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. 2021 Jan;14(1):189-199.
doi: 10.1016/j.jcmg.2020.07.043. Epub 2020 Oct 28.

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression

Marianna Fontana  1 , Ana Martinez-Naharro  2 , Liza Chacko  2 , Dorota Rowczenio  2 , Janet A Gilbertson  2 , Carol J Whelan  2 , Svetla Strehina  2 , Thirusha Lane  2 , James Moon  3 , David F Hutt  2 , Peter Kellman  4 , Aviva Petrie  5 , Philip N Hawkins  2 , Julian D Gillmore  2
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Free article

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression

Marianna Fontana et al. JACC Cardiovasc Imaging. 2021 Jan.
Free article

Abstract

Objectives: The 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).

Background: Administration 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.

Methods: Patisiran 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.

Results: Patisiran 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%).

Conclusions: Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.

Keywords: ATTR; RNAi; amyloidosis; patisiran.

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Conflict of interest statement

Author Disclosures Dr. Fontana has done consultancy for Alnylam, Akcea, Eidos, Intellia, Pfizer, and Alexion; and is funded from the British heart foundation fellowship FS/18/21/33447. Drs. Fontana and Gillmore have a research grant from Pfizer. Dr. Hawkins is an expert Advisory board member for Alnylam. Dr. Gillmore is an expert Advisory board member for Alnylam, Akcea, Eidos, and Pfizer; and has a research grant from Alnylam.

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