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Electrophysiologic Characteristics and Pharmacologic Response of Human Cardiomyocytes Isolated from a Patient with Hypertrophic Cardiomyopathy

To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/pace.12227/abstract Byline: HECTOR BARAJAS-MARTINEZ, DAN HU, ROBERT J. GOODROW, FREDERIC JOYCE, CHARLES ANTZELEVITCH Keywords: M cell; ranolazine; sodium channel current;... Full description

Journal Title: Pacing and Clinical Electrophysiology December 2013, Vol.36(12), pp.1512-1515
Main Author: Barajas‐Martínez, Hector
Other Authors: Hu, Dan , Goodrow, Robert J. , Joyce, Frederic , Antzelevitch, Charles
Format: Electronic Article Electronic Article
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ID: ISSN: 0147-8389 ; E-ISSN: 1540-8159 ; DOI: 10.1111/pace.12227
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title: Electrophysiologic Characteristics and Pharmacologic Response of Human Cardiomyocytes Isolated from a Patient with Hypertrophic Cardiomyopathy
format: Article
creator:
  • Barajas‐Martínez, Hector
  • Hu, Dan
  • Goodrow, Robert J.
  • Joyce, Frederic
  • Antzelevitch, Charles
subjects:
  • M Cell
  • Ranolazine
  • Sodium Channel Current
  • Arrhythmia
  • Action Potential
ispartof: Pacing and Clinical Electrophysiology, December 2013, Vol.36(12), pp.1512-1515
description: To purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/pace.12227/abstract Byline: HECTOR BARAJAS-MARTINEZ, DAN HU, ROBERT J. GOODROW, FREDERIC JOYCE, CHARLES ANTZELEVITCH Keywords: M cell; ranolazine; sodium channel current; arrhythmia; action potential Background Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disorder encountered in the clinic. Data relative to the electrophysiologic characteristics and pharmacologic responsiveness of human tissues and cells isolated from patients with HCM are rare. As a consequence, cellular mechanisms underlying arrhythmogenicity are poorly understood. Methods Cardiomyocytes were enzymatically dissociated from a septal myectomy surgically removed from a patient with obstructive HCM. Sharp microelectrodes and patch-clamp techniques were used to evaluate action potential and sodium channel current (I.sub.Na) characteristics. Results Action potential morphology recorded was typical of an M cell, but with a longer than normal duration (APD) and a relatively steep APD-rate relationship. APD at all rates was significantly reduced following exposure to ranolazine (10 I1/4M). Whole cell patch-clamp recording yielded robust peak I.sub.Na and large late I.sub.Na (1.1% of peak I.sub.Na vs 0.1-0.2% in healthy controls). A large window current was observed as well. Ranolazine (10 I1/4M) shifted steady-state V.sub.0.5 of inactivation by -8 mV, reduced late I.sub.Na by 82%, and significantly diminished the window current. Conclusion Our results indicate the presence of cells with M-cell characteristics in the septum of the human heart, as has previously been described in the canine heart. They also point to an ameliorative effect of ranolazine to reduce augmented late I.sub.Na and thus to reduce the prolonged APD in the setting of HCM. These results suggest a potential therapeutic role for ranolazine in HCM. Article Note: Funding sources: This work was supported by NIH grant HL47678 (CA); NYSTEM grant C026424 (CA); and New York, Florida, Massachusetts, Connecticut, and Rhode Island Freemasons. Disclosure: Dr. Antzelevitch is a consultant to and received grant support from Gilead Sciences, who provided the ranolazine used in this study. The other authors have nothing to disclose.
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identifier: ISSN: 0147-8389 ; E-ISSN: 1540-8159 ; DOI: 10.1111/pace.12227
fulltext: fulltext
issn:
  • 0147-8389
  • 01478389
  • 1540-8159
  • 15408159
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titleElectrophysiologic Characteristics and Pharmacologic Response of Human Cardiomyocytes Isolated from a Patient with Hypertrophic Cardiomyopathy
creatorBarajas‐Martínez, Hector ; Hu, Dan ; Goodrow, Robert J. ; Joyce, Frederic ; Antzelevitch, Charles
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descriptionTo purchase or authenticate to the full-text of this article, please visit this link: http://onlinelibrary.wiley.com/doi/10.1111/pace.12227/abstract Byline: HECTOR BARAJAS-MARTINEZ, DAN HU, ROBERT J. GOODROW, FREDERIC JOYCE, CHARLES ANTZELEVITCH Keywords: M cell; ranolazine; sodium channel current; arrhythmia; action potential Background Hypertrophic cardiomyopathy (HCM) is the most common monogenic cardiac disorder encountered in the clinic. Data relative to the electrophysiologic characteristics and pharmacologic responsiveness of human tissues and cells isolated from patients with HCM are rare. As a consequence, cellular mechanisms underlying arrhythmogenicity are poorly understood. Methods Cardiomyocytes were enzymatically dissociated from a septal myectomy surgically removed from a patient with obstructive HCM. Sharp microelectrodes and patch-clamp techniques were used to evaluate action potential and sodium channel current (I.sub.Na) characteristics. Results Action potential morphology recorded was typical of an M cell, but with a longer than normal duration (APD) and a relatively steep APD-rate relationship. APD at all rates was significantly reduced following exposure to ranolazine (10 I1/4M). Whole cell patch-clamp recording yielded robust peak I.sub.Na and large late I.sub.Na (1.1% of peak I.sub.Na vs 0.1-0.2% in healthy controls). A large window current was observed as well. Ranolazine (10 I1/4M) shifted steady-state V.sub.0.5 of inactivation by -8 mV, reduced late I.sub.Na by 82%, and significantly diminished the window current. Conclusion Our results indicate the presence of cells with M-cell characteristics in the septum of the human heart, as has previously been described in the canine heart. They also point to an ameliorative effect of ranolazine to reduce augmented late I.sub.Na and thus to reduce the prolonged APD in the setting of HCM. These results suggest a potential therapeutic role for ranolazine in HCM. Article Note: Funding sources: This work was supported by NIH grant HL47678 (CA); NYSTEM grant C026424 (CA); and New York, Florida, Massachusetts, Connecticut, and Rhode Island Freemasons. Disclosure: Dr. Antzelevitch is a consultant to and received grant support from Gilead Sciences, who provided the ranolazine used in this study. The other authors have nothing to disclose.
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