233 results found
Poulet C, Sanchez-Alonso J, Swiatlowska P, et al., Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes, Cardiovascular Research, ISSN: 0008-6363
Aim: In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodeling in cardiac diseases is associated with down-regulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signaling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes.Methods and results: Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodeling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with Methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2. Conclusions: JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol an
Pitoulis F, Watson S, Perbellini F, et al., Myocardial slices come to age: An intermediate complexity in vitro cardiac model for translational research, Cardiovascular Research, ISSN: 0008-6363
Although past decades have witnessed significant reductions in mortality of heart failure together with advances in our understanding of its cellular, mo-lecular, and whole-heart features, a lot of basic cardiac research still fails to translate into clinical practice.In this review we examine myocardial slices, a novel modelin the translational arena. Myocardial slices are living ultra-thin sections of heart tissue. Slices maintain the myocardium’s native function (contractility, electrophysiology) and structure (multicellularity, extracellular matrix), and can be prepared from animal and human tissue. Thediscussion9beginswith the history and current advances in the model, the different in-terlaboratory methods of preparation and their potentialimpact on results. We then contextualise slices’ advantages and limitations by comparing itwith other cardiac models. Recently, sophisticated methods have enabled slices to be cultured chronically in vitro whilepreserving thefunctional and structural phenotype. This is more timely now than ever where chronic physiologically relevant in vitro platforms for assessment of therapeutic strategies are urgently needed. We interrogate the technological developments that have per-mitted this, their limitations, and future directions. Finally, we look into the general obstacles faced by the translational field, and how implementation of research systems utilising slices could help in resolving these.
Zwi Dantsis L, Wang B, Marijon C, et al., Remote magnetic nanoparticle manipulation enables the dynamic patterning of cardiac tissues, Advanced Materials, ISSN: 0935-9648
The ability to manipulate cellular organization within soft materials has important potential in biomedicine and regenerative medicine; however, it often requires complex fabrication procedures. Here, we develop a simple, cost-effective, and one-step approach that enables the control of cell orientation within 3-dimensional (3D) collagen hydrogels to dynamically create various tailored microstructures of cardiac tissues. This isachieved by incorporating iron-oxide nanoparticles into human cardiomyocytes (CMs) and applying a short-term external magnetic field to orient the cells along the applied field to impart different shapes without any mechanical supports. The patterned constructs areviable and functional, canbe detected by T2*-weighted MRI and induceno alteration to normal cardiac function after grafting onto rat hearts. This strategy paves the way to creating customized, macroscale, 3D tissue constructs with various cell-types for therapeutic and bioengineering applications, as well as providing powerful models for investigating tissue behavior.
Fourre JD, Bardi I, King O, et al., 2019, Endothelial cell activation by pro-inflammatory cytokines exerts novel paracrine effects on cocultured cardiomyocytes, Publisher: WILEY, Pages: 91-91, ISSN: 1748-1708
Sanzari I, Dinelli F, Humphrey E, et al., 2019, Microstructured hybrid scaffolds for aligning neonatal rat ventricular myocytes, MATERIALS SCIENCE & ENGINEERING C-MATERIALS FOR BIOLOGICAL APPLICATIONS, Vol: 103, ISSN: 0928-4931
Fourre J, Bardi I, Maughan RT, et al., 2019, Endothelial cell activation by pro-inflammatory cytokines exerts novel paracrine effects on co-cultured cardiomyocytes, ESC Congress / World Congress of Cardiology, Publisher: OXFORD UNIV PRESS, Pages: 3904-3904, ISSN: 0195-668X
Ou Q, Jacobson Z, Abouleisa R, et al., 2019, Physiological Biomimetic Culture System for Pig and Human Heart Slices, Circulation Research, Vol: 125, Pages: 628-642, ISSN: 0009-7330
RATIONALE: Preclinical testing of cardiotoxicity and efficacy of novel heart failure therapies faces a major limitation: the lack of an in situ culture system that emulates the complexity of human heart tissue and maintains viability and functionality for a prolonged time. OBJECTIVE: To develop a reliable, easily reproducible, medium-throughput method to culture pig and human heart slices under physiological conditions for a prolonged period of time. METHODS AND RESULTS: Here, we describe a novel, medium-throughput biomimetic culture system that maintains viability and functionality of human and pig heart slices (300 µm thickness) for 6 days in culture. We optimized the medium and culture conditions with continuous electrical stimulation at 1.2 Hz and oxygenation of the medium. Functional viability of these slices over 6 days was confirmed by assessing their calcium homeostasis, twitch force generation, and response to β-adrenergic stimulation. Temporal transcriptome analysis using RNAseq at day 2, 6, and 10 in culture confirmed overall maintenance of normal gene expression for up to 6 days, while over 500 transcripts were differentially regulated after 10 days. Electron microscopy demonstrated intact mitochondria and Z-disc ultra-structures after 6 days in culture under our optimized conditions. This biomimetic culture system was successful in keeping human heart slices completely viable and functionally and structurally intact for 6 days in culture. We also used this system to demonstrate the effects of a novel gene therapy approach in human heart slices. Furthermore, this culture system enabled the assessment of contraction and relaxation kinetics on isolated single myofibrils from heart slices after culture. CONCLUSIONS: We have developed and optimized a reliable medium-throughput culture system for pig and human heart slices as a platform for testing the efficacy of novel heart failure therapeutics and reliable testing of cardiotoxicity in a 3D heart
Wang BX, Kit-Anan W, Whittaker T, et al., 2019, Regulation of cardiac excitation-contraction coupling by human cardiac fibroblasts in health and disease, British-Pharmacology-Society Meeting (Pharmacology), Publisher: WILEY, Pages: 3034-3035, ISSN: 0007-1188
Watson S, Duff J, Bardi I, et al., 2019, Biomimetic electromechanical stimulation to maintain adult myocardial slices in vitro, Nature Communications, Vol: 10, ISSN: 2041-1723
Adult cardiac tissue undergoes a rapid process of dedifferentiation when cultured outside the body. The in vivo environment, particularly constant electromechanical stimulation, is fundamental to the regulation of cardiac structure and function. We investigated the role of electromechanical stimulation in preventing culture-induced dedifferentiation of adult cardiac tissue using rat, rabbit and human heart failure myocardial slices. Here we report that the application of a preload equivalent to sarcomere length (SL) = 2.2 μm is optimal for the maintenance of rat myocardial slice structural, functional and transcriptional properties at 24 h. Gene sets associated with the preservation of structure and function are activated, while gene sets involved in dedifferentiation are suppressed. The maximum contractility of human heart failure myocardial slices at 24 h is also optimally maintained at SL = 2.2 μm. Rabbit myocardial slices cultured at SL = 2.2 μm remain stable for 5 days. This approach substantially prolongs the culture of adult cardiac tissue in vitro.
Jabbour R, Owen T, Reinsch M, et al., 2019, DEVELOPMENT AND PRECLINICAL TESTING OF A LARGE HEART MUSCLE PATCH, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A157-A158, ISSN: 1355-6037
Kreutzer FP, Meinecke A, Fiedler J, et al., 2019, HFWM: Natural compound-derived small molecules to target fibrosis, Publisher: WILEY, Pages: 319-319, ISSN: 1388-9842
Wang BX, Kit-Anan W, Whittaker T, et al., 2019, Human Cardiac Fibroblast-Secreted Exosomes Improve Efficiency of Human Cardiomyocyte Calcium Cycling, Publisher: SPRINGER, Pages: 269-269, ISSN: 0920-3206
Perbellini F, Watson SA, Thum T, et al., 2019, Adult myocardial slices a highly viable and functional platform to study cardiac biology, Publisher: WILEY, Pages: 42-43, ISSN: 0014-2972
Watson SA, Terracciano CM, Perbellini F, 2019, Myocardial sices: an intermediate complexity platform for translational cardiovascular research, Cardiovascular Drugs and Therapy, Vol: 33, Pages: 239-244, ISSN: 0920-3206
Myocardial slices, also known as "cardiac tissue slices" or "organotypic heart slices," are ultrathin (100-400 μm) slices of living adult ventricular myocardium prepared using a high-precision vibratome. They are a model of intermediate complexity as they retain the native multicellularity, architecture, and physiology of the heart, while their thinness ensures adequate oxygen and metabolic substrate diffusion in vitro. Myocardial slices can be produced from a variety of animal models and human biopsies, thus providing a representative human in vitro platform for translational cardiovascular research. In this review, we compare myocardial slices to other in vitro models and highlight some of the unique advantages provided by this platform. Additionally, we discuss the work performed in our laboratory to optimize myocardial slice preparation methodology, which resulted in highly viable myocardial slices from both large and small mammalian hearts with only 2-3% cardiomyocyte damage and preserved structure and function. Applications of myocardial slices span both basic and translational cardiovascular science. Our laboratory has utilized myocardial slices for the investigation of cardiac multicellularity, visualizing 3D collagen distribution and micro/macrovascular networks using tissue clearing protocols and investigating the effects of novel conductive biomaterials on cardiac physiology. Myocardial slices have been widely used for pharmacological testing. Finally, the current challenges and future directions for the technology are discussed.
Pitoulis F, Watson SA, Dries E, et al., 2019, Myocardial Slices - A Novel Platform for In Vitro Biomechanical Studies, 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 30A-30A, ISSN: 0006-3495
King O, Kermani F, Wang B, et al., 2019, Endothelial Cell Regulation of Excitation-Contraction Coupling in Induced Pluripotent Stem Cell Derived Myocardium, 63rd Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 153A-153A, ISSN: 0006-3495
Fourre J, Terracciano C, Mason J, 2019, Endothelial Cells Exert Stimulus-Specific Paracrine Effects on Co-Cultured Cardiomyocytes During Inflammation, 3rd Joint Meeting of the European-Society-for-Microcirculation (ESM) and the European-Vascular-Biology-Organization (EVBO), Publisher: KARGER, Pages: 35-35, ISSN: 1018-1172
Dubey P, Humphrey E, Majid Q, et al., 2019, Polyhydroxyalkanoates, ideal materials for cardiac regeneration, ISSN: 1526-7547
© 2019 Omnipress - All rights reserved. Statement of purpose: Polyhydroxyalkanoates (PHAs), a family of biodegradable and biocompatible polymers with a range of material properties and degradation rates are known to be particularly cardio-regenerative in nature1,2,3. Myocardial infarction results in the generation of scar tissue with limited or no regeneration due to the modest nature of intrinsic myocardial regenerative capability. The concept of a cardiac patch is tailored to meet the unmet medical need of cardiac regeneration where a biomaterial-based patch with/without cells would be used to induce efficient cardiac regeneration. Medium chain length PHAs (MCL-PHAs) with monomer chain length between C6-C16 are highly elastomeric in nature1,2 and have been shown to be excellent substrates for the growth and function of neonatal cardiomyocytes3. This work describes an in-depth study of the potential of MCL-PHAs for the development of functional cardiac patches laden with human pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), providing mechanical support and cell based therapy.
Perbellini F, Watson SA, Bardi I, et al., 2018, Heterocellularity and cellular cross-talk in the cardiovascular system, Frontiers in Cardiovascular Medicine, Vol: 5, ISSN: 2297-055X
Cellular specialization and interactions with other cell types are the essence of complex multicellular life. The orchestrated function of different cell populations in the heart, in combination with a complex network of intercellular circuits of communication, is essential to maintain a healthy heart and its disruption gives rise to pathological conditions. Over the past few years, the development of new biological research tools has facilitated more accurate identification of the cardiac cell populations and their specific roles. This review aims to provide an overview on the significance and contributions of the various cellular components: cardiomyocytes, fibroblasts, endothelial cells, vascular smooth muscle cells, pericytes, and inflammatory cells. It also aims to describe their role in cardiac development, physiology and pathology with a particular focus on the importance of heterocellularity and cellular interaction between these different cell types.
Wang BX, Kit-Anan W, Terracciano CMN, 2018, Many cells make life work-multicellularity in stem cell-based cardiac disease modelling, International Journal of Molecular Sciences, Vol: 19, ISSN: 1422-0067
Cardiac disease causes 33% of deaths worldwide but our knowledge of disease progression is still very limited. In vitro models utilising and combining multiple, differentiated cell types have been used to recapitulate the range of myocardial microenvironments in an effort to delineate the mechanical, humoral, and electrical interactions that modulate the cardiac contractile function in health and the pathogenesis of human disease. However, due to limitations in isolating these cell types and changes in their structure and function in vitro, the field is now focused on the development and use of stem cell-derived cell types, most notably, human-induced pluripotent stem cell-derived CMs (hiPSC-CMs), in modelling the CM function in health and patient-specific diseases, allowing us to build on the findings from studies using animal and adult human CMs. It is becoming increasingly appreciated that communications between cardiomyocytes (CMs), the contractile cell of the heart, and the non-myocyte components of the heart not only regulate cardiac development and maintenance of health and adult CM functions, including the contractile state, but they also regulate remodelling in diseases, which may cause the chronic impairment of the contractile function of the myocardium, ultimately leading to heart failure. Within the myocardium, each CM is surrounded by an intricate network of cell types including endothelial cells, fibroblasts, vascular smooth muscle cells, sympathetic neurons, and resident macrophages, and the extracellular matrix (ECM), forming complex interactions, and models utilizing hiPSC-derived cell types offer a great opportunity to investigate these interactions further. In this review, we outline the historical and current state of disease modelling, focusing on the major milestones in the development of stem cell-derived cell types, and how this technology has contributed to our knowledge about the interactions between CMs and key non-myocyte components of th
Armstrong J, Puetzer JL, Serio A, et al., 2018, Engineering anisotropic muscle tissue using acoustic cell patterning, Advanced Materials, Vol: 30, ISSN: 0935-9648
Tissue engineering has offered unique opportunities for disease modeling and regenerative medicine; however, the success of these strategies is dependent on faithful reproduction of native cellular organization. Here, it is reported that ultrasound standing waves can be used to organize myoblast populations in material systems for the engineering of aligned muscle tissue constructs. Patterned muscle engineered using type I collagen hydrogels exhibits significant anisotropy in tensile strength, and under mechanical constraint, produced microscale alignment on a cell and fiber level. Moreover, acoustic patterning of myoblasts in gelatin methacryloyl hydrogels significantly enhances myofibrillogenesis and promotes the formation of muscle fibers containing aligned bundles of myotubes, with a width of 120–150 µm and a spacing of 180–220 µm. The ability to remotely pattern fibers of aligned myotubes without any material cues or complex fabrication procedures represents a significant advance in the field of muscle tissue engineering. In general, these results are the first instance of engineered cell fibers formed from the differentiation of acoustically patterned cells. It is anticipated that this versatile methodology can be applied to many complex tissue morphologies, with broader relevance for spatially organized cell cultures, organoid development, and bioelectronics.
Masood E, Vesper I, Van Noorden R, et al., 2018, SIX MONTHS UNTIL BREXIT: HOW SCIENTISTS ARE PREPARING FOR THE SPLIT, NATURE, Vol: 561, Pages: 452-454, ISSN: 0028-0836
Amdursky N, Mazo M, Thomas MR, et al., 2018, Elastic serum-albumin based hydrogels: mechanism of formation and application in cardiac tissue engineering, Journal of Materials Chemistry B, Vol: 6, Pages: 5604-5612, ISSN: 2050-750X
Hydrogels are promising materials for mimicking the extra-cellular environment. Here, we present a simple methodology for the formation of a free-standing viscoelastic hydrogel from the abundant and low cost protein serum albumin. We show that the mechanical properties of the hydrogel exhibit a complicated behaviour as a function of the weight fraction of the protein component. We further use X-ray scattering to shed light on the mechanism of gelation from the formation of a fibrillary network at low weight fractions to interconnected aggregates at higher fractions. Given the match between our hydrogel elasticity and that of the myocardium, we investigated its potential for supporting cardiac cells in vitro. Interestingly, the sehydrogels support the formation of several layers of myocytes and significantly promote the maintenance of a native-likegene expression profile compared to those cultured on glass. When confronted with a multicellular ventricular cell preparation, the hydrogels can support macroscopically contracting cardiac-like tissues with a distinct cell arrangement, and form mm-long vascular-like structures. We envisage that our simple approach for the formation of an elastic substrate from an abundant protein makes the hydrogel a compelling biomedical material candidate for a wide range of cell types.
Wright PT, Sanchez-Alonso JL, Lucarelli C, et al., 2018, Partial mechanical unloading of the heart disrupts L-type calcium channel and beta-adrenoceptor signaling microdomains, Frontiers in Physiology, Vol: 9, ISSN: 1664-042X
Introduction: We investigated the effect of partial mechanical unloading (PMU) of the heart on the physiology of calcium and beta-adrenoceptor-cAMP (βAR-cAMP) microdomains. Previous studies have investigated PMU using a model of heterotopic-heart and lung transplantation (HTHAL). These studies have demonstrated that PMU disrupts the structure of cardiomyocytes and calcium handling. We sought to understand these processes by studying L-Type Calcium Channel (LTCC) activity and sub-type-specific βAR-cAMP signaling within cardiomyocyte membrane microdomains.Method: We utilized an 8-week model of HTHAL, whereby the hearts of syngeneic Lewis rats were transplanted into the abdomens of randomly assigned cage mates. A pronounced atrophy was observed in hearts after HTHAL. Cardiomyocytes were isolated via enzymatic perfusion. We utilized Förster Resonance Energy Transfer (FRET) based cAMP-biosensors and scanning ion conductance microscopy (SICM) based methodologies to study localization of LTCC and βAR-cAMP signaling.Results: β2AR-cAMP responses measured by FRET in the cardiomyocyte cytosol were reduced by PMU (loaded 28.51 ± 7.18% vs. unloaded 10.84 ± 3.27% N,n 4/10-13 mean ± SEM ∗p < 0.05). There was no effect of PMU on β2AR-cAMP signaling in RII_Protein Kinase A domains. β1AR-cAMP was unaffected by PMU in either microdomain. Consistent with this SICM/FRET analysis demonstrated that β2AR-cAMP was specifically reduced in t-tubules (TTs) after PMU (loaded TT 0.721 ± 0.106% vs. loaded crest 0.104 ± 0.062%, unloaded TT 0.112 ± 0.072% vs. unloaded crest 0.219 ± 0.084% N,n 5/6-9 mean ± SEM ∗∗p < 0.01, ∗∗∗p < 0.001 vs. loaded TT). By comparison β1AR-cAMP responses in either TT or sarcolemmal crests were unaffected by the PMU. LTCC occurrence and open probability (Po) were reduced by PMU (loaded TT Po 0.073 ± 0.011% vs. load
Kane C, Terracciano CMN, 2018, Human cardiac fibroblasts engage the sarcoplasmic reticulum in induced pluripotent stem cell-derived cardiomyocyte excitation-contraction coupling, Journal of the American College of Cardiology, Vol: 72, Pages: 1061-1063, ISSN: 0735-1097
Sanzari I, Humphrey EJ, Dinelli F, et al., 2018, Effect of patterned polyacrylamide hydrogel on morphology and orientation of cultured NRVMs, Scientific Reports, Vol: 8, ISSN: 2045-2322
We recently demonstrated that patterned Parylene C films could be effectively used as a mask for directly copolymerizing proteins on polyacrylamide hydrogel (PAm). In this work, we have proved the applicability of this technique for studying the effect such platforms render on neonatal rat ventricular myocytes (NRVMs). Firstly, we have characterised topographically and mechanically the scaffolds in liquid at the nano-scale level. We thus establish that such platforms have physical properties that closely mimics the in vivo extracellular environment of cells. We have then studied the cell morphology and physiology by comparing cultures on flat uniformly-covered and collagen-patterned scaffolds. We show that micro-patterns promote the elongation of cells along the principal axis of the ridges coated with collagen. In several cases, cells also tend to create bridges across the grooves. We have finally studied cell contraction, monitoring Ca2+ cycling at a certain stimulation. Cells seeded on patterned scaffolds present significant responses in comparison to the isotropic ones.
Watson SA, Duff JD, Bardi IB, et al., 2018, A novel platform to maintain adult cardiac tissue in vitro: myocardial slices and electromechanical stimulation with physiological preload, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 1090-1090, ISSN: 0195-668X
Jabbour R, Kapnisi K, Mawad D, et al., 2018, Conductive polymers affect myocardial conduction velocity but are not pro-arrhythmic, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 1205-1205, ISSN: 0195-668X
Wang B, Deidda G, Mitraki A, et al., 2018, Self-assembling arginine-glycine-aspartic acid-containing peptides abbreviate human cardiomyocyte calcium transients and increase sarcoplasmic reticulum contribution to excitation-contraction coupling, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 1209-1209, ISSN: 0195-668X
Mustroph J, Wagemann O, Luecht CM, et al., 2018, Empagliflozin reduces Ca/calmodulin-dependent kinase II activity in isolated ventricular cardiomyocytes, ESC Heart Failure, Vol: 5, Pages: 642-648, ISSN: 2055-5822
AimsThe EMPA‐REG OUTCOME study showed reduced mortality and hospitalization due to heart failure (HF) in diabetic patients treated with empagliflozin. Overexpression and Ca2+‐dependent activation of Ca2+/calmodulin‐dependent kinase II (CaMKII) are hallmarks of HF, leading to contractile dysfunction and arrhythmias. We tested whether empagliflozin reduces CaMKII‐ activity and improves Ca2+‐handling in human and murine ventricular myocytes.Methods and resultsMyocytes from wild‐type mice, mice with transverse aortic constriction (TAC) as a model of HF, and human failing ventricular myocytes were exposed to empagliflozin (1 μmol/L) or vehicle. CaMKII activity was assessed by CaMKII–histone deacetylase pulldown assay. Ca2+ spark frequency (CaSpF) as a measure of sarcoplasmic reticulum (SR) Ca2+ leak was investigated by confocal microscopy. [Na+]i was measured using Na+/Ca2+‐exchanger (NCX) currents (whole‐cell patch clamp). Compared with vehicle, 24 h empagliflozin exposure of murine myocytes reduced CaMKII activity (1.6 ± 0.7 vs. 4.2 ± 0.9, P < 0.05, n = 10 mice), and also CaMKII‐dependent ryanodine receptor phosphorylation (0.8 ± 0.1 vs. 1.0 ± 0.1, P < 0.05, n = 11 mice), with similar results upon TAC. In murine myocytes, empagliflozin reduced CaSpF (TAC: 1.7 ± 0.3 vs. 2.5 ± 0.4 1/100 μm−1 s−1, P < 0.05, n = 4 mice) but increased SR Ca2+ load and Ca2+ transient amplitude. Importantly, empagliflozin also significantly reduced CaSpF in human failing ventricular myocytes (1 ± 0.2 vs. 3.3 ± 0.9, P < 0.05, n = 4 patients), while Ca2+ transient amplitude was increased (F/F0: 0.53 ± 0.05 vs. 0.36 ± 0.02, P < 0.05, n = 3 patients). In contrast, 30 min exposure with empagliflozin did not affect CaMKII activity nor Ca2+‐handling but significantly reduced [Na+]i.ConclusionsWe show for the first time that empagliflozin reduces CaMKII activity and CaMKII‐dependent SR Ca2+ le
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