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Journal of Atrial Fibrillation 2020The presence of both sympathetic activation-mediated triggers and parasympathetic activation-mediated substrates are required to initiate and maintain some forms of...
OBJECTIVE
The presence of both sympathetic activation-mediated triggers and parasympathetic activation-mediated substrates are required to initiate and maintain some forms of atrial fibrillation (AF). AF predominantly precipitated by parasympathetic stimulation is known as vagally-mediated AF (VM-AF). The role of novel drugs and molecular targeted gene therapy that modulate the autonomic nervous system are therapeutic options in this unique population with VM-AF. Here, we review the role of the sympatho-vagal balance in the genesis of AF and consider drug therapy for VM-AF.
METHODS
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement, literature search was conducted using the keywords "vagal", "vagal nerve", "vagus", "vagus nerve", and "atrial fibrillation". Retrieved citations were first screened independently by 2 reviewers for inclusion and exclusion criteria.
RESULTS
A total of 14 studies and 3 practice guidelines from 1986-2017 were included. Only two clinical investigations evaluated the effectiveness of disopyramide and sotalol in human subjects with VM-AF. The potential role of antiarrhythmic drugs has been studied in animal models.
CONCLUSIONS
Growing evidence suggests that the autonomic nervous system is integral in the development of VM-AF. Novel medications and genetic targets are undergoing investigation with promising results.
PubMed: 33024510
DOI: 10.4022/jafib.2410 -
International Journal of Oncology Oct 2019Hepatocellular carcinoma (HCC) is one of the leading causes of tumor‑related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor...
Hepatocellular carcinoma (HCC) is one of the leading causes of tumor‑related mortalities worldwide. Long noncoding RNAs have been reported to be associated with tumor initiation, progression and prognosis. The present study aimed to explore the association between long noncoding RNA LINC00668 and its co‑expression correlated protein‑coding genes (PCGs) in HCC. Data of 370 HCC patients from The Cancer Genome Atlas database were used for analysis. LINC00668 and its top 10 PCGs were selected to determine their diagnostic and prognostic value. Molecular mechanisms were explored to identify metabolic processes that LINC00668 and its PCGs are involved in. Prognosis‑related clinical factors and PCGs were used to construct a nomogram for predicting prognosis in HCC. A Connectivity Map was constructed to identify candidate target drugs for HCC. The top 10 PCGs identified were: Pyrimidineregic receptor P2Y4 (P2RY4), signal peptidase complex subunit 2 (SPCS2), family with sequence similarity 86 member C1 (FAM86C1), tudor domain containing 5 (TDRD5), ferritin light chain (FTL), stratifin (SFN), nucleolar complex associated 2 homolog (NOC2L), peroxiredoxin 1 (PRDX1), cancer/testis antigen 2 CTAG2 and leucine zipper and CTNNBIP1 domain containing (LZIC). FAM86C1, CTAG2 and SFN had significant diagnostic value for HCC (total area under the curve ≥0.7, P≤0.05); LINC00668, FAM86C1, TDRD5, FTL and SFN were of significant prognostic value for HCC (all P≤0.05). Investigation into the molecular mechanism indicated that LINC00668 affects cell division, cell cycle, mitotic nuclear division, and drug metabolism cytochrome P450 (all P≤0.05). The Connectivity Map identified seven candidate target drugs for the treatment of HCC, which were: Indolylheptylamine, mimosine, disopyramide, lidocaine, NU‑1025, bumetanide, and DQNLAOWBTJPFKL‑PKZXCIMASA‑N (all P≤0.05). Our findings indicated that LINC00668 may function as an oncogene and its overexpression indicates poor prognosis of HCC. FAM86C1, CTAG2 and SFN are of diagnostic significance, while FAM86C1, TDRD5, FTL and SFN are of prognostic significance for HCC.
Topics: Carcinoma, Hepatocellular; Cell Cycle; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Genome-Wide Association Study; Humans; Liver Neoplasms; Male; Prognosis; Protein Interaction Maps; RNA, Long Noncoding; Survival Analysis; Up-Regulation
PubMed: 31432149
DOI: 10.3892/ijo.2019.4858 -
International Journal of Molecular... May 2024In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have...
In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, Democracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, Democracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.
Topics: Drug Repositioning; Humans; Drug Discovery; Neurodegenerative Diseases
PubMed: 38791356
DOI: 10.3390/ijms25105319 -
Journal of Pharmacological Sciences Aug 2020The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp...
Differential effects of class I antiarrhythmic drugs on the guinea pig pulmonary vein myocardium: Inhibition of automatic activity correlates with blockade of a diastolic sodium current component.
The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of diastolic depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp depolarization mimicking the diastolic depolarization. In conclusion, class I antiarrhythmic drugs which block the diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Guinea Pigs; In Vitro Techniques; Microelectrodes; Patch-Clamp Techniques; Pulmonary Veins; Sodium
PubMed: 32487451
DOI: 10.1016/j.jphs.2020.05.004 -
Bioorganic Chemistry May 2020A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly...
A series of 2-aryl-2-(pyridin-2-yl)acetamides were synthesized and screened for their anticonvulsant activity in animal models of epilepsy. The compounds were broadly active in the 'classical' maximal electroshock seizure (MES) and subcutaneous Metrazol (scMET) tests as well as in the 6 Hz and kindling models of pharmacoresistant seizures. Furthermore, the compounds showed good therapeutic indices between anticonvulsant activity and motor impairment. Structure-activity relationship (SAR) trends clearly showed the highest activity resides in unsubstituted phenyl derivatives or compounds having ortho- and meta- substituents on the phenyl ring. The 2-aryl-2-(pyridin-2-yl)acetamides were derived by redesign of the cardiotoxic sodium channel blocker Disopyramide (DISO). Our results show that the compounds preserve the capability of the parent compound to inhibit voltage gated sodium currents in patch-clamp experiments; however, in contrast to DISO, a representative compound from the series 1 displays high levels of cardiac safety in a panel of in vitro and in vivo experiments.
Topics: Acetamides; Animals; Anticonvulsants; Disopyramide; Dose-Response Relationship, Drug; Electroshock; Female; Injections, Intraperitoneal; Injections, Subcutaneous; Male; Mice; Molecular Structure; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Structure-Activity Relationship
PubMed: 32171994
DOI: 10.1016/j.bioorg.2020.103717 -
Yakugaku Zasshi : Journal of the... 2022The management of syncope is clinically important for heart failure (HF) patients. We herein describe a case on the efficacy of disopyramide for refractory syncope in HF...
The management of syncope is clinically important for heart failure (HF) patients. We herein describe a case on the efficacy of disopyramide for refractory syncope in HF with preserved ejection fraction (HFpEF). An 82-year-old man was hospitalized for respiratory distress and lower limb edema and was subsequently diagnosed with HFpEF. The use of diuretics improved HF symptoms; however, on day 10 after hospitalization, a rapid decrease in blood pressure and transient loss of consciousness developed. After neurologic examination, he was diagnosed with pure autonomic failure. Although he was administered midodrine 8 mg/d, fludrocortisone 0.1 mg/d, and droxidopa 300 mg/d, syncope was observed once a day on average. According to the Holter electrocardiogram, the patient's heart rate and coefficient of variation of R-R intervals (CVRR) during the day were unstable. In addition, high frequency power (parasympathetic nerve activity) was significantly higher than low frequency power (both sympathetic and parasympathetic nerves activity), suggesting that the parasympathetic nerves may have been highly active while the sympathetic nerves would have been blocked. On day 29, a pharmacist proposed disopyramide 300 mg/d, which blocks parasympathetic nerves and improves neural-mediated syncope, to the attending doctor. After the initiation of disopyramide, transient loss of consciousness was not observed. Furthermore, the diurnal variation in the heart rate and CVRR completely disappeared. In conclusion, disopyramide would be effective for refractory syncope in patients with HFpEF, and the Holter electrocardiogram may be a useful tool for the assessment of drug efficacy by pharmacists.
Topics: Aged, 80 and over; Disopyramide; Electrocardiography, Ambulatory; Heart Failure; Humans; Male; Stroke Volume; Syncope
PubMed: 35908952
DOI: 10.1248/yakushi.22-00047 -
Journal of Pharmacological and... 2023Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia....
Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition. The focus on inhibition omits potential effects of hERG channel agonist molecules and their associated QT shortening risk. It is instructive, therefore, to consider how known hERG agonists are handled by MLM. Here, two highly developed online computational tools for the prediction of hERG liability, Pred-hERG and HergSPred were probed for their ability to detect hERG activator drug molecules as hERG interactors. In total, 73 hERG blockers were tested with both computational tools giving overall good predictions for hERG blockers with reported ICs below Pred-hERG and HergSPred cut-off threshold for hERG inhibition. However, for compounds with reported ICs above this threshold such as disopyramide or sotalol discrepancies were observed. HergSPred identified all 20 hERG agonists selected as interacting with the hERG channel. Further studies are warranted to improve online MLM prediction of hERG related cardiotoxicity, by explicitly taking into account channel agonism as well as inhibition.
Topics: Humans; Potassium Channel Blockers; Ether-A-Go-Go Potassium Channels; Arrhythmias, Cardiac; Machine Learning; Internet
PubMed: 37468081
DOI: 10.1016/j.vascn.2023.107293 -
Journal of Pharmacological Sciences Aug 2022Since information is still limited whether atrial I may become a potential therapeutic target to terminate persistent atrial fibrillation (AF), we assessed it by using...
Roles of I for perpetuating atrial fibrillation: Effects of atrial-selective K channel inhibitor AVE0118 and class I drugs on the persistent atrial fibrillation canine model.
Since information is still limited whether atrial I may become a potential therapeutic target to terminate persistent atrial fibrillation (AF), we assessed it by using the persistent AF canine model with representative I inhibitor AVE0118 and class I drugs. AVE0118 (6 mg/kg, n = 7), disopyramide (3 mg/kg, n = 7) and cibenzoline (3 mg/kg, n = 6) terminated the AF in 3/7, 1/7 and 2/6 animals, respectively, whereas aprindine (3 mg/kg, n = 6) did not suppress it. These findings suggest that I inhibition in addition to open-state I suppression with slow dissociation kinetics can synergistically exert potent antiarrhythmic action against persistent AF.
Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Biphenyl Compounds; Dogs; Heart Atria
PubMed: 35717070
DOI: 10.1016/j.jphs.2022.05.004 -
JACC. Case Reports Dec 2023An adult with unrepaired tetralogy of Fallot presented with frequent tet spells. Her course was complicated by severe cyanotic spells and tachycardia-bradycardia...
An adult with unrepaired tetralogy of Fallot presented with frequent tet spells. Her course was complicated by severe cyanotic spells and tachycardia-bradycardia syndrome that limited beta blocker use to stabilize her spells. She markedly improved after disopyramide initiation and underwent successful tetralogy of Fallot repair with excellent functional outcome.
PubMed: 38204534
DOI: 10.1016/j.jaccas.2023.102093 -
The American Journal of Cardiology Aug 2020Highly reliable identification of adults with hypertrophic cardiomyopathy (HC) at risk for sudden death (SD) has been reported. A significant controversy remains,...
Highly reliable identification of adults with hypertrophic cardiomyopathy (HC) at risk for sudden death (SD) has been reported. A significant controversy remains, however, regarding the most reliable risk stratification methodology for children and adolescents with HC. The present study assesses the accuracy of SD prediction and prevention with prophylactic implantable cardioverter-defibrillators (ICDs) in young HC patients. The study group is comprised of 146 HC patients <20 years of age evaluated consecutively over 17 years with prospective risk stratification and ICD decision-making. We relied on ≥1 established individual risk markers considered major within each patient's clinical profile, based on an enhanced American College of Cardiology /American Heart Association (ACC/AHA) guidelines algorithm. Of the 60 largely asymptomatic patients implanted with primary prevention ICDs at age 15 ± 4 years, 9 (15%) experienced device therapy terminating potentially lethal ventricular tachyarrhythmias and restoring sinus rhythm at 19 ± 6 years (range 9 to 29), 5.1 ± 6.0 years after implant; 3 patients had multiple appropriate ICD discharges. The individual risk marker algorithm was associated with 100% sensitivity in predicting SD events (95%CI: 69, 100) and 63% specificity for identifying patients without events (95%CI: 54, 71). Of these patients with device therapy, massive left ventricular hypertrophy (absolute wall thickness ≥30 mm) was the most common predictor, present in 70% of patients either alone or in combination with other risk markers. Each of the 146 study patients have survived to date at 22 ± 5 years, including all 86 without ICD recommendations. In conclusion, an enhanced ACC/AHA risk stratification strategy, based on established individual risk markers, was highly reliable in prospectively predicting SD events in children and adolescents with HC, and preventing arrhythmia-based catastrophes in this susceptible high risk population.
Topics: Adolescent; Adrenergic beta-Antagonists; Adult; Anti-Arrhythmia Agents; Calcium Channel Blockers; Cardiac Resynchronization Therapy Devices; Cardiomyopathy, Hypertrophic; Child; Death, Sudden, Cardiac; Defibrillators, Implantable; Disopyramide; Female; Humans; Male; Primary Prevention; Risk Assessment; Syncope; Tachycardia, Ventricular; Young Adult
PubMed: 32650928
DOI: 10.1016/j.amjcard.2020.04.042