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BACKGROUND: A polypill that includes key medications associated with improved outcomes (aspirin, angiotensin-converting-enzyme [ACE] inhibitor, and statin) has been proposed as a simple approach to the secondary prevention of cardiovascular death and complications after myocardial infarction. METHODS: In this phase 3, randomized, controlled clinical trial, we assigned patients with myocardial infarction within the previous 6 months to a polypill-based strategy or usual care. The polypill treatment consisted of aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and atorvastatin (20 or 40 mg). The primary composite outcome was cardiovascular death, nonfatal type 1 myocardial infarction, nonfatal ischemic stroke, or urgent revascularization. The key secondary end point was a composite of cardiovascular death, nonfatal type 1 myocardial infarction, or nonfatal ischemic stroke. RESULTS: A total of 2499 patients underwent randomization and were followed for a median of 36 months. A primary-outcome event occurred in 118 of 1237 patients (9.5%) in the polypill group and in 156 of 1229 (12.7%) in the usual-care group (hazard ratio, 0.76; 95% confidence interval [CI], 0.60 to 0.96; P = 0.02). A key secondary-outcome event occurred in 101 patients (8.2%) in the polypill group and in 144 (11.7%) in the usual-care group (hazard ratio, 0.70; 95% CI, 0.54 to 0.90; P = 0.005). The results were consistent across prespecified subgroups. Medication adherence as reported by the patients was higher in the polypill group than in the usual-care group. Adverse events were similar between groups. CONCLUSIONS: Treatment with a polypill containing aspirin, ramipril, and atorvastatin within 6 months after myocardial infarction resulted in a significantly lower risk of major adverse cardiovascular events than usual care. (Funded by the European Union Horizon 2020; SECURE ClinicalTrials.gov number, NCT02596126; EudraCT number, 2015-002868-17.).
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Inhibidores de la Enzima Convertidora de Angiotensina , Enfermedades Cardiovasculares , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Inhibidores de Agregación Plaquetaria , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Aspirina/efectos adversos , Aspirina/uso terapéutico , Atorvastatina/efectos adversos , Atorvastatina/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Accidente Cerebrovascular Isquémico/prevención & control , Infarto del Miocardio/complicaciones , Infarto del Miocardio/prevención & control , Infarto del Miocardio/terapia , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Ramipril/efectos adversos , Ramipril/uso terapéutico , Prevención Secundaria/métodosRESUMEN
BACKGROUND: Acute coronary syndrome (ACS), specifically ST-segment elevation myocardial infarction is a major cause of morbidity and mortality throughout Europe. Diagnosis in the acute setting is mainly based on clinical symptoms and physician's interpretation of an electrocardiogram (ECG), which may be subject to errors. ST-segment elevation is the leading criteria to activate urgent reperfusion therapy, but a clear ST-elevation pattern might not be present in patients with coronary occlusion and ST-segment elevation might be seen in patients with normal coronary arteries. METHODS: The ASSIST project is a retrospective observational study aiming to improve the ECG-assisted assessment of ACS patients in the acute setting by incorporating an artificial intelligence platform, Willem™ to analyze 12lead ECGs. Our aim is to improve diagnostic accuracy and reduce treatment delays. ECG and clinical data collected during this study will enable the optimization and validation of Willem™. A retrospective multicenter study will collect ECG, clinical, and coronary angiography data from 10,309 patients. The primary outcome is the performance of this tool in the correct identification of acute myocardial infarction with coronary artery occlusion. Model performance will be evaluated internally with patients recruited in this retrospective study while external validation will be performed in a second stage. CONCLUSION: ASSIST will provide key data to optimize Willem™ platform to detect myocardial infarction based on ECG-assessment alone. Our hypothesis is that such a diagnostic approach may reduce time delays, enhance diagnostic accuracy, and improve clinical outcomes.
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In the context of the alarming rise of infant obesity and its health implications, the present research aims to uncover disruptions in postprandial lipid metabolism and the composition of triglyceride-rich lipoproteins in obese adolescents. A double-blind, controlled clinical trial in the postprandial phase on 23 adolescents aged 12 to 16 years was carried out. Twelve participants were categorized as obese (BMI > 30 kg/m2 and percentile > 95) and 11 as normal-weight (BMI = 20-25 kg/m2, percentile 5-85). Blood samples were collected after a 12-h overnight fast and postprandially after consumption of a standardized breakfast containing olive oil, tomato, bread, orange juice, and skimmed milk. Obese adolescents exhibited elevated triglyceride concentrations in both fasting and postprandial states and higher TG/apo-B48 ratios, indicating larger postprandial triglyceride-rich lipoprotein (TRL) particle size, which suggests impaired clearance. Obese subjects also exhibited higher n-6 PUFA concentrations, potentially linked to increased TRL hydrolysis and the release of pro-inflammatory adipokines. In contrast, TRL from normal-weight individuals showed higher concentrations of oleic acid and DHA (n-3 PUFA), with possible anti-inflammatory effects. The results indicate an interplay involving postprandial TRL metabolism and adipokines within the context of adolescent obesity, pointing to potential cardiovascular implications in the future.
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Ácidos Grasos Omega-3 , Obesidad Infantil , Lactante , Humanos , Adolescente , Adipoquinas , Pan , LipoproteínasRESUMEN
BACKGROUND: Electrocardiogram (ECG) is the gold standard for the diagnosis of cardiac arrhythmias and other heart diseases. Insertable cardiac monitors (ICMs) have been developed to continuously monitor cardiac activity over long periods of time and to detect 4 cardiac patterns (atrial tachyarrhythmias, ventricular tachycardia, bradycardia, and pause). However, interpretation of ECG or ICM subcutaneous ECG (sECG) is time-consuming for clinicians. Artificial intelligence (AI) classifies ECG and sECG with high accuracy in short times. OBJECTIVE: To demonstrate whether an AI algorithm can expand ICM arrhythmia recognition from 4 to many cardiac patterns. METHODS: We performed an exploratory retrospective study with sECG raw data coming from 20 patients wearing a Confirm Rx™ (Abbott, Sylmar, USA) ICM. The sECG data were recorded in standard conditions and then analyzed by AI (Willem™, IDOVEN, Madrid, Spain) and cardiologists, in parallel. RESULTS: In nineteen patients, ICMs recorded 2261 sECGs in an average follow-up of 23 months. Within these 2261 sECG episodes, AI identified 7882 events and classified them according to 25 different cardiac rhythm patterns with a pondered global accuracy of 88%. Global positive predictive value, sensitivity, and F1-score were 86.77%, 83.89%, and 85.52% respectively. AI was especially sensitive for bradycardias, pauses, rS complexes, premature atrial contractions, and inverted T waves, reducing the median time spent to classify each sECG compared to cardiologists. CONCLUSION: AI can process sECG raw data coming from ICMs without previous training, extending the performance of these devices and saving cardiologists' time in reviewing cardiac rhythm patterns detection.
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Fibrilación Atrial , Humanos , Fibrilación Atrial/diagnóstico , Inteligencia Artificial , Estudios Retrospectivos , Nube Computacional , Electrocardiografía , Electrocardiografía Ambulatoria , BradicardiaRESUMEN
BACKGROUND: In randomised controlled trials, fixed-dose combination treatments (or polypills) have been shown to reduce a composite of cardiovascular disease outcomes in primary prevention. However, whether or not aspirin should be included, effects on specific outcomes, and effects in key subgroups are unknown. METHODS: We did an individual participant data meta-analysis of large randomised controlled trials (each with ≥1000 participants and ≥2 years of follow-up) of a fixed-dose combination treatment strategy versus control in a primary cardiovascular disease prevention population. We included trials that evaluated a fixed-dose combination strategy of at least two blood pressure lowering agents plus a statin (with or without aspirin), compared with a control strategy (either placebo or usual care). The primary outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, stroke, or arterial revascularisation. Additional outcomes included individual cardiovascular outcomes and death from any cause. Outcomes were also evaluated in groups stratified by the inclusion of aspirin in the fixed-dose treatment strategy, and effect sizes were estimated in prespecified subgroups based on risk factors. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to compare strategies. FINDINGS: Three large randomised trials were included in the analysis (TIPS-3, HOPE-3, and PolyIran), with a total of 18 162 participants. Mean age was 63·0 years (SD 7·1), and 9038 (49·8%) participants were female. Estimated 10-year cardiovascular disease risk for the population was 17·7% (8·7). During a median follow-up of 5 years, the primary outcome occurred in 276 (3·0%) participants in the fixed-dose combination strategy group compared with 445 (4·9%) in the control group (hazard ratio 0·62, 95% CI 0·53-0·73, p<0·0001). Reductions were also observed for the separate components of the primary outcome: myocardial infarction (0·52, 0·38-0·70), revascularisation (0·54, 0·36-0·80), stroke (0·59, 0·45-0·78), and cardiovascular death (0·65, 0·52-0·81). Significant reductions in the primary outcome and its components were observed in the analyses of fixed-dose combination strategies with and without aspirin, with greater reductions for strategies including aspirin. Treatment effects were similar at different lipid and blood pressure levels, and in the presence or absence of diabetes, smoking, or obesity. Gastrointestinal bleeding was uncommon but slightly more frequent in the fixed-dose combination strategy with aspirin group versus control (19 [0·4%] vs 11 [0·2%], p=0·15). The frequencies of haemorrhagic stroke (10 [0·2%] vs 15 [0·3%]), fatal bleeding (two [<0·1%] vs four [0·1%]), and peptic ulcer disease (32 [0·7%] vs 34 [0·8%]) were low and did not differ significantly between groups. Dizziness was more common with fixed-dose combination treatment (1060 [11·7%] vs 834 [9·2%], p<0·0001). INTERPRETATION: Fixed-dose combination treatment strategies substantially reduce cardiovascular disease, myocardial infarction, stroke, revascularisation, and cardiovascular death in primary cardiovascular disease prevention. These benefits are consistent irrespective of cardiometabolic risk factors. FUNDING: Population Health Research Institute.
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Aspirina/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Quimioterapia Combinada , Metaanálisis como Asunto , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prevención Primaria , Presión Sanguínea/efectos de los fármacos , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Ensayos Clínicos Controlados Aleatorios como Asunto , Accidente Cerebrovascular/epidemiologíaRESUMEN
The unprecedented global crisis brought about by the COVID-19 pandemic has sparked numerous efforts to create predictive models for the detection and prognostication of SARS-CoV-2 infections with the goal of helping health systems allocate resources. Machine learning models, in particular, hold promise for their ability to leverage patient clinical information and medical images for prediction. However, most of the published COVID-19 prediction models thus far have little clinical utility due to methodological flaws and lack of appropriate validation. In this paper, we describe our methodology to develop and validate multi-modal models for COVID-19 mortality prediction using multi-center patient data. The models for COVID-19 mortality prediction were developed using retrospective data from Madrid, Spain (N = 2547) and were externally validated in patient cohorts from a community hospital in New Jersey, USA (N = 242) and an academic center in Seoul, Republic of Korea (N = 336). The models we developed performed differently across various clinical settings, underscoring the need for a guided strategy when employing machine learning for clinical decision-making. We demonstrated that using features from both the structured electronic health records and chest X-ray imaging data resulted in better 30-day mortality prediction performance across all three datasets (areas under the receiver operating characteristic curves: 0.85 (95% confidence interval: 0.83-0.87), 0.76 (0.70-0.82), and 0.95 (0.92-0.98)). We discuss the rationale for the decisions made at every step in developing the models and have made our code available to the research community. We employed the best machine learning practices for clinical model development. Our goal is to create a toolkit that would assist investigators and organizations in building multi-modal models for prediction, classification, and/or optimization.
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COVID-19 , Humanos , Estudios Retrospectivos , Pandemias , SARS-CoV-2 , Aprendizaje AutomáticoRESUMEN
Microglial cells can contribute to Alzheimer's disease by triggering an inflammatory response that leads to neuronal death. In addition, the presence of amyloid-ß in the brain is consistent with alterations in the blood-brain barrier integrity and triglyceride-rich lipoproteins (TRL) permeation. In the present work, we used lab-made TRL as carriers of lipophilic bioactive compounds that are commonly present in dietary oils, namely oleanolic acid (OA), α-tocopherol (AT) and ß-sitosterol (BS), to assess their ability to modulate the inflammatory response of microglial BV-2 cells. We show that treatment with lab-made TRL increases the release and gene-expression of IL-1ß, IL-6, and TNF-α, as well as NO and iNOS in microglia. On the other hand, TRL revealed bioactive compounds α-tocopherol and ß-sitosterol as suitable carriers for oleanolic acid. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. The inclusion of these biomolecules in TRL reduced the release of proinflammatory cytokines. AT reduced IL-6 release by 72%, OA reduced TNF-α release by approximately 50%, and all three biomolecules together (M) reduced IL-1ß release by 35% and TNF-α release by more than 70%. In addition, NO generation was reduced, with the inclusion of OA by 45%, BS by 80% and the presence of M by 88%. Finally, a recovery of the basal glutathione content was observed with the inclusion of OA and M in the TRL. Our results open the way to exploiting the neuro-pharmacological potential of these lipophilic bioactive compounds through their delivery to the brain as part of TRL.
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Microglía , Ácido Oleanólico , Citocinas , Interleucina-6 , Lipoproteínas , Ácido Oleanólico/farmacología , Triglicéridos , Factor de Necrosis Tumoral alfa , alfa-Tocoferol/farmacologíaRESUMEN
BACKGROUND: The clinical presentation of COVID-19 ranges from a mild, self-limiting disease, to multiple organ failure and death. Most severe COVID-19 cases present low lymphocytes counts and high leukocytes counts, and accumulated evidence suggests that in a subgroup of patients presenting severe COVID-19, there may be a hyperinflammatory response driving a severe hypercytokinaemia which may be, at least in part, signalling the presence of an underlying endothelial dysfunction. In this context, available data suggest a prognostic role of neutrophil-lymphocyte ratio (NLR) in various inflammatory diseases and oncological processes. Following this rationale, we hypothesized that NLR, as a marker of endothelial dysfunction, may be useful in identifying patients with a poor prognosis in hospitalized COVID-19 cases. DESIGN: A retrospective observational study performed at Hospital Universitario HM Puerta del Sur, Madrid, Spain, which included 119 patients with COVID-19 from 1 March to 31 March 2020. Patients were categorized according to WHO R&D Expert Group. RESULTS: Forty-five (12.1%) patients experienced severe acute respiratory failure requiring respiratory support. Forty-seven (12.6%) patients died. Those with worse outcomes were older (P = .002) and presented significantly higher NLR at admission (P = .001), greater increase in Peak NLR (P < .001) and higher increasing speed of NLR (P = .003) compared with follow-up patients. In a multivariable logistic regression, age, cardiovascular disease and C-reactive protein at admission and Peak NLR were significantly associated with death. CONCLUSIONS: NLR is an easily measurable, available, cost-effective and reliable parameter, which continuous monitoring could be useful for the diagnosis and treatment of COVID-19.
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COVID-19/sangre , Mortalidad Hospitalaria , Leucocitosis/sangre , Linfocitos , Linfopenia/sangre , Neutrófilos , Factores de Edad , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/inmunología , COVID-19/inmunología , COVID-19/mortalidad , Enfermedades Cardiovasculares/epidemiología , Comorbilidad , Diabetes Mellitus/epidemiología , Endotelio Vascular/fisiopatología , Femenino , Humanos , Hipertensión/epidemiología , L-Lactato Deshidrogenasa/sangre , Recuento de Leucocitos , Leucocitosis/inmunología , Modelos Logísticos , Recuento de Linfocitos , Linfopenia/inmunología , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad , España/epidemiologíaRESUMEN
BACKGROUND: Patients with chest pain and persistent ST segment elevation (STE) may not have acute coronary occlusions or serum troponin curves suggestive of acute necrosis. Our objective is the validation and cost-effectiveness analysis of a diagnostic model assisted by artificial intelligence (AI). METHODS: Prospective multicenter registry in two groups of patients with STE: I) coronary arteries without significant lesions and without serum troponin curve suggestive of acute necrosis, II) myocardial infarction with acute coronary occlusion. The inclusion criteria are the following: 1) age ≥ 18 years, 2) chest pain or symptoms suggestive of myocardial ischemia, 3) STE at point J in two contiguous leads ≥0.1 mV, in V2 and V3 ≥ 0,2 mV and 4) signature of informed consent. The exclusion criteria are the following: 1) left bundle branch block, 2) acute cardiac necrosis in the absence of significant epicardial coronary artery stenosis, 3) STE ≤ 0.1 mV with pathologic Q wave, 4) severe anemia (hemoglobin <8.0 g/dl). For each patient without acute cardiac necrosis, the next patient from that center of the same sex and similar age (± 5 years) with myocardial infarction and acute coronary occlusion will be included. A manual centralized electrocardiographic analysis and another by deep learning AI will be performed. CONCLUSIONS: The results of the study will provide new information for the stratification of patients with STE. Our hypothesis is that an AI analysis of the surface electrocardiogram allows a better distinction of patients with STE due to acute myocardial ischemia, from those with another etiology.
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Oclusión Coronaria , Aprendizaje Profundo , Infarto del Miocardio , Adolescente , Inteligencia Artificial , Electrocardiografía , Humanos , Infarto del Miocardio/diagnóstico , Sistema de RegistrosRESUMEN
BACKGROUND: The vast impact of COVID-19 call for the identification of clinical parameter that can help predict a torpid evolution. Among these, endothelial injury has been proposed as one of the main pathophysiological mechanisms underlying the disease, promoting a hyperinflammatory and prothrombotic state leading to worse clinical outcomes. Leukocytes and platelets play a key role in inflammation and thrombogenesis, hence the objective of the current study was to study whether neutrophil-to-lymphocyte ratio (NLR), platelets-to-lymphocyte ratio (PLR), the systemic immune-inflammation index (SII) as well as the new parameter neutrophil-to-platelet ratio (NPR), could help identify patients who at risk of admission at Intensive Care Units. METHODS: A retrospective observational study was performed at HM Hospitales including electronic health records from 2245 patients admitted due to COVID-19 from March 1 to June 10, 2020. Patients were divided into two groups, admitted at ICU or not. RESULTS: Patients who were admitted at the ICU had significantly higher values in all hemogram-derived ratios at the moment of hospital admission compared to those who did not need ICU admission. Specifically, we found significant differences in NLR (6.9 [4-11.7] vs 4.1 [2.6-7.6], p < 0.0001), PLR (2 [1.4-3.3] vs 1.9 [1.3-2.9], p = 0.023), NPR (3 [2.1-4.2] vs 2.3 [1.6-3.2], p < 0.0001) and SII (13 [6.5-25.7] vs 9 [4.9-17.5], p < 0.0001) compared to those who did not require ICU admission. After multivariable logistic regression models, NPR was the hemogram-derived ratio with the highest predictive value of ICU admission, (OR 1.11 (95% CI: 0.98-1.22, p = 0.055). CONCLUSIONS: Simple, hemogram-derived ratios obtained from early hemogram at hospital admission, especially the novelty NPR, have shown to be useful predictors of risk of ICU admission in patients hospitalized due to COVID-19.
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COVID-19/sangre , Unidades de Cuidados Intensivos , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , COVID-19/inmunología , Humanos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Recuento de Plaquetas/métodos , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Senescent cardiomyocytes exhibit a mismatch between energy demand and supply that facilitates their transition toward failing cells. Altered calcium transfer from sarcoplasmic reticulum (SR) to mitochondria has been causally linked to the pathophysiology of aging and heart failure. METHODS: Because advanced glycation-end products accumulate throughout life, we investigated whether intracellular glycation occurs in aged cardiomyocytes and its impact on SR and mitochondria. RESULTS: Quantitative proteomics, Western blot and immunofluorescence demonstrated a significant increase in advanced glycation-end product-modified proteins in the myocardium of old mice (≥20months) compared with young ones (4-6months). Glyoxalase-1 activity (responsible for detoxification of dicarbonyl intermediates) and its cofactor glutathione were decreased in aged hearts. Immunolabeling and proximity ligation assay identified the ryanodine receptor (RyR2) in the SR as prominent target of glycation in aged mice, and the sites of glycation were characterized by quantitative mass spectrometry. RyR2 glycation was associated with more pronounced calcium leak, determined by confocal microscopy in cardiomyocytes and SR vesicles. Interfibrillar mitochondria-directly exposed to SR calcium release-from aged mice had increased calcium content compared with those from young ones. Higher levels of advanced glycation-end products and reduced glyoxalase-1 activity and glutathione were also present in atrial appendages from surgical patients ≥75 years as compared with the younger ones. Elderly patients also exhibited RyR2 hyperglycation and increased mitochondrial calcium content that was associated with reduced myocardial aerobic capacity (mitochondrial O2 consumption/g) attributable to less respiring mitochondria. In contracting HL-1 cardiomyocytes, pharmacological glyoxalase-1 inhibition recapitulated RyR2 glycation and defective SR-mitochondria calcium exchange of aging. CONCLUSIONS: Mitochondria from aging hearts develop calcium overload secondary to SR calcium leak. Glycative damage of RyR2, favored by deficient dicarbonyl detoxification capacity, contributes to calcium leak and mitochondrial damage in the senescent myocardium.
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Calcio/metabolismo , Senescencia Celular , Productos Finales de Glicación Avanzada/metabolismo , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Factores de Edad , Anciano , Anciano de 80 o más Años , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Señalización del Calcio , Línea Celular , Femenino , Glicosilación , Humanos , Lactoilglutatión Liasa/metabolismo , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Mitocondrias Cardíacas/patología , Miocitos Cardíacos/patología , Retículo Sarcoplasmático/metabolismo , Retículo Sarcoplasmático/patologíaRESUMEN
AIMS: Atrial electrical remodelling (AER) is a transitional period associated with the progression and long-term maintenance of atrial fibrillation (AF). We aimed to study the progression of AER in individual patients with implantable devices and AF episodes. METHODS AND RESULTS: Observational multicentre study (51 centres) including 4618 patients with implantable cardioverter-defibrillator +/-resynchronization therapy (ICD/CRT-D) and 352 patients (2 centres) with pacemakers (median follow-up: 3.4 years). Atrial activation rate (AAR) was quantified as the frequency of the dominant peak in the signal spectrum of AF episodes with atrial bipolar electrograms. Patients with complete progression of AER, from paroxysmal AF episodes to electrically remodelled persistent AF, were used to depict patient-specific AER slopes. A total of 34 712 AF tracings from 830 patients (87 with pacemakers) were suitable for the study. Complete progression of AER was documented in 216 patients (16 with pacemakers). Patients with persistent AF after completion of AER showed â¼30% faster AAR than patients with paroxysmal AF. The slope of AAR changes during AF progression revealed patient-specific patterns that correlated with the time-to-completion of AER (R2 = 0.85). Pacemaker patients were older than patients with ICD/CRT-Ds (78.3 vs. 67.2 year olds, respectively, P < 0.001) and had a shorter median time-to-completion of AER (24.9 vs. 93.5 days, respectively, P = 0.016). Remote transmissions in patients with ICD/CRT-D devices enabled the estimation of the time-to-completion of AER using the predicted slope of AAR changes from initiation to completion of electrical remodelling (R2 = 0.45). CONCLUSION: The AF progression shows patient-specific patterns of AER, which can be estimated using available remote-monitoring technology.
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Fibrilación Atrial , Remodelación Atrial , Desfibriladores Implantables , Marcapaso Artificial , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/terapia , Preescolar , HumanosRESUMEN
Reports on the effect of obesity on the myocardial tolerance to ischemia are contradictory. We have described that obesity induced by high-fat diet (HFD) reduces infarct size in B6D2F1 mice submitted to transient coronary occlusion. In this study, we analysed the mechanism by which dietary obesity modifies the susceptibility to myocardial ischemia and the robustness of this effect. B6D2F1 (BDF), C57BL6/J (6J), C57BL6/N (6N) male mice and BDF female mice were fed with a HFD or control diet for 16â¯weeks. In all three strains, HFD induced obesity with hyperinsulinemia and hypercholesterolemia and without hyperglycemia, hypertension, ventricular remodelling or cardiac dysfunction. In obese mice from all three strains PDK4 was overexpressed and HSQC NMR spectroscopy showed reduced 13C-glutamate and increased 13C-lactate and 13C-alanine, indicating uncoupling of glycolysis from glucose oxidation. In addition, HFD induced mild respiratory uncoupling in mitochondria from BDF and 6N mice in correlation with UCP3 overexpression. In studies performed in isolated perfused hearts submitted to transient ischemia these changes were associated with reduced ATP content and myocardial PCr/ATP ratio at baseline, and delayed pHi recovery (31PNMR) and attenuated hypercontracture at the onset of reperfusion. Finally, in mice subjected to 45â¯min of coronary occlusion and 24â¯h of reperfusion, HFD significantly reduced infarct size respect to their respective control diet groups in male BDF (39.4⯱â¯6.1% vs. 19.9⯱â¯3.2%, Pâ¯=â¯0.018) and 6N mice (38.0⯱â¯4.1 vs. 24.5⯱â¯2.6%, Pâ¯=â¯0.017), and in female BDF mice (35.3⯱â¯4.4% vs. 22.3⯱â¯2.5%, Pâ¯=â¯0.029), but not in male 6J mice (40.2⯱â¯3.4% vs. 34.1⯱â¯3.8%, Pâ¯=â¯0.175). Our results indicate that the protective effect of HFD-induced obesity against myocardial ischemia/reperfusion injury is influenced by genetic background and appears to critically depend on inhibition of glucose oxidation and mild respiratory mitochondrial uncoupling resulting in prolongation of acidosis at the onset of reperfusion.
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Adaptación Fisiológica , Dieta Alta en Grasa , Metabolismo Energético , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Animales , Modelos Animales de Enfermedad , Ecocardiografía , Femenino , Glucosa/metabolismo , Concentración de Iones de Hidrógeno , Espacio Intracelular/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Metaboloma , Metabolómica/métodos , Ratones , Mitocondrias Cardíacas/metabolismo , Isquemia Miocárdica/diagnóstico , Daño por Reperfusión Miocárdica/diagnóstico , Obesidad/metabolismo , Oxidación-ReducciónRESUMEN
AIM: To assess whether the regular intake of an oleanolic acid (OA)-enriched olive oil is effective in the prevention of diabetes. METHODS: In the PREDIABOLE study, prediabetic individuals (impaired fasting glucose and impaired glucose tolerance) of both sexes (176 patients, aged 30-80 years) were randomized to receive 55 mL/day of OA-enriched olive oil (equivalent dose 30 mg OA/day) [intervention group (IG)] or the same oil not enriched [control group (CG)]. The main outcome was the incidence of new-onset type 2 diabetes in both groups. RESULTS: Forty-eight new diabetes cases occurred, 31 in the CG and 17 in the IG. The multivariate-adjusted hazard ratio was 0.45 (95% CI, 0.24-0.83) for the IG compared with the CG. Intervention-related adverse effects were not reported. CONCLUSIONS: The intake of OA-enriched olive oil reduces the risk of developing diabetes in prediabetic patients. The results of the PREDIABOLE study promote the use of OA in new functional foods and drugs for the prevention of diabetes in individuals at risk of developing it.
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Diabetes Mellitus Tipo 2 , Ácido Oleanólico/uso terapéutico , Aceite de Oliva/uso terapéutico , Estado Prediabético , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/dietoterapia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Método Doble Ciego , Femenino , Humanos , Hipoglucemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Estado Prediabético/dietoterapia , Estado Prediabético/tratamiento farmacológico , Estado Prediabético/epidemiología , Estado Prediabético/terapiaRESUMEN
Regulatory approvals for cardiovascular polypills are increasing rapidly across more than 30 countries. The evidence clearly shows polypills improve adherence and cardiovascular disease risk factors for patients with indications for use of polypill components-ie, those with established cardiovascular disease or at high risk. However, the implementation of polypills into clinical practice has many challenges. The clinical trials literature provides insights into the clinical impact of a polypill strategy, including cost-effectiveness, safety of use, substantial improvement in adherence, and better risk factor control than usual care. Despite the clear need for such a strategy and the available clinical data backing up the use of the polypill in different patient populations, challenges to widespread implementation, such as an absence of government reimbursement and poor physician uptake (identified from on the ground experience in countries following commercial rollout), have greatly obstructed real-world implementation. Obtaining the full public health benefit of polypills will require education, advocacy, endorsement, and implementation by key global agencies such as WHO and national clinical bodies, as well as endorsement from governments.
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Fármacos Cardiovasculares/administración & dosificación , Enfermedades Cardiovasculares/prevención & control , Actitud del Personal de Salud , Fármacos Cardiovasculares/efectos adversos , Aprobación de Drogas , Combinación de Medicamentos , Composición de Medicamentos , Medicamentos Esenciales , Predicción , Humanos , Estilo de Vida , Aceptación de la Atención de Salud , Pautas de la Práctica en Medicina , Prevención Primaria , Salud Pública , Ensayos Clínicos Controlados Aleatorios como Asunto , Mecanismo de Reembolso , Prevención SecundariaRESUMEN
BACKGROUND: Cardiac magnetic resonance (CMR) has demonstrated its utility in the noninvasive diagnosis of cardiac amyloidosis (CA). Our aim was to evaluate the ability of standard Look-Locker sequences to quantify amyloid deposition in CA. METHODS AND RESULTS: Consecutive patients referred for CMR for possible CA were retrospectively evaluated. Positive cardiac biopsy and/or typical pattern of late gadolinium enhancement were required for the diagnosis of CA. Postcontrast T1 values were obtained from Look-Locker sequences and correlated with markers of severity of disease and major events. When cardiac biopsies were available, histological validation was determined. A total of 174 patients were included. A final diagnosis of CA was reached in 37.4%. Myocardial and endocardial T1 times, as well as the respective ratios with blood and skeletal muscle, were lower among patients with CA and demonstrated good diagnostic performance. The best parameters were myocardial/blood (area under the curve 0.83; P < .001) and endocardial/blood (area under the curve 0.84; P < .001) T1 ratios. Among patients with CA, no associations were found between T1 ratios either with markers of amyloid burden or with prognostic variables. However, all T1 indexes showed significant correlations with histological quantification of amyloid deposition. CONCLUSIONS: Look-Looker derived postcontrast T1 shows good diagnostic accuracy to detect CA and correlation with histological amyloid burden.
Asunto(s)
Amiloide/metabolismo , Amiloidosis/diagnóstico , Cardiomiopatías/diagnóstico , Imagen por Resonancia Cinemagnética/métodos , Miocardio/metabolismo , Anciano , Amiloidosis/metabolismo , Biopsia , Cardiomiopatías/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patología , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
Death receptors are members of the tumor necrosis factor receptor superfamily involved in the extrinsic apoptotic pathway. Lifeguard (LFG) is a death receptor antagonist mainly expressed in the nervous system that specifically blocks Fas ligand (FasL)-induced apoptosis. To investigate its mechanism of action, we studied its subcellular localization and its interaction with members of the Bcl-2 family proteins. We performed an analysis of LFG subcellular localization in murine cortical neurons and found that LFG localizes mainly to the ER and Golgi. We confirmed these results with subcellular fractionation experiments. Moreover, we show by co-immunoprecipitation experiments that LFG interacts with Bcl-XL and Bcl-2, but not with Bax or Bak, and this interaction likely occurs in the endoplasmic reticulum. We further investigated the relationship between LFG and Bcl-XL in the inhibition of apoptosis and found that LFG protects only type II apoptotic cells from FasL-induced death in a Bcl-XL dependent manner. The observation that LFG itself is not located in mitochondria raises the question as to whether LFG in the ER participates in FasL-induced death. Indeed, we investigated the degree of calcium mobilization after FasL stimulation and found that LFG inhibits calcium release from the ER, a process that correlates with LFG blockage of cytochrome c release to the cytosol and caspase activation. On the basis of our observations, we propose that there is a required step in the induction of type II apoptotic cell death that involves calcium mobilization from the ER and that this step is modulated by LFG.
Asunto(s)
Apoptosis , Señalización del Calcio , Retículo Endoplásmico/metabolismo , Proteína Ligando Fas/antagonistas & inhibidores , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Animales , Línea Celular , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/metabolismo , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Femenino , Aparato de Golgi/metabolismo , Células HEK293 , Humanos , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Neuronas/citología , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Interferencia de ARN , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismoRESUMEN
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death worldwide. With atherosclerosis as the underlying cause for many CVD events, prevention or reduction of subclinical atherosclerotic plaque burden (SAPB) through a healthier lifestyle may have substantial public health benefits. OBJECTIVE: The objective was to describe the protocol of a randomized controlled trial investigating the effectiveness of a 30-month worksite-based lifestyle program aimed to promote cardiovascular health in participants having a high or a low degree of SAPB compared with standard care. METHODS: We will conduct a randomized controlled trial including middle-aged bank employees from the Progression of Early Subclinical Atherosclerosis cohort, stratified by SAPB (high SAPB n=260, low SAPB n=590). Within each stratum, participants will be randomized 1:1 to receive a lifestyle program or standard care. The program consists of 3 elements: (a) 12 personalized lifestyle counseling sessions using Motivational Interviewing over a 30-month period, (b) a wrist-worn physical activity tracker, and (c) a sit-stand workstation. Primary outcome measure is a composite score of blood pressure, physical activity, sedentary time, body weight, diet, and smoking (ie, adapted Fuster-BEWAT score) measured at baseline and at 1-, 2-, and 3-year follow-up. CONCLUSIONS: The study will provide insights into the effectiveness of a 30-month worksite-based lifestyle program to promote cardiovascular health compared with standard care in participants with a high or low degree of SAPB.