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Aims Sodium-glucose-cotransporter-2 inhibitors showed favourable cardiovascular outcomes, but the underlying mechanisms are still elusive. This study investigated the mechanisms of empagliflozin in human and murine heart failure with preserved ejection fraction (HFpEF). Methods and results The acute mechanisms of empagliflozin were investigated in human myocardium from patients with HFpEF and murine ZDF obese rats, which were treated in vivo. As shown with immunoblots and ELISA, empagliflozin significantly suppressed increased levels of ICAM-1, VCAM-1, TNF-α, and IL-6 in human and murine HFpEF myocardium and attenuated pathological oxidative parameters (H2O2, 3-nitrotyrosine, GSH, lipid peroxide) in both cardiomyocyte cytosol and mitochondria in addition to improved endothelial vasorelaxation. In HFpEF, we found higher oxidative stress-dependent activation of eNOS leading to PKGIα oxidation. Interestingly, immunofluorescence imaging and electron microscopy revealed that oxidized PKG1α in HFpEF appeared as dimers/polymers localized to the outer-membrane of the cardiomyocyte. Empagliflozin reduced oxidative stress/eNOS-dependent PKGIα oxidation and polymerization resulting in a higher fraction of PKGIα monomers, which translocated back to the cytosol. Consequently, diminished NO levels, sGC activity, cGMP concentration, and PKGIα activity in HFpEF increased upon empagliflozin leading to improved phosphorylation of myofilament proteins. In skinned HFpEF cardiomyocytes, empagliflozin improved cardiomyocyte stiffness in an anti-oxidative/PKGIα-dependent manner. Monovariate linear regression analysis confirmed the correlation of oxidative stress and PKGIα polymerization with increased cardiomyocyte stiffness and diastolic dysfunction of the HFpEF patients. Conclusion Empagliflozin reduces inflammatory and oxidative stress in HFpEF and thereby improves the NO–sGC–cGMP–cascade and PKGIα activity via reduced PKGIα oxidation and polymerization leading to less pathological cardiomyocyte stiffness. [ABSTRACT FROM AUTHOR]

Aim: Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF). Methods: We assessed mitochondrial Ca2+ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca2+ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca2+ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo. Results: At rest, mitochondrial Ca2+ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca2+ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca2+ concentration and the decay half‐times of the cytosolic Ca2+ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese. Conclusion: The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca2+ handling. This coupling between cytosolic and mitochondrial Ca2+ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca2+ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening. [ABSTRACT FROM AUTHOR]

Summary: We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling. [ABSTRACT FROM AUTHOR]

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

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, Ca2+ handling and myofilament function., Cell shortening and Ca2+ 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 Ca2+ 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. [ABSTRACT FROM AUTHOR]

Introduction:The proper folding of native proteins is critical and dynamic, but inherently unstable. Therefore, proteins eventually end up adopting misfolded conformations which compromise their function and may even trigger aggregation. Risk factors for neurodegenerative, metabolic and heart diseases compromise cellular protein quality-control systems, promoting protein aggregation. Multiple protein post-translational modifications dynamically regulate protein aggregation and disaggregation in a very complex, intricate and delicate balance. Areas covered:Herein, we overview the more promising techniques and approaches for the elucidation of the biological implications of protein aggregation. The particular insights provided by different techniques were discriminated and several examples of post-translational modifications together with their targets were pooled and critically discussed, representing promising future therapeutic targets. Expert commentary:In the years to come, differences between physiological and pathological protein aggregation will certainly become easier to determine. Techniques such as hydrogen/deuterium exchange, circular dichroism spectroscopy and novel mass spectrometry-based approaches are being optimized and are expected to introduce inhibitors of protein aggregation into the clinic. However, protein aggregation is not an isolated phenomenon, but rather influenced by multiple cellular components which complete knowledge is still far. [ABSTRACT FROM PUBLISHER]

OBJECTIVES: Persistent left ventricular (LV) hypertrophy after surgery is frequent, but its clinical relevance is controversial. We evaluated if residual LV hypertrophy (LVH) is associated with clinical outcomes after aortic valve replacement (AVR) for severe aortic stenosis (AS). METHODS: We analysed clinical and echocardiographic parameters before and after AVR, in a prospective cohort of 132 patients with severe AS. The mean follow-up was 6.0 ± 1.5 years. Clinical endpoints were all-cause death and combination of as in all-cause death and non-fatal cardiovascular hospitalization. At AVR, myocardial biopsies for collagen volume fraction (CVF) evaluation were done in 56 random patients. RESULTS: Residual LVH was present in 44% of patients after AVR. Patients with residual LVH were older, more frequently women and had hypertension (HT). Preoperatively, they had higher LV mass indices (LVMI), higher E/e0 and left atrial volume indices, as well as lower peak systolic annular velocity. Female gender, HT, LVMI and E/e0 were independent predictors of persistent LVH. CVF at the time of surgery was higher in those with residual LVH (20.0 ± 14.6 vs 13.2 ± 11.5%, P = 0.027). The risk of all-cause death and non-fatal cardiovascular hospitalization was higher in patients with residual LVH [OR 2.89 (95% CI 1.12-7.44); P = 0.035], but there were no differences in all-cause mortality. Residual LVH was associated with a worse outcome in women but not in men. CONCLUSIONS: Residual LVH after AVR is common and is associated with worse prognosis, particularly in women. In addition, HT, higher baseline LVM and worse diastolic dysfunction can help to identify patients at risk for incomplete normalization of LVM. [ABSTRACT FROM AUTHOR]

BackgroundStructural and functional changes involved in cardiac injury induced by diabetes mellitus, pressure-overload, or both conditions were evaluated.MethodsPressure-overload was established by suprarenal aortic banding in rats. Six weeks later, diabetes was induced by streptozotocin (STZ, 65 mg/kg, intraperitoneally), resulting in four groups: SHAM, banded (BA), diabetic (DM), and diabetic-banded (DM-BA). On the 12th week, left ventricular (LV) structure and function were evaluated. LV function was assessed in vivo with pressure-volume catheters and in vitro by papillary muscles' performance at baseline and in response to isoprenaline (ISO, 10−8 to 10−5 M).ResultsCompared to SHAM, we observed a significant increase of type-B natriuretic peptide (BA = 370 ± 110%; DM-BA = 580 ± 210%), LV mass (BA = 36.8 ± 3.6%; DM-BA = 32.1 ± 3.1%), cardiomyocyte diameter (BA = 19.5 ± 2.3%; DM = 14.3 ± 1.9%; DM-BA = 11.4 ± 2.0%), fibrosis (BA = 85 ± 14%; DM = 145 ± 28%; DM-BA = 155 ± 14%), advanced glycation endproduct (AGE) deposition (DM = 141 ± 29%; DM-BA = 166 ± 46%), contraction (tAT: DM = 13.7 ± 2.4%; DM-BA = 26.3 ± 7.1%); a delayed relaxation (tHR: DM = 13.8 ± 2.6%; DM-BA = 25.5 ± 9.2%) and a decrease of collagen type-I/type-III ratio (DM = −66.1 ± 4.6%; DM-BA = −51.9 ± 5.5). In SHAM animals, ISO (10−5 M) increased 86.5 ± 26.2% active tension, 105.3 ± 20.2% dT/dtmax, and 166.8 ± 29.9% dT/dtmin. Similar effects were observed in BA and DM animals, whereas in DM-BA these inotropic and lusitropic responses were blunted. Moreover, at a similar resting muscle length, ISO decreased passive tension by 12 ± 3% in SHAM and 11 ± 3% in BA, indicating an increase in myocardial distensibility, an effect that was absent in both diabetic groups.ConclusionLong-standing pressure-overload increased LV mass, while diabetes promoted AGE and collagen deposition, which might explain the abolition of ISO-induced increased myocardial distensibility. Association of pressure-overload and diabetes completely blunted the inotropic and lusitropic responses to ISO, with no additional structural damages than in pressure-overload or diabetes alone.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.159 [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. 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, 1.6×108±6.1×107, banding, 2.6×108±4.5×107, 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, 2.6×108±4.5×107, debanding, 1.96×108±6.8×107, 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. [ABSTRACT FROM AUTHOR]

The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show long-term increased risk of cardiovascular disease and mortality is unknown. We aim to profile the urinary proteome in pregnant women with/without CV risk factors to identify proteins associated with postpartum RR. Our study included a prospective cohort of 32 healthy and 27 obese and/or hypertensive and/or diabetic pregnant women who underwent transthoracic echocardiography, pulse-wave-velocity, and urine collection at the 3rd trimester and 6 months postpartum. Shotgun HPLC–MS/MS profiled proteins. Generalized linear mixed-effects models were used to identify associations between urinary proteins and left ventricle mass (LVM), a surrogate of RR. An increase in arterial stiffness was documented from 3rd trimester to 6 months after delivery, being significantly elevated in women with CV risk factors. In addition, the presence of at least one CV risk factor was associated with worse LVM RR. We identified 6 and 11 proteins associated with high and low LVM regression, respectively. These proteins were functionally linked with insulin-like growth factor (IGF) transport and uptake regulation by IGF binding-proteins, platelet activation, signaling and aggregation and the immune system's activity. The concentration of IGF-1 in urine samples was associated with low LVM regression after delivery. Urinary proteome showed a predicting potential for identifying pregnant women with incomplete postpartum RR. [ABSTRACT FROM AUTHOR]

Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1stT) and a separate group of 31 (3rd trimester, 3rdT) women [healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes)] underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and E/e' before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1stT and 3rdT, confirming AVO. LVEDV and E/e' also increased immediately after AVO (T1) in both 1stT and 3rdT. SIC adaptation (T2, 15 min after AVO) significantly decreased E/e' in both trimesters, with additional expansion of LVEDV only in the 1stT. NT-pro-BNP increased slightly after AVO but only in the 1stT. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1stT and 3rdT, which was influenced by CVR factors. The LV of 3rdT pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance. NEW & NOTEWORTHY The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) and maternal obesity (MO) increase the risk of adverse fetal outcomes, and the incidence of cardiovascular disease later in life. Extensive research has been conducted to elucidate the underlying mechanisms by which GDM and MO program the offspring to disease. This review focuses on the role of fetoplacental endothelial dysfunction in programming the offspring for cardiovascular disease in GDM and MO pregnancies. We discuss how pre-existing maternal health conditions can lead to vascular dysfunction in the fetoplacental unit and the fetus. We also examine the role of fetoplacental endothelial dysfunction in impairing fetal cardiovascular system development and the involvement of nitric oxide and hydrogen sulfide in mediating fetoplacental vascular dysfunction. Furthermore, we suggest that the L-Arginine-Nitric Oxide and the A denosine- L - A rginine- N itric O xide (ALANO) signaling pathways are pertinent targets for research. Despite significant progress in this area, there are still knowledge gaps that need to be addressed in future research. [ABSTRACT FROM AUTHOR]

Obesity is linked to perturbations in energy balance mechanisms, including ghrelin and leptin actions at the hypothalamic circuitry of neuropeptide Y (NPY) and melanocortin. However, information about the regulation of this system in the periphery is still scarce. Our objective was to study the regulation of the NPY/melanocortin system in the adipose tissue (AT) and evaluate its therapeutic potential for obesity and type 2 diabetes. The expression of the NPY/melanocortin receptors' levels was assessed in the visceral AT of individuals with obesity and altered metabolism. Protein levels of these receptors were evaluated in cultured adipocytes incubated with ghrelin (30 and 100 ng/mL) and leptin (1 and 10 nM) and in the AT of an animal model with a mutation in the leptin receptor (ZSF1 rat), to understand their regulation by leptin and ghrelin. The vertical sleeve gastrectomy animal model was used to evaluate the putative therapeutic potential of the NPY/melanocortin system. In this study, we unravelled that leptin (1 nM and 10 nM) selectively reduced the levels of NPY5R and MC3R but no other NPYR/MCRs in cultured adipocytes. In turn, acylated ghrelin (100 ng/mL) significantly increased NPY1R, but the inhibition of its receptor also abrogates MC3R levels. However, in the Lepr -deficient ZSF1 rat, both NPY5R and MC3R levels were reduced, along with other NPYRs and MCRs, suggesting that leptin resistance negatively affects NPY and melanocortin signalling. In human adipose tissue, we found a downregulation of genes encoding the NPY and melanocortin receptors in the visceral AT of individuals with obesity and insulin resistance, being correlated with genes regulating metabolic activity. Additionally, diabetic obese rats submitted to vertical sleeve gastrectomy showed increased levels of NPY, melanocortin, ghrelin, and leptin receptors in the AT, including MC3R, suggesting it may constitute a therapeutic target in obesity. Our results suggest that the AT NPY/melanocortin system, particularly the MC3R, may be involved in the neuroendocrine regulation of adipocyte metabolism. Altogether, our work shows MC3R is under the control of the ghrelin/leptin duo, is reduced in patients with obesity and prediabetes, and may constitute a therapeutic target in obesity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by impaired cardiovascular reserve in which therapeutic options are scarce. Our aim was to evaluate the inodilator levosimendan in the ZSF1 obese rat model of HFpEF. Twenty-week-old male Wistar-Kyoto (WKY), ZSF1 lean (ZSF1 Ln) and ZSF1 obese rats chronically treated for 6-weeks with either levosimendan (1 mg/kg/day, ZSF1 Ob + Levo) or vehicle (ZSF1 Ob + Veh) underwent peak-effort testing, pressure-volume (PV) haemodynamic evaluation and echocardiography (n = 7 each). Samples were collected for histology and western blotting. In obese rats, skinned and intact left ventricular (LV) cardiomyocytes underwent in vitro functional evaluation. Seven additional ZSF1 obese rats underwent PV evaluation to assess acute levosimendan effects (10 μg/kg + 0.1 μg/kg/min). ZSF1 Ob + Veh presented all hallmarks of HFpEF, namely effort intolerance, elevated end-diastolic pressures and reduced diastolic compliance as well as increased LV mass and left atrial area, cardiomyocyte hypertrophy and increased interstitial fibrosis. Levosimendan decreased systemic arterial pressures, raised cardiac index, and enhanced LV relaxation and diastolic compliance in both acute and chronic experiments. ZSF1 Ob + Levo showed pronounced attenuation of hypertrophy and interstitial fibrosis alongside increased effort tolerance (endured workload raised 38 %) and maximum O 2 consumption. Skinned cardiomyocytes from ZSF 1 Ob + Levo showed a downward shift in sarcomere length-passive tension relationship and intact cardiomyocytes showed decreased diastolic Ca2+ levels and enhanced Ca2+ sensitivity. On molecular grounds, levosimendan enhanced phosphorylation of phospholamban and mammalian target of rapamycin. The observed effects encourage future clinical trials with levosimendan in a broad population of HFpEF patients. • Acute levosimendan infusion enhances cardiac compliance in a rat HFpEF model. • Chronic levosimendan improves effort tolerance and attenuates cardiac remodelling. • Levosimendan reduces diastolic Ca2+ and improves cardiomyocyte compliance. [ABSTRACT FROM AUTHOR]