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Showing 121–140 of 2058 publications.
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Doehner, Wolfram; Anker, Stefan D.; Butler, Javed J.; Zannad, Faiez; Filippatos, Gerasimos S.; Coats, Andrew J.S.; Ferreira, Jo Pedro; Henrichmoeller, Ingrid; Brueckmann, Martina; Schueler, Elke; Pocock, Stuart J.; Januzzi, James Louis; Packer, Milton P.Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcome in patients with heart failure (HF) and reduce serum uric acid (SUA). The relevance of this metabolic effect in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. Objectives: The authors investigated the effect of empagliflozin on SUA levels in relation to the therapeutic efficacy in patients with HFpEF. Methods: This post hoc analysis of the EMPEROR-Preserved (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; NCT03057951) trial assessed the clinical effect of SUA reduction in relation to the outcome endpoints of the trial (composite primary outcome of cardiovascular mortality or hospitalization for HF, its individual components, and all-cause mortality in patients with HFpEF). Results: Hyperuricemia (SUA >5.7 mg/dL for women, >7.0 mg/dL for men) was prevalent in 49% of patients. Elevated SUA (highest tertile SUA 8.8 1.4 g/dL) was associated with advanced HF severity and with higher risk of adverse outcome (primary endpoint HR: 1.23 [95% CI: 0.98-1.53]; P = 0.07; HF hospitalization HR: 1.42 [95% CI: 1.08-1.86]; P = 0.01). SUA was reduced early (after 4 weeks vs placebo ?0.99 0.03 mg/dL; P < 0.0001) and throughout follow-up, with reduction in all prespecified subgroups. Empagliflozin reduced clinical events of hyperuricemia (acute gout, gouty arthritis, or initiation of antigout therapy) by 38% (HR: 0.62 [95% CI: 0.51-0.76]; P < 0.0001). The treatment benefit on the primary endpoint was not influenced by baseline SUA (HR: 0.79 [95% CI: 0.69-0.90]; P = 0.0004). The change in SUA was an independent correlate of the treatment benefit on the primary endpoint (P = 0.07). Conclusions: Hyperuricemia is a common complication in HFpEF and is related to advanced disease severity and adverse outcome. Empagliflozin induced a rapid and sustained reduction of SUA levels and of clinical events related to hyperuricemia. 2024 The Authors
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Khandkar, Chinmay; Fulcher, Jordan R.; Patel, Sanjay; Keech, Anthony C.[No abstract available]
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Liu, Xin Tracy; Huang, Yu; Liu, Da; Jiang, Yingxin Celia; Zhao, Min; Chung, Long Hoa; Han, Xingxing Daisy; Zhao, Yinan; Chen, Jinbiao; Coleman, Paul R.; Ting, Kaka; Tran, Collin; Su, Yingying; Dennis, C. V.; Bhatnagar, Atul; Liu, Ken; Don, Anthony Simon; Vadas, Mathew Alexander; Gorrell, Mark Douglas; Zhang, Shubiao; Murray, Michael; Kavurma, Mary M.; McCAUGHAN, G. W.; Gamble, Jennifer R.; Qi, YanfeiBackground: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. Methods: Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. Results: SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. Conclusions: This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC. 2024, The Author(s).
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Liu, Jinghan; Tan, Yuping Yolanda; Zheng, Wen; Wang, Yao; Ju, Lining Arnold; Su, Qian PeterFluorescence nanoscopy, also known as super-resolution microscopy, has transcended the conventional resolution barriers and enabled visualization of biological samples at nanometric resolutions. A series of super-resolution techniques have been developed and applied to investigate the molecular distribution, organization, and interactions in blood cells, as well as the underlying mechanisms of blood-cell-associated diseases. In this review, we provide an overview of various fluorescence nanoscopy technologies, outlining their current development stage and the challenges they are facing in terms of functionality and practicality. We specifically explore how these innovations have propelled forward the analysis of thrombocytes (platelets), erythrocytes (red blood cells) and leukocytes (white blood cells), shedding light on the nanoscale arrangement of subcellular components and molecular interactions. We spotlight novel biomarkers uncovered by fluorescence nanoscopy for disease diagnosis, such as thrombocytopathies, malignancies, and infectious diseases. Furthermore, we discuss the technological hurdles and chart out prospective avenues for future research directions. This review aims to underscore the significant contributions of fluorescence nanoscopy to the field of blood cell analysis and disease diagnosis, poised to revolutionize our approach to exploring, understanding, and managing disease at the molecular level. Graphical Abstract: (Figure presented.) The Author(s) 2024.
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Wang, Haoqing Jerry; Wang, Yao; Mirjavadi, Seyed Sajad; Andersen, Tomas; Moldovan, Laura; Vatankhah, Parham; Russell, Blake; Jin, Jasmine; Zhou, Zijing; Li, Qing; Cox, Charles David; Su, Qian Peter; Ju, Lining ArnoldThe microgeometry of the cellular microenvironment profoundly impacts cellular behaviors, yet the link between it and the ubiquitously expressed mechanosensitive ion channel PIEZO1 remains unclear. Herein, we describe a fluorescent micropipette aspiration assay that allows for simultaneous visualization of intracellular calcium dynamics and cytoskeletal architecture in real-time, under varied micropipette geometries. By integrating elastic shell finite element analysis with fluorescent lifetime imaging microscopy and employing PIEZO1-specific transgenic red blood cells and HEK cell lines, we demonstrate a direct correlation between the microscale geometry of aspiration and PIEZO1-mediated calcium signaling. We reveal that increased micropipette tip angles and physical constrictions lead to a significant reorganization of F-actin, accumulation at the aspirated cell neck, and subsequently amplify the tension stress at the dome of the cell to induce more PIEZO1s activity. Disruption of the F-actin network or inhibition of its mobility leads to a notable decline in PIEZO1 mediated calcium influx, underscoring its critical role in cellular mechanosensing amidst geometrical constraints. The Author(s) 2024.
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Williamson, Anna E.; Liyanage, Sanuri; Hassanshahi, Mohammadhossein; Dona, Malathi S.I.; Toledo-Flores, Deborah; Tran, Dang X.A.; Dimasi, Catherine G.; Schwarz, Nisha; Fernando, Sanuja; Salagaras, Thalia; Long, Aaron; Kazenwadel, J. S.; Harvey, Natasha L.; Drummond, Grant R.; Vinh, Antony; Chandrakanthan, Vashe; Misra, Ashish K.; Neufeld, Zolt; Tan, Joanne Tsui Ming; Martelotto, Luciano G.; Polo, Jose Maria; Bonder, Claudine S.; Pinto, Alexander Ruvantha; Sharma, Shiwani; Nicholls, Stephen J.; Bursill, C. A.; Psaltis, Peter JamesConverging evidence indicates that extra-embryonic yolk sac is the source of both macrophages and endothelial cells in adult mouse tissues. Prevailing views are that these embryonically derived cells are maintained after birth by proliferative self-renewal in their differentiated states. Here we identify clonogenic endothelial-macrophage (EndoMac) progenitor cells in the adventitia of embryonic and postnatal mouse aorta, that are independent of Flt3-mediated bone marrow hematopoiesis and derive from an early embryonic CX<inf>3</inf>CR1+ and CSF1R+ source. These bipotent progenitors are proliferative and vasculogenic, contributing to adventitial neovascularization and formation of perfused blood vessels after transfer into ischemic tissue. We establish a regulatory role for angiotensin II, which enhances their clonogenic and differentiation properties and rapidly stimulates their proliferative expansion in vivo. Our findings demonstrate that embryonically derived EndoMac progenitors participate in local vasculogenic responses in the aortic wall by contributing to the expansion of endothelial cells and macrophages postnatally. The Author(s) 2024.
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Liu, Yanyan; Huang, Tao; Yap, Nicole Alexis; Lim, K. S.; Ju, Lining ArnoldThrombosis, a leading cause of cardiovascular morbidity and mortality, involves the formation of blood clots within blood vessels. Current animal models and in vitro systems have limitations in recapitulating the complex human vasculature and hemodynamic conditions, limiting the research in understanding the mechanisms of thrombosis. Bioprinting has emerged as a promising approach to construct biomimetic vascular models that closely mimic the structural and mechanical properties of native blood vessels. This review discusses the key considerations for designing bioprinted vascular conduits for thrombosis studies, including the incorporation of key structural, biochemical and mechanical features, the selection of appropriate biomaterials and cell sources, and the challenges and future directions in the field. The advancements in bioprinting techniques, such as multi-material bioprinting and microfluidic integration, have enabled the development of physiologically relevant models of thrombosis. The future of bioprinted models of thrombosis lies in the integration of patient-specific data, real-time monitoring technologies, and advanced microfluidic platforms, paving the way for personalized medicine and targeted interventions. As the field of bioprinting continues to evolve, these advanced vascular models are expected to play an increasingly important role in unraveling the complexities of thrombosis and improving patient outcomes. The continued advancements in bioprinting technologies and the collaboration between researchers from various disciplines hold great promise for revolutionizing the field of thrombosis research. 2024 The Authors
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Weir, Matthew R.; Rossignol, Patrick; Pitt, Bertram A.; Lund, Lars H.; Coats, Andrew J.S.; Filippatos, Gerasimos S.; Perrin, Amandine; Waechter, Sandra; Budden, Jeffrey J.; Kosiborod, Mikhail N.; Metra, Marco; Boehm, Michael; Ezekowitz, Justin A.; Bay-Gen, Antoni; Mentz, Robert J.; Ponikowski, Piotr P.; Senni, Michele; Castro-Montes, Eliodoro; Nicolau, JosCarlos; Parkhomenko, Alexander N.; Seferovic, Petar M.; Cohen-Solal, Alain; Anker, Stefan D.; Butler, Javed J.Introduction: Renin-angiotensin-aldosterone system inhibitor (RAASi; including mineralocorticoid receptor antagonists [MRAs]) benefits are greatest in patients with heart failure with reduced ejection fraction (HFrEF) and chronic kidney disease (CKD); however, the risk of hyperkalemia (HK) is high. Methods: The DIAMOND trial (NCT03888066) assessed the ability of patiromer to control serum potassium (sK+) in patients with HFrEF with/without CKD. Prior to randomization (double-blind withdrawal, 1:1), patients on patiromer had to achieve ?50% recommended doses of RAASi and 50 mg/day of MRA with normokalemia during a run-in period. The present analysis assessed the effect of baseline estimated glomerular filtration rate (eGFR) in subgroups of ?/<60, ?/<45 (prespecified), and ?/<30 mL/min/1.73 m2 (added post hoc). Results: In total, 81.3, 78.9, and 81.1% of patients with eGFR <60, <45, and <30 mL/min/1.73 m2 at screening achieved RAASi/MRA targets. A greater efficacy of patiromer versus placebo to control sK+ in patients with more advanced CKD was reported (p-interaction ? 0.027 for all eGFR subgroups). Greater effects on secondary endpoints were observed with patiromer versus placebo in patients with eGFR <60 and <45 mL/min/1.73 m2. Adverse effects were similar between patiromer and placebo across subgroups. Conclusion: Patiromer enabled use of RAASi, controlled sK+, and minimized HK risk in patients with HFrEF, with greater effect sizes for most endpoints noted in patient subgroups with lower eGFR. Patiromer was well tolerated by patients in all eGFR subgroups. 2024 The Author(s). Published by S. Karger AG, Basel.
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Coats, Andrew J.S.; Anker, Stefan D.; Lund, Lars H.; Filippatos, Gerasimos S.; Rossignol, Patrick; Pitt, Bertram A.; Weir, Matthew R.; Kosiborod, Mikhail N.; Metra, Marco; Bm, Michael; Ezekowitz, Justin A.; Bay-Gen, Antoni; Mentz, Robert J.; Ponikowski, Piotr P.; Senni, Michele; Cleland, John G.F.; Goudev, Assen Rachev; Khintibidze, Irakli; Lindenfeld, Jo Ann M.; Merkely, Ba Peter; Waechter, Sandra; Budden, Jeffrey J.; Perrin, Amandine; Butler, Javed J.Background: For heart failure with reduced ejection fraction (HFrEF), suboptimal use of renin-angiotensin-aldosterone system inhibitors (RAASis), including mineralocorticoid receptor antagonists (MRAs), due to hyperkalemia, may be improved by potassium binders. Objectives: This prespecified analysis of the phase 3 DIAMOND (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure) trial assessed the effect of patiromer in patients with HFrEF and either current or past hyperkalemia. Methods: Patients with HFrEF and current or past (within 1 year before enrollment) hyperkalemia (serum potassium [sK+] >5.0 mmol/L) entered a single-blind, run-in phase to optimize RAASis while receiving patiromer. They were subsequently randomized, double-blind, to continue patiromer or change to placebo. Results: Of the 1,038 patients who completed run-in, 354 (83.9%) of 422 with current hyperkalemia and 524 (85.1%) of 616 with past hyperkalemia achieved RAASi optimization and were randomized to treatment. During the double-blind phase, patiromer lowered sK+ levels compared with placebo in both the current and past hyperkalemia subgroups: difference in adjusted mean change from baseline: 0.12 (95% CI: 0.17 to 0.07) and 0.08 (95% CI: 0.12 to 0.05), respectively; P<inf>interaction</inf> = 0.166. Patiromer was more effective than placebo in maintaining MRA at target dose in patients with current vs past hyperkalemia (HR: 0.45 [95% CI: 0.26-0.76] vs HR: 0.85 [95% CI: 0.54-1.32]; P<inf>interaction</inf> = 0.031). Adverse events were similar between subgroups. Conclusions: The use of patiromer facilitates achieving target doses of RAASis in patients with HFrEF with either current or past hyperkalemia. For those with current hyperkalemia before RAASi optimization, use of patiromer may be more beneficial in helping to maintain sK+ control and achieve MRA target dose. (Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure [DIAMOND]; NCT03888066) 2024 The Authors
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Din, Misbahud; Paul, Souvik; Ullah, Sana; Yang, Haoyi; Xu, Rongguang; Abidin, Nurul Aisha Zainal; Sun, Allan; Chen, Yiyao Catherine; Gao, Rui; Chowdhury, Bari; Zhou, Fangyuan; Rogers, Stephenie; Miller, Mariel; Biswas, Atreyee; Hu, Liang; Fan, Zhichao; Zahner, Christopher J.; Fan, Jing; Chen, Zi; Berman, Megan; Xue, Lingzhou; Ju, Lining Arnold; Chen, YunfengArterial thrombosis is a leading cause of death and disability worldwide with no effective bioassay for clinical prediction. As a symbolic feature of arterial thrombosis, severe stenosis in the blood vessel creates a high-shear, high-gradient flow environment that facilitates platelet aggregation towards vessel occlusion. Here, we present a thrombus profiling assay that monitors the multi-dimensional attributes of thrombi forming in such biomechanical conditions. Using this assay, we demonstrate that different receptorligand interactions contribute distinctively to the composition and activation status of the thrombus. Our investigation into hypertensive and older individuals reveals intensified biomechanical thrombogenesis and multi-dimensional thrombus profile abnormalities, endorsing the diagnostic potential of the assay. Furthermore, we identify the hyperactivity of GPIb?-integrin ?<inf>IIb</inf>?<inf>3</inf> mechanosensing axis as a molecular mechanism that contributes to hypertension-associated arterial thrombosis. By studying drug-disease interactions and inter-individual variability, our work reveals a need for personalized anti-thrombotic drug selection that accommodates each patients pathological profile. The Author(s) 2024.
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Simonenko, Maria A.; Hansen, Dominique D.; Niebauer, Josef; Volterrani, Maurizio; Adamopoulos, Stamatis N.; Amarelli, Cristiano; Ambrosetti, Marco; Anker, Stefan D.; Bay-Gen, Antoni; Ben-Gal, Tuvia; Bowen, Thomas Scott; Cacciatore, Francesco M.; Caminiti, Giuseppe; Cavarretta, Elena; Chioncel, O. Dragomir; Coats, Andrew J.S.; Cohen-Solal, Alain; D'Ascenzi, Flavio; de Pablo, Carmen; Gevaert, Andreas B.; Gustafsson, Finn; Kemps, H. M.; Hill, Loreena Michelle; Jaarsma, Tiny; Jankowska, Ewa Anita; Joyce, Emer; Krkel, Nicolle; Lain?ak, Mitja; Lund, Lars H.; Moura, Brenda; Nytrn, Kari; Osto, Elena; PIEPOLI, MASSIMO Francesco; Potena, Luciano; Rakisheva, Amina G.; Rosano, Giuseppe Massimo Claudio; Savarese, Gianluigi; Seferovic, Petar M.; Thompson, David R.; Thum, Thomas; van Craenenbroeck, Emeline M.F.Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients. 2024 Simonenko, Hansen, Niebauer, Volterrani, Adamopoulos, Amarelli, Ambrosetti, Anker, Bayes-Genis, Ben Gal, Bowen, Cacciatore, Caminiti, Cavarretta, Chioncel, Coats, Cohen-Solal, DAscenzi, de Pablo Zarzosa, Gevaert, Gustafsson, Kemps, Hill, Jaarsma, Jankowska, Joyce, Krankel, Lainscak, Lund, Moura, Nytrn, Osto, Piepoli, Potena, Rakisheva, Rosano, Savarese, Seferovic, Thompson, Thum and Van Craenenbroeck.
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Chung Ming, Clara Liu; Pienaar, Dillan; Ghorbanpour, Sahar Masoumeh; Chen, Hao; Roberts, Lynne Margaret; Cole, Louise; McGrath, Kristine C.Y.; Padula, Matthew P.; Henry, Amanda; Gentile, Carmine; McClements, LanaBackground: Hypertensive disorders of pregnancy (HDP) affect 28% of pregnancies and are associated postpartum with increased cardiovascular disease (CVD) risk, although mechanisms are poorly understood. Methods: Human induced pluripotent stem cells (iPSC)-derived cardiomyocytes, cardiac fibroblasts and coronary artery endothelial cells were cocultured to form cardiac spheroids (CSs) in collagen type-1 hydrogels containing 10% patient plasma collected five years postpartum [n = 5 per group: normotensive control, gestational hypertension (GH) and preeclampsia (PE)]. Plasma-treated CSs were assessed for cell viability and contractile function and subjected to immunofluorescence staining and imaging. A quantitative proteomic analysis of plasma samples was conducted (controls n = 21; GH n = 5; PE n = 12). Results: Contraction frequency (CF) was increased in PE-treated CSs (CF: 45.5 3.4 contractions/minute, p < 0.001) and GH-treated CSs (CF:45.7 4.0 contractions/minute, p < 0.001), compared to controls (CF = 21.8 2.6 contractions/min). Only PE-treated CSs presented significantly increased fractional shortening (FS) % (9.95 1.8%, p < 0.05) compared to controls (3.7 1.1%). GH-treated CSs showed a reduction in cell viability (p < 0.05) and an increase in ?-SMA expression (p < 0.05). Proteomics analyses identified twenty differentially abundant proteins, with hemoglobin A2 being the only protein perturbed in both GH and PE versus control plasma(p < 0.05). Conclusions: The innovative patient-relevant CS platforms led to the discovery of biomarkers/targets linked to cell death signaling and cardiac remodeling in GH-induced CVD and vascular/endothelial cell dysfunction in PE-induced CVD. The Author(s) 2024.
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Pacleb, Adrienne; Lowres, Nicole; Randall, Sue; Neubeck, Lis; Gallagher, Robyn D.This article has been retracted at the request of Prof Salvatore Pepe, Editor-in-Chief, Heart Lung and Circulation. The journal was alerted to legal concerns regarding the publication of the supplementary material (Supplements 1,2) of this paper. Neither the publication of the copyrighted BAASIS scale (https://baasis.nursing.unibas.ch/) nor publication of the adaptation of the scale was authorised by the copyright holders at University of Basel, Switzerland. The Editor-in-Chief has therefore determined that the paper should be retracted. The decision to retract this paper was not based on any concerns with the scientific validity of the paper. The corresponding author acknowledges this retraction notice. Efforts have been made to contact the first author for their consent but the journal has been unable to reach them. All other authors have given their consent to the retraction notice. The full Elsevier Policy on Article Withdrawal can be found at (https://www.elsevier.com/about/policies/article-withdrawal). 2024
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Lin, Alexander; Miano, Joseph M.; Fisher, Edward A.; Misra, Ashish K.Vascular smooth muscle cells, endothelial cells and macrophages undergo phenotypic conversions throughout atherosclerosis progression, both as a consequence of chronic inflammation and as subsequent drivers of it. The inflammatory hypothesis of atherosclerosis has been catapulted to the forefront of cardiovascular research as clinical trials have shown that anti-inflammatory therapy reduces adverse cardiovascular events. However, no current therapies have been specifically designed to target the phenotype of plaque cells. Fate mapping has revealed that plaque cells convert to detrimental and beneficial cell phenotypes during atherosclerosis, with cumulative evidence highlighting that vascular cell plasticity is intimately linked with plaque inflammation, ultimately impacting lesion stability. Here we review vascular cell plasticity during atherosclerosis in the context of the chronic inflammatory plaque microenvironment. We highlight the need to better understand how plaque cells behave during therapeutic intervention. We then propose modulating plaque cell phenotype as an unexplored therapeutic paradigm in the clinical setting. Springer Nature Limited 2024.
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Hunter, Benjamin; Li, Mengbo; Parker, Benjamin L.; Koay, Yen Chin; Harney, Dylan James; Pearson, Evangeline; Cao, Jacob Y.; Chen, Gavin T.; Guneratne, Oneka; Smyth, Gordon K.; Larance, Mark; OSullivan, John F.; Lal, Sean P.The left and right ventricles of the human heart are functionally and developmentally distinct such that genetic or acquired insults can cause dysfunction in one or both ventricles resulting in heart failure. To better understand ventricle-specific molecular changes influencing heart failure development, we first performed unbiased quantitative mass spectrometry on pre-mortem non-diseased human myocardium to compare the metabolome and proteome between the normal left and right ventricles. Constituents of gluconeogenesis, glycolysis, lipogenesis, lipolysis, fatty acid catabolism, the citrate cycle and oxidative phosphorylation were down-regulated in the left ventricle, while glycogenesis, pyruvate and ketone metabolism were up-regulated. Inter-ventricular significance of these metabolic pathways was then found to be diminished within end-stage dilated cardiomyopathy and ischaemic cardiomyopathy, while heart failure-associated pathways were increased in the left ventricle relative to the right within ischaemic cardiomyopathy, such as fluid sheer-stress, increased glutamine-glutamate ratio, and down-regulation of contractile proteins, indicating a left ventricular pathological bias. Crown 2024.
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Kirwan, Morwenna; Chiu, Christine L.; Henson, Connie; Laing, Thomas; Fermanis, Jonathon; Scott, Leah; Janszen, Jordan; Gwynne, Kylie G.Background: The Beat It program is a clinician-led, community-based group exercise intervention for adults with Type 2 Diabetes Mellitus (T2DM). While previous studies have demonstrated its effectiveness in improving physical and mental health outcomes, this study explores the perspectives of Beat It Trainers to identify key factors contributing to the programs success and areas for improvement. Methods: Semi-structured interviews were conducted with 11 Accredited Exercise Physiologists who had delivered both in-person and online versions of the program. Interviews were thematically analyzed using inductive approaches. Results: Eight main themes emerged: customization to individual needs, capability building, outcome improvement, affordability, accessibility, sustainability, and a holistic approach delivered in a group setting. Challenges identified included managing group dynamics, maintaining participant commitment in a fully subsidized program, and providing nutrition advice within the trainers scope of practice. The programs adaptability to both in-person and online delivery modes was highlighted as enhancing its accessibility and resilience. Conclusions: This study provides valuable insights into the factors contributing to the success of the Beat It program from the implementers perspective. The findings suggest that investing in comprehensive training for facilitators, particularly in group dynamics management, could benefit similar programs. While the programs fully subsidized structure reduces financial barriers to entry, innovative strategies to enhance participant engagement and perceived value should be explored. The success of the online delivery mode indicates that hybrid models offering both in-person and virtual options could increase accessibility in future supervised, community-based exercise programs for T2DM management. 2024 by the authors.
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Ratwatte, Seshika D.; Playford, David A.; Strange, G. A.; Celermajer, David S.; Stewart, S.Aims Pulmonary hypertension (PHT) appears to be very common in heart failure with preserved ejection fraction but details on its prevalence, severity and prognostic implications have not been well defined. We, therefore, aimed to document PHT and its impact on mortality among adults with left ventricular (LV) diastolic dysfunction (LVDD). Methods We analysed the profile and outcomes of 16 058 adults with LVDD (and with preserved LV ejection fraction, >50%) from the National Echocardiography Database of Australia. Subjects were classified according to their peak tricuspid regurgitation velocity (TRV), reflecting PHT risk, and we then evaluated the relationship between conventional thresholds of increasing risk of PHT and subsequent mortality, during median follow-up of 3.1 (IQR 1.65.2) years. Results Mean age was 7312 years and 9216 (57.4%) were female. Overall, 2611 (16.3%) had normal TRV levels (<2.5 m/s) indicative of no PHT, compared with 3471 (21.6%), 8450 (52.6%) and 1526 (9.5%) with TRV levels indicative of borderline (2.52.8 m/s), intermediate (2.93.4 m/s) and high-risk for PHT (>3.4 m/s). The 1-year and 5-year actuarial mortality (1701/1546 and 4232/8445 deaths, respectively) increased from 6.5% and 34.0% to 27.7% and 78.5%, respectively (p<0.0001), from normal to severely elevated TRV. Adjusted risk (HR) of mortality increased 1.28-fold (95% CI 1.15 to 1.41), 1.51-fold (95% CI 1.38 to 1.65) and 3.47-fold (95% CI 3.13 to 3.85) in those with borderline, intermediate and high risk of PHT versus normal TRV. This observation persisted when excluding atrial fibrillation cases, and when male and female cohorts were assessed separately. Mortality rates increased perceptibly at the second decile distribution of TRV (2.372.55 m/s) with a marked increase in mortality from the fifth decile (2.913.00 m/s) upwards. Conclusion We demonstrate the negative prognostic impact of elevated TRV levels in many adults with isolated LVDD. A threshold of increased mortality was observed at TRV levels equivalent to borderline risk of PHT. Author(s) (or their employer(s)) 2024.
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Seferovic, Petar M.; Coats, Andrew J.S.; Filippatos, Gerasimos S.[No abstract available]
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Wadey, Curtis; Barker, Alan R.; Graham Stuart, A.; Dorobantu, Dan Mihai; Pieles, Guido E.; Tran, Derek L.; Laohachai, Karina; Ayer, Julian Ganesh J.; Weintraub, Robert G.; Cordina, Rachael Louise; Williams, Craig A.BACKGROUND: Peak oxygen consumption (peak?VO<inf>2</inf>) is traditionally scaled by body mass, but it is most appropriately scaled by fat-free mass. However, it is unknown whether peak?VO<inf>2</inf> scaled by fat-free mass is associated with mortality and morbidity in people with a Fontan circulation. The aim of this study was to assess the associations between different expressions of peak ?VO<inf>2</inf> with mortality and morbidity in people with a Fontan circulation. METHODS AND RESULTS: Eighty-seven participants (aged 24.17.3 years; 53% women) with a Fontan circulation completed a cardiopulmonary exercise test and a dual-energy x-ray absorptiometry scan. Cox proportional hazard regressions models assessed the association (hazard ratio [HR]) between different expressions of peak?VO<inf>2</inf> with a composite outcome of Fontan failure (FF). Participants were followed up for a median of 6.5 years (95% CI, 6.46.9). Individuals experiencing FF (n=10/87) had a significantly lower absolute peak?VO<inf>2</inf>. In univariable models, peak?VO<inf>2</inf> ratio scaled to body mass was not significantly associated with FF (HR, 0.91; P=0.111). However, peak?VO<inf>2</inf> scaled by fat-free mass (HR, 0.90; P=0.020) or lean mass (HR, 0.90; P=0.017) was significantly and inversely associated with FF. These associations remained significant after adjusting for age, sex, and peak respiratory exchange ratio. CONCLUSIONS: The association between peak?VO<inf>2</inf> and FF is improved when scaled to measures of body composition. Applied clinically, a 1-unit increase in peak?VO<inf>2</inf> scaled to fat-free mass or lean mass is associated with a ?10% lower risk of FF. 2024 The Author(s).
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Simonenko, Maria A.; Hansen, Dominique D.; Niebauer, Josef; Volterrani, Maurizio; Adamopoulos, Stamatis N.; Amarelli, Cristiano; Ambrosetti, Marco; Anker, Stefan D.; Bay-Gen, Antoni; Ben-Gal, Tuvia; Bowen, Thomas Scott; Cacciatore, Francesco M.; Caminiti, Giuseppe; Cavarretta, Elena; Chioncel, O. Dragomir; Coats, Andrew J.S.; Cohen-Solal, Alain; D'Ascenzi, Flavio; de Pablo, Carmen; Gevaert, Andreas B.; Gustafsson, Finn; Kemps, H. M.; Hill, Loreena Michelle; Jaarsma, Tiny; Jankowska, Ewa Anita; Joyce, Emer; Krkel, Nicolle; Lain?ak, Mitja; Lund, Lars H.; Moura, Brenda; Nytrn, Kari; Osto, Elena; PIEPOLI, MASSIMO Francesco; Potena, Luciano; Rakisheva, Amina G.; Rosano, Giuseppe Massimo Claudio; Savarese, Gianluigi; Seferovic, Petar M.; Thompson, David R.; Thum, Thomas; van Craenenbroeck, Emeline M.F.Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus The Authors 2024. Published by John Wiley & Sons Limited and Oxford University Press on behalf of the European Society of Cardiology, and Frontiers Media SA on behalf of the European Society for Organ Transplantation.
