Download In-stent restenosis: Molecular mechanisms and therapeutic

In-stent restenosis: Molecular mechanisms and therapeutic principles
Prof Vicente Andrés
Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Científicas
Prof Rainer Wessely
Ev. Klinikum Duisburg
Last updated on 15 January 2009
Introduction
Since its introduction in 1977 by Andreas Grüntzig, percutaneous transluminal coronary angioplasty
(PTCA) has become a popular procedure used to dilate atherosclerotic vessels to alleviate angina
pectoris, eventually preventing myocardial infarction, or to revascularize the infarcted myocardium. The
major limitation of the long-term success of PTCA is restenosis, a pathological process provoking recurrent
arterial narrowing at the site of the intervention. Restenotic lesions typically lack lipid deposits and grow
during 4-6 months post-PTCA, unlike native atheromas, which normally accumulate high content of lipids
and develop over longer time periods, typically years or decades.
Excessive restenosis leads to hemodynamically relevant vessel obstruction and eventually recurrence of
clinical symptoms thus forcing target-vessel revascularization. Restenosis after conventional PTCA, which
is mainly due to negative arterial remodelling, affects 25-50% of patients. Currently, more than 90% of the
percutaneous coronary interventions (PCI) are performed using metallic prostheses named stents, which
increase the safety of interventional revascularization and, by preventing negative arterial remodelling,
reduce the rates of restenosis to 15-30%. In-stent restenosis (ISR) is further reduced using drug-eluting
stents (DES, see below). It is noteworthy that ISR has a significant economic impact, with estimated
annual costs exceeding US$ 1 billion in the western world.
Molecular mechanisms of ISR
Neointimal hyperplasia is regarded as the main cause of ISR . This proliferative process can be
considered as the arterial wall's healing response to the acute mechanical injury provoked by stent
deployment (e.g., injury of the endothelial cell lining, denudation, disruption of the lamina elastica, etc).
The acute early phase of ISR is characterized by the activation of platelets and ensuing thrombosis
accompanied by the recruitment into the intimal area of blood-borne monocytes, neutrophils and
lymphocytes. These cells engage in the production of a plethora of mitogenic and chemotactic factors
which trigger a chronic inflammatory response leading to the activation of the smooth muscle cells (SMCs)
residing in the tunica media, which then undergo aberrant cell proliferation and migration toward the
growing neointimal lesion. Moreover, activated SMCs exhibt a less (un)differentiated, so called synthetic
phenotype featuring broader and flatter shape, expression of embryonic isoforms of contractile proteins,
and abundant synthesis of extracellular matrix (ECM) components, unlike medial SMCs in normal adult
arteries, which are fusiform and exhibit a differentiated, contractile phenotype characterized by the
expression of contractile proteins and reduced proliferative and migratory activity. Although it is becoming
increasingly evident that recruitment of bone marrow-derived and adventitial SMC progenitors and
adventitial myofibroblasts also contribute to the accumulation of neointimal SMCs, their relative
contribution to restenosis remains undefined. Putative regulators of neointimal hyperplasia include
thrombogenic factors (e.g., thrombin receptor, tissue factor), cell adhesion molecules (e.g., VCAM, ICAM,
LFA-1, Mac-1), transcription factors (e.g., NF-kB, E2F, p53, AP-1, c-myc, c-myb, YY1, Gax, IRF-1), signal
transduction molecules (e.g., MEK/ERK, PI 3-kinase/Akt), inflammatory cytokines (e.g., TNFa),
chemotactic factors (e.g., CCR2, MCP-1), growth factors (e.g., PDGF-BB, TGFb, FGF, IGF, EGF, VEGF),
cell cycle regulators (e.g., CDK2, CDC2, cyclin B1, PCNA, p21, p27, pRb), and metalloproteases (e.g.,
MMP-2, MMP-9). At later stages post-PCI characterized by the resolution of inflammation and wound
healing, neointimal SMCs return to a contractile phenotype characterized by low proliferative and migratory
activity and production of ECM components to more closely resemble the undamaged arterial wall.
Drug eluting stents
In spite of encouraging results in animal models, countless systemic therapeutic approaches against
restenosis have failed in clinical trials. However, after shifting the paradigm to local, stent-based therapy,
the introduction of DES at the beginning of this millennium has revolutionized interventional cardiology
owing to a robust decrease of restenosis of up to 80% compared to bare-metal stents (BMS). The
therapeutic principle is derived from the pathophysiological evidence that ISR can be viewed as a
proliferative disorder, mainly involving proliferation and migration of SMCs to form the pathoanatomical
correlate of restenosis, the neointimal lesion. Lipophilic drugs that target the eukaryotic cell cycle, such as
the G1-phase inhibitors sirolimus (also named rapamycin). Everolimus and Biolimus, or the S-phase
inhibitor paclitaxel (also named taxol), are locally delivered at high local dosages via the stent surface into
the adjacent vascular wall, thus attenuating cell proliferation and consequently ISR. To modulate release
kinetics of the drug, the vast majority of clinically available DES utilize a polymeric coating. Due to nonspecific anti-proliferative drug effects that also prevent endothelial proliferation, the healing process can be
considered prolonged subsequent to placement of a DES compared to a BMS. To prevent life-threatening
stent thrombosis, the healing phase has to be bridged by a longer-lasting dual antiplatelet therapy,
commonly with aspirin and an ADP-dependent platelet antagonist such as Clopidogrel.
The majority of therapeutic developments are based on the principle of local stent or device-based
therapy and focus on coatings with less interference or even improvements of the healing process while
maintaining anti-restenotic efficacy, or they concentrate on biodegradable stent platforms as drug carriers
that dissolve over time. Additional goals for further optimization comprise the development of tailored
DESs adjusted to the unique needs of special lesion or patient subsets such as diabetics or patients
suffering from an acute myocardial infarction.
Diagnostic of ISR
Coronary angiography is the diagnostic gold standard for ISR. Although much effort is being devoted for
the development of non-invasive diagnostic tools, including novel direct imaging techniques such as
coronary CT (computerized tomography), lower sensitivity and specificity is still limiting their use in the
clinical setting. Functional assessment of ischemic myocardium can be undertaken by stress cardiac MRI
(magnetic resonance imaging), Sestamibi-SPECT (single positron emitting computed tomography) or
stress echocardiography.
As indicated above, the prolonged healing phase that is apparent in DES possibly owing to incomplete reendothelialization has to be bridged by a longer-lasting dual antiplatelet therapy to avoid late-stent
thrombosis that is associated with a high mortality rate. Moreover, DES are 2-3 times more expensive that
BMS. Therefore, developing diagnostic kits to predict the risk of ISR would be a valuable tool for improved
stratification of patients to individually tailored treatment (e.g. prescribe BMS and DES to patients at lowmoderate and high risk of restenosis, respectively). Known predictors of ISR are limited to certain clinical
scenarios, such as diabetes mellitus or previous ISR, as well as the number of stents per lesion, stent
length, lesion length and complexity, residual diameter stenosis, and small vessel diameter (≤2.75mm).
Assuming that the risk of developing restenosis may have a genetic component, pilot genotype-phenotype
studies have been conducted in small cohorts which identified the association between the risk of
restenosis and single nucleotide polymorphisms (SNPs)/haplotypes in several genes considered involved
in the disease (e.g., TLR-2, ADRB2, CD14, CSF2, CCL11, p22-PHOX, PON1, FABP2, THBD). Validation
of these preliminary results in larger cohorts, together with high-throughput screening for additional SNPs the human genome contains millions of SNPs - may help identify useful markers for improved stratification
of patients to individually tailored treatment for ISR.