Basic Research in Cardiology最新文献

{"title":"Chronic kidney disease activates the HDAC6-inflammatory axis in the heart and contributes to myocardial remodeling in mice: inhibition of HDAC6 alleviates chronic kidney disease-induced myocardial remodeling.","authors":"Sourav Kundu, Shobhit Gairola, Smriti Verma, Madhav Nilakanth Mugale, Bidya Dhar Sahu","doi":"10.1007/s00395-024-01056-y","DOIUrl":"10.1007/s00395-024-01056-y","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) adversely affects the heart. The underlying mechanism and the interplay between the kidney and the heart are still obscure. We examined the cardiac effect using the unilateral ureteral obstruction (UUO)-induced CKD pre-clinical model in mice. Echocardiography, histopathology of the heart, myocardial mRNA expression of ANP and BNP, the extent of fibrotic (TGF-β, α-SMA, and collagen I) and epigenetic (histone deacetylases, namely HDAC3, HDAC4, and HDAC6) proteins, and myocardial inflammatory response were assessed. Six weeks of post-UUO surgery, we observed a compromised left-ventricular wall thickness and signs of cardiac hypertrophy, accumulation of fibrosis associated, and inflammatory proteins in the heart. In addition, we observed a perturbation of epigenetic proteins, especially HDAC3, HDAC4, and HDAC6, in the heart. Pharmacological inhibition of HDAC6 using ricolinostat (RIC) lessened cardiac damage and improved left-ventricular wall thickness. The RIC treatment substantially restored the serum cardiac injury markers, namely creatine kinase-MB and lactate dehydrogenase (LDH) activities, ANP and BNP mRNA expression, and heart histological changes. The extent of myocardial fibrotic proteins, phospho-NF-κB (p65), and pro-inflammatory cytokines (TNF-α, IL-18, and IL-1β) were significantly decreased in the RIC treatment group. Further findings revealed the CKD-induced infiltration of CD3, CD8a, CD11c, and F4/80 positive inflammatory cells in the heart. Treatment with RIC substantially reduced the myocardial infiltration of these inflammatory cells. From these findings, we believe that CKD-induced myocardial HDAC6 perturbation has a deteriorative effect on the heart, and inhibition of HDAC6 can be a promising approach to alleviate CKD-induced myocardial remodeling.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"831-852"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141070075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Gα_i2 in neutrophils protects from myocardial ischemia reperfusion injury.","authors":"David Köhler, Veronika Leiss, Lukas Beichert, Simon Killinger, Daniela Grothe, Ragini Kushwaha, Agnes Schröter, Anna Roslan, Claudia Eggstein, Jule Focken, Tiago Granja, Vasudharani Devanathan, Birgit Schittek, Robert Lukowski, Bettina Weigelin, Peter Rosenberger, Bernd Nürnberg, Sandra Beer-Hammer","doi":"10.1007/s00395-024-01057-x","DOIUrl":"10.1007/s00395-024-01057-x","url":null,"abstract":"<p><p>Neutrophils are not only involved in immune defense against infection but also contribute to the exacerbation of tissue damage after ischemia and reperfusion. We have previously shown that genetic ablation of regulatory Gα_i proteins in mice has both protective and deleterious effects on myocardial ischemia reperfusion injury (mIRI), depending on which isoform is deleted. To deepen and analyze these findings in more detail the contribution of Gα_i2 proteins in resident cardiac vs circulating blood cells for mIRI was first studied in bone marrow chimeras. In fact, the absence of Gα_i2 in all blood cells reduced the extent of mIRI (22,9% infarct size of area at risk (AAR) Gnai2^-/- → wt vs 44.0% wt → wt; p < 0.001) whereas the absence of Gα_i2 in non-hematopoietic cells increased the infarct damage (66.5% wt → Gnai2^-/- vs 44.0% wt → wt; p < 0.001). Previously we have reported the impact of platelet Gα_i2 for mIRI. Here, we show that infarct size was substantially reduced when Gα_i2 signaling was either genetically ablated in neutrophils/macrophages using LysM-driven Cre recombinase (AAR: 17.9% Gnai2^fl/fl LysM-Cre^+/tg vs 42.0% Gnai2^fl/fl; p < 0.01) or selectively blocked with specific antibodies directed against Gα_i2 (AAR: 19.0% (anti-Gα_i2) vs 49.0% (IgG); p < 0.001). In addition, the number of platelet-neutrophil complexes (PNCs) in the infarcted area were reduced in both, genetically modified (PNCs: 18 (Gnai2^fl/fl; LysM-Cre^+/tg) vs 31 (Gnai2^fl/fl); p < 0.001) and in anti-Gα_i2 antibody-treated (PNCs: 9 (anti-Gα_i2) vs 33 (IgG); p < 0.001) mice. Of note, significant infarct-limiting effects were achieved with a single anti-Gα_i2 antibody challenge immediately prior to vessel reperfusion without affecting bleeding time, heart rate or cellular distribution of neutrophils. Finally, anti-Gα_i2 antibody treatment also inhibited transendothelial migration of human neutrophils (25,885 (IgG) vs 13,225 (anti-Gα_i2) neutrophils; p < 0.001), collectively suggesting that a therapeutic concept of functional Gα_i2 inhibition during thrombolysis and reperfusion in patients with myocardial infarction should be further considered.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"717-732"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141173771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SGLT1 contributes to glucose-mediated exacerbation of ischemia-reperfusion injury in ex vivo rat heart.","authors":"Alhanoof Almalki, Sapna Arjun, Idris Harding, Hussain Jasem, Maria Kolatsi-Joannou, Daniyal J Jafree, Gideon Pomeranz, David A Long, Derek M Yellon, Robert M Bell","doi":"10.1007/s00395-024-01071-z","DOIUrl":"10.1007/s00395-024-01071-z","url":null,"abstract":"<p><p>Hyperglycaemia is common during acute coronary syndromes (ACS) irrespective of diabetic status and portends excess infarct size and mortality, but the mechanisms underlying this effect are poorly understood. We hypothesized that sodium/glucose linked transporter-1 (SGLT1) might contribute to the effect of high-glucose during ACS and examined this using an ex-vivo rodent heart model of ischaemia-reperfusion injury. Langendorff-perfused rat hearts were subjected to 35 min ischemia and 2 h reperfusion, with variable glucose and reciprocal mannitol given during reperfusion in the presence of pharmacological inhibitors of SGLT1. Myocardial SGLT1 expression was determined in rat by rtPCR, RNAscope and immunohistochemistry, as well as in human by single-cell transcriptomic analysis. High glucose in non-diabetic rat heart exacerbated reperfusion injury, significantly increasing infarct size from 45 ± 3 to 65 ± 4% at 11-22 mmol/L glucose, respectively (p < 0.01), an association absent in diabetic heart (32 ± 1-37 ± 5%, p = NS). Rat heart expressed SGLT1 RNA and protein in vascular endothelium and cardiomyocytes, with similar expression found in human myocardium by single-nucleus RNA-sequencing. Rat SGLT1 expression was significantly reduced in diabetic versus non-diabetic heart (0.608 ± 0.08 compared with 1.116 ± 0.13 probe/nuclei, p < 0.01). Pharmacological inhibitors phlorizin, canagliflozin or mizagliflozoin in non-diabetic heart revealed that blockade of SGLT1 but not SGLT2, abrogated glucose-mediated excess reperfusion injury. Elevated glucose is injurious to the rat heart during reperfusion, exacerbating myocardial infarction in non-diabetic heart, whereas the diabetic heart is resistant to raised glucose, a finding which may be explained by lower myocardial SGLT1 expression. SGLT1 is expressed in vascular endothelium and cardiomyocytes and inhibiting SGLT1 abrogates excess glucose-mediated infarction. These data highlight SGLT1 as a potential clinical translational target to improve morbidity/mortality outcomes in hyperglycemic ACS patients.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"733-749"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recombinant human placental growth factor-2 in post-infarction left ventricular dysfunction: a randomized, placebo-controlled, preclinical study.","authors":"Ming Wu, Peter Pokreisz, Piet Claus, Andrea Casazza, Hilde Gillijns, Ellen Caluwé, Marzia De Petrini, Ann Belmans, Geert Reyns, Desire Collen, Stefan P Janssens","doi":"10.1007/s00395-024-01069-7","DOIUrl":"10.1007/s00395-024-01069-7","url":null,"abstract":"<p><p>Placental growth factor (PlGF)-2 induces angio- and arteriogenesis in rodents but its therapeutic potential in a clinically representative post-infarction left ventricular (LV) dysfunction model remains unclear. We, therefore, investigated the safety and efficacy of recombinant human (rh)PlGF-2 in the infarcted porcine heart in a randomized, placebo-controlled blinded study. We induced myocardial infarction (MI) in pigs using 75 min mid-LAD balloon occlusion followed by reperfusion. After 4 w, we randomized pigs with marked LV dysfunction (LVEF < 40%) to receive continuous intravenous infusion of 5, 15, 45 µg/kg/day rhPlGF-2 or PBS (CON) for 2 w using osmotic pumps. We evaluated the treatment effect at 8 w using comprehensive MRI and immunohistochemistry and measured myocardial PlGF-2 receptor transcript levels. At 4 w after MI, infarct size was 16-18 ± 4% of LV mass, resulting in significantly impaired systolic function (LVEF 34 ± 4%). In the pilot study (3 pigs/dose), PIGF administration showed sustained dose-dependent increases in plasma concentrations for 14 days without systemic toxicity and was associated with favorable post-infarct remodeling. In the second phase (n = 42), we detected no significant differences at 8 w between CON and PlGF-treated pigs in infarct size, capillary or arteriolar density, global LV function and regional myocardial blood flow at rest or during stress. Molecular analysis showed significant downregulation of the main PlGF-2 receptor, pVEGFR-1, in dysfunctional myocardium. Chronic rhPIGF-2 infusion was safe but failed to induce therapeutic neovascularization and improve global cardiac function after myocardial infarction in pigs. Our data emphasize the critical need for properly designed trials in representative large animal models before translating presumed promising therapies to patients.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"795-806"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased [¹⁸F]FDG uptake in the infarcted myocardial area displayed by combined PET/CMR correlates with snRNA-seq-detected inflammatory cell invasion.","authors":"Dominika Lukovic, Mariann Gyöngyösi, Imre J Pavo, Julia Mester-Tonczar, Patrick Einzinger, Katrin Zlabinger, Nina Kastner, Andreas Spannbauer, Denise Traxler, Noemi Pavo, Georg Goliasch, Dietmar Pils, Andras Jakab, Zsuzsanna Szankai, Ina Michel-Behnke, Lu Zhang, Yvan Devaux, Senta Graf, Dietrich Beitzke, Johannes Winkler","doi":"10.1007/s00395-024-01064-y","DOIUrl":"10.1007/s00395-024-01064-y","url":null,"abstract":"<p><p>Combined [¹⁸F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [¹⁸F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":"807-829"},"PeriodicalIF":7.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11461641/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141449506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardio-oncology: chances and challenges","authors":"Adriana E. Viñas-Mendieta, Andrea Gallardo-Grajeda, Teresa López-Fernández","doi":"10.1007/s00395-024-01080-y","DOIUrl":"https://doi.org/10.1007/s00395-024-01080-y","url":null,"abstract":"<p>Cardio-oncology is an emerging field that aims to ensure optimal cancer treatment while minimising cardiovascular toxicity. The management of cardiovascular toxicity is critical because it can lead to premature discontinuation of treatment, increasing the risk of cancer recurrence and mortality. The 2022 European Society of Cardiology guidelines were a milestone in advocating a patient-centred, multidisciplinary approach. Key components include risk stratification and a standardised criterion for adverse events, incorporating definitions from the International Cardio-Oncology Society. Effective risk stratification, supported by imaging and biomarkers, helps to anticipate cardiovascular problems and implement preventive measures. Future research should focus on understanding mechanisms, developing preventive strategies and implementing personalised medicine. Education and reducing disparities in care are essential to advance cardio-oncology and improve patient outcomes.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"31 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning segmentation model for quantification of infarct size in pigs with myocardial ischemia/reperfusion","authors":"Felix Braczko, Andreas Skyschally, Helmut Lieder, Jakob Nikolas Kather, Petra Kleinbongard, Gerd Heusch","doi":"10.1007/s00395-024-01081-x","DOIUrl":"https://doi.org/10.1007/s00395-024-01081-x","url":null,"abstract":"<p>Infarct size (IS) is the most robust end point for evaluating the success of preclinical studies on cardioprotection. The gold standard for IS quantification in ischemia/reperfusion (I/R) experiments is triphenyl tetrazolium chloride (TTC) staining, typically done manually. This study aimed to determine if automation through deep learning segmentation is a time-saving and valid alternative to standard IS quantification. High-resolution images from TTC-stained, macroscopic heart slices were retrospectively collected from pig experiments (<i>n</i> = 390) with I/R without/with cardioprotection to cover a wide IS range. Existing IS data from pig experiments, quantified using a standard method of manual and subsequent digital labeling of film-scan annotations, were used as reference. To automate the evaluation process with the aim to be more objective and save time, a deep learning pipeline was implemented; the collected images (<i>n</i> = 3869) were pre-processed by cropping and labeled (image annotations). To ensure their usability as training data for a deep learning segmentation model, IS was quantified from image annotations and compared to IS quantified using the existing film-scan annotations. A supervised deep learning segmentation model based on dynamic U-Net architecture was developed and trained. The evaluation of the trained model was performed by fivefold cross-validation (<i>n</i> = 220 experiments) and testing on an independent test set (<i>n</i> = 170 experiments). Performance metrics (Dice similarity coefficient [DSC], pixel accuracy [ACC], average precision [mAP]) were calculated. IS was then quantified from predictions and compared to IS quantified from image annotations (linear regression, Pearson’s <i>r</i>; analysis of covariance; Bland–Altman plots). Performance metrics near 1 indicated a strong model performance on cross-validated data (DSC: 0.90, ACC: 0.98, mAP: 0.90) and on the test set data (DSC: 0.89, ACC: 0.98, mAP: 0.93). IS quantified from predictions correlated well with IS quantified from image annotations in all data sets (cross-validation: <i>r</i> = 0.98; test data set: <i>r</i> = 0.95) and analysis of covariance identified no significant differences. The model reduced the IS quantification time per experiment from approximately 90 min to 20 s. The model was further tested on a preliminary test set from experiments in isolated, saline-perfused rat hearts with regional I/R without/with cardioprotection (<i>n</i> = 27). There was also no significant difference in IS between image annotations and predictions, but the performance on the test set data from rat hearts was lower (DSC: 0.66, ACC: 0.91, mAP: 0.65). IS quantification using a deep learning segmentation model is a valid and time-efficient alternative to manual and subsequent digital labeling.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"45 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiac wasting in patients with cancer","authors":"Markus S. Anker, Ahmed Mustafa Rashid, Javed Butler, Muhammad Shahzeb Khan","doi":"10.1007/s00395-024-01079-5","DOIUrl":"https://doi.org/10.1007/s00395-024-01079-5","url":null,"abstract":"<p>Patients with cancer face a significant risk of cardiovascular death, regardless of time since cancer diagnosis. Elderly patients are particularly more susceptible as cancer-associated cardiac complications present in advanced stage cancer. These patients may often present with symptoms observed in chronic heart failure (HF). Cardiac wasting, commonly observed in these patients, is a multifaceted syndrome characterized by systemic metabolic alterations and inflammatory processes that specifically affect cardiac function and structure. Experimental and clinical studies have demonstrated that cancer-associated cardiac wasting is linked with cardiac atrophy and altered cardiac morphology, which impairs cardiac function, particularly pertaining to the left ventricle. Therefore, this review aims to present a summary of epidemiologic data and pathophysiological mechanisms of cardiac wasting due to cancer, and future directions in this field.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"21 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomics reveal distinctive patterns of fibroblast activation in heart failure with preserved ejection fraction","authors":"Jan D. Lanzer, Laura M. Wienecke, Ricardo O. Ramirez Flores, Maura M. Zylla, Celina Kley, Niklas Hartmann, Florian Sicklinger, Jobst-Hendrik Schultz, Norbert Frey, Julio Saez-Rodriguez, Florian Leuschner","doi":"10.1007/s00395-024-01074-w","DOIUrl":"https://doi.org/10.1007/s00395-024-01074-w","url":null,"abstract":"<p>Inflammation, fibrosis and metabolic stress critically promote heart failure with preserved ejection fraction (HFpEF). Exposure to high-fat diet and nitric oxide synthase inhibitor N[w]-nitro-l-arginine methyl ester (L-NAME) recapitulate features of HFpEF in mice. To identify disease-specific traits during adverse remodeling, we profiled interstitial cells in early murine HFpEF using single-cell RNAseq (scRNAseq). Diastolic dysfunction and perivascular fibrosis were accompanied by an activation of cardiac fibroblast and macrophage subsets. Integration of fibroblasts from HFpEF with two murine models for heart failure with reduced ejection fraction (HFrEF) identified a catalog of conserved fibroblast phenotypes across mouse models. Moreover, HFpEF-specific characteristics included induced metabolic, hypoxic and inflammatory transcription factors and pathways, including enhanced expression of Angiopoietin-like 4 (Angptl4) next to basement membrane compounds, such as collagen IV (Col4a1). Fibroblast activation was further dissected into transcriptional and compositional shifts and thereby highly responsive cell states for each HF model were identified. In contrast to HFrEF, where myofibroblast and matrifibrocyte activation were crucial features, we found that these cell states played a subsidiary role in early HFpEF. These disease-specific fibroblast signatures were corroborated in human myocardial bulk transcriptomes. Furthermore, we identified a potential cross-talk between macrophages and fibroblasts via SPP1 and TNFɑ with estimated fibroblast target genes including Col4a1 and Angptl4. Treatment with recombinant ANGPTL4 ameliorated the murine HFpEF phenotype and diastolic dysfunction by reducing collagen IV deposition from fibroblasts in vivo and in vitro. In line, ANGPTL4, was elevated in plasma samples of HFpEF patients and particularly high levels associated with a preserved global-longitudinal strain. Taken together, our study provides a comprehensive characterization of molecular fibroblast activation patterns in murine HFpEF, as well as the identification of Angiopoietin-like 4 as central mechanistic regulator with protective effects.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":"27 1","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardioprotection strategies for anthracycline cardiotoxicity.","authors":"Andrea Moreno-Arciniegas, Laura Cádiz, Carlos Galán-Arriola, Agustín Clemente-Moragón, Borja Ibáñez","doi":"10.1007/s00395-024-01078-6","DOIUrl":"https://doi.org/10.1007/s00395-024-01078-6","url":null,"abstract":"<p><p>Thanks to the fantastic progress in cancer therapy options, there is a growing population of cancer survivors. This success has resulted in a need to focus much effort into improving the quality of life of this population. Cancer and cardiovascular disease share many common risk factors and have an interplay between them, with one condition mechanistically affecting the other and vice versa. Furthermore, widely prescribed cancer therapies have known toxic effects in the cardiovascular system. Anthracyclines are the paradigm of efficacious cancer therapy widely prescribed with a strong cardiotoxic potential. While some cancer therapies cardiovascular toxicities are transient, others are irreversible. There is a growing need to develop cardioprotective therapies that, when used in conjunction with cancer therapies, can prevent cardiovascular toxicity and thus improve long-term quality of life in survivors. The field has three main challenges: (i) identification of the ultimate mechanisms leading to cardiotoxicity to (ii) identify specific therapeutic targets, and (iii) more sensible diagnostic tools to early identify these conditions. In this review we will focus on the cardioprotective strategies tested and under investigation. We will focus this article into anthracycline cardiotoxicity since it is still the agent most widely prescribed, the one with higher toxic effects on the heart, and the most widely studied.</p>","PeriodicalId":8723,"journal":{"name":"Basic Research in Cardiology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153083","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}