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Background: The importance of nonpulmonary vein (PV) triggers for the initiation/recurrence of atrial fibrillation (AF) is well established., Objectives: This study sought to assess the incremental benefit of provocative maneuvers for identifying non-PV triggers., Methods: We included consecutive patients undergoing first-time AF ablation between 2020 and 2022. The provocation protocol included step 1, identification of spontaneous non-PV triggers after cardioversion of AF and/or during sinus rhythm; step 2, isoproterenol infusion (3, 6, 12, and 20-30 μg/min); and step 3, atrial burst pacing to induce AF followed by cardioversion during residual or low-dose isoproterenol infusion or induce focal atrial tachycardia. Non-PV triggers were defined as non-PV ectopic beats triggering AF or sustained focal atrial tachycardia., Results: Of 1,372 patients included, 883 (64.4%) underwent the complete stepwise provocation protocol with isoproterenol infusion and burst pacing, 334 (24.3%) isoproterenol infusion only, 77 (5.6%) burst pacing only, and 78 (5.7%) no provocative maneuvers (only step 1). Overall, 161 non-PV triggers were found in 135 (9.8%) patients. Of these, 51 (31.7%) non-PV triggers occurred spontaneously, and the remaining 110 (68.3%) required provocative maneuvers for induction. Among those receiving the complete stepwise provocation protocol, there was a 2.2-fold increase in the number of patients with non-PV triggers after isoproterenol infusion, and the addition of burst pacing after isoproterenol infusion led to a total increase of 3.6-fold with the complete stepwise provocation protocol., Conclusions: The majority of non-PV triggers require provocative maneuvers for induction. A stepwise provocation protocol consisting of isoproterenol infusion followed by burst pacing identifies a 3.6-fold higher number of patients with non-PV triggers., Competing Interests: Funding Support and Author Disclosures This work was supported by the Leducq Foundation FANTASY Network and the Richard T and Angela Clark Innovation Fund in Cardiovascular Medicine. Dr Marchlinski serves as a consultant for Abbott Medical, Biosense Webster, and Medtronic Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this study, nanoparticles loaded with active components from Polygonum orientale L. (PO), a traditional Chinese herb known for its anti-myocardial ischemic properties, were investigated for cardio-protective properties. Specifically, OVQ-Nanoparticles (OVQ-NPs) with Orientin (Ori), Vitexin (Vit), and Quercetin (Que) was obtained by double emulsion-solvent evaporation method. The OVQ-NPs exhibited a spherical shape, with a uniform size distribution of 136.77 ± 3.88 nm and a stable ζ-potential of -13.40 ± 2.24 mV. Notably, these nanoparticles exhibited a favorable sustained-release characteristic, resulting in an extended circulation time within the living organism. Consequently, the administration of these nanoparticles resulted in significant improvements in electrocardiograms and heart mass index of myocardial ischemic rats induced by isoproterenol, as well as decreased serum levels of CK, LDH, and AST. Furthermore, the results of histopathological examination, such as H&E staining and TUNEL staining, confirmed a reduced level of cardiac tissue pathology and apoptosis. Moreover, the quantification of biochemical indicators (SOD, MDA, GSH, NO, TNF-α, and IL-6) demonstrated that OVQ-NPs effectively mitigated myocardial ischemia by regulating oxidative stress and inflammatory pathways. In conclusion, OVQ-NPs demonstrate promising therapeutic potential as an intervention for myocardial ischemia, providing a new perspective on traditional Chinese medicine treatment in this area., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In recent years, more and more evidence has shown that the disorder of gut microbiota (GM) is closely correlated with myocardial ischemia (MI). Even though the Danshen and Honghua herb pair (DHHP) is widely used in treating cardiovascular disease in China and exhibits obvious clinical efficacy on MI, the anti-MI mechanism of DHHP remains and needs to be explored in depth. Thus, in this study, we investigated whether the amelioration effect and molecular mechanism of DHHP on MI were related to regulating GM through pharmacodynamics evaluation and metagenomic sequencing. Histopathological testing results showed that DHHP treatment could alleviate the pathological changes of myocardial tissue in the acute MI (AMI) rats induced by isoproterenol (ISO), especially structural disorder, irregular distribution, and enlargement of the myocardial space. These pathological changes were all alleviated to some extent by DHHP treatment. Biochemical analysis results suggested that compared with the control group, the serum levels of AST, CTn-I, CK-MB, and TNF-α in model group rats were notably decreased, and the CAT and SOD levels in serum were markedly increased. These abnormal trends were significantly reversed by DHHP treatment. Furthermore, metagenomic sequencing analysis results indicated that DHHP could improve disorders in the composition and function of GM in AMI rats, mainly reflected in increasing diversity and richness, and obviously enhancing the abundance of Bacteroides fluxus, B. uniformis, B. stercoris, Roseburia hominis, Schaedlerella arabinosiphila, and R. intestinalis, and reducing the abundance of Enterococcus avium and E. canintestini, which were associated with purine metabolism, tyrosine metabolism, cyanoamino acid metabolism, and glutathione metabolism. In conclusion, DHHP may attenuate ISO-induced MI by regulating the structure, composition, and function of GM, thus contributing to further our understanding of the anti-MI mechanisms of DHHP and providing new therapeutic ideas and diagnostic targets for the clinical studies of MI., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)

Ancient Chinese medicine literature and modern pharmacological studies show that Sophora tonkinensis Gagnep. (ST) has a protective effect on the heart. A biolabel research based on omics and bioinformatics and experimental validation were used to explore the application value of ST in the treatment of heart diseases. Therapeutic potential, mechanism of action, and material basis of ST in treating heart diseases were analyzed by proteomics, metabolomics, bioinformatics, and molecular docking. Cardioprotective effects and mechanisms of ST and active compounds were verified by echocardiography, HE and Masson staining, biochemical analysis, and ELISA in the isoproterenol hydrochloride-induced myocardial ischemia (MI) mice model. The biolabel research suggested that the therapeutic potential of ST for MI may be particularly significant among the heart diseases it may treat. In the isoprenaline hydrochloride-induced MI mice model, ST and its five active compounds (caffeic acid, gallic acid, betulinic acid, esculetin, and cinnamic acid) showed significant protective effects against echocardiographic changes and histopathological damages of the ischemic myocardial tissue. Meanwhile, they showed a tendency to correct mitochondrial structure and function damage and the abnormal expression of 12 biolables (DCTN1, DCTN3, and SCARB2, etc.) in the vesicle-mediated transport pathway, inflammatory cytokines (IL-1β, IL-6, and IL-10, etc.), and low density lipoprotein receptor (LDLR). The biolabel research identifies a new application value of ST in the treatment of heart diseases. ST and its active compounds inhibit mitochondrial impairments, inflammation, and LDLR deficiency through regulating the vesicle-mediated transport pathway, thus achieving the purpose of treating MI., Competing Interests: Declaration of Competing Interest All authors declare no competing interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In essence, the β 2 adrenergic receptor (β 2 AR) plays an antiproliferative role by increasing the intracellular cyclic 3',5'-adenosine monophosphate (cAMP) concentration through G αs coupling, but interestingly, β 2 AR antagonists are able to effectively inhibit fibroblast-like synoviocytes (FLSs) proliferation, thus ameliorating experimental RA, indicating that the β 2 AR signalling pathway is impaired in RA FLSs via unknown mechanisms. The local epinephrine (Epi) level was found to be much higher in inflammatory joints than in normal joints, and high-level stimulation with Epi or isoproterenol (ISO) directly promoted FLSs proliferation and migration due to impaired β 2 AR signalling and cAMP production. By applying inhibitor of receptor internalization, and small interfering RNA (siRNA) of G αs and G αi , and by using fluorescence resonance energy transfer and coimmunoprecipitation assays, a switch in G αs -G αi coupling to β 2 AR was observed in inflammatory FLSs as well as in FLSs with chronic ISO stimulation. This G αi coupling was then revealed to be initiated by G protein coupled receptor kinase 2 (GRK2) but not β-arrestin2 or protein kinase A-mediated phosphorylation of β 2 AR. Inhibiting the activity of GRK2 with the novel GRK2 inhibitor paeoniflorin-6'-O-benzene sulfonate (CP-25), a derivative of paeoniflorin, or the accepted GRK2 inhibitor paroxetine effectively reversed the switch in G αs -G αi coupling to β 2 AR during inflammation and restored the intracellular cAMP level in ISO-stimulated FLSs. As expected, CP-25 significantly inhibited the hyperplasia of FLSs in a collagen-induced arthritis (CIA) model (CIA FLSs) and normal FLSs stimulated with ISO and finally ameliorated CIA in rats. Together, our findings revealed the pathological changes in β 2 AR signalling in CIA FLSs, determined the underlying mechanisms and identified the pharmacological target of the GRK2 inhibitor CP-25 in treating CIA. Video Abstract., (© 2023. The Author(s).)

When pathological hypertrophy progresses to heart failure (HF), the prognosis is often very poor. Therefore, it is crucial to find new and effective intervention targets. Here, myocardium-specific Trim44 knockout rats were generated using CRISPR-Cas9 technology. Cardiac phenotypic observations revealed that Trim44 knockout affected cardiac morphology at baseline. Rats with Trim44 deficiency exhibited resistance to cardiac pathological changes in response to stimulation via isoproterenol (ISO) treatment, including improvement of cardiac remodeling and dysfunction by morphological and functional observations, reduced myocardial fibrosis and reduced expression of molecular markers of cardiac stress. Furthermore, signal transduction validation associated with growth and hypertrophy development in vivo and in vitro demonstrated that Trim44 deficiency inhibited the activation of signaling pathways involved in myocardial hypertrophy, especially response to pathological stress. In conclusion, the present study indicates that Trim44 knockout attenuates ISO-induced pathological cardiac remodeling through blocking the AKT/mTOR/GSK3β/P70S6K signaling pathway. This is the first study to demonstrate the function and importance of Trim44 in the heart at baseline and under pathological stress. Trim44 could be a novel therapeutic target for prevention of cardiac hypertrophy and HF., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Percutaneous left atrial appendage occlusion (LAAO) is contraindicated in presence of left atrial appendage (LAA) thrombus. It is often difficult to separate LAA sludge from an organized thrombus on transesophageal echocardiography. The inability to differentiate sludge from thrombus leads to patients not receiving LAAO despite contraindication to long-term anticoagulation. Retrospective 6-month follow-up outcomes are reported on patients undergoing LAAO in presence of LAA sludge cleared by isoproterenol. This study showed no increased risk of transient ischemic attack/stroke in the 6 months following LAAO in the presence of LAA sludge, which was cleared with isoproterenol. This study suggests a role for isoproterenol in differentiating sludge from thrombus., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In the present study, we assessed the therapeutic potential of Biochanin-A (BCA) (10 mg/kg BW/day) pretreatment for 30 days on lipid metabolic abnormalities, proinflammatory cytokines and matrix metalloproteinase expression in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. We measured the potential role of BCA on tissue and circulatory lipid profiles as well as on lipid metabolic enzymes: serum inflammatory cytokines (TNF-α, IL-1α, IL-1β, IL-6 and MCP1) and serum Matrix Metalloproteinases (particularly, MMP-2 and MMP-9) together with mRNA expressions of TNF-α, IL-6, MMP-2 and MMP-9 by RT-PCR analysis. Administration of ISO to rats significantly distorted their lipid metabolism and augmented inflammatory process, MMP expression and proteolytic activity. In addition, pretreatment with BCA of ISO-induced MI rats significantly reestablished the altered lipid metabolism and concealed the inflammation of cytokines. BCA suppressed the expressions of proinflammatory cytokines and MMPs in ISO-induced MI in rats when compared to normal untreated MI rats. Hence, these results established that BCA could improve the pathological processes of myocardial remodeling which was confirmed by histopathology of heart in MI rats and might be an effective beneficial ingredient for the management of heart failure disorders.

Aims: This raised the issue of whether in vivo long-term red wine treatment can act as a modulator of these targets., Main Methods: We monitored SBP, glucose tolerance, oxidative stress, and cardiovascular function. Aortic and atrial tissues from normotensive-WKY, hypertensive-SHR, and diabetic-STZ animals, chronically exposed to red wine (3.715 ml/kg/v.o/day) or alcohol (12%) for 21-days, were used to measure contractile/relaxation responses by force transducers. Key findings : red wine, but not alcohol, prevented the increase of SBP and hyperglycemic peak. Additionally, was observed prevention of oxidative stress metabolites formation and an improvement in ROS scavenging antioxidant capacity of SHR. We also revealed that red wine intake enhances the endothelium-dependent relaxation, decreases the hypercontractile mediated by angiotensin-II in the aorta, and via β 1 -adrenoceptors in the atrium., Significance: The long-term consumption of red wine can improve oxidative stress and the functionality of angiotensin-II and β 1 -adrenoceptors, inspiring new pharmacologic and dietetic therapeutic approaches for the treatment of hypertension and diabetes. Abbreviation Acronyms and/or abbreviations: [Ca 2+ ] cyt = Cytosolic Ca 2+ Concentration; ACh = Acetylcholine; ANG II = Angiotensin II; AT1 = ANG II type 1 receptor; AUC = Area Under the Curve; Ca 2+ = Calcium; Endo + = Endothelium Intact; Fen = Phenylephrine (1 μM); GTT = Glucose Tolerance Test; ISO = Isoprenaline (isoproterenol); KHN = Krebs-Henseleit Nutrient; LA = Left Atria; LH = Lipid Hydroperoxide; NO = Nitric Oxide; RA = Right Atria; RAS = Renin-Angiotensin System; ROS = Reactive Oxygen Species; SBP = Systolic Blood Pressure; SHR = Spontaneously Hypertensive Rats; STZ = Streptozotocin; WKY = Normotensive Wistar Kyoto Rats.

Earlier studies reported that long-term treatment with thymoquinone (TQ) at a high dose (20 mg/kg) exerts a cardioprotective effect against isoproterenol (ISO)-triggered myocardial infarction (MI) in rats. In the present study, we tested the hypothesis that TQ, as a potent molecule, can exhibit cardioprotective effects at the lower dose for a short-term regimen. The rats were administered with TQ (5 mg/kg, intraperitoneal) at the 4 h interval for 2 days. ISO (100 mg/kg/day, subcutaneous) was given for 2 days to produce MI. ISO challenge results in deformation in ECG wave front, elevated left ventricular (LV) end-diastolic pressure, and reduced LVdP/dtmax and LVdP/dtmin. The levels of the cardiac biomarker in serum, such as creatine kinase MB, alanine aminotransferase, and aspartate aminotransferase, were increased. In the myocardium, a rise in malonaldehyde and decreased superoxide dismutase, glutathione, and catalase contents were observed. Furthermore, increased levels of tumor necrotic factor-α, interleukin-6, and interleukin-1β were observed in the myocardium. TQ pretreatment significantly normalized alterations in hemodynamic parameters, strengthened the antioxidant defense system, and decreased the contents of pro-inflammatory cytokines and hepatic enzymes as compared to the ISO group. Based on the results, TQ appears to be cardioprotective at low doses, and effective even administered for a shorter duration.

Myocardial hypertrophy is a pathological feature of many heart diseases. This is a complex process involving all types of cells in the heart and interactions with circulating cells. This study is aimed at identifying the differentially expressed proteins (DEPs) in myocardial hypertrophy rats induced by isoprenaline (ISO) and treated with novel peptide Athycaltide-1 (ATH-1) and exploring the mechanism of its improvement. ITRAQ was performed to compare the three different heart states in control group, ISO group, and ATH-1 group. Pairwise comparison showed that there were 121 DEPs in ISO/control (96 upregulated and 25 downregulated), 47 DEPs in ATH-1/ISO (27 upregulated and 20 downregulated), and 116 DEPs in ATH-1/control (77 upregulated and 39 downregulated). Protein network analysis was then performed using the STRING software. Functional analysis revealed that Hspa1 protein, oxidative stress, and MAPK signaling pathway were significantly involved in the occurrence and development of myocardial hypertrophy, which was further validated by vivo model. It is proved that ATH-1 can reduce the expression of Hspa1 protein and the level of oxidative stress in hypertrophic myocardium and further inhibit the phosphorylation of p38 MAPK, JNK, and ERK1/2., Competing Interests: Athycaltide-1 has obtained a granted patent (ZL201711418314.3) in China with Liying Hao, Jingyuan Li, Zhuo Li, Ze Kang and Siqi Wang as inventors. The authors have no other conflicts of interest., (Copyright © 2022 Xi Zheng et al.)

Cardiovascular risk factors have attracted increasing attention in recent years with the acceleration of population aging, amongst which cardiac hypertrophy is the initiating link to heart failure. Pirfenidone is a promising agent for the treatment of idiopathic pulmonary fibrosis and has recently proven to exert inhibitory effects on the inflammatory response. This study proposes to explore the potential pharmacological action of Pirfenidone in treating cardiac hypertrophy in a rodent model. Four groups of mice were used in the present study: the control, ISO (5 mg/kg/day) for 7 days, Pirfenidone (200 mg/kg/day) for 14 days, and Spironolactone (SPI) (200 mg/kg/day) for 14 days groups. Increased heart weight index, left ventricle (LV) weight index, LV wall thickness, declined LV volume, and elevated serum levels of CK-MB, AST, and LDH were observed in ISO-challenged mice, all of which were dramatically reversed by the administration of Pirfenidone or SPI. Furthermore, an elevated cross-sectional area of cardiomyocytes in the wheat germ agglutinin (WGA) staining of heart cross-sections, upregulated atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), β Myosin Heavy Chain (β-MHC), and excessively released tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) in cardiac tissues were observed in the ISO group but greatly alleviated by Pirfenidone or SPI. Lastly, the promoted expression levels of p-JAK-2/JAK-2 and p-STAT3/STAT-3 in the cardiac tissues of ISO-challenged mice were significantly repressed by Pirfenidone or SPI. Collectively, our data reveals a therapeutic property of Pirfenidone on ISO-induced cardiac hypertrophy in mice.

Adrenergic receptors (AR) belong to the G protein-coupled receptor superfamily and regulate migration and proliferation in various cell types. The objective of this study was to evaluate whether β-AR stimulation affects the antiproliferative action of α2-AR agonists on B16F10 cells and, if so, to determine the relative contribution of β-AR subtypes. Using pharmacological approaches, evaluation of Ki-67 expression by flow cytometry and luciferase-based cAMP assay, we found that treatment with isoproterenol, a β-AR agonist, increased cAMP levels in B16F10 melanoma cells without affecting cell proliferation. Propranolol inhibited the cAMP response to isoproterenol. In addition, stimulation of α2-ARs with agonists such as clonidine, a well-known antihypertensive drug, decreased cancer cell proliferation. This effect on cell proliferation was suppressed by treatment with isoproterenol. In turn, the suppressive effects of isoproterenol were abolished by the treatment with either ICI 118,551, a β2-AR antagonist, or propranolol, suggesting that isoproterenol effects are mainly mediated by the β2-AR stimulation. We conclude that the crosstalk between the β2-AR and α2-AR signaling pathways regulates the proliferative activity of B16F10 cells and may therefore represent a therapeutic target for melanoma therapy.

Cardiovascular disorders are the leading cause of death globally. Rosuvastatin is a member of statins (inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase) with many pleiotropic properties. This study investigated cardioprotective effects of rosuvastatin in isoprenaline-induced myocardial injury. Male rats were given rosuvastatin (1, 5, or 10 mg/kg, oral) daily for 1 week and on seventh and eighth day isoprenaline (150 mg/kg, subcutaneous) was given to induce cardiac injury. On ninth day, rats were euthanized and different samples were harvested for analysis. Isoprenaline administration resulted in increased cardiac mass, increased cardiac injury marker levels (cTnI, CK-MB, ALT, and AST), increased lipid/protein oxidation, and increased cardiac nitrite levels. It also decreased superoxide dismutase, CAT, GST, and glutathione reductase activities, and total antioxidant activity. Isoprenaline also increased TNF-α and IL-6 levels. Decreased mRNA expression of Nrf2 and Bcl-2 along with increased mRNA expression of Bax, eNOS and iNOS genes was observed in isoprenaline treated animals. Histopathological evaluations of rosuvastatin pre-treated groups showed reduction of myocardial necrosis. Pretreatment with rosuvastatin (5 and 10 mg/kg) reduced many of these pathological changes. The current study showed that rosuvastatin significantly reduces myocardial injury induced by isoprenaline.

Mucus clearance, a primary innate defense mechanism of airways, is defective in patients with cystic fibrosis (CF) and CF animals. In previous work, the combination of a low dose of the cholinergic agonist, carbachol with forskolin or a β adrenergic agonist, isoproterenol synergistically increased mucociliary clearance velocity (MCCV) in ferret tracheas. Importantly, the present study shows that synergistic MCCV can also be produced in CF ferrets, with increases ~ 55% of WT. Synergistic MCCV was also produced in pigs. The combined agonists increased MCCV by increasing surface fluid via multiple mechanisms: increased fluid secretion from submucosal glands, increased anion secretion across surface epithelia and decreased Na + absorption. To avoid bronchoconstriction, the cAMP agonist was applied 30 min before carbachol. This approach to increasing mucus clearance warrants testing for safety and efficacy in humans as a potential therapeutic for muco-obstructive diseases., (© 2021. The Author(s).)

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.

Background: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance., Objective: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions., Methods and Results: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the β-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, β-adrenergic regulation of contraction was significantly impaired in both HF groups., Conclusions: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Complete atrioventricular block (AVB3) may be an urgent potentially lifethreatening situation. Our objective was to describe the routine management of AVB 3, with emphasis on the organizational aspects., Methods: From September 2019 to November 2019, a prospective national survey including 28 questions was electronically sent to 100 physicians (Google Form)., Results: The answers were collected from 93 physicians (response rate 93%). Permanent pacemaker implantation during weekends and nights (after 8PM) is possible for 49% of the operators (<5 times a year), for 15% (>5 times a year), impossible for 36% of the operators. For AVB3 nonresponsive to isoproterenol occurring during the night, a temporary pacing lead (TPL) is implanted by: the on-site medical staff on-duty (27%), the on-call interventional cardiologist (21%), the on-call electrophysiologist (19%), a permanent pacemaker is implanted by the electrophysiologist (12%), the strategy is not standardized (15%). An externalized active fixation lead (AFL) for AVB3 has already been implanted by 50% of the operators. 80 (86%) have already observed a dislocation of the TPL, a cardiac perforation already occurred in 57 (61%), a groin hematoma in 35 (38%), and this technique was proscribed for 4% of the operators., Conclusion: Our survey shows important disparities in terms of management of AVB3 among the different centers. An externalized AFL with a reusable generator was used by half of the centers., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects., Objectives: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats"., Methods: 25 male Wistar rats (180-220 g) were used: ISO/saline ( n = 6), ISO/CCrP (0.8 g/kg/day) ( n = 5), control/saline ( n = 5), and control/CCrP (0.8 g/kg/day) ( n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day ( n = 3) and a higher dose of 1.2 g/kg/day ( n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR)., Results: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function., Conclusions: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.

A case of J wave syndrome with ventricular fibrillation (VF) storm and severe hypercalcemia due to primary hyperparathyroidism is presented. VF storm subsided with an isoproterenol infusion. Prominent J waves and a Brugada-like electrocardiogram pattern disappeared after parathyroidectomy. Ventricular tachyarrhythmia was not induced during an electrophysiological study. The patient remained asymptomatic up to the 12-month follow-up.

Uncoupling of respiration and ATP production by myocardial mitochondria was observed in rats with chronic isoproterenol intoxication (L-isoproterenol subcutaneously, 1 mg/kg, for 10 days) in comparison with controls (injected with the solvent). Inhibitors of NHE-1 zoniporide (1 mg/kg intraperitoneally, 13 days) and BMA-1321 compound (0.92 mg/kg intraperitoneally, 13 days) improved the mitochondrial function in rats with isoproterenol-induced cardiac failure: respiratory control coefficients increased, more so for the respiratory chain complex II, the main source of ROS in heart failure. The effect of BMA-1321 was more manifest (53%; p<0.05) in comparison with zoniporide (35%; p<0.05).

Torsades de pointes (TdP) is a fatal polymorphic ventricular tachycardia in association with congenital or acquired QT prolongation. Concomitant electrolyte disturbances and drugs potentiate the development of TdP. We describe a severe case of refractory TdP in the setting of methadone, cocaine, hypokalemia and hypomagnesemia. The successful treatment was achieved with the administration of magnesium, isoproterenol, and electrolyte replacement.

Background: Although the guidelines in most countries do not recommend continuous inhalation of l-isoproterenol to treat pediatric patients with acute severe exacerbation of asthma, lower dose of l-isoproterenol has been widely used in Japan. To determine whether the efficacy of low-dose l-isoproterenol was superior to that of salbutamol, we conducted a double-blind, randomized controlled trial., Methods: Hospitalized patients aged 1-17 years were eligible if they had severe asthma exacerbation defined by the modified pulmonary index score (MPIS). Patients were randomly assigned (1:1) to receive inhalation of l-isoproterenol (10 μg/kg/h) or salbutamol (500 μg/kg/h) for 12 hours via a large-volume nebulizer with oxygen. The primary outcome was the change in MPIS from baseline to 3 hours after starting inhalation. Trial registration number UMIN000001991., Results: From December 2009 to October 2013, 83 patients (42 in the l-isoproterenol group and 41 in the salbutamol group) were enrolled into the study. Of these, one patient in the l-isoproterenol group did not receive the study drug and was excluded from the analysis. Compared with salbutamol, l-isoproterenol reduced MPIS more rapidly. Mean (SD) changes in MPIS at 3 hours were -2.9 (2.5) in the l-isoproterenol group and -0.9 (2.3) in the salbutamol group (difference -2.0, 95% confidence interval -3.1 to -0.9; P < 0.001). Adverse events occurred in 1 (2%) and 11 (27%) patients in the l-isoproterenol and salbutamol groups, respectively (P = 0.003). Hypokalemia and tachycardia occurred only in the salbutamol group., Conclusions: Low-dose l-isoproterenol has a more rapid effect with fewer adverse events than salbutamol., (Copyright © 2019 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

BACKGROUND QT prolongation is a common, easily overlooked clinical problem with potentially dire consequences. Drug-induced and congenital forms are not mutually exclusive, but are treated differently. Here, we present a case of cryptogenic underlying congenital long QT syndrome (cLQTS) successfully treated with isoproterenol, a drug contraindicated in most congenital forms of this condition. CASE REPORT We present the case of a 54-year-old man who experienced severe QT prolongation after drug administration followed by recurrent episodes of torsade de pointes (TdP) with subsequent ventricular fibrillation (VF) arrest unresponsive to typical therapy. After failing electrolyte repletion, magnesium, amiodarone, and lidocaine, the patient was started on an isoproterenol drip to achieve a heart rate of at least 90 beats per minute (bpm). Isoproterenol resulted in an immediate near-normalization of his QT interval and cessation of his recurrent TdP. The patient was subsequently found to have a mutation of undetermined significance in the KCNQ1 gene, which is implicated in long QT syndrome type 1 (LQT1). Although isoproterenol is contraindicated in LQT1, our patient had an astonishingly therapeutic benefit. CONCLUSIONS After reviewing the electrophysiology of the delayed rectifier potassium current as it relates to long QT syndrome, we propose a mechanism by which our patient's specific mutation may have allowed him to derive benefit from isoproterenol treatment. We believe that there are patients with variants of LQT1 who can be safely treated with isoproterenol.

A 30-year-old woman with polyglandular autoimmune type 2 syndrome was found collapsed at home with a cardiac arrest, which required direct current cardioversion. On admission, she was hypothermic, hypotensive and bradycardic. Initial biochemical investigations were consistent with a pre-renal acute kidney injury, metabolic acidosis and a possible sepsis. She had significantly elevated thyroid-stimulating hormone levels on admission with the clinical profile consistent with dual Addisonian and myxoedema crisis. She received intravenous liothyronine and hydrocortisone along with supportive therapy. Echo showed severe left ventricular impairment with apical ballooning although coronary angiogram disclosed nothing abnormal. She made a gradual recovery and was discharged home after 2 weeks. She was diagnosed to have primary autoimmune hypothyroidism, Addison's diseaseand type 1 diabetes and coeliac disease in October 2006, July 2007, May 2010 and September 2016, respectively. Her inability to stick to gluten-free diet at her workplace was considered a significant contributory factor for out-of-hospital cardiac arrest., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Neonatal lupus erythematosus (NLE) is an infrequent disease caused by transplacental maternal autoantibodies. The most common effects of NLE include cutaneous involvement and congenital heart block (CHB), although it might involve multiple organs, such as the liver, lungs, blood, and nervous or digestive systems. Izmirly PM1 and Tonello et al recently reported cutaneous manifestations of neonatal lupus and risk of subsequent CHB. The most serious complication of NLE is complete atrioventricular (AV) block., Patient Concerns: We experienced 2 cases of NLE that were diagnosed in the past year in our Neonatal Intensive Care Unit. These cases showed 2 different clinical spectrums (CHB, multisystemic effects). One case was a 32-week pregnant woman with combined liver damage and fever, and her fetus was premature due to bradycardia and pericardial effusion. The second case was a young pregnant woman who had systemic lupus erythematosus for 2 years and had been taking methylprednisolone and hydroxychloroquine for a long time since her illness. When prenatal testing at 28 weeks of pregnancy showed that the fetus had CHB, the mother began taking dexamethasone., Diagnosis: The first case was diagnosed as NLE with CHB after birth, while the second was diagnosed as NLE with CHB, ductus arteriosus, and atrial septal defect when she was born at 34 weeks., Interventions: Both of 2 cases were treated with steroids, intravenous immunoglobulin, and a diuretic. But the second case was treated with isoprenaline in addition to the above., Outcomes: Both of the infants was followed up and found to be clinically normal. During the clinic follow-up of the first case, the 8-month-old infant was still asymptomatic with normal growth and development. Her heart rate fluctuated from 40 to 90 beats/minute., Lessons: Autoimmune CHB is a severe, potentially life-threatening disorder associated with passive transfer of maternal anti-Sjogren's syndrome A/Ro and anti-Sjogren's syndrome B/La autoantibodies. Mothers who are positive for these autoantibodies are recommended to have serial echocardiography and obstetric ultrasonography from the early second trimester. Newborns should be delivered at an early stage of gestation if there is evidence of pericardial effusion, ascites, increasing ventricular ectopy, reduced ventricular shortening fraction, or AV valve regurgitation. Aggressive medical management after birth should be coupled with pacemaker implantation in infants who do not respond to medical therapies alone.

We report a case of primary hyperparathyroidism with hypercalcaemia in a 16-year-old boy who had spontaneous attack of ventricular tachycardia. To our knowledge, presentation of ventricular tachycardia caused by primary hyperparathyroidism in such a young patient has not been reported in medical literature so far.

The hyperinflation of isoproterenol, a 75-year-old drug, in early 2015 was unbelievable. The attention of health-care professionals, health system administrators, legislators, and the general public was quickly focused on Valeant Pharmaceuticals, purchaser of several generics solely to raise their price. With isoproterenol easily launched toward the top of drug expenditures, pharmacists in many hospitals were forced to engage stakeholders in the investigation and implementation of alternatives, explore utilization and optimize inventory, reduce cost through sterile product preparation, where possible, restrict use to settings that were beneficial to their budget, and become legislative advocates. The alternatives drugs and strategies will be reviewed.

Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff-perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 μM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Background: Population based studies showed an association of early repolarization in the electrocardiogram (ECG) and a higher rate of sudden cardiac death presumably due to ventricular fibrillation. The triggers for ventricular fibrillation in patients with early repolarization are not fully understood., Case Presentation: We describe the case of a young patient with a survived ventricular fibrillation arrest while asleep followed by multiple episodes of recurrent ventricular fibrillation. The admission ECG showed an early repolarization pattern with substantial J-point elevation in most of the ECG-leads. After initiation of a hypothermia protocol, the patient developed an electrical storm with multiple ventricular fibrillation episodes requiring multiple cardioversions. Intravenous isoproterenol infusion successfully suppressed the malignant arrhythmia., Conclusion: Hypothermia appears proarrhythmic in patients with early repolarization and may trigger ventricular fibrillation. This knowledge is particularly important when initiating temperature management protocols in patients after a survived cardiac arrest. During the acute phase of an early repolarization associated electrical storm, isoproterenol is the most effective treatment suppressing the ventricular fibrillation-inducing premature ventricular complexes at higher heart rates.

Background: The objective of the present study aimed to investigate the effect of CoQ10 treatment on isoprenaline (ISO)-induced cardiac remodeling in rats., Methods: Rats were divided into three groups namely Control group, ISO treated group and CoQ10 + ISO treated group, each consisting of 6 rats. The cardiac specific CK-MB, AST, ALT activity and other oxidative stress parameters were estimated in heart and kidneys. Additionally histological examination was also performed to visualize the inflammatory cells infiltration and fibrosis in both tissues., Results: Administration of ISO resulted in an increase in the heart-to-body weight (HW/BW) ratio and an also increased the serum CK-MB, AST and ALT enzyme activity. Serum levels of lipid peroxidation products, and oxidative stress markers showed significant increase in ISO-treated rats. Histopathological examination of heart tissue revealed focal areas of endocardium degeneration, mononuclear cells infiltration, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. Similar degeneration was also found in kidneys. Treatment with CoQ10 (100 mg/kg) significantly improved the oxidative stresses in ISO treated rats. Moreover, CoQ10 treatment prevented inflammatory cells infiltration and reduced fibrosis in ISO administered rats., Conclusion: In conclusion, our study provides evidence that CoQ10 may prevent the development of cardiac remodeling, and fibrosis in ISO administered rats.

The main driving mechanism during an asthma attack is the hyper-constrictions of airway smooth muscle (ASM), which reduces the airway lumen and makes normal breathing difficult. In spite of some noticeable side effects, bronchodilator drugs such as salbutamol are used to alleviate these symptoms by inducing temporary relaxation of the contracted ASM. In vitro studies have shown that mechanical oscillation can induce relaxation in isolated contracted ASM obtained from healthy subjects but not from asthmatics. To date, little is known about in vivo ASM behaviours, in particular in asthmatic subjects. This in vivo study aims at determining the effect of various superimposed pressure oscillation (SIPO) patterns (different to those occurring during normal breathing) on sensitized airways during an ACh challenge (mimicking an asthmatic attack) and comparing it with the effect of a widely studied broncho-relaxant drug, Isoproterenol (ISO). The study shows that superimposed pressure oscillation in the range of 5-15Hz induces approximately 50% relaxation on pre-constricted sensitized airways in vivo; however, this behaviour was not observed at 20Hz. Our finding suggests that mechanical oscillation, particularly SIPO, may act as a bronchodilator and achieve ASM relaxation., (Copyright © 2016. Published by Elsevier B.V.)

Background: Oral tyrosine kinase inhibitors (TKIs) are becoming increasingly common in oncology practice due to ease of administration and patient preference. This class of medications is relatively unknown to emergency physicians., Case Report: Here we present a case of electrical storm (ES) thought to be associated with ibrutinib, a TKI. The ES was unabated despite antidysrhythmic therapy and electrical cardioversion, and was treated with supportive care, which eventually included the use of extracorporeal membrane oxygenation. This patient had no risk factors or apparent causes of recurrent ventricular tachycardia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: ES has not previously been described with ibrutinib, but may be associated with off-target effects of the drug., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: We aimed to assess the utility of changes in systolic and diastolic function by isoproterenol challenge in predicting symptom resolution post-myectomy in selected patients with hypertrophic cardiomyopathy (HCM) and labile obstruction., Background: In a subset of symptomatic HCM patients without resting/provocable obstruction on noninvasive assessment, isoproterenol challenge during hemodynamic catheterization may elicit labile left ventricular outflow tract (LVOT) obstruction, and demonstrate the effect of obstruction on diastolic function. These changes may determine whether patients achieve complete symptom resolution post-myectomy., Methods: Between February 2003 and April 2009, 18 symptomatic HCM patients without LVOT obstruction on noninvasive testing underwent isoproterenol provocation and septal myectomy due to presence of provocable gradient and were followed for 4 (IQR 3-7) years., Results: Thirteen (72.2%) had complete symptom resolution, while 5 (27.8%) had improved, but persistent symptoms. Those with provoked gradient >100 mm Hg or increase in left atrial pressure (LAP) with isoproterenol had symptom resolution., Conclusions: Symptomatic HCM patients without LVOT gradient on noninvasive testing may demonstrate labile obstruction with isoproterenol. With isoproterenol, patients with high LVOT gradient or increase in LAP concomitant with an increase in gradient achieved complete symptom resolution post-myectomy. Thus, improved diastolic filling as well as outflow gradient production in patients with HCM may predict symptom response to myectomy. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aims: Spontaneous Ca 2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca 2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated., Methods and Results: We studied intracellular Ca 2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca 2+ transients in response to isoproterenol. β-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients., Conclusion: Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca 2+ release by mutant RyR2s as observed in vitro. β-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

The present study was carried out to evaluate the protective effect of different statins on isoproterenol (ISO) induced myocardial necrosis. Atorvastatin, rosuvastatin, fluvastatin, simvastatin and pravastatin (10 mg/kg/day) were administered for 12 weeks. After pretreatment of 12 weeks myocardial necrosis was induced by subsequent injection of ISO (85 mg/kg/day, s.c.) to wistar rats. Serum biochemical parameters like glucose, lipid profile, cardiac markers and transaminases were evaluated. Animals were killed and heart was excised for histopathology and antioxidant study. Statins pretreated rats showed significant protection against ISO induced elevation in serum biochemical parameters and serum level of cardiac marker enzymes and transaminase level as compared to ISO control group. Mild to moderate protection was observed in different statins treated heart in histopathology and TTC stained sections. Result from our study also revealed that statins could efficiently protect against ISO intoxicated myocardial necrosis by impairing membrane bound enzyme integrity and endogenous antioxidant enzyme levels. Amongst all statins used, rosuvastatin and pravastatin were found to have maximum cardio-protective activity against ISO induced myocardial necrosis as compared to other statins., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Acute exacerbation of asthma is divided qualitatively into mild, moderate, and severe attacks and respiratory failure. This system is, however, not suitable for estimating small changes in respiratory condition with time and for determining the efficacy of treatments, because it has a qualitative, but not quantitative nature., Methods: To evaluate the usefulness of quantitative estimation of asthma exacerbation, modified Pulmonary Index Score (mPIS) values were measured in 87 asthmatic children (mean age, 5.0 ± 0.4 years) during hospitalization. mPIS was calculated by adding the sum of scores for 6 items (scores of 0-3 were given for each item). These consisted of heart rate, respiratory rate, accessory muscle use, inspiratory-to-expiratory flow ratio, degree of wheezing, and oxygen saturation in room air. Measurements were made at visits and at hospitalization and were then made twice a day until discharge., Results: mPIS values were highly correlated among raters. mPIS values at visits were 9.1 ± 0.1 and 12.6 ± 0.4 in subjects with moderate and severe attacks, respectively (p < 0.001). mPIS values of subjects requiring continuous inhalation therapy (CIT) with isoproterenol in addition to systemic steroids were significantly higher than the values of those without CIT (12.0 ± 0.5 and 9.3 ± 0.2, respectively, p < 0.001). A score of 10 was suggested to be the optimal cutoff for distinguishing between subjects requiring and not requiring CIT, from the perspectives of both sensitivity and specificity. mPIS at hospitalization correlated well with the period until discharge, suggesting that this score was a useful predictor for the clinical course after hospitalization., Conclusions: mPIS could be a useful tool for several aspects during acute asthma attacks, including the determination of a treatment plan, and prediction of the period of hospitalization in admitted patients, although prospective studies would be required to establish our hypothesis., (Copyright © 2014 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

Background: The impact of amiodarone on ablation outcome in longstanding persistent atrial fibrillation (LSPAF) patients is not known yet., Objective: The purpose of this study was to assess the effect of amiodarone on procedural-outcomes in LSPAF patients undergoing catheter ablation., Methods: We enrolled 112 LSPAF patients on amiodarone and scheduled to undergo atrial fibrillation (AF) ablation. Patients were randomized to amiodarone discontinuation 4 months before ablation (group 1, n = 56) and a control group (group 2, n = 56) in which ablation was performed without amiodarone discontinuation. All patients underwent pulmonary vein (PV) antrum and posterior wall isolation, defragmentation and extra PV triggers ablation. Patients were followed up for recurrence for 32 ± 8 months post-ablation. Repeat procedures in all recurrent patients were performed off amiodarone., Results: During ablation, AF termination was more frequent in group 2 compared to group 1 [44 (79%) vs 32 (57%), P = .015]. After high-dosage isoproterenol, more non-PV triggers were disclosed in group 1 compared to group 2 (42 [75%] vs 24 [43%] respectively, P <.001). Group 2 had lower procedure, radiofrequency and fluoroscopy times compared to group 1 (2.7 ± 1 vs 3.1 ± 1 h, 69 ± 13 min vs 87 ± 11 min and 64 ± 14 min vs 85 ± 18 min respectively, p < .05). At 32 ± 8 month follow-up, on or off antiarrhythmic drug success rate was 37 (66%) in group 1 and 27 (48%) in group 2 (P = .04). During redo, new non-PV trigger sites were identified in group 2 patients., Conclusion: Periprocedural continuous amiodarone was associated with higher organization rate and lower radiofrequency ablation rate. However, masking non-PV triggers increased the late recurrence rate., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

In the setting of increased intracranial pressure (ICP), various rhythm disturbances have been associated, ranging from tachyarrhythmias to bradyarrhythmias with atrioventricular dissociation. Although most of these observations have been in patients with traumatic brain injuries, it is known that children with acute bacterial meningitis may also have severe intracranial hypertension. We present the case of a previously healthy 2-year-old boy diagnosed with listeria meningitis. Along with clinical signs suggestive of increased ICP and brainstem involvement, our patient had persistent bradyarrhythmia with hemodynamic compromise that was refractory to epinephrine and successfully managed with isoproterenol.

The stress-related catecholamine hormones and the α- and β-adrenergic receptors (α- and β-AR) may affect carcinogenesis. The β-AR GRK/β-arrestin biased agonist carvedilol can induce β-AR-mediated transactivation of the EGFR. The initial purpose of this study was to determine whether carvedilol, through activation of EGFR, can promote cancer. Carvedilol failed to promote anchorage-independent growth of JB6 P(+) cells, a skin cell model used to study tumor promotion. However, at nontoxic concentrations, carvedilol dose dependently inhibited EGF-induced malignant transformation of JB6 P(+) cells, suggesting that carvedilol has chemopreventive activity against skin cancer. Such effect was not observed for the β-AR agonist isoproterenol and the β-AR antagonist atenolol. Gene expression, receptor binding, and functional studies indicate that JB6 P(+) cells only express β2-ARs. Carvedilol, but not atenolol, inhibited EGF-mediated activator protein-1 (AP-1) activation. A topical 7,12-dimethylbenz(α)anthracene (DMBA)-induced skin hyperplasia model in SENCAR mice was utilized to determine the in vivo cancer preventative activity of carvedilol. Both topical and oral carvedilol treatment inhibited DMBA-induced epidermal hyperplasia (P < 0.05) and reduced H-ras mutations; topical treatment being the most potent. However, in models of established cancer, carvedilol had modest to no inhibitory effect on tumor growth of human lung cancer A549 cells in vitro and in vivo. In conclusion, these results suggest that the cardiovascular drug carvedilol may be repurposed for skin cancer chemoprevention, but may not be an effective treatment of established tumors. More broadly, this study suggests that β-ARs may serve as a novel target for cancer prevention., (©2014 American Association for Cancer Research.)

Context: Prescription opioid abuse is a major public health concern and an ongoing epidemic in the United States. Loperamide is a widely available and inexpensive over-the-counter antidiarrheal with peripheral mu-opioid receptor activity. Online resources discuss the use of loperamide for the amelioration of withdrawal symptoms or recreational abuse. We describe the clinical course of 5 patients abusing loperamide, 3 of whom had life-threatening cardiac arrhythmias., Methods: In this observational case series, patients with cardiac arrhythmias or history of loperamide abuse with cardiac arrhythmias were identified; 5 patients were identified and 4 of the 5 patients were seen directly at the bedside. Clinical profile and outcome of patients is reported., Results: We report 5 patients with history of loperamide abuse; 3 of the 5 patients had life-threatening cardiac arrhythmias. One of the patients experienced a second life-threatening arrhythmia after he resumed loperamide abuse. Loperamide levels were obtained in 4 of the 5 patients and were at least one order of magnitude greater than therapeutic concentrations. Discontinuation of loperamide resulted in complete resolution of cardiac conduction disturbances., Conclusion: This case series describes several patients with cardiac conduction abnormalities and life-threatening ventricular arrhythmias temporally related to loperamide abuse. With the recent efforts to restrict the diversion of prescription opioids, increasing abuse of loperamide as an opioid substitute may be seen. Toxicologists should be aware of these risks and we urge all clinicians to report such cases to FDA Medwatch(®).

Unlabelled: Acetaminophen (APAP)-induced acute liver injury (AILI) is a major health problem. Accumulating evidence suggests that the sympathetic nervous system (SNS) regulates neuronal and hematopoietic progenitors. SNS signaling affects hepatic progenitor/oval cells (HPCs) and β-adrenoceptor agonism will expand HPCs to reduce AILI. Dopamine β-hydroxylase-deficient mice (Dbh-/-), lacking catecholamine SNS neurotransmitters, isolated HPCs, and immature ductular 603B cells were initially used to investigate SNS involvement in HPC physiology. Subsequently, control mice were treated with APAP (350 mg/kg) followed by the β-adrenoceptor agonist, isoproterenol (ISO), or the β-adrenoceptor antagonist, propranolol. Mechanistic studies examined effects of non-SNS HPC expansion on AILI, involvement of the canonical Wnt/β-catenin pathway (CWP) in the action of ISO on HPC expansion and comparison of ISO with the current standard of care, N-acetylcysteine (NAC). Dbh-/- mice lacking catecholamines had low HPC numbers, reconstituted by ISO. In vitro, ISO-induced proliferation of 603B cells was CWP dependent. In control mice, AILI raised HPC numbers, further increased by ISO, with attenuation of liver injury. Delayed administration of NAC did not, but delayed ISO did, reverse AILI. Propranolol worsened AILI. AILI activated the CWP, and ISO enhanced Wnt-ligand production. HPCs were the major source of Wnt ligands. Recombinant Wnt3a and ISO-603B-conditioned media, but not ISO alone, protected isolated hepatocytes from death, reversed by DKK1-a Wnt antagonist. Additionally, tumor-associated weak inducer of apoptosis expanded HPCs and protected against AILI. Furthermore, allotransplantation of HPCs from APAP+ISO-treated mice to other APAP-injured mice improved AILI, an effect antagonized by DKK1., Conclusion: SNS catecholamines expand HPCs, which are both targets and sources of Wnt ligands. Hepatoprotection by ISO is mediated by para- and autocrine effects of Wnt signaling. ISO represents novel pharmacotherapy for AILI., (© 2014 by the American Association for the Study of Liver Diseases.)

The repeated syncopes in case of head and neck cancer are a complication rarely described in the literature. They occur when the tumor invade the carotid sinus or the afferent fibers of the glossopharyngeal nerve. We report the case of a 62-year-old man presented episodes of syncope synchronous of a recurrent hypopharyngeal tumor scheduled for chemotherapy and gastrostomy. A computerized tomography showed a voluminous tumor expanded to the carotid and parapharyngeal spaces. After treatment by isporenaline chlorhydrate in intensive care unit, a pacemaker was implanted to prevent syncopes and allowed the beginning of the chemotherapy., (Copyright © 2014. Published by Elsevier SAS.)