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New findings What is the central question of this study? Right ventricle (RV) dysfunction is highly prevalent in heart failure with preserved ejection fraction (HFpEF), nearly doubling the risk of death. Knowledge about the RV functional and structural changes in HFpEF and the effect of aerobic exercise is still limited and desirable to expand. What is the main finding and its importance? The HFpEF ZSF1 rat model presents RV structural and functional changes, mimicking the human condition. We show that aerobic exercise prevented the decline in VO2 max, lowered surrogate markers of RV overload (e.g., higher mean and maximum systolic pressure) and improved diastolic dysfunction (e.g., end-diastolic pressure and relaxation time constant). This knowledge emphasizes the importance of using exercise to manage HFpEF. Abstract Background : Right ventricular (RV) dysfunction is highly prevalent in HFpEF and is a marker of poor prognosis. We assessed the ZSF1 obese model of HFpEF to confirm if these rats also develop RV dysfunction and evaluated if aerobic exercise could prevent them. Methods and results ZSF1 obese rats were randomly allocated to aerobic exercise training group (n = 7; treadmill running, 5days/week, 60min/day, 15m/min, for 5 weeks) or to a sedentary group (n = 7). We also used ZSF1 lean rats (n = 7) as control group. After 5 weeks, rats were submitted to an exercise tolerance test, invasive hemodynamic evaluation, sacrificed and samples from RV were collected for histologic analysis. ZSF1 obese sedentary rats showed lower VO2 max, RV pressure-overload (e.g., higher mean and maximum systolic pressure) and diastolic dysfunction (e.g. higher minimal and end-diastolic pressurem and relaxation time constant), paralleled by RV cardiomyocyte hypertrophy. Except for cardiomyocyte hypertrophy, aerobic exercise prevented these functional changes.. Conclusions Our data supports that this model of HFpEF shows functional and structural changes in the RV that resemble the human HFpEF phenotype, reinforcing its utility to understand the pathophysiology and to adress novel therapeutic targets to manage HFpEF. In addition, we show that aerobic exercise is cardioprotective for the RV. A deeper knowledge of the mechanisms underlying the benefits of aerobic exercise could also lead to the identification of therapeutic targets to be further explored. This article is protected by copyright. All rights reserved.

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.

Cardiovascular diseases (CVD) remain the biggest cause of deaths worldwide and a major socio-economic impact to society. In this work, we conducted an unbiased exploratory analysis of the large-scale lipidome in human plasma samples from patients with fatal and non-fatal CVD from large cohorts. The exploratory analysis included data from 10,349 individuals from 20 countries in Asia, Australasia, Europe and North America (ADVANCE cohort), and thus representative of the worldwide population. Through the analysis of hazard ratios (HR), we found 306 lipids relevant in CV Death and 294 lipids relevant in CV Events of which 262 lipids were common to fatal and non-fatal events followed over time (3, 5 and 8 years). Our exploratory analysis reveals that, over time, the plasma lipid signature found in non-fatal CVD events is similar to that preceding CVD death. Among the common lipid signature, we found that sphingolipids (HexCer, SM, Cer and other glycosphingolipids) and phospholipids (PC and PE) were strongly associated with CVD events outcome, while polyunsaturated plasmenyl PC and PE lipids were inversely associated with CV outcome. The restricted panel of specific lipids has the potential to improve CVD risk stratification and management, and significantly reduce the time involved in the analysis and data treatment in low-resolution MS instruments making plasma lipidomics a cost-efficient approach for clinical scenario. In our view, once standardized clinical, analytical and data reporting guidelines are implemented worldwide, lipid-based discriminators can be routinely applied in the CVD risk stratification and improve the performance of current clinical, biochemical and imaging diagnostic tools assisting the decision-making process particularly in patients with multiple co-morbidities.

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

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.

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.

Septic cardiomyopathy is an increasingly relevant topic in clinical management of septic shock. However, pathophysiological mechanisms and long-term consequences of sepsis-induced myocardial injury are still poorly understood. Herein, new clinical and histological evidence is provided suggesting an association of myocardial edema formation with tissue injury and subsequent remodeling in septic shock patients. This preliminary data supports myocardial edema as a potentially relevant and largely unexplored mechanism of human septic cardiomyopathy.

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

Background/aims Heart failure with preserved ejection fraction (HFpEF) is recognised as an important cause of cardiovascular mortality and morbidity, accounting for approximately 50% of heart failure cases. Metabolic-related complications, such as obesity, have been associated with the pathophysiology of this complex syndrome. The anatomic proximity between cardiac visceral adipose tissue (CVAT) and the myocardium has been drawing attention due to its potential pathogenic role in cardiac diseases. Thus, we aimed to characterise the phenotypic and proteomic differences between CVAT from ZSF1 lean (control) and ZSF1 obese (HFpEF) rats as well as to evaluate the myocardial impact of conditioned media derived from CVAT of these 2 groups. Methods CVAT of 20-weeks-old lean and obese ZSF1 rats was collected for: 1) 24h DMEM incubation to obtain conditioned media, 2) separation of proteins to mass spectrometry identification, 3) adipokines' expression, 4) adipocytes cross-sectional area assessment. Organotypic cultures were prepared from 7 days-old Wistar Han cardiac explants and incubated for 24h with the conditioned media. After incubation, cross-section area of cardiomyocytes and fibrosis were evaluated. Cardiomyocytes were isolated from Wistar Han and incubated with conditioned media for viability studies. Results CVAT from lean rats presented a higher expression of uncoupling protein-1 (UCP-1) protein, associated with a multilocular appearance and an increased expression of brown adipose tissue markers. Contrarily, CVAT from obese rats revealed a white adipose tissue-like phenotype accompanied by hypertrophy of adipocytes. The analysis of the CVAT proteome reinforced the phenotypic differences between lean and obese CVAT, showing enrichment of proteins involved in triglyceride metabolic processes in obese CVAT. In contrast, mitochondrial proteins were prominent in lean CVAT, further suggesting a brown adipose tissue-like phenotype. The twenty-four hours-long incubation of myocardial organo-cultures with conditioned media obtained from CVAT obese (CM-obese) rats significantly reduced cell viability, induced cardiomyocytes hypertrophy and fibrosis, in stark contrast with the incubation with the conditioned media from lean rats CVAT (CM-lean). Furthermore, the deleterious effect imposed by CM-obese was associated with a pro-inflammatory profile, characterised by an increased expression of several pro-inflammatory adipokines. Conclusion Obesity promotes alterations in CVAT proteome signature, structure, composition and secretome, translating into dramatic myocardial consequences.

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.

The peptide hormone relaxin was originally linked to reproductive physiology, where it is believed to mediate systemic and renal hemodynamic adjustments to pregnancy. Recently, its broad range of effects in the cardiovascular system has been the focus of intensive research regarding its implications under pathological conditions and potential therapeutic potential. An understanding of the multitude of cardioprotective actions prompted the study of serelaxin, recombinant human relaxin-2, for the treatment of acute heart failure. Despite early promising results from phase II studies, recently revealed RELAX-AHF-2 outcomes were rather disappointing and the treatment for acute heart failure remains an unmet medical need. This article reviews the physiologic actions of relaxin on the cardiovascular system and its relevance in the pathophysiology of cardiovascular disease. We summarize the most updated clinical data and discuss future directions of serelaxin for the treatment of acute heart failure. This should encourage additional work to determine how can relaxin's beneficial effects be exploited for the treatment of cardiovascular disease.

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.

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.

Background Post-operative atrial fibrillation (POAF) is the most common complication after cardiac surgery. Recent studies had shown this phenomenon is no longer considered transitory and is associated with higher risk of thromboembolic events or death. The aim of this study was to systematically review and analyze previous studies comparing oral anticoagulation therapy with no anticoagulation, regarding these long-term outcomes. Methods PubMed/MEDLINE, EMBASE, Web of Science and Cochrane Database were systematically searched to identify the studies comparing the risk of stroke, or thromboembolic events or mortality of POAF patients who received anticoagulation compared with those who were not anticoagulated. Incidence of stroke, thromboembolic events and all-cause mortality were evaluated up to 10 years after surgery. Time-to-event outcomes were collected through hazard ratio (HR) along with their variance and the early endpoints using frequencies or odds ratio (OR). Random effect models were used to compute statistical combined measures and 95% confidence intervals (CI). Heterogeneity was evaluated through Q statistic-related measures of variance (Tau2, I2, Chi-squared test). Results Eight observational cohort studies were selected, including 15,335 patients (3492 on Oral Anticoagulants (OAC) vs 11,429 without OAC) that met the inclusion criteria for qualitative synthesis. Patients had a wide gender distribution (38.6–82.3%), each study with a mean age above 65 years (67.5–85). Vitamin K antagonists were commonly prescribed anticoagulants (74.3–100%). OAC was associated with a protective impact on all-cause mortality at a mean of 5.0 years of follow-up (HR is 0.85 [0.72–1.01]; p = 0.07; I2 = 48%). Thromboembolic events did not differ between the two treatment arms (HR 0.68 [0.40–1.15], p = 0.15). Conclusion Current literature suggests a possibly protective impact of OAC therapy for all-cause mortality in patients with new-onset atrial fibrillation after cardiac surgery. However, it does not appear to impact thromboembolism rate.

IntroductionPatients with type 2 diabetes (T2D) have an increased risk of worsening kidney function (WKF) over time compared with patients without diabetes. Data evaluating the inter-relation between WKF, cardiovascular risk, and clinical events are scarce. We aim to study the association of WKF with subsequent cardiovascular events and the probabilities of transition from WKF to hospitalization or death according to patients’ risk. We have used a large population of patients with T2D and a high cardiovascular risk enrolled in the Action to Control Cardiovascular Risk in Diabetes Study.Research design and methodsTime-updated, joint, and multistate modeling were used. WKF was defined as an estimated glomerular filtration rate (eGFR) decline greater than 40% from baseline. A total of 10 251 patients were included, of whom 1213 (11.8%) presented WKF over a median (percentile25–75) follow-up time of 5.0 (4.1–5.7) years.ResultsPatients who experienced WKF were slightly older, more frequently women, and had longer diabetes duration. Patients experiencing WKF, regardless of baseline kidney function, had a higher risk of subsequent cardiovascular events, including the composite of cardiovascular death or hospitalization for heart failure (HHF), with ≈2-fold higher risk. Joint modeling showed that renal function deterioration frequently occurs even among patients who did not experience a cardiovascular event. In multistate models, patients with a medium-high cardiovascular risk (compared with those with a low cardiovascular risk) are at higher risk of HHF or cardiovascular death first (HR=4.76, 95% CI 3.63 to 6.23) than of WKF first (HR=1.37, 95% CI 1.21 to 1.56); remarkably, the risk of cardiovascular death or HHF is highest after a WKF event (HR=6.20, 95% CI 2.71 to 14.8).ConclusionsIn patients with T2D and a high cardiovascular risk, WKF occurs in more than 10% of patients and is independently associated with risk of subsequent cardiovascular events, irrespective of baseline eGFR. Preventing serious WKF and the transition from WKF to HHF or cardiovascular death is an important objective of future trials.Trial registration numberNCT00000620.

To better understand the left ventricular (LV) reverse remodeling (RR), we describe a rodent model wherein, after aortic banding-induced LV remodeling, mice undergo RR upon removal of the aortic constriction. In this paper, we describe a step-by-step procedure to perform a minimally invasive surgical aortic debanding in mice. Echocardiography was subsequently used to assess the degree of cardiac hypertrophy and dysfunction during LV remodeling and RR and to determine the best timing for aortic debanding. At the end of the protocol, terminal hemodynamic evaluation of the cardiac function was conducted, and samples were collected for histological studies. We showed that debanding is associated with surgical survival rates of 70-80%. Moreover, two weeks after debanding, the significant reduction of ventricular afterload triggers the regression of ventricular hypertrophy (~20%) and fibrosis (~26%), recovery of diastolic dysfunction as assessed by the normalization of left ventricular filling and end-diastolic pressures (E/e' and LVEDP). Aortic debanding is a useful experimental model to study LV RR in rodents. The extent of myocardial recovery is variable between subjects, therefore, mimicking the diversity of RR that occurs in the clinical context, such as aortic valve replacement. We conclude that the aortic banding/debanding model represents a valuable tool to unravel novel insights into the mechanisms of RR, namely the regression of cardiac hypertrophy and the recovery of diastolic dysfunction.

Aging and chronic inflammation are associated with the development of heart failure with preserved ejection fraction (HFpEF). However, cellular senescence as a potential mechanistic link between both events and its pathophysiological and therapeutic role were yet unexplored. Here we show that ZSF1-obese rats, a model of cardiometabolic HFpEF, have exacerbated systemic inflammation and endothelial damage compared to ZSF1-lean littermates. In addition, ZSF1-obese rats accumulated immune and endothelial senescent cells in the peripheral blood and myocardium. Accordingly, the frequency of circulating senescent leukocytes associated with markers of disease severity in HFpEF patients. Notably, systemic treatment of ZSF1-obese rats with Navitoclax, a BCL-2 family inhibitor, reduced senescent cell burden, decreased circulating B-type natriuretic peptide levels, and attenuated inflammation, vascular remodeling and cardiac fibrosis. Our findings advance cellular senescence as a key mechanistic pathway leading to HFpEF and provide proof-of-concept evidence that senolytics are a promising treatment for this disease.

Background Patients with insulin-treated type 2 diabetes (T2D) have a high risk of major adverse cardiovascular events. Sodium-glucose cotransporter inhibitors (SGLTi) improve outcomes without hypoglycaemic risk. Aims To study the effect of SGLTi in patients with T2D with and without background insulin treatment in outcome-driven RCTs. Methods Random effects models. Results A total of 54 374 patients with T2D were included in the analysis, of which 26 551 (48.8%) were treated with insulin. For 3P-MACE in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.93 (0.81–1.05), with moderate heterogeneity (I2 = 49.2%, Q statistic P = 0.11). In insulin-treated patients, the HR (95% CI) was 0.88 (0.82–0.95), without evidence of heterogeneity (I2 =0.0%, Q statistic P =0.91). The pooled effect evidenced a 10% reduction of 3P-MACE with SGLTi (HR: 0.90, 95% CI: 0.85–0.96), without SGLTi-by-insulin interaction P = 0.53. For the composite outcome of HF hospitalisation or cardiovascular death in patients without insulin treatment, the HR (95% CI) for the effect of SGLTi vs placebo was 0.77 (0.61-0.92), with marked heterogeneity (I2 = 66.8%, Q statistic P = 0.02). In insulin-treated patients, the HR (95% CI) was 0.77 (0.68–0.86), without significant heterogeneity (I2 = 31.7%, Q statistic P = 0.25). The pooled effect evidenced a 23% reduction of HF hospitalisations or cardiovascular death with SGLTi (HR: 0.77, 95% CI: 0.68–0.85), without SGLTi-by-insulin interaction P = 0.98. Conclusion SGLTi reduces cardiovascular events regardless of insulin use. However, the treatment effect is more homogeneous among insulin-treated patients, supporting the use of SGLTi for the treatment of patients with T2D requiring insulin for glycaemic control.

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.

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

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.

Nonalcoholic fatty liver disease is increasingly recognized as the hepatic counterpart of metabolic syndrome. It is hypothesized that structural and functional cardiac changes may be associated with this metabolic disease. We aimed to gather the existing information on the association of nonalcoholic fatty liver disease with cardiac alterations, and to evaluate a possible correlation between them. Systematic review of Medline searching results for original articles studying NAFLD and cardiac parameters until August 2018. A meta-analysis was conducted to each parameter of cardiac structure and function selected, using Review Manager 5.3 software. This study was conducted according to preferred reporting items for systematic reviews and meta-analysis (PRISMA). A total of 16 studies met the eligibility criteria and were included in the meta-analysis. There was a significant association between nonalcoholic fatty liver disease and (1) higher left ventricle mass and ratios between left ventricle mass and both height and body surface area; (2) higher LVEDD; (3) higher left atrium diameter and ratio between left atrial volume and body surface area; (4) higher posterior wall and septum thickness; (5) lower E/A wave ratio; (6) higher E/E’ ratio; (7) longer deceleration time and (8) longer relaxation time. NAFLD associates with adverse structural alterations and cardiac dysfunction. Our results highlight the importance of identifying NAFLD in patients with metabolic dysfunction as this may represent an additional contributor to cardiovascular risk.

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.

Thyroid hormones have a central role in cardiovascular homeostasis. In myocardium, these hormones stimulate both diastolic myocardial relaxation and systolic myocardial contraction, have a pro-angiogenic effect and an important role in extracellular matrix maintenance. Thyroid hormones modulate cardiac mitochondrial function. Dysfunction of thyroid axis impairs myocardial bioenergetic status. Both overt and subclinical hypothyroidism are associated with a higher incidence of coronary events and an increased risk of heart failure progression. Endothelial function is also impaired in hypothyroid state, with decreased nitric oxide-mediated vascular relaxation. In heart disease, particularly in ischemic heart disease, abnormalities in thyroid hormone levels are common and are an important factor to be considered. In fact, low thyroid hormone levels should be interpreted as a cardiovascular risk factor. Regarding ischemic heart disease, during the late post-myocardial infarction period, thyroid hormones modulate left ventricular structure, function and geometry. Dysfunction of thyroid axis might even be more prevalent in the referred condition since there is an upregulation of type 3 deiodinase in myocardium, producing a state of local cardiac hypothyroidism. In this focused review, we summarize the central pathophysiological and clinical links between altered thyroid function and ischemic heart disease. Finally, we highlight the potential benefits of thyroid hormone supplementation as a therapeutic target in ischemic heart disease.

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.

Heart failure (HF) is growing in prevalence, due to an increase in aging and comorbidities. Heart failure with reduced ejection fraction (HFrEF) is more common in men, whereas heart failure with preserved ejection fraction (HFpEF) has a higher prevalence in women. However, the reasons for these epidemiological trends are not clear yet. Since HFpEF affects mostly postmenopausal women, sex hormones should play a pivotal role in HFpEF development. Furthermore, for HFpEF, contrary to HFrEF, effective therapeutic approaches are missing. Interestingly, studies evidenced that some therapies can have better results in women than in HFpEF men, emphasizing the necessity of understanding these observations at a molecular level. Thus, herein, we review the molecular mechanisms of estrogen and androgen actions in the heart in physiological conditions and explain how its dysregulation can lead to disease development. This clarification is essential in the road for an effective personalized management of HF, particularly HFpEF, towards the development of sex-specific therapeutic approaches.

The increasing prevalence of periodontal and cardiovascular diseases is the result of a sedentary lifestyle associated with poor diet, obesity, hypercholesterolaemia, smoking habits, alcohol consumption and stress. The present study aims to uncover molecular associations between periodontitis and coronary heart disease using an unbiased strategy of automatic text mining traditionally applied to bibliometric studies. A total of 1590 articles on these diseases were retrieved from the Web of knowledge database and searched using the VOS viewer to create a network of keywords associated with both diseases. These data were supplemented with data from DisGeNET, which stores known associations to either periodontitis or coronary heart disease. Overall, the automated text mining approach presented here highlighted inflammatory molecules as common associations between periodontitis and coronary heart disease. Specifically, this study showed that molecules such as C-reactive protein, interleukins 6 and 1-β, myeloperoxidase, and matrix metalloproteinase 9 are simultaneously associated with periodontitis and coronary artery disease by both text mining and DisGeNET analyses. This association validates the multiplex assessment of salivary inflammatory markers as a tool to assess cardiovascular disease risk and could become an important tool to identify common molecular targets to monitor both diseases simultaneously. In addition, the text mining protocol and subsequent data processing and methods using bioinformatics tools could be useful to uncover links between other diseases.

Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic "of-the-shelf" cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.

Background. Thyroid hormones (TH) are crucial for cardiovascular homeostasis. Recent evidence suggests that acute cardiovascular conditions, particularly acute heart failure (AHF), significantly impair the thyroid axis. Our aim was to evaluate the association of thyroid function with cardiovascular parameters and short- and long-term clinical outcomes in AHF patients. Methods. We performed a single-centre retrospective cohort study including patients hospitalized for AHF between January 2012 and December 2017. We used linear, logistic, and Cox proportional hazard regression models to analyse the association of thyroid-stimulating hormone (TSH) and free thyroxine (FT4) with inpatient cardiovascular parameters, in-hospital mortality, short-term adverse clinical outcomes, and long-term mortality. Two models were used: (1) unadjusted, and (2) adjusted for age and sex. Results. Of the 235 patients included, 59% were female, and the mean age was 77.5 (SD 10.4) years. In the adjusted model, diastolic blood pressure was positively associated with TSH [β = 2.68 (0.27 to 5.09); p = 0.030 ]; left ventricle ejection fraction (LVEF) was negatively associated with FT4 [β = -24.85 (-47.87 to -1.82); p = 0.035 ]; and a nonsignificant trend for a positive association was found between 30-day all-cause mortality and FT4 [OR = 3.40 (0.90 to 12.83); p = 0.071 ]. Among euthyroid participants, higher FT4 levels were significantly associated with a higher odds of 30-day all-cause death [OR = 4.40 (1.06 to 18.16); p = 0.041 ]. Neither TSH nor FT4 levels were relevant predictors of long-term mortality in the adjusted model. Conclusions. Thyroid function in AHF patients is associated with blood pressure and LVEF during hospitalization. FT4 might be useful as a biomarker of short-term adverse outcomes in these patients.

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.

Purpose: The management of older adults with breast cancer (BC) remains controversial. The challenging assessment of aging idiosyncrasies and the scarce evidence of therapeutic guidelines can lead to undertreatment. Our goal was to measure undertreatment and assess its impact on survival. Methods: Consecutive patients with BC aged 70 years or older were prospectively enrolled in 2014. Three frailty screening tools (G8, fTRST, and GFI) and two functional status scales (Karnofsky performance score and Eastern Cooperative Oncology Group Performance Status) were applied. Disease characteristics, treatment options, and causes of mortality were recorded during a 5-year follow-up. In addition, we defined undertreatment and correlated its survival impact with frailty. Results: A total of 92 patients were included in the study. The median age was 77 (range 70-94) years. The prevalence of frailty was discordant (G8, 41.9%; fTRST, 74.2%; GFI, 32.3%). Only 47.8% of the patients had a local disease, probably due to a late diagnosis (73.9% based on self-examination). Thirty-three patients (35.6%) died, of which 15 were from BC. We found a considerably high proportion (53.3%) of undertreatment, which had a frailty-independent negative impact on the 5-year survival (hazard ratio [HR], 5.1; 95% confidence interval [CI], 2.1-12.5). Additionally, omission of surgery had a frailty-independent negative impact on overall survival (HR, 3.9; 95% CI, 1.9-7.9). Conclusion: BC treatment in older adults should be individualized. More importantly, assessing frailty (not to treat) is essential to be aware of the risk-benefit profile and the patient's well-informed willingness to be treated. Undertreatment in daily practice is frequent and might have a negative impact on survival, as we report. This article publication was supported by National Funds through FCT - Fundação para a Ciência e a Tecnologia, I.P., within CINTESIS, R&D Unit (reference UIDB/4255/2020).

Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent and intractable form of cardiac decompensation commonly associated with diastolic dysfunction. Here, we show that diastolic dysfunction in patients with HFpEF is associated with a cardiac deficit in nicotinamide adenine dinucleotide (NAD+). Elevating NAD+ by oral supplementation of its precursor, nicotinamide, improved diastolic dysfunction induced by aging (in 2-year-old C57BL/6J mice), hypertension (in Dahl salt-sensitive rats), or cardiometabolic syndrome (in ZSF1 obese rats). This effect was mediated partly through alleviated systemic comorbidities and enhanced myocardial bioenergetics. Simultaneously, nicotinamide directly improved cardiomyocyte passive stiffness and calcium-dependent active relaxation through increased deacetylation of titin and the sarcoplasmic reticulum calcium adenosine triphosphatase 2a, respectively. In a long-term human cohort study, high dietary intake of naturally occurring NAD+ precursors was associated with lower blood pressure and reduced risk of cardiac mortality. Collectively, these results suggest NAD+ precursors, and especially nicotinamide, as potential therapeutic agents to treat diastolic dysfunction and HFpEF in humans. This study was thankfully supported by the European Research Area Network on Cardiovascular Diseases (ERACVD) through the MINOTAUR consortium: S.S. (The Austrian Science Fund – FWF, I3301-B31), G.K. (Agence National de la Recherche – ANR), W.A.L. (Bundesministerium für Bildung und Forschung – BMBF), J.A.C. (Instituto de Salud Carlos III – ISCIII, AC16/00045) and A.L.M. (Portuguese Foundation for Science and Technology – FCT). M. Abdellatif acknowledges funding received from the European Society of Cardiology in form of an ESC Research Grant and from the Austrian Society of Cardiology (Präsidentenstipendium der ÖKG). The Austrian Science Fund supports S.F. (P27166-B23), A.P. (I3165, P29328-B26) and F.M. (P27893, P31727). S.S., J.V., F.M. and S.L.H. acknowledge support from the BioTechMed–Graz. G.K. is supported by the Ligue contre le Cancer (équipe labellisée); Association pour la recherche sur le cancer (ARC); Association Ruban Rose, Cancéropôle Ile-de-France; Chancelerie des universités de Paris (Legs Poix), Fondation pour la Recherche Médicale (FRM); Institut National du Cancer (INCa); Inserm (HTE); Inserm Transfert; Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology (ANR-18-IDEX-0001); the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM). J.A.C. acknowledges funding from the Ministerio de Ciencia e Innovación (MCIN) through grant BIO2017-83640-P (AEI/FEDER, UE) and the Comunidad de Madrid (consortium Tec4Bio-CM, S2018/ NMT-4443, FEDER). A.S. acknowledges support from BioPersMed Graz. S.K. receives funding from the Austrian Research Promotion Agency FFG (VASCage; Nr. 868624). The Bruneck Study was supported by the Pustertaler Verein zur Prävention von Herz-und Hirngefäßerkrankungen, Gesundheitsbezirk Bruneck, and the Assessorat für Gesundheit, Province of Bolzano, Italy. Sí

This study aims to provide new insights into transcriptome and miRome modifications occurring in cardiac reverse remodelling (RR) upon left ventricle pressure-overload relief in mice. Pressure-overload was established in seven-week-old C57BL/6J-mice by ascending aortic constriction. A debanding (DEB) surgery was performed seven weeks later in half of the banding group (BA). Two weeks later, cardiac function was evaluated through hemodynamics and echocardiography, and the hearts were collected for histology and small/bulk-RNA-sequencing. Pressure-overload relief was confirmed by the normalization of left-ventricle-end-systolic-pressure. DEB animals were separated into two subgroups according to the extent of cardiac remodelling at seven weeks and RR: DEB1 showed an incomplete RR phenotype confirmed by diastolic dysfunction persistence (E/e&rsquo, &ge, 16 ms) and increased myocardial fibrosis. At the same time, DEB2 exhibited normal diastolic function and fibrosis, presenting a phenotype closer to myocardial recovery. Nevertheless, both subgroups showed the persistence of cardiomyocytes hypertrophy. Notably, the DEB1 subgroup presented a more severe diastolic dysfunction at the moment of debanding than the DEB2, suggesting a different degree of cardiac remodelling. Transcriptomic and miRomic data, as well as their integrated analysis, revealed significant downregulation in metabolic and hypertrophic related pathways in DEB1 when compared to DEB2 group, including fatty acid &beta, oxidation, mitochondria L-carnitine shuttle, and nuclear factor of activated T-cells pathways. Moreover, extracellular matrix remodelling, glycan metabolism and inflammation-related pathways were up-regulated in DEB1. The presence of a more severe diastolic dysfunction at the moment of pressure overload-relief on top of cardiac hypertrophy was associated with an incomplete RR. Our transcriptomic approach suggests that a cardiac inflammation, fibrosis, and metabolic-related gene expression dysregulation underlies diastolic dysfunction persistence after pressure-overload relief, despite left ventricular mass regression, as echocardiographically confirmed.

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: 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.

The role of epicardial adipose tissue (EAT) in the pathophysiology of coronary artery disease (CAD) remains unclear. The present systematic review aimed at compiling dysregulated proteins/genes from different studies to dissect the potential role of EAT in CAD pathophysiology. Exhaustive literature research was performed using the keywords “epicardial adipose tissue and coronary artery disease”, to highlight a group of proteins that were consistently regulated among all studies. Reactome, a pathway analysis database, was used to clarify the function of the selected proteins and their intertwined association. SignalP/SecretomeP was used to clarify the endocrine function of the selected proteins. Overall, 1886 proteins/genes were identified from 44 eligible studies. The proteins were separated according to the control used in each study (EAT non-CAD or subcutaneous adipose tissue (SAT) CAD) and by their regulation (up- or downregulated). Using a Venn diagram, we selected the proteins that were upregulated and downregulated (identified as 27 and 19, respectively) in EAT CAD for both comparisons. The analysis of these proteins revealed the main pathways altered in the EAT and how they could communicate with the heart, potentially contributing to CAD development. In summary, in this study, the identified dysregulated proteins highlight the importance of inflammatory processes to modulate the local environment and the progression of CAD, by cellular and metabolic adaptations of epicardial fat that facilitate the formation and progression of atherogenesis of coronaries.

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.

Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in Western countries and a common comorbidity with type 2 diabetes (T2D). It lacks effective pharmacotherapy. We aimed to summarize the evidence on the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on liver structure and function.Meta-analysis of randomized clinical trials in PubMed, Web of Science and ClinicalTrials.gov from their inception to April 2019. Trials evaluating liver function and/or structure and comparing SGLT2 inhibitors with placebo or other oral antidiabetic drugs in patients with T2D were included. Twenty studies (from 3033) were included. A total of 1950 patients with T2D, with or without NAFLD, were treated with SGLT2 inhibitors for at least 8 weeks, and 1900 patients were used as controls. Independent extraction was carried out by two observers. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis.SGLT2 inhibitors induced a significant decrease in serum alanine (-7.43U/L, [95%CI -12.14, -2.71], p0.01), in aspartate aminotransferases (-2.83U/L, [-4.71, -0.95], p0.01), as well as in gamma glutamyl transferase (-8.21U/L, [-9.52, -6.91], p0.01), and an increase in total plasma bilirubin (8.19% [0.79, 15.59], p0.01), comparing with placebo or other oral antidiabetic drugs. SGLT2 inhibitors treatment was associated with a decrease in liver steatosis (-3.39% [-6.01, -0.77], p0.0.1).Treatment with SGLT2 inhibitors improves liver structure and function in patients with T2D. This meta-analysis suggests that SGLT2 inhibitors are a promising pharmacological approach for treatment of NAFLD.

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

Persistent pulmonary hypertension of the newborn (PPHN) is one of the main causes of neonatal morbidity and mortality. It is characterized by sustained elevation of pulmonary vascular resistance (PVR), preventing an increase in pulmonary blood flow after birth. The affected neonates fail to establish blood oxygenation, precipitating severe respiratory distress, hypoxemia, and eventually death. Inhaled nitric oxide (iNO), the only approved pulmonary vasodilator for PPHN, constitutes, alongside supportive therapy, the basis of its treatment. However, nearly 40% of infants are iNO resistant. The cornerstones of increased PVR in PPHN are pulmonary vasoconstriction and vascular remodeling. A better understanding of PPHN pathophysiology may enlighten targeted and more effective therapies. Sildenafil, prostaglandins, milrinone, and bosentan, acting as vasodilators, besides glucocorticoids, playing a role on reducing inflammation, have all shown potential beneficial effects on newborns with PPHN. Furthermore, experimental evidence in PPHN animal models supports prospective use of emergent therapies, such as soluble guanylyl cyclase (sGC) activators/stimulators, l-citrulline, Rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, recombinant superoxide dismutase (rhSOD), tetrahydrobiopterin (BH4) analogs, ω-3 long-chain polyunsaturated fatty acids (LC-PUFAs), 5-HT2A receptor antagonists, and recombinant human vascular endothelial growth factor (rhVEGF). This review focuses on current knowledge on alternative and novel pathways involved in PPHN pathogenesis, as well as recent progress regarding experimental and clinical evidence on potential therapeutic approaches for PPHN.