Transient denervation of viable myocardium after myocardial infarction does not alter arrhythmia susceptibility

Diana C. Parrish, Samantha D. Francis Stuart, Antoinette Olivas, Lianguo Wang, Anders Nykjaer, Crystal M Ripplinger, Beth A. Habecker

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Cardiac sympathetic nerves stimulate heart rate and force of contraction. Myocardial infarction (MI) leads to the loss of sympathetic nerves within the heart, and clinical studies have indicated that sympathetic denervation is a risk factor for arrhythmias and cardiac arrest. Two distinct types of denervation have been identified in the mouse heart after MI caused by ischemia-reperfusion: transient denervation of peri-infarct myocardium and sustained denervation of the infarct. Sustained denervation is linked to increased arrhythmia risk, but it is not known whether acute nerve loss in peri-infarct myocardium also contributes to arrhythmia risk. Periinfarct sympathetic denervation requires the p75 neurotrophin receptor (p75NTR), but removal of p75NTR alters the pattern of sympathetic innervation in the heart and increases spontaneous arrhythmias. Therefore, we targeted the p75NTR coreceptor sortilin and the p75NTR-induced protease tumor necrosis factor-α-converting enzyme/ A disintegrin and metalloproteinase domain 17 (TACE/ ADAM17) to selectively block peri-infarct denervation. Sympathetic nerve density was quantified using immunohistochemistry for tyrosine hydroxylase. Genetic deletion of sortilin had no effect on the timing or extent of axon degeneration, but inhibition of TACE/ADAM17 with the protease inhibitor marimastat prevented the loss of axons from viable myocardium. We then asked whether retention of nerves in peri-infarct myocardium had an impact on cardiac electrophysiology 3 days after MI using ex vivo optical mapping of transmembrane potential and intracellular Ca2+. Preventing acute denervation of viable myocardium after MI did not significantly alter cardiac electrophysiology or Ca2+ handling, suggesting that transient denervation at this early time point has minimal impact on arrhythmia risk. NEW & NOTEWORTHY Sympathetic denervation after myocardial infarction is a risk factor for arrhythmias. We asked whether transient loss of nerves in viable myocardium contributed to arrhythmia risk. We found that targeting protease activity could prevent acute peri-infarct denervation but that it did not significantly alter cardiac electrophysiology or Ca2+ handling 3 days after myocardial infarction. marimastat; optical mapping; p75 neurotrophin receptor; sortilin.

Original languageEnglish (US)
Pages (from-to)H415-H423
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume314
Issue number3
DOIs
StatePublished - Mar 1 2018

Fingerprint

Denervation
Nerve Growth Factor Receptor
Cardiac Arrhythmias
Myocardium
Myocardial Infarction
Cardiac Electrophysiology
Sympathectomy
Axons
Voltage-Sensitive Dye Imaging
Peptide Hydrolases
Disintegrins
Tyrosine 3-Monooxygenase
Metalloproteases
Heart Arrest
Protease Inhibitors
Reperfusion
Ischemia
Tumor Necrosis Factor-alpha
Heart Rate
Immunohistochemistry

Keywords

  • Marimastat
  • Optical mapping
  • P75 neurotrophin receptor
  • Sortilin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Transient denervation of viable myocardium after myocardial infarction does not alter arrhythmia susceptibility. / Parrish, Diana C.; Francis Stuart, Samantha D.; Olivas, Antoinette; Wang, Lianguo; Nykjaer, Anders; Ripplinger, Crystal M; Habecker, Beth A.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 314, No. 3, 01.03.2018, p. H415-H423.

Research output: Contribution to journalArticle

Parrish, Diana C. ; Francis Stuart, Samantha D. ; Olivas, Antoinette ; Wang, Lianguo ; Nykjaer, Anders ; Ripplinger, Crystal M ; Habecker, Beth A. / Transient denervation of viable myocardium after myocardial infarction does not alter arrhythmia susceptibility. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 314, No. 3. pp. H415-H423.
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