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.

CHA2 DS2 VASc Score as a Predictor of Cardiovascular Events in Ambulatory Patients without Atrial Fibrillation.

BACKGROUND: New evidence suggests that the CHA(2)DS(2)VASc (congestive heart failure, hypertension [HTN], age, diabetes, stroke, vascular disease, and female gender) score may be a reliable tool to predict the risk of thromboembolic events in patients without documented atrial fibrillation (AF). METHODS: We performed a prospective cohort study of outpatients without AF or flutter, who were not using oral anticoagulation. Clinical characteristics were assessed and patients were stratified according to the CHA(2)DS(2)VASc score. We evaluated the incidence of major adverse cardiac outcomes and its relation to the CHA(2)DS(2)VASc score during the follow-up. RESULTS: Four hundred sixty-eight patients without AF were enrolled with a mean follow-up of 12 ± 6 months. Age was 64.9 ± 11.3 years. The prevalence of HTN was 88.4%, diabetes 37.6%, heart failure 26.3%, and vascular disease 61.7%. Overall, CHA(2)DS(2)VASc score was 3.4 ± 1.4. There were 15 major adverse cardiac outcomes during 12.2 months of follow-up (overall incidence of 3.2 per 100 person-years). We found significant differences in relation to gender, age, previous stroke, and follow-up length in patients with and without adverse outcomes. The CHA(2)DS(2)VASc score was higher in those with adverse outcomes (4.2 ± 1.7 vs 3.4 ± 1.4; P = 0.035). Patients with a CHA(2)DS(2)VASc ≥6 had a relative risk for adverse outcomes of 4.2 (95% confidence interval: 1.27-13.90). CONCLUSIONS: In our population, CHA(2)DS(2)VASc score predicts major adverse cardiac outcomes, including stroke and death, in a cohort of patients without AF.

Challenges in high-sensitive troponin assay interpretation for intensive therapy. / Desafios na interpretação dos ensaios de troponina ultrassensível em terapia intensiva.

Cardiac troponins T and I are considered highly sensitive and specific markers for the diagnosis of acute myocardial infarction. Currently, a series of nonprimary cardiac abnormalities may manifest as an elevation in high-sensitive assays. The reduction in their detection limits has allowed earlier diagnosis and the use of evidence-based therapeutic measures; however, this characteristic has increased the spectrum of detectable noncoronary heart diseases, which poses challenges for characterizing acute coronary syndromes and creates a new role for these tests in known disorders in intensive care units, especially sepsis. Management of patients through a greater understanding of how these markers behave should be re-evaluated to ensure their correct interpretation.

As troponinas cardíacas T e I são marcadores considerados altamente sensíveis e específicos para o diagnóstico de infarto agudo do miocárdio. Atualmente, com o advento dos ensaios ultrassensíveis, uma série de anormalidades não primariamente cardíacas pode se manifestar por meio da elevação destes ensaios. A redução de seu limiar de detecção promoveu maior precocidade no diagnóstico e na utilização de medidas terapêuticas baseadas em evidência, no entanto, esta característica aumentou o espectro de doenças cardíacas não coronarianas detectáveis, trazendo desafios para a caracterização das síndromes coronarianas agudas e um novo papel para estes testes nas desordens conhecidas no ambiente das unidades de tratamento intensivo, em especial na sepse. A abordagem de pacientes por meio de um maior entendimento do comportamento destes marcadores deve ser redimensionada para sua correta interpretação.

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.

Risk-Benefit Assessment of Carotid Revascularization.

Severe carotid atherosclerotic disease is responsible for 14% of all strokes, which result in a high rate of morbidity and mortality. In recent years, advances in clinical treatment of cardiovascular diseases have resulted in a significant decrease in mortality due to these causes. To review the main studies on carotid revascularization, evaluating the relationship between risks and benefits of this procedure. The data reviewed show that, for a net benefit, carotid intervention should only be performed in cases of a periprocedural risk of less than 6% in symptomatic patients. The medical therapy significantly reduced the revascularization net benefit ratio for stroke prevention in asymptomatic patients. Real life registries indicate that carotid stenting is associated with a greater periprocedural risk. The operator annual procedure volume and patient age has an important influence in the rate of stroke and death after carotid stenting. Symptomatic patients have a higher incidence of death and stroke after the procedure. Revascularization has the greatest benefit in the first weeks of the event. There is a discrepancy in the scientific literature about carotid revascularization and/or clinical treatment, both in primary and secondary prevention of patients with carotid artery injury. The identification of patients who will really benefit is a dynamic process subject to constant review.

Oral Anticoagulation in Atrial Fibrillation: Development and Evaluation of a Mobile Health Application to Support Shared Decision-Making.

BACKGROUND: Atrial fibrillation is responsible for one in four strokes, which may be prevented by oral anticoagulation, an underused therapy around the world. Considering the challenges imposed by this sort of treatment, mobile health support for shared decision-making may improve patients' knowledge and optimize the decisional process. OBJECTIVE: To develop and evaluate a mobile application to support shared decision about thromboembolic prophylaxis in atrial fibrillation. METHODS: We developed an application to be used during the clinical visit, including a video about atrial fibrillation, risk calculators, explanatory graphics and information on the drugs available for treatment. In the pilot phase, 30 patients interacted with the application, which was evaluated qualitatively and by a disease knowledge questionnaire and a decisional conflict scale. RESULTS: The number of correct answers in the questionnaire about the disease was significantly higher after the interaction with the application (from 4.7 ± 1.8 to 7.2 ± 1.0, p < 0.001). The decisional conflict scale, administered after selecting the therapy with the app support, resulted in an average of 11 ± 16/100 points, indicating a low decisional conflict. CONCLUSIONS: The use of a mobile application during medical visits on anticoagulation in atrial fibrillation improves disease knowledge, enabling a shared decision with low decisional conflict. Further studies are needed to confirm if this finding can be translated into clinical benefit.

Processes and Recommendations for Creating mHealth Apps for Low-Income Populations.

BACKGROUND: Mobile health (mHealth) apps have shown to improve health indicators, but concerns remain about the inclusion of populations from low- and medium-income countries (LMIC) in these new technologies. Atrial fibrillation (AF) is a chronic condition with a challenging management. Previous studies have shown socioeconomic differences in the prescription of anticoagulant treatment and shared decision strategies are encouraged to achieve better outcomes. mHealth can aid both doctors and patients in this matter. OBJECTIVE: We describe the development of an mHealth app (aFib) idealized to aid shared decision between doctor and patient about anticoagulation prophylaxis in AF in a low-income and low-literacy population in Brazil. On the basis of our research, we suggest the processes to be followed when developing mHealth apps in this context. METHODS: A multidisciplinary team collected information about the target population and its needs and detected the best opportunity to insert the app in their current health care. Literature about the subject was reviewed and important data were selected to be delivered through good navigability, easy terminology, and friendly design. The app was evaluated in a multimethod setting. RESULTS: The steps suggested to develop an mHealth app target to LMIC are: (1) characterize the problem and the target user, (2) review the literature, (3) translate information to knowledge, (4) protect information, and (5) evaluate usability and efficacy. CONCLUSIONS: We expect that these recommendations can guide the development of new mHealth apps in LMIC, on a scientific basis.

Clinical Differences between Subtypes of Atrial Fibrillation and Flutter: Cross-Sectional Registry of 407 Patients.

INTRODUCTION: Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce. OBJECTIVE: To investigate the arrhythmia subtype of atrial fibrillation and flutter patients in the emergency setting and compare the clinical profile, thromboembolic risk and anticoagulants use. METHODS: Cross-sectional retrospective study, with data collection from medical records of every patient treated for atrial fibrillation and flutter in the emergency department of Instituto de Cardiologia do Rio Grande do Sul during the first trimester of 2012. RESULTS: We included 407 patients (356 had atrial fibrillation and 51 had flutter). Patients with paroxysmal atrial fibrillation were in average 5 years younger than those with persistent atrial fibrillation. Compared to paroxysmal atrial fibrillation patients, those with persistent atrial fibrillation and flutter had larger atrial diameter (48.6 ± 7.2 vs. 47.2 ± 6.2 vs. 42.3 ± 6.4; p < 0.01) and lower left ventricular ejection fraction (66.8 ± 11 vs. 53.9 ± 17 vs. 57.4 ± 16; p < 0.01). The prevalence of stroke and heart failure was higher in persistent atrial fibrillation and flutter patients. Those with paroxysmal atrial fibrillation and flutter had higher prevalence of CHADS2 score of zero when compared to those with persistent atrial fibrillation (27.8% vs. 18% vs. 4.9%; p < 0.01). The prevalence of anticoagulation in patients with CHA2DS2-Vasc ≤ 2 was 40%. CONCLUSIONS: The population in our registry was similar in its comorbidities and demographic profile to those of North American and European registries. Despite the high thromboembolic risk, the use of anticoagulants was low, revealing difficulties for incorporating guideline recommendations. Public health strategies should be adopted in order to improve these rates.

Desafios na interpretação dos ensaios de troponina ultrassensível em terapia intensiva / Challenges in high-sensitive troponin assay interpretation for intensive therapy

RESUMO As troponinas cardíacas T e I são marcadores considerados altamente sensíveis e específicos para o diagnóstico de infarto agudo do miocárdio. Atualmente, com o advento dos ensaios ultrassensíveis, uma série de anormalidades não primariamente cardíacas pode se manifestar por meio da elevação destes ensaios. A redução de seu limiar de detecção promoveu maior precocidade no diagnóstico e na utilização de medidas terapêuticas baseadas em evidência, no entanto, esta característica aumentou o espectro de doenças cardíacas não coronarianas detectáveis, trazendo desafios para a caracterização das síndromes coronarianas agudas e um novo papel para estes testes nas desordens conhecidas no ambiente das unidades de tratamento intensivo, em especial na sepse. A abordagem de pacientes por meio de um maior entendimento do comportamento destes marcadores deve ser redimensionada para sua correta interpretação.

ABSTRACT Cardiac troponins T and I are considered highly sensitive and specific markers for the diagnosis of acute myocardial infarction. Currently, a series of nonprimary cardiac abnormalities may manifest as an elevation in high-sensitive assays. The reduction in their detection limits has allowed earlier diagnosis and the use of evidence-based therapeutic measures; however, this characteristic has increased the spectrum of detectable noncoronary heart diseases, which poses challenges for characterizing acute coronary syndromes and creates a new role for these tests in known disorders in intensive care units, especially sepsis. Management of patients through a greater understanding of how these markers behave should be re-evaluated to ensure their correct interpretation.

Physical Activity and Incidence of Atrial Fibrillation - Systematic Review and Meta-Analysis

The relationship between exercise and atrial fibrillation (AF) is controversial. Objectives: To analyze the effects of physical activity on the incidence of atrial fibrillation using systematic review and meta-analysis. Methods: Systematic review and meta-analysis of studies that relate physical exercise and atrial fibrillation. The following databases were searched: PubMed, BVS Saúde and Cochrane. The following descriptors were used: "atrial fibrillation", "exercise", "physical activity" and "exercise therapy". All prospective, retrospective, cross-sectional and cohort studies were investigated. All statistical analyzes were provided using Review Manager 5.3 to provide the mean difference (MD) and relative risk (RR) ratio with 95% confidence intervals (95% CI). The statistical method of heterogeneity index was used to assess heterogeneity. Level of significance was 5%. Results: Combined analysis of 11 studies totaling 276,323 participants aged between 12 and 90 years did not suggest a significant increase in AF in individuals submitted to physical exercise (RR = 0.914, 95% CI = 0.833-1.003, heterogeneity: p < 0.001). Conclusions: Physical exercise, lato sensu, without stratification by intensity, sex or age does not seem to be associated with an increase of atrial fibrillation

Risk-Benefit Assessment of Carotid Revascularization / Avaliação do Risco-Benefício da Revascularização Carotídea

Abstract Severe carotid atherosclerotic disease is responsible for 14% of all strokes, which result in a high rate of morbidity and mortality. In recent years, advances in clinical treatment of cardiovascular diseases have resulted in a significant decrease in mortality due to these causes. To review the main studies on carotid revascularization, evaluating the relationship between risks and benefits of this procedure. The data reviewed show that, for a net benefit, carotid intervention should only be performed in cases of a periprocedural risk of less than 6% in symptomatic patients. The medical therapy significantly reduced the revascularization net benefit ratio for stroke prevention in asymptomatic patients. Real life registries indicate that carotid stenting is associated with a greater periprocedural risk. The operator annual procedure volume and patient age has an important influence in the rate of stroke and death after carotid stenting. Symptomatic patients have a higher incidence of death and stroke after the procedure. Revascularization has the greatest benefit in the first weeks of the event. There is a discrepancy in the scientific literature about carotid revascularization and/or clinical treatment, both in primary and secondary prevention of patients with carotid artery injury. The identification of patients who will really benefit is a dynamic process subject to constant review.

Resumo A doença aterosclerótica carotídea grave é responsável por 14% de todos os acidentes vasculares cerebrais (AVC), que refletem em uma alta taxa de morbimortalidade. Nos últimos anos, os avanços no tratamento clínico das doenças cardiovasculares geraram um decréscimo importante na mortalidade por estas causas. Revisar principais estudos que dizem respeito à revascularização carotídea avaliando a relação entre risco e beneficio deste procedimento. Os dados encontrados indicam que o procedimento só deve ser realizado se houver um risco periprocedimento menor que 6% em pacientes sintomáticos para que haja beneficio líquido na intervenção carotídea. O tratamento clínico reduziu significativamente o benefício líquido da revascularização na prevenção de AVC em pacientes assintomáticos. Registros que refletem a prática diária demonstram que a angioplastia carotídea esta associada a um risco periprocedimento mais elevado. O volume anual de procedimentos por operador e a idade dos pacientes têm uma importante influência nas taxas de AVC e morte pós angioplastia. Pacientes sintomáticos têm uma maior incidência de AVC e morte após procedimento. A revascularização tem o maior benefício nas primeiras semanas do evento. Existem discrepâncias na literatura científica com relação à revascularização carotídea e/ou tratamento clínico, tanto na prevenção primária quanto secundária de pacientes com lesão carotídea. A identificação do paciente que realmente será beneficiado é um processo dinâmico sujeito a constante revisão.

Oral Anticoagulation in Atrial Fibrillation: Development and Evaluation of a Mobile Health Application to Support Shared Decision-Making / Anticoagulação Oral na Fibrilação Atrial: Desenvolvimento e Avaliação de um Aplicativo de Saúde Móvel para Suporte à Decisão Compartilhada

Abstract Background: Atrial fibrillation is responsible for one in four strokes, which may be prevented by oral anticoagulation, an underused therapy around the world. Considering the challenges imposed by this sort of treatment, mobile health support for shared decision-making may improve patients' knowledge and optimize the decisional process. Objective: To develop and evaluate a mobile application to support shared decision about thromboembolic prophylaxis in atrial fibrillation. Methods: We developed an application to be used during the clinical visit, including a video about atrial fibrillation, risk calculators, explanatory graphics and information on the drugs available for treatment. In the pilot phase, 30 patients interacted with the application, which was evaluated qualitatively and by a disease knowledge questionnaire and a decisional conflict scale. Results: The number of correct answers in the questionnaire about the disease was significantly higher after the interaction with the application (from 4.7 ± 1.8 to 7.2 ± 1.0, p < 0.001). The decisional conflict scale, administered after selecting the therapy with the app support, resulted in an average of 11 ± 16/100 points, indicating a low decisional conflict. Conclusions: The use of a mobile application during medical visits on anticoagulation in atrial fibrillation improves disease knowledge, enabling a shared decision with low decisional conflict. Further studies are needed to confirm if this finding can be translated into clinical benefit.

Resumo Fundamento: A fibrilação atrial é causa de um em cada quatro acidentes vasculares cerebrais, que podem ser prevenidos com anticoagulação oral, uma terapia subutilizada globalmente. Considerando os desafios desse tratamento, instrumentos de saúde móvel para suporte à decisão compartilhada podem melhorar o conhecimento do paciente e otimizar o processo decisório. Objetivo: Desenvolver e avaliar um aplicativo móvel para suporte à decisão compartilhada na profilaxia tromboembólica em fibrilação atrial. Métodos: Foi desenvolvido um aplicativo para ser usado durante a consulta médica, contendo um vídeo sobre fibrilação atrial, calculadoras de escores de risco, gráficos explicativos e orientações sobre os fármacos disponíveis para o tratamento. Durante o desenvolvimento, 30 pacientes interagiram com o aplicativo, que foi avaliado qualitativamente e pela aplicação de um questionário de conhecimento sobre a doença e de uma escala de conflito em tomadas de decisão. Resultados: O número de acertos no questionário de conhecimento sobre a doença teve um aumento significativo após a interação com o aplicativo (de 4,7 ± 1,8 para 7,2 ± 1,0, p < 0,001). A escala de conflito em tomadas de decisão, aplicada após a escolha da terapia com o suporte do aplicativo, resultou em uma média de 11 ± 16/100 pontos, indicando baixo conflito decisório. Conclusões: O uso de um aplicativo móvel durante a consulta sobre anticoagulação em fibrilação atrial melhora o conhecimento sobre a doença, permitindo uma escolha compartilhada com baixo conflito decisório. Mais estudos são necessários para verificar se isso se traduz em benefício clínico.

Clinical Differences between Subtypes of Atrial Fibrillation and Flutter: Cross-Sectional Registry of 407 Patients / Diferenças Clínicas entre Subtipos de Fibrilação Atrial e Flutter: Registro Transversal de 407 Pacientes

Atrial fibrillation and atrial flutter account for one third of hospitalizations due to arrhythmias, determining great social and economic impacts. In Brazil, data on hospital care of these patients is scarce.