The Aortic Pathologies: How Far We Understand It and Its Implications on Thoracic Aortic Surgery

Harky, Amer; Sokal, Pawel Aleksander; Hasan, Khubbaib; Papaleontiou, Andreas

doi:10.21470/1678-9741-2020-0089

Amer Harky Correspondence Address: Amer Harky, https://orcid.org/0000-0001-5507-5841, Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Thomas Drive - L14 3PE, Liverpool, United Kingdom. E-mail: aaharky@gmail.com

MRCS, MSc

Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom.

School of Medicine, University of Liverpool, Liverpool, United Kingdom.

Liverpool Centre for Cardiovascular Science, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

http://orcid.org/0000-0001-5507-5841

Pawel Aleksander Sokal

School of Medicine, University of Liverpool, Liverpool, United Kingdom.

Khubbaib Hasan

School of Medicine, University of Liverpool, Liverpool, United Kingdom.

Andreas Papaleontiou

School of Medicine, University of Liverpool, Liverpool, United Kingdom.

Correspondence Address: Amer Harky, https://orcid.org/0000-0001-5507-5841, Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Thomas Drive - L14 3PE, Liverpool, United Kingdom. E-mail: aaharky@gmail.com

No conflict of interest.

Figures (4)
Tables (9)

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Fig. 1
Immunopathology of the arterial wall in vasculitis. DEND=dendritic cell; GC=giant cell; HLA=human leukocyte antigen; IFN-γ=interferon gamma; IL=interleukin; MMPs=matrix metalloproteinases; PDGF=platelet-derived growth factor; ROIs=regions of interest; Th=T helper; TLR=Toll-like receptor; TNFα=tumour necrosis factor alpha; VEGF=vascular endothelial growth factor

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Fig. 2
Current understanding of the pathogenesis of Takayasu’s arteritis^[⁹9 Howard DP, Sideso E, Handa A, Rothwell PM. Incidence, risk factors, outcome and projected future burden of acute aortic dissection. Ann Cardiothorac Surg. 2014;3(3):278-84. doi:10.3978/j.issn.2225-319X.2014.05.14.
https://doi.org/10.3978/j.issn.2225-319X... ^]. ADCC=antibody-dependent cellular cytotoxicity; IFN-γ=interferon gamma; IL=interleukin; LPS=lipopolysaccharide; MMPs=matrix metalloproteinases; NK=natural killer; Th=T helper; TLRs=Toll-like receptors; TNFα=tumour necrosis factor alpha.

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Fig. 3
Illustrating diagram of acute aortic syndrome (AAS). Arrows indicate the possible progression of each of these aortic lesions^[²⁴24 Gornik HL, Creager MA. Aortitis. Circulation. 2008;117(23):3039-51. doi:10.1161/CIRCULATIONAHA.107.760686.
https://doi.org/10.1161/CIRCULATIONAHA.1... ^].

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Fig. 4
Classification of thoracic aortic aneurysm and dissection (TAAD) where percentage values refer to approximate prevalence. EDS=Ehlers-Danlos syndrome; LDS=Loeys-Dietz syndrome; MFS=Marfan syndrome^[³⁹39 Ostberg NP, Zafar MA, Ziganshin BA, Elefteriades JA. The genetics of thoracic aortic aneurysms and dissection: a clinical perspective. Biomolecules. 2020;10(2):182. doi:10.3390/biom10020182.
https://doi.org/10.3390/biom10020182... ^].

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Abbreviations, acronyms & symbols AA = Aortic aneurysm MMPs = Matrix metalloproteinases AAA = Abdominal aortic aneurysm MRI = Magnetic resonance imaging AAS = Acute aortic syndrome NA = No conclusive evidence ACE = Angiotensin-converting enzyme NK = Natural killer AD = Aortic dissection NT-proBNP = N-terminal pro B-type natriuretic peptide ADCC = Antibody-dependent cellular cytotoxicity PAU = Penetrating aortic ulcer ATS = Arterial tortuosity syndrome PDFG = Platelet-derived growth factor BAV = Bicuspid aortic valve RNA = Ribonucleic acid CRP = C-reactive protein ROIs = Regions of interest CT = Computer tomography SGS = Shprintzen-Goldberg syndrome DEND = Dendritic cell TA = Takayasu's arteritis ECM = Extracellular matrix TAA = Thoracic aortic aneurysm EDS = Ehlers-Danlos syndrome TAAD = Thoracic aortic aneurysm and dissection FL = False lumen TEVAR = Thoracic endovascular aortic repair GC = Giant cell TGF-β = Transforming growth factor beta GCA = Giant-cell arteritis Th = T helper HLA = Human leukocyte antigen TL = True lumen HTAD = Heritable thoracic aortic diseases TLR = Toll-like receptor IFN-γ = Interferon gamma TNFα = Tumour necrosis factor alpha IL = Interleukin TOE = Transoesophageal echocardiography IMH = Intramural haematoma TS = Turner syndrome LDS = Loeys-Dietz syndrome VEGF = Vascular endothelial growth factor LPS = Lipopolysaccharide VSRR = Valve-sparing root replacement LVV = Large vessel vasculitides WSS = Wall shear stress MFS = Marfan syndrome

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Table 1
Composition and function of the layers of a blood vessel.

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Table 2
Summary table highlighting the differences between Takayasu's arteritis and giant-cell arteritis.

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Table 3
Criteria for diagnosis of giant-cell arteritis.

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Table 4
The HTAD genes.

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Table 5
Genetic and non-genetic causes of thoracic aortic pathologies.

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Table 6
Potential TAA biomarkers.

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Table 7
Class I and Class IIa recommendations on maximal aortic diameter cutoff for treatment of aortic aneurysm in asymptomatic patients^[⁶⁷67 Hiratzka LF, Bakris GL, Beckman JA, Bersin RM, Carr VF, Casey DE Jr, et al. 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease. A report of the American college of cardiology foundation/American heart association task force on practice guidelines, American association for thoracic surgery, American college of radiology, American stroke association, society of cardiovascular anesthesiologists, society for cardiovascular angiography and interventions, society of interventional radiology, society of thoracic surgeons, and society for vascular medicine. J Am Coll Cardiol. 2010;55(14):e27-e129. Erratum in: J Am Coll Cardiol. 2013;62(11):1039-40. doi:10.1016/j.jacc.2010.02.015.
https://doi.org/10.1016/j.jacc.2010.02.0... ^,⁸⁹89 Nagpal P, Khandelwal A, Saboo SS, Bathla G, Steigner ML, Rybicki FJ. Modern imaging techniques: applications in the management of acute aortic pathologies. Postgrad Med J. 2015;91(1078):449-62. doi:10.1136/postgradmedj-2014-133178.
https://doi.org/10.1136/postgradmedj-201... ^].

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Authors' roles & responsibilities AH Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published PAS Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published KH Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published AP Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published

Abbreviations, acronyms & symbols
AA	= Aortic aneurysm	MMPs	= Matrix metalloproteinases
AAA	= Abdominal aortic aneurysm	MRI	= Magnetic resonance imaging
AAS	= Acute aortic syndrome	NA	= No conclusive evidence
ACE	= Angiotensin-converting enzyme	NK	= Natural killer
AD	= Aortic dissection	NT-proBNP	= N-terminal pro B-type natriuretic peptide
ADCC	= Antibody-dependent cellular cytotoxicity	PAU	= Penetrating aortic ulcer
ATS	= Arterial tortuosity syndrome	PDFG	= Platelet-derived growth factor
BAV	= Bicuspid aortic valve	RNA	= Ribonucleic acid
CRP	= C-reactive protein	ROIs	= Regions of interest
CT	= Computer tomography	SGS	= Shprintzen-Goldberg syndrome
DEND	= Dendritic cell	TA	= Takayasu's arteritis
ECM	= Extracellular matrix	TAA	= Thoracic aortic aneurysm
EDS	= Ehlers-Danlos syndrome	TAAD	= Thoracic aortic aneurysm and dissection
FL	= False lumen	TEVAR	= Thoracic endovascular aortic repair
GC	= Giant cell	TGF-β	= Transforming growth factor beta
GCA	= Giant-cell arteritis	Th	= T helper
HLA	= Human leukocyte antigen	TL	= True lumen
HTAD	= Heritable thoracic aortic diseases	TLR	= Toll-like receptor
IFN-γ	= Interferon gamma	TNFα	= Tumour necrosis factor alpha
IL	= Interleukin	TOE	= Transoesophageal echocardiography
IMH	= Intramural haematoma	TS	= Turner syndrome
LDS	= Loeys-Dietz syndrome	VEGF	= Vascular endothelial growth factor
LPS	= Lipopolysaccharide	VSRR	= Valve-sparing root replacement
LVV	= Large vessel vasculitides	WSS	= Wall shear stress
MFS	= Marfan syndrome

Layer	Composition	Function
Intima	It's the innermost layer and it is composed of a single layer of endothelial cells, a thin basal membrane, and a subendothelial layer of collagen fibrils	To provide a smooth surface for the blood to flow
Media	It's the middle layer and it is composed of elastic and collagen fibrils, smooth muscle, and elastic laminae separating the layer into transversely isotopic fibre-reinforced units	It allows expansion and contraction of the artery
Adventitia	It's the outermost layer, which is composed of thick bundles of collagen fibrils arranged in a helical structure and loose connective tissue	It provides support and structure

	Takayasu's arteritis	Giant-cell arteritis
Peak age of onset, years	15-30	60-80
Female:male ratio	9:1^[⁸⁶86 Watts R, Al-Taiar A, Mooney J, Scott D, Macgregor A. The epidemiology of takayasu arteritis in the UK. Rheumatology (Oxford). 2009;48(8):1008-11. doi:10.1093/rheumatology/kep153. https://doi.org/10.1093/rheumatology/kep... ^]	03:01
Racial predisposition	Eastern Asia (Japan)^[⁸⁷87 Kerr GS, Hallahan CW, Giordano J, Leavitt RY, Fauci AS, Rottem M, et al. Takayasu arteritis. Ann Intern Med. 1994;120(11):919-29. doi:10.7326/0003-4819-120-11-199406010-00004. https://doi.org/10.7326/0003-4819-120-11... ^]	Caucasian (northern Europe)
Common presentation	Symptoms of aortic branch occlusion	Headache
Common presentation	Symptoms of aortic branch occlusion	Visual impairment
Aorta affected, %	100%	40%
Common histological appearance	Excessive adventitial fibrosis Well-circumscribed intimal fibrocellular hyperplasia Increased vessel wall thickness	Prominent inflammation of inner media and intima
		Fragmentation of internal elastic lamina
		Focal aortic wall inflammation with "skip lesions"
Common genetic association	HLA-B52	HLA-DR4
Common genetic association	Non-HLA (ILI2B region)	HLA-DR4
Immunopathological features	Activation of adventitial dendritic cells
	Recruitment of activation of CD4+ T lymphocytes
	Macrophage activation with giant cell formation and release of pro-inflammatory cytokines
	Neovascularisation and intimal hyperplasia
Aetiological trigger	Unknown: maybe infective agent or autoantigen

Criterion	Definition
Age of patient at disease onset in years	Development of symptoms (headache, scalp tenderness, polymyalgia rheumatica, jaw pain, and vision changes) or findings related to giant-cell arteritis at age < 40 years
Claudication of extremities	Development and worsening of fatigue and discomfort in muscles of one or more extremity while in use, especially the upper extremities
Decreased brachial artery pulse	Decreased pulsation of both brachial arteries
Blood pressure difference -10 mmHg	Difference of > 10 mmHg in systolic blood pressure between arms
Bruit over subclavian arteries or aorta	Bruits audible on auscultation over one or both subclavian arteries or abdominal aorta
Arteriogram abnormality	Arteriographic narrowing or occlusion of the entire aorta, its primary branches, or large arteries in the proximal upper or lower extremities, not due to arteriosclerosis, fibromuscular dysplasia, or similar causes. Changes are usually focal or segmental.

Gene (locus)	Proportion of families with HTAD and with a pathogenic variant in this gene	Syndrome	Other cardiovascular findings observed
ACTA2	12-21%	Multisystem smooth muscle dysfunction syndrome
BGN	Rare	Meester-Loeys syndrome (OMIM 300989)
COL3A1	Rare	Ehlers-Danlos syndrome type IV
FBN1	3%	Marfan syndrome
FOXE3	1.4%
LOX	1.5%		Bicuspid aortic valve, abdominal aortic aneurysm, hepatic artery aneurysm
MAT2A	1%		Bicuspid aortic valve
MFAP5	0.25%		Atrial fibrillation, mitral valve prolapse, and arterial tortuosity in some patients
MYH11	1%		Patent ductus arteriosus
MYLK	1%
PRKG1	1%		Coronary artery aneurysm/dissection and arterial tortuosity in some patients
TGFB2	1%	Loeys-Dietz syndrome	Abdominal aortic aneurysms and/or intracranial and other arterial aneurysms and/or dissections
TGFB3	2 simplex cases, one 3-generation family	Rienhoff syndrome or Loeys-Dietz syndrome type 5
TGFBR1	3%	Loeys-Dietz syndrome	Abdominal aortic aneurysms and/or intracranial and other arterial aneurysms and/or dissections
TGFBR2	5%	Loeys-Dietz syndrome
SMAD3	2%	Aneurysms osteoarthritis syndrome; Loeys-Dietz syndrome
(AAT1 or FAA1)	Unknown
AAT2 or TAAD1	Unknown

	Causative genetic disorders	Other
Thoracic aortic aneurysm	Ehlers-Danlos syndrome	Non-syndromic mutations to genes such as MYH11 and ACTA2
	Marfan syndrome	Mutations leading to excessive production of MMPs
	Loeys-Dietz syndrome	Mutation in one of the heritable thoracic aortic diseases (HTAD) genes
	Turner's syndrome	Racial differences relating to hypertension
Acute aortic syndrome	Bicuspid aortic valve	Non-syndromic mutations to genes such as MYH11 and ACTA2
		Mutations leading to excessive production of MMPs
		Racial differences relating to hypertension

Biomarker	Use for diagnosis of aneurysm	Use for prediction of growth or rupture	Aortic segment involved	Comments
D-Dimer	No	No	AAA, TAA	Can be used to exclude acute aortic event in symptomatic patients
CRP, IL-6, and leucocytes	Possible	Possible	AAA, TAA	Non-specific
Homocysteine	NA	NA	TAA	Correlates with degree of atherosclerosis
Lipoprotein (a)	NA	NA	TAA	Needs further investigation
Collagen markers	Possible	NA	TAA	Tested clinically in a small study
Elastin markers	Potential	Potential	AAA	Needs to be tested in TAA
Fibrillin	Potential	Potential	TAA	Need further investigation
MMPs	Possible	NA	AAA, TAA	Strong diagnostic value shown in a small study, possibly useful for evaluation of success of treatment
ACE	NA	NA	AAA, TAA	Needs further investigation and clinical trials
41-gene expression signature	Possible	NA	TAA	Promising, needs further clinical trials
TGF-β	Potential	NA	AAA, TAA	Needs clinical trials
CLU, DES, MYH10, and FBLN5 genes	Possible	NA	TAA	Needs clinical trials
Deregulated micro RNA and messenger RNA^[⁸⁸88 Abu-Halima M, Kahraman M, Henn D, Rädle-Hurst T, Keller A, Abdul-Khaliq H, et al. Deregulated microRNA and mRNA expression profiles in the peripheral blood of patients with marfan syndrome. J Transl Med. 2018;16(1):60. doi:10.1186/s12967-018-1429-3. https://doi.org/10.1186/s12967-018-1429-... ^]	NA	NA	TAA	Needs clinical trials
Mean telomere length of leucocytes	NA	NA	TAA	Sporadic TAA detection^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]
Endothelin	Possible	Possible	AAA	Correlation with size of aneurysm
Fibulins	NA	NA	TAA	Potential detection of TAA at an early stage^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]
Filamins	NA	NA	TAA	Correlation with connective tissue disorders and BAV^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]
Osteopontin	NA	NA	TAA	Needs further investigation and clinical trials
Platelet-derived growth factor B	Possible	NA	TAA	Needs further investigation and clinical trials
Haemostatic markers (plasminogen, fibrinogen)	NA	NA	AAA	Distinguish acutely symptomatic non-ruptured AAAs from ruptured AAAs^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]
Thrombospondin-2^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]	NA	NA	TAA
Interferons	NA	NA	TAA	Potentially useful in early detection of TAA^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]
SMAD	NA	NA	TAA	Presence in familial TAAs and in aneurysm osteoarthritis syndrome
NT-proBNP	NA	NA	TAA	May detect TAAs^[⁵⁷57 van Bogerijen GH, Tolenaar JL, Grassi V, Lomazzi C, Segreti S, Rampoldi V, et al. Biomarkers in TAA-the holy grail. Prog Cardiovasc Dis. 2013;56(1):109-15. doi:10.1016/j.pcad.2013.05.004. https://doi.org/10.1016/j.pcad.2013.05.0... ^]

Ascending aortic or aortic sinus aneurysm
≥ 55 mm	▸Patients with no aortopathy
≥ 55 mm	▸BAV without risk factors*
≥ 50 mm	▸BAV with risk factor*
≥ 50 mm	▸Marfan syndrome with no other risk factor†
≥ 45 mm	▸Marfan syndrome with risk factors†
≥ 45 mm	▸Patients with BAV undergoing surgical aortic valve repair
≥ 44-46 mm	▸LDS measured with TOE
≥ 42 mm	▸LDS measured with CT or MRI
Aortic arch aneurysm
≥ 55 mm	Isolated arch aneurysm (may be planned earlier if adjacent ascending or descending thoracic aortic aneurysm repair is planned)
Descending thoracic aortic aneurysm
≥ 55 mm	If anatomy is suitable for thoracic endovascular stent repair
≥ 60 mm	Surgical repair when anatomy is not suitable for stent repair

Authors' roles & responsibilities
AH	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published
PAS	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published
KH	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published
AP	Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published

[1] Correspondence Address: Amer Harky, https://orcid.org/0000-0001-5507-5841, Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Thomas Drive - L14 3PE, Liverpool, United Kingdom. E-mail: aaharky@gmail.com

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The Aortic Pathologies: How Far We Understand It and Its Implications on Thoracic Aortic Surgery

Abstract