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Middle Aortic Syndrome and Renal Artery Stenosis:
Disease beyond the Arch
by
Rawan K. Rumman
A thesis submitted in conformity with the requirements
for the degree of Doctor of Philosophy
Institute of Medical Science, Cardiovascular Sciences Collaborative Program
University of Toronto
© Copyright by Rawan K. Rumman 2016
ii
Middle Aortic Syndrome and Renal Artery Stenosis:
Disease beyond the Arch
Rawan K. Rumman
Doctor of Philosophy
Institute of Medical Science, Cardiovascular Sciences Collaborative Program
University of Toronto
2016
Abstract
Background
Middle aortic syndrome (MAS) is a rare childhood disease, often associated with renal artery
stenosis (RAS). The etiology is unknown in most cases, but genetic and inflammatory causes
have been described. Management of the associated hypertension can be medical, endovascular,
or surgical, with variable success.
Aims
Our aims were to 1) evaluate management, and outcomes of MAS and/or RAS by etiology; 2)
assess the peripheral vascular involvement and aortic disease; and 3) evaluate cardiac structure,
function, and myocardial mechanics.
Methods
Aim 1: we conducted a systematic review of 630 MAS cases, and a retrospective cohort study of
93 children with MAS and/or RAS managed at the Hospital for Sick Children (HSC). Aim 2: a
cross-sectional prospective study of 35 children with MAS and/or RAS was initiated at HSC
(2014-2016). Carotid intima-media thickness (CIMT) and pulse wave velocity (PWV) were
iii
assessed using B-mode ultrasound and applanation tonometry. Aim 3: two-dimensional
echocardiography and speckle-tracking echocardiography were used to assess left ventricular
mass (LVM), diastolic function (E/a ratio) and myocardial strain. All cardiovascular
measurements were compared to age, sex, and body surface area- matched healthy children.
Results
Of 630 cases in the literature, 70% had RAS, and the aortic disease was confined to the peri-
renal aorta. Of 93 children managed at HSC, 70% received endovascular or surgical intervention,
with a higher risk of intervention in children with unknown disease compared to those with
genetic and inflammatory causes (HR=3, 95% CI [2,6]). Hypertension persisted in 65% of all
patients for 2 [0.4-5] years after management. CIMT was increased in children with MAS and/or
RAS compared to controls (0.54±0.10 vs. 0.44±0.05 mm, p<0.001), but peripheral PWV was
preserved. Cardiac examination revealed significantly increased LVM, preserved myocardial
strain, and mildly reduced E/a ratio compared to healthy children.
Conclusion
MAS is a narrowing of the peri-renal segment of the aorta with a high propensity for RAS.
Hypertension persists despite medical or endovascular/surgical management. Structural vascular
and ventricular changes are already present in children, with subtle changes in diastolic function.
There is no evidence of peripheral arterial disease suggesting that MAS/RAS is localized, with
hypertensive changes in the carotid arteries and left ventricle which warrant prospective
monitoring.
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Acknowledgments
I would like to thank my academic supervisor Dr. Rulan Parekh, for her incredible
support and guidance for the past 3 years. Since the beginning of my training, Dr. Parekh
encouraged me to pursue my interest in cardiac physiology, motivated me to expand the scope of
my research, and provided me with countless opportunities to develop my intellectual curiosity.
This work would not have been possible without Dr. Luc Mertens’ dedicated mentorship
and superb teaching. He provided invaluable insight to my project, and the unique opportunity to
learn echocardiography. Working under the tutelage of Dr. Mertens and attending cardiology
clinics have enriched my graduate experience and furthered my interest in pediatric cardiology.
I would also like to thank my collaborators, Drs. Joao Amaral, Armando Lorenzo,
Valerie Langlois, Mina Matsuda-Abedini, and Seetha Radhakrishnan for their mentorship,
critical review of my work, and most importantly, for taking an interest in my learning. I would
also like to thank the Nephrology clinic staff for welcoming me as an observer for the last 3
years, attending clinic and interacting with staff was instrumental to my training.
On a personal note, I would like to thank my parents, Khaled and Daisy Rumman, for
their unwavering support and for setting the best example of perseverance. Thank you to my
brothers, Amir and George, and sisters Madge and Diana, for their nurturing support and
patience over the past 3 years. A special thank you to my best friend, Marshall Rossiter, for his
tremendous support and motivation. Thank you to my friend Esther D. Kim for her heartfelt
encouragement and support.
I wish to thank my advisory committee members, Dr. Ronald Cohn, Dr. Mark Friedberg,
and Dr. Andrew Redington for taking time out of their busy schedules to provide outstanding
mentorship and critical feedback on my work.
Finally, I wish to take the time to thank all the children and their families who took the
time to participate in my research study. I cherish the time I spent with them in Nephrology
clinic and the echocardiography laboratory. My research would not have been possible without
their enthusiasm and participation. I dedicate this work to them.
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Contributions
Rawan K. Rumman (author) solely prepared this thesis. All of the following aspects of this body
of work were performed by the author: planning and study design, execution (patient
recruitment, data collection, and echocardiographic measurements of children with aortic
disease), statistical analysis, and writing of all research and publications. The following
contributors are acknowledged:
Cameron Slorach (cardiovascular sonographer)- image acquisition, vascular measurements,
echocardiographic measurements of healthy controls, and assisting in echocardiographic
measurements of children with aortic disease (Chapters 3 and 4)
Wei Hui (cardiovascular sonographer)- image acquisition and vascular measurements (Chapters
3 and 4)
Cheri Nickel (librarian)- assisting with developing and writing of the search protocol (Chapter 1)
Erin Warkentin (medical illustrator)- developing Figure 1.2 (Chapter 1)
Drs. Parekh, Mertens, Amaral, Lorenzo, Langlois, Matsuda-Abedini, and Radhakrishnan-
guidance and assistance in editing of manuscripts
This research was supported in part by the Canadian Institutes of Health Research through the
Frederick Banting and Charles Best Canada Graduate Scholarship (2014-2015)
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List of Abbreviations
MAS: Middle Aortic Syndrome
RAS: Renal artery stenosis
FMD: Fibromuscular dysplasia
SMA: Superior mesenteric artery
IMA: Inferior mesenteric artery
BP: blood pressure
PTA: percutaneous transluminal angioplasty
CIMT: Carotid intima-media thickness
PWV: Pulse wave velocity
LV: left ventricle
The list of abbreviations only includes the abbreviations used in the text portion of this thesis.
All abbreviations used in tables and figures are described in the footnotes and legends.
The international system of units (SI) and the designated units of measure were used throughout
this body of work
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Table of Contents
Acknowledgments.......................................................................................................................... iv
Contributions....................................................................................................................................v List of Abbreviations ..................................................................................................................... vi Table of Contents .......................................................................................................................... vii List of Tables ................................................................................................................................. ix List of Figures ................................................................................................................................ xi
List of Appendices ....................................................................................................................... xiii
Chapter 1 A Systematic Review of Middle Aortic Syndrome in Childhood .................................1 1.1 Introduction ..........................................................................................................................2 1.2 Methods................................................................................................................................4
1.2.1 Search strategy and selection criteria .......................................................................4 1.2.2 Data extraction and analysis ....................................................................................5
1.3 Results ..................................................................................................................................7 1.3.1 Study selection .........................................................................................................7
1.3.2 Patient characteristics.............................................................................................19 1.3.3 Etiology and associated diagnoses .........................................................................19 1.3.4 Aortic vessel disease ..............................................................................................21
1.3.5 Extra-aortic vessel involvement .............................................................................21 1.3.6 Medical management .............................................................................................26
1.3.7 Endovascular and surgical intervention .................................................................26 1.3.8 Follow-up and blood pressure control ...................................................................30
1.4 Discussion ..........................................................................................................................32
1.5 Limitations .........................................................................................................................35
1.6 Conclusion .........................................................................................................................36 1.7 Gaps in knowledge .............................................................................................................37 1.8 Conceptual model ..............................................................................................................41
1.8.1 Vascular remodelling in hypertension ...................................................................41 1.8.2 Pressure wave propagation and reflection .............................................................42 1.8.3 Hypertension and Left Ventricular Function .........................................................45
1.8.4 Ventricular-Arterial Coupling ................................................................................46 1.9 Aims and Hypotheses ........................................................................................................49 1.10 Overview of thesis structure .............................................................................................50
Chapter 2 Evaluation, Management, and Outcomes of MAS/RAS .............................................55
2.1 Introduction ........................................................................................................................56
2.2 Material and methods .........................................................................................................57
2.2.1 Patient population and inclusion criteria................................................................57 2.2.2 Data collection .......................................................................................................57 2.2.3 Statistical analysis ..................................................................................................59
2.3 Results ................................................................................................................................61 2.3.1 Clinical characteristics at presentation...................................................................61 2.3.2 Vascular phenotype ................................................................................................63 2.3.3 Management and post-operative outcomes ............................................................66
viii
2.3.4 Follow-up ...............................................................................................................73
2.3.5 Era effect ................................................................................................................79 2.4 Discussion ..........................................................................................................................81 2.5 Limitations .........................................................................................................................87
2.6 Conclusion .........................................................................................................................88
Chapter 3 Aortic and Peripheral Vascular Disease in Childhood MAS/RAS ..............................89 3.1 Introduction ........................................................................................................................90 3.2 Material and methods .........................................................................................................92
3.2.1 Patient recruitment and inclusion criteria ..............................................................92 3.2.2 Vascular measurements .........................................................................................93 3.2.3 Statistical analysis ..................................................................................................95
3.3 Results ................................................................................................................................96
3.3.1 Patient characteristics.............................................................................................96 3.3.2 Vascular properties ................................................................................................97
3.4 Discussion ........................................................................................................................112 3.5 Limitations .......................................................................................................................117
3.6 Conclusion .......................................................................................................................118
Chapter 4 Cardiac Structure, Function, and Myocardial Mechanics .........................................119
4.1 Introduction ......................................................................................................................120 4.2 Material and methods .......................................................................................................122
4.2.1 Patient recruitment and inclusion criteria ............................................................122 4.2.2 Echocardiography ................................................................................................123 4.2.3 Clinical data .........................................................................................................125
4.2.4 Statistical analysis ................................................................................................125
4.3 Results ..............................................................................................................................126 4.3.1 Patient characteristics...........................................................................................126 4.3.2 LV geometry and systolic function ......................................................................129
4.3.3 Diastolic function .................................................................................................129 4.3.4 Baseline cardiac measurements ...........................................................................136
4.4 Discussion ........................................................................................................................138 4.5 Limitations .......................................................................................................................140
4.6 Conclusion .......................................................................................................................140
Chapter 5 Discussion, Conclusions, and Future Directions .......................................................141 5.1 General discussion and implications ................................................................................142
5.1.1 Diagnosis, etiology, and management .................................................................142
5.1.2 Extent of vascular disease ....................................................................................148 5.1.3 End-organ cardiac disease ....................................................................................153
5.2 Conclusions ......................................................................................................................157 5.3 Future directions ..............................................................................................................158
References ....................................................................................................................................164 Appendices ...................................................................................................................................188 Copyright Acknowledgements.....................................................................................................190
ix
List of Tables
Chapter 1 A Systematic Review of Middle Aortic Syndrome in Childhood
Table 1.1 Inclusion and exclusion criteria used for screening articles for systematic
review
Table 1.2 Characteristics of 184 journal articles on middle aortic syndrome in childhood
selected for inclusion
Table 1.3 Patient characteristics, presentation, and clinical findings in 630 children with
middle aortic syndrome
Table 1.4 Involvement of the aorta and visceral branches in 630 children with middle
aortic syndrome
Table 1.5 Involvement of the aorta and visceral branches in patients with middle aortic
syndrome by etiology
Table 1.6 Outcomes associated with medical, endovascular and surgical management of
middle aortic syndrome by etiology
Table 1.7 Outcomes associated with endovascular and surgical management of middle
aortic syndrome
Table 1.8 Follow up data reported for 630 cases of middle aortic syndrome in childhood
following endovascular and surgical treatment
Chapter 2 Evaluation, Management, and Outcomes of MAS/RAS
Table 2.1 Clinical characteristics of 93 children with MAS/RAS at the time of
presentation
Table 2.2 Aortic, visceral and extra-aortic involvement in 93 children with MAS/RAS by
underlying etiology
Table 2.3 Medical management in 93 children with MAS/RAS by underlying etiology
Table 2.4 Surgical management and outcomes in 93 children with MAS/RAS by
underlying etiology
Table 2.5 Endovascular management and outcomes in 93 children with MAS/RAS by
underlying etiology
Table 2.6 Association between etiology of disease and risk of interventions using Cox
regression analysis
x
Table 2.7 Follow-up and outcomes following management of 93 children with
MAS/RAS by underlying etiology
Table 2.8 Association between the longitudinal change in systolic blood pressure and
patient characteristics using linear mixed-effects analysis
Table 2.9 Characteristics of children with MAS/RAS by choice of invasive or non-
invasive management
Table 2.10 Characteristics of children with MAS/RAS by time period of presentation
Chapter 3 Aortic and Peripheral Vascular Disease in Childhood MAS/RAS
Table 3.1 Clinical characteristics of children with MAS and/or RAS and matched healthy
controls
Table 3.2 Vascular properties of children with MAS and/or RAS and matched healthy
controls
Table 3.3 Association between extent of disease and etiology with average common
carotid intima-media thickness (CIMT) by linear regression
Table 3.4 Association between extent of disease and etiology with carotid to radial pulse
wave velocity (PWV) by linear regression
Table 3.5 Association between extent of disease and etiology with average common
carotid intima media thickness (CIMT), and carotid to radial pulse wave velocity (PWV)
by linear regression in children with unknown vs. genetic etiology of disease
Table 3.6 Aortic properties in healthy controls and children with MAS/RAS at the time
of study enrollment
Chapter 4 Cardiac Structure, Function, and Myocardial Mechanics
Table 4.1 Clinical characteristics of children with MAS and/or RAS at the time of study
enrollment
Table 4.2 Left ventricular geometry and function in healthy controls and children with
MAS/RAS at the time of study enrollment
Table 4.3 Tissue Doppler and myocardial mechanics in healthy controls and children
with MAS/RAS at the time of study enrollment
Table 4.4 Baseline cardiac measurements in children with MAS and/or RAS at clinical
presentation compared to follow-up measurements at study enrollment
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List of Figures
Chapter 1 A Systematic Review of Middle Aortic Syndrome in Childhood
Figure 1.1 Flow chart of systematic review of published cases of middle aortic syndrome
in childhood
Figure 1.2 Involvement of the aorta, renal and visceral arteries in 630 reported cases of
middle aortic syndrome in childhood
Figure 1.3 A) Forward and backward wave propagation in normal physiology; B)
Enhanced Forward and backward wave propagation in chronic hypertension and arterial
stiffness; C) Early pressure wave reflections in aortic stenosis
Figure 1.4 Augmented blood pressure wave during systole as a result of enhanced wave
reflection
Figure 1.5 Conceptual model of the effect of MAS and/or RAS and the associated
hypertension on aortic and cardiac properties
Figure 1.6 Overview of overall study structure
Figure 1.7 Overview of study structure for Chapter 2
Figure 1.8 Overview of study structure for Chapter 3
Figure 1.9 Overview of study structure for Chapter 4
Chapter 2 Evaluation, Management, and Outcomes of MAS/RAS
Figure 2.1 Interventional procedures (endovascular or surgical) among MAS/RAS of
unknown, genetic, or inflammatory etiology of disease
Figure 2.2 Systolic blood pressure Z-score on annual follow-up by management type
Figure 2.3 New diagnoses of childhood MAS/RAS and number of endovascular
procedures performed by calendar year
Chapter 3 Aortic and Peripheral Vascular Disease in Childhood MAS/RAS
Figure 3.1 Box plots and linear regression analysis for average common carotid intima-
media thickness (CIMT) by vascular involvement (healthy control, isolated RAS: isolated
renal artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome)
Figure 3.2 Box plots and linear regression analysis for average common carotid intima-
media thickness (CIMT) by etiology (healthy control, unknown, systemic: genetic disease
including Williams’ syndrome, Neurofibromatosis I and Alagille syndrome, and
inflammatory disease including Takayasu’s arteritis and non-specific arteritis)
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Figure 3.3 Predicted average common carotid intima-media thickness (CIMT) using the
final multivariable linear model plotted against a range of systolic blood pressure
standard deviation scores, and stratified by extent of vascular disease (healthy control,
isolated RAS: isolated renal artery stenosis, RAS/MAS: renal artery stenosis with middle
aortic syndrome).
Figure 3.4 Box plots and linear regression analysis for carotid to radial pulse wave
velocity (PWV) by vascular involvement (healthy control, isolated RAS: isolated renal
artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome)
Figure 3.5 Box plots and linear regression analysis for carotid to radial pulse wave
velocity (PWV) by etiology (healthy control, unknown, systemic: genetic disease
including Williams’ syndrome, Neurofibromatosis I and Alagille syndrome, and
inflammatory disease including Takayasu’s arteritis and non-specific arteritis)
Chapter 4 Cardiac Structure, Function, and Myocardial Mechanics
Figure 4.1 Left ventricular mass Z-score for children with MAS/RAS (n=35) at the time
of clinical presentation and at study enrollment, compared to age, sex, and body surface
area-matched healthy controls
Figure 4.2 Average global longitudinal strain for children with MAS/RAS at the time of
clinical presentation (subgroup n=20) and at study enrollment (n=35), compared to age,
sex, and body surface area-matched healthy controls
Figure 4.3 Average circumferential strain for children with MAS/RAS at the time of
clinical presentation (subgroup n=20) and at study enrollment (n=35), compared to age,
sex, and body surface area-matched healthy controls
Figure 4.4 Mitral valve E/a ratio (B) for children with MAS/RAS (n=35) at the time of
clinical presentation and at study enrollment, compared to age, sex, and body surface
area-matched healthy controls
xiii
List of Appendices
Chapter 1 A Systematic Review of Middle Aortic Syndrome in Childhood
Appendix I. Search strategy used for systematic review
1
Chapter 1 A Systematic Review of Middle Aortic Syndrome in Childhood
This chapter is adapted from the following:
Rumman RK, Nickel C, Matsuda-Abedini M, Lorenzo AJ, Langlois V, Radhakrishnan S, Amaral
J, Mertens L, and Parekh RS. Disease Beyond the Arch: A Systematic Review of Middle Aortic
Syndrome in Childhood. Am J Hypertens. 2015;28:833-46.
2
1.1 Introduction
Middle aortic syndrome (MAS) is a rare disease that presents in children and young
adults, and constitutes 0.5-2% of all the cases of aortic stenosis(Cohen, 1988, Bliznak, 1974).
The majority of cases of MAS reveal a segmental or diffuse narrowing of the abdominal and/or
distal descending thoracic aorta, with varying involvement of renal and visceral branches. MAS
is an important cause of renovascular hypertension in children and adolescents(Sethna, 2008,
Tummolo, 2009, Lin, 2008).
Although MAS was first described almost six decades ago, the etiology of the disease
remains unknown and its pathogenesis largely speculative. The majority of cases of MAS are
idiopathic, but some cases have been described in association with genetic and acquired diseases.
MAS may be an embryological defect explained by failure of normal fusion of the two dorsal
aortas(Coleman, 2012, Bleacher, 1997, Cura, 2002); however, this has never been proven. MAS
may have a genetic cause, such as Neurofibromatosis (von Recklinghausen disease) type
I(Fossali, 2000, Criado, 2002, Booth, 2002, Bergdahl, 1980, Connolly, 2002), Alagille’s
syndrome(Quek, 2000, Raas-Rothschild, 2002), or Williams’ syndrome(Radford, 2000, Rose,
2001). It can also be associated with acquired inflammatory diseases such as Takayasu’s
arteritis(Connolly, 2002, Perera, 2013, Cakar, 2008), or intra-uterine infection (particularly
rubella)(Cohen, 1988, Siassi, 1970, Vaccaro, 1986). The clinical presentations for this rare
disease are similar based on case reports; however, it is not known whether the phenotype, extent
of aortic involvement, or response to medical and surgical management may differ by potential
etiology.
3
Children with MAS typically present with severe arterial hypertension, which can lead to
serious complications such as coronary artery disease, congestive heart failure, left ventricular
hypertrophy, and cerebrovascular accidents(Ayik, 2011). The symptoms vary depending on the
degree and location of vessel stenosis, although most patients exhibit symptoms of severe
renovascular hypertension, absent femoral pulses, abdominal bruit, and claudication of the lower
limbs(Annett, 2000, Adams, 1998, Barral, 2006, Bjoerk, 1964). Patients with long-standing
refractory hypertension may present with symptoms of hypertensive encephalopathy and
retinopathy(Tummolo, 2009, Delis, 2005, Porras, 2013).
Current management of MAS is aimed at controlling arterial blood pressure, preventing
long-term complications related to hypertension, and preserving end organ function (including
heart and kidneys). Treatment can be pharmacological, endovascular, or surgical. Although
pharmacological management with oral antihypertensives may be satisfactory in some cases
(those with mild to moderate aortic and/or renal stenosis)(Nasser, 2012, Bhatti, 2011), treatment
often involves surgical or endovascular procedures, with the severity of hypertension and/or
kidney impairment being the most common triggers for intervention(Barral, 2006, Bergamini,
1995, Bergentz, 1983, Delmo Walter, 2013). Several surgical interventions have been described
for this condition, including aorto-aortic bypass grafting, graft vascular replacement, patch
angioplasty, and renal auto transplantation(Barral, 2006, Delmo Walter, 2013, De Bakey, 1967,
Stanley, 1995, Stanley, 2008). Endovascular procedures such as percutaneous transluminal
angioplasty (PTA) with or without stenting have also been performed for the management of
MAS with varying success(Barral, 2006, Stanley, 2008, Lewis, 1988, Adwani, 1996, Brzezinska-
Rajszys, 1999, Eliason, 2001). The longevity of response to these procedures is always
4
concerning, particularly in children who may develop restenosis due to differential growth and
luminal discrepancies between normal and grafted, stented or balloon-dilated vessels.
MAS has been diagnosed and reported more frequently in recent years, likely due to
heightened awareness from clinicians and improved non-invasive diagnostic imaging
technologies such as ultrasound, multiplanar Computed Tomography (CT), and Magnetic
Resonance Imaging (MRI)(Sethna, 2008, Annett, 2000, De Bakey, 1967, Poulias, 1990). Still,
there is a paucity of information regarding the pathogenesis of MAS, clinical spectrum of the
disorder, and appropriate timing of endovascular or surgical intervention(Barral, 2006). In this
systematic review, we offer a literature-based description of the etiologies and clinical features of
MAS in children, outline the vascular involvement of the aorta and visceral branches, and
provide an overview of the medical, endovascular, and surgical management of MAS and their
clinical outcomes.
1.2 Methods
1.2.1 Search strategy and selection criteria
We developed a protocol for the systematic review using PRISMA guidelines(Liberati,
2009), to address the following questions: 1) What are the etiology, characteristics, and clinical
presentation of MAS in children; 2) What is the extent of aortic, renal, and mesenteric
involvement, and the morphology of the diseased vessels, 3) What is the management of MAS,
its effectiveness and clinical outcomes, and duration of follow up reported for these cases? We
conducted searches using the Ovid interface in MEDLINE (including the “In-process & Other
Non-Indexed Citations” segment), Embase and Cochrane Central Register of Controlled Trials in
5
April 2014, from inception of the databases. Database specific subject headings (e.g. MeSH in
MEDLINE, Emtree in EMBASE) were selected for the concept of “middle aortic syndrome.”
Database subject headings were exploded, when applicable, to include narrower terms.
Numerous text word searches were generated to capture synonymous phrases and terminology.
All synonymous terms and phrases were combined first using the Boolean “OR.” The concept of
children aged 0-18 was searched using either database “Limits” (MEDLINE) or subject headings
(Embase). In all three databases, the relevant ages were also searched as text words. The
concepts of “middle aortic syndrome” and “children” were then combined with the Boolean
“AND.” In all databases, both adjacency operators and truncation symbols were used in text
word searches when appropriate, to capture variant endings of the search terms, and variant
spellings and phrases. No language or date restrictions were applied to ensure maximum yield of
relevant papers. The complete search strategies for each database are outlined in Appendix I.
1.2.2 Data extraction and analysis
The papers were screened, and the relevant data was extracted and double-checked by a
second reviewer for consistency. Any disagreements relating to eligibility or data were resolved
by discussion and consensus. Data extracted from papers included patient characteristics,
clinical phenotype, vessel involvement, investigations and interventions, outcomes, and follow
up. The analysis consisted of descriptive statistics of demographic and clinical characteristics,
distribution of vascular involvement, and management and outcomes of the reported cases.
Etiology was classified as idiopathic, genetic, inflammatory, or fibromuscular dysplasia
(FMD). Etiology was idiopathic if no specific underlying diagnosis was made, or if the etiology
6
was assumed to be congenital due to presentation during infancy. Etiology was defined as
genetic if the patient had any of the following known Mendelian disorders: Neurofibromatosis
type I, Williams’ syndrome, or Alagille’s syndrome. An inflammatory etiology was designated if
the patient had an inflammatory disease such as Takayasu’s arteritis or non-specific large vessel
arteritis, and/or was treated for an inflammatory condition. The etiology of FMD was designated
to case reports whose authors employed this diagnosis in association with coarctation of the
abdominal aorta.
Anatomic involvement of the abdominal aorta was described in reference to the renal
arteries (supra-renal, infra-renal, or inter-renal stenosis of the abdominal aorta). Cases with long
diffuse aortic stenosis were classified as a supra-renal to infra-renal involvement. Involvement of
the thoracic aorta was defined as stenosis of the descending aorta above the diaphragm.
Information regarding the location (ostial or distal) and morphology (segmental or diffuse) of the
stenotic vessel was collected if provided.
If no mention of symptoms, clinical findings, or end organ damage were reported, the
information was assumed to be missing. Outcomes of medical management of hypertension with
oral antihypertensives were classified as: blood pressure control (normotensive with
antihypertensive therapy), blood pressure improvement (BP improved but remained elevated and
still necessitated antihypertensive therapy), and treatment non response (no reduction in BP with
drug therapy). Outcomes of surgical and endovascular intervention were classified as: uneventful
(successful intervention), complicated (aortic tear, bleeding, thrombosis, aneurysm, stent
7
embolization), procedure failure (a technically failed procedure such as recoil of the vessel, or re-
intervention), or death.
Anatomic involvement, extent of vessel stenosis, and clinical presentation were reported
variably, but qualitative data was captured where available. Missing information was described
as such to highlight any inconsistency in the reporting of cases in the literature. Data were
analyzed with STATA, version 11. Categorical data are reported as proportions, and continuous
data are presented as the mean ± standard deviation or median (interquartile range), as
appropriate.
1.3 Results
1.3.1 Study selection
The search identified a total of 1,252 potentially relevant articles, of which 401 were
duplicates (Figure 1.1). The remaining 851 citations identified were independently screened
through title and abstract, and 587 papers were selected for full review if they met predefined
inclusion criteria outlined in Table 1.1. A total of 184 studies of 630 cases, published between
1953 and 2014, were included in this review(Cohen, 1988, Bliznak, 1974, Sethna, 2008,
Tummolo, 2009, Lin, 2008, Coleman, 2012, Bleacher, 1997, Cura, 2002, Fossali, 2000, Criado,
2002, Booth, 2002, Bergdahl, 1980, Connolly, 2002, Quek, 2000, Raas-Rothschild, 2002,
Radford, 2000, Rose, 2001, Cakar, 2008, Siassi, 1970, Vaccaro, 1986, Ayik, 2011, Annett, 2000,
Adams, 1998, Barral, 2006, Bjoerk, 1964, Porras, 2013, Nasser, 2012, Bergamini, 1995,
Bergentz, 1983, Delmo Walter, 2013, De Bakey, 1967, Stanley, 1995, Lewis, 1988, Adwani,
1996, Brzezinska-Rajszys, 1999, Eliason, 2001, Adelman, 2000, Akhtar, 2007, Albanese, 1953,
8
Alehan, 2004, Annamalai, 1969, Anthopoulos, 1971, Arnold, 1983, Atalabi, 2008, Bajwa, 2000,
Ballweg, 2006, Bansal, 2010, Berdat, 2003, Berkowitz, 1989, Blank, 1973, Chalmers, 2000,
Chiang, 2011, Chowdhury, 2012, Chrispin, 1973, Daghero, 2008, Danaraj, 1959, Daniels, 1987,
Das, 2008, Deal, 1992, Dejardin, 2004, D'Souza, 1998, Ekici, 2013, Ellis, 1995, Estepa, 2001,
Fitzpatrick, 2006, Flynn, 1984, Froysaker, 1973, Go, 2013, Gospin, 2012, Graham, 1979,
Grebeldinger, 2011, Gupta, 1979, Gupta, 1981, Guthrie, 1982, Hall, 2009, Hallett, 1980, Hallidie
Smith, 1968, Hata, 1976, Hejhal, 1973, Hipona, 1970, Honjo, 2005, Huang, 1970, Hwang, 2007,
Ing, 1995, Ishii, 2001, Isobe, 2005, Izraelit, 2012, Jordan, 1985, Kaas, 2013, Kabbur, 2012,
Kaneko, 2009, Kantarci, 2009, Kashani, 1996, Kaufman, 1972, Khan, 2000, Komuro, 2006,
Konig, 2006, Korematsu, 2007, Krohn, 2012, Kulkarni, 1974, Kurien, 1997, Lee, 2000, Levart,
2012, Levinsky, 1970, Lewis, 2001, Lillehei, 2001, Liu, 2012, Luscher, 1981, Marinescu, 1969,
Matsumoto, 2006, Matsuno, 2009, McCulloch, 2003, McLeary, 1996, McMahon, 2013, Messina,
1986, Mickley, 1998, Minson, 2012, Mocan, 1999, Monticone, 2012, Morgan, 2012, Moszura,
2013, Mugambi, 1980, Nanni, 1983, Nomura, 2005, Onat, 1969, O'Neill, 1995, Panayiotopoulos,
1996, Parent, 2014, Pierach, 1972, Pierce, 1975, Piercy, 2005, Pilati, 2013, Poovazhagi, 2014,
Poupalou, 2013, Prakken, 2006, Rees, 1990, Rhodes, 2005, Riemenschneider, 1969, Robicsek,
2000, Robicsek, 1965, Robinson, 1991, Roques, 1988, Salerno, 2010, Sandmann, 2014, Sautter,
1977, Saxena, 2000, Schechter, 1985, Schuerch, 1975, Schuster, 1963, Scott, 1979, Sen, 1963,
Senning, 1960, Sharma, 1990, Shefler, 1997, Sinci, 1999, Sivakumar, 2008, Siwik, 2003, Smith,
1986, Sodergaard, 1961, Sohn, 2007, Sokolic, 1984, Srinivasan, 2010, Stanley, 1981, Stelzner,
1987, Stokes, 1960, Sumboonnanonda, 1992, Suri, 1979, Svare, 1980, Tateyama, 2000, Taylor,
1991, ten Dam, 2013, Theodorides, 1979, Trimarchi, 2008, Vakili, 2013, Wada, 1978, Wang,
2013, Welch, 1993, Welsh, 1987, West, 2005, Wiest, 1980, Wilson, 2011, Wozniak, 1998, Zaki,
9
2012, Zeltser, 2003). The characteristics of the papers selected for inclusion in this review are
summarized in Table 1.2. Almost all studies are case reports or case series and none are
longitudinal cohort studies by design, hence, there is significant variability in the quality of the
data presented and little consistency in the reporting of data. Based on the design of the studies, a
validated risk of bias assessment tool could not be used to evaluate the quality of each paper.
10
Figure 1.1 Flow chart of systematic review of published cases of middle aortic syndrome in
childhood
11
Table 1.1 Inclusion and exclusion criteria used for screening articles for systematic review
Criteria Inclusion Exclusion
Population Children <18 years of age Adult patients ≥18 years of
age
Aortic vessel disease Coarctation of the distal
thoracic or abdominal aorta
with or without renal artery
stenosis
Coarctation of the aortic arch
and proximal vessels with no
associated coarctation of the
abdominal aorta (CAA),
congenital cardiac and
valvular disease without CAA
Type of lesion Non-atherosclerotic stenosis
of the vessel
Atherosclerosis or thrombosis
or aortic aneurysm without
CAA, cases with irradiation or
trauma-induced vascular
hypoplasia
Studies Case reports, case series, cross
sectional, retrospective chart
reviews
Conference abstracts or
abstracts without
accompanying articles,
literature reviews were not
directly used as they contained
no case reports.
Language Articles published in English Articles were excluded if not
available in English
12
Table 1.2 Characteristics of 184 journal articles on middle aortic syndrome in childhood selected for inclusion
Source Setting N Age, Mean (Range), years Time
period≠
Study
Design
Follow up (years)
Porras et al, 2013 Boston, USA 53 11.6 (0.7-22.6) 1981- 2012 Case series 6.6 (0.1-32)
Tummolo et al, 2009 London, UK 36 median 2.7 (10 days- 10
years)
1976- 2008 Case series median 4.5 (1.1-
19.7)
Daniels et al, 1987 Cincinnati, USA 27 6 ± 5 (5 months-20 years) 1966- 1986 Case series .
McCulloch et al, 2003 Cape Town, South Africa 24 8.5 (2.5-14) 1978- 2000 Case series .
Sandmann et al, 2014 Duisburg, Germany 19 13± 5.2 (1-19) years 1979- 2009 Case series 9.5 ± 6.75
Oneil et al, 1995 Philadelphia, USA 17 9.7 (0.4-15) 1982- 1995 Case series 4.5 (0.5-13)
Saxena et al, 2000 New Delhi, India 17 8.9 ±2.7 (4-12) 1991- 2000 Case series 0.2-7.25
Levinsky et al, 1970 Tel Aviv, Israel 14 10.8 (4.5-17) 1965- 1970 Case series 0.08- 5
D'Souza et al, 1998 Toronto, Canada 14 9.1 (4.4-17.6) 1979- 1995 Case series up to 2.5
Panayiotopoulos et al,
1996
London, UK 13 7.6 (0.2-14.2) 1976- 1996 Case series 2.9 (0.2-15.4)
Cakar et al, 2008 Ankara, Turkey 13 12.84±2.69 (8-17) 1992- 2006 Case series 3± 3.4 (0.08-14)
Berkowitz et al, 1989 Philadelphia, USA 12 10.6 (5-16) 1974- 1987 Case series 5 ± 3.7
Deal et al, 1992 London, UK 11 7 (3 months- 15 years) 1965- 1992 Case series 9.4 (1.25-25)
Lewis et al, 1988 Philadelphia, USA 11 9.7 (5 months-15 years) 1977- 1985 Case series 0.3
Rose et al, 2001 Göttingen, Germany 10 median 11.5 (2.4-26.1) 1975- 2000 Case series .
Stanley et al, 1995 Ann Arbor, USA 9 10 (0.8-17) 1963- 1993 Case series 4.4
Parent et al, 2014 Sioux Falls, USA 9 4.7 (0.1-17.3) 2001- 2012 Case series 6.2 (0.1-9.6)
De Bakey et al, 1967 Houston, USA 8 12.4 (6-17) 1954- 1967 Case series 5
Sen et al, 1963 Bombay, India 8 3-20 1960- 1963 Case series .
Stanley et al, 1981 Ann Arbor and Dallas,
USA
8 13.9 (4-17) 1963- 1981 Case series 3.5
Robinson et al, 1991 London, UK 8 7 (1 week- 16 years) 1974- 1988 Case series .
Sumboonnanonda et al,
1992
London, UK 8 8.3 (0.17-14) 1975- 1988 Case series 3.3 (1.1-10.6)
13
Graham et al, 1979 Ann Arbor, USA 6 14 (11-17) 1961- 1978 Case series 13.3 (0.5-5.8)
Barral et al, 2006 Saint-Etienne, France 6 11.5 (8-13) 1980- 1996 Case series 10.2
Estepa et al, 2001 Madrid, Spain 5 9.38 (4.2-14.5) 1977- 1998 Case series 6.5 ± 4.1
Sethna et al, 2008 Philadelphia, USA 5 5.5 (1.25-9) 1990- 2007 Case series 7 (4-12)
Srinivasan et al, 2010 Philadelphia, USA 5 10.6 (3.3-16) 1997- 2009 Case series 0.6 (0.08-1.6)
Mickley et al, 1998 Ulm, Germany 4 13 (8-16) 1971- 1992 Case series 16.75 (9-25)
Taylor et al, 1991 Munich, Germany 4 6.1 (4-8.5) 1972- 1990 Case series .
Bergamini et al, 1995 Louisville, and Chicago,
USA
4 5.1 (0.17-15) 1978- 1993 Case report 7 (2-15)
Bergdahl et al, 1980 Stockholm, Sweden 3 9,12,17 1958- 1960 Case report 14.3 (5-21)
Riemshneider et al, 1969 Torrance, USA 3 5.3 (0.019-11) 1960- 1968 Case report 1.7-7
Wada et al, 1978 Sapporo, Japan 3 11,11,16 1960- 1976 Case series 3-10
Hejhal et al, 1973 Prague, Czechoslovakia 3 13,14,12 1963- 1970 Case series .
Siassi et al, 1970 Torrance, USA 3 15 days 1965- 1968 Case report .
Vaccaro et al, 1986 Columbus, USA 3 10.7 (5-17) 1980- 1985 Case report 1.3 (0.17- 3.5)
Danaraj et al, 1959 Singapore 2 7,13 1955 Case report .
Schuster, 1963 Boston, USA 2 7,17 1958 Case report 0.5
Onat et al, 1969 Istanbul, Turkey 2 10 1964 Case report 1
Hallet et al, 1980 Boston, USA 2 12 (11-13) 1960- 1978 Case report up to 19
Booth et al, 2002 London, UK 2 10,6 1982- 2000 Case series .
Piercy et al, 2005 Winston-Salem, USA 2 7,13 1987- 2004 Case series 3.9 (0.08-11.7)
Siwik et al, 2003 Cleveland, USA 2 12,10 1989- 2000 Case series .
Konig et al, 2006 Berlin, Germany 2 2,0.42 1998- 2003 Case report 0.6- 4
Kaas et al, 2013 Baltimore, USA 2 5,7 2000- 2010 Case series 3
Albanese et al, 1953 Buenos Aires, Argentina 1 12 1952 Case report .
Bjorek et al, 1964 Uppsala, Sweden 1 13 1956 Case report 3
Stokes et al, 1960 St. Louis, USA 1 12 1959 Case report 1.6
Sodergaard et al, 1961 Aarhus, Denmark 1 4 1960 Case report .
Anthopoulos et al, 1971 Athens, Greece 1 10 1965 Case report .
Theodorides, 1979 Utrecht, the Netherlands 1 10 1965 Case report .
14
Bliznak et al, 1974 St. Louis, USA 1 16 1968 Case report .
Annamalai et al, 1969 Madras, India 1 16 1969 Case report .
Kulkarni et al, 1974 Bombay, India 1 17 1969 Case report 3
Pierach et al, 1972 Minneapolis, USA 1 6 1969 Case report 1.6
Sautter et al, 1977 Marshfield, USA 1 14 1972 Case report 3.5
Hata et al, 1976 Iseharam, Japan 1 2 1973 Case report 0.2
Pierce et al, 1975 Hershey, USA 1 11 1974 Case report 0.4
Adelman et al, 2000 Oakland, USA 1 0.17 1976 Case report 22
Guthrie et al, 1982 Lexington, USA 1 14 1980 Case report 0.5
Stelzner et al, 1987 Koln, West Germany 1 15 1985 Case report 0.25
Dejardin et al, 2004 Brussels, Belgium 1 6 1989 Case report 13
Tateyama et al, 2000 Hirosaki, Japan 1 12 1990 Case report .
Ishii et al, 2001 Oita, Japan 1 14 1991 Case report 9
Khan et al, 2000 Philadelphia, USA 1 15 1998 Case report 0.17
Criado et al, 2002 Madrid, Spain and
Baltimore, USA
1 1 1999 Case report 0.25
Isobe et al, 2005 Hiroshima, Japan 1 11 2002 Case report 0.8
Marinescu et al, 1969 Bucharest, Romania 1 17 1954- 1966 Case report 4
Senning et al, 1960 Stockholm, Sweden 1 12 1957- 1959 Case report 1.5
Chrispin et al, 1973 London, UK 1 4 1963- 1973 Case report 9
Robicsek, 2000 Charlotte, USA 1 8 1964- 1995 Case report 23
Jordan et al, 1985 Cleveland, USA 1 10 1977- 1984 Case series .
Radford et al, 2000 Brisbane, Australia 1 15 1980- 2000 Case series .
Sharma et al, 1990 New Delhi, India 1 12 1988- 1990 Case series 0.75
Chalmers at al, 2000 London, UK 1 8 1988- 1998 Case series .
Delmo et al, 2013 Cambridge, USA and
Berlin, Germany
14 6.7 ± 3.76 (8 months-11
years)
. Case series 5.8 ±1.36 (0.75-
15 )
Connolly et al, 2002 Orange, USA 7 12(8-17) . Case series 4-9
Ellis et al, 1995 Pittsburgh, USA 6 6.7 (2.8-13.9) . Case series 3.5 ± 2.8 (0.5-
10.8)
15
Messina et al, 1986 San Francisco, USA 6 14 (8-17) . Case series 4.1
Brzezinska et al, 1999 Warsaw-Miedzylesie,
Poland
5 11.4 (4-17) . Case series 0.25-1.7
Welsh et al, 1987 Buenos Aires, Argentina 5 15-17 . Case series 1-5
Bansal, 2010 Mumbai, India 4 10.8 (7-14) . Case report .
Fossali et al, 2000 Milan, Italy 4 11.6 (6.3-15.8) . Case series 2-10
Gupta, 1979 Calcutta, India 4 12.8 (8-17) . Case series .
Scott et al, 1979 Nashville, USA 4 1.6 (0.25-4.5) . Case report 2.6 (0.5-4)
Hallidie-Smith et al, 1968 London, UK 3 2.5 (0.58-5) . Case report .
Lillehei et al, 2001 Boston, USA 3 11.5 (8.5-13.5) . Case report 2-10
Roques et al, 1988 Bordeaux, France 3 13,16,15 . Case report 1-3
Ten Dam et al, 2013 Nijmegen, the
Netherland
3 6.3 (12 days- 13 years) . Case report 5.7 (1-10)
Blank et al, 1973 Tampa, USA 2 10,15 . Case report 0.08-2
Bleacher et al, 1997 Washington, and
Wilmington, USA
2 13,10 . Case report 0.6-0.7
Coleman et al, 2012 Ann Arbor, USA 2 5,13 . Case report 1.1
Gupta et al, 1981 Calcutta, India 2 10 (9-11) . Case report 0.5 (0.3-0.7)
Huang et al, 1970 Galveston, USA 2 14 (12-16) . Case report 4 (1-7)
Izraelit et al, 2012
New York, USA 2 0.25, 1 day* . Case report 0.06-0.2
Mcleary et al, 1996 Loma Linda, USA 2 13 (11-15) . Case report .
Pilati et al, 2013 Rome, Italy 2 11,15 . Case report 1.4 (1.3-1.5)
Robicsek et al, 1965 Charlotte, USA 2 1,8 . Case report .
Trimarchi et al, 2008 San Donato Milanese,
Italy
2 11 (10-12) . Case report 1.7 (1.3-2)
Adams et al, 1998 Birmingham, UK 1 13 . Case report 2
Adwani et al, 1996 Birmingham, UK 1 0.33 . Case report 0.4
Akhtar et al, 2007 Karachi, Pakistan 1 12 . Case report .
Alehan et al, 2004 Ankara, Turkey 1 3 . Case report Death
Annett et al, 2000 Australian Capital
Territory, Australia
1 17 . Case report 0.25
16
Arnold et al, 1983 Little Rock, USA 1 0.33 . Case report 0.5
Atalabi et al, 2008 Ibadan, Nigeria 1 10 . Case report .
Ayik et al, 2011 Izmir, Turkey 1 3 . Case report 0.5
Bajwa et al, 2000 Cambridge, England 1 0.25 . Case report .
Ballweg et al, 2006 Ann Arbor, USA 1 0.17 . Case report 0.3
Berdat et al, 2003 Berne, Switzerland 1 12 . Case report .
Bergentz et al, 1983 Malmö, Sweden 1 16 . Case report .
Chiang et al, 2011 Taoyuan, Taiwan 1 0.083 . Case report Death
Chowdhury et al, 2012 Dhaka, Bangladesh 1 13 . Case report .
Cohen et al, 1988 New Hyde Park, USA 1 17 . Case report 0.75
Cura et al, 2002 Miami, USA 1 10 . Case report 0.7
Daghero et al, 2008 Cordoba, Argentina and
Leuven, Belgium
1 14 . Case report .
Das et al, 2008 Louisville, USA 1 . . Case report .
Ekici et al, 2013 Ankara, Turkey 1 14 . Case report .
Eliason et al, 2001 Nashville, USA 1 17 . Case report 2
Fitzpatrick et al, 2006 San Antonio, USA 1 15 . Case report .
Flynn et al, 1984 Memphis, USA 1 5 . Case report .
Froysaker et al, 1973 Oslo, Norway 1 8 . Case series 2.5
Go et al, 2013 Columbus, USA 1 10 . Case report 2
Gospin et al, 2012
Houston, USA 1 1 day* . Case report Death
Grebeldinger et al, 2011 Sremska Kamenica,
Serbia
1 17 . Case report .
Hall et al, 2009 Philadelphia, USA 1 0.027 . Case report 1
Hipona et al, 1970 Boston, USA 1 12 . Case report 4
Honjo et al, 2005 Okayama, Japan 1 4 . Case report 1
Hwang et al, 2006 Korea 1 16 . Case report 0.8
Ing et al, 1995 New Hyde Park, USA 1 15.5 . Case report 0.5
Kabbur et al, 2012
Hatford, USA 1 1 day* . Case report Death
Kaneko, 2009 Osaka, Japan 1 0.2 . Case report 1.2
17
Kantarci et al, 2009 Erzurum, Turkey 1 3 days . Case report .
Kashani et al, 1996 San Diego, USA 1 11 . Case report 1
Kaufman, 1972 Los Angeles, USA 1 13 . Case report 0.08
Komuro et al, 2006 Ibaraki, Japan 1 0.083 . Case report 4
Korematsu et al, 2007 Kumamoto, Japan 1 0.08 . Case report 1.2
Krohn et al, 2012 Berlin, Germany 1 11 . Case report .
Kurien et al, 1997 Birmingham, UK 1 4 . Case report 0.5
Lee et al, 2000 Cambridge, England 1 0.25 . Case report 0.17
Levart et al, 2012 Ljubljana, Slovenia 1 3 . Case report 0.5
Lewis et al, 2001 Bristol, England 1 0.92 . Case report 5
Lin et al, 2008 Taipei, Taiwan 1 16 . Case report 0.5
Liu et al, 2012 Beijing, China 1 15 . Case report 0.7
Luscher et al, 1981 Zürich, Switzerland 1 15 . Case series 1
Matsumoto et al, 2006 Okayama, Japan 1 17 . Case report .
Matsuno et al, 2009 Gifu, Japan 1 11 . Case report .
McMahon et al, 2013 Dublin, Ireland 1 13 . Case report 0.13
Minson et al, 2012 London, UK 1 0.33 . Case report 3
Mocan et al, 1999 Trabzon, Turkey 1 12 . Case report 0.7
Monticone et al, 2012 Torino, Italy 1 17 . Case report 0.5
Morgan et al, 2012 Toronto, Canada 1 15 . Case report 5
Moszura et al, 2013 Lodz, Poland 1 3.5 . Case report 0.25
Mugambi et al, 1980 Nairobi, Kenya 1 12 . Case report .
Nanni et al, 1983 Gainesville, USA 1 12 . Case report 1
Nasser et al, 2012 Nancy, France 1 13 . Case report 4
Nomura et al, 2005 Saitama, Japan 1 7 . Case report .
Poovaszhagi et al, 2014 Tamil Nadu, India 1 11 . Case report .
Poupalu et al, 2013 Paris, France 1 2.5 . Case report 2
Prakken et al, 2006 Maastricht, The
Netherlands
1 0.4 . Case report 10
Quek et al, 2000 Singapore, Singapore 1 8 . Case report .
18
Raas-Rothschild et al,
2002
Jerusalem, Israel 1 14 . Case report .
Rees et al, 1990 Louisville, USA 1 0.135 . Case report 4
Rhodes et al, 2005 Washington, USA 1 15 . Case report 1.5
Salerno et al, 2010 Philadelphia, USA 1 2 . Case report 8
Schechter et al, 1985 Houston, USA 1 15 . Case report 1
Schuerch et al, 1975 Montréal, Canada 1 10 . Case report 4.5 years
Shefler et al, 1997 Oxford, UK 1 15 . Case report 0.25
Sinci et al, 1999 Ankara, Turkey 1 17 . Case report 0.08
Sivakumar et al, 2008 Chennai, India 1 16 . Case report .
Smith et al, 1986 Birmingham, UK 1 9 . Case report Death
Sohn et al, 2007 Washington, USA 1 14 . Case report 0.4
Sokolic et al, 1984 Zagreb, Yugoslavia 1 12 . Case report 0.6
Suri et al, 1979 Chandigarh, India 1 11 . Case report .
Svare et al, 1980 Copenhagen, Demark 1 13 . Case report 1.25
Vakili et al, 2013 Boston, USA 1 1 day . Case report 1.5
Wang et al, 2013 Ishikawa, Japan 1 0.7 . Case report .
Welch et al, 1993 Rochester, USA 1 6 . Case report .
West et al, 2005 Rochester, USA 1 9 . Case report 0.3
Wiest et al, 1980 Los Angeles, USA 1 13 . Case report .
Wilson et al, 2011 Hershey, USA 1 4 . Case report 0.13
Wozniak et al, 1998 Giessen, Germany 1 7.5 . Case report .
Zaki, 2012 Mumbai, India 1 8 . Case report 0.08
Zeltser et al, 2003 New York, USA 1 1 day . Case report 0.25
Total: 184 Papers --- 63
0
--- --- --- ---
≠ Year of presentation was set to missing if not specified, and not assumed to be the same as the year of publication of paper
* These cases were not included in the age calculation as they died shortly after birth
19
1.3.2 Patient characteristics
A total of 630 children reported in 184 publications are included in this review. Table 1.3
summarizes their clinical characteristics. Mean age at presentation is 9.1 (standard deviation[SD]
± 5) years, and 45% of children are male. The most common finding at presentation is
hypertension (87%). The vast majority of reports do not describe symptoms, clinical findings at
presentation, or indices of end organ damage. There is very little data available to describe the
clinical phenotype of MAS in children.
1.3.3 Etiology and associated diagnoses
Most cases of MAS are idiopathic (64%). Associated known Mendelian and
inflammatory diseases are found in 15% and 17% of reported cases, respectively. A diagnosis of
FMD is made in approximately 4% of cases, although histopathological or angiographic data to
support the diagnosis are not reported.
20
Table 1.3 Patient characteristics, presentation, and clinical findings in 630 children with middle aortic
syndrome
Variable All patients N=630 (%) Percent missing data
Demographics
Mean age at presentation (yr)± SD 9.1 ± 5 32.1
Gender (male) 286 (45.4) 11.1
Ethnicity 78.4
White 91 (14.5)
Asian 14 (2.2)
African/ African American 22 (3.5)
Other 9 (1.4)
Presentation
Hypertension* 545 (86.5) 11.1
Claudication 65 (10.3) 89.7
Dyspnea 47 (7.5) 92.5
Headache 83 (13.2) 86.8
Failure to thrive 24 (3.8) 96.2
Nausea/vomiting 15 (2.4) 97.6
Abdominal angina 26 (4.1) 95.9
Asymptomatic 35 (5.6) 94.4
Clinical Findings
Mean systolic blood pressure ± SD 167 ± 32.9 56.3
Mean diastolic blood pressure ± SD 106.7 ± 23.1 60.8
Blood pressure gradient present* 137 (21.8) 76.5
Systolic murmur* 131 (21.3) 77.9
Abdominal bruit* 142 (22.5) 76.8
Diminished femoral pulse 110 (17.5) 82.5
Absent femoral pulse 47 (7.5) 92.5
Neurologic deficit 43 (6.8) 93.2
Positive Mantoux 39 (6.2) 93.8
Facial Palsy 4 (0.6) 99.4
Seizures 4 (0.6) 99.4
End organ indicators
Cardiac
Left ventricular hypertrophy* 191 (30.3) 68.6
Congestive heart failure 54 (8.6) 91.4
Cardiomegaly 45 (7.1) 92.9
Dilated cardiomyopathy 13 (2.1) 97.9
Renal
Reduced renal function* 35 (5.6) 86.5
Acute renal failure 13 (2.1) 97.9 * Percentages do not add up to 100% as few studies report normal findings
21
1.3.4 Aortic vessel disease
Involvement of the aorta, visceral branches and other vessels is summarized in Table 1.4.
Narrowing of the abdominal aorta is reported in 97% of cases, while the distal thoracic aorta is
involved in 3% of cases. The most common anatomic site within the abdominal aorta is
suprarenal (29%), followed by suprarenal to infrarenal stenosis (12%), and infrarenal
involvement (8%). Morphology of the vessel is not reported in 62% of cases, but of those cases
with known morphology, a discrete segmental narrowing (23%) is slightly more common than
long diffuse stenosis (15%). Vascular involvement in MAS by etiology is presented in Table 1.5.
In terms of etiology, those with idiopathic MAS have a higher prevalence of infrarenal aortic
stenosis compared to other etiologies, while cases with known Mendelian disorders have a higher
prevalence of suprarenal aortic involvement. Aneurysms of the abdominal aorta are reported in
11% of cases, with the highest proportion of reports in cases with inflammatory disease.
1.3.5 Extra-aortic vessel involvement
Renal artery stenosis (RAS) at initial presentation is common (66%). Approximately 60%
of these cases have bilateral renal artery stenosis, while 20% have unilateral renal artery
involvement, and the remaining cases are not clearly defined. The stenosis is restricted to the
ostial region of the vessel in 35% of cases, although the remaining cases are not described in
enough detail. Morphology of the renal vessels is also not reported in 87% of the cases; of those
reported, a segmental narrowing of the renal artery is more commonly seen than a diffuse lesion,
and none describe a beading pattern of vessel involvement.
22
The superior mesenteric artery (SMA) is affected in 30% of the cases, and the celiac
trunk in 22% of cases. The inferior mesenteric artery is rarely involved. Collateral vessels are
noted in 15% of patients. Only 30% of cases have abdominal aortic coarctation with no other
visceral branch involvement. The remaining 70% have at least one other visceral branch
involved (SMA, celiac, or renal): 38% have one visceral arterial stenosis, 14% have two, and
18% have three arteries involved.
Retinal and cerebral vascular abnormalities are confirmed in only 10% and 3% of the
cases, respectively, with the remainder lacking information. Cases associated with genetic
disorders have more extensive extra-aortic involvement, including a higher prevalence of renal
artery stenosis, as well as SMA and celiac artery involvement, while cases with arteritis appear
to be more localized to the abdominal aorta. Data on carotid and subclavian vessel involvement
are lacking in over 95% of the cases. The SMA and celiac vessels are not affected in FMD cases
as compared to the other etiologies. Aortic and extra-aortic involvement in MAS is illustrated in
Figure 1.2.
23
Table 1.4 Involvement of the aorta and visceral branches in 630 children with middle aortic
syndrome
Vessel N=630(%) Morphology
Segmental N (%) Diffuse N (%) Percent missing
data
Aortic Involvement
Distal thoracic 19 (3) 2 (10.5) 13 (68.4) 21.1
Abdominal aorta 611 (97) 142 (23.2) 82 (13.4) 63.4
Supra renal 177 (29) 79 (44.6) 32 (18.1) 37.3
Interrenal 51 (8.3) 23 (45.1) 6 (11.8) 43.1
Infrarenal 50 (8.2) 17 (34) 14 (28) 38
Supra to
Infrarenal
70 (11.5) 17 (24.3) 14 (20) 55.7
Unspecified 263 (43) 7 (2.7) 16 (6.1) 91.2
Visceral Artery
Renal Arteries 417 (66.2) 42 (10.1) 11 (2.6) 87.3
Unilateral 83 (19.9) 9 (10.8) 4 (4.8) 84.4
Bilateral 240 (57.6) 32 (13.3) 7(2.9) 83.8
Unspecified 94 (22.5) 1 (1.1) 0 (0) 98.9
Superior mesenteric 186 (29.5) 19 (10.2) 1 (0.5) 89.3
Coeliac 141 (22.4) -- -- 77.6
Common Iliac 7 (1.1) -- -- 98.9
Collateral vessels 92 (14.6) 85.4
Other involvement
Retinal 62 (9.8) -- -- 90.2
Cerebrovascular 16 (2.5) -- -- 97.5
Carotid 19 (3) -- -- 97
Subclavian 31 (4.9) -- -- 95.1
24
Table 1.5 Involvement of the aorta and visceral branches in patients with middle aortic syndrome by etiology
Vessel/Etiology N (%) All patients Idiopathic Genetic*
Arteritis FMD†
Age at presentation ± SD 9.1 ± 5 9.2 ± 5.1 8.7 ± 5.2 10 ± 4.2 6.8 ± 4.2
Gender (male) 286 (45.4) 179 (44.6) 53 (54.6) 43 (41) 11 (40.7)
Aortic Involvement
Distal thoracic 19 (3) 8 (2) 1(1) 10 (9.5) 0 (0)
Abdominal aorta 611 (97) 393 (98) 96 (99) 95 (90.5) 27 (100)
Supra renal 177 (29) 116 (29.5) 48 (50) 13 (13.7) 0 (0)
Interrenal 51 (8.3) 41 (10.4) 8 (8.3) 0 (0) 2 (7.4)
Infrarenal 50 (8.2) 44 (11.2) 1 (1.1) 5 (5.3) 0 (0)
Supra to Infrarenal 70 (11.5) 51 (13) 12 (12.5) 6 (6.3) 1 (3.7)
Unspecified 263 (43) 141 (35.9) 27 (28.1) 71 (74.7) 24 (88.9)
Abdominal aortic
aneurysm
66 (10.5) 23 (5.7) 15 (15.5) 25 (23.8) 3 (11.1)
Visceral Artery
Renal Arteries 417 (66.2) 264 (65.8) 82 (84.5) 45 (42.9) 26 (96.3)
Unilateral 83 (19.9) 59 (22.3) 12 (14.6) 2 (4.4) 10 (38.5)
Bilateral 240 (57.6) 165 (62.5) 36 (43.9) 23 (51.1) 16 (61.5)
Unspecified 94 (22.5) 40 (15.2) 34 (41.5) 20 (44.4) 0 (0)
Superior mesenteric 186 (29.5) 112 (27.9) 43 (44.3) 28 (26.7) 3 (11.1)
Celiac 141 (22.4) 83 (20.7) 38 (39.2) 20 (19) 0 (0)
Common Iliac 7 (1.1) 4 (1) 1 (1) 2 (1.9) 0 (0)
Other involvement
Retinal 62 (9.8) 43 (10.7) 11 (11.3) 4 (3.8) 4 (14.8)
Cerebrovascular 16 (2.5) 8 (2) 1 (1) 7 (6.7) 0 (0)
Carotid 19 (3) 6 (1.5) 3 (3.1) 9 (8.6) 1 (3.7)
Subclavian 31 (4.9) 13 (3.2) 3 (3.1) 14 (13.3) 1 (3.7)
Total 630 (100) 401 (63.6) 97 (15.4) 105 (16.7) 27 (4.3) * Genetic etiology defined as the known Mendelian disorders: Neurofibromatosis type I (n=49), William’s
syndrome (n=41), and Alagille’s syndrome (n=7) †
Fibromuscular dysplasia
25
Figure 1.2 Involvement of the aorta, renal and visceral arteries in 630 reported cases of middle aortic syndrome in childhood
26
1.3.6 Medical management
A total of 383 patients (61%) received oral antihypertensive drugs upon initial
presentation, 18% did not receive antihypertensive therapy, and the remaining cases are not
clearly reported. Some cases required a regimen of multiple antihypertensive drugs. The most
commonly used agents include: beta blockers (20%), angiotensin converting enzyme inhibitors
(ACEi ; 13%), diuretics (8%), and alpha blockers (7%). Of the cases treated conservatively, 14%
became normotensive with antihypertensive medication, and 36% had an improvement in blood
pressure with drug therapy. In 44% of the cases, the hypertension was refractory to medication.
Data are not reported for the remaining 6% of cases receiving medications. Outcomes associated
with the medical management of MAS for each diagnosis are described in Table 1.6. Overall,
cases with associated with known Mendelian disorders responded better to antihypertensive
medications, while idiopathic cases had the highest rate of treatment non-response. There is little
data reported on the use of corticosteroids for management.
1.3.7 Endovascular and surgical intervention
Data on endovascular and surgical management of MAS are summarized in Table 1.7.
Approximately 28% of patients underwent an endovascular intervention, which consisted of
percutaneous transluminal angioplasty with or without stenting. The post operative course of
endovascular treatment was uneventful in half of the cases. Approximately 13% of patients had
complications related to the endovascular procedure. Failure of endovascular procedures is
reported in 28% of the cases: this consisted of technical failure or need for re-intervention.
Mortality attributable to endovascular intervention was 2.3%. Outcomes are not reported in the
remaining 6% of cases.
27
Surgical treatment was performed in 348 of the reported cases (55%), and included aorto-
aortic bypass as the treatment of choice in 42% of patients, reconstruction patch graft in 23%,
and renal auto-transplantation in 11% of cases. Of those receiving surgical intervention, 25
patients (7%) had concomitant endovascular procedures, and 41 cases (12%) had surgery
following a failed endovascular intervention. The post operative course following surgical
intervention was uneventful in the majority of cases (65%), complicated in 9% of cases, and
technical failure is reported in 8% of cases. Death attributable to surgical treatment was 2.9%.
Surgical outcomes are not reported in the remaining 14% of cases. Outcomes of endovascular
and surgical interventions by etiology are outlined in Table 1.6. Cases with associated arteritis
had the highest rate of complications during surgical interventions.
28
Table 1.6. Outcomes associated with medical, endovascular and surgical management of middle aortic syndrome
by etiology
Etiology N=630 (%) Medical Management N (%)
Total Controlled Improved Unresponsive Missing
Idiopathic 401 (63.6) 263 (65.6) 31 (11.8) 80 (30.4) 142 (54) 10 (3.8)
Genetic* 97 (15.4) 63 (64.9) 17 (27) 33 (52.4) 12 (19) 1 (1.6)
Arteritis 105 (16.7) 45 (42.9) 7 (15.6) 18 (40) 7 (15.6) 13 (28.8)
FMD#
27 (4.3) 12 (44.4) 0 (0) 6 (50) 6 (50) 0 (0)
Total 630 (100) 383 (60.8) 55 (14.4) 137 (35.8) 167 (43.6) 24 (6.2)
Endovascular Intervention N (%)
Total Uneventful Complicated Procedure
failure†
Death Missing
Idiopathic 401 (63.6) 83 (20.7) 43 (51.8) 4 (4.8) 31 (37.3) 2 (2.5) 3 (3.6)
Genetic* 97 (15.4) 41 (42.3) 24 (58.5) 10 (24.4) 5 (12.2) 2 (4.9) 0 (0)
Arteritis 105 (16.7) 41 (39) 18 (44) 7 (17) 9 (22) 0 (0) 7 (17)
FMD#
27 (4.3) 8 (29.6) 3 (37.5) 1 (12.5) 4 (50) 0 (0) 0 (0)
Total 630 (100) 173 (27.5) 88 (50.9) 22 (12.7) 49 (28.3) 4 (2.3) 10(5.8)
Surgical Intervention N (%)
Idiopathic 401 (63.6) 250 (62.3) 180 (72) 15 (6) 21 (8.4) 5 (2) 29 (11.6)
Genetic* 97 (15.4) 39 (40.2) 22 (56.4) 3 (7.7) 7 (17.9) 2 (5.1) 5 (12.9)
Arteritis 105 (16.7) 38 (36.2) 14 (36.9) 13 (34.2) 0 (0) 1 (2.6) 10 (26.3)
FMD#
27 (4.3) 21 (77.8) 11 (52.4) 1 (4.8) 1 (4.8) 2 (9.5) 6 (28.5)
Total 630 (100) 348 (55.2) 227 (65.2) 32 (9.2) 29 (8.3) 10 (2.9) 50 (14.4) * Genetic etiology defined as the known Mendelian disorders: Neurofibromatosis type I (n=49), William’s
syndrome (n=41), and Alagille’s syndrome (n=7) # Fibromuscular dysplasia
† Defined as a technical failure of the procedure
29
Table 1.7 Outcomes associated with endovascular and surgical management of middle aortic syndrome
Management N =630 (%) Post interventional course N (%)
Uneventful Complicated Procedure
failure¥
Death Missing
Endovascular 173 (27.5) 88 (50.9) 22 (12.7) 49 (28.3) 4 (2.3) 10(5.8)
PTA*
117 (67.6) 65 (55.5) 3 (2.6) 38 (32.5) 4 (3.4) 7 (6)
PTA with stent 56 (32.4) 23 (41.1) 19 (33.9) 11 (19.6) 0 (0) 3 (5.4)
Surgical 348 (55.2) 227 (65.2) 32 (9.2) 29 (8.3) 10 (2.9) 50 (14.4)
Aortic patch plasty 14 (4) 11 (78.6) 1 (7.1) 2 (14.3) 0 (0) 0 (0)
with RA≠
reimplantation 8 (2.3) 4 (50) 0 (0) 1 (12.5) 2 (25)
1 (12.5)
Aorto-aortic bypass 146 (42) 98 (67.1) 9 (6.2) 7 (4.8) 2 (1.4) 30 (20.5)
with RA
reimplantation 26 (7.4) 23 (88.6) 1 (3.8) 1 (3.8) 0 (0)
1 (3.8)
Thoracoabdominal
bypass 34 (9.8) 19 (55.9) 2 (5.9) 6 (17.6) 2 (5.9)
5 (14.7)
Reconstruction patch
graft 81 (23.3) 56 (69.2) 3 (3.7) 7 (8.6) 3 (3.7)
12 (14.8)
Renal autotransplantation 39 (11.2) 15 (38.5) 15 (38.5) 4 (10.2) 0 (0) 5 (12.8) *Percutaneous transluminal angioplasty
≠RA: renal artery
¥ Defined as a technical failure of the procedure
30
1.3.8 Follow-up and blood pressure control
Follow-up data are reported for 68% of cases, median follow-up is 4 years (Interquartile
range 1-5 years). In terms of blood pressure control, 119 cases (18.9%) were normotensive
without any antihypertensive medications, 167 cases (26.5%) were normotensive but receiving
antihypertensive therapy, 48 cases (7.6%) had uncontrolled BP, and 121 cases (19.2%) were
reported to have adequate BP control but with no mention of presence or absence of drug
therapy. Total 30-day mortality was 2.7%, and the total number of deaths reported was 33
(5.2%). No follow up data was provided for the remaining 142 (22.6%) of cases. Table 1.8
summarizes reported outcomes following surgical and endovascular interventions. A total of 136
cases (22%) needed re-intervention, and 47 cases (7.5%) had a complete or partial nephrectomy.
On follow up, restenosis of the stenotic segment was reported in 34 cases (5.4%); 9 of these
cases were after surgery, 13 were after endovascular intervention, and 12 were after receiving
both interventions.
31
Table 1.8 Follow up data reported for 630 cases of middle aortic syndrome in childhood following endovascular and surgical treatment
Outcome N (%)
BP controlled with
medication
BP controlled
without
medication
Control
with
unknown
medication
BP
uncontrolled
Total death Missing
Endovascular 173 (27.5) 63 (36.4) 31 (17.9) 16 (9.3) 23 (13.3) 5 (2.9) 35 (20.2)
PTA*
117 (67.6) 34 (29.1) 21 (17.9) 11 (9.4) 20 (17.1) 4 (3.4) 27 (23.1)
PTA with stent 56 (32.4) 29 (51.8) 10 (17.8) 5 (8.9) 3 (5.4) 1 (1.8) 8 (14.3)
Surgical 348 (55.2) 86 (24.7) 111 (31.9) 90 (25.9) 16 (4.6) 14 (4) 31 (8.9)
Aortic patch plasty 14 (4) 3 (21.4) 3 (21.4) 3 (21.4) 3 (21.4) 0 (0) 2 (14.4)
with RA≠
reimplantation 8 (2.3) 0 (0) 1 (12.5) 3 (37.5) 0 (0)
3 (37.5) 1 (12.5)
Aorto-aortic bypass 146 (42) 32 (21.9) 58 (39.7) 38 (26) 6 (4.1) 3 (2.1) 9 (6.2)
with RA reimplantation 26 (7.4) 5 (19.2) 10 (38.5) 6 (23.1) 0 (0) 0 (0) 5 (19.2)
Thoracoabdominal bypass 34 (9.8) 3 (8.8) 10 (29.4) 13 (38.3) 3 (8.8) 5 (14.7) 0 (0)
Reconstruction patch graft 81 (23.3) 30 (37) 11 (13.6) 24 (29.6) 3 (3.7) 2 (2.5) 11 (13.6)
Renal autotransplantation 39 (11.2) 13 (33.3) 18 (46.1) 3 (7.7) 1 (2.6) 1 (2.6) 3 (7.7) *Percutaneous transluminal angioplasty
≠RA: renal artery
32
1.4 Discussion
MAS is a complex clinical entity in childhood that has been recognized more frequently
in the last decade. Based on our review, we found that children often present at an older age
with the initial finding of hypertension, and the majority of MAS cases in childhood are
idiopathic. Involvement of the aorta is also relatively consistent, and confined to the peri-renal
segment of the abdominal aorta, with many having ostial stenosis of the renal arteries and
visceral branches. An interesting feature is the lack of inferior mesenteric artery involvement.
Many patients undergo surgical and endovascular interventions to better manage the
hypertension; however, with varying success, and often have residual hypertension despite
intervention.
The location and length of the aortic narrowing in patients with MAS is highly variable.
The stenosis can be a short focal constriction restricted to a few millimeters along the length of
the aorta(De Bakey, 1967), or it can be a long diffuse narrowing extending from above the renal
arteries to a point above the inferior mesenteric artery(Coleman, 2012, Dejardin, 2004). The
abdominal aortic involvement may be classified anatomically using the most proximal site of
obstruction of the aorta: supra-renal, inter-renal, or infra-renal, and can also include renal, celiac
and mesenteric vessels(Delis, 2005, Porras, 2013, Stanley, 2008, Hallett, 1980). The most
common lesion is supra-renal, although this varies by etiology of disease. This review illustrates
the high prevalence of renal artery involvement, with 70% of cases having RAS at the time of
initial presentation. RAS is more prevalent in patients with MAS than previously reported, and
may complicate management. Although the morphology and anatomy of the renal vessels are not
adequately described across all reports, the stenosis is often restricted to the ostial region of the
renal arteries, with a high propensity for bilateral stenosis of the renal vessels(Sethna, 2008,
33
Bergamini, 1995, Delmo Walter, 2013, De Bakey, 1967). Moreover, the peri-renal segment of
the aorta is almost always involved and could indicate specific developmental patterning
required for normal formation. The superior mesenteric artery and celiac trunk are involved in
30% and 20% of cases, respectively. The inferior mesenteric artery is almost never involved in
MAS, which along with the observation that disease is confined to the peri-renal segment of the
abdominal aorta, suggests that MAS may be an aberrant developmental anomaly. Data on the
extent of carotid, cerebral, and retinal vascular involvement are lacking, thus it is not known if
MAS is a systemic disorder.
The etiology of MAS remains largely unknown, and the majority of cases are idiopathic.
This is partly due to the fact that pathological studies have rarely been carried out in the reported
cases. In the few cases where specimens are studied, there is either normal histology or
pathological features are nonspecific and indistinguishable across potential etiologies(Bliznak,
1974, Adwani, 1996, Slovut, 2004). Cases described in association with recognized Mendelian
disorders, namely Williams’ Syndrome, Alagille’s syndrome, and Neurofibromatosis type I, have
more extensive vessel disease, including involvement of the renal and mesenteric arteries, as
compared to idiopathic MAS. This may suggest a common genetic pathway that could explain
the overlap in the location and morphology of the lesion. It is worth mentioning that cases of
MAS caused by fibromuscular dysplasia are mostly earlier reports made with no clear supporting
evidence from radiological studies or pathology. The string of beads pattern characteristic of
FMD is not commonly seen in children, and the diagnosis of FMD is assumed in most
cases(Stanley, 1995, Stanley, 2006, Tullus, 2013). Furthermore, the lesion in FMD is confined to
the middle or distal portion of the vessel in the majority of cases(Slovut, 2004, Olin, 2014),
which is contrary to the lesions present in MAS patients. Stenosis of the renal and visceral
34
vessels in MAS almost exclusively involves the origin of the vessel, and rarely extends beyond a
few millimeters of the origin(Cura, 2002, Gupta, 1979). Therefore, it is likely that MAS in
children represents a separate clinical entity not consistent with FMD.
Surgical or endovascular intervention is often offered to lower blood pressure and
alleviate symptoms, although indications for invasive management of MAS are not
defined(Porras, 2013, Bergamini, 1995). Location of the stenosis, length of the segment, and
extent of visceral vessel involvement are all factors to consider(Barral, 2006, Porras, 2013,
Stanley, 1995). Management is therefore multidisciplinary, requiring an individualized approach
depending on the severity of clinical presentation, response to medical therapy, and extent of end
organ damage(Sethna, 2008, Chiang, 2011, Go, 2013, Hallett, 1980, Stanley, 2006). Our data
suggests that despite improved knowledge and surgical technique over the past few decades,
endovascular and surgical interventions are associated with complications including aortic
rupture or dissection, bleeding, thrombosis, stenosis of the graft, and iatrogenic tears(Lin, 2008,
Booth, 2002, Barral, 2006, Berdat, 2003). Although endovascular and surgical management may
be acutely successful in relieving aortic obstructions(Porras, 2013), freedom from re-intervention
may not necessarily be achieved. Additionally, residual hypertension is common and requires
use of antihypertensive medication or a secondary intervention. Inadequate blood pressure
control following intervention is reported in over one third of patients, which, according to some
reports, is a poor prognostic factor that impacts event-free survival(Delis, 2005, Taketani, 2005).
Lastly, the longevity of any therapeutic response is difficult to ascertain, yet a concerning issue.
As children and adolescents grow, re-stenosis and impaired flow may develop due to fibrosis
related to instrumentation or the obvious lack of growth expected from grafts or stents.
Considering life expectancy in this patient population, duration of monitoring and medium or
35
long-term improvement remains a critical yet largely unknown aspect of care.
1.5 Limitations
There are several limitations to this review, in which data were dependent on the quality
of the studies, with a substantial amount of missing information. The clinical phenotype and
extent of end organ damage have not been adequately reported in the literature, which could be
due to incomplete investigations carried out or to a lack of systematic reporting of cases.
Addressing this paucity of information through detailed clinical phenotyping of MAS will
provide insight into the extent of the disease, and thus impact decision-making. Long term
follow-up is not adequately reported, and data on growth, intestinal ischemia, and food
intolerance are lacking. Additionally, there are inconsistencies in the reporting and terminology
used to describe vascular lesions. Reporting bias is likely present where more severe forms of
disease or surgical cases are reported more frequently. Despite the limitations, this review
provides a summary of the reported cases of MAS in terms of patient characteristics, vascular
involvement, and management, while highlighting the gaps in knowledge. There are currently no
studies on MAS that explore potential risk factors, exposures, and demographic, social or
psychosocial factors. Knowledge of the natural history of MAS is limited to early reports which
describe poor prognosis in patients treated conservatively (Bjoerk, 1964, Bergamini, 1995,
Delmo Walter, 2013, Graham, 1979, Onat, 1969, Senning, 1960). Further work is needed to
understand etiology of the disease, delineate disease progression and vascular phenotype, and
ultimately impact clinical management. Additional consideration of more advanced vascular
imaging will lead to a better understanding of the extent of disease and may point to possible
undiagnosed etiologies.
36
1.6 Conclusion
Patients with MAS often have additional visceral stenosis and most commonly renal
artery stenosis. The extent of vascular disease may also differ based on genetic or inflammatory
conditions. The pathogenesis of MAS and optimal interventions have yet to be elucidated.
Persistent hypertension after intervention is a common feature that requires further evaluation
and long-term monitoring of children.
37
1.7 Gaps in knowledge
The gaps in knowledge that were identified from the systematic review formed the basis for
the research questions chosen for this PhD thesis. The chosen areas of study can be summarized
in three categories, which form the layout and rationale for the chapters that follow. The purpose
of this section is to provide an overview of the gaps in our knowledge of childhood MAS and
RAS. Each of the subsequent chapters addresses one of these gaps in the order they are
summarized.
A. Efficacy of treatment, and outcomes following management (Chapter 2)
Medical treatment is the first line of therapy in children with MAS/RAS and is often used
in combination to control the hypertension. As the systematic review revealed, residual
hypertension is common following intervention. However, the follow-up for the reported 630 is
sparse. As a result, the effectiveness of treatment at controlling blood pressure and sustaining
optimal blood pressures is not known. Further, whether the longitudinal change in blood pressure
over time differs by etiology of disease, vascular involvement, or type of management is
unknown. This is important for both physicians and families to recognize, as children may
require long-term follow up or medical therapy despite successful initial management. In order to
plan appropriate follow-up and long-term care for these children, an understanding of the
longitudinal changes in blood pressure is paramount.
Finally, differences in the management of children, response to therapy, and outcomes
following intervention were also not compared between the various etiologies of MAS. The
differences in the aortic and extra-aortic (visceral and proximal aortic branches) vascular
involvement between the etiologies of MAS could not be directly compared in the systematic
38
review due to the high frequency of missing data, which prevented us from performing a meta-
analysis of the data.This information is relevant as it may supplement the clinical management of
children.
B. Extent of vascular involvement (Chapter 3)
The finding that renal artery stenosis is present in over two thirds of childhood MAS
raises some questions regarding the extent of vessel disease. Based on the high prevalence of
RAS among the reported cases of MAS, we have come up with a new anatomical classification:
isolated RAS, and RAS in conjunction with MAS. The rationale behind this grouping is the high
degree of bilateral ostial renal arterial involvement at the point of branching from the aorta. As
longitudinal studies in MAS are lacking, we do not know whether MAS is a progressive disease,
and whether RAS represents a mild phenotype of MAS that may progress into MAS/RAS in later
life. We use the described anatomical classification throughout this body of work.
The effects of arterial hypertension on the vasculature are well documented. Vascular
stiffness and structural remodeling have been attributed to increased distending pressure. These
effects are described in more detail in the conceptual model that follows this section.
Narrowing of the aorta has been described mainly in the context of ascending aortic narrowing or
aortic coarctation. The literature on the extent of vascular disease in aortic coarctation remains
highly debated. Studies have shown that vascular changes are localized to the regions proximal
to the stenosis with preserved vascular properties distal to the lesion. Other studies support an
underlying generalized arteriopathy. Several non-invasive vascular measurements can be used to
evaluate arterial injury and stiffness properties, which we describe in more detail in Chapter 3.
39
The question that we wanted to evaluate in this portion of the thesis is whether MAS
and/or RAS are a localized disease of the abdominal aorta or a generalized disease of the
vasculature. One of the limitations of the systematic review is the variable imaging used to
evaluate the vasculature. As a result, we were not able to determine the degree of extra-aortic or
peripheral vascular involvement. If MAS/RAS is a localized disease, we would expect the
peripheral arteries (such as the radial artery) to be unaffected and retain normal function.
Evidence of peripheral arterial stiffness would be consistent with a generalized disease of the
arteries that extends beyond the abdominal aortic narrowing.
Another rationale for evaluating aortic properties including stiffness is to study the
physiologic vascular response to chronic hypertension. Hypertensive vascular changes have not
been extensively studied in children, and may be useful in adapting blood pressure management
and defining targets for optimal blood pressure control.
C. End-organ cardiac disease (Chapter 4)
The natural history of MAS is poorly defined, however, several early case series report
outcomes in symptomatic MAS patients treated medically. In a series of 32 patients(Senning,
1960), 10 died from cerebral hemorrhage before the age of 34. Another series of 91 patients
reports hypertensive encephalopathy in 42 patients(Onat, 1969). Death from hypertension-related
compilations, namely heart failure or stroke, occurred at a mean age of 34 years (Onat, 1969).
Therefore, determining the extent of target organ damage is crucial in this population. The
chronic hypertension in children can affect cardiac structure and function. The hypertension-
induced cardiac changes are described in more detail in the conceptual model that follows.
40
End-organ disease in MAS has never been comprehensively studied and is important to
study given that target organ cardiac disease is an important consideration for intervention in
hypertensive disease. Using regional indices of cardiac function, which would allow us to detect
early changes in heart function, may be valuable in children in order to adapt their management
to prevent cardiovascular morbidity in late life. The systematic review showed a high prevalence
of persistent hypertension, which raises the question of whether this hypertension is causing
adverse remodelling of the left ventricle. Although left ventricular hypertrophy was reported in a
subset of the 630 cases reviewed, there was insufficient data in the literature regarding end-organ
cardiac disease at presentation or following management.
Our ultimate goal is to determine whether current management of MAS and/or RAS,
either through medication or endovascular and surgical intervention, can change the natural
history of the disease and result in prolonged survival and reduced cardiovascular morbidity and
mortality. This goal is beyond the scope of the current body of work, as it requires prospective
follow-up of children well into their adult lives to assess survival and cardiovascular outcomes.
However, we believe that providing a comprehensive assessment of cardiac function in children
relatively early in the disease process would allow us to better understand the cardiac physiology
of MAS and/or RAS and the effect of the associated hypertension on the cardiovascular system.
We hope to be able to assess these changes longitudinally in future studies through continuations
of this work.
The following section illustrates the conceptual model that was developed to study the
heart and vessel disease in childhood MAS and/or RAS, and forms the basis for the
cardiovascular assessment that was conducted for this thesis (Chapters 3 and 4).
41
1.8 Conceptual model
The conceptual model formed the rationale for the vascular and cardiac measurements
conducted in Chapters 3 and 4, respectively. In this model, we focus on the effect of the aortic
lesion and arterial hypertension on the central aortic properties, the peripheral vascular bed, and
the myocardium. The conceptual model is summarized in figure 1.5.
1.8.1 Vascular remodelling in hypertension
Long standing hypertension leads to vascular damage which can manifest as intimal
thickening and increased vascular stiffness of the arterial tree(Safar, 2003). Chronic increase in
vessel wall stress from high blood pressure promotes muscular cell proliferation and increases
wall thickness as an adaptive response (Safar, 2003). The increased stiffness is related to
hypertension-induced stretching of the arterial wall(Kim, 2013). When elastic fibers are
elongated, further increases in distending pressure cause recruitment of inelastic collagen fibers,
altering the elastin to collagen ratio and thus worsening vessel stiffness(Saba, 2014). As the
arterial tree stiffens, pulse wave velocity increases, which consequently elevates peak systolic
pressure in the aorta through modifying pressure wave propagation and reflection along the
arterial tree. The absolute increase in systolic pressure is called the augmentation pressure,
whereas augmentation index reflects this increment as a percentage of pulse pressure(Safar,
2003). This then results in higher pressure load on the left ventricle. Afterload can be measured
using aortic input impedance, a well established index of left ventricular afterload in animals and
humans(Mills, 1970, Nichols, 1986). The assessment of central blood pressure over brachial
blood pressure estimates more accurately the load on the left ventricle and impacts ventricular
structure and function.
42
1.8.2 Pressure wave propagation and reflection
The flow ejected from the aorta during each cardiac cycle generates a forward
propagating wave along the arterial tree(Saba, 2014). The forward wave travels away from the
heart and towards the periphery (Figure 1.3 A). At the same time, the forward waves are
reflected back to the heart at various points in the vasculature including branching points and
points of change in aortic impedance. During normal physiology, the timing of the reflected
wave occurs such that the backward reflected wave merges with the forward wave in the
ascending aorta during diastole, when the heart is relaxing(Saba, 2014, McEniery, 2007,
Westerhof, 2006). This results in some amount of blood flowing back into the heart, which
contributes to coronary perfusion.
In the case of arterial stiffening, such as arterial hypertension or aging, the speed of wave
propagation is altered so that the waves travel faster through a stiffer conduit. This state is
illustrated in Figure 1.3 B. This results in faster forward waves as well as backward waves. In
this altered physiological system, the timing of the merging of the waves occurs during systole
when the heart is contracting. The increases peak systolic pressure in the ascending aorta and
increases the afterload sensed by the left ventricle at the end of systole (Figure 1.4).
The final scenario that will be presented in this model is the effect of the aortic stenosis
on the properties of the pressure waves. Points of narrowing are points of change in flow and
impedance, and therefore introduce new reflection sites and increase the early return of backward
waves to the heart. This is illustrated in figure 1.3 C. In MAS and RAS, we would expect the
long-standing hypertension to alter the aortic properties, namely central arterial stiffness, and
result in increased central pressures and afterload.
43
Figure 1.3. A) Forward and backward wave propagation in normal physiology. The blood pressure wave propagates in the forward
direction away from the heart during systole and towards the periphery. At the same time, the forward waves are reflected back to the
heart from various points in the vasculature including branching points and points of change in aortic impedance; B) Enhanced Forward
and backward wave propagation in chronic hypertension and arterial stiffness. Chronic hypertension induced structural vascular changes
including increased wall thickness and stiffness. The speed of wave propagation is enhanced so that the waves travel faster through a
stiffer conduit, which results in early merging of waves during systole; C) Early backward wave reflection in aortic stenosis. The aortic
narrowing introduced a new reflection point, which in this case, would cause an early reflection of backward waves to the heart,
augmenting the central pressures and afterload sensed by the left ventricle.
44
Figure 1.4 Augmented blood pressure wave during systole as a result of enhanced wave
reflection. The measured wave (green) is the sum of the forward (blue) and backward (red)
waves, and determines the afterload sensed by the left ventricle. In hypertensive disease or aortic
narrowing, early wave reflections cause the forward and backward waves to merge during
systole, which leads to a higher central measured wave in the aorta.
45
1.8.3 Hypertension and Left Ventricular Function
Hypertension is a well-recognized risk factor for cardiovascular morbidity and
mortality(Atilgan, 2010). Long standing hypertension can lead to left ventricular hypertrophy
(LVH), which has been proven to directly predispose and aggravate irreversible deterioration of
LV systolic and diastolic function that ultimately results in congestive heart failure(Haider, 2003,
Cho, 2009, Oki, 2014). Early detection of LV dysfunction in arterial hypertension is therefore a
crucial issue. Conventional echocardiography detects abnormalities in LV systolic function only
in the advanced stages of hypertensive heart disease, when hypertrophy is evident(Hensel, 2014).
However, as shown in experimental studies of isolated papillary muscles in the setting of chronic
pressure overload, reduced myocardial contractility can occur prior to the more extensive LV
impairment detected by changes in LV wall and ejection fraction (EF)(Jacob, 1986, Bing, 1971,
Spann, 1967). In recent years, echocardiographic deformation imaging (strain and strain rate) has
emerged as a new non-invasive method for more comprehensive and reliable assessment of
regional and global myocardial function(Urheim, 2000, Dandel, 2009, Cramariuc, 2015,
D'Andrea, 2008, Artis, 2008), prior to overt clinical manifestations of systolic function with
lower ejection fraction. Strain imaging adds useful additional information on myocardial systolic
function in paediatric populations(Ganame, 2007, Van der Ende, 2013), as it detects subclinical
cardiac dysfunction(Dandel, 2009, Artis, 2008, Friedberg, 2012).
Hypertension is also a major determinant of left ventricular diastolic dysfunction, which
not only precedes systolic impairment, but in the absence of left ventricular systolic
abnormalities accounts for about one-third of patients with heart failure(Haider, 2003, Wang,
2005). Moreover, in patients with hypertension and preserved LV systolic function, gradual
development of diastolic LV dysfunction, referred to as diastolic heart failure with preserved
46
ejection fraction is described(Oki, 2014). Diastolic dysfunction implies myocardial relaxation
abnormalities and, if hypertension is left untreated, there is a progressive increase in myocardial
stiffness and decreased compliance. This leads to increased filling pressures and elevated LV
end-diastolic pressure(Ciobanu, 2013, Bountioukos, 2006).
The degree of diastolic and/or systolic left ventricular impairment related to increased LV
afterload in patients with MAS and/or RAS is not known but is important to determine as it may
affect the clinical management of children. For example, blood pressure is currently lowered to
less than the <95th
percentile for age, gender and height but evidence of diastolic dysfunction
suggests that further blood pressure lowering is warranted. Without first characterizing the
structural and functional response of myocardium to treatment, however, such questions cannot
be addressed.
1.8.4 Ventricular-Arterial Coupling
In patients with hypertension, increased afterload leads to abnormalities in ventricular-
vascular coupling which is a key determinant of cardiovascular performance(Little, 2009).
Adults with abnormal arterial stiffness and a mismatch between ventricular “elastance”
(contractile force) and arterial stiffness (arterial elastance) have been found to be at increased
risk of cardiovascular death(Safar, 2003, Haider, 2003). Therefore, arterial stiffness assessment
is recognized as a key component of early cardiovascular risk assessment in adults(Cohn, 2005).
The ratio of effective arterial elastance (Ea) to LV end-systolic elastance (Ees) has been
used to evaluate the characteristics of ventricular-arterial coupling, and can be obtained non-
invasively using echocardiographic measurements(Saba, 2014, Little, 2009). In children with
47
MAS and RAS, there could be significant uncoupling based on the severe aortic disease.
Abnormal ventricular-arterial coupling and the consequent combination of reduced contractility
and diastolic dysfunction may have implications on functional and exercise capacity among
children in the short-term, and on progression to heart failure in the long-term.
In the section that follows, we summarize the aims and hypotheses of this thesis, based
on the previously outlined gaps in knowledge and our conceptual model.
48
Figure 1.5 Conceptual model of the effect of MAS and/or RAS and the associated hypertension on aortic and cardiac properties.
49
1.9 Aims and Hypotheses
Aim 1: Determine differences in vascular involvement, management, and outcomes (residual
hypertension, re-stenosis, and re-intervention) of childhood MAS and/or RAS by etiology
(unknown, inflammatory, and genetic)
Hypothesis: Children with systemic (genetic or inflammatory) causes of MAS/RAS have
more severe aortic involvement including renal and visceral arterial stenosis compared to
children with unknown cause of disease. There is a higher prevalence of re-stenosis, re-
interventions, and residual hypertension in children with systemic diseases
Aim 2: Evaluate aortic and peripheral arterial properties in children with MAS/RAS compared to
healthy controls to determine the presence of a generalized arteriopathy through evaluation of
peripheral pulse wave velocity, and determine the effect of hypertension on carotid artery
structure, central blood pressures, and central pulse wave velocity
Hypothesis: Children with MAS/RAS have structural remodeling of the carotid artery
compared to healthy children. Central pulse wave velocity is increased and central blood
pressures are elevated, but there is no evidence of peripheral arterial stiffness. MAS/RAS
is localized to the central aorta with preserved peripheral arterial properties
Aim 3: Evaluate left ventricular structure (left ventricular mass), systolic function (ejection
fraction), diastolic function (mitral valve E/a ratio), and myocardial mechanics (longitudinal and
circumferential strains) in children with MAS/RAS compared to healthy controls to determine
the extent of cardiac end-organ involvement
Hypothesis: Children with MAS/RAS have increased left ventricular mass, reduced
diastolic function (lower E/a ratio) with preserved ejection fractions, and reduced systolic
strain values compared to healthy children
50
1.10 Overview of thesis structure
To address the outlined PhD aims, a prospective cohort study was initiated at the Hospital
for Sick Children in Toronto (2014-2016). The study consists of two study populations: children
with MAS and/or RAS, and a healthy cohort of children. The study also consists of a prospective
portion which was established to assess the vascular and cardiac properties of children with
MAS/RAS compared to healthy children. The retrospective portion consisted of medical chart
reviews and aimed at addressing the gaps in knowledge related to outcomes following
intervention and comparisons of risk of intervention among the different etiologies of disease.
Below is a summary of the overall study structure, followed by illustrations of the study design
for each chapter.
51
Overall study design
The prospective study recruited patients with MAS and/or RAS from complex
hypertension clinic at the Hospital for Sick Children (2014-2016). Children were also recruited
from cardiology and rheumatology clinics. Participation in the study involved vascular imaging
of the aorta and peripheral vessels, as well as a comprehensive echocardiographic assessment of
left ventricular structure, function, and myocardial mechanics. A group of healthy children who
were recruited cross-sectionally from cardiac assessment clinic (2009-2012) were used as a
comparison group to evaluate the differences in vascular and cardiac measurements. Figure 1.6
summarizes the overall study structure.
Figure 1.6 Overview of study structure, which includes a retrospective chart review portion, and
a prospective cohort study with cardiovascular imaging
Below is a brief overview of the structure and design of the studies conducted for each of
the chapters that follow. Each study focuses on a specific time point and addresses one of the
previously outlined gaps in knowledge.
52
Chapter 2- Evaluation of management and outcomes in a retrospective cohort study of
childhood MAS and/or RAS
Figure 1.7 Overview of study structure for Chapter 2
Chapter 2 is a retrospective longitudinal analysis of 93 children who were managed at
the Hospital for Sick Children over a 30-year period. This study was designed to address the first
gap in knowledge regarding differences among the etiologies of MAS, and outcomes following
management.
53
Chapter 3- Prospective vascular imaging of a concurrent cohort of childhood MAS and/or RAS
Figure 1.8 Overview of study structure for Chapter 3
Chapter 3 describes the concurrent cohort of 40 children with MAS and/or RAS who
were enrolled in a prospective cohort study at the Hospital for Sick Children in order to evaluate
the vascular and cardiac disease (2014-2016). The results presented in this chapter are the cross-
sectional measurements taken at the time of study enrollment. The measurements are compared
to a healthy control group who was imaged cross-sectionally using the same standardized
vascular protocol. In this chapter we address the second gap in knowledge which is the extent of
aortic and peripheral vascular disease.
54
Chapter 4- Prospective cardiac imaging of a concurrent cohort of childhood MAS and/or RAS
Figure 1.9 Overview of study structure for Chapter 4
In Chapter 4, we provide a comprehensive evaluation of cardiac structure and function,
as well as cardiac mechanics at the time of study enrollment. This is a cross-sectional analysis of
the results of the echocardiographic assessment collected prospectively for 40 children with
MAS and/or RAS enrolled in the study from 2014-2016. We also provide results of
echocardiographic measurements conducted retrospectively at the time of clinical presentation to
provide a comparison between baseline and post-treatment values. This chapter addresses the
third gap in knowledge, which is examining the end-organ cardiac involvement in childhood
MAS and/or RAS.
55
Chapter 2 Evaluation, Management, and Outcomes of MAS/RAS
56
2.1 Introduction
Middle aortic syndrome (MAS) is a rare disease in children which consists of a
narrowing in the peri-renal abdominal aorta, often presenting in conjunction with renal artery
stenosis (RAS). The majority of MAS cases have no known cause, but genetic and inflammatory
diseases account for 15% and 17% of cases, respectively(Porras, 2013, Rumman, 2015). The
presenting arterial hypertension is usually severe and difficult to manage, usually requiring
several antihypertensive agents to control. Some children may also require surgical or
endovascular interventions for blood pressure control. Interventional management is highly
individualized depending on the extent of vascular involvement, response to antihypertensive
therapy, and other manifestations of vascular compromise such as hypoperfusion of the lower
extremities or cerebrovascular disease.
Many aspects of the management of children with MAS/RAS are unknown including the
efficacy of interventions in controlling blood pressure, and outcomes such as re-stenosis and
secondary interventions. Although case reports have described several techniques for the
management of MAS, few data exist on outcomes in large pediatric cohorts. Additionally,
previous case series focus on specific etiologies and may not be representative of the entire
population of MAS who have associated genetic and inflammatory diseases, as well as variable
extent of aortic involvement. To date, the differences in clinical characteristics, management, and
response to treatment among the different etiologies of MAS/RAS have not been well described.
The purpose of this chapter is to summarize the clinical features, extent of vascular
involvement, blood pressure management and interventions among one of the largest cohorts of
57
children with MAS/RAS managed at a single center over a 30-year period. The results may serve
to guide clinical decision-making in this rare disease.
2.2 Material and methods
2.2.1 Patient population and inclusion criteria
A total of 93 children managed at the Hospital for Sick Children (Toronto, Canada) were
enrolled into a retrospective cohort study between 1986 and 2016. Inclusion criteria were age
<18 years, and a diagnosis of MAS and/or RAS. Eligible cases were identified by 1) reviewing
all cases presenting in hypertension clinic between 1986-2016 for a renal or abdominal aortic
disease; 2) searching cardiology database for cases with the differential diagnoses (Williams
Syndrome, Alagille Syndrome, and Neurofibromatosis) and renal and/or abdominal aortic
disease; and 3) screening the interventional radiology database for renal, abdominal aortic, and
thoracic aortic angiograms conducted between 1986-2016 with a finding of renal and/or
abdominal arterial narrowing. Etiology of disease was classified as genetic, inflammatory, or
unknown. Genetic causes included Neurofibromatosis type I, Williams syndrome, or Alagille
syndrome. Inflammatory causes included Takayasus arteritis or non-specific large vessel
arteritis. The study protocol was approved by the Research Ethics Board at the Hospital for Sick
Children.
2.2.2 Data collection
Patient electronic medical charts were retrospectively reviewed for inclusion criteria, and
the relevant data were collected from clinic visits, hospitalizations, procedures and vascular
58
imaging. Charts were abstracted by a single observer annually from the time of clinical
presentation until the latest follow-up visit (January 2016) for concurrent children, or until
discharge from nephrology clinic at age 18 and transition to adult care. Data collected included
patient characteristics, clinical presentation, aortic and extra-aortic involvement, investigations
and interventions, post-operative course and outcomes.
Height and weight at each clinic visit were collected, and body mass index (BMI) was
calculated. Annual blood pressure measurements were abstracted from nephrology clinical notes.
Standard deviation scores (SDS) for systolic and diastolic blood pressures, and BMI were
derived from the Centre for Disease and Control (CDC) growth charts(Kuczmarski, 2002).
Systolic hypertension was defined as systolic blood pressure equal to or greater than the 95th
percentile for children of the same age, sex and height(Falkner, 2004). Medications including
antihypertensive and immunosuppressant therapy were collected from clinical reports.
Arterial vascular involvement was characterized by reviewing reports from all available
imaging studies. The majority of children (88%) had either an abdominal computed tomography
(CT) scan or an angiogram, and 98% had a CT, angiogram or magnetic resonance imaging
(MRI) of the chest and abdomen available. Anatomic involvement of the abdominal aorta was
described in reference to the renal arteries (supra-renal, infra-renal, or peri-renal stenosis of the
abdominal aorta), using a previously described nomenclature(Rumman, 2015). Peri-renal
involvement was defined as a narrowing from the supra-renal to infra-renal portion of the aorta.
Involvement of the thoracic aorta was defined as stenosis of the descending aorta above the
59
diaphragm. Extent of aortic disease was classified as either isolated RAS, or MAS/RAS. The
latter included MAS in conjunction with RAS, or MAS alone.
Management of MAS and/or RAS was categorized as: antihypertensive therapy alone
(medical) or interventional management (including surgical and endovascular procedures or
both). The post-operative outcomes following surgical and endovascular interventions were
classified as: uneventful (successful intervention), complicated (aortic tear, bleeding, thrombosis,
aneurysm, stent embolization), unsuccessful procedure (a technically failed procedure such as
recoil of the vessel). Outcomes in terms of blood pressure control were classified as:
normotensive (BP<95th
percentile without antihypertensive therapy), controlled blood pressure
(BP<95th
percentile and still required antihypertensive therapy), and hypertensive (BP>95th
percentile with or without medications). Re-intervention was defined as a secondary
endovascular or surgical procedure on the same artery. Re-stenosis was defined using available
follow-up imaging as a narrowing of an artery that was previously dilated.
2.2.3 Statistical analysis
Categorical data are reported as frequency and percentage, and continuous variables are
expressed as the mean ± standard deviation (SD) or median and interquartile range [IQR]
depending on the distribution. Comparisons among the 3 etiology groups of MAS were done
using ANOVA. Differences in frequencies among the various etiology groups were assessed
using a chi-square test or Fischer exact test, as appropriate. Characteristics of children receiving
invasive and non-invasive management were compared using a student t-test.
60
Kaplan-Meier survival analysis was performed to compare probabilities of receiving
interventions in children with unknown, genetic and inflammatory etiologies. Time zero was set
to the first clinic visit. The survival curves were censored at the 10th
year of follow-up, and
compared using the log-rank test. Cox proportional hazards regression analysis was used to
compare the risk of intervention (endovascular or surgical) among those with unknown disease
and those with genetic or inflammatory disease, and to compare the risk of intervention between
those with MAS/RAS vs. isolated RAS. Multivariable adjustment for potential confounders
including age and sex, as well as time-varying covariates including systolic blood pressure and
BMI z-scores was performed using a forward model building approach. The final model included
age, sex, and systolic blood pressure z-score. The proportional hazards assumption was tested
using the Schoenfield residuals.
To determine the association of etiology, extent of disease, and management type with
the longitudinal change in systolic blood pressure Z-score, linear mixed-effects models were
used (with random slope and intercept, and unstructured covariance) to account for the
correlation among measurements within an individual patient and variations across subjects.
Potential confounders tested in the model included number of antihypertensive medications and
BMI z-score as time-varying covariates. Akaike Information Criterion (AIC) and likelihood ratio
test was used to assess the model fit. To explore an era effect, children were stratified into two
groups based on the year of presentation (1986-2005, and 2006-2016) and characteristics were
compared using a t-test. A two-tailed p-value of 0.05 was considered statistically significant. All
statistical analyses were performed using Stata 13.0 (College Station, Texas).
61
2.3 Results
2.3.1 Clinical characteristics at presentation
A total of 93 children with MAS and/or RAS met the inclusion criteria and were included
in this review. Baseline characteristics at the time of clinical presentation captured at the first
clinic visit are summarized in Table 2.1. Mean age at presentation was 7.0 ± 5.4 years and 48%
were male. Mean systolic blood pressure Z-score was 2.2 ± 1.8, and mean diastolic blood
pressure Z-score was 1.1 ± 1.5. Most children were asymptomatic at presentation (62%). The
most common clinical findings at presentation included hypertension (60%), systolic murmur
(30%), abdominal bruit (10%), and diminished femoral pulses (8%). In terms of etiology, almost
half the children had disease of unknown etiology, 27% had genetic diseases, and 24% had
inflammatory disease. Of those with genetic disease, 11 children had Neurofibromatosis type I,
10 children had Williams Syndrome, and the remainder had Alagille Syndrome. Inflammatory
disease consisted of Takayasu’s arteritis in 21 children, and non-specific arteritis in one child.
Children with genetic disease presented at a younger age compared to those with unknown
disease (4.7 ± 4.3 and 7.2 ± 4.3 years respectively, p=0.01), while those with inflammatory
disease presented at an older age (9.5 ± 5 years, p=0.01).
62
Table 2.1 Clinical characteristics of 93 children with MAS/RAS at
the time of presentation
Total (n= 93)
Variable Mean ± SD or n(%)
Patient characteristics
Age at presentation, years 7.0 ± 5.4
Male sex 45 (48.4)
Systolic blood pressure, mmHg 128.0 ± 20.5
Systolic blood pressure SDS 2.2 ± 1.8
Diastolic blood pressure, mmHg 72.2 ± 14.8
Diastolic blood pressure SDS 1.1 ± 1.5
Systolic hypertension 56 (60.2)
Body mass index, kg/m2 20.03 ± 5.2
Body mass index SDS 0.4 ± 1.2
Presentation
Asymptomatic 58 (62.4)
Headache 11 (11.8)
Claudication 5 (5.4)
Stroke/ cerebral infarct 6 (6.5)
Dyspnea 5 (5.4)
Edema 5 (5.4)
Visual disturbances 2 (2.2)
Chest pain 2 (2.2)
Nausea/vomiting 1 (1.1)
Abdominal angina 1 (1.1)
Nosebleed 1 (1.1)
Seizures 1 (1.1)
Clinical findings
Systolic murmur 28 (30.1)
Abdominal bruit 9 (9.7)
Diminished/absent femoral pulse 7 (7.5)
Neurologic deficit 6 (6.5)
Failure to thrive 3 (3.2)
SDS: Standard deviation score
63
2.3.2 Vascular phenotype
Of the total cohort, 49% had isolated RAS, and 51% had MAS/RAS (42 had both MAS
and RAS; 5 had MAS alone). Involvement of aortic and extra-aortic vessels is summarized in
Table 2.2. The abdominal aortic disease was confined to the peri-renal aortic region in 70% of
children, the supra-renal aorta was involved in 17%, infra-renal in 5%, and the remaining cases
were not adequately characterized. There was proximal aortic involvement of the ascending aorta
and aortic arch in 20% of total children, with higher proportions in those with genetic (40%) and
inflammatory disease (23%) compared to unknown disease (9%). There was descending thoracic
involvement in 12 (13%). Aortic aneurysms were reported in 3 children with inflammatory
disease.
Almost 90% of patients had renal arterial involvement, which was bilateral in 60% of the
cases and unilateral in 40%. Bilateral RAS was more common than unilateral involvement in
children with genetic disease (70% bilateral vs 20% unilateral, respectively), and similarly in
those with inflammatory disease (81% bilateral vs 19% unilateral, respectively). Superior
mesenteric artery (SMA) and celiac artery stenosis were present in 37% and 36% of children,
respectively. Children with genetic or inflammatory disease had significantly more celiac and
SMA involvement compared to the unknown etiology (44% and 64% compared to 20%,
p=0.002).
Inferior mesenteric artery involvement was reported in 7 children. Collateral vessels were
noted in nearly 50% of children at the time of presentation. Approximately 18% of children had
cerebrovascular involvement including vertebral, basilar, and cerebral arteries. Carotid
64
involvement including common, external or internal carotid arteries was reported in 17% of
children, and was more prevalent in those with systemic (genetic and inflammatory) disease
compared to unknown disease (30% vs 6% respectively, p=0.002).
65
Table 2.2 Aortic, visceral and extra-aortic involvement in 93 children with renovascular
hypertension by underlying etiology
Total Unknown Genetic
* Inflammatory
n= 93 n= 47 n= 24 n= 22
Variable Mean ± SD or n (%) p
Mean age, years 7.0 ± 5.4 7.3 ± 5.7 4.2 ± 3.7 9.5 ± 5.0 0.01
Male sex 45 (48.4) 24 (51.1) 14 (58.3) 7 (31.8) 0.2
Aortic involvement
Abdominal aorta 47 (51.0) 14 (29.8) 14 (58.3) 19 (86.4) <0.001
Peri-renal 33 (70.2) 10 (71.4) 9 (64.3) 14 (73.7) 0.7
Suprarenal 8 (17.0) 2 (14.2) 2 (14.3) 4 (21.1) .
Descending thoracic 12 (12.9) 2 (4.3) 6 (25.0) 4 (18.2) 0.02
Ascending/arch 19 (20.4) 6 (12.8) 8 (33.3) 5 (22.7) 0.01
Visceral artery involvement
Renal artery 82 (88.2) 45 (95.7) 21 (87.5) 16 (72.7) 0.02
Unilateral 30 (36.6) 23 (51.2) 4 (19.0) 3 (18.8) 0.02
Bilateral 49 (59.8) 20 (44.4) 16 (76.2) 13 (81.2) .
Multiple renal arteries 25 (26.9) 16 (34.0) 4 (16.7) 5 (22.7) 0.4
Right 19 (20.4) 12 (75.0) 2 (50.0) 5 (100.0) 0.4
Left 13 (14.0) 9 (56.3) 4 (100.0) -- 0.05
Superior mesenteric 34 (36.6) 9 (19.1) 11 (45.8) 14 (63.6) 0.002
Celiac 33 (35.5) 10 (21.3) 10 (41.7) 13 (59.1) 0.01
Inferior mesenteric 7 (7.5) 3 (6.4) 4 (16.7) -- 0.2
Extra-aortic involvement
Collaterals† 45 (48.4) 24 (51.1) 8 (33.3) 13 (59.1) 0.2
Cerebrovascular 17 (18.3) 6 (12.8) 6 (25.0) 5 (22.7) 0.8
Carotid 16 (17.2) 3 (6.4) 6 (25.0) 7 (31.8) 0.01
Common iliac 15 (16.1) 7 (14.9) 2 (8.3) 6 (27.3) 0.2
Pulmonary 15 (16.1) 2 (4.3) 9 (37.5) 4 (18.2) 0.003
Subclavian 10 (10.8) 1 (2.1) 3 (12.5) 6 (27.3) 0.01 * Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and Alagille
Syndrome †
Defined as abdominal collateral vessels
66
2.3.3 Management and post-operative outcomes
A total of 62 children (67%) received oral antihypertensive drugs upon initial
presentation. The remainder of the children had systolic blood pressures less than the 95%
percentile and did not require any antihypertensive therapy. The most commonly used agents at
baseline evaluation included calcium channel blockers (66%), followed by beta blockers
(46.8%), angiotensin converting enzyme inhibitors (ACEi; 31%), diuretics (13%), and alpha
blockers (10%). A summary of medical management is presented in Table 2.3.
A total of 65 children (70%) were managed invasively, and 28 (30%) were managed with
antihypertensive therapy alone. Twenty-nine children (31%) had a surgical procedure; including
reconstruction patch grafts, nephrectomy, aortoaortic bypass, and renal auto-transplantation.
Surgical management is summarized in Table 2.4. Post-operative course was uneventful in 66%
of children, and complications were described in 30%. Overall, children with systemic disease
had more complications compared to those with unknown disease. The first post-operative clinic
visit was 8 ± 2 months from the procedure. Mean blood pressure Z-score at that time was 1.7 ±
1.6 (compared to 1.8 ± 1.5 pre-intervention, p=0.3). Mean number of antihypertensives was 1.9 ±
1.1 (compared to 1.2 ± 1.0 pre-intervention, p=0.01).
67
Table 2.3 Medical management in 93 children with MAS/RAS by underlying etiology
Total
n(%) Unknown Genetic* Inflammatory
Variable n= 93 n= 47 n= 24 n= 22 p
Antihypertensive therapy
at presentation 62 (66.7) 31 (67.4) 18 (72.0) 13 (59.1) 0.6
Class of medication
Calcium channel blocker 41 (66.1) 22 (71.0) 10 (55.6) 9 (69.2) 0.8
Beta-blocker 29 (46.8) 12 (38.7) 11 (61.1) 6 (46.2) 0.3
RAAS blocker§ 19 (30.6) 11 (35.5) 5 (27.8) 3 (23.1) 0.6
Diuretic 8 (12.9) 2 (6.5) 1 (5.6) 5 (38.5) 0.03
Alpha-blocker 6 (9.7) 3 (9.7) 2 (11.1) 1 (7.7) 0.9
Number of medications
1 35 (56.5) 16 (51.6) 12 (66.7) 6 (46.1) 0.1
2 16 (25.8) 11 (35.5) 4 (22.2) 2 (15.4) .
3 or more 11 (17.7) 4 (12.9) 2 (11.1) 5 (38.5) .
Other medications
Immunosuppression 21 (22.6) 0 (0) 0 (0) 21 (95.5) .
* Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and Alagille
Syndrome §
Renin-Angiotensin-Aldosterone system blockers used included Angiotensin-converting enzyme
inhibitors and Angiotensin receptor blockers
68
Table 2.4 Surgical management and post-operative outcomes in 93 children with renovascular
hypertension by underlying etiology
Total Unknown Genetic
* Inflammatory
n= 93 n= 47 n= 24 n= 22
Variable Mean ± SD or n (%) p
Surgical management 29 (31.2) 13 (27.7) 9 (37.5) 7 (31.8) 0.8
Age at surgery, years 6.1 ± 5.4 4.3 ± 4.6 4.4 ± 4.6 11.1 ± 4.9 0.003
Procedure
Reconstruction patch graft 9 (31.0) 3 (23.1) 5 (55.5) 1 (14.3) 0.2
Nephrectomy 8 (27.6) 7 (53.8) 0 (0) 1 (14.3) 0.1
Aortoaortic bypass 7 (24.1) 3 (23.1) 2 (22.2) 2 (28.6) 0.1
Aortic patch plasty 4 (13.8) 2 (15.4) 2 (22.2) -- 0.3
Auto-transplantation 5 (17.2) 1 (7.7) 1 (11.1) 3 (42.8) 0.1
Post-operative outcomes
Uneventful 20 (69.0) 10 (76.9) 6 (66.7) 4 (57.1) 0.4
Complicated 9 (31.0) 3 (23.1) 3 (33.3) 3 (42.9) .
Blood pressure outcomes≠
Systolic blood pressure Z-score 1.9 ± 1.5 1.6 ± 1.1 2.3 ± 2.0 2.8 ± 0.6 0.7
Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.7 1.8 ± 1.0 2.5 ± 1.5 0.2 * Genetic etiology consists of Neurofibromatosis, Williams' Syndrome, and Alagille Syndrome
‡ 65 children had at least one intervention, including 17 children who had both a surgical and an
endovascular intervention ≠
Post-operative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after
intervention
69
Endovascular intervention were performed in 53 (57%) children, and consisted of a
percutaneous transluminal angioplasty (PTA) in 40 (75%). The remaining 13 (25%) had PTA
with stent placement (stents were placed in the aorta in 10 children, and in the renal artery in 3
children). Endovascular management is summarized in Table 2.5. Post-operative outcomes
following endovascular procedure were uneventful in 83% of children. Complications were
described in 13% of cases, and technical failure was observed in one patient (2%). The first
follow-up visit was 9 ± 2 months from the procedure. Mean blood pressure Z-score was 1.9 ± 1.5
(compared to 2.1 ± 1.2 pre-intervention, p=0.2). Mean number of antihypertensives was 1.6 ± 0.9
(compared to 1.3 ± 1.0 pre-intervention, p=0.6). A total of 17 children (18%) had both an
endovascular and a surgical procedure. Total 30-day mortality was 3.1%. Two children with
inflammatory disease died of disease-related complications; one child died following an aortic
stent placement and the other died shortly after clinical presentation. Apart from those two cases,
no deaths occurred over the observation period.
The Kaplan Meier survival curve shows the timing of first intervention by etiology
(Figure 2.1). Those with unknown etiology had the highest cumulative probability of receiving
interventional therapy, followed by those with inflammatory disease, and the lowest probability
in those with genetic conditions (p log-rank= 0.002). Median time to intervention was 0.9 [0.2-
2.2] years in children with unknown disease, 1.8 [0.4-5.2] years in those with inflammatory
disease, and 2.9 [1-4.9] years in those with genetic disease.
70
Table 2.5 Endovascular management and post-operative outcomes in 93 children with renovascular
hypertension by underlying etiology
Total Unknown Genetic
* Inflammatory
n= 93 n= 47 n= 24 n= 22
Variable Mean ± SD or n (%) p
Endovascular management‡ 53 (57.0) 33 (70.2) 9 (37.5) 11 (50.0) 0.01
Age at intervention, years 8.4 ± 5.5 9.8 ± 5.1 3.8 ± 2.8 10.8 ± 5.5 <0.001
Procedure
PTA† 40 (75.5) 30 (90.9) 6 (66.7) 4 (36.4) 0.002
PTA with stent 13 (24.5) 3 (9.1) 3 (33.3) 7 (63.6) .
Post-operative outcomes
Uneventful 44 (83.0) 29 (87.9) 7 (77.8) 8 (72.7) 0.4
Complicated 7 (13.2) 3 (9.1) 2 (22.2) 2 (18.2) .
Unsuccessful 1 (1.9) 1 (3.0) -- -- .
Blood pressure outcomes≠
Systolic blood pressure Z-score 1.7 ± 1.6 1.4 ± 1.6 2.2 ± 2.1 2.3 ± 0.9 0.5
Number of antihypertensives 1.9 ± 1.1 1.6 ± 0.8 1.8 ± 0.9 2.2 ± 1.5 0.4
PTA: percutaneous transluminal angioplasty * Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and Alagille Syndrome
‡ 65 children had at least one intervention, including 17 children who had both a surgical and an
endovascular intervention ≠
Post-operative blood pressure outcomes were assessed at first follow-up clinic 9 ± 2 months after
intervention
71
Figure 2.1 Interventional procedures (endovascular or surgical) among MAS/RAS of unknown,
genetic, or inflammatory etiology of disease
72
Results of the Cox regression are summarized in Table 2.6. After adjusting for age, sex,
and systolic BP z-score, children with unknown disease had a three times higher risk of
interventions compared to those with genetic disease (HR=3.2, 95% CI [1.6-5.3], p<0.001 ).
After adjusting for age, sex, and systolic BP z-score, those with MAS/RAS had a 60% lower risk
of receiving invasive management as compared to those with isolated RAS (HR=0.4, 95% CI
[0.2-0.8], p=0.006).
Table 2.6 Association between etiology of disease and risk of interventions using Cox
regression analysis
Univariable Multivariable*
Etiology HR 95% CI P HR 95% CI P
Systemic†
ref ref -- ref ref --
Unknown 2.6 1.5, 4.4 0.001 3.2 1.6, 5.3 <0.001
Extent of disease HR 95% CI P HR 95% CI P
Isolated RAS ref ref -- ref ref --
MAS/RAS 0.6 0.4, 1.0 0.1 0.4 0.2, 0.8 0.006
* Multivariable model adjusted for age, sex, and systolic blood pressure Z-score †
Systemic includes genetic and inflammatory etiologies
73
2.3.4 Follow-up
Median follow up time was 1.9 [0.4-4.7] years, and mean age at follow-up was 10 ± 5
years (Table 2.7). Figure 2.2 summarizes average annual systolic blood pressure Z-score over the
longitudinal follow-up period stratified by medical management or intervention. The results of
the linear mixed-effects model examining the longitudinal change in systolic blood pressure is
summarized in Table 2.8. Having MAS/RAS was associated with an increase in systolic blood
pressure Z-score compared to those with isolated RAS (unadjusted β=1.3, 95%CI 0.6, 1.9), the
association remained significant after adjusting for the number of antihypertensive agents (β=1.2,
95%CI 0.6,1.8). The longitudinal change in systolic blood pressures did not differ by etiology, or
between medical and interventional management. There were no differences in outcomes in
terms of residual hypertension and use of antihypertensive medications between those receiving
interventional management compared to those managed medically (Table 2.9).
74
Figure 2.2 Systolic blood pressure Z-score on annual follow-up by management type. The red
line depicts the 95th
percentile for age, height, and sex.
75
The majority of children (66%) were still hypertensive at follow-up, 17% were
normotensive without requiring any antihypertensive medications, and 17% had controlled blood
pressure with antihypertensive therapy (Table 2.7). Mean number of antihypertensive agents
used was 1.2 ± 1.0, and did not differ by etiology.
Of those who had received a primary endovascular or surgical intervention, 33 (51%) had
a re-stenosis of the same vessel, and 25 (39%) received a re-intervention. Re-interventions were
more common among those with genetic and inflammatory disease compared to children with
unknown disease (58% and 69% vs. 23% respectively, p<0.001). There was no progression from
isolated RAS to MAS/RAS or new visceral arterial or cerebrovascular disease throughout the
observation period, and the vascular phenotype at last follow-up was unchanged from that at the
time of initial clinical presentation. Two children initially diagnosed with RAS underwent
additional diagnostic imaging which revealed abdominal aortic involvement that was not
detected at presentation.
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Table 2.7 Follow-up and outcomes following management of 93 children with MAS/RAS by underlying
etiology
Total n(%) Unknown Genetic* Inflammatory
Variable n= 93 n= 46 n= 25 n= 22 p
Median follow-up time 1.9 [0.4-4.7] 1.7 [0.7-4.2] 2.9 [0.8-5.2] 1.8 [0.1-4.5] 0.4
Mean age at follow-up 10.1 ± 5.1 10.0 ± 5.2 8.6 ± 4.8 12.2 ± 4.7 0.04
Secondary outcomes following
intervention 65 (69.9) 40 (87.0) 12 (48.0) 13 (59.1) 0.001
Re-stenosis† 33 (50.8) 16 (40.0) 9 (36.0) 8 (36.4) 1.0
Re-intervention‡ 25 (38.5) 9 (22.5) 7 (58.3) 9 (69.2) <0.001
Blood pressure control on last
follow-up
Systolic blood pressure SDS 2.4 ± 1.7 2.2 ± 1.6 2.4 ± 1.8 2.4 ± 1.7 0.8
Diastolic blood pressure SDS 1.0 ± 1.3 1.1 ± 1.4 0.7 ± 1.2 1.1 ± 1.2 0.4
Blood pressure control status
Hypertensive 61 (65.6) 25 (54.4) 20 (80.0) 16 (72.7) 0.5
Normotensive without
medication 16 (17.2) 10 (21.7) 3 (12) 3 (13.6) .
Controlled with
antihypertensive medication 16 (17.2) 11 (23.9) 2 (8.0) 3 (13.6) .
1 medication 6 (37.5) 3 (27.3) 2 (100) 1 (33.3) .
2 medications 6 (37.5) 6 (54.5) 0 (0) 0 (0) .
3 or more medications 4 (25.0) 2 (18.2) 0 (0) 2 (66.7) .
* Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and Alagille Syndrome
† Defined as a stenosis of an artery previously dilated with an endovascular procedure
‡ Defined as a second endovascular or surgical procedure on the same artery
SDS: standard deviation score
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Table 2.8 Association between the longitudinal change in systolic blood pressure and
patient characteristics using linear mixed-effects analysis
Univariable Multivariable*
Etiology
Systemic ref ref -- ref ref --
Unknown -0.1 -0.8, 0.5 0.7 -0.2 -0.8, 0.5 0.6
Extent of disease β 95% CI P β 95% CI P
Isolated RAS ref ref -- ref ref --
MAS/RAS 1.3 0.6, 1.9 <0.001 1.2 0.6, 1.8 <0.001
Management
Medical ref ref -- ref ref --
Invasive 0.1 -0.62, 0.83 0.8 0.15 -0.56, 0.87 0.9
* Multivariable model adjusted for number of antihypertensive medications
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Table 2.9 Characteristics of children with MAS/RAS by choice of invasive or non-invasive
management
Invasive
management
Non-invasive
management
Variable n=65 n= 28 p
Baseline characteristics
Age 6.6 ± 0.7 8.0 ± 1.1 0.2
Male sex 31 (47.7) 14 (50.0) 0.8
Systolic blood pressure SDS 2.3 ± 1.9 1.6 ± 1.4 0.08
Diastolic blood pressure SDS 0.8 ± 1.1 0.6 ± 1.1 0.3
Grade
Isolated RAS 36 (55.4) 10 (35.7) 0.08
MAS +/- RAS 29 (44.6) 18 (64.3) 0.3
Number of aortic branches affected 2.2 ± 1.4 2.4 ± 1.4 0.5
Etiology
Idiopathic 40 (61.5) 7 (25.0) <0.001
Genetic* 12 (18.5) 12 (42.8) 0.008
Inflammatory 13 (20) 9 (32.2) 0.2
Follow-up
Residual hypertension 42 (64.6) 19 (67.9) 0.8
Number of medications on follow-up 1.2 ± 1.1 1.2 ± 1.2 0.9
Systolic blood pressure SDS 2.4 ± 1.8 2.2 ± 1.5 0.6
Diastolic blood pressure SDS 1.1 ± 1.5 0.8 ± 0.8 0.4
SDS: standard deviation score, MAS: middle aortic syndrome, RAS: renal artery stenosis
* Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and
Alagille Syndrome
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2.3.5 Era effect
The majority of children presented in the last 10 years of the study period (Figure 2.3).
To evaluate an era effect, children were divided into two groups based on whether they presented
during the first (1986-2005, n=41) or second (2006-2016, n=52) period of the reported
experience (Table 2.10). Children in the earlier period presented at a younger age (6 ± 5 vs. 8 ±
6, respectively, p=0.04). The earlier time period had a higher proportion of children undergoing
surgical intervention and a higher proportion of re-interventions. There was no difference in
mean age at the time of surgical or endovascular intervention between the two time periods.
Figure 2.3 New diagnoses of childhood MAS/RAS and number of endovascular procedures
performed by calendar year
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Table 2.10 Characteristics of children with MAS/RAS by time period of
presentation
1986-2005 2006-2016
Variable n=41 n= 52 p
Baseline characteristics
Age, years 5.7 ± 4.9 8.0 ± 5.5 0.04
Male sex 20 (48.8) 28 (53.85) 0.6
Grade
Isolated RAS 19 (46.3) 27 (51.9) 0.6
MAS +/- RAS 22 (53.7) 25 (48.1) 0.6
Number of aortic branches affected 2.1 ± 1.4 2.4 ± 1.5 0.4
Etiology
Idiopathic 20 (48.8) 27 (51.9) 0.6
Genetic* 7 (17.1) 17 (32.7) 0.2
Inflammatory 14 (34.1) 8 (15.4) 0.04
Management
Age at intervention 10.6 ± 5.1 7.3 ± 5.5 0.2
Surgical intervention 19 (46.3) 10 (19.2) 0.005
Endovascular intervention 28 (68.3) 25 (48.1) 0.05
Re-intervention 14 (34.2) 8 (15.4) 0.04
Follow-up
Residual hypertension 26 (63.4) 35 (67.3) 0.7
Number of medications on follow-up 1.0 ± 1.1 1.3 ± 1.2 0.1
SDS: standard deviation score, MAS: middle aortic syndrome, RAS: renal artery
stenosis
* Genetic etiology consists of Neurofibromatosis type I, Williams' Syndrome, and
Alagille Syndrome
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2.4 Discussion
In this study we describe outcomes following management in a large cohort of childhood
MAS and RAS. The etiology of most cases is unknown with disease predominantly confined to
the peri-renal segment of the aorta. Children with genetic or inflammatory causes have more
extensive disease involving proximal aortic branches. Most children were managed with
endovascular or surgical interventions, and over two thirds of children have residual or persistent
hypertension.
Despite the increased recognition of the clinical presentation of MAS/RAS in children
over the past decade, there are still many gaps in our understanding of this rare disease. One of
the main challenges in managing MAS/RAS is the lack of data on pathogenesis. This is crucial
given that etiology of disease greatly influences the choice of management in children.
Interventions are delayed in children with inflammatory disease during the acute phase of the
disease until the inflammation is treated to reduce the risk of operative complications. Children
with genetic causes are generally treated conservatively given the underlying disease and
potential risk associated with invasive management. Some diagnoses of exclusion are often
attributed to this disease including fibromuscular dysplasia (FMD) or burnt out Takayasus
arteritis(Tullus, 2008). In most reported case series of childhood RAS, there is little evidence of
the classic angiographic appearance of beading, a common feature of medial hyperplasia in
adults(Tullus, 2013). Furthermore, the vascular involvement in adult FMD compared to pediatric
cases of MAS/RAS is clearly different, with more cerebrovascular and carotid disease in adults
compared to isolated RAS or confined peri-renal aortic disease in children(Rumman, 2015,
Green, 2015, Olin, 2012). Thus, it is possible that children with unknown etiology may not meet
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diagnostic criteria for FMD. An anatomical classification of isolated RAS or RAS in conjunction
with MAS (MAS/RAS) is preferred until the pathogenesis is more clearly delineated. The second
diagnosis of exclusion in children with MAS/RAS is burnt out Takayasu’s, however, we found
differences in aortic involvement between children with unknown disease and those with
inflammatory disease. Children with unknown disease presented at a younger age and had less
extensive vascular involvement compared to children with inflammatory disease, who presented
at an older age with carotid, cerebrovascular and proximal aortic involvement including
aneurysms.
We found no evidence of vascular disease progression in terms of new aortic
involvement or expanding vascular involvement. Similar to other studies, we observed re-
stenosis of vessels in approximately half the children who were managed invasively, but this was
confined to the same vessel rather than a progressive narrowing of additional aortic segments.
Additionally, we have seen no evidence of disease progression to include carotid and
cerebrovascular disease or development of new symptoms. It is worth noting, however, that we
did not conduct systematic imaging of non-diseased vessels such as the carotid arteries. Future
studies should confirm the findings with more systematic imaging on follow-up.
An important finding is residual or persistent hypertension in children with MAS/RAS
regardless of interventional or conservative management. Given that the majority of children still
require antihypertensive management despite partial or complete relief of the renal artery
stenosis or aortic narrowing, defining treatment success as complete resolution or “cure” of
hypertension may not be realistic in this disease. Compared to other studies reporting complete
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resolution of hypertension in children(Kari, 2015), we found that most children had persistent
hypertension requiring long-term medical management. The etiology of the residual
hypertension remains elusive, with hypotheses that include an underlying arteriopathy, or an
effect of residual narrowing on proximal hemodynamics. Clinical follow-up and monitoring of
these children is still warranted and should include annual evaluation of hypertension and end-
organ disease.
In contrast to published case series from other centers, diagnostic angiography is not
routinely used in our pediatric cohort(Kari, 2015). Repeated catheter-based imaging is also not
done for follow-up after endovascular interventions. Rather, follow-up imaging is mainly
consists of abdominal ultrasound until worsening of symptoms or evidence of end-organ disease
merit further cross-sectional imaging (CT angiography or MR angiography) or a secondary
intervention. As children often outgrow any surgical graft, surgical intervention is delayed until
the child has reached optimal growth. Given that multiple endovascular procedures are likely
needed over the life of the child due to restenosis of the vessels, delaying endovascular
interventions by managing the blood pressure with antihypertensive therapy is preferred. Clear
guidelines for the diagnosis and management of MAS/RAS in children are not defined, and are
challenging to standardize given the heterogeneity of the patient population in terms of etiology,
response to medications, and vascular involvement. Previous studies have advocated residual
hypertension despite 2 or more antihypertensive agents as criteria for endovascular
intervention(Kari, 2015), however, the potential benefit of blood pressure lowering with
angioplasty needs to be balanced against the associated risk of repeated interventions especially
given the high prevalence of residual hypertension after successful endovascular result.
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Of note is the finding of multiple renal arteries in 25% of children. This has been
described in some case reports of childhood MAS, but has never been directly associated with
the pathogenesis of disease and is likely related to embryological development. Development of
kidney is very complex, as it develops from the pronephros, mesonephros and metenephros
(Sykes, 1963). The pronephros and mesonephros regress but the arterial network to those
segments may remain and lead to supernumerary renal arteries.(Manupati, 2014) The
metanephros is the functional kidney and to begin with it is located in the sacral region and it
gradually ascends to upper lumbar region during 6th to 9th week of development. During its
ascent its blood supply shifts from branches of internal iliac to common iliac artery and finally to
the abdominal aorta. Vasculature development is strictly dependent on the cephalic migration of
kidneys during embryogenesis(Cicekcibasi, 2005, Kornafel, 2010, Ozkan, 2006, Prakash, 2011,
Saldarriaga, 2008, Sampaio, 1992, Satyapal, 2001, Tarzamni, 2008, Wozniak, 2000).
Different origins of renal arteries and frequent variations are explained by the
development of mesonephric arteries. During embryogenesis, there exists a genitourinary arterial
system composed of a few mesonephric arteries that form a vascular net feeding the kidneys,
suprarenal glands, and gonads on both sides of the aorta between cervical 6 and lumbar 3
vertebrae, a region known as rete arteriosum urogenitale. In the course of the embryonic devel-
opment, these arteries degenerate, leaving only one mesonephric artery, which undertakes
arterial circulation of the kidneys. Any abnormalities of this process such as a deficiency in the
development of mesonephric arteries or a failure of degeneration of these primitive lower vessels
may lead to a higher number of renal arteries(Kornafel, 2010),(Ozkan, 2006).
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The classic description of the renal vasculature as consisting of one renal artery and one
renal vein occurs in less than 25% of cases. Variations in the renal vasculature are common and
have been well documented in previous studies, both from post mortum analysis and
spontaneously aborted fetuses(Manupati, 2014, Delasotta, 2014). Cicek et al 2005 examined the
origin, localizations and anatomic variations of 180 renal arteries in 90 human
fetuses(Cicekcibasi, 2005). They found normal RA structure in 52 out of the 90 fetuses, and
variations in the origin of the main RAs in relation to the vertebrae, and in relation to the aortic
wall. There were uni- or bilateral anatomical variations in 42% of cases. Anatomical variations
were observed more frequently in males and on the right side. There are also variations in the
level of the right and left renal ostia and take off point relative to aorta (right usually above and
more anterior as compared to the left). The prevalence of multiple renal arteries in various series
range from 20% to 75%(Cicekcibasi, 2005, Tarzamni, 2008, Wozniak, 2000, Ugurel, 2010).
Other studies used CTA examination to determine the prevalence of variations of the
main arteries branching from the abdominal aorta(Kornafel, 2010). They have shown that among
all abdominal aorta ramifications, renal arteries show the highest anatomical variability. Renal
vasculature anomalies were observed in 41.3%, and within 110/402 kidneys (27.4%). The
revealed anomalies were divided into 2 groups: early branching of the renal artery (within 2 cm
from the orifice of the renal artery at the aorta; normally observed at the level of the renal hilum)
and the presence of additional arteries. Among the additional arteries, 2 groups were identified:
renal polar arteries (superior and inferior) and hilar arteries(Kornafel, 2010). Furthermore,
variants of the renal arteries were significantly more frequent than the variants of the celiac trunk
(4.5% of patients) or of the superior mesenteric artery (2%).
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Accessory renal vessels constitute the most common, clinically important vascular
variant seen in approximately one- third of population(Manupati, 2014, Kornafel, 2010, Ozkan,
2006). Several studies to date have examined the prevalence of multiple renal arteries in the
healthy population, some reposting a prevalence as high as 40%(Sykes, 1963, Saldarriaga, 2008,
Tarzamni, 2008). In that series multiple renal arteries were unilateral in 30% of patients and
bilateral in 10% of patients(Manupati, 2014). Similar studies have found more than one renal
artery 24% of their patient cohort(Ozkan, 2006). A 20% incidence of accessory renal arteries
with a 15% unilateral and 5% bilateral is the general consensus in the literature(Manupati, 2014,
Ozkan, 2006, Prakash, 2011). Another study reports a thoracic main right renal artery off the
thoracic aorta, an otherwise unexpected location that may lead to serious complications if
overlooked during vascular procedures(Delasotta, 2014).
Since multiple renal arteries have been described in similar frequency in the healthy
population (20-40%), we cannot make any inferences regarding an embryological cause of MAS
and RAS in children.
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2.5 Limitations
This study has some limitations inherent to the retrospective study design. Children
underwent variable imaging modalities and of different vascular beds which may have limited
the extent of phenotypic description. The possibility of referral bias cannot be excluded as cases
are referred to a multidisciplinary tertiary center for consideration of interventional management.
Further, the differences in time to intervention may also be due the later diagnosis of children
with unknown disease, compared to those with genetic disease who would have been diagnosed
at a younger age due to the presence of dysmorphic features. Therefore, it is possible that those
with unknown etiology had more severe disease by the time of delayed presentation such that an
intervention is merited soon after presentation. Despite these limitations, our results demonstrate
important clinical observations from one of the largest cohorts of childhood MAS/RAS. We
found that residual hypertension following invasive and non-invasive management of MAS/RAS
is highly prevalent. This finding highlights the importance of adequate blood pressure control
and the need for close monitoring of this patient population. Further longitudinal studies are
needed to evaluate the effect of persistent hypertension on end-organ cardiac disease, and to
determine whether further blood pressure control improves outcomes in this patient population.
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2.6 Conclusion
MAS/RAS in children is a disease of the peri-renal aorta. Despite the increased diagnosis
of MAS/RAS due to new imaging modalities, the majority of cases have no known etiology.
Children with MAS/RAS have residual and persistent hypertension following both invasive and
medical management, which merits investigation of end-organ cardiac disease. Guidelines for
the management of renovascular hypertension and MAS/RAS remain unclear, specifically
criteria for endovascular or surgical intervention and clinical monitoring. Future studies with
prospective follow-up are needed to determine the potential benefit of further blood pressure
lowering.
In the next chapter, we will address the second gap in knowledge, which was to explore
the aortic disease and whether there is evidence of peripheral vascular disease in children with
MAS and/or RAS. Given the high prevalence of persistent hypertension that we have shown in
this chapter, evaluation of structural and vascular adaptations to chronic hypertension is merited.
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Chapter 3 Aortic and Peripheral Vascular Disease in Childhood MAS/RAS
90
3 «
3.1 Introduction
Middle aortic syndrome (MAS) is a rare disease characterized by stenosis of the
abdominal aorta. The etiology of MAS remains unknown, but genetic disorders such as
Williams’ syndrome, Neurofibromatosis type I and Alagille syndrome, as well as inflammatory
diseases such as Takayasu’s arteritis are known to be associated with MAS(Rumman, 2015).
The stenosis in MAS is generally confined to the peri-renal aortic segment, and renal
artery stenosis (RAS) is present in at least 70% of cases at the time of presentation(Rumman,
2015). This further complicates clinical and surgical management(Porras, 2013). Despite the
confined aortic involvement, the effects of MAS on the overall vascular system and the
involvement of peripheral arteries other than the aorta and renal vessels have not been well
studied. In the current chapter, we wanted to assess early changes in vascular structure and
function in MAS/RAS patients by measuring carotid artery intima-media thickness (CIMT),
carotid artery distensibility, and pulse wave velocities (PWV). CIMT is widely used as a marker
for early vascular remodeling in patients with atherosclerosis and arterial
hypertension(Giannarelli, 2012, Bots, 2012). Carotid artery distensibility is considered an
indicator of regional arterial function(Doyon, 2013), whereas PWV is a more global measure of
arterial stiffness(Najjar, 2008, Laurent, 2006). Both increased CIMT and elevated PWV are
considered important early markers for cardiovascular disease(Oren, 2003), and are predictive of
cardiovascular events in various adult populations(Koivistoinen, 2012, Vlachopoulos, 2010,
Lorenz, 2012). These methods have also been used in specific high-risk pediatric populations,
including children with diabetes, obesity, and aortic coarctation(Vriend, 2005, Tounian, 2001).
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In children with MAS/RAS, we hypothesize that other vessels may be affected either by the
underlying disease process, or indirectly through the commonly associated arterial hypertension.
We also wanted to assess central aortic properties to determine the physiological
adaptations to chronic hypertension. This included measurement of central blood pressures,
central pulse wave velocity, and quantification of the reflected wave by measurement of the
augmentation index, as described in our conceptual model. Assessment of central blood pressure
estimates more accurately the load acting on the left ventricle, as compared to brachial pressures
used to monitor patients clinically. Central pulse wave velocity is a global measure of central
arterial stiffness, and may reflect structural aortic changes resulting from chronic exposure to
increased distending pressures. Another measurement of aortic stiffness is characteristic
impedance. Whereas pulse wave velocity is relatively unaffected by vessel diameter,
characteristic impedance will change if the operating diameter of the vessel changes, which is the
case in children with MAS.
The interaction between the arterial system and the heart, ventricular-arterial coupling, is
an important determinant of cardiovascular performance. Therefore, the pathophysiology and
clinical implications of arterial stiffening should be considered together with cardiac function. In
addition to evaluating peripheral and aortic properties, we wanted to assess ventricular-arterial
coupling non-invasively using the ratio of arterial elastance to left ventricular end-systolic
elastance. Optimal coupling of the cardiovascular system in this group would indicate that
children are well adapted to chronic exposure to hypertensive overload.
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Detection of alterations in vascular structure and function may provide a valuable
supplement in the clinical evaluation of MAS/RAS, and may help to adapt the long-term
management of the disease. It may also add to our knowledge of the physiological adaptations of
the vasculature to aortic stenosis and chronic hypertension.
3.2 Material and methods
3.2.1 Patient recruitment and inclusion criteria
A total of 40 children recruited from the complex hypertension clinic at the Hospital for
Sick Children (Toronto, Canada) were enrolled into a prospective cohort study between 2014-
2016. Inclusion criteria were ages <18 years, and a diagnosis of MAS and/or RAS. Patients were
categorized based on the extent of vascular involvement into those with isolated RAS, and those
with RAS in conjunction with MAS (MAS/RAS). The cohort was also categorized by underlying
etiology as unknown or systemic disease. The latter category included inflammatory conditions
such as Takayasu’s arteritis, and genetic disorders including Williams’ syndrome,
Neurofibromatosis type I and Alagille syndrome.
A total of 132 healthy children recruited from the cardiac assessment clinic were
investigated cross-sectionally using the same imaging protocol. The exclusion criteria for this
group were: 1) presence of a significant cardiovascular risk factor; 2) a hemodynamically
significant cardiovascular anomaly; 3) an active disease that could interfere with cardiovascular
function; or 4) children on cardiac or vasoactive medications. We generated a matched healthy
control group based on age, sex, and body surface area (BSA) with 1:4 matching to ensure
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adequate statistical power. The study protocol was approved by the Research Ethics Board at the
Hospital for Sick Children, and written informed consent was obtained from all participants.
3.2.2 Vascular measurements
All vascular measurements were performed in a quiet room after 10 minutes of supine
rest using standardized protocols(Urbina, 2009). The left and right common carotid arteries were
examined by high resolution B-mode imaging using the Vivid 7 (GE Ultrasound, USA)
ultrasound system equipped with a 12-MHz linear-array transducer, as previously described by
our group(Sarkola, 2010). CIMT was calculated using an external software (Carotid Analyser,
Medical Imaging Applications). The mean of three CIMT measurements was calculated for each
of the right and left common carotid arteries, and the average of these two values was the
reported CIMT. Carotid artery distensibility was calculated using the equation: 1/[ln(systolic
BP/diastolic BP)/strain × CIMT], where strain was calculated as the difference between the
maximum and minimum carotid diameters, divided by carotid minimum diameter.
Peripheral (carotid to radial) and central (carotid to femoral) pulse-wave velocities were
measured by applanation tonometry (SphygmoCor, USA). Right carotid, radial and femoral
artery pulse waveforms were recorded. The time delay between the arrival of a predefined point
of the pressure waveforms at the two sites was measured. PWV was calculated using the
measured distance travelled between two recording sites. Central systolic and diastolic pressures
were recorded, and central pulse pressure was calculated, as previously described(Tounian, 2001,
Sarkola, 2010). The wave transit time was determined. Right radial artery waveforms were
recorded, and the pulse-wave analysis was used to generate a central (ascending aortic)
94
waveform using the generalized transfer function and augmentation index. Luminal diameters
during systole and diastole of the common carotid artery, ascending aorta, and abdominal aorta
were measured using echocardiography, and the distension coefficients were calculated. The
ascending aortic stiffness index was calculated as previously described(Koopman, 2012). The
reproducibility of the vascular measurements was assessed in 20 healthy volunteers. The
calculated intraobserver and interobserver coefficients of variation were 3% and 7%,
respectively, for CIMT, and 5% and 6%, respectively, for carotid to radial PWV.
Ventricular-arterial coupling was measured using noninvasive methods that were
previously validated in adults(Kass, 2005), using the ratio of arterial elastance (Ea) to LV end-
systolic elastance (Ees). The Ea was calculated as the ratio of end-systolic pressure to left
ventricular stroke volume. End-systolic pressure was calculated noninvasively as 0.9 multiplied
by brachial systolic pressure. Left ventricular stroke volume was measured by echocardiography
using the following equation: velocity-time integral of the pulsed-wave Doppler trace of the LV
outflow tract multiplied by the aortic valve orifice cross-sectional area. The Ees was estimated
using a using the obtained brachial blood pressures, left ventricular stroke volume, and estimated
normalized Ees at arterial end-diastole, which was calculated as the ratio of the aortic pre-
ejection time to total systolic time.
Height and weight were measured, and body mass index (BMI) was calculated. BSA was
calculated using Haycock’s formula. Right-arm blood pressure was measured using an arm size-
appropriate cuff as the average of three readings with an automated Dinamap
sphygmomanometer (Critikon, Tampa, FL) and recorded along with resting heart rate. Standard
95
deviation scores (SDS) for systolic and diastolic blood pressures, and BMI were derived from the
Centre for Disease and Control (CDC) growth charts and the 4th
Task Force Report(Kuczmarski,
2002, Falkner, 2004). Systolic hypertension was defined as systolic blood pressure equal to or
greater than the 95th
percentile for patients of the same age, sex and height. Management of MAS
and/or RAS was categorized as: antihypertensive therapy alone, interventional management
(including surgical and endovascular procedures), or no therapy at time of vascular assessment.
3.2.3 Statistical analysis
Categorical data are reported as frequency and percentage, and continuous variables are
expressed as the mean ± standard deviation (SD). Student t-tests were used to assess the
differences between children with and without the disease. An ANOVA test was used to
compares differences between healthy controls and the patient groups. Differences in frequencies
were assessed using a chi-square test. Linear regression analysis was used to identify
associations between vascular parameters and the degree of vascular involvement (RAS alone
versus RAS/MAS). In multivariable analysis, we examined potential confounders including
systolic and diastolic blood pressure SD scores, BMI SD score, and antihypertensive or
interventional (endovascular and surgical) therapy. The final parsimonious model reported
included systolic blood pressure SD scores as the only significant confounder. Predicted values
for CIMT were generated using the final multivariable model. Similar analyses were conducted
to examine the association between vascular parameters and etiology of disease. The normality
of the residuals was graphically assessed with plots of residuals against fitted values and
histograms.
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As a sensitivity analysis, we excluded children with inflammatory disease and examined
the association between the vascular parameters and etiology categorized as genetic versus
unknown disease. A two-tailed p-value of 0.05 was considered statistically significant. All
statistical analyses were performed using Stata 13.0 (College Station, Texas).
3.3 Results
3.3.1 Patient characteristics
A total of 33 children completed baseline vascular assessments and were included in the
current analysis. Vascular assessment could not be completed in 7 patients due to lack of patient
cooperation (n=1), logistical reasons (n=2), and age <8 years (n=4). Table 3.1 summarizes the
demographic and clinical characteristics of children with MAS and/or RAS and 132 matched
healthy controls. Mean age of children with MAS and/or RAS at the time of recruitment was
12.3 years (SD 3.1), and 48.5% were male. Mean time between clinical presentation and vascular
imaging was 6.3 ± 5.2 years. Children with MAS and/or RAS had significantly higher systolic
and diastolic blood pressure SDS compared to healthy controls. BMI and BMI SDS were higher
in children with disease compared to healthy controls.
In terms of vascular involvement, 18 children (54.5%) had isolated RAS, and 15 children
(45.5%) had RAS/MAS. Children with MAS/RAS had higher systolic BP and systolic BP SDS
compared to those with isolated RAS. Of the cases, 18 (54.5%) had systemic disease (13 genetic
and 5 inflammatory), and the remaining 15 children (45.5%) had disease of unknown etiology.
Genetic etiology consisted of 8 children with Neurofibromatosis type I, 4 children with
Williams’ Syndrome, and 1 with Alagille syndrome. Inflammatory disease included Takayasu’s
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arteritis (4) and nonspecific arteritis (1). Of the children enrolled 19 (57.6%) were receiving
antihypertensive therapy, including calcium channel blockers (33.3%), beta-blockers (30.3 %),
and angiotensin converting enzyme (ACE) inhibitors (9.1%). At the time of cardiovascular
imaging, 19 (57.6%) had already received interventional therapy (endovascular procedures in 10,
surgical correction in 5, and both surgical and endovascular procedures in 4), 7 (21.2%) were
managed with antihypertensive therapy alone, and the remaining 7 (21.2%) children had not
received therapy.
3.3.2 Vascular properties
The vascular properties of the carotid artery and tonometry-derived PWV are
summarized in Table 3.2. Average CIMT was significantly higher in children with MAS and/or
RAS compared to matched healthy controls (0.51 ± 0.09 vs. 0.44 ± 0.05 mm, p<0.001). Figure
3.1 illustrates average CIMT for healthy controls and children with MAS and/or RAS
categorized by extent of disease and underlying etiology. Children with MAS/RAS had
significantly higher CIMT compared to isolated RAS and healthy controls (p for trend <0.001).
Stratifying by etiology, a similar trend was noted with higher CIMT in those with systemic
disease as compared to those with unknown etiology and healthy controls (Figure 3.2).
In univariable linear regression analysis, having RAS or MAS/RAS was associated with
higher CIMT compared to controls (Table 3.3). After adjusting for systolic blood pressure SDS,
only the MAS/RAS group remained significantly associated with higher CIMT compared to the
controls (β= 0.07 [0.03-0.10]), whereas the isolated RAS group was no longer associated with
higher CIMT compared to healthy children (β= 0.03 [-0.004-0.06]). After adjusting for systolic
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blood pressure SDS, those with systemic etiology had significantly higher CIMT compared to
controls (β= 0.06 [0.02-0.09]), but the unknown etiology group CIMT did not significantly differ
from controls (β= 0.03 [-0.004-0.06]).
Figure 3.3 illustrates systolic blood pressure SDS plotted against the predicted CIMT
values generated using the final multivariable model of the association between CIMT and extent
of vascular disease.
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Table 3.1 Clinical characteristics and vascular properties of children with MAS and/or RAS and matched healthy controls
Healthy
controls*
n=132
Children with
disease
n=33
Isolated RAS n=18
RAS/MAS
n=15
Variable Mean ± SD Mean ± SD p† Mean ± SD Mean ± SD p -trend
‡
Clinical characteristics
Age, years 13.18 ± 3.13 12.28 ± 3.14 0.1 12.65 ± 3.59 11.84 ± 2.55 0.2
Male sex, n (%) 73 (55.30) 16 (48.5) 0.5 12 (66.7) 4 (26.7) 0.06
Time from presentation to
imaging, years . 6.27 ± 4.95 . 7.13 ± 5.47 5.20 ± 4.21 0.3
Body mass index, kg/m2 19.66 ± 3.65 21.57 ± 5.24 0.02 21.96 ± 6.38 21.10 ± 3.58 0.01
Body mass index, SDS 0.08 ± 1.11 0.71 ± 1.06 0.004 0.61 ± 1.27 0.83 ± 1.06 0.01
Systolic blood pressure, mmHg 109.05 ± 10.40 121.21 ± 10.40 <0.001 121.72 ± 12.18 120.60 ± 8.14 <0.001
Systolic blood pressure, SDS -0.03 ± 0.87 1.38 ± 0.95 <0.001 1.28 ± 0.94 1.49 ± 0.98 <0.001
Diastolic blood pressure,
mmHg 57.90 ± 7.89 65.48 ± 9.48 <0.001 67.33 ± 10.80 62.67 ± 7.14 <0.001
Diastolic blood pressure, SDS -0.52 ± 0.73 0.23 ± 0.84 <0.001 0.38 ± 0.93 0.05 ± 0.70 <0.001
Resting heart rate, beats/min 68.96 ± 12.88 76.85 ±12.76 0.002 78.39 ± 9.62 75.00 ± 15.90 0.006
Abbreviations- RAS: renal artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome, SDS: standard
deviation score *
Each case was matched to 4 healthy controls based on age, sex and body surface area †
P: comparing total cases to healthy controls using a t-test or chi-square test, as appropriate ‡
P-trend: comparing healthy controls to case groups (isolated RAS and RAS/MAS) using ANOVA or chi-square, as
appropriate
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Table 3.2 Vascular properties of children with MAS and/or RAS and matched healthy controls
Healthy
controls*
n=132
Children with
disease
n=33
Isolated RAS
n=18 RAS/MAS
n=15
Variable Mean ± SD Mean ± SD p† Mean ± SD Mean ± SD p -trend
‡
Carotid properties
Average CIMT, mm 0.44 ± 0.05 0.51 ± 0.09 <0.001 0.49 ± 0.07 0.54 ± 0.10 <0.001
Carotid artery distensibility,
mm Hg-1
. 10-3
12.98 ± 4.24 13.30 ± 5.29 0.7 13.67 ± 4.57 12.90 ± 6.17 0.9
Pulse wave analysis
Carotid to radial PWV, m/s 6.84 ± 1.17 6.81 ± 1.34 0.9 7.16 ± 1.44 6.36 ± 0.88 0.1
Carotid to femoral PWV, m/s 5.00 ± 0.90 5.58 ± 1.83 0.01 5.36 ± 1.00 5.82 ± 2.46 0.03
Central systolic blood pressure,
mmHg 89.50 ± 9.00 103.89 ±11.06 <0.001 103.50 ± 13.56 104.29 ± 8.35 <0.001
Central diastolic blood pressure,
mmHg 58.79 ± 8.08 65.21 ± 9.04 <0.001 67.14 ± 10.13 63.29 ± 7.70 <0.001
Central pulse pressure, mmHg 30.82 ± 5.87 38.68 ± 8.80 <0.001 36.36 ± 9.23 41.00 ± 7.99 <0.001
Aortic augmentation index, % -0.50 ± 12.91 12.00 ± 19.43 <0.001 2.91 ± 14.45 20.33 ± 20.17 <0.001
Abbreviations- RAS: renal artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome, SDS: standard
deviation score, CIMT: carotid intima-media thickness, PWV: pulse wave velocity *
Each case was matched to 4 healthy controls based on age, sex and body surface area †
P: comparing total cases to healthy controls using a t-test or chi-square test, as appropriate ‡
P-trend: comparing healthy controls to case groups (isolated RAS and RAS/MAS) using ANOVA or chi-square, as
appropriate
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Figure 3.1 Box plots and linear regression analysis for average common carotid intima-media
thickness (CIMT) by vascular involvement (healthy control, isolated RAS: isolated renal artery
stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome)
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Figure 3.2 Box plots and linear regression analysis for average common carotid intima-media
thickness (CIMT) by etiology (healthy control, unknown, systemic: genetic disease including
Williams’ syndrome, Neurofibromatosis I and Alagille syndrome, and inflammatory disease
including Takayasu’s arteritis and non-specific arteritis)
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Table 3.3 Association between extent of disease and etiology with average common carotid intima-media
thickness (CIMT) by linear regression
CIMT Univariable Multivariable*
Extent of disease β 95% CI P β 95% CI P
Healthy controls ref ref -- ref ref --
Isolated RAS 0.05 (0.02, 0.08) 0.001 0.03 (-0.004, 0.06) 0.09
RAS/MAS 0.1 (0.06, 0.13) <0.001 0.07 (0.03, 0.10) <0.001
Etiology β 95% CI P β 95% CI P
Healthy controls ref ref -- ref ref --
Unknown 0.05 (0.02, 0.08) 0.001 0.03 (-0.004, 0.06) 0.08
Systemic† 0.08 ( 0.06, 0.11) <0.001 0.06 (0.02, 0.09) 0. 001
Abbreviations- RAS: renal artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome,
CIMT: carotid intima-media thickness
* Multivariable model adjusted for systolic blood pressure standard deviation scores †
Systemic disease defined as the genetic disorders Williams’ syndrome, Neurofibromatosis type I, and
Alagille syndrome, and the inflammatory diseases Takayasu’s arteritis and non-specific arteritis
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Figure 3.3 Predicted average common carotid intima-media thickness (CIMT) using the final
multivariable linear model plotted against a range of systolic blood pressure standard deviation
scores, and stratified by extent of vascular disease (healthy control, isolated RAS: isolated renal
artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome)
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Carotid artery distensibility was similar between children with disease and healthy
controls (13.3 ± 5.29 and 12.98 ± 4.24 mmHg-1
·10-3
, respectively). Peripheral pulse wave
velocity was not significantly different between children with and without disease (6.84 ± 1.17
and 6.81 ± 1.34 m/s, respectively). There was no significant difference in peripheral PWV
between healthy controls and the MAS/RAS or isolated RAS groups (Figure 3.4), and no
association between PWV and etiology (Figure 3.5). In univariable and multivariable analysis,
there were no significant associations between etiology and PWV, or extent of disease and PWV
(Table 3.4).
Central (carotid to femoral) PWV was higher in children with disease compared to
matched healthy controls (5.58 ± 1.83 and 5.00 ± 0.90 m/s, respectively). Children with MAS
and/or RAS also has higher central systolic, diastolic and pulse pressures as compared to healthy
children. Aortic augmentation index was higher in children with MAS and/or RAS compared to
healthy controls (12.00 ± 19.43 compared to -0.50 ± 12.91, respectively, p=0.02). Augmentation
index was also higher in children with MAS/RAS compared to those with isolated RAS (20.33 ±
20.17 compared to 2.91 ± 14.45, respectively, p<0.001).
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Figure 3.4 Box plots and linear regression analysis for carotid to radial pulse wave velocity
(PWV) by vascular involvement (healthy control, isolated RAS: isolated renal artery stenosis,
RAS/MAS: renal artery stenosis with middle aortic syndrome)
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Figure 3.5 Box plots and linear regression analysis for carotid to radial pulse wave velocity
(PWV) by etiology (healthy control, unknown, systemic: genetic disease including Williams’
syndrome, Neurofibromatosis I and Alagille syndrome, and inflammatory disease including
Takayasu’s arteritis and non-specific arteritis)
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Table 3.4 Association between extent of disease and etiology with carotid to radial pulse wave velocity
(PWV) by linear regression
Peripheral PWV Univariable Multivariable*
Extent of disease β 95% CI P β 95% CI P
Healthy controls ref ref -- ref ref --
Isolated RAS 0.61 -0.04, 1.26 0.07 0.41 -0.26, 1.08 0.2
RAS/MAS -0.68 -1.33, -0.03 0.04 -0.82 -1.51, 0.13 0.09
Etiology β 95% CI P β 95% CI P
Healthy controls ref ref -- ref ref --
Unknown -0.44 -1.2, 0.3 0.2 -0.51 -1.27, 0.24 0.2
Systemic† 0.23 -0.4, 0.8 0.5 0.05 -0.60, 0.71 0.9
Abbreviations- RAS: renal artery stenosis, RAS/MAS: renal artery stenosis with middle aortic syndrome,
PWV: pulse wave velocity
* Multivariable model adjusted for systolic blood pressure standard deviation scores †
Systemic disease defined as the genetic disorders Williams’ syndrome, Neurofibromatosis type I, and
Alagille syndrome, and the inflammatory diseases Takayasu’s arteritis and non-specific arteritis
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The results of the sensitivity analysis comparing the vascular measurements among
children with genetic disease showed similar results (Table 3.5). After adjusting for systolic
blood pressure SDS, CIMT was higher in the genetic group compared to healthy children (β=
0.08 [0.03-0.13]), whereas peripheral PWV did not differ between children with disease and
healthy controls.
Table 3.5 Association between extent of disease and etiology with average common carotid
intima media thickness (CIMT), and carotid to radial pulse wave velocity (PWV) by linear
regression in a subgroup of patients
CIMT Univariable Multivariable*
Extent of disease β 95% CI P β 95% CI P
Healthy controls ref ref ref ref ref ref
RAS alone 0.05 (0.02, 0.09) 0.002 0.03 (-0.005, 0.07) 0.1
RAS with MAS 0.13 (0.09, 0.18) <0.001 0.09 (0.05, 0.15) <0.001
Etiology β 95% CI P β 95% CI P
Healthy controls ref ref ref ref ref ref
Unknown 0.06 (0.03, 0.09) 0.001 0.036 (-0.0004, 0.07) 0.05
Genetic 0.12 ( 0.07, 0.16) <0.001 0.081 (0.03, 0.13) 0. 001
Peripheral PWV Univariable Multivariable*
Extent of disease β 95% CI P β 95% CI P
Healthy controls ref ref ref ref ref ref
RAS alone 0.8 (0.08, 1.52) 0.04 0.45 (-0.22, 1.3) 0.09
RAS with MAS -0.65 (-1.62, 0.31) 0.2 -1.23 (-2.33, -0.15) 0.3
Etiology β 95% CI P β 95% CI P
Healthy controls ref ref ref ref ref ref
Unknown -0.06 (-0.9, 0.7) 0.9 -0.3 (-1.2, 0.6) 0.5
Genetic 0.71 (-0.2, 1.6) 0.1 0.4 (-0.7, 1.4) 0.5
* Multivariable model adjusted for systolic blood pressure standard deviation scores
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We found no differences in aortic sinus, ascending aortic, or abdominal aortic distension
between children with MAS and/or RAS and healthy children (Table 3.6). Transit time was
shorter but not significantly different from controls. Elastic modulus and stiffness index were not
significantly different between children with disease and healthy controls. Input impedance, a
measure of left ventricular afterload, was also comparable between the two groups.
Characteristic impedance was higher but not significantly different from healthy children. In
terms of ventricular-arterial coupling, both arterial and ventricular end-systolic elastance were
similar between children with MAS and /or RAS and healthy children. The ratio of these two
properties, the coupling ratio, was comparable between the two groups.
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Table 3.6 Aortic properties in healthy controls and children with MAS/RAS at the time of study
enrollment
Healthy
Controls
Children with
MAS/RAS
n=132 n=33
Variable Mean ± SD p
Biophysical properties of aorta
Aortic sinus distension, mm.Hg-1 0.2 ± 0.1 0.3 ± 0.1 0.2
Ascending aortic distension, mm.Hg-1 0.4 ± 0.1 0.3 ± 0.1 0.2
Abdominal aortic distension, mm.Hg-1 0.4 ± 0.2 0.4 ± 0.2 0.1
Transit time, msec 21.6 ± 6.3 19.8 ± 6.7 0.1
Elastic modulus, mmHg 312.8 ± 128.3 371.7 ± 167.6 0.3
Stiffness index 4.0 ± 1.6 4.1 ± 2.8 0.6
Input impedance 234.8 ± 79.5 231.7 ± 104.0 0.9
Characteristic impedance 190.2 ± 83.9 207.8 ± 68.1 0.3
Elastance
Arterial elastance (EA), mmHg/ml 1.8 ± 0.6 2.0 ± 0.8 0.1
Ventricular end systolic elastance (EES), mmHg/ml 3.7 ± 1.6 3.9 ± 1.6 0.5
Coupling (EA/EES) ratio 0.5 ± 0.1 0.5 ± 0.1 0.8
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3.4 Discussion
Children with MAS and/or RAS are at risk of significant morbidity and mortality.
Understanding the extent of vascular involvement is critical when considering management,
especially endovascular or surgical interventions. Examination of the carotid and peripheral
arteries among children with diseased aorta and renal vessels demonstrated significant changes in
carotid artery structure, but no evidence of peripheral vascular stiffness. The changes in the
carotid arteries were more prominent with higher systolic blood pressures, more extensive
vascular involvement, and in those with systemic diseases.
CIMT is a widely accepted marker for subclinical atherosclerosis, and is closely related
to cardiovascular risk in adults(Lorenz, 2012). Common carotid IMT predicts the risk of stroke
and coronary artery disease in various adult populations including diabetes and arterial
hypertension(van den Oord, 2013). It is not clear whether this is valid to the same extent for
pediatric patients. Vascular remodeling of the arterial wall also occurs as part of the normal
aging process(Juonala, 2010). In the general pediatric population, CIMT increases with age and
correlates with blood pressure, even in the normal range(Litwin, 2009). Arterial hypertension is a
modifiable risk factor for both stroke and atherosclerosis, and has been shown to accelerate the
aging process(Litwin, 2009, Luijendijk, 2014). The chronic increase in vessel wall stress caused
by elevated regional blood pressure promotes muscle cell proliferation and increases the
thickness of the vessel walls as a mechanism for normalizing wall stress(Safar, 2003, Saba,
1993). As a result, the wall thickness of the carotid arteries is increased in hypertensive patients.
Given that baseline measurements in our study were not evaluated at the time of clinical
presentation, we are not able to comment on the progression rate of CIMT in children. However,
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previous longitudinal studies evaluating CIMT in a healthy pediatric population using similar
vascular imaging protocol reported a rate of increase in CIMT of 0.01-0.02 mm per year(Litwin,
2009). We found a much larger magnitude of the difference of approximately 0.1 mm comparing
those with disease to healthy controls. Assuming a similar rate of CIMT progression, this
magnitude represents the equivalent of 5-10 years of aging in the arteries among children with
MAS/RAS.
Our findings suggest that changes in the wall thickness of the carotid arteries in MAS and
RAS are predominantly related to the local hemodynamic effect of hypertension on the vessel,
rather than a systemic arteriopathy. This is supported by the elevated central blood pressures and
central pulse wave velocity, but preserved peripheral velocities. Among children with aortic
coarctation, there is evidence of increased IMT of high pressure pre-coarctational vessels, as
compared to post-coarctational vessels which are exposed to lower arterial pressures and retain
normal geometry(Morgan, 2013, Sarkola, 2011). This suggests that structural vascular alterations
are predominately a result of the abnormal regional hemodynamics. Studies in children with high
cardiovascular risk have shown that normalization of blood pressure and metabolic abnormalities
led to regression of arterial changes and a decrease in CIMT(Koskinen, 2014). Although CIMT
measurement is not yet accepted as standard pediatric procedure, it may serve as a vascular
endpoint in the assessment of target organ damage and monitoring the efficacy of treatment in
children with cardiovascular risk.
In this cohort, carotid distensibility was not reduced or significantly different from
normotensive healthy children, which indicates that the observed carotid artery remodeling is
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primarily an adaptation to longstanding hypertension in MAS/RAS with no stiffness or
functional impairment of the arteries. Carotid distensibility takes into account the distending
pressure and the non-linearity of arterial pressure-distention relationship, and normalizes the
stress/strain relation for arterial wall thickening(Safar, 2003, Godia, 2007). Consistent with the
hypothesis that the changes in CIMT are related to structural remodeling to preserve function is
the lack of differences in the measured stiffness index and elastance modulus. Young’s elastic
modulus normalizes the stress to strain relationship and has been reported to be preserved in
hypertensive patients. This finding, along with the fact that carotid distensibility was comparable
to healthy values, supports the theory of structural adaptations to hypertension with preserved
vascular function.
The hemodynamic effects of hypertension serve as an important contributor to the
vascular damage, but may not be the only contributor. Adjusting for systolic BP z-scores did not
completely diminish the association of extent of disease and etiology on CIMT in the MAS
group and those with systemic disease, which may indicate an additional hemodynamic insult
exerted by the aortic lesion itself. Other speculations can be made to explain the findings, such as
a more permanent vascular damage due to long-standing hypertension. Interestingly, children
with MAS/RAS had elevated aortic augmentation index as compared to healthy children. This
can be explained by the earlier return of the reflected wave either due to an increase in central
pulse wave velocity or a more proximal reflection point- such as that introduced by a narrowing
in the aorta or renal artery(Kass, 2005).
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Carotid to radial pulse wave velocity, a measure of peripheral vascular stiffness, was
similar between children with MAS/RAS and healthy controls. Central PWV was higher in
children with MAS/RAS compared to healthy controls, as is expected given the abnormal peri-
renal segment of the aorta resulting in increased central pressures. This suggests that MAS/RAS
is likely a localized disease of the peri-renal segment and not a generalized disease of the
vasculature. Surprisingly, peripheral PWV was not elevated in children with genetic disease and
elastin deficiency such as Williams’ syndrome and NF-1, where a generalized arteriopathy and
stiffness would be expected. This is in contrast to previous studies showing increased stiffness in
Williams’ patients, and may be related to the younger age of our cohort(Bassareo, 2010, Kozel,
2014). Studies on central arterial stiffness in children with NF-1 also found no differences
compared to healthy controls(Tedesco, 2000). This suggests that PWV may not be as robust of a
measure of arterial stiffness in children as it is in adults, or that measureable differences in PWV
are only detected as children age. Our results were, however, consistent with previous studies in
adolescents with repaired aortic coarctation which report normal carotid to radial pulse wave
velocity(Sarkola, 2011).
Central PWV velocity was elevated in children with MAS/RAS and those with RAS.
This may indicate increased vascular stiffness related to hypertension-induced stretching of the
arterial wall(Kim, 2013). When elastic fibers are elongated, further increases in distending
pressure cause recruitment of inelastic collagen fibers, altering the elastin to collagen ratio and
thus worsening vessel stiffness(Saba, 2014). As the arterial tree stiffens, pulse wave velocity
increases, which consequently elevates peak systolic pressure in the aorta through modifying
pressure wave propagation and reflection along the arterial tree. Our findings in children with
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MAS and/or RAS are in contrast to findings in children with successfully repaired aortic
coarctation, which report preserved carotid to femoral PWV(Sarkola, 2011). This may be related
to the more distal aortic lesion in children with MAS/RAS causing more pronounced
hemodynamic changes in the aorta, and resulting in higher central blood pressures.
Consistent with increased central pulse wave velocity, we observed elevated central
pressures and increased augmentation index. The clinical consequence of pressure wave
amplification, as has previously been suggested(Saba, 2014), is that brachial blood pressures
routinely used in the assessment and monitoring of blood pressure control in this group may not
be representative of the pressure acting in the aorta. This is important as changes in cardiac and
vascular endpoint may be more closely related to proximal pressures in the aorta than peripheral
brachial pressures. Future studies are need to determine the added benefit of monitoring central
pressures as compared to brachial pressures alone, as well as the feasibility of incorporating
additional measurements in the routine clinical assessment of children with vascular diseases.
We had hypothesized that increased augmentation index would result in higher pressure
load on the left ventricle. However, afterload measured using aortic input impedance was not
different between cases and controls. Further evaluation of cardiac structure and function will
determine whether there are any cardiac adaptations related to increased afterload in this patient
population.
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3.5 Limitations
This study has some important limitations inherent to the cross-sectional study design and
small sample size. Baseline vascular measurements were not done at the time of initial clinical
presentation, therefore, we cannot attribute the observed vascular properties to current blood
pressure load or make inferences regarding treatment efficacy. In addition, the effects of the
aortic narrowing, different repair techniques and any residual repair site gradients on regional
hemodynamics cannot be excluded. Assessment of endothelial function through measurement of
brachial artery reactivity was not feasible in this cohort due to the young age and the high
proportion of genetic syndromes, which reduced patient cooperation during studies. Further, as
children with MAS and/or RAS were recruited at a different time than healthy controls, blinding
of the personnel performing the measurements to reduce observer bias was not feasible.
However, observers were blinded to our main exposures of interest: the disease process
(etiology) and extent of aortic disease, and all measurements were conducted by the same
observer, and using the same equipment and software to minimize any measurement bias. The
reproducibility of the vascular measurements was further tested in 20 subjects and showed good
inter- and intra- observer reproducibility. Lastly, any direct effect of antihypertensive therapy,
beyond an indirect blood pressure-lowering effect, on the reported vascular measurements could
not be assessed. Despite these limitations, our results demonstrate important vascular changes in
the common carotid arteries possibly due to the hemodynamic changes of hypertension. This
finding highlights the importance of adequate blood pressure control and the need for close
monitoring of this patient population. Further studies are needed to determine how different
therapies modify these vascular properties in children and young adults, and whether
normalizing blood pressure results in reverse remodeling of the carotid arteries.
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3.6 Conclusion
Children with MAS and/or RAS have structural vascular alterations in the common
carotid arteries that are closely related to blood pressure, with no evidence of peripheral vascular
stiffness. These results suggest that MAS/RAS and isolated RAS are limited to the peri-renal
segment of the abdominal aorta. Further studies are needed to delineate the reversibility of these
vascular changes and their effect on the long-term outcomes of children with MAS and/or RAS.
We found evidence of increased central pulse wave velocity, central blood pressures and
augmentation index, which merit investigation of end-organ cardiac structural and functional
changes. The chapter that follows evaluates cardiac structure and function to determine the effect
of long-standing arterial hypertension on the myocardium.
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Chapter 4 Cardiac Structure, Function, and Myocardial Mechanics
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4.1 Introduction
Middle aortic syndrome (MAS) is a rare disease characterized by narrowing of the
abdominal aorta. The pathogenesis of MAS has yet to be delineated, but genetic disorders such
as Williams’ syndrome, Neurofibromatosis type I and Alagille syndrome, as well as
inflammatory diseases such as Takayasu’s arteritis are described in a subset of children with
MAS[1]. We have demonstrated in previous chapters, through a review of the available literature
(Chapter 1) and our center’s 30-year experience (Chapter 2), that the aortic narrowing is
predominantly localized to the peri-renal segment of the abdominal aorta. Renal arterial
involvement in the form of renal artery stenosis (RAS) is an important feature of MAS and is
present in 70% of cases [1].
In assessing outcomes following management of MAS and/or RAS in children, we found
that arterial hypertension persists despite both medical management with antihypertensive
therapy, as well as following endovascular or surgical relief of aortic narrowing. Therefore, an
assessment of the effect of MAS/RAS and the associated arterial hypertension on cardiac
structure and function is merited. Hypertension-associated changes in structural and functional
properties are well documented in adult populations, and include left ventricular hypertrophy
related to myocardial proliferation in response to an increase in ventricular wall stress due to
increased afterload(Diez, 2005, Faconti, 2015). The increase in LV thickness can be associated
with contractile dysfunction, but is frequently preceded by diastolic functional changes which
can be detected with preserved ejection fractions(Bhatia, 2006). Therefore, assessment of early
subclinical changes in contractile properties is especially important in this group of children as it
121
may allow us to adapt their management of hypertension to prevent or reverse any changes in
functional properties.
Recent studies in adults and children have suggested that myocardial strain, measured
using tissue Doppler imaging or two dimensional (2D) speckle tracking echocardiography (STE),
can be useful for detecting early subclinical ventricular abnormalities(Hensel, 2014, Mignot,
2010, Kibar, 2015). Myocardial strain is the percentage change in length of a myocardial
segment in systole, and is considered a reliable predictor of prognosis in adults(Dandel, 2009).
Data relating to the use of strain imaging in children with vascular diseases is sparse, likely due
to lack of normal strain values available for comparison in the pediatric age group. Longitudinal
strain has been shown to be predictive of cardiovascular outcomes in various adult
populations(Dandel, 2009, Artis, 2008, Mignot, 2010). This has not be reproduced to the same
extent in children, and it remains to be determined whether longitudinal strain has prognostic
significance in the pediatric age group(Friedberg, 2012). Nonetheless, it is important to
determine whether regional changes in contractile function are present in children with
hypertension as it may provide insights into the pathogenesis of arterial hypertension in children
generally, and delineate the effect of the persistent hypertension on regional ventricular systolic
function in children with MAS/RAS.
Persistent hypertension has been described in children following repair of aortic
coarctation, with associated ventricular adaptive changes including left ventricular
hypertrophy(Morgan, 2013, Sarkola, 2011). Studies in children after coarctation repair have
shown that subtle changes in diastolic function can be present with preserved ejection
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fractions(Florianczyk, 2011). Subclinical changes in myocardial mechanics have also been
detected in adults with repaired coarctation using various deformation imaging modalities(Kutty,
2013, Kowalik, 2016). The extent of end-organ cardiac disease in children with MAS/RAS has
not been well studied despite the high prevalence of persistent hypertension. This is especially
important in this group given that end organ disease is a consideration in the clinical
management of patients, and the decision to intervene surgically or percutaneously is influenced
by evidence of hypertensive cardiac remodeling.
This chapter provides a comprehensive assessment of ventricular structure, systolic and
diastolic function, and myocardial mechanics in children with MAS and/or RAS compared to
healthy children. We also provide a comparison of these parameters in a subset of children
before and after treatment. The detection of subclinical functional changes in this group will
improve our understanding of the effect of long-standing renovascular hypertension on end-
organ cardiac disease, and may help to adapt the long-term management of hypertension in
children with aortic and renal arterial narrowing.
4.2 Material and methods
4.2.1 Patient recruitment and inclusion criteria
A total of 40 children recruited from the complex hypertension clinic at the Hospital for
Sick Children (Toronto, Canada) were enrolled in a prospective cohort study between 2014 and
2016. Inclusion criteria were ages <18 years, and a diagnosis of MAS and/or RAS. The
anatomical classification described in previous chapters was used to categorize children into
those with isolated RAS; and MAS/RAS, which consisted of those with RAS in conjunction with
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MAS and children with isolated MAS. The cohort was also categorized by underlying etiology,
as previously described, as unknown or systemic disease. The latter category included
inflammatory conditions such as Takayasu’s arteritis, and genetic disorders including Williams’
syndrome, Neurofibromatosis type I and Alagille syndrome.
A total of 140 healthy children recruited from the cardiac assessment clinic were
investigated cross-sectionally using the same imaging protocol. Children were excluded if they
had a significant cardiovascular risk factor, a hemodynamically significant cardiovascular
anomaly, an active disease that could interfere with cardiovascular function, or if they were on
cardiac or vasoactive medications. We generated a matched healthy control group based on age,
sex, and body surface area (BSA) with 1:4 matching (where each case was matched to 4 healthy
children). The study protocol was approved by the Research Ethics Board at the Hospital for
Sick Children, and written informed consent was obtained from all participants.
4.2.2 Echocardiography
All cardiovascular imaging was performed in a quiet room after 10 minutes of supine rest
by a single experienced cardiovascular sonographer at the time of study enrollment. All
echocardiograms were performed using a GE Vivid 7 or Vivid E9 system (General Electric
Medical Systems, USA) using a standardized functional protocol, as previously
described(Grattan, 2014). Echocardiographic images were acquired and stored in RAW data
format. All measurements were conducted offline using EchoPAC version 110.1.3 (General
Electric Medical Systems, USA). Ventricular dimensions were converted into standard deviation
scores (Z-scores) using normative reference values generated at the Hospital for Sick Children.
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Left ventricular (LV) mass was calculated using Devereux’s method and converted into a Z-
score using the Boston method, as previously described(Foster, 2008). Pulsed-wave tissue
Doppler velocities and grayscale images (parasternal short-axis images at the midventricular
level and from the apical four-chamber views) were acquired for speckle-tracking
echocardiography (STE). Ventricular systolic function was assessed by measuring ejection
fraction (biplane Simpson method), shortening fraction, and tissue Doppler s’ velocities.
Diastolic function was assessed using mitral valve and pulmonary vein Doppler and tissue
Doppler imaging (Koopman, 2012).
Measurement of myocardial strain was performed using speckle tracking
echocardiography (STE) as previously described(Koopman, 2012). Longitudinal strain was
measured from the apical two-, three- and four-chamber views. Circumferential strain was
measured from parasternal short axis images at the basal, mid-ventricular and apical levels. The
endocardial surface of the LV was traced manually, and the algorithm for longitudinal and
circumferential strain was applied. Tracking of the myocardium was automatically performed,
and inspected visually to ensure adequate tracking. If tracking was suboptimal, the endocardial
surface of the LV was retraced. If tracking remained inadequate, the particular segment was
excluded. A minimum of 4 out of 6 segments were required to be adequately tracked for each
view in order to calculate mean strain values. Where available, baseline cardiac measurements
were conducted retrospectively from echocardiographic studies conducted at the time of clinical
presentation using the same technique.
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Intraobserver and interobserver variability of the STE-derived longitudinal and
circumferential strain measurements were evaluated in 20 randomly selected healthy subjects.
The calculated intraobserver and interobserver coefficients of variation were 6% and 9%,
respectively, for longitudinal strain, and 5% and 9% for circumferential strain.
4.2.3 Clinical data
Height and weight were measured, and body mass index (BMI) was calculated. BSA was
calculated using Haycock’s formula. Right-arm blood pressure was measured using an arm size-
appropriate cuff as the average of three readings with an automated Dinamap
sphygmomanometer (Critikon, Tampa, FL) and recorded along with resting heart rate. Standard
deviation scores (SDS) for systolic and diastolic blood pressures, and BMI were derived from the
Centre for Disease and Control (CDC) growth charts and the 4th
Task Force Report(Kuczmarski,
2002, Falkner, 2004). Systolic hypertension was defined as systolic blood pressure equal to or
greater than the 95th
percentile for patients of the same age, sex and height. Management of MAS
and/or RAS was categorized as: antihypertensive therapy alone, interventional management
(including surgical and endovascular procedures), or no therapy at time of vascular assessment.
4.2.4 Statistical analysis
Categorical data are reported as frequency and percentage, and continuous variables are
expressed as the mean ± standard deviation (SD), or the median and interquartile range [IQR], as
appropriate. Student t-tests were used to assess the differences in cardiac parameters between
children with MAS/RAS and the healthy controls, and differences between baseline and follow-
up cardiac measurements. Differences in frequencies were assessed using a chi-square test. A
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two-tailed p-value of 0.05 was considered statistically significant. All statistical analyses were
performed using Stata 13.0 (College Station, Texas).
4.3 Results
4.3.1 Patient characteristics
A total of 35 children completed baseline imaging and were included in the current
analysis. Cardiovascular imaging could not be completed in 5 patients due to lack of patient
cooperation and age <8 years. Children presented at a mean age of 5.5 years (SD 4.0), and
median time from clinical presentation to study enrollment was 6.1 [IQR 3.8-9.9] years. Table
4.1 summarizes the demographic and clinical characteristics of children with MAS and/or RAS
and 140 matched healthy controls. Mean age of children with MAS and/or RAS at the time of
study enrollment was 12.5 ± 3.0 years, and 50% were male. Children with MAS and/or RAS had
significantly higher systolic and diastolic blood pressure Z-scores compared to healthy controls.
BMI and BMI Z-score were higher in children with disease compared to healthy controls.
In terms of vascular involvement, 16 children (45.7%) had isolated RAS, and 19 children
(54.3%) had RAS/MAS (17 with both MAS and RAS, and 2 with MAS only). Of the cases, 19
(54.3%) had systemic disease (14 genetic and 5 inflammatory), and the remaining 16 children
(45.7%) had disease of unknown etiology. Genetic etiology consisted of 8 children with
Neurofibromatosis type I, 4 children with Williams’ Syndrome, and 2 with Alagille syndrome.
Inflammatory disease included Takayasu’s arteritis (4) and nonspecific arteritis (1). Of the
children enrolled 24 (68.6%) were receiving antihypertensive therapy, including calcium channel
blockers (42.9%), beta-blockers (42.9 %), and angiotensin converting enzyme (ACE) inhibitors
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(11.4%). At the time of cardiovascular imaging, 22 (62.9%) had already received interventional
therapy (endovascular procedures in 11, surgical correction in 4, and both surgical and
endovascular procedures in 7), 8 (22.9%) were managed with antihypertensive therapy alone,
and the remaining 5 (14.3%) children had not received therapy.
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Table 4.1 Clinical characteristics of children with MAS and/or RAS at the time of study
enrollment
Healthy
controls n=140
Children with
MAS/RAS
n=35
Variable Mean ± SD p
Age, years 12.5 ± 3.0 12.5 ± 3.0 0.9
Male sex, n (%) 69 (49.3) 17 (50.0) 0.5
Body surface area, m2 1.4 ± 0.3 1.5 ± 0.4 0.6
Body mass index, kg/m2 19.66 ± 3.65 21.57 ± 5.24 0.02
Body mass index Z-score 0.2 ± 1.0 0.7 ± 1.1 0.01
Systolic blood pressure, mmHg 109.05 ± 10.40 121.21 ± 10.40 <0.001
Systolic blood pressure Z-score -0.06 ± 0.9 1.3 ± 10 <0.001
Diastolic blood pressure, mmHg 57.90 ± 7.89 65.48 ± 9.48 <0.001
Diastolic blood pressure Z-score -0.5 ± 0.7 0.2 ± 0.9 <0.001
Resting heart rate, beats/min 68.96 ± 12.88 76.85 ±12.76 0.002
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4.3.2 LV geometry and systolic function
Ventricular geometry and systolic functional parameters at the time of study enrollment
are summarized in Table 4.2. LV posterior wall dimension was significantly higher in children
with MAS/RAS compared to matched controls. Chamber dimensions and interventricular septum
thickness were similar between the two groups. LV mass z-score was significantly higher in
children with MAS/RAS compared to matched healthy controls (Figure 4.1). There were no
significant differences in shortening fraction or ejection fraction between children with
MAS/RAS and the control group. Tissue Doppler velocities and myocardial strain measurements
are summarized in Table 4.3. Systolic tissue Doppler velocities were lower at the level of the
MV lateral annulus and the septum compared to healthy controls. LV longitudinal systolic strain
was similar between children with MAS/RAS and the control group (Figure 4.2). LV
circumferential strain was significantly higher in children with disease compared to healthy
controls (Figure 4.3).
4.3.3 Diastolic function
Early mitral inflow velocity (E) was not different between children with MAS/RAS and
healthy controls. Children with MAS/RAS had higher mitral A-wave velocity and A-wave
duration, and reduced E/A ratio compared to controls (Figure 4.4). Mitral inflow deceleration
time and isovolumic relaxation time were not different between children with MAS/RAS and
healthy controls. Pulmonary venous A-wave velocities were similar to healthy controls. Tissue
Doppler e’ velocities were lower in the disease group compared with the control group, and a’
velocities were higher at all locations. E/e’ ratios were significantly higher in children with
disease compared to controls at MV lateral and septal annular levels.
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Table 4.2 Left ventricular geometry and function in healthy controls and children with MAS/RAS
at the time of study enrollment
Healthy Controls Children with MAS/RAS
n=140 n=35
Variable Mean ± SD p
LV geometry and systolic function
RVEDD, cm 1.9 ± 0.4 1.8 ± 0.4 0.6
IVSEDD, cm 0.7 ± 0.1 0.8 ± 0.1 0.3
LVEDD, cm 4.5 ± 0.5 4.6 ± 0.6 0.9
LVESD, cm 2.9 ± 0.4 2.7 ± 0.4 0.2
LVPWD, cm 0.6 ± 0.1 0.7 ± 0.2 0.01
LVM, g 95.9 ± 35.0 107.1 ± 48.1 0.1
LVM z-score† -1.3 ± 0.1 -0.4 ± 0.2 0.003
Shortening fraction, % 37.1 ± 4.0 38.9 ± 5.5 0.04
Ejection fraction, % 67.83 ± 7.5 69.2 ± 6.7 0.3
Mitral inflow
E-wave velocity, cm/s 100.0 ± 16.8 104.5 ± 21.1 0.2
A-wave velocity, cm/s 42.4 ± 11.9 53.5 ± 17.1 <0.001
E-wave Deceleration Time, ms 146.4 ± 19.6 151.3 ± 21.0 0.2
A-wave Duration, ms 113.6 ± 21.5 124.6 ± 31.9 0.02
E/A Ratio 2.5 ± 0.8 2.1 ± 0.9 0.01
IVRT, ms 72.7 ± 8.9 72.4 ± 11.9 0.9
Pulmonary Vein
Systolic wave velocity, cm/s 44.4 ± 12.3 49.9± 12.1 0.03
Diastolic wave velocity, cm/s 62.2 ± 10.9 64.8 ± 14.0 0.3
A-wave velocity, cm/s 18.34 ± 5.3 22.9 ± 6.9 0.07
A-wave duration, cm/s 100.4 ± 26.6 107.2 ± 32.4 0.3
LV: left ventricle, RVEDD: right ventricular end-diastolic dimension, IVSEDD: Intraventricular
septal end-diastolic dimension, LVEDD: LV end-diastolic dimension, LVESD: LV end-systolic
dimension, LVPWD: LV posterior wall dimension is diastole, LVM: left ventricular mass, E: early
mitral inflow velocity; A, late mitral inflow velocity
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Figure 4.1 Left ventricular mass Z-score for children with MAS/RAS (n=35) at the time of
clinical presentation and at study enrollment, compared to age, sex, and body surface area-
matched healthy controls
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Table 4.3 Tissue Doppler and myocardial mechanics in healthy controls and children with
MAS/RAS at the time of study enrollment
Healthy Controls Children with MAS/RAS
n=140 n=35
Variable Mean ± SD p
LV Tissue Doppler
Lateral S', cm/s 11.0 ± 2.1 9.8 ± 2.3 0.005
Lateral E', cm/s 18.9 ± 2.5 17.1 ± 3.0 <0.001
Lateral A', cm/s 6.1 ± 1.5 7.4 ± 2.9 <0.001
Lateral E/E' Ratio 5.3 ± 1.0 6.3 ± 1.6 0.001
Septal S', cm/s 8.5 ± 0.9 8.2 ± 1.4 0.06
Septal E', cm/s 15.1 ± 2.2 13.4 ± 2.7 <0.001
Septal A', cm/s 6.0 ± 1.2 6.9 ± 2.7 0.005
Septal E/E' Ratio 6.7 ± 1.3 8.1 ± 2.2 <0.001
Strain Measurements
Average circumferential strain, % -19.7 ± 1.5 -22.6 ± 2.3 <0.001
Average global longitudinal strain, % -20.0 ± 1.6 -20.2 ± 1.5 0.8
LV: left ventricle, S′: systolic velocity with TDI, E′: early diastolic myocardial velocity, A′: late
diastolic myocardial velocity
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Figure 4.2 Average global longitudinal strain for children with MAS/RAS at the time of clinical
presentation (subgroup n=20) and at study enrollment (n=35), compared to age, sex, and body
surface area-matched healthy controls
134
Figure 4.3 Average circumferential strain for children with MAS/RAS at the time of clinical
presentation (subgroup n=20) and at study enrollment (n=35), compared to age, sex, and body
surface area-matched healthy controls
135
Figure 4.4 Mitral valve E/a ratio (B) for children with MAS/RAS (n=35) at the time of clinical
presentation and at study enrollment, compared to age, sex, and body surface area-matched
healthy controls
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4.3.4 Baseline cardiac measurements
Cardiac measurements obtained at the time of clinical presentation are presented in Table
4.4. At clinical presentation, children with MAS/RAS had higher LV mass Z-score (Figure 4.1),
and lower E/a ratio (Figure 4.4) compared to healthy controls. STE analysis was feasible in 20
out of 35 children. At the time of clinical presentation, children with MAS/RAS had lower GLS
(Figure 4.2) compared to matched healthy children, whereas GCS was not different from healthy
controls (Figure 4.3).
Systolic and diastolic blood pressure Z-scores were significantly lower at study
enrollment compared to baseline values at presentation. Compared to baseline measurements,
LV ejection fraction was significantly higher at the time of enrollment, whereas LV mass Z-
score at study enrollment was similar to presentation values. GLS and GCS were significantly
improved at study enrollment compared to baseline levels.
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Table 4.4 Baseline cardiac measurements in children with MAS and/or RAS at clinical
presentation compared to follow-up measurements at study enrollment
Presentation
n=35 Follow-up
n=35
Variable Mean ± SD p
Age at imaging, years 5.5 ± 4.0 12.5 ± 3.0 <0.001
Median time from presentation, years . 6.1 [3.8-9.9] .
Male sex, % 17 (50) 17 (50) 1.0
Body surface area, m2 0.8 ± 0.5 1.5 ± 0.4 <0.001
Systolic BP Z-score 2.5 ± 2.4 1.3 ± 1.0 0.01
Diastolic BP Z-score 1.3 ± 1.4 0.2 ± 0.8 <0.001
BMI Z-score 0.3 ± 1.1 0.7 ± 1.1 0.2
LV Geometry and systolic function
LVM, g 64.4 ± 43.6 107.1 ± 48.1 0.002
LVM z-score 0.2 ± 1.7 -0.5 ± 1.4 0.08
LV Ejection fraction, % 61.6 ± 11.7 69.2 ± 6.7 0.002
Mitral inflow
E-wave velocity, cm/s 96.8 ± 16.0 108.0 ± 22.3 0.1
A-wave velocity, cm/s 70.5 ± 26.8 59.0 ± 20.7 0.2
E/A Ratio 1.5 ± 0.5 2.0 ± 0.9 0.1
Strain measurements*
Average circumferential strain, % -19.8 ± 1.5 -22.7 ± 2.3 <0.001
Average global longitudinal strain, % -18.6 ± 1.9 -20.2 ± 1.6 0.007 * Strain measurements were only available in 20 patients at presentation
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4.4 Discussion
In this chapter, we provide a comprehensive evaluation of ventricular structure and
function in children with MAS and/or RAS. Our results suggest that systolic function and
myocardial strain are preserved in children with MAS/RAS, with changes in early relaxation of
the left ventricle. Some of these parameters are significantly improved compared to values at
clinical presentation prior to treatment; however, some of the changes observed at the time of
presentation persisted despite management. The prognostic significance of these changes and the
reversibility with further blood pressure lowering require prospective follow-up with monitoring
of cardiac parameters.
Children with MAS/RAS had elevated systolic blood pressures at clinical presentation.
At that time, left ventricular mass was increased, longitudinal strain was reduced, and diastolic
parameters were lower than healthy controls. These changes are consistent with previously
described adaptations to the increased ventricular wall stress due to chronic hypertension(Saba,
2014, Borlaug, 2009). At the time of study enrollment, most children had been treated either
medically or with endovascular and surgical intervention. This resulted in a decrease in systolic
blood pressure Z-scores compared to baseline values, however, blood pressures remained
elevated compared to healthy children. It may be that children with increased LV mass have not
had sufficient time to reverse remodel, or that blood pressure management is still not optimal. As
we have discussed in earlier chapters, antihypertensive management of childhood renovascular
disease is not standardized, and may vary between physicians even in one clinical center.
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Systolic function including ejection fraction was preserved in children with MAS/RAS,
with significant improvement in longitudinal strain at follow-up compared to baseline levels.
However, left ventricular mass remained significantly elevated at a median of 6 years after
presentation. Interestingly, circumferential strain values were higher in children with MAS/RAS
at follow-up compared to controls. This may be a combined effect of reduced afterload due to
blood pressure lowering with treatment, and the persistent ventricular hypertrophy, resulting in
increased contraction of the midmyocardial circumferential fibers.
We observed differences in diastolic parameters between children with MAS/RAS and
healthy controls, with mildly reduced e’ velocities and lower E/a ratio in children with
MAS/RAS, which suggests that there are subtle differences in early relaxation. These differences
may be related to the increased LV mass in our cohort, and are consistent with early diastolic
changes in the context of chronic arterial hypertension. As children with MAS/RAS remain
hypertensive for many years, strategies for optimal blood pressure management are paramount.
In adults with hypertension, diastolic changes precede changes in systolic properties, and can
develop into systolic abnormalities or isolated diastolic failure in later life(de Simone, 2000).
Whether these findings are true to the same extent in children remains unclear, and prospective
studies with longitudinal follow-up are needed to determine the prognostic significance of these
changes in children with chronic hypertension.
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4.5 Limitations
This study has some limitations inherent to the small sample size in a rare vascular
disease. Baseline strain measurements at clinical presentation were only available in a subset of
children due to insufficient image quality for strain analysis. Further, blinding of the personnel
performing the measurements to reduce observer bias was not feasible as children with MAS
and/or RAS were recruited at a different time than healthy controls. However, observers were
blinded to the etiology and extent of aortic disease of the study subjects. The reproducibility of
the strain parameters was further tested in 20 subjects and showed good inter- and intra- observer
reproducibility. Despite these limitations, our results demonstrate important left ventricular
changes, including increased mass and early changes in relaxation properties, which may be
related to the hemodynamic changes of hypertension. These finding highlights the importance of
adequate blood pressure control and the need for close monitoring of this patient population,
even after successful endovascular or surgical repair. Further studies are needed to determine the
reversibility and prognostic significance of these changes in later life.
4.6 Conclusion
Children with MAS and/or RAS have increased left ventricular mass compared to healthy
children with subtle changes in early relaxation properties. Systolic function is overall preserved.
Even though treatment resulted in improvement in systolic parameters, structural remodeling of
the left ventricle was evident years after presentation. Further studies are needed to delineate the
reversibility of these changes and their effect on the long-term outcomes and risk of future
cardiovascular disease in children with MAS and/or RAS.
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Chapter 5 Discussion, Conclusions, and Future Directions
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5.1 General discussion and implications
This body of work aimed to shed light on the presentation and management of childhood
MAS and RAS, as well as provide a comprehensive evaluation of the cardiovascular system
including central and peripheral arteries, cardiac structure and function, and myocardial
mechanics. We were able to add to the existing knowledge on vascular and end-organ cardiac
involvement, as well as emphasize the importance of blood pressure control in this group of
patients.
5.1.1 Diagnosis, etiology, and management
Diagnosis and clinical presentation
Children with MAS and/or RAS usually present with an incidental finding of
hypertension. Upon review of 630 cases from the literature, and 93 cases in our center, we found
that children are often asymptomatic at presentation. Systolic murmur, abdominal bruit, and
reduced or absent femoral pulses are some of the reported clinical findings. Cerebrovascular
events or congestive heart failure, although reported in some case, are less common presentations
in children. This raises the possibility that MAS and RAS in children could be under diagnosed,
and underscore the importance of proper investigation of a renovascular cause of hypertension in
children. An important observation is the increased number of cases of MAS and RAS in our
clinical center over the past 30 years, and the increased recognition of MAS and renovascular
causes of hypertension in the literature. The increased prevalence may be due to the improved
imaging techniques including computed tomography (CT) and magnetic resonance imaging
(MRI).
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Detection of aortic narrowing in children may be challenging as invasive catheter-based
imaging is not routinely conducted. Without symptoms of vascular compromise or end-organ
disease, children do not usually undergo comprehensive imaging of the abdominal aorta and
visceral branches. In our cohort, 50% of children had collateral vessels in the abdomen which
may explain why they did not display advanced clinical signs of vascular compromise. A
limitation of our study, however, is the lack of systematic imaging of all visceral and extra-aortic
vessels using the same imaging modality over time, which may have resulted in incomplete
vascular phenotyping of children. Recognition of RAS or MAS in children invariably requires
detailed vascular imaging, but extensive imaging of all children presenting with idiopathic
hypertension may not be merited or cost-effective. Perhaps part of the preliminary ultrasound
examination of the urinary tract and renal parenchymal disease in children with hypertension
should include evaluation of the abdominal aorta to determine anatomy and patency.
Etiology
The pathogenesis of MAS and RAS is poorly understood and has not been well studied
since the initial cases were described almost 6 decades ago. Very few case reports have
examined the histopathology of the aorta and renal arteries, but those who have investigated the
pathology describe changes consistent with intimal fibroplasia. Such change to the intima of the
vessel is non-specific and likely explained by regional hemodynamic changes such as turbulence
and hypertension, or intimal damage related to the processing of the specimen. The importance
of delineating the pathogenesis of this disease stems from the fact that etiology of the vascular
disease may affect response to medications, response to endovascular interventions, and
outcomes following management. For example, elastic recoil of the vessels following
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angioplasty has been reported in children with Neurofibromatosis(Delis, 2005). Our own
experience with MAS/RAS also shows higher frequency of restenosis, re-interventions, and
operative complications in those with genetic and inflammatory diseases.
MAS and RAS overlap in vascular phenotype with known Mendelian diseases including
Williams’ and Alagille syndromes, and Neurofibromatosis. To the best of our knowledge,
genetic studies have not been conducted to explore a possible genetic overlap between MAS and
RAS of unknown etiology and the Mendelian diseases. Given the localized nature of the vascular
disease in MAS and RAS, exploring a genetic variant may be a reasonable next step. The other
overlap is with inflammatory vascular diseases including Takayasu’s arteritis. Some reports
suggest that MAS and RAS may represent burnt out vasculitis, however, we have found marked
differences in the extent of vascular disease which suggest that these two etiologies may
represent distinct pathophysiological processes. In children with inflammatory disease, there is
ascending aortic and proximal aortic branch involvement which is dissimilar to children with
unknown etiology of disease. Further, children with unknown cause of disease present at a
younger age and do not exhibit the classic female predilection reported in Takayasu’s arteritis (of
up to 9:1 female dominance)(Bagga, 2010). We found no sex predilection in our cohort and the
630 reported cases of MAS.
We have discussed the use of FMD as a differential diagnosis for MAS and RAS in
previous chapters. Briefly, we believe that there is insufficient knowledge regarding the
pathogenesis of MAS/RAS to make this diagnosis. Due to absence of angiographic evidence of
medial fibroplasia, and inconsistencies between the observed anatomy of the arterial lesions
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compared to reported FMD cases (predominately ostial stenosis in our pediatric cohort, whereas
FMD predominately affects the distal portion of the artery), we prefer to use the anatomical
diagnosis of RAS and/or MAS. Lastly, another speculated cause for MAS and RAS is an
aberrant embryological development of the aorta or renal arteries, namely an over fusion or
incomplete fusion of the two dorsal aortas. This is largely uninvestigated and little is currently
known about the embryological development of the peri-renal segment of the abdominal aorta.
As we have shown from the retrospective analysis of risk of first intervention, etiology of
disease is an important consideration. We found that children with unknown etiology of disease
were more likely to receive endovascular and surgical procedures, and at a shorter time from
presentation. This is likely multi-factorial. The perceived risk of operating on isolated aortic
lesions with no associated genetic or inflammatory diagnosis is reduced. Another explanation
could be that children with unknown disease present later in the course of their disease due to the
lack of inflammatory or genetic manifestations of disease, and have more severe disease by the
time of delayed presentation such that an intervention is merited soon after presentation.
Children with genetic disorders presented at a younger age compared to those with unknown
etiology of disease, and had longer times to intervention. Children with inflammatory disease
presented at an older age compared to those with unknown etiology of disease, and due to
management of active inflammatory disease, received interventions at a later time.
Management
Initial medical management of hypertension in children has variable success depending
on the child’s response to medications. Antihypertensive medications can lower blood pressures
146
to satisfactory levels in some children, but the results of the systematic review and our cohort
study suggest that this is not the case in the majority of children. Hypertension may be refractory
to medications, or may require a combination of multiple classes of antihypertensive medications
to control. An important point to address is the lack of standardization of antihypertensive
therapy in children with renovascular hypertension, including choice of first line agent, optimal
dosing, and choice of combination therapy. This is in part due to the risk of complications from
reducing the blood pressure to levels that may compromise perfusion of the kidneys. Moreover,
there is concern regarding the use of ACE inhibitors in children with RAS as it may lead to
compromised kidney function. Thus, there may be permissive hypertension in our cohort based
on these concerns; however, as few studies address optimal blood pressure control and use of
ACE inhibitors in childhood RAS, it is not clear if this is only a theoretical risk. Further, children
may experience side effects to certain medications, or respond differently depending on the
extent of arterial involvement. Standardization of antihypertensive therapy and guidelines for
adding additional agents for optimal blood pressure reduction may be useful in this patient
population.
The choice of antihypertensive medication is especially relevant in this disease model, as
certain agents such as beta blockers have direct effects on pressure wave propagation and
reflection, as well as vascular remodeling(Saba, 2014). Since children with MAS and/or RAS
have changes in central pulse wave velocities and central blood pressures, it is worth considering
incorporating the physiology and resulting hemodynamic changes in the choice of
antihypertensive agent. How different antihypertensive agents affect the measured vascular and
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cardiac endpoints in children has not been extensively studied, and could be a future direction to
explore in this patient population.
The criteria for endovascular and surgical interventions are highly dependent on the
individual child’s response to medications, anatomy, and growth. To date, there is little
consensus on indications for interventional management. Some suggested criteria include
hypertension despite two or three hypertensive agents, evidence of vascular compromise or end-
organ cardiac or renal disease. Criteria for secondary intervention are also unclear, with lower
threshold for re-intervention if there is evidence of residual narrowing in some clinical centers
(Kari, 2015). Future studies are needed to assess the benefit of delayed intervention compared to
repeated angioplasty on long-term outcomes in this group. It is worth noting that such studies
may be difficult to conduct given the rarity of this lesion in children and the heterogeneity in the
vascular involvement, which may prevent adequate sample sizes for appropriate comparison.
In assessing outcomes following management of MAS and RAS in children, we found
that hypertension persists despite both medical management with antihypertensive therapy, as
well as following endovascular or surgical relief of aortic narrowing. The etiology of the
persistent hypertension is unclear and is an important challenge in treating children with MAS or
RAS. The residual hypertension may be due to incomplete resolution of aortic or renal artery
narrowing resulting in residual stenosis with associated hemodynamic changes. Another
plausible explanation may be that children have adapted to operate at a higher blood pressure set
point, with structural vascular and cardiac remodeling that matches the higher operating pressure.
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Another hypothesis that future studies may explore include reduced baroreceptor sensitivity
(Beekman, 1983, Polson, 2006).
Lastly, long-term outcomes following surgical repair of aortic stenosis are not well
described in the literature. Most published case reports describe 1-3 surgical cases with
insufficient follow-up to provide insight into the impact of surgery on physical development,
graft durability, and quality of life. Larger series of surgically corrected childhood RAS and
MAS show that successful outcomes (with >80% achieving complete resolution of hypertension)
can be attained with careful selection and execution of surgical cases(Stanley, 2008, Stanley,
1981, Stanley, 2006).Over the past few decades, considerable variation and evolution in the
operative management of childhood renovascular hypertension has occurred, in part due to the
recognition that long-term benefit of initial surgical intervention may not be sustained. As
advances in surgical techniques continue to develop, outcomes need to be re-assessed to
determine the efficacy of the different surgical repair techniques, and guide clinical decision-
making in concurrent cohorts. Data on longer-term outcomes in later life following surgical
correction of MAS/RAS in childhood may assist in determining the optimal timing of
intervention to delay or avoid re-interventions and complications.
5.1.2 Extent of vascular disease
An important finding of the systematic review is the presentation of renal artery stenosis
in approximately 70% of childhood cases of MAS. This finding was confirmed in our cohort of
93 children managed at the Hospital for Sick Children, and formed the basis for our anatomical
classification of isolated RAS and MAS in conjunction with RAS. The progression from isolated
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RAS to include MAS is not described in the literature, and although we found no evidence of this
progression in our pediatric cohort, we did not perform systematic imaging of the same arterial
bed over time to completely rule out the possibility of a progressive arteriopathy in children with
MAS and/or RAS.
Using non-invasive imaging of central and peripheral arteries, we were able to add to our
knowledge of the extent of vascular involvement in this rare disease. Examination of the carotid
intima-media thickness revealed significant increases in vessel wall thickness compared to
healthy children. This increase was more prominent in children with both MAS and RAS
compared to those with isolated RAS. Due to the cross-sectional nature of the vascular imaging,
we were not able to attribute the observed changes in the carotid arteries to current blood
pressure values, or make inferences regarding the effect of treatment on the carotid artery wall
thickness. Given that baseline measurements were not evaluated at the time of clinical
presentation, as CIMT is currently not considered standard pediatric procedure in the assessment
of hypertension, we are not able to comment on the progression of CIMT in children. However,
previous longitudinal studies evaluating CIMT in a healthy pediatric population using similar
vascular imaging protocol have reported a rate of increase in CIMT of 0.01-0.02 mm per
year(Litwin, 2009). Our cohort had significantly elevated CIMT compared to age, sex, and BSA-
matched healthy children; and the magnitude of the difference was approximately 0.1 mm.
Assuming a similar rate of CIMT progression, this magnitude of difference represents the
equivalent of 5-10 years of aging to the vasculature in children with MAS/RAS compared to
healthy children of the same age. That arterial hypertension accelerates the aging process has
previously been reported. It is also well documented that CIMT increased with age even in the
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healthy population. It may be that the hypertension associated with MAS results in changes in
the vessels that resemble accelerated aging in children. Further prospective studies are needed to
determine the effect of the observed early vascular changes on the long-term risk of
cardiovascular disease.
It is likely that the structural changes in the carotid artery are related to the increased
regional blood pressure, as children with higher systolic blood pressure Z-score also had higher
CIMT in both the healthy and diseased populations. Further examination of the distensibility of
the carotid artery revealed no changes compared to healthy children, suggesting that the increase
in CIMT may be an adaptation to normalize the stress/strain relationship. This was also
consistent with the lack of differences in the elastance and stiffness indices of the aorta compared
to healthy children, which suggests that the central arteries have remodeled in response to the
increased pressure, with preserved function and ability to respond to changes in stroke volume.
Consistent with this hypothesis, children with MAS and/or RAS had significantly elevated
central blood pressures, which may have provided the stimulus to induce thickening of the vessel
wall. The prognostic significance of increased CIMT in children remains to be determined.
Longitudinal studies in adult patients with repaired aortic coarctation report a 15-fold increase in
cardiovascular risk over a 10-year follow-up period in those with CIMT greater than 0.8 mm,
after adjusting for hypertension and dyslipidemia(Luijendijk, 2014). This suggests that CIMT
measurement could be incorporated in routine clinical assessment of patients and may contribute
to risk assessment in coarctation patients. Studies in pediatric populations are needed to
determine whether CIMT is predictive of risk of cardiovascular events to the same extent. We
propose that CIMT may serve as a valuable supplement in the clinical evaluation of children
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with vascular disease as it provides a vascular endpoint to monitor subclinical hypertensive
changes, and may provide insight into treatment efficacy.
One of the questions that we aimed to address in the vascular portion of this thesis was
whether MAS/RAS is an isolated disease of the peri-renal aorta, or a generalized arteriopathy.
The extent of vessel disease is a highly debated topic in aortic coarctation literature. Studies have
reported evidence of arterial stiffness and impaired vascular reactivity in non-diseased (radial)
arteries in children with aortic coarctation, suggesting that the aortic disease is not confined to
the aortic lesion itself, but rather manifests itself as a generalized arteriopathy elsewhere in the
arterial tree(Trojnarska, 2011). Other studies report disparities in arterial properties proximal to
the aortic narrowing as compared to distal vessels which remain largely unaffected(Sarkola,
2010, Sarkola, 2011). These latter studies support the hypothesis that aortic narrowing is a
localized phenomenon with no evidence of arteriopathy distal to the diseased segment. To
address this question in children with MAS and/or RAS, we chose to measure peripheral
(carotid-to-radial) pulse wave velocity. We found no evidence of increased peripheral velocities
in children with MAS or RAS compared to healthy children, suggesting that the disease is
localized to the peri-renal aortic segment with evidence of structural vascular changes related to
the elevated central blood pressures. A surprising finding was that peripheral PWV was not
elevated in children with known elastin mutation such as Williams’ syndrome, where a
generalized arterial stiffness would be expected. We discussed the possibility that pulse wave
velocity may not be an appropriate indicator of arterial stiffness in children given that
measureable differences may take many years to manifest. However, differences in central PWV
were observed in children with MAS/RAS using the same imaging technique, and therefore we
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concluded that central aortic properties may be affected in our cohort with preserved peripheral
velocities, indicative of a localized vascular involvement. This conclusion was consistent with
the results of pulse wave analysis in children with successfully repaired aortic coarctation, which
report preserved carotid to radial PWV using similar imaging protocol(Sarkola, 2011).
Consistent with the elevated central blood pressures, we found increases in central pulse
wave velocity. Given the aortic and renal arterial disease in this cohort, we hypothesized that
central pulse wave velocities would be elevated. Our finding of increased central PWV in
children with MAS and RAS is in contrast to findings in children with repaired aortic
coractation, which report normal central PWV compared to healthy children(Sarkola, 2011). This
may be related to a more pronounced effect of distal abdominal aortic narrowing on central
aortic hemodynamics, compared to the effect of more proximal ascending aortic narrowing. The
direct comparison between aortic coarctation and MAS has not been evaluated, but may shed
light on the effect of the proximity of the aortic lesion on the severity of hypertension, and the
different physiological responses to aortic narrowing.
Taken together, our results from the vascular assessment suggest that childhood MAS
and/or RAS is a localized vascular disease resulting in increased central blood pressures,
sufficient to induce structural adaptations in the thickness of the vessel walls. This emphasizes
the need for close monitoring and optimal blood pressure control in this high risk group. Future
studies will determine whether the observed structural vascular changes can be reversed with
further blood pressure lowering, and whether clinical screening for these vascular endpoints can
assist in the early identification of children with the worst prognosis.
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5.1.3 End-organ cardiac disease
Given that children with MAS/RAS present with severe arterial hypertension, and the
persistence of hypertension for years following medical or interventional management,
evaluation of end-organ cardiac disease was merited. We chose to conduct a comprehensive
cardiac assessment of left ventricular structure, systolic function, diastolic function, as well as
myocardial mechanics.
We hypothesized that patients would present with some degree of ventricular remodeling
associated with the hypertension at clinical presentation. Measurement of left ventricular mass at
clinical presentation revealed significantly higher LV mass compared to age, sex, and body
surface area-matched healthy controls. Although ejection fraction was preserved in children at
presentation, we found reduced systolic longitudinal strain values. Circumferential strain was not
different from healthy controls. Although the clinical significance of reduced longitudinal strain
in children with aortic disease and hypertension has yet to be determined, detection of these
systolic changes has been shown to have prognostic significance in adult populations(Dandel,
2009). Future studies with longitudinal follow-up will determine whether this is true to the same
extent in children as they age. A limitation of our cardiac assessment is that complete baseline
evaluation at the time of presentation was not feasible due to the retrospective nature of that
portion of the study. Some of the images obtained were not of sufficient quality to conduct strain
analysis, which limited the assessment of myocardial mechanics to a subgroup of children.
Nonetheless, we wanted to perform some retrospective studies to determine the degree of
improvement in structural and functional cardiac indices.
154
Consistent with LV remodeling, we found subtle differences in early relaxation of the left
ventricle, with lower E/a wave ratios in children with MAS/RAS. Detection of early diastolic
changes is important in the pediatric age group and emphasizes the need for optimal blood
pressure control. As children with MAS/RAS are often asymptomatic at presentation or are
referred based on an incidental finding of hypertension, it is crucial to evaluate cardiac function
as they may already demonstrate functional changes without exhibiting any symptoms of
hypertension.
The comprehensive cardiac assessment which was conducted prospectively at the time of
study enrollment confirmed our hypothesis of cardiac adaptations to hypertension. At the time of
enrollment, most children had been treated either medically or with surgical and endovascular
procedures. However, children had significantly higher systolic and diastolic blood pressures at
enrollment compared to healthy children. Evaluation of left ventricular mass showed increased
Z-scores compared to controls. Although there was some improvement in LV mass compared to
baseline values at presentation, values were not significantly different and remained elevated
compared to healthy controls. Systolic blood pressure decreased significantly from the time of
clinical presentation, but remained higher than healthy controls. It is unclear why LV mass did
not regress with this decrease in blood pressure. It may be that insufficient time has lapsed to
allow for LV remodeling to occur and for the LV to adapt to the new (reduced) afterload. We
cannot exclude the possibility that the increased mass may also be due to irreversible changes
that are blood pressure-independent, such as fibrosis or scarring of the left ventricle. Myocardial
fibrosis has been described in various hypertensive adult populations(Diez, 2005, Edwards,
2015, Diez, 2007), and may be a contributor to the observed increase in LV mass; however, this
155
has not been investigated in the pediatric age group. The current study did not assess the degree
of fibrosis and future studies can determine whether there is evidence of pathologic remodeling
of the left ventricle. Prospective follow-up will allow us to determine whether LV regression
occurs at a later time, or whether further lowering of blood pressure results in normalization of
LV mass.
At the time of enrollment, we observed significant improvements in ejection fractions
compared to baseline values. Assessment of myocardial mechanics revealed a marked
improvement in systolic longitudinal strain and circumferential strain. The longitudinal strain
values were comparable to healthy levels, whereas circumferential strain was significantly higher
than healthy controls. We hypothesize that the supra-normal strain values may be related to the
increased LV mass and the reduced blood pressures following treatment, which may result in a
thickened muscle pumping against a reduced afterload. The clinical significance of this finding
remains unclear.
The subtle changes in diastolic parameters observed at clinical presentation persisted at
the time of enrolment. These changes may be due to the elevated blood pressure, or to the
increased LV mass. We expect changes in early relaxation to be reversible after normalization of
blood pressure and LV mass regression, however, this remains to be confirmed with prospective
follow-up. It is unknown whether these changes progress into diastolic heart failure, similar to
adults, or whether they progress into systolic dysfunction. Therefore, it is important to monitor
these changes with annual echocardiographic assessment of children with MAS and/or RAS.
156
It is likely that the observed changes in LV structure and subtle changes in LV function
are related to the persistent hypertension, which along with our findings of vascular remodeling,
emphasize the importance of adequate blood pressure control and close monitoring of end-organ
disease in children with MAS and/or RAS.
157
5.2 Conclusions
Through this body of work, we were able to address some of the gaps in knowledge
regarding the presentation, management, vascular and cardiac involvement in a rare vascular
disease in children. Our results suggest that RAS is an important presentation in children with
MAS and is more prevalent than previously reported. By evaluating outcomes in one of the
largest cohort studies of children MAS and RAS, we were able to show a high prevalence of
persistent hypertension despite medical and interventional (endovascular and surgical)
management.
Investigation of the aorta and peripheral arteries in our concurrent cohort has
demonstrated no evidence of peripheral vascular disease, and confirmed the presence of
structural remodeling of the carotid arteries and elevated central blood pressures. Evaluation of
cardiac structure and function revealed increased left ventricular mass with mild changes in early
relaxation properties. The observed vascular and cardiac changes are consistent with adaptations
of the cardiovascular system induced by chronic arterial hypertension. Children with MAS and
RAS already exhibit structural and functional cardiovascular changes which merit close
monitoring of blood pressure with longitudinal assessment of end-organ cardiac disease. One of
the most important implications of our results is that strategies for blood pressure control in
children with renovascular causes of hypertension need to be developed and further studied. This
includes developing guidelines for optimal antihypertensive management of blood pressure, and
defining clear criteria for endovascular or surgical intervention.
158
5.3 Future directions
Future directions that may answer some of the remaining gaps in knowledge, and address
the limitations of the presented body of work, are summarized below:
1- Delineating the embryology of the abdominal aorta
Conventionally, the aorta has been considered a homogenous vascular conduit with
identical cellular and extracellular structure and function. However, evidence is accumulating to
suggest that variations exist not only between the thoracic and abdominal aorta, but also between
different segments of the same vessel(Ruddy, 2008, Sinha, 2014, Lillvis, 2011). This regional
heterogeneity includes structural, mechanical, and hemodynamic differences(Ruddy, 2008,
Ruddy, 2013, Majesky, 2007). Studies into the differential expression of certain genes and
response to growth factors have yielded results that support a hypothesis of distinct development
of the aortic segments. Such studies stem from the clinical observation that many vascular
diseases have the tendency to manifest at specific sites in the vasculature. Aortic aneurysms are
one such disease with approximately 90% developing between the renal arteries and iliac
bifurcation(Ruddy, 2013). Aneurysms develop less frequently in the ascending and descending
thoracic aorta, and are distinct from abdominal aortic aneurysms (AAAs) in prevalence, risk
factors, genetics and histology(Lillvis, 2011, Ruddy, 2013, Bonert, 2003). Another example is
Atherosclerotic lesions which form at specific sites in the arterial tree, such as bifurcations,
branch points, and regions of curvature.
The pathophysiology of the aorta above and below the diaphragm has demonstrated
disparities in atherosclerotic susceptibility, vessel mechanics, proteolytic profiles, and cell
159
signaling pathways that have implications in the development of vascular diseases(Ruddy, 2008,
Lillvis, 2011). A less documented variability is between different segments along the abdominal
aorta, namely the supra-renal, infra-renal, and inter-renal segments. Such variability is relevant
as certain vascular diseases, such as MAS, appear to be localized to one segment of the
abdominal aorta(Collins, 2011, Rumman, 2015). Reviewing the literature on the fetal abdominal
aorta, we failed to find data on the embryological development of the abdominal aorta, and
specifically the development of aorta in the region of renal and visceral branch take off. There
are currently no animal models of the abdominal aorta or renal arteries. A better understanding of
the embryological development of the abdominal aorta, and specifically the region of visceral
branch take off may provide insight into the genesis and progression of abdominal aortic lesions.
2- Re-evaluate targets for blood pressure control
Current blood pressure management in children aims to lower blood pressures to less
than the 95% percentile for age, height, and sex. Given the persistent hypertension despite
medical and interventional management, and the evidence of vascular and cardiac remodeling in
children with MAS/RAS, targets for optimal blood pressure control may need to be lowered.
This requires studies to evaluate the benefit of further blood pressure lowering, and explore the
effect of lower blood pressures on risk of cerebrovascular disease and vascular compromise. This
is especially important in children with cerebrovascular involvement and children with aortic
grafts, who may require higher than optimal blood pressure to ensure adequate cerebral or graft
perfusion. It may be that different thresholds for blood pressure need to be developed depending
on the extent of arterial involvement and the vascular anatomy of the individual child.
160
3- Choice of antihypertensive agent
The different classes of antihypertensive agents have different effects on vascular
properties and pressure wave propagation and reflection (Delis, 2005). Angiotensin converting
enzyme (ACE) inhibitors have an effect on the remodeling of small arteries and arterioles, which
in turn also affects the wave reflection properties(Zieman, 2005). Another class of
antihypertensive medications which affect central aortic properties are beta blockers, which have
been shown to affect central hemodynamics including pulse pressures(Saba, 2014). Therapies
designed to target specific arterial and wave reflection properties may be useful in MAS and
RAS, where either the central arterial stiffness or the aortic narrowing may be causing early
wave reflection or augmentation of central pressures. The differential effect of certain
antihypertensive agents on vascular endpoints in children has not been investigated, and may
have therapeutic implication in the future management of renovascular hypertension in children.
4- Longer-term follow up of children with MAS/RAS
Although we were able to describe outcomes such as restenosis and re-intervention in
children following initial management, longer term outcomes in children who have transitioned
to adult care may provide additional information regarding risk of cardiovascular disease in this
group. We have shown that left ventricular mass remained elevated at a median of 6 years
following clinical presentation. Further prospective studies should monitor whether these values
normalize in later life, possibly with more optimal blood pressure control. Additionally, the
prognostic significance of the observed early changes in diastolic function requires long-term
follow up and longitudinal assessment. The reversibility of the observed vascular changes,
161
including increased CIMT and increased central PWV, and whether these changes impart
increased risk of cardiovascular morbidity and mortality also need to be determined.
5- Describe the normal abdominal aorta in humans
A limitation of the studies describing regional differences in mechanical and
hemodynamic vessel properties is the lack of detailed mapping of the wall shear stress and
intimal thickening in the abdominal aorta(Bonert, 2003). Another important limitation is the lack
of an anatomically-faithful model that is patient-specific. Further, it is important to define the
normal growth patterns for all cardiovascular structures to recognize abnormal development as
early as possible(Ozguner, 2011). The normal dimensions of the abdominal aorta and the effects
of age and sex on growth and dimensions have not been well described. This is relevant as
advancing resolution of ultrasound and magnetic resonance imaging devices allow for earlier
detection of abnormal growth and aberrant development such as narrowings and aneurismal
dilatations.
6- End organ renal disease
Another avenue for research would be to determine the extent of end-organ renal disease.
This includes determining kidney function as well as kidney growth at the time of clinical
presentation and throughout the course of disease. Future studies can assess whether
interventional management such as renal artery angioplasty may confer improvements in renal
function and growth of the kidney, even if the procedure does not reduce blood pressures. Such
findings would support endovascular intervention in children and a lower threshold for re-
intervention. End-organ kidney disease is an important aspect of renovascular hypertension that
162
is largely under-investigated in children and may add to our understanding of the
pathophysiology and management of renovascular disease in children.
7- Explore the genetics of MAS/RAS
Despite the documented overlap between children with MAS and known Mendelian
disorders, a genetic cause for MAS or RAS has not been investigated. Whole exome or whole
genome studies would be useful in determining whether there is an underlying genetic cause for
the observed phenotypic overlap. It is worth noting that children with isolated RAS or MAS do
not undergo genetic testing as part of their clinical care if they do not exhibit typical features to
suggest a genetic disorder. However, complete phenotyping of children with idiopathic
hypertension is also not part of routine clinical assessment. Therefore, it is unclear whether
children with isolated RAS and MAS do not express features of known genetic diseases or are
simply not evaluated for a genetic cause. Exploring a potential genetic component of childhood
MAS/RAS may point to undiagnosed etiologies and may improve our understanding of the
pathobiology of this rare disease.
8- A better understanding of the vascular biology of aortic disease
In diseases of the aorta such as aortic coarctation and vessel hypoplasia, the underlying
pathology is unknown. Histological evidence is rare and in the few cases where it is investigated,
the changes are non-specific or completely normal. Quantifying the time course of vascular
lesion development and maturation, particularly related to structural changes and release of
proteolytic molecules that may influence aortic wall composition or mechanical properties will
advance our understanding of the underlying disease etiology.
163
9- Incorporating knowledge of vascular biology into care and management
There is a pressing need to advance and incorporate our understanding of the underlying
mechanobiology and pathobiology in patient-specific management well beyond focusing on
lesion geometry alone. A better understanding of the underlying pathological changes may
contribute to a move towards personalized medicine wherein interventional planning will be
based on an understanding of the biological status of the lesion, not just overall lesion size and
extent of aortic involvement.
164
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Appendices
Appendix I: Research strategy for systematic review
Database: Ovid MEDLINE(R) 1946 to Present with Daily Update, Ovid MEDLINE(R) In-
Process & Other Non-Indexed Citations <April 23, 2014>
Search Strategy:
--------------------------------------------------------------------------------
1 (mid* adj3 aort* adj3 (syndrome* or disease*)).tw. (133)
2 (midaortic adj3 (syndrome* or disease*)).tw. (31)
3 exp Abdomen/ (80362)
4 Aorta, Abdominal/ (18181)
5 3 or 4 (97979)
6 Aortic Coarctation/ (7819)
7 Constriction, Pathologic/ (19239)
8 6 or 7 (26977)
9 5 and 8 (871)
10 ((hypoplas* or stenos* or coarctation* or co-arctation* or constrict*) adj6 abdom* adj6
aort*).tw. (1112)
11 (idiopath* adj6 abdom* adj6 (coarctation* or co-arctation* or constrict* or stenos* or
hypoplas*)).tw. (3)
12 1 or 2 or 9 or 10 or 11 (1795)
13 limit 12 to "all child (0 to 18 years)" (450)
14 (infan* or newborn* or new-born* or neonat* or baby or babies or child* or youth or kid or
kids or toddler* or boy* or girl* or adolescen* or teen* or juvenile* or p?ediatric*).mp.
(3381915)
15 12 and 14 (515)
16 13 or 15 (515)
***************************
Database: Embase Classic+Embase <1947 to 2014 Week 16>
Search Strategy:
--------------------------------------------------------------------------------
1 (mid* adj3 aort* adj3 (syndrome* or disease*)).tw. (170)
2 (midaortic adj3 (syndrome* or disease*)).tw. (42)
3 exp abdomen/ (151665)
4 abdominal aorta/ (16916)
5 3 or 4 (167837)
6 aorta stenosis/ (15040)
7 aorta coarctation/ or aorta constriction/ (14363)
8 stenosis/ (32212)
9 6 or 7 or 8 (59745)
10 5 and 9 (1853)
11 ((hypoplas* or stenos* or coarctation* or co-arctation* or constrict*) adj6 abdom* adj6
aort*).tw. (1551)
12 (idiopath* adj6 abdom* adj6 (coarctation* or co-arctation* or constrict* or stenos* or
hypoplas*)).tw. (3)
13 1 or 2 or 10 or 11 or 12 (2985)
189
14 juvenile/ or exp adolescent/ or exp child/ (2857145)
15 exp adolescence/ or exp childhood/ or newborn period/ (143821)
16 (infan* or newborn* or new-born* or neonat* or baby or babies or child* or youth or kid or
kids or toddler* or boy* or girl* or adolescen* or teen* or juvenile* or p?ediatric*).mp.
(3610118)
17 14 or 15 or 16 (3620969)
18 13 and 17 (736)
***************************
Database: EBM Reviews - Cochrane Central Register of Controlled Trials <January 2014>
Search Strategy:
--------------------------------------------------------------------------------
1 (mid* adj3 aort* adj3 (syndrome* or disease*)).tw. (0)
2 (midaortic adj3 (syndrome* or disease*)).tw. (0)
3 exp Abdomen/ (2194)
4 Aorta, Abdominal/ (286)
5 3 or 4 (2469)
6 Aortic Coarctation/ (32)
7 Constriction, Pathologic/ (287)
8 6 or 7 (319)
9 5 and 8 (3)
10 ((hypoplas* or stenos* or coarctation* or co-arctation* or constrict*) adj6 abdom* adj6
aort*).tw. (1)
11 (idiopath* adj6 abdom* adj6 (coarctation* or co-arctation* or constrict* or stenos* or
hypoplas*)).tw. (0)
12 1 or 2 or 9 or 10 or 11 (4)
13 (infan* or newborn* or new-born* or neonat* or baby or babies or child* or youth or kid or
kids or toddler* or boy* or girl* or adolescen* or teen* or juvenile* or p?ediatric*).mp.
(144104)
14 12 and 13 (1)
190
Copyright Acknowledgements
Disease Beyond the Arch: A Systematic Review of Middle Aortic Syndrome in Childhood.
Published by the American Journal of Hypertension, 2015; 28:833-46.
Rumman RK, Nickel C, Matsuda-Abedini M, Lorenzo AJ, Langlois V, Radhakrishnan S, Amaral
J, Mertens L, and Parekh RS.