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Early onset epilepsy and sudden unexpected death in epilepsy with cardiac arrhythmia in mice carrying the early infantile epileptic encephalopathy 47 gain-of-function FHF1(FGF12) missense mutation

Velíšková, Jana; Marra, Christopher; Liu, Yue; Shekhar, Akshay; Park, David S; Iatckova, Vasilisa; Xie, Ying; Fishman, Glenn I; Velíšek, Libor; Goldfarb, Mitchell
OBJECTIVE:Fibroblast growth factor homologous factors (FHFs) are brain and cardiac sodium channel-binding proteins that modulate channel density and inactivation gating. A recurrent de novo gain-of-function missense mutation in the FHF1(FGF12) gene (p.Arg52His) is associated with early infantile epileptic encephalopathy 47 (EIEE47; Online Mendelian Inheritance in Man database 617166). To determine whether the FHF1 missense mutation is sufficient to cause EIEE and to establish an animal model for EIEE47, we sought to engineer this mutation into mice. METHODS:protein. RESULTS:mice prior to seizure. SIGNIFICANCE/CONCLUSIONS:1.6 functional axis underlying altered brain sodium channel gating in epileptic encephalopathy.
PMID: 33982289
ISSN: 1528-1167
CID: 4867612

Neural cell adhesion molecule is required for ventricular conduction system development

Delgado, Camila; Bu, Lei; Zhang, Jie; Liu, Fang-Yu; Sall, Joseph; Liang, Feng-Xia; Furley, Andrew J; Fishman, Glenn I
The most distal portion of the ventricular conduction system (VCS) contains cardiac Purkinje cells (PCs), which are essential for synchronous activation of the ventricular myocardium. Contactin-2 (CNTN2), a member of the immunoglobulin superfamily of cell adhesion molecules (IgSF-CAMs), was previously identified as a marker of the VCS. Through differential transcriptional profiling, we discovered two additional highly enriched IgSF-CAMs in the VCS: NCAM-1 and ALCAM. Immunofluorescence staining showed dynamic expression patterns for each IgSF-CAM during embryonic and early postnatal stages, but ultimately all three proteins became highly enriched in mature PCs. Mice deficient in NCAM-1, but not CNTN2 or ALCAM, exhibited defects in PC gene expression and VCS patterning, as well as cardiac conduction disease. Moreover, using ST8sia2 and ST8sia4 knockout mice, we show that inhibition of post-translational modification of NCAM-1 by polysialic acid leads to disrupted trafficking of sarcolemmal intercalated disc proteins to junctional membranes and abnormal expansion of the extracellular space between apposing PCs. Taken together, our data provide insights into the complex developmental biology of the ventricular conduction system.
PMID: 34100064
ISSN: 1477-9129
CID: 4899742

Multiple Biomarker Approach to Risk Stratification in COVID-19 [Letter]

Smilowitz, Nathaniel R; Nguy, Vuthy; Aphinyanaphongs, Yindalon; Newman, Jonathan D; Xia, Yuhe; Reynolds, Harmony R; Hochman, Judith S; Fishman, Glenn I; Berger, Jeffrey S
PMID: 33587646
ISSN: 1524-4539
CID: 4786532

Characterization of vortex flow in a mouse model of ventricular dyssynchrony by plane-wave ultrasound using hexplex processing

Shekhar, Akshay; Aristizabal, Orlando; Fishman, Glenn I; Phoon, Colin K L; Ketterling, Jeffrey A
The rodent heart is frequently used to study human cardiovascular disease (CVD). Although advanced cardiovascular ultrasound imaging methods are available for human clinical practice, application of these techniques to small animals remains limited due to the temporal and spatial-resolution demands. Here, an ultrasound vector-flow workflow is demonstrated that enables visualization and quantification of the complex hemodynamics within the mouse heart. Wild type (WT) and fibroblast growth factor homologous factor 2 (FHF2)-deficient mice (Fhf2KO/Y), which present with hyperthermia-induced ECG abnormalities highly reminiscent of Brugada syndrome, were used as a mouse model of human CVD. An 18-MHz linear array was used to acquire high-speed (30 kHz), plane-wave data of the left ventricle (LV) while increasing core body temperature up to 41.5°C. Hexplex (i.e., six output) processing of the raw data sets produced the output of vector-flow estimates (magnitude and phase); B-mode and color-Doppler images; Doppler spectrograms; and local time histories of vorticity and pericardium motion. Fhf2WT/Y mice had repeatable beat-to-beat cardiac function, including vortex formation during diastole, at all temperatures. In contrast, Fhf2KO/Y mice displayed dyssynchronous contractile motion that disrupted normal inflow vortex formation and impaired LV filling as temperature rose. The hexplex processing approach demonstrates the ability to visualize and quantify the interplay between hemodynamic and mechanical function in a mouse model of human CVD.
PMID: 32763851
ISSN: 1525-8955
CID: 4555602

A Pilot Open-label Study of Aldose Reductase Inhibition with AT-001 (caficrestat) in Patients Hospitalized for COVID-19 Infection: Results from a Registry-based Matched-control Analysis [Meeting Abstract]

Gaztanaga, Juan; Ramasamy, Ravichandran; Schmidt, Ann Marie; Fishman, Glenn; Shendelman, Shoshana; Thangavelu, Karthinathan; Perfetti, Riccardo; Katz, Stuart D.
ISI:000746754900022
ISSN: 0002-8703
CID: 5208602

Myocardial Injury in Adults Hospitalized with COVID-19 [Letter]

Smilowitz, Nathaniel R; Jethani, Neil; Chen, Ji; Aphinyanaphongs, Yindalon; Zhang, Ruina; Dogra, Siddhant; Alviar, Carlos L; Keller, Norma Mary; Razzouk, Louai; Quinones-Camacho, Adriana; Jung, Albert S; Fishman, Glenn I; Hochman, Judith S; Berger, Jeffrey S
PMID: 33151762
ISSN: 1524-4539
CID: 4664312

Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart

Park, David S; Shekhar, Akshay; Santucci Iii, John; Redel-Traub, Gabriel; Solinas, Sergio Mg; Mintz, Shana; Lin, Xianming; Chang, Ernest W; Narke, Deven; Xia, Yuhe; Goldfarb, Mitchell; Fishman, Glenn I
Rationale: Fibroblast growth factor homologous factors (FHFs) are key regulators of sodium channel inactivation. Mutations in these critical proteins have been implicated in human diseases including Brugada syndrome, idiopathic ventricular arrhythmias, and epileptic encephalopathy. The underlying ionic mechanisms by which reduced sodium channel availability in Fhf2 knockout mice predisposes to abnormal excitability at the tissue level are not well defined. Objective: Using animal models and theoretical multicellular linear strands, we examined how FHF2 orchestrates the interdependency of sodium, calcium, and gap junctional conductances to safeguard cardiac conduction. Methods and Results:Fhf2KO mice were challenged by reducing calcium conductance using verapamil or by reducing gap junctional conductance using carbenoxolone or by backcrossing into a connexin 43 heterozygous (Cx43+/-) background. All conditions produced conduction block in Fhf2KO mice, with Fhf2WT showing normal impulse propagation. To explore the ionic mechanisms of block in Fhf2KO hearts, multicellular linear strand models incorporating FHF2-deficient sodium channel inactivation properties were constructed and faithfully recapitulated conduction abnormalities seen in mutant hearts. The mechanisms of conduction block in mutant strands with reduced calcium conductance or gap junction uncoupling are very different. Enhanced sodium channel inactivation due to FHF2 deficiency shifts dependence onto calcium current to sustain electrotonic driving force, axial current flow, and action potential generation from cell-to-cell. In the setting of gap junction uncoupling, slower charging time from upstream cells conspires with accelerated sodium channel inactivation in mutant strands to prevent sufficient downstream cell charging for action potential propagation. Conclusions: FHF2-dependent effects on sodium channel inactivation ensure adequate sodium current reserve to safeguard against numerous threats to reliable cardiac impulse propagation.
PMID: 32962518
ISSN: 1524-4571
CID: 4605692

High-frequency, vector-flow imaging in the left ventricle of FHF2 deficient murine heart

Chapter by: Ketterling, Jeffrey A.; Shekhar, Akshay; Fishman, Glenn I.; Aristizabal, Orlando; Phoon, Colin K.L.
in: IEEE International Ultrasonics Symposium, IUS by
[S.l.] : IEEE Computer Society, 2020
pp. ?-?
ISBN: 9781728154480
CID: 4733942

COVID-19 and the Heart and Vasculature: Novel Approaches to Reduce Virus-Induced Inflammation in Patients With Cardiovascular Disease

Kadosh, Bernard S; Garshick, Michael S; Gaztanaga, Juan; Moore, Kathryn J; Newman, Jonathan D; Pillinger, Michael; Ramasamy, Ravichandran; Reynolds, Harmony R; Shah, Binita; Hochman, Judith; Fishman, Glenn I; Katz, Stuart D
The coronavirus disease 2019 (COVID-19) pandemic presents an unprecedented challenge and opportunity for translational investigators to rapidly develop safe and effective therapeutic interventions. Greater risk of severe disease in COVID-19 patients with comorbid diabetes mellitus, obesity, and heart disease may be attributable to synergistic activation of vascular inflammation pathways associated with both COVID-19 and cardiometabolic disease. This mechanistic link provides a scientific framework for translational studies of drugs developed for treatment of cardiometabolic disease as novel therapeutic interventions to mitigate inflammation and improve outcomes in patients with COVID-19.
PMID: 32687400
ISSN: 1524-4636
CID: 4551152

T for Two: T-Box Factors and the Functional Dichotomy of the Conduction System [Editorial]

Park, David S; Fishman, Glenn I
PMCID:7371245
PMID: 32673534
ISSN: 1524-4571
CID: 4546082