RESUMO
BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI) with multivessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown. METHODS: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year. RESULTS: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCI. A primary end-point event occurred in 35 patients (8.5%) in the immediate group as compared with 68 patients (16.3%) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P<0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.0%) and 17 patients (4.1%), respectively, in the immediate group and in 22 patients (5.3%) and 39 patients (9.3%), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event. CONCLUSIONS: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275.).
Assuntos
Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/cirurgia , Vasos Coronários/cirurgia , Europa (Continente) , Insuficiência Cardíaca/etiologia , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/cirurgia , Revascularização Miocárdica/efeitos adversos , Revascularização Miocárdica/métodos , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Intervenção Coronária Percutânea/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Acidente Vascular Cerebral/etiologia , Fatores de Tempo , Resultado do Tratamento , Tempo para o TratamentoRESUMO
BACKGROUND: Left atrial appendage closure (LAAC) represents an alternative to oral anticoagulation for stroke prevention in patients with non-valvular atrial fibrillation (AF). While transoesophageal echocardiography is the current standard for guiding LAAC procedures, several centers have employed fluoroscopic guidance alone. However, data on long-term outcomes are lacking. METHODS: A total of 536 patients with AF undergoing LAAC and with available data on long-term follow-up were included in the retrospective, single-center analysis. Outcomes of patients undergoing fluoroscopy-guided LAAC were compared with those undergoing echocardiography guided LAAC. Time-dependent analysis was performed with the Kaplan-Meier method. RESULTS: A total of 234 (44%) and 302 (56%) patients were treated with echocardiography and fluoroscopy guidance, respectively. Baseline characteristics did not differ between the two groups. Procedural success rates were high in both groups (97% of fluoroscopy vs. 98% of echocardiography guided procedures; p = 0.92) and rates of relevant peri-device leaks (p = 0.50) and device-related thrombus formation (p = 0.22) did not differ between groups. Median clinical follow-up time was 48 (IQR 19-73) months. Rates of all-cause mortality (p = 0.15, HR 0.83, CI 0.64-1.07) and stroke (p = 0.076, HR 2.23, CI 0.90-5.54) were comparable among groups. CONCLUSION: LAAC with fluoroscopy guidance alone is equally safe and leads to similar clinical outcome compared to LAAC with additional echocardiography guidance.
Assuntos
Apêndice Atrial , Fibrilação Atrial , Cateterismo Cardíaco , Ecocardiografia Transesofagiana , Radiografia Intervencionista , Acidente Vascular Cerebral , Ultrassonografia de Intervenção , Humanos , Apêndice Atrial/diagnóstico por imagem , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/mortalidade , Fibrilação Atrial/complicações , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/terapia , Estudos Retrospectivos , Fluoroscopia , Masculino , Feminino , Idoso , Fatores de Tempo , Resultado do Tratamento , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/instrumentação , Acidente Vascular Cerebral/prevenção & controle , Acidente Vascular Cerebral/etiologia , Ultrassonografia de Intervenção/efeitos adversos , Fatores de Risco , Radiografia Intervencionista/efeitos adversos , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Oclusão do Apêndice Atrial EsquerdoRESUMO
OBJECTIVES: The aim of this study was to determine the role of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the prognostication of patients ≥80 years of age undergoing percutaneous coronary intervention (PCI). BACKGROUND: Elderly patients with coronary artery disease in need of PCI represent a growing patient population. Advanced risk prediction in this frail and comorbid patient population is important. METHODS: A total of 460 consecutive patients ≥80 years of age undergoing PCI for acute (ACS) or chronic coronary syndromes (CCS) at the University Hospital Zurich, Switzerland, between January 2016 and December 2018 and with available baseline NT-proBNP levels were included in the analysis. Patients were stratified according to baseline NT-proBNP levels. The primary endpoint was all-cause mortality at a median follow-up of 33 (interquartile range: 3-392) days. RESULTS: Median baseline NT-proBNP levels were 1411 (457-3984) ng/L. All-cause mortality was 7.8% in the lowest and 27.8% in the highest NT-proBNP quartile group (p < 0.001). In patients with ACS, all-cause mortality was 4.8% and 30.4% in the lowest and the highest NT-proBNP quartile (p < 0.001), and corresponding rates in patients with CCS were 11.1% and 22.2% (p = 0.38). In multivariable Cox regression analysis, baseline NT-proBNP levels were independently associated with an increased risk of all-cause mortality (adjusted hazard ratio: 1.00, 95% confidence interval: 1.00-1.00, p = 0.04). CONCLUSIONS: Baseline NT-proBNP levels were identified as independent predictor of mortality in elderly (≥80 years) patients undergoing PCI. Hence, baseline NT-proBNP allows for the identification of a high-risk elderly patient subset.
Assuntos
Peptídeo Natriurético Encefálico , Intervenção Coronária Percutânea , Idoso , Biomarcadores , Humanos , Fragmentos de Peptídeos , Intervenção Coronária Percutânea/efeitos adversos , Prognóstico , Resultado do TratamentoRESUMO
We report the case of a 78-year-old female with Sapien 3 transcatheter heart valve implantation in the transcaval approach. In this setting, we describe the step-by-step management and technique of the transcaval transcatheter aortic valve implantation.
Assuntos
Estenose da Valva Aórtica , Doença da Válvula Aórtica Bicúspide , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Idoso , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Feminino , Humanos , Substituição da Valva Aórtica Transcateter/métodos , Resultado do TratamentoRESUMO
OBJECTIVES: The number of elderly patients undergoing coronary revascularization is steadily increasing, and data on the impact of gender on outcomes are scarce. This study sought to assess gender-related differences in outcomes in elderly patients with acute coronary syndromes (ACS). METHODS: We investigated outcomes in elderly ACS patients referred for coronary angiography and prospectively enrolled in the Swiss ACS Cohort between December 2009 and October 2012. Adjudicated major adverse cardiovascular and cerebrovascular events (MACCE) included all-cause death, non-fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke. RESULTS: Among 2,168 patients recruited, 481 (22%) patients were >75 years of age (37% women). In patients >75 years, 1-year MACCE rates were 15% and 23% in women and men (OR 0.59, 95% CI 0.36-0.97, P = 0.04), respectively, and differences remained significant after adjustments for baseline variables (adjusted OR 0.48, 95% CI 0.26-0.90, P = 0.02). Women >75 years had a lower cardiovascular mortality (6% versus 12%, adjusted OR 0.31, 95% CI 0.12-0.81, P = 0.02). In patients ≤75 years, 1-year MACCE rates did not differ between gender (10% and 8% for women and men, adjusted OR 1.28, 95% CI 0.77-2.14, P = 0.34). Rates of TIMI major bleeding for women and men were 4% and 4% in patients >75 years (P = 0.96), and 5% and 3% in those ≤75 years (P = 0.11). CONCLUSIONS: The low rates of MACCE observed in elderly women in this patient cohort suggest that with current interventional strategies the gender gap in ACS management has been attenuated.
Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Síndrome Coronariana Aguda/terapia , Angiografia Coronária/tendências , Ponte de Artéria Coronária/tendências , Disparidades em Assistência à Saúde/tendências , Intervenção Coronária Percutânea/tendências , Encaminhamento e Consulta/tendências , Síndrome Coronariana Aguda/mortalidade , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Ponte de Artéria Coronária/efeitos adversos , Ponte de Artéria Coronária/mortalidade , Feminino , Humanos , Masculino , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Suíça , Resultado do TratamentoRESUMO
Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.
Assuntos
Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/tratamento farmacológico , Terapia de Alvo Molecular , RNA não Traduzido/antagonistas & inibidores , RNA não Traduzido/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/genética , Inativação Gênica , Humanos , MicroRNAs/sangue , Medicina de Precisão , Prognóstico , RNA Longo não Codificante/sangue , RNA Interferente Pequeno/uso terapêutico , RNA não Traduzido/uso terapêutico , Pesquisa Translacional BiomédicaRESUMO
AIMS: MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome has not been performed in patients with an acute coronary syndrome (ACS). METHODS AND RESULTS: In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case-control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels (P = 0.038) were decreased, whereas miR-320a (P = 0.047) and miR-660-5p (P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR-660-5p has been related to active platelet production. This suggests that miR-26b-5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls [area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672]. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases. CONCLUSION: This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI.
Assuntos
MicroRNA Circulante/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Estudos Prospectivos , Recidiva , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Resultado do TratamentoRESUMO
AIMS: Several intracellular mediators have been implicated as new therapeutic targets against myocardial ischaemia and reperfusion injury. However, clinically effective salvage pathways remain undiscovered. Here, we focused on the potential role of the adaptor protein p66(Shc) as a regulator of myocardial injury in a mouse model of cardiac ischaemia and reperfusion. METHODS AND RESULTS: Adult male p66(Shc) deficient (p66(Shc) (-/-)) and C57Bl/6 wild-type (WT) mice were exposed to 30, 45, or 60 min of ischaemia and reperfusion (5, 15 min, or 24 h). Infarct size, systemic and intracardiac inflammation and oxidants, as well as cytosolic and mitochondrial apoptotic pathways were investigated. Following 30, but not 45 or 60 min of ischaemia, genetic p66(Shc) deficiency was associated with larger infarcts. In WT mice, in vivo p66(Shc) knock down by siRNA with transient protein deficiency confirmed these findings. P66(Shc) inhibition was not associated with any modification in post-infarction inflammation, oxidative burst nor cardiac vessel density or structure. However, in p66(Shc) (-/-) mice activation of the protective and anti-apoptotic Reperfusion Injury Salvage Kinases and Survivor Activating Factor Enhancement pathways were blunted and mitochondrial swelling and cellular apoptosis via the caspase-3 pathway increased compared with WT. CONCLUSIONS: Genetic deletion of p66(Shc) increased susceptibility to myocardial injury in response to short-term ischaemia and reperfusion in mice. Still, additional studies are needed for assessing the role of this pathway in acute coronary syndrome patients.
Assuntos
Deleção de Genes , Traumatismo por Reperfusão Miocárdica/genética , Proteínas Adaptadoras da Sinalização Shc/genética , Animais , Apoptose/genética , Biomarcadores/metabolismo , Técnicas de Silenciamento de Genes , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos Endogâmicos C57BL , Dilatação Mitocondrial/genética , Reperfusão Miocárdica/métodos , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/metabolismo , Fator de Transcrição STAT3/genética , Proteínas Adaptadoras da Sinalização Shc/deficiência , Proteínas Adaptadoras da Sinalização Shc/metabolismo , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src , Troponina I/metabolismoRESUMO
Several peripheral blood mononuclear cell (PBMC)-derived cell populations can promote angiogenesis, and differences in CD34(+) or CD14(+) surface expression have been used to separate PBMC subpopulations in this respect. AngiomiRs, microRNAs regulating angiogenesis, are key regulators of angiogenic processes. The present study examines differential angiomiR expression/secretion from CD34(+)/CD14(+), CD34(+)/CD14(-), CD34(-)/CD14(+), and CD34(-)/CD14(-) PBMC subsets and their relevance for different proangiogenic properties. Notably, both circulating human CD34(+)/14(+) and CD34(+)/14(-) PBMC subsets and their supernatants exerted more potent proangiogenic effects compared with CD34(-) PBMC subsets. MiR-126 was identified as most differentially expressed angiomiR in CD34(+) compared with CD34(-) PBMC subsets, determined by miR-array and RT-PCR validation. Modulation of miR-126 by anti-miR-126 or miR-mimic-126 treatment resulted in significant loss or increase of proangiogenic effects of CD34(+) PBMCs. MiR-126 levels in supernatants of CD34(+) PBMC subsets were substantially higher compared with CD34(-) PBMC subsets. MiR-126 was secreted in microvesicles/exosomes, and inhibition of their release impaired CD34(+) PBMCs proangiogenic effects. Notably, high-glucose treatment or diabetes reduced miR-126 levels of CD34(+) PBMCs, associated with impaired proangiogenic properties that could be rescued by miR-mimic-126 treatment. The present findings provide a novel molecular mechanism underlying increased proangiogenic effects of CD34(+) PBMCs, that is, angiomiR-126 expression/secretion. Moreover, an alteration of angiomiR-126 expression in CD34(+) PBMCs in diabetes provides a novel pathway causing impaired proangiogenic effects.
Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Leucócitos Mononucleares/fisiologia , MicroRNAs/fisiologia , Neovascularização Fisiológica/fisiologia , Animais , Antígenos CD34/análise , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Células Endoteliais/citologia , Exossomos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/farmacologia , Hemangioblastos/citologia , Hemangioblastos/metabolismo , Humanos , Leucócitos Mononucleares/classificação , Receptores de Lipopolissacarídeos/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , MicroRNAs/biossíntese , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Neovascularização Fisiológica/genética , Organismos Livres de Patógenos Específicos , TransfecçãoAssuntos
Diabetes Mellitus Tipo 1 , Doenças Vasculares , Adolescente , Humanos , Inflamação , Lipoproteínas HDLRESUMO
BACKGROUND: Impaired re-endothelialization and stent thrombosis are a safety concern associated with drug-eluting stents (DES). PI3K/p110α controls cellular wound healing pathways, thereby representing an emerging drug target to modulate vascular homoeostasis after injury. METHODS AND RESULTS: PI3K/p110α was inhibited by treatment with the small molecule inhibitor PIK75 or a specific siRNA. Arterial thrombosis, neointima formation, and re-endothelialization were studied in a murine carotid artery injury model. Proliferation and migration of human vascular smooth muscle cell (VSMC) and endothelial cell (EC) were assessed by cell number and Boyden chamber, respectively. Endothelial senescence was evaluated by the ß-galactosidase assay, endothelial dysfunction by organ chambers for isometric tension. Arterial thrombus formation was delayed in mice treated with PIK75 when compared with controls. PIK75 impaired arterial expression and activity of tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1); in contrast, plasma clotting and platelet aggregation did not differ. In VSMC and EC, PIK75 inhibited expression and activity of TF and PAI-1. These effects occurred at the transcriptional level via the RhoA signalling cascade and the transcription factor NFkB. Furthermore, inhibition of PI3K/p110α with PIK75 or a specific siRNA selectively impaired proliferation and migration of VSMC while sparing EC completely. Treatment with PIK75 did not induce endothelial senescence nor inhibit endothelium-dependent relaxations. In line with this observation, treatment with PIK75 selectively inhibited neointima formation without affecting re-endothelialization following vascular injury. CONCLUSION: Following vascular injury, PI3K/p110α inhibition selectively interferes with arterial thrombosis and neointima formation, but not re-endothelialization. Hence, PI3K/p110α represents an attractive new target in DES design.
Assuntos
Stents Farmacológicos , Inibidores de Fosfoinositídeo-3 Quinase , Trombose/enzimologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiotaxia/efeitos dos fármacos , Endotélio Vascular/enzimologia , GTP Fosfo-Hidrolases/metabolismo , Hidrazonas/farmacologia , Imunossupressores/farmacologia , Leucócitos Mononucleares/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Neointima/enzimologia , Óxido Nítrico/biossíntese , Paclitaxel/farmacologia , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Sirolimo/farmacologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Quinase Induzida por NF-kappaBRESUMO
BACKGROUND: MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34(+) cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34(+) cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. METHODS AND RESULTS: Angiogenic EOCs and CD34(+) cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34(+) cells. Anti-miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. CONCLUSIONS: The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34(+) cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.
Assuntos
Insuficiência Cardíaca/fisiopatologia , Coração/fisiopatologia , MicroRNAs/fisiologia , Neovascularização Fisiológica , Proteínas Adaptadoras de Transdução de Sinal , Animais , Antígenos CD34/análise , Doença Crônica , Feminino , Proteínas de Homeodomínio/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Masculino , Proteínas de Membrana/fisiologia , Camundongos , MicroRNAs/análise , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Isquemia Miocárdica/fisiopatologiaRESUMO
In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell-based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future.
Assuntos
Insuficiência Cardíaca/terapia , Transplante de Células-Tronco/métodos , Transplante de Medula Óssea/métodos , Células-Tronco Embrionárias/transplante , Humanos , Transplante de Células-Tronco Mesenquimais/métodos , Condicionamento Pré-Transplante/métodosRESUMO
Vitamin D is essential to bone health and is a major regulator of calcium homeostasis. Many recent reports demonstrated worldwide high rates of vitamin D deficiency, but few studies have been published on the vitamin D status of orthopaedic patients. The present study aimed to investigate the extent of hypovitaminosis D of orthopaedic patients and possible variations in vitamin D status according to the body region which was scheduled to undergo surgery. We measured the vitamin D level of 1119 patients consecutively admitted to an orthopaedic surgery department of a university hospital in Germany in 2011. The prevalence of normal (< or =30 ng/ml), insufficient (20-30 ng/ml) and deficient (< or =20 ng/ml) 25-OH-D levels was determined. Serum Vitamin D levels and rates of insufficiency and deficiency were compared between the different cohorts using two-tailed tests. The level of significance was set at p < or =0.05. The serum 25-OH-D levels for all participants were normally distributed, with a mean of 2057 ng/ml. Overall, we noted an alarmingly high rate of vitamin D insufficiency or deficiency among orthopaedic patients. No significant difference was found related with the various body regions scheduled to undergo surgery. Given the well-known effects of vitamin D on bone metabolism and muscle health, vitamin D insufficiency may negatively affect patients.
Assuntos
Doenças Ósseas/epidemiologia , Deficiência de Vitamina D/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Ósseas/cirurgia , Criança , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Procedimentos Ortopédicos , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND: As numbers and complexity of percutaneous coronary interventions are constantly increasing, optimal radiation protection is required to ensure operator safety. Suspended radiation protection systems (SRPS) and protective scatter-radiation absorbing drapes (PAD) are novel methods to mitigate fluoroscopic scattered radiation exposure. The aim of the study was to investigate the effectiveness regarding radiation protection of a SRPS and a PAD in comparison with conventional protection. METHODS: A total of 229 cardiac catheterization procedures with SRPS (N = 73), PAD (N = 82) and standard radiation protection (N = 74) were prospectively included. Real-time dosimeter data were collected from the first operator and the assistant. Endpoints were the cumulative operator exposure relative to the dose area product [standardized operator exposure (SOE)] for the first operator and the assistant. RESULTS: For the first operator, the SRPS and the PAD significantly decreased the overall SOE compared to conventional shielding by 93.9% and 66.4%, respectively (P < 0.001). The protective effect of the SRPS was significantly higher compared to the PAD (P < 0.001). For the assistant, the SRPS and the PAD provided a not statistically significant reduction compared to conventional shielding in the overall SOE by 38.0% and 30.6%, respectively. CONCLUSIONS: The SRPS and the PAD enhance radiation protection significantly compared to conventional protection. In most clinical scenarios, the protective effect of SRPS is significantly higher than the additional protection provided by the PAD. Comparison of the additional radiation protection provided by protective scatter-radiation absorbing drapes (PAD) and the suspended radiation protection system (SRPS) system over standard protection with lead aprons.
Assuntos
Exposição Ocupacional , Exposição à Radiação , Proteção Radiológica , Humanos , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/prevenção & controle , Exposição à Radiação/efeitos adversos , Exposição à Radiação/prevenção & controle , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/métodos , Doses de Radiação , Radiografia Intervencionista/efeitos adversosRESUMO
Ischemic cardiomyopathy, driven by loss of cardiomyocytes and inadequate proliferative response, persists to be a major global health problem. Using a functional high-throughput screening, we assessed differential proliferative potential of 2019 miRNAs after transient hypoxia by transfecting both miR-inhibitor and miR-mimic libraries in human iPSC-CM. Whereas miR-inhibitors failed to enhance EdU uptake, overexpression of 28 miRNAs substantially induced proliferative activity in hiPSC-CM, with an overrepresentation of miRNAs belonging to the primate-specific C19MC-cluster. Two of these miRNAs, miR-515-3p and miR-519e-3p, increased markers of early and late mitosis, indicative of cell division, and substantially alter signaling pathways relevant for cardiomyocyte proliferation in hiPSC-CM.
RESUMO
Personalized Therapeutic Concepts in Chronic Coronary Syndromes Abstract. Chronic coronary syndromes (CCS) are related to substantial morbidity and mortality. Myocardial ischemia in CCS is caused by either obstructive or non-obstructive alterations of the coronary arteries, including both morphological and functional changes of epicardial vessels and the coronary microvasculature. Diagnostic algorithms of patients with suspected CCS include non-invasive and invasive imaging and functional testing. Therapeutic management comprises lifestyle changes, optimal medical therapy, and coronary revascularization when indicated. This review summarizes the contemporary management of patients with CCS, focusing on the role of invasive assessment and treatment.
Assuntos
Doença da Artéria Coronariana , Isquemia Miocárdica , Intervenção Coronária Percutânea , Angiografia Coronária , Doença da Artéria Coronariana/terapia , Coração , Humanos , SíndromeRESUMO
The retrograde valve-crossing of a stenotic aortic valve is a crucial step in the transcatheter aortic valve implantation procedure. In addition to being time-consuming and associated with an increased stroke risk, inappropriate valve-crossing may cause devastating complications. This tutorial review summarizes systematic and detailed techniques to cross the aortic valve. First, the main challenges in retrograde valve-crossing are depicted. Next, a step-by-step guidance on valve-crossing is provided, along with an in-depth description of the three-dimensional anatomy under a two-dimensional fluoroscopy view. Finally, modified techniques for different anatomies are described.
Assuntos
Estenose da Valva Aórtica , Próteses Valvulares Cardíacas , Substituição da Valva Aórtica Transcateter , Algoritmos , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/cirurgia , Fluoroscopia , Humanos , Substituição da Valva Aórtica Transcateter/efeitos adversos , Substituição da Valva Aórtica Transcateter/métodos , Resultado do TratamentoRESUMO
Yohimbine is a highly selective and potent α2-adrenoceptor antagonist, which is usually treated as an adjunction for impotence, as well for weight loss and natural bodybuilding aids. However, it was recently reported that Yohimbine causes myocardial injury and controversial results were reported in the setting of cardiac diseases. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) as a model system to explore electrophysiologic characterization after exposure to Yohimbine. HiPSC-CMs were differentiated by employment of inhibitory Wnt compounds. For analysis of electrophysiological properties, conventional whole-cell patch-clamp recording was used. Specifically, spontaneous action potentials, pacemaker currents (If), sodium (Na+) channel (INa), and calcium (Ca++) channel currents (ICa) were assessed in hiPSC-CMs after exposure to Yohimbine. HiPSC-CMs expressed sarcomeric-α-actinin and MLC2V proteins, as well as exhibited ventricular-like spontaneous action potential waveform. Yohimbine inhibited frequency of hiPSC-CMs spontaneous action potentials and significantly prolonged action potential duration in a dose-dependent manner. In addition, rest potential, threshold potential, amplitude, and maximal diastolic potential were decreased, whereas APD50/APD90 was prolonged. Yohimbine inhibited the amplitude of INa in low doses (IC50 = 14.2 µM, n = 5) and inhibited ICa in high doses (IC50 = 139.7 µM, n = 5). Whereas Yohimbine did not affect the activation curves, treatment resulted in left shifts in inactivation curves of both Na+ and Ca++ channels. Here, we show that Yohimbine induces direct cardiotoxic effects on spontaneous action potentials of INa and ICa in hiPSC-CMs. Importantly, these effects were not mediated by α2-adrenoceptor signaling. Our results strongly suggest that Yohimbine directly and negatively affects electrophysiological properties of human cardiomyocytes. These findings are highly relevant for potential application of Yohimbine in patients with atrioventricular conduction disorder.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Antagonistas de Receptores Adrenérgicos alfa 2/toxicidade , Arritmias Cardíacas/induzido quimicamente , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Ioimbina/toxicidade , Arritmias Cardíacas/metabolismo , Arritmias Cardíacas/fisiopatologia , Canais de Cálcio/metabolismo , Cardiotoxicidade , Linhagem Celular , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Miócitos Cardíacos/metabolismo , Canais de Sódio/metabolismoRESUMO
Inflammasomes are crucial gatekeepers of the immune response, but their maladaptive activation associates with inflammatory pathologies. Besides canonical activation, monocytes can trigger non-transcriptional or rapid inflammasome activation that has not been well defined in the context of acute myocardial infarction (AMI). Rapid transcription-independent inflammasome activation induced by simultaneous TLR priming and triggering stimulus was measured by caspase-1 (CASP1) activity and interleukin release. Both classical and intermediate monocytes from healthy donors exhibited robust CASP1 activation, but only classical monocytes produced high mature interleukin-18 (IL18) release. We also recruited a limited number of coronary artery disease (CAD, n=31) and AMI (n=29) patients to evaluate their inflammasome function and expression profiles. Surprisingly, monocyte subpopulations isolated from blood collected during percutaneous coronary intervention (PCI) from AMI patients presented diminished CASP1 activity and abrogated IL18 release despite increased NLRP3 gene expression. This unexpected attenuated rapid inflammasome activation was accompanied by a significant increase of TNFAIP3 and IRAKM expression. Moreover, TNFAIP3 protein levels of circulating monocytes showed positive correlation with high sensitive troponin T (hsTnT), implying an association between TNFAIP3 upregulation and the severity of tissue injury. We suggest this monocyte attenuation to be a protective phenotype aftermath following a very early inflammatory wave in the ischemic area. Damage-associated molecular patterns (DAMPs) or other signals trigger a transitory negative feedback loop within newly recruited circulating monocytes as a mechanism to reduce post-injury tissue damage.