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Original research article
Calcification and extracellular matrix dysregulation in human postmortem and surgical aortic valves
  1. M Victoria Gomez-Stallons1,
  2. Justin T Tretter2,
  3. Keira Hassel1,
  4. Osniel Gonzalez-Ramos1,
  5. Dorothy Amofa1,
  6. Nicholas J Ollberding3,
  7. Wojciech Mazur4,
  8. Joseph K Choo4,
  9. J Michael Smith5,
  10. Dean J Kereiakes4,
  11. Katherine E Yutzey1
  1. 1 Molecular Cardiovascular Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  2. 2 Division of Cardiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  3. 3 Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  4. 4 The Ohio Heart and Vascular Center, The Christ Hospital, Cincinnati, Ohio, USA
  5. 5 Cardiac Surgery, TriHealth, Cincinnati, Ohio, USA
  1. Correspondence to Dr Katherine E Yutzey, Division of Molecular Cardiovascular Biology, Cincinnati Children’s Medical Center, Cincinnati, OH 45229, USA; katherine.yutzey{at}


Objectives Calcific aortic valve disease (CAVD) is a progressive disease ranging from aortic valve (AoV) sclerosis to AoV stenosis (AS), characterised by severe calcification with impaired leaflet function. Due to the lack of early symptoms, the pathological progression towards valve dysfunction is poorly understood. The early patterns of AoV calcification and altered extracellular matrix (ECM) organisation were analysed in individuals postmortem without clinical AS compared with clinical AS.

Methods Histological patterns of calcification and ECM organisation in postmortem AoV leaflets without clinical AS obtained from a tissue repository and surgical specimens obtained from individuals with clinical AS were compared with in vivo imaging prior to transcatheter AoV implantation.

Results AoV calcification was detected in all samples from individuals >50 years old, with severity increasing with age, independent of known CAVD risk factors. Two distinct types of calcification were identified: ‘Intrinsic’, primarily found at the leaflet hinge of postmortem leaflets, accompanied by abnormal collagen and proteoglycan deposition; and ‘Nodular’, extending from the middle to the tip regions in more severely affected postmortem leaflets and surgical specimens, associated with increased elastin fragmentation and loss of elastin integrity. Even in the absence of increased thickening, abnormalities in ECM composition were observed in postmortem leaflets without clinical AS and worsen in clinical AS.

Conclusions Two distinct phenotypes of AoV calcification are apparent. While the ‘nodular’ form is recognised on in vivo imaging and is present with CAVD and valve dysfunction, it is unclear if the ‘intrinsic’ form is pathological or detected on in vivo imaging.

  • valvular heart disease
  • aortic stenosis
  • transcatheter valve interventions
  • valve disease surgery
  • cardiac computer tomographic (ct) imaging

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  • Contributors Study design: MVG-S, OG-R, JTT, WM, DK, KY. Data generation and analysis: MVG-S, JTT, KH, OG-R, DA, NO, KY. Statistical analysis: MVG-S, NO. Procurement of human tissue, imaging and study design: OG-R, JTT, WM, JC, JMS, DK. Wrote the manuscript with feedback from all authors: MVG-S, JTT, KY.

  • Funding This study was funded by NIH R01 HL114682 (KY).

  • Competing interests DK is on the scientific advisory board and is a consultant for Boston Scientific.

  • Ethics approval All studies have been approved by the institutional review boards of Cincinnati Children’s Hospital Medical Center, TriHealth and The Christ Hospital. Cincinnati Children’s is the institution of record. The study IDs are 2016-6506 for Cincinnati Children’s and 17-43 for The Christ Hospital. Informed consent was obtained from all subjects prior to inclusion in the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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