However, some patients may continue to experience persistent severe hypoxemia despite being treated with VV-ECMO. To achieve this, moderate hypothermia and short-acting selective β1-blockers have been proposed.MethodsUsing a swine model of severe ARDS treated with VV-ECMO, this study investigated the efficacy of moderate hypothermia or β-blockade in improving arterial oxygen saturation (SaO2) three hours after VV-ECMO initiation. Primary endpoints included the ratio of VV-ECMO flow to cardiac output and arterial oxygen saturation before VV-ECMO start (H0) and three hours after ECMO start (H3). Secondary safety criteria encompassed hemodynamics and oxygenation parameters.ResultsTwenty-two male pigs were randomized into three groups: control (n = 6), hypothermia (n = 9) and β-blockade (n = 7). At H0, all groups demonstrated similar hemodynamic and respiratory parameters. Both moderate hypothermia and β-blockade groups exhibited a significant increase in the ratio of VV-ECMO flow to cardiac output at H3, resulting in improved SaO2. At H3, despite a decrease in oxygen delivery and consumption in the intervention groups compared to the control group, oxygen extraction ratios across groups remained unchanged and lactate levels were normal.ConclusionsIn a swine model of severe ARDS treated with VV-ECMO, both moderate hypothermia and β-blockade led to an increase in the ratio of VV-ECMO flow to cardiac output resulting in improved arterial oxygen saturation without any impact on tissue perfusion.

Real world prescription of beta-blockers in patients with asthma.

This study aimed to investigate the prescription of beta-blockers (β-blockers) for patients with asthma. In this retrospective cross-sectional study using the National Patient Sample (NPS) of the Health Insurance Review and Assessment Service (HIRA) of South Korea, β-blockers and asthma medications were investigated using generic name codes provided by HIRA. Concomitant administration was identified when a β-blocker and an asthma medication were co-prescribed in one billing statement or when separate β-blocker and asthma prescriptions had overlapping dates of use. In the 1027 patients with asthma who were prescribed non-selective β-blockers (non-SBs), 3087 non-SB prescriptions were identified, of which 62.3% and 37.3% were for carvedilol and propranolol, respectively. Of the 906 patients with asthma prescribed selective β-blockers (SBs), 2942 SB prescriptions were identified, of which 48.5%, 28.3%, and 20.3% were for bisoprolol, atenolol, and nebivolol, respectively. Overall, 2149 non-SB and 2124 SB prescriptions with overlapping use dates with asthma medications were identified, which were prescribed to 726 and 657 patients, accounting for 70.7% and 72.5% of the patients receiving non-SBs and SBs, respectively. β2-agonists accounted for 39.9% of the concomitant asthma medications with overlapping dates of use with non-SBs. Co-prescribing of bronchodilators occurred at a rate of 38.7% and 45.1% for the 3087 non-SB prescriptions and 2942 SB prescriptions, respectively. Carvedilol and propranolol accounted for half of all β-blockers prescribed to asthma patients. Prescribing β-blockers to patients with asthma requires caution to prevent exacerbation of asthma and drug interactions between β-blockers and co-prescribed asthma medications.

Beta-1 Receptor (β1) in the Heart Specific Indicate to Stereoselectivity

The β1 receptor is one of the three beta receptors present in the human body, namely β1, β2, and β3. The β1 receptor is predominantly located in the heart, where it plays a crucial role in regulating the heart rate and the force of contraction, thereby increasing the cardiac output and the efficiency of blood pumping throughout the body. This receptor is targeted by a variety of pharmaceutical agents known as beta-blockers, which are commonly used in the treatment of cardiovascular conditions such as hypertension, angina, and arrhythmias.The β1 receptor exhibits stereoselectivity, meaning that different enantiomers (chiral molecules) of beta blockers can have varying levels of effectiveness and side effects. This study focuses on the stereoselectivity of the β1 receptor and the clinical implications of this property. It includes an examination of various β1 blockers, such as propranolol (a non-selective beta blocker), and selective β1 blockers like atenolol, bisoprolol, nebivolol, metoprolol, esmolol, acebutolol, and betaxolol. Each of these drugs has a unique chemical structure, with specific functional groups that contribute to their selective action on the β1 receptor. Furthermore, the β2 receptor, which is mainly present in the bronchi and bronchioles, is responsible for bronchodilation, and the β3 receptor, found in the bladder, helps reduce urinary urgency. Understanding the distinct locations and functions of these receptors allows for the development of targeted therapies with minimal off-target effects. This review highlights the importance of stereoselectivity in the development and use of β1 blockers, discussing their chemical structures, pharmacological activities, and therapeutic uses. It also explores the potential for future research and development of more selective and effective β1 receptor agonists and antagonists, which could offer improved therapeutic outcomes for patients with cardiovascular diseases. This study underscores the significant role of the β1 receptor in cardiovascular health and provides insights into the ongoing advancements in beta-blocker therapy. By delving into the stereoselectivity and specific actions of these drugs, the research aims to enhance the understanding and optimization of β1 receptor-targeted treatments in clinical practice.

Non-invasive assessment of proarrhythmic risks associated with isoprenaline and the dietary supplement ingredient synephrine using human induced pluripotent stem cell-derived cardiomyocytes.

There have been conflicting reports about the proarrhythmic risk of p-synephrine (SYN). To address this, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with the microelectrode array (MEA) system have been utilized to assess arrhythmia risks, particularly in the context of adrenomimetic drugs. This study aims to determine whether MEA recordings from hiPSC-CMs could predict the proarrhythmic risk of adrenomimetic drugs and to investigate the cardiovascular effects and mechanisms of SYN. We employed MEA recordings to assess the electrophysiological properties of hiPSC-CMs and conducted concentration-response analyses to evaluate the effects of SYN and Isoprenaline (ISO) on beating rate and contractility. A risk scoring system for proarrhythmic risks was established based on hiPSC-CMs in this study. ISO, a classic beta-adrenergic drug, was also evaluated. Furthermore, the study evaluated the risk of SYN and recorded the concentration-response of beating rate, contractility and the change in the presence or absence of selective β1, β2 and β3 adrenergic blockers. Our results suggested that ISO carries a high risk of inducing arrhythmias, aligning with existing literature. SYN caused a 30% prolongation of the field potential duration (FPD) at a concentration of 206.326 μM, a change significantly different from baseline measurements and control treatments. The half maximal effective concentration (EC50) of SYN (3.31 μM) to affect hiPSC-CM beating rate is much higher than that of ISO (18.00 nM). The effect of SYN at an EC50 of 3.31 μM is about ten times more potent in hiPSC-CMs compared to neonatal rat cardiomyocytes (34.12 μM). SYN increased the contractility of cardiomyocytes by 29.97 ± 11.65%, compared to ISO's increase of 50.56 ± 24.15%. β1 receptor blockers almost eliminated the beating rate increase induced by both ISO and SYN, while neither β2 nor β3 blockers had a complete inhibitory effect. The MEA and hiPSC-CM system could effectively predict the risk of adrenomimetic drugs. The study concludes that the proarrhythmia risk of SYN at conventional doses is low. SYN is more sensitive in increasing beating rate and contractility in human cardiomyocytes compared to rats, primarily activating β1 receptor.

Consensus Statement from India on the Renal Benefits of ARNi, SGLT-2i, and Bisoprolol in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major contributor to morbidity and mortality in India. CKD often coexists with heart failure (HF), diabetes, and hypertension. All these comorbidities are risk factors for renal impairment. HF and CKD are pathophysiologically intertwined, and the deterioration of one can worsen the prognosis of the other. There is a need for safe renal pharmacological therapies that target both CKD and HF and are also useful in hypertension and diabetes. Neurohormonal activation achieved through the activation of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and the natriuretic peptide system (NPS) is fundamental in the pathogenesis and progression of CKD and HF. Angiotensin receptor neprilysin inhibitor (ARNi), sodium-glucose cotransporter 2 inhibitors (SGLT-2i), and selective β1-blocker (B1B) bisoprolol suppress this neurohormonal activation. They also have many other cardiorenal benefits across a wide range of CKD patients with or without concomitant HF, diabetes, or hypertension. This consensus statement from India explores the place of ARNi, SGLT-2i, and bisoprolol in the management of CKD patients with or without HF and other comorbidities.

The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart?

Catecholamines and β-adrenergic receptors (β-ARs) play an important role in the regulation of cardiac tolerance to the impact of ischemia and reperfusion. This systematic review analyzed the molecular mechanisms of the cardioprotective activity of β-AR ligands. We performed an electronic search of topical articles using PubMed databases from 1966 to 2023. We cited original in vitro and in vivo studies and review articles that documented the cardioprotective properties of β-AR agonists and antagonists. The infarct-reducing effect of β-AR antagonists did not depend on a decrease in the heart rate. The target for β-blockers is not only cardiomyocytes but also neutrophils. β1-blockers (metoprolol, propranolol, timolol) and the selective β2-AR agonist arformoterol have an infarct-reducing effect in coronary artery occlusion (CAO) in animals. Antagonists of β1- and β2-АR (metoprolol, propranolol, nadolol, carvedilol, bisoprolol, esmolol) are able to prevent reperfusion cardiac injury. All β-AR ligands that reduced infarct size are the selective or nonselective β1-blockers. It was hypothesized that β1-AR blocking promotes an increase in cardiac tolerance to I/R. The activation of β1-AR, β2-AR, and β3-AR can increase cardiac tolerance to I/R. The cardioprotective effect of β-AR agonists is mediated via the activation of kinases and reactive oxygen species production. It is unclear why β-blockers with the similar receptor selectivity have the infarct-sparing effect while other β-blockers with the same selectivity do not affect infarct size. What is the molecular mechanism of the infarct-reducing effect of β-blockers in reperfusion? Why did in early studies β-blockers decrease the mortality rate in patients with acute myocardial infarction (AMI) and without reperfusion and in more recent studies β-blockers had no effect on the mortality rate in patients with AMI and reperfusion? The creation of more effective β-AR ligands depends on the answers to these questions.

Landiolol, an intravenous β1-selective blocker, is useful for dissociating a fusion of atrial activation via accessory pathway and atrioventricular node.

During ventricular pacing, a fusion of atrial activation may occur owing to the simultaneous retrograde conduction of the atrioventricular (AV) node and accessory pathway (AP), potentially leading to an inaccurate mapping of the atrial AP insertion site. We tested the hypothesis that landiolol, an ultra-short-acting intravenous β1-blocker, could dissociate a fusion of atrial activation. We conducted a prospective before-and-after study to investigate the effect of landiolol on retrograde conduction via the AV node and AP. We enrolled 21 consecutive patients with orthodromic AV reciprocating tachycardia who underwent electrophysiological studies at our hospital between January 1, 2018, and August 31, 2020. Six patients exhibited a fusion of atrial activation. After landiolol administration (10 μg/kg/min), the effective refractory period was unchanged in AP (280 [240-290] ms vs. 280 [245-295] ms, p = .91), whereas that of the AV node was prolonged (275 [215-380] ms vs. 332 [278-445] ms, p = .03). The Wenckebach pacing rate via retrograde AV node decreased after landiolol administration (180 [140-200] beats per minute [bpm] vs. 140 [120-180] bpm, p = .02). Thus, landiolol decreased the minimum ventricular pacing rate required to dissociate a fusion of atrial activation (180 [160-200] bpm vs. 140 [128-155] bpm, p = .007). Radiofrequency catheter ablation under landiolol administration successfully eliminated AP in all patients during ventricular pacing without complications or recurrence. Landiolol inhibited the AV node without affecting the AP and helped dissociate a fusion of atrial activation at a lower ventricular pacing rate.

The Use of β-Blockers and the Risk of Undergoing a Knee Arthroplasty: A Nested Case-Control Study.

Research has indicated that β-blockers may downregulate various inflammatory mediators that are involved in osteoarthritis (OA). The objective of this study was to analyze the likelihood of total knee arthroplasty (TKA) among patients with OA who were being treated with β-blockers. A nested case-control study was conducted with use of clinical records from our institutional database. We included patients who attended our outpatient clinic with a history of new-onset knee pain between 2010 and 2019. The case group included individuals who had undergone primary TKA between 2018 and 2019, whereas the control group included subjects who had not undergone TKA. Controls were matched by date of birth ±2 years, sex, calendar time (first outpatient visit ±1 year), and the grade of arthritis; the control-to-case ratio was 1:1. Adherence to β-blocker use was measured with use of the proportion of days covered (PDC) (i.e.,<0.25, ≥0.25 to <0.75, ≥0.75), and the cumulative effect was measured on the basis of the total number of years of treatment with β-blockers. A binary logistic regression analysis adjusted to potential confounders was carried out to assess the risk of TKA associated with the intake of β-blockers. A total of 600 patients were included (300 in the case group and 300 in the control group). Compared with non-users, any use of β-blockers during the follow-up period was associated with a reduction in the likelihood of undergoing TKA (adjusted odds ratio [OR], 0.51; 95% confidence interval [CI], 0.34-0.77). The adjusted ORs for the use of selective β1-blockers and nonselective β1-blockers were 0.69 (95% CI, 0.36 to 1.31) and 0.42 (95% CI, 0.24 to 0.70), respectively. The adjusted ORs for any recent use, PDC of <0.25, PDC of ≥0.25 to <0.75, and PDC of ≥0.75 were 0.65 (95% CI, 0.51 to 0.99), 0.62 (95% CI, 0.21 to 1.85), 0.32 (95% CI, 0.09 to 1.22), and 0.55 (95% CI, 0.34 to 0.88), respectively. Regarding the cumulative effect of β-blockers, the adjusted ORs for the use for <1 year, ≥1 to <5 years, and ≥5 years were 0.41 (95% CI, 0.20 to 0.85), 0.52 (95% CI, 0.21 to 1.33), and 0.36 (95% CI, 0.22 to 0.60), respectively. The use of nonselective β-blockers was associated with a lower likelihood of undergoing TKA. Patients treated for prolonged periods were at a lower likelihood for undergoing TKA. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

При коморбидной кардиореспираторной патологии инициальное назначение β2-агонистов снижает риск бронхоспазма, вызванного β1-адреноблокаторами

In the treatment of patients with cardiorespiratory pathology, it is often necessary to simultaneously administer drugs that affect β-adrenergic receptors: β1-adrenoblockers and β2-agonists. β1-blockers can trigger a bronchospasm in patients with bronchoobstructive diseases, therefore, practitioners often decide not to prescribe them. This work aimed to evaluate functional parameters of patients with cardiovascular and bronchoobstructive diseases in the context of different sequences of administration of selective β1-blockers (bisoprolol) and long-acting β2-agonists (formoterol). This prospective, single-center 2-week pilot study involved 30 individuals suffering the aforementioned diseases. Using the envelopes method, we divided the patients into two groups of 15 people each. First group started therapy with a long-acting β2-agonist, second group — with a selective β1-adrenoblocker. While taking the β1-adrenoblocker, patients underwent a four-hour spirometric test enabling assessment of the external respiration function parameters. The tests and assessments have shown that the value of FEV1 went down in 33.3% of those who started therapy with a selective β1-adrenoblocker (bisoprolol 2.5 mg), and in the group that first took a long-acting β2-agonist for a week and then added bisoprolol 2.5 mg to the regimen the said value dropped in 7% of patients only. Thus, preceding long-acting β2-agonists, formoterol in particular, reduced the risk of bronchospastic incidents triggered by selective β1-adrenoblocker (bisoprolol) in patients with cardiorespiratory pathology.

A Paradox Explained: Why a Super Selective β1-blocker Works in Acute Heart Failure

A Paradox Explained: Why a Super Selective β1-blocker Works in Acute Heart Failure

Chinese expert consensus on the management of cardiovascular comorbidities in patients with chronic obstructive pulmonary disease

Patients with chronic obstructive pulmonary disease(COPD) often have co-existent systemic diseases(comorbidities), among which cardiovascular diseases (CVD) are the most common. The interactions between COPD and CVD are manifested in shared risk factors, disease severity, common symptoms, risks for exacerbations and disease progression, as well as therapeutic interventions. However, there is a knowledge gap in the management of COPD comorbidities. This expert consensus aims to increase the awareness, and to promote early diagnosis and proper management of cardiovascular comorbidities of COPD in medical professionals in China. The experts recommend that differential diagnosis should be performed for exertional dyspnea, a common symptom of COPD and cardiovascular diseases especially heart failure. Screening for cardiovascular diseases is needed in patients with COPD, and should be managed accordingly. COPD and comorbid CVD should be treated according to usual guidelines. Patients with COPD tolerate well to most of the medications for CVD. Selective β1-blockers for cardiovascular diseases are not contraindicated in COPD, but should be initiated from lower doses, and symptoms of airflow limitation be monitored. Likewise, β2-agonists and antimuscarinic drugs for COPD are generally safe for patients with comorbid CVD. Optimization of COPD management can improve heart function and cardiovascular outcomes.

Targeting the β2 -adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism.

While multi-drug combinations and continuous treatment have become standard for multiple myeloma, the disease remains incurable. Repurposing drugs that are currently used for other indications could provide a novel approach to improve the therapeutic efficacy of standard multiple myeloma treatments. Here, we assessed the anti-tumor effects of cardiac drugs called β-blockers as a single agent and in combination with commonly used anti-myeloma therapies. Expression of the β2 -adrenergic receptor correlated with poor survival outcomes in patients with multiple myeloma. Targeting the β2 -adrenergic receptor (β2 AR) using either selective or non-selective β-blockers reduced multiple myeloma cell viability, and induced apoptosis and autophagy. Blockade of the β2 AR modulated cancer cell metabolism by reducing the mitochondrial respiration as well as the glycolytic activity. These effects were not observed by blockade of β1 -adrenergic receptors. Combining β2 AR blockade with the chemotherapy drug melphalan or the proteasome inhibitor bortezomib significantly increased apoptosis in multiple myeloma cells. These data identify the therapeutic potential of β2 AR-blockers as a complementary or additive approach in multiple myeloma treatment and support the future clinical evaluation of non-selective β-blockers in a randomized controlled trial. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

6-NitroDopamine is an endogenous modulator of rat heart chronotropism

6-Nitrodopamine (6-ND) is released by rat vas deferens and exerts a potent contractile response that is antagonized by tricyclic antidepressants and α1-, β1- and β1/β2-adrenoceptor antagonists. The release of 6-ND, noradrenaline, adrenaline and dopamine from rat isolated right atria was assessed by tandem mass spectrometry. The effects of the catecholamines were evaluated in both rat isolated right atria and in anaesthetized rats. 6-ND was the major catecholamine released from the isolated atria and the release was significantly reduced in nitric oxide synthase inhibitor L-NAME pre-treated atria or in atria obtained from L-NAME chronically treated animals, but unaffected by tetrodotoxin. 6-ND (1 pM) significantly increased the atrial frequency, being 100 times more potent than noradrenaline and adrenaline. Selective β1-blockers reduced the atrial frequency only at concentrations that prevented the increases in atrial frequency induced by 6-ND 1pM. Conversely, β1-blockade did not affect dopamine (10 nM), noradrenaline (100 pM) or adrenaline (100 pM) effect. The reductions in atrial frequency induced by the β1-adrenoceptor antagonists were absent in L-NAME pre-treated atria and in atria obtained from chronic L-NAME-treated animals. Tetrodotoxin did not prevent the reduction in atrial frequency induced by L-NAME or by β1-blockers treated preparations. In anaesthetized rats, at 1 pmol/kg, only 6-ND caused a significant increase in heart rate. Inhibition of 6-ND synthesis by chronic L-NAME treatment reduced both atrial frequency and heart rate. The results indicate that 6-ND is a major modulator of rat heart chronotropism and the reduction in heart rate caused by β1-blockers are due to selective blockade of 6-ND receptor.

Can Pediatric Heart Failure Therapy Be Improved? Yes It Can, But….

Given the heterogenous etiology of pediatric heart failure (pHF), evidence-based studies improving pHF are unlikely. A paradigm shift towards updated medicine-based evidence is therefore necessary. In view of the life expectancy of children, cardiac regeneration strategies are required. Therefore, age- and disease-related differences in myocardial (receptor) physiology require individualized precision medicine. First-line diuretic therapy, adopted from the treatment of adults with HF with no chance for recovery, should be questioned in the treatment of pHF with potential for recovery. Inadequate use of diuretics is a common reason for additional stimulation of the neurohumoral axis. Consecutive intravascular volume depletion led to an inadequate treatment with β-blocker and renin–angiotensin–aldosterone antagonists. Given the age-related catecholamine-driven cardiovascular (patho-) physiology, highly selective β1-blockers (bisoprolol) protect against β1-(noradrenaline)-related myocytic apoptosis and necrosis, but allow β2-receptor-mediated myocardial regeneration. Based on its high safety–efficacy profile with rarely seen adverse effects but easily monitorable efficacy by the surrogate of heart rate (reduction), bisoprolol is our first-line drug in infancy. Reduced heart rate economizes the heart and full body oxygen consumption and extends the diastolic filling and coronary perfusion time. Based on our many years of institutional experience, physicians should be encouraged to use β1-selected blockers in infants with dilated cardiomyopathy and hypoplastic left heart syndrome after stage-1 procedure, but also to treat ventricular septal defects with a significant left-to-right shunt. In summary, individualized pHF therapy is the prerequisite for a causal treatment to improve HF symptoms, but above all for the most functional regeneration possible.

Dissecting the role of cell signaling versus CD8+ T cell modulation in propranolol antitumor activity.

Preclinical and early clinical mechanistic studies of antitumor activity from the beta-adrenergic receptor (β-AR) blocker propranolol have revealed both cell signaling and immune function pathway effects. Intertumoral studies were performed using propranolol, a β1-AR selective agent (atenolol), and a β2-AR selective agent (ICI 118,551) in a preclinical in vivo model, as a step to dissect the contribution of cell signaling and CD8+ immunological effects on anticancer activity. We found that repression of β2-AR but not β1-AR signaling selectively suppressed cell viability and inhibited xenograft growth in vivo. Moreover, western blot analysis indicated that the phosphorylation levels of AKT/MEK/ERK were significantly decreased following the inhibition of β2-AR. Furthermore, propranolol was found to activate the tumor microenvironment by inducing an increased intratumoral frequency of CD8+ T cells, whereas neither selective β1 nor β2-AR blockers had a significant effect on the tumor immune microenvironment. Thus, the results of this mechanistic dissection support a predominant role of tumor cell signaling, rather than the accumulation of CD8+ T cells, as the basis for propranolol antitumor activity. KEY MESSAGES : Molecular signaling of AKT/MAPK pathway contributes to propranolol caused cancer control. CD8+ T cells in tumor microenvironment were activated upon propranolol exposure. The basis for propranolol antitumor activity was predominantly dependent on cell signaling, rather than the activation of CD8+ T cells.

Beta-blocker use and urothelial bladder cancer survival: a Swedish register-based cohort study

Background Recent observational studies linked β-adrenergic receptor blocker use with improved survival in patients with several cancer types, but there is no information on the potential effects of β-blockers in patients with bladder cancer. Literature from pre-clinical studies is also limited, but urothelial cancer can exhibit significant overexpression of β-adrenergic receptors relative to normal urothelial tissue, suggesting that urothelial cancer may benefit from β-blockade therapy. We thus aimed to explore the possible association between β-blocker use and bladder cancer-specific mortality (BCSM) among patients with urothelial bladder cancer. Material and methods Patients diagnosed during 2006–2014 and identified from the Swedish Cancer Register (n = 16,669) were followed until 31 December 2015. Cox regression was used to evaluate the association of β-blockers dispensed within 90 days prior to cancer diagnosis with BCSM (primary outcome) and all-cause mortality, while controlling for socio-demographic factors, tumor characteristics, comorbidity, other medications and surgical procedures. Hazard ratios (HR) with 95% confidence intervals (CI) were reported. Results Overall, β-blocker use was associated with lower BCSM [HR 0.88 (95%CI 0.81–0.96)]. Especially use of nonselective β-blockers showed a clear inverse association in comparison with both nonuse [0.66 (0.50–0.86)] and use of other antihypertensive medications [0.72 (0.54–0.95)]. The inverse association was most pronounced among patients with locally advanced/metastatic disease: [0.35 (0.18–0.68)]. A lower-magnitude inverse association was observed for selective β-blocker use [0.91 (0.83–0.99)]. Largely similar inverse associations were observed for hydrophilic [0.82 (0.70–0.95)] and lipophilic [0.91 (0.83–1.00)] β-blocker use. Conclusion β-blocker use, particularly of the nonselective type, was associated with lower BCSM, especially in patients with locally advanced/metastatic urothelial bladder cancer.