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the 69th Scientific Session
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Mikamo Lecture

PCI: From Mechanics to Gene Therapy.

Patrick Serruys

Thorax Centre
Rotterdam, The Netherlands

 

Historical milestones in percutaneous intervention include:

  • 1977: first successful angioplasty performed by Gruntzig
  • 1986: first human implants of coronary stents by Sigwart in Lausanne
  • 1994: Benestent I study results showed reduction in restenosis rate from 32% with balloon to 22% with stent and a reduction of any event at 7 months from 29.6% to 20.1%.
  • July 1999: the new era of drug-eluting stents (DES) began

The “first-in-man” results with the rapamycin-eluting stent reported by Serruys at the European Society of Cardiology meeting in September 2000 showed no restenosis or target vessel revascularization (TVR) at the 4-month follow-up in the 15 patients with a fast-release DES and in the 15 patients with a slow-release DES in Sao Paulo, Brazil and in the 15 patients with a slow release DES in Rotterdam. Serruys’ “rosy prophecy” reported at that time was that in ARTS II with drug-eluting stents, better results could be achieved than with bypass surgery in CABRI and ARTS. The 32% difference in favor of bypass surgery versus balloon angioplasty for freedom from death, MI, CABG, and re-PTCA at 1 year in the CABRI trial in 1994 was reduced to 14% in the ARTS trial in 1999 using multivessel stenting.

The RAVEL results reported in September 2001 comparing 120 patients with a sirolimus-eluting stent and the 118 patients with a bare metal stent (BMS) showed no late loss, no restenosis compared to 26% with the BMS, no TLR compared to 22% with BMS, and a 97% event-free survival compared to 72% with BMS. A comparison of the trials comparing DES and BMS (RAVEL, the SIRIUS trials, TAXUS trials) showed statistically significant reductions with DES for clinical outcomes.

Future directions in percutaneous intervention (PCI)

Drug-eluting stents in daily practice

DES is the default strategy for every patient undergoing PCI in daily practice at Serruys’ institution since April 2002, when sirolimus became commercially available in Rotterdam. Through March 2005, 3741 patents receiving more than 8000 DES through March 2005 have been included in either of two registries [RESEARCH (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital registry); TSEARCH (Taxus-Stent Evaluated at Rotterdam Cardiology Hospital registry)].

The registries showed that the cumulative incidence of clinically-driven TVR was reduced by 66% (from 13.9% pre-SES to 4.8% with SES). Some 33 publications in major medical journals that analyze the data from the registries have shown powerful treatment effects. Specifically:

  • Global population: TVR reduced 65%
  • Acute MI: TVR↓ 79% (zero stenosis)
  • Renal failure: TVR↓ 63%
  • Previous surgery: TVR↓ 77%
  • Chronic total occlusion: TVR↓ 80%
  • Very long lesion: TVR↓ 6.2%
  • Bifurcation: TVR↓ 8.6%
  • Undersized SES: TVR↓ 6.0%
  • In-stent restenosis: TVR↓ 5% (vs 5% with brachytherapy)
  • Mild stenosis: no target lesion revascularization (TLR)
  • Very small vessel: TLR 5.5% (RD 1.8mm)
  • Main stem: 8% restenosis
  • Multivessel stent: MACE 14% (11% surgery)

Multivessel stenting versus surgery

A meta-analysis of SOS, ERACI, and ARTS, which compared surgery to multivessel stenting, showed at 1-year a 11% lower cumulative event rate (24% stent, 13% surgery). Notably, with SES, there is a 14% cumulative event rate. In the ARTS II trial, 54% of patients had 3-vessel disease, with
 
The rosy prophecy made by Serruys in 2000 was shown to be true in March 2005, when he presented the results of the ARTS III trial at the late-breaking trials session of the American College of Cardiology meeting. In ARTS III, freedom from death, MI, CABG, and re-PCI was 89.2%, compared to 88.4% in ARTS I (bypass surgery trial) and 73.5% in ARTS II (PCI trial). In ARTS III, 54% of patients had 3-vessel disease, compared to 30% in ARTS I and 27% in ARTS II.

The SYNTAX study of 3-vessel and left main disease will include a “heart team” of a surgeon and interventionalist who will jointly determine whether a patient is amenable to both treatments before patients are randomized either to surgery or PCI with a Taxus-eluting stent to define the most appropriate treatment through a randomized trial. The goal is to randomize 1500 patients. Two registries will also be established, with the goal of profiling the larger pool of non-randomizable patients and their subsequent outcomes.

Beyond “conventional” DES

The Conor stent, is a depot stent with a large reservoir that has abluminal elution for the prevention of restenosis and also endoluminal elution for induction of angiogenesis in total occlusion, prevention of vulnerable plaque, and prevention of reperfusion injury in acute MI, and induction of vessel remodeling in diffuse small vessel disease. The Yukon stent is a customized stent with a porous surface which can coated with the drug of choice.

Endothelial progenitor cell coating is a novel approach, in which the stent has a CD34antibody layer to capture the circulating endothelial cells and then accelerate the endothelialization of the stent. This is the first demonstration of a successful technique for the endothelialization of an intravascular device by “autoseeding” with autologous endothelial cells.

The VEGF-2 gene eluting stent with naked plasmid DNA encoding for human VEGF-2 has a clear effect on the neointimal hyperplasia in animal studies. The C-Myc antisense-eluting PC stent uses antisense technology to inactivate the gene and thereby prevent proliferation. Some 10 different antisense compounds are being studied in clinical trials. In animal studies, a clear reduction in neointimal hyperplasia has been shown with the local delivery of AVI-4126 blocking expression of c-myc.

The nitric oxide (NO) eluting stent has highly pure NO-gas loaded directly into a polymer under high pressure, and then under contact with physiologic liquids the pure NO is released. Clinical work with the NO-eluting stent will begin soon.

Bioabsorbable stents are a fully resorbable DES, with steel-like scaffolding, uses standard balloon deployment, is inherently radiopaque, MRI compatible, and can be loaded with drug. Bioabsorbable metal stents made with magnesium is absorbed in 5 days, is MRI compatible, there is evidence for positive remodeling in animals, and in humans after 1 month there is no artifact. The bioabsorbable DES with paclitaxel at 3 months is not visible and neointimal hyperplasia is reduced.

New directions in PCI

The new target is the thin cap fibro-atheroma (TCFA) or vulnerable plaque, characterized by a large necrotic lipid core, thin fibrous cap, few smooth muscle cells (SMCs), dense macrophage infiltration, progressive matrix degeneration, angiographically non-significant with positive remodeling. Three other types of plaques are the prone to erosion, calcified nodule, and intra-plaque hemorrhage.

New diagnostic tools for these plaques include the multislice CT (MSCT) scan, which has been shown by Serruys and colleagues to have a sensitivity of 74% and specificity of 73% compared to IVUS. The 64 MSCT coronary angiography scan, with a resolution of 0.4 mm voxel and tube rotation of 330 ms, allows for assessment of the total plaque burden. Serruys believes the non-invasive imaging will have an increasing triage/dispatching function, between the flow limiting lesion for which patients are sent to surgery or PCI, and non-flow limiting, for which medical therapy is used. But the question remains about treatment for the asymptomatic non-flow limiting lesion, which is potentially vulnerable.

Although proteomics is revolutionizing the use of biomarkers, so far the clustering of numerous biomarkers do not seem to predict an acute event. While this research continues to move forward, the use of a certain biomarkers, such as an elevated CRP level, along with a suspicious lesion on MSCT and chest pain, can direct a patient to the catheterization lab. In the lab, the use of 4D IVUS with ECG-gated acquisition can reveal early plaque rapture, lesions that appear to be vulnerable. However, IVUS has a very low sensitivity and specificity, so is not the proper method to predict plaque rupture.

Analysis of the mechanical properties of the plaques has been suggested to be useful. Intravascular ultrasonic palpation is one method, in which palpation of the vessel wall attempts to identify plaque using backscattering of radiofrequency signal at two levels of blood pressure. Areas of low strain are hard, stiff and rigid, while areas of high strain are soft, deformable, fragile and breakable. The sensitivity and specificity of this approach are 88% and 89%, respectively, in the human coronary artery.

The Rotterdam Classification (ROC) characterizes the evolution of these plaques over time. Grade IV has a strain >1.2; Grade III strain of 0.9-1.2; Grade II 0.6-09; and Grade I 0.0-0.6. Palpography has been shown to have diagnostic value, and there is a relation between the grade of strain and CRP level.

Virtual histology

This is an attempt at tissue characterization based on the backscattering of radiofrequency signals from the vessel wall which is correlated to a human histology specimen. Through their in vitro experience, Serruys and colleagues have developed a definition of TCFA on virtual histology: focal lesion (adjacent to non-TCFA), lipid core ≥10%; in direct contact with the lumen, and the percent area of obstruction ≥40%. They have found that TCFA on virtual histology is ubiquitous in patients with stable angina and acute coronary syndromes.

Chronic Total Occlusion

This is the only field in interventional cardiology that has clearly demonstrated a reduction in mortality compared to surgery (93.5% with revascularization, 88% with surgery). However, the success rate in the only randomized trial to date (TOTAL trial) was 63.5%.

New approaches to chronic total occlusion (TCO) are being developed. Plaque “digestion with collegenases has been successful in an animal model. Controlled blunt micro dissection technique uses the elastic properties of the adventitia against the non-elastic properties of the fibrocalcific plaque to create fracture planes in the vessels. Acoustic energy technique delivers a low-power acoustic energy to create microfragment particles to less than 10 microns without harming healthy surrounding tissue. Another approach is lumen re-entry, which is a subintimal angioplasty technique used for long peripheral occlusions, diffuse disease, and in situations where transluminal technique has failed. The venture catheter is another approach, which has a tip that can be deflected from straight to 90 degrees, deflected mechanically by turning a knob on the proximal handle.

Magnetic navigation for TCO has been introduced at the Thorax Centre in Rotterdam, which is non-manual and has remote steering of the wire. Future techniques to be explored for TCO are either optical coherence tomography or optical coherence reflectometry.

For the occlusion of the left atrial appendage (LAA), the PLAATO procedure has been developed by Serruys and colleagues for placing an occlusion implant designed to fit the left LAA anatomy. A device that is a nitinol frame cage is used with a tissue-anchoring system, and non-thrombogenic ePTFE membrane. There is a registry of 150 patients in Europe. In the canine model this technique has resulted in a closed left appendage at 3 months.

Angiogenesis and myogenesis

Phase 2 and 3 trials of angiogenesis in coronary heart disease have shown some negative and positive results. Adenovirus-FGF in the AGENT 1 and 2 trials was positive. However, the AGENT-3 trial, the largest gene therapy trial, with a primary endpoint of change in exercise duration from baseline, was stopped prematurely in January 2004 because an interim data analysis indicated the study would not provide sufficient evidence of efficacy.

The only success story so far is E2F. By blocking the E2F transcription factor, E2F decoy treatment prevents the activation of the gene responsible for the proliferation of the SMCs that cause neointimal hyperplasia. The randomized, placebo-controlled PREVENT II trial with 202 patients (101 received the E2F decoy) undergoing bypass surgery for at least 2 grafts showed a 40% reduction in critical stenosis on angiography and a 40% reduction in mean neointimal volume on IVUS. The PREVENT III and IV trials are now underway.

Skeletal myoblasts have been successfully grafted, but the question is whether or not they are actually “alive and kicking”. The problem is the mechanical and electrical junctions between skeletal myotubes and cardiomyocytes. It has been successful in cell culture, but not always in the host. Some improvement in ejection fraction has been seen in the 5 trials completed so far, providing some hope for this approach. Monitoring with a pressure volume loop is ongoing in the patients who have undergone myogenesis at the Thorax Centre.

Serruys believes that skeletal myoblasts and other cell types engraftment and proliferation is possible, but he is uncertain of the best cell type, nor that it will meaningfully impact ventricular function to the degree that will result in clinically beneficial improvements in heart failure symptoms or mortality.

The key finding of resident cardiac stem cells research are the multilineage capability, which has a tremendous impact on future research. However, while work goes on to determine whether stem cells from the bone marrow or muscle are more appropriate for repairing the myocardium, a pressing question is whether or not resident cardiac stem cell manipulation possible.

From surgery to percutaneous valve replacement

The principle of percutaneous mitral valve annuloplasty is to take advantage of the proximity of the coronary sinus to the annulus to try to crimp and re-shape the annulus for easy access to the coronary sinus. Some of the questions for this approach include the ability to reduce the annulus if there is a calcified annulus and whether this will worsen the leaks at the commissure. There is the potential for pinching of the circumflex coronary artery, the risk of coronary sinus thrombosis/occlusion, and the risk of coronary sinus erosion/perforation over the long term. However, if this approach works, it would be simple and practical for many interventional cardiologists.

The percutaneous approach to mitral valve edge-to-edge repair with creation of a double orifice has been used successfully in 27 patients. Magnet-guided placement of implants from the left ventricle to the left atrium, through the posterior annulus, has been used for trans-ventricular placation of the posterior annulus.

 

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