INTERNATIONAL LECTURE
Fourth Annual American College of Cardiology International Lecture
A Journey in the Interventional Field
Patrick W. Serruys, MD, PhD, FESC, FACC*
Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands.
Manuscript received August 16, 2005;
revised manuscript received December 15, 2005,
accepted December 21, 2005.
* Reprint requests and correspondence: Prof. Patrick W. Serruys, Thoraxcenter, Ba 583, Dr. Molewaterplein 40, 3015-GD Rotterdam, the Netherlands (Email: p.w.j.c.serruys{at}erasmusmc.nl).
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Abbreviations and Acronyms
| | CABG = coronary artery bypass graft | | CT = computed tomography | | CTO = chronic tomography occlusion | | EEM = external elastic membrane | | EPC = endothelial progenitor cell | | IVUS = intravascular ultrasound | | MACE = major adverse cardiac event | | MI = myocardial infarction | | MRI = magnetic resonance imaging | | OCT = optical coherence tomography | | PCI = percutaneous coronary intervention | | PTCA = percutaneous transluminal coronary angioplasty | | TCFA = thin-cap fibroatheroma |
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Historical milestones
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On September 16, 1977, the first successful angioplasty was performed by Andreas Gruentzig. Ten years later, the patient underwent recatheterization, which showed that the previously instrumented coronary artery was widely patent (1). The year 1986 marked the beginning of the stent era, with the first implantation of the self-expanding Wallstent by Ulrich Sigwart in Lausanne (2). In 1994, the results from Stent Restenosis Study (STRESS) investigators (3) and the Benestent Study Group (4) became available. The Belgium Netherlands Stent Arterial Revascularization Therapies Study (BENESTENT)-1 demonstrated that the implantation of metallic stents results in a reduction in the restenosis rate from 32% to 22%. Similarly, the occurrence of any adverse event at seven months was reduced from 29.6% to 20.1%.
July 1999 was a fresh new start for me. I had been invited to the headquarters of Cordis Corporation in Warren, New Jersey, where I was introduced to a rapamycin-eluting stent and asked how to begin a Phase II program for it. I was impressed by the molecular biology behind the principles: sirolimus (which is attached to the internal receptor, FKBP12), by acting on mTOR, influences the up-regulation and down-regulation of p27 and, therefore, blocks cell proliferation. The original plan of the first-in-human study was to conduct the trial in a country outside the U.S., with safety monitoring (i.e., subacute thrombosis, myocardial infarction, death) for 60 days, and to treat these patients for 60 days with ticlopidine and aspirin. After discussion, the final plan was made to perform quantitative coronary angiography and quantitative intravascular ultrasound (IVUS) motorized pullback in 15 patients in Rotterdam and 30 patients in Sao Paulo (5,6). It was a happy time, commuting between Amsterdam and Sao Paulo on KLM flight 797. One day we succeeded in performing 15 consecutive angiographic and IVUS follow-up studies, with a debriefing at the end of the day. At the end of that memorable day, a bottle of champagne was opened to celebrate the end of an iatrogenic disease: restenosis by intrastent neointimal hyperplasia. The holy grail of 25 years of fighting against restenosis was completed.
At the Andreas Gruentzig Lecture of the ESC Congress in September 2000, presenting these results, I begged the audience by telling them, "Don’t wake me up. Don’t pinch me. Let me keep dreaming," because at that time we had the angiographic control of the first 45 patients showing the absence of late loss, restenosis, and target vessel revascularization (7). At the same meeting in September 2000, I presented my vision of the future, the so-called rosy prophecy (Fig. 1). The Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI) trial, which was conducted in the early 1990s and compared balloon angioplasty and bypass surgery, showed a gap of 32% in clinical outcome between the two methods of revascularization. In 1999, the gap between the outcome of surgery and the outcome of the percutaneous treatment was reduced to 14% in the Arterial Revascularization Therapies Study (ARTS) trial (8). My rosy prophecy predicted that in the future the Kaplan-Meier estimate of freedom from major adverse events with eluting stents would be even greater that of surgery, which was, and still remains, quite a provocative statement.
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Figure 1 The rosy prophecy. ARTS = Arterial Revascularization Therapies Study; CABG = coronary artery bypass graft; CABRI = Coronary Angioplasty versus Bypass Revascularization Investigation; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty.
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In those days, The Wall Street Journal interviewed me. I said to the journalists that "we are not talking about some kind of reduction of restenosis. We are talking about the radical abolition of what we normally see. There is basically no tissue visible in the stent." In another very "scientific" publication, The New York Times, Dr. Spencer King, III, said that "he was encouraged by the early findings, but wished cardiologists would tone down the rhetoric a little. And that the pilot trials cry out for larger and more rigorously designed studies known as randomized double-blind placebo-controlled trials to provide definitive answers."
The Randomized Study with the Sirolimus-Coated Bx Velocity (RAVEL) trial, presented by Marie-Claude Morice at the European Society of Cardiology Congress of 2001, showed a zero late-loss, a zero restenosis rate, a target lesion revascularization percentage of zero, and an astonishing 97% event-free survival. In 2002, we published the report in the New England Journal of Medicine: this was the real beginning of the drug-eluting stent era (9). To date, many trials with sirolimus and paclitaxel have confirmed these first observations (10–15). In all these trials, a treatment effect of approximately 70% to 80% exists: the events at 6 and 12 months are less than the two digits for the drug-eluting stent. The question is, where are we going now? In this lecture, I will review the future of interventional cardiology.
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Drug-eluting stents
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Where are we heading to?.
Let’s start analyzing what can be expected beyond the published randomized trials on drug-eluting stents. The drug-eluting stent revolution has ushered into clinical practice. In Rotterdam, since April 2002, the implantation of drug-eluting stents has been the default strategy for all patients treated using percutaneous coronary intervention (PCI) in our daily practice, which means more than 3,700 patients and more than 8,000 eluting stents (14,15). In addition, we have shown that there is a 66% relative reduction in the need for clinically driven target vessel revascularization, from 13.9% to 4.8%, which is a major achievement, indeed! We have scrutinized the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry quite intensively, I would say, which has resulted in a large number of publications in well-known peer-reviewed journals. We have summarized our experience in a monograph entitled "From RESEARCH to Clinical Practice" (16). We documented a systematic treatment effect in reducing reintervention from 60% to 80% in the global population, which also holds true in specific subsets of patients, such as those with acute MI, renal failure, previous bypass surgery, chronic total occlusions, very long lesions, in those undergoing bifurcation stenting, or in those receiving undersized stents, to treat in-stent restenosis, mild stenosis, very small vessels, main-stem stenting, or multivessel stenting.
I would like to draw your attention to the main-stem subgroup with a restenosis rate of 8% (17) and the multivessel stented subgroup with a major adverse cardiac event (MACE) rate of 14%, which is not far away from the MACE rate of 11% observed in ARTS-I after surgery (8). We have published a meta-analysis of Stent or Surgery (SoS), Argentine Randomized Trial of Coronary Stents versus Bypass Surgery in Multivessel Disease (ERACI), and ARTS, which indicates that the cumulative incidence of death, nonfatal myocardial infarction (MI), stroke, and repeat revascularization (18) is 13% in the bypass group: I cannot resist the temptation to compare our current MACE rare in multivessel eluting stenting (i.e., 14%) with the cumulative event rate observed in the surgical arm of the meta-analysis (i.e., 13%).
Recently, we reported the results of ARTS-II as compared with the surgical and PCI arm of ARTS-I (19,20). Despite the fact that we had a majority of three-vessel disease and despite the fact that an average of 3.2 lesions were stented using 3.7 stents, with a total average stent length of 73 mm (compared with 48 mm in ARTS-I), freedom from death, stroke, MI, coronary artery bypass grafting, and re-percutaneous transluminal coronary angioplasty curve was 89.5%. Figure 1 shows the Kaplan-Meier curve of ARTS-II: it is well above the surgical arm of ARTS-I and the PCI arm of ARTS-I. Therefore, the rosy prophecy has come true.
The next logical step is to confirm these results in a randomized trial. We set up the SYNergy between Percutaneous Coronary Intervention with TAXus and Cardiac Surgery (SYNTAX) trial for this purpose (21). In this study, we are going to define the most appropriate treatment (coronary artery surgery vs. drug-eluting stents) through a randomized approach. Around this randomized arm, two registries will be nested, coronary artery bypass grafting (CABG) with 2,750 patients and a PCI registry, to profile a large pool of nonrandomized patients and their subsequent outcomes. Thus, we will address three-vessel diseased and left main diseased all-comers. Valentin Fuster is the chairman of the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial, which exclusively is enrolling patients with diabetes mellitus and two- or three-vessel disease. The structure of the FREEDOM trial is very similar to SYNTAX, with a randomized arm and registries including patients who can only be treated by bypass surgery or by PCI. Undoubtedly, these two trials will impact on the strategy of revascularization of our coronary artery disease patients in the future.
Beyond conventional drug-eluting stents.
The Conor is a stent with multiple laser-drilled holes in the struts, which serves as wells for drugs (22). They are filled with a fully resorbable polymer and can elute drugs in two directions: toward the lumen, but also in the direction of the vessel wall. Using paclitaxel, we have investigated six kinetic profiles (23). The two doses with long-lasting elution—10 or 30 µg over 30 days resulted in the best outcome. A prolonged elution, not necessarily of the highest dose, proved to be crucial to induce a drastic reduction of neointimal volume, late-loss, obstruction volume, and binary restenosis. But my interest in this stent is not so much the prevention of restenosis. For me, it is a conceptually new instrument in our interventional armamentarium because of the bidirectional elution; we can now elute drugs into the lumen of the vessel for specific purposes. Among the first targets that we would like to address is the treatment of acute MI: the industry has created a stent delivering insulin to the infracted region attempting at accelerating and improving myocardial recovery. Insulin increases the glycolytic metabolism and the generation of adenosine triphosphate in ischemic cells, decreases the transcellular flux of free-fatty acids, and stimulates growth factors, which may well translate in clinical benefits.
The Yukon stent is what we call a customized stent. The surface of a stent is usually very smooth, through electropolishing treatment. At variance with the conventional stent, the surface of the Yukon stent is very porous to absorb the drug in the superficial layers of the metal. Therefore, the operator can load the drug of his or her choice on the surface of this stent. Dr. Kastrati recently has reported the results obtained with increasing doses of rapamycin, from 0.5% to 2%; there is a decrease in late lumen loss and restenosis rate (24,25). It’s, thus, a kind of customized "homemade" eluting stent.
Endothelial progenitor cell (EPC) capture stent coating is another fascinating concept (26). The principle is to coat the surface of the stent with monoclonal antibodies against CD34. CD34, a well-known marker of staminality, is one of the antigens at the surface of the human progenitor cell. The idea behind this technology is to capture these EPCs to cover the luminal surface of the entire stent, accelerating the stent endothelialization. The EPCs, once captured by the monoclonal antibody on the surface of the stent, have a tendency to flatten, to converge, and to grow rapidly within hours. Figure 2A shows a bare stent explanted after one hour; on scanning electron microscopy they have maybe 50 cells, potentially EPCs, attached on the surface of the stent. On a stent coated with the monoclonal antibody against CD34 (Fig. 2B), there is great abundance of cells on the struts; therefore, it is not surprising to see that 48 hours later the struts, and also the surface between the struts, are entirely covered by these endothelial cells, with very few gaps. It is amazing to see that these cells are oriented in the direction of the flow already few hours after stent implantation.
Two human trials are currently in progress correlating the number of CD34, KDR-positive cells in the circulating blood with the reduction in intrastent neointimal volume at six months to document the antirestenosis effect of these CD34+ capture stents. This demonstration is the first of a successful technique for the endothelialization of an intravascular device by in vivo capture of autologous endothelial cells.
In recent animal work, some investigators have used a naked plasmid deoxyribonucleic acid-eluting stent encoding for human vascular endothelial growth factor-2 to promote re-endothelialization (27). A clear reduction of neointimal hyperplasia was demonstrated and undoubtedly the quality of the endothelium, analyzed by silver staining or scanning electron microscopy, was superior in the treated group when compared with placebo.
The c-myc antisense-eluting stent is another attempt at reducing the intrastent neointimal hyperplasia (28). Antisense is a complimentary sequence of deoxyribonucleic acid, of ribonucleic acid, created to block the sense of the genetic code (therefore, the name antisense) thereby preventing proliferation by blocking messenger ribonucleic acid. There are 10 different antisense compounds under investigation and, very recently, Dr. Kipshidze has reported quite encouraging results on stent eluting antisense, against, c-myc, in a porcine model.
Nitric oxide-eluting stent is another novelty. The stretch of an artery induces contraction and spasm; concomitantly there is some signaling message triggering smooth muscle cell migration; the endothelial cells are removed, thereby decreasing the natural healing process; platelet aggregation and smooth muscle cell proliferation occur (Fig. 3). Nitric oxide can theoretically block all these reactions. What is fascinating is that today we have a polymer (polyethyleneimine) on which we can load highly pure nitric oxide under high pressure and, upon contact with physiological liquid containing hydrogen, pure nitric oxide is released. In addition, nanoelectrospin technology was used to create very tiny microfilaments of this polymer that can be pulverized on the surface of the balloon or on the surface of a stent. This process creates a three-dimensional adhesion matrix containing nitric oxide that awaits release by interaction with hydrogen molecules.
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Figure 3 (A) Normal mechanism of vessel stress; (B) effect of a device eluting nitric oxide. SMC = smooth muscle cell.
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A new generation of bioabsorbable stents has emerged. Among them is a stent made of tyrosine-derived poly-DTE carbonate that has many interesting properties. It is completely reabsorbable; second, it has scaffolding properties comparable with steel; third, it can be deployed by a standard balloon and, finally, it is inherently radio-opaque but compatible with magnetic resonance imaging (MRI) and can be loaded with drugs. The deployment of this resorbable stent is not achieved by stretching the polymer during the deployment but by using a lock-out mechanism with sliding parts.
A bioabsorbable metal stent made from magnesium is potentially another phenomenal development (29). Basically, certain magnesium alloys placed in a 0.9% sodium chloride solution at 37°C, pH 7, will melt and progressively dissolve. Various dissolution kinetics are feasible and depending on the alloy, you can dissolve this stent in 60 days but you can also dissolve in fewer than 5 days, depending on the composition of magnesium with the other oligo-elements. It is an interesting concept because the stents are MRI compatible. It is seems that in animals it does not preclude positive remodeling. In pigs, the stents are barely visible at 30 days and the metal has disappeared with only some remnants of the stent. These stents have been implanted in human coronary arteries and in peripheral vessels.
As for bioabsorbable drug-eluting stents, one version of these stents has been published in the European Heart Journal (30). The stent is loaded with paclitaxel. Complete expansion of the stent is reached at 6-bar insufflation. The radial strength resists an outside pressure of 0.5 bar, without relevant diameter shrinkage. The histomorphometric analysis of this stent at three weeks shows remnants of the polymer, but at three months the presence of the polymer stent is no longer detected; the eluting paclitaxel stent shows a larger lumen with a reduction in neointimal area when compared with the noneluting version.
Thus, during the last 20 years, the technology has evolved from balloon to mechanical ablation, atherectomy, stenting, and radiation to the current technology, focused on drug-eluting stents, including absorbable stents, drug-coated absorbable stents, and gene modifiers (Fig. 4).
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Figure 4 Where we have come from and where we are going: the next innovative steps in vascular intervention.
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Vulnerable plaque
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The vulnerable plaque is potentially a new target for the interventional cardiologist. The classic vulnerable plaque is the so-called thin-cap fibroatheroma (TCFA), which stands for the thin-cap fibroatheroma, defined by a large necrotic lipid core beneath a thin fibrous cap. There exists other vulnerable plaques; the one that is prone to erosion without a necrotic lipid pool, that lacks a thin fibrous cap, and that is prone to inflammation; one that is characterized by disruptive calcified nodules in the fibrous cap; and the vulnerable plaque characterized by intraplaque hemorrhage likely because of leakage of vasa vasorum in the adventitia.
We are entering into a new diagnostic world (Fig. 5). In an individual with a single episode of chest pain and with high levels of biomarkers, it is tempting to look noninvasively at his/her coronary arteries with a multislice computed tomography (CT) scan and see whether this high-risk individual has a large plaque burden and is at risk in the near future. Figure 6A is a right coronary artery on angiography, with an equivalent angiographic view on a multislice CT scan (Fig. 6B). A small nucleus of calcium is identified; on a cross section of this vessel (Fig. 6C), we see clearly the lumen of the vessel, filled by contrast medium, and the calcium in the vessel wall (Fig. 6D). An IVUS was performed in this patient, which showed at the same site the echocardiographic shadowing due to calcium (Fig. 6E).
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Figure 6 (A) Angiographic image of an intermediate lesion in the proximal right coronary artery; (B) corresponding multislice computed tomographic image of the lesion (vertical view); (C) corresponding multislice computed tomographic image of the lesion (horizontal view); (D) enlarged view of the clacified plaque in panel C; and (E) corresponding intravascular ultrasonic image of the calcified plaque. AV = atrioventricular.
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During the last two years, we (31) and others have attempted to correlate the plaque characteristics observed on IVUS to with those detected by multislice CT; we have divided plaques in small, medium, and large and defined the respective Hounsfield units of these plaques and we have investigated the sensitivity and specificity of the relationship between the multislice CT-defined plaque and the IVUS-confirmed plaque, defined as an external elastic membrane (EEM) obstruction greater than 50% or the presence of calcium. Today, the sensitivity and specificity are 74% and 73%, respectively. The number of plaques you can find in a single individual is impressive: plaque growth is a ubiquitous phenomenon, with some clustering in the proximal segments of the major epicardial vessels (Fig. 7).
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Figure 7 Multislice computed tomography (MSCT) plaque burden: an ubiquitous phenomenon. Results: distribution of any plaque-% (large plaque-%). LCA = left coronary artery; RCA = right coronary artery.
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The question for the cardiologist is not whether, but when will noninvasive imaging definitively serve in a triage function? In a symptomatic, flow-limiting lesion, at what level of diagnostic precision (64, 128 slices) will we decide to send directly the patient either to surgery or PCI, based on this diagnostic information? The problem is really what we are going to do with the non–flow-limiting lesion. What do we do with the asymptomatic non–flow-limiting potentially vulnerable plaque that is detected accidentally on a multislice CT scan?
Another outstanding issue we have to give an answer to is what can we expect from biomarkers? Biomarkers, such as C-reactive protein, interleukin-6, B-type natriuretic peptide, and Lp-PLA2, are in our experience quite useful, to differentiate a patient who had just an acute MI or who are unstable, from those who are stable. Discrimination based on a biomarker is possible. However, recently in a small cohort of 85 patients, we performed a proteomic analysis of plasma, in which we determined up to 78 analytes. It appears that the clustering of these numerous biomarkers does not seem to predict the imminence of an acute event. Using hierarchical clustering statistics, we tried to find a cluster of biomarkers, potentially indicative of unstable angina, pre-MI, or stable angina, but even assisted by this sophisticated approach, we failed to identify relevant prognostic markers.
Now, let us assume that we have an individual with a single episode of chest pain with abnormal levels of biomarkers (including troponins) and non–flow-limiting plaque who is brought to the catheter laboratory for invasive assessment. With that scenario, further assessment of this non–flow-limiting lesion may become even more complicated because you may use a battery of tests to further characterize this non-flow limiting lesion. We know that the four-dimensional IVUS (three-dimensional image dynamically analyzed in time) acquired with electrocardiographic gating is very appealing and suggestive of early stage of plaque rupture. However, we must realize that the sensitivity and the specificity of the grayscale IVUS in predicting plaque rupture are still totally unknown today.
Palpography.
Intravascular ultrasound palpography is a technique that has been developed by our bioengineering group in Rotterdam. It is basically an analysis of backscattering of radiofrequency at two levels of blood pressure using the stress of the blood pressure on the vessel wall to evaluate the mechanical properties of the vessel, as if we could "palpate" the lumen from inside. On the color-coded scale of strain, purple indicates a low-strain region which is hard, stiff, and rigid, whereas yellow indicates a region of high strain that is soft, deformable, and therefore potentially fragile and breakable.
We have demonstrated using ex vivo human coronary arteries that the sensitivity and specificity of the palpogram is high and that a region of high strain with a deformation of more than 2% corresponds quite accurately to an accumulation of macrophage and to a defect in smooth muscle cell or collagen (32). Therefore, we are quite confident that this technique in the near future will help us detecting "high-strain spots." From a practical standpoint, the information is obtained though a conventional IVUS pullback. We were impressed recently with how many of these high-strain regions are identifiable in a single patients throughout the coronary arteries. We have observed important dynamic changes in palpography over a period of six months, particularly in patients with ST-segment elevation myocardial infarction, who were statin naive at the start of the clinical observation. We have created a classification called the ROtterdam Classification (ROC), dividing the strain in four subclasses of which the worst is ROC IV with a deformation >1.2% (33).
We have recently reported the following observations: first, that the number of high-strain spots rises in parallel with the level of C-reactive protein (33); second, that the density of these high-strain spots is greater at presentation in ST-segment elevation myocardial infarction than in unstable, or stable patients; and third, that an aggressive treatment using statins, angiotensin-converting enzyme inhibitors, clopidogrel, and aspirin can reduce, over a period of six months, the intensity and frequency of these high-strain spots (Fig. 8).
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Figure 8 Diagnostic value of palpography. CRP = C-reactive protein; ROC = receiver-operating characteristic.
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Virtual histology.
Virtual histology is an attempt to characterize tissue composition based also on the backscatter of radiofrequency signals (34). A correlation between these radiofrequency signals and histological structures of fresh coronary arteries was statistically established. Virtual histology converts grayscale IVUS images into a color-coded histological cross section using the following virtual histology legend: green, fibrous tissue; yellow, fibrofatty; white, calcium; and red, lipid core. Renu Virmani, interested by the concept of virtual histology, has tried to create a common language between the virtual histology and the true histology. Figure 9 illustrates her attempt to correlate virtual histology. According to her suggestion, a TCFA could be identified in virtual histology as a focal spot with a lipid core of more than 10%, which is in direct contact with the lumen (implying the absence of a thick fibrous cap of more than 200 to 400 µm, the actual resolution of the ultrasound technique) and associated with a percent area obstruction of the EEM of more than 40% (35). Using this IVUS-derived definition of TCFA, we have recently established the frequency of TCFA per centimeter of arteries in patients with stable or unstable syndromes, in whom we found it more frequently. Optical coherence tomography (OCT) is the next diagnostic modality potentially useful in the detection of TCFA. The imaging of this technique is based on the use of the backscatter of light by tissue. This imaging technology has excellent resolution between 1 and 15 µ. Figure 10 shows the normal appearance of a vessel with an intima of 70 µ and a media of 130 µ, as well as the interface with the adventitia.
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Figure 9 Virtual histology or ... how to convert an ex vivo (pressurized) intravascular ultrasound image into a color-coded histological cross section. (A) Intravascular ultrasound cross section; (B) in vivo virtual histology color-coded of same cross section; (C) ex vivo histology of same cross section; (D) color pencil sketch of ex vivo histology cross section.
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Excellent correlations between the thickness of the thin caps on histological specimens and measurement by OCT have been published. Today we can identify in vivo a TCFA lesion (Fig. 11). The region with the thin fibrous cap can be easily visualized; the tiny vessel that is joining the central lumen at the edge of this fibrous cap may be interconnected with the network of the vasa vasorum in the adventitia (Figs. 11B and 11C).
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Figure 11 (A) Optical coherence tomography showing thin cap fibrous atheroma and (B and C) intramuscular capillary.
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We are currently working on an attempt to combine the imaging of the cap with the assessment of its mechanical properties. To achieve that goal, we use a very compliant balloon inflated at a low pressure of 200 mm Hg, which is still physiological. Through the transparent polymer of the balloon, the fibrous cap can be imaged whereas the elastogram helps us to assess the mechanical properties of the plaque.
Intravascular MRI.
The last tool for the detection of vulnerable plaques is the intravascular MRI. In a fibrotic structure, molecules of water are free to move and do not affect substantially the decay of the magnetic resonance signal (blue signal) whereas in the mainly lipidic structures, the free motion of the water is considerably impeded, thereby slowing down the decay of the magnetic resonance signal (yellow signal). Therefore, this technique potentially can differentiate a fibrous cap from a rich lipid core. Currently, 122 patients have been investigated in a multicenter study in Europe.
Nonetheless, the major question is: What is the prognostic value of all these diagnostic tools? Undoubtedly, their prognostic value has to be established in longitudinal studies. However, as predicted by Peter Libby a few years ago, "If we could identify potentially unstable atheroma before they are evident, clinically we might even contemplate angioplasty on non-significant stenosis to induce smooth muscle cell proliferation and reinforce the plaque fibrous cap" (36). At the present stage, we have not yet a scheme of triaging vulnerable plaques. Asymptomatic high-risk patients (by Framingham score) should be treated for primary prevention with systemic therapy (Fig. 12); however, if as the result of noninvasive imaging they are invasively investigated, and we search for criteria of vulnerability in non–flow-limiting lesions proximal and focal with an EEM obstruction >50%, positive remodeling, and large lipid core in direct contact with the lumen on virtual histology at the site of a high strain spot on palpography, the clinical temptation might be to treat these lesions with drug-eluting stents.
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Figure 12 Vulnerable plaque triage. CRP = C-reactive protein; DES = drug-eluting stents; EEM = external elastic membrane.
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The last coronary frontier: Chronic Total Occlusion (CTO)
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Opening a CTO may confer to patients a significant five-year survival advantage compared with those in whom the recanalization procedure failed. However, the success rate of recanalization of CTOs is still low. Many new technologies are emerging but, so far, the only trial having randomized conventional guide wires with a new technology such as the laser wire is the Total Occlusion with Angioplasty by using Laser guidewire (TOTAL), which showed an overall success rate in both arms of 63.9%, which is quite sobering (37).
Therefore, what are the novelties in the field? The first is plaque digestion with collagenase (38). In an animal model treated with collagenase, extensive plaque digestion occurs. The external elastic membrane remains intact whereas the fibrotic occlusion within the vessel is partially digested. There are other new devices, such as the Frontrunner, which is a device using the principle of controlled blunt microdissection to recanalize CTOs (39). Taking advantage of the elastic properties of the adventitia versus the relative stiffness of the fibrocalcific plaque to create fracture planes, the device has been used in clinical practice with some success. Other devices use acoustic energy, which is designed to create microparticle fragments of <10 µ without harming the surrounding healthy tissue. The "Crosser" device uses piezoelectric crystals to convert alternative current into a high-frequency mechanical vibration at a frequency of 21 kHz, which is propagated to the tip of the catheter. This type of energy is not harmful to soft tissue but can easily penetrate and cross a long piece of chalk in 3 to 5 min. It is compatible with a 6-F guide and a standard 0.014-inch wire.
Another technique that is gaining ground is the so-called subintimal angioplasty. This is a technique used in a situation in which conventional transluminal techniques already have failed and have induced a subintimal dissection (40). When subintimal, the operator introduces an IVUS catheter in which a small needle is incorporated that, under ultrasonic imaging control, can be pointed toward the lumen of the vessel in the dissection space created between the lumen and the adventitia. Then, the operator advances this small needle, which is hollow, and pushes the needle through a conventional wire, "wiring" the lesion outside the plaque and stenting the vessel. This approach works well in the peripheral vessels and also has been applied to the coronary artery as an investigational technique. The next simple device consists of a catheter that can accommodate a 0.014-inch wire (the Venture catheter; Veloicmed, Inc., Maple Grove, Minnesota). The tip of the catheter can be deflected from straight up to 90 degrees by turning the knob on a proximal handle.
Personally, I believe specific strategy is needed for CTOs using the following concepts: first, a nonmanual remote steering of the wire, maybe through the use of magnetic navigation; second: a technology to look forward, either through the use of an optical coherence tomographic system, an optical low-coherence reflectometry system, or an IVUS system; finally, some ablative power is needed at the tip of the wire to be able to recanalize these CTOs. At our institution in Rotterdam, we have installed a magnetic stereotactic system that we have been experimenting for more than one year. We are still exploring ways to use the magnet to steer a guide wire in total chronic occlusions. However, in a 3-mm diameter vessel, exquisite control of the tip of your guide wire can be achieved without guidance or ablative power with the current state of the hardware.
The next step is to design a forward imaging technique. For example, we have designed an OCT wire that can look 60° forward, so that the operator can see forward directly and accurately the interface between the media and the adventitia. The concept is to have the target of the CTO continuously in front of you (the cross section of the occluded vessel) as a circle (the interface between the media and the adventitia) (Fig. 13). The goal is to remain at the center of the target with your guide wire. In this scenario, you have guidance but not navigation capabilities or ablating power. Finally, we have currently at our disposal radiofrequency ablation techniques to ablate tissue. Therefore, the final dream on which we are working on is a combination of a looking-forward technique mounted on an ablating wire that can be steered by an external magnetic field.
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Figure 13 Phantom made of cryogel mimicking a total occlusion of which the cross section is seen by a forward-looking (60°) optical coherence imaging wire (0.014 inch). OCT = optical coherence tomography.
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Angiogenesis and myogenesis
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Table 1 (41) summarizes the studies that have been published with some negative but also positive outcomes using either recombinant protein or an adenovirus, plasma liposome like in Angiogenic Gene Therapy (AGENT) (42) and AGENT-2 (43). What is disappointing is that the last major clinical attempt to achieve some treatment effect with angiogenesis was the AGENT-3 trial. This trial was the largest gene therapy trial so far; however in January of last year, enrollment was stopped because the interim data analysis indicated that the study would provide insufficient evidence of efficacy. Mann et al. (44) are still working on a genetic decoy approach specifically for the pretreatment of bypass grafts before implantation; the preliminary results are encouraging.
A few words about cell transplantation (Tables 2 and 3).
The demonstration has been made that transplanted myoblasts or myotubes may stay "alive and kicking" in the myocardium (45). The question that remains is whether the mechanical and electrical junction between the skeletal myotube and the cardiomyocyte is effective and operational. Of course, in situations in which skeletal myoblasts are cocultured with myocytes, the electromechanical coupling works because there is an up-regulation of the cadherin and connexin-43. However, in hosts, we do not have any proof that this up-regulation takes place in vivo (46). Nevertheless, there are few published studies in major peer-review journals (47–51) suggesting that myoblast transplantation, which is associated with bypass surgery, results in some modest increase in ejection fraction (47,50,51). However, these studies were monocenter investigations, not randomized and without core laboratory assessment. In our patients treated with intramyocardial injections of myoblasts, change in left ventricular function, assessed by pressure volume loop analysis during volume unloading performed at 6 and 12 months showed some encouraging results (52). We see, for instance, that the preload recruitable stroke work increases over time after treatment and that the end-systolic volume, normalized for a blood pressure of 120 mm Hg, is significantly decreased; together, some increase in ejection fraction and in dP/dT is noted; however, the end-systolic elasticity and the end-diastolic stiffness are not affected.
At the time of the publication, we were very puzzled by the findings of the group from Houston on the transdifferentiation of human peripheral blood into cardiomyocytes, endothelial cells, and smooth muscle cells (53). Basically, in their experiment, they showed hat human peripheral cells injected in immunotolerant mice with subacute MI were apparently incorporated into the vessel wall and into the myocardium. Shortly after this publication, Murry et al. (54) reported in Nature that they could not confirm this transdifferentiation into cardiomyocytes. They concluded that their results indicate that hematopoietic stem cells do not readily acquire a cardiac phenotype and raised a cautionary note for clinical studies on infarct repair. Other authors also have shown that wild-type bone marrow-derived stem cells are indeed readily incorporated into cardiac muscle but that these cells fail to express sarcoglycan and thus are unable to repair the tissue, suggesting that this stem cell population has limited potential for cardiac cell or cardiac muscle regeneration (55).
Table 3 summarizes the results of studies on acute MI (56–65). Most of these studies show some positive treatment effects (increase in left ventricular ejection fraction, segmental wall motion, or myocardial perfusion or decrease in infarct size or prevention of myocardial remodelling, and so on) except for Autologous Stem Cell Transplantation in Acute Myocardial Infarction (ASTAMI) (63) and Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL-2) trials (65); in one study, we even observed a deterioration in an infarct-related artery following the cell transplantation (occurrence of in-stent reocclusion, in-stent restenosis, and significant de novo lesion) (60). In other words, may types of cells seem to work. However, when you examine the result of the first randomized trial, BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) (59), it is amazing to see that some difference in ejection fractions between the two groups was achieved, although there was no change in end-diastolic volume, end-systolic volume, left ventricular mass, or late contrast enhancements on MRI. Furthermore, the difference in ejection fraction was no longer significant at 18 months.
Therefore, my personal view on cell therapy (sharing the views of Daniel Burkhoff) is that, with skeletal myoblasts and other cell types, engraftment and proliferation are possible. However, the techniques to achieve this result consistently and on a large-scale basis have not been established. We are not certain of the best cell type. There is no convincing evidence to conclude that one cell type is better than another. There is no evidence that any particular cell type, including stem cells, is differentiating to an actual cardiomyocyte, and there is no evidence that cell survival or transdifferentiation is required to realize benefits on function. Therefore, we are certain that cell therapy will meaningfully impact ventricular function to a degree that will yield clinically beneficial results on heart failure symptoms or mortality. Therefore, what we need to avoid is what we have seen before, and I think what we need is careful basic science, realistic expectations, and cohesion in clinical studies.
One thing I would like to emphasize is that I have been impressed by the report of Beltramie et al. (66) in Cell. Figure 14, which has been reproduced from their publication, shows in the myocardium, of 13 cells, 5 are c-Kit+ cells (long arrow); c-Kit+ is an antigen of staminality. Its expression is a proof of staminal potential of these cells. In other words, these cells are still uncommitted. There are eight cells expressing MEF2C (short arrow), which is a transcription factor expressed early in the myocyte lineage. These cells are thus committed early to myocyte lineage. And, finally, there is one cell (asterisk), which already contains alpha-sarcomeric actin. This cell is engaged in a more advanced stage of myocyte lineage. Therefore, the question is, has the myocardium its own resident stem cell? If the key finding of resident cardiac stem cells, showing multilineage capability, is confirmed, it will have a tremendous impact on our future research. Although we are still looking at whether stem cells from bone marrow or muscle are the most appropriate to repair the myocardium, a new pressing question arose: Is resident cardiac stem cell manipulation possible? Can we recolonize scar tissue or its surrounding with these resident cardiac stem cells?
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Figure 14 Has the myocardium its own stem cells? Arrows = C-Kit+ cells. C-Kit is an antigen of staminality. Its expression is a proof of staminal potential of these cells. These cells are still uncommitted. Arrowheads = cells expressing MEF2C. MEF2C is a transcription factor expressed early in the myocyte lineage. These cells are committed early to myocyte lineage. *Alpha-sarcomeric actin. This cell is engaged in a more advanced stage of myocyte lineage. Reprinted, with permission, from Beltrami et al. (66).
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Percutaneous valve repair and replacement
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The last dream (Table 4)! There are two fields of investigation, the mitral valve repair and the aortic valve replacement. The mitral annuloplasty approach is an attempt to crimp and reshape the mitral annulus through the coronary sinus, taking advantage of the proximity of the coronary sinus with the annulus. An example from Viacor consists of a permanent implant of a device in the coronary sinus, which pushes forward the midportion of the posterior leaflet and exerts an outward counterforce on the coronary sinus near the commissure: the result is a reshaping of the annulus. The first-in-human was performed by Stephen Ellis in Cleveland. There are other quite efficient technologies. The issue with the coronary sinus approach is that the ability to reduce the annulus can be limited by the calcification of the mitral annulus, which can potentially worsen the leak at the commissure. In addition, these devices can create potential pinching of the circumflex artery. Additionally, there are risks of thrombosis, occlusion, or erosion. But, nevertheless, it is worth exploring these techniques.
The edge-to-edge repair of Alfieri, a surgical procedure, has now been converted into a percutaneous approach by a company called E-valve. The concept consists of a clip, which is attached to the two extremities of the mitral valve. Clipping of the two extremities of the mitral valve results in a considerable reduction of the mitral insufficiency. The Efficacy of Vasopressin Antagonism in Heart FailurE: Outcome Study With Tolvaptan (EVEREST) trial has included 27 such patients.
Donald Baim and his team are currently testing a more complex technique, with a transvascular and transventricular approach of the posterior annulus using a complex magnetic guide placement of an implant from the left ventricle. Initially, a magnetic catheter is advanced in the coronary sinus and another magnetic catheter is advanced behind the posterior mitral valve to facilitate the attachment of a first anchoring implant to which a wire is attached. On this wire, a multilumen catheter is slid over. On both sides of the mitral valve, two more anchoring sutures are attached. Finally, the operator puts the sutures under tension, thereby clinching the annulus.
One of the most recent developments in the field is the percutaneous aortic valve replacement pioneered by Cribier et al. (67). There is an antegrade approach through the vena cava, crossing the interatrial septum, the mitral valve, and making a loop and then crossing the aortic valve with the stented valve from the left ventricle. Rapid pacing (220 beats/min) is used to reduce the flow across the valve during the balloon deployment of the stented valve. The results are quite encouraging, with a complete disappearance of the aortic gradient. The results of REVIVE show an increase of the aortic valve area from 0.6 cm2 to 1.7 cm2, an improvement in ejection fraction, an improvement in functional class, and the disappearance of the gradient.
There is another interesting technology (CoreValve) that uses a nitinol self-expanding stent containing a tricuspid valve introduced retrogradely across the aortic valve. Finally, Khambadkone et al. (68) carefully have succeeded with their pulmonary valve replacement; to date, more than 100 patients have been treated, with no mortality and a 98% success rate. The average duration of the implant is 12.3 months.
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Conclusions
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More than ever, the field of interventional cardiology is moving forward. Now, all these novelties described in this lecture, are they realistic or unrealistic? I will have a very short answer to this question. I will tell you what I keep saying to the fellows in the department: If the future is unrealistic, it will remain the future; if the future is realistic, it will soon become the past.
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References
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- Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosispercutaneous transluminal coronary angioplasty. N Engl J Med 1979;301:61-68.[Abstract]
- Sigwart U, Puel J, Mirkovitch V, Joffre F, Kappenberger L. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty N Engl J Med 1987;316:701-706.[Abstract]
- Fischman DL, Leon MB, Baim DS, et al. Stent Restenosis Study Investigators A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease N Engl J Med 1994;331:496-501.[Abstract/Free Full Text]
- Serruys PW, de Jaegere P, Kiemeneij F, et al. Benestent Study Group A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease N Engl J Med 1994;331:489-495.[Abstract/Free Full Text]
- Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteriesa quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001;103:192-195.[Abstract/Free Full Text]
- Rensing BJ, Vos J, Smits PC, et al. Coronary restenosis elimination with a sirolimus eluting stentfirst European human experience with 6-month angiographic and intravascular ultrasonic follow-up. Eur Heart J 2001;22:2125-2130.[Abstract/Free Full Text]
- Serruys PW. ARTS I— the rapamycin eluting stent; ARTS II— the rosy prophecy Eur Heart J 2002;23:757-759.[Free Full Text]
- Serruys PW, Unger F, Sousa JE, et al. Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease N Engl J Med 2001;344:1117-1124.[Abstract/Free Full Text]
- Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization N Engl J Med 2002;346:1773-1780.[Abstract/Free Full Text]
- Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery N Engl J Med 2003;349:1315-1323.[Abstract/Free Full Text]
- Grube E, Silber S, Hauptmann KE, et al. TAXUS Isix- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107:38-42.[Abstract/Free Full Text]
- Colombo A, Drzewiecki J, Banning A, et al. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions Circulation 2003;108:788-794.[Abstract/Free Full Text]
- Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004;350:221-231.[Abstract/Free Full Text]
- Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the "real world"the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. Circulation 2004;109:190-195.[Abstract/Free Full Text]
- Ong AT, Serruys PW, Aoki J, et al. The unrestricted use of paclitaxel versus sirolimus-eluting stents for coronary artery disease in an unselected population—one year results of The Taxus-Stent Evaluated At Rotterdam Cardiology Hospital (T-SEARCH) Registry J Am Coll Cardiol 2005;45:1135-1141.[Abstract/Free Full Text]
- Serruys PW, Lemos P. From RESEARCH to Clinical Practice. 1st edition.. London: Taylor and Francis Group; 2004.
- Arampatzis CA, Lemos PA, Hoye A, et al. Elective sirolimus-eluting stent implantation for left main coronary artery diseasesix-month angiographic follow-up and 1-year clinical outcome. Catheter Cardiovasc Interv 2004;62:292-296discussion 297.[CrossRef][ISI][Medline]
- Mercado N, Wijns W, Serruys P, et al. One-year outcomes of coronary artery bypass graft surgery versus percutaneous coronary intervention with multiple stenting for multisystem diseasea meta-analysis of individual patient data from randomized clinical trials. J Thorac Cardiovasc Surg 2005;130:512-519.[Abstract/Free Full Text]
- Serruys PW. A.R.T.S. II. Arterial Revascularization Therapies Study, part II, of the sirolimus-eluting stent in the treatment of patients with multivessel de novo coronary artery lesions 2005Paper presented at: 54th Annual Scientific Session of the American College of Cardiology; Orlando, FL.
- Serruys PW, Ong AT, Morice MC, et al. Arterial revascularisation therapies study part II—sirolimus-eluting stents for the treatment of patients with multivessel de novo coronary artery lesions EuroIntervention 2005;1:147-156.
- Ong AT, Serruys PW, Mohr FW, et al. The SYNergy between Percutaneous Coronary Intervention with TAXusTM and Cardiac Surgery (SYNTAX) studydesign, rationale and run-in phase. Am Heart J 2006In Press.
- Finkelstein A, McClean D, Kar S, et al. Local drug delivery via a coronary stent with programmable release pharmacokinetics Circulation 2003;107:777-784.[Abstract/Free Full Text]
- Serruys PW, Sianos G, Abizaid A, et al. The effect of variable dose and release kinetics on neointimal hyperplasia using a novel paclitaxel-eluting stent platformthe Paclitaxel In-Stent Controlled Elution Study (PISCES). J Am Coll Cardiol 2005;46:253-260.[Abstract/Free Full Text]
- Hausleiter J, Kastrati A, Wessely R, et al. Dose-finding study with a novel drug eluting stent system with the use of an on-site, polymer-free coating with rapamycin J Am Coll Cardiol 2005;45:44A.
- Hausleiter J, Kastrati A, Wessely R, et al. Prevention of restenosis by a novel drug-eluting stent system with a dose-adjustable, polymer-free, on-site stent coating Eur Heart J 2005;26:1475-1481.[Abstract/Free Full Text]
- Aoki J, Serruys PW, van Beusekom HM, et al. The HEALING-FIM (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth-First In Man) Registry Endothelial progenitor cell capture by stents coated with antibody against CD34 J Am Coll Cardiol 2005;45:1574-1579.[Abstract/Free Full Text]
- Walter DH, Cejna M, Diaz-Sandoval L, et al. Local gene transfer of phVEGF-2 plasmid by gene-eluting stentsan alternative strategy for inhibition of restenosis. Circulation 2004;110:36-45.[Abstract/Free Full Text]
- Kipshidze NN, Iversen P, Kim HS, et al. Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model Catheter Cardiovasc Interv 2004;61:518-527.[Medline]
- Di Mario C, Griffiths H, Goktekin O, et al. Drug-eluting bioabsorbable magnesium stent J Interv Cardiol 2004;17:391-395.[CrossRef][Medline]
- Vogt F, Stein A, Rettemeier G, et al. Long-term assessment of a novel biodegradable paclitaxel-eluting coronary polylactide stent Eur Heart J 2004;25:1330-1340.[Abstract/Free Full Text]
- Van Mieghem CA, McFadden EP, de Feyter PJ, et al. Non-invasive detection of subclinical coronary atherosclerosis coupled with assessment of changes in plaque characteristics using novel invasive imaging modalitiesthe Integrated Biomarker and Imaging Studay (IBIS). J Am Coll Cardiol 2006;47:1134-1142.[Abstract/Free Full Text]
- Schaar JA, De Korte CL, Mastik F, et al. Characterizing vulnerable plaque features with intravascular elastography Circulation 2003;108:2636-2641.[Abstract/Free Full Text]
- Schaar JA, Regar E, Mastik F, et al. Incidence of high-strain patterns in human coronary arteriesassessment with three-dimensional intravascular palpography and correlation with clinical presentation. Circulation 2004;109:2716-2719.[Abstract/Free Full Text]
- Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary plaque classification with intravascular ultrasound radiofrequency data analysis Circulation 2002;106:2200-2206.[Abstract/Free Full Text]
- Rodriguez-Granillo GA, Garcia-Garcia HM, McFadden EP, et al. In vivo intravascular ultrasound-derived thin-cap fibroatheroma detection using ultrasound radiofrequency data analysis J Am Coll Cardiol 2005;46:2038-2042.
- Lafont A, Libby P. The smooth muscle cellsinner or saint in restenosis and the acute coronary syndromes?. J Am Coll Cardiol 1998;32:283-285.[Free Full Text]
- Serruys PW, Hamburger JN, Koolen JJ, et al. Total occlusion trial with angioplasty by using laser guidewire. The TOTAL trial Eur Heart J 2000;21:1797-1805.[Abstract/Free Full Text]
- Strauss BH, Goldman L, Qiang B, et al. Collagenase plaque digestion for facilitating guide wire crossing in chronic total occlusions Circulation 2003;108:1259-1262.[Abstract/Free Full Text]
- Yang YM, Mehran R, Dangas G, et al. Successful use of the frontrunner catheter in the treatment of in-stent coronary chronic total occlusions Catheter Cardiovasc Interv 2004;63:462-468.[Medline]
- Colombo A, Mikhail GW, Michev I, et al. Treating chronic total occlusions using subintimal tracking and reentrythe STAR Technique. Catheter Cardiovasc Interv 2005;64:407-411.[Medline]
- Ylä-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth Nat Med 2003;9:694-701.[CrossRef][ISI][Medline]
- Grines CL, Watkins MW, Helmer G, et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris Circulation 2002;105:1291-1297.[Abstract/Free Full Text]
- Grines CL, Watkins MW, Mahmarian JJ, et al. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina J Am Coll Cardiol 2003;42:1339-1347.[Abstract/Free Full Text]
- Mann MJ, Whittemore AD, Donaldson MC, et al. Ex-vivo gene therapy of human vascular bypass grafts with E2F decoythe PREVENT single-centre, randomised, controlled trial. Lancet 1999;354:1493-1498.[CrossRef][ISI][Medline]
- Hagege AA, Carrion C, Menasche P, et al. Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy Lancet 2003;361:491-492.[CrossRef][ISI][Medline]
- Reinecke H, MacDonald GH, Hauschka SD, Murry CE. Electromechanical coupling between skeletal and cardiac muscle. Implications for infarct repair J Cell Biol 2000;149:731-740.[Abstract/Free Full Text]
- Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J Am Coll Cardiol 2003;41:1078-1083.[Abstract/Free Full Text]
- Pagani FD, DerSimonian H, Zawadzka A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation J Am Coll Cardiol 2003;41:879-888.[Abstract/Free Full Text]
- Smits PC, van Geuns RJ, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failureclinical experience with six-month follow-up. J Am Coll Cardiol 2003;42:2063-2069.[Abstract/Free Full Text]
- Herreros J, Prosper F, Perez A, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction Eur Heart J 2003;24:2012-2020.[Abstract/Free Full Text]
- Siminiak T, Kalawski R, Fiszer D, et al. Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injuryphase I clinical study with 12 months of follow-up. Am Heart J 2004;148:531-537.[CrossRef][ISI][Medline]
- Steendijk P, Smits PC, Valgimigli M, et al. Intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Long-term follow-up with pressure-volume loops Nat Clin Pract Cardiovasc Med 2006;3(Suppl 1):S94-S100.
- Yeh ET, Zhang S, Wu HD, Korbling M, Willerson
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Historical milestones
Drug-eluting stents
