Atherosclerosis: Practical Implications for Pathologists
Section 7 -
This 56 year old woman with known ischemic cardiomyopathy was admitted to
hospital with tachycardia and was found to have LBBB (at 181 bpm) (2003), with presyncope ? cyanosis.
She had a history of anterior myocardial infarction in 1996 and underwent a percutaneous coronary
intervention (PCI) to the LAD. Her symptoms recurred of and on and in 2002. She underwent PCI to the
RCA. She had several hospitalizations for congestive heart failure, the last one three months prior to
admission. 2D echocardiogram: cardiomegaly and LV enlargement (Grade IV LV). Moderate MR, NSR, and
LBBB. Peripheral arterial Doppler: bilateral aortoiliac occlusion. (no right radial pulse - since
PCI). Moderate AV nodal conduction disease. REC: Dual chamber ICD implantation ASAP. A second PCI and
stent was put into the LAD. Developed ischemic bowel and had cecal resection. She has diabetes mellitus
(type 2) and hyperlipidemia.
You just heard about the role of several contemporary coronary interventional techniques including
angioplasty for the management of coronary artery disease.
The last 20 or more years have underscored the significance of rapidly reopening an occluded vessel
that was associated with ST elevation and myocardial infarction (STEMI). When dilatation of coronary
arteries at angioplasty was first performed in 1979, the technique came to be known as percutaneous
transluminal angioplasty (PTA or PTCA). The procedure, while initially widely accepted, was found to be
complicated by early and late vessel changes. The early complications were acute vessel occlusion and
the late was restenosis. The incidence of these lesions was reportedly between 30 and 50% of all
coronary balloon angioplasties, at the end of one year. 
Acute occlusion of the coronary vessels was attributed to:
An effort to try and prevent the early vessel occlusion or acute vessel occlusion was the use of
anti-thrombotic agents. These however were not very successful. Later treatment modalities planned were
the use of steel stents to mechanically hold the vessel open
This resulted in a
decrease in acute occlusion, decrease in the overall rate of early re-intervention and a decrease in the
angiographic incidence of restenosis, when compared to PTCA alone  However, a later
metaanalysis of six clinical trials by Cutlip et al, showed that with clinical end points of target
lesion revascularization (TLR) target vessel revascularization (TVR) and target vessel failure (TVF),
were associated with a restenosis rate of 46.2% at one year . These results were not much
different from the results of PTCA alone. It is not coronary artery stents alone that are associated
with these results arterial stenting at other sites also has similar results.
- Elastic recoil of the vessel.
- Rupture of plaque
- Dissection of the plaque or the vessels
The peripheral vessel studies also include the iliac artery and renal arteries. The renal arteries
have shown an angiographic restenosis rate of 11 - 26% at end points greater than six months and iliac
vessels demonstrated at 68 - 93% primary patency rate at one year, on clinical examination in
The potential for underreporting and peripheral vascular disease is
considerably higher than in PTCA studies as the follow-up is less rigorous, that is angiography is
performed much less often, and greater reliance is placed on non-invasive and clinical end points.
The pathology associated with stents :
This was first reported by Farb and Virmani in their report on acute examinations the stent of the
mechanical support provided by it, prevents acute vessel occlusion related to elastic recoil or vasospasm
or dissection or plaque rupture after the angioplasty . In the study by Farb et al, which
evaluated 55 stents and 33 coronary vessels at autopsy, these vessels are divided into groups based on
the time post implantation: less than three days, greater than four to less than 11 days, greater than
12 to less than 30 days and greater than 30 days. A total of 142 arterial sections were examined. The
struts showed inflammatory cells surrounding them and these were counted, as up to 20 inflammatory cells
in those scrubs in contact with damaged vessel wall, that is damaged media. Struts there were in contact
with fibrocalcific plaque, showed far less inflammatory reaction (3%) (P=0.001) .
Cellular hyperplasia, comprised of spindle shaped cells, positive for alpha-actin on
immunohistochemistry, that is positive for muscle cells, with a proteoglycan rich matrix were not seen at
less than 11 days (18 patients), but were found in all sections greater than 30 days (10 patients) after
implantation. The neointimal thickness associated with stent struts was doubled and associated with
medial injury, compared to struts in contact with fibrous plaques or intact media
Other non-specific systemic markers of inflammation have been noted to be raised during or after
angioplasty and stenting of coronary vessels. These include C-reactive protein (CRP) and these appear to
be independent predictors of restenosis after PTA of femoral popliteal vessels. CRP and other markers
are significantly elevated in the femoral popliteal angioplasty / stent groups when compared to other
sites such as carotid, iliac and femoral popliteal vessels. Concern was raised regarding the
significance of distal embolization of atherothrombotic material, and its role in increasing infarct
size. However, studies using devices to protect against atherothrombotic embolism, have shown no benefit
or even shown negative effects on reduction of infarct size It is possible
then that atherothrombotic emboli do not occur, that the devices used had limitations with regard to
embolus trapping, or that this form of the embolization has little impact on myocardial damage following
PCI 's .
It would be fair therefore to wonder why an expensive procedure such as a stent with questionable
results, continues to be used. The reasons for the routine clinical implementation of coronary stents
This list of advantages and the knowledge that stents while beneficial do develop restenoses led
fairly rapidly led to research into mechanisms to prevent in-stent restenosis. The initial approach was
the use of systemic strategies, such as anti-platelet agents. This was not effective except for reducing
the incidence of early thrombotic occlusion.
- Stents provide favorable and predictable acute angiographic result
- Stents improved the safety of angioplasty by successfully treating and acute and
- Stents improve long-term clinical outcomes by reducing restenosis
- Stents are easy to use and do not add any significant time to the angioplasty
- The use of stents often significantly decreases total procedure time
- Stents provide favorable angiographic and clinical results in most complex lesions,
which are poorly treated by balloon angioplasty alone. (These would include
saphenous vein graft lesions, ostial stenosis, eccentric lesions and total occlusions).
The next approach was the use of brachytherapy. (This was the only
effective treatment for in-stent restenosis and has a target lesion revascularization rate of 11% and
target vessel revascularization of 20%.)  Brachytherapy or the intravascular use of
radiation was used because of its antiproliferative effect and resulting in chromosomal damage and
apoptotic cell death.  The radiation sources used today are beta and gamma radiation. Beta
radiation emitters have much lower penetration of tissue, thus do not require special shielding
techniques. It does however require more precise delivery technique to ensure proper dosing of the
arterial wall. On the other hand, gamma radiation has high tissue penetration and thus requires a
significant amount of shielding. The sources used include phosphorous 32, strontium-90 and in addition
stents coated with radioactive P-32.The results of brachytherapy are still controversial. Its major
limiting factor so far have been luminal occlusion from late thrombosis and end of stent lesions or
"candy wrapper" lesions which actually are intimal hyperplasia at the junction of the vessel wall with
the stent, that is at the two ends. Thrombosis has been reported at two to six months. The practical
problem in implementing intravascular brachytherapy (in essence intravascular radiation) as a commonly
used mode of treatment is the concerns about it, not only because of the concerns about radiation but
about the need to build or rebuild or refit interventional suites or operating rooms, the appropriate
shielding for radiative material, the cost of the material, the disposal of the material, the potential
concerns about the disposal of the stents or tissues in patients who die after the procedure and the need
to develop an appropriate centering catheter and computer supports to operate it.
These concerns have led to the development of a whole new field, that of drug
eluting stents and more broadly drug eluting devices. Drug eluting stents have recently come into
the market and some of these are:
1. A stainless steel stent - In flow stent, Inflow Dynamics, Munich Germany, coated
with a polylactic acid (PLA) carrier containing 5% polyethylene glycol - harridan and
1% prostaglandin I-2 (PGI2) - analog (Iloprost). This has shown promising in-vitro
and pre-clinical results.
2. A cellulose polymer, which passively absorbed glycoprotein 2B / 3A receptor
antibody. TR2 stents immersed in a solution of anti-GP 2B / 3A antibody caused the
coating to swell and absorb the FAB fragment because of the concentration of protein and the
time of immersion. The active compound elutes from the stents in an experiential manner and in-vitro 48%
of the bound agent eluted at 12 days. In a rabbit iliac artery model, these cellulose - polymer coated
stents significantly reduce platelet aggregation in the stent microenvironment and reduced thrombus
formation, improved blood flow and arterial patency rates. Drug eluting stents have also inhibited
neointimal hyperplasia . Amongst the most intensely studied agents for local stent delivery,
to prevent restenosis, is paclitaxel. Paclitaxel is a potent antiproliferative agent that inhibits the
disassembly of microtubules and is used in anti-cancer therapy. The microtubules become dysfunctional
and cell replication is inhibited in the G0-G1 and G2 - M phases.  Because of its
properties paclitaxel can easily pass through cell membranes resulting in long lasting antiproliferative
action, and the efficacy of paclitaxel - loaded, coated stainless steel stents by reducing in-stent
restenosis has been shown in several animal models including the rat, rabbit and pig
In conclusion, drug eluting stents held promise to prevent thrombosis and inhibit neointimal
hyperplasia. Initial data was, encouraging and paclitaxel coated stents appear to be the frontrunners
with several clinical trials using them. Other coating agents, such as Sirolimus (rapamycin) showed
great promise. Sirolimus, a macrolite antibiotic helps inhibit cyclin induced transition from G0 to G1
cell cycle, thus aborting cell division / multiplication. The restenosis rate (RAVEL-Trial) was 0% at
six months, in 238 patients, vs. 26% in the "naked" stent controls. Other trials have substantiated
these results. The Sirolimus-eluting stent (SES) is approved in the United States and Europe, and coated
stents are the "hottest" stents in the market. Longer term results have not been quite so promising ,
with late thrombosis occurring in statistically significant numbers of patients. This has reopened the
controversies about stents, and seems to be leading to a "modest " resurgence in CABG surgery. !
A problem associated with stents was restenosis. This has been reduced by 70 to 90% with the use of
drug-eluting stents in comparison to the their bare-metal or naked stents . Stents increase the procedural success rates as well as increase of the safety of
procedures, by decreasing the need for emergency coronary bypass graft surgery . In some
centers, at least one stent is now placed in virtually all patients undergoing a PCI procedure.
I have not changed the above text significantly (from that presented 2 years
ago), to be able to highlight the changes that have occurred in the considerations for usage of coated
stents vs bare metal stents and the role of the old CABG( in todays world).
The last few months have seen an explosion of data about drug eluting stents.
From the great hope , they are now viewed with much more caution, and we strongly urge you to ask your
clinical staff to consider the indications and complications of these stents before using/deploying
them. The indications and the instructions for "best use", are changing and hopefully future results
will bear out their claims-"the last stent you will need"!
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