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© 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients' functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate. Based on the most recently published clinical evidence, and the panel members' clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks., A insuficiência cardíaca (IC) com fração de ejeção reduzida (ICFEr) está associada a níveis elevados de hospitalização e mortalidade. A ICFEr também tem um impacto negativo na capacidade funcional e na qualidade de vida dos doentes, bem como na despesa em saúde. Nos últimos anos, surgiram novos medicamentos modificadores do prognóstico da ICFEr, originando um intenso debate na comunidade científica internacional em relação a uma mudança de paradigma para o tratamento da ICFEr. Neste artigo, relatamos a contribuição de um painel de especialistas portugueses em IC para o debate em curso. Com base na evidência clínica publicada mais recentemente e no julgamento clínico dos membros do painel, três princípios-chave são destacados: (i) sacubitril/valsartan deve ser preferido como terapia de primeira linha para a ICFEr, em vez de um inibidor da enzima de conversão da angiotensina ou um bloqueador do recetor da angiotensina; (ii) os quatro medicamentos básicos para a ICFEr são o inibidor do recetor da angiotensina e da neprilisina, os agentes bloqueadores beta-adrenérgicos, os antagonistas do recetor mineralocorticoide e os inibidores do cotransportador sódio-glucose 2, independentemente da presença de diabetes mellitus tipo 2; (iii) essas quatro classes de medicamentos para a ICFEr devem ser rapidamente introduzidas num período curto de 4-6 semanas, seguindo um protocolo de segurança, e depois tituladas durante as oito semanas seguintes.

Aims The number of patients with both chronic obstructive pulmonary disease (COPD) and heart failure (HF) is increasing in Asia, and these conditions often coexist. We previously revealed a tendency of beta‐blocker underuse among patients with HF with reduced ejection fraction (HFrEF) and COPD in Asian countries other than Japan. Here, we evaluated the impact of cardio‐selective beta‐blocker use on the long‐term outcomes of patients with HF and COPD. Methods and results Among the 5232 patients with HFrEF (left ventricular ejection fraction of

Aim To compare risk algorithms (HCMRisk-Kids, ECG Risk-score) in hypertrophic cardiomyopathy (HCM) without syndrome association (ns-HCM) and with Noonan-like syndromes (RAS-HCM). Methods A national paediatric HCM cohort (n = 151), presenting = 6% at diagnosis had C-statistic of 0.69 for predicting SCD/CA during first 5 years of follow-up and positive predictive value (PPV) of 22%. After 7 years of age (HCMRisk-Kids7plus), C-statistic was 0.76. ECG Risk-score >= 6 at diagnosis had C-statistic 0.87 and PPV of 31%. Independent risk factors for SCD/CA were HCMRisk-Kids7plus score (p = 0.005) and ECG risk-score (p < 0.001), whereas early beta-blocker dose (p = 0.001) and myectomy (p = 0.004) reduced risk. The sum of HCMRisk-Kids7yplus and ECG Risk-score7yplus >= 14 best predicted SCD/CA within 5 years in ns-HCM with C-statistic of 0.90 [0.83-0.96], sensitivity 100% and PPV 38%. Conclusion Combining the ECG Risk-score with HCMRisk-Kids improves risk stratification in ns-HCM and shows promise in RAS-HCM. Funding Agencies|Swedish Heart-and Lung FoundationSwedish Heart-Lung Foundation [20080510]; Swedish government; ALF agreement [ALFgbg-544981]; Region Ostergotland (ALF); Strategic Research Area in Forensic Science; FORSS (Medical Research Council of Southeast Sweden)

الملخص: أهداف البحث: ينبغي البدء باستعمال مانع بيتا مع المرضى الذين يعانون من فشل القلب الحاد المستقر. وينبغي إجراء معايرة بعد فترة أسبوعين من استعمال مانع بيتا. ولا تزال فوائد معايرة مانع بيتا الدقيقة غير واضحة. تهدف هذه الدراسة إلى التحقيق في نتائج المعايرة لمانع بيتا الدقيقة لدى مرضى فشل القلب الحاد المستقر مع انخفاض كسر طرد البطين الأيسر. طرق البحث: في هذه الدراسة الأترابية الاستعادية، قمنا بتحليل البيانات السريرية من سجل قصور القلب. تم تقسيم مرضى فشل القلب الحاد الذين يعانون من انخفاض كسر طرد البطين الأيسر>٤٠٪ إلى مجموعتين، مجموعة معايرة مانع بيتا الدقيقة ومجموعة موجهة حسب المبادئ التوجيهية. تم تعريف النتائج الأولية على أنها مجموعة من ارتفاع تفاقم قصور القلب، وعدم انتظام ضربات القلب البطينية، والوفيات أثناء دخول المستشفى. وقد اعتبرنا النتائج الثانوية مكونات للنتائج الأولية وكذلك النتائج خلال المتابعة التي تستغرق ٩٠ يوما بعد الخروج من المستشفى، بما في ذلك إعادة التنويم بقصور القلب والوفيات. النتائج: لم تكن النتائج الأولية بين المجموعتين مختلفة بشكل كبير (١٢.٣٪ مقابل ٢٤.٤٪؛ المخاطر النسبية ٠.٥١). ومع ذلك، فإن معايرة مانع بيتا الدقيقة خفضت عدم انتظام ضربات القلب البطينية (٥.٧٪ مقابل ١٧.٨٪؛ ٠.٣٢). ومعدل إعادة التنويم بقصور القلب (٢.٦٪ مقابل ٧.٥٪؛ ٠.٣٥) ومعدل الوفيات (٤.٣٪ مقابل ٥٪؛ ٠.٨٧)، ولم يتم العثور على اختلاف بشكل ملحوظ في الوفيات بين المجموعتين. الاستنتاجات: بالمقارنة مع معايرة مانع بيتا حسب توجيهات المبادئ التوجيهية، كانت معايرة مانع بيتا الدقيقة أكثر أمانا في مرضى فشل القلب الحاد المستقر وانخفاض كسر طرد البطين الأيسر الذين تم تثبيت حالتهم سابقا. بالإضافة إلى ذلك، فإن معايرة مانع بيتا الدقيقة قللت بشكل فاعل من أحداث عدم انتظام ضربات القلب البطينية. Abstract: Objectives: A beta-blocker should be initiated in patients with stable acute heart failure (AHF). Beta-blocker titration should be conducted after a two-week interval. The benefits of aggressive beta-blocker titration are still unclear. This study aimed to investigate the aggressive beta-blocker titration outcomes in stabilized AHF patients with low left ventricular ejection fraction (LVEF). Methods: In this retrospective cohort study, we analysed clinical data from the heart failure (HF) registry. AHF Patients with LVEF

Aims : The utility of beta-blocker therapy in infants with heart failure (HF) due to significant left-to-right shunt lesions is not known. The study aimed to assess the efficacy and safety of propranolol in infants with HF due to moderate-to-large ventricular septal defect (VSD). Methods : The prospective randomized trial included 80 infants with HF and moderate-to-large VSD, randomly allocated to receive either conventional therapy alone (n = 40) or propranolol plus conventional therapy (n = 40). The primary endpoint was a composite of all-cause mortality, hospitalization for HF and/or chest infection, and referral for surgery. The secondary clinical outcomes were the individual components of the composite endpoint. In addition, the patients were followed up to detect safety outcomes, for example, bronchospasm, bradyarrhythmia, and worsening HF symptoms. Results : The addition of propranolol therapy to the conventional medications did not result in significant improvement in the primary composite endpoint (32.50% vs. 52.50%; P = 0.07). There was a trend toward improvement, but the study is underpowered for this important question. However, propranolol therapy significantly decreased the risk of hospitalization (12.50% vs. 32.50%; P = 0.03) and worsening of Ross HF class (5.41% vs. 28.21%; P = 0.01) as compared to conventional therapy (estimated number needed to treat = 5). Propranolol did not result in any significant safety concerns in these infants except bronchospasm in an infant. Conclusions : Propranolol therapy in infants with significant left-to-right shunt may prevent worsening in HF symptoms and hospitalization and is well tolerated. However, it does not reduce mortality or need for surgery.

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.

International audience; Background: Achieving target doses of angiotensin-converting-enzyme inhibitor/angiotensin-receptor blockers (ACEi/ARB) and beta-blockers in heart failure with reduced ejection fraction (HFrEF) is often underperformed. In BIOlogy Study to TAilored Treatment in chronic heart failure (BIOSTAT-CHF) study, many patients were not up-titrated for which no clear reason was reported. Therefore, we hypothesized that perceived-risk profile might influence treatment optimization.Methods: We studied 2100 patients with HFrEF (LVEF≤40%) to compare the clinical characteristics and adverse events associated with treatment up-titration (after a 3-month titration protocol) between; a) patients not reaching target doses for unclear reason; b) patients not reaching target doses due to symptoms and/or side effects; c) patients reaching target doses.Results: For ACEi/ARB, (a), (b) and (c) was observed in 51.3%, 25.9% and 22.7% of patients, respectively. For beta-blockers, (a), (b) and (c) was observed in 67.5%, 20.2% and 12.3% of patients, respectively. By multinomial logistic regression analysis for ACEi/ARB, patients in group (a) and (b) had lower blood pressure and poorer renal function, and patients in group (a) were older and had lower ejection fraction. For beta-blockers, patients in group (a) and (b) had more severe congestion and lower heart rate. At 9 months, adverse events (i.e., hypotension, bradycardia, renal impairment, and hyperkalemia) occurred similarly among the three groups.Conclusions: Patients in whom clinicians did not give a reason why up-titration was missed were older and had more co-morbidities. Patients in whom up-titration was achieved did not have excess adverse events. However, from these observational findings, the pattern of subsequent adverse events among patients in whom up-titration was missed cannot be determined.

Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor–neprilysin inhibitor, a beta‐blocker, a mineralocorticoid receptor antagonist and a sodium–glucose co‐transporter 2 (SGLT2) inhibitor. However, the conventional approach to the implementation is based on a historically‐driven sequence that is not strongly evidence‐based, typically requires ≥6 months, and frequently leads to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2–4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease‐of‐use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over up‐titration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated three‐step approach, which consists of the simultaneous initiation of a beta‐blocker and an SGLT2 inhibitor, followed 1–2 weeks later by the initiation of sacubitril/valsartan, and 1–2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be re‐ordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence‐based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction., Comparison of conventional and rapid sequencing approaches to the implementation of foundational drug treatments for heart failure and a reduced ejection fraction. Rapid sequencing involves simultaneous initiation of a beta‐blocker and sodium–glucose co‐transporter 2 (SGLT2) inhibitor, followed 1–2 weeks later by an angiotensin receptor–neprilysin inhibitor, and 1–2 weeks later, by a mineralocorticoid receptor antagonist. The ordering of Step 2 and 3 may be reversed in a patient with a borderline systolic blood pressure. Patients already receiving a conventional inhibitor of the renin–angiotensin system may be switched to sacubitril/valsartan and started on a mineralocorticoid receptor antagonist at the same time. Reproduced and adapted with permission from McMurray and Packer.3

OBJECTIVE: The global rise in type 2 diabetes is associated with a concomitant increase in diabetic complications. Diabetic polyneuropathy is the most frequent type 2 diabetes complication and is associated with poor outcomes. The metabolic syndrome has emerged as a major risk factor for diabetic polyneuropathy; however, the metabolites associated with the metabolic syndrome that correlate with diabetic polyneuropathy are unknown.METHODS: We conducted a global metabolomics analysis on plasma samples from a subcohort of participants from the Danish arm of Anglo-Danish-Dutch study of Intensive Treatment of Diabetes in Primary Care (ADDITION-Denmark) with and without diabetic polyneuropathy versus lean control participants.RESULTS: Compared to lean controls, type 2 diabetes participants had significantly higher HbA1c (p = 0.0028), BMI (p = 0.0004), and waist circumference (p = 0.0001), but lower total cholesterol (p = 0.0001). Out of 991 total metabolites, we identified 15 plasma metabolites that differed in type 2 diabetes participants by diabetic polyneuropathy status, including metabolites belonging to energy, lipid, and xenobiotic pathways, among others. Additionally, these metabolites correlated with alterations in plasma lipid metabolites in type 2 diabetes participants based on neuropathy status. Further evaluating all plasma lipid metabolites identified a shift in abundance, chain length, and saturation of free fatty acids in type 2 diabetes participants. Importantly, the presence of diabetic polyneuropathy impacted the abundance of plasma complex lipids, including acylcarnitines and sphingolipids.INTERPRETATION: Our explorative study suggests that diabetic polyneuropathy in type 2 diabetes is associated with novel alterations in plasma metabolites related to lipid metabolism.

Hypertension is one of the most common morbidities in COVID-19. Previous studies demonstrated that hypertension increases composite poor outcomes in patients with COVID-19. Beta-blockers is widely used as one of the most common antihypertensive agents. Beta-blockers may hold potential benefits in COVID-19 treatment, with current evidence of the potential mechanism of beta-blockers remains scarce. However, several mechanisms were suggested, including decreasing RAAS pathway activity and lowering the ACE2 levels, reducing cytokine storms, and may be beneficial in reducing mortality in ARDS related COVID-19. Further large-scale randomized clinical trials should be conducted before a definite recommendation can be drawn.

Aims Despite medical therapy for heart failure (HF) having proven benefits of improving quality of life and survival, many patients remain under‐treated. This may be due to a combination of under‐prescription by medical professionals and poor adherence from patients. In HF, as with many other chronic diseases, adherence to medication can deteriorate over time particularly when symptoms are well controlled. Therefore, detecting and addressing non‐adherence has a crucial role in the management of HF. Significant flaws and inaccuracies exist in the methods currently used to assess adherence such as patient reporting, pill counts, and pharmacy fill records. We aim to use high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS) to detect metabolites of HF medications in the urine samples of chronic HF patients. Methods and results Urine samples were collected from 35 patients in a specialist HF clinic. Patients were included if they had an ejection fraction

Albaraa Alsini,1 Ishraq Alkhodaidi,2 Yasir Alsini,3 Sarh Alsseeni,4 Shrooq Alkhodaidi,5 Ehsan Alsini,6 Asim Alsini,7 Hamzah Sindi,8 Khaled Alswat9 1Resident, Department of Otolaryngology Head & Neck Surgery, Alhada Armed Forces Hospital, Taif, Saudi Arabia; 2Medical Student, Faculty of Medicine, Taif University, Taif, Saudi Arabia; 3PharmD, Alhada Armed Forces Hospital, Taif, Saudi Arabia; 4PharmD Student, Taif University, Taif, Saudi Arabia; 5Resident, Department of Dermatology, King Abdulaziz Hospital, Makkah, Saudi Arabia; 6PharmD, Medical Representative in Eli Lilly and Company, Taif, Saudi Arabia; 7Medical Intern, Faculty of Medicine, Taif University, Taif, Saudi Arabia; 8Medical Student, Faculty of Medicine, Umm AlQura University, Makkah, Saudi Arabia; 9Professor of Medicine, Department of Medicine, School of Medicine, Taif University, Taif, 21944, Saudi ArabiaCorrespondence: Albaraa AlsiniDepartment of Otolaryngology Head & Neck Surgery, Alhada Armed Forces Hospital, Alhada District, Taif, Saudi ArabiaTel +966530006201Email Dr.albaraa2015@gmail.comBackground: The development of beta-blocker (BB) medications is considered one of the most critical milestones of drug research. Several trials showed possible anti-anxiety effects of BBs. Our primary goal is to investigate the prevalence of anxiety disorder and the use of BBs as anxiolytic without medical prescription among medical and pharmacological students in Saudi Arabia.Methods: A cross-sectional study was conducted at multiple universities in Saudi Arabia. Students were given a questionnaire containing 44 questions that included demographic data, school location, BB usage behavior, GPA status before and after using BBs, and a GAD-7 anxiety screening questionnaire.Results: A total of 3326 mainly female senior students participated in the study with a mean age of 21.9± 1.7 years. According to the GAD-7 score, half of the sampled students did not meet criteria indicative of anxiety disorder, and one-third were considered to have mild anxiety with a significant positive correlation between the BB usage and the GAD-7 score. A total of 6.4% of the sample reported usage of BBs. Therapeutics and Internal Medicine were the most common subjects for which BBs were used. When compared to pharmacy students, medical students were more likely to be male, smokers, diagnosed with psychiatric illness, having a higher mean GAD-7 score, report BB usage, and correctly identified common and serious BB side effects.Conclusion: The inappropriate use of BB drugs without medical advice might have short- and long-term effects, and those may be more vulnerable to have psychological issues in the future. Our findings shed light on the need to identify students who are taking BBs as being at high risk of underlying anxiety disorders.Keywords: beta-blocker, anxiety, student anxiety, self-prescription, undiagnosed anxiety

Bleeding stomal varices are often difficult to manage given the comorbidities that are associated with their presentation. Here, we report a case of a 62-year-old female with stomal variceal hemorrhage in the setting of chronic portal vein thrombosis who was ineligible for transhepatic intrajugular portosystemic shunt or surgery as a result of her challenging anatomy and peri-operative risks. Despite coil embolization, this patient experienced refractory bleeds which ceased following the initiation of a non-selective beta-blocker (NSBB). This case provides further evidence for the expanding role of NSBBs as an important therapeutic agent for complicated ectopic varices.

Donepezil toxicity can present similarly to beta‐blocker overdose and colitis. Symptoms include confusion, diaphoresis, and bradycardia. In patients with suspected medication‐related toxicities, it is important to consider all possible causative agents in the active medication list.

Background It has been postulated that the hyperadrenergic state caused by surgical trauma is associated with worse outcomes and that β-blockade may improve overall outcome by downregulation of adrenergic activity. Esophageal resection is a surgical procedure with substantial risk for postoperative mortality. There is insufficient data to extrapolate the existing association between preoperative β-blockade and postoperative mortality to esophageal cancer surgery. This study assessed whether preoperative β-blocker therapy affects short-term postoperative mortality for patients undergoing esophageal cancer surgery. Methods All patients with an esophageal cancer diagnosis that underwent surgical resection with curative intent from 2007 to 2017 were retrospectively identified from the Swedish National Register for Esophagus and Gastric Cancers (NREV). Patients were subdivided into β-blocker exposed and unexposed groups. Propensity score matching was carried out in a 1:1 ratio. The outcome of interest was 90-day postoperative mortality. Results A total of 1466 patients met inclusion criteria, of whom 35% (n = 513) were on regular preoperative β-blocker therapy. Patients on β-blockers were significantly older, more comorbid and less fit for surgery based on their ASA score. After propensity score matching, 513 matched pairs were available for analysis. No difference in 90-day mortality was detected between β-blocker exposed and unexposed patients (6.0% vs. 6.6%, p = 0.798). Conclusion Preoperative β-blocker therapy is not associated with better short-term survival in patients subjected to curative esophageal tumor resection.

A 44-year-old man diagnosed with idiopathic dilated cardiomyopathy was admitted to our hospital with acute decompensated heart failure. Seven years before this admission, the first introduction of medication resulted in left ventricular (LV) recovery, which was sustained for several years. However, the patient stopped taking his medication, resulting in worsening of the LV function. Despite the second introduction of medication, the LV function did not improve. We performed cardiac magnetic resonance imaging and an endomyocardial biopsy, which revealed the significant development of cardiac fibrosis that had not been present at the time of the initial diagnosis.

Aims Current guidelines recommend beta‐blocker therapy in chronic heart failure with reduced ejection fraction (HFrEF) titrated according to tolerated target dose. The efficiency of this strategy to obtain adequate heart rate (HR) control remains unclear in clinical practice. The aim of this study was to determine, in a real‐world setting, the proportion of HFrEF patients who fail to achieve beta‐blocker target doses, whether target doses of beta‐blockers have a relationship with the adequacy in reducing resting HR over time. Methods and results Beta‐blocker dose and resting HR of consecutive ambulatory patients with a diagnosis of HFrEF (ejection fraction ≤ 35%) in sinus rhythm were reviewed at the first outpatient contact in the Cleveland Clinic Health System from the year 2000 to 2015. Patients who did not receive beta‐blocker therapy, have congenital heart disease and hypertrophic cardiomyopathy, were not in sinus rhythm, or have a history of heart transplant were excluded. Patients were followed up until their last known visit at the Cleveland Clinic. Median resting HR was 71 b.p.m. [inter‐quartile range (IQR) 60–84 b.p.m.] in 8041 patients (median age 65; 68% male) with 67% on carvedilol, 32% on metoprolol succinate, and 1% on bisoprolol. In 3674 subjects (56%), resting HR was ≥70 b.p.m. At final follow‐up after a median of 21 months (IQR 0.1–7.2 years), resting HR was 72 b.p.m. (IQR 60–84 b.p.m.) in the subset of patients with persistently low ejection fraction ≤ 35%. HR ≥ 70 b.p.m. was observed in 55% of this group. Beta‐blocker target dose was achieved in 19%, 5%, and 15% of those receiving carvedilol, metoprolol succinate, and bisoprolol, respectively. In the subset of patients who experienced beta‐blocker up‐titration, reduced mortality or hospitalization due to heart failure was observed in patients who experienced the lowest HR after titration. Conclusions In our single‐centre experience, the majority of patients with chronic HFrEF treated with beta‐blocker therapy did not achieve target doses over time, and a substantial proportion had inadequate control of resting HR. There was no relationship between achieved beta‐blocker target dose and resting HR control.

While patients with acute heart failure often have tachycardia with atrial fibrillation, there have been no established medical tools that control tachycardia safely and definitely. Digoxin has been recommended as a first choice in the former guidelines, but it takes time to affect and has a risk of adverse events particularly for those with chronic kidney disease. Landiolol is a recently innovated ultra‐short‐acting beta‐blocker with 251‐fold β1/β2 selectivity, which was originally indicated only to control peri‐operative supra‐ventricular tachyarrhythmia by 2013 in Japan. We aimed to review how to use landiolol in patients with cardiac dysfunction and tachycardia due to atrial fibrillation. We reviewed recently conducted randomized control trials using landiolol, recently updated guidelines, as well as current practical use of landiolol. Japan landiolol vs. Digoxin (J‐Land) study demonstrated that landiolol was more effective to control tachycardia than digoxin in atrial fibrillation patients with left ventricular dysfunction in 2013. Given the result, the revised Japanese heart failure guideline recommends landiolol for rate control during atrial fibrillation in acute heart failure patients as Class IIa with evidence level B. Currently in Japan, landiolol is used for rate control, even in patients with advanced heart failure receiving continuous infusion of inotropes. The clinical use of landiolol in patients with cardiac dysfunction and tachycardia due to atrial fibrillation is increasing. Further studies are warranted to investigate the implication of faster and safer rate control using landiolol.

Background: Post hoc analysis was used to investigate the effects of renal function on the efficacy and safety of landiolol using data from the J-Land II study, which evaluated landiolol in patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF) who were refractory to Class III antiarrhythmic drugs. Methods and Results: Patient data from the J-Land II study (n=29) were stratified by renal function (estimated glomerular filtration rate [eGFR]

International audience; Low blood pressure is common in patients with heart failure and reduced ejection fraction (HFrEF). While spontaneous hypotension predicts risk in HFrEF, there is only limited evidence regarding the relationship between hypotension observed during heart failure (HF) drug titration and outcome. Nevertheless, hypotension (especially orthostatic hypotension) is an important factor limiting the titration of HFrEF treatments in routine practice. In patients with signs of shock and/or severe congestion, hospitalization is advised. However, in the very frequent cases of non-severe and asymptomatic hypotension observed while taking drugs with a class I indication in HFrEF, European and US guidelines recommend maintaining the same drug dosage. In instances of symptomatic or severe persistent hypotension (systolic blood pressure < 90 mmHg), it is recommended to first decrease blood pressure reducing drugs not indicated in HFrEF as well as the loop diuretic dose in the absence of associated signs of congestion. Unless the management of hypotension appears urgent, a HF specialist should then be sought rather than stopping or decreasing drugs with a class I indication in HFrEF. If symptoms or severe hypotension persist, no recommendations exist. Our HF group reviewed available evidence and proposes certain steps to follow in such situations in order to improve the pharmacological management of these patients.

Right ventricular (RV) function and autonomic dysfunction are important determinants of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). Although successful in animal studies, effects of beta-blocker therapy on RV function in clinical trials were disappointing. To understand this discrepancy, we studied whether beta-blocker therapy changes RV sympathetic activity. Idiopathic PAH (IPAH) patients received beta-blocker therapy (uptitrated to a maximal tolerated dose) and underwent cardiac magnetic resonance imaging, right heart catheterization, and a [ 11 C]-hydroxyephedrine positron emission tomography ([ 11 C]HED PET) scan at baseline to determine, respectively, RV ejection fraction (RVEF), RV pressures, and sympathetic activity. [ 11 C]HED, a norepinephrine analogue, allows determination of sympathetic innervation of the RV. [ 11 C]HED retention index reflects norepinephrine transporter activity. As a consequence of excessive catecholamine levels in the synaptic cleft, this transporter may be downregulated. Therefore, low [ 11 C]HED retention index indicates high sympathetic activity. 13 IPAH patients underwent [ 11 C]HED PET scans at baseline and after bisoprolol treatment. Although heart rate was reduced, systemic modulation of autonomic activity by bisoprolol did not affect local RV sympathetic nerve activity, RV function, or RV wall tension. In PAH patients, RV [ 11 C]HED retention index was lower compared to LV tracer uptake (p

Aims:\ud Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up‐titration of angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta‐blockers on outcome across the age spectrum in HFrEF patients.\ud \ud Methods and results:\ud We analysed HFrEF patients on sub‐optimal doses of ACEI/ARB and/or beta‐blockers from the BIOSTAT‐CHF study stratified by age. Patients underwent a 3‐month up‐titration period. We used inverse probability weighting to adjust for the likelihood of successful up‐titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow‐up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta‐blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI‐ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P

Introduction. Daily oral beta-adrenoreceptor antagonist has been shown to be effective in preventing migraine headaches. Timolol 0.5% ophthalmic solution is a non-selective beta-adrenoreceptor antago- nist, where the primary use is for glaucoma. There have been case reports that timolol is effective in aborting or improving an acute migraine headache. The objective of this study was to assess the efficacy (decrease of ≥ 50% in pain scale at 120 minutes) of timolol 0.5% ophthalmic solution compared to placebo in acute treatment of migraine headache. Methods.We performed a randomized, double-blind, crossover, placebo-controlled, study. Study entry criteria required subjects to have one to eight migraine episodes per month. The primary outcome was comparison of the change in a visual analog pain scale (VAS) at 120 minutes after taking the study medication. Study subjects were given a pain scale with a range of 1 (no pain) to 10 (most severe pain) to complete after onset of migraine but before administration of study drops and 120 minutes after administration of study drops. Improve- ment was defined as a ≥ 50% decrease in pain scale. Results. Nineteen subjects completed the study and were used for analysis. The primary outcome changes in pain scale, 120 minutes after dose, showed a similar decrease for placebo and drug with a slightly wider 95% CI for placebo. Six subjects in each arm experi- enced a ≥ 50% decrease in pain scale. Conclusion. These results support that timolol 0.5% ophthalmic solution is not an efficacious treatment for acute migraine headache.

Background In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate and outcomes in HFrEF is not well-known. Hence, we identified a large, national, real-world cohort of HFrEF to examine the association of pulse rate and outcomes. Methods Using Veterans Affairs (VA) national electronic health records we identified incident HFrEF cases between 2006 and 2012. We examined the associations of both baseline and serially measured pulse rates, with mortality and days hospitalized per year for heart failure and for any cause, using crude and multivariable Cox proportional hazards and Poisson or negative binomial models, respectively. The exposure was examined as continuous, dichotomous, and categorical. Post-hoc analyses addressed the interaction of pulse rate and beta-blocker target dose. Results We identified 51,194 incident HFrEF cases (67 ± 12 years, 98% male, 77% white. A significant positive, near linear relationship was observed for both baseline and serially measured pulse rates with all-cause mortality, all-cause hospitalization and heart failure hospitalization after adjusting for covariates including beta-blocker use. Patients who had a pulse rate ≥ 70 bpm in the past 6 months had 36% (95% CI: 31–42%), 25% (95% CI: 19–32%), and 51% (95% CI: 33–72%) increased rates of mortality, all-cause hospitalization, and heart failure hospitalization, respectively, compared to patients with pulse rates Conclusions High pulse rate, both at the time of diagnosis and during follow-up, is strongly associated with increased risk of adverse outcomes in HFrEF patients, independent of the use of beta-blockers. In a real-world setting, the majority of HFrEF patients do not achieve target dose of beta-blockade; greater use of strategies to reduce heart rate may improve outcomes in HFrEF.

Mortality in the setting of septic shock varies between 20% and 100%. Refractory septic shock leads to early circulatory failure and carries the worst prognosis. The pathophysiology is poorly understood despite studies of the microcirculatory defects and the immuno-paralysis. The acute circulatory distress is treated with volume expansion, administration of vasopressors (usually noradrenaline: NA), and inotropes. Ventilation and anti-infectious strategy shall not be discussed here. When circulation is considered, the literature is segregated between interventions directed to the systemic circulation vs. interventions directed to the micro-circulation. Our thesis is that, after stabilization of the acute cardioventilatory distress, the prolonged sympathetic hyperactivity is detrimental in the setting of septic shock. Our hypothesis is that the sympathetic hyperactivity observed in septic shock being normalized towards baseline activity will improve the microcirculation by recoupling the capillaries and the systemic circulation. Therefore, counterintuitively, antihypertensive agents such as beta-blockers or alpha-2 adrenergic agonists (clonidine, dexmedetomidine) are useful. They would reduce the noradrenaline requirements. Adjuncts (vitamins, steroids, NO donors/inhibitors, etc.) proposed to normalize the sepsis-evoked vasodilation are not reviewed. This itemized approach (systemic vs. microcirculation) requires physiological and epidemiological studies to look for reduced mortality.

ObjectiveControversial, heterogeneous, and inconsistent responses to beta-blockers have been reported in some cases of infantile proliferative hemangiomas. On the basis of these clinical observations, we aimed to examine the β1 adrenergic receptor (β1-AR) protein expression distribution among different types of pediatric vascular anomalies.MethodsImmunohistochemistry (IHC) was performed for β1-AR on 43 surgical specimens.ResultsWe found positive β1-AR IHC staining in all intramuscular hemangiomas, capillary–lymphatic, lymphatic, venous, and combined malformations, and Masson’s tumor cases, as well as in 7 of 10 cases of proliferative infantile hemangiomas.ConclusionsOur research demonstrates, for the first time, the degree of heterogeneous expression of β1-AR among pediatric vascular malformations. Our results support the need for β1-AR assessment in pediatric vascular anomalies to select cases with a robust response to β1-selective blockers. β1-AR assessment may have a strong impact on therapeutic refinement for pediatric vascular anomalies by selecting cases with a stronger response to beta-blockers.

The administration of beta-blockers is challenging and their efficacy is unclear in heart failure (HF) patients with chronic obstructive pulmonary disease (COPD). This study aimed to investigate the association of beta-blockers with mortality in such patients. This multicenter observational cohort study included hospitalized HF patients with a left ventricular ejection fraction &lt, 50% and evaluated them retrospectively. COPD was diagnosed based on medical records and/or the clinical judgment of each investigator. The study endpoints were two-year all-cause, cardiac, and non-cardiac mortality. This study included 83 patients with COPD and 1760 patients without. Two-year all-cause, cardiac, and non-cardiac mortality were observed in 315 (17%), 149 (8%), and 166 (9%) patients, respectively. Beta-blockers were associated with lower all-cause mortality regardless of COPD (COPD: hazard ratio [HR] 0.39, 95% CI 0.16–0.98, p = 0.044, non-COPD: HR 0.62, 95% CI 0.46–0.83, p = 0.001). This association in HF patients with COPD persisted after multivariate analysis and inverse probability weighting and was due to lower non-cardiac mortality (HR 0.40, 95% CI 0.14–1.18. p = 0.098), not cardiac mortality (HR 0.37, 95% CI 0.07–2.01, p = 0.248). Beta-blockers were associated with lower all-cause mortality in HF patients with COPD due to lower non-cardiac mortality. This may reflect selection biases in beta-blocker prescription.

Background Cardiogenic shock (CS) is associated with significant morbidity and mortality. The impact of beta-blocker (BB) use on patients who develop CS remains unknown. We sought to evaluate the clinical outcomes and hemodynamic response profiles in patients treated with BB in the 24 h prior to the development of CS. Methods Patients with CS enrolled in the DObutamine compaREd to MIlrinone trial were analyzed. The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, need for cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite and hemodynamic response profiles derived from pulmonary artery catheters. Results Among 192 participants, 93 patients (48%) had received BB therapy. The primary outcome occurred in 47 patients (51%) in the BB group and in 52 (53%) in the no BB group (RR 0.96; 95% CI 0.73–1.27; P = 0.78) throughout the in-hospital period. There were fewer early deaths in the BB group (RR 0.41; 95% CI 0.18–0.95; P = 0.03). There were no differences in other individual components of the primary outcome or in hemodynamic response between the two groups throughout the remainder of the hospitalization. Conclusions BB therapy in the 24 h preceding the development of CS did not negatively influence clinical outcomes or hemodynamic parameters. On the contrary, BB use was associated with fewer deaths in the early resuscitation period, suggesting a paradoxically protective effect in patients with CS. Trial registration ClinicalTrials.gov Identifier: NCT03207165

(1) Background: Topical antiglaucoma medications may alter the microcirculation in the optic nerve head. We aimed to evaluate the changes in retinal vessel density (VD) on optical coherence tomography angiography (OCTA) in patients with newly diagnosed normal-tension glaucoma (NTG) treated with a topical beta-blocker. (2) Methods: This study included 80 patients diagnosed with NTG not using systemic medication, who received topical carteolol treatment between December 2019 and November 2020. We studied the changes in the OCTA VD/signal strength index (SSI) after the 6-month treatment period and determined the predictive factors affecting the changes in VD/SSI. (3) Results: After the 6-month treatment period, the peripapillary VD increased in 40 patients but decreased in the other 40 patients. The univariate and multivariate analyses revealed that old age and hypertension were significant factors associated with a VD/SSI decrease after carteolol treatment. Moreover, high baseline peripapillary, superficial, and deep macular VDs were significantly associated with the VD decrease after carteolol treatment. (4) Conclusions: Carteolol treatment could increase or decrease the VD in patients with NTG. The baseline VD, age, and hypertension could affect these VD changes. Patients with NTG and higher baseline peripapillary or macular VD, older age, and hypertension are more likely to have a decreased VD after carteolol treatment.

Background Although beta‐blockers are recommended following myocardial infarction (MI), the benefits of long‐term treatment have not been established. The study's aim was to evaluate beta‐blocker efficacy by dose in 1‐year post‐MI survivors. Methods and Results The OBTAIN (Outcomes of Beta‐Blocker Therapy After Myocardial Infarction) registry included 7057 patients with acute MI, with 6077 one‐year survivors. For this landmark analysis, beta‐blocker dose status was available in 3004 patients and analyzed by use (binary) and dose at 1 year after MI. Doses were classified as no beta‐blocker and >0% to 12.5%, >12.5% to 25%, >25% to 50%, and >50% of target doses used in randomized clinical trials. Age was 63 to 64 years, and approximately two thirds were men. Median follow‐up duration was 1.05 years (interquartile range, 0.98–1.22). When analyzed dichotomously, beta‐blocker therapy was not associated with improved survival. When analyzed by dose, propensity score analysis showed significantly increased mortality in the no–beta‐blocker group (hazard ratio,1.997; 95% CI, 1.118–3.568; P 0% to 12.5% group (hazard ratio, 1.817; 95% CI, 1.094–3.016; P 25% to 50% group (hazard ratio, 1.764; 95% CI, 1.105–2.815; P 12.5% to 25% dose group. The mortality in the full‐dose group was not significantly higher (hazard ratio, 1.196; 95% CI, 0.687–2.083). In subgroup analyses, only history of congestive heart failure demonstrated significant interaction with beta‐blocker effects on survival. Conclusions This analysis suggests that patients treated with >12.5% to 25% of the target dose used in prior randomized clinical trials beyond 1 year after MI may have enhanced survival compared with no beta‐blocker and other beta‐blocker doses. A new paradigm for post‐MI beta‐blocker therapy is needed that addresses which patients should be treated, for how long, and at what dose.

Background It remains unclear whether beta‐blocker use at hospital admission is associated with better in‐hospital outcomes in patients with acute decompensated heart failure. Methods and Results We evaluated the factors independently associated with beta‐blocker use at admission, and the effect of beta‐blocker use at admission on in‐hospital mortality in 3817 patients with acute decompensated heart failure enrolled in the Kyoto Congestive Heart Failure registry. There were 1512 patients (39.7%) receiving, and 2305 patients (60.3%) not receiving beta‐blockers at admission for the index acute decompensated heart failure hospitalization. Factors independently associated with beta‐blocker use at admission were previous heart failure hospitalization, history of myocardial infarction, atrial fibrillation, cardiomyopathy, and estimated glomerular filtration rate 2 . Factors independently associated with no beta‐blocker use were asthma, chronic obstructive pulmonary disease, lower body mass index, dementia, older age, and left ventricular ejection fraction P P P for interaction 0.04). Conclusions Beta‐blocker use at admission was associated with lower in‐hospital mortality in patients with acute decompensated heart failure. Registration URL: https://www.upload.umin.ac.jp/ ; Unique identifier: UMIN000015238.

Background Recurrence of cancer after curative surgery is a major problem after most cancer treatments. Increased sympathetic activity during the perioperative period could promote cancer cell invasion to blood vessels and angiogenesis, resulting in cancer metastasis. Recent studies showed that use of beta blockers can be associated with the prolonged survival of patients with cancer. The objective of this study is to evaluate the preventive effects of landiolol hydrochloride, which is an ultra-short-acting beta-1-selective blocker that has been developed in Japan, on reducing recurrence of cancer after curative surgery for patients with lung cancer. Methods The present study is a phase III, multicenter, randomized trial with two parallel groups of patients with lung cancer, comparing surgery alone and surgery with landiolol administration for three days during the perioperative period. A total of 400 patients will be enrolled from 12 Japanese institutions. The primary endpoint is two-year relapse-free survival and overall survival after curative surgery for lung cancer. The secondary endpoints are additional treatment after recurrence of cancer, safety events, and the incidence of postoperative complications. Discussion The principal question addressed in this trial is whether landiolol can reduce recurrence of cancer after curative surgery for lung cancer. Trial registration Japan Registry of Clinical Trials, jRCT2011180004. Registered 17 January 2019.

Introduction The role of losartan in preventing aortic root dilatation in Marfan syndrome has been evaluated in many clinical trials; however, the results are conflicting. Methods We performed a computerized search of MEDLINE, EMBASE and COCHRANE databases through February 2019 for randomized clinical trials evaluating the effect of losartan in patients with Marfan syndrome. The main outcome was the change in the aortic root diameter in the losartan versus control groups. Results Our final analysis included seven randomized trials with a total of 1352 patients and average weighted follow-up of 37.8 months. Change in aortic root diameter was significantly smaller with losartan compared with control [weighted means: 0.44 vs. 0.58 mm, mean difference (MD) = −0.13; 95% CI −0.24 to −0.02; p = 0.02]. Subgroup analysis according to the control group showed no significant subgroup interaction when comparing losartan with beta-blockers versus with standard therapy (pinteraction= 0.27). The composite outcome of aortic surgery, dissection or mortality did not differ between the losartan and control groups (risk ratio = 1.03; 95% CI 0.72–1.49, p = 0.86). Conclusion In this meta-analysis including seven randomized trials, the use of losartan was associated with a significantly smaller change in aortic root diameter in patients with Marfan syndrome. Electronic supplementary material The online version of this article (10.1007/s40119-019-00149-3) contains supplementary material, which is available to authorized users.

Background/Aims It is unknown whether different β-blockers (BBs) have variable effects on long-term survival of patients with heart failure with reduced ejection fraction (HFrEF). This study compares the effects of two BBs, carvedilol and bisoprolol, on survival in patients with HFrEF. Methods The Korean Acute Heart Failure (KorAHF) registry is a prospective multicenter cohort that includes 5,625 patients who were hospitalized for acute heart failure (AHF). We selected 3,016 patients with HFrEF and divided this study population into two groups: BB at discharge (n = 1,707) or no BB at discharge (n = 1,309). Among patients with BB at discharge, subgroups were formed based on carvedilol prescription (n = 831), or bisoprolol prescription (n = 553). Propensity score matching analysis was performed. Results Among patients who were prescribed a BB at discharge, 60.5% received carvedilol and 32.7% received bisoprolol. There was a significant reduction in allcause mortality in those patients with HFrEF prescribed a BB at discharge compared to those who were not (BB vs. no BB, 26.1% vs. 40.8%; hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.52 to 0.67; p < 0.001). However, there was no significant difference in the rate of all-cause mortality between those receiving different types of BB (carvedilol vs. bisoprolol, 27.5% vs. 23.5%; HR, 1.21; 95% CI, 0.99 to 1.47; p = 0.07). Similar results were observed after propensity score matching analysis (508 pairs, 26.2% vs. 23.8%; HR, 1.10; 95% CI, 0.86 to 1.40; p = 0.47). Conclusions In the treatment of AHF with reduced EF after hospitalization, mortality benefits of carvedilol and bisoprolol were comparable.

Background: We investigated the clinical usefulness of landiolol for rapid atrial fibrillation (AF) in patients with acute decompensated heart failure (ADHF) and identify the patients eligible for landiolol. Methods and Results: A total of 101 ADHF patients with reduced ejection fraction (HFrEF) with rapid AF were enrolled. Immediately after admission, an initial dose of landiolol was given (1 μg/kg−1/min−1), and then the dose was increased to decrease heart rate (HR) to 20% in ≤24 h. Thirty-seven were monitored using right heart catheterization at 3 points (baseline, 1 μg/kg−1/min−1, and maximum dose). We checked the major adverse events (MAE) during initial hospitalization, which included cardiac death, HF prolongation (required i.v. treatment at 30 days), and worsening renal function. The average maximum dose of landiolol was 3.8±2.3 μg/kg−1/min−1. HR (P97 mmHg had less frequent MAE (P

Introduction The antianginal effectiveness of ivabradine administration in addition to beta-blockers has been shown in patients with stable angina. The first fixed-dose combination (FDC) of ivabradine and metoprolol is now available and its evaluation in various stable angina patient populations relevant to clinical practice would be useful. Methods In this 4-month, prospective, multicenter, observational study, the effectiveness and tolerability of the metoprolol/ivabradine FDC was assessed in patient subgroups specified according to age, coronary artery disease (CAD) duration, Canadian Cardiovascular Society (CCS) class, co-morbidities, and previous myocardial infarction (MI) or revascularization. Heart rate (HR), angina attack frequency, short-acting nitrate (SAN) consumption, functional status, and medication adherence were documented at baseline and after 4 months of follow-up. Results A total of 747 stable angina patients were included and divided into subgroups. At 4 months, a significant decrease in HR, angina attack frequency, and SAN consumption per week was consistently observed across all patient subgroups. The proportion of CCS class I patients increased significantly from baseline to month 4. In all patient subgroups, at 4 months, a significant increase was observed in the proportion of patients with self-reported complete adherence. Complete adherence at the final visit was found to decrease with an increasing number of medications. Physicians evaluated the effectiveness and tolerability of the FDC as ‘very good’ and ‘good’ for more than 96% of patients in all analyzed patient subgroups. Conclusions Treatment with metoprolol/ivabradine FDC significantly improved angina symptoms and adherence, with an excellent tolerability profile, in stable angina patient subgroups relevant to real-life clinical practice, regardless of age, CAD duration, CCS class, comorbidities, previous MI, or history of revascularization. Trial registration ISRCTN51906157. Funding This study was sponsored by Servier Deutschland GmbH. Editorial assistance and the Rapid Service Fee were funded by Servier, France. Plain Language Summary Plain language summary available for this article.

Background: The comparative tolerability, efficacy, and safety of bisoprolol and carvedilol have not been established in Japanese patients with heart failure and reduced ejection fraction (HFrEF). Methods and Results: The CIBIS-J trial is a multicenter, open-label, non-inferiority randomized controlled trial of bisoprolol vs. carvedilol in 217 patients with HFrEF (EF

Midventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare form of hypertrophic cardiomyopathy (HCM). An 80-year-old man was administered bisoprolol and warfarin therapies as treatment for MVOHCM with an apex aneurysm due to myocardial damage and intra-aneurysmal thrombus not complicated by atrial fibrillation. The pressure gradient in the midventricle successfully improved from 53.9 to 21.8 mmHg, and the intra-aneurysmal thrombus disappeared.

Background: Although beta-blocker treatment is generally contraindicated in patients presenting with acute cocaine intoxication due to concern for unopposed alpha-receptor stimulation, some studies have reported that beta-blocker treatment did not increase adverse events in these patients. As this treatment is still controversial, we performed a meta-analysis of observational studies on this topic. Methods: By searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to June 11, 2018, we identified eight observational studies with 2,048 patients who presented to hospital with cocaine-associated chest pain or after recent cocaine use. Outcomes of interest were myocardial necrosis or infarction (MI) and death during hospital stay or follow-up. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated by using a random-effects meta-analysis based on the DerSimonian-Laird method. Results: Among patients presenting with cocaine-associated chest pain or recent cocaine use, there was no significant difference in in-hospital all-cause mortality (RR, 0.59; 95% CI, 0.24 - 1.47) and MI (RR, 1.24; 95% CI, 0.74 - 2.06) between patients who did and did not receive beta-blocker treatment during their hospital stay. During long-term follow-up (mean 2.6 years), there was no significant difference in all-cause mortality (RR, 0.79; 95% CI, 0.44 - 1.41) and MI (RR, 0.96; 95% CI, 0.40 - 2.33) between the two groups. Conclusions: These results suggest that beta-blocker treatment in patients presenting with cocaine intoxication may not be as harmful as originally believed. Further clinical studies are needed to investigate this topic. Cardiol Res. 2019;10(1):40-47 doi: https://doi.org/10.14740/cr831

Propranolol is a beta-adrenergic receptor antagonist that was developed by the British scientist Sir James Black primarily for the treatment of angina pectoris, more than 50 years ago. It was not long before several other cardiovascular as well as noncardiovascular therapeutic uses of propranolol were discovered. Propranolol soon became a powerful tool for physicians in the treatment of numerous conditions such as hypertension, cardiac arrhythmias, myocardial infarction, migraine, portal hypertension, anxiety, essential tremors, hyperthyroidism, and pheochromocytoma. Owing to its action at multiple receptor sites, propranolol exerts several central and peripheral effects and is therefore useful in various conditions. Right from reduction in postmyocardial mortality to control of anxiety in performers, propranolol plays an important role in a plethora of medical conditions. Interestingly, even today, newer indications of this age-old drug are being discovered. Moreover, propranolol treatment has been found to be cost-effective when compared to other corresponding treatment options for individual indications. In this article, we attempt to recount the journey of propranolol right from its inception to the present day.

Background A case report published in 2019 described a patient who presented with difficult-to-manage atrial fibrillation (AF) that consistently was associated with alcohol consumption. After the patient did not respond to drug therapy, a novel beta-blocker (BB) pretreatment regimen initiated immediately before alcohol consumption successfully prevented AF occurrence. Objective The purpose of this study was to test the hypothesis that a novel prophylactic BB therapy given before alcohol consumption could prevent AF in a rat model. Methods An alcohol-induced AF model was developed in adult Sprague-Dawley rats of both sexes by administering alcohol (2 g/kg intraperitoneal [IP]) once every other day for a total of 4 times. Three groups were enrolled: alcohol (EtOH; n = 10); alcohol plus BB (metoprolol 50 mg/kg IP) pretreatment (EtOH+BB; n = 10); and control (n = 9). Cardiac function (assessed by echocardiography and left ventricular hemodynamics) and in vivo atrial electrophysiology and AF inducibility tests were performed 24 hours after the last injection. Results All but 1 rat completed the study. Alcohol exposure did not significantly impact cardiac function and the atrial effective refractory period. However, alcohol exposure significantly increased AF inducibility [median (first and third quartile [Q1-Q3]) 0% (0%-0%) in control vs 60% (25%-100%) in the EtOH group; P

Background: The prevalence rate of hypertension and breast cancer increases with advancing age. Renin-angiotensin system inhibitors (RASIs), β-blockers (BBs), calcium channel blockers (CCBs), and diuretics are widely used to treat patients with hypertension. Although, the association between the use of antihypertensive medication and breast cancer has been highly debated, recent evidence supporting this association remains controversial.Objective: To evaluate the association between the use of antihypertensive medication and the risk of breast cancer and its prognosis.Methods: This study was conducted using data from the PubMed, Embase, and Cochrane Library databases retrieved for the period from January 2000 to April 2021. Articles and their references were checked and summary effects were calculated using random- and fixed-effects models. Heterogeneity test and sensitivity analysis were also performed.Results: This meta-analysis included 57 articles, which were all related to breast cancer risk or prognosis. Assessment of breast cancer risk using the pooled data showed that the use of BBs or CCBs or diuretics was associated with increased cancer risk [BB: relative risk (RR) = 1.20, 95% confidence interval (CI) = 1.09–1.32; CCBs: RR = 1.06, 95% CI 1.03–1.08; diuretics: RR = 1.06, 95% CI 1.01–1.11]. Long-term use of diuretic increased the risk of breast cancer (RR = 1.10, 95% CI 1.01–1.20), whereas long-term RASIs treatment reduced the risk (RR = 0.78, 95% CI 0.68–0.91). In addition, we found that diuretic users may be related to elevated breast cancer-specific mortality [hazard ratio (HR) = 1.18, 95% CI 1.04–1.33], whereas using other antihypertensive medications was not associated with this prognosis in patients with breast cancer.Conclusion: Using CCBs, BBs, and diuretics increased the risk of breast cancer. In addition, diuretics may elevate the risk of breast cancer-specific mortality. The long-term use of RASIs was associated with a significantly lower breast cancer risk, compared with non-users. Thus, this analysis provides evidence to support the benefits of the routine use of RASIs in patients with hypertension, which has important public health implications.

Background Withdrawal of optimal medical therapy has been reported to relapse cardiac dysfunction in patients with dilated cardiomyopathy (DCM) whose cardiac function had improved. However, it is unknown whether beta‐blockers can prevent deterioration of cardiac function in those patients. We examined the effect of beta‐blockers on left ventricular ejection fraction (LVEF) in recovered DCM. Methods and Results We analyzed the clinical personal record of DCM, a national database of the Japanese Ministry of Health, Labor and Welfare, between 2003 and 2014. Recovered DCM was defined as a previously documented LVEF 10% at 2 years of follow‐up. Of 5370 eligible patients, 4104 received beta‐blockers. Propensity score matching yielded 1087 pairs. Mean age was 61.9 years, and 1619 (74.5%) were men. Mean LVEF was 49.3±8.2%, and median B‐type natriuretic peptide was 46.6 (interquartile range, 18.0–118.1) pg/mL. The primary outcome was observed less frequently in the beta‐blocker group than in the no‐beta‐blocker group (19.6% versus 24.0%; odds ratio [OR], 0.77; 95% CI, 0.63–0.95; P =0.013). Subgroup analysis demonstrated that female patients (women: OR, 0.54; 95% CI, 0.36–0.81; men: OR, 0.88; 95% CI, 0.69–1.12; P for interaction=0.040) were benefited by beta‐blockers. Conclusions Beta‐blocker use could prevent deterioration of left ventricular systolic function in patients with recovered DCM.

BACKGROUND: Preclinical and retrospective studies suggest that beta-blockers are active against breast cancer. We carried out a systematic review and meta-analysis to assess the impact of beta-blockers on the outcomes of patients with early-stage breast cancer. METHODS: A systematic literature search was performed to identify studies comparing outcomes of patients with early-stage breast cancer according to beta-blocker use (yes versus no). The primary endpoint was recurrence-free survival (RFS), defined as the occurrence of breast cancer recurrence or death. Secondary objectives were pathologic complete response (pCR), breast cancer recurrence, breast cancer-specific mortality and overall survival (OS). Hazard ratios (HRs) or odds ratios (ORs) and 95% confidence intervals (CIs) were extracted from each study and a pooled analysis with the random-effect model was conducted. The Higgins' I-squared test was used to quantify heterogeneity. Egger's test was applied to assess publication bias. All P values were two-sided and considered significant if ≤0.05. RESULTS: Overall, 13 studies were included as follows: RFS (6), pCR (2), breast cancer recurrence (6), breast cancer-specific mortality (7) and OS (5). The use of beta-blockers was associated with a significant RFS improvement in the overall population (N = 21 570; HR 0.73; 95% CI, 0.56-0.96; P = 0.025) and in patients with triple-negative disease (N = 1212; HR 0.53; 95% CI, 0.35-0.81; P = 0.003). No significant differences in terms of pCR (N = 1554; OR 0.77; 95% CI, 0.44-1.36; P = 0.371), breast cancer recurrence (N = 37 957; OR 0.66; 95% CI, 0.42-1.03; P = 0.065), breast cancer-specific mortality (N = 64 830; HR 0.77; 95% CI, 0.56-1.08; P = 0.130) or OS (N = 103 065; HR 1.03; 95% CI, 0.87-1.23; P = 0.692) were observed according to beta-blocker use. DISCUSSION: In this meta-analysis, beta-blocker use was associated with a longer RFS in patients with early-stage breast cancer, with a more pronounced effect observed in those with triple-negative disease. Beta-blockers arise as an interesting option to be explored in prospective studies for patients with early-stage breast cancer., SCOPUS: re.j, info:eu-repo/semantics/published

Purpose of Review Controversy exists whether beta-blockers should be given before primary percutaneous coronary intervention (PCI) or to defer their administration for up to 24 hours. Recent Findings Animal studies, most of them conducted in the 1970s and 1980s, showed evidence that early beta-blocker administration may reduce infarct size. Subsequent human studies had mixed results on infarct size and survival. More specifically, in the current primary PCI era, only four studies evaluated the impact of early intravenous beta-blocker administration after acute myocardial infarction, only two of them before PCI. All studies agree that in hemodynamically stable patients, early intravenous beta-blocker administration is safe and protected against malignant arrhythmias. Nevertheless, results on infarct size and mortality are equivocal. Summary Considering the heterogeneity of currently available data, further studies are still needed to assess the benefit of early injection of metoprolol in STEMI patients in a large double-blinded and randomized design versus placebo.

Background/aims Long-term benefit of vasodilating β-blockers is unknown. This study aimed to investigate the long-term benefit of vasodilating β-blockers over conventional β-blockers in patients with acute myocardial infarction (AMI). Methods Using nationwide prospective multicenter Korean Acute Myocardial Infarction Registry data, we analyzed 3-year clinical outcomes of 7,269 patients with AMI who received percutaneous coronary intervention (PCI) and β-blocker therapy. Patients were classified according to treatment strategy (vasodilating β-blockers vs. conventional β-blockers). The primary endpoint was a composite of cardiac death, myocardial infarction (MI), and hospitalization for heart failure (HF) at 3 years. Secondary outcomes were each component of the primary outcome. Propensity score matching was performed to adjust for differences of baseline characteristics. Results In 3,079 pairs (6,158 patients) of propensity score-matched patients, the primary outcome occurred significantly less in the vasodilating β-blockers group compared with the conventional β-blockers group (7.6% vs. 9.8%, p = 0.003). Among the secondary outcomes, cardiac death occurred significantly less in the vasodilating β-blockers group than in the conventional group (3.5% vs. 4.8%, p = 0.015). The incidence rates of MI (2.4% vs. 3.0%, p = 0.160) or hospitalization for HF (2.6% vs. 3.2%, p = 0.192) were not significantly different between the two groups. Conclusions Vasodilating β-blocker therapy was associated with better clinical outcomes compared with conventional β-blocker therapy in AMI patients undergoing PCI during 3 years follow-up. Vasodilating β-blockers could be recommended preferentially for these patients.

Aim It has been suggested that repeated activation of the adrenergic system during antecedent episodes of hypoglycaemia contributes to the development of counterregulatory failure. We previously reported that treatment with carvedilol, a non‐specific β‐blocker, prevented the development of counterregulatory failure and improved hypoglycaemia awareness in recurrently hypoglycaemic non‐diabetic rats. The current study investigated whether carvedilol has similar benefits in diabetic rats. Methods Recurrently hypoglycaemic streptozotocin‐diabetic rats (STZ+RH) were treated with carvedilol for one week prior to undergoing a hypoglycaemic clamp. Hypoglycaemia awareness was evaluated in streptozotocin‐diabetic rats made hypoglycaemia unaware using repeated injections of 2‐deoxyglucose. Results Compared to hypoglycaemia‐naïve STZ‐diabetic controls, exogenous glucose requirements were more than doubled in the STZ+RH animals and this was associated with a 49% reduction in the epinephrine response to hypoglycaemia. Treating STZ+RH animals with carvedilol improved the epinephrine response to hypoglycaemia. Of note, neither recurrent hypoglycaemia nor carvedilol treatment affected the glucagon response in diabetic animals. Additionally, carvedilol treatment improved the feeding response to insulin‐induced hypoglycaemia in diabetic animals made ‘hypoglycaemia unaware’ using repeated injections of 2‐deoxyglucose, suggesting the treatment improved awareness of hypoglycaemia as well. Conclusion Our data suggest that carvedilol may be useful in preventing impairments of the sympathoadrenal response and the development of hypoglycaemia unawareness during recurring episodes of hypoglycaemia in diabetic animals., Patients with type 1 diabetes lose the ability to recognize when their blood glucose levels go low, and this is due in part to loss of the sympathoadrenal response. Treatment of diabetic rats with low doses of carvedilol improves the sympathoadrenal response to hypoglycemia and their ability to recognize hypoglycemia.

Potassium is an extracellular ion that plays an important role in the electrophysiological function of the heart. Any change in the extracellular concentration of potassium can have a marked impression upon cardiac electrophysiology. Underlying kidney disease, certain medical conditions, dietary indiscretions, and medications can precipitate hyperkalemia. Drug-induced hyperkalemia is one of the most important causes of increased serum potassium in everyday clinical practice. Hyperkalemia can lead to various life-threatening dysrhythmias and if left untreated, it will ultimately cause ventricular arrhythmias and asystole. This case report describes an end-stage renal disease (ESRD) patient taking atenolol who presented with hyperkalemia and type II second degree atrioventricular (AV) block. He presented with hyperkalemia when atenolol was introduced and normalized when atenolol was discontinued. The heart block completely resolved after treatment of hyperkalemia.

Background The use of preoperative beta-blockers has been accepted as a quality standard for patients undergoing coronary artery bypass graft (CABG) surgery. However, conflicting results from recent studies have raised questions concerning the effectiveness of this quality metric. We sought to determine the influence of preoperative beta-blocker administration before CABG in patients with left ventricular dysfunction. Methods The authors analyzed all cases of isolated CABGs in patients with left ventricular ejection fraction less than 50%, performed between 2012 January and 2017 June, at 94 centres recorded in the China Heart Failure Surgery Registry database. In addition to the use of multivariate regression models, a 1–1 propensity scores matched analysis was performed. Results Of 6116 eligible patients, 61.7% received a preoperative beta-blocker. No difference in operative mortality was found between two cohorts (3.7% for the non-beta-blockers group vs. 3.0% for the beta-blocker group; adjusted odds ratio [OR] 0.82 [95% CI 0.58–1.15]). Few differences in the incidence of other postoperative clinical end points were observed as a function of preoperative beta-blockers except in stroke (0.7% for the non-beta-blocker group vs. 0.3 for the beta-blocker group; adjusted OR 0.39 [95% CI 0.16–0.96]). Results of propensity-matched analyses were broadly consistent. Conclusions In this study, the administration of beta-blockers before CABG was not associated with improved operative mortality and complications except the incidence of postoperative stroke in patients with left ventricular dysfunction. A more granular quality metric which would guide the use of beta-blockers should be developed.