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BioRxiv : the Preprint Server For... May 2024Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining...
BACKGROUND
Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining intracellular sodium and potassium gradients. However, the role of NKA in platelet function and thrombosis remains unclear.
METHODS
We utilized wild-type (WT, α) and NKA α1 heterozygous (α) mice, aged 8 to 16 weeks, of both sexes. An intravital microscopy-based, FeCl-induced carotid artery injury thrombosis model was employed for in vivo thrombosis assessment. Platelet transfusion assays were used to evaluate platelet NKA α1 function on thrombosis. Human platelets isolated from healthy donors and heart failure patients treated with/without digoxin were used for platelet function and signaling assay. Complementary molecular approaches were used for mechanistic studies.
RESULTS
NKA α1 haplodeficiency significantly reduced its expression on platelets without affecting sodium homeostasis. It significantly inhibited 7.5% FeCl-induced thrombosis in male but not female mice without disturbing hemostasis. Transfusion of α, but not α, platelets to thrombocytopenic WT mice substantially prolonged thrombosis. Treating WT mice with low-dose ouabain or marinobufagenin, both binding NKA α1 and inhibiting its ion-transporting function, markedly inhibited thrombosis in vivo. NKA α1 formed complexes with leucine-glycine-leucine (LGL)-containing platelet receptors, including P2Y12, PAR4, and thromboxane A2 receptor. This binding was significantly attenuated by LGL>SFT mutation or LGL peptide. Haplodeficiency of NKA α1 in mice or ouabain treatment of human platelets notably inhibited ADP-induced platelet aggregation. While not affecting 10% FeCl-induced thrombosis, NKA α1 haplodeficiency significantly prolonged thrombosis time in mice treated with an ineffective dose of clopidogrel.
CONCLUSION
NKA α1 plays an essential role in enhancing platelet activation through binding to LGL-containing platelet GPCRs. NKA α1 haplodeficiency or inhibition with low-dose ouabain and marinobufagenin significantly inhibited thrombosis and sensitized clopidogrel's anti-thrombotic effect. Targeting NKA α1 emerges as a promising antiplatelet and antithrombotic therapeutic strategy.
PubMed: 38798556
DOI: 10.1101/2024.05.13.593923 -
Internal and Emergency Medicine May 2024The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV)...
Combination therapy of beta-blockers and digoxin is associated with increased risk of major adverse cardiovascular events and all-cause mortality in patients with atrial fibrillation: a report from the GLORIA-AF registry.
The effect of digoxin and beta-blockers on cardiovascular outcomes and mortality remains unclear. The study aimed to determine differences in cardiovascular (CV) outcomes and death rates among patients with atrial fibrillation (AF) who were prescribed with beta-blockers, digoxin or combination therapy. Data from phase II/III of the prospective Global Registry on Long-Term Oral Anti-thrombotic Treatment in Patients with Atrial Fibrillation (GLORIA-AF) were analysed. The risk of major cardiovascular events (MACE) and death among patients with different prescriptions using COX proportional hazard regression was considered. Propensity score (PS) matching and weighting were further used to adjust for potential confounders of prescription use. A total of 14,201 patients [median age: 71.0 (IQR 64.0-77.0) years; 46.2% female] were recruited. After a median follow-up of 3.0 (IQR 2.4-3.1) years, 864 MACE, and 988 all-cause deaths were recorded. The incidence rate (IR) of MACE was 22.4 (95%CI 21.0-24.0) per 1000 person-years, while the IR of all-cause death was 25.4 (95%CI 23.8-27.0) per 1000 person-years. After multivariate adjustment with Cox regression, the risk of MACE (HR 1.35, 95% CI 1.09-1.68) and the risk of all-cause death (HR 1.28, 95%CI 1.04-1.57) were significantly higher in the combination therapy group, compared to the beta-blockers alone group. The risks of MACE and all-cause death remained significant in both PS matched and PS weighted cohort Among AF patients, combination therapy of beta-blockers and digoxin was associated with higher risks of MACE and all-cause death compared to beta-blockers alone.
PubMed: 38780748
DOI: 10.1007/s11739-024-03629-0 -
Scientific Reports May 2024Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely...
Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.
Topics: Humans; Drug Monitoring; Retrospective Studies; Male; Female; Tacrolimus; Vancomycin; Middle Aged; Aged; Digoxin; Intensive Care Units; Adult; Creatinine; Blood Urea Nitrogen; Natriuretic Peptide, Brain
PubMed: 38769456
DOI: 10.1038/s41598-024-62402-7 -
The Australian Journal of Rural Health May 2024Direct current cardioversion (DCCV) remains one of the recommended management strategies for symptomatic atrial fibrillation (AF). Antiarrhythmic drugs (AAD) are...
INTRODUCTION
Direct current cardioversion (DCCV) remains one of the recommended management strategies for symptomatic atrial fibrillation (AF). Antiarrhythmic drugs (AAD) are prescribed post procedure to maintain sinus rhythm (SR). Limited literature exists on the AAD prescribing practices and their efficacy, post-DCCV in rural Australia.
OBJECTIVE
The primary aim was to determine the preferred AAD post-DCCV and the factors affecting AAD prescribing practices. The secondary aim was to assess the efficacy of the AAD in maintaining SR.
DESIGN
A retrospective observational audit of patients with non-valvular AF who underwent successful elective DCCV for symptomatic AF, during 2015-2020 at a regional hospital in New South Wales (NSW) (Dubbo Base Hospital). Patients were followed up for a duration of 12 months post-DCCV.
RESULTS
233 patients underwent successful DCCV during the study duration. Amiodarone was the preferred AAD of choice post-DCCV followed by sotalol and flecainide, respectively (36.5% vs. 27.8% vs. 1.3%). 35.2% patients were not prescribed AAD. Amiodarone and sotalol had similar but modest efficacies and neither were superior to no AAD, in maintaining SR 12 months post-DCCV (AF recurrence rate 61.5% vs. 68.2% vs. 71.6% respectively, p = 0.37). Antecedent cerebrovascular accident (CVA), pulmonary disease, smoking, prior treatment with digoxin, diuretics and left ventricular (LV) dysfunction were factors that influenced AAD prescribing practices.
CONCLUSION
The study demonstrates equal efficacies of amiodarone, sotalol and no AAD in maintaining SR 12 months post-DCCV. Prescribing practices post-DCCV at Dubbo Base Hospital differ from observed national trends and guidelines. AAD prescription requires a multifaceted approach with a key consideration to prioritise safety over efficacy, being mindful of challenges in delivering optimal healthcare in a rural setting.
PubMed: 38766693
DOI: 10.1111/ajr.13138 -
Frontiers in Nutrition 2024Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites...
BACKGROUND
Nephritis is a pivotal catalyst in chronic kidney disease (CKD) progression. Although epidemiological studies have explored the impact of plasma circulating metabolites and drugs on nephritis, few have harnessed genetic methodologies to establish causal relationships.
METHODS
Through Mendelian randomization (MR) in two substantial cohorts, spanning large sample sizes, we evaluated over 100 plasma circulating metabolites and 263 drugs to discern their causal effects on nephritis risk. The primary analytical tool was the inverse variance weighted (IVW) analysis. Our bioinformatic scrutiny of GSE115857 (IgA nephropathy, 86 samples) and GSE72326 (lupus nephritis, 238 samples) unveiled anomalies in lipid metabolism and immunological characteristics in nephritis. Thorough sensitivity analyses (MR-Egger, MR-PRESSO, leave-one-out analysis) were undertaken to verify the instrumental variables' (IVs) assumptions.
RESULTS
Unique lipoprotein-related molecules established causal links with diverse nephritis subtypes. Notably, docosahexaenoic acid (DHA) emerged as a protective factor for acute tubulointerstitial nephritis (ATIN) (OR1 = 0.84, [95% CI 0.78-0.90], p1 = 0.013; OR2 = 0.89, [95% CI 0.82-0.97], p2 = 0.007). Conversely, multivitamin supplementation minus minerals notably increased the risk of ATIN (OR = 31.25, [95% CI 9.23-105.85], = 0.004). Reduced α-linolenic acid (ALA) levels due to lipid-lowering drugs were linked to both ATIN (OR = 4.88, [95% CI 3.52-6.77], < 0.001) and tubulointerstitial nephritis (TIN) (OR = 7.52, [95% CI 2.78-20.30], = 0.042). While the non-renal drug indivina showed promise for TIN treatment, the use of digoxin, hydroxocobalamin, and liothyronine elevated the risk of chronic tubulointerstitial nephritis (CTIN). Transcriptome analysis affirmed that anomalous lipid metabolism and immune infiltration are characteristic of IgA nephropathy and lupus nephritis. The robustness of these causal links was reinforced by sensitivity analyses and leave-one-out tests, indicating no signs of pleiotropy.
CONCLUSION
Dyslipidemia significantly contributes to nephritis development. Strategies aimed at reducing plasma low-density lipoprotein levels or ALA supplementation may enhance the efficacy of existing lipid-lowering drug regimens for nephritis treatment. Renal functional status should also be judiciously considered with regard to the use of nonrenal medications.
PubMed: 38765814
DOI: 10.3389/fnut.2024.1364841 -
BMC Cardiovascular Disorders May 2024Despite the strong evidence supporting guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF), prescription... (Comparative Study)
Comparative Study
BACKGROUND
Despite the strong evidence supporting guideline-directed medical therapy (GDMT) in patients with heart failure with reduced ejection fraction (HFrEF), prescription rates in clinical practice are still lacking.
METHODS
A survey containing 20 clinical vignettes of patients with HFrEF was answered by a national sample of 127 cardiologists and 68 internal/family medicine physicians. Each vignette had 4-5 options for adjusting GDMT and the option to make no medication changes. Survey respondents could only select one option. For analysis, responses were dichotomized to the answer of interest.
RESULTS
Cardiologists were more likely to make GDMT changes than general medicine physicians (91.8% vs. 82.0%; OR 1.84 [1.07-3.19]; p = 0.020). Cardiologists were more likely to initiate beta-blockers (46.3% vs. 32.0%; OR 2.38 [1.18-4.81], p = 0.016), angiotensin receptor blocker/neprilysin inhibitor (ARNI) (63.8% vs. 48.1%; OR 1.76 [1.01-3.09], p = 0.047), and hydralazine and isosorbide dinitrate (HYD/ISDN) (38.2% vs. 23.7%; OR 2.47 [1.48-4.12], p < 0.001) compared to general medicine physicians. No differences were found in initiating angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEi/ARBs), initiating mineralocorticoid receptor antagonist (MRA), sodium-glucose transporter protein 2 (SGLT2) inhibitors, digoxin, or ivabradine.
CONCLUSIONS
Our results demonstrate cardiologists were more likely to adjust GDMT than general medicine physicians. Future focus on improving GDMT prescribing should target providers other than cardiologists to improve care in patients with HFrEF.
Topics: Humans; Heart Failure; Practice Patterns, Physicians'; Stroke Volume; Practice Guidelines as Topic; Guideline Adherence; Male; Cardiologists; Female; Cardiovascular Agents; Health Care Surveys; Ventricular Function, Left; Middle Aged; Treatment Outcome; Clinical Decision-Making; Healthcare Disparities; Internal Medicine; General Practitioners; Aged; United States
PubMed: 38730379
DOI: 10.1186/s12872-024-03911-1 -
The American Journal of Emergency... Jul 2024Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status... (Observational Study)
Observational Study
BACKGROUND
Digoxin poisonings are relatively common and potentially fatal, requiring immediate therapeutic intervention, with special attention to the patient's hemodynamic status and the presence of electrocardiographic and electrolytic disturbances.
OBJECTIVE
To identify factors associated with seven-day and thirty-day mortality in digoxin poisoning.
DESIGN, SETTINGS AND PARTICIPANTS
A retrospective, observational, multicenter study was conducted across 15 Hospital Emergency Departments (HED) in Spain. All patients over 18 years of age who presented to participating HEDs from 2015 to 2021 were included. The inclusion criteria encompassed individuals meeting the criteria for digoxin poisoning, whether acute or chronic.
OUTCOMES MEASURE AND ANALYSIS
To identify independent factors associated with 7-day and 30-day mortality, a multivariate analysis was conducted. This analysis included variables of clinical significance, as well as those exhibiting a trend (p < 0.1) or significance in the bivariate analysis.
MAIN FINDINGS
A total of 658 cases of digoxin poisoning were identified. Mortality rates were 4.5% (30 patients) at seven days and 11.1% (73 patients) at thirty days. Regarding 7-day mortality, the mean age of deceased patients was comparable to survivors (84.7 (8.9) vs 83.9 (7.9) years; p = ns). The multivariate analysis revealed that factors independently associated with 7-day mortality encompassed the extent of dependence assessed by the Barthel Index (BI 60-89 OR 0.28; 95% CI 0.10-0.77; p = 0.014 and BI>90 OR 0.22; 95% CI 0.08-0.63; p = 0.005), the identification of ventricular arrhythmias (OR 1.34; 95% CI 1.34-25.21; p = 0.019), and the presence of circulatory (OR 2.84; 95% CI 1.19-6.27; p = 0.019) and neurological manifestations (OR 2.67; 95% CI 1.13-6.27; p = 0.025). Factors independently associated with 30-day mortality encompassed extent of dependence (BI 60-89 OR 0.37; 95% CI 0.20-0.71; p = 0.003 and BI>90 OR 0.18; 95% CI 0.09-0.39; p < 0.001) and the identification of circulatory (OR 2.13; 95% CI 1.10-4.15; p = 0.025) and neurological manifestations (OR 2.39; 95% CI 1.25-3.89; p = 0.006).
CONCLUSIONS
The study identifies the degree of dependency assessed by the Barthel Index and the presence of cardiovascular and neurological symptoms as independent predictors of both 7-day and 30-day mortality. Additionally, the detection of ventricular arrhythmia is also an independent factor for 7-day mortality.
Topics: Humans; Female; Digoxin; Male; Retrospective Studies; Aged; Aged, 80 and over; Spain; Emergency Service, Hospital; Risk Factors; Middle Aged
PubMed: 38713933
DOI: 10.1016/j.ajem.2024.04.048 -
British Journal of Cancer Jun 2024The National Institute for Health and Care Excellence (NICE) recommends that people aged 60+ years with newly diagnosed diabetes and weight loss undergo abdominal...
BACKGROUND
The National Institute for Health and Care Excellence (NICE) recommends that people aged 60+ years with newly diagnosed diabetes and weight loss undergo abdominal imaging to assess for pancreatic cancer. More nuanced stratification could lead to enrichment of these referral pathways.
METHODS
Population-based cohort study of adults aged 30-85 years at type 2 diabetes diagnosis (2010-2021) using the QResearch primary care database in England linked to secondary care data, the national cancer registry and mortality registers. Clinical prediction models were developed to estimate risks of pancreatic cancer diagnosis within 2 years and evaluated using internal-external cross-validation.
RESULTS
Seven hundred and sixty-seven of 253,766 individuals were diagnosed with pancreatic cancer within 2 years. Models included age, sex, BMI, prior venous thromboembolism, digoxin prescription, HbA1c, ALT, creatinine, haemoglobin, platelet count; and the presence of abdominal pain, weight loss, jaundice, heartburn, indigestion or nausea (previous 6 months). The Cox model had the highest discrimination (Harrell's C-index 0.802 (95% CI: 0.797-0.817)), the highest clinical utility, and was well calibrated. The model's highest 1% of predicted risks captured 12.51% of pancreatic cancer cases. NICE guidance had 3.95% sensitivity.
DISCUSSION
A new prediction model could have clinical utility in identifying individuals with recent onset diabetes suitable for fast-track abdominal imaging.
Topics: Humans; Pancreatic Neoplasms; Middle Aged; Female; Male; Aged; Adult; Diabetes Mellitus, Type 2; Risk Assessment; Aged, 80 and over; Risk Factors; Cohort Studies; England; Proportional Hazards Models
PubMed: 38702436
DOI: 10.1038/s41416-024-02693-9 -
Texas Heart Institute Journal Apr 2024Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart...
BACKGROUND
Atrial tachyarrhythmias are common and difficult to treat in adults with congenital heart disease. Dronedarone has proven effective in patients without congenital heart disease, but data are limited about its use in adults with congenital heart disease of moderate to great complexity.
METHODS
A single-center, retrospective chart review of 21 adults with congenital heart disease of moderate to great complexity who were treated with dronedarone for atrial tachyarrhythmias was performed.
RESULTS
The median (IQR) age at dronedarone initiation was 35 (27.5-39) years. Eleven patients (52%) were male. Ten patients (48%) had New York Heart Association class I disease, 10 (48%) had class II disease, and 1 (5%) had class III disease. Ejection fraction at initiation was greater than 55% in 11 patients (52%), 35% to 55% in 9 patients (43%), and less than 35% in 1 patient (5%). Prior treatments included β-blockers (71%), sotalol (38%), amiodarone (24%), digoxin (24%), and catheter ablation (38%). Rhythm control was complete in 5 patients (24%), partial in 6 (29%), and inadequate in 10 (48%). Two patients (10%) experienced adverse events, including nausea in 1 (5%) and cardiac arrest in 1 (5%), which occurred 48 months after initiation of treatment. There were no deaths during the follow-up period. The median (IQR) follow-up time for patients with complete or partial rhythm control was 20 (1-54) months.
CONCLUSION
Dronedarone can be effective for adult patients with congenital heart disease and atrial arrhythmias for whom more established therapies have failed, and with close monitoring it can be safely tolerated.
Topics: Humans; Dronedarone; Male; Retrospective Studies; Female; Adult; Heart Defects, Congenital; Anti-Arrhythmia Agents; Treatment Outcome; Heart Rate; Atrial Fibrillation; Amiodarone; Time Factors
PubMed: 38686681
DOI: 10.14503/THIJ-22-7993 -
International Journal of Molecular... Apr 2024Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous...
Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain-blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs' applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC-MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: C = 882.88 ± 21.82 ng/g; T = 0.08 ± 0.01 h; T = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: C = 145.24 ± 44.03 ng/g (undetectable at 60 min); T = 0.08 ± 0.02 h; T = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: C = 1072.3 ± 260.8 ng/g; T = 0.35 ± 0.19 h; T = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: C = 2558.0 ± 382.4 ng/g; T = 0.35 ± 0.13 h; T = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS.
Topics: Animals; Ouabain; Tissue Distribution; Injections, Intraperitoneal; Mice; Mice, Inbred C57BL; Male; Blood-Brain Barrier; Brain; Mass Spectrometry; Kidney; Liver; Chromatography, High Pressure Liquid; Myocardium; Cardiotonic Agents
PubMed: 38673903
DOI: 10.3390/ijms25084318