Alain Poncelet

Characterization of Acute and Chronic Myocardial Infarcts by Multidetector Computed Tomography Comparison With Contrast-Enhanced Magnetic Resonance

Background— We evaluated whether contrast-enhanced multidetector computed tomography (CE-MDCT) might characterize myocardial infarct (MI) with patterns similar to those obtained by contrast-enhanced magnetic resonance (CE-MR) and studied the underlying mechanisms. Methods and Results— In vivo infarct characterization by CE-MDCT was shown to be feasible between 4 and 20 minutes after contrast injection in 7 pigs with MI. Subsequently, in 16 patients with acute MI and 21 patients with chronic MI, contrast patterns by CE-MDCT were related to CE-MR. Eighteen patients had hypoenhanced regions on early CE-MDCT images at the time of coronary imaging, and 34 patients had hyperenhanced regions on images acquired 10 minutes later. On a segmental basis, there was moderately good concordance of early hypoenhanced regions (92%, &kgr;=0.54, P<0.001) and late hyperenhanced regions (82%, &kgr;=0.61, P<0.001) between CE-MDCT and CE-MR. Absolute sizes of early hypoenhanced (6±16 versus 7±16 g, P=0.25) and late hyperenhanced (36±34 versus 31±40 g, P=0.14) regions were similar on CE-MDCT and CE-MR and were highly correlated (r=0.93, P<0.001 and r=0.89, P<0.001 respectively). In 8 retrogradely perfused infarcted rabbit hearts, contrast kinetics of iomeprol were similar to gadodiamide, ie, slow wash in (8.7±6.7 versus 1.2±0.3 minutes, P<0.001) in infarct core and slow washout (20±12 versus 2.5±0.5 minutes, P<0.001) in both infarct core and rim compared with the remote region. Conclusions— Because iodated contrast agents have similar kinetics in infarcted and noninfarcted myocardium as gadolinium DPTA, CE-MDCT can characterize acute and chronic MI with contrast patterns similar to CE-MR. CE-MDCT may thus provide important information on infarct size and viability at the time of noninvasive coronary imaging.

Although pig allogeneic mesenchymal stem cells are not immunogenic in vitro, intracardiac injection elicits an immune response in vivo.

Background. In vitro, mesenchymal stem cells (MSCs) have demonstrated a low immunogenic profile. In this study, we tested the immune response to allogeneic MSCs in immunocompetent swines both in vitro and in vivo. Methods. Major histocompatibility complex–controlled swine leukocyte antigen (SLA)cd and SLAdd were used as donor and recipient, respectively. In vitro, proliferative responses were tested by mixed lymphocyte reaction (MLR) or cocultures and cytokine profiling by enzyme-linked immunosorbent assay. In vivo, allogeneic MSCs were injected in cardiac infarcted area (n=3) and compared with subcutaneous injections of either MSCs (n=2) or peripheral blood mononuclear cells (PBMCs; n=2). Two additional animals received a skin graft as controls. No immunosuppression was used. Specific antidonor humoral responses were tested by flow cytometry and complement-dependent cytotoxicity assay. Results. In vitro, either unstimulated MSCs or interferon (IFN)-&ggr; stimulated MSC failed to elicit a proliferative response (stimulation index: 1.23 vs. 1.12 vs. 36.9 for controls, P<.001). Concomitantly to the absence of proliferation to MSCs, low production of IFN-&ggr; and interleukin-2 was evidenced in supernatants while the production of Th2 cytokines was comparable to controls. In vivo, all animals receiving skin grafts, subcutaneous PBMCs and intracardiac MSCs injections developed donor-specific cellular and humoral responses (immunoglobulins M and G) with antibody-complement-mediated cytotoxicity. Subcutaneous MSCs injection needed a rechallenge to similarly develop a cytotoxic humoral response. Conclusions. Intracardiac allogeneic porcine mesenchymal stem cells elicit an immune response despite their low immunogenic profile in vitro. This result suggests that in vivo characteristics of allogeneic MSCs might differ and emphasizes the importance of pursuing research both in vitro and in vivo.

Long-term outcome and alloantibody production in a non-myeloablative regimen for induction of renal allograft tolerance

BACKGROUND Multilineage chimerism and long-term acceptance of renal allografts has been produced in non-human primates conditioned with a nonmyeloablative regimen. Our study was undertaken to evaluate the immunological and pathological status of long-term survivors and to define the role of splenectomy and of the primarily vascularized kidney in the regimen. METHOD Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; group A (n=13): KTx and splenectomy on the day of donor bone marrow transplantation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C (n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor bone marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. RESULTS In group A, 11 of 13 monkeys developed chimerism and 9 monkeys achieved long-term survival of 4 to 70 months without evidence of chronic vascular rejection. Alloantibodies were detected in only one long-term survivor. In contrast, all three monkeys in group B developed alloantibodies and rejected their allografts. In group C, long-term survival without alloantibody production was observed in two of three monkeys that had developed chimerism. In group D, all three recipients were sensitized and rejected the kidney allografts rapidly after transplantation. CONCLUSIONS 1) Production of anti-donor antibody was prevented in most recipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not included in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and allograft rejection. 3) Immediate transplantation of the kidney at the time of recipient conditioning is not essential for induction of donor specific hyporesponsiveness by bone marrow transplantation.

Gradient-based delineation of the primary GTV on FDG-PET in non-small cell lung cancer: A comparison with threshold-based approaches, CT and surgical specimens.

PURPOSE The aim of this study was to validate a gradient-based segmentation method for GTV delineation on FDG-PET in NSCLC through surgical specimen, in comparison with threshold-based approaches and CT. MATERIALS AND METHODS Ten patients with stage I-II NSCLC were prospectively enrolled. Before lobectomy, all patients underwent contrast enhanced CT and gated FDG-PET. Next, the surgical specimen was removed, inflated with gelatin, frozen and sliced. The digitized slices were used to reconstruct the 3D macroscopic specimen. GTVs were manually delineated on the macroscopic specimen and on CT images. GTVs were automatically segmented on PET images using a gradient-based method, a source to background ratio method and fixed threshold values at 40% and 50% of SUV(max). All images were finally registered. Analyses of raw volumes and logarithmic differences between GTVs and GTV(macro) were performed on all patients and on a subgroup excluding the poorly defined tumors. A matching analysis between the different GTVs was also conducted using Dices similarity index. RESULTS Considering all patients, both lung and mediastinal windowed CT overestimated the macroscopy, while FDG-PET provided closer values. Among various PET segmentation methods, the gradient-based technique best estimated the true tumor volume. When analysis was restricted to well defined tumors without lung fibrosis or atelectasis, the mediastinal windowed CT accurately assessed the macroscopic specimen. Finally, the matching analysis did not reveal significant difference between the different imaging modalities. CONCLUSIONS FDG-PET improved the GTV definition in NSCLC including when the primary tumor was surrounded by modifications of the lung parenchyma. In this context, the gradient-based method outperformed the threshold-based ones in terms of accuracy and robustness. In other cases, the conventional mediastinal windowed CT remained appropriate.

Prognostic value of FDG uptake in early stage non-small cell lung cancer

BACKGROUND Non-small cell lung cancer (NSCLC) has a poor prognosis even for early stages of the disease (stage I and II). We studied the prognostic value of PET FDG in patients with completely resected stage I and II NSCLC. METHODS Retrospective study of 96 patients with NSCLC whose staging included 18F-FDG PET (fluoro deoxy glucose positron emission tomography). Histopathological stage was either stage I (75) or stage II (n=21). FDG uptake was measured as maximal standardized uptake value for body weight (SUVmax). Mean follow-up was 45+/-30 months (1-142 months). Overall and cancer-free survival rates were recorded. RESULTS SUVmax were higher for stage II than for stage I (10.5+/-4.5 vs 8.5+/-5, p=0.04). Mean tumor volumes were equivalent for both stages (33 cm3, p=0.18), excluding a partial volume effect. The median SUVmax in the whole study population was 7.8. The median survival was significantly longer in patients with a lower (SUVmax<or=7.8) FDG uptake (127 months vs 69 months, p=0.001). For stage I tumors (n=75), high FDG uptake was significantly associated with reduced median survival: 127 months if SUVmax<or=7.8 and 69 months if SUVmax>7.8 (p=0.001). For stage II tumors (n=21), no statistical difference was observed: 72 months vs 40 months for SUVmax<or=7.8 and for SUVmax>7.8, respectively (p=0.11), although there was a clear trend towards reduced survival for highly metabolic tumors. Disease-free survival was also significantly better for lower metabolic tumors: 96.1 months vs 87.7 months (p=0.01). CONCLUSION High FDG uptake is associated with reduced overall survival and disease-free survival of patients with completely resected stage I-II NSCLC. Whether patients with highly metabolic tumors should undergo a closer postoperative surveillance or adjuvant chemotherapy has to be addressed in a properly designed prospective trial.

Repair of Bicuspid Aortic Valves in Patients With Aortic Regurgitation

Background— Bicuspid aortic valve regurgitation can be caused by a defect in the valve itself or by dysfunction of one or more components of the aortic root complex. A successful repair thus requires correction of all aspects of the problem simultaneously. We review our experience addressing both the valve and the aortic root when correcting bicuspid valve regurgitation. Methods and Results— Between 1996 and 2004, we treated 68 patients for aortic regurgitation. Thirty patients had isolated aortic regurgitation, and 38 had an associated ascending aortic aneurysm. All patients were treated using a standardized and integrated surgical technique, which included resection of the median raphe or leaflet plication, subcommissural annuloplasty, reinforcement of the leaflet free edge, and sinotubular junction plication. In the 38 patients with proximal aortic dilatation, reimplantation or remodeling of the aortic root was performed. Immediate postoperative echocardiography showed grade ≤1 aortic regurgitation in all patients. Three patients nonetheless needed an early re-operation because of recurrent regurgitation. No hospital mortality was observed. At a mean follow-up of 34 months after surgery, all patients were in New York Heart Association (NYHA) class 1 or 2. Two patients needed a re-operation (23 and 92 months, respectively). Echocardiographic follow-up showed no progression of the regurgitation in 58 surviving patients. Four patients progressed to grade 2 regurgitation. Conclusion— Our data indicate that regurgitant bicuspid aortic valves, whether alone or in association with a proximal aortic dilatation, can be repaired successfully provided that both the valve and the aortic root problems are treated simultaneously.

Effects of Preoperative Aortic Insufficiency on Outcome After Aortic Valve–Sparing Surgery

Background— The presence of significant preoperative aortic insufficiency (AI) or the need for cusp repair has been suggested as a risk factor for poorer outcomes after aortic valve (AV)–sparing surgery. We analyzed the influence of these factors on the mid-term outcomes of AV surgery. Methods and Results— Between 1996 and 2008, 164 consecutive patients underwent elective AV-sparing surgery. Severe preoperative AI (grade ≥3+) was present in 93 patients (57%), and 54 (33%) had a bicuspid valve. Root repair was performed with either the reimplantation (74%) or the remodeling (26%) technique, and cusp repair was performed in 90 patients (55%). Mean clinical follow-up was 57 months. Hospital mortality was 0.6%. Cusp repair was required in 52% of the patients with preoperative AI ≤2+ and in 57% of those with AI ≥3+ (P=0.6). Cusp repair was required more frequently in bicuspid versus tricuspid valves (91% versus 38%, P<0.001). Overall survival at 8 years was 88±8%. Freedom from AV reoperation at 8 years was similar with preoperative AI ≤2+ versus preoperative AI ≥3+ (89±11% versus 90±7%, P=0.7) and with versus without cusp repair (84±17% versus 92±8%, P=0.5). Freedom from recurrent AI (grade ≥3+) at 5 years was also similar between groups (90±10% versus 89±8%, P=0.9, and 90±8% versus 89±9%, P=0.8, respectively). By multivariate analyses, predictors of recurrent AI ≥2+ were preoperative left ventricle end-diastolic diameter and AI >1+ on discharge echocardiography. Conclusions— With a systematic approach to cusp assessment and repair, AV-sparing surgery for root pathology has an acceptable mid-term outcome, irrespective of preoperative AI or need for cusp repair.

Lower incidence of cytomegalovirus infection with everolimus versus mycophenolate mofetil in de novo cardiac transplant recipients: a randomized, multicenter study

M. Viganò, T. Dengler, M.F. Mattei, A. Poncelet, J. Vanhaecke, E. Vermes, R. Kleinloog, Y. Li, Y. Gezahegen, J.F. Delgado, on behalf of the RAD A2411 Study Investigators. Lower incidence of cytomegalovirus infection with everolimus versus mycophenolate mofetil in de novo cardiac transplant recipients: a randomized, multicenter study.
Transpl Infect Dis 2010: 12: 23–30. All rights reserved

The Athlete's Heart - Gender Aspects

Background— Bilateral internal thoracic arteries (BITA) demonstrated superiority over other grafts to the left coronary system in terms of patency and survival benefit. Several BITA configurations are proposed for left-sided myocardial revascularization, but the ideal BITA assemblage is still unidentified. Methods and Results— From 03/2003 to 08/2006, 1297 consecutive patients underwent isolated bypass surgery in our institution. 481 patients met the inclusion criteria for randomization, and 304 (64%) were randomized. Patients were allocated to BITA in situ grafting (n=147) or Y configuration (n=152) then evaluated for clinical, functional, and angiographic outcome after 6 months and 3 years. Patient telephone interviews were conducted every 3 months and a stress test performed twice yearly under the referring cardiologist’s supervision. Angiographic follow-up was performed 6 months after surgery. The primary and secondary end points were, respectively, major adverse cerebrocardiovascular events (MACCE) and the proportion of ITA grafts that were completely occluded at follow-up angiography. More arterial anastomoses were performed in patients randomized to the Y than the in situ configuration (3.2 versus 2.4; P<0.001). No significant difference between the 2 groups in terms of hospital mortality or morbidity was found. At follow-up, there was no significant difference in any MACCE rate between the 2 groups. 450 out of 464 anastomosis (97%) in the BITA Y group and 287 of 295 (97%) in the BITA in situ group were controlled patent (P=0.99). Conclusion— Excellent patency rates were achieved using both BITA configurations with no significant differences in terms of MACCE up to 19 months postoperatively, but longer-term results remain to be established.BACKGROUND: Bilateral internal thoracic arteries (BITA) demonstrated superiority over other grafts to the left coronary system in terms of patency and survival benefit. Several BITA configurations are proposed for left-sided myocardial revascularization, but the ideal BITA assemblage is still unidentified. METHODS AND RESULTS: From 03/2003 to 08/2006, 1297 consecutive patients underwent isolated bypass surgery in our institution. 481 patients met the inclusion criteria for randomization, and 304 (64%) were randomized. Patients were allocated to BITA in situ grafting (n=147) or Y configuration (n=152) then evaluated for clinical, functional, and angiographic outcome after 6 months and 3 years. Patient telephone interviews were conducted every 3 months and a stress test performed twice yearly under the referring cardiologists supervision. Angiographic follow-up was performed 6 months after surgery. The primary and secondary end points were, respectively, major adverse cerebrocardiovascular events (MACCE) and the proportion of ITA grafts that were completely occluded at follow-up angiography. More arterial anastomoses were performed in patients randomized to the Y than the in situ configuration (3.2 versus 2.4; P>0.001). No significant difference between the 2 groups in terms of hospital mortality or morbidity was found. At follow-up, there was no significant difference in any MACCE rate between the 2 groups. 450 out of 464 anastomosis (97%) in the BITA Y group and 287 of 295 (97%) in the BITA in situ group were controlled patent (P=0.99). CONCLUSIONS: Excellent patency rates were achieved using both BITA configurations with no significant differences in terms of MACCE up to 19 months postoperatively, but longer-term results remain to be established.

Exercise capacity in patients supported with rotary blood pumps is improved by a spontaneous increase of pump flow at constant pump speed and by a rise in native cardiac output.

Exercise capacity is improved in patients supported with continuous flow rotary blood pumps (RP). The aim of this study was to investigate the mechanisms underlying this improvement. Ten patients implanted with a RP underwent cardiopulmonary exercise testing (CPET) at 6 months after surgery with hemodynamic and metabolic measurements (RP group). A group of 10 matched heart failure patients were extracted from our heart transplant database, and the results of their last CPET before transplantation were used for comparison (heart failure [HF] group). Peak VO(2) was significantly higher in RP than in HF patients (15.8 ± 6.2 vs. 10.9 ± 3 mL O(2)/kg.min) reaching 52 ± 16% of their predicted peak VO(2). The total output measured by a Swan-Ganz catheter increased from 5.6 ± 1.6 to 9.2 ± 1.8 L/min in the RP group and was significantly higher at rest and at peak exercise than in the HF group, whose output increased from 3.5 ± 0.4 to 5.6 ± 1.6 L/min. In the RP group, the estimated pump flow increased from 5.3 ± 0.4 to 6.2 ± 0.8, whereas the native cardiac output increased from 0.0 ± 0.5 to 3 ± 1.7 L/min. Cardiac output at peak exercise was inversely correlated with age (r = -0.86, P = 0.001) and mean pulmonary artery pressure (r = -0.75, P = 0.012). Maximal exercise capacity is improved in patients supported by RP as compared to matched HF patients and reaches about 50% of the expected values. Both a spontaneous increase of pump flow at constant pump speed and an increase of the native cardiac output contribute to total flow elevation. These findings may suggest that an automatic pump speed adaptation during exercise would further improve the exercise capacity. This hypothesis should be examined.