Gregorio Rábago

Different expression of MMPs/TIMP-1 in human atherosclerotic lesions. Relation to plaque features and vascular bed

BACKGROUND Proteolytic imbalance might determine arterial remodeling and plaque destabilization in atherosclerotic vessels. The aim of this study was to examine differences in the patterns of metalloproteinases (MMPs) and MMP inhibitor (TIMP-1) expression in advanced human atheromas, both in relation to the plaque features and the vascular bed involved. METHODS AND RESULTS Immunohistochemistry for MMP-1, -3, -9 and TIMP-1 as well as the collagen content were measured in vascular sections from patients undergoing peripheral revascularization (carotid n=11, femoral n=23) and aorto-coronary bypass surgery (mammary arteries n=20, as controls). Increased expression of all MMPs was detected in atherosclerotic as compared with control sections (P<0.01). Aneurysmal plaques showed a significant increase of MMP-1 and-3 and a reduction in total collagen (P<0.05) in relation to occlusive lesions. Calcification areas in atherosclerotic plaques were consistently associated with increased TIMP-1 expression (P<0.01). Finally, MMP-9 expression was higher in occlusive lesions from carotid than femoral arteries (P<0.01). CONCLUSIONS Aneurysm lesions expressed higher MMP-1 and-3 expression than occlusive plaques, and MMP-9 was mainly detected in carotid as compared with femoral arteries. TIMP-1 was associated with arterial calcification. These differences in the MMPs/TIMP-1 expression might determine the evolution of advanced atherosclerotic plaques and contribute to its vulnerability.

Malignancy After Heart Transplantation: Incidence, Prognosis and Risk Factors

The Spanish Post‐Heart‐Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984–2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post‐HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post‐HT (from respectively 5.2 and 8.9 per 1000 person‐years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R‐blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post‐HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post‐HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre‐HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five‐year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

TachoSil surgical patch versus conventional haemostatic fleece material for control of bleeding in cardiovascular surgery: a randomised controlled trial

OBJECTIVE Prolonged bleeding during cardiovascular surgery presents a risk for the patient and increases the time and cost of surgery. TachoSil is a ready-to-use haemostatic agent that consists of an equine collagen patch coated with human fibrinogen and thrombin. This trial evaluated the efficacy and safety (< or =30 days post-surgery) of TachoSil surgical patch compared with standard haemostatic fleece for the control of bleeding in patients undergoing cardiovascular surgery. METHODS Patients scheduled for elective surgery on the heart, ascending aorta or aortic arch requiring cardiopulmonary bypass were eligible for this open-label multicentre trial. After primary haemostatic measures, patients were randomised to TachoSil or conventional haemostatic fleece if an area of persisting haemorrhage was identified (target area). After the application of trial treatment, haemostasis was evaluated at 3 min (primary endpoint). If haemostasis was not achieved, trial treatment was re-applied and haemostasis assessed at 6 min (secondary endpoint). RESULTS A total of 120 patients were randomised and 119 received trial treatment (TachoSil, n=59; standard treatment, n=60). Twenty-six percent of patients were female and the mean age was 67 years (range: 23-86 years). Baseline characteristics were similar in both the groups. Bleeding occurred mainly from the aorta (56%), right ventricle (16%) or right atrium (13%), more often from a vessel (68%) than tissue (32%), and was assessed to be arterial in 74% of cases. TachoSil was significantly superior to standard haemostatic fleece in controlling bleeding after insufficient primary haemostasis, with 75% (95% confidence interval (CI): 0.64-0.86) of the TachoSil group achieving haemostasis at 3 min compared with only 33% (95% CI: 0.21-0.45) of the standard treatment group (p<0.0001). This difference persisted at 6 min, with 95% of patients achieving haemostasis in the TachoSil group compared with 72% in the standard treatment group (p=0.0006). Three (5%) TachoSil patients compared with 17 (28%) standard treatment patients failed to achieve haemostasis at 6 min and received rescue treatment. TachoSil was well tolerated with adverse events generally similar in the two treatment groups. CONCLUSIONS TachoSil was significantly superior to standard haemostatic fleece material in obtaining effective and fast intra-operative haemostasis in cardiovascular surgical procedures. TachoSil was safe and well tolerated.

Assessment of left atrial volumes and function in orthotopic heart transplant recipients by dual-source CT: comparison with MRI.

Introduction:To compare left atrial performance with dual-source CT (DSCT) with respect to magnetic resonance imaging (MRI) in orthotopic heart transplant recipients. Methods:Twenty-nine consecutive heart transplant recipients (27 male; mean age 64.1 ± 13 years; mean time from transplantation 122.8 ± 69.7 months) referred for exclusion of cardiac allograft vasculopathy underwent cardiac DSCT and MRI. Standard biatrial technique was employed in 13 subjects whereas 16 were transplanted after the bicaval technique. Axial 5-mm slice-thickness DSCT datasets reconstructed in 5% steps of the cardiac cycle and axial 5-mm SSFP-MRI images were analyzed. Two blinded readers manually traced left atrial contours in random order to estimate end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF). Parameters were compared with a paired sample Student t test. Concordance correlation coefficient (CCC) was calculated to determine measurement agreement between techniques and observers. Results:Left atrial volumes were significantly higher with cardiac DSCT (EDV: 170.9 ± 78.1 mL; ESV: 139.5 ± 76.6 mL) than with MRI (EDV: 158.2 ± 72.5 mL; ESV: 124.2 ± 68.2 mL), whereas left atrial EF was lower with DSCT (EF: 20.8% ± 7.5% vs. 23.6% ± 7.7%) (P < 0.05). Measurement agreement between DSCT and MRI was excellent for all parameters (CCC ≥0.82). Individuals operated with the biatrial anastomosis technique presented significantly higher left atrial volumes and lower EF compared with subjects with bicaval anastomosis. Interobserver agreement was excellent for all parameters (CCC ≥0.80). Conclusion:Even if DSCT slightly overestimates left atrial volumes with respect to MRI, results remain clinically valid. Bicaval surgical technique offers improved left atrial performance compared with standard biatrial anastomosis. DSCT may be used as a reliable tool to estimate left atrial parameters in orthotopic heart transplant recipients.

Incidence and risk factors for nonmelanoma skin cancer after heart transplantation

INTRODUCTION The incidence of skin cancer in heart transplant (HT) patients is higher than in the general population, reversing the proportion of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with a predominance of the former. The etiologic role of new immunosuppressants is not well known. We sought to ascertain the incidence of SCC and BCC in HT patients and the risk factors for its occurrence. PATIENTS AND METHODS We report the incidence of all types of post-HT skin cancer, SCC, and BCC among adult HT patients in Spain (4089 subjects) as well as the influence of gender, age at heart transplant, immunosuppression, and sunlight exposure. RESULTS The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant. CONCLUSION Age at transplantation>45 years, induction therapy use, and high sunshine zone were risk factors for both SCC and BCC. Different immunosuppressive agents have different risks of nonmelanoma skin cancer, as AZA increases the risk of SCC and MMF is a protective factor. The relative risk of BCC was not affected by any immunosuppressor.

Primary graft failure after heart transplantation: Characteristics in a contemporary cohort and performance of the RADIAL risk score

BACKGROUND Primary graft failure (PGF) is the leading cause of early heart transplantation (HT) mortality. Our aim was to analyze PGF currently and explore the ability of a dedicated score for PGF risk stratification. METHODS After applying a dedicated PGF definition, we analyzed its incidence, mortality, and associated factors in a multicenter cohort of 857 HTs performed in 2006 to 2009. We used the following criteria: recipient right (R) atrial pressure ≥ 10 mm Hg; age (A) ≥ 60 years; diabetes (D) mellitus, and inotrope (I) dependence; donor age (A) ≥ 30 years, and length (L) of ischemia ≥ 240 minutes to calculate the RADIAL score for PGF risk prediction. RESULTS PGF incidence was 22%. The right ventricle was almost always affected, alone (45%) or as part of biventricular failure (47%). Mechanical circulatory support was used in 55%. Mortality attributable to PGF was 53% and extended through the third month after HT, but thereafter, PGF had little influence in long-term outcome. The RADIAL score was higher in PGF patients (2.78 ± 1.1 vs. 2.42 ± 1.1, p = 0.001) and stratified 3 groups with incremental PGF incidence: low risk (12.1%), intermediate risk (19.4%), and high risk (27.5%, p = 0.001). CONCLUSIONS PGF had a strong impact, with an incidence of 22% and a mortality exceeding 50% that extends through the third post-HT month. The RADIAL score classified patients into 3 groups with incremental risk for PGF and may be useful for its prevention and early therapy.

Dual-Source CT for Visualization of the Coronary Arteries in Heart Transplant Patients with High Heart Rates

OBJECTIVE The purpose of this study was to evaluate the quality of dual-source CT images of the coronary arteries in heart transplant recipients with high heart rates. SUBJECTS AND METHODS Contrast-enhanced dual-source CT coronary angiography was performed on 23 heart transplant recipients (20 men, three women; mean age, 61.1 +/- 12.8 years). Data sets were reconstructed in 5% steps from 30% to 80% of the R-R interval. Two blinded independent readers using a 5-point scale (0, not evaluative; 4, excellent quality) assessed the quality of images of coronary segments. RESULTS The mean heart rate during scanning was 89.2 +/- 10.4 beats/min. Interobserver agreement on the quality of images of the whole coronary tree was a kappa value of 0.78 and for selection of the optimal reconstruction interval was a kappa value of 0.82. The optimal reconstruction interval was systole in 17 (74%) of the 23 of heart transplant recipients. At the best reconstruction interval, diagnostic image quality (score >or= 2) was obtained in 92.1% (303 of 329) of the coronary artery segments. The mean image quality score for the whole coronary tree was 3.1 +/- 1.01. No significant correlation between mean heart rate (rho = 0.31) or heart rate variability (rho = 0.23) and overall image quality score was observed (p = not significant). CONCLUSION Dual-source CT acquisition yields coronary angiograms of diagnostic quality in heart transplant recipients. Mean heart rate and heart rate variability during scanning do not have a negative effect on the overall quality of images of the coronary arteries.

Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study

J.F. Delgado, N. Manito, L. Almenar, M. Crespo‐Leiro, E. Roig, J. Segovia, J.A. Vázquez de Prada, E. Lage, J. Palomo, M. Campreciós, J.M. Arizón, J.L. Rodríguez‐Lambert, T. Blasco, L. de la Fuente, D. Pascual, G. Rábago. Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study
Transpl Infect Dis 2011: 13: 136–144. All rights reserved

Dual-source CT coronary angiogram in heart transplant recipients in comparison with dobutamine stress echocardiography for detection of cardiac allograft vasculopathy.

Conventional coronary angiography (CCA) is the gold standard in the diagnosis of cardiac allograft vasculopathy (CAV) in heart transplant recipients. Dobutamine stress echocardiography (DSE) is a useful technique for screening. Dual-source computed tomography (DSCT) is the last generation of computed tomography scanners, which could be useful to noninvasively assess CAV. Thirty cardiac transplant recipients underwent DSE and DSCT coronary angiogram. Exclusion criteria were as follows: renal insufficiency, iodinated contrast media allergy, less than 12 months since transplant, and unstable clinical conditions. DSE showed ischemia in two patients. At DSCT scan 13 patients had a normal angiogram, 13 ones wall thickening and four significant diseases. DSCT showed a sensitivity of 100% with a specificity of 92%. DSCT allowed detection of more patients with CAV than DSE. Four patients showed significant CAV at DSCT compared with two at DSE. Thirteen patients showed initial signs of disease at DSCT despite a normal DSE.

Lung Cancer after Heart Transplantation: Results from a Large Multicenter Registry

In this study we analyzed Spanish Post‐Heart‐Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post‐HT follow‐up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post‐HT. Incidence increased with age at HT from 149 per 100 000 person‐years among under‐45s to 542 among over‐64s; was 4.6 times greater among men than women; and was four times greater among pre‐HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age‐at‐diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan–Meier 2−year survival to 70% versus 16% among inoperable patients.