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Current Problems in Cardiology May 2023Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high... (Review)
Review
Heart failure with reduced ejection fraction (HFrEF) is a complex and progressive clinical condition characterized by dyspnea and functional impairment. HFrEF has a high burden of mortality and readmission rate making it one of the most significant public health challenges. Basic treatment strategies include diuretics for symptom relief and use of quadruple therapy (Angiotensin receptor blocker/neprilysin inhibitors, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors) for reduction in hospitalizations, all-cause mortality, and cardiovascular mortality. Despite compelling evidence of clinical benefit, guideline directed medical therapy is vastly underutilized in the real-world clinical practice. Other medications such as intravenous iron, ivabradine, hydralazine/nitrates and vericiguat may also have a role in certain subgroup of HFrEF patients. Specific groups of patients with HFrEF may also be candidates for various device therapies such as implanted cardioverter defibrillators, cardiac resynchronization therapy and trans catheter mitral valve repair. This review provides a comprehensive overview of drug and device management approaches for patients with HFrEF, recommendations for initiation and titrations of therapies, and challenges associated with guideline directed medical therapy in the management of patients with HFrEF (Graphical abstract).
Topics: Humans; Heart Failure; Angiotensin-Converting Enzyme Inhibitors; Stroke Volume; Adrenergic beta-Antagonists; Diuretics
PubMed: 36681212
DOI: 10.1016/j.cpcardiol.2023.101596 -
Annals of Medicine Dec 2022Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant... (Review)
Review
Phytochemicals have garnered much attention because they are useful in managing several human diseases. Yohimbine is one such phytochemical with significant pharmacological potential and could be exploited for research by medicinal chemists. It is an indole alkaloid obtained from various natural/synthetic sources. The research on yohimbine started early, and its use as a stimulant and aphrodisiac by humans has been reported for a long time. The pharmacological activity of yohimbine is mediated by the combined action of the central and peripheral nervous systems. It selectively blocks the pre and postsynaptic α-adrenergic receptors and has a moderate affinity for 1 and 2 subtypes. Yohimbine also binds to other behaviourally relevant monoaminergic receptors in the following order: α-2 NE > 5HT-1A>, 5HT-1B > 1-D > D3 > D2 receptors. The current review highlights some significant findings that contribute to developing yohimbine-based drugs. It also highlights the therapeutic potential of yohimbine against selected human diseases. However, further research is recommended on the pharmacokinetics, molecular mechanisms, and drug safety requirements using well-designed randomized clinical trials to produce yohimbine as a pharmaceutical agent for human use.Key MessagesYohimbine is a natural indole alkaloid with significant pharmacological potential.Humans have used it as a stimulant and aphrodisiac from a relatively early time.It blocks the pre- and postsynaptic α2-adrenergic receptors that could be exploited for managing erectile dysfunction, myocardial dysfunction, inflammatory disorders, and cancer.
Topics: Male; Humans; Yohimbine; Adrenergic alpha-Antagonists; Aphrodisiacs; Receptors, Adrenergic, alpha-2; Pharmaceutical Preparations
PubMed: 36263866
DOI: 10.1080/07853890.2022.2131330 -
Annales Pharmaceutiques Francaises Sep 2022Beta-blockers have long been successfully used for the treatment of both supraventricular and ventricular arrhythmias. However, differences exist between their chemical... (Review)
Review
OBJECTIVES
Beta-blockers have long been successfully used for the treatment of both supraventricular and ventricular arrhythmias. However, differences exist between their chemical structure, pharmacokinetic and pharmacodynamic properties (absorption, bioavailability, metabolism, hydrophilic or lipophilic character, selective or non-selective nature, the presence or absence of intrinsic sympathomimetic activity), which may confer different antiarrhythmic properties to different beta-blockers. The aim of this study was to analyze the current existing evidence for bisoprolol for the treatment of both supraventricular and ventricular arrhythmias.
MATERIAL AND METHODS
Using the keywords "bisoprolol" and "arrhythmias" or "atrial fibrillation" or "ventricular tachycardia" or "premature ventricular complexes" or "ventricular fibrillation", the Medline database was searched for articles in English or French until April 2020 assessing the role of bisoprolol in the treatment of arrhythmias. Data was then analyzed according to the type of arrhythmia treated and the quality of evidence using the GRADE approach.
RESULTS
A total of 325 studies were identified, of which 28 were considered relevant to the current topic. Among these studies, 19 assessed the role of bisoprolol for the treatment of supraventricular arrhythmias, 8 its role in treating ventricular arrhythmias and 1 its role in supraventricular and ventricular arrhythmias. The quality of evidence varied from low (7 studies) to high (5 studies).
CONCLUSION
Current evidence exists supporting the use of bisoprolol for the treatment of supraventricular arrhythmias, especially for rate control during atrial fibrillation. Evidence also exists for its efficacy in the treatment of ventricular arrhythmias, both in primary and in secondary prevention.
Topics: Adrenergic beta-Antagonists; Atrial Fibrillation; Bisoprolol; Humans
PubMed: 35093388
DOI: 10.1016/j.pharma.2022.01.007 -
Nature Nov 2023Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI). Noradrenaline levels are increased after TBI, and the amplitude of the...
Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI). Noradrenaline levels are increased after TBI, and the amplitude of the increase in noradrenaline predicts both the extent of injury and the likelihood of mortality. Glymphatic impairment is both a feature of and a contributor to brain injury, but its relationship with the injury-associated surge in noradrenaline is unclear. Here we report that acute post-traumatic oedema results from a suppression of glymphatic and lymphatic fluid flow that occurs in response to excessive systemic release of noradrenaline. This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.
Topics: Animals; Mice; Adrenergic Antagonists; Brain Edema; Brain Injuries, Traumatic; Disease Models, Animal; Glymphatic System; Inflammation; Lymphatic Vessels; Norepinephrine; Phosphorylation; Receptors, Adrenergic
PubMed: 37968397
DOI: 10.1038/s41586-023-06737-7 -
Psychiatry Research Nov 2022Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from... (Review)
Review
Algorithms for posttraumatic stress disorder were published by this team in 1999 and 2011. Developments since then warrant revision. New studies and review articles from January 2011 to November 2021 were identified via PubMed and analyzed for evidence supporting changes. Following consideration of variations required by special patient populations, treatment of sleep impairments remains as the first recommended step. Nightmares and non-nightmare disturbed awakenings are best addressed with the anti-adrenergic agent prazosin, with doxazosin and clonidine as alternatives. First choices for difficulty initiating sleep include hydroxyzine and trazodone. If significant non-sleep PTSD symptoms remain, an SSRI should be tried, followed by a second SSRI or venlafaxine as a third step. Second generation antipsychotics can be considered, particularly for SSRI augmentation when PTSD-associated psychotic symptoms are present, with the caveat that positive evidence is limited and side effects are considerable. Anti-adrenergic agents can also be considered for general PTSD symptoms if not already tried, though evidence for daytime use lags that available for sleep. Regarding other pharmacological and procedural options, e.g., transcranial magnetic stimulation, cannabinoids, ketamine, psychedelics, and stellate ganglion block, evidence does not yet support firm inclusion in the algorithm. An interactive version of this work can be found at www.psychopharm.mobi.
Topics: Humans; Stress Disorders, Post-Traumatic; Psychopharmacology; Prazosin; Dreams; Sleep Wake Disorders; Sleep Initiation and Maintenance Disorders; Adrenergic Antagonists
PubMed: 36162349
DOI: 10.1016/j.psychres.2022.114840 -
Pharmacological Research Jan 2020The pharmacological class of β-blockers includes a plea of molecules with largely different pharmacokinetic and pharmacodynamic characteristics with a protective effect... (Review)
Review
The pharmacological class of β-blockers includes a plea of molecules with largely different pharmacokinetic and pharmacodynamic characteristics with a protective effect that may span far beyond the cardiovascular system. Although all these compounds share the pharmacological blockade of the adrenergic receptors, each of them is characterized by specific pharmacological properties, including selectivity of action depending on the adrenergic receptors subtypes, intrinsic sympathomimetic activity (ISA), lipid solubility, pharmacokinetic profile, and also other ancillary properties that impact their clinical effect. Their use in the treatment of hypertension has been extensively debated and at the moment a class indication is not present. However, in specific niche of patients, such as in those young individuals in which hypertension is mainly driven by a sympathetic hyperactivation, strong evidence pose β-Blockers as a highly reasonable first-line treatment. Lipophilic β-blockers, specifically propranolol and metoprolol, can cross the Blood Brain Barrier and have a Class A indication for the prophylactic treatment of migraine attacks. Moreover, since β-adrenergic receptors affect the proliferative process of both cancer and immune cells, their blockade has been associated with metastasis reduction in several epithelial and solid organ tumors posing β-Blockers as a new attractive, inexpensive and relatively safe therapeutic strategy in patients with several types of cancer. However, further dedicated prospective, randomized, placebo-controlled studies are needed to determine the real efficacy of these compounds.
Topics: Adrenergic beta-Antagonists; Animals; Humans; Hypertension; Migraine Disorders; Neoplasms
PubMed: 31809852
DOI: 10.1016/j.phrs.2019.104587 -
The New England Journal of Medicine Dec 2019Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.
METHODS
In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.
RESULTS
A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.
CONCLUSIONS
Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.).
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Aged, 80 and over; Disease Progression; Female; Forced Expiratory Volume; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Metoprolol; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Treatment Failure
PubMed: 31633896
DOI: 10.1056/NEJMoa1908142 -
Journal of the American College of... Dec 2021The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The use of β-adrenergic receptor blocking agents in symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM) rests on clinical experience and observational cohort studies.
OBJECTIVES
This study aimed to investigate the effects of metoprolol on left ventricular outflow tract (LVOT) obstruction, symptoms, and exercise capacity in patients with obstructive HCM.
METHODS
This double-blind, placebo-controlled, randomized crossover trial enrolled 29 patients with obstructive HCM and New York Heart Association (NYHA) functional class II or higher symptoms from May 2018 to September 2020. Patients received metoprolol or placebo for 2 consecutive 2-week periods in random order. The effect parameters were LVOT gradients, NYHA functional class, Canadian Cardiovascular Society (CCS) angina class, Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), and cardiopulmonary exercise testing.
RESULTS
Compared with placebo, the LVOT gradient during metoprolol was lower at rest (25 mm Hg [interquartile range (IQR): 15-58 mm Hg] vs 72 mm Hg [IQR: 28-87 mm Hg]; P = 0.007), at peak exercise (28 mm Hg [IQR: 18-40 mm Hg] vs 62 mm Hg [IQR: 31-113 mm Hg]; P < 0.001), and postexercise (45 mm Hg [IQR: 24-100 mm Hg] vs 115 mm Hg [IQR: 55-171 mm Hg]; P < 0.0001). During metoprolol treatment, 14% of patients were in NYHA functional class III or higher compared with 38% of patients receiving placebo (P < 0.01). Similarly, no patients were in CCS class III or higher during metoprolol treatment compared with 10% during placebo treatment (P < 0.01). These findings were confirmed by higher KCCQ-OSS during metoprolol treatment (76.2 ± 16.2 vs 73.8 ± 19.5; P = 0.039). Measures of exercise capacity, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide did not differ between the study arms.
CONCLUSIONS
Compared with placebo, metoprolol reduced LVOT obstruction at rest and during exercise, provided symptom relief, and improved quality of life in patients with obstructive HCM. Maximum exercise capacity remained unchanged. (The Effect of Metoprolol in Patients with Hypertrophic Obstructive Cardiomyopathy [TEMPO]; NCT03532802).
Topics: Adrenergic beta-1 Receptor Antagonists; Aged; Cardiomyopathy, Hypertrophic; Cross-Over Studies; Double-Blind Method; Exercise Tolerance; Female; Humans; Male; Metoprolol; Middle Aged; Ventricular Outflow Obstruction
PubMed: 34915981
DOI: 10.1016/j.jacc.2021.07.065 -
Circulation Nov 2023Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor...
BACKGROUND
Hypercontractility and arrhythmia are key pathophysiologic features of hypertrophic cardiomyopathy (HCM), the most common inherited heart disease. β-Adrenergic receptor antagonists (β-blockers) are the first-line therapy for HCM. However, β-blockers commonly selected for this disease are often poorly tolerated in patients, where heart-rate reduction and noncardiac effects can lead to reduced cardiac output and fatigue. Mavacamten, myosin ATPase inhibitor recently approved by the US Food and Drug Administration, has demonstrated the ability to ameliorate hypercontractility without lowering heart rate, but its benefits are so far limited to patients with left ventricular (LV) outflow tract obstruction, and its effect on arrhythmia is unknown.
METHODS
We screened 21 β-blockers for their impact on myocyte contractility and evaluated the antiarrhythmic properties of the most promising drug in a ventricular myocyte arrhythmia model. We then examined its in vivo effect on LV function by hemodynamic pressure-volume loop analysis. The efficacy of the drug was tested in vitro and in vivo compared with current therapeutic options (metoprolol, verapamil, and mavacamten) for HCM in an established mouse model of HCM ( and induced pluripotent stem cell (iPSC)-derived cardiomyocytes from patients with HCM ().
RESULTS
We identified that carvedilol, a β-blocker not commonly used in HCM, suppresses contractile function and arrhythmia by inhibiting RyR2 (ryanodine receptor type 2). Unlike metoprolol (a β-blocker), carvedilol markedly reduced LV contractility through RyR2 inhibition, while maintaining stroke volume through α-adrenergic receptor inhibition in vivo. Clinically available carvedilol is a racemic mixture, and the R-enantiomer, devoid of β-blocking effect, retains the ability to inhibit both α-receptor and RyR2, thereby suppressing contractile function and arrhythmias without lowering heart rate and cardiac output. In mice, R-carvedilol normalized hyperdynamic contraction, suppressed arrhythmia, and increased cardiac output better than metoprolol, verapamil, and mavacamten. The ability of R-carvedilol to suppress contractile function was well retained in iPSC-derived cardiomyocytes.
CONCLUSIONS
R-enantiomer carvedilol attenuates hyperdynamic contraction, suppresses arrhythmia, and at the same time, improves cardiac output without lowering heart rate by dual blockade of α-adrenergic receptor and RyR2 in mouse and human models of HCM. This combination of therapeutic effects is unique among current therapeutic options for HCM and may particularly benefit patients without LV outflow tract obstruction.
Topics: Humans; Mice; Animals; Carvedilol; Metoprolol; Ryanodine Receptor Calcium Release Channel; Cardiomyopathy, Hypertrophic; Arrhythmias, Cardiac; Adrenergic beta-Antagonists; Myocytes, Cardiac; Verapamil; Receptors, Adrenergic
PubMed: 37850394
DOI: 10.1161/CIRCULATIONAHA.123.065017 -
Nature Feb 2020The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres...
The solid tumour microenvironment includes nerve fibres that arise from the peripheral nervous system. Recent work indicates that newly formed adrenergic nerve fibres promote tumour growth, but the origin of these nerves and the mechanism of their inception are unknown. Here, by comparing the transcriptomes of cancer-associated trigeminal sensory neurons with those of endogenous neurons in mouse models of oral cancer, we identified an adrenergic differentiation signature. We show that loss of TP53 leads to adrenergic transdifferentiation of tumour-associated sensory nerves through loss of the microRNA miR-34a. Tumour growth was inhibited by sensory denervation or pharmacological blockade of adrenergic receptors, but not by chemical sympathectomy of pre-existing adrenergic nerves. A retrospective analysis of samples from oral cancer revealed that p53 status was associated with nerve density, which was in turn associated with poor clinical outcomes. This crosstalk between cancer cells and neurons represents mechanism by which tumour-associated neurons are reprogrammed towards an adrenergic phenotype that can stimulate tumour progression, and is a potential target for anticancer therapy.
Topics: Adrenergic Antagonists; Adrenergic Neurons; Animals; Cell Division; Cell Transdifferentiation; Cellular Reprogramming; Disease Models, Animal; Disease Progression; Female; Humans; Male; Mice; Mice, Inbred BALB C; MicroRNAs; Mouth Neoplasms; Nerve Fibers; Neurites; Receptors, Adrenergic; Retrospective Studies; Sensory Receptor Cells; Tumor Microenvironment; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays
PubMed: 32051587
DOI: 10.1038/s41586-020-1996-3