Effects of small platform catheter-based left ventricular assist device support on regional myocardial signal transduction

J Thorac Cardiovasc Surg. 2015 Nov;150(5):1332-41. doi: 10.1016/j.jtcvs.2015.08.035. Epub 2015 Aug 15.

Abstract

Objectives: Left ventricular (LV) assist device (LVAD) support reduces pathological loading. However, load-induced adaptive responses may be suppressed. Pathological loading dysregulates cardiac G protein-coupled receptor (GPCR) signaling. Signaling through G proteins is deleterious, whereas beta (β)-arrestin-mediated signaling is cardioprotective. We examined the effects of pathological LV loading/LV dysfunction and treatment via LVAD, on β-arrestin-mediated signaling, and genetic networks downstream of load.

Methods: An ovine myocardial infarction (MI) model was used. Sheep underwent sham thoracotomy (n = 3), mid-left anterior descending coronary artery ligation to produce MI (n = 3), or MI with placement of a small-platform catheter-based LVAD (n = 3). LVAD support was continued for 2 weeks. Animals were maintained for a total of 12 weeks. Myocardial specimens were harvested and analyzed.

Results: MI induced β-arrestin activation. Increased interactions between epidermal growth factor receptor and β-arrestins were observed. LVAD support inhibited these responses to MI (P < .05). LVAD support inhibited the activation of cardioprotective signaling effectors Akt (P < .05), and, to a lesser extent, extracellular regulated kinase 1/2 (P not significant); however, MI resulted in regional activation of load-induced GPCR signaling via G proteins, as assessed by the induction of atrial natriuretic peptide mRNA expression in the MI-adjacent zone relative to the MI-remote zone (P < .05). MI-adjacent zone atrial natriuretic peptide expression was renormalized with LVAD support.

Conclusions: LVAD support inhibited cardioprotective β-arrestin-mediated signaling. However, net benefits of normalization of load-induced GPCR signaling were observed in the MI-adjacent zone. These findings may have implications for the optimal extent and duration of unloading, and for the development of adjunctive medical therapies.

Keywords: intracellular signaling; left ventricular dysfunction; mechanical circulatory support; mechanotransduction; myocardial infarction.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Atrial Natriuretic Factor / genetics
  • Atrial Natriuretic Factor / metabolism
  • Cardiac Catheterization / instrumentation*
  • Cardiac Catheters*
  • Disease Models, Animal
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Heart-Assist Devices*
  • Materials Testing
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / therapy*
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Phosphorylation
  • Prosthesis Design
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • Recovery of Function
  • Sheep
  • Signal Transduction*
  • Time Factors
  • Ventricular Dysfunction, Left / diagnosis
  • Ventricular Dysfunction, Left / metabolism
  • Ventricular Dysfunction, Left / physiopathology
  • Ventricular Dysfunction, Left / therapy*
  • Ventricular Function, Left*
  • beta-Arrestins

Substances

  • Arrestins
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • beta-Arrestins
  • Atrial Natriuretic Factor
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases