The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually

BACKGROUND: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. AIMS: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. METHODS: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. RESULTS: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. CONCLUSION: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease.

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually.

BACKGROUND: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. AIMS: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. METHODS: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. RESULTS: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. CONCLUSION: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease.

Serial Assessment of Coronary Artery Healing of a Biodegradable Polymer Drug-Eluting Stent at 1, 2, and 3 Months by Optical Coherence Tomography (OCT)-The REPAIR Trial.

BACKGROUND: Although first-generation drug-eluting stent (DES) devices have effectively achieved their main goal of reducing restenosis, their safety has been limited by suboptimal polymer biocompatibility, delayed stent endothelialization, and local drug toxicity, which ultimately prompted the development of new-generation DES options carrying biocompatible or even biodegradable polymers. AIMS: We sought to assess the vessel-healing pattern of the novel sirolimus-eluting Inspiron DES (Scitech Medical) using serial optical coherence tomography (OCT) and assuming the hypothesis that this thin-strut (75-µm), biodegradable-polymer DES promotes a faster healing, with very early strut coverage. METHODS: This is a prospective, multicenter, open-label, single-arm study enrolling 68 patients who underwent percutaneous coronary intervention guided by OCT. These patients were consecutively assigned into 3 groups. The first group had its OCT imaging follow-up performed at 3 months, the second group at 2 months, and the third group at 1 month. RESULTS: Mean age was 59.5 years, 70.6% were male, 41.2% had type 2 diabetes, and 29.4% presented with acute coronary syndrome. A total of 72 lesions were treated and 1.06 stents were implanted per patient. OCT assessment of the stents at 1, 2, and 3 months showed a strut coverage of 90.41%, 93.96%, and 97.21%, respectively (P=.04). CONCLUSION: The Inspiron DES showed an early strut healing pattern, with >90% of the struts covered by neointima within the first month and with almost all struts covered by the third month.

Serial assessment of coronary artery healing of a biodegradable polymer drug-eluting stent at 1, 2, and 3 months by optical coherence tomography (OCT)­the REPAIR trial

BACKGROUND: Although first-generation drug-eluting stent (DES) devices have effectively achieved their main goal of reducing restenosis, their safety has been limited by suboptimal polymer biocompatibility, delayed stent endothelialization, and local drug toxicity, which ultimately prompted the development of new-generation DES options carrying biocompatible or even biodegradable polymers. Aims. We sought to assess the vessel-healing pattern of the novel sirolimus-eluting Inspiron DES (Scitech Medical) using serial optical coherence tomography (OCT) and assuming the hypothesis that this thin-strut (75-µm), biodegradable-polymer DES promotes a faster healing, with very early strut coverage. METHODS. This is a prospective, multicenter, open-label, single-arm study enrolling 68 patients who underwent percutaneous coronary intervention guided by OCT. These patients were consecutively assigned into 3 groups. The first group had its OCT imaging follow-up performed at 3 months, the second group at 2 months, and the third group at 1 month. RESULTS: Mean age was 59.5 years, 70.6% were male, 41.2% had type 2 diabetes, and 29.4% presented with acute coronary syndrome. A total of 72 lesions were treated and 1.06 stents were implanted per patient. OCT assessment of the stents at 1, 2, and 3 months showed a strut coverage of 90.41%, 93.96%, and 97.21%, respectively (P=.04). CONCLUSION: The Inspiron DES showed an early strut healing pattern, with >90% of the struts covered by neointima within the first month and with almost all struts covered by the third month.

Experiência inicial com a extensão de cateter-guia ExpressmanTM em um centro terciário de cardiologia de alto volume / Initial experience with the ExpressmanTM guide catheter extension in a high-volume tertiary cardiology center

Introdução: As extensões de cateter-guia fornecem maior suporte em intervenções coronárias percutâneas complexas. O ExpressmanTM é uma nova extensão de cateter-guia, e nosso objetivo foi avaliar o impacto de seu uso no sucesso do procedimento e nas complicações ocorridas em um centro de referência de alto volume. Métodos: Analisamos os dados de todos os procedimentos consecutivos em que foi usada uma extensão de cateter-guia ExpressmanTM. A decisão de usar uma extensão de cateter-guia ficou a critério do operador. O sucesso do dispositivo foi definido como o posicionamento bem-sucedido da extensão de cateter-guia dentro do vaso coronário, e o sucesso do procedimento foi definido como <20% de estenose residual e fluxo TIMI 3, sem perda significativa de ramos laterais. Eventos adversos cardíacos e cerebrovasculares maiores foram definidos como a combinação morte por todas as causas, infarto do miocárdio, revascularização do vaso-alvo e acidente vascular cerebral. Resultados: Foram incluídos 34 procedimentos entre abril de 2022 e janeiro de 2023. A maioria dos pacientes era do sexo masculino (59%), e a média de idade foi 66,5 anos. O uso da extensão de cateter-guia não foi planejado antes do procedimento em 17 procedimentos (50%). Os motivos mais comuns para o uso da extensão de cateter-guia foram angulação ou tortuosidade do vaso-alvo e posição desfavorável do óstio coronário. O sucesso do dispositivo foi obtido em 88% e o da revascularização, em 91%. Houve três oclusões de ramo lateral. Durante o acompanhamento clínico intra-hospitalar, não ocorreram sangramento e nem eventos adversos cardíacos e cerebrovasculares maiores. Conclusão: O sucesso do dispositivo e do procedimento foi alto, e a taxa de complicações foi baixa. O uso da extensão de cateter-guia como técnica de resgate em anatomias complexas permitiu o sucesso do procedimento na maioria dos pacientes que, de outro modo, não poderiam ser tratados.

Background: Guide catheter extensions provide increased support in complex percutaneous coronary interventions. The ExpressmanTM is a novel guide catheter extension and the objective was to assess the impact of its use on procedural success and complications in a high-volume reference center. Methods: We analyzed data from all consecutive procedures in which the ExpressmanTM guide catheter extension was used. The decision to use a guide catheter extension was at operator's discretion. Device success was defined as the successful positioning of the guide catheter extension in the coronary vessel and procedural success was defined as <20% residual stenosis and TIMI 3 flow, with no loss of significant side branches. Major adverse cardiac and cerebrovascular events were defined as the composite of all-cause death, myocardial infarction, target vessel revascularization and stroke. Results: From April 2022 to January 2023, 34 procedures were included. The majority of the patients were male (59%) and the mean age was 66.5 years. Guide catheter extension use was not planned pre-procedure in 17 procedures (50%). The most common reasons for guide catheter extension use were target vessel angulation or tortuosity and unfavorable coronary ostium position. Device success was obtained in 88% and revascularization success in 91%. There were three side branch occlusions. During in-hospital clinical follow-up, no major adverse cardiac and cerebrovascular events or major bleeding occurred. Conclusion: The device success and procedural success were high and the rate of complications was low. Guide catheter extension use as bailout technique in complex anatomies allowed procedural success in the vast majority of otherwise untreatable patients.

Biomarker-associated Monocyte Inflammatory Signaling in Myocardial Infarction

Abstract Background: Monocytes are essential components in inflammatory signaling, and their recruitment is crucial in the signaling pathway, which directs and determines cell adhesion to the activated endothelium. A better understanding of the correlation between monocyte subsets and inflammatory signaling in patients with atherosclerotic disease in acute coronary syndrome (ACS) is essential for the development of more effective therapies for the prevention and treatment of cardiovascular diseases. Objective: To analyze differences between biomarkers and monocyte activation in the setting of ischemic heart disease. Methods: This was a case-control study comparing biomarkers and monocyte subsets between patients with ACS with and without ST-segment elevation and individuals without coronary stenosis. The nonparametric Kruskal-Wallis test was used to assess differences between groups, and Dunn's post hoc test was used to identify which groups were different. Cuzick's test for ordered group trends was used to assess falling or rising trends. Participants were classified into 3 groups: control (0); non-ST-elevation myocardial infarction (NSTEMI) (1); ST-elevation myocardial infarction (STEMI) D1 (2). Results: Forty-seven patients with ACS and 19 controls with no obstructive lesions on coronary angiography were recruited. Monocyte profile assessment was statistically different regarding time of symptom onset and the presence or absence of atherosclerotic disease (Kruskal-Wallis, p = 0.0009). Dunn's post hoc test showed a significant difference between the control group and the STEMI D1 (p = 0.0014), STEMI D3 (p = 0.0036), and STEMI D7 (p = 0.0195) groups, corresponding to a 2-fold increase in classical (p = 0.0022) and nonclassical (p = 0.0031) monocytes compared with controls. For classical monocytes, there was a difference between the control group and all STEMI groups and between the NSTEMI group and the STEMI D1, D3, and D7 groups. For nonclassical monocytes, there was a difference between the control group and the STEMI D7 group (p = 0.0056) and between the NSTEMI group and the STEMI D7 group (p = 0.0166). Conclusion: This study found that there was an increase in total and classical monocyte mobilization at the time of acute myocardial infarction in patients with ACS.

Reparação tecidual em pacientes submetidos à intervenção coronária percutânea com stent eluidor de sirolimus e polímero bioabsorvível: avaliação seriada através da tomografia de coerência óptica (ESTUDO REPAIR) / Tissue repair in patients undergoing percutaneous coronary intervention with sirolimus-eluting stent and bioabsorbable polymer: serial evaluation using optical coherence tomography (REPAIR STUDY)

INTRODUÇÃO: Os stents farmacológicos de novas gerações passaram por aprimoramentos para melhorar seu perfil de cicatrização, visando melhorar a segurança da intervenção coronária percutânea (ICP) relacionada à trombose de stents. Estes dispositivos passaram a ter hastes mais finas, polímeros mais biocompatíveis e mudanças nas doses e cinética de liberação dos fármacos. O stent Inspiron® compreende uma plataforma metálica de Cromo-Cobalto com hastes finas (75 mm), coberta em sua face abluminal por polímero bioabsorvível (PLLA + PLGA) e que libera baixa dose de sirolimus (80% da dose em 30 dias). OBJETIVO: Documentar o padrão de cobertura tecidual das hastes do stent Inspiron® através da avaliação seriada com tomografia de coerência óptica (TCO). Nossa hipótese é que stents com hastes finas e com polímeros bioabsorvíveis apresentam cobertura tecidual rápida e homogênea. MÉTODOS: Estudo prospectivo, multicêntrico que recrutou pacientes tratados com o stent Inspiron®, divididos em 3 grupos. O primeiro grupo realizou reestudo com TCO após 3 meses, o segundo após 2 meses e o terceiro após 1 mês. O desfecho primário foi a comparação entre o percentual de hastes cobertas pela neoíntima nos diferentes tempos pré-determinados. As análises foram realizadas em um corelab independente, cego em relação ao tempo em que o reestudo foi realizado. RESULTADOS: Foram tratadas 72 lesões em 68 pacientes. A média de idade foi de 59,5 anos, sendo 41,2% diabéticos e 29,4% com síndrome coronária aguda. Em relação ao desfecho primário, 90,41 ± 8,8% das hastes estavam cobertas após 1 mês, 93,96 ± 8,73% após 2 meses e 97,21 ± 3,03% após 3 meses (p = 0,042). A espessura da hiperplasia neointimal foi de 60 mm no 1º mês, 90 mm no 2º mês e 120 mm no 3º mês, demonstrando que a cicatrização ocorreu de forma homogênea e controlada nos primeiros 3 meses enquanto a média de obstrução pela hiperplasia neointimal foi de 4,45%, 6,95% e 10,11% e a área de hiperplasia neointimal foi de 0,54 mm2, 0,85 mm2 e 1,16mm2 após 1, 2 e 3 meses respectivamente (figura 1). CONCLUSÃO: O stent Inspiron® apresenta ótimo padrão de cicatrização precoce, com > 90% das hastes cobertas por tecido neointimal no primeiro mês e com praticamente todas as hastes cobertas no terceiro mês. Estes dados servirão como base para formulação de ensaios clínicos randomizados para avaliar a eficácia e segurança da ICP em pacientes submetidos ao implante de stents de nova geração e tempo de dupla antiagregação abreviado.

Registro brasileiro para documentação das práticas de manejo de pacientes portadores de estenoses coronárias intermediárias (EMPIRE BRAZIL) / Brazilian registry for documentation of management practices for patients with intermediate coronary stenoses (EMPIRE BRAZIL)

INTRODUÇÃO: A proporção de pacientes submetidos à cinecoronariografia eletiva que necessitam complementação diagnóstica adicional para a tomada de decisão terapêutica é desconhecida no Brasil, assim como o seu manejo na prática clínica atual. OBJETIVOS: Avaliar a prevalência de estenoses coronárias intermediárias (40-70%) em pacientes submetidos à cinecoronariografia, e seu manejo atual nos diferentes níveis de suplementação de saúde no Brasil. MÉTODOS: Registro prospectivo, multicêntrico, de braço único, em que foram incluídos todos os pacientes consecutivos submetidos à cinecoronariografia entre JUN/21 e SET/21 em 5 hospitais de referência em Cardiologia no Brasil (2 públicos e 3 privados). O desfecho primário foi a ocorrência de eventos cardiovasculares adversos maiores (ECAM: morte, infarto, re-internação por recorrência de angina e revascularização não planejada da lesão alvo). RESULTADOS: 503 pacientes foram incluídos. A média das idades foi 63±11 anos, 69,8% são homens, 35,6% são diabéticos, e 44,1% se apresentaram com síndrome estável. Menos da metade (41,7%) possuíam alguma avaliação funcional prévia à cinecoronariografia. Algum grau de estenose coronária foi documentado em 421 pacientes (84%), dos quais 177 (42%) apresentavam redução luminal entre 40-70%. As informações clínicas e angiográficas foram consideradas insuficientes para tomada de decisão em 223 pacientes (44.3%). Destes, fisiologia invasiva foi realizada no momento da cinecoronariografia em 27 pacientes (12,1%), imagem intravascular em 5 (2,2%), avaliação funcional não invasiva solicitada para 32 (14,3%) e 161 (72,2%) liberados sem qualquer avaliação adicional. No seguimento médio de 180±68 dias, 148 pacientes foram contatados, e 18,9% apresentaram ECAM. Dentre os 148 pacientes sem resolução diagnóstica durante a cinecoronariografia, 28 pacientes (18,9%) permaneceram sintomáticos e necessitaram atendimento médico posterior, 17 (11,5%) foram hospitalizados, 6 (4,1%) sofreram revascularização não planejada, e 8 (5,4%) sofreram infarto fatal. CONCLUSÕES: Dentre os pacientes submetidos à cinecoronariografia, proporção não desprezível possui estenoses coronárias para as quais avaliação adicional é necessária para a tomada de decisão. A grande maioria destes pacientes é liberada sem qualquer investigação adicional. O tempo para complementação diagnóstica impacta na ocorrência de desfechos clínicos e qualidade de vida

Oxidized Low-Density Lipoprotein Induces Macrophage Production of Prothrombotic Microparticles.

Background Activated vascular cells produce submicron prothrombotic and proinflammatory microparticle vesicles. Atherosclerotic plaques contain high levels of microparticles. Plasma microparticle levels increase during acute coronary syndromes and the thrombotic consequences of plaque rupture likely involve macrophage-derived microparticles (MΦMPs). The activation pathways that promote MΦMP production remain poorly defined. This study tested the hypothesis that signals implicated in atherogenesis also stimulate MΦMP production. Methods and Results We stimulated human primary MΦs with proinflammatory cytokines and atherogenic lipids, and measured MΦMP production by flow cytometry. Oxidized low-density lipoprotein (oxLDL; 25 µg/mL) induced MΦMP production in a concentration-dependent manner (293% increase; P<0.001), and these oxLDL MΦMP stimulatory effects were mediated by CD36. OxLDL stimulation increased MΦMP tissue factor content by 78% (P<0.05), and oxLDL-induced MΦMP production correlated with activation of caspase 3/7 signaling pathways. Salvionolic acid B, a CD36 inhibitor and a CD36 inhibitor antibody reduced oxLDL-induced MΦMP by 67% and 60%, respectively. Caspase 3/7 inhibition reduced MΦMP release by 52% (P<0.01) and caspase 3/7 activation increased MΦMP production by 208% (P<0.01). Mevastatin pretreatment (10 µM) decreased oxLDL-induced caspase 3/7 activation and attenuated oxLDL-stimulated MΦMP production and tissue factor content by 60% (P<0.01) and 43% (P<0.05), respectively. Conclusions OxLDL induces the production of prothrombotic microparticles in macrophages. This process depends on caspases 3 and 7 and CD36 and is inhibited by mevastatin pretreatment. These findings link atherogenic signaling pathways, inflammation, and plaque thrombogenicity and identify a novel potential mechanism for antithrombotic effects of statins independent of LDL lowering.

MiR-4674 regulates angiogenesis in tissue injury by targeting p38K signaling in endothelial cells.

Neoangiogenesis is critical for tissue repair in response to injury such as myocardial ischemia or dermal wound healing. MicroRNAs are small noncoding RNAs and important regulators of angiogenesis under physiological and pathological disease states. Therefore, identification of microRNAs that may restore impaired angiogenesis in response to tissue injury may provide new targets for therapy. Using a microRNA microarray profiling approach, we identified a human-specific microRNA, miR-4674, that was significantly decreased in patients after myocardial tissue injury and had an endothelial cell (EC)-enriched expression pattern. Functionally, overexpression of miR-4674 markedly attenuated EC proliferation, migration, network tube formation, and spheroid sprouting, whereas blockade of miR-4674 had the opposite effects. Transcriptomic profiling, gene set enrichment analyses, bioinformatics, 3'-untranslated region (3'-UTR) reporter and microribonucleoprotein immunoprecipitation (miRNP-IP) assays, and small interfering RNA dependency studies revealed that miR-4674 regulates VEGF stimulated-p38 mitogen-activated protein kinase (MAPK) signaling and targets interleukin 1 receptor-associated kinase 1 (Irak1) and BICD cargo adaptor 2 (Bicd2) in ECs. Furthermore, Irak1 and Bicd2 were necessary for miR-4674-driven EC proliferation and migration. Finally, neutralization of miR-4674 increased angiogenesis, Irak1 and Bicd2 expression, and p38 phosphorylation in human skin organoids as a model of tissue injury. Collectively, targeting miR-4674 may provide a novel therapeutic target for tissue repair in pathological disease states associated with impaired angiogenesis.

MicroRNA-615-5p Regulates Angiogenesis and Tissue Repair by Targeting AKT/eNOS (Protein Kinase B/Endothelial Nitric Oxide Synthase) Signaling in Endothelial Cells.

Objective- In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and characterize microRNAs that regulate angiogenesis in response to tissue injury. Approach and Results- We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3' untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury. Conclusions- These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS-mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury. Visual Overview- An online visual overview is available for this article.

MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro- and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR-135a-3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR-135a-3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR-135-3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3'-UTR reporter and miRNA ribonucleoprotein complex -immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR-135a-3p inhibits the p38 signaling pathway in ECs by targeting huntingtin-interacting protein 1 (HIP1). Local delivery of miR-135a-3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR-135a-3p mimics impaired these effects. Finally, through gain- and loss-of-function studies in human skin organoids as a model of tissue injury, we demonstrated that miR-135a-3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR-135a-3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF-HIP1-p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.-Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA-135a-3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells.

Implante transcateter valvar aórtico (TAVI): onde estamos em 2018 / Transcatheter aortic valve implant (TAVI): where we are in 2018

Por cerca de 15 anos, o Implante Transcateter Valvar Aórtico (TAVI) passou por avanços tecnológicos, adquiriu experiência acumulada e tornou-se alternativa à cirurgia convencional. A principal indicação é a estenose aórtica degenerativa do idoso. Evidências atuais foram ampliadas para aqueles de risco intermediário e se tornaram mais robustas nos pacientes de alto risco e inoperáveis. Em situações específicas, como valva aórtica bicúspide, regurgitação aórtica pura, pacientes de baixo risco e bioprótese cirúrgica degenerada, os resultados ainda não são totalmente previsíveis, mas muito promissores. Os tipos de dispositivos atualmente liberados para uso clinico são divididos em: da geração inicial e os da nova geração, assim como em auto expansível, balão expansível e expansível mecanicamente. O sítio de acesso preferencial na atualidade é a via transfemoral. Outras alternativas de acessos também têm se mostrado viáveis e confiáveis. As principais complicações são vasculares, eventos neurológicos, distúrbios de condução e regurgitação paravalvar. Apesar da baixa incidência, a ruptura aórtica e a oclusão coronária são uma fonte de maior interesse, devido ao seu potencial impacto na morbimortalidade. A realização mais recente do procedimento em pacientes mais jovens faz necessária mais atenção à questões referentes à durabilidade e ao risco de trombose. Embora o TAVI ainda possa ser um procedimento complexo, após atingida experiência, existe a tendência de migração para uma abordagem mais simplificada com segurança. A seleção do paciente deve, idealmente, ser feita por uma equipe multidisciplinar e uma completa avaliação por imagem, em que a angitomografia é imprescindível, mandatória

For around fifteen years, Transcatheter Aortic Valve Implant (TAVI) has undergone technological advances, acquired accumulated experience, and become an alternative to conventional surgery. The main indication is degenerative aortic stenosis in the elderly patient. Current evidence has been extended to those with intermediate risk, and has become more robust in high-risk and inoperable patients. In specific situations, such as bicuspid aortic valve, pure aortic regurgitation, low-risk patients, and degenerated surgical bioprosthesis, the results are not totally predictable, but are very promising. The types of device currently released for clinical use are divided into first generation and new generation devices, and into auto-expandable, balloon-expandable, and mechanically-expandable. The preferential access site is currently the transfermoral route. Other access alternatives have also proven viable and reliable. The main complications are vascular, neurological events, conduction disturbances, and paravalvular regurgitation. Despite their low incidence, aortic rupture and coronary occlusion have attracted greater interest due to their potential impact on morbimortality. The more recent use of the procedure in younger patients raises issues related to durability and the risk of thrombosis. Although TAVI is still a complex procedure, after gaining experience, there is a tendency to move towards a more simplified, safer approach. The patient selection should ideally be carried out by a multidisciplinary team, and a complete imaging assessment that includes angiotomography is absolutely essential

Monophasic and biphasic shock for transthoracic conversion of atrial fibrillation: Systematic review and network meta-analysis.

OBJECTIVES: Conduct a systematic review of the literature to compare the efficacy of different biphasic and monophasic shock waveforms technologies for transthoracic cardioversion of Atrial Fibrillation (AF). METHODS: We searched PubMed, EMBASE, The Cochrane Library, LILACS and ClinicalTrials.gov databases for randomized clinical trials comparing two or more defibrillation waveforms when performing elective transthoracic cardioversion of AF. The outcomes assessed were 1st shock success, overall success, cumulative energy and number of shocks to restore Normal Sinus Rhythm. RESULTS: Were included 23 trials involving 3046 patients, 5 biphasic and the monophasic waveform. Direct meta-analysis revealed that Biphasic waveforms have higher chance to achieve cardioversion in the 1st shock (OR: 3.2; 95% CI 2.2-4.7) and after a sequence of attempts (OR:2.4; 95% CI 1.5-3.9), requiring 296 less Joules (95% CI 356-237) and 0.74 less shocks (95%CI 1.03-0.44) when compared to Monophasic. Network meta-analysis showed no significant differences between the Biphasic technologies of PhysioControl ADAPTIV, Philips SMART and ZOLL Rectilinear, in any of the four outcomes. CONCLUSION: The evidences points to a Biphasic waveform superiority over Monophasic to perform AF cardioversion, supporting current guidelines to use less energy when using a Biphasic defibrillator. It is suggested that the Biphasic defibrillators from PhysioControl ADAPTIV, Philips SMART and ZOLL Rectilinear have similar efficacy and the use of any of them may result in similar chances, energy and number of shocks to achieve successful AF cardioversion.

Impacto da cirurgia de revascularização miocárdica prévia em desfechos clínicos de pacientes submetidos à intervenção coronária percutânea primária / Impact of prior coronary bypass graft surgery on the outcomes of patients undergoing primary percutaneous coronary intervention

Introdução: Historicamente, pacientes com cirurgia de revascularização do miocárdio (CRM) prévia submetidos à intervenção coronária percutânea (ICP) primária têm pior prognóstico que pacientes semCRM prévia. No entanto, análises mais contemporâneas contestam esses achados. Nosso objetivo foi avaliar os desfechos clínicos de 30 dias em pacientes com e sem CRM prévia submetidos à ICP primária. Métodos: Estudo de coorte prospectivo extraído do banco de dados do Instituto de Cardiologia do RioGrande do Sul, contendo 1.854 pacientes submetidos à ICP primária. Resultados: Pacientes com CRM prévia (3,8%) mostraram perfil clínico, em geral, mais grave. O tempo deinício dos sintomas até a chegada ao hospital foi menor nesse grupo (2,50 horas [1,46-3,66] vs. 3,99 horas[1,99-6,50]; p < 0,001) e o tempo porta-balão foi semelhante (1,33 hora [0,85-2,07] vs. 1,16 hora [0,88-1,58];p = 0,12). O acesso femoral foi mais usado no grupo com CRM prévia (91,5% vs. 62,5%; p < 0,001). O uso de tromboaspiração manual foi menor nesse grupo (16,9% vs. 31,1%; p = 0,007), mas não houve diferença no uso de inibidor da glicoproteína IIb/IIIa (28,2% vs. 32,4%; p = 0,28). O sucesso angiográfico foi menor no grupo com CRM prévia (80,3% vs. 93,3%; p = 0,009). Aos 30 dias, pacientes com CRM prévia apresentaram taxas similares de eventos cardíacos adversos maiores (14,1% vs. 11,2%; p = 0,28), e a mortalidade, embora numericamente mais alta, não foi estatisticamente significativa (13,2% vs. 7,0%; p = 0,07).Conclusões: Nessa análise contemporânea, pacientes com CRM prévia submetidos à ICP primária apresentaram perfil clínico mais grave e menor sucesso angiográfico, porém não mostraram diferenças nos desfechos clínicos em 30 dias.

Background: Historically, patients with prior coronary artery bypass graft (CABG) surgery undergoing primary percutaneous coronary intervention (PCI) have a worse prognosis than patients without prior CABG. However, more contemporary analyses have contested these findings. This study’s aim was to evaluate the 30-day clinical outcomes in patients with and without prior CABG submitted to primary PCI. Methods: Prospective cohort study, extracted from the database of Instituto de Cardiologia do Rio Grandedo Sul, containing 1,854 patients undergoing primary PCI. Results: Patients with prior CABG (3.8%) showed, in general, a more severe clinical profile. The time of symptom onset until arrival at the hospital was shorter in this group (2.50 hours [1.46 to 3.66] vs. 3.99 hour [1.99 to 6.50]; p < 0.001), while the door-to-balloon time was similar (1.33 hour [0.85 to 2.07] vs.1.16 hour [0.88 to 1.58]; p = 0.12). Femoral access was more often used in the group with prior CABG(91.5% vs. 62.5%; p < 0.001). Manual thrombus aspiration was less often performed in this group (16.9% vs. 31.1%; p = 0.007), but there was no difference regarding the use of glycoprotein IIb/IIIa inhibitors (28.2% vs. 32.4%, p = 0.28). Angiographic success was lower in the group with prior CABG (80.3% vs. 93.3%; p = 0.009). At 30 days, patients with prior CABG had similar rates of major adverse cardiac events (14.1%vs. 11.2%; p = 0.28), and mortality, although numerically higher, was not statistically significant (13.2%vs. 7.0%, p = 0.07). Conclusions: In this contemporary analysis, patients with prior CABG undergoing primary PCI had amore severe clinical profile and lower angiographic success, but showed no differences regarding 30-day clinical outcomes.

N-acetylcysteine administration prevents nonthyroidal illness syndrome in patients with acute myocardial infarction: a randomized clinical trial.

CONTEXT: The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism. OBJECTIVE: The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction. DESIGN: This was a randomized, multicenter clinical trial. SETTINGS: Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected. MAIN OUTCOME: Variation of serum T3 and rT3 levels was measured. RESULTS: Baseline characteristics were similar between groups (all P > .05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P > .05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P < .001). CONCLUSIONS: NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology.

CD47 plays a critical role in T-cell recruitment by regulation of LFA-1 and VLA-4 integrin adhesive functions.

CD47 plays an important but incompletely understood role in the innate and adaptive immune responses. CD47, also called integrin-associated protein, has been demonstrated to associate in cis with ß1 and ß3 integrins. Here we test the hypothesis that CD47 regulates adhesive functions of T-cell α4ß1 (VLA-4) and αLß2 (LFA-1) in in vivo and in vitro models of inflammation. Intravital microscopy studies reveal that CD47(-/-) Th1 cells exhibit reduced interactions with wild-type (WT) inflamed cremaster muscle microvessels. Similarly, murine CD47(-/-) Th1 cells, as compared with WT, showed defects in adhesion and transmigration across tumor necrosis factor-α (TNF-α)-activated murine endothelium and in adhesion to immobilized intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion protein 1 (VCAM-1) under flow conditions. Human Jurkat T-cells lacking CD47 also showed reduced adhesion to TNF-α-activated endothelium and ICAM-1 and VCAM-1. In cis interactions between Jurkat T-cell ß2 integrins and CD47 were detected by fluorescence lifetime imaging microscopy. Unexpectedly, Jurkat CD47 null cells exhibited a striking defect in ß1 and ß2 integrin activation in response to Mn(2+) or Mg(2+)/ethylene glycol tetraacetic acid treatment. Our results demonstrate that CD47 associates with ß2 integrins and is necessary to induce high-affinity conformations of LFA-1 and VLA-4 that recognize their endothelial cell ligands and support leukocyte adhesion and transendothelial migration.

Bone marrow-derived Kruppel-like factor 10 controls reendothelialization in response to arterial injury.

OBJECTIVE: The objective of this study was to investigate the role of Kruppel-like factor (KLF) 10, a zinc-finger transcription factor, in bone marrow (BM)-derived cell responses to arterial endothelial injury. Accumulating evidence indicates that BM-derived progenitors are recruited to sites of vascular injury and contribute to endothelial repair. APPROACH AND RESULTS: In response to carotid artery endothelial denudation, KLF10 mRNA expression was markedly increased in both BM and circulating lin(-) progenitor cells. To examine the specific role of KLF10 in arterial reendothelialization, we used 2 models of endothelial denudation (wire- and thermal-induced injury) of the carotid artery in wild-type (WT) and KLF10(-/-) mice. WT mice displayed higher areas of reendothelialization compared with KLF10(-/-) mice after endothelial injury using either method. BM transplant studies revealed that reconstitution of KLF10(-/-) mice with WT BM fully rescued the defect in reendothelialization and increased lin(-)CD34(+)kinase insert domain receptor(+) progenitors in the blood and injured carotid arteries. Conversely, reconstitution of WT mice with KLF10(-/-) BM recapitulated the defects in reendothelialization and peripheral cell progenitors. The media from cultured KLF10(-)/(-) BM progenitors was markedly inefficient in promoting endothelial cell growth and migration compared with the media from WT progenitors, indicative of defective paracrine trophic effects from KLF10(-)/(-) BM progenitors. Finally, BM-derived KLF10(-/-) lin(-) progenitors from reconstituted mice had reduced CXC-chemokine receptor 4 expression and impaired migratory responses. CONCLUSIONS: Collectively, these observations demonstrate a protective role for BM-derived KLF10 in paracrine and homing responses important for arterial endothelial injury and highlight KLF10 as a possible therapeutic target to promote endothelial repair in vascular disease states.

Prevalence of high platelet reactivity in aspirin-treated patients referred for coronary angiography.

BACKGROUND: Aspirin (ASA) reduces adverse events in coronary artery disease (CAD) patients by inhibiting platelets. Some CAD patients have high platelet reactivity (HPR) despite ASA therapy and these individuals have increased risk of adverse events. OBJECTIVE: The purpose of this study was to determine the prevalence of HPR in ASA-treated patients referred for coronary angiography and to assess whether the HPR correlates with the severity of CAD. METHODS: This single center investigation enrolled 115 consecutive ASA-treated patients with stable CAD. ADP- and collagen-induced platelet reactivity were evaluated by light transmittance aggregometry (LTA). Patients with greater than 70% ADP- and collagen-induced aggregation were determined to have HPR and, in this group, ASA compliance was assessed by examining blood salicylate levels. Mean age was 60.9 years and average ASA dose was 164.2 mg. RESULTS: Smoking and DM were present in 28.7% and 31.5% respectively. HPR was found in 14 patients (13%) however 7 of the 14 patients (50%) with HPR had low serum salicylate levels (< 2.0 µg/mL) suggesting medication noncompliance. Of the entire cohort, 6.5% of patients had HPR and detectable serum salicylate levels suggesting reduced ASA efficacy. HPR correlated with number and severity of coronary stenosis (p = 0.04). CONCLUSION: In a general population of ASA-treated patients referred for coronary angiography, elevated platelet reactivity is prevalent (13%) with 50% related to noncompliance and 50% related to reduced aspirin efficacy.

Prevalência de alta reatividade plaquetária em pacientes tratados com aspirina encaminhados para angiografia coronária / Prevalence of high platelet reactivity in aspirin-treated patients referred for coronary angiography

FUNDAMENTO: A aspirina (Ácido Acetilsalicílico - AAS) é capaz de reduzir eventos adversos cardiovasculares em pacientes portadores de Doença Arterial Coronariana (DAC) através da inibição da atividade plaquetária. Alguns pacientes com DAC, apesar da terapia com AAS, apresentam Alta Reatividade Plaquetária (ARP), o que determina um maior risco para o desenvolvimento de eventos cardiovasculares. OBJETIVO: O objetivo deste estudo foi determinar a prevalência de ARP em pacientes tratados com AAS e encaminhados para cinecoronariografia, além de avaliar se existe uma possível correlação entre a gravidade da DAC e o desenvolvimento de ARP. MÉTODOS: Estudo de centro único onde foram incluídos 115 pacientes consecutivos, tratados com AAS e portadores de DAC estável. A reatividade plaquetária induzida pelo ADP e colágeno foram avaliadas através da Agregometria de Transmitância Luminosa (ATL). Pacientes com agregação plaquetária maior que 70%, induzida por ambos os reagentes, foram classificados como tendo ARP e, neste grupo, a adesão ao tratamento com AAS foi avaliada através da dosagem dos níveis séricos de salicilato. RESULTADOS: A média de idade foi de 60,9 anos e a dose média de AAS foi de 164,2 mg. Tabagismo e diabetes melito estavam presentes em 28,7% e 31,5% dos pacientes, respectivamente. Foi encontrada ARP em 14 pacientes (13%), entretanto, em sete indivíduos (50%) com ARP observaram-se baixos níveis séricos de salicilato (< 2,0 µg/mL), sugerindo não adesão à terapia medicamentosa. Em 6,5% dos pacientes com ARP identificou-se níveis detectáveis de salicilato sérico, sugerindo uma eficácia reduzida do AAS. A ARP se correlacionou com o número e a gravidade das estenoses coronárias (p = 0,04). CONCLUSÃO: Em uma população de pacientes tratados com AAS e encaminhados para angiografia coronária, a reatividade plaquetária elevada é prevalente (13%), sendo 50% destes pacientes não aderentes à terapia farmacológica e 50% apresentam redução da efetividade da droga.

BACKGROUND: Aspirin (ASA) reduces adverse events in coronary artery disease (CAD) patients by inhibiting platelets. Some CAD patients have high platelet reactivity (HPR) despite ASA therapy and these individuals have increased risk of adverse events. OBJECTIVE: The purpose of this study was to determine the prevalence of HPR in ASA-treated patients referred for coronary angiography and to assess whether the HPR correlates with the severity of CAD. METHODS: This single center investigation enrolled 115 consecutive ASA-treated patients with stable CAD. ADP- and collagen-induced platelet reactivity were evaluated by light transmittance aggregometry (LTA). Patients with greater than 70% ADP- and collagen-induced aggregation were determined to have HPR and, in this group, ASA compliance was assessed by examining blood salicylate levels. Mean age was 60.9 years and average ASA dose was 164.2 mg. RESULTS: Smoking and DM were present in 28.7% and 31.5% respectively. HPR was found in 14 patients (13%) however 7 of the 14 patients (50%) with HPR had low serum salicylate levels (< 2.0 µg/mL) suggesting medication noncompliance. Of the entire cohort, 6.5% of patients had HPR and detectable serum salicylate levels suggesting reduced ASA efficacy. HPR correlated with number and severity of coronary stenosis (p = 0.04). CONCLUSION: In a general population of ASA-treated patients referred for coronary angiography, elevated platelet reactivity is prevalent (13%) with 50% related to noncompliance and 50% related to reduced aspirin efficacy.