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International Heart Journal Sep 2021High-degree atrioventricular block (HAVB) or complete heart block (CHB) is a common complication associated with transcatheter aortic valve replacement (TAVR). However,... (Observational Study)
Observational Study
High-degree atrioventricular block (HAVB) or complete heart block (CHB) is a common complication associated with transcatheter aortic valve replacement (TAVR). However, some patients with HAVB/CHB recover with time. The results of electrophysiological studies (EPSs) using permanent pacemaker implantation (PPI) in patients with suspicious HAVB/CHB are considered controversial.This study aimed to evaluate whether HAVB/CHB induction at the bedside using a temporary pacemaker can predict recurrence in patients who had recovered from HAVB/CHB after TAVR.We enrolled a total of 11 patients who had recovered from HAVB/CHB and evaluated their electrophysiology using right ventricular pacing and/or procainamide administration.HAVB/CHB induction was positive. Three patients tested positive for HAVB/CHB, whereas 8 tested negative. The ejection fraction and the interval between HAVB/CHB onset and EPS were found to be significant. HAVB/CHB positive patients underwent PPI. A patient with a balloon-expandable valve tested positive just before recovery of CHB, but tested negative 5 days later and was included in the negative group. The 4 patients who tested negative received a cardiovascular implantable electric device (CIED). We observed HAVB/CHB in 2 patients who had previously tested positive after 3 months. Among those who tested negative, those with CIED had no HAVB/CHB, and others showed neither HAVB/CHB on electrocardiogram nor experienced syncope or sudden death.Our EPS revealed that HAVB/CHB induction may predict HAVB/CHB recurrence after TAVR. Valve type and EPS timing may affect the results.
Topics: Administration, Intravenous; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Aortic Valve Stenosis; Atrioventricular Block; Bundle-Branch Block; Cardiac Electrophysiology; Electrocardiography; Female; Heart Valve Prosthesis; Humans; Male; Pacemaker, Artificial; Point-of-Care Testing; Predictive Value of Tests; Procainamide; Recurrence; Retrospective Studies; Transcatheter Aortic Valve Replacement; Treatment Outcome
PubMed: 34544981
DOI: 10.1536/ihj.21-145 -
PLoS Neglected Tropical Diseases Feb 2021African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional...
African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naïve tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type N-glycans. In overlay assays, these sugars were differentially recognized by the mannose receptor and DC-SIGN C-type lectins. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.
Topics: Animals; Chromatography, Liquid; Concanavalin A; Glycoproteins; Glycoside Hydrolases; Insect Vectors; Lectins, C-Type; Polysaccharides; Saliva; Salivary Glands; Salivary Proteins and Peptides; Tandem Mass Spectrometry; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis, African; Tsetse Flies
PubMed: 33529215
DOI: 10.1371/journal.pntd.0009071 -
Cell Reports. Medicine Oct 2020Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show...
Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.
Topics: Animals; Capsid Proteins; Coxsackievirus Infections; DNA (Cytosine-5-)-Methyltransferase 1; Diabetes Mellitus, Type 2; Disease Models, Animal; Enterovirus B, Human; Female; Gene Expression Regulation; Glucose; Homeodomain Proteins; Humans; Insulin-Secreting Cells; Male; Mice; Mice, Transgenic; Procainamide; Rats; Repressor Proteins; Signal Transduction; Trans-Activators; Transplantation, Heterologous
PubMed: 33205075
DOI: 10.1016/j.xcrm.2020.100125 -
Cureus Apr 2021Myocardial ischemia may lead to lethal arrhythmias. Treatment of these arrhythmias without addressing the cause of ischemia may be futile. The length of resuscitation is...
BACKGROUND
Myocardial ischemia may lead to lethal arrhythmias. Treatment of these arrhythmias without addressing the cause of ischemia may be futile. The length of resuscitation is an important parameter for determining when to stop resuscitation but with shockable rhythms and reversible cause of the cardiac arrest, the decision to terminate resuscitation is complex. Case Summary: A patient with a three-month history of shortness of breath with effort developed pulseless ventricular tachycardia (VT) at the early stages of a stress test. In coronary angiography, a critical lesion in the right coronary artery (RCA) was observed and treated with two stents. During the procedure and for a total of five hours, the patient had more than 100 separate episodes of VT and ventricular fibrillation (VF) that were treated by 150 defibrillations, artificial ventilation, intra-aortic counter-pulsation balloon insertion, and multiple drugs. One hour after the initial stenting procedure, thrombosis of the RCA was demonstrated and treated successfully with angioplasty. Use of procainamide resolved the arrhythmias and the patient recovered completely without neurological deficit, ejection fraction of 45%, and is asymptomatic at one year following the event.
DISCUSSION
Our case shows that with a revisable cause of cardiac arrest, resuscitation should be directed at maintaining perfusion of essential organs and treating the reversible cause. Without re-opening the RCA, we could not have saved the patient's life. The use of an extracorporeal membrane oxygenator, if available, should be considered in similar cases. Finally, the quality of cardiopulmonary resuscitation determines the neurological outcome regardless of the length of resuscitation, as was evident in our patient who recovered completely.
PubMed: 33954068
DOI: 10.7759/cureus.14255 -
Cureus Oct 2020Amiodarone is widely used as an antiarrhythmic agent for the treatment of both supraventricular and ventricular arrhythmias in various inpatient as well as outpatient...
Amiodarone is widely used as an antiarrhythmic agent for the treatment of both supraventricular and ventricular arrhythmias in various inpatient as well as outpatient settings. Classified as a class III antiarrhythmic agent, it acts mainly by inhibition of potassium channels in the cardiac muscle. Adverse effects are quite common and usually involve pulmonary, gastrointestinal, endocrine, dermatologic, or neuromuscular systems. Although hematologic side effects including thrombocytopenia have also been reported, amiodarone-induced neutropenia is quite rare. We present a case of amiodarone-induced neutropenia in a 66-year-old Caucasian gentleman. He presented to our hospital with cardiac arrest due to ventricular-fibrillation and had received amiodarone as a part of his therapy. His hospital course was complicated by neutropenia which was found to have a clear temporal relation with amiodarone. His initial white blood cell count was 6400/mm3 with an absolute neutrophil count (ANC) of 4800/mm3. His ANC started to downtrend and reached a nadir of 400/mm3 at day six of therapy. This improved significantly after stopping amiodarone, without any change in other medications. Given the rapid improvement of his neutropenia with the discontinuation of amiodarone, further workup with a bone marrow biopsy was not performed. Severe selective neutropenia, also known as agranulocytosis, is a life-threatening condition due to increased risk of severe infections. Antiarrhythmic agents such as tocainamide, procainamide, and flecainide are generally known to cause agranulocytosis. The mechanism of agranulocytosis or neutropenia is thought to be mediated by either immune-mediated destruction or direct and indirect toxicity to myeloid precursors. Although amiodarone has been in use for over 20 years in the management of tachyarrhythmias, agranulocytosis as a direct side effect of amiodarone therapy has been rarely reported. It is important to keep in mind this rare but potentially life-threatening adverse effect of amiodarone when initiating therapy.
PubMed: 33194480
DOI: 10.7759/cureus.10913 -
The Journal of Innovations in Cardiac... Jul 2023Pediatric postoperative junctional ectopic tachycardia (JET), although usually self-limited, may lead to significant morbidity and mortality. Anti-arrhythmic medications...
Pediatric postoperative junctional ectopic tachycardia (JET), although usually self-limited, may lead to significant morbidity and mortality. Anti-arrhythmic medications are often necessary to restore atrioventricular synchrony when non-pharmacological measures fail. Multiple drugs have been described for the management of postoperative JET, with enteral ivabradine being the latest addition. While safe administration of ivabradine has been described in combination with other anti-arrhythmics (amiodarone, flecainide), no study has described the use of ivabradine in conjunction with intravenous procainamide for the management of postoperative JET. Our case report describes the safe use of ivabradine and procainamide combination therapy in a young patient.
PubMed: 37492694
DOI: 10.19102/icrm.2023.14075 -
Molecular Medicine Reports May 2024Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase‑activating proteins (GAPs) serve essential roles...
Cardiac hypertrophy is one of the key processes in the development of heart failure. Notably, small GTPases and GTPase‑activating proteins (GAPs) serve essential roles in cardiac hypertrophy. RhoGAP interacting with CIP4 homologs protein 1 (RICH1) is a RhoGAP that can regulate Cdc42/Rac1 and F‑actin dynamics. RICH1 is involved in cell proliferation and adhesion; however, to the best of our knowledge, its role in cardiac hypertrophy remains unknown. In the present study, the role of RICH1 in cardiomyocyte hypertrophy was assessed. Cell viability was analyzed using the Cell Counting Kit‑8 assay and cells surface area (CSA) was determined by cell fluorescence staining. Reverse transcription‑quantitative PCR and western blotting were used to assess the mRNA expression levels of hypertrophic marker genes, such as Nppa, Nppb and Myh7, and the protein expression levels of RICH1, respectively. RICH1 was shown to be downregulated in isoproterenol (ISO)‑ or angiotensin II (Ang II)‑treated H9c2 cells. Notably, overexpression of RICH1 attenuated the upregulation of hypertrophy‑related markers, such as Nppa, Nppb and Myh7, and the enlargement of CSA induced by ISO and Ang II. By contrast, the knockdown of RICH1 exacerbated these effects. These findings suggested that RICH1 may be a novel suppressor of ISO‑ or Ang II‑induced cardiomyocyte hypertrophy. The results of the present study will be beneficial to further studies assessing the role of RICH1 and its downstream molecules in inhibiting cardiac hypertrophy.
Topics: Humans; Myocytes, Cardiac; Angiotensin II; Isoproterenol; Cardiomegaly; Heart Defects, Congenital; Nitrobenzoates; Procainamide
PubMed: 38456539
DOI: 10.3892/mmr.2024.13193 -
Academic Emergency Medicine : Official... Sep 2019Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Emergency department (ED) patients with uncomplicated atrial fibrillation (AF) of less than 48 hours may be safely managed with rhythm control. Although both chemical-first and electrical-first strategies have been advocated, there are no comparative effectiveness data to guide clinicians.
METHODS
At six urban Canadian centers, ED patients ages 18 to 75 with uncomplicated symptomatic AF of less than 48 hours and CHADS score of 0 or 1 were randomized using concealed allocation in a 1:1 ratio to one of the following strategies: 1) chemical cardioversion with procainamide infusion, followed by electrical countershock if unsuccessful; or 2) electrical cardioversion, followed by procainamide infusion if unsuccessful. The primary outcome was the proportion of patients discharged within 4 hours of arrival. Secondary outcomes included ED length-of-stay (LOS); prespecified ED-based adverse events; and 30-day ED revisits, hospitalizations, strokes, deaths, and quality of life (QoL).
RESULTS
Eighty-four patients were analyzed: 41 in the chemical-first group and 43 in the electrical-first group. Groups were balanced in terms of age, sex, vital signs, and CHADS scores. All patients were discharged home, with 83 (99%) in sinus rhythm. In the chemical-first group, 13 of 41 patients (32%) were discharged within 4 hours compared to 29 of 43 patients (67%) in the electrical-first group (p = 0.001). In the chemical-first group, the median ED LOS was 5.1 hours (interquartile range [IQR] = 3.5 to 5.9 hours) compared to 3.5 hours (IQR = 2.4 to 4.6 hours) in the electrical-first group, for a median difference of 1.2 hours (95% confidence interval = 0.4 to 2.0 hours, p < 0.001). No patients experienced stroke or death. All other outcomes, including adverse events, ED revisits, and QoL, were similar.
CONCLUSION
In uncomplicated ED AF patients managed with rhythm control, chemical-first and electrical-first strategies both appear to be successful and well tolerated; however, an electrical-first strategy results in a significantly shorter ED LOS.
Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Canada; Electric Countershock; Emergency Service, Hospital; Female; Humans; Length of Stay; Male; Middle Aged; Procainamide; Quality of Life; Young Adult
PubMed: 31423687
DOI: 10.1111/acem.13669 -
Molecules (Basel, Switzerland) Jan 2023As a result of the paucity of treatment, Leishmaniasis continues to provoke about 60,000 deaths every year worldwide. New molecules are needed, and drug discovery...
BACKGROUND
As a result of the paucity of treatment, Leishmaniasis continues to provoke about 60,000 deaths every year worldwide. New molecules are needed, and drug discovery research is oriented toward targeting proteins crucial for parasite survival. Among them, trypanothione reductase (TR) is of remarkable interest owing to its vital role in species protozoan parasite life. Our previously identified compound is a novel chemotype endowed with a unique mode of TR inhibition thanks to its binding to a formerly unknown but druggable site at the entrance of the NADPH binding cavity, absent in human glutathione reductase (hGR).
METHODS
We designed and synthesized new 3-amino-1-arylpropan-1-one derivatives structurally related to compound and evaluated their potential inhibition activity on TR from (LiTR). Cluster docking was performed to assess the binding poses of the compounds.
RESULTS
The newly synthesized compounds were screened at a concentration of 100 μM in in vitro assays and all of them proved to be active with residual activity percentages lower than 75%.
CONCLUSIONS
Compounds and were the most potent inhibitors found, suggesting that an additional aromatic ring might be promising for enzymatic inhibition. Further structure-activity relationships are needed to optimize our compounds activity.
Topics: Humans; Leishmania infantum; NADP; Models, Molecular; NADH, NADPH Oxidoreductases; Binding Sites; Antiprotozoal Agents
PubMed: 36615531
DOI: 10.3390/molecules28010338 -
Molecular Omics Aug 2020Small molecule monosaccharide analogs (e.g. 4F-GlcNAc, 4F-GalNAc) and acceptor decoys (e.g. ONAP, SNAP) are commonly used as metabolic glycoengineering tools to perturb...
Robustness in glycosylation systems: effect of modified monosaccharides, acceptor decoys and azido sugars on cellular nucleotide-sugar levels and pattern of N-linked glycosylation.
Small molecule monosaccharide analogs (e.g. 4F-GlcNAc, 4F-GalNAc) and acceptor decoys (e.g. ONAP, SNAP) are commonly used as metabolic glycoengineering tools to perturb molecular and cellular recognition processes. Azido-derivatized sugars (e.g. ManNAz, GlcNAz, GalNAz) are also used as bioorthogonal probes to assay the glycosylation status of cells and tissue. With the goal of obtaining a systems-level understanding of how these compounds work, we cultured cells with these molecules and systematically evaluated their impact on: (i) cellular nucleotide-sugar levels, and (ii) N-linked glycosylation. To this end, we developed a streamlined, simple workflow to quantify nucleotide-sugar levels using amide-based hydrophilic interaction liquid chromatography (HILIC) separation followed by negative-mode electrospray ionization mass spectrometry (ESI-MS/MS) using an Orbitrap detector. N-Glycans released from cells were also procainamide functionalized and quantified using positive-mode ESI-MS/MS. Results show that all tested compounds changed the baseline nucleotide-sugar levels, with the effect being most pronounced for the fluoro-HexNAc compounds. These molecules depressed UDP-HexNAc levels in cells by up to 80%, while concomitantly elevating UDP-4F-GalNAc and UDP-4F-GlcNAc. While the measured changes in nucleotide-sugar concentration were substantial in many cases, their impact on N-linked glycosylation was relatively small. This may be due to the high nucleotide-sugar concentrations in the Golgi, which far exceed the K values of the glycosylating enzymes. Thus, the glycosylation system output exhibits 'robustness' even in the face of significant changes in cellular nucleotide-sugar concentrations.
Topics: Azides; Chromatography, Liquid; Glycomics; Glycosylation; HL-60 Cells; Humans; Intracellular Space; Monosaccharides; Nucleotides; Polysaccharides; Sugars; Tandem Mass Spectrometry
PubMed: 32352119
DOI: 10.1039/d0mo00023j