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BMC Pulm Med ; 19(1): 258, 2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31864342


BACKGROUND: There is little information about vitamin D (Vit D) deficiency in patients with pulmonary hypertension (PH). The objective of this study was: 1) compare Vit D levels between patients with PH, left ventricular failure (LVF) and healthy subjects (HS); 2) correlate, in patients with PH, Vit D levels with prognosis-related variables, such as the 6-min walk test (6MWT). METHODS: Vitamin D levels were measured in a cross-sectional study in 126 patients from one of three groups: patients with PH (n = 53), patients with LVF (n = 42) and healthy subjects (n = 31). In all groups, 8-h fasting blood samples were obtained in the morning. In the PH and the LVF group, functional class (WHO criteria), metres covered in the 6MWT and echocardiographic parameters were analysed. In the PH group, plasma N terminal pro B type natriuretic peptide (NT-proBNP) level was analysed and a complete haemodynamic evaluation by right heart catheterisation was made. RESULTS: Mean Vit D levels were lower in PH than in both other groups (ng/ml, mean ± SD): PH 19.25 ± 10, LVF 25.68 ± 12, HS 28.8 ± 12 (PH vs LVF p = 0.017, PH vs HS p = 0.001 and HS vs LVF p = 0.46). Vit D deficiency prevalence was higher in PH as compared to the other groups (PH 53.8%, LVF 45.2%, HS 25%, p = 0.01). Patients with PH in functional class (FC; WHO criteria) III-IV had higher Vit D deficiency prevalence than those in FC I-II (86.7% vs 40.5%, p = 0.003). There was a significant linear correlation between the 6MWT and Vit D levels in PH (p < 0.01), but not in LVF (p = 0.69). CONCLUSIONS: Vit D levels were lower in patients with PH as compared to patients with LVF and HS and correlated directly with 6-min walk distance.

Artigo em Inglês | MEDLINE | ID: mdl-31538307


Objectives of the study were the prevalence and clinical consequences of balloon rupture with compliant balloons in balloon aortic valvuloplasty (BAV). Compliant low-profile balloons have been developed to reduce access site complications. Made by thinner materials, these balloons are more prone to rupture. This is a single-center retrospective analysis (2016-2018) of patients undergoing BAV with compliant balloons. Baseline echocardiography and computed tomography (CT) were analyzed. Best cutoff point for calcium score was assessed. Long-term mortality was analyzed with Kaplan-Maier. In vitro test was performed. Rupture occurred in 30/90 (33%) of BAVs independent of risk factors, surgical risk and frailty scores. Patients experiencing rupture had increased mean gradient [53.5 (44-64) vs 44 (35-49) mmHg, p < 0.05] and reduced aortic valve area [0.61 (0.46-0.76) vs 0.76 (0.64-0.83) mm2, p < 0.05]. Valve calcium score on CT > 2686 AU was more frequent in the rupture group (41% vs 10%, p < 0.05) and more patients in the third tertile of calcium score experienced rupture (75% vs 23% vs 41% for second and first tertile, p < 0.05). Median gradient reduction from baseline was similar among groups [30 (20-50) vs 30 (17-39) mmHg]. No patient with rupture had any complication. One-month and long-term mortality were similar (rupture 0% vs 3.5% no rupture from 1 month). In vitro test required more volume and strength to rupture the balloon than used in BAV. Balloon rupture is frequent in BAV using compliant balloons, occurs with more severe aortic stenosis, does not affect BAV efficacy and does not impair outcomes.

Mediators Inflamm ; 2018: 8696543, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30524200


Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension.

Galectina 1/metabolismo , Inflamação/metabolismo , Animais , Homeostase/fisiologia , Humanos , Linfócitos T Reguladores/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
Rev. argent. cardiol ; 86(2): 110-115, abr. 2018.
Artigo em Espanhol | LILACS-Express | ID: biblio-1003186


RESUMEN: Introducción: La angioplastia coronaria en octogenarios aumenta, pero esta población está poco representada en los estudios aleatorizados por su alto riesgo. Objetivos: Evaluar los resultados de angioplastia coronaria de pacientes octogenarios e identificar predictores independientes de mala evolución en el seguimiento. Material y métodos: Estudio retrospectivo, pacientes consecutivos con angioplastia coronaria junio 2011 a Septiembre 2013 en un Hospital Polivalente. Se compararon octogenarios (edad ≥ 80 años) con el resto. Se evaluaron las características basales y del procedimiento. Se evaluó la mortalidad y los eventos cardiovasculares mayores (MACE, muerte, infarto o stroke) a 30 días, 1 y 3 años. Se realizó un análisis univariado y multivariado para predictores de mala evolución. Resultados: Se incluyeron 1030 pacientes, 20,2% octogenarios. La edad promedio de los octogenarios era de 83 años (RIC 81-86). Estos presentaron más factores de riesgo y comorbilidades. La tasa de éxito y la cantidad de stents fue similar entre los grupos. La tasa de MACE fue mayor en octogenarios a 30 días (14,4% vs. 4,9%; p < 0,001), 1 año (23,9% vs. 8,5%; p < 0,001) y a 3 años (p < 0,0001), a expensas de mortalidad sin diferencias en el infarto (4,8% vs. 3,8%), el stroke (1,7% vs. 1,6%), ni en complicaciones del procedimiento. Los predictores independientes de muerte en octogenarios incluyen IRC, EPOC y deterioro de la función ventricular. La edad ≥ 80 años fue un predictor independiente de MACE en la población general. Conclusiones: Observamos una aceptable tasa de éxito de angioplastia coronaria en pacientes octogenarios, asociada con un aumento de la mortalidad inmediata y alejada que no parece relacionada con el procedimiento. La IRC, el EPOC y el deterioro de la función ventricular son predictores independientes de mal pronóstico en estos pacientes.

ESC Heart Fail ; 5(1): 149-156, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28758719


AIMS: The aim of this study was to evaluate whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) predict outcome in heart failure (HF) patients undergoing heart transplantation (HTX). METHODS AND RESULTS: Data from 111 HF patients undergoing HTX 2010-2015 were retrospectively reviewed. NLR and PLR were calculated before HTX, immediately after HTX, and at 6 and 24 hours. Primary endpoint was in-hospital mortality, and secondary endpoints were 1 year mortality and renal replacement therapy (RRT). Prognostic factors were assessed by multivariate analysis, and the predictive values of NLR and PLR for mortality were compared. The discriminatory performance for predicting in-hospital mortality was better for NLR [area under the receiver operating characteristic curve (AUC) = 0.644, 95% confidence interval 0.492-0.797] than for PLR (AUC = 0.599, 95% confidence interval 0.423-0.776). Best cut-off value was 2.41 for NLR (sensitivity 86%, specificity 67%) and 92.5 for PLR (sensitivity 86%, specificity 68%). When divided according to best cut-off value, in-hospital mortality was significantly higher in the high NLR group (17.5% vs. 3.2%, P < 0.05), but not in the high PLR group (16.5% vs. 6.3%, P = ns). One year mortality was not significantly higher for either group (37.5% vs. 6.5% for NLR; 36.7% vs. 9.4% for PLR, P = ns for both), while RRT was significantly higher in both the NLR and PLR high groups (33.8% vs. 0%; 32.9% vs. 3.1%, respectively, P < 0.001). Multivariate analysis indicated that only high NLR (hazard ratio = 3.403, P < 0.05) and pre-transplant diabetes (hazard ratio = 3.364, P < 0.05) were independent prognostic factors for 1 year mortality. CONCLUSIONS: High NLR was a predictor for in-hospital mortality, and an independent prognostic factor for 1 year mortality. Both high NLR and high PLR were predictors for RRT.

Plaquetas/patologia , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Linfócitos/patologia , Neutrófilos/patologia , Argentina/epidemiologia , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/mortalidade , Mortalidade Hospitalar/tendências , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Curva ROC , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
Catheter Cardiovasc Interv ; 90(1): 104-111, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27566914


OBJECTIVES: To report a series of consecutive patients that developed retroperitoneal hemorrhage (RPH) and persistent hypotension treated with endovascular approach. BACKGROUND: RPH is a rare complication of percutaneous cardiovascular interventions associated with high morbidity and mortality. The standard approach to treat this complication has been a conservative management for stable patients, and urgent vascular surgery for those with persistent hypovolemic shock. Percutaneous endovascular treatment has evolved as an alternative treatment option. METHODS: We implemented a management algorithm for patients with suspected RPH and persistent hypotension which embraced systematic use of emergency endovascular evaluation and treatment following clinical assessment without the use of non-invasive diagnostic testing. We report a series of 8 consecutive patients that developed RPH with persistent hypotension. RESULTS: Successful percutaneous treatment was achieved in all cases with the use of a covered stent. No patient required vascular surgery. The average blood transfusion was 3.4 ± 2.7 units per patient. There were no deaths; one patient experienced acute stent thrombosis that was successfully treated via endovascular approach. At 1-year follow-up, no further events were reported. CONCLUSION: The incorporation of a standardized protocol using only clinical evaluation followed by emergency percutaneous approach without delays attributed to non-invasive diagnostic work-up showed to be feasible and associated with favorable outcomes. © 2016 Wiley Periodicals, Inc.

Procedimentos Endovasculares , Hemodinâmica , Hemorragia/terapia , Hipotensão/terapia , Intervenção Coronária Percutânea/efeitos adversos , Choque Hemorrágico/terapia , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Angiografia , Procedimentos Clínicos , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/instrumentação , Feminino , Hemorragia/diagnóstico por imagem , Hemorragia/etiologia , Hemorragia/fisiopatologia , Humanos , Hipotensão/diagnóstico , Hipotensão/etiologia , Hipotensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Espaço Retroperitoneal , Choque Hemorrágico/diagnóstico , Choque Hemorrágico/etiologia , Choque Hemorrágico/fisiopatologia , Stents , Resultado do Tratamento
Eur Heart J Acute Cardiovasc Care ; 5(4): 382-95, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25681486


After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression.

Biomarcadores/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/imunologia , Quimiocinas/sangue , Citocinas/sangue , Humanos , Contagem de Leucócitos , Prognóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Remodelação Ventricular
J Am Coll Cardiol ; 63(16): 1593-603, 2014 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-24530674


Acute myocardial infarction (AMI) leads to molecular, structural, geometric, and functional changes in the heart in a process known as ventricular remodeling. An intense organized inflammatory response is triggered after myocardial ischemia and necrosis and involves all components of the innate immunity, affecting both cardiomyocytes and noncardiomyocyte cells. Inflammation is triggered by tissue injury; it mediates wound healing and scar formation and affects ventricular remodeling. Many therapeutic attempts aimed at reducing inflammation in AMI during the past 3 decades presented issues of impaired healing or increased risk of cardiac rupture or failed to show any additional benefit in addition to standard therapies. More recent strategies aimed at selectively blocking one of the key factors upstream rather than globally suppressing the response downstream have shown some promising results in pilot trials. We herein review the pathophysiological mechanisms of inflammation and ventricular remodeling after AMI and the results of clinical trials with anti-inflammatory strategies.

Anti-Inflamatórios/uso terapêutico , Inflamação/tratamento farmacológico , Infarto do Miocárdio/tratamento farmacológico , Remodelação Ventricular/fisiologia , Animais , Proteína C-Reativa/metabolismo , Citocinas/metabolismo , Humanos , Inflamação/metabolismo , Integrinas/metabolismo , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia
Am J Physiol Heart Circ Physiol ; 306(7): H1025-31, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24531812


Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1ß in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30-50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1ß induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1ß failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1ß induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1ß. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.

Insuficiência Cardíaca/metabolismo , Interleucina-18/metabolismo , Interleucina-1beta , Disfunção Ventricular Esquerda/metabolismo , Função Ventricular Esquerda , Animais , Anticorpos/farmacologia , Modelos Animais de Doenças , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/deficiência , Interleucina-18/genética , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Sístole , Fatores de Tempo , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos
Inflamm Res ; 62(7): 637-40, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23649041


BACKGROUND: Inflammatory mediators play a key role in the development and progression of heart failure. Interleukin-1ß (IL-1ß) is a prototypical inflammatory cytokine that suppresses myocyte contractility following acute administration. METHODS: Healthy mice were randomly assigned to daily intraperitoneal injections of recombinant murine IL-1ß (3 µg/kg in 0.2 ml) or matching volumes of NaCl 0.9 % solution (vehicle) for 15 days. Echocardiography was performed at baseline and 4 h (acute), followed by repeat measurements immediately prior to IL-1ß or saline injections on days 5, 10, and 15 (chronic). Final echocardiography was performed on day 20 (5 days after last treatment). A subgroup of animals underwent isoproterenol challenge to evaluate contractile reserve at baseline, 4 h (acute), 15 days (chronic) and 20 days (recovery). RESULTS: IL-1ß reduced left ventricular fractional shortening (LVFS) at 4 h versus vehicle (-24 vs. 0 %, respectively, P < 0.05). This reduction was maintained throughout chronic dosing at day 15. IL-1ß-treated mice also showed impaired contractile reserve with a right shift of the dose-response curve to isoproterenol (P < 0.05) at 4 h and 15 days. By day 20, 5 days after stopping IL-1ß, LVFS and contractile reserve had returned to baseline. CONCLUSIONS: IL-1ß induces a reversible contractile dysfunction associated with impaired response to ß-receptor stimulation.

Cardiomiopatias/induzido quimicamente , Interleucina-1beta/efeitos adversos , Agonistas Adrenérgicos beta/farmacologia , Animais , Cardiomiopatias/fisiopatologia , Interleucina-1beta/administração & dosagem , Isoproterenol/farmacologia , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
PLoS One ; 8(3): e58421, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23516478


PURPOSE: The antineoplastic efficacy of anthracyclines is limited by their cardiac toxicity. In this study, we evaluated the toxicity of doxorubicin, non-pegylated liposomal-delivered doxorubicin, and epirubicin in HL-1 adult cardiomyocytes in culture as well as in the mouse in vivo. METHODS: The cardiomyocytes were incubated with the three anthracyclines (1 µM) to assess reactive oxygen generation, DNA damage and apoptotic cell death. CF-1 mice (10/group) received doxorubicin, epirubicin or non-pegylated liposomal-doxorubicin (10 mg/kg) and cardiac function was monitored by Doppler echocardiography to measure left ventricular ejection fraction (LVEF), heart rate (HR) and cardiac output (CO) both prior to and 10 days after drug treatment. RESULTS: In HL-1 cells, non-pegylated liposomal-doxorubicin generated significantly less reactive oxygen species (ROS), as well as less DNA damage and apoptosis activation when compared with doxorubicin and epirubicin. Cultured breast tumor cells showed similar sensitivity to the three anthracyclines. In the healthy mouse, non-pegylated liposomal doxorubicin showed a minimal and non-significant decrease in LVEF with no change in HR or CO, compared to doxorubicin and epirubicin. CONCLUSION: This study provides evidence for reduced cardiac toxicity of non-pegylated-liposomal doxorubicin characterized by attenuation of ROS generation, DNA damage and apoptosis in comparison to epirubicin and doxorubicin.

Antraciclinas/toxicidade , Antineoplásicos/toxicidade , Coração/efeitos dos fármacos , Animais , Antraciclinas/efeitos adversos , Antineoplásicos/efeitos adversos , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Doxorrubicina/toxicidade , Ecocardiografia , Coração/fisiopatologia , Humanos , Masculino , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo
Artigo em Espanhol | MEDLINE | ID: mdl-24650652


Vitamin D (VitD) deficiency is associated with increased morbidity and mortality. We evaluated the association of VitD deficiency (<50 mmol/l) and cardiovascular risk factors in a healthy population, from July-November 2012, in a private center at Buenos Aires province. 333 people were included, aged 41.6±12.4 years (58.6% men), 49.2% practiced no physical activity, 56.8% were overweight (70.3% man vs 37.7% women, p<0.001), 12.5% with systolic blood pressure (SBP) >140 mmHg and 6% diastolic blood pressure (DBP) >90 mmHg. VitD deficiency was observed in 29.1% (31.3% man vs 26.1% women, p=0.3), more frequent with obesity (OR 1.85, IC95:1.05-3.25, p=0.02), HDL-cholesterol (HDL-C)<50 mg/dl (OR 1.71, IC95:1.06-2.76, p=0.02) and triglycerides>150 mg/dl (OR 1.77, IC95:1.02-3.06, p=0.03). A trend towards VitD deficiency and SBP>140 mmHg (OR 1.88, IC95:0.93-3.77, p=0.07) or DBP>90 mmHg (OR 1.39, IC95:0.5-3.65, p=0.5) was observed. Lineal correlation between VitD and HDL-C (p<0.001) or triglycerides (p<0.001) was observed. Multiple logistic regression showed that VitD deficiency association with low HDL-C was independent of age, female sex, obesity and physical activity. Association of VitD deficiency with hypetriglyceridemia was independent of age, female sex and obesity. This study shows an association between VitD deficiency and cardiovascular risk factors like obesity, low HDL <50 mg/dl and hypertriglyceridemia. A trend toward higher SBP was also observed. Experimental studies are granted in order to establish a cause-effect relationship.

Doenças Cardiovasculares/complicações , Deficiência de Vitamina D/complicações , Adulto , Fatores Etários , Pressão Sanguínea/fisiologia , HDL-Colesterol/sangue , Feminino , Humanos , Hipertrigliceridemia/sangue , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Obesidade/sangue , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
Am J Pathol ; 182(1): 29-40, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23142379


Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, plays essential roles in the control of inflammation and neovascularization. Although identified as a major component of the contractile apparatus of cardiomyocytes, the potential role of Gal-1 in modulating heart pathophysiology is uncertain. Here, we aimed to characterize Gal-1 expression and function in the infarcted heart. Expression of Gal-1 was substantially increased in the mouse heart 7 days after acute myocardial infarction (AMI) and in hearts from patients with end-stage chronic heart failure. This lectin was localized mainly in cardiomyocytes and inflammatory infiltrates in peri-infarct areas, but not in remote areas. Both simulated hypoxia and proinflammatory cytokines selectively up-regulated Gal-1 expression in mouse cardiomyocytes, whereas anti-inflammatory cytokines inhibited expression of this lectin or had no considerable effect. Compared with their wild-type counterpart, Gal-1-deficient (Lgals1(-/-)) mice showed enhanced cardiac inflammation, characterized by increased numbers of macrophages, natural killer cells, and total T cells, but reduced frequency of regulatory T cells, leading to impaired cardiac function at baseline and impaired ventricular remodeling 7 days after nonreperfused AMI. Treatment of mice with recombinant Gal-1 attenuated cardiac damage in reperfused AMI. Taken together, our results indicate a protective role for Gal-1 in normal cardiac homeostasis and postinfarction remodeling by preventing cardiac inflammation. Thus, Gal-1 treatment represents a potential novel strategy to attenuate heart failure in AMI.

Galectina 1/fisiologia , Infarto do Miocárdio/fisiopatologia , Miocardite/metabolismo , Remodelação Ventricular/fisiologia , Adulto , Idoso , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipóxia Celular/fisiologia , Células Cultivadas , Citocinas/farmacologia , Feminino , Galectina 1/biossíntese , Galectina 1/farmacologia , Galectina 1/uso terapêutico , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Humanos , Mediadores da Inflamação/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miocardite/etiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Proteínas Recombinantes/uso terapêutico , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia , Função Ventricular Esquerda/fisiologia , Adulto Jovem
Artigo em Espanhol | BINACIS | ID: bin-132689


Vitamin D (VitD) deficiency is associated with increased morbidity and mortality. We evaluated the association of VitD deficiency (<50 mmol/l) and cardiovascular risk factors in a healthy population, from July-November 2012, in a private center at Buenos Aires province. 333 people were included, aged 41.6±12.4 years (58.6

men), 49.2

practiced no physical activity, 56.8

were overweight (70.3

man vs 37.7

women, p<0.001), 12.5

with systolic blood pressure (SBP) >140 mmHg and 6

diastolic blood pressure (DBP) >90 mmHg. VitD deficiency was observed in 29.1


man vs 26.1

women, p=0.3), more frequent with obesity (OR 1.85, IC95:1.05-3.25, p=0.02), HDL-cholesterol (HDL-C)<50 mg/dl (OR 1.71, IC95:1.06-2.76, p=0.02) and triglycerides>150 mg/dl (OR 1.77, IC95:1.02-3.06, p=0.03). A trend towards VitD deficiency and SBP>140 mmHg (OR 1.88, IC95:0.93-3.77, p=0.07) or DBP>90 mmHg (OR 1.39, IC95:0.5-3.65, p=0.5) was observed. Lineal correlation between VitD and HDL-C (p<0.001) or triglycerides (p<0.001) was observed. Multiple logistic regression showed that VitD deficiency association with low HDL-C was independent of age, female sex, obesity and physical activity. Association of VitD deficiency with hypetriglyceridemia was independent of age, female sex and obesity. This study shows an association between VitD deficiency and cardiovascular risk factors like obesity, low HDL <50 mg/dl and hypertriglyceridemia. A trend toward higher SBP was also observed. Experimental studies are granted in order to establish a cause-effect relationship.

Doenças Cardiovasculares/complicações , Deficiência de Vitamina D/complicações , Adulto , Fatores Etários , Pressão Sanguínea/fisiologia , HDL-Colesterol/sangue , Feminino , Humanos , Hipertrigliceridemia/sangue , Masculino , Pessoa de Meia-Idade , Atividade Motora/fisiologia , Obesidade/sangue , Estudos Prospectivos , Fatores de Risco , Fatores Sexuais , Deficiência de Vitamina D/sangue , Deficiência de Vitamina D/epidemiologia
PLoS One ; 7(3): e33438, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22438931


BACKGROUND: Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1ß (IL-1ß) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. METHODS AND RESULTS: We developed a model of IL-1ß-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1ß 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO(2)) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL · kg(-1) · min(-1) (P = 0.016 vs. baseline) and median ventilator efficiency (V(E)/VCO(2) slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). CONCLUSIONS: These findings suggest that IL-1ß activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1ß blockade as a novel strategy for pharmacologic intervention. TRIAL REGISTRATION: NCT01300650.

Tolerância ao Exercício/fisiologia , Insuficiência Cardíaca Sistólica/fisiopatologia , Interleucina-1beta/fisiologia , Adulto , Animais , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Teste de Esforço , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Mediadores da Inflamação/sangue , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/administração & dosagem , Interleucina-1beta/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Consumo de Oxigênio/efeitos dos fármacos , Proteínas Recombinantes/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
Proc Natl Acad Sci U S A ; 108(49): 19725-30, 2011 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-22106299


Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

Inflamassomos/metabolismo , Infarto do Miocárdio/metabolismo , Remodelação Ventricular , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Western Blotting , Proteínas Adaptadoras de Sinalização CARD , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Caspase 1/genética , Caspase 1/metabolismo , Linhagem Celular , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Imunofluorescência , Expressão Gênica , Inflamassomos/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fosfato de Piridoxal/análogos & derivados , Fosfato de Piridoxal/farmacologia , Interferência de RNA , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
Mol Med ; 17(9-10): 1012-21, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21637911


Diabetes is associated with an increased risk of heart failure, in part explained by endoplasmic reticulum stress and apoptosis. Protein disulfide isomerase (PDI) prevents stressed cardiomyocytes apoptosis. We hypothesized that diabetes impairs PDI function by an alteration in its oxido-reductive state. Myocardial biopsies harvested from the anterolateral left ventricular wall from diabetic (n = 7) and nondiabetic (n = 8) patients were used to assess PDI expression and cardiomyocyte death. A mouse model of diabetes (streptozotocin injection, 130 mg/mL) was used to study PDI expression and its redox state after ischemia/reperfusion injury induced by 30-min occlusion of the left anterior coronary artery followed by reperfusion. Transthoracic echocardiography was performed to assess cardiac remodeling after 1 wk. Western blot analysis was used to analyze PDI expression, and methoxy-polyethyleneglycol-maleimide was used to assess its redox state. Dehydroascorbate (DHA) administration was used to restore the PDI redox state. Diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells than nondiabetic patients despite a greater myocardial PDI expression suggesting altered PDI function. Diabetic mice had a worse postinfarction remodeling associated with an altered PDI redox state. DHA treatment restored functional PDI redox state and ameliorated post-myocardial infarction remodeling. An increase in PDI levels with a paradoxical decrease of its active form occurs in the diabetic heart after ischemia and may explain the lack of protective effects of PDI in diabetes. Restoration of PDI redox state prevents adverse remodeling. The potential significance of these findings deserves to be validated in a clinical setting.

Diabetes Mellitus/enzimologia , Insuficiência Cardíaca/enzimologia , Miocárdio/enzimologia , Isomerases de Dissulfetos de Proteínas/metabolismo , Idoso , Animais , Apoptose , Pressão Sanguínea , Western Blotting , Células Cultivadas , Ácido Desidroascórbico/farmacologia , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/fisiopatologia , Ecocardiografia , Feminino , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Camundongos , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/enzimologia , Oxirredução/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/fisiopatologia , Remodelação Ventricular
J Mol Cell Cardiol ; 51(2): 244-51, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21600901


Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia-reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30 min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7 days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (-30% day 1 and -55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling.

Inibidores de Caspase , Traumatismo por Reperfusão Miocárdica/enzimologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Inibidores de Serino Proteinase/farmacologia , alfa 1-Antitripsina/farmacologia , Doença Aguda , Animais , Caspase 1/metabolismo , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miócitos Cardíacos/enzimologia , Inibidores de Serino Proteinase/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , alfa 1-Antitripsina/uso terapêutico
PLoS One ; 6(3): e18102, 2011 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-21455304


BACKGROUND: Cardiac remodelling after AMI is characterized by molecular and cellular mechanisms involving both the ischemic and non-ischemic myocardium. The extent of right ventricular (RV) dilatation and dysfunction and its relation to pulmonary hypertension (PH) following AMI are unknown. The aim of the current study was to evaluate changes in dimensions and function of the RV following acute myocardial infarction (AMI) involving the left ventricle (LV). METHODS: We assessed changes in RV dimensions and function 1 week following experimental AMI involving the LV free wall in 10 mice and assessed for LV and RV dimensions and function and for the presence and degree of PH. RESULTS: RV fractional area change and tricuspidal annular plane systolic excursion significantly declined by 33% (P = 0.021) and 28% (P = 0.001) respectively. Right ventricular systolic pressure measured invasively in the mouse was within the normal values and unchanged following AMI. CONCLUSION: AMI involving the LV and sparing the RV induces a significant acute decline in RV systolic function in the absence of pulmonary hypertension in the mouse indicating that RV dysfunction developed independent of changes in RV afterload.

Hipertensão Pulmonar/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Animais , Masculino , Camundongos