title: Longitudinal structural, functional, and cellular myocardial alterations with chronic centrifugal continuous-flow left ventricular assist device support.
abstract: BACKGROUND
  Left ventricular assist device (LVAD) support triggers adaptations within failing hearts. The HeartWare (HeartWare International, Inc., Framingham, MA) LVAD exhibits different flow profiles and afterload dependence compared with previous-generation devices, which may alter remodelling patterns. We sought to characterize myocardial adaptation to third-generation centrifugal-flow LVADs at a functional, hemodynamic, and structural level in addition to profiling transcriptomal changes using next-generation sequencing platforms.
  
  
  METHODS
  We studied 37 patients supported with the HeartWare device with paired measurements of invasive hemodynamics, serial longitudinal left ventricular (LV) and right ventricular (RV) 3-dimensional echocardiography, and N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) measurements. Paired samples for comparison of histologic myocardial cellular size and transcriptomal profiling were performed on specimens taken at pump implant and transplantation.
  
  
  RESULTS
  The mean support duration was 280 ± 163 days. Mechanical unloading after HeartWare support resulted in reduced filling pressures (mean pulmonary capillary wedge pressure 27.1 ± 6.6 to 14.8 ± 5.1 mm Hg, p < 0.0001). Mean LV cardiomyocyte cell size decreased from 2,789.7 ± 671.8 to 2,290.8 ± 494.2 μm2(p = 0.02). LV and RV ejection fractions improved significantly (24% ± 8% to 35% ± 9% [p < 0.001] and 35% ± 11% to 40% ± 8% [p < 0.02], respectively). NT-proBNP levels fell 4.8-fold by Day 90 after support, consistent with a decrease in LV wall stress. Despite these concordant beneficial findings, the microRNA transcriptome did not change significantly across the group.
  
  
  CONCLUSIONS
  Reverse remodelling is evident at multiple levels with chronic HeartWare support in the absence of changes in the microRNA transcriptome. Successful myocardial unloading is associated with a decrease in wall stress, regression of cardiomyocyte hypertrophy, and an improvement in LV and RV ejection fractions.
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Muthiah
authors.affiliation: Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: David T
authors.initials: DT
authors.lastname: Humphreys
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Desiree
authors.initials: D
authors.lastname: Robson
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: Kumud
authors.initials: K
authors.lastname: Dhital
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Spratt
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Jansz
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Macdonald
authors.affiliation: Heart Failure and Transplant Unit, St. Vincent's Hospital, Sydney, New South Wales, Australia; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia; Victor Chang Cardiac Research Institute, Sydney, New South Wales, Australia. Electronic address: cshayward@stvincents.com.au.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Hayward
mesh_terms: D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology*; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D013997:Time Factors; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain
keywords: 3D echocardiography; N-terminal pro-BNP; left ventricular assist device; microRNA transcriptome; myocardial adaptation; remodeling pattern