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Circulation Nov 2023Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin... (Randomized Controlled Trial)
Randomized Controlled Trial
Multicenter, Prospective, Randomized Controlled Trial of High-Sensitivity Cardiac Troponin I-Guided Combination Angiotensin Receptor Blockade and Beta-Blocker Therapy to Prevent Anthracycline Cardiotoxicity: The Cardiac CARE Trial.
BACKGROUND
Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy.
METHODS
In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%.
RESULTS
Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; =0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; =0.92, not equivalent).
CONCLUSIONS
Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline.
REGISTRATION
URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.
Topics: Humans; Female; Middle Aged; Male; Anthracyclines; Troponin I; Stroke Volume; Carvedilol; Cardiotoxicity; Ventricular Function, Left; Prospective Studies; Antibiotics, Antineoplastic; Breast Neoplasms; Adrenergic beta-Antagonists
PubMed: 37746692
DOI: 10.1161/CIRCULATIONAHA.123.064274 -
BMC Medicine Nov 2023People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
People with hypertension have a higher risk of developing Parkinson's disease (PD), epidemiological evidence suggests that multiple antihypertensives may affect the occurrence and development of PD with inconsistent results. With multisource data, we sought to determine whether specific antihypertensive classes elevated or reduced the risk for PD.
METHODS
We used a mixed methods approach that combines 4 methodologies. First, we conducted a disproportionality analysis using the reports causing adverse events in the US Food and Drug Administration Adverse Events Reporting System (FAERS) to explore the effect of different classes of antihypertensive medications on the risk of PD; based on the findings from FAERS, a meta-analysis and a UK Biobank cohort analysis were used to further assess the association of drug use with PD; finally, we employed Mendelian randomization (MR) analysis to validate the causal relationship between the drug target and the occurrence of PD.
RESULTS
In the disproportionality analysis using the FAERS (N = 187,266), nonselective beta-adrenoceptor blockers (NBBs) were demonstrated to have a significant association with PD (reporting odds ratio (ROR) = 3.13; 95% CI 2.33-4.22). In the meta-analysis of 12 studies with 12,183,809 participants, PD risk was elevated in NBBs (RR, 1.64; 95% CI, 1.19-2.09) when stratified by subtypes of BBs. Among the 105,763 participants included in the cohort analysis using data from the UK Biobank, individuals who used NBBs had a significantly increased risk of PD compared to nonusers (HR, 1.47; 95% CI 1.04-2.06). The MR analysis revealed a significant association between higher expression of the β2 adrenergic receptor (ADRB2) gene, a drug target blocked by NBBs, and a reduced risk of PD (OR, 0.85; 95% CI 0.73-0.99).
CONCLUSIONS
Our comprehensive study indicated that regular NBB use is associated with an increased risk of PD. In light of the detrimental effects of NBBs on PD, some people should choose alternative antihypertensive treatments.
Topics: Humans; Antihypertensive Agents; Parkinson Disease; Adrenergic beta-Antagonists; Receptors, Adrenergic; Benzenesulfonamides
PubMed: 37964359
DOI: 10.1186/s12916-023-03122-z -
Neuron Mar 2024Glucose homeostasis is controlled by brain-gut communications. Yet our understanding of the neuron-gut interface in the glucoregulatory system remains incomplete. Here,...
Glucose homeostasis is controlled by brain-gut communications. Yet our understanding of the neuron-gut interface in the glucoregulatory system remains incomplete. Here, we find that sympathetic nerves elevate postprandial blood glucose but restrict brain glucose utilization by repressing the release of glucagon-like peptide-1 (GLP-1) from enteroendocrine L cells. Sympathetic nerves are in close apposition with the L cells. Importantly, sympathetic denervation or intestinal deletion of the adrenergic receptor α2 (Adra2a) augments postprandial GLP-1 secretion, leading to reduced blood glucose levels and increased brain glucose uptake. Conversely, sympathetic activation shows the opposite effects. At the cellular level, adrenergic signaling suppresses calcium flux to limit GLP-1 secretion upon sugar ingestion. Consequently, abrogation of adrenergic signal results in a significant improvement in learning and memory ability. Together, our results reveal a sympathetic nerve-enteroendocrine unit in constraining GLP-1 secretion, thus providing a therapeutic nexus of mobilizing endogenous GLP-1 for glucose management and cognitive improvement.
Topics: Glucose; Glucagon-Like Peptide 1; Blood Glucose; Cell Communication; Brain; Cognition; Adrenergic Agents
PubMed: 38242116
DOI: 10.1016/j.neuron.2023.12.012 -
European Review For Medical and... Aug 2023The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for... (Review)
Review
The current opioid overdose crisis is characterized by the presence of unknown psychoactive adulterants. Xylazine is an alpha-2 receptor agonist that is not approved for human use but is commonly used in veterinary medicine due to its sedative and muscle-relaxant properties. Cases of human intoxication due to accidental or voluntary use have been reported since the 1980s. However, reports of adulteration of illicit opioids (heroin and illicit fentanyl) with xylazine have been increasing all over Western countries. In humans, xylazine causes respiratory depression, bradycardia, and hypotension-posing individuals, using xylazine-adulterated opioids. We present a narrative review of the latest intoxication cases related to xylazine, to bring awareness to readers and also to help pathologists to detect and deal with xylazine cases.
Topics: Humans; Xylazine; Analgesics, Opioid; Adrenergic alpha-2 Receptor Agonists; Hypnotics and Sedatives; Bradycardia
PubMed: 37606142
DOI: 10.26355/eurrev_202308_33305 -
Medicina Clinica Jun 2024In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological... (Review)
Review
In the last decades there has been progress in the treatment of essential tremor (TE) especially in the surgical field and to a lesser extent in the pharmacological field. We carry out a review of the currently available treatments. The first intervention is the use of non-pharmacological and non-surgical strategies (general advice, occupational therapy, speech therapy, psychotherapy). With discrete advances, the pharmacological treatment is not very satisfactory. Only 30-60% of patients have a positive response, and in these the anti-tremor effectiveness is 40-60%. The first-line drugs are still propranolol and primidone. In cases with severe tremor we will consider a surgical option, the method of choice being thalamotomy using high-intensity focused ultrasound. In the future we must continue to study the pathophysiology of TE, develop drugs specifically designed for TE and improve the technology of available invasive techniques.
Topics: Essential Tremor; Humans; Propranolol; Primidone; High-Intensity Focused Ultrasound Ablation; Anticonvulsants; Thalamus; Adrenergic beta-Antagonists
PubMed: 38553256
DOI: 10.1016/j.medcli.2023.12.013 -
Cleveland Clinic Journal of Medicine Mar 2024Medical management of benign prostatic hyperplasia (BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking... (Review)
Review
Medical management of benign prostatic hyperplasia (BPH) has progressed gradually in recent years and remains the starting point for most symptomatic patients seeking treatment. Beyond well-known alpha-blockers and 5-alpha reductase inhibitors, there is growing evidence for the use of phosphodiesterase-5 inhibitors and beta-3 agonists in managing the condition, which may afford additional relief of "bothersome" symptoms in some patients. This review details contemporary medical management of BPH with an emphasis on the indications for certain classes of pharmacotherapy and their relative benefits and side effects. Surgical and procedural treatment of BPH is covered in a separate review.
Topics: Male; Humans; Prostatic Hyperplasia; 5-alpha Reductase Inhibitors; Adrenergic alpha-Antagonists
PubMed: 38429006
DOI: 10.3949/ccjm.91a.23027 -
MMW Fortschritte Der Medizin May 2024
Topics: Humans; Myocardial Infarction; Adrenergic beta-Antagonists; Prognosis
PubMed: 38693364
DOI: 10.1007/s15006-024-3908-1 -
Hypertension (Dallas, Tex. : 1979) Nov 2023Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred... (Review)
Review
Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective β-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective β-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.
Topics: Humans; Aged; Antihypertensive Agents; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Hypertension; Adrenergic beta-Antagonists; Adrenergic alpha-Antagonists; Fractures, Bone; Osteoporosis; Receptors, Adrenergic, beta; Diuretics
PubMed: 37675564
DOI: 10.1161/HYPERTENSIONAHA.123.21648 -
Developmental Cell Nov 2023The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative...
The autonomic nervous system plays a pivotal role in cardiac repair. Here, we describe the mechanistic underpinning of adrenergic signaling in fibrotic and regenerative response of the heart to be dependent on immunomodulation. A pharmacological approach identified adrenergic receptor alpha-1 as a key regulator of macrophage phenotypic diversification following myocardial damage in zebrafish. Genetic manipulation and single-cell transcriptomics showed that the receptor signals activation of an "extracellular matrix remodeling" transcriptional program in a macrophage subset, which serves as a key regulator of matrix composition and turnover. Mechanistically, adrenergic receptor alpha-1-activated macrophages determine activation of collagen-12-expressing fibroblasts, a cellular determinant of cardiac regenerative niche, through midkine-mediated paracrine crosstalk, allowing lymphatic and blood vessel growth and cardiomyocyte proliferation at the lesion site. These findings identify the mechanism of adrenergic signaling in macrophage phenotypic and functional determination and highlight the potential of neural modulation for regulation of fibrosis and coordination of myocardial regenerative response.
Topics: Animals; Zebrafish; Adrenergic Agents; Myocardium; Extracellular Matrix; Macrophages; Fibrosis; Fibroblasts; Receptors, Adrenergic; Myocytes, Cardiac
PubMed: 37875117
DOI: 10.1016/j.devcel.2023.09.011 -
Journal of Molecular and Cellular... Jul 2023β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent...
β-adrenergic (β-AR) signaling is essential for the adaptation of the heart to exercise and stress. Chronic stress leads to the activation of Ca/calmodulin-dependent kinase II (CaMKII) and protein kinase D (PKD). Unlike CaMKII, the effects of PKD on excitation-contraction coupling (ECC) remain unclear. To elucidate the mechanisms of PKD-dependent ECC regulation, we used hearts from cardiac-specific PKD1 knockout (PKD1 cKO) mice and wild-type (WT) littermates. We measured calcium transients (CaT), Ca sparks, contraction and L-type Ca current in paced cardiomyocytes under acute β-AR stimulation with isoproterenol (ISO; 100 nM). Sarcoplasmic reticulum (SR) Ca load was assessed by rapid caffeine (10 mM) induced Ca release. Expression and phosphorylation of ECC proteins phospholambam (PLB), troponin I (TnI), ryanodine receptor (RyR), sarcoendoplasmic reticulum Ca ATPase (SERCA) were evaluated by western blotting. At baseline, CaT amplitude and decay tau, Ca spark frequency, SR Ca load, L-type Ca current, contractility, and expression and phosphorylation of ECC protein were all similar in PKD1 cKO vs. WT. However, PKD1 cKO cardiomyocytes presented a diminished ISO response vs. WT with less increase in CaT amplitude, slower [Ca] decline, lower Ca spark rate and lower RyR phosphorylation, but with similar SR Ca load, L-type Ca current, contraction and phosphorylation of PLB and TnI. We infer that the presence of PKD1 allows full cardiomyocyte β-adrenergic responsiveness by allowing optimal enhancement in SR Ca uptake and RyR sensitivity, but not altering L-type Ca current, TnI phosphorylation or contractile response. Further studies are necessary to elucidate the specific mechanisms by which PKD1 is regulating RyR sensitivity. We conclude that the presence of basal PKD1 activity in cardiac ventricular myocytes contributes to normal β-adrenergic responses in Ca handling.
Topics: Animals; Mice; Adrenergic Agents; Adrenergic beta-Agonists; Calcium; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Mice, Knockout; Myocytes, Cardiac; Phosphorylation; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum; Protein Kinase C
PubMed: 37149124
DOI: 10.1016/j.yjmcc.2023.05.001