Multislice

CT

angiography

in

the

selection

of

patients

with

ruptured

intracranial

aneurysms

suitable

for

clipping

or

coiling

Introduction

We

sought

to

establish

whether

CT

angiography

-LRB-

CTA

-RRB-

can

be

applied

to

the

planning

and

performance

of

clipping

or

coiling

in

ruptured

intracranial

aneurysms

without

recourse

to

intraarterial

digital

subtraction

angiography

-LRB-

IA-DSA

-RRB-

Introduction

Subarachnoid

haemorrhage

-LRB-

SAH

-RRB-

is

caused

by

aneurysmal

rupture

in

of

patients

-LSB-

-RSB-

In

a

systematic

review

Hop

et

al.

found

fatality

rates

ranging

from

to

-LSB-

-RSB-

Furthermore

of

patients

remained

functionally

dependent

after

SAH

Rapid

diagnostic

evaluation

and

treatment

are

crucial

for

the

patient

's

outcome

Intraarterial

digital

subtraction

angiography

-LRB-

IA-DSA

-RRB-

has

been

the

main

technique

for

detecting

and

characterizing

intracranial

aneurysms

and

remains

the

gold

standard

However

IA-DSA

is

invasive

and

time

consuming

and

carries

a

risk

of

neurological

complications

of

with

permanent

deficit

in

-LSB-

-RSB-

Serious

non-neurological

complications

which

occur

in

of

patients

include

groin

hematoma

peripheral

thromboembolism

transient

hypotension

and

arteriovenous

fistulas

-LSB-

-RSB-

Furthermore

IA-DSA

may

increase

the

risk

of

rebleeding

-LSB-

-RSB-

It

has

been

demonstrated

that

three-dimensional

CT

angiography

-LRB-

-RRB-

can

reliably

detect

intracranial

aneurysms

-LSB-

-RSB-

Only

after

replacement

of

IA-DSA

by

CTA

can

the

advantages

of

CTA

be

fully

realized

in

the

clinical

setting

We

report

here

our

clinical

experience

with

both

and

row

CTA

as

the

first

and

intended

only

diagnostic

and

treatment

decision-making

study

for

intracranial

aneurysms

in

patients

with

acute

SAH

Materials

and

methods

Subjects

Between

April

and

January

all

patients

presenting

with

a

SAH

to

the

University

Medical

Centre

Groningen

consecutively

underwent

CTA

as

the

first

diagnostic

study

Based

on

the

CTA

findings

patients

were

selected

for

surgical

clipping

or

endovascular

coiling

of

a

ruptured

intracranial

aneurysm

SAH

was

suspected

on

clinical

grounds

and

confirmed

by

unenhanced

CT

or

by

blood

pigments

on

lumbar

puncture

Imaging

protocols

The

CT

examinations

were

performed

on

a

or

row

spiral

CT

machine

-LRB-

Somatom

Sensation

or

Siemens

Medical

Systems

Erlangen

Germany

-RRB-

based

on

a

standard

protocol

The

CT

was

implemented

in

the

Emergency

Department

in

December

Parameters

for

CT

for

diagnosis

of

aneurysm

via

an

intravenous

cannula

in

the

antecubital

fossa

ml

of

contrast

agent

-LRB-

Visipaque

-RRB-

was

injected

with

a

power

injector

at

a

rate

of

ml/s

Injection

of

contrast

agent

was

followed

by

a

flush

of

ml

saline

-LRB-

Stellant

NaCl

Neck

Angio

-RRB-

injected

at

the

same

rate

A

manual

fluoroscopic

bolus-triggered

system

with

the

internal

carotid

arteries

as

reference

point

and

a

delay

of

s

determined

the

optimal

timing

The

CTA

protocol

parameters

were

as

follows

spiral

mode

rotation

time

s

reconstruction

interval

mm

at

Kernel

mAs

acquisition

time

s

scan

range

from

the

vertebral

body

to

the

vertex

parallel

to

the

orbitomeatal

line

Parameters

for

CT

for

diagnosis

of

SAH

gantry

un-angled

spiral

mode

rotation

time

s

rows

at

intervals

table

speed

mm/rotation

reconstruction

interval

mm

at

Kernel

and

acquisition

parameters

mAs

The

actual

acquisition

time

was

approximately

s.

Parameters

for

CTA

for

diagnosis

of

aneurysm

rotation

time

s

table

speed

mm/rotation

reconstruction

interval

mm

at

Kernel

mAs

acquisition

time

s

and

scan

range

extending

from

the

vertebral

body

to

the

vertex

parallel

to

the

orbitomeatal

line

The

protocol

parameters

for

contrast

agent

injection

remained

unchanged

Parameters

for

CT

for

diagnosis

of

SAH

gantry

un-angled

spiral

mode

rotation

time

s

detector

rows

at

intervals

table

speed

mm/rotation

reconstruction

interval

mm

at

Kernel

acquisition

parameters

mAs

and

acquisition

time

s.

Postprocessing

of

CTA

Source

images

were

transferred

to

a

remote

computer

workstation

-LRB-

Odelft

Benelux

diagnostic

imaging

-RRB-

for

viewing

Initial

careful

review

of

axial

images

was

considered

imperative

During

this

review

any

areas

of

concern

could

be

noted

Two-dimensional

maximum

intensity

projection

-LRB-

MIP

-RRB-

views

and

three-dimensional

-LRB-

-RRB-

surface-rendered

and

volume-rendered

reconstructions

were

reformatted

from

the

raw

image

date

on

a

Vitrea

computer

workstation

by

one

of

the

neuroradiologists

Parameters

for

IA-DSA

and

postprocessing

From

April

until

April

the

IA-DSA

studies

were

produced

on

a

digital

angiographic

unit

-LRB-

Siemens

Multiskop

with

InfiMed

image

processing

-RRB-

with

a

pixel

matrix

From

April

onwards

the

studies

were

performed

on

a

Siemens

Axiom

Artis

angiographic

unit

with

a

pixel

matrix

Selective

four

or

six-vessel

angiography

using

a

standard

projection

format

was

performed

initially

and

additional

views

were

obtained

if

required

to

identify

the

parent

vessel

and

aneurysm

neck

more

clearly

The

amount

of

contrast

medium

-LRB-

Visipaque

-RRB-

used

was

ml

for

the

internal

carotid

artery

and

ml

for

the

external

carotid

artery

and

the

injection

rate

was

ml/s

when

the

tip

of

the

catheter

was

in

the

internal

carotid

artery

and

ml/s

when

the

tip

of

the

catheter

was

in

the

external

carotid

artery

The

rate

of

injection

into

the

vertebrobasilar

system

was

ml/s

to

a

total

amount

of

ml

In

certain

situations

rotational

angiography

was

performed

to

better

delineate

the

anatomic

details

of

an

aneurysm

Rotational

angiography

was

performed

on

a

Siemens

Axiom

Artis

angiographic

unit

The

C-arm

rotates

in

a

continuous

arc

around

the

patient

's

head

during

a

prolonged

intraarterial

catheter

injection

of

contrast

medium

-LRB-

ml

Visipaque

injection

rate

ml/s

-RRB-

The

raw

date

images

were

transferred

to

a

Leonardo

workstation

-LRB-

AX

Applications

-RRB-

from

which

volume-rendered

reconstructions

were

reformatted

Image

review

and

data

analysis

The

presence

of

an

aneurysm

its

size

and

morphology

its

parent

and

feeding

vessels

and

the

collateral

circulation

at

the

circle

of

Willis

were

determined

by

one

of

the

diagnostic

or

interventional

neuroradiologists

If

multiple

aneurysms

were

detected

the

usual

criteria

were

applied

to

decide

which

aneurysm

was

responsible

for

the

haemorrhage

These

criteria

included

the

unenhanced

CT

findings

-LRB-

distribution

of

blood

-RRB-

and

the

size

and

irregularity

of

the

aneurysm

All

diagnostic

findings

were

discussed

with

the

neurosurgeons

The

CTA

results

were

categorized

into

proven

ruptured

aneurysm

inconclusive

or

negative

Patients

with

a

proven

ruptured

aneurysm

were

selected

subsequently

for

coiling

or

clipping

The

surgical

and

endovascular

findings

were

compared

to

the

CTA

findings

In

general

ruptured

aneurysms

in

the

anterior

circulation

were

selected

for

either

coiling

or

clipping

Ruptured

aneurysms

located

in

the

posterior

circulation

were

preferably

coiled

Giant

intracranial

aneurysms

were

preferably

treated

surgically

A

ruptured

aneurysm

in

association

with

an

intraparenchymatous

haemorrhage

was

most

often

selected

for

clipping

of

the

aneurysm

and

surgical

evacuation

of

the

haematoma

Patients

categorized

as

inconclusive

or

negative

underwent

IA-DSA

In

patients

with

a

perimesencephalic

blood

distribution

one

IA-DSA

examination

was

performed

In

patients

with

a

nonperimesencephalic

blood

distribution

a

second

IA-DSA

was

performed

if

the

first

one

was

negative

IA-DSA

was

considered

the

gold

standard

CTA

was

considered

false-negative

when

IA-DSA

revealed

a

ruptured

aneurysm

or

when

rebleeding

occurred

The

positive

predictive

value

negative

predictive

value

sensitivity

specificity

and

accuracy

of

CTA

per

patient

were

calculated

The

chi-squared

test

was

used

to

compare

the

performance

of

CTA

and

CTA

for

the

identification

of

intracranial

aneurysms

Differences

with

a

P

value

less

than

were

considered

significant

The

IA-DSA

findings

in

patients

in

the

inconclusive

category

were

compared

with

the

CTA

findings

to

assess

whether

IA-DSA

actually

provided

any

additional

information

Results

Patient

population

From

April

until

January

patients

with

SAH

underwent

CTA

Excluded

from

the

study

were

patients

of

whom

were

excluded

because

of

a

nonaneurysmal

cause

of

the

SAH

including

trauma

-LRB-

n

-RRB-

arteriovenous

malformation

-LRB-

n

-RRB-

and

anticoagulant

therapy

-LRB-

n

-RRB-

because

of

hypertension

and

intracerebral

haematoma

because

of

comorbidity

or

advanced

age

were

excluded

because

of

poor

clinical

condition

and

because

if

poor

clinical

grading

and

advanced

age

and

died

from

the

initial

effect

of

SAH

rebleed

or

vasospasm

with

ischemia

Two

patients

refused

therapy

and

one

patient

was

referred

to

another

hospital

for

treatment

The

study

included

patients

men

and

women

with

a

mean

-LRB-

SD

-RRB-

age

of

years

-LRB-

range

years

-RRB-

Their

clinical

condition

just

before

treatment

was

classified

according

to

the

original

Hunt

and

Hess

grading

system

patients

were

classified

as

grade

I

as

grade

II

as

grade

III

as

grade

IV

and

as

grade

V

-LSB-

-RSB-

Detection

of

intracranial

aneurysms

Of

the

patients

underwent

CTA

and

underwent

CTA

The

CTA

results

were

categorized

as

proven

ruptured

intracranial

aneurysm

-LRB-

patients

-RRB-

inconclusive

-LRB-

patients

-RRB-

or

negative

for

aneurysm

-LRB-

patients

-RRB-

Positive

CTA

result

In

this

category

ruptured

aneurysms

were

diagnosed

in

patients

In

patients

associated

unruptured

aneurysms

were

diagnosed

The

distributions

of

the

locations

and

sizes

of

the

aneurysms

are

shown

in

Tables

and

An

overview

of

the

results

in

this

subgroup

is

presented

in

Fig.

Table

of

symptomatic

intracranial

aneurysms

in

patientsAneurysm

locationCTA-positive

-LRB-

n

-RRB-

CTA-inconclusive

-LRB-

n

-RRB-

aCTA-negative

-LRB-

n

-RRB-

bCoiling

-LRB-

n

-RRB-

Clipping

-LRB-

n

-RRB-

Coiling

-LRB-

n

-RRB-

Clipping

-LRB-

n

-RRB-

Anterior

circulationAnterior

communicating

cerebral

carotid

communicating

choroideal

circulationBasilar

cerebral

inferior

cerebellar

cerebellar

patients

had

no

proven

aneurysm.bFive

patients

had

false-negative

CTA

in

four

of

whom

a

ruptured

aneurysm

was

diagnosed

on

repeat

angiography.Table

distribution

of

symptomatic

intracranial

aneurysms

in

patientsSize

-LRB-

mm

-RRB-

CTA-positive

-LRB-

n

-RRB-

CTA-inconclusive

-LRB-

n

-RRB-

aCTA-negative

-LRB-

n

-RRB-

b

patients

had

no

proven

aneurysm.bFive

patients

had

false-negative

CTA

in

four

of

whom

a

ruptured

aneurysm

was

diagnosed

on

repeat

angiography.Table

of

asymptomatic

intracranial

aneurysms

in

patientsAneurysm

locationCTA-positiveCTA

inconclusiveAnterior

circulationAnterior

communicating

cerebral

carotid

communicating

circulationBasilar

of

vertebral

inferior

cerebellar

false-negative

on

CTA.bTwo

false-negatives

on

CTA.Table

distribution

of

asymptomatic

intracranial

aneurysms

in

patients

Size

-LRB-

mm

-RRB-

CTA-positiveCTA-inconclusive

false-negative

on

CTA.Fig

chart

of

CTA

results

The

majority

of

patients

were

treated

within

days

of

SAH

-LRB-

n

-RRB-

Of

the

CTA-positive

patients

-LRB-

-RRB-

were

coiled

and

-LRB-

-RRB-

were

clipped

Treatment

conversion

was

needed

in

three

patients

in

two

because

of

difficult

aneurysm

morphology

and

in

one

because

of

rebleeding

during

surgery

-LRB-

dura

not

yet

opened

-RRB-

In

two

patients

treatment

conversion

was

necessary

because

of

incorrect

treatment

selection

based

on

CTA

-LRB-

Fig.

-RRB-

Fig.

and

IA-DSA

results

in

a

woman

with

SAH

Hunt

and

Hess

grade

III

CTA

showed

four

aneurysms

an

aneurysm

of

the

anterior

communicating

artery

-LRB-

AComA

-RRB-

and

two

bilateral

aneurysms

of

the

middle

cerebral

artery

and

one

aneurysm

of

the

pericallosal

artery

The

aneurysm

of

the

AComA

was

regarded

as

symptomatic

at

the

time

of

initial

SAH

and

its

CTA-proven

morphology

showed

both

coiling

and

clipping

to

be

a

difficult

challenge

Coiling

of

the

AComA

aneurysm

was

tried

on

the

day

The

session

was

aborted

because

the

neck

of

the

aneurysm

was

broad

and

the

aneurysm

incorporated

both

segments

Unfortunately

rebleeding

occurred

after

coiling

The

morphology

of

the

aneurysm

excluded

complete

occlusion

by

clipping

on

the

day

In

the

postoperative

course

again

two

rebleedings

occurred

and

the

patient

died

At

autopsy

a

ruptured

pericallosal

aneurysm

was

seen

more

distal

to

the

clipped

aneurysm

a

Coronal

MIP

CTA

b

volume-rendered

CTA

c

AP

view

DSA

selective

catheterization

of

left

internal

carotid

artery

d

volume-rendered

IA-DSA

e

f

autopsy

-LRB-

red

arrow

anterior

communicating

artery

aneurysm

yellow

arrow

middle

cerebral

aneurysm

black

arrow

anterior

cerebral

artery

-LRB-

segment

-RRB-

blue

arrow

pericallosal

artery

aneurysm

All

ruptured

intracranial

aneurysms

were

confirmed

by

surgery

or

endovascular

treatment

In

two

patients

IA-DSA

was

performed

after

surgical

treatment

for

evaluation

of

coiling

of

asymptomatic

aneurysms

In

four

patients

-LRB-

-RRB-

a

fatal

rebleeding

occurred

during

follow-up

in

one

patient

soon

after

complete

occlusion

of

the

aneurysm

with

coiling

in

one

patient

on

the

day

after

clipping

in

one

patient

weeks

after

incomplete

occlusion

of

the

aneurysm

with

coiling

and

in

one

patient

almost

years

after

clipping

In

all

patients

the

blood

distribution

of

the

rebleeding

was

the

same

as

that

of

the

primary

SAH

Although

permission

was

not

granted

for

an

autopsy

in

two

patients

it

was

considered

most

probable

that

the

rebleeding

was

caused

by

the

treated

aneurysm

In

two

patients

an

autopsy

was

performed

In

one

a

ruptured

pericallosal

aneurysm

was

seen

cm

more

distal

from

the

clipped

anterior

communicating

artery

aneurysm

which

was

regarded

as

symptomatic

at

the

time

of

initial

SAH

-LRB-

Fig.

-RRB-

and

in

the

other

a

haematoma

surrounding

a

prepontine

cavernous

haemangioma

and

an

endovascular

treated

dissecting

aneurysm

of

the

basilar

artery

were

seen

The

presence

of

CT-diagnosed

additional

asymptomatic

aneurysms

was

checked

in

patients

These

patients

had

aneurysms

Five

aneurysms

were

confirmed

at

surgery

and

subsequently

clipped

aneurysms

were

checked

with

IA-DSA

and

subsequently

coiled

and

aneurysms

were

confirmed

with

IA-DSA

Three

aneurysms

in

three

patients

were

not

verified

In

four

patients

five

asymptomatic

aneurysms

were

false-negative

on

CTA

All

were

smaller

than

mm

Four

aneurysms

were

diagnosed

with

IA-DSA

during

an

embolization

session

one

of

them

was

also

embolized

Another

aneurysm

was

considered

a

vessel

loop

of

the

middle

cerebral

artery

on

CTA

However

an

aneurysm

of

the

middle

cerebral

artery

was

seen

during

surgery

of

a

ruptured

aneurysm

of

the

anterior

communicating

artery

Clipping

of

the

aneurysm

of

the

middle

cerebral

artery

was

also

performed

Inconclusive

CTA

result

In

patients

IA-DSA

was

performed

because

of

inconclusive

CTA

results

The

indications

for

IA-DSA

examination

are

presented

in

Table

An

overview

of

the

results

in

patients

in

this

category

is

presented

in

Fig.

Table

for

IA-DSA

examination

in

patientsIndicationNo

of

patientsMore

information

required

regarding

location

and

orientationSymptomatic

information

required

regarding

presence

of

intraaneurysmal

thrombus

in

symptomatic

giant

between

asymptomatic

and

symptomatic

between

infundibulum

vessel

loop

and

grade

IV

between

diagnosed

intracranial

aneurysm

and

distribution

of

angiography

of

circle

of

of

venous

of

normal

intracranial

vessel

In

patients

-LRB-

-RRB-

IA-DSA

confirmed

the

results

of

CTA

In

patients

-LRB-

-RRB-

IA-DSA

was

able

to

give

further

diagnostic

information

required

for

a

correct

patient

selection

for

therapy

In

two

patients

-LRB-

-RRB-

no

additional

diagnostic

information

could

was

obtained

from

IA-DSA

In

both

patients

vasospasm

of

a

vertebral

artery

resulted

in

an

inconclusive

CTA

but

also

excluded

selective

catheterization

with

IA-DSA

A

second

CTA

was

negative

in

both

patients

In

one

patient

-LRB-

-RRB-

treatment

selection

was

based

on

a

false-positive

IA-DSA

CTA

was

inconclusive

because

of

amalgam

artefacts

in

the

region

of

the

right

posterior

inferior

cerebellar

artery

-LRB-

PICA

-RRB-

An

aneurysm

of

the

right

PICA

was

diagnosed

on

the

first

IA-DSA

A

second

IA-DSA

was

performed

with

the

intention

of

coiling

However

with

additional

views

the

aneurysm

turned

out

to

be

a

vessel

loop

No

ruptured

aneurysms

were

found

in

ten

patients

-LRB-

four

nonperimesencephalic

SAH

four

with

perimesencephalic

SAH

and

two

negative

on

unenhanced

CT

-RRB-

In

patients

ruptured

intracranial

aneurysms

and

additional

unruptured

aneurysms

were

found

In

one

patient

only

an

asymptomatic

aneurysm

was

diagnosed

-LRB-

Tables

and

-RRB-

Of

the

ruptured

aneurysms

were

clipped

and

were

coiled

Two

ruptured

aneurysms

were

clipped

after

failure

of

endovascular

treatment

Two

asymptomatic

aneurysms

were

clipped

Negative

CTA

result

In

patients

CTA

was

considered

negative

An

overview

of

the

results

in

this

category

of

patients

is

presented

in

Fig.

Of

these

patients

-LRB-

-RRB-

had

negative

findings

on

unenhanced

CT

and

-LRB-

-RRB-

had

positive

findings

on

unenhanced

CT

and

of

the

latter

had

a

perimesencephalic

blood

distribution

and

had

a

nonperimesencephalic

SAH

-LSB-

-RSB-

In

-LRB-

-RRB-

of

those

with

negative

findings

on

unenhanced

CT

one

IA-DSA

was

done

In

one

patient

a

second

IA-DSA

was

performed

and

in

one

patient

a

second

CTA

was

performed

No

rebleedings

occurred

CTA

was

true-negative

in

all

these

patients

In

patients

-LRB-

-RRB-

with

perimesencephalic

SAH

IA-DSA

was

performed

once

and

in

one

of

them

CTA

was

repeated

once

and

in

one

CTA

was

repeated

twice

In

eight

patients

IA-DSA

was

repeated

once

and

in

one

patient

IA-DSA

was

repeated

twice

In

this

category

CTA

was

true-negative

in

all

these

patients

No

rebleedings

occurred

In

nine

patients

-LRB-

-RRB-

with

nonperimesencephalic

SAH

IA-DSA

was

performed

once

and

in

two

of

them

a

follow-up

MRA

was

done

and

in

one

CTA

was

repeated

In

seven

patients

a

second

IA-DSA

was

done

In

one

patient

IA-DSA

was

repeated

twice

In

five

patients

-LRB-

-RRB-

with

nonperimesencephalic

SAH

CTA

was

false-negative

-LRB-

Tables

and

-RRB-

In

one

of

these

patients

only

IA-DSA

was

able

to

detect

a

ruptured

aneurysm

of

the

anterior

communicating

artery

and

in

the

other

four

a

rebleeding

occurred

despite

an

initially

negative

CTA

and

IA-DSA

Repeat

angiography

was

performed

in

three

patients

a

ruptured

aneurysm

was

shown

by

CTA

in

two

and

by

IA-DSA

in

one

One

patient

died

before

repeat

angiography

Two

patients

were

treated

successfully

One

patient

died

before

treatment

due

to

the

direct

effect

of

the

rebleeding

The

explanations

for

false-negative

results

were

interpretation

mistakes

-LRB-

two

aneurysms

recognized

retrospectively

on

CTA

and

IA-DSA

-RRB-

and

haematoma

demonstrated

on

CTA

surrounding

and

compressing

the

aneurysm

leading

to

interpretation

error

on

both

CTA

and

IA-DSA

in

one

patient

and

on

only

CTA

in

another

-LRB-

IA-DSA

showed

the

aneurysm

-RRB-

the

findings

were

uncertain

in

one

patient

Statistical

analysis

The

diagnostic

value

of

both

and

CTA

are

outlined

in

Tables

and

A

comparison

of

the

results

of

CTA

is

presented

in

Table

No

statistically

significant

differences

were

found

Table

value

of

CTA

in

ruptured

aneurysmsDiagnostic

valueTrue

patientsFalse

patientTrue

patientsFalse

patientsPositive

predictive

Negative

predictive

Table

value

of

CTA

in

additional

aneurysmsDiagnostic

valueTotal

number

detected

with

patients

-LRB-

aneurysms

-RRB-

Presence

patients

-LRB-

aneurysms

-RRB-

True

patients

-LRB-

aneurysms

-RRB-

False

patientsaFalse

patients

-LRB-

aneurysms

-RRB-

Positive

predictive

Negative

predictive

aIncluding

CTA-negative

patients

and

CTA-positive

patients

Of

the

CTA-positive

patients

were

not

examined

with

IA-DSA

as

standard

control.Table

of

results

of

and

CTA

for

detection

of

intracranial

aneurysms

-LRB-

n

patients

-RRB-

-LRB-

n

patients

-RRB-

CTA

aneurysmsTrue

predictive

value

-LRB-

-RRB-

predictive

value

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aneurysmsTotal

number

on

-LRB-

aneurysms

-RRB-

-LRB-

aneurysms

-RRB-

Presence

-LRB-

aneurysms

-RRB-

-LRB-

aneurysms

-RRB-

True

-LRB-

aneurysms

-RRB-

-LRB-

aneurysms

-RRB-

False

-LRB-

aneurysm

-RRB-

-LRB-

aneurysms

-RRB-

Positive

predictive

value

-LRB-

-RRB-

predictive

value

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

with

an

inconclusive

result

were

not

included

in

the

statistical

analysis.bIncluding

one

CTA-positive

patient.cIncluding

CTA-negative

patients

and

CTA-positive

patients

Of

the

CTA-positive

patients

were

not

examined

with

IA-DSA

as

standard

control.dIncluding

CTA-negative

patients

and

CTA-positive

patients

Of

the

CTA-positive

patients

were

not

examined

with

IA

DSA

Discussion

Our

primary

aim

was

to

assess

whether

CTA

is

useful

clinically

in

planning

and

performing

clipping

or

coiling

especially

in

the

acute

phase

in

ruptured

intracranial

aneurysms

without

recourse

to

IA-DSA

We

demonstrated

that

it

was

possible

to

treat

more

than

half

of

all

patients

with

a

ruptured

intracranial

aneurysm

using

only

CTA

By

avoiding

conventional

angiography

it

was

possible

to

streamline

the

management

of

ruptured

aneurysm

during

the

acute

phase

Further

was

able

to

help

in

deciding

whether

to

clip

or

to

coil

in

only

two

patients

was

treatment

conversion

needed

due

to

incorrect

treatment

selection

based

on

CTA

We

found

to

be

a

simple

reliable

quick

and

minimally

invasive

imaging

modality

that

reduces

the

risk

of

complications

caused

by

conventional

angiography

and

reduces

the

delay

between

the

patient

's

arrival

at

the

hospital

and

treatment

leading

to

diminished

rebleeding

Matsumoto

et

al.

analyzed

the

rate

of

rebleeding

of

ruptured

aneurysms

during

CTA

and

conventional

angiography

and

found

-LRB-

of

patients

-RRB-

for

CTA

and

-LRB-

of

patients

-RRB-

for

conventional

angiography

-LSB-

-RSB-

In

patients

with

a

ruptured

aneurysm

and

intracerebral

haemorrhage

CTA

saves

time

when

aiming

for

a

fast

clot

removal

Another

advantage

is

that

the

radiation

dosage

is

low

compared

to

IA-DSA

-LRB-

mSv

at

mAs

with

the

CTA

Siemens

Sensation

and

mSv

at

mAs

with

the

CTA

Siemens

Sensation

compared

with

mSv

with

conventional

angiography

-RRB-

Furthermore

the

cost

of

CTA

is

one-fourth

that

of

conventional

angiography

Several

other

studies

assessing

whether

CTA

may

serve

as

the

sole

imaging

method

for

the

preoperative

work-up

of

patients

with

ruptured

intracranial

aneurysms

have

been

published

-LSB-

-RSB-

An

overview

of

these

previous

studies

is

presented

in

Table

There

is

a

wide

variation

in

the

percentage

of

patients

who

have

had

their

symptomatic

aneurysms

treated

based

on

CTA

This

may

be

influenced

positively

by

the

very

high

aneurysm

prevalence

and

the

subsequent

very

low

negative

rates

of

CTA

in

some

studies

-LSB-

-RSB-

In

other

studies

patients

with

a

negative

CTA

were

not

enrolled

at

all

-LSB-

-RSB-

In

general

a

mean

of

negative

angiographies

after

SAH

is

accepted

-LSB-

-RSB-

The

present

study

showed

a

high

negative

rate

for

CTA

This

may

reflect

the

good

awareness

of

the

diagnosis

SAH

in

first-line

and

second-line

health-care

and

the

good

access

to

CTA

when

the

diagnosis

SAH

is

considered

Furthermore

the

wide

variation

in

CTA-based

treatment

may

be

partially

explained

by

differences

in

hardware

and

software

used

by

each

group

the

rate

of

technical

failures

in

performing

CTA

scanning

parameters

set

for

screening

the

circle

of

Willis

and

more

peripheral

vessels

the

experience

and

scrutiny

of

the

neuroradiologist

evaluating

each

CTA

and

the

willingness

of

the

neurosurgeon

and

neurointerventional

radiologist

to

rely

on

CTA

alone

in

each

individual

case

Table

of

previous

studies

and

present

studyStudyNo

of

patientsCTA-positiveCTA-negativeCTA

inconclusive

or

no

CTA-based

treatmentTotal

patientsCTA-based

treatmentTrue-positive

CTATotal

patientsTrue-negative

CTATotal

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

Present

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

-LRB-

-RRB-

aOne

false-negative

and

one

false-positive

ruptured

aneurysm

in

one

patient.bIn

five

patients

with

perimesencephalic

SAH

IA-DSA

as

the

gold

standard

control

was

not

performed

In

the

present

study

CTA

was

false-negative

in

of

patients

The

risk

of

rebleeding

after

a

negative

initial

CTA

was

All

false-negatives

were

in

patients

with

a

nonperimesencephalic

blood

distribution

giving

a

false-negative

rate

of

and

a

risk

of

rebleeding

of

It

seems

unlikely

that

the

false-negative

rate

of

initial

CTA

and

the

risk

of

rebleeding

despite

a

negative

initial

CTA

in

patients

with

a

nonperimesencephalic

SAH

might

be

influenced

negatively

by

the

use

of

CTA

as

the

first

diagnostic

tool

Firstly

in

all

patients

with

a

rebleeding

repeat

IA-DSA

was

also

false-negative

Secondly

repeat

angiography

with

CTA

performed

after

a

rebleeding

still

demonstrated

an

aneurysm

Furthermore

the

findings

of

other

studies

using

IA-DSA

as

the

first

diagnostic

tool

were

similar

In

the

study

by

Urbach

et

al.

in

patients

with

a

negative

initial

angiogram

after

SAH

four

ruptured

aneurysms

were

revealed

by

repeat

angiography

-LSB-

-RSB-

Three

patients

presented

with

a

nonperimesencephalic

SAH

and

one

presented

with

a

perimesencephalic

SAH

In

the

study

by

Bradac

et

al.

of

the

patients

presenting

with

spontaneous

SAH

had

a

negative

angiogram

-LSB-

-RSB-

A

second

angiogram

performed

weeks

later

revealed

a

ruptured

aneurysm

in

of

the

patients

Of

these

patients

had

a

second

SAH

In

all

patients

a

nonperimesencephalic

blood

distribution

was

seen

on

CT.

Because

in

the

present

study

some

aneurysms

could

be

correctly

identified

retrospectively

we

suggest

that

if

under

strong

clinical

suspicion

of

a

ruptured

aneurysm

the

CTA

is

reported

as

normal

the

study

should

be

reviewed

by

a

second

neuroradiologist

before

proceeding

to

repeat

angiography

It

is

essential

to

perform

a

review

of

axial

raw

source

images

Next

we

recommend

repeat

CTA

or

IA-DSA

when

the

initial

CTA

is

negative

in

patients

with

a

nonperimesencephalic

SAH

There

is

no

consensus

about

the

time

interval

for

repeat

angiography

In

practice

the

guideline

is

to

repeat

angiography

after

several

days

to

months

The

substantial

risk

of

rebleeding

in

patients

with

an

aneurysmal

pattern

of

haemorrhage

in

the

present

study

indicates

that

some

cerebral

aneurysms

are

occult

on

initial

CTA

Several

factors

may

explain

this

finding

Most

importantly

there

is

a

learning

curve

in

assessing

aneurysms

on

CTA

Pedersen

et

al.

reported

an

increase

in

sensitivity

from

to

after

year

's

experience

-LSB-

-RSB-

Small

aneurysms

can

be

missed

when

using

CTA

CTA

had

a

sensitivity

of

for

aneurysms

mm

in

the

study

of

Wintermark

et

al.

-LSB-

-RSB-

Distal

pericallosal

and

PICA

aneurysms

can

be

missed

when

restricting

the

area

of

coverage

to

the

proximal

circle

of

Willis

-LSB-

-RSB-

Thrombosis

of

the

neck

of

the

aneurysm

or

of

the

entire

sac

is

another

possible

reason

-LSB-

-RSB-

Perianeurysmal

blood

or

haematoma

may

reduce

lesion

conspicuity

-LSB-

-RSB-

Aneurysms

may

be

mistaken

for

vascular

infundibula

-LRB-

persistent

fetal

nonaneurysmal

dilatation

of

the

proximal

vessel

-RRB-

of

the

posterior

communicating

or

anterior

choroidal

artery

origins

if

a

vessel

can

not

be

identified

arising

from

them

-LSB-

-RSB-

Aneurysms

may

masquerade

as

tight

vascular

loops

if

the

MIP

thickness

is

wide

-LRB-

mm

-RRB-

-LSB-

-RSB-

In

patients

with

multiple

intracranial

aneurysms

large

aneurysms

may

obscure

smaller

ones

on

the

CT

reconstruction

-LSB-

-RSB-

Aneurysms

close

to

bone

-LRB-

e.g.

carotid

siphon

ophthalmic

and

posterior

communicating

artery

-RRB-

may

be

overlooked

when

relying

on

surface-rendering

and

volume-rendering

techniques

or

using

MIP

with

bone

editing

-LSB-

-RSB-

Aneurysms

located

within

or

close

to

the

cavernous

sinuses

are

easy

to

overlook

unless

thin-section

axial

and

coronal

MIP

images

are

reviewed

on

a

slightly

wider

window

width

-LSB-

-RSB-

In

patients

with

a

perimesencephalic

SAH

the

chance

of

finding

a

posterior

fossa

aneurysm

is

low

-LSB-

-RSB-

Nonaneurysmal

perimesencephalic

haemorrhage

carries

no

risk

of

vasospasm

and

rebleeding

and

has

been

shown

to

follow

a

benign

course

with

an

excellent

prognosis

-LSB-

-RSB-

The

chance

of

finding

an

aneurysm

in

of

patients

has

to

be

weighed

against

the

risk

of

complications

from

angiography

imposed

upon

the

remaining

of

patients

CTA

has

a

high

accuracy

for

diagnosis

of

vertebrobasilar

aneurysms

and

of

intracranial

aneurysms

in

general

-LSB-

-RSB-

In

the

present

study

in

patients

with

a

perimesencephalic

SAH

and

a

negative

initial

CTA

no

rebleedings

occurred

and

CTA

was

true-negative

in

all

Similarly

in

the

prospective

study

of

Huttner

et

al.

patients

with

a

perimesencephalic

SAH

had

a

negative

initial

CTA

and

IA-DSA

-LSB-

-RSB-

A

repeat

IA-DSA

was

performed

in

patients

-LRB-

-RRB-

of

the

repeat

IA-DSAs

showed

any

additional

distinctive

features

with

respect

to

the

first

IA-DSA

It

therefore

seems

practical

and

safe

to

perform

CTA

as

the

first

diagnostic

tool

and

to

omit

repeat

angiography

if

CTA

is

negative

A

formal

decision

analysis

based

on

these

observations

confirmed

that

a

strategy

where

CTA

is

performed

and

not

followed

by

conventional

angiography

if

negative

results

in

a

better

utility

than

a

strategy

of

CTA

followed

by

conventional

angiography

or

of

conventional

angiography

as

primary

investigation

-LSB-

-RSB-

According

to

the

results

of

the

present

study

it

seems

important

to

distinguish

the

two

patterns

of

SAH

on

CT.

The

CT

criteria

of

perimesencephalic

bleeding

have

been

defined

-LSB-

-RSB-

Different

data

show

that

experienced

radiologists

can

accurately

discriminate

between

a

perimesencephalic

and

nonperimesencephalic

SAH

-LSB-

-RSB-

Early

CT

within

days

is

necessary

for

reliable

assessment

of

the

pattern

of

haemorrhage

-LSB-

-RSB-

A

criticism

of

this

study

might

be

that

patients

treated

with

endovascular

coiling

underwent

IA-DSA

as

part

of

the

endovascular

procedure

and

thus

should

not

be

counted

in

the

analysis

of

efficacy

of

the

prospective

protocol

However

a

shift

in

management

of

ruptured

intracranial

aneurysm

from

surgery

to

endovascular

treatment

has

appeared

-LSB-

-RSB-

Endovascular

treatment

is

replacing

clipping

The

use

of

CTA

as

the

initial

investigation

for

cerebral

aneurysms

may

offset

some

of

this

increased

workload

whilst

also

improving

workflow

In

conclusion

in

this

evaluation

of

the

use

of

and

multislice

CTA

in

the

management

of

ruptured

intracranial

aneurysms

we

demonstrated

that

CTA

can

be

used

as

the

first-line

diagnostic

modality

for

the

management

of

SAH

patients

In

CTA-negative

patients

IA-DSA

provided

no

or

marginal

added

value

IA-DSA

is

not

needed

in

patients

with

negative

CTA

and

classic

perimesencephalic

SAH

Repeat

IA-DSA

or

CTA

should

still

be

performed

in

patients

with

a

nonperimesencephalic

SAH

due

to

false-negative

CTAs

and

IA-DSAs

in

this

patient

group

The

remaining

true

indication

for

IA-DSA

was

in

patients

with

an

inconclusive

CTA

result

In

more

than

half

of

those

IA-DSA

provided

relevant

new

diagnostic

information

O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O B O O B O O O O O O B B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O B O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O B O O O O O O B O O O O O O O O B O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B B O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O

subarachnoid haemorrhage
cta
intracranial
aneurysm


Muscle

wasting

in

chronic

kidney

disease

the

role

of

the

ubiquitin

proteasome

system

and

its

clinical

impact

Muscle

wasting

in

chronic

kidney

disease

-LRB-

CKD

-RRB-

and

other

catabolic

diseases

-LRB-

e.g.

sepsis

diabetes

cancer

-RRB-

can

occur

despite

adequate

nutritional

intake

It

is

now

known

that

complications

of

these

various

disorders

including

acidosis

insulin

resistance

inflammation

and

increased

glucocorticoid

and

angiotensin

II

production

all

activate

the

ubiquitin

proteasome

system

-LRB-

UPS

-RRB-

to

degrade

muscle

proteins

The

initial

step

in

this

process

is

activation

of

to

cleave

the

myofibril

into

its

components

-LRB-

actin

myosin

troponin

and

tropomyosin

-RRB-

is

required

because

the

UPS

minimally

degrades

the

myofibril

but

rapidly

degrades

its

component

proteins

activity

is

easily

detected

because

it

leaves

a

characteristic

actin

fragment

in

muscle

samples

Preliminary

evidence

from

several

experimental

models

of

catabolic

diseases

as

well

as

from

studies

in

patients

indicates

that

this

fragment

could

be

a

useful

biomarker

because

it

correlates

well

with

the

degree

of

muscle

degradation

in

dialysis

patients

and

in

other

catabolic

conditions

Maintenance

of

protein

stores

in

chronic

kidney

disease

In

uremic

patients

protein

stores

are

frequently

depressed

when

assessed

by

a

low

serum

prealbumin

and

weight

loss

which

includes

loss

of

muscle

mass

-LSB-

-RSB-

In

pediatric

patients

with

chronic

kidney

disease

-LRB-

CKD

-RRB-

linear

growth

is

impaired

and

muscle

mass

is

reduced

Although

these

findings

have

been

attributed

to

malnutrition

many

uremic

patients

with

muscle

wasting

have

not

developed

the

problems

because

of

inadequate

diet

instead

they

have

complications

that

induce

a

complex

series

of

physiological

and

biochemical

adaptations

resulting

in

protein

catabolism

-LSB-

-RSB-

In

children

and

adults

with

CKD

these

complications

include

metabolic

acidosis

insulin

resistance

increased

glucocorticoid

production

high

levels

of

angiotensin

II

-LRB-

Ang

II

-RRB-

and

inflammation

-LSB-

-RSB-

Many

observational

studies

and

mechanistic

investigations

have

attempted

to

explain

this

loss

of

protein

stores

and

especially

the

loss

of

muscle

mass

There

are

at

least

three

conclusions

from

these

studies

First

rates

of

protein

synthesis

in

muscle

are

generally

unchanged

whereas

rates

of

protein

degradation

tend

to

increase

-LSB-

-RSB-

Second

the

daily

rates

of

protein

turnover

in

cells

are

so

high

-LRB-

g

protein/kg

per

day

-RRB-

that

even

a

small

increase

in

protein

degradation

-LRB-

and/or

a

decrease

in

protein

synthesis

-RRB-

will

cause

marked

protein

depletion

over

time

-LSB-

-RSB-

Third

the

increase

in

muscle

protein

degradation

in

uremia

and

most

other

catabolic

disease

states

is

mostly

due

to

programmed

activation

of

the

ubiquitin

proteasome

system

-LRB-

UPS

-RRB-

-LSB-

-RSB-

Therefore

to

understand

muscle

wasting

one

must

understand

the

UPS

The

ATP-dependent

ubiquitin

proteasome

system

-LRB-

UPS

-RRB-

Over

the

past

two

decades

progress

in

understanding

the

action

and

regulation

of

the

UPS

has

been

at

the

center

of

attempts

to

understand

the

control

of

protein

turnover

The

UPS

includes

concerted

actions

of

enzymes

that

link

ubiquitin

-LRB-

Ub

-RRB-

a

member

of

the

heat-shock

protein

family

to

protein

substrates

that

are

destined

for

degradation

-LRB-

Fig.

-RRB-

When

a

chain

of

at

least

four

to

five

ubiquitins

are

linked

to

a

protein

it

is

marked

for

degradation

in

a

second

step

mediated

by

the

proteasome

-LSB-

-RSB-

Specifically

the

tagged

protein

will

be

recognized

by

the

proteasome

a

very

large

multicatalytic

protease

complex

that

not

only

recognizes

Ub-conjugated

proteins

but

also

removes

Ub

unwinds

the

protein

and

injects

it

into

the

central

core

of

the

proteasome

Once

inside

this

central

tube-like

structure

the

protein

substrate

is

degraded

into

small

peptides

-LSB-

-RSB-

Fig.

ubiquitin

proteasome

pathway

of

protein

degradation

Ubiquitin

-LRB-

Ub

-RRB-

is

conjugated

to

proteins

destined

for

degradation

by

an

ATP-dependent

process

that

involves

three

enzymes

-LRB-

-RRB-

A

chain

of

five

Ub

molecules

attached

to

the

protein

substrate

is

recognized

by

the

proteasome

which

removes

Ub

and

digests

the

protein

into

peptides

The

peptides

are

degraded

to

amino

acids

by

peptidases

in

the

cytoplasm

or

used

in

antigen

presentation

-LRB-

Reproduced

with

permission

from

-LSB-

-RSB-

-RRB-

Three

enzymatic

components

are

required

to

link

Ub

to

proteins

that

are

destined

for

degradation

There

appears

to

be

only

one

-LRB-

Ub-activating

-RRB-

enzyme

and

around

-LRB-

Ub-carrier

or

conjugating

-RRB-

proteins

The

key

enzyme

however

is

the

enzyme

which

accounts

for

the

exquisite

specificity

of

proteins

to

be

degraded

There

are

at

least

a

thousand

enzymes

-LRB-

Ub

ligase

-RRB-

and

each

can

recognize

a

specific

protein

substrate

and

catalyze

the

transfer

of

an

activated

Ub

from

the

carrier

protein

to

the

substrate

protein

-LSB-

-RSB-

Since

the

initial

reports

that

the

UPS

recognizes

specific

proteins

and

tags

them

for

destruction

knowledge

about

proteolytic

processes

in

the

proteasome

has

exploded

Thousands

of

proteins

have

been

recognized

as

being

degraded

by

the

UPS

and

novel

cellular

functions

are

now

known

to

be

regulated

by

Ub

conjugation

In

terms

of

protein

breakdown

the

major

functions

of

the

pathway

are

Rapid

removal

of

proteins

Protein

degradation

is

irreversible

and

hence

destruction

of

a

protein

generally

leads

to

a

complete

termination

of

cellular

process

mediated

by

the

protein

Consequently

protein

degradation

is

critical

for

the

regulation

of

metabolism

and

cell

turnover

The

rapid

degradation

of

specific

proteins

also

permits

cells

-LRB-

as

well

as

the

organism

-RRB-

to

rapidly

adapt

to

a

change

in

physiological

conditions

-LRB-

e.g.

requiring

a

switch

to

glucose

as

an

energy

source

involves

converting

protein

stores

into

amino

acids

that

can

be

used

in

gluconeogenesis

-RRB-

Regulation

of

gene

transcription

Ub

conjugation

affects

gene

transcription

because

many

transcription

factors

become

conjugated

to

Ub

and

transcription

activators

are

degraded

by

the

proteasome

-LSB-

-RSB-

This

process

regulates

transcriptional

activity

by

removing

spent

activators

and

resetting

a

promoter

for

additional

rounds

of

transcription

-LSB-

-RSB-

Second

the

ability

of

transcription

factors

to

function

varies

with

their

location

within

the

cell

For

example

nuclear

factor

-LRB-

NF

-RRB-

κB

a

proinflammatory

transcriptional

factor

is

kept

outside

the

nucleus

because

movement

into

the

nucleus

is

blocked

by

its

association

with

an

inhibitory

protein

IκB

Destruction

of

IκB

initiated

by

the

IKK

kinase

and

carried

out

by

the

UPS

frees

NF-κB

which

then

translocates

to

the

nucleus

to

stimulate

gene

transcription

-LSB-

-RSB-

A

clinical

application

of

this

function

of

the

UPS

has

developed

in

oncology

Bortezomib

-LRB-

Velcade

-RRB-

a

proteasome

inhibitor

has

proven

to

be

beneficial

in

patients

with

multiple

myeloma

and

is

currently

in

clinical

trials

for

the

treatment

of

other

cancers

-LSB-

-RSB-

The

proposed

mechanism

of

action

involves

the

ability

of

bortezomib

to

prevent

the

UPS-induced

destruction

of

IκB

thereby

blocking

the

activation

of

NF-κB

-LRB-

an

antiapoptosis

transcription

factor

-RRB-

leading

to

an

increase

in

apoptosis

-LSB-

-RSB-

Inhibition

of

the

proteasome

therefore

will

induce

apoptosis

of

the

neoplastic

cells

-LSB-

-RSB-

In

addition

myeloma

cells

are

also

particularly

dependent

upon

NF-κB

to

produce

essential

growth

factors

-LSB-

especially

inerleukin

-LRB-

-RRB-

-RSB-

when

NF-κB

is

inactive

the

growth

of

myeloma

cells

is

depressed

Quality-control

mechanism

The

UPS

selectively

eliminates

abnormally

folded

or

damaged

proteins

that

have

arisen

because

of

missense

or

nonsense

mutations

biosynthetic

errors

proteins

damaged

by

oxygen

radicals

or

by

denaturation

For

example

in

cystic

fibrosis

the

mutant

form

of

the

transmembrane

conductance

regulator

protein

-LRB-

CFTR

-RRB-

is

selectively

degraded

before

it

reaches

the

cell

surface

-LSB-

-RSB-

The

UPS

catalyzes

destruction

of

this

mutant

CFTR

because

its

tertiary

structure

is

abnormal

Another

example

is

the

degradation

of

misfolded

proteins

within

the

endoplasmic

reticulum

Endoplasmic-reticulum-associated

degradation

-LRB-

ERAD

-RRB-

of

proteins

removes

misfolded

proteins

by

targeting

them

for

destruction

by

proteasomes

in

the

cytoplasm

-LSB-

-RSB-

Influencing

the

function

of

the

immune

system

The

UPS

is

responsible

for

creating

antigens

from

the

degradation

of

foreign

proteins

-LRB-

e.g.

viral

particles

-RRB-

The

antigens

are

presented

on

the

major

histocompatibility

complex

as

class

I

molecules

In

this

way

the

proteasome

exerts

dual

roles

of

removing

foreign

proteins

and

creating

a

stimulus

of

the

immune

system

-LSB-

-RSB-

As

a

source

of

amino

acids

When

carbohydrate

calories

are

rapidly

needed

or

when

cells

must

respond

to

catabolic

diseases/conditions

there

is

breakdown

of

cell

proteins

especially

skeletal

muscle

proteins

The

UPS

degrades

muscle

proteins

to

provide

amino

acids

that

can

be

converted

to

glucose

-LRB-

i.e.

gluconeogenesis

-RRB-

An

undesired

consequence

of

this

activity

could

be

an

inappropriate

loss

of

muscle

protein

Functions

of

Ub

not

associated

with

proteolysis

Ub

can

also

be

conjugated

to

proteins

as

a

monomer

-LRB-

rather

than

as

the

typical

Ub

chain

-RRB-

When

this

occurs

on

cell-surface

proteins

the

protein

is

internalized

into

the

endocytic

pathway

to

be

degraded

in

lysosomes

-LSB-

-RSB-

Uremia-activated

mechanisms

that

accelerate

loss

of

muscle

protein

Results

from

rodent

models

of

CKD

have

established

that

accelerated

muscle

protein

catabolism

involves

many

of

the

same

cellular

mechanisms

that

cause

muscle

wasting

in

other

catabolic

conditions

such

as

cancer

starvation

insulin

deficiency/resistance

or

sepsis

-LSB-

-RSB-

The

principal

mechanism

causing

muscle

atrophy

in

CKD

involves

activation

of

the

UPS

Evidence

for

this

includes

the

presence

of

higher

levels

of

mRNAs

encoding

certain

components

of

the

UPS

as

well

as

a

similar

pattern

of

increases

and

decreases

in

the

expression

of

about

atrophy-related

genes

-LRB-

also

called

atrogenes

-RRB-

-LSB-

-RSB-

Changes

in

atrogenes

include

decreased

expression

of

various

growth-related

genes

and

increased

expression

of

components

of

the

UPS

Patients

with

different

clinical

conditions

associated

with

muscle

atrophy

exhibit

similar

increases

in

mRNAs

encoding

components

of

the

UPS

-LRB-

e.g.

an

increase

in

mRNAs

encoding

Ub

and

proteasome

subunits

-RRB-

-LSB-

-RSB-

In

these

cases

changes

in

gene

expression

are

most

likely

due

to

transcriptional

regulation

because

we

have

shown

that

uremia

or

abnormal

insulin

responses

increase

the

transcription

of

Ub

and

subunits

of

the

proteasome

-LSB-

-RSB-

Additional

evidence

linking

the

UPS

to

protein

degradation

in

catabolism

is

the

finding

that

the

increase

in

protein

degradation

in

the

muscle

of

rats

with

CKD

-LRB-

and

other

muscle-wasting

conditions

-RRB-

can

be

blocked

by

inhibitors

of

the

proteasome

-LSB-

-RSB-

Considered

together

these

results

indicate

that

muscle

wasting

is

a

specific

and

carefully

orchestrated

program

Other

questions

are

why

are

proteins

degraded

and

how

is

the

complex

program

triggered

in

widely

varied

pathological

conditions

-LRB-

e.g.

acidosis

in

renal

failure

low

insulin

levels

in

fasting

and

diabetes

inactivity

or

glucocorticoids

and

cytokines

in

sepsis

and

other

inflammatory

conditions

-RRB-

In

fasting

and

in

other

disease

states

acceleration

of

muscle-protein

breakdown

mobilizes

amino

acids

which

are

used

for

protein

synthesis

in

tissues

and

for

conversion

to

glucose

in

the

liver

-LSB-

-RSB-

However

if

excessive

protein

degradation

persists

the

protein

loss

will

have

deleterious

effects

In

CKD

the

breakdown

of

tissue

protein

produces

nitrogenous

waste

products

which

must

be

excreted

to

prevent

the

accumulation

of

uremic

toxins

-LSB-

-RSB-

Finally

in

muscle

wasting

conditions

contractile

proteins

are

lost

differentially

whereas

in

conditions

causing

atrophy

-LRB-

e.g.

aging

-RRB-

all

components

of

muscle

cells

seem

to

be

affected

What

accounts

for

muscle-specific

response

The

answer

to

this

question

lies

in

the

involvement

of

the

UPS

The

UPS

degrades

a

specific

protein

depending

on

which

ubiquitin

ligase

is

activated

For

example

two

Ub

ligases

-LRB-

also

known

as

MAFbx

-RRB-

and

are

found

specifically

in

muscle

and

their

expression

increases

dramatically

-LRB-

to

-RRB-

in

catabolic

states

causing

loss

of

muscle

protein

-LSB-

-RSB-

In

mice

lacking

the

genes

for

either

or

muscles

grow

normally

but

in

response

to

muscle

denervation

the

ensuing

atrophy

is

slower

-LSB-

-RSB-

In

addition

the

muscle

's

content

of

mRNA

can

be

considered

a

biomarker

for

the

rate

of

proteolysis

in

muscles

responding

to

a

catabolic

condition

-LSB-

-RSB-

In

uremia

the

initial

cleavage

of

myofibrillar

proteins

is

mediated

by

Myofibrillar

proteins

-LRB-

including

actomyosin

-RRB-

comprise

about

two

thirds

of

the

protein

in

muscle

the

major

store

of

amino

acids

for

new

protein

synthesis

and

for

gluconeogenesis

The

UPS

readily

degrades

the

main

proteins

in

myofibrils

-LRB-

i.e.

actin

myosin

troponin

or

tropomyosin

-RRB-

but

it

does

not

readily

break

up

the

myofibril

into

its

main

component

proteins

-LSB-

-RSB-

This

means

that

another

proteolytic

system

must

initially

digest

myofibrils

to

create

substrates

that

can

be

degraded

by

the

UPS

-LSB-

-RSB-

Many

catabolic

conditions

are

associated

with

inflammation

and/or

cell

injury

and

these

conditions

activate

a

cysteine

protease

called

We

tested

in

an

in

vitro

system

using

purified

actomyosin

and

found

that

cleaves

actomyosin

and

leaves

a

characteristic

actin

fragment

-LSB-

-RSB-

When

we

activated

in

cultured

muscle

cells

we

found

that

UPS

rapidly

degraded

myofibrillar

component

proteins

and

again

the

C-terminal

fragment

of

actin

was

left

in

the

muscle

cells

-LSB-

-RSB-

The

protein-cleaving

action

of

is

important

because

blocking

will

reduce

overall

protein

degradation

in

muscle

-LSB-

-RSB-

In

addition

we

have

found

the

same

cleavage

processes

are

present

in

muscles

of

rodent

models

of

uremia

or

diabetes

or

in

Ang-II-induced

hypertension

-LSB-

-RSB-

Moreover

we

found

that

the

actin

fragment

also

accumulates

in

muscles

of

patients

with

loss

of

muscle

mass

due

to

painful

osteodystrophy

uremia

or

burn

injury

-LSB-

-RSB-

In

the

latter

study

we

found

that

the

rate

of

protein

degradation

in

muscle

-LRB-

measured

from

the

turnover

of

labeled

amino

acids

-RRB-

directly

correlated

-LRB-

r

-RRB-

with

the

level

of

the

actin

fragment

in

the

same

muscle

In

addition

there

was

a

lower

level

of

the

actin

fragment

in

muscle

of

hemodialysis

patients

who

participated

in

weeks

of

an

endurance

exercise

training

program

In

summary

the

level

of

the

actin

fragment

is

directly

associated

with

measured

protein

degradation

in

muscle

and

the

accumulation

of

the

fragment

responds

to

a

beneficial

therapeutic

intervention

If

these

properties

hold

up

in

other

trials

the

level

of

the

actin

fragment

could

be

used

as

a

biomarker

of

increased

muscle

protein

degradation

-LSB-

-RSB-

Signals

triggering

muscle

atrophy

in

kidney

disease

and

other

catabolic

states

Complications

of

CKD

as

well

as

the

complex

syndrome

of

uremia

can

trigger

muscle

protein

breakdown

The

triggering

complications

include

metabolic

acidosis

decreased

insulin

action

-LRB-

including

insulin

resistance

-RRB-

increased

glucocorticoid

production

high

levels

of

Ang

II

and

inflammation

-LSB-

-RSB-

Metabolic

acidosis

is

known

to

cause

accelerated

protein

degradation

in

infants

children

adults

the

elderly

and

patients

with

CKD

-LRB-

Table

-RRB-

The

mechanism

by

which

metabolic

acidosis

causes

muscle

wasting

involves

activation

of

the

UPS

and

-LSB-

-RSB-

In

addition

acidosis

changes

hormone

actions

such

as

insulin

resistance

and

increased

glucocorticoid

production

which

are

involved

in

activating

protein

degradation

-LSB-

-RSB-

-LRB-

Table

-RRB-

It

is

important

to

emphasize

that

the

correction

of

metabolic

acidosis

has

been

shown

to

decrease

protein

breakdown

in

various

clinical

trials

indicating

why

maintaining

normal

serum

bicarbonate

levels

should

be

part

of

standard

clinical

care

-LRB-

Table

-RRB-

Table

that

metabolic

acidosis

induces

catabolism

of

protein

and

amino

acids

in

normal

infants

children

and

adults

as

well

as

in

patients

with

chronic

kidney

disease

-LRB-

CKD

-RRB-

Subjects

investigatedOutcome

measurementsTrial

outcomeInfants

-LSB-

-RSB-

Low-birth-weight

acidotic

infants

were

given

or

supplement

improved

growthChildren

with

CKD

-LSB-

-RSB-

Measured

rates

of

protein

degradation

in

children

with

CKDProtein

loss

was

higher

when

was

mM

compared

with

mMNormal

adults

-LSB-

-RSB-

Acidosis

induced

and

then

measured

amino

acid

and

protein

metabolismAcidosis

increased

amino

acid

and

protein

degradationNormal

adults

-LSB-

-RSB-

Induced

acidosis

and

then

measured

nitrogen

balance

and

albumin

synthesisAcidosis

induced

negative

nitrogen

balance

and

suppressed

albumin

synthesisChronic

renal

failure

-LSB-

-RSB-

Nitrogen

balance

before

and

after

treatment

of

improved

nitrogen

balanceChronic

renal

failure

-LSB-

-RSB-

Essential

amino

acid

and

protein

degradation

before

and

after

treatment

of

suppressed

amino

acid

and

protein

degradationChronic

renal

failure

-LSB-

-RSB-

Muscle

protein

degradation

and

degree

of

acidosisProteolysis

was

proportional

to

acidosis

and

blood

cortisolChronic

renal

failure

-LSB-

-RSB-

Nitrogen

balance

before

and

after

treatment

of

reduced

urea

production

and

improved

nitrogen

balanceHemodialysis

-LSB-

-RSB-

Protein

degradation

before

and

after

treatment

of

decreased

protein

degradationHemodialysis

-LSB-

-RSB-

Serum

albumin

before

and

after

treatment

of

increased

serum

albuminCAPD

-LSB-

-RSB-

Protein

degradation

before

and

after

treatment

of

decreased

protein

degradationCAPD

-LSB-

-RSB-

Weight

and

muscle

gain

before

and

after

treatment

of

acidosisRaising

dialysis

buffer

increased

weight

and

muscle

massCAPD

continuous

ambulatory

peritoneal

dialysisTable

acidosis

in

otherwise

normal

humans

changed

hormonal

levels

or

responses

to

hormonesHormoneAcidosis-induced

responseGrowth

hormone

-LRB-

GH

-RRB-

-LSB-

-RSB-

Suppressed

GH

secretionLower

responseInsulin

-LSB-

-RSB-

Suppressed

insulin-stimulated

glucose

metabolismInsulin-like

growth

factor

-LRB-

IGF

-RRB-

-LSB-

-RSB-

Decreased

in

plasma

and

kidney

and

liver

-LRB-

but

not

in

muscle

-RRB-

Thyroid

hormone

-LSB-

-RSB-

Decreased

plasma

and

levels

plus

a

higher

plasma

thyroid-stimulating

hormoneGlucocorticoids

-LSB-

-RSB-

Increased

glucocorticoid

productionParathyroid

hormone

-LRB-

PTH

-RRB-

-LSB-

-RSB-

Decreased

sensitivity

of

PTH

secretion

to

changes

in

plasma

calciumVitamin

D

-LSB-

-RSB-

Suppressed

activation

to

-LRB-

OH

-RRB-

cholecalciferol

The

finding

that

various

diseases

with

muscle

wasting

are

caused

by

activation

of

the

UPS

plus

the

fact

that

coordinated

changes

in

the

expression

of

genes

in

muscle

occur

in

different

catabolic

states

suggest

that

catabolic

states

activate

a

common

cellular

signaling

pathway

-LSB-

-RSB-

One

signaling

pathway

is

a

decrease

in

phosphatidylinositol

-LRB-

-RRB-

activity

-LRB-

Fig.

-RRB-

The

involvement

of

this

signaling

pathway

follows

from

the

finding

that

several

catabolic

illnesses

including

sepsis

acidosis

uremia

and

diabetes

are

characterized

by

insulin

resistance

-LSB-

-RSB-

In

normal

muscle

binding

of

insulin

or

insulin-like

growth

factor

-LRB-

IGF

-RRB-

to

their

receptors

increases

the

activities

of

and

its

downstream

target

Akt

In

insulin-resistant

conditions

or

with

deficiency

of

the

activity

of

this

signaling

pathway

is

depressed

-LSB-

-RSB-

When

activity

falls

there

is

decreased

production

of

phosphate

-LRB-

-RRB-

leading

to

decreased

phosphorylation

and

activity

of

the

downstream

serine/threonine

kinase

Akt

This

is

a

key

step

because

activated

Akt

is

a

major

stimulator

of

growth-related

processes

via

phosphorylation

of

the

downstream

kinases

and

stimulating

protein

synthesis

On

the

other

hand

reduced

signaling

-LRB-

as

occurs

in

insulin

resistance

-RRB-

enhances

protein

breakdown

in

muscle

-LSB-

-RSB-

The

rise

in

muscle

protein

losses

is

associated

with

two

catalytic

processes

first

is

activated

to

break

down

the

complex

structure

of

muscle

second

there

is

increased

expression

of

the

ubiquitin

ligases

and

to

degrade

the

proteins

made

available

by

-LSB-

-RSB-

-LRB-

Fig.

-RRB-

The

result

is

muscle

wasting

Fig.

balance

between

muscle

hypertrophy

and

atrophy

depends

on

whether

protein

synthesis

is

more

active

than

degradation

or

vice

versa

In

protein

synthesis

insulin-like

growth

factor

-LRB-

IGF

-RRB-

and

insulin

signaling

leads

to

increased

phosphatidylinositol

-LRB-

-RRB-

which

promotes

Akt

phosphorylation

-LRB-

Akt-P

-RRB-

Akt-P

promotes

phosphorylation

of

and

kinases

leading

to

increased

protein

synthesis

Akt-P

also

phosphorylates

the

forkhead

-LRB-

FoxO

-RRB-

transcription

factor

preventing

it

from

entering

the

nucleus

to

promote

expression

of

and

other

atrogenes

thereby

blocking

protein

degradation

In

protein

degradation

the

opposite

pathway

happens

but

additionally

decreased

Akt-P

leads

to

increased

activity

further

promoting

degradation

In

inflammation

it

is

thought

that

tumor

necrosis

factor

-LRB-

TNF

-RRB-

α

and

other

inflammatory

cytokines

phosphorylate

the

inhibitor

of

nuclear

factor

-LRB-

NF

-RRB-

κB

-LRB-

IκB

-RRB-

to

free

NF-B

to

enter

the

nucleus

and

promote

expression

and

ultimately

muscle

protein

degradation

-LRB-

Reproduced

with

permission

from

-LSB-

-RSB-

-RRB-

How

are

the

two

mechanisms

activated

In

studies

of

muscles

from

insulin-deficient

rats

or

db/db

mice

-LRB-

a

model

of

insulin

resistance

-RRB-

we

found

that

accelerated

muscle

protein

degradation

increases

the

level

of

the

proapoptotic

factor

Bax

-LSB-

-RSB-

This

is

relevant

because

activated

Bax

causes

the

release

of

cytochrome

C

from

mitochondria

Cytochrome

C

release

in

turn

activates

to

trigger

actomyosin/myofibril

cleavage

leaving

behind

the

actin

fragment

marker

-LSB-

-RSB-

The

activation

of

and

hence

the

UPS

involves

another

mechanism

changes

in

activity

of

the

fork-head

transcription

factors

-LRB-

FoxO

and

-RRB-

When

these

transcription

factors

are

phosphorylated

by

Akt

they

can

not

enter

the

nucleus

to

stimulate

transcription

of

However

when

activities

are

low

the

FoxOs

are

not

phosphorylated

so

they

can

enter

the

nucleus

to

increase

the

transcription

of

resulting

in

an

increase

in

muscle

protein

degradation

-LSB-

-RSB-

The

influence

of

Akt

on

the

other

ubiquitin

ligase

involved

in

muscle

proteolysis

is

not

as

clearly

established

and

it

may

be

linked

to

inflammation

as

activation

of

NF-κB

will

cause

overproduction

of

and

muscle

atrophy

-LSB-

-RSB-

Besides

acidosis

and

depressed

insulin/IGF

action

another

complication

of

CKD

that

participates

in

muscle

wasting

is

increased

glucocorticoid

production

The

complexity

of

these

interactions

is

great

because

increased

glucocorticoids

can

cause

insulin

insensitivity

-LSB-

-RSB-

and

both

insulin

deficiency

and

insulin

resistance

increase

glucocorticoid

production

Glucocorticoids

exert

a

permissive

effect

on

protein

degradation

in

muscle

caused

by

several

catabolic

conditions

For

example

activation

of

muscle

protein

breakdown

does

not

occur

in

adrenalectomized

animals

with

metabolic

acidosis

or

with

acute

diabetes

unless

the

animals

are

also

given

a

physiological

dose

of

glucocorticoids

-LSB-

-RSB-

Similarly

the

increase

in

muscle

proteolysis

induced

by

Ang

II

or

sepsis

is

largely

eliminated

by

inhibiting

the

glucocorticoid

receptor

-LSB-

-RSB-

This

response

to

glucocorticoids

is

permissive

because

the

same

physiological

level

of

glucocorticoids

does

not

stimulate

muscle

protein

degradation

unless

the

animals

are

either

acidotic

or

insulin

deficient

These

complex

interactions

actually

make

physiological

sense

because

glucocorticoids

evolved

to

integrate

stress

responses

in

different

tissues

When

glucose

is

needed

glucocorticoids

mobilize

amino

acids

from

muscle

protein

At

the

same

time

glucocorticoids

induce

gluconeogenic

enzymes

in

liver

to

catalyze

the

conversion

of

the

amino

acids

to

glucose

and

urea

In

children

accelerated

loss

of

protein

stores

associated

with

glucocorticoid

therapy

frequently

results

in

impaired

linear

growth

One

glucocorticoid-dependent

mechanism

causing

these

defects

is

impaired

response

to

insulin

-LRB-

insulin

insensitivity

-RRB-

An

allied

mechanism

is

impaired

response

to

arising

from

decreased

or

impaired

action

of

growth

hormone

Indeed

administration

of

growth

hormone

has

been

shown

to

improve

linear

growth

of

children

being

treated

chronically

with

glucocorticoids

-LSB-

-RSB-

Moreover

growth

hormone

has

been

shown

to

improve

growth

of

children

with

chronic

catabolic

diseases

such

as

CKD

whereas

growth

hormone

improves

growth

it

does

not

improve

growth

in

children

to

-LRB-

or

close

to

-RRB-

a

normal

height

for

age

-LSB-

-RSB-

The

impaired

response

is

likely

due

to

the

multiple

complications

of

CKD

resulting

in

retarded

growth

Interestingly

there

is

a

small

uncontrolled

study

of

five

children

who

were

being

treated

with

chronic

intermittent

hemodialysis

and

growth

hormone

The

children

were

then

placed

on

an

intensified

daily

hemodialysis

regimen

-LRB-

h/day

five

to

six

times

a

week

-RRB-

for

a

median

time

of

years

-LSB-

-RSB-

The

new

regimen

led

to

significant

catchup

growth

into

the

range

of

a

normal

height

for

age

Intensified

dialysis

plus

growth

hormone

could

correct

acidosis

improve

insulin

and

signaling

and

responses

to

other

hormones

and

remove

unidentified

uremic

toxins

These

responses

emphasize

the

complexity

of

sorting

out

mechanisms

for

muscle

wasting

in

CKD

Another

catabolic

factor

associated

with

CKD

is

Ang

II

Infusion

of

Ang

II

into

rodents

causes

both

anorexia

and

muscle

protein

loss

by

mechanisms

that

depend

on

glucocorticoids

-LSB-

-RSB-

Also

there

is

the

knotty

problem

of

understanding

the

influence

of

inflammation

In

this

case

the

mechanism

-LRB-

s

-RRB-

causing

muscle

wasting

in

inflammation

is

not

clear

Suggested

responses

include

the

ability

of

certain

inflammatory

mediators

to

cause

insulin

resistance

as

well

as

a

more

direct

influence

of

inflammatory

mediators

on

muscle

protein

metabolism

-LRB-

Fig.

-RRB-

The

problem

is

difficult

because

the

link

between

an

increase

in

inflammatory

markers

in

uremic

patients

-LRB-

e.g.

C-reactive

protein

-RRB-

to

loss

of

muscle

mass

has

not

been

established

-LSB-

-RSB-

Finally

there

is

an

intriguing

protein

myostatin

a

member

of

the

transforming

growth

factor

-LRB-

TGF

-RRB-

β

family

of

cytokines

It

is

produced

in

skeletal

and

cardiac

muscle

and

regulates

muscle

growth

by

limiting

it

-LSB-

-RSB-

Overexpression

of

myostatin

in

muscle

leads

to

loss

of

protein

mass

via

inhibition

of

Akt

phosphorylation

with

an

increase

in

active

this

increases

the

expression

of

atrophy-related

genes

-LSB-

-RSB-

Underexpression

of

myostatin

results

in

skeletal

muscle

hypertrophy

-LSB-

-RSB-

An

increase

in

myostatin

expression

is

found

in

several

cachexia-associated

disease

states

However

there

is

limited

information

about

the

influence

of

kidney

disease

on

myostatin

expression

and

function

beyond

changes

in

myostatin

mRNA

-LSB-

-RSB-

Conclusion

In

this

brief

review

of

mechanisms

causing

muscle

protein

losses

we

discussed

how

a

complex

series

of

biochemical

reactions

are

coordinated

to

create

a

genetic

program

that

degrades

muscle

proteins

We

also

identified

an

initial

step

in

muscle

proteolysis

that

leaves

behind

a

biomarker

in

muscle

the

actin

fragment

resulting

from

We

emphasized

how

the

UPS

causes

muscle

wasting

in

uremia

as

well

as

the

role

UPS

plays

in

the

regulation

of

cellular

functions

ranging

from

the

control

of

the

cell

cycle

to

activities

that

promote

cancer

Indeed

inhibitors

of

proteasome

activity

have

emerged

as

novel

chemotherapeutic

agents

Involvement

of

the

UPS

in

such

a

wide

range

of

functions

explains

why

the

Nobel

Prize

in

Chemistry

was

awarded

to

Avram

Hershko

Aaron

Ciechanover

and

Irwin

Rose

for

their

discovery

of

Ub

and

its

role

in

orchestrating

cellular

protein

turnover

-LRB-

-RRB-

B I O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I 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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O B I O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O

14kd actin fragment
muscle wasting
protein degradation
muscle atrophy
uremia

ubiquitin-proteasome system (ups)
caspase-3
chronic kidney disease (ckd)