Cardiac myocyte alternans in intact heart: Influence of cell-cell coupling and β-adrenergic stimulation

Karin P. Hammer, Senka Ljubojevic, Crystal M Ripplinger, Burkert M. Pieske, Donald M Bers

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Background: Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca<sup>2+</sup> transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca<sup>2+</sup> alternans and sarcoplasmic reticulum (SR) Ca<sup>2+</sup> release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in the intact heart remains unknown. Objective: We assessed the effects of cell-to-cell coupling on local alternans in intact Langendorff-perfused mouse hearts, measuring single myocyte [Ca<sup>2+</sup>] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and results: Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo8-AM to record cardiac myocyte [Ca<sup>2+</sup>] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca<sup>2+</sup> alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions: Ca<sup>2+</sup> alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca<sup>2+</sup> alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume84
DOIs
StatePublished - Jul 1 2015

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Cardiac Myocytes
Adrenergic Agents
Gap Junctions
Muscle Cells
Action Potentials
Carbenoxolone
Sudden Cardiac Death
Sarcoplasmic Reticulum
Inbred C57BL Mouse
Confocal Microscopy
Adrenergic Receptors

Keywords

  • Alternans
  • Calcium
  • Whole heart
  • β-Adrenergic receptor activation

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiac myocyte alternans in intact heart : Influence of cell-cell coupling and β-adrenergic stimulation. / Hammer, Karin P.; Ljubojevic, Senka; Ripplinger, Crystal M; Pieske, Burkert M.; Bers, Donald M.

In: Journal of Molecular and Cellular Cardiology, Vol. 84, 01.07.2015, p. 1-9.

Research output: Contribution to journalArticle

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AU - Pieske, Burkert M.

AU - Bers, Donald M

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N2 - Background: Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca2+ transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca2+ alternans and sarcoplasmic reticulum (SR) Ca2+ release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in the intact heart remains unknown. Objective: We assessed the effects of cell-to-cell coupling on local alternans in intact Langendorff-perfused mouse hearts, measuring single myocyte [Ca2+] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and results: Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo8-AM to record cardiac myocyte [Ca2+] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca2+ alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions: Ca2+ alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca2+ alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established.

AB - Background: Cardiac alternans are proarrhythmic and mechanistically link cardiac mechanical dysfunction and sudden cardiac death. Beat-to-beat alternans occur when beats with large Ca2+ transients and long action potential duration (APD) alternate with the converse. APD alternans are typically driven by Ca2+ alternans and sarcoplasmic reticulum (SR) Ca2+ release alternans. But the effect of intercellular communication via gap junctions (GJ) on alternans in the intact heart remains unknown. Objective: We assessed the effects of cell-to-cell coupling on local alternans in intact Langendorff-perfused mouse hearts, measuring single myocyte [Ca2+] alternans synchronization among neighboring cells, and effects of β-adrenergic receptor (β-AR) activation and reduced GJ coupling. Methods and results: Mouse hearts (C57BL/6) were retrogradely perfused and loaded with Fluo8-AM to record cardiac myocyte [Ca2+] in situ with confocal microscopy. Single cell resolution allowed analysis of alternans within the intact organ during alternans induction. Carbenoxolone (25μM), a GJ inhibitor, significantly increased the occurrence and amplitude of alternans in single cells within the intact heart. Alternans were concordant between neighboring cells throughout the field of view, except transiently during onset. β-AR stimulation only reduced Ca2+ alternans in tissue that had reduced GJ coupling, matching effects seen in isolated myocytes. Conclusions: Ca2+ alternans among neighboring myocytes is predominantly concordant, likely because of electrical coupling between cells. Consistent with this, partial GJ uncoupling increased propensity and amplitude of Ca2+ alternans, and made them more sensitive to reversal by β-AR activation, as in isolated myocytes. Electrical coupling between myocytes may thus limit the alternans initiation, but also allow alternans to be more stable once established.

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