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Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression
Authors:Marianna Fontana  Ana Martinez-Naharro  Liza Chacko  Dorota Rowczenio  Janet A. Gilbertson  Carol J. Whelan  Svetla Strehina  Thirusha Lane  James Moon  David F. Hutt  Peter Kellman  Aviva Petrie  Philip N. Hawkins  Julian D. Gillmore
Affiliation:1. Division of Medicine, National Amyloidosis Centre, University College London, London, United Kingdom;2. Institute of Cardiovascular Science, University College London, London, United Kingdom;3. Barts Heart Centre, West Smithfield, London, United Kingdom;4. National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;5. Eastman Dental Institute, University College London, London, United Kingdom
Abstract:
ObjectivesThe purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM).BackgroundAdministration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain.MethodsPatisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a “TTR-stabilizing” drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results.ResultsPatisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: ?6.2% [95% confidence interval [CI]: ?9.5% to ?3.0%]; p = 0.001) accompanied by a fall in N-terminal pro–B-type natriuretic peptide concentrations (adjusted mean difference between groups: ?1,342 ng/l [95% CI: ?2,364 to ?322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%).ConclusionsReductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.
Keywords:amyloidosis  ATTR  patisiran  RNAi  6MWT"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0035"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  6-min walking test  ATTR amyloidosis"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0045"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  transthyretin amyloidosis  ATTR-CM"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0055"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  transthyretin cardiomyopathy  isotope-labeled DPD"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0065"  },"  $$"  :[{"  #name"  :"  text"  ,"  $$"  :[{"  #name"  :"  sup"  ,"  $"  :{"  loc"  :"  post"  },"  _"  :"  99m"  },{"  #name"  :"  __text__"  ,"  _"  :"  Tc-3,3-diphosphono-1,2-propanodicarboxylic acid  ECV"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0075"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  extracellular volume  LGE"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0085"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  late gadolinium enhancement  LVH"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0095"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  left ventricular hypertrophy  NT-proBNP"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0105"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  N-terminal pro–B-type natriuretic peptide  PND"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  kwrd0115"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  polyneuropathy disability score
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