Intermittent pacing therapy favorably modulates infarct remodeling.

Despite early revascularization, remodeling and dysfunction of the left ventricle (LV) after acute myocardial infarction (AMI) remain important therapeutic targets. Intermittent pacing therapy (IPT) of the LV can limit infarct size, when applied during early reperfusion. However, the effects of IPT on post-AMI LV remodeling and infarct healing are unknown. We therefore investigated the effects of IPT on global LV remodeling and infarct geometry in swine with a 3-day old AMI. For this purpose, fifteen pigs underwent 2 h ligation of the left circumflex coronary artery followed by reperfusion. An epicardial pacing lead was implanted in the peri-infarct zone. After three days, global LV remodeling and infarct geometry were assessed using magnetic resonance imaging (MRI). Animals were stratified into MI control and IPT groups. Thirty-five days post-AMI, follow-up MRI was obtained and myofibroblast content, markers of extracellular matrix (ECM) turnover and Wnt/frizzled signaling in infarct and non-infarct control tissue were studied. Results showed that IPT had no significant effect on global LV remodeling, function or infarct mass, but modulated infarct healing. In MI control pigs, infarct mass reduction was principally due to a 26.2 ± 4.4% reduction in infarct thickness (P ≤ 0.05), whereas in IPT pigs it was mainly due to a 35.7 ± 4.5% decrease in the number of infarct segments (P ≤ 0.05), with no significant change in infarct thickness. Myofibroblast content of the infarct zone was higher in IPT (10.9 ± 2.1%) compared to MI control (5.4 ± 1.6%; P ≤ 0.05). Higher myofibroblast presence did not coincide with alterations in expression of genes involved in ECM turnover or Wnt/frizzled signaling at 5 weeks follow-up. Taken together, IPT limited infarct expansion and altered infarct composition, showing that IPT influences remodeling of the infarct zone, likely by increasing regional myofibroblast content.

VEGF165A microsphere therapy for myocardial infarction suppresses acute cytokine release and increases microvascular density but does not improve cardiac function.

Angiogenesis induced by growth factor-releasing microspheres can be an off-the-shelf and immediate alternative to stem cell therapy for acute myocardial infarction (AMI), independent of stem cell yield and comorbidity-induced dysfunction. Reliable and prolonged local delivery of intact proteins such as VEGF is, however, notoriously difficult. Our objective was to create a platform for local angiogenesis in human-sized hearts, using polyethylene-glycol/polybutylene-terephthalate (PEG-PBT) microsphere-based VEGF165A delivery. PEG-PBT microspheres were biocompatible, distribution was size dependent, and a regimen of 10 × 10(6) 15-µm microspheres at 0.5 × 10(6)/min did not induce cardiac necrosis. Efficacy, studied in a porcine model of AMI with reperfusion rather than chronic ischemia used for most reported VEGF studies, shows that microspheres were retained for at least 35 days. Acute VEGF165A release attenuated early cytokine release upon reperfusion and produced a dose-dependent increase in microvascular density at 5 wk following AMI. However, it did not improve major variables for global cardiac function, left ventricular dimensions, infarct size, or scar composition (collagen and myocyte content). Taken together, controlled VEGF165A delivery is safe, attenuates early cytokine release, and leads to a dose-dependent increase in microvascular density in the infarct zone but does not translate into changes in global or regional cardiac function and scar composition.

Serial measurement of hFABP and high-sensitivity troponin I post-PCI in STEMI: how fast and accurate can myocardial infarct size and no-reflow be predicted?

The objective of this study was to compare heart-specific fatty acid binding protein (hFABP) and high-sensitivity troponin I (hsTnI) via serial measurements to identify early time points to accurately quantify infarct size and no-reflow in a preclinical swine model of ST-elevated myocardial infarction (STEMI). Myocardial necrosis, usually confirmed by hsTnI or TnT, takes several hours of ischemia before plasma levels rise in the absence of reperfusion. We evaluated the fast marker hFABP compared with hsTnI to estimate infarct size and no-reflow upon reperfused (2 h occlusion) and nonreperfused (8 h occlusion) STEMI in swine. In STEMI (n = 4) and STEMI + reperfusion (n = 8) induced in swine, serial blood samples were taken for hFABP and hsTnI and compared with triphenyl tetrazolium chloride and thioflavin-S staining for infarct size and no-reflow at the time of euthanasia. hFABP increased faster than hsTnI upon occlusion (82 ± 29 vs. 180 ± 73 min, P < 0.05) and increased immediately upon reperfusion while hsTnI release was delayed 16 ± 3 min (P < 0.05). Peak hFABP and hsTnI reperfusion values were reached at 30 ± 5 and 139 ± 21 min, respectively (P < 0.05). Infarct size (containing 84 ± 0.6% no-reflow) correlated well with area under the curve for hFABP (r(2) = 0.92) but less for hsTnI (r(2) = 0.53). At 50 and 60 min reperfusion, hFABP correlated best with infarct size (r(2) = 0.94 and 0.93) and no-reflow (r(2) = 0.96 and 0.94) and showed high sensitivity for myocardial necrosis (2.3 ± 0.6 and 0.4 ± 0.6 g). hFABP rises faster and correlates better with infarct size and no-reflow than hsTnI in STEMI + reperfusion when measured early after reperfusion. The highest sensitivity detecting myocardial necrosis, 0.4 ± 0.6 g at 60 min postreperfusion, provides an accurate and early measurement of infarct size and no-reflow.

Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes.

Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.

The Genous™ endothelial progenitor cell capture stent accelerates stent re-endothelialization but does not affect intimal hyperplasia in porcine coronary arteries.

OBJECTIVES: To study the effect of endothelial progenitor cell (EPC) capture on the vascular response to coronary stenting. BACKGROUND: The introduction of drug-eluting stents has reduced the need for target lesion revascularization, but their effect on delayed healing, inflammation, and vascular dysfunction has emphasized the need to design strategies that improve current DES. One such strategy is to improve endothelialization by capturing CD34-positive cells (EPC) by the stent surface. The first human clinical trial using coronary EPC capture stents showed stent safety but neointimal thickness (NIT) was not reduced compared to bare metal stents (BMS). To understand these responses we studied the coronary response to the EPC capture stent in swine. METHODS AND RESULTS: The stent, coated with murine antihuman monoclonal CD34 antibodies, was assessed with QCA guided stent implantation in normal swine coronary arteries for early endothelialization at 2 and 5 days, and NIT at 28 and 90 days in comparison to control stents carrying a non-specific murine antibody or to BMS. The main finding was that while the EPC capture stent significantly improved early endothelialization it did not reduce NIT at 28 and 90 days. CONCLUSIONS: The EPC capture stent improves early endothelialization in swine but this does not affect neointimal thickness as compared to control stents at 28 and 90 days.

Impact of renal insufficiency on safety and efficacy of drug-eluting stents compared to bare-metal stents at 6 years.

BACKGROUND: There is few information on the long-term efficacy and safety of sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES) compared to bare metal stents (BMS) in all-comer percutaneous coronary intervention (PCI)-patients complicated by renal insufficiency (RI). OBJECTIVE: Our aim was to assess the 6-year clinical outcome of PCI-patients with RI treated exclusively with BMS, SES, or PES in our academic hospital. METHODS: A total of 1382 patients, included in three cohorts of consecutive PCI-patients (BMS = 392; SES = 498; PES = 492), were categorized by creatinine clearance calculated by the Cockroft-Gault formula (normal kidney function ≥ 90; mild RI = 60-89; moderate RI < 60) and systematically followed for the occurrence of major adverse cardiac events (MACE). RESULTS: Mortality rates were significantly higher for patients with moderate RI compared to mild RI and normal kidney function at 6 years (Kaplan-Meier estimate: moderate RI (34%) vs. mild RI (12%), P < 0.001; moderate RI (34%) vs. normal kidney function (8%), P < 0.001). After multivariate Cox-regression analysis, SES and PES decreased the occurrence of target-vessel revascularization (TVR) and MACE at 6 years in patients with a normal creatinine clearance compared to BMS [adjusted hazard ratio (aHR) = 0.48, 95% CI: 0.28-0.84; aHR = 0.75, 95% CI: 0.57-0.97, respectively] with no significant effect on mortality. Safety- and efficacy end points were comparable for the three stent types in patients with mild- and moderate renal function. CONCLUSION: Patients with a normal creatinine clearance had significant improvement in TVR and MACE rates after SES- or PES implantation compared to BMS at 6 years. However, there was no superiority of both drug-eluting stents over BMS in safety and efficacy end points for patients with impaired renal function.

Randomized comparison of the magnetic navigation system vs. standard wires in the treatment of bifurcations.

Aims Randomly compare the magnetic navigation system (MNS) to standard guidewire techniques in managing bifurcating lesions. Methods and results Thirty-one consecutive patients with bifurcating lesions were randomized to cross the bifurcating vessels prior to treatment and thereafter the struts of deployed stents with either magnetic or standard guidewires. Crossing success, crossing/fluoroscopy times, and contrast media usage were directly compared. Similar times were noted in both the magnetic wire crossings (median, IQR; 68 s, 45-138 s vs. 59 s, 32-133 s) and fluoroscopic times (median, IQR; 62 s, 44-135 s vs. 55 s, 27-133 s) when compared with standard conventional wires passage through the deployed struts. The MNS successful crossings were 30/31 (96.8%) compared with 28/31 (90.0%) observed with the standard wires. Two previously failed standard wire cases were successfully crossed with magnetic guidewires. Conclusion In contemporary stented bifurcations, the MNS achieved equivalent crossing/fluoroscopy times through deployed stents struts and may be useful in salvaging failed standard wire cases.

Evaluating the 'all-comers' design: a comparison of participants in two 'all-comers' PCI trials with non-participants.

AIMS: We aimed to asses the generalizability of two 'all-comers' randomized clinical trials (AC-RCTs) in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: Recently two large AC-RCT's comparing drug-eluting stents were performed in our institution (LEADERS and RESOLUTE-III). During the inclusion period of these trials 1242 consecutive PCI patients were treated of whom 579 (48%) were actually included. The most important reasons for non-participation were inability to provide informed consent (33.5%), refused to participate (19%), or patient met one of the other exclusion criteria (26.9%). Trial participants more frequently had stable angina (42.5 vs. 34.4%) and less frequently acute myocardial infarction as indication for PCI (31.4 vs. 42.4%) than non-participants. Hypertension (52.8 vs. 49.1%) and hypercholesterolaemia (56.3 vs. 49.1%) were seen more frequently in trial participants; heart failure was less common (2.1 vs. 4.4%). A significant difference in 30-day mortality was observed between AC-RCT participants and non-participants [0.7 vs. 4.5% events; adjusted hazard ratio (aHR) 0.18 and 95% confidence interval (CI) 0.06-0.52]. One-year mortality was also lower (3.1 vs. 6.9% events; aHR: 0.51 and 95% CI: 0.29-0.91, but 1-year mortality in 48 h survivors was similar (3.1 vs. 4.2% events; aHR: 0.74 and 95% CI: 0.41-1.34). CONCLUSION: Applying the all-comers design did not result in inclusion of all consecutive patients, as only half of the target population was enrolled. It should be noted, however, that this design included more patients than observed in classical RCTs. AC-RCT participants and non-participants were different in terms of baseline characteristics and outcome.

Tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent vs. a fluoropolymer-coated everolimus-eluting stent at 13-month follow-up: an optical coherence tomography substudy from the RESOLUTE All Comers trial.

AIMS: To compare the tissue coverage of a hydrophilic polymer-coated zotarolimus-eluting stent (ZES) vs. a fluoropolymer-coated everolimus-eluting stent (EES) at 13 months, using optical coherence tomography (OCT) in an 'all-comers' population of patients, in order to clarify the mechanism of eventual differences in the biocompatibility and thrombogenicity of the devices. METHODS AND RESULTS: Patients randomized to angiographic follow-up in the RESOLUTE All Comers trial (NCT00617084) at pre-specified OCT sites underwent OCT follow-up at 13 months. Tissue coverage and apposition were assessed strut by strut, and the results in both treatment groups were compared using multilevel logistic or linear regression, as appropriate, with clustering at three different levels: patient, lesion, and stent. Fifty-eight patients (30 ZES and 28 EES), 72 lesions, 107 stents, and 23 197 struts were analysed. Eight hundred and eighty-seven and 654 uncovered struts (7.4 and 5.8%, P= 0.378), and 216 and 161 malapposed struts (1.8 and 1.4%, P= 0.569) were found in the ZES and EES groups, respectively. The mean thickness of coverage was 116 ± 99 µm in ZES and 142 ± 113 µm in EES (P= 0.466). No differences in per cent neointimal volume obstruction (12.5 ± 7.9 vs. 15.0 ± 10.7%) or other areas-volumetric parameters were found between ZES and EES, respectively. CONCLUSION: No significant differences in tissue coverage, malapposition, or lumen/stent areas and volumes were detected by OCT between the hydrophilic polymer-coated ZES and the fluoropolymer-coated EES at 13-month follow-up.

Intracoronary infusion of mononuclear cells from bone marrow or peripheral blood compared with standard therapy in patients after acute myocardial infarction treated by primary percutaneous coronary intervention: results of the randomized controlled HEBE trial.

AIMS: Previous trials that investigated cell therapy as an adjunctive therapy after acute myocardial infarction (AMI) have shown conflicting results. We designed a randomized controlled trial to determine the effect of intracoronary infusion of mononuclear cells from bone marrow (BM) or peripheral blood in patients with AMI. METHODS AND RESULTS: In a multicentre trial, 200 patients with large first AMI treated with primary percutaneous coronary intervention were randomly assigned to either intracoronary infusion of mononuclear BM cells (n = 69), mononuclear peripheral blood cells (n = 66), or standard therapy (without placebo infusion) (n = 65). Mononuclear cells were delivered intracoronary between 3 and 8 days after AMI. Regional and global left ventricular myocardial function and volumes were assessed by magnetic resonance imaging before randomization and at 4 months, and clinical events were reported. The primary endpoint of the percentage of dysfunctional left ventricular segments that improved during follow-up did not differ significantly between either of the treatment groups and control: 38.6 ± 24.7% in the BM group, 36.8 ± 20.9% in the peripheral blood group, and 42.4 ± 18.7% in the control group (P = 0.33 and P = 0.14). Improvement of left ventricular ejection fraction was 3.8 ± 7.4% in the BM group, 4.2 ± 6.2% in the peripheral blood group when compared with 4.0 ± 5.8% in the control group (P = 0.94 and P = 0.90). Furthermore, the three groups did not differ significantly in changes in left ventricular volumes, mass, and infarct size and had similar rates of clinical events. CONCLUSION: Intracoronary infusion of mononuclear cells from BM or peripheral blood following AMI does not improve regional or global systolic myocardial function in the HEBE trial. REGISTRATION: The Netherlands Trial Register #NTR166 (www.trialregister.nl) and the International Standard Randomised Controlled Trial, #ISRCTN95796863 (http://isrctn.org).

Intracoronary optical coherence tomography and histology at 1 month and 2, 3, and 4 years after implantation of everolimus-eluting bioresorbable vascular scaffolds in a porcine coronary artery model: an attempt to decipher the human optical coherence tomography images in the ABSORB trial.

BACKGROUND: With the use of optical coherence tomography (OCT), alterations of the reflectance characteristics of everolimus-eluting bioresorbable vascular scaffold (BVS) struts have been reported in humans. In the absence of histology, the interpretation of the appearances of the struts by OCT remains speculative. We therefore report OCT findings with corresponding histology in the porcine coronary artery model immediately after and at 28 days and 2, 3, and 4 years after BVS implantation. METHODS AND RESULTS: Thirty-five polymeric BVS (3.0×12.0 mm) were singly implanted in the main coronary arteries of 17 pigs that underwent OCT and were then euthanized immediately (n=2), at 28 days (n=2), at 2 years (n=3), at 3 years (n=5), or at 4 years (n=5) after implantation. All BVS-implanted arteries in these animals were evaluated by histology except for 5 arteries examined at 2 years with gel permeation chromatography to assess the biodegradation of the polymeric device. Fourteen arteries with BVS from an additional 6 pigs were examined by gel permeation chromatography at 1 (n=1), 1.5 (n=2), and 3 (n=2) years. Corresponding OCT and histology images were selected with the distal and proximal radiopaque markers used as landmarks. At 28 days, by OCT, 82% of struts showed sharply defined, bright reflection borders, best described as a box-shaped appearance. Histologically, all struts appeared intact with no evidence of resorption. At 2 years, by OCT, 60±20 struts were discernible per BVS with 80.4% of the strut sites as a box-shaped appearance. Despite their defined appearance by OCT, by histology, these structures appeared to be composed of proteoglycan, with polymeric material being at such low level as to be no longer quantifiable by chromatography. At 3 years, by OCT, recognizable struts decreased to 28±9 struts per BVS: 43.7% showed dissolved black box; 34.8%, dissolved bright box; 16.1%, open box; and 5.4%, preserved box appearance. Histology shows that connective tissue cells within a proteoglycan-rich matrix replaced the areas previously occupied by the polymeric struts and coalesced into the arterial wall. At 4 years, by OCT, 10±6 struts were recognizable as either dissolved black or dissolved bright box. In histology, these struts are minimally discernible as foci of low-cellular-density connective tissue. Relative to the prediction of histological type by OCT appearance, the preserved box appearance of OCT corresponds well with 2-year histology (86.4%), whereas the dissolved bright and black box appearances correspond to 3-year histology (88.0% and 90.7%, respectively). Struts indiscernible by OCT correspond to the integrated strut footprints seen at 4 years (100%). CONCLUSIONS: Struts that are still discernible by OCT at 2 years are compatible with largely bioresorbed struts, as demonstrated by histological and gel permeation chromatography analysis. At 3 and 4 years, both OCT and histology confirm complete integration of the struts into the arterial wall.

Value of the SYNTAX score in patients treated by primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: The MI SYNTAXscore study.

AIMS: The aims of this study were to evaluate the SYNTAX score (SXscore) calculated at 2 stages during a primary percutaneous intervention (PPCI), that is, SXscore I (diagnostic) and SXscore II (postwiring), and assess its additional value to standard clinical risk scores in acute myocardial infarction. METHODS AND RESULTS: SXscores I and II were applied to 736 consecutive acute ST-elevation myocardial infarction patients referred for PPCI between November 2006 and February 2008. SXscore changed significantly before (I: 16, interquartile range 9.5-23) and after wiring (II: 11, interquartile range 6-19), P < .001. Kaplan-Meier methods were used to compare the primary end point major adverse coronary events (MACE; composite of repeat MI, target vessel revascularization [TVR], and mortality) and secondary end point mortality at 1.5 years in tertiles of SXscore I and SXscore II. Major adverse coronary event was highest in the higher SXscore I tertile (11% vs 15% vs 23%, log-rank <0.01), driven primarily by increased rate of mortality (9% vs 11% vs 17%, log-rank 0.02). Major adverse coronary event was also highest in SXscore II tertile, by a combination of increased mortality and also TVR (TVR rate 2% vs 3% vs 9%, log-rank <0.01). Predictive Cox regression models for mortality and MACE were significantly and similarly improved by the addition of either SXscore I or SXscore II (hazard ratio 1.63, 95% CI 1.18-2.26, P < .01 for MACE) with respective c indices of 0.61 and 0.63 for MACE and 0.60 and 0.61 for mortality. CONCLUSIONS: SXscore during PPCI is a useful tool that provides additional risk stratification to known risk factors of long-term mortality and MACE in patients with ST-elevation myocardial infarction.

Long-term tissue coverage of a biodegradable polylactide polymer-coated biolimus-eluting stent: comparative sequential assessment with optical coherence tomography until complete resorption of the polymer.

BACKGROUND: Biolimus-eluting stents (BESs) with a biodegradable polymer in abluminal coating achieve more complete coverage at 9 months compared with sirolimus-eluting stents (SESs) with a durable polymer, as assessed by optical coherence tomography (OCT). Whether this advantage persists or augments after complete resorption of the polymer (>12 months) is unknown. METHODS: The LEADERS trial compared the performance of BES with that of SES. Patients were randomly allocated to a sequential angiographic follow-up, including OCT in selected sites, at 9 and 24 months. Struts coverage was compared using Bayesian hierarchical models as the primary outcome for the OCT substudy. RESULTS: Fifty-six patients (26 BES, 30 SES) were enrolled in the OCT substudy. Twenty-one patients (10 BES, 11 SES) agreed to perform a second OCT follow-up at 24 months. Eleven lesions and 12 stents were analyzed sequentially in the BES group (2,455 struts at 9 months, 2,131 struts at 24 months) and 11 lesions and 18 stents in the SES group (3,421 struts at 9 months, 4,170 struts at 24 months). The previously reported advantage of BES over SES in terms of better strut coverage at 9 months was followed by improvement in coverage of the SES, resulting in identical coverage in both BES and SES at 24 months: 1.5% versus 1.8% uncovered struts, difference -0.2%, 95% credibility interval, -3.2% to 2.6%, P = .84. CONCLUSIONS: More complete strut coverage of BES as compared with SES at 9 months was followed by improvement of coverage in SES between 9 and 24 months and a similar long-term coverage in both stent types at 24 months.

An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: a LEADERS trial sub-study.

AIMS: Incomplete endothelialization has been found to be associated with late stent thrombosis, a rare but devastating phenomenon, more frequent after drug-eluting stent implantation. Optical coherence tomography (OCT) has 10 times greater resolution than intravascular ultrasound and thus appears to be a valuable modality for the assessment of stent strut coverage. The LEADERS trial was a multi-centre, randomized comparison of a biolimus-eluting stent (BES) with biodegradable polymer with a sirolimus-eluting stent (SES) using a durable polymer. This study sought to evaluate tissue coverage and apposition of stents using OCT in a group of patients from the randomized LEADERS trial. METHODS AND RESULTS: Fifty-six consecutive patients underwent OCT during angiographic follow-up at 9 months. OCT images were acquired using a non-occlusive technique at a pullback speed of 3 mm/s. Data were analysed using a Bayesian hierarchical random-effects model, which accounted for the correlation of lesion characteristics within patients and implicitly assigned analytical weights to each lesion depending on the number of struts observed per lesion. Primary outcome was the difference in percentage of uncovered struts between BESs and SESs. Twenty patients were included in the analysis in the BES group (29 lesions with 4592 struts) and 26 patients in the SES group (35 lesions with 6476 struts). A total of 83 struts were uncovered in the BES group and 407 out of 6476 struts were uncovered in the SES group [weighted difference -1.4%, 95% confidence interval (CI) -3.7 to 0.0, P = 0.04]. Results were similar after adjustment for pre-procedure lesion length, reference vessel diameter, number of implanted study stents, and presence of stent overlap. There were three lesions in the BES group and 15 lesions in the SES group that had > or =5% of all struts uncovered (difference -33.1%, 95% CI -61.7 to -10.3, P < 0.01). CONCLUSION: Strut coverage at an average follow-up of 9 months appears to be more complete in patients allocated to BESs when compared with SESs. The impact of this difference on clinical outcome and, in particular, on the risk of late stent thrombosis is yet to be determined.

MAHOROBA, first-in-man study: 6-month results of a biodegradable polymer sustained release tacrolimus-eluting stent in de novo coronary stenoses.

AIMS: To report the 4-month angiographic and 6-month clinical follow-up in first-in-man study using the tacrolimus-eluting bioabsorbable polymer-coated cobalt-chromium MAHOROBA stent. METHODS AND RESULTS: A total of 47 patients with either stable angina or unstable angina, or silent myocardial ischaemia, based on a de novo coronary stenosis that could be covered by a single 18 mm stent in a native coronary artery with a diameter between 3.0 and 3.5 mm were enrolled at three sites. The primary endpoint was in-stent late loss at 4 months. The secondary endpoints include %volume obstruction of the stents assessed by intravascular ultrasound (IVUS) at 4 months and major adverse cardiac events (MACE) at 6 months. Forty-seven patients were enrolled. Procedural success was achieved in 97.9%. At 4-month follow-up, in-stent late loss was 0.99 +/- 0.46 mm, whereas in-stent %volume obstruction in IVUS was 34.8 +/- 15.8%. At 6 months, there were no deaths, but 2 patients suffered from a myocardial infarction and 11 patients required ischaemia-driven repeat revascularization. The composite MACE rate was 23.4%. CONCLUSION: This tacrolimus-eluting stent failed to prevent neointimal hyperplasia, despite the theoretical advantages of the tacrolimus, which has less inhibitory effects on endothelial cells than smooth muscle cells.

Diverging associations of an intended early invasive strategy compared with actual revascularization, and outcome in patients with non-ST-segment elevation acute coronary syndrome: the problem of treatment selection bias.

AIMS: In several observational studies, revascularization is associated with substantial reduction in mortality in patients with non-ST-segment elevation acute coronary syndrome (nSTE-ACS). This has strengthened the belief that routine early angiography would lead to a reduction in mortality. We investigated the association between actual in-hospital revascularization and long-term outcome in patients with nSTE-ACS included in the ICTUS trial. METHODS AND RESULTS: The study population of the present analysis consists of ICTUS participants who were discharged alive after initial hospitalization. The ICTUS trial was a randomized, controlled trial in which 1200 patients were randomized to an early invasive or selective invasive strategy. The endpoints were death from hospital discharge until 4 year follow-up and death or spontaneous myocardial infarction (MI) until 3 years. Among 1189 patients discharged alive, 691 (58%) underwent revascularization during initial hospitalization. In multivariable Cox regression analyses, in-hospital revascularization was independently associated with a reduction in 4 year mortality and 3 year event rate of death or spontaneous MI: hazard ratio (HR) 0.59 [95% confidence interval (CI) 0.37-0.96] and 0.46 (95% CI 0.31-0.68). However, when intention-to-treat analysis was performed, no differences in cumulative event rates were observed between the early invasive and selective invasive strategies: HR 1.10 (95% CI 0.70-1.74) for death and 1.27 (95% CI 0.88-1.85) for death or spontaneous MI. CONCLUSION: The ICTUS trial did not show that an early invasive strategy resulted in a better outcome than a selective invasive strategy in patients with nSTE-ACS. However, similar to retrospective analyses from observational studies, actual revascularization was associated with lower mortality and fewer MI. Whether an early invasive strategy leads to a better outcome than a selective invasive strategy cannot be inferred from the observation that revascularized patients have a better prognosis in non-randomized studies.

Assessment of culprit and remote coronary narrowings using optical coherence tomography with long-term outcomes.

Much currently known information about vulnerable plaque stems from postmortem studies that identified several characteristics making them prone to rupture, including the presence of a thin fibrous cap and a large lipid core. This study used optical coherence tomography (OCT) to assess culprit and remote coronary narrowings and investigate whether intracoronary OCT in living patients was able to visualize morphologic features associated with vulnerable plaque in postmortem studies. Twenty-three patients successfully underwent OCT before percutaneous coronary intervention. The culprit lesion and mild to moderate coronary narrowings remote from the target stenosis were investigated. Using OCT, the culprit lesion was found to be fibrous in 39.1%, fibrocalcific in 34.4%, and lipid rich in 26.1% of cases. Two patients met criteria for thin-cap fibroatheroma (TCFA; defined as the presence of a signal-rich fibrous cap covering a signal-poor lipid/necrotic core with cap thickness <0.2 mm). Most plaques at remote segments were proximal to the culprit lesion (73.9%) and predominantly fibrous and lipid rich. OCT identified 7 TCFA lesions in 6 patients with a mean cap thickness of 0.19 +/- 0.05 mm, extending for 103 degrees +/- 49 degrees of the total vessel circumference. At 24 months of clinical follow-up, the only event occurred in a patient with in-stent restenosis who underwent repeated percutaneous revascularization. There were no clinically apparent plaque rupture-related events in the 6 patients found to have remote TCFA. This study showed that OCT can be safely applied to image beyond the culprit lesion and can detect in vivo morphologic features associated with plaque vulnerability using retrospective pathologic examination. In conclusion, detection of TCFA, particularly in stable patients, is desirable and may principally allow for early intervention and prevention of adverse events.

First direct in vivo comparison of two commercially available three-dimensional quantitative coronary angiography systems.

AIM: The in vivo comparison of the accuracy of two 3-dimensional quantitative coronary angiography (QCA) systems. METHODS: Precision-drilled plexiglass phantoms with five different luminal diameters (0.5-1.9 mm) were percutaneously inserted into the coronary arteries of four Yorkshire pigs. Twenty-one angiographic images of these stenotic phantoms were acquired for in vivo validation testing. Quantitative assessments of the minimum, maximum, and mean luminal diameters together with the minimum luminal area were determined using two 3D QCA systems, the CardiOp-B and CAAS 5. RESULTS: The CardiOp-B system significantly underestimated the minimum luminal diameter MLD whilst both systems significantly overestimated the maximum luminal diameter at the minimal luminal area (MLA) over the phantom's true value. The CAAS 5 system had a greater degree of accuracy/mm (mean difference = 0.01 vs. 0.03) and precision/mm (SD = 0.09 vs. 0.23) than the CardiOp-B in assessing the minimal LD. An increased precision/mm (SD = 0.01 vs. 0.29) and accuracy/mm (mean difference = 0.03 vs. 0.11) in the mean LD was observed with the CAAS 5. In comparing the MLA/mm(2) the CAAS 5 was more precise/mm(2) (SD = 0.14 vs. 0.55) and accurate/mm(2) (mean difference = 0.12 vs. 0.02) to the true phantom MLA compared to the CardiOp-B system. CONCLUSIONS: In a 21 phantom study, the CAAS 5 3D QCA system had a greater degree of accuracy and precision in both the luminal and area measurements than the CardiOp-B 3D QCA system.

A randomized comparison of the magnetic navigation system versus conventional percutaneous coronary intervention.

OBJECTIVE: A randomized comparison of the magnetic navigation system (MNS) to conventional guidewire techniques in percutaneous coronary interventions. BACKGROUND: The MNS precisely directs a magnetized guidewire in vivo through two permanent external magnets. METHODS: A total of 111 consecutive patients were enrolled. Crossing success, crossing-/fluoroscopy times, and contrast usage were directly compared. Lesions were classified according to the AHA/ACC criteria. Three tertiles of vessel/lesion complexity [low (<5), medium (6-10) and high (>10)] were defined using 3D reconstructions and angiographic information. RESULTS: The crossing success for magnetic and the conventional wires were 93.3 and 95.6%, respectively. Crossing and fluoroscopy times were longer with the magnetic wires (72.9 +/- 50.3 sec vs. 58.1 +/- 47.2 sec, P < 0.001 and 66.2 +/- 44.1 sec vs. 55.2 +/- 44.4 sec, P = 0.03, respectively). In vessels with low and medium complexity the magnetic wires had significantly longer times (P < 0.001) but for those with high scores (>10) a trend towards shorter times was observed. The MNS resulted in a small but significant reduction in contrast usage (2.3 +/- 3.5 ml vs. 4.5 +/- 4.4 ml, P < 0.001). Moreover by superimposing a virtual roadmap of the vessel on the live fluoroscopy image 48% of the lesions were crossed without requiring contrast agents with the MNS. CONCLUSION: The MNS has comparable crossing success to conventional PCI. It is relatively slower but there is a trend to support a potential advantage in more complex vessels. By simultaneously employing a virtual roadmap there is a small but significant reduction in contrast usage.

Intracoronary infusion of autologous mononuclear bone marrow cells in patients with acute myocardial infarction treated with primary PCI: Pilot study of the multicenter HEBE trial.

OBJECTIVE: This study was a pilot trial to determine safety and feasibility of intracoronary infusion of mononuclear bone marrow cells (MBMC) in patients with acute myocardial infarction (MI). BACKGROUND: Studies reporting the effect of MBMC therapy on improvement of left ventricular (LV) function have shown variable results. The HEBE trial is a large multicenter, randomized trial that currently enrolls patients. Prior to this trial we performed a pilot study. METHODS: Twenty-six patients with a first acute MI were prospectively enrolled in eight centers. Bone marrow aspiration was performed at a median of 6 days after primary PCI (interquartile range, 5-7 days). MBMC were isolated by gradient centrifugation and were infused intracoronary the same day. All patients underwent magnetic resonance imaging before cell infusion and after 4 months. Clinical events were assessed up to 12 months. RESULTS: Within 10 hr after bone marrow aspiration, 246 +/- 133 x 10(6) MBMC were infused, of which 3.9 +/- 2.3 x 10(6) cells were CD34(+). In one patient, this procedure was complicated by local dissection. LV ejection fraction significantly increased from 45.0 +/- 6.3% to 47.2 +/- 6.5% (P = 0.03). Systolic wall thickening in dysfunctional segments at baseline improved with 0.9 +/- 0.7 mm (P < 0.001). Infarct size decreased 37% from 17.8 +/- 8.2 to 11.2 +/- 4.2 gram (P < 0.001). During 12-month follow-up, 3 additional revascularizations were performed and an ICD was implanted in one patient, 3 weeks after PCI. CONCLUSION: In patients with acute MI, intracoronary infusion of MBMC is safe in a multicenter setting. At 4-month follow-up, a modest increase in global and regional LV function was observed, with a concomitant decrease in infarct size.