title: Left ventricular assist device support normalizes left and right ventricular beta-adrenergic pathway properties.
abstract: OBJECTIVE
  We hypothesized that some aspects of left ventricular assist device (LVAD) reverse remodeling could be independent of hemodynamic factors and would primarily depend upon normalization of neurohormonal milieu.
  
  
  BACKGROUND
  The relative contributions of LVAD-induced hemodynamic unloading (provided to the left ventricle [LV]) and normalized neurohormonal milieu (provided to LV and right ventricle [RV]) to reverse remodeling are not understood.
  
  
  METHODS
  Structural and functional characteristics were measured from hearts of 65 medically managed transplant patients (MED), 30 patients supported with an LVAD, and 5 nonfailing donor hearts not suitable for transplantation.
  
  
  RESULTS
  Compared with MED patients, diastolic pulmonary pressures trended lower (p < 0.01) and cardiac output higher (p < 0.001) in LVAD patients; V(30) (ex vivo ventricular volume yielding 30 mm Hg, an index of ventricular size) in LVAD patients was decreased in the LV (p < 0.05) but did not change significantly in RV. The LVAD support improved force generation in response to beta-adrenergic stimulation in isolated LV (increase in developed force from 6.3 +/- 0.6 to 18.5 +/- 4.4 mN/m(2), p < 0.01) and RV (increase in developed force, from 10.9 +/- 2.0 to 20.5 +/- 3.1 mN/m(2), p < 0.05) trabeculae. The LVAD patients had higher myocardial beta-adrenergic receptor density in LV (p < 0.01) and RV (p < 0.01). Protein kinase A (PKA) hyperphosphorylation of the ryanodine receptor 2 (RyR2)/calcium release channel was significantly reduced by LVAD in both RV and LV (p < 0.01).
  
  
  CONCLUSIONS
  Improved beta-adrenergic responsiveness, normalization of the RyR2 PKA phosphorylation, and increased beta-adrenergic receptor density in LV and RV after LVAD support suggest a primary role of neurohormonal environment in determining reverse remodeling of the beta-adrenergic pathway.
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klotz
authors.forename: Alessandro
authors.initials: A
authors.lastname: Barbone
authors.forename: Steven
authors.initials: S
authors.lastname: Reiken
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Holmes
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Naka
authors.forename: Mehmet C
authors.initials: MC
authors.lastname: Oz
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
authors.forename: Daniel
authors.initials: D
authors.lastname: Burkhoff
mesh_terms: D000328:Adult; D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000503:physiopathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005260:Female; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D014019:Tissue Donors; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000628:therapy*; D018497:Ventricular Dysfunction, Right / Q000503:physiopathology / Q000628:therapy*
chemical_list: D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D017868:Cyclic AMP-Dependent Protein Kinases