La inhibición de Rho quinasa post infarto mejora el remodelado y la función ventricular: mecanismos involucrados a nivel preclínico / Rho-kinase inhibition post myocardial infarction improves remodeling and systolic function: a preclinical study of intervening factors in a pre-clinical study

Resumen: Objetivo: Determinar algunos mecanismos moleculares por los cuales la activación de ROCK cardíaca post infarto del miocardio (IAM) participa en el remodelado y en deterioro de la función sistólica. Métodos: Determinación simultánea de niveles de proteínas blanco de ROCK cardíaca, de función sistólica in vivo del ventrículo izquierdo (VI) y de fibrosis e hipertrofia cardíaca en ratas con IAM en condiciones de inhibición de ROCK con fasudil. Resultados : Siete días post IAM la masa ventricular relativa aumentó significativamente en un 30% en el grupo MI y se redujo con fasudil. La disfunción sistólica VI mejoró significativamente con fasudil mientras que la activación de ROCK cardíaca se redujo a niveles del grupo control. El inhibidor de ROCK también redujo significativamente los niveles cardíacos elevados de las isoformas ROCK1 y ROCK2, de MHC-β y del colágeno miocárdico. En el grupo con IAM aumentaron significativamente los niveles de fosforilación de ERK 42 y ERK 44 (en 2 veces y en 63%, respectivamente), mientras que en el grupo IAM tratado con fasudil estos niveles fueron similares a los del grupo control. El IAM aumentó significativamente los niveles fosforilados del factor de transcripción GATA-4, que se normalizaron con el inhibidor de ROCK. Conclusiones: La disfunción sistólica post IAM se asoció fuertemente con la activación del ROCK cardíaca y con la fosforilación de proteínas río abajo de ROCK que promueven remodelado cardíaco como β-MHC y la vía ERK / GATA-4.

Abstracts: Objective: to determine some molecular mechanisms by which cardiac ROCK activation after myocardial infarction (MI) intervene in cardiac systolic function decline and remodeling. Methods: simultaneous measurement of different cardiac ROCK target proteins levels, in vivo left ventricular (LV) systolic function, myocardial fibrosis, and hypertrophy in rats with MI under ROCK inhibition with fasudil were performed. Results: seven days after MI the relative ventricular mass increased significantly by 30% in the MI groupand was reduced with fasudil. LV systolic dysfunction improved significantly with fasudil whereas at the same time cardiac ROCK activation was reduced to sham levels. The ROCK inhibitor also reduced increased cardiac levels of both ROCK1 and ROCK2 isoforms, β-MHC levels and myocardial collagen volume fraction decline. MI significantly increased phosphorylation levels of ERK 42 and ERK 44 by 2-fold and 63% respectively whereas in the fasudil-treated MI group these levels were similar to those in the sham group. MI significantly increased phosphorylated levels of the transcription factor GATA-4 which were normalyzed by the ROCK inhibitor. Conclusion: LV systolic dysfunction after MI was strongly associated to cardiac ROCK activation and subsequent phosphorylation of ROCK target proteins that promote ventricular remodeling, such as β-MHC and the ERK/GATA-4 pathway. ROCK inhibition with fasudil significantly improved systolic function, diminished myocardial fibrosis, and normalized β-MHC and ERK/GATA-4 phosphorylation levels.

A Comparison of Peri-Procedural Myocardial Infarction between Paclitaxel-Coated Balloon and Drug-Eluting Stent on De Novo Coronary Lesions

PURPOSE: This study compared the impact of paclitaxel-coated balloons (PCB) or drug eluting stents (DES) on peri-procedural myocardial infarction (PMI) on de novo coronary lesion in stable patients. MATERIALS AND METHODS: In this observational study, we compared the incidence of PMI amongst patients with single vessel de novo coronary lesions who underwent treatment with a PCB or DES. Propensity score-matching analysis was used to assemble a cohort of patients with similar baseline characteristics. PMI was classified as myocardial infarction occurring within 48 hours after percutaneous coronary intervention with a threshold of 5 x the 99th percentile upper reference limit of normal for creatine kinase-myocardial band (CK-MB) or troponin T (TnT). RESULTS: One hundred four patients (52 receiving PCB and 52 receiving DES) were enrolled in this study. The peak mean values of CK-MB and TnT were significantly higher in the DES group. There was a significantly higher rate of PMI in the DES group (23.1% vs. 1.9%, p=0.002). Total occlusion of the side-branch occurred in two patients treated with DES, while no patients treated with PCB. In multivariable analysis, DES was the only independent predictor of PMI compared with PCB (odds ratio 42.85, 95% confidence interval: 3.44–533.87, p=0.004). CONCLUSION: Treatment with a PCB on de novo coronary lesion might be associated with a significant reduction in the risk of PMI compared to DES.

Economic evaluation in the context of rare diseases: is it possible? / Evaluación económica en el contexto de enfermedades raras: ¿es posible? / Avaliação econômica no âmbito das doenças raras: isto é possível?

This study analyzes the available evidence on the adequacy of economic evaluation for decision-making on the incorporation or exclusion of technologies for rare diseases. The authors conducted a structured literature review in MEDLINE via PubMed, CRD, LILACS, SciELO, and Google Scholar (gray literature). Economic evaluation studies had their origins in Welfare Economics, in which individuals maximize their utilities based on allocative efficiency. There is no widely accepted criterion in the literature to weigh the expected utilities, in the sense of assigning more weight to individuals with greater health needs. Thus, economic evaluation studies do not usually weigh utilities asymmetrically (that is, everyone is treated equally, which in Brazil is also a Constitutional principle). Healthcare systems have ratified the use of economic evaluation as the main tool to assist decision-making. However, this approach does not rule out the use of other methodologies to complement cost-effectiveness studies, such as Person Trade-Off and Rule of Rescue.

El objetivo fue sistematizar las evidencias disponibles sobre la pertinencia de utilizar la evaluación económica para la incorporación/exclusión de tecnología en enfermedades raras. Se realizó una revisión sistemática de la literatura en MEDLINE vía PubMed, CRD, LILACS, SciELO y Google Académico (literatura gris). Los estudios de evaluación económica se originan de la Economía del Bienestar, en la que los individuos maximizan sus utilidades, basándose en la eficiencia de asignación. No existe un criterio ampliamente aceptado para examinar las utilidades, a fin de dar más peso a los individuos con mayores necesidades. Generalmente, los estudios no equilibran asimétricamente las utilidades, todas son consideradas iguales, lo que en Brasil es también un principio constitucional. Los sistemas de salud han ratificado el uso de la evaluación económica como la principal herramienta para ayudar en la toma de decisiones. Sin embargo, este abordaje no excluye el uso de otras metodologías complementarias a los estudios de coste-efectividad, como la técnica de compensación personal o la regla del rescate.

O objetivo deste estudo foi analisar as evidências disponíveis sobre a adequação do uso de avaliação econômica sobre incorporação/exclusão de tecnologias para doenças raras. Foi realizada uma revisão estruturada da literatura, nas bases MEDLINE, via PubMed, CRD, LILACS, SciELO e Google Acadêmico (literatura cinzenta). Os estudos de avaliação econômica têm origem na Economia do Bem-Estar, na qual os indivíduos maximizam suas utilidades, fundamentando-se na eficiência alocativa. Não há um critério amplamente aceito para ponderar as utilidades esperadas, no sentido de dar mais peso aos indivíduos com maiores necessidades em saúde. Geralmente não se ponderam assimetricamente as utilidades; todas são tratadas de forma igualitária, que, no caso brasileiro, também é um princípio constitucional. Os sistemas de saúde têm ratificado o uso de avaliação econômica como principal instrumento para auxiliar na tomada de decisão. No entanto, essa postura não exclui o uso de outras metodologias complementares aos estudos de custo-efetividade, como Person Trade-Off e regra de resgate.

Metaloproteinases 2 e 9 são preditoras de remodelação ventricular esquerda após o infarto do miocárdio / Metalloproteinases-2 and -9 predict left ventricular remodeling after myocardial infarction

FUNDAMENTO: O papel de metaloproteinases (MMP) séricas após o infarto do miocárdio (IM) é desconhecido. OBJETIVO: O objetivo deste estudo foi o de avaliar o papel das MMP-2 e -9 séricas como marcadores prognósticos da remodelação ventricular seis meses após o IM anterior. MÉTODOS: Fizemos um registro prospectivo dos pacientes após o seu primeiro IM anterior. A atividade de MMP foi analisada entre 12 a 72 horas após o IM. Foi feito um ecocardiograma durante a internação e seis meses depois. RESULTADOS: Incluímos 29 pacientes; 62% mostraram remodelação ventricular. Os pacientes que mostraram remodelação tinham maior tamanho de infarto baseado nos valores pico da creatinofosfoquinase (CPK) (p = 0,037), alta prevalência de insuficiência cardíaca congestiva em hospitais (p = 0,004), e redução da fração de ejeção (FE) (p = 0,007). Os pacientes com remodelação ventricular tiveram menores níveis séricos de MMP-9 inativa (p = 0,007) e maiores níveis da forma ativa da MMP-2 (p = 0,011). Em um modelo de regressão logística multivariada, ajustado pela idade, pico de CPK, FE e prevalência de insuficiência cardíaca, os níveis séricos da MMP-2 e -9 estavam associados à remodelação (p = 0,033 e 0,044, respectivamente). CONCLUSÃO: Níveis séricos mais elevados da MMP-9 inativa foram associados com a preservação dos volumes ventriculares esquerdos, e níveis séricos mais elevados da forma ativa da MMP-2 foram um preditor da remodelação seis meses após o IM.

BACKGROUND: The role of serum metalloproteinases (MMP) after myocardial infarction (MI) is unknown. OBJECTIVE: The aim of this study was to evaluate the role of serum MMP-2 and -9 as predictors of ventricular remodeling six months after anterior MI. METHODS: We prospectively enrolled patients after their first anterior MI. MMP activity was assayed 12 to 72 hours after the MI. An echocardiogram was performed during the hospitalization and six months later. RESULTS: We included 29 patients; 62% exhibited ventricular remodeling. The patients who exhibited remodeling had higher infarct size based on creatine phosphokinase (CPK) peak values (p = 0.037), higher prevalence of in-hospital congestive heart failure (p = 0.004), and decreased ejection fraction (EF) (p = 0.007). The patients with ventricular remodeling had significantly lower serum levels of inactive MMP-9 (p = 0.007) and significantly higher levels of the active form of MMP-2 (p = 0.011). In a multivariate logistic regression model, adjusted by age, CPK peak, EF and prevalence of heart failure, MMP-2 and -9 serum levels remained associated with remodeling (p = 0.033 and 0.044, respectively). CONCLUSIONS: Higher serum levels of inactive MMP-9 were associated with the preservation of left ventricular volumes, and higher serum levels of the active form of MMP-2 were a predictor of remodeling 6 months after MI.

Novel inflammatory biomarkers in acute coronary syndrome

No abstract available.

High admission levels of γ-glutamyltransferase predict poor myocardial perfusion after primary percutaneous intervention

OBJECTIVE: This retrospective study aimed to investigate the relationship between admission levels of serum y-glutamyltransferase and poor myocardial perfusion after primary percutaneous coronary intervention in patients with acute myocardial infarction. INTRODUCTION: Reperfusion injury caused by free radical release and increased oxidative stress is responsible for the pathophysiology of the no-reflow phenomenon in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Serum ϒ-glutamyltransferase is an established marker of increased oxidative stress. METHODS: The study population consisted of 80 patients (64 men and 16 women, mean age = 67.5 + 6.6 years) with thrombolysis in myocardial infarction 0/1 flow pre-procedurally. The patients were divided into two groups according to thrombolysis in myocardial perfusion grades that were assessed immediately following primary percutaneous coronary intervention. The two groups (group 1 and group 2) each consisted of 40 patients with thrombolysis in myocardial perfusion grades 0-1 and thrombolysis in myocardial perfusion grades 2-3, respectively. RESULTS: Admission pain to balloon time, ϒ-glutamyltransferase and creatine kinase-MB isoenzyme levels of group 1 patients were significantly higher than those of group 2 patients. Pain to balloon time, ϒ-glutamyltransferase, peak creatine kinase-MB isoenzyme, low left ventricular ejection fraction and poor pre-procedural thrombolysis in myocardial infarction grade were significantly associated with poor myocardial perfusion by univariate analysis. However, only pain to balloon time and ϒ-glutamyltransferase levels showed a significant independent association with poor myocardial perfusion by backward logistic regression analysis. Adjusted odds ratios were calculated as 4.92 for pain to balloon time and 1.13 for ϒ-glutamyltransferase. CONCLUSION: High admission ϒ-glutamyltransferase levels are associated with poor myocardial perfusion in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention, particularly in patients with prolonged pain to balloon time.

Disfunción ventricular post infarto: niveles de expresión de enzima convertidora de angiotensina I y homóloga / Ventricular dysfunction after miocardial infarction: expression levels of angiotensin converting enzyme I and its homologue

INTRODUCCION: Para mantener la funcionalidad del corazón luego de un infarto agudo al miocardio (IAM), se activa entre otros, el sistema renina-angiotensina (SRA). En condiciones fisiológicas existe un equilibrio enzimático dentro de este sistema entre la enzima convertidora de angiotensina I (ECA) y su homóloga (ECA-2). La primera aumenta el remodelamiento miocárdico (RM) contribuyendo a la disfunción del ventrículo y la segunda lo disminuye. Este equilibrio podría verse afectado frente a condiciones fisiopatológicas como el IAM. HIPOTESIS: La progresión de la disfunción ventricular post IAM se asocia a un aumento de los niveles de ARNm de la ECA y a una disminución del ARNm para ECA-2. OBJETIVO: Medir niveles de expresión génica, de ambas vías enzimáticas, en el ventrículo de ratas a corto y largo plazo post IAM. METODO: Se determinaron los niveles de ARNm de ECA y ECA-2 mediante RT-PCR a partir de ventrículos infartados en ratas Sprague Dawley sacrificadas1 y 8 semanas post IAM. RESULTADOS: Los niveles de ARNm para ECA-2 disminuyeron 8 semanas post IAM respecto a su grupo control (IAM=0.6+-0.1 v/s Sham=1.0+-0.1, p<0,008). Los niveles de expresión de ECA a las 8 semanas post IAM muestran un aumento significativo respecto del grupo control (IAM=4.7+- 0.9 v/s Sham=1.0+-0.3, p<0,05). CONCLUSIONES: Se puede concluir que luego de 8 semanas de sufrido un IAM, se produce un desbalance en la expresión de los componentes del SRA que favorece su vía enzimática de ECA y atenúa su vía enzimática de ECA-2 contribuyendo al RM y aumento de la disfunción miocárdica.

INTRODUCTION: To keep the heart function after a miocardial infarction (MI), there is an activation of the Renin-Angiotensin system (RAS). Under physiologic conditions this system has anenzymatic balance between the Angiotensin Converting EnzymeI (ACE) and its homologue (ACE-2). While ACE enhance the miocardial remodeling (MR), wich contributes to the ventricular dysfunction, ACE-2 decreases it. This balance could be afected in physiopathologic conditions like MI. HYPOTHESIS: The progression of the ventricular dysfunction after a MI is associated with an increase in the levels of mRNA of the ACE and a decrease in mRNA for ACE-2. OBJECTIVE: To measure gene expression levels of both enzymatic ways in rat ventricles at short and long term after a MI. METHOD: We established differences in the mRNA levels for ACE and ACE-2 by RT-PCR. We obtained them RNA from the infarcted ventricles of Sprague Dawley rats, sacrified 1 and 8 weeks after MI. RESULTS: The mRNA levels for ACE-2 were lower at 8 weeks after MI than the control group (MI=0.6+-0.1 v/s Control=1.0+-0.1, p<0.008). The expression levels of ACE show a significative increase at 8 weeks after MI in comparison with the control group (MI=4.7+-0.9 v/s Control=1.0+-0.3, p<0.05). CONCLUTIONS: After eight weeks of a MI there is an imbalance in the expression of the components of the RAS that favors the ACE enzymatic way and disfavor theACE-2 way. Thus, contributing to MR and miocardial dysfuntion.

Ventricular performance and Na+-K+ ATPase activity are reduced early and late after myocardial infarction in rats

Myocardial infarction leads to compensatory ventricular remodeling. Disturbances in myocardial contractility depend on the active transport of Ca2+ and Na+, which are regulated by Na+-K+ ATPase. Inappropriate regulation of Na+-K+ ATPase activity leads to excessive loss of K+ and gain of Na+ by the cell. We determined the participation of Na+-K+ ATPase in ventricular performance early and late after myocardial infarction. Wistar rats (8-10 per group) underwent left coronary artery ligation (infarcted, Inf) or sham-operation (Sham). Ventricular performance was measured at 3 and 30 days after surgery using the Langendorff technique. Left ventricular systolic pressure was obtained under different ventricular diastolic pressures and increased extracellular Ca2+ concentrations (Ca2+e) and after low and high ouabain concentrations. The baseline coronary perfusion pressure increased 3 days after myocardial infarction and normalized by 30 days (Sham 3 = 88 ± 6; Inf 3 = 130 ± 9; Inf 30 = 92 ± 7 mmHg; P < 0.05). The inotropic response to Ca2+e and ouabain was reduced at 3 and 30 days after myocardial infarction (Ca2+ = 1.25 mM; Sham 3 = 70 ± 3; Inf 3 = 45 ± 2; Inf 30 = 29 ± 3 mmHg; P < 0.05), while the Frank-Starling mechanism was preserved. At 3 and 30 days after myocardial infarction, ventricular Na+-K+ ATPase activity and contractility were reduced. This Na+-K+ ATPase hypoactivity may modify the Na+, K+ and Ca2+ transport across the sarcolemma resulting in ventricular dysfunction.

Selective cyclooxygenase-2 inhibition protects against myocardial damage in experimental acute ischemia

BACKGROUND: Acute myocardial infarction is associated with tissue inflammation. Early coronary reperfusion clearly improves the outcome but may help propagate the inflammatory response and enhance tissue damage. Cyclooxygenase-2 is an enzyme that catalyzes the initial step in the formation of inflammatory prostaglandins from arachidonic acid. Cyclooxygenase-2 levels are increased when ischemic cardiac events occur. The overall function of COX-2 in the inflammatory process generated by myocardial ischemic damage has not yet been elucidated. GOAL: The objective of this study was to determine whether a selective cyclooxygenase-2 inhibitor (rofecoxib) could alter the evolution of acute myocardial infarction after reperfusion. METHODS AND RESULTS: This study was performed with 48 mongrel dogs divided into two groups: controls and those treated with the drug. All animals were prepared for left anterior descending coronary artery occlusion. The dogs then underwent 180 minutes of coronary occlusion, followed by 30 minutes of reperfusion. Blood samples were collected from the venous sinus immediately before coronary occlusion and after 30 minutes of reperfusion for measurements of CPK-MB, CPK-MBm and troponin I. During the experiment we observed the mean blood pressure, heart rate and coronary flow. The coronary flow and heart rate did not change, but in the control group, there was blood pressure instability, in addition to maximal levels of CPK-MB post-infarction. The same results were observed for CPK-MBm and troponin I. CONCLUSION: In a canine model of myocardial ischemia-reperfusion, selective inhibition of Cyclooxygenase-2 with rofecoxib was not associated with early detrimental effects on the hemodynamic profile or the gross extent of infarction; in fact, it may be beneficial by limiting cell necrosis.

Actividades paraoxonasa y arilesterasa bajas en sujetos mexicanos con enfermedad arterial coronaria / Low paraoxonase and arylesterase plasma activities in mexican patients with coronary artery disease

PURPOSE: To determine the Paraoxonase-1 (PON1) activity as well as its pheno- and genotypes at position 192 in Mexican subjects with diagnosis of coronary heart disease (CHD). METHODS: We determined the PON1-192 polymorphism by PCR-RFLP, and serum PON1 activity, using either paraoxon (PONase activity) or phenylacetate (ARE activity) as substrates, in 155 clinically healthy individuals (control group), and 155 patients with at least one myocardial infarction (CHD group). The biochemical A/B phenotype was determined by the ratio of the NaCI 1 M-stimulated PONase activity divided by the ARE activity. RESULTS: We found significantly lower PONase and ARE activities in CHD patients as compared to controls (233.1 +/- 102.1 vs. 295.8 +/- 159.1 nmol/min/mL, and 103.1 +/- 33.7 vs 220.2 +/- 120.7 micromol/min/mL, respectively, p<0.05 for both). Allele and genotype frequencies for PON1-192 were similar in CHD patients and healthy controls. Moreover, in the control group, the PON1-192 Q/R genotype did not matched with the A/B phenotype as has been proposed by other studies. CONCLUSIONS: There were important differences in the ARE and PONase activities between Mexican CHD patients and controls, suggesting that PON1 activity could be a good marker of CHD risk, whereas PON1-192 lacks of value to assess such risk.

Role of renin-angiotensin system in development of heart failure induced by myocardial infarction in rats

We investigated the morphologic and functional changes of infarcted rat hearts under a paradigm of angiotensinconverting enzyme inhibition. Myocardial infarction was induced by left coronary artery ligation and a control group (SHAM) underwent sham-operation. Infarcted rats received normal drinking water with (CAP group) or without (INF group) captopril. Functional assessment was performed by electro (ECG) and echocardiogram (ECHO) just before and 21 days after surgery. The ECG of INF and CAP showed similar values and resembled healed infarct after surgery. The most outstanding differences between INF and CAP were the prevention of the increase of P-wave and attenuation both in rightward deviation of the QRS axis and Q-wave amplitude in CAP compared with INF. The ECHO showed that captopril treatment improved the diastolic filling more than systolic performance. Cardiac dilatation and left congestive heart failure were observed only in INF. Both infarcted groups showed a scar tissue in the left ventricular wall, but the INF showed a higher scar area than CAP (49.7 ± 5.24 vs. 22.33 ± 6.19 respectively). These data suggest that the renin-angiotensin system induces morphologic and functional changes in post-infarcted rat hearts and which can be assessed by non-invasive exams.

Nós investigamos as alterações funcionais e morfológicas em corações de ratos infartados, sob o paradigma de inibição da enzima conversora de angiotensina. O infarto do miocárdio foi produzido pela ligadura da artéria coronária esquerda e um grupo falso-operado serviu de controle para o experimento. Os ratos infartados receberam água normal com (grupo CAP) ou sem (grupo INF) captopril. A avaliação funcional foi feita através de eletro (ECG) e ecocardiografia (ECO) momentos antes e 21 dias depois da cirurgia. O ECG dos grupos INF e CAP foram similares e compatíveis com infarto cicatrizado após a cirurgia. As principais diferenças entre os grupos INF e CAP foram: a prevenção do aumento da onda P e a atenuação tanto do desvio do eixo de despolarização ventricular como da amplitude da onda Q no CAP comparado com o INF. O ECO revelou que o tratamento com captopril foi mais efetivo em melhorar o enchimento diastólico do que aumentar a função sistólica. A dilatação e a falência cardíaca congestiva foram observadas apenas no INF. Ambos os grupos infartados exibiram um tecido cicatricial no ventrículo esquerdo, mas no INF esta se mostrou maior do que no CAP (49.7 ±5.24 vs. 22.33 ±6.19 respectivamente). Estes dados sugerem que o sistema renina angiotensina produz alterações morfológicas e funcionais em corações de ratos infartados e que estas podem ser detectadas por exames não invasivos.

Study of leukocytic hydrolytic enzymes in patients with acute stage of coronary heart disease.

BACKGROUND: Coronary heart disease (CHD) is a major killer worldwide. Atherosclerosis, which is the basis of CHD, is believed to be an inflammatory disorder. Though various aspects of atherosclerosis are extensively studied, leukocytic hydrolytic enzymes are not studied very well with respect to CHD. AIM: This study was planned to assess changes associated with leukocytic hydrolases in CHD patients. SETTING AND DESIGN: A tertiary care hospital; case-control study. MATERIALS AND METHODS: 106 patients with acute myocardial infarction, 60 patients with unstable angina and 45 healthy controls were included in the study. Acid phosphatase, lysozyme, adenosine deaminase (ADA) and cathepsin-G levels were estimated from leukocytes. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were measured. STATISTICAL ANALYSIS: Statistical comparison of data was done using student's t-test (unpaired). Correlation difference was calculated by using Pearson correlation coefficient. RESULTS: Significantly higher levels of acid phosphatase, lysozyme, ADA with lower levels of cathepsin G in leukocytes were observed in CHD group. We also found significantly higher levels of serum MDA with lower concentrations of blood GSH in CHD group. In diabetic CHD group, significantly higher levels of leukocytic acid phosphatase, lysozyme, ADA and serum MDA with lower levels of cathepsin G and blood GSH were observed. CONCLUSIONS: Our study indicates that leukocyte hydrolytic enzymes, mainly acid phosphatase, lysozyme and ADA were more active in CHD patients and may contribute to inflammation related with CHD. Its also indicates that leukocyte cathepsin-G may have antiinflammatory role.

El aumento de la actividad y expresión de la enzima convertidora de angiotensina I homóloga (ECA2) inducido por enalapril se asocia a menor fibrosis e hipertrofia ventricular izquierda post infarto al miocardio en la rata / Enalapril induced increase in Homologous Angiotensin I converting enzyme (ECA2) is associated to decreased fibrosis and decreased left ventricular hypertrophy post myocardial infarction in rats

Recientemente se ha descubierto el gen de una nueva enzima convertidora de angiotensina I- homóloga a ECA y denominada ECA-2 que finalmente lleva a producir angiotensina 1-7. Esta segunda vía del sistema reninaangiotensina (SRA), con la ECA-2 tendría acciones opuestas a la ECA. Objetivo y Métodos: Determinar la actividad y expresión de la ECA2 en el tratamiento de la hipertrofia y fibrosis ventricular izquierda tardía post IAM en la rata. Se usaron ratas Sprague Dawley 200 +/- 10 g sometidas a ligadura de la coronaria izquierda. Como controles se usaron ratas sham (S). 48 hrs. post cirugía, un grupo de ratas IAM recibió enalapril (IAM-ENA; 10 mg/kg, gavage). A las 8 semanas post-operatorias se determinó la presión arterial sistólica (PAS), masa corporal(MC), masa cardíaca relativa (MCR, mg VI/100 g MC, expresión proteica de la cadena pesada de la miosina beta(betaMHC) por Western blot, mRNA por RT-PCR, las actividades enzimáticas de ECA y de ECA-2 por fluorimetría tanto circulante como en ventrículo izquierdo (VI), el contenido de colágeno total por rojo picrosirio y la actividad de metaloproteasa 2 (MMP-2) por zimografía. Conclusión: El aumento de la actividad y expresión de la ECA2 (a nivel circulante y tisular cardíaco) se asocia a menor fibrosis e hipertrofia ventricular izquierda, lo que podría aumentar – en ese periodo - el efecto cardioprotector de Ang-(1-7).

Background. Recently the gene of a new angiotensin-1 converting homologous enzyme (ACE-2) which leads to the production of angiotensin 1-7 (Ang (1-7) has been reported. This new pathway of the renin-angiotensin system(RAS) is supposed to have opposite effects to those of ACE. Aim: To determine the activity and expression of ACE-2 in the development of left ventricular hypertrophy and fibrosis late after induced myocardial infarction (AMI) in rats. Methods: 200 +/- 10g Sprague-Dawley rats were submitted to left coronary artery ligation. Sham operated rats were used as controls. 48 hr after surgery, one group of AMI rats received enalapril (AMI-En), 10mg/Kg. 8 weeks after surgery the systolic blood pressure (SBP), body mass (BM) and relative cardiac mass (RCM, mg/100g BM) were measured. The protein expression of heavy weight chain beta myosin (beta HCM) was determined by Western Blot, mRNA through RT-PCR, circulating and left ventricular ACE and ACE-2 activities through fluorometry, total collagen content by the pycrosirius red method and metaloproteinase-2 (MMP-2) through zymography were determined. Conclusion: The increased activity and expression of ACE-2 both in plasma and the LV is associated to less fibrosis and left ventricular hypertrophy after AMI. This could temporarily boost the cardioproctive effect of Ang (1-7).

Interregulación de ECA y ECA-2 (enzima convertidora de angiotensina I homóloga) en el remodelamiento y disfunción ventricular temprano y tardío post infarto del miocardio en la rata / Inter regulation of ACE and ACE-2 (homologous angiotensin I converting enzyme) in left ventricular remodeling early and long term after myocardial infarction in rats

Antecedentes: El sistema renina angiotensina (SRA) es bastante complejo pues a la vía clásica, vasoconstrictora e hipertrofiante, se suma una vía paralela vasodilatadora y antiproliferativa cuyo componente principal es la ECA-2. Objetivo y Métodos: Determinar los cambios en la actividad de ECA y ECA-2 y niveles de angiotensinas (Ang) en el remodelamiento y disfunción ventricular temprano y tardío post infarto al miocardio (IAM) experimental. Se usaron ratas Sprague Dawley 200 +/- 10 g peso, las cuales se sometieron a ligadura de la arteria coronaria izquierda. Como controles se usaron ratas sham (S). La función ventricular se determinó por ecocardiografía transtoráxica bidimiensional después de 1 y 8 semanas de la cirugía, al igual que las actividades enzimáticas de ECA y de ECA-2 (fluorimetría) circulantes y en ventrículo izquierdo (VI), y los niveles circulantes de Ang I, II, (1-7) y (1-9) (HPLC y RIA). Conclusión: La progresión del remodelamiento miocárdico post infarto se asocia a un aumento de la actividad enzimática de ECA, y a una disminución de la actividad enzimática de ECA-2. Estos cambios favorecen la vasocontricción arterial, la fibrosis miocárdica y la hipertrofia ventricular patológica.

Background: The physiology of the renin angiotensin system (RAS) is complex: the vasodilator and anti proliferative effects of ACE-2 are added to the vasoconstrictor and hypertrophy induced effects of traditional ACE. Aim and methods: To determine the changes in ACE and ACE-2 along with angiotensin levels in relation to left ventricular remodeling and dysfunction, early an late after experimental myocardial infarction (MI). Sprague-Daley rats with weight 200 +/- 10 g were submitted to left coronary artery legation. Left ventricular function was estimated by transthoracic bidimensional echocardiography, one and 8 weeks after surgery. Activities of ACE and ACE-2 were determined y photometry both in plasma and in the left ventricle: angiotensin I and II (1-7 and 1-9) were measure by HPLC and RIA. Conclusion: Evolving myocardial remodeling after myocardial infarction is associated to increased levels of ACE and decreased levels of ACE-2. These changes would lead to arterial vasoconstriction, myocardial fibrosis and pathologic left ventricular hypertrophy.

La actividad de metaloproteinasa-9 se asocia a estrés oxidativo en el síndrome coronario agudo / Metalloproteinase-9 activity is associated with oxidative stress in acute coronary syndrome

Antecedentes: La metaloproteinasas (MMPs) son enzimas proteolíticas que participan en la inestabilidad de la placa aterosclerótica. En cultivos celulares, la actividad de metaloproteinasas-2 y 9 (MMP-2 y MMP-9) aumenta en presencia de radicales libres del oxígeno. En una experiencia preliminar en pacientes con síndrome coronario agudo (SCA) hemos encontrado una posible asociación entre ambos fenómenos. Objetivo: Evaluar la relación entre actividad de enzimas de degradación de la matriz extracelular y estrés oxidativo (EO) en el SCA. Métodos: Estudiamos en forma prospectiva a 40 pacientes con SCA sin supradesnivel del segmento ST, puntaje TIMI ≥ 3 y alteraciones al electrocardiograma o elevación de Troponina I, que no presentaran un proceso inflamatorio. Se midió actividad de MMP-2 y MMP-9 (por zimografía en geles), malondialdehido (MDA) (mediante sustancias reactivas al ácido tiobarbitúrico) y PCR ultrasensible (PCRus) (ELISA), al ingreso y al quinto día. Se utilizó test t de Student para muestras pareadas y correlación lineal de Pearson. Resultados: De los 40 pacientes, 31 fueron hombres, la edad promedio fue 61+/-12 (38-85) años, todos con elevación de Troponina I. El puntaje TIMI fue de 4 (3-7). El 85 por ciento de los pacientes presentaron elevación de PCRus al ingreso (15,0+/-28,7 mg/L) y ésta aumentó al día 5 (35,3+/-38 mg/L, p=0,01); los niveles plasmáticos de MDA se encontraron elevados al ingreso (1,54+/-0,75 µM/L) y descendieron al quinto día (1,04+/-0,32 µM/L, p<0,0001). Al quinto día, la actividad de MMP-9 cayó a un 74+/-27 por ciento del valor basal (p<0,0001). No se observó cambio en la actividad de MMP-2. Se demostró una correlación positiva entre las fracciones de cambio de MDA y MMP-9 (r=0,43, p<0,0001). Conclusiones: En pacientes con SCA se observa un aumento precoz en el grado de inflamación, actividad de MMP-9 y de EO...

Background: Metalloproteinases are proteolytic enzymes that participate in atherosclerotic plaque instability. In cellular cultures there is increased activity of metalloproteinases-2 and 9 (MMP-2 and MMP-9) in the presence of free oxygen radicals. In a preliminary experience in patients with acute coronary syndrome (ACS) we have found a possible association between both phenomena. Objective: To evaluate the relation between activity of matrix degradation proteins and oxidative stress (OS) in acute coronary syndrome. Methods: Fourty patients with non-ST segment elevation acute coronary syndrome were prospectively studied. All had a TIMI risk score ≥ 3, ischemic changes on electrocardiogram or Troponin I elevation, without a concomitant inflammatory condition. We determined MMP-2 and MMP-9 activities (gel zymography), malondialdehyde (MDA) (thiobarbituric acid reactive species) and high sensitive C reactive protein (hsCRP) plasma levels at admission and 5 days later. Paired samples Student’ t test and Pearson’s lineal correlation were used for statistical analysis. Results: Of the 40 patients, 31 were male, mean age 61+/-12 years old (range 38-85), all of them with Troponin I elevation. The TIMI risk score was 4 (3-7). 85 percent presented hsCRP elevation (15.0+/-28,7 mg/L at admission and 35.3+/-38 mg/L at day 5). MDA plasma levels were increased at admission (1,54+/-0,75 µM/L) and diminished at day 5 (1,04+/-0,32 µM/L, p<0,0001). Compared to basal values, MMP-9 activity decreased to 74+/- 27 percent at day 5, (p<0,001). No significant change was observed in MMP-2 activity between both measurements. A significant positive correlation was found between change fractions of MDA levels and MMP-9 activity (r=0,43, p<0,0001). Conclusions: In patients with ACS we observed an early increase in inflammation markers, MMP-9 activity and OS. The correlation demonstrated between MMP-9 activity and OS suggests a common role of both phenomena in the pathophysiology...

value of troponin T in the coronary care unit

To assess the value of troponin T [TpT] in the coronary care unit [CCU] setting compared to creatinine phosphokinase [CK-MB] in patients admitted with acute coronary syndrome. This was a prospective study conducted over a period of 2 months between May 2003 and June 2003. All patients who were admitted to the CCU at Queen Alia Heart Institute, Amman, Jordan with acute coronary syndrome were included. Troponin T and CK-MB were performed simultaneously on all patients upon admission and serially every 4 hours for 24 hours. The times of the serial measurements from the onset of chest pain and the results were recorded. The result of coronary angiography was recorded in those patients who underwent this procedure during the index hospitalization. Patients with chest pain more than 48 hours prior to admission and those with renal impairment were excluded. One hundred and ninety-seven patients were enrolled in our study. Sixty-one% were males. The mean age was 60 years with a range of 28-90 years. The total number of patients with a positive biomarker [TpT or CK-MB] was 136. Forty-nine patients [36%] had a positive TpT without an accompanying CK-MB leak. Only 2 patients [1.4%] had a CK-MB without a positive TpT. The positive predictive value of TpT was 94%, with a negative predictive value of 96%, giving 98.5% sensitivity and 97% specificity. The earliest time from the onset of pain to having a positive TpT was one hour. Out of the 197 patients 173 [87.8%] had cardiac catheterization and it did not seem to have been affected by a negative TpT or CK-MB. There were 5 deaths, and their TpT results were well above the average positive value. Troponin T is a more sensitive and specific biomarker than CK-MB in detecting myocardial injury. It can become positive as early as one hour from the onset of chest pain. The decision whether to do coronary angiography remains based on clinical assessment rather than laboratory data

N-Acetyl-beta-D-glucosaminidase in acute myocardial infarction

The objective of the study was to investigate whether the lysosomal enzyme, N-Acetyl-beta-D-glucosaminidase (NAG) activity is increased in plasma of patients with acute myocardial infarction (AMI) and to determine if there is any association between plasma levels of NAG and severity of myocardial infarction (MI). NAG activity in plasma was monitored in 69 patients with AMI and 135 normal healthy subjects using a spectrofluorimetric method. A modified Aldrich ST elevation score was used to gauge the severity of MI in terms of size of the infarct. Plasma NAG levels in AMI patients and normal healthy subjects were found to be 10.92+/-7.5 U/l and 6.8+/-2.2 U/l, respectively. These two mean value when compared by Student's t-test were significantly different P = 0.0001. No statistically significant differences in NAG activity were observed in patients in terms of gender, age, location of infarct, time from onset of chest pain to blood sampling in the hospital and size of the infarct.

Role of oxygen free radicals in causing endothelial damage in acute myocardial infarction.

OBJECTIVES: This work was done in order to study the oxidant and anti-oxidant status in a disease resulting from endothelial injury. The disease selected for study was acute myocardial infarction. METHODS: Sixty patients of acute myocardial infarction were selected after being diagnosed in accordance to the guidelines laid down by the WHO. Thirty subjects were included as controls. Plasma levels of certain markers of oxidative stress and anti oxidant activity were measured in all the subjects. Malonaldehyde (MDA) and nitrite (NO2) were measured as markers of free radical mediated endothelial injury, and superoxide dismutase (SOD) enzyme as an indicator of antioxidant activity. RESULTS: It was found that the plasma levels of MDA and nitrite were significantly elevated in the patients of acute myocardial infarction compared to the control group (7.29 +/- 3.28 v/s 4.57 +/- 0.63 nmol/ml and 12.85 +/- 8.71 v/s 0.97 +/- 0.25 microM respectively), thereby indicating that oxygen free radicals cause endothelial damage in them. The superoxide dismutase levels were also found to be elevated in these patients (5.57 +/- 1.47 v/s 3.91 +/- 0.66 U/ml). CONCLUSION: These results indicate that acute myocardial infarction is a state of enhanced free radical activity, which causes endothelial damage. The elevated SOD levels may imply that the body attempts to combat this oxidative stress by raising it's level of anti-oxidants.

Cardioprotective effect of magnesium chloride in experimental acute myocardial infarction.

Cardioprotective role of intravenous administration of magnesium chloride was evaluated in rabbits by biochemical and histopathological parameters. Myocardial damage was induced by injecting (i.v.) isoprenaline 1, 2.5, 5 and 7.5 mg/kg body weight of animal. There was a dose dependent increase in the activity of cardiac enzyme creatinine kinase CK (C Max). Maximal elevation of CK (C Max) was observed with 2.5 mg isoprenaline. The mean T-max (mean of the time duration in hr at which maximum creatinine kinase activity of individual rabbit was observed in a group) shifted early, significantly with 2.5, 5 and 7.5 mg isoprenaline compared to control group. Histopathologically, myocardial damage was quite significant in 2.5 mg isoprenaline subgroup of animals. A mortality of 29% was observed in animals injected with 5 and 7.5 mg isoprenaline, whereas all animals subjected with 1 and 2.5 mg isoprenaline were alive for 72 hr. Considering the data on serial determination of cardiac enzyme CK and histopathological changes, 2.5 mg isoprenaline was chosen as standard dose to study efficacy of cardioprotection by gold standard verapamil and magnesium chloride. Verapamil (5 microM) injected prior to 2.5 mg isoprenaline administration revealed significant reduction of CK (C Max) activity (P < 0.05) compared to animals infused with isoprenaline alone. T-max value did not show any alteration in both the groups. Histopathological findings showed no areas of necrosis and cellular infiltrates in animals primed with 2.5 mg isoprenaline following verapamil. Highly significant reduction in CK (C-max) activity was observed in animals administered with 40 mg magnesium chloride prior to isoprenaline compared to animals treated with isoprenaline alone (P < 0.001). In addition to this, significant delay in T-max of CK activity was observed in group treated with 40 mg magnesium chloride and isoprenaline compared to group treated with only isoprenaline (P < 0.01). The study clearly highlighted and confirmed the valuable role of magnesium chloride as cardioprotective agent.