Microcalcification and thoracic aortopathy: a window into disease severity

Alexander J Fletcher; Jennifer Nash; Maaz Syed; Mark Macaskill; Adriana A S Tavares; Niki Walker; Hannah  Salcudean; Jonathon A. Leipsic; Kelvin  Lim; Jillian  Madine; William  Wallace; Mark  Field; David E Newby; Rihab Bouchareb; Michael Seidman; Riaz Akhtar; Stephanie  Sellers

doi:10.1161/ATVBAHA.122.317111

Microcalcification and thoracic aortopathy: a window into disease severity

Alexander J Fletcher^*, Jennifer Nash, Maaz Syed, Mark Macaskill, Adriana A S Tavares, Niki Walker, Hannah Salcudean, Jonathon A. Leipsic, Kelvin Lim, Jillian Madine, William Wallace, Mark Field, David E Newby, Rihab Bouchareb, Michael Seidman, Riaz Akhtar, Stephanie Sellers

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

Objective
Patients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established.

Approach and Results
One hundred and one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathological scores, immunohistochemistry and nanoindentation (tissue elastic modulus) were compared to the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography.

Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate histopathological degeneration (n=30; 3.74 [0.87, to 11.80], p<0.042) compared with control samples (n=18, 0.79 [0.36 to 1.90]). Alkaline phosphatase (n=26, p=0.0019) and osteopontin (n=26, p=0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathological degeneration was related to reduced microcalcification (n=82, Spearman’s rho -0.51, p<0.0001), a process closely linked with elastin loss (n=82; Spearman’s rho = -0.43, p<0.0001) and lower tissue elastic modulus (n=28; Spearman’s rho = 0.43, p=0.026). 18F-Sodium fluoride autoradiography demonstrated very good correlation with histologically quantified microcalcification (n=66; r=0.76, p<0.001), and identified areas of focal weakness in vivo.

Conclusions
Medial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification. 18F-Sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible non-invasive imaging modality for identifying aortic wall disruption with major translational promise.

Original language	English
Journal	Arteriosclerosis, Thrombosis, and Vascular Biology
DOIs	https://doi.org/10.1161/ATVBAHA.122.317111
Publication status	Published - 30 Jun 2022

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10.1161/ATVBAHA.122.317111

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Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET)
Tavares, A. & Grant, S.
UK-based charities
1/11/20 → 31/10/25
Project: Research
Myocardial Fibrosis And Left Ventricular Remodelling In Cardiovascular Disease
Tavares, A., Baker, A. & Newby, D.
UK-based charities
1/10/19 → 30/09/24
Project: Research
Dissecting activation, heterogeneity and crosstalk of PDGFRa/b+ cells in valvular stenosis and left ventricular remodelling following aortic stenosis
Henderson, N.
UK-based charities
1/09/19 → 1/10/22
Project: Research

Edinburgh Preclinical Imaging
Carmel Moran (Manager), Adrian Thomson (Manager), Ross J Lennen (Manager), Adriana Tavares (Manager), Carlos J. Alcaide-Corral (Manager), Tim Morgan (Other), Islay Cranston (Other) & Kerry O'Rourke (Other)
Deanery of Clinical Sciences
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Fletcher, A. J., Nash, J., Syed, M., Macaskill, M., Tavares, A. A. S., Walker, N., Salcudean, H., Leipsic, J. A., Lim, K., Madine, J., Wallace, W., Field, M., Newby, D. E., Bouchareb, R., Seidman, M., Akhtar, R., & Sellers , S. (2022). Microcalcification and thoracic aortopathy: a window into disease severity. Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/ATVBAHA.122.317111

@article{7224e9fe3ced43098d7e9348817ff949,

title = "Microcalcification and thoracic aortopathy: a window into disease severity",

abstract = "ObjectivePatients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established.Approach and ResultsOne hundred and one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathological scores, immunohistochemistry and nanoindentation (tissue elastic modulus) were compared to the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography. Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate histopathological degeneration (n=30; 3.74 [0.87, to 11.80], p<0.042) compared with control samples (n=18, 0.79 [0.36 to 1.90]). Alkaline phosphatase (n=26, p=0.0019) and osteopontin (n=26, p=0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathological degeneration was related to reduced microcalcification (n=82, Spearman{\textquoteright}s rho -0.51, p<0.0001), a process closely linked with elastin loss (n=82; Spearman{\textquoteright}s rho = -0.43, p<0.0001) and lower tissue elastic modulus (n=28; Spearman{\textquoteright}s rho = 0.43, p=0.026). 18F-Sodium fluoride autoradiography demonstrated very good correlation with histologically quantified microcalcification (n=66; r=0.76, p<0.001), and identified areas of focal weakness in vivo.ConclusionsMedial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification. 18F-Sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible non-invasive imaging modality for identifying aortic wall disruption with major translational promise.",

author = "Fletcher, {Alexander J} and Jennifer Nash and Maaz Syed and Mark Macaskill and Tavares, {Adriana A S} and Niki Walker and Hannah Salcudean and Leipsic, {Jonathon A.} and Kelvin Lim and Jillian Madine and William Wallace and Mark Field and Newby, {David E} and Rihab Bouchareb and Michael Seidman and Riaz Akhtar and Stephanie Sellers",

note = "Funding Information: The authors acknowledge the involvement of Othman, Nawaytou, Harrington, and Kuduvalli in tissue collection and the Aortic Fellows in the consenting process at the Liverpool Heart and Chest Hospital. The authors also would like to thank Drs Ya Hua Chim and Hannah Davies for assisting with the biomechanical and biochemical analysis at Liverpool. The authors also acknowledge the assistance of Edinburgh Imaging facilities supported by the National Health Service Research Scotland through the National Health Service Lothian Health Board and Craig Marshall and the BioResource team at the Royal Infirmary of Edinburgh. For the purpose of open access, the author has applied a Creative Commons Attribution (CC-BY) licence to any author accepted manuscript version arising from this submission. Funding Information: A.J. Fletcher (FS/19/15/34155), M.G. Macaskill (RG/16/10/32375 and PG/17/83/33370), and D.E. Newby is supported by the British Heart Foundation (CH/09/002, RG/16/10/32375, and RE/18/5/34216) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Biomechanical and biochemical assessment was supported by the British Heart Foundation to R. Akhtar and J. Madine, respectively (PG/16/107/32681 and FS/12/61/29877). A.A.S. Tavares is funded by the British Heart Foundation (FS/19/34/34354). A.A.S. Tavares is a recipient of a Wellcome Trust Technology Development Award (221295/Z/20/Z). S. Sellers is supported by a Providence Health Care Research Institute Early Career Initiative. Publisher Copyright: {\textcopyright} 2022 American Heart Association, Inc.",

year = "2022",

month = jun,

day = "30",

doi = "10.1161/ATVBAHA.122.317111",

language = "English",

journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",

issn = "1079-5642",

publisher = "Lippincott Williams & Wilkins",

}

Fletcher, AJ, Nash, J, Syed, M, Macaskill, M , Tavares, AAS , Walker, N, Salcudean, H, Leipsic, JA, Lim, K, Madine, J, Wallace, W, Field, M, Newby, DE, Bouchareb, R, Seidman, M, Akhtar, R & Sellers , S 2022, 'Microcalcification and thoracic aortopathy: a window into disease severity', Arteriosclerosis, Thrombosis, and Vascular Biology. https://doi.org/10.1161/ATVBAHA.122.317111

TY - JOUR

T1 - Microcalcification and thoracic aortopathy: a window into disease severity

AU - Fletcher, Alexander J

AU - Nash, Jennifer

AU - Syed, Maaz

AU - Macaskill, Mark

AU - Tavares, Adriana A S

AU - Walker, Niki

AU - Salcudean, Hannah

AU - Leipsic, Jonathon A.

AU - Lim, Kelvin

AU - Madine, Jillian

AU - Wallace, William

AU - Field, Mark

AU - Newby, David E

AU - Bouchareb, Rihab

AU - Seidman, Michael

AU - Akhtar, Riaz

AU - Sellers , Stephanie

N1 - Funding Information: The authors acknowledge the involvement of Othman, Nawaytou, Harrington, and Kuduvalli in tissue collection and the Aortic Fellows in the consenting process at the Liverpool Heart and Chest Hospital. The authors also would like to thank Drs Ya Hua Chim and Hannah Davies for assisting with the biomechanical and biochemical analysis at Liverpool. The authors also acknowledge the assistance of Edinburgh Imaging facilities supported by the National Health Service Research Scotland through the National Health Service Lothian Health Board and Craig Marshall and the BioResource team at the Royal Infirmary of Edinburgh. For the purpose of open access, the author has applied a Creative Commons Attribution (CC-BY) licence to any author accepted manuscript version arising from this submission. Funding Information: A.J. Fletcher (FS/19/15/34155), M.G. Macaskill (RG/16/10/32375 and PG/17/83/33370), and D.E. Newby is supported by the British Heart Foundation (CH/09/002, RG/16/10/32375, and RE/18/5/34216) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Biomechanical and biochemical assessment was supported by the British Heart Foundation to R. Akhtar and J. Madine, respectively (PG/16/107/32681 and FS/12/61/29877). A.A.S. Tavares is funded by the British Heart Foundation (FS/19/34/34354). A.A.S. Tavares is a recipient of a Wellcome Trust Technology Development Award (221295/Z/20/Z). S. Sellers is supported by a Providence Health Care Research Institute Early Career Initiative. Publisher Copyright: © 2022 American Heart Association, Inc.

PY - 2022/6/30

Y1 - 2022/6/30

N2 - ObjectivePatients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established.Approach and ResultsOne hundred and one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathological scores, immunohistochemistry and nanoindentation (tissue elastic modulus) were compared to the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography. Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate histopathological degeneration (n=30; 3.74 [0.87, to 11.80], p<0.042) compared with control samples (n=18, 0.79 [0.36 to 1.90]). Alkaline phosphatase (n=26, p=0.0019) and osteopontin (n=26, p=0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathological degeneration was related to reduced microcalcification (n=82, Spearman’s rho -0.51, p<0.0001), a process closely linked with elastin loss (n=82; Spearman’s rho = -0.43, p<0.0001) and lower tissue elastic modulus (n=28; Spearman’s rho = 0.43, p=0.026). 18F-Sodium fluoride autoradiography demonstrated very good correlation with histologically quantified microcalcification (n=66; r=0.76, p<0.001), and identified areas of focal weakness in vivo.ConclusionsMedial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification. 18F-Sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible non-invasive imaging modality for identifying aortic wall disruption with major translational promise.

AB - ObjectivePatients with thoracic aortopathy are at increased risk of catastrophic aortic dissection, carrying with it substantial mortality and morbidity. Although granular medial calcinosis (medial microcalcification) has been associated with thoracic aortopathy, its relationship to disease severity has yet to be established.Approach and ResultsOne hundred and one thoracic aortic specimens were collected from 57 patients with thoracic aortopathy and 18 control subjects. Standardized histopathological scores, immunohistochemistry and nanoindentation (tissue elastic modulus) were compared to the extent of microcalcification on von Kossa histology and 18F-sodium fluoride autoradiography. Microcalcification content was higher in thoracic aortopathy samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate histopathological degeneration (n=30; 3.74 [0.87, to 11.80], p<0.042) compared with control samples (n=18, 0.79 [0.36 to 1.90]). Alkaline phosphatase (n=26, p=0.0019) and osteopontin (n=26, p=0.0045) staining were increased in tissue with early aortopathy. Increasingly severe histopathological degeneration was related to reduced microcalcification (n=82, Spearman’s rho -0.51, p<0.0001), a process closely linked with elastin loss (n=82; Spearman’s rho = -0.43, p<0.0001) and lower tissue elastic modulus (n=28; Spearman’s rho = 0.43, p=0.026). 18F-Sodium fluoride autoradiography demonstrated very good correlation with histologically quantified microcalcification (n=66; r=0.76, p<0.001), and identified areas of focal weakness in vivo.ConclusionsMedial microcalcification is a marker of aortopathy, although progression to severe aortopathy is associated with loss of both elastin fibers and microcalcification. 18F-Sodium fluoride positron emission tomography quantifies medial microcalcification and is a feasible non-invasive imaging modality for identifying aortic wall disruption with major translational promise.

U2 - 10.1161/ATVBAHA.122.317111

DO - 10.1161/ATVBAHA.122.317111

M3 - Article

SN - 1079-5642

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

ER -

Microcalcification and thoracic aortopathy: a window into disease severity

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Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET)

Myocardial Fibrosis And Left Ventricular Remodelling In Cardiovascular Disease

Dissecting activation, heterogeneity and crosstalk of PDGFRa/b+ cells in valvular stenosis and left ventricular remodelling following aortic stenosis

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Edinburgh Preclinical Imaging

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