RESUMEN
A growing body of evidence is pointing out the pathophysiological role of fat accumulation in different organs. Ectopic fat depots within heart, liver, skeletal muscle, kidney, and pancreas as well as around blood vessels might be more associated to cardiometabolic risk than classical variables, such as body mass index. Among different mechanisms, lipid metabolism appears to be particularly influenced by ectopic fat depots. Indeed, intracellular accumulation of nonesterified fatty acids, and triglycerides promotes endoplasmic reticulum stress, mitochondrial uncoupling, oxidative stress, and altered membrane composition/function, finally promoting inflammatory response and cell death. The dysfunctional adipose tissue was shown to induce both local and systemic effects, with relevant clinical consequences. Epicardial fat and myocardial steatosis have been associated with the development of atrial fibrillation and ventricular dysfunction. Similarly perivascular adipose tissue appears to trigger atherosclerosis and hypertension. Nonalcoholic fatty liver disease has been recognized both as the hepatic manifestation of metabolic syndrome and as a cardiovascular (CV) risk factor. Importantly, the renal sinus fat emerged as a potential player in kidney dysfunction. Finally, both skeletal muscle and pancreatic fat depots have been indicated as potential endocrine modulators of insulin resistance. Considering the global rise in the prevalence of obesity, the understanding of mechanisms underlying ectopic fat accumulation represents an urgent need, with potential clinical implications for CV risk stratification. Here, we attempt to update the current knowledge of the different ectopic fat depots, focusing on underlying mechanisms and potential clinical implications.
Asunto(s)
Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Grasas/metabolismo , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/patología , Animales , Índice de Masa Corporal , Enfermedades Cardiovasculares/etiología , Humanos , Hígado/metabolismo , Hígado/patología , Enfermedades Metabólicas/etiologíaRESUMEN
Monoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each nivolumab administration, clinical information and blood samples were collected. Median age was 71, with a prevalence of the male sex. The most represented histological type of lung cancer was adenocarcinoma. The majority of patients were former smokers (72.1%). Median PCSK9 levels were 123.59 (86.32-169.89) ng/mL and 117.17 (80.46-147.79) ng/mL at cycle 1 and 2, respectively. Based on a receiver operating characteristic curve analysis, a PCSK9 value at cycle 2 of 95 ng/mL was found as the best cutoff point for OS. Kaplan-Meier analysis demonstrated that patients below the PCSK9 cutoff (< 95 ng/mL) experienced a better OS, as confirmed by Cox proportional hazard regression analysis. In this pilot study, circulating levels of PCSK9 < 95 ng/mL at the time of the second cycle of nivolumab treatment could independently predict a better OS in elderly patients with advanced, pre-treated NSCLC. However, further studies are warranted to validate these preliminary results.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/sangre , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Inmunoterapia/métodos , Neoplasias Pulmonares/diagnóstico , Nivolumab/uso terapéutico , Proproteína Convertasa 9/sangre , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Femenino , Humanos , Italia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Masculino , Estadificación de Neoplasias , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Ultrasound evaluation of carotid intima-media thickness (cIMT) has been extensively used for potentially improving cardiovascular (CV) risk stratification in several patients' categories. Subjects with systemic lupus erythematosus (SLE) have been investigated by both imaging and molecular biomarker approaches with contrasting results. Here, we focused on the role of osteopontin (OPN) as biomarker of subclinical atherosclerosis associated with SLE. MATERIALS AND METHODS: Eighty females (age 18-65 years) affected by SLE and eighty age-matched healthy female controls without a clinical history of CV disease underwent ultrasound evaluation of cIMT and blood sample assay of high-sensitivity C-reactive protein (hs-CRP) and OPN. RESULTS: Healthy controls and SLE patients significantly differed for CV risk factors (ie, waist circumference, hypertension and dyslipidaemia) and the inflammatory status. Noteworthy, an opposite association between cIMT and OPN was observed in the two study groups. Whereas OPN was positively associated with mean cIMT (r = 0.364; P = 0.001) in SLE patients, a negative correlation was found in healthy controls. Furthermore, in SLE patients increased circulating levels of OPN were associated with the use of hydroxychloroquine and the positivity for the anti-dsDNA autoantibodies. At linear regression analysis, only OPN remained independently associated with cIMT also after adjustment for age, smoking pack-year, Heart SCORE, disease length and steroid therapy length. CONCLUSIONS: These results indicate that serum OPN levels were strongly associated with subclinical atherosclerosis in patients with LES and it might be a useful CV biomarker that requires additional validation in larger trials.
Asunto(s)
Aterosclerosis/diagnóstico , Lupus Eritematoso Sistémico/complicaciones , Osteopontina/metabolismo , Adolescente , Adulto , Anciano , Aterosclerosis/sangre , Aterosclerosis/etiología , Biomarcadores/metabolismo , Proteína C-Reactiva/metabolismo , Arteria Carótida Común/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , Femenino , Humanos , Inflamación/sangre , Lupus Eritematoso Sistémico/sangre , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Inflammation, overweight and other cardiovascular risk factors might negatively impact on hypertension remission in metabolic syndrome (MetS), independently of the pharmacological treatment. Here, the potential influence of systemic inflammation (assessed by serum high-sensitivity C-reactive protein [hs-CRP]) on hypertension remission will be investigated in a cohort of hypertensive patients with MetS. MATERIAL AND METHODS: Hypertensive patients with MetS (n = 100) were enrolled, treated under current behavior/dietary/pharmacological recommendations and followed up for 12 months. All patients received medications and nutritional advice based on Mediterranean-like dietary pattern in addition to psychological and physical activity counselling. At baseline (T0), 6 (T1) and 12 (T2) months of follow-up, clinical data, haematological and biochemical profiles and serum hs-CRP were measured. RESULTS: As compared to T0, at T2 patients displayed improvements in anthropometric and metabolic profiles. At T2, the hypertension remission rate was 13.0%. Serum hs-CRP did not change overtime in the overall cohort. Surprisingly, patients who experienced hypertension remission were less treated with antihypertensive drugs, but developed a weak improvement in anthropometric measures during follow-up. The hypertension remission group had lower baseline levels of hs-CRP as compared to non-remission. Low baseline hs-CRP (<2 µg/mL, cut-off value identified by ROC curve) predicted hypertension remission, independently of antihypertensive treatment implementation, baseline systolic blood pressure and waist circumference improvement. CONCLUSIONS: Remission of hypertension in MetS is independently associated with baseline low CRP levels, which might suggest a critical role for inflammation in sustaining high blood pressure levels.
Asunto(s)
Proteína C-Reactiva/metabolismo , Hipertensión/sangre , Síndrome Metabólico/sangre , Adulto , Antropometría , Antihipertensivos/uso terapéutico , Estudios de Cohortes , Dieta , Femenino , Humanos , Hipertensión/diagnóstico , Hipertensión/dietoterapia , Hipertensión/tratamiento farmacológico , Inflamación/dietoterapia , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/dietoterapia , Síndrome Metabólico/tratamiento farmacológico , Metaboloma , Persona de Mediana Edad , Sobrepeso/complicaciones , Curva ROC , Remisión Espontánea , Circunferencia de la Cintura , Adulto JovenRESUMEN
BACKGROUND: Growing evidence indicates tissue inhibitors of matrix metalloproteinases (TIMPs) as potential players in inflammatory bowel disease (IBD), but, no prospective data are available in IBD remission/relapse. MATERIAL & METHODS: In this prospective pilot study, a cohort of IBD patients (n = 32) was enrolled and treated with monoclonal anti-TNF-α antibodies. Patients were clinically followed up for a median period of 54 weeks. Serum circulating levels of C-reactive protein (CRP), TIMP-1 and -2, matrix metalloproteinase (MMP)-9 and -8, myeloperoxidase (MPO) and neutrophil elastase (NE) were assessed by ELISA at enrolment and at the end of the treatment. RESULTS: The percentage (%) TIMP-2 reduction from baseline to end of treatment was independently associated with IBD remission at the end of treatment and follow-up as well. ROC curve analysis further confirmed the good prognostic accuracy of % TIMP-2 reduction over the treatment period. Conversely, no other change in inflammatory molecule concentrations was able to predict short- or long-term IBD remission. CONCLUSIONS: This study indicates TIMP-2 reduction during IBD treatment with monoclonal anti-TNF-α antibodies as a potential prognostic parameter of short and long term remission. To understand if TIMP-2 is an innocent biomarker or an active pathophysiological factor in IBD remains to be clarified.
Asunto(s)
Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inhibidor Tisular de Metaloproteinasa-2/metabolismo , Adulto , Anticuerpos Monoclonales/uso terapéutico , Área Bajo la Curva , Biomarcadores/metabolismo , Femenino , Humanos , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/sangre , Masculino , Mesalamina/uso terapéutico , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Inducción de Remisión , Adulto JovenRESUMEN
BACKGROUND: Different cut-off values of serum lipoprotein (a) [Lp (a)] were recently identified to better stratify cardiovascular risk categories. Both pathophysiological and prognostic values of Lp (a) remain unclear. MATERIALS AND METHODS: Here, the prognostic value of Lp (a) and its correlation with intraplaque features were assessed in patients with severe carotid artery stenosis undergoing endarterectomy (n = 180). The cut-off value of 10 mg/dL for serum Lp (a) was selected to predict 24-month follow-up acute coronary syndrome (ACS). In addition, the association between serum Lp (a) and intraplaque lipids, collagen, inflammatory and vascular cells was assessed. Serum Lp (a) levels were measured by nephelometric assay. RESULTS: Patients with high Lp (a) had similar comorbidities, medications and laboratory parameters as compared to low Lp (a) levels. At 24-month follow-up, patients with high Lp (a) had more ACS as compared to low levels. Histological parameters within plaques were comparable in the study groups. No significant correlation between Lp (a) serum levels and intraplaque parameters was found, except for a weak positive association with smooth muscle cells in upstream plaque portions. When adjusted for gender, the presence of dyslipidaemia and chronic coronary artery disease, Lp (a) ≥10 mg/dL remained predictive for ACS. CONCLUSIONS: Lp (a) determination could be a useful tool to predict ACS in patients with severe carotid stenosis.
Asunto(s)
Síndrome Coronario Agudo/diagnóstico , Estenosis Carotídea/complicaciones , Lipoproteína(a)/metabolismo , Síndrome Coronario Agudo/sangre , Cuidados Posteriores , Anciano , Biomarcadores/metabolismo , Estenosis Carotídea/sangre , Femenino , Humanos , Masculino , Proyectos Piloto , Placa Aterosclerótica/sangre , Placa Aterosclerótica/diagnósticoRESUMEN
BACKGROUND: Acute ischaemic stroke (AIS) triggers both systemic and neurovascular inflammation, influencing poststroke recovery. In smokers with AIS, inflammation might be further upregulated, increasing ischaemia/reperfusion injury. Here, the predictive value of leucocyte and adhesion molecules levels on poststroke outcomes was investigated. MATERIALS AND METHODS: A total of 89 patients with AIS (n = 30 smokers and n = 59 nonsmokers) were recruited and evaluated 1, 7 and 90 days after the onset to assess stroke severity by the National Institute of Health Stroke Scale (NIHSS) score as well as clinical recovery at 90 days by the modified Rankin Scale (mRS). Lesion volume was assessed by noncontrast computed tomography. Haematological parameters, blood chemistry and soluble adhesion molecules were measured. RESULTS: Smokers experienced a more severe stroke and at a younger age with respect to nonsmokers, moreover, they had higher circulating levels of monocytes, neutrophils and soluble adhesion molecules. Baseline monocytes positively correlated with stroke severity and disability across all time points in the overall cohort. No correlation was shown between adhesion molecules and poststroke outcomes. A monocyte count >0·63 × 109 /L predicted worse stroke severity (defined as NIHSS ≥5) at day 90 independently of age, hypertension, thrombolysis and active smoking in the overall cohort. Similarly, a monocyte count >0·64 × 109 /L predicted poor neurological recovery at day 90 (defined as mRS > 2). CONCLUSIONS: Smoker had more severe AIS and higher leucocytes and adhesion molecule levels. In the overall cohort, monocyte count was an independent predictor of worse poststroke outcome. Although larger trials are needed, monocyte count might be a cheap prognostic parameter in AIS.
Asunto(s)
Isquemia Encefálica/sangre , Molécula 1 de Adhesión Intercelular/análisis , Monocitos/fisiología , Fumar/efectos adversos , Rehabilitación de Accidente Cerebrovascular/métodos , Accidente Cerebrovascular/sangre , Anciano , Biomarcadores/sangre , Recuento de Células Sanguíneas , Isquemia Encefálica/mortalidad , Isquemia Encefálica/fisiopatología , Isquemia Encefálica/terapia , Estudios de Cohortes , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Accidente Cerebrovascular/mortalidad , Accidente Cerebrovascular/terapia , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Neutrophil-mediated inflammation was recently identified as an active contributor to athero-progression. Therapeutic strategies inhibiting neutrophil degranulation or recruitment were hypothesized to positively impact on plaque vulnerability. In this study, we investigated whether treatment with the recently discovered agonist of the Mas-related G-coupled receptor type D (MrgD) alamandine would impact on neutrophil degranulation in vivo and in vitro. MATERIALS AND METHODS: Fifteen-week-old ApoE-/- mice were fed with a Western-type diet for an additional 11 weeks. After the first 2 weeks of diet, mice were surgically implanted with a carotid 'cast' device that alters the blood shear stress and induces different carotid plaque phenotypes. During the last 4 weeks before euthanasia, mice were randomly assigned to subcutaneously receive vehicle (NaCl 0·15 M) or alamandine (24 µg/kg/h) by micropump. For in vitro experiments, neutrophils were obtained after thioglycollate intraperitoneal injection in ApoE-/- mice. RESULTS: Treatment with alamandine was well-tolerated, but failed to affect lipid, macrophage, neutrophil or collagen content within carotid and aortic root plaques. Also, treatment with alamandine did not affect Th-cell polarization in lymphoid organs. Conversely, alamandine administration was associated with a reduction in serum levels of neutrophil granule enzymes, such as MMP-9 and MPO as well as MMP-9 content within aortic root plaques. In vitro, preincubation with alamandine dose-dependently abrogated PMA-induced neutrophil degranulation of MMP-9 and MPO. CONCLUSION: These results suggest that treatment with the MrgD agonist alamandine led to a reduced release of neutrophil granule products, potentially interfering with pro-atherosclerotic neutrophil activation.
Asunto(s)
Aterosclerosis/fisiopatología , Degranulación de la Célula/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Oligopéptidos/farmacología , Placa Aterosclerótica/fisiopatología , Animales , Aorta Torácica/efectos de los fármacos , Aterosclerosis/tratamiento farmacológico , Arterias Carótidas/efectos de los fármacos , Progresión de la Enfermedad , Técnicas In Vitro , Metabolismo de los Lípidos/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Noqueados , Neutrófilos/fisiología , Peroxidasa/metabolismo , Placa Aterosclerótica/tratamiento farmacológico , Distribución Aleatoria , Receptores Acoplados a Proteínas G/agonistasRESUMEN
PURPOSE OF REVIEW: The aim of this review is to update the pathophysiological role of innate immune response in the cardiovascular (CV) disease outcomes, particularly focusing on coronary atherosclerosis and heart failure. RECENT FINDINGS: Inflammatory processes comprised with the innate immunity reaction are believed to actively trigger CV disease development and final clinical events. For instance, by releasing proteases and neutrophil extracellular traps, neutrophil recruitment and activation might strongly influence atherosclerotic plaque stability. Similarly, neutrophils drive the early inflammatory response following a myocardial infarction. However, these cells contribute themselves to infarct healing by orchestrating monocyte/macrophage recruitment and polarization within the ischemic myocardium. Given their heterogeneity and plasticity, the balance between recruitment, proliferation, and polarization of monocyte/macrophage is a further leading determinant of advanced plaque maturation. Moreover, timely shift from a pro-inflammatory to a resolving macrophage phenotype may influence cardiac remodeling as well as development of heart failure (HF). Alongside macrophage recruitment and activation into the remote, non-ischemic myocardium also contributes to cardiac remodeling and HF development. Innate immune response is a tightly regulated process where a timely modulation of the balance between damaging and resolving properties critically impacts on CV outcome. Further progress may improve the determination of the prognostic relevance of inflammatory biomarkers on clinical CV outcome.
Asunto(s)
Enfermedad de la Arteria Coronaria/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Inmunidad Innata/inmunología , Inflamación/fisiopatología , Animales , Enfermedad de la Arteria Coronaria/inmunología , Corazón/fisiopatología , Insuficiencia Cardíaca/inmunología , Humanos , Inflamación/inmunología , Infarto del Miocardio/inmunología , Infarto del Miocardio/fisiopatología , Placa Aterosclerótica/inmunología , Placa Aterosclerótica/fisiopatologíaRESUMEN
PURPOSE OF REVIEW: The aim of this review is to overview the pathophysiological role of adipocytokines in atherogenesis, focusing on their potential role as biomarkers of coronary disease. RECENT FINDINGS: Several lines of evidence indicated adipose tissue not only as depot but rather as an endocrine organ. In this context, the balance between pro- and anti-inflammatory adipocytokines has been shown to critically regulate vascular homeostasis in both physiological and pathophysiological conditions. Overweight and obesity are characterized by dysfunctional adipose tissue and then the prevalence of pro-inflammatory mediators, with a detrimental effect on vascular health. As opposite to adiponectin, pro-inflammatory adipocytokines, such as leptin and resistin, promote endothelial dysfunction and inflammatory processes involved in atherosclerotic plaque progression and vulnerability. Therefore, many adipocytokines have been investigated as potential biomarkers of cardiovascular (CV) risk, but their role has not yet been clearly established. Furthermore, the perivascular adipose tissue recently emerged as a critical modulator of atherosclerotic processes, due to the close interaction with the underlying vascular tissue. The ongoing discovery of new adipocytokines and the complex pathophysiological role of the different adipose tissue depots strongly contribute to define the complexity of adipocytokines network. Understanding those complex interactions may allow determining new potential biomarkers of CV risk and potential therapeutic targets.
Asunto(s)
Adipoquinas/metabolismo , Aterosclerosis/metabolismo , Enfermedad Coronaria/metabolismo , Tejido Adiposo/metabolismo , Animales , Aterosclerosis/diagnóstico , Enfermedad Coronaria/diagnóstico , Progresión de la Enfermedad , Humanos , Factores de RiesgoRESUMEN
BACKGROUND: Myocardial infarction (MI) is strictly linked to atherosclerosis. Beyond the mechanical narrowing of coronary vessels lumen, during MI a great burden of inflammation is carried out. One of the crucial events is represented by the ischaemia/reperfusion injury, a complex event involving inflammatory cells (such as neutrophils, platelets, monocytes/macrophages, lymphocytes and mast cells) and key activating signals (such as cytokines, chemokines and growth factors). Cardiac repair following myocardial infarction is dependent on a finely regulated response involving a sequential recruitment and the clearance of different subsets of inflammatory cells. MATERIALS AND METHODS: This narrative review was based on the works detected on PubMed and MEDLINE up to November 2015. RESULTS: Infarct healing classically follows three overlapping phases: the inflammatory phase, in which the innate immune pathways are activated and inflammatory leucocytes are recruited in order to clear the wound from dead cells; the proliferative phase, characterized by the suppression of pro-inflammatory signalling and infiltration of 'repairing' cells secreting matrix proteins in the injured area; and the maturation phase, which is associated with the quiescence and the elimination of the reparative cells together with cross-linking of the matrix. All these phases are timely regulated by the production of soluble mediators, such as cytokines, chemokines and growth factors. CONCLUSION: Targeting inflammatory cell recruitment early during reperfusion and healing might be promising to selectively inhibit injury and favour repair. This approach might substantially improve adverse postischaemic left ventricle remodelling, characterized by dilation, hypertrophy of viable segments and progressive dysfunction.
Asunto(s)
Citocinas/inmunología , Inflamación/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Isquemia Miocárdica/inmunología , Daño por Reperfusión Miocárdica/inmunología , Miocitos Cardíacos/fisiología , Plaquetas/inmunología , Proliferación Celular/fisiología , Quimiocinas/inmunología , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Humanos , Macrófagos/inmunología , Mastocitos/inmunología , Monocitos/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , RegeneraciónRESUMEN
BACKGROUND: The role of neutrophils in the beginning and the progression of the atherosclerotic process did not receive much attention until the last years. On the contrary, recent data, in both the experimental animals and humans, suggest important effects of these cells with possible clinical consequences. MATERIALS AND METHODS: This narrative review was based on the papers found on PubMed and MEDLINE up to July 2015. The search terms used were 'neutrophil, atherosclerosis' in combination with 'recruitment, chemokine, plaque destabilization and pathophysiology'. RESULTS: Different models demonstrate the presence and the actions of neutrophils in the early steps of the atherogenesis confirming the fundamental role of these cells in the response of the innate immune system to different pathogens (in this context the modified lipoproteins). However, also the late phases of the atherosclerotic process, in particular the destabilization of a mature plaque, seem to be modulated by the neutrophils, possibly through the interaction with recently discovered biological systems such as the endocannabinoids. CONCLUSIONS: The understanding of the mechanisms involved in the modulation exerted by neutrophils in atherosclerosis is pivotal in terms of the complete definition of the overall picture. This approach will certainly give us new targets and new pharmacological opportunities for the anti-inflammatory strategy of the cardiovascular prevention.
Asunto(s)
Aterosclerosis/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Placa Aterosclerótica/inmunología , Animales , Aterosclerosis/fisiopatología , Quimiocinas/inmunología , Progresión de la Enfermedad , Endocannabinoides/inmunología , Humanos , Inmunidad Innata/inmunología , Neutrófilos/citología , Placa Aterosclerótica/fisiopatologíaRESUMEN
BACKGROUND: Soluble mediators have been investigated to predict the prognosis of acute ischaemic stroke (AIS). Among them, proprotein convertase subtilisin/kexin type 9 (PCSK9) might have both clinical and pathophysiological relevance. MATERIALS AND METHODS: All available serum samples from a cohort of patients with first AIS (n = 72) were tested for PCSK9 and included in this substudy analysis. The primary endpoint investigated the predictive value of early PCSK9 level variations (ΔPCSK9) from AIS onset to day 7 or from day 1 to day 7, towards a 90-day outcome by modified Rankin Scale (mRS). The secondary endpoint explored the association between ΔPCSK9 and the risk of major adverse cardiovascular events (MACEs). RESULTS: Decreased serum PCSK9 levels at days 1 and 7 were associated with poor clinical outcomes at day 90. At the cut-off point identified by ROC curve analysis (-61·28 ng/mL), ΔPCSK9 day 7-day 1 predicted a poor mRS at day 90 after AIS. ΔPCSK9 day 7-day 1 ≤ -61·28 ng/mL was associated with an increased rate of MACEs. CONCLUSION: A decrease in PCSK9 levels was a predictor for poor outcome and increased MACEs after AIS. Additional studies targeting post-AIS PCSK9 levels and activity are required to clarify the prognostic and pathophysiological relevance of PCSK9 after AIS.
Asunto(s)
Enfermedades Cardiovasculares/mortalidad , Infarto del Miocardio/epidemiología , Proproteína Convertasa 9/sangre , Accidente Cerebrovascular/sangre , Anciano , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Curva ROC , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/fisiopatologíaRESUMEN
BACKGROUND: Autoantibodies to apolipoprotein A-1 (anti-ApoA-1 IgG) were shown to predict major adverse cardiovascular events and promote atherogenesis. However, their potential relationship with clinical disability and ischaemic lesion volume after acute ischaemic stroke (AIS) remains unexplored. MATERIALS AND METHODS: We included n = 76 patients admitted for AIS and we investigated whether baseline serum anti-ApoA-1 IgG levels could predict (i) AIS-induced clinical disability [assessed by the modified Rankin Scale (mRS)], and (ii) AIS-related ischaemic lesion volume [assessed by Computed Tomography (CT)]. We also evaluated the possible pro-apoptotic and pro-necrotic effects of anti-ApoA-1 IgG on human astrocytoma cell line (U251) using flow cytometry. RESULTS: High levels of anti-ApoA-1 IgG were retrieved in 15·8% (12/76) of patients. Increased baseline levels of anti-ApoA-1 IgG were independently correlated with worse mRS [ß = 0·364; P = 0·002; adjusted odds ratio (OR): 1·05 (95% CI 1·01-1·09); P = 0·017] and CT-assessed ischaemic lesion volume [ß = 0·333; P < 0·001; adjusted OR: 1·06 (95% CI 1·01-1·12); P = 0·048] at 3 months. No difference in baseline clinical, biochemical and radiological characteristics was observed between patients with high vs. low levels of anti-ApoA-1 IgG. Incubating human astrocytoma cells with anti-ApoA-1 IgG dose dependently induced necrosis and apoptosis of U251 cells in vitro. CONCLUSION: Anti-ApoA-1 IgG serum levels at AIS onset are associated with poorer clinical recovery and worse brain lesion volume 3 months after AIS. These observations could be partly explained by the deleterious effect of anti-ApoA-1 IgG on human brain cell survival in vitro and may have clinical implication in the prediction of poor outcome in AIS.
Asunto(s)
Apolipoproteína A-I/inmunología , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Accidente Cerebrovascular/inmunología , Anciano , Apoptosis/efectos de los fármacos , Astrocitos/efectos de los fármacos , Astrocitos/metabolismo , Autoanticuerpos/farmacología , Línea Celular Tumoral , Femenino , Citometría de Flujo , Estudios de Seguimiento , Proteína Ácida Fibrilar de la Glía/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Técnicas In Vitro , Receptores de Lipopolisacáridos/efectos de los fármacos , Receptores de Lipopolisacáridos/metabolismo , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Necrosis , Oportunidad Relativa , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Recuperación de la Función , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/fisiopatología , Receptor Toll-Like 2/efectos de los fármacos , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Blue rubber bleb nevus syndrome (BRBNS) is a rare disease characterized by vascular malformations mostly involving skin and gastrointestinal tract. This disease is often associated with sideropenic anemia and occult bleeding. METHODS: We report the case of chronic severe anemia in an old patient under oral anticoagulation treatment for chronic atrial fibrillation. RESULTS: At admission, the patient also presented fever and increased laboratory parameters of systemic inflammation (ferritin 308 mcg/L, C-reactive protein (CRP) 244 mg/L). A small bluish-colored lesion over the left ear lobe was observed. Fecal occult blood test was negative as well as other signs of active bleeding. Lower gastrointestinal endoscopy revealed internal hemorrhoids and multiple teleangiectasias that were treated with argon plasma coagulation. Videocapsule endoscopy demonstrated multiple bluish nodular lesions in the small intestine. Unexpectedly, chronic severe anemia due to systemic inflammation was diagnosed in an old anticoagulated patient with BRNBS. The patient was treated with blood transfusions, hydration, antibiotic treatment, and long-acting octreotide acetate, without stopping warfarin. Fever and inflammation disappeared without any acute gastrointestinal bleeding and improvement of hemoglobin levels at three-month follow up. CONCLUSIONS: This is the oldest patient presenting with chronic anemia, in which BRNBS was also diagnosed. Surprisingly, anemia was mainly caused by systemic inflammation instead of chronic gastrointestinal bleeding. However, we would recommend investigating this disease also in old subjects with mild signs and symptoms.
Asunto(s)
Anemia/etiología , Anticoagulantes/uso terapéutico , Fibrilación Atrial/tratamiento farmacológico , Neoplasias Gastrointestinales/complicaciones , Inflamación/etiología , Nevo Azul/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Neoplasias Cutáneas/complicaciones , Anciano de 80 o más Años , Anemia/sangre , Anemia/diagnóstico , Anemia/terapia , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Enfermedad Crónica , Progresión de la Enfermedad , Endoscopía Gastrointestinal , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/terapia , Humanos , Inflamación/diagnóstico , Inflamación/terapia , Masculino , Nevo Azul/diagnóstico , Nevo Azul/terapia , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/terapia , Factores de Riesgo , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/terapia , Resultado del TratamientoRESUMEN
Serum c-reactive protein (CRP) was suggested for the assessment of intermediate cardiovascular (CV) risk. Here, systemic or intraplaque CRP levels were investigated as predictors of major adverse cardiovascular events (MACEs) in patients with severe carotid stenosis. CRP levels were assessed in the serum and within different portions (upstream and downstream) of carotid plaques of 217 patients undergoing endarterectomy. The association between CRP and intraplaque lipids, collagen, neutrophils, smooth muscle cells (SMC), and macrophage subsets was determined. No correlation between serum CRP and intraplaque biomarkers was observed. In upstream portions, CRP content was directly correlated with intraplaque neutrophils, total macrophages, and M1 macrophages and inversely correlated with SMC content. In downstream portions, intraplaque CRP correlated with M1 and M2 macrophages. According to the cut-off point (CRP > 2.9%) identified by ROC analysis in upstream portions, Kaplan-Meier analysis showed that patients with high CRP levels had a greater rate of MACEs. This risk of MACEs increased independently of age, male gender, serum CRP, and statin use. In conclusion, in patients with severe carotid artery stenosis, high CRP levels within upstream portions of carotid plaques directly and positively correlate with intraplaque inflammatory cells and predict MACEs at an 18-month follow-up period.
Asunto(s)
Proteína C-Reactiva/metabolismo , Estenosis Carotídea/metabolismo , Factores de Edad , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Estenosis Carotídea/sangre , Femenino , Humanos , Estimación de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Miocitos del Músculo Liso/metabolismo , Neutrófilos/metabolismo , Curva ROC , Factores de Riesgo , Factores SexualesRESUMEN
After an acute ischemic stroke (AIS), inflammatory processes are able to concomitantly induce both beneficial and detrimental effects. In this narrative review, we updated evidence on the inflammatory pathways and mediators that are investigated as promising therapeutic targets. We searched for papers on PubMed and MEDLINE up to August 2016. The terms searched alone or in combination were: ischemic stroke, inflammation, oxidative stress, ischemia reperfusion, innate immunity, adaptive immunity, autoimmunity. Inflammation in AIS is characterized by a storm of cytokines, chemokines, and Damage-Associated Molecular Patterns (DAMPs) released by several cells contributing to exacerbate the tissue injury both in the acute and reparative phases. Interestingly, many biomarkers have been studied, but none of these reflected the complexity of systemic immune response. Reperfusion therapies showed a good efficacy in the recovery after an AIS. New therapies appear promising both in pre-clinical and clinical studies, but still need more detailed studies to be translated in the ordinary clinical practice. In spite of clinical progresses, no beneficial long-term interventions targeting inflammation are currently available. Our knowledge about cells, biomarkers, and inflammatory markers is growing and is hoped to better evaluate the impact of new treatments, such as monoclonal antibodies and cell-based therapies.
Asunto(s)
Biomarcadores/metabolismo , Inflamación/metabolismo , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/metabolismo , Animales , Autoanticuerpos/metabolismo , Humanos , Modelos Biológicos , Neutrófilos/metabolismoRESUMEN
BACKGROUND AND AIMS: Different adipokines have been associated with atherosclerotic plaque rupture and cardiovascular events, such as acute ischaemic stroke (AIS). However, the potential role of these molecules in postischaemic brain injury remains largely unknown. METHODS AND METHODS: We performed a substudy analysis on nonobese patients with first atherothrombotic stroke (n = 35) from a recently published prospective cohort. Primary endpoint was to investigate the predictive value of serum leptin/adiponectin ratio on neurological recovery at 90 days after AIS. The secondary endpoint was the predictive value of serum adipokine levels of clinical and radiological outcomes at a shorter follow-up (at days 1 and 7 after AIS). The radiological evaluation included ischaemic lesion volume and haemorrhagic transformation (HT). The clinical examination was based on National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS). RESULTS: At day 1 after AIS, serum leptin and leptin/adiponectin ratio were increased and inversely correlated with both radiological and clinical parameters at all follow-up time points. Once identified the best cut-off points by receiver operating characteristic (ROC) analysis, risk analysis showed that higher circulating leptin improved neurological recovery at day 90. In addition, leptin/adiponectin ratio maintained statistical significance after adjustment for age, gender and thrombolysis, also predicting the occurrence of HT in the first 7 days after AIS (adjusted OR 0·15 [95% CI 0·03-0·83); P = 0·030]). CONCLUSIONS: Higher leptin/adiponectin ratio at day 1 predicted better neurological outcomes in patients with atherothrombotic AIS and might be potentially useful as a prognostic biomarker of the disease.
Asunto(s)
Adiponectina/sangre , Isquemia Encefálica/sangre , Leptina/sangre , Recuperación de la Función , Accidente Cerebrovascular/sangre , Anciano , Área Bajo la Curva , Isquemia Encefálica/complicaciones , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Prospectivos , Resistina/sangre , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: After an acute ischaemic stroke (AIS), several inflammatory biomarkers have been investigated, but their predictive role on functional recovery remains to be validated. Here, we investigated the prognostic relevance of biomarkers related to atherosclerotic plaque calcification, such as osteopontin (OPN), osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) in a cohort of patients with AIS (n = 90) during 90-day follow-up. MATERIALS AND METHODS: Radiological and clinical examinations as well as blood sampling were performed at admission and at days 1, 7 and 90 from the event. Validated scores [such as modified Rankin scale (mRS) and the National Institutes of Health Stroke Scale (NIHSS)] were used to assess poststroke outcome. Serum levels of OPN, OPG and RANKL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA). RESULTS: When compared to the admission, OPN serum levels increased at day 7. Serum OPN levels at this time point were positively correlated with both ischaemic lesion volume and NIHSS at days 7 and 90. A cut-off of 30.53 ng/mL was identified for serum OPN by receiver operating characteristic (ROC) curve analysis. Adjusted logistic regression showed that serum OPN levels at day 7 predicted worse mRS at day 90 [OR 4.13 (95% CI 1.64-10.36); P = 0.002] and NIHSS [1.49 (95% CI 1.16-1.99); P = 0.007], independently of age, gender, hypertension and thrombolysis. CONCLUSIONS: Serum levels of OPN, but not OPG and RANKL, peaked at day 7 after AIS and predicted worse neurological scores. Therefore, OPN might have a pathophysiological and clinical relevance after AIS.
Asunto(s)
Isquemia Encefálica/sangre , Personas con Discapacidad , Osteopontina/metabolismo , Accidente Cerebrovascular/sangre , Anciano , Biomarcadores/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteoprotegerina/metabolismo , Pronóstico , Estudios Prospectivos , Ligando RANK/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: Both pathophysiology and treatments of carotid atherosclerotic plaque stenosis represent two interesting fields of strong scientific investigation. Among different drugs, safety and efficacy of statin treatment have been widely investigated and proved. MATERIALS AND METHODS: This narrative review is based on the material searched for and obtained via MEDLINE and PubMed up to March 2014. The search terms we used were: 'carotid plaque, intima-media thickness, plaque burden, stroke' in combination with 'statins, pleiotropic effects, HMG-CoA reductase inhibitors, lipid-lowering drugs'. RESULTS: Carotid stenosis represents both a useful parameter to evaluate the atherosclerotic burden and a target for therapeutic (medical or surgical) decisions. Statins do not only improve the lipid profile, but also induce some 'pleiotropic' anti-inflammatory activities that contribute to carotid plaque stabilization. Statin-mediated protective activities are under active investigation at subclinical levels with the potential benefit of advanced imaging techniques. However, considering that some new techniques (excepted B-mode ultrasound) remain quite expensive, they can have for the moment an important role in research, but not in the clinical field. CONCLUSIONS: Emerging evidence suggests that statin treatment improves carotid atherosclerosis, inducing a partial regression of plaque inflammation and size. Innovative imaging techniques might also ameliorate the identification of patients at high risk of cerebrovascular and coronary events, for which preventive statin treatments might be essential.