SEA 2022 Standards for Global Control of Cardiovascular Risk. / Estándares SEA 2022 para el control global del riesgo cardiovascular.

One of the objectives of the Spanish Society of Arteriosclerosis is to contribute to better knowledge of vascular disease, its prevention and treatment. It is well known that cardiovascular diseases are the leading cause of death in our country and entail a high degree of disability and health care costs. Arteriosclerosis is a multifactorial disease and therefore its prevention requires a global approach that takes into account the different risk factors with which it is associated. Therefore, this document summarizes the current level of knowledge and includes recommendations and procedures to be followed in patients with established cardiovascular disease or at high vascular risk. Specifically, this document reviews the main symptoms and signs to be evaluated during the clinical visit, the laboratory and imaging procedures to be routinely requested or requested for those in special situations. It also includes vascular risk estimation, the diagnostic criteria of the different entities that are cardiovascular risk factors, and makes general and specific recommendations for the treatment of the different cardiovascular risk factors and their final objectives. Finally, the document includes aspects that are not usually referenced in the literature, such as the organization of a vascular risk consultation.

Impact of the mutation profile on thrombotic risk in cancer patients.

Patients with cancer present with an elevated risk of thrombosis, which entails high morbidity and mortality. Various predictive scales that incorporate clinical and biological data have been developed to identify those at high risk of thrombosis, but, in general, they do not allow for the optimal selection of subjects who are candidates for thromboprophylaxis. Recent studies have demonstrated that the mutation profile has a high impact on the risk of thrombosis; this will facilitate developing new predictive models of thrombosis in patients with cancer.

Neutrophils as instigators of thrombosis: Beyond antimicrobial protection. / Neutrófilos como instigadores de trombosis: más allá de la protección antimicrobiana.

When activated, neutrophils release structures (NETs) composed of DNA, histones and granular proteins that provide an ideal matrix for platelet activation and coagulation mechanisms, thereby contributing to the pathogenesis of thrombosis in venous and arterial territories, as well as cancer-associated thrombosis. NETs play a key role in immunothrombosis, a term that describes the relationship between the immune response and coagulation.

Improvement of appropriate pharmacological prophylaxis in hospitalised cancer patients with a multiscreen e-alert system: a single-centre experience.

PURPOSE: Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. METHODS: Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. RESULTS: E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043-0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. CONCLUSIONS: E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.

Durable complete remission with aromatase inhibitor therapy in a patient with metastatic uterine carcinosarcoma with poor performance status and coagulation disorders: a case report.

BACKGROUND: Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response. CASE PRESENTATION: A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life. CONCLUSIONS: This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.

[Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document)]. / Documento multidisciplinar de consenso sobre elmanejo de la hemorragia masiva (document HEMOMAS)

Massive haemorrhage is common and often associated with high morbidity and mortality. We perform a systematic review of the literature, with extraction of the recommendations from the existing evidences because of the need for its improvement and the management standardization. From the results we found, we wrote a multidisciplinary consensus document. We begin with the agreement in the definitions of massive haemorrhage and massive transfusion, and we do structured recommendations on their general management (clinical assessment of bleeding, hypothermia management, fluid therapy, hypotensive resuscitation and damage control surgery), blood volume monitoring, blood products transfusion (red blood cells, fresh frozen plasma, platelets and their best transfusion ratio), and administration of hemostatic components (prothrombin complex, fibrinogen, factor VIIa, antifibrinolytic agents).

Multidisciplinary consensus document on the management of massive haemorrhage (HEMOMAS document).

Massive haemorrhage is common and often associated with high morbidity and mortality. We perform a systematic review of the literature, with extraction of the recommendations from the existing evidences because of the need for its improvement and the management standardization. From the results we found, we wrote a multidisciplinary consensus document. We begin with the agreement in the definitions of massive haemorrhage and massive transfusion, and we do structured recommendations on their general management (clinical assessment of bleeding, hypothermia management, fluid therapy, hypotensive resuscitation and damage control surgery), blood volume monitoring, blood products transfusion (red blood cells, fresh frozen plasma, platelets and their best transfusion ratio), and administration of hemostatic components (prothrombin complex, fibrinogen, factor VIIa, antifibrinolytic agents).

Haemostatic activation and inflammatory response after three methods of treatment of great saphenous vein incompetence.

OBJECTIVE: The purpose of this study was to compare the activation of haemostasis and inflammatory response after three different methods of treatment of great saphenous vein (GSV) incompetence. MATERIAL AND METHODS: Forty-five patients with GSV incompetence were assigned to one of the three types of treatment: high ligation and stripping (HL&S), radiofrequency ablation with ClosureFast (RFA) and endovenous laser ablation (EVLA) with 810 nm diode laser with miniphlebectomy if required. Peripheral blood samples were obtained in the morning before the surgery and 24 hours and 10 days after the procedure. The concentrations of C-reactive protein (CRP), D-dimer, prothrombin fragment 1 + 2 (F1 + 2), antigen of tissue plasminogen activator (t-PA) and von Willebrand factor (vWF) antigen and activity of plasminogen activator inhibitor (PAI-1) were determined. The results were statistically analysed with SPSS for Windows 15.0. RESULTS: Thirty-eight patients completed the study: 13 from RFA, 14 from EVLA and 11 from HL&S group. The baseline data did not differ among groups. There was a significant increase of D-dimer in HL&S group after 24 hours (P = 0.002). The changes in RFA and EVLA groups did not show statistical significance (P = 0.092). PAI-1 decreased in RFA patients after 24 hours (P = 0.02), did not change in EVLA patients, and tended to increase after HL&S (P = 0.08). The highest CRP increase was observed in HL&S group (P = 0.003). No significant changes in F1 + 2, t-PA and vWF were observed in any group of patients at 24 hours. At 10 days, a further significant increase of D-dimer (P = 0.04) and CRP (P = 0.018) concentrations in HL&S but not RFA and EVLA patients was observed. CONCLUSIONS: Endovenous thermal ablation is associated with significantly less activation of haemostasis and inflammatory response when compared with HL&S.

proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke.

BACKGROUND: Matrix metalloproteinases (MMPs) mediate tissue injury during stroke but also neurovascular remodeling and we have shown that MMP-10 is involved in atherothrombosis. OBJECTIVE: The purpose of this study was to examine the relationship between proMMP-10 and clinical outcome, assessing inflammatory and proteolytic markers, in patients with acute ischemic stroke. METHODS: We prospectively studied 76 patients with ischemic stroke treated with tPA within the first 3 h from symptom onset, compared with 202 non-tPA-treated ischemic stroke patients and 83 asymptomatic subjects. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Hemorrhagic transformation (HT) and severe brain edema were diagnosed by cranial CT. Good functional outcome was defined as a modified Rankin scale score ≤ 2 at 90 days. Serum levels of MMP-9, proMMP-10, TIMP-1, tumor necrosis factor-α (TNFα), interleukin-6 and cellular fibronectin were measured at admission. The effect of TNFα on endothelial proMMP-10 was assessed in vitro. RESULTS: Serum proMMP-10 concentration in ischemic stroke patients, non-treated or treated with t-PA, which was higher than age-matched healthy subjects (P < 0.0001), was independently associated with higher infarct volume, severe brain edema, neurological deterioration and poor functional outcome at 3 months (all P < 0.05), but not with HT. proMMP-10 levels were also independently and positively associated with circulating levels of TNFα (P < 0.0001), which induced its endothelial expression in vitro, both mRNA and protein. MMP-9, however, was only associated with HT and severe edema (all P < 0.05). CONCLUSIONS: Increased serum proMMP-10 after acute ischemic stroke, associated with TNFα, is a new marker of brain damage and poor outcome.

Tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients.

A prothrombotic state is one of the hallmarks of malignancy and a major contributor to morbidity and mortality in cancer patients.Tissue factor (TF) is often overexpressed in malignancy and is a prime candidate in predicting the hypercoagulable state. Moreover, increased number of TF-exposing microparticles (MPs) in cancer patients may contribute to venous thromboembolism (VTE). We have conducted a prospective cohort study to determine whether elevated TF antigen, TF activity and TF associated to MPs (MPs-TF) are predictive of VTE and mortality in cancer patients. The studied population consisted of 252 cancer patients and 36 healthy controls. TF antigen and activity and MPs-TF were determined by ELISA and chromogenic assays. During a median follow-up of 10 months, 40 thrombotic events were recorded in 34 patients (13.5%), and 73 patients (28.9%) died. TF antigen and activity were significantly higher in patients than in controls (p<0.01) mainly in patients with advanced stages, whereas no differences were observed for TF activity of isolated MPs. We did not find a statistically significant association of TF variables with the risk of VTE. Multivariate analysis adjusting for age, sex, type of cancer and other confounding variables showed that TF activity (p<0.01) and MPs-TF activity (p<0.05) were independently associated with mortality. In conclusion, while TF variables were not associated with future VTE in cancer patients, we found a strong association of TF and MPs-TF activity with mortality, thus suggesting they might be good prognostic markers in cancer patients.

[Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia]. / Evaluación económica del tratamiento de la trombocitopenia inmune primaria crónica refractaria con agonistas del receptor de la trombopoyetina.

PURPOSE: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). METHODS: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. RESULTS: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). CONCLUSIONS: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.

Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.

[2013: The Seville document on consensus on the alternatives to allogenic blood transfusion. Update to the Seville document. Spanish Societies of Anaesthesiology (SEDAR), Haematology and Haemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Haemostasis (SETH) and Blood Transfusion (SETS)]. / 2013: Documento «Sevilla¼ de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla

As allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to TSA (AABT) have emerged, but there is a huge variability with respect to their indications and appropriate use. This variability results from the interplay of a number of factors, which include physicians specialty, knowledge and preferences, degree of anaemia, transfusion policy, and AABT availability. Since the ABBT are not harmless and may not meet costeffectiveness criteria, such avariability is unacceptable. The Spanish Societies of Anaesthesiology (SEDAR), Haematology and Haemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Haemostasis (SETH) and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these six Societies have conducted a systematic review of the medical literature and developed the «2013. Seville Document of Consensus on Alternatives to Allogeneic Blood Transfusion¼, which only considers those AABT aimed to decrease the transfusion of packed red cells. The AABTs are defined as any pharmacological and non-pharmacological measure aimed to decrease the transfusion of of red blood cell concentrates, while preserving the patient safety. For each AABT, the main question is formulated, positively or negatively, as: «Does or does not this particular AABT reduce the transfusion rate?¼ All the recommendations on the use of AABTs were formulated according to the GRADE (Grades of Recommendation Assessment, Development and Evaluation) methodology.

La transfusión de sangre alogénica (TSA) no es inocua, y como consecuencia han surgido múltiples alternativas a la TSA (ATSA). Existe variabilidad respecto a las indicaciones y buen uso de las ATSA. Dependiendo de la especialidad de los médicos que tratan a los pacientes, grado de anemia, política transfusional, disponibilidad de las ATSA y criterio personal, las ATSA se usan de forma variable. Puesto que las ATSA tampoco son inocuas y pueden no cumplir criterios de coste-efectividad, la variabilidad en su uso es inaceptable. Las sociedades españolas de Anestesiología y Reanimación (SEDAR), Hematología y Hemoterapia (SEHH), Farmacia Hospitalaria (SEFH), Medicina Intensiva y Unidades Coronarias (SEMICYUC), Trombosis y Hemostasia (SETH) y Transfusiones Sanguíneas (SETS) han elaborado un documento de consenso para el buen uso de la ATSA. Un panel de expertos de las seis sociedades han llevado a cabo una revisión sistemática de la literatura médica y elaborado el «2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica¼. Solo se contempla las ATSA dirigidas a disminuir la transfusión de concentrado de hematíes. Se definen las ATSA como toda medida farmacológica y no farmacológica, encaminada a disminuir la transfusión de concentrado de hematíes, preservando siempre la seguridad del paciente. La cuestión principal que se plantea en cada ítem se formula, en forma positiva o negativa, como: «La ATSA en cuestión reduce / no reduce la Tasa Transfusional¼. Para formular el grado de recomendación se ha usado la metodología GRADE (Grades of Recommendation Assessment, Development and Evaluation).

[The 2013 Seville Consensus Document on alternatives to allogenic blood transfusion. An update on the Seville Document]. / 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla.

Since allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to ABT (AABT) have emerged, though there is great variability in their indications and appropriate use. This variability results from the interaction of a number of factors, including the specialty of the physician, knowledge and preferences, the degree of anemia, transfusion policy, and AABT availability. Since AABTs are not harmless and may not meet cost-effectiveness criteria, such variability is unacceptable. The Spanish Societies of Anesthesiology (SEDAR), Hematology and Hemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Hemostasis (SETH) and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these 6 Societies have conducted a systematic review of the medical literature and have developed the 2013 Seville Consensus Document on Alternatives to Allogeneic Blood Transfusion, which only considers those AABT aimed at decreasing the transfusion of packed red cells. AABTs are defined as any pharmacological or non-pharmacological measure aimed at decreasing the transfusion of red blood cell concentrates, while preserving patient safety. For each AABT, the main question formulated, positively or negatively, is: « Does this particular AABT reduce the transfusion rate or not?¼ All the recommendations on the use of AABTs were formulated according to the Grades of Recommendation Assessment, Development and Evaluation (GRADE) methodology.

[The 2013 Seville Consensus Document on alternatives to allogenic blood transfusion. An update on the Seville Document]. / 2013. Documento Sevilla de Consenso sobre Alternativas a la Transfusión de Sangre Alogénica. Actualización del Documento Sevilla.

Since allogeneic blood transfusion (ABT) is not harmless, multiple alternatives to ABT (AABT) have emerged, though there is great variability in their indications and appropriate use. This variability results from the interaction of a number of factors, including the specialty of the physician, knowledge and preferences, the degree of anemia, transfusion policy, and AABT availability. Since AABTs are not harmless and may not meet cost-effectiveness criteria, such variability is unacceptable. The Spanish Societies of Anesthesiology (SEDAR), Hematology and Hemotherapy (SEHH), Hospital Pharmacy (SEFH), Critical Care Medicine (SEMICYUC), Thrombosis and Hemostasis (SETH) and Blood Transfusion (SETS) have developed a Consensus Document for the proper use of AABTs. A panel of experts convened by these 6 Societies have conducted a systematic review of the medical literature and have developed the 2013 Seville Consensus Document on Alternatives to Allogeneic Blood Transfusion, which only considers those AABT aimed at decreasing the transfusion of packed red cells. AABTs are defined as any pharmacological or non-pharmacological measure aimed at decreasing the transfusion of red blood cell concentrates, while preserving patient safety. For each AABT, the main question formulated, positively or negatively, is: "Does this particular AABT reduce the transfusion rate or not?" All the recommendations on the use of AABTs were formulated according to the Grades of Recommendation Assessment, Development and Evaluation (GRADE) methodology.

Prothrombin fragments in cardiovascular disease.

Prothrombin fragment 1+2 (F1+2), which comes from in vivo cleavage of prothrombin by factor Xa, is considered to be useful for diagnosis of thrombosis. Recognition of the central role of thrombosis in the pathogenesis ofcardiovascular disease has prompted growing interest in the association o F1+2 with cardiovascular clinical syndromes. Increased F1+2 levels have reported in venous thromboembolism, inflammation, cancer, sepsis, acute coronary syndromes, stroke, peripheral arterial disease, atrial fibrillation and during the postoperative period. However, a clear relationship with the appearance of thrombosis has not always been consistently demonstrated. Besides its potential prognostic and diagnostic value, it could also be usefu in assessing the impact of various therapies. However, it should be kept in mind that measurement of hemostasis activation markers has several important biological and methodological disadvantages. Activation markers reflect the presence of thrombosis in any vascular bed, so they are not specific. Furthermore, elevations occur not only in the presence of overt thrombosis but also during the hypercoagulable state. The cutoff level to be used for the definition of elevations is still largely unknown due to the use of different analytical methods, none of which have been standardized until know. Finally, the prognostic value of F1+2 and other markers of coagulation activation remains to be fully defined in future studies.

Angiogenic and prothrombotic markers in extensive slow-flow vascular malformations: implications for antiangiogenic/antithrombotic strategies.

BACKGROUND: Venous and combined malformations are slow-flow haemodynamically inactive lesions that are present at birth and worsen slowly with advancing age, showing no tendency towards involution. The pathogenesis of vascular anomalies has not been fully elucidated, but their formation and progression are closely related to angiogenesis. Localized intravascular coagulation associated with venous or combined malformations is characterized by low fibrinogen, high D-dimers, and normal platelet count. OBJECTIVES: To assess the relationship of angiogenic factors with prothrombotic and endothelial damage/dysfunction markers in patients with extensive slow-flow vascular malformations. METHODS: A 2-year study (2005-2007) included 31 consecutive patients with extensive slow-flow vascular malformations from one centre. RESULTS: Serum levels of the endothelial receptor tyrosine kinase TIE-2, matrix metalloproteinase (MMP)-9 and angiopoietin (Ang)-2 and plasma levels of D-dimer, plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator and von Willebrand factor (vWf) were significantly increased in patients compared with healthy controls, whereas serum levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, MMP-2, Ang-1, platelet-derived growth factor (PDGF)-AB and PDGF-BB were significantly decreased in patients compared with controls. A strong positive correlation was present between Ang-1 and PDGF-AB levels (r = 0.63, P < 0.001), between PDGF-AB and PDGF-BB levels (r = 0.67, P < 0.001), and between fibrinogen and PAI-1 levels (r = 0.41, P = 0.031). A strong negative correlation was present between Ang-1 and vWf levels (r = -0.48, P = 0.006), between D-dimer and fibrinogen levels (r = -0.71, P < 0.001), and between PDGF-AB and vWf levels (r = -0.42, P = 0.017). CONCLUSIONS: These findings suggest that angiogenic, coagulation and endothelial damage/dysfunction markers are possibly linked in pathogenesis of extensive slow-flow vascular malformations, and might have therapeutic implications.

Independent association of matrix metalloproteinase-10, cardiovascular risk factors and subclinical atherosclerosis.

OBJECTIVES: Circulating levels of matrix metalloproteinase (MMP)-10 are related to inflammation in asymptomatic subjects with cardiovascular risk factors. Whether MMP-10 is associated with the severity of atherosclerosis remains to be determined. This study examines the relationship of systemic MMP-10 levels with atherosclerotic risk factors and subclinical atherosclerosis. METHODS AND RESULTS: Circulating levels of MMP-1, -9 and -10, and markers of inflammation [fibrinogen, interleukin-6, von Willebrand factor, and high-sensitivity C-reactive protein (hs-CRP)] were measured in 400 subjects (mean age 54.3 years, 77.7% men) with cardiovascular risk factors but free from clinical cardiovascular disease. Subclinical atherosclerosis was evaluated by both the mean carotid intima-media thickness (IMT) and the presence of atherosclerotic plaques with the use of B-mode ultrasound in all subjects. MMP-10 levels were positively correlated with fibrinogen (r = 0.24, P < 0.001), hs-CRP (r = 0.14, P < 0.01) and carotid IMT (r = 0.17, P < 0.01). The association between MMP-10 and IMT remained significant in multiple regression analysis (P < 0.02) when controlling for traditional atherosclerotic risk factors and inflammatory markers. Such an association was not observed for MMP-1 and -9. Subjects in the highest MMP-10 tertile had significantly higher carotid IMT (adjusted odds ratio 6.3, 95% confidence interval 1.3-31.4, P = 0.024). In addition, MMP-10 levels were significantly higher in patients with carotid plaques (n = 78) than in those with no plaques after adjusting for age and sex (P < 0.01). CONCLUSION: Higher serum MMP-10 levels were associated with inflammatory markers, increased carotid IMT and atherosclerotic plaques in asymptomatic subjects. Circulating MMP-10 may be useful to identify subclinical atherosclerosis in subjects free from cardiovascular disease.

Protective effect of the G-765C COX-2 polymorphism on subclinical atherosclerosis and inflammatory markers in asymptomatic subjects with cardiovascular risk factors.

BACKGROUND: Cyclooxygenase (COX)-2, a key regulatory enzyme in prostanoid synthesis, plays an important role in inflammatory processes. The -765G>C COX-2 polymorphism has been associated with lower promoter activity in vitro and reduced levels of C-reactive protein (CRP) in atherosclerotic carriers of the C allele. However, its pathophysiological relevance in vivo has not been fully elucidated. METHODS AND RESULTS: We assessed the -765G>C polymorphism and COX-2 expression in 220 asymptomatic subjects free of cardiovascular disease, in relation to global vascular risk, carotid intima-media thickness (IMT), and inflammatory markers (fibrinogen, C-reactive protein [CRP], von Willebrand factor [vWF] and interleukin-6 [IL-6]). Genotype frequencies were: CC (7.7%), CG (34.5%), GG (57.7%). Among hypercholesterolemic subjects (n=140), C allele carriers had lower COX-2 expression (p<0.05), reduced carotid IMT (p<0.01) and diminished levels of inflammatory markers CRP, vWF and IL-6 (p<0.05), as compared to GG homozygous subjects. The association between carotid IMT and COX-2 polymorphism remained significant after adjusting for cardiovascular risk factors and inflammatory markers (p=0.008). CONCLUSIONS: In asymptomatic hypercholesterolemic subjects the C allele of -765G>C COX-2 polymorphism was associated with lower COX-2 expression, and reduced subclinical atherosclerosis and systemic inflammation compared with GG homozygous, thus conferring atherosclerosis protection in this cardiovascular risk population.