Intracranial Atherosclerotic Disease:
Adnan I. Qureshi, MD,1,2Edward Feldmann, MD,3Camilo R. Gomez, MD,4S. Claiborne Johnston, MD,5,6
Scott E. Kasner, MD,7Donald C. Quick, PhD,2Peter A. Rasmussen, MD,8M. Fareed K. Suri, MD,1,2
Robert A. Taylor, MD,1,2and Osama O. Zaidat, MD9
The consensus conference on intracranial atherosclerosis provides a comprehensive review of the existing literature relevant to the
epidemiology, diagnosis, prevention, and treatment of intracranial atherosclerosis, and identifies principles of management and
research priorities. Patients who have suffered a stroke or transient ischemic attack attributed to stenosis (50–99%) of a major
intracranial artery face a 12 to 14% risk for subsequent stroke during the 2-year period after the initial ischemic event, despite
treatment with antithrombotic medications. The annual risk for subsequent stroke may exceed 20% in high-risk groups. In
patients with intracranial atherosclerotic disease, short-term and long-term anticoagulation is not superior to antiplatelet treat-
ment. Overall, the subgroup analyses from randomized trials provide evidence about benefit of aggressive atherogenic risk factor
management. Intracranial angioplasty with or without stent placement has evolved as a therapeutic option for patients with
symptomatic intracranial atherosclerotic disease, particularly those with high-grade stenosis with recurrent ischemic symptoms,
medication failure, or both. A multicenter randomized trial is currently under way to compare stent placement with intense
medical management for patients with high-grade symptomatic intracranial atherosclerotic disease.
Ann Neurol 2009;66:730–738
This comprehensive review was prepared during pro-
ceedings of a consensus conference on intracranial ath-
erosclerotic disease (ICAD) and summarizes the exist-
interpretation of the quality of evidence provided and
implications for practice and research. Although steno-
sis is commonly secondary to ICAD, current studies do
not analyze nonatherosclerotic diseases separately be-
cause such distinction can only be made pathologically.
Approximately 100,000 patients every year suffer from isch-
emic events related to ICADs in the United States, with an
estimated prevalence of 20 to 40 persons per 100,000 people
worldwide.1In the Northern Manhattan Stroke Study in the
1993 to 1997 period,2the prevalence ICAD-related strokes
was 3, 15, and 13 per 100,000 persons for white, African
American, and Hispanic subjects, respectively. ICAD-related
strokes comprise 9, 17, and 15% of all ischemic strokes
among white, African American, and Hispanic patients, re-
spectively. ICAD-related strokes comprise 33 to 37% of all
ischemic strokes among Chinese populations.3,4However,
limited data on the prevalence of asymptomatic ICAD are
available in the general population. In asymptomatic pre-
dominantly white US patients referred for carotid Doppler
ultrasound, ICAD was identified by transcranial Doppler ul-
trasound (TCD) in 13% of predominantly white US popul-
tion.5ICAD was detected by TCD in 7% of people 40 years
or older6and in 6% of 1,068 asymptomatic Chinese indi-
viduals aged 50 years or older. Baker and colleagues7exam-
ined 5,035 intracranial arteries during autopsy at 22 pre-
defined anatomic areas and identified severe ICAD in 43,
65, and 80% of populations aged 60 to 69, 70 to 79, and
?80 years, respectively.
Risk factors for ICAD are categorized as nonmodifi-
able, well documented and modifiable, or less well doc-
umentedregardless of whether
ble).3,8–38Most of the studies of risk factors for ICAD
were conducted in symptomatic patients. Age, hyper-
tension, and diabetes mellitus are identified as indepen-
From the1Zeenat Qureshi Stroke Research Center;2Minnesota Stroke
Initiative, University of Minnesota, Minneapolis, MN;3Department of
Neurosciences, Brown University, Rhode Island Hospital, Providence,
RI;4Alabama Neurological Institute, Birmingham, AL;5Clinical and
Translational Science Institute;6Stroke Service, Department of Neurol-
ogy and Epidemiology, University of California, San Francisco,
San Francisco, CA;7Comprehensive Stroke Center, Department of
Neurology, Hospital of the University of Pennsylvania, Philadelphia,
Cleveland, OH; and9Department of Neurology and Neurosurgery,
Neurointerventional Program, Froedtert Hospital and Medical Col-
lege of Wisconsin, Milwaukee, WI.
8Department of Neurosurgery, Cleveland Clinic Foundation,
Address correspondence to Dr Qureshi, Department of Neurology,
University of Minnesota, 12-100 PWB, 516 Delaware Street SE,
Minneapolis, MN 55455. E-mail: firstname.lastname@example.org
Potential conflict of interest: Dr Qureshi has received funding from
National Institutes of Health RO-1-NS44976-01A2 (medication
provided by ESP Pharma), American Heart Association Established
Investigator Award 0840053N, and Minnesota Medical Founda-
tion, Minneapolis, MN.
Received Mar 23, 2009, and in revised form Mar 23. Accepted for
publication May 21, 2009. Published online in Wiley InterScience
(www.interscience.wiley.com). DOI: 10.1002/ana.21768
© 2009 American Neurological Association
dent risk factors for ICAD.8Other studies have also
suggested that ICAD is more common in men, partic-
ularly in younger age groups12,13and in particular lo-
cations, such as the basilar artery.14Several studies have
demonstrated the relation between ICAD and total se-
rum cholesterol and its various components (see the
Table3,8–38). There are also some preliminary data that
ICAD in younger patients affects different anatomic
regions and occurs in the absence of atherosclerotic risk
Natural History of Asymptomatic Intracranial
A substantial proportion among the 569 patients with
symptomatic ICAD in the Warfarin versus Aspirin
Symptomatic Intracranial Disease Study for Stroke
(WASID)40also had asymptomatic stenosis of 50 to
99% involving other arteries identified by digital sub-
traction angiography (DSA) or magnetic resonance an-
giography (MRA).41There were no strokes in the ter-
ritory of these asymptomatic stenoses among 35
patients with 40 coexistent asymptomatic stenoses de-
tected by DSA (9 lesions ? 70%) during the mean
follow-up period of 1.8 years. There were 5 strokes in
the territory of the 85 asymptomatic stenoses detected
by MRA in 65 additional patients, yielding a 1-year
risk rate of 3.5% (relative risk, 3.5%; 95% confidence
interval, 0.8–9.0%). Impaired vasoreactivity on com-
puted tomographic perfusion, magnetic resonance per-
fusion, and single-positron emission computed tomog-
raphy, and increased oxygen extraction fraction on
positron emission tomography42–46may have a role in
predicting future stroke risk in patients with asymp-
tomatic intracranial stenoocclusive disease.
Natural History of Symptomatic Intracranial
The primary end point (ischemic stroke in any vascular
territory, intracranial hemorrhage, or vascular death
not caused by ischemic stroke) occurred in 22% of the
symptomatic patients in WASID.40An ischemic stroke
in the territory of the symptomatic artery47or in any
vascular territory occurred in 14 and 19% of the 569
patients, respectively. Sixty of the 77 strokes (78%) oc-
curred within the first year. The 1-year risk for stroke
in the symptomatic ICAD territory was 19% for a ste-
nosis ?70%. Multivariate analysis showed the risk for
ipsilateral stroke was greatest for a stenosis ?70%, for
patients enrolled early (?17 days) after qualifying
event, and for women. The Groupe d’Etude des Ste-
noses Intra-Craniennes Atheromateuses symptoma-
tiques (GESICA) study48demonstrated a risk rate of
14% for subsequent stroke among prospectively fol-
lowed 102 medically treated patients with symptomatic
ICAD over a mean of 23 months. Interestingly, the
subsequent combined stroke and transient ischemic at-
tack (TIA) rate was 61% (compared with 38% as de-
scribed earlier) among patients with hemodynamic
Diagnosis and Quantitation
TCD, MRA, and computed tomographic angiography
(CTA) are noninvasive methods that have demon-
strated value in screening for ICAD.49The Stroke
Table. Risk Factors for Intracranial Stenosis
Less Well-Documented ? Modifiable
endothelial growth factor
omega-1 gene polymorphism20
Plasma homocyst(e)ine levels21
Serum beta lipoprotein21
Total serum cholesterol21,24
Serum apolipoprotein (a)25,26
Tuberculosis and cryptococcal meningitis36
Sickle cell disease27,28
Family history of stroke23
Extracranial carotid stenosis38
LDL ? low-density lipoprotein; HDL ? high-density lipoprotein.
Qureshi et al: Consensus Conference on ICAD
Outcomes and Neuroimaging of Intracranial Athero-
sclerosis (SONIA) trial50compared the accuracy of
TCD, MRA, and CTA (noninvasive tests) with DSA.
SONIA reported results from 46 centers on more than
1,000 vessels: positive predictive value of TCD and
MRA ranged from 57 to 83%, and negative predictive
value ranged from 72 to 86%. CTA negative predictive
value was 84%.51SONIA demonstrated that TCD,
MRA, and CTA have a good negative predictive value
for excluding the presence of 50 to 99% ICAD but
relatively low positive predictive value. More recent
smaller, single studies have shown better predictive val-
ues for CTA than those found in SONIA.52Recent
studies are also focusing on developing noninvasive
tests for identifying in-stent restenosis after stent place-
Prevention of Intraluminal Thromboembolism
Short- and long-term anticoagulation (compared with
aspirin) has not been found to be superior to antiplate-
let treatment. The WASID40trial randomly assigned
569 patients with TIA or stroke caused by ?50% ste-
nosis by DSA to receive warfarin (target international
normalized ratio, 2.0–3.0) or aspirin (1,300mg/day).
During a mean follow-up period of 1.8 years, the cu-
mulative end point of ischemic stroke, brain hemor-
rhage, or death from other vascular causes occurred in
22% in each treatment group. The rates of death (4 vs
10%), major hemorrhage (3 vs 8%), and myocardial
infarction or sudden death (3 vs 7%) occurred in a
lower proportion of patients in the aspirin group com-
pared with the warfarin group. Another trial23com-
pared the efficacy of 10 days of subcutaneous nadropa-
rin calcium 3,800 anti–factor Xa IU/0.4ml twice daily
(n ? 180) with oral aspirin 160mg daily (n ? 173) in
Asian patients with acute ischemic stroke (within 48
hours of symptom onset), and noninvasive tests diag-
nosed large-artery occlusive disease (ICAD in 342 pa-
tients) followed by daily aspirin 80 to 300mg for 6
months. The proportion of patients with good out-
comes at 6 months defined by Barthel index of 85 or
greater was 73% in the nadroparin group and 69% in
the aspirin group, with no difference in the rates of
There are no recommendations for prevention of
stroke in patients with symptomatic ICAD, but only
for the broader category of “noncardioembolic” isch-
emic stroke and TIA. The American Heart Association
(AHA)/American Stroke Association (ASA) recom-
mends54aspirin monotherapy, aspirin/extended-release
dipyridamole combination, and clopidogrel mono-
therapy (rather than oral anticoagulants) as acceptable
options. The aspirin/extended-release dipyridamole
combination is recommended over aspirin alone. Clo-
pidogrel may be preferentially considered over aspirin
alone by direct-comparison trials and is also a reason-
able alternative for patients allergic to aspirin.
Plaque Stabilization and Regression
Atherosclerosis includes atherosis caused by intracellular
and extracellular lipid infiltration, and sclerosis second-
ary to connective tissue deposition and endothelium dys-
function, leading to reduced arterial compliance.55,56
Cilostazol, a phosphodiesterase inhibitor, reduces reste-
nosis rate after percutaneous coronary intervention
(PCI). A study57randomized 135 patients with acute
symptomatic ICAD on aspirin 100mg/day to either
cilostazol 200mg/day or placebo for 6 months. Twenty
patients in the cilostazol group and 14 in the placebo
group did not complete the trial. There was no stroke
recurrence in either the cilostazol or placebo group, but
there was one death and two coronary events in each
group. Progression of ICAD on 6-month MRA was sig-
nificantly less in the cilostazol group than that in the
placebo group (7 vs 29%). Regression of lesion was seen
in 24 and 15% of the patients in the cilostazol and pla-
cebo groups, respectively.
Management of Atherogenic Risk Factors
Subset analyses58from the WASID study demon-
strated that systolic blood pressure ? 140mm Hg and
cholesterol ? 200mg/dl were associated with an in-
creased risk for stroke, myocardial infarction, or vascu-
lar death. Ischemic stroke risk increased with increasing
mean systolic and diastolic blood pressures.58Another
analysis59from the WASID study found that the time
to the first of ischemic stroke, myocardial infarction, or
vascular death was shorter among patients with meta-
bolic syndrome during the follow-up period. Based on
the Stroke Prevention by Aggressive Reduction in Cho-
lesterol Levels (SPARCL) trial,60AHA/ASA54recom-
mend statin therapy with intensive lipid-lowering ef-
fects for patients with atherosclerotic ischemic stroke or
TIA and without known coronary artery disease to re-
duce the risk for stroke and cardiovascular events. For
those patients with atherosclerotic ischemic stroke or
TIA and a history of coronary artery disease, statin
agents are recommended with a target of low-density
lipoprotein (LDL)-cholesterol level of less than 100mg/
dl, and an LDL-cholesterol level of less than 70mg/dl
for very-high-risk patients with multiple risk factors. In
view of relatively high rate of concurrent existence cor-
onary artery disease, the Councils of the AHA/ASA
Coronary Risk Evaluation61recommend routine test-
ing for coronary artery disease in patients with carotid
or other large-vessel disease.
Evolution of Endovascular Treatment of
Intracranial Atherosclerotic Disease
Intracranial angioplasty and/or stent placement (IAS) for
ICAD initially started using percutaneous coronary in-
Annals of NeurologyVol 66 No 6 December 2009
tervention (PCI) balloons,62,63later followed by balloon-
mounted stents. The treatment of ICAD with balloon-
mounted stents was associated with relatively high rates
of technical failure and somewhat acceptable periproce-
dural morbidity and mortality.64,65
WASID trial40and subset analyses47demonstrated a rel-
atively high risk for stroke among certain medically
treated subgroups of patients with ICAD. That same
year, the Food and Drug Administration approved the
Gateway balloon/Wingspan stent system (Boston Scien-
tific, Watertown, MA) under a Humanitarian Device
Exemption providing the first “on-label” treatment for
treatment of ICAD (Fig).36
In 2005, the
Results from Studies Evaluating Endovascular
Treatment of ICAS
Cruz-Flores and Diamond66report a rate of 8% periop-
erative stroke, 3% perioperative death, 10% periopera-
tive stroke or death, and 10% other perioperative com-
plications (such as groin hematoma and arterial
dissection) based on a systematic review of 79 studies
(1,999 cases of ICAD). In studies with at least 1 year
follow-up, the 1 year risk of stroke or death was esti-
mated at 6%.
The self-expanding nitinol Wingspan Stent System
(see Fig) was approved based on a 45-patient Wing-
span Humanitarian Device Exemption Safety Study
with ICAD ? 50%.36The mean severity of angio-
graphic stenosis was reduced from 75 to 32% in 44
treated patients (lesion could not be traversed in 1 pa-
tient). The study reported a procedural success rate of
98% and a 30-day rate of death or ipsilateral stroke of
4% after procedure. Among the 43 patients with
6-month follow-up, the rate of death or ipsilateral
stroke was 7.0%. Further lesion reduction was ob-
served in 24 of the 40 patients who underwent
follow-up DSA at 6 months.
In the US Wingspan registry,67IAS treatment re-
sulted in successful treatment in 99% of 78 patients
with 82 ICADs. There were 5 (6%) major periproce-
dural neurological complications (4 deaths) within 30
days. Follow-up imaging68demonstrated in-stent reste-
nosis in 30% (n ? 29) of the patients (more frequent
within the anterior circulation); 8 were symptomatic (4
with stroke, 4 with TIA), and 15 required retreatment.
In the National Institutes of Health multicenter
Wingspan IAS registry study,69technical success rate
was 97% (?50% residual stenosis) among 129 patients
with symptomatic ?70% ICAD. The frequency of any
stroke or death within 30 days or ipsilateral stroke be-
yond 30 days was 14% at 6 months. The frequency of
?50% restenosis on follow-up DSA was 25% in 52
Fig. Patient with high-grade symptomatic stenosis of the middle cerebral artery. (A) Anteroposterior view of the middle cerebral ar-
tery stenosis (arrow). (B) Angioplasty of the stenosis with radiopaque markers of the balloon identified (arrows). (C) Placement of
the self-expanding stent across the lesion with radiopaque markers of the stent identified (arrows) and distal end of the outer sheath
(dotted arrow). (D) Partial deployment of the stent with radiopaque markers identified at expanded distal end (arrow) by retro-
grade movement of the outer sheath (dotted arrow). (E) Complete deployment of the stent with radiopaque markers identified at
both ends (arrows). (F) Poststent deployment appearance of the lesion with near-complete resolution (arrow).
Qureshi et al: Consensus Conference on ICAD
Comparison of Primary Angioplasty and
In a multicenter review,65there was no difference in
follow-up survival (stroke rates or combined rate of
stroke or death) between the 95 angioplasty-treated ver-
sus the 98 stent-treated groups after adjusting for age,
gender, and center. The stroke-free survival at 2 years for
the angioplasty group and the stent-treated group was
92 ? 4% and 89 ? 5%, respectively. Significant
restenosis-free survival at 12 months was 68% for the 66
angioplasty-treated patients and 64% for the 68 stent-
treated patients with DSA follow-up. In a systematic re-
view70of 69 studies (1,027 primary angioplasty-treated
patients and 1,291 stent-treated patients), 91 and 104
patients experienced stroke, death, or both in the
angioplasty-treated and stent-treated groups, respectively,
during the 1-month period. A greater rate of 1-year
stroke and death was observed in angioplasty-treated pa-
tients (20%) compared with stent-treated patients
(14%). The pooled restenosis rate was 14 and 11% in
the angioplasty-treated and stent-treated groups, respec-
tively. There was no effect of the publication year of the
studies on the risk for stroke and death.
Comparison of Endovascular Treatment with
Best Medical Treatment
A comparison71between 254 matched patients recruited
in the WASID trial and 158 entered in the National
Institutes of Health Wingspan multicenter stent registry
determined the differential rate of stroke or death within
30 days or ipsilateral stroke beyond 30 days within pa-
tients with 50 to 69% and 70 to 99% stenosis. The
primary event rates at 1 and 6 months in WASID pa-
tients with 70 to 99% stenosis were 7 and 16%, respec-
tively; the comparable rates in stent-treated patients were
10 and 13%, respectively, suggesting a possible benefit.
No clear benefit was observed in the patients with 50 to
69% stenosis because of the low event rates in the med-
ically treated patients. In 2007, the National Institutes
of Health funded a 5-year, multicenter, prospective, ran-
domized study, Stenting and Aggressive Medical Man-
agement for Preventing Recurrent stroke in Intracranial
Stenosis (SAMMPRIS),72comparing intensive medical
therapy alone with IAS combined with intensive medical
therapy. The procedure is expected to decrease the risk
of the primary end point by 35% among 764 patients
over a mean follow-up period of 2 years in patients with
70 to 99% ICAS who had a TIA or stroke within 30
days before enrollment.69
The American Society of Interventional and Therapeu-
tic Neuroradiology, Society of Interventional Radiol-
ogy, and American Society of Neuroradiology73recom-
mend that IAS should be offered to symptomatic
patients with intracranial stenoses more than 50% who
have not responded favorably to medical therapy. The
Brain Attack Coalition74considers IAS an optional
component for a comprehensive stroke center, al-
though there are selected cases in which such tech-
niques may be of value. The AHA/ASA guidelines75
consider IAS of uncertain benefit and therefore inves-
tigational in patients with hemodynamically significant
ICAD who have symptoms despite medical therapies
(antithrombotics, statins, and other treatments for risk
The Practice Guidelines Committee of the American
Society of Neuroimaging and the Society of Vascular
and Interventional Neurology76recommend for physi-
cians requesting privileges for performing IAS, a mini-
mum of 50 procedures requiring microcatheter and
microwire placement in intracranial vessels beyond in-
tracranial internal carotid artery or vertebral artery and
at least 25 IAS performed under supervision in addi-
tion to meeting the training period and overall case
volume requirements set by the Accredited Council of
Graduation Medical Education for endovascular surgi-
cal neuroradiology residency education.
Periprocedural Management after
A meta-analysis of 25 trials comparing antiplatelet
therapies after PCI demonstrated that clopidogrel and
aspirin combination are superior to aspirin alone or
warfarin and aspirin combination in preventing major
cardiac adverse events.77Other medications before
stent placement such as cilostazol and dipyridamole
have shown some benefit over single agent alone in
preventing thrombotic events after stent placement.77
Based on PCI data, practitioners are continuing dual
antiplatelet agents for a total of 3 months after the
IAS, although the range of 4 to 12 weeks is common
and accepted practice. Clopidogrel 75mg daily with as-
pirin (81–325mg) for at least 72 hours before the in-
tervention is recommended. If not feasible, loading
dose of 300mg within 6 and 24 hours or 600mg
within 6 hours is reasonable.78In patients allergic to
clopidogrel, ticlopidine is a reasonable alternative at
250mg twice daily or a 500mg loading dose within 24
hours of the procedure. Placing a drug eluting stent
(DES) during PCI requires 1 year of dual antiplatelet
therapy,77which is reasonable in patients with intra-
cranial DES placement.
Existing Experimental Models
The Watanabe heritable hyperlipidemic rabbits experi-
ence development of ICAD with a high content of
smooth muscle and fibrous tissue.79These rabbits expe-
rience development of lesions within 6 months after
nephrectomy-induced hypertension.80Other hyperten-
sive rabbits species fed cholesterol rich diet experience
Annals of Neurology Vol 66No 6 December 2009
development of ICAD in posterior circulation81mainly
composed of foam cells and smooth muscles. There is
increased insudation of fibrinogen and LDL-cholesterol
in the subendothelial spaces82consistent with human
pathological findings.83,84In cynomolgus monkeys, hy-
pertension induced by surgical thoracic aorta coarctation
and hypercholesterolemic diet for 12 months induces
ICAD85with associated ischemic strokes.86Infiltration
of lipid-laden foam cells and lipid droplet–filled smooth
muscle cells have been described in the basilar artery in
this model.87ICADs develop in dogs88fed atherogenic
diets. ICAD in this model is associated with thickening
of the walls, and arteriosclerotic changes involve the in-
ternal carotid artery, middle cerebral artery, and the ver-
tebrobasilar arteries after 48 months with associated ce-
rebral infarction.89,90Segmental vascular lesions contain
lipid-laden macrophages, cholesterol crystal clefts, and
myointimal cells, appearing as fibroblasts and smooth
muscle cells. The canine (mongrel) basilar artery without
atherosclerosis has been used to study the effect of stent
deployment in the intracranial vasculature on endothe-
lization, smooth muscle proliferation, intimal fibrin den-
sity, and inflammatory response.91Some studies have
studied ICAD in swine and cockerels.92,93
Characterization of Intracranial
Arterial wall characteristics studied with spin-echo MRI
with contrast94demonstrated definite and thick en-
hancement in 11 of 30 patients with intracranial verte-
bral artery disease and 13 of 62 patients with intracranial
internal carotid artery disease. There is also increasing
interest in the use of intravascular ultrasonography
(IVUS) in intracranial arteries95,96to better understand
plaque morphology and progression based on data de-
rived from coronary arteries.97IVUS provides accurate
real-time dynamic measurements and virtual histology
maps of the plaque, and detects inflammation within
plaques.98IVUS can also provide two-dimensional im-
ages, which are then postprocessed into longitudinal
three-dimensional or volume reconstructions99resem-
bling angiographic images that can be viewed as three-
dimensional images in longitudinal axis. Microbubble
contrast agents with specific ultrasound signal can iden-
tify adventitial microvessels such as vasa vasorum.100Mi-
crobubbles coated with albumin or lipid shells bind with
tissue leukocytes and can identify leukocyte activation
and expression of adhesion molecules in regions of in-
flammation within the plaque by generating an oscilla-
tory ultrasound contrast effect.100Thermographic guide-
wires101can detect intraarterial temperature increases
between 0.1°C and 0.3°C detecting inflammatory
plaques at high risk for rupture. Vulnerable plaques can
alsobe identifiedby radiotracer
fluorodeoxyglucose because of higher metabolic activity
of the inflamed cap.102Intravascular MRI has demon-
strated feasibility in in vitro models for reliably identify-
ing plaque composition and size in arteries deep within
the body,103and can adequately visualize inner and
outer plaque boundaries in all arteries.
Quantification and Validation of
The treatment with statins to promote plaque regres-
sion of ICAD is largely inferred from data in the cor-
onary literature. High-intensity statin therapy (atorva-
statin 80mg/day) compared with moderate-intensity
statin therapy (pravastatin [Pravachol] 40mg/day) for
18 months was shown to reduce atherosclerotic plaque
area in the coronary arteries by IVUS in the Reversal of
Atherosclerosis with Aggressive Lipid Lowering Ther-
apy (REVERSAL) trial.104Similarly, high-dose rosu-
vastatin (40mg/day) reduced atherosclerotic plaque vol-
ume as measured by serial IVUS in the ASTEROID
trial.105These results correlated with a large reduction
in the mean LDL cholesterol from 130.4 to 60.8mg/dl.
An analysis of these and similar trials show a linear
relation between LDL cholesterol reduction and plaque
regression.105However, IVUS is not easily advanced
into the intracranial circulation, which limits its appli-
cation to ICAD. Therefore, new ways to assess ICAD
are warranted to evaluate the efficacy of statins and
other therapies that induce plaque regression.
Enhancement of Collateral Flow
In patients with multisegmented ICADs with no other
therapeutic option, angiogenic growth factors may rep-
resent a new venue. Angiogenic growth factors can stim-
ulate new blood vessel growth and restore perfusion in
animal models of myocardial ischemia.106Vascular en-
dothelial growth factor (VEGF), particularly highly dif-
fusible VEGF121 (VEGF A), may be the best suited for
cardiac proangiogenesis gene therapy.107In the
REVASC study,107direct intramyocardial injections of
replication-deficient adenovirus-containing AdVEGF121
resulted in objective improvement in exercise-induced
ischemia in patients with severe angina caused by coro-
nary artery disease and no conventional options for re-
vascularization. In the EUROINJECT-ONE double-
blind, randomized trial,108injections of phVEGF A165
plasmid improved the stress-induced myocardial perfu-
sion abnormalities108and regional wall motion, al-
though there was no clear improvement in symp-
toms.109The Angiogenic Gene Therapy (AGENT)
trial,110which delivered an adenoviral vector containing
fibroblast growth factor-4 via intracoronary infusion,
failed to show statistically significant clinical benefit in
the treated group, presumably because of inefficient up-
take of the viral vector by the myocardium.
Qureshi et al: Consensus Conference on ICAD
Efforts such as this consensus conference serve to in-
crease the awareness of the importance of a relatively
underappreciated disease entity. The proceedings of the
consensus conference provide a template for standard-
izing management of patients with ICAD and deter-
mining research priorities.
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