Search

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 (Tau 2 , I 2 , 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; I 2  = 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., (© 2021. The Author(s).)

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.

Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

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., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)

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 <0.001) and augmented mitochondrial function. After 8 to 9 weeks, half of the banding animals underwent overload relief by an aortic debanding surgery (n=10)., 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 <0.001) and diastolic dysfunction improved simultaneously (E/E': banding, 18.5±4.1, debanding, 15.1±1.8, 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.

Introduction and Objectives: Several mechanisms contribute to myocardial hypertrophy and fibrosis in aortic stenosis (AS). MicroRNAs are post-transcriptional modulators of such processes. We hypothesized that their expression in myocardial biopsies from patients with AS could be linked with the degree of left ventricular (LV) hypertrophy and remodeling and to plasma levels of important biomarkers of extracellular matrix turnover., Methods: We performed myocardial biopsies in eleven patients with isolated severe AS undergoing aortic valve replacement. Echocardiographic exams and biomarker quantification were also performed. Five explanted hearts were used as controls for microRNA expression., Results: Overexpression of microRNA-101-3p was found in AS, which correlated with higher levels of preoperative valvuloarterial impedance, angiotensin II receptor and angiotensin-converting enzyme, and LV mass regression after surgery. Although not differently expressed in AS compared to controls, both upregulation of miR-4268 and downregulation of microRNA-125-5p were associated with higher LV mass. MicroRNA-125b-5p correlated negatively with LV mass and with relative wall thickness at six-month follow-up. MicroRNA-4268 correlated positively with LV mass regression and was associated with higher plasma angiotensin II receptor levels., Conclusions: MicroRNA-101-3p and microRNA-4268 have potential new roles in the modulation of the hypertrophic response to AS via the renin-angiotensin-aldosterone system and as predictors of reverse remodeling after aortic valve replacement. Our results open new avenues in the understanding of myocardial response to pressure overload and of reverse remodeling after unloading. They also support the possibility of medical therapy to modulate the renin-angiotensin-aldosterone system in hypertrophic hearts., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

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-α (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., (Copyright © 2020. Published by Elsevier Ltd.)

Rationale: Efficient communication between heart cells is vital to ensure the anisotropic propagation of electrical impulses, a function mainly accomplished by gap junctions (GJ) composed of Cx43 (connexin 43). Although the molecular mechanisms remain unclear, altered distribution and function of gap junctions have been associated with acute myocardial infarction and heart failure., Objective: A recent proteomic study from our laboratory identified EHD1 (Eps15 [endocytic adaptor epidermal growth factor receptor substrate 15] homology domain-containing protein 1) as a novel interactor of Cx43 in the heart., Methods and Results: In the present work, we demonstrate that knockdown of EHD1 impaired the internalization of Cx43, preserving gap junction-intercellular coupling in cardiomyocytes. Interaction of Cx43 with EHD1 was mediated by Eps15 and promoted by phosphorylation and ubiquitination of Cx43. Overexpression of wild-type EHD1 accelerated internalization of Cx43 and exacerbated ischemia-induced lateralization of Cx43 in isolated adult cardiomyocytes. In addition, we show that EHDs associate with Cx43 in human and murine failing hearts., Conclusions: Overall, we identified EHDs as novel regulators of endocytic trafficking of Cx43, participating in the pathological remodeling of gap junctions, paving the way to innovative therapeutic strategies aiming at preserving intercellular communication in the heart.

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., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Background: Worldwide, diabetes mellitus and heart failure represent frequent comorbidities with high socioeconomic impact and steadily growing incidence, calling for a better understanding of how diabetic metabolism promotes cardiac dysfunction. Paradoxically, some glucose-lowering drugs have been shown to worsen heart failure, raising the question of how glucose mediates protective versus detrimental cardiac signaling. Here, we identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart., Methods: A conditional HDAC4 allele was used to delete HDAC4 specifically in cardiomyocytes (HDAC4-knockout). Mice were subjected to diabetes mellitus either by streptozotocin injections (type 1 diabetes mellitus model) or by crossing into mice carrying a leptin receptor mutation (db/db; type 2 diabetes mellitus model) and monitored for remodeling and cardiac function. Effects of glucose and the posttranslational modification by β-linked N-acetylglucosamine (O-GlcNAc) on HDAC4 were investigated in vivo and in vitro by biochemical and cellular assays., Results: We show that the cardio-protective N-terminal proteolytic fragment of HDAC4 is enhanced in vivo in patients with diabetes mellitus and mouse models, as well as in vitro under high-glucose and high-O-GlcNAc conditions. HDAC4-knockout mice develop heart failure in models of type 1 and type 2 diabetes mellitus, whereas wild-type mice do not develop clear signs of heart failure, indicating that HDAC4 protects the diabetic heart. Reexpression of the N-terminal fragment of HDAC4 prevents HDAC4-dependent diabetic cardiomyopathy. Mechanistically, the posttranslational modification of HDAC4 at serine (Ser)-642 by O-GlcNAcylation is an essential step for production of the N-terminal fragment of HDAC4, which was attenuated by Ca 2+ /calmodulin-dependent protein kinase II-mediated phosphorylation at Ser-632. Preventing O-GlcNAcylation at Ser-642 not only entirely precluded production of the N-terminal fragment of HDAC4 but also promoted Ca 2+ /calmodulin-dependent protein kinase II-mediated phosphorylation at Ser-632, pointing to a mutual posttranslational modification cross talk of (cardio-detrimental) phosphorylation at Ser-632 and (cardio-protective) O-GlcNAcylation at Ser-642., Conclusions: In this study, we found that O-GlcNAcylation of HDAC4 at Ser-642 is cardio-protective in diabetes mellitus and counteracts pathological Ca 2+ /calmodulin-dependent protein kinase II signaling. We introduce a molecular model explaining how diabetic metabolism possesses important cardio-protective features besides its known detrimental effects. A deeper understanding of the here-described posttranslational modification cross talk may lay the groundwork for the development of specific therapeutic concepts to treat heart failure in the context of diabetes mellitus.

Background: The interplay between the stiffened heart and vessels has long been viewed as a core mechanism in heart failure with preserved ejection fraction, but the incremental vascular molecular remodeling mechanisms from systemic arterial hypertension to heart failure with preserved ejection fraction remain poorly investigated. Our aim was to characterize central arterial remodeling and dysfunction in ZSF1 obese rats and to compare it with hypertensive ZSF1 lean and healthy Wistar-Kyoto controls., Methods and Results: Twenty-week-old male ZSF1 obese (n=9), lean (n=9), and Wistar-Kyoto rats (n=9) underwent left ventricular pressure-volume loop evaluation and synchronous acquisition of ascending aortic flow and pressure. Aortic rings underwent functional evaluation, histology, and molecular biology studies. Although mean arterial pressure, characteristic aortic impedance, and reactivity to phenylephrine were similarly increased in hypertensive ZSF1 lean and obese, only ZSF1 obese showed impaired relaxation and upward-shifted end-diastolic pressure-volume relationships despite preserved systolic function indexes, denoting heart failure with preserved ejection fraction. ZSF1 obese phenotype further showed decreased aortic compliance, increased wave reflection, and impaired direct NO donor and endothelial-mediated vasodilation which were accompanied on structural and molecular grounds by aortic media thickening, higher collagen content and collagen/elastin ratio, increased fibronectin and α-5 integrin protein expression and upregulated TGF (transforming growth factor)-β and CTGF (connective tissue growth factor) levels., Conclusions: Functional, molecular, and structural disturbances of central vessels and their potentially underlying pathways were newly characterized in experimental heart failure with preserved ejection fraction rendering the ZSF1 obese rat model suitable for preclinical testing.

Several studies have demonstrated that administration of doxorubicin (DOXO) results in cardiotoxicity, which eventually progresses to dilated cardiomyopathy. The present work aimed to evaluate the early myocardial changes of DOXO-induced cardiotoxicity. Male New Zealand White rabbits were injected intravenously with DOXO twice weekly for 8 wk [DOXO-induced heart failure (DOXO-HF)] or with an equivolumetric dose of saline (control). Echocardiographic evaluation was performed, and myocardial samples were collected to evaluate myocardial cellular and molecular modifications. The DOXO-HF group presented cardiac hypertrophy and higher left ventricular cavity diameters, showing a dilated phenotype but preserved ejection fraction. Concerning cardiomyocyte function, the DOXO-HF group presented a trend toward increased active tension without significant differences in passive tension. The myocardial GSSG-to-GSH ratio and interstitial fibrosis were increased and Bax-to- Bcl-2 ratio presented a trend toward an increase, suggesting the activation of apoptosis signaling pathways. The macromolecule titin shifted toward the more compliant isoform (N2BA), whereas the stiffer one (N2B) was shown to be hypophosphorylated. Differential protein analysis from the aggregate-enriched fraction through gel liquid chromatography-tandem mass spectrometry revealed an increase in the histidine-rich glycoprotein fragment in DOXO-HF animals. This work describes novel and early myocardial effects of DOXO-induced cardiotoxicity. Thus, tracking these changes appears to be of extreme relevance for the early detection of cardiac damage (as soon as ventricular dilation becomes evident) before irreversible cardiac function deterioration occurs (reduced ejection fraction). Moreover, it allows for the adjustment of the therapeutic approach and thus the prevention of cardiomyopathy progression. NEW & NOTEWORTHY Identification of early myocardial effects of doxorubicin in the heart is essential to hinder the development of cardiac complications and adjust the therapeutic approach. This study describes doxorubicin-induced cellular and molecular modifications before the onset of dilated cardiomyopathy. Myocardial samples from doxorubicin-treated rabbits showed a tendency for higher cardiomyocyte active tension, titin isoform shift from N2B to N2BA, hypophosphorylation of N2B, increased apoptotic genes, left ventricular interstitial fibrosis, and increased aggregation of histidine-rich glycoprotein.

Aortic Stenosis (AS) is the most frequent valvulopathy in the western world. Traditionally aortic valve replacement (AVR) has been recommended immediately after the onset of heart failure (HF) symptoms. However, recent evidence suggests that AVR outcome can be improved if performed earlier. After AVR, the process of left ventricle (LV) reverse remodelling (RR) is variable and frequently incomplete. In this study, we aimed at detecting mechanism underlying the process of LV RR regarding myocardial structural, functional and molecular changes before the onset of HF symptoms. Wistar-Han rats were subjected to 7-weeks of ascending aortic-banding followed by a 2-week period of debanding to resemble AS-induced LV remodelling and the early events of AVR-induced RR, respectively. This resulted in 3 groups: Sham (n = 10), Banding (Ba, n = 15) and Debanding (Deb, n = 10). Concentric hypertrophy and diastolic dysfunction (DD) were patent in the Ba group. Aortic-debanding induced RR, which promoted LV functional recovery, while cardiac structure did not normalise. Cardiac parameters of RV dysfunction, assessed by echocardiography and at the cardiomyocyte level prevailed altered after debanding. After debanding, these alterations were accompanied by persistent changes in pathways associated to myocardial hypertrophy, fibrosis and LV inflammation. Aortic banding induced pulmonary arterial wall thickness to increase and correlates negatively with effort intolerance and positively with E/e' and left atrial area. We described dysregulated pathways in LV and RV remodelling and RR after AVR. Importantly we showed important RV-side effects of aortic constriction, highlighting the impact that LV-reverse remodelling has on both ventricles.

The remote but heart-encircling location of pericardial fluid confers this biofluid unique properties. Once past the limitation of the invasive collection, for instance, on occasion of heart surgery or pericardiocentesis, the scrutiny of pericardial fluid content can be of great interest in cardiovascular research. This liquid concentrates many heart-derived factors, thus enclosing several surrogate markers for the diagnosis or prognosis of a large spectrum of diseases either pericardial (e.g. malignant or tuberculous pericarditis) or non-pericardial/heart diseases (e.g. coronary artery disease or valvular heart diseases). Herein, for the first time, the molecular knowledge of pericardial fluid is reviewed, through an in-depth literature search and mining, and then translated into a network map of the diseases influencing pericardial fluid composition. The suitability of pericardial fluid for biomarker research could be demonstrated by evident molecular profiles between different conditions as well as by stronger correlations to cardiac structural and functional parameters, fainter or lacking in plasma/serum. Also highlighted here are the results of mechanistic research conducted with pericardial fluid in several hot topics of research, such as chronotropy, inotropy, coronary perfusion and cardiac electrophysiology. Moreover, the progress in intrapericardial therapeutics, motivated by pericardial fluid's low clearance rates, higher efficiency and lesser risk of systemic effects over conventional delivery methods, is surveyed and discussed.

Nowadays we are surrounded by a plethora of bioinformatics tools, powerful enough to deal with the large amounts of data arising from proteomic studies, but whose application is sometimes hard to find. Therefore, we used a specific clinical problem - to discriminate pathophysiology and potential biomarkers between two similar cardiovascular diseases, aortic valve stenosis (AVS) and coronary artery disease (CAD) - to make a step-by-step guide through four bioinformatics tools: STRING, DisGeNET, Cytoscape and ClueGO. Proteome data was collected from articles available on PubMed centered on proteomic studies enrolling subjects with AVS or CAD. Through the analysis of gene ontology provided by STRING and ClueGO we could find specific biological phenomena associated with AVS, such as down-regulation of elastic fiber assembly, and with CAD, such as up-regulation of plasminogen activation. Moreover, through Cytoscape and DisGeNET we could pinpoint surrogate markers either for AVS (e.g. popeye domain containing protein 2 and 28S ribosomal protein S36, mitochondrial) or for CAD (e.g. ankyrin repeat and SOCS box protein 7) which deserve future validation. Data recycling and integration as well as research orientation are among the main advantages of resorting to bioinformatics analysis, hence these tutorials can be of great convenience for proteomics investigators., Biological Significance: As we saw for aortic valve stenosis and coronary artery disease, it can be of great relevance to perform preliminary bioinformatics analysis with already published proteomics data. It not only saves us time in the lab (avoiding work duplication) as it points out new hypothesis to explain the phenotypical presentation of the diseases as well as new surrogate markers with clinical relevance, deserving future scrutiny. These essential steps can be easily overcome if one follows the steps proposed in our tutorial for STRING, DisGeNET, Cytoscape and ClueGO utilization., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In the quest to fully comprehend the proteolytic events leading to the generation of the salivary peptidome, we have developed a method for the sequential elution of salivary peptides throughout progressive endogenous proteolysis. By screening the time-dependent changes in the salivary peptidome we can predict the activity pattern of salivary proteases responsible for such peptide fingerprint and identify susceptible protein targets. Herein, we describe a step-by-step tutorial based on a filter-aided sample preparation (FASP) method, taking advantage of the endogenous salivary proteases armamentarium (endoProteoFASP), to produce new peptides from the salivary proteins, adding to those present in the sample at the time of collection. In this protocol, the different sets of peptides retrieved after sample elution are identified following a liquid chromatography-tandem mass spectrometry approach. The likelihood of a large set of endogenous proteases (collected from several public sources) to be responsible for the generation of such peptides can be predicted by the analysis of the cleavage site specificity by Proteasix ( http://proteasix.cs.man.ac.uk /) algorithm. The attained peptidome-protease profile can be useful to elucidate the peptidome dynamics and the proteolytic events underpinning pathophysiological phenomena taking place locally within the oral cavity. This may help clinicians to diagnose oral pathologies and develop preventive therapeutic plans.

Urine is a highly attractive source of biological information and disease biomarkers, whose proteome characterization is ongoing. To that end, depletion/enrichment strategies for protein analysis can be of great convenience. We have thus developed a method based on the use of EDTA-functionalized magnetic nanoparticles (NPs@EDTA), to fractionate urine samples before liquid chromatography-mass spectrometry analysis and compared the identified proteins with those obtained from ultrafiltrated/unfractionated (UF) urine samples. NPs@EDTA allowed larger urine volumes to be processed, resulting in a greater number of protein identifications (~2-fold) at a lower cost when compared to UF samples. Proteins of greater abundance (such as albumin and uromodulin) were, at least partially, depleted with NPs@EDTA while those of lower abundance were enriched. Bioinformatics analysis showed that approximately 27% of NPs@EDTA-enriched proteins were annotated as displaying enzymatic activity, most of these being hydrolytic enzymes (56%), particularly proteases/peptidases (48%). Also, post-translational modifications were prominently predicted across NPs@EDTA-enriched proteins (90%), particularly glycosylation (52%), phosphorylation (47%) and acetylation (30%). NPs@EDTA allowed the identification of 109 proteins in urine for the first time, showing high potential as a platform for urine's fractionation prior to proteomic analysis., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Key Points: This paper describes a novel model that allows exploration of matrix-induced cardiomyocyte adaptations independent of the passive effect of matrix rigidity on cardiomyocyte function. Detachment of adult cardiomyocytes from the matrix enables the study of matrix effects on cell shortening, Ca 2+ handling and myofilament function. Cell shortening and Ca 2+ handling are altered in cardiomyocytes cultured for 24 h on a stiff matrix. Matrix stiffness-impaired cardiomyocyte contractility is reversed upon normalization of extracellular stiffness. Matrix stiffness-induced reduction in unloaded shortening is more pronounced in cardiomyocytes isolated from obese ZSF1 rats with heart failure with preserved ejection fraction compared to lean ZSF1 rats., Abstract: Extracellular matrix (ECM) stiffening is a key element of cardiac disease. Increased rigidity of the ECM passively inhibits cardiac contraction, but if and how matrix stiffening also actively alters cardiomyocyte contractility is incompletely understood. In vitro models designed to study cardiomyocyte-matrix interaction lack the possibility to separate passive inhibition by a stiff matrix from active matrix-induced alterations of cardiomyocyte properties. Here we introduce a novel experimental model that allows exploration of cardiomyocyte functional alterations in response to matrix stiffening. Adult rat cardiomyocytes were cultured for 24 h on matrices of tuneable stiffness representing the healthy and the diseased heart and detached from their matrix before functional measurements. We demonstrate that matrix stiffening, independent of passive inhibition, reduces cell shortening and Ca 2+ handling but does not alter myofilament-generated force. Additionally, detachment of adult cultured cardiomyocytes allowed the transfer of cells from one matrix to another. This revealed that stiffness-induced cardiomyocyte changes are reversed when matrix stiffness is normalized. These matrix stiffness-induced changes in cardiomyocyte function could not be explained by adaptation in the microtubules. Additionally, cardiomyocytes isolated from stiff hearts of the obese ZSF1 rat model of heart failure with preserved ejection fraction show more pronounced reduction in unloaded shortening in response to matrix stiffening. Taken together, we introduce a method that allows evaluation of the influence of ECM properties on cardiomyocyte function separate from the passive inhibitory component of a stiff matrix. As such, it adds an important and physiologically relevant tool to investigate the functional consequences of cardiomyocyte-matrix interactions., (© 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Today there is an increasing demand for heart transplantations for patients diagnosed with heart failure. Though, shortage of donors as well as the large number of ineligible patients hurdle such treatment option. This, in addition to the considerable number of transplant rejections, has driven the clinical research towards the field of regenerative medicine. Nonetheless, to date, several stem cell therapies tested in animal models fall by the wayside and when they meet the criteria to clinical trials, subjects often exhibit modest improvements. A main issue slowing down the admission of such therapies in the domain of human trials is the lack of protocol standardization between research groups, which hampers comparison between different approaches as well as the lack of thought regarding the clinical translation. In this sense, given the large amount of reports on stem cell therapy studies in animal models reported in the last 3years, we sought to evaluate their advantages and limitations towards the clinical setting and provide some suggestions for the forthcoming investigations. We expect, with this review, to start a new paradigm on regenerative medicine, by evoking the debate on how to plan novel stem cell therapy studies with animal models in order to achieve more consistent scientific production and accelerate the admission of stem cell therapies in the clinical setting., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: Change in the architecture and composition of cardiac extracellular matrix is a key element in adverse cardiac remodeling that occurs during heart failure. Most of the times, the result is the development of fibrosis, which has a huge impact on the pathophysiology and clinical outcomes of heart failure syndromes. Several molecules related to collagen metabolism detectable in the blood have been proposed as biomarkers of myocardial fibrosis. Despite concerns regarding the true ability of these biomarkers to reflect quantitative and qualitative changes in myocardial collagen, a growing body of evidence suggests that they may play a potential role in several aspects of heart failure management., Methods: This review aimed to summarize published data regarding the role of circulating biomarkers of collagen metabolism in the assessment of prognosis in patients with heart failure with reduced or mid-range LVEF ventricular ejection fraction (LVEF < 40% or LVEF 40-49%, respectively). Medline electronic database was searched to identify relevant studies published through October 2016., Results: Most evidence regarding the prognostic value of collagen biomarkers in HF with reduced or mid-range LVEF lies on data concerning PIIINP and several MMPs and TIMP-1. Several prospective studies found that higher levels of PIIINP, several MMPs and TIMP-1 are associated with higher rates of mortality and/or HF hospital admissions in HF patients with LVEF < 50%., Conclusion: Circulating collagen biomarkers have been shown to play a role in prognostic stratification in heart failure patients with reduced or mid-range ejection fraction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions., (Copyright © 2016 the American Physiological Society.)

"Obesity cardiomyopathy" effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before "clinical" overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity., (Copyright © 2016 the American Physiological Society.)

Objetives: The present study aimed to explore the risk factors associated with de novo atrial fibrillation following isolated aortic valve replacement surgery and its prevalence in a high volume cardiothoracic surgery center., Methods: This is a cross-sectional retrospective observational study including all patients submitted to isolated aortic valve replacement surgery during 2014 and the corresponding data. Patients with previous history of atrial fibrillation, endocarditis or aortic valve prosthesis were excluded. The statistical analysis was conducted according to the type of variables concerned., Results: One hundred and seventy-three patients were included and 45.1% had de novo atrial fibrillation, with a median occurrence on 2.4 ±1.5 days of the postoperative period. Age was significantly associated with the arrhythmia (p=0.028). Atrial fibrillation patients had a significantly lower minimum of postoperative creatinine clearance (p=0.026) and a higher postoperative plasmatic C-reactive protein peak (p=0.025). Arrhythmic patients had a median time of hospital stay significantly superior to those who did not develop atrial fibrillation (p=0.008). Hospital mortality was low and similar between groups (3%, p=0.796)., Discussion/conclusion: This study confirms the high prevalence of atrial fibrillation following aortic valve replacement surgery. The increased C-reactive protein and decreased creatinine clearance reinforce the importance of inflammation in its pathophysiology. The longer hospital stay in these patients also contributes to the importance of atrial fibrillation prevention and risk stratification.

Preserved ejection fraction heart failure (HFpEF) diagnosis remains controversial, and invasive left ventricular (LV) hemodynamic evaluation and/or exercise testing is advocated by many. The stiffer HFpEF myocardium may show impaired stroke volume (SV) variation induced by fluctuating LV filling pressure during ventilation. Our aim was to investigate spectral transfer function (STF) gain from end-diastolic pressure (EDP) to indexed SV (SVi) in experimental HFpEF. Eighteen-week-old Wistar-Kyoto (WKY) and ZSF1 lean (ZSF1 Ln) and obese rats (ZSF1 Ob) randomly underwent LV open-chest (OC, n = 8 each group) or closed-chest hemodynamic evaluation (CC, n = 6 each group) under halogenate anesthesia and positive-pressure ventilation at constant inspiratory pressure. Beat-to-beat fluctuations in hemodynamic parameters during ventilation were assessed by STF. End-diastolic stiffness (βi) and end-systolic elastance (Eesi) for indexed volumes were obtained by inferior vena cava occlusion in OC (multibeat) or single-beat method estimates in CC. ZSF1 Ob showed higher EDP spectrum (P < 0.001), higher STF gain between end-diastolic volume and EDP, and impaired STF gain between EDP and SVi compared with both hypertensive ZSF1 Ln and normotensive WKY controls (P < 0.001). Likewise βi was only higher in ZSF1 Ob while Eesi was raised in both ZSF1 groups. On multivariate analysis βi and not Eesi correlated with impaired STF gain from EDP to SVi (P < 0.001), and receiver-operating characteristics analysis showed an area under curve of 0.89 for higher βi prediction (P < 0.001). Results support further clinical testing of STF analysis from right heart catheterization-derived EDP surrogates to noninvasively determined SV as screening/diagnostic tool to assess myocardial stiffness in HFpEF., (Copyright © 2016 the American Physiological Society.)

Myocardial stiffness and upward-shifted end-diastolic pressure-volume (P-V) relationship (EDPVR) are the key to high filling pressures in heart failure with preserved ejection fraction (HFpEF). Nevertheless, many patients may remain asymptomatic unless hemodynamic stress is imposed on the myocardium. Whether delayed relaxation induced by pressure challenge may contribute to high end-diastolic pressure (EDP) remains unsettled. Our aim was to assess the effect of suddenly imposed isovolumic afterload on relaxation and EDP, exploiting a highly controlled P-V experimental evaluation setup in the ZSF1 obese rat (ZSF1 Ob) model of HFpEF. Twenty-week-old ZSF1 Ob (n = 12), healthy Wistar-Kyoto rats (WKY, n = 11), and hypertensive ZSF1 lean control rats (ZSF1 Ln, n = 10) underwent open-thorax left ventricular (LV) P-V hemodynamic evaluation under anesthesia with sevoflurane. EDPVR was obtained by inferior vena cava occlusions to assess LV ED chamber stiffness constant β, and single-beat isovolumic afterload acquisitions were obtained by swift occlusions of the ascending aorta. ZSF1 Ob showed increased ED stiffness, delayed relaxation, as assessed by time constant of isovolumic relaxation (τ), and elevated EDP with normal ejection fraction. Isovolumic afterload increased EDP without concomitant changes in ED volume or heart rate. In isovolumic beats, relaxation was delayed to the extent that time for complete relaxation as predicted by 3.5 × monoexponentially derived τ (τexp) exceeded effective filling time. EDP elevation correlated with reduced time available to relax, which was the only independent predictor of EDP rise in multiple linear regression. Our results suggest that delayed relaxation during pressure challenge is an important contributor to lung congestion and effort intolerance in HFpEF., (Copyright © 2015 the American Physiological Society.)

Inclusion of exercise testing in diagnostic guidelines for heart failure with preserved ejection fraction (HFpEF) has been advocated, but the target population, technical challenges, and underlying pathophysiological complexity raise difficulties to implementation. Hemodynamic stress tests may be feasible alternatives. Our aim was to test Trendelenburg positioning, phenylephrine, and dobutamine in the ZSF1 obese rat model to find echocardiographic surrogates for end-diastolic pressure (EDP) elevation and HFpEF. Seventeen-week-old Wistar-Kyoto, ZSF1 lean, and obese rats (n = 7 each) randomly and sequentially underwent (crossover) Trendelenburg (30°), 5 μg·Kg(-1)·min(-1) dobutamine, and 7.5 μg·Kg(-1)·min(-1) phenylephrine with simultaneous left ventricular (LV) pressure-volume loop and echocardiography evaluation under halogenate anesthesia. Effort testing with maximum O2 consumption (V̇o 2 max) determination was performed 1 wk later. Obese ZSF1 showed lower effort tolerance and V̇o 2 max along with higher resting EDP. Both Trendelenburg and phenylephrine increased EDP, whereas dobutamine decreased it. Significant correlations were found between EDP and 1) peak early filling Doppler velocity of transmitral flow (E) to corresponding myocardial tissue Doppler velocity (E') ratio, 2) E to E-wave deceleration time (E/DT) ratio, and 3) left atrial area (LAA). Diagnostic efficiency of E/DT*LAA by receiver-operating characteristic curve analysis for elevation of EDP above a cut-off of 13 mmHg during hemodynamic stress was high (area under curve, AUC = 0.95) but not higher than that of E/E' (AUC = 0.77, P = 0.15). Results in ZSF1 obese rats suggest that noninvasive echocardiography after hemodynamic stress induced by phenylephrine or Trendelenburg can enhance diagnosis of stable HFpEF and constitute an alternative to effort testing., (Copyright © 2015 the American Physiological Society.)

Morbidity from degenerative aortic valve disease (AVS) is increasing worldwide, concomitant with the ageing of the population and the growing consumption of high caloric and cholesterol diets of the western countries. Despite the increasing prevalence of AVS, with its high mortality and morbidity, studies on the molecular and cellular mechanisms underlying the onset of aortic valve degeneration have only advanced in the last 15 years. The result of this effort is now beginning to reveal several mechanisms with great therapeutic targeting potential that may alter the natural history of this progressive pathology. Indeed, the view of this disease has changed from being an unmodifiable degenerative disease to an active biological process regulated by highly conserved cellular pathways. The progression of AVS includes inflammation, angiogenesis and remodelling of the extracellular matrix leading to osteogenesis in the aortic valve and revealing many mechanisms and risk factors similar to atherosclerosis. Therefore statins and angiotensin II antagonists seemed promising treatment options; however, experimental results are still controversial. Nonetheless, valvular degeneration results in dramatic myocardial changes induced by chronic pressure overload such as left ventricular hypertrophy as well as other paramount myocardial extracellular changes. Currently, a strong impulse for future research to investigate the pathophysiological mechanisms and their modulation in order to prevent/delay the onset or progression of valve degeneration is needed. In the present review, we focused on the molecular and cellular mechanisms underlying degenerative AVS and its myocardial impact.

Aortic stenosis is the most common type of valvular heart disease and its recent increase is related to aging. The decreased aortic valve area imposes a chronic systolic pressure overload to the left ventricle. In response, the ventricle hypertrophies in an attempt to normalize the increased wall stress, but this response is not uniform in patients with similar degrees of stenosis and its regression after surgical correction is variable, suggesting that several factors, other than load, can explain these differences. These findings are particularly important since the presence of left ventricular hypertrophy after aortic valve replacement is an independent predictor of worse outcome, probably because it indicates irreversible remodeling. Age, gender, hypertension, patient-prosthesis mismatch and interstitial remodeling also play an important role in this setting, raising the possibility of intervention beyond valve replacement. The possibility of combining estrogen treatment, antihypertensive agents, antioxidants and modulators of the renin-angiotensin-aldosterone system with surgical treatment to promote reverse remodeling is very appealing. On the other hand, a preventive strategy to intervene earlier in patients with significant left ventricular mass and avoid patient-prosthesis mismatch, especially in the younger and those with systolic dysfunction, can have a significant impact on prognosis. Further evidence, with well designed clinical trials, is needed but the spotlight must be in the ventricle, not the valve.

Titin is a giant sarcomeric protein that extends from the Z-line to the M-line. Due to its location, it represents an important biomechanical sensor, which has a crucial role in the maintenance of the sarcomere structural integrity. Titin works as a "bidireactional spring" that regulates the sarcomeric length and performs adequate adjustments of passive tension whenever the length varies. Therefore, it determines not only ventricular rigidity and diastolic function, but also systolic cardiac function, modulating the Frank-Starling mechanism. The myocardium expresses two isoforms of this macromolecule: the N2B, more rigid and the isoform N2BA, more compliant. The alterations in the relative expression of the two titin isoforms or alterations in their state of phosphorylation have been implicated in the pathophysiology of several diseases, such as diastolic heart failure, dilated cardiomyopathy, ischemic cardiomyopathy and aortic stenosis. The aim of this study is to describe, in brief, the structure and location of titin, its association with different cardiomyopathies and understand how alterations in this macromolecule influence the pathophysiology of diastolic heart failure, emphasizing the therapeutic potential of the manipulation of this macromolecule.

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle (day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 microg*kg(-1)*day(-1) ip) or a similar volume of saline, resulting in four groups: sham (n = 11), sham-AP (n = 11), MCT (n = 16), and MCT-AP (n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 +/- 38%), diameter of cardiomyocyte (40 +/- 10%), myocardial fibrosis (95 +/- 20%), peak systolic pressure (99 +/- 22%), peak rate of ventricular pressure rise (dP/dt(max); 74 +/- 24%), peak rate of ventricular pressure decline (dP/dt(min); 73 +/- 19%), and time constant tau (55 +/- 16%). In these animals, RV expression of apelin (-73 +/- 10%) and its receptor APJ (-61 +/- 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 +/- 713%), angiotensinogen (191 +/- 147%), endothelin-1 (RV, 497 +/- 156%; and LV, 799 +/- 309%), plasmatic levels of apelin (104 +/- 48%), and angiotensin 1-7 (161 +/- 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Apelin is a recently discovered vasoactive peptide that has been demonstrated to be the endogenous ligand of the APJ receptor. It was named 'apelin' after APJ endogenous ligand. This G protein-coupled receptor (GPCR), originally identified by O'Dowd et al. in 1993, has a close identity with the angiotensin II type 1 (AT1) receptor, but does not bind angiotensin-II. Although apelin and APJ have been found to be ubiquitously expressed in peripheral tissues, particularly the heart and lungs, as well as various regions of the central nervous system, the physiologic actions of apelin remain largely unknown. Nevertheless, some cardiovascular functions of the apelin/APJ system have been described, such as endothelium-dependent vasodilatation, vasoconstriction by direct action on the smooth muscle and positive inotropism. Other reported physiologic actions of apelin include: (1) its role as endocrine adipokine; (2) contribution to fluid homeostasis and thirst regulation; (3) participation as coreceptor in the process of human immunodeficiency virus type 1 infection; and (4) regulation of immune response. The involvement of apelin/APJ in the pathophysiology of heart failure (HF) and its potential as a therapeutic target in this syndrome have also been proposed. In the course of HF progression, plasma levels of apelin are significantly increased in the early stages, decreasing progressively towards normal in the advanced stages of the disease. Given the increasing number of studies focusing on the apelin/APJ system, the goal of this paper was to make an up-to-date review of existing information on apelin and APJ, with particular focus on their cardiovascular actions and potential use as a therapeutic target in HF.