Polyunsaturated fatty acids in atrial fibrillation: Looking for the proper candidates

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permissionAtrial fibrillation (AF) is the most common sustained arrhythmia encountered in clinical practice with growing prevalence in developed countries. Several medical and interventional therapies, such as atrial specific drugs and pulmonary vein isolation, have demonstrated prevention of recurrences. However, their suboptimal long-term success and significant rate of secondary effects have led to intensive research in the last decade focused on novel alternative and supplemental therapies. One such candidate is polyunsaturated fatty acids (PUFAs). Because of their biological properties, safety, simplicity, and relatively cheap cost, there is a special clinical interest in omega-3 PUFAs as a possible antiarrhythmic agent. Obtained from diets rich in fish, they represent one of the current supplemental therapies. At the cellular level, an increasing body of evidence has shown that n-3 PUFAs exert a variety of effects on cardiac ion channels, membrane dynamic properties, inflammatory cascade, and other targets related to AF prevention. In this article, we review the current basic and clinical evidence pertinent to n-3 PUFAs in AF treatment and prevention.We also discuss controversial outcomes among clinical studies and propose specific subsets of AF patients who will benefit most from n-3 PUFAsNHLBI Grant K99-HL105574 to SFN and the Alfonso Martín Escudero Foundation Grant to DF

A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart

Evidence supports the expression of brain‐type sodium channels in the heart. Their functional role, however, remains controversial. We used global NaV1.6‐null mice to test the hypothesis that NaV1.6 contributes to the maintenance of propagation in the myocardium and to excitation‐contraction (EC) coupling. We demonstrated expression of transcripts encoding full‐length NaV1.6 in isolated ventricular myocytes and confirmed the striated pattern of NaV1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca2+ transients were longer in the null cells. Under patch clamping, at holding potential (HP) = –120 mV, the peak INa was similar in both phenotypes. However, at HP = –70 mV, the peak INa was smaller in the nulls. In optical mapping, at 4 mM [K+]o, 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild‐type hearts. At 12 mM [K+]o, CV was 25% slower in a subset of 9 null vs. 9 wild‐type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby NaV1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.—Noujaim, S. F., Kaur, K., Milstein, M., Jones, J. M., Furspan, P., Jiang, D., Auerbach, D. S., Herron, T., Meisler, M. H., Jalife, J. A null mutation of the neuronal sodium channel NaV1.6 disrupts action potential propagation and excitation‐contraction coupling in the mouse heart. FASEB J. 26, 63–72 (2012). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154524/1/fsb2fj10179770.pd

Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154620/1/fsb2fj201700349r.pd

Human influenza A virus causes myocardial and cardiac-specific conduction system infections associated with early inflammation and premature death.

Human influenza A virus (hIAV) infection is associated with important cardiovascular complications, although cardiac infection pathophysiology is poorly understood. We aimed to study the ability of hIAV of different pathogenicity to infect the mouse heart, and establish the relationship between the infective capacity and the associated in vivo, cellular and molecular alterations. We evaluated lung and heart viral titres in mice infected with either one of several hIAV strains inoculated intranasally. 3D reconstructions of infected cardiac tissue were used to identify viral proteins inside mouse cardiomyocytes, Purkinje cells, and cardiac vessels. Viral replication was measured in mouse cultured cardiomyocytes. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to confirm infection and study underlying molecular alterations associated with the in vivo electrophysiological phenotype. Pathogenic and attenuated hIAV strains infected and replicated in cardiomyocytes, Purkinje cells, and hiPSC-CMs. The infection was also present in cardiac endothelial cells. Remarkably, lung viral titres did not statistically correlate with viral titres in the mouse heart. The highly pathogenic human recombinant virus PAmut showed faster replication, higher level of inflammatory cytokines in cardiac tissue and higher viral titres in cardiac HL-1 mouse cells and hiPSC-CMs compared with PB2mut-attenuated virus. Correspondingly, cardiac conduction alterations were especially pronounced in PAmut-infected mice, associated with high mortality rates, compared with PB2mut-infected animals. Consistently, connexin43 and NaV1.5 expression decreased acutely in hiPSC-CMs infected with PAmut virus. YEM1L protease also decreased more rapidly and to lower levels in PAmut-infected hiPSC-CMs compared with PB2mut-infected cells, consistent with mitochondrial dysfunction. Human IAV infection did not increase myocardial fibrosis at 4-day post-infection, although PAmut-infected mice showed an early increase in mRNAs expression of lysyl oxidase. Human IAV can infect the heart and cardiac-specific conduction system, which may contribute to cardiac complications and premature death.JV is a PhD fellow of the La Caixa Foundation International Fellowship Programme (La Caixa/CNB). This work was supported by the European Molecular Biology Organizat ion (STF-7649 to AF), the Spanish Ministry of Science, Innovation and Universities (MCIU), (BFU2011-26175 and BFU2014-57797-R to AN), and the network Ciber de Enfermedades Respiratorias (CIBERES) including the Improvement and Mobilit y Programme. The CNIC is a Severo Ochoa Center of Excellence (SEV-2015-0505). CNIC is supported by MCIU and the Pro CNIC Foundation. This study was supported by grants from Fondo Europeo de Desarrollo Regional (CB16/11/00458), grants SAF2015-65607-R and SAF2016-80324-R from MCIU (A.H. and D.F-R.) and fellowship SVP-2014-068595 to J.A.N-A. This study was supported by Frankel Cardiovascular Centre, Michigan Medicine (Grant 332475). JJ is supported in part by the National Heart, Lung, and Blood Institute (R01 Grant HL122352). S.F.N is supported in part by the National Heart, Lung, and Blood Institute grants R21HL138064 and R01HL129136.S

The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents

G-protein-gated inwardly-rectifying K+ (GIRK) channels are targets of Gi/o-protein-signaling systems that inhibit cell excitability. GIRK channels exist as homotetramers (GIRK2 and GIRK4) or heterotetramers with nonfunctional homomeric subunits (GIRK1 and GIRK3). Although they have been implicated in multiple conditions, the lack of selective GIRK drugs that discriminate among the different GIRK channel subtypes has hampered investigations into their precise physiological relevance and therapeutic potential. Here, we report on a highly-specific, potent, and efficacious activator of brain GIRK1/2 channels. Using a chemical screen and electrophysiological assays, we found that this activator, the bromothiophene-substituted small molecule GAT1508, is specific for brain-expressed GIRK1/2 channels rather than for cardiac GIRK1/4 channels. Computational models predicted a GAT1508-binding site validated by experimental mutagenesis experiments, providing insights into how urea-based compounds engage distant GIRK1 residues required for channel activation. Furthermore, we provide computational and experimental evidence that GAT1508 is an allosteric modulator of channel-phosphatidylinositol 4,5-bisphosphate interactions. Through brain-slice electrophysiology, we show that subthreshold GAT1508 concentrations directly stimulate GIRK currents in the basolateral amygdala (BLA) and potentiate baclofen-induced currents. Of note, GAT1508 effectively extinguished conditioned fear in rodents and lacked cardiac and behavioral side effects, suggesting its potential for use in pharmacotherapy for post-traumatic stress disorder. In summary, our findings indicate that the small molecule GAT1508 has high specificity for brain GIRK1/2 channel subunits, directly or allosterically activates GIRK1/2 channels in the BLA, and facilitates fear extinction in a rodent model

Nerves projecting from the intrinsic cardiac ganglia of the pulmonary veins modulate sinoatrial node pacemaker function

Rationale: Autonomic nerves from sinoatrial node (SAN) ganglia are known to regulate SAN function. However, it is unclear whether remote pulmonary vein ganglia (PVG) also modulate SAN pacemaker rhythm. Objective: To investigate whether in the mouse heart PVG modulate SAN function. Methods and Results: In hearts from 45 C57BL and 7 Connexin40+/GFP mice, we used tyrosine-hydroxylase (TH) and choline-acetyltransferase (ChAT) immunofluorescence labeling to characterize adrenergic and cholinergic elements, repectively, within the PVG and SAN. PVG project postganglionic nerves to the SAN. TH and ChAT stained nerves, enter the SAN as an extensive, dense mesh-like neural network. Neurons in PVG are biphenotypic, containing ChAT and TH positive neurons. In Langendorff-perfused hearts, we compared effects of electrical stimulation of PVG, posterior (PRCVG) and anterior right vena cava ganglia (ARCVG) using 200-2000 ms trains of pulses (300μs, 0.2-0.6mA, 200Hz). Sympathetic and/or parasympathetic blockade was achieved using 0.5μM propranolol and 1μM atropine, respectively. Epicardial optical mapping of SAN activation was performed before, during and after ganglion stimulation. PVG stimulation increased the P-P interval by 36±9%; PRCVG stimulation increased the P-P interval by 42±11%. ARCVG stimulation produced no change. Propranolol perfusion increased the PVG stimulation effect to 43±13%. Atropine caused a 5±6% decrease. In optical mapping experiments of whole hearts and isolated atrial preparations, PVG stimulation shifted the origin of SAN discharges to varying locations. Conclusions: PVG contain cholinergic, adrenergic and biphenotipic neurons whose axons project across the right atrium to richly innervate the SAN region and contribute significantly to regulation of SAN function.Zarzoso Muñoz, M.; Rysevaite, K.; Milstein, ML.; Calvo Saiz, CJ.; Kean, AC.; Atienza Fernández, F.; Pauza, DH.... (2013). 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The nervous heart

Many cardiac electrophysiological abnormalities are accompanied by autonomic nervous system dysfunction. Here, we review mechanisms by which the cardiac nervous system controls normal and abnormal excitability and may contribute to atrial and ventricular tachyarrhythmias. Moreover, we explore the potential antiarrhythmic and/or arrhythmogenic effects of modulating the autonomic nervous system by several strategies, including ganglionated plexi ablation, vagal and spinal cord stimulations, and renal sympathetic denervation as therapies for atrial and ventricular arrhythmias