Isolation of pulmonary veins using a thermoreactive implantable device with external energy transfer: Evaluation in a porcine model.

BACKGROUND: Pulmonary vein isolation (PVI) is a well-established method for the treatment of symptomatic paroxysmal atrial fibrillation, but is only partly successful with a high rate of electrical reconnection. We introduce a novel technique in which PVI is accomplished by noninvasive heating of a dedicated thermoresponse implant inserted into the pulmonary veins (PV), demonstrated in a porcine model. METHODS: A self-expanding nitinol-based implant was positioned in the common inferior PV of 11 pigs, using a fluoroscopy-guided transatrial appendage approach. Ablation was performed through contactless energy transfer from a primary extracorporal coil to a secondary heat ring (HR) embedded in the proximal part of the implant. Electrophysiological conduction was assessed prior to and postablation, and at 3 months. Histological samples were obtained acutely (n  =  4) and after 3 months (n  =  7). RESULTS: In total, 13 PV implants were successfully positioned in the inferior PVs of 11 animals. Ablation was performed without injury of adjacent structures. PVI and bidirectional block was electrophysiologically confirmed in all cases immediately at the time of implantation and 3 months later in seven chronic animals in whom testing was repeated. Marked evidence of ablation around the proximal HR was evident at 3 months postprocedure, with scar tissue formation and only mild neointimal proliferation. CONCLUSIONS: Successful PVI can be obtained by external electromagnetic heat transfer to a novel pulmonary vein implant.

A preliminary study of pulmonary vein implant applicability and safety as a potential ablation platform in a follow-up study in pigs.

BACKGROUND: Recurrence of atrial fibrillation after an ablation procedure remains a major problem which emphasizes the need for improved pulmonary vein isolation techniques. AIMS: The aim of this study was to describe an implantation procedure of a pulmonary vein-stent which may possibly serve as an ablation technique in the future and to examine stent safety in a follow-up study in pigs. METHODS AND RESULTS: Eight pigs were catheterized and nine self-expanding nitinol stents were implanted through a transfemoral or transatrial approach into the antra of the pulmonary veins. After 3 months' follow-up, the animals were euthanized for further examination. During the follow-up phase, no complications were observed. Absence of thrombus formation or pulmonary vein wall dissection was noticed during anatomical and histological evaluation of the heart-lung packages. All implants were almost completely covered by neo-intima, of which thickness varied between 0.2 and 3.9 mm. CONCLUSIONS: Stents can safely be positioned and deployed into the antra of the pulmonary veins without any acute or long-term (3 months) adverse effects. In the future, these implants could function as a permanently implanted ablation device and provide new therapeutic strategies for pulmonary vein isolation in patients with atrial fibrillation.

A Preclinical Study of an Implanted Device in the Pulmonary Veins, Intended for the Treatment of Atrial Fibrillation in an Ovine Model.

BACKGROUND: Atrial fibrillation is the most frequent arrhythmia in adults of which the interventional cure is hampered by high recurrence rates. Recurrence after ablation is due to an incomplete isolation of the pulmonary veins. A new ablation technique was performed, in the antra of ovine pulmonary veins, by device implantation, which was heated through a wireless heat-generating system. METHODS AND RESULTS: Implants were placed transatrially in the pulmonary veins of sheep. Using a wireless heating system, the energy was afterward transferred through wires to the implanted device according to a defined protocol. The position of the implant and the applied lesions were macroscopically evaluated. Samples of the ablated tissue of the atrio-pulmonary vein junction were histologically and immunohistochemically examined. CONCLUSIONS: Six ablation procedures in four sheep were successfully performed without adverse cardiac reactions. Implantation of the device and the wireless heat generation was feasible. Sufficient heat was produced at the level of the antra of the pulmonary veins to create ablation lesions, which were histologically and immunohistochemically confirmed.

Incidence and potential mechanism of resolved, persistent and newly acquired malapposition three days after implantation of self-expanding or balloon-expandable stents in a STEMI population: insights from optical coherence tomography in the APPOSITION II study.

AIMS: The aim of the current study was to investigate the frequency and mechanisms of sequential incomplete stent apposition (ISA) changes such as persistent, resolved or newly acquired ISA during the first three days after primary PCI (pPCI) in a matched segment-level analysis, with the comparison between self-expanding and balloon-expandable stents assessed by optical coherence tomography (OCT). METHODS AND RESULTS: The current analysis is a substudy of the APPOSITION II study that included 69 patients (self-expanding: 35, balloon-expandable: 34) using serial optical coherence tomography (OCT) post procedure and three days after pPCI. In order to evaluate a temporal change in ISA, stented regions were segmented using fiduciary landmarks. In a total of 228 corresponding segments, persistent and newly acquired ISA were less frequently observed in self-expanding stents than in balloon-expandable stents (11.5% vs. 33.9%, p<0.01, 2.7% vs. 14.8%, p<0.01, respectively). New appearances of ISA were caused by tissue resorption, vasorelaxation and "early" recoil in balloon-expandable stents, and only tissue resorption in self-expanding stents. CONCLUSIONS: Three days after pPCI, tissue resorption and vasorelaxation were biological factors associated with new appearance of ISA while "early" recoil of balloon-expandable stents was a mechanical factor. Both persistent ISA and newly acquired ISA occurred less frequently in self-expanding stents, resulting in a low number of ISA segments compared to balloon-expandable stents. Clinical Trials Registration Information: Randomised Comparison Between the STENTYS Self-expanding Coronary Stent and a Balloon-expandable Stent in Acute Myocardial Infarction (APPOSITION II). ClinicalTrials.gov Identifier: NCT01008085

Iatrogenic left main coronary artery dissection and intramural hematoma caused by diagnostic transradial cardiac catheterization.

The growing use of the transradial approach for percutaneous coronary interventions has been shown to decrease the risk of major vascular complications. However, in this case report we describe a iatrogenic left main dissection during diagnostic coronary catheterization, which remains a rare, but still life-threatening condition. The adjunctive use of intravascular ultrasound may assist in the accurate diagnosis and treatment process.

Self-expanding versus balloon-expandable stents in acute myocardial infarction: results from the APPOSITION II study: self-expanding stents in ST-segment elevation myocardial infarction.

OBJECTIVES: This study sought to investigate whether self-expanding stents are more effective than balloon-expandable stents for reducing stent malapposition at 3 days after implantation in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. BACKGROUND: Acute myocardial infarction is associated with vasoconstriction and large thrombus burden. Resolution of vasoconstriction and thrombus load during the first hours to days after primary percutaneous coronary intervention may lead to stent undersizing and malapposition, which may subsequently lead to stent thrombosis or restenosis. In addition, aggressive stent deployment may cause distal embolization. METHODS: Eighty patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomized to receive a self-expanding stent (STENTYS, STENTYS SA, Paris, France) (n = 43) or a balloon-expandable stent (VISION, Abbott Vascular, Santa Clara, California; or Driver, Medtronic, Minneapolis, Minnesota) (n = 37) at 9 European centers. The primary endpoint was the proportion of stent strut malapposition at 3 days after implantation measured by optical coherence tomography. Secondary endpoints included major adverse cardiac events (cardiac death, recurrent myocardial infarction, emergent bypass surgery, or clinically driven target lesion revascularization). RESULTS: At 3 days after implantation, on a per-strut basis, a lower rate of malapposed stent struts was observed by optical coherence tomography in the self-expanding stent group than in the balloon-expandable group (0.58% vs. 5.46%, p < 0.001). On a per-patient basis, none of the patients in the self-expanding stent group versus 28% in the balloon-expandable group presented ≥5% malapposed struts (p < 0.001). At 6 months, major adverse cardiac events were 2.3% versus 0% in the self-expanding and balloon-expandable groups, respectively (p = NS). CONCLUSIONS: Strut malapposition at 3 days is significantly lower in ST-segment elevation myocardial infarction patients allocated to self-expanding stents when than in those allocated to balloon-expandable stents. The impact of this difference on clinical outcome and the risk of late stent thrombosis need to be evaluated further. (Randomized Comparison Between the STENTYS Self-expanding Coronary Stent and a Balloon-expandable Stent in Acute Myocardial Infarction [APPOSITION II]; NCT01008085).

The ProLimus trial: a prospective, non-randomised, multicentre trial to evaluate the safety and clinical performance of the pimecrolimus eluting stent system (ProGenic).

AIMS: The aim of this multicentre, non-randomised trial was to evaluate the safety and efficacy at 180+/-14 days of a pimecrolimus eluting coronary stent based on a cobalt-chromium platform and a poly-L-lactic acid (PLLA) bioresorbable polymer. METHODS AND RESULTS: Sixty-one patients, with single de novo coronary lesions <14 mm in length and a reference vessel diameter of 3.0 to 3.5 mm, were enrolled in five centres (Germany and Belgium). Angiography and IVUS were performed at baseline, post-procedure and 180+/-14 days later. The primary endpoint was a composite of major adverse cardiac events (MACE) at 180+/-14 days and expected to be below 20%. Patients had single vessel disease in 59%, 2-vessel disease in 28% and 3-vessel disease in 13% of cases. MACE rate at 180+/-14 days was 18.0%. Binary in-stent restenosis was 32.7% due to in-stent late lumen loss of 1.11+/-0.65 mm by QCA. Stent thrombosis rate at 30+/-7 and 180+/-14 days was 1.6% and 3.3%, respectively. Overall TLR rate at 30+/-7, 180+/-14 days and 12+/-1 months was 1.6%, 27.9% and 32.8% respectively. CONCLUSIONS: The primary endpoint was met at 180+/-14 days. However, the anti-restenotic effect of the pimecrolimus eluting stent did not reach levels similar to clinically established DES.

Re-examining minimal luminal diameter relocation and quantitative coronary angiography--intravascular ultrasound correlations in stented saphenous vein grafts: methodological insights from the randomised RRISC trial.

AIMS: Angiographic parameters (such as late luminal loss) are common endpoints in drug-eluting stent trials, but their correlation with the neointimal process and their reliability in predicting restenosis are debated. METHODS AND RESULTS: Using quantitative coronary angiography (QCA) data (49 bare metal stent and 44 sirolimus-eluting stent lesions) and intravascular ultrasound (IVUS) data (39 bare metal stent and 34 sirolimus-eluting stent lesions) from the randomised Reduction of Restenosis In Saphenous vein grafts with Cypher stent (RRISC) trial, we analysed the "relocation phenomenon" of QCA-based in-stent minimal luminal diameter (MLD) between post-procedure and follow-up and we correlated QCA-based and IVUS-based restenotic parameters in stented saphenous vein grafts. We expected the presence of MLD relocation for low late loss values, as MLD can "migrate" along the stent if minimal re-narrowing occurs, while we anticipated follow-up MLD to be located close to post-procedural MLD position for higher late loss. QCA-based MLD relocation occurred frequently: the site of MLD shifted from post-procedure to follow-up an "absolute" distance of 5.8 mm [2.5-10.2] and a "relative" value of 29% [10-46]. MLD relocation failed to correlate with in-stent late loss (rho = 0.14 for "absolute" MLD relocation [p = 0.17], and rho=0.03 for "relative" relocation [p = 0.811). Follow-up QCA-based and IVUS-based MLD values well correlated in the overall population (rho = 0.76, p < 0.001), but QCA underestimated MLD on average 0.55 +/- 0.49 mm, and this was mainly evident for lower MLD values. Conversely, the location of QCA-based MLD failed to correlate with the location of IVUS-based MLD (rho = 0.01 for "absolute" values--in mm [p = 0.911, rho = 0.19 for "relative" values--in % [p = 0.111). Overall, the ability of late loss to "predict" IVUS parameters of restenosis (maximum neointimal hyperplasia diameter, neointimal hyperplasia index and maximum neointimal hyperplasia area) was moderate (rho between 0.46 and 0.54 for the 3 IVUS parameters). CONCLUSIONS: These findings suggest the need for a critical re-evaluation of angiographic parameters (such as late loss) as endpoints for drug-eluting stent trials and the use of more precise techniques to describe accurately and properly the restenotic process.

Rotational vs. standard coronary angiography: an image content analysis.

OBJECTIVE: To evaluate the clinical utility of images acquired from rotational coronary angiographic (RA) acquisitions compared to standard "fixed" coronary angiography (SA). BACKGROUND: RA is a novel angiographic modality that has been enabled by new gantry systems that allow calibrated automatic angiographic rotations and has been shown to reduce radiation and contrast exposure compared to SA. RA provides a dynamic multiple-angle perspective of the coronaries during a single contrast injection. METHODS: The screening adequacy, lesion assessment, and a quantitative coronary analysis (QCA) of both SA and RA were compared by independent blinded review in 100 patients with coronary artery disease (CAD). RESULTS: SA and RA recognize a similar total number of lesions (P = 0.61). The qualitative assessment of lesion characteristics and severity between modalities was comparable and lead to similar clinical decisions. Visualization of several vessel segments (diagonal, distal RCA, postero-lateral branches and posterior-descending) was superior with RA when compared to SA (P < 0.05). A QCA comparison (MLD, MLA, LL, % DS) revealed no difference between SA and RA. The volume of contrast (23.5 +/- 3.1 mL vs. 39.4 +/- 4.1; P = 0.0001), total radiation exposure (27.1 +/- 4 vs. 32.1 +/- 3.8 Gycm(2); P = 0.002) and image acquisition time (54.3 +/- 36.8 vs. 77.67 +/- 49.64 sec; P = 0.003) all favored RA. CONCLUSION: Coronary lesion assessment, coronary screening adequacy, and QCA evaluations are comparable in SA and RA acquisition modalities in the diagnosis of CAD however RA decreases contrast volume, image acquisition time, and radiation exposure.

"Virtual" in-vivo bench test for bifurcation stenting with "StentBoost".

"StentBoost" is a new angiographic technique that allows improved angiographic visualization of stents deployed in coronary arteries, by enhancing the X-ray focus of the region where the stent is placed. Using this technique we were able to assess the deformation and the expansion of a stent deployed to treat a bifurcation lesion between the mid-left anterior descending (LAD) artery and a big second diagonal branch, during sequential inflations of: (1) the stent per se in the LAD, (2) the ostium of the diagonal branch through the stent struts, (3) the stent again with a non compliant balloon, and (4) both branches with the kissing balloon technique. "StentBoost" guided our clinical and angiographic decision-making process and allowed us to create a "virtual" bench test of the stent deployed at the level of the bifurcation treated.

Compositional volumetry of non-calcified coronary plaques by multislice computed tomography: an ex vivo feasibility study.

AIMS: Non-invasive quantitative compositional analysis of coronary plaque would be a major advantage to study coronary artery disease. This study explores the application to use the Hounsfield units (HU) distribution of coronary plaques imaged by multislice computed tomography-coronary angiography (MSCT-CA). METHODS AND RESULTS: A dedicated computer-assisted method was developed to measure the HU distribution within a coronary plaque by MSCT-CA. To test the feasibility of the method, an ex vivo left anterior descending (LAD) coronary specimen, excised during autopsy, was imaged both by non-enhanced and enhanced MSCT-CA. Quantitative histology was used as a reference. To test the feasibility of the new volumetric analytic method, the MSCT-CA data were compared with volumetric histopathology. The coronary specimen, with a heterogeneously distributed plaque composition without large areas of calcification, was histologically sampled at five different locations, 5 mm apart, where at each location 15 sections were taken at 100 microm intervals, resulting in 75 individual histology sections. Tri-chrome Masson staining was used for histology quantification of three plaque/tissue components: smooth muscle cells (SMC), collagen and calcium. MSCT plaque composition was defined as "lower-HU" or "higher-HU" plaque and "calcium" based on the HU distribution. Comparison of the MSCT defined tissue components against histology showed a good relationship without significant differences. CONCLUSIONS: This ex vivo study shows the feasibility of using the Hounsfield unit distribution to perform compositional coronary plaque volumetry by MSCT-CA. The results are encouraging.

Comparison of assessment of native coronary arteries by standard versus three-dimensional coronary angiography.

Vessel foreshortening is a major limitation of standard coronary angiography due to the 2-dimensional representation of 3-dimensional structures. Three-dimensional models may overcome it. The aim of this study was to compare measurements of coronary segments from quantitative coronary angiography (QCA) in an operator-selected "working view" of standard 2-dimensional coronary angiography with those from 3-dimensional coronary angiography (3D-CA) reconstruction models, which are automatically generated from software applied to rotational coronary angiographic acquisitions. Patients who underwent percutaneous coronary intervention were considered. Two or 3 segments of the artery needing treatment were prespecified, using bifurcations as edges. The operator selected a working view from standard angiography as the view best representing each segment. Rotational angiography was performed, allowing 3-dimensional reconstruction of the selected segments. Additionally a marker guidewire (with 4 markers 10 mm away from one another at the distal tip) was used to further measure segment length, and it was considered the "gold standard" reference. In 36 patients, 81 segments from 12 left anterior descending, 12 circumflex, and 12 right coronary arteries were evaluated. Three-dimensional coronary angiography was always feasible. Although reference vessel diameter was not different between 3D-CA and QCA (p >0.05), segment length measurements were on average 2.3 +/- 2.5 mm longer with 3D-CA than with QCA (p <0.001) and 0.4 +/- 1.8 mm longer than with marker guidewire measurement (p = 0.047). Marker guidewire measurements were 1.9 +/- 2.8 mm longer than QCA measurements (p <0.001). According to Bland-Altman plots, 3D-CA and marker guidewire measurements had the best agreement. In conclusion, 3-dimensional coronary modeling is highly feasible and yields more accurate assessments of the lengths of coronary segments than standard QCA.

Mitochondrial uncoupling protein 2 mediates temperature heterogeneity in atherosclerotic plaques.

AIMS: Rupture-prone atherosclerotic plaques show an elevated temperature, but a molecular explanation for this phenomenon is unknown. Here, we investigated whether mitochondrial uncoupling protein 2 (UCP2) could be involved because this protein is a macrophage homologue of thermogenin in brown fat tissue. METHODS AND RESULTS: Immunohistochemistry, western blotting, and real-time quantitative polymerase chain reaction were used to detect UCP2 expression in human and rabbit atherosclerotic plaques. Temperature was measured in plaques with thermography catheters and in cultured cells with precision thermometers. UCP2 was abundantly expressed in subendothelial macrophages of atherosclerotic plaques but not in deeper layers of the plaque. Ex vivo temperature measurements in atherosclerotic rabbit thoracic aorta demonstrated a correlation between local plaque temperature, total macrophage mass, and UCP2 expression. In vitro, chemical uncoupling of macrophages with sodium cyanide resulted in heat production (DeltaT = 0.13 +/- 0.04 degrees C vs. controls). Also, overexpression of UCP2 in cultured cells led to a similar increase in temperature. CONCLUSION: Our findings provide evidence that temperature heterogeneity in atherosclerotic plaques is at least in part attributed to UCP2 expression in macrophages. The heat generated might be used to detect unstable, macrophage-rich, atherosclerotic plaques via thermography.

Three-dimensional and quantitative analysis of atherosclerotic plaque composition by automated differential echogenicity.

OBJECTIVE: To validate automated and quantitative three-dimensional analysis of coronary plaque composition using intracoronary ultrasound (ICUS). BACKGROUND: ICUS displays different tissue components based on their acoustic properties in 256 grey-levels. We hypothesised that computer-assisted image analysis (differential echogenicity) would permit automated quantification of several tissue components in atherosclerotic plaques. METHODS AND RESULTS: Ten 40-mm-long left anterior descending specimens were excised during autopsy of which eight could be successfully imaged by ICUS. Histological sections were taken at 5 mm intervals and analyzed. Since most of the plaques were calcified and having a homogeneous appearance, one specimen with a more heterogeneous composition was further examined: at each interval of 5 mm, 15 additional sections (every 100 microm) were evaluated. Plaques were scored for echogenicity against the adventitia: brighter (hyperechogenic) or less bright (hypoechogenic). Areas of hypoechogenicity correlated with the presence of smooth muscle cells. Areas of hyperechogenicity correlated with presence of collagen, and areas of hyperechogenicity with acoustic shadowing correlated with calcium. None of these comparisons showed statistical significant differences. CONCLUSION: This ex vivo feasibility study shows that automated three-dimensional differential echogenicity analysis of ICUS images allows identification of different tissue types within atherosclerotic plaques. This technology may play a role as an additional tool in longitudinal studies to trace possible changes in plaque composition.

Increased late mortality after sirolimus-eluting stents versus bare-metal stents in diseased saphenous vein grafts: results from the randomized DELAYED RRISC Trial.

OBJECTIVES: We sought to provide long-term follow-up data of sirolimus-eluting stents (SES) versus bare-metal stents (BMS) in saphenous vein grafts (SVG) from the RRISC (Reduction of Restenosis In Saphenous vein grafts with Cypher) trial. BACKGROUND: We have previously shown that, in SVG, the use of SES reduces 6-month restenosis and repeated revascularization procedures versus the use of BMS. These data are consistent with trials in native coronary arteries. However, recently published long-term follow-up data of these trials have revealed an increased risk of adverse events (particularly very late stent thrombosis) after SES. METHODS: A total of 75 patients with 96 SVG lesions were randomized to SES versus BMS. All patients underwent clinical follow-up up to 3 years. Specific outcomes assessed in this secondary post-hoc analysis were all-cause mortality, myocardial infarction, and target vessel revascularization. RESULTS: Thirty-eight patients received 60 SES for 47 lesions, whereas 37 patients received 54 BMS for 49 lesions. At a median follow-up time of 32 months (interquartile range 26.5 to 36 months), 11 deaths (7 cardiac, of which 1 was caused by very late stent thrombosis and, 3 were sudden) occurred after SES (29% [95% confidence interval (CI) 17% to 45%]) versus 0 after BMS (0% [95% CI 0% to 9%]) with an absolute difference of 29% ([95% CI 14% to 45%], p < 0.001). The rates of myocardial infarction and target vessel revascularization were not different: 18% and 34% after SES, respectively, versus 5% and 38% after BMS, respectively (p = 0.15 and p = 0.74, respectively). CONCLUSIONS: In this secondary post-hoc analysis, BMS were associated with lower long-term mortality than SES for SVG disease. Also, the 6-month reduction in repeated revascularization procedures with SES was lost at longer-term follow-up. (RRISC Study: Reduction of Restenosis In Saphenous Vein Grafts With Cypher Sirolimus-Eluting Stent; http://clinicaltrials.gov/ct/show/NCT00263263?order=1; NCT00263263).

Intravascular ultrasound comparison of sirolimus-eluting stent versus bare metal stent implantation in diseased saphenous vein grafts (from the RRISC [Reduction of Restenosis In Saphenous Vein Grafts With Cypher Sirolimus-Eluting Stent] trial).

The randomized Reduction of Restenosis In Saphenous Vein Grafts with Cypher Sirolimus-Eluting Stent trial compared angiographic outcomes of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs) in saphenous vein grafts (SVG). Using intravascular ultrasound (IVUS) performed during 6-month follow-up angiography, we compared the vascular effects of the 2 types of stent on SVGs. Of 75 patients (96 lesions) included, 59 patients underwent IVUS in 61 SVGs; 29 patients received 40 SESs for 34 lesions, and 30 patients received 42 BMSs for 39 lesions. IVUS parameters (diameters, areas, and volumes) were compared in the 2 groups. A specific analysis was performed for overlapping SESs. Median neointimal volume was 1.3 mm(3) (interquartile range 0 to 13.1) in SESs versus 24.5 (7.8 to 39.5) in BMSs (p <0.001). Minimal incomplete stent apposition was detected at only 3 stent edges (2 BMSs, 1 SES) next to ectatic regions of the SVG. Compared with single SESs, overlapping SESs showed significant increases in neointimal reaction, with a neointimal volume of 0.6 mm(3)/mm of stent (0.1 to 1.8) versus 0 (0 to 0.4) in single SESs (p = 0.03), and this phenomenon was mainly localized in overlapping SES segments, where neointimal volume per millimeter of stent was 1.1 mm(3)/mm (0.6 to 4.4) versus 0 (0 to 1.3) in nonoverlapping segments (p = 0.05). In conclusion, SESs effectively inhibit neointimal hyperplasia volume compared with BMSs in diseased vein grafts, without evidence of increased incomplete apposition risk. The neointimal response to overlapping SES layers seems higher than to a single SES layer.