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Daytime variation affects the tolerance of cardiomyocytes to ischemia–reperfusion injury (IRI). This study aims to evaluate the impact of time-of-day reperfusion on clinical outcomes of remote ischemic conditioning (RIC) as an adjuvant to primary percutaneous coronary intervention(PPCI) in ST-elevation myocardial infarction(STEMI) patients. A post-hoc analysis of a prospective, single-center parallel 1:1 randomized trial (RIC-STEMI) was performed. This analysis included 448 STEMI patients previously randomized to either PPCI alone (PPCI group) (n = 217) or RIC as an adjuvant to PPCI (RIC + PPCI group) (n = 231). Moreover, the sample was divided according to the time of PPCI: night-morning (22 h-11h59min) (n = 216) or afternoon (12 h-21h59min) (n = 232) groups. The primary follow-up endpoint was a composite of cardiac death and hospitalization due to heart failure. There were no significant differences in the clinical characteristics and the follow-up outcomes between groups. The afternoon period (HR = 0.474; 95% CI 0.230–0.977; p = 0.043) and RIC (HR = 0.423; 95% CI 0.195–0.917; p = 0.029) were independent predictors of the primary follow-up endpoint. An univariate analysis showed a lower frequency of primary follow-up endpoint, just in the afternoon period (10.3%vs0.9%; p = 0.002), in the RIC + PPCI group. A multivariate analysis revealed that RIC was an independent predictor of the primary follow-up endpoint in the afternoon group (HR = 0.098; 95% CI 0.012–0.785; p = 0.029), but not in the night-morning group. In addition, the afternoon period was not an independent predictor of the primary follow-up endpoint when the multivariate analysis was performed in the PPCI group. In conclusion, this study showed an important cardioprotective effect of RIC, namely in the afternoon period, suggesting that the afternoon period enhances the cardioprotection induced by RIC.

Heart failure (HF) is a high prevalent syndrome with significant burden worldwide. B-type natriuretic peptide (BNP) and N-terminal proBNP are the gold standard biomarkers in HF management. Although useful in clinical practice, they have limitations as their expression can be influenced by ventricular function, aging, obesity, renal failure and atrial arrhythmias. MicroRNAs have recently emerged as potential diagnostic and prognostic biomarkers, given that they are related to cell growth, proliferation, differentiation, and metabolism. An increasing amount of research has highlighted some microRNAs for their potential as HF biomarkers. However, different study designs, methods and study groups have led to inconsistent results.We performed a systematic search of available literature on Pubmed and Scopus reporting the prognostic value of microRNAs in HF, followed by a review of risk of bias, according to Quadas Group Standards. Simultaneously, microRNAs' potential as differential diagnosis and severity biomarkers was also analyzed. Studies have described circulating microRNA as potential diagnostic, prognostic, and severity markers. Mir-622, -519 and -499 were significantly related to HF with reduced ejection fraction, whereas miR-22-3p revealed greater ability as a severity biomarker. Let-7i-5p, miR-223-5p, miR-423-5p, miR-21, miR-1306-5p and miR-122 serum expressions presented a consistent correlation with HF prognosis. Furthermore, identified miR targets were associated with signaling pathways already known to be involved in HF progression.Several miRs were related to HF pathophysiology and demonstrated potential as biomarkers for disease progression. MicroRNAs have a promising role in HF, and although unquestionable, we require a deeper and broader understanding of their role and function for future research.

Background In countries without organized population screening, incidental detection remains the major form of abdominal aortic aneurysm (AAA) diagnosis. Despite the presumed homogeneity in AAA prevalence, its rate of repair is highly variable, with Portugal treating 2 to 6 times fewer AAA per habitant than other western countries. Objectives To evaluate the detection rate and monitoring of incidental AAA in a multicentre cohort from Portuguese hospitals. Methods All abdominal CT scans performed in men ≥ 65 years old in three major Portuguese hospitals between January and June 2018 were selected for review. CT scans prescribed by the Vascular Surgery or Emergency Departments were excluded. Patients with previously known AAA were also excluded. Subjects with newly detected aneurysms were assessed for the two primary outcomes: the description of the finding by the radiologist in the written report; the effective follow-up recommendations by the prescriber of the CT or by the general practitioner (GP). Patients with newly found AAA that met criteria for monitoring or treatment and failed to be given guidance were contacted and included in surveillance programs. Results Overall, 3292 abdominal CT scans were selected for review. A total of 133 newly found aneurysms were detected (4.2% prevalence in the cohort). Of those, 48 cases (36%) were not described by the radiologist in the written report. Further 42 patients (32%) were not successfully oriented by the ordering physician or GP, despite having had their AAA mentioned. Overall, only 32% (n = 42) of the newly diagnosed AAA were correctly identified and referred to monitoring. Conclusions Incidental AAA is a common occurrence in in-hospital abdominal CTs. A significant number is not documented by the radiologist and the vast majority is not referred to monitoring. This could be a major reason for the low elective treatment rate of AAA in Portugal.

Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg−1·d−1 dissolved in drinking water (ZSF1 Ob SIL, n = 8), or placebo (ZSF1 Ob PL, n = 8). A group of Wistar-Kyoto rats served as control (WKY, n = 8). Four weeks later animals underwent effort tests, glucose metabolism studies, hemodynamic evaluation, and samples were collected for aortic ring preparation, left ventricular (LV) myocardial adenosine triphosphate (ATP) quantification, immunoblotting and histology. ZSF1 Ob PL rats showed systemic hypertension, aortic stiffening, impaired LV relaxation and increased LV stiffness, with preserved ejection fraction and cardiac index. Their endurance capacity was decreased as assessed by maximum workload and peak oxygen consumption (V˙O2) and respiratory quotient were increased, denoting more reliance on anaerobic metabolism. Additionally, ATP levels were decreased. Chronic sildenafil treatment attenuated hypertension and decreased LV stiffness, modestly enhancing effort tolerance with a concomitant increase in peak, ATP levels and VASP phosphorylation. Chronic sildenafil therapy in this model of HFpEF of the young male with extensive and poorly controlled comorbidities has beneficial cardiovascular effects which support RCTs in HFpEF patient subgroups with similar features.

Introduction and objectives: In severe aortic stenosis (AS), the impact of aortic valve replacement (AVR) on left ventricular (LV) systolic function assessed by strain and measured by echocardiography or cardiac magnetic resonance (CMR) has been controversial. We aimed to investigate LV systolic myocardial function changes six months after AVR using global longitudinal (GLS), circumferential (GCS) and radial (GRS) strain derived from CMR imaging. Methods: We included 39 severe AS patients (69.3±7.8 years; 61.5% male) with preserved LV ejection fraction (LVEF) who were recruited as part of the EPICHEART study and underwent successful AVR (aortic valvular area: 0.8 cm2 (IQR: 0.2) pre- to 1.8 cm2 (IQR:0.5) post-AVR). Structural and functional parameters were assessed at baseline and six months after AVR, including LV GRS, GCS and GLS analysis by CMR, using cine short-axial and two-, three-, and four-chamber long-axial view. Comparison between baseline and postoperative LV remodeling was performed using Student t-test and Wilcoxon test. Results: At six-month follow-up, LV mass, end-diastolic and end-systolic volumes, stroke volume, cardiac output, lateral E/e’, tricuspid annular plane systolic excursion, right ventricular (RV) S wave velocity, GLS [-15.6% (IQR: 4.39) to -13.7% (IQR: 4.62)] and GCS [-17.8±3.58% to -16.1±2.94%] reduced significantly, while LVEF and GRS remained unchanged and lateral e’ velocity increased. Conclusions: Despite favorable reverse LV structural and diastolic functional remodeling six months following AVR, GLS and GCS assessed by CMR reduced compared to baseline, LVEF remained unchanged. The clinical utility and timing of assessment of postoperative strain changes as a marker of systolic function progression needs further research. Resumo: Introdução e objetivos: Na estenose aórtica (EA), o impacto da substituição da válvula aórtica (SVA) na função sistólica do ventrículo esquerdo (VE), avaliado por strain medido por ecografia ou ressonância magnética cardíaca (RMC), ainda é controverso. Neste estudo, pretendemos investigar as alterações na função sistólica do VE seis meses após SVA, avaliadas por strain global longitudinal (SGL), circunferencial (SGC) e radial (SGR) medidos por RMC. Métodos: Foram incluídos 39 doentes com EA severa (69,3±7,8 anos; 61,5% sexo masculino) com fração de ejeção do VE (FEVE) preservada, recrutados no estudo EPICHEART, que foram submetidos a SVA bem-sucedida [área valvular aórtica (AVA): 0,8 cm2 (VIQ:0,2) pré-SVA para 1,8 cm2 (VIQ:0,5) pós-SVA]. Foram avaliados parâmetros de estrutura e função, incluindo SGL, SGC e SGR do VE por RMC, através da avaliação de imagens de eixo-curto e de eixo-longo de duas, três e quatro câmaras, antes e seis meses após SVA. Os valores pré e pós-operatórios da função e estrutura do VE foram comparados com o teste t de Student e com o teste de Wilcoxon. Resultados: Aos seis meses após SVA, verificou-se redução significativa da massa do VE, volumes telediastólico e telessistólico, volume de ejeção, débito cardíaco, rácio E/e’ lateral, TAPSE e onda S do ventrículo direito (VD), tal como do SGL [-15,6% (VIQ:4,39) para -13,7% (VIQ:4,62)] e do SGC [-17,8±3,58% para -16,1 ± 2,94%), enquanto a FEVE e o SGR não sofreram alterações significativas e a velocidade e’ aumentou. Conclusões: Apesar de uma remodelagem reversa estrutural e funcional diastólica favorável seis meses após SVA, o SGL e SGC medidos por RMC diminuíram e a FEVE não sofreu alterações significativas. A utilidade clínica e o tempo após intervenção para avaliar as alterações pós-operatórias do strain, como marcador de função sistólica, requerem investigação adicional.

Resumo Fundamento: Pouco se sabe sobre o impacto da estenose aórtica (EA) grave na rigidez aórtica e se ocorre alguma alteração após a remoção da barreira de EA com a cirurgia de substituição da válvula aórtica (SVA). Objetivo: Estimar as mudanças na velocidade de onda de pulso carotídeo-femoral (VOP) após a cirurgia de SVA e definir os preditores de VOP alta em pacientes com EA grave. Métodos: Estudo de coorte retrospectivo unicêntrico, incluindo pacientes com EA grave submetidos à cirurgia de SVA com bioprótese, entre fevereiro de 2017 e janeiro de 2019, e medições da VOP (Complior®) antes e depois do procedimento (2±1 meses). Antes e depois da SVA, os valores da VOP foram comparados por meio de testes pareados. foram analisadas as associações de VOP com dados clínicos, bem como aplicados modelos de regressão linear multivariada para estimar os preditores independentes da VOP pré- e pós-operatória. O nível de significância foi estabelecido em 5%. Resultados: Foram incluídos na amostra 150 pacientes, com média de idade de 72±8 anos, sendo 51% deles do sexo masculino. Identificamos um aumento estatisticamente significativo nos valores de VOP após a cirurgia (9,0 ± 2,1 m/s vs. 9,9 ± 2,2, p

Aims Assessing reversibility of pulmonary vascular changes through vasoreactivity testing (VRT) optimizes end‐stage heart failure patient selection for heart transplant. All efforts should be made to unload the left ventricle and reduce pulmonary vascular resistance to effectively exclude irreversible pulmonary hypertension. Methods and results We reviewed our centre's cardiac transplant registry database (2009–2017) for VRT and compared haemodynamic responses with 40 ppm inhaled NO (n = 14), 14–17 μg inhaled iloprost (n = 7), and 24 h 0.1 μg/kg/min intravenous levosimendan (n = 14). Response to levosimendan was assessed by repeat right heart catheterization within 72 h. Baseline clinical and haemodynamic features were similar between groups. VRT was well tolerated in all patients. All drugs effectively reduced pulmonary artery pressures and transpulmonary gradient while increasing cardiac index, although levosimendan had a greater impact on cardiac index increase (P = 0.036). Levosimendan was the only drug that reduced pulmonary artery wedge pressure (P = 0.004) and central venous pressures (P

Heart failure with preserved ejection fraction (HFpEF) is a multifaceted syndrome with a complex aetiology often associated with several comorbidities, such as left ventricle pressure overload, diabetes mellitus, obesity, and kidney disease. Its pathophysiology remains obscure mainly due to the complex phenotype induced by all these associated comorbidities and to the scarcity of animal models that adequately mimic HFpEF. Increased oxidative stress, inflammation, and endothelial dysfunction are currently accepted as key players in HFpEF pathophysiology. However, we have just started to unveil HFpEF complexity and the role of calcium handling, energetic metabolism, and mitochondrial function remain to clarify. Indeed, the enlightenment of such cellular and molecular mechanisms represents an opportunity to develop novel therapeutic approaches and thus to improve HFpEF treatment options. In the last decades, the number of research groups dedicated to studying HFpEF has increased, denoting the importance and the magnitude achieved by this syndrome. In the current technological and web world, the amount of information is overwhelming, driving us not only to compile the most relevant information about the theme but also to explore beyond the tip of the iceberg. Thus, this review aims to encompass the most recent knowledge related to HFpEF or HFpEF-associated comorbidities, focusing mainly on myocardial metabolism, oxidative stress, and energetic pathways.

Introduction: Accumulation of epicardial adipose tissue (EAT) is associated with coronary artery disease (CAD) and increased risk of coronary events in asymptomatic subjects and low-risk patients, suggesting that EAT promotes atherosclerosis in its early stage. Recent studies have shown that the presence of CAD affects the properties of adjacent EAT, leading to dynamic changes in the molecular players involved in the interplay between EAT and the coronary arteries over the history of the disease. The role of EAT in late-stage CAD has not been investigated. Objectives: In a comparative analysis with mediastinal and subcutaneous adipose tissue, we aim to investigate whether the volume of EAT assessed by computed tomography and its proteome assessed by SWATH-MS mass spectrometry are associated with late stages of CAD in an elderly cohort of severe aortic stenosis patients. Methods: The EPICHEART study (NCT03280433) is a prospective study enrolling patients with severe degenerative aortic stenosis referred for elective aortic valve replacement, whose protocol includes preoperative clinical, nutritional, echocardiographic, cardiac computed tomography and invasive coronary angiographic assessments. During cardiac surgery, samples of EAT and mediastinal and subcutaneous thoracic adipose tissue are collected for proteomics analysis by SWATH-MS. In addition, pericardial fluid and peripheral and coronary sinus blood samples are collected to identify circulating and local adipose tissue-derived biomarkers of CAD. Conclusion: We designed a translational study to explore the association of EAT quantity and quality with advanced CAD. We expect to identify new biochemical factors and biomarkers in the crosstalk between EAT and the coronary arteries that are involved in the pathogenesis of late coronary atherosclerosis, especially coronary calcification, which might be translated into new therapeutic targets and imaging tools by biomedical engineering. Resumo: Introdução: Acumulação de tecido adiposo epicárdico (TAE) tem sido associado a doença coronária aterosclerótica (DC) e aumento do risco de eventos coronários em indivíduos assintomáticos e doentes de baixo risco, sugerindo que o TAE pode promover fases precoces da DC. Estudo recentes mostraram que a presença de DC afeta as características do TAE adjacente levando a modificações dinâmicas nos mediadores envolvidos na comunicação entre o TAE e as artérias coronárias ao longo da história da DC. O papel doTAE nas fases avançadas da aterosclerose coronária não foi investigado. Objetivos: Através de análise comparativa com o tecido adiposo mediastínico e subcutâneo, pretendemos investigar se o volume do TAE, avaliado por tomografia computadorizada (TC), e o seu proteoma, avaliado por espectrometria de massa técnica de SWATH, estão associados a estadios avançados da DC numa coorte de estenose aórtica grave. Métodos: O estudo EPICHEART (NCT03280433) é um estudo prospetivo que inclui doentes com estenose aórtica grave referenciados para substituição eletiva da válvula aórtica, cujo protocolo envolve avaliação pré-operatória clínica, nutricional, ecocardiográfica, por TC e angiografia coronária invasiva. Durante a cirurgia cardíaca, colhemos amostras de tecido adiposo epicárdico, mediastínico e subcutâneo para análise do seu proteoma por espectrometria de massa técnica de SWATH. Adicionalmente, colhemos líquido pericárdico, sangue venoso periférico e do seio coronário para investigar mediadores de DC derivados do TAE na circulação sistémica e local. Conclusão: Desenhámos um estudo de translação para explorar a associação da quantidade e qualidade do TAE com a DC tardia. Esperamos identificar mediadores da comunicação recíproca entre o TAE e as artérias coronárias que estão envolvidos na patogénese das fases avançadas da DC, especialmente, calcificação coronária, os quais podem servir como novos alvos terapêuticos e soluções de engenharia biomédica para visualização da DC.

Prevalence of congenital heart diseases worldwide is around 9 per 1000 newborns, 20% of which affect the pulmonary valve or right ventricular outflow tract. As survival after surgical repair of these defects has improved over time, there is the need to address the long-term issues of older children and young adults with "repaired" congenital heart diseases. In recent decades, the most used types of valves are the mechanical and bioprosthetic valves. Despite improving patients' quality of life, these effects are suboptimal due to their limitations, such as the inability to grow and adapt to hemodynamic changes. These issues have led to the search for living valve solutions through tissue engineering to respond to these challenges. This article aims to review the performance of traditional pulmonary valves and understand how tissue engineering-based valves can improve the management of these patients.

INTRODUCTION The benefit of adding a second arterial conduit is still controversial, mainly in specific subgroups. We conducted a meta-analysis of randomized controlled trials (RCTs) and propensity score (PS) studies comparing survival and early results in elderly patients who underwent coronary artery bypass grafting (CABG) with multiple (MAG) versus single arterial grafting (SAG). EVIDENCE ACQUISITION MEDLINE, Web of Science and Cochrane Library were used to find relevant literature (1960-April 2020). Survival at a ≥ 1-year follow-up and early outcomes were evaluated. Outcomes were collected from matched samples or PS adjusted analysis: hazard ratio (HR) along with their variance, frequencies or odds ratios. Random effect models were used to compute combined statistical measures and 95% confidence intervals (CI) through generic inverse variance method (time-to-event) or Mantel-Haenszel method (binary events). EVIDENCE SYNTHESIS Eleven PS cohorts and 1 RCT comprising > 18,800 patients older than 70 (>6200 MAG and >12,500 SAG) were included in this meta-analysis. MAG was associated with lower long-term mortality (pooled HR: 0.81, 95%CI: 0.72-0.91, p

Background: Atrial fibrillation (AF) is the most common arrhythmia with adverse clinical outcomes. Aortic valve replacement (AVR) is one of the most frequently performed cardiac surgeries, although there is scarce evidence on arrhythmic outcomes. We aimed to evaluate AF during the first year post- isolated aortic valve replacement surgery and its clinical, analytical, and echocardiographic predictors. Methods: Severe aortic stenosis patients with no prior atrial fibrillation submitted to isolated aortic valve replacement surgery were included in our study, of which 316 remained in sinus rhythm and 24 developed AF. We performed logistic regression searching for AF predictors and a longitudinal comparison between pre and post-operative echocardiographic data. Results: Postoperative AF (POAF), diabetes, and follow-up indexed Left Atrium Diameter (iLAD) were significantly higher in the group of patients developing AF. POAF and iLAD were independent AF predictors at follow-up. No differences between groups were found regarding baseline and follow-up echocardiographic data except for indexed Left Ventricle End-diastolic Diameter (LVED), which failed to decrease after surgery in the AF group. Conclusions: POAF and iLAD independently predicted AF at 1 year following isolated AVR surgery in aortic stenosis patients with no AF history. iLVED did not decrease significantly at follow-up in AF patients, possibly reflecting adverse ventricular remodeling.

Ruptured abdominal aortic aneurysm (rAAA) is a lethal condition that requires acute repair to prevent death. This analysis aims to assess the nationwide trends in rAAA admission, repair and mortality in a country, Portugal, without national screening for AAA.rAAA registered in the hospital administrative database of the National Health Service and all nationally registered deaths due to rAAA based on death certificate data were analysed. Three time periods (2000-2004, 2005-2009, and 2010-2015) were compared in patients ≥ 50 years old to assess the variations over time.A total of 2 275 patients ≥50 years old with rAAA were identified in the two databases from 2000 to 2015. The age standardised incidence of rAAA was 2.78 ± 0.24/100 000/year in 2000-2004, 3.17 ± 0.39/100 000/year in 2005-2009 and 3.21 ± 0.28/100 000/year in 2010-2015 (p .001). When comparing the time periods 2000-2004 to 2005-2009, the age standardised rate of admission (n = 1460) increased from 1.57 ± 0.25/100 000/year to 2.24 ± 0.32/100 000/year (p .001). The operative mortality rates decreased during this time period (from 55.3 ± 4.7% to 48.8 ± 4.7%, p .001). In 2010-2015, the age standardised rate of admissions due to rAAA decreased (1.98 ± 0.22/100 000/year). Operative mortality remained stable (48.9 ± 6.2%). The rate of patient deaths outside the hospital decreased from the first to the second period (1.21 ± 0.10/100 000/year and 0.93 ± 0.29/100 000/year, respectively) but later increased (1.14 ± 0.22/100 000/year). This resulted in a higher overall rAAA related mortality in Portugal in the third period (2.20 ± 0.18/100 000/year, 2.21 ± 0.27/100 000/year and 2.26 ± 0.26/100 000/year in 2000-2004, 2005-2009, and 2010-2015, respectively, p .001).Overall, the incidence of rAAA in Portugal has been stable over the past 10 years. The rates of admission, repair, and death due to rAAA repair seem to have reached an inflection point and are now decreasing. Mortality outside the hospital remains a matter of concern, warranting further planning of streamlined transfer networks and vascular surgical departments.

Resumo Fundamento A aptidão física é um importante determinante da qualidade de vida (QV) em pacientes com insuficiência cardíaca com fração de ejeção preservada (ICFEP). No entanto, ainda não se sabe como os diferentes componentes da aptidão física se relacionam com as dimensões específicas da QV em pacientes com ICFEP. Objetivo Avaliar a associação entre diferentes componentes da aptidão física e dimensões da QV em pacientes com ICFEP, e examinar quais componentes da aptidão física foram independentemente associados à QV. Métodos Os pacientes com ICFEP foram avaliados quanto à aptidão física [equilíbrio dinâmico e mobilidade (“teste 8-feet Up-and-go ”), força da parte superior do corpo (Teste de força de preensão manual), aptidão cardiorrespiratória (ACR) (teste de caminhada de 6 minutos) e composição corporal (índice de massa corporal)] e para QV ( Minnesota Living With Heart Failure Questionnaire ). Uma correlação parcial foi utilizada para verificar a associação entre os componentes da aptidão física e as dimensões da QV. A análise das dimensões dos preditores independentes de QV foi realizada através da análise de regressão linear multivariada stepwise . A significância estatística foi estabelecida em p

Aortic coarctation is a common congenital heart defect that often requires correction at a young age. Currently, success is defined by the achievement of a durable repair with low morbidity and mortality. We sought to systematically review the literature on risk factors for recoarctation and mortality in infants submitted to aortic arch coarctation repair under 1 year of age. PubMed and Scopus were searched for studies reporting risk factors for recoarctation and mortality from January 1989 to August 2019. Among the 1038 retrieved articles, 18 met the inclusion criteria, with a total of 2891 patients. The extracted risk factors for recoarctation were comprehensively summarized in the following categories: demographic variables, associated anomalies, clinical and repair variables, and morphometric variables. Younger age and lower weight were weak determinants of need for reintervention, while smaller aortic arch was a strong predictor of recoarctation. While balloon angioplasty is a clear risk factor for arch restenosis, the chosen surgical technique is not a strong risk factor. Associated minor cardiac anomalies and lower weight at surgery were important risk factors for death. Younger and smaller infants are at increased risk for adverse outcomes when submitted to aortic arch coarctation repair. This is particularly important when associated with smaller arch morphology. Strategies to improve the management of these patients may play a key role in improving their outcomes. Notably, surgical technique was not a strong predictor of recoarctation and mortality, suggesting that the choice of one over the other should be tailored.

Purpose: Postoperative atrial fibrillation (POAF) after coronary artery bypass grafting (CABG) has been associated with increased risk of death in women but not in men. We aimed to explore predictors and long-term mortality in POAF following isolated aortic valve replacement (AVR) surgery in men and women. Methods: This study included 379 severe aortic stenosis patients with no prior atrial fibrillation (AF) who underwent isolated AVR surgery. We used multiple logistic regression to investigate independent gender-specific predictors of new-onset POAF, and we performed Kaplan–Meier (KM) to determine the impact of POAF in long-term mortality according to gender. Results: Advanced age and coronary artery disease prevalence were higher among POAF patients in both genders. On multiple analysis, increased postoperative peak lactate was independently associated with POAF in men, while lower mean aortic valve gradient was associated with POAF in women. Area under the curve (AUC) for the model was 0.77 [0.68–0.86] and 0.69 [0.60–0.78] for men and women, respectively. At 4-year follow-up, POAF was linked to increased risk of death in men but not in women. Conclusion: In severe aortic stenosis, factors associated with POAF and its impact on mortality differed between genders, with an increased risk of death observed only in men.

While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.

Introduction: Diastolic dysfunction is highly prevalent and a key pathophysiological contributor to several cardiovascular diseases, especially heart failure with preserved ejection fraction. In addition, some evidence suggests diastolic dysfunction is a risk factor for major adverse cardiovascular events. This study aimed to systematically review the evidence and to quantify the association between diastolic dysfunction and risk of cardiovascular events and death. Methods: MEDLINE was systematically searched from 1974 up to October 2017. We included cohort studies that assessed diastolic function in adults in the community, providing a definition of diastolic dysfunction regarding the occurrence of any cardiovascular event or mortality. For the quantitative analysis, relative risk estimates comparing individuals with versus without diastolic dysfunction were combined using a random effects model. Results: Nineteen studies were identified for inclusion in the systematic review, assessing a total of 63 802 participants. Nine studies were included in the meta-analysis. Diagnostic criteria and classification of diastolic dysfunction differed substantially between studies. The median prevalence of diastolic dysfunction in studies including individuals with and without diastolic dysfunction was 35.1% (range 5.3-65.2%). Comparing diastolic dysfunction with normal diastolic function, the summary relative risk estimate for cardiovascular events or mortality was 3.53 (95% CI: 2.75-4.53; I2=85.5%; nine studies). Conclusions: Although the definitions found in the literature differ, the diagnosis of diastolic dysfunction is associated with a 3.53-fold increased risk of cardiovascular events or death. This finding highlights the importance of developing easily applicable and consensual diagnostic criteria, as well as fostering research on effective treatment strategies when diastolic dysfunction is identified in the subclinical stage. Resumo: Introdução: A disfunção diastólica (DD) é muito prevalente e representa um mecanismo fisiopatológico central para várias doenças cardiovasculares, especialmente para a insuficiência cardíaca com fração de ejeção preservada. Além disso, alguns estudos sugerem que a DD se associa a um aumento do risco de eventos cardiovasculares. Este estudo pretende determinar se a DD é um preditor de eventos cardiovasculares e mortalidade através de uma revisão sistemática e meta-análise. Métodos: Foi realizada uma pesquisa na Medline, desde 1974 até outubro de 2017. Foram incluídos estudos de coorte que avaliassem a função diastólica em adultos da comunidade, comparando participantes com e sem DD, no que diz respeito ao desenvolvimento de eventos cardiovasculares ou morte. Na meta-análise, os riscos relativos foram combinados usando um modelo de random-effects analysis. Resultados: Foram identificados dezanove estudos para a revisão sistemática, avaliando um total de 63 802 participantes, dos quais nove foram incluídos na meta-análise. Observámos que os critérios de diagnóstico e classificação de DD foram bastante diferentes entre os estudos. A prevalência mediana de DD foi 35,1% (variabilidade 5,3%-65,2%). A presença de DD associou-se a um aumento significativo do risco relativo combinado de evento cardiovascular ou mortalidade (3,53; IC 95%: 2,75-4,53; I2=85,5%; 9 estudos). Conclusões: Apesar da heterogeneidade na definição de DD, a sua presença está associada a um aumento marcado do risco de eventos cardiovasculares ou morte. Este resultado realça a importância de desenvolver critérios objetivos e consensuais para o diagnóstico de DD, de modo a promover a sua identificação numa fase subclínica e eventualmente estimular uma investigação dirigida à abordagem terapêutica precoce. Keywords: Diastole, Myocardial relaxation, Diastolic dysfunction, Prognosis, Cardiovascular events, Heart failure, Palavras-chave: Diástole, Relaxamento miocárdico, Disfunção diastólica, Prognóstico, Eventos cardiovasculares, Insuficiência cardíaca

Aim Comparison of short and mid-term outcomes between off-pump CABG (OPCAB) and on-pump CABG (ONCAB) in patients older than 65 throughout a meta-analysis of randomized clinical trials (RCTs). Evidence acquisition A literature search was conducted using 3 databases. RCTs reporting mortality outcomes of OPCAB versus ONCAB among the elderly were included. Data on myocardial infarction, stroke, re-revascularization, renal failure and composite endpoints after CABG were also collected. Random effects models were used to compute statistical combined measures and 95% confidence intervals (CI). Evidence synthesis Five RCTs encompassing 6221 patients were included (3105 OPCAB and 3116 ONCAB). There were no significant differences on mid-term mortality (pooled HR: 1.02, 95%CI: 0.89-1.17, p=0.80) and composite endpoint incidence (pooled HR: 0.98, 95%CI: 0.88-1.09, p=0.72) between OPCAB and ONCAB. At 30-day, there were no differences in mortality, myocardial infarction, stroke and renal complications. The need for early re-revascularization was significantly higher in OPCAB (pooled OR: 3.22, 95%CI: 1.28-8.09, p=0.01), with a higher percentage of incomplete revascularization being reported for OPCAB in trials included in this pooled result (34% in OPCAB vs 29% in ONCAB, p Conclusions Data from RCTs in elderly patients showed that OPCAB and ONCAB provide similar mid-term results. OPCAB was associated with a higher risk of early rerevascularization. As CABG on the elderly is still insufficiently explored, further RCTs, specifically designed targeting this population, are needed to establish a better CABG strategy for these patients.

Myocardial fluid homeostasis relies on a complex interplay between microvascular filtration, interstitial hydration, cardiomyocyte water uptake and lymphatic removal. Dysregulation of one or more of these mechanisms may result in myocardial oedema. Interstitial and intracellular fluid accumulation disrupts myocardial architecture, intercellular communication, and metabolic pathways, decreasing contractility and increasing myocardial stiffness. The widespread use of cardiac magnetic resonance enabled the identification of myocardial oedema as a clinically relevant imaging finding with prognostic implications in several types of heart failure. Furthermore, growing experimental evidence has contributed to a better understanding of the physical and molecular interactions in the microvascular barrier, myocardial interstitium and lymphatics and how they might be disrupted in heart failure. In this review, we summarize current knowledge on the factors controlling myocardial water balance in the healthy and failing heart and pinpoint the new potential therapeutic avenues.

The rapid pace of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges to the robust collection of population-scale data to address this global health crisis. We established the COronavirus Pandemic Epidemiology (COPE) Consortium to unite scientists with expertise in big data research and epidemiology to develop the COVID Symptom Study, previously known as the COVID Symptom Tracker, mobile application. This application-which offers data on risk factors, predictive symptoms, clinical outcomes, and geographical hotspots-was launched in the United Kingdom on 24 March 2020 and the United States on 29 March 2020 and has garnered more than 2.8 million users as of 2 May 2020. Our initiative offers a proof of concept for the repurposing of existing approaches to enable rapidly scalable epidemiologic data collection and analysis, which is critical for a data-driven response to this public health challenge.

Urocortin-2 (Ucn-2) is a peptide of the corticotrophin releasing factor-related family with several effects within the cardiovascular system. A variety of molecular mechanisms has been proposed to underlie some of these effects, although others remain mostly hypothetical. Growing interest in the cardiovascular properties of this peptide promoted several pre-clinical studies in the settings of heart failure and ischemia, as well as some experiments in the fields of systemic and pulmonary arterial hypertension. Most of these studies report promising results, with Ucn-2 showing therapeutic potential in these settings, and few clinical trials to date are trying to translate this potential to human cardiovascular disease. Ucn-2 also appears to have potential as a biomarker of diagnostic/prognostic relevance in cardiovascular disease, this being a recent field in the study of this peptide needing further corroboration. Regarding the increasing amount of evidence in Ucn-2 investigation, this work aims to make an updated review on its cardiovascular effects and molecular mechanisms of action and therapeutic potential, and to identify some research barriers and gaps in the study of this cardioprotective peptide.

Background The incidence of abdominal aortic aneurysm (AAA) repairs in Portugal is one of the lowest mentioned in the literature. This phenomenon can be justified either by a low prevalence of the disease or by its low detection rate. To date, the prevalence of the pathology is unknown. The objective of the study was to estimate the prevalence of AAA and its associated risk factors, in men aged ≥65 years and to evaluate the population's disease awareness. Methods All males aged ≥65 years registered in a Portuguese primary health care unit were invited to participate. The abdominal aorta was measured by ultrasound (inner to inner method). Concomitant risk factors and patient's AAA awareness were also assessed. An aortic diameter >30 mm was considered aneurysmatic. Results Nine hundred thirty-three patients were invited for the screening. Of these, 715 participated in the study (participation rate of 76.6%). The AAA prevalence in this sample was 2.1%. Eighty-five percent of the evaluated patients had never heard of the disease before. The mean age of the assessed population was 72.3 years; Multiple logistic regression analysis showed a positive association between AAA and history of smoking (odds ratio [OR] 8.8, P = 0.037) and history of dyslipidemia (OR 9.6, P = 0.035). A negative association was found between diabetes and AAA (OR 0.33, P = 0.045). Conclusions The found prevalence shows that a significant number of potentially fatal AAAs remains to be diagnosed in Portugal. These results highlight the need for an effective program of AAA detection in Portugal. The lack of awareness in the Portuguese population for this pathology should also prompt reflexion.

Objective/background Several abdominal aortic aneurysm (AAA) screening programs have demonstrated a similar prevalence of this disease in Westerns countries, ranging from 1.2% to 2.8%. However, the annual rate of AAA repair is significantly less even, and its relationship to AAA prevalence is not clear. The objective was to perform a systematic review, describing an international overview in the yearly rate of AAA repairs. Methods The number of elective and emergency AAA repairs was obtained via thorough review of publications indexed in PubMed and Scopus from 2010 to October 2018. Portuguese data were obtained from the national administrative database of health care. Data from the UK were extracted from the National Vascular Registry's 2015 annual report. Each country's population was assessed from published national censuses, thus allowing estimation of the number of AAAs treated per 100,000 habitants. Results Data from 14 countries were obtained. The yearly number of elective operations per 100,000 habitants was 2.2 in Hungary, 3.8 in Portugal, 5.3 in Spain, 5.9 in Iceland, 6.5 in Finland, 7.0 in New Zealand, 7.8 in the UK, 10.0 in Denmark, 10.2 in Sweden, 13.3 in the USA, 14.8 in Norway, 15.3 in the Netherlands, 15.6 in Italy, and 17.3 in Germany. The yearly rate of ruptured repairs was 0.5 in Hungary, 1.5 in Portugal, 1.8 in Spain, 1.7 in Iceland, 1.7 in Finland, 1.3 in New Zealand, 1.8 in the UK, 3.3 in Denmark (2013), 2.7 in Sweden (2013), 1.7 in the USA, 2.1 in Norway, 3.1 in the Netherlands, 2.3 in Italy, and 2.7 in Germany. Conclusion The rate of AAA treatment is highly variable, with a nearly eightfold variance between the countries with the highest and lowest rates of elective repair. Correlation between elective and ruptured repairs was not clear. A deeper understanding of the reasons for the disparities in AAA treatment among Western countries is of the utmost importance.

Introduction and objectives Which is the best carotid stenosis treatment remains a controversial issue. To present day, no study has compared the results of carotid artery stenting versus carotid endarterectomy in Portugal. We aim to provide real life numbers regarding the outcomes of both procedures in Portuguese public hospitals. Methods Every patient registered between 2005 and 2015 with the main diagnosis of carotid stenosis and submitted to carotid endarterectomy or carotid artery stenting was included. The information was obtained through the Central National Healthcare Administrative database, a mandatory registry for hospital refunding. Primary outcomes were hospital mortality and stroke. Patient demographics, comorbidities and hospital length of stay were also evaluated. Results The study included 6094 patients: 1399 were symptomatic (mention of prior stroke) and 4695 asymptomatic. Carotid artery stenting was performed on 22% of the symptomatic and 18% of the asymptomatic patients. In the symptomatic patients, the in-hospital mortality was significantly higher in those submitted to stenting (3.6% vs. 1.6% in carotid endarterectomy, p = 0.025). No significant differences in outcomes were observed in the asymptomatic group (mortality 0.9% vs. 0.8%, p = 0.852; stroke rate of 2.6% vs. 2.3%, p = 0.652 – carotid artery stenting vs. carotid endarterectomy). In both groups, there was an important increase in the proportion of stenting between 2005 and 2012, followed by a gradual decline until 2015. Conclusion Despite its increasing frequency, a higher early mortality was documented for CAS in symptomatic patients. No worse outcome was observed in asymptomatic patients.

The prognostic role of high-sensitivity C-reactive protein (hsCRP) in acute heart failure is less well established than for chronic heart failure and the impact of its variation is unknown. We studied the impact of hsCRP variation in acute heart failure and whether it differed according to left ventricular function.We analyzed patients prospectively included in an acute heart failure registry. Admission and discharge hsCRP were evaluated as part of the registry's protocol and its relative variation (ΔhsCRP) was assessed. ΔhsCRP during hospitalization = [(admission hsCRP - discharge hsCRP)/admission hsCRP] × 100. Endpoint: all-cause death; follow-up: 3 years. A multivariate Cox-regression model was used to assess the prognostic value of ΔhsCRP (continuous and categorical variable: cut-off 40% decrease); analysis was stratified according to ventricular function.We studied 439 patients: mean age 75 years, 50.1% men and 69.2% had heart failure with reduced ejection fraction (HFrEF). Median discharge hsCRP was 12.4 mg/l and median ΔhsCRP was ∼40%. During follow-up 247 patients (56.3%) died: 73 (54.1%) heart failure with preserved ejection fraction (HFpEF) patients and 174 (57.2%) HFrEF patients. The multivariate-adjusted hazard ratio of 3-year mortality in HFpEF patients with hsCRP decrease of at least 40% during hospitalization was 0.56 (95% CI 0.32-0.99). A decrease of at least 40% in hsCRP was not mortality-associated in HFrEF patients. There was interaction between ΔhsCRP and left ventricular ejection fraction.A decrease of at least 40% in hsCRP in acute heart failure was associated with a 44% decrease in 3-year death risk in HFpEF patients. No association between ΔhsCRP and prognosis existed in HFrEF patients. Inflammation appears to play a different role according to left ventricular function.

Resumen Introduccion y objetivos La hipertension causa cambios subclinicos en la estructura y la funcion del ventriculo izquierdo, es decir, disfuncion diastolica. La disfuncion diastolica es un predictor de insuficiencia cardiaca, pues participa en la asociacion entre hipertension e insuficiencia cardiaca con fraccion de eyeccion conservada. El objetivo es evaluar en una gran cohorte poblacional de adultos asintomaticos si los pacientes con prehipertension tienen cambios precoces en la funcion diastolica. Metodos Se evaluo de manera transversal una cohorte poblacional consistente en 925 adultos de 45 anos o mas sin enfermedad cardiovascular conocida. Todos los participantes se sometieron a un examen clinico y ecocardiografico detallado. Se clasifico a los participantes, segun las guias europeas para la clasificacion de la presion arterial (PA) en la consulta, como optima, prehipertension (normal y normal-alta) e hipertension. La funcion diastolica se evaluo mediante ecocardiografia usando las velocidades de e’ y la razon E/e’. La disfuncion diastolica se definio utilizando las recomendaciones conjuntas de ASE/EACVI de 2016 y un algoritmo de orientacion clinica de 2017. Resultados En esta cohorte (61,5 ± 10,5 anos; el 37% varones), tenia prehipertension el 30,4% e hipertension el 51,0%. Se utilizo la PA optima como referencia, y se observo una disminucion progresiva de la velocidad e’ en los individuos prehipertensos e hipertensos (12,2 ± 3,5 frente a 11,3 ± 3,1 frente a 9,6 ± 2,9 cm/s respectivamente; p de tendencia Conclusiones En esta cohorte poblacional, los adultos con prehipertension mostraron una relajacion cardiaca alterada antes del inicio de la hipertension.

Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Merck Background Metabolic syndrome (MetS) affects one out of 3 adults in the western world and is associated with preclinical diastolic dysfunction that impairs functional capacity and quality of life (QoL). Purpose This randomized trial was designed to evaluate if the addition of metformin to the standard treatment of non-diabetic patients with MetS improves diastolic dysfunction. Methods Prospective, randomized, open-label, blinded-endpoint trial. Fifty-four non-diabetic adults with MetS and diastolic dysfunction were randomized to lifestyle counseling or lifestyle counseling plus metformin (target dose 1000 mg bid). The primary endpoint was the change in mean e’ velocity (assessed at baseline, 6, 12 and 24 months). Secondary endpoints were improvements in insulin resistance, functional capacity and QoL. Linear mixed effects modelling was used for longitudinal data analysis using modified intention-to-treat (mITT) and per-protocol (PP) approaches. Results Forty-nine patients were included in the mITT analysis (mean age = 51.8 ± 6.4; 55% males). Metformin treatment was associated with a significant decrease in HOMA-IR. There was a significantly different mean change in e’ velocity during the study period between trial arms, both in the mITT (at 24 months, change of +0.67 ± 1.90cm/s in metformin arm vs. -0.33 ± 1.50cm/s in control arm) and PP populations (+0.80 ± 1.99cm/s in metformin arm vs. -0.37 ± 1.52cm/s in control arm), using a random intercept linear mixed model. There were no significant differences in peak oxygen uptake and SF-36 scores between trial arms. Conclusion Treatment with metformin of non-diabetic MetS patients with diastolic dysfunction, on top of lifestyle counseling, is associated with improved diastolic function. Abstract Figure.

Background: Often, pressure overload–induced myocardial remodeling does not undergo complete reverse remodeling after decreasing afterload. Recently, mitochondrial abnormalities and oxidative stress have been successively implicated in the pathogenesis of several chronic pressure overload cardiac diseases. Therefore, we aim to clarify the myocardial energetic dysregulation in (reverse) remodeling, mainly focusing on the mitochondria. Methods: Thirty-five Wistar Han male rats randomly underwent sham or ascending (supravalvular) aortic banding procedure. Echocardiography revealed that banding induced concentric hypertrophy and diastolic dysfunction (early diastolic transmitral flow velocity to peak early-diastolic annular velocity ratio, E/E′: sham, 13.6±2.1, banding, 18.5±4.1, P =0.014) accompanied by increased oxidative stress (dihydroethidium fluorescence: sham, 1.6×10 8 ±6.1×10 7 , banding, 2.6×10 8 ±4.5×10 7 , P Results: Two weeks later, hypertrophy decreased with the decline of oxidative stress (dihydroethidium fluorescence: banding, 2.6×10 8 ±4.5×10 7 , debanding, 1.96×10 8 ±6.8×10 7 , P P =0.029). The reduction of energetic demands imposed by overload relief allowed the mitochondria to reduce its activity and myocardial levels of phosphocreatine, phosphocreatine/ATP, and ATP/ADP to normalize in debanding towards sham values (phosphocreatine: sham, 38.4±7.4, debanding, 35.6±8.7, P =0.71; phosphocreatine/ATP: sham, 1.22±0.23 debanding, 1.11±0.24, P =0.59; ATP/ADP: sham, 6.2±0.9, debanding, 5.6±1.6, P =0.66). Despite the decreased mitochondrial area, complex III and V expression increased in debanding compared with sham or banding. Autophagy and mitophagy-related markers increased in banding and remained higher in debanding rats. Conclusions: During compensatory and maladaptive hypertrophy, mitochondria become more active. However, as the disease progresses, the myocardial energetic demands increase and the myocardium becomes energy deficient. During reverse remodeling, the concomitant attenuation of cardiac hypertrophy and oxidative stress allowed myocardial energetics, left ventricle hypertrophy, and diastolic dysfunction to recover. Autophagy and mitophagy are probably involved in the myocardial adaptation to overload and to unload. We conclude that these mitochondrial reversible changes underlie diastolic function adaptations during myocardial (reverse) remodeling.

Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (P = 0.022), hepatomegaly (P = 0.007) and sodium retention score (ρ = 0.37, P = 0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρ = -0.37, P = 0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (P = 0.027), right ventricle dilation (P = 0.008), and higher systolic pulmonary artery pressure (ρ = 0.34, P = 0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (r = 0.22, P = 0.055) and inversely with uric acid (r = 0.24, P = 0.029) and total (r = -0.30, P = 0.007) and low-density lipoprotein cholesterol (r = -0.23, P = 0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients.

Background. This study aimed to evaluate atrium extracellular matrix remodeling in atrial fibrillation (AF) patients with severe aortic stenosis, through histological fibrosis quantification and extracellular matrix gene expression analysis, as well as serum quantification of selected protein targets. Methods. A posthoc analysis of a prospective study was performed in a cohort of aortic stenosis patients. Between 2014 and 2019, 56 patients with severe aortic stenosis submitted to aortic valve replacement surgery in a tertiary hospital were selected. Results. Fibrosis was significantly increased in the AF group when compared to sinus rhythm (SR) patients (p = 0.024). Moreover, cardiomyocyte area was significantly higher in AF patients versus SR patients (p = 0.008). Conversely, collagen III gene expression was increased in AF patients (p = 0.038). TIMP1 was less expressed in the atria of AF patients. MMP16/TIMP4 ratio was significantly decreased in AF patients (p = 0.006). TIMP1 (p = 0.004) and TIMP2 (p = 0.012) were significantly increased in the serum of AF patients. Aortic valve maximum (p = 0.0159) and mean (p = 0.031) gradients demonstrated a negative association with serum TIMP1. Conclusions. Atrial fibrillation patients with severe aortic stenosis present increased atrial fibrosis and collagen type III synthesis, with extracellular matrix remodelling demonstrated by a decrease in the MMP16/TIMP4 ratio, along with an increased serum TIMP1 and TIMP2 proteins. This study was supported by the Cardiovascular R&D Center, financed by national funds through FCT—Fundação para a Ciência e Tecnologia, I.P., under the scope of the projects UID/IC/00051/2019 and UIDP/00051/2020, and Fundo Europeu de Desenvolvimento Regional (FEDER) through Compete 2020 – Programa Operacional Competitividade E Internacionalização (POCI), the project DOCNET (Norte-01-0145-FEDER-000003), supported by Norte Portugal regional operational programme (Norte 2020), under the Portugal 2020 partnership agreement, through the European Regional Development Fund (ERDF), the project NETDIAMOND (POCI-01-0145-FEDER-016385), supported by European Structural And Investment Funds, Lisbon’s regional operational program 2020.

Objectives: We conducted a meta-analysis of randomized controlled trials (RCTs) and propensity score (PS) studies comparing survival and major adverse cardiac and cerebrovascular events (MACCEs) of patients who underwent coronary artery bypass grafting (CABG) with multiple (MAG) versus single arterial grafting (SAG). Methods: MEDLINE, Web of Science and Cochrane Library were used to find relevant literature (1960-2018). Survival at a follow-up ≥ 1 year, MACCEs and early outcomes were evaluated. Time-to-event outcomes were collected through hazard ratio (HR) along with their variance, and the other endpoints using frequencies from matched sample or adjusted odds ratios. Random effect models were used to compute combined statistical measures and 95% confidence intervals (CI) through generic inverse variance method (time-to-event) or Mantel-Haenszel method (binary events). Results: Twenty-nine PS cohorts and 8 RCTs comprising 122832 patients (52178 MAG and 70654 SAG) were included in this meta-analysis. MAG was associated with lower early mortality (OR: 0.82, 95%CI: 0.71-0.95, p=0.007), long-term mortality (HR: 0.76, 95%CI: 0.73-0.78, p

INTRODUCAO: A evidencia existente relativamente aos outcomes da terapia de dupla antiagregacao (DAPT) em pacientes submetidos a cirurgia de revascularizacao do miocardio (CABG) e conflituosa. Com este estudo, pretendemos comparar outcomes de sobrevivencia e seguranca da DAPT versus aspirina (ASA) numa janela temporal de 24h apos CABG. METODOS: Estudo unicentrico de coorte retrospetiva, em pacientes submetidos consecutivamente a primeiro CABG isolado em 2010. A analise de sobrevivencia (mediana de follow-up de 9 anos) foi realizada com curvas Kaplan-Meier e regressao multivariada Cox utilizando Propensity Score (PS) como covariavel com DAPT. A hemorragia foi avaliada atraves da transfusao de globulos rubros (RBC), re-exploracao do torax e drenagem pos-operatoria. RESULTADOS: Incluimos 351 pacientes, 251 dos quais sob DAPT (71.5%). As curvas Kaplan-Meier demonstram sobrevivencia cumulativa similar entre grupos (9a: 75% DAPT vs. 67% ASA, Log-rank p=0.103), bem como na analise ajustada por PS (HR DAPT: 0.93, 95%CI:0.57-1.51). Tendo em conta outcomes de seguranca, nao encontramos diferencas na mortalidade precoce (2 no grupo DAPT e 1 no grupo ASA). A transfusao mediana total do cell-saver (300mL vs. 250mL, p=0.318) e a re-exploracao do torax devido a hemorragia (1.6% vs. 4%, p=0.231) tambem nao mostra diferenca estatisticamente significativa. Por outro lado, a drenagem toracica pos-operatoria foi superior no grupo ASA (1220mL DAPT vs. 1300mL ASA, p=0.043). Tambem verificamos, nos pacientes DAPT, uma necessidade inferior de ≥3 transfusoes RBC no peri e pos-operatorio (8.5% vs. 13.3% p

Conventional treatments for heart failure have failed to improve survival in heart failure with preserved ejection fraction (HFpEF). The current therapy recommendations highlight the importance of symptom management and improvement of patient's well-being or other health-related outcomes. Physical activity/exercise training might be an adjuvant treatment option, since several studies in HFpEF patients reported beneficial effects on exercise intolerance, which is the main symptom associated with this disease. In addition, exercise training was shown to improve quality of life and, in some studies, to improve cardiac function. However, the mechanisms behind these effects are not completely known. The objective of this narrative review is to summarize the main clinical findings regarding the role of physical activity/exercise training in several outcomes, such as hospitalization and mortality, exercise capacity, quality of life, and cardiac function and remodeling. In addition, we will briefly discuss the findings provided by pre-clinical studies. In conclusion, while the impact of physical activity/exercise training on exercise intolerance and quality of life is already well known, its effect on mortality and hospitalization is not well documented, and whether it benefits diastolic function needs further investigation. Some clinical studies showed that exercise training can improve diastolic function, and evidences from pre-clinical studies suggest that this effect is mediated through reduced myocardial stiffness.

Endothelial dysfunction is one of the earliest indicators of cardiovascular (CV) dysfunction, and its evaluation would be of considerable importance to stratify CV risk of many diseases and to assess the efficacy of atheroprotective treatments. Flow-mediated dilation is the most widely used method to study endothelial function. However, it is operator-dependent and can be influenced by physiological variations. Circulating biomarkers are a promising alternative. Due to the complexity of endothelial function, many of the biomarkers studied do not provide consistent information about the endothelium when measured alone. New circulating markers are being explored and some of them are thought to be suitable for the clinical setting. In this review, we focus on novel biomarkers of endothelial dysfunction, particularly endothelial microparticles, endocan, and endoglin, and discuss whether they fulfill the criteria to be applied in clinical practice.

Objective. (i) To compare daily physical activity (PA) levels evaluated by the International Physical Activity Questionnaire (IPAQ) and by triaxial accelerometry in heart failure with preserved ejection fraction (HFpEF) patients; (ii) to describe daily PA patterns based in objective measurements; and (iii) to observe the association between prognostic indicators and PA measurements. Design. This is a cross-sectional study with 24 stable HFpEF patients. PA was assessed through the IPAQ short version and triaxial accelerometer. Time spent in moderate-to-vigorous PA (MVPA) from IPAQ was computed as self-reported walking and MVPA. Prognostic indicators were: distance on the 6-minute-walking test (6MWT), oxygen consumption (VO2) during the test, quality of life (QoL), BNP plasma level, and E/e' ratio. Results. Compared to accelerometry, IPAQ underestimated sedentary time (253 ± 156 vs. 392 ± 104 min/day, p = .001) and overestimated MVPA (44 ± 56 vs. 19.3 ± 26 min/day, p < .001). Accelerometer-derived data showed that HFpEF patients spent 50% of their waking time in sedentary behaviours and 2.5% in MVPA. Of measured surrogate prognostic markers, functional capacity (6MWT, r = 0.652, p = .04; VO2, r = 0.512, p = .02) and QoL (r=-0.490, p = .04) were correlated with MVPA. Conclusions. The IPAQ underestimated sedentary time and over-estimated MVPA in HFpEF patients. Using accelerometer-derived data, HFpEF patients spent only a minority of their time involved in MVPA, which was the only PA pattern positively associated with prognostic indicators. info:eu-repo/semantics/publishedVersion

Aims: The metabolic syndrome and associated comorbidities, like diabetes, hypertension and obesity, have been implicated in the development of heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms underlying the development of HFpEF remain to be elucidated. We developed a cardiome-directed network analysis and applied this to high throughput cardiac RNA-sequencing data from a well-established rat model of HFpEF, the obese and hypertensive ZSF1 rat. With this novel system biology approach, we explored the mechanisms underlying HFpEF.Methods and results: Unlike ZSF1-Lean, ZSF1-Obese and ZSF1-Obese rats fed with a high-fat diet (HFD) developed diastolic dysfunction and reduced exercise capacity. The number of differentially expressed genes amounted to 1591 and 1961 for the ZSF1-Obese vs. Lean and ZSF1-Obese+HFD vs. Lean comparison, respectively. For the cardiome-directed network analysis (CDNA) eleven biological processes related to cardiac disease were selected and used as input for the STRING protein-protein interaction database. The resulting STRING network comprised 3.460 genes and 186.653 edges. Subsequently differentially expressed genes were projected onto this network. The connectivity between the core processes within the network was assessed and important bottleneck and hub genes were identified based on their network topology.Classical gene enrichment analysis highlighted many processes related to mitochondrial oxidative metabolism. The CDNA indicated high interconnectivity between five core processes: endothelial function, inflammation, apoptosis/autophagy, sarcomere/cytoskeleton and extracellular matrix. The transcription factors Myc and Peroxisome Proliferator-Activated Receptor-alpha (Ppara) were identified as important bottlenecks in the overall network topology, with Ppara acting as important link between cardiac metabolism, inflammation and endothelial function.Conclusions: This study presents a novel systems biology approach, directly applicable to other cardiac disease related transcriptome data sets. The CDNA approach enabled the identification of critical processes and genes, including Myc and Ppara, that are putatively involved in the development of HFpEF.

Objective: To report the hemodynamic profile and short- and medium-term outcomes of Freedom Solo and Solo Smart stentless aortic valves implanted at our center. Methods: Between 2009 and 2015, all patients undergoing aortic valve replacement using Solo stentless valves at our center were enrolled. Clinical and echocardiographic follow-up was carried out six months postoperatively. Survival and major events, including structural valve deterioration and non-structural valve dysfunction, endocarditis, reoperation and stroke, were assessed through medical records or telephone interview with the referring cardiologist up to November 2015 (mean and maximum follow-up 39±22 and 78 months, respectively). Results: Patients’ (n=345) mean age was 72±8 years, 52% were female and median euroSCORE II was 2.7 (1.5-4.7). There was no intraoperative mortality and in-hospital mortality was 2.6%. Postoperatively, mean transvalvular gradient was 11.9±4.5 mmHg and effective orifice area was 1.9±0.5 cm2. Patient-prosthesis mismatch occurred in 14% but was severe in only one patient. Cumulative survival at six years was 72%. Six patients were reoperated: three due to endocarditis, two for structural prosthesis deterioration and one because of periprosthetic fistula. Five patients suffered stroke, three had medically-treated endocarditis and one had structural valve deterioration but was not considered suitable for reoperation. None of the remainder had structural valve deterioration or non-structural valve dysfunction. Conclusions: Solo stentless aortic valves are safe to implant, with promising clinical outcomes in short- and medium-term assessment. Moreover, they show an excellent hemodynamic performance: low transvalvular gradients, large effective orifice areas and low incidence of patient-prosthesis mismatch. Resumo: Objetivo: Descrever o perfil hemodinâmico e resultados clínicos a curto e médio prazo das biopróteses aórticas stentless Freedom SOLO e SOLO Smart implantadas no nosso Centro. Métodos: Foram incluídos todos os doentes submetidos a substituição valvular aórtica por biopróteses stentless SOLO no nosso Centro, entre 2009 e 2015. O follow-up clínico e ecocardiográfico foi aos seis meses de pós-operatório. A sobrevida e eventos major (deterioração valvular estrutural, disfunção valvular não estrutural, endocardite, reoperação, acidente vascular cerebral) foram aferidos através de registos clínicos e entrevista telefónica com o Cardiologista assistente até novembro de 2015 (follow-up médio 39±22 meses, máximo 78). Resultados: A idade média dos doentes (n=345) foi 72±8 anos, 52% eram do sexo feminino e a mediana de euroSCORE II foi 2,7 (1,5–4,7). A mortalidade hospitalar foi 2,6%, não havendo mortalidade intra-operatória. O gradiente transvalvular médio pós-operatório e a média da área de orifício efetivo foram 11,9 ±4,5 mmHg e 1,9 ±0,5 cm2, respetivamente. O mismatch prótese-doente ocorreu em 14% dos casos, sendo um severo. A sobrevida cumulativa aos seis anos foi 72%. Seis indivíduos foram reoperados: três por endocardite infeciosa, dois por deterioração protésica e um por fístula periprotésica. Registaram-se cinco acidentes vasculares cerebrais, três endocardites tratadas farmacologicamente e um caso de deterioração valvular sem condições clínicas para reoperação. Não se registaram outras deteriorações valvulares estruturais ou disfunções valvulares não estruturais. Conclusões: As biopróteses stentless SOLO apresentaram resultados a curto e médio prazo promissores, revelando um excelente perfil hemodinâmico: baixos gradientes transvalvulares, áreas de orifício efetivo grandes e baixa incidência de mismatch prótese-doente. Keywords: Aortic valve replacement, Stentless aortic bioprosthesis, Cardiac surgery, Palavras-chave: Substituição valvular aórtica, Bioprótese aórtica stentless, Cirurgia cardíaca

Disturbed metabolism as a consequence of obesity and diabetes may cause cardiac diseases (recently highlighted in the cardiovascular research spotlight issue on metabolic cardiomyopathies).1 In turn, the metabolism of the heart may also be disturbed in genetic and acquired forms of hypertrophic cardiac disease. Herein, we provide an overview of recent insights on metabolic changes in genetic hypertrophic cardiomyopathy and discuss several therapies, which may be explored to target disturbed metabolism and prevent onset of cardiac hypertrophy.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology. ispartof: CARDIOVASCULAR RESEARCH vol:114 issue:10 pages:1273-1280 ispartof: location:England status: published

Aims Pulmonary arterial hypertension (PAH) is a devastating disease and treatment options are limited. Urocortin-2 (Ucn-2) has shown promising therapeutic effects in experimental and clinical left ventricular heart failure (HF). Our aim was to analyse the expression of Ucn-2 in human and experimental PAH, and to investigate the effects of human Ucn-2 (hUcn-2) administration in rats with monocrotaline (MCT)-induced pulmonary hypertension (PH). Methods and results Tissue samples were collected from patients with and without PAH and from rats with MCT-induced PH. hUcn-2 (5 μg/kg, bi-daily, i.p., for 10 days) or vehicle was administered to male wistar rats subjected to MCT injection or to pulmonary artery banding (PAB) to induce right ventricular (RV) overload without PAH. Expression of Ucn-2 and its receptor was increased in the RV of patients and rats with PAH. hUcn-2 treatment reduced PAH in MCT rats, resulting in decreased morbidity, improved exercise capacity and attenuated pulmonary arterial and RV remodelling and dysfunction. Additionally, RV gene expression of hypertrophy and failure signalling pathways were attenuated. hUcn-2 treatment also attenuated PAB-induced RV hypertrophy. Conclusions Ucn-2 levels are altered in human and experimental PAH. hUcn-2 treatment attenuates PAH and RV dysfunction in MCT-induced PH, has direct anti-remodelling effects on the pressure-overloaded RV, and improves pulmonary vascular function.

Objectives The goal of this study was to compare the stentless Freedom Solo® (FS) and the stented Trifecta® (TF) aortic bioprostheses with regard to haemodynamic profile, left ventricular mass regression and early and late postoperative outcomes and survival. Methods A longitudinal cohort study of consecutive patients undergoing aortic valve replacement (2009-16) with either the FS or TF at 1 centre was performed. Local databases and national records were queried. Prosthesis haemodynamics and left ventricular dimensions were obtained from postoperative echocardiograms. After propensity score matching (21 covariates), the Kaplan-Meier and competing risk analyses were performed for survival and the combined outcome of structural valve deterioration and endocarditis, respectively. Haemodynamics and mass regression were assessed by a mixed-effects model including propensity score as a covariate. Results From a total sample of 397 patients with the FS and 525 TF bioprostheses with a median follow-up time of 4.0 (2.2-6.0) and 2.4 (1.4-3.7) years, respectively, a matched sample of 329 pairs was obtained. Matched groups showed no differences in survival (hazard ratio = 1.04, 95% confidence interval = 0.69-1.56) or cumulative hazards of combined outcome (subdistribution hazard ratio = 0.54, 95% confidence interval = 0.21-1.39). Although the TF showed an improved haemodynamic profile, no difference was found in mass regression. Patients with TF bioprostheses had higher rates of prolonged mechanical ventilation, whereas patients with the FS bioprosthesis showed higher rates of thrombocytopenia. Conclusions The TF showed an improved haemodynamic profile compared to the FS, but this did not translate into further reverse remodelling. Postoperative outcomes and survival rates were comparable for both bioprostheses. Long-term follow-up is needed for comparisons with classical bioprosthesis models.

Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.

Aims The heart is constantly challenged with acute bouts of stretching or overload. Systolic adaptations to these challenges are known but adaptations in diastolic stiffness remain unknown. We evaluated adaptations in myocardial stiffness due to acute stretching and characterized the underlying mechanisms. Methods and results Left ventricles (LVs) of intact rat hearts, rabbit papillary muscles and myocardial strips from cardiac surgery patients were stretched. After stretching, there was a sustained >40% decrease in end-diastolic pressure (EDP) or passive tension (PT) for 15 min in all species and experimental preparations. Stretching by volume loading in volunteers and cardiac surgery patients resulted in E/E’ and EDP decreases, respectively, after sustained stretching. Stretched samples had increased myocardial cGMP levels, increased phosphorylated vasodilator-stimulated phosphoprotein phosphorylation, as well as, increased titin phosphorylation, which was reduced by prior protein kinase G (PKG) inhibition (PKGi). Skinned cardiomyocytes from stretched and non-stretched myocardia were studied. Skinned cardiomyocytes from stretched hearts showed decreased PT, which was abrogated by protein phosphatase incubation; whereas those from non-stretched hearts decreased PT after PKG incubation. Pharmacological studies assessed the role of nitric oxide (NO) and natriuretic peptides (NPs). PT decay after stretching was significantly reduced by combined NP antagonism, NO synthase inhibition and NO scavenging, or by PKGi. Response to stretching was remarkably reduced in a rat model of LV hypertrophy, which also failed to increase titin phosphorylation. Conclusions We describe and translate to human physiology a novel adaptive mechanism, partly mediated by titin phosphorylation through cGMP–PKG signalling, whereby myocardial compliance increases in response to acute stretching. This mechanism may not function in the hypertrophic heart.

As heart failure with preserved ejection fraction (HFpEF) rises to epidemic proportions, major steps in patient management and therapeutic development are badly needed. With the current position paper we seek to update our view on HFpEF as a highly complex systemic syndrome, from risk factors and mechanisms to long-term clinical manifestations. We will revise recent advances in animal model development, experimental set-ups and basic and translational science approaches to HFpEF research, highlighting their drawbacks and advantages. Directions are provided for proper model selection as well as for integrative functional evaluation from the in vivo setting to in vitro cell function testing. Additionally, we address new research challenges that require integration of higher-order inter-organ and inter-cell communication to achieve a full systems biology perspective of HFpEF.

Resumen Introduccion y objetivos La obesidad es un importante factor de riesgo cardiovascular, y parece ser que la localizacion de los depositos de grasa determina de manera importante su impacto metabolico. El tejido adiposo visceral (TAV) ejerce un efecto perjudicial en la homeostasis metabolica, pero pocos estudios longitudinales han evaluado el impacto pronostico de la relacion entre el TAV y el tejido adiposo subcutaneo (TAS). Este estudio tiene por objetivo evaluar si el cociente TAV/TAS se asocia con la mortalidad por todas las causas y los eventos cardiacos. Metodos Registro basado en estudio de cohortes retrospectivo. Se eligio para el estudio a pacientes sin enfermedad cardiaca conocida remitidos a coronariografia por tomografia computarizada (TC) por sospecha de enfermedad arterial coronaria (EAC). Se incluyo a todos los pacientes con informacion disponible sobre el TAV, las areas del TAS y el score de calcio de las arterias coronarias (CAC). Se evaluo el criterio de valoracion combinado de mortalidad por todas las causas, infarto de miocardio o revascularizacion al menos 1 mes despues de la TC cardiaca. Resultados La poblacion final incluida fue de 713 participantes (el 61% varones; media de edad, 57,7 ± 10,2 anos), seguidos una media de 1,3 anos. Sufrieron el criterio de valoracion combinado 66 pacientes, que mostraron una mayor relacion TAV/TAS (1,06 ± 0,74 frente a 0,80 ± 0,52; p = 0,0001). El cociente TAV/TAS fue un predictor independiente de muerte y eventos cardiacos (HR = 1,43; IC95%, 1,03-1,99), independientemente de los factores de riesgo cardiovascular, la CAC y la presencia de EAC. Conclusiones El cociente TAV/TAS a nivel abdominal fue un predictor independiente de eventos coronarios y muerte, independientemente de los factores de riesgo cardiovascular, la CAC o la presencia de EAC. Esta relacion es una medida derivada de la TC y puede ser util para identificar mejor a los pacientes con mayor riesgo de muerte o eventos cardiacos.

Objectives To review the effectiveness of manual thrombectomy (MT) in a series of patients with ST-elevation myocardial infarction (STEMI) exclusively presenting with TIMI 0-1 flow undergoing percutaneous coronary intervention (PCI), in accordance to the angiographically estimated area at risk (AAR). Second, to assess major in-hospital clinical events, emphasizing neurological outcomes. Background The routine utilization of MT in STEMI is not recommended. However, in recent trials, a significant proportion of patients had neither large thrombus burden nor a totally occluded coronary segment, neutralizing the expected benefits of MT. In addition, the efficiency of MT to remove thrombus has rarely been addressed. Finally, MT diminished distal embolization, which has been related to mortality. Results In 850 consecutive STEMI-patients, MT was utilized in 525 (62%) and it was considered efficient (TIMI 2-3 flow after MT) in 445 (85%). We found a significant interaction between the AAR and the effectiveness of MT to reduce infarct size (P-interaction = 0.014). In patients having AAR ≥ 28% (n = 184), efficient MT conferred lesser infarct size compared to inefficient MT (Ln-transformed peak CK): 7.87 ± 0.86 versus 8.36 ± 0.41 IU/L, P = 0.005, with no impact for AAR

We read with great interest the paper by Aquaro et al. ([1][1]), reporting an association between cardiac magnetic resonance remodeling patterns at the 6-month follow-up and prognosis in acute myocarditis (AM). We recently reported the presence of subepicardial edema in patients with septic