2. Academic Validation
  3. Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients

Antithrombotic properties of Tafamidis: An additional protective effect for transthyretin amyloid cardiomyopathy patients

  • Vascul Pharmacol. 2024 Jul 17:156:107411. doi: 10.1016/j.vph.2024.107411.
Stefano Ministrini 1,  Rebecca Niederberger 1,  Alexander Akhmedov 1,  Georgia Beer 1,  Yustina M Puspitasari 1,  Maria Franzini 2,  Giuseppe Vergaro 3,  Douglas E Cannie 4,  Perry Elliott 4,  Peter C Kahr 5,  Christoph Hock 6,  Richard Kobza 7,  Stefan Toggweiler 7,  Thomas F Lüscher 8,  Giovanni G Camici 9,  Simon F Stämpfli 10
Affiliations

Affiliations

  • 1 Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
  • 2 Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Via Savi 10, 56126 Pisa, Italy.
  • 3 Cardiology Division, Fondazione Toscana Gabriele Monasterio, Via Giuseppe Moruzzi 1, 56126 Pisa, Italy.
  • 4 Institute of Cardiovascular Science, University College London, 62 Huntley St, Wc1E 6Dd London, UK; Barts Heart Center, St. Bartholomew's Hospital, West Smithfield, Ec1A 7Be London, UK.
  • 5 Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Neurimmune, Wagistrasse 18, 8952 Schlieren, Switzerland.
  • 6 Neurimmune, Wagistrasse 18, 8952 Schlieren, Switzerland; Institute for Regenerative Medicine (IREM), Wagistrasse 12, 8952 Schlieren, Switzerland.
  • 7 Cardiology Division, Heart Center, Luzerner Kantonsspital, Spitalstrasse 16, 6000 Lucerne, Switzerland.
  • 8 Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Royal Brompton and Harefield Hospitals and Imperial College, London, UK.
  • 9 Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Department of Research and Education, University Hospital Zurich, Rämistrasse 100, 8092 Zurich, Switzerland.
  • 10 Center for Molecular Cardiology, Schlieren Campus, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland,; Cardiology Division, Heart Center, Luzerner Kantonsspital, Spitalstrasse 16, 6000 Lucerne, Switzerland. Electronic address: simon.staempfli@luks.ch.
PMID: 39029855 DOI: 10.1016/j.vph.2024.107411
Abstract

Introduction: Tafamidis is a molecular chaperone that stabilizes the transthyretin (TTR) homo-tetramer, preventing its dissociation and consequent deposition as amyloid fibrils in organ tissues. Tafamidis reduces mortality and the incidence of hospitalization for cardiovascular causes in patients with TTR amyloid (ATTR) cardiomyopathy. As ATTR cardiomyopathy is associated with a high risk of thromboembolic complications, we hypothesized that tafamidis may have a direct ancillary anti-thrombotic effect.

Methods: Primary human aortic endothelial cells (HAECs) were treated with tafamidis at clinically relevant concentrations and with plasma of patients, before and after the initiation of treatment with tafamidis. The expression of TF was induced by incubation with Tumor Necrosis Factor α (TNFα). Intracellular expression of tissue factor (TF) was measured by western blot. TF activity was measured by a colorimetric assay. Gene expressions of TF were measured by quantitative polymerase chain reaction.

Results: Treatment with tafamidis dose-dependently reduced the expression and activity of TNFα-induced TF. This effect was confirmed in cells treated with patients' plasma. Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation was significantly inhibited by tafamidis. Incubation of HAECs with tafamidis and the STAT3 Activator colivelin partially rescued the expression of TF.

Conclusions: Treatment with tafamidis lowers the thrombotic potential in human primary endothelial cells by reducing TF expression and activity. This previously unknown off-target effect may provide a novel mechanistic explanation for the lower number of thromboembolic complications in ATTR cardiomyopathy patients treated with tafamidis.

Keywords

Arterial thrombosis; Cardiac amyloidosis; Endothelial function; Pleiotropic effects; Tafamidis.

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