Validación de escalas multiparamétricas de predicción de riesgo de muerte súbita en pacientes con síndrome de Brugada y estudio electrofisiológico / Validation of multiparametric approaches for the prediction of sudden cardiac death in patients with Brugada syndrome and electrophysiological study

Introducción y objetivos: Se han desarrollado puntuaciones multiparamétricas para una mejor estratificación del riesgo en el síndrome de Brugada (SBr). Nuestro objetivo es validar 3 abordajes multiparamétricos (las escalas Delise, Sieira y Shanghai BrS) en una cohorte de pacientes con síndrome de Brugada y estudio electrofisiológico (EEF). Métodos: Pacientes diagnosticados de SBr y con un EEF previo entre 1998-2019 en 23 hospitales. Se utilizaron análisis mediante estadístico C y modelos de regresión de riesgos proporcionales de Cox. Resultados: Se incluyó en total a 831 pacientes con una media de edad de 42,8±13,1 años; 623 (75%) eran varones; 386 (46,5%) tenían patrón electrocardiográfico (ECG) tipo 1; 677 (81,5%) estaban asintomáticos y 319 (38,4%) tenían un desfibrilador automático implantable. Durante un seguimiento de 10,2±4,7 años, 47 (5,7%) sufrieron un evento cardiovascular. En la cohorte total, un ECG tipo 1 y síncope fueron predictivos de eventos arrítmicos. Todas las puntuaciones de riesgo se asociaron significativamente con los eventos. Las capacidades discriminatorias de las 3 escalas fueron discretas (particularmente al aplicarlas a pacientes asintomáticos). La evaluación de las puntuaciones de Delise y Sieira con diferente número de extraestímulos (1 o 2 frente a 3) no mejoró sustancialmente el índice c de predicción de eventos. Conclusiones: En el SBr, los factores de riesgo clásicos como el ECG y el síncope previo predicen eventos arrítmicos. El número de extraestímulos necesarios para inducir arritmias ventriculares influye en las capacidades predictivas del EEF. Las escalas que combinan factores de riesgo clínico con EEF ayudan a identificar las poblaciones con más riesgo, aunque sus capacidades predictivas siguen siendo discretas tanto en población general con SBr como en pacientes asintomáticos (AU)

Introduction and objectives: Multiparametric scores have been designed for better risk stratification in Brugada syndrome (BrS). We aimed to validate 3 multiparametric approaches (the Delise score, Sieira score and the Shanghai BrS Score) in a cohort with Brugada syndrome and electrophysiological study (EPS). Methods: We included patients diagnosed with BrS and previous EPS between 1998 and 2019 in 23 hospitals. C-statistic analysis and Cox proportional hazard regression models were used. Results: A total of 831 patients were included (mean age, 42.8±13.1; 623 [75%] men; 386 [46.5%] had a type 1 electrocardiogram (ECG) pattern, 677 [81.5%] were asymptomatic, and 319 [38.4%] had an implantable cardioverter-defibrillator). During a follow-up of 10.2±4.7 years, 47 (5.7%) experienced a cardiovascular event. In the global cohort, a type 1 ECG and syncope were predictive of arrhythmic events. All risk scores were significantly associated with events. The discriminatory abilities of the 3 scores were modest (particularly when these scores were evaluated in asymptomatic patients). Evaluation of the Delise and Sieira scores with different numbers of extra stimuli (1 or 2 vs 3) did not substantially improve the event prediction c-index. Conclusions: In BrS, classic risk factors such as ECG pattern and previous syncope predict arrhythmic events. The predictive capabilities of the EPS are affected by the number of extra stimuli required to induce ventricular arrhythmias. Scores combining clinical risk factors with EPS help to identify the populations at highest risk, although their predictive abilities remain modest in the general BrS population and in asymptomatic patients (AU)

Role of microRNAs in gynecological pathology.

microRNAs (miRNAs) are 21-22 nucleotide non-coding RNAs that regulate gene expression and play fundamental roles in biological processes. These small molecules bind to target mRNAs, leading to translational repression and/or mRNA degradation. Aberrant miRNA expression is associated with several human diseases such as cancer, cardiovascular disorders, inflammatory diseases and gynecological pathology. The present article reviews the role of miRNAs in four gynecological disorders that affect the ovary or the uterus, one benign and frequent disease (endometriosis) that is classified as a tumor-like lesion and three malignant gynecological diseases (endometrial, cervical and ovarian cancers). Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent benign gynecological diseases. Similarly to tumor metastasis, endometriotic implants require neovascularization to proliferate, invade the extracellular matrix and establish an endometriotic lesion. Despite its high prevalence and incapacitating symptoms, the exact pathogenic mechanism of endometriosis remains unsolved. A relationship between endometriosis and gynecological cancer, especially ovarian cancer, has been reported. Endometriosis is a multifactorial and polygenic disease, and emerging data provide evidence that a dysregulation of miRNA expression may be involved. miRNAs appear to be potent regulators of gene expression in endometriosis, raising the prospect of using miRNAs as biomarkers and therapeutic tools in this disease. In cancer, miRNAs have an important role as regulatory molecules, acting as oncogenes (oncomiRs) or tumor suppressors. Endometrial cancer is one of the most frequent gynecological malignancies in the developed countries. Cervical cancer, also one of the most common cancers in women, is associated with high-risk human papillomaviruses although this infection alone may not be enough to induce the malignant transformation. Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. Over 80% of cases are diagnosed at an advanced stage, with a reduced five-year survival rate. Recent studies have shown that miRNAs are aberrantly expressed in different human cancer types, including endometrial, cervical and ovarian cancer, and that specific dysregulated miRNAs may act as biomarkers of patients' outcome. Recently, miRNAs have been detected in serum and plasma, and circulating miRNA expression profiles have now been associated with a range of different tumor types. Their accessibility in peripheral blood and stability given the fact that miRNAs circulate confined within exosomes, make researchers foster hope in their role as emerging biomarkers of cancer and other disorders. The development of therapies that might block the expression or mimic the functions of miRNAs could represent new therapeutic strategies for any of the aforementioned gynecological disorders.

Síndrome de Kounis: una posibilidad a tener en cuenta como causa de muerte súbita cardiaca / Kounis syndrome: a possibility to be considered as a cause of sudden cardiac death

El llamado síndrome miocárdico alérgico, angina alérgica o síndrome de Kounis, se define como la aparición de un síndrome coronario agudo por vasoespasmo secundario a la activación de mastocitos y células inflamatorias interrelacionadas que se produce en las reacciones de hipersensibilidad, anafilácticas y anafilactoides. Presentamos un caso de muerte súbita en un adulto joven compatible con un síndrome de Kounis, donde el estudio histopatológico demuestra patología asmática y una trombosis en la arteria coronaria descendente anterior sobre una placa erosionada con numerosos eosinófilos y mastocitos en el trombo, en la placa subyacente, en la pared muscular y en la adventicia. La entrevista familiar posterior confirmó el antecedente de atopia y una clínica previa al fallecimiento compatible con un episodio asmático. Como dicen muchos expertos, el Síndrome de Kounis no es una enfermedad rara, pero sí es una enfermedad raramente diagnosticada. Debemos tenerla presente y descartarla ante una muerte súbita en el contexto de una reacción alérgica o de antecedentes de atopia, alergia o asma alérgico (AU)

Kounis syndrome has been defined as the concurrence of an acute coronary syndromes with allergic or hypersensitivity as well as with anaphylactic or anaphylactoid reactions. The main pathophysiological mechanism is the vasospasm of epicardial coronary arteries due to increased inflammatory mediators that are released during the underlaying allergic events. We present a case of sudden death in an atopic young adult with histopathological findings of asthma and thrombosis in left anterior descending coronary artery with presence of eosinophils and mast cell. Kounis syndrome is not a rare disease but is a rarely diagnosed condition which should always be kept in mind when dealing with a cardiac sudden death with clinical history of atopy or allergy or in a context of allergic reactions (AU)

Insights into the role of microRNAs in cardiac diseases: from biological signalling to therapeutic targets.

microRNAs have recently opened new pathways to explain gene expression and disease biology in many scenarios, including cardiac diseases. microRNAs are endogenous small non-coding RNAs that mediate post-transcriptional repression or messenger RNA degradation. By annealing to inexactly complementary sequences in the 3' untranslated region of the target messenger RNA, protein level is down-regulated. Several microRNAs appear to act cooperatively through multiple target sites in one gene and, conversely, most microRNAs can target several genes. miR-133 and miR-1 are specifically expressed in cardiac and skeletal muscle and control myogenesis, cardiac development, cardiac performance and cardiomyocyte hypertrophy (mainly by tuning transcription factors and other growth-related targets). They also modulate the expression of certain cardiac ion channels and related proteins with proarrhythmic effect. Besides them, other microRNAs have been shown to exert influence on the myocardial growth, the electrical balance and the angiogenesis processes that take place in the heart. Bioinformatics is a useful tool to identify potential targets of a given microRNA, although there is still substantial concern about their reliability. Experimental manipulation of microRNAs has provided a tantalizing basis to speculate that future research on microRNAs may yield important progress in the prevention of sudden cardiac death and in the treatment of cardiac heart failure. However, the final effect of the blockage of microRNAs in vivo remains unclear, since each of them can target hundreds of genes with different intensity. The era of the microRNAs in cardiovascular diseases has just started.

The -589C>T polymorphism in the interleukin-4 gene (IL-4) is associated with a reduced risk of myocardial infarction in young individuals.

BACKGROUND: Inflammatory reactions contribute to the development of arterial disease. We investigated the role of interleukin-4 (IL-4) in the development of myocardial infarction (MI) by genotyping patients with MI and control subjects for the -589C>T (rs2243250) single nucleotide polymorphism (SNP), which tags a functional haplotype of IL-4. METHODS AND RESULTS: Study of Myocardial Infarctions Leiden (SMILE) included 560 men with a first MI and 646 control subjects. The Valencia study included 305 patients with MI at T genotype was found [odds ratio (OR) 0.84; 95% CI 0.37-1.95 for -589TT and 0.82; 95% CI 0.62-1.07 for -589CT compared with -589CC]. In patients younger than 50 years, carriership of one or two -589T alleles was associated with a reduced risk of MI (OR 0.57: 95% CI 0.34-0.95). This result was replicated in the Valencia study, where carriers of one or two -589T alleles had a reduced risk of MI (OR 0.67: 95% CI 0.47-0.95), with a strong protective effect of the -598T allele in homozygous -589T (OR 0.33: 95% CI 0.10-1.05). In the control subjects of the Valencia study, the -589T allele was associated with reduced levels of F1+2. CONCLUSION: Our data indicate that the IL-4 haplotype tagged by the -589T allele reduces the risk of MI in young individuals.

Does amiodarone influence early mortality in heart transplantation?

The use of amiodarone before transplantation has been linked to an increased number of complications, acute graft failures, and early mortality after a heart graft. We undertook a retrospective, descriptive, case-controlled study involving early mortality and acute graft failure. The 396 consecutive patients included 25 subjects who had been prescribed amiodarone for at least 30 days before transplantation. We excluded retransplantations, pediatric transplantations, and combined transplantations. The endpoints were early mortality and acute graft failure. No significant differences were observed in early mortality and acute graft failures. The multivariate analysis did not reveal any variable that correlated with early mortality. Our study did not support the idea that amiodarone constituted a negative predictor of early survival or acute graft failure.

Is there a correlation between brain naturietic peptide levels and echocardiographic and hemodynamic parameters in heart transplant patients?

BACKGROUND: Brain naturietic peptide (BNP) elevations have been reported in heart transplant patients both at baseline and during rejection. An association between BNP levels and certain echocardiographic and hemodynamic abnormalities has also been found in nontransplanted heart disease patients. We sought to determine whether BNP values were correlated with echocardiographic and hemodynamic parameters among a large cohort of heart transplant patients. MATERIALS AND METHODS: We studied 71 consecutive heart transplant patients, excluding combined grafts, retransplants, and pediatric cases. We performed 488 BNP determinations during catheterization and within 48 hours of echocardiography. Hemodynamic parameters included mean pulmonary artery pressure, right ventricular systolic and diastolic pressures. Doppler echocardiography parameters were wall thickness, ventricular mass, left and right ventricular end-diastolic and end-systolic diameters, isovolumic relaxation time, and mitral flow deceleration time. RESULTS: We observed significant correlations between BNP values and left ventricular size, ventricular mass, and a restrictive filling pattern. BNP levels were also significantly correlated with right ventricular size, mean pulmonary artery pressure, and right ventricular diastolic and end-diastolic pressures. CONCLUSIONS: In heart transplant patients, BNP levels positively correlated with ventricular diameters and a restrictive filling pattern. An increase in right ventricle and pulmonary artery pressures was associated with elevated BNP values.

Induction therapy with daclizumab in heart transplantation--how many doses?

UNLABELLED: Since their introduction onto the market, interleukin-2 antagonists have been increasingly used by a growing number of transplant units. Their benefits versus OKT3 appear evident, although the optimal dose remains to be established. Our objective was to establish possible differences related to the use of two versus five doses of daclizumab. MATERIALS AND METHODS: This study evaluated 81 consecutive patients treated with two bolus doses of daclizumab (1 mg/kg) on days 1 and 14 posttransplantation. We excluded retransplantations, pediatric transplantations, and combined transplantations. We compared our series to a previous trial involving the administration of a single bolus dose every 14 days (five boluses in total). Study variables included the number of graft rejections, the number of infections, and the mortality. Statistical analysis was performed using the chi square and Student's t tests. Significance was set at P < .05. RESULTS: There were no differences between groups in the baseline characteristics of the patients. The number of rejection episodes during the first year was significantly lower among the patients in our series treated with two bolus doses of daclizumab than in the series of patients treated with five bolus doses: 24 (30%) vs 17 (61%) episodes (P = .003). No significant differences were observed for mortality: the group receiving two boluses registered 10 deaths (12%) versus two (7%) in the group receiving five boluses (P = .4), or infection rate: 11 patients (40%) in the group receiving five bolus versus 31 patients (38%) in the group given two bolus doses (P = .9). CONCLUSIONS: Our results suggested that induction therapy with two doses of daclizumab was at least as effective in preventing rejection as five doses, with no negative effects on patient survival.

Influence of immunosuppression regimen on heart transplantation survival.

OBJECTIVE: To perform an analysis comparing long-term survival in heart transplant (HT) patients depending on the immunosuppressive regimen. MATERIALS AND METHODS: The study included 317 consecutive HT patients. We excluded pediatric cases, retransplants, combined transplants (lung and kidney), and immunosuppressive regimens with fewer than 10 cases. The six groups analyzed were: (1) OKT3 7 days + cyclosporine (CsA) + mycophenolate mofetil (MMF) + steroids (S); (2) OKT3 7 days + CsA + azathioprine (AZA) + S; (3) OKT3 10 days + CsA + MMF + S; (4) OKT3 10 days + CsA + AZA + S; (5) interleukin-2 (IL-2) antagonists + CsA + MMF + S; and (6) IL-2 antagonists + tacrolimus + MMF + S. Probability of survival was analyzed by Kaplan-Meier and log-rank methods. RESULTS: The groups were heterogeneous regarding the number of patients and follow-up. The baseline characteristics were similar, although there were differences in surgery times. The survivals by groups at the end of the follow-up period were: group 1: 75.8%; group 2: 51.2%; group 3: 63.6%; group 4: 25.3%; group 5: 91.2%; and group 6: 84.6%. A major reduction in survival was observed in the groups that were given induction with OKT3 monoclonal antibodies (groups 1, 2, 3, and 4), particularly when AZA was combined in the maintenance phase (groups 2 and 4) and when the induction dose was high (10-day therapy in groups 3 and 4). CONCLUSIONS: Our study suggested an association between the immunosuppressive regimen and the long-term survival of HT patients. The best results were obtained with an induction regimen based on IL-2 antagonists. On the basis of the survivals observed in this study, the maintenance combination we regard as "optimal" at this time is based on a combination of CsA, MMF, and steroids.

Evolutional changes in maintenance immunosuppression following heart transplantation.

UNLABELLED: Patients with a heart transplant (HT) may require changes in their immunosuppressive maintenance medication. The basic treatment regimen in our patients consisted of an anticalcineurin agent, an antimetabolite, and a steroid. OBJECTIVE: We undertook a descriptive study to quantify the incidence and causes of these changes and determine how they occur. MATERIALS AND METHODS: We included the 432 HT performed at our center from November 1987 to October 2005. The baseline treatment was considered to be the treatment given following HT, and the maintenance treatment was that taken at the time of data collection. Kaplan-Meier survival curves were constructed for the analysis. RESULTS: The most significant change was the switch from azathioprine to mycophenolate mofetil. The survival rate after 17 years was 66%. CONCLUSIONS: As in the international registries, there has been an evident reduction in the use of cyclosporine and more particularly of azathioprine, in favor of tacrolimus and mycophenolate mofetil, respectively. No changes in the use of steroids have been observed. These data reflect an increasingly greater use of immunosuppressive agents with reduced side effect profiles.

Variations in the frequency and type of infections in heart transplantation according to the immunosuppression regimen.

OBJECTIVE: To evaluate the frequency of infection according to the immunosuppressive regimens used in our center. MATERIALS AND METHODS: From 259 consecutive heart transplants we excluded pediatric cases, retransplants, combined transplants (lung and kidney) and immunosuppressive regimens with fewer than 10 cases. The six groups analyzed were: (1) OKT3 (7 days) + cyclosporine (CsA) + mycophenolate mofetil (MMF) + steroids (S); (2) OKT3 (7 days) + CsA + azathioprine (AZA) + S; (3) OKT3 (10 days) + CsA + MMF + S; (4) OKT3 (10 days) + CsA + AZA + S; (5) interleukin-2 (IL-2) antagonists + CsA + MMF + S; (6) IL-2 antagonists + tacrolimus + MMF + S. Infection was considered significant when it causal hospital admission or prolonged hospitalization. RESULTS: With a total mean follow-up of 54 +/- 43 months, the total percentage of infection-free patients at the end of follow-up was 45.5%. Infection-free survival was lower among patients administered induction with OKT3 antibodies for 10 days, combined with cyclosporine, either with MMF (10%, group 3) or with azathioprine (27%, group 4), compared to those given IL-2 antagonists (particularly in combination with tacrolimus and MMF-69.2%, group 6). CONCLUSIONS: The results of this study showed that infection was frequent in heart transplantation. Furthermore, induction therapy with OKT3 monoclonal antibodies was associated with an important number of infections (particularly viral infections). Comparison of the treatment groups showed that the regimen associated with fever infections included an IL-2 receptor antagonist with tacrolimus, MMF, and S.

Circulating activated protein C is reduced in young survivors of myocardial infarction and inversely correlates with the severity of coronary lesions.

BACKGROUND: Cardiovascular risk factors for myocardial infarction (MI) are less frequent in younger than in older MI survivors. Therefore, the thrombotic component of MI may play a more important role at a young age. As activated protein C (APC) provides systemic anticoagulant and anti-inflammatory protection, a low plasma APC level may be an arterial thrombotic risk factor. AIM: To determine whether there is an association between reduced APC levels and early MI and severe coronary lesions. METHODS: APC was measured in 231 young MI survivors and 231 controls. RESULTS: Low APC levels were significantly associated with MI. Compared with the fourth quartile, the odds ratio (OR) for APC values in the first quartile was 3.7 [95% confidence interval (CI) = 2.1-6.4], and 3.2 (1.5-7.0) after adjustment for cardiovascular risk factors. Moreover, each decrease of 0.43 ng mL(-1) (1 SD) in APC increased the OR 1.7 times (1.4-2.2), and 1.5 times (1.2-1.9) after adjustment for cardiovascular risk factors. Low APC levels were also associated with the number of coronary arteries affected and with the severity of coronary lesions (P < 0.001). CONCLUSIONS: There is a significant association between low circulating APC levels and both early MI and the extent and severity of coronary atherosclerosis, which might be related to the anticoagulant and anti-inflammatory properties of APC.

The multifunctional protein C system.

The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.

Risk factors affecting survival in heart transplant patients.

BACKGROUND: Certain cardiovascular risk factors have been linked to morbidity and mortality in heart transplant (HT) patients. The sum of various risk factors may have a large cumulative negative effect, leading to a substantially worse prognosis and the need to consider whether HT is contraindicated. The objective of this study was to determine whether the risk factors usually available prior to HT result in an excess mortality in our setting that contraindicates transplantation. MATERIALS AND METHODS: Consecutive patients who underwent heart transplantation from November 1987 to January 2004 were included. Heart-lung transplants, retransplants, and pediatric transplants were excluded. Of the 384 patients, 89% were men. Mean age was 52 years (range, 12 to 67). Underlying disease included ischemic heart disease (52%), idiopathic dilated cardiomyopathy (36%), valvular disease (8%), and other (4%). Variables considered risk factors were obesity (BMI >25), dyslipidemia, hypertension, prior thoracic surgery, diabetes, and history of ischemic heart disease. Survival curves by number of risk factors using Kaplan-Meier and log-rank for comparison of curves. RESULTS: Overall patient survival at 1, 5, 10, and 13 years was 76%, 68%, 54%, and 47%, respectively. Survival at 10 years, if fewer than two risk factors were present, was 69%; 59% if two or three factors were present; and 37% if more than three associated risk factors were present (P = .04). CONCLUSIONS: The presence of certain risk factors in patients undergoing HT resulted in lower survival rates. The combination of various risk factors clearly worsened outcomes. However, we do not believe this should be an absolute contraindication for transplantation.

Influence of induction therapy on rejection and survival in heart transplantation.

BACKGROUND AND AIMS: Immunosuppressive therapy has undergone great changes in recent years as a result of the introduction of new drugs, presumed a prior to be more effective and better tolerated. The greatest advance seems to have been the introduction of interleukin-2 (IL-2) receptor antagonists. The objective of this study was to determine whether the use of IL-2 receptor antagonists in induction therapy has implications for the development of rejection and survival. MATERIALS AND METHODS: Three hundred sixty-five consecutive cardiac transplant patients who received induction therapy were included. Heart-lung and transplants in children under 10 years were excluded. Three groups were compared according to the induction therapy (OKT3, 10 days; OKT3, 7 days; and IL-2R antagonists). Each treatment corresponded to a time period: OKT3 10 days from June 1989 to April 1994; OKT3 7 days from May 1994 to October 2002; and IL-2R antagonists from November 2002 to May 2004. Baseline characteristics of recipient and donor, surgical times, postsurgical complications, maintenance immunosuppression, number of rejections, time (days) to first rejection, and probability of survival at 1 year were recorded. We used analysis of variance, chi(2) test, Kaplan-Meier curves, and log-rank test as appropriate. A P-value < .05 was considered significant. RESULTS: There were significant differences in the characteristics of the transplanted patients in the various time periods. Thus, recipients in the OKT3 10 day group had worse status but better donors, whereas recipients in the IL-2R antagonists group had better status but older donors with longer duration of ischemia. The incidence of acute graft failure was similar in the three groups. The number of rejection episodes in the first year was higher among the OKT3 groups (OKT3 10 days, 1.7 +/- 1.3; OKT3 7 days, 1.2 +/- 1.2; IL-2R antagonists, 1.0 +/- 1.2; P = .02) and the probability of survival at 1 year was also lower (OKT3 10 days, 74%; OKT3 7 days, 77%; IL-2R antagonists, 94%; P = .0007). CONCLUSIONS: Induction therapy with IL-2 antagonists offers important advantages over treatment with OKT3 in terms of survival, with absolute and relative risk reductions of 20% and 27%. Furthermore, it did not increase the number of rejections, although this may have been due to the greater use of MMF versus azathioprine.

Expression of several components of the plasminogen activator and matrix metalloproteinase systems in endometriosis.

BACKGROUND: Endometriosis is considered a benign disease that has the ability to invade normal tissue. As in neoplastic growth, local extracellular proteolysis may take place. The aim of this study is to analyse several components of the plasminogen activator (PA) pathway and the matrix metalloproteinase (MMP) system in endometriotic tissue, endometrium and peritoneal fluid from women with and without endometriosis (controls). METHODS AND RESULTS: Thirty-nine women with endometriosis and 35 controls were studied. In eutopic endometrium of women with endometriosis, the antigenic levels of urokinase-type PA (uPA) and MMP-3 were elevated when compared with endometrium from controls. Ovarian endometriotic tissues had higher antigenic levels of PA inhibitor type 1 (PAI-1) and tissue inhibitor of metalloproteinases type 1 (TIMP-1) than endometrium. The peritoneal fluid from women with endometriosis showed a significant increase in uPA levels compared with controls. CONCLUSIONS: The increase in antigenic levels of uPA and MMP-3 in endometrium of women with endometriosis might contribute to the invasive potential of endometrial cells. Once the ovarian endometriotic cyst is developed, an increase in PAI-1 and TIMP-1 is detected and significant proteolytic activity is no longer observed. This increase in inhibitors and decrease in proteolytic activity could explain the frequent clinical finding of isolated endometriotic cyst without invasion of the surrounding ovarian tissue.