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OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.
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Fibrilación Atrial , Procedimientos Quirúrgicos Cardíacos , Accidente Cerebrovascular , Humanos , Interleucina-5 , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/epidemiología , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Biomarcadores , Factores de Crecimiento Nervioso , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Factores de RiesgoRESUMEN
BACKGROUND: The use of glucocorticoids has given contradictory results for treating acute respiratory distress syndrome (ARDS). The use of intravenous Interferon beta (IFN ß) for the treatment of ARDS was recently tested in a phase III ARDS trial (INTEREST), in which more than half of the patients simultaneously received glucocorticoids. Trial results showed deleterious effects of glucocorticoids when administered together with IFN ß, and therefore, we aimed at finding the reason behind this. METHODS: We first sequenced the genes encoding the IFN α/ß receptor of the patients, who participated in the INTEREST study (ClinicalTrials.gov Identifier: NCT02622724 , November 24, 2015) in which the patients were randomized to receive an intravenous injection of IFN ß-1a (144 patients) or placebo (152 patients). Genetic background was analyzed against clinical outcome, concomitant medication, and pro-inflammatory cytokine levels. Thereafter, we tested the influence of the genetic background on IFN α/ß receptor expression in lung organ cultures and whether, it has any effect on transcription factors STAT1 and STAT2 involved in IFN signaling. RESULTS: We found a novel disease association of a SNP rs9984273, which is situated in the interferon α/ß receptor subunit 2 (IFNAR2) gene in an area corresponding to a binding motif of the glucocorticoid receptor (GR). The minor allele of SNP rs9984273 associates with higher IFNAR expression, more rapid decrease of IFN γ and interleukin-6 (IL-6) levels and better outcome in IFN ß treated patients with ARDS, while the major allele associates with a poor outcome especially under concomitant IFN ß and glucocorticoid treatment. Moreover, the minor allele of rs9984273 associates with a less severe form of coronavirus diseases (COVID-19) according to the COVID-19 Host Genetics Initiative database. CONCLUSIONS: The distribution of this SNP within clinical study arms may explain the contradictory results of multiple ARDS studies and outcomes in COVID-19 concerning type I IFN signaling and glucocorticoids.
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COVID-19 , Síndrome de Dificultad Respiratoria , Humanos , Glucocorticoides/farmacología , Glucocorticoides/uso terapéutico , COVID-19/genética , Interferón beta/farmacología , Interferón beta/uso terapéutico , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/genética , Interferón-alfaRESUMEN
OBJECTIVE: The present study evaluates the association of aortic calcification with mortality and major adverse cardiovascular and leg events (MACEs and MALEs) in patients with peripheral artery disease (PAD). The risk for mortality and MACEs and MALEs is considered in clinical decision-making. METHODS: This cohort found in 2012-2013 consists of 226 patients with symptomatic PAD referred to Turku University Hospital for invasive treatment. Follow-up data about mortality and survival without MACEs and MALEs were collected up to 5 years from the inclusion date, and aortic calcification index (ACI) was measured from patients with available imaging studies (164 of 226). ACIs' association with events and mortality was evaluated in Cox regression, Kaplan-Meier, and classification and regression tree analysis. RESULTS: All-cause mortality at 1, 3, and 5 years was 13.7% (31), 26.1% (59), and 46.9% (106), respectively. In multivariable Cox regression analysis, ACI and ACI > 43 were independent risk factors for all-cause mortality (hazard ratio [HR]: 1.13 per 10 units, 95% confidence interval [CI]: 1.00-1.22 and HR: 1.83, 95% CI: 1.01-3.32, respectively) and for MACEs (HR: 1.10 per 10 units, 95% CI: 1.00-1.22 and HR: 3.14, 95% CI: 1.67-5.91, respectively), but not for MALEs. Classification and regression tree analysis showed that ACI = 43 best divides cohort in relation to mortality. Kaplan-Meier analyses showed that ACI > 43 is associated with greater mortality and occurrence of MACEs compared with those who have ACI ≤ 43 (log-rank P value .005 and .0012, respectively). CONCLUSIONS: Risk for mortality and MACEs is associated with high ACI. ACI can expose the risk in patients with PAD for further cardiovascular events and mortality.
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Enfermedad Arterial Periférica , Masculino , Humanos , Estudios de Seguimiento , Estudios Prospectivos , Pronóstico , Factores de Riesgo , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/cirugía , Medición de RiesgoRESUMEN
BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models. METHODS: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations. RESULTS: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models. CONCLUSIONS: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.
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Fibrilación Atrial , Mutación , Miocitos Cardíacos , Cadenas Ligeras de Miosina , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/metabolismo , Fibrilación Atrial/genética , Fibrilación Atrial/metabolismo , Fibrilación Atrial/patología , Línea Celular , Conexina 43/genética , Conexina 43/metabolismo , Técnicas de Inactivación de Genes , Atrios Cardíacos/metabolismo , Atrios Cardíacos/patología , Células Madre Embrionarias Humanas/metabolismo , Células Madre Embrionarias Humanas/patología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Cadenas Ligeras de Miosina/genética , Cadenas Ligeras de Miosina/metabolismo , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismoRESUMEN
BACKGROUND: To investigate the potential of intravenously administered porcine recombinant interferon-ß1a (IFN-ß1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model. METHODS: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-ß1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue. RESULTS: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01). CONCLUSION: In this acute IR injury animal model, IFN-ß1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.
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Interferón beta-1a/administración & dosificación , Infarto del Miocardio/complicaciones , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Miocardio/patología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Apoptosis , Modelos Animales de Enfermedad , Inyecciones Intravenosas , Infarto del Miocardio/diagnóstico , Daño por Reperfusión Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/etiología , PorcinosRESUMEN
AIM: Peripheral arterial disease is frequently associated with significant atherosclerosis of other vascular beds. The aim of the present study was to investigate a possible association between peripheral arterial disease segment-specific disease burden and cerebrovascular disease. METHODS: Two-hundred and twenty-six patients with clinically symptomatic peripheral arterial disease from the prospective PureASO registry were followed up after revascularization. The breadth of peripheral arterial disease was quantified at the time patients entered the study. The segment-specific peripheral arterial disease burden was correlated to cerebrovascular disease and imaging findings during a five-year follow-up. RESULTS: At five years, cerebrovascular disease-free survival after lower limb revascularization was 31%. Patients with peripheral arterial disease involving the crural arteries had significantly more ischemic degenerative changes at brain imaging (p = 0.031), whereas patients with aorto-iliac and femoropopliteal segment peripheral arterial disease had more significant (>50% uni- or bilaterally) internal carotid artery stenosis compared to patients with crural peripheral arterial disease (p = 0.006). According to Cox regression analyses, crural arteries burden was associated with a significantly increased risk of mortality (adjusted HR 2.07, CI 95% 1.12-3.28, p = 0.021) and cerebrovascular events (adjusted HR 1.97, CI 95% 1.19-3.26, p = 0.008). CONCLUSIONS: Present results suggest that atherosclerosis burden at different lower limb artery segments is associated with defined cerebrovascular disease. This further suggests that risk factors and pathophysiological mechanisms are congruent across particular vascular beds.
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Trastornos Cerebrovasculares/epidemiología , Enfermedad Arterial Periférica/epidemiología , Anciano , Anciano de 80 o más Años , Angiografía de Substracción Digital , Angiografía Cerebral , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/mortalidad , Procedimientos Endovasculares , Femenino , Finlandia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/terapia , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de TiempoRESUMEN
Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) ß-1a may prevent the underlying event of vascular leakage. Objective: To determine the efficacy and adverse events of IFN-ß-1a in patients with moderate to severe ARDS. Design, Setting, and Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions: Patients were randomized to receive an intravenous injection of 10 µg of IFN-ß-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-ß-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-ß-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-ß-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance: Among adults with moderate or severe ARDS, intravenous IFN-ß-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-ß-1a in the management of ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.
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Adyuvantes Inmunológicos/administración & dosificación , Interferón beta-1a/administración & dosificación , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Adyuvantes Inmunológicos/efectos adversos , Corticoesteroides/uso terapéutico , Adulto , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Inyecciones Intravenosas , Interferón beta-1a/efectos adversos , Masculino , Persona de Mediana Edad , Respiración Artificial , Síndrome de Dificultad Respiratoria/mortalidad , Síndrome de Dificultad Respiratoria/terapia , Tamaño de la Muestra , Insuficiencia del Tratamiento , Desconexión del VentiladorRESUMEN
OBJECTIVE: Based on our previous reports, ipsilateral systolic toe pressure (STP) and toe-brachial index (TBI) have a strong association with midterm cardiovascular and overall mortality as well as with amputation-free survival in patients with symptomatic lower extremity peripheral artery disease (PAD). The effect of the often overlooked contralateral lower limb on patient outcome remains unknown. This study aimed to resolve the significance of contralateral STP (CL_STP) and contralateral TBI for long-term overall and cardiovascular mortality. METHODS: This is a retrospective cohort study of 727 consecutive patients with symptomatic lower extremity PAD. All patients admitted to the Department of Vascular Surgery at Turku University Hospital for digital subtraction angiography between January 2009 and August 2011 and for whom STP measurements were available were recruited and observed for up to 7 years. Dates and causes of death were collected from the national cause of death registry of Statistics Finland. RESULTS: In the study cohort, STP was <30 mm Hg in 67 contralateral limbs and 227 ipsilateral limbs. CL_STP <30 mm Hg resulted in a 60-month estimated freedom from cardiovascular death and overall survival of 39% (standard deviation [SD], 0.57) and 25% (SD, 0.41), respectively, and contralateral TBI <0.25, of 45% (SD, 0.54) and 36% (SD, 0.54), respectively. Cumulative freedom from cardiovascular death and overall survival at 60 months for patients with ipsilateral STP <30 mm Hg varied by CL_STP as follows: CL_STP <30 mm Hg: 41% (SD, 0.58) and 25% (SD, 0.43); CL_STP of 30 to 49 mm Hg: 56% (SD, 0.49) and 44% (SD, 0.49); STP ≥50 mm Hg: 62% (SD, 0.52) and 47% (SD, 0.52), respectively. In Cox regression analysis, low STP or TBI of either extremity was associated with significant (P < .001) risk of death for cardiovascular or any reason. CONCLUSIONS: Low STP and TBI of both contralateral and ipsilateral lower extremities are associated with high cardiovascular and overall mortality in symptomatic PAD patients. Bilaterally low STP and TBI are associated with a particularly poor prognosis.
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Arteria Braquial/fisiopatología , Enfermedades Cardiovasculares/mortalidad , Enfermedad Arterial Periférica/mortalidad , Enfermedad Arterial Periférica/fisiopatología , Dedos del Pie/irrigación sanguínea , Anciano , Presión Sanguínea , Femenino , Finlandia , Humanos , Masculino , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Different cardiovascular risk factors present a heterogenic manifestation of lower limb atherosclerosis. The molecular mechanisms behind this phenomenon remain unknown. We aimed to clarify this phenomenon by studying the association of major cardiovascular risk factors with the profile of serum cytokines in 226 consecutive patients with lower limb atherosclerosis treated at a department of Vascular Surgery during a one-year enrollment period. Increasing age independently associated with higher levels of IFN-γ inducible factors MIG, CTACK and IP-10 (Pâ¯<â¯0.001 for all). Patients with chronic kidney disease had higher serum levels of MIF, IL-16 and SCF (Pâ¯=â¯0.001 or less for all). Smoking and hypertension associated with IL-17 (Pâ¯=â¯0.037 and 0.015, respectively). In addition, smoking associated with growth factors known to induce myeloid progenitor cell proliferation: GM-CSF (Pâ¯=â¯0.035), PDGF (Pâ¯=â¯0.024), bFGF (Pâ¯=â¯0.026), and HGF (Pâ¯=â¯0.030). Dyslipidemia also associated with myeloproliferative factors: MIB-1α (Pâ¯=â¯0.005) and PDGF (Pâ¯=â¯0.01). Type II diabetes associated with Th2 mediated inflammation: IL-5 (Pâ¯<â¯0.001), IL-7 (Pâ¯=â¯0.004) and IL-13 (Pâ¯=â¯0.015). Major cardiovascular risk factors are associated with different circulating cytokines implicating different immunological pathology.
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Aterosclerosis/sangre , Enfermedades Cardiovasculares/sangre , Citocinas/sangre , Extremidad Inferior/patología , Anciano , Anciano de 80 o más Años , Quimiocinas/sangre , Estudios de Cohortes , Femenino , Humanos , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Persona de Mediana Edad , Análisis Multivariante , Factores de RiesgoRESUMEN
INTRODUCTION: The aim of the present study was to assess the circulating levels of vascular endothelial growth factor (VEGF) and other suggested therapeutic growth factors with the degree of ischemia in patients with different clinical manifestations of peripheral arterial disease (PAD) according to the Rutherford grades. METHODS: The study cohort consists of 226 consecutive patients admitted to a Department of Vascular Surgery for elective invasive procedures. PAD patients were grouped according to the Rutherford grades after a clinical assessment. Ankle-brachial pressure indices (ABI) and absolute toe pressure (TP) values were measured. Serum levels of circulating VEGF, hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF) were measured from serum and analysed against Rutherford grades and peripheral hemodynamic measurements. RESULTS: The levels of VEGF (Pâ¯=â¯0.009) and HGF (Pâ¯<â¯0.001) increased significantly as the ischaemic burden became more severe according to the Rutherford grades. PDGF behaved in opposite manner and declined along increasing Rutherford grades (Pâ¯=â¯0.004). A significant, inverse correlations between Rutherford grades was detected as follows; VEGF (Pearson's correlationâ¯=â¯0.183, Pâ¯=â¯0.004), HGF (Pearson's correlationâ¯=â¯0.253, Pâ¯<â¯0.001), bFGF (Pearson's correlationâ¯=â¯0.169, Pâ¯=â¯0.008) and PDGF (Pearson's correlationâ¯=â¯0.296, Pâ¯<â¯0.001). In addition, VEGF had a clear direct negative correlation with ABI (Pearson's correlation -0.19, Pâ¯=â¯0.009) and TP (Pearson's correlation -0.20, Pâ¯=â¯0.005) measurements. CONCLUSIONS: Our present observations show that the circulating levels of VEGF and other suggested therapeutic growth factors are significantly increased along with increasing ischemia. These findings present a new perspective to anticipated positive effects of gene therapies utilizing VEGF, HGF, and bFGF, because the levels of these growth factors are endogenously high in end-stage PAD.
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Isquemia/sangre , Isquemia/metabolismo , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/metabolismo , Factores de Crecimiento Endotelial Vascular/sangre , Factores de Crecimiento Endotelial Vascular/metabolismo , Anciano , Femenino , Factor 2 de Crecimiento de Fibroblastos/sangre , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Factor de Crecimiento de Hepatocito/sangre , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/sangre , Neovascularización Patológica/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Presión , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
RATIONALE: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans. OBJECTIVE: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease. METHODS AND RESULTS: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015). CONCLUSIONS: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.
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5'-Nucleotidasa/sangre , Adenosina Difosfato/sangre , Adenosina Trifosfato/sangre , Antígenos CD/sangre , Apirasa/sangre , Aterosclerosis/sangre , Enfermedad Arterial Periférica/sangre , Trombofilia/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/sangre , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Artefactos , Aterosclerosis/epidemiología , Biomarcadores , Enfermedad Crónica , Comorbilidad , Progresión de la Enfermedad , Utilización de Medicamentos , Femenino , Finlandia/epidemiología , Proteínas Ligadas a GPI/sangre , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipertensión/sangre , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipoxia/sangre , Masculino , Persona de Mediana Edad , Modelos Cardiovasculares , Enfermedad Arterial Periférica/epidemiología , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico , Factores de Riesgo , Sistemas de Mensajero Secundario , Fumar/efectos adversos , Fumar/sangre , Fumar/epidemiología , Trombofilia/epidemiología , Trombofilia/etiologíaRESUMEN
Atherosclerosis is an inflammatory process of the arterial wall. CD73 (also known as ecto-5'-nucleotidase) is a key regulator of cell signaling in response to inflammation and hypoxia, and may be important in the development of atherosclerosis. Recently, we have shown that high CD73 activity can be detected in the serum of patients with peripheral arterial disease (PAD). Using this same PAD patient cohort of 226 subjects with 38 femoral artery samples obtained during surgical endarcterectomy and control artery samples taken during autopsy, we explored the association of serum CD73 activity with overall atherosclerotic burden and the expression of CD73 in mature and developing plaques. Interestingly, we found that CD73 activity had a tendency to increase along with more severe presentation of PAD (from 249 nmol/mL/h in moderate disease to 332 nmol/mL/h in severe disease; P = 0.013) and that CD73 expression is elevated in the vasa vasorum of developing plaques, but completely lost in mature occlusive plaques removed during endarcterectomy (P < 0.001). The current findings implicate that as a result of shedding and loss of CD73 from the arterial wall, CD73 activity is elevated in the serum of patients with widespread atherosclerosis. These findings highlight the importance of a better understanding of the local role of CD73 in the development and maturation of arterial atherosclerotic plaques in man.
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5'-Nucleotidasa/metabolismo , Aterosclerosis/metabolismo , Enfermedad Arterial Periférica/metabolismo , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Extremidad Inferior , Masculino , Persona de Mediana Edad , Transducción de SeñalAsunto(s)
Antivirales/administración & dosificación , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Interferón beta-1a/administración & dosificación , Neumonía Viral/tratamiento farmacológico , COVID-19 , Relación Dosis-Respuesta a Droga , Humanos , Inyecciones Intramusculares , Inyecciones Intravenosas , Pandemias , SARS-CoV-2RESUMEN
Biotechnology and small pharma companies must recognize the opportunity presented by FDA Breakthrough Therapy Designation (BTD) to expedite drug development for serious conditions. This paper evaluates BTD economic and developmental impacts on such companies. Analysis of 29 BTD events from 2017 to 2022 revealed immediate share price boosts and improved drug approval rates, alongside faster development times. Yet, long-term share prices underperformed relative to the broader market, underscoring the persistent risks in pharma investments. Although offering new insights, the limited sample size calls for further investigation.
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Biotecnología , Inversiones en Salud , Estados Unidos , Aprobación de Drogas , United States Food and Drug AdministrationRESUMEN
Background: Systemic inflammation has a critical role in the development of symptomatic coronary artery disease (CAD). Identification of inflammatory pathways may provide a platform for novel therapeutic approaches. We sought to determine whether there are differences in circulating cytokine profiles between patients with CAD and disease-free controls as well as according to the severity of the disease. Methods: Case-control study's population consisted of 452 patients who underwent diagnostic invasive coronary angiography due to clinical indications. We measured the serum concentrations of 48 circulating cytokines. Extent of CAD was assessed using the SYNTAX Score in 116 patients. Cytokine differences between groups were tested using Mann-Whitney U test and associations with CAD were explored using a logistic regression model. Results: Overall, 310 patients had angiographically verified CAD whereas 142 had no angiographically-detected coronary atherosclerosis. In multivariable logistic regression models adjusted for age, sex, hypertension, atrial fibrillation, history of smoking and treatment for diabetes and hyperlipidemia, increased levels of interleukin 9 (OR 1.359, 95%CI 1.046-1.766, p = 0.022), IL-17 (1.491, 95%CI 1.115-1.994, p = 0.007) and tumor necrosis factor alpha (TNF-α) (OR 1.440, 95%CI 1.089-1.904, p = 0.011) were independently associated with CAD. Patients with SYNTAX Score>22 had increased levels of stromal cell-derived factor 1 alfa (SDF-1α), beta-nerve growth factor (ß-NGF), IL-3 and decreased level of IL-17 compared to those with score ≤22 when adjusted for smoking and use of beta-blockers. Conclusions: Patients with CAD have distinct circulating cytokine profiles compared to disease-free controls. Distinct cytokines may have pivotal roles at different stages of coronary atherosclerosis. ClinicalTrials.gov Identifier: NCT03444259 (https://clinicaltrials.gov/study/NCT03444259).
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Chronic inflammation plays a crucial role in coronary artery disease (CAD), but differences in specific cytokine profiles between acute coronary syndrome (ACS) and stable CAD remain unknown. We investigated cytokine differences between these two manifestations of CAD. The study included 308 patients with angiographically detected, hemodynamically significant CAD: 150 patients undergone angiography for ACS, 158 patients undergone angiography for stable CAD. To assess dynamic changes, 116 patients had index angiogram at least 3 months earlier. We measured the serum concentrations of 48 circulating cytokines. The ACS group had decreased interleukin (IL) 4 (p = 0.005), and increased IL-8 (p = 0.008), hepatocyte growth factor (HGF) (p < 0.001) and macrophage colony-stimulating factor (M-CSF) (p = 0.002) levels compared with the stable CAD group. Multivariable logistic regression revealed increased levels of HGF (OR 18.050 [95% CI 4.372-74.517], p < 0.001), M-CSF (OR 2.257 [1.375-3.705], p = 0.001) and IL-6 (OR 1.586 [1.131-2.224], p = 0.007), independently associated with ACS. In the post-angiography group, only diminished platelet-derived growth factor-BB levels in ACS-manifested patients were observed (OR 0.478, [0.279-0.818], p = 0.007). Cytokine profiles differ between ACS and stable CAD. Such differences seem to be mainly reversible within 3 months after ACS. Thus, targeting one or two cytokines only might not offer one-size fits all-therapeutic approach for CAD-associated inflammation.Trial registration: NCT03444259.
Asunto(s)
Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Citocinas , Humanos , Masculino , Femenino , Síndrome Coronario Agudo/sangre , Enfermedad de la Arteria Coronaria/sangre , Citocinas/sangre , Persona de Mediana Edad , Anciano , Angiografía Coronaria , Biomarcadores/sangre , Factor de Crecimiento de Hepatocito/sangreRESUMEN
Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.
Asunto(s)
Atrios Cardíacos , Microvasos , Isquemia Miocárdica , Transcriptoma , Humanos , Atrios Cardíacos/patología , Atrios Cardíacos/metabolismo , Isquemia Miocárdica/genética , Isquemia Miocárdica/patología , Isquemia Miocárdica/metabolismo , Transcriptoma/genética , Microvasos/patología , Inflamación/patología , Inflamación/genética , Masculino , Femenino , Persona de Mediana Edad , Anciano , Regulación de la Expresión GénicaRESUMEN
Many small pharmaceutical companies find that they lack the resources, knowledge and expertise of the regulatory landscape for adequate vendor management in clinical trials, making the organization vulnerable. Recent research suggests that some pharmaceutical companies have found themselves out of compliance with ICH, FDA or EMA guidelines. This paper aims to perform a comprehensive review of the regulatory landscape for vendor selection, oversight and ongoing evaluation in clinical trials. In addition, the case study performed studies the practices recently implemented at small pharmaceutical company Faron Pharmaceuticals to assess regulatory compliance and identify any potential best practices. Faron Pharmaceuticals conducted a process improvement activity at the beginning of 2022 to improve the vendor selection, oversight and evaluation of their clinical trial partners. The results of this case study indicate that Faron Pharmaceuticals' processes are regulatory compliant, suggesting that QTLs, KPIs, SOPs and communication plans are effective vendor oversight mechanisms for small pharmaceutical companies to utilize.
Asunto(s)
Comunicación , Industria Farmacéutica , Pequeña Empresa , Preparaciones FarmacéuticasRESUMEN
Objective: Patients undergoing heart surgery are at high risk of postoperative fluid accumulation due to long procedures and cardiopulmonary bypass. In the present study, we sought to investigate the prevalence of postoperative fluid accumulation and its relation to adverse events in patients undergoing cardiac surgery. Methods: CAREBANK is prospective, single-center cohort study focusing on the adverse events after cardiac surgery. The study population was divided into 2 groups based on 5% postoperative weight gain. All the in-hospital adverse events are registered on the database. The end points of the present study were length of hospital stay, length of intensive care unit stay, occurrence of new-onset atrial fibrillation after hospital major bleeding episodes major cardiac events, cerebrovascular events, and death. Three-month and 1-year follow-up data also include all major adverse events. Results: Altogether 1001 adult cardiac surgery patients were enrolled. The most frequent operations were coronary artery bypass grafting (56.3%). Five hundred fifty-four out of 939 (59.0%) patients had ≥5% weight gain during index hospitalization. Patients with a weight gain ≥5% were more likely to be women, have lower body mass index, had heart failure, and more often had preoperative atrial fibrillation. In-hospital period fluid accumulation was associated with reoperation due bleeding and longer total hospital stay. At 3 months' follow-up, weight gain 5% or more was associated with increased occurrence of new-onset atrial fibrillation, this was not reflected in the occurrence of strokes, transient ischemic attacks, or myocardial infarctions. Conclusions: Postoperative fluid excess is associated with adverse outcomes in cardiac surgery. Women, low-weight patients, and patients with cardiac failure or atrial fibrillation are prone to perioperative fluid accumulation.