Effects Of Digoxin Research Articles

Utilization and safety of digoxin in patients with chronic heart failure and atrial fibrillation with rapid ventricular rate

Abstract Background Digoxin can reduce symptoms and the risk of tachycardia-induced cardiomyopathy in patients with heart failure (HF) and concomitant atrial fibrillation (AF) with rapid ventricular rate. The effect of digoxin in HF and AF has not been tested in randomized controlled trials, and observational data have shown conflicting results linking digoxin to increased mortality in AF, though the nature of observational data makes it prone to bias and results difficult to interpret. Purpose To assess the utilization of digoxin in patients with HF and AF, and its association with New York Heart Association (NYHA) functional class and survival. Methods We used data from the Norwegian HF registry that collected data from all Norwegian HF clinics between 2013-2022. Data was collected from the first and last visit during optimizization of HF medical therapy. Associations with mortality status from Statistics Norway were assessed in unadjusted time-to-event analysis, and after adjustment for age, sex, body mass index, estimated glomerular filtration rate, aldosterone antagonists, renin-angiotensin-aldosterone system inhibitors, and beta blockers. Results The study included 4,877 HF patients, consisting of 4,067 (83.4%) with ejection fraction (EF) ≤40% and 810 (16.6%) with EF >40%.. The mean age was 67.7±12.0 years; 25.1% were women, and 27.3% had NYHA functional class III/IV. At the first visit, 1,339 (27.5%) patients had AF and 829 (61.9%) of these were treated with ≥50% of the beta-blocker target dose. AF with a ventricular rate ≥100 bpm was present in 277 (20.1%) patients, and 188 (67.9%) of these were on ≥50% beta-blocker target dose. Similarly, 262 (19.6%) of all AF patients and 44 (15.9%) of those with a ventricular rate ≥100 bpm were treated with digoxin. After optimization of HF medical therapy (median duration 140 [Q1–Q3 82–237] days), 1,039 (21.3%) patients had AF. Among these, 227 (21.9%) were treated with digoxin, including 9 (18.0%) patients with ventricular rate ≥100 bpm. Patients with AF who were started on digoxin experienced during the optimization period a larger decline in heart rate compared to those who were not (mean change -23.7±17.2 vs. -5.7±16.7 bpm, p=0.001), and more often an improvement in NYHA functional class (45% vs 30%, p=0.018). During median 779 [Q1–Q3 386–1,334)] days of follow-up after the last optimization visit, digoxin use was associated with lower mortality in HF patients with AF in unadjusted analysis (HR 0.67 [0.46–0.97]). After adjustment for baseline characteristics and other HF medical therapies, the association with mortality was attenuated and no longer significant (HR 0.96 [0.65–1.42]). Conclusion Digoxin was infrequently used in patients with HF and AF with rapid ventricular rate but was associated with a greater decrease in heart rate and improvement in NYHA functional class. The use of digoxin appears safe and was not associated with increased mortality.

The effects of digoxin on heart failure mortality and re-admission in a single center cross-sectional study.

Mortality benefit of digoxin prescription in patients suffering from heart failure has been questioned many time. We evaluated these effects among admitted symptomatic heart failure patients. We retrospectively divided our patients into two groups: group A (n=205) were digoxin prescribed, and group B (n=96) were digoxin naïve patients. Both groups' medical records were gathered for one year, and the study endpoints were compared between the two groups. The mean age was 62.3±12.1 years and 54.8 % were male. All-cause mortality and readmission occurred in 26.7% and 31.7% of individuals, respectively, without significant differences between the two groups. However, in subgroup analysis, there was a significant relationship between in-hospital mortality and the presence of cardiovascular risk factors. Digoxin might increase in-hospital mortality in patients with underlying cardiovascular risk factors.

Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial.

Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low-dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment. The DECISION trial is a randomized, double-blind, parallel-group, placebo-controlled event-driven outcome trial which will investigate the efficacy and safety of low-dose digoxin in patients with chronic HF and LVEF <50%. Both patients with sinus rhythm and atrial fibrillation will be enrolled and will be randomized (1:1) to low-dose digoxin or matching placebo. To maintain a target serum digoxin concentration of 0.5-0.9 ng/ml, dose adjustments are made throughout follow-up based on serum digoxin measurements with dummy values for the placebo group. The primary endpoint is a composite of CV mortality and total HF hospitalizations or total urgent hospital visits for worsening HF, and all endpoints are adjudicated blindly by a Clinical Event Committee. The estimated sample size was 982 patients who will be followed for a median of 3 years, and in December 2023 enrolment was completed after 1002 patients. The DECISION trial will provide important evidence regarding the effect of (low-dose) digoxin on CV mortality and total HF hospitalizations and urgent hospital visits when added to contemporary HF treatment of patients with reduced or mildly reduced LVEF. ClinicalTrials.gov identifier: NCT03783429.

Mechanical Stretch Induces Senescence of Lung Epithelial Cells and Drives Fibroblast Activation by Paracrine Mechanisms.

Severe lung injury requiring mechanical ventilation may lead to secondary fibrosis. Senescence, a cell response characterized by cell cycle arrest and a shift towards a proinflammatory/profibrotic phenotype, is one of the involved mechanisms. Here, we explore the contribution of mechanical stretch as trigger of senescence of the respiratory epithelium and its link with fibrosis. Human lung epithelial cells and fibroblasts were exposed in vitro to mechanical stretch, and senescence assessed. In addition, fibroblasts were exposed to culture media preconditioned by senescent epithelial cells and their activation was studied. Transcriptomic profiles from stretched, senescent epithelial cells and activated fibroblasts were combined to identify potential activated pathways. Finally, the senolytic effects of digoxin were tested in these models. Mechanical stretch induced senescence in lung epithelial cells, but not in fibroblasts. This stretch-induced senescence has specific features compared to senescence induced by doxorubicin. Fibroblasts were activated after exposure to supernatants conditioned by epithelial senescent cells. Transcriptomic analyses revealed notch signaling as a potential responsible for the epithelial-mesenchymal crosstalk, as blockade of this pathway inhibits fibroblast activation. Treatment with digoxin reduced the percentage of senescent cells after stretch and ameliorated the fibroblast response to preconditioned media. These results suggest that lung fibrosis in response to mechanical stretch may be caused by the paracrine effects of senescent cells. This pathogenetic mechanism can be pharmacologically manipulated to improve lung repair.

Factors affecting the expression and stability of full-length and truncated SRSF3 proteins in human cancer cells

Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for regulating the alternative splicing of its own mRNA and ensuring that its expression is balanced to maintain homeostasis. Moreover, the exon skipping of SRSF3 leads to the production of a truncated protein instead of a frameshift mutation that generates a premature termination codon (PTC). However, the precise regulatory mechanism involved in the splicing of SRSF3 remains unclear. In this study, we first established a platform for coexpressing full-length SRSF3 (SRSF3-FL) and SRSF3-PTC and further identified a specific antibody against the SRSF3-FL and truncated SRSF3 (SRSF3-TR) proteins. Next, we found that exogenously overexpressing SRSF3-FL or SRSF3-PTC failed to reverse the effects of digoxin, caffeine, or both in combination on this molecule and its targets. Endoplasmic reticulum-related pathways, transcription factors, and chemicals such as palmitic acid and phosphate were found to be involved in the regulation of SRSF3 expression. The downregulation of SRSF3-FL by palmitic acid and phosphate was mediated via different regulatory mechanisms in HeLa cells. In summary, we provide new insights into the altered expression of the SRSF3-FL and SRSF3-TR proteins for the identification of the functions of SRSF3 in cells.

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.

Abstract PO5-18-04: Effect of Digoxin on clusters of circulating tumor cells in patients with metastatic breast cancer (DICCT)

Abstract Background: The presence of circulating tumor cell (CTC) clusters is associated with tumor progression and with a bad prognosis in various cancer types1,2. In breast cancer, a pre-clinical model demonstrated that Na/K-ATPase inhibitors such as digoxin could dissolve CTC clusters and reduce metastasis3. DICCT is a single-arm, therapeutic exploratory phase I study aimed to examine whether digoxin can disrupt CTC clusters in metastatic breast cancer patients (NCT03928210). Material and methods: Metastatic breast cancer patients in whom clusters of CTCs have been detected were eligible. Patients with concomitant heart disease were excluded. After progressive disease in any line of therapy, a window of opportunity before initiation of subsequent systemic therapy was used to administer digoxin treatment for seven (7) days. For CTC detection, blood samples were processed with the FDA-cleared Parsortix system (ANGLE plc, UK). Captured CTCs were stained for EPCAM, HER2, EGFR (positive CTC selection) and CD45 (exclusion marker). To gain insight into the cluster-dissolution ability of digoxin, the primary endpoint was size of CTC clusters (i.e. number of cells within each cluster) under digoxin therapy. The cumulative effect of digoxin treatment on the primary endpoint was assessed by a linear regression model. Results: Nine (9) patients with CTC clusters detected at baseline were enrolled. A target level of digoxin above 0.7 ng/ml could be confirmed at day 7 for all patients. For quantitative and qualitative analysis of CTC clusters, 5.5 to 27 ml of blood were analyzed at baseline, at day 0 pre-treatment, and post 2 hours, 3 days and 7 days of digoxin treatment. The average cluster size ranged between 2 and 11.8 cells (median 2.9) considering all samples from all patients. Digoxin treatment reduced cluster size in 8 patients (88.9%) to different extents, and the proportion of CTC cluster over single CTCs was also reduced in 6 patients (66.7%). The effect of digoxin was evident in both homotypic (cancer cells only) and heterotypic (aggregates of CTCs and white blood cells) clusters. The treatment was well tolerated, and no adverse events related to the study treatment occurred. All patients completed the treatment according to the protocol. Conclusion: DICCT provides the first-in-human proof-of-principle that digoxin induces a partial dissolution of CTC clusters in patients with metastatic breast cancer at drug levels that are safe and well tolerated. Conceptualization of follow-up trials including Na/K-ATPase inhibitors and patient outcome endpoints are underway.

Sensational site: the sodium pump ouabain-binding site and its ligands.

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+/Ca2+ 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 Ca2+-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.

Effect of digoxin, sodium valproate, their combination and celecoxib on neuroactive amino acids content and cerebral Na+, K+-ATPase activity in pentylenetetrazole-kindled mice

Effect of digoxin, sodium valproate, their combination and celecoxib on neuroactive amino acids content and cerebral Na+, K+-ATPase activity in pentylenetetrazole-kindled mice

Safety profile of intravenous digoxin in Chinese patients with acute heart failure with reduced ejection fraction: a small-scale prospective cohort study.

Background: Adverse effects of intravenous digoxin vary from patients and disease status, which should be closely monitored. Aims: To explore the safety profile of intravenous digoxin in acute heart failure with reduced ejection fraction (HFrEF) among Chinese patients. Methods: A clinical prospective, single-center, single-arm, open-label exploratory clinical trial was performed in patients with acute HFrEF at Wuhan Asia Heart Hospital. A fixed dose of 0.5mg digoxin was used intravenously once per day for 3days. The normalized dosage of digoxin (NDD), toxic serum digoxin concentration (SDC), and adverse reactions of intravenous digoxin were recorded. Results: A total of 40 patients were recruited in the study. The SDC increased from 1.03 ± 0.34ng/mL to 1.95 ± 0.52ng/mL during treatment. 50% (20/40) patients reached a toxic SDC of 2.0ng/mL, and toxic effects were seen in 30% (12/40) patients. Estimated glomerular filtration rate (eGFR) < 60mL/min [HR: 5.269; 95% CI: 1.905-14.575, p = 0.001], NDD ≥7μg/kg [HR: 3.028; 95% CI: 1.119-8.194, p = 0.029], and ischemic cardiomyopathy [HR: 2.658; 95% CI: 1.025-6.894, p = 0.044] were independent risk factors for toxic SDC. Toxic SDC was effectively identified [area under the receiver operating characteristic (ROC) curve = 0.85, p < 0.001] using this model, and patients would have a higher risk of toxicity with more risk factors. Conclusion: Intravenous digoxin of 0.5mg was safe and effective for initial dose but not suitable for maintenance treatment in Chinese patients with acute HFrEF. Patients who had lower eGFR, received higher NDD, and had ischemic cardiomyopathy should be closely monitored to avoid digoxin toxicity.

Oral digoxin effects on Lac- regulation during intense intermittent exercise using small and large contracting muscle mass in healthy humans

Oral digoxin effects on Lac- regulation during intense intermittent exercise using small and large contracting muscle mass in healthy humans

Digoxin protects against intervertebral disc degeneration via TNF/NF-κB and LRP4 signaling.

Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP). The pathological process of IVDD is associated with inflammatory reactions and extracellular matrix (ECM) disorders. Digoxin is widely used for treating heart failure, and it has been reported to have anti-inflammatory effects. This study is to investigate the role of digoxin in the pathogenesis of intervertebral disc degeneration as well as the involved molecular mechanism, particularly the potential target protein. We exploited a rat needle model to investigate digoxin's role in intervertebral disc degeneration in vivo. Safranin O staining was used to measure cartilaginous tissue in the intervertebral disc. The morphological changes of intervertebral discs in animal models were determined by Hematoxylin-Eosin (H&E) staining and the pathological score. Primary nucleus pulposus cells (NP cells) from intervertebral discs of patients and murine were used in the present study. Western-Blotting assay, Real-time PCR assay, immunofluorescence staining, and immunochemistry were used to detect the role of digoxin in anti-TNF-α-induced inflammatory effects in vitro. Transfection of siRNA was used to regulate low-density lipoprotein receptor-related protein 4 (LRP4) expression in NP cells to investigate the potential protein target of digoxin. Digoxin protected against intervertebral disc degeneration in rat needle models. Digoxin was found to exert its disc-protective effects through at least three different pathways by a) suppressing TNF-α-induced inflammation, b) attenuating ECM destruction, c) significantly promoting ECM anabolism. Additionally, LRP4 was found to be the downstream molecule of digoxin in NP cells for anti-inflammation and regulation of ECM metabolism. The knockdown of LRP4 downregulated the protective effect of digoxin in NP cells. These findings suggest that digoxin may be a potential therapeutic agent for intervertebral disc degeneration through anti-catabolism and pro-anabolism. Digoxin might also work as an alternative for other inflammation-related diseases.

Potential Effects of Digoxin on Renal Functions in Patients With Congestive Heart Failure.

Renal dysfunction is a common complication among patients with congestive heart failure (CHF) and can significantly impact their management, especially when medications like digoxin are involved. The clearance of digoxin is closely tied to the glomerular filtration rate (GFR), which suggests that the safety and efficacy of digoxin may vary with renal function. Therefore, this study aimed to assess the potential effects of digoxin on renal function in patients diagnosed with CHF at a tertiary hospital in the Asir region of Saudi Arabia. A retrospective study examined the records of 30 CHF patients treated with digoxin. Renal function markers like estimated GFR (eGFR), creatinine, blood urea nitrogen (BUN), albumin, and urine levels were compared before and after digoxin treatment. Liver enzymes and other relevant parameters were also examined. A statistical analysis using t-tests was conducted to evaluate the changes in renal function indicators before and after digoxin treatment. The mean eGFR decreased significantly from 65.4 ± 8.9 mL/min/1.73m2 before digoxin to 57.7 ± 7.8 mL/min/1.73m2 after (p = 0.001). Creatinine, BUN, albumin, and urine levels showed no significant changes. Digoxin significantly increased aspartate aminotransferase (AST) from 34.5 ± 11.6 U/L to 53.8 ± 14.6 U/L (p = 0.002), alanine aminotransferase (ALT) from 38.5 ± 12.6 U/L to 55.3 ± 17.6 U/L (p = 0.013), and creatine kinase from 117.7 ± 22.5 U/L to 133.9 ± 15.8 U/L (p = 0.012). Hemoglobin decreased significantly from 12.8 ± 1.4 g/dL to 12.1 ± 1.4 g/dL (p = 0.034). No significant changes occurred in myoglobin, troponin, bilirubin, platelets, potassium, calcium, or chloride levels. Effects on kidney function did not differ significantly by gender or age, except blood urea nitrogen was higher in patients over 50 years (8.3 ± 2.3 vs. 5.6 ± 2.7 mg/dL, p = 0.015). This study suggests digoxin may adversely affect renal function in CHF patients, as evidenced by reduced eGFR. However, the small retrospective design limits definitive conclusions. Further prospective research with larger samples is warranted to elucidate digoxin's renal effects in CHF patients.

Development and validation of a risk prediction nomogram for serious arrhythmias in acute digoxin toxicity among pediatrics: A multicenter study

Digoxin is a cardiac glycoside obtained from the leaves of the foxglove plant, Digitalis lanata. Several studies have described the safety of digoxin including various life-threatening events, notably cardiac arrhythmias. Early identification of high-risk patients and subsequent initiation of the utmost medical care are associated with a better prognosis. The assessment of serum digoxin levels, which is not always convenient, is the only tool used to evaluate the severity of digoxin exposure. However, the feasibility of this tool, particularly in resource-restricted countries, remains unclear. Therefore, the current study aimed to establish and validate a feasible alternative tool, a bedside nomogram, to identify pediatric patients diagnosed with acute digoxin intoxication who are at risk of developing serious arrhythmias. This was a two-phase, multicenter, retrospective study. The prevalence of serious arrhythmias was approximately 17%. Patients diagnosed with serious arrhythmias showed significantly higher serum digoxin, random blood glucose, and potassium levels but lower sodium, magnesium, and hemoglobin levels. Serious arrhythmias were associated with significantly lower P-R intervals, shorter QTc intervals, and more frequent digoxin effects (p < 0.05). The proposed nomogram showed that combining age and initial random blood glucose, sodium, and potassium levels could predict the future incidence of serious arrhythmia with an accuracy of 96.2% (sensitivity = 94.4%, specificity = 96.5%), an area under the curve (AUC) of 0.977, and p < 0.001. Validation of the proposed nomogram yielded an AUC for the nomogram probability of approximately 81%, and the AUC for the predicted probability using the developed model was 98.3%, indicating that both the validated model and the developed nomogram were significant predictors of serious arrhythmia. The utility of using the four-factor nomogram to determine the risk of serious arrhythmia in children exposed to an overdose of digoxin is comparable, if not superior, to the serum digoxin level.

The effects of Digoxin use on long-term prognosis in patients with heart failure with reduced ejection fraction.

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. 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. 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. Our results show that digoxin use does not affect mortality in HFrEF patients. However, rehospitalization decreased in patients taking digoxin in HFrEF.

Joint modelling of longitudinal processes and time-to-event outcomes in heart failure: systematic review and exemplar examining the relationship between serum digoxin levels and mortality

BackgroundJoint modelling combines two or more statistical models to reduce bias and increase efficiency. As the use of joint modelling increases it is important to understand how and why it is being applied to heart failure research.MethodsA systematic review of major medical databases of studies which used joint modelling within heart failure alongside an exemplar; joint modelling repeat measurements of serum digoxin with all-cause mortality using data from the Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure (DIG) trial.ResultsOverall, 28 studies were included that used joint models, 25 (89%) used data from cohort studies, the remaining 3 (11%) using data from clinical trials. 21 (75%) of the studies used biomarkers and the remaining studies used imaging parameters and functional parameters. The exemplar findings show that a per unit increase of square root serum digoxin is associated with the hazard of all-cause mortality increasing by 1.77 (1.34–2.33) times when adjusting for clinically relevant covariates.ConclusionRecently, there has been a rise in publications of joint modelling being applied to heart failure. Where appropriate, joint models should be preferred over traditional models allowing for the inclusion of repeated measures while accounting for the biological nature of biomarkers and measurement error.

Digoxin is a potent inhibitor of Bunyamwera virus infection in cell culture.

Drug repurposing is a valuable source of new antivirals because many compounds used to treat a variety of pathologies can also inhibit viral infections. In this work, we have tested the antiviral capacity of four repurposed drugs to treat Bunyamwera virus (BUNV) infection in cell cultures. BUNV is the prototype of the Bunyavirales order, a large group of RNA viruses that includes important pathogens for humans, animals and plants. Mock- and BUNV-infected Vero and HEK293T cells were treated with non-toxic concentrations of digoxin, cyclosporin A, sunitinib and chloroquine. The four drugs inhibited BUNV infection with varying potency in Vero cells, and all except sunitinib also in HEK293T cells, with digoxin rendering the lowest half maximal inhibitory concentration (IC50). Since digoxin rendered the best results, we selected this drug for a more detailed study. Digoxin is an inhibitor of the Na+/K+ ATPase, a plasma membrane enzyme responsible for the energy-dependent exchange of cytoplasmic Na+ for extracellular K+ in mammalian cells and involved in many signalling pathways. Digoxin was shown to act at an early time point after viral entry reducing the expression of the viral proteins Gc and N. Effects on the cell cycle caused by BUNV and digoxin were also analysed. In Vero cells, digoxin favoured the transition from G1 phase of the cell cycle to S phase, an effect that might contribute to the anti-BUNV effect of digoxin in this cell type. Transmission electron microscopy showed that digoxin impedes the assembly of the characteristic spherules that harbour the BUNV replication complexes and the morphogenesis of new viral particles. Both BUNV and digoxin induce similar changes in the morphology of mitochondria that become more electron-dense and have swollen cristae. The alterations of this essential organelle might be one of the factors responsible for digoxin-induced inhibition of viral infection. Digoxin did not inhibit BUNV infection in BHK-21 cells that have a digoxin-resistant Na+/K+ ATPase, which suggests that the effects of the blockade of this enzyme is a key factor of the antiviral activity of digoxin in BUNV-infected Vero cells.

Towards automated assessment of drug efficacy on cardiomyopathic human heart function.

Structural and functional abnormalities of ventricular myocardium related to Hypertrophic and Dilated Cardiomyopathies (HCM and DCM) are commonly caused by inherited mutations in sarcomeric proteins. Automating predictions of mutation and drug effects on human cardiac muscle function could enhance early diagnosis and evaluation of response to treatments for cardiomyopathies. However, the development of automation tools that integrate results from multiple experiments, conducted under various experimental conditions at different time and spatial scales from multiple species, is a significant challenge. Such automation tools usually require large sets of training data, which are extremely limited or even nonexistent from humans, thus any information generated could be significantly inaccurate or even misleading. Recent advances in multiscale computational tools, coupled with multiple experiments, for the translation of data concerning sarcomere level molecular interactions, including the effect of drugs, to the level of cardiac muscle fibers and tissues, might provide the most relevant approach for generating databases for automation algorithms. Using the MUSICO platform for precise modeling of protein-protein interactions and Ca2+ regulation in cardiac muscle cells, coupled with the finite element (FE) solver Mexie via Mijailovich-Prodanovic surrogate model, we can simulate experimental data from various sources. These tools collectively enable quantitative assessment of the changes in human cardiac muscle contractile responses caused by HCM and DCM extending from the molecular level to whole organ function, as well as prediction of improvements of cardiac muscle function by drugs. Our simulations successfully predicted pressure and volume changes due to troponin-C mutations and the effect of drugs, disopyramide and digoxin, in improving heart function in HCM and DCM, respectively, during multiple heartbeats in human heart. These simulations can potentially provide sufficient information for physicians to evaluate the progress of disease and the efficacy of administrated therapeutics.

Association between the risk of heart failure hospitalization and end-stage renal disease with digoxin usage in patients with cardiorenal syndrome: A population-based study.

The management of the coexistence of heart disease and kidney disease is increasingly challenging for clinicians. Chronic kidney disease (CKD) is not only a prevalent comorbidity of patients with heart failure but has also been identified as a noteworthy risk factor for all-cause mortality and poor clinical outcomes. Digoxin is one of the commonest treatments for heart disease. There are few trials investigating the role of digoxin in patients with cardiorenal syndrome (CRS). This study aims to examine the association between digoxin usage and clinical outcomes in patients with CRS in a nationwide cohort. We conducted a population-based study that included 705 digoxin users with CRS; each patient was age, sex, comorbidities, and medications matched with three non-users who were randomly selected from the CRS population. Cox proportional hazards regression analysis was conducted to estimate the effects of digoxin on the incidence of all-cause mortality, congestive heart failure (CHF) hospitalization, coronary artery disease (CAD) hospitalization, and end-stage renal disease (ESRD). The all-cause mortality rate was significantly higher in digoxin users than in non-users (adjusted hazard ratio [aHR] = 1.26; 95% confidence interval [CI] = 1.09-1.46, p = 0.002). In a subgroup analysis, there was significantly high mortality in the 0.26-0.75 defined daily dose (DDD) subgroup of digoxin users (aHR = 1.49; 95% CI = 1.23-1.82, p<0.001). Thus, the p for trend was 0.013. With digoxin prescription, the CHF hospitalization was significantly higher [subdistribution HR (sHR) = 1.17; 95% CI = 1.05-1.30, p = 0.004], especially in the >0.75 DDD subgroup (sHR = 1.19; 95% CI = 1.01-1.41, p = 0.046; p for trend = 0.006). The digoxin usage lowered the coronary artery disease (CAD) hospitalization in the > 0.75 DDD subgroup (sHR = 0.79; 95% CI = 0.63-0.99, p = 0.048). In renal function progression, more patients with CRS entered ESRD with digoxin usage (sHR = 1.34; 95% CI = 1.16-1.54, p<0.001). There was a significantly greater incidence of ESRD in the < 0.26 DDD and 0.26-0.75 DDD subgroups of digoxin users (sHR = 1.32; 95% CI = 1.06-1.66, p = 0.015; sHR = 1.44; 95% CI = 1.18-1.75; p for trend<0.001). Digoxin should be prescribed with caution to patients with CRS.

Effect of digoxin, sodium valproate, and celecoxib on the cerebral cyclooxygenase pathway and neuron-specific enolase under the pentylenetetrazole-induced kindling in mice

Neuroinflammation plays an important role in the pathogenesis of epilepsy, so it is necessary to clarify the influence of standard antiepileptic drugs as well as adjuvant agents (e.g., cardiac glycoside digoxin, which previously showed a clear anticonvuls