RESUMEN
BACKGROUND: To evaluate cardiac sympathetic innervation in hypertensive patients with left ventricular (LV) hypertrophy (H) and aortic stenosis (AS) submitted to transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Twenty-two hypertensive elders (82 ± 5 years) with severe AS and significant LVH (> 122 g·m-2 in women and > 149 g·m-2 in men) were compared with 14 patients with uncomplicated essential hypertension (HT) with similar degree of LVH and 10 controls. 123I-metaiodobenzylguanidine (MIBG) and 99mTc-tetrofosmin SPECT acquisitions were obtained to assess sympathetic innervation and LV perfusion. The innervation/perfusion mismatch score was taken as an indicator of cardiac sympathetic dysfunction. The imaging protocol was repeated 6 months after TAVI. Regional MIBG uptake was more heterogeneous in HT and AS patients than controls, and therefore, innervation/perfusion mismatch score was higher in both AS (9 ± 8) and HT (5 ± 2) than controls (1 ± 1, P < .001). On multivariate analysis, significant LVH was the major predictor of impaired LV sympathetic innervation (OR 19.45, 95% CI 1.87-201.92; P = .013). After TAVI, no differences in measures of LV sympathetic innervation were evident, although only a marginal LV mass reduction was observed (- 5.4 ± 2.4 g). CONCLUSIONS: Cardiac sympathetic innervation is impaired in patients with LVH, either with AS or not, and is not impacted significantly by TAVI procedure.
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Estenosis de la Válvula Aórtica , Hipertensión , 3-Yodobencilguanidina , Anciano , Estenosis de la Válvula Aórtica/complicaciones , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Femenino , Humanos , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Masculino , Sistema Nervioso Simpático/diagnóstico por imagenRESUMEN
BACKGROUND: Proprotein convertase subtilisin kexin 9 (PCSK9) is a serin protease synthesized mainly in the liver that binds the receptor of low-density lipoprotein and promotes its degradation in lysosomes. PCSK9 is considered a promising target for the development of new therapies for the treatment of hypercholesterolemia and related cardiovascular diseases. Extracellular vesicles represent a heterogeneous population of vesicles, ranging in size between 0.05 and 1 µm involved in numerous pathophysiological processes, including blood coagulation. We investigated whether PCSK9 stimulation induces the release of procoagulant extracellular vesicles from human mononuclear cells (PBMCs) and THP-1 cells. METHODS AND RESULTS: PBMCs and THP-1 cells were stimulated whit PCSK9, the generation of EV was assessed by the prothrombinase assay and by cytofluorimetric analysis. EV-associated tissue factor activity was assessed by a one-stage clotting assay. PCSK9 induced an increase in extracellular generation by PBMCs and THP-1 cells as well as an increase in extracellular vesicle-associated tissue factor. Pre-treatment with inhibitors of the toll like receptor, TLR4 (C34), and of NF-κB signaling (BAY 11-7082), downregulated PCSK9-induced extracellular vesicle generation and of extracellular- bound tissue factor. Similar effect was obtained by an anti-PCSK9 human-monoclonal antibody. CONCLUSIONS: PCSK9-mediated generation of procoagulant EV could contribute to increase the prothrombotic status in patients with cardiovascular diseases.
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Enfermedades Cardiovasculares , Vesículas Extracelulares , Vesículas Extracelulares/metabolismo , Humanos , Proproteína Convertasa 9/metabolismo , Receptores de LDL , Subtilisinas , TromboplastinaRESUMEN
Gamma-glutamyl transferase (GGT) is involved in the progression of atherosclerosis, since its enzymatic activity promotes the generation of reactive oxygen species (ROS). Besides, GGT may act as a prothrombotic factor by inducing tissue factor (TF) expression, independently of its enzymatic activity. The aim of this study was to assess whether GGT-induced TF stimulation was a consequence of binding to toll-like receptor 4 (TLR4) expressed on monocytes, the precursors of macrophages and foam cells which colocalize with GGT activity within atherosclerotic plaques. Experiments were performed in human peripheral blood mononuclear cells (PBMCs), THP-1 cells (a monocytic cellular model), and HEK293 cells, which were genetically modified to study the activation of TLR4. TF procoagulant activity was assessed by a one-stage clotting time test, and TF protein expression was estimated by western blot. Human recombinant (hr) GGT protein increased TF procoagulant activity and protein expression in both PBMCs and THP-1 cells. The GGT-induced TF stimulation was prevented by cellular pretreatment with TLR4/NF-κB inhibitors (LPS-Rs, CLI-095, and BAY-11-7082), and HEK293 cells lacking TLR4 confirmed that TLR4 is essential for GGT-induced activation of NF-κB. In conclusion, hrGGT induced TF expression in monocytes through a cytokine-like mechanism that involved the activation of TLR4/NF-κB signaling.
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Tromboplastina , Receptor Toll-Like 4 , Humanos , Receptor Toll-Like 4/metabolismo , Tromboplastina/metabolismo , Monocitos/metabolismo , FN-kappa B/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Lipopolisacáridos/farmacología , Leucocitos Mononucleares/metabolismo , Células HEK293 , Citocinas/metabolismo , Transferasas/metabolismoRESUMEN
AIM: This review represents a joint effort of the Italian Societies of Cardiology (SIC) and Diabetes (SID) to define the state of the art in a field of great clinical and scientific interest which is experiencing a moment of major cultural advancements, the cardiovascular risk management in type 2 diabetes mellitus. DATA SYNTHESIS: Consists of six chapters that examine various aspects of pathophysiology, diagnosis and therapy which in recent months have seen numerous scientific innovations and several clinical studies that require extensive sharing. CONCLUSIONS: The continuous evolution of our knowledge in this field confirms the great cultural vitality of these two cultural spheres, which requires, under the leadership of the scientific Societies, an ever greater and effective collaboration.
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Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Antihipertensivos/efectos adversos , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/fisiopatología , Dislipidemias/diagnóstico , Dislipidemias/epidemiología , Dislipidemias/fisiopatología , Factores de Riesgo de Enfermedad Cardiaca , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/fisiopatología , Hipoglucemiantes/efectos adversos , Hipolipemiantes/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prevalencia , Medición de Riesgo , Resultado del TratamientoRESUMEN
AIMS: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). METHODS AND RESULTS: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). CONCLUSION: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.
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Betacoronavirus , Infecciones por Coronavirus , Hospitalización/tendencias , Infarto del Miocardio , Pandemias , Neumonía Viral , Anciano , Anciano de 80 o más Años , COVID-19 , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/mortalidad , Infarto del Miocardio/terapia , SARS-CoV-2RESUMEN
Proprotein convertase subtilisin kexin 9 (PCSK9) increases LDL cholesterol (C) concentration by accelerating the hepatic degradation of the LDL receptor (R) thus promoting atherogenesis. The molecule, however, also exerts proinflammatory effects independent of circulating LDL-C by enhancing local cytokine production and activation of NFkB, a process that might involve Toll-like receptor 4 (TLR4), a crucial component of the innate immunity system. Tissue factor (TF), a glycoprotein which plays an essential role in coagulation and inflammation, is rapidly induced by circulating monocytes stimulated by proinflammatory agents through NFkB-dependent mechanisms. The aims of our study were (1) to assess whether PCSK9 may induce monocytic TF expression and (2) to evaluate whether the TLR4/NFkB signaling pathway may contribute to that effect. Experiments were carried out in peripheral blood mononuclear cells (PBMCs), THP-1 cells, and HEK293 cells transfected with plasmids encoding the human TLR4 complex. PCSK9 increased procoagulant activity (PCA), mRNA and TF protein expression in both PBMCs and THP-1 cultures. Pre-treatment with inhibitors of TLR4/NFkB signaling such as LPS-RS, CLI-095, and BAY 11-7082, downregulated PCSK9-induced TF expression. A similar effect was obtained by incubating cell cultures with anti-PCSK9 human monoclonal antibody. In TLR4-HEK293 cells, PCSK9 activated the TLR4/NFkB signaling pathway to an extent comparable to LPS, the specific agonist of TLR4s and quantitative confocal microscopy documented the colocalization of PCSK9 and TLR4s. In conclusion, PCSK9 induces TF expression through activation of TLR4/NFkB signaling.
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Monocitos/citología , Proproteína Convertasa 9/metabolismo , Tromboplastina/genética , Tromboplastina/metabolismo , Receptor Toll-Like 4/genética , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Microscopía Confocal , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Nitrilos/farmacología , Transducción de Señal/efectos de los fármacos , Sulfonamidas/farmacología , Sulfonas/farmacología , Células THP-1 , Receptor Toll-Like 4/metabolismo , Transfección , Regulación hacia Arriba/efectos de los fármacosRESUMEN
PURPOSE: Lipodystrophy is a collection of rare disorders defined by complete or partial loss of adipose tissue, due to abnormal adipocyte production, function, or distribution; it shares the main metabolic complications with obesity. Aims of the present study were to investigate the psychopathological characteristics of non-HIV lipodystrophic patients in comparison with a group of obese patients, a group of patients affected by oncologic chronic illness, and a control group of healthy subjects. METHODS: All participants were female: 16 non-HIV lipodystrophic women (mean age 42 ± 12 years), 20 women with breast cancer (adenocarcinoma with a positive sentinel lymph node in outpatients awaiting chemotherapy, mean age 44 ± 5 years), 20 obese women (mean age 40 ± 3 years), and 20 healthy women (mean age 40 ± 2 years). Each lipodystrophic patient received a psychiatric assessment, following the diagnostic criteria for DSM-5. Patients and controls received a battery of self-report instruments measuring general psychopathology, body image concerns, eating habits and food craving, and pain concerns. The following psychopathological rating scales were used: SCL-90-R (Symptom Check List) for general psychopathology, BUT (Body Uneasiness Test) for body image, FCQ-T (Food Cravings Questionnaire Trait) for food craving, and WHYMPI (West Haven Yale Multidimensional Pain Inventory) for multidimensional pain inventory. RESULTS: The psychiatric assessment of the 16 lipodystrophic patients revealed: three lifetime mood disorder, six current mood disorder, six lifetime anxiety disorder, five current anxiety disorder, four current somatic symptom disorder with predominant pain, six current binge eating disorder, 11 eating disorder not otherwise specified, two borderline personality disorder, one obsessive-compulsive personality disorder, one avoidant personality disorder, and five personality disorder not otherwise specified. In SCL-90-R scale, the subscale sensitivity showed a significantly higher score in the lipodystrophic and oncologic groups compared to healthy subjects. The subscale paranoid ideation showed a significantly higher score in the lipodystrophic group vs all the other groups. The total score of BUT scale was significantly higher in the lipodystrophic compared to healthy subjects. In WHYMPI scale, the scores of pain interference and family support were significantly higher in the lipodystrophic group. The scores of negative responses were significantly higher in the lipodystrophic group vs healthy subjects. In FCQ-T scale, the score of Cues dimension in lipodystrophic patients was significantly lower as compared with all the other groups. CONCLUSIONS: Our findings suggest that lipodystrophic patients have an increased prevalence of mood, anxiety, pain, and eating disorders. LEVEL OF EVIDENCE: Level III. Evidence obtained from case-control analytic study.
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Trastorno por Atracón , Trastornos de Alimentación y de la Ingestión de Alimentos , Lipodistrofia , Adulto , Trastornos de Ansiedad , Femenino , Humanos , Lipodistrofia/complicaciones , Lipodistrofia/diagnóstico , Masculino , Persona de Mediana Edad , Trastornos de la Personalidad , Escalas de Valoración PsiquiátricaRESUMEN
BACKGROUND: Single-photon emission computed tomography has shown relevant limitations in the quantification of left ventricular (LV) mass. We sought to compare the estimates of LV mass on Cadmium-Zinc-Telluride (CZT) myocardial perfusion imaging (MPI) as compared to cardiac magnetic resonance (CMR). METHODS AND RESULTS: Twenty-five patients underwent MPI on a CZT camera and CMR on a 1.5 T scanner within 12 ± 3 weeks. LV mass was quantified on CZT images using two softwares: 4D-MSPECT (4DM) and Emory Cardiac Toolbox (ECTb). LV mass by CMR was quantified using MASS software (Medis, Leiden, The Netherlands). LV mass values obtained with 4DM and ECTb were highly reproducible [intraclass correlation coefficients .98 (95% CI .97-.99), and .98 (95% CI 0.97-.99), respectively]. The mean LVM mass values were 151 ± 44 g on CMR, 151 ± 43 g with 4DM (P = NS vs CMR), and 157 ± 42 g with ECTb (P < .001 vs CMR; P = .007 vs 4DM) CZT images. There was an excellent correlation between LV mass values between CMR and both 4DM (R2 = .95; P < .001) and ECTb (R2 = .98; P < .001) with narrow limits of agreement (- 13.6% to + 13.4% for 4DM, and - 5.6% to + 14.1% for ECTb). CONCLUSIONS: The evaluation of LV mass is feasible on CZT images, showing excellent agreement with CMR.
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Cadmio , Neoplasias Cardíacas/diagnóstico por imagen , Imagen de Perfusión Miocárdica , Telurio , Tomografía Computarizada de Emisión de Fotón Único , Zinc , Anciano , Anciano de 80 o más Años , Femenino , Ventrículos Cardíacos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Extracellular vesicles are submicron vesicles that upregulate the synthesis of proinflammatory mediators by lung epithelial cells. We investigated whether these structures adhere to lung epithelial cells, and whether adhesion is a prerequisite for their proinflammatory activity. Extracellular vesicles were generated by stimulation of normal human mononuclear cells with the calcium ionophore A23187, and labelled with carboxyfluorescein diacetate succinimidyl ester. Adhesion of vesicles to monolayers of immortalized bronchial epithelial (16HBE) and alveolar (A549) cells was analyzed by fluorescence microscopy. The role of candidate adhesion receptors was evaluated with inhibitory monoclonal antibodies and soluble peptides. The synthesis of proinflammatory mediators was assessed by ELISA. Transmission electron microscopy confirmed the generation of closed vesicles with an approximate size range between 50 and 600â¯nm. Adhesion of extracellular vesicles to epithelial cells was upregulated upon stimulation of the latter with tumor necrosis factor-α. Adhesion was blocked by an anti-CD18 antibody, by peptides containing the sequence RGD and, to a lesser extent, by an antibody to ICAM-1. The same molecules also blocked the upregulation of the synthesis of interleukin-8 and monocyte chemotactic protein-1 induced by extracellular vesicles. CD18-mediated adhesion of extracellular vesicles is a prerequisite for their proinflammatory activity.
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Adhesión Celular/fisiología , Células Epiteliales/metabolismo , Vesículas Extracelulares/metabolismo , Inflamación/metabolismo , Interleucina-8/metabolismo , Pulmón/metabolismo , Células A549 , Anticuerpos Monoclonales/metabolismo , Bronquios/metabolismo , Bronquios/fisiología , Línea Celular Tumoral , Células Epiteliales/fisiología , Vesículas Extracelulares/fisiología , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Pulmón/fisiología , Monocitos/metabolismo , Monocitos/fisiología , Fenotipo , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
BACKGROUND: The contractile response of patients with heart failure (HF) may be assessed by exercise stress echocardiography (ESE)-derived indexes. We sought to test whether ESE parameters are useful to identify the risk of adverse left ventricular (LV) remodeling in patients with chronic HF and reduced or mildly reduced LV ejection fraction (EF). METHODS: We enrolled 155 stabilized patients (age: 62 ± 11 years, 17% female, coronary artery disease 47%) with chronic HF, LV EF ≤50% and LV end-diastolic volume index > 75 ml/m2. All patients underwent a symptom-limited graded bicycle semi-supine ESE, with evaluation of peak stress LV EF, end-systolic pressure-volume relation (ESPVR, i.e. LV elastance) and cardiac power output to LV mass (CPOM). A complete echocardiographic study was performed at baseline and after 6 ± 3 months. Adverse LV remodeling was defined as the association of eccentric LV hypertrophy (LV mass: ≥115 g/m2 for male and ≥ 95 g/m2 for women, and relative wall thickness < 0.32) with an increase in LV end-systolic volume index ≥10% at six months. RESULTS: Adverse LV remodeling was detected in 34 (22%) patients. After adjustment for clinical, biochemical and echocardiographic data, peak ESPVR resulted in the most powerful independent predictor of adverse LV remodeling (OR: 12.5 [95% CI 4.5-33]; p < 0.0001) followed by ischemic aetiology (OR: 2.64 [95% 1.04-6.73]; p = 0.04). CONCLUSION: In patients with HF and reduced or mildly reduced EF, a compromised ESE-derived peak ESPVR, that reflects impaired LV contractility, resulted to be the most powerful predictor of adverse LV remodeling.
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Ecocardiografía de Estrés/métodos , Insuficiencia Cardíaca/diagnóstico , Ventrículos Cardíacos/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico , Volumen Sistólico/fisiología , Presión Ventricular/fisiología , Remodelación Ventricular/fisiología , Anciano , Femenino , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertrofia Ventricular Izquierda/complicaciones , Hipertrofia Ventricular Izquierda/fisiopatología , Masculino , Persona de Mediana Edad , Función Ventricular Izquierda/fisiologíaRESUMEN
Sympathetic nervous system plays a pivotal role in essential hypertension and in the development of left ventricular hypertrophy. Moreover, cardiac sympathetic dys-regulation has been demonstrated as a key con-causal factor in the genesis and progression of pathologic conditions such as congestive heart failure and ischemic heart disease to which hypertension predisposes as a risk factor. However, despite its fundamental role in cardiac pathophysiology, the evaluation of cardiac sympathetic nervous system has never gained a wide clinical application, remaining mostly a research tool. In this context, nuclear imaging techniques are the only modalities to allow the direct evaluation of cardiac sympathetic nervous integrity, giving the chance to obtain objective measures of the sympathetic tone. This review, while summarizing the general profile of currently available tests for autonomic evaluation, focuses on 123I-metaiodobenzylguanidine nuclear imaging as a preferential tool to assess cardiac sympathetic status. Specifically, the review discusses the available evidence on cardiac 123I-metaiodobenzylguanidine scintigraphy in arterial hypertension and left ventricular hypertrophy and its diagnostic and prognostic potential in congestive heart failure and ischemic heart disease.
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Insuficiencia Cardíaca/diagnóstico por imagen , Corazón/diagnóstico por imagen , Hipertrofia Ventricular Izquierda/diagnóstico por imagen , Isquemia Miocárdica/diagnóstico por imagen , Miocardio/patología , Sistema Nervioso Simpático/fisiopatología , 3-Yodobencilguanidina , Animales , Barorreflejo , Modelos Animales de Enfermedad , Ecocardiografía , Corazón/fisiopatología , Humanos , Hipertensión/complicaciones , Pronóstico , Factores de Riesgo , Transmisión Sináptica , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
AIM: Functional analysis and measurement of left atrium are an integral part of cardiac evaluation, and they represent a key element during non-invasive analysis of diastolic function in patients with hypertension (HT) and/or heart failure with preserved ejection fraction (HFpEF). However, diastolic dysfunction remains quite elusive regarding classification, and atrial size and function are two key factors for left ventricular (LV) filling evaluation. Chronic left atrial (LA) remodelling is the final step of chronic intra-cavitary pressure overload, and it accompanies increased neurohormonal, proarrhythmic and prothrombotic activities. In this systematic review, we aim to purpose a multi-modality approach for LA geometry and function analysis, which integrates diastolic flow with LA characteristics and remodelling through application of both traditional and new diagnostic tools. METHODS: The most important studies published in the literature on LA size, function and diastolic dysfunction in patients with HFpEF, HT and/or atrial fibrillation (AF) are considered and discussed. RESULTS: In HFpEF and HT, pulsed and tissue Doppler assessments are useful tools to estimate LV filling pressure, atrio-ventricular coupling and LV relaxation but they need to be enriched with LA evaluation in terms of morphology and function. An integrated evaluation should be also applied to patients with a high arrhythmic risk, in whom eccentric LA remodelling and higher LA stiffness are associated with a greater AF risk. CONCLUSION: Evaluation of LA size, volume, function and structure are mandatory in the management of patients with HT, HFpEF and AF. A multi-modality approach could provide additional information, identifying subjects with more severe LA remodelling. Left atrium assessment deserves an accurate study inside the cardiac imaging approach and optimised measurement with established cut-offs need to be better recognised through multicenter studies.
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Atrios Cardíacos/patología , Atrios Cardíacos/fisiopatología , Insuficiencia Cardíaca/fisiopatología , Hipertensión/fisiopatología , Fibrilación Atrial/fisiopatología , Ecocardiografía/métodos , Atrios Cardíacos/diagnóstico por imagen , Humanos , Hipertrofia/diagnóstico por imagen , Imagen por Resonancia Magnética , Volumen Sistólico , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Left ventricular (LV) diastolic dysfunction (DD) is a frequent finding in obesity and may predispose to the development of heart failure (HF). However, no data are available on the prevalence of DD after the introduction of the 2016 Recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. METHODS AND RESULTS: To assess the impact of the new Recommendations on the prevalence of DD and on their clinical and echocardiographic correlates in obesity, a prospective study was performed in 588 subjects with an ejection fraction (EF) ≥50% and no history of HF either obese (n = 402; mean age: 47 ± 12 years; women 71%; body mass index [BMI]: 44 ± 8 kg/m2 ), overweight (n = 86; BMI: 28 ± 1 kg/m2 ), or with a normal weight (n = 100; BMI: 22 ± 2 kg/m2 ). All subjects underwent an echocardiographic and Doppler study, including the assessment of global longitudinal strain (GLS). DD occurred in 19% of obese patients, 12% of overweight subjects, and 2% of normal weight subjects. We used multivariable logistic analysis to assess the risk of DD. In patients with BMI ≥30 kg/m2 , LV mass normalized to height (2.7) (OR: 1.04, P = .0028), and GLS (OR: 0.85, P = .0032) were associated with an increased risk of DD followed by EF (OR: 0.91, P = .045), diabetes (OR: 1.91, P = .065), and systolic blood pressure (OR: 1.02, P = .076). CONCLUSION: These results show that DD is highly prevalent among obese subjects and impairment of longitudinal systolic mechanics, as reflected by GLS reduction, and LV mass normalized to height are major independent predictors of DD in this patients' population.
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Índice de Masa Corporal , Ecocardiografía Doppler/métodos , Ventrículos Cardíacos/diagnóstico por imagen , Obesidad/complicaciones , Sobrepeso/complicaciones , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/epidemiología , Estatura , Femenino , Estudios de Seguimiento , Ventrículos Cardíacos/fisiopatología , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Obesidad/fisiopatología , Sobrepeso/fisiopatología , Prevalencia , Estudios Prospectivos , Sístole , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
BACKGROUND: Obesity is linked to increased thrombotic risk. Circulating leptin concentration correlates with body mass index. Microparticles are small (.05-1 µm) vesicles shed by activated and apoptotic cells, involved in numerous pathophysiologically relevant phenomena including blood coagulation and thrombosis. We tested the hypothesis that leptin induces the shedding of procoagulant, tissue factor bearing microparticles by human peripheral blood mononuclear cells, and investigated the intracellular mechanisms leading to microparticle release upon incubation with leptin. METHODS: Peripheral blood mononuclear cells were isolated from healthy donors. Cells were incubated with leptin in the presence or in the absence of a phospholipase C inhibitor, U73122, a calmodulin inhibitor, W-7, and three inhibitors of mitogen activated protein kinases. Microparticle generation was assessed as phosphatidylserine concentration with a prothrombinase assay and by cytofluorimetric analysis. Tissue factor expression on microparticles was measured with a one-stage clotting assay. Intracellular calcium concentration was assessed by a fluorescent probe. RESULTS: Leptin increased intracellular calcium mobilization and stimulated the generation of tissue factor-bearing MP by peripheral blood mononuclear cells, as assessed by phosphatidylserine quantification, clotting tests and flow-cytometry. U73122, PD98059 (an extracellular signal-regulated kinase1/2 inhibitor), and W-7, significantly inhibited leptin-induced MP release. SB203580 (a p38 inhibitor), and SP600125 (a c-Jun N-terminal kinase inhibitor) had no effect. CONCLUSION: Leptin-induced generation of procoagulant microparticles might represent a link between obesity and atherothrombotic risk. Inhibition of leptin-induced microparticle generation might prove a viable strategy for the reduction of such risk in obese individuals.
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Factores de Coagulación Sanguínea/biosíntesis , Micropartículas Derivadas de Células/efectos de los fármacos , Leptina/farmacología , Leucocitos Mononucleares/metabolismo , Tromboplastina/biosíntesis , Calcio/metabolismo , Calmodulina/fisiología , Micropartículas Derivadas de Células/fisiología , Células Cultivadas , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Humanos , Fosfolipasas de Tipo C/fisiologíaRESUMEN
Pirfenidone is a drug recently approved for idiopathic pulmonary fibrosis but its mechanisms of action are partially unknown. We have previously demonstrated that the airways of patients with idiopathic pulmonary fibrosis contain procoagulant microparticles that activate coagulation factor X to its active form, Xa, a proteinase that signals fibroblast growth and differentiation, thus potentially contributing to the pathogenesis of the disease. We also reported that in vitro exposure of human alveolar cells to H2O2 causes microparticle generation. Since p38 activation is involved in microparticle generation in some cell models and p38 inhibition is one of the mechanisms of action of pirfenidone, we investigated the hypothesis that H2O2-induced generation of microparticles by alveolar cells is dependent on p38 phosphorylation and is inhibited by pirfenidone. H2O2 stimulation of alveolar cells caused p38 phosphorylation that was inhibited by pirfenidone. The drug also inhibited H2O2 induced microparticle generation as assessed by two independent methods (solid phase thrombin generation and flow cytometry). The shedding of microparticle-bound tissue factor activity was also inhibited by pirfenidone. Inhibition of p38-mediated generation of procoagulant microparticle is a previously unrecognized mechanism of action of the antifibrotic drug, pirfenidone.
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Células Epiteliales Alveolares/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Piridonas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Células A549 , Células Epiteliales Alveolares/metabolismo , Micropartículas Derivadas de Células , Humanos , Peróxido de Hidrógeno/farmacología , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/fisiopatología , Fosforilación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
BACKGROUND: Besides maintaining intracellular glutathione stores, gamma-glutamyltransferase(GGT) generates reactive oxygen species and activates NFkB, a redox-sensitive transcription factor key in the induction of Tissue Factor (TF) gene expression, the principal initiator of the clotting cascade. Thus, GGT might be involved in TF-mediated coagulation processes, an assumption untested insofar. METHODS: Experiments were run with either equine, enzymatically active GGT or human recombinant (hr) GGT, a wheat germ-derived protein enzymatically inert because of missing post-translational glycosylation. TF Procoagulant Activity (PCA, one-stage clotting assay), TF antigen(ELISA) and TFmRNA(real-time PCR) were assessed in unpooled human peripheral blood mononuclear cell(PBMC) suspensions obtained from healthy donors through discontinuous Ficoll/Hystopaque density gradient. RESULTS: Equine GGT increased PCA, an effect insensitive to GGT inhibition by acivicin suggesting mechanisms independent of its enzymatic activity, a possibility confirmed by the maintained stimulation in response to hrGGT, an enzymatically inactive molecule. Endotoxin(LPS) contamination of GGT preparations was excluded by heat inactivation studies and direct determination(LAL method) of LPS concentrations <0.1 ng/mL practically devoid of procoagulant effect. Inhibition by anti-GGT antibodies corroborated that conclusion. Upregulation by hrGGT of TF antigen and mRNA and its downregulation by BAY-11-7082, a NFkB inhibitor, and N-acetyl-L-cysteine, an antioxidant, was consistent with a NFkB-driven, redox-sensitive transcriptional site of action. CONCLUSIONS: GGT upregulates TF expression independent of its enzymatic activity, a cytokine-like behaviour mediated by NFκB activation, a mechanism contributing to promote acute thrombotic events, a possibility in need, however, of further evaluation.
RESUMEN
OBJECTIVES: Microparticles are membrane vesicles shed by cells upon activation and apoptosis. Agonists capable of inducing microparticle generation include cytokines, bacterial products, P-selectin, histamine. Cigarette smoke extract has also been recognized as an agonist involved in microparticle generation with an apoptosis-dependent mechanism. We investigated the possibility that cigarette smoke extract induces the rapid generation of proinflammatory microparticles by human mononuclear cells with a calcium-dependent mechanism. MATERIALS AND METHODS: Human mononuclear cells were exposed to cigarette smoke extract. [Ca(2+)]i mobilization was assessed with the fluorescent probe Fluo-4 NW. Microparticles were quantified with a prothrombinase assay and by flow cytometry. Normal human bronchial epithelial cells and A549 alveolar cells were incubated with cigarette smoke extract-induced microparticles and the generation of ICAM-1, IL-8, and MCP-1 was assessed by ELISA. RESULTS: Exposure to cigarette smoke extract induced a rapid increase in [Ca(2+)]i mobilization. Microparticle generation was also increased. EGTA, verapamil and the calmodulin inhibitor, W-7, inhibited microparticle generation. Incubation of lung epithelial cells with cigarette smoke extract-induced microparticles increased the expression of proinflammatory mediators. CONCLUSIONS: Exposure of mononuclear cells to cigarette smoke extract causes a rapid shedding of microparticles with a proinflammatory potential that might add to the mechanisms of disease from tobacco use.
Asunto(s)
Calcio/metabolismo , Micropartículas Derivadas de Células/efectos de los fármacos , Mezclas Complejas/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Nicotiana , Humo , Apoptosis/efectos de los fármacos , Bronquios/citología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Células Epiteliales , Humanos , Molécula 1 de Adhesión Intercelular/metabolismo , Interleucina-8/metabolismo , Leucocitos Mononucleares/metabolismoRESUMEN
Systemic hypertension has been considered mainly as an adult health issue for a long time, but it is now being increasingly acknowledged as a significant problem also among pediatric patients. The frequency of pediatric hypertension has grown mostly because of increases in childhood obesity and sedentary lifestyles, but secondary forms of hypertension play a role as well. Considering that unaddressed hypertension during childhood can result in enduring cardiovascular complications, timely identification and intervention are essential. Strategies for addressing this disease encompass not only lifestyle adjustments, but also the use of medications when needed. Lifestyle modifications entail encouraging a nutritious diet, consistent physical activity, and the maintenance of a healthy weight. Moreover, educating both children and their caregivers about monitoring blood pressure at home can aid in long-term management. Thus, the aim of this review is to discuss the etiologies, classification, and principles of the treatment of hypertension in pediatric patients.
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Pregnancy represents a stress test for every woman's cardiovascular (CV) system, and a pre-existing maternal unfavorable cardio-metabolic phenotype can uncover both adverse pregnancy outcomes and the subsequent development of cardiovascular disease (CVD) risk factors during and after pregnancy. Moreover, the maternal cardiac and extracardiac environment can affect offspring's cardiovascular health through a complex mechanism called developmental programming, in which fetal growth can be influenced by maternal conditions. This interaction continues later in life, as adverse developmental programming, along with lifestyle risk factors and genetic predisposition, can exacerbate and accelerate the development of CV risk factors and CVD in childhood and adolescence. The aim of this narrative review is to summarize the latest evidences regarding maternal-fetal dyad and its role on primordial, primary and secondary CV prevention.
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Enfermedades Cardiovasculares , Desarrollo Fetal , Humanos , Femenino , Embarazo , Enfermedades Cardiovasculares/prevención & control , Desarrollo Fetal/fisiología , Prevención Primaria/métodos , Complicaciones Cardiovasculares del Embarazo/prevención & control , Factores de Riesgo , Efectos Tardíos de la Exposición Prenatal/prevención & controlRESUMEN
Chronic coronary syndrome (CCS) is one of the leading cardiovascular causes of morbidity, mortality, and use of medical resources. After the introduction by international guidelines of the same level of recommendation to non-invasive imaging techniques in CCS evaluation, a large debate arose about the dilemma of choosing anatomical (with coronary computed tomography angiography (CCTA)) or functional imaging (with stress echocardiography (SE), cardiovascular magnetic resonance (CMR), or nuclear imaging techniques) as a first diagnostic evaluation. The determinant role of the atherosclerotic burden in defining cardiovascular risk and prognosis more than myocardial inducible ischemia has progressively increased the use of a first anatomical evaluation with CCTA in a wide range of pre-test probability in CCS patients. Functional testing holds importance, both because the role of revascularization in symptomatic patients with proven ischemia is well defined and because functional imaging, particularly with stress cardiac magnetic resonance (s-CMR), gives further prognostic information regarding LV function, detection of myocardial viability, and tissue characterization. Emerging techniques such as stress computed tomography perfusion (s-CTP) and fractional flow reserve derived from CT (FFRCT), combining anatomical and functional evaluation, appear capable of addressing the need for a single non-invasive examination, especially in patients with high risk or previous revascularization. Furthermore, CCTA in peri-procedural planning is promising to acquire greater importance in the non-invasive planning and guiding of complex coronary revascularization procedures, both by defining the correct strategy of interventional procedure and by improving patient selection. This review explores the different roles of non-invasive imaging techniques in managing CCS patients, also providing insights into preoperative planning for percutaneous or surgical myocardial revascularization.