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Heart failure (HF) is characterised by an impaired heart function, several causes can lead to the development of this pathology. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are antidiabetics that showed an important reduction of the morbimortality of patients with heart failure. However, SGLT2 is not expressed in the heart and therefore the mechanism of action inducing SGLT2i cardioprotective effects is unknown. Intracellular calcium concentration being a critical regulator of cardiomyocytes (CM) contraction and thus the pump function of the heart, we explored in our study the "off-target" effect of dapagliflozin, an SGLT2i, on the regulation of calcium dynamics and its consequences on isolated cardiomyocytes contractility. Ventricular CM were isolated from left ventricules of 3 months old healthy Wistar rats. CM were electrically field stimulated; calcium dynamic was studied using Fluo-4 calcium probe and contraction was measured by analysing sarcomeres lenght. Calcium current ICaL was measured with voltage clamp technique in whole cell configuration. Western blot technique was used to measure protein expression levels of major calcium regulators in CM. Our results show that dapagliflozin increases the amplitude of calcium transient while decreasing its time constant of decay. This result suggests a modulation of cytoplasmic calcium cycle, which was shown to be independent of an effect on ICaL. The increased kinetics resulted in a reduction in contraction duration. Pharmacological studies showed a significant increase (27.5 ± 6.1%, n = 12, P = 0.0005) of the activity of sarcoplasmic reticulum calcium ATPase (SERCA2a) and thus an increase of the reuptake of calcium in the SR in presence of dapagliflozin. Preliminary molecular biology studies showed in dapagliflozin treated cardiomyocytes an increase of the expression of calcium/calmodulin kinase II, a key regulator of CM intracellular calcium homeostasis, as well as an increase of SERCA2a expression. The observed increase of the calcium exchanges kinetics in CM might be responsible of the improvement of the outcome of patients with heart failure treated with dapagliflozin. [ABSTRACT FROM AUTHOR]

Pathological left ventricular remodeling is a complex process involving the architectural disorganisation of cardiac tissue following a myocardial infarction. This is characterised by the exaggerated development of fibrotic scar tissue that can lead to heart failure. In an attempt to understand this, we hypothesised that an altered response of cardiac fibroblasts, subjected to cellular stress-induced by coronary occlusion, could be involved in this pathological remodelling. Their response is orchestrated by molecular switches that enable them to detect their environment, survive during cellular stress and regulates their response. Among these molecular switches, P2X4 appears to play a pivotal role due to its sensitivity to extracellular ATP, a molecule released during cellular stress that modulates the tissue response to the environment. Interestingly, P2X4, which can also be found at the membrane of lysosomes, is involved in regulating autophagy, a critical pathway for cell survival in the event of nutrient and oxygen deprivation. Elucidate P2X4 role in governing the behavior of cardiac fibroblasts during oxygen and nutrient deprivation, and its potential contribution to cardiac remodeling. Characterizing the response of a primary culture of cardiac fibroblasts to oxygen and nutrient deprivation stress: assessing fibrosis and autophagy markers together with P2X4 expression by Western Blot The impact of P2X4 is further elucidated using siRNA methodology and in vivo experiments involving coronary ligation in P2X4 KO mice. Our results suggest that fibroblasts subjected to nutrient and oxygen deprivation differentiate towards a myofibroblastic profile, the initiator of fibrosis. At the same time, autophagy markers decrease, indicating an increased autophagic flux. This autophagic flux is accompanied by protein overexpression of P2X4 in these cells. When cells loose P2X4 expression, whose subjected to stress overexpress fibrotic markers compared with siCTL. Together autophagy markers increased, suggesting a disruption of autophagic flow. Using a coronary ligation model, we can see that the at-risk areas of the ligated hearts of KO P2X4 mice show an accumulation of fibrosis markers as well as those studied for autophagy. Our work reveals P2X4 role in orienting cardiac fibroblasts towards a healing profile when subjected to stress-induced deprivation. Its role is potentially explained by the modulation of autophagic flux, disturbing the balance in the elimination of pro-fibrotic factors. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Pathological ventricular remodelling is an abnormal healing process following myocardial infarction (MI), which mechanisms remain debated. Several hypotheses have been proposed to explain the links between inflammatory response secondary to MI and the evolution towards pathological remodelling, including the involvement of ATP and its cellular receptors: the purinergic receptors. Our working hypothesis is that there is a maintenance/resurgence of a tissue inflammatory response in MI patients with pathological remodelling that would hinder the healing process and may be associated with a specific purinergic profile. The objective of the project is to study the impact of ischemia-reperfusion on cardiac fibroblast's' profiles and to identify an associated purinergic signature. First, we studied the effect of ischaemia (5 h) and reperfusion (24, 48 h) on human primary cardiac fibroblasts (HCF) phenotype by studying the expression of markers associated with the activated state: periostin and the differentiated state: smooth muscle alpha-actin (αSMA) by Western blot. Simultaneously, the expression level of P2 purinergic receptors (P2R) was quantified by RT-qPCR and WB over time. In a second step, we chose to investigate the involvement of P2X4 in the activation and differentiation of cardiac fibroblasts. Therefore, we blocked its activity during reperfusion with its specific antagonist 5-BDBD (5 μM). In addition, wound healing studies were conducted with and without P2X4's antagonist to investigate its involvement in the migratory capacity of cardiac fibroblasts. Ischaemia-reperfusion (IR) appears to induce an initial increase in periostin expression at 24 h followed by a decrease at 48 h as compared to normoxia. This may be related to a more important secretion of periostin at 48 h, as suggested by its increase in supernatants. Concerning αSMA, IR induces a decrease in its expression in a sustained manner over time. Regarding P2X4, there is a decrease in its mRNA and protein levels. The use of its antagonist in normoxia and IR decreases αSMA expression but does not affect periostin expression. Similarly, its blockade decreases the basal migratory capacity of fibroblasts. IR seems to prevent fibroblast differentiation by maintaining them into an activated state. P2X4 could potentially be involved by decreasing fibroblast differentiation, thus impacting αSMA expression. Yet, other purinergic receptors whose expression levels vary following MI might also be involved. [ABSTRACT FROM AUTHOR]

Background Information on the long-term prognosis of patients with infective endocarditis (IE) and valve surgical procedures is scarce, and most analyses are based on registries. This study described outcomes and predictors of mortality in a cohort of consecutive patients with IE with a long-term follow-up. Methods A total of 616 of patients with IE seen in an academic institution between 1990 and 2012 were identified and followed. The mean follow-up period was 4.8 ± 5.7 years (median, 2.6 years). Results Cardiac surgical procedures were performed in 47% of the patients, among whom 77% had surgical procedures in the first 6 months. Six-month and long-term (≥6 month) mortality rates were 15% and 40%, respectively. Older age, male sex, infection in a mechanical valve, Staphylococcus aureus infection, presence of vegetation, stroke, and atrioventricular block were independent predictors of mortality, whereas Streptococcus infection was independently associated with a better prognosis. Valve surgical procedures were independently associated with a decrease in mortality: hazard ratio (HR): 0.38; 95% confidence interval (CI): 0.26 to 0.56 for surgical treatment within 45 days; HR 0.36; 95% CI: 0.22 to 0.61 for surgical treatment between 45 and 180 days; and HR: 0.42; 95% CI: 0.25 to 0.73 for surgical treatment beyond 6 months. Decrease in mortality with valve surgical procedures was found in the two subgroups of patients with definite IE (adjusted HR: 0.36; 95% CI: 0.24 to 0.54; p < 0.0001) and in those with possible IE (HR: 0.40; 95% CI: 0.24 to 0.67; p = 0.0005). Conclusions In unselected patients with IE, prognostic factors for long-term mortality were consistent with those identified in previous studies for short-term mortality. These results confirm the apparent benefit associated with valve surgical procedures on long-term prognosis. [ABSTRACT FROM AUTHOR]

Copyright of Archives of Cardiovascular Diseases is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Aortic valve replacement using a bioprosthesis remains controversial for patients younger than 60 years because of missing data on long-term outcomes in this age group. Methods From 1984 to 2008, 383 Carpentier-Edwards Perimount pericardial aortic bioprostheses were implanted in 373 patients 60 years or younger (mean age, 51.0 ± 9.2 years; 19% female). Multiple valve replacements were excluded from our cohort. Baseline clinical, perioperative, and follow-up data were recorded prospectively. The mean follow-up was 8.6 ± 5.9 years, for a total of 3,299 valve-years. Follow-up was complete for 95.3% of patients included. Results Operative mortality rate was 1.3%. Eighty-five late deaths occurred, for a linearized rate of 2.6%/valve-year. Actuarial survival rates averaged 78.1% ± 2.6%, 65.6% ± 3.5%, and 46.8% ± 6.0% after 10, 15, and 20 years of follow-up, respectively. Mortality rate associated with reoperation was 2.3%. Actuarial freedom from reoperation rates attributable to structural valve deterioration at 10, 15, and 20 years were, respectively, 88.3% ± 2.4%, 70.8% ± 4.1%, and 38.1% ± 5.6%. Competing risk analysis demonstrated an actual risk of explantation secondary to structural valve deterioration at 20 years of 41.6% ± 4.1%. Expected valve durability was 17.6 years for this age group. Conclusions In selected patients 60 years or younger undergoing aortic valve replacement with the Carpentier-Edwards Perimount bioprosthesis, the expected valve durability was 17.6 years. Reoperation for structural valve deterioration was associated with a low risk of mortality. [ABSTRACT FROM AUTHOR]

Objective The aim of the present study was to evaluate the very-long-term results of the Carpentier-Edwards pericardial bioprosthesis in the mitral position. Methods From 1984 to 2011, 450 Carpentier-Edwards PERIMOUNT pericardial mitral bioprostheses were implanted in 404 consecutive patients (mean age, 68 years; 53% female). Patients undergoing multiple valve replacements were excluded. The clinical, operative, and follow-up data were prospectively recorded. The mean follow-up was 7.2 ± 5.1 years, for a total of 3258 valve-years. The follow-up data were 97.8% complete. Results The operative mortality rate was 3.3%. A total of 188 late deaths occurred, for a linearized rate of 5.8%/valve-year. At 20 years, the overall actuarial survival rate was 16.9% ± 3.9%. Age at implantation, preoperative New York Heart Association class III or IV, and redo procedure were significant risk factors affecting late survival. The actuarial freedom from complications at 20 years was thromboembolism, 83.9% ± 7.6%; hemorrhage, 80.2% ± 10.8%; endocarditis, 94.8% ± 1.4%; structural valve deterioration, 23.7% ± 6.9%; and explantation owing to structural valve deterioration, 40.5% ± 8.0%. The competing risk analysis demonstrated an actual risk of explantation owing to structural valve deterioration at 20 years of 25.5% ± 2.9%. The expected valve durability was 16.6 years for the entire cohort (11.4, 16.6, and 19.4 years for patients aged <60, 60 to 70, and >70 years, respectively). Conclusions With a low rate of valve-related events at 20 years and, in particular, a low rate of structural valve deterioration, the Carpentier-Edwards PERIMOUNT pericardial bioprosthesis remains a reliable choice for a mitral tissue valve, especially in patients >60 years old. [ABSTRACT FROM AUTHOR]

Vascular complications (VCs) occurring in transcatheter aortic valve implantation (TAVI) procedures have frequently been reported in the past. Considering significant technical improvements in delivery systems and vascular closure devices, the goal of this study was to determine the incidence, impact, and prognostic factors of VCs in a recent real-world cohort. We report a bicentric prospective analysis of 479 consecutive patients who underwent TAVI between January 2017 and December 2017. VCs were defined according to criteria set out by the Valve Academic Research Consortium (VARC)-2. The incidence of VCs was 26.1% (n = 125 patients), of which 2.9% were major (n = 14) and 23.2% were minor (n = 111). VCs were related to the primary puncture point in 69% of cases compared with 31% at the secondary puncture site. Treatments implemented were medical in 76% of cases and surgical in 24% of cases. The risk factors for VCs were as follows: iliac morphology score, sheath to iliofemoral artery ratio (SIFAR), and moderate-severe iliofemoral calcifications or tortuosity. In the case of major VCs, only sheath to iliofemoral artery ratio was a risk factor. Major VCs significantly increased intrahospital mortality (30.7% vs 1.1% for minor VCs and 1.3% for no VCs; log-rank, P <.0001) and 1-year mortality (40.6% vs 5.6% for minor VCs and 5.6% for no VCs; log-rank, P <.0001). Using strictly VARC-2 end point definitions, more than one-quarter of TAVI procedures were associated with VCs, primarily minor ones. Secondary puncture points were responsible for one-third of VCs and should therefore also be actively monitored. Major VCs have a significant impact on short-term and midterm survival. [ABSTRACT FROM AUTHOR]

We describe a simple and reproducible technique permitting both effective left atrial reduction plasty and safe mitral annulus reconstruction, using a patch of left atrium tissue. In a 64-year-old patient undergoing redo mitral valve replacement for mechanical prosthesis disinsertion, a giant left atrium and extensive calcification of the mitral annulus were noted. This technique permitted a safe mechanical mitral prosthesis re-replacement and a significant reduction of left atrial volume by 70%. [ABSTRACT FROM AUTHOR]

Myocardial ischemia reperfusion is a major cause of cell injury during cardiac transplantation and is responsible for increased graft rejection. Several in vitro studies demonstrated the protective effect of P2Y11-like purinoreceptor stimulation in the context of myocardial ischemia/reperfusion. In this study, we hypothesized a possible cardioprotective role of P2Y11R stimulation against ischemia/reperfusion lesions and validated its clinical effect in vivo in a heart transplantation model. We subjected H9c2 rat cardiomyocyte-derived cell line to 5 hours of hypoxia and 1 hour of reoxygenation. P2Y11R selective agonist NF546 and antagonist NF340 were added at the onset of reoxygenation. Cell injuries were assessed by microculture tetrazolium reduction and intracellular adenosine triphosphate level. Clinical effect of P2Y11R stimulation was further investigated in vivo. Hearts from BALB/c mice were transplanted intra-abdominally into allogenic C57BL/6 mice (n = 104). Recipient mice were injected with P2Y11R agonist. Mice in the sham group were injected with saline solution. In the control group, hearts from C57BL/6 were transplanted into syngeneic C57BL/6 mice. Rejection lesions were investigated using histology and immunohistochemistry at days 3, 5, and 7 after transplantation. We measured caspase activities to quantify apoptosis. Production of proinflammatory and anti-inflammatory cytokines was investigated. P2Y11R stimulation at the onset of reoxygenation significantly reduced in vitro hypoxia/reoxygenation injuries. This protection was suppressed with P2Y11R antagonist. In vivo, cardiac allograft survival was significantly prolonged after P2Y11R stimulation. Rejection lesions, classified according to the International Society of Heart Lung Transplantation guidelines and quantified using the mean number of inflammatory cells per field, were significantly reduced in the treated group. At day 5 after transplantation, P2Y11R agonist pretreated allografts also demonstrated less apoptotic lesions. Our data suggest a novel cardioprotective role of P2Y11R at the onset of reoxygenation/reperfusion against reperfusion injuries. Pharmacologic conditioning using P2Y11 agonist may be beneficial after cardiac transplantation in improving myocardial ischemia/reperfusion outcomes and decreasing graft rejection lesions. [ABSTRACT FROM AUTHOR]

Introduction Graft rejection is the main complication after heart transplantation. We recently demonstrated in vitro that the stimulation of P2Y11 receptor reduces ischemia/reperfusion lesions in human cardiomyocytes and is responsible for dendritic cells maturation, down-modulating the inflammatory response. The objective of this in vivo study was to specify the effect of P2Y11R stimulation on heart graft rejection lesions and its role in the maturation of dendritic cells. Material Hearts from BalbC mice were transplanted intraabdominally into allogenic C57BL6 mice (n=60, females). Mice were injected in the retroorbital sinus with P2Y11R agonist (NF546). Mice in the sham group were injected with saline solution. In the control group, hearts from C57BL6 were transplanted into syngenic C57BL6 mice. Cardiac rejection was defined by cessation of palpable heartbeat and was confirmed by echocardiography. Rejection lesions were investigated using histology and immunohistochemistery (CD3, CD11c, CD45) in allografts at days 3, 5 and 7 after transplantation. To quantify apoptosis, activity of caspase 1, 3 and 9 was measured. Maturation of dendritic cells was investigated by studying expression of markers CD83, CD25, CCR7, CXCR4, and production of cytokines IL6, IL10, IL12, IFN-γ. Results Cardiac allograft survival was significantly prolonged after stimulation of P2Y11R by its agonist (9.6±1.9 vs 8.2±1.4 days; p=0.04). Rejection lesions, classified according to ISHLT guidelines and quantified using the mean number of inflammatory cells per field, were significantly reduced in the treated group. At day 5 after transplantation, P2Y11R agonist pretreated allografts also demonstrated less apoptotic lesions. Conclusion Stimulation of P2Y11 receptor reduces rejection lesions observed after allogenic heart transplantation. Our previous results suggest that this protective role may imply dendritic cells maturation towards an anti inflammatory profile, depending on P2Y11 signaling pathway. The author hereby declares no conflict of interest [ABSTRACT FROM AUTHOR]

• Acute kidney injury (AKI) occurred in 52.7% of patients with infective endocarditis. • Staphylococcus aureus was the most common species and was associated with AKI. • An infectious disease consultation appeared to be a protective factor for AKI. • Exploration of AKI needs to be systematic to conclude on its aetiologies. • Among the 69% patients who survived at one year, 32% had chronic kidney disease. The incidence of acute kidney injury (AKI) in infective endocarditis (IE), its risk factors and consequences on patient and renal survival remain debated. Patients hospitalized for a first episode of IE (possible or definite according to modified Duke criteria) between 2013 and 2016 were included. The primary endpoint was to determine risk factors for early AKI (E-AKI) during the first week of management of IE. A total of 276 patients were included: 220 (79.7%) had definite IE and 56 (20.3%) had possible IE. E-AKI occurred in 150 patients (53%). IE due to Staphylococcus aureus (OR 3.41; 95% CI 1.83–6.39; p < 0.01), history of diabetes (OR 2.34; 95% CI 1.25–4.37; p < 0.01), peripheral arterial disease (OR 2.59; 95% CI 1.07–6.23; p < 0.05), immunological manifestations (OR 3.11; 95% CI 1.31–7.39; p = 0.01), and use of norepinephrine (OR 3.44; 95% CI 1.72–7.02; p < 0.01) were associated with E-AKI. In subgroup analysis, infectious disease consultation was associated with a lower risk of AKI at day 7 (OR 0.41; 95% CI 0.16–0.88; p = 0.04). E-AKI was associated with 1-year mortality (OR 1.65; 95% CI 1.03–2.64; p = 0.04) and chronic kidney disease progression (OR 2.23; 95% CI 1.30–3.82; p < 0.01). E-AKI is common in IE and often associated with non-modifiable variables. Multidisciplinary management should be mandatory, and awareness of AKI diagnosis and etiological explorations should be raised. [ABSTRACT FROM AUTHOR]

Background: Valve-in-valve (VIV) transcatheter aortic valve replacement (TAVR) and redo surgical aortic valve replacement (SAVR) represent the 2 treatments for aortic bioprosthesis failure. Clinical comparison of both therapies remains limited by the number of patients analyzed.Objectives: The purpose of this study was to analyze the outcomes of VIV TAVR versus redo SAVR at a nationwide level in France.Methods: Based on the French administrative hospital-discharge database, the study collected information for patients treated for aortic bioprosthesis failure with isolated VIV TAVR or redo SAVR between 2010 and 2019. Propensity score matching was used for the analysis of outcomes.Results: A total of 4,327 patients were found in the database. After matching on baseline characteristics, 717 patients were analyzed in each arm. At 30 days, VIV TAVR was associated with lower rates of the composite of all-cause mortality, all-cause stroke, myocardial infarction, and major or life-threatening bleeding (odds ratio: 0.62; 95% confidence interval: 0.44 to 0.88; p = 0.03). During follow-up (median 516 days), the combined endpoint of cardiovascular death, all-cause stroke, myocardial infarction, or rehospitalization for heart failure was not different between the 2 groups (odds ratio: 1.18; 95% confidence interval: 0.99 to 1.41; p = 0.26). Rehospitalization for heart failure and pacemaker implantation were more frequently reported in the VIV TAVR group. A time-dependent interaction between all-cause and cardiovascular mortality following VIV TAVR was reported (p-interaction <0.05).Conclusions: VIV TAVR was observed to be associated with better short-term outcomes than redo SAVR. Major cardiovascular outcomes were not different between the 2 treatments during long-term follow-up. [ABSTRACT FROM AUTHOR]