ic re stenos is

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Restenosis

Interventional Fellow

12/2008


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Gruntzig et al. 1979

Non-operative dilatation of coronary-

artery stenosis

6/32 patients undergoing initial successful

dilatation, suffered restenosis; a rate of

19%.

Most important factors in restenosis:

1)Lesion length

>20mm OR:1.51; p=0.031

2)Diabetes

OR: 1.71; p=0.0043

3)Final vessel diameter

OR: 1.48; p=0.041


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Endothelial injury

post implantation

Stent implantation causes arterial injury, which can initiate restenosis. The restenosisStent implantation causes arterial injury, which can initiate restenosis. The restenosisprocess includes inflammation, migration of smooth muscle cells, smooth muscle cellprocess includes inflammation, migration of smooth muscle cells, smooth muscle cell

proliferation and extracellular matrix formation.proliferation and extracellular matrix formation.

Implanted

stent

Plaque


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Platelet aggregation

and activationDrug-eluting stent struts

Platelets

Inflammatory cells

Platelet deposition and activation occur at the injury site, leading to the release ofPlatelet deposition and activation occur at the injury site, leading to the release ofcell-signaling molecules.cell-signaling molecules.

Red blood cells


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Activated inflammatory cellsActivated inflammatory cells

MediaMedia

Cell surface receptorsCell surface receptors

Transmigration of

inflammatory cells (I)

The cell-signaling molecules induce expression of cell surface receptors that bindThe cell-signaling molecules induce expression of cell surface receptors that bindto circulating inflammatory cells.to circulating inflammatory cells.

IntimaIntima

Inflammatory cellsInflammatory cells


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Transmigration of

inflammatory cells (II)

Smooth muscle cellsSmooth muscle cells

Inflammatory cellsInflammatory cellssecreting cell-signalingsecreting cell-signalingmoleculesmolecules

Transmigration ofTransmigration ofinflammatory cellsinflammatory cells

Once activated, these inflammatory cells roll across the endothelial surface andOnce activated, these inflammatory cells roll across the endothelial surface andtransmigrate into the lesion.transmigrate into the lesion.

Endothelial cells


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Activation of smooth

muscle cells (I)

Cell signaling

molecules activate

smooth muscle cells

Smooth muscle cell

surface receptor

The activated inflammatory cells secrete molecules that bind to specific receptorsThe activated inflammatory cells secrete molecules that bind to specific receptorson smooth muscle cells.on smooth muscle cells.

Smooth muscle cell extracellular view


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muscle cells (II)

Activated

smooth muscle

cell receptor

mTOR activates

smooth muscle

cells to enter

cell cycle

Bound smooth muscle cell receptors activate various intracellular smooth muscleBound smooth muscle cell receptors activate various intracellular smooth musclecell proteins. One such protein, mTOR, plays a central regulatory role in the cell cycle.cell proteins. One such protein, mTOR, plays a central regulatory role in the cell cycle.

Smooth muscle cell intracellular view


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muscle cells (III)Cell responds to growth factor stimulationCell responds to growth factor stimulation

DNA synthesisDNA synthesisCell preparesCell preparesfor mitosisfor mitosis

MitosisMitosis

Cell resting phaseCell resting phase

Restriction pointRestriction point

Activated mTOR stimulates smooth muscle cells to advance from the G1 phase toActivated mTOR stimulates smooth muscle cells to advance from the G1 phase tothe S phase where DNA replication occurs, causing the smooth muscle cells tothe S phase where DNA replication occurs, causing the smooth muscle cells to

undergo mitosis (ie, cell proliferation).undergo mitosis (ie, cell proliferation).


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muscle cells (IV)

Proliferating smooth

muscle cells

Extracellular

matrix

Proliferation of smooth muscle cells increases the cellular mass in the neointima,Proliferation of smooth muscle cells increases the cellular mass in the neointima,leading to restenosis.leading to restenosis.


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PTCA restenosis rate of 30-60% defined as renarrowing of the vessel exceeding

50% of MLD achieved at time of PTCA its main Achilles heel

-Negative remodeling

Ability of the artery to contract or relax

Increased number of fibroblasts, actin, myosin, desmin cause

vascular constriction

-Vessel recoil

Acute process

-Neointimal proliferation

Initial dissection causes endothelial denudation causing the

previously illustrated inflammatory cascade. VSMC proliferate

and deposit extracellular matrix proteins that produce the loss in

lumen

BMS reduced the restenosis rate to 15-30%


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Reduction in restenosis rate with BMS

!! BMS implantation actually promotes neo-intimal proliferation to

a greater degree than PTCA

Late Lumen loss is greater with BMS than PTCA

The initial gain in lumen diameter outweighs the increased proliferation

post delivery


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Defining Restenosis in the Cath Lab


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Frequency of Restenosis


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On average TLR rates in trials

have varied from 1-5%


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Therapies for Restenosis


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Post-PTCA TLR for ISR

Average = 30%


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Early EU dataLarge

Japanese

DatabaseNo

Randomized

Controlled

Trials

One Year TLR for Cutting balloon

Registry Data

E i L f F l


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Excimer Laser for Focal

Restenosis Lesions

Not Statistically

significant


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Brachytherapy for Restenosis


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Cypher better

thanbrachytherapy


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DES ON ISR


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Cypher better than Taxus


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Significantly better MLD post stentmay translate to better long-term

outcome.


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Cypher better

thanbrachytherapy


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Taxus better than

brachytherapy

TLR reduction 50%


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What to Do

1. Place a drug eluting stent whenever

possible

2. Any other modality of opening the

restenosis is generally equivalent

ic re stenos is

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