Literature Review

Role of Hemodynamic Forces in Unruptured Intracranial Aneurysms: An Overview of a

Complex Scenario
Marcello Longo1, Francesca Granata1, Sergio Racchiusa1, Enricomaria Mormina1, Giovanni Grasso2,
Giuseppe Maria Longo1, Giada Garufi3, Francesco M. Salpietro4, Concetta Alafaci3

Key words - BACKGROUND: An understanding of the natural history of unruptured intra-

- Cerebral aneurysm
- Computational fluid dynamics
- Hemodynamics
- Intracranial aneurysms
- Wall shear stress
Abbreviations and Acronyms
AFI: Aneurysm formation indicator
CFD: Computed fluid dynamics
CT: Computed tomography
DSA: Digital subtraction angiography
GON: Gradient oscillatory number
MR: Magnetic resonance
MRFD: Magnetic resonance fluid dynamics
OSI: Oscillatory shear index
UIA: Unruptured intracranial aneurysm
WSS: Wall shear stress
WSSG: Wall shear stress gradient
From the Departments of 1Biomedical Sciences and
Morphological and Functional Imaging and 3Neurosurgery,
University of Messina, Policlinico G. Martino, Messina;
2
Section of Neurosurgery, Department of Experimental
Biomedicine and Clinical Neurosciences (BIONEC), University
of Palermo, Palermo; and 4Section of Neurosurgery,
Department of Human Pathology, University of Messina,
Messina, Italy
To whom correspondence should be addressed:
Giovanni Grasso, M.D., Ph.D.
[E-mail: giovanni.grasso@unipa.it]
cranial aneurysms (IAs) has always played a critical role in presurgical or
endovascular planning, to avoid possibly fatal events. Size, shape, morphology,
and location are known risk factors for rupture of an aneurysm, but morphologic
parameters alone may not be sufficient to perform proper rupture risk
stratification.
- METHODS: We performed a systematic PubMed search and focused on he-
modynamics forces that may influence aneurysmal initiation, growth, and rupture.
- RESULTS:
We included 223 studies describing several hemodynamic param-
eters related to aneurysm natural history. In these studies, different modalities of
aneurysm model creation have been used to evaluate flow and to comprehen-
sively analyze the evolution of IAs. Controversy exists about the correlation
between these parameters and initiation, growth, rupture risk, or stabilization of
the aneurysmal sac. Recent findings have also shown the importance of flow
patterns in this process and the relationship between unruptured IA geometry
and hemodynamic parameters.
- CONCLUSIONS:
The role of hemodynamic forces in evaluation of the natural
history of unruptured IAs presents is inherently complex and is still not
completely understood. In this complex scenario, although several attempts
have been described in the literature, a proper risk rupture stratification and
treatment strategy selection based on hemodynamic forces has not yet been
created. Further efforts should be made to accomplish this important goal.

Marcello Longo and Francesca Granata contributed equally

to the article.
Citation: World Neurosurg. (2017) 105:632-642.
http://dx.doi.org/10.1016/j.wneu.2017.06.035
Journal homepage: www.WORLDNEUROSURGERY.org
Available online: www.sciencedirect.com
1878-8750/$ - see front matter 2017 Elsevier Inc. All
rights reserved.
INTRODUCTION
Prevalence of unruptured intracranial an-
eurysms (UIAs) varies considerably accord-
ing to different studies. The prevalence of
IAs, as an incidental nding, in the general
population is 2%e3%.1,2 An understanding
of the natural history of IAs may play an
important role in treatment planning,
whether surgical or endovascular, to prevent
fatal events.3 Aneurysm rupture and the
following subarachnoid hemorrhage has a
mortality of approximately 45%, with a
signicant residual neurologic decit in
nearly half of survivors.4 With the
improvement of neuroradiology
techniques, the detection of UIAs has
increased and their management has
become challenging in reducing both
morbidity and mortality.5 The ideal clinical
scenario should be based on proper
evaluation of risk of aneurysm rupture to
treat only UIAs with a high risk of rupture.
Size, shape, morphology, and location (in
anterior or posterior circulation) have been
identied as known risk factors for
aneurysm rupture,6-10 whereas other
nonmorphologic parameters, such as
smoke exposure and atherosclerosis, have
been associated as independent risk
factors.4 Therefore, morphologic
parameters may not be sufcient to
perform a complete rupture risk
stratication, which is related to more
complex mechanisms, such as histologic
features, caliber of the arterial walls, and
blood ow dynamics. Several studies have
recently highlighted the pivotal role of
hemodynamic forces in initiation, growth,
and rupture of intracranial aneurysms
(IAs), although this interaction is complex
and poorly understood.11-17 The main goal
of our work is to provide an overview of
the role of the several hemodynamic
parameters available, to better evaluate the
risk rupture of UIAs and their natural
history.
METHODS
We conducted a baseline literature search
using the MEDLINE (National Library of
Medicine) electronic database combining

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MARCELLO LONGO ET AL.
the following words in article titles, key-
words, and abstracts (if necessary, the full
text): the keyword intracranial aneu-
rysms was combined with hemody-
namic, shear stress, wall shear stress,
laminar ow, turbulent ow, CFD, DISCUSSION
computational uid dynamics, or intra-
aneurysmal ow. Moreover, we searched
a reference list of relevant articles for
additional publications. We selected only
articles that described at least 2 hemody-
namic parameters in UIAs, excluding ar-
ticles that discussed only morphologic
aspects of UIAs without any hemodynamic
correlation. Articles discussing in vitro
simulations not based on real aneurysm
models, aneurysm evaluation in animal
models, ruptured aneurysms only, aneu-
rysms treated with different devices (coils
and ow diverters), and other aneurysm
sites (such as thoracoabdominal) were
also excluded from our study. Because our
review is focused on understanding the
relationship of hemodynamic parameters
with the natural history of UIAs, by means
of computed tomography (CT), magnetic
resonance (MR), and digital subtraction
angiography (DSA) investigation, articles
not discussing the specic topic were
excluded from the analysis, as well as
articles focusing mainly on technical
aspects, methodological issues, or not in
English.
RESULTS
A literature search of the keyword intra-
cranial aneurysms found 29,142 articles,
as of May 18, 2017. To better lter these
results, we decided to combine this
keyword with others, focusing mainly on
the role of hemodynamic parameters in
evaluation of rupture risk and natural his-
tory of UIAs. We found 2501 articles with
the intracranial aneurysms/hemody-
namic keywords association; 377 results
for intracranial aneurysms and shear
stress; 44 results for intracranial aneu-
rysms and turbulent ow; 36 results for (Siemens Healthcare, Erlangen, Germany),
intracranial aneurysms and laminar
ow; 186 results for intracranial aneu-
rysms and intra-aneurysmal ow; 185 ware allow, for example, display and
results for intracranial aneurysms and
CFD; and 322 results for intracranial
aneurysms and computational uid dy-
namics. A total of 3651 articles were
evaluated for the nal selection in this re-
view. Among these 3651, only 223 articles
WORLD NEUROSURGERY 105: 632-642, SEPTEMBER 2017
HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS
(6.1%) fullled the inclusion criteria and
were further selected for this review
accordingly to their relevance and unicity.
selected slice, four-dimensional ow se-
Imaging Techniques in Evaluation of UIA
Hemodynamics
Fluidodynamics analyzes the hemody-
namic stress of the vascular wall and helps
understand the complex natural history of
UIAs.13,14,18-20 There are several methods to
assess the complexity of hemodynamic
forces in vivo, and most use models based
on the real anatomy of human
aneurysms.8,21,22 Among these, computed
uid dynamics (CFD) is able to investigate
uidodynamics by a computed simulation
of vascular stress ow inside an IA.23-27
CFD is a technique that is able to make
virtual vectors, also known as streamlines,
by data analysis from CT and MR angiog-
raphy or rotational DSA.11,16,20,28-32 CFD is
not performed routinely in UIA evaluation
because it requires dedicated software33,34
and proper training. These ow simula-
tion models are made by using the con-
stants for the density and dynamic blood
viscosity, expressed respectively in kg/m3
and Pascal second (Pa$s). Properties of
blood as a non-Newtonian uid and elas-
ticity of vessels wall are not always taken
into account during CFD simulations.35-37
Because this technique is time consuming
and difcult to apply in real-time evalua-
tion of IAs, its use is mainly conned to
research. Furthermore, CFD provides the
best results when associated with DSA,
which requires arterial catheterization,
iodinated contrast administration, radia-
tion exposure, and an experienced oper-
ator.38-43 The possibility of a quantitative
assessment of blood ow by means of
quantitative and semiquantitative color-
coded DSA is provided by recent software
such as QFlow software (Philips Health-
care, Best, the Netherlands), syngo iFlow
or AngioViz (GE Healthcare, Waukesha,
Wisconsin, USA).44-47 These types of soft-
calculation of ow curves and blood ow
parameters for single pixels and to mark
inow and outow of contrast in selected
regions of interest.47,48 An alternative for
blood ow evaluation is the MR uid dy-
namics (MRFD)-based technique.49 MRFD
LITERATURE REVIEW
has been proposed with 7-T,50,51 3-T,28,35
and 1.5-T MR scanners,49,52,53 using also
phase-contrast four-dimensional ow se-
quences. Compared with two-dimensional
cine MR, which are limited to a single
quences can provide information on blood
inow and outow inside the aneurysm,
with full brain coverage. These sequences
take advantage of a direct relationship be-
tween blood ow velocity and the phase of
the MR signal, which is acquired with
electrocardiographic synchronization. The
MRFD of IAs is elaborated by commercially
available software35 able to assess the
background ow around the vascular wall
of UIAs and the bloodstream information
over time.
Hemodynamic Parameters: Overview of a
Complex Scenario
Several known hemodynamic parameters
are used to describe and evaluate the
blood ow effect on arteriosus vessel walls
and, in particular, on UIAs. Different
techniques provide different parameters
for UIA evaluation, and thus, a good un-
derstanding of their meaning and their
management is an important factor in a
proper approach to UIA evaluation. An
adequate selection of these parameters
may be inuenced by several assumptions,
such as aneurysm shape, laminar and
turbulent blood ow, parent vessel curva-
ture, Newtonian and non-Newtonian
blood ow.37,54-59 Shear stress is a dy-
namic force induced by a viscous uid
moving across the surface of a solid ma-
terial, and its role in UIA formation,
growth, and rupture has been studied for
several years.14 Shear stress is usually
evaluated as one of the main forces in
UIA analysis and several parameters are
used to best characterize it.13,60,61 For
blood vessels, it is described as wall
shear stress (WSS),15,62 which represents
the dynamic frictional and tangential
force exerted by the viscosity of blood
ow on the blood wall and has a normal
value that ranges from 1.0 to 2.0 N/m2
(Pa). Its characterization across time is
evaluated by the time-averaged WSS,
which is dened as the standard time
average of each nodal WSS vector magni-
tude at the wall, across a cardiac cycle (it is
measured in Pa and its normal value
ranges from 1.5 to 10).63,64 During the
cardiac cycle, WSS presents a highly
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MARCELLO LONGO ET AL.

Table 1. List of the Most Used Hemodynamic Parameters in Blood Flow and Aneurysm Evaluation
Hemodynamic Parameter Equation Definition
Z
www.SCIENCEDIRECT.com

T
Time-averaged wall shear stress (TAWSS)64 TAWSS is the standard time average of wall shear stress (magnitude)It is
TAWSS 1
T
kskdt
0 measured in Pa.
ksk is defined as the magnitude of the time average
of WSS vector, where the averaging time is typically T
T is the duration of one cardiac cycle, assuming the flow is periodic

s
 ! 2  ! 2  ! 2
Wall shear stress gradient (WSSG)63 v s      WSSG is a spatial derivative measure along the direction of the flow. It is
WSSG  w  v s w  v s w  used in unruptured intracranial aneurysms with complex geometries and/or
 vx   vy   vz 
with arising vessels. It is measured in Pa/mm
!
s w is the WSS vector
!
TWSSG v svt w
72
Temporal wall shear stress gradient (TWSSG) TWSSG is the rate of change in WSS magnitude vector over the cardiac cycle
!
s w is the WSS vector

Oscillatory shear index (OSI)64  8 9 OSI indicates WSS fluctuations magnitude and describes the tangential force
RT > 
 WSSi dt >
>
> >
 0 < >
=
ksk
oscillation as a function of the cardiac cycle. It is a nondimensional parameter
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2017.06.035

OSI 2 1  R T
1
1 ranging from 0 (unidirectional WSS) to 0.5 (WSS with no preferred direction)
> > > jWSSi jdt >
TAWSS
>
: 0 >
;

HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS

WSSi is the instantaneous WSS vector
T is the duration of one cardiac cycle

Relative residence time (RRT)12 RRT assesses the possibility of platelet activation, based on oscillating WSS.
RRT 1

1

12OSITAWSS RT !  The RRT is a robust parameter as a single metric of low and high oscillating
1
T

 0 s 
w dt 
shear stress. It is measured in 1/Pa
!
s w is the WSS vector

Gradient oscillatory number (GON)75   GON quantifies the disturbance of the blood flow-induced tangential forces
R T 
 Gdt  acting on the arterial wall surfaces in pulsatile flow. It is a nondimensional
 0 
GON 1  R T parameter. It depends on the degree of temporal fluctuations in the spatial
jGjdt
0 WSSG vectors during a cardiac cycle
G is the spatial wall shear stress gradient vector
T is the duration of one cardiac cycle
Aneurysm formation indicator (AFI)76 AFI detects flow stagnation zones. It calculates the direction of the WSS
AFI cos q WSSi WSSav
jWSSi jjWSSav j vector on the blood wall, over the course of the cardiac cycle. It may
(potentially) correlate with aneurysm formation positions
WSSi is the instantaneous WSS vector
WSSav is the time-averaged WSS vector
 
RT 
v !
!

LITERATURE REVIEW
Oscillation velocity index (OVI)81  r ; tdt  OVI quantifies the flow pattern variations during the cardiac cycle
 0
OVI!
r 1  RT !
0
v r ; tdt
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MARCELLO LONGO ET AL.

Inflow concentration index (ICI)78 ICI
Qin Qv ICI measures concentration degree of the flow stream entering the aneurysm.
Ain Ao
It is defined as the percent of the flow rate of the parent artery that enters the
Q in is the flow rate into the aneurysm (inflow) aneurysm divided by the percent of the aneurysm ostium area that
Q v is the flow rate in the parent artery corresponds to positive inflow velocity
Ain is the area of the inflow region
Ao is the area of the ostium surface
Fh =Fa
Shear concentration index (SCI)78 SCI SCI measures the concentration degree of the WSS distribution
Ah =Aa

F h and F a represent respectively the total viscous shear forces computed

over Ah and Aa
Ah is the region of high WSS; Aa the area of the aneurysm sac

Low shear index (LSI)78 LSI Fl Al LSI measures the relative amount of the total shear force applied in regions of
Fa Aa
abnormally low WSS
F l represents the total shear force applied in the area of low WSS
Al (the area under low WSS)
F a represents the total shear force applied over Aa (the area of the
aneurysm sac)

Low wall shear stress area (LSA)78 LSA Al

Aa LSA indicates the areas of the aneurysm wall exposed to a WSS value <10%
Al is the area under low WSS of the mean parent vessel WSS. It is measured in mm2
Aa the area of the aneurysm sac

HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS

Low wall shear stress area ratio (LSAR)78 LSAR LSA LSAR is the area of the aneurysm wall exposed to a WSS <10% of the mean
aneurism dome area
parent arterial WSS normalized by the dome area
 2  2
Invariant Q80  
Q 12U  S  Invariant Q (or vortex core region) identifies zones of swirling motion and is
based on the local velocity gradient tensor. High invariant Q values indicate a
D is the velocity gradient tensor high proportion of the aneurysm is occupied by the whirlpool domain. It is
S is known as the rate-of-strain tensor measured in 102/second2
U is the vorticity tensor
Turbulent kinetic energy (TKE) 82
k 12 ui0 ui0 TKE is the kinetic energy per unit mass of the turbulent fluctuations u 0i in a
u 0i is a turbulent fluctuation turbulent flow. It is measured in m2/s2
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Fluctuating kinetic energy (FKE)83 FKE 12 urms

2
vrms
2
wrms
2
FKE measures cycle-to-cycle variations in a turbulent flow, and also its
u 2rms ; v 2rms ; w 2rms are the root mean square values of the velocity fluctuations turbulent activity
in the 3 directions of the space
R
Kinetic energy ratio (KER)78 1=2u 2 dV =Va KER measures the amount of kinetic energy in the aneurysm relative to the
KER R Va
1=2u 2 dV =Vnear contiguous vasculature
R
Vnear

Viscous dissipation ratio (VDR)78 2m=reij eij dV =Va VDR quantifies the amount of mechanical energy dissipation by viscous effects
VDR R Va
2m=reij eij dV =Vnear in the aneurysm relative to that in the near parent artery
 
Vnear

1 vui vuj
e ij 2 vxj vxi is the strain rate tensor

LITERATURE REVIEW
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MARCELLO LONGO ET AL. HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS

ow near the aneurysm is quantiable by a

parameter called relative residence time
(RRT), which indicates the residence time
of blood near the wall and derives from a
combination of WSS and OSI.12,67,68
Commonly, to account for the change in
magnitude of the WSS vector in the ow
direction, with respect to the streamwise
distance, the WSS gradient (WSSG) is
used.69-71 The change in magnitude of the
WSS vector can be also evaluated as a
temporal derivative measure, the time-
averaged WSSG.72,73
All these parameters are intertwined
and if used together describe the ow
condition on a vessel wall in a given
instant, over the whole cardiac cycle, and
Figure 1. Graphic model of an arterial bifurcation with the 3 distinct zones of
impact of the stream, according to Meng et al.14: area 1 or flow impact zone:
in different types of blood ow.13,15,69,74
WSS is normal and WSSG has a positive value, which increases rapidly. This Furthermore, to describe and thus
condition causes intimal hyperplasia; area 2 or acceleration zone: both WSS analyze more complex blood ow condi-
and WSSG undergo a significant increment; WSSG slowly decreases after tions (i.e., aneurysm with complex ge-
reaching a high peak, WSS reaches its maximum value (about 13Pa). At this
level, destructive phenomena become more evident and there is a thickness ometries or with arising vessels), other
reduction of intima and media tunica. Furthermore, a loss of the internal derivative hemodynamic parameters have
elastic lamina occurs, typical condition for the formation of aneurysms; area 3 been created, such as gradient oscillatory
or flow deceleration zone: located at the entrance of efferent vessels. It is
characterized by a low WSSG and a WSS that decreases slowly. At this level,
number (GON),75 potential aneurysm
the vascular wall does not present histopathologic alterations. formation indicator (AFI),76 oscillation
velocity index,77 inow concentration
index, shear concentration index, low
oscillating direction on the vessel wall, preferred time-averaged direction), known shear index, low WSS area and its ratio
which is described by a nondimensional as the oscillatory shear index (OSI). OSI is (low WSS area ratio), kinetic energy,78,79
parameter ranging from 0 (in a steady dened as the magnitude of the WSS and vortex core region descriptors.80
state ow in which WSS is unidirectional) uctuations as a function of the cardiac Because a complete description of this
to 0.5 (in a ow in which WSS has no cycle.64-67 The state of a disturbed or a low complex scenario is beyond the aim of

Figure 2. Time-averaged wall shear stress distribution on very small stress (WSS) was significantly lower in ruptured very small intracranial
intracranial aneurysms. The top row shows a series of ruptured aneurysms aneurysms compared with unruptured aneurysms. From Zhang et al. 2016
and the bottom row shows a series of unruptured aneurysms. Wall shear (Creative Commons license).105

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 LITERATURE REVIEW
MARCELLO LONGO ET AL. HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS

Figure 3. Contour maps of relative residence time (RRT) (A) and atherosclerotic changes (AN2), had long RRT and low WSS.
(D), time-averaged wall shear stress (WSS) (B) and (E), and Black arrows show the point with the longest RRT (117.3 [1/Pa]),
oscillatory shear index (C) and (F) in a patient with 4 aneurysms the lowest WSS (0.02 [Pa]), and the highest OSI (0.36) in AN2.
of left anterior circulation. One of these aneurysms, with From Sugiyama et al. 2016 (Creative Commons license).68

this study, an overview of the mainly used
parameters is provided in Table 1.
Hemodynamic Forces Interaction in UIA
Natural History
Aneurysm Formation. The ow environ-
ment in a blood vessel, able to trigger the
initiation of IAs, is not fully understood.
The interaction of hemodynamic forces
with the vessel wall generates a shear
stress, which causes an imbalance of the
homeostatic condition of the endothelial
layer.13 Several studies have shown that
aneurysm initiation is related to ow
acceleration; in these areas, vascular
remodeling, with different gene
expression by endothelial cells, occurs as
a result of a high WSS and a positive
WSSG.70,84-86 This shear stress
modication was also detected in some
patients, who presented with de novo
aneurysm formation in the proximity of
proximal stenosis, and thus, in a
condition of turbulent ow.10,22,87 The
potential location of aneurysm formation
has been evaluated by the AFI,
introduced by Mantha et al.,88 which
recognizes the low WSS areas coupled
with a rotating WSS vector.22
Nonetheless, some investigators were not
able to detect the link of this index with
the spatial WSSG, especially when
harboring vessels originate nearby. For
this reason, a new parameter that
describes the WSS vector uctuation over
1 cardiac cycle was introduced: the GON.89
Hemodynamic forces in IA formation
were analyzed widely in animal models, to
study vascular response to shear stress
insults. In this regard, Meng et al.90 and
Sejkorova et al.91 identied 3 distinct
zones located in correspondence to an
arterial bifurcation cusp and in the
nearby areas (Figure 1). At the peak level
(area 1 or the ow impact zone), the
WSS is normal (2 Pa), whereas the
WSSG presents positive values (with a
range from 1 to 10 Pa/mm) with a trend
toward rapid increase. This condition
may result in intimal hyperplasia.90 In
the area immediately adjacent to the
cusp (area 2 or acceleration zone), both
WSS and WSSG have a considerable
increase. WSSG decreases after a peak,
still maintaining high values, whereas
WSS reaches its maximum values of
about 13 Pa. In this area, aneurysm
formation may be caused by the
interaction of several destructive
phenomena, such as matrix degradation,
media thinning, and average loss of
internal elastic lamina. The inlet of the
efferent vessel (area 3 or ow
deceleration zone) is characterized by a
low WSSG and a WSS that decreases
slowly.90
WSS reaches the highest peak in the
very early stage of aneurysm formation and
tends to decrease after this phase (with
mean values of about 1.5 N/m2).69,86,90,92,93
Aneurysm Growth. Although there is
agreement among studies on the role of
the interaction of hemodynamic forces in
aneurysmal formation, the exact mecha-
nism of aneurysmal growth is un-
clear.74,94-96 Two different theories have
tried to elucidate this mechanism: modi-
cation of ow, respectively as a result of
an increase or reduction in WSS.13,65,95-100
According to the high WSS theory,
shear stress may cause endothelial dam-
age, proinammatory changes, and
vascular remodeling, thus supporting IA
growth.78,101 This process, leading to a
disproportion between IA wall stress and
high blood ow, induces local dilatation
of the vessel wall.16,102 On the other hand,
the low shear stress theory has been sup-
ported by several studies15,95,103-105

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MARCELLO LONGO ET AL.
(Figure 2). Boussel et al.95 analyzed the
hemodynamic forces linked to
aneurysmal growth in 7 patient-specic
models of UIAs, detecting that when the
endothelial cells are exposed to low WSS,
there is a higher probability of aneurysmal
progression. Inammatory cell inltration
of the endothelial layer, induced by
nitrous oxide and thus increased perme-
ability, is a well-known effect of low
WSS.62,106 Conversely, Sugiyama et al.,94
in their analysis of WSS-derivative mea-
sures of tandem aneurysms, showed that
aneurysmal growth may occur in both
high WSS and low WSS areas at the inow
zone with a high OSI.
Aneurysm Progression: Stabilization or
Rupture. Several studies107,108 have
attempted to understand UIA progression
and to forecast where UIAs may undergo
rupture or stabilization. Sforza et al.101 in a
longitudinal study, comparing a group of
16 growing and 17 stable aneurysms,
showed that complex intrasaccular ow
patterns are more likely related to IA
growth than to its stabilization. To
perform this evaluation, these
investigators analyzed the complexity of
blood ow with different parameters,
such as WSS, OSI, shear concentration
index, low WSS area, inow
concentration index, kinetic energy ratio,
and viscous dissipation ratio.
Miura et al.,109 in a series of 106
aneurysms of the middle cerebral artery
(63 unruptured, 43 ruptured), reported
that multivariate analysis detected low
WSS to be associated with higher risk
rupture; on the other hand, WSSG,
normalized WSS, OSI, AFI, and aspect
ratio were signicant only in the
univariate analysis; GON and aneurysmal
ratio did not differ in the 2 groups.
Low WSS values associated with
increased OSI levels indicate that the
portion of less shear resistance in IAs may
rupture. These ndings were also reported
in uid dynamic studies performed after
surgical aneurysmal repair,64,104,110 which
showed that the bleeding point area had
low WSS and high OSI values. In a recent
CFD study performed by DSA on 56 pa-
tients with intracranial mirror aneurysms,
Tian et al.111 showed that a large aneurysm
size and low WSS values were
independently associated with aneurysm
rupture.95 On the other hand, there is
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HEMODYNAMIC FORCES IN UNRUPTURED INTRACRANIAL ANEURYSMS
evidence suggesting that the breaking
point of the aneurysm can be related to
increased WSS values.112 Cebral et al.,78
in a CFD study of 210 cerebral aneurysms
with different ow conditions, observed
that rupture occurred more often in IAs
with high inow concentrations, high
maximum WSS values, and lower viscous
dissipation ratios.
Clearly, there is controversial evidence
on the correlation between the different
hemodynamic parameters and the poten-
tial rupture risk of the aneurysmal sac. To
clarify these conicting results, a unifying
theory has recently been proposed.15 This
hypothesis stated that 2 independent
pathways may be implied in IA growth
and rupture: low WSS and high OSI
could be associated with growth and
rupture of large and atherosclerotic
aneurysm phenotypes, by an
inammatory cell mediated pathway
(Figure 3). On the other hand, high WSS,
with positive WSSG, may be responsible
for growth and rupture of smaller thin-
walled aneurysms by a mural cell medi-
ated pathway.15 Thus, hemodynamic
alterations, in both patients with low and
patients with high WSS, produce
potential forces causing extracellular
matrix degradation and cell death, which
may facilitate initiation, growth, and
aneurysmal rupture. In some IAs, these
phenomena may act simultaneously in
different parts of the aneurysm sac,
depending on local hemodynamic
conditions. Moreover, the complex
relationship between ow patterns and
IA geometry can be the cause of a more
articulated response, which is expressed
at different points in the natural history
and in different regions of IAs.15 The
rupture risk evaluation should also
account for different ow
patterns.12,101,113 In this regard, Cebral
et al. classied the intra-aneurysmal
blood ow into 4 ow patterns: type I,
unchanging direction of the blood inow
jet inside the UIAs, with a single associ-
ated vortex; type II, unchanging direction
of the blood inow jet with several asso-
ciated vortices without any change of
vortices number during the cardiac cycle;
type III, changing direction of the blood
inow jet with creation of a single vortex;
and type IV, changing direction of the
blood inow jet with the generation and
disruption of multiple vortices.113 This
WORLD NEUROSURGERY, http://dx.doi.org/10.1016/j.wneu.2017.06.035
LITERATURE REVIEW
study showed how simple stable patterns
and jet sizes were more commonly
related to UIAs. On the other hand,
ruptured aneurysms were more likely
associated with ow patterns type III and
type IV, small impingement regions, and
narrow jets. Accordingly, Xiang et al.,12
in a DSA and CFD study of 119 UIAs,
showed that most ruptured IAs had
complex ow patterns with multiple
vortices, whereas UIAs had simple ow
patterns with a single vortex.
Interaction Between Aneurysm Geometry and
Hemodynamic Forces. WSS may act like a
mechanotransducer on endothelial cells
lining lumen vessels, sending biochemical
signals to sustain vascular homeostasis.
WSS regulates not only the vascular tone
but also inuences vessel geometry and
aneurysmal shape.14,15,114,115 High values
of WSS were also found at the tip of UIA
blebs, which usually arise in areas in
which WSS values reach the maximum
peak.116 Therefore, variations in
hemodynamic forces and aneurysmal
geometry may inuence and cause each
other in a self-sustaining
loop.8,10,14,15,92,117-120 Geometric structure
of IAs, such as neck width, parent artery
curvature, angulation of the branching
vessels, and wall thickness, are critical is-
sues for variation of ow patterns on ves-
sels walls, thus inuencing WSS and wall
tension.8,14,88,116,121 In a study of patient-
specic models of 4 cerebral aneurysms,
Castro et al.19 showed that parent artery
geometry, which is upstream to the
aneurysm, might inuence intra-
aneurysmal hemodynamic factors.
Furthermore, Szikora et al.,122 in a study of
21 UIAs, assessed the effect of aneurysm
geometry on hemodynamic parameters
such as intra-aneurysmal ow pressure
and WSS. This study showed that aneu-
rysms with the main axis parallel to the
parent artery have a jet ow pattern and
unsteady distribution pressure. These an-
eurysms are characterized by a higher
rupture rate compared with those with the
main axis perpendicular to the parent
artery.
CONCLUSIONS
The role of hemodynamic parameters as
image-derived metrics in the initiation,
growth, and rupture of aneurysm are not

MARCELLO LONGO ET AL.
entirely understood.10,15,77 Although
several studies agree on the theory for IA
initiation, mechanisms supporting growth
and progression (stabilization or rupture)
are still widely controversial. The lack of
univocal evidence in the understanding of
the natural history IAs does not allow re-
searchers to provide comprehensive and
reliable risk stratication of rupture,
which may inuence therapeutic strate-
gies. The heterogeneity of aneurysmal
geometries, and their interaction on
aneurysmal blood ow patterns and he-
modynamic metrics, make the develop-
ment of reproducible IAs models
challenging. Further studies are needed to
clarify these aspects and to shed new light
on this complex scenario.
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Conflict of interest statement: The authors declare that the
article content was composed in the absence of any
commercial or financial relationships that could be construed
as a potential conflict of interest.
Received 18 April 2017; accepted 5 June 2017
Citation: World Neurosurg. (2017) 105:632-642.
http://dx.doi.org/10.1016/j.wneu.2017.06.035
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