NKG2A Expression among CD8 Cells Is Associated with COVID-19 Progression in Hypertensive Patients: Insights from the BRACE CORONA Randomized Trial.

Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.

Discontinuing vs continuing ACEIs and ARBs in hospitalized patients with COVID-19 according to disease severity: Insights from the BRACE CORONA trial.

BACKGROUND: We explored the effect of discontinuing versus continuing angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on clinical outcomes in patients with COVID-19 according to baseline disease severity. METHODS: We randomized 659 patients with a confirmed diagnosis of COVID-19 and classified them as having mild or moderate COVID-19 disease severity at hospital presentation using blood oxygen saturation and lung imaging. The primary outcome was the mean ratio of number of days alive and out of the hospital at 30 days according to disease severity. RESULTS: At presentation, 376 patients (57.1%) had mild and 283 (42.9%) had moderate COVID-19. In patients with mild disease, there was no significant difference in the number of days alive and out of the hospital between ACEI/ARB discontinuation (mean 23.5 [SD 6.3] days) and continuation (mean 23.8 [SD 6.5] days), with a mean ratio of 0.98 (95% CI 0.92-1.04). However, in patients with moderate disease, there were fewer days alive and out of the hospital with ACEI/ARB discontinuation (mean 19.6 [SD 9.5] days) than continuation (mean 21.6 [SD 7.6] days), with a mean ratio of 0.90 (95% CI 0.81-1.00; P-interaction = .01). The impact of discontinuing versus continuing ACEIs/ARBs on days alive and out of hospital through 30 days differed according to baseline COVID-19 disease severity. CONCLUSIONS: Unlike patients with mild disease, patients with moderate disease who continued ACEIs/ARBs had more days alive and out of hospital through 30 days than those who discontinued ACEIs/ARBs. This suggests that ACEIs/ARBs should be continued for patients with moderate COVID-19 disease severity. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04364893).

IL-10 and IL-12 (P70) Levels Predict the Risk of Covid-19 Progression in Hypertensive Patients: Insights From the BRACE-CORONA Trial.

Background: Cardiovascular comorbidities such as hypertension and inflammatory response dysregulation are associated with worse COVID-19 prognoses. Different cytokines have been proposed to play vital pathophysiological roles in COVID-19 progression, but appropriate prognostic biomarkers remain lacking. We hypothesized that the combination of immunological and clinical variables at admission could predict the clinical progression of COVID-19 in hypertensive patients. Methods: The levels of biomarkers, including C-reactive protein, lymphocytes, monocytes, and a panel of 29 cytokines, were measured in blood samples from 167 hypertensive patients included in the BRACE-CORONA trial. The primary outcome was the highest score during hospitalization on the modified WHO Ordinal Scale for Clinical Improvement. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and biomarkers associated significantly with the primary outcome. Results: During hospitalization, 13 (7.8%) patients showed progression to more severe forms of COVID-19, including three deaths. Obesity, diabetes, oxygen saturation, lung involvement on computed tomography examination, the C-reactive protein level, levels of 15 cytokines, and lymphopenia on admission were associated with progression to severe COVID-19. Elevated levels of interleukin-10 and interleukin-12 (p70) combined with two or three of the abovementioned clinical comorbidities were associated strongly with progression to severe COVID-19. The risk of progression to severe disease reached 97.5% in the presence of the five variables included in our model. Conclusions: This study demonstrated that interleukin-10 and interleukin-12 (p70) levels, in combination with clinical variables, at hospital admission are key biomarkers associated with an increased risk of disease progression in hypertensive patients with COVID-19.

Effect of Discontinuing vs Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) have a positive, neutral, or negative effect on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). Objective: To determine whether discontinuation compared with continuation of ACEIs or ARBs changed the number of days alive and out of the hospital through 30 days. Design, Setting, and Participants: A randomized clinical trial of 659 patients hospitalized in Brazil with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization (enrolled: April 9-June 26, 2020; final follow-up: July 26, 2020). Interventions: Discontinuation (n = 334) or continuation (n = 325) of ACEIs or ARBs. Main Outcomes and Measures: The primary outcome was the number of days alive and out of the hospital through 30 days. Secondary outcomes included death, cardiovascular death, and COVID-19 progression. Results: Among 659 patients, the median age was 55.1 years (interquartile range [IQR], 46.1-65.0 years), 14.7% were aged 70 years or older, 40.4% were women, and 100% completed the trial. The median time from symptom onset to hospital admission was 6 days (IQR, 4-9 days) and 27.2% of patients had an oxygen saturation of less than 94% of room air at baseline. In terms of clinical severity, 57.1% of patients were considered mild at hospital admission and 42.9% were considered moderate. There was no significant difference in the number of days alive and out of the hospital in patients in the discontinuation group (mean, 21.9 days [SD, 8 days]) vs patients in the continuation group (mean, 22.9 days [SD, 7.1 days]) and the mean ratio was 0.95 (95% CI, 0.90-1.01). There also was no statistically significant difference in death (2.7% for the discontinuation group vs 2.8% for the continuation group; odds ratio [OR], 0.97 [95% CI, 0.38-2.52]), cardiovascular death (0.6% vs 0.3%, respectively; OR, 1.95 [95% CI, 0.19-42.12]), or COVID-19 progression (38.3% vs 32.3%; OR, 1.30 [95% CI, 0.95-1.80]). The most common adverse events were respiratory failure requiring invasive mechanical ventilation (9.6% in the discontinuation group vs 7.7% in the continuation group), shock requiring vasopressors (8.4% vs 7.1%, respectively), acute myocardial infarction (7.5% vs 4.6%), new or worsening heart failure (4.2% vs 4.9%), and acute kidney failure requiring hemodialysis (3.3% vs 2.8%). Conclusions and Relevance: Among patients hospitalized with mild to moderate COVID-19 and who were taking ACEIs or ARBs before hospital admission, there was no significant difference in the mean number of days alive and out of the hospital for those assigned to discontinue vs continue these medications. These findings do not support routinely discontinuing ACEIs or ARBs among patients hospitalized with mild to moderate COVID-19 if there is an indication for treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT04364893.

Continuing versus suspending angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: Impact on adverse outcomes in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)--The BRACE CORONA Trial.

Angiotensin-converting enzyme-2 (ACE2) expression may increase due to upregulation in patients using angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs). Because renin-angiotensin system blockers increase levels of ACE2, a protein that facilitates coronavirus entry into cells, there is concern that these drugs could increase the risk of developing a severe and fatal form of COVID-19. The impact of discontinuing ACEI and ARBs in patients with COVID-19 remains uncertain. DESIGN: BRACE CORONA is a pragmatic, multicenter, randomized, phase IV, clinical trial that aims to enroll around 500 participants at 34 sites in Brazil. Participants will be identified from an ongoing national registry of suspected and confirmed cases of COVID-19. Eligible patients using renin-angiotensin system blockers (ACEI/ARBs) with a confirmed diagnosis of COVID-19 will be randomized to a strategy of continued ACEI/ARB treatment versus temporary discontinuation for 30 days. The primary outcome is the median days alive and out of the hospital at 30 days. Secondary outcomes include progression of COVID-19 disease, all-cause mortality, death from cardiovascular causes, myocardial infarction, stroke, transient ischemic attack, new or worsening heart failure, myocarditis, pericarditis, arrhythmias, thromboembolic events, hypertensive crisis, respiratory failure, hemodynamic decompensation, sepsis, renal failure, and troponin, B-type natriuretic peptide (BNP), N-terminal-proBNP, and D-dimer levels. SUMMARY: BRACE CORONA will evaluate whether the strategy of continued ACEI/ARB therapy compared with temporary discontinuation of these drugs impacts clinical outcomes among patients with COVID-19.

Dysregulation of microRNAs and target genes networks in human abdominal aortic aneurysm tissues.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a pathological enlargement of infrarenal aorta close to the aortic bifurcation, and it is an important cause of mortality in the elderly. Therefore, the biomarker identification for early diagnosis is of great interest for clinical benefit. It is known that microRNAs (miRNAs) have important roles via target genes regulation in many diseases. This study aimed to identify miRNAs and their target genes involved in the pathogenesis of AAA. METHODS: Tissue samples were obtained from patients who underwent AAA surgery and from organ donors (control group). Quantitative PCR Array was applied to assess 84 genes and 384 miRNAs aiming to identify differentially expressed targets (AAA n = 6, control n = 6), followed by validation in a new cohort (AAA n = 18, control n = 6) by regular qPCR. The functional interaction between validated miRNAs and target genes was performed by the Ingenuity Pathway Analysis (IPA) software. RESULTS: The screening cohort assessed by PCR array identified 10 genes and 59 miRNAs differentially expressed (≥2-fold change, p<0.05). Among these, IPA identified 5 genes and 9 miRNAs with paired interaction. ALOX5, PTGIS, CX3CL1 genes, and miR-193a-3p, 125b-5p, 150-5p maintained a statistical significance in the validation cohort. IPA analysis based on the validated genes and miRNAs revealed that eicosanoid and metalloproteinase/TIMP synthesis are potentially involved in AAA. CONCLUSION: Paired interactions of differentially expressed ALOX5, PTGIS, CX3CL1 genes, and miR-193b-3p, 125b-5p, 150-5p revealed a potentially significant role of the eicosanoid synthesis and metalloproteinase/TIMP pathways in the AAA pathogenesis.

Analysis of Circulating miR-1, miR-23a, and miR-26a in Atrial Fibrillation Patients Undergoing Coronary Bypass Artery Grafting Surgery.

Atrial fibrillation (AF) is the most common arrhythmia after cardiac surgery. From a pathophysiological point of view, a myriad of factors such as trauma, atrial dilation, ischemia, mechanical myopericarditis, autonomic imbalance, loss of connexins, AF nest remodeling, inflammation, sutures, and dysfunction caused by postextracorporeal circulation can contribute to postoperative atrial fibrillation (POAF) resulting in a longer hospital stay and consequently higher cost. Recent studies showed that short fragments of RNA, called microRNA (miRNA), can contribute to the development of several cardiovascular diseases, including AF. The aim of this study was to evaluate the levels of circulating miRNAs (miR-1, -23a, and -26a) that can be involved in POAF. Patients submitted to coronary artery bypass graft surgery were grouped in POAF (24 patients) and without POAF (24 patients). Results showed older age, longer clamp-time, and more days in the intensive care unit as well as a longer total hospital stay in the POAF group. Preoperative levels of circulating miRNAs were similar. Analysis of miRNAs revealed significantly lower circulating levels of miRNA-23a (P = 0.02) and -26a (P = 0.01) in the POAF group during the postoperative period. Receiver operating characteristic (ROC) analysis showed the area under the ROC curve of miR-23a and miR-26a for predicting FA was 0.63 (95% confidence interval [CI]: 0.51-0.74; P = 0.02) and 0.66 (95% CI: 0.55-0.77; P = 0.01), respectively. Our data suggests that circulating miRNA-23a and -26a may be involved in the underlying biology of postoperative AF development.

Reasons for refusing a donor heart for transplantation in Brazil.

BACKGROUND: Major advances have been made in heart transplantation, but there is a discrepancy between the number of patients potentially treatable by transplantation and the limited number of viable grafts. The aim of this study was to evaluate the reasons for refusal of donor hearts. METHODS: This was a retrospective analysis of donor data from an organ procurement organization in the state of São Paulo (Brazil) between 2010 and 2012. Fisher's exact test, Student's t-test, and the Mann-Whitney U-test were used in the statistical analysis. RESULTS: Only 26 (7.9%) of 328 potential heart donors actually became donors. Most donors were men (18/26, 69.2%), Caucasians (14/26, 53.8%), and had a mean age of 23.5 yr. There were significant associations of use of donor hearts with the variables: brain death after trauma (p = 0.002), history of hypertension (p = 0.001), electrocardiographic changes (p = 0.007), and age (p = 0.001). Older age (n = 101, 33.4%) was the main reason for refusal of donor hearts, followed by poor medical history (n = 44, 14.6%), cardiac arrest of the donor during donor care (n = 25, 8.3%), use of vasopressor drugs (n = 23, 7.6%), and hemodynamic instability (n = 20, 6.6%). CONCLUSIONS: Age, poor medical history, cardiac arrest, use of vasopressors, and hemodynamic instability were the most prevalent reasons for refusal of donor hearts. Echocardiogram evaluation is a potential intervention to improve heart transplantation conversion in Brazil.

Análise da expressão de miRNAs em pacientes com fibrilação atrial aguda no pós-operatório de cirurgia de revascularização miocárdica / Expression analysis of miRNA in patients with acute atrial fibrillation in the post-operative period of coronary artery bypass graft surgery

A fibrilação atrial (FA) é a arritmia mais comum no pós-operatório de cirurgia cardíaca. Apesar de estar relacionada a alterações estruturais, alguns pacientes, mesmo que sem tais condições, ainda assim, cursam com fibrilação atrial no pós-operatório (FAPO) causando aumento no tempo de internação e custos. Estudos recentes vem ampliando o conhecimento sobre pequenos fragmentos de RNA, chamados de microRNAs (miRNAs) que podem interferir diretamente no aparecimento de algumas doenças na área cardiovascular. O objetivo do presente estudo é: 1) comparar a expressão dos miRNAs 1, 23 e 26 entre pacientes com e sem FAPO; 2) comparar nos grupos a expressão destes miRNAs entre os período pré e pós-cirúrgico; 3)comparar a expressão dos genes GJA1, KCNJ2, CACNB1, CACNA1C e KCNN3 entre os tempos pré e pós-cirúrgico no grupo FAPO; 4) comparar estes últimos genes no tecido atrial; 5) comparar os genes relacionados à produção de interleucinas (IL)-1, 6 e fator de necrose tumoral alfa (TNF?) entre os grupos e entre os tempos pré e pós-cirúrgico; 6)avaliar as características clínicas e evolutivas da população estudada. Pacientes submetidos à cirurgia de revascularização miocárdica foram submetidos à coleta de 20ml de sangue pré e pós-cirurgia bem como fragmento de tecido atrial. Um total de 143 pacientes compuseram os grupos: FAPO (24 pacientes), controle genético (24 pacientes) e controle total (97 pacientes + 24 grupo controle genético). Do ponto de vista clínico observou-se maior idade, tempo de anóxia, tempo de internação em terapia intensiva e hospitalar no grupo FAPO...

Terapia celular no infarto do miocárdio: mito ou realidade? / Cell therapy in myocardial infarction: myth or reality?

A doença isquêmica do coração ainda permance como uma das causas de maior morbidade e mortalidade no mundo atual. Embora suas opções terapêuticas tenham-se desenvolvido muito nos últimos anosl, o infarto agudo do miocárdio, além das elevadas morbidade e mortalidade, associa-se ao desenvolvimento de quadros de cardiomiopatia isquêmica crônica, insuficiência ventricular e baixa qualidade de vida para muitos pacientes. A terapia celular para recuperação da função ventricular, para esses pacientes traz consigo uma nova perspectiva de vida. Os autores se propõem a revisar os principaisavanços, técnicas de realização e promessas em terapia celular para pacientes acometidos por infarto agudo do miocárdio com grande perda de função ventricular...

Prevalência de tabagismo em estudantes de faculdade de medicina / Prevalency of smoking in medicine students

O tabagismo é atualmente a principal causa de enfermidades evitáveis e incapacidades prematuras em âmbito mundial, sendo que a Organização Mundial de Saúde (OMS) estima cerca de 10 milhões de mortes anuais nos próximos 30 a 40 anos em virtude de complicações de saúde decorrentes do tabaco. Apesar de possuir uma função preventiva em programas antitabagistas, estudos recentes revelam que a classe médica possui porcentagem significativa de profissionais fumantes...

This is a epidemiological paper concerning the use of cigarettes by medicine students and also a literature review based on several different articles. According to the World Health Organization (WHO), smoking is the main cause of preventable diseases in the planet and is directly responsable for about 8 millions deaths a year. Such numbers aren't a big surprise for any educated reader, but what is intersting is that despite this, the number of smokers are progressively growing. The medical class, which are the people responsable for informing and warning the population have a great percentage of smokers...

Segurança e efetividade da enoxaparina versus heparina não-fracionada no tratamento de pacientes submetidos a implante eletivo de stents não-farmacológicos: resultados imediatos e tardios / Safety and efficacy of enoxaparin versus unfractionated heparin in patients undergoing elective percutaneous coronary intervention with bare-metal stent implantation: immediate and long-term clinical outcomes

A heparina não fracionada (HNF) é terapia anticoagulante clássica na intervenção percutânea, prevenindo complicações trombóticas agudas. Estudos sugerem que as heparinas de baixo peso molecular podem ser uma alternativa segura e eficaz. Objetivos: Avaliar a segurança e a efetividade da enoxaparina (ENO) versus HNF em pacientes tratado por intervenção percutânea eletiva nas fases hospitalar (FH) e tardia (FT). Método: No período de outubro a novembro de 2004, incluímos 57 pacientes consecutivos tratados com ENO 0,75 mg/kg (G2) versus grupo controle de 143 pacientes tratados com UI/kg (G1) nos três meses prévios. Todos receberam stents não-farmacológicos e foram pré-tratados com aspirina mais ticlopidina. Analisamos as complicações vasculares (CV) e hemorrágicas (CH) e os eventos combinados (EC) morte, infarto agudo do miocárdio (IAM), acidente vascular encefálico (AVE) e revascularização de urgência (RU) na FH e EC morte, IAM, AVE e nova revascularização na FT. No G2-ENO, mensuramos o fator anti-Xa 10 minutos após bolus EV e no fim da intervenção percutânea. Resultados: A média de idade foi de 59,8 mais ou menos 9,8 anos, 30 por cento eram diabéticos...

Background: Unfractionated heparin (UFH) is the classic anticoagulant therapy used during percutaneous intervention (PCI) to prevent acute thrombotic events. Preliminary studies with low molecular weight heparin have demonstrated the safety and efficacy of this alternative regimen during PCI. Our objective was to evaluate in-hospital and long-term safety and efficacy of enoxaparin (ENO) compared to UFH in patients (P) undergoing elective PCI. Methods: From 10/2004-11/2004, 57 P treated with ENO 0.75 mg/kg IV (G2) were enrolled and compared to a control group of 143 consecutive P treated with UFH 100 IU/kg IV (G1) during the preceding 3 months. All P received a baremetal stent and were pre-treated with ASA + ticlopidine. We analyzed the in-hospital vascular and bleeding complications as well as in-hospital and long-term composite clinical outcome of death, myocardial infarction (MI), stroke or target-vessel revascularization (TVR). Anti-Xa levels were measured in G2-ENO at the beginning (10 minutes after IV bolus) and at the end of PCI. Results: The mean age was 59.8 ± 9.8 years, 30% were diabetics, and clinical and angiographic characteristics were similar in both groups. Procedure success ocurred in 100% without in-hospital major bleedings nor vascular complications in both groups; a non-significant increase in minor bleedings in G2-ENO (p = 0.15) was observed and CKMB > 3x occurred in 2...

Doença arterial coronária na mulher: epidemiologia, métodos diagnósticos e manejo na síndrome coronária aguda / Coronary artery disease in women: epidemiology, diagnosis and management of acute coronary syndrome

Em todo o mundo, as doenças cardiovasculares são as maiores causas de morte entre mulheres, contabilizando um terço de todas as causas de mortalidade. Por causa de sua alta prevalência e da direta interferência na qualidade e na expectativa de vida da mulher, esse tema tem sido amplamente estudado nos últimos anos . Este trabalho teve como objetivo revisar a doença arterial coronária (DAC) na mulher, reportando dados atuais em relação ao tema, tendo em vista a otimização do tratamento nessa população. Muitas diferenças são observadas na apresentação e no manejo da DAC na mulher, como por exemplo, a ocorrência de isquemia sem dor, menor hospitalização, menor abordagem invasiva e menos placas de ateroma. Assim como nos homens, os principais fatores de risco para DAC em mulheres são: idade avançada, dislipidemia, história familiar de DAC, diabetes mellito, tabagismo e hipertensão arterial sistêmica. A apresentação clínica da DAC na mulher pode se dar de forma muito diferente ao habitualmente encontrado nos homens; portanto, a avaliação adequada dos sintomas tem papel fundamental. A realização de exames complemntares diagnósticos e imperiosa, ressaltand-se a menor acurácia do do teste ergométrico em mulheres. Por vezes, o diagnóstico de doença isquêmica é subestimado pelo profissional da saúde, acarretando atraso no início do tratamento e maior incidência de procedimentos de urgência, o que leva a maior mortalidade em relação aos homens.