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<p>In heart failure, β-adrenergic receptor (β-AR)-Gsα-cAMP-protein kinase A (PKA) signalling predisposes to delayed-afterdepolarisation-mediated arrhythmias. Phosphodiesterases (PDEs) hydrolyse cAMP, and PDE3 restrains β<sub>1</sub>-AR, β<sub>2</sub>-AR-mediated inotropic responses in failing hearts from β-blocker-treated patients. Whether these receptors provoke arrhythmias through ryanodine receptor (RyR2) dysregulation, and how PDE activity and prior β-blockade treatment modify this, is undefined.&#xa0;We sought to define how β<sub>1</sub>-AR and β<sub>2</sub>-AR activation provokes arrhythmias through RyR2 mechanisms in explanted human failing hearts, and how PDE activity and prior β-blocker therapy modulate this response.&#xa0;A diastolic model of ventricular arrhythmia using human right ventricular trabeculae with pacing stopped was used. Trabeculae were exposed to (-)-noradrenaline/(-)-adrenaline to activate β<sub>1</sub>-AR/β<sub>2</sub>-AR respectively with or without PDE inhibitors and monitored for spontaneous contractions. In parallel, sarcoplasmic reticulum vesicles from trabeculae were used to assess RyR2 channel function, phosphorylation and oxidation.&#xa0;Activation of β<sub>1</sub>-AR or β<sub>2</sub>-AR increased the frequency of spontaneous contractions, concomitant increases in diastolic RyR2 channel opening, phosphorylation and oxidation. Trabeculae from carvedilol-treated patients showed fewer β<sub>2</sub>-AR-mediated spontaneous contractions than those treated with β<sub>1</sub>-AR blockers. The PDE3 inhibitor cilostamide augmented β<sub>2</sub>-AR-mediated spontaneous contractions, RyR2 channel opening and Ser2808 phosphorylation.&#xa0;In human failing heart, β<sub>1</sub>-AR or β<sub>2</sub>-AR activation increased arrhythmic contractions associated with greater diastolic RyR2 channel opening, phosphorylation and oxidation. PDE3 attenuated β<sub>2</sub>-AR-mediated arrhythmic contractions, RyR2 channel opening and Ser2808 hyperphosphorylation. These findings suggest that combining β<sub>1</sub>- and β<sub>2</sub>-AR blockade with strategies that reduce RyR2 Ca<sup>2+</sup> leak and preserve RyR2-associated PDE3 activity may improve arrhythmia control in heart failure.</p> Graphical abstract <p>The arrhythmogenic human failing heart. Figure shows β<sub>1</sub>-AR, β<sub>2</sub>-AR mediated arrhythmia mechanisms in human HF. Activated β<sub>1</sub>-AR or β<sub>2</sub>-AR couple to the Gsα-protein-adenylyl cyclase signalling pathway to increase cyclic AMP, activation of PKA with consequent phosphorylation of RyR2. Other changes to RyR2 include oxidation and dissociation of FKBP12.6 (Walweel et al. <CitationRef CitationID="CR74">2017</CitationRef>;&#xa0;Denniss et al. <CitationRef CitationID="CR17">2020</CitationRef>). The changes contribute to Ca<sup>2+</sup> leak from the sarcoplasmic reticulum through RyR2 during diastole to cause outward transport of Ca<sup>2+</sup>/inward transport of Na<sup>+</sup> through the Na<sup>+</sup>/Ca<sup>2+</sup>exchanger resulting in DAD induced action potentials, depolarization of the myocyte and arrhythmic contractions (Walweel et al. <CitationRef CitationID="CR74">2017</CitationRef>;&#xa0;Denniss et al. <CitationRef CitationID="CR17">2020</CitationRef>). The β<sub>2</sub>-AR pathway that mediates arrhythmia generation is under the control of PDE3 (this paper).&#xa0;</p> <p></p>

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β1- and β2-adrenergic receptor mediated spontaneous contractions and ryanodine receptor channel opening in human failing heart

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月1日

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  • Weilan Mo,
  • Nicole A. Beard,
  • Katherine T. Gillette-Browne,
  • Karen Hay,
  • Elizabeth Cheesman,
  • Alexander Dashwood,
  • Melanie Spratt,
  • Annalese B. Semmler,
  • Yee Weng Wong,
  • Haris Haqqani,
  • Derek R. Laver,
  • Torsten Christ,
  • Kafa Walweel,
  • Peter Molenaar

摘要

In heart failure, β-adrenergic receptor (β-AR)-Gsα-cAMP-protein kinase A (PKA) signalling predisposes to delayed-afterdepolarisation-mediated arrhythmias. Phosphodiesterases (PDEs) hydrolyse cAMP, and PDE3 restrains β1-AR, β2-AR-mediated inotropic responses in failing hearts from β-blocker-treated patients. Whether these receptors provoke arrhythmias through ryanodine receptor (RyR2) dysregulation, and how PDE activity and prior β-blockade treatment modify this, is undefined. We sought to define how β1-AR and β2-AR activation provokes arrhythmias through RyR2 mechanisms in explanted human failing hearts, and how PDE activity and prior β-blocker therapy modulate this response. A diastolic model of ventricular arrhythmia using human right ventricular trabeculae with pacing stopped was used. Trabeculae were exposed to (-)-noradrenaline/(-)-adrenaline to activate β1-AR/β2-AR respectively with or without PDE inhibitors and monitored for spontaneous contractions. In parallel, sarcoplasmic reticulum vesicles from trabeculae were used to assess RyR2 channel function, phosphorylation and oxidation. Activation of β1-AR or β2-AR increased the frequency of spontaneous contractions, concomitant increases in diastolic RyR2 channel opening, phosphorylation and oxidation. Trabeculae from carvedilol-treated patients showed fewer β2-AR-mediated spontaneous contractions than those treated with β1-AR blockers. The PDE3 inhibitor cilostamide augmented β2-AR-mediated spontaneous contractions, RyR2 channel opening and Ser2808 phosphorylation. In human failing heart, β1-AR or β2-AR activation increased arrhythmic contractions associated with greater diastolic RyR2 channel opening, phosphorylation and oxidation. PDE3 attenuated β2-AR-mediated arrhythmic contractions, RyR2 channel opening and Ser2808 hyperphosphorylation. These findings suggest that combining β1- and β2-AR blockade with strategies that reduce RyR2 Ca2+ leak and preserve RyR2-associated PDE3 activity may improve arrhythmia control in heart failure.

Graphical abstract

The arrhythmogenic human failing heart. Figure shows β1-AR, β2-AR mediated arrhythmia mechanisms in human HF. Activated β1-AR or β2-AR couple to the Gsα-protein-adenylyl cyclase signalling pathway to increase cyclic AMP, activation of PKA with consequent phosphorylation of RyR2. Other changes to RyR2 include oxidation and dissociation of FKBP12.6 (Walweel et al. 2017; Denniss et al. 2020). The changes contribute to Ca2+ leak from the sarcoplasmic reticulum through RyR2 during diastole to cause outward transport of Ca2+/inward transport of Na+ through the Na+/Ca2+exchanger resulting in DAD induced action potentials, depolarization of the myocyte and arrhythmic contractions (Walweel et al. 2017; Denniss et al. 2020). The β2-AR pathway that mediates arrhythmia generation is under the control of PDE3 (this paper).