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  • Deo, Makarand  (2)
  • Mironov, Sergey  (2)
  • 1
    Online Resource
    Online Resource
    Mechanisms by Which Ranolazine Terminates Paroxysmal but Not Persistent Atrial Fibrillation
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Circulation: Arrhythmia and Electrophysiology Vol. 12, No. 10 ( 2019-10)
    Details
    In: Circulation: Arrhythmia and Electrophysiology, Ovid Technologies (Wolters Kluwer Health), Vol. 12, No. 10 ( 2019-10)
    Abstract: Ranolazine inhibits Na + current (I Na ), but whether it can convert atrial fibrillation (AF) to sinus rhythm remains unclear. We investigated antiarrhythmic mechanisms of ranolazine in sheep models of paroxysmal (PxAF) and persistent AF (PsAF). Methods: PxAF was maintained during acute stretch (N=8), and PsAF was induced by long-term atrial tachypacing (N=9). Isolated, Langendorff-perfused sheep hearts were optically mapped. Results: In PxAF ranolazine (10 μmol/L) reduced dominant frequency from 8.3±0.4 to 6.2±0.5 Hz ( P 〈 0.01) before converting to sinus rhythm, decreased singularity point density from 0.070±0.007 to 0.039±0.005 cm −2 s − 1 ( P 〈 0.001) in left atrial epicardium (LA epi ), and prolonged AF cycle length (AFCL); rotor duration, tip trajectory, and variance of AFCL were unaltered. In PsAF, ranolazine reduced dominant frequency (8.3±0.5 to 6.5±0.4 Hz; P 〈 0.01), prolonged AFCL, increased the variance of AFCL, had no effect on singularity point density (0.048±0.011 to 0.042±0.016 cm − 2 s − 1 ; P =ns) and failed to convert AF to sinus rhythm. Doubling the ranolazine concentration (20 μmol/L) or supplementing with dofetilide (1 μmol/L) failed to convert PsAF to sinus rhythm. In computer simulations of rotors, reducing I Na decreased dominant frequency, increased tip meandering and produced vortex shedding on wave interaction with unexcitable regions. Conclusions: PxAF and PsAF respond differently to ranolazine. Cardioversion in the former can be attributed partly to decreased dominant frequency and singularity point density, and prolongation of AFCL. In the latter, increased dispersion of AFCL and likely vortex shedding contributes to rotor formation, compensating for any rotor loss, and may underlie the inefficacy of ranolazine to terminate PsAF.
    Type of Medium: Online Resource
    ISSN: 1941-3149 , 1941-3084
    URL: Article
    DOI: 10.1161/CIRCEP.117.005557
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2425487-3
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  • 2
    Online Resource
    Online Resource
    A Major Role for hERG in Determining Frequency of Reentry in Neonatal Rat Ventricular Myocyte Monolayer
    Ovid Technologies (Wolters Kluwer Health) ; 2010
    In:  Circulation Research Vol. 107, No. 12 ( 2010-12-10), p. 1503-1511
    Details
    In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 107, No. 12 ( 2010-12-10), p. 1503-1511
    Abstract: The rapid delayed rectifier potassium current, I Kr , which flows through the human ether-a-go-go-related (hERG) channel, is a major determinant of the shape and duration of the human cardiac action potential (APD). However, it is unknown whether the time dependency of I Kr enables it to control APD, conduction velocity (CV), and wavelength (WL) at the exceedingly high activation frequencies that are relevant to cardiac reentry and fibrillation. Objective: To test the hypothesis that upregulation of hERG increases functional reentry frequency and contributes to its stability. Methods and Results: Using optical mapping, we investigated the effects of I Kr upregulation on reentry frequency, APD, CV, and WL in neonatal rat ventricular myocyte (NRVM) monolayers infected with GFP (control), hERG ( I Kr ), or dominant negative mutant hERG G628S. Reentry frequency was higher in the I Kr -infected monolayers (21.12±0.8 Hz; n=43 versus 9.21±0.58 Hz; n=16; P 〈 0.001) but slightly reduced in G628S-infected monolayers. APD 80 in the I Kr -infected monolayers was shorter ( 〉 50%) than control during pacing at 1 to 5 Hz. CV was similar in both groups at low frequency pacing. In contrast, during high-frequency reentry, the CV measured at varying distances from the center of rotation was significantly faster in I Kr -infected monolayers than controls. Simulations using a modified NRVM model predicted that rotor acceleration was attributable, in part, to a transient hyperpolarization immediately following the AP. The transient hyperpolarization was confirmed experimentally. Conclusions: hERG overexpression dramatically accelerates reentry frequency in NRVM monolayers. Both APD and WL shortening, together with transient hyperpolarization, underlies the increased rotor frequency and stability.
    Type of Medium: Online Resource
    ISSN: 0009-7330 , 1524-4571
    URL: Article
    DOI: 10.1161/CIRCRESAHA.110.232470
    RVK:
    XA 10000
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2010
    detail.hit.zdb_id: 1467838-X
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