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July 3, 2008Pflügers Archiv - European Journal of PhysiologyOpen Access

Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart

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Key result

Epac activation with 8-CPT provoked ventricular tachycardia in 50% of extrinsically paced murine hearts compared to 0% in controls, associating arrhythmogenesis with altered cellular calcium homeostasis.

Population

Wild-type murine hearts (129 background, male and female, aged 5-7 months) and isolated ventricular myocytes

Comparison

Epac activation using 8-pCPT-2'-O-Me-cAMP or… vs Control conditions

Design

Preclinical

Authors

SHSandeep S HothiIGIman S. GurungJHJennifer C. Heathcote

Discussion

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Overview

No immediate clinical implications for arrhythmia management; hypothesis-generating for Epac-targeted therapies in humans.

Structured PICO

P
Population
Isolated Langendorff-perfused wild-type murine hearts from mice aged 5-7 months used to study ventricular arrhythmogenesis.
I
Intervention
Epac activation using 8-pCPT-2'-O-Me-cAMP (8-CPT, 1 microM) or isoproterenol (100 nM) with PKA inhibitor H-89 (2 microM)
C
Comparator
Control conditions (Krebs-Henseleit solution without Epac activators)
O
Outcome
Ventricular arrhythmogenesis (triggered activity and ventricular tachycardia) and cellular Ca2+ homeostasissurrogate

Main Result

Absolute Event Rate: 50% vs 0%

p-value: p=<0.001

Epac activation induces ventricular arrhythmias in intact murine hearts via altered cellular calcium homeostasis, independent of repolarization gradients.

Limitations

  • Findings are from an isolated murine heart model, which may not fully translate to intact human physiology
  • The study relies on pharmacological activation and inhibition, which may have off-target effects despite the chosen concentrations

Cite This Study

Hothi et al. (2008) studied Ventricular arrhythmogenesis. 8-pCPT-2′-O-Me-cAMP (8-CPT) vs. Control conditions (Krebs-Henseleit solution) was evaluated on Provoked ventricular tachycardia (VT) during programmed electrical stimulation (p=<0.001). Epac activation with 8-CPT provoked ventricular tachycardia in 50% of extrinsically paced murine hearts compared to 0% in controls, associating arrhythmogenesis with altered cellular calcium homeostasis.

synapsesocial.com/papers/6a202057eaa49a33b5fbedb9https://doi.org/10.1007/s00424-008-0508-3
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Epac-mediated Activation of Phospholipase Cɛ Plays a Critical Role in β-Adrenergic Receptor-dependent Enhancement of Ca2+ Mobilization in Cardiac Myocytes2006 · 183 citations
  2. 2cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy2005 · 181 citations
  3. 3Arrhythmogenic mechanisms in the isolated perfused hypokalaemic murine heart2007 · 70 citations
  4. 4Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca<sup>2+</sup> homeostasis2005 · 43 citations
  5. 5Cellular origins of the transient inward current in cardiac myocytes. Role of fluctuations and waves of elevated intracellular calcium.1989 · 225 citations