RESUMEN
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up-to-date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.
Asunto(s)
Aterosclerosis , Vesículas Extracelulares , Aterosclerosis/diagnóstico , Aterosclerosis/terapia , Biomarcadores , Humanos , Fosfolípidos , Medicina de PrecisiónRESUMEN
BACKGROUND AND AIMS: The ecto-nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI). METHODS: Ticagrelor-treated pigs underwent balloon-induced MI (90â min) and, before reperfusion, received intravenously either vehicle, 1â mg/kg AZD3366 or 3â mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed. RESULTS: Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3â mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3â mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3â mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time. CONCLUSIONS: Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.
Asunto(s)
Adenosina Trifosfatasas , Apirasa , Infarto del Miocardio , Ticagrelor , Animales , Humanos , Masculino , Adenosina/análogos & derivados , Adenosina/farmacología , Antígenos CD , Apirasa/metabolismo , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Modelos Animales de Enfermedad , Infarto del Miocardio/tratamiento farmacológico , Agregación Plaquetaria/efectos de los fármacos , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Porcinos , Ticagrelor/farmacología , Ticagrelor/uso terapéutico , Adenosina Trifosfatasas/farmacología , Adenosina Trifosfatasas/uso terapéuticoRESUMEN
BACKGROUND: Dyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first-time presentation of chest pain and on-target LDL-C levels and intermediate FRS/ESC-Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re-event rate up to 6 years follow-up. METHODS: Blind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil-to-Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission. RESULTS: cTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL-6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(-) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL-6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re-event rate at follow-up. CONCLUSIONS: Inflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re-event rate over a follow-up period of up to 6 years.
RESUMEN
The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.
Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular , Reemplazo de la Válvula Aórtica Transcatéter , Humanos , Anciano , Fibrinolíticos/efectos adversos , Resultado del Tratamiento , Aspirina/efectos adversos , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Hemorragia/inducido químicamente , Hemorragia/prevención & control , Anticoagulantes , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Accidente Cerebrovascular/tratamiento farmacológico , Fibrilación Atrial/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversosRESUMEN
Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.
Asunto(s)
Aterosclerosis , Sepsis , Trombosis , Humanos , Fibrinolíticos/uso terapéutico , Anticoagulantes/uso terapéutico , Trombosis/tratamiento farmacológico , Trombosis/etiología , Trombosis/prevención & control , Hemorragia/inducido químicamente , Aterosclerosis/tratamiento farmacológico , Hemostasis , Sepsis/complicaciones , Sepsis/tratamiento farmacológico , BiologíaRESUMEN
Low-density lipoprotein receptor-related protein 5 (LRP5) is a constitutively expressed receptor with observed roles in bone homeostasis, retinal development, and cardiac metabolism. However, the function of LRP5 in the brain remains unexplored. This study investigates LRP5's role in the central nervous system by conducting an extensive analysis using RNA-seq tools and in silico assessments. Two protein-coding Lrp5 transcripts are expressed in mice: full-length Lrp5-201 and a truncated form encoded by Lrp5-202. Wt mice express Lrp5-201 in the liver and brain and do not express the truncated form. Lrp5-/- mice express Lrp5-202 in the liver and brain and do not express Lrp5-201 in the liver. Interestingly, Lrp5-/- mouse brains show full-length Lrp5-201 expression, suggesting that LRP5 has a role in preserving brain function during development. Functional gene enrichment analysis on RNA-seq unveils dysregulated expression of genes associated with neuronal differentiation and synapse formation in the brains of Lrp5-/- mice compared to Wt mice. Furthermore, Gene Set Enrichment Analysis highlights downregulated expression of genes involved in retinol and linoleic acid metabolism in Lrp5-/- mouse brains. Tissue-specific alternative splicing of Lrp5 in Lrp5-/- mice supports that the expression of LRP5 in the brain is needed for the correct synthesis of vitamins and fatty acids, and it is indispensable for correct brain development.
Asunto(s)
Empalme Alternativo , Encéfalo , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad , Animales , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Encéfalo/metabolismo , Encéfalo/crecimiento & desarrollo , Ratones , Ratones Noqueados , Hígado/metabolismo , Hígado/crecimiento & desarrollo , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Gut microbiota is thought to modulate cardiovascular risk. However, the effect of cardiovascular primary prevention strategies on gut microbiota remains largely unknown. This study investigates the impact of diet and rosuvastatin interventions on gut microbiota composition in hypercholesterolemic pigs and associated potential changes in host metabolic pathways. METHODS: Diet-induced hypercholesterolemic pigs (n = 32) were randomly distributed to receive one of the following 30-day interventions: (I) continued hypercholesterolemic diet (HCD; n = 9), (II) normocholesterolemic diet (NCD; n = 8), (III) continued HCD plus 40 mg rosuvastatin/daily (n = 7), or (IV) NCD plus 40 mg rosuvastatin/daily (n = 8). Faeces were collected at study endpoint for characterisation of the gut microbiome and metabolic profile prediction (PICRUSt2). TMAO levels and biochemical parameters were determined. RESULTS: Principal coordinate analyses (beta-diversity) showed clear differences in the microbiota of NCD vs HCD pigs (PERMANOVA, p = .001). NCD-fed animals displayed significantly higher alpha-diversity, which inversely correlated with total cholesterol and LDL-cholesterol levels (p < .0003). NCD and HCD animals differed in the abundance of 12 genera (ANCOM; p = .001 vs HCD), and PICRUSt2 analysis revealed detrimental changes in HCD-related microbiota metabolic capacities. These latter findings were associated with a significant fivefold increase in TMAO levels in HCD-fed pigs (p < .0001 vs NCD). The addition of a 30-day rosuvastatin treatment to either of the diets exerted no effects in microbiota nor lipid profile. CONCLUSION: In hypercholesterolemic animals, the ingestion of a low-fat diet for 30 days modifies gut microbiota composition in favour of alpha-diversity and towards a healthy metabolic profile, whereas rosuvastatin treatment for this period exerts no effects.
Asunto(s)
Microbioma Gastrointestinal , Enfermedades no Transmisibles , Animales , Colesterol , Dieta , Dieta Alta en Grasa , Disbiosis/metabolismo , Rosuvastatina Cálcica , PorcinosRESUMEN
OBJECTIVES: We performed a comprehensive assessment of the effect of myocardial ischemia duration on cardiac structural and functional parameters by serial cardiac magnetic resonance (CMR) and characterized the evolving scar. BACKGROUND: CMR follow-up on the cardiac impact of time of ischemia in a closed-chest animal model of myocardial infarction with human resemblance is missing. METHODS: Pigs underwent MI induction by occlusion of the left anterior descending (LAD) coronary artery for 30, 60, 90 or 120 min and then revascularized. Serial CMR was performed on day 3 and day 42 post-MI. CMR measurements were also run in a sham-operated group. Cellular and molecular changes were investigated. RESULTS: On day 3, cardiac damage and function were similar in sham and pigs subjected to 30 min of ischemia. Cardiac damage (oedema and necrosis) significantly increased from 60 min onwards. Microvascular obstruction was extensively seen in animals with ≥90 min of ischemia and correlated with cardiac damage. A drop in global systolic function and wall motion of the jeopardized segments was seen in pigs subjected to ≥60 min of ischemia. On day 42, scar size and cardiac dysfunction followed the same pattern in the animals subjected to ≥60 min of ischemia. Adverse left ventricular remodelling (worsening of both LV volumes) was only present in animals subjected to 120 min of ischemia. Cardiac fibrosis, myocyte hypertrophy and vessel rarefaction were similar in the infarcted myocardium of pigs subjected to ≥60 min of ischemia. No changes were observed in the remote myocardium. CONCLUSION: Sixty-minute LAD coronary occlusion already induces cardiac structural and functional alterations with longer ischemic time (120 min) causing adverse LV remodelling.
Asunto(s)
Enfermedad de la Arteria Coronaria , Oclusión Coronaria , Infarto del Miocardio , Humanos , Animales , Porcinos , Miocardio , Corazón , Infarto del Miocardio/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , Modelos Animales , Oclusión Coronaria/diagnóstico por imagen , Modelos Animales de Enfermedad , Función Ventricular IzquierdaRESUMEN
The clearance of low-density lipoprotein (LDL) particles from the circulation is regulated by the LDL receptor (LDLR) and proprotein convertase subtilisin/kexin 9 (PCSK9) interaction. Its disruption reduces blood cholesterol levels and delays atherosclerosis progression. Whether other members of the LDLR superfamily are in vivo targets of PCSK9 has been poorly explored. The aim of this work was to study the interaction between PCSK9 and members of the LDLR superfamily in the regulation of liver cholesterol homeostasis in an in vivo low-density lipoprotein receptor related protein 5 (LRP5) deficient mice model challenged with high-fat diet. Our results show that Wt and Lrp5-/- mice fed a hypercholesterolemic diet (HC) have increased cholesterol ester accumulation and decreased liver LDLR and LRP5 gene and protein expression. Very low-density lipoprotein receptor (VLDLR), LRP6, LRP2, and LRP1 expression levels were analyzed in liver samples and show that they do not participate in Lrp5-/- liver cholesterol uptake. Immunoprecipitation experiments show that LRP5 forms a complex with PCSK9 in liver-specific fat-storing stellate cells but not in structural HepG2 cells. Hepatic stellate cells silenced for LRP5 and/or PCSK9 expression and challenged with lipids show reduced cholesterol ester accumulation, indicating that both proteins are involved in lipid processing in the liver. Our results indicate that cholesterol esters accumulate in livers of Wt mice in a LDLR-family-members dependent manner as VLDLR, LRP2, and LRP6 show increased expression in HC mice. However, this increase is lost in livers of Lrp5-/- mice, where scavenger receptors are involved in cholesterol uptake. PCSK9 expression is strongly downregulated in mice livers after HC feeding. However PCSK9 and LRP5 bind in the cytoplasm of fat storing liver cells, indicating that this PCSK9-LRP5 interaction is cell-type specific and that both proteins contribute to lipid uptake.
Asunto(s)
Ésteres del Colesterol , Hígado , Proproteína Convertasa 9 , Animales , Ésteres del Colesterol/metabolismo , Células Hep G2 , Humanos , Lipoproteínas LDL/metabolismo , Hígado/metabolismo , Ratones , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Receptores de LDL/metabolismo , Serina Endopeptidasas/metabolismoRESUMEN
Platelets exert fundamental roles in thrombosis, inflammation, and angiogenesis, contributing to different pathologies from cardiovascular diseases to cancer. We previously reported that platelets release extracellular vesicles (pEVs) which contribute to thrombus formation. However, pEV composition remains poorly defined. Indeed, pEV quality and type, rather than quantity, may be relevant in intravascular cross-talk with either circulating or vascular cells. We aimed to define the phenotypic characteristics of pEVs released spontaneously and those induced by thrombin activation to better understand their role in disease dissemination. pEVs obtained from washed platelets from healthy donor blood were characterized by flow cytometry. pEVs from thrombin-activated platelets (T-pEVs) showed higher levels of P-selectin and active form of glycoprotein IIb/IIIa than baseline non-activated platelets (B-pEVs). Following mass spectrometry-based differential proteomic analysis, significant changes in the abundance of proteins secreted in T-pEVs compared to B-pEVs were found. These differential proteins were involved in coagulation, adhesion, cytoskeleton, signal transduction, metabolism, and vesicle-mediated transport. Interestingly, release of proteins relevant for cell adhesion, intrinsic pathway coagulation, and platelet activation signalling was significantly modified by thrombin stimulation. A novel pEV-associated protein (protocadherin-α4) was found to be significantly reduced in T-pEVs showing a shift towards increased expression in the membranes of activated platelets. In summary, platelet activation induced by thrombin triggers the shedding of pEVs with a complex proteomic pattern rich in procoagulant and proadhesive proteins. Crosstalk with other vascular and blood cells in a paracrine regulatory mode could extend the prothrombotic signalling as well as promote proteostasic changes in other cellular types.
Asunto(s)
Plaquetas/citología , Vesículas Extracelulares/metabolismo , Proteínas/metabolismo , Trombina/metabolismo , Animales , Aterosclerosis/metabolismo , Plaquetas/metabolismo , Humanos , Activación Plaquetaria/fisiología , Proteínas/análisis , Porcinos , Trombosis/metabolismoRESUMEN
AIM: Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI. METHODS AND RESULTS: Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008). CONCLUSIONS: These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.
Asunto(s)
Clusterina , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Animales , Clusterina/sangre , Clusterina/química , Enfermedad de la Arteria Coronaria/sangre , Glicosilación , Humanos , Isquemia , Infarto del Miocardio/sangre , Porcinos , Troponina TRESUMEN
Patients admitted for acute coronary syndrome (ACS) usually have high cardiovascular risk scores with low levels of high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels. Here, we investigated the role of lipoprotein functionality as well as particle number and size in patients with a first-onset ACS with on-target LDL-C levels. Ninety-seven patients with chest pain and first-onset ACS with LDL-C levels of 100 ± 4 mg/dL and non-HDL-C levels of 128 ± 4.0 mg/dL were included in the study. Patients were categorized as ACS and non-ACS after all diagnostic tests were performed (electrocardiogram, echocardiogram, troponin levels and angiography) on admission. HDL-C and LDL-C functionality and particle number/size by nuclear magnetic resonance (NMR) were blindly investigated. A group of matched healthy volunteers (n = 31) was included as a reference for these novel laboratory variables. LDL susceptibility to oxidation was higher and HDL-antioxidant capacity lower in the ACS patients than in the non-ACS individuals. ACS patients had lower HDL-C and Apolipoprotein A-I levels than non-ACS patients despite the same prevalence of classical cardiovascular risk factors. Cholesterol efflux potential was impaired only in the ACS patients. ACS-STEMI (Acute Coronary Syndrome-ST-segment-elevation myocardial infarction) patients, had a larger HDL particle diameter than non-ACS individuals (8.4 ± 0.02 vs. 8.3 ± 0.02 and, ANOVA test, p = 0.004). In conclusion, patients admitted for chest pain with a first-onset ACS and on-target lipid levels had impaired lipoprotein functionality and NMR measured larger HDL particles. This study shows the relevance of HDL functionality rather than HDL-C concentration in ACS patients.
Asunto(s)
Síndrome Coronario Agudo , Infarto del Miocardio con Elevación del ST , Humanos , Síndrome Coronario Agudo/diagnóstico , LDL-Colesterol , Colesterol , HDL-Colesterol , Lipoproteínas , Dolor en el PechoRESUMEN
Whilst there is a clear clinical benefit of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision to initiate and continue anticoagulation is often based on a careful assessment of both the thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug-drug and food-drug interactions. Bleeding risk is also not a static 'one off' assessment based on baseline factors but is dynamic, being influenced by ageing, incident comorbidities, and drug therapies. In this Consensus Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with the view to summarizing 'best practice' when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, review established bleeding risk factors, and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice.
Asunto(s)
Fibrilación Atrial , Accidente Cerebrovascular , Trombosis , Tromboembolia Venosa , Humanos , Fibrilación Atrial/complicaciones , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/tratamiento farmacológico , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/epidemiología , Tromboembolia Venosa/prevención & control , Fibrinolíticos/efectos adversos , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Anticoagulantes/efectos adversosRESUMEN
Ischemic heart disease remains the leading cause of morbidity and mortality worldwide. Despite the advances in medical management and catheter-based therapy, mortality remains high, as does the risk of developing heart failure. Regenerative therapies have been widely used as an alternative option to repair the damaged heart mainly because of their paracrine-related beneficial effects. Although cell-based therapy has been demonstrated as feasible and safe, randomized controlled trials and meta-analyses show little consistent benefit from treatments with adult-derived stem cells. Mounting evidence from our group and others supports that cardiovascular risk factors and comorbidities impair stem cell potential thus hampering their autologous use. This review aims to better understand the influence of diabetes on stem cell potential. For this purpose, we will first discuss the most recent advances in the mechanistic understanding of the effects of diabetes on stem cell phenotype, function, and molecular fingerprint to further elaborate on diabetes-induced alterations in stem cell extracellular vesicle profile. Although we acknowledge that multiple sources of stem or progenitor cells are used for regenerative purposes, we will focus on bone marrow hematopoietic stem/progenitor cells, mesenchymal stem cells residing in the bone marrow, and adipose tissue and briefly discuss endothelial colony-forming cells.
Asunto(s)
Diabetes Mellitus , Células Madre Mesenquimatosas , Isquemia Miocárdica , Tejido Adiposo , Diabetes Mellitus/terapia , Humanos , Isquemia Miocárdica/terapia , Trasplante de Células Madre/efectos adversos , Células MadreRESUMEN
AIMS: This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia-reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. METHODS AND RESULTS: A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). CONCLUSION: Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine).
RESUMEN
Cardiovascular disease remains the main cause of mortality in individuals with diabetes mellitus (DM) and also results in significant morbidity. Premature and more aggressive atherosclerotic disease, coupled with an enhanced thrombotic environment, contributes to the high vascular risk in individuals with DM. This prothrombotic milieu is due to increased platelet activity together with impaired fibrinolysis secondary to quantitative and qualitative changes in coagulation factors. However, management strategies to reduce thrombosis risk remain largely similar in individuals with and without DM. The current review covers the latest in the field of antithrombotic management in DM. The role of primary vascular prevention is discussed together with options for secondary prevention following an ischaemic event in different clinical scenarios including coronary, cerebrovascular, and peripheral artery diseases. Antiplatelet therapy combinations as well as combination of antiplatelet and anticoagulant agents are examined in both the acute phase and long term, including management of individuals with sinus rhythm and those with atrial fibrillation. The difficulties in tailoring therapy according to the variable atherothrombotic risk in different individuals are emphasized, in addition to the varying risk within an individual secondary to DM duration, presence of complications and predisposition to bleeding events. This review provides the reader with an up-to-date guide for antithrombotic management of individuals with DM and highlights gaps in knowledge that represent areas for future research, aiming to improve clinical outcome in this high-risk population.
Asunto(s)
Diabetes Mellitus , Fibrinolíticos , Anticoagulantes , Diabetes Mellitus/tratamiento farmacológico , Fibrinolíticos/uso terapéutico , Humanos , Inhibidores de Agregación Plaquetaria/uso terapéutico , Prevención SecundariaRESUMEN
Transcatheter aortic valve implantation (TAVI) is effective in older patients with symptomatic severe aortic stenosis, while the indication has recently broadened to younger patients at lower risk. Although thromboembolic and bleeding complications after TAVI have decreased over time, such adverse events are still common. The recommendations of the latest 2017 ESC/EACTS Guidelines for the management of valvular heart disease on antithrombotic therapy in patients undergoing TAVI are mostly based on expert opinion. Based on recent studies and randomized controlled trials, this viewpoint document provides updated therapeutic insights in antithrombotic treatment during and after TAVI.
Asunto(s)
Estenosis de la Válvula Aórtica , Enfermedades de las Válvulas Cardíacas , Implantación de Prótesis de Válvulas Cardíacas , Trombosis , Reemplazo de la Válvula Aórtica Transcatéter , Anciano , Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/tratamiento farmacológico , Estenosis de la Válvula Aórtica/cirugía , Consenso , Fibrinolíticos/uso terapéutico , Humanos , Trombosis/tratamiento farmacológico , Trombosis/etiología , Trombosis/prevención & control , Reemplazo de la Válvula Aórtica Transcatéter/efectos adversos , Resultado del TratamientoRESUMEN
Infarct size is the major risk predictor for developing heart failure after an acute myocardial infarction (AMI). The discovery of the conditioning phenomena (i.e., repetitive brief cycles of ischemia applied either before or after a prolonged ischemic insult) has highlighted the existence of endogenous protective mechanisms of the heart potentially limiting infarct size after revascularization. However, most cardioprotective strategies, aiming at infarct size reduction, have failed in clinical studies. Thus, cardioprotection is an unmet clinical need. In the present study, we took a network-assisted systems biology approach to explore the mitochondrial proteomic signature of the myocardium after ischemia, ischemia with direct revascularization, and ischemia with re-establishment of blood flow by post-conditioning in a swine model of AMI. Furthermore, network extension with the ENCODE project human regulatory data allowed the prediction of potential transcription factors at play in the response to post-conditioning of the myocardium. Collectively, our results identify cardiac metabolism as a driver of cardioprotection, highlighting a dual role for post-conditioning promoting metabolic reprogramming of the myocardium, and a protective response mediated by VDAC2 and DJ-1 in the mitochondria.
Asunto(s)
Isquemia/metabolismo , Mitocondrias/metabolismo , Proteoma/metabolismo , Animales , Corazón/fisiología , Infarto/metabolismo , Precondicionamiento Isquémico Miocárdico/métodos , Infarto del Miocardio/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Miocardio/metabolismo , Proteómica/métodos , Transducción de Señal/fisiología , Porcinos , Biología de Sistemas/métodosRESUMEN
High-density lipoproteins (HDL) undergo adverse remodeling and loss of function in the presence of comorbidities. We assessed the potential of lipid-lowering approaches (diet and rosuvastatin) to rescue hypercholesterolemia-induced HDL dysfunction. Hypercholesterolemia was induced in 32 pigs for 10 days. Then, they randomly received one of the 30-day interventions: (I) hypercholesterolemic (HC) diet; (II) HC diet + rosuvastatin; (III) normocholesterolemic (NC) diet; (IV) NC diet + rosuvastatin. We determined cholesterol efflux capacity (CEC), antioxidant potential, HDL particle number, HDL apolipoprotein content, LDL oxidation, and lipid levels. Hypercholesterolemia time-dependently impaired HDL function (−62% CEC, −11% antioxidant index (AOI); p < 0.01), increased HDL particles numbers 2.8-fold (p < 0.0001), reduced HDL-bound APOM (−23%; p < 0.0001), and increased LDL oxidation 1.7-fold (p < 0.0001). These parameters remained unchanged in animals on HC diet alone up to day 40, while AOI deteriorated up to day 25 (−30%). The switch to NC diet reversed HDL dysfunction, restored apolipoprotein M content and particle numbers, and normalized cholesterol levels at day 40. Rosuvastatin improved HDL, AOI, and apolipoprotein M content. Apolipoprotein A-I and apolipoprotein C-III remained unchanged. Lowering LDL-C levels with a low-fat diet rescues HDL CEC and antioxidant potential, while the addition of rosuvastatin enhances HDL antioxidant capacity in a pig model of hypercholesterolemia. Both strategies restore HDL-bound apolipoprotein M content.
Asunto(s)
Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Apolipoproteínas M , Colesterol/uso terapéutico , HDL-Colesterol , Dieta , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/tratamiento farmacológico , Hipercolesterolemia/etiología , Lipoproteínas HDL/uso terapéutico , Lipoproteínas LDL , Modelos Animales , Rosuvastatina Cálcica/farmacología , Rosuvastatina Cálcica/uso terapéutico , PorcinosRESUMEN
Microvesicles (MV) contribute to cell-to-cell communication through their transported proteins and nucleic acids. MV, released into the extracellular space, exert paracrine regulation by modulating cellular responses after interaction with near and far target cells. MV are released at high concentrations by activated inflammatory cells. Different subtypes of human macrophages have been characterized based on surface epitopes being CD16+ macrophages associated with anti-inflammatory phenotypes. We have previously shown that low-density lipoprotein receptor-related protein 5 (LRP5), a member of the LDLR family that participates in lipid homeostasis, is expressed in macrophage CD16+ with repair and survival functions. The goal of our study was to characterize the cargo and tentative function of macrophage-derived MV, whether LRP5 is delivered into MV and whether these MV are able to induce inflammatory cell differentiation to a specific CD16- or CD16+ phenotype. We show, for the first time, that lipid-loaded macrophages release MV containing LRP5. LDL loading induces increased expression of macrophage pro-inflammatory markers and increased release of MV containing pro-inflammatory markers. Conditioning of fresh macrophages with MV released by Lrp5-silenced macrophages induced the transcription of inflammatory genes and reduced the transcription of anti-inflammatory genes. Thus, MV containing LRP5 induce anti-inflammatory phenotypes in macrophages.