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European Review For Medical and... Aug 2023This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure...
OBJECTIVE
This study aimed to investigate the effect of digoxin on mortality and rehospitalization in heart failure with reduced ejection fraction (HFrEF) patients. Heart failure is a clinical syndrome that requires frequent rehospitalization and has a high mortality. This study aimed to investigate the effect of digoxin on mortality and rehospitalization in patients with heart failure with reduced ejection fraction.
PATIENTS AND METHODS
The study included 326 patients with HFrEF that were hospitalized for decompensation between September 2014 and January 2016. The patients were divided into two groups: digoxin users and a control group. The study's endpoints were cardiovascular death and rehospitalization after 24-month long-term follow-ups.
RESULTS
Rehospitalization was lower in patients taking digoxin (25% vs. 47%, p = 0.001). The mean age of patients taking digoxin (n: 78) was 63.7 ± 12.4 years, among which 64% were males. The mean age of the control group was 65.4 ± 11.8 years, among which 74% were males. However, there was no difference in mortality between the two groups (34% vs. 45%, p = 0.10). While Kaplan-Meier curves revealed no significant differences between mortality rates in the groups (log-rank p = 0.508), a statistical difference was found between the groups in rehospitalization rates (log-rank p = 0.013). A multiple linear regression analysis revealed that smoking (HR: 1.97, CI: 1.24-3.11, p = 0.004), systolic blood pressure (HR: 0.983, CI: 0.974-0.992, p < 0.001), atrial fibrillation (HR: 2.09, CI: 1.17-3.72, p = 0.012), C-reactive protein (CRP) (HR: 1.009, CI: 1.003-1.015, p = 0.004), beta-blockers (HR: 0.891, CI: 0.799-0.972, p = 0.009), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (HR: 0.778, CI: 0.641-0.956, p < 0.001), mineralocorticoid receptor antagonists (HR: 0.41, CI:0.26-0.65, p < 0.001), and digoxin use (HR: 0.59, CI: 0.43-0.80, p = 0.001) are independent predictors of rehospitalization in patients with HFrEF.
CONCLUSIONS
Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.
Topics: Male; Humans; Middle Aged; Aged; Female; Heart Failure; Digoxin; Stroke Volume; Atrial Fibrillation; Prognosis
PubMed: 37606130
DOI: 10.26355/eurrev_202308_33294 -
Journal of Arrhythmia Dec 2023Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF....
OBJECTIVE
Depression and anxiety show a bidirectional relationship with atrial fibrillation (AF). Antidepressant use is associated with a reduction in the incidence of AF. However, no studies have examined the relationship between antidepressant use and AF burden (time in AF). This retrospective cohort study examined cardiac implantable device-detected AF episodes and their relationship with antidepressant use, among other treatment factors.
METHODS
Consecutive patients from the Western Health Cardiology Department attending pacemaker checks between 2015 and 2021 were included. Patients with permanent AF were excluded, yielding 285 patients with no or paroxysmal AF, with a total of 772 patient encounters. Generalized estimating equations were used to model two processes: binary AF (present/absent) and the number of days in AF for patients with AF.
RESULTS
Each yearly increase with age was associated with an increase in the odds of developing AF (OR 1.03 [1.00-1.05], = .027). Male gender conferred a reduction in AF incidence (OR 0.30 [0.13-0.68], = .004). Digoxin use was associated with incident AF (OR 4.43 [1.07-18.4], = .04). Sotalol and heart-failure beta blocker use were associated with a decrease in AF burden (IRR 0.30 [0.12-0.78], = .013 and 0.33 [0.14-0.81], = .015). Selective serotonin reuptake inhibitor antidepressant use was associated with reduced AF burden (IRR 0.27 [0.09-0.81], = .019), as was selective serotonin/noradrenaline reuptake inhibitor use (IRR 0.07 [0.03-0.15], < .001).
CONCLUSIONS
Older age, female gender and digoxin are associated with a higher odds of developing incident AF. Sotalol, heart failure beta blockers and serotonin-based antidepressants are associated with reduced AF burden. Further prospective study into the effects of antidepressants on atrial arrhythmias is warranted.
PubMed: 38045466
DOI: 10.1002/joa3.12948 -
Pediatric Cardiology Apr 2024Digoxin is used in children with heart failure and tachyarrhythmia. Its use in patients with single ventricle anatomy has increased following evidence of improved... (Review)
Review
Digoxin is used in children with heart failure and tachyarrhythmia. Its use in patients with single ventricle anatomy has increased following evidence of improved interstage survival after the Norwood procedure. Digoxin has a narrow therapeutic window and may alter serum potassium balance, inducing arrhythmias. We hypothesized digoxin use in the setting of abnormal serum potassium levels is associated with arrhythmias. We reviewed all patients ≤ 18 years who received digoxin while admitted at our institution from 2014 to 2021. Admissions < 2 nights were excluded. We compared patients with a hemodynamically significant arrhythmia to those without. We performed adjusted mixed-effects logistic regression with arrhythmia as the outcome variable and potassium status as the predictor variable; adjusting for weight, route of digoxin administration, digoxin indication, serum creatinine, and number of interacting drugs prescribed. Abnormal potassium was defined as serum levels < 3.5 mmol/L or > 6.0 mmol/L. There were 268 encounters in 171 patients. Potassium levels were abnormal in 75.5% of patients who experienced an arrhythmia during digoxin administration, compared to 42.6% who did not (p < 0.001). Odds of arrhythmia was 138% higher in patients with abnormal potassium receiving digoxin (AOR = 2.38, 95% CI 1.07-5.29, p = 0.03). Receiving intravenous digoxin was also associated with a 7.35 odds of cardiac arrhythmia (AOR 7.35, p = 0.006, 95% CI 1.79-30.26). Odds of arrhythmia is increased during digoxin administration when pediatric patients have abnormal potassium levels. Vigilant attention to potassium levels is essential to prevent adverse outcomes during digoxin therapy.
Topics: Humans; Child; Digoxin; Potassium; Arrhythmias, Cardiac; Tachycardia; Norwood Procedures
PubMed: 36403164
DOI: 10.1007/s00246-022-03051-3 -
American Journal of Physiology. Cell... Apr 2024Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the... (Review)
Review
Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na/Ca exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology.
Topics: Humans; Rats; Animals; Ouabain; Sodium-Potassium-Exchanging ATPase; Ligands; Digoxin; Cardiotonic Agents; Hypertension; Heart Failure; Enzyme Inhibitors; Calcium Signaling; Binding Sites
PubMed: 38223926
DOI: 10.1152/ajpcell.00273.2023 -
Europace : European Pacing,... Dec 2023Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in...
AIMS
Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in contemporary global cohorts. We aimed to investigate the association between AF and COPD, in relation to treatment patterns and major outcomes.
METHODS AND RESULTS
From the prospective, global GLORIA-AF registry, we analysed factors associated with COPD diagnosis, as well as treatment patterns and risk of major outcomes in relation to COPD. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACEs). A total of 36 263 patients (mean age 70.1 ± 10.5 years, 45.2% females) were included; 2,261 (6.2%) had COPD. The prevalence of COPD was lower in Asia and higher in North America. Age, female sex, smoking, body mass index, and cardiovascular comorbidities were associated with the presence of COPD. Chronic obstructive pulmonary disease was associated with higher use of oral anticoagulant (OAC) [adjusted odds ratio (aOR) and 95% confidence interval (CI): 1.29 (1.13-1.47)] and higher OAC discontinuation [adjusted hazard ratio (aHR) and 95% CI: 1.12 (1.01-1.25)]. Chronic obstructive pulmonary disease was associated with less use of beta-blocker [aOR (95% CI): 0.79 (0.72-0.87)], amiodarone and propafenone, and higher use of digoxin and verapamil/diltiazem. Patients with COPD had a higher hazard of primary composite outcome [aHR (95% CI): 1.78 (1.58-2.00)]; no interaction was observed regarding beta-blocker use. Chronic obstructive pulmonary disease was also associated with all-cause death [aHR (95% CI): 2.01 (1.77-2.28)], MACEs [aHR (95% CI): 1.41 (1.18-1.68)], and major bleeding [aHR (95% CI): 1.48 (1.16-1.88)].
CONCLUSION
In AF patients, COPD was associated with differences in OAC treatment and use of other drugs; Patients with AF and COPD had worse outcomes, including higher mortality, MACE, and major bleeding.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Atrial Fibrillation; Prospective Studies; Risk Factors; Pulmonary Disease, Chronic Obstructive; Hemorrhage; Anticoagulants; Registries; Stroke
PubMed: 38266129
DOI: 10.1093/europace/euae021 -
Journal of Applied Oral Science :... 2023To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL).
OBJECTIVE
To evaluate the influence of RORγT inhibition by digoxin on inflammatory changes related to interleukin-17 (IL-17) in the pulp of rats treated with zoledronate (ZOL).
METHODOLOGY
Forty male Wistar rats were divided into a negative control group (NCG) treated with saline solution, a positive control group (PCG) treated with ZOL (0.20 mg/kg), and three groups treated with ZOL and co-treated with digoxin 1, 2, or 4 mg/kg (DG1, 2, and 4). After four intravenous administrations of ZOL or saline solution in a 70-day protocol, the right molars were evaluated by histomorphometry (number of blood vessels, blood vessels/µm2, cells/µm2, total blood vessel area, and average blood vessel area) and immunohistochemistry (IL-17, TNF-α, IL-6, and TGF-β). The Kruskal-Wallis/Dunn test was used for statistical analysis.
RESULTS
PCG showed an increase in total blood vessel area (p=0.008) and average blood vessel area (p=0.014), and digoxin treatment reversed these changes. DG4 showed a reduction in blood vessels/µm2 (p<0.001). In PCG odontoblasts, there was an increase in IL-17 (p=0.002) and TNF-α (p=0.002) immunostaining, and in DG4, these changes were reversed. Odontoblasts in the digoxin-treated groups also showed an increase in IL-6 immunostaining (p<0.001) and a reduction in TGF-β immunostaining (p=0.002), and all ZOL-treated groups showed an increase in IL-17 (p=0.011) and TNF-α (p=0.017) in non-odontoblasts cells.
CONCLUSION
ZOL induces TNF-α- and IL-17-dependent vasodilation and ectasia, and the classical Th17 response activation pathway does not seem to participate in this process.
Topics: Rats; Male; Animals; Zoledronic Acid; Interleukin-17; Rats, Wistar; Dental Pulp; Tumor Necrosis Factor-alpha; Interleukin-6; Saline Solution; Inflammation; Transforming Growth Factor beta; Digoxin; Immunity
PubMed: 37820184
DOI: 10.1590/1678-7757-2023-0230 -
International Journal of Molecular... Mar 2024Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for... (Review)
Review
Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.
Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include β-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.
Topics: Humans; Heart Failure; Stroke Volume; Hydralazine; Isosorbide Dinitrate; Angiotensin Receptor Antagonists; Multicenter Studies as Topic; Urea
PubMed: 38542088
DOI: 10.3390/ijms25063113 -
Cells Dec 2023Inflamed and infected tissues can display increased local sodium (Na) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a...
Inflamed and infected tissues can display increased local sodium (Na) levels, which can have various effects on immune cells. In macrophages, high salt (HS) leads to a Na/Ca-exchanger 1 (NCX1)-dependent increase in intracellular Na levels. This results in augmented osmoprotective signaling and enhanced proinflammatory activation, such as enhanced expression of type 2 nitric oxide synthase and antimicrobial function. In this study, the role of elevated intracellular Na levels in macrophages was investigated. Therefore, the Na/K-ATPase (NKA) was pharmacologically inhibited with two cardiac glycosides (CGs), ouabain (OUA) and digoxin (DIG), to raise intracellular Na without increasing extracellular Na levels. Exposure to HS conditions and treatment with both inhibitors resulted in intracellular Na accumulation and subsequent phosphorylation of p38/MAPK. The CGs had different effects on intracellular Ca and K compared to HS stimulation. Moreover, the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5) was not upregulated on RNA and protein levels upon OUA and DIG treatment. Accordingly, OUA and DIG did not boost nitric oxide (NO) production and showed heterogeneous effects toward eliminating intracellular bacteria. While HS environments cause hypertonic stress and ionic perturbations, cardiac glycosides only induce the latter. Cotreatment of macrophages with OUA and non-ionic osmolyte mannitol (MAN) partially mimicked the HS-boosted antimicrobial macrophage activity. These findings suggest that intracellular Na accumulation and hypertonic stress are required but not sufficient to mimic boosted macrophage function induced by increased extracellular sodium availability.
Topics: Humans; Sodium; Cardiac Glycosides; Ouabain; Macrophages; Sodium Chloride; Sodium Chloride, Dietary; Caffeine; Anti-Infective Agents
PubMed: 38132136
DOI: 10.3390/cells12242816 -
Cureus Mar 2024Digoxin, a cardiac glycoside derived from the foxglove plant ( spp.), has been utilized for centuries in managing various cardiac conditions due to its ability to... (Review)
Review
Digoxin, a cardiac glycoside derived from the foxglove plant ( spp.), has been utilized for centuries in managing various cardiac conditions due to its ability to increase myocardial contractility and regulate heart rate. This comprehensive review explores the historical context, pharmacological properties, clinical applications, efficacy, safety profile, challenges, and future perspectives of digoxin. Tracing its journey from traditional medicine to modern cardiovascular therapeutics, we delve into its mechanism of action, therapeutic indications, and clinical guidelines. While digoxin remains a cornerstone therapy for heart failure and atrial fibrillation, its narrow therapeutic index and individual variability in response pose challenges in clinical practice. Nevertheless, ongoing research efforts aim to elucidate its role in emerging therapeutic areas and technological advancements in drug delivery. Despite the advent of newer pharmacological agents, digoxin's enduring relevance lies in its established efficacy, affordability, and global accessibility. This review underscores the symbiotic relationship between tradition and progress in cardiovascular medicine, highlighting the timeless pursuit of medical innovation to optimize patient care.
PubMed: 38650769
DOI: 10.7759/cureus.56755 -
Effects of rifampin coadministration on the pharmacokinetics of digoxin: a real-world data approach.Translational and Clinical Pharmacology Sep 2023Digoxin, a cardiac glycoside, is commonly prescribed to treat heart failure and atrial fibrillation. Because digoxin acts as a substrate of P-glycoprotein (P-gp), its...
Digoxin, a cardiac glycoside, is commonly prescribed to treat heart failure and atrial fibrillation. Because digoxin acts as a substrate of P-glycoprotein (P-gp), its blood concentration may be reduced by P-gp inducers such as rifampin. To assess the real-world implications of this drug-drug interaction, a retrospective analysis was carried out on the Clinical Data Warehouse at Seoul National University Hospital between 2012 and 2017. Eleven patients who received both digoxin and rifampin with satisfying the inclusion/exclusion criteria were identified. The C values of digoxin monotherapy were compared to those of the combination therapy with rifampin. Results demonstrated that the systemic exposure of orally administered digoxin decreased by 40% with the concurrent use of rifampin. Clinicians should be aware of potential drug interactions between digoxin and rifampin, as adjustments to digoxin dosage might be necessary for patients receiving rifampin or other P-gp inducer drugs.
PubMed: 37810625
DOI: 10.12793/tcp.2023.31.e13