Impact of autoantibodies against the M2-muscarinic acetylcholine receptor on clinical outcomes in peripartum cardiomyopathy patients with standard treatment

Objectives To evaluate the impact of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on the clinical outcomes of patients receiving the standard treatment for peripartum cardiomyopathy (PPCM). Methods A total of 107 PPCM patients who received standard heart failure (HF) treatment between January 1998 and June 2020 were enrolled in this study. According to anti-M2-R reactivity, they were classified into negative (n = 59) and positive (n = 48) groups, denoted as the anti-M2-R (−) and anti-M2-R (+) groups. Echocardiography, 6-min walk distance, serum digoxin concentration (SDC), and routine laboratory tests were performed regularly for 2 years. The all-cause mortality, cardiovascular mortality, and rehospitalisation rate for HF were compared between the two groups. Results A total of 103 patients were included in the final data analysis, with 46 in the anti-M2-R (+) group and 57 in the anti-M2-R (−) group. Heart rate was lower in the anti-M2-R (+) group than in the anti-M2-R (−) group at the baseline (102.7 ± 6.1 bpm vs. 96.0 ± 6.4 bpm, p < 0.001). The initial SDC was higher in the anti-M2-R (+) group than in the anti-M2-R (−) group with the same dosage of digoxin (1.25 ± 0.45 vs. 0.78 ± 0.24 ng/mL, p < 0.001). The dosages of metoprolol and digoxin were higher in the anti-M2-R (−) patients than in the anti-M2-R (+) patients (38.8 ± 4.6 mg b.i.d. vs. 27.8 ± 5.3 mg b.i.d., p < 0.0001, respectively, for metoprolol; 0.12 ± 0.02 mg/day vs. 0.08 ± 0.04 mg/day, p < 0.0001, respectively, for digoxin). Furthermore, there was a greater improvement in cardiac function in the anti-M2-R (−) patients than in the anti-M2-R (+) patients. Multivariate analysis identified negativity for anti-M2-R as the independent predictor for the improvement of cardiac function. Rehospitalisation for HF was lower in the anti-M2-R (−) group, but all-cause mortality and cardiovascular mortality were the same. Conclusions There were no differences in all-cause mortality or cardiovascular mortality between the two groups. Rehospitalisation rate for HF decreased in the anti-M2-R (−) group. This difference may be related to the regulation of the autonomic nervous system by anti-M2-R.

Updates in Digoxin Toxicity and Outcome of Management: A Review

Cardiac glycosides, including digitalis and digoxin, have long-standing use in clinical practice. Digoxin has a half-life that varies from 36 to 48 hours, which may increase in cases of renal failure. Approximately 1% of Congestive Heart Failure patients treated with digoxin develop toxicity. The clinical features of toxicity are often non-specific. Diagnosis is difficult and usually made clinically, as levels of digoxin in the blood do not necessarily correlate with toxicity. Treatment involves early recognition and the administration of antibodies specifically against digoxin also known as Fab fragments. Digoxin concentration does not necessarily correlate with clinical symptoms of toxicity however digoxin concentrations may be used for calculating the amount of antidote therapy. Digoxin-specific antibody fragments are used when there is a risk of a life-threatening arrhythmia.

Effects of autoantibody against M2-muscarinic acetylcholine receptor in peripartum cardiomyopathy patients on digoxin additional to standard treatment

Objectives To evaluate the effects of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on digoxin additional to standard treatment in peripartum cardiomyopathy (PPCM) patients. Methods 107 PPCM patients, receiving digoxin and standard treatment regimen for HF, were enrolled between January 1998 and June 2020, who were separated into anti-M2-R negative (n = 59) or positive (n = 48) group according to the anti-M2-R reactivity. Echocardiography and serum digoxin concentration (SDC) were performed regularly. All-cause mortality, cardiovascular mortality and re-hospitalization for heart failure were compared. Results 103 patients completed the final data analysis, including 46 in the anti-M2-R (+) group and 57 in the anti-M2-R (-) group. Heart rate of the positive group was lower than that of the negative group at baseline (102.7 ± 6.1 vs. 96.0 ± 6.4, p < 0.001). The initial SDC of patients in the positive group was higher than that of patients in the negative group with the same dosage of digoxin (1.25 ± 0.45 vs. 0.78 ± 0.24 ng/mL, p < 0.001). Anti-M2-R (-) patients had better tolerance to metoprolol (38.4 ± 4.6 mg b.i.d. vs. 27.4 ± 5.0 mg b.i.d., p < 0.0001) and digoxin (0.12 ± 0.02 mg/day vs. 0.08 ± 0.04 mg/day, p < 0.0001). The improvement of heart function was obvious in the first year, especially in the first half. Furthermore, anti-M2-R (-) patients showed better improvement than that in anti-M2-R (+) patients. Re-hospitalization for heart failure was decreased in the negative group, but not of all-cause or cardiovascular mortality. Conclusions Anti-M2-R maybe a predictor for vagus nerve overactivation and is associated with poor response to digoxin in PPCM patients.

Therapeutic Monitoring of Plasma Digoxin for COVID-19 Patients Using a Simple UPLC-MS/MS Method

Background:: Cardiovascular diseases (CVD) were reported in 8% - 16% of patients with 2019 coronavirus disease (COVID-19). Digoxin was one of the main drugs to treat CVD. Objective:: The clinician applied for therapeutic drug monitoring (TDM) of digoxin according to the drug usage of the patients to monitor their concentration of digoxin , so as to avoid its toxic and side effects, and provide a theoretical reference for clinical usage of digoxin in patients with COVID-19. Methods:: A method for quantifying digoxin concentration in plasma with ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed . After a simple protein precipitation of plasma with methanol, digoxin and its internal standard (digoxin-d3) were detected in positive ion mode using multiple reaction monitoring .Results: Plasma digoxin in the range of 0.2 - 10 ng/mL had a good linearity. The UPLC-MS/MS method was validated with inter-run accuracies from 91.3% to 107.4% and precisions less than 13%. Nine plasma samples (5 at valley concentration and 4 at follow-up after stopping dosing) from three patients with COVID-19 were tested. The mean plasma digoxin concentration was 0.73 ng/mL (ranged from 0 to 1.31 ng/mL). Digoxin was detected at the concentration of 0.93 ng/mL after stopping drug administration for 14 days. Conclusion:: In this study, we established a simple UPLC-MS/MS method using protein-precipitation to perform TDM of digoxin in patients with COVID-19, and found that about 56% of digoxin plasma concentration was within the treatment window (0.8 - 2.0 ng/mL). Digoxin can be remained in the body for nearly 14 days in severe patients with COVID-19 after stopping dosing.

The effect of autoantibody against M2-muscarinic acetylcholine receptor in peripartum cardiomyopathy patients on digoxin additional to standard treatment

Background: To evaluate the effects of autoantibodies against the M2-muscarinic receptor (anti-M2-R) on digoxin additional to standard treatment in peripartum cardiomyopathy (PPCM) patients.Methods: 86 PPCM patients were separated into anti-M2-R negative or positive group according to the anti-M2-R reactivity. All the patients received digoxin additional to standard treatment regimen. Echocardiography was performed at baseline and after 5 years treatment. Serum digoxin concentration (SDC) were performed every 3 to 6 months. All-cause mortality, cardiovascular mortality and re-hospitalization for heart failure were compared after 5 years of follow-up.Results: There were 82 patients completed the final data analysis, including 38 in the anti-M2-R (+) group and 44 in the anti-M2-R (-) group. The heart rate of the positive group was higher than that of the negative group at baseline (102.3 ± 6.3 vs. 95.9 ± 6.8, p < 0.001). The initial SDC of patients in the positive group was higher than that of patients in the negative group with the same dose of digoxin (1.21 ± 0.41 vs. 0.73 ± 0.16 ng/mL, p < 0.001). Patients in the anti-M2-R (-) group had better tolerance to metoprolol and digoxin (p < 0.05). All the PPCM patients showed prominent improvement in cardiac function, especially in the anti-M2-R (-) group. Re-hospitalization for heart failure was decreased in the negative group, but not of all-cause or cardiovascular mortality. Conclusions: Patients negative for anti-M2-R showed better tolerance to metoprolol and digoxin. Anti-M2-R maybe a predictor for vagus nerve overactivation and is associated with poor response to digoxin treatment in PPCM patients.

Predicting the serum digoxin concentrations of infants in the neonatal intensive care unit through an artificial neural network

Background Given its narrow therapeutic range, digoxin’s pharmacokinetic parameters in infants are difficult to predict due to variation in birth weight and gestational age, especially for critically ill newborns. There is limited evidence to support the safety and dosage requirements of digoxin, let alone to predict its concentrations in infants. This study aimed to compare the concentrations of digoxin predicted by traditional regression modeling and artificial neural network (ANN) modeling for newborn infants given digoxin for clinically significant patent ductus arteriosus (PDA). Methods A retrospective chart review was conducted to obtain data on digoxin use for clinically significant PDA in a neonatal intensive care unit. Newborn infants who were given digoxin and had digoxin concentration(s) within the acceptable range were identified as subjects in the training model and validation datasets, accordingly. Their demographics, disease, and medication information, which were potentially associated with heart failure, were used for model training and analysis of digoxin concentration prediction. The models were generated using backward standard multivariable linear regressions (MLRs) and a standard backpropagation algorithm of ANN, respectively. The common goodness-of-fit estimates, receiver operating characteristic curves, and classification of sensitivity and specificity of the toxic concentrations in the validation dataset obtained from MLR or ANN models were compared to identify the final better predictive model. Results Given the weakness of correlations between actual observed digoxin concentrations and pre-specified variables in newborn infants, the performance of all ANN models was better than that of MLR models for digoxin concentration prediction. In particular, the nine-parameter ANN model has better forecasting accuracy and differentiation ability for toxic concentrations. Conclusion The nine-parameter ANN model is the best alternative than the other models to predict serum digoxin concentrations whenever therapeutic drug monitoring is not available. Further cross-validations using diverse samples from different hospitals for newborn infants are needed.

The Concentration of Digoxin Activity after Intravenous in Three Compartments Mathematical Model

Present paper is designed to compare the distribution of digoxin in three compartment model administered through an intravenous (i.v). These models under consideration is denoted by a system of non-linear ordinary differential equations. The Eigenvalue and the Laplace transform methods were used to solve the system of equations. Digoxin was administered to five subjects through Intravenous then, the serum digoxin concentrations were measured respectively over a period of 72 hours. The transfer coefficients were obtained from observed digoxin concentrations using method of residuals and the variation of digoxin concentration – time curves plotted using MATLAB.