Treatment of in-stent restenosis--back to the future?
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Biomedical subjects
Publications and source records attributed to Edoardo Camenzind.
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A 48-year-old woman was admitted for an acute infero-lateral myocardial infarction (AMI). The coronary angiography showed an occluded aberrant left circumflex artery taking off from the right sinus of Valsalva of the aortic root. This rare coronary anomaly represents a challenge for interventional cardiologists, especially in the setting of AMI, since it may be difficult to identify an aberrant occluded vessel, to predict its origin and course and finally to choose the material which offers an adequate support during the revascularization procedure. In this particular case, the percutaneous treatment of initially occluded aberrant circumflex artery was performed successfully.
OBJECTIVE: Characterize the phenotypic features of media and intima coronary artery smooth muscle cells (SMCs) in mildly stenotic plaques, erosions, stable plaques, and in-stent restenosis. METHODS AND RESULTS: Expression of alpha-smooth muscle actin (alpha-SMA), smooth muscle myosin heavy chains (SMMHCs), and smoothelin was investigated by immunohistochemistry followed by morphometric quantification. The cross-sectional area and the expression of cytoskeletal proteins in the media were lower in restenotic lesions and, to a lesser extent, in stable plaques compared with mildly stenotic plaques and erosions. An important expression of alpha-SMA was detected in the intima of the different lesions; moreover, alpha-SMA staining was significantly larger in erosions compared with all other conditions. In the same location, a striking decrease of SMMHCs and a disappearance of smoothelin were observed in all situations. CONCLUSIONS: Medial atrophy is prevalent in restenotic lesions and stable plaques compared with mildly stenotic plaques and erosions. Intimal SMCs of all situations exhibit a phenotypic profile, suggesting that they have modulated into myofibroblasts (MFs). The high accumulation of alpha-SMA-positive MFs in erosions compared with stable plaques correlates with the higher appearance of thrombotic complications in this situation.
Percutaneous left ventricular assist devices could nowadays offer a valid support to percutaneous coronary interventions even in very high risk patients. This case illustrates a successful distal left main coronary artery V-stenting supported by the Tandem Heart in a patient with severe left ventricular dysfunction, severe aortic stenosis, and refractory myocardial ischemia.
BACKGROUND: Heparin coating is an attractive alternative to counterbalance intrinsic stent thrombogenicity and to decrease the incidence of stent thrombosis. METHODS: We compared, based on the data of an international multicenter prospective registry, the rates of stent thrombosis after percutaneous coronary interventions in native coronary arteries using a Bx VELOCITY heparin-coated stent versus a bare metal stent of the same design in a total of 3098 patients at high risk for stent thrombosis. Most patients in both groups underwent percutaneous coronary intervention for unstable angina (48.4% vs 47.5%, respectively) with > 25% of the patients treated for acute myocardial infarction (30.8% and 28.1%, respectively). RESULTS: Procedural success was high and very similar in patients with heparin-coated and bare metal stents (99.3% vs 98.8%, respectively, P = .11). The primary end point, a 30-day stent thrombosis, occurred in 0.6% of the 1417 patients treated with the heparin-coated stent and 0.9% of the 1681 patients treated with the bare metal stent (relative risk reduction 33%, P = .41). The rates of cardiac death, myocardial infarction, and target lesion revascularization did not differ significantly between the groups. By multivariate analysis, variables independently associated with 30-day stent thrombosis included the evidence of thrombus at baseline (odds ratio [OR] 3.0, 95% CI 1.29-7.0, P = .01), small vessel stenting (OR 2.41, 95% CI 1.01-5.74, P = .05), and target left anterior descending artery (OR 2.32, 95% CI 1.00-5.38, P = .05). CONCLUSION: This large-scale registry comparing the use of heparin-coated stent versus bare metal stent in the reality of daily practice showed no significant difference in stent thrombosis in patients with a high-risk profile for thrombotic complications.
Pacemakers are used more and more in modern cardiology, because of the increasing age of patients and the increasing number of cases of congestive heart failure treated with biventricular stimulation. Twelve lead ECG traces of electro-stimulated patients normally can be interpreted correctly, but in emergency circumstances where only a three lead ECG trace is available (i.e. the usual monitoring setting in the pre-hospital arena or intensive care unit) recognition of the underlying baseline rhythm may be difficult. The case described illustrates how differentiation between true asystole and fine ventricular fibrillation in the presence of some confounding elements (e.g. pacemaker meditated spikes) can be challenging for the physician and life-threatening for the patient. Therefore, after selecting the best diagnostic ECG trace, direct current defibrillation should be used in the presence of a persistent but uncertain cardiac rhythm, even if it may be thought to be asystole or pulse-less electrical activity.
The investigators examined 326 pairs of angiograms from 2 randomized dose-finding (0.2 to 3.1 microg paclitaxel/mm(2) of stent surface area) clinical trials of polymer-free paclitaxel-eluting stents in de novo lesions (the ASian Paclitaxel-Eluting stent Clinical Trial [ASPECT] and the European evaLUation of Taxol Eluting Stent [ELUTES]). A dose-dependent effect was observed: the largest dose of paclitaxel in the 2 trials resulted in a significantly larger proportion of lesions at follow-up with <10% diameter stenosis (54% vs 16%, p = 0.00012 in ASPECT; 53% vs 21%, p = 0.013 in ELUTES) and with minimal luminal diameter located outside the stent compared with control stents (62% vs 20% in ASPECT, 48% vs 18% in ELUTES; p <0.05). Also, significantly shorter lesion lengths at 6-month follow-up were observed for the doses of 0.7 to 3.1 microg/mm(2) (p <0.03) relative to their respective lengths before the procedure compared with control stents.
Isolated left ventricular hypertrophy, in the absence of hypertension or aortic stenosis, is commonly attributed to hypertrophic cardiomyopathy (HCM). According to the clinical setting, however, other differential diagnoses should be considered. The diagnosis of cardiac amyloidosis may be very challenging especially when the clinician is confronted with various aspects typical of both pathologies. The work-up of this case shows how non-invasive cardiac investigations are sometimes not sufficiently conclusive for distinguishing between the two pathologies, and that only endomyocardial biopsy (EMB) can confirm cardiac involvement secondary to systemic amyloidosis. The prognostic and therapeutic differences between the two diseases, as well as the contextual aspects of the case in point--namely a case of multiorgan failure--serve as an example of how a definitive diagnosis can be attained by means of a multidisciplinary approach in order to reach a definitive treatment plan.
BACKGROUND: On the basis of brachytherapy experience, edge stenosis has been raised as a potential limitation for drug-eluting stents. We used serial intravascular ultrasound (IVUS) to prospectively analyze vessel responses in adjacent reference segments after implantation of polymer-controlled paclitaxel-eluting stents. METHODS AND RESULTS: TAXUS II was a randomized, double-blind trial with 2 consecutive patient cohorts that compared slow-release (SR) and moderate-release (MR) paclitaxel-eluting stents with control bare metal stents (BMS). By protocol, all patients had postprocedure and 6-month follow-up IVUS. Quantitative IVUS analysis was performed by an independent core laboratory, blinded to treatment allocation, in 5-mm vessel segments immediately proximal and distal to the stent. Serial IVUS was available for 106 SR, 107 MR, and 214 BMS patients. For all 3 groups, a significant decrease in proximal-edge lumen area was observed at 6 months. The decrease was comparable (by ANOVA, P=0.194) for patients in the SR (-0.54+/-2.1 mm2) and MR (-0.88+/-1.9 mm2) groups compared with the BMS (-1.02+/-1.9 mm2) group. For the distal edge, a significant decrease in lumen area was only observed with BMS (-0.91+/-2.0 mm2, P<0.0001); this decrease was significantly attenuated with SR (0.08+/-2.0 mm2) and MR (-0.19+/-1.7 mm2) stents (P<0.0001 by ANOVA). Negative vessel remodeling was observed at the proximal (-0.48+/-2.2 mm2, P=0.011) but not the distal edges of BMS and at neither edge of SR or MR stents. CONCLUSIONS: The marked reduction in in-stent restenosis with SR or MR stents is not associated with increased edge stenosis at 6-month follow-up IVUS. In fact, compared with BMS, there is instead a significant reduction in late lumen loss at the distal edge with TAXUS stents.
BACKGROUND: The use of a stent to deliver a drug may reduce in-stent restenosis. Paclitaxel interrupts the smooth muscle cell cycle by stabilizing microtubules, thereby arresting mitosis. METHODS AND RESULTS: On the basis of prior animal studies, the European evaLUation of the pacliTaxel Eluting Stent (ELUTES) pilot clinical trial (n=190) investigated the safety and efficacy of V-Flex Plus coronary stents (Cook Inc) coated with escalating doses of paclitaxel (0.2, 0.7, 1.4, and 2.7 microg/mm2 stent surface area) applied directly to the abluminal surface of the stent in de novo lesions compared with bare stent alone. The primary efficacy end point was angiographic percent diameter stenosis at 6 months. At angiographic follow-up, percent diameter stenosis was 33.9+/-26.7% in controls (n=34) and 14.2+/-16.6% in the 2.7-microg/mm2 group (n=31; P=0.006). Late loss decreased from 0.73+/-0.73 to 0.11+/-0.50 mm (P=0.002). Binary restenosis (> or =50% at follow-up) decreased from 20.6% to 3.2% (P=0.056), with no significant benefit from intermediate paclitaxel doses. Freedom from major adverse cardiac events in the highest (effective) dose group was 92%, 89%, and 86% at 1, 6, and 12 months, respectively (P=NS versus control). No late stent thromboses were seen in any treated group despite clopidogrel treatment for 3 months only. CONCLUSIONS: Paclitaxel applied directly to the abluminal surface of a bare metal coronary stent, at a dose density of 2.7 microg/mm2, reduced angiographic indicators of in-stent restenosis without short- or medium-term side effects.
In patients with coronary artery disease, the presence of left ventricular hypertrophy secondary to hypertension is associated with an increased collateral development. A patient is described who was admitted for myocardial ischemia and severe hypertension. One day after admission, coronary angiography revealed a proximal chronic occlusion of the left anterior descending artery with an extensive collateral vascularization originating from the right and circumflex coronary arteries. In addition, left ventriculography showed antero-apical akinesia that was resolved 5 days later, indicating myocardial stunning. This case illustrates the vulnerability of collateral coronary blood flow to an episode of hypertension, giving rise to myocardial ischemia and even myocardial stunning. This finding advocates aggressive antihypertensive therapy in patients with coronary artery disease and regional myocardial perfusion, which exclusively depends on collateral blood flow.
Somatostatin analogues have been shown to inhibit smooth muscle cell proliferation after local administration in vivo in animal models and in vitro using human coronary smooth muscle cell cultures. However, the optimal dosage for attaining effective site-specific administration remains undefined. This study was performed to determine the required theoretical dose of the somatostatin analogue, octreotide, to be delivered site specifically, for prevention of restenosis after coronary angioplasty in humans using a previously described methodology to determine regional pharmacokinetics of site-specific intracoronary administrated compounds. In 7 patients, 111In-octreotide, a gamma-labeled somatostatin analogue, was infused post angioplasty at the site of dilatation via a coil-balloon and quantified using a radio-isotopic technique. Efficiency of delivery ranged from 0.1% to 2.7% of the total infused dose of 0.18 microg, corresponding to a mean peak delivered amount of 1.8 +/- 1.9 ng. Total locally bioavailable 111In-octreotide reached 2.28 +/- 2.15 ng h. Based on current in vitro bioavailability and peak concentration data to inhibit proliferation and thymidine incorporation in human coronary smooth muscle cells, a 4000x higher averaged dose (approximately 700 microg) should be infused site specifically to obtain a biologic efficacy in 50% of the treated patients (ED50). Quantification of regional pharmacokinetics enables the determination of a theoretical site-specific dose for achieving appropriate bioavailability above the therapeutic threshold concentration for smooth muscle cell inhibition. This approach is proposed for the determination of the appropriate site-specific coronary infusion dose for the inhibition of restenosis after balloon angioplasty.
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OBJECTIVE: Heterogeneous smooth muscle cell (SMC) populations have been described in the arteries of several species. We have investigated whether SMC heterogeneity is present in the porcine coronary artery, which is widely used as a model of restenosis. METHODS AND RESULTS: By using 2 isolation methods, distinct medial populations were identified: spindle-shaped SMCs (S-SMCs) after enzymatic digestion, with a "hill-and-valley" growth pattern, and rhomboid SMCs (R-SMCs) after explantation, which grow as a monolayer. Moreover, the intimal thickening that was induced after stent implantation yielded a large proportion of R-SMCs. R-SMCs exhibited high proliferative and migratory activities and high urokinase activity and were poorly differentiated compared with S-SMCs. Heparin and transforming growth factor-beta2 inhibited proliferation and increased differentiation in both populations, whereas fibroblast growth factor-2 and platelet-derived growth factor-BB had the opposite effect. In addition, S-SMCs treated with fibroblast growth factor-2 or platelet-derived growth factor-BB or placed in coculture with coronary artery endothelial cells acquired a rhomboid phenotype. This change was reversible and was also observed with S-SMC clones, suggesting that it depends on phenotypic modulation rather than on selection. CONCLUSIONS: Our results show that 2 distinct SMC subpopulations can be recovered from the pig coronary artery media. The study of these subpopulations will be useful for understanding the mechanisms of restenosis.