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Nitisinone Attenuates Aortic Stenosis Disease Progression in Patients with Alkaponuria: An Analysis of the SONIA 2 Study
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  • Callum Bruce,
  • Priyanka Meenamkuzhy-Hariharan,
  • Shahdat Hussain,
  • Antonio Eleuteri,
  • Lakshminarayan Ranganath,
  • Michael Fisher,
  • Richard Imrich,
  • Jean-Baptiste Arnoux,
  • Birgitta Olsson,
  • Mattias Rudebeck
Callum Bruce
Royal Liverpool University Hospital

Corresponding Author:callumrbruce@gmail.com

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Priyanka Meenamkuzhy-Hariharan
Royal Liverpool University Hospital
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Shahdat Hussain
Aintree University Hospital
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Antonio Eleuteri
Royal Liverpool University Hospital
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Lakshminarayan Ranganath
Royal Liverpool University Hospital
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Michael Fisher
Royal Liverpool University Hospital
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Richard Imrich
Slovak Academy of Sciences
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Jean-Baptiste Arnoux
Necker-Enfants Malades Hospitals
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Birgitta Olsson
Gariguella AB
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Mattias Rudebeck
University of Liverpool
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Abstract

Background and Purpose: Alkaptonuria (AKU) is a rare metabolic disorder characterised by the accumulation of homogentisic acid (HGA). Deposition of HGA in the aortic valve leading to progressive aortic stenosis is a serious complication. Nitisinone has been shown to improve morbidity and slow disease progression in AKU but the effects of this treatment on aortic stenosis progression have not yet been described. This review extrapolated from the data set of SONIA 2, a 4-year multi-centre randomised controlled trial investigating the effect of nitisinone on AKU disease activity, but specifically examined measures of aortic stenosis disease progression. Methods: Data were obtained from echocardiograms performed on 138 patients over 48 months of follow-up. A linear mixed effects regression model was used to ascertain the difference in aortic valve pressure (AVP) at baseline and 48 months between the treatment and control groups. Key Results: At baseline, 18/138 patients (13.0%) had aortic stenosis of varying degrees of severity and 25/138 (18.1%) had aortic sclerosis. The difference in AVP between the control (N=69) and treatment (N=69) groups at baseline was 0.063mmHg [95% CI: -0.054mmHg to 0.18mmHg) and did not reach statistical significance (p=0.23). At the end of the 4-year treatment period, the difference in AVP was 0.10mmHg [95% CI: -0.0007mmHg to 0.20mmHg] and was statistically significant (p=0.05). Conclusion and Implications: Nitisinone slowed progression of aortic stenosis in patients with AKU. This supports the argument for timely initiation of nitisinone to reduce the incidence and severity of aortic valvular disease in AKU patients.