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Showing 1–20 of 2058 publications.
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Ruban, Sasha; Lloyd, Larissa K.; Badal, Tanya; Strange, G. A.; Celermajer, David S.; Bonner, CarissaBackground/Objectives: Congenital heart disease (CHD) refers to a spectrum of structural abnormalities of the heart at birth. Survival and outcomes have improved due to advances in surgery and post-operative care, resulting in more patients transitioning from paediatric to adult healthcare settings. This study aimed to explore varied experiences of this transition and identify ways to improve processes to enable continuity of care in Australia. Methods: Purposive sampling was used to recruit a diverse sample of CHD patients from a larger study. In semi-structured online interviews, adult participants were asked to reflect on their childhood transition experience. Interviews were audio recorded, transcribed and coded using framework analysis. Results: 4 main themes were identified: i) perceived experience of transition, (ii) impact on family and wider support network, (iii) psychosocial needs of the patient, and (iv) the role of evolving independence. Facilitators of a positive transition experience included education, proactive handover and clear information about what to expect. Barriers included lack of empowerment for patients and lack of empathy and holistic care from clinicians. Family impacts included the changing parental role and need for reassurance for caregivers. Psychosocial needs included support for mental health. Evolving independence and maturity influenced individuals ability to manage their transition and ongoing care. Conclusions: The findings suggest a need to improve processes and communication, to facilitate a more holistic model of care for CHD patients in Australia. This includes planned coordination of transition, clear information and support for mental health and overall wellbeing of CHD patients and their caregivers. Practice implications: Structural changes to improve the chance of successful transition could lead to better long-term health outcomes for individuals with CHD. 2025
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Lloyd, Larissa K.; Nicholson, Calum; Strange, G. A.; Celermajer, David S.Objective: This paper aims to identify and describe legislative and administrative barriers to hospital participation and national data linkage for the National Australian Congenital Heart Disease (CHD) Registry. Methods: A narrative review based on the National Australian CHD Registry experience of establishing participating hospital sites and national linkages associated with each jurisdiction. Results: There were numerous identified barriers that could be overcome with additional resources/time, and barriers that could not be overcome, reported by jurisdiction. Conclusions: There is a pressing need for greater harmonisation of state-based legislation governing research and harmonisation of administration to reduce duplication. Substantial state-based differences hinder the establishment of a truly national registry. 2025 The Author(s) (or their employer(s)).
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Ratwatte, Seshika D.; Stewart, S.; Playford, David A.; Strange, G. A.; Celermajer, David S.Background and objectives Left ventricular diastolic dysfunction (LVDD) is commonly associated with pulmonary hypertension (PHT); however, the factors associated with the presence and severity of PHT in patients with LVDD have not been well characterised. Methods We analysed the profiles and echo characteristics of 16 058 adults with LVDD and preserved left ventricular ejection fraction (LVEF, >50%) from the National Echocardiography Database of Australia. Peak tricuspid regurgitation velocity (TRV) was used to determine the presence of PHT. Univariate and multivariate analyses were performed to evaluate the parameters associated with the presence/increasing severity of PHT. Results Mean age was 7312 years and 9216 (57.4%) were women. 2503 (15.6%) subjects had atrial fibrillation (AF) and 13 555 (84.4%) were in sinus rhythm. Overall, 9976 (62.1%) had PHT (TRV >2.9 m/s). There was a progressive increase in indexed left atrial volume with rising TRV levels. AF and right ventricular (RV) dilation were strongly associated with the presence of PHT (adjusted OR (aOR) 1.27 (95% CI 1.12 to 1.43) and aOR 4.99 (95% CI 4.44 to 5.62), respectively). Increased age, LVEF and body mass index were also independently associated with PHT (p<0.001). On multivariate analysis, older age, female sex, AF, lower E/e' and LVEF were independently associated with the severity of PHT (p<0.001). The presence of AF increased the TRV by an average of 0.32 m/s, RV dilation by 1.82 m/s, female sex by 0.32 m/s and age (per decade) by 0.3 m/s. Conclusion In this large study, PHT was common in LVDD and was strongly associated with the presence of enlarged left atrium, AF and older age, in particular. Trial registration number ACTRN12617001387314. Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
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Lam, Nicholas T.; Nguyen, Ngoc Uyen Nhi; Elhelaly, Waleed M.; Hsu, Chingcheng; Menendez-Montes, Ivan; Xiao, Feng; Ali, Shah Rukh; Vo, Nelson; Briard, Nathan; El-Feky, Lobna; Omari, Qamar M.; Cardoso, Alisson Campos; Liu, Yan; Ahmed, Mahmoud Salama; Li, Shujuan; Thet, Suwannee; Xing, Chao; Zangi, Lior; Sadek, Hesham A.BACKGROUND: Cytokinesis is the last step in the eukaryotic cell cycle, which physically separates a mitotic cell into 2 daughter cells. A few days after birth in mouse cardiomyocytes, DNA synthesis occurs without cytokinesis, leading to the majority of cardiomyocytes becoming binucleated instead of generating 2 daughter cells with 1 nucleus each. This results in cell cycle arrest of cardiomyocytes, and the mouse heart is no longer able to regenerate. A longstanding unanswered question is whether binucleation of cardiomyocytes is a result of cytokinesis failure. METHODS: To address this, we generated several transgenic mouse models to determine whether forced induction of cardiomyocyte cytokinesis generates mononucleated cardiomyocytes and restores the endogenous regenerative properties of the myocardium. We focused on 2 complementary regulators of cytokinesis: Plk1 (polo-like kinase 1) and Ect2 (epithelial cell-transformation sequence 2). RESULTS: We found that cardiomyocyte-specific transgenic overexpression of constitutively active Plk1(T210D) promotes mitosisandcytokinesisinadulthearts,whereasoverexpressionofEct2alonepromotesonlycytokinesis.Cardiomyocyte-specific overexpression of both Plk1(T210D) and Ect2 concomitantly (double transgenic) prevents binucleation of cardiomyocytes postnatally and results in widespread cardiomyocyte mitosis, cardiac enlargement, contractile failure, and death before 2 weeks of age. In contrast, doxycycline-inducible cardiomyocyte-specific overexpression of both genes (inducible double transgenic) in the adult heart results in cardiomyocyte mitosis and transient contractile dysfunction. Importantly, this transient induction of cytokinesis in adult mice improves left ventricular systolic function after myocardial infarction. CONCLUSIONS: These results collectively demonstrate that cytokinesis failure mediates cardiomyocyte multinucleation and cell cycle exit of postnatal cardiomyocytes, but may be a protective mechanism to preserve the contractile function of the myocardium. 2025 American Heart Association, Inc.
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Kany, Shinwan; R?, Joel T.; Playford, David A.; Strange, G. A.; Hou, Cody R.; Jurgens, Sean J.; Nauffal, Victor D.; Cunningham, Jonathan W.; Lau, Emily S.; Butte, Atul Janardhan; Ho, Jennifer E.; Olgin, Jeffrey E.; Elmariah, Sammy; Lindsay, Mark Evan; Chan, Yih Kai; Stewart, S.; Ellinor, Patrick T.; Pirruccello, James P.Background: Mild aortic stenosis (AS) is associated with adverse outcomes but is incompletely defined. Objectives: The purpose of this study was to examine the epidemiology of AV function measured without clinical indications. Methods: We developed a deep learning model to measure aortic valve (AV) area, peak velocity, and mean gradient in velocity-encoded cardiac magnetic resonance imaging in 62,902 UK Biobank participants. Study findings were externally validated in NEDA (National Echo Database Australia), a clinical cohort of 365,870 people. Results: From measuring reference ranges of AV function in a healthy subcohort (n = 41,859), we observed a natural boundary between normal and abnormal AV hemodynamics (>95th percentile) that we refer to as mild AS<inf>proposed</inf>: peak velocity >1.65 m/s, mean gradient >4.9 mm Hg, or aortic valve area <2.1 cm2 (men) or <1.7 cm2 (women). In the full cohort, 3,676 (5.8%) participants met these novel criteria; the HR for a subsequent AV replacement for each severity category was 31.7 (mild AS<inf>proposed</inf>), 522.4 (moderate AS), and 3,057.4 (severe AS), all P < 0.001. Over a mean 3.9 years of follow-up, those with mild AS<inf>proposed</inf> also had a higher risk of atrial fibrillation (110 events; HR: 1.86; P = 1.4 10?9) and heart failure (70 events; HR: 2.37; P = 5.9 10?11) compared with those without AS. In NEDA, the 101,335 participants with mild AS<inf>proposed</inf> identified with echocardiography using the same cardiac magnetic resonance imagingdefined criteria had increased all-cause mortality (HR: 1.25; 95% CI: 1.24-1.27). Conclusions: We report a large-scale study of AV hemodynamics and identify a population threshold between normal and abnormal AV function. Mild AS, as defined by the proposed criteria, was linked to adverse outcomes in the UK Biobank and in NEDA. 2025 American College of Cardiology Foundation
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Bm, Michael; Butler, Javed; Coats, Andrew J.S.; Lauder, Lucas; Mahfoud, Felix; Filippatos, Gerasimos S.; Ferreira, Jo Pedro; Pocock, Stuart J.; Brueckmann, Martina; Hauske, Sibylle Jenny; Schueler, Elke; Wanner, Christoph; Verma, Subodh G.; Zannad, Faiez; Packer, Milton P.; Anker, Stefan D.Background and Aims: Hypertension has a high prevalence in heart failure with preserved ejection fraction (HFpEF), which can be controlled, uncontrolled, or even resistant. The effects of empagliflozin on systolic blood pressure (SBP), time in target range, incidence of hypertensive urgencies, and studied cardiovascular and renal outcomes in different hypertension categories and after treatment with empagliflozin in the EMPEROR-Preserved trial were explored. Methods: A total of 5533 patients were studied and the population was separated into resistant (resHTN), uncontrolled (uctrHTN), and controlled (ctrHTN) hypertension. The effect of SBP on outcomes and treatment effects of empagliflozin were explored. Analyses were done with Cox regression analyses adjusted for demographic and clinical confounders and with a mixed model for repeated measures. Results: Empagliflozin reduced SBP in resHTN slightly more than in the other categories in the first weeks, while thereafter there were no significant differences. The modest reduction in SBP resulted in a moderate increase in time at target and reduced hypertensive urgencies. The primary endpoint was more prevalent in resHTN (P =. 0358), but the treatment effect of empagliflozin on the primary endpoint was similar in resHTN, uctrHTN, and ctrHTN (P for interaction =. 92) as was the improvement of the estimated glomerular filtration rate slope (P for interaction =. 95) and change in quality of life by empagliflozin. Conclusions: In HFpEF, the prevalence of resHTN is high and is associated with frequently higher outcome rates compared with ctrHTN and uctrHTN. The treatment effect was not modified by hypertension categories. This indicates that in HFpEF, moderate modifications of blood pressure do not affect overall outcomes and treatment effects of empagliflozin. 2025 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology.
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Sun, Allan; Nasser, Arian; Yap, Nicole Alexis; Gao, Rui; Ju, Lining ArnoldArterial thrombosis remains a significant global health concern, with shear-induced platelet aggregation (SIPA) playing a crucial role. This review focuses on the integration of three key engineering approachesComputational Modeling Microfluidics and Mechanobiology (3 M)in understanding and combating high-shear thrombosis. We discuss the biomechanical mechanisms of SIPA, highlighting how platelet mechanoreceptors and von Willebrand factor interactions drive thrombosis under pathological flow conditions. Through computational fluid dynamics (CFD), key hemodynamic metrics including time-averaged wall shear stress, oscillatory shear index, and relative residence time have been developed to predict thrombosis risk. Microfluidic platforms, ranging from straight channels to stenotic geometries, provide insights into platelet behavior under various shear conditions while enabling rapid screening of antithrombotic therapies. The integration of these experimental approaches with CFD analysis offers powerful tools for predicting thrombosis risk and optimizing device designs, particularly in mechanical circulatory support devices (MCSDs). Recent advances in mechanobiology have revealed how mechanical forces trigger cellular responses through membrane damage and mechanosensitive channels, offering new therapeutic targets. This review underscores how the synergy between these 3 M engineering approaches advances our understanding of the complex interplay between hemodynamics and thrombosis, paving the way for improved antithrombotic therapies and medical device designs essential to optimizing MCSDs, such as left ventricular assist devices and extracorporeal membrane oxygenators. 2025 The Authors
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Belkin, Teleah G.; Masterman, Emma I.; Yildiz, Gunes S.; Kiriazis, Helen; Mellett, Natalie Ann; Cross, Jonathon H.; Grigolon, Kyah; Dogra, Akshima; Donner, Daniel G.; Chooi, Roger; Liang, Amy; Kompa, Andrew R.; Sadoshima, J.; Edgley, Amanda J.; Greening, David W.; Meikle, Peter J.; Tham, Yow Keat; McMullen, Julie R.We previously reported that plasmalogens, a class of phospholipids, were decreased in a setting of dilated cardiomyopathy (DCM). Plasmalogen levels can be modulated via a dietary supplement called alkylglycerols (AG) which has demonstrated benefits in some disease settings. However, its therapeutic potential in DCM remained unknown. To determine whether an optimized AG supplement could restore plasmalogen levels and attenuate cardiac dysfunction/pathology, we placed a cardiac-specific transgenic DCM mouse model of both sexes on chow +/?1.5 % AG supplementation at ?10 weeks of age for 16 weeks. Cardiac function was assessed by echocardiography, tissues were collected for histological and molecular analyses including lipidomics and proteomics via liquid chromatography-mass spectrometry. AG supplementation increased total plasmalogens in DCM hearts and attenuated lung congestion of both sexes, but only prevented cardiac dysfunction in males. This was associated with attenuated cardiac and renal enlargement, a more favorable pro-cardiac gene expression profile, and a trend for lower cardiac fibrosis. By lipidomics, specific d18:1 ceramide species associated with cardiac pathology were lower in the DCM hearts from mice on the AG diet, and tetralinoleoyl cardiolipins, a lipid crucial for mitochondrial function was restored with AG supplementation. Proteomic analysis of hearts from male DCM mice receiving AG supplementation revealed enrichment in mitochondrial protein network, as well as upregulation of extracellular matrix binding proteins including agrin, a protein associated with cardiac regeneration. In summary, AG supplementation restored plasmalogens in DCM hearts but showed greater therapeutic potential in males than females. 2024 The Author(s)
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Zieroth, Shelley R.; Saldarriaga-Giraldo, Clara In; Pinto, Fausto J.; Anker, Stefan D.; Abraham, William T.; Atherton, John James; Butler, Javed J.; Chopra, Vijay Kumar; Coats, Andrew J.S.; Dean, Veronica; Filippatos, Gerasimos S.; Zamorano, JosLuis; Zhang, Yuhui; Weiskopf, Richard B.; Colardelle, YannAims: Clinical practice guidelines are commonly written by professional societies in high-income countries (HIC) with limited anticipation of implementation obstacles in other environments. We used heart failure (HF) guidelines as a paradigm to examine this concern, by conducting a survey to understand clinicians' ability to implement HF guidelines and their perceptions of the current HF guideline applicability in low- and middle-income countries (LMIC). Methods and results: An online survey of physicians in the database of the Translational Medicine Academy who treat HF patients was offered by email from 5 October to 27 November 2023, inquiring of participants' demographic information, experience, and views of HF guidelines as related to their practice. Of 2622 participating clinicians, 1592 partially completed, and an additional 1030 fully completed the survey. Participants were from 138 countries; 668 practiced in HIC, and 1954 in LMIC. Those from LMIC regarded HF guidelines to be less applicable in their country than did those from HIC (p = 0.0002). Of all those responding, 75.3% indicated that it was somewhat or mostly true that the HF guidelines were mostly applicable to HIC. Those from LMIC, but not HIC indicated that the greatest implementation obstacle was that the guidelines were for HIC (51.3% vs. 43.1%; p = 0.0387). A significantly higher proportion of respondents from LMIC indicated that resources for caring for their patients were somewhat or mostly limiting in most cases, than did those in HIC (41.6% vs. 32.5%, p = 0.0068). Conclusion: This survey examined the widely-held thought that HF guidelines are broadly applicable to all regions of the world, concluding that such a perception is incorrect. Clinicians from LMIC view the absence of consideration of local resource limitations as the greatest obstacle for guideline implementation. The results regarding HF guidelines likely also have implications for other guidelines and resultant patient outcomes. 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Misra, Ashish K.; Psaltis, Peter James; Mondal, Amandeep Rashid; Nelson, Adam James; Nidorf, Stefan MarkLow-dose colchicine is the only anti-inflammatory drug approved for secondary prevention of coronary disease. The CLEAR-SYNGERY trial of colchicine in acute myocardial infarction challenges the results of previous colchicine trials; however, clinicians should be aware of how its design and the COVID-19 pandemic affected the trial outcome. Springer Nature Limited 2025.
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Doehner, Wolfram; Boriani, Giuseppe; Potpara, Tatjana S.; Blomstr-Lundqvist, Carina M.; Passman, Rod Stuart; Sposato, Luciano A.; Dobrev, Dobromir; Freedman, Ben; van Gelder, Isabelle C.; Glotzer, Taya V.; Healey, Jeff S.; Karapanayiotides, Theodoros; Lip, Gregory Y.H.; Merino, JosLuis; Ntaios, George C.; Schnabel, Renate B.; Svendsen, Jesper Hastrup; Svennberg, Emma; Wachter, Rolf; Haeusler, Karl Georg; Camm, Alan JohnAtrial fibrillation (AF) is one of the most common cardiac diseases and a complicating comorbidity for multiple associated diseases. Many clinical decisions regarding AF are currently based on the binary recognition of AF being present or absent with the categorical appraisal of AF as continued or intermittent. Assessment of AF in clinical trials is largely limited to the time to (first) detection of an AF episode. Substantial evidence shows, however, that the quantitative characteristic of intermittent AF has a relevant impact on symptoms, onset, and progression of AF and AF-related outcomes, including mortality. Atrial fibrillation burden is increasingly recognized as a suitable quantitative measure of intermittent AF that provides an estimate of risk attributable to AF, the efficacy of antiarrhythmic treatment, and the need for oral anticoagulation. However, the diversity of assessment methods and the lack of a consistent definition of AF burden prevent a wider clinical applicability and validation of actionable thresholds of AF burden. To facilitate progress in this field, the AF burden Consensus Group, an international and multidisciplinary collaboration, proposes a unified definition of AF burden. Based on current evidence and using a modified Delphi technique, consensus statements were attained on the four main areas describing AF burden: Defining the characteristics of AF burden, the recording principles, the clinical relevance in major clinical conditions, and implementation as an outcome in the clinic and in clinical trials. According to this consensus, AF burden is defined as the proportion of time spent in AF expressed as a percentage of the recording time, undertaken during a specified monitoring duration. A pivotal requirement for validity and comparability of AF burden assessment is a continuous or near-continuous duration of monitoring that needs to be reported together with the AF burden assessment. This proposed unified definition of AF burden applies independent of comorbidities and outcomes. However, the disease-specific actionable thresholds of AF burden need to be defined according to the targeted clinical outcomes in specific populations. The duration of the longest episode of uninterrupted AF expressed as a time duration should also be reported when appropriate. A unified definition of AF burden will allow for comparability of clinical study data to expand evidence and to establish actionable thresholds of AF burden in various clinical conditions. This proposed definition of AF burden will support risk evaluation and clinical treatment decisions in AF-related disease. It will further promote the development of clinical trials studying the clinical relevance of intermittent AF. A unified approach on AF burden will finally inform the technology development of heart rhythm monitoring towards validated technology to meet clinical needs. The European Society of Cardiology 2025. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.
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Ratwatte, Seshika D.; Cordina, Rachael Louise; Baker, David William; Lau, Edmund M.T.; Celermajer, David S.We evaluated whether fluid status could be accurately assessed (and corrected if necessary) prior to right heart catheterisation (RHC), to diagnose accurately post-capillary pulmonary hypertension (PHT) in patients with left heart disease risk factors. A non-invasive measure of fluid status prior to RHC identified fluid-depleted patients. Baseline RHC measurements were performed, and a novel provocation technique (passive leg raise) was compared to a one-dose-fits-all fluid challenge and found to be equivalent. 2024 Royal Australasian College of Physicians.
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Filippatos, Gerasimos S.; Anker, Stefan D.; Bakris, George L.; Rossing, Peter R.; Ruilope, Lu Miguel; Coats, Andrew J.S.; von Haehling, Stephan; Ponikowski, Piotr P.; Rosano, Giuseppe Massimo Claudio; Brinker, Meike D.; Farjat, Alfredo E.; Roberts, Luke; Pitt, Bertram A.Aims: Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co-morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double-blind, placebo-controlled, multicentre FIDELIO-DKD and FIGARO-DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. Methods and results: A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator-reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR)?57% from baseline over ?4weeks, or kidney-related death. Safety outcomes by baseline LVH were reported as treatment-emergent adverse events. At baseline out of 13026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator-reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (P<inf>interaction</inf>=0.1075 for composite CV outcome and P<inf>interaction</inf>=0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (P<inf>interaction</inf>=0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment-emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. Conclusions: In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF. 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
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Dockerill, Millicent; Ford, Daniel J.; Angerani, Simona; Alwis, Imala D.; Dowman, Luke J.; Ripoll-Rozada, Jorge; Smythe, Rhyll E.; Liu, Joanna Shu Ting; Pereira, Pedro JosBarbosa; Jackson, Shaun P.; Payne, Richard J.; Winssinger, NicolasDrugs are administered at a dosing schedule set by their therapeutic index, and termination of action is achieved by clearance and metabolism of the drug. In some cases, such as anticoagulant drugs or immunotherapeutics, it is important to be able to quickly reverse the drugs action. Here, we report a general strategy to achieve on-demand reversibility by designing a supramolecular drug (a noncovalent assembly of two cooperatively interacting drug fragments held together by transient hybridization of peptide nucleic acid (PNA)) that can be reversed with a PNA antidote that outcompetes the hybridization between the fragments. We demonstrate the approach with thrombin-inhibiting anticoagulants, creating very potent and reversible bivalent direct thrombin inhibitors (K<inf>i</inf> = 74 pM). The supramolecular inhibitor effectively inhibited thrombus formation in mice in a needle injury thrombosis model, and this activity could be reversed by administration of the PNA antidote. This design is applicable to therapeutic targets where two binding sites can be identified. The Author(s) 2024.
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Psaltis, Peter James; Nguyen, Mau T.; Singh, Kuljit; Sinhal, Ajay R.; Wong, Dennis T.L.; Alcock, Richard F.; Rajendran, Sharmalar; Dautov, Rustem F.; Barlis, Peter; Patel, Sanjay; Salagaras, Thalia; Marathe, Jessica A.; Bursill, C. A.; Montarello, Nicholas Joseph; Nidorf, Stefan Mark; Thompson, Peter Lindsay; Butters, Julie; Cuthbert, Alana R.; Yelland, Lisa Nicole; Ottaway, Juanita L.; Kataoka, Yu; Di Giovanni, Giuseppe A.; Nicholls, Stephen J.Aims Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT). Methods COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with and results acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery that contained at least one lipid-rich plaque causing ?20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0 35.1% vs. colchicine +62.4 38.1%, P = 0.18) or absolute changes in minimum FCT (+29.2 20.9 m vs. + 37.2 21.3 m, P = 0.18), or change in maximum lipid arc (?38.8 32.2 vs. ?54.8 46.9, P = 0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P = 0.03). In post hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7 25.4% vs. colchicine +64.7 34.1%, P = 0.005). Conclusion In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests that longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT. The Author(s) 2024.
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Major, Gretel S.; Joukhdar, Habib; Choi, Yu Suk; Rnjak-Kovacina, Jelena; Wise, Steven G.; Ju, Lining Arnold; Cox, Thomas R.; Xu, Chun; Yeo, Giselle C.; Young, Jennifer L.; Lim, K. S.Photochemistry has emerged as a powerful tool for manipulating the dynamic and heterogeneous properties of hydrogel microenvironments in tissue engineering and mechanobiology. Enhanced spatiotemporal control over hydrogel mechanical properties can be achieved by incorporating an array of photosensitive functional groups within polymer networks and controlling photokinetics through light illumination. This review explores how light-stimulated photocleavage, addition, exchange, and isomerization reactions are utilized to generate hydrogels that soften and stiffen in situ, enabling precise control over cell functionality in tissue-engineered constructs. Advancements in polymer design and biofabrication platforms that have enhanced control over these reactions and that permit local modulation of mechanical properties within larger microenvironments are discussed. The applications of these dynamic hydrogels in understanding cellular mechanosensation, investigating fibrotic disease, and directing stem cell differentiation and tissue formation are examined. While significant progress has been made toward on-demand platforms that switch between multiple mechanical conditions, this review highlights the need for materials that undergo progressive dynamic stiffening. The review also explores emerging applications of photochemistry in intracellular environments and its potential integration with advanced force spectroscopy techniques for live-cell mechanobiology studies. Overall, using light as a stimulus for reactions within hydrogels has enhanced tunability, reaction kinetics, and spatiotemporal control compared to other stimuli-driven systems, opening new avenues for biomimetic material design and mechanobiological investigations. 2024 The Author(s)
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Integrating microfluidics, hydrogels, and 3D bioprinting for personalized vessel-on-a-chip platformsAye, San Seint; Fang, Zhongqi; Wu, Mike C.L.; Lim, K. S.; Ju, Lining ArnoldThrombosis, a major cause of morbidity and mortality worldwide, presents a complex challenge in cardiovascular medicine due to the intricacy of clotting mechanisms in living organisms. Traditional research approaches, including clinical studies and animal models, often yield conflicting results due to the inability to control variables in these complex systems, highlighting the need for more precise investigative tools. This review explores the evolution of in vitro thrombosis models, from conventional polydimethylsiloxane (PDMS)-based microfluidic devices to advanced hydrogel-based systems and cutting-edge 3D bioprinted vascular constructs. We discuss how these emerging technologies, particularly vessel-on-a-chip platforms, are enabling researchers to control previously unmanageable factors, thereby offering unprecedented opportunities to pinpoint specific clotting mechanisms. While PDMS-based devices offer optical transparency and fabrication ease, their inherent limitations, including non-physiological rigidity and surface properties, have driven the development of hydrogel-based systems that better mimic the extracellular matrix of blood vessels. The integration of microfluidics with biomimetic materials and tissue engineering approaches has led to the development of sophisticated models capable of simulating patient-specific vascular geometries, flow dynamics, and cellular interactions under highly controlled conditions. The advent of 3D bioprinting further enables the creation of complex, multi-layered vascular structures with precise spatial control over geometry and cellular composition. Despite significant progress, challenges remain in achieving long-term stability, incorporating immune components, and translating these models to clinical applications. By providing a comprehensive overview of current advancements and future prospects, this review aims to stimulate further innovation in thrombosis research and accelerate the development of more effective, personalized approaches to thrombosis prevention and treatment. 2025 The Royal Society of Chemistry.
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Tarsitano, Martine; Ming, Clara Liu Chung; Idais, Dana; Mahmodi, Hadi; Wyllie, Kaitlin; Isella, Benedetta; Cox, Thomas R.; Kabakova, Irina V.; Paolino, Donatella; Gentile, CarmineBiofabrication of cardiac patches is a challenging strategy proposed as an alternative to transplantation for end-stage heart failure patients. The optimization of the bioink used for this strategy can be limited by costs, properties, and biocompatibility of its building blocks. Lately, sericin has emerged within a wide range of natural proteins, thanks to its bioadhesive and biocompatibility potential. In this study, we assessed for the first time the effects of adding silk sericin on alginate-gelatin hydrogels, proposed for cardiac applications. To this aim, we first biofabricated sericin-containing hydrogels with increasing protein concentrations. Thus, we characterized hydrogels mechanical behavior, porosity and structure through rheology, Brillouin microspectroscopy, and scanning electron microscopy. Then, we bioprinted the formulated hydrogels and evaluated their effects on human cardiac spheroids (CSs) in vitro. Our mechanical characterization demonstrated that adding sericin significantly enhanced the elasticity and the viscosity of alginate-gelatin hydrogels. Sericin also modified hydrogels swelling behavior and their pore size, increasing by 20%, 62%, and 92% in Ser1%, Ser2%, and Ser3%, respectively. Although Ser1% did not exhibit significant effects on CSs, Ser2% and Ser3% enhanced cardiac cell viability for up to 14 days compared to the sericin-free hydrogel by acting on the fibroblast population. Sericin-based bioinks showed better printability and durability with +33% and +28% intact patches after 28 days of culture at 37C compared to alginate-gelatin. Taken together, our results validated the use of sericin as a promising component for the optimization of bioink intended for cardiac applications. 2024 Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution, and reproduction in any medium, provided the original work is properly cited.
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Ratwatte, Seshika D.; Coelho, Bianca; Ng, Martin K.C.; Celermajer, David S.Background: The prevalence and predictors of right ventricular (RV) dysfunction before and after transcatheter aortic valve implantation (TAVI) are not known. We aimed to document this and sought to identify specific RV echo thresholds, below which RV improvement was unlikely to occur. Method: Consecutive patients who underwent TAVI between 2017 and 2021 at Macquarie University Hospital (MUH) were included if ?2 RV functional parameters were available on baseline echo; tricuspid annular plane systolic excursion, tissue Doppler (S) and/or RV fractional area change. Prevalence and predictors of baseline RV dysfunction were documented. Patients with a repeat echo performed at MUH at 13 months post-TAVI were included in further analyses to assess serial changes in RV function. Results: Overall, 343 patients had an eligible baseline echo and 97 of these patients (28.2%) had RV dysfunction, pre-TAVI. These patients had significantly higher rates of atrial fibrillation, ischaemic heart disease, and chronic lung disease, than those without (p<0.05 for all). Of 239 patients with 13 month follow-up echo data, 66 of these had had baseline RV dysfunction; of these, 20 (30.3%) patients showed improvement and 46 (69.7%) patients showed persistent RV dysfunction. Thresholds with a greater than 90% predictive value for persistent RV dysfunction were identified for each baseline RV functional parameter: tricuspid annular plane systolic excursion <1.4 cm, S<6, fractional area change <25%. Conclusions: Baseline RV dysfunction was present in over a quarter of pre-TAVI patients and persisted at short-term follow-up in over two-thirds of such patients. There were clear thresholds to identify patients where RV recovery was unlikely, after TAVI. 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ)
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Sen, Melodi Gizem; Chooi, Roger; McMullen, Julie R.Cardiovascular disease affects millions of people worldwide and often presents with other conditions including metabolic, renal and neurological disorders. A variety of secreted factors from multiple organs/tissues (proteins, nucleic acids and lipids) have been implicated in facilitating organ cross-talk that may contribute to the development of multimorbidity. Secreted proteins have received the most attention, with the greatest body of research related to factors released from adipose tissue (adipokines), followed by skeletal muscle (myokines). To date, there have been fewer studies on proteins released from the heart (cardiokines) implicated with organ cross-talk. Early evidence for the secretion of cardiac-specific factors facilitating organ cross-talk came in the form of natriuretic peptides which are secreted via the classical endoplasmic reticulumGolgi pathway. More recently, studies in cardiomyocyte-specific genetic mouse models have revealed cardiac-initiated organ cross-talk. Cardiomyocyte-specific modulation of microRNAs (miR-208a and miR-23-27-24 cluster) and proteins such as the mediator complex subunit 13 (MED13), G-protein-coupled receptor kinase 2 (GRK2), mutant ?-myosin heavy-chain (?MHC), ubiquitin-like modifier-activating enzyme (ATG7), oestrogen receptor alpha (ER?) and fibroblast growth factor 21 (FGF21) have resulted in metabolic and renal phenotypes. These studies have implicated a variety of factors which can be secreted via the classical pathway or via non-classical mechanisms including the release of extracellular vesicles. Cross-talk between the heart and the brain has also been described (e.g. via miR-1 and an emerging concept, interoception: detection of internal neural signals). Here we summarize these studies taking into consideration that factors may be secreted in both settings of health and in disease. (Figure presented.). 2025 The Authors. The Journal of Physiology 2025 The Physiological Society.
