RESUMO
The aim of the study is to evaluate the prognostic value of early PCSK9 levels in non-intubated septic patients admitted to the emergency department. This report utilized a portion of the data collected in a prospective study, with the aim of identifying reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit from the emergency department with a diagnosis of sepsis. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24). The primary endpoint was in-hospital mortality rate. PCSK9 circulating levels were higher than the normal value (≤ 313 ng/mL): at T0 661 ± 405 ng/mL, at T6 687 ± 417 ng/mL, at T24 718 ± 430 ng/mL. We divided the study population based on T0 quartiles distribution (≤ 370, 370-600, 600-900 and > 900 ng/ml). At T0, patients with normal PCSK9 showed the highest mortality compared to those in higher quartiles (T0: 39%, 20%, 23% and 18%, p = 0.036). By T6, the mortality curve tended to become U-shaped, with the lowest mortality among patients in the intermediate subgroups and an adverse prognosis in the presence of normal or very high levels of PCSK9 (35%, 26%, 18% and 23%, p = 0.235). A Kaplan-Meier analysis showed an increased mortality in patients with T0 and T6 PCSK9 ≤ 313 ng/ml (T0: 55 vs. 80%, p = 0.001; T6: 62 vs. 78%, p = 0.034). In subgroups with increasing levels of PCSK9, we found the best prognosis in the intermediate subgroups and an increased mortality among patients with normal and high values.
Assuntos
Biomarcadores/sangue , Testes Diagnósticos de Rotina/métodos , Diagnóstico Precoce , Serviço Hospitalar de Emergência/estatística & dados numéricos , Pró-Proteína Convertase 9/sangue , Sepse/diagnóstico , Índice de Gravidade de Doença , Idoso , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Prospectivos , Curva ROC , Sepse/sangueRESUMO
Increasing evidence shows an association between high lipoprotein(a) [Lp(a)] levels and atherothrombotic diseases. Lp(a) trait is largely controlled by kringle-IV type 2 (KIV-2) size polymorphism in LPA gene, encoding for apo(a). Environmental factors are considered to determinate minor phenotypic variability in Lp(a) levels. In the present study, we investigated the possible gene-environment interaction between KIV-2 polymorphism and Mediterranean diet adherence or fish weekly intake in determining Lp(a) levels. We evaluated Lp(a), KIV-2 polymorphism, fish intake and Mediterranean diet adherence in 452 subjects [median age (range) 66 (46-80)years] from Montignoso Heart and Lung Project (MEHLP) population. In subjects with high KIV-2 repeats number, influence of Mediterranean diet adherence in reducing Lp(a) levels was observed (p = 0.049). No significant difference in subjects with low KIV-2 repeats according to diet was found. Moreover, in high-KIV-2-repeat subjects, we observed a trend towards influence of fish intake on reducing Lp(a) levels (p = 0.186). At multivariate linear regression analysis, high adherence to Mediterranean diet remains a significant and independent determinant of lower Lp(a) levels (ß = - 64.97, standard error = 26.55, p = 0.015). In conclusion, this study showed that only subjects with high KIV-2 repeats can take advantage to lower Lp(a) levels from correct nutritional habits and, in particular, from Mediterranean diet.
Assuntos
Dieta Mediterrânea , Interação Gene-Ambiente , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Peixes , Genótipo , Humanos , Itália , Kringles/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Hemodynamic valvular impairment is a frequent determinant of the natural history of bicuspid aortic valve (BAV). The role of elevated Lp(a) levels and LPA Kringle IV type 2 (KIV-2) size polymorphism in influencing aortic valve calcification and stenosis development in patients with tricuspid aortic valve was recognized. In this study, we investigate the association between Lp(a) and LPA KIV-2 repeat number, and the presence of calcification and stenosis in BAV patients. Sixty-nine patients [79.7% males; median age 45(30-53) yrs], consecutively referred to Center for Cardiovascular Diagnosis or Referral Center for Marfan syndrome or related disorders, AOU Careggi, from June to November 2014, were investigated. For each patient, clinical (ECG and echocardiography) and laboratory [Lp(a) (Immunoturbidimetric assay) and LPA KIV-2 repeat number (real-time PCR)] evaluation were performed. Patients were compared with 69 control subjects. No significant association between Lp(a) circulating levels and LPA KIV-2 repeat number and BAV was evidenced. Among BAV patients, significantly higher Lp(a) levels according to calcification degree were found [no calcifications:78(42-159) mg/L, mild/moderate: 134(69-189) mg/L; severe: 560(286-1511) mg/L, p = 0.008]. Conversely, lower LPA KIV-2 repeat numbers in subjects with more severe calcification degree were observed. Furthermore, higher Lp(a) levels in patients with aortic stenosis [214(67-501) mg/L vs 104(56-169) mg/L, p = 0.043] were also found. In conclusion, present data suggest the potential role for Lp(a) as a possible risk marker useful to stratify, among BAV patients, those with a higher chance to develop valvular calcifications and aortic stenosis.
Assuntos
Estenose da Valva Aórtica/genética , Valva Aórtica/anormalidades , Valva Aórtica/patologia , Calcinose/genética , Doenças das Valvas Cardíacas/genética , Kringles/genética , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Polimorfismo de Nucleotídeo Único , Adulto , Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/diagnóstico por imagem , Doença da Válvula Aórtica Bicúspide , Biomarcadores/sangue , Calcinose/sangue , Calcinose/diagnóstico por imagem , Estudos de Casos e Controles , Ecocardiografia , Feminino , Predisposição Genética para Doença , Genótipo , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Reação em Cadeia da Polimerase em Tempo Real , Fatores de RiscoRESUMO
To evaluate if the assessment of coagulation abnormalities at ED admission could improve prognostic assessment of septic patients. This report utilizes a portion of the data collected in a prospective study, with the aim to identify reliable biomarkers for an early sepsis diagnosis. In the period November 2011-December 2016, we enrolled 268 patients, admitted to our High-Dependency Unit with a diagnosis severe sepsis/septic shock. Study-related blood samplings were performed at ED-HDU admission (T0), after 6 h (T6) and 24 h (T24): D-dimer, thrombin-antithrombin complex (TAT) and prothrombin fragment F1 + 2 levels were analyzed. The primary end-points were day-7 and in-hospital mortality. Day-7 mortality rate was 16%. D-dimer (T0: 4661 ± 4562 µg/ml vs 3190 ± 7188 µg/ml; T6: 4498 ± 4931 µg/ml vs 2822 ± 5623 µg/ml; T24 2905 ± 2823 µg/ml vs 2465 ± 4988 µg/ml, all p < 0.05) and TAT levels (T0 29 ± 45 vs 22 ± 83; T6 21 ± 22 vs 15 ± 35; T24 16 ± 19 vs 13 ± 30, all p < 0.05) were higher among non-survivors compared to survivors. We defined an abnormal coagulation activation (COAG+) as D-dimer > 500 µg/ml and TAT > 8 ng/ml (for both, twice the upper normal value). Compared to COAG-, COAG+ patients showed higher lactate levels at the earliest evaluations (T0: 3.3 ± 2.7 vs 2.5 ± 2.3, p = 0.041; T6: 2.8 ± 3.4 vs 1.8 ± 1.6, p = 0.015); SOFA score was higher after 24 h (T24: 6.7 ± 3.1 vs 5.4 ± 2.9, p = 0.008). At T0, COAG+ patients showed a higher day-7 mortality rate (HR 2.64; 95% CI 1.14-6.11, p = 0.023), after adjustment for SOFA score and lactate level. Presence of abnormal coagulation at ED admission shows an independent association with an increased short-term mortality rate.
Assuntos
Transtornos da Coagulação Sanguínea/etiologia , Valor Preditivo dos Testes , Sepse/complicações , Idoso , Idoso de 80 Anos ou mais , Antitrombina III/análise , Biomarcadores/análise , Biomarcadores/sangue , Serviço Hospitalar de Emergência/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Peptídeo Hidrolases/análise , Peptídeo Hidrolases/sangue , Prognóstico , Estudos ProspectivosRESUMO
Small vessel disease (SVD) is frequent in aging and stroke patients. Inflammation and remodeling of extracellular matrix have been suggested as concurrent mechanisms of SVD. We investigated the relationship between imaging features of SVD and circulating metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in patients with ischaemic stroke. In patients treated with intravenous thrombolysis, we took blood samples before intravenous thrombolysis and 90 days after the acute stroke and analysed levels of MMPs and TIMPs. We assessed leukoaraiosis, number of lacunes and brain atrophy on pre-treatment CT scan and graded global SVD burden combining such features. We investigated associations between single features, global SVD and MMPs and TIMPs at baseline and at follow-up, retaining univariate statistically significant associations in multivariate linear regression analysis and adjusting for clinical confounders. A total of 255 patients [mean (±SD) = 68.6 (± 12.7) years, 154 (59%) males] were included, 107 (42%) had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. A total of 107 (42%) patients had no signs of SVD; 47 (19%) had from moderate to severe SVD burden. After adjustment, only TIMP-4 proved associations with SVD features. Brain atrophy was associated with baseline TIMP-4 (ß = 0.20;p = 0.019) and leukoaraiosis with 90 days TIMP-4 (ß = 0.19; p = 0.013). Global SVD score was not associated with baseline TIMP-4 levels (ß = 0.10; p = 0.072), whereas was associated with 90 days TIMP-4 levels (ß = 0.21; p = 0.003). Total SVD burden was associated with higher TIMP-4 levels 90 days after stroke, whereas was not during the acute phase. Our results support a biological relationship between SVD grade and TIMP-4.
Assuntos
Doenças de Pequenos Vasos Cerebrais/sangue , Doenças de Pequenos Vasos Cerebrais/etiologia , Acidente Vascular Cerebral/complicações , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidores Teciduais de Metaloproteinases/sangue , Ativador de Plasminogênio Tecidual/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Isquemia Encefálica/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Tomógrafos Computadorizados , Tomografia Computadorizada por Raios X , Inibidor Tecidual 4 de MetaloproteinaseRESUMO
INTRODUCTION: Treatments aiming at reperfusion of the acutely ischaemic brain tissue may result futile or even detrimental because of the so-called reperfusion injury. The processes contributing to reperfusion injury involve a number of factors, ranging from blood-brain barrier (BBB) disruption to circulating biomarkers. Our aim is to evaluate the relative effect of imaging and circulating biomarkers in relation to reperfusion injury. METHODS AND ANALYSIS: Observational hospital-based study that will include 140 patients who had ischaemic stroke, treated with systemic thrombolysis, endovascular treatment or both. BBB disruption will be assessed with CT perfusion (CTP) before treatment, and levels of a large panel of biomarkers will be measured before intervention and after 24 hours. Relevant outcomes will include: (1) reperfusion injury, defined as radiologically relevant haemorrhagic transformation at 24 hours and (2) clinical status 3 months after the index stroke. We will investigate the separate and combined effect of pretreatment BBB disruption and circulating biomarkers on reperfusion injury and clinical status at 3 months. Study protocol is registered at http://www.clinicaltrials.gov (ClinicalTrials.gov ID: NCT03041753). ETHICS AND DISSEMINATION: The study protocol has been approved by ethics committee of the Azienda Ospedaliero Universitaria Careggi (Università degli Studi di Firenze). Informed consent is obtained by each patient at time of enrolment or deferred when the participant lacks the capacity to provide consent during the acute phase. Researchers interested in testing hypotheses with the data are encouraged to contact the corresponding author. Results from the study will be disseminated at national and international conferences and in medical thesis. TRIAL REGISTRATION NUMBER: NCT03041753.
Assuntos
Barreira Hematoencefálica , Isquemia Encefálica/terapia , Traumatismo por Reperfusão/diagnóstico , Reperfusão/efeitos adversos , Acidente Vascular Cerebral/terapia , Terapia Trombolítica/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Feminino , Humanos , Hemorragias Intracranianas/diagnóstico , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/etiologia , Itália , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reperfusão/métodos , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/diagnóstico por imagem , Traumatismo por Reperfusão/etiologia , Projetos de Pesquisa , Terapia Trombolítica/métodos , Tomografia Computadorizada por Raios X/métodos , Adulto JovemRESUMO
BACKGROUND: Only a few randomized dietary intervention studies that investigated the effects of lacto-ovo vegetarian diet (Vd) in clinically healthy omnivorous subjects are available. METHODS: We randomly assigned to overweight omnivores with a low-to-moderate cardiovascular risk profile a low-calorie Vd compared with a low-calorie Mediterranean diet (MD), each lasting 3 months, with a crossover design. The primary outcome was the difference in body weight, body mass index, and fat mass changes between the 2 groups. Secondary outcomes were differences in circulating cardiovascular disease risk parameters changes between the 2 groups. RESULTS: One hundred eighteen subjects (mean age: 51.1 years, females: 78%) were enrolled. The total participation rate at the end of the study was 84.7%. No differences between the 2 diets in body weight were observed, as reported by similar and significant reductions obtained by both Vd (-1.88 kg) and MD (-1.77 kg). Similar results were observed for body mass index and fat mass. In contrast, significant differences between the 2 interventions were obtained for low-density lipoprotein cholesterol, triglycerides, and vitamin B12 levels. The difference between the Vd and MD groups, in terms of end-of-diet values, was recorded at 9.10 mg/dL for low-density lipoprotein cholesterol (P=0.01), 12.70 mg/dL for triglycerides (P<0.01), and 32.32 pg/mL for vitamin B12 (P<0.01). Finally, no significant difference was found between Vd and MD interventions in oxidative stress markers and inflammatory cytokines, except for interleukin-17, which improved only in the MD group. Forty-six participants during the Vd period and 35 during the MD period reached the target values for ≥1 cardiovascular risk factor. CONCLUSIONS: Both Vd and MD were effective in reducing body weight, body mass index, and fat mass, with no significant differences between them. However, Vd was more effective in reducing low-density lipoprotein cholesterol levels, whereas MD led to a greater reduction in triglyceride levels. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02641834.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Dieta Saudável , Dieta Mediterrânea , Dieta Vegetariana , Ingestão de Energia , Obesidade/dietoterapia , Redução de Peso , Adiposidade , Adulto , Idoso , Índice de Massa Corporal , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , LDL-Colesterol/sangue , Estudos Cross-Over , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Valor Nutritivo , Obesidade/sangue , Obesidade/complicações , Obesidade/fisiopatologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Triglicerídeos/sangue , Adulto JovemRESUMO
BACKGROUND: The risk of developing red blood cell (RBC) transfusion-associated necrotizing enterocolitis (TANEC) in preterm infants has recently been emphasized. Our aim was to assess changes in cytokine serum levels after RBC transfusions in a cohort of very preterm infants to evaluate their possible proinflammatory effect. STUDY DESIGN AND METHODS: We carried out a prospective observational study. One transfusion event was studied in infants less than 32 weeks' gestation and more than 7 days old (n = 20) admitted to a tertiary neonatal intensive care unit. Interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor-α, interferon-γ (IFN-γ), IL-17, monocyte chemoattractant protein-1 (MCP-1), interferon-γ-induced protein 10 (IP-10), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule serum levels were measured in enrolled patients within 120 minutes before (T0 ) the RBC transfusion and then within 120 minutes (T1 ), 12 ± 3 hours (T2 ), 24 ± 6 hours (T3 ), and 48 ± 6 hours (T4 ) after the end of RBC transfusion. RESULTS: Infants received 19.8 ± 3.0 mL of RBCs at the mean age of 50 ± 18 days. Their hematocrit level increased from 24.1 ± 1.2% to 39.4 ± 2.9%. IL-1ß, IL-8, IFN-γ, IL-17, MCP-1, IP-10, and ICAM-1 increased significantly after RBC transfusions. CONCLUSION: Proinflammatory cytokines are increased after RBC transfusion. These findings may contribute to explaining the pathogenesis of TANEC and suggest the opportunity of adopting wise transfusion guidelines that would help to avoid detrimental risks of transfusion-related immunomodulation and of undertransfusion.
Assuntos
Citocinas/sangue , Transfusão de Eritrócitos/efeitos adversos , Citocinas/genética , Enterocolite Necrosante/etiologia , Feminino , Idade Gestacional , Humanos , Imunomodulação , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Mediadores da Inflamação , Unidades de Terapia Intensiva Neonatal , Masculino , Estudos Prospectivos , Ativação TranscricionalRESUMO
Inflammatory mediators and metalloproteinases are altered in acute ischemic stroke (AIS) and play a detrimental effect on clinical severity and hemorrhagic transformation of the ischemic brain lesion. Using data from the Italian multicenter observational MAGIC (MArker bioloGici nell'Ictus Cerebrale) Study, we evaluated the effect of inflammatory and metalloproteinases profiles on three-month functional outcome, hemorrhagic transformation and mortality in 327 patients with AIS treated with intravenous thrombolys in according to SITS-MOST (Safe Implementation of Thrombolysis in Stroke-MOnitoring STudy) criteria. Circulating biomarkers were assessed at baseline and 24 h after thrombolysis. Adjusting for age, sex, baseline glycemia and National Institute of Health Stroke Scale, history of atrial fibrillation or congestive heart failure, and of inflammatory diseases or infections, baseline alpha-2macroglobulin (A2M), baseline serum amyloid protein (SAP) and pre-post tissue-plasminogen activator (tPA) variations (Δ) of metalloproteinase 9, remained significantly and independently associated with three-month death [OR (95% CI):A2M:2.99 (1.19-7.53); SAP:5.46 (1.64-18.74); Δmetalloproteinase 9:1.60 (1.12-2.27)]. The addition of baseline A2M and Δmetalloproteinase 9 or baseline SAP and Δmetalloproteinase 9 (model-2 or model-3) to clinical variables (model-1) significantly improved the area under curve for prediction of death [model-2 with A2M: p = 0.0205; model-3 with SAP: p = 0.001]. In conclusion, among AIS patients treated with thrombolysis, circulating A2M, SAP and Δmetalloproteinase 9 are independent markers of poor outcome. These results may prompt controlled clinical research about agents antagonizing their effect.
Assuntos
Citocinas/sangue , Metaloproteases/sangue , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica , Idoso , Biomarcadores/sangue , Feminino , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Curva ROC , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
Ancient grain varieties have been shown to have some beneficial effects on health. Forty-five clinically healthy subjects were included in a randomized, double-blinded crossover trial aimed at evaluating the effect of a replacement diet with bread derived from ancient grain varieties versus modern grain variety on cardiovascular risk profile. After 8 weeks of intervention, consumption of bread obtained by the ancient varieties showed a significant amelioration of various cardiovascular parameters. Indeed, the ancient varieties were shown to result in a significant reduction of total cholesterol, low-density lipoprotein (LDL)-cholesterol and blood glucose, whereas no significant differences during the phase with the modern variety were reported. Moreover, a significant increase in circulating endothelial progenitor cells were reported after the consumption of products made from the ancient "Verna" variety. The present results suggest that a dietary consumption of bread obtained from ancient grain varieties was effective in reducing cardiovascular risk factors.
Assuntos
Pão , Doenças Cardiovasculares/prevenção & controle , Alimento Funcional , Grãos Integrais , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Estudos Cross-Over , Método Duplo-Cego , Células Progenitoras Endoteliais/metabolismo , Feminino , Alimentos Orgânicos , Indústria de Processamento de Alimentos , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/fisiopatologia , Hipercolesterolemia/prevenção & controle , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Hiperglicemia/fisiopatologia , Hiperglicemia/prevenção & controle , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Especificidade da Espécie , Recursos HumanosRESUMO
AIM: We aimed to identify specific polymorphisms of genes encoding for vascular endothelial growth factor A (VEGFA), endothelial nitric oxide synthase (eNOS), renin-angiotensin system (angiotensinogen gene [AGT], angiotensinogen type 1 receptor [AGTR1], angiotensin-converting enzyme [ACE]), and heme oxygenase-1 (HMOX-1) in a cohort of preterm infants and correlate their presence with the development of respiratory distress syndrome (RDS) requiring mechanical ventilation (MV), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH) and retinopathy of prematurity (ROP). STUDY DESIGN: We carried out a retrospective study to evaluate the allele frequency and genotype distribution of polymorphisms of VEGFA, eNOS, AGT, AGTR1, ACE, and HMOX-1 in a population of preterm neonates (n=342) with a gestational age ≤28 weeks according to the presence or absence of RDS requiring MV, BPD, IVH, or ROP. Moreover, we evaluated through the haplotype reconstruction analysis whether combinations of the selected polymorphisms are related to the occurrence of RDS, BPD, IVH and ROP. RESULTS: In our population 157 infants developed RDS requiring MV, 71 BPD, 70 IVH, and 43 ROP. We found that TC+CC rs2070744 eNOS (41.7 vs. 25.4%, p=0.01) and GT+TT rs1799983 eNOS (51.8 vs. 35.2%, p=0.01) polymorphisms are independent risk factors for BPD. Haplotype reconstruction showed that haplotypes in VEGF and eNOS are significantly associated with different effects on RDS, BPD, IVH, and ROP in our population. CONCLUSIONS: We found that TC+CC rs2070744 eNOS and GT+TT rs1799983 eNOS polymorphisms are independent predictors of an increased risk of developing BPD. Haplotypes of VEGFA and eNOS may be independent protective or risk markers for prematurity complications.
Assuntos
Polimorfismo de Nucleotídeo Único , Nascimento Prematuro/genética , Angiotensinogênio/genética , Displasia Broncopulmonar/complicações , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Heme Oxigenase-1/genética , Humanos , Recém-Nascido , Hemorragias Intracranianas/complicações , Masculino , Óxido Nítrico Sintase Tipo III/genética , Peptidil Dipeptidase A/genética , Gravidez , Nascimento Prematuro/enzimologia , Nascimento Prematuro/terapia , Receptor Tipo 1 de Angiotensina/genética , Respiração Artificial , Síndrome do Desconforto Respiratório do Recém-Nascido/complicações , Retinopatia da Prematuridade/complicações , Estudos Retrospectivos , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). METHODS: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. RESULTS: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. CONCLUSIONS: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation.
Assuntos
Doxiciclina/administração & dosagem , Eletrocardiografia , Metaloproteinases da Matriz/sangue , Infarto do Miocárdio/terapia , Reperfusão Miocárdica/métodos , Inibidor Tecidual de Metaloproteinase-1/uso terapêutico , Disfunção Ventricular Esquerda/tratamento farmacológico , Administração Oral , Idoso , Antibacterianos/administração & dosagem , Angiografia Coronária , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Masculino , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/fisiopatologia , Estudos Prospectivos , Inibidores de Proteases/uso terapêutico , Tomografia Computadorizada de Emissão de Fóton Único , Resultado do Tratamento , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação VentricularRESUMO
BACKGROUND: Experimentally, metalloproteinases (MMPs) play a detrimental role related to the severity of ischemic brain lesions. Both MMPs activity and function in tissues reflect the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs). We aimed to evaluate the role of MMPs/TIMPs balance in the setting of rtPA-treated stroke patients. METHODS: Blood was taken before and 24-h after rtPA from 327 patients (mean age 68 years, median NIHSS 11) with acute ischemic stroke. Delta median values of each MMP/TIMP ratio [(post rtPA MMP/TIMP-baseline MMP/TIMP)/(baseline MMP/TIMP)] were analyzed related to symptomatic intracranial hemorrhage (sICH) according to NINDS criteria, relevant hemorrhagic transformation (HT) defined as confluent petechiae within the infarcted area or any parenchymal hemorrhage, stroke subtypes (according to Oxfordshire Community Stroke Project) and 3-month death. The net effect of each MMP/TIMP ratio was estimated by a logistic regression model including major clinical determinants of outcomes. RESULTS: Adjusting for major clinical determinants, only increase in MMP9/TIMP1 and MMP9/TIMP2 ratios remained significantly associated with sICH (odds ratio [95% confidence interval], 1.67 [1.17-2.38], p = 0.005; 1.74 [1.21-2.49], p = 0.003, respectively). Only relative increase in MMP9/TIMP1 ratio proved significantly associated with relevant HT (odds ratio [95% confidence interval], 1.74 [1.17-2.57], p = 0.006) with a trend toward significance for MMP9/TIMP2 ratio (p = 0.007). DISCUSSION: Our data add substantial clinical evidence about the role of MMPs/TIMPs balance in rtPA-treated stroke patients. These results may serve to generate hypotheses on MMPs inhibitors to be administered together with rtPA in order to counteract its deleterious effect.