Computational Structural Validation of CYP2C9 Mutations and Evaluation of Machine Learning Algorithms in Predicting the Therapeutic Outcomes of Warfarin.

AIM: The study aimed to identify the key pharmacogenetic variable influencing the therapeutic outcomes of warfarin using machine learning algorithms and bioinformatics tools. BACKGROUND: Warfarin, a commonly used anticoagulant drug, is influenced by cytochrome P450 (CYP) enzymes, particularly CYP2C9. MLAs have been identified to have great potential in personalized therapy. OBJECTIVE: The purpose of the study was to evaluate MLAs in predicting the critical outcomes of warfarin therapy and validate the key predictor genotyping variable using bioinformatics tools. METHODS: An observational study was conducted on adults receiving warfarin. Allele discrimination method was used for estimating the single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and CYP4F2. MLAs were used for identifying the significant genetic and clinical variables in predicting the poor anticoagulation status (ACS) and stable warfarin dose. Advanced computational methods (SNPs' deleteriousness and impact on protein destabilization, molecular dockings, and 200 ns molecular dynamics simulations) were employed for examining the influence of CYP2C9 SNPs on structure and function. RESULTS: Machine learning algorithms revealed CYP2C9 to be the most important predictor for both outcomes compared to the classical methods. Computational validation confirmed the altered structural activity, stability, and impaired functions of protein products of CYP2C9 SNPs. Molecular docking and dynamics simulations revealed significant conformational changes with mutations R144C and I359L in CYP2C9. CONCLUSION: We evaluated various MLAs in predicting the critical outcome measures associated with warfarin and observed CYP2C9 as the most critical predictor variable. The results of our study provide insight into the molecular basis of warfarin and the CYP2C9 gene. A prospective study validating the MLAs is urgently needed.

Evaluation of supervised machine learning algorithms in predicting the poor anticoagulation control and stable weekly doses of warfarin.

BACKGROUND: Machine learning algorithms (MLAs) carry a huge potential in identifying predicting factors and are being explored for their utility in the field of personalized medicine. AIM: We aimed to investigate MLAs for identifying predictors (clinical and genetic) of poor anticoagulation status (ACS) and stable weekly warfarin dose (SWWD). METHOD: Clinical factors, in addition to the CYP2C9, VKORC1, and CYP4F2 genotypes, were obtained for patients receiving warfarin for at least the previous six months. The C5.0 decision tree classification algorithm was used to predict poor ACS while classification and regression tree analysis (CART), in addition to the Chi-square automatic interaction detector (CHAID), was used to predict SWWD. The percentage of patients within 20% of the actual dose, root mean squared error (RMSE), and area under the receiver-operating characteristics curve (AUROC) were identified as performance indicators of the models. RESULTS: In the C5.0 classification decision tree, the CYP4F2 genotype was the strongest predictor of ACS (AUROC = 0.53). In the CART analysis of SWWD, VKORC1 polymorphisms were the most significant predictor, followed by the CYP2C9 genotype (percentage of patients within 20% of the actual dose = 38.2%, RMSE = 13.6). For the CHAID algorithm, the percentage of patients within 20% of the actual dose was 49%, while the RMSE was found to be 13.4. CONCLUSION: Genetic and non-genetic predictive factors were identified by the MLAs for ACS and SWWD. Further, the need to externally validate the MLAs in a prospective study was highlighted.

Is there a circannual variation in the anticoagulation control of warfarin?

BACKGROUND: The literature regarding the seasonal variation in the therapeutic response to warfarin is somewhat contradictory, with several discrepancies. We assessed the influence of seasons on various pharmacodynamic indices of warfarin. METHODS: A retrospective study was carried out in adults receiving warfarin for at least 6 months. Details of their demographic characteristics, duration and dose of warfarin therapy and values of prothrombin time international normalised ratio (PT-INR) were retrieved. Standard definitions were followed for defining various seasons, time in therapeutic range (TTR), log-INR variability and warfarin sensitivity index (WSI). National Institute for Health and Care Excellence (NICE) criteria were used for defining TTR into good (≥65%) and poor (<65%) anticoagulation control. RESULTS: Two hundred and four patients were recruited. Only a subtle statistically significant difference was observed between the numbers of patients in the various PT-INR categories. However, no significant intra-individual differences were observed in mean TTR. Similarly, the proportion of patients with poor anticoagulation control, high INR variability and high WSI was not significantly different between summer, transition period 1, winter and transition period 2. CONCLUSION: No clinically significant seasonal variations were observed in the therapeutic response to warfarin.

Influence of CYP2C9, VKORC1, and CYP4F2 polymorphisms on the pharmacodynamic parameters of warfarin: a cross-sectional study.

BACKGROUND: Warfarin is the most commonly evaluated drug in pharmacogenetic-guided dosing studies. However, gaps remain regarding the influence of the genetic polymorphisms of CYP2C9, VKORC1, and CYP4F2 on specific pharmacodynamic parameters like the warfarin sensitivity index (WSI), prothrombin time international normalized ratio (PT-INR), and log-INR variability. METHODS: A cross-sectional study was conducted in non-smoking adults receiving warfarin for at least 6 months. Their demographics, diagnoses, warfarin dosing regimen, concomitant drugs, PT-INR, and bleeding episodes were obtained. CYP2C9 (rs1057910-*3 and rs1799853-*2 alleles), CYP4F2 (rs2108622), and VKORC1 (rs9923231) polymorphisms were assessed using real-time polymerase chain reaction. Three genotype groups (I-III) were defined based on the combined genetic polymorphisms of CYP2C9 and VKORC1 from the FDA's recommendations. Key outcome measures included anticoagulation control, time spent in therapeutic range, stable warfarin dose, WSI, log-INR variability, and Warfarin Composite Measure (WCM). RESULTS: The study recruited 236 patients; 75 (31.8%) carried a functional CYP2C9 variant allele, and, 143 (60.6%) had at least one T allele in CYP4F2 and 133 (56.4%) had at least one T allele in VKORC1. Groups' II and III CYP2C9 and VKORC1 genotypes were observed with reduced stable warfarin dose, increased WSI, higher log-INR variability, and increased bleeding risk. The presence of *2 or *3 allele in CYP2C9 was observed with reduced stable warfarin doses akin to the presence of T alleles in VKORC1; however, the doses increased with T alleles in CYP4F2. CONCLUSION: The evaluated genetic polymorphisms significantly influenced all the pharmacodynamic parameters of warfarin. Evaluating CYP2C9, VKORC1, and CYP4F2 genetic polymorphisms prior to warfarin initiation is likely to optimize therapeutic response.

Evaluation of pharmacokinetics of warfarin from validated pharmacokinetic-pharmacodynamic model.

Background: Pharmacokinetics of warfarin has not been described in our population. We derived the pharmacokinetic parameters from a validated pharmacokinetic-pharmacodynamic model. Methods: Patients receiving warfarin for at least 6 months were recruited and their demographic characteristics, prothrombin time international normalized ratio (PT-INR), warfarin doses and concomitant drugs were collected. Using a validated pharmacokinetic-pharmacodynamic model, we predicted maximum plasma concentration (C max), total clearance (C L), volume of distribution (V d) and elimination rate (k). Warfarin sensitive index (WSI) and warfarin composite measures (WCM) were estimated from the dose and INR values. Liver weight was predicted using validated formula. Results: Two-hundred and twenty patients were recruited. The following were the predicted pharmacokinetic parameters: C max (mg/L) was 5.8 (0.4); k (L/day) was 1 (0.1); CL (L/day) was 2.1 (0.2); and V d (L) was 7.6 (0.2). Patients with C max and elimination rate outside the mean+1.96 SD had significantly lower WSI and higher WCM. Significant correlations were observed between C max with CL, V d, and k of warfarin. Significant correlations were also observed between CL and V d of warfarin with liver weight of the study participants. Conclusion: We predicted pharmacokinetic parameters of warfarin from the validated pharmacokinetic-pharmacodynamic model in our population. More studies are needed exploring the relationship between various pharmacodynamic indices of warfarin and pharmacokinetic parameters of warfarin.

Does fasting during Ramadan influence the therapeutic effect of warfarin?

WHAT IS KNOWN AND OBJECTIVES: The changes in the therapeutic effect of warfarin during Ramadan fasting are controversial. Hence, we carried out the present study to assess if there are any alterations in the anticoagulation response to warfarin and identify the associated risk factors. METHODS: Patients receiving warfarin for at least 1 year were included in the present study. Their demographic details, warfarin doses, prothrombin time-international normalized ratio (PT-INR) values and concomitant diseases/drugs were retrieved. The dates of Ramadan periods for the calendar years were obtained, and these periods were considered as Ramadan periods. One month before the start dates of Ramadan was considered as pre-Ramadan, and 1 month later than the last dates was considered as post-Ramadan periods. Warfarin sensitivity index (WSI), PT-INR category and time spent in therapeutic range (TTR) were assessed. National Institute of Clinical Health Excellence (NICE) criteria for anticoagulation status were adhered to where TTR (%) <65 was considered as poor anticoagulation. RESULTS AND DISCUSSION: One hundred and eighty-three patients were recruited. No significant differences were observed in warfarin doses between the study participants between pre-Ramadan, Ramadan and post-Ramadan periods. Significantly more numbers of PT-INR tests were carried out during Ramadan compared with pre- and post-Ramadan periods. A higher WSI was akin to PT-INR, and lower intra-individual variability was observed in middle-aged and older adults in the post-Ramadan period. Significantly fewer patients had their PT-INR in the therapeutic range and more in the subtherapeutic range during Ramadan periods. Greater proportion of patients had PT-INR in the supratherapeutic range during post-Ramadan periods, particularly the elderly. Although 38.3% had poor anticoagulation status overall, 92.4% met the NICE criteria for poor anticoagulation during the 3 months (pre-Ramadan, Ramadan and post-Ramadan periods). WHAT IS NEW AND CONCLUSION: Ramadan fasting influences the therapeutic effect of warfarin in terms of lowered TTR (%), reduced proportion of patients achieving therapeutic PT-INR and increased risk of poor anticoagulation control. Greater caution is required during the post-Ramadan period, particularly in the elderly category as they are more prone for over-anticoagulation and consequently the risk of bleeding.

Evaluation of inter-patient variability in the pharmacodynamic indices of warfarin.

OBJECTIVES: Warfarin exhibits huge inter-individual variability in therapeutic response. We assessed the extent and the factors affecting inter-individual variability in the anticoagulation control using pre-validated pharmacodynamic indices. METHODS: Patients receiving warfarin for at least 6 months were recruited. CHA2DS2-VASc, HASBLED, SAMe-TT2R2 scores, warfarin sensitive index (WSI), log-INR variability, and warfarin composite measure (WCM) were assessed. National Institute for Health and Care Excellence (NICE) guideline was adhered for assessing the anticoagulation control using time in therapeutic range (TTR) (TTR < 65%-poor; and TTR ≥ 65%-good). Odds ratio [95% confidence interval] was the effect estimate measure. RESULTS: Eighty-seven (39.5%) of the patients were poorly anticoagulated. Those with lower HASBLED [OR: 0.3; 0.1, 0.6] and SAMe-TT2R2 scores [OR: 0.2; 0.04, 0.7] and higher CHA2DS2-VASc score [OR: 1.8; 1.1, 1.3] predicted good anticoagulation control. Thirty-five (15.9%) patients had high INR variability. Lower TTR, shorter duration of therapy, and higher WSI were observed in patients with high INR variability, and presence of drugs with potential interaction significantly predicted high INR variability. CONCLUSION: Significant numbers of our patients on warfarin had poor anticoagulation control and high INR variability. We have identified duration of therapy, CHA2DS2-VASc score, and WSI as reliable predictors for anticoagulation control and INR variability.

Ventricular arrhythmia and tachycardia-induced cardiomyopathy in Gitelman syndrome, hypokalaemia is not the only culpable.

Gitelman syndrome (GS) is an autosomal recessive tubulopathy recently implicated in cases with ventricular arrhythmias (VAs), the latter being considered linked to electrolytes' imbalance. However, a direct causal relationship is considered to be an oversimplification for a complex molecular dysfunction. Recent work has suggested a degree of microvascular dysfunction in patients with GS that might be attributed as a mechanism of arrhythmia. We report a case of GS presenting with VAs complicated by cardiomyopathy. The high load of premature ventricular contractions that were attributed to the hypokalaemia has masked the presence of the left ventricular (LV) outflow tract tachycardia. Her LV systolic function recovered after successful electrophysiology ablation procedure. Atrioventricular nodal re-entry tachycardia was discovered incidentally during the study and was ablated successfully.

Design and Rationale of Gulf Documentation of Ambulatory Sick Patients with Heart Failure (Gulf DYSPNEA) Registry.

AIM: The aim of this study is to describe the clinical characteristics of ambulatory patients with chronic heart failure (HF) in the Arabian Gulf and to examine several aspects including types of HF, causes, and adherence to management guidelines. METHODS: Gulf documentation of ambulatory sick patients with HF (Gulf DYSPNEA) registry is a multicenter, cross-sectional study, recruiting adult ambulatory HF patients from 24 hospitals in five Arabian Gulf countries. Consecutive patients are recruited prospectively from participating clinics with no follow-up data collection. Recruitment started on November 07, 2016 and will stop when 3,500 patients are enrolled in this study. Collected data explore demographics, baseline patient characteristics, symptoms, previous medical history, comorbidities, physical signs, presenting electrocardiogram, echocardiographic findings, types of HF, and management. CONCLUSION: This registry is expected to provide useful data on several important aspects and features of ambulatory patients with chronic HF in Arabian Gulf countries. The trial registration number is "ClinicalTrials.gov number, NCT02793180".

Fetal supraventricular tachycardia, treating the baby by targeting the mother.

Fetal supraventricular tachycardia (SVT) is the most common form of fetal tachycardia. If started early in pregnancy, it can cause non-immune fetal hydrops. Echocardiography is the preferred method for the diagnosis with simultaneous pulsed Doppler recording from the superior vena cava and ascending aorta. Transplacental therapy with digoxin is the most common way of treatment. We present a case of fetal SVT detected at 26 weeks of pregnancy. Digoxin therapy restored the rhythm initially, but later paroxysms of fetal SVT persisted necessitating the addition of second antiarrhythmic medication which was discussed with the parents. The couple chose to proceed for premature delivery at 32 weeks.

Reversible cushing dilated cardiomyopathy mimicking peripartum cardiomyopathy with successful subsequent pregnancy.

A 29-year-old lady G4P3A0 has been admitted in her last trimester with features of peripartum cardiomyopathy. She was treated accordingly with comprehensive antifailure therapy. She lost follow-up but reappeared 12 weeks later with further deterioration of her heart failure, severe depression and osteoporotic multiple lumbar fractures. She turned to be having Cushing syndrome secondary to adrenal adenoma. Post adrenalectomy all her symptoms subsided and her cardiac function fully recovered as shown by stress echocardiography. She reconceived with uneventful pregnancy and delivery.

Suppurative pericarditis complicated by mycotic aneurysm of the pulmonary artery.

Aneurysms of the pulmonary artery are very rare. Here, the authors report the clinical scenario of a middle aged diabetic who presented with suppurative cardiac tamponade that was complicated by mycotic aneurysm of the pulmonary artery. In addition to the clinical presentation, aetiology, diagnostic modalities and therapeutic options are discussed.

Reversible severe biventricular dysfunction postpericardiocentesis for tuberculous pericardial tamponade.

Transient severe biventricular systolic dysfunction is a rare phenomenon postpericardiocentesis. Here, the authors report the clinical scenario of a young male who presented with pericardial tamponade that was tuberculous in origin. Soon postpericardiocentesis, he had biventricular dysfunction that recovered spontaneously. The authors discuss the clinical presentation, investigations and pathogenesis of this complication.